Autism Spectrum Disorder

AUTISM SPECTRUM DISORDER
AUTISM
SPECTRUM
DISORDER
Edited by
Christopher J. McDougle, MD
Director, Lurie Center for Autism
Professor of Psychiatry and Pediatrics
Massachusetts General Hospital and
MassGeneral Hospital for Children
Nancy Lurie Marks Professor in the Field of Autism
Harvard Medical School
1
1
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CONTENTS
Foreword ix
Contributors xi
SECTION 1: BACKGROUND AND DIAGNOSTIC ASSESSMENT
1. From Infantile Autism to Autism Spectrum: Evolution

of the Diagnostic Concept 3
Fred R. Volkmar
2. Social, Cognitive, and Behavioral Development of Children
and Adolescents With Autism Spectrum Disorder 19
Kirstin Brown Birtwell, Brian Willoughby, and Lisa Nowinski
3. Social, Cognitive, and Affective Development of Adults
With Autism Spectrum Disorder 31
Patricia Howlin and Iliana Magiati
4. Differential Diagnosis of Autism Spectrum Disorder Across
the Lifespan 47
Isobel W. Green, Christen L. Kidd, and Robert E. Accordino
5. Medical Evaluation of Patients With Autism Spectrum Disorder 67
Yamini J. Howe, Michelle L. Palumbo, and Ann Neumeyer
6. Psychiatric Comorbidity in Autism Spectrum Disorder 85
Susan E. Folstein and Luis M. Carcache
7. Neurological Comorbidities in Autism Spectrum Disorder 99
Fiona Baumer and Mustafa Sahin
8. Genetic Disorders Associated With the Autism Spectrum
Disorder Phenotype 117
Lawrence K. Fung and Allan L. Reiss
9. Autism Spectrum Disorder in the Elderly 139
Peter V. Rabins
vi / / Contents
SECTION 2: ETIOLOGY
10. Neuroimaging of Autism Spectrum Disorder 149

Nicole R. Zürcher and Jacob M. Hooker
11. Genetics of Autism Spectrum Disorder 161
Yamini J. Howe, Harrison Brand, and Michael E. Talkowski
12. Epidemiology of Autism Spectrum Disorder 181
Allison Presmanes Hill, Katharine Zuckerman, and Eric Fombonne
13. Neuropathology of Autism Spectrum Disorder 205
Matthew P. Anderson
14. Immunological Aspects of Autism Spectrum Disorder 225
Thayne L. Sweeten and Christopher J. McDougle
SECTION 3: TREATMENT
15. Behavioral Treatment of Autism Spectrum Disorder 253

Suzannah Iadarola and Tristram Smith
16. Psychopharmacology of Autism Spectrum Disorder 275
James T. McCracken and Michael Gandal
17. Complementary and Alternative (Biomedical) Treatments
for Autism Spectrum Disorder 301
Robert L. Hendren
18. Speech and Language Assessment and Treatment for Autism
Spectrum Disorder 321
Katelyn A. Bruno, Kristina L. Gulati, and Maria Mody
19. Occupational Therapy for Autism Spectrum Disorder 339
Jennifer L. Stornelli
20. Social Skills Training for Autism Spectrum Disorder 369
D. Scott McLeod, Kristin W. Malatino, and Dorothy Lucci
SECTION 4: OTHER CARE DELIVERY SERVICES AND PERSPECTIVES
21. Educational Issues in Autism Spectrum Disorder 387

Samuel L. Odom, Veronica P. Fleury, Leslie C. Fox, Susan H. Hedges,
Nigel P. Pierce, and Melissa A. Sreckovic
22. Vocational Rehabilitation and Training for Adults With Autism Spectrum
Disorder: History, Practices, and New Directions 413
Marji Erickson Warfield
Contents // vii
23. Adults With Autism Spectrum Disorder: Transition Issues 429

Edward S. Brodkin
24. Effective Communication and Management With the Family and
in the Community 447
Naomi B. Swiezy, Tiffany J. Neal, Danielle Warner, and Kimberly Lo
25. Autism Spectrum Disorder From a Family Perspective 465
Nancy Lurie Marks, Cathy Lurie, and Clarence E. Schutt
26. From the Perspective of a Person With Autism Spectrum Disorder 475
John M. Williams
Index 485
FOREWORD
When I was a medical student in the mid-1980s, autism was considered a rare disorder with
a prevalence of 2–4 individuals per 10,000. To my knowledge, I had never met anyone with
autism. Autism was never mentioned in a lecture, and I did not encounter a patient with
autism during my clinical rotations. It was not until I was a postgraduate year two (PGY- II)
resident in psychiatry that I met people with autism. These were all young adults living at a
residential facility in Connecticut called Ben Haven. I was there visiting the site along with
my residency colleagues as part of our training experience.
Three decades later, significant changes have occurred in the field of autism, now called
“autism spectrum disorder.” The prevalence estimates have increased exponentially. Most
of us have a colleague, classmate, or friend with a family member with an autism-related
disorder. Behavioral and pharmacological treatments have been developed that are of some
benefit, and educational programs and specialized schools have been created that offer ser-
vices to enhance learning and to improve communication and social skills. Scientists from
the fields of neuroimaging, genetics, epidemiology, cognitive neuroscience, and immunol-
ogy have joined in the search for potential causes of autism.
Despite what we have learned about autism in the past 30 years, we continue to know
so very little. We have conceptualized autism as a group of heterogeneous neurodevelop-
mental disorders rather than a single entity. The heterogeneity spans the phenotype and
genotype and everything in between. This has made the identification of specific causes of
autism challenging to say the least. Along these lines, individuals with autism with a similar
clinical presentation may have radically different underlying pathophysiologies. This has
limited our ability to match targeted treatments with particular patients. In fact, the field
has made very little progress in developing therapies that result in consistent, significant
improvement in what have historically been considered the core clinical domains of autism
(social and communication impairment and restricted, repetitive patterns of behavior).
Thirty years ago, society had not realized that children with autism grow up and live as
long as the rest of us. As a result, there has been insufficient thought about where these indi-
viduals will live, work, and go to school beyond the age of 22 years. Similarly, the amount of
research involving adults with autism lags far behind that occurring in infants, toddlers, and
school-age children. Practically speaking, society has little meaningful knowledge about
how to provide adults with autism the basic necessities of life. This is unlikely to change
until additional research helps us to address the many unanswered questions surrounding
adults with autism.
This book is designed as an easy-to-use, clinically oriented, evidence-based guide for
trainees and early stage clinicians. It was written with medical students, graduate students
and interns in psychology, residents and fellows in neurology, psychiatry, and pediatrics,
ix
x / / F oreword
and those clinicians and researchers who have recently completed training in mind. It is
intended to be read and understood during a 4- to 12-week rotation focused on autism
spectrum disorder and potentially other neurodevelopmental disorders and also during
review and preparation for board examinations that occur throughout professional school,
postgraduate training, and for specialty-board certification after training is completed. The
chapters related to clinical diagnosis and treatment aspects of autism spectrum disorder
will provide a “nuts and bolts” approach on how to conduct these evaluations and inter-
ventions from a high view perspective. The chapters related to a body of scientific knowl-
edge, such as those dedicated to neuroimaging, genetics, epidemiology, neuropathology,
and immunology, highlight the relevance of the data in summary fashion and make the
clinical implications of the findings explicit. Clinical case vignettes are provided wherever
appropriate to aid instruction. At the end of each chapter, five “Key Points” are listed that
highlight the intended takeaway message for the learner. The book concludes with chapters
written by family members of adult children with autism and a young man with autism,
respectively. Their perspectives convey the human aspects of living with autism, which we
hope will motivate the reader to want to learn even more about the field.
It is our hope that this text provides the reader with the knowledge needed to derive
maximal benefit from clinical rotations related to autism spectrum disorder and for suc-
cessful preparation for board examinations. If the book helps to lead some of you toward a
career related to caring for individuals with autism and their families or learning more about
the biology and psychology of the syndrome, then even more will have been accomplished.
Christopher J. McDougle, MD
Boston, Massachusetts
September 1, 2015
CONTRIBUTORS
Robert E. Accordino, MD, MSc Edward S. Brodkin, MD

Child and Adolescent Psychiatry Fellow Director, Adult Autism Spectrum Program
Massachusetts General Hospital/McLean Penn Medicine
Hospital Philadelphia, PA
Boston/Belmont, MA Associate Professor of Psychiatry
Harvard Medical School Perelman School of Medicine at the
Boston, MA University of Pennsylvania
Philadelphia, PA
Matthew P. Anderson, MD, PhD
Director of Neuropathology Kirstin Brown Birtwell, PhD
Beth Israel Deaconess Medical Center Postdoctoral Fellow in Psychology
Boston, MA Department of Psychiatry
Associate Professor of Pathology Massachusetts General Hospital
Harvard Medical School Lurie Center for Autism
Boston, MA Lexington, MA
Postdoctoral Fellow in Psychiatry
Fiona Baumer, MD Harvard Medical School
Chief Resident in Child Neurology Boston, MA
Department of Neurology
Boston Children’s Hospital Katelyn A. Bruno, MA, CCC-SLP
Boston, MA Speech and Language Pathologist
Harvard Medical School Spaulding Rehabilitation Hospital
Boston, MA Lurie Center for Autism
Lexington, MA
Harrison Brand, PhD
Research Fellow Luis M. Carcache, MD
Psychiatric and Neurodevelopmental Assistant Professor
Genetics Unit Department of Psychiatry &
Molecular Neurogenetics Unit Behavioral Health
Center for Human Genetic Research Florida International University
Massachusetts General Hospital School of Medicine
Boston, MA Miami, FL
Research Fellow in Neurology
Boston, MA
xi
xii / / Contributors
Marji Erickson Warfield, PhD Michael Gandal, MD, PhD

Director and Senior Scientist General Psychiatry Resident
The Nathan and Toby Starr Center Research Track
on Intellectual and Developmental Department of Psychiatry and
Disabilities Biobehavioral Sciences
The Heller School for Social Policy and David Geffen School of Medicine at UCLA
Management Los Angeles, CA
Brandeis University
Waltham, MA Isobel W. Green
Harvard University
Veronica P. Fleury, PhD, BCBA Cambridge, MA
Autism Spectrum Disorder Program
Coordinator Kristina L. Gulati, MA, CCC-SLP
Assistant Professor Speech and Language Pathologist
Special Education Spaulding Rehabilitation Hospital
Department of Educational Psychology Lurie Center for Autism
University of Minnesota Lexington, MA
Minneapolis, MN
Susan H. Hedges, MA
Susan E. Folstein, MD Doctoral Candidate
Adjunct Clinical Professor Frank Porter Graham Child Development
Department of Psychiatry & Institute
Behavioral Health University of North Carolina at Chapel Hill
Florida International University Chapel Hill, NC
School of Medicine
Miami, FL Robert L. Hendren, DO
Director, Child and Adolescent Psychiatry
Eric Fombonne, MD Director, Autism and Neurodevelopment
Director of Autism Research Program
Institute for Development & Disability UCSF Benioff Children’s Hospital
Professor of Psychiatry San Francisco, CA
Oregon Health & Science University Professor and Vice Chair
Portland, OR Department of Psychiatry
UCSF School of Medicine
Leslie C. Fox, PhD San Francisco, CA
Research Assistant
Frank Porter Graham Child Development Allison Presmanes Hill, PhD
Institute Research Assistant Professor
University of North Carolina at Chapel Hill Center for Spoken Language
Chapel Hill, NC Understanding
Institute for Development & Disability
Lawrence K. Fung, MD, PhD Department of Pediatrics
Center for Interdisciplinary Brain Sciences Oregon Health & Science University
Research Portland, OR
Instructor, Department of Psychiatry &
Behavioral Sciences
Stanford University School of Medicine
Palo Alto, CA
Contributors // xiii
Jacob M. Hooker, PhD Kimberly Lo, MD

Director of Radiochemistry Triple Board Resident
Athinoula A. Martinos Center for Departments of Psychiatry and Pediatrics
Biomedical Imaging Indiana University School of Medicine
Massachusetts General Hospital Indianapolis, IN
Charlestown, MA
Associate Professor of Radiology Dorothy Lucci, MEd, CAGS
Harvard Medical School Program Director
Boston, MA Aspire
Massachusetts General Hospital
Yamini J. Howe, MD Lurie Center for Autism
Lurie Center for Autism Lexington, MA
MassGeneral Hospital for Children
Lexington, MA Cathy Lurie
Instructor in Pediatrics The Nancy Lurie Marks Family Foundation
Harvard Medical School Wellesley, MA
Boston, MA
Nancy Lurie Marks, PhDhc
Patricia Howlin, PhD The Nancy Lurie Marks Family Foundation
Emeritus Professor of Clinical Child Wellesley, MA
Psychiatry
Institute of Psychiatry Iliana Magiati, PhD, DClinPsy
King’s College Assistant Professor/Chartered Clinical
London, United Kingdom Psychologist
Professor of Developmental Disabilities Department of Psychology
Brain and Mind Research Institute National University of Singapore
University of Sydney Singapore, Singapore
Sidney, Australia
Kristin W. Malatino, PhD
Suzannah Iadarola, PhD, BCBA-D Private Practice
Strong Center for Developmental Celebration, FL
Disabilities
Division of Neurodevelopmental and
James T. McCracken, MD
Behavioral Pediatrics
Semel Institute for Neuroscience and
Assistant Professor of Pediatrics
Human Behavior
University of Rochester Medical Center
Center for Autism Research and
Rochester, NY
Treatment (CART)
Los Angeles, CA
Christen L. Kidd, MD Joseph Campbell Professor of Child
Resident in Psychiatry Psychiatry and Vice Chair
New York-Presbyterian Hospital Department of Psychiatry and
Weill Cornell Medical Center Biobehavioral Sciences
New York, NY David Geffen School of Medicine at UCLA
Los Angeles, CA
xiv / / Contributors
Christopher J. McDougle, MD Lisa Nowinski, PhD

Director, Lurie Center for Autism Staff Psychologist
Massachusetts General Hospital Department of Psychiatry
Lexington, MA Massachusetts General Hospital
Nancy Lurie Marks Professor of Psychiatry Lurie Center for Autism
Harvard Medical School Lexington, MA
Boston, MA Instructor in Psychiatry
Boston, MA
D. Scott McLeod, PhD
Executive Director Samuel L. Odom, PhD
Aspire Director
Massachusetts General Hospital Frank Porter Graham Child
Lurie Center for Autism Development Institute
Lexington, MA University of North Carolina at
Instructor in Psychiatry Chapel Hill
Harvard Medical School Chapel Hill, NC
Boston, MA Professor
School of Education
Maria Mody, PhD University of North Carolina at
Assistant Neuroscientist Chapel Hill
Athinoula A. Martinos Center for Chapel Hill, NC
Biomedical Imaging
Massachusetts General Hospital Michelle L. Palumbo, MD
Charlestown, MA Lurie Center for Autism
Lurie Center for Autism MassGeneral Hospital for Children
MassGeneral Hospital for Children Lexington, MA
Lexington, MA Instructor in Pediatrics
Assistant Professor of Radiology Harvard Medical School
Harvard Medical School Boston, MA
Boston, MA
Nigel P. Pierce, PhD
Tiffany J. Neal, PhD Assistant Professor
Assistant Director School of Education
HANDS in Autism Interdisciplinary North Carolina Central University
Training and Resource Center Durham, NC
Indiana University School of Medicine
Indianapolis, IN Peter V. Rabins, MD, MPH
Member, Berman Institute of
Ann Neumeyer, MD Bioethics
Medical Director, Lurie Center for Autism Johns Hopkins University
MassGeneral Hospital for Children Baltimore, MD
Lexington, MA Professor of Psychiatry and Behavioral
Assistant Professor of Neurology Sciences
Harvard Medical School Johns Hopkins School of Medicine
Boston, MA Baltimore, MD
Contributors // xv
Allan L. Reiss, MD Thayne L. Sweeten, PhD

Robbins Professor and Director, Center Senior Lecturer
for Interdisciplinary Brain Sciences Department of Biology
Research Utah State University
Vice Chair, Department of Psychiatry & Logan, UT
Behavioral Sciences
Professor of Radiology and of Naomi B. Swiezy, PhD, HSPP
Pediatrics Director
Stanford University School of HANDS in Autism Interdisciplinary
Medicine Training and Resource Center
Palo Alto, CA Alan H. Cohen Family Professor of
Psychiatry
Mustafa Sahin, MD, PhD Indiana University School of Medicine
Department of Neurology Indianapolis, IN
Boston Children’s Hospital
Boston, MA Michael E. Talkowski, PhD
Associate Professor of Neurology Director, Genomics and
Harvard Medical School Technology Core
Boston, MA Psychiatric and Neurodevelopmental
Genetics Unit
Clarence E. Schutt, PhD Molecular Neurogenetics Unit
The Nancy Lurie Marks Family Foundation Center for Human Genetic Research
Wellesley, MA Massachusetts General Hospital
Princeton University Boston, MA
Princeton, NJ Assistant Professor of Neurology
Tristram Smith, PhD Boston, MA
Strong Center for Developmental
Disabilities Fred R. Volkmar, MD
Division of Neurodevelopmental and Director, Child Study Center
Behavioral Pediatrics Irving B. Harris Professor of Pediatrics,
Professor of Pediatrics Psychiatry and Psychology
University of Rochester Medical Center Yale University School of Medicine
Rochester, NY New Haven, CT
Melissa A. Sreckovic, MEd Danielle Warner, MA

Doctoral Candidate Community and Research Liaison
Frank Porter Graham Child Development HANDS in Autism Interdisciplinary
Institute Training and Resource Center
University of North Carolina at Chapel Hill Indiana University School of
Chapel Hill, NC Medicine
Indianapolis, IN
Jennifer L. Stornelli, MOT, OTR/L
Occupational Therapist John M. Williams, BFA
Spaulding Rehabilitation Hospital Winchester, MA
Lurie Center for Autism
Lexington, MA
xvi / / Contributors
Brian Willoughby, PhD Nicole R. Zürcher, PhD

Staff Psychologist Research Fellow
Department of Psychiatry Athinoula A. Martinos Center for
Massachusetts General Hospital Biomedical Imaging
Learning and Emotional Assessment Massachusetts General Hospital
Program (LEAP) Charlestown, MA
Boston, MA Research Fellow in Radiology
Instructor in Psychiatry Harvard Medical School
Harvard Medical School Boston, MA
Boston, MA
Katharine Zuckerman, MD, MPH

Assistant Professor
Division of General Pediatrics
Oregon Health & Science University
Portland, OR

/ / / / / / / / / / / / / / / / / / / SE CTION 1/ / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / /
BACKGROUND AND
DIAGNOSTIC ASSESSMENT
1 / / /
/ / / FROM INFANTILE AUTISM
TO AUTISM SPECTRUM
Evolution of the Diagnostic Concept
FRED R. VOLKMAR
HISTORICAL BACKGROUND AND AN OVERVIEW OF DIAGNOSTIC APPROACHES
Interest in both developmental and mental disorders increased markedly in the 19th cen-
tury. Children with severe developmental problems (or what is now referred to as intellec-
tual disability) became the focus both of research and of new approaches to care. Interest
in so-called “feral” or “wild” children (presumably raised by animals but likely having
autism) stimulated work on rehabilitation and the “nature–nurture” controversy (Wood,
1975) (Figure 1.1).
In the field of severe psychiatric disorders, the delineation of specific types of disorders
in adults, such as schizophrenia (Bleuler, 1911/1950), further stimulated work on psychi-
atric taxonomies. The convergence of developmental factors with mental disorders in chil-
dren also quickly led to extrapolation of “adult” disorders, particularly relative to what we
now recognize as schizophrenia (de Sanctis, 1906/1973). In this context, the development
of a new field—child psychiatry—by Leo Kanner (1935) led to diagnostic approaches
unique to children.
Issues of diagnosis and classification of childhood-onset disorders began to be addressed
in official diagnostic systems such as the American Psychiatric Association’s Diagnostic and
Statistical Manual of Mental Disorders (DSM), which is now in its 5th edition (DSM-5;
American Psychiatric Association (APA), 2013), and the World Health Organization’s
International Classification of Disease, currently in its 10th edition (ICD-10), with both a
clinical and research version (World Health Organization, 1987, 1990).
There are various purposes for classification systems, including facilitation of commu-
nication and clinical service, research, and policy/public health planning. In the United
States, diagnostic labels also have importance for entitlement to service. Classification
schemes face many challenges, including appropriate consideration of age and developmen-
tal aspects of syndrome expression, gender, and cultural factors. Tensions arise around the
balance of comprehensive clinical coverage and research definitions—the latter of course
tending to usually be more stringent (Volkmar, Schwab-Stone, & First, 2002; Rutter, 2011).
Other issues arise when dealing with the complex issue of comorbidity—that is, of having
3
4 / / B ac kg roun d an d Dia g nostic A ssessment
FIGURE 1.1 Victor of Aveyron (c. 1788–1828) was a French feral child who was found in 1800
after apparently spending the majority of his childhood alone in the woods. Upon his discov-
ery, his case was taken up by a young physician, Jean Marc Gaspard Itard, who worked with
the boy for five years and gave him his name, Victor. Itard was interested in determining what
Victor could learn. He devised procedures to teach the boy words and recorded his progress.
Based on his work with Victor, Itard broke new ground in the education of the developmen-
tally delayed. Itard, J.M.G. (1962). Der Wilde von Aveyron [portrait]. The Wild Boy of Aveyron.
New York, NY: Appleton-Century-Crofts. (Original works published 1802).
more than one disorder (Rutter, 1997). Although categorical approaches to diagnosis have
tended to dominate in medicine, these are not incompatible with dimensional approaches.
Increasingly, dimensional and categorical approaches have had complex relationships and,
as discussed later with regard to DSM-5, have featured even more prominently in new diag-
nostic approaches. There are complex issues of developmental consideration for diagnostic
systems in terms of both onset and impact, and the risk for other problems should not be
underappreciated, particularly for early onset disorders such as autism. The advance of a
multiaxial approach to diagnosis (Rutter, Shaffer, & Shepherd, 1975) led to more careful
consideration of these and other factors, and the complex changes attempted in DSM-5 may
or may not improve on this older approach (Rutter, 2011). Finally, the issue of consider-
ation of etiology in diagnosis presents challenges for diagnostic systems. For example, even
for a disorder such as Down syndrome (trisomy 21), there may be considerable heterogene-
ity in outcome. In the case of Rett’s disorder—a condition included specifically in DSM-IV
From Infantile Autism to Autism Spectrum // 5
(APA, 1994) because it was thought that it would likely have a specific etiology—the dis-
covery of a genetic basis led to a decision in DSM-5 not to give the condition specific diag-
nostic status, presumably in part because it was believed that it is more its own distinct
entity. In addition, the more “autistic-like” features of Rett’s disorder were believed to be
confined to the preschool years, thus making it less suitable for inclusion in the new Autism
Spectrum Disorder (ASD) category. Changes in diagnostic systems present both opportu-
nities and challenges. Opportunities arise given the potential for strongly data-based revi-
sions to improve the diagnostic system; on the other hand, major changes have potential for
disrupting ongoing studies, complicating epidemiological studies, and potentially compli-
cating interpretation of previous research and impacting service provision.
FROM KANNER’S REPORT TO DSM-III
Although it seems likely that children with autism had been observed by others (Candland,
1995; Wolff, 2004), Kanner was the first person to recognize the condition now known as
autistic disorder or ASD. In 1943, he published the classic work on this topic reporting on
11 children who Kanner believed had a congenital inability to be social (Kanner, 1943).
He was careful to frame his description developmentally citing the work of Arnold Gesell
at Yale University that documented how social typical infants were with others (Gesell,
1934). Kanner emphasized that the condition he described was characterized by two essen-
tial features—autism (extreme social isolation) and a need for sameness (i.e., intolerance of
change) in the nonsocial world. He suggested that the condition was congenital and noted
many, if not most, of the features still recognized as typical in “classic” autism (Volkmar,
Reichow, & McPartland, 2012). His work also noted features such as high educational lev-
els among parents and his impression of the potential for normal intellectual functioning.
His use of the word “autism” led to a mistaken impression that the disorder was related to
schizophrenia (Volkmar et al., 2012) (Figure 1.2).
Subsequent work suggested that most children with autism also had overall IQs in the
intellectual deficient range even though marked scatter of abilities was sometimes observed
(Goldstein, Naglieri, & Ozonoff, 2009; Harris, 2006). There was the mistaken impression in
the 1950s that autism might result from some form of parental neglect, “refrigerator moth-
ers.” However, as longitudinal data were collected, the presence of distinctive features (e.g.,
adolescent-onset seizures) (Volkmar & Nelson, 1990), the apparently strong genetic basis
of the condition (Folstein & Rutter, 1977), and differences in clinical phenomenology and
onset pattern (Kolvin, 1972) clarified its strong neurobiological and genetic basis. Other
work made it clear that there was no particular social class bias for autism (Wing, 1980).
As these issues were clarified in the 1960s and 1970s, research on autism began to
increase. The pioneering work of a father, Bernard Rimland, helped refocus research on
neurobiological mechanisms and provided the first diagnostic rating instrument for the
condition (Rimland, 1964). During the 1970s, studies of treatment suggested that struc-
tured, behaviorally focused interventions were much more effective than the previously
dominant unstructured, psychodynamic approaches (Rutter & Bartak, 1973).
The growing consensus on autism’s validity as a diagnostic category led to the elab-
oration, in the late 1970s, of two sets of diagnostic guidelines. Rutter’s (1978) approach
emphasized abnormal social and communication development (not just due to associated
intellectual disability) associated with the pattern of unusual behavioral responses (stereo-
typed mannerisms and difficulties with change) and early onset. In contrast, the National
Society for Autistic Children’s definition (Ritvo & Freeman, 1978) focused on issues such
FIGURE 1.2 Leo Kanner, M.D. was a child psychiatrist at Johns Hopkins University School of
Medicine. He published the first American textbook on child psychiatry in 1935. A portrait of Leo
Kanner, M.D. by Nicholas Pavloff. Reprinted with permission of the Alan Mason Chesney Medical
Archives of the Johns Hopkins Medical Institutions.
as unusual rates or sequences of development and hyper/hyposensitivity to the environ-

ment. These attempts were influential given the move within psychiatry toward a more
research-based diagnostic criteria approach as exemplified by the group at Washington
University (Spitzer, Endicott, & Robbins, 1978). As noted previously, the advent of a mul-
tiaxial classification scheme seemed to offer considerable promise for developmental disor-
ders, and a major re-undertaking of the DSM occurred with DSM-III (APA, 1980; Spitzer
et al., 1978). Changes in approaches to diagnosis in DSM are summarized in Box 1.1.
DSM-III AND DSM-III-R
Given the body of work showing the distinctiveness of autism, a decision was made to
include “infantile autism” in DSM-III (APA, 1980) as part of a new class of disorders
(Pervasive Developmental Disorders (PDD)). As might be suspected, the original defini-
tion focused on the more “classic” presentation of autism, and to address developmental
change, a category of “residual infantile autism” was included for cases who had once met
the more rigorous “infantile autism” criteria. The definition used for infantile autism was
BOX 1.1
CHANGES IN APPROACHES TO AUTISM DIAGNOSIS
FROM DSM-I TO DSM-5
DSM-I (1952) and DSM-II (1968)

Autism was not officially recognized. A limited number of diagnoses existed for
childhood-onset disorders.
DSM-III (1980)
Infantile autism and residual autism were included in a new “class” of disorder
(Pervasive Developmental Disorders (PDD)) along with a “late-onset” form of autism
(childhood-onset PDD) and “subthreshold” PDD (atypical PDD). Advantages included
use of a multiaxial approach and a research criteria approach to definition. A major
disadvantage was the lack of a developmental orientation.
DSM-III-R (1987)
Autistic disorder and a new term for “subthreshold” PDD (Pervasive Developmental
Disorder, Not Otherwise Specified (PDD-NOS)) were put forth. An advantage included
a greater developmental orientation (polythetic criteria) but likely an overly broad diag-
nostic concept.
DSM-IV (1994)
In addition to autistic disorder, other conditions (Asperger’s disorder, Rett’s disor-
der, and childhood disintegrative disorder) were recognized along with PDD-NOS.
Advantages for autism included convergence with the ICD-10 definition and good
balance of sensitivity and specificity over IQ range as well as flexible polythetic
definitions. Disadvantages included controversy regarding inclusion of “new” disor-
ders, particularly Asperger’s disorder. With the convergence of DSM-IV and ICD-10,
research comparability was enhanced and resulted in an explosion of research papers.
DSM-IV-TR (text revision) (2004)

There were no changes in criteria (although there was a minor change in the descrip-
tion of PDD-NOS to make it clear that social difficulties have to be present). Major
changes were made in the text description of Asperger’s disorder.
DSM-5 (2013)
Autism spectrum disorder and the new concept of social communication disorder
(the latter being a communication disorder) were put forth. Autism spectrum disor-
der replaces autistic disorder as well as the PDD term. Although use of “spectrum”
implies broader definition, the actual definition is probably much more focused on
“classic” autism, with many more able cases likely facing loss of label. As a result,
a “grandfathering” rule was adopted (for cases with an older diagnosis but not for
new cases). The subthreshold concept was dropped, and reliance was placed on data
from diagnostic instruments rather than field trials. Adoption of a grandfathering rule
effectively keeps both the old and the new system in current use, likely complicating
research—particularly epidemiological and longitudinal studies.
“monothetic” (every criterion had to be met) and rather inflexible. The failure to address
developmental change seemed to suggest that older and more able individuals were not
significantly in need of services, and this was unfortunate. On the other hand, just the
recognition of autism was an advance, as were other aspects of DSM-III (e.g., the multi-
axial system). Various changes were made in the revision of DSM-III (DSM-III-R), which
appeared in 1987 (APA, 1987).
In DSM-III-R, a major attempt was made to provide a more flexible and developmen-
tally oriented set of criteria. The name of the disorder was changed to autistic disorder, and
16 detailed criteria were listed. These were grouped into three major domains of dysfunc-
tion: qualitative impairment in reciprocal social interaction and in communication, as well
as restricted interests. Eight criteria from the 16 had to be present, with at least 2 from
the social interaction domain and 1 each from the other two categories. The polythetic
approach gave greater flexibility, although the final definition was also problematic in that
the IQ level impacted the diagnosis significantly (Volkmar, Cicchetti, Bregman, & Cohen,
1992). This may have resulted from some weaknesses in the field trial used to develop the
final scoring rule (Spitzer & Siegel, 1990). Unlike DSM-III, which relied heavily on his-
torical information, DSM-III-R emphasized current examination. Unfortunately, it also
became clear that it diverged significantly from the draft ICD-10 revision.
ICD-10 AND DSM-IV
The draft of the World Health Organization’s ICD-10 differed from DSM-III-R in several
ways. A major difference was the ICD-10 “two-book” approach with one book of clinical
guidelines and a different book that presented research diagnostic criteria. Other differ-
ences existed as well, including, for autism, the tentative decision to have a rather different
approach both to the diagnosis of autism and to the potential inclusion of other disor-
ders (e.g., Asperger syndrome) as part of the overarching PDD class of conditions. It was
clear that the potential for markedly different US and international approaches to diagno-
sis might significantly impact research, for example, in generalizing results across studies
(Volkmar et al., 1992).
There were multiple facets of the DSM-IV (APA, 1994) revision process. These
included reviewing specific issues and a series of commissioned literature reviews that
appeared well early in the revision process. For autism, a major issue was the ICD-10’s list-
ing of other disorders in the overarching PDD category—that is, Asperger syndrome, Rett’s
syndrome, and childhood disintegrative disorder. There was general agreement that having
some consensus between DSM-IV and ICD-10 would enhance research. Another set of
papers focused on data analysis/reanalysis of differences between DSM-III-R and ICD-10
(the latter in its draft version). On balance, DSM-III-R was clearly more developmentally
oriented but probably overdiagnosed autism in the more cognitively disabled and possibly
underdiagnosed it in the most able (Volkmar et al., 1992). A large international field trial
was undertaken in conjunction with an evaluation of the draft ICD-10 criteria (Volkmar
et al., 1994). This included more than 20 sites throughout the world, with more than 100
raters providing information on nearly 1000 cases. Unlike the DSM-III-R field trial, for a
case to be included, the clinician had to believe that autism was a reasonable possibility in
the differential diagnosis. Information on raters was also collected. Typically, the raters had
multiple sources of information available to them.
The results suggested that DSM-III-R had a high rate of false positives if significant
intellectual disability was present (nearly 60%). The draft ICD-10 criteria worked well
but were quite detailed and more numerous than was typical for DSM. A series of statisti-
cal analyses, including inter-rater reliability and factor analysis, were undertaken. Several
different potential solutions emerged in the factor analysis. One included the traditional
triad of domains of difficulty (social, communication, and restricted interests), but other
potential solutions included a two-factor approach (social communication and restricted
interests) and a five-factor solution (in which restricted interests criteria were sorted into
three groups). Efforts were made to reduce the number of criteria in ICD-10, and the final
version of DSM-IV/ICD-10 had a good balance of clinical and research utility.
In terms of compatibility with ICD-10, another set of issues for DSM-IV had to do with
inclusion of other conditions within the overarching PDD category. For all these potential
“new” categories, literature reviews were commissioned and, to the extent possible, data
were obtained from reviews of existing data or data reanalysis and, to some extent, from
the DSM-IV field trial. Two of these conditions—Rett’s disorder and childhood disintegra-
tive disorder—were characterized by developmental regression and loss of skills. For Rett’s
disorder, the subsequent course and other clinical features of the disorder (e.g., it appeared
to be largely, if not entirely, confined to girls) were quite distinctive, although there was a
period, particularly during the preschool years, when there was potential for confusion with
autism (Tsai, 1997; VanAcker, Loncola, & VanAcker, 2005).
Although the decision to include it was somewhat controversial, it appeared important
to include it somewhere in DSM because the genetic etiology of the condition had been
identified (Gillberg, 1994; Rutter, 1994; VanAcker et al., 2005). Childhood disintegrative
disorder (sometimes referred to in the past as disintegrative psychosis or Heller’s syndrome)
was a clearly rare condition in which children developed a relatively “classic” autism presen-
tation but after years, sometimes many years, of normal development. Here, data from ear-
lier studies of its differences from autism (Volkmar & Cohen, 1989) and results of data from
the field trial (Volkmar et al., 1994; Volkmar & Rutter, 1995) supported its inclusion—not
because it was common but because the onset was so distinctive. For Asperger’s disorder,
inclusion of the condition in DSM-IV was more controversial. Following its first descrip-
tion in 1944 (Asperger, 1944), interest in the condition was minimal until the publication
of Lorna Wing’s (1981) review and case series (Figure 1.3).
Subsequent to Wing’s description, rather divergent views of the condition proliferated
(Gillberg, 1986; Klin, McPartland, & Volkmar, 2005; Szatmari, 1991). Although not a
major focus of the DSM-IV field trial, data on a number of cases with a clinician-assigned
diagnosis of Asperger’s disorder had been submitted, and the data suggested differences
both from higher functioning autism and from PDD, Not Otherwise Specified (PDD-
NOS) (Volkmar et al., 1994). After much debate, the condition was included, although
ambivalence about its inclusion led to several unfortunate and problematic aspects of its
definition—thus inadvertently contributing to ongoing debate about it (Bennett et al.,
2008; Miller & Ozonoff, 1997; Woodbury-Smith, Klin, & Volkmar, 2005). It clearly is the
case that inclusion of the condition markedly stimulated research interest (approximately
75 papers were published between 1944 and 1993, and nearly 2000 papers have been pub-
lished subsequent to DSM-IV). As a practical matter, its inclusion increased compatibility
with ICD-10, suggested (given better preserved verbal language and differences in clinical
presentation) potentially different treatments, and, given the impression of a strong family
history of similar problems in male relatives, suggested a research importance as well (Klin,
Pauls, Schultz, & Volkmar, 2005).
The “subthreshold” category of PDD-NOS was included, consistent with the rest of
DSM-IV, to be available for individuals whose difficulties were clinically significant and sug-
gestive of autism without meeting full criteria for the condition. PDD-NOS (previously
10 / / B ac kg round an d Dia g nostic A ssessment
FIGURE 1.3 Univ. -Prof. Dr. Hans Asperger als junger Assistenzarzt in der Heilpädagogischen
Ambulanz der Wiener Universitäts—Kinderklinik [photograph]. Fotoarchiv der ehemaligen
Heilpädagogischen Station. Reprinted with permission from the private collection of Dr. Maria
Asperger Felder. **Caption roughly translates to “University Professor Dr. Hans Asperger as a
young doctor in the outpatient clinic of the University of Vienna, Special Education—Children’s
Hospital”.
called atypical PDD) had its conceptual roots, in some ways, with early descriptions of
unusual personality patterns characterized by unusual sensitivities and social difficulties
(Rank, 1949, 1955; Towbin, 2005). It had been clear for some time that such cases sig-
nificantly outnumbered those with “classic” autism, and debate centered on the degree to
which these conditions were part of a broader autism phenotype (Scheeren & Stauder,
2008, Towbin, 2005).
DIMENSIONAL DIAGNOSTIC APPROACHES
Dimensional diagnostic approaches have had an increasing impact on both research and
categorical approaches. This has been particularly true of DSM, for which such instruments
have been used to develop new definitions. In autism, the first diagnostic checklist was
developed by Rimland (1964). It has been followed by a host of other instruments—some
for screening and others for formal diagnostic assessment and still others as research tools
(e.g., for assessing social impairment) (Constantino et al., 2003; Coonrod & Stone, 2005;
Gillham, Carter, Volkmar, & Sparrow, 2003; Lord & Corsello, 2005). Some instruments
focus specifically on special populations, such as very young children or the more cog-
nitively able; some are based on parent or teacher report, and others are based on direct
observation/interaction. For more complicated instruments, extensive training and dem-
onstration of reliability are needed.
Challenges for dimensional approaches include the broad range of syndrome expres-
sion over both age and IQ levels. Other issues arise with regard to approach (historical
information or current assessment), and still others arise relative to behaviors that are
highly atypical or infrequent but important (e.g., self-injury). Some instruments allow clini-
cal judgment to enter in, whereas others are less flexible. As a general rule, such instruments
work best for school-age children and those with borderline to mild intellectual impair-
ments. Challenges arise for the very young and for both low and high cognitive functioning
individuals.
Clearly, the ability to characterize relevant clinical areas with dimensional measures
has many advantages for research, particularly relative to issues of “broader phenotype.”
Measures of symptom severity may also be useful in monitoring progress in treatment.
These issues have special relevance in DSM-5, which relied considerably on dimensional
research instruments. On the one hand, the desire to use such well-standardized instru-
ments is understandable (Regier, Narrow, Kuhl, & Kupfer, 2010). It may also create impor-
tant challenges—that is, as items are moved from a highly structured and supervised
research context to “real-world” settings.
MOVING TOWARD DSM-5
For DSM-5 criteria, an attempt was made to use the detailed data from research diagnostic
instruments to improve on DSM-IV. Note that DSM-IV has the advantage of being con-
sistent with ICD-10, and it provided a flexible and developmentally oriented criteria set
that appeared to work well over the range of IQ and intellectual ability. Indeed, in the two
decades after DSM-IV was published, there has been a truly dramatic increase in research in
autism (Volkmar, 2014). It appears that having had very comparable international and US
systems helped stimulate this research and comparability of findings across countries. The
growing body of interest and research on autism also appeared to be associated with grad-
ual improvement in outcome (Howlin, 2013), as well as increased understanding of basic
mechanisms—both genetic (Rutter & Thapar, 2013) and neural (McPartland, Coffman, &
Pelphrey, 2011).
Although research grew dramatically since DSM-IV and ICD-10 appeared, some areas
of concern also arose. The DSM-IV field trial was very large and international but not truly
epidemiological, and concerns were raised that the criteria proposed might be less appli-
cable to very young children, many of whom did not always show all required features until
ages 2 or 3 years (Chawarska, Klin, & Volkmar, 2008). Other issues were raised about either
the validity or the definition of the DSM-IV PDD subtypes—particularly concerning
Asperger’s disorder (Howlin, 2003; Mayes, Calhoun, & Crites, 2001; Ozonoff & Griffith,
2000)—although, as noted previously, it is clear that diagnostic consensus is most diver-
gent around very high functioning cases and other reports suggested both that the DSM-IV
Asperger’s disorder criteria could be used (Woodbury-Smith et al., 2005) and that rigorous
definitions of Asperger’s disorder were more likely to be associated with independent vali-
dators of the condition (IQ profiles, psychiatric history, and family history) (Klin, Volkmar,
Sparrow, Ciccetti, & Rourke, 1995; Klin et al., 2005; Lincoln, Bloom, Katz, & Boksenbaum,
1998). In DSM-IV-TR (APA, 2000), the entire text for Asperger’s disorder was replaced,
although no changes were allowed in criteria. The diverse approaches to the diagnosis of
Asperger’s disorder (many originating in the 1980s, well before DSM-IV appeared) con-
tributed to confusion on these issues. Lord (2011) suggested that assessment location was
a major determinant of consistent use of Asperger’s disorder. Other issues had to do with
inclusion of Rett’s disorder in DSM-5, given its strong genetic basis, and whether the rare
condition of childhood disintegrative disorder could be reliably identified and was most
appropriately included with autism. Finally, concern about the lack of an explicit approach
to the definition of the broader PDD-NOS group was expressed.
DSM-5 AND AUTISM SPECTRUM DISORDER
Several overall decisions led to major changes in the approach to the diagnosis of autism
in DSM-5 (APA, 2013). These included the decision to eliminate as much as possible sub-
threshold conditions, to move to dimensional ratings of symptoms, to no longer use the
multiaxial system, and to utilize data from diagnostic instruments rather than field trials as
the primary basis for testing the efficiency of criteria proposed. For autism and related dis-
orders, the older class of PDDs was dropped in favor of a single Autism Spectrum Disorder
(ASD), with a related disorder, Social Communication Disorder (SCD) (coded in the com-
munication section of DSM-5), added. On the basis of factor analysis of a large body of
data from diagnostic instruments, a decision was made to drop the traditional three-factor
approach to diagnosis (social problems, communication problems, and restricted interests/
behaviors) in favor of a two-factor (social–communication and restricted interests) model.
The number of criteria was reduced and for the social–communication category became
monothetic (the individual had to exhibit all features), whereas in the restricted and repeti-
tive criteria, two of four symptom groupings were needed. A sensory criterion was also
added to this grouping. The new SCD was defined by pragmatic difficulties and problems
in the use of verbal and nonverbal communication in social situations, and although similar
to PDD-NOS, the condition was included as a communication disorder rather than ASD.
Changes were also made so that the severity of symptoms could be specified, and modifica-
tions were made in the approach to early onset as a diagnostic feature. As noted later, the
worry that DSM-5 would disqualify individuals for a diagnosis led to an additional rule so
that patients with well-established DSM-IV diagnoses on the autism spectrum could retain
them, thus effectively creating two systems in current use. Given the abandonment of the
multiaxial approach, specifiers could be used to indicate if a known etiological factor was
present, as well as the level of need for support objectives. Other specifiers allowed for an
indication of intellectual disability and language impairment. A final specifier could be used
to note that catatonia was present.
Even before DSM-5 appeared, several studies were published evaluating the new
approach. The focus of many such studies was how well the new approach worked in
more “real-world” settings (i.e., apart from the diagnostic instruments) and whether major
changes in diagnostic practice would result. These studies generally indicated that higher
functioning individuals—particularly those with Asperger’s disorder and PDD-NOS
in DSM-IV terms—were likely to lose their diagnosis (Gibbs, Aldridge, Chandler,
Witzlsperger, & Smith, 2012; Mattila et al., 2011; McPartland, Reichow, & Volkmar, 2012;
Taheri & Perry, 2012; Wilson et al., 2013; Worley & Matson, 2012). This was also true,
to a lesser extent, for more cognitively able individuals with autistic disorder in DSM-IV
terms. Other studies raised concerns about the application of criteria to younger children, a
major concern given the need for early intervention (Matson, Kozlowski, Hattier, Horovitz,
& Sipes, 2012). In some ways, these results should not be viewed as surprising given that
the diagnostic instruments chosen to develop the new criteria worked best (as most such
instruments do) for school-age children with borderline to mild intellectual impairments.
Thus, most of the studies now available suggest that DSM-5 criteria offer greater specific-
ity but with lowered sensitivity for specific subgroups such as the more cognitively able,
but socially impaired, young children and cases with the DSM-IV “PDD-NOS” diagnosis.
As Tsai (2012) noted, the sensitivity and specificity that will be evident in purely clinical
(i.e., rather than research) settings remain unclear. Several investigators have already made
recommendations for improvements in DSM-5 (Barton, Robins, Jashar, Brennan, & Fein,
2013; Wilson et al., 2013).
Other work has addressed the change from a three- to a two-factor grouping of symp-
tom domains (Sipes & Matson, 2014) and suggested that several different factor solutions
are possible. Similarly, the DSM-IV field trial factor analysis yielded reasonable two-, three-,
or five-factor solutions (Volkmar et al., 1994), but the three-factor solution was adopted in
DSM-IV and ICD-10 to give the most robust set of possible combinations of criteria (more
than 2000 possible combinations of the 12 criteria could result in a diagnosis of autism).
The reduced number of items and factors in DSM-5 vastly reduced the number of potential
combinations.
The advent of DSM-5 brings potential opportunities, as well as some concerns. The
use of research instruments in research settings is clearly of great benefit—their applica-
bility in clinical settings in which individuals do not have extensive experience or train-
ing remains unclear. The potential for creating effectively two systems (the new and the
old “grandfathered” approach) can present challenges, for example, for longitudinal and
epidemiological studies. Another major concern is the potential for a more stringent sys-
tem to reduce access to services both for the very young and for the more cognitively
able—many of whom already face challenges in securing services. Ghaziuddin (2010)
has questioned the potential loss of information for research using DSM-5. Other chal-
lenges arise given pending changes in ICD-11 (currently in preparation), with the real
possibility that multiple diagnostic approaches will be in current use, potentially severely
compromising comparability of samples. Clearly, collapsing or removing subtypes makes
it difficult to validate them (Baron-Cohen, 2009; Ghanizadeh, 2011; Mandy, Charman,
& Skuse, 2011). Other investigators have raised a range of concerns. For example, Wing,
Gould, and Gillberg (2011) noted a potential difficulty given nonspecificity of sensory
behavior. Given all these issues, it is possible that DSM-5 groupings may become less rel-
evant to research, as the former director of the National Institute of Mental Health has
suggested (Insel, 2013).
SUMMARY
This chapter reviewed the emergence and evolution of the diagnosis and conceptualization
of autism from the early work of Leo Kanner to the fifth edition of the DSM. Dimensional
and categorical approaches to diagnosis were used, and the challenges and benefits of both
approaches were identified. Attempts were made to consider the criteria in both the DSM
and the ICD because changes were anticipated in one or the other so that commonalities
could continue for the purposes of clinical and research classification of autism and related
disorders throughout the world. It is hoped that the new Research Diagnostic Criteria
(RDoC) for research on mental disorders will enhance the field’s ability to diagnose
meaningful subtypes of autism-related disorders so that targeted treatment approaches for

individuals may one day be realized.
KEY POINTS
• The purposes of classification systems include facilitation of communication and
clinical service, research, policy/public health planning, and entitlement to service.
• Leo Kanner, MD, was the first person to recognize and describe the condition now
known as autism spectrum disorder.
• “Infantile Autism” first appeared in DSM-III as part of a new class of disorders called
Pervasive Developmental Disorders.
• The diagnosis of Asperger’s disorder first appeared in DSM-IV. This disorder is largely
differentiated from “classic autism” based on normal language development and nor-
mal cognitive development.
• In DSM-5, the five subtypes of Pervasive Developmental Disorder were collapsed
into one broad diagnostic category called Autism Spectrum Disorder.
DISCLOSURE STATEMENT
Dr. Fred R. Volkmar has nothing to disclose.
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2 / / /
/ / / SOCIAL, COGNITIVE, AND
BEHAVIORAL DEVELOPMENT
OF CHILDREN AND
ADOLESCENTS WITH AUTISM
SPECTRUM DISORDER
KIRSTIN BROWN BIRTWELL,

BRIAN WILLOUGHBY, AND LISA NOWINSKI
INTRODUCTION
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition

composed of a wide “spectrum” of topographical characteristics and neuropsychological
impairments. Although the ASD diagnosis has been found to be relatively stable across
time (Gotham, Pickles, & Lord, 2012; Woolfenden, Sarkozy, Ridley, & Williams, 2012),
developmental and functional trajectories of individuals with ASD vary considerably.
Consequently, children at various developmental stages present to pediatricians, psycholo-
gists, psychiatrists, neurologists, and other health care professionals with concerns that may
ultimately lead to an ASD diagnosis.
Recent research suggests that the broader phenotype of ASD may be detectable before
12 months of age (Ozonoff et al., 2014; Zwaigenbaum et al., 2005); however, ASD symp-
toms are typically visible between 12 and 24 months and may include delayed language
development, unusual communication patterns, lack of social interest, atypical social inter-
action, and odd patterns of play (American Psychiatric Association (APA), 2013; Guthrie,
Swineford, Nottke, & Wetherby, 2013). Nonetheless, in large community-based samples,
the median age of diagnosis is older than age 4 years (Centers for Disease Control and
Prevention, 2014; Shattuck et al., 2009). In some cases, in which early childhood symp-
toms may be more subtle, a diagnosis may not be made until late childhood or early adoles-
cence (e.g., when increased social demands may elucidate skill deficits).
Determining the predictability and reliability of ASD over time has proven to be
a challenging task for both the scientific community and the clinical community. For
example, one-fourth to one-third of children with ASD experience significant social and
19
communication skill regression in the second year of life (APA, 2013; Lord & Spence,
2006). Throughout early childhood and adolescence, the overall functional capacity among
individuals diagnosed with ASD may differ extensively. For example, some children with
ASD never develop functional expressive language abilities, whereas others present with
superior verbal skills. Within ASD, individuals without structural language impairments
have been found to present with fewer diagnostic symptoms and stronger adaptive com-
munication, daily living, and socialization skills compared to those with structural language
impairments when followed from early childhood to adolescence (Szatmari et al., 2009).
Similarly, Baghdadli and colleagues (2012) demonstrated that language impairments and
level of ASD symptom severity serve as risk factors for decreased social and communica-
tion functioning 10 years later. Although ASD is believed to be associated with innate neu-
robiological deficits that lead to chronic lifelong dysfunction, many individuals show global
improvements in adolescence (McGovern & Sigman, 2005). Conversely, a small percent-
age of individuals deteriorate behaviorally in adolescence (APA, 2013).
Despite the heterogeneity within ASD, increased research, public awareness, and state-
and federal-specific legislation and advocacy have led to important findings during the past
two decades. There is still much to learn, but the field has made significant gains in under-
standing the social, cognitive, and behavioral developmental underpinnings of ASD.
SOCIAL FUNCTIONING
Given that social impairment is the hallmark characteristic of ASD, several researchers to
date have explored how early social deficits disrupt the social and communicative develop-
mental course. The current underlying social theories of neurodevelopment in ASD focus
on the social motivation and the social cognition domains of functioning. Social motiva-
tion is an important area of focus given that these delays and disruptions are some of the
first diagnostic indicators of ASD. For example, Wu and Chiang (2014) found that both
typically developing infants and children aged 2–4 years with developmental delays fol-
lowed a different sequence of social skill acquisition than children aged 2–4 years with ASD.
Specifically, typically developing infants and developmentally delayed toddlers developed
joint attention skills first, followed by object imitation and play, and referential language
last, whereas children with ASD developed object imitation first, followed by responding to
joint attention, play, referential language, and initiating joint attention skills last. Compared
to their peers, children with ASD not only exhibit atypical social behaviors (e.g., repetitive
behaviors) but also may develop different social skills at different times, further highlight-
ing the need to more accurately identify the neurological origin of these social motivation
deficiencies.
To this end, Dawson and colleagues proposed that an innate deficit in early attentional
preferences for social stimuli may contribute to the larger social–behavioral profile of ASD,
including attenuated joint attention, social orienting, emotion perception, imitation, and
affective sharing (Bernier, Webb, & Dawson, 2006; Dawson, Meltzoff, Osterling, Rinaldi,
& Brown, 1998). A central tenet to this theory is that the inherent social reward system in
infant brain circuitry is disrupted, with most research to date identifying the dopaminergic
system, modulated by oxytocin and vasopressin, as the central site of derailment (Rozga,
Anderson, & Robins, 2011). Oxytocin, in particular, has garnered a tremendous amount
of attention, with new research suggesting that deficient oxytocin function in ASD may
directly contribute to decreased social motivation (Stavropoulos & Carver, 2013). Earlier
research by Waterhouse, Fein, and Modahl (1996) also highlighted the importance of the
Social, Cognitive, and Behavioral Development of Children and Adolescents With ASD // 21
amygdala and how a potentially ineffective social stimuli–emotional salience association

may also contribute to decreased social motivation and initiation. Although the evidence
regarding etiology is still emerging, impaired amygdala and oxytocin function appear to
play important roles in the social–developmental deterioration associated with ASD.
In addition to the social motivation hypothesis, social cognitive theories, which address
the inability to predict, process, and explain the behavior of others, highlight another
important area of developmental disturbance in ASD. A widely accepted phenomenon,
theory of mind (ToM), includes the difficulties that individuals with ASD have with
perspective-taking skills and is credited to the work of Baron-Cohen, Leslie, and Frith
(1985). Their work has indicated that children with ASD not only show significant delays
in ToM skills but also may never acquire these skills to the extent that typical adolescents
and adults do (Baron-Cohen, Jolliffe, Mortimore, & Robertson, 1997). These difficulties
may explain both social and communicative deficits in ASD because meaningful and recip-
rocal conversation with others (a skill absent or significantly impaired in ASD) requires
this ability to take the listener’s perspective (Hale & Tager-Flusberg, 2005; Tager-Flusberg,
1996). Along with extensive behavioral research in ToM deficits, neuropsychological stud-
ies indicate that brain regions responsible for these skills (e.g., medial prefrontal cortex,
anterior cingulate cortex, temporal poles adjacent to the amygdala, and superior temporal
sulcus) may exhibit reduced activation in individuals with ASD (Rozga et al., 2011). In
summary, both social motivation and social cognitive theories, and their neurobiological
foundations, continue to be studied as potentially precipitating factors in the developmen-
tal emergence of ASD.
COGNITIVE FUNCTIONING
Among cognitive theories of development, executive functioning impairments and infor-

mation processing models carry the most reliable empirical research support to date
(Rozga et al., 2011). Executive functioning (EF) refers to a specific group of higher-level
cognitive skills that are mediated by the prefrontal cortex region and required for complex
problem-solving and goal-oriented behavior. EF skills include planning, organizing, work-
ing memory, cognitive flexibility, inhibition, and behavioral control, and impairments in
this domain have been associated with learning disorders as well as psychiatric conditions
such as attention deficit hyperactivity disorder and ASD (Corbett, Constantine, Hendren,
Rocke, & Ozonoff, 2009). In ASD in particular, the restricted, repetitive, and stereotyped
behaviors and interests characteristic of ASD appear to be related to the rigidity, difficulty
with change, and lack of planning associated with EF deficits (Ozonoff, Pennington, &
Rogers, 1991). For example, children with ASD typically have trouble when previously
established routines (e.g., bedtime routine) are disrupted or rearranged. Given that EF
deficits are observed across a wide variety of neurodevelopmental and learning disorders,
recent research in this area has been tasked with determining what the unique ASD–EF
profile may be. Some literature suggests that in individuals with ASD, cognitive and motor
inhibition appears to be intact while deficits are primarily found in cognitive flexibility and
attention (Ozonoff, South, & Provencal, 2005). Nonetheless, more research is needed in
order to accurately determine the distinct EF profiles across diagnostic categories.
The second category of cognitive theories of development includes weak central
coherence (WCC) theory (Happé & Frith, 2006) and complex information processing
theories. WCC, first described by Uta Frith (1989), refers to the diminished ability to
integrate smaller components of information from the environment into a more cohesive,
TABLE 2.1 Current Theories of Development in Autism Spectrum Disorder

Domain of Theory Summary
Functioning
Social Social motivation Disruption in the early social reward system
Social cognitive Innate theory of mind (ToM) skill deficits
Cognitive Executive functioning Innate difficulties with higher-level cognitive skills of
planning, organizing, cognitive flexibility, inhibition, and
behavioral control
Information processing Diminished ability to integrate smaller parts into a
meaningful whole and greater difficulty with complex
problem-solving, skilled motor, and higher-order
memory- and language-based tasks
contextually appropriate, meaningful whole. Whereas the EF theory may adequately

explain the cognitive flexibility and gestalt processing deficits in ASD, the WCC model also
addresses the relative visuospatial and localized attentional strengths in these individuals.
In other words, individuals with ASD tend to perform well on tasks that require increased
attention to detail and worse on tasks of more global, contextual attention and process-
ing. For example, an individual with ASD may be able to recall the color of a television
character’s shoes or the instrument that another character was playing in a short scene but
may be unable to explain the relational dynamic between the characters or the moral of the
story/plot. Similarly, the complex information processing theory (Minshew & Goldstein,
1998) helps to explain both strengths and weaknesses in the ASD cognitive profile. This
theory, based on a complex battery of neuropsychological tasks, suggests that individuals
with ASD have greater difficulty than their typically developing peers with higher-order
information processing tasks, such as complex problem solving, skilled motor tasks, con-
cept formation, and higher-order memory and language tasks (Minshew, Webb, Williams,
& Dawson, 2006). Conversely, the complex information processing theory emphasizes the
rote memory, simple language, sensory perception, and visuospatial strengths of the ASD
neurocognitive profile (Table 2.1).
BEHAVIORAL FUNCTIONING
In addition to social and cognitive impairments, children and adolescents with ASD com-
monly present with co-occurring behavioral difficulties, including behavioral dysregulation
and adaptive skill deficits. Although these difficulties are common in children with ASD,
the presence and severity of these symptoms may vary by several factors, including the fol-
lowing: the age of the child or adolescent, intelligence level, family history of mental health
issues, severity of the ASD symptoms, language, and access to interventions (Levy & Perry,
2011). Similar to social and cognitive profiles, there is great heterogeneity regarding behav-
ioral dysregulation and adaptive skills in children with ASD.
Many children with ASD are more likely than their typically developing peers to pres-
ent with aggressive and/or self-injurious behaviors. For instance, Kanne and Mazurek
(2011) found that 68% of children (ages 4–17 years) had behaved aggressively toward care-
givers and 49% toward non-caregivers. These rates are especially high compared to those
for people who have other developmental conditions but not ASD. For example, aggressive
behavior has been documented in only 7–11% of children with intellectual disabilities
(IDs) alone (Emerson et al., 2001). Furthermore, as per Reese, Richman, Belmont, and
Morse (2005), the likelihood of aggression toward others is increased when a child with
ASD demonstrates more repetitive behaviors, especially self-injurious or ritualistic behav-
iors, or extreme resistance to change. Behavioral dysregulation also changes across devel-
opment. In young children, these behavioral symptoms may manifest as difficulties being
soothed, as well as intense and prolonged outbursts (e.g., crying and temper tantrums). In
older children and adolescents, difficulties with behavioral regulation may present as over-
reactivity to minor problems (e.g., not getting one’s own way), threatening to harm oneself
(e.g., engaging in self-injury following a seemingly minor upset), and poor frustration toler-
ance when challenged. Of note, aggressive and disruptive behaviors are the strongest pre-
dictors of parenting stress in families of children with ASD (Baker et al., 2003).
Researchers and theorists have proposed explanations as to why behavioral regulation
is a common struggle in children with ASD. For instance, Loveland (2001) notes that the
regulation of one’s behavior is largely dependent on perceptions regarding others’ inten-
tions, emotions, and mental states. Thus, given that social perception is a core impairment
in ASD, this may lead to extreme behavioral responses that are not appropriate to the con-
text. Furthermore, given that functional communication is also a common deficit, children
with ASD may have trouble verbally expressing their needs and, instead, communicate in
reactive and/or volatile ways (Goldstein, 2002). Biological explanations, such as dysfunc-
tion in the orbitofrontal–amygdala circuit in children with ASD, have also been proposed
(Bachevalier & Loveland, 2006).
Adaptive skills, defined as an individual’s social and practical competence to meet the
demands of everyday living, are commonly impaired in children with ASD. Examples of
adaptive behaviors include functional communication (e.g., indicating needs), socializa-
tion (e.g., asking a friend for a play date), and self-care skills (e.g., following a bedtime rou-
tine). Klin et al. (2007) found that the adaptive living skills of children (ages 7–18 years)
with ASD were between one and three standard deviations below the population mean.
The greatest adaptive impairments were in the areas of socialization and daily living skills,
with communication impaired but to a lesser degree (Lee & Park, 2007). Although studies
have documented adaptive skills deficits in lower-functioning children with ASD (i.e., chil-
dren with a co-occurring ID), significant adaptive deficits may also be pronounced in more
cognitively capable children with ASD. Furthermore, for individuals with ASD, the discrep-
ancy between adaptive skills and intellectual ability widens with age, indicating that adap-
tive behavior does not keep the expected pace with chronological age or intellect (Kanne
et al., 2011; Lopata et al., 2013).
CAN WE PREDICT OUTCOMES?
Given that ASD is a neurodevelopmental disorder, evidence of the diagnosis will present
in early childhood; however, many factors influence the course of the disorder throughout
childhood and across the lifespan. Factors such as underlying cognitive ability or IQ, lan-
guage skills, social awareness and motivation to engage with others, and the presence or
absence of severe dysregulation (e.g., aggression and self-injury) are thought to be impor-
tant predictors of long-term outcomes. Furthermore, research continues to demonstrate
that early and intensive therapy programs are effective for improving IQ, language ability,
and social interactions of children with ASD (Dawson et al., 2010), thus helping to opti-
mize outcomes for children with ASD.
The following case examples illustrate some of the social, cognitive, and behavioral
developmental variability within ASD. Case 1 describes the course and outcomes for
a young man who experienced a developmental regression in language skills at approxi-
mately age 2 years and never resumed speaking. Case 2 describes a relatively high function-
ing young man who has maintained strong verbal and cognitive abilities.
CASE STUDY 1: “SAM”
Sam is a 19-year-old young man with ASD who remains entirely nonverbal. He was born at
full-term following an uncomplicated pregnancy and delivery. During the first year of life,
Sam was quite colicky and difficult to soothe. He experienced frequent and extremely high
fevers greater than 104°F. This required several emergency room visits to reduce the fever,
although no specific cause was ever determined. By age 18 months, Sam was using a few
single words consistently to express his wants and needs (e.g., “milk” and “momma”);
however, his parents were concerned that he was not babbling or talking as much as his
older sister had at the same age. He was evaluated by his pediatrician, who suggested
that they continue to monitor his development for a while longer. Fine and gross motor
development was within normal limits through the first few years of life. He sat up and
started to crawl and walk at the usual times, although he tended to walk on his toes and
his parents noted frequent episodes of uncontrollable “excitement” during which he would
spin his body in circles with his back arched, head tilted up, and hands flapping by his side.
His mother described that he could spend hours examining his collection of toy trains but
never seemed interested in the train track table or other toys such as action figures or dolls.
Soon after his second birthday, Sam stopped using any words to communicate. He con-
tinued to make some noncontextual vocalizations and eventually began using some sign
language, including signs for “more” and “all done.” His play remained limited, and he was
not interested in interacting with other children at the park or in his play group. Instead, he
focused his attention on stacking or lining up toys in a nonfunctional manner. He also carried
with him a favorite toy train and searched for small, round items such as buttons and coins
wherever he went. He was ultimately diagnosed with ASD following a specialist evaluation
and was referred for early intervention (EI) services, including 25 hours per week of inten-
sive applied behavior analysis (ABA).
Sam continued in intensive educational programming throughout his elementary and
middle school years in a specialized, substantially separate program for children with ASD.
Each new skill that Sam mastered had to be systematically taught and practiced over time.
He was slow to master toilet training and continues to require hand-over-hand prompting
for other basic hygiene tasks, such as toothbrushing and showering. With prompting, he
will follow a visual schedule, but hygiene tasks often need to be repeated by a caretaker to
ensure thorough completion.
As he entered puberty, Sam began to exhibit episodes of severe self-injury and aggres-
sion. Particularly during transitions and unexpected changes in routine, he would become
increasingly agitated, biting his hands and arms and hitting at people around him if they tried
to redirect this behavior. These behaviors increased in frequency and intensity, ultimately
requiring placement in a highly structured residential placement. With the help of his psy-
chiatrist, behaviorist, and well-trained residential staff, his self-injury has come under much
better control. He is now able to successfully participate in community outings and works
3 days per week in a medical office building helping with basic cleaning and office tasks
such as stuffing envelopes with direct supervision. Sam remains nonverbal, although he
recently began using an augmentative communication program on his iPad to express his
wants and needs to others. Although he requires prompting to use the device consistently,
he has shown proficiency in navigating the program and attempts to use the program on his
own when he is getting frustrated.
CASE STUDY 2: “PETER”
Peter is an engaging 22-year-old young man who was diagnosed with ASD when he was
9 years old. He was born following an uncomplicated pregnancy and delivery. As a baby, he
was happy and easy to care for. His parents describe that he would lay for hours in his crib
watching the mobile spin. With regard to early developmental milestones, Peter’s language
development was on time to advanced. He did have some difficulty with fine motor skills,
and he continues to struggle with handwriting and bilateral motor coordination.
From an early age, Peter showed interest in other children around him, although it
was difficult for him to interact appropriately. At the park, he would often sit near a
group of children, intently watching their play. If invited to join, he would retreat to his
parents without saying anything. He rarely initiated conversation or play with his peers,
but he talked quite comfortably with adults about various topics that interested him. In
fact, his parents described that he often would not stop talking about his favorite video
game unless he was told to do so. Occasionally, he would repetitively quote lines from
his favorite movie. His peers found this bothersome, and Peter began to have increas-
ing difficulty making and maintaining peer relationships. Over time, he became known
for his depth of knowledge on particular topics such as video games, movie characters,
and animals, but he continued to have difficulty relating to peers, unless the interaction
centered around one of his specific areas of interest. As he got older, he struggled to
control his body and often invaded the personal space of those around him. He also
spoke loudly and in a monotone, robotic-like voice and needed support to monitor his
speech and behavior.
In contrast to these social challenges, Peter thrived in academic settings. He was placed
in advanced-level classes through middle and high school, and his teachers consistently
commented on his ability to quickly learn and remember detailed information. He showed a
particular affinity for animal science and biology. He has maintained a 3.5 grade point aver-
age in high school and plans to pursue an animal care degree at a local community college.
Peter now has two good friends who are also interested in similar topics. Although they do
not see each other outside of school, they regularly engage in role-play video games online
and will message each other about the game regularly.
As demonstrated in the previous case studies, two individuals can both fully meet cri-
teria for ASD but present rather differently throughout childhood and adolescence. These
individuals’ social, cognitive, and behavioral developmental profiles include a wide range of
strengths and vulnerabilities. Given this heterogeneity and the numerous compelling under-
lying theories of psychopathology (outlined in this chapter thus far), our ability to predict
long-term outcomes is somewhat limited due to these confounding factors.
CAN WE IMPROVE OUTCOMES?
The following is a common question from parents: “What can we do to reduce my child’s

symptoms of ASD?” As mentioned previously, the wide symptom array both within ASD
and across time further complicates the answer. One key factor that has consistently been
related to ASD symptom reduction and improvements in social, emotional, and adaptive
outcomes is early identification and, subsequently, access to EI (Remington et al., 2007).
A strong body of empirical evidence has emerged suggesting that children with ASD who
enter into intensive ASD-specialized intervention services at young ages may show larger
gains in cognitive and adaptive functioning than children who do not (Warren et al., 2011).
Several modalities for early treatment of ASD have been developed during the past sev-
eral decades. Perhaps the most well-known and well-supported intervention for children
with ASD is ABA, although other methods have also been empirically validated as effective
interventions. Examples of interventions beyond traditional ABA include the Early Start
Denver Model (Dawson et al., 2010), Floortime (Greenspan & Wieder, 1997), and the
Learning Experiences and Alternate Program for Preschoolers and Their Parents (LEAP
model; Strain & Bovey, 2011).
In addition to access to EI programs for children with ASD, there is also a substantial
body of research suggesting family based and contextual factors may be related to child out-
comes. For instance, the literature suggests that parents of children with ASD experience
higher levels of stress and depression relative to parents of neurotypical children and even
compared to parents of children with other developmental disorders (Hayes & Watson,
2013; Singer, 2006). Parenting stress appears to have effects that extend beyond individual
psychological functioning because parents of children with ASD report significantly higher
levels of marital maladjustment (Lee et al., 2009), marital strains (Rivers & Stoneman,
2003), increased family conflict (Koegel, Schreibman, O’Neill, & Burke, 1983), and an
increased number of medical and therapy appointments relative to controls (Ganz, 2007).
The stress experienced by caregivers can exacerbate their child’s symptoms
(Greenberg, Seltzer, Hong, & Orsmond, 2006). In addition, a number of research-
ers have shown that high parenting stress is predictive of fewer positive outcomes for
children in intervention programs and a decreased acquisition of skills for caregivers
in parent training (Hastings & Beck, 2004). Thus, outcomes of children and families
may be improved when there is access to parent support programs and parent train-
ing. Examples of such programs are the EarlyBird program (Schields, 2001) and the
Autism Spectrum Conditions—Enhancing Nurture and Development (ASCEND)
program (Wright & Williams, 2007). This latter program is a 14-week group treatment
for parents of children with ASD (ages 4–18 years) focused on parent empowerment
and psychoeducation. In addition, an emerging literature on the application of mind-
ful parenting approaches has been shown to not only decrease parenting stress but also
improve aggression, noncompliance, and self-injury in children with ASD (Blackledge
& Hayes, 2006; Singh et al., 2006, 2010). Given the significant levels of caregiver stress
secondary to raising a child with ASD, parent training and support groups have the
potential to decrease symptoms of ASD, increase positive social and adaptive outcomes
in children, and also improve overall parental and family functioning.
SUMMARY
Autism spectrum disorder is a diverse condition. The social, cognitive, and behavioral
characteristics associated with ASD differ both across individuals and throughout devel-
opment. Therefore, identifying the exact origin of a potential developmental disruption
has been a difficult undertaking. Theories to date have inconsistently and inefficiently
explained the three core deficits that characterize ASD—namely social functioning, com-
munication and restricted, and repetitive and stereotyped behaviors. For example, social
motivation theories may adequately account for social and communication deficits but fail
to address the restricted, repetitive, and stereotyped behaviors that are compulsory for the
full diagnosis. Conversely, emerging evidence may indicate that specific brain circuits lead
to behavioral dysregulation in ASD but may not explain social and communication impair-
ments. In addition, the paucity of longitudinal studies in these areas makes it difficult to
draw clear conclusions about the developmental origin and course of promising theories
such as social motivation, social cognitive, executive functioning, and information process-
ing hypotheses.
In many ways, there is still much to discover about the developmental trajectory of ASD.
Nonetheless, vital gains have been made to optimize early diagnosis and lifelong interven-
tion strategies. Despite its largely unknown etiology, some of the most productive lines of
research to date (e.g., biological and genetic findings) have been those that have pinpointed
where and how the early developmental path becomes interrupted.
KEY POINTS
• Within the diagnostic category of ASD, children and adolescents present with a wide
variety of social, cognitive, and behavioral characteristics.
• An individual’s specific social, cognitive, and behavioral presentation can also shift
significantly across development.
• Current theories of development in ASD include social motivation, social cognitive,
executive functioning, and information processing models.
• Factors believed to improve outcomes include cognitive capacity, language skills,
social awareness and motivation, behavior regulation skills, and, most important, ini-
tiating intervention as early in development as possible.
• Because ASD impacts not only the individual but also his or her family system and
environment throughout the lifespan, treatment should include systemic interven-
tions such as parent support and training, as well as individual treatment for the indi-
vidual with ASD.
Dr. Kirstin Brown Birtwell, Dr. Brian Willoughby, and Dr. Lisa Nowinski have nothing to
disclose.
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3 / / /
/ / / SOCIAL, COGNITIVE, AND
AFFECTIVE DEVELOPMENT
OF ADULTS WITH AUTISM
SPECTRUM DISORDER
PATRICIA HOWLIN AND ILIANA MAGIATI
WHAT HAPPENS TO INDIVIDUALS WITH AUTISM SPECTRUM

DISORDER IN ADULTHOOD?
It is now more than 70 years since Kanner (1943) first described the syndrome that he
believed was primarily characterized by an “inborn autistic disturbance of affective contact”
and an “inability to relate oneself to people and situations from the beginning of life.” Since
then, many thousands of papers on autism have been published, and year by year we learn
more about possible causes, potential treatments, and diagnostic and assessment proce-
dures. However, despite the fact that people are adults with autism for many decades longer
than they are children with autism, the focus of the vast majority of these publications is
on childhood (Edwards, Watkins, Lotfizadeh, & Poling, 2012). Only a tiny proportion of
studies involve adults, and fewer still have systematically investigated trajectories of devel-
opment into adult life. This chapter describes what we know about adult development with
respect to cognitive, social, and affective outcomes, and it highlights the need for far more,
and better quality, studies in this area.
SOCIAL INTEGRATION AND INDEPENDENCE IN ADULTHOOD
One of the first accounts of what happens to adults with autism (now termed autism spec-
trum disorder (ASD); American Psychiatric Association, 2013) was written by Kanner
himself 30 years after he published his original papers. In 1973, he reported on 96 individu-
als whom he had initially diagnosed as children and whom he then re-assessed when they
were approximately 20–30 years of age. One of the most striking findings was the great
variation in adult outcomes. Some individuals had made very little progress since first seen
and were in long-stay institutional care. Others had shown improvements but, neverthe-
less, remained highly dependent on their families or on services for people with intellectual
31
disabilities. In contrast, others were functioning relatively well, lived independently, and
had managed to obtain academic qualifications and find employment. Several had friends
or local acquaintances, and one man (a successful music composer) was married with a
child. A fascinating account of one of Kanner’s early cases, now in his 70s, living inde-
pendently and well integrated within his rural community was published in The Atlantic
(Donovan & Zucker, 2010).
Subsequent studies have continued to note the very wide range of outcomes in adult-
hood, with some individuals requiring intensive and highly specialized care throughout
their lives, whereas others achieve very highly as adults. The latter group, however, tends
to be in the minority, with most adults requiring substantial support and being poorly inte-
grated within society. In a recent systematic review, Magiati, Tay, and Howlin (2014) evalu-
ated studies that had followed up individuals with ASD as children through to adulthood.
All included studies had a sample size of at least 10, and the average age of participants at
follow-up was 16 years or older. A total of 25 studies published between 1984 and 2013
were identified, and although most were relatively small in size (50% comprised fewer
than 50 participants), some involved several hundred individuals. The average age of par-
ticipants when first assessed was 7 years, and their average age at follow-up in adulthood
was 24 years (range, 17–44 years). The average IQ of the cohorts involved fell just within
the borderline-average range (mean, 79.0). Despite this, social outcomes were generally
reported to be “poor” or “very poor” (i.e., no friends, no job, and in residential care/living
with parents). Although there was great variability between studies (with the number of
participants rated as having a “good outcome”—that is, employed with or without support;
having some friends; living semi/independently—ranging from 3% to 74%), at least 50%
or more of participants remained highly dependent on others for their care. The majority
of adults were socially isolated and had few friendships or romantic relationships. Rates of
independent living and employment were also low; social independence was particularly
poor for individuals with intellectual disability.
Despite variability between studies, the conclusion that the overall prognosis, up to
now, for adults with ASD is poor is supported by a number of other reviews (Henninger &
Taylor, 2013; Howlin & Moss, 2012; Levy & Perry, 2011). Of significant concern is the fact
that although interventions and educational provisions for young children with ASD have
improved markedly during recent years, these changes seem not to be reflected in signifi-
cant improvements in the lives of adults.
Figures 3.1 and 3.2, for example, summarize changes in adult outcomes reported in
follow-up studies conducted from the mid-1960s to 1999 compared with those completed
between 2000 and 2012, as reviewed by Howlin and Moss (2012). No clearly observable
improvements could be detected in the proportions of individuals living independently,
in work, or in close relationships. Overall outcome ratings also indicate no major changes
in the proportions rated as having “good,” “fair,” or “poor” social outcomes. It is true that
fewer individuals now spend their adult lives in the long-stay institutions in which many of
Kanner’s original patients lived. Similarly, the number of individuals who continue living
with their parents also seems to have declined; nevertheless, the quality and availability of
adult provision remains limited. Indeed, access to services and special assistance tends to
decline rapidly from secondary school onwards (Shattuck, Wagner, Narendorf, Sterzing,
& Hensley, 2011). After young people with ASD exit high school, many receive no formal
services and social isolation appears to increase. For example, a prevalence study of adults
with ASD in the United Kingdom, including individuals of normal IQ, found that they were
significantly less likely to be in work and far more likely to be economically and socially
disadvantaged than their peers without ASD (Brugha et al., 2011). Data from large-scale
Social, Cognitive, and Affective Development of Adults With ASD // 33
60
50
40
Percent
30
20
Pre-2000
10 Post-2000
ps
nt
n
nt
ar
ar
tio
de
hi
re
lc
lc
ca
ns
en
pa
ia
ta
du
tio
ep
nt
pi
ith
/e
la
de
os
nd
k
w
re
H
or
si
i/i
ng
Re
rm
w
m
vi
Se
In
-te
Li
ng
Lo
FIGURE 3.1 Outcomes for adults with autism spectrum disorder in studies published pre- and
post-2000.
cohort studies in the United States confirm that, compared with their peers with intellec-
tual, emotional, behavioral, or learning disabilities, young adults with ASD are significantly
more socially isolated; thus, they are more likely never to see or be called by friends or to be
invited to activities (Orsmond, Shattuck, Cooper, Sterzing, & Anderson, 2013). Taylor and
Seltzer (2011) also found that day services for adults with ASD were significantly poorer
than the services to which they had access when they were still in school; provision was par-
ticularly poor for adults of normal intellectual ability. It is estimated that approximately half
of all young people with ASD have no vocational or educational services in the years imme-
diately following high school (Shattuck et al., 2012), and many reviews report employment
rates of 30% or less (e.g., Magiati et al., 2014). Again, even when compared with groups
of individuals with other disabilities, young adults with ASD are significantly less likely
60
50
40
Percent
30 Pre-2000
Post-2000
20
10
0
Good outcome Fair outcome Poor outcome
FIGURE 3.2 Overall outcome ratings for adults with autism spectrum disorder in studies pub-
lished pre- and post-2000.
to be employed (Roux, Shattuck, & Cooper, 2013), and among those who are employed,
jobs tend to be low-skilled, part-time, and very poorly paid (Mavranezouli et al., 2014).
Moreover, these disadvantages are not just a temporary setback immediately post-school,
after which individuals then go on to catch up with their peer group. Instead, educational,
vocational, and employment opportunities continue to diminish, resulting in many adults
having access to very limited and very poor-quality provision.
At a societal level, high levels of unemployment and dependency on government
subsidies are two of the main factors contributing to the very high costs of ASD (Ganz,
2007; Knapp, Romeo, & Beecham, 2009). At a personal level, too, the costs are enormous.
Without a job, most individuals have little chance of living independently and remain
both economically and emotionally dependent on their families. Being unemployed also
means they have little or no opportunity to meet with their peers, and this, together with
the social difficulties that are core to ASD, frequently leads to increasing isolation with age.
An overview of the rates of marriage and/or close friendships reported in studies of adults
suggested that only approximately 20% of individuals develop intimate relationships that
involve reciprocity and sharing (Howlin, 2014). Moreover, despite the high heritability of
ASD (Rutter, 2013), there are no data on the numbers of individuals with ASD who have
children of their own, and we know almost nothing about the difficulties they may experi-
ence or the quality of childrearing in these families. Personal accounts suggest that although
individuals with ASD can succeed in maintaining close relationships and are able to parent
well (Slater-Walker & Slater-Walker, 2002; Willey, 1999), successful relationships require
many adaptations by both partners. Also, when difficulties are experienced, adequate sup-
port is rarely available (Lawson, 2002).
COGNITIVE AND LANGUAGE FUNCTIONING
Although for many years after Kanner it was believed that most individuals with ASD
were severely cognitively and linguistically impaired, it is now recognized that a substan-
tial minority (probably approximately 40%) are of average or above average IQ (Charman
et al., 2011). There is also evidence that the majority of those with ASD acquire at least some
degree of useful language, even if its development is often rather delayed (Wodka, Mathy,
& Kalb, 2013). Nevertheless, there has been little research on trajectories of cognitive and
language development from child to adulthood, and findings are often contradictory.
Whereas some studies report an overall decrease in IQ with age, others report general
stability; still others have recorded improvements in IQ scores. However, perhaps the most
consistent finding is one of great individual heterogeneity (Magiati et al., 2014). Variability
is particularly evident among individuals who have an average or above average nonverbal
IQ as children, but those with a childhood nonverbal IQ below 70 almost always remain in
the intellectually impaired range. In a 40-year follow-up of 60 individuals who were all of
average nonverbal IQ as children, Howlin, Savage, Moss, Tempier, and Rutter (2014) found
that, although IQ generally remained stable over four decades, a minority showed a signifi-
cant decline in cognitive ability, mostly associated with epilepsy or very severe behavioral
disturbance. Although improvements in IQ can occur, these tend to be among individuals
who as children had an average or above average nonverbal IQ, but whose language was ini-
tially severely delayed (Magiati et al., 2014). In their follow-up study of 85 young adults,
Anderson, Liang, and Lord (2014) found average increases of more than 50 points in verbal
IQ from age 2 to age 19 years among participants with a nonverbal childhood IQ of 70 or
greater; those with a nonverbal childhood IQ less than 70 showed no improvement. Howlin
et al. (2014) also found significant changes in verbal IQ among their cohort of individuals
with average nonverbal IQ scores in childhood.
Many other studies have reported at least some improvements on tests of lan-
guage over time. Nevertheless, even among individuals who do develop useful speech,
scores on standardized language assessments are typically below chronological age,
and functional language for the purposes of social communication tends to remain
limited (Magiati et al., 2014). For example, only 35% of the 99 adults followed up by
Ballaban-Gil, Rapin, Tuchman, and Shinnar (1996) achieved normal or near-normal
speech fluency or comprehension; similarly, only 12% of 725 adults in the large cohort
studied by Liptak, Kennedy, and Dosa (2011) were reported to be able to converse
fluently.
ADAPTIVE BEHAVIOR
Although IQ is an important issue in any study of adult outcomes, it is important to be

aware that in ASD, the strong positive association between IQ and adaptive functioning
(e.g., self-help, social competence, daily living skills, and communication skills) that is char-
acteristic of typical development is often disrupted. Thus, whereas in typically developing
children, IQ and adaptive behavior scores tend to be at a similar level, in ASD, adaptive
behavior scores may be much lower than scores on a standard IQ test (Charman et al.,
2011). Data from Anderson et al. (2014) indicate that this discrepancy may be particularly
marked among individuals of higher intellectual ability. For example, a young adult with
ASD with an IQ in the superior range (i.e., 130 or greater) may still be unable to complete
basic household or self-care tasks effectively without support. Relatively few studies have
assessed adaptive behavior skills in adulthood and, again, those that have report consider-
able individual variability. The review by Magiati et al. (2014) suggests that although there
are improvements in adaptive functioning with age, the overall level of competence in this
area remains relatively low in comparison with that of peers of the same age and/or IQ.
Studies of profiles of adaptive functioning also suggest that abilities in adulthood tend to be
comparatively better in the domains of daily living and communication than in socializa-
tion skills (Farley et al., 2009).
MENTAL HEALTH
Given the social isolation, lack of employment, and high rates of dependence on others
often experienced by adults with ASD, it might be expected that rates of mental health
problems would be significantly elevated in this group. However, there are few systematic
data on rates of mental health problems among adults with ASD, and the findings that are
available are often inconsistent. Although some studies report that up to 84% of individuals
with ASD have a diagnosable psychiatric condition (e.g., Ghaziuddin, 2005; Levy & Perry,
2011), these figures are often based on individuals attending psychiatric clinics. Data from
a small number of non-referred cohorts suggest somewhat lower rates of approximately
25–30% (Howlin, 2014), but nevertheless these are still considerably higher than rates in
the general population. Despite the variability in prevalence rates, there is more agreement
on the types of mental health problems that are more likely to be experienced, with anxi-
ety, depression, and obsessive–compulsive problems being the most frequently reported.
In contrast, rates of schizophrenia appear to be relatively low, despite research suggesting
some genetic overlap between ASD and schizophrenia (Cross-Disorder Group of the
Psychiatric Genomics Consortium, 2013; Smoller, 2013).
Relatively little is known about the possible factors associated with mental health prob-
lems in ASD. For example, although there is some indication that major life events or tran-
sition points (e.g., leaving school and coping with college or employment) are associated
with the onset of mental health problems (Esbensen, Greenberg, Seltzer, & Aman, 2009;
Hutton, Goode, Murphy, Le Couteur, & Rutter, 2008), there have been no systematic stud-
ies in this area. There is also some evidence that individuals with ASD of higher IQ (who
may have greater insight into their difficulties) are more likely to experience depression and
anxiety than those with intellectual impairments (Ghaziuddin, 2005; Sterling, Dawson,
Estes, & Greenson, 2008). However, other studies have found that psychiatric disorders
occur equally among individuals with ASD of all intellectual ability levels (Farley et al.,
2009; Hutton et al., 2008; Tsakanikos et al., 2006).
A major problem in determining rates of mental health difficulties in ASD is the scarcity
of well-validated mental health measures for use in this population (Ghaziuddin, 2005).
Self-report measures may be less appropriate for those individuals with ASD who have dif-
ficulties describing their inner thoughts and emotions; on the other hand, informants (e.g.,
caregivers, teachers, or keyworkers) may not be able to report accurately on the internal
states of the adult with ASD. Diagnosis of comorbid psychopathology is further compli-
cated by the fact that there can be overlap between ASD and symptoms associated with
other mental health problems, such as obsessive–compulsive disorder or attention deficit
hyperactivity disorder (ADHD). The presentation of mental health problems in individuals
with ASD may also be atypical (Hutton et al., 2008). For example, the onset of depression
may be characterized by an increase in stereotyped and ritualistic behaviors or in aggression
and/or self-injury.
Underwood, McCarthy, and Tsakanikos (2010) highlight the lack of professionals who
have expertise in diagnosing mental health problems in adults with ASD, but there is an
equally great need for knowledge about effective interventions. Although there is some,
albeit very limited, evidence that cognitive and/or behaviorally based therapies can be
effective with this group (Bishop-Fitzpatrick, Minshew, & Eack, 2013), pharmacological
interventions tend to be the most commonly used. These are of variable effectiveness; nev-
ertheless, up to 80% of young adults with ASD in the United States are on medication, with
rates of medication use increasing over time. Moreover, once medication commences, it is
likely to be given long term (Esbensen et al., 2009).
CHANGES OVER TIME: SEVERITY OF AUTISM SPECTRUM DISORDER SYMPTOMS

Despite the many challenges faced by young people with ASD as they enter adult life, the
one area that does seem to show positive change is the severity of their ASD-related symp-
toms. This pattern of steady improvement over time was first reported by Kanner, who
noted that for some individuals, particularly those who became more aware of their difficul-
ties and managed to find ways to overcome or circumvent them, mid-adolescence was often
a period of marked improvement (Kanner, 1973). Similar findings were noted in the early
follow-up studies of Rutter and his group (e.g., Rutter, Greenfield, & Lockyer, 1967), and
many subsequent outcome studies document improvements in ASD symptoms over time.
For example, in a study of more than 400 individuals with ASD who were 10–53 years old,
Seltzer et al. (2003) found evidence of a decrease in ASD severity, particularly in repetitive
behaviors; there were also improvements in reciprocal social interaction and in verbal and
nonverbal communication. In another large-scale study of 241 young adults, Shattuck and
colleagues (2007) reported significant improvements in severity of ASD symptoms (again,
especially in repetitive behaviors) and in maladaptive behaviors during a 4-year period.
Similar positive findings have been noted in a number of other follow-up studies (e.g.,
Anderson et al., 2014; Farley et al., 2009; Seltzer, Shattuck, Abbeduto, & Greenberg, 2004).
The improvements reported for cohorts of young adults also appear to continue into
later adulthood. For example, Howlin, Moss, Savage, and Rutter (2013) followed up 44
adults (all of average IQ when initially diagnosed as children) from the age of 26 years to age
46 years. When assessed in their mid-forties, all still met criteria for a diagnosis of ASD, but
the severity of ASD symptoms (particularly in repetitive and stereotyped behaviors) had
continued to decrease during the two decades of the study. Despite these improvements in
ASD symptom severity, however, social integration was often more limited than it had been
for the same individuals as younger adults.
In summary, studies of trajectories of development into adulthood suggest that the
majority of individuals continue to show improvements as they grow older, although social
and adaptive functioning typically remain considerably impaired for many. There are also
major individual differences in the extent of improvement over time. Increases in ability
tend to be most marked in individuals who are less intellectually impaired, but they are also
occasionally reported for those who are of very low IQ (Beadle-Brown, Murphy, Wing,
Shah, & Holmes, 2000). However, the social support structures required to help adults
with ASD make the best of their potential for development and to foster social inclusion
and independence are too often lacking.
CAN WE PREDICT OUTCOMES IN ADULTHOOD?
Despite improvements in the severity of ASD symptoms that occur in many adults with
ASD, social integration tends to remain very limited (for more details, see Magiati et al.,
2014). Several follow-up studies also indicate that a minority of individuals show a signifi-
cant decline in cognitive and other skills with age (Howlin et al., 2013). The highly variable
outcomes of individuals with ASD in adulthood have led to exploration of childhood fac-
tors that may be related to later prognosis. On the whole, data on the association between
adult outcomes and childhood variables such as the severity of symptoms in childhood or
the presence of other comorbid conditions are inconsistent, and there is almost no research
on the impact of other individual characteristics, genetic or socioeconomic factors, or qual-
ity of family life. The very small number of female participants in most studies precludes any
conclusions about the role of gender (Magiati et al., 2014). There is evidence that the devel-
opment of epilepsy is an important risk factor, whereas better language and responsiveness
to joint attention are positive predictors of social and adaptive functioning some decades
later (Gillespie-Lynch et al., 2012).
Only two factors—childhood IQ and the development of language by the age of 5 or
6 years—have been consistently found to be strong predictors of adult outcome. Thus,
outcomes for individuals with ASD and intellectual disability and for those who do not
acquire some level of useful language before school age are typically poor. Nevertheless,
it is much more difficult to predict the long-term outcome for those children who are
of average IQ and have developed language. Some of these individuals go on to achieve
highly in their adult lives, whereas others remain dependent and a minority show an
increase in difficulties and/or a decline in functioning over time (Anderson et al., 2014;
Howlin et al., 2013).
For example, “Mark” and “Jonathan” are two adults followed up throughout the years
by the first author. Their cases illustrate the different developmental trajectories of indi-
viduals with ASD.
CASE STUDY #1: “MARK”
Mark was diagnosed with an intellectual disability when he was 3 years old but was redi-
agnosed with ASD at age 4 years. At that time, he had very limited speech and severe
behavioral problems. During his elementary school years, he attended an autism school,
where he made good progress behaviorally and in his academic and communication skills.
He was then able to transfer to a very structured, mainstream school, where his interest
in mathematics was encouraged; during this time, his school and family maintained close
contact with the specialized autism service.
As a young adult, Mark obtained a place in university to study mathematics, although he
continued to live at home because his independence skills were still poor. Whenever prob-
lems or challenges arose (mainly involving difficulties in peer relations or having very fixed
and unorthodox views about how mathematics should be taught, which brought him into
conflict with his university teachers), these were managed well by professionals from the
specialized autism service who supported Mark, his family, and university staff.
At the age of 24 years, Mark obtained a master’s degree in mathematics, but he failed
to secure employment for several years because of his inability to cope with job interviews.
Professionals from the autism team then became involved in helping him find suitable
employment, and subsequently Mark has remained with the same design company for
25 years. His mathematical and programming skills are much valued. The autism team has
kept contact and provided advice on support and management throughout the years. The
difficulties that have arisen relate mostly to communication problems (e.g., he is rapidly
able to identify and correct flaws in others’ programs but is poor at explaining what these
errors are), poor social understanding (giving unwitting offense by standing too close to
female colleagues or making personal or inappropriate remarks), or poor self-hygiene (cloth-
ing dirty or ill-kempt, infrequent bathing/shaving/hair washing, and leaving lavatory in unac-
ceptable state). Support has involved providing direct advice and information about ASD to
staff and individual counseling and practical advice and instructions to Mark (e.g., regarding
hygiene or social behaviors). In this way, almost all problems have resolved rapidly, without
in any way demeaning Mark’s status in the workplace.
CASE STUDY #2: “JONATHAN”
In his early years, Jonathan’s language development was advanced, but his behavior was
very difficult to manage at home or in nursery (he was “expelled” from several nurser-
ies because of aggression). Although he showed significant behavior problems, Jonathan’s
parents were unsuccessful in their attempts to obtain a diagnosis or support from child
psychiatry services. Despite his very rigid behaviors and significant difficulties in social
understanding and social interaction, his problems were variously attributed to his being
“intellectually gifted” or to his parents’ poor management skills and/or their marital
problems.
During his elementary school years, Jonathan went through a series of different school
placements. He was seen by an educational psychologist, but the only diagnosis given
was “emotional disturbance,” whereas his parents were offered intervention for marital
problems. Jonathan finally settled in a small, highly structured religious school, but he
remained isolated and without friends and often became aggressive because he was
unable to tolerate anyone with different views/behaviors from his own. He then attended
a private, highly academic mainstream school where initially he appeared to settle well.
However, he subsequently had major problems with bullying (as both victim and perpetra-
tor), was often aggressive to school staff, and became increasingly abusive to his father
at home.
At the age of 15 years, he was finally seen by the child psychiatry services and diag-
nosed with ASD. Jonathan refused to accept this diagnosis and blamed all his difficulties on
his father. He became increasingly aggressive to staff and other students at school, refused
to complete homework assignments, and, following a severe incident of bullying by other
students, was then homeschooled. At age 16 years, he was transferred to a specialized
unit for students with Asperger’s syndrome. He settled well initially, but he grew increas-
ingly more resentful of his diagnosis of autism. Increasing physical aggression toward his
parents and school staff resulted in transfer to a residential college for students with ASD
at the age of 17 years. There, he viewed all other pupils and staff as inferior; he refused to
follow the college’s academic program and left at age 20 years.
Currently, Jonathan is 22 years old. He occasionally works in short-term jobs when he
needs money. He makes “friends” easily but then rapidly alienates everyone with whom
he has contact. He can be very violent toward his parents, resulting in occasional involve-
ment with the police, and he continues to refuse any help from specialized services. Much
of the time, his parents do not know where he is or what he is doing, and they are deeply
fearful about his future.
What made the outcome for Mark so different from that for Jonathan? Was it the earlier
diagnosis, the professional support available for him and his family during his school and
college years, the fact that he was initially educated in a highly specialized autism place-
ment, or was it because of genetic underpinnings and/or having a totally different tempera-
ment and personality?
We still know virtually nothing about the factors that influence outcome in this higher
ability group, and although there are some indications that early intervention programs
may make a positive difference (Anderson et al., 2014), this is an issue that requires much
more systematic research. Currently, there are no longitudinal studies into adulthood to
support claims (e.g., by Chasson, Harris, & Neely, 2007) that children who undergo highly
intensive behavioral interventions in their pre-school years are significantly less likely to
need specialist services in adult life.
CAN WE IMPROVE OUTCOMES IN ADULTHOOD?
The inadequacy of research on adults with ASD, and in particular the lack of well-controlled
intervention studies, has been highlighted in two systematic reviews from the United
States and United Kingdom (Lounds-Taylor et al., 2012; National Institute for Health
and Clinical Excellence (NICE), 2012; see also Howlin, 2014; Piven et al., 2011). For
example, in a review of psychosocial interventions for adults with ASD, Bishop-Fitzpatrick
et al. (2013) found that out of a total of 1217 studies reviewed, only 13 met basic meth-
odological requirements, and only 4 of these were randomized controlled trials. Although
there are a considerable number of case studies or small case series testifying to the value
of behavioral techniques for modifying behavioral difficulties or increasing functional
skills, particularly in individuals with ASD and severe intellectual disabilities, there are very
few well-controlled studies of other psychosocial interventions or services for individuals
with ASD.
This lack of research on effective interventions for adults is particularly concerning
given indications that access to adequate support networks in adulthood can have a signifi-
cant impact on subsequent outcomes. The study by Farley and colleagues (2009) provides
a strong argument for more cohesive community support. Compared with other adult out-
come studies involving individuals of similar age and IQ, the young adults in the Farley
study were more likely to be in work and to have married or to have formed close relation-
ships, and approximately half were rated as having “good” or “very good” overall outcomes.
One major factor here appears to be that almost all the participants had grown up and con-
tinue to live in communities belonging to a church organization that provides lifelong sup-
port for its members and also values the inclusion of individuals with disabilities.
The transition from school to college or from school to work can be especially challeng-
ing for individuals with ASD, and these particular life stages are often associated with an
increase in psychiatric difficulties (Hutton et al., 2008). Post-school programs are needed
in many different areas. Provision of sheltered or semisheltered housing, together with
training and support to develop appropriate self-care and healthy living skills, is another
area of (usually unmet) need. Opportunities to develop social contacts in adulthood are
also crucial, but for many, as indicated in the studies by Shattuck et al. (2007) and Seltzer
and colleagues (2003, 2004), such provision is generally nonexistent. Social skills interven-
tions for adolescents and young adults show some promise in helping individuals develop
greater social understanding and competence (e.g., Beaumont & Sofronoff, 2008), but very
few studies have been systematically evaluated and even fewer have been tested in com-
munity settings (Bishop-Fitzpatrick et al., 2013). High-functioning adults with ASD also
tend to experience a poorer quality of life compared with individuals with ADHD or other
psychiatric disorders diagnosed in childhood (Barneveld, Swaab, Fagel, van Engeland, &
de Sonneville, 2014). It is also evident that even when people with ASD do develop close
relationships, marry, or have children of their own, both they and their families can face
many challenges (Slater-Walker & Slater–Walker, 2002; Willey, 1999). However, there is
very little research on interventions or support systems that can help avoid or minimize the
interpersonal or social issues that may arise.
One area in which there has been some positive developments, and which poten-
tially can have a major impact on many aspects of individuals’ lives (including men-
tal health, social relationships, financial stability, and general independence), is that of
supported employment. Employment rates for individuals with ASD are known to be
very low. In a review of outcome studies, Howlin and Moss (2012) found that only
approximately one-third of adults were in any form of education or employment, and
in cohorts including individuals of lower cognitive ability, employment rates were typi-
cally less than 25%. Because generic employment services for people with intellectual
or mental disabilities rarely meet the needs of individuals with ASD, during the past two
decades a number of supported employment schemes have been developed specifically
for this group. These provide help to find work and offer direct support in the workplace
(typically to avoid or manage social interaction problems), as well as provide guidance
for work managers and colleagues to help them understand the needs, difficulties, and
potential skills of employees with ASD. The number of studies evaluating the success of
supported employment programs remains small (NICE, 2012; Shattuck et al., 2012),
but there is growing evidence that these schemes are superior to alternative employ-
ment models (e.g., sheltered workshops) in terms of job level, pay, quality of life, and
cost-effectiveness (Mavranezouli et al., 2014).
CAN THERE BE RECOVERY FROM AUTISM SPECTRUM DISORDER?
Although ASD is generally described as a lifelong disorder, there have been occasional
accounts in the literature of individuals who have reportedly undergone “miracle cures,” in
most cases as a “result” of a specific intervention. Although most such claims lack any sound
evidence base, the issue of whether some children could “recover from autism” was initially
raised by Lovaas (1987), who reported that 47% of children receiving intensive behavioral
treatment for more than 2 years achieved “normal intellectual and educational functioning”
and were “indistinguishable” from their normal peers. These conclusions gave rise to much
controversy, partly because the total sample comprised only 19 children (9 of whom were
said to have possibly “recovered”) and because of the very limited definition of “normal
functioning” used.
However, in a series of studies, Fein and colleagues (Fein et al., 2013; Sutera et al.,
2007) described a small number of children who, despite meeting full criteria for autism
as preschoolers, no longer appeared to show any significant autistic impairments in ado-
lescence. Anderson et al. (2014) also reported on a small number of individuals (8 out
of a cohort of 85) who by the age of 19 years appeared to show no ASD symptoms.
Neither research group refers to these individuals as “cured”; rather, they are described
as having “optimal outcomes.” Fein and colleagues, for example, do not rule out the pos-
sibility that these individuals might still retain some subtle deficits in social communi-
cation skills. Nevertheless, these studies, which were carefully conducted and involved
detailed assessments over time, raise intriguing questions about the factors determining
optimal outcomes. For example, why do other studies of adults with ASD (e.g., Farley
et al., 2009; Howlin et al., 2013) fail to find individuals who no longer show any symp-
toms of ASD, even though several individuals in those cohorts are achieving highly?
Is it because some subtle difficulties may become more apparent with age? Does the
relatively early diagnosis of the Fein and Anderson cohorts make a difference, or is it the
fact that more individuals in these cohorts received specialized interventions as chil-
dren? Neither Fein and colleagues (Fein et al., 2013; Sutera et al., 2007) nor Anderson
et al. (2014) were able to identify any specific characteristics that reliably predicted
who, among individuals with an average IQ in childhood, would attain “optimal out-
comes.” Although less severe social impairments in infancy, better motor or other adap-
tive skills, and access to specialized intervention were associated with better outcomes
for some, none of these variables accurately differentiated the “optimal outcome” from
non-optimal outcome groups.
These studies are important in suggesting factors that are potentially associated with
more positive outcomes, and the systematic testing of such hypotheses is now a signifi-
cant challenge for future research. Identification of variables that modify outcome may not
result in “recovery” but could well have a major impact on improving quality of life for both
individuals with ASD and their families.
SUMMARY
A great deal more needs to be known about trajectories of change and outcomes of indi-
viduals with ASD in adulthood. It would be particularly informative to follow-up into adult-
hood those children who in the past 20–30 years have benefited from early, ASD-specific,
and comprehensive educational and behavioral/developmental interventions. Only in this
way can we establish whether, and to what extent, these programs result in improved adult
outcomes. We also know very little about the development of females with ASD in adult-
hood, and virtually nothing is known about the physical, social, or mental health difficul-
ties that older individuals with ASD may face (for a review of aging in ASD, see Happé
& Charlton, 2012). For example, are rates of dementia higher or lower than those of the
general population? What happens to older individuals with ASD when their parents die or
can no longer care for them?
What we do know, however, is that the planning of and provision for specialized ser-
vices for individuals with ASD in adulthood and older age are inadequate. Thus, studies of
the effectiveness of various interventions and support services for adults with ASD in both
clinical and community settings are urgently required. Finally, it is important to investigate,
alongside individual and early childhood predictors, whether there are particular social or
environmental factors that can enhance social integration and independence and contrib-
ute to improved outcomes for future generations of adults with ASD.
KEY POINTS
• The number of research studies published relating to the diagnosis, assessment, devel-
opment, and treatment of the long-term developmental trajectories and outcomes of
adults with ASD is far less than that related to children.
• Future ASD research studies should focus on the trajectory of change and out-
comes of children with ASD who participated in programs and services target-
ing interventions specific to ASD to determine if these programs improve adult
outcomes.
• ASD does not protect individuals from developing other medical and psychiatric
comorbidities that can have a profound effect on their ultimate mental and social
well-being.
• Society is not yet prepared to handle the influx of individuals currently diagnosed
with an ASD who are yet to become adults; it is unclear how this will impact the
individuals’ ability to function independently and become productive members of
society.
• Further studies on how to best care for and support adults with ASD in both clinical
and community settings will provide a platform for improved outcomes for future
generations of adults with ASD.
Dr. Patricia Howlin and Dr. Iliana Magiati have nothing to disclose.
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4 / / DIFFERENTIAL
/ / / / DIAGNOSIS
OF AUTISM SPECTRUM
DISORDER ACROSS
THE LIFESPAN
ISOBEL W. GREEN, CHRISTEN L. KIDD,

AND ROBERT E. ACCORDINO
INTRODUCTION
When a patient presents with a suspected diagnosis of autism spectrum disorder (ASD), the
clinician should thoroughly consider medical and psychiatric conditions with overlapping
symptoms before making the diagnosis. The medical workup of these patients is discussed
in Chapter 5. To facilitate our discussion of the differential diagnosis of ASD throughout
the lifespan, we have divided the chapter between childhood and adulthood because the
differential diagnosis changes considerably based on the age of the patient in question.
DIFFERENTIAL DIAGNOSIS IN CHILDHOOD
Early signs such as impaired social interaction, communication deficits, and stereotypic
behavioral patterns have been consistently found in the first 2 years of life in retrospective
studies of children diagnosed with ASD (Nadel & Poss, 2007). Such findings are impor-
tant because early diagnosis is strongly associated with good outcome in individuals with
ASD (Limon, 2007). Increased sensitivity to early signs of ASD, however, also increases
the complexity of diagnosis because many early symptoms overlap significantly with those
of other psychiatric conditions presenting at the same age and may be difficult to parse,
especially in young children with difficulty communicating their subjective experience.
Differential diagnoses continue to introduce complexity in the diagnosis of ASD through-
out childhood, and clinicians should take care to consider such alternative explanations of
presenting symptoms before diagnosing ASD.
Clinicians diagnose ASD on the basis of the presence of early developmental abnor-
malities, as well as the presence of characteristic symptoms (Bölte, Westerwald, Holtmann,
47
BOX 4.1
THE DIFFERENTIAL DIAGNOSIS OF AUTISM SPECTRUM
DISORDER IN CHILDHOOD
Neurodevelopmental
Specific language impairment
Intellectual disability/global developmental delay
Mental and Behavioral
Attention deficit hyperactivity disorder
Oppositional defiant disorder
Conduct disorder
Attachment disorders
Social anxiety disorder
Major depressive disorder
Obsessive–compulsive disorder
Psychosis
Tourette’s disorder
Selective mutism
Freitag, & Poustka, 2011). Differential diagnoses include symptoms that closely align with
the two core symptom groups of ASD: deficient social communication and interaction
and restricted, repetitive patterns of behavior or interests. Such differential diagnoses may
be considered in two main areas: (1) neurodevelopmental and (2) mental and behavioral
(Box 4.1). Neurodevelopmental differential diagnoses tend to involve early language devel-
opment and communication deficits similar to those seen in children with ASD, whereas
mental and behavioral differential diagnoses tend to mimic most closely the impaired social
interaction and behavioral rigidity also characteristic of ASD.
Neurodevelopmental Disorders
Delayed speech development is the most common cause for referral to a clinician for ASD
evaluation in preschool-aged children (Kuravackel & Ruble, 2014). Parents report impair-
ment in receptive and expressive language, as well as an inability to communicate appropri-
ately through language. Similar symptoms are seen both in specific language impairment
and in global developmental delay and general intellectual disability (ID), and diagnosing
clinicians should carefully consider the possibility of the child’s symptoms emerging purely
from a language disorder or intellectual impairment rather than ASD.
Specific Language Impairment

Specific language impairment (SLI) is diagnosed on the basis of deficits in speech produc-
tion or interpretation, which impact a child’s ability to interpret (receive) and produce
(express) meaningful language (Prelock, Hutchins, & Glascoe, 2008). Like ASD, language
disorders may also present with delayed play and imagination, as well as impaired social
Differential Diagnosis of Autism Spectrum Disorder Across the Lifespan // 49
communication. Children with SLI, however, may be differentiated from those with ASD
by the degree of deficits in social motivation: Children with SLI will generally compen-
sate for their impoverished verbal communication by using nonverbal methods, including
pointing and gesturing, and as such develop a relatively normal profile of social interaction
(Macferran, Major, Fussel, & Hihg, 2011). Children with ASD, in contrast, will show con-
sistent poverty of social interaction and a lack of empathy or interest in others.
If a child presenting with impaired use or understanding of language shows empathy
and interest in social interaction (even if the experience of interaction itself is impaired)
and exhibits developmentally appropriate imaginative play, the differential diagnosis of SLI
should be considered. For unclear cases, specific language testing may also be useful: Verbal
children with ASD tend to perform better on expressive than receptive language tests,
whereas children with language deficits alone will be more likely to show greater impair-
ment in expressive than receptive language. In addition, the level of competency detected
on language tests is more likely to align with social language performance in children with
pure language impairment, whereas children with ASD may well exhibit a lower level of lan-
guage usage than they are shown to be capable of (National Institute for Health and Clinical
Excellence (NICE), 2011).
Intellectual Disability/Global Developmental Delay

Intellectual disability is a broad diagnosis given to individuals with developmental deficits
in general mental abilities. According to the fifth edition of the Diagnostic and Statistical
Manual of Mental Disorders (DSM-5; American Psychiatric Association (APA), 2013),
individuals must show the developmental onset of impairment in both intellectual and
adaptive functioning, demonstrating deficiency in both areas, such as reasoning, problem
solving, abstracting, and learning, and in the ability to participate and function in society at
a developmentally expected level (APA, 2013, p. 37). When the diagnosis of ID is made in
children too young to be administered a classic IQ test, the condition is termed ASD (Weis,
2014); because the vast majority of referrals for an assessment of ASD in intellectually/
developmentally delayed children occur within the first several years of life, global develop-
mental delay is thus pertinent to the differential diagnosis. Like children with pure global
developmental delay, those with ASD show delays in language use and comprehension,
lack play and social skills, and exhibit difficulty communicating with others.
In children with severe global developmental delay, impairment is likely to appear
across the developmental profile; intelligence tests tend to produce a globally low measure
of cognition and functioning. This profile may be used to separate children with pure global
developmental delay from those with co-occurring ASD because those with ASD will
likely show relative strength in areas other than language and social understanding. In addi-
tion, children with global developmental delay alone will usually show developmentally
appropriate social motivation, as well as interest in peers and efforts at imitation. Children
with ASD, on the other hand, will present with marked deficits in social communication,
play, and flexibility, as well as the characteristic sensory sensitivity, rigidity in behavior, and
hyperfocused interests seen across the autism spectrum (NICE, 2011).
Mental and Behavioral Disorders
The developmental deficits seen in the early years of ASD are soon joined by the behav-
ioral and social correlates of the condition. These later deficits may not emerge as early as
developmental impairments in speech and language comprehension, but they introduce
just as much diagnostic complexity, given their high concordance of symptoms with many
psychiatric conditions. Indeed, the social and communicative dysfunction and rigid, repeti-
tive behaviors considered hallmarks of ASD may also indicate a wide variety of mood and
behavioral conditions. As such, the diagnosing clinician, especially when examining chil-
dren referred slightly later in childhood, should proceed methodically by considering sev-
eral psychiatric conditions that align closely with the presentation of ASD before making
the diagnosis of ASD.
Attention Deficit Hyperactivity Disorder

Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral
condition diagnosed in childhood (Wolraich et al., 2011). Characterized by impaired func-
tioning or development due to persistent inattention and/or hyperactivity/impulsivity,
the DSM-5 specifies that six or more symptoms of inattention and hyperactivity/impulsiv-
ity, each, must be present for diagnosis. Many of the symptoms listed in DSM-5 correlate
closely with the behavioral patterns seen in individuals with ASD. Statements such as “often
does not seem to listen when spoken to directly,” “often does not follow through on instruc-
tions,” “often runs about or climbs in situations where it is not appropriate,” “often talks
excessively,” and “often interrupts or intrudes on others” demonstrate overlapping symp-
toms between ADHD and ASD (APA, 2013, p. 60).
Despite the significant concordance between profiles of childhood ADHD and ASD
and recent findings of high comorbidity between the two conditions, an ADHD diagno-
sis remains in the differential of ASD with a profile separable from ASD with and with-
out comorbid ADHD. Of note, whereas the DSM-IV specified the conditions as mutually
exclusive, the DSM-5 allows for dual diagnosis (Leitner, 2014). A child with ADHD in the
absence of ASD may present with the poor social skills and intrusive social behavior often
exhibited in children with ASD but, unlike the child with ASD, will show appropriate com-
prehension of social norms (if not adherence to them). In addition, the child with ADHD
will show appropriate social reciprocity and nonverbal communication. Although children
with ADHD, like those with ASD, may engage in dangerous behavior, those with ADHD
will likely show an appreciation of its potential dangers. Children with ASD, on the other
hand, may show little understanding of social rules and exhibit deficits in reciprocity and
nonverbal interaction. In addition, their dangerous behaviors may arise from an unaware-
ness of common dangers rather than from impulsivity (NICE, 2011).
Oppositional Defiant Disorder

Oppositional defiant disorder (ODD), diagnosed most frequently in the preschool years,
is characterized by a persistent negativity, defiance, and disobedience toward author-
ity (Hamilton & Armando, 2008). Although it may be initially difficult to determine
whether children presenting with ODD-like symptoms truly have the condition or are
rather merely experiencing a “phase” of difficult behavior, individuals with ODD will
maintain a reliable pattern of defiance and disobedience into later childhood and will
typically show tense relations with their parents, instructors, teachers, and classmates
(Hamilton & Armando, 2008). ODD’s most marked presentation, therefore, is deficiency
in social interaction; the defiant, disruptive behavior of children with ODD isolates them
from their community (Loeber, Burke, & Pardini, 2009). Because a similar degree of
social ineptitude and subsequent alienation may be seen in ASD, clinicians should care-
fully consider the diagnosis of ODD before confirming the diagnosis of ASD in children
referred for poor social ability.
Although oppositional behavior is frequently present in children with ASD, several

characteristics differentiate full ODD from the set of oppositional symptoms seen in ASD.
When a child with ASD acts in opposition of others, the behavior often occurs inadver-
tently, as a product of hyperfocus on a personal pursuit or interest rather than in a purpose-
ful act of defiance. When children with ASD are informed of the negative impact of their
behavior on others, they are likely to become distraught. Children with ODD, on the other
hand, are generally aware of the oppositional nature of their behavior and may act deliber-
ately. In addition, children with ODD will show an ability to modulate the disruptive nature
of their behavior at will, evincing a degree of social understanding beyond the child with
ASD. In addition, children with ODD will generally lack the rigid, repetitive behavioral
profile of ASD (NICE, 2011).
Conduct Disorder
Like ODD, conduct disorder involves marked social impairment. In individuals with con-
duct disorder, this impairment emerges from a persistent pattern of violation of others’
basic rights and flouting of major social norms and standards. Conduct disorder is marked
by aggression to people and animals, destruction of property, deceitfulness or theft, and
consistent violation of societal or community rules (e.g., running away from home and
skipping class in elementary school). Like ODD, childhood-onset conduct disorder may
present with a level of social impairment comparable to that seen in children with ASD.
Clinicians should thus consider conduct disorder in individuals referred for ASD assess-
ment on the basis of marked social impairment.
As is the case for distinguishing children with ODD from those on the autism spec-
trum, individuals whose social impairment stems from conduct disorder, rather than ASD,
may be differentiated on the basis of their level of social comprehension (NICE, 2011).
If the child’s antisocial behavior seems purposefully harmful or the child exhibits under-
standing of the harm he or she induces but is not distressed by this understanding, conduct
disorder should be considered. As in the ODD diagnosis, the child should also be examined
for signs of the stereotyped, repetitive behaviors characteristic of ASD, which are unlikely
to present in conduct disorder (Efstratopoulou, Janssen, & Simons, 2012). Children with
conduct disorder can also be differentiated from those with ASD through an examination
of their early social communication, which generally will have developed normally in those
with conduct disorder. Children with conduct disorder are also more likely to demonstrate
an unimpaired “theory of mind,” showing full appreciation of the fact that others have idio-
syncratic mental experiences that differ from their own.
Because the assessment process for the differential diagnosis of conduct disorder closely
parallels that of ODD, the diagnosing clinician may differentiate these two diagnoses by
examining the specific nature of the child’s antisocial behavior; children with ODD are more
likely to show globally problematic peer relationships, whereas children with conduct disor-
der may demonstrate social competence in certain settings, associating with a deviant group
(Pardini & Fite, 2010). Children with conduct disorder will also generally show a pattern of
physical cruelty, theft, and deceit not characteristic of children with ODD (Loeber, Burke,
Lahey, Winters, & Zera, 2000). The DSM-5’s removal of the exclusion criterion for conduct
disorder in children with ODD also allows for a comorbid diagnosis (APA, 2013).
Attachment Disorders
The DSM-5 specifies two distinct types of attachment disorder: disinhibited social engage-
ment disorder and reactive attachment disorder. The disorders by definition arise in children
with a history of pathogenic care, often involving abuse or neglect. Disinhibited social
engagement disorder is marked by abnormally disinhibited social behavior, with affected
children regularly violating social boundaries and indiscriminately attaching to and seeking
comfort from strangers (Gleason et al., 2011). Reactive attachment disorder, on the other
hand, is characterized by significant emotional withdrawal, with diagnosed children pre-
senting with low levels of social responsiveness and a lack of expressed attachment behav-
iors even to central caregivers; children with reactive attachment disorder characteristically
fail to seek or respond to comfort when upset. Symptoms of the attachment disorders align
with those of ASD in that children with ASD often also show abnormal behavior at separa-
tion from and reunion with caregivers and limited response to and consideration of oth-
ers’ distress. In addition, children with histories of social deprivation may have developed
self-soothing behaviors that are repetitive and stereotyped, as are characteristic of children
with ASD (NICE, 2011).
In investigating the potential diagnosis of attachment disorder in children referred
for atypical social behavior, the clinician should first consider the child’s developmental
history: Without a history of emotional or physical neglect or maltreatment, a diagnosis
of attachment disorder cannot be made. If the degree of social deprivation is unclear
or maltreatment is known to have occurred, the diagnosing clinician may examine
other factors: Children with attachment disorders will show relatively typical imagina-
tive play and will generally lack the hyperintense interests characteristic of those with
ASD. To assess for reactive attachment disorder, social communication may be exam-
ined: Communication in reactive attachment disorder will appear markedly avoidant,
as opposed to merely poorly regulated. To assess for disinhibited social engagement
disorder, motivation behind abnormal boundaries may be examined: If intrusive behav-
ior is distinctly attention-seeking, disinhibited social engagement disorder is indicated,
whereas if the violation occurs merely out of inconsideration, ASD is more likely. The
National Institute for Health and Clinical Excellence’s “differential diagnosis advice
for healthcare professionals” gives the example of a child climbing onto a stranger’s
lap: A child with disinhibited social engagement disorder will do so to seek comfort from
the stranger, whereas a child with ASD is more likely to clamber over the adult to access
an object that the adult is blocking (NICE, 2011).
In children referred for atypical social behavior, clinicians should solicit a developmen-
tal and social history; if children come from nurturing households, attachment disorder
is not indicated. If social history is unknown or tumultuous, the diagnosing clinician may
look to the child’s apparent motivation behind the atypical behavior: Avoidance mark-
edly underlying deficient social communication or boundary violations clearly driven by
attention-seeking point to diagnoses of reactive attachment disorder and disinhibited social
engagement disorder, respectively. In addition, children with attachment disorders may
progress rapidly when placed in a consistently nurturing environment, whereas those with
ASD are more likely to maintain their clinical profile (NICE, 2011).
Social Anxiety Disorder

Social anxiety disorder is characterized by a persistent, overblown fear or anxiety of social
situations. Children with social anxiety disorder will appear shy and withdrawn in unfamil-
iar social situations, and they may show clear discomfort in interactions with others—for
example, not making eye contact. They often attempt to avoid school, given the high level of
social engagement the classroom requires (Stein & Stein, 2008). The deficient social profile
seen in social anxiety disorder may be reminiscent of that shown by children with ASD,
with symptoms of childhood social anxiety disorder such as reduced eye contact common
to ASD. In addition, children with social anxiety disorder may show repetitive questioning
behavior that aligns with the persistent behavioral profile of ASD (Schneier, Rodebaugh,
Blanco, Lewin, & Liebowitz, 2011). As such, social anxiety disorder should be considered
in the differential diagnosis of children referred for ASD screening due to impaired social
interaction.
Social anxiety disorder may be readily differentiated from ASD through the assess-
ment of social communication in familiar situations. Although children with social anxiety
disorder may show impaired social communication when confronted with a novel social
situation and/or strangers, when interacting with familiar individuals, they will demon-
strate developmentally appropriate social communication (Bölte et al., 2011). In addition,
although children with social anxiety disorder may show repetitive behaviors in the form
of persistent anxious questioning, this behavior will not have the stereotyped, ritualistic
quality seen in children with ASD; the response need not be exactly the same to satisfy the
questioning child (NICE, 2011).
In evaluating children referred for impaired social interaction, clinicians should inves-
tigate whether the impairment is present in all social situations or only in unfamiliar or
performance-based scenarios. If the child shows appropriate social functioning with famil-
iar individuals (e.g., when among family members), social anxiety disorder, rather than
ASD, is indicated. If the child shows such a capacity for typical communication and also
lacks other symptoms of ASD, such as a stereotyped set of behaviors and abnormal or idio-
syncratic linguistic presentation (echolalia, using minimal language, and odd phraseology),
a differential diagnosis of social anxiety disorder merits strong consideration. Finally, the
clinician may consider the motivation behind the child’s avoidant behavior; children with
social anxiety disorder will characteristically express or evince fear of judgment or critique
from others as a driving factor in their avoidance, whereas children with ASD will not show
this preoccupation and may in fact demonstrate markedly low concern regarding others’
opinions of their behavior (NICE, 2011).
Major Depressive Disorder

Major depressive disorder (MDD) in children is characterized by the presence of a
depressed mood along with a constellation of affective, neurovegetative, and cognitive
symptoms such as sleep and appetite disturbance, psychomotor changes, feelings of worth-
lessness and guilt, anhedonia (loss of interest in activities once enjoyed), reduced energy,
impaired concentration, and suicidality (APA, 2013, p. 161). The withdrawn behavior,
reduced verbalization, and lack of engagement with or interest in developmentally appro-
priate activities that mark childhood depression may create a behavioral profile that mimics
ASD. As such, the differential diagnosis of depression requires consideration in children
referred for impaired social engagement (NICE, 2011).
Children affected by MDD may, during depressive episodes, show a similar pattern of
social withdrawal to children on the autism spectrum, but they will lack the developmental
profile of ASD, as well as other characteristic symptoms, such as stereotyped, repetitive
behaviors. In addition, their social impairment will present with an episodic course and
may be situational.
In children referred for an ASD evaluation due to impaired social engagement, the diag-
nosing clinician should obtain an early developmental history. If the child has shown periods
of normalized social behavior, with only sporadic social deficiency, depression is indicated
over ASD, which is characterized by a pervasive developmental course (NICE, 2011).
Obsessive–Compulsive Disorder
Obsessive–compulsive disorder (OCD) in childhood presents as patterns of obses-
sions and compulsions that are time-consuming and cause marked distress and impair-
ment in daily life (APA, 2013, p. 237). Obsessions are intrusive and recurrent thoughts
or impulses that provoke significant anxiety, and compulsions are ritualistic behaviors
that the child performs to relieve the obsession-induced anxiety. Such rituals—common
compulsions include washing, checking, and ordering—may be repeated a set number of
times or until anxiety is reduced and the child feels “just right” (Kalra & Swedo, 2009).
Because the obsessive, ritualistic, and repetitive behavior patterns seen in children with
OCD may appear similar to the stereotyped and repetitive behaviors characteristic of
children with ASD, OCD should be considered in children referred for such rigid, ritu-
alistic behaviors.
In evaluating children referred for such behavioral patterns, clinicians should exam-
ine the patient for evidence of the other cardinal characteristic of ASD—impaired social
communication. Children with OCD generally show a capacity for typical social com-
munication (Wouters & Spek, 2011). Although those with OCD may be hindered in
social interaction by the intrusiveness of obsessional thoughts and the disruptiveness of
compulsions, they will show appropriate social reciprocity and appropriate consideration
for others. In addition, the repetitive behaviors seen in children with OCD are generally
associated with avoiding harm, whereas those observed in children with ASD tend to be
associated with preserving “sameness” from day to day. Children with OCD are far more
likely to be bothered by their obsessions and to perceive them in an ego-dystonic manner,
as opposed to children with ASD, who will be upset only if their rituals are interrupted.
Rituals associated with ASD generally do not hold the magical thinking quality of those
seen in OCD (e.g., “If I tap the door handle 10 times, no planes will crash in the next min-
ute”) (NICE, 2011).
Psychosis
Psychosis refers to a group of conditions characterized by (1) disorganized thinking,
(2) delusions or hallucinations, and (3) altered thought processes. Although the diagnosis
of psychosis in children is made more difficult by the evolving state of a child’s mind and
a natural propensity toward imaginative thought, it is now recognized that children can
indeed experience true psychosis, including both disconnected thoughts and pure halluci-
nations ( Joshi & Towbin, 2002). The various childhood psychotic disorders show a broad
range of clinical presentations, but there remain common symptomatic threads across the
group. Atypical social interaction, notably social withdrawal and lack of friends, is often
the first symptom detected, across multiple forms of psychosis (Eggers, Bunk, & Krause,
2000). The profile created by such social symptoms may look like that seen in children
with ASD, so in children referred for social disengagement and withdrawal, a primary
psychotic disorder should be considered. Further confounding diagnosis, developmental
language and motor deficits consistent with those present in children with ASD are seen
in childhood-onset schizophrenia, and children with childhood-onset schizophrenia also
show stereotypies such as hand flapping (Courvoisie, Labellarte, & Riddle, 2011). As such,
childhood-onset schizophrenia and other presentations on the spectrum of psychotic
behavior (schizotypal disorder and schizoaffective disorder), although rare, may closely
mimic ASD at least in their surface presentation. Diagnosing clinicians should always con-
sider a diagnosis of psychosis before diagnosing ASD—although if the child is nonverbal, a
determination of psychotic processes cannot be made with confidence, so clinicians should

proceed with caution in evaluating language-impaired children.
Although the social and developmental presentation of children with childhood-onset
schizophrenia and other psychotic disorders may mimic the social deficits seen in ASD,
the two conditions are differentiated by the presence of hallucinations and delusions,
which will persist as a core feature in the child with childhood-onset schizophrenia. If
auditory or visual hallucinations remain present throughout childhood, and it becomes
clear that such symptoms are not merely attributable to the imaginative processes of child-
hood, childhood-onset schizophrenia may be present ( Joshi & Towbin, 2002) because
persistent perceptual changes are not part of the ASD profile. In addition, although
unusual thought patterns and fixations are seen in children with ASD, reality testing of
children with ASD will generally show that atypical thought processes are not delusion-
ary (Solomon, Ozonoff, Carter, & Caplan, 2008). Children with ASD perform typically
on reality monitoring tasks (Farrant, Blades, & Boucher, 1998), whereas individuals
with childhood-onset schizophrenia classically present with impaired reality monitoring
(Subramaniam et al., 2012). Also, because psychotic symptoms will typically have a late-
childhood onset (NICE, 2011), disordered communication and unusual pronunciation in
younger children with ASD are more likely to be due to pragmatic language impairment
(e.g., idiosyncratic or overly concrete language use and switching topics without providing
context for the listener) than to delusional thoughts (Solomon et al., 2008).
Of note, before diagnosing psychosis, a clinician should carefully examine whether
reports of psychotic symptoms in fact come from an overly literal interpretation of ques-
tions. When asked, for example, if he or she hears voices when no one else is in the room, a
child with ASD may respond affirmatively despite having no auditory hallucinations due to
the previous experience of hearing a voice when in an empty room, perhaps carrying over
from a neighboring room or emitting from a television (NICE, 2011).
Tourette’s Disorder
Tourette’s disorder is a childhood-onset condition characterized by chronic motor and
vocal tics (diagnosis requires that tics be present for at least 1 year). The motor tics observed
in children with Tourette’s disorder often appear similar to the stereotyped motor move-
ments apparent in those with ASD (Volkmar, 2007), and vocal tics may involve echolalia
(Ganos, Ogrzal, Schnitzler, & Münchau, 2012), which is also characteristic of children
with ASD.
In a child referred for repetitive behaviors reminiscent of stereotypies, the diagnosing
clinician should closely examine the behaviors to determine whether they are voluntary,
rhythmic, and lingering. If the behaviors are instead involuntary, nonrhythmic, and rapid,
they are not likely to be true stereotypies, and a diagnosis of Tourette’s disorder, rather than
ASD, may be indicated (Ozonoff, Rogers, & Hendren, 2003). In addition, children with
Tourette’s disorder will not show diminished capacity for social communication and reci-
procity, although they may present with social isolation due to embarrassment or isolation
by peers (Macferran et al., 2011).
Selective Mutism
Selective mutism is characterized by a persistent lack of speech in select social situations,
despite normal speech present in other settings. Children with selective mutism will often
fail to speak at school or with peers, despite communicating typically at home (Sharp,
Sherman, & Gross, 2007). The lack of social engagement seen in children with selective
mutism may appear superficially similar to that arising in children with ASD, and the fact
that many children with selective mutism will also have a history of language disorder or
delay may also lead parents and clinicians to consider a diagnosis of ASD.
In the classroom, children with selective mutism may present very similarly to the child
with ASD, given their social reticence and detachment. The child with selective mutism,
however, will show entirely appropriate interaction in other situations; for instance, with
family members, communication will usually be typical. In addition, a child with selec-
tive mutism will not show the stereotyped, rigid behaviors or hyperintense interests seen
in ASD and will usually demonstrate appropriate nonverbal communication and normal
imaginative play (NICE, 2011).
DIFFERENTIAL DIAGNOSIS IN ADULTHOOD
Recognition of ASD in adulthood presents a diagnostic challenge for several reasons. First
and foremost is a universal challenge that is shared by all psychiatric and some neurological
conditions—that of making a diagnosis based on behavioral criteria. Behavioral diagnoses
are always more challenging and subject to discrepancies than diagnoses based on genetic,
biochemical, or physical criteria, as in the examples of Huntington’s disease, diabetes, and a
fractured femur, respectively.
Relatively little is known about the course and manifestations of ASD in adults com-
pared to the clinical expertise that has developed during approximately the past 25 years in
the diagnosis and treatment of ASD in children and adolescents (Lehnhardt et al., 2013).
Individuals with ASD can present with evolving manifestations over the course of their
lifespan. According to what limited studies have found about the presentation of ASD
in adults, the most prominent impairments exist in nonverbal communication and social
reciprocity (Shattuck et al., 2007). Problems in verbal communication and with repeti-
tive behaviors or stereotyped interests are less prominent. Indeed, studies have shown
that of all ASD symptoms, repetitive behaviors decline most strongly with age (Seltzer
et al., 2003).
Comorbidity of other psychiatric conditions also presents a challenge to the diagnosis
of ASD in adults. Studies have shown that 50–70% of adults receiving a first-time diagno-
sis of ASD also carry or develop a diagnosis of a comorbid anxiety disorder, depression,
or other psychiatric illness (Hofvander et al., 2009; Lehnhardt et al., 2013; Lugnegard,
Hallerback, & Gillberg, 2011). Individuals who receive a first-time diagnosis of ASD in
adulthood are more likely, by definition, to have a more subtle presentation than those
whose ASD symptoms are obvious in childhood. These individuals usually have higher ver-
bal competence and above average intelligence, and they “may achieve a comparatively high
level of psychosocial functioning that often appears unremarkable, at least on the surface”
(Lehnhardt et al., 2013).
Taken together, all of the previously mentioned aspects of the presentation of ASD
in adulthood mean that the condition may easily be missed because it is intertwined
with comorbid psychiatric symptoms or hidden behind social or cognitive compensa-
tions that come with age and experience. Therefore, the differential diagnosis for ASD in
adulthood is broad, encompassing anxiety and mood disorders, personality disorders,
and psychotic disorders (e.g., schizophrenia with predominant negative symptoms)
(Box 4.2).
BOX 4.2
THE DIFFERENTIAL DIAGNOSIS OF AUTISM SPECTRUM
DISORDER IN ADULTHOOD
Anxiety and Mood Disorders

