Autism Spectrum Disorders

Autism Spectrum
Disorders
edited by
Eric Hollander
Mount Sinai School of Medicine
New York, New York, U.S.A.
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Medical Psychiatry
Series Editor Emeritus
William A. Frosch, M.D.
Weill Medical College of Cornell University
New York, New York, USA
Advisory Board
Jonathan E. Alpert, M.D., Ph.D. Siegfried Kasper, M.D.

Massachusetts General Hospital and University Hospital for Psychiatry
Harvard University School of Medicine and University of Vienna
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University of Chicago School of Medicine Cedars-Sinai Medical Center
Chicago, Illinois, USA Los Angeles, California, USA
1 Handbook of Depression and Anxiety: A Biological Approach, edi-

ted by Johan A den Boer and J. M. Ad Sitsen
2 Anticonvulsants in Mood Disorders, edited by Russell T. Joffe and
Joseph R Calabrese
3 Serotonin in Antipsychotic Treatment: Mechanisms and Clinical
Practice, edited by John M Kane, H.-J. Moller, and Frans Awou-
ters
4. Handbook of Functional Gastrointestinal Disorders, edited by Kevin
W. Olden
5 Clinical Management of Anxiety, edited by Johan A den Boer
6 Obsessive-Compulsive Disorders1 Diagnosis • Etiology • Treat-
ment, edited by Eric Hollander and Dan J. Stein
7 Bipolar Disorder: Biological Models and Their Clinical Application,
edited by L. Trevor Young and Russell T. Joffe
8. Dual Diagnosis and Treatment' Substance Abuse and Comorbid
Medical and Psychiatric Disorders, edited by Henry R. Kranzlerand
Bruce J. Rounsaville
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10. Panic Disorder and Its Treatment, edited by Jerrold F. Rosenbaum
and Mark H Pollack
11 Comorbidity in Affective Disorders, edited by Mauricio Tohen
12 Practical Management of the Side Effects of Psychotropic Drugs,
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13. Psychiatric Treatment of the Medically III, edited by Robert G.
Robinson and William R. Yates
14. Medical Management of the Violent Patient- Clinical Assessment
and Therapy, edited by Kenneth Tardiff
15. Bipolar Disorders Basic Mechanisms and Therapeutic Implica-
tions, edited by Jair C. Scares and Samuel Gershon
16. Schizophrenia. A New Guide for Clinicians, edited by John G.
Csernansky
17. Polypharmacy in Psychiatry, edited by S. Nassir Ghaemi
18. Pharmacotherapy for Child and Adolescent Psychiatric Disorders
Second Edition, Revised and Expanded, David R Rosenberg,
Pablo A, Davanzo, and Samuel Gershon
19. Brain Imaging in Affective Disorders, edited by Jair C. Scares
20. Handbook of Medical Psychiatry, edited by Jair C Scares and
Samuel Gershon
21. Handbook of Depression and Anxiety Second Edition, Revised
and Expanded, edited by Siegfried Kasper, Johan A. den Boer, and
J. M. Ad Sitsen
22. Aggression Psychiatric Assessment and Treatment, edited by Emit
F. Coccaro
23 Depression in Later Life. A Multidisciplmary Psychiatric Approach,
edited by James M. Ellison and Sumer Verma
24. Autism Spectrum Disorders, edited by Eric Hollander
ADDITIONAL VOLUMES IN PREPARATION
Handbook of Chronic Depression' Diagnosis and Therapeutic Man-

agement, edited by Maurizio Fava and Jonathan Alpert
Autism: A Historical Perspective
It is intriguing that conditions which clearly have always existed may nonetheless
only be recognized and accorded significance relatively late. This is the case with
autism. It was only in the 1940s that the first clinical descriptions were provided
by Kanner and Asperger (these were published almost simultaneously, although
both researchers seem to have been unaware of the other’s work). And yet it is
certain that severe, classical cases of autism occurred long before this. Uta Frith
and Rab Houston, in their recent book Autism in History, present the most detailed
evidence for such a diagnosis in the case of a young man living in the 18th
century, and in an earlier book, Frith hazarded the thought that autism might
explain the otherwise almost unintelligible behavior of the Franciscan monk
Brother Juniper, of the ‘‘blessed fools’’ of old Russia, and so on.
While Asperger regarded autism as organic, a biological defect of affective
contact, Kanner saw it as psychological, or reactive, a reaction to a supposed
lack of parental love or care, and, in particular, to a cold, “refrigerator mother.”
Asperger’s paper did not become widely known (it was only translated into En-
glish in the 1980s), and Kanner’s unfortunate formulation was rather widely ac-
cepted during the 1950s and 1960s, with sometimes dire consequences to both
autistic children and their parents. (Kanner’s psychological theory is still accepted
in many parts of the world.) But by the late 1960s it had become apparent that
autism was organic, although not a “disease” in the usual sense—not specifically
a disorder of childhood, but rather a disorder of development, the development
of certain parts of the mind and brain, and, as such, a lifelong condition.
Up to this point approaches had been purely clinical and epidemiological—
what was the incidence of autism? What were its causes? How did autism present
itself, evolve, change with time? What could be done with drugs, or behavioral
iii
iv A Historical Perspective
approaches, to mitigate or control the symptoms, and allow the autistic person
a more normal life?
There was little sense of the deep psychological structure of autism, much
less of its neurobiological basis. Attempts to delineate a deep, invariable core in
the syndrome started in the 1970s, and soon homed in on the social and communi-
cational problems of the autistic, and these were seen by some in the 1980s as
expressions of a very belated, slow, and at best very partial development of what
primate ethologists were now terming “theory of mind.” And yet, it was clear,
no such theory sufficed by itself: there were nearly always sensory symptoms,
strange sensitivities and insensitivities, never the same in any two individuals
(Temple Grandin writes of these, from her own experience, in the present vol-
ume). There were repetitive and compulsive behaviors; there could be impulsiv-
ity, explosiveness, aggressiveness; there were sometimes specific language disor-
ders. Sometimes there were seizures or EEG abnormalities.
And a large proportion of the autistic—at least, those with classical infan-
tile autism such as Kanner had described—were markedly retarded; language
and intelligence, by contrast, seemed normal in those with Asperger’s syndrome.
All this complicated matters. Was one dealing with a single core disorder, or
with a complex phenotype which could include much else? Could some autistic
traits appear in relatives of the autistic, even though one would never see them
as clinically autistic? What was the relation of Kanner-type autism to Asperger’s
syndrome? What of pervasive developmental disorders, so-called, or Rett’s syn-
drome, chilhood disintegrative disorder, etc.? Should one not speak of an entire
spectrum of such disorders?
(And the relationship of savant syndrome to autism, while strong—at least
10% of those with classical infantile autism exhibit savant traits—remains myste-
rious, so much so that it has become widely regarded as a syndrome unto itself,
and as such is not treated in this volume. While Langdon Down coined the term
“idiot savant” in the 19th century, and a most detailed analysis of such a patient
was provided by Kurt Goldstein a few years before the writings of Kanner and
Asperger, we still know very little about the neurobiology of savant talents, nor
why they should so often be associated with autism.)
The need for sorting out these varied but related conditions—all of which
can have different presentations and prognoses, different responses to drugs and
other treatments, and different neurobiological bases—became pressing by the
late 1980s, and it is especially such a sorting-out, such a dimensional approach,
which has so fruitfully occupied Eric Hollander and his colleagues, and which is
set out here, systematically and comprehensively, in Autism Spectrum Disorders.
The organization of this book begins with the initial clinical encounter, the
making of a diagnosis—not perhaps intellectually difficult, but a diagnosis which
is emotionally and morally charged, for what one is diagnosing is a lifelong
condition which will have to be lived with, negotiated with, for decades ahead.
A Historical Perspective v
Then there is the assessment—the detailed dimensional evaluation of different

mental domains: cognitive, linguistic, emotional, executive—essential for any
logical treatment plan.
There follow valuable chapters integrating the latest information and ideas
about the molecular genetics of autism, immune dysfunction in autism, autism
and serotonin function, autism and different brain structures, and autism as a
possible consequence of certain environmental toxins. The remainder of the book
returns to the immediate needs of patients, and deals very fully with not only a
variety of pharmacological approaches (from antipsychotics and antidepressants
to the treatment of movement disorders and seizures), but a variety of other bio-
logical treatments, and of behavioral and educational approaches. There is an
important chapter on consumer advocacy and autism, especially pertinent now
that many autistic people are becoming self-aware, and forming organizations of
various types, writing books, and taking an increasingly active role in seeking
their own proper respect and autonomy, a theme which is echoed in Temple
Grandin’s highly personal chapter.
When Uta Frith published her classic text in 1987, she spoke of the
“enigma” of autism. The last dozen years have seen great advances, especially
in relation to new diagnostic criteria, and new data on brain structure and brain
function—but much remains deeply tantalizing and mysterious. Autism Spectrum
Disorders gives one a vivid idea of where we are, in relation to autism, in 2003,
and reaches out imaginatively to what the future may hold.
Oliver Sacks, M.D.

Preface
Autism, the third commonest developmental disorder, is a complex and fascinat-

ing disorder with wide variability in the way it manifests and changes over time.
There is considerable evidence to indicate that autism and related disorders are
the final common pathway of both genetic and environmental factors.
A dimensional approach to this disorder has enabled us to develop new
insights and to formulate treatments targeting specific symptoms and behaviors.
This approach identifies three core dimensions in autism—the areas of social
interaction, language and communication, and compulsivity and repetitive behav-
iors—that have been linked to specific brain mechanisms. Findings in these areas
enable clinicians to target the specific symptoms and behaviors more effectively.
This book presents the scientific findings from several related disciplines
that support a dimensional approach. There have been tremendous strides in the
understanding of the genetic mechanisms underlying the development of autism
spectrum disorders. The exciting prospect exists that specific genes and brain
mechanisms involved in autism will be identified within the next few years. These
findings will open up new avenues for potential diagnosis and treatment. We
believe that a fruitful avenue of research is to identify links between specific
genes, brain mechanisms, and particular autistic dimensions. With advancing
technology in the field of neuroimaging, new findings reveal distinct neuronal
tracts and dysfunctional neurotransmitter systems in autism. Treatments that tar-
get these specific areas of abnormality are now possible, along with more sophis-
ticated techniques to evaluate clinical response to these treatments.
The identification of environmental factors implicated in the development
of autism is an area that is ill-defined and controversial. We review the possible
vii
viii Preface
role of oxytocin, immunization, and infections in the causation of autism spec-

trum disorders.
The goal of this book is to integrate the latest scientific findings on the
neurobiology of autism in a clinically meaningful way. This involves a conver-
gence of clinical, functional, and neuroanatomical data to make sense of this
often confusing and challenging spectrum of disorders. This book is aimed at
professionals who are treating individuals with autism, with an emphasis on phar-
macological strategies targeting specific symptom dimensions. We emphasize the
need to integrate treatments supported by clear empirical data (pharmacological,
behavioral, language-based) so as to provide optimal clinical care.
ACKNOWLEDGMENTS
I would like to thank:
Beth, Evan, and Zachary for their love and support
Hirschell and Deanna Levine and the Seaver Foundation for their support
and championing the needs of autism research
Kenneth L. Davis, M.D., Dean, Mount Sinai School of Medicine, for scien-
tific guidance
Eric Hollander
Contents
Autism: A Historical Perspective Oliver Sacks iii

Preface vii
Contributors xiii
The Clinical Condition
1. Autism: Diagnosis and Epidemiology 1

Fred R. Volkmar, Kathleen Koenig, and Malia McCarthy
2. Core Symptoms, Related Disorders, and Course of Autism 15

Eric Hollander and Caralynn V. Nowinski
Assessment
3. Autism Screening and Neurodevelopmental Assessment 39

Sarah J. Spence and Daniel H. Geschwind
4. Assessment and Early Identification of Autism Spectrum and

Other Disorders of Relating and Communicating 57
Stanley I. Greenspan and Serena Wieder
ix
x Contents
5. Cognitive and Neuropsychological Assessment of Children with

Autism Spectrum Disorders 87
Audrey F. King, Ronald R. Rawitt, Katherine C. Barboza, and
Eric Hollander
6. Assessment and Diagnosis of Pervasive Developmental Disorder 101

Cecelia McCarton
The Neurobiology of Autism
7. Molecular Genetics of Autism 133

Jennifer G. Reichert, Mario Kilifarski, Irina Bespalova, Nicolas
Ramoz, and Joseph D. Buxbaum
8. Immune Dysfunction in Autism 153

Gina DelGiudice and Eric Hollander
9. Autism and Environmental Toxins 175

Martin Evers, Sherie Novotny, and Eric Hollander
10. Neurobioloy of Serotonin Function in Autism 199

Christopher J. McDougle, David J. Posey, and Marc N.
Potenza
11. Autism, Serotonin, and the Cerebellum: A New,

Comprehensive Hypothesis 221
Donatella Marazziti
Psychopharmacological Treatments
12. Antidepressants and Anticonvulsants/Mood Stabilizers in the

Treatment of Autism 231
Sherie Novotny and Eric Hollander
13. Use of Atypical Antipsychotics in Autism 247

David J. Posey and Christopher J. McDougle
Contents xi
14. Treatment of Seizures in Children with Autism Spectrum

Disorders 265
Roberto Tuchman
15. Treatment of Movement Disorders in Autism Spectrum

Disorders 273
James Robert Brasic
16. Alternative Biological Treatments for Autism 347

Charles Cartwright and Rachael Power
Other Treatment Approaches
17. Behavioral Assessment and Treatment 369

Tristram Smith and Caroline Magyar
18. Educational Intervention: Inclusion vs. Self-Contained Classes 383

Audrey F. King
19. Consumer Advocacy and Autism 393

John Maltby
20. Autism: A Personal Perspective 409

Temple Grandin
21. Future Trends 419

Eric Hollander and Ronald R. Rawitt
Index 423
Contributors
Katherine C. Barboza, B.A. Mount Sinai School of Medicine, New York,

New York, U.S.A.
Irina Bespalova Seaver Autism Research Center and Laboratory of Molecular

Neuropsychiatry, Department of Psychiatry, Mount Sinai School of Medicine,
James Robert Brašić, M.D., M.P.H. Postdoctoral Fellow in PET/SPECT/

fMRI Imaging, Division of Nuclear Medicine, the Russell H. Morgan Department
of Radiology and Radiological Science, The Johns Hopkins University School
of Medicine, Baltimore, Maryland; Clinical Assistant in Psychiatry, Bellevue
Hospital Center, New York, New York; and Adjunct Assistant Professor of Psy-
chiatry, New York University School of Medicine, New York, New York, U.S.A.
Joseph D. Buxbaum, M.D. Laboratory of Molecular Neuropsychiatry, Depart-

ments of Psychiatry and Neurobiology, and Seaver Autism Research Center,
Mount Sinai School of Medicine, New York, New York, U.S.A.
Charles Cartwright, M.D. Assistant Professor, Department of Psychiatry,

University of Medicine and Dentistry of New Jersey–New Jersey Medical
School, Newark, New Jersey, U.S.A.
Gina DelGiudice, M.D. Seaver Autism Research Center and Department of

xiii
xiv Contributors
Psychiatry, Mount Sinai School of Medicine, and Department of Rheumatology,

Hospital for Special Surgery, New York, New York, U.S.A.
Martin Evers, B.S. Department of Psychiatry and Seaver Autism Research

Center, Mount Sinai School of Medicine, New York, New York, U.S.A.
Daniel H. Geschwind, M.D., Ph.D. Assistant Professor, Program in Neurogen-

etics, Departments of Neurology and Pediatric Neurology, David Geffen School
of Medicine at UCLA, Los Angeles, California, U.S.A.
Temple Grandin, Ph.D. Assistant Professor, Department of Animal Sciences,

Colorado State University, Fort Collins, Colorado, U.S.A.
Stanley I. Greenspan, M.D. Bethesda, Maryland, U.S.A.
Eric Hollander, M.D. Professor, Department of Psychiatry; Clinical Director,

Seaver Autism Research Center; Director, Compulsive, Impulsive and Anxiety
Disorders Program; and Director of Clinical Psychopharmacology, Mount Sinai
School of Medicine, New York, New York, U.S.A.
Mario Kilifarski Laboratory of Molecular Neuropsychiatry, Department of

Psychiatry, and Seaver Autism Research Center, Mount Sinai School of Medi-
cine, New York, New York, U.S.A.
Audrey F. King, Ph.D. Department of Psychiatry and Seaver Autism Research

Kathleen Koenig, M.S.N. Yale University, New Haven, Connecticut, U.S.A.
Caroline Magyar, Ph.D. Strong Center for Developmental Disabilities, Uni-

versity of Rochester Medical Center, Rochester, New York, U.S.A.
John Maltby Autism advocate, Sleepy Hollow, New York, U.S.A.
Donatella Marazziti, M.D., Ph.D. Department of Psychiatry, Pharmacology,

Neurobiology, and Biotechnology, University of Pisa, Pisa, Italy
Malia McCarthy, M.D. Yale University, New Haven, Connecticut, U.S.A.
Cecelia McCarton, M.D. Albert Einstein College of Medicine and McCarton

Center for Developmental Pediatrics, New York, New York, U.S.A.
Contributors xv
Christopher J. McDougle, M.D. Albert E. Sterne Professor and Chairman,

Department of Psychiatry, Indiana University School of Medicine, and James
Whitcomb Riley Hospital for Children, Indianapolis, Indiana, U.S.A.
Sherie Novotny, M.D. Department of Psychiatry and Seaver Autism Research

Caralynn V. Nowinski, B.S. Seaver Autism Research Center, Mount Sinai

School of Medicine, New York, New York, U.S.A.
David J. Posey, M.D. Assistant Professor of Psychiatry, Riley Child and Ado-
lescent Psychiatry Clinic, Department of Psychiatry, Indiana University School
of Medicine, Indianapolis, Indiana, U.S.A.
Marc N. Potenza, M.D., Ph.D. Assistant Professor, Problem Gambling Clinic,

Department of Psychiatry, Yale University School of Medicine, and Substance
Abuse Center, Connecticut Mental Health Center, New Haven, Connecticut,
U.S.A.
Rachael Power, M.D. Resident, Department of Psychiatry, University of Med-

icine and Dentistry of New Jersey–New Jersey Medical School, Newark, New
Jersey, U.S.A.
Nicolas Ramoz Seaver Autism Research Center and Laboratory of Molecular

Neuropsychiatry, Department of Psychiatry, Mount Sinai School of Medicine,
Ronald R. Rawitt, M.D. Seaver Autism Research Center, Mount Sinai School
of Medicine, New York, New York, U.S.A.
Jennifer G. Reichert Laboratory of Molecular Neuropsychiatry, Department

of Psychiatry, and Seaver Autism Research Center, Mount Sinai School of Medi-
cine, New York, New York, U.S.A.
Tristram Smith, Ph.D. Strong Center for Developmental Disabilities, Univer-

sity of Rochester Medical Center, Rochester, New York, U.S.A.
Sarah J. Spence, M.D., Ph.D. Assistant Professor, Program in Neurogenetics,

Departments of Neurology and Pediatric Neurology, David Geffen School of
Medicine at UCLA, Los Angeles, California, U.S.A.
xvi Contributors
Roberto Tuchman, M.D. Dan Marino Center, Miami Children’s Hospital, Mi-
ami, Florida, U.S.A.
Fred R. Volkmar, M.D. Yale University, New Haven, Connecticut, U.S.A.
Serena Wieder, Ph.D. Bethesda, Maryland, U.S.A.

1
Autism: Diagnosis and Epidemiology
Fred R. Volkmar, Kathleen Koenig, and Malia McCarthy

Yale University
New Haven, Connecticut, U.S.A.
DEVELOPMENT OF THE DIAGNOSTIC CONCEPT: EARLY

CONTROVERSIES
Leo Kanner’s (1) classic description of “autistic disturbances of affective con-
tact,” or early infantile autism, suggested that autism was an inborn, congenital
disorder in which a child comes into the world lacking the usual motivation for
social interaction. His use of the word “autism” was meant to convey this self-
contained quality but was, in some respects, an unfortunate choice of term since
it introduced some confusion with the earlier use of the word, which described
the idiosyncratic, self-centered thinking of schizophrenia. In addition to the prob-
lems in social interaction, Kanner noted the difficulties his patients had with many
aspects of symbolization, abstraction, and communication. When language was
present, it was remarkable for its literalness as well as other unusual aspects such
as echolalia and pronoun reversal. In contrast to the child’s lack of interest in
the social world, Kanner noted that there was often a remarkable oversensitivity
to the inanimate world, e.g., oversensitivites to sounds or other stimuli and sensi-
tivity to even minor environmental changes. Kanner’s description has proven
remarkably enduring and remains the fundamental basis of current definitions of
autism.
Unfortunately, various controversies complicated early work on the condi-
tion and in some instances continue to complicate interpretation of the early re-
search literature. Some of these controversies arose as a result of aspects of Kan-
ner’s original description; others related more to basic questions concerning the
1
2 Volkmar et al.
validity of autism as a diagnosis (2). For example, in his original report Kanner
mentioned that the parents of the majority of his cases were remarkably successful
academically or professionally. This led some clinicians to believe that parental
psychopathology or some aspects of early experience might have a role in syn-
drome pathogenesis, a notion incompatible with the idea that children were born
with autism. However, the question of the role of experience in pathogenesis
plagued the field for many years and was resolved only as it became clear that
when one controls for ascertainment bias there is no particular social class pre-
dominance in autism (3). Second, it became clear that children with autism have
trouble interacting with all people—not just their parents—and that problems in
parent–child interaction may arise from the side of the child and not the par-
ents (4).
Kanner initially speculated that autism was not related to other medical
conditions, but subsequent research has shown that various conditions are associ-
ated with autism, including fragile X syndrome, tuberous sclerosis, and seizure
disorders (5). An additional source of confusion arose because of Kanner’s origi-
nal speculation that children with autism were not mentally retarded. This impres-
sion reflected his observation that these children looked intelligent and that on
some parts of IQ testing they did rather well. It took several decades to realize
that poor performance on other aspects of tests of intelligence was quite real and
did not simply reflect lack of motivation or child cooperation, and that a majority
of children with autism do exhibit some degree of mental handicap (6).
Probably the main source of dispute involved the confusion of autism with
childhood schizophrenia. The speculation that autism was the earliest form of
schizophrenia was quite common in the late 1940s and 1950s (2), and compli-
cated psychological phenomena such as hallucinations and delusions were attrib-
uted to mute, autistic children. Subsequent research has confirmed that autism is
not the earliest manifestation of schizophrenia (7).
CATEGORICAL DEFINITIONS OF AUTISM

Several problems complicate the development of categorical definitions of au-
tism. First, there is a tremendous range in syndrome expression over the course
of age and intellectual level. Second, because of the communication problems
in autism, the individual often cannot be interviewed directly and so emphasis
during assessment is given to reports of parents or caregivers, with consequent
issues of reliability and validity of historical report. Third, given the broad range
of difficulties and multiple lines of development and behavior which are impacted
by autism, potentially any number of behavioral features could be included in
the definition. For example, should the emphasis be on the symptoms and signs
that most robustly differentiate one condition from another, or should it be on
Diagnosis and Epidemiology 3
features such as overanxiety and activity that may be important targets for treat-
ment?
In 1978 Rutter (8) synthesized Kanner’s original report and subsequent
research in what later became a highly influential definition of autism. This defi-
nition included four essential features: early onset; impaired social development
(not due to mental retardation); impaired communicative development (not due
to mental retardation); and unusual behaviors of the type Kanner had described,
including, for example, resistance to change, idiosyncratic responses to the envi-
ronment, and motor mannerisms. These criteria largely comprised the basis for
the definition of autism in the third edition of the Diagnostic and Statistical Man-
ual of Mental Disorders (DSM-III), in which it was included, for the first time,
as part of a new class of disorders—the pervasive developmental disorders (9).
Although the inclusion of autism in DSM-III was a major advance, the definition
proposed was not developmentally oriented and was overly stringent in some
respects. As a result, major changes were made in the revised third edition (DSM-
III-R) (10), in which the definition employed was much more developmentally
oriented but also somewhat broader than that used previously (11). Also, the
changes made increased the differences between the DSM definition and that in
the pending revision of the international diagnostic system (ICD-10). In addition
to the differences between the DSM definition and that in the definition of autism,
another major difference from ICD-10 was that the latter included a number of
new conditions within the PDD class, e.g., Asperger’s disorder, Rett’s disorder,
childhood disintegrative disorder, and atypical autism. These, and other consider-
ations, were encompassed in DSM-IV (12).
For DSM-IV, a series of literature reviews and data reanalyses were used
in an attempt to identify areas of consensus as well as controversy. A multisite,
international field trial (13) was then undertaken that included nearly 1000 cases
evaluated by over 100 raters around the world. The results suggested that a defi-
nition convergent with that used in ICD-10 had a good balance of sensitivity
and specificity. Furthermore, the data available did provide some support for the
inclusion of other conditions in the PDD class in DSM-IV. The DSM-IV defini-
tion requires the presence of at least six criteria, including at least two criteria
relating to social abnormalities (group 1) and one each relating to impaired com-
munication (group 2) and range of interests and activities (group 3) with onset
of the condition before age 3. The qualitative impairment in social interaction
can take the form of markedly impaired nonverbal behaviors, failure to develop
appropriate peer relationships, lack of shared enjoyment or pleasure, or lack of
social-emotional reciprocity. Impairments in communication can include delay
or lack of spoken language, impairment in conversational ability, stereotyped
language use, and deficits in imaginative play with no attempt to compensate for
the language problems through other means. The final group of features includes
4 Volkmar et al.
restricted patterns of behavior, interests, and/or activities, which may include

encompassing preoccupations that are abnormal in either focus or intensity, ad-
herence to nonfunctional routines or rituals, stereotyped motor movements, and
persistent preoccupation with parts of objects.
The definitions of other disorders in the PDD class in DSM-IV are much
less detailed than those for autism and undoubtedly will be further refined over
time, or, of course, the diagnostic concepts may be discarded (14). Clearly much
additional work is needed with regard to Asperger’s disorder (15). The category
of atypical autism and PDD not otherwise specified (NOS) is one that is used
broadly but also inconsistently. It almost certainly encompasses what ultimately
will be recognized as a number of different conditions (16).
DIMENSIONAL APPROACHES TO DIAGNOSIS

Dimensional approaches to the diagnosis of autism have also been developed
(17). In the simplest sense, the use of measures such as standard assessments of
intelligence, adaptive skills, or communication are examples of such instruments
(6). For autism more specific instruments have been developed, generally based
either on parent or teacher report or, in some cases, on direct observation of, or
interaction with, the child. However, these methods have some particular prob-
lems—retrospective parent reports are subject to bias, which impacts validity
and reliability, and direct observation may not capture highly unusual behaviors
that occur infrequently. Further complications are posed by changes in syndrome
expression over age and developmental level. In some cases (18,19) instruments
are specifically keyed to categorical diagnostic criteria and thus help to both for-
malize and standardize these criteria; in other cases instruments have been devel-
oped primarily for screening purposes. Typically, dimensional instruments yield a
total score that represents severity of autism; these scores may be used as dependent
measures as well. Specific instruments are extensively reviewed elsewhere (17).
EPIDEMIOLOGY
Epidemiological studies provide information regarding the prevalence of autistic
disorder and related conditions. Such studies also provide insight into aspects of
syndrome pathogenesis and natural history and are important in clarifying needs
for intervention. Well-designed, large, epidemiological studies are crucial for an-
swering the most pressing question posed in the last two decades regarding these
disorders: is the incidence of autism and pervasive developmental disorders in-
creasing? Reports of increased prevalence of these disorders in some surveys and
reports of clusters of affected children within particular geographical regions have
alarmed parents and policymakers alike. These reports have had two specific
effects: they have heightened awareness of the disorders that may impact the
delivery of clinical services and research funding, and they have established the
need for carefully done studies concerning the prevalence of autism and related
conditions.
These issues underscore the need to use standardized, rigorous procedures.
The most accurate prevalence rates are obtained when a large area is sampled,
as opposed to a clinically referred population (20). The case-finding method
should be initially overly inclusive, to guard against cases being missed. Finer
discrimination of diagnostic categories can be accomplished after an initial
screening has identified all possible cases; at this stage a critical issue is the finer-
grained distinctions between autism and related disorders, particularly since it is
clear that such distinctions are, of necessity, somewhat arbitrarily drawn (21).
Kanner’s historical description of autism was that of a behavioral syn-
drome, and provided the most narrow syndrome definition (1). In contrast, Wing
and Gould’s “triad of impairments” encompassed a much larger group (3). The
three editions of the DSM (III, III-R, and IV) provided behavioral descriptions
with varying degrees of specificity. As noted previously, DSM-III-R included
the broadest definition of autism, yielding a 40% false-positive rate for case iden-
tification, which most certainly impacted epidemiological surveys (11). In fact,
prevalence rates are positively correlated with date of publication, suggesting an
influence of syndrome definition on the calculation of rates (20). Thus, historical
changes in the classification system have affected prevalence rates, and perhaps
confounded the estimation of the “true” incidence of autism.
True epidemiological samples offer several advantages over clinically re-
ferred samples. The latter are biased toward those who need services at a particu-
lar time and families aware of the availability of such services. In fact, the use
of clinically referred samples may have contributed to the early notion that autism
was associated with higher socioeconomic class (20). Sample size influences epi-
demiological outcomes as well—smaller sample sizes have yielded greater rates
of the disorder. Confidence intervals reflect the variability within a sample, and
indicate the precision of calculation of rates (22). Epidemiological studies with
extremely wide confidence intervals show predicted rates that are likely quite
imprecise. In addition, an understanding of the way in which age trends affect
rates is needed for interpretation of epidemiological studies (20). Because
changes in the absolute number of a certain age cohort over time will influence
numbers of affected children but not rates, absolute numbers cannot be reliably
compared. Finally, case finding affects the results obtained at different ages; for
example, typically, more school-aged children with autism are identified than
preschoolers, probably an effect of case finding and not reflecting overall changes
in rates.
Lotter (23) provided one of the earliest epidemiological studies of autism,
screening 78,000 children between the ages of 8 and 10 in a borough outside of
London. The large sample size, the use of a prescreening survey, parent inter-
6 Volkmar et al.
views, and clinical assessment of identified children enhanced the reliability of