Social anxiety disorder
Major depressive disorder with melancholic features
Obsessive–compulsive disorder
Personality Disorders
Obsessive–compulsive personality disorder
Avoidant personality disorder
Schizotypal personality disorder
Schizoid personality disorder
Psychotic Disorders
Schizophrenia with predominant negative symptoms
Anxiety and Mood Disorders

Social Anxiety Disorder
Social anxiety disorder is characterized by a fear of the scrutiny and judgment of others.
In social situations—especially new, unfamiliar situations or group settings—individuals
with social anxiety disorder fear that they will say or do something that will result in
embarrassment or humiliation. Their fears can be so profound that these individuals will
avoid most interpersonal encounters or endure them with intense physical and emotional
discomfort (e.g., fear, trouble concentrating, avoiding eye contact, trembling, sweating,
and heart racing) (Stein & Stein, 2008). Nevertheless, individuals with social anxiety dis-
order desire connection, company, and the good opinion of others.
Adults with ASD may appear similar to those with social anxiety disorder because indi-
viduals with either condition may exhibit social withdrawal in addition to being quiet in
social situations. For these reasons, the diagnosis of either ASD or social anxiety disorder
may be missed or delayed (Bejerot, Eriksson, & Mortberg, 2014). However, in certain situ-
ations, such as one-on-one settings with someone with whom the individual with social
anxiety disorder feels comfortable, the symptoms of social anxiety will abate. In the indi-
vidual with ASD, although symptoms may be less prominent in situations in which the
individual feels safe and calm, the symptoms will not abate to the degree that they will in
the patient with social anxiety disorder. In addition, individuals with social anxiety disor-
der are extremely sensitive to verbal and nonverbal signs of judgment or criticism, whereas
interpreting social cues is one of the main areas of deficit in individuals with ASD. In other
words, individuals with social anxiety disorder are highly attuned to nonverbal communi-
cation and social reciprocity, the precise diagnostic areas in which adults with ASD show
impairment. Furthermore, individuals with ASD do not show the physical signs (e.g.,
tremor, sweating, and blushing) of anxiety in social situations that individuals with social
anxiety disorder show.
Major Depressive Disorder With Melancholic Features

Melancholia is the term used to describe a particular type of severe depression character-
ized by an almost complete loss of the capacity for pleasure and by severe neurovegetative
symptoms (changes in sleep, appetite, and energy). Specifically, in addition to loss of plea-
sure in all, or almost all, activities (anhedonia), it is characterized most notably by lack of
mood reactivity, early morning awakening with depression worse in the mornings, marked
psychomotor retardation or agitation, and significant appetite and/or weight loss (APA,
2013). It is sometimes thought to be more biologically driven and less the direct result of
external stressors than other types of depression, although this etiologic aspect of melan-
cholia is controversial.
An individual with melancholic depression—anhedonia, a noticeable lack of mood
reactivity, and significant psychomotor slowing or agitation—might at first appear similar
to an individual with ASD because of the social withdrawal and impairment generated by
these particular depressive symptoms. Psychomotor slowing may appear as the impairment
in eye contact, facial expressions, and gestures of social interaction evident in individuals
with ASD. Similarly, anhedonia may appear as the lack of spontaneous seeking to share
enjoyment, interests, or achievements seen in individuals with ASD. However, because
melancholia is often an episodic, remitting illness, individuals with this type of depression,
even in the midst of an episode, will be able to articulate that a fundamental change in them
has occurred, as is not the case in those with ASD. Individuals with melancholic depression
will have an abrupt decline in functioning associated with each episode, whereas in indi-
viduals with ASD, functioning remains relatively constant, at least in the absence of serious
psychiatric comorbidity.
Obsessive–Compulsive Disorder
As discussed in relation to the childhood differential diagnosis of ASD, OCD is marked by
the presence of obsessions and compulsions, with the former characterized as recurrent,
intrusive thoughts or impulses that cause significant anxiety, and the latter characterized
as ritualistic behaviors performed to relieve the obsession-induced anxiety (APA, 2013).
Common obsessions include contamination, symmetry, ordering/counting, forbidden
thoughts, and harm. The compulsions undertaken to soothe obsessive processes present
as rigid behavioral patterns and as such may be mistaken for the ritualistic stereotypies of
individuals with ASD; as such, OCD is in the differential for adults referred for ASD assess-
ment (Seibell & Hollander, 2014).
In adults referred for assessment of ASD traits who present with rigid, repetitive behav-
iors, clinicians should first investigate whether the patient views his or her behaviors in an
ego-syntonic or ego-dystonic manner. Unlike children with OCD, who may lack the lexi-
con or insight to describe their obsessions as unreasonable (Storch et al., 2008), the vast
majority of adults with OCD will readily acknowledge the irrationality of their thoughts
and behaviors, despite feeling powerless to stop them (Geller et al., 2001). Individuals with
ASD, on the other hand, generally view their repetitive behaviors as sensible and produc-
tive (Lehnhardt et al., 2013).
As such, an ego-dystonic presentation suggests a diagnosis of OCD. In addition,
empathy and social cognition are not generally impaired in individuals with OCD,
so if the individual referred for repetitive behaviors presents with typical social and
emotional understanding and reciprocity, OCD is further implicated and ASD is less
likely.
Personality Disorders
Obsessive–Compulsive Personality Disorder
Obsessive–compulsive personality disorder (OCPD) is characterized in the DSM-5 as a
condition involving impairments in self-functioning due to a rigid obsession with produc-
tivity, morality, or other personal or social codes. It also causes impairments in social func-
tioning due to individuals’ lacking empathy and hyperrigidity. Individuals with OCPD also
show rigid perfectionism and inability to see more than one “correct” means of operating,
as well as perseveration and inability to disengage from a task (APA, 2013). Unlike indi-
viduals with OCD, those with OCPD tend to view their compulsions in an ego-syntonic
manner, believing that their self-imposed rules represent the “right and best way” to oper-
ate (International OCD Foundation, 2010). As such, individuals with OCPD tend not to
report intrusive and upsetting thoughts or images, and their compulsions tend to center on
achieving optimal states of, for example, productivity, morality, or order (Pinto, Steinglass,
Greene, Weber, & Simpson, 2014). Because the repetitive, rigid behaviors seen in OCPD
present similarly to the stereotypies of ASD, and lacking empathy and social impairment
are also present in individuals with OCPD, clinicians should consider the diagnosis in
adults referred for ASD assessment.
In adults presenting with the rigid behaviors and social impairment common in
OCPD and ASD, clinicians should first consider the age of onset of symptoms. Because
OCPD is considered an adult-onset disorder, if the individual reports behaviors extend-
ing into childhood, ASD is more likely. If the clinician confirms an adult onset of
symptoms, the diagnostician may seek to differentiate between the two conditions by
performing tests of effortful control and reward delay. Recent research has shown a sig-
nificantly increased ability to delay gratification in individuals with OCPD compared to
control participants without OCPD, with people with OCPD exhibiting a hypercapac-
ity for self-inhibition (Pinto et al., 2014). Individuals with ASD, on the other hand, tend
to show a significantly reduced ability to delay gratification and exercise effortful con-
trol, an impairment appearing across the lifespan of those with ASD (Faja & Dawson,
2015; Garon et al., 2009). As such, impairment on an effortful control and delayed grati-
fication task would suggest ASD, whereas high performance would correlate with an
OCPD diagnosis. In addition to effortful control presentation, clinicians may search
for other ASD characteristics—such as impairment in nonverbal communication and
sensory issues—that are not implicated in OCPD. Finally, clinicians may examine the
particular profile of social impairment: Individuals with OCPD are more likely to be
well-functioning in the broader community and show their most severe social deficits
in intimate or familial relationships due less to social unawareness than to an unwilling-
ness or inability to sacrifice productivity for intimacy (Costa, Samuels, Bagby, Daffin,
& Norton, 2005). Those with ASD, on the other hand, generally show a more global
impairment and misunderstanding of social principles.
Avoidant Personality Disorder

Avoidant personality disorder is very similar in presentation to social anxiety disorder. In
fact, multiple studies have been carried out to examine whether an additional diagnosis
of avoidant personality disorder in someone with social anxiety disorder adds anything
helpful in terms of understanding the patient’s illness (Chambless, Fydrich, & Rodebaugh,
2008; Cox, Pagura, Stein, & Sareen, 2009; Marques et al., 2012). Avoidant personality dis-
order is described as a “pervasive pattern of social inhibition, feelings of inadequacy, and
hypersensitivity to negative evaluation, beginning by early adulthood and present in a vari-

ety of contexts” (APA, 2013, p. 673).
According to one study, although some features of avoidant personality disorder are
important, a diagnosis of avoidant personality disorder in someone with generalized social
anxiety disorder may have little clinical utility beyond being a marker of severity in the lat-
ter (Marques et al., 2012). However, the feature of “emotional guardedness” in avoidant
personality disorder may be important in differentiating it from more severe cases of gener-
alized social anxiety disorder. In this study, “emotional guardedness,” assessed primarily by
response to the Structured Clinical Interview for the DSM (SCID) scale item of “difficulty
being open even with people you are close to,” was found to most consistently differentiate
avoidant personality disorder symptoms in patients with generalized social anxiety disor-
der (Marques et al., 2012).
These findings suggest that patients with avoidant personality disorder may appear
even more similar to patients with ASD than do patients with social anxiety disorder
alone. To differentiate avoidant personality disorder and ASD in adults, first it is impor-
tant to observe patients’ verbal and nonverbal communication during the interview.
Patients with avoidant personality disorder may be very guarded but will be attuned,
as are patients with social anxiety disorder, to social cues in a way that patients with
ASD typically are not. For patients with avoidant personality disorder, although they
may struggle and suffer in interpersonal relationships, particularly close ones, it is not
the case that “how to make friends and socialize is a mystery,” as is the case in patients
with ASD (see Social Anxiety Disorder). Second, avoidant personality disorder, as with
personality disorders generally, is not evident symptomatically until early adulthood, so
a good psychiatric history can help enormously in differentiating avoidant personality
disorder, and other personality disorders, from ASD. Finally, individuals with avoidant
personality disorder will not use stereotyped or idiosyncratic language in the way that
individuals with ASD may.
Schizotypal Personality Disorder

Schizotypal personality disorder is described as “a pervasive pattern of social and interper-
sonal deficits marked by acute discomfort with, and reduced capacity for, close relationships,
as well as by cognitive or perceptual distortions and eccentricities of behavior” (APA, 2013,
p. 656). Criteria for the disorder include odd or eccentric thinking, speech, and behavior,
as well as “excessive social anxiety that does not diminish with familiarity and tends to be
associated with paranoid fears rather than negative judgments about self ” (p. 656). Criteria
also include nondelusional ideas of reference, “odd beliefs or magical thinking that is incon-
sistent with subcultural norms,” and suspiciousness or paranoid ideation.
Long-standing controversy exists about the conceptual and phenotypic overlap between
ASD and the so-called schizophrenia spectrum disorders (SSD) (schizoid and schizotypal
personality disorders and schizophrenia) (Barneveld et al., 2011). The conceptual blurring
between the two areas began in the 1940s when Leo Kanner, in his classic paper on infantile
autism, “Autistic Disturbances of Affective Contact” (Kanner, 1943), borrowed the term
“autism” from Swiss psychiatrist Eugen Bleuler, who had coined it in 1911 to describe the
socially withdrawn behaviors of individuals with schizophrenia. Since then, many research-
ers have argued about the boundaries between the two diagnostic categories. Studies in
the 1970s for the most part argued that ASD and SSD were mutually exclusive categorical
diagnoses with distinct developmental pathways (Barneveld et al., 2011). More recently,
however, studies have shown empirical evidence for conceptual and phenotypic overlap
of ASD and SSD (Barneveld et al., 2011; Hurst, Nelson-Gray, Mitchell, & Kwapil, 2007;
Lugnegard et al., 2011).
The previously discussed history and recent findings demonstrate the difficulty with
differentiating schizotypal personality disorder from ASD. As is evident from the criteria
and previous discussion, ASD behavior traits can overlap with schizotypal ones, as has
been confirmed in studies (Brugha et al., 2011; Pilling, Baron-Cohen, Megnin-Viggars, Lee,
& Taylor, 2012). One study found that 40% of a group of individuals with ASD met for-
mal criteria for schizotypal personality disorder (Barneveld et al., 2011). A key difference
between the two groups is that individuals with schizotypal personality disorder have a
paranoid dimension to their personality that individuals with ASD generally, although not
always, do not. Patients with schizotypal personality disorder may exhibit magical thinking,
nondelusional ideas of reference, and paranoid ideation, all of which are rooted in a certain
suspiciousness about the motives and thinking of others. In contrast, individuals with ASD
have impairments in their ability to conceptualize the mental state of others. They may be
called “hypo-mentalizers,” whereas individuals with schizotypal personality disorder tend
to overinterpret the mental state of others in a suspicious or paranoid way and might be
called “hyper-mentalizers” (Barneveld et al., 2011; Lehnhardt et al., 2013). Questioning
patients along these lines, to help tease out whether this kind of mentally overinterpretive
paranoid or suspicious thinking is present, will help greatly in differentiating patients with
ASD from those with schizotypal personality disorder. Finally, as with all personality disor-
ders, the patterns of the disorder generally appear during puberty or later, whereas in ASD,
patterns are present from early childhood (Lehnhardt et al., 2013).
Schizoid Personality Disorder

Schizoid personality disorder is described as “a pervasive pattern of detachment from social
relationships and a restricted range of expression of emotions in interpersonal settings,
beginning by early adulthood and present in a variety of contexts” (APA, 2013, p. 653).
Criteria for the diagnosis include “neither desires nor enjoys close relationships, including
being part of a family”; “almost always chooses solitary activities”; “takes pleasure in few, if
any, activities”; and “appears indifferent to the praise or criticism of others” (p. 653).
Interestingly, the term “schizoid,” like the term “autism,” was coined by Swiss psychia-
trist Eugen Bleuler. Bleuler first used the term in 1908 to describe an individual’s tendency
to direct attention toward his inner life and away from the outside world. Bleuler called the
exaggeration of this tendency the “schizoid personality.” The existence of schizoid personal-
ity disorder as a discrete entity, however, has been controversial, and there is a paucity of
empirical research validating it (Triebwasser, Chemerinski, Roussos, & Siever, 2012). It has
been argued based on empirical evidence that it is not a personality disorder but, rather, a
personality trait.
Individuals with schizoid personality disorder do not have a paranoid dimension to
their personality, and this aspect makes it more challenging to differentiate schizoid per-
sonality disorder from ASD than it is to differentiate schizotypal personality disorder from
ASD. As with schizotypal personality disorder, studies have confirmed overlap between
schizoid and ASD behavioral traits (Brugha et al., 2011; Pilling et al., 2012). Therefore, if
a patient fulfills criteria for schizoid personality disorder, it is probably most important to
try to obtain a childhood developmental history to determine whether the patient actually
has an undiagnosed ASD. If the answer is yes, the diagnosis of ASD would take precedence
over the diagnosis of schizoid personality disorder because schizoid personality disorder
“should not be diagnosed if the pattern of behavior occurs exclusively during the course of
schizophrenia, a bipolar or depressive disorder with psychotic features, another psychotic

disorder, or autism spectrum disorder” (APA, 2013, p. 656). That is, a patient cannot have
a diagnosis of both ASD and schizoid personality disorder because it is understood that the
schizoid symptoms are etiologically rooted in ASD and not a personality disorder. Finally,
to make a diagnosis of schizoid personality disorder, it would be necessary to establish
with certainty a childhood developmental history without patterns of behavior suggestive
of ASD.
Psychotic Disorders
Schizophrenia With Predominant Negative Symptoms
Schizophrenia is characterized by both positive and negative symptoms of psychiatric ill-
ness. Positive symptoms are overtly psychotic; they are expressions of a loss of ability to par-
ticipate with other people in a shared sense of reality. Positive symptoms include thought
content not based in reality, such as paranoid delusions, and perceptual disturbances, such
as auditory and visual hallucinations. Negative symptoms are not overtly psychotic. They
are evidence of the loss of aspects of the sense of self. Negative symptoms include, among
others, avolition, or loss of motivation, and blunted affect, or loss of emotional expressivity
in facial expressions, gestures, and tone of voice. A given individual with schizophrenia can
display any combination of symptoms—predominantly positive, predominantly negative,
or a fairly balanced mix of both.
The presentation of schizophrenia with predominantly negative symptoms can appear
similar to ASD. Negative symptoms can be described in a variety of ways, and there is a large
body of research devoted to how to best characterize them. According to the most recent
National Institute of Mental Health consensus statement in 2005, negative symptoms are
most accurately categorized in five symptom domains: blunted affect, alogia (or poverty of
speech), asociality (social withdrawal), anhedonia (loss of pleasure in activities), and avoli-
tion (loss of motivation) (Marder & Kirkpatrick, 2014). Studies have shown that although
ASD and schizophrenia have different developmental trajectories, their clinical presenta-
tions at any one given time can overlap (Frith & Happe, 2005; Goldstein, Minshew, Allen,
& Seaton, 2002). In particular, individuals with schizophrenia with predominantly negative
symptoms have shown many of the same social deficits as individuals with ASD (Frith &
Happe, 2005).
There are a few approaches that may be taken in trying to differentiate these two
diagnoses. For an individual to qualify for a diagnosis of schizophrenia, he or she must
at some point have had at least one of the following symptoms persisting for a signif-
icant portion of time for at least 1 month: delusions, hallucinations, or disorganized
speech (e.g., “frequent derailment or incoherence”) (APA, 2013, p. 99). Delusions or
hallucinations persisting for this amount of time do not typically appear in ASD. The
disorganized speech in schizophrenia is qualitatively different from the stereotyped and
repetitive or idiosyncratic use of language in ASD. If a patient with schizophrenia, how-
ever, presents during a period of time when negative symptoms are predominant and
the patient’s only history of positive symptoms is disorganized speech, it may be dif-
ficult to tease out by history-taking the presence of disorganized speech if only alogia,
or poverty of speech, is present on exam. If, however, a clear history of disorganized
speech can be provided by a family member or close friend, this information can help to
point toward a diagnosis of schizophrenia and not ASD. Of course, it is important, as in
every case, to take as detailed as possible a history of childhood development because a
patient with schizophrenia will not display prodromal symptoms as early as the patterns
of ASD will appear in a child.
SUMMARY
The diagnosis of ASD across the lifespan remains a continuing clinical challenge, given the
significant overlap between symptoms of ASD and those marking a wide variety of psychi-
atric conditions. Depending on the age and presentation of the patient, it may be appro-
priate for the clinician to consider a wide range of neurodevelopmental, anxiety, mood,
personality, and psychotic disorders prior to making an ASD diagnosis. The most promi-
nent presenting symptom should serve as a launching point for consideration of aligning
differential diagnoses.
KEY POINTS
• When evaluating a child referred for possible ASD, consider both neurodevelopmen-
tal and mental and behavioral conditions based on the patient’s symptoms. When
evaluating an adult referred for possible ASD, consider anxiety, mood, personality,
and psychotic disorders based on the patient’s symptoms.
• Rather than marking a symptom as merely present, consider its particular profile in
children and adults referred for possible ASD. For example, individuals with ASD
will show global social impairment; those with social anxiety disorder will show
impairment only in certain situations. Individuals with ASD will show inaccurate
comprehension of others’ mental states, but the misunderstanding will not hold the
paranoid and suspicious quality seen in schizotypal personality disorder.
• Often, the holistic constellation of symptoms is more informative than the presence
of any one characteristic. Search for symptom combinations: ASD diagnosis is more
reliable if a child with a lack of social reciprocity also shows repetitive behaviors, non-
verbal communication deficits, and intense interests.
• Move methodically through the diagnostic process. If an individual is referred for
social impairment, consider, individually, each differential diagnosis involving social
impairment, and compare that condition’s profile to the patient’s unique presentation.
• Tests outside of the usual clinical canon, such as measures of gratification delay and
empathy, may be useful in parsing differential diagnoses.
Dr. Robert Accordino, Dr. Isobel Green, and Dr. Christen Kidd have nothing to disclose.
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5 / / /
/ / / MEDICAL EVALUATION
OF PATIENTS WITH AUTISM
SPECTRUM DISORDER
YAMINI J. HOWE, MICHELLE L. PALUMBO,

AND ANN NEUMEYER
INTRODUCTION
Autism spectrum disorder (ASD) is a highly heritable, biologically based, neurodevel-

opmental condition characterized by impairments in social communication and social
interaction as well as restricted, repetitive patterns of behaviors (American Psychiatric
Association, 2013; Hallmayer et al., 2011). This chapter addresses the medical aspects of
caring for children, adolescents, and adults with ASD, focusing on important information
to be obtained when taking a history and conducting a physical examination, as well as
additional steps that are often necessary to complete a thorough evaluation and medical
workup.
HISTORY
This section highlights key questions important to consider in taking the medical history of
children, adolescents, and adults with ASD. A careful medical evaluation of patients with
ASD should include taking a thorough developmental history, in addition to past medical
history, review of systems, and social and family history, and it is to be generally conducted
for all patients.
Developmental History
Taking a developmental history includes consideration of several developmental domains,

including communication, cognition, play/leisure, motor, sensory, and emotional/behav-
ioral. Within each domain, the clinician should be aware of the typical progression of devel-
opmental skills and elicit historical information to determine the individual patient’s abilities
compared with the norm. Even adolescents and adults with ASD can have challenges in
67
simple developmental tasks that affect their functional abilities or activities of daily living. For
example, skills may be highly developed in some areas (e.g., map reading) but may be quite
impaired in others (e.g., maintaining oral hygiene). Therefore, a thorough and comprehensive
assessment is needed in order to understand each individual’s overall pattern of developmen-
tal strengths and weaknesses. Monitoring progress over time will give the clinician informa-
tion necessary to tailor treatments and therapies for each individual. Furthermore, any loss of
skills should alert the clinician to consider further medical or psychiatric evaluation.
Neuropsychological testing may be needed in order to inform clinical diagnosis and
treatment, as well as to determine whether an individual may qualify for additional ser-
vices through early intervention (or Birth-to-Three), school departments, and state-funded
programs for individuals with intellectual or developmental disabilities (e.g., through a
Department of Mental Retardation or Department of Developmental Services) (Ozonoff,
Goodlin-Jones, & Solomon, 2005). Various aspects of cognitive function can be evaluated
with neuropsychological testing. This should include verbal and nonverbal intelligence
quotient (IQ), attention and executive functioning, adaptive functioning, severity of ASD
symptomatology, as well as emotional and behavioral functioning.
Communication
Communication involves the ability to convey and comprehend the exchange of informa-
tion with others and may be through a variety of means, including verbal, gestural, or graphic
symbols (American Speech–Language–Hearing Association, 1993). Typical development
of communication skills starts in infancy, when the infant learns to respond to his or her
caregiver’s cues and environmental stimuli through movements, facial expressions, and
vocalizations. Between 6 and 12 months, verbal language progresses from babbling to pro-
duction of single words. Between 12 and 18 months, vocabulary increases and speech devel-
ops to include typical prosody. The ability to share interests with others follows, including
the integration of eye contact, verbalization, and gestures to direct another’s attention (i.e.,
joint attention). Two-word combinations develop between 18 and 24 months, and by age 3
years, most are able to speak in simple sentences of three or four words.
Signs of verbal and nonverbal communication impairments for individuals with ASD
may become apparent between 12 and 24 months of age, and they may present as failure
to achieve language milestones. Language regression may also occur in 20–50% of children
with ASD, and it typically presents as a loss of previously mastered language skills, usu-
ally beginning at approximately 18–24 months (Barger, Campbell, & McDonough, 2013;
Zwaigenbaum et al., 2009). Language regression at approximately this age is considered a
“hallmark” of ASD, but later onset of language regression and any motor regression is atypi-
cal and should prompt further medical workup. In addition, hearing loss may contribute
to language delay, and part of the initial medical workup in a patient with possible ASD
should include audiology evaluation (American Speech–Language–Hearing Association,
1991; Johnson & Myers, 2007).
Some individuals with ASD remain nonverbal, and others may develop fluent verbal
abilities. Older children, adolescents, and adults who have developed more advanced lan-
guage skills may have difficulty with nuances of language, such as use of irony and humor, or
in engaging in reciprocal conversation. The use of verbal and nonverbal language for social
interactions (known as social or pragmatic language skills) continues to be an area of weak-
ness over the lifespan for those with ASD.
A formal evaluation by a speech–language pathologist is needed to determine the pat-
tern of expressive, receptive, and social pragmatic skills for each patient. A speech–language
Medical Evaluation of Patients With Autism Spectrum Disorder // 69
pathologist can also consider alternative and augmentative communication (AAC) strate-
gies (e.g., pictures, signs, or electronic devices) to assist in communication or aid in learning.
Medical providers and caretakers should ask about the means by which the individ-
ual communicates, verbal and/or nonverbal, and whether assistive devices are needed to
ensure a successful patient encounter. Remember that a patient might use more than one
mode of communication to express his or her needs or thoughts.
Cognition
Approximately 60% of children with ASD will have impairment in intellectual function-
ing. The Centers for Disease Control and Prevention (2014) estimates that 31% of chil-
dren with ASD are classified in the range of intellectual disability (IQ ≤ 70), 23% with
IQ in the borderline range (71–85), and 46% with average to above average intellectual
abilities. Neuropsychological testing should be conducted on a periodic basis, starting
at approximately age 5 years or early school age, in order to consider whether cogni-
tive impairment or any learning disabilities may be present. This can be very important
information for determining the most appropriate and effective school placement, out-
patient treatments, or job-skills training program. Neuropsychological testing can also
be helpful to determine whether academic or daily life functioning may be affected by
behavioral comorbidities such as attention deficit hyperactivity disorder (ADHD) or
anxiety, which may be amenable to psychopharmacological treatment. Finally, neuro-
psychological testing is important in determining the types and amount of services or
benefits an individual may receive from the state in which he or she resides; having an
intellectual disability can qualify some children and many adults for social security ben-
efits or funding from the state’s Department of Developmental Services (or Department
of Mental Retardation).
Play/Leisure
Play skills in children with ASD are often delayed or discrepant with the child’s develop-
mental or cognitive level. Children may persist in enjoying play activities (e.g., play with
blocks or dolls) when their peers have moved on to other areas of interest. They may have
difficulty engaging others in play and knowing how to interact with peers. Referral for
outpatient social skills groups or additional support for social skills may be necessary in
the school setting. Older children and adults may develop highly focused interests in an
unusual topic (e.g., weathervanes and lighting fixtures) that interferes with academic and/
or vocational pursuits or social interactions. Questions about whether the child has friends,
eats alone at school, plays alone at recess, or is invited to parties can inform the examiner
about the child’s social abilities.
Persistent sensory play and repetitive forms of play are also characteristic of ASD. Some
patients may line up or sort objects, or they may explore the sensory aspect of items such as
inspecting them at close range or shaking an object to hear a particular sound over and over.
They may just play with part of a toy (e.g., the wheels of a truck) or focus on a certain
scene in a video. These behaviors may be rewarding to the patient, but they appear unusual
to peers or strangers.
Motor
Individuals with ASD often have an early history of achieving motor milestones toward
the later range of normal, and they may have generally low muscle tone ( Jeste, 2011).
Children may appear to slouch or appear “floppy.” Some children may appear weak, but
asking about what the child is like when angry may help to distinguish true weakness from
low tone. Many children with ASD prefer not to exercise or may not have the opportunity,
which may contribute to a general deconditioned status exacerbating underlying low tone.
Encouraging exercise is important for general health and well-being. Referral to occupa-
tional therapists and physical therapists is needed for careful assessment and treatment of
fine and gross motor impairments, with the goals of helping individuals to attain functional
skills at school as well as in daily life. Some children may get weaker with exercise or after
infection or illness, and in those cases a muscle disorder (e.g., muscular dystrophy), disor-
der of energy metabolism, or mitochondrial disorder should be considered.
Motor stereotypies are repetitive motor movements that are voluntary, rhythmic, and
apparently purposeless. They are a core feature of ASD, although they can also be seen in the
general population and in other developmental disabilities (Goldman et al., 2009). Hand
flapping and toe walking are common, particularly when the individual is excited or agitated.
Sensory Processing Differences

Sensory processing differences, also called sensory integration dysfunction or disorder, are
a feature of ASD and have been included in the Diagnostic and Statistical Manual of Mental
Disorders, 5th edition (DSM-5), criteria (American Psychiatric Association, 2013). Many
individuals with ASD may under- or overreact to sensory stimuli. For example, caregiv-
ers may describe them as being intolerant of particular clothing, sounds, or sensations. In
particular, medical providers should question parents on how avoidance of certain foods
or textures may impact nutrition. As mentioned previously, it is important to establish an
individual’s baseline patterns of behavior because a change in sensory-seeking or repeti-
tive behaviors can be a sign of medical illness. Occasionally, sensory-seeking behaviors may
pose a safety risk. For example, if a patient is excessively mouthing or swallowing nonfood
items (i.e., pica), medical workup might include screening lead levels (for those living in
older homes in which lead paint was used or in high-risk geographic areas) or screening for
anemia (pica can be a symptom of iron deficiency). An increase in mouthing behaviors can
also be seen at times of a loose tooth or may be an indication of dental cavity, abscess, or
symptoms of gastroesophageal reflux (Filipek et al., 2000).
Emotional/Behavioral Development
Psychiatric comorbidity is addressed further in Chapter 6. Understanding the individual’s
baseline emotional and behavioral profile is important because any change in status might
alert the clinician caring for the patient’s medical needs to elicit further history pertaining
to potential underlying medical illness. For example, individuals may become less interac-
tive or communicative with others in the setting of an infectious process.
Self-injurious behaviors may be related to general frustration with the inability to
communicate needs in general or may be a way to indicate pain or discomfort. Worsening
emotional or behavioral problems should prompt the clinician to elicit whether there
may be any localizing features (e.g., self-injurious behaviors around the ear may be an
expression of ear pain due to otitis media). Irritability is common in ASD and may
manifest as being difficult to please, always seeming angry, or being set off by seemingly
innocuous things. Before irritability is determined to represent a behavioral or psychi-
atric issue, however, the medical provider first needs to focus on ruling out a possible
identifiable medical illness.
Past Medical History
As for all children, a careful birth and medical history should be obtained, as well as details
of past medical or psychiatric facility stay and surgeries. In particular, gastrointestinal
(GI) and sleep complaints are common among patients with ASD, and these are further
described here. Concern for possible seizure activity and macrocephaly should also be
considered, and this is addressed in more detail in Chapter 7. In addition, developmental
regression with illness could be a sign of a metabolic or mitochondrial disorder and should
prompt further workup.
Gastrointestinal
Children with ASD have unusually high rates of GI disorders (Coury et al., 2012). Common
concerns include constipation, abdominal pain with or without diarrhea and encopresis,
gastroesophageal reflux disease (GERD), and inflammation along the GI tract or colitis.
Symptoms can present as behavioral changes such as insomnia, self-injurious behaviors,
pica, spitting/drooling, and irritability (Buie et al., 2010). Belly pain might be expressed
as tummy rubbing or pressing the belly up against objects. Rumination, or the effortless
regurgitation of meals, can be a sign of a motility disorder. GERD can present as tonic neck
movements in children and adults, as seen in Sandifer syndrome in infants (Lehwald et al.,
2007; Nowak, Strzelczyk, Oertel, Hamer, & Rosenow, 2012). A referral back to the primary
care provider or a gastroenterologist could help with further diagnosis and treatment of
these conditions.
Sleep
Sleep problems are seen in 40–86% of children with ASD, which is higher than in children
with other developmental delays. Sleep problems can lead to daytime behavioral difficul-
ties in children with ASD, including inattention, impulsivity, and decreased tolerance for
change (Sikora, Johnson, Clemons, & Katz, 2012). Problems may be due in part to difficul-
ties falling asleep often related to anxiety, as well as wakefulness during the night (Goldman,
Richdale, Clemons, & Malow, 2012). Insomnia may be due to core behavioral problems in
ASD and/or associated comorbidities (psychiatric disorders, epilepsy, GI problems, and
sleep-disordered breathing). Multiple studies have shown problems with melatonin pro-
duction/regulation in individuals with ASD, and melatonin supplementation may provide
benefit (Rossignol & Frye, 2011). There are other sleep disorders, such as restless leg syn-
drome and obstructive sleep apnea, that need to be addressed, as in a typical child. Night
terrors, a brief and dramatic awakening during the first 3 hours of sleep, are often more
upsetting for the parents than the child, who has no memory of the event.
Review of Systems
Clinicians should elicit a thorough review of systems, as with all patients, but should also
include questions relevant to issues described in other sections of this chapter. Issues par-
ticularly pertinent to caring for individuals with ASD are presented here.
Constitutional
Does the patient have a history of recurrent severe illnesses that might suggest metabolic
disease?
Head, Eyes, Ears, Nose, and Throat

Have hearing and vision been screened? Individuals with ASD may have difficulty com-
plying with routine vision screening, and a referral to an ophthalmologist or optometrist
experienced in working with individuals with developmental disabilities is often needed.
A formal evaluation of hearing should also be conducted by an audiologist to rule out hear-
ing loss as a contributing factor to language delay.
Dental
Does the patient have regular visits with a dentist? Referral to a dentist experienced in car-
ing for those with developmental disabilities should be considered.
Respiratory/Cardiovascular
Many psychotropic medications have cardiovascular side effects, and nonverbal individuals
may have difficulty expressing chest pain, so the clinician should inquire as to whether there
has been any change in activity or levels of exertion.
Gastrointestinal/Genitourinary
In addition to eliciting information about bowel patterns, a delay in achieving toileting
skills is common among individuals with ASD. This is often a major concern for caregivers.
The clinician should also ask about enuresis.
Musculoskeletal
As mentioned previously, a delay in achieving motor milestones and advanced coordina-
tion skills is common, but myalgia, muscle weakness, and muscle pain are uncommon and
should warrant further medical workup by a neurologist.
Neurological
In addition to the neurological concerns mentioned previously, a history of head trauma,
headaches, seizures, or loss of consciousness is important in considering developmental
progress and need for brain imaging.
Dermatologic
History of unusual birthmarks or rash might alert clinicians to screen for specific genetic
or metabolic syndromes. As with all patients, eczema is common, but in particular exten-
sive skin rash and itchiness can lead to chronic irritability and self-injurious behavior.
Individuals residing in group living facilities are more likely to develop common infec-
tious skin conditions, such as tinea pedis and common warts, that can also be irritating
or painful. Those who wear diapers for extended periods are more susceptible to diaper
dermatitis.
Endocrinologic
Are there symptoms to suggest thyroid disease, diabetes, or metabolic syndrome? Weight
loss and weight gain are common side effects of medications.
Hematologic
With individuals who may eat a limited diet due to sensory preferences or ritualized pat-
terns of behavior, are there symptoms suggestive for anemia due to inadequate dietary iron
intake?
Immunologic
As with all patients, it is important to consider whether there is a history of asthma or
allergy because allergy symptoms can lead to discomfort and affect behavior.
Sleep
As mentioned previously, taking a careful sleep history is important. Does the patient have
snoring or restless sleep that might disrupt sleep? What is the usual bedtime and wake time?
Where does the patient sleep? Does the patient’s behavior in the night disrupt the sleep of
others in the household? Does being awake at night when others are sleeping impact the
patient’s safety?
Social and Family History
As with all medical visits, a thorough social and family history should be obtained
in order to determine what further supports are needed and to target further genetic
workup. Drawing a family pedigree can be a useful way to elicit this information. This
section presents additional topics to be considered as part of a careful history in indi-
viduals with ASD.
Living Situation
With whom and in what type of setting does the individual live?
Educational History
For children younger than age 3 years, it is important to elicit whether they are enrolled in
early intervention (EI) or Birth-to-Three services. From age 3 to age 18–22 years, depend-
ing on the state, individuals may qualify for special education services through their local
school district. With EI and school services, it is important to understand what services are
being provided and what the goals are of these services, the training background of service
delivery providers, and how many hours of services are being provided, as well as where
the services are being delivered. If the individual is in a school setting, the provider may ask
questions about class size, whether it is a private or public school, the ratio of students to
teachers, and where the child receives services (e.g., at home, in a general education setting,
in a smaller separate special education classroom, or individually at school).
Vocational History
At age 14 years, schools should start planning the transition from adolescent to adult ser-
vices, as well as planning for vocational training needs.
Neuropsychological (described previously), educational, and/or vocational evalua-
tions may be needed at this time. For those who are working, what level of supervision
and independence does the patient have at work, and what supports are in place to ensure
success?
Additional Supports
Individuals with ASD may receive funding or other supports through the state’s Department
of Developmental Services (or Department of Mental Retardation). Considering whether
the individual has been able to receive health insurance through local Medicaid or sup-
plemental insurance programs (e.g., Katie Beckett medical waivers in some states) is also
important to understand what further resources may be available.
Legal History
Has the child or young adult ever been arrested or had interactions with the law?
Safety
Consideration of the safety of the individual’s environment is important. For example, indi-
viduals who lack safety awareness may try to escape from the home, they may be at higher
risk for falls if they recklessly climb up on high places such as counters or windows, and
additional locks or other safety measures may be needed. Special car seats or harnesses may
be needed to ensure safety in vehicles. Individuals with ASD or other developmental dis-
abilities are also particularly prone to become targets of bullying or teasing. Furthermore,
as for all individuals, eliciting whether they may have witnessed violence or whether they
themselves may have been victims of physical or sexual abuse are important consider-
ations and can lead to changes in behavior patterns (Mandell, Walrath, Manteuffel, Sgro, &
Pinto-Martin, 2005).
Sexual History
Adolescents and adults with intellectual disabilities may lack awareness of appropriateness
of romantic partnerships, and issues of sexuality should be addressed as for all individuals.
PHYSICAL EXAMINATION
This section discusses particular considerations for physical examination for patients with
ASD; however, as with all patients, a thorough physical examination should be conducted.
When conducting a general physical and neurological examination for individuals with
ASD, clinicians should also take into consideration the common comorbidities presented
previously and further etiological workup. Gradual exposure to medical equipment and the
routines of medical visits and examinations may be needed to help patients tolerate proce-
dures that may be stressful. Practice at home with medical equipment and collaboration
with other providers, such as behavioral therapists and school nurses, may help patients feel
more comfortable in the medical setting.
Vital Signs and Growth
Routine vital signs, such as heart rate and blood pressure, and growth parameters such
as height, weight, and body mass index (BMI) are important clinical parameters for
monitoring general health as well as medication side effects. Tachycardia and hypertension
may indicate the presence of anxiety. A head circumference should be obtained and plotted
on standardized curves by age. A small head size might indicate a neurogenetic disorder
such as Rett syndrome, whereas a large head size might be seen with Sotos syndrome or
other disorders that may warrant genetic testing.
General
A general observation of the individual’s behavioral profile and developmental skills (as
discussed previously) and ASD symptoms as evident in the examination room should
be documented to monitor symptoms over time. A general dysmorphology examination
should be conducted to guide medical and genetic workup (discussed later).
Head, Eyes, Ears, Nose, and Throat
Macrocephaly or microcephaly may be noted, as mentioned previously. The examination

of the eye can reveal findings suggestive of a tic disorder with bilateral eye blinking; dilated
pupils might be a sign of anxiety. A limited range of motion of the eyes might be a sign of
a mitochondrial disorder. Gaze aversion and visual stereotypies should be noted if present
because they are quite common in ASD. Ear examination is particularly important in indi-
viduals with ASD because they may not alert caregivers to ear pain due to a high pain toler-
ance or lack of an effective communication method; a foreign body or ear infection may be
otherwise missed. Examination of the mouth may reveal oral motor coordination difficul-
ties and weakness, which may accompany impaired verbal communication abilities. This
might manifest as drooling or as inarticulate speech. In addition, clinicians should evaluate
for tonsillar hypertrophy to rule out obstructive sleep apnea as a contributor to sleep dif-
ficulties, which are commonly seen in ASD, as mentioned previously. Dental problems such
as infection or inflammation, with associated pain and discomfort, can lead to behavioral
changes, as can teething in young children.
Gastrointestinal
Abdominal examination may reveal fullness suggestive of constipation or hepatospleno-

megaly suggestive of a metabolic disease.
Skin
Dermatological examination should search for any neurocutaneous abnormalities

suggestive of neurofibromatosis or tuberous sclerosis complex (TSC), and it should
include Wood’s lamp examination to search for hypopigmented macules (also called
ash leaf spots). Calluses may be seen in children who have chronic self-injurious biting
or gnawing. Tenting of the skin or loose ligaments can be a sign of a connective tissue
disorder. In addition, the clinician should assess for evidence of skin picking or tricho-
tillomania (hair pulling) and should monitor for superinfection of chronically irritated
areas of skin.
CASE STUDY #1: “WILLIAM”
William is a 36-month-old boy who was evaluated for the diagnosis of ASD. At the age of
18 months, he had no words, poor eye contact, and no communication other than crying.
At the age of 26 months, he was started in speech therapy. He then developed three words
but still did not point. He was noted to engage in hand and finger stereotypies. He liked to
stack toys or play with trains. He had no interest in other children. At the age of 33 months,
he had a febrile seizure. Family history is notable for seizures in the father.
On physical examination, William was found to have a head circumference of 51 cm
(75th percentile). He was a well-appearing boy who engaged in frequent hand-flapping
behaviors. He had no eye contact with the examiner. He used no words. He cried to com-
municate his needs. He stared at the wheels of a toy truck and spun them frequently.
His general examination was notable for three hypomelanotic macules (white or ash leaf
spots) on his trunk visualized best with a Wood’s lamp. There were no hypermelanotic (café
au lait spots) macules. There were two ungual (nail bed) fibromas as well. The neurologic
examination was otherwise notable for normal cranial nerves, although the patient was not
cooperative with fundoscopy or tests of visual acuity. He was noted to have low muscle
tone and yet walked on his toes.
What Can We Learn From This Case?
The important features are twofold. First, William is a child with “classic” autism, with defi-
cits in social communication and social interaction, along with restricted, repetitive patterns
of behavior such as hand flapping, fixation on parts of objects, and restricted stereotypical
play. He meets DSM-5 criteria for ASD.
Second, the results of this child’s physical examination (the ash leaf spots and fibromas
in the nail beds) indicate he may have an underlying neurogenetic disorder, such as TSC.
TSC is a genetic disorder resulting in abnormal nonmalignant tumor formation in differ-
ent organs, typically the brain, eyes, skin, heart, kidneys, and lungs. The tumors seen are
usually caused by mutations in either of two tumor suppressor genes: TSC1 (located on
9q34) or TSC2 (located on 16p13) (Borkowska, Schwartz, Kotulska, & Jozwiak, 2011;
Dabora et al., 2001). There is an autosomal dominant pattern of inheritance and a high rate
of associated ASD in children with TSC (approximately 43–86%) (Harrison & Bolton,
1997; Jeste, Sahin, Bolton, Ploubidis, & Humphrey, 2008). Although most children with
ASD do not need neuroimaging, given these physical examination findings, it is important
to refer this child to a neurologist or geneticist for further diagnostic evaluation, including
an MRI of the head and kidneys and an ultrasound of the heart. Furthermore, the tumors
of the brain can cause seizures, which are best managed by a neurologist.
Neurological
The neurological examination is typically reassuringly normal in individuals with ASD

except for low muscle tone, which is common. The examiner should observe the patient’s
movements, ability to imitate, and level of communication and comprehension. One should
observe the patient for motor tics as well as attention and focus because both tic disorders
and ADHD are more common in individuals with ASD. General neurological examination
should be conducted, including evaluation of muscle tone and bulk, gait, coordination, and
performance of the Gower’s maneuver in children (arising from prone to a stand) to look
for proximal muscle weakness. Asymmetries in gait might indicate that the child has a focal
injury or cerebral palsy. Remember that pain can also cause an asymmetric gait.
Because many individuals with ASD are toe walkers, it is important to check the heel
cords to ensure that the ankles have normal range of motion and there is no tendon tighten-
ing. If so, a referral to physical therapy is indicated.
The next section further discusses laboratory and diagnostic workup for individuals
with ASD. In general, an extensive diagnostic workup is not recommended for all cases of
ASD, but it may be beneficial when there are concerning features on history and physical
examination. For all the testing discussed next, genetic testing is the only type of testing
that is routinely recommended.
GENETIC TESTING
A genetic abnormality can be identified in approximately 10–20% of cases of ASD.

Currently, more than 100 genetic and genomic abnormalities have been associated with
ASD (Betancur, 2011).
Small submicroscopic gene deletions or duplications are the most commonly identi-
fied abnormality (10–35%), followed by larger gene duplications or deletions that can be
seen on a standard karyotype (up to 5%) and single gene mutations (<5%). Although the
diagnosis of ASD remains a clinical diagnosis and genetic testing may not alter the clinical
management of the patient, the results may be helpful in providing an explanation to the
family, avoiding unnecessary tests, and identifying any potential comorbidities and condi-
tions that are currently existing or may occur in the future (Schaefer et al., 2013).
The current recommendations of the American College of Medical Genetics and the
American Academy of Pediatrics are to obtain a chromosomal microarray (CMA) as part
of the first tier of the genetic workup (Schaefer et al., 2013; Shen et al., 2010). This is
a departure from earlier guidelines that recommended ordering a karyotype. A CMA
analyzes submicroscopic regions of a chromosome searching for either extra (duplica-
tion) or missing (deletion) genetic material in these regions. A karyotype examines the
number of chromosomes and studies their appearance under a microscope, looking for
abnormalities such as missing or extra chromosomes and abnormal shapes and sizes.
Although no longer recommended as the first genetic test, ordering a karyotype may be
useful in patients in whom clinical features may be indicative of a syndrome associated
with a known chromosomal abnormality, such as Down syndrome or Turner syndrome
(Schaefer et al., 2013).
In addition to a CMA, testing for fragile X syndrome (FXS) is recommended for both
males and females who present with mild to moderate intellectual disabilities. Physical fea-
tures, such as large ears, a prominent jaw, macrocephaly, and postpubertal macroorchidism
in males, and a family history suggestive of an X-linked inherited disorder are often seen
with this condition.
X-linked disorders, including FXS, can be seen in females; however, they are usually
more mildly affected (Flore & Milunsky, 2012).
CASE STUDY #2: “JACOB”
Jacob is a 5-year-old boy from Costa Rica who came for evaluation of developmental delay
with signs of ASD. Jacob had delayed developmental milestones, with sitting at the age of
15 months and walking at the age of 2 years. At the age of 3 years, he was using only three
words to indicate his desire to eat or drink. He had no social greetings and used someone
else’s hand as a tool to gesture. He had repetitive rocking behaviors and some self-injurious
behaviors with gnawing on his wrist and head slapping. He started speech therapy, as well
as physical and occupational therapy, and his vocabulary improved such that he could iden-
tify many objects and express his needs with short phrases. However, he was unusually
picky about eating and would only eat “white” foods such as pasta, bananas, crackers, and
chips. He was not toilet trained and had chronic constipation. His mother had placed him on
a gluten- and casein-free diet.
On physical examination at the age of 5 years, he was a happy and well-appearing
boy with low tone in both his face and his extremities. He had a long face, large ears,
and hyperextensible joints. Testicular size was normal. He had a callous on his left wrist.
During the visit, he was fed crackers when he fussed. He did occasionally slap his head
and gnaw on his wrist when frustrated. His eye contact was poor, and he used few
spontaneous words.
Questions
What other testing would you like to order?
What are concerning features of this history and physical examination?
Testing
The features of long face, large ears, and low tone raise the question of fragile X syndrome
(FXS). Although this child had already had the testing once in Costa Rica, it was repeated
and found to be consistent with FXS. Remember that the large testes associated with FXS
are mostly seen in postpubertal males. This diagnosis has implications for the rest of the
family when there are siblings, so genetic counseling is also necessary.
Concerning features
1. Diet: The gluten-free and casein-free diet may be helpful for some children, but this
and other special diets often pose nutritional challenges for children who do not get
adequate calcium and vitamin D and are therefore at risk for low bone density.
2. Picky eaters are similarly at risk for poor nutrition and constipation with their
low-fiber diet.
3. Incontinence: Many children with ASD, especially those who have some verbal
abilities, can be toilet trained by the age of 5 years. However, chronic constipation,
which is common in children with ASD and more common in children on poor
diets, will impair a child’s ability to toilet train. The constipation often needs to be
addressed before a child can be toilet trained.
In rare cases in which findings from the history and physical examination are consistent
with a syndrome associated with a single gene disorder (Table 5.1), such as phosphatase
and tensin homolog (PTEN) gene mutations and Rett syndrome, it may be more appropri-
ate to test for the specific genetic disorder in question (Flore & Milunsky, 2012; Schaefer
et al., 2013).
METABOLIC TESTING
The inborn errors of metabolism (IEM) are a large heterogeneous group of disorders.
These disorders result from a genetic abnormality resulting in deficits in enzymes or
transport proteins required to metabolize carbohydrates, amino acids, or lipids. Toxic
metabolic products accumulate and can lead to multiple organ damage, including the
central nervous system (CNS) (Ghaziuddin & Al-Owain, 2013). In the United States, a
large proportion of these disorders are diagnosed in infancy via universal newborn met-
abolic screening, commonly called the “newborn screen” or “newborn bloodspot.” This
generally involves a small sample of blood obtained from the newborn after birth, which
is analyzed and reported by state labs. Newborn screening varies throughout the United
States; therefore, it is essential to know which disorders are screened for in a particular
state. However, all 50 states screen for congenital hypothyroidism, galactosemia, and
phenylketonuria (PKU). The individual’s pediatrician should have a copy of these results
or be familiar with how the results may be obtained if he or she does not have a copy on
TABLE 5.1 Common Single Gene Disorders Associated With Autism Spectrum Disorder
Syndrome Prevalence Common Features Inheritance Genes
Pattern
Neurofibromatosis-1 1/3,000 live births Café au lait spots, neurofibromas, Autosomal NF-1
axillary freckling, optic glioma dominant
Fragile X 16–25/100,000 live Long face, large ears, postpubertal X-linked FMR-1
syndrome male births macroorchidism dominant
Tuberous sclerosis 1/5,800 live births Ash leaf spots; angiofibromas; Autosomal TSC1,
complex cardiac, renal, and brain tumors; dominant TSC2
ungal fibromas; shagreen patch;
seizures
Rett syndrome 1/8,500 females by Microcephaly, postnatal onset, X-linked MECP2
age 15 years developmental regression, hand dominant
motions
Angelman 1/ 12,000–20,000 Intellectual disability, hypotonia, Maternal UBE3A
syndrome live births microcephaly, ataxia or inheritance
movement disorder, seizures usually
PTEN hamartoma Exact prevalence Intellectual disability, Autosomal PTEN
tumor syndrome unknown macrocephaly, skin pigment dominant
changes, skin tumors
Source: Adapted from Kandt (2003), Pagon et al. (1993–2014), Siegel and Smith (2010), and
Toriello (2008).
TABLE 5.2 Features Suggestive of an Inborn Error of Metabolism on History

and Physical Examination
Regression after the age of 3 years

Family history of an IEM
Parental consanguinity
Periods of decompensation with illness/stress
Enlarged organs
Coarse facial features
Ataxia or difficulties with coordinating voluntary muscle movements
Movement disorders
White matter changes seen with neuroimaging
Born in a country that does not have newborn screening
Cyclic vomiting
Hearing loss
Concerns on newborn screen
Acid–base or electrolyte imbalance
Source: Adapted from Flore and Milunsky (2012) and Goldman et al. (2012).
file. There is a wide array of presentations across these disorders, as well as within spe-
cific disorders; however, each specific IEM has certain key features. A discussion of the
specific key features specific to each disorder is beyond the scope of this chapter. There
are certain features in the history and physical examination that may make the diagnosis
of an IEM more likely (Table 5.2). For example, PKU, an inborn error of phenylalanine
metabolism, usually presents soon after birth, whereas San Fillipo syndrome, which
is a disorder of mucopolysaccharide breakdown, typically presents between the ages
of 2 and 6 years (Manzi, Loizzo, Giana, & Curatolo, 2008). With the exception of the
newborn screen, screening for metabolic disorders is not generally recommended for
patients with ASD. As a group, the IEMs account for less than 5% of cases of ASD. The
diagnostic workup of an IEM is very extensive, and the recommended initial workup is
highly variable among clinicians. The workup for an IEM typically includes urine and
serum amino acids, electrolyte panel, blood urea nitrogen, creatinine, liver function
tests, urinalysis, complete blood count, and ammonia (Kamboj, 2008).
It is recommended that metabolic screening be reserved for children who have features
such as regression with loss of milestones or cognitive skills after the age of 3 years, repeated
regressions with illnesses such as fevers and colds, early onset or neonatal seizures, coarse
or thick-appearing facial features, slowly progressive regression, or failure to learn any new
skills during a 6-month period of time.
MITOCHONDRIAL DISORDERS
Mitochondrial disorders as a group are rare, with an estimated prevalence of 11.5 cases
per 100,000. In mitochondrial disorders, the liver, brain, heart, and muscle are most com-
monly affected. Mitochondria have their own DNA called mitochondrial DNA (mtDNA).
Alteration of either mtDNA or nuclear DNA can cause mitochondrial disorders. Of note,
mtDNA is inherited only from the mother. Furthermore, not all mtDNA is the same in
a particular cell, which means that there can be a mix between normal and abnormal
mtDNA; this is referred to as heteroplasmy. Hypotonia, regression after the age of 3 years,
multiple organ system involvement, lactic acidosis seen on an arterial blood gas, and exac-
erbation of symptoms such as weakness with illnesses such as acute GI viruses are some
common findings in mitochondrial disorders. Diagnostic tests for mitochondrial disorders
include serum lactate, serum pyruvate, serum creatine kinase, plasma and urine acylcarni-
tines, urine organic acids, urine and serum amino acids, and muscle biopsy. If CNS involve-
ment is present, cerebrospinal fluid (CSF) lactate and CSF pyruvate are recommended
(Turner & Schapira, 2012). The interpretation of the results is complicated and typically
best deferred to specialists in mitochondrial disorders. Testing for mitochondrial disorders
is not recommended as part of the routine medical workup for ASD.
MEDICAL TESTING IN PATIENTS WITH AUTISM SPECTRUM DISORDER
Electroencephalogram
The electroencephalogram (EEG) need not be routinely obtained in patients with ASD. It
should be performed only when there is a clinical suspicion of seizures, such as the patient
having behaviors or spells suggestive of seizures. For example, grand mal or tonic–clonic
seizures consist of arm and leg shaking with loss of consciousness and eye rolling. Petit
mal seizures are characterized by brief staring spells. Focal or partial seizures might not
impair consciousness and might include shaking in just one part of the body. An EEG can
be quite difficult to perform in a minimally to nonverbal patient who is not able to lie still
for 45 minutes or a patient who cannot tolerate the sensory aspects of the lead placement
on the head. Although children with ASD do have an increased risk of seizures, the relative
risk of seizures is quite low if younger than age 12 years and if there is no associated intel-
lectual disability. A clinical study found epilepsy in 1.8% of patients without intellectual
disability and younger than 12 years old, 6.1% if younger than 12 years old with intellec-
tual disability, 8.9% if older than age 12 years and no intellectual disability, and 23.7% if
older than age 12 years with intellectual disability (Woolfenden, Sarkozy, Ridley, Coory, &
Williams, 2012).
Children with ASD are also known to have a higher rate of EEG abnormalities without
clinical seizures and may often have “seizure-like” events with no epileptic EEG correlate.
It remains unclear whether these EEG abnormalities should be treated with anticonvulsant
medication in the absence of clinical seizures (Tharp, 2004; Yasuhara, 2010).
Neuroimaging
There is yet no neuroimaging test such as magnetic resonance imaging (MRI), computer-
ized tomography, magnetic resonance spectroscopy, or positron emission tomography for
the diagnosis of ASD. To date, no typical, replicable changes in the brain have been identi-
fied with MRI in ASD. Because of the need to lie still for up to 1 hour, sometimes requiring
general anesthesia, it is recommended that neuroimaging only be performed in patients
with an abnormal neurological examination; findings of a neurocutaneous disorder such
as hypopigmented macules (ash leaf spots) on the skin, which are associated with TSC;
first seizures; or a child with an unusual clinical course, such as a late regression or repeated
developmental regressions.
SUMMARY
The medical and clinical care of individuals with ASD needs to be approached differ-
ently than in a typically developing child, adolescent, or adult because ASD symptom-
atology as well as common behavioral and medical comorbidities can affect daily life
and medical treatment. This chapter recommended important questions to consider
and areas on which to focus when obtaining a clinical history and physical examination.
Genetic evaluation, as outlined previously, is indicated for all patients with ASD, and
further medical workup should be tailored based on the individual’s clinical presenta-
tion and physical findings.
KEY POINTS
• The history should be adjusted for patients with ASD to include information about
communication, intelligence, school, and sensory dysfunction as well as regression.
• The physical examination of a child with ASD needs to be adjusted because of the
patient’s anxieties and sensory dysfunction.
• Individuals with ASD are more likely to have gastrointestinal, sleep, and neurological
disorders.
• The examiner needs to focus on metabolic, neurologic, and genetic disorders that
could cause ASD.
• Medical testing is not routine in patients with ASD unless specific signs or symptoms
are found to warrant specific tests.
Dr. Yamini J. Howe, Dr. Michelle L. Palumbo, and Dr. Ann Neumeyer have nothing to
disclose.
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6 / / /
/ / / PSYCHIATRIC COMORBIDITY
IN AUTISM SPECTRUM
DISORDER
SUSAN E. FOLSTEIN AND LUIS M. CARCACHE
INTRODUCTION
Persons with comorbid autism spectrum disorder (ASD) have disabilities stemming
not only from the clinical features necessary for diagnosis but also from comorbid psy-
chiatric disorders and other associated abnormal behaviors. It has been known for many
years that children with developmental difficulties of all kinds have a higher frequency
of emotional and behavioral symptoms than typically developing children (Rutter,
Graham, & Yule, 1970). These behaviors were assumed by many clinicians and scien-
tists to be secondary to their cognitive impairments, and although this is a reasonable
assumption, it led to a nihilistic attitude toward diagnosis and treatment. It is now clear
that it is possible to diagnose psychiatric disorders in children with developmental dis-
abilities, including ASD; that these disorders for the most part meet the same diagnostic
criteria used in the general population (Leyfer et al., 2006); and that they respond to
treatment.
The estimates of prevalence of psychiatric comorbidity vary, depending on whether
the sample was drawn from a psychiatric clinic or from some other source (De Bruin,
Ferdinand, Meester, De Nijs, & Verheij, 2007; Leyfer et al., 2006; Simonoff et al., 2008),
but it probably occurs in the majority of persons with ASD. These conditions interfere with
optimal functioning but often go undiagnosed and untreated. When anxious, depressed,
overactive, or inattentive, persons with ASD are less available for teaching and less able to
participate in family life and in the community. With careful observation over time, most
comorbid psychiatric disorders can be diagnosed regardless of the patient’s cognitive and
language capacity; some are identical to those seen in persons without ASD, but others may
present in unusual ways that make their identification difficult at first. Persons with ASD
also have abnormal associated behaviors that do not fit easily into the psychiatric nomen-
clature (Dominick et al., 2007). This chapter describes the clinical features of the psychiat-
ric disorders and abnormal associated behaviors often seen in persons with ASD, provides
diagnostic pointers, and recommends psychopharmacological and behavioral treatments
85
that may be considered. The data presented and the case examples are based on a case series
of 300 clinically diagnosed patients with ASD who were systematically examined by the
authors.
TAKING A HISTORY
The first and most important task is to take a thorough history, including family history of psy-
chiatric disorder; pregnancy; problems during delivery; and medical and developmental fac-
tors, including motor, language, and social aspects. A detailed school history should inquire
about attainment, peer interactions, and behavior over time. Results of other evaluations
including neuropsychological testing are useful. The history of present illness should ask about
episodic symptoms, as well as more chronic difficulties that occur in particular situations.
MENTAL STATUS EXAMINATION
First, note the physical appearance of the patient. There may be dysmorphic features that
require further evaluation with a geneticist for syndrome identification. If a genetic disorder
is diagnosed, it may have implications for other family members. Document height, weight,
and head circumference, all of which may be outside the normal range. Next, note physical
activity level. Many people with ASD are fidgety, and some are very hyperactive, particu-
larly as children. Occasionally, they sit too still. Be vigilant for signs of catatonia—trouble
arising from the chair, hesitancy about crossing the threshold of the doorway to your office,
difficulty in deciding to pick up a pencil when you ask them to write, and becoming frozen
in a particular posture.
Next, note the patient’s affect. This is one of the most important observations. Anxious
affect is very common and can present as it does typically in developing persons: knitted
brows, fidgeting, continually looking at the parent for reassurance, handwringing, and pac-
ing. If it is severe, the patient may not be willing to enter the room and may bang his or her
head or bite him- or herself. The patient may pinch his mother or try to sit on her lap or
attempt to get her to take him out of the room. If the patient has useful language, you can
ask how he or she feels, but the answers may not be helpful; many persons with ASD have
little insight into their internal feeling state or mood. Sometimes, if you give them some
choices, they can choose one: Do you feel worried or happy? Even this approach may not
accurately reflect their mood: They may try to please the examiner with their answer. The
parent’s history often gives more accurate information.
The next most common disturbance of affect is the one usually associated with depres-
sion. Children may sit very still and look downcast (most persons with ASD do not look
at you, but they do not look downcast) and miserable. If they have useful language, they
will often agree that no one likes them and that they are not good enough. Sometimes it
is necessary to break the rule about asking leading questions because persons with ASD,
even those with good language, often find it impossible to respond to indirect questions,
particularly about feelings. Again, you may get more accurate information from the par-
ents: They often report things the child has said that indicate low mood, including talk
of suicide. The depressed mood usually represents a change, and parents may be able to
link it to an approximate date. They may be able to contrast the present depressed mood
with a more cheerful one from the past, albeit the patient may have had an anxious mood
in some situations. Parents may not always have an accurate assessment of their child’s
sleep. Although some children go to their parents’ bedroom if they wake in the night and
Psychiatric Comorbidity in Autism Spectrum Disorder // 87
get into their bed, others do not. They may have learned to stay in their room even if they
are awake.
It can be difficult or impossible to decide if persons with ASD are hallucinating. They
may stare into the middle distance and seem to be attending to and sometimes responding
to something. However, this behavior is also seen when patients are attending to a movie
that they have seen and are “playing the tape” in their heads. Staring spells may also be
indicative of absence seizures. Except for more intelligent verbal patients, it is usually not
possible to be certain about delusions; when present, however, they are often mood con-
gruent and part of a depressive episode. Patients may say that people are looking at them. If
asked why, they might say that it is because they are so bad. However, getting this quality of
information is not always possible.
Obsessions and compulsions may also be difficult to be sure of, although occasionally
very typical features of obsessive–compulsive disorder (OCD) are seen, with a distress-
ing thought that is resisted and a related compulsive behavior that is not pleasurable but
“required.” OCD can also be diagnosed in nonverbal patients if a repetitive behavior seems
to cause distress; in these cases, the behavior will most likely be related to checking, clean-
ing, grooming, or ordering and arranging. Insistence on sameness can be very similar to
behavior that occurs in OCD: Things must be in the right place or occur as expected, and
the patient is upset if something is moved or occurs out of sequence. Conversely, many of
the repetitive behaviors are rewarding, such as watching the same video clip or drawing the
same object repeatedly.
Testing cognition necessarily varies; sometimes the patient is both nonverbal and
unable to express thoughts in writing. At a minimum, ask patients to state their name,
address, and phone number; these are usually taught to them by rote. Note fine motor prob-
lems with writing. Those who have some language should be asked to read a simple passage;
if they succeed, increase the difficulty to try to assess grade level. Mathematics attainment
can be similarly tested. When doing this, some children become extremely anxious; many
children with ASD complete their schoolwork at a slower pace. If appropriate to their level
of cognition, it is instructive to do the Mini-Mental Status Examination (MMSE) (Folstein,
Folstein, Whites, & Meiser, 2009). Even in fully verbal patients, the pattern of strengths and
weaknesses varies tremendously, from their ability to do serial sevens rapidly to a complete
inability. Patients may appear disoriented or very precise in their orientation. Handwriting
is often effortful. They write very interesting sentences; a few of these are shown in Box 6.1.
If using the MMSE-2, which includes symbol-digit and a story recall task, you can screen
for processing speed and story memory. Almost uniformly, even the brightest patients are
slow on the symbol-digit task, and they have great difficulty in recalling parts of the story
that were just read to them.
PSYCHIATRIC DISORDERS
Attention deficit hyperactivity disorder (ADHD) presents the same way in individuals
with ASD as in other children: hyperactivity from the time they can walk, inattention, and
impulsiveness. They can be treated with the same medications used for ADHD in typical
children. Some patients do not respond as expected, often becoming irritable or tearful, but
this is sometimes because their restlessness and inattention are related to a mood or anxiety
disorder rather than ADHD. The behaviors can be superficially similar: Children may be
too anxious to listen in class; when doing homework, they get up, pace around, cry, and
look worried and upset. Generally, children with ADHD sleep well compared with those
BOX 6.1
MMSE SENTENCES WRITTEN BY PERSONS WITH AUTISM
SPECTRUM DISORDER
I honst to mommy.
I want to be a kid forever. (He just had his 21st birthday.)
Mosquitos are anoying because they bite.
Water is to keep you hydrated.
The pentagons have a diamond in the middle.
I want to move to the verdant state of Vermont.
I am going to be a quadruple instrumented.
A hexagon is a type of shape that is round.
Mr. Monkey parts is on fire!
Don’t look at me.
Somtimes (sic) I dream about cheese.
I will go recycling at Villa Maria Nursing Center.
I’ll just take it essy for eterything, like new friend. The reason is not to get angry at
home. I’ll be a good boy. I will get more friends. Bad no nothing.
who are anxious or depressed. Quite a number of children with ASD who present to psy-
chiatrists have both ADHD and anxiety. If both seem to be present, consider treating the
anxiety first because the inattention and pacing often improve without the use of stimulants
and some children are poor eaters at baseline (stimulants can reduce appetite). However, if
the hyperactivity is prominent and severe, it should be treated first. As with other children,
those with ASD may not respond equally well to all the stimulants; children with ASD
have the usual side effects but at a higher rate, partly because of misdiagnosis (Mahajan
et al., 2012).
Anxiety in ASD is more of a trait than a state, although it does worsen in certain sit-
uations. Panic disorder is uncommon, but children with ASD may get sweaty palms,
worry, appear distressed, and pace around, and they are often unable to pay attention in
anxiety-provoking situations, including school. They often sleep poorly, with both initial
and middle-of-the-night insomnia. Situations that commonly provoke anxiety are shown
in Box 6.2 (Monroy & Folstein, 2012). The manifestations of anxiety in persons with ASD
can be unusual: screaming, running away, biting themselves, or hitting their heads. They
bite and damage their nails, sometimes to a pathological extent (e.g., pulling the nail out
entirely) (Box 6.3).
Most persons with ASD feel least anxious at home, following their own routines and
preferences. Sometimes their anxiety prevents them from going to school and family
events; crowds and noise are particularly upsetting. For higher functioning children, fam-
ily gatherings can provoke anxiety because of the expectation that they at least attempt to
follow social conventions; for lower functioning persons, the noise and confusion often
upset them. Sometimes anxiety is provoked by fears of bees, butterflies, storms, dogs, and
high-pitched screams such as babies crying or little girls screaming. They can also become
phobic of elevators, heights, and driving, much as can typical people.
BOX 6.2
SITUATIONS THAT OFTEN PROVOKE ANXIETY
Looking frightened
Repetitive questioning
Pacing
Cannot sit still
Having a “meltdown” (tantrum)
Biting nails
Picking scabs
Biting self
Stammer
Biting others
Anxiety can also lead to self-injurious behavior and aggression. Patients become so dis-
tressed that they bite themselves or bang their heads or lash out at others. This self-directed
aggression is often treated first with atypical antipsychotics, but response is usually only
partial. Occasionally, low-dose selective serotonin reuptake inhibitors (SSRIs) are helpful;
patients with severe, long-standing calluses on their arms and open sores often stop injur-
ing themselves entirely, as shown in Table 6.1 (Carbajal & Folstein, 2012). However, as
discussed later, if their moods are unstable, a mood stabilizer should be considered first to
prevent behavioral activation from the SSRI.
Some studies show that anxiety can be treated behaviorally in high-functioning
patients with adequate language (Sofronoff, Attwood, & Hinton, 2005; Wood et al., 2009).
However, if the anxiety is severe or if it is difficult for the person to understand how to
self-modulate his or her anxiety, SSRIs should be considered; sometimes the dose needs
BOX 6.3
BEHAVIORS RELATED TO ANXIETY, IN ORDER OF FREQUENCY
Wanting to obtain an object related to a special interest

Misplaced valuable object
Excessive noise
Noisy environments
Children screaming
Loud talk with high emotional content such as parents
arguing
Change in plans
Awaiting a future event
Doctor or dentist visit
TABLE 6.1 Self-Injurious Behavior: Response to SSRIs Versus Other

Medication From Retrospective Chart Review of Clinical Treatment (N = 79)
Response SSRI (%) Other Medication (%)
Worse 14 3
No change 8 53
Transient improvement 1 6
Improvement 10 28
Remission 67 10
to be very low—the usual doses can precipitate irritability, overactivity, and sleeplessness.
Sometimes this behavioral activation may resemble hypomania; other times it resembles
the symptoms of serotonin syndrome. Other patients respond to the usual therapeu-
tic doses of SSRIs. Fluoxetine or sertraline are available in liquid preparations that allow
very low dosing (Birmaher et al., 2003; Steingard, Zimnitzky, DeMaso, Bauman, & Bucci,
1997). If they are ineffective, other anxiolytics can be tried, such as buspirone, venlafaxine,
or mirtazapine. If the mood is unstable (discussed later), patients can become hypomanic
from SSRIs. If this happens (mostly in adolescents and older persons), a mood stabilizer
may need to be added if some benefits were seen with the SSRI.
Anxiety from specific fears and phobias responds partly to anxiolytics, such as SSRIs,
but these often have to be treated with behavioral therapy in addition to the anxiolytics. It
is often helpful to use anxiolytics temporarily to make it easier for the patient to participate
in the behavioral approaches that often themselves provoke anxiety and may initially make
the symptoms worse.
Social anxiety is common in ASD, particularly when the patients’ cognitive function
allows them to realize that they are different from others. They believe that they never say
the right thing and that people avoid them (Bauminger & Kasari, 2000). Sometimes they
stop trying, rarely to the point of selective mutism. Others try to learn how to “pass” and
may be able to participate in superficial conversation. Behavioral and psychotherapeutic
approaches can occasionally be helpful.
OCD in its classical presentation is not common in ASD. It requires having an intrusive
thought that the person realizes is not reasonable and that leads to compulsive behaviors
related to the thought. In our case series of 300 children and adults with ASD, 15 cases were
diagnosed with OCD. Not all are classical, but they share the feature of feeling compelled to
do something that is not enjoyable. For example, one nonverbal boy had to touch everything
that his mother had just touched. He was exhausted by this and was only happy when she sat
quietly and did not touch anything. This behavior did not respond to a variety of anxiolyt-
ics, but one morning when he woke up, the touching behaviors stopped and did not recur.
Usually, OCD is diagnosed in children with sufficiently developed verbal skills to describe
obsessional thoughts. For example, one boy whose father worked in a hospital emergency
room could not be around his father because he feared contamination; he washed his hands
and body many times daily. He also did not respond to any treatments, including electrocon-
vulsive therapy. Studies of repetitive behaviors in ASD, which occasionally meet criteria for
OCD, have not found benefit of SSRIs over placebo, especially in children with ASD.
OCD in ASD is easily confused with insistence on sameness, one of the characteris-
tic features of ASD. It differs from OCD in that the sameness is often related to a broad
range of things in one individual, whereas OCD is usually related to one or two specific
issues. Persons with insistence on sameness want to take the same route, do not want their
belongings touched, and need to order and arrange things in a particular way. However,
it can sometimes be difficult to distinguish the two if the patient has no speech or if the
patient does not obviously enjoy the activities required to keep things the same. The child
may become upset and aggressive if the need is violated. Although it is part and parcel of
ASD, it sometimes improves with low doses of anxiolytics, but it does not disappear.
Another phenomenon that can be difficult to distinguish from OCD is the narrow range
of intense interests—for example, a child who has the intense desire (the patient would call it
a need) for the most recent Thomas the Tank Engine model and asks incessantly, sometimes
resulting in a tantrum, until the model can be purchased. It is tempting for parents to use these
intense interests as rewards for good behavior, but this can worsen the situation over time.
For example, one child liked to collect stuffed animals, and his parents used them as rewards.
Eventually, his whole life became consumed by making lists of stuffed animals that he wished
to purchase. He followed his mother around demanding that she get all the rewards on the list.
He became aggressive toward her when she refused. A behavior plan was developed that even-
tually stopped the behavior. He was no longer rewarded and finally gave it up as a lost cause.
Major depressive disorder (MDD) can also present in the same way as in more neu-
rotypical people. It is not usually chronic, although it can be. There is often a clear onset,
with episodes lasting on average from 1 to 6 months (Simonoff et al., 2012). The patient
develops the three features of MDD: a change in mood, a change in self-attitude, and neu-
rovegetative signs. A low mood that can be observed as a change in affect from generally
cheerful (except when anxious) to downcast and sad is often present. Verbal patients may
say that they are sad but are not always able to label their emotions. Their mood may also
be irritable, and aggression may increase. This can also happen in hypomania; in depres-
sion, they are “irritable and miserable,” and in mania (discussed later), they are “irritable
and confident.” Second, there is a change in self-attitude: Patients who can speak make
statements such as “no one likes me,” “I’m no good,” and “I never do anything right.”
Sometimes these statements seem reasonable, given the patient’s social and academic lim-
itations, but the patient does not usually feel this way. These changes in self-attitude can
become delusional. Also, there can be simple auditory hallucinations, usually heard inside
their head, with a voice telling them that they are bad or making other derogatory remarks.
Sometimes higher functioning adolescents and adults with ASD make suicide attempts
or kill themselves. Drowning is a common cause of death that may sometimes be suicidal
in origin; it is usually thought to be related to an epileptic seizure. Suicidal behavior can
be seen in younger children: One boy put a belt around his neck when he was depressed.
The third and easiest feature of depression to notice, particularly in nonverbal patients,
is the neurovegetative signs of depression: worsened sleep; low energy; and loss of inter-
est in formerly pleasurable activities, such as bowling, going to movies, riding the bus to
the end of the line, or whatever they formerly enjoyed. They will usually still play video
games or other activities that they find relaxing and easy. There may be more hand flap-
ping or other repetitive motor activities. Some children lose their appetite and thus lose
weight. Commonly, they dislike leaving the house, particularly for school. For example,
one nonverbal child refused to get dressed and stayed in bed on school days. Self-injurious
behavior may start or worsen.
Sometimes it is difficult to distinguish depression from anxiety except that depression
tends to be episodic. The mid-night awakenings, tearfulness about doing homework, and
irritability about particularly stressful things can be seen in both. Like MDD in typical peo-
ple, depression can be seasonal; parents may attribute the change in mood to starting a new
school year, leaving for vacation, or returning from vacation. These situations do occur, but
change-related mood/anxiety symptoms do not usually last more than 1 or 2 weeks.
Surprisingly, there have been no double-blind, placebo-controlled trials of medications

for the treatment of MDD in ASD. Thus, standard approaches to treatment of MDD in
children and adults are followed, although smaller initial doses are used because of the fre-
quency of “activation” at more standard doses. Psychiatrists who are experienced in treating
depression in ASD are in agreement that SSRIs can be effective. When treating adolescents
or adults with ASD, it is necessary to be vigilant about causing hypomania because their
moods often become unstable at puberty.
Bipolar disorder can start at any time, as in typical persons, but it usually begins at or
after puberty. The patient may have formerly been anxious or depressed or have ADHD
that responded to antidepressants or stimulants, but at puberty these may stop working.
The patient’s mood becomes very unstable; the patient commonly has short periods of irri-
tability during which she or he may appear to be overconfident or overbearing, followed by
apologies for her or his behavior with tearfulness and remorse. When “irritable and confi-
dent,” patients tell people what to do, act as if they know better, and may talk more, demand
more activities, and sleep less. They may be up during the night, turning on the lights and
the TV. One nonverbal patient in the case series wanted to go for endless rides in the car
and visit malls. These brief high periods are usually followed by an “irritable and miser-
able” mood. This low mood is usually obvious from their affect, and they may cry. Unstable
moods occur equally often in verbal and nonverbal patients. These alterations may not last
long enough to qualify for true bipolar disorder, especially at first, as in typical adolescents.
In order to treat anxiety and depression without worsening the mood swings, it is first
necessary to stabilize the mood. Because aggression is often part of the presentation, people
often treat the unstable mood with risperidone or other atypical antipsychotics. These often
help but have serious long-term side effects. It is usually possible to treat the mood instability
with more traditional mood stabilizers, such as valproic acid or lamotrigine, or other anti-
convulsants that have mood-stabilizing properties. Occasionally, particularly if the bipolar
disorder has a classical presentation, lithium may be the only effective medication. Once the
mood stabilizer is at a therapeutic dose (a blood level of 85 mg/dL or greater with valproic
acid), antidepressants can usually be safely added for any remaining depression or anxiety.
Stimulants can also be used for symptoms of ADHD once the mood is stable.
Occasionally, patients become manic or depressed only once or twice a year for a lim-
ited period of time. Because of the time-limited nature and infrequency of the episodes,
it can take some time to determine if a medication led to the end of the episode or if the
symptomatic improvement was the result of the patient’s natural cycle.
Catatonia has been well described in ASD (Dhossche, Reti, & Wachtel, 2009; Dhossche,
Wing, Ohta, & Neumarker, 2006; Kakooza-Mwesige, Wachtel, & Dhossche, 2008). If it
occurs, it usually starts at or after adolescence. One adolescent patient began to follow his
father around the house, copying all his motor movements. Next, he started to have trouble
picking up a fork or food and became increasingly more stiff. Finally, he could not open his
jaw, and he was hospitalized in order to have a nasogastric tube placed. He was treated with
antipsychotics and got slightly better, but he continued to have trouble eating: He would
pick up the fork and set it down several times. The catatonia, as yet undiagnosed, recurred
again exactly 1 year later. After beginning and then increasing lorazepam to 8 mg/day, his
symptoms resolved. Later, he became manic, and a mood stabilizer was added. The catato-
nia has not recurred; he remains on both medications.
Schizophrenia following an initial presentation of ASD has been well documented in
case series ascertained for childhood-onset schizophrenia (Rapoport, Chavez, Greenstein,
Addington, & Gogtay, 2009). Approximately one-fourth of the cases meet criteria for ASD
in early life before the onset of hallucinations and delusions that characterize early onset
schizophrenia. In the authors’ clinical series of 300 patients with ASD, two such cases were
observed. Both boys had marked delusions and hallucinations that began in adolescence
and were not associated with depression or mania. One responded to aripiprazole, but the
other responded only to clozapine.
Usually when an adolescent or adult with ASD has auditory hallucinations, it is in the
context of MDD and there is one voice, usually heard inside the head, making deprecating
comments such as “You’re no good” or “Just kill yourself.”
Sometimes it can be difficult to determine when an apparent voice or vision is part of a
psychiatric illness or just the vivid re-experiencing of a video or movie. This sort of “eidetic
imagery” that is seen in small children often persists in ASD well into adult life. If the person
has no features of depression or schizophrenia, it may not need to be treated. Parents some-
times say, “He’s playing his tape.” Sometimes the patient can tell you what he or she is viewing.
ABNORMAL BEHAVIORS ASSOCIATED WITH AUTISM SPECTRUM DISORDER
Abnormally intense interests are common in ASD. The interests are of many types—for
example, dinosaurs or other prehistoric animals, radiators, key rings, various action figures,
fancy sneakers, music, and occasionally firearms. The more able patients may become real
experts in their area of interest. Sometimes the interest can lead to thievery: For example,
one boy took key rings from the cabinets in parking lots or valet parking desks. Usually, the
interest leads to relentless pursuit of the parents until the next new thing can be purchased.
Sometimes a very strong interest can lead to difficulties in convincing high-functioning
adults with ASD to get a job. For example, one young man who had always been interested
in sports statistics would only consider a job as a sportscaster. An interest in firearms can
be dangerous. Adolescents may become interested in the technical workings of guns and
hang around gun shops, where dangerous contacts can be made. One adolescent said that
he wanted to join the army so he could shoot people. The interest in weapons is particularly
dangerous if the patient is also depressed and isolated because it can lead to either mur-
der or suicide. Such patients need to be closely monitored, and their parents must be sure
they take their medications, even over the adolescents’ objections. Obviously, guns must be
removed from the house rather than encouraging the interest.
Insistence on sameness can also cause problems. Children often have meltdowns
when their computer does not work, someone moves one of their possessions, or parents
are unable to take the same route or follow some detail of the usual daily routine. One
patient insisted that everyone leave the house on school days in the same order and wear-
ing the same coat, taken in order from the same rack. An adult who lived in a nursing home
hoarded plastic. An occupational therapist developed a therapeutic relationship with him
so that together they cleared out most of the plastic from his room once a month. One day,
she made a tiny, seemingly trivial, change in the monthly routine and he became aggressive
toward her. Most people with ASD and problematic insistence on sameness are extremely
anxious and benefit from either behavioral or pharmacological treatment.
Abnormal eating behavior is very common in persons with ASD, rarely leading to mal-
nutrition. Mostly, they eat a very narrow range of foods of a particular type, texture, or color.
Rarely do they eat fruits or vegetables. The Repetitive Behavior Scale–Revised (RBS-R)
(Bodfish, Symons, Parker, & Lewis, 2000) and the Brief Autism Mealtime Behavior
Inventory (BAMBI), an eating abnormality scale developed for ASD (Lukens & Linscheid,
2008), were completed by the parents of patients in the case series. The severity of abnor-
mal eating behavior was related to several of the subscales of the RBS-R, including rituals
and insistence on sameness (Almeida & Folstein, 2012).
Social naïveté is nearly universal and can lead patients into dangerous situations.
Children and particularly adolescents who want to have “regular friends” will do almost
anything to be allowed to hang out with them (Bauminger & Kasari, 2000). This makes
them easy targets for bullying and teasing. The bullying involves anything from taking their
lunch money to asking them to do the bully’s math homework and getting them to approach
a girl and kiss her or pull up her dress. The boys (and sometimes girls) get a laugh and the
child with ASD gets into trouble. Adolescents with ASD may try very hard to “be a regular
kid,” usually, but not always, without much success. One boy assiduously studied how to
talk to girls and have conversations on acceptable topics. Some adolescent boys with ASD
approach and kiss girls, as they see other boys doing with their girlfriends between classes.
This kind of behavior may be tolerated at first by kindhearted adolescent girls, knowing that
the boys have ASD, but this sometimes means to the boys with ASD that the girls want a
romantic relationship. They may start calling and texting, sometimes with persistence that
is interpreted as stalking. These kinds of social behaviors are difficult to stop, and it may be
necessary to remove these adolescents from regular public schools.
Inappropriate sexual behavior is often related to social naïveté. For example, two female
adolescent patients’ parents allowed them—on just one occasion—to stay home alone.
Both immediately texted a boy to come over; both had unprotected sexual intercourse. It is
usually necessary to disallow the use of cell phones and access to social media. The adoles-
cents view this as very unfair, but when given access, they often make unwise choices and
can get into dangerous relationships.
Pornography and masturbation are often seen in adolescent boys, and this is equally
true of boys with ASD. Masturbation is usually not a problem, and the boy quickly learns
that it must be done in private. A few boys, most with marked intellectual disability, con-
tinue to masturbate in inappropriate places or try to involve any female who is easily avail-
able, including their mother or schoolmates. If it becomes problematical such that the boy
is excluded from school, or parents believe that they can no longer care for the adolescent at
home, hormonal treatments should be considered. Sometimes sexual aggression is related
to manic episodes, but often it is independent of them.
Pornography sometimes becomes problematical if the teen spends so much time on it
that it interferes with other functions. Sometimes parents object not to the pornography
but to the types of sites visited that show unusual (or illegal) kinds of sexual behavior. This
requires very close supervision, and often it is necessary to block these types of sites.
A rigid sense of right and wrong can cause difficulties, although it is not usually dan-
gerous. One patient was called “the enforcer” at his school because he expected perfect
behavior not only from himself but also from his classmates. Sometimes, children become
very upset because they see something as unjust. One boy asked to sharpen his pencil after
class had started. Because other children had sharpened theirs before the class began, he
thought it was not fair that he could not sharpen his pencil. He had such a meltdown over
this that his mother had to take him home from school. Another young man worked for a
landscape company. The company had two contracts for apartments that were across the
street from each other. The company lost the contract for one of them, but the young man,
soon after being diagnosed for the first time with Asperger’s disorder, kept trimming hedges
for both properties. After repeatedly telling him to stop this, his boss fired him. The young
man harassed and threatened his former boss for unfair treatment until the man called the
police. Once the police came, he stopped the behavior.
Self-injurious behavior can be extremely severe, mainly in persons with ASD and mod-
erate or severe intellectual disability, although it can be seen in persons with normal IQ. The
most common types are wrist and arm biting, head banging, and skin picking. They often
result in scars from bites on the thenar eminence and wrist and in calluses on the chosen
area of the skull. Others pick at their skin until it bleeds. They may get infections, including
methicillin-resistant Staphylococcus aureus. Usually, this is related to overwhelming anxiety.
It can get worse during a depressive episode.
WHEN NOTHING WORKS
Some patients seem to have atypical responses to virtually every medication. Occasional
reports of unusual reactions can be related to parental anxiety about using medications
so that they interpret random events as side effects. Once this is ruled out, the only
recourse is trial and error. Obviously, as stressed throughout, the first step is to take a
careful history and make the most likely psychiatric diagnosis. Based on that, a class of
medication is chosen, starting with a low dose. However, some patients have marked
side effects even at low doses or have idiosyncratic responses to many different classes
of medication. Sometimes a medication has an unexpected positive effect: One girl
stopped daytime enuresis when a stimulant was started for her ADHD. Another prob-
lem can be the home environment: People with ASD do not do well in noisy environ-
ments with high levels of expressed emotion. They need quiet and routine, which can
sometimes be impossible to provide at home.
When aggression, sexual or physical, is severe or if the anxiety or OCD is overwhelming,
patients often do better in a residential setting. In a residence, the routine is unvarying: There
are very few unexpected events, and there is often less noise and confusion. Also, medication
trials can be more systematic: All the doses are given, and the effects are more reliably reported.
When patients who have been doing well suddenly get worse, a medical illness should
be considered first. Some persons with ASD seem not to feel or recognize pain so that cel-
lulitis, otitis media, appendicitis, and even a broken bone can go undetected. An adolescent
who liked running suddenly became irritable and uncooperative. It was eventually discov-
ered that he had broken his ankle. After it was set, he remained upset but denied he was in
pain. After starting regular pain medication, his behavior returned to baseline.
SUMMARY
Persons with ASD suffer from a variety of psychiatric disorders and abnormal associated
behaviors. These interfere greatly with optimal functioning and should be diagnosed and
treated. Diagnosis is fundamentally the same as for psychiatric disorders in persons without
ASD, but it focuses more on history often provided by the parents and on observable mani-
festations of the conditions. Aggression is a prominent but nonspecific feature of many of
the conditions, so diagnosis and treatment should be focused on more specific clinical fea-
tures of each disorder.
KEY POINTS
• Individuals with neurodevelopmental disorders have a higher frequency of emo-
tional and behavioral disorders than neurotypical individuals.
• The estimates of the prevalence of psychiatric comorbidity in individuals with neuro-
developmental disorders vary, but these diagnoses probably occur in the majority of
persons with ASD.
• The diagnosis of psychiatric disorders in persons with ASD may rely more on the
history provided by the parents and on observable manifestations of the condition
compared with that of neurotypical individuals.
• It may be difficult for patients with ASD to describe their internal feeling state (mood)
either because they are minimally to nonverbal or because they have little insight into
their mood.
• When patients whose neuropsychiatric symptoms have been stable for some time
suddenly worsen, the onset of a medical illness must be considered first.
Dr. Susan E. Folstein and Dr. Luis Carcache have nothing to disclose.
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/ / /
7 / / / NEUROLOGICAL
COMORBIDITIES IN AUTISM
SPECTRUM DISORDER
FIONA BAUMER AND MUSTAFA SAHIN
INTRODUCTION
Clinicians have noted that, in addition to the core criteria of social and communication
deficits and repetitive behaviors, children with autism spectrum disorder (ASD) also have
a very high prevalence of other neurologic problems, including epilepsy, sleep disturbances,
and motor disorders. These observations have raised interesting questions about the patho-
physiology of ASD and are also of clinical importance to practitioners caring for these
patients.
Those writing about neurologic deficits in ASD consistently raise the following three
questions:
1. Do these neurologic problems directly cause the ASD phenotype? For example, do
seizures or interictal discharges seen on electroencephalogram (EEG) lead to ASD
symptoms?
2. Do the core features of ASD cause other neurologic problems? For example, do fre-
quent stereotypies explain sleep disturbances?
3. Is there a common anatomic or biochemical process that gives rise to both the ASD
phenotype and these other neurologic problems? If so, can these other problems be
helpful in understanding the anatomy and pathophysiology of ASD?
Considering the neurologic comorbidities of ASD is clinically relevant for two important
reasons. First, because patients with ASD have a high prevalence of these problems, it is
important for clinicians to screen for them because they independently affect health and
quality of life. Second, given that there may be significant interactions between these prob-
lems and the ASD phenotype, it is possible that addressing these issues will alleviate some
of the symptoms of ASD.
99
100 / / B ac kground an d Dia g nostic A ssessment
EPILEPSY
Definitions
• Seizures: Excessive synchronized electrical discharges that occur in the brain, last for
a certain duration, and evolve over space and/or time. Seizures may or may not have
an obvious outward manifestation.
• Interictal epileptiform discharges: Abnormal electrical activity in the brain that
does not meet all the spatial or temporal criteria of a seizure.
• Epilepsy: A condition of repetitive, unprovoked seizures (i.e., not brought on by
illness or substance use). Epilepsy affects approximately 1% or 2% of the general
population.
• Electroencephalogram (EEG): A test that measures electrical activity in the brain
and therefore can assess for seizures and interictal epileptiform discharges.
CASE STUDY #1: “SARA”
Sara is a girl with a diagnosis of ASD who presented to the emergency room at 3 years of
age after a 5-minute episode of right eye and head deviation, drooling from the right side
of her mouth, and decreased use of her right arm. After sleeping for 3 hours, Sara woke
up and was back to her normal self with no focal findings on neurologic examination, so
she was discharged home for outpatient workup. She had brain magnetic resonance imag-
ing (MRI) that was normal and an EEG that demonstrated frequent generalized spike and
waves activated in sleep. Given the concerning clinical event and abnormal EEG, Sara was
started on levetiracetam. Two months after initiation of levetiracetam, Sara underwent a
repeat EEG that continued to show multifocal spikes potentiated by sleep. There was a
discussion about whether or not to increase the medication due to these abnormalities on
EEG, but it was decided that this would not be helpful. Sara had developed increased irri-
tability and violent outbursts after starting the medication, so vitamin B6 was added empiri-
cally to try to improve the irritability with some effect.
Two years later, Sara developed new episodes of staring straight ahead, during which
she was unresponsive to verbal and tactile stimuli. These occurred several times a day
and did not improve after empiric increases in the levetiracetam dose. An ambulatory EEG
was obtained that captured 10 such staring spells. This EEG was notable for persistence
of the multifocal spikes seen previously, but there was no change in the EEG during the
staring episodes, suggesting that these were unlikely to be seizures. Sara then developed
additional episodes of right eye deviation and right facial twitching that continued despite
maximization of the dose of levetiracetam, so the decision was made to add lamotrigine to
the regimen.
Demographics
Many children with ASD go on to develop seizures during childhood, with reported
prevalence rates usually cited as 30% but varying substantially among studies (5–50%)
Neurological Comorbidities in Autism Spectrum Disorder // 101
(Maski, Jeste, & Spence, 2011). Part of this variation may be attributed to sampling tech-
niques because population-based studies find substantially lower rates of comorbid epi-
lepsy than do clinic-based ones. In addition, there are two peaks of seizure onset in this
population—the first in early childhood and the second in adolescence—so some of the
variability in reported prevalence may be related to the age of the population sampled.
Given the wide range in reported prevalence, researchers have evaluated other risk factors
that modulate the risk of epilepsy in ASD. The prevalence of seizure disorders certainly is
highest for children with ASD and intellectual disability, approaching 21.5%, but even chil-
dren with normal intelligence have an approximately 8% risk of developing epilepsy; this is
substantially higher than the general population risk of 1% or 2%. Patients with ASD and
known genetic conditions are also more likely to have epilepsy. For example, patients with
tuberous sclerosis complex have approximately a 50% chance of developing ASD and up to
a 90% lifetime risk of epilepsy. Children with “idiopathic” ASD without clear genetic vari-
ants or structural lesions, however, are still at an elevated risk of epilepsy approaching 15%
(range, 13–17%). Several studies suggest that epilepsy may be more common in females
with ASD than in males, but these reports were confounded by the fact that the females had
lower IQs and more genetic abnormalities (Spence & Schneider, 2009).
Interictal Discharges
As EEGs have been performed more frequently in patients with ASD, another question that
has arisen is the importance of interictal epileptiform discharges without seizures. These
discharges have been reported in approximately 6–30% but up to 60% of children with
ASD. Estimates are likely skewed because so far all studies have been performed on subjects
from referred clinic samples who received an EEG because there was at least some suspicion
of seizures. Therefore, population-based studies of all-comers with ASD would be required
to better refine this estimate. A recent retrospective longitudinal study compared children
with ASD without any EEG abnormalities, with isolated interictal epileptiform discharges,
and with known epilepsy and interictal discharges. The study found that isolated discharges
were more prevalent in younger children, and epilepsy was more prevalent as age increased;
by early adulthood, the frequency of isolated discharges had decreased significantly. This
does suggest that, much as with normally developing children, the interictal discharges may
be a marker indicating a high risk for developing epilepsy (Parmeggiani et al., 2010).
Infantile Spasms
Infantile spasms are a type of brief tonic seizures that develop in the first year of life. In many
cases, EEG shows not only the seizures but also a very abnormal background pattern in
between seizures, which in its most severe form is called hypsarrhythmia. Infantile spasms
have been highly associated with poor cognitive outcomes, including intellectual disability
and ASD. One population study found that 35% of children with infantile spasms went
on to develop ASD, with the vast majority of these children also showing profound intel-
lectual disability (Saemundsen, Ludvigsson, & Rafnsson, 2007). Because infantile spasms
are detected in the first year of life and ASD is not usually detected until the second or
third year, there has been some question as to whether infantile spasms are more associ-
ated than other early onset seizures with a later diagnosis of ASD. To address this ques-
tion, Saemundsen, Ludvigsson, and Rafnsson (2008) used a retrospective cohort study of
children with infantile spasms versus other types of seizures that developed before the age
of 1 year. They concluded that children with any seizure type with an obvious underly-
ing cause—such as a brain malformation, metabolic disorder, or genetic syndrome—had
a higher risk of going on to develop ASD than those previously healthy, normally develop-
ing children with “cryptogenic seizures.” In general, an underlying etiology of epilepsy was
more likely to be found in those with infantile spasms. Therefore, all children with seizures
early in life, including those with infantile spasms, should be monitored closely for the
development of ASD.
Consequences
As in any other patient, seizures in those with ASD are concerning because they can have
significant health consequences and can be very socially disruptive as well. Adults with ASD
and epilepsy tend to be severely disabled with very poor social functioning (Danielsson,
Gillberg, Billstedt, Gillberg, & Olsson, 2005). In addition, young adults with ASD have
a much higher mortality rate than the general population, and many of these deaths are
attributed to epilepsy (Gillberg, Billstedt, Sundh, & Gillberg, 2010). Epilepsy-related
deaths can be associated with cardiorespiratory compromise during a seizure or due to
unexplained cardiorespiratory failure after a seizure—a problem known as sudden unex-
pected death in epilepsy (SUDEP). SUDEP is more likely in those with poorly controlled
seizures (Tomson, Walczak, Sillanpaa, & Sander, 2005), which is a problem for many indi-
viduals with ASD.
Isolated epileptiform discharges have been of particular interest because the question has
been raised as to whether these discharges cause autistic symptoms in some patients. This
question first stemmed from the observation that epileptic encephalopathies—disorders
in which seizures or persistent abnormal interictal discharges are thought to directly affect
cognition—can cause regression in language skills. The most prominent example of this
is Landau–Kleffner syndrome, in which healthy children have loss of language in the set-
ting of an EEG pattern know as electrical status epilepticus of sleep (ESES) (Trevathan,
2004); see Figure 7.1 for an example of this EEG pattern. Approximately 30% of children
with ASD have a pattern of “autistic regression” that includes seemingly normal develop-
ment until approximately 2 years of age, after which they lose the language and social skills
they had previously acquired. Researchers have hypothesized that, like language regres-
sion in Landau–Kleffner syndrome, autistic regression could also be a result of an epileptic
encephalopathy. Several studies have found an association between autistic regression and
interictal discharges on EEG, but the data in this field are conflicting (Chez et al., 2006;
Kim, Donnelly, Tournay, Book, & Filipek, 2006; Tuchman, Alessandri, & Cuccaro, 2010;
Tuchman & Rapin, 2002).
Evaluation
Patients with ASD are at risk for any type of seizures but most frequently have complex
partial seizures. Because this seizure type often manifests as alteration in consciousness
and unusual focal movements, it can be difficult to differentiate seizures from other behav-
iors seen in ASD. This can be challenging for the clinician because there is risk of both
over- and underreporting of seizures by caretakers. Therefore, it is recommended that
EEGs be obtained for any behavior that is clinically suspicious for seizures (Maski et al.,
FIGURE 7.1 EEG recording of electrical status epilepticus of sleep (ESES). ESES is an EEG pattern of generalized (occurring in all leads) and frequent par-
oxysmal discharges or spikes that are present in greater than 85% of slow wave sleep. This pattern is often associated with developmental regression.
Source: Image courtesy of Dr. Jeffrey Bolton, Boston Children’s Hospital, Boston.
2011). Ideally, an EEG should be an overnight study because there can be many epilep-
tiform abnormalities brought out only in sleep. For any patient found to have seizures, a
thorough workup for known genetic or metabolic etiologies of ASD (i.e., tuberous sclerosis
complex, Rett’s disorder, 15q11–13 duplication, MECP2 duplication, Phelan–McDermid
syndrome, and metabolic disorders) should be undertaken. At this point, although there is
not clear evidence that interictal discharges can cause autistic regression, an EEG should
also be considered in patients with ASD and an abrupt decline in language, social, or cogni-
tive functioning (Kagan-Kushnir, Roberts, & Snead, 2005; Tuchman, Hirtz, & Mamounas,
2013; Tuchman & Rapin, 2002).
Treatment
Although treatment for epilepsy in patients with ASD will be specific to the patient and
the characteristics of his or her seizure disorder, there are some potential issues that
should be considered in advance. First, several antiepileptic drugs, especially levetirace-
tam and certain benzodiazepines, can cause worsening of behavioral problems. This
should be kept in mind when selecting appropriate treatment for seizures in patients with
ASD. A second issue is that those with ASD and epilepsy are much more likely to have
seizures that are refractory to treatment. In a study of patients referred to an epilepsy
clinic with idiopathic ASD (specifically, no genetic or infectious cause and no tuberous
sclerosis or history of infantile spasms), approximately one-third had treatment refrac-
tory epilepsy defined as failure to respond to two adequate trials of antiepileptic drugs.
Those with a younger age of onset of seizures were more likely to have severe, difficult-to-
treat epilepsy (Sansa et al., 2011). Often, some seizures are tolerated in patients with
ASD and treatment refractory epilepsy if the seizures do not interfere with the patient’s
functioning and further treatment is limited by medication side effects. It should be kept
in mind, however, that untreated seizures increase the risk of morbidity in patients with
ASD (Danielsson et al., 2005).
Treatment of patients with isolated epileptiform discharges but without clear seizures
must be undertaken only with extreme care because it is still unclear if this will benefit the
patient. If it is believed that the onset of these discharges correlates well with a marked
change in the patient’s cognitive, language, or social functioning, a short and closely
observed course of treatment can be considered. Treatment options have included medica-
tions used to treat epileptic encephalopathies such as steroids or benzodiazepines, as well
as antiepileptic medications known to decrease spikes, such as valproate. If pharmacologic
therapy is undertaken, it is critical that clinicians establish whether there is improvement
in symptoms and correlate this with an improvement in the background EEG (Tuchman
et al., 2010).
Basic Science
Given the significant comorbidity between ASD, epilepsy, and intellectual disability, much
research has focused on whether or not there is a causal relationship between these condi-
tions or instead if there is an underlying pathology that has the potential to cause them
all. All three disorders are considered distributed processes that affect multiple neural net-
works. Therefore, the primary hypothesis currently under investigation is that abnormal
synaptic plasticity early in life gives rise to neural networks that can cause epilepsy and
ASD, as well as other neurologic phenotypes. On a structural level, this hypothesis has been
supported by neuropathologic examination of brains of patients with ASD that found evi-
dence of cellular disorganization—including heterotopias, dysplasias, and abnormalities in
neurogenesis and neuronal migration—similar to that seen in patients with epilepsy even
though only one-third of the subjects with ASD in this group had seizures (Wegiel et al.,
2010). Currently, most research in this field is directed at genetic studies of copy number
variants (CNVs). CNVs are genetic deletions, duplications, and insertions in the genome,
and several CNVs in genes associated with synaptic plasticity have been identified in sub-
jects with both idiopathic epilepsy and ASD. In large genetic studies, several CNVs emerge,
including duplications of chromosome 15q11–13, duplications and deletions of 16p11,
and deletions of 22q11–13. Each of these is believed to be responsible for approximately
0.5–1% of sporadic cases of ASD. It is now estimated that an additional 10% of sporadic
cases of ASD are caused by rare but identifiable CNVs; therefore, there is significant inter-
est in identifying rare CNVs that lead to phenotypes of ASD and/or epilepsy (Geschwind,
2009; Tuchman & Cuccaro, 2011).
SLEEP DISORDERS
Definitions
• Insomnia: Difficulty initiating or maintaining sleep.
• Sleep efficiency: Percentage of time in bed that is spent sleeping.
• Sleep latency: Time to fall asleep after getting in bed.
• Actigraphy: A clinical test in which a small wristwatch-like device is worn and mea-
sures movement. It can be used to assess activity overnight and infer time spent
asleep.
• Polysomnography: A multifaceted study that utilizes EEG, electrocardiogram, and
respiratory monitoring to specifically assess a person’s sleep, including the frequency
and duration of different sleep stages, as well as respiratory problems that emerge
during sleep.
CASE STUDY #1—CONTINUED
In addition to the seizures, Sara has had significant difficulty with sleep throughout her life.
Starting at 2 years of age, Sara began to have temper tantrums at bedtime, during which
she would jump and scream by the front door until her parents would take her for a ride in
the car. While riding in the car, she was able to fall asleep and maintain sleep throughout
the night. These behaviors eventually improved when the family stopped taking her on rides
and implemented a more consistent bedtime routine.
Approximately 2 years later, Sara developed two new sleep problems—trouble falling
asleep and inability to sleep through the night. Although she continued with the same bed-
time routine, Sara would now remain awake for 60–90 minutes after being put to bed. Her
neurologist prescribed melatonin to be given 1 hour before bedtime, and there was some
improvement after the dose was up-titrated to 5 mg. The family also observed that Sara’s
trouble falling asleep was worse in the spring and fall when she had allergy symptoms, and
her sleep latency improved after being started on an antihistamine medication during these
seasons.
More concerning to the family, Sara began waking up at 3 am with agitated, destructive
behavior. Fortuitously, one such nocturnal awakening occurred when she was undergoing
her ambulatory EEG, and there was no seizure activity seen. Because her sleep seemed
so disturbed immediately before these awakenings, there was concern for restless leg
syndrome and a ferritin level was checked, which was 30 ng/mL. Consequently, a 4-month
course of ferrous sulfate was started and continued until the ferritin level increased to
greater than 50 ng/mL; on repeat testing 1 month after discontinuation of ferrous sulfate,
the ferritin level remained at this level. With this intervention, Sara seemed to have fewer
nighttime awakenings.
Demographics
Sleep disorders are quite common in all children but are particularly prevalent in
those with ASD, even compared to patients with other developmental disorders.
Based on parental surveys, it is estimated that 50–80% of children with ASD com-
pared with approximately 10–50% of typically developing children have significant
trouble sleeping. Studies relying on parental reports and actigraphy have consistently
found that children with ASD have prolonged sleep latency, disrupted sleep, and early
morning awakenings (Malow, 2004). Several studies have also used polysomnogra-
phy to describe specific alterations in sleep architecture in patients with ASD. This
research found abnormalities in, as well as a decreased amount of, rapid eye move-
ment (REM) sleep in these patients compared with both typically developing children
and IQ-matched subjects with other developmental disorders (Buckley et al., 2010;
Diomedi et al., 1999; Elia et al., 2000). One group also reported subtle differences in
non-REM sleep (Miano et al., 2007).
Sleep problems persist across the lifespan in patients with ASD, but the specific causes
and consequences of insomnia change as children age. A survey study of 1859 patients
with ASD showed that younger children demonstrated symptoms of a behavioral insom-
nia syndrome, consisting of more nighttime anxiety and bedtime resistance. They also had
poor sleep efficiency secondary to nocturnal awakenings and parasomnias, such as sleep-
walking (Kotagal & Broomall, 2012). Some of the core and associated features of ASD,
including perseverative thoughts and actions and poor emotional regulation, contribute
to the behavioral insomnia syndrome (Maski et al., 2011). Adolescents often manifest
symptoms of circadian rhythm sleep disturbances, including a delayed sleep phase and
prolonged sleep latency, leading to chronic sleep deprivation and daytime sleepiness
(Goldman, Richdale, Clemons, & Malow, 2012). Research has suggested that distur-
bances in melatonin physiology contribute to these sleep disorders in ASD (Rossignol
& Frye, 2011). In addition to insomnia, other prevalent sleep disorders in ASD include
REM sleep behavior disorder that presents as aggressive or violent dream reenactment;
disorders of excessive normal movements such as restless leg syndrome; and sleep prob-
lems related to other medical comorbidities, such as gastrointestinal discomfort and poor
vision (Kotagal & Broomall, 2012). As in much of the typically developing population,
respiratory disorders such as obstructive sleep apnea are also common, especially among
obese patients.
Significance
Adequate sleep is important for memory consolidation and appropriate modulation of

response to emotional stimuli, so it is therefore not surprising that the severity of disor-
dered sleep directly correlates with symptoms of cognitive dysfunction and emotional
dysregulation in children with ASD (Kotagal & Broomall, 2012). Sleep researchers theo-
rize that REM sleep in particular is important in learning because it tends to increase after
intensive educational sessions; thus, a decreased amount in ASD may cause problems
in processing new information and consolidating memories (Buckley et al., 2010). In
addition, there is a relevant feedback loop that develops due to poor sleep in children
with ASD: Sleep deprivation leads to emotional lability and difficulty with cognitive
processing that leads to bedtime resistance and perhaps worsening stereotypies or dis-
ruptive thoughts, which in turn leads to sleep deprivation. Interestingly, supporting the
observation that sleep problems can precipitate or worsen autistic features, one study
found that children with autistic regression were more likely than children with ASD
without regression to have disordered sleep (Giannotti, Cortesi, Cerquiglini, Vagnoni, &
Valente, 2011).
Evaluation
Given the prevalence of sleep disorders in patients with ASD, experts recommend that both
primary physicians and specialists who work with patients with ASD screen for insomnia.
This can be done with simple targeted questions such as those found on the Children’s
Sleep Habits Questionnaire (CSHQ) (Box 7.1), a tool that is applicable for children ages
4–10 years old. Specifically, questions about patterns of activity surrounding bedtime can
help uncover behavioral insomnias, whereas exploring sleep patterns such as a consistently
delayed bedtime can suggest circadian rhythm disorders. In addition, effects of sleep dis-
orders, including daytime sleepiness or poor attention, should be assessed. The clinician
should remember that sometimes sleep problems will manifest as other behavioral com-
plaints, and he or she should inquire about sleep whenever there is a parental concern for
irritability, aggression, or emotional lability (Malow et al., 2012).
BOX 7.1
CHILDREN’S SLEEP HABITS QUESTIONNAIRE (CSHQ)
SCREEN FOR INSOMNIA
1. Does your child fall asleep within 20 minutes after going to bed?
2. Does your child fall asleep in the parents’ or sibling’s bed?
3. Does your child sleep too little?
4. Does your child awaken once during the night?
5. Do you think these behaviors are a problem?
Experts from the Sleep Committee of the Autism Treatment Network (ATN) agreed
on these five screening questions based on their experience and review of the ATN
database (N = 4887). The CSHQ is a 45-question tool.
If the family does endorse symptoms of insomnia, then the patient should be screened
with a standard review of systems for medical problems that could contribute to disrupted
sleep, including epilepsy, pain, gastrointestinal problems, nutritional deficiencies, obesity,
and psychiatric conditions. Lastly, medications should be reviewed because many can
affect sleep, and psychotropic medications such as selective serotonin reuptake inhibitors
(SSRIs) and stimulants used to treat the behavioral problems often seen in ASD are fre-
quent offenders. In addition, the clinician should evaluate for respiratory disorders of sleep,
such as obstructive sleep apnea, and movement disorders, such as restless leg syndrome.
Clinicians should have a low threshold to check a ferritin level if there is any suspicion of
disrupted sleep or nighttime awakenings because low iron stores can contribute to restless
leg syndrome and these movements often respond well to iron supplementation. If either
respiratory problems or nocturnal seizures are suspected, the patient should be referred to
a sleep specialist for consideration of polysomnography. Other reasons for referral to a sleep
specialist include severe insomnia that is threatening the patient’s safety due to daytime
sleepiness or insomnia that does not respond to the behavioral and initial pharmacologic
treatments described later (Malow et al., 2012; Maski et al., 2011). Children with ASD may
have more difficulty than most completing a polysomnography because the test requires
sleeping in a new environment with significant monitoring. Overall, working with a sleep
specialist in a pediatric hospital may be helpful given the familiarity of the staff with work-
ing with children with behavioral disorders.
Treatment
The initial treatment for insomnia in all children includes behavioral interventions that
reinforce good sleep hygiene and addressing other medical issues that may be contributing
to poor sleep. Establishing a bedtime routine may be more difficult in those with ASD due
to their trouble with emotional regulation and transitions, as well as confusion about paren-
tal expectations caused by deficits in language. Conversely, some children do well when
given a routine due to their preference for consistency. Behavioral modifications, including
behavioral extinction and positive reinforcement, may encourage more appropriate sleep
patterns as well (Malow et al., 2012).
Many children with ASD eventually do require pharmacologic therapy to manage
insomnia. Melatonin clearly has the most evidence in pediatric insomnia, and there are now
studies that suggest that deficits in the melatonin pathway may contribute to sleep disor-
ders in patients with ASD specifically (Rossignol & Frye, 2011). To date, the only drug for
sleep disorders in patients with ASD to be studied in a blinded, placebo-controlled manner
is melatonin. After a trial of melatonin, other pharmacologic agents can be offered based
on the clinician’s assessment and comfort level. Clonidine is frequently tried, although tol-
erance often develops and results in a reduced duration of action (Malow, 2004). If the
patient has medical or psychiatric problems that require pharmacologic treatment, a drug
that secondarily promotes sleep can be preferentially chosen. For patients with ferritin lev-
els less than 50 ng/mL, supplementation with ferrous sulfate can be considered, although
response should be monitored every 3 months to prevent iron toxicity; families should also
be counseled ahead of time on the management of the gastrointestinal upset and constipa-
tion often seen with iron supplementation (Kotagal, 2012). Otherwise, referral to a pediat-
ric sleep specialist can be considered. Regardless of the intervention, it is important that the
patient be followed closely to assess the impact of the therapy on quality of sleep (Malow
et al., 2012).
Basic Science
Researchers are currently exploring the physiologic basis of why people with ASD are at
such high risk for developing sleep disturbances. In their review on sleep in ASD, Kotagal
and Broomall (2012) summarize several such studies and particularly highlight papers
examining the imbalance between inhibitory and excitatory neural activity. In general, glu-
tamate is thought to be an excitatory neurotransmitter and γ-aminobutyric acid (GABA)
an inhibitory one. Pathology studies have shown a decreased concentration of GABAB
receptors in the cingulate and fusiform cortex in postmortem brain samples of patients with
ASD. There has been parallel research suggesting that a decrease in GABA activity in the
cingulate cortex is also present in primary insomnia. In addition, certain genetic mutations
found in ASD—particularly those affecting synaptic proteins in the neurexin and neuroli-
gin families—affect whether synapses will be glutamatergic or GABAergic and thus can tip
the brain toward an excitatory state, contributing to difficulty in sleep maintenance. Finally,
melatonin is important in the establishment of the GABA system in neurons, and mul-
tiple studies have demonstrated a decreased concentration of melatonin in patients with
ASD. There is increasing evidence that an excess of excitation compared to inhibition in
the brains of children with ASD is correlated with clinical problems such as sleep disorders
or even epilepsy, although additional research is required to determine if this imbalance is
truly causative. Furthermore, deeper understanding of the excitation/inhibition imbalance
in the brain will be required to devise new therapeutic option.
MOTOR DISORDERS
Definitions
• Motor delay: Failure to meet expected gross motor milestones (independently sit-
ting, walking, jumping, etc.) and fine motor milestones (developing a raking and then
pincer grasp, manipulating objects, etc.) at the expected time.
• Hypotonia: Reduced resistance during passive movement of muscles, leading to
postural instability or increased joint mobility.
• Dyspraxia or apraxia: Impairment in the ability to carry out skilled movements or
gestures, despite having the desire and physical ability to perform them. Dyspraxia
can affect many movements, including oral movements associated with speech, feed-
ing, or management of secretions; hand movements such as those needed to manipu-
late tools or to write; and leg movements needed for a normal gait. Ideomotor apraxia
is difficulty recognizing skilled gestures performed by others.
• Stereotypies: Repetitive, seemingly purposeless movements that can involve multi-
ple body parts. They constitute a core diagnostic criterion in ASD and were tradition-
ally thought to be self-stimulatory behavior, although that notion is now changing.
CASE STUDY #2: “CRAIG”
Craig is an 8-year-old boy with a history of nonverbal ASD who had multiple repetitive behav-
iors. Since he was much younger, he has had frequent episodes of hand waving and hand
biting that occur more often when he is sleep deprived or in unusual or stressful situations.
As he has gotten older, these movements have begun to interfere with his participation
at school and have become more difficult to redirect. Currently, Craig has started to wake
in the middle of the night and perform these behaviors, making it more difficult for him to
fall back asleep. In addition, although Craig has been noted to walk on his tiptoes since he
began walking at 13 months of age, he has more recently had more trouble with balance
both at home and at school, with occasional falls. This was initially thought to be secondary
to an infection and then to the clonidine that was started to improve his sleep, but the inco-
ordination persisted even after the infection resolved and the medication was withdrawn.
Demographics
Repetitive behaviors are one of the core symptoms of ASD, and it has been increasingly
recognized that a high percentage of people with this disorder (60–80%) have other defi-
cits in motor skills. Of those with a genetic cause for their ASD, approximately 90% have
motor delays (Geschwind, 2009). Compared with the literature investigating seizures and
sleep disturbances in ASD, however, the research on motor problems to date has arrived
at less cohesive conclusions. Overall, the work suggests that problems with movement in
patients with ASD begin in infancy or early childhood and evolve through the lifespan. In
young children with motor delay, a subsequent diagnosis of ASD is also a risk factor for
persistence of motor problems throughout life (Van Waelvelde, Oostra, Dewitte, Van Den
Broeck, & Jongmans, 2010).
Most research on motor dysfunction in ASD has focused on older children who have
more subtle problems with gait, coordination, and praxis that persist through childhood
(Ming, Brimacombe, & Wagner, 2007; Ozonoff et al., 2008). Reported gait abnormali-
ties include toe walking and trouble with ankle movement, ataxia, incoordination, and
asymmetry of stride (Calhoun, Longworth, & Chester, 2011; Esposito, Venuti, Apicella,
& Muratori, 2011; Rinehart et al., 2006); of these problems, it seems that limitation in
ankle motion emerges most consistently across studies as a significant problem in both
children and adults with ASD (Calhoun et al., 2011; Hallett et al., 1993). At least one
study utilizing gait analysis suggested gait patterns similar to that seen in Parkinson’s dis-
ease, indicating basal ganglia involvement as well (Vilensky, Damasio, Maurer, 1980).
Incoordination—including postural instability, difficulty with hand–eye coordination, and
other difficulty in limb positioning—is strongly associated with ASD (Fournier, Hass, Naik,
Lodha, & Cauraugh, 2010). Perhaps most interesting, dyspraxia, or difficulty perform-
ing skilled movements, is quite consistently reported in patients with ASD. Performance
on tests of praxis, including identifying skilled movements made by others, is poorest in
those subjects with the most severe social and communication deficits, suggesting a com-
mon underlying etiology between the motor and language problems (Dowell, Mahone, &
Mostofsky, 2009). It has also been suggested that problems of praxis may be specific to ASD
more so than to other developmental disorders that also affect motion, such as attention
deficit hyperactivity disorder (MacNeil & Mostofsky, 2012).
Although motor problems in older children with ASD have long been recognized, tra-
ditional teaching was that motor function early in childhood was generally intact. More
recent work, however, suggests that many infants and young children with ASD have motor
problems as well. One study of 154 children with a diagnosis of ASD found that the major-
ity of young children (63% of the 2- to 6-year-olds) had hypotonia and that this problem
persisted in 38% of the older group (7- to 18-year-olds). In this study, 9% of subjects also
had gross motor delay, although they all ultimately achieved their motor milestones (Ming
et al., 2007). Teitelbaum and colleagues retrospectively assessed home videos of children
with ASD (Teitelbaum et al., 1998) and Asperger’s disorder (Teitelbaum et al., 2004), and
they reported that characteristic motor differences were observable at 4–6 months of age.
Further video-analysis studies have had mixed results. Esposito et al. (2011) evaluated pre-
ambulatory movements as well as early gait and found asymmetry in both types of move-
ments that were specific to ASD compared to movements in children with other forms
of developmental delay or typical development. Ozonoff et al. (2008) could not replicate
Teitelbaum et al.’s findings. Based on these studies, it seems that there is a high incidence of
motor problems in infancy and early childhood in patients with ASD, although the specific
nature of these differences in still under research.
Stereotypies are the one motor phenomenon included in the core diagnostic criteria
for ASD. These repetitive, seemingly purposeless movements are now considered an envi-
ronmentally mediated movement disorder. Although children with other forms of develop-
mental delay also frequently exhibit stereotypies, they are much more common in children
with ASD. In one study, 63–70% of children with ASD exhibited stereotypies compared to
18–30% of those with other forms of developmental delay. In particular, stereotypies of gait
(i.e., pacing, spinning, or skipping) and hand–finger movements (shaking, tapping, waving,
clapping, opening–closing, or twirling) were more specific to ASD. The incidence and sever-
ity of stereotypies correlated with lower IQ and with more significant autistic symptoms,
suggesting that stereotypies are a marker of the severity of ASD (Goldman et al., 2009).
Significance
Motor problems in ASD are of special interest to researchers and clinicians because early motor
development is more easily observable and quantifiable than early language or social devel-
opment, and therefore such problems may allow for earlier detection of ASD. As described
previously, there has been much research focusing on identifying patterns of motor dysfunc-
tion specific to ASD with overall mixed results. In general, it appears that children with motor
delays early in life are at risk for having an ASD, and particular attention should be paid to
screening their language and social development. Stereotypies, especially those involving the
hands or gait, may be more concerning for ASD than for other forms of developmental delay.
Motor symptoms are also important in children with ASD because the severity of motor defi-
cits may be a marker of disease severity and predict development of later language or social
skills. For example, there is evidence that early oral and manual motor skills are strongly cor-
related with later speech fluency (Bhat, Galloway, & Landa, 2012; Gernsbacher, Sauer, Geye,
Schweigert, & Hill Goldsmith, 2008). In addition to permitting earlier diagnosis and serv-
ing as a marker of illness severity, motor problems in ASD may be an important therapeu-
tic target. Researchers hypothesize that intervening early may improve not only the motor
symptoms but also possibly other traits of ASD, including language and socialization, whose
development could be limited by poor motor function (Jeste, 2011).
Evaluation and Treatment
Although there is a growing interest in motor problems in ASD, the evaluation and treatment
of these issues has not yet been well established. Because stereotypies are a core feature of
the disorder, there has been significant research on behavioral interventions to reduce their
frequency with multiple forms of behavioral conditioning. Even exercise is shown to lead
to some improvement. At this point, no particular form of behavioral therapy has emerged
as being specifically effective in reducing stereotypies; thus, applied behavior analysis ther-
apy is still recommended (Boyd, McDonough, & Bodfish, 2012). Psychopharmacologic
treatments such as SSRIs have also been used to treat stereotypies, but their efficacy for
this purpose is under question (Carrasco, Volkmar, & Bloch, 2012). Although standards of
evaluation and treatment are still not formalized, clinicians should screen all children with
ASD for motor deficits, including hypotonia and gross delay in younger children, as well as
more subtle issues such as dyspraxia in older children.
Basic Science
Based on history and examination findings in patients with ASD, clinicians and research-
ers have localized motor problems to the cerebellar and frontostriatal pathways, and recent
imaging research further supports this localization ( Jeste, 2011). In a series of articles,
Mostofsky and colleagues reported that left motor cortex and premotor cortical white mat-
ter volumes (Mostofsky, Burgess, & Gidley Larson, 2007) and basal ganglia shape (Qiu,
Adler, Crocetti, Miller, & Mostofsky, 2010) were associated with poor motor performances
and problems with praxis. They also found differences in cerebellar activation during motor
tasks compared to controls (Mostofsky et al., 2009; Tsai et al., 2012). Recently, a consensus
group reviewing the role of the cerebellum in ASD concluded that the anatomy and neu-
rochemistry of the cerebellum are affected in a significant proportion of patients with ASD
and that these changes underlie motor and some cognitive deficits in this disorder (Fatemi
et al., 2012).
SUMMARY
As described in this chapter, patients with ASD are susceptible to a number of other under-
lying neurologic problems that can have a severe impact on daily functioning as well as
general health. Although this chapter focuses on three of the more frequent and severe
comorbidities, patients with ASD often face many other neurologic problems, including
intellectual disability, sensory integration problems, and pain. We still do not clearly under-
stand whether neurologic problems—such as epileptiform discharges, severely disturbed
sleep, or significant apraxia—can be the cause of the core symptoms of ASD, but there
is building evidence that at the very least, such problems exacerbate these symptoms by
affecting attention and ability to participate in behavioral treatments usually offered to
patients with ASD. Clinicians who work with patients with ASD, therefore, should not only
be aware of such comorbidities but also actively screen for them because many of these are
treatable conditions, such as seizures or insomnia, and caregivers may fail to mention or
may not notice these issues.
KEY POINTS
• Children with ASD often have other neurological problems, such as epilepsy, dis-
turbed sleep, or movement disorders. Screening for and addressing these problems is
a shared responsibility of all medical providers caring for these patients.
• It can be difficult to distinguish seizures from unusual behaviors in children with

ASD by history alone, so EEG should be considered before considering treatment.
• Many children with ASD have seizures, but even more have abnormal EEGs
without clear seizures. Treatment of these abnormalities is a controversial and
evolving field.
• There is a high incidence of sleep disturbances in children with ASD, and the etiology
changes across the lifespan. Sleep disturbances should be considered whenever there
are concerns for daytime irritability or emotional lability.
• Motor problems, including stereotypies and apraxia, can be both a marker of clinical
severity and an important therapeutic target for children with ASD.
Dr. Fiona Baumer has nothing to disclose.

Dr. Mustafa Sahin has served on the scientific advisory board for the Tuberous
Sclerosis Alliance and has received research support from Children’s Hospital Boston
Translational Research Program, Autism Speaks, the Tuberous Sclerosis Alliance,
Novartis Pharmaceuticals Inc., Hoffmann-La Roche, Shire, the Department of Defense/
Congressionally Directed Medical Research Program, the Nancy Lurie Marks Family
Foundation, and the National Institutes of Health (NIH U01 NS082320,U54 NS092090
and P30 HD018655-31).
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8 / / GENETIC
/ / / / DISORDERS
ASSOCIATED WITH
THE AUTISM SPECTRUM
DISORDER PHENOTYPE
LAWRENCE K. FUNG AND ALLAN L. REISS
INTRODUCTION
Core symptoms of autism spectrum disorder (ASD)—deficits in social communication,

social interaction, and the presence of restricted, repetitive patterns of behavior, interests,
or activities—have been reported in a growing list of genetic diseases. This chapter pro-
vides an introduction to the genetic diseases that include ASD symptomatology as a com-
ponent of the phenotype. Four major classes of genetic diseases are described: monogenic,
chromosomal, metabolic, and mitochondrial. As shown in Tables 8.1 and 8.2, many genetic
syndromes exhibit features of ASD. Eight are discussed in more detail in this chapter. This
discussion is followed by an approach for detecting syndromic features of ASD in a diag-
nostic evaluation. To illustrate some of the key concepts in this chapter, two case examples
of genetic diseases are presented.
Monogenic Diseases
Monogenic or single-gene diseases result from modifications in a single gene occurring in

all cells in the body. More than 10,000 human diseases are estimated to be monogenic disor-
ders. These diseases are further categorized into three main categories: dominant, recessive,
and X-linked. Autosomal dominant diseases involve damage to one gene copy on non-sex
chromosomes, whereas autosomal recessive diseases involve both gene copies. X-linked
monogenic diseases are associated with defective genes on the X chromosome. Men carry
only one copy of the X chromosome, whereas women carry two. Therefore, women with
X-linked monogenic diseases are usually carriers with no symptoms or milder manifesta-
tions relative to men with X-linked diseases, who tend to have more severe symptoms.
Many syndromic ASDs belong to autosomal dominant monogenic diseases (see
Table 8.1)—for example, neurofibromatosis type 1 (NF1; Garg et al., 2013), tuberous
117
TABLE 8.1 Partial List of Monogenic and Chromosomal Diseases Exhibiting Autism Spectrum
Disorder Symptoms
Genetic Syndrome Classification Location of Genetic Reference
Defect Abnormality
Bannayan–Riley– Monogenic; AD 10q23.31 Mutation in Lynch et al. (2009)
Ruvalcaba syndromea PTEN gene
CHARGE syndrome Monogenic; AD 8q12.1–q12.2 Mutation in Bergman et al.
7q21.11 CHD7 gene (2011)
Mutation in
SEMA3E gene
Cohen syndrome Monogenic; AR 8q22.2 Mutation in Douzgou and
COH1 gene Petersen (2011)
Cornelia de Lange Monogenic; AD 5p13.2 Mutation in Schrier et al.
syndrome CDLS1 gene (2011)
Cowden syndromea Monogenic; AD 10q23 Mutation in Conti et al. (2012)
PTEN gene
Fragile X syndrome Monogenic; Xq27.3 Mutation in Fung et al. (2012)
X-linked FMR1 gene
Joubert syndrome Monogenic; AR 9q34.3 Mutation in Alvarez Retuerto
AHI1 gene et al. (2008)
Lujan–Fryns Monogenic; Xq13.1 Mutation in Lerma-Carrillo
syndrome X-linked MED12 gene et al. (2006)
Neurofibromatosis Monogenic, AD 17q11.2 Mutation in Garg et al. (2013)
type 1 NF1 gene
Phelan–McDermid Monogenic; AD 22q13.33 Mutation in Sarasua et al.
syndrome SHANK3 gene (2014)
Rett syndrome Monogenic; Xq28 Mutation in Castro et al.
X-linked 14q13 MeCP2 gene (2013)
Mutation in
FOXG1 gene
Sotos syndrome Monogenic; AD 5q35.2–q35.3 Mutation in Buxbaum et al.
NSD1 gene (2007)
Timothy Monogenic; AD 12p13.33 Mutation in Lu et al. (2012)
syndrome CACNA1C gene
Tuberous sclerosis Monogenic, AD 9q34 Mutation in Curatolo et al.
complex 16p13 TSC1 gene (2010)
Mutation in
TSC2 gene
15q13.3 deletion Chromosomal 15q13.3 Deletion involving Hoppman-Chaney
syndrome CHRNA7 gene et al. (2013)
15q13.3 duplication Chromosomal 15q13.3 Duplication Beal (2014)
syndrome
Genetic Disorders Associated With the Autism Spectrum Disorder Phenotype // 119
TABLE 8.1 Continued
Genetic Syndrome Classification Location of Genetic Reference
Defect Abnormality
16p11.2 deletion Chromosomal 16p11.2 Deletion Zufferey et al.

syndrome (2012)
16p11.2 duplication Chromosomal 16p11.2 Duplication Barber et al.
syndrome (2013)
22q13 duplication Chromosomal 22q13 Duplication Frye (2012)
syndrome
Angelman Chromosomal; 15q11-13 Maternal deletions Thibert et al.
syndrome imprinting involving UBE3A (2013)
gene
Down syndrome Chromosomal Chromosome Trisomy 21 Carter et al. (2007)
21
Prader–Willi Chromosomal; 15q11-13 Paternal deletions Dykens, Lee, and
syndrome imprinting involving SNRPN Roof (2011)
and NDN genes
Potocki–Lupski Chromosomal 17p11.2 Duplication Treadwell-Deering,
syndrome Powell, and
Potocki (2010)
Smith–Magenis Chromosomal 17p11.2 Deletion involving Laje et al. (2010)
syndrome RAI1 gene
Velocardiofacial Chromosomal 22q11.21 Deletion involving Jonas et al.
syndrome haploinsufficiency (2014)
of TBX1 gene
Williams–Beuren Chromosomal 7q11.23 Hemizygous Tordjman et al.
syndrome deletion of (2013)
1.5–1.8 Mb on
7q11.23
Williams–Beuren region Chromosomal 7q11.23 Duplication Sanders et al.
duplication syndrome (2011)
Klinefelter (47,XXY) Chromosomal X chromosome Aneuploidy Ross et al.
syndrome (2012)
47,XYY syndrome Chromosomal Y chromosome Aneuploidy Margari et al.
(2014)
Classified under PTEN-associated disorders.
a
AD, autosomal dominant; AR, autosomal recessive.
sclerosis (Curatolo, Napolioni, & Moavero, 2010), CHARGE syndrome (Bergman et al.,
2011), Cornelia de Lange syndrome (Schrier et al., 2011), Phelan–McDermid syndrome
(Sarasua et al., 2014), Sotos syndrome (Buxbaum et al., 2007), Timothy syndrome (Lu, Dai,
Martinez-Agosto, & Cantor, 2012), phosphatase and tensin homolog (PTEN)-associated dis-
orders (including Bannayan–Riley–Ruvalcaba syndrome) (Lynch, Lynch, McMenamin, &
TABLE 8.2 Partial List of Metabolic Diseases Exhibiting Autism Spectrum Disorder Symptoms
Genetic Location of Genetic Reference
Syndrome Defect Abnormality
6-N-trimethyllysine Xq28 Mutation in TMLHE Celestino-Soper et al.
dioxygenase deficiency gene (2012)
Cerebral folate 5q11.2–q13.2 Mutation in DHFR Ramaekers, Blau, Sequeira,
deficiency gene Nassogne, and Quadros
(2007)
Cytosolic 5′ nucleotidase 7p14.3 Mutation in NT5C3A Page, Yu, Fontanesi, and
superactivity gene Nyhan (1997)
Phenylketonuria 12q23.2 Mutation in PAH Baieli, Pavone, Meli,
gene Fiumara, and Coleman
(2003)
Smith–Lemli–Opitz 11q13.4 Mutation in DHCR7 Nowaczyk and Irons (2012)
syndrome gene
Succinic semialdehyde 6p22.3 Mutation in ALDH5A1 Knerr, Gibson, Jakobs, and
dehydrogenase (SSADH) gene Pearl (2008)
deficiency
Webb, 2009), and Cowden syndrome (Conti et al., 2012). Fewer syndromic ASDs are
autosomal recessive—for example, Cohen syndrome (Douzgou & Petersen, 2011) and
Joubert syndrome (Alvarez Retuerto et al., 2008). Two of the most well-known syndromic
ASDs are X-linked monogenic diseases—fragile X syndrome (FXS; Fung, Quintin, Haas,
& Reiss, 2012) and Rett syndrome (RTT; Castro, Mellios, & Sur, 2013).
Chromosomal Diseases
Chromosomal diseases can arise from alterations of the number of chromosomes (aneu-
ploidy) or changes in a fragment (portion) of a chromosome. Changes of a chromosomal
fragment can take the form of deletion, duplication, or translocation. Deletions and dupli-
cations are also known as copy number variations (CNVs).
Table 8.1 lists representative chromosomal diseases in which ASD symptoms com-
monly occur. Individuals with 47,XYY syndrome (Margari, Lamanna, Craig, Simone,
& Gentile, 2014), a relatively common sex chromosome aneuploidy, often manifest
ASD symptoms. ASD symptoms can also occur infrequently in association with Down
syndrome(Carter, Capone, Gray, Cox, & Kaufmann, 2007). Microdeletions of small
fragments of chromosomes have also been found in several syndromes associated with
ASD—for example, Angelman syndrome (Thibert, Larson, Hsieh, Raby, & Thiele,
2013), Prader–Willi syndrome, Smith–Magenis syndrome (Laje et al., 2010), velocar-
diofacial syndrome ( Jonas, Montojo, & Bearden, 2014), and Williams–Beuren syn-
drome (Tordjman et al., 2013). Duplications or deletions of certain regions of the DNA
are known to be especially associated with ASD; for example, either duplication or dele-
tion of 16p11.2 (Barber et al., 2013; Zufferey et al., 2012) and 15q11–q13 (Beal, 2014;
Hoppman-Chaney, Wain, Seger, Superneau, & Hodge, 2013) are associated with ASD.
Metabolic Diseases
Various metabolic diseases are reported to be associated with ASD (see Table 8.2)
(Schaefer & Mendelsohn, 2013). These diseases are relatively rare, and they gener-
ally present early in life. Inborn errors of metabolism include the following: carbo-
hydrate metabolism defects, amino acid metabolism defects, organic acid disorders,
fatty acid oxidation disorders, purine metabolism disorders, lysosomal storage disor-
ders, and peroxisomal disorders. Most metabolic disorders are associated with serious
medical problems, such as seizures, extrapyramidal symptoms, and failure to thrive.
Developmental regression is common for children with metabolic diseases. The abil-
ity to diagnose metabolic diseases has had a major impact on public health. The most
notable example is neonatal screening for phenylketonuria (PKU), a genetic disor-
der in which the body cannot metabolize the essential amino acid phenylalanine. All
infants born in hospitals in the United States and many other countries are required to
be screened for PKU. If PKU is diagnosed early, an affected newborn can be managed
through a combination of diet and medication and can grow up with essentially normal
brain development. Before newborn screening for PKU became common, untreated
PKU was known to be one of the most common causes of ASD symptoms and intel-
lectual disability.
Mitochondrial Diseases
Mitochondrial diseases are rare conditions involving the mitochondria, an organ-

elle responsible for energy metabolism, storage of calcium ions, and steroid synthesis.
Recently, mitochondrial dysfunction was hypothesized to be associated with ASD.
Possible mechanisms for such association include mitochondrial-induced oxidative
stress, abnormal mitochondrial calcium handling, and mitochondrial activation of the
immune system (Legido, Jethva, & Goldenthal, 2013). Similar to metabolic disorders,
mitochondrial disorders often involve serious medical problems including neurologic
symptoms. In one cohort study, 25 patients with a primary diagnosis of ASD and evi-
dence of a disorder of mitochondrial energy metabolism were examined. Sixty-four per-
cent of this cohort had significant deficits (median enzyme activity was 7% of normal;
range, 0–20%) in complex I of the electron transport chain (ETC); 20% had deficiency
(median enzyme activity was 20% of normal; range, 14–32%) in complex III of the ETC
(Weissman et al., 2008).
SPECIFIC SYNDROMES
Specific genetic syndromes have been catalogued at the Genetics Home Reference admin-
istered by the U.S. National Library of Medicine (http://ghr.nlm.nih.gov) and the Online
Mendelian Inheritance in Man (OMIM; http://omim.org) maintained by the National
Human Genome Research Institute, Johns Hopkins University, and the Institute of Genetic
Medicine. Here, eight syndromes have been selected for further discussion regarding their
physical phenotypes, cognitive–behavioral phenotypes, genetics, as well as molecular biol-
ogy. Figure 8.1 shows pictures of representative school-age children with each specific
genetic syndrome.
(A) (E)
(B) (F)
(C) (G)
(D) (H)
FIGURE 8.1 School-age children with (A) fragile X syndrome, (B) Rett syndrome, (C) neurofi-
bromatosis type 1, (D) tuberous sclerosis, (E) Smith–Magenis syndrome, (F) velocardiofacial
syndrome, (G) XYY syndrome, and (H) Smith–Lemli–Opitz syndrome. Sources: A, Jorde, L. B.,
Carey, J. C., Bamshad, M. J., & White, R. L. (2000). Medical Genetics (2nd ed.). St. Louis: Mosby (http://
medgen.genetics.utah.edu/photographs/pages/fragile_x.htm); B, The Eva Fini Fund (http://evafinifund.
Fragile X Syndrome
Fragile X syndrome (FXS; aka Martin–Bell syndrome, marker X syndrome, or Escalante’s

syndrome) is the most common genetic cause of ASD (Reiss & Dant, 2003) and inher-
ited cause of intellectual disability (Freund & Reiss, 1991). FXS was first described as a
particular form of X-linked mental retardation by Purdon Martin and Julia Bell in London
in 1943. In 1969, Herbert Lubs at Yale University showed that the X chromosome of a
would-be FXS patient contained a marked secondary constriction. A derivation of this
karyotype test for FXS became gradually used for diagnostic purposes in the 1970s. In
1991, researchers identified the FMR1 gene that causes FXS (Verkerk et al., 1991). The
society at large is clearly impacted by this neuropsychiatric–neurodevelopmental dis-
ease. The general prevalence of males with a full mutation of the affected gene FMR1 is
estimated as 1 in 4000, whereas the female prevalence is approximately 1 in 5000–8000
(Hill, Archibald, Cohen, & Metcalfe, 2010). Families of children with FXS experience
substantial financial burden.
Physical Phenotypes
Individuals with FMR1 full mutations can have mild dysmorphic features (long face with
large mandible, large everted ears, and high-arched palate), as well as mild to severe cogni-
tive deficits and behavioral abnormalities.
Cognitive–Behavioral Phenotypes
These individuals particularly exhibit deficits in executive function (Van der Molen et al.,
2010), including attention, inhibition, working memory, and impulse control. Children
and adults with FXS often exhibit gaze aversion, increased social anxiety, and social avoid-
ance (Feinstein & Singh, 2007). Furthermore, impairments in visuospatial processing are
common. Collectively, these factors may contribute to profound difficulties in maintaining
appropriate social interactions with others.
Because FXS is a condition due to mutations within a specific gene on the X chro-
mosome, males with this disease tend to have more severe symptoms than their female
counterparts. Among females with FXS, the range in severity of symptoms is large; it is
thought to be mainly due to the genetic variation in the form of X-inactivation, a process
by which one of the two copies of the X chromosome present in females is inactivated.
Whereas females with FMR1 full mutation demonstrate intellectual abilities ranging from
average function to moderate disability, males with full mutation can suffer from severe to
FIGURE 8.1 Continued
org/?page_id=57); C, The New England Genetics Collaborative (http://www.gemssforschools.org/conditions/
nf1/default.aspx); D, Tuberous Sclerosis Australia (https://www.atss.org.au); E, Smith, A. C., McGavran, L.,
Robinson, J., Waldstein, G., Macfarlane, J., Zonona, J., et al. (1986). Interstitial deletion of (17)(p11.2p11.2)
in nine patients. American Journal of Medical Genetics, 24(3), 393–414; F, Tewfik TL, Manoukian JJ. The
Syndromal Child. In: Bailey BJ, Johnson JT, Newlands SD, eds. Head & Neck Surgery - Otolaryngology.
Vol 1. Philadelphia, PA: Lippincott Williams & Wilkins; 2006; G, geneticdisease2 (http://geneticdisease2.wiki-
spaces.com/XYY+Syndrome+(an+extra+Y+chromosome+in+each+cell+of+a+male)); H, Nowaczyk, J. M., &
Irons, M. B. (2012). Smith–Lemli–Opitz syndrome: Phenotype, natural history, and epidemiology. American
Journal of Medical Genetics Part C: Seminars in Medical Genetics, 160C(4), 250–262.
profound intellectual disability. Most boys and approximately one-third of girls with FXS
satisfy the criteria for attention deficit hyperactivity disorder (ADHD) per the Diagnostic
and Statistical Manual of Mental Disorders (DSM), with the hyperactivity subtype more
common in boys and inattentiveness more common in girls (Mazzocco, Baumgardner,
Freund, & Reiss, 1998).
Genetics and Molecular Biology

The mutation responsible for FXS consists of large expansions of trinucleotide CGG repeats
within the 5′ untranslated region of the FMR1 gene on the long arm of the X chromosome.
Typically developing individuals have approximately 30 CGG repeats, whereas those with
the FMR1 premutation have repeat lengths ranging between 50 and 200 copies. Individuals
with the FMR1 full mutation (and hence the diagnosis of FXS) typically have more than
200 CGG repeats. This expansion leads to DNA hypermethylation within FMR1, resulting
in its transcriptional silencing, and therefore the absence or attenuation of the gene prod-
uct, FMR1 protein (FMRP).
Individuals with FXS have absent or reduced levels of FMRP, a protein that plays a
prominent role in regulating the translation of a subset of mRNAs associated with syn-
aptic plasticity, dendritic pruning, and axonal development (Santoro, Bray, & Warren,
2012). One of the most influential theories of FXS involves the glutamatergic pathways.
In particular, long-term depression (LTD), a form of synaptic plasticity, is known to be
regulated by the group 5 metabotropic glutamate receptor (mGluR5) (Huber, Gallagher,
Warren, & Bear, 2002). Activation of mGluR5 leads to cascades of signaling events
driving the activation of protein synthesis involved in the internalization of α-amino-3
-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). In the absence or
substantial attenuation of FMRP, some of the proteins important for AMPAR traffick-
ing become too abundant, thus increasing the internalization of AMPARs and resulting
in exaggerated mGluR5-dependent LTD (Chowdhury et al., 2006). In addition to the
glutamatergic system, many components of the GABAergic system are known to be dys-
functional in FXS. For example, the mRNA for the δ subunit of the GABA AR is a known
target of FMRP. Abnormal levels of the α, β, and γ subunits of the GABA AR, GABA AR’s
scaffolding protein, and enzymes involved in the metabolism of GABA, as well as the cel-
lular transport of GABA, were found in Fmr1 knockout mice (Paluszkiewicz, Martin, &
Huntsman, 2011). FMRP was also shown to have a role in synaptic plasticity and signal-
ing that involves retinoic acid (RA) (Soden & Chen, 2010). In normal mice, synaptic RA
signaling was found to regulate inhibitory synaptic transmission in response to reduced
synaptic excitation (Sarti, Zhang, Schroeder, & Chen, 2013). Different from RA’s action
at excitatory synapses, RA at inhibitory synapses was shown to cause a loss of GABA ARs.
Interestingly, in the absence of FMRP (as in Fmr1 knockout mice), RA fails to regulate
inhibitory synaptic strength, resulting in an imbalance between synaptic excitation and
inhibition that may contribute to the pathogenesis of FXS and ASD symptoms (Sarti
et al., 2013).
Rett Syndrome
In the early 1960s, Austrian pediatrician Andreas Rett described two female patients
who were wringing their hands in an unusual manner and rocking with autistic-like
movements. After years of clinical and basic investigations, it was discovered in 1999
that mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2) are
associated with both familial and sporadic forms of Rett syndrome (RTT). RTT affects
an estimated 1 in 8500 females.
Physical Phenotypes
Although affected girls have normal head circumference at birth, microcephaly is frequently
noted after the regression period. Phenotypic features of RTT are listed under the most cur-
rent diagnostic criteria (Neul et al., 2010). There are two types of RTT diagnoses: (1) typi-
cal or classic RTT and (2) atypical or variant RTT. Both diagnoses require the identification
of a period of regression followed by recovery or stabilization. In the case of typical or classic
RTT, all main criteria and exclusion criteria (presented next) are met. In contrast, atypical
or variant RTT can be diagnosed when two or more main criteria and five or more support-
ive criteria are met. The main criteria include the following: (1) partial or complete loss of
acquired purposeful hand skills; (2) partial or complete loss of acquired spoken language;
(3) gait abnormalities; and (4) stereotypic hand movements such as hand wringing/squeez-
ing, mouthing, clapping/tapping, and washing/rubbing automatisms. Exclusionary criteria
consist of (1) brain injury secondary to trauma, neurometabolic disease, or severe infection
that causes neurological problems; and (2) grossly abnormal psychomotor development in
the first 6 months of life. Supportive criteria comprise the following: (1) breathing distur-
bances when awake; (2) bruxism when awake; (3) impaired sleep pattern; (4) abnormal
muscle tone; (5) peripheral vasomotor disturbances; (6) scoliosis/kyphosis; (7) growth
retardation; (8) small, cold hands and feet; (9) inappropriate laughing/screaming spells;
(10) diminished response to pain; and (11) intense eye communication—“eye pointing.”
Most girls with RTT develop relatively normally for the first 6 months of life, followed by a
period of developmental regression. Regression starts between the ages of 6 and 18 months,
and the girls do not reach normal developmental milestones thereafter. During the period
of developmental regression, stereotyped movements replace purposeful hand movements.
These stereotyped hand movements are accompanied by abnormal gait and sometimes an
inability to walk (Berger-Sweeney, 2011). Individuals with RTT often have communication
deficits. In contrast to the findings of pervasive impairments in cognition, there are reports
that girls with RTT develop increased social interaction with caregivers over time, suggest-
ing that elements of social memory are intact.

RTT is caused by mutations in the gene coding for MeCP2. Although MeCP2 has diverse
functions, examination of MeCP2 mutant mice supports the hypothesis that MeCP2 defi-
ciency leads to aberrant maturation and maintenance of synapses and circuits in multiple
brain systems. Some of the deficits arise from alterations in specific intracellular pathways,
such as the PI3K/Akt signaling pathway. These abnormalities can be at least partially res-
cued in MeCP2 mutant mice by treatment with targeted therapeutic agents.
Neurofibromatosis Type 1
The earliest description of neurofibromatosis type 1 (NF1) dates back to the 16th cen-
tury. In the late 19th century, Friedrich von Recklinghausen provided the first clinical
and pathological description of NF1. The NF1 gene was cloned in 1990, and its gene
product, neurofibromin, was identified. NF1 is one of the most common single-gene
disorders to affect the human nervous system, with a frequency of approximately 1 in
3500. Population-based prevalence rates range from approximately 1 in 1000 in Israel
to 1 in 7000 in Italy. NF1 has been identified in all ethnic groups; it occurs with equal
frequency in males and females, and an estimated 2–3 million individuals are affected
worldwide.
Physical Phenotypes
An NF1 diagnosis is usually first considered from a clinical examination, using diagnos-
tic criteria developed by the National Institutes of Health. These criteria include two or
more of the following manifestations: (1) six or more café au lait macules, (2) two or more
neurofibromas or one plexiform neurofibroma, (3) axillary or inguinal freckling, (4) optic
glioma, (5) two or more Lisch nodules, (6) sphenoid dysplasia or tibial pseudarthrosis, and
(7) first-degree relative (parent or sibling) with confirmed NF1.
One of the most common complications of NF1 in childhood is cognitive dysfunction.
Approximately 80% of children with NF1 experience significant impairment in one or more
areas of cognitive functioning (Hyman, Shores, & North, 2005). Overall, intellectual dis-
ability is not a typical manifestation of NF1 (Hyman et al., 2005). However, children with
NF1 experience impairments of executive function, including attention, working memory,
spatial planning, and organization (Hyman, Arthur Shores, & North, 2006). Concerns
regarding social skills and peer interaction are often reported for individuals with NF1.
Parent and teacher questionnaires reveal that children with NF1 experience greater levels
of anxiety, withdrawal, depression, and somatic complaints compared to their unaffected
siblings (Barton & North, 2004). In a recent study, it was estimated that as many of 47%
of patients with NF1 are likely to have significant symptoms within the autism spectrum
(Garg et al., 2013).

NF1 is caused by mutations in NF1, the gene coding for neurofibromin. Neurofibromin
regulates the activity of the rat sarcoma protein (Ras)-bound intracellular signaling path-
way, which in turn regulates complex cellular processes, including cell differentiation,
growth, and apoptosis.
Tuberous Sclerosis Complex
Skin manifestations of tuberous sclerosis complex (TSC) were first illustrated in Pierre
Francois Olive Rayer’s Treatise on Skin Diseases in 1835. It was not until 1862 that
Frederich von Recklinghausen reported the first pathological description of the lesions
found in TSC. More than a century later, two genes responsible for TSC were identified.
TSC1 was found by Fryer and colleagues at the Royal United Hospital in Bath, United
Kingdom, in 1987. TSC2 was identified and cloned by the European Chromosome 16
Tuberous Sclerosis Consortium in 1993. The prevalence of TSC is approximately 1 in
6000 live births.
Physical Phenotypes
TSC is a genetic disorder that causes nonmalignant tumors to form in multiple organs,
primarily in the brain, eyes, heart, kidney, and skin. TSC is also commonly associated with
seizures, developmental delay, intellectual disability, and ASD. The diagnostic criteria for
TSC, which largely depend on physical characterization, were updated in 2012 (Northrup
et al., 2013). Major features of TSC include (1) hypomelanotic macules (≥3, at least 5-mm
diameter), (2) angiofibromas (≥3) or fibrous cephalic plaque, (3) ungual fibromas (≥2),
(4) shagreen patch, (5) multiple retinal hamartomas, (6) cortical dysplasias, (7) subep-
endymal nodules, (8) subependymal giant cell astrocytoma, (9) cardiac rhabdomyoma,
(10) lymphangioleiomyomatosis, and (11) angiomyolipomas (≥2). Minor features of TSC
consist of the following: (1) “confetti” skin lesions, (2) dental enamel pits (>3), (3) intra-
oral fibromas (≥2), (4) retinal achromic patch, (5) multiple renal cysts, and (6) nonrenal
hamartomas. Definite diagnosis is defined as having two major features or one major feature
with two or more minor features, whereas possible diagnosis is defined as having either one
major feature or more than two minor features.
Children with TSC and cognitive impairment are more likely to have autistic features (Curatolo
et al., 2010). Hyperactive behavior in children with TSC is also common. Stereotypies and pur-
poseless movements are observed in approximately one-third of children with TSC. Individuals
with TSC2 mutations are significantly more likely to have a history of infantile spasms, a low
intelligent quotient, and autistic disorder compared to those with TSC1 mutations.

Tuberous sclerosis is caused by the silencing of a single gene (TSC1 at 9q34 or TSC2 at
16p13) that codes for hamartin and tuberin, respectively. Hamartin and tuberin form a bio-
chemical complex that inhibits the signal transduction pathway that controls translation,
proliferation, and cell growth.
Smith–Magenis Syndrome
Smith–Magenis syndrome (SMS or 17p deletion syndrome) was first described in 1986 in a
case series by Ann C. M. Smith, a genetics counselor at the National Institutes of Health, and
Ruth Ellen Magenis, a pediatrician and geneticist at the Oregon Health Sciences University
(Smith et al., 1986). They reported that eight patients with deletion of a portion of 17p11.2
had similar phenotype, including “brachycephaly, midface hypoplasia, prognathism, hoarse
voice, and speech delay with or without hearing loss, psychomotor and growth retardation,
and behavior problems.” SMS affects an estimated 1 in 15,000 individuals.
Physical Phenotypes
Children with SMS are often described to have a broad, square-shaped face with deep-set
eyes, flat nose bridge, full cheeks, a prominent lower jaw, and a full, outward-curving upper lip.
Variable levels of cognitive impairment, most frequently in the moderate range of intel-
lectual disability, are universal in individuals with SMS. Language development delays are
present in most cases, with receptive skills generally better than expressive skills. Learning
abilities are characterized by strength in visual reasoning tasks and weakness in sequen-
tial processing. Short-term memory is poor, but long-term memory is considered a relative
strength. Autistic-like behaviors and symptoms start to emerge between 18 and 36 months
of age. A study of individuals with SMS with a confirmed deletion (del 17p11.2) found that
90% of the sample had symptoms on the autism spectrum (Laje et al., 2010). Symptoms of
ADHD are also common in individuals with SMS.
Irritability and aggressive behaviors toward both self and others are common in SMS.
In particular, onychotillomania (i.e., pulling out nails/nail yanking) and polyembolokoila-
mania (the insertion of foreign bodies into one’s body orifices) are self-injurious behaviors
(SIB) relatively unique to SMS as a genetic condition. Other manifestations of SIB in chil-
dren with SMS include skin picking, wrist biting, head banging, and hitting self or objects.
The SIB can be so severe that in some cases, parents have been reported to social services
for suspicion of child abuse.
An additional characteristic feature of SMS is an involuntary upper body squeeze or
“self-hug.” Two types of self-hugging are described as (1) self-hugging and tensing the
upper body and (2) hand clasping at chest level or under the chin while squeezing one’s
arms against one’s sides and chests. These movements have a tic-like quality and appear as
an expression of excitement.

The majority of cases of SMS are due to a common deletion in chromosome 17p11.2 that
includes the RAI1 gene (Laje et al., 2010). Approximately 10% of cases of SMS are due to
heterozygous mutations of the RAI1 gene. The mechanisms by which the deletion or muta-
tion of RAI1 and contiguous genes cause psychopathology are unknown.
47,XYY Syndrome
The first published case of 47,XYY syndrome was reported by Avery Sandberg and col-
leagues at Roswell Park Memorial Institute in Buffalo, New York, in 1961. The patient was
described as a 44-year-old obese white man of average intelligence with large facial features.
47,XYY syndrome is among the most common of human genetic disorders, occurring in
approximately 1 in 1000 live male births.
Physical Phenotypes
The addition of the extra Y chromosome leads to tall stature and long legs. Clinodactyly
and pes planus (flat feet) are commonly described in individuals with 47,XYY syndrome.
There is no distinct set of dysmorphic facial features among males with this syndrome.
Testicular size, pubertal progression, and testosterone levels are usually normal in affected
individuals.
Cognitive abilities are typically in the average to low average range. Whereas
visual–perceptual skills are considered a relative strength in persons with XYY trisomy,
verbal skills are often a relative weakness. Social difficulties and social withdrawal were
reported in a case series of 47,XYY syndrome. In the largest cohort of 52 individuals with
47,XYY syndrome, approximately 20% of the participants fulfilled the criteria for an ASD
diagnosis (Bishop et al., 2011).

47,XYY occurs as a result of a random event during the formation of sperm cells. This event,
called nondysjunction, occurs when two copies of the Y chromosome fail to separate dur-
ing anaphase II of meiosis II. When a sperm with such genetic defect contributes to the
genetic makeup of a child, the child will have an extra Y chromosome in some or all of the
body’s cells.
Velocardiofacial Syndrome (DiGeorge Syndrome)
Velocardiofacial syndrome (VCFS) is also known as DiGeorge syndrome, Shprintzen syn-

drome, and 22q11 deletion syndrome (22q11DS). This syndrome was first described by
Angelo DiGeorge and John Kirkpatrick in 1968 and later by speech pathologist Robert
Shprintzen and colleagues at Montefiore Hospital in New York in 1978. The prevalence of
VCFS is estimated as 1 in 4000 live births ( Jonas et al., 2014).
Physical Phenotypes
Physical characteristics of patients with VCFS can be summarized by the mnemonic
CATCH-22, which refers to cardiac anomaly (especially tetralogy of Fallot), abnormal
facies, thymic aplasia, cleft palate, and hypocalcemia/hypoparathyroidism, with the 22
referring to the genetic abnormality found in chromosome 22. Shprintzen first described
the faces of VCFS patients as characterized by “a large, fleshy nose with a broad nasal bridge,
flattened malar region, narrow palpebral fissures with a downward obliquity, deep overbite
with a class II malocclusion and retruded mandible, mild synophrys, abundant scalp hair,
and a vertically long face” (Shprintzen et al., 1978, p. 57).
One of the most intriguing aspects of the syndrome is the variability in clinical and cogni-
tive presentation. Children with 22q11.2 microdeletion have a high prevalence of ASD,
ADHD, anxiety disorders (most commonly specific and social phobia), mood disorder,
and psychotic disorder. Generally, however, as a group, they often have deficits in receptive
language development and abstract reasoning. Younger children with VCFS often manifest
social withdrawal, awkwardness, and shyness; they also frequently exhibit inattention, as
well as hyperactivity. Visual–spatial deficits are common. Approximately 30% of individu-
als with VCFS are diagnosed with a psychotic disorder (schizophrenia or schizoaffective
disorder) by adolescence or young adulthood.

VCFS is caused by a hemizygous microdeletion of approximately 1.5–3 Mb on the long arm
of chromosome 22. This syndrome represents one of the most common known recurrent
CNVs. The 3-Mb region contains approximately 60 genes, some of which are expressed
primarily in the brain. COMT and PRODH are two candidate genes that have been hypoth-
esized to contribute to the behavioral phenotype of VCFS. The gene product of COMT
is catechol-O-methyltransferase, a postsynaptic enzyme that modulates the clearance of
dopamine. PRODH encodes for proline dehydrogenase, an enzyme that converts proline
to glutamate in mitochondria.
Smith–Lemli–Opitz Syndrome
Smith–Lemli–Opitz syndrome (SLOS) was first described in 1964 by pediatricians David

Smith, Luc Lemli, and John Opitz at the University of Wisconsin at Madison. SLOS was the
first human multiple malformation syndrome attributed to an inborn error of sterol synthe-
sis. The prevalence of SLOS is approximately 1 in 10,000–60,000 births.
Physical Phenotypes
In their first report, Smith et al. (1964) described three male patients with distinctive facial
features, intellectual disability, microcephaly, developmental delay, and hypospadias. The
severity of physical defects correlates with the severity of the cholesterol deficiency.
Behavioral abnormalities occur commonly in individuals with SLOS. Hyperactivity, SIB,
sensory hypersensitivity, affect dysregulation, aggressiveness, stereotypic behaviors, persis-
tence to sameness, and severe sleep cycle disturbances occur, even in the least physically
affected individuals (Diaz-Stransky & Tierney, 2012). Approximately 75% of individuals
with SLOS fulfill the criteria for ASD (Diaz-Stransky & Tierney, 2012).

SLOS is caused by a mutation of the DHCR7 gene on chromosome 11. This genetic insult
results in elevated levels of the enzyme 7-dehydrocholesterol (7-DHC) reductase, which is
responsible for the last step of cholesterol synthesis. Low levels of cholesterol are seen in
90% of patients.
EVALUATION OF INDIVIDUALS WITH AUTISM SPECTRUM DISORDER
The American Academy of Child and Adolescent Psychiatry (AACAP; Volkmar et al.,
2014), American Association of Pediatrics (AAP; Johnson et al., 2007), American
Association of Neurology (AAN; Filipek et al., 2000), and American College of Medical
Genetics (ACMG; Schaefer & Mendelsohn, 2013) have published guidelines in the
workup for ASD. The most updated versions of these guidelines have all included strate-
gies to detect familial and genetic factors of ASD. Next, a systematic approach for detecting
signs of syndromic ASD in a nongeneticist’s clinic setting is presented.
History and Physical
Just like any medical and psychiatric evaluation, a diagnostic evaluation for ASD begins
with the chief complaint and history of present illness. Although core symptoms (i.e., social
communication impediment and repetitive behaviors/restricted interests) are important in
establishing the diagnosis of ASD, other comorbid symptoms, such as inattention, hyperac-
tivity, impulsivity, obsessions, compulsions, maladaptive eating habits, disruptive behaviors,
aggression, and SIB, are also important. Many children with syndromic ASD (e.g., FXS
and VCFS) often manifest ADHD symptoms. Young children who are obese (as a result of
extreme and insatiable appetite) and have ASD should be considered for genetic evaluation
to rule out Prader–Willi syndrome. Specific SIBs such as onychotillomania and polyembolo-
koilamania should trigger the clinician to evaluate for genetic causes such as SMS.
Past psychiatric history may include the usual information of past psychiatric diagno-
ses, history of hospitalizations, medication history, and history of aggression toward self
and others. As mentioned previously, many syndromic ASDs have comorbid conditions.
Intellectual disability is very common in most syndromic ASDs. Impulse control disorders
are sometimes diagnosed in individuals with FXS.
Medical problems are highly prevalent in syndromic ASD. Past medical history(PMH)
should capture specific medical problems. Seizures are common in individuals with RTT,
TSC, Phelan–McDermid syndrome, FXS, and metabolic disorders. Individuals with meta-
bolic or mitochondrial diseases often have other severe neurologic symptoms. Individuals
with VCFS often have congenital malformations of the cardiovascular system. In addition
to cardiovascular problems, individuals with VCFS may have recurrent infections due to
thymic dysfunction, and they may have convulsions due to hypocalcemia secondary to
malfunctioning parathyroid glands. Due to the frequent occurrence of brain tumors in
NF1, TSC, and PTEN-related conditions, focal neurologic deficits may be reported in
PMH. Extremely low cholesterol level may be related to a mutation of the DHCR7 gene
(i.e., SLOS).
Developmental history may include an account of any problems during pregnancy
and labor, as well as a thorough history of developmental milestones. Environmental
contributions due to hypoxia during pregnancy and labor should be noted. Regression
of gained developmental milestones should also prompt the clinician to include RTT
and mitochondrial diseases as differential diagnoses and to consider referral for genetic
workup. In taking the family history, a three-generation family history with pedigree
analysis is recommended. This analysis will help the clinician determine patterns of
inheritance. For example, a boy with a maternal uncle with FXS (or symptoms com-
mon in FXS) and/or a mother with a mild learning disability should be considered for
referral for genetic evaluation and specific genetic testing for FXS. Social history may
include the usual information on the patient’s living environment, along with the par-
ents’ occupations and ages. Increased paternal age is associated with de novo mutations
of ASD-related genes.
Physical examination may include heart auscultation; examination of the face, head,
skin, hands, and feet; as well as determination of height, weight, and head circumference.
Facial fibrous angiomatous lesions (adenoma sebaceum), hypopigmented macules (ash leaf
spots and confetti hypopigmentation), shagreen patches, and periungual fibromas (deter-
mined with Wood’s lamp) are classic findings of TSC. Submucosal cleft palate and nasal
speech are sometimes found in patients with VCFS. Finger syndactyly can be found in indi-
viduals with Timothy syndrome. Macrocephaly can be found in patients with PTEN muta-
tions, FXS, and Sotos syndrome. Microcephaly is a common feature of individuals with
RTT (especially when the head size is normal in the first few months of life), MeCP2 dupli-
cation, and certain metabolic syndromes (e.g., methylene tetrahydrofolate reductase defi-
ciency). Readers interested in advanced examination of dysmorphic features are referred to
the Autism Dysmorphology Measure (Miles et al., 2008).
The mental status examination is dependent on developmental age, and it may con-
sist mainly of behavioral observations. Hand wringing in a girl with ASD symptoms
may remind the clinician of RTT. Frequent inappropriate laughter is sometimes found in
individuals with Pitt–Hopkins syndrome, Angelman syndrome, Christianson syndrome,

Mowat–Wilson syndrome, and adenylosuccinate lyase deficiency.
Decision on Referral for Further Workup and Consultations of Other Specialists
As of March 2015, there were 706 genes associated with ASD. (The Simons Foundation
Autism Research Initiative (https://gene.sfari.org/autdb/HG_Home.do) maintains a
comprehensive, up-to-date database for all known human genes associated with ASD.) In
a community sample of children with ASD, the diagnostic yield for chromosomal microar-
ray was 24% (McGrew, Peters, Crittendon, & Veenstra-Vanderweele, 2012). Due to the
importance of the genetic component of ASD, the 2014 practice parameter for the assess-
ment and treatment of individuals with ASD published by AACAP recommended routine
genetic testing of children with a diagnosis of ASD (Volkmar et al., 2014). As a first tier,
in addition to microarray, the ACMG practice guidelines recommend the inclusion of
DNA testing for FXS. DNA testing for FXS ( Johnson et al., 2007; Schaefer & Mendelsohn,
2013) should be performed routinely for male or female patients with ASD; it should
also be ordered for male or female patients with unexplained intellectual disability. For
patients with symptoms of seizures, extrapyramidal signs, failure to thrive, or regression,
metabolic and/or mitochondrial testing are recommended. The AAP, AAN, and ACMG all
recommended audiogram as part of the evaluation occurring early in the workup for ASD.
Electroencephalogram is also recommended if there is a history or suspicion of seizures.
Referral to geneticists will be obtained when physical examination suggests dys-
morphology and/or history indicates unusual features (as described in the previous
section). According to the ACMG practice guidelines, geneticists’ second-tier workup
may include MeCP2 sequencing (to be performed for all females with ASDs), MeCP2
duplication testing (in males, if phenotype is suggestive), PTEN testing (only if the head
circumference is greater than 2.5 SD above the mean), and fibroblast karyotype (if pig-
mentary anomaly is evident). For patients with microcephaly, regression, seizures, sus-
pected diagnosis of TSC, and history of stupor/coma, magnetic resonance imaging of the
brain is recommended.
CLINICAL CASES
CASE STUDY #1
A 23-year-old woman is referred to you for long-standing symptoms of anxiety and social
avoidance and recent onset of depression. In the process of conducting your history and
mental status examination, you discover that she lives at home and has a history of learn-
ing and attentional problems with below-average grades throughout school. She also has a
brother with significant intellectual disability and ASD and a (maternal) grandfather with a
progressive tremor–ataxia syndrome. Diagnostically, she might meet current or past criteria
for social or generalized anxiety disorder, ADHD, specific learning disorder or intellectual
disability, and a depressive disorder. Indeed, based on the DSM, she might receive two
or more “comorbid” diagnoses. In the best of circumstances, you might offer this patient
individual and/or group therapy, perhaps an antidepressant, and work with the patient and
her family to determine how to optimize her social supports and vocational potential given
her cognitive and psychiatric disabilities. This approach is symptom-focused and (it is hoped)
based on the clinician’s knowledge of evidence-based clinical trial results. Alternatively, the
clinician conducting the initial evaluation might be aware that the patient’s personal and
family history, as well as current symptoms, is consistent with a diagnosis of FXS, a rela-
tively common genetic condition associated with mutations of the FMR1 gene on the X
chromosome.
You send this young woman for genetic testing, and she is confirmed to be heterozy-
gous for the fragile X full mutation. You then refer this patient (and her family) to a genetic
counselor. Based on the recommendations of the National Society of Genetic Counselors
(McConkie-Rosell et al., 2005), your patient and her family are counseled on reproduc-
tive issues, medical issues (e.g., premature ovarian insufficiency in female carriers of the
premutation and fragile X-associated tremor–ataxia syndrome in older male carriers of the
premutation), and family planning, and they are given resources to consult with knowledge-
able health care providers in the patient’s area and support groups.
CASE STUDY #2
A 17-year-old male teenager with mild developmental disability, poor social motivation,
history of mild obsessive–compulsive symptoms, and possible paranoia is brought to the
emergency room by police after he threw a DVD case at his father and pushed his mother.
After a psychiatric evaluation, he is diagnosed with impulse control disorder and is admitted
to an inpatient psychiatric unit, where you are one of the attending psychiatrists.
As you enter the interview room, you see that the patient has mildly dysmorphic facial
features (narrow palpebral fissures and a broad nasal bridge). You further note that he
has nasal speech. After you speak with him and his parents, you come to the preliminary
conclusion that past and present aggressive behaviors are likely associated with parents’
limit-setting and noncompliance with parental instructions. The teenager also discloses to
you that his classmates have been ganging up on him. His parents endorse that he has
been a victim of bullying for years, and he has no friends at school. The patient has a long
history of problems with anxiety, including mild obsessive–compulsive symptoms, and has
been taking citalopram for 8 years. Past medical history is significant for early surgery to
repair a congenital cardiac defect.
As you formulate this case, you wonder if the aggressive behaviors, developmental
disability, dysmorphic facial features, and medical history could be explained by a single
genetic diagnosis. You order chromosomal microarray analysis, which shows a hemizygous
microdeletion of 2 Mb on the long arm of chromosome 22. This patient is diagnosed with
22q11 deletion syndrome (or VCFS), which is often associated with ASD and a variety of
psychiatric problems, including psychosis.
KEY POINTS
• The combination of ASD phenotype and specific characteristics (physical pheno-
types, other cognitive–behavioral phenotypes, medical history, and family history)
may be used to support testing for genetic abnormalities and confirming diagnosis of
genetic disorders.
• The major classes of genetic disorders are monogenic diseases, chromosomal dis-
eases, metabolic diseases, and mitochondrial diseases.
• The most salient cognitive–behavioral and physical features as well as genetics and
molecular biology of eight syndromes (fragile X syndrome, Rett syndrome, neuro-
fibromatosis type 1, tuberous sclerosis, Smith–Magenis syndrome, velocardiofacial
syndrome, XYY syndrome, and Smith–Lemli–Opitz syndrome) are discussed.
• Due to the importance of the genetic contribution to ASD, the American Academy
of Child and Adolescent Psychiatry recommends routine genetic testing of children
with a diagnosis of ASD. A systematic approach for considering genetic evalua-
tion of individuals with ASD diagnosis is presented in this chapter to guide clini-
cians to make decisions on ordering genetic testing and further referrals to medical
geneticists.
• Recognition of genetic syndromes is not only helpful in understanding psychiatric
symptoms but also critical in triggering support for medical problems associated with
the genetic abnormalities.
Dr. Lawrence K. Fung has nothing to disclose.

Dr. Allan L. Reiss was a consultant for Novartis and Genentech.
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9 / / /
/ / / AUTISM SPECTRUM DISORDER
IN THE ELDERLY
PETER V. RABINS
INTRODUCTION
A perusal of geriatric psychiatry textbooks published in English reveals nothing written

about the care of elderly individuals with autism spectrum disorder (ASD). It is only in
recent years, with the increasing recognition of ASD as a prevalent disorder of children
(Boyce et al., 2011; Fombonne, 2003), that questions about the life course and progno-
sis of childhood ASD have begun to emerge (Howlin & Moss, 2012; Piven & Rabins,
2011; Smith, Maenner, & Selzer, 2012). This chapter initially uses the terms “autism” and
“Asperger syndrome” to examine autism in the elderly because those were the terms in use
before publication of the fifth edition of the Diagnostic and Statistical Manual of Mental
Disorders (DSM-5; American Psychiatric Association, 2013), when currently elderly indi-
viduals would have been initially diagnosed and treated. The term “autism spectrum disor-
der” (ASD) is used when appropriate.
There are several possible explanations for the paucity of information about ASD in
older persons. One plausible reason is that Leo Kanner’s initial 1943 description of 11 cases
of “autistic disturbances of affective contact” (p. 250) as a syndrome characterized by a
“combination of extreme autism, obsessiveness, stereotypy, and echolalia” (Kanner, 1943,
p. 248) described children who would now be in their 70s and 80s. Because there were so
few child psychiatrists at that time, it is plausible that the condition was significantly under-
diagnosed in the 1940s and 1950s, when the current cohort of elders was born.
Although Kanner (1943) believed that the “pathognomonic” feature was “the children’s’
inability to relate themselves in the ordinary way to people and to situations from the begin-
ning of life” (p. 242) and distinguished this illness from schizophrenia because of its lack of
hallucinations and delusions and by its onset very early in life, other American psychiatrists
disagreed and included the disorder within the construct of childhood schizophrenia. This
is illustrated in the DSM-I and DSM-II criteria used in the 1950s–1970s. Thus, misdiag-
nosis early in life followed by lack of reconsideration once individuals achieved adulthood
is another possible explanation for the dearth of elderly cases seen in clinical settings and
research.
A third possible explanation for the paucity of elderly persons identified as having ASD
is that the disorder changes over time. This would require that the symptoms completely
139
(or mostly) resolve (it is “outgrown”) or that they evolve into a different set of symptoms
(e.g., dementia).
A fourth possibility to explain the seeming rarity of autism in the elderly is differential
mortality or “survival bias.” This would include early death from autism compared to the
general population, early death from medical or social conditions associated with autism,
or both.
Kanner was very focused on using outcome as a measure of both prognosis and validity
of the syndrome. In 1971, he reported the 28-year follow-up of some of the first 11 cases
he had diagnosed. He described 4 as having a poor outcome, 1 “a state of limited but posi-
tive usefulness,” and 2 “real success stories.” This suggests that, at least into early and mid-
adulthood, the syndrome does not dramatically change for many individuals, but Kanner
emphasized the improvement in several of his cases and attributed that improvement to
supportive care. A similar conclusion was reached by Kanner in 1973 when he reported on
the long-term follow-up of 96 individuals followed for 15–30 years. He reported that 7%
lived independently, 11% were working, and that intelligence quotient (IQ) was the best
predictor of a positive outcome.
Howlin, Goode, Hutton, and Rutter (2004) reported similar outcomes in a cohort from
Britain followed for a mean of 28 years. Twenty-two percent of the individuals they fol-
lowed had a good or very good outcome, 4% were living independently, and 18% had a poor
or very poor outcome. They too found that outcome was better if IQ was greater than 70
but that a “normal IQ” was not necessarily associated with positive outcome.
Hans Asperger, a Viennese pediatrician, first described what he called “autistic psy-
chopaths” in 1944. His work did not come to the attention of the English-speaking world
until the early 1980s when renowned British child psychiatrist Lorna Wing identified it as
a neglected but important childhood syndrome. Hippler and Klicpera (2003) were able to
identify 74 cases seen by either Asperger or his major assistants between 1950 and 1986.
All had an IQ greater than 84. They described 95% as having language “deviancies,” 82%
as having “special narrow interests,” and 35% as having “deviant eye contact.” Twenty-five
percent met DSM criteria for autism.
Taken together, these follow-up studies suggest that many individuals with ASD con-
tinue to be symptomatic at least through mid-life, but they also show that a minority of indi-
viduals have improved. They do not eliminate the possibility that improved early treatment
would alter the course of ASD. Neither do they eliminate the possibility of higher mortality
rates in persons with ASD, but they indicate that this is unlikely to be the primary reason for
the very low rate of diagnosed ASD in older adults.
EPIDEMIOLOGY
The best population-based data for examining the prevalence of autism in later life are
from the British epidemiologic study of Brugha et al. (2011). They reported an overall
prevalence in adults of 9.8/1000 or approximately 1%, similar to the rate reported by
the Centers for Disease Control and Prevention of 1/110 births in the United States
at the time the British study was being carried out. More relevant to the current dis-
cussion, Brugha et al. also found a non-statistically significant decline in prevalence
across the adult age span. This is in contrast to US epidemiological studies that report
no cases after age 60 years. The Brugha et al. study was specifically designed to identify
persons with autism, suggesting that epidemiologic studies designed to detect psychi-
atric disorders in adults, broadly defined, either do not identify autism in the elderly
or systematically exclude them based on method, instrumentation, or sampling frame.
Autism Spectrum Disorder in the Elderly // 141
The non-statistically significant decline in autism prevalence reported by Brugha et al.

does not eliminate differential mortality or an evolution of symptoms because the small
number of older cases lacks statistical power to detect such a change, but it does demon-
strate that the use of current criteria can identify elderly individuals with the disorder.
However, as Brugha et al. noted, their results are strongly influenced by their use of the
standard Autism Diagnostic Observation Schedule-4 (ADOS-4) cutoff of 10 to deter-
mine prevalence. A higher or lower cutoff on this continuous scale would yield very
different results, and it is plausible that a different cutoff would better balance sensitivity
and specificity across the adult age span. In univariable analyses, male sex, not owning
one’s own home, having lower education, and having a lower verbal IQ all correlated
with the presence of ASD. In a multivariable model, however, only male sex, low educa-
tion, and lack of home ownership correlated with ASD.
CHANGES IN DIAGNOSTIC CRITERIA
From the perspective of persons currently older than age 60 or 65 years, autism was first
identified when they were children or adolescents, and Asperger syndrome was not rec-
ognized in the English-speaking world until they were adults. Disagreements over classi-
fication when they were young are likely to have contributed to underrecognition because
some individuals would have been diagnosed with childhood schizophrenia, whereas indi-
viduals with Asperger syndrome would not have been diagnosed because the diagnosis was
not known in the English-speaking world during their youth.
Diagnostic practices have undoubtedly improved during the past two decades and led
to enhanced recognition of ASD in children. However, this cannot be said with any con-
fidence about adults who were not recognized when they were children. These changes
in diagnostic practice are well illustrated by the widely cited study of Croen, Grether, and
Selvin (2002), which demonstrated that between 1987 and 1994, the diagnosis of men-
tal retardation declined by 9/10,000 and the diagnosis of autism increased by 9/10,000.
Another change in diagnostic practice that would lead to underrecognition of ASD in now
elderly individuals is the recognition that it can be comorbid with other disorders. For
example, 30-50% of children with fragile X syndrome and 15-30% of children with Down
syndrome are now identified as also having features of ASD. (It is worth noting that fragile
X syndrome had not been identified when the current cohort of elders was young.) Hence,
older individuals with ASD and lifelong intellectual disability would likely carry a diagnosis
of only intellectual disability.
Strong support for the claim that misdiagnosis significantly contributes to low reported
rates of ASD in American elders is provided by the intriguing study of Mandel and cowork-
ers (2012), who found that 9.9% of elderly adults in one state hospital in Pennsylvania met
criteria for lifelong autism but had all been diagnosed in adulthood as having schizophre-
nia even though their records documented that they had not experienced hallucinations
or delusions at any time during their many years of hospitalization. A small British case
series suggests that misdiagnosis and nonrecognition similarly occur in older adults with
Asperger syndrome ( James, Mukaetova-Ladinska, Reichelt, Briel, & Scully, 2006).
PROGNOSIS OF AUTISM SPECTRUM DISORDER ACROSS THE LIFESPAN
As noted previously, Kanner examined the prognosis in cases he had diagnosed with child-
hood autism and found improvement over time in some individuals but a persistence of
symptoms and sustained impairment in many. Subsequent studies (Smith et al., 2012) have
borne out this finding.
However, excess mortality in persons with autism has long been known and appears to
continue to the present. For example, studies by Shavelle, Strauss, and Pickett (2001) and
Mouridsen, Brønnum-Hansen, Rich, and Isager (2008) demonstrate two or three times
higher rates of mortality in children with autism. Seizures and accidents appear to be the
primary causes. In addition, intellectual disability is associated with a 13-year shorter life
expectancy (Heslop et al., 2014), and this is likely true of persons with both intellectual
disability and ASD. Thus, the possible decline in prevalence found by Brugha et al. (2011)
across adulthood might, in part, reflect differential mortality. This is likely to be less of
an issue in the future for two reasons. First, medical care has improved over time so that
cohorts of persons with ASD born in recent years are likely to survive medically comorbid
disorders that they might have succumbed to in the past. However, seizure disorder still
carries an elevated risk of early mortality (Sillanpää, Jalava, Kaleva, & Shinnar, 1998), so
this increased mortality risk will persist until this issue is resolved. Second, the provision of
services in the community might avoid some of the mortality that would have been associ-
ated with institutionalization in the past. Third, the broadening of the concept of autism to
ASD includes more individuals without the medical comorbidity associated with the more
severe phenotype.
Longitudinal studies demonstrate that daily function abilities decline as persons with
ASD age (Smith et al., 2012). Whether such decline is different than that experienced by
those without ASD as they age is unknown, but persons with intellectual disability have
more significant impairments (Smith et al., 2012).
CURRENT PERSPECTIVES
The question posed at the beginning of this chapter concerning why so few elders are
diagnosed with ASD seems to have multiple answers. Lack of recognition when they were
young, misdiagnosis, shorter life expectancy, and a failure to consider the diagnosis in an
older person with lifelong psychiatric symptoms all contribute. Heightened awareness
might bring needed services to elders who meet criteria for ASD, although this has not
been demonstrated empirically.
As reviewed elsewhere in this text, the incidence and prevalence of ASD have been
increasing dramatically. Although some of this change is likely due to evolving diagnostic
practice, this does not appear to explain the entire phenomena. As the current cohort of
individuals with ASD moves through adulthood into older age, several challenges will need
to be addressed and should begin to be studied now.
First, what is the prognosis and course of autism into old age? For example, are there
cognitive (Guerts & Vissers, 2012) and functional (Smith et al., 2012) changes that are
specific or more likely to occur in persons with ASD than in age-matched individuals with-
out ASD? Second, are there specific therapeutic, psychosocial, and environmental issues
that occur with age that will affect persons with ASD differentially than those aging with-
out ASD? For example, effective therapies have been developed to help persons with ASD
address developmental transitions such as starting school, graduating from high school,
and moving into the workforce. Are there similar transitions experienced in older age—for
example, death of a parent, the development of new-onset health conditions, or the need to
move to a new living setting—that would benefit from specific intervention? Are there spe-
cific medical conditions that persons with ASD are prone to develop as they age, or might
medical care need to be provided in a specific way that would address the impairments with
which ASD is associated? As more effective therapies are developed for children and young
adults with ASD, will they need to continue in their present or an altered form as individu-
als move into older age? This possibility is highlighted by the finding of Kats, Payne, Parlier,
and Piven (2013) that 40–60% of adults identified as having ASD required services to man-
age destructive, disruptive, or self-injurious behaviors. Although the individuals identified
in this study are likely to represent those with more severe ASD, the increasing prevalence
of ASD suggests that more such services will be required unless methods for preventing
such outcomes are developed.
Clinical experience suggests that individuals with more severe ASD fare poorly when
faced with the many changes in social support, medical care, and living arrangements that
are common in later life. Descriptive studies and intervention trials are needed to deter-
mine whether this is the case; whether people with ASD are at higher risk of developing
specific psychiatric, neurologic, or medical comorbidities, including dementia, than older
individuals without ASD; and whether specific interventions can moderate or eliminate
any increased risk of adverse outcome. The case described next illustrates the potential
benefits of such research. This individual had a lifelong disorder that impaired his ability
to function socially. However, the lack of recognition that he had features of ASD led to
chronic institutionalization, chronic exposure to high-dose neuroleptics, tardive dyskine-
sia, and the lack of access to an environment that could meet his needs. Improved recogni-
tion of ASD and the development of services to meet the needs of people with ASD across
the lifespan should mitigate such unnecessary and inappropriate outcomes.
CASE STUDY #1
A 62-year-old man was referred to a geriatric psychiatry outpatient clinic by the nursing
home where he had resided for 3 years. It was requesting assessment of intermittent,
physically aggressive behavior. He had been on high-dose neuroleptic medications for
years because of these “outbursts,” and the facility was concerned that there might not
be justification for continuing neuroleptic medications under CMS (Medicare) guidelines.
There was a paucity of history. His parents had died many years before, and other fam-
ily had not been identified. As a result, he was a ward of the state. He had resided in a
state psychiatric hospital for much of his adult life, but these records were not available
at the time of the initial consultation. The accompanying note described the episodes of
“aggression” as occurring once or twice a month; being very upsetting to other residents
and staff; and consisting of yelling out, shaking his fists at people, and hitting furniture or
walls very hard. The referring facility was concerned that he would harm himself or oth-
ers during the episodes and wanted to continue the quetiapine 250 mg QHS that he had
been on since admission. When asked, the staff reported no behavior suggesting hal-
lucinations or delusions. Except for hypertension, he was in good health. His only other
medications were lisinopril and docusate sodium. Mental status examination revealed a
round-faced, well-nourished man who sat throughout the examination. He looked at the
examiner only fleetingly; most of the time, he looked laterally to the right of the exam-
iner but occasionally made very brief eye contact when asked a question. He was able
to move his eyes in all directions when asked to do so. He had dyskinetic movements
of his lips, jaw, and fingers. In addition, he would tap his fingers in a stereotyped man-
ner for 30- to 60-second stretches throughout the examination. Spontaneous speech
was sparse. He did not answer many questions. The answers he did give consisted
of very few words. He usually repeated the phrase, “You bet your life,” when a “yes”
answer was indicated. No language errors were noted, and when he did speak, his
answers were congruent with the situation. When asked if he liked where he was living,
he replied, “It’s ok.” He had limited range of emotional expression but denied sadness.
He answered “no” when asked about hallucinations. No suspiciousness or delusions
were elicited. He did not answer questions about suicide. On cognitive examination, he
was oriented to city, month, and year but not day, date, or place. He knew the name of
the president. He recalled one of three objects in 2 minutes, but he did not attempt to
do math or spell a five-letter word backwards. He was able to follow a three-step com-
mand, name common and uncommon objects, and copy interlocking pentagons. He did
not answer questions about insight or his illness. A screening neurological examination
was normal except for the dyskinetic mouth and hand movements.
A working diagnosis of ASD was made based on a many-year (probably lifelong) history
of social isolation, poor eye contact, stereotyped finger tapping, sparse and stereotyped
but grammatically correct language, lack of any history of hallucinations and delusions,
intact activities of daily living, and stable cognition during the several-year period that he
had lived in the facility. The “outbursts” were interpreted as occurring when routines were
changed or when staff “insisted” that he do an activity.
A treatment plan was devised that emphasized avoidance of confrontation and ultima-
tums by the staff. They could recognize when he was becoming frustrated or upset and
were instructed to “back off” rather than persist. A gradual tapering schedule for the que-
tiapine was initiated.
The state hospital records were received 3 months later. He had entered the state hos-
pital system at age 18 years, 6 weeks after starting a job as a firefighter, the occupation of
his father. He had gotten into an altercation with an instructor and had been remanded to
the state hospital by the judge who oversaw the initial arraignment. A diagnosis of chronic
undifferentiated schizophrenia had been made based on his social isolation, “uncoopera-
tiveness,” seeming inability to adapt to social expectations, and lack of hallucinations and
delusions. Numerous attempts at placement throughout his adult life had failed; his records
attributed this to an “inability to adapt” to the demands and routine of the placements and
his development of “violent” behavior for that reason. The records confirmed that he had
not declined functionally or cognitively throughout adulthood.
At 6-month follow-up, the quetiapine had been discontinued. The staff reported that
he still became “upset” once or twice a month but that they could quickly “de-escalate”
the situation by early recognition, avoidance of pressure on him, and “apologizing” for
“stressing him.”
KEY POINTS
• The life course of ASD is poorly studied, but variable outcome is likely.
• Broad epidemiologic studies have not been adequately designed to detect autism
in older individuals, but focused studies in England suggest a prevalence after age
60 years of approximately 1%.
• Older adults with ASD likely have unique medical, occupational, and social needs,
but these are yet to be explicated.
• Whether early intervention will change the life course of ASD is unknown, but many
individuals born before the current era were not recognized or diagnosed when
young and therefore did not have early treatment.
• It is unknown if individuals with ASD are more or less likely to develop comorbid
dementing illness compared to neurotypical individuals.
Dr. Peter V. Rabins has provided legal testimony for Janssen Pharmaceutica.
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(2011). Trends in the prevalence of developmental disabilities in US children 1997–2008. Pediatrics,
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of autism spectrum disorders in adults in the community in England. Archives of General Psychiatry, 68,
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Kats, D., Payne, L., Parlier, M., & Piven, J. (2013). Prevalence of selected clinical problems in older adults
with autism and intellectual disability. Journal of Neurodevelopmental Disorders, 5, 27–39.
Mandel, D. S., Lawer, L. J., Branch, K., Brodkin, E. S., Healey, K., Eitalec, R., . . . Gur, R. E. (2012). Prevalence
and correlates of autism in a state psychiatric hospital. Autism, 16, 557–567.
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Smith, L. E., Maenner, M. J., & Selzer, M. M. (2012). Developmental trajectories in adolescents and adults
with autism: The case of daily living skills. Journal of the American Academy of Child and Adolescent

/////////////////// S ECT ION 2 / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / /
ETIOLOGY
/ / /
10 / / / NEUROIMAGING OF AUTISM
SPECTRUM DISORDER
NICOLE R. ZÜRCHER AND JACOB M. HOOKER
MAGNETIC RESONANCE IMAGING

Anatomical/Structural Magnetic Resonance Imaging
Anatomical magnetic resonance imaging (aMRI), also known as structural MRI (sMRI),
refers to magnetic resonance imaging that allows in vivo investigation of brain anatomy.
MRI is a noninvasive technique that provides high spatial resolution (state of the art is at
~1 mm and routine clinical is at ~2 or 3 mm), excellent soft tissue contrast, and is generally
considered safe. See the top left panel of Figure 10.1 for an example of an anatomical scan
image obtained using MRI.
Although numerous studies have reported neuroanatomical abnormalities in individu-
als with autism spectrum disorder (ASD), there is no consensus on which brain regions are
the most affected. According to findings from sMRI experiments, the frontal and temporal
lobes, cerebellum, corpus callosum, as well as the limbic system (including the amygdala)
are the brain regions most often implicated in ASD.
Early sMRI reports described abnormalities in the cerebellum (reviewed in Courchesne
et al., 2007). Developmental differences in cerebellar volume indicate that the normal time
course of neural development is disturbed in ASD compared to typically developing con-
trols. Current findings suggest that although individuals with ASD exhibit early brain over-
growth during infancy and toddlerhood, they show a faster rate of decline in cerebellum
size later in life (Courchesne, Campbell, & Solso, 2011). Interestingly, abnormalities in the
cerebellum were among the earliest reported neuroanatomical findings from postmortem
histological studies in ASD (Bauman & Kemper, 1985) and have been replicated numerous
times. In addition, histological studies have shown loss of Purkinje cells in the cerebellum
(e.g., Kemper & Bauman, 1998), leading researchers to suggest that this decrease in cerebel-
lar size could be due, at least in part, to a loss of Purkinje cells.
Another brain region for which neuroanatomical abnormalities have been reported in
ASD are limbic structures, for which both increases and decreases in volume have been
reported (for a review, see Palmen, van Engeland, Hof, & Schmitz, 2004). Differences
in amygdala size observed between individuals with ASD and typically developing indi-
viduals seem to result from abnormal growth trajectory in ASD (reviewed in Amaral,
149
150 / / E tio l og y
STRUCTURE • Neuroanatomy
• White matter fiber tracts
aMRI diffusion MRI
FUNCTION • Brain function during task or rest
fMRI EEG
MOLECULAR • Neurochemical targets

INFORMATION (e.g. neurotransmitter systems,
density of proteins and receptors)
• Glucose metabolism
• Cerebral blood flow
PET SPECT
FIGURE 10.1 Illustration of the different neuroimaging techniques discussed. Top panels show an
anatomical MRI scan (left) and tractography from a diffusion scan (right). Middle panels show
a statistical map of a functional MRI scan projected onto the surface of the brain (left) and EEG
spectrograms at different electrode sites. Bottom panels illustrate a color scale representation of
PET (left) and SPECT (right) radiotracer binding overlaid on an anatomical MRI image.
Schumann, & Nordahl, 2008). In accordance with sMRI studies, histological studies have
also reported abnormalities in the amygdala, such as decreased neuron number (Schumann
& Amaral, 2006).
To address the effect of age on ASD neuroanatomy, longitudinal studies will need to be
performed. To date, most sMRI studies have been based on cross-sectional study designs,
which compare individuals with ASD to healthy controls at one point in time. In the first
longitudinal sMRI study of ASD, children were scanned multiple times between the ages
of 1½ and 5 years in order to investigate differences in growth trajectory. This study found
an abnormal growth rate in cerebral white matter and the gray matter of all lobes except
the occipital lobe—that is, the frontal, temporal, and parietal lobes, as well as the cingulate
(Schumann et al., 2010).
In addition to abnormalities in volume of anatomical structures such as the cerebel-
lum and the amygdala, changes in cortical thickness have also been observed in ASD.
In cross-sectional studies, both increases and decreases in cortical thickness have been
reported in brain regions across all lobes in ASD (for a review, see Chen, Jiao, & Herskovits,
2011). The first longitudinal study investigating developmental changes in cortical thick-
ness in children with ASD (8–12 years at baseline, subsequent follow-up ~2 years later)
showed that the decrease in cortical thickness over time across frontal, temporal, and occip-
ital lobes was greater in ASD compared to controls (Hardan, Libove, Keshavan, Melhem,
& Minshew, 2009). Recently, a large longitudinal study that included individuals with ASD
Neuroimaging of Autism Spectrum Disorder // 151
from early childhood (3 years) to adulthood (up to 36 years), scanned at an average inter-
scan interval of 2.6 years, showed that group differences in cortical thickness were region
specific, changed depending on developmental age, and were influenced by intelligence
quotient (Zielinski et al., 2014). In this study, Zielinski and colleagues showed increased
cortical thickness in childhood and decreased cortical thickness in adulthood, suggesting
that in individuals with ASD, regional volume and cortical thickness measurements follow
a similar path of early overgrowth followed by accelerated decline.
Diffusion Magnetic Resonance Imaging
Diffusion imaging allows assessment of the structural organization of white matter. See the
top right panel of Figure 10.1 for an example of white matter fiber tract data obtained using
a diffusion scan. The technique relies on the principle that water is more likely to diffuse
along white matter fiber tracts than to diffuse across them. Fractional anisotropy (FA) is a
measurement used to assess the spatial symmetry of the diffusion. If water can diffuse in all
directions equally, the diffusion is referred to as isotropic, whereas diffusion restricted in a
specific direction, thereby resulting in higher FA values, is referred to as anisotropic.
Diffusion experiments have shown that individuals with ASD exhibit altered diffu-
sivity in the corpus callosum, cingulum, and areas of the temporal lobe (for a review of
diffusion studies in ASD, see Travers et al., 2012). However, diffusion experiments are
highly sensitive to motion artifacts and must be interpreted with caution unless specific
measures have been taken to control for between-group differences in motion. A recent
study that controlled for differences in motion between children with ASD and controls
found that children with ASD showed abnormalities in the right inferior longitudinal fas-
ciculus that connects the temporal lobe to the occipital lobe. The abnormalities included
reduced FA, suggesting reduced tract integrity in this particular brain region in children
with ASD (Koldewyn et al., 2014).
MRI technology is still being optimized, and the latest generation scanners, such as the
Connectome scanner (Setsompop et al., 2013), now allow more detailed investigation of
neuroanatomy in ASD.
Functional Magnetic Resonance Imaging
The vast majority of functional MRI (fMRI) experiments use blood oxygen level-dependent
(BOLD) contrast to investigate brain activity while participants perform a specific
task or are at rest (resting state fMRI). The BOLD contrast arises from the fact that the
quantity of oxygen in the blood—that is, the concentration of oxyhemoglobin versus
deoxyhemoglobin—will affect the magnetic susceptibility of blood. The combined effects
of increases in the cerebral metabolic rate for oxygen, cerebral blood volume (CBV), and
cerebral blood flow (CBF) lead to an increase in BOLD signal, which is used as a proxy for
an increase in neural activity. BOLD therefore does not directly measure neural activity
but instead represents a hemodynamic signal that depends on changes in the blood sup-
ply. Although BOLD is the most widely used contrast, others, such as CBF or CBV, can be
used. Compared to CBF measurements assessed using arterial spin labeling, BOLD has a
higher spatial resolution and a higher signal-to-noise ratio. This chapter focuses on BOLD
contrast experiments. For an example of a BOLD fMRI map, see the middle left panel of
Figure 10.1.
Not surprisingly, a large number of fMRI studies of ASD have focused on social cogni-
tion, given that social deficits lie at the core of the disorder. A meta-analysis of fMRI stud-
ies of ASD conducted by Philip and colleagues (2012) concluded that abnormalities in
social brain regions are the most replicated findings. Numerous abnormalities have been
observed in individuals with ASD during sociocognitive tasks, including face processing,
eye gaze, and emotion processing. Earlier studies reported decreased fusiform face area
(FFA) activation when individuals with ASD passively view faces (Schultz et al., 2000).
However, more recent studies have shown that when participants with ASD are cued to the
eye region, they display FFA activation to the same extent as controls (Hadjikhani et al.,
2004). In addition, whereas individuals with ASD show reduced activation in the FFA for
unfamiliar faces, they show normal activation for familiar faces (Pierce & Redcay, 2008).
These studies suggest that attentional and motivational processes likely play a key role in
face processing in ASD.
Theory of mind (ToM), which refers to the ability to attribute intentions, feelings, and
beliefs to others, is impaired in most individuals with ASD. The brain regions involved in
ToM include the medial prefrontal cortex, superior temporal sulcus, inferior frontal regions,
and the temporal pole (Frith & Frith, 2003; Gallagher & Frith, 2003). Studies using fMRI
have started to investigate the neural underpinnings of deficits in mentalizing (ToM) abili-
ties in ASD and have found decreased activation in the brain regions associated with ToM
in individuals with ASD (reviewed in Philip et al., 2012). Some fMRI studies have also
suggested involvement of the mirror neuron system in ASD (e.g., Dapretto et al., 2006).
Atypical neural activation has also been observed in tasks assessing motor function,
visual processing, audition, language processing, communication, and executive function-
ing in individuals with ASD (reviewed in Philip et al., 2012; Stigler, McDonald, Anand,
Saykin, & McDougle, 2011).
Functional Connectivity
Studies involving task-based and resting state functional connectivity MRI (fcMRI) experi-
ments are used to investigate functional connectivity between brain regions. Functional
connectivity examines how activity in one brain region correlates with the activity of
another brain region, thereby allowing investigation of functional nodes within a net-
work (Stevenson, 2012). Whereas diffusion imaging investigates structural connectivity
between brain regions (i.e., the presence of white matter fiber tracts connecting one part of
the brain to another), functional connectivity assesses the temporal correlation in BOLD
signal between brain regions.
In ASD, underconnectivity of brain areas has most often been observed, but overcon-
nectivity has also been reported (for a review, see Muller et al., 2011). Network dysfunction
leading to deficits in interregional information exchange may be related to ASD symptoms
because large-scale brain circuits are likely essential for intact social and communication
skills (Courchesne et al., 2007).
ELECTROENCEPHALOGRAPHY
Electroencephalography (EEG) is a noninvasive neuroimaging technique that involves

recording electrical signals through electrodes placed on the surface of the scalp. A major
advantage of using EEG is that it provides high temporal resolution, in the millisecond
range, which currently cannot be achieved with MRI. Another advantage of EEG is that
experiments can be designed without requiring participants to have language skills or the
ability to perform a task, which gives researchers the option of enrolling infants or non-
verbal individuals with ASD. However, compared to MRI, EEG has a much lower spatial
resolution. In addition, the EEG signal is strongly dominated by cortical activity and has
rather poor sensitivity for subcortical structures, such as the amygdala and hippocampus.
EEG activity is the ensemble of ionic currents generated by neurons in the range of the
electrode. It is characterized by the power of oscillations in specific frequency bands (EEG
power spectrum). These different frequency ranges are referred to as delta (1–3 Hz), theta
(4–7 Hz), alpha (8–12 Hz), beta (13–35 Hz), and gamma (>35 Hz) bands. Different pro-
cesses, such as sleep, attention, memory, and motor function, are characterized by a specific
pattern of activity in these frequency bands. In addition, the electrical activity of the brain
in response to a specific stimulus (e.g., a sensory or motor stimulus or cognitive task) can
be detected as event-related potentials (ERPs). These ERPs are considered “time-locked” in
response to an external stimulus and are composed of positive or negative peaks (indicated
by a P or N, respectively), which occur at a specific time (measured in milliseconds) follow-
ing stimulus presentation. Neural activation in response to sensory processing is observed
in the earlier components of the ERP signal, whereas later components reflect cognitive
processing. In addition to frequency bands and ERPs, recent studies have focused on coher-
ence, in which functional relationships are assessed between brain regions based on phase
correlation. See the middle right panel of Figure 10.1.
EEG was one of the first methods used in research to examine the underlying pathology
of ASD, and it has a long history in ASD research, with numerous studies reporting abnor-
mal EEG patterns in individuals with ASD. Another reason for the discussion of EEG mea-
sures in ASD research is the usefulness of EEG in diagnosing epileptic seizures. Given that
epilepsy is a common comorbidity with ASD, many individuals with ASD may undergo an
EEG procedure at some point to test for epilepsy, either as part of a clinical assessment or
as part of a research study.
Instead of EEG, magnetoencephalography (MEG) is sometimes used. Although MEG
also has high temporal resolution, those systems are currently less available than EEG.
Task-Based Studies
Numerous task-based studies have focused on perception and cognitive tasks especially in
the auditory and visual domains. Among others, experiments have included face and eye
gaze processing, attention, and language.
A number of ERP studies have focused on selective attention and attentional novelty
detection of auditory stimuli in ASD. The key component of those studies is the P300 ERP
(P3), which can be subdivided into P3a and P3b components. The P3a, with maximum
amplitude over frontal and central brain regions, is an index of attentional orienting, whereas
the late visual evoked parietal component P3b reflects higher-level processing. An ERP
study investigating sound processing found that individuals with ASD showed normal sen-
sory response to different sounds, including speech sounds (vowel changes), but reduced
P3a amplitudes, specifically in response to speech sounds (Ceponiene et al., 2003). Given
that the P3a component reflects attentional orienting, the authors concluded that audi-
tory orienting deficits in ASD might be speech–sound specific. Attention to novelty ERP
studies repeatedly found that auditory P3b response amplitudes are smaller for individuals
with ASD compared to the control group (reviewed in Jeste & Nelson, 2009). Courchesne
and colleagues reported decreased auditory P3b amplitude in high-functioning individu-

als with ASD, although the target detection task was performed as accurately and rapidly
as in controls, suggesting that individuals with ASD may be using alternative mechanisms
for target detection (Courchesne, Lincoln, Yeung-Courchesne, Elmasian, & Grillon, 1989).
Additional evidence suggesting that attention processing is atypical in ASD derives from
studies showing that in attentional tasks, individuals with ASD display increased connec-
tivity and synchronization and greater gamma activity compared to healthy individuals
(reviewed in Gepner & Feron, 2009).
Given its noninvasive nature and that it simply requires the participant to wear an elec-
trode cap, EEG can be used in young infants to search for the presence of abnormalities
in perceptual or cognitive processes early in life (Banaschewski & Brandeis, 2007). In an
interesting study, Elsabbagh and colleagues (2009) used EEG to investigate the broader
ASD phenotype by examining the response to direct eye gaze by infants with siblings with
autism compared to that of infants with unaffected siblings. For the P400 ERP, infants at
higher risk for developing ASD took longer to respond to the direct gaze stimuli compared
to infants with unaffected siblings. In infants, the P400 ERP is important for face process-
ing and has been suggested to be a precursor to the N170 ERP. N170 is associated with
face processing in adults and referred to as a face-sensitive component, which is localized
over the occipital/temporal electrodes—consistent with face processing areas including
the fusiform gyrus.
Resting State Studies
As is the case for fMRI, EEG can also be done in the absence of a specific stimulus presen-
tation or task to be performed and is referred to as resting state EEG. Resting state EEG
studies in individuals with ASD have often reported increased power in both low-frequency
(delta and theta) and high-frequency (beta and gamma) bands but decreased power in the
middle-range frequency (alpha) band (for a review, see Wang et al., 2013). In addition,
some resting state studies have found evidence of atypical lateralization, with increased
power observed in one hemisphere versus the other (reviewed in Wang et al., 2013).
For both task and resting state EEG, researchers have started searching for abnor-
malities in coherence, the correlation between signals measured at different electrodes.
Abnormalities in signal correlation across brain regions would suggest altered functional
integration between different areas. Whether deficits in functional connectivity of sponta-
neous EEG measures may underlie some of the core difficulties experienced by individuals
with ASD is currently the source of active investigation.
POSITRON EMISSION TOMOGRAPHY AND SINGLE PHOTON

EMISSION COMPUTED TOMOGRAPHY
The key strength of positron emission tomography (PET) and single photon emission
computed tomography (SPECT) is that each technique has high sensitivity and allows
for visualization and in many cases quantification of molecular events, such as the den-
sity of proteins and receptors. PET and SPECT can also be used to measure neurotrans-
mitter release and occupancy. In addition, PET can be used to investigate cerebral blood
flow and glucose metabolism, which have so far generated the highest number of stud-
ies in the field of ASD. In a typical PET or SPECT imaging experiment, a radioactive
contrast agent (known as a radiotracer) is administered intravenously to a research par-

ticipant or patient. Radioactivity (measured indirectly through positron annihilation in
PET or directly through gamma rays in SPECT) is detected in a scanner. The radiotracer
is administered at a very low mass dose and is intended to measure, but not perturb, the
biological state. Many study designs exist, but for rigorously quantitative data, PET is
preferred over SPECT with the disadvantage being that PET quantification can often
require arterial blood sampling, which can be potentially challenging for studies includ-
ing patients with ASD. For images of PET and SPECT scans, see the bottom panels of
Figure 10.1.
By far the most common techniques used in PET for ASD have been blood flow (typi-
cally with oxygen-15 radiotracers such as [15O]-water) and glucose metabolism, which
relies on the uptake and retention of the glucose analog 2-deoxy-2-(18F)fluoro-d-glucose
(often simply referred to as FDG).
One of the most interesting findings of CBF studies in ASD is the observation of
decreased blood flow toward the temporal lobe in children with ASD (Zilbovicius et al.,
2000). In addition, when listening to speech-like sounds, both children and adults with
ASD exhibit decreased blood flow toward the left temporal cortex and associated speech
areas, highlighting abnormal auditory cortical processing (Boddaert et al., 2003, 2004).
There is currently no consensus concerning glucose metabolism in individuals with
ASD because studies have reported hypometabolism, hypermetabolism, or no difference
when comparing individuals with ASD to controls (Buchsbaum et al., 1992; De Volder,
Bol, Michel, Congneau, & Goffinet, 1987; Haznedar et al., 2006; Herold, Frackowiak, Le
Couteur, Rutter, & Howlin, 1988; Rumsey et al., 1985; Siegel et al., 1992).
The most-studied neurotransmitter in ASD is serotonin. Abnormalities in serotonin
synthesis have been observed using the tracer α-[11C]methyl-l-tryptophan (AMT) in
the dentatothalamocortical pathway in individuals with ASD compared to their siblings
(Chugani et al., 1997). In addition, developmental abnormalities and an atypical trajec-
tory between 5 and 14 years have also been reported (Chugani et al., 1999). In children
with ASD, abnormalities in the dentatothalamocortical pathway, which consisted of local
increases or decreases in serotonin synthesis, were reported to be related to language func-
tion (Chandana et al., 2005). Two studies investigating the serotonin transporter (SERT)
found decreased levels of SERT in brain regions that included the medial frontal cortex
(Makkonen, Riikonen, Kokki, Airaksinen, & Kuikka, 2008), anterior cingulate, posterior
cingulate, and precuneus (Nakamura et al., 2010). Studies using tracers to target the sero-
tonin receptor have so far yielded mixed results, with one study reporting decreases and the
other reporting no difference compared to the control group (Girgis et al., 2011; Murphy
et al., 2006).
Although some studies have investigated neurotransmitters other than serotonin in
ASD (including dopamine, γ-aminobutyric acid, glutamate, and acetylcholine), more stud-
ies using radiotracers are needed to obtain a more clear understanding of the respective
neurotransmitter function/dysfunction in ASD.
SUMMARY
Key contributions from MRI, EEG, and PET/SPECT have furthered our understanding
of ASD because all these neuroimaging techniques allow the study of brain structure and
function in vivo. Differences in the underlying neuroanatomy have been observed in indi-
viduals with ASD using aMRI (especially in the cerebellum and limbic system), whereas
fMRI experiments have shed light on social cognition deficits in individuals with ASD.
EEG experiments have highlighted abnormalities in auditory processing of language, per-
ception, and processing of social stimuli as well as attention in individuals with ASD of all
ages, including infants. PET studies have investigated a number of neurotransmitter sys-
tems and revealed abnormalities in the serotonergic system and others.
Aims of ongoing and future neuroimaging studies in ASD include early endophenotype
identification (preceding behavioral diagnosis), an improved understanding of develop-
mental trajectory using longitudinal study designs, and stratification of the autism spec-
trum into subtypes based on biological signatures.
KEY POINTS
• Structural MRI allows investigation of neuroanatomy, and although differences have
been observed in individuals with ASD, they seem to be mostly based on differences
in developmental trajectory.
• Functional MRI experiments have shown that brain regions involved in social cogni-
tion (including face processing, emotion processing, and nonverbal as well as verbal
communication) are abnormally activated in ASD.
• EEG is the method that can most easily be used in young infants and therefore
holds promise for early endophenotype identification, potentially leading to earlier
diagnosis.
• PET/SPECT studies have shown abnormalities in neurotransmitter systems, par-
ticularly in serotonin. Other neurochemical targets are being investigated.
• Future neuroimaging studies may be able to help in uncovering the pathophysiology
underlying different subtypes of ASD and may promote the development of more
targeted pharmacological or behavioral interventions.
Dr. Nicole Zürcher has no conflicts of interest to disclose. She is funded by an Autism
Speaks Meixner Translational Postdoctoral Fellowship (No. 9258).
Dr. Jacob M. Hooker’s research interests and program relate to the content of this chapter.
He receives funding from several government funding agencies (e.g., National Institutes of
Health and the U.S. Department of Energy), pharmaceutical companies, and philanthropic
donations. None of the support he receives creates a conflict of interest with the material
presented in this chapter.
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/ / /
11 / / / GENETICS OF AUTISM
SPECTRUM DISORDER
YAMINI J. HOWE, HARRISON BRAND,

AND MICHAEL E. TALKOWSKI
INTRODUCTION
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition character-

ized by impairments in social interactions and communication, as well as by repetitive pat-
terns of behavior (American Psychiatric Association, 2013). The estimated prevalence of
ASD has been steadily rising based on changes in diagnostic classification, public awareness,
and treatment availability. The most recent Centers for Disease Control and Prevention
prevalence data estimate that 1 in 68 children have been diagnosed with ASD as of 2010
(Centers for Disease Control and Prevention, 2014). This is in stark contrast with early esti-
mates of approximately 4 in 10,000 noted by studies in the 1960s and 1970s (Fombonne,
2003). The high prevalence of ASD highlights the importance of identifying the biological
mechanisms that drive the disorder. Although the etiology of ASD is likely to also be influ-
enced by environmental factors (e.g., prenatal maternal stress (Walder et al., 2014) or zinc
deficiency (Yasuda, Yoshida, Yasuda, & Tsutsui, 2011)), the heritability of the disorder is
high and there is substantial evidence to indicate a strong genetic component to its etiology.
Autism Spectrum Disorder Heritability
Twin studies from as early as the 1970s have demonstrated the importance of genetic fac-
tors in the development of ASD. An early meta-analysis of twin studies and case reports
found that identical twins with ASD had an average concordance of 64% and an average
fraternal twin concordance of 9%, compared to population prevalence estimated to be
0.05% at the time of the study (Smalley, Asarnow, & Spence, 1988). More recent stud-
ies have shown that in families that have one child with ASD, subsequent children are
more likely to also develop ASD, with a recurrence risk reported to be as high as 10–18%
(Constantino, Zhang, Frazier, Abbacchi, & Law, 2010; Ozonoff et al., 2011). Researchers
who conducted a large-scale study in Sweden suggested that heritability for ASD is
approximately 50% (Sandin et al., 2014), whereas another study estimated heritability to
161
be as high as 90% (Bailey et al., 1995), suggesting that at least half, if not most, of ASD risk
is due to genetics.
Recent technological advances in genomics have yielded seminal findings that have
dramatically advanced our understanding of ASD (Talkowski, Minikel, & Gusella, 2014).
First, a variety of different mutation classes, including rare single nucleotide variants
(Iossifov et al., 2012; Lim et al., 2013; Neale et al., 2012; O’Roak et al., 2012a; Sanders et
al., 2012; Yu et al., 2013), copy number variants (CNVs) (Beunders et al., 2013; Girirajan,
Johnson, et al., 2013; Handrigan et al., 2013; Lionel et al., 2013; Michaelson et al., 2012;
Pinto et al., 2010; Sebat et al., 2007; Talkowski et al., 2012), chromosomal abnormali-
ties (Marshall et al., 2008; Talkowski et al., 2012), and common polymorphic variations,
have been shown to contribute to the etiology of the disorder (Anney et al., 2010; Klei
et al., 2012; Wang et al., 2009; Weiss, Arking, Daly, & Chakravarti, 2009). Second, new
mutations that are not inherited from parents (de novo mutations) have been found to
be dramatically increased in individuals with ASD compared to their unaffected siblings
or general expectations under the null hypothesis; and the penetrance of de novo loss-of-
function (LOF) mutations in individuals with ASD is substantial (Beunders et al., 2013;
Girirajan, Johnson, et al., 2013; Handrigan et al., 2013; Lionel et al., 2013; Neale et al.,
2012; O’Roak et al., 2012a; Sanders et al., 2012; Sebat et al., 2007; Talkowski et al., 2012).
Third, regions of recurrent microdeletions and duplications mediated by non-allelic
homologous recombination (NAHR; e.g., 16.p11.2,15q11–13) occur in a significant pro-
portion of individuals with ASD (Cooper et al., 2011), whereas frequent CNV regions
that are not mediated by NAHR have led to the identification of individual necessary and
sufficient strong effect loci within microdeletion/duplication syndrome regions (e.g.,
MBD5 in 2q23.1 or SATB2 in 2q33.1) (Rosenfeld et al., 2010; Talkowski, Mullegama,
et al., 2011; Talkowski et al., 2012; Williams et al., 2010). Fourth, genes that contribute
to ASD represent diverse biological pathways, including synaptic function (Ben-David &
Shifman, 2012; Iossifov et al., 2012), chromatin modification, and transcriptional regula-
tion (Ben-David & Shifman, 2012; Iossifov et al., 2014; O’Roak et al., 2012a; Talkowski
et al., 2012). Finally, many genes associated with ASD confer shared risk to a range of
neurodevelopmental abnormalities and psychopathology (Cross-Disorder Group of the
Psychiatric Genomics Consortium, 2013; Talkowski et al., 2012). Taken together, these
studies demonstrate that a highly heterogeneous collection of genes can lead to a similar
clinical presentation, and conversely, highly specific genetic lesions can be associated with
widely variable clinical outcomes.
Recent Technological Advances

Early research into the genetics of ASD, prior to the availability of unbiased genome-wide
surveys, focused on syndromic forms of the disorder and its comorbidity with known
Mendelian syndromes such as fragile X syndrome, Rett syndrome, tuberous sclerosis, neuro-
fibromatosis, Angelman syndrome, and macrocephaly associated with PTEN (phosphatase
and tensin homolog) mutations (Betancur, 2011; Bolton & Griffiths, 1997; Brown et al.,
1982; Butler et al., 2005; Gillberg & Forsell, 1984; Lam et al., 2000; Miles, 2011; Steffenburg,
Gillberg, Steffenburg, & Kyllerman, 1996). With the completion of the Human Genome
Project, studies investigating variation in select candidate genes were used to compare com-
mon polymorphisms between cases and controls to identify genetic risk for ASD (for an
overview of historical milestones in genetic research in ASD, see Table 11.1). These studies
were almost universally underpowered to detect modest effect sizes (e.g., odds ratios of 2
Genetics of Autism Spectrum Disorder // 163
TABLE 11.1 Timeline of Milestones in Genetic Research as It Relates to Autism Spectrum Disorder
1953 Crick and Watson propose model for structure of DNA.

1959 Lejeune, Gautier, and Turpin identify trisomy 21 as the cause of Down syndrome.
1969 Development of Southern blot technique by Edwin Southern allowed detection of specific
DNA sequences.
1977 Fred Sanger develops technique for DNA sequencing.
1982 Autism is associated with fragile X syndrome (Brown et al., 1982).
1983 PCR technique is developed.
1990s Array techniques began to be developed; further sequencing technologies are developed.
1995–2000 Syndromes such as Angelman syndrome, neurofibromatosis, and tuberous sclerosis are
noted to be associated with ASD (Bolton & Griffiths, 1997; Lam et al., 2000; Steffenburg
et al., 1996).
1997 Autism Genetics Resource Exchange (AGRE) is founded (Lajonchere, 2010).
2003 Human Genome Project is completed.
2000–2010 PTEN is associated with autism (Butler et al., 2005); autism also associated with neuroligin
and SHANK genes (Jamain et al., 2003; Leblond et al., 2014; Strauss et al., 2006).
2005–Present Next-generation sequencing techniques are further developed.
2006 Autism Consortium–Boston is founded.
2008 Simons Simplex Collection (SSC) starts recruiting participants (Fischbach & Lord, 2010).
or less), but they did identify associations with several biological candidate genes and gene
families that are still considered in neurobiological studies of ASD (e.g., neuroligins ( Jamain
et al., 2003), SHANK genes (Leblond et al., 2014), and neurexins (Strauss et al., 2006)).
In approximately the past decade, the development of array-based technologies to
detect small DNA dosage changes (array comparative genomics hybridization (aCGH))
(Manning & Hudgins, 2007) as well as technology capable of simultaneously genotyping
hundreds of thousands to millions of single nucleotide polymorphisms (SNPs) has allowed
the unbiased genome-wide assessment of loci conferring risk to ASD. In the past several
years, the advent of massively parallel sequencing (also called next-generation sequenc-
ing (NGS)) and targeted DNA-capture technology has allowed researchers to focus on
either all 3.1 billion bases that comprise the human genome or the approximately 1% of the
genome that is known to code for proteins through a technique referred to as whole-exome
sequencing (WES). An overview of several of the most significant findings from these stud-
ies is provided next, although there are many others that are not reviewed here that have
also helped to shape the emerging view of ASD etiology. For an overview of genes and loci
implicated in ASD etiology, see Figure 11.4.
Single Nucleotide Variants
The effects of both common and rare single base mutations have provided significant
insight into ASD etiology (Figure 11.1). Common variants have been studied using
FIGURE 11.1 Single nucleotide variant. This drawing depicts a change in a single base pair.
Source: Adapted from David Eccles (http://commons.wikimedia.org/wiki/File:Dna-SNP.svg#file).
genome-wide association studies (GWAS), and rare variants have been studied predomi-
nantly using WES.
Genome-Wide Association Studies
The development of SNP-based microarrays has enabled researchers to investigate com-

mon variants across the entire genome using an association study design through analyses
of both cases and controls as well as transmission from parents to affected offspring. Thus
far, 2,111 GWAS studies have been published, identifying 15,396 trait-associated SNPs at
the empirical threshold of statistical significance (www.genome.gov/gwastudies; accessed
August 3, 2015). This approach has yielded remarkable new insights into several neuropsy-
chiatric disorders, most notably schizophrenia, through a series of large-scale studies sug-
gesting a strong polygenic risk of this disorder (Schizophrenia Psychiatric Genome-Wide
Association Study (GWAS) Consortium, 2014). Ongoing large-scale studies across psychi-
atric disorders have also suggested a significant degree of shared genetic risk among mul-
tiple neurodevelopmental and psychiatric disorders (Cross-Disorder Group, 2013).
In ASD, however, progress from GWAS studies has been slower because power has
been significantly limited compared to that of studies of schizophrenia. GWAS and fam-
ily linkage analyses from SNP microarrays in three studies of ASD identified independent
genome-wide significant associations (Anney et al., 2010; Wang et al., 2009; Weiss et al.,
2009), but a meta-analysis of these studies did not support consistent effects of any loci
(Devlin, Melhem, & Roeder, 2011). Recently, Devlin and colleagues have shown that com-
mon variants exerting weak additive effects collectively represent a major component of
ASD risk (Gaugler et al., 2014). Thus, although none of the existing ASD GWAS studies
have approached the yield that has been achieved in other psychiatric disorders, there is
a growing consensus that a significant increase in sample size will produce substantially
stronger effects of common variation in the population, which is likely to account for a
meaningful portion of the heritability estimates for this disorder.
Whole Exome Sequencing
Whole exome sequencing (WES) is a powerful new technique for exploring the role of rare
and de novo coding variations in ASD. The banking of genetic material and phenotypic data
from individuals with ASD and their families has played a major role in the availability of
well-characterized subjects for research. Large-scale consortia such as the Simons Simplex
Collection (SSC; Fischbach & Lord, 2010), the Autism Genetic Resource Exchange
(AGRE; Lajonchere, 2010), the Autism Consortium of Boston (http://autismconsortium.
org), and the Autism Simplex Collection (Buxbaum et al., 2014) have all accumulated sub-
stantial sample resources for genetic studies. WES studies using data sets have confirmed
advanced parental age as a significant risk factor for increased de novo mutation rates and
have elucidated particular biological pathways as potential causal mechanisms. Several
hypotheses-driven approaches have been used to uncover rare variations, including analysis
of homozygous LOF mutations, or “complete knockouts” in the general ASD population
and in individuals with ASD whose parents have shared ancestry, as well as gene-burden
analysis of de novo LOF mutations among individuals with ASD and unrelated parents.
Loss-of-Function Mutations
Healthy individuals are estimated to carry approximately 100 mutations per genome that
confer loss of function of the gene involved (Macarthur et al., 2012). A hypothesis for a
recessive model of ASD inheritance would suggest that some individuals with ASD have by
chance developed combinations of LOF alleles in critical genes, such that they have a com-
plete knockout of the function of a particular gene. The possible mechanisms that could
result in this mode of inheritance could be inheriting two copies of the same LOF allele
(a homozygous state) or inheriting two different LOF alleles (a compound heterozygous
state), or only having one copy of an allele that has the LOF mutation on the X chromosome
in males. Among individuals with ASD, the chance of occurrence of such rare complete
knockouts has been shown in case–control WES studies to be twofold greater than for typi-
cally developing controls, with a trend toward brain-expressed genes being overrepresented
(Lim et al., 2013). In one study, complete knockouts were rare in both cases and controls,
and a recessive LOF mode of inheritance is thought to explain up to approximately 5% of
ASD cases (3% by autosomes and 2% by the X chromosome) (Nava et al., 2012).
An individual is more likely to inherit two copies of a complete knockout LOF muta-
tion in instances in which parents are more closely related. In cases in which parents share
ancestry, large regions of the genome may be identical between maternally inherited and
paternally inherited DNA. These areas are called runs of homozygosity (ROH), and they
represent the individual having inherited two copies of the same ancestral chromosomes.
ROH have been studied in consanguineous families, isolated populations, and also in a
small number of individuals whose parents are not known to be related in order to identify
the role that homozygous LOF mutations may play in ASD risk. One such study specifically
targeted consanguineous families that have multiple family members with ASD (Yu et al.,
2013). In this study, the investigators implicated two genes, AMT and PEX7, for which
partial LOF was found and total LOF was associated with more severe developmental
phenotypes. The fraction of the genome covered by ROH is highly variable because even
in families not known to be consanguineous, some common ancestry may exist. One study
selected the 16 patients with the highest degree of homozygosity from the 1000 AGRE fam-
ilies and performed WES, finding candidate missense mutations in four genes (Chahrour
et al., 2012).
Dominant De Novo Coding Variations

Much work has been done recently in elucidating the role of de novo coding variations in
ASD risk. In families in which a child with ASD is born to unrelated parents, and no other
relatives are affected, de novo mutations are more likely to occur in that child (Levy et al.,
2011; Sanders et al., 2012; Sebat et al., 2007). Although de novo mutations may not be
inherited or may arise from germline mosaics, they do contribute to some methodologi-
cal approaches to estimating ASD heritability because they are usually shared between
monozygotic twins. WES studies of parent–child trios have been very fruitful in recent
years in identifying heterozygous de novo coding mutations in affected children (Iossifov
et al., 2012, 2014; Neal et al., 2012; O’Roak et al., 2012a; Poultney et al., 2014; Sanders et
al., 2012). These studies have shown that advanced parental age is associated with a higher
total number of de novo coding variations in siblings, both affected (those with ASD)
and unaffected (those without ASD) (Neal et al., 2012; O’Roak et al., 2012a; Sanders et
al., 2012). Mutations found in affected siblings were more likely to be variants of func-
tional importance than were those found in unaffected siblings. Affected siblings were
more likely to have de novo nonsense and missense mutations (Iossifov et al., 2014; Neale
et al., 2012; O’Roak et al., 2012a; Sanders et al., 2012). Using novel statistical methods,
Poultney et al. (2014) found that 22 genes were implicated in autism cases, as well as a
set of 107 genes likely to affect risk in greater than 5% of individuals with ASD in their
study. The genes identified encode proteins for synapse formation, regulation of transcrip-
tion, and remodeling of chromatin, and many were implicated in other conditions, such
as epilepsy, schizophrenia, and intellectual disability. Another study in SSC conducted
by Iossifov et al. (2014) examined affected children, unaffected siblings, and parents and
similarly found chromatin modifiers to be affected, as well as fragile X mental retardation
protein (FMRP)-associated genes and genes that had been previously implicated in intel-
lectual disability and schizophrenia.
Structural Variants
Perhaps the most productive approach to understanding the genetic architecture of ASD
has thus far come from studies investigating variations in genome structure. Structural
variants (SVs) can be broadly subdivided into two categories: balanced and unbalanced.
Balanced chromosomal rearrangements (BCRs) involve changing structure but without
significant gain or loss of genetic material. Unbalanced SVs result in dosage changes of
genome segments (i.e., CNVs). Conventional analysis of structural alterations to the
chromosomes was reliant on karyotyping, a microscopic technique that enables visu-
alization of chromosome number and structure at approximately 5–10 Mb resolution,
depending on banding patterns. In an initial study of SVs at microscopic resolution,
Scherer and colleagues reported a rate of karyotypically visible SVs (aneuploidies, trans-
locations, inversions, deletions, and duplications) to be 5.8% in independent ASD cases
(Marshall et al., 2008) (Figure 11.2).
Before translocation After translocation
Derivative
Chromosome B Chromosome B
Derivative
Chromosome A
Chromosome A
FIGURE 11.2 Translocation is an example of a chromosomal unbalanced structural variation. This

drawing depicts an unbalanced translocation between two chromosomes. Source: Adapted from the
National Human Genome Research Institute (http://commons.wikimedia.org/wiki/File:Translocation-4-20.png).
The availability of higher resolution aCGH and SNP microarray technologies has now
made submicroscopic CNVs routinely accessible in basic research and clinical diagnostics;
CNVs have been the predominant SV mutational class investigated in ASD to date. Early
studies using array-based technologies were able to establish CNVs as a major source of
genomic variation (Iafrate et al., 2004; Redon et al., 2006; Sebat et al., 2004), and as reviewed
later, such structural chromosomal changes have been robustly established as major con-
tributors to the genetic etiology of ASD. The evaluation of BCRs has been more challenging
due to the fact that they are not detected by array technology because the absolute quan-
tity of genetic material is preserved even though structure is not. Thus, karyotyping and
labor-intensive serial positional cloning techniques have traditionally been necessary to find
genes disrupted by BCRs. However, recent innovations in massively parallel sequencing have
rapidly increased the resolution over conventional methods and have opened ready access to
such rearrangements for basic research (Korbel et al., 2007; Talkowski, Ernst, et al., 2011).
Copy Number Variations
Reports of the impact of large, de novo CNVs in ASD have been remarkably consistent
(Cook & Scherer, 2008), and this has been replicated in virtually every study conducted
(Marshall et al., 2008; Pinto et al., 2010; Sanders et al., 2011) (Figure 11.3). These genomic
imbalances associated with ASD can be recurrent or non-recurrent events. Recurrent
events are usually caused by NAHR between regions of the genome with high homology
(or similarity). Rearrangements and copy errors occur in these regions during replication in
gametes (during meiosis), leading to development of chromosomes with reciprocal dosage
imbalances (deletion and duplication) that are subsequently divided between the resulting
Duplicated area
Before
duplication
After
duplication
FIGURE 11.3 Copy number variation. This drawing depicts a copy number variation in which a
region of a chromosome has been duplicated. Source: Adapted from the National Human Genome
Research Institute (http://en.wikipedia.org/wiki/File:Gene-duplication.png).
ova or spermatozoa. This excess or depletion of genetic material occurs at a significantly

increased frequency in individuals with ASD, as well as in those with other disorders, com-
pared to developmentally normal controls. A classic example is the 16p11.2 microdele-
tion/microduplication syndrome, which confers susceptibility to ASD (Weiss et al., 2008).
Other regions of recurrent CNV that have met significant statistical thresholds for associa-
tion with ASD include 15q11–13 (Van Bon et al., 2009), 22q11.2 (Vorstman et al., 2006),
and 1q21.1 (Girirajan, Dennis, et al., 2013).
Studies of recurrent CNVs have also provided insight into the impact of gene dosage on
developing ASD. In many ASD-associated loci, risk for similar phenotypes is conferred by
reciprocal copy number changes, suggesting the presence of genes whose normal function
requires tight dosage control. For example, although associated with a broad spectrum of
psychiatric and developmental phenotypes, as well as anthropometric traits ( Jacquemont
et al., 2011; McCarthy et al., 2009; Walters et al., 2010), both reciprocal gains and losses of
16p11.2 are associated with increased risk of ASD (Kumar et al., 2008; Weiss et al., 2008).
Similar findings have been reported for other loci, including 22q11.2, 15q11–13, 1q21.1,
and 2q23.1 (Cooper et al., 2011; Pinto et al., 2010; Schneider et al., 2014; Talkowski et al.,
2012). The mechanisms by which these reciprocal alterations confer similar phenotypes
are unknown and are a focus of ongoing research.
There are other CNVs that commonly disrupt specific genomic regions but are
non-recurrent (e.g., not mediated by NAHR due to flanking repetitive sequences). The
CNVs from these disruptions are of different sizes and include microdeletion/duplication
regions such as 9q34.3 (Smalley, 1998), 2q23.1 (Talkowski, Mullegama, et al., 2011), 1q21
(Mefford et al., 2008), 2q33.1 (Balasubramanian et al., 2011; de Ravel, Balikova, Thiry,
Vermeesch, & Frijns, 2009; Rosenfeld, Ballif, et al., 2009; Talkowski, Ernst, et al., 2011),
and 16q24.2 (Handrigan et al., 2013).
Initial research into CNVs revealed association with large genomic segments that
included many genes and regulatory elements. However, much like linkage-based
approaches, these studies rarely pointed directly to individual genes. Recently, the estab-
lishment of large patient cohorts has enabled the identification of critical regions that
represent the minimal genomic segment in which non-recurrent CNVs overlap across
many cases. Using this strategy, single genes have been identified as contributing to
pathology in particular microdeletion or microduplication syndromes; these include
MBD5 in 2q23.1 (Hodge et al., 2014; Talkowski, Mullegama, et al., 2011; Williams et al.,
2010), SATB2 in 2q33.1 (Rosenfeld, Ballif, et al., 2009), EHMT1 in 9q34.3 (Kleefstra
et al., 2012), CHD1L in 1q21.1, and ACACA in 17p21 (Girirajan, Dennis, et al., 2013).
Overall, these discoveries have led to a hypothesis that many of the recurrent changes to
genomic segments associated with human disease are attributable to one or a few strong
effect genes in the regions affected. It is hoped that these genes may serve as targets for
therapeutic intervention.
Unfortunately, this method of using large patient cohorts to identify affected regions
is not applicable to recurrent NAHR-mediated imbalances because they are localized to
repeated sequences. In one study, researchers performed a series of individual gene knock-
downs and overexpression in zebrafish in order to implicate a single contributory locus,
KCTD13, in neuroanatomical phenotypes of the recurrent 16p11.2 microdeletion/dupli-
cation syndrome (Golzio et al., 2012). Similar approaches in other model organisms could
provide a feasible approach to dissecting NAHR-mediated recurrent rearrangements,
although direct association to the ASD phenotype in animals such as zebrafish is more dif-
ficult. In these settings, researchers rely instead on finding a measurable morphological trait
or biomarker.
Balanced Chromosomal Rearrangements
In contrast to the large number of studies on the role of CNVs in ASD, few studies have
evaluated the impact of BCRs. BCRs can involve balanced translocations, inversions, or
excision/insertion events, and in each instance one or more genes can be disrupted at the
breakpoints in a relatively balanced manner. Karyotyping at microscopic resolution has
traditionally been used to identify BCRs, which has significantly limited the capacity to
define individual loci disrupted at the breakpoints without labor- and cost-intensive posi-
tional cloning studies. Despite these challenges, positional cloning studies have uncovered
a number of highly penetrant gene defects contributing to ASD, including those in AUTS2
(Sultana et al., 2002), NRXN1 (Kim et al., 2008), and EHMT1 (Golzio et al., 2012).
Recently, innovations in massively parallel sequencing have enabled detection of BCRs
at sequence-based resolution (Chen et al., 2008, 2010; Chiang et al., 2012; Korbel et al.,
2007; Talkowski, Ernst, et al., 2011; Talkowski et al., 2012). Snyder and colleagues initially
demonstrated the feasibility of the detection of all classes of SV by using NGS methods
(Korbel et al., 2007). Talkowski and colleagues performed the first large-scale sequencing
study of constitutional BCRs, which revealed a highly complex chromosomal architecture
associated with some BCRs in ASD (Chiang et al., 2012), including clustered rearrange-
ments that have been recently dubbed in cancer studies as “chromothripsis”—once thought
to be catastrophic chromosomal events that were exclusively somatic in origin (Stephens
et al., 2011). Subsequent sequencing of de novo BCRs associated with ASD and related
neurodevelopmental phenotypes has revealed a large number of genes whose disruption

potentially contributes to these disorders. In these studies, as in exome sequencing studies,
it is a challenge to distinguish among the LOF mutations that are benign and well tolerated,
that represent highly penetrant pathogenic variations, or that represent moderately pen-
etrant oligogenic/polygenic risk factors.
In one study of 38 subjects, 33 independent genes were found to be disrupted by BCR
breakpoints, many of which were novel loci not previously associated with ASD, such as
CHD8, KIRREL3, METTL2B, and many others (Talkowski et al., 2012). This study used
a “convergent genomics” approach to interpret the significance of each gene disrupted by
the BCR from the integration of gene expression data, CNVs, and GWAS. For many of the
33 genes, the approach identified a significantly increased CNV burden among more than
33,000 independent cases compared to almost 14,000 independent controls. Importantly,
the study also found a significant association of ASD with common SNP alleles from the
GWAS approach when considering these 33 genes, suggesting that outright inactivation
in some persons and polymorphic variation of the same gene in many more individuals
can both contribute to risk of neurodevelopmental abnormality. The study also found that
these same genes were enriched for polygenic risk loci for schizophrenia GWAS studies,
suggesting that these loci, many of which were involved in chromatin modification and
transcriptional regulation, could confer pleiotropic effects across formal diagnostic bound-
aries. These data firmly support the hypothesis that many ASD-associated SVs disrupt
genes that are under tight dosage regulation and that perturbations of their normal dosage
of expression can affect the risk of developing a spectrum of neurodevelopmental pheno-
types, including ASD.
FUNCTIONAL AND CLINICAL IMPLICATIONS
The initial fundamental hypothesis about ASD is that it is a clinical phenotype with
a neurobiological cause distinct from other genetic or neurodevelopmental disorders,
related to pathological processes that affect the development and function of neuro-
nal synapses. This hypothesis has been partially supported by genetic research. For
example, mutations in genes encoding members of protein families involved in cell
signaling, cell adhesion, synaptic function, or plasticity have been strongly aligned
with this hypothesis, including SHANK (Berkel et al., 2012; Gauthier et al., 2009;
Leblond et al., 2012, 2014; Moessner et al., 2007; Pinto et al., 2010; Sato et al., 2012),
neurexins (Gauthier et al., 2011; Kim et al., 2008; Vaags et al., 2012), neuroligin pro-
teins (Glessner et al., 2009; Jamain et al., 2003), glutamate receptors (Talkowski et al.,
2012), brain-derived neurotrophic factor (Ernst et al., 2012), KIRREL3 (Talkowski
et al., 2012), and TSC1–TSC2 and mTOR and FMRP signaling pathways (Auerbach,
Osterwell, & Bear, 2011). All of these proteins play a role in the interconnected network
of proteins related to synaptic function, and many have been specifically implicated in
ASD (Ebert & Greenberg, 2013).
However, a significant number of genetic discoveries in ASD suggest that diverse bio-
logical pathways contribute to this disorder and that these ASD-related genes have an etio-
logical role in a spectrum of human developmental abnormalities and psychopathology
rather than ASD alone. Gene network and gene set enrichment analyses have implicated
a variety of networks and pathways associated with ASD (Ben-David & Shifman, 2012,
2013; Pinto et al., 2010; Voineagu et al., 2011). One such risk factor is CHD8, a chro-
modomain helicase involved in chromatin remodeling and transcriptional repression that
was discovered to be disrupted by translocation in an individual with ASD (Talkowski

et al., 2012), as well as by de novo LOF mutations in multiple exome sequencing studies
(Neale et al., 2012; O’Roak et al., 2012b; Sanders et al., 2012). The CHD8 gene was also
associated with an increased CNV burden from both deletion and duplication in individu-
als with ASD or with macrocephaly and various developmental outcomes (O’Roak et al.,
2012b; Talkowski et al., 2012). Follow-up studies of patients with CHD8 mutations and
functional genomic analyses of neuronal cells with suppression of CHD8 have both sug-
gested that CHD8 alterations may define a subtype of ASD early in development (Bernier
et al., 2014; Sugathan et al., 2014). Point mutations in TCF4, which encodes a transcrip-
tional regulator, have been shown to result in Pitt–Hopkins syndrome (Pitt & Hopkins,
1978; Rosenfeld, Leppig, et al., 2009), and disruption by a balanced translocation has
been associated with ASD and other neurodevelopmental outcomes (Rosenfeld, Leppig,
et al., 2009; Talkowski et al., 2012). Common variants in TCF4 have also been among the
most significant genome-wide risk factors for schizophrenia and other psychiatric disor-
ders (Cross-Disorder Group, 2013; Ripke et al., 2013). Disruption of MBD5 by multiple
independent BCRs has also been shown in patients with ASD, intellectual disability, epi-
lepsy, and even later onset neurobehavioral regression (Chung et al., 2011; Hodge et al.,
2014; Mullegama et al., 2014; Talkowski, Mullegama, et al., 2011; Talkowski et al., 2012;
Williams et al., 2010). MBD5 encodes a member of the methyl CpG-binding domain fam-
ily of proteins that includes MeCP2, a known causal locus in Rett syndrome. Numerous
other genes encoding transcriptional regulators and chromatin modifiers have emerged
from SV and exome sequencing studies that have strongly implicated these global regula-
tors of gene expression in ASD, as well as other diverse developmental and psychiatric
phenotypes.
The heterogeneity in ASD is commonly thought to be related to a “final common
pathway” model, relating ultimately to synaptic dysfunction. However, it is unclear
how the genes and proteins presented previously would fit within this model, given
that they are not limited to synapses. Thus, this is an active area of research. The links
between ASD and other developmental phenotypes, as well psychiatric traits, are now
well recognized from numerous CNV, BCR, and GWAS studies, as reviewed previously.
Future research on the complex biological pathways involved in developing ASD will
include determining whether there are definable endophenotypes with distinct genetic
etiologies embedded among broader disease phenotypes. Furthermore, elucidating the
genetic modifiers or environmental effects that may predispose an individual to a spe-
cific phenotypic outcome will be fundamental to understanding the etiology of ASD
(Figure 11.4).
In all of the large studies reviewed previously, each individual genetic alteration identi-
fied explains a meaningful, but still small, proportion of the overall disease variance, with the
most common risk factors, such as 16p11.2 alterations, accounting for approximately 1% of
all ASD cases. However, it is important to recognize that all approaches discussed (GWAS,
WES, and SV) have been applied in studies that were underpowered and therefore could
detect only the strongest, most frequent contributors. The evidence from many other neu-
ropsychiatric disorders, such as schizophrenia, indicates that polygenic effects are relatively
weak but are increasingly detectable with adequate statistical power. To date, researchers
studying rare exome variants have been able to investigate only the risk associated with de
novo LOF mutations and have not been able to perform tests adequately powered for the
full mutational spectrum, including synonymous, non-synonymous, and inherited variants,
although such studies are ongoing. Similarly, studies of SVs have generally not accounted
for small or multiallelic CNVs or for recurrent BCRs. Finally, submicroscopic balanced
FIGURE 11.4 Autism risk is affected by overlapping sets of genes and loci. Exome sequencing
has identified single nucleotide variants and small insertions/deletions. Unbalanced structural
variations (whole-gene or chromosomal region deletions and duplications) and balanced struc-
tural variations (translocation, inversions, and chromothripsis) are shown. Genes and loci impli-
cated are listed (specific studies are cited in the chapter). Also listed are signals reported in
genome-wide association studies. Source: Updated from Talkowski et al. (2014).
events and small CNVs have not been studied in any capacity to date due to methodologi-
cal limitations, although such studies are also ongoing.
The discoveries to date in the genetics of ASD show great promise, and we anticipate
further contributions from future studies, especially those that address the interaction
of genetic background and environmental factors that drive phenotypic outcomes. The
discovery of a strong association between ASD and genes involved in epigenetic regula-
tion opens at least one route to exploring potential environmental influences on such
regulation. These studies could then potentially lead to identifying modifiable risk fac-
tors, as well as identifying targets for potential therapeutics.
SUMMARY
As reviewed in this chapter, the discovery of novel genetic factors contributing to ASD eti-
ology has yielded remarkable insight in the past several years. There remains much debate
in the field regarding the precise genetic architecture of ASD, with models ranging from
those with common variation explaining the largest proportion of disease risk to those
implicating rare but relatively penetrant risk factors that, although collectively important,
individually explain very little of the overall disease risk of an individual. However, the
advancement of genomic technologies and the capacity to perform unbiased genome-wide
surveys for genomic variants that contribute risk to ASD have definitively proven a major
genetic basis for ASD etiology.
KEY POINTS
• Identical twins with ASD have an average concordance rate of 64%, and fraternal
twins have a concordance rate of 9% for ASD.
• Whole-exome sequencing studies of parent–child trios have shown that advanced
paternal age is associated with a higher total number of de novo coding variants in
siblings, both affected and unaffected.
• One hypothesis states that mutations in genes encoding members of protein fami-
lies involved in cell signaling, cell adhesion, synaptic function, or plasticity result in a
clinical phenotype with a neurobiological cause distinct from other genetic or neuro-
developmental disorders.
• Another hypothesis states the diverse biological pathways may contribute to ASD
and that underlying ASD-related genes have an etiological role in a spectrum of
human developmental abnormalities and psychopathology, rather than ASD alone.
• Future studies will address the interaction of genetic background and environmental
factors that drive phenotypic outcomes.
Dr. Yamini J. Howe has received funding from Autism Consortium for a research study in
biomarkers in autism.
Dr. Harrison Brand has no conflicts to disclose. He is funded by the National Institutes of
Health (T32HD007396).
Dr. Michael E. Talkowski has no conflicts to disclose. He is funded by the National
Institutes of Health (R00MH095867 and R01HD081256), the Simons Foundation for
Autism Research, the Nancy Lurie Marks Family Foundation, the March of Dimes, the
Charles Hood Foundation, NARSAD, the Collaborative Center for X-Linked Dystonia
Parkinsonism, and the CHARGE syndrome foundation.
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/ / /
12 / / / EPIDEMIOLOGY OF AUTISM
SPECTRUM DISORDER
ALLISON PRESMANES HILL, KATHARINE

ZUCKERMAN, AND ERIC FOMBONNE
INTRODUCTION
Epidemiological surveys of autism were first initiated in the mid-1960s in England (Lotter,
1966, 1967) and have since been conducted in more than 20 countries. This chapter pro-
vides a comprehensive review of the findings and methodological features of many pub-
lished epidemiological surveys about the prevalence of autism spectrum disorder (ASD).1
This chapter builds on previous reviews (Fombonne, 2003, 2005; Hill, Zuckerman, &
Fombonne, 2014). The following are the specific questions addressed: (1) What is the
range of prevalence estimates for ASD? and (2) How should the time trends observed in
the current prevalence rates of ASD be interpreted?
Study Design and Methodological Issues
Epidemiologists use several measures of disease occurrence, including incidence, cumula-

tive incidence, and prevalence. Prevalence is a measure used in cross-sectional surveys (in
which there is no passage of time) and reflects the proportion of subjects in a given popu-
lation who suffer from the disease at that point in time. Most epidemiological studies of
ASD have assessed prevalence (point prevalence or period prevalence) as a cross-sectional
approach that is more appropriate for disorders for which timing of diagnosis lags behind
onset of symptoms and is likely to be influenced by a range of factors unrelated to risk. In
designing a prevalence study, three elements are critical: case definition, case identification
(or case ascertainment), and case evaluation methods (Fombonne, 2007).
Case Definition
The definition and diagnostic criteria of autism have changed over time. Starting with
Kanner’s (1943) description of autism, case definitions have progressively broadened to
1
Autism spectrum disorder (ASD) is the modern term that replaces the former pervasive developmental
disorder (PDD).
181
include criteria proposed by Rutter (1970) and subsequently the International Classification
of Diseases, ninth revision (ICD-9; World Health Organization, 1977), and the Diagnostic
and Statistical Manual of Mental Disorders, third edition (DSM-III; American Psychiatric
Association(APA), 1980). Eventually, two more recent nosographies were adopted world-
wide, the ICD-10 (World Health Organization, 1992) and the Diagnostic and Statistical
Manual of Mental Disorders, fourth edition and text revision (DSM-IV and DSM-IV-TR,
respectively; APA, 1994, 2000).
Early diagnostic criteria reflected the more qualitatively severe behavioral phenotypes,
usually associated with severe delays in language and cognitive skills. In the 1980s, less
severe forms of autism were recognized, either as a qualifier for autism occurring without
intellectual disability (ID) (i.e., high-functioning autism) or as separate diagnostic catego-
ries (e.g., Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) or
ASD). Asperger’s disorder appeared in the 1990s, with unclear validity, particularly with
respect to its differentiation from high-functioning autism. Some ASD subtypes that were
described in DSM-III subsequently disappeared (e.g., Autism-Residual State); however,
other nomenclatures have since added new diagnostic categories, such as “atypical autism”
and “PDD unspecified” (ICD-10).
The changes occurring with the introduction of the Diagnostic and Statistical Manual of
Mental Disorders, fifth edition (DSM-5; APA, 2013), may impact prevalence estimates in
the future. DSM-5 proposes a single new category of Autism Spectrum Disorder, conceptu-
ally equivalent to the previous diagnostic class of PDDs. However, fewer diagnostic criteria
have been retained that are combined in two clusters of social communication deficits and
restricted patterns of behavior and interests. The removal of the loosely defined PDD-NOS
that was in DSM-IV-TR will likely increase the specificity of the ASD diagnostic category,
and the removal of Asperger’s disorder as a separate category is consistent with research
that has generally failed to provide evidence for the discriminant validity of this diagnos-
tic concept vis-à-vis forms of autistic disorder that are not associated with severe language
impairments or intellectual deficits.
The impact of DSM-5 changes remains to be fully assessed in the context of epidemio-
logical surveys. Two recent population-based surveys have addressed this issue. Maenner
and colleagues (2014) retrospectively applied the new diagnostic criteria to a previously
obtained population-based sample from the Centers for Disease Control and Prevention
(CDC) 2006 and 2008 surveillance years. They found that 81.2% of children classi-
fied as having the equivalent of ASD according to DSM-IV-TR also met DSM-5 criteria,
resulting in a DSM-5-based prevalence of 100/10,000—an estimate lower than the 2006
and 2008 estimates. In addition, 304 children met DSM-5 but not DSM-IV-TR criteria.
In a similar study, Kim and colleagues (2014) reported that 92% of children with ASD
according to DSM-IV-TR also met DSM-5 criteria. However, when DSM-5 ASD and
Social Communication Disorder (a new diagnostic category in DSM-5) were considered
together, there was no significant change in the prevalence estimate (Kim et al., 2014). It is
important to note that new diagnostic information required in DSM-5 (e.g., emphasis on
sensory processing deficits) is generally not available in prior studies, leading to potentially
biased estimates. In addition, previous studies are often constrained in sampling children
with a DSM-IV PDD diagnosis and cannot therefore accurately estimate the proportion of
children who did not meet criteria for DSM-IV but would have met those for DSM-5.
Although there is currently high inter-rater reliability overall regarding diagnosis of
ASD and commonality of concepts across experts, differences still persist between nomen-
clatures about the terminology and operationalized criteria of ASD. It is unclear to what
extent the changing nomenclature of ASD plays a role in prevalence estimates described in
Epidemiology of Autism Spectrum Disorder // 183
epidemiological studies. Studies are currently under way that will provide further examina-
tion of the impact on prevalence estimates of narrowing the ASD definition in DSM-5.
Case Identification/Ascertainment
When a population is identified for a survey, different strategies are employed to find individ-
uals matching the study’s case definition. Some studies rely solely on service provider data-
bases (Croen, Grether, Hoogstrate, & Selvin, 2002; Davidovitch, Hemo, Manning-Courtney,
& Fombonne, 2013), special education databases (Fombonne, Zakarian, Bennett, Meng, &
McLean-Heywood, 2006; Gurney et al., 2003; Maenner & Durkin, 2010), or national regis-
ters (Al-Farsi et al., 2011; Samadi, Mahmoodizadeh, & McConkey, 2011) for case identifica-
tion. These studies have the common limitation of relying on a population group that was
readily accessible rather than sampling from the population at large. As a result, individuals
with the disorder who are not in contact with services are not included as cases, leading to
an underestimation of prevalence. This limitation is particularly problematic in communities
with recognized limitations in available services.
Other investigations have relied on a multistage approach to identify cases in under-
lying populations (e.g., CDC, 2014; Idring et al., 2012; Kim et al., 2011). In these stud-
ies’ first screening stage, a wide net is cast to identify subjects possibly affected with ASD,
with the final diagnostic status being determined at subsequent stages. This process often
consists of sending letters or screeners to school and health professionals, searching for
possible cases of autism. Few such investigations rely on systematic sampling techniques
that would ensure a near complete coverage of the target population, and screening often
varies substantially in ascertainment of all relevant data sources. In addition, surveyed areas
often differ in terms of specific educational or health care systems available, and inclusion
information sent often varies in reliability and validity. Finally, uneven participation rates in
the screening stage can lead to variation in the screening efficiency of surveys.
To illustrate how differential participation in the screening stage affects prevalence esti-
mates, two hypothetical scenarios are illustrated in Figure 12.1, both of which are based on
a true ASD prevalence of 150/10,000 and a sensitivity of 100% for the screening process
and total accuracy in the diagnostic confirmation. In scenario A, we assume 60% participa-
tion for ASD and non-ASD cases in the first screening stage, resulting in 90 participating
ASD cases that screen positive. With 70% participation for both ASD and non-ASD cases
in the diagnostic stage, we would identify and confirm 63 ASD cases in the second phase.
Weighting back phase 2 data, we would obtain an unbiased prevalence estimate of 1.5%
(or 150/10,000) in this scenario. In scenario B, we also assume 60% overall participation,
but with an 80% participation rate for ASD cases, reflecting a scenario in which individu-
als with ASD are more likely to participate in the first screening stage than non-ASD cases.
Thus, with the same participation rates in the first screening (60%) and final diagnostic
stages (70%), we identify 84 ASD cases and calculate a biased prevalence estimate of 2%
(200/10,000), an estimate that is 0.5% higher than true prevalence. The bias arises for two
reasons: (1) Participation in screening is associated with case status (here, with ASD cases
more likely to participate than non-cases); and (2) because investigators typically have no
such information, weights used for prevalence estimation were not adjusted correspond-
ingly, resulting in the upward bias.
It is also possible that individuals with ASD participate less than non-cases, which
would result in underestimates of prevalence. For example, Posserud, Lundervold, Lie, and
Gillberg (2010) reported ASD prevalence of 72/10,000 in their identified sample and esti-
mated a prevalence of 128/10,000 in nonresponders (based on teacher ratings during the
FIGURE 12.1 Assuming a true autism spectrum disorder prevalence of 150/10,000 and a sensitivity of 100% for the screening process and total accuracy in the diagnostic
confirmation, weighting back phase 2 data results in an unbiased prevalence estimate when caseness is unrelated to participation in screening (Scenario A), but when
participation in screening is more likely for autism spectrum disorder cases than for non-cases (Scenario B), prevalence will be overestimated (see discussion in text).
screening phase), indicating increased refusal rates among those with more ASD symp-
toms. Unfortunately, few studies have been able to estimate the extent to which willingness
or refusal to participate is associated with final caseness, so it is not known what effect dif-
ferential participation rates at different phases in population surveys may have on preva-
lence estimates.
The sensitivity of the screening methodology is difficult to gauge in autism surveys
because the proportion of children truly affected with the disorder but not identified in the
screening stage (false negatives) remains generally unmeasured. Few studies have provided
an estimate of the reliability of the screening procedure. The usual approach, which consists
of randomly sampling screen-negative subjects to adjust estimates, has not been generally
used, mainly due to the relatively low frequency of ASD, which makes such a strategy both
imprecise and costly.
As an example, the surveys conducted by the CDC (2007a, 2007b, 2009, 2012,
2014) rely, for case ascertainment, on scrutinizing educational and medical records.
Children not accessing such services cannot be identified. Although some recent sur-
veys that systematically screen the normal school population might detect a large pool of
unidentified cases (Kim et al., 2011), it remains to be determined if this applies to most
populations and requires change in sampling approaches for surveying autism. Of note,
the CDC methodology identifies ASD cases without prior official ASD diagnosis (21% of
identified cases in 2008; CDC, 2012), suggesting that underidentification is a widespread
phenomenon.
Because more recent prevalence studies suggest that autism can no longer be regarded
as rare, screening for false negatives may become a more common strategy. Currently, how-
ever, prevalence estimates must be understood as underestimates of “true” prevalence rates,
with the magnitude of this underestimation unknown in each survey.
Case Evaluation
When the screening phase is completed, subjects identified as positive go through a more
in-depth diagnostic evaluation to confirm case status. Similar considerations about meth-
odological variability across studies apply in more intensive assessment phases. The infor-
mation used to determine diagnosis usually involves a combination of data from informants
(parents, teachers, pediatricians, other health professionals, etc.) and data sources (medi-
cal records and educational sources), with a direct assessment of the person with autism
being offered in some but not all studies. When subjects are directly examined, assessments
typically use various diagnostic instruments, ranging from a typical unstructured exami-
nation by a clinical expert (but without demonstrated psychometric properties) to the
use of batteries of standardized measures by trained research staff. The Autism Diagnostic
Interview–Revised (ADI-R; Lord, Rutter, & Couteur, 1994) and/or the Autism Diagnostic
Observation Schedule (ADOS; Lord et al., 2000) have been increasingly used in the most
recent surveys.
Obviously, surveys of large populations, such as those conducted in the United States’
CDC Autism and Developmental Disabilities Monitoring (ADDM) Network (2007a,
2007b, 2009, 2012, 2014) or in national registers (Idring et al., 2012), cannot include
direct diagnostic assessment of all subjects by researchers. However, investigators generally
improve the accuracy of caseness determinations by undertaking, on a randomly selected
subsample, a more complete diagnostic workup (Rice et al., 2007). The CDC surveys
have established a methodology for surveys of large populations based on screening of the
population using multiple data sources, standardized records abstraction, and systematic
review and scoring of the data gathered in the screening phase. In the less obvious cases,
this information is combined with input from experienced clinicians with known reliability
and validity. This methodology is adequate for large samples, and it is likely to be used in
the future for surveillance efforts.
SYSTEMATIC REVIEW OF PREVALENCE ESTIMATES
Unspecified Autism Spectrum Disorder in Earlier Surveys
A new objective of recent epidemiological surveys has been to estimate the prevalence
of all disorders falling onto the autism spectrum, thereby prompting important changes
in the conceptualization and design of surveys. However, in previous reviews, we docu-
mented that several studies performed in the 1960s and 1970s provided useful information
on rates of syndromes similar to autism but not meeting the strict diagnostic criteria for
autistic disorder then in use (Fombonne, 2003, 2005). At the time, different labels were
used by authors to characterize these clinical pictures, such as the triad of impairments
involving deficits in reciprocal social interaction, communication, and imagination (Wing
& Gould, 1979); autistic mental retardation (Hoshino, Kumashiro, Yashima, Tachibana,
& Watanabe, 1982); borderline childhood psychoses (Brask, 1970); or autistic-like syn-
dromes (Burd, Fisher, & Kerbeshian, 1987). These syndromes would fall within our cur-
rently defined autistic spectrum, probably with diagnostic labels such as atypical autism
and/or PDD-NOS. In 8 of 12 surveys providing separate estimates of the prevalence of
these developmental disorders, higher rates for the atypical forms were actually found com-
pared to those for more narrowly defined autistic disorder (Fombonne, 2003). However,
this atypical group received little attention in previous epidemiological studies; these sub-
jects were not defined as “cases” and were not included in the numerators of prevalence cal-
culations, thereby underestimating systematically the prevalence of what would be defined
today as the spectrum of autistic disorders.
For example, in the first survey by Lotter (1966), the prevalence would increase from
4.1 to 7.8/10,000 if these atypical forms of autism had been included in the case defini-
tion. Similarly, in Wing, Yeates, Brierly, and Gould’s study (1976), the prevalence was
4.9/10,000 for autistic disorder, but the prevalence for the whole ASD spectrum was in
fact 21.1/10,000 after the figure of 16.3/10,000 (Wing & Gould, 1979), corresponding to
the triad of impairments, was added. The progressive recognition of the importance and
relevance of these less typical clinical presentations has led to changes in the design of more
recent epidemiological surveys that use case definitions that incorporate a priori these
milder phenotypes.
Prevalence Estimates for Combined Autism Spectrum Disorder Since 2000

There have been 53 surveys that estimated the prevalence of the entire spectrum of ASD
published since 2000, with the majority (55%) published in 2009 or later. The studies were
performed in 18 different countries (including 14 studies in the United Kingdom and 12
in the United States, of which 5 were conducted by the CDC). Sample sizes ranged from
5007 to 4.5 million (median, 58,654; mean, 346,776). Ages of the surveyed populations
ranged from 0 to 98 years (median, 8 years; mean, 9 years). One study was specifically
conducted on adults and provided the only estimate (98.2/10,000) thus far available for
adults (Brugha et al., 2011). Two surveys focusing on toddlers (Nygren et al., 2012) and
preschoolers (Nicholas, Carpenter, King, Jenner, & Charles, 2009) provided estimates of
approximately 80 per 10,000. In the 50 remaining surveys, the average median age was
8.23 years (standard deviation = 2.8).
The diagnostic criteria used in the 53 studies reflected the reliance on modern diagnos-
tic schemes (11 studies used ICD-10, and 25 used the DSM-III, DSM-IV, or DSM-IV-TR;
both schemes were used simultaneously in 9 studies). Assessments were often performed
with standardized diagnostic measures (i.e., ADI-R and ADOS). In 26 studies in which
IQ measures were reported, the proportion of subjects within the normal IQ range var-
ied from 0% to 100% (median, 55.4%; mean, 53.9%)—a proportion that reflects the
lesser association, or lack thereof, between intellectual impairment and milder forms of
ASD. Overrepresentation of males was seen in the 47 studies reporting gender ratios, with
male:female ratio ranging from 1.8:1 to 15.7:1 (median, 4.5:1; mean, 4.9:1).
There was a 189-fold variation in ASD prevalence, ranging from 1.4/10,000 to
264/10,000 (Figure 12.2). There was also substantial variation in confidence interval
width, reflecting variation in sample sizes and consequently in each study’s precision
(range, 0.5–146; mean interval width, 22.4). However, some consistency in ASD preva-
lence is found in the center of this distribution, with a median rate of 61.9/10,000 and a
mean rate of 68.9/10,000 (interquartile range, 44.2–84.0/10,000). Prevalence was nega-
tively associated with sample size (Kendall’s tau, –.23; p = .01), with small-scale studies
reporting higher prevalence.
There was also a significant positive correlation between ASD prevalence estimates
and publication year (Kendall’s tau, .26; p = .007), with higher rates in more recent sur-
veys. Since 2000, a number of studies have reported ASD prevalence estimates higher
than 100/10,000 (Baird et al., 2006; CDC, 2012, 2014; Idring et al., 2012; Kawamura,
Takahashi, & Ishii, 2008; Kim et al., 2011; Ouellette-Kuntz et al., 2006). Baird et al. (2006)
and Kim et al. (2011) both employed proactive case finding techniques, relying on multiple
and repeated screening phases, involving both different informants at each phase and sur-
veying the same cohorts at different ages, which certainly enhanced the sensitivity of case
identification. Multisource active surveillance techniques, as employed in the Stockholm
Youth Cohort (Idring et al., 2012) and by the CDC’s ADDM Network (2007a, 2007b,
2009, 2012, 2014), also improve identification of individuals with ASD. The most recent
CDC prevalence estimate of 147 per 10,000 reflects the highest estimate to date across all
of the previous ADDM Network reports (CDC, 2014).
Overall, results of recent surveys are in agreement that an average figure of 69/10,000
can be used as the current estimate for the spectrum of ASD. The convergence of esti-
mates around 60 to 90 per 10,000 for all ASD combined, conducted in different regions
and countries by different teams, is striking, especially when derived from studies with
improved methodology. The prevalence figure of 69/10,000 (equivalent to 6.9/1,000
or .69%) translates into 1 child out of 145 with an ASD diagnosis. This estimate is now
the best current estimate for the ASD prevalence. However, it represents an average and
conservative figure, and substantial variability exists between studies and within studies,
across sites or areas.
TIME TRENDS IN PREVALENCE AND THEIR INTERPRETATION
The debate on the hypothesis of a secular increase in rates of ASD has been obscured
by a lack of clarity in the measures of disease occurrence. As noted previously, it is cru-
cial to differentiate prevalence from incidence because only incidence rates can be used
for causal research, and prevalence and incidence will increase when case definition is
Powell et al. (2000)
Baird et al. (2000)
Fombonne et al. (2001)
Chakrabarti and Fombonne (2001)
Bertrand et al. (2001)
Scott et al. (2002)
Yeargin-Allsopp et al. (2003)
Lingam et al. (2003)
Gurney et al. (2003)
Icasiano et al. (2004)
Chakrabarti and Fombonne (2005)
Ouellette-Kuntz et al. (2006)
Harrison et al. (2006)
Gillberg et al. (2006)
Fombonne et al. (2006)
Baird et al. (2006)
Latif and Williams (2007)
Croen et al. (2007)
CDC (2007b) Approximate
CDC (2007a) Population Size
Wong and Hui (2008)
Williams et al. (2008)
Montiel-Nava et al. (2008)
Kawamura et al. (2008) 1000000
van Balkom et al. (2009)
Nicholas et al. (2009)
CDC (2009)
Baron-Cohen et al. (2009)
Posserud et al. (2010) 100000
Maenner and Durkin (2010)
Lazoff et al. (2010)
Fernell and Gillberg (2010)
Barnevik-Olsson et al. (2010)
Windham et al. (2011) 10000
Samadi et al. (2011)
Parner et al. (2011)
Mattila et al. (2011)
Kim et al. (2011)
Chien et al. (2011)
Brugha et al. (2011)
Al-Farsi et al. (2011)
Parner et al. (2012)
Nygren et al. (2012)
Kocovska, Biskupsto et al. (2012)
Isaksen et al. (2012)
Idring et al. (2012)
CDC (2012)
Taylor et al. (2013)
Saemundsen et al. (2013)
Ouellette-Kuntz et al. (2013)
Davidovitch et al. (2013)
Atladottir et al. (2014)
CDC (2014)
0 100 200 300
ASD Prevalence (per 10,000)
FIGURE 12.2 Prevalence estimates for autism spectrum disorder since 2000 (per 10,000 with 95% confidence intervals; also see Figure 12.4). The dashed vertical line
denotes the mean prevalence of 69/10,000 across all 53 surveys.
broadened or case ascertainment is improved. Moreover, epidemiological surveys of ASD

possess unique design features that could account almost entirely for between-study varia-
tion in prevalence estimates, making time trends even more difficult to gauge. Time trends
in prevalence estimates can therefore only be evaluated in investigations that hold meth-
odological parameters under strict control over time. Such requirements must be con-
sidered when reviewing evidence for a secular increase in rates of ASD or testing for the
“epidemic” hypothesis.
The epidemic hypothesis emerged in the 1990s when, in most countries, increasing
numbers were diagnosed with ASD leading to an upward trend in children registered
in service providers’ databases that was paralleled by higher prevalence rates in epide-
miological surveys. These trends were interpreted as evidence that the actual population
incidence of ASD was increasing. However, because methodological factors contribute
to variability in prevalence estimates, these must be considered before concluding that
there is a true increase in the number of children diagnosed with ASD. These factors are
discussed here.
Use of Referral Statistics
Increasing numbers of children referred to specialist services or known to special education

registers have been taken as evidence for increased ASD incidence. Such upward trends
have been seen in many different countries (Gurney et al., 2003; Lotter, 1966; Shattuck,
2006), all occurring in the late 1980s and early 1990s. However, trends over time in referred
samples are confounded by referral patterns, availability of services, heightened public
awareness, decreasing age at diagnosis, and changes over time in diagnostic concepts and
practices.
As an illustration, Figure 12.3 contrasts two methods for surveying ASD using hypo-
thetical data—one based on sampling from the total population and the other relying
solely on service access counts. Here, assuming a constant incidence and prevalence of
100/10,000 between Time 1 and Time 2 (meaning there is no epidemic), population
surveys at two time points result in prevalence estimates that are not only accurate but
also stable over time, showing no prevalence change in the target population. However,
if prevalence is estimated based only on service access counts where the number of ASD
individuals accessing services increases from 20% to 60% over time, prevalence would be
underestimated at both time points but would appear to rise 200% while the underlying
true incidence and prevalence remained stable. Such a pattern of results was reported
based on special education data in Wisconsin (Maenner & Durkin, 2010), in which
ASD prevalence rates were stable between 2002 and 2008 in school districts with ini-
tially high baseline prevalence rates (≈120/10,000), whereas school districts with low
baseline rates experienced significant increases in prevalence (e.g., in one district, rates
increased from 5 to 70/10,000, corresponding to a 1300% increase in 6 years). Failure
to control for these confounding factors was obvious in previous reports (Fombonne,
2001), including widely quoted reports from the California Developmental Database
Services (CDDS, 2003).
In addition, the decreasing age at diagnosis results in increasing numbers of young chil-
dren being identified in official statistics (Wazana, Bresnahan, & Kline, 2007) or referred
to specialist medical and educational services. Earlier identification of children from the
prevalence pool may therefore result in increased service activity that may lead to a misper-
ception by professionals of an epidemic.
120
True population prevalence is 100/10,000; if prevalence is

100 estimated by population surveys at 2 time points,
ASD cases per 10,000
prevalence estimates are accurate and stable over time.