this study in accurately identifying affected children. The rate from this study
was 4.5 per 10,000, with boys more commonly identified than girls, at a ratio of
2.6:1. Several subsequent large-scale studies confirmed this rate (24,25). In con-
trast, Treffert (26) reported a rate of 0.7/10,000 in a large sample and Steinhausen
and colleagues (27) also found a lower rate (1.9/10,000). Unfortunately, these
studies had major methodological flaws in case finding and confirmation of diag-
nosis, such that the rates are probably underestimates.
Studies suggesting the highest rates (28) were most likely influenced by
the broadened definition of autism reflected in Wing and Gould’s influential paper
(3) and DSM-III-R. Onset before age 30 months was not part of the clinical
criteria; thus, many of the children included in the sample may have had social
impairments that were milder in degree or differed qualitatively from those tradi-
tionally classified within the autistic spectrum.
Fombonne (20) conducted a comprehensive meta-analysis of 23 epidemio-
logical studies of autism that encompassed over 4 million children. Consideration
of sample size and the associated confidence intervals helped to gauge the accu-
racy of each study in the estimation of prevalence. The best estimate for current
prevalence of autism was between 5.2 per 10,000, although estimates ranged
from 0.7 to 21.1 per 10,000. Estimates of the rate of pervasive developmental
disorders excluding autism was 3 per 10,000, so that for every two children diag-
nosed with autism, more than three were found to have related impairments that
nevertheless fell short of meeting strict diagnostic criteria for autism. Information
on clinical characteristics obtained from such studies provides important informa-
tion on clinical features of autism as well as its course.
Overall, the sex ratio reported in the majority of studies is 4: 1, with boys
clearly overrepresented (20). When restricted to the most severely mentally re-
tarded individuals, the sex ratio is 2: 1. Most studies indicate that when girls are
affected, they are more severely retarded; this has been taken to suggest that the
underlying insult must be more severe in girls than in boys. Alternatively, more
capable females may be less likely to be identified if their social disability is
attenuated relative to that of their male counterparts (21).
Approximately 75% of all individuals classified as autistic have measured
intelligence in the mentally retarded range (21). The majority of affected individ-
uals are in the mild and moderate range of mental retardation. When syndrome
definitions are broadened, a greater proportion of high-IQ individuals are identi-
fied.
Unequal distribution of social class in some early surveys resulted in the
unfounded conclusion that autism is more likely to occur in the higher social
classes. As noted above, careful epidemiological studies have not supported this
notion, and earlier reports most likely reflect ascertainment bias (20). A similar
sampling confound exists regarding reports of higher rates of autism in immi-
grants (29). Review of the methods used to ascertain these samples reveals that
a large proportion of immigrants moving in and out of the surveyed regions may
have skewed the estimation of rates (20). Additionally, the likelihood that fami-
lies with disabled children may emigrate to a more developed country to obtain
better services for their child should be considered.
The identification of geographical clusters of persons affected with autism
has raised suspicion regarding environmental causes of autism (30). However,
the approach taken in reviewing the incidence of autism in these clusters has
not been statistically sound (23). Rates within a geographical cluster cannot be
compared with population rates, simply because the boundaries of the cluster are
predefined in such a way as to select for autism cases. A more reliable method
is to track subsequent cases in a geographical region, or to use statistical tech-
niques that specifically evaluate the reality of the cluster phenomenon while elim-
inating bias in data collection (23). Finally, Fombonne (31) makes the point that
since autism is probably a disorder with strong genetic underpinnings, changes
in prevalence would not occur over as short a timespan as is indicated by some
studies.
COMORBID CONDITIONS
Interest in the issue of comorbidity in autism has increased in recent years. This
is a complicated issue for more general reasons as well as for reasons more spe-
cific to autism. For example, the hierarchical rules employed in official diagnostic
systems may artificially limit comorbid diagnoses, as in the current approach to
comorbid diagnosis of autism and attention-deficit disorder. On the other hand,
if all such rules are discarded, diagnoses tend to become more of a symptom
checklist. For many years it was assumed that if an individual had autism then all
his or her difficulties were a function of the autism, a notion known as “diagnostic
overshadowing” (32,33). It was as if having autism “immunized” the individual
against other disorders rather than, as would more reasonably be expected, serv-
ing as a factor that increased risk.
Autism has been reported to co-occur with various other developmental,
psychiatric, and medical conditions; some such associations are frequent while
others are quite rare. A critical statistical issue is whether such associations are
significantly more frequent than would be related by chance alone; e.g., it appears
that individuals with autism do develop schizophrenia but not at higher rates than
would be expected given the rate of schizophrenia in the general population (34).
When autism occurs at a greater-than-expected rate with another disorder, the
issue arises as to whether the two disorders are related to the same underlying
cause or whether one disorder causes the other (35).
Of the various conditions associated with autism, it is clear that mental
retardation is the most frequently associated one (6). Despite a substantial body
8 Volkmar et al.
of research into the nature of the cognitive deficit(s) involved in autism (36), the
fundamental mechanism remains unclear. Interestingly, genetic research suggests
that mental retardation per se is not one of the features commonly transmitted
in immediate family members (37). In terms of medical conditions, the most
commonly recognized associations include seizure disorders ( in perhaps 20–
25% of cases), fragile X syndrome (in about 1% of cases), and, much less fre-
quently, tuberous sclerosis (5).
Various other behavioral and psychiatric difficulties have been described
in individuals with autism. Unfortunately, much of the evidence in favor of such
associations is based on case reports; the significance of such reports is always
difficult to interpret given the bias for only positive reports to be published and
the lack of more controlled studies. Reported difficulties include hyperactivity,
obsessive-compulsive phenomena, self-injury and stereotypy, tics, and affective
symptoms (38–44). While it is clear that symptoms of these conditions can be
observed, the questions of syndromic interpretation and, more importantly, of
causal relationships are complex. For example, when is a diagnosis of Tourette’s
disorder justified? When do the perseverative and ritualistic behaviors often ob-
served in autism constitute evidence for obsessive-compulsive disorder (OCD)?
In some cases, e.g., stereotyped-movement disorder, a comorbid diagnosis of
autism is prohibited because stereotyped movements are included as a defining
feature of autism. Given the high rates of mutism and major communication
problems in autistic individuals, issues of assessment for related comorbid condi-
tions are often quite complex. Ideally what are needed are independent validators
of comorbid associations, for example, independently collected data on family
history. Family studies have suggested some important associations such as social
difficulties, language and learning problems, anxiety, and affective difficulties in
family members (37).
The issue of comorbidity might also be approached through response to
treatment. For example, it is clearly the case that phenomena reminiscent of at
least some aspects of obsessive-compulsive disorder are frequently observed in
adults with autism (45). These behaviors may respond to medications such as
selective serotonin-reuptake inhibitors (SSRIs) that have been used in more typi-
cal presentations of obsessive-compulsive disorder (44,46). However, response
to medication may be a function of many factors, and some investigators have
questioned the notion that autism and OCD are specifically related and suggested
that the seeming relationship may be a function of many factors. Various disor-
ders may be ameliorated with the same medication (e.g., tricyclic antidepressants
are helpful in the treatment of depression and enuresis, and both hyperactive and
normal children may respond to stimulant medication with improved attention).
In this context, investigators have noted that the ritualistic phenomena of autism
and typical obsessions and compulsions cannot be simply equated (47). Similarly,
there have been various reports of associations of autism with tic disorders, spe-
cifically Tourette’s syndrome (41,43,48). Diagnostic complexities including the

differentiation of tics and stereotyped motor mannerisms can be confusing, and
family data are, unfortunately, lacking.
Affective symptoms in autism include labile mood and inappropriate af-
fective responses, as well as anxiety and depression. Clinical depression and bipo-
lar disorders have been reported and may respond to pharmacological interven-
tion (49,50). Although attentional problems are frequently observed in autism, the
frequency of association with mental retardation and problems in communication
complicate the issue of whether these problems truly reflect an attentional disor-
der; in essence the two diagnoses cannot be jointly given in DSM-IV. Solid data
on this issue are lacking, although there have been occasional reports of children
with autism who respond well to stimulant medications (51). The use of such
medications and the question of comorbid attentional problems may have greater
relevance to the large group of children with PDD-NOS, in which several investi-
gators have noted a sizable subgroup with major attentional problems (16,52).
DIFFERENTIAL DIAGNOSIS
An alternative way of conceptualizing the PDDs is through a dimensional ap-
proach, which links symptom clusters with neurobiology and treatment (53). The
categorical approach of DSM provides for multiaxial assessment. The axes are
a useful tool for describing associated and underlying conditions, and tracking
changes in the developmental expression of the disorder.
Differential diagnosis of autism should begin with consideration of other
disorders within the PDD class. Other PDDs described in DSM-IV include Rett’s
disorder, childhood disintegrative disorder (Heller’s syndrome), Asperger’s dis-
order, and PDD-NOS.
Rett’s disorder and childhood disintegrative disorder present after a period
of apparently normal development. Fortunately, both conditions are quite rare.
Rett’s disorder, described by Andreas Rett in 1966 (54), is characterized by decel-
eration of head growth, loss of purposeful hand movements with substitution of
hand-washing stereotypies, motor and language impairment, mental retardation,
and loss of social engagement. This disorder has been described primarily in
girls. Childhood disintegrative disorder, originally described by Heller in 1906,
is distinct from autism and often associated with severe mental retardation. It
presents after a minimum of 2 years of normal development and affects children
in multiple areas of functioning, including deterioration in two of the following
five areas—language functioning, social skills, toileting, play, and motor skills—
as well as abnormal functioning in two of the three symptom clusters of autism.
Underlying neuropathological processes may be identified in some cases (55).
Asperger’s disorder was initially described in 1944 (56). It differs from
autism in that language and cognition are generally preserved, and unusual behav-
10 Volkmar et al.
iors and unusual environmental responsiveness are less likely to be present. Social
behavior is characterized by a desire for social relationships coupled with an
impaired ability to participate in a reciprocal fashion. Circumscribed interests,
about which the child may speak in a pedantic way, are frequently seen. Motor
deficits may be prominent, and, unlike the characteristic profile in autism, verbal
IQ may be significantly higher than performance IQ. Asperger’s disorder is gener-
ally diagnosed later than autism.
PDD-NOS is the diagnosis reserved for cases that do not meet the full
criteria for autism disorder. The majority of children diagnosed with a PDD carry
this diagnosis, which in DSM-IV was broadened so that instead of having deficits
in social interaction and deficits in communication or restricted interests, one
need only have difficulties in any one of the three spheres.
In addition to the various other PDDs, other conditions sometimes present
in ways suggestive of autism. For children with hearing deficits, disability in
spheres other than communication should be relatively preserved. Other disorders
in which presentation may mimic aspects of autism include untreated seizure
disorders, developmental language disorder, stereotyped movement disorder, and
psychotic disorders. Severe or profound mental retardation may involve stereoty-
pies and may resemble autism except that social and communicative functioning
is intact relative to the individual’s overall level of functioning. Other disorders
to be considered in the differential diagnosis of autism include selective mutism,
OCD, reactive attachment disorder, social phobia, and schizoid and avoidant per-
sonality disorders (57).
Associated medical conditions may, in an apparent minority of cases (esti-
mated between 10% and 25%) underlie autistic-like presentations (58,59). Spe-
cifically, fragile X syndrome and tuberous sclerosis are seen with greater-than-
chance frequency in the autistic population. Associations with congenital rubella,
cerebral palsy, phenylketonuria, neurofibromatosis, and Down’s syndrome ap-
pear to occur at chance rates in individuals with autism (58).
CONCLUSIONS
In summary, Leo Kanner’s description of autism has remained the fundamental
basis of current definitions. Categorical definitions, while useful, have impacted
epidemiological estimates and research strategies. Further work is required in
delineating the diagnoses of Asperger’s disorder, Rett’s disorder, and childhood
disintegrative disorder. Perhaps most critical for exploring neurobiological mech-
anisms, the diagnosis of PDD-NOS will benefit from further refinement: dimen-
sional definitions may prove to be the best strategy for elucidating this broad
diagnosis. Given that dimensional definitions will be most useful in linking the
neurobiology of the disorders to specific symptom clusters, greater refinement
of instruments measuring various dimensions of symptomatology is needed.
The available evidence does not support the view that the prevalence of
autism, or autism spectrum conditions, is increasing. Studies that report higher
prevalence rates consistently demonstrate methodological flaws in ascertainment
and sampling, and widely varying syndrome definitions. Most studies confirm a
sex ratio of 4:1, although some have suggested that girls may be underrepresented
for a variety of reasons. No conclusive evidence supports the contention that
children with autism are likely to come from the higher socioeconomic classes,
and, similarly, no evidence exists to support the view that immigrants have higher
rates of the disorder than nonimmigrants.
Investigation of comorbid conditions in PDDs is critical for clarifying neu-
robiological mechanisms and designing appropriate intervention. Family genetic
studies are a useful methodology for identifying the presence of comorbid condi-
tions. Data supporting whether associations arise by chance or at a greater-than-
chance rate are critical as well. The current nosology will be enhanced by greater
certainty regarding associated conditions combined with more precise conceptu-
alization of these conditions.
ACKNOWLEDGMENTS
This work was supported by National Institute of Child Health and Development
grant 1 P01 HD35482-01 and Yale Children’s Clinical Research Center grant
M01 RR06022, the General Clinical Research Centers Program, the National
Center for Research Resources and, the National Institutes of Health.
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2
Core Symptoms, Related Disorders,
and Course of Autism
Eric Hollander and Caralynn V. Nowinski

INTRODUCTION
Autism, originally described by Kanner in 1943, is among the most severe of all
neurodevelopmental disorders. It is a pervasive disorder associated with substan-
tial deficits in reciprocal social interaction and communication, and the presence
of repetitive and stereotyped behaviors and unusual interests (1). These classic
features of autism typically appear in infancy, and the syndrome, by definition,
is always present by the age of 3 years. Its manifestations and course often change
throughout development, yet autism remains a chronic, lifelong, and disabling
condition.
Epidemiological studies indicate a lifetime prevalence of autistic disorder
of five to 17 per 10,000 individuals, with the rate of autism among siblings esti-
mated even higher, between 50 and 175 per 10,000 (2–4). Recent reports of
the rising incidence of autism have generated considerable support for increased
research into the causes and treatment of autism (5). Of note, the Child Health
Act of 2000 was the first U.S. governmental initiative to specifically address the
need for comprehensive research to elucidate the presumably complex causes and
nature of this disorder, thereby aiding diagnosis, detection, prevention, prognostic
accuracy, and treatment.
Autism is a developmental disorder and, as such, symptoms and behaviors
change over the course of development. It is heterogeneous with regard to clinical
15
16 Hollander and Nowinski
symptoms—there is a wide range of abilities and varied patterns of deficit within

the autism spectrum. While every individual with autism has a slightly different
presentation of the disorder, the symptoms can be classified in terms of three
core domains, the focus of this chapter. Briefly, these core symptom domains
are: 1) social interaction, 2) speech/communication, and 3) compulsive/repetitive
behaviors.
THE AUTISM SPECTRUM

The great heterogeneity of autism clearly impacts the study of this population,
and autism researchers and clinicians often describe a continuum referred to as
the autism spectrum to encompass the broad range of and clinical differences
in symptomatology, developmental course, functioning, and treatment response.
“Classic autism” is thought to lie on a broader spectrum, and thus related disor-
ders are referred to as “autism spectrum disorders.” The psychiatric diagnostic
systems—the fourth edition of the Diagnostic and Statistical Manual of Mental
Disorders (DSM-IV) and the tenth edition of the International Statistical Classi-
fication of Diseases and Related Health Problems (ICD-10)—have outlined the
disorders that lie on this spectrum, namely Autistic disorder, Asperger’s disorder,
childhood disintegrative disorder (CDD), Rett’s disorder, and pervasive develop-
mental disorder–not otherwise specified (PDD-NOS), under the larger category
of pervasive developmental disorders (PDD) (1,6). Although included within the
broad category of PDD, Rett’s disorder tends to be classified and studied sepa-
rately because of its distinct course and neurological presentation. Rett’s disorder
and CDD appear rarely and have unusual clinical presentations.
Over the past two decades, the idea of the autism spectrum has gained
much support. Various epidemiological and family studies have demonstrated
the link between the disorders in the PDD family and asserted the validity of the
concept of an autism spectrum (e.g., Ref. 7). The DSM-IV uses a categorical
approach to diagnoses, dividing mental disorders according to sets of diagnostic
criteria that define the disorder. Autistic disorder is included within the DSM-
IV category of PDD, which also includes Asperger’s disorder and PDD-NOS,
the two most autistic-like diagnoses within the group. However, the literature
supports the idea of a dimension rather than discrete, well-defined clinical groups.
Since the DSM-IV and ICD-10 do not account for individuals who do not fully
meet the criteria for a specific neurodevelopmental disorder, milder variants of
autism have been termed borderline autism, atypical autism, or simply autism
spectrum disorders.
While there is general agreement on the diagnostic criteria for autistic disor-
der, there is less reliable use of the criteria for related disorders. For instance,
there is considerable disagreement about whether Asperger’s disorder can be
meaningfully differentiated from high-functioning autism. Asperger’s disorder
Symptoms, Related Disorders, and Course 17
involves social deficits and repetitive, restricted interests but no delay in the de-
velopment of language, cognition or age-appropriate self-help skills. Thus, it is
difficult to clinically distinguish it from high-functioning autism, i.e., an individ-
ual with autism who also has average intellectual functioning and no language
delay.
Differences among autism spectrum disorders seem to be linked to intelli-
gence, level of adaptive functioning, and number of autistic symptoms rather
than to the presence of distinct symptoms. Yet, if one takes a dimensional view
of the pervasive developmental disorders, one can clearly see that the three core
areas of deficit that define autism manifest in various ways and to varying degrees.
Social impairments may range from inappropriate seeking of affection from
strangers to complete withdrawal. Communication deficits can range from good
language abilities with deviant language use within a social setting to mutism.
Impairments in behavior and activities may range from an ability to engage in
symbolic play but a preoccupation with one limited interest to a constant involve-
ment in nonfunctional repetitive actions. The child with autism may be mute but
able to perform certain sophisticated technical actions. These often contradictory
symptoms make sense within the idea of an autism continuum.
Autism does not appear to be a reflection of a single gene defect; rather,
several genes may play a role in shaping the core and associated symptoms of
this disorder. Moreover, autistic symptoms may be a final common pathway re-
sulting from a variety of genetic and/or environmental factors (e.g., birth compli-
cations, exposure to toxins, etc.) affecting various brain systems. The disorder
presents a broad phenotype, with multiple clinical symptoms of differing severity
from the three core symptom domains: social interaction, communication, and
repetitive behaviors. Current literature describes the “broad autism phenotype”
(BAP) to represent the wide range of symptoms observed in individuals with
autism spectrum disorders. Defining the BAP allows researchers to study autism
spectrum disorders by including individuals, specifically siblings, with autism-
related symptoms into population samples (8,9). By using larger samples in re-
search, scientists can increase the level of confidence that their findings are accu-
rate and significant. The more inclusive definition has been particularly useful
in examining the genetic influence on autism by studying groups of subjects with
similar phenotypes or symptom presentations (e.g., Ref. 10).
Our understanding of the numerous presentations of autism and how they
relate to variations within the normal population is still unclear. The three core
deficits can be viewed on a dimension, with the milder variants falling within
the BAP and the severe variants, when all are present concurrently, forming the
classic autistic phenotype. Since autism is a developmental disorder, its symp-
toms may change over the course of illness in line with important changes in brain
development, making it even more difficult to diagnose and treat this disorder.
Comorbid neurological conditions, e.g., mental retardation and seizure disorder,
also complicate the picture. To some extent, better definition of clinical symptoms
through the development of valid and reliable diagnostic instruments, such as
the Autism Diagnostic Interview–Revised (ADI-R) (11), has allowed for the col-
lection of more homogeneous, or similar, study populations. Nevertheless, the
above issues of heterogeneity, developmental variation, neurological comorbid-
ity, and multiple-gene involvement contribute to difficulty in determining the
neurobiology, brain mechanisms, and selective treatment response of autism.
A significant limitation in research on the neurobiology and treatment of
autism has been the lack of attention to this heterogeneity and comorbidity. It
remains to be seen whether the disorders on the autism spectrum have multiple
etiologies and varied neural systems but result in the same core deficits that define
the spectrum—social, communication, and repetitive behaviors—or whether
there is a specific, common neural substrate that underlies autism, with different
cases showing different levels of severity of symptoms. Since multiple genes
appear to be involved in autism (e.g., Ref. 12), it may be hypothesized that spe-
cific genes may be linked to specific behavioral dimensions. It is the complex
interaction of these genes that gives rise to the overall clinical picture. Environ-
mental factors have been viewed as possible “second hits” that, in the context of
the BAP, lead to more severe deficits and produce the classic autistic phenotype.
Questions remain regarding the boundaries of this broader autistic phenotype.
For example, are features of one of the dimensions alone necessary or are deficits
from all three dimensions required in order to fall within the spectrum?
CATEGORIZING AUTISM
One potentially fruitful approach to increasing our understanding of autism in-
volves better characterizing specific core symptom domains and associated symp-
tom features of autistic phenomenology. The DSM-IV clearly identifies three
core dimensions of autism: 1) social interaction, 2) speech/communication, and
3) compulsive/repetitive behaviors (1). The categorical approach of the DSM-
IV specifies that patients must have at least one abnormality in each of the three
dimensions to meet criteria for autistic disorder (1). Despite prior views that the
social and language domains were inseparable, these deficits have been shown
to occur in isolation and neither appears to be a result of the other (13). Further-
more, the DSM-IV field trial for autism supports the independence of all three
dimensions and the necessity of symptoms in each domain to accurately diagnose
autism (14).
Since the late 1970s, researchers have attempted to categorize autistic pa-
tients to better define the population. A recent review of approaches to subtyping
autism (15) describes four methods: 1) social interaction/communication subtyp-
ing, 2) intellectual/developmental level and adaptive functioning subtyping, 3)
medical condition/biological subtypes, and 4) combination subtyping. Social

interaction/communication subtypes date back several decades and include the
longstanding Wing system (aloof, passive, active-but-odd) (16) as well as more
recent classification systems based on affective reciprocity, joint attention, and
theory of mind (17). Subtyping by intellectual/developmental/functioning level
appears to be a simple means of indicating autistic subtype. The Autism and
Language Disorders Nosology Project specifically demonstrates benefits from
subtyping autistic individuals as either high- or low-functioning (18–20). On the
other hand, biological/medical subtypes may be useful for only a small subset
of the autistic population. Rutter shows that only 10% of autistic cases can be
easily separated on the basis of comorbid medical condition (21). Such cases
include individuals with fragile X syndrome, tuberous sclerosis, neurofibro-
matosis, hypomelanosis of Ito, marker chromosome, Moebius syndrome, or
Rett’s syndrome (22).
Most recently, success in the advancement of autism research has resulted
from characterizing subjects based on core symptom domains. For example, ge-
netic studies have applied a dimensional approach to identify potential chromo-
somal regions that may contribute to autism (e.g., Ref. 10). It is encouraging that
results gained from this approach have been replicated (23). Replication with
different subject samples lends more credibility to the findings. Family studies
have demonstrated that these core symptom domains run in families (24,25).
Similarly, pharmacological treatment studies with fluvoxamine (26) and risperi-
done (27) demonstrate the value of such a dimensional approach in measuring
response to treatment and potentially identifying subjects responsive to specific
treatment approaches, whereas earlier treatment studies focused on global sever-
ity. The effects of these drugs on different core dimensions were evident. Fluvox-
amine targeted all three dimensions, causing improvements in repetitive
thoughts/behaviors, social relatedness, and language usage, while risperidone tar-
geted repetitive behaviors/restricted interests with no measurable change in social
behavior and language.
Nevertheless, it is still necessary to determine whether each dimension has
distinct neurobiological/genetic mechanisms and differential treatment response.
Other associated problem behaviors occur within the autistic syndrome (atten-
tional difficulties, self-injurious behavior, mental retardation, self-stimulation, af-
fective instability, EEG abnormalities), but the three core symptom domains ap-
pear to be necessary and minimum dimensional components of the syndrome.
Thus, by identifying and clarifying specific components that drive the autistic
syndrome from a dimensional standpoint, we are in a better position to determine
neurobiology, pathophysiology, and targeted treatment of the specific autistic di-
mensions. A dimensional approach to the study of autism is valuable in linking
key symptoms to the neurobiology and treatment of the disorder in a clinically
meaningful way. It offers the opportunity to identify appropriate treatments and

understand the behavioral, educational, and social needs of the developmentally
disabled individual from a symptom-targeted approach.
THE CORE SYMPTOM DOMAINS

Postulating core autistic symptom domains is an essential first step not only for
clarifying the nature of the disease but also for developing individualized treat-
ments for specific symptom dimensions. Although there is reason to believe that
the three hypothesized dimensions (social, communication, repetitive behaviors/
compulsivity) have distinct neural bases as stated above, it remains unresolved
at this point to what extent they are truly orthogonal and independent or are
overlapping and influence one another. Although the domains may be indepen-
dent such that elemental behaviors are nonoverlapping, an interdependence exists
such that symptoms present within a single domain are insufficient in differentiat-
ing autism from other developmental disorders. Lord et al. (28) demonstrated
this phenomenon by showing that correlations exist between the domains as mea-
sured by scores on the Autism Diagnostic Observation Scale–Generic. Figure 1
depicts the dimensional model and suggests that a complex interaction exists
among the core symptom domains. This model presupposes an interdependent
relationship among the domains of autism, accounting for the BAP described in
the literature.
Figure 1 The core dimensions of autism, plus associated features and related disorders.
In this section, we describe three core dimensions of autism: the social

domain, the communication domain, and the repetitive behaviors/compulsivity
domain. These three dimensions overlap with other disorders. The social dimen-
sion extends into the areas of personality disorders (schizoid and schizotypal)
and social anxiety (social phobia) and presents such features as lack of empathy,
hypersensitivity to criticism, poor rapport, reduced emotional responsiveness, and
the single-minded pursuit of special interests. The communication dimension
shares commonalities with the primary language disorders and includes pragmatic
language difficulties as well as excessive and deficient communicativeness. The
repetitive behaviors/compulsivity dimension overlaps with obsessive-compulsive
disorder (OCD). This section outlines the three core symptom domains from a
clinical perspective, and presents selected examples from the literature that high-
light the utility of a dimensional approach in the research of autism.
The Social Domain

The social deficits of autism, which have been extensively studied from a phe-
nomenological standpoint, consist of failure to develop reciprocal social interac-
tions and difficulty with social relatedness (i.e., the inability to view situations
from another person’s standpoint). Social deficits are present in all individuals
with autism spectrum disorders. They include impairments in various nonverbal
behaviors, such as aversion to eye-to-eye gaze, limited range of facial expression,
inappropriate body postures and gestures, a disinclination to spontaneously seek
shared interests and enjoyment in activities, and a lack of social and emotional
interchange. Autistic children fail to develop relationships with their peers to the
extent appropriate to their developmental level. While autistic children may be
affectionate and may have an interest in participating in social interactions, such
interactions are often with inanimate objects, animals, and adults, more than with
peers. Autistic individuals lack the fundamental ability to understand what others
are thinking or expecting, to recognize verbal and nonverbal social cues, and to
visually comprehend emotional expression (29). Often, social impairments are
the first observable and identifiable autistic impairments. Deficits in social skills
can be observed in the first 6 months of life, including impaired early anticipation
of being held or social smiling (30). Joint attention with mothers, which normally
develops within the first year, does not occur in most cases of childhood autism
(31).
As mentioned above, Wing and Gould described three subtypes of children
with autism: “aloof,” “passive,” and “active but odd” (16). The aloof children
had little interest in social interactions, seemed oblivious to the social world
around them, avoided eye contact, and were nonresponsive to verbal contact.
Children of the passive subtype showed little spontaneity or pleasure in social
interactions but did passively accept other people’s approaches. The active-but-
odd children were more spontaneous in their social approaches, but these were
odd and idiosyncratic. They were more aware of other people’s emotional reac-
tions. An example is an autistic child who approaches adults to feel their clothes
or hair.
The social dimension extends into the areas of personality disorders, e.g.,
schizoid and schizotypal personality, and social anxiety or phobia, although autis-
tic patients exhibit only selected symptoms of these disorders and do so in combi-
nation with a variety of behaviors from the other domains. There is overlap of
autistic social deficits with schizoid personality disorder, in which there is a de-
tachment from social relationships and a restricted range of emotional expression.
Wolff and Chick (32) described a group of children diagnosed with schizoid
personality disorder as resembling those with Asperger’s syndrome but differenti-
ating from children with autism spectrum disorders by the absence of delayed
language development, emotional unresponsiveness, gaze avoidance, and
ritualistic/compulsive behaviors. These children did, however, display features
of social isolation, reduced capacity for empathy, hypersensitivity, rigidity of
mental set, and an odd style of communication.
In schizotypal personality disorder, there is a pervasive pattern of social and
interpersonal deficits. Affected individuals experience considerable discomfort
in close intimate relationships, exhibit eccentric behavior, and display distinct
cognitive and perceptual distortions. They have significant social anxiety, which
is associated with suspiciousness of other people’s motives. Both schizoid and
schizoptypal personality disorders have a higher prevalence among first-degree
relatives of those diagnosed with schizophrenia.
The individual with social phobia fears social/performance situations, such
as exposure to unfamiliar people in which embarrassment may occur. Exposure to
the feared situation leads to the anxiety response, which in turn leads to significant
avoidance behavior, and, if chronic, the disorder overlaps significantly with
avoidant personality disorder. A significantly higher rate of social phobia has
been found in the family members of nonmentally retarded individuals with au-
tism (33).
Using a dimensional approach in autism research has been useful in charac-
terizing the social domain. For example, researchers have examined the role of
neuropeptide systems, specifically the oxytocin system, in relationship to this
symptom domain in determining possible etiological factors leading to autism.
Studies of highly social and asocial animal species have documented increased
oxytocin receptor density in limbic structures such as the anterior cingulate gyrus,
which has been implicated in autism (34). This finding suggested that peptide
systems, particularly the oxytocin system, may promote normal and appropriate
social functioning. Panksepp first hypothesized that a failure to shift oxytocin
receptor density from an infantile to a mature pattern may underlie the develop-
ment of autism (35). Decreased levels of plasma oxytocin have been found in
autistic children compared with normal control subjects, and social impairments
were associated with changes in plasma oxytocin levels (20,36). While normal
children showed an increase in plasma oxytocin levels, children with autism
failed to show a similar developmental increase in levels. Furthermore, elevated
levels of oxytocin were associated with lower functioning in skills of daily living
and interpersonal relations in autistic subjects, unlike normal children who exhib-
ited a positive association (36).
To better clarify the role of oxytocin, Green and colleagues (37) investi-
gated precursor peptide forms of oxytocin. They found elevated oxytocin precur-
sor peptide levels in contrast with reduced plasma oxytocin levels, which may
indicate incomplete processing of oxytocin prohormone in autism (37). A pro-
cessing deficiency is likely due to other biochemical factors, e.g., prohormone
convertases, although future studies must address these patterns of alteration.
Green et al. propose a genetic explanation for oxytocin processing and regulation
and describes such an investigation as the next step in studying the relationship
among social impairment, the oxytocin system, and autism (37). This example
describes the utility of focusing on symptom domains in autism and linking these
with underlying neurobiological/genetic mechanisms that could potentially con-
tribute to the development of targeted treatment approaches for individuals with
autism.
The Communication Domain

The speech and communication deficits in autism include mutism, echolalia, idio-
syncratic uses of speech, and deficits in pragmatic use of speech, or the ability
to use speech in its fullest social context to interact with and navigate through
the world. The ability to use speech to facilitate reciprocal social interactions is
grossly impaired. Speech is often repetitive and stereotyped, containing echolalia
and neologisms. There is overlap between the speech and communication deficits
in autism with the expressive and receptive-expressive language disorders. While
some children with primary language disorders exhibit social withdrawal, they
are differentiated from individuals with autism by the absence of core social
deficits and of repetitive and stereotypic behaviors.
Symptoms in the communication domain may refer to nonverbal communi-
cation as well as presence and level of phrase speech and the age at which it
occurs. Communication and language deficits in autism include a delay in or lack
of development of spoken language. Autistic individuals who do develop lan-
guage have an impaired ability to initiate and sustain a conversation and demon-
strate severe deficits in the use of language, as described above. On the other
hand, those with Asperger’s disorder, by definition, have no language delay or
mental retardation. While individuals with Asperger’s develop language at
roughly the same age as normally developing children and have grossly intact
speech and communication skills, they too frequently show some deviance in the
language dimension, particularly in their pragmatic language skills, such as the
use of idiosyncratic tone and volume, a formal, professorial style of speech, and
difficulty using speech to interact fully with the world.
As briefly described above, recent research advances have resulted from
looking at the BAP. This approach has been particularly useful in studying defi-
cits in the communication domain. By extending the definition of autism beyond
that of classic autism, researchers can include subjects with milder variants, such
as PDD-NOS and Asperger’s syndrome. Studies that examined milder language
phenotypes found higher rates of language impairment in relatives of autistic
patients. In particular, one twin study revealed a familial relationship in impair-
ment in nonverbal communication and verbal/nonverbal status as shown by the
ADI-R (38). Therefore, the use of language/communication as a means to subtype
autism appears to be a logical approach for genetics studies (39).
By specifically looking at the language phenotype, investigators may have
an increased ability to locate genes contributing to the BAP (40). Silverman et
al. (25) found reduced variation within families compared with between families
in the level of deficits in nonverbal communication, the presence of phrase
speech, and the age of onset of phrase speech. Although increased similarity
among biologically related siblings does not directly implicate genetic factors
(environmental factors might also explain evidence of “familiality”), the familial
factors identified led to obvious ways in which families might be stratified
for molecular genetic studies. In their sample, Silverman et al. found that the
variance within siblings was reduced for the repetitive behavior domain and
for delays in and the presence of useful phrase speech. These features and also
the nonverbal communication subdomain provided even somewhat stronger evi-
dence of familiality when the authors restricted the sibling groups to include only
those carrying the narrow diagnosis of autism to define multiply affected sibling
groups.
In accordance with these findings of familial patterns in the communication
domain, Buxbaum and colleagues (10) found that restricting autism-affected rela-
tive pairs to those with phrase speech delay was useful in locating an autism
susceptibility gene. Restricting the analysis to the subset of families with two or
more individuals having a narrow diagnosis of autism with phrase-speech delay
generated increased scores for linkage probability (10). An earlier linkage study
used a stricter definition of autism than that defined by the DSM-IV or the ADI-
R, specifically in language-impairment criteria, yet produced strong linkage that
implicated chromosome 7 as a susceptibility gene (41). A more recent study
showed that linkage signals on chromosomes 7 and 13 were due primarily to the
language phenotype (23). Such studies provide evidence for the usefulness of
subcategorizing families based on symptoms within the communication domain,
particularly in linkage analyses.
The Repetitive Behaviors/Compulsivity Domain