80
60 If prevalence is estimated by individuals accessing services

at 2 time points, prevalence estimates could create the
illusion of an increase in prevalence (here, 200%) over time,
40 yet still under-estimate true prevalence at both time points.
20
0
Time 1 Time 2
ASD cases
accessing ASD
services cases not
20% accessing
services ASD
ASD 40% cases
cases not accessing
accessing services
services 60%
80%
FIGURE 12.3 Assuming a constant incidence and prevalence of 100/10,000 between Time 1 and
Time 2 (meaning there is no “epidemic”), prevalence estimates that rely solely on service access
counts not only underestimate the true prevalence but may also create the illusion of rising
prevalence over time (see discussion in text).
Diagnostic Substitution
Another possible explanation for increased prevalence in a diagnostic category is that chil-
dren presenting with the same developmental disability may receive one particular diagno-
sis initially and another diagnosis subsequently. Such diagnostic substitution (or switching)
may occur when diagnostic categories become increasingly familiar to health professionals
and/or when access to better services is ensured by using a new diagnostic category.
The strongest evidence of diagnostic substitution contributing to ASD prevalence
increase was shown in a complex analysis of US Department of Education data in 50 US
states (Shattuck, 2006), indicating that a relatively high proportion of children previ-
ously diagnosed with mental retardation (MR) were subsequently identified as having
ASD. Shattuck showed that the odds of having ASD increased by 1.21 during 1994–2003,
whereas the odds of having learning disability (LD) (odds ratio (OR) = 0.98) and MR
(OR = 0.97) decreased. Shattuck further demonstrated that the growing ASD prevalence
was directly associated with decreasing prevalence of LD and MR within states and that a
significant downward deflection in the historical trajectories of LD and MR occurred when
ASD became reported in the United States as an independent category in 1993–1994.
Using individual-level data, a more recent study re-examined the hypothesis of diag-
nostic substitution in the California DDS data set (King & Bearman, 2009) and showed
that 24% of the increase in caseload was attributable to diagnostic substitution (from MR
to ASD). It is important to keep in mind that other types of diagnostic substitution are
likely to have occurred as well for milder forms of ASD. For example, children currently
diagnosed with Asperger’s disorder may have been previously diagnosed with other psy-
chiatric diagnoses (i.e., obsessive–compulsive disorder, school phobia, social anxiety, etc.)
in clinical settings before the developmental nature of their condition was fully recognized
(Fombonne, 2009).
Cross-Sectional Variability in Epidemiological Surveys
Evidence that method factors could account for most of the variability in published preva-
lence estimates derives from a direct comparison of eight recent surveys conducted in the
United Kingdom and the United States (Fombonne, 2005). In each country, four surveys
were conducted during approximately the same year and with similar age groups. Because
there is no reason to expect large variations in between-area differences in rates, prevalence
estimates should be comparable within each country. However, there was a 6-fold varia-
tion in rates for UK surveys and a 14-fold variation in US rates. In each set of studies, high
rates were found when intensive population-based screening techniques were employed,
whereas lower rates were found in studies relying on passive administrative methods for
case finding. Because no passage of time was involved, the magnitude of these gradients in
rates is likely to reflect methodological differences.
Even more convincing evidence derives from the most recent survey by the CDC on
363,749 children aged 8 years in 2010, in which an average prevalence of 147/10,000
was reported across 11 US states (CDC, 2014). One striking finding in this report is
the almost fourfold variation in prevalence rates by state (range, 57–219 per 10,000;
see Figure 12.4). Across individual states, Alabama had the lowest rate of 57/10,000,
whereas New Jersey had the highest rate of 219/10,000 (CDC, 2014). Estimated ASD
prevalence was significantly lower in states that had access to health data sources only
compared to that of states where educational data were also available (97.7 vs. 149 out
Alabama
Wisconsin
Colorado Approximate
Population Size
Missouri 45000
Georgia
35000
Arkansas
25000
Arizona
Records Access
Maryland Primarily health-care
sources
Access to education
North Carolina records throughout
most or all of
Utah surveillance area
New Jersey
0 50 100 150 200 250

ASD Prevalence (per 10,000)
FIGURE 12.4 Estimated prevalence of autism spectrum disorders (with 95% confidence intervals)
among children aged 8 years in the United States by ADDM site and type of records access in
the 2010 surveillance year (CDC, 2014). The dashed vertical line denotes the average prevalence
estimate of 147/10,000 across all sites.
of 10,000, respectively), a factor that is consistently associated with higher prevalence

rates in the ADDM Network. It would be surprising if there were truly this much inher-
ent state-to-state variability in the number of children with autism in the United States.
Thus, these differences likely reflect ascertainment variability across sites in a study that
was otherwise performed with the same methods, at the same time, on children of the
same age, and within the same country.
Repeated Surveys in Defined Geographical Areas
Repeated surveys, using the same methodology and conducted in the same geographi-
cal area at different time points, can potentially yield useful information on time trends
if methods are kept relatively constant. The Göteborg studies (Gillberg, 1984; Gillberg,
Steffenburg, & Schaumann, 1991) provided three prevalence estimates that increased dur-
ing a short period of time from 4.0 (1980) to 6.6 (1984) to 9.5/10,000 (1988), with the
gradient being even steeper in urban areas only (Gillberg et al., 1991). However, compari-
son of these rates is not straightforward because different age groups were included in each
survey. Furthermore, increased prevalence was associated with improved detection among
those with intellectual delays in the second survey and with improved detection of cases
born to immigrant parents in the third survey, suggesting that migration into the area could
be a key explanation. Taken in conjunction with a change in local services and a progres-
sive broadening of the autism definition over time (Gillberg et al., 1991), findings provide
weak evidence for increased autism incidence. Similarly, studies conducted in Japan at dif-
ferent points in time in Toyota (Kawamura et al., 2008) and Yokohama (Honda, Shimizu,
Misumi, Niimi, & Ohashi, 1996; Honda, Shimizu, & Rutter, 2005) showed increases in
prevalence rates that their authors interpreted as reflecting the effect of both improved
population screening of preschoolers and a broadening of diagnostic concepts and criteria.
Two separate surveys of children born between 1992 and 1995 and between 1996 and
1998 in Staffordshire, United Kingdom (Chakrabarti & Fombonne, 2001, 2005), were per-
formed with rigorously identical methods for case definition and case identification. The
prevalence for combined ASD was comparable and not statistically different in the two
surveys (Chakrabarti & Fombonne, 2005), suggesting no upward trend in overall rates of
ASD, at least during the short time interval between studies.
Birth Cohorts
In large surveys encompassing wide age ranges, increasing prevalence among most recent
birth cohorts could be interpreted as indicating a secular increase in ASD incidence, pro-
vided that alternative explanations can be confidently eliminated. This analysis was used in
two large French surveys (Fombonne & Du Mazaubrun, 1992; Fombonne, Du Mazaubrun,
Cans, & Grandjean, 1997). The surveys included birth cohorts from 1972 to 1985 (735,000
children, 389 of whom had autism). When pooling the data of both surveys, age-specific
rates showed no upward trend (Fombonne et al., 1997).
However, data assessing birth cohorts can be problematic, as illustrated in Figure 12.5,
which shows an increase in the prevalence of ASD by year of birth across three hypothetical
successive birth cohorts (a cohort effect; Figure 12.5, left). Within each birth cohort, fol-
lowed longitudinally, prevalence increases as children age (Figure 12.5, right): For children
in the 2000 birth cohort, based on previous ASD prevalence estimates, age 6 years preva-
lence is 20/10,000, whereas at age 12 years, we may expect prevalence of 80/10,000 for
100 100
1990 Birth Cohort
Age 6
90 90 1995 Birth Cohort
Age 8
80 80 2000 Birth Cohort
Age 12
70 70
ASD cases per 10,000
60 60
50 50
40 40
30 30
20 20
10 10
0 0
1990 1995 2000 6 7 8 9 10 11 12
Year of Birth Child Age in Years
FIGURE 12.5 Using hypothetical data, Figure 5a illustrates rising prevalence rates among 6-, 8-, and
12-year-old children across three different birth cohorts. Prevalence rates also increase within birth
cohorts as they age (Figure 5b), potentially coinciding with changes in patterns of referral, service
availability, public awareness, and diagnostic concepts and practices (see discussion in text).
the same birth cohort. Increasing prevalence rates with age within birth cohorts is unlikely
to reflect the onset of ASD in later childhood and early adolescence. It is more likely that
observed increases in prevalence reflect underdiagnosis in the preschool years as well as
changes in public awareness, service availability, and diagnostic concepts and practices.
For example, an analysis of special educational data from Minnesota showed a 16-fold
increase in children identified with ASD from 1991–1992 to 2001–2002 (Gurney et al.,
2003). However, during the same time period, an increase of 50% was observed for all dis-
ability categories (except severe ID), especially for the category including attention defi-
cit hyperactivity disorder. The large sample size allowed the authors to assess age, period,
and cohort effects. Prevalence increased regularly in successive birth cohorts; for example,
among 7-year-olds, prevalence increased from 18/10,000 among those born in 1989 to
29/10,000 among those born in 1991 and 55/10,000 in those born in 1993. Within the
same birth cohorts, age effects were also apparent because for children born in 1989, the
prevalence increased with age from 13/10,000 at age 6 years to 21/10,000 at age 9 years
and 33/10,000 at age 11 years. As argued by Gurney et al., this pattern is not consistent
with the natural etiology of ASD, which first manifests in early childhood. Gurney et al.’s
analysis also showed a marked period effect, where rates started to increase in all ages and
birth cohorts in the 1990s. The authors noted that this phenomenon coincided closely with
the inclusion of ASD in the federal Individuals with Disabilities Educational Act in the
United States. A similar interpretation of upward trends had been put forward by Croen
and colleagues (2002) in their analysis of the CDDS data and also by Shattuck (2006) in
his analysis of trends in US Department of Education data.
CORRELATES OF AUTISM SPECTRUM DISORDER IN EPIDEMIOLOGICAL SURVEYS
Studies of associations between ASD and socioeconomic status (SES), race/ethnicity,

and immigrant status have shown variable results and face numerous technical challenges.
In general, studies that base diagnosis rates on developmental service utilization may
undercount minority and low SES children. Underprivileged children have less health
services access overall (Shi & Stevens, 2005) and particularly low mental health services
access (Kataoka, Zhang, & Wells, 2002), which can lead to underidentification of ASD. In
contrast, children with more educated, wealthier, or more health-literate parents may have
resources to make their way to ASD diagnostic services and, therefore, an ASD diagnosis
(Tsai, Stewart, Faust, & Shook, 1982). Cross-sectional studies based on parent report of
ASD are problematic for the same reason, as parent report of ASD is more likely among
families who have adequate access to ASD-related services. Undercounting of minorities
may additionally occur in the context of multistage, population-based research. Minority
and low SES families may participate in such research studies at disproportionately low
rates due to higher rates of distrust of scientific researchers (Rajakumar, Thomas, Musa,
Almario, & Garza, 2009) or less access to research opportunities. They also may be excluded
from studies or incorrectly assessed if forms are not available in appropriate languages or if a
language-congruent assessor is not available (Laing & Kamhi, 2003). Finally, because ASD
is a relatively rare event, population-based studies of ASD prevalence may have relatively
small numbers of low SES, minority, or immigrant children meeting case criteria, making
data difficult to interpret (Powell et al., 2000).
Socioeconomic Status
Socioeconomic status can be defined variously, with the most common methods being
parental education, income, parental occupation, or some combination of these fac-
tors. More than 20 studies have investigated associations between these factors and ASD
prevalence.
Many recent US-based studies suggest an association between higher SES (as assessed
by one of the previously mentioned factors) and higher ASD prevalence. Several studies
have used CDC ADDM data combined with imputed sociodemographic data from US
Census tracts to show a link between parental income/education and ASD diagnosis. Using
2007 data from New Jersey, Thomas et al. (2012) showed that the ASD prevalence ratio
between the highest income tract (>$90,000) and the lowest income tract (<$30,000) was
2.2. In addition, children in the higher income tracts were more likely to have a higher num-
ber of professional evaluations and a lower age of diagnosis, suggesting a referral bias or an
underdiagnosis of children at the lower end of the SES spectrum. Using CDC ADDM data
from all 14 participating states, Durkin et al. (2010) developed a composite SES indicator
that took into account both parental education and household income. This study found
a dose–response relationship between SES and ASD prevalence, regardless of gender and
data source. SES-based differences in prevalence were significantly weaker when children
with a previous ASD diagnosis (as opposed to a new diagnosis in the context of the study)
were excluded—a finding that suggests that prior access to ASD diagnostic services may
explain some of the difference. Both of these studies benefit from a population-based data
collection framework; however, they are limited in that no individual-level SES data were
available.
Similarly, Bhasin and Schendel (2007) conducted a population-based case–control
study, directly measuring maternal education and imputing household income from cen-
sus tract data in Atlanta, Georgia. Higher median family income was significantly asso-
ciated with autism overall. Both markers of higher SES (higher maternal education and
higher median family income) were significantly associated with autism without ID but
not autism with ID, suggesting that, in addition to biases based on service access, diagnostic
substitution may be occurring more frequently among children with higher SES. Leonard
et al. (2011) observed a similar finding in Western Australian children born from 1984 to
1999. The prevalence of ASD without ID was significantly increased among children whose
mothers had more economic resources.
One criticism of these recent studies, particularly the studies based in the United States,
is that SES has been confounded by inequitable health services access and that in a setting
where health services access is more equitable, the effects of SES might be lessened or even
reversed. In a Denmark population-based case–control study, Larsson et al. (2005) found
that the risk of ASD was actually higher among children with less parental wealth in bivari-
ate analyses but that after adjusting for other demographic factors, there was no association
of either parental education or wealth with ASD. In a Swedish case–control study by Rai,
Lewis, and colleagues (2012), children in families with lower income and whose parents
had manual occupations were at higher risk for ASD diagnosis after multivariate adjust-
ment. In England, which also has national health insurance, Brugha et al. (2011) found that
ASD adults with higher educational attainment had lower rates of autism after multivari-
ate adjustment; however, it is likely that an ASD diagnosis may have reduced the subjects’
educational attainment. In contrast, in a study performed in Israel, where access to and
coverage of ASD-related services was reported to be excellent, Davidovitch et al. (2013)
found lower prevalence of ASD in children who lived in low-income versus higher-income
communities or whose families did not purchase supplemental private insurance.
Overall, many recent large-scale studies have shown an association between ASD prev-
alence and SES, although it appears that these differences were due to decreased access
to diagnostic services among children with lower SES or diagnostic substitution between
ID and ASD among children with higher SES. In settings where health care is more acces-
sible, these effects seem to lessen or even reverse. To date, no plausible biological mecha-
nism has been proposed or supported that might explain SES-related differences in ASD
prevalence. The fact that older studies either did not show SES associations (Gillberg &
Schaumann, 1982; Tsai et al., 1982) or showed variability based on referral source (Wing,
1980) or autism subtype (Sanua, 1987) also supports the fact that SES differences are due
to differences in ASD ascertainment as opposed to an underlying biological or psychosocial
mechanism.
Race and Ethnicity
Many studies of racial/ethnic minorities show lower rates of ASD compared to white or
European populations, although these differences appear to be narrowing in more current
studies. The evidence is strongest for African American and Hispanic populations in the
United States. Several recent studies are highlighted here, although other recent studies
show similar findings (Liptak et al., 2008; Mandell et al., 2009). Because minority race and
ethnic status often correlates with lower SES and worse health care access, studies attempt-
ing to assess the effects of race/ethnicity on ASD diagnosis should control for SES and
health care accessibility factors in their analyses.
Using administrative data from Texas school districts, Palmer, Walker, Mandell, Bayles,
and Miller (2010) showed that the number of autism diagnoses in a school district was
inversely proportional to the number of Hispanic schoolchildren in that district, after
adjusting for number of pediatricians, child psychologists, and neurologists by county,
as well as county median household income. One strength of this approach is that it did
attempt to adjust for SES and differential services availability, as well as comorbid ID and
LDs on a population level. Interestingly, these factors better explained variability in ASD
diagnoses among white non-Hispanic children than Hispanic children, suggesting that SES
and access factors alone do not explain lower diagnosis rates in Hispanics, at least on a
population level. However, this ecological study did not measure individual-level access
factors (e.g., insurance adequacy) or factors such as provider bias that may also impact ASD
diagnostic rates.
The most recent CDC ADDM data (CDC, 2014) also suggest an overall lower rate of
ASD among non-Hispanic black (123/10,000) and Hispanic children (108/10,000) com-
pared to white children (158/10,000) in the United States. Although there was consider-
able variability among the states, all 11 sites reported higher rates of ASD among whites than
among black and Hispanic children. However, the prevalence of ASD without ID among
white children was nearly double the prevalence among either black or Hispanic children
(OR = 1.8; p < .01), indicating that underdiagnosis of ASD in minority populations in the
United States may be magnified in those children without comorbid ID. Pedersen et al.
(2012) examined racial/ethnic differences more thoroughly using several waves of ADDM
data in Arizona, which has a large Hispanic population. That study also found a lower rate
of ASD in Hispanic children compared to non-Hispanic white children. ASD prevalence
increased in both populations during the study years, and the gap in prevalence between
racial/ethnic groups decreased. The authors speculated that much of this difference might
be attributable to underutilization and lack of access to ASD services by Hispanic families.
They also speculated that these differences might reflect the “Hispanic paradox” or “healthy
immigrant” effect, in which Hispanic immigrants to the United States have lower rates of
multiple adverse health outcomes despite multiple SES and health care access risk factors
(Franzini, Ribble, & Keddie, 2001). However, the fact that differences in diagnostic rates
are narrowing rather rapidly suggests that changes in awareness and utilization of services
may be more likely than inherent genetic or developmental differences by race/ethnicity.
Windham et al. (2011) used a large administrative sample from multiple sources in
northern California to show a lower prevalence of ASD among children of Hispanic and black
mothers compared to children of white non-Hispanic mothers, after adjusting for maternal
education and age, with similar decreases in racial differences during the study years. However,
the observed racial variation was attenuated by adjustment for SES and varied significantly by
data source, suggesting that variable health services utilization may have affected ASD rates.
Finally, in a US population-based study using parent report of ASD diagnosis, Kogan
et al. (2009) found lower rates of ASD diagnosis in non-Hispanic black and multiracial
children compared to white children, after adjusting for parental education and income.
This study also noted a disproportionately high number of black children whose parents
reported a past diagnosis of ASD that subsequently resolved, which runs contrary to most
epidemiologic data about ASD lifetime trajectories. This finding suggests that low rates of
ASD among black children may be due to racial differences in parent health beliefs about
ASD. This study found no significant difference in ASD diagnoses by Hispanic versus
non-Hispanic ethnicity; however, follow-up analysis of the same data set by Schieve et al.
(2012) showed that there were significantly lower rates of ASD among Hispanic children
with foreign-born parents compared to white children. Schieve et al. concluded that by fail-
ing to take into account the heterogeneity of Hispanic children with ASD, previous stud-
ies that grouped all Hispanics together might have been biased toward a null result. The
authors believed that the findings were likely related to differences in parental awareness
and access to care stemming from a lower level of acculturation for this subgroup. They also
speculated that the findings might reflect the healthy immigrant effect.
In studies outside of the United States, reports about racial/ethnic differences in ASD
prevalence have been more mixed, and most studies are not adjusted for SES, which makes
it difficult to assess the unique effect of race/ethnicity from other confounders. In addition,
these studies are difficult to interpret because what constitutes a minority race or ethnicity
is quite variable by country. In Israel, Davidovitch et al. (2013) found a lower prevalence of
ASD among Arab Israelis in rural settlements and in ultra-Orthodox Jews than in the general
Israeli population, although prevalence was not adjusted for SES differences. Findings from
a 1999–2003 census report in Stockholm, Sweden (Barnevik-Olsson, Gillberg, & Fernell,
2010), revealed that the prevalence rate of autism (autism and PDD-NOS/autistic-like
condition) with LD was higher in Somali- versus non-Somali Swedish children. The study
did not adjust for SES differences between these mothers and other Swedish mothers. The
authors hypothesized that lower levels of vitamin D in immigrant Somali mothers may
have affected fetal brain development and possibly led to autism and other concerning
behavioral characteristics; however, the study did not measure vitamin D in any of the par-
ticipants (see Kočovská, Fernell, Billstedt, Minnis, & Gillberg, 2012). Several older, unad-
justed studies also suggest a higher prevalence of ASD among recent Swedish immigrants,
although these immigrants’ countries of origins were so mixed that it is difficult to interpret
this information in terms of ethnic or racial differences (Gillberg, Steffenburg, Börjesson,
& Andersson, 1987; Gillberg et al., 1991).
Overall, most recent studies on racial/ethnic differences in ASD diagnosis do suggest
that race/ethnicity affects diagnostic rates above and beyond SES alone, at least in US-based
populations. However, given that the racial/ethnic effects are present in several tradition-
ally underserved racial/ethnic groups, are quite variable by data source and study type, and
have narrowed over time, they are most likely explained by differential health services uti-
lization, parental health beliefs, and acculturation. Little high-quality data are available on
the effects of race/ethnicity in non-US settings.
Migration and Prenatal Exposure to Stressful Events
Migration has historically been implicated as a possible risk factor for autism, based on
observed higher rates of autism among immigrant populations in some epidemiological
surveys (Barnevik-Olsson et al., 2010; Gillberg et al., 1987, 1991; Wing, 1980). However,
evidence for an association between migration and ASD has been inconsistent, with some
studies reporting increased ASD risk among immigrant populations (Keen, Reid, & Arnone,
2010; Lauritsen, Pedersen, & Mortensen, 2005) and others reporting equivalent and even
decreased ASD risk in some populations (Gillberg et al., 1987; Lauritsen et al., 2005). Most
of the early claims about migration as a possible correlate of autism derived from post hoc
observations of very small samples and were not subjected to rigorous statistical testing.
However, recent studies have attempted to re-examine the association between migration
and ASD. For example, in a study using a population-based Swedish cohort, Magnusson
et al. (2012) found that children of migrant parents were at increased risk for ASD with
ID compared to children of Swedish-born parents. However, the reverse was true for ASD
without ID: Children of Swedish-born parents were at significantly higher risk than chil-
dren of migrant parents, particularly those from countries with low human development
indices. The authors suggest that the most plausible explanation for this pattern of findings
is the underdiagnosis of ASD in migrant children with high cognitive abilities; for these
children, the more subtle social deficits associated with ASD may be overlooked or misat-
tributed to language or cultural differences. In addition, because case ascertainment was
based on service use, migrant families may have been less aware of or less likely to seek ser-
vices in the community in the absence of clear developmental or cognitive delays. However,
the researchers also suggest that the possibility of environmental factors associated with
migration and acting in utero that may contribute to ASD cannot be dismissed.
One environmental factor associated with migration that has been posited to contrib-
ute to ASD risk is prenatal exposure to stressful life events due to the fact that migration
itself is likely to be a stressful event because it may occur when families flee armed con-
flict or other extreme conditions in their home country (Magnusson et al., 2012). Using
a population-based cohort of approximately 1.5 million singleton children in Denmark,
Li et al. (2009) examined whether prenatal exposure to maternal bereavement, defined by
the loss of a child, spouse, parent, or sibling during or up to 1 year prior to pregnancy, was
associated with increased risk of ASD. Li et al. found no evidence of an effect of maternal
bereavement on autism risk, even after accounting for the timing, nature, and severity of
the exposure, although maternal bereavement was rare even in the total population (expe-
rienced by 2.5%). Similarly, in a study utilizing population-based cohorts in Sweden and
England, Rai, Golding, et al. (2012) also found no evidence for an association between
ASD risk and prenatal exposure to stressful life events such as deaths, serious accidents,
and diagnosis of serious illnesses in first-degree relatives, although again these events
were extremely rare (experienced by 1% of the population). Thus, the hypothesis of an
association between migration, as well as exposure to other prenatal stressful events, and
ASD remains largely unsupported by the empirical results. However, note that even with
large-scale population-based cohorts, these events were extremely rare.
Implications and Unmet Research Needs
Overall, the research findings related to low SES, minority, and immigrant populations pri-
marily point to problems of underdiagnosis due to problems in access to health care services
and health literacy. Evidence for a biological difference based on SES, race/ethnicity, or immi-
gration is weak, as is the case for multiple other chronic health conditions among children and
adults (Pearce, Foliaki, Sporle, & Cunningham, 2004). In order to obtain an accurate depic-
tion of ASD prevalence in underserved populations, investigators will need to specifically
reach out to these populations to ensure equal participation and also oversample these groups
so that sample sizes are adequate. In addition, there is a need for validated screening and diag-
nostic tools in multiple languages to ensure that diagnoses, when they occur, are accurate.
Finally, key variables in these analyses, such as parental education, income, and race/ethnicity,
need to be directly measured as opposed to imputed from census tract data.
SUMMARY
Epidemiological surveys of ASD pose substantial challenges to researchers seeking to mea-

sure rates of ASD, particularly given the range of case definition, case identification, and
case evaluation methods employed across surveys. However, from recent studies, a best
estimate of 69/10,000 (equivalences = 6.9/1000 or .69% or 1 child in approximately 145
children) can be derived for the prevalence of ASD. Currently, the recent upward trend in
rates of prevalence cannot be directly attributed to an increase in the incidence of the disorder
or to an epidemic of autism. Although power to detect time trends is seriously limited in
existing data sets, there is good evidence that changes in diagnostic criteria and practices,
policies for special education, service availability, and awareness of ASD in both the lay and
the professional public may be responsible for increasing prevalence over time. It is also
noteworthy that the increase in the number of children diagnosed occurred concurrently
in many countries in the 1990s, when services for children with ASD also expanded sig-
nificantly. Statistical power may also be a significant limitation in most investigations; thus,
variations of small magnitude in ASD incidence may be undetected or should be inter-
preted with caution.
Nonetheless, the possibility that a true increase in the incidence of ASD has also partially
contributed to the upward trend in prevalence rates cannot, and should not, be completely
eliminated based on available data. To assess whether the incidence has increased, method-
ological factors that account for an important proportion of the variability in rates must be
stringently controlled for. New survey methods have been developed for use in multinational
comparisons; ongoing surveillance programs are currently underway and will soon provide
more meaningful data to evaluate this hypothesis. In addition, it remains to be determined
how changes to diagnostic criteria introduced in the DSM-5 will impact ASD prevalence esti-
mates going forward. Meanwhile, the available prevalence data carry straightforward implica-
tions for current and future needs in services and early educational intervention programs.
KEY POINTS
• Based on recent studies, a best estimate of 69/10,000 (equivalences = 6.9/1000 or
.69% or 1 child in approximately 145 children) can be derived for the prevalence
of ASD.
• Although prevalence estimates for ASD have been steadily increasing, epidemiologi-
cal surveys of ASD possess unique design features that could account almost entirely
for between-study variation in prevalence estimates, making time trends difficult
to gauge.
• There is good evidence that changes in diagnostic criteria and practices, policies for
special education, service availability, and awareness of ASD in both the lay and the
professional public may be responsible for increasing prevalence over time.
• Research findings related to low socioeconomic status, minority, and immigrant pop-
ulations primarily point to problems of underdetection and underdiagnosis due to
problems in access to health care services and health literacy.
• It remains to be determined how changes to diagnostic criteria introduced in the
DSM-5 will impact ASD prevalence estimates going forward.
Dr. Alison Presmanes Hill, Dr. Katharine Zuckerman, and Dr. Eric Fombonne have nothing
to disclose.
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/ / /
13 / / / NEUROPATHOLOGY OF AUTISM
SPECTRUM DISORDER
MATTHEW P. ANDERSON
INTRODUCTION
Recent studies indicate that genetic defects, sometimes inherited but often de novo, under-
lie a large proportion of autism spectrum disorder (ASD) cases. The findings indicate that
ASD is extremely heterogeneous, with each genetic abnormality accounting for less than
1% of cases. Heterogeneity was already evident clinically by the variable severity of each of
the core behavioral domains and the variable comorbidities.
In light of the known genetic and clinical heterogeneity of ASD, one might expect het-
erogeneity in the neuropathological findings of postmortem brains as well; indeed, this is
the case. Future studies of the postmortem brain in ASD would be strengthened by focus-
ing on cases with the same genetic defect. A study focused on brains with the shared mater-
nal 15q11–13 duplication is included later in this chapter as a representative example of
this approach. There is also evidence for nongenetic causes in some cases of ASD. Defining
these distinct nongenetic etiologies of ASD will be important to create a homogenous case
series for studies of the postmortem brain.
Many neuropathologic studies of ASD have focused on the cerebral cortex, hippocam-
pus, or cerebellum. Only a few have focused on the amygdala or brain stem. However, the
behavioral deficits of ASD, whether core diagnostic components or frequent comorbidi-
ties, will each arise from distinct neuronal circuitries within the brain. Each subtype of ASD
will have a distinctive set of behavioral deficits that will demand studies aimed at a distinct
neuronal circuitry. These issues must also be considered when interpreting the significance
of the current postmortem brain literature in ASD and deciding on the direction of future
studies.
Technical and Other Issues in Postmortem Brain Analysis
Matching the brains of control subjects for age, sex, and postmortem interval will be very
important in postmortem brain studies in ASD. Brain weight is affected by sex (male brains
are larger than female brains) and age. There are a large number of sexually dimorphic
properties of neuronal circuits that include differences in neuron numbers, dendritic arbor
205
branching and spine densities, and regional and cellular gene and protein expression (for
examples, see Yang & Shah, 2014).
Even more significant are the clinical conditions preceding death. Individuals experi-
encing cardiopulmonary insufficiency and support for prolonged periods of time will dis-
play the effects of episodic hypoxia (low oxygen supply to the brain) and/or ischemia (low
blood flow to the brain) that can alter morphology, cause inflammatory cell reactions and
infiltrates, and affect mRNA and protein expression levels. Similarly, if a patient died in
status epilepticus (prolonged unremitting discharges of neuronal circuits), there will be
changes due to excitotoxic cell death, innate immune responses, changes related to neural
circuit plasticity, and anti-epileptic (homeostatic) and pro-epileptic changes in mRNA and
protein expression; depending on the seizure type, these changes will be variable across
many brain regions. The structural, transcriptional, and protein changes caused by a seizure
can last for weeks. The hippocampus, thalamus, cerebellum, and cortex are just a few of the
well-described sites that are strongly affected by generalized seizures. As described next, a
number of ASD cases are associated with mutations in known epilepsy genes, and epilepsy
is a frequent comorbidity in ASD; therefore, a large proportion of these postmortem brains
will have changes related to recent or remote seizures.
Genetic and Postmortem Brain Studies of a Genetically Defined Type

of Autism Spectrum Disorder: Idic15
In 1997, Cook et al. reported a family with a mother who transmitted supernumerary
inverted duplicated chromosome15 (isodicentric chromosome 15, or Idic15, with two
extra copies of the genomic region) to two children with ASD but not to one unaffected
sibling. Significantly, the mother, who had inherited the Idic15 chromosome from her
father, was unaffected, suggesting an imprinted gene was important. In 2010, Hogart, Wu,
LaSalle, and Schanen reported that of 54 Idic15 subjects studied, 81% met strict criteria for
ASD using the Autism Diagnostic Interview–Revised. In recent genome-wide transcrip-
tional profiling studies, brain tissue from Idic15 ASD was compared to that of controls and
undefined ASD cases, and similar transcriptional disturbances were reported in Idic15 and
idiopathic ASD (Belgard & Geschwind, 2014, unpublished results). A neuropathologic
comparison found Idic15 ASD brains (7 of 9 with epilepsy) to be microcephalic (1177 g),
being significantly smaller than those of the idiopathic ASD cohort (1477 g; 4 of 10 with
epilepsy) (Wegiel et al., 2012). Another difference was the finding of hippocampal gran-
ule neuron heterotopias (in CA4 alveus or dentate molecular layer) in 8 of 9 Idic15 cases
but only 1 of the idiopathic ASD cases (Wegiel et al., 2012). Other types of hippocampal
dysplasia were also more frequent in Idic15 than undefined ASD. Heterotopias in cerebel-
lar white matter were found at an equivalent frequency (50% of cases for both Idic15 and
idiopathic ASD). Similarly, three types of dysplastic changes were found in the cerebellum
of the Idic15 and idiopathic ASD cases. These included dysplasia in parts of the nodulus
and flocculus, vermis dysplasia, and focal polymicrogyria. By contrast, 50% of idiopathic
ASD cases had dysplasia of the cerebral cortex (focal polymicrogyria, multifocal cortical
dysplasia, and bottom-of-a-sulcus dysplasia), whereas cortical dysplasia was not found in
any of the Idic15 ASD cases. Premorbid clinical electrophysiological studies to map the
seizure foci can sometimes localize to regions of cortical dysplasia, but these were not pre-
sented in the study. Focal cortical and hippocampal dysplasia is often found in neurosurgi-
cal resections where the region was removed as a treatment for partial epilepsy clinically
mapped to those sites. One can only speculate on whether any of these regions of dysplasia
Neuropathology of Autism Spectrum Disorder // 207
FIGURE 13.1 Some of the earliest studies of the neuropathology of autism were pioneered in the
mid 1980’s by Dr. Margaret L. Bauman (shown) and Dr. Thomas L. Kemper.
were epileptic foci and whether they had any role in producing the behavioral symptoms
related to ASD or any of their associated comorbidities. Importantly, a correlation between
the severity of the behavioral deficits and the seizure disorder has been noted in the litera-
ture for Idic15 (Dennis et al., 2006), and seizure-associated regression has been observed
(http://www.dup15q.org). Knowing that heterogeneous genetic forms of ASD could
account for as many as one-third of cases, one would anticipate heterogeneity in the neuro-
pathology of ASD. This was illustrated previously when comparing the neuropathology of
Idic15 and idiopathic ASD.
A common feature across published postmortem studies in ASD is the varied neuro-
pathologies: (1) brain size: megalencephaly to microencephaly; (2) developmental mal-
formations: cortical, hippocampal, or cerebellar dysplasia to absent brain stem nuclei;
(3) cerebellar Purkinje neuron loss: severe to none; and (4) innate immune activa-
tion: severe, moderate, mild, or none.
Additional neuropathological findings in ASD can also be found in the following
reviews: Blatt (2012); Amaral, Schumann, and Nordahl (2008); Bauman and Kemper
(2005); and Palmen, van Engeland, Hof, and Schmitz (2004) (Figure 13.1).
MEGALENCEPHALY AND MICROCEPHALY IN AUTISM SPECTRUM DISORDER
Brains from individuals with ASD have been found in some cases to be larger (megalen-
cephaly) or smaller (microcephaly) than those of control cohorts. Brain size could serve
as a biomarker for ASD subtypes when trying to achieve efficacy in therapeutic trials and
could cluster genetic subtypes into specific cellular and molecular pathways. Because ASD
begins at an early age while the brain is still growing, it is important to compare brain size
to that of age- and sex-matched controls. It is also important to monitor the brain growth
trajectory. Seizures can have a delayed onset in ASD, and in some severe epilepsy disorders,
regression in brain size and behavior are correlated with the onset and severity of seizures.
Severe epileptiform discharges are known to cause gross brain atrophy, excitotoxic neuro-
nal cell death, and behavioral regression. Other ASD subtypes that begin with a normal
brain size and behavior will regress in both domains in a pattern that appears to be indepen-
dent of seizures (e.g., Rett’s disorder).
Megalencephaly
Heterozygous mutations in chromodomain helicase DNA-binding protein 8 (CHD8)

were originally discovered as rare missense mutations in whole exome sequencing studies
of ASD cohorts (Neale et al., 2012; O’Roak et al., 2012), and CHD8 was disrupted in a
rare balanced chromosome rearrangement (Talkowski et al., 2012). Subsequent sequenc-
ing of larger ASD and control cohorts identified 15 truncating mutations in 3730 cases
(0.4%) while finding no mutations in 8792 unaffected siblings (Bernier et al., 2014). ASD
was diagnosed in 13 of the 15 mutation-carrying individuals, indicating strong penetrance
of the core behavioral deficits. Macrocephaly was also strongly penetrant (80%).
Phosphatase and tensin homolog deleted in chromosome 10 (PTEN) has dual protein
and lipid phosphatase activity, and its tumor suppressor activity is dependent on its lipid
phosphatase activity, which negatively regulates the phosphatidylinositol 3-kinase/Akt
pathway. Mutations in the PTEN gene are associated with a broad spectrum of disorders,
including Cowden disease-1 (CWD1; OMIM 158350), Bannayan–Riley–Ruvalcaba syn-
drome (OMIM 153480), and Lhermitte–Duclos disease. In a case series of 33 patients with
ASD and macrocephaly, Klein, Sharifi-Hannauer, and Martinez-Agosto (2013) found that
22% harbored heterozygous mutations in PTEN in association with extreme macrocephaly
(standard deviation >3; 99.7th percentile). O’Roak et al. (2012) identified three de novo
mutations (two missense and one frameshift, all with macrocephaly) in the PTEN gene
while sequencing 44 candidate genes among 2446 ASD probands, indicating the overall
incidence among ASD cases is relatively low at 0.1%. Proteus syndrome (OMIM 176920),
which is associated with gigantism of hands and feet, nevi, hemihypertrophy, and macro-
cephaly, is due to somatic activating mutations in the AKT1 gene.
Amaral et al. (2008) reviewed the magnetic resonance imaging (MRI) evidence for
an abnormal brain size and found that there may be a 5–10% enlargement (with a slightly
greater increase of white matter volume) that may not persist into later childhood and ado-
lescence. Neuropathological studies have reported increased brain weight in individual
cases within cohorts of ASD (Bailey et al., 1998; Casanova, Buxhoeveden, Switala, & Roy,
2002a; Courchesne, Müller, & Saitoh, 1999; Kemper & Bauman, 1998; Williams, Hauser,
Purpura, DeLong, & Swisher, 1980) (Figure 13.2).
Microcephaly
A subset of ASD cases present with brains that are small relative to those of controls. Cohen
syndrome (ASD with mild facial dysmorphism and joint laxity) is one example (Hennies
et al., 2004); Idic15 is another example (Wegiel et al., 2012). Heterozygous loss-of-
function mutations in DYRK1A, another ASD gene, produce microcephaly in humans (van
Bon et al., 2011). Christianson syndrome, a condition that presents as ASD or Angelman
syndrome with mutism, intellectual disability, and generalized tonic–clonic epilepsy, is
due to loss-of-function mutations in the X-linked gene NHE6, a sodium–proton exchange
protein, and is characterized by a delayed onset postnatal microcephaly and cerebellar and
brain stem atrophy (Pescosolido et al., 2014).
FIGURE 13.2 An example of human megalencephalic brain (left) as compared to a control (right),

found in a subset of cases of autism spectrum disorder.
CEREBRAL CORTEX IN THE POSTMORTEM BRAIN IN AUTISM SPECTRUM

DISORDER
Altered Cortical Thickness and Cortical Dysplasia
Increased cortical thickness and heterotopic and mal-oriented pyramidal neurons were
reported in cases by Bailey et al. (1998). Polymicrogyria has been seen in two postmortem
cases (Kemper & Bauman, 1998; Ritvo et al., 1986), and several MRI studies have observed
developmental cortical abnormalities in a small proportion of subjects (Gaffney & Tsai,
1987; Piven et al., 1990). Bailey et al. (1998) reported cortical dysgenesis in four of six
autistic cases, with thickened cortices, high neuronal density, the presence of neurons in the
molecular layer, irregular laminar patterns, and poor gray–white matter boundaries. White
matter abnormalities were also found in four cases, including ectopic gray matter in three
cases and an increased number of white matter neurons in one case.
Cortical Tubers and Hemimegalencephaly
Somatic mutations in early progenitor cells that contribute to normal brain development
underlie a subset of children and adults with drug-refractory epilepsy and comorbid intel-
lectual disability and ASD. Somatic mutations within genes controlling cellular growth
(tumor suppressor genes) are well-known to occur in cancer. A similar mechanism is
thought to occur in the brains of individuals with the neurodevelopmental disorder tuber-
ous sclerosis (TSc), in which individuals carry a germline mutation in either the TSC1
or the TSC2 gene. These individuals can often develop severe drug-refractory epilepsy
disorders that are driven by a cortical tuber—an abnormally large cerebral cortex region
(gyrus) that contains disorganized, often heterotopic, and abnormally large astroglia and
neurons. The regions of cortical dysplasia are thought to arise from a second hit to the
remaining normal TSC1 or TSC2 gene in the progenitor cell pool during cerebral cortical
development. Some individuals without TSc can also present with drug-refractory focal
seizures that on brain imaging show abnormal cerebral cortex gyri which are then treated
through neurosurgery. These abnormal regions of cortex are removed surgically and are
found histologically to be regions of cortical dysplasia. Again, the normal layered pattern
of the cerebral cortex is often disorganized, sometimes with neurons of abnormal size,
location, and numbers. Studies have shown that these abnormal cells often have consti-
tutive activation of the same pathways affected by TSc mutations that promote aberrant
growth, again suggesting somatic mutations of growth control genes as occurs in cancer.
In some cases of refractory seizures, a very large proportion of one of the two hemispheres
is expanded, called hemimegalencephaly. Recent studies identified somatic mutations in
these brain overgrowth disorders of hemimegalencephaly associated with epilepsy and
often intellectual disability (Lee et al., 2012; Poduri et al., 2012). For example, somatic
mutations in several genes (PIK3CA, AKT3, and mTOR) were found in the neurons of
these enlargements of just one hemisphere of the brain. The regions of dysplasia described
previously in the neuropathological comparison between Idic15 and idiopathic ASD are
likely to have resulted through similar somatic mutations in neural progenitor cell pools
early during brain development.
Cortical Minicolumns
The configuration of so-called minicolumns was investigated in ASD and Asperger’s dis-
order (Casanova, Buxhoeveden, Switala, & Roy, 2002b). More numerous, smaller, and
less compact minicolumns were reported in 9 ASD subjects (7 with intellectual disability,
5 with epilepsy, and 4 with macroencephaly) compared with 9 control cases (Casanova
et al., 2002b) and in 2 adults with Asperger’s disorder compared with 18 control subjects
(Casanova et al., 2002b).
Cortical Neuron Density Changes
Courchesne et al. (2011) reported an increase in the density of neurons in dorsolateral

(78%) and mesial (28%) prefrontal cortex that statistically correlated with the increase
in brain weight relative to an age-matched reference control weight. The ages of the
male ASD cohort were 2, 3, 3, 4, 7, 8, and 16 years, with only one ASD case with known
epilepsy.
Cortical Patches: Focal Loss of Molecular Markers

In a subsequent study by the Courchesne group (Stoner et al., 2014), in situ hybridization
was performed using neuron layer-specific mRNAs. Based on the overgrowth pattern previ-
ously reported, one might have expected a poor demarcation of cortical layers with vertical
dispersion of layer-specific mRNA markers. Instead, they found patches of morphologi-
cally normal cortex in which there was reduced or lost mRNA expression in the prefrontal
or temporal cortex in 10 of 11 cases of ASD but in only 1 of 11 control cases. Interneuron
markers (e.g., PVALB and CALB1) showed mild abnormalities, which were inconsistently
present within patches across case samples, with a few exceptions (e.g., GAD1 and VIP)
that appeared to be relatively unaffected. Similarly, the glial markers were also unaffected
with rare exceptions. The foci of reduced mRNA staining did not correspond to decreases
in cell number. Foci of mRNA loss were not observed in occipital cortex. The significance
of the finding remains undefined.
Cortical Neuron Spine Density Increases
Hutsler and Zhang (2010) reported increased spine density in cortical layer II pyramidal
neurons. Tang et al. (2014) reported that in a small cohort of postmortem brains, the devel-
opmental decrease (pruning) in temporal lobe layer V pyramidal neuron basal dendrite
spine density that normally occurs between childhood (2–8 years old) and adolescence
(13–18 years old) failed to occur in age-matched ASD cases. However, when comparing the
childhood age groups, there were no preexisting differences between ASD and control sub-
jects. They also observed that during the period of childhood to adolescence, mTOR and
S6 protein phosphorylation decreased in controls and that no significant decrease could be
observed when averaged across the ASD cases. The postsynaptic density protein PSD95
also decreased across this developmental time period in controls, but it failed to decrease in
ASD. They also found that LC3-II, a biomarker of autophagosomes, was reduced in ASD.
CEREBELLUM CHANGES IN POSTMORTEM BRAIN

IN AUTISM SPECTRUM DISORDER
Purkinje Neuron Depletion
Williams et al. (1980) were the first to perform a detailed neuropathological analysis
on four individuals with autistic behavior (three males, 12, 27, and 33 years of age; one
female, 3 years of age; all presented with intellectual disability and two with seizures).
Reduced Purkinje cell density was seen in one case, with concomitant epilepsy and pro-
found intellectual disability. Ritvo et al. (1986) counted Purkinje cells in the cerebellum
of four autistic cases (all males, three with intellectual disability and none with seizures)
and three male controls. Autistic cases showed a decreased number of Purkinje cells in the
cerebellar hemisphere and vermis. Kemper and Bauman (1998) also reported alterations
in the cerebellum. All six autistic cases showed decreased numbers of Purkinje cells. Bailey
et al. (1998), in their study of six ASD cases (all with intellectual disability and three with
epilepsy) and seven age- and sex-matched controls, reported low Purkinje cell counts in
all five adult ASD cases. Lee et al. (2002) examined two ASD cases (both with intellectual
disability and one with epilepsy) and observed a decreased number of Purkinje cells in
both cases. Fatemi, Halt, Realmuto, et al. (2002) were the first to examine the size of the
cerebellar Purkinje cells. A 24% decrease in mean Purkinje cell size was reported in the
ASD group.
NEUROTRANSMITTER SYSTEM CHANGES IN POSTMORTEM

BRAIN IN AUTISM SPECTRUM DISORDER
GABAergic Neurons and Neurotransmission
Blatt (2012) reported on the GABAergic, serotonergic, cholinergic, and glutamatergic

receptor binding sites in the postmortem ASD brain. They used radiolabeled muscimol
and flunitrazepam binding to assess the GABA A receptor density. In 2007, Guptill et al.
reported a 20% decrease in GABA A receptor binding sites in the hippocampus of ASD
subjects compared to controls. In 2009 and 2011, Oblak, Gibbs, and Blatt found reduced
GABA A receptor binding sites in superficial layers of anterior cingulate cortex (47%), pos-
terior cingulate cortex (49%), and fusiform gyrus (31%) of subjects with ASD relative
to control brains. In 2010, Oblak et al. also reported reduced GABAB receptor binding
sites in anterior and posterior cingulate cortex, again most prominent in superficial layers
(35% decrease). In the cases reported in 2009, four of the seven cases had known epilepsy,
and three were on antiseizure medications. Fatemi, Halt, Stary, et al. (2002) showed that
glutamic acid decarboxylase (GAD), the rate-limiting enzyme responsible for the conver-
sion of glutamate to GABA in the brain, is reduced in ASD (five ASD and eight controls).
GAD65 protein was reduced by 50% in the cerebellum and by 48% in the parietal cortex
of ASD cases. GAD67 protein was reduced by 51% in the cerebellum and by 61% in the
parietal cortex of ASD cases. Yip, Soghomonian, and Blatt (2007) demonstrated a 40%
decrease in GAD67 mRNA in Purkinje neurons of posterolateral cerebellar cortex in ASD.
Yip et al. (2008) also reported a 28% increase in GAD67 mRNA staining of cerebellar
basket cells.
Serotonergic Neurons and Receptors
Azmitia, Singh, and Whitaker-Azmitia (2011) reported increased numbers of serotonergic

axon terminals in the cortex of individuals with ASD. Oblak et al. (2013) reported reduced
5HT1A and 5HT2A receptor binding sites in the posterior cingulate cortex and fusiform
gyrus in the brains of subjects with ASD relative to those of controls.
NEURODEGENERATIVE-TYPE CHANGES IN POSTMORTEM

BRAIN IN AUTISM SPECTRUM DISORDER
Tauopathy in ASD-Related Neurodevelopmental Disorders
Christianson syndrome due to X-linked NHE6 mutations shows tau-positive and

Bielchowsky-positive neuronal and glial inclusions, as well as phosphorylated neu-
rofilament inclusions particularly prominent in brain stem and subcortical regions
(Garbern et al., 2010). Heterozygous deletion of ADNP in mice causes a tauopathy,
neuronal cell death, and abnormalities in social behavior and cognitive functioning
(Vulih-Shultzman et al., 2007), suggesting a similar change may be found in the brain of
ASD cases with haploinsufficiency of ADNP (Helsmoortel et al., 2014). Interestingly,
numerous neurofibrillary tangles were found in layers II and III of the cerebral cortex,
especially in the temporal region, of a 24-year-old woman with ASD and intellectual
disability attributed in this case to severe self-injurious behavior (Hof, Knabe, Bovier,
& Bouras, 1991).
COMORBIDITY OF AUTISM SPECTRUM DISORDER AND EPILEPSY
De novo mutations in SCN2A and SCN1A are found in cases of ASD (reviewed in
Krumm, O’Roak, Shendure, & Eichler, 2014). Interestingly, heterozygous missense
mutations of these same genes are known to underlie forms of infantile epilepsy. Two
of the genes are voltage-gated sodium channels SCN2A (Nav1.2) and SCN1A (Nav1.1).
In Idic15, one of the more frequent strongly penetrant cytogenetic causes of ASD,
seizures were reported in 63% of the 83 cases surveyed (Conant et al., 2014). In the
postmortem neuropathology study described by Wegiel et al. (2012), the majority of
Idic15 cases had epilepsy, and this was frequently the cause of premature death (sudden
unexpected death in epilepsy). In a study of the clinical features of 65 individuals with

2q23.1 microdeletion syndrome in which microdeletion overlaps and balanced chro-
mosomal rearrangements point to the MBD5 gene, ASD and intellectual disability were
comorbid with epilepsy in 85% of cases (Talkowski et al., 2011). These findings indicate
that the neuropathology of ASD could variably include changes secondary to prolonged
repetitive seizures such as hippocampal sclerosis, cerebral atrophy with astrogliosis and
microgliosis, and cerebellar atrophy with loss of Purkinje cells and secondary Bergmann
gliosis. A clinical clue is that these cases will also often have a history of regression some-
times coincident with seizures.
Seizure-Associated Neuropathology in Autism Spectrum Disorder
A subset of ASD cases present with hippocampal sclerosis, as recently reported in two
cases of Idic15 (Boronat, Mehan, Shaaya, Thibert, & Caruso, 2014). In the SCN2A
case reported by Kamiya et al. (2004), there was moderate diffuse atrophy by MRI,
associated epilepsy, intellectual disability, psychomotor retardation, and ASD fea-
tures. Cases of SCN1A mutation-associated migrating partial epilepsy of infancy, an
epileptic encephalopathy, have been reported to show regression and an acquired
progressive microcephaly (Carranza Rojo et al., 2011). Thus, some cases of micro-
cephaly might result from the ongoing epileptiform discharge of circuits. Genetic
forms of generalized epilepsy such as SCN1A (Mantegazza et al., 2005) develop a
delayed mesial temporal sclerosis that then evolves into mesial temporal lobe epilepsy
(focal seizures arising from the hippocampal formation and medial temporal lobe).
Evidence suggests that repeated forebrain discharges travel to the hippocampal for-
mation, where they cause excitotoxic cell death. Hyperexcitability then arises in the
damaged local hippocampal circuits, which then become a new source of spontaneous
epileptiform discharge. In studies of adult epilepsy patients, it is well documented that
unilateral cortical status epilepticus (prolonged uncontrolled seizures, independent
of medications) can cause a crossed cerebellar diaschisis with Purkinje cell and inter-
nal granule neuron depletion and associated cerebellar atrophy (Samaniego, Stuckert,
Fischbein, & Wijman, 2010). Crossed cerebellar diaschisis is thought to represent
cerebellar circuit injury caused by excessive neuronal transmission from prolonged
excitatory synaptic activity via the corticopontine–cerebellar pathways. Based on the
high incidence of epilepsy and the frequent Purkinje cell and granule neuron deple-
tion and cerebellar atrophy in ASD, it is plausible that these types of changes in the
cerebellum that have been reported in ASD postmortem brain studies result from
chronic seizures. The behavioral significance of these histopathological defects in cer-
ebellar circuits remains a subject of speculation but could in principle underlie some
of the cognitive and/or social deficits present in ASD (for review, see Wang, Kloth, &
Badura, 2014). Evidence supporting this notion is the finding that homozygous dele-
tions of the TSC1 or TSC2 gene targeted to Purkinje neurons impair social behavior
in mice (Reith et al., 2013; Tsai et al., 2012). Future conditional genetics approaches
should facilitate mapping of the social behavior deficits and other comorbidities of
the nonsyndromic genetic forms of ASD to specific neuronal circuits. Such studies
are critical to helping focus the neuropathological studies of the ASD postmortem
brain to specific behaviorally relevant neuronal circuitries, particularly when examin-
ing genetically defined subtypes of the condition.
Seizure Discharges During Sleep
In a number of the genetic ASD–epilepsy comorbidity disorders, seizures are prominent

during sleep. This suggests that much of the epileptiform discharge could be clinically
hidden. In the SCN2A case reported by Kamiya et al. (2004), the electroencephalogram
showed frequent bilateral sharp waves or spike waves with maximum amplitude over the
centroparietotemporal region that were semicontinuous during sleep. Similar bilateral
sharp waves or spike waves during sleep are prominent in Idic15 (R. L. Thibert, personal
communication).
INNATE IMMUNE SYSTEM IN POSTMORTEM BRAIN IN

Molecular Markers of the Innate Immune System in Autism

Spectrum Disorder Brain
Increased cytokines, chemokines, and growth factors have been identified in ASD brain
tissue (anterior cingulate and cerebellum) and cerebrospinal fluid (Vargas, Nascimbene,
Krishnan, Zimmerman, & Pardo, 2005) in some studies. Using an enzyme-linked
immunosorbent assay approach focused on specific cytokines and chemokines, Li
et al. (2009) confirmed an increase of tumor necrosis factor-α, interleukin-6 (IL-6),
granulocyte–macrophage colony-stimulating factor, interferon-γ, and IL-8 in ASD com-
pared to control brains. An increase of immune system-related mRNAs was also found in
ASD postmortem brain tissue analyzed using unbiased genome-wide studies of transcripts
(Garbett et al., 2008; Voineagu et al., 2011).
Activated Microglia in the Autism Spectrum Disorder Brain
In samples of postmortem prefrontal cortex, microglia-specific transcripts that are involved

in their cellular responses were elevated in ASD relative to controls (Edmonson, Ziats,
& Rennert, 2014): TREM2 (1.75-fold), DAP12 (1.5-fold), and CX3CR1 (1.34-fold).
However, another marker of activated microglia, IBA1, was not significantly elevated in
ASD. Microglia play a critical role in synaptic pruning during postnatal brain develop-
ment. In mice lacking CX3CR1, a chemokine receptor expressed by microglia in the brain,
microglial cell numbers were transiently decreased and synaptic pruning was concur-
rently temporarily delayed (Paolicelli et al., 2011). The transient deficit in microglial num-
bers and increase in spine density were associated with a persistent deficit of prefrontal
cortex–hippocampus connectivity as assessed by local field potential oscillatory coherence
and functional MRI measurements, as well as some deficits in social behavior (Zhan et al.,
2014). These model organism studies indicate that defects in microglial function could
result in an increase in spine density as recently reported in ASD.
Activated Astroglia in the Autism Spectrum Disorder Brain
In samples of postmortem prefrontal cortex, the marker of activated astroglia, GFAP

mRNA, was elevated 1.7-fold in ASD relative to controls. GFAP mRNA was even more
strongly increased in cerebellum (2.63-fold) in ASD, but surprisingly, the microglial
markers were instead slightly decreased in this brain region (Edmonson et al., 2014). In
a separate study, GFAP protein was also increased 45–75% in frontal, parietal, and cere-
bellar cortex of ASD relative to control (Laurence & Fatemi, 2005). Another study found
that the astroglia density was increased, whereas the number of branching processes and
the branch lengths were reduced, in postmortem frontal cortex of ASD brains relative to
those of controls, but these structural properties of astroglia were not altered in cerebel-
lum (Cao et al., 2012). Aquaporin 4 protein, which localizes to the astroglia perivascular
foot processes and functions as a water channel for fluid homeostasis, was reduced in ASD
cerebellum relative to controls (Fatemi, Folsom, Reutiman, & Lee, 2008). Interestingly, the
decrease of aquaporin 4 is opposite the change found in other neuropathologic conditions
such as hypoxia/ischemia and trauma of the central nervous system, in which aquaporin 4
is increased (Benarroch, 2007).
Innate Immune Activity Indicates Neuropathology, Not Etiology
The fine delicate branches of the astrocyte become thickened and fewer and the quan-
tity of somatic cytoplasm next to the nucleus increases with increased GFAP staining
in a wide variety of neuropathological states. Astroglia and microglia become activated
adjacent to regions of ischemic infarction in which early in the process, there are eosino-
philic neurons, and later in the process there is loss of neurons with replacement foamy
macrophages. In excitotoxic neuronal cell death due to a toxin, drug, or severe seizure,
the distribution of neuronal death is scattered rather than in a vascular territory, but the
same process of individual neuron degeneration with reactive microglia, foamy mac-
rophages, and reactive astrocytes is seen. In areas of white matter demyelination, as in
immune-mediated multiple sclerosis or progressive multifocal leukoencephalopathy
due to polyoma JC virus infection, there is a microglial and macrophage infiltrate within
the white matter with loss of myelin by luxol fast blue staining but relative preservation
of axons by neurofilament or Bodian staining and many perivascular lymphocytic cuffs.
There are also reactive microglia and astrocytes in brain regions infiltrated by tumor cells,
whether an infiltrating glioma, a lymphoma, or a metastatic tumor. In addition, there
are reactive astroglia and microglia in neurodegenerative diseases such as Alzheimer’s
disease, often prominent adjacent to neuritic plaques containing deposits of amyloid.
A small subset of Alzheimer’s cases result from genetic mutations or copy number vari-
ants within amyloid or amyloid processing proteins. In these situations, there are extra-
cellular deposits of amyloid visible with β-amyloid staining and intracellular deposits
visible with Bielshowski silver stain but more readily seen using antibodies to ubiquitin
or τ- or α-synuclein. Interestingly, there appear to be rare subsets of ASD that have intra-
neuronal τ inclusions. ASD due to NHE6 mutations (Christianson syndrome) display
τ-positive inclusions (Garbern et al., 2010) and may progress as a neurodegenerative
disease with age (E. Morrow, personal communication). Similarly, ASD due to haplo-
insufficiency of ADNP (Helsmoortel et al., 2014) is associated with τ inclusions in ani-
mal models of this condition. There are also reactive astrocytes and microglia in some
genetic neuronal storage disorders, but there are no reports of increased intracellular
storage material (glycogen, lipid, and lipofuscin) in the ASD neuropathology literature.
Reactive astrocytes and microglia are found within regions of autoimmune encephalitis,
such as Rasmussen’s (antibodies to glutamate receptor type 3, α7-acetylcholine receptor,
and NMDA-type GluRε2 receptor); however, in these conditions there are also con-
current T lymphocytes cuffing vessels and within the parenchyma and microglial nod-
ules are found “attacking” cortical pyramidal neurons. These features have not yet been
reported in any ASD postmortem brain cases. Astroglial and microglial activation is also
observed within regions of viral encephalitis, but again, there are typically T lympho-
cyte cuffs and microglial nodules surrounding infected neurons. In some cases of viral
encephalitis, the intraneuronal inclusions contain dense collections of viral particles on
electron microscopy. The lymphocytic and microglial reactions typical of a viral infec-
tion of neurons or of an autoimmune disease have not been reported in the ASD neu-
ropathology literature. Therefore, although these quantitative measures of microglial
and astrocytic changes in ASD are helpful in establishing the presence of a pathological
condition and the magnitude of this change might someday become a biomarker that
correlates with the severity of clinical signs and symptoms in ASD, the findings alone
are not sufficient to implicate a specific etiology. Again, one must also keep in mind that
the neuropathology of ASD will be as heterogeneous as we are finding for the genet-
ics of ASD. If ASD is anything like epilepsy, there will be genetic, autoimmune, viral,
toxic–metabolic, and focal lesional causes. In the nongenetic epilepsies, there is often a
distinctive neuropathology that can implicate one specific class of etiologies (e.g., corti-
cal dysplasia). The same might be expected to be true for ASD.
Developmental Circuit Pruning Defects: Speculations on a Neuropathology

Unique to Autism Spectrum Disorder
Chung et al. (2013) demonstrated that the genetic loss of two phagocytic receptors,
Megf10 and Mertk, expressed on astroglia, impairs the ability of astroglia to phagocy-
tize synapses and causes a failure to developmentally prune connections in the neuro-
nal circuits that relay visual signals from the retina to the thalamus. The implication
is that impaired astroglial function might arrest axonal pruning in all neuronal cir-
cuits that normally must undergo postnatal developmental remodeling. Interestingly,
the combined dominant negative and haploid insufficient loss of LGI1 function in a
human partial epilepsy (Kalachikov et al., 2002) also partially arrests developmen-
tal pruning of hippocampal dentate gyrus synapses (Zhou et al., 2009) and retino-
geniculate axons (Zhou et al., 2012) and leads to a severe epilepsy with premature
early death when fully deleted only in glutamatergic neurons (Boillot et al., 2014).
The retinogeniculate circuit is convenient for such studies because it undergoes quite
dramatic changes—initially the axons of 6–10 retinal ganglion cells innervate each tha-
lamic relay neuron, but then they prune to only a single or pair (with the second much
weaker) of retinogeniculate axonal inputs to each relay neuron. This pruning occurs
at approximately age 16–20 days in mice, probably equivalent to approximately age 1
or 2 years in the humans. Concurrent with this pruning, the strength of single axonal
inputs is dramatically increased as the dendritic arbor of a single retinal ganglion cell’s
axon reoccupies the sites on the thalamic relay neuron dendrite that become exposed
as the other retinal ganglion neuron axonal synapses are removed. The pruning process
is sensory experience/neuronal activity-dependent and enables sensory experiences
and features of the sensory organ to sculpt the sensory topographic map. The surpris-
ing finding is that astrocytes play a critical role in this process. The implication is that
genetic or other insults that impair astrocyte function during this critical period of
circuit remodeling could partially block developmental circuit pruning to impair the
fidelity and efficacy of transmission across sensory pathways. Far less is known about
developmental pruning in other important neural systems that might underlie the non-
sensory behavioral problems found in ASD.
ETIOLOGIES OF THE ACTIVATED INNATE IMMUNE SYSTEM

IN THE BRAIN IN AUTISM SPECTRUM DISORDER
Maternal–Fetal Autoantibodies
Goines et al. (2011) reported the presence of antibodies to cerebellum proteins in
individuals with ASD, but the same antibodies were also variably found in controls.
Piras et al. (2014) correlated more severe ASD behavioral symptoms with increased
anti-brain antibodies. Nordhal et al. (2013) correlated maternal–fetal autoantibodies
to brain enlargement in ASD. As an approach to establish causal relationships between
these antibodies and the autism-associated behavioral deficits, the Amaral group intro-
duced the ASD-associated maternal autoantibodies into monkeys during pregnancy and
found that progeny displayed aberrant social behaviors and an enlarged brain (Bauman
et al., 2013).
Infections
A number of ASD cases have been associated with congenital cytomegalovirus infec-
tion (Yamashita, Fujimoto, Nakajima, Isagai, & Matsuishi, 2003). Cases of ASD and
enterovirus encephalitis have also been reported (Marques, Brito, Conde, Pinto, &
Moreira, 2014). As a step toward establishing causality between viral infection and
some of the ASD brain postmortem findings, it was reported that in utero exposure
to maternal influenza virus infection (Fatemi, Earle, et al., 2002) or viral analogs
(Smith, Elliott, & Anderson, 2012) in pregnant mice resulted in an excessive num-
ber of neurons in the cerebral cortex at birth. The increased cell density was most
prominent at birth and then partially receded with age. The changes triggered by
the in utero viral infection/analog resemble those found in ASD postmortem brain,
including the recently confirmed reduced neuronal soma size (Wegiel et al., 2014),
the increased frontal lobe neuronal densities (Courchesne et al., 2011), and the early
increased brain growth reported by many MRI studies in vivo (reviewed in Amaral
et al., 2008). Activation of the maternal immune system during pregnancy is also suf-
ficient to cause behavioral deficits of reduced social interaction (Smith, Li, Garbett,
Mirnics, & Patterson, 2007) and increased fetal and early postnatal brain cytokines
(Garay, Hsiao, Patterson, & McAllister, 2013) resembling those changes found in
human ASD. Social deficits and increased repetitive behavior were also produced in
monkeys when the mother was exposed to a viral analog during the first trimester
(Bauman et al., 2014).
Seizures/Epileptiform Discharge
Dysplastic changes in cerebral cortex (a known source of epileptiform discharge; e.g., focal
cortical dysplasia or cortical tubers of TSc) or cerebellum appear to be found in a higher
proportion of ASD cases than controls (Weigel et al., 2012). As described previously, many
of the recently identified rare single gene loss-of-function mutations found in ASD are also
known to occur in cases of infantile epileptic encephalopathy. There is a very high incidence
of epilepsy in ASD, and it is well documented that seizures activate the innate immune
system.
Molecular Changes
Studies of the mRNAs in postmortem brain in ASD found increases in immune

system-related gene expression (Garbett et al., 2008; Voineagu et al., 2011). Voineagu
et al. identified a large increase of S100a8 mRNA, a native toll-like receptor 4 (TLR4)
agonist in ASD. Systemic or direct brain inoculation with the TLR4 agonist lipopoly-
saccharide has been shown to be a robust stimulant of the brain’s innate immune sys-
tem. TLR4 receptors were recently shown to be important as an acute and chronic
pro-epilepsy pathway (Maroso et al., 2010). TLR4 is increased in neurons and astro-
glia (not in microglia) of human mesial temporal lobe resection specimens removed for
temporal lobe epilepsy, and the levels correlate with the frequency of seizures per month
prior to removal (Pernhorst et al., 2013). However, in the same study, IL-8 expression
was inversely related to seizure frequency in the human samples, but it is elevated in
ASD postmortem brain (Garbett et al., 2008).
SUMMARY
This chapter reviewed results from studies of the postmortem brain in ASD. As with the
clinical presentation and genetic causes in ASD, the heterogeneity of findings is apparent.
Future studies in neuropathology will focus on cases with the same genetic defect. In addi-
tion, distinct nongenetic etiologies, such as immune, infectious, toxic–metabolic, and focal
lesional causes, will be found to have a distinctive neuropathology.
KEY POINTS
• To date, the results from neuropathologic studies of ASD have yielded heterogeneous
findings of brain abnormality.
• Cases of larger (megalencephaly) and smaller (microcephaly) brains in ASD have
been identified in postmortem studies; some of these abnormalities have been linked
to specific genetic defects.
• The areas of the brain that have most consistently been found to be abnormal in the
postmortem brain in ASD are the cerebral cortex and the cerebellum.
• Seizures occur in 25–33% of individuals with ASD; as a result, changes in postmor-
tem brain secondary to repetitive seizures will need to be considered in the findings.
• Evidence for activation of the innate immune system has been found in the postmor-
tem brain of some individuals with ASD in some studies.
Dr. Matthew P. Anderson has nothing to disclose.
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/ / /
14 / / / IMMUNOLOGICAL ASPECTS
OF AUTISM SPECTRUM
DISORDER
THAYNE L. SWEETEN AND CHRISTOPHER

J. MCDOUGLE
INTRODUCTION
Since the first description of autism spectrum disorder (ASD) by Leo Kanner (1943), clini-
cians and researchers have sought to understand the pathological mechanisms underlying
these conditions. In the 1970s, twin and family studies revealed a strong genetic compo-
nent to these developmental disorders (Folstein & Rutter, 1977). During the same decade,
evidence emerged implicating infection and/or a possible role for immune factors in some
cases (Chess, 1971; Money, Bobrow, & Clarke, 1971). Initially, immune-related studies
were few and far between and of uncertain contribution; however, throughout the decades,
research using increasingly powerful designs and innovative methods continued to detect
immunological abnormalities in subjects with ASD and their families. These findings
included abnormal immune cell responses, along with altered production of cytokines and
antibodies (Stigler, Sweeten, Posey, & McDougle, 2009). Immune genes in the major histo-
compatibility complex region of chromosome 6 were also implicated (Warren et al., 1991),
and family histories revealed an increased frequency of immune-mediated diseases (i.e.,
autoimmune) in relatives of probands with ASD (Comi, Zimmerman, Frye, Law, & Peeden,
1999). Taken together, these studies suggested that infectious or immune-mediated mecha-
nisms might contribute to the pathophysiology of at least a subtype of ASD; however, more
definitive neuroimmune studies were lacking. Prior to the turn of the century, postmortem
histological investigations revealed that approximately one out of six brains from individu-
als with ASD showed signs of immune cell infiltration (reviewed in Stigler et al., 2009), but
research specifically investigating immune parameters in postmortem brain tissue was not
published until 2005 (Vargas, Nascimbene, Krishnan, Zimmerman, & Pardo, 2005).
Theories and supporting data implicating the immune system and infection in the
pathophysiology of a subtype of those with ASD are explored in this chapter. Results from
preliminary drug treatment studies targeting dysregulated immune mechanisms are also
discussed.
225
NEUROINFLAMMATION
The brain is considered an immunologically privileged organ. Under normal conditions,

the blood–brain barrier limits the movement of most immune cell types and proteins
from the capillaries into brain tissue. Therefore, the brain relies heavily on its own resi-
dent immune cells, the microglia, to provide innate immune surveillance and protec-
tion. Making up approximately 10% of the glial cells in the brain, microglia are derived
from monocyte lineage. In the adult, new microglia can be generated from hematog-
enous monocytes/macrophages (Lawson, Perry, & Gordon, 1992; Zhang et al., 2007).
Microglia contain cellular processes that continually probe their immediate surround-
ing area. They become activated when their processes encounter damaged tissue, meta-
bolic waste products such as oxidized lipoproteins, or invading microorganisms. Upon
activation, they undergo morphological changes to engulf materials and secrete immu-
nomodulatory chemicals such as cytokines and chemokines (Wake, Moorhouse, Jinno,
Kohsaka, & Nabekura, 2009). Acting as the brain’s “electricians,” it appears that microg-
lial processes can strip axon terminals away from dendrites, thereby modifying neuronal
synapses in development and plasticity (Graeber, Bise, & Mehraein, 1993). Postnatal
synaptic pruning by microglia utilizes complement-dependent mechanisms (Schafer
et al., 2012).
A seminal case–control study examined postmortem brain tissue from 11 individuals
with ASD along with cerebrospinal fluid (CSF) from six living subjects. Results revealed
active neuroinflammation in the cerebral cortex, white matter, and cerebellum, includ-
ing marked activation of microglia and astroglia. CSF and immunocytochemical studies
showed a proinflammatory profile of cytokines, including a substantial increase in macro-
phage chemoattractant protein-1 and tumor growth factor (TGF)-β1 (Vargas et al., 2005).
Subsequent neuropathological studies have confirmed and built upon these findings, show-
ing activated microglia in a majority of postmortem brains observed among individuals
with ASD, independent of age, in various cortical regions and in white matter (Li et al.,
2009; Morgan et al., 2010, 2012; Tetreault et al., 2012). Activated microglia are more fre-
quently present near neurons, indicating a neuron-directed microglial response (Morgan
et al., 2012). A positron emission tomography study measuring microglial activation in liv-
ing young adults found excessive microglial activation in multiple brain regions, most prom-
inently the cerebellum, in subjects with ASD compared to controls (Suzuki et al., 2013).
Gene expression profiling of brain tissue from individuals with ASD shows increased
messenger RNA transcription levels of many immune system-related genes among the
transcript levels that are abnormal (Garbett et al., 2008). Similar results have been seen
in subsequent genome and transcriptome analysis studies (Saxena et al., 2012; Voineagu
et al., 2011). Summarizing their data, Garbett et al. (2008) state, “Overall, these expres-
sion patterns appear to be more associated with the late recovery phase of autoimmune
brain disorders, than with the innate immune response characteristic of neurodegenerative
diseases.” (p. 303)
In studying and treating individuals with ASD, it is important to note that the relatively
consistent behavioral phenotype likely contains multiple etiologic subtypes. Approximately
10% of cases of ASD are linked to disorders of genetic etiology, such as fragile X syndrome,
tuberous sclerosis, and Rett’s disorder, whereas environmental factors are believed to play
a role in some cases. However, the majority of cases remain idiopathic. It now appears that
immune activation in the brain is also associated with a subset of cases. Yet, many questions
remain regarding this subset, such as what triggers immune activation and what influence it
has, if any, on neurodevelopment and behavior.
Immunological Aspects of Autism Spectrum Disorder // 227
INFECTION
One etiological theory is that either a congenital infection or an infection early in life
could alter brain development and lead to ASD. Evidence to support this theory emerged
after the rubella viral epidemic of 1964. Congenital rubella or German measles is caused
by first-trimester infection with rubella virus. A resultant syndrome in some infected
infants may include deafness, developmental delay, intellectual disability (ID), and sei-
zures. The epidemic of 1964 resulted in the birth of approximately 20,000 infants with
congenital rubella syndrome in the United States. Investigation of this population discov-
ered a larger than expected subset of children who developed ASD as an additional sequela
(Chess, 1971).
Rubella is included in the group of infectious agents most commonly causing con-
genital anomalies represented by TORCH, an acronym for toxoplasmosis, other (syphilis,
varicella-zoster, and parvovirus B19), rubella, cytomegalovirus (CMV), and herpes infec-
tions. CMV infection, the most common cause of congenital and perinatal viral infection,
can develop into clinically apparent cytomegalic inclusion disease in a minority of cases.
Sequelae of CMV inclusion disease can include hepatosplenomegaly, microcephaly, ID,
petechiae, motor disability, jaundice, cerebral calcifications, hearing loss, seizures, chorio-
retinitis, and death.
CMV and other viruses of the Herpesviridae family, such as herpes simplex virus
(HSV), are of much interest in ASD because they are known to cause encephalitis (HSV)
or congenital infection of the brain (CMV). At least 15 cases of ASD diagnosed following
intrauterine CMV infection have been described in the literature (Stubbs, 1978; Sweeten,
Posey, & McDougle, 2004), and other case studies have described the development of
autistic symptoms in association with HSV encephalitis (Delong, Bean, & Brown, 1981;
Ghaziuddin, Al-Khouri, & Ghaziuddin, 2002). Most of these HSV-associated cases are
unique in that the infections were acquired after the age of 5 years and in some patients
the autistic symptoms were transient. For instance, DeLong et al. described two children,
ages 5 and 7½ years of age, respectively, with acute HSV encephalitis leading to an autistic
syndrome. The cases were described as examples of “acquired and reversible autistic syn-
drome” because both children fully recovered.
An estimate of the incidence of cases of ASD associated with rubella or herpes fam-
ily virus infection was inferred from a medical record review of 233 patients with ASD
born in Utah. Ritvo, Mason-Brothers, Freeman, and Pingree (1990) found that 6 of the
233 subjects had congenital viral infection or suspected viral infection from rubella virus
(n = 2), CMV (n = 1), and HSV (n = 3). Vaccination efforts have protected the public
against rubella-associated ASD in many countries, including the United States; vaccina-
tion resulted in the elimination of endemic rubella in 2004. It is important to note that the
“autistic” behavior seen in these infection-associated cases is typically seen in conjunction
with other physical sequelae as part of a particular viral syndrome. Individuals with idio-
pathic ASD do not generally have these associated medical conditions.
Infection with a specific pathogen typically results in a long-term increase in blood anti-
body levels against the pathogen. Therefore, case–control studies have measured sera anti-
body titers in subjects with ASD and controls to help determine the association between
ASD and previous infection with specific pathogens. These studies have found no replicable
results implicating a particular pathogen (Libbey, Sweeten, McMahon, & Fujinami, 2005).
Studies using molecular techniques to detect viral nucleic acids in tissue from subjects with
ASD compared to controls are few in number and also have yielded no conclusive results
implicating a particular pathogen.
Some retrospective epidemiological studies investigating rates of infection in indi-

viduals with ASD as children have found little to no difference compared with controls
(Atladóttir et al., 2012a; Rosen, Yoshida, & Croen, 2007). A more recent publication sug-
gested that children with ASD have an increased risk of hospital admission due to infec-
tion (Abdallah et al., 2012). Some, but not all, studies have shown that individuals with
ASD experience more frequent otitis media than control comparisons (Comi et al., 1999;
Konstantareas & Homatidis, 1987; Tanoue & Oda, 1989).
Two Danish studies found little evidence for an association between various types of
mild common infectious diseases in mothers during pregnancy and ASD (Abdallah et al.,
2012; Atladóttir, Henriksen, Schendel, & Parner, 2012b). Maternal influenza infection was
associated with a twofold increased risk of ASD in one study, but this was not reported by
others (Atladóttir et al., 2012b; Zerbo et al., 2013a). An investigation of all children born in
Denmark from 1980 through 2005 revealed no association between maternal infection and
ASD considering the entire period of gestation. However, admission to the hospital due to
maternal viral infection in the first trimester and maternal bacterial infection in the second
trimester were found to be associated with the diagnosis of ASD in the offspring (Atladóttir
et al., 2010). Similarly, Zerbo et al. (2013b) found no overall association between maternal
infection during pregnancy and ASD. However, women with infections diagnosed during
a hospital admission, particularly bacterial infections, were at increased risk of deliver-
ing a child with ASD. Maternal fever during pregnancy has also been associated with an
increased risk of ASD or developmental delay (Atladóttir et al., 2012b; Zerbo et al., 2013a).
ALLOIMMUNITY
It is still not well understood why a fetus is not rejected by the maternal immune system.
Because half of the fetal genes are derived from the father, the developing embryo and pla-
centa must be considered a “semi-allograft.” If an organ donation were mismatched in a
similar way, powerful immunosuppressant drugs would be required to prevent rejection.
However, the mother’s immune system typically recognizes the fetus as “temporary self ”
and does not attack it. There are exceptions, such as when IgG autoantibodies from moth-
ers with systemic lupus erythematosus, Graves’ disease, or Hashimoto’s thyroiditis cross
the placenta and cause disease in newborns. Likewise, maternal antibodies can target pater-
nal antigens, such as in the disease erythroblastosis fetalis, in which paternally derived Rh
determinants on fetal red blood cells can be attacked by maternal antibodies, leading to
hemolytic anemia in the fetus.
Alloimmunity is an immune response to foreign antigens (alloantigens) from members
of the same species. It has been hypothesized that a subset of ASD could be the result of an
alloimmune-type reaction in which maternal antibodies and/or other maternal immune
responses against the fetus disrupt normal neurodevelopment in utero. In evaluating this
theory, three criteria should be met with reasonable certainty pertaining to both alloim-
mune and autoimmune disorders: direct evidence, indirect evidence, and circumstantial
evidence (Rose & Bona, 1993).
Direct Evidence
Direct evidence requires that pathogenic antibodies or T cells transferred from a diseased
individual will cause similar disease in a healthy recipient. Data in this category are limited
to models in which maternal antibodies are transferred to pregnant animals and the resul-
tant offspring are observed. The antibodies do not cause disease in the mothers but can pro-
duce abnormal behavior and pathology in offspring by disrupting in utero development,
presumably prior to full development of the blood–brain barrier.
The first study to test this pathological mechanism injected serum from the mother of
a child with ASD into pregnant mice. This mother was of interest because immunohisto-
chemistry and flow cytometry showed that antibodies in her blood bound to mice cerebel-
lar Purkinje cells, as well as to other brain cells. Mice exposed in utero to the blood of the
mother showed altered exploratory behavior and reduced motor coordination compared to
controls (Dalton et al., 2003).
A second investigation using a similar pregnant dam mouse model pooled purified IgG
antibody from 63 mothers of children with ASD. IgG antibodies are the only class of anti-
bodies that cross the placenta. Purified antibody from 63 mothers of unaffected children
served as the control. Offspring of damns injected with antibody from mothers of children
with ASD demonstrated differences in motor activity, anxiety, startle response, and socia-
bility. Evidence of cytokine and glial activation was observed in the embryonic brains of the
offspring exposed to IgG from mothers of children with ASD. Of interest, no gross anatom-
ical abnormalities were seen in brain sections, and alterations in behavior persisted in ado-
lescent and adult offspring (Singer et al., 2009). These findings are consistent with ASD and
the lifelong nature of the disorder. In a subsequent study, Braunschweig et al. (2012b) dem-
onstrated that even a single gestational exposure of IgG derived from individual mothers
of children with ASD caused alterations in early growth trajectories, significantly impaired
motor and sensory development, and increased anxiety in mice offspring.
Although rodent models of disease can provide valuable information, they are lim-
ited in their ability to mirror complex behaviors present in neurobehavioral disorders of
humans. The use of more advanced species, such as nonhuman primates, can be more
revealing. For example, Martin et al. (2008) injected four pregnant rhesus monkeys with
purified IgG antibody pooled from the sera of 12 mothers who had at least one child with
ASD or purified IgG antibody pooled from the sera of mothers of children without ASD.
The monkeys born to the mothers that were injected with IgG from mothers with at least
one child with ASD consistently demonstrated increased whole-body stereotypies across
multiple testing paradigms and also displayed more hyperactivity compared to controls.
Stereotypies are considered one of the defining features of ASD, whereas approximately
50% of children with ASD display symptoms of attention deficit hyperactivity disorder
(Gadow & DeVincent, 2005; Gadow, DeVincent, Pomeroy, & Azizian, 2004). A subse-
quent study utilizing a similar design observed abnormal social behavior and enlarged brain
volumes in offspring of monkeys that had been injected with IgG isolated from mothers of
children with ASD compared to controls (Bauman et al., 2013). Enlarged brain volumes
are frequently seen in individuals with ASD (Courchesne et al., 2001; Piven et al., 1995).
Indirect Evidence
The most common type of indirect evidence requires the isolation and characterization of
the pathogenic antibodies or T cells. Numerous studies have investigated mothers of chil-
dren with ASD for the presence of antibodies that react against fetal brain antigens.
Using immunoblotting, Zimmerman et al. (2007) screened serum from mothers of
children with ASD and found specific patterns of antibody reactivity to rat prenatal brain,
but not to postnatal or adult rat brain proteins, in each of the 11 mothers tested. Similar
antibody binding patterns were seen in 12 of 12 children with ASD, as well as in many
children with other neurodevelopmental disorders. Subsequent research found that IgG
from 7 of 61 (11.5%) mothers of children with ASD, but none of 62 mothers of typically
developing children or 40 mothers of children with non-ASD developmental delay, dem-
onstrated IgG reactivity against human fetal brain proteins at approximately 37 and 73 kDa
(Braunschweig et al., 2008). Similar results have been found by other researchers, including
one group using mid-pregnancy blood specimens from mothers of children with ASD and
another utilizing subjects from Spain (Croen et al., 2008; Rossi, Fuentes, Van de Water, &
Amaral, 2014; Singer et al., 2008) (Table 14.1).
Further characterization of the maternal antibodies that recognize fetal brain has revealed
specificity for seven primary antigens: lactate dehydrogenase A and B, cypin, stress-induced
phosphoprotein 1, collapsing response mediator proteins 1 and 2, and Y-box-binding pro-
tein. These proteins are highly expressed in developing brain, and most are involved in neu-
rodevelopment. Exclusive reactivity to specific antigen combinations was noted in 23% of
mothers of children with ASD and only 1% of controls (Braunschweig et al., 2013). A num-
ber of investigators have expressed caution regarding any proposed antibody test until these
results have been replicated by independent laboratories (Underwood, 2013).
Circumstantial Evidence
Genetic alleles associated with autoimmune disease in family members of children with
ASD, especially mothers, can provide circumstantial evidence for alloimmunity, assum-
ing that immune regulatory genes that contribute to autoimmune disease would also
TABLE 14.1 Maternal Antibodies Against Fetal Brain in Autism Spectrum Disorder
Reference Reacts Against No. of Subjects (% positive)

Dalton et al. (2003) Purkinje cells; brain stem neurons 1 case (100%); 4 controls (0%)
Zimmerman et al. (2007) Protein > 250 kDa; protein bands 11 cases (100%); 10 controls (0%)
between 20 and 30 kDa
Braunschweig et al. (2008) Both 37- and 73-kDa protein bands 84 cases (11.5%); 152 controls (0%)
Croen et al. (2008) Both 39- and 73-kDa protein bands 84 cases (3.6%); 200 controls (0%)
Singer et al. (2008) 36-kDa protein band 100 cases (10%); 100 controls (2%)
Goines et al. (2011) Both 37- and 73-kDa protein bands 259 cases (9.3%); 180 controls (0%)
Both 39- and 73-kDa protein bands 259 cases (8.9%); 180 controls (1.7%)
Braunschweig et al. (2012a) Both 37- and 73-kDa protein bands 143 cases (7%); 183 controls (0%)
Nordahl et al. (2013) Both 37- and 73-kDa protein bands 131 cases (7.6%); 50 controls (0%)
Brimberg, Sadiq, Gregersen, Neurons in frontal cortex, 2431 cases (10.5%); 653 controls
and Diamond (2013) hippocampus, and cerebellum (2.6%); 318 cases (8.8%), 2nd
cohort
Rossi et al. (2014) Both 37- and 73-kDa protein bands 37 cases (5%); 37 controls (0%)
Both 39- and 73-kDa protein bands 37 cases (3%); 37 controls (0%)
predispose to alloimmunity. Family members often share autoimmune susceptibility genes;

therefore, if a child has a specific autoimmune disease, then family members are more likely
to have the same or another type of autoimmune disease (Broadley, Dean, Sawcer, Clayton,
& Compston, 2000; Prahalad, Shear, Thompson, Giannini, & Glass, 2002). Thus, knowing
if families with children with ASD have an increased prevalence of autoimmune diseases
compared to a control population can provide meaningful etiological clues.
A case report published more than 40 years ago described an unusually high number
of autoimmune disorders in family members of a child with ASD (Money et al., 1971).
It was not until 1999, however, that this observation was followed up on a larger scale by
surveying families with children with ASD and families with healthy children regarding
the occurrence of autoimmune disease in first- and second-degree relatives. The frequency
of autoimmune disorders in the families with children with ASD was found to be higher
than that in controls, particularly among parents—and especially mothers—of children
with ASD (Comi et al., 1999). Other researchers replicated this finding, noting a numerical
increase of autoimmune diseases in grandmothers and uncles, as well as mothers and broth-
ers, of probands with ASD, suggesting a possible mother-to-son transmission of suscepti-
bility to autoimmune disease in relatives of a proband with ASD (Sweeten, Bowyer, Posey,
Halberstadt, & McDougle, 2003). Most studies, many using large populations and medical
record verification, have replicated the finding of increased autoimmune diseases in family
members of subjects with autism (Table 14.2). A wide variety of autoimmune diseases,
including rheumatoid arthritis, type 1 diabetes mellitus, and autoimmune thyroid disease,
have been found in family members. As circumstantial evidence, these findings do not spe-
cifically implicate ASD as an alloimmune or autoimmune disease, but they do suggest that
genes involved in immune regulation could play a role.
One such gene of interest, the null allele of C4B, has been shown to be associated with
ASD and to be increased in children with ASD with a family history of autoimmune disease
(Mostafa & Shehab, 2010; Warren et al., 1991). The C4B gene codes for a complement
protein involved in innate immunity. It is found on chromosome 6 in the human leukocyte
antigen (HLA) region—a region containing many important genes for immune function.
The null allele is a deficient allele that does not produce protein. Complement C4 pro-
teins are involved in numerous immune functions, including lysing pathogens and marking
pathogens for clearance by immune cells. A deficiency in C4 protein is among the strongest
genetic risk factors for the development of the autoimmune disease systemic lupus erythe-
matosus (Yang et al., 2004).
Although much of the research investigating immunoregulatory genes in ASD has
focused solely on affected children, recent interest has turned toward maternal genetics.
Certain alleles of important immunoregulatory genes have been associated with mothers
of children with ASD. For instance, the frequency of HLA-DR4 appears to be increased in
mothers, as well as individuals with ASD (Lee et al., 2006; Warren et al., 1996). Mothers of
children with ASD are more likely to inherit HLA-DR4 alleles from their parents who have
this gene ( Johnson et al., 2009). HLA-DR4 is a class II HLA gene that codes for a protein
important in antigen presentation to T cells. The DR4 allele has been identified as one of
the susceptibility markers for certain autoimmune diseases, such as rheumatoid arthritis,
and is strongly associated with others such as hypothyroidism and type 1 diabetes mellitus
(Levin et al., 2004; Wordsworth et al., 1989). Some studies indicate that these disorders are
increased in family members of children with ASD, especially in mothers of children with
ASD (Comi et al., 1999; Malloy et al., 2006; Sweeten et al., 2003).
Natural killer (NK) cells are of pivotal importance in innate immune reactions. Upon
activation, they produce inflammatory cytokines such as interferon (IFN)-γ and tumor
TABLE 14.2 Epidemiological Studies of Autoimmune Disease and Related Conditions in Families

of Children With Autism Spectrum Disorder
Reference No. of Assessment Associated Associated Autoimmune
Subjects With ASD Disease or Immune Condition
Comi et al. (1999) 61 cases; 46 Self-report Yes General autoimmunity,
controls rheumatoid arthritis
Sweeten et al. 101 cases; 202 Self-report Yes General autoimmunity,
(2003) controls hypothyroidism and
Hashimoto’s thyroiditis,
rheumatic fever
Micali, Chakrabarti, 79 cases; 61 Self-report No None
and Fombonne controls
(2004)
Croen et al. 420 cases; 2,100 Medical Yes Psoriasis, asthma, allergies
(2005) controls records
Molloy et al. 308 cases Self-report Yes General autoimmunity,
(2006) autoimmune thyroid disease
Mouridsen, Rich, 111 cases; 330 Medical Yes Ulcerative colitis,
Isager, and controls records type 1 diabetes
Nedergaard (2007)
Valicenti-McDermott, 100 cases Self-report Yes Rheumatoid arthritis, celiac
McVicar, Cohen, disease, inflammatory
Wershil, and bowel disease
Shinnar (2008)
Atladóttir et al. 3,325 cases; Medical Yes Rheumatoid arthritis, celiac
(2009) 685,871 controls records disease, type 1 diabetes
Keil et al. (2010) 1227 cases; Medical Yes General parental autoimmune
30,693 controls records disease, idiopathic
thrombocytopenia purpura,
myasthenia gravis,
rheumatic fever
necrosis factor (TNF)-α, generating an inflammatory environment helpful in controlling

infections but potentially pathological in autoimmune conditions. Decreased killing by NK
cells (Vojdani et al., 2008; Warren, Foster, & Margaretten, 1987) and increased numbers
of circulating NK cells have been observed in ASD (Ashwood et al., 2011a). On a genetic
level, two groups have shown a genetic milieu that favors NK cell activation in children with
ASD (Guerini et al., 2014; Torres, Westover, Gibbons, Johnson, & Ward, 2012). An even
stronger skewing toward NK cell activating genotypes is observed in mothers of children
with ASD (Guerini et al., 2014). This may be of importance in ASD because the uterus is
known to host a large number of NK cells at the fetal–maternal interface. There is evidence
from animal models that maternal immune activation at the placenta, involving inflamma-
tory cytokines such as interleukin (IL)-6, can cause neuroimmune abnormalities in the
fetus, as well as behavioral abnormalities reminiscent of ASD (Hsiao & Patterson, 2011;
Parker-Athill & Tan, 2010).
AUTOIMMUNITY
Autoimmunity is a long-standing theory in the etiology of ASD with speculation that an

aberrant response from the child’s own immune system disrupts normal brain function.
Autoimmune diseases typically occur in females and increase in prevalence with age. In
contrast, ASD has a male-to-female ratio of approximately 4:1. However, a substantial
subset of autoimmune disorders occurring predominately in males does exist, including
amyotrophic lateral sclerosis, ankylosing spondylitis, and type 1 diabetes mellitus (Beeson,
1994). The onset of type 1 diabetes mellitus typically occurs in childhood and, similar to
ASD, its incidence has been on the rise (Craig, Howard, Silink, & Chan, 2000).
There is no direct evidence to indicate that ASD is an autoimmune disease. Support for
this theory derives from indirect and circumstantial evidence. Many studies have identi-
fied increased levels of autoantibodies to adult brain antigens in the blood of a small frac-
tion of children with ASD. Antibody targets vary between studies, and many of the results
have not been replicated (Stigler et al., 2009). Antigens of interest have included myelin
basic protein, neuron–axon acidic protein, brain-derived neurotrophic factor, glial filament
protein, cerebellar proteins, and other brain tissue proteins that have not yet been iden-
tified. Autoantibodies have also been found against neuronal progenitor cell proteins by
some researchers (Mazur-Kolecka et al., 2014), but others did not find abnormal reactivity
to fetal brain in individuals with ASD (Morris, Zimmerman, & Singer, 2009; Rossi et al.,
2014). Although autoantibodies are more frequently seen in subjects with ASD, they are
also frequently seen in control subjects and are not unique to ASD. It is unclear whether
these antibodies have direct pathologic significance.
There is a wide variety of circumstantial evidence to implicate autoimmunity in ASD,
some of which has been described previously. Many studies report an increase or decrease
in the frequency of various immune-related genes such as HLA alleles or haplotypes in
ASD. These genes could play a role in autoimmunity or other immune abnormalities in
ASD (Table 14.3). Also, peripheral immune abnormalities commonly found in ASD (dis-
cussed next) could result from autoimmune mechanisms.
PERIPHERAL IMMUNE ACTIVATION

Although many peripheral immune parameters appear to be abnormal in ASD, the cause of
these abnormalities is unknown. Factors that could contribute to these often inconsistent
findings include autoimmunity, infection, allergies, tissue damage, inflammation, or per-
haps other unknown genetic or neurological factors related to ASD.
Some peripheral evidence suggests increased immune activity in those with ASD. For
instance, neopterin, a chemical produced by monocytes and macrophages during periods
of immune activation, has been found to be elevated in blood samples of individuals with
ASD (Sweeten, Posey, & McDougle, 2003). An upregulation of the CD95 marker on cir-
culating monocytes is indicative of activation of these cells in ASD subjects (Ashwood
et al., 2011a). These finding could be relevant to the brain because an increased infiltration
of monocytes and perivascular macrophages is observed in postmortem brain samples of
individuals with ASD (Vargas et al., 2005). Multiple studies have reported abnormalities in
TABLE 14.3 Immune Genes, Alleles, and Haplotypes Repeatedly

Associated With Autism Spectrum disorder
Gene/Allele/Haplotype Reference
HLA-DR4 Torres et al. (2002)
Lee et al. (2006)
Johnson et al. (2009)
Chien et al. (2012)
C4B null allele Warren et al. (1991)
Odell et al. (2005)
Mostafa and Shehab (2010)
HLA-A2 Stubbs and Magenis (1980)
Torres et al. (2006)
B44-SC30-DR4 Warren et al. (1992)
Daniels et al. (1995)
Odell et al. (2005)
KIR/HLA complexes Torres et al. (2012)
Guerini et al. (2014)
T cell ratios and increased T, B, or NK cell numbers, including evidence for increased T and
B cell activity in subjects with ASD compared to controls (Ashwood et al., 2011a; Denney,
Frei, & Gaffney, 1996; Plioplys, Greaves, Kazemi, & Silverman, 1994). Some measures
show that children with ASD have reductions in certain immune parameters, such as low
NK cell cytotoxicity (Vojdani et al., 2008; Warren et al., 1987) or decreased levels of IgM
and IgG classes of immunoglobulin (Heuer et al., 2008).
Complement protein irregularities have also been reported in ASD. A proteomic study
quantifying 6348 peptide components derived from serum samples of children with ASD
found elevated complement protein C1q among the few implicated proteins (Corbett
et al., 2007). C1q is part of the first component of the classical complement pathway. It
is involved in synaptic pruning and opsonizing synapses to prepare them for removal by
macrophages (Stevens et al., 2007). Uncontrolled complement biosynthesis and activa-
tion in the central nervous system is thought to contribute to neurodegenerative disorders
(Gasque, Dean, McGreal, VanBeek, & Morgan, 2000). Complement can bind to antibod-
ies to trigger cell death or damage through the formation of membrane attack complexes,
providing a possible mechanism whereby autoreactive antibodies could produce pathology
and alter behavior in some persons with ASD (Goines et al., 2011).
Many peripheral immune findings have been associated with ASD-related behaviors
(reviewed in Onore, Careaga, & Ashwood, 2012). For instance, lower levels of the soluble
adhesion molecule P-selectin have been associated with greater impairment in social skills
(Iwata et al., 2008), and children with ASD appear to show transient improvement in cer-
tain aberrant behaviors during periods of fever (Curran et al., 2007).
CYTOKINES
The term cytokine derives from the Greek roots cyto for cell and kinos for movement.
Cytokines are either peptides, proteins, or glycoproteins that are released from one cell
to regulate activity of other cells by binding to specific cell membrane receptors and trig-
gering signal transduction pathways that ultimately alter gene expression in the target
cells. Cytokines have pronounced effects on many cellular functions in all branches of the
immune system. Many cytokines can alter brain chemistry and profoundly affect neuronal
development, migration, differentiation, and synapse formation (Deverman & Patterson,
2009). Abnormal cytokine levels have been implicated by many researchers to play a role in
the pathophysiology of ASD (Onore et al., 2012).
Elevated plasma levels of proinflammatory cytokines and macrophage migration inhib-
itory factor have been detected in plasma of individuals with ASD (Ashwood et al., 2011b;
Grigorenko et al., 2008). In contrast, the anti-inflammatory cytokine, transforming growth
factor-β, appears to be low in adults and neonatal blood samples from individuals with ASD
(Abdallah et al., 2013; Okada et al., 2007). Others have not seen different plasma cytokine
levels between children with ASD and their typically developing siblings, although correla-
tions between cytokine levels and quantitative clinical traits have been reported (Napolioni
et al., 2013).
Analysis of postmortem brain samples from subjects with ASD has revealed an active
neuroinflammatory process in the cerebral cortex, white matter, and cerebellum. The pro-
duction of many cytokines was increased, with macrophage chemoattractant protein-1
and TGF-β1 being the most prevalent. Macrophage chemoattractant protein-1 and IFN-γ,
among others, have been found to be markedly increased in the CSF of individuals with
ASD (Vargas et al., 2005). The cause of this neuroinflammation is unknown, but it could
represent an autoinflammatory condition, perhaps resulting from a maternal alloimmune
attack, autoimmune disease, or reaction to a pathogen or an inflammatory response to
another unknown pathological process (Doria et al., 2012).
IFN-γ provides a hypothetical example for cytokine involvement in ASD pathology.
IFN-γ levels have been found to be elevated in brain tissue of individuals with ASD,
as well as in their CSF, by 232.5-fold (Li et al., 2009; Vargas et al., 2005). IFN-γ can
upregulate production of the enzyme inducible nitric oxide synthase in astrocytes and
microglia, thereby enabling increased production of nitric oxide (NO) in the brain.
The free radical NO is secreted by activated immune cells such as macrophages, and
it is toxic to pathogens (Seguin et al., 1994). In the brain, NO is typically produced by
neurons and it acts as an intercellular messenger modulating synaptogenesis, dendrite
and axonal growth, and neuronal release of various neurotransmitters (Hess, Patterson,
Smith, & Skene, 1993; Lizasoain, Weiner, Knowles, & Moncada, 1996; Lonart, Wang,
& Johnson, 1992). Increased NO production by IFN-γ responsive immune cells in
the brain would likely alter these processes that are important for synaptic plasticity
and function. Problems with synaptic development and plasticity are implicated in the
neuropathology of ASD (Ebert & Greenberg, 2013). In some studies, blood samples
showed evidence of elevated NO production in subjects with ASD, which was positively
correlated with plasma IFN-γ concentration (Sweeten, Posey, Shankar, & McDougle,
2004; Tostes, Teixeira, Gattaz, Brandão, & Raposo, 2012).
OTHER IMMUNE CONSIDERATIONS: GASTROINTESTINAL INFLAMMATION AND

THE MEASLES, MUMPS, AND RUBELLA VACCINE
Clinicians treating children with ASD will encounter patients with gastrointestinal (GI)
conditions that are similar to those seen in individuals without ASD. These conditions can
be challenging to evaluate in minimally verbal or nonverbal persons with ASD. Possible
associated conditions include food allergies or other adverse reactions to foods, inflamma-
tion, and immunological dysfunction in the GI tract. The prevalence of GI abnormalities in
individuals with ASD is not well understood, ranging from 9% (equal to the typical popula-
tion) to 70% or higher (Buie et al., 2010). After reviewing prevalence studies, a multidisci-
plinary panel of experts summarized, “The preponderance of data were consistent with the
likelihood of a high prevalence of GI symptoms and associated disorders associated with
ASDs” (Buie et al., 2010, p. S4). Overall, however, there is an absence of high-quality clini-
cal research data in this area.
The GI tract serves as a barrier to many harmful materials and pathogens; accordingly,
it is also the largest immune organ in the body. Some researchers have suggested a relation-
ship between inflammation in the GI tract and the GI symptoms seen in ASD. Pan-enteric
infiltration of lymphocytes and eosinophils in the gut mucosa has consistently been shown
in children with ASD (Torrente et al., 2004). One group reported IgG and complement
deposition on the surface epithelium of the GI tract that is characteristic of autoimmune
pathology (Torrente et al., 2002). Because GI pathology is a relatively understudied area in
ASD, more research is needed to better understand the GI/immune relationship and how
this contributes to the pathophysiology of a subtype of individuals with ASD.
Some researchers and health care providers have proposed the existence of a specific
“autistic enterocolitis” ostensibly triggered by the measles, mumps, and rubella (MMR)
vaccine in a setting of abnormal immune function or increased gut permeability (Wakefield
et al., 1998). Based on correlational observations published in The Lancet, these researchers
set off a firestorm in the general public by claiming that the MMR vaccine led to not only
enterocolitis but also regressive ASD.
Since this claim, more than 20 studies of thousands of children from multiple coun-
tries have been published to investigate the possible association of the MMR vaccine and
ASD. No connection between the MMR vaccine and ASD has been verified (Allan & Ivers,
2010; DeStefano, 2007; Libbey et al., 2007). In 2004, 10 of the 13 authors of the Wakefield
et al. (1998) article retracted the interpretation of their results, followed by the editors of
The Lancet retracting the entire article (The Lancet Editors, 2010; Murch et al., 2004). Not
only did the Wakefield et al. study have limitations in the study design, including inade-
quate control groups, lack of validated and standardized definitions, and speculative inter-
pretation, but also Britain’s General Medical Council and others exposed multiple ethical
breeches committed by the lead author and others involved (Allen & Ivers, 2010; Deer,
2011; Dyer, 2010).
DRUG TREATMENT STUDIES
There have been a number of reports on the use of anti-inflammatory and immunomodu-
latory drugs in individuals with ASDs. These have consisted of case reports, case series,
open-label trials, and a limited number of double-blind, placebo-controlled studies. The
results of these preliminary investigations are summarized here.
Corticosteroids
Corticosteroids are anti-inflammatory and immunosuppressive agents that inhibit pro-

inflammatory cytokine production, alter T lymphocyte activity, and may also modu-
late microglial activation (Ros-Bernal et al., 2011; Schweingruber, Reichardt, Lühder, &
Reichardt, 2012). There have been a number of reports of improvement in symptoms of

ASD in individuals treated with corticosteroids.
An almost 3-year-old boy with regressive ASD and an autoimmune lymphoproliferative
condition showed improved social interaction and vocalization with chronic oral predniso-
lone treatment (Shenoy, Arnold, & Chatila, 2000). To treat the autoimmune condition, the
patient initially received prednisolone at a dose of 2 mg/kg/day for a period of 10 weeks.
During the first month of treatment, the boy was described as having increased social inter-
action. Eventually, a dose of 0.5 mg/kg every other day was found to be an effective main-
tenance dose for treatment of the autoimmune condition, as well as the ASD symptoms.
Continuing improvement in speech was noted during the subsequent 12 months of treat-
ment, with the emergence of a vocabulary of more than 200 words. Improvement was also
seen in gesturing, nonverbal communication, and language expression and comprehension.
A 6-year-old boy with ASD also showed improved symptoms with prednisolone treat-
ment (Stefanatos, Grover, & Geller, 1995). The patient was diagnosed with ASD based
on prominent language and behavioral regression at the age of 22 months, with persis-
tent impaired social interactions, motor stereotypies, and echolalia. A 28-week course of
prednisolone at a dose of 2 mg/kg/day was initiated, followed by a gradual reduction in
dose during the treatment period. Within a few weeks of beginning treatment, significant
improvement in social communication was noted. By the end of treatment, the boy had
made relative gains of 26–36 months in expressive and receptive vocabulary in less than
18 months.
A report of two children with ASD, seizures, and motor deficits treated with corti-
costeroids has also been published (Mordekar, Prendergast, Chattopadhyay, & Baxter,
2009). The children, one male and one female (both aged 4.5 years), were given a course
of prednisolone (initial dose 2 mg/kg/day) for 10 and 3 weeks, respectively. Both patients
demonstrated a return of previously lost spoken language and a reduction in psychomo-
tor agitation. They reportedly maintained this improvement following discontinuation of
the drug.
An open-label study was used to investigate high-dose corticosteroid treatment in 44
children with ASD and evidence of abnormal epileptiform activity on electroencephalo-
gram (EEG) (mean age, 5.6 years) (Chez et al., 1998). Prednisolone or methylprednisolone
at a dose of 10 mg/kg/week was added to ongoing treatment with divalproex sodium for
18 months. Among the 25 children that had clinical and EEG outcomes reported after addi-
tion of a corticosteroid, clinical improvement in speech and EEG was noted in 82 and 60%
of cases, respectively. No significant adverse effects were observed, even after 18 months of
treatment.
A retrospective study of open-label prednisolone (2 mg/kg) treatment (mean duration,
9.125 ± 3.26 months) of 20 children with ASD (aged 3–5 years) compared the effects on
the 4-Hz frequency modulated evoked response (FMAER) arising from language cortex
of the superior temporal gyrus, and on EEG background activity, language, and behavior,
to measures obtained in an untreated clinical convenience sample of age-matched children
with ASD (Duffy et al., 2014). None of the children had Landau–Kleffner syndrome. The
prednisolone-treated group showed a significant increase in the 4-Hz FMAER spectral
response and a significant reduction in response distortion compared to the untreated
group (Figure 14.1). The treated group’s language ratings were significantly improved, and
more subjects who received prednisolone compared to those who were untreated showed
significant language improvement. Most treated subjects also showed significant behav-
ioral improvement, based on diagnostic criteria of the fourth edition of the Diagnostic
and Statistical Manual of Mental Disorders (American Psychiatric Association, 1994).
FIGURE 14.1 FMAER and corresponding FFT, before and after steroids in regressive autism. 4
Hz FMAER waveform data are shown within schematic ovals in vertex view with nose up, and
left side of scalp to image left. The corresponding power spectra are shown to the immediate
right. The top waveform and FFT displays were obtained prior to steroid administration. The bot-
tom, corresponding displays were obtained after steroid administration. The vertical arrow to
the lower left of each image represents 10 μV and the horizontal arrow beneath represents one
second waveform length. The labels adjacent to the FMAER waveforms correspond to the stan-
dard EEG electrode 10–10 naming convention. Twenty-four electrodes’ waveforms are shown.
The FFT power spectral data horizontal axis covers the 0–30 Hz range. Note the near absent
4 Hz FMAER waveform response before and excellent 4 Hz waveform response after steroid
administration. Note the spread of spectral power over many frequencies in the FFT display
before (above) which represents a distorted response. This contrasts to the nearly perfect 4 Hz
response after steroid treatment (below) which shows little spectral spread (little distortion). For
the vertex view display, waveforms are shown overlying their standard ‘10-10’ locations. For the
FFT graphs, channel order from top to bottom is: F3, F4, C3, C4, P3, P4, O1, O2, Fp1, Fp2, F7, F8,
T7, T8, P7, P8, FT9, FT10, TP9, TP10, Fz, Cz, Pz, Oz. The common average reference is utilized for the
displayed data (a reference free or ‘rfr’ technique) [10]. Abbreviations: A = anterior, P = posterior,
L-left, R = right, FMAER = 4 Hz frequency modulated auditory evoked response, FFT = fast Fourier
transform -power spectrum analysis shown as μV2/Hz, μV =microvolt, Hz = Hertz or cycles per
second. This figure is made available by Biomedical Central under its Open Access policy.
Language and behavioral improvement persisted for 1 year after prednisolone discon-
tinuation. The two groups did not differ in terms of minor EEG abnormalities. Almost all
prednisolone-treated subjects demonstrated Cushingoid appearance and weight gain asso-
ciated with increased appetite. For all subjects, however, weight and appearance returned
to normal within several months of discontinuation of prednisolone. Half of the treated
subjects initially experienced behavioral worsening, typically irritability, that was usually
managed by a slight reduction of steroid medication.
Pregnenolone
Pregnenolone is a naturally occurring neurosteroid directly metabolized from cholesterol

and the precursor of many neurosteroids. Pregnenolone is converted to multiple metabo-
lites when given orally to humans, including the most abundant of the metabolites, allopreg-
nanolone. Allopregnanolone regulates and positively modulates GABAA receptors. Fung,
Libove, Phillips, Haddad, and Hardan (2014) conducted a 12-week open-label pilot trial
of pregnenolone in 12 adults with ASD. Pregnenolone resulted in a statistically significant
improvement in the primary outcome measure, the Aberrant Behavior Checklist (ABC)–
Irritability subscale score (from 17.4 ± 7.4 to 11.2 ± 7.0). Statistically significant improve-
ment was also found on the ABC–Lethargy/Social Withdrawal subscale and the total
Short Sensory Profile score; no significant change occurred on the Social Responsiveness
Scale. Pregnenolone was well tolerated other than single reports of tiredness, diarrhea, and
depressive affect.
Adrenocorticotropic Hormone
Adrenocorticotropic hormone (ACTH) is a hormone produced by the anterior pituitary

gland that stimulates the release of corticosteroids from the adrenal cells. Children with
ASD have been reported to have both abnormal circulating levels and physiologic responses
to ACTH (Hamza, Hewedi, & Ismail, 2010; Marinović-Curin et al., 2008).
An 8-week controlled crossover trial investigated the use of synthetic ACTH (40
mg/day) in 21 children (aged 5–15 years) with ASD (Buitelaar et al., 1992a). Significant
improvement was seen in overall ASD symptom severity alongside improvements in
social interaction. Although use of ACTH was generally well tolerated, 6 children had an
increase in mood lability and “inner tension” by parent or teacher report compared to only
2 children on placebo. These findings supported the results of a previous double-blind,
placebo-controlled crossover trial involving 14 children with ASD (aged 5–13 years). In
that study, treatment with ACTH (20 mg/day) was noted to improve stereotypic behav-
iors and enhance social interaction in the subjects (Buitelaar, van Engeland, van Ree, & de
Wied, 1990; Buitelaar et al., 1992b).
Lenalidomide
Lenalidomide, an immunomodulatory agent and an analog of thalidomide, is com-

monly used to treat hematologic and solid malignancies. Lenalidomide inhibits release
of the proinflammatory cytokines IL-1, IL-6, IL-12, and in particular TNF-α, while
also increasing release of the anti-inflammatory cytokine IL-10 (Kotla et al., 2009).
In a 12-week, open-label study of lenalidomide (2.5 mg/day) in seven children with