Compulsive and repetitive behaviors have also been studied in light of core di-
mensions of autism. Compulsive behaviors include craving for sameness, need
for uniformity, hoarding, narrow restricted interests, and unusual preoccupations
and activities. Motor stereotypies such as hand flapping and finger flicking are
often, but not universally, present. Autistic individuals may rigidly adhere to
routine and become extremely agitated when there are sudden changes, or they
may engage in nonfunctional rituals. They generally show little curiosity in ex-
ploring the environment and may rather repetitively examine or handle particular
objects. Compulsive symptoms often persist into adulthood and can include stereo-
typic pacing, rocking, perseveration, stuttering, need for sameness, and narrow
repetitive interests (42).
There is a significant overlap between this dimension and OCD. Individuals
with both disorders experience the need for routine and order and experience
anxiety when this is disrupted. There is also a high rate of comorbidity of these
disorders. It is frequently diagnostically challenging to differentiate between au-
tism and OCD; however, the nature of the obsessions and compulsions of the
autistic individual may differ from those of the individual with OCD. McDougle
and colleagues (43) compared the types of obsessions and compulsions exhibited
by adults with autism and adults with OCD. They found that in the autism group,
compulsions were more common than obsessions and no patient had obsessions
alone. In contrast to the OCD patients, the autism group’s repetitive behaviors
frequently involved ordering, hoarding, telling and asking, touching, tapping, rub-
bing, and self-mutilation. The commonly reported OCD compulsions of cleaning,
checking, and counting were less common. The autism group had significantly
fewer obsessions involving aggression, sex, religion, symmetry, contamination,
and somatic concerns. Since autistic symptom complexes often resemble the com-
pulsive symptoms associated with OCD, research has investigated systems impli-
cated in OCD to account for repetitive behaviors/compulsivity dimensional
symptoms observed in ASD.
The serotonin (5-hydroxytryptamine, 5-HT) system is the most consistently
implicated neurotransmitter system in the pathophysiology of autism. As first
reported by Schain and Freedman in 1961 (44), elevated whole blood 5-HT levels
have been observed in up to one-third of autistic individuals. Affected individuals
in multiplex families (families in which more than one member has a diagnosis
of autistic disorder) have even greater rates of increased 5-HT levels than individ-
uals from singleton families (108). Studies that alter levels of peripheral
and central 5-HT suggest that disturbing the serotonin system exacerbates repeti-
tive and OCD-like behaviors, and a net deficiency in serotonergic function has
been proposed as being responsible for autistic symptomatology in this domain
(45).
For example, studies of acute tryptophan depletion (46) and sumatriptan

challenge (47) in autistic subjects demonstrated an inverse relationship between
lower 5-HT levels and greater repetitive behaviors and compulsivity. In the suma-
triptan study, Hollander et al. (47) found that the sensitivity of the 5-HT1D recep-
tor—measured by growth hormone (GH) response to sumatriptan—was posi-
tively correlated with the severity of the repetitive behavior domain rather than
the severity of the overall autistic symptom complex or the other symptom do-
mains. This suggests that a specific component of the 5-HT system, the 5-HT1D
receptor, may play a role in mediating one core symptom domain—the repetitive
behavior domain—rather than global severity in autism. Serotonin reuptake in-
hibitors, such as clomipramine, and selective serotonin-reuptake inhibitors
(SSRIs), such as fluoxetine, are promising treatments in addressing the repetitive
behaviors/compulsivity domain. Decreases in repetitive behaviors, as well as im-
provements in other domains, have been observed (26,48–53).
Interestingly, the oxytocin system has also been associated with obsessive-
compulsive symptoms (54,55), and hence it has been implicated in the repetitive
behavior domain of autism in addition to the social domain. Green et al. (37)
found a positive correlation between oxytocin peptide levels and the presence of
stereotypic behaviors in autistic subjects. Additionally, Hollander and colleagues
(56) demonstrated that synthetic oxytocin infusion significantly decreased the
severity of symptoms in the repetitive behavior domain in adults with autism.
These results suggest that dysfunction of the oxytocin system might contribute
to characteristics of autistic disorder beyond those of the social dimension,
strengthening the theory that oxytocin dysfunction plays a role in the etiology
of autism. Furthermore, the findings are potentially clinically relevant in helping
to evaluate the contribution of oxytocin to the repetitive behavior domain in au-
tism and complement prior studies that link this behavioral domain to specific
alterations in serotonin subsystems.
Neuroimaging studies propose that autism may be characterized by structural
and functional alterations in the anterior cingulate gyrus. Using MRI and PET
coregistered scans, one study (57) showed that the right anterior cingulate area
was significantly smaller in relative volume and less metabolically active in autistic
patients compared with matched controls. A follow-up to this study (58) examined
volume and activity of not only the cingulate but also the amygdala and hippocam-
pus in patients with autism spectrum disorders and matched controls. Significant
metabolic reductions in both the anterior and posterior cingulate gyri and reduced
volume in the right anterior cingulate gyrus were visualized in the patients with
autism spectrum disorders; however, no group differences in either metabolism
or volume were found in the amygdala or hippocampus. A study of the effects of
fluoxetine on regional cerebral metabolism in adult patients with autism spectrum
disorders showed significantly higher metabolic activity in the right frontal lobe
following fluoxetine treatment, especially in the anterior cingulate gyrus and the
orbitofrontal cortex (52). Unmedicated patients with higher metabolism in these

areas were more likely to respond favorably to fluoxetine, indicating that higher
cingulate gyrus metabolic rates at baseline may predict SRI response.
Once again, as with the social and communication domains, we see the
utility of treating and studying autism according to a dimensional approach.
ASSOCIATED FEATURES AND RELATED DISORDERS

In addition to the complex and variable expression of its core symptoms, autism is
further complicated by the frequent presence of comorbid impairments, including
mental retardation, seizures, affective instability, impulsivity, aggression, and
self-injurious behavior.
There is an association between mental retardation and autistic disorder,
with 75% of autistic individuals functioning in the retarded range (59,60),
whereas only 30% of individuals in the BAP have mental retardation (3). A key
criterion in the diagnosis of autism is the establishment of a discrepancy between
the child’s level of social function and the overall cognitive and adaptive function
(61). Research has demonstrated specific profiles on cognitive batteries, with
spared performance on tasks that rely on rote, mechanical, or perceptual processes
and deficits in performance on tasks requiring higher-order conceptual processes,
reasoning, interpretation, integration, or abstraction (61). Typically, verbal IQ is
significantly lower than nonverbal IQ. The presence of low IQ, severe autistic
symptoms, and lack of meaningful communication before the age of 5 years may
be predictive factors for poor adult outcome (62). Although the popular movie
image of the individual with autism is that of an “autistic savant,” this phenome-
non is actually quite rare.
Epilepsy develops in approximately 20% to 33% of autistic individuals
(13,63,64). A recent review of epidemiological studies indicated that the median
prevalence rate of epilepsy in autism is 16.8% (2). Generally, peak occurrences
are prior to age 5 and at adolescence (63–68). It was found that autism symptoms
preceded seizures in the infantile autism cases (69). Of note, major risk factors
for epilepsy include severe mental deficiency and motor deficits, while perinatal
maternal disorder, difficult perinatal course, and family history of epilepsy were
not risk factors. Volkmar and Nelson (64) found that autistic patients with IQ
scores below 50 were particularly likely to develop seizures (84.1%), and females
were slightly more likely than males to suffer from seizures. Likewise, Rutter
(70) found that seizure disorder regardless of age of onset in autistic patients is
negatively associated with IQ and presumably with ultimate outcome.
Various types of seizures occur in autism, including infantile spasms, com-
plex partial seizures, absence seizures (typical and atypical), generalized tonic
clonic seizures, and myoclonic seizures (64,71). The most common types of epi-
lepsy in autistic populations are generalized tonic-clonic, and atypical absence,
followed by myoclonic and partial seizures, followed by atonic seizures and in-
fantile spasms (67). In addition to the high rate of seizures, approximately half
of all persons with autism have abnormal EEGs that demonstrate nonspecific
abnormalities including focal slowing, generalized slowing, focal or centropari-
etal spikes, bilateral or multifocal spikes, and generalized spikes (72). Studies
have failed to establish specific patterns of pathology (72,73).
Psychiatric symptoms of affective instability, aggression, impulsivity, and
self-injurious behavior are also common associated features of autism. Lainhart
and Folstein (74) reviewed 17 published cases and found 35% of the autistic
individuals to have an affective disorder. Among patients with Asperger’s syn-
drome, 24% were found to have an affective disorder. Recent data suggest that
depression is common among mentally retarded, emotionally disturbed patients
(75), and one study (76) estimates the prevalence rate at 9% for depressive mood
in that population. However, depression may be underdiagnosed in autism; symp-
toms of depression may be confused with autistic symptomatology and, because
of difficulties of communication, are rarely reported by the afflicted individual.
This may explain why most reported cases of affective disorder in autism have
described patients with higher levels of intelligence and better verbal skills (77).
Increased rates of affective disorders in first-degree relatives of autistic
probands would lend support to the diagnostic validity of affective disorders in
this population (74). Studies have reported increased rates of bipolar disorder
(78) and elevated rates of major depressive disorder and social difficulties (33,79)
in relatives of autistic probands compared to controls. Bolton et al. (80) found
that the rate of affective illness (minor/major/bipolar disorder) in first-degree
relatives of autistic probands was twice as high as in Down’s syndrome controls
(35% vs. 17.3%). In autistic probands, the proportion having a positive family
history of mood disorders increases significantly when the proband receives a
diagnosis of depression (81).
Aggression, both self- and other-directed, is another common associated
feature of autism (82), as is impulsivity (83). In a report on comorbid diagnoses
in autism, Tsai found a prevalence rate of 25–43% of self-injurious behavior,
considered to be one form of aggression, in autistic children, a finding supported
by other independent studies (76,84,85). The prevalence rate of self-injurious
behavior is 2–9% among noninstitutionalized mentally retarded individuals and
up to 40% among institutionalized mentally retarded individuals (86,87). Esti-
mates of aggressive behavior in mentally retarded individuals range from 8.9%
to 24% (88,89), with rates of up to 45% of institutionalized mentally retarded
individuals (90). Of child patients with autism entered into a placebo-controlled,
double-blind study of fluoxetine treatment, approximately 50% presented with
aggressive behavior as a significant comorbid symptom (Hollander et al., unpub-
lished data). There is also evidence of increased expression of an impulsivity trait
in relatives of autistic probands (91).
The variety of associated features and comorbid disorders undoubtedly con-

tributes to the complex presentation of autism spectrum disorders. Similarly, as
discussed in the next section, the course of autism is also extremely variable.
THE COURSE OF AUTISM

Autism stays true to its classification as a neurodevelopmental disorder with
symptoms varying throughout the affected individual’s lifetime. Although defi-
ciency within the core domains tends to remain constant over time and develop-
ment, the specific symptoms and behaviors associated with a particular domain
may change (62,63,70,92–100). A toddler may retreat from social play, yet the
same child at school age may attempt social interactions although by inappropri-
ate means. As a teenager, this person may inadvertently resort to aggressive be-
havior to attract attention from his peers, but as an adult may again retreat from
social interactions, approaching others only when necessary. In this example,
severe deficits in social interaction were constant, yet specific social behaviors
changed with age and experience.
The literature states that autistic features typically appear during infancy
and are always present by age 3 (59). Analyses of videotaped behavior during
the first year of life show social and motor oddities that may serve as a first sign
of autism (101). Nonetheless, diagnosis of autistic disorder is often difficult prior
to age 2, and even the gold standard of diagnostic instruments—the ADI-R
(11)—is not recommended for use in children younger than 2 years. It is fre-
quently a delay in speech development or the failure of the child to use words
to communicate in the second year of life that is a cause for concern for parents.
Still, other individuals with disorders lying on the autistic spectrum begin to
develop normal speech and communication, then regress around age 2, prompting
cause for alarm. Most autistic children can be clearly distinguished from normally
developing children by 2 years old and may even be differentiated from children
with other forms of developmental delay (102–104).
Social deficits may become more obvious at a slightly older age, when
children are expected to socialize more with their peers. Autistic children fail to
engage in reciprocal interactions, either expressing themselves by “acting out”
or removing themselves from social situations. Preschool-age children may begin
to show repetitive behaviors such as spending lengthy periods spinning the
wheels of a toy truck, or using specific hand or whole-body movements. Stereo-
typic behaviors such as arm flapping and finger picking are very common signs
of autism in young children.
As autistic children enter elementary school, they are often placed in spe-
cial-needs classrooms or integrated within the normal system with a one-to-one
aide. School education is frequently supplemented with aggressive therapy pro-
grams, including behavioral therapy, speech and language therapy, occupational
therapy, and/or a variety of other nontraditional therapy programs, as described

in later chapters. A child who managed with assistance in a regular elementary
school classroom may experience great difficulties in high school due to the in-
creased cognitive demands of those school years and the greater complexity of
the social interactions. The onset of puberty may exacerbate autistic symptoms,
and new symptoms may appear, further hindering the transition into high school.
However, differing opinions exist as to the course of autism during adolescence
and adulthood (e.g., Refs. 99,105). The presence of comorbid psychiatric disor-
ders and associated features pose difficulty in predicting developmental course
as they often contribute to the degree of impairment. For example, mental retarda-
tion and seizure disorder may be associated not only with one another but also
with functioning during adolescence and ultimate outcome (62,63,70).
It is well substantiated that autism continues into adulthood; however, it
appears that specific symptom domains may be more affected than others (e.g.,
Refs. 63,92,100,106). Improvement in the social and communication domains is
often greater than improvement in the repetitive behaviors/compulsivity domain
(92). Still, individuals continue to retain social impairments and/or eccentric or
odd behaviors in adulthood (98,100,107). While autistic individuals may eventu-
ally function independently and even disqualify for diagnosis of autistic disorder,
age-related autistic symptoms persist over time and affect daily living, especially
social interactions.
Higher education is a possibility for some autistic individuals, while spe-
cific job training is often a more realistic next step after high school. Success
stories, such as that of Dr. Temple Grandin, renowned professor of animal sci-
ence, may not be the norm, but many people with autistic disorders succeed in
other capacities. Along with the deficits of autism often come special skills, such
as keen visual perception and visual memory. The desire for sameness, which is
considered a core deficit of autism, may actually improve an autistic person’s
suitability for a career in assembly plants, for example, as well as other fields
that rely on rote behaviors.
Understandably, the future of an individual diagnosed with autism can and
does vary greatly from one person to another because of the great variability
among autism-spectrum disorders.
CONCLUDING THOUGHTS
We have discussed a dimensional approach to the autism spectrum in which dif-
ferent but overlapping groups of children with PDD exist on a continuum, having
similar qualitative features but distinguished by the degree of impairment. The
fact that data from many disparate areas come together to implicate neurobiologi-
cal and genetic factors modulating core symptom domains in autism speaks to
the explanatory power of the conceptualization. It is clear that no single gene
accounts for the transmission of autism, but rather that several genes may contrib-
ute, each contributing a small amount of the overall variance. It appears that core
symptom domains have greater variation between families than within families,
suggesting that the severity of these domains runs within families. Stratifying
the autistic population based on severity of the core symptom domains may pro-
vide more homogeneous populations with which to elucidate genes that mediate
the core domain phenotype. Various neurotransmitters, neuropeptide abnormali-
ties, and neurocircuitry abnormalities have been reported in autistic subjects, but
lack of replication has been the rule, rather than the exception, in autism. An
important contribution to this variance has been heterogeneity of autism. Further,
abnormalities in neurobiological mechanisms have not correlated with autistic
severity. However, specific neurobiological abnormalities, such as the 5-HT re-
ceptor subsystem, oxytocin function, autoimmune markers, and regional meta-
bolic activity, have been tightly mapped to the severity of specific core symptom
domains. Thus, elucidating the pathophysiology and etiology of autism may be
hampered by heterogeneity, but elucidating the pathophysiology and etiology of
core domains may be successful even in the face of heterogeneity. Finally, no
single treatment appears helpful in addressing all aspects of autism or all afflicted
individuals. Nevertheless, the development of targeted treatments for specific
core and associated features of autism may be successfully undertaken, may im-
prove global severity and quality of life in subjects, and may lead to determining
which patients and which symptom clusters respond to which targeted treatments.
Still, we must address the pitfalls of using the core domain approach to
both clinically and scientifically understand autism. First, the core symptom do-
mains may not be completely independent or orthogonal dimensions. For exam-
ple, patients with severe social deficits may also have severe speech/language
deficits and severe repetitive behaviors. Second, brain systems that mediate core
domains may also mediate other domains, such that oxytocin and serotonin abnor-
malities may mediate both repetitive behaviors and social-deficit domains. Third,
treatments that address one symptom domain may also modulate other symptom
domains either directly or indirectly. For instance, SSRIs, which improve repeti-
tive behaviors, may also improve social deficits. This could be directly due to
effects of 5-HT on social functioning, or indirectly in that patients less impaired
by severe compulsivity, craving for sameness, and rigid adherence to routines may
have greater opportunities for improving social functioning. Fourth, in addition
to the core symptom domains, autistic patients are often impaired by comorbid
conditions (e.g., seizures, mental retardation) and associated features (e.g.,
impulsivity/aggression, affective instability). Thus, genetic, neurobiological, and
treatment studies must also address these comorbid conditions and associated fea-
tures to have a more robust impact on understanding and treating autistic patients.
Future research must address the need to refine our categories of different
groups of individuals with autism. By identifying the diagnostic boundaries of
autism, we may better understand the causes, features, and course of this disorder
and provide viable treatment options for individuals with autism. In the mean-
time, the core symptom domains of autism may allow clinicians and researchers
alike to best examine, understand, and treat the autism spectrum given our current
limitations.
ACKNOWLEDGMENT
This chapter was supported in part by the Seaver Foundation, Food and Drug
Administration (FDA) grants FDR001520 and FDR002026, and National Insti-
tute of Neurological Diseases and Stroke grant NS43979.
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3
Autism Screening and
Neurodevelopmental Assessment
Sarah J. Spence and Daniel H. Geschwind

David Geffen School of Medicine at UCLA
Los Angeles, California, U.S.A.
INTRODUCTION
Autism and the related pervasive developmental disorders (PDDs) are neuropsy-
chiatric syndromes characterized by abnormalities in social relatedness, verbal
and nonverbal communication deficits, and the presence of restricted and stereo-
typed behaviors and interests. These disorders are unique in that the children are
often not diagnosed until years after the symptoms first emerge. The reasons for
delay are multiple. Between the wide spectrum of clinical presentations and the
changes in the definition and diagnostic criteria over the years—see the third,
third–revised, and fourth editions of the Diagnostic and Statistical Manual of
Mental Disorders (DSM-III, III-R, and IV)—clinicians who are not very familiar
with the spectrum may not recognize the disorder. Also, there is often the fear
of imposing an improper label on a child, as well as the hope that the child will
“catch up.” And finally, for years there were no uniform guidelines for the work-
up and evaluation of children with suspected autism spectrum disorders. Yet there
is increasing evidence that early intervention can improve outcomes (1–8), so
the speed and accuracy with which the diagnosis is made are crucial.
In recent years, three different sets of guidelines for the evaluation of chil-
dren with suspected autism have been published. In 1997, a meeting sponsored
by the Cure Autism Now (CAN) foundation resulted in the CAN consensus
guidelines for screening and diagnostic referral, which appeared in CNS Spec-
39
40 Spence and Geschwind
trums in 1998 (9). In 1998, selected members of the American Academy of Child
and Adolescent Psychiatry (AACAP) met to establish a set of practice parameters
for the Academy, which were published in the Journal of the American Academy
of Child and Adolescent Psychiatry in 1999 (10). Most recently, the American
Academy of Neurology (AAN) and the Child Neurology Society (CNS) formed
a committee with representatives from a wide range of organizations with exper-
tise in autism and related disorders to create their own practice parameters for
screening and diagnosis; these were published in Neurology in 2000 (11). A first,
more detailed paper based on this consensus-building approach had appeared in
the Journal of Autism and Developmental Disorders in 1999 (12). This chapter
reviews and summarizes these various guidelines as the state of the science in
screening and neurodevelopmental assessment for autism and autism spectrum
disorders.
INITIAL SCREENING
Many pediatricians are unclear about what to do with a child who presents with
language delay and/or social behavioral problems, especially in the setting of
normal motor development. Often, there is a significant reluctance to acknowl-
edge the problem and thus a delay in making the proper referrals for further
assessment. The most recent set of practice parameters published by the AAN/
CNS emphasizes that this is a major issue in the diagnosis of autism, stating that
part of the problem is that, in general, developmental concerns are not taken
seriously enough. They estimate that up to 25% of children in any primary-care
setting present with some type of developmental concern, yet fewer than 30%
of primary-care providers routinely use standardized tests to screen for develop-
mental issues (11). Thus, the AAN/CNS committee (12) made strong recommen-
dations about basic developmental screening at all well-child visits. Their ap-
proach is divided into two levels. The first is a general screen for all
developmental issues including autism, and the second is more specific to the
formal diagnosis of autism.
General Developmental Screening

The cornerstone of the first-tier screening philosophy is that “primary-care pro-
viders must change their approach to well-child care, so as to perform proactive
screening for developmental disorders” and that “developmental screening must
become an absolutely essential part of each and every well-child visit throughout
infancy, toddler, and pre-school years” (11, p. 450). The paper describes many
of the standardized screening tools, most of which are parental questionnaires
(for details, see Ref. 11). It is important to note that they suggest that the more
traditional tools such as the Denver Developmental Screening Test–II (DDST-
Screening and Neurodevelopment Assessment 41
II) or the Revised Denver Pre-Screening Developmental Questionnaire (R-

DPSQ) are not sensitive or specific enough for this purpose. They recommend
using several tests, including the Ages and Stages Questionnaire (ASQ) (13), the
BRIGANCE Screens (14), the Child Development Inventories (CDI) (15), and
the Parent’s Evaluation of Developmental Status (PEDS) (16), all of which have
been standardized and validated as tools for detecting developmental abnormali-
ties. They further propose the following absolute indications for immediate evalu-
ation: no babbling by 12 months, no pointing or other gesture by 12 months, no
single word by 16 months, no two-word spontaneous (non-echolalic) phrases by
24 months, or any loss of any language or social skills at any age (12) (see Table 1).
Table 1 Necessary Routine Developmental Screening and Surveillance in

Primary Care
General developmental screening toolsa

1. The Ages and Stages Questionnaire (ASQ) (13)
2. The BRIGANCE Screens (14)
3. The Child Development Inventories (CDI) (15)
4. The Parent’s Evaluation of Developmental Status (PEDS) (16)
Listening to parental concerns regarding developmental abnormalitiesb

Communication problems: child has language delay or loss of language previously
acquired, child is not responding to name, child has difficulty indicating wants or
needs, child is not following directions, child appears deaf at some times but not
others, child does not gesture (e.g., point or wave).
Social problems: child is not smiling socially, child has poor eye contact, child prefers
to play alone and is not interested in other children, child appears to be “in his own
world.”
Behavioral problems: child frequently has tantrums and/or is hyperactive or
oppositional, child has odd pattern of playing with toys (e.g., lines things up, has
unusual attachments to objects, does not appear to know how to play with toys in
the usual manner), child has odd movement patterns such as repetitive movements
or toe walking, child appears extremely sensitive to certain textures or sounds.
Absolute indications for further evaluation

1. Absence of babbling at 12 months
2. Absence of gesturing at 12 months
3. Absence of single words at 16 months
4. Absence of spontaneous (not echolalic) phrases (at least two words) at 24 months
5. The loss or regression of any language or social skills at any age
Source: aAdapted from AAN/CNS Practice Parameter Algorithm–Level 1.

b
Adapted from Ref. 11, Table III.
The AAN/CNS guidelines also emphasize that parents’ concerns about

their child’s development are almost always valid (17–20) and must not be ig-
nored. So, a parallel step in the screening process should be to listen to the spe-
cifics of the parents’ complaints. Any parental concerns about speech or language
delay, development of social skills, loss of specific skills or anything that implies
regression, or the development of a younger sibling of a child known to be on
the autistic spectrum should raise red flags (11) (see Table 1 for specifics).
Specific Autism Screening

Once a concern is raised about development, whether by parental report or routine
screening, the next phase is to distinguish autism spectrum disorders from other
developmental disorders. Because there are no pathognomonic signs or diagnostic
biological markers for autism, the provider must focus on the history and behavior
of the child. Filipek et al. (11) recommend certain specific questions and screen-
ing tools that are more specific to autism (see Table 2). Once autism is suspected,
then a referral for full diagnosis should be made immediately.
The existing controversy over the age at which a diagnosis of autism can
be reliably made probably contributes to the delay. However, research has shown
certain behavioral deficits that may be most helpful in differentiating autism from
other developmental disorders such as deficits in eye contact, orienting to name,
joint attention, pretend play and imitation, nonverbal communication and lan-
guage development (21–25), some of which can be identified as early as 1 year
of age (26,27). Thus, these are the symptoms that need to be targeted for early
screening tools. Studies have also shown that the symptoms of autism are measur-
able by 18–20 months and remain stable through toddler and preschool age,
supporting the idea that reliable diagnosis can indeed be made early (22,23).
Unfortunately, only a few screening tools are currently available, and none
is in widespread use. For very young children, both the CAN consensus and the
AAN/CNS panel recommended using the Checklist for Autism in Toddlers (CHAT)
(9,12). This brief test, designed to be used in the primary-care setting at the 18-
month visit, combines nine items from parent report and five items from observation
of the child (28,29). The tool has been validated in a large population in Britain
and was originally thought to predict 90% of children who will develop autism
spectrum disorder (29). Since then, however, Charman and colleagues (25) showed
the instrument to be less sensitive to the milder symptoms of autism, missing some
children who went on to develop Asperger’s, PDD–not otherwise specified (NOS)
or atypical autism later. And most recently, the long-term follow-up showed that
while the specificity was near 100% the sensitivity was only 38% (30).
The AAN/CNS practice parameters also recommended three other tests
(12). The ASQ, for use in children age 4 and older, has been validated on a large
population of children and appears to differentiate PDD from non-PDD disorders
Table 2 Specific Screening for Autism Spectrum Disorders

Autism-specific screening instruments
1. Checklist for Autism in Toddlers (CHAT) (28,29)
2. Pervasive Developmental Disorders Screening Test–Stage I (PDDST) (33)
3. Autism Screening Questionnaire (31)
4. Australian Scale for Asperger’s syndrome (32)
5. Symptoms of Autism in Babies (SAB) questionnaire (34,35) (see Ref. 36 for
discussion)
6. Parental Interview for Autism (PIA) (37)
7. Screening Tool for Autism in Two-Year-Olds (STAT) (38,39)
8. Vineland Adaptive Behavior Scale (40)
Autism-specific developmental probesa

Inquire about socialization: cuddling, eye contact when talking or playing, responsive
smile, reciprocal play, social imitation games, interest in other children
Inquire about communication: use of gestures (e.g., pointing, nodding), directing
others’ attention by holding things up or showing them to others, inconsistent
responses to name or commands, speech abnormalities (e.g., repetitive or echolalic
speech or scripts from movies or books)
Inquire about behavior: repetitive, stereotyped, or odd motor behavior; restricted
interests or preoccupations; interest in parts of objects; abnormal play activities (e.g.,
limited pretend play, always playing with toys in exactly the same way); strong
attachments to specific objects
Source: aAdapted from Ref. 11, Table IV.
at all IQ levels (31). For older, more verbal children, there is the Australian Scale
for Asperger’s syndrome (32), a tool filled out by a parent or teacher to identify
high-functioning children of school age who have gone undetected. From birth
to age 3, there is the Pervasive Developmental Disorders Screening Test–Stage
I (PDDST), which was designed for use in the primary-care setting and is in the
process of being validated (33).
Gillberg and colleagues have developed a screening model for autism in
very young children based on the Symptoms of Autism in Babies (SAB) question-
naire used in both retrospective and prospective studies of children referred for
evaluation of autism (34,35) (see Ref. 36 for discussion). Stone and colleagues
have developed two tools: the Parental Interview for Autism (PIA) (37) and the
Screening Tool for Autism in Two-Year-Olds (STAT), the latter of which is
undergoing validation (38,39). Their group also recently reported that the Vine-
land Adaptive Behavior Scale could be reliably used to differentiate autism from
nonautistic developmental delay (40).
ANCILLARY SCREENING
Historically it was left up to the discretion of individual practitioners regarding
when and what to obtain for laboratory studies. This point was addressed in the
recent guidelines, and although no specific complete laboratory testing has yet
been delineated, there is agreement regarding the basic screening studies that
should be performed in any child failing the screening described above (9,10,12).
Audiological Evaluation
Any child with language and/or social delays requires formal audiological testing
(9,10,12). All groups agree that the assessment should be behaviorally based and
performed by an experienced pediatric audiologist. Electrophysiological test-
ing—e.g., brainstem auditory evoked response (BAER)—is probably necessary
only if the behavioral assessment is considered inconclusive or there is a specific
concern about a central nervous system abnormality. In this case, frequency-
specific testing or tone-evoked responses rather than clicks should be used be-
cause these have been shown to better estimate behavioral hearing thresholds
(41). Evoked otoacoustic emissions are another time- and cost-effective way of
testing cochlear function that can be used in children with autism (42).
Lead Screening
Children with developmental delay are at increased risk of lead toxicity because
of the prolonged period spent in oral-motor stages of play (with frequent mouth-
ing of objects) and the occurrence of pica. Substantially higher lead levels have
been reported in children with autism than in nonautistic controls (43). Another
study found that children with autism were older at time of diagnosis, had sub-
stantially prolonged lead-level elevations, and were at increased risk of re-expo-
sure despite close monitoring compared to a group of nonautistic children with
lead poisoning (44). Thus, the AACAP and CAN consensus committees suggest
lead screening in all children with suspected autism (9,10). The AAN/CNS guide-
lines recommend it only in the cases in which pica is reported (12), but they do
point out that the Centers for Disease Control and Prevention’s 1997 guidelines
for lead screening in the United States recommend that all children with any
developmental delay be screened for lead poisoning.
THE NEXT STEP: AUTISM DIAGNOSIS

The next step in the process is a referral for a formal assessment, that is, a referral
to a practitioner or practitioners with specific expertise in the diagnosis and evalu-
ation of autism. These might include a child psychiatrist, a child psychologist,
a child neuropsychologist, a pediatric neurologist, and/or a developmental pedia-
trician. It is generally agreed that a multidisciplinary approach would aid in the

most comprehensive evaluation. Ideally there would be members from the above
specialties plus pediatric audiologists, speech and language therapists, occupa-
tional therapists, physical therapists, and behavioral therapists. This not only en-
ables the proper diagnosis but also facilitates treatment planning (11). Unfortu-
nately, in current practice, not enough centers take such a comprehensive
approach and thus both the practitioner and the family are left to gather all the
resources. The panels from CAN, AACAP, and the AAN/CNS have all made
recommendations regarding tools for the proper diagnosis, but these are not cov-
ered here (refer to Refs. 9, 10, and 12 for details).
MEDICAL EVALUATION
History and Physical Examination
All the panels have put forth guidelines for further medical and neurological
work-up at the specialist level and uniformly recommend a detailed history and
physical examination in all children with autism or PDD. This should include
probes specific to birth history, medical history, developmental history, and fam-
ily history. The relationship between autism and other medical diseases is still
uncertain (9,10), and it is unclear exactly what percentage of cases of autism are
attributable to general medical conditions—some say it is low (45) and others
have found up to 25% (46). Thus, attention to these details may, in fact, aid in
diagnosis.
All published guidelines have made similar recommendations regarding the
further medical and/or neurological evaluation. The focus of these assessments
should be on finding any conditions that may be medically treatable or may have
genetic implications for the family (10). The CAN consensus group suggests at
least a thorough developmental and family history, a medical and neurological
examination, including a mental-status exam, and a comprehensive speech and
language evaluation. They also suggest an assessment of the child’s social and
emotional development, with special attention to the communication deficits
and behavioral problems often associated with autism (9).
The AAN/CNS guidelines go into more detail regarding several medical
issues that must be taken into account in evaluating children with autism. Infor-
mation can be obtained from the family history, medical history, and physical
exam. There are significant epidemiological data to support the increased preva-
lence (50- to 100-fold) in first-degree relatives of autistic children (47–49). Other
psychiatric disorders (especially affective disorder, obsessive compulsive disor-
der, and anxiety disorder) are also seen at a higher-than-expected frequency (50–
54). The association with fragile X syndrome necessitates that family histories
be examined for mental retardation and/or autism inherited in an X-linked pat-
tern. While early screening studies had reported rates of up to 25%, more recent
studies have reported much lower percentages (e.g., ⬍5%) of autistic patients
with the fragile X mutation (55–57), including the Autism Genetic Resource
Exchange (AGRE) sample (58). Further, it should be noted that several groups
have found no evidence of the expansion of the (CGG) trinucleotide repeat in
the FMR-1 gene in patients with autism spectrum disorders, leading them to
question whether there is any causal link at all (59–61). Finally, there is a strong
association with tuberous sclerosis complex (TSC), an inherited neurocutan-
eous disease with an autosomal dominant pattern of transmission. Estimates are
that from 20% (62) or 25% (63) to as much as 50 to 60% (64,65) of patients
with TSC have autism. Seizures (especially infantile spasms) and mental retarda-
tion appear to be risk factors for the development of autism in TCS patients
(66,67). However, the percentage of autistic patients who have TSC is much
lower: 0.4% to 3% overall and 8–14% in patients with epilepsy (67). Diagnosing
TSC is important not only for genetic counseling but also for health mainten-
ance because of the associated abnormalities in multiple organ systems requiring
monitoring.
A careful physical exam can reveal other features that may be associated
with autism. General observation can identify dysmorphic features such as those
consistent with the fragile X syndrome or other inherited syndromes. These might
lead to specific genetic testing or a referral for a thorough genetic evaluation.
Skin examination could demonstrate hypopigmented macules or ash-leaf spots
(best seen using an ultraviolet light source or a Wood’s lamp) or other cutaneous
findings associated with TSC. It has also been reported that many children with
autism have relatively large head circumferences that may not be present at birth
(68), but this does not appear indicative of any neuropathology. After a careful
review of the literature, Filipek concluded that macrocephaly alone in an autistic
child in the absence of any signs or symptoms of structural lesions is not an
indication for neuroimaging (69). Finally, there are frequently reported mild sen-
sorimotor deficits. The most common motor problems are hypotonia, limb
apraxia, and motor stereotypies (e.g., rocking, hand or finger mannerisms, un-
usual posturing) (70). The most common sensory difficulties are over- or under-
sensitivity or paradoxical reactions to environmental stimuli (71).
Laboratory and Other Ancillary Testing