ASD (aged 7–12 years), participants had improvement in symptoms of autism and
expressive language, although statistical significance was not achieved (Chez, Low,
Parise, & Donnel, 2012). The subjects also had elevated levels of TNF-α in their CSF.
Biochemical outcomes included CSF and serum levels of TNF-α. Serum TNF-α was
significantly reduced by 57%, and although CSF TNF-α was also reduced by 57%, this
reduction did not reach statistical significance. There was a significant improvement in
expressive and receptive language after 6 weeks of treatment, although at 12 weeks, only
improvement in expressive language remained statistically significant. Three children
had to be removed from the study—two due to the development of a rash and one due
to a marked drop in neutrophil count. The rashes and reduced neutrophil count resolved
with the discontinuation of lenalidomide.
Celecoxib
Celecoxib, a cyclooxygenase-2 inhibitor with anti-inflammatory effects, in combination with

risperidone, was studied in a 10-week randomized double-blind, placebo-controlled trial
involving 40 children with ASD (aged 5–11 years) (Asadabadi et al., 2013). Subjects were
assigned to risperidone plus celecoxib or risperidone plus placebo. Celecoxib was initiated
at 100 mg/day and titrated to either 200 or 300 mg/day depending on body weight (limited
to 200 mg/day if the child weighed less than 30 kg). Risperidone was started at a dose of 0.5
mg/day with an increase of 0.5 mg/week to 2 or 3 mg/day depending on body weight.
Outcomes were measured using the subscales of the ABC at 2, 4, 6, and 10 weeks. By
the end of the study, the risperidone plus celecoxib arm demonstrated significant improve-
ment in irritability, social withdrawal, and stereotypic behavior compared to risperidone
plus placebo. In addition, whereas risperidone plus placebo resulted in a treatment response
in 20% of subjects, a significantly higher percentage (55%) responded to risperidone plus
celecoxib. Response was defined as a 50% reduction in the ABC–Irritability subscale score.
Adverse effects were similar between treatment groups, with extrapyramidal symptoms,
likely due to risperidone, reported in half of participants (50% celecoxib group and 45%
placebo group). Abdominal pain was reported in three patients receiving risperidone plus
celecoxib compared to only one patient given risperidone plus placebo.
Pentoxifylline
Pentoxifylline has also been studied as a treatment for ASD (reviewed in Gupta, Rimland,
& Schilling, 1996). Pentoxifylline is a compound that exhibits immunomodulatory effects,
including inhibition of proinflammatory cytokines. A 10-week randomized double-blind,
placebo-controlled study investigated pentoxifylline as an adjunctive treatment to risperi-
done in the treatment of irritability in ASD (Akhondzadeh et al., 2010). Forty children
with ASD (aged 4–12 years) were randomly assigned to risperidone plus pentoxifylline or
risperidone plus placebo. Initial dosing and dose limits for pentoxifylline were dependent
on body weight, with children less than 40 kg receiving an initial dose of 200 mg/day with
a dose limit of 400 mg/day compared to those more than 40 kg who received an initial
dose of 300 mg/day with a dose limit of 600 mg/day. Risperidone was started at a dose of
0.5 mg for all participants, with the final dose dependent on body weight (2 mg/day for
those less than 40 kg and 3 mg/day for those more than 40 kg). Compared to risperidone
plus placebo, risperidone plus pentoxifylline was associated with significantly greater
improvement in the five ABC subscales, namely Irritability, Lethargy/Social Withdrawal,
Stereotypic Behavior, Hyperactivity, and Inappropriate Speech.
Pioglitazone
Pioglitazone, a member of the thiazolidinedione class of medication, is commonly used

to treat diabetes mellitus. Thiazolidinediones have also demonstrated anti-inflammatory
effects that may well extend to glial cells in the brain. They are useful in a range of autoim-
mune conditions and have been investigated for the treatment of ASD in one open-label
pilot study. Twenty-five children with ASD received pioglitazone for up to 4 months (30
mg/day for 3- to 5-year-olds and 60 mg/day for 6- to 17-year-olds) (Boris et al., 2007).
Outcomes were measured with the ABC, with significant improvement seen in the
Irritability, Social Withdrawal, Stereotypy, and Hyperactivity subscales.
Oral Human Immunoglobulin
One 8-week open-label trial of oral human immunoglobulin (IGOH) (420 mg/day) in 12
male children (aged 3–7 years) with ASD and GI disturbances found that 50% of those
treated had symptomatic improvement of both conditions (Schneider et al., 2006). GI out-
comes were measured using the Gastrointestinal Severity Index, whereas symptoms of ASD
were measured with the Clinical Global Impression–Improvement (CGI-I) and –Severity
scales and the ABC. Significant improvement in ASD symptoms, as measured by the ABC,
were seen not only at 8 weeks but also at 30 days after discontinuation of medication. Three
of the children withdrew from the study while receiving IGOH following the development
of vomiting and fever, vomiting and nausea, and rash, respectively.
There has been one double-blind, placebo-controlled, randomized trial of IGOH in the
treatment of ASD (Handen et al., 2009). This study involved 125 children with ASD and
chronic GI symptoms. The treatment phase was of 12 weeks’ duration with four treatment
arms, including placebo and three different dosages of IGOH (140, 420, and 840 mg/day).
In contrast to the open-label study, IGOH was not found to be beneficial in reducing ASD
or GI symptoms in this controlled trial.
Intravenous Immunoglobulin
Several open-label studies examining the effects of intravenous immunoglobulin (IVIG)
in ASD have yielded mixed results. One study involving seven children with ASD, aged
3½–6 years, reported on the effects of IVIG given at monthly intervals for 6 months
(400 mg/kg/month) (DelGiudice-Asch, Simon, Schmeidler, Cunningham-Rundles,
& Hollander, 1999). Two children did not finish the study: In one case, a diagnosis of
Landau–Kleffner syndrome was suspected, and in the other case the family received the
last 2 months of IVIG outside of the study. There was no significant improvement in behav-
iors or ASD severity as measured by several scales, including the Childrens Yale–Brown
Obsessive Compulsive Scale, the Ritvo–Freeman Real Life Rating Scale, and the CGI-I.
In a study involving 10 children with ASD (aged 4–17 years) and documented immu-
nologic abnormalities, IVIG was administered every 6 weeks for a total of four infu-
sions (dose, 200–400 mg/kg). Eight of the 10 children had been noted to have had ASD
diagnosed following regression in early life. In this study, 5 children did not have any change
in symptoms, 4 children had minor improvements that the authors suggested could have
been due to placebo effect, and 1 child had an “almost total amelioration” of ASD symp-
toms with treatment (Plioplys, 1998). The improvements were temporary, with symptoms
returning to their baseline levels 5 months after treatment cessation. The authors concluded
that the response rate of 10% was too low to justify the high economic costs associated with
immunologic testing and IVIG administration.
However, there have been more favorable reports of IVIG, including one involving
10 children with ASD and immunological abnormalities (Gupta, Aggarwal, & Heads,
1996). The children were given IVIG on a monthly basis for 6 months (dose, 400 mg/kg).
Following treatment, half of the children (n = 5) were deemed to have had a marked (n = 4)
or striking (n = 1) clinical improvement. Enhanced language use, eye contact, and a reduc-
tion in agitation were specifically identified.
In addition, favorable reports were obtained from one open-label retrospective study
involving 26 children with ASD who were treated with IVIG for 6 months (dose, 400 mg/
kg/month) (Fudenberg, 1996). Treatment resulted in a significant decrease in the total
ABC score alongside each of the ABC subscales (Irritability, Social Withdrawal, Stereotypy,
Hyperactivity, and Inappropriate Speech). Biochemical investigations on the participants
revealed evidence of substantial immunological and inflammatory abnormalities, includ-
ing 54% as having an elevated erythrocyte sedimentation rate, 65% having antibodies to
myelin, and 31% having thyroid antibodies.
SUMMARY
This chapter discussed neuroinflammatory processes in ASD; reviewed evidence for poten-
tial causes of neuroinflammation, including infection, alloimmunity, and autoimmunity;
described results from studies of peripheral immune activation in humans; and summarized
the literature on drug treatment studies with anti-inflammatory and immune modulating
drugs in ASD. In this context, this chapter provided evidence for central nervous system
microglia activation and inflammation from postmortem and neuroimaging studies in indi-
viduals with ASD. The chapter presented findings from animal models that antibodies from
mothers of children with ASD injected into laboratory animals during gestation can pro-
duce offspring with a behavioral syndrome similar to that seen in ASD. It also described
results from small, pilot treatment studies of drugs with effects on immune function that
have provided benefit to some individuals with ASD, including core disturbances of social
and communication ability. Although significantly more research is necessary, evidence to
date suggests there may be an identifiable subtype of ASD associated with primary or sec-
ondary immune dysregulation.
KEY POINTS
• Examination of postmortem brain tissue from subjects with ASD has revealed evi-
dence of neuroinflammation.
• Injection of blood from mothers of children with ASD into pregnant rodents and
nonhuman primates can result in ASD-like behavior in the progeny.
• An increased prevalence of autoimmune disorders has been found in first- and
second-degree relatives of probands with ASD compared to control probands in
some studies.
• In addition to neuroinflammation, inflammation in the gastrointestinal tract has been

found in a subgroup of subjects with ASD.
• Small open-label studies have found that some drugs with anti-inflammatory or
immune modulating properties can improve some symptoms associated with ASD.
ACKNOWLEDGMENT
This work was supported in part by the Robert and Donna Landreth Fund.
Dr. Thayne L. Sweeten and Dr. Christopher J. McDougle have no conflicts of interest to

disclose.
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/ / / / / / / / / / / / / / / / / / / SE CTION 3 / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / /
TREATMENT
/ / /
15 / / / BEHAVIORAL TREATMENT
OF AUTISM SPECTRUM
DISORDER
SUZANNAH IADAROLA AND TRISTRAM SMITH
INTRODUCTION
CASE STUDY #1: “SAMUEL”
The Reyes family has presented for an initial consultation with you. Their son Samuel is
almost 3 years old and has been recently diagnosed with autism spectrum disorder (ASD).
For the past 18 months, Samuel has been receiving home-based early intervention (EI)
services, including speech therapy, occupational therapy, and physical therapy. Although he
has made some progress, his language is still very limited. Samuel will soon transition out
of EI, and his parents are wondering what the best placement for him will be. They have
considered preschool, but because Samuel has difficulty communicating, they are con-
cerned he will “get lost” among his classmates. In addition, Samuel sometimes hits and
kicks others when he is frustrated. The Reyes family would like to know where Samuel’s
next placement should be and what supports they should ask for.
How would you advise the Reyes family? What information is necessary to adequately
counsel them on next steps? For families of newly diagnosed children with ASD, a pivotal
decision is whether to continue with EI and preschool services as usual or seek specialized
behavioral treatment. Often, another pressing concern is how to deal with problem behaviors
that occur at home or in the community. As children with ASD grow up and become adults,
families (and eventually the children themselves) face many additional decisions about
whether and how to obtain behavioral treatment. What guidance or direct help can you offer?
Although ASD is a neurodevelopmental disorder, psychosocial and educational inter-
ventions are currently the primary treatments (Odom, Collet-Klingenberg, Rogers, &
Hatton, 2010). Of these, treatments described as “behavioral” have been studied extensively
and are potentially useful for individuals with ASD at all ages and stages of development.
253
254 / / T reatment
Therefore, a working knowledge of behavioral treatment is indispensible for clinicians who

serve this population. This chapter gives an overview of the defining features of behavioral
treatment and some of the many and varied applications of this treatment available to meet
the particular needs of individuals with ASD. The chapter also presents considerations to
guide decision-making and resources to facilitate access to treatment.
APPLIED BEHAVIOR ANALYSIS AND OTHER BEHAVIORAL TREATMENTS
One form of “practical” behaviorism that is particularly relevant to ASD is applied behav-
ior analysis (ABA). ABA focuses on interpreting and changing the behavior of indi-
viduals through systematic environmental manipulations. Like many other behavioral
approaches, ABA is based on what is called the three-term contingency of antecedent–
behavior–consequence. Specifically, ABA aims to understand behavior through system-
atic evaluation of what comes before a behavior (antecedents) and what comes after (con-
sequences). Both antecedents and consequences are essential for maintaining or changing
behavior. Although commonly associated with ASD and related disorders, ABA is cer-
tainly not specific to this population. Rather, the principles of ABA are generally appli-
cable to all individuals, including children, students, parents, colleagues, and significant
others (Cooper, Heron, & Heward, 2007). As human beings, we have a remarkable innate
capacity for subtly, and sometimes overtly, influencing the behavior of those with whom
we interact. The study and practice of ABA represents a more systematic approach to strat-
egies we already use.
Much behavioral treatment for ASD is based on ABA. Furthermore, of the numerous
intervention approaches for treatment of ASD symptoms, ABA has by far the longest his-
tory of research, dating back to the early 1960s (Smith, 2010), and now has a large evidence
base (Reichow, Doehring, Cicchetti, & Volkmar, 2011). However, other behavioral inter-
ventions such as outpatient therapy for social skills (see Chapter 20) and developmental
approaches, which emphasize continuous back-and-forth social communication in the
context of playful interactions (Dawson et al., 2010), have been increasingly studied since
the mid-2000s (Maglione, Gans, Das, Timbie, & Kasari, 2012).
PROVIDERS OF BEHAVIORAL SERVICES AND SETTINGS
To review programs and recommend services for individuals with ASD, it is important to
be aware that a variety of professionals provide behavioral services. These providers repre-
sent a complicated network of services with sometimes overlapping roles and responsibili-
ties that can vary by state, region, and school. Moreover, providers can have quite different
titles, despite having similar backgrounds and expertise. Professionals who work with indi-
viduals with ASD often seek specialized training in ABA skills, such as systematically assess-
ing and tracking behavior; designing, implementing, and evaluating behavior intervention
plans; and teaching functional skills. Those with a degree in an educational, medical, or
mental health-related field can complete additional coursework and clinical internships to
become a Board Certified Behavior Analyst (BCBA) or Board Certified Assistant Behavior
Analyst (BCaBA). BCBAs should ideally be incorporated into ABA treatment planning for
individuals with ASD. They may supervise or consult with other professionals (outlined in
Table 15.1) with experience in behavioral interventions who fulfill important roles on the
treatment team.
TABLE 15.1 Providers of Behavioral Services
Provider Title Education and Training Instructional Setting Role
Board Certified Behavior Bachelor’s degree: Assistant Level (BCaBA) Classrooms, home, community, Systematically assess and track behavior; design, implement,
Analysts (BCBAs) Master’s degree: BCBA vocational, outpatient and evaluate behavior intervention plans; teach
Doctoral degree: BCBA-D functional skills through individual instruction; coordinate
National certification exam classroom-wide behavioral supports; develop and implement
Supervised practicum hours educational interventions
Special education teachers Bachelor’s/master’s degree in special Self-contained or inclusion Implement curricular modifications, instructional/
education or related field classrooms environmental adaptations, behavior intervention plans,
State-issued license or certification social supports; coordinate support staff
Direct service providers (behavioral Varied Classrooms,home, community, Provide individualized behavioral support for the learner in his
therapists, paraprofessionals, vocational or her daily environment (e.g., implement behavior plans,
special education itinerant teachers, promote attention, provide academic assistance, facilitate
therapeutic support staff, aides) social interactions)
School Master’s/doctoral degree Public and private schools Support the academic and social–emotional development of
psychologists State and sometimes students; educational consultation; liaise with families; conduct
national certification psychoeducational testing; facilitate social interactions; provide
direct instruction/counseling in socioemotional skills
Clinical Doctoral degree Outpatient clinic, Conduct diagnostic evaluations; provide psychoeducational
psychologists National and sometimes state home, school testing; provide behavioral intervention to children and
licensure families (e.g., decrease challenging behavior, improve
attention, cope with anxiety and depression, social skills
training, family therapy, parent training)
Job coaches Varied Home, vocational Facilitate vocational success through conducting vocational
assessments, finding a good job match, teaching job-related
skills, helping the individual maintain effective interpersonal
relationships with coworkers and supervisors
256 / / T reatment
The makeup of the team usually depends on the setting and type of services provided.
The following are common examples:
• Private, ABA agencies. Many children younger than age 5 years participate in ABA
programs run by private, nonprofit ABA agencies that are supported through pub-
lic funding or insurance reimbursement. These programs are usually led by a BCBA
and may also employ special education teachers, speech and language pathologists
(SLPs), occupational therapists (OTs), and other professionals. Specialized ABA
schools are less common for older children, although they do exist in some areas.
• Public early intervention programs. Young children may receive behavioral treatments
in developmental or early childhood special education classes funded through the
state or local school district. These classes usually have a special education teacher
and specialized providers such as SLPs and OTs. Alternatively, children and families
may receive behavioral treatment in their homes or through a combination of center-
and home-based services.
• School-based services. Children and youth with ASD who attend public school may
be included in the general education setting. Alternatively, they may be placed in a
self-contained classroom (i.e., a classroom in which all students have special educa-
tion needs), which is taught by a special education teacher with assistance from para-
professionals and preferably supported by an ASD specialist or outside behavioral
consultant. Behavioral treatment can take place within the classroom, or students
may be pulled out for therapy sessions. Often, SLPs and OTs implement behav-
ioral strategies for teaching new skills. School psychologists frequently help develop
behavior intervention plans to address challenging behavior when necessary and pro-
vide counseling on issues such as improving peer interactions or reducing anxiety.
• Wraparound services. In some regions, ABA wraparound services are available to sup-
port children and families before and after school. Goals often relate to socialization,
self-help, safety, and community skills.
• Adult services. Adults who require a high level of care may live at residential facilities
that include staff members with behavioral training. ABA-based vocational training
can also be provided through a job coach or supported employment programs.
• Outpatient clinics. Outpatient, clinic-based ABA services are available in some locations.
Service providers are usually licensed mental health professionals with training in behav-
ioral strategies. They may provide ongoing care or targeted, time-limited behavioral
interventions such as cognitive–behavioral therapy (CBT), and social skills instruction.
• Inpatient programs. Partial day treatment centers and inpatient programs exist at a
few centers nationally, where expert ABA providers support individuals with severe
problems such as dangerous self-injury or aggression.
APPLIED BEHAVIOR ANALYSIS STRATEGIES
Rather than representing one specific teaching approach, ABA provides the overarching
framework for implementing a large assortment of strategies. Core characteristics of ABA
across the range of strategies include the following:
• A focus on observable and measureable behaviors that are important for the indi-
vidual’s functioning
Behavioral Treatment of Autism Spectrum Disorder // 257
• Individualization of instruction to the learner’s abilities, needs, and interests

• Systematic manipulation of antecedents and consequences (i.e., reliance on behav-
ioral principles)
• The use of data collection to evaluate progress
While maintaining these core features, ABA programs may differ markedly from one
another. This reflects the importance placed on designing programming to best meet the
learner’s particular needs and capitalize on his or her strengths.
Intervention programs vary along several dimensions, including the teaching for-
mat, techniques, and provider of the treatment. Intervention can occur one-to-one (in a
teacher–student dyad), in small groups, or in a large group setting (e.g., classroom-wide).
Generally, one-to-one instruction best suits very young learners, with the goal of progressing
to group instruction over time. ABA teaching techniques extend from highly structured and
adult-led to incidental and child-led. For example, discrete trial teaching (DTT) is a carefully
prearranged, didactic approach to teaching skills that is fast-paced, breaks skills down into
small units of instruction, provides ample learning opportunities per session, and is highly
individualized. These characteristics make DTT a good instructional match for new learners
and new skills (Smith, 2001). Incidental approaches differ from DTT in that they take advan-
tage of natural learning opportunities that arise throughout an individual’s day, as opposed
to the more contrived format associated with DTT. Although incidental teaching strategies
are intended to be integrated into the learner’s daily routine, the environment can be modi-
fied somewhat to create teaching moments. For example, providers can encourage a learner
to make requests by placing favorite objects in sight but out of reach. Incidental strategies
also utilize naturally occurring reinforcers and focus on learner motivation (e.g., helping the
learner communicate in the context of preferred materials and activities). Because the teach-
ing environment closely mirrors the daily routine, incidental teaching is often associated
with long-term maintenance and skill generalization (the transfer of skills across contexts, set-
tings, and people; Ingersoll & Schreibman, 2006). To promote generalization, it can also be
helpful to augment adult-facilitated treatment by guiding typically developing peers or fam-
ily members to act as models and coaches to teach skills. Some teaching approaches repre-
sent a blend between structured and incidental techniques. For example, activity schedules
(McClannahan & Krantz, 2010) involve visual supports, such as pictures or checklists to help
learners complete daily routines (e.g., classroom schedule and getting dressed). Although
schedules are frequently created and taught in a structured way by adults, they become more
akin to incidental teaching as the individual learns to complete each step independently.
APPLIED BEHAVIOR ANALYSIS INTERVENTION MODELS
ABA intervention models exist for individuals with ASD at all ages and stages of devel-
opment. Some models are comprehensive, designed to address all areas of need, whereas
others are directed toward a more circumscribed set of goals (Odom, Boyd, Hall, & Hume,
2010). Table 15.2 summarizes some of these models.
Early Intensive Behavioral Intervention
Early intensive behavioral intervention (EIBI) consists of 20–40 hours per week of treatment
for 2 or 3 years, beginning prior to age 5 years. EIBI involves individualized intervention
TABLE 15.2 Behavioral Intervention Across the Lifespan
Stage of Development Setting Overarching Goals Language Social–Emotional Adaptive Family Interventions
Toddler/preschooler EIBI Catch up in skills and Functional Functional play Feeding Psychoeducation
Specialized or development communication (e.g., Parallel play with peers Toileting Family support
developmental PECS, sign, words) Orienting to a speaker Dressing Parent management
preschool Requesting Eye contact training
Center-based program Labeling
Young school age School-based Academics Increasing language Creative play Personal care routines Educational consultation
(K–5th grade) Outpatient services Daily living skills complexity Group games Visual schedules Parent management
(e.g., speech, Vocabulary Cooperative play with to increase training
occupational, and Increasing spontaneity peers independence
physical therapy; of language Safety
counseling) Conversation with
adults and peers
Older school age School-based Academics Written communication Cooperative play Chores
(6–12th grade) Outpatient Daily living skills Jokes/sarcasm Friendships Self-care
Community Community skills Frustration tolerance
Transition planning and emotional
Social skills regulation
Transition age Community Job readiness Friendships Cooking Transition planning
Worksite Community-based skills Romantic relationships Cleaning Decision-making for
Daily living skills Independent self-care long-term placement
Increasing independence
Adult Community Increase independence Coworker relationships Financial responsibility Transfer of medical care
Worksite Vocational skills Romantic relationships Leisure activities Ongoing placement
Independent living decisions
based on a broad curriculum that addresses communication; social skills; self-management;

cognition; and pre-academic skills such as imitation, matching, and letter and number con-
cepts (Smith, 2011). Many EIBI models exist (Handleman & Harris, 2001), of which the
best known was developed by Lovaas and colleagues at UCLA (Smith, 2010). Intervention
in this approach begins in children’s homes, with a focus on highly structured one-to-one
instruction, especially DTT. The initial goal is to help children learn foundational skills that
are considered prerequisites for learning other, more advanced skills. Examples of such
skills are cooperation with simple instructions, imitation of others, and discriminating
among objects and pictures. Once a child has learned these foundational skills, the prior-
ity shifts to teaching skills that will improve the child’s everyday functioning. Of particular
importance are communication skills such as requesting or labeling objects, daily living
skills such as dressing, and play skills such as completing puzzles. The later stages of inter-
vention use naturalistic strategies to promote peer interaction and support children’s entry
into community settings such as schools.
Many other EIBI models resemble the UCLA/Lovaas model in that they rely exten-
sively on structured, one-to-one instruction (Handleman & Harris, 2001; Maurice,
Green, & Foxx, 2001; Maurice, Green, & Luce, 1996). Still other early intervention pro-
grams place a greater emphasis on incidental ABA teaching procedures. Notably, Learning
Experiences: An Alternative Program for Preschoolers and Parents (LEAP) integrates chil-
dren with ASD with typically developing peers in early childhood education and focuses
extensively on improving peer interaction. However, evidence on the efficacy of this pro-
gram is mixed (Boyd et al., 2014; Strain & Bovey, 2011). Another prominent early inter-
vention approach, which can be adapted for use with older children, is Pivotal Response
Treatment (PRT). This intervention aims to teach “pivotal” responses that, when acquired,
have the potential to improve performance across many other skill areas (Koegel & Kern
Koegel, 2006). A number of studies document short-term benefits from PRT, but data on
long-term outcomes are unavailable. The Early Start Denver Model (ESDM) is another
example of a comprehensive intervention that blends ABA strategies with developmen-
tal approaches that emphasize child preference and play-based interactions (Rogers &
Dawson, 2010). Initial studies (Dawson et al., 2010) on ESDM indicate that it is a promis-
ing intervention that merits additional research.
Overall, despite some important studies failing to show gains from EIBI (Boyd et al.,
2014), most experts consider EIBI to be efficacious and regard the UCLA/Lovaas model
as having the strongest support (Reichow, 2012). Nevertheless, EIBI has important limi-
tations. Notably, outcomes vary greatly across children. Some catch up to their typically
developing peers on IQ tests and other standardized measures, whereas others learn much
more slowly. Moreover, little is known about optimal delivery of EIBI (e.g., how many hours
a week are needed and for how long), the relative efficacy of different EIBI approaches,
mechanisms of change, or the durability of improvements over time.
CASE STUDY #1 CONTINUED
Given the current state of the science, Samuel’s pediatrician, Dr. Nolan, strongly encour-
aged the Reyes family to investigate the EIBI program offered by the school district. She
said it could give Samuel the push he needs to start speaking communicatively and increase
his overall readiness for school. In addition, the program’s service providers would also
be able to consistently address Samuel’s mild aggression. Dr. Nolan noted that there is
260 / / T reatment
considerable evidence that EIBI produces these benefits for many children with ASD. She
added that most professionals believe that intervening early and intensively, as occurs in
EIBI, is quite important for children with ASD. However, she was careful to make clear that
improvements vary greatly across children and that it was difficult to predict how much
Samuel might gain. She also emphasized that EIBI would demand a high level of commit-
ment from Samuel, the family, and the EIBI providers, even above what would be entailed
in a less intensive program. However, the extra commitment should be time-limited (no
more than 2 or 3 years).
Essentially, Dr. Nolan is recommending that the Reyes family consider an empirical
trial of EIBI for Samuel during his preschool years. If the parents choose to enroll him in
EIBI, they may then have additional questions about the quality of the program and the
progress Samuel is making. Although characteristics of a high-quality treatment program
are specific to each learner, some general indicators are listed here (see Behavior Analysis
Certification Board (BACB), 2012):
• The program is supervised by a BCBA, although treatment may be carried out by

other professionals.
• The program is sufficiently intensive, such as fulfilling the number of hours per week
outlined by the BACB practice guidelines.
• The program involves shared decision-making among the interdisciplinary team and
caregivers.
• Data collection is regularly used to develop intervention plans (e.g., through
curriculum-based assessment or goal benchmarking) and to monitor progress (e.g.,
skill acquisition and reduction in challenging behavior).
• The program incorporates caregiver training and consultation.
Although Samuel’s parents have some difficult choices to make, they are fortunate to have
options that include placing Samuel in an evidence-based program. What if the family was
not offered different options? What if, as often happens, the parents had already learned about
EIBI from other families or from their own research and had decided to seek EIBI for Samuel,
but this intervention was not available from the school? Clinicians are usually not in a posi-
tion to recommend any particular EIBI provider, but they can identify some consensus “best
practices” for early intervention and preschool services. An authoritative statement on best
practices was issued by a National Academy of Sciences working group (National Research
Council, 2001). These practices included 25 or more hours per week of intervention, with
curriculum specifically targeting the social–communication deficits characteristic of ASD,
ongoing data collection to monitor a child’s progress, and use of these data to customize the
child’s intervention. Clinicians also can direct families to online information (see Table 15.3).
Other Comprehensive Applied Behavior Analysis Models
Although EIBI was developed for toddlers and preschoolers with ASD and thus is appropri-
ate for that age group, comprehensive ABA models have also been developed for older chil-
dren and adults with ASD throughout the lifespan. These programs take place in specialized
TABLE 15.3 Resources for Parents and Professionals
Online Resources
Resource Website Description
Association for Science in Autism http://www.asatonline.org Evidence-based practice and dissemination of findings from the scientific
Treatment (ASAT) literature to practitioners and consumers
Autism Speaks Tool Kits https://www.autismspeaks.org/family- Review common behavioral strategies to address a wide variety of issues for
services/tool-kits individuals with ASD (e.g., new diagnosis, accessing behavioral services, sleep,
feeding, toileting, medication, constipation, blood draws)
Autism Wandering Awareness Alerts http://awaare.nationalautismassociation.org Caregiver and first responder toolkits from the National Autism Association to
Response and Education (AWAARE) improve safety for children who are at-risk for wandering
Collaboration
Devereux http://www. autismhandbook.org Transition planning guide
Ohio Center for Autism and Low http://www.ocali.org/media/videos Webcasts and videos on ABA techniques, antibullying, assistive technology,
Incidence (OCALI) community support programs, vocational issues, guardianship, school
placement, and social skills interventions
Organization for Autism Research http://www.researchautism.org Transition to adulthood guide
Parent Center Network http://www.parentcenternetwork.org Information on locating services, coordinators, and advocates by state
Manuals and Books
Autism Resource Toolkits from the American Academy of Pediatrics (https://www.aap.org)

Building Social Relationships: A Systematic Approach to Teaching Social Interaction Skills to Children and Adolescents With Autism Spectrum Disorders and Other Social
Difficulties, by Scott Bellini (2006)
Behavioral intervention for Young Children With Autism: A Manual for Parents and Professionals, by Catherine Maurice, Gina Green, and Stephen Luce (1996)
Early Start Denver Model for Young Children With Autism: Promoting Language, Learning, and Engagement, by Sally Rogers and Geraldine Dawson (2010)
Handbook of Adolescent Transition Education for Youth With Disabilities, by Michael Wehmeyer and Kristine Webb (2012)
Making a Difference: Behavioral Intervention for Autism, by Catherine Maurice, Gina Green, and Richard Foxx (2001)
Making Inclusion Work for Students With Autism Spectrum Disorders, edited by Tristram Smith (2012)
(continued)
TABLE 15.3 Continued
Manuals and Books
Making Sense of Autism, by Travis Thompson (2007)

Prevent, Teach, Reinforce: The School-Based Model of Individualized Positive Behavior Support, by Glen Dunlap, Rose Iovannone, Donald Kincaid, Kelly Wilson, Kathy
Christiansen, Phillip Strain, and Carie English (2010)
Sleep Better! A Guide to Improving Sleep for Children With Special Needs, by V. Mark Durand (2014)
Social Thinking Curriculum, by Michelle Garcia Winner (http://www.socialthinking.com)
Taking Care of Myself: A Hygiene, Puberty and Personal Curriculum for Young Persons With Autism, by Mary Wrobel (2003)
Toilet Training for Individuals With Autism or Other Developmental Issues (2nd ed.), by Maria Wheeler and Carol Kranowitz (2007)
Topics in Autism book series (Woodbine House)
Treating Eating Problems of Children With Autism Spectrum Disorders and Developmental Disabilities: Interventions for Professionals and Parents, by Keith Williams and Richard
Foxx (2007)
classrooms, residences, or occupational settings. They differ from EIBI in that they provide
less one-to-one, structured teaching and focus instead on participation in group activities
and promoting independence (i.e., without direct supervision). The goals of intervention
also differ based on the age and functioning level of the individual with ASD. For example,
children with ASD in elementary school might receive ABA instruction on playing with
peers, taking care of personal hygiene, and mastering early academic skills. Youth with ASD
in middle or high school might receive ABA instruction related to puberty and sexuality,
household chores, and participation in peer groups. As they approach adulthood, instruc-
tion might focus on independent living skills (e.g., using public transportation or managing
finances), job readiness, and comprehension of romantic relationships. Adults might take
part in vocational training, as well as social skills training on how to interact effectively with
coworkers and with friends or family at home. Research shows that persons with ASD in
these comprehensive programs learn many new skills (McClannahan, MacDuff, & Krantz,
2002). Still, little information is available on long-term outcomes such as whether gradu-
ates of the programs succeed afterward in less specialized settings.
Skills-Focused Techniques
Intervention strategies that target specific skills (e.g., communication and social interac-
tions) can be used as part of, in conjunction with, or separately from more comprehensive
treatment packages. These more focused interventions may involve individual instruction
with the learner with ASD, as well as teaching others (e.g., parents, siblings, peers, and pro-
viders) to use behavioral strategies. Empirical support for engaging these individuals to
deliver ABA interventions under professional supervision is well documented in the litera-
ture (Sarokoff & Sturmey, 2004), and doing so increases dissemination of these important
treatments. Because skill-based interventions can be mediated through various teachers
or “coaches,” instruction can occur in structured programs (e.g., classroom and vocational
placement) and everyday settings (e.g., home and community). Training typically involves
psychoeducation (e.g., the relevance of ASD symptomatology to the target skills), assess-
ment of learner strengths and needs within the skill area, instruction and in vivo feedback
on implementing ABA strategies, data collection, and a collaborative team-based approach
(e.g., high communication and shared goal-setting and decision-making). Specific inter-
vention strategies are usually introduced in a workshop or other intensive training format.
Program implementation is then monitored via ongoing consultation, first on an intensive
basis (e.g., 1 or 2 hours per week) and then faded over time.
Communication
Because deficits in communication are a defining feature of ASD, many individuals with ASD
receive ABA interventions to increase functional communication skills. Enhancing an indi-
vidual’s communication skills helps him or her more successfully interact with the world and
concurrently may decrease problem behavior (Tiger, Hanley, & Bruzek, 2008). Vocal com-
munication goals range from producing word approximations and first words (for minimally
verbal learners) to using complete sentences (for learners with phrase speech), improving
articulation, syntax, and grammar (for learners with complex speech), and engaging in con-
versation (for more fluent speakers; Koegel & Kern Koegel, 2006; Maurice et al., 1996).
Augmentative and alternative communication (AAC) systems such as sign language,
gestures, or pictures are used to increase communication in minimally verbal learners. One
264 / / T reatment
of the most common ABA-based systems for AAC is the Picture Exchange Communication
System (PECS), in which children with ASD are taught to select a picture symbol and
hand it to another person in order to make requests or comments (Bondy & Frost, 2001).
Alternatively, voice output communication aides, which incorporate technology into this
process by translating pictorial or textual icons into spoken words, may be a useful advance
for those with limited spoken language (Shane et al., 2012). Because individuals with ASD
often struggle with natural motivation to communicate, spontaneous language remains a
concern, even after initial skills have been learned (Smith, 2001). Thus, a key component of
intervention is to promote initiation of communication and generalization across a variety
of people and situations (Yoder & Warren, 1999).
Samuel’s parents have been pleased with their son’s progress in his new EIBI program.
However, early on they shared concerns with the speech therapist that Samuel did not seem
to be progressing in his language. Through his EI services, he had started vocalizing but was
not yet using single words or gestures to communicate. This was especially frustrating for
Mrs. Reyes because she spent the most time with Samuel and felt that she never knew what
he wanted. When the speech therapist suggested starting the PECS program with Samuel,
Mrs. Reyes was reluctant. She worried that if Samuel could use pictures to communicate, he
would never want to speak. The speech therapist explained that the initial goal of PECS is to
teach children how to communicate (not just how to talk) because young children with ASD
do not always learn this naturally. She talked about the high success rate of increasing com-
munication with PECS and shared research findings suggesting that using PECS may actually
help children learn spoken language. Reassured, Mr. and Mrs. Reyes agreed to start using
PECS with Samuel at home to supplement what he learns during speech therapy sessions.
Social Skills
The social interaction difficulties associated with ASD necessitate structured interven-
tion to increase social skills. Although the quality of the empirical literature in this area
is uneven, a number of well-designed studies support ABA social skills interventions.
For young children, common intervention targets include early socialization skills such
as joint attention, play, and imitation (Ingersoll & Dvortcsak, 2010; Maurice et al.,
1996, 2001). Involving peers in intervention is often helpful because peers may be less
intrusive and stigmatizing than service providers in settings such as play groups, and
skills that are learned from peers may be more likely to generalize to typical social situ-
ations outside of treatment (Weiss & Harris, 2001). Strategies that may improve gener-
alization and maintenance include teaching individuals with ASD to self-monitor their
responses to others, implementing classwide interventions, providing scripts or cues of
social interactions that the child can use across a variety of peers or situations, and using
strategies to expand on social initiations that some individuals with ASD spontaneously
direct toward peers (Bellini, 2006). For school-age children, social interventions more
directly target peer-related social interaction skills and expanding the individual’s social
network. Examples include the use of “peer buddies” and video modeling techniques
(Bellini, 2006).
CASE STUDY #2: “JACKSON”
Jackson Williams is a 10-year-old boy with ASD who is currently placed in a general education
classroom, with support from an aide. Although Jackson is doing well academically, he strug-
gles to form friendships with his classmates. Often, he prefers to sit alone reading rather
than joining in with peers during recess. Jackson’s teachers have also noticed that he some-
times approaches other students in an awkward way. For example, he loves planets and will
frequently share facts about them with his peers, even when they are not interested.
Based on a recommendation from Jackson’s therapist, he will soon be starting social skills
instruction at school. In addition to working individually with the school psychologist, Jackson
will work with Shawn, another boy in his class. Shawn’s role will be to help Jackson interact
with his classmates by asking him to join group games and ensuring he is included in conver-
sations. Jackson will also participate in the school’s “Lunch Bunch” program, which provides
adult-mediated opportunities for interaction among children with various social needs. In order
to ensure that these changes are implemented consistently, Jackson’s therapist recommended
that this social treatment program be incorporated into Jackson’s Individualized Education
Program, the document that outlines the school-based services that Jackson receives.
Given that social demands change across the lifespan, it is unclear how effective these
approaches are for adolescents and adults with ASD. Research on social interventions in
this group has been fairly limited, although some encouraging findings have been reported
(McClannahan et al., 2002).
Daily Living, Community, and Vocational Skills

Adaptive behavior represents an individual’s ability to demonstrate skills as part of his or
her daily functioning, and these skills allow an individual to be as independent as possible.
Individuals with ASD may have limited skills across self-help domains, such as dressing,
maintaining personal hygiene, engaging in community activities, preparing food, and devel-
oping vocational skills (Anderson, Jablonski, Thomeer, & Knapp, 2007), as well as commu-
nity skills such as purchasing (McClannahan et al., 2002).
Techniques such as task analysis, which involves breaking down a complex behavior
into small steps, and the use of visual schedules, in which steps of an activity are displayed
in separate pictures or photographs, appear especially useful. In addition, ABA curricula
have been developed to teach academic and vocational skills; these curricula are based on
task analyses of the skills and involve developing the skills in a series of carefully planned,
small steps (Engelmann, Becker, Carnine, & Gersten, 1988). However, because evaluations
of the effectiveness of these curricula for individuals with ASD are sparse, this is an area that
merits further research (Wehman et al., 2013).
During a parent–teacher conference, Jackson’s father mentions that Jackson has diffi-
culty independently caring for himself at home. He still requires frequent reminders and
266 / / T reatment
assistance for getting dressed in the morning, brushing his teeth, and cleaning up after
himself. Because the teacher reports that visual checklists have helped Jackson organize
his assignments at school, Jackson’s father decides to try using them at home as well. He
posts a checklist of Jackson’s routine for getting dressed (e.g., put on shirt, pull up pants,
button pants, pull on socks) on the wall in his room and a picture schedule of Jackson’s
teeth-brushing routine in the bathroom. As Jackson completes each step, he checks them
off with a marker. After 2 weeks, Jackson’s father notices that it is taking Jackson less time
to get ready in the morning.
Decreasing Problem Behavior

Some individuals with ASD engage in problem behaviors that impede learning or interfere
with daily living skills. These behaviors range from mild (e.g., noncompliance) to moder-
ate (e.g., disruption and tantrums) and severe (e.g., dangerous aggression, self-injury, and
property destruction; Matson & Rivet, 2008). Related to the limited social awareness and
circumscribed interests that are characteristic of ASD, the behavior may take unusual or
unsettling forms, such as undressing in public or becoming excessively preoccupied with
a particular person. Intervention is informed by a functional behavioral assessment (FBA).
An FBA involves systematic data collection on multiple aspects of the problem behavior,
including what it looks like, how frequently it happens, how long it lasts, and what are the
antecedents and consequences (O’Neill et al., 1997). Data are then analyzed to identify
patterns in behavior and to generate a hypothesis regarding the function (or maintaining
variables) of the behavior. In the ASD literature, the functions of challenging behavior most
commonly include access to attention; access to a tangible, desired item or activity; escape
from an unwanted demand; and automatic reinforcement (e.g., sensory feedback produced
by the behavior itself).
Information gathered from an FBA should be used to develop a behavior intervention
plan to break associations among antecedents, consequences, and the behavior (O’Neill
et al., 1997; see Table 15.4). Antecedent manipulations are prevention strategies that
reduce the likelihood that the behavior will occur in the first place. Consequence-based
strategies involve changing the environmental response such as how others react to the
behavior. Problem behavior can also occur when an individual does not have the skills to
complete a presented task. To alleviate frustration in this situation, instructional supports
are indicated, such as teaching prerequisite skills and matching goals to the individual’s
developmental level or cognitive functioning. Finally, teaching skills to “replace” a challeng-
ing behavior (e.g., saying “I’m hungry” instead of having a tantrum) is often associated with
positive behavioral outcomes (Tiger et al., 2008).
Although Jackson has generally been adjusting well to his new classroom this school year,
he occasionally has outbursts that include yelling, throwing classroom materials, and hit-
ting his teacher. These tantrums usually occur when Jackson is asked to work on a difficult
assignment. The school team meets to discuss how to address these tantrums because
they are disruptive to the rest of the class. The team’s BCBA suggests an intervention
plan that addresses both the antecedents and the consequences of Jackson’s behavior. In
TABLE 15.4 Function-Based Intervention for Challenging Behavior
Function Change Antecedents Teach Appropriate Behavior Consequences
Attention Provide ample attention at regularly scheduled times Teach appropriate ways to get attention Withhold attention in response to
Provide attention for appropriate behavior (e.g., “Excuse me,” tapping someone’s inappropriate behavior
Increase opportunities for appropriate interactions shoulder) Provide time-out from attention for a
Move desk away from other students brief period (e.g., 1 minute)
Loss of privileges
Escape/ Provide regular breaks throughout the learner’s day Teach the learner to ask for a break (either Ignore the problem behavior, but
avoidance Provide a mixture of easy and difficult tasks with words or use of a “break” card) calmly redirect the student every
Minimize the number of non-preferred activities Teach the learner to ask for help during few seconds to complete the task
Use motivating materials during non-preferred activities difficult tasks or an alternate task
Provide the learner with choices about which task to do next Loss of tokens (if the student has an
Provide instruction through visual supports (e.g., pictures, established reinforcement system
checklists) for earning breaks from instruction)
Use a timer to signal the amount of time left until tasks
are complete
Tangible items Provide access to the item throughout the learner’s day Teach the learner a variety of ways to Do not provide access to the item in
Increase opportunities to appropriately request and earn items request the item appropriately response to problem behavior
Use visual supports (e.g., timer) to show how long the learner Gradually teach the learner to wait before
can use the item receiving an item
Automatic/ Provide limited access to the behavior at appropriate times Teach the learner to follow class/job/ Do not provide attention in response
sensory (i.e., when it will not interfere with learning), if the behavior is house rules to the problem behavior
not dangerous Teach the learner to engage in a behavior Use gentle physical guidance to
Reinforce the learner for engaging in other, appropriate behavior that is incompatible with the problem redirect the learner
Provide the learner with an object that can “compete” with the behavior (e.g., hands in pockets versus
behavior hand flapping)
Provide regular access to activities that the learner enjoys
Limit access to items that may contribute to the problem behavior
268 / / T reatment
collaboration with Jackson’s teacher, he develops several strategies to help Jackson seek
assistance when he encounters difficult material, including placing a visual “ask for help”
cue on Jackson’s desk and reminding the class as a whole that they can ask the teacher
questions. The teacher will also implement a “token” reward system, wherein Jackson earns
checkmarks each time he completes an academic activity without having a tantrum. At the
end of the day, Jackson can exchange his checkmarks for a small treat or privilege (e.g., first
choice of games at recess or being the line leader). Finally, the team will monitor Jackson’s
behavior and will pursue a formal FBA if his tantrums get worse or more frequent over time.
Addressing Anxiety and Rigidity

Anxiety can be a substantial source of distress for individuals with ASD and their caregiv-
ers. CBT is one of the most empirically supported treatments for anxiety disorders, and
with some adaptations, its success has been replicated in the ASD population (Wood et al.,
2009). Inflexibly adhering to the daily schedule, feeling compelled to complete repetitive
sequences of behavior, or insisting on others acting in a certain way can also be distressing.
Although pharmacological management is often used to address rigidity, behavioral inter-
ventions also can be considered (Cotugno, 2009).
Samuel’s parents are seeking home-based support because lately he has been unlocking the
front door and running out into the street. This poses a serious risk because the family lives
on a main road. Because this behavior happens at unpredictable times, Mr. and Mrs. Reyes
believe they have to be with Samuel constantly. They would like to know more about what they
can do to keep Samuel safe. The behavioral team recommends that the Reyes family make
some environmental changes (e.g., installing childproof covers on the door handles) to make it
more difficult for Samuel to leave the house. Samuel should also be taught safety skills, such
as stopping when directed by an adult and following visual cues (e.g., a large STOP sign on the
front door). Additional supports should be put in place in case Samuel does make it out of his
house. For instance, he should carry a card with his name and address on it, and the neighbors
and local businesses should be educated on how to help Samuel return home safely.
Biobehavioral Problems
Individuals with ASD often have physiological symptoms or co-occurring medical condi-
tions. Although pharmacological intervention is sometimes the best approach to treating
these difficulties, if there is not a clear medical etiology, behavioral strategies can also be
indicated, either as the primary intervention or in combination with medication.
Sleep
Difficulties falling asleep and sleeping through the night are extremely common in ASD,
and they are linked to daytime problem behavior, ASD symptomatology, and family stress
(Malow et al., 2012). Although medical interventions such as administration of melatonin
can be considered, behavioral treatment is also an option (Malow et al., 2012). Common
behavioral strategies include establishing good sleep hygiene—for example, implementing a
consistent bedtime routine, providing a relaxing bedtime environment, reducing opportuni-
ties for daytime sleep, limiting electronics prior to bedtime, fading out sleep associations (e.g.,
with a parent in the room or the television on), and using visual supports (e.g., picture sched-
ules, sticker charts, and nightlights that turn off when it is time to get up) (Durand, 2014).
Feeding
The most commonly reported feeding problems in ASD are behavioral in nature (e.g., food
refusal, food selectivity, gagging, and disruptive mealtime behavior) and related to sensory
sensitivity (e.g., avoiding food with specific textures or appearances; Schwarz, 2003). These
problems are often associated with elimination problems such as constipation or diarrhea,
and they can lead to nutritional deficiencies, although, fortunately, medically urgent mal-
nutrition appears to be rare (Hyman et al., 2012). Behavioral approaches to feeding prob-
lems include graduated exposure to non-preferred foods, escape extinction (not removing
the food until the individual consumes it), shaping procedures (reinforcing gradual food
tolerance), texture fading, and establishing good mealtime habits (instituting a consistent
schedule and standard location to eat, limiting grazing at other times, and turning off elec-
tronics; Williams & Foxx, 2007). It is often prudent to collaborate with a dietitian to evalu-
ate the nutritional adequacy of the individual’s diet and recommend foods to introduce, as
well as an SLP or OT to determine whether the individual has impairments in chewing or
swallowing (Volkmar & Weisner, 2004).
Some individuals with ASD engage in pica (ingesting non-food substances; McAdam,
Sherman, Sheldon, & Napolitano, 2004). This behavior may warrant a medical evaluation
because it can reflect nutritional deficiencies and can lead individuals to consume toxic, infec-
tious, or unsafe items, such as large or sharp objects. Behavioral strategies for pica include
teaching individuals to distinguish between food and non-food items, identifying the func-
tion of the behavior, and implementing function-based interventions (McAdam et al., 2004).
Toilet Training
Many individuals with ASD are delayed in developing daytime and nighttime bladder control,
and they often do not achieve bowel control until much later. In addition, they may resist
giving up habits such as defecating in a pull-up (Dalrymple & Ruble, 1992). Behavioral tech-
niques for toilet training include gradual exposure to the toilet, frequent practice of toileting
skills (sometimes encouraged by increasing the child’s fluid intake), systematic reinforcement
for sitting on the toilet and for successfully urinating in it, and helping the child overcome bar-
riers such as fears of sights and sounds in the bathroom (Wheeler & Kranowitz, 2007). Other
strategies include scheduling regular times for children to sit on the toilet, video modeling,
and the use of moisture alarms (e.g., bell and pad alarms; Wheeler & Kranowitz, 2007).
Mr. and Mrs. Reyes schedule a visit with Dr. Nolan because during the past few months,
Samuel has been refusing to stay in bed. As soon as his parents are gone, he cries and tries
to leave his room. Mr. and Mrs. Reyes struggle to keep Samuel in his room until he finally
falls asleep in their bed at approximately 10:30 p.m. This is problematic for both parents,
270 / / T reatment
who wake up early to go to work. The Reyes family is exhausted and wants to know how
they can help Samuel sleep in his own bed.
In talking more about the bedtime routine, Dr. Nolan learns that Samuel is put in bed any-
time between 7:00 and 8:00 p.m., depending on when the family finishes dinner, whether
Samuel gets a bath, and whether they decide to let him watch an episode of his favorite
television show. She suggests that his parents consider a more structured routine that
includes a predictable sequence of evening activities, such as dinner, bath time, and a con-
sistent bedtime at 7:30 p.m. Dr. Nolan also counsels Mr. and Mrs. Reyes on how exposure
to the artificial light in televisions and computers can interfere with falling asleep. Instead
of watching a television show, she asks if Samuel’s parents could read him his favorite
books. She also compliments them on their persistence in taking Samuel back to his room
so many times. If they can consistently keep it up until he falls asleep in his own bed, he
will likely begin staying in his room at bedtime. Dr. Nolan warns the Reyes’ that learning
new sleep habits can sometimes take a while, and she tells them not to get discouraged if
Samuel’s sleep does not improve for several weeks.
Combining Behavioral Interventions With Medication
Although not effective in treating the core features of ASD, psychotropic medication (dis-
cussed in Chapter 16) can be used in concert with behavioral interventions to maximize out-
comes in treatment for aggression and other disruptive behavior (Aman et al., 2009). Although
little research is available, many clinicians believe that combined medication and behavioral
treatment also may be helpful for other symptoms associated with ASD, such as sleep prob-
lems, anxiety, mood disruption, aggression, and inattention or impulsivity. Behavioral strate-
gies such as systematic, data-based monitoring on and off medication are also informative
for comprehensively evaluating potential benefits and adverse reactions (LaRue et al., 2008).
WHEN TO REFER TO A SPECIALIST
With a solid understanding of behavioral strategies, it is often straightforward and efficient

to counsel families on implementing behavioral interventions to address their concerns
about the individual with ASD. For medical providers, this counseling is generally accom-
plished within the confines of a relatively brief office visit (Malow et al., 2014). Providers
who deliver ongoing therapeutic services can implement behaviorally based treatment in
their sessions, offer parent training, and consult with other providers. If the problem per-
sists or becomes exacerbated over time, referral to a specialist may be indicated. Initially,
providers should review the usual considerations, especially the severity of the behavior
(e.g., How long has it lasted? Is the individual’s functioning impaired? Is there a safety
risk?). However, additional factors also may be relevant, including the following:
• Is the intervention developmentally appropriate? Ensuring a good match between

the intervention and the individual’s strengths and weaknesses will maximize the
likelihood of improvement. Programming may be too remedial (e.g., EIBI services
that extend beyond early elementary school) or too challenging (e.g., school place-
ment in which the student does not have the skills necessary to meet expectations).
• Have strategies been implemented consistently for an adequate amount of time?

Behavioral treatment usually requires weeks or months to yield practical benefit,
although signs of incremental improvement should be apparent from data on the
individual’s progress. Rates of learning vary greatly across individuals (Reichow,
2012). Consistent use of techniques across people, settings, and time is necessary for
promoting communication or resolving behavior problems.
• Has the individual experienced a recent life transition? Physical changes such as
puberty and psychosocial events such as moving, divorce, or school placement
transitions can be disruptive to individuals with ASD, who may be more sensi-
tive to these changes than their peers. Increases in problem behavior, biobehav-
ioral issues, and rigidity may be associated with such changes. However, these
problems are often temporary and are likely to respond well to brief behavioral
intervention or resolve on their own. If they persist or begin to significantly
interfere with the individual’s functioning, the behavior may warrant specialized
intervention.
KEY POINTS
• Behavioral interventions teach skills and decrease challenging behavior by changing
what comes before (i.e., antecedents) and what comes after (i.e., consequences) the
behavior.
• ABA-based interventions take many forms and can be relevant for individuals with
ASD at all ages and developmental stages and for a variety of skills.
• Although behavioral intervention plans should be highly individualized, there are
several quality indicators, such as supervision by a BCBA, service intensity that
adheres to published practice guidelines, shared decision-making among team mem-
bers and families, and systematic data collection.
• Comprehensive approaches such as early intensive behavioral intervention address
skill-building across all areas of development in young children with ASD.
• Problem behavior is most effectively addressed through functional behavioral assess-
ment and function-based intervention procedures.
Dr. Tristram Smith and Dr. Suzannah Iadarola receive research funding from the National
Institutes of Health. Dr. Smith also receives research funding from the Institute of Education
Sciences, Autism Speaks, and the Maternal Child Health Bureau of the Health Resources
and Services Administration.
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/ / /
16 / / / PSYCHOPHARMACOLOGY
OF AUTISM SPECTRUM
DISORDER
JAMES T. MCCRACKEN
AND MICHAEL GANDAL
INTRODUCTION
The use of a broad range of medications as a component of treatment for children and adults
with autism spectrum disorder (ASD) has become common clinical practice. Most surveys
report that by 8 years of age, as many as 60–70% of individuals with ASD will receive a med-
ication for management of behavioral or emotional problems within 12 months (Esbensen,
Greenberg, Seltzer, & Aman, 2009; Oswald & Sonenklar, 2007). The use of medications in
ASD climbs with increasing age, as does combination pharmacotherapy. In part, this prac-
tice pattern reflects a growing body of evidence demonstrating the safety and benefits of
psychotropic medications in this population. However, it is not without concern, given the
continued large gaps in appropriate studies needed to establish a more comprehensive base
of knowledge of medication efficacy and safety in ASD. In this light, note that most psycho-
tropic use in ASD is “off-label” because there are currently only two medications approved
by the US Food and Drug Administration (FDA) for individuals with ASD, both of which
are approved only for the treatment of associated behaviors. Moreover, in efforts to find
treatments that reduce disability and improve outcomes, the history of ASD treatments
is rife with examples of purported “cures” rapidly taken up in community settings, which
ultimately failed when subjected to rigorous study (e.g., secretin and hyperbaric oxygen).
No current psychotropics have definitively shown major benefits on the core deficits of
ASD— social communication deficits and delays and the intense preoccupations, repetitive
behaviors, and marked sensory sensitivities that make up the syndrome—although this is a
subject of intensive research efforts (see Emerging Therapies). Therefore, it behooves pro-
fessionals to maintain the same standards for evidence for any ASD therapy that would be
required for any other medical intervention. However, many treatments are now accepted
as indicated or possibly indicated to treat a range of commonly associated and impairing
behavioral targets in individuals with ASD. This chapter helps orient the clinician in iden-
tifying those targets for possible intervention with pharmacotherapy in ASD; indicates
275
276 / / T reatment
what choices are best supported by their known efficacy and safety; and provides suggested
approaches to initiate, evaluate, and monitor safety of these treatments. The emphasis in
this review relies on empirical evidence and usual standards used to evaluate medical treat-
ments. After reviewing the currently best-supported treatments, the chapter reviews cur-
rent practice patterns against the state of the science of psychopharmacology in ASD in
order to highlight areas of concern. Finally, emerging research efforts to identify possible
medications for core deficits of ASD are briefly described.
TARGETING PSYCHOPHARMACOLOGIC TREATMENT IN AUTISM SPECTRUM

DISORDER: WHAT’S TO TREAT?
Individuals with ASD present with a wide array of challenges, behaviors, and impairments
that may merit intervention. It is well-known that individuals with any developmental or
intellectual disability are at markedly increased risk for co-occurring problems, especially
all forms of psychiatric disorders. At the broadest level, rates of psychopathology are often
reported to be two- or threefold greater among samples of children and adults with intel-
lectual disabilities compared to non-intellectually disabled comparison groups. The same
increased risk certainly holds for ASD. Depending on the age range studied, 33–41% of
individuals with intellectual disabilities meet definite criteria for psychiatric diagnoses
(Einfeld & Tonge, 1996). In one representative study of children with ASD, 81% of the
children were described as impaired by symptoms of a psychiatric disorder based on parent
and teacher report of diagnostic symptoms listed in the fourth edition of the Diagnostic and
Statistical Manual of Mental Disorders (American Psychiatric Association, 2004). Although
establishing categorical diagnoses is challenging in a population in which communication
of emotional symptoms and disordered thinking is often difficult, rates of co-occurring psy-
chopathology show solid agreement from study to study. The patterns of reported impairing
behaviors and symptoms appear to hold true across reports, with inattentive, hyperactive,
and impulsive behaviors, oppositional–defiant behaviors, anxious/withdrawal symptoms,
aggression, and self-injurious behaviors being most commonly identified by parents and
teachers (Figure 16.1). Other efforts to characterize the behavioral problems commonly
brought to clinician attention highlight the high rates of parent and individual complaints
of sleep–wake disruptions. Taken together, these constellations of symptoms are often so
impairing as to interfere with learning, ability to be retained in a more inclusive classroom
or school setting, or even threaten the safety and well-being of the individual with ASD
and/or his or her family members, despite the individual’s access to behavioral or other
therapies. Such symptoms form the majority of the behavioral targets considered for psy-
chopharmacologic treatment. Because treatment goals are currently symptom-based, this
chapter later reviews clinically useful tools to assess and monitor treatment outcomes. In
the next section, the best-studied behavioral targets that possess evidence for pharmaco-
therapeutic management are reviewed.
PSYCHOPHARMACOLOGIC TREATMENT OF TARGETED BEHAVIORS IN AUTISM

SPECTRUM DISORDER
Irritability, Aggression, and Self-Injury
Aggression and related symptoms such as agitation, severe tantrumming, and mood lability,
often referred to collectively as “irritability,” are associated problems that often elicit concern
Psychopharmacology of Autism Spectrum Disorder // 277
Sleep ADHD
Disruption
Hyperactivity
Depression Impulsivity
Anxiety
Inattention
Social
Communication Repetitive
Deficits Behaviors
Irr
ita
bi
lit
Language Aggression
y
Impairment
Self- Tantrums
injurious
In
ll e
te
ctu Behaviour
al
D is
a b i li t
y
FIGURE 16.1 Common co-occurring maladaptive behaviors and medication targets in autism

spectrum disorder.
in ASD. Although the term “aggression” can encompass different subtypes of symptoms with
varying behavioral and functional mechanisms, taken together this is a very common accom-
panying complaint in ASD. Analysis of data on 1584 children aged 2–17 years in clinics com-
prising the Autism Treatment Network estimated a prevalence of aggression of 53.7% based
on a “yes” or “no” response from parents on a single question about aggression. Another
prevalence study involving 1380 subjects with ASD showed that 68% demonstrated aggres-
sion to a caregiver and 49% to non-caregivers (Einfeld & Tonge, 1996). The “subtype” of
self-aggression, or self-injurious behavior (SIB), is also a common and frequently severe
challenge: More than 50% of children with autism show SIB, and as many as 15% suffer
from severe levels of SIB. Overall, aggression may lead to hospitalization, family disruption,
institutionalization, removal from less restrictive school settings, and a worse prognosis
(Baghdadli, Pascal, Grisi, & Aussilloux, 2003; Nazeer, 2011). The causes of irritability and
aggression are multifactorial: comprehension difficulties; decreased ability to communicate
and express needs and desires; reduced confrontation skills; conflict with teachers, supervi-
sors, and authority figures; psychosocial dysfunction; and undiagnosed pain and mood and
anxiety disorders (Nazeer, 2011). The first step to address the aggressive behavior is to per-
form a “functional analysis” of the behavior, carefully delineating the contexts, antecedents,
environmental responses or consequences, and other causative or maintaining influences.
The deeper understanding of the behavior generally guides clinicians to the most appropri-
ate therapeutic approach (behavioral management and/or medication). Although behav-
ioral and environmental approaches are recommended as the initial treatment, persistent,
severe, or even dangerous behaviors are complaints that lead to consideration of pharma-
cological intervention. The following classes of medications have empirical support for the
management of irritability and its aggressive, agitated, and self-injurious behaviors.
278 / / T reatment
Antipsychotics
First- and second-generation antipsychotics have shown moderate to large benefits in con-
trolling aggressive symptoms in autism (Nazeer, 2011), beginning with early controlled tri-
als of haloperidol, a conventional dopamine 2 receptor subtype antagonist (Campbell et al.,
1978). Antipsychotics, predominately second-generation agents, have become commonly
used medications in ASD for the treatment of irritability (Mandell et al., 2008), perhaps
influenced by observations of possible additional benefits for a variety of other associated
behaviors and the fact that two of these agents, risperidone and aripiprazole, represent the
only FDA-approved medications for ASD.
In 2002, the National Institute of Mental Health’s Research Units on Pediatric
Psychopharmacology (RUPP) Autism Network reported on a multicenter randomized
clinical trial (RCT) that evaluated the efficacy and safety of short- and intermediate-term
risperidone in children and adolescents aged 5–17 years with autistic disorder accompa-
nied by severe tantrums, aggression, and SIB (McCracken et al., 2002). The results showed
that short-term, low-dose risperidone treatment was markedly superior to placebo (posi-
tive responders, 75% vs. 12%, respectively). In addition to major decreases in irritability
(aggression, SIB, and severe temper outbursts) associated with risperidone, broader ben-
efits on other maladaptive behaviors were also documented versus placebo, including
decreased hyperactivity and reductions in stereotypies. Risperidone treatment has been
shown to be well tolerated for up to 6 months. Importantly, common extrapyramidal side
effects seen with haloperidol in earlier studies were comparatively lower with risperidone.
Sedation, drowsiness, weight gain, and hyperprolactinemia were the most commonly
reported side effects, with reductions in these adverse effects over time noted. From a total
of eight randomized clinical trials with risperidone, two meta-analyses and two associa-
tion studies demonstrated consistent efficacy over placebo for irritability for risperidone
(Aman, Hollway, et al., 2008; Canitano & Scandurra, 2011; Gencer et al., 2008; Kent,
Hough, Singh, Karcher, & Pandina, 2013; Kent, Kushner, et al., 2013; Luby et al., 2006;
McDougle, Stigler, Erickson, & Posey, 2008; Nagaraj, Singhi, & Malhi, 2006; Pandina,
Bossie, Youssef, Zhu, & Dunbar, 2007; Shea et al., 2004; Troost et al., 2005). Effective doses
were low, averaging 2 mg/day, although lower doses (0.125–0.175 mg/day) were not effec-
tive compared to placebo (Kent, Kushner, et al., 2013). No evidence of tolerance or need
for dose escalation over time have been reported for subjects followed for up to 6 months
of treatment. Paliperidone, the active 9-hydroxy metabolite of risperidone, showed similar
effectiveness in an 8-week open-label clinical trial involving adolescents and young adults
with ASD (Stigler, Mullett, Erickson, Posey, & McDougle, 2012).
The FDA has also approved aripiprazole for treatment of severe irritability in chil-
dren with autistic disorder aged 6–17 years. Two double-blind, placebo-controlled RCTs
showed that aripiprazole is effective in treating irritability in ASD (Marcus et al., 2009;
Owen et al., 2009; Siegel & Beaulieu, 2012), with secondary improvements also noted for
hyperactivity and stereotypies. Aripiprazole is well tolerated in dose ranges of 5–15 mg/
day, and it is associated with lower mean weight gain compared to several other atypical
antipsychotics, as measured during the initial 8 weeks of exposure. The efficacy and side
effect profile of aripiprazole and risperidone were similar when compared head-to-head in
a recent prospective, double-blind 8-week clinical trial (Ghanizadeh, Sahraeizadeh, & Berk,
2014), although overall clinical positive responder rates were modestly lower for aripipra-
zole versus risperidone (55% vs. 75%, respectively).
Two RCTs with children with ASD using haloperidol showed significant positive
effects on behavioral symptoms and global functioning (Anderson et al., 1984, 1989).
Comparing broad-based measures of maladaptive behaviors and ASD symptoms, a small,
head-to-head, 12-week, randomized double-blind comparator trial of haloperidol versus

risperidone found risperidone to be superior to haloperidol across most measures and to
be associated with lower side effect ratings (including rigidity) versus haloperidol at equal
doses (mean, 2 mg/day) (Miral et al., 2008). In summary, although haloperidol has shown
consistent behavioral benefits versus placebo in reducing aggressive and disruptive behav-
iors in children with autism accompanied by severe and challenging behaviors (Canitano &
Scandurra, 2011), the high rates of extrapyramidal side effects, including withdrawal dyski-
nesias, have led to its infrequent use.
Other atypical antipsychotics need further clinical evaluation. Olanzapine has not
been studied in randomized placebo-controlled trials of adequate sample size in children
or adults with ASD. However, some case studies and an open-label trial reported posi-
tive results (Heimann, 1999; Horrigan, Barnhill, & Courvoisie, 1997; Potenza, Holmes,
Kanes, & McDougle, 1999). In addition, a randomized trial with a parallel control group
treated with haloperidol reported positive results, although patients had significant
weight gain (Malone, Cater, Sheikh, Choudhury, & Delaney, 2001). The prolonged use
of olanzapine may induce significant metabolic changes, which can restrict its long-term
use in ASD (Bonanno, Davydov, & Botts, 2001). Ziprasidone was investigated in one
open-label study that included 12 adolescents with ASD treated with doses ranging from
20 to 160 mg/day. A 75% response rate to ziprasidone was observed according to Clinical
Global Impression–Improvement (CGI-I) scale ratings. In addition, improvements in
the Aberrant Behavior Checklist (ABC) subscales of irritability and hyperactivity were
noted. Ziprasidone did not cause weight gain, but a regular increase in the QTc interval
of 14.7 msec in the sample was described (Malone, Delaney, Hyman, & Cater, 2007),
implying the need for special monitoring. Another open-label clinical study and a retro-
spective review of clinical records showed promising results for ziprasidone in patients
with ASD (Cohen, Fitzgerald, Khan, & Khan, 2004; McDougle, Kem, & Posey, 2002).
Double-blind, placebo-controlled studies are needed to validate the use of ziprasidone
in this population. Three small, open-label trials have failed to demonstrate efficacy for
quetiapine in ASD, with mixed reports on its tolerability (Findling et al., 2004; Golubchik,
Sever, & Weizman, 2011; Martin, Koenig, Scahill, & Bregman, 1999). Given the risk of
potentially serious side effects of seizures and agranulocytosis, there is no evidence to sub-
stantiate clozapine as an ASD treatment, with only case reports available (Chen, Bedair,
McKay, Bowers, & Mazure, 2001). No data are available for lurasidone or asenapine in
ASD. Thus, comparatively speaking, only risperidone and aripiprazole possess sufficient
evidence for firm support for treating the target behaviors of irritability in ASD, with pali-
peridone possibly indicated, whereas the other antipsychotics lack data to support use as
first- or second-line therapies. Haloperidol has been shown to be more efficacious than
placebo for irritability in children with ASD, but its short- and longer-term side effect pro-
files often limit treatment.
Adverse Effects of Antipsychotics

All antipsychotics in children carry the risk of potentially serious side effects, such as neu-
roleptic malignant syndrome, hyperprolactinemia with associated galactorrhea (except for
aripiprazole), dyskinesias, cardiovascular changes, and allergic reactions. Fortunately, these
serious adverse events are estimated to be rare or uncommon; a review estimated the annu-
alized risk for tardive dyskinesia to be less than 0.5%, and remission of the disorder after
drug discontinuation is a common observation (Correll & Kane, 2007). Nevertheless, it
is of obvious importance to systematically monitor for the appearance of such untoward
280 / / T reatment
effects and develop strategies to minimize them. Although a comprehensive discussion of

this topic is beyond the scope of this chapter, an excellent review is available (Correll, 2008).
Other Agents
There is evidence that agents other than antipsychotics may be effective for irritability
and agitated behaviors in ASD. The anticonvulsant and mood stabilizer valproic acid has
shown some efficacy for these target symptoms, although results are mixed. A randomized,
double-blind, placebo-controlled trial of valproic acid in 55 children and adolescents with
ASD found a significantly higher response rate in the treatment group (62.5%) compared
with placebo (9%), as measured by CGI-I ratings focused on irritability (Hollander et al.,
2010). However, a smaller trial of 30 subjects aged 6–20 years with pervasive developmental
disorders failed to find an effect (Hellings et al., 2005). An early open-label study of valproic
acid in 14 subjects with autism found a significant response rate (70%) with improvements
in affective instability, impulsivity, and aggression (Hollander, Dolgoff-Kaspar, Cartwright,
Rawitt, & Novotny, 2001). Valproic acid’s less robust benefits coupled with its requirement
for added monitoring of hematologic and liver functions, and the need for therapeutic
drug-level testing, relegate it to lesser status as a third- or fourth-line treatment option for
irritability in ASD.
Emerging evidence suggests that the glutamatergic modulator and antioxidant
N-acetylcysteine (NAC) may also be effective for disruptive behaviors in autism. A 12-week
double-blind, placebo-controlled trial involving 33 subjects with autism (aged 3–11 years)
demonstrated significant reduction in the ABC-Irritability subscale (primary outcome),
with treatment response of 78% for NAC versus 50% for placebo (Hardan et al., 2012).
Likewise, an 8-week double-blind, placebo-controlled add-on trial of NAC to ongoing ris-
peridone in 40 children and adolescents with autism showed a significant benefit of NAC
compared with risperidone plus placebo on irritability (Ghanizadeh & Moghimi-Sarani,
2013). At least two other studies of NAC in patients with autism have been performed but
not published (NCT00453180 and NCT00889538). NAC deserves additional exploration
as a treatment, and it is potentially appealing given its relatively benign side effect profile.
Limited evidence, mostly from uncontrolled case series, on possible benefits of esci-
talopram, mirtazapine, clonidine, and methylphenidate for the treatment of aggression
and irritability in ASD have also been reported. Depending on the constellation of pre-
senting symptoms in the individual, these agents are often considered, although none have
achieved sufficient evidence to support their routine use as first-line treatments for irritabil-
ity in ASD.
Self-Injurious Behavior
The literature is mixed with respect to drug effects on the irritability subtype of SIB.
Naltrexone, an opioid receptor antagonist, has received the greatest amount of research
attention on its effects in samples of individuals, mostly adults, with ASD and other intel-
lectual disabilities, with some summaries finding support for its benefits. However, a
Cochrane meta-analytic review did not find evidence to support naltrexone’s efficacy for
managing SIB in adults, nor for any other medication (Rana, Gormez, & Varghese, 2013).
Clinically, assessing for other treatable comorbidities commonly associated with SIB, such
as depression, anxiety, or an underlying medical illness, may provide the best guidance for
empirical treatment selection.
Clinical Implications
Aggressive behaviors toward self and others displayed by many children with ASD rep-
resent an important and often seriously impairing target for treatment. The clinical chal-
lenge of evaluating aggressive behaviors is to identify any other potentially treatable
“primary” or contributing psychiatric symptoms, such as anxiety, depression, or hyperac-
tivity/impulsivity, as well as comorbid medical conditions. If no such conditions are evi-
dent, or treatment of these other targets is ineffective at reducing aggression, the atypical
antipsychotics risperidone and aripiprazole represent the most studied agents in ASD,
are FDA-approved for treating irritability (not ASD per se), and have shown solid evi-
dence of efficacy. Paliperidone, the risperidone metabolite, and older haloperidol studies
also provide favorable evidence for their off-label use. However, the evidence is also high
for the risk of developing clinically limiting side effects for all antipsychotics, such as
the extrapyramidal effects of conventional agents or the metabolic changes of atypical
neuroleptics (Campbell et al., 1978; McCracken et al., 2002; Owen et al., 2009). Close
monitoring of patients on these agents is essential. Divalproex and NAC are off-label
options with modest evidence of effectiveness. The decision to initiate pharmacological
treatment should be based on severity of symptomatology, degree of impairment, risk
to self or others, and prevention of hospitalization. Although no clinical treatment algo-
rithms for treatment choice for aggression have been widely endorsed, clinicians gener-
ally attempt initial treatment with lower-risk alternatives to antipsychotics. However, in
the context of poor response or tolerability, or severe and dangerous symptoms, clini-
cians often turn to one of the two FDA-approved antipsychotics for rapid management
and stabilization. Length of recommended treatment is difficult to derive from published
evidence, but treatment benefits appear durable for up to 6–12 months. Efforts to gradu-
ally reduce and possibly discontinue such treatment at the end of this period should be
strongly considered.
Hyperactivity, Impulsivity, and Inattention
Symptoms of attention deficit hyperactivity disorder (ADHD) are very common in individ-
uals with ASD, affecting between 28% and 74% of children (Aman, Lam, & Collier-Crespin,
2003; Goldstein & Schwebach, 2004). Inattention has been described in 50% of children
with autism, with hyperactivity in 49% and 21% according to parents and teachers, respec-
tively (Aman, Farmer, Hollway, & Arnold, 2008). To date, RCT for this set of symptoms
have only been conducted with methylphenidate and atomoxetine in ASD. Three RCTs
have investigated the effects of methylphenidate in children with ASD (Handen, Johnson,
& Lubetsky, 2000; Quintana et al., 1995; Research Units on Pediatric Psychopharmacology
Autism Network, 2005). In the largest of these, low to moderate doses of methylphenidate
were compared to placebo in a study of 66 participants with ASD in a crossover design
(Research Units on Pediatric Psychopharmacology Autism Network, 2005). This study
was classified as showing strong clinical evidence of benefit, with 49% of subjects rated to
be positive responders to methylphenidate versus 18% on placebo by virtue of showing a
25% decrease in ADHD symptoms from baseline and a CGI-I rating of “much improved”
or “very much improved.” However, 18% dropped out of the trial due to inability to tol-
erate the medication, most commonly due to irritability (Siegel & Beaulieu, 2012). Two
other small studies with 10 and 13 children, respectively, have been judged to be solidly
designed, leading to the determination of a promising level of evidence for treatment with
methylphenidate for hyperactivity in children with ASD (Reichow, Volkmar, & Bloch,
282 / / T reatment
2013). Importantly, best or “optimal” methylphenidate doses in the RUPP study were often
found to be moderate (0.25 mg/kg) or even low (0.125 mg/kg) administered three times
daily, suggesting that initiating stimulant treatment in children with ASD should begin at
low doses and increase more gradually compared to usual titration in typically develop-
ing children with ADHD. Children with ASD and comorbid ADHD also have higher but
acceptable risks of adverse effects from stimulant treatment compared to typically develop-
ing children with ADHD (Nikolov, Jonker, & Scahill, 2006).
Atomoxetine is a selective norepinephrine reuptake inhibitor that is FDA-approved
for treatment of ADHD in typically developing children and adults. A small RCT was
conducted with atomoxetine in 16 children aged 5–15 years with autism and ADHD.
The treatment resulted in a response rate of 43%, defined as a 25% improvement on
the ABC-Hyperactivity subscale and a CGI-I rating of “much improved” or “very much
improved.” A significant improvement over placebo in hyperactive/impulsive symptoms
was also observed (Arnold et al., 2006). Adverse effects were relatively mild. A recent, large
(N = 97) European RCT found evidence for superiority of atomoxetine versus placebo
on ADHD symptom measures but no difference in response rates, which were low (21%
vs. 9%, respectively) (Harfterkamp et al., 2012). In a 20-week open-label extension period
after the initial 8-week trial, there was continued improvement in ADHD symptoms, in
both inattention and hyperactivity domains, with a concomitant decrease in adverse events,
although response rates were not reported (Harfterkamp et al., 2013).
The alpha-2 (α2) agonists clonidine (0.004–0.01 mg/kg/day) and guanfacine (1–3 mg/
day immediate release) have inconclusive but suggestive evidence for benefit for the target
of hyperactive–impulsive behaviors in ASD from small controlled or open-label trials. In
general, these agents are well tolerated, with expected side effects of drowsiness, sedation,
fatigue, mood changes, and mild hypotension and bradycardia. Only sparse data are avail-
able on the cognitive effects of the stimulants, atomoxetine, and α2 agonists from studies of
subjects with ASD.
Atypical Antipsychotics
Secondary analyses of the ABC-Hyperactivity subscale from large RCTs demonstrated that
risperidone and aripiprazole are associated with major reductions in hyperactivity in chil-
dren with ASD (McCracken et al., 2002; Owen et al., 2009).
Hyperactive, inattentive, and impulsive behaviors are among the most common
co-occurring maladaptive behaviors in ASD. Greater efforts are needed to identify indi-
viduals with this often unrecognized but treatable behavioral target. Stimulants, espe-
cially methylphenidate, have data supporting their use for this target, and atomoxetine
and the α2 agonists are possibly indicated as off-label interventions for those individuals
who are refractory or intolerant of stimulants. Because of the identified increase in risk
of adverse effects, dosing of stimulants should be conservative, starting with low mil-
ligram per kilogram initial doses and proceeding to titrate slowly with small increments
while carefully monitoring symptoms and adverse effects. α2 agonists represent promis-
ing therapies for hyperactivity in ASD, and they often form a solid second-line treatment
choice. Although antipsychotics have also shown effectiveness for marked hyperactivity,
their side effect risk with long-term exposure should temper their use for this behavioral
target.
Repetitive Behaviors
Behavioral therapies are the first-line treatment for restricted, repetitive behaviors (RRBs)
in ASD, but these behaviors can be quite difficult to manage with psychosocial interven-
tions alone. RRBs, when severe and frequent, can greatly interfere with educational and
social performance; as a result, pharmacological treatment is often considered. The medica-
tions discussed next have been evaluated and are often prescribed for the target of RRBs.
Selective Serotonin Reuptake Inhibitors

Because of the superficial similarity of RRBs with the phenomenology of selective serotonin
reuptake inhibitor (SSRI)-responsive obsessions and compulsions, and modest evidence of
serotoninergic dysfunction in ASD, SSRIs have been examined for management of RRBs.
Meta-analysis of available studies of SSRIs has shown lack of clinically significant effi-
cacy in the treatment of repetitive behaviors and restricted interests in pediatric subjects
with ASD (Williams, Brignell, Randall, Silove, & Hazell, 2013). Only one methodologically
sound study showed modest positive results of an SSRI (fluoxetine) compared to placebo
in children with ASD, but improvements were minor (Hollander et al., 2005). In the larg-
est RCT of the treatment of repetitive behaviors in ASD comparing citalopram to placebo,
no benefits were found for citalopram, and side effects such as hyperactivity, insomnia,
and behavioral deterioration were common (King et al., 2009). Interestingly, in contrast
to studies in children, two rigorous RCTs showed benefits for fluvoxamine and fluoxetine
on measures of repetitive behaviors for adults; however, again the benefits in the fluoxetine
study were minor relative to placebo (Hollander et al., 2012; McDougle et al., 1996). Taken
together, there is limited evidence to support the use of SSRIs as treatment for repetitive
behaviors in ASD, especially in youth. No large-scale controlled trials have examined their
effects for the treatment of anxiety or depressive symptoms in individuals with ASD.
Atypical Antipsychotics
Although not designed to test benefits for RRBs, secondary analyses of pivotal trials for
risperidone and aripiprazole both showed significant reductions in RRBs versus placebo.
In the RUPP risperidone study of irritability, risperidone achieved significantly greater
reduction of repetitive behavior than did placebo (35% vs. 15% reductions from baseline,
respectively), as reflected in clinician ratings of compulsions on the Childrens Yale–Brown
Obsessive Compulsive Scale modified for ASD (McDougle et al., 2005). Pivotal tri-
als of aripiprazole showed twofold greater reductions in RRBs in aripiprazole- versus
placebo-treated subjects in secondary analyses (Marcus et al., 2009; Owen et al., 2009).
Divalproex
A small 8-week RCT of divalproex sodium (mean dose, 823 mg/day) versus placebo in
13 individuals with ASD showed a significant group difference for divalproex on improve-
ment in repetitive behaviors. However, reductions were small and clinically insignificant
(decrease of 6% in divalproex group) (Hollander et al., 2006).
RRBs are a core and impairing behavior in many individuals with ASD, but treatment
options are limited. Few medications have any consistent evidence to support their use for
284 / / T reatment
treating RRBs, and those that do—primarily the atypical antipsychotics—carry significant
risks of side effects. Identifying contributing symptoms such as anxiety or mood symptoms
temporally associated with increasing RRBs can be useful in treatment selection.
Depression and Anxiety
Despite the common features of mood lability, apparent dysphoria, and anxiety in many
individuals with ASD, there are no controlled trials of available agents to form a solid evi-
dence base to guide clinical treatment of these targets in this population. Acknowledging
that there is strong empirical support for the efficacy of SSRIs as treatments for typically
developing children, adolescents, and adults with anxiety disorders, it is reasonable though
unproven whether benefits seen in typical individuals can be extrapolated to children with
ASD. The consistent finding of increased sensitivity to SSRI side effects in children with
ASD should increase caution for their use. However, the two controlled studies in adults
with fluvoxamine and fluoxetine do suggest possible benefit for the treatment of anxiety
and depression in ASD, although neither study selected subjects on the basis of impairing
anxiety or depression. Clinicians need to evaluate the options on a case-by-case basis and
attempt to discern medication effects by careful monitoring.
Sleep Disorders
ASD patients show much higher rates of insomnia and circadian rhythm disorders than
typically developing children (Richdale, 1999). Behavioral approaches to managing sleep
problems in ASD have been developed and are recommended as the first step in treatment.
However, these measures often fail, and physicians are faced with impairing sleep disrup-
tions and insufficiency that can have a wide negative impact on functioning. Although there
are no FDA-approved treatments for this problem in ASD, a significant number of RCTs
have consistently shown benefits for melatonin in doses from 3 to 15 mg 1 or 2 hours before
desired bedtime. These doses of melatonin are very well tolerated, and they yield advance-
ments in sleep onset time of up to 1 hour and lengthening of sleep duration by a similar
amount. The effects of long-term melatonin treatment in ASD have not been examined.
Because a number of other psychotropics used in the treatment of ASD can have sedative
side effects, they are often given at bedtime in an effort to promote sleep onset. α2 agonists,
atypical antipsychotics, and atypical antidepressants such as trazodone and mirtazapine may
aid sleep onset, but they lack studies to document their benefit and safety for this purpose.
COMMUNITY PRACTICE PATTERNS IN AUTISM SPECTRUM DISORDER
A number of recent reports have examined the prevalence of psychotropic use in different
samples of youth with ASD. The frequency of psychotropic use by drug class is included in
Table 16.1. Overall, these reports are in agreement that psychotropic use in children with ASD
is very common; more than half of all children with ASD who are older than age 6 years have
histories of receiving at least one psychotropic, and polypharmacology (receiving two or more
psychotropics concurrently) is seen in nearly 20% or more of 6- to 17-year-olds. Although
increasing age is clearly associated with higher rates of psychotropic usage, psychotropic
treatment is not uncommon in children with ASD who are 3–5 years old. In addition to age,
absolute rates of psychotropic use are also influenced by practice setting, region, comorbidity,
TABLE 16.1 Selected Surveys of Psychotropic Use in Children With Autism Spectrum Disorder
Reference Sample Size Medication Usage Factors Associated
Age Range Overall With Higher
Mean Age Drug Class Psychotropic Use
Langworthy-Lam, 1,538 46% Age, autism severity,
Aman, and Van 3–56 years PPha 14% ID severity,
Bourgondien (2002) 16 years AD 22% restricted housing
AP 17%
STM 14%
AED 17%
AAG 10%
SED 7%
Oswald and 1,942 83% Age
Sonenklar (2007) 0–20 years AD 40%
9 years STM 33%
AP 29%
AED 18%
AAG 15%
Mandell et al. (2008) 60,641 Medicaid 56% Age, male, white
0–21 years PPhb 11% race, foster care,
AD 25% comorbidity, urban
AP 31% density
STM 22%
AED 21%
Coury et al. (2012) 2,843 27% Age, private
2–17 years PPha 7% insurance, white
53% <6 years race, comorbidity
Frazier et al. (2011) 890 42% ADHD, white race
13–17 years AD 58%
15 years AP 42%
STM 31%
AED 21%
Rosenberg et al. (2010) 5,181 IAN Registry 35% Age, ID, comorbidity,
0–17 years PPh 9%
b
poor county, region
49% 6–11 years AD 14% (South, Midwest)
AP 15%
AED 7%
AAG 8%
(continued)
286 / / T reatment
Reference Sample Size Medication Usage Factors Associated
Age Range Overall With Higher
Mean Age Drug Class Psychotropic Use
Schubart, Camacho, and 12,843–18,562 65% Age, secular trend,

Leslie (2013) Medicaid PPh a
26% poverty, foster care,
2000–2003 AD 29% white race
3–17 years AP 39%
50% 6–11 years STM 25%
AED 16%
SED 14%
ANX 11%
Spencer et al. (2013) 33,565 64% Age, psychiatrist visit,
0–20 years PPha 35% comorbidity, white
60% 2–10 years race
a
Two or more concurrent medications between drug classes.
b
Three or more concurrent medications between drug classes.
AAG, α2 agonists; AD, antidepressants; ADHD, attention deficit hyperactivity disorder; AED,
anticonvulsants + mood stabilizers; ANX, anxiolytics; AP, antipsychotics; IAN, Interactive
Autism Network; ID, intellectual disability; PPh, polypharmacy; SED, sedative/hypnotics; STM,
stimulants.
degree of intellectual disability, and ethnicity and race. Trends in prescribing practices appear
more variable; however, studies that have examined multiyear periods tend to report increas-
ing usage of antidepressants and antipsychotics, although not necessarily at as great a rate of
increase as seen in comparison to children without ASD from the same cohorts.
What conclusions about community use of psychotropics can be drawn from the extant
data? As described previously, maladaptive, sometimes severe, co-occurring behaviors are
common in ASD and may well merit pharmacological intervention. However, some devia-
tions from the available evidence base are notable. First, the common use of psychotropics
of all types in children with ASD younger than 5 years of age, despite the almost complete
absence of data on safety and efficacy of psychotropics in this age group, is a cause for con-
cern. The risk of harm in most cases would seem unacceptably high. Second, the continued
high rate of antidepressant use, especially the SSRIs, in children and adolescents—in some
samples approaching 50%—stands in the face of the limited support for efficacy and sen-
sitivity to adverse events reviewed previously. Clinicians should develop strong evidence
for the presence of an anxiety or depressive disorder comorbidity before instituting SSRIs.
Another concern is the not uncommon rate of polypharmacy within the same drug class
noted in some studies, despite this practice being summarily disapproved of in psychiatric
practice. Lastly, atypical antipsychotic usage is common. Although several members of this
class of drugs have solid support for their efficacy, long-term use has not been well stud-
ied with regard to safety, especially concerning tardive dyskinesia risk, as well as metabolic
and growth effects. It is reassuring that rates of tardive dyskinesia in children treated with
antipsychotics for 1 year are approximately half those seen in adults (0.4% vs. 0.8%, respec-
tively) (Correll & Kane, 2007). However, early antipsychotic use portends possible longer
exposures over the lifetime, and cross-sectional rates of tardive dyskinesia in children
have been reportedly as high as 38%, in contrast to results from the prospective studies.
Therefore, clinicians must continually re-evaluate the need for and benefits of antipsychotic
treatment against the ever-increasing risks associated with long-term exposure. They also
need to consider cautious tapering or discontinuation periods along with the possible sub-
stitution of safer alternatives, if necessary.
CASE STUDY #1: “FRED”
Fred is a 7-year-old boy with a prior diagnosis of autistic disorder who was brought to the
psychiatrist by his parents for evaluation and possible treatment of his difficult classroom
behavior and peer problems. His prior history was notable for initial concerns about speech
delay, lack of interest in peers, and limited play skills that first became evident by his limited
word use and lack of development of phrase speech by 24 months of age. A comprehen-
sive developmental assessment at 30 months of age led to a diagnosis of autistic disorder,
and Fred was subsequently placed in a 20-hour/week early intervention program. By parent
report, Fred made excellent progress during the next 3 years, especially in his impressive
increase of receptive and expressive language, so much so that he was able to enter a
mainstream kindergarten class 1 year prior to this evaluation. During his kindergarten year,
Fred received the support of a classroom aide. Academically, Fred reportedly did well, and
he stayed at grade level. Behaviorally, he required frequent prompting from his aide to stay
in his seat or with his group to persist with the classroom activities. Socially, Fred was well
accepted by his peers, but he often preferred more solitary activities on the playground dur-
ing recess. Even when joining play with other classmates was supported by the aide, even-
tually Fred would drift away from the group. At other times, he would become easily upset or
frustrated, and he would tantrum, which would alarm his peers. This year, his school district
no longer provided an aide, believing that Fred had become overly reliant on external support
and needed to develop better self-control. During the past 3 months, teachers had begun
to express concern that Fred’s learning was not keeping pace with the class and that his
frequent off-task behavior, self-stimming, and occasional tantrums were impairing his overall
progress. His parents are also worried about his social behavior: When they observe him at
school, he rarely seems to be included in play with others, and Fred has said that he has been
teased following some of his angry and tearful outbursts. Overall, especially at home when
he is allowed to play freely, his parents see Fred as usually happy, although minor frustra-
tions or deviations from some routines can provoke angry, brief protests. Teacher reports on
the Child Behavior Checklist show elevations on subscales of externalizing behaviors, with-
drawn/depressed, attention problems, social problems, and rule-breaking behavior. Parent
report on the Child Behavior Checklist showed elevations on subscales of social problems
and attention problems. Parent report on the Social Responsiveness Scale-2 was elevated,
consistent with ASD. On exam, Fred showed little eye contact, moved about the exam
room without exploring toys, and needed frequent repetition of questions. Repetitive move-
ments of his hands were observed. Mood appeared euthymic. The psychiatrist noted the
long-standing history of disruptive behaviors in addition to Fred’s prior diagnosis of ASD, and
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she suspected that the removal of the school aide had unmasked Fred’s difficulties in regu-
lating his behavior in a more structured environment compared to his home. She requested
parents and teacher complete the SNAP scale and the Aberrant Behavior Checklist. Both
parent and teacher SNAP ratings of ADHD symptoms were elevated compared to norms,
and the ABC-Hyperactivity subscale score was similarly increased. The diagnosis of ADHD
was made, and a trial of a stimulant, methylphenidate long-acting (methylphenidate-LA),
was prescribed at an initial dose of 10 mg each morning. After 1 week, the teacher reported
no change as based on SNAP ratings, but his parents noted some improvement at home
with sitting longer during meals and rated a 15% decrease on SNAP scores. An increase to
20 mg each morning was tried, with both teacher and parents endorsing improvement. An
additional week of 30 mg of methylphenidate-LA each morning was associated with mark-
edly reduced appetite, initial insomnia, and Fred seeming withdrawn at home. After Fred’s
dosage was reduced to 20 mg daily and monitored for the next 3 weeks, both teacher and
parent SNAP ratings showed declines from initial ratings of more than 50%, and Fred’s
schoolwork and cooperation were noticeably improved. Fred was also observed to be more
able to persist with play activities with peers during recess, and he began to describe his
interactions with particular students as friendly. He showed fewer emotional outbursts at
school. At home, Fred for the first time showed interest in exploring books and playing
games with his older brother. After 3 months, he remained improved. Blood pressure and
heart rate showed minor increases, and his weight had not changed.
CASE STUDY #2: FRED (CONTINUED)
Six years after his initial evaluation and institution of stimulant treatment, Fred’s parents con-
tacted the psychiatrist and requested an urgent appointment. Fred’s parents explained that
he had continued to do well overall while continuing the stimulant, enjoyed school and was
learning at grade level, and had made two friends that he had maintained for some time.
However, they reported that Fred entered middle school this year. In their view, the transi-
tion had been extremely challenging for him. The new school was much larger, and Fred
was no longer among as many children that he knew from elementary school. The require-
ment of multiple classrooms and teachers was also stressful for Fred to manage because
he had difficulty tracking classroom assignments and a heavier workload. Most concerning
to the parents was the emergence of emotional outbursts, occurring both at home and at
school. In response to minor upsets or frustrations, Fred was described as becoming loud,
screaming, and difficult to calm down. Sometimes if approached during an outburst, Fred
would lash out physically to push away or possibly strike out, and twice at school he had
been accused of knocking down another student. At home, his parents tried to manage the
behavior by ignoring and withdrawing themselves or Fred from the situation, but frequently
if Fred was left alone in his room to calm down, he would throw things or hit the wall with
his fists, and he had knocked three holes in his bedroom wall. The parents stated that
these outbursts initially occurred once or twice per week, but in the past month, they had
escalated to daily explosions of a significant degree. Parents had sought out an outpatient
therapist who had been advising them on strategies to manage these behaviors, but to no
avail. Additional history was pertinent for Fred’s refusal to maintain a regular sleep pattern.
He was staying up late at night. Although his parents noted that at times Fred could be
engaged in other activities and seem happy, they emphasized his volatile moods and quick
temper. Appetite was normal. Fred continued to show his interest in a particular video game
and two friends that shared his interest in the same game, but he had had several outbursts
while spending time with them. In interview, Fred acknowledged often feeling “mad” and
being easily upset. He did not express any remorse or guilt over the effects of his behaviors.
He said he disliked school and hoped he would be suspended. Activity level was normal,
occasional repetitive speech was noted, and he often returned to discussing his favored
video game. The parents completed an ABC scale, and Fred completed a Child Depression
Inventory with the psychiatrist. Parent ratings showed an elevated ABC-Irritability subscale
score =22; several depressive symptoms were endorsed by Fred but below clinical cut-
offs. Although several symptoms of major depressive disorder were noted, they lacked the
persistence and overall number to meet criteria for the disorder. The diagnosis of Mood
Disorder, Not Otherwise Specified was made, and the psychiatrist recommended treat-
ment with risperidone, starting at 0.5 mg each evening. After 1 week, some improvements
with increased sleep and reduced irritability were noted, but Fred reportedly had three
major outbursts. An increase in risperidone to 0.5 mg twice daily was made; then after 1
more week, due to complaints of daytime drowsiness and continued mood lability, this was
changed to 1.5 mg at bedtime. His parents noted much improvement overall, with temper
outbursts occurring much less frequently and with less intensity. They were often able to
avert outbursts by redirecting Fred or encouraging him to distract himself with a quiet activ-
ity. The ABC-Irritability subscale score dropped to 10—a 55% decrease. The psychiatrist
assisted the parents in obtaining an Individualized Education Plan in order to implement
accommodations at school to assist Fred’s acclimation and need for academic and social
support. After 6 months, the ABC-Irritability subscale score was 6, the AIMS score was 0,
fasting blood glucose was 90, and a lipid panel was normal except for elevated triglycerides,
but Fred had gained 10 pounds. The parents were instructed in dietary changes to reduce
high-caloric foods and drinks, to increase activity, and consider dose decreases of risperi-
done during the upcoming summer school break.
ASSESSMENTS FOR TREATMENT PLANNING AND MONITORING
A positive development in the field of ASD treatment is the emerging consensus for appro-
priate measures of behaviors often considered as possible treatment targets. The standard of
care has evolved to now mandate careful attempts to document need for treatment and treat-
ment outcomes. Fortunately, a number of readily available and easily obtained measures can
be applied in clinical settings. Several of these are “broad-band,” meaning that they capture
a wide range of possible and common behaviors; others are “narrow-band” assessments of
particular dimensions of behavior, such as disruptive or ADHD-like symptoms. Those most
commonly employed measures in clinical treatment studies are shown in Table 16.2.
TABLE 16.2 Assessment and Monitoring Measures for Pharmacotherapy in Autism Spectrum Disorder
Measure Type Domain(s) Content Administration Scoring Reference Strengths/weaknesses
Broad
Clinical Global Overall severity of core + Clinician (using all 1–7 (not ill— Guy (1976) Widely used, ease of use,
Impression-Severity associated behaviors available information) extremely ill) treatment sensitive
(CGI-S)
Clinical Global Overall change observed Clinician (using all 1–7 (very much Guy (1976) Widely used, ease of use,
Impression– with treatment available information) improved— treatment sensitive
Improvement (CGI-I) very much worse)
Aberrant Behavior Measures core and Parent, caregiver, and Items scored 0–3 Aman, Singh, Widely used in clinical trials,
Checklist–Community associated behaviors teacher report; Stewart, and drug sensitive, ease of use
Version (ABC-CV) across five factors 58 items Field (1985) and scoring, norms and
comparative data, multiple
translations
Child Behavior Checklist Broad measure of Parent, teacher, and Items scored 0–2 Achenbach and Widely used in child mental
(CBCL) psychopathology; self-report Edelbrock (1983) health, not developed for
subscales relate to (high functioning intellectually disabled
diagnostic groups + adolescents + adults) populations, not commonly
social competence used as a treatment measure
Behavior Problems Measure of common Parent, caregiver, and Frequency 0–4 Rojahn et al. Ease of use, appropriate for
Inventory–Short Form maladaptive behaviors teacher report on 30 (never—hourly); (2012) population, few tests of
(BPI-S) in intellectual items; three subscales Severity 0–3 (no treatment sensitivity
disability of SIB, Stereotypy, problem—severe)
Aggressive/Destructive
behaviors
Pervasive Developmental Broad measure of core Parent (188 items), Scored 0–4 (never— Cohen and Breadth of symptoms, age
Disorder Behavior and associated teacher (180 items); often) Sudhalter (2005) norms, limited use in
Inventory (PDDBI) maladaptive behaviors nine domains intervention studies, lengthy
in ASD
Child and Adolescent Multiple DSM cardinal Parent and teacher Scored 0–3 Gadow and Utility and validity in assessing
Symptom Inventory–4R symptoms report (never—very often) Sprafkin (2005) categories of behavior,
(CASI-4R) subscales may be suitable for
monitoring (e.g., anxiety)
Narrow
Anxiety Depression and Mood and anxiety Parent, teacher, and Scored 0–3 (not a Esbensen, Rojahn, Evidence for validity
Mood Scale (ADAMS) symptoms clinician report on 28 problem— Aman, and
items very much) Ruedrich (2003)
Swanson, Nolan, and Disruptive behaviors Parent and teacher report Scored 0–3 (not at Swanson et al. Ease of use and scoring, drug
Pelham, version IV (40 items) keyed to all—very much) (2001) sensitive, norms
(SNAP-IV) DSM ADHD,
Oppositional Defiant
Disorder
Pervasive Developmental Compulsive, repetitive Clinician rated Compulsion items Scahill et al. Demonstrated
Disorder Children’s behaviors rated 0–4 on severity (2006) reliability
Yale–Brown Obsessive
Compulsive Scale (PDD
CYBOCS)
Repetitive Behavior Repetitive, stereotypic Parent and caregiver Scored 0–3 (does Bodfish, Symons, Reliable, may be
Scale–Revised (RBSR) behaviors report not occur—severe and Lewis (1999) treatment sensitive
problem)
ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; DSM, Diagnostic and Statistical Manual of Mental Disorders; SIB, self-injurious
behavior.
292 / / T reatment
EMERGING THERAPIES
Significant efforts are underway to identify pharmacologic treatments that target core symp-
toms of autism. Preclinical investigation in rodent models of autism and fragile X syndrome
(FXS), a monogenic disorder with considerable overlap with ASDs, has identified abnormal
balance of synaptic inhibitory and excitatory signaling in brain circuits as a key target for
therapeutic intervention (Delorme et al., 2013). This work prompted a recent randomized,
double-blind, placebo-controlled crossover trial of the GABAB receptor agonist arbaclofen
in 63 subjects with FXS, aged 6–39 years, with mixed results (Berry-Kravis et al., 2012).
Although the drug showed no difference from placebo on the trial’s primary endpoint, the
ABC-Irritability subscale, secondary analyses indicated a significant treatment effect on the
ABC-Social withdrawal subscale. In an 8-week open-label study of 32 children and adoles-
cents with ASD, arbaclofen was well tolerated and significantly reduced irritability (primary
endpoint), as well as measures of social withdrawal, hyperactivity, and repetitive behaviors,
among others. The loop diuretic and chloride antagonist bumetanide is another GABA-
activating agent that has been recently investigated in autism (Lemonnier et al., 2012). In a
3-month, randomized, double-blind, placebo-controlled trial of 60 children with ASD, the
treatment group showed significant improvement on the Childhood Autism Rating Scale
(primary endpoint), as well as clinical impression (77% response to drug vs. 33% response
to placebo). Replication and extension of these studies of GABAergic agents in autism are
warranted and, in some cases, are currently underway (NCT01966679).
Recent work has identified excessive glutamatergic signaling as a potential target for
therapeutic intervention in autism (Delorme et al., 2013). Extensive preclinical evi-
dence has demonstrated that blockade of metabotropic glutamate receptor 5 (mGluR5)-
mediated signaling can reverse neural abnormalities in animal models of FXS and autism.
However, a randomized, double-blind, placebo-controlled crossover trial of the mGluR5
antagonist AFQ056 in 30 adults with FXS found no treatment effect on the ABC scale
(primary endpoint) ( Jacquemont et al., 2011). Studies of other glutamatergic antago-
nists in autism have included memantine, an NMDA receptor antagonist FDA-approved
for Alzheimer’s dementia, which has shown promise in several open-label studies and
case reports and has been generally well tolerated (Doyle & McDougle, 2012). An
open-label, add-on study of memantine addition to ongoing psychotropic treatments in
151 subjects with ASD aged 2–26 years showed significant improvement in language,
behavior, and self-stimulatory behaviors with 82% of subjects continuing the medication
during a 21-month follow-up period (Chez et al., 2007). The only published randomized,
double-blind, placebo-controlled clinical trial showed that memantine addition to risper-
idone was superior to risperidone plus placebo for irritability, hyperactivity, and stereo-
typic behavior in 40 children with autism during a 10-week period (Ghaleiha et al., 2013).
However, an unpublished randomized, placebo-controlled clinical trial of memantine in
104 children and adolescents with autism failed to show a treatment effect on the Social
Responsiveness Scale (SRS; primary endpoint) during 12 weeks (NCT00872898). Based
on these results, several additional clinical trials are currently underway.
Finally, there has been considerable recent interest in the use of oxytocin and vasopres-
sin as potential therapeutic interventions for ASD. Oxytocin and vasopressin are highly evo-
lutionarily conserved endogenous neuropeptides integrally involved in the development
of social affiliative behaviors and the regulation of social cognition (Meyer-Lindenberg,
Domes, Kirsch, & Heinrichs, 2011). Genetic variation in the neural receptors for oxyto-
cin and vasopressin has been linked to autism, and decreased levels of these hormones
have been reported in patients (Meyer-Lindenberg et al., 2011). Studies of oxytocin in
autism are limited by the drug’s short half-life and difficulty crossing the blood–brain bar-
rier, requiring frequent intranasal dosing to maintain therapeutic levels. Several small, ran-
domized, double-blind, placebo-controlled studies involving single intravenous infusions
of oxytocin have been conducted on subjects with autism, with demonstrated efficacy on
repetitive behaviors (Hollander et al., 2003), emotion recognition (Guastella et al., 2010),
and affective speech comprehension (Hollander et al., 2007). However, two recent trials
with repeated intranasal dosing schedules have shown mixed results. In a randomized,
double-blind, placebo-controlled trial of 38 adolescents with ASD, daily dosing of oxyto-
cin for 4 consecutive days failed to show an effect compared with placebo on a range of
measures, including emotional recognition, social interaction skills, and general behavioral
adjustment (Dadds et al., 2014). In a 6-week randomized, double-blind, placebo-controlled
trial involving 19 adults with ASD, twice-daily dosing of intranasal oxytocin did not dif-
fer from placebo on primary outcome measures of social cognition, social function (30%
responders in treatment group vs. 10% placebo), or repetitive behaviors. However, oxyto-
cin was well tolerated and did show efficacy on some secondary measures, including social
perception and quality of life (Anagnostou et al., 2012).
SUMMARY
An evidence base to guide the safe and effective use of medications as adjunctive treatments
in ASD has been growing rapidly. For several targeted behaviors, especially irritability and
aggression, hyperactive–impulsive symptoms, and sleep problems, clinicians can rely on
several treatment approaches that have been well-established through positive controlled
studies. When faced with other common ASD-associated behaviors such as RRBs, social
and communication impairments, and anxiety/depression, clinicians lack solid evidence on
which medication to choose as the most appropriate and effective intervention. As empha-
sized previously, careful assessment is crucial to accurately identifying the underlying nature
of the presenting behavioral problems. Clinicians need to be prepared to discuss these chal-
lenging clinical situations openly with parents and patients and to resist the common com-
munity practice of “adding on” multiple medications in the face of inadequate responses.
A careful stepwise empirical approach with extensive monitoring of targeted symptoms is
key to the evaluation of ongoing treatment response and to minimize untoward effects of
pharmacotherapy. Pharmacological treatment should always be viewed as one component
of a broader, comprehensive treatment plan that augments other educational, behavioral,
and social interventions. Substantial gaps in information still exist for ASD, especially for
effectively treating mood and anxiety symptoms. Emerging medication treatments hold the
promise of addressing the core symptoms of ASD, based on a growing appreciation of dis-
rupted molecular pathways that may be causative. The use of widely available clinical tools
for monitoring response and side effects should be considered a part of standard practice.
KEY POINTS
• Although the use of medications in the management of ASD is becoming increas-
ingly common, available therapeutics are symptom-based and do not modify disease
trajectory.
• No current medications have consistently shown major benefits on the core social
and communication deficits of ASD.
294 / / T reatment
• The only FDA-approved medications for ASD are the antipsychotics risperidone and
aripiprazole, which are effective for irritability, hyperactivity, and possibly repetitive
behaviors; the use of all other psychotropics is considered “off-label.”
• Stimulants, especially methylphenidate, and α2 agonists, especially guanfacine, are
effective for co-occurring hyperactive, inattentive, and impulsive symptoms in ASD.
• The use of widely available clinical tools for monitoring response to medication and
side effects should be considered a part of standard practice.
ACKNOWLEDGMENTS
Support for preparation of this chapter was provided by grant UA3 MC 11055 AIR-B from
the Maternal and Child Health Research Program, Maternal and Child Health Bureau
(Combating Autism Act Initiative), Health Resources and Services Administration, US
Department of Health and Human Services, grant 2P50 HD055784-06 from the National
Institute of Child Health and Human Development, and grant 1R01MH083747-01A2
from the National Institute of Mental Health.
Dr. James T. McCracken has received consultant income from Roche and DART
Neuroscience, and research contract support from Roche.
Dr. Michael Gandal has no financial interests to disclose.
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17 / / / COMPLEMENTARY AND
ALTERNATIVE (BIOMEDICAL)
TREATMENTS FOR AUTISM
SPECTRUM DISORDER
ROBERT L. HENDREN
INTRODUCTION
The National Center for Complementary and Alternative Medicine (NCCAM) has
referred to complementary and alternative medicine (CAM) as a group of diverse medi-
cal and health care systems, practices, and products that are not generally considered to
be part of conventional medicine. More recently, NCCAM refers to CAM as an array of
health care approaches with a history of use or origins outside of mainstream medicine
(NCCAM, 2008) and divides CAM into natural products and mind and body practices.
However, NCCAM notes that some approaches, such as the practices of traditional healers,
Ayurvedic medicine from India, traditional Chinese medicine, homeopathy, and naturopa-
thy, may not fit neatly into either of these groups. This chapter focuses primarily on natural
products but briefly reviews mind/body practices as potential therapeutic approaches in
autism spectrum disorder (ASD).
The list of potential biomedical CAM treatments is long, and most have inadequate
evidence to judge potential efficacy. See Box 17.1 for a list of most of the biomedical/CAM
treatments for ASD. Three comprehensive reviews of these treatments with some efficacy
data have been published (Cheng, Widjaja, Choi, & Hendren, 2013; Hendren, 2013;
Lofthouse, Hendren, Hurt, Arnold, & Butter, 2012). In this chapter, the biomedical CAM
treatments that have the most published evidence, that have generated the greatest inter-
est, and/or that nonetheless have significant promise for treating ASD or ASD-associated
symptoms are briefly discussed. These treatments include melatonin, omega-3 fatty acids,
injectable methylcobalamin (methyl B12), N-acetylcysteine (NAC), memantine, pancreatic
digestive enzymes, probiotics, micronutrients, and immune therapies.
Twelve percent of children and adolescents in the United States use CAM (Birdee,
Phillips, Davis, & Gardiner, 2010). Up to 70% of children with ASD are reported to be
using some form of biological treatment (Wong & Smith, 2006). Twenty-eight to 82% of
children recently diagnosed with ASD use CAM. The main reasons for choosing CAM
301
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BOX 17.1
POTENTIAL CAM BIOMEDICAL TREATMENTS OF
Acupuncture
Amino acids
Animal-assisted therapy
Antibiotics
Antifungals (fluconazole (Diflucan), nystatin)
Antiviral (valacyclovir hydrochloride (Valtrex))
Auditory integration therapy (music therapy)
Chelation
Chiropractic
Cholestyramine
Coenzyme Q10
Craniosacral therapy
Curcumin
Cyproheptadine
Dehydroepiandrosterone (DHEA)
Digestive enzymes
Dimethylglycine (DMG), trimethylglycine (TMG)
Fatty acids (omega-3)
Folic/folinic acid
Glutathione (GSH)
Gluten-free casein-free (GFCF) diet
Food-allergy treatment
5-Hydroxytryptophan
Hyperbaric oxygen treatment
Infliximab (Remicade)
Immune therapies
Intravenous Immune Globulin (IVIG)
Iron
l-Carnosine
Magnesium
Melatonin
Methylcobalamin (methyl B12)
N-acetylcysteine (NAC)
Naltrexone
Neurofeedback
Oxalate (low) diet
Oxytocin
Complementary and Alternative (Biomedical) Treatments for Autism Spectrum Disorder // 303
Pioglitazone hydrochloride (Actos)

Probiotics
Pyridoxal phosphate
Ribose and dehydroepiandrosterone
S-adenosyl-methionine
Secretin
Sensory integration therapy
Specific carbohydrate therapy
St. John’s wort
Steroids
Transfer factor
Vitamin A
Vitamin B3
Vitamin B6 with magnesium
Vitamin C
Zinc
Source: Hendren (2013).
given by parents are related to concerns with the safety and side effects of prescribed medi-
cations (Hanson et al., 2007), but there is concern that traditional physicians are not famil-
iar with CAM.
CAM might be better named as it is becoming less likely to refer to assessments and
treatments that are complementary, alternative, or where there are not published studies
to consider. Often, integrative medicine is placed in the CAM category, as are biomedi-
cal treatments, in large part because historically they have not been well studied and the
evidence for their efficacy is limited. However, this is changing as medicine is increasingly
studying nutritional or nutraceutical treatments for cancer, vascular disease, and, recently,
central nervous system disorders. In part, the scientific basis for this shift is the increasing
evidence for gene–environment interactions as key to understanding the endophenotype
and phenotype of medical disorders.
ASD clearly has a genetic basis. Multiple genes have been identified, and a clear genetic
etiology accounts for as many as 25% of cases of ASD. It also appears that for the majority,
hundreds of genetic mutations, some de novo, lead to many ways to develop ASD (Iossifov
et al., 2012; Levy et al., 2011; Miles, 2011; Murdoch & State, 2013). A number of recent
studies have concluded that it is the gene–environment interaction that provides the best
explanation for the etiology of ASD. Susceptibility to ASD has moderate genetic herita-
bility and a substantial shared twin environmental component (Hallmayer et al., 2011).
Polygenic models exist in which spontaneous coding mutations in any of a large num-
ber of genes increase risk for ASD by 5- to 20-fold (Neale et al., 2012). Among children
born in Sweden, the individual risk of ASD increased with increasing genetic relatedness.
Heritability of ASD and autistic disorder was estimated to be approximately 50% (Sandin
et al., 2014).
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What are these environmental contributors that add to genetic risk and lead to ASD?
Documented environmental contributors to ASD include prenatal or early postnatal expo-
sure to viral infections (rubella), valproic acid, and thalidomide (Herbert, 2010; Landrigan,
2010). There is increasing evidence for the contribution of parental age (Durkin et al., 2008;
Frans et al., 2013; Herbert, 2010; Shelton, Tancredi, & Hertz-Picciotto, 2010), maternal
metabolic conditions (Krakowiak et al., 2012), influenza or fever during pregnancy (Zerbo
et al., 2013), environmental pollution (Schuler, 2013), and epigenetics (Hagerman &
Hendren, 2014).
This epigenetic or gene expression approach is leading to a paradigm shift in thinking
about disorders to the point where we are now considering whole body systems rather than
a single organ in the etiology and treatment of disordered development. Epigenetics refers
to the reversible regulation of various genomic functions, independent of DNA sequence,
mediated principally through DNA methylation, chromatin sequence, and RNA-mediated
gene expression ( Jaenisch & Bird, 2003). The related endophenotypes (measurable com-
ponents along the epigenetic pathway between the genotype and the distal symptom,
personal characteristic, or phenotype) are simple biologic aspects of a disease that can
be observed in people with a similar endophenotype at a higher rate than in the general
population (Saresella et al., 2009) and that are potentially reversible through nutrition,
social factors, behavioral interventions, and drugs (Rutten & Mill, 2009). Finding ways
to improve this epigenetic interaction during the disease process using health-enhancing
strategies found in CAM or biomedical approaches through interventions such as dietary
supplements or nutraceuticals is increasingly attractive.
Assessment is based on understanding the elements of gene expression, not just DNA
and symptoms. Treatment is based on targeting processes rather than a diagnosis, and
there is increasing interest in studying biomarker targets (Hagerman & Hendren, 2014;
Insel, 2014).
Significant subsets of children with ASD have an endophenotype of intestinal inflam-
mation, digestive enzyme abnormalities, metabolic impairments, oxidative stress, mito-
chondrial dysfunction, and immune problems, which range from immune deficiency to
hypersensitivity and autoimmunity (Box 17.2). In many cases, improvement of autistic
symptoms is achieved by a combination of nutritional recommendations, prescription
medications, and addressing the underlying medical conditions seen in these children
(Frye & Rossignol, 2014; Hagerman & Hendren, 2014; Mumper, 2012). For instance, a
BOX 17.2
EPIGENETIC PROCESSES IN AUTISM SPECTRUM DISORDER
• Immune abnormalities/inflammation (Goines & Van de Water, 2010)

• Oxidative stress (James et al., 2009)
• Disturbed methylation (James et al., 2009)
• Mitochondrial dysfunction (Frye & Rossignol, 2011; Manji et al., 2012)
• Free fatty acid metabolism (Bell et al., 2010)
• Excitatory/inhibitory imbalance (Rubenstein, 2010)
• Hormonal effects (Harony & Wagner, 2010)
• Microglia (Cunningham, Martinez-Cerdeno, & Noctor, 2013)
subset of children with ASD have mitochondrial dysfunction, which can be inherited or
acquired. Evidence links oxidative stress, mitochondrial dysfunction, and immune dysregu-
lation/inflammation to brain regions involved in speech and auditory processing and social
behavior (Rossignol, Genuis, & Frye, 2014). Treatments used for mitochondrial disease
(l-carnitine, multivitamins with B vitamins, antioxidants, vitamin E, coenzyme Q10, vita-
min C, methyl B12, NAC, ubiquinol, and carnosine), all thought of as CAM treatments,
have demonstrated significant improvements in ASD (Frye, Sequeira, Quadros, James, &
Rossignol, 2013).
There are a number of reasons why CAM/biomedical treatments have not been well
studied (Bent & Hendren, 2010), including the following:
1. Most treatments have a small effect requiring a large sample size.