There are a number of ancillary tests that are not, as yet, uniformly performed
during the work-up of autism. Most of the panels suggest that these be performed
at the discretion of the provider who has become familiar with the child’s history
and examination. However, it should be noted that there are controversies sur-
rounding the indications for most of this testing and that no standard of care has
been set defining a routine battery for every patient.
Genetic Testing
Currently the area that has drawn the most interest is genetic testing. As men-
tioned above, many practitioners are testing for fragile X, but most do not perform
routine chromosomal analyses. With the rapidly evolving tools of molecular ge-
netics this is an area of very active research, and multiple loci have been posited
to contribute to autism susceptibility. In the past few years there have been several
reports of full genomic screens looking for putative autism genes (72–75) and
many more reports testing individual candidate genes (see Refs. 49 and 76–78
for reviews). These studies have implicated loci on chromosomes 1, 4, 5, 6, 7,
10, 13, 15, 16, 18, 19, 22, and X. However, it should be noted that the studies
sometimes do not agree, and some of these loci have not been confirmed when
tested in another cohort (77). We are currently involved in ascertaining and study-
ing a large number of multiplex families in the United States, through the AGRE.
The project entails collection of DNA, family histories, and neurological, psychi-
atric, and behavioral data on affected siblings and first-degree relatives in over
400 multiplex families. Most importantly, these data and the biomaterials are
rapidly made available to the scientific community, providing an unprecedented
resource (www.agre.org) (58).
A thorough review is certainly beyond the scope of this chapter, but emerg-
ing genetic data are obviously something to which investigators and clinicians
alike need to pay close attention. So far, the AAN practice parameters are the
only ones to have set a standard of karyotyping and DNA analysis for fragile X
in any autistic child with mental retardation, or with a family history of fragile
X or undiagnosed mental retardation, or with dysmorphic features. However,
there has been at least one reported case of a chromosome 15 abnormality in the
absence of mental retardation (79). This raises the question of whether karyotyp-
ing should be done even in nonretarded autistic patients. Although the overall
incidence of chromosomal abnormalities is probably quite low, it does have major
implications for genetic counseling. Also, karyotyping is an expensive test and
the decision to do widespread screening may ultimately come down to cost.
EEG
Epidemiological studies have shown that there is a significant percentage of chil-
dren with autism who have epilepsy. Estimates range from 7 to 21% in children
(80,81) and up to 35% by adulthood (82). Practitioners should be aware that the
age of onset of the seizures is bimodal, with peaks in early childhood and adoles-
cence (82). Any type of seizure can be seen in autistic children, but complex
partial seizures are probably most prevalent (83). The diagnosis of seizure activity
in autistic individuals is also made more difficult because the behavioral ab-
normalities associated with complex partial seizures (e.g., staring, being unre-
sponsive to one’s name, repetitive motor behaviors) can all be attributed to the
autism (82). Obviously an EEG is recommended and is the standard of care for
all children with clinical or suspected subclinical seizures. The difficulty and
controversy arise when trying to decide whether all children with autism should
have an EEG.
One aspect of this controversy is the discordance of EEG abnormalities
and clinical seizures (e.g., seizures with normal EEG and abnormal EEG without
seizures). Most neurologists will treat clinical seizures regardless of EEG find-
ings, but most do not consider an abnormal EEG in the absence of clinical sei-
zures an indication for anticonvulsant medication. The true incidence of isolated
EEG abnormalities in autistic patients is difficult to estimate since routine EEGs
are not part of the work-up. Tuchman and Rapin (84) reported abnormal EEGs
in 8% of their cohort of over 500 autistic children without clinical epilepsy.
Numerous papers in the literature have explored the possible connection
between autism and Landau-Kleffner syndrome (LKS). LKS is an acquired epi-
leptic aphasia clinically described as the occurrence of auditory agnosia (the in-
ability to understand spoken language) in a typically developing child. This is
often characterized as a regression, and is usually accompanied by seizures
(85,86). It is this language regression, and the question of whether it could be
likened to that seen in the subset of children with autistic regression, that caught
the attention of those studying and treating autism (84).
LKS is also associated with a severe EEG abnormality present in the deep-
est stages of sleep, referred to as continuous spike and wave in slow-wave sleep
(CSWS) or electrical status epilepticus in sleep (ESES). LKS has been treated
with traditional anticonvulsant medications (87), corticosteroids (88), IVIg (89),
and even epilepsy surgery (90) (see Ref. 91 for review), and in many instances
both the seizures and the language impairment improve.
However, there is currently much debate about how much of a connection
exists between autism spectrum disorders and LKS. Does LKS, like autism, exist
on a spectrum and should it be considered in autistic children with abnormal
EEGs or even in all autistic children (91–93)? Anecdotal evidence indicates that
there is a subset of children with abnormalities in their EEG whose language
disturbance improves when treated with anticonvulsants even in the absence of
clinical seizures (91). A recent paper even suggests a causal relationship between
the EEG findings consistent with a benign form of childhood epilepsy, Rolandic
(e.g., centrotemporal spikes), and autistic regression (94). It is certainly tempting
to think that the EEG abnormalities play a role in the abnormal speech and or
behaviors in autistic children as they are presumed to do in LKS (84), because
if this is the case, then perhaps treatment might prove beneficial. But even then
the risks of treatments, which are so far of unproven value, need to be considered
very carefully (95). Thus, until there is more evidence, it seems unreasonable to
make recommendations regarding either routine monitoring or treatment of iso-
lated EEG abnormalities in children with autism spectrum disorders (91).
Finally it is extremely important to consider the practicalities of obtaining

EEGs in autistic children. The 30–60-minute routine office EEG is inadequate
to capture slow-wave sleep. This necessitates a prolonged recording, which pre-
sents a myriad of problems in many of these children. Often they need to be
admitted for overnight EEG recording at a specialized center, an endeavor that
poses significant hardship on the caregivers and the children, not to mention the
financial aspects.
The existing practice parameters reflect all of this uncertainty. The AACAP
guidelines state that an EEG is recommended only if there are any symptoms of a
seizure disorder (10). The AAN/CNS panel recommends an EEG (with adequate
sampling of slow-wave sleep) in children with clinical or suspected subclinical
seizures or any developmental regression (12). Finally, the CAN panel recom-
mends a prolonged EEG (capturing all four stages of sleep) in any child who
has regressed, has poor phonology, or is nonverbal (9).
Neuroimaging
Another area of relative controversy in the work-up of autism is neuroimaging.
However, the controversy here comes less from the literature than from the expec-
tations of patients’ parents or caregivers. Because the technology exists to “see
into the brain,” parents and caregivers often assume that a scan will reveal the
problem. Certainly that was a hope in the scientific community as well, and re-
searchers have been scanning autistic children since scans have been available.
Unfortunately, while studies in the literature have suggested certain structural
differences between children with autism and those without, they often appear
to be irreproducible. Even the more consistent differences are very subtle and
have not been considered useful from a diagnostic standpoint (see Refs. 96 and
97 for reviews). In fact, all three sets of published guidelines state that neuroimag-
ing is indicated only in cases in which there are seizures or some sort of focal
abnormality on EEG or neurological exam (9,10,12). A variety of other neuro-
imaging techniques, such as magnetoencephalography (MEG) and other func-
tional techniques such as functional MRI (fMRI), positron-emission tomography
(PET) or single-photon emission tomography (SPECT), and magnetic resonance
spectroscopy (MRS), are currently being used only as research tools and are not
considered useful for routine diagnostic purposes in autistic children (see Ref.
98 for review).
Metabolic Testing
Indications for metabolic testing are similar to those for imaging. While there
have been reports of certain metabolic diseases associated with autism (see Ref.
99 for review), there are no data to support widespread or routine metabolic
screening in all patients at this time (11). However, testing for specific disorders
is definitely indicated if there is information in the clinical history or exam sug-
gestive of a metabolic disease such as episodic vomiting or lethargy or encephalo-

pathic changes, very early-onset seizures, dysmorphic features suggestive of a
storage disease, or significant hypotonia, or if there is a questionable history of
the proper newborn screening. The CAN consensus group (9) suggests that stud-
ies could include quantitative amino acids in plasma and organic acids in urine,
lactate, pyruvate, carnitine, thyroid studies (100), and uric acid (101).
Other Medical Evaluations
Finally, the CAN consensus group discusses the observation that children with
autism may have a higher incidence of certain childhood ailments, including in-
fections (especially otitis media) (102), allergies (especially to food) and/or al-
tered immune parameters (103–105), and gastrointestinal maladies (especially
altered bowel patterns) (106–109). These associations have been the focus not
only of ongoing research into a possible causal relationship between these ail-
ments and the occurrence of autism, but also of intense debate. If and when any
causal connections are identified, they could aid in understanding the pathophysi-
ology of autism. However, the research is only at the preliminary stages at this
time (see Ref. 11 for review and discussion of tests of “unproven value”). From
a practical standpoint, there is not enough evidence to recommend routine testing.
Instead, the clinician must look at each patient individually and make proper
referrals to specialists according to the symptomatology. And this can be espe-
cially challenging in the many autistic patients who have poor communication
skills and behavioral problems at baseline (9).
Cognitive, Language, Neuropsychological, and Behavioral

Evaluation
All the panels also acknowledged the importance of formal assessment of cogni-
tive status, communicative (verbal and nonverbal) abilities, and adaptive behavior
(9,10,12). The AACAP and AAN/CNS panels also recommend sensorimotor and
occupational-therapy assessments for functional status and a family evaluation
to probe for understanding of the disorder and determine proper resources for
referral (10,12). A discussion by the AACAP panel focuses on the comorbid
behavioral/developmental and psychiatric conditions that frequently occur in au-
tistic individuals (10), pointing out that it is often difficult to determine whether
many of these symptoms should be viewed as part of the autism diagnosis itself or
as separate behavioral issues. Thus, they recommend a comprehensive psychiatric
evaluation in all patients, as does the CAN consensus group (9,10).
CONCLUSION
It is encouraging that expert clinical panels are now addressing the difficult prob-
lems and controversies regarding screening and diagnosing autism and PDD. The
benefits of the move toward uniform work-up and diagnosis extend beyond those
conveyed to the individual child and family; it will undoubtedly serve to further
research into this disorder. Proper and prompt diagnosis will aid in research re-
garding early intervention and outcomes. Comprehensive reporting of associa-
tions with other diseases, abnormal laboratory values, genetic evaluations, and
other ancillary testing will ultimately shed light on what is certain to be the multi-
factorial etiology of this disorder. It may be that tests now considered to be of
“unproven value” will turn out to be crucial in the evaluation, but this cannot be
determined until more rigorous data collection is completed.
REFERENCES
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4
Assessment and Early Identification of
Autism Spectrum and Other Disorders
of Relating and Communicating
Stanley I. Greenspan and Serena Wieder

Bethesda, Maryland, U.S.A.
A FUNCTIONAL DEVELOPMENTAL APPROACH TO AUTISM

SPECTRUM DISORDERS
Most nonprogressive developmental and learning disorders, including autism
spectrum disorders (ASDs), are nonspecific with regard to etiology and patho-
physiology. Nonprogressive developmental disorders are, therefore, best charac-
terized in terms of types and degrees of limitations in fundamental developmental
areas of functioning such as auditory processing and engaging with others pur-
posefully, as well as symptoms (e.g., echolalia). Yet, both historically and re-
cently, we have focused on symptoms and groups of symptoms comprising
syndromes and very specific behaviors, such as saying “hello,” with only par-
tial emphasis on identifying and working with functional developmental cap-
acities that often underlie symptoms and determine overall adaptation. By func-
tional we mean a child’s ability to use a capacity toward an emotional goal or
to satisfy a need. It is timely to further systematize a functional developmental
approach and explore its implications for improving assessment and intervention
practices.
As indicated, because there is not yet a clearly identified etiological mecha-
nism or well-described pathophysiological pathway for autism, we must be mod-
est in our assumptions and base assessments and interventions on what is clearly
57
58 Greenspan and Wieder
observable and known. What is observable and known are the functional develop-
mental limitations in critical areas, including emotional and social functioning,
language, motor planning and sequencing, and sensory processing and modula-
tion. In fact, as most clinicians recognize, there are huge differences among chil-
dren with autism: one may be relatively strong in visual-spatial processing and
another in auditory-verbal memory. In terms of motor planning or visual-spatial
processing, a child with autism may be more similar to one with Down’s syn-
drome than to another child with autism. A functional developmental approach
enables us to study all the relevant problems in their unique configurations and,
in this way, improve assessments and intervention for a range of developmental
disorders, including autism.
In the functional approach, assessments and interventions must include all
relevant areas of developmental functioning and deal with each child and family
in terms of their unique profiles. We have developed a model that identifies the
relevant areas of functioning, helps with the construction of each child’s func-
tional developmental profile, and provides a developmental framework for the
assessment and intervention process: the Developmental, Individual-Difference,
Relationship-Based (DIR) model (1,2). In this chapter, we describe the DIR
model and discuss its application to assessment, intervention, classification, and
prognosis.
The DIR model looks at all of the child’s developmental capacities in the
context of his unique, biologically based processing profile and his family rela-
tionships and interactive patterns. As a functional approach, it uses the complex
interactions between biology and experience to understand behavior. Using this
model requires the assessment of each infant’s or child’s relative strengths as
well as challenges as they simultaneously impact on functioning at each develop-
mental level. This contrasts with the typical deficit model, which describes the
deficits within each developmental domain—fine motor, gross motor, speech and
language, social, and other skills are evaluated independently by teams using
standardized instruments, often working in single-session arena style. In the defi-
cit model, results are typically presented from the point of view of deficits in
each domain with general recommendations. Crucial areas of interactive relation-
ships and emotional functioning are often omitted.
The model described below is distinguished in its emphasis on multiple
observations and in-depth interviews over time both in the natural environments
and in child-centered settings. In the developmental functional approach, the eval-
uations go beyond the assessment of skills to the assessment of functioning within
relationships. Standardized tools are used only for strategic purposes rather than
for the core assessment. The evaluation always includes multiple observations
of infant/child–parent (all significant caregivers) interactions and play, as well
as interaction with the evaluator whose relationship with the family effects the
evaluation, interpretation, and implementation of the intervention plan.
Assessment and Early Identification 59
The DIR Model

The basic developmental model guiding the evaluation process can be visualized
with the infant’s or child’s constitutional-maturational patterns on one side and
the infant’s or child’s environment, including caregivers, family, community, and
culture, on the other side. Both sets of factors operate through the infant–care-
giver relationship which can be pictured in the middle. These factors and the
infant–caregiver relationship, in turn, contribute to the organization of experience
at each of six developmental levels, which may be pictured just beneath the in-
fant–caregiver relationship.
Each developmental level involves different tasks or goals. The relative
effect of the constitutional-maturational, environmental, or interactive variables
will, therefore, depend on and can only be understood in the context of the devel-
opmental level they relate to. The influencing variables are thus best understood,
not as they might be traditionally, as general influences on development or behav-
ior, but as distinct and different influences on the six distinct developmental and
experiential levels. For example, as a child is negotiating the formation of a rela-
tionship (engaging), his mother’s tendency to be very intellectual and prefer talk-
ing over holding may make it relatively harder for him to become deeply engaged
in emotional terms. If constitutionally he has slightly lower than average muscle
tone and is hyposensitive with regard to touch and sound, his mother’s intellectual
and slightly aloof style may be doubly difficult for him, as neither she nor the
child is able to take the initiative in engaging the other.
Functional Developmental Levels
In this model, there are six functional developmental levels. They include the
infant/child’s ability to accomplish the following:
1. Attend to multisensory affective experience and at the same time orga-
nize a calm, regulated state and experience pleasure.
2. Engage with and evince affective preference and pleasure for a care-
giver.
3. Initiate and respond to two-way presymbolic gestural communication.
4. Organize chains of two-way communication (opening and closing
many circles of communication in a row), maintain communication
across space, integrate affective polarities, and synthesize an emerging
prerepresentational organization of self and other.
5. Represent (symbolize) affective experience (e.g., pretend-play, func-
tional use of language). It should be noted that this ability calls for
higher-level auditory and verbal sequencing ability.
6. Create representational (symbolic) categories and gradually build con-
ceptual bridges among these categories. This ability creates the founda-
tion for such basic personality functions as reality testing, impulse con-
trol, self–other representational differentiation, affect labeling and

discrimination, stable mood, and a sense of time and space that allows
for logical planning. It should be noted that this ability rests not only
on complex auditory and verbal processing abilities, but on visual-
spatial abstracting capacities as well.
The theoretical, clinical, and empirical rationale for these developmental levels
is discussed in The Development of the Ego (3) and Intelligence and Adapta-
tion (4).
To make a developmental assessment of the functional level, the clinician
should make a determination regarding each of the six developmental levels in
terms of whether they have been successfully negotiated, and whether there is a
deficit at any level that has not been successfully negotiated. Sometimes these
levels have been successfully negotiated but are not applied to the full range of
emotional themes. For example, a toddler may use two-way gestural communica-
tion to negotiate assertiveness and exploration by, for example, pointing at a
certain toy and vocalizing for his parent to play with him. The same child may
either withdraw or cry in a disorganized way when he wishes for increased close-
ness and dependency instead of, for example, reaching out to be picked up or
coming over and initiating a cuddle. This would indicate a constriction at that
level.
Sometimes children are able to negotiate a level with one parent and not
the other, with one sibling and not another, or with one substitute caregiver but
not another. If it should reasonably be expected that a particular relationship
is secure and stable enough to support a certain developmental level but that
level is not evident in that relationship, then there is a constriction at that level
as well.
It is useful to indicate which areas or relationships are not incorporated
into the developmental level. Consider the following areas of expected emotional
range: dependency (closeness, pleasure, assertiveness [exploration], curiosity,
anger, empathy [for children over 31/2 years]); stable forms of love, self-limit-
setting (for children over 18 months); interest and collaboration with peers (for
children over 2 years); participation in a peer group (for children over 21/2 years);
and the ability to deal with competition and rivalry (for children over 31/2 years).
If the child has reached a developmental level but the slightest stress, such
as being tired, having a mild illness (e.g., a cold), or playing with a new peer,
leads to a loss of that level, then there is an instability at that level.
A child may have a defect, constriction, or instability at more than one
level. Also, a child may have a defect at one level and a constriction or instability
at another. Therefore, the clinician should make a “developmental” judgment
based on the following developmental levels. The Functional Emotional Develop-
Table 1 Sample Assessment Form Based on the Functional Emotional

Developmental Scale
Developmental level Defect constriction Instability
1. Regulation and interest in the world

2. Attachment
3. Intentional communication
4. Behavioral organization (complex sense of
self )
5. Representational elaboration
6. Representational differentiation
mental Scale clinical and research applications have been developed and include
reliability and validity studies (5) (Table 1).
Individual Processing Differences: Constitutional-
Maturational Patterns
In addition to the functional developmental levels, the DIR model focuses on
constitutional-maturational characteristics. Constitutional patterns are the result
of genetic, prenatal, perinatal, and maturational variations and/or deficits. They
are expressed in and can be observed as part of the following individual pro-
cessing differences:
Sensory reactivity, including hypo- and hyperreactivity in each sensory mo-
dality (tactile, auditory, visual, vestibular, olfactory)
Sensory processing in each sensory modality (e.g., the capacity to decode
sequences, configurations, or abstract patterns), including auditory pro-
cessing and visual-spatial processing
Sensory affective processing in each modality (e.g., the ability to process
and modulate affects and connect affective “intent” to motor planning
and sequencing, symbol formation, and other sensory processing capaci-
ties) (6)
Muscle tone
Motor planning and sequencing
An instrument to clinically assess aspects of sensory functions in a reliable
manner has been developed and is available (7–9). The following section further
considers the constitutional and maturational patterns.
Sensory reactivity (hypo- or hyper-) and sensory processing can be ob-
served clinically. Is the child hyper- or hyposensitive to touch or sound? The
same question must be asked in terms of vision and movement in space. In each
sensory modality, does the 4-month-old “process” a complicated pattern of infor-
mation input or only a simple one? Does the 41/2-year-old have a receptive lan-
guage (i.e., auditory processing) problem and is therefore unable to sequence
words he hears together or follow complex directions? Is the 3-year-old an early
comprehender and talker but slower in visual-spatial processing? If spatial pat-
terns are poorly comprehended, a child may be facile with words and sensitive
to every emotional nuance, but have no context, never see the big picture (the
“forest”); such children get lost in the “trees.” In the clinician’s office, they may
forget where the door is or have a hard time picturing that their mother is only
a few feet away in the waiting room. In addition to straightforward “pictures”
of spatial relationship (e.g., how to get to the playground), they may also have
difficulty with seeing the emotional big picture. If the mother is angry, the child
may think that the earth is opening up and he is falling in because he cannot
comprehend that she was nice before and will probably be nice again. Such a
child may be strong on the auditory processing side but weak on the visual-spatial
processing side. Our impression is that children with a lag in the visual-spatial
area can become overwhelmed by the affect of the moment. This is often intensi-
fied by precocious auditory-verbal skills. The child, in a sense, overloads himself
and does not have the ability to see how it all fits together.
Thus, at a minimum, it is necessary to have a sense of how the child reacts
in each sensory modality, how he or she processes information in each modality,
and particularly, as the child gets older, a sense of the auditory-verbal processing
skills in comparison to visual-spatial processing skills.
It is also necessary to look at the motor system, including muscle tone, motor
planning (fine and gross), and postural control. Observing how a child sits, crawls,
or runs; maintains posture; holds a crayon; hops, scribbles, or draws; and makes
rapid alternating movements and plans and executes complex actions (such as using
a toy in an innovative four-step manner) will provide a picture of the child’s motor
system. His security in regulating and controlling his body plays an important role
in how he uses gestures to communicate his ability to regulate dependency (being
close or far away), his confidence in regulating aggression (“Can I control my hand
that wants to hit?”), and his overall physical sense of self.
Other constitutional and maturational variables have to do with movement
in space, attention, and dealing with transitions.
Parent and Family Contributions
In addition to the functional developmental levels and individual processing dif-
ferences based on constitutional and maturational factors, it is important to de-
scribe family patterns. It is especially useful to describe family interactions with
regard to each functional developmental level. If a family system is aloof, it may
not negotiate engagement well; if a family system is intrusive, it may overwhelm
or overstimulate a baby or child. Obviously, if a child is already overly sensitive

to touch or sound, the caregiver’s intrusiveness will be all the more difficult for
the child to handle. We see, therefore, the interaction between the maturational
pattern and the family pattern.
A family system may throw so many meanings at a child that he or she is
unable to organize a sense of reality. Categories of me/not-me may become con-
fused, because one day a feeling is yours, the next day it is the mother’s, the
following day it is the father’s, the day after that it is little brother’s; anger may
turn into dependency, and vice versa. If meanings shift too quickly, a child may
be unable to reach the fourth level: emotional thinking. A child with difficulties
in auditory-verbal sequencing will have an especially difficult time (3).
The couple is a unit in itself. How do husband and wife operate, not only
with each other but how do they negotiate on behalf of the children, in terms of the
developmental processes? A couple with marital problems could still successfully
negotiate shared attention, engagement, two-way communication, shared mean-
ings, and emotional thinking with their children. But the marital difficulties could
disrupt any one or a number of these developmental processes.
Each parent is also an individual. How does each personality operate vis-
à-vis these processes? While it may be desirable to have a general mental-health
diagnosis for each caregiver, one also needs to functionally observe which of
these levels each caregiver can naturally and easily support. Is the parent engaged,
warm, and interactive (a good reader of cues)? Is he or she oriented toward sym-
bolic meanings (verbalizing meanings), and engaging in pretend-play, and can
the caregiver organize feelings and thoughts, or does one or the other get lost
between reality and fantasy? Are there limitations in terms of these levels; if so,
what are they?
Each parent also has specific fantasies that may be projected onto the chil-
dren and interfere with any of the levels. Does a mother see her motorically
active, distractible, labile baby or child as a menace and therefore overcontrol,
overintrude, or withdraw? Her fantasy may govern her behavior. Does a father
whose son has low muscle tone see his boy as passive and inept, and therefore
pull away from him or impatiently “rev him up”?
In working only with the parent–child interaction and not the parent’s fan-
tasy, one may be dealing with only the tip of the iceberg. The father may be
worried that he has an overly passive son, or the mother may be worried that
she has a monster for a daughter (who reminds her of her retarded sister). All
these feelings may be “cooking,” and they can drive the parent–child interactions.
Infant/Child–Caregiver Relationship Patterns
It is the caregiver–infant relationship that mediates these other variables and, in
addition, determines how each of the developmental processes is successfully or
unsuccessfully negotiated.
Often, parents will bring a baby in, and we will watch the parent–infant
interaction in the first session, while we are hearing about their concerns. With
an older child—a 4-year-old, for example—we may have them wait to bring the
child in, because we want them to talk freely at the outset.
Usually, we let each parent interact and play with the child for 20 minutes
or more, and then we will interact with the child for about the same amount of
time. We look for a pattern of interaction in the context of the developmental
processes. We observe which levels are present and not present, and also look
for the range of emotional themes in each of the core processes and the stability
of these processes. For example, a 4-year-old may be self-absorbed and only
occasionally purposeful, pulling mom to the door, for example. We look at how
the child is relating with his caregiver (and later on with us), and the breadth of
emotion and the stability of the relatedness. We observe the degree to which the
child can interact with purposeful gestures, problem-solve with a continuous flow
of interactive gestures, use ideas, and think logically. We also observe the child’s
processing capacities (does he understand mom’s verbal comments?) and the
natural interactive patterns his parents employ.
For each of the developmental levels, or core processes, it is necessary to
look at the child’s constitutional and maturational status, the family and parent
and couple patterns, and the actual caregiver/parent–infant interaction (see Figure
1). For each level, one must look at what is influencing the successful or compro-
mised negotiation at that level. Therefore, a therapist wants to be able to reach
a conclusion on all levels about a child 3 years old and up, and for the child less
than 3 years, on the levels they should have attained (e.g., for a 21/2-year-old,
Figure 1 The DIR model.

through the first three levels; for a 14-month-old, the first two levels: attention/
engagement and two-way communication).
It is also often necessary to conduct evaluation of speech and language
functions, motor and sensory capacities, and educational skills, and conduct a
thorough biomedical evaluation (see Table 2).
Table 2 Formal Assessment

I. Review of current challenges and functioning, including:
Each functional developmental capacity (e.g., from attention and engagement to
thinking)
Each processing capacity (e.g., auditory, motor planning and sequencing,
visual-spatial, sensory modulation)
In relevant contexts (e.g., at home with caregivers and siblings, with peers, in
educational settings)
II. History, including history of the above, beginning with prenatal development
III. One or two or more observational sessions of child–caregiver interactions with
coaching and/or interactions with clinician (each session should be 45 minutes
or more). These observational sessions should provide the basis for forming a
hypothesis about the child’s functional emotional developmental capacities,
individual processing and motor planning differences, and interactive and
family patterns.
IV. Exploration of marital and family patterns, siblings, and personality of
caregiver(s). This exploration should focus on the caregiver/family/sibling
patterns both in their own right and in relationship to their role in enabling the
child to negotiate the functional developmental milestones (minimum of one
45-minute session).
V. Biomedical evaluations, including ruling out genetic, metabolic, and other
diagnosable disorders. Depending on history and presenting symptoms, may
also include neurological consultation, standard EEG, extended sleep EEG,
metabolic work-up, genetic studies, and nutrition.
VI. Speech and language evaluation
VII. Evaluation of motor and sensory processing, including:
Motor planning
Sensory modulation
Perceptual motor capacities
Visual-spatial capacities
VIII. Evaluation of cognitive functions, including neuropsychological and educational
assessments
IX. Mental-health evaluations of family members, family patterns, and family needs
The evaluations listed in V–IX should be carried out only to answer specific questions that arise
from the history, review of challenges, and current functioning and observations of the child–care-
giver interaction patterns and family functioning.
THE PROCESS OF CLINICAL ASSESSMENT

Each clinician may develop his own way of doing an evaluation. A comprehen-
sive assessment usually involves the following elements: the presenting “com-
plaints” and current functioning, developmental history, family patterns, child
and parent sessions, additional consultations, and formulation. Table 2 presents
a brief outline, followed by a discussion of clinical processes involved in selected
elements of the evaluation.
The Presenting “Complaints” (Overall Picture)

We frequently spend a whole session on the presenting “complaints,” or picture,
which includes the development of the “problems,” the infant/child’s and fami-
ly’s current functioning, and preliminary observation of the infant/child both with
the caregiver(s) and, in the case of a child over 3, without.
The initial session should also establish rapport with the family and child
in order to begin a collaborative process. The developmental process discussed
earlier in relation to the child—mutual attention, engagement, gestural communi-
cation, shared meanings, and the categorizing and connecting of meanings—may
occur between an empathetic clinician and the parents. How the clinician relates
to the parents reflects how they will be encouraged to relate to their baby or
child. If the therapist asks hurried questions with yes-or-no answers, he or she
sets up an untherapeutic model. It usually takes parents a long time to decide to
come for help. They should be able to tell their story without being hurried or
criticized.
As part of this presenting picture it is important to learn about all the areas
of the child’s current functioning. One considers whether the child is at the age-
appropriate developmental level and, if so, the full range of emotional inclina-
tions. Is the child 8 months old or more capable of reciprocal cause-and-effect
interchanges? Is a 4-month-old wooing and engaging? Is a 21/2-year-old exhibiting
symbolic or representational capacities? Does he do pretend-play? Does he use
language functionally? How does he negotiate his needs? At each of these levels,
how is he dealing with dependency, pleasure, assertiveness, anger, and so forth?
Toward the end of the first session, we may fill in more gaps by asking
questions about sensory, language, cognitive, and fine and gross motor function-
ing. Usually, we have a sense of these capacities and patterns from anecdotes
and more general descriptions of behavior. We listen for indications of the child’s
ability to retain information, how he does or does not follow commands, word-
retrieval and -association skills, and fine and gross motor and motor planning
skills.
Developmental History
In the second session, we construct a developmental history for the child. (How-
ever, sometimes marital or other family problems erupt during the first session.
The parents may be at each other’s throats; the mother and/or the father may be
extremely depressed. In such cases, in the second session we focus on the individ-
ual parent problems, as well as family functioning.)
We will usually start the session in an unstructured manner. We want to
hear how development unfolded and what the parents thought was important.
We encourage them to alternate between what the baby or child was like at differ-
ent stages and what they felt was going on as a family and as individuals in each
of those stages. We try to start with the planning for the child and progress
through the pregnancy and delivery. Next, we cover the six developmental stages,
outlined earlier, in order to organize the developmental history.
Family Patterns
The next session focuses in greater depth on the functioning of the caregiver and
family at each developmental phase. For example, the mother may say that she
was a little depressed or angry, or that there were marital problems at different
stages in the child’s development.
Sometimes clinicians who are only beginning to work with infants and
family feel reluctant to talk to the parents about any difficulties in the marriage.
However, an open and supportive approach can elicit relevant information. One
might ask, “What can you tell me about yourselves as people, as a married couple,
as a family?” We are also interested in concrete details of a history of mental
illness, learning disabilities, or special developmental patterns in either of the
parent’s families.
Child (or Infant) and Parent Sessions

We spend the next one or two sessions with a focus on the child or infant. We
conduct the session differently with an older child who has close to age-expected
language skills (a 3- or 4-year-old, for example) than with an infant or child with
significant developmental delay. With a child with delays or an infant, we may
ask the parent to play with the baby to “show me how you like to be with or
play with your baby or child.” The parents may ask, “What do you want me to
do?” “Anything you like,” is our response. We offer the use of the toys in the
office or tell them they may bring a special toy from home.
We watch each parent with the child, playing in an unstructured way, for
about 20 minutes or more. We are looking for the developmental level, the range
of emotional themes at each level, and the use of and support that the child is
able to derive from motor, language, sensory, and cognitive skills. We are also
watching for the parent’s ability to support or undermine the developmental level,
the range in that level, and use of sensory, language, and motor systems. After
we watch the mother and father separately, we watch the three of them together
to see how they interact as a group, because sometimes the group situation is
more challenging. Later, we will join them do some coaching and/or start to play
with the child.
During this time, we want to see the child interacting at his or her highest
developmental level, as well as how he relates to a new person whom he knows
only slightly. In addition, we want to determine how to bring out the highest
developmental level at which the child can function. For example, if a child is
withdrawn or self-absorbed and repetitively moving a truck, we will suggest join-
ing his play, trying to move the truck together or put up a fence (one’s hands),
or take another car and, with great joy and enthusiasm, announce “Here I come!”
to entice the child into interaction. Sometimes marching or jumping with an aim-
less child or lying next to a passive, withdrawn child and offering a backrub or
tickle will draw him in. If a child shows signs of symbolic functioning and the
parents do not support symbolic functioning (e.g., in their 3-year-old), we will
try, through coaching or directing, to get pretend play going.
We observe the way the child relates to us, that is, the quality of engage-
ment—overly familiar, overly cautious, or warm. We look for how intentional
he is in the use of gestures and how well he sizes up the situation and us (without
words). We try to determine his emotional range and his way of dealing with
anxiety (e.g., does he become aggressive or withdrawn?). During interaction with
a child, we also note his physical status, speech, receptive language, visuospatial
problem-solving skills (e.g., whether he can search for a toy), gross and fine
motor skills, and general state of health and mood.
In general, we want to systematically describe the child’s ability to attend,
engage, initiate and be purposeful with affects and motor gestures, open and close
many communication circles to solve problems, create ideas (pretend-play), and
converse and think logically.
The next step is to learn what is on the child’s mind. If the child is symbolic,
one looks at the content of the play and dialog, as well as the sequence of themes
that emerge from them. Often, observing how a child shifts from one activity or
theme to another (e.g., separation to perseveration and self-stimulation, aggres-
sion to protectiveness, or exploration to repetition) will provide some initial
hypotheses. The therapist’s job is to be reasonably warm, supportive, and skillful
in engaging the child and helping him evidence his capacities and elaborate.
Formulation
After learning about the child’s current functioning and history and observing
the child and family first-hand, there should be a convergence of impressions. If
a picture is not emerging, one may need to spend another session or two devel-
oping the history or observing further.
One then asks oneself a number of questions. How high up in the develop-
mental progression has the child gone, in terms of 1) attending, 2) regulating and
engaging, 3) establishing two-way intentional communication, 4) engaging in

preverbal problem-solving chains of interaction, 5) sharing ideas and meanings,
and 6) emotional thinking? How well are the earlier phases mastered, and, if not
fully mastered, what are the unresolved issues? For example, does a child still
have challenges in terms of his attentional capacities, the quality of engagement,
and/or his intentional abilities?
Determining the developmental level tells you how the child organizes ex-
perience. For example, if a child is not engaged with other people, he may be
perseverative and self-stimulatory because he can’t interact or he may be aggres-
sive because he basically has no sense of other people’s feelings. He may not
even see people as human. Alternatively, another child may be aggressive because
he cannot represent feelings and therefore acts them out. Still another child may
represent and partially differentiate his feelings but have conflicts about his de-
pendency needs.
One also looks at the range of experience organized at a particular develop-
mental level. If a child is at an ageappropriate developmental level, does she
accommodate such things as dependency, assertiveness, curiosity, sexuality, and
aggression at that level? On the other hand, even if a child is at the right develop-
mental level, the stage may be narrow. In other words, he might be at that devel-
opmental stage only when it comes to assertiveness, but when it comes to depen-
dency he is not quite there, and when it comes to excitement he functions at a
much lower level.
Next, one wants to know about the contributing factors. One set of factors
relates to observations about family functioning; the other set of factors relates
to the assessment of the child’s individual biological differences (see “Individual
Processing Differences” above) and diagnosable medical disorders. The parent–
child interactions are the mediating factors. The developmental formulation or
profile describes 1) the child’s functional developmental level, 2) the contributing
processing profile (e.g., overreactive to sound; auditory, visuospatial, and motor
planning difficulties; and biomedical factors), and 3) the contributing family pat-
terns (e.g., high energy, overloading, confusing family pattern), as well as the
observed interaction patterns of each of the significant caregivers and the types
of interactions that would be hypothesized to enable the child to move up the
developmental ladder and improve his processing skills.
FROM ASSESSMENT TO INTERVENTION

Although a number of intervention and educational strategies have been devel-
oped for children with autism spectrum disorders (10,11), there has not been
sufficient emphasis on working with individual processing and developmental
differences. The widely used intensive, discrete trial, behavioral intervention is
a primary example. It focuses on surface behaviors, with relatively less emphasis
on underlying processing dysfunctions and affective interactions with caregivers

and family members. In addition, in the major outcome study on intensive behav-
ioral approaches (12,13), the entry criteria excluded children with the most typical
presenting autistic profiles and selected for higher-functioning children who could
already imitate and engage in social problem-solving behaviors. Failure to use
a representative population of children with autism and other well-documented
methodological flaws such as not using a clinical trial methodology (10,11,14–
16) have been widely discussed. Also, in one study, intensive behavioral work
with children with more typical types of autism involving severe cognitive defi-
cits did not enable the children to make clinically meaningful progress (17), and
more recent replication efforts are showing more modest gains (18,19).
In contrast to the behavioral model, the DIR model builds on traditional
therapeutic practices, especially those that focus on processing differences and
affective involvement (3,4,20–26). It integrates and extends these traditionally
helpful approaches with an understanding of three unique features: the child’s
functional developmental level, his individual processing differences, and the
affective interactions likely to broaden his functional developmental capacities
and enable him to move to higher developmental levels.
In this approach, the child’s affect or intent is harnessed by following his
lead or natural interests. He is not, however, followed into aimless or persevera-
tive behavior. His affective interests are used as a guide to mobilize attention,
engagement, purposeful interactions, preverbal problem solving, and, eventually,
to create ideas and build bridges between them. Focusing on these fundamental
functional developmental processes rather than specific behaviors or skills (which
are often part of these broader processes) helps to re-establish the developmental
sequence that went awry. For example, rather than trying to teach a child who
is perseveratively spinning the wheels on a car to play with something else or
to play with the car appropriately, the caregiver uses the child’s interest and
gently spins the wheel in the opposite direction to get reciprocal, affective interac-
tions going. These affective interactions are tailored to the child’s individual dif-
ferences: soothing or energetic interactions, visual or auditory patterns, complex
or simple motor patterns may be emphasized, depending on the child’s profile.
Components of a Comprehensive Program

A comprehensive program often includes interactive speech therapy (three to five
times per week), occupational therapy (two to five times per week), appropriate
biomedical intervention, a developmentally appropriate education program, and a
home-based program of developmentally appropriate interactions, which includes
consultations working on caregiver–child interactions and, if needed, direct thera-
peutic work with the child. It also includes regular family consultations and team
meetings, which include reviewing the overall therapeutic and educational pro-
gram and coordination of relevant biomedical interventions.
The home-based program of developmentally appropriate interactions is

especially important. It is related to the recommendation by the National Associa-
tion for the Education of Young Children (NAEYC) of developmentally appro-
priate practices for all children (27). Such practices, however, are difficult for a
child with severe processing problems who may spend hours perseverating and
self-stimulating, including repetitively watching the same videotapes. To help
such a child become involved in developmentally appropriate interactions re-
quires tailoring the interactions to the child’s natural interests (mood and mental
state), functional developmental level, and individual processing differences. It
often includes three types of interactions: 1) spontaneous, follow-the-child’s-lead
interactions geared to enable the child to work on the six functional develop-
mental levels, 2) semistructured problem-solving interactions to work on specific
cognitive, language, and social skills as determined by the team of parents and
educators (e.g., helping the child to say “open” when her toy is put outside the
door), and 3) motor, sensory, and spatial activities geared to improve these typi-
cally vulnerable processing capacities. These developmentally appropriate types
of interactions are needed for much of the child’s waking hours to mobilize
growth because it is what a child does most of the time that determines her pattern
of progress and because, as indicated, without them, she will often shift into
perseverative, self-stimulatory, or aimless patterns.
When a child develops some capacity for relating, gesturing, and imitating,
including imitating words, an important component of the overall program during
the preschool years is an integrated preschool (i.e., 1/4 of the class is children
with special needs and 3/4 is children without special needs) that has teachers
especially gifted in interacting with challenging children and working with them
on interactive gesturing, affective cueing, and early symbolic communication. It
enables children with special needs to interact with children who are interactive
and communicative (e.g., as a child reaches out for relationships and communica-
tion, there are peers who reach back). Four or more play sessions a week with
a peer who is interactive and verbal are also essential at this point, so that the child
can practice his emerging abilities with a friend. To minimize self-absorption and
perseveration and to enable the children and their parents to be re-engaged, it is
important for the therapeutic program to begin as soon as possible.
The DIR intervention approach, which focuses on the delayed child’s de-
velopmental level and individual differences, is different from psychotherapy or
play therapy. What often occurs in traditional play therapy with children with
autism is a type of parallel play, rather than true developmentally based interac-
tions (1,2,28,29).
EARLY IDENTIFICATION
The DIR model of assessment and intervention planning also lends itself to the
early identification of autism spectrum and other developmental disorders.
One of the most important components of a functional approach to interven-

tion is the clinician’s initiation of the interventions at the earliest possible time.
Early intervention minimizes a child’s ongoing functional impairments and
missed opportunities for mastering critical functional skills. For example, many
children who are diagnosed between ages 21/2 and 4 with autism spectrum disor-
ders began evidencing a subtle deficit in affective reciprocity and complex, pre-
verbal, interactive problem-solving patterns between 12 and 16 months of age
(30), and by 18 months of age are unable to engage in joint attention tasks,
purposeful pointing, and early forms of pretend-play (31). The children who are
not helped to engage in complex social problem-solving interactions at this age
(e.g., leading Daddy by the hand to the toy area and pointing to the desired play
object) miss an opportunity for mastering critical social, emotional, language,
and cognitive skills.
There is mounting evidence that the absence of critical functional capacities
is associated with increased likelihood of severe developmental disorders. For
example, in studies of autism spectrum and related developmental disorders, the
following capacities are often not present: joint attention (32), social reciprocity
(33–38), functional language (39), selected early motor capacities (40) and motor
planning and sequencing (41), and early indications of symbolic functioning (e.g.,
pretend-play) (31,42).
There is a confluence of studies showing the presence of certain milestones
in healthy development and their absence in children at risk for or evidencing
disorders of relating, thinking, and communicating. These studies, together with
the growing roadmap of social, emotional, cognitive, language, and motor mile-
stones, provide the basis for delineating essential functional developmental land-
marks (1,43). Therefore, just as a child’s physical growth can be charted, func-
tional developmental progress should be monitored to help identify difficulties at
the earliest possible age. There are three levels to monitoring a child’s functional
development. The first involves broadening and updating the frame of reference
that pediatricians and other primary health-care professionals, educators, and par-
ents use for clinical observations and/or questions about an infant and young
child’s development. This involves using the functional developmental mile-
stones outlined earlier. These milestones incorporate the well-known motor, lan-
guage, social, and cognitive landmarks such as crawling, walking, first sounds
and words, smiling, and imitating, as well as developmental indicators described
by the Child Neurology Society of the American Academy of Neurology as
“nearly universally present by the age indicated” (no babbling by 12 months; no
gesturing, pointing, waving “bye-bye,” etc., by 12 months; no single words by
16 months; no two-word spontaneous (e.g., functional) phrases by 24 months;
and any loss of language or social skills at any age) (44). The functional develop-
mental milestones, however, go beyond these well-known indicators and focus on
integrated developmental capacities identified in more recent studies and clinical
observations (1,2,24,28).
Historically, clinicians have approached children’s development in terms

of isolated areas, such as motor development, the functioning of the senses, as-
pects of language and cognition, spatial problem solving, and social functioning.
When looking at separate areas of development, a child can operate at a relatively
advanced level in one area (e.g., motor development) and yet have significant
challenges in another area (e.g., language development). Although specific as-
pects of development are very important to identify and assess, it is more useful
for monitoring purposes to look at the full range of a child’s functional capacities.
These capacities represent the way in which the child uses all his abilities to-
gether.
The child’s functional developmental capacities require a coming together
of motor skills and sensory processing, cognitive, and language capacities, under
the guidance of his or her emotional intent and proclivities. These functional
emotional capacities include the child’s ability to focus and attend, engage with
others, initiate reciprocal interactions to intentionally communicate needs (such
as reaching to be picked up), and move on to complex problem-solving interac-
tions (such as taking the caregiver by the hand to find the desired toy). They also
include the child’s ability to use ideas and words to communicate basic needs,
as well as to explore imaginative thinking (make-believe) and use logical bridges
to combine ideas as a basis for rational thinking, advanced logical communica-
tion, and problem solving involving a functional sequence.
Each of these capacities has an emotional, language, motor, sensory, and
cognitive component. For example, the capacity for back-and-forth interaction
(reciprocity) has a social and emotional component (the child’s desire or intent
to communicate, get a toy, or smile), a motor component (purposeful smiles or
hand movements), a language component (using sounds for communicative in-
tent), a sensory component (visual and auditory processing and responding to the
gestures of the other person), and a cognitive component (engaging in “means/
ends”—i.e., purposeful—interactions). The clinician, however, does not need to
consider all the separate components or all possible examples of a particular
milestone. He need only ascertain through a simple question or observation if
the milestone is present or absent, e.g., whether a 9-month-old infant can initiate
and respond to purposeful actions. Each of these readily identifiable milestones
(no more difficult to ascertain than a child’s ability to walk) can be readily asked
about (and/or observed). For example, a simple question or observation could
determine the presence or absence of back-and-forth interaction.
When a child is unable to master these functional milestones, different com-
ponents of development might be contributing to the child’s difficulty. Simply
having a mild motor delay, for example, may not derail relating, communicating,
or thinking. On the other hand, a mild motor delay coupled with severe family
dysfunction or a very severe motor delay might derail one or more functional
milestones. The functional milestones are the common pathways or the doors
through which the child navigates. The child’s ability or inability to walk through
these doors provides an important picture of his adaptive and maladaptive devel-
opment and the need for further evaluation and, possibly, intervention.
If observing and/or asking about a child’s functional developmental capaci-
ties raises questions about appropriate progress, a second level of monitoring
should be considered. This should involve screening questionnaires that have
been used with a large number of children and shown to identify different types
of developmental problems. Screening questionnaires that cover a broad range of
developmental competence include the Communication and Symbolic Behavior
Scales Developmental Profile (45) and the Ages and Stages Questionnaire (ASQ):
A Parent-Completed, Child-Monitoring System, Second Edition (46).
If a systematic screening questionnaire supports the impression from clini-
cal observations and questions, then a third level should be considered: a compre-
hensive developmental evaluation to determine the nature and extent of a sus-
pected problem.
In order to broaden our frame of reference and implement the first level
of monitoring of an infant or child’s progress, it may prove helpful to have a
functional developmental growth chart and questionnaire that identify the mile-
stones to be observed or asked about. The growth chart and questionnaire must
provide straightforward, clear descriptions that can readily be observed by par-
ents, health-care providers, and educators. It must cover all the areas of develop-
mental functioning—emotional, social, cognitive, language, motor, and sen-
sory—and all the stages of infancy and early childhood.
Figure 2 presents a functional developmental growth chart (followed by
the functional developmental questionnaire) similar to a physical growth chart.
The developmental growth chart enables clinicians to look at the pattern of a
child’s growth, rather than simply at a few items at a certain age. Patterns of
change over time often provide the most useful information about a child’s abili-
ties.
In Figure 2, the functional developmental capacities to be monitored are
listed on the horizontal axis. The child’s age is on the vertical axis. A 45-degree
line shows the expected age range at which a child is expected to master each
capacity. As can be observed, a child’s functional developmental accomplish-
ments can be charted in relation to the age at which the accomplishment is ex-
pected to emerge and the age at which it does emerge. When a child does not
evidence the next milestone during the expected time interval, the last functional
capacity mastered is recorded on the chart. The next milestone, if it occurs, is
then recorded at whatever later time it is manifested. The 45-degree line indicates
a typical developmental curve. A child who is precocious in a predictable manner
(e.g., 3 months ahead of expectations) will have a functional developmental curve
that parallels the typical one and is a little above it. A child who is a little behind
the expected curve (e.g., 3 months behind on the functional developmental mile-
stones) will have a curve that parallels the typical curve but may fall just below
Figure 2 The Functional Development Growth Chart.

it. When a child’s curve is below the norm, the child should be evaluated to
identify the factors that may be contributing to the developmental lag and what
may be a helpful response.
Most worrisome, and a red flag, is a curve that arcs away from the line;
that is, the distance from the line keeps growing, indicating a delay that is increas-
ing as the child becomes older (shown as the lowest line on the chart). The point
at which the curve begins arcing is where immediate assessment and possible
intervention are indicated. It is also a red flag if the developmental curve is run-
ning parallel to the typical curve but is significantly below it.
This developmental chart can be used by parents, educators (including day-
care staff), and other child-care facilitators to monitor a child’s functional capaci-
ties. In general, a child will have mastered a milestone when she can, most of
the time, engage in the behavior associated with the milestone. Mastery is not
indicated in a child who is only occasionally able to mobilize the age-appropriate
milestone or requires extraordinary support to perform it. The Functional Devel-
opmental Growth Chart Questionnaire following the chart will help in determin-
ing the child’s functional developmental level.
SUBTYPES OF DISORDERS OF RELATING

AND COMMUNICATING
The DIR model of assessment has led to the identification of subtypes of disorders
of relating and communicating based on individual processing differences and
functional developmental capacities.
In working clinically with a large number of cases, we have observed pat-
terns, including processing profiles, that have permitted us to form hypotheses
on the relationship between presenting patterns and different types of progress.
While one must be cautious in suggesting new ways to classify disorders of re-
lating and communicating (47), clinical observations leading to hypotheses are
an important first step in generating new research. Ongoing efforts to observe
subtle clinical features in children with autism spectrum disorders are creating
finer-grained classifications, such as those of the Autism Diagnostic Observation
Schedule (ADOS), to designate children as mild, moderate, or severe (48,49).
In earlier reports, we suggested the category of multisystem developmental
disorder to further individualize the classification of children with disorders in
relating and communicating (1,50). After studying more cases, we have identified
additional developmentally based prognostic indicators that may be more helpful
than the severity of symptoms such as perseveration and self-stimulation. In our
review of 200 cases, children with little or no progress were four times as likely
to have severe motor planning difficulties (i.e., ability to sequence behaviors,
such as to put a toy car in a garage and take it out) and operate below the complex
social problem-solving functional level as children who made consistent and/or
good progress (28). The degree of auditory processing, visual-spatial processing,

and sensory modulation dysfunction (less extreme hyper- or hyposensitivities to
sensation) were also important clinical prognostic indicators.
The way the child responds to the early phases of a comprehensive interven-
tion program brings together his individual differences and the way he is being
worked with, and therefore provides important additional prognostic information.
Based on clinical experience with these factors, we have been able to describe
four subtypes that have prognostic implications (51). This classification should
be viewed as preliminary. We are currently conducting field studies on it.
Subtypes of Severe Disorders of Relating and Communicating

Type I (Constricted Early Symbolic Type)
Tends to make relatively rapid progress—mild to moderate processing dysfunc-
tion, perseverative, and intermittently symbolic. Type I children can be persevera-
tive and self-stimulatory, with scripted and echolalic language, but are also able to
intermittently relate to caregivers, use gestures purposefully, and form problem-
solving sequences (in a narrow range). With a comprehensive program, they can
quickly expand imitative abilities to learn new words and pretend-play. They
may go through a rapid hyperideation phase. Gradually, the type I child becomes
more creative and abstract, often eventually developing precocious language and
verbal skills, but continues to have challenges in motor planning and sequencing
capacities, with variable visual-spatial capacities. These children are often capa-
ble of great warmth, a sense of humor, appropriate peer relationships, and prog-
ressing in a regular education program.
Processing profile: type I has four subtypes that follow the above pattern,
each one characterized by the different motor planning, sensory processing, and
sensory modulation profiles.
Type IA: Relatively strong motor planning, auditory processing, visual-
spatial capacities, and hypersensitive to sensation.
Type IB: Relatively strong auditory processing, weaker visual-spatial ca-
pacities, weaker motor planning and mixed reactivity to sensation.
Type IC: Relatively stronger visual-spatial capacities and motor plan-
ning and weaker auditory processing, with underreactivity to sensation.
Type ID: Relatively strong auditory memory, but relatively weak audi-
tory comprehension, relatively strong visual memory, but weak comprehension,
and mixed reactivity to sensation.
Type II (Variable Complex Problem-Solving Type)
Consistent, but slow progress—moderate to severe processing dysfunction and
intermittently purposeful. Type II children can be perseverative and self-stimula-
tory, with little or no language, intermittent relating, and a very narrow range
of intermittent, purposeful, and problem-solving gestural sequences, and mixed
reactivity to sensations. Very gradually, a type II child expands purposeful and
problem-solving gestural interactions as well as imitative abilities. This type of
child very slowly acquires the use of words and pretend-play and, with a compre-
hensive program, makes very gradual but consistent progress, tending to remain
at a fragmented level of language capacity (i.e., using ideas but having a very
difficult time connecting ideas in a logical sequence). Receptive language is often
stronger than expressive language. Type II children are interested in peers but
have difficulty developing fully interactive communication.
Processing profile: type II is characterized by moderate motor planning
dysfunction (three- to four-step sequences) and more significant sensory pro-
cessing problems. This type has two subtypes.
Type IIA: Hypersensitive to sensation.
Type IIB: Underreactive to sensation.
Type III (Partially Purposeful and Engaged Type)
Very slow progress—severe processing dysfunction; self-absorbed and intermit-
tently engaged. Self-absorbed or avoidant, type III children evidence only inter-
mittent use of simple purposeful gestures (i.e., an “in-and-out” quality) with no
language initially. They can very slowly become more purposeful and engaged
and evidence intermittent problem-solving, gestural sequences. Eventually, iso-
lated words and intermittent use of phrases are possible.
Processing profile: type III is characterized by severe motor planning dys-
function (one- to two-step sequences), weaker auditory and visual-spatial pro-
cessing than type II, and more extreme sensory modulation difficulties (usually
underreactivity, but can be mixed).
Type IV (Aimless, Unpurposeful Type)
Very slow progress with no development of expressive language—very severe
processing dysfunction, aimless, and nonverbal. Very self-absorbed or avoidant,
type IV children are only intermittently and partially engaged, with only fleeting
purposeful interactions. They often evidence extreme motor planning difficulties,
especially oral-motor dysfunctions, making sound production very difficult. Over
time, they can become more purposeful and engaged and eventually use pictures
or other visual aids for intermittent communication, but do not develop consistent
motor planning, problem solving, vocal imitative, or expressive language.
Processing profile: type IV evidences very severe motor planning problems
(aimless to one-step sequences), with very severe oral motor capacity and more
severe auditory, visual-spatial, and sensory modulation problems (usually under-
or mixed reactivity) than in type III.
Type IVA: May make limited progress and become more related, but
does not progress to full purposeful or problem-solving interactions.
Type IVB: No progress, or vacillations between small gains and losses
of functions. Often evidences more overt neurological symptoms.
Children characterized as type I can often do especially well and develop
levels of empathy and creativity not thought possible in children diagnosed with
autism spectrum disorder. In our review of 200 cases, we found that a group of
children with these characteristics progressed through the stages of relating with
greater and greater warmth and longer and longer sequences of gestural and af-
fective, problem-solving interactions. Over a period of years, they learned to use
language both creatively and logically, eventually enjoying peer relationships
and functioning well in regular educational settings. They are now bright, warm,
empathetic, creative youngsters with a range of interests. When we compared the
20 children from this group who had made the most progress with a matched group
of children with no history of developmental and/or learning problems, we found
that they were indistinguishable on assessments of their emotional capacities and
interactions with parents (as measured through analysis of videotaped interactions)
and in their adaptive behavior (as measured on the Vineland Scales) (30).
The type of progress this group of children can make raises an important
question: do these children have a more transient set of autistic symptoms that
is very responsive to an intensive, dynamic intervention? At present, many chil-
dren with autistic disorders are unable to progress to complex functional interac-
tions and pragmatic language. In our chart review, we observed that children
characterized as type II, while engaging and speaking, were still having signifi-
cant challenges in developing creative and abstract language use, as well as full
peer relationships. Type III and IV children tended to have continuing difficulties
in being fully engaged and purposeful, as well as in problem-solving, and had
limited or no verbal abilities.
CONCLUSION
In this chapter we have presented a developmentally based approach (DIR model)
to assessing children with autism spectrum disorder and other disorders of re-
lating and communicating. We have discussed its implications for intervention
planning, early identification, and the classification of clinically useful subtypes.
APPENDIX: FUNCTIONAL DEVELOPMENTAL GROWTH

CHART SCREENING QUESTIONNAIRE
To assess whether a child has achieved a new functional milestone, the answer
must be “yes” to all the questions under that milestone. If the answer is
“no” to even one question, the child has not yet mastered the stage. Remem-
ber, the growth chart is simply a visual tool to draw attention to the develop-
mental areas in which a child is progressing as expected and those in which
he or she may be facing some challenges.
By 3 Months (Stage 1: Focusing and Attention)

Does your infant usually show an interest in things around him or her by looking
at sights and turning toward sounds?
By 5 Months (Stage 2: Engaging in Relationships)

(Ask the question from the prior category plus the new one from this category.)
Does your baby seem happy or pleased to see favorite people: looking and smil-
ing, making sounds or some other gesture, such as moving arms, that indi-
cates pleasure or delight?
By 9 Months (Stage 3: Interacts in a Purposeful Manner)

(Ask the questions from all prior categories plus the new ones from this category.)
Is your baby able to show what he or she wants by reaching for or pointing
at something, reaching out to be picked up, or making purposeful special
noises?
Does your baby respond to people talking or playing with him or her by making
sounds, faces, initiating gestures (reaching), etc.?
By 14 to 18 Months (Stage 4: Organizes Chains of Interaction;

Problem Solving)
(Ask the questions from all prior categories plus the new ones for this category.)
Is your toddler (by 14 months) able to show what he or she wants or needs by
using actions, such as leading you by the hand to open a door or pointing
to find a toy?
Is your toddler (by 18 months) able to orchestrate more complex chains of interac-
tion as he or she solves problems and shows you what he or she wants,
including such things as getting food. For example, does he or she take
your hand, lead you to the refrigerator, tug on the handle, and point to a
particular food or bottle of juice or milk?
Is your toddler (by 18 months) able to use imitation, such as copying your sounds,
words, or motor gestures, as part of a playful, ongoing interaction?
By 24 to 30 Months (Stage 5: Uses Ideas—Words or Symbols—

to Convey Intentions or Feelings)
Does your toddler (by 24 months) ever respond to people talking with or playing
with him or her by using words or sequences of sounds that are clearly an
attempt to convey a word?
Is your toddler (by 24 months) able to imitate familiar pretend-like actions, such
as feeding or hugging a doll?
Is your toddler (by 24 months) able to meet some basic needs with one or a few
words, such as “juice,” “open,” or “kiss”? (A parent may have to say the
word first.)
Is your toddler (by 24 months) able to follow simple one-step directions from a
caregiver to meet some basic need, for example, “The toy is there” or
“Come give Mommy a kiss.”
Is your toddler (by 30 months) able to engage in interactive pretend-play with
an adult or another child (feeding dollies, tea parties, etc.)?
Is your toddler (by 30 months) able to use ideas—words or symbols—to share
his or her delight or interest (“See truck!”)?
Is your toddler able to use symbols—words, pictures, organized games—while
enjoying and interacting with one or more peers?
By 36 to 48 Months (Stage 6: Creates Logical Bridges Between

Ideas)
Is your toddler (by 36 months) able to use words or other symbols (for example,
pictures) to convey likes or dislikes, such as “want that” or “no want that”?
Is your toddler (by 36 months) able to engage in pretend-play with another person
in which the story or drama makes sense? (For example, in the story, do
the bears go visit grandmother and then have a big lunch?)
Is your toddler (by 36 months) able to begin to explain wishes or needs? (For
example, a conversation may contain an exchange such as: “Mommy, go
out.” “What are you going to do outside?” “Play.” The child may need
multiple-choice help from the parent, such as “What will you do, play or
sleep?”)
Can your preschooler (by 48 months) explain reasons for wanting something or
wanting to do something? (For example, “Why do you want the juice?”
“Because I’m thirsty.”)
Is your preschooler (by 48 months) occasionally able to use feelings as a reason
for a wish or behavior? (For example, “I don’t want to do that because I’m
[happy/excited/sad].”
Is your preschooler (by 48 months) able to engage in interactive pretend dramas
with both peers and adults in which there are a number of elements that
logically fit together? (For example, the children go to school, do work,
have lunch, and meet an elephant on the way home.)
Is your preschooler (by 48 months) able to make logical conversation with four
or more give-and-take sequences about a variety of topics, ranging from

negotiating foods and bedtimes to talking about friends or school?
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5
Cognitive and Neuropsychological
Assessment of Children with Autism
Spectrum Disorders
Audrey F. King, Ronald R. Rawitt, Katherine C. Barboza,

and Eric Hollander
INTRODUCTION
Three core features characterize autism spectrum disorders (ASDs): impairment
in socialization, impaired communication, and restrictive or repetitive behaviors,
interests, or activities (1). Since early and intensive behavioral intervention is
essential in the successful treatment of these disorders, early diagnosis is particu-
larly crucial. The diagnosis of ASD is a multistep process, beginning with screen-
ing and followed by more comprehensive assessments (2). This full evaluation
is necessary in order to rule out other disorders (such as verbal and nonverbal
learning disabilities or organic brain disorder), and to guide treatment and educa-
tional planning. Full evaluations include, in addition to diagnosis, cognitive as-
sessment, adaptive functioning assessment, and neuropsychological testing (e.g.,
memory, problem solving, planning, language, and visual-spatial reasoning).
Cognitive and neuropsychological evaluations of children with ASD are
useful to pediatricians and child psychiatrists in clarifying the diagnosis by ruling
out developmental learning disorders, disorders of speech and language, and be-
havioral disorders, and by ruling out/in mental retardation. Cognitive and neuro-
psychological evaluations are essential for school personnel in developing Indi-
vidual Education Plans (IEP), and are important in supporting educational
87
88
Table 1 Generally Used Cognitive, Adaptive, and Neuropsychological Tests
Scale Authors, year Assesses Description
Tests of general intel-

lectual functioning
Wechsler Intelligence Wechsler D (1991) IQ in children aged 6–16 Individually administered; 12 subtests: picture comple-
Scale for Children, tion, information, coding, similarities, picture arrange-
3rd (WISC-III) ment, arithmetic, block design, vocabulary, object as-
sembly, comprehension, digit span, and mazes and a
symbol search subtest
Leiter International Per- Roid GH, Miller JN Performance IQ in chil- Nonverbal, culturally fair measure; visual matching test
formance Scale–R (1997) dren ages 2–18
Raven’s Coloured Pro- Raven JC (1947) Reasoning. Child through Untimed intelligence test intended for the entire range
gressive Matrices adult. of intellectual development; does not require verbal-
ization, skilled manipulation ability, or subtle differ-
entiation of visual-spatial information.
Adaptive functioning
Vineland Adaptive Be- Sparrow S, Balla D, Performance of daily ac- Semistructured interview for caregiver; four domains:
havior Scale Cicchetti DV tivities required for per- communication, daily living skills, socialization, and
(1984) sonal and social suffi- motor skills; can be used with all populations to de-
ciency of individuals termine levels of adaptive behavior and the extent to
from birth to adulthood which handicaps affect daily functioning
Visual and sensory per-
ception
Rey-Osterrieth Com Osterrieth PA (1944) Perceptual organization Timed test; measures visual perception/long-term vi-
plex Figure and visual memory. sual memory; the order and accuracy with which the
Children and adults. figure is copied and drawn from recall provides use-
ful information concerning the location and extent of
King et al.
any brain damage.