2. The trials have been of relatively short duration.
3. ASD is a heterogeneous disorder.
4. Few biomarkers used for subject inclusion in studies have been validated.
5. The need to hold other treatments constant during the study period in order to show
an effect may present ethical concerns.
6. Blinding is often a challenge.
7. There is formulation variability.
8. Institutional review boards typically have concerns about CAM treatments.
9. Funding is often challenging because many of these treatments would not be eligible
for patents, making them less desirable to pharmaceutical companies.
Nevertheless, there are an increasing number of studies of potential biomarkers that might
be used for assessment and outcome measures for treatment studies of compounds that
have traditionally been thought of as CAM.
ASSESSMENT
The strongest evidence for biomarkers in the assessment of ASD continues to be routine
laboratory tests, most of which have a low yield (Goldani, Downs, Widjaja, Lawton, &
Hendren, 2015). These include a metabolic panel that includes glucose and liver function
tests and a compete blood count with differential and platelet count. Increasingly, prac-
titioners interested in taking more of an integrative medicine approach (especially when
supported by the history and physical) will include magnesium, selenium, zinc/copper,
vitamin C, vitamin D3 (usually 1,25(OH)), fat-soluble vitamins, ferritin, total iron, total
iron binding capacity, percentage iron saturation, lead screening, serum amino and urine
organic acids, cholesterol (lipid panel if indicated), red blood cell folate, and vitamin B12
(Boxes 17.3–17.5).
CAM/BIOMEDICAL TREATMENTS
Melatonin
Melatonin is an endogenous neurohormone that causes drowsiness, establishes circadian

rhythms and synchronization of peripheral oscillators, and is produced from serotonin
(Tordjman et al., 2013). It has been suggested that melatonin may also benefit social
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BOX 17.3
POSSIBLE OXIDATIVE STRESS BIOMARKERS
• Glutathione—reduced/oxidized
• Methionine
• Cysteine
• Organic acid test—α-hydroxybutyrate, pyroglutamate, and sulfate
• Plasma F2t-isoprostanes (F2-IsoPs)
• Urine 8-OHdG
• Transferrin
• Ceruloplasmin
• Plasma 3-chlortyrosine (3CT)
• 3-Nitrotyrosine (3NT)
BOX 17.4
POSSIBLE MITOCHONDRIAL FUNCTION BIOMARKERS
• Lactate
• Pyruvate
• Lactate:pyruvate ratio
• Carnitine (free and total)
• Alanine
• Quantitative plasma amino acids
• Ubiquinone
• Ammonia
• CD
• AST/ALT
• CO2
• Aspartate aminotransferase
• Serum creatine kinase
communication impairments and stereotyped behaviors or interests (Tordjman et al.,

2013). A review and meta-analysis of 35 studies reported that of 18 treatment studies, there
were 5 randomized controlled trials (RCTs) (N = 61, 2–10 mg/day) in which sleep dura-
tion was increased (44 min, Effect size [ES] = 0.93), sleep onset latency was decreased (39
min, ES = 1.28), but nighttime awakenings were unchanged (Rossignol & Frye, 2011). The
duration of the studies varied between 4 weeks and 4 years. One study indicated a loss of
benefit at 4 weeks, whereas a study of 4 years reported continued benefits. Side effects were
minimal to none (Table 17.1).
BOX 17.5
POSSIBLE IMMUNE/INFLAMMATORY BIOMARKERS
Subjects With Autism Spectrum Disorder

• TGF-β
• CCL2
• CCL5
• IGM
• IgG
• Th1/Th2
• Neopterin
• S110B protein
• Anti-ganglioside M1 antibodies
• Antineuronal antibodies
• Serum antinuclear antibodies
• BDNF
• C-reactive protein
• Cytokines
Mothers of Subjects With Autism Spectrum Disorder

• IFN-γ
• IL-4
• IL-5
• IL-6
Melatonin is one of the best studied CAM/biomedical treatments of ASD. Although

small sample sizes, variability in sleep assessments, and lack of follow-up limit the value of
these studies in supporting its use, treatment with melatonin has a clear physiologic ratio-
nale, and it is easy to use, inexpensive, and safe.
Vitamin D
The “ecological evidence” for the role of vitamin D in the etiology of ASD is mostly anec-
dotal and includes speculation that the incidence of ASD may be higher in northern
latitudes, where there is more rainfall, and in those with greater skin pigment in low sun-
light areas (Cannell, 2013). Low levels of vitamin D are reported in the pediatric popu-
lation, but especially so among children with ASD (Cannell, 2013). Vitamin D activates
a serotonin-synthesizing gene (Patrick & Ames, 2014) and is a “potent neurosteroid”
(McGrath, Feron, Eyles, & Mackay-Sim, 2001). There are no published studies of vitamin
D treatment of ASD, but therapeutic doses are commonly given, especially if the 25(OH)
D level is at or below 30 ng/mL.
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TABLE 17.1 Biomedical Therapeutic Strategies
Immune/Inflammation Oxidative Stress

Melatonin Glutathioned
IV/IG Methyl B12e
Curcuminf—anti-inflammatory and antioxidant activity
Corticosteroids Neurotransmitter Production
Tetrahydrobioptering
Celecoxib: RCT for irritability, Rivastigmineh—parasympathomimetic or cholinergic agent
withdrawal, and stereotypy a
Galantaminei—acetylcholinesterase inhibitor
Methylation GABA
Folic/folinic acidb Arbaclofenj (STX209)
Mitochondrial Functionc Bumetanidek—diuretic
Carnitine Glutamate
Coenzyme Q10 Riluzolel—used to treat amyotrophic lateral sclerosis
Vitamin C d-Cycloserinem—partial agonist of the neuronal NMDA receptor
Lipoic acid
Pantothenate
Vitamin E
l-Carnosine
a
Asadabadi et al. (2013).
b
Surenet al. (2013).
c
Rossignol and Frye (2012).
d
Kern et al. (2011).
e
Bertoglio et al. (2010).
f
Darvesh et al. (2012).
g
Frye, Delatorre, et al. (2013).
h
Chez et al. (2004).
i
Nicolson, Craven-Thuss, and Smith (2006).
j
Wang et al. (2011).
k
Hadjikhani et al. (2015).
l
Wink, Erickson, Stigler, and McDougle (2011).
m
Posey et al. (2004).
IVIG, intravenous immunoglobulin; NMDA, N-methyl-d-aspartate; RCT, randomized controlled
trial.
Hyperbaric Oxygen Treatment
Although some uncontrolled and controlled studies have suggested that hyperbaric oxygen
treatment (HBOT) is effective for the treatment of ASD, these promising effects have not
been replicated (Ghanizadeh, 2012). Two negative RCTs have been reported (Granpeesheh
et al., 2010; Jepson et al., 2011).
One open-label study of change in cytokines as a possible mechanism for the benefit
of HBOT included 10 children with ASD who underwent 80 sessions at 1.5 atmospheres
absolute and 100% oxygen (Bent, Bertoglio, Ashwood, Nemeth, & Hendren, 2012). Nine
of 10 parents reported that their child was “much improved” or “very much improved,”
and they reported improvements in irritability, lethargy, hyperactivity, aggressiveness, and

learning and memory. However, enrolled children did not exhibit abnormal cytokine levels
at baseline, and no significant changes in mean cytokine levels were observed. Study raters
did not report improvements. The evidence at this point does not support the use of HBOT
for the treatment of ASD.
Methylcobalamine
Methylcobalamine (Methyl B12) is a vital cofactor for the regeneration of methionine

from homocysteine by providing methyl groups for metabolic pathways involving trans-
methylation and transsulfuration. Reduced activity in the transsulfuration pathway can
lead to reduced levels of cysteine and glutathione (GSH), which are crucial antioxi-
dants responsible for minimizing macromolecular damage produced by oxidative stress.
Metabolic biomarkers of increased oxidative stress and impaired methylation capacity
have been reported in children with ASD ( James et al., 2004). One study that included
30 patients with ASD in a 12-week double-blind, crossover trial of methyl B12 admin-
istered subcutaneously (SubQ) in the buttocks at a dosage of 67.5 μg/kg every 3 days
for 6 weeks found no statistically significant mean differences in behavioral outcome
measures or in glutathione status between active and placebo groups. Minor trauma
from SubQ injections and increased hyperactivity were the only side effects reported.
Nine patients demonstrated clinically significant improvement on the Clinical Global
Impression–Improvement scale (CGI-I) and at least two additional behavioral measures.
Responders exhibited significantly increased plasma concentrations of GSH and sig-
nificantly increased GSH:glutathione disulfide ratio (Bertoglio, James, Deprey, Brule, &
Hendren, 2010).
In a study from the same group, 53 newly recruited children with ASD between the ages
of 3 and 7 years were randomly assigned to 8 weeks of treatment with methyl B12 at 75 μg/kg
or placebo given SubQ every 3 days. The mean CGI-I at 8 weeks showed significantly more
improvement in the methyl B12 group compared to the placebo group. Improvement on the
CGI-I was significantly correlated with methionine, decreases in S-adenosylhomocysteine
(SAH), and an increase in the S-adenosylmethionine (SAM/SAH) ratio (Hendren et al.,
2015). Although these initial studies are promising for a subgroup of children with ASD,
and SubQ methyl B12 supplementation seems to be safe and well tolerated, additional study
is needed to determine whether this will become a recommended treatment for ASD.
N-Acetylcysteine
N-Acetylcysteine (NAC) is a glutamatergic modulator and an antioxidant. In a 12-week

randomized double-blind, placebo-controlled study of NAC in 33 children with ASD (3.2–
10.7 years), the compound resulted in significant improvement compared to placebo on
the Aberrant Behavior Checklist–Irritability subscale (ABC-I). NAC was initiated at 900
mg daily for 4 weeks, increased to 900 mg twice daily for 4 weeks, and then increased again
to 900 mg three times daily for 4 weeks. Oral NAC was well tolerated with limited side
effects (Hardan et al., 2012). The results are promising, especially because the supplement
is well tolerated and many current treatments for irritability in ASD are associated with
significant side effects. This study will need to be replicated before recommendations can
be offered, however.
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Omega-3 Fatty Acids
Omega-3 fatty acids are a type of polyunsaturated fatty acid (PUFA); they are long-chain
orthomolecules that are essential for brain health and growth and that aide in synaptic
plasticity and neuroprotection (Freeman et al., 2006). They are a critical component
of neuronal membranes, essential for their optimal functioning. They also serve as sub-
strates for the production of the eicosanoids, such as prostaglandins, which are neces-
sary for cell communication and immune regulation. The two omega-3 fatty acids of
primary interest are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
Based on data from studies of other disorders, these fatty acids might be expected to
improve mood, attention, and activity level, as well as—conceivably—core symptoms
of ASD. Low levels of omega-3 fatty acids have been reported in children with ASD (Bell
et al., 2004; Meguid, Atta, Gouda, & Khalil, 2008; Vancassel et al., 2001). Published evi-
dence in support of the clinical benefit for ASD is limited, however (Bent, Bertoglio, &
Hendren, 2009).
In one study, children aged 3–8 years with ASD were randomly assigned to 12 weeks of
omega-3 fatty acids (1.3 g/day) or placebo. Hyperactivity improved more in the omega-3
group compared to the placebo group, but not to a statistically significant level. Correlations
were found between decreases in five fatty acid levels and decreases in hyperactivity (Bent,
Bertoglio, Ashwood, Bostrom, & Hendren, 2011).
A recent study was conducted via the Internet and included 58 subjects with ASD and
also teacher ratings. The results showed that omega-3 fatty acids led to a greater improve-
ment on the ABC–Hyperactivity subscale score compared to placebo, but again, not to a
statistically significant degree. The sample size of the study was not powered to determine
the efficacy of omega-3 fatty acids with confidence (Bent et al., 2014).
In addition to the previously mentioned studies, there have been four open-label tri-
als (Meguid et al., 2008; Meiri, Bichovsky, & Belmaker, 2009) and two randomized
double-blind, placebo-controlled pilot trials of omega-3 fatty acids in children with ASD
(Amminger et al., 2007; Johnson, Handen, Zimmer, & Sacco, 2010). Amminger and col-
leagues randomized 13 children with ASD (aged 5–17 years) to EPA 840 mg/day and
DHA 700 mg/day (n = 7) or placebo (n = 6) for 6 weeks. There were no significant differ-
ences between groups on the ABC, possibly because of the small sample and insufficient
power. Omega-3 fatty acids seemed nominally superior to placebo for the ABC subscales
for stereotypy, hyperactivity, and inappropriate speech.
Despite the weak evidence and the modest effect, there is some rationale for the use of
omega-3 fatty acids in ASD, and they are easy to use, inexpensive, and safe.
Cerebral Folate Deficiency
A high prevalence (75%) of folate receptor-α autoantibodies (FRAs) is found in sub-

jects with ASD. FRAs are autoantibodies that prevent folic acid from entering the
brain. Improvement in ASD symptoms with high-dose folinic acid (2 mg/kg/day;
maximum 50 mg/day in two divided doses) was found in a 12-week trial in children
with ASD. There is the possibility that this treatment improves mitochondria func-
tion, specifically the ability of the mitochondria to be resilient against oxidative stress
in this population (Frye, Sequeira, et al., 2013; Ramaekers, Quadros, & Sequeira,
2013). Although promising, this study needs to be replicated for FRAs to become
routinely considered.
Vitamin Mineral Supplement
Although multivitamin and mineral levels generally are not found to be abnormal in chil-
dren with ASD, biomarkers of general nutritional status have been reported to be associ-
ated with the severity of ASD (Adams et al., 2011b). An RCT of an oral vitamin/mineral
supplement was given for 3 months to 141 children and adults with ASD and was found
to improve the nutritional and metabolic status of children with ASD, including improve-
ments in methylation, glutathione, oxidative stress, sulfation, ATP, NADH, and NADPH.
The supplement group had significantly greater improvements compared to the placebo
group on the Parental Global Impression–Revised Average Change, Hyperactivity, and
Tantrumming scale (Adams et al., 2011a).
Diet
Inconsistencies between parent reports and the results of clinical trials are reported for a
gluten-free casein-free (GFCF) diet in children with ASD, with no RCT showing benefit
(Cheng et al., 2013). Several studies suggest a relationship between non-celiac gluten sen-
sitivity (NCGS) and ASD (Catassi et al., 2013). Detailed metabolic screening in a Greek
cohort of ASD patients revealed biomarkers (urine 3-hydroxyisovaleric acid and serum
β-hydroxybutyrate) in 7% (13/187) of patients with ASD for whom biotin supplementa-
tion or institution of a ketogenic diet resulted in mild to significant clinical improvement in
autistic features (Spilioti et al., 2013). The Specific Carbohydrate Diet has been anecdot-
ally shown to improve symptoms of ASD, and an RCT is underway (Autism Network for
Dietary Intervention, 2014; Catassi et al., 2013; Cheng et al., 2013; Spilioti et al., 2013).
Other Vitamin and Mineral Treatments
A number of other vitamin and mineral treatments are thought by some to benefit ASD,
but studies have been inconclusive or limited. These include B6/magnesium, folic acid,
iron, l-carnosine, ascorbic acid, zinc and copper, and inositol. Further discussion of these
potential treatments can be found in more extensive reviews (Cheng et al., 2013; Lofthouse
et al., 2012).
Microbiome
The human microbiome (or human microbiota) is the aggregate of the ecological commu-
nity of commensal, symbiotic, and pathogenic microorganisms that reside on the surface
and in deep layers of skin, in saliva and oral mucosa, in conjunctiva, and in the gastrointesti-
nal (GI) tract. They include bacteria, fungi, and archaea. Some of these organisms perform
tasks that are useful for the human host, but their functions are poorly understood.
Probiotics
Probiotics (consisting of microorganisms thought to improve digestive health by repopu-

lating the GI tract with favorable flora) have also been proposed to improve digestion and
gut–brain activity in children with ASD. Some proponents suggest that these agents may
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also help remove toxins and improve immune function (Critchfield, Van Hemert, Ash,
Mulder, & Ashwood, 2011). A recent study, using the maternal immune activation (MIA)
mouse model that displays features of ASD, demonstrated GI barrier defects and microbiota
alterations. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis
(a probiotic) corrected gut permeability; altered microbial composition; and ameliorated
defects in communicative, stereotypic, anxiety-like, and sensorimotor behaviors. This sup-
ports a gut–microbiome–brain connection in a mouse model of ASD and identifies a poten-
tial probiotic therapy for GI and particular behavioral symptoms (Hsiao et al., 2013). There
are no reported trials of probiotics in persons with ASD, but use is common and safe.
Pancreatic Digestive Enzymes
Enzyme deficiencies in some children with ASD result in an inability to digest protein
(Williams et al., 2011), which affects the production of amino acids, essential for brain func-
tion, and suggests a target for treatment (de Theije et al., 2011). This finding suggests a pos-
sible benefit from a comprehensive digestive enzyme supplement with meals to aid digestion
of all proteins and peptides, especially for children with ASD who have GI disturbance.
A commercially developed product (CM-AT by Curemark) has been specifically
developed to target enzyme deficiencies that affect the availability of amino acids in chil-
dren with ASD, and a multisite clinical trial has been completed. Fecal chymotrypsin
was used as a biomarker for study entry. Curemark notes that it has reached its targeted
enrollment for a phase III study of a total of 170 children with ASD at 18 sites (Curemark,
2014). The results from the Curemark study are currently unpublished, and the U.S.
Food and Drug Administration is reviewing the findings (ClinicalTrials.gov, 2009 April
13—Identifier: NCT00881452; 2009 June 2—Identifier NCT00912691).
Oxytocin
Genetic studies have shown that some patients with ASD have decreased expression in
the gene that controls expression of the oxytocin receptor (Gregory et al., 2009). One
RCT crossover study of intranasal oxytocin in 16 male participants with ASD, aged 12–19
years, found improvement in the ability to recognize others’ emotions (Guastella et al.,
2010). Long-term administration (7 months) of intranasal oxytocin was found to be a safe
and promising therapy for early adolescents with ASD. Six of the 8 participants showed
improved scores on Autism Diagnostic Observation Schedule communication and social
interaction scores (Tachibana et al., 2013). All dose levels tested, including a 0.4 IU/kg/
dose, were well tolerated over 12 weeks, and several measures of social cognition/function,
repetitive behaviors, and anxiety improved (Anagnostou et al., 2014; Gregory et al., 2009;
Guastella et al., 2010; Tachibana et al., 2013).
Immune Therapies
Evidence is accumulating that there are subgroups of patients with ASD who have immune
deficiencies and signs of autoimmunity, such as atopy (Goines & Van de Water, 2010).
Various approaches have been tried to boost immune function or block autoimmunity. One
of the most obvious candidates has been intravenous immunoglobulin (IVIG) treatment,
and there are now six published open-label trials of IVIG treatment in ASD.
In one open-label study, IVIG treatment improved eye contact, speech, behav-
ior, echolalia, and other autistic features (Gupta, 1999). Others have claimed that
IVIG treatment led to improvements in GI signs and symptoms, as well as behavior.
Subsequent studies have shown questionable benefits and mixed results for language
and behavior.
IVIG is a biomedical treatment whose overall results have been limited; it carries some
significant risks. Other immune-boosting therapies may be of benefit but have not been
adequately studied. For future studies, it is unclear if an underlying immunologic dysfunc-
tion is present in all individuals with ASD or if treatment trials should target the patients
with demonstrable inflammatory/immune changes.
Prescribed Medications
A number of off-label uses of approved medications have demonstrated at least theoreti-

cal benefit for symptoms of ASD, but results have been limited by sample size and other
factors. These include propranolol (Narayanan et al., 2010; Zamzow et al., 2014), aman-
tadine (King et al., 2001), d-cycloserine (Posey et al., 2004), cholinesterase inhibitors
(Chez, Aimonovitch, Buchanan, Mrazek, & Tremb, 2004), nicotinic agonists (Deutsch,
Urbano, Neumann, Burket, & Katz, 2010), naltrexone (Brown & Panksepp, 2009), bus-
pirone (Buitelaar, Van Der Gaag, & Van Der Hoeven, 1998), risperidone plus memantine
(Ghaleiha et al., 2013), and amitriptyline (Bhatti et al., 2013).
Although memantine was thought to be of potential benefit for symptoms of ASD based
on open-label studies (Chez et al., 2007) and a plausible theoretical foundation that aber-
rant functioning of N-methyl-d-aspartate (NMDA) receptors and/or altered glutamate
may play a role in ASD, a recent multisite RCT did not show separation of active drug from
placebo (Hendren, 2014). A high placebo response rate limited the ability of memantine to
demonstrate significant benefit, but the longer term extension study and blinded taper-off
of the drug also did not demonstrate separation from placebo (Hendren et al., 2014).
Mind and Body Practices

Mind and body practices include a large and diverse group of procedures or techniques
administered or taught by a trained practitioner or teacher. These include acupuncture,
massage therapy, meditation, movement therapies, music therapy, relaxation techniques,
spinal manipulation, cranial manipulation, tai chi and qi gong, yoga, neurofeedback, and
animal-assisted therapy (AAT). Acupuncture (Cheuk, Wong, & Chen, 2011), exercise,
music therapy, and AAT have adequate evidence to warrant further RCTs (Lofthouse
et al., 2012).
SUMMARY
Some CAM/biomedical therapies have a place in an integrated approach to the treatment

of ASD. A first priority is the medical evaluation that includes the assessment of genetic,
neurologic, GI, and other medical symptoms. Speech, language, and occupational therapy
are an essential part of most treatment programs. Behavioral treatments have the most evi-
dence for efficacy and should be part of all treatment plans. Associated symptoms causing
significant distress might be treated with more traditional psychopharmacology. In addition
314 / / T reatment
to these, biomedical assessments and treatments should be considered even if only to help
understand the family’s point of view and desires and to help provide an informed plan of
action. Based on the literature and safety profiles, it is reasonable to consider melatonin,
omega-3 fatty acids, vitamin D3, probiotics, and digestive enzymes as potential treatments
for ASD (Hendren, 2013). As interest, expertise, and the scientific literature grows, consid-
eration might be given to methyl B12, folinic acid, magnesium, pycnogenol, zinc–copper,
l-carnitine, coenzyme Q10, oxytocin nasal spray, naltrexone, and inositol.
CASE STUDY #1: “ERIC”
Eric is a 5-year-old boy with moderately impairing symptoms of ASD who is receiving applied
behavioral analysis treatment at preschool and home and speech and language therapy at
school. He has no significant behavioral problems, but he does not initiate social interaction
with other children, is mildly anxious on occasion but does not “melt down,” and is mak-
ing slow but steady progress in his treatment programs. However, Eric has difficulty falling
asleep at night, and his parents consult you to consider what they can do about his sleeping
patterns and to determine if there are any medications that might help him with chronic
constipation and to help him progress faster in treatment. You suggest the family consider
a trial of melatonin starting at 2 or 3 mg and increasing up to 9 or 10 mg if needed, 30–60
minutes before his bedtime for his initial insomnia. You also suggest adding 1 g of omega-3
fatty acids per day and, considering the addition of a high-potency multiple vitamin, and pro-
biotics two or three times a day. You state that there are no conventional medications with
an indication for the social impairment experienced by Eric at this time, but there are several
undergoing clinical trials that may be helpful in the future. If the melatonin is not successful,
there are several conventional medications, with some side effects such as daytime seda-
tion and weight gain, that can be considered if necessary for his sleep.
KEY POINTS
• The National Center for Complementary and Alternative Medicine refers to CAM
as an array of healthcare approaches with a history of use or origins outside of main-
stream medicine.
• Families commonly seek alternative and complementary biomedical treatments for
their children with ASD.
• A rationale for CAM/biomedical treatments for ASD is their potentially beneficial
effect on epigenetic processes, which are increasingly demonstrated to be part of the
gene–environment interactions that underlie the development of ASD.
• Three agents with a rationale for use with ASD, and at least one RCT showing efficacy
and safety data, are melatonin, omega-3 fatty acids, and micronutrients.
• Additional agents with promise include NAC, methyl B12, and digestive enzymes.
Dr. Robert L. Hendren has received research grants from Forest Pharmaceuticals, Inc.,
Curemark, BioMarin Pharmaceutical, Roche, Shire, Autism Speaks, Sunovion, and the
Vitamin D Council. He is on advisory boards for Curemark, BioMarin, Forest, Coronado

Biosciences, and Janssen. He is on no speakers bureaus.
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/ 18
/ / / / / SPEECH AND LANGUAGE
ASSESSMENT AND
TREATMENT FOR AUTISM
SPECTRUM DISORDER
KATELYN A. BRUNO, KRISTINA L. GULATI,

AND MARIA MODY
INTRODUCTION
Autism spectrum disorder (ASD) comprises a wide array of symptoms and levels of impair-
ment that negatively impact communication. Individuals with the disorder can range from
being verbal to minimally verbal or nonverbal. The recent increase in prevalence rates of
autism (1:68; Centers for Disease Control and Prevention, 2014) has led to an increase in
the number of children with ASD on the caseload of speech–language pathologists (SLPs).
As a specialist in the treatment of communication disorders, the SLP is an important mem-
ber of the care team of the individual with ASD, which may include pediatricians, neu-
rologists, psychiatrists, occupational therapists, behavioral therapists, neuropsychologists,
teachers, social workers, and parents—all of whom contribute to treatment decisions.
The complex nature of ASD and the wide range of associated symptoms make it chal-
lenging to evaluate for the SLP. In addition, the role of the SLP in the treatment of the
disorder has greatly expanded throughout the years with rapid developments in alternative
and augmentative communication (AAC), a popular intervention tool used with individu-
als on the spectrum. As the terms implies, AAC refers to a set of procedures and strate-
gies by which an individual’s receptive and expressive language skills can be maximized
for functional and effective communication. It entails supplementing or replacing natural
speech and/or writing with aided symbols (i.e., involving the use of additional equipment)
and/or unaided symbols (ASHA, 2002). Regardless of whether the approach is traditional
speech–language therapy or involves AAC, it is critical to start intervention early—before
3 years of age or immediately following diagnosis—because it impacts communication out-
comes in later years (Rutter, Mahwood, & Howlin, 1992).
321
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CORE DEFICITS IN SPEECH AND LANGUAGE IN ASD
As mentioned previously, individuals with ASD have a wide range of speech and language
deficits of varying severity. Most notable are their deficits in social communication and
their struggles from early on with intentional communication (Paul, 2007). Here, the core
speech and language deficits in ASD are summarized under the broad headings of receptive
and expressive language.
Receptive Language
Receptive language refers to the comprehension of spoken language. It is known to

develop at a quicker pace than expressive language during the early years of normal lan-
guage acquisition (Hudry et al., 2010). Although children on the autism spectrum also
start out understanding more words than they are able to produce, the gap between what
they understand and what they say does not close. In contrast, this receptive–expressive
gap reduces significantly in typically developing children as they start producing more
words (Flusberg, Paul, & Lord, 2005). Furthermore, unlike other neurodevelopmental
disorders involving language, children with ASD have a significantly greater receptive lan-
guage deficit, resulting in substantially reduced development of receptive over expressive
ability (Rutter et al., 1992).
Difficulties with spoken language comprehension are evident in nonverbal as well as
higher functioning individuals with ASD, although as one can expect, it is more difficult
to judge the true receptive language abilities of the former. Individuals with ASD may have
difficulty comprehending simple directions (e.g., “Turn off the lights,” “Put your shoes on,”
and “Raise your hand”), “wh-“ questions (e.g., “Where is mom?”), figurative language (e.g.,
“You have ants in your pants!”), and inferences (e.g., “How do you think the boy felt?”), as
well as understanding ordinary conversation (e.g., “Hi! How are you?”). These difficulties
appear to extend to wide-ranging atypicalities in auditory perception, including (1) supe-
rior pitch perception, making them more inclined toward music; (2) heightened percep-
tion of loudness and sensitivity toward sounds in general; (3) abnormal orientation to
auditory stimuli (i.e., they are less responsive toward speech or their name being called);
(4) abnormal processing of prosody or intonation; and (5) difficulty understanding speech
in background noise (for review, see O’Connor, 2012). However, difficulties with attention,
lack of motivation, and failure to engage with unfamiliar test stimuli in individuals with
ASD may also contribute to some of these findings.
Expressive Language
Expressive language refers to an individual’s ability to verbally express wants, needs, and
thoughts. Due to their limited speech and/or use of AAC, little is known about the verbal
capacity of individuals on the spectrum who are nonverbal. Those who are verbal pres-
ent with a unique expressive language profile. For the most part, articulation has been
found to be within normal limits in individuals with ASD (Kjelgaard & Tager-Flusberg,
2001). However, difficulties with speech initiation and planning, especially in minimally
verbal children with ASD, have led to speculations about childhood apraxia of speech as a
basis for the disorder (Gernsbacher, Sauer, Geye, Schweigert, & Goldsmith, 2008; Page &
Boucher, 1998), although the evidence appears to be lacking (Shriberg, Paul, Black, & van
Speech and Language Assessment and Treatment for Autism Spectrum Disorder // 323
Santen, 2011). The acquisition of morphology (i.e., the ability to meaningfully combine
the smallest units of language called morphemes) and syntax in ASD has also been found
to be comparable to that in typically developing children, although perhaps at a slightly
slower rate (Rapin, Dunn, Allen, Stevens, & Fein, 2009). Interestingly, high-functioning
children with ASD tend to have rich vocabularies but do not use their word knowledge
in normal ways. Semantic deficits (e.g., atypical word associations, idiosyncratic word use,
neologisms, and excessively literal interpretation of statements) are among the few con-
sistent language findings in ASD (Vogindroukas, Papageorgiou, & Vostanis, 2003). Not
surprisingly, these children also have difficulty interpreting and using social–emotional
vocabulary (i.e., “sad,” “mad,” “feel,” etc.) (Eskes, Bryson, & McCormick, 1990), in keep-
ing with the impaired prosody (i.e., lexical stress and affective intonation) and pragmatics
(i.e., contextually appropriate responses during social interactions) that have come to be
accepted as hallmarks of their social communication impairment (Mundy & Markus, 1997;
Shriberg et al., 2001).
In summary, individuals with ASD may vary widely in their language profiles
(Tager-Flusberg, Lindgren, & Mody, 2008). For the SLP, the challenge is one of assessing
and treating a communication system that is linguistically fragmented, socially disengaged,
and frequently weighed down by sensory issues.
COMMUNICATION ASSESSMENT IN AUTISM SPECTRUM DISORDER
Speech–language assessment of individuals with ASD is a challenging task, mainly due to

the fact that it is a very complex, heterogeneous population. Individuals who are higher
functioning and verbal may perform well on standardized measures but have difficulty
interacting with other children in everyday situations, such as on the playground (Ozonoff,
Goodlin-Jones, & Solomon, 2005). Nonverbal individuals with ASD, on the other hand,
are difficult to assess accurately during standardized testing due to attention issues, in addi-
tion to difficulties interacting with others and producing spoken responses. Taken together,
these characteristics make it challenging to obtain a baseline test score in minimally verbal
individuals with ASD.
Speech and language assessment of individuals with ASD is typically composed of both
formal and informal measures based on a combination of parent report, standardized testing,
and language sampling during informal or semistructured play activities (Tager-Flusberg,
Paul, & Lord, 2005), which help provide a more complete picture of the individual’s recep-
tive, expressive, and social–pragmatic language skills. In addition, for individuals on the
spectrum who do not speak or whose speech is difficult to understand, a full AAC assess-
ment may be required. As mentioned previously, the term AAC is used to describe vari-
ous methods of communication that help people who do not use speech to express their
thoughts and needs. An AAC assessment resembles a standard speech–language evaluation
in that the clinician must first examine the individual’s current communicative capabilities.
This is typically composed of informal measures such as parent report and observation.
After a baseline is obtained, the clinician proceeds with “feature matching,” a process used
to assess and match the communication needs of the individual with ASD with an appro-
priate AAC system (Gosnell, Costello, & Shane, 2011; Lloyd, Fuller, & Arvidson, 1997).
Regardless of whether we are speaking of a standard speech–language assessment or an
AAC assessment, the final objective of the evaluation is to capture the true language abili-
ties of the individual in order to develop an appropriate treatment plan tailored to his or her
communication needs and potential.
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COMPONENTS OF THE COMMUNICATION ASSESSMENT PROCESS
An important first step in any evaluation is to gather pertinent information regarding the
individual with ASD, including the patient’s diagnoses, age, family history, medical his-
tory, developmental milestones, educational history, and current services. This can be done
through a combination of parent/caregiver interview, chart review, and completion of an
intake form by the caregiver. Whereas the final speech and language report may vary widely
among clinicians, a standard speech and language evaluation of a patient with ASD will
include the following:
• Background and history: Medical, educational, and family

• Receptive language skills
• Expressive language skills
• Articulation and oral motor skills
• Pragmatic language skills
• Summary and recommendations
• Treatment objectives
• Treatment plan
Throughout the session, the clinician makes detailed notes and observations about the indi-
vidual’s energy level, ability to focus, mood, social disposition, and any maladaptive behav-
iors because these will help determine the treatment approach. For the individual who does
not speak or is minimally verbal, the clinician completes an AAC evaluation. In the next
two sections, a broad overview of the evaluation process is presented.
Speech and Language Evaluation
The assessment of speech and language is composed of formal and informal measures.
Easy-to-administer standardized tests of receptive language such as the Peabody Picture
Vocabulary Test–Fourth Edition (PPVT-4) and the Receptive One Word Picture
Vocabulary Test (ROWPVT) may be used with a wide range of individuals with ASD,
from those who speak to those who are nonverbal. Each of these tests involves listening to
a spoken word and identifying the picture that best represents that word. However, indi-
viduals with comorbid attention difficulties and hyperactivity may have difficulty focusing
and pointing to the appropriate picture. Furthermore, some individuals will have difficulty
comprehending the directions of the test and may point to all the pictures or randomly
point without looking. For high-functioning individuals on the spectrum, the clinician may
administer language tests to assess the individuals’ ability to make comparisons, under-
stand cause–effect relationships, and process sentences of increasing length and complexity
(e.g., subtests of the Clinical Evaluation of Language Fundamentals (CELFP-2, CELF-5)
or the Comprehensive Assessment of Spoken Language (CASL)). Given the challenges of
formal, structured testing with individuals on the spectrum, a clinician may also informally
examine the patient’s ability to follow familiar compared to novel directions and make sim-
ple inferences.
In contrast to receptive language measures, use of standardized expressive language
tests (e.g., the Expressive One Word Picture Vocabulary Test (EOWPVT), the Expressive
Vocabulary Test (EVT), or subtests of the CELF or CASL) is limited to those individuals
who can respond verbally. For individuals with ASD who are primarily nonverbal, clinicians
rely on parent report and language samples from informal play sessions or on some form
of AAC (e.g., picture symbols, communication books, speech-generating devices, sign
language, and gestures). Popular tests such as the Goldman–Fristoe Test of Articulation
(GFTA-2), used to assess speech sound production, naturally pose a problem as well. All
individuals with ASD, however, undergo an oral motor examination to assess more basic
aspects of speech production, including the intactness of the speech structures (e.g., lips,
teeth, tongue, velum, and jaw), their associated movements (e.g., oral agility as in producing
sound sequences), and quality of phonation.
With regard to social pragmatics, there are few standardized tests designed to assess
language use and interactions across different environments. For the most part, the field
relies on checklists and observation scales (e.g., CELF-Descriptive Pragmatics Profile), but
these tend to be subjective. Nevertheless, having communication partners from different
environments (e.g., parent, teacher, and social worker) complete these scales can provide
useful insight about the individual’s daily struggles with communication.
Finally, care must be taken never to underestimate the current language skills of an indi-
vidual with ASD because they may know more than they show at the time of evaluation.
Speech and language assessment in these individuals should be an ongoing process as they
acquire skills over time.
Augmentative and Alternative Communication Evaluation
One of the greatest challenges for SLPs is best serving individuals with ASD who are
primarily nonverbal or limited in their verbal expression. Approximately one-third to
one-half of individuals with ASD do not use speech functionally (Mirenda, 2003). That
a certain percentage of these individuals with ASD will never or rarely speak their entire
lives highlights the significance of AAC intervention to enable them to express them-
selves. First, various AAC methods are reviewed before the AAC evaluation process is
discussed.
AAC can be divided into two major categories: unaided and aided. Unaided AAC
includes methods of communication that do not require additional equipment, such as
manual sign, body language, finger spelling, gesturing, and facial expressions. Aided AAC
includes methods of communication that require additional equipment, aids, or tools, such
as picture exchange, communication books, voice output communication aids, and/or
speech-generating devices. Aided AAC can be further divided into three types: low–tech,
mid-tech, and high-tech. “Lite” or “low- tech” AAC consists of a communication system
that does not require a power source, such as picture communication books and boards.
Among the more commonly used low-tech systems for individuals with ASD are the Picture
Exchange Communication System (PECS; Bondy & Frost, 1998; see Figure 18.1) and the
Pragmatic Organization Dynamic Display (PODD; Porter & Cafiero, 2009). Based on evi-
dence from neuroimaging research that suggests that individuals with ASD often exhibit
strengths in the ability to identify visual patterns and perceive visual objects (Samson,
Mottron, Soulières, & Zeffiro, 2012; Sahyoun, Belliveau, Soulières, Schwartz, & Mody,
2010), these low-tech visual supports are a promising option for use with individuals with
ASD. Low-tech AAC systems also offer the advantages of being relatively inexpensive, easy
to replace, easy to customize, and portable. On the other hand, size limitations (e.g., the
amount of vocabulary available to the individual), the manpower required to create these
systems, and the lack of knowledge of how to systematically use and implement these sys-
tems are some of their most frequently cited disadvantages.
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FIGURE 18.1 Sample low-tech AAC system: Flip’n Talk (2007 Inman Innovations, LLC).
“Mid-tech” AAC refers to any communication system that requires a source of power,
uses recorded speech, and requires some level of training to program and maintain the
device. It typically includes some combination of buttons and/or pictures with prere-
corded or recordable messages. Common examples of mid-tech devices are Step by Step
and Big Mack (recordable voice-output buttons), the GoTalk series of devices (Attainment,
Verona, WI), and S32 (Tobii, Dedham, MA). The advantages of mid-tech devices are that
they are less expensive than high-tech devices, messages are fairly easy to record and change
as necessary, and they provide a helpful transition for individuals who are moving from a
low-tech communication system to higher tech forms of AAC. However, one disadvantage
of mid-tech devices is that they are limited in the number of messages that can be recorded,
although the message limit varies greatly with the device.
Finally, a “high-tech” AAC device is a communication system that requires a power
source and extensive training to competently program and maintain the device. These
devices are often referred to as having a “dynamic display” because the display pages in
these devices change when the user touches them (Figure 18.2). High-tech devices
incorporate sophisticated electronics or computers. Examples of high-tech devices are
the Accent series (Prentke Romich, Wooster, OH); Tobii’s C8, C12, and P10 devices;
NovaChat and ALT-Chat (Saltillo, Millersburg, OH); and the Maestro and T10 (DynaVox,
Pittsburg, PA). In addition to dedicated communication devices, several AAC applications
are available for the iPad, including Proloquo2Go, LAMP Words for Life, TouchChat HD,
and Speak for Yourself. Among these, the Language Acquisition through Motor Planning
(LAMP) approach is gaining significant popularity. It is based on neurological and motor
learning principles, and it requires the user to learn the visuomotor plan corresponding to
FIGURE 18.2 Sample high-tech AAC device: Vantage Lite Speech Generating Device (Prentke
Romich Company).
the physical locations of various target word categories on the device’s display page. The
placement of these categories in the display remains the same even when more vocabulary
items are added, thereby leveraging the visual processing strengths of individuals with ASD
for purposes of learning and recall. The advantages of high-tech devices are that they are
dynamic, customizable, and, most important, their vocabulary can “grow” with the user.
However, these devices are expensive; funding can be difficult; technical problems can
occur; and their use requires training and support for families, caregivers, and school staff
who regularly interact with the user.
In summary, AAC devices, including speech-generating devices that feature voice
output, can enhance both receptive and expressive language in individuals with ASD by
providing them audio and/or visual supports as a way to express themselves. Importantly,
these devices are yielding positive results by motivating the nonverbal child to produce
speech, as well as independently initiate communication (Binger, Berens, Kent-Walsh, &
Hickman, 2008).
The main goal of an AAC evaluation in ASD is to match the individual to an appropriate
device or method of communication based on his or her communication needs and abili-
ties. This is a lengthy process and can occur over several sessions. The feature matching and
final clinical decision process entails the consideration of several parameters:
• Access: Can the individual direct select—that is, physically isolate one finger to touch
the screen or display? Is a keyboard keyguard, which is an overlay designed to help
users with limited motor skills access the keys through corresponding holes, needed
to aid the individual to more accurately select a specific key? Does the individual
have motor impairments requiring the use of assistive technologies such as a but-
ton, switch, or a joystick or eye-operated communication and control? Where is the
access point located (e.g., hand, chin, or cheek)?
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• Symbol type: Does the individual do best with symbols or photograph representation?

• Symbol size and display type: How large do the symbols have to be and how many
per page can the individual handle?
• Type of system needed: Does the individual require a high-, mid-, or low-tech system?
• Keyboard access: Can the user type and spell? Can he or she use word prediction, a
software that incorporates user vocabularies to predict which word is being typed?
By finishing typing the word for the user, the program reduces the number of key-
strokes needed for typing, thereby saving the patient time and energy and facilitating
language expression. What about the ability to sequence or combine? That is, can the
individual access a board with one, two, three, or four hits? Regarding language capa-
bilities, what kind of grammar does the individual use? Does the individual under-
stand categories? Is a phrase-based or core word system needed? Or are visual scene
displays more appropriate?
• Speech: Does the individual produce spoken words? What is the individual’s mean
length of utterance? Does the length of utterance increase when using AAC?
• Durability: Is the device likely to be thrown, dropped, handled roughly, etc.?
• Portability: Can the individual carry the device? Is a mount required to attach the
device to a wheelchair or walker? Does the individual require a lightweight system?
Clearly, the success of an AAC evaluation in ASD depends on how best to select and tai-
lor the individual’s AAC device to match his or her strengths and weaknesses while keeping
in mind the user’s vision, hearing, and general cognitive skills. It is important to remember
that a high-tech device is not necessarily better than a low-tech device. Some individuals
with ASD have not been exposed to high-tech speech-generating devices, iPads, or other
types of technology, and they have difficulty grasping the cause–effect relationship. In addi-
tion, some individuals perseverate on the voice-output and dynamic features of a high-tech
device, and they may not be able to view the system as a way to communicate. Typically, the
SLP will recommend a formal trial period with the selected AAC device across all settings
before a purchase is made. Finally, whereas individuals with ASD may benefit from learning
words and concepts, incorporating phrase-based representations can be useful to socially
communicate with peers in real time during conversations and interactions.
In summary, a thorough and accurate assessment of the communication abilities of
individuals with ASD is a challenge even for the experienced clinician. The sensory issues in
this population (e.g., tactile and auditory sensitivities; Kern et al., 2006; Rogers, Hepburn,
& Wehner, 2003) add to the challenge and serve to emphasize the importance of increased
collaboration among professionals for a complete assessment of an individual’s abilities and
more accurate decision-making during the AAC evaluation process.
SPEECH AND LANGUAGE TREATMENT IN AUTISM SPECTRUM DISORDER
Speech–language treatment of individuals with ASD can vary widely due to the hetero-
geneous nature of the disorder, but the ultimate goal of treatment is to help the individual
with ASD to successfully and spontaneously communicate across multiple environments.
There are several different evidence-based approaches that SLPs can utilize during treat-
ment sessions to optimize outcomes in the receptive, expressive, and pragmatic language
domains. In addition, there are several evidence-based strategies and components of occu-
pational therapy, physical therapy, and behavioral therapy programs that SLPs can draw
on to help individuals with ASD achieve their communicative goals. With the boom in
technology during the past decade, SLPs increasingly find themselves using AAC methods
and strategies with individuals across the spectrum.
The National Research Council (2001) identified a number of aspects of effective treat-
ment for individuals with ASD, including the following:
1. Children who received early intensive intervention by age 3 years had much better
outcomes than children who began intervention after 5 years of age.
2. Active engagement in intensive instructional programming is very beneficial for chil-
dren with ASD.
3. Repeated, planned teaching opportunities should be implemented in a series of
short intervals and focus heavily on the individual objectives or goals.
4. Speech–language intervention for individuals with ASD should include parent train-
ing and family involvement. The treating SLP should focus heavily on teaching the
caregivers strategies to help the child communicate in order to maximize the benefits
of the extended time spent together.
5. A low student:teacher ratio is beneficial for the child with ASD to be able to receive
adequate individualized instruction, as well as attain goals.
6. Treatment objectives should be measured on an ongoing basis and modified as
needed.
Based on a review of the evidence, the New Hampshire Task Force on Autism (2001)
concluded that there are numerous approaches to the treatment of ASD and strong opin-
ions about the efficacy of each. It concluded that “there is no one treatment or intervention
that works well for all people (with ASD). However, there are many approaches that are
effective and work well for specific individuals.” (p. 24)
Treatment Approaches
A number of different intervention approaches are used with individuals with ASD. These
approaches fall along a continuum of naturalness and include child-centered, hybrid, and
clinician-directed approaches (Fey, 1986). Child-centered treatment approaches are the
most natural in that the child directs the session. The key component of this approach is for
the clinician to both wait and then respond to the child’s communicative behavior. Several
techniques can be used by the clinician when responding to the child, including playing
at the child’s level, self-talk, parallel talk, and imitation, as well as expansions, extensions,
build ups, break downs, and recasts, in which the clinician expands or adds information
to the child’s utterance or modifies and restates what the child initially says (Paul, 2007).
Floor Time, a Developmental, Individual-differences, Relationship-based model (DIR;
Greenspan & Weider, 2009), and SCERTS (Social Communication, Emotional Regulation,
and Transactional Support; Prizant, Wetherby, Rubin, Laurent, & Rydell, 2006) are two
well-known examples of child-centered approaches.
In the hybrid approach, the clinician controls a good portion of the therapy activity and
materials selection but also allows the child to make spontaneous comments. Focused stim-
ulation, which relies heavily on the clinician modeling target words, and vertical structur-
ing, in which the clinician expands on a child’s initial utterance and then asks a contingent
question as a way of engaging the child in active listening and conversation, are examples
of a hybrid approach.
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At the other end of Fey’s (1986) continuum of naturalness is the clinician-directed

approach. Here, the clinician controls all aspects of the intervention from the therapy mate-
rials used to the type and frequency of reinforcement utilized and the order of activities.
It is a much less naturalistic approach that maximizes the opportunities for the child to
produce targeted words or skills. Clinician-directed approaches can be effective in helping
children efficiently acquire new language forms and increase joint attention. A very com-
mon clinician-directed approach is applied behavioral analysis (ABA). Developed specifi-
cally for individuals with ASD, the primary emphasis in ABA is the use of intensive, direct
instructional methods that alter behavior in systematic and measurable ways (Anderson,
Taras, & O’Malley-Cannon, 1996). The main goal of ABA is to reduce inappropriate behav-
ior and increase communication, learning, and appropriate social behavior. Thus, ABA uses
instructional methods such as discrete trial training (DTT) and reinforcements. In general,
students learn smaller, easier skills first and then progress toward larger, more complicated
skills as each smaller one is mastered through structured drill procedures. Both reinforce-
ment and prompting are used in DTT and are faded over time until the child is completely
independent. Behavioral approaches such as ABA have been found to be effective in ini-
tially developing attention and understanding of language, in addition to aiding speech pro-
duction in preverbal children with ASD (Goldstein, 2002; Rogers, 2006), although DTT,
which is often used in ABA, can limit generalization outside of treatment sessions.
LANGUAGE AREAS AND TREATMENT STRATEGIES

IN AUTISM SPECTRUM DISORDER
Speech and language treatment in ASD typically focuses on receptive, expressive, and prag-
matic language deficits. Here, some of the common objectives and strategies to improve
language in these areas are reviewed.
Receptive Language Treatment
The ability of individuals with ASD to comprehend language used around them is highly
dependent on their mood, attention, and motivation. Thus, clinicians need to engage their
patient while targeting receptive language. Active listening and aided language stimulation,
during which a communication partner points to a graphic symbol while simultaneously
producing the corresponding spoken word during natural communication, have proven to
be useful strategies here. During treatment of receptive language, the clinician typically tar-
gets the following areas:
• Following directions: The focus here is on the ability of individuals with ASD to be

able to follow directions ranging from functional, everyday directions (e.g., “Sit down”
and “Turn on the lights”) to novel directions (e.g., “ Put the small blue ball in the
box”). Embedded in these are basic language concepts such as temporal concepts (e.g.,
before, after, and then), location (e.g., next to, closest to, farthest, and top/bottom),
dimension/size (e.g., tallest and big/little), sequence (e.g., first/last, second/third,
and last), and inclusion/exclusion (e.g., both, all, except, and either/or). Typically, the
therapist moves from highly familiar, functional one-step directions to less familiar,
multiple-step directions with basic language concepts embedded within them.
• Receptive vocabulary: A major area of receptive language treatment is improving
receptive vocabulary. One simple technique is through the creation of word webs,
which involves selecting a central “target” word (written or drawn) and then coming
up with words that expand on its attributes (e.g., texture, shape, and category) in the
form of strands of a web emanating from the center. Another common approach used
to improve receptive vocabulary is the Lindamood–Bell Visualizing and Verbalizing
(V–V) program, which helps to strengthen word associations and connections
through concept imagery. It builds on the visual strengths of individuals with ASD
by having them imagine what the word makes them think of, which in turn is used to
stimulate new words and multiple sentences. Clinicians need training and certifica-
tion to use the program, although similar strategies are informally used in therapy.
• Sequencing events: The ability to sequence a series of events is very important and
often a part of speech–language treatment for individuals with ASD. This can be tar-
geted in several ways, ranging from sequencing very basic, everyday events such as
brushing one’s teeth to sequencing a story. For individuals with ASD who are higher
functioning and verbal, sequencing can be taught by presenting a series of photos cor-
responding to the progression of a story they have just heard and asking them to put
the photos in the correct order. After they can put them in the correct order, they will
then be asked to verbally state the sequence.
• Answering “wh-” questions: This is a very important, functional area of receptive
language to address in individuals with ASD because they frequently encounter
questions in their everyday interactions. Wh- questions can range from very basic
questions such as the what, who, and where to more abstract wh- questions including
when and why. Wh- questions should focus heavily on functional, common ques-
tions to which the child with ASD is most likely to be exposed. Therapy can address
wh- questions through interactive play with activities such as bingo games.
• Comprehension of higher language and inferential skills: Individuals with ASD tend
to be very concrete and have a difficult time comprehending abstract language, which
can be a barrier in communicating with peers and adults on a daily basis. It can hin-
der their academic performance as well. One way to increase word flexibility is for
the clinician to work with words that have multiple meanings. This, in turn, can help
individuals with ASD better understand idioms, metaphors, and similes. Storyboards
have also been found useful in training inference and reasoning skills, important not
just for academic work but also for interpreting social situations.
Expressive Language Treatment
A common goal in speech and language treatment of high- and low-functioning individuals
with ASD is to improve expressive vocabulary. For those who are higher functioning and
verbal (see Case Study 1), expressive language treatment may involve objectives such as
enhancing meaningful use of expressive vocabulary, speaking in grammatically sound sen-
tences, expanding mean length of utterance, and being able to retell stories. Each of these
areas addressed in treatment is briefly described next.
Case Study #1 Verbal Child With Autism Spectrum Disorder: “Jack”
Jack is an 8-year-old verbal child diagnosed with ASD. He lives with his mother and is an only
child. He currently attends public school and is in an integrated classroom. He is pulled out
of his classroom a few times a week to receive individual speech–language therapy, social
332 / / T reatment
skills group therapy, and occupational therapy. Jack’s receptive and expressive language
skills are mildly reduced for his chronological age; however, his pragmatic or social language
skills are significantly weaker in comparison. Jack has a very difficult time interacting with
peers and prefers to play on his own. He is also very concrete and inflexible in his thinking.
He has difficulty dealing with any change to his routine and has frequent meltdowns over
this. Jack’s mother was concerned that he was not making enough progress in school and
wanted him to be successful with his peers, as well as improve his overall language skills.
Thus, Jack was referred for a speech–language evaluation, and individual speech–language
therapy as well as a social skills group were recommended. Individual speech–language
sessions focused on improving his comprehension of higher level language such as idioms,
metaphors, and expressions. In addition, the clinician focused on improving his ability to
make verbal inferences using visual supports. During the individual sessions, specific social
skills were also explicitly taught and practiced for Jack to apply during social skills group
therapy with age- and skills-matched peers. Jack made excellent progress and after 1 year
was discharged from outpatient therapy.
A diverse expressive vocabulary is essential for an individual with ASD to succeed

in multiple settings and contexts. In speech–language therapy, an important first step is
to identify the target vocabulary items for the individual with ASD. This can be done
through a variety of structured language activities in conjunction with receptive lan-
guage activities such as word webs and the V–V program. The clinician may also use
pictures to have the child with ASD retell a story he or she has just heard to hone in on
specific vocabulary targets. Ample use of visuals with this population is crucial because
they tend to be visual learners. Unlike vocabulary, syntax and grammar are most likely
to be targeted in high-functioning individuals, although they may be addressed in non-
verbal individuals later on in treatment with the help of AAC, depending on their cogni-
tive level. Generally, the treatment of syntactic errors progresses from highly structured
activities to less structured activities in which the child has to spontaneously use the
correct targeted grammatical form. For individuals with ASD who use AAC, grammar
is taught and targeted as they learn to communicate using their AAC system, with cli-
nicians often using aided language stimulation to first model morphological and syn-
tactical structures on an AAC device. Expanding the mean length of utterance (MLU)
in both written and spoken language is yet another common speech–language goal for
individuals with ASD. Again, this can be done through structured language activities,
including story retelling with visual supports. In general, it is important to always model
one step ahead of the child. For example, if the child has an MLU of 2—that is, on
average the child produces two-word combinations—then the clinician should model
three-word combinations.
Pragmatic Language Treatment
Difficulty with social skills and pragmatic language skills is one of the core defining fea-
tures of ASD. Social skill deficits can affect both lower and higher functioning individu-
als with the disorder. Pragmatic language skills may be targeted within speech–language
therapy in which the clinician explicitly teaches the skills and then role-plays with the
child. However, a more effective treatment approach is to address social language defi-
cits within the natural context of a group setting with peers. Social skills groups address
the following areas:
• Improved interpersonal communication or conversational skills: The aim here is to

improve the individual with ASD’s ability to converse with both peers and adults.
Common components of conversation typically addressed in treatment include
improving ability to initiate conversation, turn-taking, staying on topic, asking rel-
evant questions and making comments, and successfully terminating a conversation.
Ideally, the individual with ASD will learn explicit skills at the beginning of a social
skills group session, will practice the specific skill with peers, and will generalize the
skill to everyday conversation.
• Interpreting nonverbal behavior and body language: Another important area com-
monly addressed within social skills training is the ability to correctly interpret non-
verbal behavior or body language. Individuals with ASD often have a very difficult
time interpreting emotions and do not know what to do. Again, interpreting body
language or nonverbal behavior can be taught either individually or within a social
skills group setting. Within a session, the clinician will work with the individual to
pay attention to the clinician’s emotions. The clinician can direct basic activities such
as identifying and labeling facial expressions and emotions, as well as answering ques-
tions about how a person might feel in a given situation. Another way to work on
interpreting body language is to role play, in which the clinician can turn his or her
back to the individual or not look at the individual while he or she is talking. During
these instances, the individual learns to identify when the clinician is not paying
attention.
• Ability to problem solve and make social inferences: Training social skills in individu-
als with ASD also involves problem solving and making social inferences or guesses.
This is a key area of struggle for many individuals with ASD and can be addressed
during individual speech–language treatment sessions or social group settings.
The clinician may have the individual look at various pictures and then answer sev-
eral questions, moving from close-ended questions with answer choices to a more
open-ended question format. In addition, the individual learns to make social infer-
ences based on what he or she saw in the pictures.
Social Thinking (Winner, 2007) is one of the most commonly used programs to treat
social pragmatic skills in ASD. Increasingly, video modeling techniques have also been
effective in improving a number of skills in individuals with ASD, including social interac-
tions, play, and daily living skills (Ganz, Earles-Vollrath, & Cook, 2011).
THE ROLE OF AAC IN SPEECH–LANGUAGE THERAPY IN AUTISM

SPECTRUM DISORDER
Following the completion of a speech–language evaluation and/or AAC evaluation, the

clinician is ready to make appropriate recommendations, which may or may not include the
use of AAC. The implementation of AAC varies among individuals with lower functioning
ASD and those with higher functioning ASD. For individuals with ASD who are nonver-
bal (see Case Study 2), important components in AAC treatment are feature matching the
individual to a specific system; teaching core vocabulary; providing an ample amount of
334 / / T reatment
aided language modeling; communication partner training; and addressing the major lan-
guage areas, including receptive, expressive, and pragmatic language skills, using the indi-
vidual’s AAC system.
Case Study #2 Nonverbal Adult With Autism Spectrum Disorder: “Steven”
Steven is a 31-year-old man with a diagnosis of ASD. He lives in a group home and attends
a day program for adults with developmental disabilities during the week. Steven has a his-
tory of aggression and disruptive behaviors that have interfered with his ability to participate
in therapy and in activities at his day program. Steven is nonverbal and communicates through
sign, some vocalizations, a communication book, and a GoTalk 20 voice-output device. He
can produce several clearly spoken words, such as “no” and “bye,” but his primary means
of communication are his communication book and GoTalk 20 device. These AAC systems
were recommended 2 years ago following a complex AAC evaluation. When using these
forms of AAC, Steven is able to produce greetings, answer questions, request items and
activities, combine two to four words, respond yes/no, ask questions, and label. He can also
communicate about feelings and medical needs by pointing to symbols in his communica-
tion book. Steven attends speech–language therapy sessions each week, in which he uses
each AAC system to work on increasing his expressive and receptive language abilities. His
parents are very supportive and attend each therapy session. They report one difficult issue
is that of carryover of the use of AAC into Steven’s group home and day program because
staff are often unfamiliar with each AAC system and do not use them with Steven very often.
This issue has been addressed during meetings at his day program and by inviting staff to
attend speech–language therapy sessions. Sessions have also been videotaped in order to
show Steven’s success in communicating with his book and GoTalk device.
Higher functioning individuals with ASD who speak may also benefit from AAC strate-
gies and visual supports that help improve general language comprehension, social com-
munication, and expressive language.
The use of AAC techniques and strategies in teaching core language has made a sig-
nificant contribution to the field of speech and language treatment in ASD. Core language
consists of high-frequency, reusable words that comprise approximately 80% of words
used on a daily basis (Banajee, Dicarlo, & Striclin, 2003) and that a child can combine in
a number of ways to produce spontaneous utterances. The remaining 20% of words are
referred to as “fringe vocabulary” because they are specific to the child (van Tatenhove,
2009). Prentke Romich Company, a well-known manufacturer in the field of AAC devices,
has developed six stages (ranging from the emergent communicator with 85 one-word
utterances to the full-blown communicator who uses all parts of language to form com-
plete sentences spontaneously) for use by clinicians to guide their development of goals
and objectives related to the teaching of core language. Overall, teaching core language
gives the individual much more communicative power and allows the individual to pro-
duce an unlimited number of spontaneous novel utterances or word combinations. Core
language can be taught in several ways, and there are numerous activities that can occur
across multiple environments and natural contexts to help develop core language use. As
such, some important considerations for the clinician when implementing core language
intervention include using focused aided language stimulation, teaching new core words
using highly structured language activities, engaging in practice activities, continuously
providing repeated exposure to new core words, and periodically checking continued
comprehension of core words (Zangari, 2012). Finally, it is important to constantly pro-
vide support to the individual and honor any attempt to use core language, even when
words are used incorrectly; this provides an opportunity for the communication partner
to model a correct response. Ultimately, the AAC user must learn to generalize his or her
communication skills to situations outside of the treatment environment to be effective
in all settings. Although families often have concerns about AAC negatively impacting the
development of speech, as mentioned previously, there is no evidence to support this;
rather, studies indicate gains in speech production following AAC intervention (Binger
et al., 2008; Schlosser & Wendt, 2008).
SUMMARY
Communication deficits lie at the core of ASD. Although speech and language treatment of
individuals with ASD may vary widely, the ultimate goal is to help individuals on the spec-
trum spontaneously and successfully communicate across multiple environments. Exciting
new advances in the field of neuroimaging are paving the way for the development of robust
biomarkers for use in speech–language intervention (Mody et al., 2013). These findings
will help inform the work of the SLPs as they guide individuals with ASD in navigating a
path to successful and independent communication.
KEY POINTS
• Consider how each area of sensory processing (e.g., auditory, visual, tactile, and
motor) may impact a patient with ASD.
• Remember the importance of family support and counseling when working with this
population.
• Collaboration and regular communication between all members of the care team,
including parents and teachers, is critical for the individual with ASD to make
progress.
• Do not underestimate what individuals with ASD understand or judge their abilities
based on whether they are verbal or nonverbal.
• In selecting an AAC device, plan ahead so as to optimize its use based on the patient’s
needs and profile while maximizing potential for growth in communication skills.
Katelyn A. Bruno, Kristina L. Gulati, and Dr. Maria Mody have nothing to disclose.
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/ 19
/ / / / / OCCUPATIONAL THERAPY
FOR AUTISM SPECTRUM
DISORDER
JENNIFER L. STORNELLI
INTRODUCTION
Occupational therapy (OT) is a critical component of treatment for many individuals with
autism spectrum disorder (ASD). There is strong evidence that treatment by a qualified
occupational therapist can improve functioning and reduce impairing symptoms in both
children and adults with ASD. This chapter describes the symptoms with which OT can be
helpful, and it describes the approach that an occupational therapist may take in evaluating
and treating an individual with ASD.
Goals of Occupational Therapy
The occupational therapist’s primary focus is on supporting functional participation

in daily life activities and routines. Engagement in meaningful and purposeful activity
(“occupation”) can lead to increased “health, well-being, and life satisfaction” (American
Occupational Therapy Association (AOTA), 2002). The World Health Organization
(2001) has recognized the impact that an inability to successfully perform daily tasks and
participate in meaningful activities can have on one’s overall health. Engaging in motivat-
ing and meaningful occupations not only serves as a medium for developing lost or absent
skills but also is often, in itself, the desired outcome of intervention.
The domain of OT is broad but well-defined by the practice framework in terms of
scope, function, and relevance to life roles and routines. Consideration of performance
in areas of occupation is made, including activities of daily living (ADLs), instrumental
activities of daily living (IADLs), education, work, play, leisure, and social participation
(AOTA, 2002). An OT assessment examines an individual’s ability to care for him- or
herself (bathe, dress, groom, and feed), care for his or her home and family (do laundry,
vacuum, and prepare a meal), access education, participate in leisure activities, and inter-
act with others.
339
340 / / T reatment
When considering these areas of occupation and how they are impacted by disabil-
ity, the occupational therapist examines the performance skills and performance patterns
relevant to the activity. Performance skills may include motor skills (posture, mobility,
coordination, strength and effort, and energy/endurance), process skills (knowledge, tem-
poral organization including initiation/sequencing/termination, and organizing space/
objects), and communication/interaction skills. Impairments in one or many of these
areas may contribute to the disability observed in the areas of occupation described previ-
ously. Performance patterns refer to the habits, routines, and roles that shape an individual’s
day-to-day life (Figure 19.1).
Evaluation
The evaluation process consists of two main parts: the occupational profile and the analy-
sis of occupational performance. An “occupational profile” as defined by the OT prac-
tice framework (AOTA, 2002) is a collection of information that “describes the client’s
occupational history and experiences, patterns of daily living, interests, values, and needs”
(p. 616). This information is generally gathered through patient or caregiver interview and
provides an understanding of the priorities and desired outcomes of the patient and his
or her family.
Once the patient’s occupational profile has been pieced together, an analysis of occu-
pational performance must occur. This starts with a close examination of the performance
skills and patterns relevant to that occupation that may be impacting function, as discussed
previously. Identifying factors that inhibit as well as support occupation is critical to this
process. Patient priorities and goals identified in the occupational profile help guide the
direction and focus of this analysis.
Performance Areas
Activities of Daily Living
Instrumental Activities of
Daily Living
Work
Education
Play
Leisure
Social Participation
Performance Skills Performance Patterns
Motor Skills Habits
Process Skills Routines
Communication/Interaction Skills Roles
Context Activity Demands Client Factors
Cultural Objects and Actions Body Functions &
Physical Space Demands Structures
Social Social Demands
Temporal Required Body Functions &
Structure
FIGURE 19.1 Domain of occupational therapy. Source: Adapted from American Occupational Therapy
Association (2002).
Occupational Therapy for Autism Spectrum Disorder // 341
Intervention: Therapeutic Use of Occupations and Activities
Once the performance skills, patterns, contexts, activity demands, and patient factors
that are compromising function have been identified, an intervention plan to address
these factors is created and implemented in collaboration with the patient. Specific inter-
ventions are selected with the goal of engagement in meaningful activities to support
greater independence and a better quality of life. Some interventions target performance
skills directly (e.g., home exercise program to increase standing balance for lower body
dressing), whereas others focus on retraining at the performance area level with adap-
tations and accommodations in place (e.g., using adaptive equipment to get dressed
independently).
The therapeutic use of occupation or activity is central to the occupational therapist’s
intervention approach. Three types of intervention are identified in the practice frame-
work as follows: (1) occupation-based activities (activities in context that hold meaning
for the patient), (2) purposeful activity (goal-directed behavior that leads to participation
in occupation), and (3) preparatory methods (methods that support or make one ready for
engagement in meaningful activity) (Table 19.1).
Whether intervention addresses performance skills or habits, works directly on per-
formance areas (ADLs, IADLs, etc.), or focuses on the impact of patient factors, activ-
ity demands, and context, all of these factors are interrelated and dynamic in nature.
Assessment is an ongoing process that occurs throughout intervention, guiding the course
of treatment and shaping the plan of care.
OCCUPATIONAL THERAPY IN AUTISM SPECTRUM

DISORDER: TARGET SYMPTOMS
Many individuals with ASD have impairments that are amenable to the approach of OT.
These symptoms include sensory dysfunction, disordered or maladaptive play behavior,
impairments in ADLs, social impairments, behavioral problems, and, for adults, difficulties
in learning skills for independent living. Any impairment that interferes with an individual’s
ability to safely and successfully participate in daily activities and routines falls within the
realm of OT. This section discusses these impairments in more detail from the occupational
therapist’s perspective.
TABLE 19.1 Types of Occupational Therapy Intervention

Intervention Purpose Examples
Occupation-based Engagement in the actual Preparing a meal
activity occupations that relate to Making one’s bed
client goals Getting dressed independently
Purposeful activity Engagement in goal-directed Practice slicing and spreading with a knife
activities that lead to an Practice fastening buttons on a button strip
occupation
Preparatory methods Prepares the client for activity Sensory input to achieve optimal arousal level
Stretching/range-of-motion exercises
Source: Adapted from the American Occupational Therapy Association (2002).

342 / / T reatment
Reasons for Seeking Referral
Individuals with ASD frequently suffer from functional impairments that can be addressed
within the OT framework. According to a survey by the Interactive Autism Network
(IAN, 2008), OT is the third most requested service by parents of children with ASD.
According to IAN, the most common reasons why parents seek OT for their children are
to address concerns with executive functioning (planning, organizational skills, and prob-
lem solving) and social interaction. Specifically, the two most common reasons for seeking
sensory-integrative therapy in particular are to address maladaptive behaviors and stereo-
typic behaviors (e.g., hand flapping and spinning).
Cohn, Miller, and Tickle-Degnen (2000) examined parents’ hopes prior to the start
of OT and identified three main themes relating to their child’s functioning: social par-
ticipation, self-regulation, and perceived competence. Other common themes identified
in the study included the parents’ own need for support and the desire to support their
child through learned strategies and personal validation of their own experience as a parent.
Cohn et al. (2000) examined this question even further by asking parents directly why they
sought OT for their child. All of the parents asked revealed that they sought OT because
their child was not “fitting in” or “keeping up” with the other children (at school). They did
not seek OT because of deficits in specific skills but, rather, to address the larger issue of
social rejection.
Other studies examined parents’ satisfaction following OT intervention and their per-
ceptions of its effectiveness. Anderson (1993) found that parents reported progress in their
children in several areas, including “willingness to try new play activities, socialization with
other children, and the ability to express emotions and desires.” Other parent testimonials
have suggested that OT intervention (using a sensory integration approach) improves the
overall quality of life for their family (Anderson & Emmons, 1995; Occupational Therapy
Associates, 1995).
Sensory Symptoms
Disturbances in sensory processing and responsivity are among the most common symp-
toms that occupational therapists are asked to treat in individuals with ASD. As many
as 94% of individuals with ASD have abnormalities in sensory processing compared to
65% of individuals with other developmental disabilities (Leekham, Nieto, Libby, Wing,
& Gould, 2007). Furthermore, these symptoms often involve multiple sensory domains.
Sensory symptoms widely reported in ASD include impairments in the modulation of
sensory input, deficits in auditory processing (hypo- or hyperresponsivity), unusual visual
behaviors (poor eye contact, gaze aversion, visual inspection of objects, and overreliance
on peripheral vision), and tactile sensitivity (Tomcheck & Dunn, 2007). Individuals with
ASD often experience a combination of over- and underresponsivity to various stimuli
across sensory systems. Retrospective studies using videotape analysis have found evi-
dence that some of these sensory symptoms may be evident in early infancy (Tomcheck
& Dunn, 2007). Some of the common sensory processing difficulties in ASD are outlined
in Table 19.2.
Specific examples of overresponsivity (or hyperresponsivity) may be a child who cov-
ers his ears when he hears a toilet flushing or screams when his parents try to dress him
in the morning. Examples of underresponsivity (or hyporesponsivity) include a child
who does not respond to his or her name or does not notice that his or her face or hands
are messy.
TABLE 19.2 Common Sensory Processing Difficulties in Autism Spectrum Disorder

Factor Related Behavioral Outcomes
Sensory Seeking Seeks all kinds of movement that interferes with daily routines
Twirls/spins self frequently throughout the day
Takes excessive risks during play; takes movement or climbing risks that
compromise personal safety
Seeks opportunities to fall without regard for personal safety
Frequently “on the go”
Jumps from one activity to another
Emotional Reactivity Anxiety or distress that interferes with daily routines
Difficulty tolerating changes in routines
Poor frustration tolerance
Difficulty making friends
Inattention/Distractibility Is distracted by or has trouble functioning with background noise
Appears not to hear what you say; doesn’t respond to name when called
despite normal hearing
Poor Registration Decreased awareness of pain and temperature
Doesn’t notice when people enter the room
Does not seem to smell strong odors
Does not notice when hands or face are messy
Sensory Sensitivity Becomes anxious/distressed when feet leave the ground
Difficulty tolerating various food textures
Avoids certain tastes or food smells that are typically part of children’s diets
Difficulty tolerating tags on clothing, seams on socks
Withdrawal from touch; signs of distress when touched
Source: From Dunn, W. (1999). Sensory Profile: Caregiver Questionnaire. Copyright © 1999 NCS

Pearson, Inc. Reproduced with permission. All rights reserved. “Sensory Profile” is a trade-
mark, in the US and/or other countries, of Pearson Education, Inc. or its affiliates(s).
Hyporesponsivity can be understood in more than one way. It may suggest a higher
threshold for that particular sensation, whereas a stronger stimulus would be needed to elicit
a response. However, it may also be the result of poor filtering or prioritizing of sensory input,
which impacts the individual’s ability to register the new stimulus effectively. In other cases,
a lack of response to a stimulus can occur when a sensory system is “overloaded” and unable
to process additional information. Individuals with ASD may require more sensory feedback
from their environment than others due to higher neurological thresholds in certain systems.
This may manifest in a pattern of sensory-seeking behaviors such as seeking out excessive
movement, licking or mouthing nonfood items, or touching things/people in excess.
The ability to filter out background information (the sound of the clock ticking, the
flicker of the fluorescent light bulb, etc.) is also often a challenge for those with ASD. Poor
habituation to sensory stimuli can lead to increased arousal or anxiety and difficulty reg-
istering more relevant stimuli, such as someone calling one’s name or the sight of a car
approaching in a parking lot, in the immediate environment.
344 / / T reatment
Difficulty regulating responses to sensations and environmental stimuli can manifest

in a variety of ways and behavioral patterns. Each individual with ASD presents with a
unique pattern of responses, which may include overresponsivity, underresponsivity, and
sensory-craving across various sensory systems. Furthermore, these responses can vary
depending on the contextual factors in which the sensory input is experienced.
Children with ASD often seek proprioceptive input through actions such as jumping off
pieces of equipment or furniture, hanging from a jungle gym, or pushing their bodies into
furniture or surfaces (Mailloux & Roley, 2010). Proprioceptive information can be alerting or
calming, but it almost always has an organizing effect. It is a unique sensory system in this way
in that too much information to this system does not tend to lead to overload or dysregulation.
The vestibular system, located in the inner ear, contributes to our sense of balance and
spatial orientation. Various components of the inner ear detect linear or rotational move-
ments as well as vertical or horizontal accelerations, providing us with a sense of body-in-
space when stationary or in motion. Vestibular input can have dramatic effects on alertness,
and it can quickly become disorganizing if one’s system is overstimulated. Effects of over-
stimulation include dizziness, nausea, and sometimes vomiting. These symptoms are often
transient, but at times they can have lasting effects (e.g., seasickness).
Different types of movement elicit different reactions in the inner ear, resulting in varied
effects on arousal, posture, and sometimes emotional state. The type, speed, and rhythmic-
ity of the movement can be altered to elicit different reactions. In general, slow, rhythmic,
linear movement will have a calming effect, whereas fast, arrhythmical, or rotary movement
will be alerting. Furthermore, positioning (upright, prone, etc.) is another variable that can
be used to vary the movement experience and related postural challenges. Individuals vary
significantly in their processing of vestibular sensation. Children often seek more vestibular
input compared to adults, with vestibular systems becoming more sensitive as people age.
In an OT sensory integration (SI) treatment session, equipment such as platform swings,
tire swings, bolster swings, suspended hammocks and nets, and large exercise balls are used
to create a variety of movement experiences and challenges in a variety of positions.
Outside of therapy sessions, children with ASD often seek out vestibular input by spin-
ning themselves, running or pacing back and forth, jumping or bouncing up and down,
or swinging for long periods of time. Other children with ASD may have a more sensitive
vestibular system and may avoid movement activities, or they may demonstrate fear or dis-
tress during activities in which their head is not in an upright position relative to gravity. For
these children, providing graded movement experiences in a controlled and supportive way
with opportunities for adaptive responses is important.
The ability to process tactile sensations effectively is also of great significance to one’s
development of body scheme and, in conjunction with the proprioceptive system, one’s
awareness of body in the absence of vision. The tactile system has important functions that
are both discriminatory and protective in nature. Tactile discrimination allows us to iden-
tify or manipulate an object within our grasp without relying on vision (e.g., reaching into a
purse to get keys). It is very important for our ability to manipulate tools or objects and to
adjust our grasp spontaneously on objects as needed. The tactile system also provides criti-
cal information about pain and temperature that serves a protective function (e.g., pulling
hand from a hot stove).
Although tactile sensitivity is an issue for many individuals with ASD, poor discrim-
ination of tactile information may also be present. Poor tactile discrimination can affect
fine motor skills, and it may result in actions that appear clumsy, messy, and miscalcu-
lated. Ineffective processing of tactile information can also affect physical appearance, for
instance, if a child does not feel his shirt twisted on his body or toothpaste or food on his
face. This can in turn impact social participation and acceptance and also the development
of self-esteem.
Behaviors such as hand flapping, spinning, aimless running, aggression, self-stimulatory
behaviors, and sometimes self-injury have also been correlated with the sensory processing
deficits seen in ASD (Watling & Dietz, 2007). Some individuals with ASD have explained
the regulatory function that self-stimulatory behaviors serve, allowing the individual to bet-
ter respond to the sensory stimuli around him or her and avoid sensory overload (Shoener,
Kinnealey, & Koenig, 2008). The manifestation of these sensory behaviors in ASD can not
only interfere with functional skills and daily routines but also have a significant impact
on social participation and can lead to isolation and rejection by peer groups. Identifying
environmental factors that support one’s sensory needs while helping the individual learn
strategies for self-regulation across contexts is a key component of the occupational thera-
pist’s role with this population and can greatly improve one’s quality of life.
Motor Skills
Individuals with ASD have often been described as “clumsy” or “uncoordinated,” having
poor body awareness, bumping into things and people, and having difficulty with basic
skills such as tying their shoes or buttoning their shirts. Although motor deficits were not
traditionally included in the criteria for an ASD diagnosis, recent research suggests that dif-
ferences in motor skills and praxis may in fact comprise an important feature of ASD.
Several researchers have described a range of gross and fine motor differences in ASD
that have included measures of muscle tone, postural reactions, and dyspraxia (Bhat,
Landa, & Galloway, 2011; Ming, Brimacombe, & Wagner, 2007). Differences in gait and
impairments in anticipatory postural control are among these findings (Bhat et al., 2011).
Furthermore, studies have shown that motor differences can be seen as early as infancy
and may include delayed acquisition of gross motor milestones, abnormal muscle tone,
decreased motor activity, and postural asymmetries (Bhat et al., 2011; Phagava et al., 2008).
Poor motor and gestural imitation in infants later diagnosed with ASD has been linked to
deficits in communication and social skills in the second and third years of life (Bhat et al.,
2011). Deficits in praxis seen in ASD have been well documented during the past several
years, with recent studies showing the presence of dyspraxia even in the absence of cogni-
tive delay (Bhat et al., 2011). Some researchers have examined various areas of the brain
related to praxis and have described impairments in individuals with ASD related to the
formation of spatial representations (parietal regions), poor linking of sensory informa-
tion with motor areas (premotor cortex), and deficits in motor execution (motor cor-
tex) (Dowell, Mahone, & Mostofsky, 2009). Another key finding in motor research is the
delayed or atypical cerebral lateralization and dominance (Escalante-Mead, Minshew, &
Sweeney, 2003; Hauck & Dewey, 2001), which may contribute to the poor bilateral skills
and sequencing observed in children with ASD. Furthermore, difficulty establishing cere-
bral dominance has been speculated to contribute to the disordered language development
seen in this population (Escalante-Mead et al., 2003) (Table 19.3).
Play: The Occupation of Childhood
Play is as critical to a child’s early development as learning to dress or feed oneself because
it is through play that many of the other building blocks of development emerge. Engaging
in play not only draws on the underlying skills of social engagement, imitation, and the
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TABLE 19.3 Motor Differences in Autism Spectrum Disordera

Motor Skill/Foundation Presentation in Children With Autism Spectrum Disorder
Postural control Differences in quality of muscle tone
Use of feedback rather than feedforward mechanism to maintain
postural stability
Praxis skills Difficulty with initiation of motor sequences
and motor coordination Poor timing of movements in space
Poor bilateral integration and interlimb coordination
Poor motor imitation (gestures, postures)
Decrease in variability and complexity of movement repertoire
Diminished ideation for novel actions/concepts
Gross motor skills Poor force modulation; difficulty regulating speed/pace
Delays and/or disordered learning of early developmental positions
and sequential movement patterns (rolling, crawling)
Anticipatory motor control Poor postural readiness in preparation for movement/action
Overreliance on visual guidance to aid body awareness
Fine motor skills Decreased quality in grasp patterns and manipulation
Poor lateralization; delay or deficiency in differentiated hand use
Oral motor Decreased quality of sucking, chewing, blowing
Poorly coordinated breath support for both speech and feeding
Ocular motor Poor functional use of vision to guide movements, anticipate actions
This is not an exhaustive list of motor findings.

a
Source: Adapted from Stackhouse (2010).
generation of new ideas but also can be used as a platform for developing these same skills.
Because play is often described as the primary occupation of childhood, an examination of
play skills and behaviors is a relevant component of a pediatric OT evaluation. Because the
play activities and behaviors of children with ASD are often strikingly different than those
of typically developing children, interventions that address the components of play (e.g.,
imitation, body awareness, motor skills, and praxis) are often key elements of the occupa-
tional therapist’s plan of care.
Play is a complex behavior, and there are multiple factors that may be involved in the
play of a child with ASD. May-Benson (2010) notes that children with ASD often engage
in stereotypic play that focuses on the sensorimotor properties afforded by an object rather
than their assumed function. Caution should be used not to interpret the actions of a per-
son with ASD through one’s own lens of social or cultural expectations because the function
of that behavior for them may be quite different. This is illustrated through the following
example: A young child with ASD bangs one block against another that is positioned on the
table. An onlooker might assume the child is trying to stack the blocks by placing one on
top of the other and is either lacking the refined skill to do so or is demonstrating willful-
ness in refusing to meet the expectation. However, the child with ASD may simply find the
noise created by the collusion of the two blocks to be a more salient reinforcer than the act
of stacking.
Abnormalities in sensory processing, described previously, are often a strong contribu-

tor to the atypical play behavior in children with ASD. Bundy, Shia, Qi, and Miller (2007)
found that children with sensory processing disorders scored significantly lower on the Test
of Playfulness compared to typical peers. Children with ASD tend toward interactions with
objects based on their sensory qualities (visual appeal, sound, texture, and temperature) rather
than the affordances of objects for action (ability to bounce it, throw it, and catch it). They may
engage in repetitive actions with the objects to meet a sensory need (e.g., banging an object
to hear the sound that it makes or spinning the wheels on a toy car for the visual stimulation).
Play might also be affected by impairments in praxis. Praxis refers to the ability to con-
ceptualize and formulate a plan for a motor act or sequence and then execute this plan.
When discussing praxis, there are three different steps (Ayres, 1972): ideation (generat-
ing an idea for action: “I will climb into that tent”), motor planning (creation of a plan of
action: “First I will bend down and pull back the flap at the door entrance. . .”), and execu-
tion of the plan. An impairment in any one of these steps may impact an individual’s ability
to play; however, for individuals with ASD, difficulties with ideation and planning tend to
be the greatest challenges with praxis.
Effective ideation allows for the many affordances of objects to be recognizable, which
fosters the generation of ideas for play (May-Benson, 2010). Furthermore, an inability to gen-
erate ideas for action can lead to play that is stereotypical and repetitive in nature rather than
representational (Ozonoff, 1997). In turn, the engagement in repetitive actions with objects
can further limit exploration. Effective motor planning relies on our ability to access our vast
repertoire of sensorimotor experiences and apply this information to a novel situation and
context. Early sensorimotor experiences provide the foundation for the development of one’s
own body “map” and body-in-space perception. When the ability to form this body map is
hindered by a paucity of sensorimotor experience or poor integration of information from
sensory systems, accurate planning of movements in space is affected. This can result in move-
ments that appear clumsy, poorly timed, and sometimes dangerous (May-Benson, 2010).
Activities of Daily Living
Children and some adults with ASD often face challenges with even the most basic self-care
activities and daily routines, such as getting dressed, brushing teeth, bathing, and prepar-
ing or eating a simple meal. Sensitivity to certain sensory inputs (touch, temperature, and
sound), the craving and preoccupation with other sensations, difficulty with motor plan-
ning and sequencing, and a lack of intrinsic motivation to perform such tasks (due to lim-
ited concern for, or awareness of, the social relevance of personal hygiene) are all factors
that may contribute to poor self-care skills. Jasmine et al. (2009) found that sensory overre-
sponsivity and fine motor skills were highly correlated with daily living skills for young chil-
dren with ASD, even when accounting for cognition. Using activity analysis, occupational
therapists can help identify the specific sensory and motor impairments underlying these
functional challenges. OT intervention often includes a combination of targeted skill reme-
diation, paired with environmental and task modifications needed to support function.
Social Participation: Family, Community, and Peers
One of the core features of ASD is marked impairment in social functioning. This impair-
ment often causes major disruption in family routines, participation in community
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activities, and social interactions. Occupational therapy has a role in mitigating the impact
that symptoms of ASD can have in these domains and in bolstering the social functioning
of the individual.
Family and Community
Anecdotal evidence suggests that having a child with ASD can add tremendous stress to a
family and can result in a significant shift in family routines, roles, and lifestyle. Many com-
promises may be necessary to accommodate the special needs and functional limitations
of the child. Basic daily routines such as getting dressed and ready for school, eating break-
fast, and going to the bathroom can become very time-consuming and energy-demanding
events that impact all members of the family unit. Children with ASD often require much
more of their parents’ resources with regard to time, energy, and financial investment than
their siblings, which may have an impact on sibling relationships. Furthermore, family
routines such as mealtime may be difficult to coordinate given the sensory needs, dietary
restrictions, and busy schedule (including medical and therapy appointments) of the child
with ASD.
The different sensory experiences of children with ASD can have a notable impact on
family occupations, particularly with regard to activity selection and how the family pre-
pares for those activities or events (Bagby, Dickie, & Baranek, 2012). Basic routines such
as going to the grocery store, going to the park or library, or eating at a restaurant may
present conflicts so significant that a withdrawal from these activities may occur. Bagby
et al. (2012) interviewed parents of children with ASD and found that they choose family
activities and outings based on what situations need to be avoided (e.g., bowling alleys may
be too loud and movie theaters are too dark). Furthermore, these parents reported the need
for much more time to prepare for such activities, as well as the need to have alternate plans
in place just in case. Events that would otherwise be highly valued (e.g., birthday parties)
are often avoided altogether.
Participation in family activities and meaningful events is an important aspect of an
individual’s overall functioning. Occupational therapists can help establish strategies to
improve participation in these activities and help restore the ability to engage in meaning-
ful activities as a family unit.
Social Skills
One of the key features of ASD is impaired social skills often characterized by poor or
inconsistent eye contact, difficulty initiating or maintaining social interaction, difficulty
interpreting nonverbal communication cues, and a poor understanding of social norms.
Challenges with social interaction often result in difficulty developing close relationships
with others, which can lead to alienation at school and within other peer groups. The ability
to interact successfully with those around us is critical not just for getting basic needs met
but also as a platform for participation in all of life’s activities. Successful social participation
does not hinge only on the ability to communicate verbally with another but also involves
a much greater skill set that allows us to share space, time, and ideas with other people in
a way that promotes participation in meaningful activities. Individuals with ASD have dif-
ficulty with these critical components of interaction and often do things that are not aligned
with accepted social norms, often perpetuating a cycle of negative responses from those
around them. Furthermore, behaviors associated with sensory-seeking and sensory overre-
sponsivity, as well as the tendency toward repetitive or stereotypical behaviors, can further
alienate these individuals. Difficulties with social interaction pose a significant barrier to
occupational performance and can significantly affect an individual’s ability to participate
in work, leisure, and educational endeavors.
Addressing these social issues through social skills training, participation in small peer
groups, and consistent opportunities for social modeling is an important piece of the inter-
vention plan for a child with ASD. Social skill curricula often involve a multidisciplinary
team that may include speech/language pathologists, child psychologists, teachers, devel-
opmental specialists, and occupational therapists. The occupational therapist’s role in social
skills training often focuses on how one uses and manages his or her body in social inter-
actions, strategies for emotional regulation and the regulation of arousal level, managing
self-stimulating or sensory-seeking behaviors that interfere with social participation, and
environmental considerations.
The ability to have successful social interactions relies on the ability to share physical
space with others, not only in a way that is safe but also in a way that promotes and sup-
ports that interaction. Things that become intuitive for typically developing children at a
young age are not intuitive for those with ASD. For example, the concept of personal space
is one that often needs to be taught overtly to children and adolescents with ASD. A certain
proximity to our communication partner is necessary to indicate intent and to allow for
successful interaction. However, when someone violates this space, it can feel very uncom-
fortable and sometimes threatening, and it can very easily result in an unsuccessful interac-
tion. When someone stands too close, the person who is being approached may take a step
back, and a typical individual would likely take that cue as a sign that he or she may have
been too close. A person with ASD, however, may not notice or correctly interpret that
nonverbal cue and may violate that personal space boundary once again. Understanding
how personal space etiquette may differ from one situation to another (e.g., how close to
a peer to sit during circle time and how close to stand to peers in line at school) poses an
additional challenge for children and adolescents with ASD who are often very rule-based
and concrete in their thinking.
Personal space is not the only consideration for how we use our body in social situa-
tions. Michelle Garcia Winner discusses the concept of keeping one’s “body in the group”
to communicate participation in a shared activity or idea (Winner & Crooke, 2008). In the
book, You Are a Social Detective! Explaining Social Thinking to Kids, Winner and Crooke illus-
trate the importance of body position and posture in being part of a social group. Simple
behaviors such as turning your body toward the others in the group, looking at the person
who is talking, and staying in close proximity to the group can have a significant impact on
how the others think about you and accept you. These nonverbal cues are difficult for indi-
viduals with ASD and often have to be taught as discrete skills and then implemented into
practice across various settings.
Modulating the volume and tone of one’s voice during social interaction is another chal-
lenge that can compromise social interaction for individuals with ASD and an area in which
OT can be helpful. Some children with ASD speak very loudly and with an atypical pros-
ody. Others may speak too softly, making it difficult for others to hear. The ability to modify
voice volume in response to changes in the environment (e.g., a loud fire truck driving by
or entering quiet library space) can present a challenge because it relies on an awareness
of these environmental and social cues. Using a voice that is too loud for the context may
relay anger or aggression, and it can shift the tone of the interaction. Likewise, a voice that
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is too soft can be difficult to hear and may not be sufficient to sustain the attention of the
conversational partner.
Many social interactions involve some sort of physical contact, such as a handshake, a
pat on the back, or a hug. Understanding the appropriate use of these gestures is critical to
avoid awkward or potentially offensive situations. For individuals with ASD, differentiating
what action is appropriate under a particular set of circumstances is often a struggle. It relies
on an appreciation of different types of relationships (e.g., family member vs. acquaintance)
and an awareness of social context. Using the appropriate amount of force during these
physical interactions can also be a challenge for individuals with ASD. Squeezing someone
too hard when hugging or hitting them on the back when attempting to pat them lightly are
the types of behaviors that might result. These can be interpreted as intentional behaviors
or aggressive acts, but often they are simply a result of poor proprioceptive awareness. They
may not be able to anticipate the correct amount of force needed for the action, may have
difficulty grading the force, and may not realize even after the event that too much force was
applied.
The sensory-seeking behaviors observed with many children with ASD can also impact
social interactions with peers and others. Behaviors such as seeking out constant movement
(e.g., moving around the room when supposed to be seated or repositioning frequently in a
chair), pushing feet against things/people, and fidgeting with everything in close proximity
can interfere with social interaction in that they can be very distracting, can draw the person
away from the social encounter, and can be confusing or concerning to the other party.
Teaching strategies to manage these sensory-seeking behaviors is an important role of
the occupational therapist and often involves the implementation of sensory materials that
will provide the desired input but in a more subtle or socially acceptable manner. For exam-
ple, for children who have difficulty sitting in one place and have a tendency to frequently
get up from their chair during school, a (textured) air cushion on their chair can sometimes
be very effective in limiting their need for movement out of the chair. Likewise, for children
who tend to reach out and touch everything in close proximity in such a manner that it
interferes with participation and social interaction, attaching fidgets (items that are stretchy,
textured, bendable, or plush) to the inside of their pants’ pocket or to the underside of their
desk is often effective.
In assessing social interaction skills, the occupational therapist must consider environ-
mental factors that either support or hinder social participation. Assessing the need for
adaptive materials and/or seating for participation in age-appropriate play and/or leisure
skills may be necessary to allow for opportunities for more natural social interaction and
engagement in similar activities. Adapting the environment to promote social participation
may involve change to the physical space, reducing excessive auditory distractions, and/or
limiting visual clutter that can lead to overstimulation. Creating defined space for activities
(e.g., carpet squares during circle time) is important for some children with ASD.
Problems in School
Children spend a large part of their day in school; therefore, ensuring that the supports
and environment that they need within this context to be successful are in place is critical
to their overall well-being and progress. School brings with it many challenges for a child
with ASD beyond the curriculum. Busy hallways, waiting in line, tolerating loud noises of
crowds and bells, and frequent transitions are just some of the factors that can serve as bar-
riers to success in this setting. An occupational therapist can help implement a variety of
strategies (behavioral, environmental, and sensory) to support children with ASD within
their school program.
Many school-based OT programs focus primarily on fine motor skills, the ability to use
classroom tools, and handwriting. These are important skills. However, for children with
ASD, an examination of their physical and sensory environment is also critical. Specifically,
the use of visual supports to facilitate transitions, preferential seating to support attention,
reduction of visual clutter, an organized and consistent physical environment, and the imple-
mentation of a “sensory diet” (Wilbarger, 1984) are key components of the OT intervention
within the classroom/school. A sensory diet is a scheduled regimen of sensory-enhanced
activities that is designed to meet an individual’s unique sensory cravings and needs in a
way that is safe, appropriate, and predictable. By building these sensorimotor experiences
into one’s schedule proactively, sensory-seeking behaviors that may be disruptive, unsafe, or
inappropriate to context/place can often be avoided. For others, the right sensory diet can
help with arousal regulation and mood. The occupational therapist’s role here, ultimately, is
to determine what strategies and/or modifications would be most effective in supporting the
child’s functioning within the given context. A list of common challenges faced by children
with ASD within their school setting and suggested strategies are provided in Table 19.4.
Independent Living and the Transition to Adulthood
The transition to adulthood brings with it many changes and challenges for individuals with
ASD. For some, this involves a transition to independent living, the branching out of one’s
TABLE 19.4 Common School Challenges for Children With Autism Spectrum Disorder and Related
Strategies
Challenge Strategies
Difficulty navigating safely Allow child to travel hallways at less busy times (e.g., 5 minutes
through crowded before bell rings)
hallways—bumps into peers, Practice route to and from classroom(s), gym, library, and cafeteria
too stimulating, etc. during off hours to familiarize child with layout and routine
Difficulty standing in line Allow child to be at end of line so that no one is in his or her
“backspace”
Reinforce “one arm’s length” rule for personal space
Remaining at desk during Provide an air cushion for seat to create dynamic seating
seated work Allow child to shift position or stand at desk for brief periods as
needed to regulate arousal level
Provide brief movement breaks for whole class or engage child in
movement through classroom activities (e.g., passing out materials
and collecting papers)
Difficulty processing auditory Provide visual supports or written instructions at desk to supplement
instructions verbal instructions
Distractibility Allow the use of noise-cancellation headphones in class
Offer preferential seating (front row, away from door/window)
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social network, and entrance into the workforce. The occupational therapist can play a criti-
cal role in preparing for this transition. Career planning can be a stressful and complicated
process for anyone, let alone someone with a disability. Choosing a job that is a good fit
involves exploring not only one’s current skill set and capacity for growth and learning but
also one’s personal interests and vocational goals. It is also important to consider job envi-
ronment, schedule, and the occupational demands of a given line of work. For example,
some individuals with ASD may find more success in a job in which they have limited social
contact and work more or less independently in a private workspace. Others may do better
with a job that involves constant movement and being on one’s feet, as opposed to a desk
job, because sitting for long periods may be difficult. Many individuals with ASD thrive on
concrete and consistent tasks and outcomes, for whom a job involving more rote activity
may be the best fit. Others may succeed in a more creative capacity where adhering to a
specific protocol is neither required nor encouraged. Occupational therapists can play a
key role in this process for individuals with ASD given their unique ability to anticipate the
occupational demands of various jobs through activity analysis, assess the unique skills and
limitations of an individual, and make considerations for environmental and task modifica-
tion to support vocational success.
The occupational therapist’s role, however, extends beyond job selection and often
involves training in related life skills needed to secure employment. For example, writing
a resume and attending a job interview are necessary skills that are often very difficult for
individuals with ASD. Job interviews arguably pose one of the major challenges due to the
heavy focus on social interaction, the ability to respond to introspective questions on the
spot, perspective taking (including the interpretation of nonverbal cues), and first impres-
sions. Occupational therapists, in conjunction with other related professions, often play
a key role in preparing individuals for these inevitable and challenging interactions. This
often involves a discussion of anticipated scenarios; rehearsal of greeting, introductions,
and responses to expected questions; and assistance with presentation (wardrobe, personal
appearance, portfolio, etc.). Compensatory strategies such as providing or bringing written
materials (e.g., cover letter and hard copies of resume), using notes (written list of key points
for discussion), and implementing any of their own learned strategies for self-regulation or
impulse control can be very helpful. In some cases, suggesting the interview take place in a
less stimulating or distracting environment (private room, one interviewer) or opting for a
phone interview versus face-to-face, if possible, may trigger less anxiety.
Once a job placement or career path has been determined, the occupational therapist
in some cases may assist with job skill training (learning the specific skills needed for the
job), including strategies for compensation. Establishing healthy work routines and habits
to promote success is also important. Learning how to drive or successfully access public
transportation may be necessary to secure employment. Furthermore, for some, the con-
cepts of money management and financial planning come into play.
IADLs: The Skills for Independent Living
Many individuals with ASD live at home with their parents or other family members well
into adulthood. A 2005 study by Wagner, Newman, Cameto, Garza, and Levine found
that only 4% of adults with ASD live alone. A recent study found that young adults with
ASD were more likely to live with their parents or other family members and least likely
to have ever lived independently compared to adults with other developmental disabilities
(Anderson, Liang, & Lord, 2014).
The skills needed to live alone greatly exceed the basic skills of self-care. Instrumental
skills of living are the basic life skills needed to successfully manage one’s life both at home
and within the community. These skills include completing household chores, telephone
use, managing finances, using or accessing transportation, caring for plants or pets, doing
laundry, grocery shopping, and meal preparation. Many of the specific skills required to
perform these tasks can be taught. However, overall safety and well-being may be compro-
mised by poor executive functioning. Individuals with ASD may not anticipate or identify
potential safety hazards or concerns. Furthermore, difficulty with social skills can impact
their relationship with neighbors and their ability to use neighbors as a resource when
needed. Time management can also be an issue affecting punctuality at work, as well as the
timely completion of personal or household responsibilities.
OCCUPATIONAL THERAPY ASSESSMENT FOR INDIVIDUALS WITH

The occupational therapist’s assessment process, as outlined at the beginning of this chap-
ter, begins with an examination of an individual’s occupational profile and an analysis of
occupational performance. This often begins with a patient and/or caregiver interview to
determine how the patient’s day-to-day life is impacted by his or her disability. A top-down
approach such as this allows the occupational therapist to first consider the impact of the
disability on function as it plays out in the course of one’s actual day or week and then to
break it down further to determine what impairments or skill deficits may be at the root.
Methods of assessment often include a combination of interview, questionnaire, standard-
ized testing, and skilled observation.
Parent/Caregiver Interview
When evaluating a child with ASD, an interview with the child’s parent(s) or primary care-
giver is essential in gaining a true perspective on the impact that the child’s disability has
on daily activities and family routines. Understanding how the child’s challenges play out
in a typical day provides a more complete perspective on the reason for referral than would
review of the patient’s medical record alone. Gathering information from the child’s teacher,
school-based therapists, and others who work with or interact with the child regularly can
be another very valuable piece of the assessment process because it allows for a broad per-
spective of how the child behaves, performs, and interacts across contexts. Questions gen-
erally focus on daily routines, behavior, play, and specific age-level skills. An understanding
of the impact that the child’s disability has on his or her family and the degree to which it
inhibits or compromises participation in community and school activities is essential.
Sensory Questionnaires
Sensory questionnaires are a common part of the OT evaluation for a child with ASD.
These questionnaires are generally filled out by the child’s parents or primary caregiver;
however, some formats, such as the Adolescent Sensory Profile: Self Assessment (Brown
& Dunn, 2002) and Sensory Processing Measure: School & Classroom forms (Kuhaneck,
Henry, & Glennon, 2007), are created for completion by the patient or school staff/teacher,
respectively. These questionnaires are composed of statements relating to the behavioral
354 / / T reatment
outcomes of sensory processing. Interpretation by the occupational therapist of not only

individual responses but also, more important, the pattern of responses across sensory sys-
tems and related factors is critical to being able to use this information to create an appro-
priate and effective plan of care.
Standardized Testing
The inclusion of standardized test measures in a complex evaluation is useful not only for
comparison to normative data to determine skill deficit and delay but also to show measur-
able, objective change over time. The ability to document quantifiable data such as this is
often necessary to determine eligibility for services. A variety of standardized tests are uti-
lized by occupational therapists when evaluating children with ASD and related disorders.
For lower functioning or nonverbal patients, standardized testing may be difficult. Even if
receptive language is poor, many test items can be taught through demonstration; however,
basic imitation skills are often necessary.
Standardized tests used by occupational therapists to evaluate children with ASD focus
on the assessment of skills in the following areas: (1) fine motor skills and upper extrem-
ity functioning, (2) gross motor coordination and planning, (3) visual–perceptual skills,
(4) visual–motor integration, and (5) sensory discrimination and praxis. In many cases,
adaptations to standardized administration may be necessary in order to engage the child
and ensure comprehension of the requested task. Adaptations may include the need for
additional verbal cues or prompting, rewording of the task instructions, the provision of
visual supports to aid in comprehension, and/or demonstration of the task in cases in
which performance on verbal instruction alone would be otherwise expected. These devia-
tions from standardized protocol must be documented and can affect validity. A brief list
of assessments commonly used by occupational therapists when evaluating children with
ASD is provided in Table 19.5.
Skilled Observation
One of the most valuable methods of assessment that occupational therapists use when
evaluating a child with ASD is observation. Observing children during both structured
and unstructured tasks provides an array of information about how they interact with their
environment, what motivates them, how they approach a task and engage in problem solv-
ing, and what barriers or limitations they face along the way. Observations can be formal or
informal, and they may or may not require direct therapist intervention (Watling, 2010).
Simply observing a child at play can provide rich information about his or her language
ability, attention, interests, and motor skills. Therapist involvement may be necessary to
set up opportunities for new challenges and experiences and also to grade or adapt the
activities as needed along the way. For example, observing a child interacting with a puzzle
can provide information about that child’s visual perceptual skills and the ability to both
visualize where the piece should be inserted and manipulate the piece effectively for place-
ment. Furthermore, if the task appears challenging, observations can be made with regard
to the child’s frustration tolerance and ability to problem solve in order to successfully
complete the task. Simultaneously, observations about the child’s sitting posture, grasp,
and bilateral coordination are made as the child attempts to complete the puzzle. Factors
that should also be considered include the child’s attention, distractibility, tendency to
become preoccupied or to give up, and general affect during play. If in a social or group
TABLE 19.5 Assessments Used by Occupational Therapists to Assess Children/Adolescents

With Autism Spectrum Disordera
Type of Assessment Examples of Assessment Tools Areas Measured
Sensory Sensory Profile: Caregiver Responses to various sensory input, body
questionnaires Questionnaire awareness and planning, behavioral/
Sensory Processing Measure emotional outcomes to sensory
processing
Developmental motor Bruininks–Osertesky Test of Motor Measures fine motor skills, motor
assessments Proficiency, Second Edition coordination, balance, etc.
Peabody Developmental Motor Measures grasping and early visual motor
Scales, Second Edition skills
Perceptual–motor Developmental Test of Visual Measures various aspects of visual
skills Perception, Second Edition perception and visual motor integration
Motor-free Visual Perceptual Measures various aspects of visual
Test, Third Edition perception in the absence of motor
demand
Beery–Buktenica Test of Visual Measures ability to copy shapes and line
Motor Integration designs of increasing complexity
Tests of sensory Miller Assessment of Preschoolers Measures tactile discrimination, visual
discrimination Sensory Integration & Praxis Tests discrimination and perception, postural/
constructional/oral praxis, etc.
This is not an exhaustive list of assessment measures.

a
situation, such as day care or school, then observations about social interaction and play
skills in a peer setting can also be made as other children approach the child and attempt
parallel or cooperative play.
Skilled observations are used by occupational therapists as a means not only to learn
about specific skills and abilities but also to understand the big picture of how that child
interacts with the world around him or her. These observations can be categorized into
many areas, including posture and movement, ideation and planning, attention and arousal,
sensory-seeking or -avoiding behaviors that interfere with play or functioning, communica-
tion ability, and general affect.
OCCUPATIONAL THERAPY INTERVENTION IN AUTISM SPECTRUM DISORDER
Once a thorough evaluation has been conducted and the effect of the child’s impairments
on occupational performance has been outlined, a plan of care can be created. The occupa-
tional therapist must determine if OT intervention is indicated or not and, if so, in what set-
ting, at what frequency, and in what format the services should be delivered. For example,
if a focus on fine motor skills, tool use, and handwriting is emphasized, then services deliv-
ered within the child’s school program may be most appropriate. Alternatively, if working
on increasing independence with self-care activities within the context of the child’s morn-
ing routine is determined to be a priority, then services delivered within the child’s home
may be most beneficial.
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Delivering services within a child’s natural environment, such as at home or in school,

limits the need to generalize a skill from one setting to another and allows the skills to
be learned in real time in the space in which they would naturally occur. Simulated tasks
in an outside setting, such as an outpatient clinic, can be beneficial but may not general-
ize well to other settings. Unfortunately, home-based services are not always feasible and
sometimes require significant out-of-pocket expense. In addition, home services are lim-
ited by the space, physical layout, and the materials and equipment available within the
child’s home.
For many children with ASD who have profound sensory processing dysfunction, an
outpatient center or private therapy clinic may offer a more optimal treatment venue in
that it allows for access to a variety of therapy materials, equipment, and resources that
may not be available within the child’s natural environment. Treatment in these settings
should include parent education through direct participation, observation, or discussion
to ensure that carryover of therapeutic activities and implementation of strategies at home
are successful.
Addressing Sensory Issues in Autism Spectrum Disorder
Given the significant impact of sensory processing challenges on daily occupations and per-
formance, treatment strategies to ameliorate these symptoms and related issues are often a
central focus of intervention. Watling, Dietz, Kanny, and McLaughlin (1999) surveyed 72
occupational therapists who worked extensively with children with ASD and found that the
most common treatment approach utilized with this population was SI.
Ayres Sensory Integration
Ayres Sensory Integration (ASI) is both a theory and an intervention approach used com-
monly by occupational therapists working with children with ASD. Sensory integration
theory was developed by Jean Ayres, an occupational therapist and researcher with a back-
ground in both educational psychology and neuroscience. The theory is based on the prem-
ise that effective processing and integrating of sensory information from one’s environment
is necessary for adaptive behavior. She theorized that poor sensory integration often resulted
in behavior and learning challenges, and that the inability of higher centers to modulate and
regulate lower brain centers (sensorimotor) is the cause (Ayres, 1972). Sensory integra-
tion theory is based on a few key postulates that include the following: (1) The nervous
system is capable of change (plasticity), (2) interactions between an individual and the
environment are critical for brain development, and (3) meaningful sensorimotor activity
is an important substrate for learning and neural change (Schaaf & Miller, 2005). Sensory
integration therapy is a child-directed approach that emphasizes active participation in
sensory-rich activities that provide the “just right challenge” to stimulate problem solv-
ing and the scaffolding of new skills and ideas. The therapist, using a sensory integration
approach, introduces sensorimotor activities that are rich in tactile, proprioceptive, and
vestibular sensations and that provide the child with opportunities to build on her current
abilities as she engages in new experiences with the environment. The therapist grades the
activities to provide a meaningful challenge while taking care not to exceed the threshold of
what is possible for that child. The four basic principles of the sensory integration approach
are outlined in Table 19.6.
TABLE 19.6 The Four Principles of Sensory Integration Therapy

Principle Description
The “just right challenge” Creating a challenge that is not so much that it interferes with success.
Adaptive response The creation of new useful strategies in response to novel challenges.
Active engagement It is essential that the child is an active participant and not a passive
recipient in the activities; active exploration of a sensory-rich environment
that presents a myriad of novel motor experiences and challenges is key.
Child directed The therapist follows the child’s lead and reads his or her cues to modify the
environment as needed.
Source: Adapted from Schaaf and Miller (2005).
Whereas interventions such as the implementation of a sensory diet can be used in a

variety of settings (home, school, and community), ASI therapy is a treatment approach
that requires a more structured environment. ASI is frequently provided in a clinic space
equipped with floor mats, suspended equipment, balls, bolsters, and other materials to cre-
ate the potential for a variety of sensorimotor challenges. The environment is designed to
provide a variety of movement experiences in time and space, paired with various tactile
and proprioceptive inputs to increase body perception through somatosensory awareness.
Visual and auditory stimuli can be manipulated to reduce distractions or to heighten aware-
ness, as needed. The therapist, in playful collaboration with the child, creates new situations
that require motor planning and execution and then modifies or adapts the activities as
needed to promote success (see Figure 19.2). The environment is structured to promote
praxis and increase organization of behavior through carefully graded vestibular, proprio-
ceptive, and tactile experiences (Mailloux & Roley, 2010).
Praxis relies on the underlying concept of body scheme, awareness of body move-
ments in space, and the ability to anticipate and plan movements and actions seamlessly
in a dynamic environment. Children with ASD often do not process body sensations effec-
tively, nor do they integrate these sensations to get an overall sense of their body in space.
ASI therapy provides a framework for building these skills by targeting the underlying
foundations of sensory processing and the effective integration of information from differ-
ent sensory systems to produce an adaptive response.
Currently, there is no consensus in the literature regarding the effectiveness of the ASI
approach with children with ASD (May-Benson & Koomar, 2010), but the use of this
treatment approach by occupational therapists working with this population is widespread.
Watling et al. (1999) surveyed a group of pediatric occupational therapists and found that
99% of the occupational therapists working with children with ASD used a sensory inte-
gration frame of reference frequently or always and that this was the most frequently used
treatment approach with this population. Other researchers have suggested that up to 90%
of occupational therapists working in schools use an SI frame of reference when working
with children with ASD and other disorders that may be associated with difficulties pro-
cessing and organizing sensory information (Miller & Fuller, 2006).
Although further study regarding the efficacy of the ASI approach is needed, there is a
great deal of evidence to support its use. A 2010 review by May-Benson and Koomar specif-
ically examined 27 individual studies of the effectiveness of the ASI approach with children
with sensory processing challenges using various outcome measures. With regard to motor
performance, 10 of the 14 related studies found positive gains with ASI that were at least
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FIGURE 19.2 Many children with autism spectrum disorder have difficulty with praxis; occupa-
tional therapists create sensorimotor challenges to work on the timing and sequencing of move-
ments within a motivating and sensory-rich context.
equal to, if not greater than, those of alternative interventions. Furthermore, measurable
gains were maintained over time even after direct intervention was discontinued. Earlier
reviews of the effectiveness of SI treatment with children with learning disabilities found
a pattern of findings suggesting that OT–SI with this population is at least as effective as
alternative interventions, with the greatest gains reported in motor performance (Polatajko,
Kaplan, & Wilson, 1992). Similarly, Humphries, Wright, McDougall, and Vertes (1990)
and Humphries, Wright, Snider, and McDougall (1992) found that although OT inter-
vention using ASI and treatment using a perceptual–motor approach both yielded more
positive results than no treatment at all, the gains observed varied by treatment approach.
Specifically, the SI approach had the greatest impact on improving gross motor skills, bilat-
eral coordination, strength, and motor accuracy, whereas the perceptual–motor approach
yielded the greatest gains in visual motor ability and balance.
Other researchers have compared the effectiveness of the OT–SI approach to that of
non-OT intervention that was activity-based for children with sensory processing issues
(Miller, Coll, & Schoen, 2007). These researchers found that the children receiving the
SI treatment had more significant gains in attention, cognitive, and social skills compared
to the alternative group. Furthermore, the SI group demonstrated significantly greater
improvements in individual goals relating to daily living skills. Similarly, Pfeiffer, Koenig,
Kinnealey, Sheppard, and Henderson (2011) compared the effectiveness of OT–SI for
school-age children with ASD to OT treatment targeting fine motor skills (tabletop activi-
ties) and found a significant reduction in autistic mannerisms (stereotypical behaviors,
highly restricted interests, etc.) in the SI group compared to the fine motor group. An ear-
lier study by Smith, Press, Koenig, and Kinnealey (2005) found similar findings, including
a reduction in self-stimulatory behaviors, following a course of treatment employing SI.
Interestingly, Miller et al. (2007) also examined a group of children with poor sen-
sory modulation and, using electrodermal responses as an outcome measure, found
decreased stress response (to repetitive sensory stimuli) following SI therapy. These find-
ings are interesting in light of testimonials from individuals with ASD who have described
self-stimulatory behaviors as modulators of stress, used to self-regulate with the function of
effectively avoiding sensory overload (Shoener et al., 2008).
Other studies examined the effect of OT–SI specifically with children with ASD.
A review by Baranek (2002) examined the effects of OT–SI on children with ASD and
found a trend of positive outcomes particularly in social skills, play, and sensory overre-
sponsivity. Recent research has reported similar findings. A case study by Schaaf, Hunt,
and Benevides (2012) demonstrated improved sensory discrimination, regulation, motor
skills, communication, and overall behavior of a child with ASD following a 10-week course
of OT–SI. Parent report indicated significant positive change specifically with regard to
activity level, safety and impulsivity, self-care tasks, and play skills. Specific parent observa-
tions included greater independence with dressing, better bedtime routine and sleep hab-
its, and increased participation in family activities. School staff also reported observable
differences, including improved play skills, an increase in social participation, improved
attention to task, and more successful completion of schoolwork. Improvements in both
standardized test measures, as well as parent and teacher report of changes in behavior and
functioning, reflect positive outcomes with both proximal (sensory and motor) and dis-
tal (behavior and participation) factors. This provides further evidence that changes at the
level of sensory and motor processes can lead to improvements in participation and overall
occupational performance.
Recent investigation into brain plasticity and the impact of sensory processing on neu-
ronal structure and function may provide further support for ASI, as well as a framework for
understanding its effects. A review by Lane and Schaaf (2010) examined studies of the rela-
tionship between sensory input, brain function, and behavior. The findings indicated that
direct sensory input or exposure to an enriched sensory environment resulted in changes in
neuronal structure and function, which were sometimes reflected in behavioral outcomes.
Furthermore, these changes were observed primarily in the areas of the brain related to
learning and memory. Some effects observed were found to be long-lasting, although this
was found to be highly dependent on personal and environmental factors. The review con-
cluded that there is ample support for the postulate that rich sensory input provided in the
context of meaningful activity facilitates neuroplasticity, with active engagement and inter-
est in task being important factors.
Despite these findings that support the use of ASI as a viable treatment approach with
children with ASD, many studies had reported inconclusive findings. Inconsistencies in
research results, small sample sizes, and methodological weaknesses continue to compro-
mise the integrity of this research and limit our ability to fully understand and demonstrate
the effects of this treatment approach compared to other interventions. Further research is
most certainly necessary.
Sensory Diets
As discussed previously, the sensory symptoms observed in ASD are widespread and
highly variable. Regardless of variability in presentation, however, they frequently inter-
fere with successful participation in daily activities, completion of important routines, and
productive and meaningful interactions with others. It is important to examine how these
360 / / T reatment
behaviors interfere with occupational performance across contexts and determine how
these sensory needs can be honored while simultaneously supporting successful engage-
ment in occupation.
A sensory diet, as discussed previously, is a regimen of structured sensory-based activi-
ties provided at regular intervals throughout the day that provide the types of sensory input
that the child craves and seeks. Embedding these activities into the child’s daily routines
helps with consistency and can facilitate better carryover across settings such as home, day
care, or school. For example, for a child who is spinning herself, rocking, or in frequent
motion, participating in certain activities at recess, including swinging on the swing set, sit-
ting on the seesaw, or engaging in games such as Ring Around the Rosie or duck-duck-goose,
can provide some of that extra input that she needs to stay regulated. Likewise, a child who
is touching everything or everyone around her may benefit from a sensory diet rich in tac-
tile sensation. Activities such as finger painting, playing in a sensory/tactile bin (e.g., a tub
filled with dried beans and rice), or playing with clay or Play Doh can help meet the child’s
sensory needs in a more adaptive, less intrusive way (Figure 19.3).
In addition to activities that provide specific sensory input that the child is seeking,
it is important to introduce strategies or accommodations to assist with attention and
self-regulation during specific activities. Strategies might include adaptive or preferential
seating, opportunities for breaks, reduction of distractions, and access to materials such as
fidgets or weighted lap pads. Furthermore, children who tend to present with overrespon-
sivity may need opportunities to retreat to a quiet space when overstimulated (e.g., indoor
tent, ball pit, or cozy corner). Breaks such as this can often improve overall participation
(Figure 19.4). A sample sensory diet is provided in Table 19.7.
For children who experience overresponsivity to certain sensations, providing oppor-
tunities for graded exposure to these stimuli throughout the day can foster a gradual
desensitization. For example, a child who has tactile defensiveness may avoid playing in
the sandbox at recess. In some cases, avoidance of the playground altogether may ensue.
FIGURE 19.3 A rice bin is an excellent medium for tactile play.

FIGURE 19.4 Many children with autism spectrum disorder (ASD) retreat to cozy spaces to self-
regulate; burrowing in a ball pit (or under couch cushions, in a sleeping bag, etc.) can be calming
and organizing for a child with ASD.
Providing graded exposure to the sandbox, for instance, in a way that is safe and controlled
can help the child acclimate to this over time.
For some children, social stories (Gray, 2000) can be very helpful in introducing the
event or situation through discussion and pictures only (e.g., a social story about playing
in the sandbox during recess). A next step may be seeing the activity or stimulus from a
distance (e.g., standing on the playground at recess several feet away from the sandbox).
Seeing others interact with the stimulus in a positive way without negative consequence
can minimize the aversion and be a starting point in building trust. Eventually, direct con-
tact may be made (e.g., touching the sand with one finger, then with whole hand, then two
hands, etc.), although not until success has been met at these prerequisite levels. If the child
has a meltdown when he sees the sandbox, then forcing him to play in it will likely exacer-
bate this reaction and can lead to a more significant aversion and withdrawal.
It is the role of the occupational therapist to determine the appropriate type, frequency,
and intensity of sensory input based on the individual needs of the patient and to monitor
responses to the input over time in order to make the appropriate changes and modifica-
tions that are needed.
ENVIRONMENTAL CONSIDERATIONS
Providing selected sensory inputs via a structured sensory diet can have a significant impact
on the regulatory abilities of a child with ASD. However, environmental factors can also
play a major role in arousal and regulation. Visual factors such as lighting, visual clutter,
TABLE 19.7 Sample Sensory Diet
Time of Day/ Sensory Input/ Environmental Behavioral/
Routine Activity Modification Organizational
Techniques
Waking up Bouncing on physioball to Lights on; gradual Allow child to wake
increase arousal as needed. introduction of more up at his or her
sounds/music. own pace with
support as needed.
Breakfast Provide air cushion on chair to Reduce unnecessary Avoid offering too
increase sitting tolerance distractions (background many choices
and help maintain awake/ noise, TV, etc.).
alert state.
In classroom: Provide hand fidgets as needed Offer preferential seating Keep classroom
desk work to maintain attention during (front of class, away from materials
listening activities and windows); close windows well-organized and
seated work. to reduce excess noise. highly visual.
Lunchtime: If sound sensitivity is an issue, Consider seating away Make child aware
cafeteria provide noise-cancellation from high-traffic area of menu prior
headphones; allow child to and farther from to lunchtime;
move around as needed to kitchen, particularly if encourage bag
self-regulate during lunch overresponsive to food lunch from home
break (provide structured smells. if child has food
movement breaks if sensitivities.
possible—access to gym/
outdoor playground).
After school: Provide a sensory break for Keep demands and Provide visual
transition home child upon arriving home; distractions low during supports as needed
consider child’s own transition, when possible, to review evening
sensory needs: quiet space to allow child to regroup. schedule (e.g.
versus movement and heavy dinner, homework,
work. book/TV, bedtime).
Dinner time Same as breakfast.
Bedtime Offer child “quiet time” with Keep materials and Keep bedtime routine
dimmed lights, relaxing music, supplies for bedtime routine very consistent
and books to look at (or audio well-organized and stored with regard to time
books). Avoid video games in consistent locations (e.g., and sequence of
or TV shows that are very pajamas and toothpaste/ events. Provide visual
visually stimulating; avoid toothbrush). supports for this as
tasks requiring high cognitive needed (e.g., visual
demand. timer to indicate
bedtime and picture
schedule to review
nighttime routine).
crowds and movement, and visual distractions can set a very different mood and can over-
load a visual system or hinder the processing of other, more relevant stimuli. Similarly, audi-
tory factors such as background noise (humming of a fan or clock ticking), environmental
sounds (traffic, beeping of the crosswalk signal, or rain on a rooftop), and the sound of
people talking can be received in various ways by different individuals with ASD, and at
times the cumulative nature of these sounds can be too much to process even when the
individual sounds may be benign. These visual and auditory factors may be more rele-
vant at certain times of day or during daily activities that require more concentration and
effort. Suggestions for home might include the use of soft or natural light in place of fluo-
rescent light or the reduction of background noise during mealtime or self-care routines.
Considering the scheduling of certain tasks can be helpful as well. For instance, running the
dishwasher or washing machine during the day when school is in session can help avoid a
challenging situation later.
In the community, finding ways to alter the environment can be much more challeng-
ing. In these cases, it may be necessary to implement strategies, as discussed previously, to
make challenging environmental stimuli more tolerable. Examples of this include wearing
noise-cancellation headphones at the airport or when walking through the grocery store or
wearing sunglasses or a visor when outside at the park. These are simple strategies that, for
some children with ASD, make a major difference in their ability to function in the world
around them.
Improving Self-Regulation
Williams and Shellenberger (1996) define self-regulation as “the ability to attain, main-
tain, and change arousal appropriately for a task or situation” (pp. 1–5). The ability to
self-regulate begins in infancy and is driven mostly by processes in the autonomic nervous
system, reticular formation, and limbic system relating to automatic body functions and
state maintenance. As the child begins to interact more with his or her physical world, sen-
sorimotor strategies for self-regulation are discovered. However, for young children, the
ability to self-regulate is still not a conscious process, with changes in arousal level (or alert-
ness) often being facilitated by parent/caregiver. As children grow older, however, they
develop greater awareness of their own arousal state, as well as a greater capacity to regulate
it. However, for many children, including children with ASD, the development of these
higher level processes may be impaired. As a result, they may have more difficulty monitor-
ing and affecting positive change on their state of arousal in a way that effectively matches
and supports the current context and task demands.
The Alert Program (“How Does Your Engine Run?”) was created by two occupa-
tional therapists to teach strategies for self-regulation to school-age children and young
adults who may struggle in this area (Williams & Shellenberger, 1996). The program is
broken into stages that include recognizing one’s own arousal level using visual supports
and simple language and metaphors, observing changes in arousal level when various
activities or inputs are introduced, and, finally, the spontaneous regulation of one’s own
arousal state.
Williams and Shellenberger (1996) emphasize the importance of using a bottom-up
approach to inhibition (e.g., body sending messages to brain) through sensorimotor strat-
egies rather than relying solely on the less efficient top-down approach involving mind
over body. The concept of the “sensory diet” discussed previously is based on this premise
as well.
364 / / T reatment
When using The Alert Program, children are asked to think about their body as an
engine. Different “engine speeds” (high, low, and just right) are discussed and illustrated
through simple pictures. Using visual supports, children learn to identify their own arousal
level at various times throughout the day. As strategies for regulation are introduced, con-
nections are made between certain inputs/activities (as well as environmental factors) and
corresponding changes in alertness. Parents can begin to understand how their child’s state
of arousal fluctuates over the course of the day and begin to better understand their child’s
sensory needs over time (see Table 19.2).
Interventions for Praxis
Praxis has historically been defined as the ability of the brain to conceptualize, plan out,
and perform a series of unfamiliar actions (Ayres, 1972). Intervention strategies to address
praxis issues depend on what component(s) of praxis is impaired. Furthermore, these defi-
cits should be addressed through both remediation and compensation. Remediation often
includes both addressing the underlying sensorimotor mechanisms relating to praxis and
the direct teaching of specific skills within an occupational framework.
For children who have difficulty with ideation, strategies might include direct practice
with idea generation in context. For example, during a play activity, a child might be pro-
vided with a simple item (e.g., a hula hoop) and asked to generate three ideas for action with
this object. One action might be the obvious one involving spinning the hoop around one’s
torso. However, ideation would be needed to come up with additional ideas of how to inter-
act with the hoop based on its basic attributes and affordances. If the child becomes stuck,
simple clues could be provided either verbally (“Its round. I wonder if it rolls?”) or visually
(e.g., by placing the hoop flat on the ground to generate ideas of jumping into it or running
around it or holding it up vertically to suggest that it may be used to throw things into).
Likewise, if a child is engaging in repetitive play with a toy (e.g., pushing a car back and
forth repeatedly in one spot), demonstrating other actions with the toy (e.g., rolling the car
down a ramp or moving the car along a drawn-out path) can help expand the play scheme
and may lead to the exploration of other possibilities. Strategies such as this can help increase
the child’s play repertoire. The strategy chosen needs to match the language and cognitive
abilities of the child. Compensatory strategies for a child with poor ideation might include
providing the child with choices (either verbally or visually) for action given an object or
scenario and/or demonstrating the action for the child to imitate. Demonstration can be
used both to improve ideational abilities and to compensate for this deficit.
To address deficits specifically with motor planning that relate to the learning of new
motor skills or engagement in a novel activity, the following strategies are often imple-
mented: (1) Break tasks down into smaller components—teach the individual compo-
nents and then begin to piece them back together one piece at a time; (2) allow more time
to practice new skills—encourage repetition; (3) slow down the pace of an action or motor
sequence—learn it in slow motion, and then build up pace as possible; and (4) provide
visual feedback (mirror, video playback, etc.) when possible to foster self-correction and
compensate for poor body awareness.
Compensatory strategies implemented by occupational therapists to address these
motor planning deficits might include (1) providing physical assistance for the child dur-
ing novel or challenging motor tasks; (2) avoiding situations that will likely present such
challenges without available support; (3) allowing the child to perform certain actions in a
modified manner; and/or (4) modifying the task, physical environment, or social context
to support success.
Children with dyspraxia (with or without ASD) do not just have difficulty with the
discrete learning of new motor skills. Dyspraxia can make any activity or situation that is
open-ended, difficult to predict, or out of sight very distressing or anxiety-provoking. For
instance, going to a place where the child has never been or transitioning away from a famil-
iar routine or place without an understanding of what is happening next can cause much
distress for a child with praxis issues. This may be one explanation for the consistent dif-
ficulties with transitions reported by parents of children with ASD.
Other strategies often used by occupational therapists include (1) providing a visual
schedule (picture schedule) to outline daily activities in sequence, (2) using a visual timer
(see http://www.timetimer.com) to create a visual endpoint for otherwise open-ended
tasks, (3) using social stories (Gray, 2000) to introduce new places or situations that may
occur (e.g., social story about going to the grocery store or riding the school bus), (4) edu-
cating parents on the importance of keeping living space well-organized with the child’s
personal belongings stored in consistent locations (toothbrush/paste, clothing, toys, etc.),
and (5) providing verbal warnings when a change to the schedule or routine is anticipated.
These strategies can help prevent distress and create an environment that is predictable and
safe while simultaneously allowing for a more manageable way to approach unavoidable
changes in routine or schedule that may arise.
Deficits specifically in motor execution are less common in individuals with ASD.
However, if ideation and planning are impaired, then smooth execution of movements and
actions in real time will be affected. Likewise, when support is provided for ideation and the
motor planning process, improvements in motor output are often observed.
Using Ayres Sensory Integration to Improve Praxis
Ayres Sensory Integration is based on the premise that the nervous system is capable of
change and that meaningful sensorimotor activity is a powerful mediator of this plasticity
(Schaaf & Miller, 2005). As discussed previously, active participation by the child is critical
in order to elicit these changes. Using an SI approach, occupational therapists can address
the underlying praxis deficits of children with ASD by providing opportunities for ideation,
motor planning, and execution of novel motor sequences within a controlled environment.
By providing a rich sensory environment with graded motor challenges that match the
child’s ability, motor learning can occur.
SUMMARY
Individuals with ASD experience many sensory and motor impairments that impact their
lives in a variety of ways. Occupational therapists play an important role in identifying how
these deficits impact the individual’s daily life skills including self-care, household chores,
vocational skills, and the ability to fulfill meaningful roles within his or her family and com-
munity. Occupational therapists often work closely with physical therapists and speech/
language pathologists in addressing functional limitations and improving safety and quality
of life. Occupational therapists use a variety of assessment tools and intervention techniques
in evaluating and treating individuals with ASD. A combination of skill remediation, task
modification, and environmental adaptation is often implemented to improve functional
366 / / T reatment
outcomes. A referral to OT is indicated when functional limitations are interfering with an

individual’s ability to successfully and safely participate in daily life activities and/or ful-
fill basic life roles. Occupational therapists are an important component of the health care
team for children and adults with ASDs.
KEY POINTS
• The focus of occupational therapy is on improving function, participation, and inde-
pendence in daily activities and routines.
• Identifying an individual’s values, interests, and life experiences is critical to the anal-
ysis of occupational performance and in determining appropriate and meaningful
goals for intervention.
• Occupational therapy often involves a combination of skill remediation, task modifi-
cation, and environmental adaptation to improve functional outcomes.
• Individuals with ASD experience the world differently than others; the way they
take in, integrate, and interpret the sensory information from their immediate envi-
ronment (through sight, touch, movement, hearing, etc.) leads to a unique way of
responding to the things, people, and events that unfold around them.
• In ASD, we must caution ourselves not to interpret a single behavior as simply a devi-
ation from the norm that must be corrected; instead, we must search for a pattern of
behaviors that defines how that individual responds to the world around him or her.
Through that understanding, we can mold the world around the individual and build
the skills needed for success.
Jennifer L. Stornelli is currently employed by Spaulding Rehabilitation Hospital, an entity

of Partners HealthCare, as an occupational therapist and clinical supervisor, responsible for
program development and the coordination of service delivery for the patient population,
which is composed in large part of individuals with autism spectrum disorder.
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/ 20
/ / / / / SOCIAL SKILLS TRAINING
FOR AUTISM SPECTRUM
DISORDER
D. SCOTT MCLEOD, KRISTIN W. MALATINO,