Learning and memory tests
Wide Range Assess- Sheslow D, Adams Ability to actively learn Three domains tested: verbal memory scale, visual
ment of Memory and W (1990) and memorize a variety memory scale, and learning scale
Learning (WRAML) of information in chil-
dren aged 5–17
Buschke Selective Re- Buschke H (1973) Verbal memory deficits Measures the acquisition and retention of eight unre-
minding Test lated, common words across 10 trials
Tests of attention and
Assessment of Children
executive function
Trail Making Test Reitan RM (1969) Speed for attention, se- Subject draws a line through 25 stimuli in numerical or-
quencing, flexibility, vi- der (part A) and of 25 encircled numbers and letters
sual search and motor in alternating order (part B)
function; child and
adult versions
VIGIL Continuous Per- For Thought, Ltd. Brain damage, in subjects Computerized flash task requiring the execution of one re-
formance Test (1996) aged 6 to adulthood sponse with simultaneous inhibition of another of stim-
uli presented visually, auditorally, or in both modalities.
Measures vigilance or the maintenance of concentration
on a simple or relatively complex task over time.
Matching Familiar Fig- Kagan J, et al. Reflection versus impul- Timed with two practice and 12 experimental items;
ures Test (MFFT) (1964) sivity in children, ado- measures delay of decision making in situations
lescents, and adults where a correct response is not obvious (reflection)
vs. the quick choice of an alternative without ade-
quate consideration of options (impulsivity).
Wisconsin Card Sorting Heaton RK, Chelune Cognitive set-shifting and Measure requires the ability to develop and maintain
Test (WCST) GJ, Talley JL, maintenance ability in re- an appropriate problem-solving strategy across chang-
Kay GG, Curtiss sponse to reinforcement ing stimulus conditions in order to achieve a future
G (1993) contingencies and non- goal
verbal abstract concept
89
formation. All ages.

90
Table 1 Continued
Scale Authors, year Assesses Description
Stroop Color and Word Golden CJ (1978) Cognitive flexibility, resis- Used in diagnosis of brain dysfunction in the evalua-
Test tance to interference tion of stress, personality, cognition, and psycho-
from outside stimuli, pathology
and reaction to cogni-
tive stress. Ages 17 to
adult.
Motor and graphomo-
tor function
Motor-Free Visual Per- Colarusso RP, Ham- Visual-perceptual abilities Assess visual perception in children; especially useful
ception Test mill DD (1996) without involving mo- for those who may have learning, cognitive, motor,
tor skills of children or physical disabilities. Measures five areas of per-
ages 4–12 ception: spatial relationship, visual discrimination,
figure-ground, visual closure, and visual memory.
Purdue Pegboard Test Tiffin J (1968) Finger dexterity and Tests individual’s ability to move right, left, and both
hand–eye coordination hands, fingers and arms (gross movement), and to con-
trol movements of small objects (fingertip dexterity)
Denckla Motor Perfor- Denckla MB (1985) Soft neurological signs in Looks for signs of adventitious movements as child fo-
mance Battery children with motor co- cuses on a delicate or difficult task (e.g., sticking out the
ordination problems in tongue while attempting to write, or grimacing, or mov-
the absence of diagnosing the mouth to the side while focusing on a delicate ac-
able neurological condi- tivity), simultaneous movements of another part of the
tions body like gesticulations and grimacing while moving a
another part of the body, or the mirror movements of
overflow indicating that difficulty exists in the specific
activation of a pathway without causing activation of
King et al.
the counterpart on the other side of the body

Developmental Test of Beery KE, Bukten- Visual-motor integration Screens for visual-motor deficits that can lead to learn-
Visual-Motor Inte- ica NA (1989) in children, adoles- ing and behavioral problems
gration (VMI) cents, and adults
Facial recognition,
emotional labeling, and
empathy
Benton Facial Recogni- Benton AL, et al. Ability to recognize faces A three-part standardized measure of the ability to
tion Test (1994) match unfamiliar faces; contains a 27-item short
Assessment of Children
form and a 54-item long form; provides additional

substantive data in the evaluation of brain-damaged
patients
Pictures of Facial Af- Ekman P, Friesen Ability to recognize fa- Consists of 110 black-and-white photographs of 14
fect Test WV (1976) cial affect models; six emotions are represented in the set of
photographs: “happiness,” “sadness,” “fear,” “anger,”
“disgust,” and “surprise”; used to determine treat-
ment effects of social skills training with persons
with mental retardation
Rosenzweig Picture Rosenzweig S Patterns of frustration and Consists of 24 cartoon-like pictures, each depicting two
Frustration Test (1978) aggressive response to people in a mildly frustrating situation of common
everyday stress occurrences. The task is to provide a reply for the
anonymous frustrated person in the picture; three
types of aggression (extrapunitive, intropunitive, im-
punitive) and three directions of aggression (obsta-
cle-dominance, ego-defense, need-persistence) are as-
sessed, yielding a total of nine scored factors.
91
92 King et al.
placement decisions (i.e., special-education placement, full inclusion). These

evaluations are also an essential foundation for the treatment planning process,
providing valuable treatment targets for occupational, physical, and behavioral
therapies. Overall, full evaluations are crucial in guiding treatment, yielding a
clear picture of a child’s unique strengths and weaknesses, and in estimating
prognosis.
Throughout this chapter, standardized tests that have been validated
through use in research studies in autistic populations are discussed. Although
this selection is a very small sample of available tests, it represents those that
have successfully characterized ASD populations or differentiated the cognitive
and neuropsychological differences between ASD and other disorders. Table 1
provides a wider range and brief overview of neuropsychological and cognitive
tests available for clinical child populations in general.
COGNITIVE EVALUATION
A cognitive evaluation yields critical information concerning a child’s abilities,
disabilities, strengths, and weaknesses. Research has revealed specific cognitive
profiles of individuals with ASDs, including spared performance on tasks that
are rote, mechanical, or perceptual, and impaired performance on tasks that are
complex or abstract (2). This “saw tooth” profile—common in children with
ASDs—reveals significant inter-subtest peaks and valleys. This profile suggests
relative task-specific strengths in simple memory, visual-spatial problem solving,
and visual reasoning. Relative weaknesses include those in fine motor skills, com-
plex information processing, verbal comprehension, and planning (3). However,
this profile, although clinically common, has not been shown to be universally
diagnostic, reinforcing the belief that children with autism show great variability
in skills compared with one another as well as with other children (4).
The choice of test for a cognitive evaluation depends on the child’s verbal
ability and age. Children with verbal ability may be tested using the Wechsler
Preschool and Primary Scales of Intelligence–Revised (WPPSI-R) (5) or the
Wechsler Intelligence Scale for Children–Third Edition (WISC-III) (6). The in-
formation gathered from these tests reveals functioning in attention, memory,
visual-spatial problem solving, abstract thinking, processing speed, fund of infor-
mation, and comprehension. Another verbal test of intelligence is the Stanford-
Binet Intelligence Scale (SBIS–Fourth Edition) (7). The subtests that comprise
this battery cover four broad areas: verbal reasoning, abstract/visual reasoning,
quantitative reasoning, and short-term memory (8). Notably, the SBIS cannot
assess for mental retardation in 2-year-olds, and more severe MR cannot be as-
sessed in 3- to 4-year-olds due to the floor effect on this measure which truncates
results at the low end for children between 2 and 5 years of age. Although the
Assessment of Children 93
WPPSI-R, WISC-III, and SBIS have no normative data for children with develop-
mental delays, they are widely considered “gold standard” indices of cognitive
functioning and an integral component of neuropsychological evaluations.
Another cognitive test widely used with children is the Kaufman Assess-
ment Battery for Children (K-ABC) (9). This test battery assesses simultaneous
and sequential mental processing. Six of these 10 subtests are considered nonver-
bal and are well suited for children with communication deficits. However, al-
though the K-ABC battery is otherwise well standardized, normative data are
lacking for children with developmental disabilities.
Overall, verbal children who exhibit difficulty with attention, interpersonal
interaction (e.g., looking at the examiner, following the examiner’s instructions),
and negative behaviors will experience greater difficulty in completing these tests,
and the accuracy of the cognitive profiles should be judged with caution.
For youngsters who lack verbal communication, a nonverbal test of cogni-
tive ability is necessary to adequately assess the child’s nonverbal intelligence.
However, the same caveats apply as for children with verbal abilities: negative
behaviors (self- and other-directed aggression), repetitive behaviors, noncompli-
ance, attentional deficits, and over- or underactivity will compromise the validity
of the profile. Nonverbal measures of intelligence assess cognitive skills and apti-
tudes such as reasoning, spatial visualization, memory, attention, and speed of
processing. These concepts are evaluated through the use of pictures, figural illus-
trations, and coded symbols, with no reliance on perceiving or manipulating
words or numbers that are printed or verbally presented (10).
The Leiter International Performance Scale–Revised (Leiter-R) (10) is a
nonverbal cognitive battery designed for populations for whom verbally based
evaluations are not appropriate. The Leiter-R has been shown useful for testing
children who do not speak English, speak English as a second language, are
hearing-impaired, or have significant problems with overactivity (e.g., attention-
deficit/hyperactivity disorder), and may thus be especially useful for use in ASD
populations.
Other nonverbal measures of intelligence include Raven’s Progressive Ma-
trices (11), a series of tests of inductive reasoning. This series is appropriate for
nonverbal populations because it requires no verbal ability, skilled manipulative
ability, or subtle differentiation of visuospatial information on the part of the
examinee. It consists of three forms: the Standard Progressive Matrices (11,12),
the Colored Progressive Matrices (13,14), and the Advanced Progressive Matri-
ces (16). There are several shortcomings to this battery. First, because normative
data for these tests are outdated, percentiles obtained by an individual taking the
test today may not be comparable with those obtained by an individual 40 years
ago. Additionally, there are no normative data for use of Raven’s Progressive
Matrices with a developmentally delayed population.
94 King et al.
ADAPTIVE BEHAVIOR EVALUATION

The assessment of a child’s capacity for self-sufficiency in day-to-day functioning
is a critical component when a developmental disability or mental retardation is
suspected. A diagnosis of mental retardation requires an IQ score in the below-
average range (⬍70) and deficits in adaptive behavior (1). The Vineland Adaptive
Behavior Scales (VABS) (17) evaluate children’s personal and social sufficiency
in a semistructured interview with a primary caregiver. In addition, the VABS
have recently added normative data for the autistic population (18). These scales
have been found to assess social deficits in autism (19–21) and relative strengths
in daily living skills (18). Items are classified under four major adaptive domains:
communication, daily living skills, socialization, and motor skills. The VABS
yield a summary score referred to as the Adaptive Behavior Composite, which
is predictive of social adaptation and long-term outcome (22). Of several avail-
able scales of adaptive behavior, the VABS are rated as having excellent psycho-
metric properties and usefulness because of the availability of supplementary
groups (ambulatory and nonambulatory mentally retarded institutionalized indi-
viduals, noninstitutionalized individuals, emotionally disturbed individuals, and
hearing- and/or visually handicapped children) (23).
NEUROPSYCHOLOGICAL EVALUATION
Impairment in neuropsychological functioning is an important component in the
evaluation of children with autism. Children with autism show diverse neuropsy-
chological impairments in explicit and working memory, establishing rules, plan-
ning, and response inhibition (2,24,25). The evaluation of attention, executive
functions (e.g., memory), praxis, and visual processing can guide treatment and
educational strategies aimed specifically at the child’s individual strengths and
weaknesses, and, to a lesser extent, may predict outcome. Neuropsychological
evaluation of the child with autism increases in difficulty with the severity of the
child’s illness. Important factors to consider when testing children with autism
are that attentional difficulties can interfere with testing memory and visual pro-
cessing while the presence of negative behaviors (self- and other-directed aggres-
sion), repetitive behaviors, and noncompliance can significantly compromise the
validity of the testing results.
Memory
Many published tests are available for testing memory in children; however, few
have been used with an autistic population. A search of the literature (PsychInfo
and PubMed) revealed that the Wisconsin Card Sort Test (WCST) and the Cali-
fornia Verbal Learning Test–Children are two of the tests most often used for
memory research in an autistic population.
The California Verbal Learning Test (CVLT-C) (26) assesses strategies

and processes in learning and remembering verbal material and is appropriate
for ages 5–16. It consists of two “shopping lists”: list A, composed of five words
in each of three categories (fruits, vegetables, and clothes) and list B, composed
of five words in each category of fruits, tools, and baked goods. The child is
asked to use several phases of memory in order to recall items from each list.
The CVLT-C shows moderate to high estimates of internal consistency and mod-
est test–retest reliability while showing good validity. The CVLT-C has demon-
strated utility in characterizing memory deficits in individuals with head injury;
epilepsy; Alzheimer’s, Parkinson’s, and Huntington’s diseases; vascular demen-
tia; depression; and schizophrenia (8). The CVLT-C has also been used with
autistic populations to study visual and auditory memory (37), prediction of adap-
tive behavior functioning (27), and recall readiness (metacognitive ability) (28)
and explicit versus implicit memory (29).
The WCST (30,31) is another popular and well-standardized and well-
normed test that has been used in autistic populations in testing working memory
(32) in addition to other executive functions such as planning, organization, cog-
nitive flexibility, and attention. The normative data for this test, provided by
Heaton et al. (33), range from age 6 years 5 months to 89 years of age. This test
is composed of two packs of 64 response cards that the test subject must match
to one of four key cards. The examiner changes the rules for matching the cards
while the subject is given feedback about whether each response is correct or
incorrect as he or she attempts to adapt to the shifting rules. The WCST has
demonstrated good reliability and validity.
A shortcoming of both the WCST and the CVLT-C is that they both require
the child to understand verbal instructions, and in the case of the CVLT-C require
verbal responses. Thus, these tests may have limited usefulness with children
with more severe autism; however, no publications uncovered in a literature
search reported the use of measures that do not rely as heavily on verbal ability
to test memory functioning (such as the Rey-Osterrieth).
Executive Functions
Inability to establish rules and to plan are neuropsychological deficits often found
in children with autism. These skills fall under the broad category of executive
functioning, along with initiation, hypothesis generation, cognitive flexibility, de-
cision making, regulation, judgment, feedback utilization, and self-perception.
These functions are important to assess, formally or informally, especially when
determining whether an individual can live independently.
Planning and rule generation are important higher-order cognitive functions
that affect major areas of functioning, including decision making and daily living.
Of the neuropsychological tests developed to study planning and rule generation
96 King et al.
in children with autism, the WCST is among the most popular and has been used
as a measure of executive functions in several studies (27,32).
Attention
Attention and concentration impact children with autism in many ways. Deficits
in these areas impact learning, memory, daily living skills, and cognitive ability.
The abilities to inhibit responses, distinguish relevant from nonrelevant informa-
tion, develop a system of rules, and solve problems are dependent on a child’s
memory and concentration. Tests that have been used to study attention in chil-
dren with autism include the Continuous Performance Test (CPT) and the WCST
(34).
Conners’ CPT (35) is a widely used test of attention, primarily because
of the wide range of subject-response parameters evaluated and because of the
flexibility of the program (8). It is appropriate for ages 4 through 70, although
normative data for the test indicate a bias toward a younger sample (subjects
aged 4 to 34) (8). A computerized task, it requires the test subject to strike the
appropriate key for any letter except when an X appears on the computer screen.
There are six blocks, each with 20-trial sub-blocks. The interstimulus intervals
vary between blocks, providing a new stimulus at 1, 2, or 4 seconds. Conners’
CPT scores reflect several categories of response style, including number of Hits
(correct responses), Omissions (not responding to a target), Commissions (re-
sponding to a nontarget), Hit rate (mean response time), Hit Rate Standard Error
(consistency of response times), Attentiveness, and Risk Taking (response ten-
dency to be cautious or more impulsive).
Conners’ CPT shows low to moderate correlations with other measures of
attention, but good ability to distinguish clinical from nonclinical populations
(35). The advantage of Conners’ CPT is the considerable amount of data that
can be collected on a number of important aspects of attention. Also, the detailed
analysis allows for detailed characterization of an individual’s deficits.
General Neuropsychological Functioning

The NEPSY (Developmental Neuropsychological Assessment) (36) is a compre-
hensive neuropsychological test designed to assess basic and complex cognitive
capacities critical to a child’s ability to learn and function productively in and
outside school settings. The subtests of the NEPSY are designed specifically for
children between the ages of 3 and 12, whereas other neuropsychological tests
are designed for use across the lifespan, which is a strength of this measure. The
NEPSY consists of a range of subtests that assess neuropsychological functioning
in five domains: Attention/Executive Functions, Language, Sensorimotor Func-
tions, Visuospatial Processing, and Memory and Learning. The NEPSY provides
a percentile rank score based on comparison with a nonclinical child population.
Reliability of the NEPSY is moderate to high, ranging from an internal

consistency coefficient of 0.64 to 0.91 across subtests and age. Stability coeffi-
cients of the NEPSY are also good, ranging from 0.59 to 0.90 across subtests
and age. Construct and content validity were also carefully studied and developed
(36). The strengths of the NEPSY are its careful construction, good psychometric
properties, and design for use specifically with child populations. However, its
usefulness for autistic populations has not been explored.
CONCLUSION
Cognitive and neuropsychological evaluations of children with ASD serve many
purposes for clinicians. These evaluations can assist in clarifying an ASD diagno-
sis by ruling out other disorders, developing and supporting educational place-
ment decisions (e.g., special-education vs. full inclusion), and guide treatment
planning by providing valuable treatment targets for occupation, physical, and
behavioral therapies.
Although great strides have been made in understanding the diagnosis and
treatment of autism in the past two decades, controversy continues regarding
adequate cognitive and neuropsychological testing for low-functioning children
with autism. Currently, many measures used to assess autistic individuals are not
designed specifically for use with autism and do not provide normative data for
autistic populations. Measures that are used in general clinical populations are
typically useful in testing autistic children who are relatively high-functioning
because of their reliance on verbal comprehension and communication.
The measures discussed in this chapter have been used in research with
high-functioning autistic populations, providing a greater understanding of the
strengths, deficits, and neuropsychological components of autism that are crucial
for clarifying the initial diagnosis, ruling out disorders that better explain the
symptoms, and guiding education and treatment. However, a gap remains in de-
termining the specific cognitive and neuropsychological deficits in lower-func-
tioning autistic children because of the lack of instruments developed for use in
nonverbal and minimally communicative populations. This gap must be filled
with further research. Specifically, significant progress must be made in the abil-
ity to assess the cognitive ability of low-functioning children with autism so that
they can be better served by treatment and, especially, in educational placement.
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6
Assessment and Diagnosis of Pervasive
Developmental Disorder
Cecelia McCarton
Albert Einstein College of Medicine
and McCarton Center for Developmental Pediatrics
HISTORICAL PERSPECTIVE
Kanner (1) first described the behaviors of 11 children between the ages of 2
and 8 years who presented with common characteristics of a profound lack of
social engagement, a range of communication problems, and unusual responses
to inanimate objects and the environment. He called these behaviors “autistic
disturbances.”
Kanner believed that the 11 children he studied had one fundamental distur-
bance: “an inability to relate themselves in an ordinary way to people and situa-
tions from the beginning of life.” He reported that as infants these children failed
to make direct and sustained eye contact and often resisted being held. Lan-
guage—in terms of prosody, content, and usage—was impaired, with echolalia,
pronoun reversal, and a language-processing deficit. Play was repetitive and ste-
reotypic, often lacking imaginative themes. Finally, the desire for sameness often
overwhelmed the children behaviorally if any change was introduced into their
schedule or environment. Kanner’s lucid and clinically precise description of
these behaviors remains the hallmark of the diagnosis described in the fourth
edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)
(2).
101
102 McCarton
DEFINING PERVASIVE DEVELOPMENTAL DISORDERS/AUTISM

SPECTRUM DISORDERS
Although Kanner did an excellent job describing these “autistic disturbances” in
his sample of children, many terms through the years have been used to refer to
these behaviors (childhood schizophrenia, autistic psychoses, and atypical au-
tism). The study and research of this complex disorder over the past three decades
have eventually brought these behaviors under the heading of pervasive develop-
mental disorders or autism spectrum disorders. These terms describe a continuum
of neurological disorders that must have at least three core facets: an impairment
in socialization, an impairment in verbal and nonverbal communication, and re-
stricted or repetitive patterns of behavior (2).
Under the heading of pervasive developmental disorder, there are five spe-
cific diagnoses:
1. Autistic disorder
2. Pervasive developmental disorder–not otherwise specified
3. Asperger’s syndrome
4. Rett’s syndrome
5. Childhood disintegrative disorder
Autism Disorder
For the purpose of this chapter, the term autism spectrum disorder (ASD) is used
synonymously with pervasive developmental disorder (PDD) as umbrella terms.
The term autism disorder, or autism, is used to refer to the specific diagnosis
defined by specific criteria in DSM-IV (2).
The presentation of autism can vary greatly in its severity. However, in
order to be diagnosed with autism disorder, a child must meet six of the 12 criteria
listed in DSM-IV (2) and these symptoms must appear prior to 3 years of age.
The criteria fall into three broad categories:
1. Impairment in communication and imaginative activity
2. Impairment in reciprocal social interaction
3. Markedly restricted repertoire of activities and interests
Additional behavioral and motoric abnormalities are also described as part
of this disorder but do not have to be present to make the diagnosis. The severity
of autism is a spectrum with presenting symptomatology ranging from mild to
severe. One can have a child with normal or above-average intelligence as well
as a child with mental retardation.
Communication Impairment
Children with autism often do not develop an index point or respond consistently
to their name. A portion of children often have a verbal apraxia, which is an
Pervasive Developmental Disorder 103
interruption in the neuromotor signals to the mouth, tongue, and lips necessary
to form sounds and words consistently. Other children have echolalia; they repeat,
parrot-like, what is said to them. Echolalia may be immediate: e.g., when a parent
asks, “Are you hungry?,” the child replies, “Are you hungry?” In delayed echola-
lia, the child recites dialog, scripts from videos, TV commercials, or stories read
to them days or weeks ago. Pronoun reversal is also common, particularly with
you and I. They may refer to themselves in the third person or by name. Jargoning
can also be present, as well as using words and phrases out of context. Compre-
hension of language is often poor; the child, at best, may understand simple com-
mands or directives that have been said many, many times before and that have
often been associated with a visual cue or prompt or said in a particular context.
Prosody—the tone of a child’s voice—can also be affected. It may have a mono-
tone or singsong quality or be loud and high-pitched.
Impaired Social Interactional Skills
One of the first behaviors reported by parents is lack of eye contact or variable
eye contact. Children may have better eye contact with one or both parents than
with any other individual. Parents describe children as “being in a world of their
own,” “zoning out,” “looking through people,” or “preferring to be alone.” Often,
children will not reach out to be held or cuddled, and in fact squirm or stiffen
to get away. Some children do not mind being held or cuddled but accept it in
a more passive way. Joint attention is often lacking, and they do not share in
doing or seeing something with another person.
In terms of their peers, children with autism will play by themselves, engage
in parallel play, or observe from the periphery. They tend to prefer children who
are younger or older than they are. They will often actively engage in chase games
or follow children in activities that occur in a park or outdoor setting. However,
the social cues of others (a smile, a frown, a wave) may be meaningless to them.
Abnormal Behaviors
Children with PDD/ASD may not play at all or have very unusual play patterns.
A child may demonstrate no pretend-play based on imaginative themes and in-
stead use toys in a functional cause-and-effect manner. Toys may be lined up or
carried about or used in unusual ways (e.g., dropping a toy continuously on a
surface or spinning the wheels of a car). Many children require a “sameness or
routine” in their play activities, and any intrusion or interruption is likely to result
in a tantrum. Transitions are often difficult throughout the day’s activities and
may result in “meltdowns.” Stereotypic movements such as hand and/or arm
flapping, finger flicking, rocking, spinning, and teeth grinding may also become
prominent whenever the child is excited or upset.
A preoccupation with certain objects may also be present. Some children
engage in repetitive actions such as opening and closing drawers, turning light
104 McCarton
switches on and off, and spinning objects. Strings, lights, water, and ceiling fans
are particularly attractive. Often children must smell or lick an object before they
engage with it. Lines and the edges of objects (e.g., a desk or a piece of paper)
can be especially appealing, sometimes with the child squinting or looking out
of the corner of his eye at the object.
Associated Impairments
Sensory: Besides the senses of sight, touch, taste, smell, and hearing, our
nervous system also senses pressure, movement, body position, and the force of
gravity. These senses are known as tactile (touch), vestibular (movement), and
proprioceptive (body position). These systems work closely to help a child make
appropriate responses to incoming sensations and to the environment. Children
with autism may greatly overreact to sensory stimuli or have almost no reaction
to it. They have difficulty “filtering out” sensations and stimuli. They may walk
around and cover their ears to block sounds we might not hear or consider moder-
ate (e.g., a hair dryer). On the other hand, they may delight in a blaring police
or fire siren. They may be fascinated with color patterns, lights, shapes, or the
configuration of letters and numbers. They may be preoccupied by certain tex-
tures and rub against a particular surface or avoid certain foods because of a
particular texture. After a child has engaged in spinning or rough-housing, parents
have reported greater alertness, verbalizations, or eye contact. Reactions to pain
may also be abnormal—many parents report that their child has a high tolerance
to pain. Finally, the senses of smell and taste seem to be used more often to
explore objects.
Motor: Atypical motor movements and motor stereotypies can occur in

over 40% of children with PDD/ASD. These can be represented by hand clapping
or flapping when a child is excited or upset, sometimes accompanied by jumping
up and down or dancing in place, often called a “happy dance” by parents. Other
behaviors include rocking, spinning, and running back and forth repetitively. Be-
sides hand flapping, children will sometimes finger-flick or hold objects in their
hands or hold their hand in front of their eyes and stare at it.
Another motor abnormality is dyspraxia, particularly of the hands, evinced
by poor motor planning skills in the manipulation and use of objects. Rapin (3)
reported that limb apraxia occurs in approximately 30% of autistic children with
normal IQ and 75% of retarded autistic children.
Hypotonia is also a common finding in about 25% of children with PDD/
ASD. This may be specifically confined to the hands or fingers or be globally
present. Children who are unable to sit upright will slump in their chairs. They
often fall off their chairs for no apparent reason. Hypotonia in their hands often
results in severe fine motor and graphomotor delays because of their inability to
manipulate objects and control a pencil.
Pervasive Developmental Disorder–Not Otherwise Specified

It is essential that a disorder be well defined. Although DSM-IV (2) has clear
operational criteria for autistic disorder (i.e., it requires at least six or more from
a total of 12 criteria behaviors), there are no specific operational criteria for perva-
sive developmental disorder–not otherwise specified (PDD-NOS). DSM-IV calls
for a diagnosis of PDD-NOS “when there is a severe and pervasive impairment
in the development of reciprocal social interaction, verbal and nonverbal commu-
nication skills, or the development of stereotyped behavior, interests and activities
but the criteria are not met for a specific PDD (i.e., Autistic Disorder, Rett’s
Syndrome, Childhood Disintegrative Disorder)”.
Clinically, the term PDD-NOS is often used to describe children with
milder autistic features. However, often it is used because a practitioner does not
want to use the A word—autism—with a family. Parents are usually much
smarter than they are given credit for and inevitably, after doing some reading
on their own, they return to ask the practitioner to distinguish between autism
and PDD-NOS with respect to their particular child. Despite the difficulty of
giving the diagnosis of autism to a family and having to discuss its ramifications,
it is much better to “bite the bullet” than to later appear foolish. Indeed, PDD-
NOS should be viewed as a diagnosis by exclusion of the other PDDs (4).
It is important to note that caution should be used on the part of practitioners
who make the diagnosis of PDD-NOS in a child under 2 years old. It is not
unusual for some of these children, as they mature, to lose their autistic features
and ultimately be diagnosed with a language-based deficit. Severe language de-
lays have a ripple effect in other developmental areas. If a child is not speaking
or processing language, he often has limited social interactions, plays by himself,
and lacks sufficient language for imaginative play themes.
Asperger’s Syndrome
One year after Kanner (1) described autistic behaviors, a pediatrician named
Asperger (5) also described four children with “autistic psychopathy.” The main
features of Asperger’s syndrome are a severe and sustained impairment in social
interactions and the development of restricted, repetitive patterns of behavior
interests and activities (2). There is no evidence of a clinical delay in language
development, although children with Asperger’s often have a pedantic style of
speaking, with mechanical or formal phrasing. They are often described as “little
professors” and initially can fool adults who marvel at their speaking skills. How-
ever, they can be quite concrete, and often their responses or answers miss the
essence of what was asked. Overall, children with this disorder tend to be bright,
and many master reading (hyperlexia) at an early age.
Socially, individuals with Asperger’s syndrome are quite inept and are usu-
ally unable to form friendships. Tragically, they often desire to form these social
106 McCarton
bonds but do not know how to go about making a friend (6). Older children
with Asperger’s syndrome exhibit unusual interests and preoccupation with train
schedules, animal categorizations, maps, and sports statistics. They often have
both fine and gross motor deficits including clumsy, uncoordinated movements
and odd postures. Indeed, in formalized standardized testing, there is often a
marked discrepancy between their high scores on verbal tests and their poor
visual-spatial/visual-perceptual abilities (performance IQ). An excellent book on
Asperger’s syndrome edited by Klin et al. (7) covers the wide breadth of this
fascinating and tragic disorder.
Rett’s Syndrome
Rett’s syndrome is a progressive neurological disorder essentially limited to girls.
Children initially develop normally during the first year of life, but there is then
a rapid deterioration consisting of decelerating head growth, loss of purposeful
hand movements, development of ataxia, and severely impaired social, cognitive,
and language skills. Stereotypic hand movements consist of hand-washing move-
ments, licking, clapping, or wringing. Mental retardation becomes prominent, and
clinical seizures occur in about one-third of cases (8–12). Although the condition
stabilizes over a period of many years, global neurological cognitive, behavioral,
and language deficits remain prominent.
Childhood Disintegrative Disorder

Childhood disintegrative disorder (CDD) is also known as Heller’s syndrome,
dementia infantilism, or disintegrative psychosis. It is a rare disorder of child-
hood, with only about 100 cases reported in various reviews (13–15). Children
with CDD initially develop normally. Usually between 3 and 4 years of age,
there is a rapid deterioration and loss of previously normal cognitive, behavioral,
social, language, and motor skills accompanied by stereotypic, restricted, persev-
erative behaviors. The social, communicative, and behavioral impairments are
those typically seen in autistic disorder. The similarities and differences between
the late regression seen in CDD and the earlier regression seen in autism between
18 and 24 months (16) are not understood.
PREVALENCE OF PDD/ASD
In the past 10 years, the overall prevalence of PDD/ASD has reached alarming
proportions. Early epidemiological studies indicated a prevalence of 4–5 per
10,000, or one in every 2000 people (17–19). However, increased numbers of
children have now been identified with this disorder. Whether it is because of
broader clinical definitions of inclusion or greater clinical recognition on the part
of professionals is still open to debate. Regardless of the reason, current preva-
lence rates range from 10 to 20 per 10,000 or one in every 500 to 1000 children
(19–30). Rett’s syndrome and childhood disintegrative disorder are rarer, each
occurring in fewer than one per 10,000 live births. The male-to-female ratio for
PDD/ASD is 4:1, with the exception of Rett’s syndrome, which occurs only in
girls.
Studies in the United States have mirrored this same increase in prevalence
rates. In an April 1999 report, the California Department of Developmental Ser-
vices found a 273% increase between 1987 and 1998 in the number of new chil-
dren entering the California developmental services system with a professional
diagnosis of autism. The report further stated that “the number of persons with
autism grew markedly faster than the number of people with other developmental
disabilities (i.e., cerebral palsy, epilepsy, mental retardation” and “compared to
characteristics of 11 years ago, the present population of persons with autism is
younger and has a greater chance of exhibiting no or milder forms of mental
retardation” (31).
Other states are also reporting dramatic increases. Data from the 1998
Maryland Special Education Census revealed that the state experienced a 513%
increase in autism between 1993 and 1998, while the general population in Mary-
land from 1990 to 1998 increased only 7%. A comparative analysis of the 16th
and 20th annual reports to Congress on the implementation of the Individuals
with Disabilities Education Act (IDEA) showed increases of more than 300% in
autistic children served under IDEA between 1992 and 1997 in 25 states: Ala-
bama, Alaska, Arkansas, Colorado, Delaware, Illinois, Indiana, Iowa, Kentucky,
Maine, Maryland, Michigan, Montana, Nebraska, Nevada, New Mexico, North
Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, South Carolina,
Vermont, and Wisconsin (31).
The Centers for Disease Control and Prevention, in a report released in
April 2000, found that the incidence of autism in Brick Township, New Jersey,
in 1998 was one in 150 children. The Autism Society of America estimates that
“more than 500,000 people in the United States have autism or some form of
a pervasive developmental disorder,” making autism one of the most common
developmental disabilities (31).
Indeed, many clinicians consider this the “new epidemic.” PDD/ASD is
not a rare disorder; it is more prevalent in the pediatric population than cancer,
diabetes, spina bifida, and Down’s syndrome. Because this disorder is growing
at such an alarming rate, numerous national professional organizations and the
National Institutes of Health have attempted to combine resources to establish
centers of research and formulate practice parameters for the diagnosis and evalu-
ation of this entity (32,33).
ETIOLOGY OF PDD/ASD
The wide variation in the presenting symptoms of children with PDD/ASD points
to multiple etiologies that ultimately result in abnormal brain development. Origi-
108 McCarton
nally thought of in the 1950s and 1960s as an emotional or psychological distur-

bance brought on by “cold” and “aloof ” parents, PDD/ASD is now understood
to be a neurological abnormality that is biological in nature (34).
Interest has always focused on complications during pregnancy or the peri-
natal period as somehow putting a child at risk of developing PDD/ASD. How-
ever, numerous studies indicate that complications in pregnancy, labor, delivery,
and the immediate neonatal period do not increase the risk of PDD (35–41).
A genetic basis has been suggested for this disorder in multiple studies.
Family studies have shown that the rate of autism in first-degree relatives is 50
to 100% higher (42,43). Twin studies have shown a 95% concordance for identi-
cal twins and 24% for fraternal twins (44–46). Recurrent risks of autism in subse-
quent pregnancies ranged from 4% to 9% (47,48). A detailed family history of
children with PDD/ASD also reveals an increased risk of mental diseases (i.e.,
obsessive-compulsive behaviors, manic depression, chronic depression, and
schizophrenia, as well as social awkwardness, isolation, and anxiety within the
families (47,49–52).
Many known medical disorders are associated with an increased risk of
PDD/ASD. Fragile X was originally reported as having a significant association
with autism (53,54). Later studies suggested a much lower incidence—3% to
7%—of fragile X in patients with autism (55). The belief now held is that only
a few children with autism have fragile X syndrome, while many children with
fragile X have autistic symptoms (56). Neurocutaneous disorders such as neuro-
fibromatosis and tuberous sclerosis (TS) also have strong associations with au-
tism. Recent studies (57–59) demonstrate that 17% to over 60% of individuals
with TS and epilepsy are also autistic. Children with genetic disorders such as
phenylketomuria and congenital untreated hypothyroidism also have a greater
risk of PDD/ASD symptoms (60), as do those exposed to fetal drug toxins such
as thalidomide and congenital intrauterine infections such as rubella and cyto-
megalovirus (61). Children with severe mental retardation also have a high inci-
dence of PDD/ASD characteristics (62).
A constant source of investigation has been the possibility of a particular
brain formation or brain function as the etiology of PDD/ASD. Indeed, this is
now where most of the research effort, along with genetics, is focused. Abnormal-
ities in the limbic system in the brain as well as hypoplastic cerebellum and
brainstem have been reported (34,63–67). Various disturbances in the serotonin,
dopamine, and opioid transmitter systems (68–73) have generated much research
interest. Despite all the neurochemical, neuroanatomical, and neuroimaging stud-
ies, the etiology of PDD/ASD remains unknown. Recently, considerable interest
has focused on other possible causes of PDD/ASD. All of these remain specula-
tive.
Wakefield and his colleagues (74) generated intense controversy in the
medical world when they reported evidence that the measles-mumps-rubella
(MMR) vaccine may cause gastrointestinal problems that, in turn, lead to autistic
behaviors. Wakefield studied a group of children referred because of diarrhea
and abdominal pain, along with a history of normal behavior followed by a loss
of language and acquired skills within 2 weeks after receiving the MMR vaccina-
tions. Gastrointestinal abnormalities following MMR vaccination included
chronic inflammation of the colon, abnormal growth of small nodules of
lymphoid tissue, thrush-like ulcers, and swellings in the small bowel.
Wakefield’s research suggested that the immune system of certain children
with a genetic predisposition to autism may not be able to handle certain viruses
appropriately, possibly including attenuated strains used in vaccines. In these
individuals, the MMR vaccine may lead to impaired gastrointestinal function,
allowing food by-products called peptides, which can exhibit opium-like proper-
ties, to pass through the intestinal walls. These particles may disrupt normal brain
function and development. In addition, most subjects had elevated urinary con-
centrations of methylmalonic acid, which is indicative of a functional vitamin
B12 deficiency often seen in other gastrointestinal disorders. Vitamin B12 is essen-
tial for normal myelination of nerve cells, a process not completed until around
10 years of age. Wakefield has subsequently collected a sample of over 100
children who presented with the same profile. However, reanalysis of data from
a population study of autism performed in the late 1980s by Gillberg and Heijbel
(75) failed to support this connection between MMR and PDD/ASD.
The fact that mercury, in the form of thimerosal, is used as a preservative
in some vaccines has led to the theory that the vaccines have caused mercury
poisoning, which causes many traits and behaviors similar to those seen in autistic
children (31). Thimerosal is used in DPT, DPTH, tetanus, DT, Td, influenza,
meningococcal, and most DtaP, Hib, and hepatitis B vaccines. The total amount
of mercury that babies under 6 months old have been exposed to in childhood
vaccines has exceeded the Environmental Protection Agency (EPA) limit. Thi-
merosal-free vaccines are available, but parents must request them.
Abnormalities in the breakdown of peptides, especially those found in glu-
ten and casein, have also been implicated in a subset of children with PDD/ASD.
Removal of gluten and casein from the diet has been reported to reduce autistic
symptoms, increase attention, and improve language and socialization (76–79).
Gupta and coworkers (80) demonstrated a marked deregulated immune sys-
tem in children with autism, including abnormalities of T cells, B cells, and natu-
ral killer (NK) cells, as well as various immunoglobulin classes. This deregulation
may account for the autoimmune and allergic reactions common in autistic chil-
dren as well as a susceptibility to fungal, viral, and bacterial infections.
Finally, Singh and colleagues (81) found evidence suggesting that viruses,
or the immunizations against them, play a role in causing autism. The serum of
both autistic and nonautistic controls was analyzed for antibodies to measles and
human herpesvirus 6. Serum samples for two brain autoantibodies (anti-MBP
110 McCarton
and anti-NAFP), the presence of which indicates that the body is attacking its
own cells, were also analyzed.
The researchers reported that measles and herpes antibody titers were only
moderately higher in autistic subjects than in controls. However, all the normal
controls were negative for brain autoantibodies, while the majority of autistic
samples (90%) positive for virus antibodies were also positive for brain autoanti-
bodies. This finding supported the hypothesis that a virus-induced autoimmune
response may play a causal role in autism.
DIFFERENTIAL DIAGNOSIS OF PDD/ASD

The most common disorders that are mistaken for PDD/ASD include mental
retardation, childhood psychoses, language disorders, and sensory impairments.
Children with mental retardation usually exhibit across-the-board delays in lan-
guage and visual perceptive abilities, while those with autism usually have more
prominent language delays. Socially, children with PDD/ASD tend to be isolated
and shun interactions, while children with mental retardation usually enjoy social
contact. The confusion in differentiating these two diagnoses rests in the fact that
many mentally retarded children have autistic features and many children with
autism are mentally retarded.
PDD/ASD can also be confused with childhood schizophrenia. Characteris-
tically, a child with schizophrenia has hallucinations and delusions and has a rich
fantasy or imaginative world. An autistic child, on the other hand, usually lacks
imagination in his play and does not exhibit a delusional pattern.
Children with a sensory disorder, such as a hearing impairment, can appear
to be aloof, nonresponsive to language, and socially isolated. Like autistic chil-
dren, they do not respond to their name and often appear to be in their own world.
This can also be a particular problem in terms of a differential diagnosis with
children who have chronic ear infections, compounded by chronic fluid in the
middle ear. Unsuspectingly, these children can have a severe hearing loss that
may go undetected for long periods of time. Usually, though, in the majority of
these children with hearing loss, overall cognitive skills and the desire for social
interaction remain, in comparison with children with autism.
Developmental language disorders may also be confused in their presenta-
tion with autism. Often, these children exhibit an expressive and/or a receptive
language delay. Lack of verbal communication or understanding of language of-
ten leads to social withdrawal, echolalia, and poor eye contact. However, the
other behaviors typical of autism—rigidity, stereotypic behaviors, perseverative
activities—are often absent.
Obsessive-compulsive disorder (OCD) presents in children with unusual
interests and rigid behaviors. There is often a family history of these same traits,
which may or may not have been diagnosed in the past. Although these atypical
behaviors are present, usually social skills and language development are normal.
Recently, a new diagnostic entity called sensory integration disorder (SID)
has been widely used to describe children who have difficulty organizing external
tactile, auditory, or visual stimuli (82). They are referred to as being “out-of-
sync” with the environment and often have difficulty entering a room in which
other children are present, going to birthday parties or circuses, and playing with
children, and become overwhelmed with smells and sounds. Many of these chil-
dren display prominent tactile defensiveness, often not wanting to touch certain
textures or objects and being particularly sensitive on their skin. Some of these
behaviors are also seen in children with PDD/ASD, but with pure SID communi-
cative and cognitive skills are usually preserved.
THE IMPORTANCE OF A DIAGNOSIS

Getting a diagnosis has several important purposes. The first is to establish that
the behaviors exhibited by the child fall into a recognizable pattern. Many parents
fear a diagnosis because they feel it “labels” their child. It does label the child
but also allows the parents to explore a whole body of literature in order to better
understand their child’s disorder in terms of etiology, treatment, and prognosis.
The diagnosis allows the parents to accumulate accurate knowledge about the
disorder, which empowers them to obtain the best-known therapies and interven-
tions for their child.
Finally, the sooner a diagnosis is made, the sooner treatment can be started.
Often, a pediatrician will tell a family to wait and see what happens over the
next few months or that it is too early for therapy to be effective. These are the
usual reasons offered by doctors to discourage speech/language therapy in a child
less than 2 years old. Unfortunately, this is poor advice and valuable time is lost
in addressing the child’s needs. The brain of a young child is still actively grow-
ing, and many fundamental aspects of learning take place in the early years. A
child’s brain is quite “plastic,” and the ideal time to try to develop alternative
neurological wiring circuits for learning is in these crucial preschool years.
EVALUATION OF PDD/ASD
The diagnosis of PDD/ASD is behaviorally defined. It is based on clinical rather
than laboratory findings. There are no medical tests (chromosomal, radiological,
electrophysiological, or biochemical) that can be administered to establish a diag-
nosis of PDD/ASD, although tests can rule out or identify other underlying prob-
lems. In order to determine a diagnosis of PDD/ASD, professionals depend on
112 McCarton
observation of the behavioral characteristics of the child. The more abnormal

behaviors a person exhibits, the more likely the diagnosis of PDD/ASD.
Once a child is suspected of having atypical or abnormal behaviors charac-
terized by a communicative and social impairment and a restricted or repetitive
pattern of behavior, he should be immediately referred for an evaluation. The
referral can be to a clinician who has an expertise in developmental disabilities.
It is critical that the individual have experience in making the diagnosis of PDD/
ASD in young children (33,83–85).
Parents can also self-refer directly to Early Intervention agencies. Children
under 36 months old can be referred to a Zero-to-Three intervention system in
their community. Children who are at least 3 years old can be referred to their
local school district. Often, whether evaluations are done through the school dis-
trict or the Zero-to-Three programs, a diagnosis is not given. Rather, the child
is described in terms of areas of delay: a speech/language delay, fine and/or gross
motor delay, a cognitive delay, a motor planning problem. Unfortunately, this
often delays the interventions a child may need in terms of scope and intensity.
This is why it is so important to obtain a medical diagnosis as early as possible
in the evaluation process.
To adequately evaluate a child with possible PDD/ASD, interdisciplinary
evaluations are often indicated. The evaluation should adequately stress not only
areas of deficit in the child but also, in particular, strengths. The strengths and
weaknesses are crucial elements in planning an intervention program specific to
the child. It also goes without saying that parents should be actively involved in
the evaluation process.
A multidisciplinary approach, however, demands that an experienced clini-
cian be the final coordinator who puts together all the individual results of the
evaluations to form a cohesive diagnostic picture. This person is also responsible
in formulating an intervention plan based on the evaluation. A diagnosis without
an intervention plan is meaningless to the child and parents. These evaluation
efforts can include a wide array of specialists, including a developmental pediatri-
cian, neurologist, child psychiatrist, psychologist, audiologist, speech/language
therapist, and occupational and physical therapist. Parents play a critical role in
the diagnosis by providing information on the child’s behaviors and develop-
mental history. Parental input is important, and all professionals should investi-
gate concerns carefully and thoroughly when parents raise them. All too often,
parents report that they were puzzled or alarmed by behaviors manifested by their
children but were told by their pediatrician to wait, and that “boys are always
slow to develop speech”—“don’t be a hysterical mother,” “he’s too young to get
therapy.” First and foremost, if the parents raise a concern, any child professional
should take notice and investigate it; otherwise, valuable time in the intervention
process can be lost, ultimately slowing the process to recovery. Early intervention
is most effective when it is begun early in a child’s life (86–89).
Specific Evaluations to Determine PDD/ASD

The diagnosis of PDD/ASD requires a comprehensive multidisciplinary ap-
proach. Evaluations may include all or some of the following.
Detailed History (Medical, Developmental, Family)

Information should be gathered about the pregnancy, labor, delivery, and immedi-
ate newborn period, along with achievement of developmental milestones. Medi-
cal complications such as seizures, head trauma, brain infections or injuries, and
lead exposure should be noted. A family history of affective disorders (depres-
sion, OCD, manic depression) and anxiety should be explored because of their
association with autism in childhood (49–51,90–93). Specific questions should
be asked about atypical behaviors in eye contact, response to one’s name, pretend-
play, joint attention, imitation, and language development.
Physical and Neurological Examinations
Physical and neurological examinations are often very difficult to complete in
an autistic child because of their fear or inability to cooperate because of self-
directed behavior. A key element of the evaluation is head size, which in autism
is usually greater than the 75th percentile (3,94–98). Neurocutaneous lesions
should be considered, and a Wood’s lamp may be necessary to screen for tuberous
sclerosis. Neurological signs may include global hypotonia or specifically de-
creased strength in the hands and fingers, clumsy uncoordinated movements, and
motor planning problems in imitation of gestures or fine motor tasks and motor
stereotypies (hand flapping, spinning, licking, jumping up and down in place in
what is often called a “happy dance”). Behaviorally, play should be observed to
see whether imaginative themes are evident. Often, an autistic child will repeti-
tively put objects into a container and take them out, line up toys randomly and
quickly move from one toy to the next without actually playing with it, become
preoccupied with objects in the room (air vents, lights, mirrors, patterns on a
rug), and smell or lick objects before using them. Social interactions should be
noted between parent and child and examiner and child, and the practitioner
should make an effort to evaluate joint attention.
In terms of language, observations should be made to see whether a child
makes direct and sustained eye contact, uses his index finger to point, responds
to his name when called, understands simple directives, and requests and uses
words to express his needs.
Diagnostic Parental Questionnaires/Interviews
The Childhood Autism Rating Scale (99) is a structured interview and observa-
tion instrument that can be used in any child over 2 years old. It is widely recog-
nized and used as a reliable instrument for the diagnosis of autism.
114 McCarton
The Autism Diagnostic Interview–Revised (ADI-R) (84,100,101) is a com-

prehensive structured parent interview that examines autistic symptoms in social
interactions, communication, and ritualistic behaviors. The Autism Diagnostic
Observation Schedule–Generic (102,103) is a semistructured observational as-
sessment that evaluates the same domains as the ADI-R but in less time (30 to
45 minutes). Both instruments are considered the “gold standard” of diagnostic
instruments in all appropriate autism research protocols. As important as these
instruments are in the research world, they are not used by clinicians because
they require specific training and validation procedures.
Cognitive Measures
Although standardized cognitive tests may be difficult to administer because of
a child’s behavior, knowing the child’s cognitive status is important in determin-
ing his overall level of functioning. It is important for both parents and prac-
titioner not to view the scores as indicative of the child’s IQ. The purpose of
these tests is to determine the strengths and weaknesses of the child in planning
an adequate intervention and assist in differential diagnosis. In general, psycho-
logical tests show that children with PDD/ASD have high nonverbal skills
(visual-perceptual, visual-spatial tasks) and depressed language skills and
higher-order conceptualization or abstraction processes (104).
Many different standardized tests can be used: the Bayley Scales of Infant
Development–II (105), the Stanford-Binet IV (106), the Wechsler Preschool Pri-
mary Scale of Intelligence (WPPSI) (107), and the Wechsler Intelligence Scale
for Children–III (WISC) (108). The pattern of better nonverbal skills than verbal
skills is seen in all these tests. No cognitive pattern confirms or excludes a diagno-
sis of PDD/ASD.
Adaptive Behavior Evaluations
The Vineland Adaptive Behavior Scale (109) is the most widely used instrument
to assess adaptive function (110). Adaptive behavior is the performance of the
day-to-day activities necessary to take care of oneself and get along with others.
It is age-based and defined by the standards and expectations of others. Adaptive
behavior represents the typical performance rather than the potential ability of
the person—what a person does as opposed to what a person is capable of doing.
Four areas of adaptive function are assessed: communication, daily living, social-
ization, and motor skills.
Hearing Test
Any child who has a delay in speech and language development should have a
formal audiological hearing evaluation. Parental report of lack of response by
the child to his name or extreme sensitivity or atypical responses to sound (putting
hands over their ears) should be a reason for referral to an experienced pediatric
audiologist. Children with PDD/ASD are often thought to have a hearing loss
because of their lack of response to language. A hearing evaluation is usually
the first one ordered by a pediatrician. Moreover, a hearing loss (conductive,
sensorineural, or mixed) can co-occur in a child with autism (111,112). However,
accompanying behaviors of stereotypic activities, loss of language skills, and
social deficits often differentiate the child with autism from the child with a hear-
ing loss. In any event, a hearing evaluation consisting of a behavioral evaluation
(visual-reinforcement audiometry) or an electrophysiological assessment (brain-
stem auditory evoked responses) and tympanometry are the usual methods em-
ployed.
Measures of Fine and Gross Motor Skills/Sensory
Integration
Many children with PDD/ASD demonstrate problems with fine and gross motor
skills, hypotonia (3), motor planning or sequencing of movement patterns, organi-
zation of materials, and increased sensitivity to tactile and auditory environmental
stimuli (113,114). These behaviors are usually evaluated by an occupational ther-
apist and physical therapist. Assessment of these skills utilizes a variety of stan-
dardized tools appropriate to the developmental level of the child. Once again,
the most important aspect is that the evaluator be experienced in assessing chil-
dren with autistic behaviors because the testing may require adaptations.
Speech/Language Evaluation
Speech and language therapists who have experience in assessing children with
PDD/ASD are important in the comprehensive evaluation of a child suspected
of PDD/ASD. All aspects of language function—expressive, receptive, prag-
matic, and prosody (voice and speech production)—should be evaluated.
Wetherby and Prizant (115) and Crais (116) recommend that all evaluations do
the following:
1. Focus on functions of communication
2. Analyze preverbal communication (gaze, gestures, vocalizations)
3. Assess social-affective signaling
4. Profile social, communicative, and symbolic abilities
5. Directly assess the child
6. Make observations of spontaneous and initiated communication
7. Directly involve parents or caregivers during the assessment
No standardized test can provide an opportunity to assess all these areas, but the
most commonly used instruments include the Rossetti Infant-Toddler Language
Scale (117), the Preschool Language Scale–3 (PLS) (118), the Clinical Evalua-
116 McCarton
tion and Language Fundamentals–3 (CELF-3) (119), the Expressive One-Word

Picture Vocabulary Test–Revised (EOWPVT-R ) (120), and the Receptive One-
Word Picture Vocabulary Test–Revised (ROWPVT-R) (121). In all evaluations,
it is very important to determine whether specific neuromotor speech disorders
are involved. A subset of children with autism exhibit a verbal apraxia, which
is a motor planning disorder in producing the coordinated movements required
to make single and sequenced speech sounds. Other children with PDD/ASD
can demonstrate a dysarthria, which is a weakness or hypotonia of the oral motor
muscles.
Social Family History
A social worker should assess the child’s parents, caregivers, and environmental
setting. The ability of the family to cope and develop adequate strategies as well
as the financial and emotional support systems should be candidly evaluated with
sensitivity and understanding.
Laboratory Evaluations
Metabolic testing may include studies of inborn errors in amino acid, carbohy-
drate, purine, peptide, and mitochondrial metabolism. These should be done only
in the presence of specific clinical findings such as seizures, cyclic vomiting,
lethargy, mental retardation, or dysmorphic features (122). Recent evidence sug-
gests that the number of children with PDD/ASD who have a metabolic disorder
as its etiology is well less than 5% (42,57).
Genetic Testing
Despite intense and ongoing current genetic research, no particular chromosomal
abnormality has been found as the primary lesion in PDD/ASD. Abnormalities
involving the long arm of chromosome 15 have been reported in 1% to 4% of
cases of autistic disorder. These include Angelman’s syndrome and Prader-Willi
syndrome. DNA analysis for fragile X should also be done on boys who present
with speech/language delay, a family history of undiagnosed mental retardation,
or the presence of dysmorphic features. There are currently no prenatal tests for
the detection of PDD/ASD.
EEG
Approximately one-third of individuals with PDD/ASD experience seizures,
which occur primarily in early childhood and adolescence (123). A prolonged
EEG (24 to 48 hours) is indicated if there is evidence of clinical seizures, a high
index of suspicion of seizures (i.e., behaviors such as staring, interruption of an
activity, aggressive behavior) or a regressive developmental pattern, e.g., severe
loss of language or social skills (124–126).
BEYOND THE DIAGNOSIS

Treatment of PDD/ASD
Rutter (127) has outlined five main goals for the treatment of autism:
1. Fostering of development
2. Promotion of learning
3. Reduction of rigidity and stereotypy
4. Elimination of nonspecific maladaptive behaviors
5. Alleviation of family stress
Treatment of PDD/ASD must be intense, continuous, and comprehensive.

A multidisciplinary approach should be used that specifically includes Applied
Behavioral Analysis (ABA) therapy, speech/language therapy, occupational
therapy/sensory integration, family support, schooling, and medication.
Behavioral Therapy
In 1993, Dr. Ivan Lovaas (128) reported a 47% recovery rate for children with
autism given ABA therapy—a 40-hour-a-week comprehensive one-on-one teach-
ing program (1:1 discrete trials). Learning consisted of breaking down hundreds
of language, cognitive, and social tasks to their least common denominator and,
once the child mastered these tasks, using them as the foundation to raise the
task or activity to a more complex level. Goals of the therapy include increasing
expressive and receptive language; expanding play skills; learning cognitive con-
cepts; increasing eye contact, attention, and focus; promoting social interactional
skills; eliminating rigid or perseverative behaviors; and decreasing tantrums or
aggression.
Many parents feel that ABA therapy is the only one that “works” and attest
to the “cures” it has brought about in their PDD/ASD children. In fact, although
the original Lovaas study has been criticized on scientific grounds, it remains
the only technique for which long-term positive cognitive effects have been re-
ported in a group of PDD/ASD children.
Recently, Smith (129) compared two groups of children who began treat-
ment between the ages of 18 and 42 months. The children were divided into two
groups:
1. Seven children with autism and eight with PDD received 30 hours
per week, for 2–3 years, of intensive training based on the techniques
used in the UCLA Young Autism Project. Professional therapists con-
ducted most of the training, with parents assisting for several hours
per week.
118 McCarton
2. Seven children with autism and six with PDD received therapy pro-
vided by parents who were trained by professional therapists. In addi-
tion, the children were enrolled in special-education classes for 10 to
15 hours per week.
At 7 to 8 years of age, the children were re-evaluated. At follow-up, the intensive-

treatment group outperformed the parent-trained group on measures of intelli-
gence, visual-spatial skills, language, and academics. IQ gains in the intensive-
intervention group averaged 16 points. In the new study, 27% of the children
were able to enter regular mainstream classes, compared with 47% in Lovaas’
earlier work.
A similar study by Sheinkopf and Siegel (130) also showed significant
effects on cognitive and behavioral abilities following intense home-based behav-
ioral treatment utilizing Lovaas methodology. The mean difference in IQ was
approximately 25 points (89.7 for the experimental group, 64.3 for the control
group). Moreover, children in the experimental group with more than 28 hours
of ABA therapy had greater cognitive gains than children with ⬍27 hours of
ABA therapy.
Speech/Language Therapy
Because one aspect of PDD/ASD is a communicative disorder, intensive speech/
language therapy is an essential part of any intervention program. Therapy should
emphasize all aspects of language development: expressive, receptive, and prag-
matic skills. Children with PDD/ASD often exhibit hypotonia (low tone) of their
oral motor muscles and/or a verbal/oral apraxia. Therapists must be skilled in
working with these conditions and should have an expertise in oral motor therapy
and PROMPT methodology (a tactile kinesthetic method of facilitating sound
production).
The comprehension or understanding of language is often a major weak-
ness. Words have little or no meaning to children with PDD/ASD, and they often
look blankly when spoken to. A major hurdle for children with this diagnosis is
the pragmatic use of language—children need long hours of practice and expo-
sure to have interactive and meaningful conversations. This is often best accom-
plished by having the child work with another child (dyad). In this kind of setting,
the speech/language therapist can promote eye contact, turn-taking, initiation of
a topic, and topic maintenance.
Occupational Therapy
Occupational therapy is needed to address two common problems in children
with PDD/ASD. One is the fine motor/graphomotor delays due to hypotonia or
dyspraxia (motor planning problems). In addition, since sensory defensiveness
is such a common finding, sensory integration therapy is usually a necessary

component of the intervention program (131,132).
Medication
More and more children with PDD/ASD are now receiving medications at
younger and younger ages. It is important to remember that no medication can
cure autism. It can only help ameliorate behaviors that may interfere with the
child’s effective participation in his therapies or with his daily activities. Medica-
tion should be used only after educational and behavioral treatments have been
given an extended trial. Drugs should be used with caution, and only by a physi-
cian with extensive experience in treating children with PDD/ASD.
Stereotypic behaviors: Serotonin-uptake inhibitors (Prozac, Zoloft, Paxil,

Luvox) are primarily used to treat ritualistic behavior in children with PDD/ASD.
Since DeLong and his colleagues (49–51) first described their benefits in this
disorder, there has been a steady increase in their usage. Side effects appear to
be minimal: sleepiness (counteracted by giving the drug before the child goes to
bed), disruption of the sleep cycle, and anxiety. Worsening of behaviors (disinhi-
bition) is a rare event and may occur in a child who has a manic-depressive
tendency.
Hyperactivity and attentional disorders: Decreased attention, in-

creased activity, and impulsivity are common findings in PDD/ASD. Some indi-
viduals respond favorably to stimulants such as Ritalin or Adderall (133,134), but
the percentage is much lower than in pure attention-deficit/hyperactivity disorder.
Stimulants can bring about a worsening of stereotypies, tics and irritability (135).
The usual side effects that occur with stimulants, such as weight loss and sleep
disturbances, can be exacerbated in PDD/ASD because many of these children
already have a limited diet and poor sleeping habits (136).
Aggression and self-injury: Aggression is common in children with

PDD/ASD. Haldol has been found to be effective in reducing aggression as well
as decreasing stereotypies and increasing socialization. However, the major side
effects of dyskinesia and dystonia have limited its usefulness. Newer neurolep-
tics, such as Risperdal, cause fewer dyskinetic symptoms and have been very
successful in reducing repetitive behaviors and decreasing aggression (137,138).
The one drawback is the steady weight gain seen in the majority of children who
take Risperdal. Other drugs that have been used to control aggression include
the J-blocker popranolol (Inderal), the antiepileptic drugs carbamazepine (Te-
gretol) and valporic acid (Depakene, Depakote), lithium, and serotonin-reuptake
inhibitors.
120 McCarton
Seizure disorder: Seizures are a common finding in PDD/ASD. Anti-

convulsants used include valporic acid (Depakene, Depakote) and carbamazepine
(Tegretol). Because common drugs such as phenytoxin (Dilantin) and phenobar-
bital can produce irritability and hyperactivity, they should be avoided.
Alternative Therapies
Because the etiology of PDD/ASD is unknown, there are no cures for autism. Some
therapies—e.g., ABA, speech/language, occupational, sensory integration, and med-
ications—help change specific behaviors associated with the disorder but do not cure
the underlying cause. Parents, obviously, want to help their children overcome this
disorder and will therefore often explore alternative approaches. It is important to
note that none of these therapies has been subjected to a randomized clinical trial,
and they remain the subject of great debate within the medical community.
Current alternative approaches include the following.
Dietary intervention: Some research studies have indicated that individ-
uals with PDD/ASD may have trouble metabolizing peptides into amino acids
because of an enzyme defect. Two sources of protein—gluten (found in wheat,
rye, oats, and other cereals) and casein (protein from milk)—are particularly
suspect. Urine samples of autistic subjects have also indicated a higher than nor-
mal level of peptides. Some success in terms of changes in behaviors (more
focused, more socially related, better eye contact, less hyperactive) has been
noted when diets were modified to exclude casein and gluten (76,139).
Anti-yeast therapy: Candida albicans is a yeastlike fungus. It is nor-
mally present in the body to some degree, but certain circumstances may lead
to an overgrowth of yeast. Some children with PDD/ASD have a history of
chronic ear infections or upper respiratory illnesses and may have been chroni-
cally treated with antibiotics that can change the intestinal flora, resulting in an
overgrowth of yeast. A stool analysis can be used to test for excessive yeast.
Treatment usually includes treatment with an antifungal medication (e.g., Ny-
statin) and a diet that eliminates sugar and yeast. Symptoms may get worse at
the onset of treatment but is likely to gradually improve if candida is indeed
contributing to the child’s behaviors.
Vitamin therapy: Many parents firmly believe that large doses of vita-
min B6, in combination with magnesium, help improve behaviors in children with
PDD/ASD. This includes a decrease in hyperactivity and increased attention.
However, a double-blind placebo-controlled study from Case Western Reserve
and the University Hospitals of Cleveland found no clinical effectiveness of vita-
min B6 and magnesium in improving autistic behavior (140).
Dimethylglycine (DMG) is a food substance that resembles in its make-
up vitamin B15. Anecdotal reports from parents claim improvements in speech,
eye contact, social behavior, and attention span.
Auditory Integration Training (AIT): Pioneered in France by Dr. Al-

fred Tomatis, an ENT physician, AIT was introduced in the United States in
1990. The Tomatis method is a noninvasive program of sound stimulation and
audiovisual activities. It addresses listening-related problems such as language
processing, attention, and communication. Individuals typically listen to 2 hours
daily of unfiltered and/or filtered music and voice processed through an Elec-
tronic Ear in order to achieve specific goals. While listening, individuals can
participate in activities that help to integrate the tactile sensory system. Stehli
(141) reported on the successful use of the AIT method to “cure” her autistic
daughter, and she oriented the use of AIT primarily toward autistic children.
Edelson and Rimland (142) also reported on the positive effects of AIT in PDD/
autistic children. Betteson (143), in her 1996 report on auditory training, reported
significant increases in verbal and performance IQ 3 to 12 months after treatment
as well as behavioral improvements in sound sensitivity.
Music therapy: Children with PDD/ASD have been treated with music
therapy for many years, with varying degrees of success. Music therapy uses
music as a facilitating tool. Its proponents believe that music therapy can help
children with PDD/ASD because it may require no verbal interaction, it can
facilitate play, it can aid in socialization, and it can be structured (144).
Craniosacral therapy: Dr. John Upledger developed a manipulative

touch therapy in the early 1970s. According to him, movement of the fluid up
and down the spinal cord creates movement in the membranes that affects connec-
tive tissue in the body. An imbalance in the craniosacral system can affect the
development of the brain and spinal cord, which can result in various bodily
dysfunctions. Craniosacral therapy provides a way to free these structures from
restriction by means of gentle pressure from the therapist. Upledger believed
that autistic children showed patterns of restriction in the craniosacral system
(145,146), and, following treatment, there was a reduction in self-injurious behav-
ior and hyperactivity as well as an increase in communication.
Intravenous immunoglobulin therapy: Gupta and coworkers (80) re-
ported on a disrupted immune system in children with autism. In their study,
10 autistic children received 6 months of intravenous immunoglobulin (IVIG)
treatment, and a marked improvement in communication and autistic behaviors
was reported. However, DelGiudice-Asch and colleagues (147), in a pilot open
clinical trial of IVIG that used systematic behavioral assessments, reported that
IVIG did not improve speech, eye contact, or autistic behaviors.
Many other “therapies” have been tried by parents (holding therapy, dol-
phin therapy, hyperbaric oxygen therapy) in the quest to unlock their children
from the strangling effects of PDD/ASD. All these alternative therapies remain
essentially unproven in an objective scientific sense, although abundant anecdotal
122 McCarton
claims, both positive and negative, accompany each of them. To truly evaluate
the efficacy of these alternative therapies, it is imperative that each be subjected
to randomized clinical trials. This will, first of all, prove whether they work. If
they are efficacious, it will also determine which specific children would benefit
the most from these interventions. Until this happens, parents and children with
PDD/ASD often wander from therapy to therapy in hopes of finding help.
Family Coping
How does a family adjust to their child’s diagnosis of PDD/ASD? Do they ever
adjust? Initially, the diagnosis of PDD/ASD is a shock, even if the family has
suspected this might be the case, because to hear the diagnosis from a stranger
is overwhelming for most parents. Stereotypes of “autistic” children usually flood
a parent’s mind, along with a long list of why this could or could not apply to
their child. Many parents report that the blackest and worst day of their lives
was the day they were told their child had PDD/ASD. Waves of despair and
helplessness usually overwhelm parents, even though they may seem to be coping
well as they ask the doctor what they need to do next to help their child. Elements
of guilt, anger, resentment, and sadness often form a backdrop of emotions that
are ever-present but varying in intensity as the child’s developmental picture
unfolds. These emotions are all normal parental reactions to the diagnosis of
PDD/ASD. Parents will probably experience these emotions many times—not
only in the beginning but also later, after they think they have finally adjusted
to their child’s condition. These emotions are always very close to the surface
and never really scar over. Minor experiences, seemingly innocent and unex-
pected, often open the floodgates of tears and renewed pain.
The first step toward moving on is to acknowledge these feelings. They
are normal and natural. It takes a long time to adjust to the diagnosis of PDD/
ASD, and the healing process is a long journey. It is also important that parents
educate themselves about PDD/ASD. Numerous associations are ready to pro-
vide information to parents through books and other reading material and meet-
ings, as well as to be supportive. There are parent groups in almost every part
of the country; these are invaluable in showing parents that many other people
just like themselves have children with the same diagnosis. The Internet is also an
invaluable means of meeting other parents, getting information, and establishing a
support system. It is a source of instant knowledge to parents throughout the
United States and even the world. Some of the information is excellent, and some
of it is quite subjective. The most important aspect, though, is the power and
interconnectedness it offers parents, almost instantly.
Parents should also look for support within their own families—their parents,
siblings, and extended ring of relatives and friends. Often, parents desperately want
the support of family and friends but at the same time worry abut how they will
take the news. The parents may need to provide their family and friends with the
information they have gleaned and allow them to ask questions. It may take some
time for the extended family to enter into a circle of support. Some of them may
not be able, but the ones who can will prove to be invaluable assets to both the
parents and the child throughout the future years of development.
Finally, parents should try to form an ongoing relationship with a profes-
sional who is knowledgeable about all aspects of PDD/ASD. Such an invaluable
resource will assist the parents in the myriad of decisions that will need to be
made about the child’s therapies, education, and medical care. The person can
be a physician, social worker, or service coordinator. The most important factors
are that the person be knowledgeable, available, and willing to go through the
life experience with the parent and child.
COMMON MYTHS ASSOCIATED WITH PDD/ASD