AND DOROTHY LUCCI
SOCIAL SKILLS IN INDIVIDUALS WITH AUTISM SPECTRUM DISORDER
Social skills can be defined as interpersonal responses that allow an individual to adapt
to the environment through verbal and nonverbal communication (Matson, Matson, &
Rivet, 2007). Social skills are necessary for engaging appropriately with others, establish-
ing relationships, and maintaining friendships. Throughout development, social behaviors
are learned naturally through interactions with others in various contexts. Social skills are
generally observable, and they can be both verbal and nonverbal. Typically, these skills
can be learned by watching others and through trial and error. However, individuals diag-
nosed with autism spectrum disorder (ASD) or social communication disorder experience
marked social challenges (American Psychiatric Association (APA), 2013).
A central component of ASD includes “persistent deficits in social communication
and social interaction across multiple contexts” (APA, 2013, p. 50). Social problems may
include deficits in (1) social–emotional reciprocity; (2) nonverbal communication behav-
iors; and/or (3) developing, maintaining, and understanding relationships (APA, 2013).
Although the social impairments of ASD fall on a spectrum from “requiring very substan-
tial support” to “requiring supports,” this chapter focuses primarily on individuals with
high-functioning ASD (HFA) or Asperger’s disorder (Asperger’s syndrome (AS)), as for-
merly classified in the Diagnostic and Statistical Manual of Mental Disorders (fourth edition,
text revision) (APA, 2000). These classifications generally include individuals who have
average to above average intelligence and do not experience a language delay. Within this
classification, individuals may experience deficits in social interactions (e.g., initiating com-
munication, negotiating personal space, and engaging in to-and-fro conversation), nonver-
bal communication (e.g., modulating eye contact, and reading facial expressions in others),
perspective taking (e.g., understanding the thoughts and feelings of others), or emotional
reciprocity (Baron-Cohen, Tager-Flusberg, & Lombardo, 2013). For example, these skills
369
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would be necessary in asking for help at school, initiating play on the playground, asking a
peer out on a date, or interviewing for a job.
The negative consequences of social skill deficits can be quite profound. Poor social
skills are related to significant social problems across the lifespan, including peer rejec-
tion, bullying, and difficulty establishing romantic relationships (Church, Alisanski, &
Amanullah, 2000; Krasny, Williams, Provencal, & Ozonoff, 2003). Beyond the relational
consequences, poor social skills have also been linked to increased mental health issues,
such as anxiety and depression (Attwood, 2006; Sterling, Dawson, Estes, & Gleeson,
2008; White, Oswald, Ollendick, & Scahill, 2009). Social skill deficits can also impact aca-
demic achievement and performance evaluations at school and work (Church et al., 2000;
Hendricks, 2010). In fact, adults with ASD have higher rates of unemployment and are
frequently employed below their skill level (Hendricks, 2010).
A key element of social communication that often poses a challenge for persons with
ASD is perspective taking, or theory of mind. Happé (1994) defines theory of mind as
“the ability to attribute independent mental states to oneself and others, in order to explain
behaviour” (p. 39). Figure 20.1 represents the classic Smarties task, which is an example of
a theory of mind assessment tool. A child is shown a container, recognizes the label, and
thinks that he or she knows what is in it (candy). However, prior to showing the child the
container, the examiner placed a pencil in it. The examiner shows the child that the pencil,
not the expected candy, is placed in the container. The child is asked to guess what another
boy, who is not privy to what is in the container, will say is in it. Typically developing chil-
dren will predict that the boy who is naive to the replacement will expect to see candy in
a candy container. Some individuals with ASD will have weaker theory of mind and inac-
curately think that the other will expect a pencil.
Winner (2007) stresses that social interaction requires the ability to consider the per-
spective of the other. The Smarties task is one method to test this ability. When a person
exhibits the ability to integrate the perspective of the other within a social interaction, the
person is said to be “thinking social” or using “social thinking” (Winner, 2007).
Social deficits create a vicious cycle for individuals with ASD because their poor social
thinking and skills prevent them from creating social connections that could have offered
prosocial modeling and feedback. Also, even when social skills are learned, individuals with
ASD struggle to generalize the skills to novel situations. For example, an individual with
ASD may learn an appropriate greeting for a teacher in school (e.g., eye contact and saying
“good morning”) but may not understand that a similar greeting would be appropriate with
a doctor or on a job interview. These social challenges often lead to difficulties establishing
relationships and functioning appropriately across contexts.
Although individuals with social challenges may lack self-awareness and appropriate
behavior in social situations, they are often keenly aware of their social skill deficits. Given
their average to above average intelligence, they often know what good social skills look like
and who in their peer group has those skills, whether or not they are able to implement these
skills themselves. For example, in a study by Knott, Dunlop, and MacKay (2006), children
with HFA/AS rated themselves as having significantly lower social skills (e.g., temper man-
agement and joining groups) and social competence (e.g., development of close friendships)
than typically developing children. Notably, in the same study, these children’s parents rated
them as having even lower skills than they rated themselves (Knott et al., 2006).
Given the profound and pervasive influence of social skills on healthy development and
functioning, social skill development has become a critical area of focus for interventions
with individuals with ASD. Interventions that address social skill development are of criti-
cal importance throughout the lifespan because “individuals with ASD do not ‘outgrow’
Social Skills Training for Autism Spectrum Disorder // 371
FIGURE 20.1 Theory of mind—Smarties task.
social skill deficits, but they persist into adulthood” (Rao, Beidel, & Murray, 2008, p. 354).
Social skill interventions seek to teach the skills that do not come naturally to individuals
with ASD while also giving opportunities to apply these skills in real-world settings. These
interventions move beyond a simple focus on social skills to address the needs of the whole
person because social skills cannot be viewed in isolation.
Interventions have been developed to assist individuals with ASD to improve social skills
and develop healthy and meaningful relationships. Historically, social skill interventions
focused on direct remediation of skill deficits (National Autism Center, 2009). However,
current approaches to treatment are more holistic and utilize a multidisciplinary approach.
In fact, the best treatments include integrated delivery of multiple intervention modalities
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(e.g., education, communication, and sensorimotor; individual, family, and group therapy;
and psychopharmacology) implemented across contexts (e.g., home, school, and commu-
nity). These treatments address the myriad of symptoms that may be present (e.g., social skill
deficits, executive dysfunction, sensory issues, anxiety, and allergies) and are tailored to the
individual. Although a treatment plan would rarely view social skills in isolation, this chapter
focuses on social skill interventions specifically while taking into account the strengths and
weaknesses of the whole person. Other chapters in this book provide for more information
on behavioral therapy (Chapter 15), psychopharmacology (Chapter 16), speech and lan-
guage therapy (Chapter 18), and occupational therapy (Chapter 19).
SOCIAL SKILLS ASSESSMENT
Before a social skill intervention can be identified, a thorough assessment is necessary. ASD
is a spectrum disorder. Individuals will have vastly different strengths and weaknesses, par-
ticularly with regard to their social skills. To plan for appropriate treatment, the following
areas need to be considered during evaluation: perspective taking (e.g., theory of mind and
understanding the thoughts of others), self-awareness (e.g., the level of knowledge about
personal strengths/weaknesses), executive functioning skills (e.g., cognitive flexibility,
problem solving, and processing speed), sensory processing, and comorbid mental health
difficulties (e.g., anxiety and depression). Assessments should include formal and informal
components as well as observations of the individual in a variety of settings. Observations
are indicated because individuals with ASD may score well on standardized assessments
and/or they may look higher functioning in the structured clinical assessment. The results
of this evaluation are critical for providers to understand when determining the type of
treatment indicated for each individual, which may vary based on Kasari and Locke’s
(2011) “active ingredients,” which are defined later. For example, many individuals with
ASD have comorbid anxiety disorders (White et al., 2009), which may interfere with their
social relationships and need to be addressed in the course of their treatment. Moreover,
even when not diagnosed with an anxiety disorder, individuals with ASD often experience
subclinical levels of anxiety that will interfere with their social performance.
Regarding assessment of theory of mind, Michelle Garcia Winner offers a tool for
classifying individuals by levels of social communication. The levels include significantly
challenged, challenged, emerging, nuanced challenged, neurotypical, and resistant social
communicators. Individuals are classified into one of these categories based on under-
standing one’s own and others’ minds, emotional coping, social problem solving, peer
interaction, self-awareness, academic skills, and mental manipulation (Winner, Crooke, &
Madrigal, 2011). In addition to Garcia Winner’s evaluation model, clinical interview and
structured group assessment have been utilized to determine one’s social skill profile and
pattern of strengths and weaknesses.
When assessing for group participation, assessment of social skills needs to go beyond
individual evaluation and consider group composition and group formation (Cotugno,
2009). A structured, intentional, and clinically informed system for group formation is criti-
cal to facilitating the success of group interventions. Individuals may be matched within
groups based on similar levels of perspective taking, previous exposure to social skill content,
and developmental level, along with numerous other factors. Depending on the individuals’
needs, group composition may also vary based on number of participants (e.g., dyads and
small group), interests, comorbid diagnosis, processing speed, or attention. Groups should
not be formed simply based on shared diagnostic label or convenience factors.
SOCIAL SKILLS INTERVENTION
Based on the results of the assessment process, interventions are determined that best fit
with the unique needs of the individual and/or the group. The primary goal of social skill
interventions is to teach the social behavior and social thinking necessary to build and fos-
ter relationships and socially adapt to different people in various contexts (Winner, 2013).
Social skill interventions provide individuals with ASD social knowledge, including educa-
tion in how to understand the mental and emotional states of others by interpreting the
context and observable behaviors and using prior knowledge.
Social skill interventions can vary immensely. Kasari and Locke (2011) identify five “active
ingredients” in social skill interventions: (1) the context of implementation (e.g., home, school,
and community), (2) the method of implementation (e.g., applied behavior analysis and social
scripts), (3) the agent of intervention (e.g., peer-, sibling-, and adult-mediated), (4) the con-
tent (e.g., peer engagement, social knowledge, and perspective taking), and (5) the dose (e.g.,
how often and how long). Based on the variability within these five factors, interventions can
take many forms. For example, an intervention may provide direct instruction about skills
and strategies for applying them. Other interventions may rely on peer or sibling modeling of
social behavior. The content of interventions may also focus on skills that are related to social
competence, such as a stress management curriculum for managing anxiety in social situations.
Another type of intervention may focus on increasing self-awareness through self-assessment
of strengths and weaknesses in order to facilitate an understanding of self in relation to others.
Regardless of their variability, an important shared goal of social skill interventions should be
to help individuals generalize the skills and knowledge to novel settings.
There are numerous existing social skill treatment models. These interventions
include social stories (Grey, 2010); video modeling of appropriate skills (Bellini &
Akullian, 2007; Mason, Rispoli, Ganz, Boles, & Orr, 2012); social skills group interven-
tions (Cotugno, 2009); Relational Developmental Intervention (Gutstein & Sheeley,
2002), Social Communication, Emotional Regulation, and Transactional Analysis
(Prizant, Wetherby, Rubin, Laurent, & Rydell, 2005); and the use of peers in integrated
classroom settings (Strain, Kohler, & Goldstein, 1996). Mindfulness-based interven-
tions, which help individuals increase their awareness of themselves and others, can
facilitate increased attention to internal states. Singh et al. (2011a, 2011b) obtained
promising results by teaching adolescents with ASD to shift their attention within a
9-week mindfulness-based stress reduction (MBSR) class. Participants in the MBSR
group were able to shift their attention from their negative emotions to the soles of
their feet. McLeod and Lucci (2009) and Lucci, Levine, Challen-Wittmer, and McLeod
(2014) embrace an integrated approach to educating individuals with ASD and have
shown promise in teaching self-awareness, mindfulness, and stress reduction tech-
niques. Groden, Kantor, Woodard, and Lipsitt (2011) have implemented a positive psy-
chology approach to educating students with ASD.
Case Study #1: “John”
John is an 8-year-old boy with high cognitive ASD. His verbal IQ is well above average, and
his performance IQ is average. He has read all the Harry Potter books, plays jazz piano, and
abhors sports and physical activity. In the parlance of Michelle Garcia Winner (2007), he is
a weak interactive social communicator. John adheres to rules rigidly and expects others
to do the same. His quirky style gathers the attention of peers who typically overestimate
374 / / T reatment
his social competency. He does well in small, structured, academically focused groups and
often proves to be a leader in that context. At recess, he barges into the personal space
of peers and initiates monologues about topics of his interest. Peers tend to listen inat-
tentively for a moment and then walk away. John has received more than adequate social
pragmatics instruction and scores very well on paper assessments of his social knowledge.
His pediatrician has noted that John has an abnormally high heart rate, his sleep is limited,
and he demonstrates restricted food interests. He denies experiencing anxiety. In fact, he
has difficulty naming any emotion.
Assessment and Intervention
John’s cognitive ability and history of social skill instruction have supported his excellent
knowledge of age and context-appropriate social competence. Further direct instruction will
likely lead him to feel patronized and misunderstood. Traditional individual therapy with an
adult counselor or therapist will likely include in-depth conversations about social pragmat-
ics with little transfer and generalization of what is learned to his social environment. John’s
alexithymia, the inability to identify emotion, requires immediate attention. He appears to
struggle to identify emotions and may quite well be affected by, but not having a phenom-
enological experience of, anxiety.
Treatment should be brought into his personal living environment. In school, this would
mean having the speech and language pathologist or school guidance counselor provide
whole classroom instruction on a variety of topics, including the naming of emotions, non-
verbal communication of emotional states, and social awareness strategies such as direct
instruction about “reading” the emotional state of the group. Advice for “reading the room”
can be communicated verbally or visually. The purpose is to have the student make a con-
scious effort to scan the environment to assess the tone, attitude, and intentions of others
so that he can match his interactions to the context. At the Aspire summer camp, groups
would engage in activities of interest and counselors would teach and support skill develop-
ment in vivo. For example, in the activity of canoeing, social goals would be attended to.
Navigation of a two-person canoe requires explicit communication regarding each person’s
intention: Prior to setting off, John would be coached by his counselor on how to determine
the intention of his peer and to negotiate differences. Once on the water, the counselor
could supportively intervene with comments such as, “Great job asking Mike about going
fast! I like the way you listened when he said he wants to go slow!” Treatment foci would
be shared with parents and other providers so they can reinforce progress across contexts.
John would be taught less pragmatics and more on a metacognitive level: He would be
taught the purpose of the skill rather than the skill itself. He would be supported to better
know his own strengths, weaknesses, and preferred methods and styles of communication.
GROUP VERSUS INDIVIDUAL INTERVENTIONS
Interventions directed at improving social interactions take the form of individual or group
treatments. Group training models are particularly effective and important because they
offer opportunities for structured and facilitated peer interactions. The group context also
provides opportunities to give and receive peer feedback. The norms of peer culture also
emerge within the group setting. For example, individuals are exposed to age-appropriate
topics of conversation and other individuals who may have shared interests. Furthermore,
and notably, group interventions provide an environment for genuine application of
learned social skills. As individuals with ASD learn the skills needed to compensate for
their social deficits, they require opportunities to practice these skills and to generalize the
skills to novel situations. In this way, group treatments provide a more “real-life” milieu than
individual treatments. For example, in Aspire groups, handheld computers were employed
to record real-time self and counselor assessments of factors that effected social success.
Data were tracked and graphically represented to teach how factors such as sleep duration
or anxiety might influence social engagement. Through a pilot study, McLeod and Lucci
(2009) found that individuals with ASD were able to use this technology to improve their
understanding of their personal components of social success.
In addition to group models, individual treatment for social skills can also be effective.
Individual treatment, with one client and one therapist, can take many forms, but it is often
grounded in cognitive–behavioral theory (CBT) and social learning theory (Attwood,
2008; Bauminger, 2002, 2007; Ho, Stephenson, & Carter, 2014; Matson et al., 2007).
However, both individual and group treatments can be grounded in CBT (Ho et al., 2014).
CBT is based on the theory that thoughts, feelings, and behaviors are interrelated, and by
changing one of these three areas, typically thoughts or behaviors, the others are subse-
quently altered. CBT is often applied to maladaptive thought patterns (e.g., black-and-white
thinking) and behavior patterns (e.g., social avoidance) that inhibit healthy social relation-
ships. Cognitive–behavioral interventions have been found to be effective in improving
social skills, social competence, and social cognition for individuals with HFA (Bauminger,
2002, 2007). Weiss and Lunsky (2010) found promising results for treating anxiety and
depression in adults with ASD by using CBT. To obtain some of the previously stated
benefits of group treatment, individual counseling may include opportunities for in vivo
practice within community settings (e.g., practice with an assigned peer), assigned home-
work to practice skills, or role-play and videotaping within the session (Bauminger, 2002).
Individual therapy may also provide a more appropriate context for addressing sensitive
personal issues, such as comorbid mental health problems or family issues.
Case Study #2: “Samantha”
Samantha is a 15-year-old student with generally average cognitive abilities with the excep-
tion of a mild weakness in processing speed. Samantha has a difficult time with comprehen-
sion in situations in which there are more than one peer and/or when peers communicate
with any rapidity. She enjoys the Twilight movie series but shows no other special interests.
She exhibits and acknowledges a high level of generalized anxiety and occasional panic
attacks. She expects to attain near perfect grades and works approximately triple the time
of a typical student on homework. Her peer group finds her repeated worries about the
same topics tiresome. She tends to be shy and expects peers to dislike her. She agrees
to all treatment suggestions yet rarely follows through. Samantha acknowledges she has
ASD but can only articulate a superficial understanding of its meaning for her. She would be
considered an emerging social communicator according to Winner (2007). Samantha tends
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to share her worries in a manner that seems to expect everyone to know and care as deeply
about them as she does.
Samantha, like John, has learned basic social pragmatics. Teaching to these skills will offer
only modest improvement to her overall social success. Given her limited social aware-
ness combined with her being generally pleasant and socially nonthreatening, Samantha
should be given simple “scripts” to communicate her worries in a more socially acceptable
manner. For example, she could state, “I know I worry too much. I really don’t mean to bur-
den you. Sometimes I just can’t stop talking about it.” Greater self-awareness can support
more successful self-disclosure. In schools in which Aspire provides consultation, a general
education curriculum called “Science of Me” has been created (Lucci et al., 2014). All stu-
dents are taught about the brain, neuropsychology, stress, and relaxation; the effects on the
brain due to sleep and nutrition are among the numerous topics covered. Samantha can be
directly taught about stress, coping, and relaxation. She can learn that her brain is respond-
ing to the construct of “low grades” in a manner more similar to a person in a life-or-death/
fight-or-flight response. Knowing this about herself, Samantha can learn to modulate her
response. A simple intervention might include a picture of a thermometer with levels of
anxiety on one side paired with the appropriate types of responses on the other.
Other modalities of instruction can be used as well. Sensors have been developed that
can be worn on the wrist or ankle to measure psychophysiological correlates of stress,
including galvanic skin response, heart rate, and movement. Data collected from the sen-
sors can inform Samantha’s counselors about her changing anxiety states but also triggers
to her anxiety. Given Samantha’s profile, she may not easily make the connection between
triggers and responses. The data can be graphically presented to highlight, for example, that
classes with frequent quizzes elicit the greatest amount of anxiety. Sample data collection
screens and a single graph are shown in Figure 20.2. The upper portion depicts screens that
staff and student use to concurrently record data. The lower portion depicts the collected
data graphically. For example, staff and Samantha review the graphs to help her better
understand how she perceives and responds to stress.
EVIDENCE-BASED TREATMENTS
A review of the research on the effectiveness of social skill interventions for individuals with
ASD generally suggests positive effects of treatment with children and adolescents (Woods,
Mahdavi, & Ryan, 2013). However, “despite their widespread clinical use, empirical sup-
port for social skill interventions for HFA/AS is minimal at this time” (Rao et al., 2008,
p. 353). There are numerous empirical issues that make social skill interventions difficult
to study, such as a lack of consistent definition of social skills; small sample sizes; variabil-
ity in measurement tools; lack of generalization of treatment effects to contexts outside of
the treatment environment; limited follow-up assessments to determine maintenance of
treatment gains over time; and differences in the levels, intensity, duration, or context of
implementation (Cappadocia & Weiss, 2011; Rao et al., 2008; Williams White, Keonig,
& Scahill, 2007; Woods et al., 2013). Furthermore, of the existing research, many studies
FIGURE 20.2 Data collection screens and a graph of student (solid dot) and staff (open dot) data points.
are not randomized controlled trials or do not utilize a comparison group (Cappadocia
& Weiss, 2011). Despite these empirical challenges, comprehensive literature reviews and
meta-analytic studies have been conducted and have found that there is empirical support
for the use of social skills training for improving social skills among youth with ASD.
Cappadocia and Weiss (2011) conducted a review of group social skill interventions.
They classified the group treatments into three categories: traditional (3 studies reviewed),
cognitive–behavioral (3 studies reviewed), and parent inclusive (4 studies reviewed).
Notwithstanding the empirical limitations noted by the authors, as a result of this review,
they concluded that there is preliminary evidence for the efficacy of social skill interven-
tions with children and youth diagnosed with ASD.
Rao and colleagues (2008) reviewed the literature for both group and individual social
skill training programs in children diagnosed with HFA and AS. Their review consisted of
10 peer-reviewed journal articles meeting selection criteria (e.g., children and adolescents
aged 18 years or younger and direct measurement of change in social skills). The authors
classified the studies as including “traditional social skills training” in either a clinic or a
classroom setting or “social skills training plus generalization,” which included a commu-
nity practice or homework to increase opportunities for generalization (p. 355). The results
of this literature review revealed that 70% of the studies reported positive treatment effects.
Williams White and colleagues (2007) conducted a review of all published studies of
group social skill interventions between 1985 and 2006 involving individuals with ASD.
Based on 14 reviewed studies, the authors proposed the following promising intervention
strategies for social skills training in ASD: (1) increased social motivation, (2) increased
social initiation, (3) improvement in appropriate social responding, (4) reduction of inter-
fering behaviors, and (5) promotion of skill generalization (Williams White et al., 2007).
This brief review of existing literature indicates that there is a growing research body to
support the efficacy of social skill interventions for individuals with ASD. However, there is
a clear need for more research in this area, including randomized controlled trials and stud-
ies of social skill interventions with adults. Future research should work to understand the
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mechanisms of change (i.e., mediators and moderators) through which social skill interven-
tions are effective (Lerner, White, & McPartland, 2012).
THE ASPIRE PROGRAM
As discussed herein, many approaches address the social learning needs of individuals with
ASD. Most of them focus on acquiring a series of skills and behaviors while decreasing
aberrant behaviors. Individuals with ASD can and should learn more than how to exhibit
prosocial behaviors. The Aspire model includes deeper assessment about the etiology of
social challenges. For example, many individuals with ASD often have heightened levels of
anxiety and/or depression. Pharmacologic intervention is often used to treat these symp-
toms. Symptom relief can also be found with other approaches. Especially for persons with
ASD, these symptoms often stem from an individual’s limited emotional understanding
and regulation. Bellini (2004) and other researchers proposed models that teach individu-
als with ASD that there are different ways to label affective experiences (emotional reap-
praisal). The emotional responses that influence the amount of anxiety and depression
experienced can be modified, which can lead to symptom reduction. Samson, Huber, and
Gross (2012) found that individuals with ASD use emotional reappraisal less than typical
peers. Individuals with ASD instead utilize emotional suppression when faced with nega-
tive emotions. By understanding how individuals with ASD process emotional informa-
tion, targeted interventions may positively impact reduction in anxiety and depression and
improved social performance. Symptom relief and social development can and should be
enhanced through an integrated and systemic view.
The Aspire approach capitalizes on the strengths and interests of individuals with
ASD. Aspire promotes this growth through our three pillars of instruction: social compe-
tence, self-awareness, and stress management. The Collaborative for Academic, Social, and
Emotional Learning (2003) supports this more broad approach. It defines the following
areas as core competencies of social–emotional learning that have positive outcomes on
student development: self-management, self-awareness, responsible decision-making, rela-
tionship skills, and social awareness.
Case Study #3: “Eric”
Eric graduated high school with excellent grades in math and science and passing grades
in all other courses. His superior collegiate aptitude scores landed him in a highly competi-
tive engineering university. He acknowledged his diagnosis of ASD due to several years of
social skill training as an adolescent. However, in college, he never sought help because
his raw cognitive abilities rarely let him down in terms of academic achievement. After 3
weeks into his first year, he stopped attending classes and began to disregard his hygiene
and spent more than 20 hours per day on Internet-based multiplayer games. Socially, Eric
withdrew totally. He did not interact with his hallmates in the dormitory, and he did not
return e-mails from his professors. He had been prescribed a benzodiazepine to be used as
needed to prevent panic attacks. He stopped using it. His parents believed him when he
told them that he was enjoying college and doing “fine.” According to Winner (2007), Eric
would be considered a socially anxious communicator. His, relatively speaking, higher level
of perspective-taking ability would lead a clinician to infer that his communication with his
parents was purposefully deceptive: He anticipated that his parents would be concerned
about his school performance. He lied to avoid the overwhelming anxiety that would occur
had his troubles come out in the open.
Eric’s social isolation began with weak executive functioning skills that made it difficult for
him to follow a schedule and plan ahead for long-term assignments. This led to challenges
dealing with growing anxiety with the realization that he was quickly falling behind. Eric had
little practice with disclosure and self-advocacy. When he started to experience trouble,
he did not have a written or internal template to access support. Upon recognition of his
impending challenges, he coped with his anxiety by dismissing it outright and engaging in
pleasurable activities. This cycle was self-perpetuating.
As with the other two case studies, the etiology of Eric’s social difficulties was not
about social competence. Indeed, in his multiplayer games, he is viewed as a leader and
helper: He organizes many of the games and counsels these peers on personal issues that
are discussed while game playing. Telling him that he “should” be showering or that he
“should” be attending class would lead to his agreement but not action. Given the level of
dysfunction, it would be recommended that Eric leave school temporarily so that he can
make a more firm connection in his thinking about school performance and work success.
Having work experience prior to immersion in college provides the purpose behind
school success. At the Aspire Internship Program, young adults such as Eric experience
the work environment and the specific components that support success (e.g., timeliness,
reporting to a boss, and meeting deadlines). In group therapy that runs concurrently with
the internship, peers are encouraged to talk with each other about the effects of tardiness,
social faux pas, and poor planning. They also receive support with mapping out how college
and work success may contribute to life satisfaction.
SOCIAL COMPETENCE
As discussed previously, direct instruction of social skills is necessary but not sufficient in
maximizing social performance (Winner, 2014). It has been reported anecdotally that many
children and adolescents with high cognitive skills score well on tests of social pragmatics
such as the Test of Pragmatic Language (TOPL-2) but functionally perform at a lower level
than the test would predict. Intellectual understanding of appropriate social behavior does
not directly lead to good social performance. The transfer and generalization of social skills
often requires instruction and support in their own right.
Many individuals with ASD learn new material in a context-dependent manner.
Application of a skill in one context requires support to be enacted in another. Social com-
petence involves social knowledge, social executive functioning, and dynamic intelligence
that allows for fluid appraisal of ever-changing social feedback.
Aspire programming includes lessons on social skills across settings and then direct
practice with using those skills in real-world contexts. For example, as cited in the adult
case of Eric, he learns appropriate workplace behaviors in his Aspire group and then
380 / / T reatment
practices those skills in the workplace with the support of a job coach. Eric may also prac-
tice generalizing these skills to a lunchroom or break room setting where he interacts with
coworkers.
SELF-AWARENESS
For social success, it is essential that individuals with ASD have a strong understanding
of their particular strengths and weaknesses, their cognitive profile, their social impact on
others, and their personal motive/intentions and social goals. As discussed previously,
individuals with ASD often have compromised abilities in terms of theory of mind or per-
spective taking. Self-awareness instruction focuses on improving accurate understanding
of one’s issues and desires. Such instruction also focuses on improving the awareness of
how one is perceived by others. Even on the level of psychophysiology, persons with ASD
often are inaccurate reporters of physical pain, moods states, and arousal levels. The broad
area of self-awareness includes recognizing one’s emotions, intrinsic values, strengths, and
challenges; knowing what brings one joy, anger, sadness, etc.; knowing how one perceives
the world through one’s personality and outlook (e.g., optimist or pessimist); and one’s
mindset (e.g., growth-oriented or fixed). Improvement in self-awareness allows individuals
with ASD to become better at self-advocacy.
Aspire seeks to foster self-awareness. It may include identification of thoughts and feel-
ings in younger children or completion and interpretation of self-assessment tools (e.g.,
personality inventories, career assessments, and executive function questionnaires) in ado-
lescents and adults. In the child case of John, he would be challenged by counselors to learn
about how to label feelings and where in his body he experiences emotions. In the case of
Eric, he would be directly instructed about how he processes social information. Staff may
review his neuropsychological assessments with him. He would be taught how to disclose
this information judiciously with school, family, or employer.
STRESS MANAGEMENT
Individuals with ASD often experience heightened levels of anxiety and stress, and they
have limited coping skills for managing them. Our autonomic nervous system (ANS)
consists of the parasympathetic and sympathetic branches. The parasympathetic branch
is responsible for “rest-and-digest” activities that occur when the body is calm. The sym-
pathetic branch is responsible for stimulating activities related to the “fight-or-flight”
response. Stressors can be external (being under attack) or internal (worried about a test).
Porges (1992, 2011) proposes a three-stage response to stress and social engagement in his
polyvagal theory. The first stage is the activation of the parasympathetic branch that immo-
bilizes the system (fright). The second stage mobilizes the system for action (fight/flight).
The third stage controls cardiac output, which can influence engagement or disengagement
with the social world. Heart rate and heart rate variability measures provide information in
vivo about the ANS (McCraty, 2005; Porges, 1992, 2011). This information can be com-
municated to the person experiencing stress so that he or she can implement stress man-
agement strategies and react in a healthier manner. Experiencing the world as persistently
stressful, which many individuals with ASD do, can lead to a chronic stress response. This
can have a serious negative impact on the body and produce symptoms, such as a lower
stress response threshold and heightened anxiety, that can lead to chronic illness and dis-
ease and hinder social engagement (Seligman, 2006).
A frequent trigger for stress in individuals with ASD is their rigid thought patterns. In
addition to frequently misperceiving relatively benign situations as anxiety provoking, they
can retain negative inaccurate beliefs for inappropriately long periods of time. These inac-
curate beliefs negatively impact social interactions, which inhibits social success. Repeated
social failure weakens a sense of resiliency and competence. Improved emotional regula-
tion can have long-lasting positive effects on social performance (Dickerson & Kemeny,
2004). Cognitive coping skills are also helpful for teaching skills to identify and address the
inaccurate thought patterns that lead to stress.
Learning stress management skills is a critical component of fostering healthy develop-
ment. In the adolescent case of Samantha, she attends classes in a program called Science
of Me, which is facilitated through Aspire consultation. In these classes, Samantha learns
about her nervous system, stress responses, physiological responses, and stress reduction
techniques. The lessons include education and practice with recognizing that stressors are
internal or external and linking stressors to thoughts, feelings, and behaviors. Samantha is
exposed to a variety of stress reduction methods (e.g., progressive muscle relaxation, mind-
fulness, and relaxation breathing) that are coupled with the use of visual supports and tech-
nology to enhance her ability to regulate her responses. The stress management tools are
generalized to other settings through homework practice and opportunities for reinforce-
ment from teachers and parents.
THE ASPIRE PROGRAM
Grounded in the three S’s (social competence, self-awareness, and stress management),
Aspire helps individuals with ASD to better understand themselves and others to help fos-
ter healthy development across the lifespan.
Aspire’s programs are developmentally focused, group based, and take place in nat-
ural settings (e.g., community and schools) to provide an authentic learning environ-
ment. Programs are tailored to individuals across the lifespan and help them learn about
themselves and others as emotional, social, and mental beings. This includes learning
about their own strengths and weaknesses to better understand themselves, similarities
and differences with others, and how others perceive them. Aspire participants engage
in some direct instruction using creative strategies and hands-on learning activities
(e.g., verbal and nonverbal, theory of mind, and relational). They also learn to apply
these skills within real-world settings (e.g., on the job, at the store, at school, and in res-
taurants), both as an individual and while attending to the needs of a larger group (e.g.,
budgeting and team projects).
By combining the three S’s model into a lifespan program, individuals with ASD can be
taught to embrace the traits and virtues that lead to a more fulfilling life. By helping indi-
viduals gain knowledge about the three S’s, they can experience the rewards of mastery of
the concepts and they are better able to be active participants in their own lives.
SUMMARY
This chapter highlights the complexity and the importance of social skill training in indi-
viduals with ASD. Understanding a person’s social skill development entails close consider-
ation of both the person and the environment because social interactions inherently involve
more than just the individual. In addition, to understand one’s social skills, there is a need
382 / / T reatment
for in-depth assessment and careful treatment planning. Social skills cannot be viewed in
isolation but instead as interacting skills along with emotional, behavioral, academic, and
cultural factors that influence development.
Social skill interventions must match this level of complexity by taking into account
individual and contextual factors, a developmental perspective, and a comprehensive
whole person approach. It is only through comprehensive assessment of an individual and
the etiology of his or her social struggles that an appropriate treatment plan can be created.
This chapter gives an overview of important components of social skill interventions for
individuals with ASD, and it provides examples from the Aspire model, which is grounded
in the three S’s (social competence, self-awareness, and stress management).
Current research generally supports the effectiveness of social skill interventions for
individuals with ASD. However, despite the widespread use of social skill interventions,
there is a critical need for increased research. A primary challenge to effective evaluation
and assessment of these interventions is the complexity of individual profiles and the
equally complex nature of appropriate social skill interventions. Nonetheless, there is a
need for more evidence-based support for social skill treatments.
In summary, social skills deficits can be quite profound for individuals with ASD, and
comprehensive, integrated, and developmentally appropriate evidence-based treatments
are necessary to remediate these areas of weakness. Social skills training, such as the pro-
grams described previously, can foster healthy social development and build satisfying
reciprocal relationships for individuals with ASD.
KEY POINTS
• Social skills deficits are a primary and defining core symptom domain of ASD.
• To plan for appropriate social skills treatment, comprehensive assessment is necessary,
and the following areas should be considered: perspective taking, self-awareness, exec-
utive functioning skills, sensory processing, and comorbid mental health difficulties.
• Group training models for social skills are particularly effective and important
because they offer a more “real-life” milieu than individual treatments.
• A structured, intentional, and clinically informed system for group formation is criti-
cal to facilitating the success of group interventions.
• Effective social skills training programs should be developmentally focused, group
based, and take place in natural settings (e.g., community and schools) to provide an
authentic learning environment.
Dr. D. Scott McLeod and Dr. Kristin W. Malatino have nothing to disclose.

Dorothy Lucci serves on the Clinical Scientific Leadership Board of SymTrend, Inc. She
does not receive financial compensation or salary support for her participation as an advisor.
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SE C T I O N 4 / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / /
OTHER CARE DELIVERY

SERVICES AND
PERSPECTIVES
/ 21
/ / / / / EDUCATIONAL ISSUES
IN AUTISM SPECTRUM
DISORDER
SAMUEL L. ODOM, VERONICA P. FLEURY,

LESLIE C. FOX, SUSAN H. HEDGES, NIGEL
P. PIERCE, AND MELISSA A. SRECKOVIC
INTRODUCTION
At an international meeting for research on autism spectrum disorder (ASD), Peter Mundy,
a prominent cognitive and developmental scientist, stated that school-based intervention,
treatment, and instructional programs may be “the best hope” for children and youth
with ASD (McIntyre et al., 2013). In the United States, children and youth with ASD are
in schools for a significant period of their week, for the majority of the year, from child-
hood into early adulthood. Schools have the mandate to provide a free and appropriate
public education for children with all types of disabilities, including ASD. Professionals
should plan programs with parents and, at times, students should be involved. This chapter
describes the educational process for children and youth with ASD in the United States and
addresses current and future educational issues.
The primary focus of this chapter is on public educational programs, which can begin at
age 3 years and continue up to age 22 years in many states. The early intervention system for
infants and toddlers with ASD in the United States operates primarily outside of the public
education system (i.e., often implemented through state health departments), but when
issues arise that are pertinent for infants and toddlers and their families, they are addressed.
This chapter begins with a brief review of diagnostic criteria and the parallel eligibility defi-
nitions that exist in US federal law. The continuum of educational services across childhood
and adolescence, the unique learning needs of individuals with ASD during those years,
the quality features of programs that address learning needs, and validated, evidence-based
intervention practices are delineated. The chapter describes issues related to families in the
educational process and concludes with a discussion of the use of technology in education
for students with ASD.
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388 / / O ther C are D eli v ery S er v ices and Perspecti ves
DIAGNOSTIC AND EDUCATIONAL ELIGIBILITY DEFINITIONS

OF AUTISM SPECTRUM DISORDER
Common agreement about ASD as a disorder is essential when discussing both science
and services for students with ASD. Diagnostic criteria are situated in the psychiatric and
medical communities. To qualify for educational services in the United States, however,
children and youth with ASD must meet “eligibility” requirements, which have a parallel
set of definitional criteria.
Diagnostic Criteria
The 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5;
American Psychiatric Association, 2013) provides the diagnostic criteria primarily fol-
lowed in the United States. The defining characteristics of ASD are deficits in social com-
munication and the presence of restrictive and repetitive behavior, with characteristics
being manifest before the age of 3 years. DSM-5 eliminated the classifications of autistic
disorder, Asperger’s disorder, Rett’s disorder, childhood disintegrative disorder, and per-
vasive developmental disorder, not otherwise specified, which were in the previous edi-
tion. The international community often employs the 10th edition of the International
Classification of Diseases (ICD-10; World Health Organization, 1992) for diagnosis of
autism. Grouped with a superordinate category called Pervasive Developmental Disorders,
there are diagnostic classifications termed childhood autism, atypical autism, Rett’s syn-
drome, childhood disintegrative disorder, and Asperger’s syndrome. These disorders share
the common characteristics of having difficulties in forming social relationships, language
delays/disorder, and/or repetitive or challenging behavior. The World Health Organization
(2013) recently grouped these disorders under the ASD umbrella term, which makes it
consistent with the US terminology. A more detailed discussion of psychiatric diagnosis
and classification appears in Chapter 1 of this book.
Educational Eligibility Criteria
Children and youth with ASD, like all children in the United States, are entitled to a
free and appropriate public education. The Individuals With Disabilities Education Act
(IDEA; 34 C.F.R. §§ 300.1 et seq., 2009) stipulates that special education services be
made available to children with disabilities who meet eligibility criteria. The eligibility
definition for children with ASD, which is termed “autism” in the federal regulation,
states the following:
Autism means a developmental disability significantly affecting verbal and nonverbal

communication and social interaction, generally evident before age three that adversely
affects a child’s educational performance. Other characteristics often associated with
autism are engagement in repetitive activities and stereotyped movements, resistance
to environmental change or change in daily routines, and unusual responses to sensory
experiences. (IDEA, 300.8.c.1.i; http://idea.ed.gov/explore/view/p/,root,regs,300,A,
300%252E8)
A multidisciplinary team conducts a variety of assessments to determine a child’s qualifica-

tion for special education services under the autism definition.
Educational Issues in Autism Spectrum Disorder // 389
THE CONTINUUM OF EDUCATIONAL SERVICES
IDEA separates services for children with special needs into two programs. Part B of
IDEA delineates the timeline and minimum requirements for school-age children (i.e.,
3–21 years). Part C of IDEA governs the early childhood intervention (ECI) programs for
children birth to age 3 years. There are commonalities between Part B and Part C services.
They each seek to identify children with special needs and use multidisciplinary teams to
conduct developmental assessments and make service recommendations. However, there
are several notable differences between the two processes related to referrals: location of
services, degree of parent involvement, philosophical foundations, cost, and the referral-to-
service implementation timeline.
ECI services in a given community may be sponsored by a school district, private/non-
profit organization, or county mental health program. Either parents or health care provid-
ers typically initiate referrals to ECI programs. Because primary care physicians routinely
see children younger than the age of 5 years for well child appointments, they are often the
first to field questions from parents regarding their child’s developmental skills and abilities.
It is not necessary for infants and toddlers to have a formal diagnosis in order for families
to receive ECI services. If a child shows a significant delay in one or more areas of develop-
ment (e.g., cognition, communication, physical–motor, social–emotional, and self-help/
adaptive skills), then an assessment team can establish eligibility. Many children who later
receive an ASD diagnosis initially qualify for ECI services based on developmental delays
in communication, but they may also present with unusual motor patterns and social skills.
Early physician referrals and provision of information to parents on available services are
associated not only with early access to intervention but also parent ratings of satisfaction with
medical care (Liptak et al., 2006). In fact, early developmental as well as ASD-specific screen-
ings are recommended practices for pediatricians (American Academy of Pediatrics, 2012).
Once a referral is submitted to an ECI program, the program has up to 45 calendar days to
complete an evaluation and develop an Individualized Family Service Plan (IFSP). The IFSP
is a parent-driven document that reflects functional goals and outcomes relative to the child’s
skills and abilities. Services are provided year-round in the child’s “natural environment,” such
as the child’s home or day care, but may also take place in other settings identified by parents.
After a child’s third birthday, the ECI will arrange a transition planning conference
with the local education agency (LEA). If a child were not identified prior to age 3 years,
the responsibility for evaluation and service provision would fall to the LEA. Parents fre-
quently initiate referrals for children 3–5 years old often based on information provided by
health care providers. Classroom teachers and related service providers typically initiate
special education referrals for children kindergarten age or older. Once a referral is sub-
mitted to the special education program, schools must complete the evaluation, eligibility
determination, and development of an Individualized Education Program (IEP) within 45
school days. The goals of the IEP are less parent-driven than the IFSP and more specific to
academic objectives. These services are usually provided during the regular academic year
and rarely extend over summer and holiday breaks.
The IEP services are provided in the “least restrictive environment” available to meet
the child’s educational goals. To the maximum extent appropriate, a child with ASD should
be included in the general education classroom and provided access to the general cur-
riculum. Inclusion of students with disabilities in the general education classroom with
typically developing peers is dependent on the individual needs of the child and can be
established by providing additional supports such as assistive technology, a special educa-
tor, a paraprofessional, or other specialist.
Parents participate in the development of the IEP and act as consenting authorities
for school-based services. When appropriate, children with special needs are expected
to attend IEP meetings, and as they grow and transition from childhood to adolescence
they are encouraged to actively participate. By age 16 years, each child’s IEP must include
an Individual Transition Plan (IDEA; 34 C.F.R. §§ 300.1 et seq., 2009), and the student
must be invited to attend the meeting. Transition plans are developed by the IEP team and
outline specific measureable post-secondary goals related to education/training, employ-
ment, and independent living (if appropriate) along with specific transition activities to
help achieve those goals. Most states have vocational rehabilitation agencies that may be
invited to attend transition IEP meetings and assist with the transition out of high school
for adolescents with disabilities.
Some individuals with disabilities graduate from high school and are accepted into
post-secondary education settings. This transition can be difficult because many parents are
unaware of the different laws that govern accommodations and access in post-secondary
settings (US Department of Education, Office of Civil Rights, 2007). Families who are
not knowledgeable of such differences may struggle to prepare their child to access accom-
modations when starting college. Even though a student may have had a diagnosis of ASD
from a young age, additional diagnostic information or documentation may be required
when transitioning into the post-secondary setting if the student has not recently been
evaluated.
LEARNING NEEDS OF STUDENTS WITH AUTISM SPECTRUM DISORDER
Individuals with ASD may exhibit specific learning needs across the age range; however,
those needs may vary by individual. In educational settings, student success is often mea-
sured by academic achievement. Research suggests that some individuals with ASD are
behind their same-age peers in academic areas, and as children get older and enter second-
ary school, the gap often continues to widen. In addition to academics, individuals with
ASD often struggle to keep up socially with their same-age peers, which may limit their par-
ticipation in class and schoolwide activities. Children who enter formal schooling lacking
social and emotional competence, a core feature of ASD, will likely have difficulty succeed-
ing in school (National Center for Special Education Research, 2006). These difficulties
begin early in life. Very young children with ASD may lack or lag behind in developing
foundational social communication skills, such as joint attention and imitation. Without
early intervention, these difficulties may persist, hindering children’s performance in edu-
cational settings. For example, children with ASD may have trouble following a teacher’s
direction, staying on task, and/or participating in group activities. In addition, an intense
focus or preoccupation with a restricted range of interests creates challenges for children
with ASD and may limit their participation in classroom activities.
Individuals who are unresponsive to a teacher’s direction, unable to independently
complete tasks, or engage in stereotypic behaviors usually cannot fully participate in, and
thereby benefit from, classroom activities without appropriate support. These behaviors
may result in students being placed in more restrictive school settings (Machalicek, O’Reilly,
Beretvas, Sigafoos, & Lancioni, 2007), which in turn limits access to the general education
curriculum and typically developing peers. It is helpful for practitioners to understand how
core behaviors characteristic of ASD can affect an individual’s ability to learn in educational
settings. The core features of ASD are described next in relation to how they may impact
students regarding academics, social competence, and independence.
Academics
Federal legislative acts such as the No Child Left Behind Act (2002) and the Individuals
With Disabilities Education Improvement Act (IDEA, 2004) hold schools accountable for
student achievement in core curricular areas such as math, reading, and science. The IDEA
specifically requires that students with disabilities have access to and make progress in the
general education curriculum to the fullest extent appropriate. Students who are educated
in inclusive settings have been found to spend more time engaged in curricular activities and
demonstrate significant gains in academic achievement compared to students with ASD
who are educated primarily in self-contained classrooms (Kurth & Mastergeorge, 2012).
Most individuals with ASD who take courses in general education classrooms receive some
type of academic accommodation (e.g., untimed testing). Two-thirds have the curriculum
modified (e.g., simplifying the text in a reading passage), and roughly one-half take modi-
fied tests in which they work toward the same grade-level standards as their same-age peers
who are nondisabled, but with alternate achievement targets (Newman, 2007).
Although the diagnostic criteria for ASD do not imply academic difficulties, impair-
ments in the social communication domain, as well as engagement in restricted, repetitive,
and stereotypic behaviors, may contribute to the challenges around academic performance
and have proven to be predictive of future academic achievement (Estes, Rivera, Bryan,
Cali, & Dawson, 2011). Understanding the academic profile of individuals with ASD is
complex due to a high prevalence of comorbid intellectual disability (ID), a higher preva-
lence of learning disabilities than occurs in the general population, and splinter skills or
uneven skill profiles that make accurate assessment difficult. Generally, individuals with
ASD have an overall strength for rote or procedural skills. For an elementary-age student,
this may be reflected in above average ability to decode words (e.g., letter–sound identifica-
tion), spell, and memorize math facts. Conversely, this same student may have a weakness in
abstract or inferential skills. This weakness may become more apparent during high school,
when the same student may have difficulty comprehending complex texts and applied math
problems and writing analytical essays (Kurth & Mastergeorge, 2010).
Social Competence
Schools are highly social contexts and success is often dependent on the relationships that
develop between students with ASD, their teachers, and their peers. Across the age range,
students are expected to work with peers in groups and contribute to group projects in a
meaningful way. Starting as early as preschool, students are expected to interact with their
peers by sharing classroom materials, taking turns, and participating in cooperative play
and work. As students enter middle and high school, the social dynamic becomes more
complex. They often place greater emphasis on friendships and become more selective in
their peer groups. For students with ASD, developing and maintaining peer relationships
can be difficult. In fact, elementary-age students with ASD have reported poorer friend-
ship quality and fewer reciprocal friendships compared to their peers without ASD (Kasari,
Locke, Gulsrud, & Rotheram-Fuller, 2011). Wagner, Cadwallader, Garza, and Cameto
(2004) reported that adolescent students with ASD participating in a national longitudinal
study were the least likely (in comparison with students having other disabilities) to fre-
quently see friends outside of school, receive telephone calls from friends, and get invited
to another student’s social event. Unfortunately, not only do these students have difficulties
making positive peer relationships but also they are bullied by their peers at alarmingly
high rates across the elementary, middle, and high school years (Sreckovic, Brunsting, &
Able, 2014).
The core diagnostic features of ASD imply difficulties developing social competence and
establishing relationships. For instance, due to deficits in social interaction and communi-
cation, students may not understand how to join a conversation or may dominate a conver-
sation by excessively talking about their special interests. For example, an elementary-age
student with an intense interest in trains may dominate conversations and persist on talk-
ing about Thomas the Tank Engine. Similarly, a middle or high school student may have
a special interest in US highways, which becomes the central theme of his conversations.
Although some students may be impressed with the ASD student’s vast knowledge of US
highways, most students will find the obsessive interest odd, further isolating the student
with ASD. In addition, students may have difficulty reading facial expressions, body lan-
guage, and prosody, making comprehending conversations challenging. For students who
engage in unusually restrictive and repetitive behaviors, their behaviors may hinder their
ability to participate in school activities. The presence of unusual behaviors can make stu-
dents with ASD stand out from their peers and make them vulnerable to being bullied.
Students with ASD also often have difficulty understanding the intentions and thoughts of
others (Baron-Cohen, Leslie, & Frith, 1985), making it difficult for them to discriminate
when their peers have ill intentions. At the elementary, middle, and high school levels, peers
may take advantage of the gullibility of students with ASD. For example, peers may tell
the student with ASD to make inappropriate comments to the teacher or a student of the
opposite sex. Students with ASD who may have difficulty recognizing these ill intentions
are often compliant to their peers’ requests, making them easy targets for bullying victim-
ization (Sofronoff, Dark, & Stone, 2011). To develop social competence and establish peer
relationships, individuals with ASD need explicit instruction as well as authentic opportu-
nities to practice social skills and foster friendships (Carter et al., 2014).
Independence
In educational settings, independent functioning (i.e., “on-task engagement in an activity

in the absence of adult prompting”; Hume & Odom, 2007, p. 1172) is a necessary skill in
school and beyond. Starting as early as kindergarten, students are expected to complete
classroom tasks independently without adult assistance. As students enter late elemen-
tary school and secondary school, autonomy increases; students are expected to man-
age not only in-class assignments but also homework and class projects independently.
Independence is also necessary for post-school success. Unfortunately, research has found
very poor post-school outcomes for students with ASD. In a national survey, less than 40%
of young adults with ASD participated in some type of independent employment since
leaving high school, and only 17% were living independently (Newman et al., 2011).
The diagnostic criteria and core features of ASD do not specifically include difficulties
with independence. However, limited social interaction and social communication skills
may contribute to challenges of independence. For example, many students learn skills
necessary for independence by observing others. However, challenges within the social
and communication domain often limit the ability of students with ASD to observe peers
and learn necessary skills for independent functioning because these students often have
difficulty discriminating among the multiple social cues in the environment (Plavnick &
Hume, 2014). Asking questions and seeking clarification may also be difficult for students
with ASD because they may not know what questions to ask or who to ask (Hurlbutt &
Chalmers, 2004). In addition, the preference for sameness and limited flexibility can make
changes in daily routines extremely challenging and disruptive. Children and youth with
ASD often become dependent on adult prompts, and withdrawing such prompts may be
difficult for students who prefer sameness (Hume, Loftin, & Lantz, 2009).
Difficulties with independence can appear similar across grade levels. For example, an
elementary student who does not understand a writing assignment may sit at his or her
desk, staring at the paper, rather than asking a peer or the teacher for help. This same stu-
dent might express similar difficulties in middle and high school. However, at the middle
and high school level, students may demonstrate more difficulties around independence
because they are expected to navigate several classes a day, which can entail managing mul-
tiple materials, assignments, projects, and teacher expectations. For students with ASD and
ID, the challenges of achieving independence are even greater because research suggests
they have lower levels of daily living skills and gain skills at a slower rate compared to their
counterparts with ASD without ID (Smith, Maenner, & Seltzer, 2012). The heightened
importance of independence starting in preschool and extending to post-school highlights
the need for interventions focused on building independence across the age range. Given
the multifaceted needs of children and youth with ASD, high-quality and effective educa-
tional programs are needed.
ESSENTIAL FEATURES OF EDUCATION PROGRAM QUALITY
Educational programs vary in quality, as do all human services. To be advocates for chil-
dren with ASD, it is important for professionals and family members to understand the
features of an educational program that reflect quality. Researchers and service provid-
ers have developed instruments to measure program quality. In 2001, the New York State
Education Department developed the Autism Program Quality Indicators guide, which was
subsequently adapted by New Jersey (New Jersey Department of Education, 2004). This
guide focuses on program characteristics (e.g., personnel and curriculum) and student con-
siderations (e.g., assessment and IEPs). In their research on program efficacy of two com-
prehensive preschool models, Hume et al. (2011) developed a measure of program quality
for preschool programs for children with ASD. Called the PDA Fidelity Form, this rating
scale focused on eight features of programs for children with ASD (e.g., teaming, environ-
ment, and family involvement). To assist in their work with schools to improve services for
children and youth with ASD, investigators with the National Professional Development
Center on ASD (NPDC) developed a comprehensive assessment of program quality called
the Autism Program Environment Rating Scale (APERS; APERS Research Group, 2014).
Similar in content to the PDA Fidelity Form, the APERS conceptual framework contains
sections that address teaming, program ecology, and families (Figure 21.1), with subdo-
mains in each section. This framework is used to discuss features of quality in educational
programs.
Teaming
Teaming refers to the promotion of collaborative relationships and ongoing interactions

among service providers to ensure that the outcomes and goals of students with ASD are
being met. High-quality teaming in support of students with ASD is interdisciplinary in
nature and includes, in addition to special and general education teachers, any number of
Interdisciplinary
Teaming
Program Ecology
Classroom Environment
Structure-Schedule
Positive Classroom Climate
Curriculum
Progam Learner
Communication Quality Outcomes
Social Relationships
Independence
Functional Behavior
Assessment
Family
Participation
FIGURE 21.1 Conceptualization of quality features of programs for children and youth with
autism spectrum disorder.
related service providers, such as speech and language pathologists, occupational therapists,
psychologists, counselors, transition coordinators, autism specialists, behavior specialists,
and vocational specialists. It is essential that family members are included on the team and,
when appropriate, the student should be invited to attend IEP meetings (a requirement
beginning no later than age 16 years). Medical professionals may also participate in the
team as necessary depending on the individual needs of the student (e.g., related to medica-
tions, seizures, and affective behavior). It is important that the team members have training
and experience working with students with ASD.
Having a key team member who is responsible for the student’s program is an essen-
tial feature of teaming. The key team member coordinates instructional plans among the
team and facilitates frequent communication with and among all relevant team members.
Technologies such as e-mail, text, and video conferencing can help facilitate more fre-
quent collaboration. Responsibilities of the team may include assessing needs, identifying
problems and problem solving, brainstorming, reaching consensus, setting goals, making
plans, and implementing and evaluating plans. A component of particular importance for
high-quality teaming includes a system of follow-up to assess the implementation of the
team’s decisions.
Program Ecology
The ecology of an educational program consists of structural quality and instructional quality
(Odom & Bailey, 2001). Structural quality includes the characteristics of the class settings,
the structure and schedule, and the social climate of the program. High-quality programs
have age and instructionally appropriate materials that are accessible to the learner. They
incorporate clearly articulated and predictable schedules, which are often supplemented by
visual supports for students (e.g., individual activity schedules). In addition, high-quality
programs have a positive instructional “climate,” one indicator of which is that the teachers
and/or staff direct more positive than negative statements to the students with ASD.
Instructional quality refers to opportunities for students to engage in meaningful learn-
ing activities with learning opportunities focusing on areas that are primarily related to indi-
vidual goals for students with ASD (e.g., communication, social skills, independence, and
reduction of challenging behavior). In high-quality programs, staff plan instruction in dif-
ferent formats (e.g., one-on-one instruction and whole class instruction) that fit the learning
needs of the students; may use specific behavioral techniques (e.g., reinforce assessment,
task analysis, and prompting hierarchy) as appropriate for learner needs; and assess student
performance in order to make instructional decisions (i.e., change instructional approach
if the student is not making progress). In addition, high-quality programs employ interven-
tion and instructional strategies that focus on communication skills, social skills and peer
relationships, independence, and reduction of challenging behavior.
Families
A strong home–school relationship is an important foundation for a positive educational

experience for all children with disabilities (Berry & Hardman, 1998). It is for this reason
that the IDEA requires that parents have the opportunity to participate in the development
of the IEP. The intent is to include the parents as members of the educational team and
build a collaborative partnership between parents and educators. Although the legal frame-
work exists, in practice there is great variability in implementation.
In high-quality programs for students with ASD, family involvement is characterized
by a strong, positive school–family rapport. To accomplish this, school personnel have a
system for regular, frequent, and individualized communication aided by technology (e.g.,
e-mail and text) as appropriate. It is important that school staff members demonstrate
respect for families’ knowledge, cultural beliefs, and priorities and avoid jargon and acro-
nyms or technical terms. In addition, schools must be flexible in meeting times to facili-
tate participation. Throughout the school experience, family involvement is considered an
essential support for students with ASD (Test, Smith, & Carter, 2014).
Quality in Early Intervention Programs
As noted previously, early intervention programs differ from most public school-based pro-
grams in that they are often administered by a different agency, are more often home-based
rather than school- or center-based, more often deliver services through a visiting/consult-
ing therapist or educator, and operate from an IFSP rather than an IEP. In extending their
work on the APERS to infant/toddler early intervention programs, NPDC investigators
(Cox, Kucharczyk, Shaw, Rogers, & Odom, 2014) created a new program environment
measure for infants and toddlers with ASD, their families, and subsequent care providers.
Quality features include (1) establishing a positive relationship with the care provider;
(2) helping the family organize predictable physical environments, activities, and daily rou-
tines; (3) using specific intervention strategies (i.e., as noted in the subsequent section on
evidence-based practices); (4) providing ongoing assessment for developing the IFSP and
monitoring child progress; (5) addressing behavioral issues when they occur; and (6) lead-
ing interdisciplinary teaming.
A Last Note on Intensity
In their 2001 review of educational programs for children with ASD, a National Academy
of Sciences committee stated that programs had to be intense to produce positive outcomes
for children with ASD (National Research Council, 2001). By intensity, the committee
specified 25 hours per week of intervention, and in subsequent years researchers have
proposed that student engagement in productive learning experiences during interven-
tion or instruction is also an important feature of intensity (Thompson, 2011). For public
school programs, it is reasonable to expect that children and youth with ASD receive at
least the same number of service hours as do typically developing children, which usually
exceeds 25 hours per week, and that they engage in meaningful learning experiences dur-
ing the majority of those hours (APERS Research Group, 2014; New York State Education
Department, 2001).
EVIDENCE-BASED PRACTICE
The concept of evidence-based practice (EBP) is central to the provision of educational

services to children and youth with ASD in the United States. The federal laws govern-
ing education (i.e., No Child Left Behind) and special education (i.e., IDEA) emphasize
that instruction and intervention for students must be research-based—that is, supported
by empirical findings that document efficacy of the approach. This evidence-based educa-
tion movement emerged from two sources. One source was educational leaders’ frustra-
tion with the distance between research and practice (Carnine, 1999). Another primary
influence was from the field of evidence-based medicine (EBM), which was based on
the work of Cochrane (1972) and colleagues in the United Kingdom and led by Sackett
(Sackett, Rosenberg, Gray, Haynes, & Richardson, 1996) and colleagues in Canada and
the United Kingdom as well. EBM proposes that medical practitioners should use the best
available scientific evidence to guide their practice as well as their expert knowledge about
the patient and treatment (Sackett et al., 1996). This combination of EBP and professional
knowledge of interventions and ASD guides effective education for students with ASD, and
it is a theme to which this chapter returns later.
Comprehensive Treatment Models
Beginning early in the history of intervention research for children and youth with ASD,
comprehensive treatment models (CTMs) emerged as a form of treatment. CTMs are
programs guided by a conceptual model, documented in procedural manuals, and avail-
able for adoption or replication (Odom, Boyd, Hall, & Hume, 2014). They are intensive
in nature (i.e., often 25 or more hours per week), have a conceptual framework, extend
across a long period of time (e.g., school year), focus on the multiple learning needs of
students with ASD (e.g., social, communication, and behavior), use assessment and data to
make instructional decisions, and have a family component (National Research Council,
2001). Two of the first CTMs were the UCLA Young Autism Project established by Lovaas
(1987) and the Treatment and Education of Autistic and Communication Handicapped
Children (TEACCH) project established by Schopler, Mesibov, and Hearsey (1995). At
least 30 such models have appeared in the professional literature (Odom, Boyd, Hall, &
Hume, 2010).
Many CTMs are clinic- or home-based (e.g., Early Start Denver Model; Lovaas
Institute). However, some models are amenable to adoption by public schools or specifically
designed for use in public school settings. In their research on the TEACCH and Learning
Experiences and Alternate Program for Preschoolers and Their Parents (LEAP) CTMs,
Boyd et al. (2014) found both types of CTMs implemented in school systems in four states,
and research indicates that the STAR model (Arick et al., 2003) has been implemented
successfully in public schools. Also, developers have designed school-based versions of the
Pivotal Response Treatment Model (Stahmer, Suhrheinrich, Reed, Bolduc, & Schreibman,
2010) and the Social Communication, Emotional Regulation, and Transactional Support
(SCERTS) models (Prizant, Wetherby, Rubin, Laurent, & Rydell, 2005). For school sys-
tem personnel to use these models appropriately, they need to be trained by the developers
or authorized trainers and implement them with a high level of fidelity.
A limitation of CTM use in the public schools is that nearly all models have been devel-
oped for and validated with preschool and elementary school children. Although schools
provide educational services for preschool and elementary children, they also enroll middle
and high school students with ASD, and no CTMs have been developed for those groups.
A second limitation for the broad CTM literature is that few empirical studies have docu-
mented their efficacy and can thus be called evidence-based. The models with random-
ized controlled trial (RCT) or quasi-experimental design evidence are the Lovaas model
(Lovaas, 1987), LEAP (Strain & Bovey, 2011), TEACCH (Boyd et al., 2014), and Early
Start Denver Model (Dawson et al., 2010). Although others have accumulated, in some
cases, extensive evidence (e.g., single case design studies of individual procedures), it is not
in the form of experimental efficacy studies of the model.
A Note on Applied Behavior Analysis

Much confusion now exists over the term “applied behavior analysis” (ABA) and the
model of services it implies. ABA represents a wide array of practices based on behavioral
principles, although the common erroneous assumption often is that the only practice fol-
lowed is discrete trial training. The ABA professional community has attempted to ensure
some uniformity in the quality of ABA interventions implemented by establishing Board
Certificated Behavior Analysis (BCBA) training programs and certification. However,
BCBA training does not specifically require any content or supervised experience related
to ASD. As mentioned later in the discussion of EBPs, many individual practices have a
theoretical ABA foundation.
Focused Intervention Practices
Focused intervention practices are individual interventions that target specific goals for stu-
dents with ASD. For example, discrete trial training (i.e., a one-on-one form of adult-child
instruction) is a focused intervention practice that a teacher might use to address a goal
for an individual student, and it is also one of a set of procedures that make up the Lovaas
CTM. In most cases, schools do not adopt entire CTMs, but instead teachers design indi-
vidualized programs for children and youth with ASD, as noted previously. When teachers
select evidence-based, focused intervention practices to use with students, they follow a
“technical eclectic” model, which is a teaching process that uses instruction/intervention
procedures validated by efficacy research (Odom, Hume, Boyd, & Stabel, 2012). The nec-
essary requirement for such an approach is that researchers have identified the EBPs.
Investigators have conducted systematic reviews of the literature to identify EBPs for
children and youth with ASD. The National Standards Project (National Autism Center,
2009) conducted an extensive review of the literature that covered multiple decades and
followed a systematic procedure for evaluating studies. The project identified 11 practices or
sets of practices that it calls treatments. Drawing from a narrower time period (1997–2007),
investigators with the NPDC also did a systematic search and evaluation of research articles
(Odom, Collet-Klingenberg, Rogers, & Hatton, 2010). They found that 24 practices met
their criteria for being classified as evidence-based (i.e., had at least two acceptable RCT
or quasi-experimental studies or five single case design studies by two different research
groups). In an update of this review, Wong et al. (2014) found support for 27 EBPs. These
practices are presented in Table 21.1. The majority of the practices are based on foundational
ABA concepts (e.g., prompting, reinforcement, and task analysis) or organized into a multi-
component intervention that incorporates the foundational concepts (e.g., functional com-
munication training, pivotal response training, and naturalistic intervention). In addition,
there are a set of practices that have been routinely incorporated into a package of positive
behavior intervention and support (e.g., functional assessment, extinction, redirection, ante-
cedent interventions, and direct reinforcement of other behavior), which are described later.
Positive Behavior Intervention and Support
The presence of behavior problems poses significant challenges to effective classroom

instruction. In school settings, children with ASD demonstrate significantly higher
TABLE 21.1 Evidence-Based Practices Identified by the National Professional Development Center
on Autism Spectrum Disorder
Antecedent-based Cognitive–behavior Differential reinforcement

interventions (ABI) interventions (CBI) (DRA/I/O)
Discrete trial training (DTT) Exercise (ECE) Extinction (EXT)
Functional behavior Functional communication Modeling (MD)
assessment (FBA) training (FCT)
Naturalistic interventions (NI) Parent-implemented Peer-mediated intervention (PMII)
interventions (PII)
Picture Exchange Communication Pivotal response training Prompting (PP)
System (PECS) (PRT)
Reinforcement (R+) Response interruption/ Scripting (SC)
redirection (RIR)
Self-management (SM) Social narrative (SN) Social skills training (SST)
Structured play groups (SPG) Task analysis (TA) Technology-aided intervention
and instruction (TAII)
Time delay (TD) Video modeling (VM) Visual supports (VS)
Source: Adapted from Wong, C., Odom, S. L., Hume, K., Cox, A. W., Fettig, A., Kucharczyk, S., …
Schultz, T. R. (2014). Evidence-based practices for children, youth, and young adults with autism
spectrum disorder. Chapel Hill, NC: The University of North Carolina, Frank Porter Graham
Child Development Institute, Autism Evidence-Based Practice Review Group.
behavioral excesses and deficits, including limited communication, difficulty participat-

ing in the school routine, and aggression or self-injurious behavior, compared to typically
developing peers (Ashburner, Ziviani, & Rodger, 2010). Educators have taken different
approaches to address problematic behavior that occurs in their classroom. Early on, some
forms of punishment such as verbal reprimands, school suspension, and even aversive con-
ditioning for more severe problem behavior were used (Friman, 1984). In addition to rais-
ing ethical concerns regarding the use of punishment as a primary disciplinary measure,
researchers have also found that punishment procedures are generally ineffective over time
because they do not address the underlying reasons why the individual may be engaging
in the behavior and do not teach students how to engage in more appropriate behavior
( Johns, Mather, & McGrath, 2003).
Currently, many school staff members employ a more proactive approach to discipline
and behavior management. Positive Behavior Interventions & Supports (PBIS; see http://
www.pbis.org) has been widely adopted by schools throughout the United States as a
model for dealing with problem behaviors that arise in school. The PBIS model is adapted
from public health research on prevention medicine, and it gives educators a systematic
process for beginning with prevention strategies and moving to more intensive interven-
tion as needed. The PBIS model depicted in Figure 21.2 identifies preventative strategies
Tertiary Prevention
Specified intervention individualized for students
Students with
chronic intese
problem behavior
1-7% of student
population
Secondary Prevention
Specialized group interventions Students at-risk for problem behavior
5-15% of student population
Primary Prevention
Universal interventions
(schoolwide, classroom, school timing) Students without serious problem behavior
80-90% of student population
FIGURE 21.2 Levels of prevention in the positive behavior intervention and support model.
Source: Adapted from Sugai, G., Horner, R. H., Dunlap, G., Hieneman, M., Lewis, T. J., Nelson, C. M., … Ruef, M.
(1999). Applying positive behavior support and functional behavioral assessment in schools. Washington,
DC: Office of Special Education Programs, Center on Positive Behavioral Interventions and Supports, p. 11.
taking place at the three tiers of prevention: primary, secondary, and tertiary prevention
levels (Sugai et al., 1999).
The goal of primary prevention (tier 1/schoolwide positive behavior support) is to pre-
vent challenging behavior for all students by teaching students the behaviors they should
demonstrate at school. Prevention efforts at this level involve establishing clear school
expectations, designing a system for promoting positive behavior (e.g., incentive programs
for following school rules), and manipulating environmental factors that contribute to
problem behavior (e.g., increasing supervision in hallways and playgrounds). Secondary pre-
vention (tier 2) is used when students continue to engage in challenging behaviors, which
requires additional support than is afforded by primary strategies alone. Approaches at this
level target students who share common concerns (e.g., family disruption) and who require
intensive instruction in a specific area (e.g., social skills groups; Check-in/Check-out with
adults). Students who persist in engaging in problem behavior are referred to tertiary pre-
vention (tier 3). Interventions at this level involve conducting a functional behavior assess-
ment to identify possible function(s) of the behavior and developing a support plan that
includes strategies to address the behavior based on the individualized assessment.
Adopting a Preventative Approach to Reducing Victimization

As previously mentioned, students with ASD are bullied at alarmingly high rates. In one
study, 77% of parents reported that their children with ASD (5–21 years old) were bullied
within the previous month (Cappadocia, Weiss, & Pepler, 2012). These students have been
coined by researchers as “perfect victims” due to their severe deficits in social skills and
difficulties establishing and maintaining relationships with peers (Klin & Volkmar, 2000,
p. 6). For example, when students with ASD do not adopt similar clothing, hair styles,
and mannerisms as those of their peers, they become vulnerable to bullying victimization
(Bukowski & Sippola, 2001). In elementary school, bullying is typically expressed physi-
cally and verbally. However, as students enter middle and high school and gain better social
skills, they begin to manipulate relationships and use more relational forms of victimiza-
tion. The student with ASD, who likely already has difficulty with social competence and
peer relationships, is often easily manipulated by peers and therefore becomes an easy tar-
get for perpetrators. PBIS provides a promising approach to reduce the frequency of bul-
lying behaviors. At the primary level, the goal is to reduce new cases of bullying through
whole-school and classwide practices. At the secondary level, the goal is to reduce student
engagement in bullying behaviors by implementing interventions aimed at bystanders and
perpetrators of bullying. At the tertiary level, the goal is to reduce the frequency and sever-
ity of bullying behaviors by implementing individualized interventions for students who
continue to engage in frequent bullying behaviors (Espelage & Swearer, 2008). The extent
to which interventions implemented within the PBIS framework reduce the frequency of
bullying victimization and perpetration specifically among youth with ASD is unknown.
However, to reduce bullying behaviors among the general population, a coordinated effort
between all stakeholders is crucial.
Moving From Goals to Evidence-Based Practices
As in EBM, in which medical care is based on the scientific evidence of treatment effects and
clinicians’ professional knowledge, a similar process is followed in the evidence-based edu-
cational process. The process (as described in Odom et al., 2012) begins with professionals
establishing measureable goals for students, as noted previously. Professionals match goals
to the types of outcomes researchers have reported in their efficacy studies documenting
EBPs. An example of a matrix that describes outcomes (in columns and organized by age
level) and EBPs (in rows) is shown in Table 21.2. Practitioners can use this matrix as a tool
to begin the process. In most cases, more than one EBP will be available as a possible inter-
vention. In making the final selection of the evidence-based focused intervention to be used
with a student, the teacher must use his or her own professional wisdom and judgment.
That is, the teacher should consider the student’s previous history and response to specific
interventions, the current settings and resources, parents’ priorities and advice about the
student, and possibly the student’s choice about intervention type if self-determination
is an appropriate option. Last, the teacher should collect data on student performance to
determine if the specific EBP results in progress toward the goal and be prepared to select a
different approach if there is no progress.
FAMILIES
The structure and definition of families have changed during the past 20 years. Not only are
families more culturally diverse but also children with disabilities are being raised with dif-
ferent life experiences. The stereotypical family structure that once consisted of two hetero-
sexual parents with children who are biologically related is no longer the norm (Anyan &
Pryor, 2002). These changing dynamics in family structure have significant implications on
how health care and education systems provide services to children and youth with ASD.
Families, Schools, and Health Care
Children with ASD present with lifelong challenges that require parents to seek, under-
stand, and act on information from education and health care practitioners. Physicians are
often the first to field questions from parents who have concerns and to make referrals to
intervention programs. They can also be a source of continuity as children grow and move
through the education system. Children from lower socioeconomic status (SES) or minor-
ity groups often receive a diagnosis of ASD, and therefore access to intervention services,
later in development than their middle-class, Caucasian peers (Mandell, Listerud, Levy, &
Pinto-Martin, 2002). Furthermore, parents frequently report frustration with the evalu-
ation and eligibility process, making it critical that physicians acknowledge and are sup-
portive of parents’ efforts to access special education services (Osborne & Reed, 2008).
Research suggests that families and children experience the most difficulty during points
of transition between education service delivery systems (Baer, Davis, McMahan Queen,
& Flexer, 2011). When uncertain or vulnerable, families may seek counsel from medical
providers on what to expect in the upcoming years, alternative treatments or therapies, and
available parent-support groups (Rhoades, Scarpa, & Salley, 2007).
Since the inception of IDEA, parents have been at the forefront of advocacy for children
with disabilities. This advocacy resulted in strong provisions for privacy and informed con-
sent in order for schools to release information to those outside the education system. As a
result, it is the responsibility of parents to be conduits of information between health care
and education providers. Although intervention is primarily delivered by education-based
personnel, medical and health care providers may play a significant role as partners in a
comprehensive treatment plan. Parents of children with ASD may have concerns related
TABLE 21.2 Matrix of Evidence-Based Practices by Outcome and Age (Years)a
EBP Social Communication Behavior Joint Attention Play
15–22
15–22
15–22
15–22
15–22
6–14
6–14
6–14
6–14
6–14
0–5
0–5
0–5
0–5
0–5
ABI
CBI
DRA/I/O
DTT
ECE
EXT
FBA
FCT
MD
NI
PII
PMII
PECS
PRT
PP
R+
RIR
SC
SM
SN
SST
SPG
TA
TAII
TD
VM
VS
Pink = 0–5 years of age; Yellow = 6–14 years of age; aqua = 15–22 years of age.

Abbreviations for practices are from Table 21.1.
a
ABI = Antecedent-based interventions; CBI = Cognitive-behavior interventions; DRA/I/O = Differential

reinforcement; DTT = Discrete trial training; ECE = Exercise; EXT = Extinction; FBA = Functional behavior
assessment; FCT = Functional communication training; MDI = Modeling; NI = Naturalistic interventions;
PII = Parent-implemented interventions; PMII = Peer-mediated intervention; PECS = Picture Exchange
Communication System; PRT = Pivotal response training; PP = Prompting; R+ = Reinforcement;
RIR = Response interruption/redirection; SC = Scripting; SM = Self management; SN = Social narrative;
SST = Social skills training; SPG = Structured play groups; TA = Task analysis; TAII = Technology-aided
intervention and instruction; TD = Time delay; VM = Video monitoring; VS = Visual supports.
Source: Adapted from Wong, C., Odom, S. L., Hume, K., Cox, A. W., Fettig, A., Kucharczyk, S., … Schultz,
T. R. (2014). Evidence-based practices for children, youth, and young adults with autism spectrum
disorder. Chapel Hill, NC: The University of North Carolina, Frank Porter Graham Child Development
Institute, Autism Evidence-Based Practice Review Group, p. 23.
0–5
6–14
Cognitive
15–22
0–5
6–14
15–22
School Readiness
0–5
6–14
Academic
15–22
0–5
6–14
Motor
15–22
0–5
6–14
Adaptive
15–22
0–5
6–14
Vocational
15–22
0–5
6–14
Mental Health
15–22
to sensory challenges, sleep disturbances, and diet and food sensitivities that educators
and related service providers are not able to address. In addition to the core diagnostic fea-
tures of social–communication impairment and restricted interests/stereotypic behaviors,
individuals with ASD often have comorbid conditions that require medical and pharma-
cologic intervention. Depression, anxiety, seizure disorders, attention deficit hyperactiv-
ity disorder, and oppositional defiant disorder are some of the psychiatric conditions that
are prevalent within the ASD population (Simonoff et al., 2008). The side effects of medi-
cations prescribed to treat these conditions may negatively impact a child’s attention and
energy levels in school, resulting in increased hurdles for learning. It is the responsibility of
parents to communicate to educators whether or not children are prescribed medications
with such side effects. Conversely, parents must also communicate to health care provid-
ers any behavioral changes reported by teachers once medications are started or discontin-
ued. Supporting parents as they navigate the benefits and challenges of various treatment
options is important for both medical providers and educators if parents are expected to
make informed decisions and communicate between the two systems’ providers. Parent
input and involvement is less emphasized as children age and move through their education
programs. Self-determination or the rights of youth and young adults with ASD to choose
and refuse services becomes more prominent in IEP discussions and may also be relevant
to medical care.
Rights and Advocacy of Families
Families of children with ASD frequently have to advocate for quality services offered
through public education systems. Parental and family advocacy can include petitioning
for “due process rights” as a result of an IEP meeting or requesting diagnoses and assess-
ment from health care providers. Research suggests that parents who possess the skill set
to advocate in the school system also demonstrate the ability to advocate with health care
providers (Rehm, Fisher, Fuentes-Afflick, & Chesla, 2013). The availability and types of
services may be determined by several factors associated with families, including cultural
differences, SES, and marital status. Considering that physicians also have the ability to
advocate on behalf of a child with ASD, some of these barriers to access and care can be
diminished with proactive physician support of all families.
Finally, the goal of any program or provision of care is to support families and promote
independence and self-advocacy. Because there has been continuous change in how fami-
lies are defined, public schools, like health care organizations, must be responsive to this
changing dynamic in family structure if high-quality, comprehensive services are to be pro-
vided to individuals with ASD. Sensitivity to language differences and cultural beliefs about
special education, disability, labeling, and medication is relevant to both medical and edu-
cation providers. The objective is the same from both perspectives: that individuals with
ASD and their families receive the highest quality of care to support their health, learning,
and relationships.
TECHNOLOGY
The use of technology in support of students with ASD is an area showing great promise,
but the evidence base remains sparse as researchers struggle to keep up with the rapid
pace of innovation (Grynszpan, Weiss, Perez-Diaz, & Gal, 2014). Much of the enthusiasm
surrounding the use of new technologies (e.g., tablets and smartphones) to support
children with ASD is undoubtedly due to the affinity students with ASD exhibit for
screen-based media (Kuo, Orsmond, Coster, & Cohn, 2014). Studies have revealed that
screen-based technology use is a primary and preferred activity for the majority of youth
with ASD across the spectrum (Mazurek, Shattuck, Wagner, & Cooper, 2012). A possible
explanation for this attraction is that individuals with ASD have strengths in the areas of
visual perception (Shane & Albert, 2008) and visual search (Kaldy, Giserman, Carter, &
Blaser, 2013). A national survey of the post-secondary outcomes of students with ASD
found that those students who attend college major in computer science at a rate much
higher than the general population (16.22% vs. 6.6%; Wei, Yu, Shattuck, McCracken, &
Blackorby, 2013).
There are other reasons for enthusiasm surrounding technology as a support,
including the way it can address the core deficits of ASD through its consistency of
clearly defined tasks, visually cued instructions, and by providing freedom from social
demands (Grynszpan, Weiss, Perez-Diaz, & Gal, 2014). Researchers anticipate poten-
tial positive outcomes for students with ASD from technology especially in the areas of
motivating task engagement and increasing positive behaviors (Mazurek & Wenstrup,
2013). Social media may help improve social interactions for students with ASD and
their peers, as it can be far less intimidating for students who often struggle to engage
in face-to-face relations. Virtual reality is showing promise as a way to practice social
encounters using avatars (Hopkins et al., 2011). Expensive speech-generating tech-
nology that has helped some nonverbal students with ASD to communicate is now
available as applications for smartphones, iPods, and tablets, making it more accessible
(Kagohara et al., 2013). Adding to the potential of new handheld technologies as a
support is the fact that, in addition to being portable and low in price, these tools can
be nonstigmatizing for students with ASD because they are now in the hands of the
majority of students. Some parents and autism support groups anxious to spread the
word have created websites and blogs to share personal technology experiences and
recommendations.
Technology can indirectly benefit students with ASD in a variety of additional ways.
Texting, e-mail, Skype, and other such tools can improve communication among those
who support students with ASD. Teachers can text a parent to help problem solve a
youngster’s meltdown in real time, or an adolescent who is reluctant to attend an IEP
meeting with a room full of adults may feel more comfortable doing so from an adjoin-
ing room via Skype. Web-based professional development (e.g., Internet modules and
coaching via Skype) can help raise the skill levels of professionals who support students
with ASD.
SUMMARY
ASD has the most rapidly advancing prevalence of any disability, and its current impact
on the educational system in the United States is substantial. For many children and youth
with ASD and their families, the educational system will be the primary mode of behav-
ioral treatment available. This chapter described the core features of ASD and the learning
needs that they generate. The process of responding to those needs requires an emphasis
on program quality and a technical eclectic approach to selecting evidence-based interven-
tion practices that address individual student goals. A partnership among school personnel,
family members, possibly the student him- or herself, and potentially the family physician
or health care workers will serve as the foundation for planning and implementing effective
and personalized educational programs for students with ASD.
Case Study #1: “Ethan”
Ethan’s parents thought that things were finally coming together for their son as he moved
through high school with a plan to attend college. Ethan had always loved tinkering with com-
puters and wanted to major in computer engineering. At his IEP meetings, his team talked
about college application requirements and deadlines to help Ethan fulfill his goal of attending
a 4-year college. Although his critical reading score on the SAT was on the low side, his 750
on the mathematics section was impressive. What the IEP team did not discuss were the
skills he would need to be successful in the university setting that may be different from high
school. Although he had attended the weekly lunch social group for students with ASD, Ethan
rarely saw anyone outside of school for social activities. Throughout the years, his parents had
become used to the minimal opportunities for social interaction and thought Ethan seemed
content in his room playing video games on his computer. His anxiety and depression, they
thought, were well managed with medications. Every morning, Ethan’s mom woke him up,
made his breakfast, and drove him to the front door of the school. After school, his dad made
sure that Ethan completed all his homework assignments and even communicated with his
teachers when there were problems. At school, Ethan’s resource teacher made sure all of
his assignments were written down in his planner at the end of the day and would add in
anything that Ethan had forgotten to note. If Ethan came to school without his homework, his
teachers would give him an extra day to turn it in. If Ethan had a meltdown, everyone knew
that he would get up and run out of the room and go straight to the special education office to
see his resource teacher, who would let him put on headphones and watch a movie to calm
down. These routines had evolved throughout the years to minimize Ethan’s frustrations and
maximize his academic performance. What his team was not doing was thinking about the
context that Ethan would find himself in when he arrived at university. How was he being
prepared for life in a dorm? How was he being prepared for independent learning and man-
agement of his work? How would he be able to handle communicating with his professors?
Ethan’s team members thought they were supporting him for success by focusing on his
academic requirements, overlooking some of the areas in which students with ASD need the
most help: independence, initiation, self-management, and social communication.
When Ethan arrived at university, he discovered that although there was a disability ser-
vices department that knew about his ASD diagnosis, the responsibility fell to him to initiate
requests for assistance. Despite daily reminders from his parents to go to the disability ser-
vices office, Ethan could not bring himself to do it. Overwhelmed by all the new demands
being placed on him, Ethan began to feel anxious and did not want to get out of bed in the
mornings. He started missing classes and missing deadlines. This downward spiral quickly
led to Ethan’s withdrawal from college. He returned home to live with his parents without a
plan for what happens next and without a support system other than his parents.
KEY POINTS
• A continuum of intervention and educational services exist for children and youth
with ASD and their families in the United States. The quality and intensity of these
services vary, which requires parents to be active consumers for their children.
• Practitioners base interventions and educational services on the specific learning
needs of children with ASD. The learning needs are often in the areas of social com-
petence, independence, behavior, and academics.
• Resources are now available that allow educational practitioners and service
providers to select and employ intervention/instructional practices that are
evidence-based.
• Quality of educational program environments provide the foundation for imple-
mentation of evidence-based practices and positive outcomes for children and youth
with ASD.
• Educational practitioners’ application and utilization of technology in programs for
children and youth with ASD holds great promise for the future.
ACKNOWLEDGMENTS
This chapter was supported in part by the Postdoctoral Research Training in Special
Education Project funded by the Institute of Education Science (R324C1200C12006) and
the Vinnie Ireland Fellowship award to the School of Education at the University of North
Carolina at Chapel Hill. The authors thank Ms. Stephanie Ridley for her helpful editing.
Dr. Samuel L. Odom, Dr. Veronica P. Fleury, Dr. Leslie C. Fox, Susan Hedges, Dr. Nigel P.
Pierce, and Melissa A. Sreckovic have no conflicts to disclose.
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/ 22
/ / / / / VOCATIONAL REHABILITATION
AND TRAINING FOR ADULTS
WITH AUTISM SPECTRUM
DISORDER
History, Practices, and New Directions
MARJI ERICKSON WARFIELD
INTRODUCTION
“What do you do for a living?” This question is often asked when people meet for the first
time because employment is a pervasive marker of adulthood. Disparities in obtaining and
maintaining employment are stark, however, when examining the extent to which the gen-
eral population works compared to the population of individuals with disabilities and even
more glaring when compared to those with autism spectrum disorder (ASD). Although
good jobs can be difficult to find given today’s economic climate, various data sources
generally are in agreement that whereas more than two-thirds of working-age adults are
employed, only between one-fifth and one-third of adults with disabilities are employed.
Furthermore, national estimates suggest that although the difference in employment rates
has been persistent for more than 30 years, some modest reduction in size of the employ-
ment gap has occurred.
Vocational rehabilitation and training programs are designed to maximize employ-
ment opportunities for individuals with disabilities by providing a variety of services, such
as assessment and diagnosis, counseling, job search assistance, assistive technology, and
on-the-job training, in different settings (Escorpizo et al., 2011). Since the Rehabilitation
Act of 1973, a variety of programs and policies have used different approaches to try to
reduce the persistent disparities in employment between those with and those without dis-
abilities, with little success.
This chapter provides an overview of the current employment picture for adults with
disabilities and an introduction to the vocational training and rehabilitation field by defining
common terms and approaches. A review of the history of vocational training is presented
that outlines the significant pieces of legislation that have attempted to reduce employment
413
disparities, the fragmented system in existence today, and the huge variation in vocational
practices across the United States that have resulted from these policies. The chapter then
describes the employment picture specifically for individuals with ASD and identifies their
unique vocational needs. The chapter concludes with a discussion of successful vocational
rehabilitation service models for individuals with ASD and a case example.
THE EMPLOYMENT PICTURE FOR ADULTS WITH DISABILITIES
Various sources of data confirm that there are wide differences between the employment
rate for the general population of adults and the employment rate among the population
of adults with disabilities. The 2010 Current Population Survey estimates the employment
rate for people (aged 21–64 years) with disabilities is 16.2% compared with 75.5% for peo-
ple without disabilities. Also, according to the Bureau of Labor Statistics, in 2012, 28.4%
of individuals with disabilities aged 16 years or older participated in the labor force com-
pared with 71.0% of persons without disabilities. The 2011 American Community Survey
estimates that 32.4% of working-age adults with disabilities are employed, compared with
70.5% of people without disabilities (Butterworth et al., 2013). Furthermore, the disparity
in employment rates widens when only individuals with intellectual and developmental dis-
abilities (IDD) are considered. Only approximately one in seven (14.7%) adults with IDD
was employed in the community based on data from the 2012 National Core Indicators
Project (Human Services Research Institute, 2012). These differences persist despite evi-
dence that individuals with disabilities can be employed successfully and that they want
to be employed in the community in order to reach goals of self-sufficiency and economic
independence (Migliore, Grossi, Mank, & Rogan, 2008; Migliore, Mank, Grossi, & Rogan,
2007). In addition, these differences persist despite evidence of financial gains associated
with employment for people with disabilities (Cimera, 2008; Cimera & Cowan, 2009).
INTRODUCTION TO VOCATIONAL REHABILITATION AND TRAINING APPROACHES
The major goal of vocational rehabilitation and training services and supports is to assist
individuals with disabilities to become employed in the community (Targett & Wehman,
2011). These services can be provided in a number of different settings, including in schools
for youth transitioning out of secondary education and in community-based programs for
adults. Vocational support services include two major categories: (1) day programs and
sheltered workshops and (2) competitive integrated employment models.
Day Programs and Sheltered Workshops
These programs are often described as “facility-based” because all employment and
non-employment services are provided in one location where the vast majority of indi-
viduals have a disability (Butterworth et al., 2013). These programs typically oper-
ate on a weekday schedule from 9 a.m. to 3 p.m. and can support anywhere between
50 to several hundred individuals with disabilities (Targett & Wehman, 2011). These
programs offer skill training, prevocational training, “make-work” vocational activities
(i.e., work created to keep a person from being unemployed), field trips, recreation,
and other types of special education curricula for people with more severe cogni-
tive, physical, and emotional disabilities (Wehman & Brooke, 2013). Within these
Vocational Rehabilitation and Training for Adults With Autism Spectrum Disorder // 415
facility-based programs, services can be work-focused or non-work-focused or a mix of

the two. Work-focused programs are variously referred to as sheltered workshops, work
activity centers, or extended employment programs. The premise behind the approach
taken by facility-based programs focused on work is that individuals with disabilities
must demonstrate that they are employable before moving on to getting assistance
finding a job in the community (Targett & Wehman, 2011). However, most programs
fail to offer a continuum of services geared toward movement to community-based
employment and thus tend to provide only segregated employment where pay is less
than the minimum wage (Wehman & Brooke, 2013). Legislation dating from as far
back as the National Industrial Recovery Act in 1934 that was part of the New Deal
made it permissible to pay individuals with disabilities less than the minimum wage
as a way to increase their access to employment (National Disability Rights Network,
2012). As described later in the chapter, more recent legislation and other initia-
tives are attempting to phase out these programs and replace them with competitive
employment models.
Competitive Integrated Employment Models
Competitive employment models focus on attaining “real work for real pay” (Targett &
Wehman, 2011). Kiernan, Hoff, Freeze, and Mank (2011) define competitive integrated
employment as a job that is compensated by the minimum or prevailing wage, provides
similar benefits to all employees, occurs where employees with disabilities interact continu-
ously with employees without disabilities, provides opportunities for advancement, and is
full-time unless the employee desires or needs a part-time schedule.
Three approaches to competitive employment are common: (1) supported employ-
ment, (2) customized employment, and (3) self-employment (Targett & Wehman, 2011).
Supported employment options enable individuals with significant support needs to
become employed in the community. When supported employment began in the 1970s
and 1980s, groups of individuals with disabilities would work together in a business
under the supervision of an adult service provider (Targett & Wehman, 2011). In the past
20 years, however, individualized approaches to supported employment have been devel-
oped in which a vocational rehabilitation specialist (also known as a job coach or employ-
ment specialist) provides an array of supports (e.g., on-the-job skills training, arranging for
assistive technology, and facilitating communications and relationships with coworkers) to
assist an individual with significant disabilities to obtain and maintain a competitive job in
the community (Targett & Wehman, 2011).
Customized employment shares many features of supported employment but is fur-
ther characterized by the following principles (Elinson, Frey, Li, Palan, & Horne, 2008;
US Department of Labor, 2007): (1) The individual with a disability who is seeking a job
decides on the direction of the job search; (2) the individual controls the planning pro-
cess in order to maximize his or her preferences, interests, and connections in the com-
munity; (3) time is taken to explore the individual’s unique needs and abilities; (4) the
employer negotiates specific job duties and employee expectations; and (5) the job that
emerges meets both the needs of the employer and the needs, strengths, and interests of
the individual seeking the job. The goal of utilizing these principles is to yield a job that is
a good fit and creates the possibility for advancement. Sometimes a personal representa-
tive is hired to assist an individual through the customized employment process (Targett &
Wehman, 2011).
Finally, pursuing self-employment or entrepreneur opportunities begins with matching

a person’s talents and desires with a defined product, service, or activity (Targett & Wehman,
2011). Individuals alone or with professional and/or family support will spend time doing
person-centered planning to formulate an idea. Then a business plan is developed and a
study launched to assess the idea’s feasibility and likelihood for success. Implementation
then follows on those plans that seem most viable.
HISTORY AND NEW DIRECTIONS
The vocational rehabilitation and training approaches just described have emerged from a
history of legal action and legislation related to the general movement of individuals with
disabilities from institutional residential settings to community-based settings; changes in
educational practices; and efforts to expand employment opportunities through a mix of
state and federal disability, workforce development, income maintenance, and health care
policies. Thus, the current approach to vocational training for adults with disabilities is
fragmented and complex (Wehman, 2013). The patchwork system of vocational training
and supports available to individuals with disabilities is described in the following sections.
Initiatives to reduce the facility-based options and expand community-based competitive
employment opportunities are also discussed.
Overview
The deinstitutionalization movement that occurred in the late 1960s and into the 1970s
involved closing residential institutions that housed large numbers of adults with intellectual
and developmental disabilities and establishing community-based residences (Stancliffe &
Lakin, 2005). Deinstitutionalization was the result of court decisions and new laws that
eventually led to the establishment of more than 8000 facility-based day programs and
sheltered workshops nationally to care for and support individuals now living in the com-
munity (Wehman & Brooke, 2013). From this base of segregated programs, advocacy and
legislative efforts during the past 40 years have attempted to build a system of vocational
training services that can provide more individualized choices and options for competitive
employment to individuals with disabilities (Table 22.1) (Nord, Luecking, Mank, Kiernan,
& Wray, 2013). The fragmented system that has resulted is characterized by vast differences
across states in terms of the kinds of services and supports available, the use of different
eligibility criteria to determine entrance into different systems, and limits on access due to
funding restrictions because there is no entitlement to services (Hall, Butterworth, Winsor,
Gilmore, & Metzel, 2007; Wehman & Brooke, 2013). Several initiatives are attempting
to address this fragmentation and shift resources toward integrated employment options
(Butterworth et al., 2013; Kiernan, 2011; Rogan & Rinne, 2011).
Systems Involved in Providing Vocational Training and Employment Supports
Individuals may qualify for publicly funded Vocational Rehabilitation (VR) services if
their disability presents a barrier to obtaining competitive employment or maintaining
competitive employment (Wehman, 2013). The Rehabilitation legislation provides states
with federal grants to operate comprehensive programs of VR services for individuals with
disabilities. VR is a federal–state cooperative program operated by the Department of
TABLE 22.1 Federal Legislation Related to Vocational Training and Employment by Policy Areaa

Year Legislation Description of Key Provisions
VOCATIONAL REHABILITATION (VR) PROGRAMS
1973 Rehabilitation Act of Extended the authorization of grants to states for

1973 (PL 93-112) vocational rehabilitation services with an emphasis on
services to those with the most severe disabilities
Included Section 504, which prohibited discrimination
on the basis of disability in federal programs and in
programs receiving federal funds
1986 Rehabilitation Act Defined supported employment and provided funding for
Amendments of 1986 projects and demonstrations in supported employment
(PL 99-506)
1992 Rehabilitation Act Defined the responsibilities of the vocational rehabilitation
Amendments of system as including developing an individualized
1992 (PL 102-569) rehabilitation program with the full participation of the
individual with a disability, finding appropriate services
and supports to implement the individualized plan, and
fostering cooperative relationships with other agencies
and programs to unify the system
1998 Rehabilitation Act Promotes the increased employment of individuals with
Amendments of 1998 disabilities through the implementation of workforce
(PL 105-220) investment systems under Title I of the Workforce
Investment Act
Workforce Investment Act—initiated major reform of
the nation’s job training system primarily through the
implementation of One Stop Career Centers
DEVELOPMENTAL DISABILITIES SERVICE SYSTEM
1984 Developmental Disabilities Acknowledged the employability of persons with

Act Amendment of 1984 disabilities and promoted supported employment
(PL 98-527) options
1987 Developmental Disabilities Put national goals regarding employing persons with
Assistance and Bill of Rights disabilities in legislation
Act of 1987 (PL 100-146)
EDUCATION
1990 Individuals with Disabilities Added language associated with transition planning so
Education Act (IDEA) that the Individualized Education Plan would include
(PL 101-476) transition goals and linkages to other agencies to
support transition prior to leaving school
1997 Individuals with Disabilities States given permission to use funds to develop and
Education Act Amendments implement transition programs
of 1997 (PL 105-17)
(continued)
Year Legislation Description of Key Provisions
2004 Individuals with Disabilities Established parameters to guide the participation of

Education Improvement Act vocational rehabilitation counselors in the transition
of 2004 (IDEIA) (PL 108-446) planning process
HEALTH CARE
1981 Medicaid Home and Identified supported employment services as an

Community-Based Services appropriate means for assisting individuals with
Waiver Program of 1981 significant disabilities
(PL 97-35)
INCOME MAINTENANCE
1999 Ticket to Work and Work Established funding for the ticket to work program that
Incentives Improvement Act of is operated under the Social Security Administration
1999 (PL 106-170) to help Social Security disability beneficiaries obtain
employment and work toward greater independence and
self-sufficiency
Included work incentives to allow beneficiaries to explore
work options while still receiving health care and cash
benefits
The table utilizes information reported and organized by Wehman (2013).
a
Education that exists in all 50 states, the District of Columbia, and all territories. Once an
individual with a disability applies for support from the VR system, a rehabilitation coun-
selor processes the application for service and determines eligibility. Eligibility is based
on the presence of a disability that presents a barrier to employment and an expectation
that the provision of VR services will help the individual achieve an employment outcome.
After eligibility is determined, an Individualized Plan for Employment (IPE) must be
developed. VR counselors have access to funds to be used to purchase services from autho-
rized vendors. Services that can be purchased if they support the goals on the IPE include
post-secondary education, training, supported employment, transportation, tools, and uni-
forms. Reforms to the VR system were enacted in 1998 under the Workforce Investment
Act, which set up One Stop Career Centers aimed at consolidating vocational training and
employment services and setting standards of performance (Targett et al., 2007).
State developmental disability (DD) agencies operate under a variety of different names
and structures. In some states, services are managed locally, whereas in others services are
operated by direct state supervision through local providers or offices. Eligibility for these
services is usually based on the presence of a disability that meets specific state guidelines
that often include standards related to cognitive functioning (Braddock, Hemp, & Rizzolo,
2008). State DD agencies provide, fund, and manage a range of services, including employ-
ment supports, as well as facility-based options that include both sheltered workshops and
non-work day habilitation programs (Butterworth et al., 2013).
Youth with disabilities who are in the process of transitioning out of the public educa-
tion system are also eligible for vocational training and employment services under federal
legislation. The Individuals with Disabilities Education Act (IDEA) included a focus on
transition in 1990, and subsequent amendments added requirements for greater collabo-
ration between school and VR personnel in the community to build stronger linkages to
improve post-school outcomes for youth with disabilities.
Policies related to vocational training and employment are also part of legislation ema-
nating from programs under Medicaid and the Social Security Administration (SSA).
Medicaid-eligible individuals with disabilities may receive supported employment services
under the Medicaid Title XIX Home and Community-Based Waiver Services (HCBS)
program. The ability of states to use Medicaid funding for integrated employment services
increased under the Balanced Budget Act Amendments of 1997 when eligibility was no
longer restricted to individuals who had previously been institutionalized (Hall, Freeze,
Butterworth, & Hoff, 2011). Participation in supported employment increased under the
waiver but mostly in a small number of states (West et al., 2002).
Finally, the Ticket to Work program is operated under the SSA. The goal is to help
Social Security disability beneficiaries obtain employment and work toward greater inde-
pendence and self-sufficiency (Fraker & Rangarajan, 2009). The SSA issues a ticket to a
beneficiary, and the individual then gives the ticket to an employment network or state VR
agency. If the ticket is accepted, the agency works with the individual to create an individu-
alized employment plan and, as needed, provides specialized services such as career coun-
seling and job placement. Other provisions include work incentives and work incentive
planning and assistance services that enable a beneficiary to explore work options while still
receiving health care and cash benefits (Miller, O’Mara, & Getzel, 2009).
Thus, individuals with disabilities have many avenues through which to seek support
for vocational training and employment. At the local level, community rehabilitation pro-
viders (CRPs) typically contract with these agencies and systems in order to directly assist
people with disabilities in obtaining and maintaining employment of various kinds and
accessing vocational training and day programs (Wehman, 2013). CRPs can be for-profit
or not-for-profit and usually provide services based on a contract or fee-for-service arrange-
ments. Thus, access to these services requires a funding authorization from a VR agency,
through the state DD office, through IDEA regulations, through Medicaid, or through the
SSA. CRPs that have contracts from all of these sources have a more diversified economic
base and thus tend to be more successful (Hall et al., 2011). The different eligibility require-
ments associated with each system, however, create a difficult maze for individuals and their
families to navigate.
In addition, despite the legislative efforts to encourage improved employment out-
comes, national surveys of the more than 8000 CRPs that offer vocational and related
services to individuals with disabilities reveal that on average, there is little focus on com-
petitive employment (Butterworth et al., 2013). Overall, there are few resources that
reward integrated community employment (Niemeic et al., 2009). For example, based on
the 2010–2011 National CRP Survey, more than 70% of those served by CRPs are individ-
uals with intellectual and developmental disabilities (Butterworth et al., 2013). Of these,
however, only 19% participated in individual, integrated employment services, whereas
25.2% participated in facility-based work and 43% participated in non-work services.
The participation in integrated employment services represents a decrease from a high
of approximately 25% in 2001. In contrast, participation in non-work services increased
approximately 10% from 2002 (Sulewski, 2010).
These low percentages in competitive employment and increases in non-work activi-
ties mask the tremendous variation in services delivered in different states. The 2010–2011
National CRP Survey gathered extensive data from 37 states on day and employment
services for individuals with intellectual and developmental disabilities every year from
1999 to 2011. More than half (21; 57%) of these 37 states reduced the number of individu-
als receiving integrated employment services over this time period. The remaining 16 states
(43%) changed in the other direction and increased the number of individuals in integrated
employment. In 8 of these states, the number of individuals in integrated employment
increased by more than 500 individuals (Butterfield et al., 2013).
Research on why there is such variation between states reveals several important factors
that are associated with greater systemic change toward more positive employment out-
comes. These states, identified as high-performing states, tend to use the flexibility offered
in many policies to enable service providers to develop innovative solutions for individuals,
make accommodations for individuals as their support needs change, effectively combine
funding from multiple sources, use incentives to encourage the implementation of inte-
grated employment services, continuously monitor and evaluate their progress, and invest
in the training and development of their professional vocational and employment coun-
seling staff (Butterworth, Migliore, Nord, & Gelb, 2012; Hall et al., 2007, 2011; Migliore,
Butterworth, Nord, Cox, & Gelb, 2012).
System Change Initiatives
The persistently low rate of integrated employment among individuals with disabilities
has generated several efforts by advocates, self-advocates, providers, and state policymak-
ers to develop new initiatives aimed at system-level change. Twenty-three states that are
committed to making integrated employment among individuals with disabilities a prior-
ity have formed the State Employment Leadership Network, whose mission is to operate
under “a presumption of employability or the option of employment for all persons with
disabilities” (Kiernan et al., 2011, p. 300). These states operate under an Employment First
principle that demands that employment be the first option offered to any adult with a dis-
ability. Other efforts include the US Business Leadership Network and the VR Business
Network, which are focused on developing public–private partnerships (Wehman, 2013).
THE EMPLOYMENT PICTURE FOR ADULTS WITH AUTISM

SPECTRUM DISORDER
Understanding where adults with ASD fit into the vocational training and employment pic-
ture is critical given the size of this population now entering their adolescent and young
adult ages and the expectations regarding the increased size of future cohorts. In 2008,
approximately 11 children per every 1000 people in the general population received a diag-
nosis of ASD (Centers for Disease Control and Prevention, 2012). Because 8-year-old chil-
dren diagnosed with autism in 2008 will reach transition age in 2016, it is likely that the
number of youth with ASD seeking vocational training and employment assistance will
increase (Migliore & Zalewska, 2012).
Recent data have documented that only between 4.1% and 11.8% of individuals with
ASD are employed (Taylor & Seltzer, 2011). Regardless of their level of skills and abilities,
individuals with ASD participate less in vocational or technical education and employment
than their peers with other types of disabilities, including speech and language impair-
ments, learning disabilities, or intellectual disabilities (Henninger & Taylor, 2012; Shattuck
et al., 2012). Even among those youth with ASD who gain employment, the long-term
success is poor (Wagner, Newman, Cameto, Levine, & Garza, 2006). Furthermore, youth
with ASD have been found to be more likely to have no participation in any post-schooling
activities compared to youth with speech and language impairments, learning disabilities,
or intellectual disabilities. These differences were greatest during the first 2 years after high
school (Shattuck et al., 2012).
Of particular concern among those youth with ASD who had no or few formal day
activities after exiting high school were those without intellectual disability (ID) (Taylor
& Seltzer, 2011). Youth with ASD but without ID were three times more likely to have no
day activities than youth with ASD who also had comorbid ID. These significant group
differences raise questions about the ability of the service system to meet the needs of this
subgroup.
THE UNIQUE VOCATIONAL NEEDS OF ADULTS WITH AUTISM

SPECTRUM DISORDER
Individuals with ASD have markedly different vocational needs than individuals with
other developmental disabilities (Hendricks, 2010). The uneven cognitive and social abili-
ties associated with ASD result in a diverse set of vocational needs that are challenging to
address with usual practices, create problems with employment stability, and result in iso-
lated work opportunities. Gabriels (2011) identified five unique ASD learning styles that
have relevance for vocational training and employment. According to Gabriels, individuals
with ASD (1) tend to think concretely and may be confused by social situations or con-
versations; (2) struggle to understand others’ intentions, emotional states, or behaviors;
(3) tend to focus on details at the expense of seeing things in context or getting the “big
picture”; (4) have difficulty with organization and sequencing; and (5) tend to be very
distractible yet able to focus intensely on things of particular interest to them.
Holwerda, van der Klink, Groothoff, and Brouwer (2012) conducted a systematic lit-
erature review and identified factors consistently connected with hindering work participa-
tion among individuals with ASD. The most consistent factor was limited cognitive ability.
Eight other factors were noted, although they were not as consistent across studies. These
were (1) severity of the disorder; (2) comorbidity of psychiatric disorders, oppositional
personality, or epilepsy; (3) gender, with females being more likely to have a poor outcome;
(4) lower speech and language abilities; (5) the presence of maladaptive behavior; (6) the
presence of social impairments and poor social skills; (7) lack of drive; and (8) prior insti-
tutionalization. Holwerda et al. also identified two factors that had positive impacts on job
participation: higher educational attainment and family support for work.
ACCESS TO VOCATIONAL REHABILITATION AND TRAINING BY

ADULTS WITH AUTISM SPECTRUM DISORDER
VR programs are struggling to adapt to the unique vocational and employment needs of
individuals with ASD (Hendricks, 2010; Lawer, Brusilovskiy, Salzer, & Mandell, 2009;
Wehman et al., 2014). This is significant given the finding that between 1995 and 2005,
the percentage of people with ASD seeking VR services tripled from 1% to 3% (Migliore &
Butterworth, 2008). Lawer et al. (2009) found that relative to other individuals served by
the VR system, individuals with ASD were more likely to be denied services because it was
believed that their disability was too severe for them to benefit.
Recent data from the US state VR programs from the years 2006–2010 yielded some-
what more promising results for youth with ASD, but overall, more improvement is needed
(Migliore, Butterworth, & Zalewska, 2014). Specifically, four key findings emerged. First,
although the number of individuals with ASD who utilized the VR system doubled during
this time period, it remained small compared to the numbers of other disability groups.
Second, although youth with ASD received similar levels of services and reported similar
employment outcomes compared with their peers with other disabilities, across all dis-
ability groups, only approximately half received services and only approximately half who
received services left the VR system with integrated employment. Third, both the percent-
age receiving services and those who exited with integrated employment declined slightly
during the time period studied. Finally, overall the differences in these outcomes were
larger across states than across disability groups.
SUCCESSFUL VOCATIONAL REHABILITATION SERVICE MODELS

FOR INDIVIDUALS WITH AUTISM SPECTRUM DISORDER
Research and evaluation projects have assessed various vocational training intervention
models for individuals with ASD. There is general consensus on the eight critical steps
needed to ensure successful employment for individuals with ASD (Schall, Targett, &
Wehman, 2013). These eight steps are (1) assess job and task preferences carefully before
placement; (2) assess social, communication, and job skill needs; (3) make a careful match
between the job, the person’s preferences, the social and communication demands in the
environment, and the tolerance of coworkers for diversity; (4) teach the social and commu-
nication skills required in the job in addition to the actual job skills; (5) prepare employers
and coworkers for the diverse behaviors that a person with ASD may display; (6) teach
coworker/employee/employer relationship behaviors to the person with ASD; (7) make
modifications and adaptations in the job environment to meet the social and communica-
tion needs of the worker; and (8) support the person through job challenges and crises.
The job modifications and adaptations that may be needed include providing a con-
sistent schedule, decreasing or developing predictable social interactions, providing visual
organizers for job tasks, providing direct supervisory feedback, explaining and preparing
the person for changes at the work site before they occur, and encouraging coworkers in
initiating interactions with the person (Schall, Targett, & Wehman, 2013).
Finally, the Vocational Rehabilitation Service Models for Individuals with Autism
Spectrum Disorders project, an effort funded by the National Institute on Disability and
Rehabilitation Research, engaged a national advisory board of experts to identify “best
practice” VR service models for individuals with ASD. Ten programs were selected, and
their descriptions can be accessed at http://autism.sedl.org/index.php/resources/gep.
SUMMARY
The overview and critique presented in this chapter of the existing vocational training and
employment services for individuals with disabilities, and specifically for individuals with
ASD, reveals four key themes. First, the vocational system is fragmented and complex, and
it struggles to meet the desires of individuals with disabilities and ASD for “real work for
real pay.” The major difference between the employment rate of the general population
and that of people with ASD remains a persistent problem. Second, there is wide variation
between states in whether or not their vocational offerings are more or less focused on
competitive employment. Third, although access to VR services has improved for indi-
viduals with ASD, much more progress is needed. Finally, successful methods for train-
ing and employing individuals with ASD have been identified and tested but need to be
implemented more widely.
Case Study #1: “J.W.”
J.W. is a 21-year-old man with a diagnosis of ASD. He has a full-scale IQ of 133, with
the verbal subscale significantly higher than the performance subscale. Despite this above
average score on cognitive testing, J.W.’s social–emotional functioning is well below aver-
age. J.W. has continued in the community public high school beyond the age of 18 years
to participate in a program geared toward providing him with ongoing assistance with his
impaired social interaction abilities, preparing him for vocational opportunities, and helping
him to develop a resume and practice interviewing skills for possible job interviews. In
this extended program, school personnel have been working with J.W. to determine what
particular skills he has that might be valuable to potential employers. It was well-known
that J.W. has an encyclopedic knowledge of birds native to the United States. He has been
interested in this topic since the second grade, when he was required to give an oral pre-
sentation on a topic of his interest to his class. Throughout the years, J.W. has continued
to learn increasingly more about birds by reading books from the library, searching the
Internet, and watching television shows on the National Geographic channel, as well as old
reruns of Wild Kingdom.
Despite his cognitive ability and extensive knowledge of birds, J.W. struggles with sig-
nificant social impairment. He is unable to make eye contact with others without experienc-
ing intense anxiety. His voice is quite loud and monotone. His hair is often unkempt, and
he does not show much interest in the clothes he wears, often wearing stripes and plaids
together or colors that do not match. When his parents try to help him choose more appro-
priate outfits, he becomes angry and refuses their assistance.
The majority of the other students in the 18- to 22-year extended program have more
significant cognitive impairment than J.W. He told the school personnel that he was not
“retarded” and did not understand why he was grouped with these other students. When
he tried to initiate conversation with some of the students he considered more like him-
self, he became frustrated because they did not show great interest in his desire to talk
about birds.
The extended school program was to end on J.W.’s 22nd birthday in February, well before
the school year ended. Soon after the first of the year, J.W. had an interview for a job as a
tour guide for the section on birds at a science and nature history museum at a prominent
local university. He was chosen for the position, and a community organization funded a job
coach to assist J.W. with the specific duties and responsibilities of his job until the team
believed he was able to handle things on his own. The job coach, a woman in her early 20s,
was also present to assist J.W. with emotional issues such as anxiety that might arise dur-
ing times of stress.
For the first 2 weeks, J.W. did reasonably well. He was working only in the mornings
from 9 a.m. until noon. During that time, he led three tours, with a 15-minute break between
tours. His job coach would gather among those going on the tour and acted as though she
was a member of the group. One day, a group of seventh-grade students from a local
middle school attended the tour on a field trip. A 13-year-old boy noticed that J.W. dressed
in an unusual manner and that he talked loudly and without looking at the members of the
tour. He began to tell J.W. that he did not know what he was talking about and that he
needed to go back to school to learn more about birds. J.W.’s job coach quietly approached
the boy’s teacher in an effort to have her intervene. However, J.W. became embarrassed
and ran from the corridor and out of the building.
This case study demonstrates the challenges that those with ASD and advanced
knowledge of a particular subject can face. In a supportive educational or therapeutic envi-
ronment, these individuals can be relatively successful. Compared to their peers with
cognitive limitations, they often appear more typical and they can be given opportunities to
demonstrate their special knowledge to others without excess and with limitations placed
by supportive staff. When placed in a public setting among strangers who are usually less
knowledgeable about and accepting of those with ASD, however, these individuals may be
viewed as odd and unusual. In such settings, despite superior cognitive intelligence, their
impaired social–emotional ability can quickly result in overwhelming anxiety, manifest by
an angry or tearful outburst or an effort to flee the situation. Although good intentioned,
many employers are unable to continue to employ these individuals; and maintaining an
available job coach is not always practical or affordable. In many ways, finding successful
employment opportunities for “higher functioning” persons with ASD can be more difficult
than identifying and supporting those for individuals with ASD and cognitive impairment.
Thus, continuing supports are needed to enable individuals such as J.W. to have multiple
opportunities to be employed in order to find a sustainable job that fits their skills and
abilities.
KEY POINTS
• Adults with ASD are employed at a lower rate than both the general population and
the population of adults with other types of disabilities.
• Efforts to expand employment opportunities have occurred through a mix of state
and federal disability funding, workforce development, income maintenance, and
health care policies, creating an employment service system that is fragmented and
difficult to navigate.
• Increasing numbers of adults with ASD are seeking employment supports, but pro-
viders are struggling to adapt to their unique vocational and employment needs.
• Investments in the training and development of professional vocational and employ-
ment counseling staff have shown promise in improving employment outcomes for
adults with ASD.
• There is general consensus on the eight critical steps needed to ensure successful
employment for individuals with ASD but these approaches need to be implemented
more widely.
Dr. Marji Erickson Warfield has no conflicts to disclose. Her research work is currently
funded by National Institute of Child Health and Human Development and two foun-
dations, the Special Hope Foundation and the Deborah Munroe Noonan Memorial
Research Fund.
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/ 23
/ / / / / ADULTS WITH AUTISM
SPECTRUM DISORDER
Transition Issues
EDWARD S. BRODKIN
INTRODUCTION
The symptoms of autism spectrum disorder (ASD) begin in early childhood and continue
throughout life in the vast majority of individuals with ASD (Kanner, 1971), although
recent evidence indicates that approximately 8–10% of individuals diagnosed with ASD in
childhood do not meet full diagnostic criteria by the time they reach adolescence or adult-
hood (Anderson, Liang, & Lord, 2014; Orinstein et al., 2014; Seltzer, Shattuck, Abbeduto,
& Greenberg, 2004). Given the striking increase in rates of diagnosis of ASD in childhood
(Centers for Disease Control and Prevention, 2015), large numbers of youths with ASD are
now transitioning to adulthood. As of 2012, approximately 50,000 individuals with ASD
per year turn 18 years old in the United States (Shattuck, Narendorf, et al., 2012; Shattuck,
Roux, et al., 2012). Therefore, the challenges of transition to adulthood in ASD are now a
significant public health issue (Gerhardt & Lainer, 2011; Howlin, 2008).
One of the major challenges in addressing transition to adulthood adequately is the
tremendous heterogeneity of ASD, including heterogeneity of underlying etiology, clinical
manifestations, levels of cognitive and adaptive functioning, and demographics of individu-
als with ASD (Taylor, 2009). This heterogeneity makes it difficult to craft “one size fits all”
transition plans, and, instead, there is a need for a thorough clinical evaluation and to tailor
transition plans, services, and interventions to the goals and needs of the particular individ-
ual. Our understanding of the large number of etiological factors (e.g., genes and environ-
mental factors) underlying ASD is still quite limited, but part of transition planning should
ideally include a consideration of any potential identifiable etiological factors that may
prove useful in understanding prognosis and guiding transition planning, interventions,
and services. Approximately 10% or more of individuals with ASD will have an identifiable
genetic syndrome, genomic copy number variant, or other mutation that may underlie the
ASD and may have associated behavioral or medical implications; others may have had
exposure to a teratogen that increased the risk for ASD. A thorough developmental history
and modern genetics evaluation, such as a chromosomal microarray analysis, would ide-
ally be included as part of the information to be considered in transition planning (Shen
429
et al., 2010). This can be helpful not only with regard to genetic counseling but also for
management of any medical or behavioral comorbidities that are associated with particular
genetic syndromes. Also, in order to appropriately tailor a transition plan to each individu-
al’s goals and needs, clinicians should conduct a careful evaluation of current symptoms, a
neuropsychological evaluation of cognitive and adaptive functioning, and an assessment of
the interests and abilities of each individual.
In addition to heterogeneity, another major challenge of transition planning is the rel-
ative lack of developed services and lack of evidence base for the efficacy of treatments
and services for adults with ASD, although there is increasing recognition of the need for
more research in this area (Gerhardt & Lainer, 2011; Howlin, 2008; Howlin & Moss, 2012;
Shattuck, Roux, et al., 2012; Taylor, 2009). Despite the limited evidence base, the current
chapter makes some recommendations for fostering improved transition to adulthood;
these recommendations are based on the available evidence as well as the author’s clinical
experience.
OUTCOMES FOR ADULTS WITH AUTISM SPECTRUM DISORDER
Despite growing recognition and early intervention for children with ASD, and despite
some evidence that ASD symptoms tend to become somewhat less severe from childhood
to early adulthood on average (Anderson et al., 2014; Farley et al., 2009; Fecteau, Mottron,
Berthiaume, & Burack, 2003; Howlin, Moss, Savage, & Rutter, 2013; McGovern & Sigman,
2005; Seltzer et al., 2003, 2004; Shattuck et al., 2007; Taylor & Seltzer, 2010), most adults
with ASD are still left with marked difficulties functioning in various domains, and out-
comes for adults with ASD are generally disappointing (Howlin, Goode, Hutton, & Rutter,
2004; Howlin et al., 2013; Seltzer et al., 2004). In a review of published studies from 2000
to 2011 (Howlin & Moss, 2012), on average less than 20% adults with ASD were rated
as having good or very good outcomes, or as living independently or semi-independently.
Slightly less than 50% were involved in some form of work (paid, sheltered, or volunteer)
or educational program.
As individuals on the spectrum go through puberty and enter early adolescence, a
subset develops increasing interest in social interactions and in developing friendships or
romantic relationships (Rutter, Greenfeld, & Lockeyer, 1967). Despite this, individuals
often have ongoing difficulties with social understanding and social skills and, therefore,
difficulties in meeting the increasing social subtlety of adolescent interactions (e.g., roman-
tic relationships) relative to childhood social interactions. Most adults with ASD have sub-
stantial difficulties with social reciprocity and tend to remain socially isolated (Billstedt,
Gillberg, & Gillberg, 2007; Howlin et al., 2013). In one study, only 14% of adults were
married or had a long-term intimate relationship, and only 25% had at least one friend
(Howlin & Moss, 2012). Several studies have found that approximately 50% of adults with
ASD have no friends at all. For example, in one study, more than 50% of adults with ASD
had no friendships (Howlin et al., 2004). In a study of 235 adolescents and adults with
ASD, 30% reported having at least one friend, whereas almost 50% had no peer friendships
(Orsmond, Krauss, & Seltzer, 2004). Another study reported that 16% of young adults with
high-functioning autism had at least one friend, whereas 47% had no friends (Mawhood,
Howlin, & Rutter, 2000). Of the friendships that adults with ASD do have, some data sug-
gest that the friendships tend to be less close and supportive, on average, than those seen
in typically developing adults (Baron-Cohen & Wheelwright, 2003). For another example
of data on social relationships in adults with ASD, see Table 23.1. Some evidence indicates
Adults With Autism Spectrum Disorder // 431
TABLE 23.1 Social Relationships in a Sample of 60 Adults With Autism Spectrum Disordera
Rating Relationship n (%)
FRIENDS/ACQUAINTANCES (N = 59)
A B
0 One or more friends of approximately same age 5 (9)

1 One or more friends but restricted range of interests 9 (15)
2 No specific friendships but seeks contact with others in group situations 8 (14)
3 Never any peer relationships involving selectivity/sharing 37 (63)
CLOSE RELATIONSHIP A (N = 60)
0 Close reciprocal relationship(s) (e.g., sexual relationship/marriage), past or 4 (7)

present
1 Some reciprocal relationships but short duration and/or reduced sharing of 6 (10)
activities
2 Only ever very brief relationships, involving minimal sharing of activities 4 (7)
3 No reciprocal relationships lasting >1 month or never had relationship 46 (77)
Note: aFriends are characterized as individuals seen for outings, visits outside the home but not
necessarily invoking emotional intimacy/sharing of feelings. Close relationships are character-
ized as involving close personal contacts (including sexual); sharing of feelings and activities.
b
One informant could not report on this area.
Source: From Howlin et al. (2013).
that restricted and repetitive behaviors characteristic of ASD tend to become less frequent
and less severe as individuals move into adulthood, especially in individuals without intel-
lectual disability (Esbensen, Seltzer, Lam, & Bodfish, 2009; Shattuck et al., 2007), although
many adults continue to have unusual responses to sensory stimuli (Billstedt et al., 2007;
Howlin et al., 2013).
During adolescence, individuals on the spectrum are at increased risk for periods of
aggravation of behavioral symptoms (e.g., aggression, hyperactivity, and insistence on
sameness) and for seizures (Gillberg & Steffenburg, 1987; Seltzer et al., 2004), but these
symptoms are sometimes transient. Due to these neurobehavioral symptoms, psychotro-
pic medication usage—including use of antipsychotics, antidepressants, mood stabilizers/
anticonvulsants, and anxiolytics—tends to increase in individuals with ASD as they enter
adolescence and adulthood (Aman, Lam, & Collier-Crespin, 2003), despite the fact that
the evidence base for use of medications in adults with ASD is very limited (Dove et al.,
2012; Doyle & McDougle, 2012).
Intellectual functioning and language abilities are important prognostic factors that
tend to correlate with positive outcomes in adults with ASD, including ability to complete
more years of education, ability to live and work independently, and ability to form and
maintain relationships (Seltzer et al., 2004). Very few individuals with a childhood IQ
below 75 live independently as adults (Howlin & Moss, 2012). Individuals who did not
develop speech until after the age of 5 years tend to have poorer outcomes as adults, on
average (Howlin & Moss, 2012). However, intellectual disability alone is not the full expla-
nation for the adaptive difficulties of adults with ASD. Adults with ASD appear to have a
higher degree of difficulty in some areas than those with intellectual disability without ASD.
For example, relative to those with trisomy 21 (Down syndrome), adults with ASD and
intellectual disability had less residential independence and more limited social function-
ing (Esbensen, Bishop, Seltzer, Greenberg, & Taylor, 2010). In a comparison of adolescents
and adults with ASD versus adolescents and adults with intellectual disability but no ASD,
the group with ASD had significantly more stereotypies, compulsions, and self-injurious
behaviors (Bodfish, Symons, Parker, & Lewis, 2000). Moreover, individuals on the autism
spectrum with an IQ greater than 70 often still have substantial challenges and difficulties
in adulthood (Szatmari, Bartolucci, Bremner, Bond, & Rich, 1989; Howlin & Moss, 2012).
A study of individuals with a nonverbal IQ of 70 or greater found that a childhood rating of
Reciprocal Social Interaction, a domain of the Autism Diagnostic Interview, was the stron-
gest predictor of adult outcomes (Howlin et al., 2013).
Adolescents and adults with ASD have higher rates of mood disorders, anxiety dis-
orders, obsessive–compulsive disorder, and attention deficit hyperactivity disorder than
typically developing individuals, and thus they have higher mental health service needs
(Bellini, 2004; Bradley, Summers, Wood, & Bryson, 2004; Ghaziuddin, Ghaziuddin, &
Greden, 2002; Ghaziuddin & Zafar, 2008; Hill & Furniss, 2006; Hofvander et al., 2009;
Howlin, 2004; Joshi et al., 2013; Kim, Szatmari, Bryson, Streiner, & Wilson, 2000; LoVullo
& Matson, 2009; Lugnegard, Hallerback, & Gillberg, 2011; Mouridsen, Rich, Isager,
& Nedergaard, 2008; Simonoff et al., 2013). These psychiatric comorbidities often have
an adverse effect on general functioning (Ghaziuddin & Zafar, 2008; Howlin & Moss,
2012). The social isolation, social exclusion, and unemployment or underemployment of
adults with ASD may contribute to their development of depression and suicidal ideation
(Cassidy et al., 2014). Individuals with comorbid psychiatric disorders should be referred
for treatment to a psychologist and/or a psychiatrist, ideally one with some experience in
treating adolescents or adults on the autism spectrum.
The relatively poor outcomes for adults with ASD may be attributable, at least in part, to
the relative lack of services for adults and research on adults with ASD. In many areas of the
United States, mandated services and supports for individuals with ASD either disappear or
are dramatically reduced after the age of 21–22 years, which is sometimes referred to as “fall-
ing off the cliff ” (Howlin & Moss, 2012; Taylor & Seltzer, 2010, 2011) or at least an impor-
tant turning point in the lives of individuals with ASD (Taylor & Seltzer, 2010). The period
of time after leaving high school has been associated with a slowing of improvement in symp-
toms and behaviors, perhaps due to lack of services, daily structure, and engaging daytime
activities (Shattuck, Narendorf, et al., 2012). Moreover, relative to the attention that children
with ASD have received, much less empirical research has been conducted on treatments,
including medication treatments, for adults with ASD, which limits the evidence base for
supporting and treating adults (Dove et al., 2012; Howlin & Moss, 2012). Together with the
growth of early intervention for children with ASD, there is a growing imperative for more
research on transition to adulthood and more service development and reimbursement for
adults with ASD, and it is hoped that this will lead to better outcomes for adolescents and
adults over time (Gerhardt & Lainer, 2011; Howlin, 2008; Shattuck, Roux, et al., 2012).
STRESS ON FAMILY MEMBERS
The transition to adulthood is often a period of considerable stress and adjustment for close
family members of those on the autism spectrum (Seltzer, Krauss, Orsmond, & Vestal, 2001).
Many parents serve as primary caregivers and/or care coordinators for adolescent and adult
children with ASD, and sustained efforts on the part of parents are needed to coordinate many
types of health, educational, and other services. Parents of adolescents on the spectrum often
have immediate concerns about challenging behaviors, social and communication skills,
behavioral and academic issues with schools, as well as the need for some respite from the
stresses of caregiving (Fong, Wilgosh, & Sobsey, 1993; Seltzer et al., 2004). As children grow
physically larger in adolescence, certain behaviors that were more manageable in early child-
hood, such as tantrums, may become more stressful and difficult to manage.
In looking ahead to the near future, parents often have considerable worries about
their child’s capacity to move out of the home and to function in post-secondary edu-
cation, employment, and activities of daily living. Also, it may be difficult for some par-
ents to contemplate issues related to their son’s or daughter’s sexuality and interest in
romantic relationships. Parents often have longer term concerns about what will happen
to their child when the parents become older, sick, or pass away and questions about
how to address those issues, including legal issues about guardianship and financial and
health decision-making. Parents of children with ASD tend to experience higher caregiv-
ing demands, higher levels of stress, more mental health symptoms, and higher rates of
divorce compared to parents of typically developing children or parents of children with
trisomy 21 or intellectual disability of unknown etiology (Abbeduto et al., 2004; Dumas,
Wolf, Fisman, & Culligan, 1991; Wolf, Noh, Fisman, & Speechley, 1989). Due to the costs
of treatments and loss of parent income, raising a child with ASD is also a major financial
undertaking that can leave families under severe financial stress (Buescher, Cidav, Knapp,
& Mandell, 2014; Ganz, 2007). Lower family socioeconomic status also has been associ-
ated with slower improvement in maladaptive behaviors during the transition to adult-
hood (Taylor & Seltzer, 2010).
Parents should be offered resources for support for themselves, as well as for their
child. These include a series of frank and thorough discussions of the many issues
involved in transition to adulthood, the particular adaptive strengths and talents of
their own child, as well as areas in which their child will need more support and ser-
vices. Many issues should be addressed in the discussions, such as the following: find-
ing post-secondary educational opportunities when appropriate, as well as educational
settings that will be a good match for their young adult son or daughter; preparing as
early as possible for vocational development and any services or supports that will be
helpful to function in work; options for housing and level of independence that will
be sustainable, and finding residential support when necessary; the development of
social relationships; ongoing behavioral issues and the potential role of behavioral
and medication treatments; planning for emergencies; and finding appropriate legal
and financial counseling for longer term planning regarding financial and health care
decision-making (Howlin & Moss, 2012; Pilling, Baron-Cohen, Megnin-Viggars, Lee,
& Taylor, 2012). There are an increasing number of attorneys with expertise in assisting
families of children with special needs regarding guardianship, trusts, education, work,
and residential issues. Resources to help individuals and families with transition plan-
ning have been developed by various organizations, including Autism Speaks (https://
www.autismspeaks.org/family-services/tool-kits/transition-tool-kit). When necessary,
parents should be offered resources for stress management and/or mental health treat-
ment for themselves. Recent research suggests that mindfulness-based stress reduction
approaches may be helpful to parents in reducing symptoms of depression and anxiety
(Dykens, Fisher, Taylor, Lambert, & Miodrag, 2014). Many parents may also find it
helpful to talk with other parents in similar situations or participate in support groups
in which experiences and coping strategies can be shared.
It is important to encourage individuals, families, and school systems to plan far ahead
for the transition to adulthood because there are numerous complex issues that will take
time and planning to address. Planning should begin when the individual is approximately
10–13 years of age, with more effort put into transition planning from 13–16 years of age
and older (Hendricks & Wehman, 2009). This transition work should include develop-
ment of vocational direction and education about independent living skills and adult
relationships. Ideally, the student, parents, teachers, and other professionals should all
participate in formulating the transition plan, and there should be coordination between
efforts of school and community agencies (Everson & Reid, 1999; Hendricks & Wehman,
2009). The transition plan should be paired with an educational program to help students
develop necessary skills and reach goals. It is often useful to teach skills in the context in
which they will be applied—that is, to teach in community settings, not just in the class-
room (Hendricks & Wehman, 2009).
EDUCATION
As measured by high school graduation rates and by performance on academic achieve-

ment tests, adolescents with ASD have lower levels of academic achievement, on aver-
age, compared with their typically developing peers (Hendricks & Wehman, 2009). A
majority of students with ASD have post-school services as part of their transition plan.
A study of a nationally representative survey of parents, guardians, and young adults
with ASD in the United States found that 34.7% of those with ASD attended college in
the first 6 years after high school, and more than 50% of youth who had left high school
in the past 2 years had no participation in further education (Shattuck, Narendorf, et al.,
2012). Participation rates were lower for individuals who belonged to minority groups
or whose family had lower income. These data are generally consistent with previous
reports indicating that 40% or fewer individuals with ASD attend college, and a smaller
percentage graduate from college, with lower rates among those with more severe symp-
toms or lack of access to services (Cederlund, Hagberg, Billstedt, Gillberg, & Gillberg,
2008; Eaves & Ho, 2008; Howlin, Alcock, & Burkin, 2005; Howlin, Mawhood, & Rutter,
2000; Taylor & Seltzer, 2011).
For those young adults who have the intellectual ability to attend college and even gradu-
ate or pursue professional education, their ability to do so may be thwarted by issues of living
away from home, managing their own activities of daily living and finances, managing the
unpredictability and inevitable stresses of more independent living, and navigating the rela-
tively complex social environment of higher education. Clinicians should inform individuals
and families that there are an increasing number of programs that are designed to prepare
and support young adults on the spectrum prior to and during college, as well as an increas-
ing number of colleges that are oriented to the needs of those students on the spectrum. In
addition, there are organizations, such as Achieving in Higher Education with Autism and
Developmental Disabilities (AHEADD; http://www.aheadd.org) that provide professional
support staff and peer mentoring during college, as well as other online resources.
LIVING ARRANGEMENTS AND ACTIVITIES OF DAILY LIVING
Depending on the individual’s preferences and independent living skills, various levels of
living independence are possible, including living with family, fully supported living, par-
tially supported living, and independent living either by oneself or in a group living set-
ting (Hendricks & Wehman, 2009). Many individuals with ASD do not live independently
(Table 23.2). There are advantages and disadvantages to these various living arrangements,
TABLE 23.2 Residential Status of a Sample of 60 Adults With Autism Spectrum Disordera
Rating Where Livinga n (%)
0 Independently 8 (13)
1 Semi-sheltered accommodation (n = 5) or with parents but high degree of 8 (13)
autonomy (n = 3)
2 At home, limited autonomy 10 (17)
Residential home, limited autonomy 12 (20)
3 Specialist autistic placement or another placement with little/no autonomy 20 (33)
Secure hospital care 2 (3)
Note: aAll individuals in residential care had been there since early adulthood (age 18–21).
both to adults on the spectrum and to their families of origin (Hendricks & Wehman,
2009; Krauss, Seltzer, & Jacobson, 2005). Many skills are involved in independent living,
including managing safety, cooking, cleaning, laundry, dressing, and personal finances. As
with other transition issues, teaching and practice of these independent living skills should
be part of behavior and transition plans relatively early on so there is sufficient time for
these skills to be acquired. There are an increasing number of agencies and clinicians that
can be helpful in implementing plans to teach these skills and providing various levels of
supported housing, but access to these services may depend on individuals’ and families’
particular benefits and entitlements. In addition, groups of parents have worked together
to form group homes for their adult children on the spectrum, as well as organizations
devoted to housing and residential issues.
VOCATION/EMPLOYMENT
Development of a vocation is a major priority during the transition to adulthood because

finding and keeping satisfying work plays an important role in developing a sense of pur-
pose and well-being, self-esteem, social and mental engagement, and financial indepen-
dence. According to recent studies, only 25–55% of adults with ASD, and perhaps less,
participate in any type of paid employment, including competitive or supported employ-
ment and full-time or part-time work (Hendricks, 2010; Shattuck, Narendorf, et al., 2012).
In some samples, 25–55% of young adults with ASD are not engaged in work of any sort
(Cederlund et al., 2008; Eaves & Ho, 2008; Howlin et al., 2013; Taylor & Seltzer, 2011) (see
Table 23.3).
Lower levels of cognitive or language skills are associated with lower rates of employ-
ment in adults with ASD (Graetz, 2010; Shattuck, Narendorf, et al., 2012). However, intel-
lectual disability is not the full explanation for low rates of employment in this population.
In fact, adults with ASD have lower rates of paid employment than adults with intellectual
disability without ASD, learning disabilities, or speech/language impairment (Shattuck,
Narendorf, et al., 2012). Individuals on the spectrum without intellectual disability are
employed at rates lower than one would expect on the basis of their intellectual functioning
(Howlin et al., 2004). In fact, in one study, adults with ASD without intellectual disability
were three times more likely to have no daytime activities than adults with ASD and an
intellectual disability (Taylor & Seltzer, 2011). The authors concluded that there seems
TABLE 23.3 Employment Status of a Sample of 60 Adults With Autism Spectrum Disorder
Highest Occupation Job Type (N = 60) n (%)
Professional or Computer programmer (construction design), engineer 2 (3)
highly skilled (nuclear research)
Non-manual skilled Project manager (×2) (civil service; telecom), artist (self- 7 (12)
employed), accounts clerk (×2), town planner, civil servant
Manual skilled Electronics work 1 (2)
Partly skilled Postal workers (×2) 2 (3)
Unskilled and Postal work (family firm), McDonald’s, sales assistant, 5 (8)
untrained cleaning/sorting in theatrical costumiers, factory
assembly/packing work
PhD student/voluntary 1(2)
lobbying work
Sheltered/voluntary Basic industrial work, cleaning (×2), care–home, 9 (15)
employment charity shop, railway guard, kitchen, gardening work (×2)
Never worked/long-term 33 (55)
unemployed
to be a subgroup of young adults who “fall through the cracks”—those who do not have
severe enough symptoms to receive adult day services but who are not able to function
independently.
Gaining and keeping competitive employment is very challenging for many individu-
als on the spectrum, often due, in large part, to the social demands and sensory issues in
the workplace. Gaining competitive employment often requires a job interview, which is
extremely difficult for many adults with ASD, given their difficulties with social under-
standing and social skills. Once one has employment, one then has to navigate interac-
tions with bosses, supervisors, and coworkers, as well as workplace “politics,” which are
very challenging for many adults on the spectrum. Adults with ASD tend to switch jobs
more often, and it is more difficult for them to adjust to new job settings (Hendricks &
Wehman, 2009; Hurlbutt & Chalmers, 2004; Muller, Schuler, Burton, & Yates, 2003).
For those adults on the autism spectrum who are employed, many are underemployed in
menial jobs that they find uninteresting and that may pay lower than a living wage (Taylor
& Seltzer, 2011; Taylor et al., 2012). Individuals who are able to get competitive employ-
ment will likely benefit from continued support outside of the workplace setting in under-
standing and navigating the social demands and office politics that often are part of the
workplace. This support may come from a family member, clinician, or vocational support
or rehabilitation program.
Clinicians and others who are caring for or supporting adolescents or young adults
on the spectrum should not assume that these individuals, even if they are intellectually
disabled, do not have an interest or ability to engage in work. In fact, the vast majority of
individuals, including those who are intellectually disabled, prefer to have engaging work or
other activities and prefer to play an important role in choosing the type of work (Burchardt,
2004; Shattuck, Roux, et al., 2012). Behavioral problems can worsen when young adults are
bored and unstimulated by engaging daytime work or activities.
For individuals with ASD who do want to work, it should be a major goal of transition
planning. It is important to give students in high school work experiences and opportuni-
ties to explore career options. This can help develop an interest and understanding of work
and jobs, develop work skills, and also develop interpersonal skills that can be applied in
job settings (Hendricks & Wehman, 2009; Targett, 2006). Many individuals on the autism
spectrum have areas of special interest, and rather than viewing these only as pathologi-
cal symptoms or restricted interests to be treated, these special interests can sometimes by
parlayed into a kind of work that is enjoyable and meaningful to individuals (Grandin &
Duffy, 2004).
What other strategies can be used to maximize work opportunities and functioning for
adults with ASD? Unfortunately, the evidence base on vocational interventions for adoles-
cents and adults with ASD is quite sparse (Taylor et al., 2012). The few studies that have
been published mostly focus on supported employment programs, which involve individu-
alized supports, such as a job coach, in a community-based workplace to make employ-
ment in community settings more feasible (Taylor et al., 2012). Supported employment
programs also may help with writing resumes and job applications, preparing for inter-
views, job training, matching the person with appropriate jobs, advising employers on mak-
ing necessary adjustments to the workplace environment, supporting the individual once
he or she starts the job, and supporting the employer with advice regarding ASD (Pilling
et al., 2012). There is evidence that supported employment increases employment rates
(Howlin et al., 2005), quality of life (Garcia-Villamisar, Wehman, & Navarro, 2002), and
cognitive functioning (Garcia-Villamisar & Hughes, 2007) for particular sets of individuals
on the spectrum, and it may have a long-lasting positive effect on employment (Howlin
et al., 2005; Lawer, Brusilovskiy, Salzer, & Mandell, 2009). There is also evidence from a
cross-sectional study that supports such as on-the-job training, job search assistance, and
assistive technology are associated with a high likelihood of employment in the community
(Lawer et al., 2009; Taylor et al., 2012).
Historically, vocational rehabilitation programs have not necessarily been oriented
toward helping individuals on the autism spectrum, but there is growing recognition for
the need for vocational rehabilitation, or habilitation, for that population, and an increasing
number of agencies are providing help customized to adults on the autism spectrum. For
those who are not able to participate in supported employment, sheltered workshops or
adult day activity centers are options. Sheltered workshops consist of work in a segregated
program (not community-based) with coworkers who also have disabilities (Taylor et al.,
2012). As a prelude or supplement to paid work, participation on a volunteer work team
can help in developing and practicing work and social skills and can give socially isolated
individuals a sense of mattering in the world (Fegan & Cook, 2014; Piliavin & Siegel, 2007).
Although ASD is highly heterogeneous, and it is difficult to make generalizations about
individuals with ASD, a few rules of thumb are useful regarding work and daytime activi-
ties. First, many people on the autism spectrum tend to thrive on a structured and fairly
predictable schedule, but they also prefer to have a role in making choices about the types
of activities in which they engage. To the extent that work or daytime activities can have a
predictable schedule, that is often helpful, and a visual calendar and schedule can often be
quite helpful as well so that individuals know what to expect. The areas of work life that are
often most difficult for individuals on the spectrum are the social demands (job interview-
ing, small talk on the job, office politics, communicating with bosses, and tailoring com-
munication to the particular person and context), executive functioning demands (staying
organized and timing), and managing stress. One important issue is trying to find the right
fit—that is, finding a kind of work that matches as well as possible with the individual’s
particular interests and strengths. In addition, individuals on the spectrum also may need
ongoing support from clinicians, family members, job coaches, peer mentors, or vocational
rehabilitation personnel regarding social understanding, social skills, organization, and
stress relief in order to make a particular job feasible and sustainable.
INTERFERING BEHAVIORS
Adolescents and adults with ASD may have ongoing difficulties with challenging behav-
iors, such as tantrums, aggression, or self-injurious behaviors, which can pose safety con-
cerns and interfere with family, social, and occupational functioning. Adults with ASD
who are nonverbal or who have severe difficulties with communication may not be able
to convey that they feel ill or in pain, and they may only express this through aggressive
or self-injurious behaviors (Carr & Owen-DeSchryve, 2007). Therefore, one should first
assess the patient for any medical problems, sources of physical pain, or comorbid psychi-
atric issues (e.g., anxiety and depression) that may be contributing to challenging behaviors
and about which the patient may have difficulty communicating, especially if the patient
is intellectually disabled or nonverbal. It is typically also very useful to refer the patient to
a psychologist, such as a Board Certified Behavior Analyst (BCBA), who can carry out a
functional behavior assessment (FBA) to collect data in the patient’s natural environment
and identify other environmental or social factors (including antecedent and consequent
events—that is, events that occur before and after the behavior, respectively) that may be
contributing to the behaviors and to identify ways in which the behaviors may be serv-
ing a communicative function or function of fulfilling a particular need. The FBA typically
should include efforts to manipulate aspects of the environment to determine the effects
on the frequency and intensity of the interfering behaviors in order to establish a causal
relationship and formulate a strategy for intervention. The BCBA can then implement a
behavioral intervention plan to modify aspects of the social environment to try to reduce
the frequency and/or intensity of the interfering behaviors and to teach the patient more
functional means of communicating his or her needs (National Autism Center, 2009). If
the therapeutic response to an adequate trial of a behavioral intervention is not sufficient,
and challenging behaviors are still significantly interfering with day-to-day functioning, one
should consider treatment with one of the antipsychotic drugs that are approved by the US
Food and Drug Administration for this indication, including risperidone or aripiprazole
(Dove et al., 2012; Doyle & McDougle, 2012). Medication treatment may also be neces-
sary earlier in the course of treatment if there are more imminent safety concerns, and it
can be implemented at the same time as behavioral interventions. More verbal patients may
also benefit from regular psychotherapy treatment.
SOCIAL AND COMMUNICATION SKILLS FOR ADULT LIFE
Transition plans should address social and communication skill development and general-
ization of these skills to a variety of contexts, including home, school, work, and commu-
nity settings (Hendricks & Wehman, 2009). Speech–language therapy may be necessary in
adolescence to improve verbal communication skills. For those who are nonverbal, alter-
native methods of communication, such as use of the Picture Exchange Communication
System (PECS), should be employed for communication. Although much of the evidence
base for use of applied behavioral approaches to improve social and communication skills
derives from children with ASD, it is likely that similar approaches will be very helpful to
adults with ASD in developing social and communication skills (Howlin & Moss, 2012;
National Autism Center, 2009).
Social functioning of adolescents and adults with ASD may be adversely affected by low
motivation to engage socially, lack of social understanding (social cognition), lack of social
skills, anxiety and difficulties with emotion regulation, and/or difficulty in tailoring social
behaviors to particular contexts (Chevallier, Kohls, Troiani, Brodkin, & Schultz, 2012;
Samson, Huber, & Gross, 2012; Volkmar, 2011). Many adolescents and adults on the autism
spectrum spend a very large number of waking hours on solitary activities such as video
games and Internet use, and these activities provide few, if any, opportunities to develop
social understanding or practice social skills in “live” interactions with others. The “social
gap” between individuals on the spectrum and typically developing individuals tends to
widen during adolescence and the transition to adulthood (Hendricks & Wehman, 2009).
However, many individuals on the autism spectrum express a desire for friendships and
intimate relationships and feel lonely, but they do not possess the understanding of social
relationships or the social communication skills to form and maintain such relationships
(Hendricks & Wehman, 2009). Also, many individuals with ASD have a libido and an inter-
est in romantic and sexual relationships but lack an understanding of the rules of dating and
romantic relationships and also lack social skills. This may lead these individuals to engage
in behaviors that are misinterpreted or get them into trouble, such as “stalking” behaviors
(Stokes, Newton, & Kaur, 2007). Relative to the tolerance for mistakes in childhood, there
is reduced tolerance in society for a lack of understanding of social mores in adults, and
poor social decision-making in adults with ASD can have severe consequences, including
loss of opportunities for employment, social isolation, or even criminal prosecution.
Compared with treatments and services that have been developed for children, rela-
tively few treatments and services have been developed and rigorously tested to improve
social functioning for late adolescents and adults with ASD. However, there has been
a growing interest in this area and a realization that it is very important, considering the
large numbers of individuals transitioning to adulthood. Some social skills groups have
been developed for late adolescents and young adults with ASD, and some work has been
done in developing video modeling programs to teach social skills (Bishop-Fitzpatrick,
Minshew, & Eack, 2013; Day-Watkins, Murray, & Connell, 2014; Gantman, Kapp, Orenski,
& Laugeson, 2012; Laugeson, Frankel, Gantman, Dillon, & Mogil, 2012; Turner-Brown,
Perry, Dichter, Bodfish, & Penn, 2008). Increasing numbers of social skills groups and pro-
grams for adults are being developed by clinicians in various areas of the country. However,
much more work is needed in this area to develop evidence-based treatments and services
because social and communication skills are vital for virtually all aspects of adult life.
Case Study #1: “John”
Studies of transition to adulthood tend to focus, understandably, on very noticeable and

major outcomes of concern in individuals with ASD, such as interrupted education, unem-
ployment, inability to live independently, and repetitive behaviors that may result in injury.
However, it is important for clinicians to recognize that even those individuals with ASD
with seemingly the very best long-term outcomes according to the usual criteria—excellent
cognitive functioning, completed higher education, a well-developed career, independent
living, and even marriage—may still have very significant difficulties with social functioning
that cause impairments in their relationships and substantial distress in themselves and
in their loved ones. Therefore, even if the education, employment, and housing issues of
transition to adulthood are navigated very well, many adults still need substantial help with
social understanding, emotion regulation, and relationships. This area of need may not be
reflected well in studies that present aggregated group data on transition to adulthood, but
it is illustrated in this case example.
John is a 47-year-old man with a history of ASD symptoms since childhood, including
marked impairment in social–emotional reciprocity, difficulty in using and interpreting non-
verbal social communication, very few peer friendships throughout childhood, sensitivities
to sound and particular clothing textures, spending many hours per day in pursuing vari-
ous solitary interests (e.g., video games), and tendency to stick to an inflexible schedule.
However, he is very bright intellectually, and he did well academically in school, ultimately
graduating from college, where he majored in business and computer engineering. Although
his diagnosis of ASD was not made until he was an adult, he realized even before the diag-
nosis was made that he had some difficulty in understanding social interactions. He com-
pensated for this by teaching himself certain scripts and ways of conversing in structured
situations, by reading various sales and self-help books. This has given him sufficient social
skill to adequately navigate his workplace for the most part. He has built a career in the
computer software field and has been fairly successful financially. Intermittently, however,
he has had significant interpersonal difficulties at work related to difficulty in reading and
navigating social situations, which has led to multiple changes of jobs and compromised
the growth of his career, to some extent, and has recently put his current job in jeopardy.
In his teens and early twenties, he never dated, but in his early thirties he met a woman
named Susan at a work meeting who showed an interest in him and whom he ultimately
married. Their marriage has lasted for 15 years, and they have a 13-year-old daughter.
Susan used to work in the computer field, but she stopped working to raise their daughter.
Despite the marriage lasting 15 years, their family life has been marked by great difficulties,
and Susan has increasingly considered divorce. She feels that he is emotionally cold and
that they are unable to connect. He spends virtually all of his time in his study, working or
pursuing his own areas of special interest on the computer—topics that do not interest
her at all. After asking her a few standard questions about her day, which seem to her to
be scripted, he does not know how to respond to her beyond that. Conversations tend to
fall flat. Sometimes John speaks at length about his own areas of interest, but he does not
seem to notice that Susan is not interested unless she tells him quite bluntly. He seems to
not be aware of his own emotions or hers, unless she expresses them very obviously when
she becomes frustrated with their relationship, but then he generally does not understand
why she is acting that way and does not know how to respond. He makes little eye contact,
and his affect is usually quite constricted. Their teenage daughter feels that she generally
cannot connect with her father, and she feels quite distant from him. Susan has become
increasingly depressed, and her talk about divorce makes John very anxious, to the point
of panic symptoms, because he would feel devastated if he were to lose his marriage,
although he has difficulty expressing that to his wife. Although he generally expresses little
emotion, he sometimes has yelling temper tantrums when he feels overwhelmed with
stress and anxiety, and he does not know how to manage the feelings. Susan brought John
to a specialty clinic for adults with ASD, encouraging him to seek help with his social under-
standing and social skills, in order to have a better chance of saving his job and marriage. If
ASD had been recognized earlier in this quite “high-functioning” individual, and John had
received help with social functioning in childhood and around the transition to adulthood, he
may have had less distress and greater ability to navigate work and relationships.
SUMMARY
Planning for the transition to adulthood should begin early in adolescence, and it should be
tailored to the particular goals and needs of the patient and family. Such planning should
ideally include input from the patient, family, teachers, clinicians, and other professionals.
To optimize functioning and outcomes, various areas need to be addressed, including fam-
ily stress, education, vocational development, adaptive living skills, interfering behaviors,
and social and communication skills. There has been a relative lack of development of treat-
ments and services for adults with ASD, but this is starting to change. Clinicians should
become aware of existing or newly developed resources in their area so they can best assist
patients and families in navigating the opportunities and challenges of transition and also
so that adults with ASD can develop a sense of well-being and higher quality of life in their
communities.
KEY POINTS
• Developing plans for transition to adulthood should begin well before the age of
18 years, ideally at the age of 10–13 years, and should involve a collaborative effort of
the patient, family, teachers, clinicians, and other professionals.
• Outcomes for adults with ASD have been generally disappointing, including high
rates of social isolation, interrupted education, unemployment, and lack of indepen-
dent living. These outcomes may be attributable, in part, to lack of established ser-
vices and supports for adults.
• Parents and other family members of adults with ASD tend to be under significant
chronic stress, and they may need help from a variety of professionals in managing
transition issues.
• The majority of individuals on the autism spectrum, including those who are intel-
lectually disabled, prefer to have engaging work or other activities and prefer to play
an important role in choosing the type of work.
• Many adults with ASD feel lonely and have a desire for friendships or romantic rela-
tionships, but they may lack the social understanding and skills necessary to initiate
and sustain relationships. More treatments and services are needed to help adults
with ASD navigate social relationships.
ACKNOWLEDGMENTS
This work was funded by the National Institutes of Health (grants R34MH104407;
R34MH100356; and P50MH096891, subproject 6773) and the Autism Services,
Education, Resources, and Training (ASERT) Collaborative, Bureau of Autism Services,
Pennsylvania Department of Human Resources. The content of the chapter is solely the
responsibility of the author and does not represent the official views of the National Institute
of Mental Health, the National Institutes of Health, or the Pennsylvania Department of
Human Resources.
Dr. Edward S. Brodkin has no conflicts to disclose.
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/ 24
/ / / / / EFFECTIVE COMMUNICATION
AND MANAGEMENT WITH
THE FAMILY AND IN THE
COMMUNITY
NAOMI B. SWIEZY, TIFFANY J. NEAL,

DANIELLE WARNER, AND KIMBERLY LO
INTRODUCTION
Collaboration is essential to the care of individuals with autism spectrum disorder (ASD),
although it is often an elusive concept. Collaboration is a construct that is understood and
conceptualized differently across disciplines (Kelly & Tincani, 2013), making it challenging
to contextualize the construct in a cohesive, effective manner. Swiezy, Stuart, and Korzekwa
(2008) suggest that
integration of care across medical, educational, and social service systems is challenging
to both families and health care professionals due to the time required, cost of staff time
and services, knowledge, training, availability of services, and lack of support for the
collaborative effort itself. (p. 1156)
Nevertheless, providing the most effective and integrated care for individuals with ASD
and their families involves collaboration across multiple disciplines and domains and is
imperative. With this consideration in mind, awareness of the meaning, purpose, and com-
ponents of collaboration is essential. In addition to this awareness, it is similarly important
to have a contextual understanding of selected models of collaboration and the outcomes
that can be derived through such context.
In seeking to establish a shared definition of collaboration, reference to various sources
serves to pull essential elements together across disciplines. Collaboration in the health
care field, according to Kelly and Tincani (2013), is
447
a component of consultation involving voluntary, interpersonal interactions comprising

of two or more professionals engaging in communication modalities . . . for the purpose
of shared decision-making and problem solving toward a common goal. Collaboration
results in changes to tasks and solutions that would not have been achieved in isolation.
(p. 129)
Collaboration can also be thought of as a partnership, with literature demonstrat-

ing the saliency of “mutually agreed upon goals, shared expertise, shared responsi-
bility, ecocultural fit, collaborative problem solving, and a strength-based approach”
(Brookman-Frazee & Koegel, 2004, p. 197) in deriving improved outcomes across
consumers and providers. Furthermore, the manner in which providers, families, and
individuals involved in the care and support of those with ASD work together and col-
laborate is paramount in strengthening and maintaining integrated and continuous sup-
ports to maximize outcomes.
Given the importance of collaboration and the impact it has on the quality of treatment
and care for individuals with ASD, this chapter further discusses the necessity and func-
tion of collaboration, the components of collaboration, and the way collaboration looks in
practice. The chapter aims to provide an understanding of the ways in which professionals
and caregivers can facilitate truly effective care for individuals with ASD by considering the
necessary components of collaboration and the ways in which such collaboration allows for
consistent individually oriented treatment.
NECESSITY FOR COLLABORATION
Individuals with ASD present with a spectrum of abilities and impairments, both physical
and psychological. These characteristics vary between individuals and are influenced by
multiple factors, including those that are genetic, environmental, and psychosocial. Given
the unique presentation of ASD in each individual, the best treatment for one individual
may look different from that of another. Therefore, “to ensure that the many needs of these
children are met across multiple settings, collaboration among medical, psychological,
and educational experts is necessary in order to determine the best course of treatment”
(Power, DuPaul, Shapiro, & Kazak, 2003, as cited in Ellis, Lutz, Schaefer, & Woods, 2007,
p. 742).
Individuals with ASD may be unable to convey their needs and may therefore rely
on others to advocate on their behalf (Vakil & Welton, 2013). Keeping this in mind,
it is important to consider how individuals at any level of functioning may present
differently across settings. For example, a child’s behavior at school with his or her
teacher may be very different from his or her behavior at home with parents and/or
caregivers due to differences within the environment ranging from the presence of cer-
tain persons, tasks requested or demands being placed, time of day, behavioral strate-
gies being used, or disciplinary techniques used by caregivers, among other factors.
Therefore, it is crucial to seek input from caregivers across various settings in order
to fully understand the scope of functioning, current and historical challenges, strate-
gies or techniques used, supports in place, and strengths of each individual with ASD.
This describes a shift from the child-only-focus that continues to be held in certain
fields. The importance of seeking to understand a child in the context of his or her
family, culture, and community is now well understood. Family context is especially
important given the breadth of information that parents can contribute with regard to
Effective Communication and Management With the Family and in the Community // 449
their children. Parents should be used “as integral members of the care team respon-
sible for coordinating services and disseminating information across settings” (Swiezy
et al., 2008, p. 911). Family systems theory supports this premise given the consequent
impacts, direct or indirect, that occur across the family system when one family mem-
ber is affected (Kalyva, 2013). Given that family systems may be significantly affected
with the initial diagnosis and resulting course of ASD in one of its family members,
family support and collaboration throughout all facets of treatment should be an area
of focus.
The incorporation of varying perspectives to inform programming for individuals with
ASD, support consistency in program implementation, and evaluate program effectiveness
is made possible through collaboration (Swiezy et al., 2008). Many individuals contribute
in regard to treatment planning when providing care for an individual with ASD across
the lifespan. Such individuals include, but are not limited to, educational and medical pro-
fessionals, specialists, community service providers, and parents or caregivers. Without
collaboration, each party involved may have a different understanding of the individual’s
needs. Each may be working toward differing goals using varied strategies, thus creating
and potentially exacerbating difficulties related to generalization and maintenance of skills
for the individual with ASD due to disparate approaches. These issues are minimized when
treatment plans develop from a collaborative consultation model, with this approach hav-
ing increased likelihood to result in more consistent programming across settings (Sheridan
& Steck, 1995; Wahler & Fox, 1981).
Evidence shows that collaborative consultation models involving shared decision-
making between stakeholders lead to improved outcomes across environments. A review
by Kelly and Tincani (2013) demonstrated consistent, increased consumer outcomes
with the use of either direct or conjoint behavioral consultation models. With a focus
on communication between stakeholders (i.e., providers, family members, and school
or community providers) and shared responsibility in decision-making across the
problem-solving process, improved outcomes are witnessed with respect to behavioral
and academic skills, changes in referral patterns, increased treatment integrity, mainte-
nance of gains, and enhanced consumer acceptability. In addition, collaboration rein-
forces the intent of foundational special education laws, such as the Individuals With
Disabilities Education Improvement Act (IDEIA, 2004), with emphases placed on
meaningful parent involvement that fosters opportunities for parents and school person-
nel alongside or inclusive of medical professionals when opportunity is extended to work
together.
Given the aforementioned outcomes, collaboration is essential in providing the best
quality care for all individuals on the autism spectrum despite presenting challenges.
Models of collaboration built solely on cooperation with professionals assuming the role
of experts and with parental participation seen as secondary to care result in disagreement
and strife related to treatment plans and goals with decreased adherence and satisfaction
(Cunningham & Davis, 1985). Models that account for collaboration in a co-therapy
context may fail to consider differences that present in parenting styles, family resources,
and cultural context, thereby negating salient elements that result in improved outcomes
(Mittler & Mittler, 1983). Furthermore, collaboration models reliant upon parents serving
both as the consumer and the primary informant for selection of program elements risk the
loss of a more systematic and evidence-based approach that is more appropriately advised
and followed with trained professionals guiding the treatment planning and programming
(Appleton & Minchom, 1991).
ELEMENTS OF COLLABORATION
Collaboration with parents may look differently depending on their comfort level advo-
cating for their child and ability to express their needs. By validating and empowering the
parent, greater trust and ultimately a greater partnership can lead to better outcomes for the
child and improve the quality of care provided. However, it is first important to bring the
parent to the table. Brookman-Frazee and Koegel (2004) note that
in a partnership between a parent and a professional, the professional may be the

“expert” with regards to particular behavioral intervention procedures, whereas the
parent is the “expert” on his or her own child and should be responsible for deciding
how the procedures are incorporated into the family’s daily routines. (p. 197)
Not only are parents able to provide information about their children but also they are
often the primary conduit for dissemination of information across systems (Swiezy
et al., 2008).
In order to facilitate individually oriented treatment, certain components of collabora-
tion with families are necessary. These components are explored next. Furthermore, the
nature of individually oriented treatment is discussed with an emphasis on its importance
in the effort to provide effective care to individuals with ASD.
PROVIDING SUPPORT
Collaboration with parents and caregivers includes supporting the parent as he or she
comes to terms with a child’s diagnosis and continuing such support as the parent
faces the ongoing needs involved with treatment across disciplines. The impact of
having a child with a disability has been well documented in the literature. Often, par-
ents initially go through and may cycle back through a mourning period after receipt
of the diagnosis of ASD for their child. Such mourning and the consequent emo-
tions are comparable to the five stages of grief—denial, anger, bargaining, depression,
and acceptance—put forth by Elizabeth Kübler-Ross (Elder, 2013). In addition to
emotional impacts, a qualitative study by Fletcher, Markoulakis, and Bryden (2012)
illustrated the substantial financial burden assumed by families in order to cover the
costs of treatment and related needs (e.g., dietary needs, child care, private care, and
home cleaning and repair) in caring for their child with ASD. Furthermore, it was
found that mothers’ health was often compromised while they put their child’s needs
before their own, often resulting in depression, exhaustion, weight gain, and increased
stress. Similar health issues have been reported to affect fathers and siblings. Many
mothers report a loss of friends and an overall social strain following their child’s diag-
nosis, including strain within marital relationships (Fletcher, Markoulakis, & Bryden,
2012). Consideration of parental needs with respect to support, coordination of care,
awareness of increased stress, and potential mental health issues is an aspect that war-
rants discussion and attention by providers (Stahmer, Brookman-Frazee, Lee, Searcy,
& Reed, 2011). Without such attention, a parent’s appraisal of communication with
professionals is often reported as an area resulting in high levels of stress (Brogan &
Knussen, 2003).
Trust
Equity Communication
Factors
Essential for
Supportive
Relationships
Skills Commitment
Respect
FIGURE 24.1 Six factors essential for supportive relationships. This figure illustrates the compo-
nents necessary to foster in order to effectively collaborate in a relationship that is supportive.
Given the significant impact that high parental stress can have on the success of early
teaching interventions, it is of great importance to take care in all facets of contact and
communication with parents leading up to, and during, the diagnostic and/or evaluative
process (Osborne & Reed, 2008). Such care includes asking parents questions about their
experience and allowing their responses to inform their child’s treatment, as well as the sup-
ports and resources they are offered. The following factors were listed in Kalyva (2013) as
essential components in the development of supportive relationships between parents and
mental health professionals (see Figure 24.1):
1. Communication: This should be reciprocal in nature with open, honest, and fre-
quent communication that is free from jargon being fostered across parties.
2. Commitment: Professionals should demonstrate commitment in awareness of and
value placed upon the dynamics of the family in serving the whole child.
3. Equity: Conscious effort should be made to seek parental input and empower fam-
ily members with acknowledgment of the necessary balance between parental input
and professional judgment within the therapeutic process.
4. Skills: The professional’s skills are highly appreciated by parents when practical help
is given both for the care of their child with disabilities and for themselves.
5. Trust: Feelings of trust by parents account for the dimensions of reliability in care
and service delivery, physical and emotional security with respect to the care of their
children in the presence and planning of providers, and discretion in informational
sharing among providers and colleagues.
6. Respect: The individual with a disability should be treated first and foremost as a

human being. (pp. 530–531)
The presence and importance of these factors may vary among parents, but they holistically
encourage parents and caregivers to feel more supported in their relationship with provid-
ers across systems (Brogan & Knussen, 2003).
FACILITATING EMPOWERMENT
Family and parental empowerment is another essential component of effective collabora-

tion. Similar to collaboration, empowerment may have different meanings across disciplines.
Within the fields of social work and community psychology, advocacy is posited as a central
tenant to empowerment of families and caregivers. However, empowerment within the con-
text of child mental health emphasizes “effective parenting skills, knowledge, parent partici-
pation and involvement, and self-efficacy” (Brookman-Frazee & Koegel, 2004, p. 195).
In part, empowerment comes through the delivery and sharing of information. It is
important for providers to offer honest answers, refer to other professionals if they do not
have the answers, and educate themselves on the presenting disability and effective treat-
ments. The provision of education and support to families of individuals with ASD is one
of the treatment goals suggested by the American Academy of Pediatrics’ (AAP) Council
on Children with Disabilities (Myers & Johnson, 2007). Additional recommendations put
forth by the AAP build on such education and support with respect to increasing the child’s
ability to function independently, maximizing the child’s quality of life by minimizing the
core features of his or her disability, facilitating the child’s development and learning, encour-
aging socialization, and working toward reduction of behaviors that are maladaptive (Myers
& Johnson, 2007). In order to achieve such recommendations, effective collaboration across
systems with education, support, and empowerment of parents is of great importance.
As an example of empowering parents through education and support, the HANDS
in Autism Interdisciplinary Training and Resource Center (2013) uses the HANDS in
Autism Next Steps manual and workshop to detail the most salient “next steps” needed after
diagnosis and to provide a reference for parents to look to as they navigate their child’s care.
Within the manual, seven major areas are covered to provide parents and caregivers with
information after their child has received a diagnosis, including basic information about
ASD; family considerations with respect to how the family system may be affected by the
diagnosis; available supports statewide and nationwide to make use of across the child’s
lifespan; information related to rights and regulations that are in place to protect themselves
and their children, including insurance, Medicaid, and other governmental funding; and
references and tools to be aware of with regard to the availability and evaluation of interven-
tions and treatments. Last, within the manual and in collaboration contexts, it is essential to
provide parents with information regarding “practical strategies that can be applied across
the variety of environments and settings that [their] child will be engaged in on a regular
basis or will encounter throughout their life” (HANDS in Autism, 2013, p. 5).
INTEGRATING CARE
The integration of care for individuals with ASD and their families requires regular communi-
cation and an exchange of ideas. At times, this requires professionals to take the role of student
and be willing to listen to and learn from other professionals as well as caregivers to increase
the opportunity for effective multidisciplinary intervention efforts. In fact, professionals and all
stakeholders need to think of everyone who provides a service to the child as a part of the same
team (Vakil & Welton, 2013). Each service provider, educator, specialist, medical professional,
and caregiver provides a unique view of the child and needs to be on the same page regarding
the child’s behaviors, communicative abilities, and functioning level in order to ensure that the
type and level of care being provided are consistent across settings. Communication is impor-
tant not only between the various professionals and caregivers but also between the various
disciplines of professionals involved. For example, communication between educators and
psychiatrists allows the psychiatrists to have a greater understanding of the child’s behaviors
while allowing for educators to gain an awareness of changes in medication or other medical
issues the child may be dealing with at any point in time (Vakil & Welton, 2013). Such active
communication should take place not only during diagnosis but also on an ongoing basis as a
child and family adjust to the diagnosis and begin addressing various challenges that may arise.
To illustrate the way integration of care can significantly impact the ability of an inter-
disciplinary team of professionals to best meet the needs of those on the autism spectrum,
consider the following case. A 25-year-old individual with ASD and a long history of anxi-
ety around dental and other medical procedures required general anesthesia in order to be
able to undergo even simple medical procedures, including teeth cleaning. Administering
the anesthesia required an injection and subsequently several adults’ strength to hold the
individual down, often resulting in wrestling to sustain grip and administering the injec-
tion through the individual’s jeans. This struggle to administer the anesthesia was often
distressing for all who were involved. Upon the scheduling of a teeth cleaning with an oral
surgeon who had previously collaborated with HANDS in Autism, the physician recom-
mended to the family (who had also collaborated previously with HANDS) that HANDS
integrate and coordinate care across dentistry, anesthesiology, and the family. In this way, an
integrated and coordinated effort served to incorporate all perspectives and components,
fostering a sustainable plan that could cultivate increased successes and decreased distress
surrounding the process of teeth cleaning in the future. This effort involved preplanning to
determine common goals and to outline best practice strategies inclusive of preexposure to
the treatment area and staff, development of tools for structure, choice and motivation, as
well as video modeling and social narratives for use at home prior to the visit. On the day of
the visit, HANDS staff accompanied the individual with ASD to the surgery prep area and
supported the culminating acts of a needle stick for anesthesia administration and success-
ful completion of a thorough teeth cleaning. As such, with careful planning, practice, coach-
ing, and mentoring across care providers, family, and the individual, the procedures were
successful and were repeated subsequently for an unrelated minor medical procedure a few
months later. In this case, when the family contacted HANDS for assistance but learned
that HANDS was not available, it opted to go forward with the procedure as planned.
The success of this subsequent procedure and those since illustrates the overall successful
implementation of interventions once taught and supported through an integrated inter-
disciplinary approach leading to generalization and success potential of the procedures and
the team with progressively increased independence and ease.
INDIVIDUALLY ORIENTED TREATMENT
Regardless of the strategies used across settings, it is essential for professionals to keep in
mind that “each intervention needs to be specifically tailored to the individual child for
Integrating Providing
Care Support
Individual
Oriented
Treatment
Facilitating
Empowerment
FIGURE 24.2 Components of individual-oriented treatment. This figure illustrates salient compo-

nents of the collaborative relationship, including the provision of support, facilitation of empow-
erment, and the integration of care, that allow for individual-oriented treatment.
whom no ‘one size fits all’ methodology can address” (Swiezy et al., 2008, p. 910). As Figure
24.2 illustrates, the aforementioned provision of support, facilitation of empowerment,
and integration of care allow for such individually oriented treatment. The Committee of
Educational Interventions for Children with Autism, which was formed by the National
Research Council, put forth recommendations that reinforce the need for individually ori-
ented treatment (National Research Council, 2001). Recommendations reflect eligibility
for special education services regardless of level of severity or function, as well as support
of families through consistent presentation of information by local school systems, ongoing
consultation and individualized problem solving, and the opportunity to learn techniques
for teaching their children new skills and reducing behavioral problems.
Ongoing measurement of treatment objectives and progress should inform the range of
skill areas in which a child may benefit from a particular intervention and that those inter-
ventions (educational, behavioral, or other) should always be individualized and adjusted
accordingly. Objectives identified for interventions should address observable and mea-
surable behaviors and skills. These objectives should be able to be accomplished within a
realistic time period (e.g., 1 year) and be anticipated to affect a child’s participation in edu-
cation, the community, and family life. Services may vary according to a child’s chronologi-
cal age, developmental level, specific strengths and weaknesses, and family needs. However,
each child must receive sufficient individualized attention to promote the implementation
of objectives with fidelity. Priorities for interventions will include those to address the edu-
cational, functional (e.g., communication, social skills, play skills, and independence), and
behavioral goals. As further recommended by the National Autism Center (NAC) commit-
tee, interventions should include specialized instruction in settings in which ongoing inter-
actions occur with typically developing children and should include coordination across
services, systems, and funding at federal and state levels. These efforts should be part of
the coordination and collaboration with the already established infrastructure for educa-
tion, medical and community services, regional resource centers, and technical assistance
programs.
When such programming according to best practice and fidelity of implementation is
carried out across community systems for a whole child and whole community approach,
the practical and very real impact on children and families is positive, pervasive, and far
reaching. Communities with this integration and coordination more readily develop the
local capacity to best support the consistent use of effective strategies and practices for
greatest impact on individual and family potentials. As a case example, HANDS in Autism
facilitates community groups called Local Community Cadres (LCCs) composed initially
of family, school, and medical representation and eventually encompassing a larger breadth
of community participation. As a participant of one of the more vital and active LCCs, a
staff psychologist at a local medical center provided an account of a family attending ther-
apy coming to a treatment session one day elated to see some of the visual tools that the psy-
chologist had started incorporating after some training of the LCCs by the HANDS team.
As remarked by the enthused parent, she had witnessed the same tools and strategies that
the psychologist was using being utilized at the child’s school as well. As such, with both
the educational and medical system modeling the consistent use of the tools and strategies,
the family had consistent models for the process for utilizing the strategies, and the parents
were more comfortable and satisfied with the interventions being applied with their child
and were more motivated and clear as to how to institute similar strategies at home with
fidelity, purpose, and impact on both child and family outcomes.
FOSTERING FAMILY AND PARTNERSHIP CENTEREDNESS
With a focus on educating, supporting, and strengthening family functioning, services

and partnerships that focus on family or caregiver needs and strengths foster a positive
and proactive rather than deficit-based or categorical approach (Dunst & Deal, 1994).
Use of a family-centeredness approach in service delivery ensures services account for
family-identified needs, build on family strengths, and work to strengthen social supports.
Aligned with the aforementioned need to facilitate empowerment, helping to support fami-
lies in proactively identifying their needs, mobilizing and connecting them to resources and
supports, and setting, monitoring, and accomplishing goals through the identification and
strengthening of personal capacities, strengths, and abilities tie together both individualiza-
tion of care and family centeredness (Dunst, Trivette, Davis, & Cornwall, 1988).
Determination of “where the family is” when beginning or supporting services and
treatment rather than solely treating the problem or remediating deficiencies promotes the
acquisition of family and individual competencies. If focus is centered on correcting prob-
lems without such determination and recognition, results may be limited to short-term
resolution of only one presenting concern instead of developing strengths, assets, and skills
on behalf of the parent and individual. When such skills are developed, there is increased
likelihood that families, caregivers, and individuals will generalize resources and strategies
across settings and situations to address a range of presenting challenges at present as well as
in the future. Collaborative identification of needs, short- and long-term goals, and immedi-
ate and proximal foci for intervention results in more appropriate determination of needed
services and supports to facilitate acquisition of skills and commitment to change, resulting
in increased treatment adherence and outcomes (Sheridan, Warnes, Cowan, Schemm, &
Clarke, 2004).
However, it is important to recognize that family systems represent only one component
or system within the entities necessary in coordinated care across systems. Other partners,
including, but not limited to, medical providers, mental health professionals, school per-
sonnel, community organizations, and advocacy groups, are also contributors within mul-
tisystem, coordinated care. Partnership centeredness attends to the need for collaboration,
skill acquisition, and strength-based approaches in not only identifying individual needs,
strengths, and skills but also building upon the needs and strengths within partnerships
to enhance outcomes (Sheridan, Clarke, & Burt, 2008; Sheridan, Eagle, & Dowd, 2005).
Given the necessary components for effective partnerships with families, it is under-
stood that such effectiveness is most readily accomplished when partnering is a fully
intentional process. A framework that accommodates this process reflects the relational
prerequisites (i.e., approach, attitudes, and atmosphere) to successful collaborative actions
(Christenson, 2004) (Figure 24.3). Use of a meaningful approach that accounts for effec-
tive communication and shared decision-making, constructive attitudes that begin “where
the family is” rather than where providers feel they should or could be, and a positive atmo-
sphere with clearly articulated options for involvement and engagement set the stage for
successful implementation of partnership actions and improved outcomes as denoted by
the AAP recommendations (Myers & Johnson, 2007).
As a case example of these concepts, impact was realized through interdisciplinary and
interagency collaborations to serve the reported and implicit needs of a specific individual
and family. Specifically, a family attending therapies at a medical center in an area with an
active HANDS/LCC partnership consulted its child’s therapist about the family’s daughter
with ASD. When the therapist, as part of the full medical team, determined the need for an
invasive medical procedure, the team had to consider the best course of intervention for
the family and child. Although well-versed with the principles and strategies promulgated
through HANDS and effectively applied to this individual, the team did not believe that it
was best suited to conduct the computed tomography scan at its facility; rather, the recom-
mendation was to visit a partner medical center in a different area of the state. Although the
Approach Attitudes Atmosphere
Actions:
Conveying a tone of partnership through
multi-directional communication; Fostering
family and professional engagement through
involvement in treatment across settings,
continuity of care across environments
Successful goal attainment:

Healthy social-emotional-behavioral
development; Positive outcomes for
individuals with ASD
FIGURE 24.3 The four A’s. This figure illustrates the way in which the relational prerequisites of
approach, attitudes, and atmosphere contribute to the actions of participating stakeholders
and ultimately the success of the individual with ASD. Source: Adapted from Conjoint Behavioral
Consultation: Promoting Family–School Connections and Interventions, 2, edited by S. M. Sheridan & T. R.
Kratochwill, 2007, New York: Springer Science and Business Media.
family was confident that the staff of the local medical center was effective in utilizing strat-
egies specifically tailored to the child, it concurred that going to a partner medical center
where staff was best able to accommodate the needed medical procedures was of highest
import. Ultimately, the family opted for the latter and the HANDS team, as the common-
ality across both medical teams, provided tools and explanation to support the consistent
implementation of the intervention successfully despite the new team, new procedure, and
new setting. In the end, the procedure was accomplished while accounting for the family’s
needs, generalizing the use of successful and individualized strategies for the child across
settings and providers, and all the while proceeding with minimal stress for staff, family,
and child.
COLLABORATION IN PRACTICE
Collaboration while working with individuals with ASD ideally involves families and care-
takers, mental health providers, primary care providers, medical subspecialty providers,
educators and other school personnel, community organizations, and advocacy groups. An
individual’s support team may also extend to include employers, residential or group home
staff, day program personnel, and other providers or community members. In addition, col-
laboration with legislators, media, and the public becomes relevant when we move beyond
treatment at the individual level to increasing advocacy, awareness, services, and support in
relationship to needs related to ASD across the lifespan.
A specific collaboration model is the medical home model. Within this model, specific
elements and relationships are detailed that are particularly relevant for psychiatrists and
trainees working with children with ASD. Collaboration must occur across all levels and
systems, with examples of established and trialed models and practices available to pro-
vide guidance in creating programs or developing individual collaborative relationships in
practice. Further explanation of the medical home model is detailed next, along with a brief
discussion of the other systems involved in the treatment and care of individuals with ASD
across their lifetime.
MEDICAL HOME MODEL
The medical home model may be viewed as a broad and overarching model of collabora-
tion. The concept of the medical home was first introduced by the AAP in 1967. In its initial
format, the care of children with special health care needs was the primary focus of the
medical home concept, although over time the concept has evolved to include all children
and adults. Currently, the medical home is a basis for any child’s medical and non-medical
care and is a cultivated partnership or collaboration between the patient, family, and pri-
mary provider in cooperation with specialists and support from the community. According
to the AAP (2002), medical home care must be “accessible, continuous, comprehensive,
family centered, compassionate, culturally effective, and coordinated with specialized ser-
vices” (p. 184). In 2007, the AAP joined with the American Academy of Family Physicians,
the American College of Physicians, and the American Osteopathic Association to form the
Joint Principles of the Patient Centered Medical Home. According to the Joint Principles, a
medical home consists of a personal physician, physician-directed medical practice, whole
person orientation, coordinated and integrated care, quality and safety, enhanced access to
care, and payment for services (Kastner & Walsh, 2012).
Care in a medical home model is associated with improved outcomes with regard to
health status, timeliness of care, family centeredness, and family functioning (Homer et al.,
2008). Due to the complexities associated with treatment of children with ASD, intuitively,
this population benefits from medical home care. Kogan and colleagues (2008) found that
medical home care improved health and decreased financial burdens on the family for chil-
dren with ASD. Golnik, Scal, Wey, and Gaillard (2012) found that ASD-specific medical
home intervention resulted in higher satisfaction and shared decision-making, as well as
fewer unmet needs, in comparison to controls.
Despite these findings, children with ASD are only half (25% compared to 42%) as
likely as children with other special health care needs to have medical care consistent with a
medical home model, regardless of condition severity, personal and family characteristics,
or insurance status (Brachlow, Ness, McPheeters, & Gurney, 2007). Families of children
with ASD are less likely to report that care received was family centered, comprehensive, or
coordinated. Families with children with ASD reported 3.39 times more difficulty getting
therapeutic services than other children with special health care needs (Montes, Halterman,
& Magyar, 2009). In addition, many families of children with ASD remain unfamiliar with
the concept of a medical home (Carbone, Behl, Azor, & Murphy, 2010).
Montes et al. (2009) found that parents of children with ASD reported significant
difficulty using school and community services (27.6%) and dissatisfaction with services
(19.8%). The barriers to obtaining services were reported to be mostly related to chal-
lenges in information transfer and communication between health care providers. In a
qualitative study by Carbone et al. (2010), parents reported often feeling the need to
take on the role of care coordinators themselves and feeling “isolation, anger, frustration,
and fatigue in independently identifying, accessing, and financing appropriate services”
(p. 320). Half of the families of children with ASD reported that a caregiver had to reduce
or stop work because of their child’s needs, and more than one-fourth of families spent
10 or more hours per week coordinating care. In the same study, pediatricians reported
feeling ill-equipped to meet the needs of families of children with ASD and identified lack
of time as a major barrier to the development of expertise and care coordination. Both
parents and pediatricians described a need for interdisciplinary models of care (Carbone
et al., 2010).
Children with ASD are not the only population for which medical home care is under-
provided and underutilized. Strickland, Jones, Ghandour, Kogan, and Newacheck (2011)
found significant disparities in receipt of care in medical homes by race, ethnicity, income,
as well as health status. Even within the group of children with ASD and other develop-
mental delays, children from immigrant families are more than twice as likely to lack the
usual source of care and report physicians not spending enough time with the family (Lin,
Yu, & Harwood, 2012). In addition, access to mental health care is universally under-
served. In attempts to move toward a medical home, mental health services have worked
on increasing accessibility using multiple methods, such as increasing or changing ser-
vice hours, establishing services within primary care settings, establishing elemental
health services, as well as developing innovative consultation services. A major difficulty
in implementing the medical home model, particularly in certain populations, is financial
viability.
As progress continues to be made toward a medical home model of care for all indi-
viduals, it is clear that system-level changes are needed to produce sustainable advance-
ment toward effective community systems of services for families of children in vulnerable
populations. Collaboration in advocacy by families, physicians, other health care providers,
educators, and community groups is and will continue to be an important piece in driving
these changes.
COLLABORATION ACROSS SYSTEMS
Parents and caregivers should be collaborative partners during all phases of planning,
implementation, and evaluation of approaches, services, and treatments. The relationship
between caregivers and medical professionals should be that of a partnership. In such col-
laboration, “a partner is a person that one works with in order to achieve a common goal
through shared decision-making and risk-taking” (Kalyva, 2013, p. 521). Given that parents
and health professionals have their own unique needs, concerns, priorities, and responsibil-
ities within their partnership, a supportive relationship is essential to their communication
of realistic goals (Kalyva, 2013).
A study by Kelly and Tincani (2013) found that a majority of behavioral profession-
als had little or no formal training in the area of collaboration and would have appreci-
ated models to follow. This study also found that current “collaboration” among practicing
behavior analysts and nonbehavioral professionals is mostly a unidirectional, didactic
process imposed from professional to the lay caregiver. However, many of the state-of-
the-art evidence-based practices or services recommended in the treatment of individuals
with ASD stress the importance of parental participation in the process. Comprehensive
practices evolving from applied behavior analysis, such as the Treatment and Education
of Autistic and Related Communication Handicapped Children (TEACCH) and the
HANDS in Autism model, emphasize the significance of collaboration with parents or
caregivers (Lovaas, 1987; Schopler, Mesibov, & Hearsey, 1995; Swiezy et al., 2006).
Additional emphasis regarding collaboration across multiple systems is a significant focus
and overarching premise of the HANDS in Autism model for which additional details are
provided next.
The HANDS in Autism model is integrative of a number of the aforementioned ele-
ments and is novel in its approach, with specific alignment to the following core beliefs:
1. Strength based: A focus on building strengths and successes of individuals with an

emphasis on proactive planning and teaching practical skills (Iovannone, Dunlap,
Huber, & Kincaid, 2003; National Research Council (NRC), 2001)
2. Collaborative: Delivery across community stakeholders for consistency, coordina-
tion, and positive collaboration for individuals with disabilities (Baker et al., 2005;
Swiezy et al., 2008)
3. Data-driven: A relationship to data-driven decision-making practices across all set-
tings to affect best outcomes through systematic planning and individualization of
efforts (Iovannone et al., 2003; NRC, 2001)
4. Scientifically based: A basis from current research in special education, psychol-
ogy, and related fields with relevance to ASD and other developmental disabilities
and a focus on the practical and effective blending of scientifically based strategies
(Horner, Carr, Strain, Todd, & Reed, 2002; NAC, 2009; Odom et al., 2003)
5. Interactive: An incorporation of implementation and systems training research
that indicate the need to appeal to varied learning styles (Fixsen, Naoom, Blase,
Friedman, & Wallace, 2005) and the need for more interactive strategies to ensure
usage in naturalistic settings ( Joyce & Showers, 2002)
6. Practical and accessible: Delivery through accessible materials, training, technology,

and consultative staff in efforts to decrease barriers, increase support, and improve
implementation and utilization of the strategies taught
7. Process-driven: An infusion with a fluid and integrated process for effectively edu-
cating all individuals by incorporating data-driven strategies, research-based meth-
ods, and collaboration and individualized needs to develop effective programming
(Iovannone et al., 2003; Kazdin, 2001; NRC, 2001)
The curriculum inherent within the HANDS in Autism model highlights core elements
noted for effective practices with focus on “individualized supports and services, system-
atic instruction, comprehensive and structured learning environments, specific curriculum
content, [and a] functional approach to problem behavior and family involvement” (Yell,
Drasgow, & Lowrey, 2005) (p. 136, Table 2) (Figure 24.4).
The literature details the evidence-based interventions and practices that are found to
be effective strategies and supports for the treatment of individuals with ASD. However,
for these practices to be effectively implemented with fidelity to increase the opportunities
for success, educators, families, and medical practitioners must understand not only the
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FIGURE 24.4 HANDS in Autism Model: The HOUSE curriculum. This figure illustrates the HANDS
in Autism Model, detailing the core components believed to be of greatest importance for the
treatment of individuals with ASD, including collaboration.
logistics of the standardized application but also that to be truly effective, interdisciplinary
collaboration must occur. Strategies and practices without collaborative efforts cannot be
as widely implemented across settings and lack consistency, thus hindering the opportunity
for successful generalization of skills and concepts and a shared understanding of goals.
However, when collaborative efforts are intentional and made with the aforementioned
components in mind, the success and goal attainment that can be achieved are significant.
SUMMARY
Collaborative efforts between medical professionals, parents and other caregivers of indi-
viduals with ASD, and community members are essential for the delivery of quality care
and programming across settings. In the previous sections, the meaning, purpose, and com-
ponents of collaboration, as well as models of collaboration that have been shown to be
effective, were discussed. Ultimately, a collaborative approach with shared decision-making
between professionals and consumers leads to improved outcomes, as well as increased
success for individuals with ASD and their families.
KEY POINTS
• ASD includes a wide range of individuals with some commonalities but many
differences.
• Individualization is a key aspect to successful treatment planning and management.
• Parents are the experts on their children.
• It is important to empower families with education/knowledge and integrated
supports.
• Communities must take shared responsibility for the successful outcomes of indi-
viduals with ASD and their families.
Dr. Naomi Swiezy, Dr. Tiffany Neal, Danielle Warner, and Dr. Kimberly Lo have nothing
to disclose.
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/ / / / / AUTISM SPECTRUM DISORDER
FROM A FAMILY PERSPECTIVE
NANCY LURIE MARKS, CATHY LURIE,

AND CLARENCE E. SCHUTT
INTRODUCTION
It is often said that when one meets one person with autism spectrum disorder (ASD), one
has simply met one person with ASD. This disarmingly simple statement, wrought with
meaning, conveys what is known not only from decades of clinical observation but also
from the revelations of the many studies underway to understand the genetics and systems
biology of ASD. Perhaps the same is true with families, and even within a family, where
each member sees ASD through the prism of one person, and each family presents a unique
challenge to the medical profession. Certainly the viewpoint of a parent raising a child is
far different from that of a sibling, and each family constellation poses different challenges.
Many families are torn apart as parents struggle with one income, diminished career
expectations, loss of intimacy, and social isolation (Smith et al., 2010). If asked for one
word to describe their lives, the answer is invariably “stressful” (Barker et al., 2011), often
followed by fears of “what happens when we are gone?” However, remarkably, while bravely
accepting their situation and often finding extreme ways to adapt—moving to another state
to find services, taking on part-time work to pay for early intervention, developing thera-
pies on their own, and giving up vacations—the majority of family members show great
resiliency and creativity in seeking ways to channel their talents and abilities to create better
lives for their own as well as others with ASD.
The family perspective presented here is based on experiences over many years during
which the authors have had the privilege of living with, meeting, and hearing from many
individuals with ASD, their families, and numerous dedicated professionals, clinicians, and
researchers. The purpose of this chapter is to offer medical practitioners new to the field
a way to appreciate how profoundly ASD impacts the rhythms and patterns of family life.
THE PHYSICIAN AND THE FAMILY
The great range of behaviors and medical issues associated with ASD presents a challenge
for the physician meeting with the family of a person with ASD for the first time. However,
465
as with every medical encounter, a physician, trained over many years in the practice of
close clinical examination, chooses what information to privilege, a subtle aspect of the
doctor’s art, and the choice of frames into which to formulate a treatment plan.
Parents arrive at an examination ready to give detailed reports on eating behavior; sei-
zures; gastrointestinal complaints; self-injurious and other-directed scratching, biting, and
pinching; as well as obsessions with all manner of systems and structures. Self-injurious
behavior is not uncommon: It includes hand biting, head banging, and face scratching
as well as other unusual and incomprehensible behaviors, such as spinning, hand flap-
ping, and bouncing. Parents are wondering what they might have done to bring this ASD
on—something in their diet during pregnancy, or a stressful event, obstetric complication,
or a family history of psychiatric illness—and they are hopeful that the physician has some
answers.
Each individual case may appear to fit the broad definition of ASD in terms of deficits in
social communication, and obsessive and repetitive behaviors, that the doctor has undoubt-
edly encountered in the medical literature or from the Diagnostic and Statistical Manual of
Mental Disorders, fifth edition (American Psychiatric Association, 2013). But parents enter-
tain a hope that their individual experiences might offer important clues leading to a more
physiological or neurological explanation for the obvious distress their child is feeling, and
often with no means, other than “aggressive behavior,” to communicate where it is coming
from. During the examination, the person with ASD may have little or no speech or may
be highly talkative; he or she might be hyperkinetic—biting a wrist, flapping hands, spin-
ning about, shrieking, and exhibiting various tics—or might just sit quietly staring off into
middle space.
Fortunately, physicians are now in a position to give a more informed response to fami-
lies in the examination room. This is because it is becoming accepted that ASD in most
cases is caused by some event during development that may have affected the nervous,
endocrine, or immune systems and their mutual interactions. As a result of these scientific
advances, it is becoming more common for teams of medical professionals to make the first
diagnosis of ASD and to set the agenda for integrated treatment and care.
Nevertheless, it is not a simple matter to connect the possibility that someone’s synaptic
machinery may be leaky, one explanation for ASD based on genetic findings, to the behav-
ior of the person in the office who is darting to the cupboard to liberate bandages, surgi-
cal gloves, and syringes from their sterile wrappings or to another person sitting calmly,
perhaps silently, observing with subtle sideways glances the events around him or her. For
the physician, fashionable ideas about ASD from the neurocognitive sciences, such as the
notion that these individuals lack “a theory of mind” or that they have strong local brain
connectivity but weak global or “central” coherence, seem to lose relevance and serve up
little in the way of wisdom that can be imparted to the anxious family member sitting oppo-
site, or even to help structure the information the family brings. It would behoove a physi-
cian treating this population to become acquainted with the full range of treatments and
remedies that a family might be considering, as well as to develop some sensitivity to the
idea that ASD is not only about the brain (Herbert & Weintraub, 2013).
There was a time when it was common for doctors to assume that poor parenting caused
ASD and to recommend that the parents see a psychiatrist. In that era, ASD, if viewed at all,
was seen by experts as a psychiatric disorder, and the child was viewed as being lost in his
or her own world, “choosing” isolation where, in reality, the child might be working hard
to free him- or herself from it. These views still persist, having migrated to other forms of
ostracism and insulting, sometimes abusive, treatment by those who have no comprehen-
sion of ASD, adding to the anxiety and stress on family members. Recently, more attention
Autism Spectrum Disorder From a Family Perspective // 467
is being paid to treating primary caregivers with “mindfulness” training and other forms
of relaxation therapy. It is reported in a study from Vanderbilt University that mothers of
individuals with neurodevelopmental disorders have significantly elevated levels of stress
and clinical depression (Dykens, Fisher, Taylor, & Miodrag, 2014).
PERSONAL NARRATIVES
A good way for physicians to educate themselves about the impact of ASD on families is to
read parent narratives (Greenfeld, 1970; Iversen, 2007; Parks, 1982), often written by pro-
fessional writers (Savarese, 2007) or academics (Grinker, 2007). Although each describes
unique and unforgettable scenes from everyday life, they share a nearly universal expression
of love, commitment, and fear for the future beyond their own lives, reflecting the reality
that ASD is a lifelong condition, not a lifespan-limiting disease. A theme running through
many of these stories is the questioning of the assumptions behind the facile classification
of persons with ASD as “low-functioning” and “high-functioning,” as if human beings are
appliances that break down in the workplace and are not covered by a warranty. A careful
reading of these books is probably the best introduction a young physician can have to the
full range of devastation and adaptation experienced by a family.
Parents of children with ASD, already stressed emotionally and financially, are also
beset by worries about the future of their child, a long adulthood and perhaps an old age
without the emotional anchorage provided by their parents during their middle age. A valu-
able lesson to be shared with young parents is that some things do get better, especially after
adolescence, as individuals with ASD develop an understanding of the world and achieve,
in some cases, greater calmness and self-sufficiency in personal care and choice-making in
daily life. Parents will be concerned about how to help their growing adults form friend-
ships; safely learn about their sexuality and potential desire for intimacy; and deal with
normative human experiences of loneliness, loss, and rejection.
It is important to realize that a person with ASD is not a closed book but, rather, capable
of growth and change in many dimensions like the rest of us. Many adults with ASD, and
not only those more recognizably labeled as “savants,” engage in the visual and musical arts,
poetry, and writing—sometimes producing work of commercial value, but always with a
sense of self-satisfaction and accomplishment. A few pioneers have gone on to college, with
some earning degrees and some with aims to be advocates for others with ASD. One may
see adults working today in supermarkets, warehouses, and local businesses; in libraries;
and even in the computer and technology sectors, where their spatial and systems recogni-
tion abilities may hold special value.
We know a little about the internal world(s) of persons labeled autistic from the writ-
ings of Donna Williams (1992, 1994, 1996), Temple Grandin (1995), Tito Mukhopadhyay
(2000), Naoki Higashida (2013), and others. Reading these four narratives should be
enough to convince anyone that the human brain, fed by the senses, moved by the emo-
tions, and experiencing muscular activity, can produce a staggering range of metaphors,
artistic creations, and insights, even though it may be connected to a somewhat uncoopera-
tive body. Yet, many somehow see fit to attribute internal states to the outward appearances
of behaviors and difficulties and to interpret severe problems in communication and social
behaviors, or apparent misunderstanding, as a lack of interest in, or a paucity of emotional
feeling for, others.
It is difficult to ignore the surface appearances and behavioral manifestations of ASD
to get to the feeling, thinking person beneath, but confusing these outward signs and
impairments with definitive conclusions about affection, motivation, and capacity is a mis-
take. Inevitably, the result is to dehumanize the person with ASD, adding a veil of isolation
to the person’s already isolating difficulties.
One attempt to redefine ASD (Markram & Markram, 2010), by neuroscientists who
are parents of an individual with ASD, posits that each person with ASD inhabits a unique,
but almost unbearably intense, world in which each sensation or memory contributes to
conscious thought with a weight, influence, or affinity outside what is considered normal.
This causes one to wonder why anyone should be valued simply by how they fit into our
everyday world of consumption, constant electronic bombardment, and frenetic movement
when the novel combinations formed in isolated human minds, given means of expression,
can give rise to delight, invention, and insight into what we all are or could be.
Increasingly, individuals with ASD are playing more active roles in planning their lives
and defining their interests. As they become confident in creating new avenues for them-
selves, they begin to engage more in their own communities. These efforts are leading to
an increase in activities for both young and old in sports (e.g., skiing, bowling, golf, and
swimming), theater-going (including relaxed performance opportunities), hobbies (crafts,
gardening, computers, yoga, and cooking), and interests in continuing education or partici-
pation in their religious or social communities.
A meaningful life need not be one of only working for a living, not always possible, or
of achieving professional success but, rather, of having projects and involvement that offer
opportunities for self-expression and participation in their communities.
THE CENTRAL IMPORTANCE OF COMMUNICATION
Opening any door to communication can change the life of the 30% of those with ASD
who lack speech or have only minimally verbal means of expression. Throughout the 1960s,
1970s, and 1980s, there was very little expectation placed on these persons, and little in the
way of hope—even the use of sign language was discouraged because it was thought to offer
an easy way out of learning to speak. Today, we are learning much from the experiences of
those who, either as children or as adults, have been taught new ways and methods to access
communication through technologies such as computers, voice output devices, structured
interfaces, and haptic anticipation. This may take years of hard work to accomplish, but it
is of immense importance to family members who hope (and often awake from sleep with
this dream fresh) to one day hear their silenced child or sibling express thoughts, feelings,
and personality. New interests, educational opportunities, and relationships with others
will evolve, opening up a world for that person and the lives of those around him or her.
Perhaps, with the means to express themselves for the first time, these individuals can
explain where they feel pain to a doctor or describe aspects of their ASD such as noise
sensitivities, or problems with certain clothing, or how their outward appearance may or
may not match what they feel is going on inside them. Indeed, some clinicians (Robinson,
2011) conduct examinations in situations in which augmentative communications are
encouraged and used as the patient types answers to questions posed by the doctor.
They may be treated for the first time in life as a “you” rather than spoken about in the
third person, or over their heads, in their presence, as if they are not there; all the while, they
may be listening and taking in the conversations, whether distortedly or clearly, even if their
appearance may be distracted and nontypical. Achieving communication does not mean
that the individual is no longer autistic by any means, but it does diminish the possibility
that it is not ASD alone that defines him or her as a person. This view is strengthened by the
growing literature produced by writers with ASD, once classified as “low-functioning” and
“retarded” (Biklen et al., 2005). Some professionals will acknowledge, if not publicly then
privately, that the old assessments of intelligence are, or at least may be, mistaken; that test-
ing methods are inadequate for those who poorly respond to tests or who cannot speak; and
that the capacities and potentials of those with ASD may be often quite underestimated.
It is to be hoped that every school, clinic, doctor, or family involved in the life of an indi-
vidual with ASD endeavor to solve this often central predicament for each and every child
or adult in their lifetimes, whether through augmentative and alternative communication
approaches or others. Technology holds the promise to deliver better means to enable com-
munication and meet the challenge of unlocking the doors to the inner person. Although
someday research will uncover the internal biological and systemic processes that interfere
with the ability to communicate, and offer interventions or solutions at the source, there
remain, in the meantime, lives that are being intensely lived, and the possibility of redirect-
ing real-life trajectories sooner rather than later. By not acting, lives are being circumscribed
and consigned to an isolation and loneliness few of us can imagine enduring, even if sur-
rounded by the most caring people.
SIBLING PERSPECTIVES
Although parent narratives, and increasingly self-reports from individuals with ASD, appear
regularly, the stories and experiences of siblings are less rarely seen. A notable exception
(Greenfeld, 2009), by the brother of Noah, whose story and his family’s adaptive reaction
were so movingly told by his father (Greenfeld, 1970) a generation ago, powerfully chron-
icles his and his brother’s transition to adulthood. Siblings who are close in age, such as
Jonah and Karl, bring a very different perspective on ASD than a parent or an older sibling.
Young children, unlike parents, enter a world with no a priori expectation that the new-
born or young child is anything but “normal.” They gradually come to realize that their
sibling acts significantly different from themselves and their peers. A young sibling grows
and experiences life with an autistic brother or sister, like any other family, first with all the
joy and pleasure of playful growth and shared learning and then with love and affection,
and the creation of private worlds. Gradually, awareness that something might be different,
but not “wrong,” with their sibling appears, and they find themselves adapting inexorably,
somewhat confusedly, and not always smoothly.
Young siblings today may be exposed earlier to what is happening as early diagnosis,
specialized interventions, and altered household routines, such as the machinery of applied
behavioral analysis, descend and family tensions increase (Orsmond & Seltzer, 2009).
Autism spectrum disorder was once a term rarely heard, unlike today when it is often in
the media and public mind, as well as firmly situated within a growing body, even enter-
prise, of professional approaches and research. At one point, children if asked about their
own siblings were told to say “he is autistic,” and often heard back, “Oh, he is artistic, how
nice!” This had to be disconcerting for a young person beginning to engage the social world
outside of the home. Later, ASD came to be called “retarded” or “emotionally disturbed.”
What was not appreciated in those times was that siblings may have lacked a framework to
understand what those odd words meant and were unable to grasp fully the derogatory or
sometimes sinister import of these labels, resulting in an uncomfortable, gnawing, realiza-
tion that something is not right with the little person growing next to them.
The sibling may bring no notion of disability, judgments, prejudices, deficits, or any
notions whatsoever of ASD or anything else; it is simply one’s own brother or sister—a
very real person both alike and different than oneself, endowed with all the intriguing,
delightful, messy, irritating, and curious facts of personhood, even if he or she may well
express him- or herself differently, as becomes more apparent over time. There can be
a window of acceptance and relatedness, which one later learns is not necessarily the
window the larger world has. Unencumbered by the responsibilities and worries of a
parent, the child may find natural ways to relate to his or her sibling. In many cases, it is
through activities enjoyed by both, whether through song, music, dancing, swimming,
or other novel ways and games. This childhood oasis of ignorance can, in a sense, be a
blessing. Strong childhood bonds are formed, even if they appear atypical compared to
bonds with other peers.
But the outside world intrudes and forces upon a sibling what may be the most trou-
bling aspect of all in growing up with ASD in the form of bullying, teasing, and taunting of
a sibling because of the unusual sounds they make, things they say, or their preoccupations,
generating an early stance of protectiveness. These episodes are not lost on the child with
ASD, and they fall back on their brother or sister for comfort and understanding, even if
it is not apparent. Adult siblings today report incidences of bullying or outright prejudice
and intolerance from adults, sometimes on hospital wards, but most often in supermarkets,
malls, and convenience stores. This is relatively new because ASD was once pretty invis-
ible and the spectrum very much more narrowly defined; there were no special education
mandates, and children with ASD were usually rarely seen or included in social gatherings,
religious institutions, community life, and in family celebrations of weddings or religious
holidays. Adults with ASD were a complete absence, perhaps hidden away or institutional-
ized, with visits from aged parents and siblings, portrayed with great impact in the movie
“Rain Man” ( Johnson & Levinson, 1988).
Despite all the positive changes that have occurred socially today, it would be helpful
for parents (and professionals counseling them) to find good explanations and language,
geared to a child’s age and maturation, to help a “typically” developing sibling not only
understand more about his or her brother or sister with ASD but also offer the sibling a
way to explain to his or her friends, who may be curious or fearful about the child with
ASD, what is going on. It is essential, however, to shape these explanations in terms
that give the child an opportunity to relate (and help others relate) to his or her sibling
rather than teaching the child to diminish the value of his or her sibling due to differ-
ences or difficulties. This can be a tall order in a society in which a person with ASD is
more generally seen as alien, an outsider or less than fully human, even though that too
is changing (Murray, 2008).
As one grows into adulthood, there can be a push–pull between the personal need
to move beyond the family—entering into a more independent existence, going off to
college, starting a career, or getting married—and the needs of the grownup sibling with
ASD, which require ongoing strong family focus and involvement. Some siblings have
spoken of feeling of guilt as they move on and out into life arenas their sibling did not
enter. These are complicated emotions, involving feelings of leaving the parents to deal
alone with issues at home but also the pain of separating from one so loved and so close.
Some siblings feel the necessity of appraising future life mates, in part, in terms of how
they relate to the sibling with ASD, knowing this relationship is both a valued part of life
and one that the future mate would share in. As parents grow old and die, siblings often
take on the role of supporting or navigating life planning for their maturing brother
or sister with ASD, often putting stress on their own resources, both emotional and
financial.
THE FAMILY AND THE SYSTEM
The physician treating a person with ASD will, of course, be well aware of the import of an
ASD diagnosis, including the insurance and reimbursement practices in the community
and state in which they practice. But what happens for the parents post diagnosis? What
else in their lives demands attention beyond what the medical profession can give?
Many feel they are stepping off of a cliff, with few clear supports in place to help navi-
gate the world with and for their child. First and foremost, they must figure out how to
care for their child, often at home and with few extra resources to help in this care. They
must learn about and engage in negotiations for appropriate therapies and interventions
and determine how to pay for them after insurance coverage ends. The search for an appro-
priate school placement can be daunting, at times involving battles with administrators and
teachers to secure a good educational setting. Extended family and social circles may or
may not provide a welcoming atmosphere for the family with a child with ASD. Holiday
celebrations and other family events (e.g., weddings, birthdays, and graduations) can be
especially stressful.
Preparing for young adulthood, a time when educational benefits and supports end,
requires extensive planning for employment training and exploring of options. Securing a
residential placement or working out how to live at home well into middle age is a major
concern. Arranging for ongoing supports and services for their family member often puts
them into confrontational and contentious situations with social service systems and case
workers who barely know the person with ASD. The tasks of financial planning and the
securing of government benefits in those situations in which the autistic adult may not be
self-supporting can be a full-time job unto itself. All the while parents must worry about
who will care about and advocate for their young adult when they grow old or pass away.
Siblings, if they exist, may or may not be able to provide continuity of support and emo-
tional care as the parents have done, and themselves must carry on with life planning needs
as they unfold, often with no professional or other network of support. Finally, all must
think about the aging adult and what kinds of living, medical, and social supports should
and will be in place when the immediate family may not be around.
FAMILIES RISING
These life challenges can be met with resiliency, compassion, and, often, an ethic and value
placed on caring, empathy, and open-mindedness to the differences, vulnerabilities, and
capacities of others with significant challenges, not just those with ASD. As in many aspects
of life, sometimes seemingly difficult or nontypical experiences thrust in one’s way prove
to be instructive in surprisingly positive ways. This “silver lining” in no way diminishes the
pain, uncertainty, and doubt experienced by the family, nor does it alleviate the sometimes
difficult emotional and practical problems with which the family members grapple and that
often cannot be shared with peers who have no such life experiences.
Parents, families, individuals with ASD, and the diverse networks they form can be a
great inspiration and often driving forces in pushing the envelope for what is possible in the
world of ASD, whether opening up new scientific directions, paving the way for new medi-
cal treatments and educational therapies, or in the social realm in terms of searching for new
life options. Families often do not give up on the potentials that may unfold in a person’s
life, nor take as final or determinative “expert” pronouncements as to future capacities and
growth in their own lives, and they often seek to drive progress in their communities or in
public advocacy. Of course, they do not necessarily see eye to eye on what form this prog-
ress should take because there is no one path applicable to all, and professionals should take
heed and even embrace the open-mindedness of the families in their quest for a better life.
A recent gripping account of human nature and variation situates ASD in the context of the
disability movement and presents a comprehensive picture of what families face and how
they are coping (Solomon, 2012).
SUMMARY
Over many years and many encounters, whether with families, those with ASD, or pro-
fessionals, the authors have encountered multiple views of ASD as a concept, with some
viewing it as a tragedy in need of cure and elimination; others perceiving ASD as a scien-
tific, medical, or societal challenge; many seeing ASD as containing talents to be discovered
and nurtured in the face of real and tough obstacles; some who value their ASD and have
no wish to exchange it (or only parts of it) for another place in the world; those who see
the “neurotypical world” as in need of change; and any number of variations in a wide arc
of vantage points. As our understanding of ASD unfolds, this arc will no doubt shift and
broaden with much to teach us all about our common human family.
KEY POINTS
• Parents often wonder what they might have done or how the environment might have
caused ASD in their child. They are hopeful that the physician has some answers. As a
result of recent scientific advances, it is becoming more common for teams of medical
professionals to make the first diagnosis of ASD and to set the agenda for integrated
treatment and care.
• A good way for physicians to educate themselves about the impact of ASD on families
is to read parent accounts and personal narratives by individuals with ASD. These
books are probably the best introduction a young physician can have to the full range
of devastation and adaptation experienced by a family.
• The most pressing, central, and frustrating aspect of ASD is the difficulty of communi-
cating. This has a profound effect on the family, especially for siblings, who construct a
social consciousness for themselves that might be without parallel among their peers.
• Parents need to determine appropriate therapies and interventions, supports and ser-
vices, and educational settings, as well as meet financial challenges related to residen-
tial planning for adulthood and prepare for a time when the immediate family may
not be around.
• Families confronting ASD show great resiliency in adapting to the realities they face
in providing a home environment, seeking schooling, employment, recreation, and
medical care while at the same time trying to look after their own emotional and
marital health. Many still manage to find time and energy to advocate for others and
share their experiences.
Dr. Nancy Lurie Marks, Cathy Lurie, and Dr. Clarence E. Schutt have nothing to disclose.
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/ 26
/ / / / / FROM THE PERSPECTIVE
OF A PERSON WITH AUTISM
SPECTRUM DISORDER
JOHN M. WILLIAMS
INTRODUCTION
Living with autism feels like there is a TV turned on in your head with the channel changer
broken, constantly cycling through all the channels, bombarding your head with stimuli.
Every sense is on fire at the same time. Thoughts swirl endlessly and every type of stim-
uli hits with the same intensity—sounds, sights, smells, and the feel of the fabric in your
clothes. The whole world feels out of control. You just feel like screaming!
GROWING UP AUTISTIC
To escape the chaos as a child, I withdrew into my own world. It was easier to spend
time alone with my own thoughts. It was like living in a bubble of my own creation. I was
self-absorbed, perseverating on subjects I was interested in such as dinosaurs, cartoons,
or movies that I watched over and over. I easily memorized the names of all the dino-
saurs by age 4 years and the script of entire movies by age 7 years. This gave me a pretty
impressive-sounding vocabulary, but it was all rote learning. I sounded smart but did not
really understand the context and certainly had no feel for conversation. I used the memo-
rized material as a way of starting a conversation with peers, trying to get them interested in
me since I had no idea how to have a “normal” conversation.
I enjoyed spending time outdoors, wandering around the yard and engaging in repeti-
tive behaviors such as stripping twigs off the bushes. I talked out loud to myself, often just
repeating the dialogue from favorite movies. I was unaware of others and what they might
think about this behavior. There were also a series of “tics” through the years, from picking
my face to flapping my arms and hands, the latter continuing through middle school. This
was all part of the self-absorbed, perseverative behavior pattern that has persisted through-
out my life. I guess it was a way of comforting me.
In social settings, I have always been extremely anxious and uncomfortable. Auditory
processing deficits make it hard to understand language and, as a result, I was resistant to
475
476 / / other C are D eli v ery S er v ices and Perspecti ves
learning in school. Transitions and changes in schedule were so hard to process that I might
throw tantrums or punch the wall with frustration. I needed a very steady, dependable
schedule with lots of structure in order to function.
I was not very aware of my peers and made little effort to engage them, although my
mother says my interactions at home with my brother were pretty normal when we were
small. It was not until age 4 years when I attended nursery school that my social deficits
became obvious. That is when I began attending special classes designed for kids like me.
The teachers were very good at providing a structured environment where I could learn to
focus. They used behavior modification techniques for rewarding achievement and appro-
priate behavior. My mom remembers how they employed techniques to help my brain func-
tion better and to desensitize my nerves. For example, every morning before class I spent
time on a swing or marched around swinging my arms. Holding a pencil was very uncom-
fortable, so my occupational therapist massaged my shoulder and elbow joints and then
rolled a heavily bristled brush down my arms, which calmed my nerves and allowed me to
hold a pencil with a large grip. Eventually, the grips were reduced in size until I didn’t need
them anymore.
The breakthrough in school came for me when I finally learned to read around age
8 years. After that I learned quickly and was eventually mainstreamed for math class with an
aide. I attended the Concord Area Special Collaborative (CASE) in Massachusetts, which
has separate classrooms in regular schools so kids like me can interact with neurotypical
kids and join in regular activities such as assemblies or recess. Through the years I was main-
streamed more, although the CASE classroom was always my home base.
Auditory learning is an ongoing challenge for me. When the teacher talks, I can’t pro-
cess the words and find the context or main idea. I need visual tools such as pictures, story-
boards, and assignments written on the blackboard. It is hard to hear the words and create
a picture of their meaning in my head. Visual learning works best. I look for books with
photos to help process the subject matter. Much of my historical knowledge is gained by
watching DVDs or documentaries. I can watch them repeatedly, processing the pictures
and gradually assimilating the dialogue.
In junior high, I began interacting more with my peers through my talent for memoriz-
ing. By memorizing movie dialogue, I could make them laugh. Since conversation was hard
for me, I became more of an entertainer. I still use this technique today when I can, espe-
cially in relating to younger kids. I feel more comfortable relating to younger people, prob-
ably because my development was delayed. Emotionally, I feel I am in early adolescence
even though I am now over 30 years old.
Eventually I left the CASE program and went to a regular high school with an aide for
support. High school was scary! The kids were tall and loud. There was graffiti in the bath-
rooms. All the sensations bothered me—noise, hustle bustle, body odors. To help me cope,
my aide arranged modifications such as letting me pass classes early and have extra time for
tests. If I melted down in class, I could escape to the resource center where it was quiet, like
an oasis. As I became more comfortable in later years, I stayed in class more and needed my
aide less. My favorite class was drama. This may seem surprising but my memorization skills
really gave me an edge. The teacher was reassuring and the other students were nice to me
and appreciated my skills.
For the last 2 years of high school, I was invited to join the swim team. It was a small
group so I felt more at ease. This was the most interaction I can recall having with peers. I felt
“part of it” for the first time. Swimming is an individual sport and everyone just tried to do
their best. The environment was more congenial than competitive. I was elected co-captain
in my senior year and received a trophy and two varsity letters. I always felt I lagged behind
From the Perspective of a Person With Autism Spectrum Disorder // 477
my brother in sports, but later I realized that I had two varsity letters and he had none. For
once I was not second-string. I’m not a boastful person, but this still made me feel proud.
In high school, I was becoming aware of sexuality but it was confusing. I did not know
how to talk to girls and never had physical contact with anyone. I maintained a safety blan-
ket by developing a routine, working at the resource center during school hours and then
coming directly home. That kept me out of trouble. Luckily, I was never bullied in school,
but I was glad to get out of there all the same.
After graduation at age 19 years, I was lucky enough to be accepted into college. First
I attended a community college where there was a resource room and extra help similar
to high school. I took my tests in the resource center and had extra time to finish. I could
talk to a counselor when I felt out of control. My class load was reduced to three courses
per semester. After graduation I moved on to the state university and eventually earned a
bachelor’s in fine arts. It took 7 years in total but I made it! Graduation day was one of the
happiest of my life.
FAMILY RELATIONSHIPS
The person who has guided and supported me most is my mom. She was always there when
I needed help with homework, not to mention love and support. Although my parents were
divorced when I was 4 years old, they both stayed connected to me. Dad taught me to ride a
bike and encouraged me to learn to drive. Along the way, Dad explained that he had symp-
toms similar to mine, as did his father even though they were not diagnosed with autism.
His sister has bipolar disorder. I know autism has a familial connection, so this helps to
explain my disability. It was good to know where it came from and that I was not the first
“oddball” in the family.
My brother, James, is 2 years younger. He is not autistic, although he admitted to me that
he feels anxious at times. When we were very young, we played together, but as we grew older
our relationship became more problematic. Looking back, I would not expect him to under-
stand, but I wanted to be left alone and he talked too much and teased me. I wish someone
had sat us down and explained things to him from my perspective, how challenging interac-
tions can be. Maybe we could have been better friends. Now that we’re both grown, we have
a friendlier relationship, although James still finds it hard to interact easily with me. I know he
is proud of me, and I am counting on him to help me in the future when my parents are gone.
FEELINGS
Anxiety is the biggest issue for me. I have many fears and they can often be overwhelm-
ing. The scariest things are those beyond my control. For example, I worry on a daily basis
about bad weather and climate change. I become very upset when severe weather is fore-
cast, especially tornadoes or hurricanes. The constant news about climate change drives me
crazy. I avoid hearing the nightly news because so much of it is negative and frightening. My
concerns about the future seem much more pronounced than other people’s. Maybe it’s
that difficulty with screening out the extraneous stimuli. My mother tells me to focus on the
things I can control in the next few weeks or months, but the old fears keep looming up. My
anxiety was seriously heightened after 9/11, and I have felt much more insecure since then.
I have focused a lot of attention on learning about other parts of the world, especially the
Middle East, in an effort to understand their cultures and worldviews, hoping to find some
thread of commonality that may lead to peace in the future.
Although other people tell me they feel anxious at times, my feelings are overwhelm-
ing. My pulse races, my nerves are jittery, and the veins feel like they are jumping out of
my head. The scariest feeling is that I may lose control and spin away. Even though I take
medicine (a selective serotonin reuptake inhibitor (SSRI) that helps with anxiety, I still
feel anxious at some time almost every day. This really affects my ability to function and
interact with others. When anxiety or frustration gets the best of me, I have meltdowns
where I scream and hit the wall with my fist. As a child, I needed to be restrained physically
at times to help me calm down. As I got older, the need was to vent verbally for extended
periods to anyone who would listen. Through this process, I eventually calm down and
start to feel better.
One thing that leads to a feeling of extreme frustration is an unexpected change to the
schedule. I need to know what will happen, when, and with whom. If a change is required,
I need lots of time to process it. My mom tries to prepare me when changes are coming,
which helps a lot. I know change is inevitable, but it is still very unsettling. This goes along
with my perfectionist tendencies—wanting things to be done a certain way. I am neat and
orderly, often imposing my needs on others—by organizing my brother’s bedroom, for
example, and throwing away things that seem extraneous. This has led to lots of conflicts in
the household, but I take pride in keeping myself and my belongings well-organized.
Another feeling I experience is loneliness. I stay to myself as a means of self-protection,
causing people to think of me of as a loner but this is not totally true. My auditory process-
ing challenges inhibit my conversational ability. With the help of language therapy, I am
gradually learning conversational skills. My therapist is helping me to understand how
conversations flow and how to appropriately engage with other people. I need help know-
ing what to say once the conversation gets going. It does not come naturally for me to focus
on the other person’s interest, to ask questions to draw him or her out, to stay focused on
the other person’s side of the conversation. As a result, I tend to use one-sided monologues
rather than engaging in dialogue. Sometimes I start my thoughts in the middle and circle
around to the point I want to make so people tend to get lost and stop listening. This really
inhibits my ability to interact successfully, even with my own family members. Learning
better conversational skills is a major goal that will significantly improve my life.
ADULTHOOD
How do I feel now that I am an autistic adult? I remember hoping when I was younger that
somehow I would grow out of autism when I grew up—that I could be normal like everyone
else in my family. Unfortunately, that did not happen, and life still feels scary much of the
time, especially in new situations. Even changes at home can be upsetting—for example,
when the schedule is changed or when the house is being renovated. I feel really stressed
out when forced into a social situation I did not expect or where I do not feel comfortable.
A good example is the Asperger’s Artist Collaborative meetings that my mom facilitates
every month. The other members seem to be able to participate in the meeting discussion,
but I feel lost, not able to follow the discussion. I just want to escape and often refuse to
attend.
From a behavioral perspective, I am more self-aware today but I still fall back on old
mannerisms at times, such as talking out loud even outside the house, pacing the floor at
night, and trying to lead conversations by sharing information rather than really engaging
with the other person. I still find comfort in staying in my own space, watching movies and
producing my art. This gives me some control over my environment. For physical comfort,
I often tie a sweatshirt around my waist or hold a blanket on my lap at home. I yearn for the
blissful days of childhood when I was oblivious to the world around me.
My dreams for the future are to continue producing art and to find a safe, comfortable
place to live with a dog to keep me company. I can drive and take care of my basic needs, but
it is scary to think about the time when my parents are gone. I will need help with finances,
for example. Although I would like to have female companionship, I am fearful of having
children. I can barely take care of myself, let alone others. Hopefully my brother will have
kids because I would be a terrific uncle.
CLINICAL EXPERIENCE AND MEDICATIONS
From age 4 years when my disability was first noted by my nursery school teachers until age
11 years when I received a formal diagnosis of Asperger’s disorder, the doctors didn’t seem
to know exactly how to describe my condition (Asperger’s disorder no longer exists as a
specific diagnosis. All forms of autism are now called Autism Spectrum Disorder—ASD)
(American Psychiatric Association, 2013). Although I had autistic tendencies such as
perseverative behavior, I was verbal and bright. Tests for fragile X syndrome were nega-
tive. I often had staring spells, as if I were in a trance. As a result, I was tested at Children’s
Hospital in Boston for seizures, but the tests were negative. It was unclear whether this
behavior was willful or organic in origin, but it stopped after a few years. I would guess it
was a means of retreating from the stimuli bombarding me.
I took methylphenidate (a Ritalin-type medication) for most of my childhood during
the school week. It seemed to help me focus, but my mom thought it made me more isolated
socially. When I stopped taking it as a freshman in high school, I felt more sociable. I tried
paroxetine (an SSRI) for a month or so, but I could not sleep and had suicidal thoughts, so
the doctor switched me to buspirone for anxiety. It seemed to help some, so I stayed on it
through high school and college. When I let it lapse, I did not feel much different, so I tried
going without medication for a few years.
When I was 30 years old, I wanted to try something new for anxiety to help slow down
my racing thoughts. My new psychiatrist recommended sertraline, which I am now taking.
It took a while to get to the right dosage, and even then it took a while to feel the effect. It
does seem to be calming me down, and I am doing better with social interactions, eye con-
tact, and conversation. My old anxiety is still there in the background, and it flares up from
time to time, but overall I am feeling less intense, a little happier with less mood swings, and
more focused.
Through my childhood, I visited a psychologist periodically. He has known me since
age 4 years and was the consulting psychologist in my school program so he has watched
me grow up. I enjoyed going to see him as he was always calm and a good listener. He
encouraged me to talk about how I was feeling and gave me ideas on ways to manage my
anxiety. I did not see him continuously but episodically when my anxiety became over-
whelming or when a tough subject such as sexuality was on my mind. It is a comfort know-
ing he is available when I need his support, and we already have an established connection
so it’s not like starting over every time.
I need doctors who are calm, quiet, soft-spoken, and understanding. It is very
nerve-wracking to go to the doctor, making it hard to interact and stay calm. At the begin-
ning of the appointment, the doctor should speak slowly in a soft voice, engaging me in gen-
eral conversation to help settle my nerves before proceeding with medical questions. I can
be slow to respond, so the doctor needs to be patient to allow me to express my thoughts
my way. I find it hard to take criticism from the doctor, especially about my weight gain,
which has increased due to medications. This criticism makes me feel defensive and I don’t
process it well. It is certainly not motivating.
Before any procedures begin, the doctor should explain what will be done—for exam-
ple, taking my blood pressure or drawing blood—and what it will feel like if it is invasive
or new to me. I am not afraid of having shots or blood tests. I can be defensive about being
touched unexpectedly, but its fine when I know what to expect. Recently I underwent a
lengthy (1 hour) MRI and PET scan. Since the staff had taken me through a dry run and
explained all of the steps involved, including an IV of radioactive material, the scanner
noises, the time required for each step, and a communication process, I was able to control
my nerves and get through it in one session. I was pretty nervous but felt well prepared and
the staff consisted of young people approximately my age who showed a lot of interest in me
and were very supportive through the whole procedure. I felt really proud when it was over.
Sometimes my mother is present during medical appointments to make sure all the
necessary information is provided and to help me process the instructions, but I am not
afraid to go alone, especially for routine appointments with doctors I know. However, if
there is something complicated or negative coming out of the examination, I would prefer
to have this information provided first to my mother, who will share it with me in a way
I can process.
One of the best things for medical people to talk to me about is my art. I really enjoy
hearing their feedback on my work, and I like to chat about my new projects. This interest
provides a great basis for a positive conversation and puts me at ease.
THE ROLE OF ART IN MY LIFE
Artistic creation has played an integral role in my life and development. I began modeling
with clay when I was 4 years old, and my talent began to blossom. I could lose myself in
my creative activity. It was harmonious compared to the chaotic world around me. My first
creations were copied from TV shows, such as Godzilla, or from books, such as dinosaurs.
The combination of visual images and my imagination played out in my head, leading me to
add my own twists, creating entirely unique characters. Like a writer who gets an idea and
just can’t stop until he gets it down on paper, I felt compelled to create my clay models. I did
what came naturally without thinking about other’s opinions of my work, and I still do this.
All through school, I continued clay modeling and excelling in art classes. In college,
I focused mostly on sculpting, but at the end of my senior year I began experimenting with
producing collage portraits and landscapes using small pieces of paper cut from magazines.
This has become my specialty.
In high school, a friend gave me a book about the Civil War and it became my passion.
I began reading everything about it, looking at pictures, photos, maps, movies, and docu-
mentaries about that period in our history. Over time, I became very knowledgeable about
the Civil War and other eras of history. This is a consuming interest for me, and my strong
memorization skills help me retain all the details. Once I landed on the collage process,
I focused on creating historical art pieces such as the Civil War generals, US presidents, and
the War in the Pacific in World War II. The combination of my passion for history, my art
skills, and a vivid imagination is a winning formula.
Art is more than self-expression for me. It is a way of exploring and understanding
the world. I study my subjects in great detail before beginning a collage to find out what
kind of personality and character they had. For example, how did a Civil War general treat
his troops? Was he well-liked? Was he grumpy? What effect did his actions have on the
course of events? This all effects how I present the person’s face in a portrait. I often include
background elements to tell the person’s story. I consider this an important aspect of my
work—telling a story visually, sharing my knowledge with others.
My concern about the Middle East led me to reading a biography about the Shah of
Iran. I learned that much of what we see in Iran today was an outgrowth of his reign. To help
people understand this, I made a collage of the Shah with a tapestry background showing
the influences on him and his era. He was a pivotal person of his time. I learned he was an
insecure man, so I tried to reflect that in his face. He put on a good front by wearing fancy
uniforms, but deep inside he was indecisive and weak. I can relate to him because I often
have to put up a front, pretending to be braver or more social than I feel. Maybe that’s why
I spent more time on this portrait than any other so far.
Fairness is important to me. In my artwork, I try to represent my subjects in a fair and
balanced way. Sometimes I choose to depict people who were not popular, such as the Shah
or Richard Nixon, because I am curious about what made them tick. They are complex
characters, not easy to understand. In representing them, I try to be fair, not lionizing or
demonizing them but showing both their good and bad features. I try to pierce through the
subject, to capture the essence or soul of the real person, leaving the viewer to draw his or
her own judgment.
As most people know, autistics have great difficulty making eye contact. We do not
learn this naturally as most people do. Looking directly at someone is really challenging,
although I don’t know why. I am learning to do better, but it takes conscious effort and
practice. It is ironic that in my portraits eyes play a central role, usually looking directly at
the viewer. Everyone who sees my work comments on the eyes. It seems that through my
art I have learned to compensate for this aspect of my disability.
I often describe my artistic process as an analogy for living with autism: trying to make
sense of the world by sorting out the chaos. In my collages, I place hundreds of small pieces
of paper together to create a unified image. The end product, while recognizable, presents
an entirely new perspective on the subject. When I am working, I do not envision the end
product. The piece designs itself through a discovery process as the paper is applied. It is
like breathing life into the subject. I don’t know how it happens. It just comes naturally
to me, imparting a new vitality to my subjects. Perhaps the one good thing about having
autism is that I have a unique way of seeing the world and passing on my vision through art.
MY LEGACY
I would like my life to have meaning and to leave a legacy. I would like to impart my knowl-
edge to others through teaching in some way. Through my artwork, I tell the stories of my
subjects, illuminating their lives. I hope the story of my life will be meaningful to others and
inspire them to use their gifts to create meaningful lives of their own.
SUMMARY
In this chapter, I have done my best to describe what it is like to have autism from my
personal perspective. As a child, the world was a confusing place. I was self-absorbed and
generally unaware of others. Over time, I found myself begin bombarded by sensory stim-
uli and felt almost hyper-aware of things. I became extremely anxious in social settings.
Predictability and structure allow me to function better. Yet the world is a very free-flowing,
spontaneous place filled with transitions and constant change. I am doing my best to adapt,
but it remains a day-to-day challenge.
My interest in the Civil War and leaders of different nations, in the context of my art-
work, serves as a consistent safe base for me. Because of the confidence I have in my knowl-
edge of these topics, they serve as a platform from which I can interact with others. I have
been fortunate to be able to develop my knowledge of these topics into a passion and voca-
tion. Transforming what I know about Civil War generals into visual images that reflect
their personality and characteristics, for example, brings me great joy; I hope the same is
true for those who view my work.
It is somewhat unusual for a person with autism to accomplish many of the things
I have in my life. Most do not graduate from high school, let alone college. Not many
are awarded letters in a varsity sport. Very few are able to drive. Despite these accom-
plishments, of which I am proud, I am lonely. I worry about my future. Society needs
to make significant strides in the way it views adults with autism. We need the same
opportunities that are available to typical people. I am hopeful things will improve dur-
ing my lifetime.
I have tried to provide some tips for medical providers caring for individuals with autism
in this chapter. It has been helpful to me for the doctor to be calm, soft spoken, understand-
ing, and a good listener. Sometimes, especially when I am anxious, it takes me some time to
respond to a question. I have appreciated the times when the doctor doesn’t rush me or try
to speak for me in order to hurry through the appointment. If any medical procedures or
tests are to be scheduled, it is useful if the doctor and staff can create a visual image of what
this will look like rather than simply providing a verbal explanation. Finally, it is terrific if
the doctor remembers me as John Williams, not just a young man with autism. Having the
doctor ask me about my recent art projects and showing interest in me as a person, not just
a patient, is quite important to me.
KEY POINTS
• Anxiety rules my life. Constant worries and fears plague me, sometimes leading to
dysfunction. Managing these feelings is the biggest challenge I face.
• My most severe observable deficit is in social skills—comprehending conversation,
figuring out how to respond appropriately, staying on topic, and making eye contact.
Improving conversational skills is a major goal.
• Adulthood is very challenging for me. Gone is the carefree childhood freedom to
withdraw and live in my own world. The fears loom larger now as my view expands
and the world seems so out of control. It is scary!
• Medications have so far been moderately helpful in reducing anxiety—not the silver
bullet I was hoping for. Behavior modification has been most helpful in managing
anxiety and improving social skills.
• Through my artistic process, I try to explore and understand the world—dissecting
my subject and reassembling the pieces to create a new perspective. The one good
thing about autism is my unique way of seeing the world and passing on my vision
through art.
ENDNOTE
John Williams’ artwork can be viewed at the John M. Williams Fine Art website at http://
johnmwilliamsfineart.com.
John M. Williams has nothing to disclose.
REFERENCE
INDEX
17P deletion syndrome, 119t, 120, 122f, 127–128 clinical implications, 281

22q11 deletion syndrome, 119t, 120, 122f, other agents, 280
129–130, 133 Alert Program, 363–364
47,XYY syndrome, 119t, 120, 128–129 Alloimmunity, 228–233
circumstantial evidence, 230–231
Academics, 391 direct evidence, 228–229
Actigraphy, 105 indirect evidence, 229–230, 230t
Activities of daily living (ADLs) Alternative and augmentative communication
adults, 435 (AAC), 69, 263–264, 321
occupational therapy, 339, 347–348 evaluation, 323, 325–328, 326f, 327f
Adaptive behavior and skills treatment, 333–335
adult, 35 Alternative treatments. See Complementary and
children and adolescents, 23 alternative treatments
Adrenocorticotropic hormone (ACTH), 239 Amygdala, 20–21
Adults, 429–441 Anatomical MRI (aMRI), 149–151, 150f
case study, 439–441 Angelman syndrome, 79t, 119t
development, 31–42 (See also Development, adult) Antipsychotics
education, 434 adverse effects, 279–280
etiology, 429 for irritability and aggression, 278–279
family member stress, 432–434 Antipsychotics, atypical
genetics, 429–430 for hyperactivity, impulsivity, and inattention, 282
hetereogeneity, 429 for repetitive behaviors, 283
incidence, 429 Anxiety. See also specific disorders
interfering behaviors, 438 comorbid, 88–90, 89b
lack of services, 430 differential diagnosis, adult, 57–58
living arrangements and ADLs, 434–435, 435t differential diagnosis, childhood, 52–53
outcomes, 430–432, 431t personal narrative, 477–478
personal narratives, 475–482 Anxiety medications, 284
social and communication skills, 438–439 Applied behavior analysis (ABA), 253, 256–270,
vocation and employment, 435–438, 436t 330, 397
Advocacy, family, 404 anxiety and rigidity, 268
Aggression biobehavioral problems, 268–269
adults, 23 early intensive intervention, 257–260
children and adolescents, 22–23 lifespan, 258t
clinical implications, 281 resources, 261t–262t
etiology, 277 skills-focused techniques, 263–268
prevalence and consequences, 276–277 (See also Skills-focused techniques)
Aggression medication, 276–280 strategies, 256–257
antipsychotics, 278–280 Apraxia, 109
485
486 / / I ndex
Arbaclofen, 292 applied behavior analysis intervention,

Art, 478, 480–481 256–270, 330, 397 (See also Applied behavior
A’s, four, 456, 456f analysis (ABA))
Asperger, Hans, 9, 10f, 140 case study, 253, 259–260, 264–267, 269–270
ASPIRE program, 378–381 medication with, 270
case study, 378–379 other comprehensive models, 260, 263
effectiveness, 382 providers and settings, 254–256, 255t
fundamentals, 378, 381–382 referral, 270–271
self-awareness, 380 Biobehavioral problem interventions, 268–269
social competence, 379–380 feeding, 269
stress management, 380–381 sleep, 268–269
Assessment toilet training, 269
case, 183–185, 184f Biomedical treatments, alternative. See
communication, 323–328 Complementary and alternative treatments
complementary and alternative treatments, 304, Bipolar disorder, comorbid, 92
305, 306b–307b Birth cohorts, 192–193, 193f
functional behavioral, 266 Blood oxygen level-dependent (BOLD)
occupational therapy, 353–355, 355t contrast, 151
psychopharmacology, 289, 290t–291t Board Certified Assistant Behavior Analyst
social skills, 372 (BCaBA), 254, 255t
theory of mind, 372 Board Certified Behavior Analyst (BCBA), 254,
treatment, 289, 290t–291t 255t, 438
Astroglia, activated, 214–215 Bullying, 94, 400
Atomoxetine, 281–282 Bumetanide, 292
Attachment disorders, 51–52
Attention deficit hyperactivity disorder (ADHD) Case definition, 181–183
comorbid, 87–88 Case evaluation, 185–186
differential diagnosis, 50 Case identification/assessment, 183–185, 184f
Attention deficit hyperactivity disorder (ADHD) Catatonia, 92
medications, 281–282 Celecoxib, 240
atypical antipsychotics, 282 Cerebellum, 211
clinical implications, 282 Cerebral cortex, 209–211
methylphenidate and atomoxetine, 281–282 Cerebral folate deficiency, 310
Atypical antipsychotics Child-centered treatment, 329
for hyperactivity, impulsivity, and inattention, 282 Chromosomal diseases, 105, 118t–119t, 120
for repetitive behaviors, 283 Chromosomal microarray (CMA), 77
Autoimmunity, 233, 234t Classification. See Diagnosis and classification, ASD
Avoidant personality disorder, 59–60 Clinical experience, personal narrative, 479–480
Ayres Sensory Integration (ASI), 356–359, 357t, Clinician-directed treatment, 330
358f, 365 Clonidine, 282
Cognitive-behavioral therapy (CBT), 374–375
Balanced chromosomal rearrangements (BCRs), Cognitive functioning
166, 169–170 adult, 34–35
Behavioral functioning children and adolescents, 21–22, 22t
abnormal, 93–95 medical history, 69
adults, 431, 438 Collaboration, 447–461
children and adolescents, 22–23 across systems, 459–461, 460f
development history, 70 definition and importance, 447–448
Behavioral regulation theories, 23 elements, 449
Behavioral treatment, 253–271 empowerment, 452
applied behavior analysis, 253 family and partnership centeredness, 455–457, 456f
Index // 487
individually oriented treatment, 453–455, 454f potential, 301, 302b–303b

integrating care, 452–453 prescribed medications, off-label, 313
medical home model, 457–459 research, 305
necessity, 448–449 use, 301–303
practice, 457 vitamin and mineral supplementation, 311
shared decision-making, 449 vitamin D, 304
support, 450–452, 451f Complement protein irregularities, 234
Communication Comprehensive treatment models (CTMs),
adults, 438–439 396–397
community, 447–461 Conduct disorder, 51
family, 447–461, 468–469 (See also Collaboration) Copy number variations (CNVs), 105, 120, 162,
interventions, 263–264 166–169, 168f
medical history, 68–69 Cortical minicolumns, 210
Communication assessment, 323–328 Cortical neuron density, 210
alternative and augmentative communication Cortical patches, 210
evaluation, 323, 325–328, 327f, 328f Cortical spine density, 211
challenges, 323 Cortical tubers, 209–210
components, 324 Corticosteroids, 236–239, 238f
fundamentals, 323 Cross-sectional variability, 191–192, 191f
speech and language evaluation, 324–325 Customized employment, 415
Community rehabilitation providers (CRPs), 419 Cytokines, 234–235
Community skills interventions, 265 Cytomegalovirus, 217, 227
Comorbidities, psychiatric, 85–95. See also
Psychiatric comorbidities Daily living skills interventions, 265. See also
Competitive integrated employment models, Activities of daily living (ADLs); Instrumental
415–416 activities of daily living (IADLs)
Complementary and alternative treatments, Day programs, 414–415
301–314 Depression. See Major depressive disorder
assessments, 304, 305, 306b–307b Development, adult, 31–42
case study, 314 adaptive behavior, 35
definition and scope, 301 case studies, 38–39
diet, 311 cognitive and language functioning, 34–35
endophenotypes, 304–305 mental health, 35–36
environmental contributors, 304 outcome improvement, 40–41
epigenetics and gene expression, 304, 304b outcome prediction, 37–38
folinic acid, 310 recovery, possibility, 41–42
genetics, 303 social integration and independence, 31–34, 33f
hyperbaric oxygen treatment, 308–309 symptom severity, over time, 36–37
immune/inflammatory biomarkers, 307b Developmental circuit pruning defects, 216
immune therapies, 312–313 Development, child and adolescent, 19–27
integrative medicine, 303 adaptive skills, 23
melatonin, 305–307, 308t behavioral functioning, 22–23
methylcobalamine, 309 case studies, 24–26
microbiome, 311–312 cognitive functioning, 21–22, 22t
mind and body practices, 313 early detection, 19–20
mitochondrial function biomarkers, 306b outcome improvement, 26–27
N-acetylcysteine, 280, 309 outcome prediction, 23–24
omega-3 fatty acids, 310 social functioning, 20–21, 22t
oxidative stress biomarkers, 306b theories, 21–22, 22t
oxytocin, 312 Development, history, 67–70
pancreatic digestive enzymes, 312 cognition, 69
488 / / I ndex
communication, 68–69 fundamentals, 47–48, 48b

emotional/behavioral development, 70 global developmental delay, 49
motor, 69–70 intellectual disability, 49
play/leisure, 69 major depressive disorder, 53
progression, 67–68 neurodevelopmental disorders, 48–49
sensory processing, 70 obsessive–compulsive disorder, 54
Diagnosis and classification, ASD, 3–13, 182–183. oppositional defiant disorder, 50–51
See also Differential diagnosis psychosis, 54–55
Asperger, 9, 10f selective mutism, 55–56
dimensional approaches, 10–11 social anxiety disorder, 52–53
DSM-I to DSM-5 changes, 7b specific language impairment, 48–49
DSM-III and DSM-III-R, 6–9, 7b, 182 Tourette’s disorder, 55
DSM-5, 7b, 11–13, 182–183 Diffusion MRI, 150f, 151
historical background, 3–5 DiGeorge syndrome, 119t, 120, 122f, 129–130, 133
ICD-10 and DSM-IV, 7b, 8–10, 182 Discrete trial training (DTT), 257, 330
Kanner, 5, 6f Divalproex sodium, 283
Pervasive Developmental Disorder Not Otherwise Dominant de novo coding variations, 166
Specified, 9–10, 182 Drug treatment studies, 236–242
Rimland, 5, 10 DSM-III, 6–8, 7b, 182
Rutter, 5–6 DSM-III-R, 7b, 8–9
Diagnosis and classification, children and DSM-IV, 7b, 8–10, 182
adolescents DSM-IV-TR, 7b, 182
<12 months, 19 DSM-5, 7b, 11–13, 182–183
age 2, 19–20 Dyspraxia, 109, 110, 365
developmental theories, 20–23, 21t
overview, 19 Early intensive behavioral intervention (EIBI),
symptom severity range, 20 257–260
Diagnostic substitution, 190–191 Early intervention programs, 395
Diets Eating behavior, 93
nutritional, 311 Ecology, educational program, 394–395
sensory, 359–361, 360f, 361f, 362t Educational eligibility criteria, 388
Differential diagnosis, adult, 56–63 Educational history, 73
anxiety and mood disorders, 57–58 Educational issues, 387–406
avoidant personality disorder, 59–60 adults, 434
fundamentals, 56, 57b applied behavioral analysis, 397
major depressive disorder with melancholic case study, 406
features, 58 comprehensive treatment models, 396–397
obsessive–compulsive disorder, 58 continuum of services, 389–390
obsessive–compulsive personality disorder, 59 diagnostic criteria, 388
personality disorders, 59–62 eligibility criteria, 388
psychotic disorders, 62–63 evidence-based practice, 396–401, 398t, 402t–403t
schizoid personality disorder, 61–62 families, 395, 401–404 (See also Families, in
schizophrenia with predominant negative education)
symptoms, 62–63 focused intervention, 397–398
schizotypal personality disorder, 60–61 fundamentals, 387
social anxiety disorder, 57 goals to evidence-based practices, 400–401,
Differential diagnosis, childhood, 47–56 402t–403t
attachment disorders, 51–52 historical background, 387
attention deficit hyperactivity disorder, 50 Individuals With Disabilities Education Act
conduct disorder, 51 (IDEA), 388–391
early signs, 47 intensity, 396
Index // 489
learning needs, 390–393 (See also Learning needs) case study, 100

positive behavior intervention and support, consequences, 102
398–400, 399f definition, 100
programs, early intervention, 395 demographics, 100–101
programs, ecology, 394–395 electrical status epilepticus of sleep, 102
programs, quality features, 393–396, 394f evaluation, 102–103, 102–104, 103f
school problems, occupational therapy, infantile spasms, 101–102
350–351, 351t interictal epileptiform discharges, 100, 101
teaming, 393–394 isolated epileptiform discharges, 102
technology, 404–405 seizure-associated neuropathology, 213
Elderly, 139–144 sleep seizure discharges, 214
case study, 143–144 treatment, 104
current perspectives, 142–143 Epileptiform discharges, 217
diagnostic criteria, 141 interictal, 100, 101
epidemiology, 140–141 isolated, 102
historical background, 139–140 Ethnicity, 195–197
prognosis, 141–142 Event-related potentials (ERPs), 153–154
rarity, 139–140 Examination, physical, 74–77
Electrical status epilepticus of sleep (ESES), 102 Executive functioning theory, 21, 22t
Electroencephalography (EEG), 81, 150f, 152–154 Expressive language, 322–323
definition, 100 treatment, 331–332
fundamentals, 152–153
resting state–based, 154 Facility-based vocational programs, 414–415
task-based, 153–154 Families
Emotional development, 70. See also Psychiatric adults with ASD, stress, 432–434
comorbidities educational programs, 395
Employment, adult, 435–438, 436t personal narrative, 477
ASD, 420 Families, in education, 394, 401–404
disabilities, 414 healthcare and schools, 401–404
Empowerment, 452 rights and advocacy, 404
Environment Family centeredness, 455–457, 456f
considerations, 361–363 Family communication, 447–461. See also
contributions, 304 Collaboration
Epidemiology, 181–199 Family history, 73–74
case definition, 181–183 Family perspective, 465–472
case evaluation, 185–186 communication, importance, 468–469
case identification/assessment, 183–185, 184f inspiring and driving forces, 471–472
correlates, epidemiology, 193–198 personal narratives, 467–468
historical background, 181 physician, 465–467
implications and unmet research needs, 198 resiliency, compassion, and ethics, 471
migration, 197–198 sibling perspectives, 469–470
prevalence estimates, 186–187, 188f stress, 432–434, 465
prevalence time trends, 187–193 system and, 471
(See also Prevalence time trends) Feeding interventions, 269
race and ethnicity, 195–197 Focused intervention practices, 397–398, 398t
socioeconomic status, 194–195 Folate deficiency, 310
stress, prenatal, 198 Folate receptor-α autoantibodies (FRAs), 310
study design and methodological issues, 181–186 Folinic acid, 310
Epigenetics, 304, 304b 47,XYY syndrome, 119t, 120, 128–129
Epilepsy, 100–105, 212–214 Four As, 456, 456f
basic science, 104–105 Fragile X syndrome, 77–79, 79t, 122f, 123–124
490 / / I ndex
case study, 132–133 single nucleotide variants, 163–164, 164f

emerging therapies, 292 structural variants, 166–167, 167f
gene mutations, 118t, 120 technological advances, 162–164, 163t
Fringe vocabulary, 334 whole exome sequencing, 165–166
Functional behavioral assessment (FBA), 266, 438 Genetic testing, 77–79, 79t
Functional connectivity MRI (fcMRI), 151–152 Genome-wide association studies (GWAS),
Functional magnetic resonance imaging (fMRI), 164–165
150f, 151–152 Global developmental delay, 49
Function-based interventions, 266, 267t Glucose metabolism, 155
Glutamatergic antagonists, 292
GABAB receptor agonist, 292 Glutamatergic signaling, 292
GABAergic neurons, 211–212 Gluten-free casein-free (GFCF), 311
Gait abnormalities, 110 Gluten sensitivity, non-celiac, 311
Gastrointestinal disorders Grief stages, 450
history, 71 Group participation assessment, 372
inflammation, 235–236 Guanfacine, 282
Gene expression, 304
Genetic disorders, 117–133 HANDS in Autism, 452–457, 459–461, 460f.
47,XYY syndrome, 119t, 120, 128–129 See also Collaboration
case studies, 132–133 Healthcare, schools and, 401–404
chromosomal diseases, 118t–119t, 120 Hemimegalencephaly, 210
copy number variations, 105, 120, 162, Heritability, 67, 161–162
166–169, 168f Herpes simplex virus, 227
evaluation, 130–132 Heterogeneity, 19, 205
fragile X syndrome (See Fragile X syndrome) behavioral, 22
metabolic diseases, 120t, 121 cognitive and language, 34
mitochondrial diseases, 121 genetic, 162, 171, 205
monogenic diseases, 117–119, 118t–119t Historical background, childhood-onset
neurofibromatosis type 1, 79t, 118t, 122f, 125–126 disorders, 3–5
referral and consultations, 132 19th century, 3
Rett syndrome (See Rett syndrome) child psychiatry beginnings, 3
Smith–Lemli–Opitz syndrome, 120t, 122f, 130 diagnosis and classification, 3–14 (See also
Smith–Magenis syndrome, 119t, 120, 122f, Diagnosis and classification, ASD)
127–128 Kanner, Leo, 5–6, 6f
specific syndromes, 121–123, 122f Wild Boy of Aveyron, 3–4f
tuberous sclerosis complex, 79t, 118t, 122f, History, medical, 67–71
126–127 cognition, 69
velocardiofacial syndrome, 119t, 120, 122f, communication, 68–69
129–130, 133 developmental, 67–70
Genetics, of ASD, 161–172, 303 emotional/behavioral development, 70
adults, 429–430 gastrointestinal, 71
balanced chromosomal rearrangements, 169–170 motor, 69–70
copy number variations, 105, 120, 162, past, 71
166–169, 168f play/leisure, 69
functional and clinical implications, 170–172, 172f psychiatric comorbidity, 86
genome-wide association studies, 164–165 sensory processing differences, 70
heritability, 67, 161–162 sleep, 71
Idic15, 206–207, 207f History, social and family, 73–74
milestones, 163t Home and Community-Based Waiver Services
prevalence and, 161 (HCBS), 419
risk, overlapping genes and loci, 171, 172f “How Does Your Engine Run?,” 363–364
Index // 491
Hybrid approach, 329 Individuals With Disabilities Education Act

Hyperactivity medications, 281–282 (IDEA), 388–391, 419
Hyperbaric oxygen treatment, 308–309 Infantile spasms, 101–102
Hyperresponsivity, 342, 343t Infections, maternal, 217
Hyporesponsivity, 342–343, 343t Inflammation, 227–228
Hypotonia, 109I biomarkers, 307b
gastrointestinal, 235–236
ICD-10, 8–10, 182 neuroinflammation, 226
Idic15, 206–207, 207f Information processing theory, 21–22, 22t
IFN-γ, 231, 235 Innate immune system, 214–216
Immune/inflammatory biomarkers, 307b Insomnia, 105. See also Sleep disorders
Immune system Instrumental activities of daily living
activated, etiologies, 217–218 (IADLs), 339, 352–353. See also Occupational
innate, 214–216 therapy
Immune therapies, 312–313 Integrating care, 452–453
Immunoglobulin Integrative medicine, 303. See also Complementary
intravenous, 241–242, 312–313 and alternative treatments
oral human, 241 Intellectual functioning, 49, 431–432
Immunology, 225–242 adults, 431–432
adrenocorticotropic hormone, 239 children and adolescents, 49
alloimmunity, 228–233 (See also Alloimmunity) Intensity, educational program, 396
autoimmunity, 233 Interfering behaviors, adult, 438
celecoxib, 240 Interictal epileptiform discharges, 100, 101
corticosteroids for, 236–239, 238f Intravenous immunoglobulin (IVIG), 241–242,
cytokines, 234–235 312–313
drug treatment studies, 236–242 IQ. See Cognitive functioning
GI inflammation, 235–236 Irritability, 70, 277
historical background, 225 Irritability medications, 276–280
inflammation, 227–228 antipsychotics, 278–280
lenalidomide, 239–240 clinical implications, 281
MMR vaccine, 236 other agents, 280
neuroinflammation, 226 Isolated epileptiform discharges, 102
oral human immunoglobulin, 241
pentoxifylline, 240–241 Kanner, Leo
peripheral immune activation, 233–234 adult autism, 31
pioglitazone, 241 autism diagnosis and classification, 5–6, 6f
pregnenolone for, 239 outcome and prognosis, 140
Impulsivity medications, 281–282
Inattention medications, 281–282 Landau–Kleffner syndrome, 102
Inborn errors of metabolism, 79–80, 80t Language. See also Speech and language
Incidental approaches, 257 evaluation, 324–325
Incoordination, 110 functioning, adult, 34–35, 431–432
Independence impairment, 48–49
adult, 31–34, 33f Learning Experiences and Alternate Program for
learning needs, 392–393 Preschoolers and Their Parents (LEAP), 26,
Independent living, occupational 259, 397
therapy, 351–352 Learning needs, 390–393
Individualized Education Program (IEP), 389–390 academics, 391
Individualized Family Service Plan (IFSP), 389 independence, 392–393
Individualized Transition Plan, 390 individual variation, 390
Individually oriented treatment, 453–455, 454f restrictive school settings, 390
492 / / I ndex
social competence, 391–392 differential diagnosis, adult, 56–63

Leisure, history, 69 differential diagnosis, childhood, 49–56
Lenalidomide, 239–240 Mental status examination (MSE), 86–87, 88b
Living arrangements, adults, ASD, 434–435, 435t Metabolic diseases, 120t, 121
Local Community Cadres (LCCs), 455 Metabolic testing, 79–80, 80t
Loneliness, personal narrative, 478 Methodological issues, 181–186. See also Study
Loss-of-function (LOF) mutations, 162, 165–166 design and methodological issues
Methylcobalamine (methyl B12), 309
Magnetic resonance imaging (MRI), 81, 149–152 Methylphenidate, 281–282
anatomical/structural, 149–151, 150f Microbiome, 311–312
diffusion, 150f, 151 Microcephaly, 207–208
functional, 150f, 151–152 Microglia, 226
functional connectivity, 151–152 activated, 214
Major depressive disorder Migration, 197–198
comorbid, 91–92 Mind and body practices, 313
differential diagnosis, children, 53 Mindfulness-based stress reduction (MBSR), 373
medications, 284 Mineral supplementation, 311
with melancholic features, adult, 58 Mini-mental status examination (MMSE), 87, 88b
Masturbation, 94 Mitochondrial diseases, 80–81, 121
Maternal–fetal autoantibodies, 217 Mitochondrial function biomarkers, 306b
Medicaid and the Social Security Administration MMR vaccine, 236
(SSA), vocational rehabilitation and Monogenic diseases, 117–119, 118t–119t
training, 419 Mood disorders, 57–58
Medicaid Title XIX Home and Community-Based Motor delay, 109
Waiver Services (HCBS), 419 Motor disorders, 69–70, 109–112
Medical evaluation, 67–82. See also specific basic science, 112
components case study, 109–110
case studies, 76, 78 definitions, 109
EEG, 81 demographics, 110–111
genetic testing, 77–79, 79t evaluation and treatment, 111–112
heritability, 67, 161–162 significance, 111
medical history, 67–70 Motor execution deficits, 365
medical history, past, 71 Motor planning deficits, 364–365
metabolic testing, 79–80, 80t Motor skills, 345, 346t
mitochondrial disorders, 80–81 Movement, reactions, 344
neuroimaging, 81 Mutations. See also Genetics, of ASD; specific types
physical examination, 74–77 fragile X syndrome, 118t, 120 (See also Fragile X
review of systems, 71–73 syndrome)
social and family history, 73–74 loss-of-function, 162, 165–166
Medical history, 67–70 Rett syndrome, 79, 79t, 118t, 120 (See also Rett
gastrointestinal, 71 syndrome)
past, 71 Mutism, selective, 55–56N
sensory processing differences, 70
sleep, 71 N-acetylcysteine (NAC), 280, 309
Medical home model, 457–459 Naltrexone, 280–281
Megalencephaly, 207–208, 209f Narratives, personal, 475–482
Melatonin, 284, 305–307, 308t adulthood, 478–479
Memantine, 292 art, 478, 480–481
Mental health. See also Differential diagnosis; clinical experience and medications, 479–480
specific disorders family, 467–468, 477
adult, 35–36 feelings, 477–478
Index // 493
growing up autistic, 475–477 interventions, 341, 341t

legacy, 481–482 motor skills, 345, 346t
Natural killer (NK) cells, 231–232 play, 345–347
Neurodegenerative changes, 212 referral, 342
Neurodevelopmental disorders, 48–49 school problems, 350–351, 351t
Neurofibromatosis type 1, 79t, 118t, 122f, 125–126 sensory symptoms, 342–345, 343t
Neuroimaging, 81, 149–156. See also specific types social participation, 347–348
electroencephalography, 150f, 152–154 social skills, 348–350
positron emission tomography, 150f, 154–155 target symptoms, 341
single photon emission tomography, 150f, 154–155 Occupational therapy interventions, 355–365
Neuroinflammation, 226 Ayres Sensory Integration, 356–359, 357t, 358f
Neurological comorbidities, 99–112. See also specific environment, 361–363
disorders fundamentals, 355–356
epilepsy, 100–105 praxis, 364–365
fundamental questions, 99 self-regulation, 363–364
motor disorders, 109–112 sensory diets, 359–361, 360f, 361f, 362t
sleep disorders, 105–109 Off-label medication uses, 313
Neuropathology, 205–218 Omega-3 fatty acids, 310
activated immune system etiologies, 217–218 Oppositional defiant disorder, 50–51
cerebellum, 211 Oral human immunoglobulin, 241
cerebral cortex, 209–211 OT-SI approach, 358–359
developmental circuit pruning defects, 216 Outcome, adult, 31–34, 33f
epilepsy comorbidity, 212–214 (See also Epilepsy) Outcome improvement
heterogeneity, 19, 22, 34, 162, 171, 205 adults, 40–41
Idic15, 206–207, 207f children and adolescents, 26–27
innate immune system, 214–216 Outcome prediction
megalencephaly and microencephaly, adults, 37–38
207–208, 209f children and adolescents, 23–24
neurodegenerative changes, 212 Overresponsivity, 342, 343t
neurotransmitter system, 211–212 Oxidative stress biomarkers, 306b
postmortem brain analysis issues, 205–206 Oxygen treatment, hyperbaric, 308–309
Neurotransmitter system, 211–212 Oxytocin, 20–21
Next Steps, 452 Oxytocin treatment, 292–293, 312
NMDA receptor antagonists, 292
Non-celiac gluten sensitivity, 311 Pancreatic digestive enzymes, 312
Parent/caregiver interview, 353
Observation, skilled, 354–355 Partnership centeredness, 455–457, 456f
Obsessive–compulsive disorder, 87, 90–91 Pentoxifylline, 240–241
differential diagnosis, adult, 58 Personality disorders, 59–62
differential diagnosis, childhood, 54 Personal narratives, 475–482. See also Narratives,
Obsessive–compulsive personality disorder, 59 personal
Occupational profile, 340 Personal space, 349
Occupational therapy, 339–355 Perspective taking, 21, 152, 370, 371f, 372
activities of daily living, 347–348 Pervasive Developmental Disorder Not Otherwise
assessment, 353–355, 355t Specified (PDD-NOS), 9–10, 182
evaluation, 340 Pharmacology. See Psychopharmacology
family and community, 348 Physical examination, 74–77
goals and domain, 339–340, 340f Physician, family and, 465–467
independent living and transition to adulthood, Picture Exchange Communication System (PECS),
351–352 264, 325, 398t, 438
instrumental activities of daily living, 352–353 Pioglitazone, 241
494 / / I ndex
Play, 69, 345–347 assessments, treatment planning and monitoring,

Polysomnography, 105 289, 290t–291t
Pornography, 94 with behavioral treatment, 270
Positioning, 344 case studies, 287–289
Positive behavior intervention and support, community practice patterns, 284–287, 285t–286t
398–400, 399f for depression and anxiety, 284
Positron emission tomography (PET), 150f, emerging therapies, 292–293
154–155 fundamentals, 275–276
Pragmatic language treatment, 332–333 for hyperactivity, impulsivity, and inattention,
Praxis 281–282
deficits, 345, 346t for irritability and aggression, 276–280
definition, 364 maladaptive behaviors, co-occurring, 276, 277f
interventions, 364–365 personal narrative, 479–480
therapy, 357, 357t for repetitive behaviors, 283–284
Pregnenolone, 239 for self-injury, 280–281
Prevalence, 161 for sleep disorders, 284
estimates, 186–187, 188f targets, 276, 277f
vs. incidence, 181, 187–189 Psychotic disorders
psychiatric comorbidities, 85–86 adult, 62–63
Prevalence time trends, 187–193 childhood, 54–55
birth cohorts, 192–193, 193f PTEN hamartoma tumor syndrome, 79, 79t
cross-sectional variability, 191–192, 191f Purkinje neuron depletion, 211
diagnostic substitution, 190–191
prevalence vs. incidence, 181, 187–189 Race, 195–197
referral statistics, 189, 190f Receptive language, 322, 330–331
repeated surveys, geographical, 192 Recovery, possibility, 41–42
Prevention Referral statistics, 189, 190f
positive behavior intervention and support, Repeated surveys, geographical, 192
398–400, 399f Repetitive behaviors, 20, 21, 23, 109–112
primary, secondary, and tertiary, 400 aging on, 36–37
victimization reduction, 400 basic science, 112
Problem behavior, 266, 267t case studies, 25, 76, 78, 109–110
Proprioceptive input, 344 definitions, 109
Providers, behavioral service, 254–256, 255t demographics, 110–111
Pruning defects, developmental circuit, 216 differential diagnosis, adults, 56
Psychiatric comorbidities, 85–95 differential diagnosis, children and adolescents, 48,
abnormal behavior, 93–95 50, 51, 53
adults, 432 differential diagnosis, vs. OCD, 54, 58, 59, 87
anxiety, 88–90, 89b evaluation and treatment, 111–112
attention deficit hyperactivity disorder, 87–88 medications, 283–284
bipolar disorder, 92 motor, 70
catatonia, 92 play, 69
history taking, 86 significance, 111
major depressive disorder, 91–92 Residential setting, 95
mental status examination, 86–87, 88b Restricted, repetitive behaviors. See Repetitive
obsessive-compulsive disorder, 87, 90–91 behaviors
prevalence, 85–86 Rett syndrome, 122f, 124–125
schizophrenia, 92–93 classification, 4–5, 7b, 8, 9, 12
social anxiety, 90 gene mutations, 79, 79t, 118t, 120
when nothing works, 95 head size, 75
Psychopharmacology, 275–294 historical background, 4–5
Index // 495
Review of systems, 71–73 Sibling perspectives, 469–470

Right and wrong, rigid sense, 94 Single nucleotide variants, 163–164, 164f
Rights, family, 404 Single photon emission tomography (SPECT),
Rigid behaviors. See Repetitive behaviors 150f, 154–155
Rubella, 227 Skilled observation, 354–355
Runs of homozygosity (ROH), 165–166 Skill generalization, 257
Skills-focused techniques, 263–266
Safety, 74 communication, 263–264
Sameness, insistence on/need for, 5, 93, 393 daily living, community, and vocational skills, 265
adolescents, 431 function based interventions, 266, 267t
vs. obsessive-compulsive disorder, 54, 87, 90–91 problem behavior, 266, 267t
Smith–Lemli–Opitz syndrome, 130 social skills, 264–265
Schizoid personality disorder, 61–62 Sleep disorders, 71, 105–109
Schizophrenia, comorbid, 92–93 basic science, 109
Schizophrenia spectrum disorders, 60–61 case study, 105–106
Schizophrenia with predominant negative definitions, 105
symptoms, 62–63 demographics, 106
Schizotypal personality disorder, 60–61 evaluation, 107–108, 107b
School. See Education interventions, 268–269
Screen-based media, 405 medications, 284
Screening methodology, 183–185, 184f seizure discharges, 214
Seizures, 100, 213, 217. See also Epilepsy significance, 107
Selective mutism, 55–56 treatment, 108
Selective serotonin reuptake inhibitors (SSRIs) Sleep efficiency, 105
depression and anxiety, 284 Sleep latency, 105
repetitive behaviors, 283 Smarties task, 370, 371f
Self-awareness interventions, 380 Smith–Lemli–Opitz syndrome, 120t, 122f, 130
Self-injurious behaviors, 89, 90t, 94–95 Smith–Magenis syndrome, 119t, 120, 122f,
adults, 438 127–128
clinical implications, 281 Social anxiety disorder
history, 70 comorbid, 90
medications, 280–281 differential diagnosis, adult, 57
prediction, 22–23 differential diagnosis, childhood, 52–53
prevalence and consequences, 277 Social cognitive theories, 21, 22t
Self-regulation, 363–364 Social competence and functioning
Sensory diets, 359–361, 360f, 361f, 362t adult, 31–34, 33f, 430–432, 431t
Sensory questionnaires, 353–354, 355t children and adolescents, 20–21, 22t
Sensory symptoms, 342–343, 343t interventions, 379–380
history, 70 learning needs, 391–392
hyperresponsivity, 342, 343t Social history, 73–74
hyporesponsivity, 342–343, 343t Social media, 405
occupational therapy, 342–345 Social motivation theory, 20–21, 22t
Serotonergic neurons and receptors, 212 Social naïveté, 94
Serotonin, 155 Social participation, 347–348
Serotonin transporter (SERT), 155 Social relationships, adult, 430–431, 431t
Settings, behavioral service, 254–256, 255t Social skills, 369–372. See also specific types
17P deletion syndrome, 119t, 120, 122f, 127–128 adult, 438–439
Sexual behavior, inappropriate, 94 assessment, 371, 371f, 372
Sheltered workshops, 414–415 components, 369–370
Shprintzen syndrome, 119t, 120, 122f, consequences and vicious cycle, 370–371
129–130, 133 deficits, 370
496 / / I ndex
perspective taking (theory of mind), 21, 152, 370, definition, 70, 109

371f, 372 demographics, 110–111
Social skills interventions, 370–382 evaluation and treatment, 111–112
ASPIRE program, 378–381 (See also ASPIRE significance, 111
program) visual, 75
behavioral, 264–265 Stereotypies, differential diagnosis
case studies, 373–379, 377f adults, 56, 58, 59
cognitive-behavioral therapy, 374–375 children, 47
effectiveness, 382 vs. OCD, 54, 58, 59
evidence-based, 376–378 vs. Tourette’s disorder, 55
group vs. individual, 374–375 Stress
holistic and multidisciplinary, 371–372 family, 432–434, 465
importance, 370–371 prenatal, 198
mindfulness-based stress reduction, 373 Stress management
occupational therapy, 348–350 interventions, 380–381
overview, 373 mindfulness-based stress reduction, 373
Social Thinking, 262t, 333, 349, 370, 373 Structural MRI (sMRI), 149–151, 150f
Socioeconomic status, 194–195 Structural variants (SVs), 166–167, 167f
Space, personal, 349 Study design and methodological
Spasms, infantile, 101–102 issues, 181–186
Specific language impairment, 48–49 case definition, 181–183
Speech and language, 321–328 case evaluation, 185–186
communication assessment, 323–328 (See also case identification/assessment, 183–185, 184f
Communication assessment) Sudden unexpected death in epilepsy
core deficits, 322–323 (SUDEP), 102
evaluation, 324–325 Support, 450–452, 451f
expressive language, 322–323 Symptom severity over time, adult, 36–37
fundamentals and challenges, 321
receptive language, 322 Tactile sensations, 344–345
Speech and language treatment, 328–335 Taopathy, 212
adults, 438–439 Teaming, educational, 393–394
alternative and augmentative communication, Technology, educational, 404–405
333–335 Testing
applied behavioral analysis, 330 genetic, 77–79, 79t
case studies, 331–332, 334 metabolic, 79–80, 80t
child-centered, 330 Theory of mind, 21, 152
clinician-directed, 330 assessment, 372
discrete trial training, 330 social skills, 370, 371f
evidence-based, 328–329 Ticket to Work program, 419
expressive language, 331–332 Toilet training, 269
hybrid approach, 329 Tourette’s disorder, 55
NRC recommendations, 329 Transition to adulthood, occupational therapy,
pragmatic language, 332–333 351–352
receptive language, 330–331 Translocations, 166–167, 167f
Speech-generating technology, 405 Treatment. See also specific types
Standardized testing, 354, 355t assessments for, 289, 290t–291t
State developmental disability (DD) agencies, 418 Treatment and Education of Autistic and Related
Stereotypies, 5, 21, 36, 37, 109–112. See also Communication Handicapped Children
Repetitive behaviors (TEACCH), 396–397, 459
basic science, 112 Tuberous sclerosis complex, 79t, 118t, 122f,
case study, 76, 109–110 126–127
Index // 497
cortical tubers, 209–210 competitive integrated employment models,

Tumor necrosis factor α (TNF-α), 231–232 415–416
22q11 deletion syndrome, 119t, 120, 122f, day programs and sheltered workshops, 414–415
129–130, 133 employment, adults with ASD, 420–421
employment, adults with disabilities, 414
Underresponsivity, 342–343, 343t goal, 414
historical background, 416
Valproic acid, 280 purpose, 413
Vasopressin, 20, 292–293 successful models, 422
Velocardiofacial syndrome, 119t, 120, 122f, system change initiatives, 420
129–130, 133 systems and legislation, 416–420, 417t–418t
Vestibular system, 344 vocational needs, adults with ASD, 421
Victimization, 94, 400 Vocational Rehabilitation (VR) services, 416–418,
Virtual reality, 405 417t–418t
Vitamin D, 304 Vocational skills interventions, 265
Vitamin supplementation, 311 Voice modulation, 349–350
Vocation
adult, 435–438 Weak central coherence (WCC) theory, 21–22
history, 73 Whole exome sequencing (WES), 165–166
Vocational rehabilitation and training, 413–424 Wild Boy of Aveyron, 3–4f
access, adult, 421–422
adult, 437 X-linked disorders, 77
case study, 423–424 47,XYY syndrome, 119t, 120, 128–129

Autism Spectrum Disorder

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AUTISM SPECTRUM DISORDER

Published in the United States of America by Oxford University Press

© Oxford University Press 2016

First Edition published in 2016

All rights reserved. No part of this publication may be reproduced, stored in

You must not circulate this work in any other form

Cataloging-in-Publication data is on file at the Library of Congress

Printed by Sheridan, USA

SECTION 1: BACKGROUND AND DIAGNOSTIC ASSESSMENT

1. From Infantile Autism to Autism Spectrum: Evolution

10. Neuroimaging of Autism Spectrum Disorder 149

15. Behavioral Treatment of Autism Spectrum Disorder 253

SECTION 4: OTHER CARE DELIVERY SERVICES AND PERSPECTIVES

21. Educational Issues in Autism Spectrum Disorder 387

23. Adults With Autism Spectrum Disorder: Transition Issues 429

Robert E. Accordino, MD, MSc Edward S. Brodkin, MD

Marji Erickson Warfield, PhD Michael Gandal, MD, PhD

Jacob M. Hooker, PhD Kimberly Lo, MD

Christopher J. McDougle, MD Lisa Nowinski, PhD

Allan L. Reiss, MD Thayne L. Sweeten, PhD

Melissa A. Sreckovic, MEd Danielle Warner, MA

Brian Willoughby, PhD Nicole R. Zürcher, PhD

Katharine Zuckerman, MD, MPH

HISTORICAL BACKGROUND AND AN OVERVIEW OF DIAGNOSTIC APPROACHES

FROM KANNER’S REPORT TO DSM-III

as unusual rates or sequences of development and hyper/hyposensitivity to the environ-

DSM-III AND DSM-III-R

DSM-I (1952) and DSM-II (1968)

DSM-IV-TR (text revision) (2004)

DIMENSIONAL DIAGNOSTIC APPROACHES

DSM-5 AND AUTISM SPECTRUM DISORDER

meaningful subtypes of autism-related disorders so that targeted treatment approaches for

Dr. Fred R. Volkmar has nothing to disclose.

KIRSTIN BROWN BIRTWELL,

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition

amygdala and how a potentially ineffective social stimuli–emotional salience association

Among cognitive theories of development, executive functioning impairments and infor-

TABLE 2.1 Current Theories of Development in Autism Spectrum Disorder

contextually appropriate, meaningful whole. Whereas the EF theory may adequately

CAN WE PREDICT OUTCOMES?

CASE STUDY 1: “SAM”

CASE STUDY 2: “PETER”

CAN WE IMPROVE OUTCOMES?

The following is a common question from parents: “What can we do to reduce my child’s

PATRICIA HOWLIN AND ILIANA MAGIATI

WHAT HAPPENS TO INDIVIDUALS WITH AUTISM SPECTRUM

SOCIAL INTEGRATION AND INDEPENDENCE IN ADULTHOOD

COGNITIVE AND LANGUAGE FUNCTIONING

Although IQ is an important issue in any study of adult outcomes, it is important to be

CHANGES OVER TIME: SEVERITY OF AUTISM SPECTRUM DISORDER SYMPTOMS

CAN WE PREDICT OUTCOMES IN ADULTHOOD?

CASE STUDY #1: “MARK”

CASE STUDY #2: “JONATHAN”

CAN WE IMPROVE OUTCOMES IN ADULTHOOD?

CAN THERE BE RECOVERY FROM AUTISM SPECTRUM DISORDER?

Dr. Patricia Howlin and Dr. Iliana Magiati have nothing to disclose.

ISOBEL W. GREEN, CHRISTEN L. KIDD,

DIFFERENTIAL DIAGNOSIS IN CHILDHOOD