Because of the wide variability of symptoms of children afflicted by this disorder,
a number of myths have arisen that tend to cloud issues of diagnosis and treat-
ment. Parents of children who exhibit PDD/ASD behaviors may be utterly con-
fused by the differing opinions offered by physicians or educational professionals
from whom they seek assistance. It is worthwhile, therefore, to explore some of
the most common myths and misconceptions and to describe some clinical reali-
ties of this mysterious childhood disorder.
Myth: PDD/ASD Children Do Not Make Eye Contact

Reality: While some PDD/ASD patients avoid making eye contact, others make
very direct eye contact with their parents or very familiar figures. Eye contact
with these individuals is usually much better than with others, with whom it is
usually fleeting, variable, and quite limited. Often, children with PDD/ASD will
use direct eye contact with their parents when they specifically want something.
Their direct eye contact is thus on their own terms and clearly conveys communi-
cative intent.
Myth: Children with PDD/ASD Do Not Like To Be Held

Reality: There are some children with this diagnosis who clearly resist being held
and often stiffen. However, the majority of children do like being held, hugged,
and kissed. They may not initiate these actions but they do not resist them, and
often seem to relax more in their parents’ arms.
Myth: PDD/ASD Children Never Develop Relationships with

Other People
Reality: Most PDD/ASD children recognize their families and prefer some people
over others. The children usually have a close and sometimes exclusive bond
124 McCarton
with one or both parents who act as a lifeline and interpreter of the world. Often,
PDD/ASD children have a very difficult time if separated from that special parent
and will become very upset. Some PDD/ASD children completely ignore most
unfamiliar people, while others are indiscriminately “friendly” with strangers.
Most of these children relate better to adults than to other children except when
the other child is older or younger.
Myth: All PDD/ASD Children Are Retarded

Reality: While it is true that many PDD/ASD children are mentally deficient,
other children with these diagnoses may have average to superior cognitive abili-
ties. Often, the figure of 70% retardation is cited with this diagnosis. However,
no primary reference has ever been found that documents that figure. The hall-
mark of this disorder is an uneven profile in which severe deficits in some area
of cognitive function co-occur with areas of superior functioning, especially in
auditory and visual memory abilities. It is important to explore any area of normal
intellectual functioning since this may provide a critical avenue of remediation.
Myth: PDD/ASD Is Caused by Poor Parenting

Reality: PDD/ASD is a neurological disorder whose etiology is still unknown.
Current research provides no evidence of a single cause for this disorder. The
parents of PDD/ASD children are usually quite capable of rearing their normal
children and their autistic child. Any parenting difficulties appear to be the result,
not the cause, of their PDD/ASD child’s maladaptive behaviors. Parenting a child
with this disorder is very difficult and stressful. Parents need a support network
around them to know they are not alone.
Myth: PDD/ASD Is a Hopeless Condition

Reality: The prognosis in PDD/ASD is quite variable. It is not the diagnosis
itself that determines the course; rather, each child’s capabilities and response to
remediation will dictate the eventual outcome. PDD/ASD requires a comprehen-
sive, intense, consistent program of intervention. Various individuals and inter-
vention programs claim a 20% to 50% recovery rate. However, all children with
these diagnoses can derive some benefit from global intervention programs that
emphasize communication and language development, social skills, behavioral
management, expansion of play skills, and self-help skills.
SUMMARY
PDD/ASD is a neurological disorder of unknown etiology that is characterized
by a triad of atypical behavioral manifestations: an impairment in socialization, an
impairment in verbal and nonverbal communication, and restricted or repetitive

patterns of behavior. Recent studies indicate a prevalence of one in every 500
to 1000 children. The reason for the increasing numbers of children identified
with this disorder is still open to debate and ranges from broader clinical defini-
tions of inclusion to greater clinical recognition on the part of professionals to
environmental and medical causes. At the present time, the etiology for PDD/
ASD remains unknown.
The diagnosis of PDD/ASD is based exclusively on behavioral observa-
tions. The evaluation requires a multidisciplinary team knowledgeable about the
disorder and with experience evaluating children who are often difficult to assess.
Specific evaluations include a detailed medical, developmental, and family his-
tory; physical and neurological examinations; a diagnostic parental questionnaire;
cognitive measures; adaptive behavioral evaluation; a hearing test; speech/lan-
guage evaluation; assessment of fine and gross motor skills and sensory integra-
tion; and a social family history.
The treatments most often used include Applied Behavioral Analysis ther-
apy, speech/language therapy, occupational therapy, sensory integration therapy,
educational intervention, medication, and family support.
Because the etiology of PDD/ASD is unknown, there is no current “cure.”
However, early aggressive, comprehensive, and intensive therapies and interven-
tion are bringing about substantial—and in some cases remarkable—changes in
the behavioral manifestations of PDD/ASD.
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Brief report: a pilot open clinical trial of intravenous immunoglobulin in childhood
7
Molecular Genetics of Autism
Jennifer G. Reichert, Mario Kilifarski, Irina Bespalova, Nicolas

Ramoz, and Joseph D. Buxbaum
INTRODUCTION
Autism is a pervasive developmental disorder (PDD) characterized by communi-
cation and language impairments, social deficits, and stereotyped or repetitive
behaviors. These developmental abnormalities are apparent by early childhood,
or 36 months of age. Autism is a complex psychiatric disorder with oligogenic
inheritance (1). Twin studies and family studies show substantial evidence for
genetic predisposition in the majority of idiopathic cases (2–9). The population
prevalence of autism has been estimated at approximately 0.5–2 per 1000, but
the rate among siblings of affected probands is estimated from multiple studies
at 1–3%, which is profoundly higher (approximately 10–15 times greater) than
the general population prevalence (6–9). The concordance rate for dizygotic (DZ)
twins is similar to the rate for nontwin siblings, whereas the concordance rate
for monozygotic (MZ) twins is approximately 60–90% (2). This suggests that
the heritability for autism is greater than 90%, if you assume a multifactorial
threshold model (10), which exceeds that of other common psychiatric disorders
such as bipolar disorder, alcoholism, and schizophrenia. Other twin studies show
that this predisposition extends to a broader autism phenotype of milder, related
developmental disorders (2,3). This spectrum of nonpathological abnormalities
in behavior is present in parents and siblings of autistic individuals (11). Most
MZ co-twins who were nonautistic exhibited milder abnormalities similar to fea-
tures of autism. Concordance for the broader phenotype of autism for DZ twins
133
134 Reichert et al.
is considerably lower than the concordance for MZ twins: 10% and 92%, respec-
tively (2). Concordance and relative risk continue to drop off dramatically for
relatives outside the immediate family, such as cousins, although the concordance
rates for relatives are still greater than the population prevalence (6,11).
This, combined with the difference in concordance rates between MZ and
DZ twins, suggests the action of several genes acting together. Latent class mod-
eling suggests two to 10 genetic loci interacting, with three interactive loci being
the best model (12), while other studies point to the possibility of 10–100 loci,
each of weak effect (13).
GENETIC STUDIES
Three types of genetic studies are being conducted to identify susceptibility
loci for autism. The first is identifying chromosomal and cytogenetic abnormali-
ties in autistic individuals. The second includes candidate gene studies, while
genome-wide linkage studies constitute the third.
STUDIES OF CYTOGENETIC ABNORMALITIES

Chromosomal abnormalities, such as terminal interstitial deletions, transloca-
tions, inversions, and aneuploidies, account for a small, but significant, percent
of the total incidence of autism. However, studying the location of these abnor-
malities can be useful in identifying and mapping genes that predispose to autism.
Most chromosomal abnormalities for autism are de novo mutations and are very
rare in multiplex families. Several chromosomal breakpoints have been found in
regions that have also been implicated in autism linkage and association studies.
Regions that have been studied include an unstable region of chromosome 15,
which is the most frequent abnormality documented, as well as chromosome
7, among others. Typical chromosome 15 abnormalities associated with autism
spectrum disorders include an interstitial duplication on 15q11–q13, a microdele-
tion, and supernumerary isodicentric chromosome 15 (14–20). The association
of chromosome 15 abnormalities with autism appears especially in cases that
involve mental retardation and epilepsy. Chromosome 15 contains large dupli-
cated genomic segments, which may lead to rearrangements and duplications
(21). Abnormalities on the long arm of chromosome 15 (15q11-q13) are the most
common, accounting for 1-4% of cases of autism, and are also associated with
autism spectrum disorders. This region (15q11–q13) has several genes subject
to imprinting, and is the critical region for Angelman and Prader-Willi syn-
dromes, which have clinical features similar to those of autism (22). Angelman
syndrome is caused by a de novo microdeletion in this region or, more rarely,
paternal uniparental disomy. Among the abnormalities in 15q11–q13 are mater-
nally inherited duplications, either pseudodicentric 15 or other atypical marker
Molecular Genetics 135
chromosomes with one or two extra copies of the area corresponding to the
Angelman/Prader-Willi critical region. These patients usually have mental retar-
dation (18,23,24).
Chromosome 15 has a high frequency of deletion events, and accounts for
approximately 50% of all supernumerary marker chromosomes in humans (25).
Smith et al. described a 1-Mb deletion in the region 15q22-23 in a patient with
autism, developmental delay, and a mild dysmorphism, and showed that DNA
segments are shared between this region and region 15q11-q13 (26). A 5-kb
deletion was recently found at D15S822, and occurred in families with autism
more frequently than in a control group (27).
A study of linkage analysis results on chromosomes 7, 8, 15, and 16 in
105 multiplex families revealed null alleles at the sites of four markers—D7S630,
D7S517, D8S264, and D8S272—which were the result of deletions ranging in
size from 5 to ⬎260 kb in 12 families with autism (28). When controls were
screened for deletions at these 4 sites, the deletion at D8S272 was found in all
populations. The remaining three deletion sites remained specific to multiplex
families with autism. These could be potential autism-susceptibility deletions, or
it is possible that autism-susceptibility alleles elsewhere induced errors during
meiosis, causing these deletions. The D7S630 deletion occurred close to regions
found to be positive for linkage (29,30). This marker is also very close to the
proximal breakpoint for the interstitial 7q inversion reported in a subject with
autism (31).
Numerous translocations have been found in patients with autism. Several
balanced and complex translocations involve chromosome 7q. Among them are
the reciprocal balanced translocations t(1;7)(p22:q21) (32) and t(5,7)(q14;q32)
(33) and a balanced chromosome rearrangement involving a breakpoint at 7q31.3
(34).
Ashley-Koch et al. studied an autistic disorder family with three affected
siblings: two autistic males, and a female with expressive language disorder (31).
All three had a paracentric inversion, inv(7)(q22–q31.2), inherited from the
mother, who did not have autism. Another group identified a novel gene, RAY1,
on chromosome 7q31 that was interrupted by a translocation breakpoint, t(7;13)
(q31.3;q21) in an individual with autism (35). The failure to identify phenotype-
specific variants in a mutation screening of 27 unrelated autistic individuals sug-
gested to them that the coding region mutations were not likely to be involved
in the etiology of autism. In a study of a kindred, KE, a three-generation pedigree
in which half the members are affected with a severe speech and language disor-
der, a gene (SPCH1) was localized to 7q31, which the authors proposed was
responsible for the disorder (36). The SPCH1 critical interval was narrowed from
a 5.6-cM region between D7S2459 and D7S643 to a 6.1 MB region of completed
sequence between new markers 013A and 330B. They also studied two unrelated
individuals with de novo translocations in 7q31, and a similar speech and lan-
136 Reichert et al.
guage disorder. One of these was found to have a translocation breakpoint to a

200-bp region in the intron between exons 3b and 4 of the FOXP2 gene (37).
This disruption of FOXP2 is implicated in the etiology of this patient’s speech
and language disorder, but apparently not in autism (38).
Deletions in patients with autism were also found at 22q13.3 (39), 6q24.2–
26 (40), Xp22 (41), and 16q23.1 (42). Several patients with autism and facial
dysmorphism were found to have deletions at 2q37.3 (43,44). The region 2q has
more than 10 reported cases of chromosomal abnormalities.
CANDIDATE GENE STUDIES

Chromosome 15 is also the focus of several candidate gene studies, since the
many reports of chromosomal abnormalities indicate potential genes for autistic
disorder, or a possible susceptibility gene. The gamma-aminobutyric acidA (GA-
BAA) receptor cluster—which has been implicated in epilepsy, as well as Prader-
Willi and Angelman syndromes—is in 15q11–q13. Cook et al. (45) screened
nine loci for allelic association in 140 singleton families with autistic disorder.
Using the multiallelic transmission disequilibrium test (MTDT), they found link-
age disequilibrium between GABRB3 155CA-2 and autism (MTDT 28.63, 10df;
p ⫽ 0.0014). They found no evidence for linkage disequilibrium with the two
closest flanking markers (45). In one genome-wide scan with 51 autistic multiplex
families, a broad peak was revealed over the GABRB3 region, with a LOD score
of about 1 (46). Another group demonstrated a peak Z-score of 1.78 over this
region, near the marker D15S217, using multipoint analyses (47). They also
found suggestive association with another marker in this region, GABRB3, al-
though they did not observe significant linkage disequilibrium with 155CA-2
(48). Other genome-wide scans found no evidence for linkage in this region
(49,50). The IMGSAC also found no evidence for association in the same region,
using seven markers, including 155CA-2 (51). Another group found no evidence
for association using eight markers, including 155CA-2, in 139 families (52).
Nurmi et al. tested 13 markers in 94 CLSA families, and found significant linkage
disequilibrium for D15S122, at the 5′ end of UBE3A, but no significant evidence
for linkage disequilibrium with GABRB3-155CA2 (27).
One study (53) did replicate the association of GABRB3 155CA-2 with au-
tism. They tested a set of 80 families using five markers (69CA, 155CA-1, 155CA-
2, 85CA, and A55CA-1) in the Prader-Willi/Angelman syndrome critical region.
Using the MTDT, they demonstrated association between autistic disorder and
155CA-2 in 80 families (p ⬍ 0.002). Evidence for linkage was absent, despite the
significant association values, implying that it is a modifying gene or risk factor
for autistic disorder that lies within the GABA receptor gene complex in 15q11–
q13. This study also included meta-analyses of the published results of other studies
performed on the 15q11–q13 region (Table 1). These meta-analyses demonstrate
Table 1 Summary of Published Results for GABRB3 155CA-2

Number of
Study (Ref.) families MTDT df p
Cook et al., 1998 (45) 138 28.63 10 0.0014

Maestrini et al., 1999 (51) (transmissions to 99 17.21 a 10 a 0.070a
all affected)
Maestrini et al., 1999 (51) (transmissions to 99 13.79 b 9b 0.13b
a single affected)
Salmon et al., 1999 (52) 139 17.57 d 11 d 0.092c
Martin et al., 2000 (54) 123 — — 0.73d
Nurmi et al., 2001 (27) 94 — — 0.71e
Buxbaum et al., 2001 (53) 80 27.67 9 0.0011
a
Derived from Ref. 51, Table 2, pooling alleles 3 and 11.
b
Derived from Ref. 51, Table 2, pooling alleles 3, 10, and 11.
c
From Ref. 52, Table 2. Note that there is an error in the reported transmissions for the 114-bp allele
due to a typographical error; the reported χ2 value for this allele is correct (J Hallmeyer, personal
communication).
d
From Ref. 54, Table 1, where the p value for the Tsp statistic is reported, but no transmission data
is reported.
e
From Ref. 27, Table 1, where the p value for the Tsp statistic is reported, but no transmission data
is reported.
that studies that use tests other than the MTDT, such as the TDT (51,52), do not
appear to represent evidence against association when converted to MTDT results.
The presence of hyperserotonemia in a subset of autistic subjects has sug-
gested that the serotonergic system may play a role in the etiology of autism.
The serotonin transporter gene, 5-HTT, has been considered a candidate gene
for autism. One report has suggested association, using the TDT, between the
short variant of HTTLPR and autism (55). Another report, attempting replication,
demonstrated preferential transmission of the long variant of HTTLPR in 65 sin-
gleton families (56). A third study by the International Molecular Genetic Study
of Autism Consortium (IMGSAC) found no significant evidence for linkage or
association for the HTTLPR locus or the HTT-VNTR locus, in a sample of 99
multiplex families (51). In another study of the serotonin transporter gene
SLC6A4, the TDT was conducted with 81 trios (57). The investigators found
transmission disequilibrium but not preferential transmission of 5-HTTPLR. In
this study, they sequenced SLC6A4 and its flanking regions in 10 probands, and
found 20 single-nucleotide polymorphisms (SNPs) and seven simple sequence
repeat (SSR) polymorphisms, which they typed in 115 autism trios. TDT analysis
of individual markers showed seven SNP markers and four SSR markers to have
nominally significant evidence of transmission disequilibrium.
138 Reichert et al.
A recent genome scan indicated 6q21 as a candidate region for an autism-

susceptibility locus (58). One of the candidate genes in this region is the glutamate
receptor 6 gene (GluR6 or GRIK2). Glutamate, a neurotransmitter in the brain, is
involved in memory and learning. To investigate linkage between GluR6 and autism,
the affected sib-pair (ASP) method was used, which showed a significant excess of
allele sharing among 59 sibling pairs, generating an MLS of 3.28. The TDT, per-
formed with one affected proband per family, showed significant maternal transmis-
sion disequilibrium and association between GluR6 and autism (TDT association p
⫽ 0.008). Several SNPs, which included one amino acid change (M867I) in a highly
conserved domain of the intracytoplasmic C-terminal region of the protein, were
found in a mutation screening of 33 affected individuals. This change was found in
only 8% of the autistic patients, and also in 4% of the controls. The results of this
study suggest that GluR6 is in linkage disequilibrium with autistic disorder.
The reelin gene (RELN) is another candidate for involvement in autistic
disorder. Reelin participates in the development of the cerebellum, cerebral cor-
tex, hippocampus, and several brainstem nuclei. Persico et al. (59) performed
family-based analyses and case-control studies, which showed a significant asso-
ciation between autism and a polymorphic GGC repeat. These findings suggest
that the length of the triplet repeat (GGC) located immediately 5′ of the reelin
gene ATG initiator codon may play a role in autistic disorder.
WNT2 is another candidate gene for autism because it is located in the
region of 7q31–q33 linked to autism, as well as near a chromosomal breakpoint
in an individual with autism. Also, the WNT2 family of genes influences the
development of the central nervous system and other organs, and a knockout
mouse shows a behavioral phenotype defined by diminished social interactions.
Wassink et al. (60) screened the WNT2 coding region for mutations in autistic
probands, and two families were found with coding sequence variants segregating
with autism in those families. Linkage disequilibrium (LD) was also found be-
tween a WNT2 3′UTR SNP and a subgroup of ASP families with severe language
abnormalities. As a result, they posited that common, as yet unidentified WNT2
alleles may contribute to autism susceptibility, but rare mutations in the WNT2
gene, even when present in single copies, increase susceptibility to autism to a
greater degree (60). Another group found no evidence for association between
autism and WNT2 in 82 multiplex and 132 singleton families (61).
The HOXA1 gene may play a role in susceptibility to autism. It was noted
that mice with null mutations of Hoxa1 or Hoxb1, genes that are critical to hind-
brain development, exhibit phenotypic features that are often observed in autism.
Sequencing of these two genes in patients with autism and autism spectrum disor-
ders (ASDs) detected variants in coding regions of HOXA1 and HOXB1 genes
(62). In the ASD families, the HOXA1 genotype ratios deviated significantly
from the expected Hardy-Weinberg proportions ( p ⫽ 0.005). Gene transmission
among affected offspring also deviated significantly ( p ⫽ 0.011) from Mendelian
expectation. Analysis of the HOXB1 locus did not reveal any statistically signifi-
cant results, although there was evidence of interaction between HOXB1,
HOXA1, and gender in ASD susceptibility. Another screening of the 24 exons
of HoxA1 and HoxB2 for DNA polymorphisms, in 24 autistic individuals, identi-
fied the same sequence variants (63). However, a TDT in 110 multiplex families
showed no association with autism.
GENOME-WIDE SCREENS
The cosegregation of polymorphic DNA markers with a disorder such as autism
can be tracked in families in order to map genes. By identifying DNA markers
with a known genetic location that significantly cosegregate with autism within
families, linkage mapping can infer the location and inheritance mode of nearby
susceptibility loci. Since multigenerational families with numerous affecteds are
Table 2 Genome-Wide and Focused Linkage Studies in Autism

IMGSAC 1998 (99 families)a PARISS (51 families)b Stanford (139 families)c
Position Nearest Position Nearest Position Nearest

Chromosome (cM) marker MSL (cM) marker MLS (cM) marker MLS
1p 149 D1S1675 2.15

2q 192 D2S364 0.64
3
4p 4.8 D4S412 1.55
4q 199 D4S1535 0.88
4q
5p 5 D5S417 0.84
6q 109 D6S283 2.23
7p 42 D7S2564 1.01
7q 140.5 D7S2533 3.63 147.2 D7S684 0.62
7q 144.7 D7S530 2.53 125 D7S486 0.83 138 D7S1804 0.93
8q
9
10p 51.9 D10S197 1.36
10q 167 D10S217 0.84
11q
13q 85.0 D13S193 0.59 55 D13S800 0.68
14q 32.2 D14S70 0.99
15q
15q 32 D15S118 1.10
16p 17.3 D16S407 1.51 21 D16S3075 0.74
16q
17p 11 D17S1876 1.21
18q 94 D18S68 0.62 100 D18S878 1.00
19q 48.2 D19S49 0.99 41 D19S226 1.37
22q 5.0 D22S264 1.39
Xq
140 Reichert et al.
Table 2 (Continued)
CLSA (75 families)d SARC (35 families)e IMGSAC 2001 (152 sib-pairs)f
Position Nearest Position Nearest Multipoint HLOD HLOD Position Nearest Multipoint
Chromosome (cM) marker MLS (cM) marker NPL (dom) (rec) (cM) marker MLS
1p
2q 186.2 D2S364 2.45 2.25 1.65
2q 204.5 D2S325 1.52 0.67 0.65 206.4 D2S2188 3.74
3
4p
4q 72.5 D4S3248 1.33
4q 167.6 D4S2368 1.52
5p
6q
7p
7q 104 D7S1813 2.20 119.6 D7S477 3.2
7q 150 D7S1824 0.80
8q 60.3 D8S1477 1.02
9
10p
10q
11q 147.8 D11S968 1.22
13q 55 D13S800 3.00
14q
15q 13.1 D15S975 0.50
15q 32 ACTC 0.54
16p 23.1 D16S3102 2.93
16q 100.4 D16S516 1.03
17p
18q
19q
22q
Xq
rare in autism, other methods of linkage mapping can assess linkage within many
nuclear families. In order to identify autism susceptibility loci, eight groups have
reported systematic scans of the entire genome of multiplex families (29,46,49,
50,64,65,67,71). The results are summarized in Table 2, showing overlapping
regions between studies and the most significant results for each. The results of
several focused linkage scans have also been reported (30,31,47,66), as well as
a genome-wide QTL analysis (Table 2) (71).
The IMGSAC group (50) performed the first genome-wide screen in two
stages, with 99 families, including 87 ASPs and 12 affected nonsib-pairs. The
first stage typed 354 markers in 39 families. A subset of 175 markers was used
in the second stage to genotype 60 additional families, focusing on regions of
interest from the first stage. Six chromosomes (4, 7, 10, 16, 19, and 22), with
regions generating a multipoint maximum LOD score (MLS) ⬎1, were identified.
Table 2 (Continued)
Columbia (110 families)g Duke 2002 (99 families)h Alarcon et al. (152 families)I
Position Nearest Multipoint Position Nearest Multipoint Position Nearest Z-score

Chromosome (cM) marker MLS (cM) marker MLS (cM) marker (HE LOD)
1p
2q
198 D2S116 2.86
3 36 D3S3680 1.51
4p
4q
4q
5p 45 D5S2494 2.55 Broad
6q
7p
7q 123 D7S523 1.02 145 D7S495 1.66 152 D7S1824 2.85 (0.84)
7q 165 D7S483 2.13
8q 134 D8S1179 1.66 Broad
9
10p
10q
11q
13q
14q
15q
15q
16q 28 D16S2619 1.91 Narrow
16q
17p
18q
19q 52 D19S433 2.46 Narrow 60 D19S425 1.21
22q
Xq 82 DXS1047 2.67 Narrow 63 DXS6789 2.49
a
IMGSAC, 1998 (50).
b
Philippe et al., 1999 (46).
c
Risch et al., 1999 (49).
d
Barrett et al., 1999 (29).
e
Buxbaum et al., 2001 (67).
f
IMGSAC, 2001 (30).
g
Liu et al., 2001 (64).
h
Shao et al., 2002 (65,72).
i
Alarcon et al., 2002 (71).
The most significant region was between D7S530 and D7S684, and had a
multipoint MLS of 2.53. The region between D16S407 and D16S3114 was the
next most significant, with a multipoint MLS of 1.51. They found no evidence
for linkage in the Prader-Willi/Angelman critical region, 15q11–q13.
They performed a follow-up study (66) of 7q32–q35 by fine-mapping the
142 Reichert et al.
region. They genotyped 51 markers in 131 families, including the 99 original

families plus 32 subsequently identified families. The results generated a
multipoint MLS of 4.45, providing further evidence for linkage, and an autism
susceptibility locus, in this region. Additionally, chromosomes 1, 2, 9, and 17
had MLS scores greater than 1. They also completed linkage analysis on 170
multiplex families, to characterize a susceptibility locus on 7q (68). A multipoint
MLS of 2.15 at D7S477 was obtained with analysis of 125 sib-pairs, using a 5-
cM marker grid. Two regions of association were identified using linkage disequi-
librium mapping. One region underlies the peak of linkage and the other is 27
cM distal.
Recently, IMGSAC completed another linkage analysis study with addi-
tional families (30). Using 152 sib-pairs, including 83 sib-pairs from the original
99 families, and 119 markers, four chromosomes (2, 7, 16, and 17) generated a
multipoint MLS ⬎1.5, while the evidence for linkage reported previously for an
additional four chromosomes (4, 14, 19, and 22) was diminished. The highest
multipoint MLS was 3.74 at D2S2188 on 2q, and the next highest multipoint
MLS was 3.20 at D7S477. A third peak on 16p produced a multipoint MLS of
2.93 at D16S102.
The Paris Autism Research International Sibpair Study (PARISS) (46) re-
ported a genome-wide screen of 51 families, with 264 markers. Twelve markers
on 10 chromosomes (2, 4, 5, 6, 10, 15, 16, 18, 19, and X) generated a multipoint
MLS ⬎ 0.6 ( p ⬍ 0.05). Multipoint analysis generated significant results for re-
gions on chromosomes 4, 5, 6, 10, 15, 16, and 19. Another potential susceptibility
region on chromosome 7 was identified at D7S486. The most significant result
was an MLS of 2.23 for marker D6S283. Four of the regions with excess of
alleles shared identical by descent (IBD), identified in this study (2q, 7q, 16p,
19p), overlap with significant IMGSAC findings. This group also had positive
linkage results in the chromosome 15q11–q13 region with marker D15S118
(20cM distal to the GABRB3 subunit gene) with an MLS score of 1.10.
The Stanford University group (49) conducted a large genome-wide scans
in two stages. The first consisted of 519 markers in 90 families, and then a subset
149 markers was genotyped in 49 additional families. They observed an increase
in IBD between ASPs (51.6%) versus the discordant sib-pairs (DSPs) (50.8%).
This was the result of a moderate increase of IBD over nearly every chromosomal
region, rather than the effect of a small number of loci. This suggested to them
a disease model with a large number of loci, possibly more than 15. The most
significant finding was an MLS score of 2.15 on chromosome 1p for marker
D1S1675. Other significant results included regions on chromosomes 7p, 17p,
and 18q, with MLS scores ⬎1. The finding on 18q overlaps with the PARISS
study results, and modestly positive scores on 7q and 13q overlap with IMGSAC
and CLSA results. They found no evidence for linkage in 15q11–q13.
The Collaborative Linkage Study of Autism (CLSA) (29) performed a two-
stage genome-wide screen. In the first stage, 416 microsatellite markers were
genotyped to 75 families. Their most significant results were for regions on chro-
mosomes 13 and 7, using a recessive model. Marker D13S800 had a maximum
multipoint heterogeneity LOD (HLOD) score of 3.0. A peak between D13S217
and D13S1229 scored a 2.3 HLOD, and marker D7S1813 had an HLOD score
of 2.2. These results overlap with the IMGSAC and Stanford findings for chromo-
somes 7 and 13. They also observed a 0.51 HLOD score at marker D15S975.
The Columbia Genome Center (64) performed a genome-wide screening
for autism susceptibility loci using 335 microsatellite markers and 110 multiplex
families. In addition to more modest evidence for linkage at 12 marker sites (2,
3, 4, 5, 8, 10, 11, 12, 15, 16, 18, 19, and 20), they found significant evidence
for linkage with regions on chromosomes 5, 19, and X. They analyzed their
results using both broader (autism, Asperger’s, or pervasive developmental disor-
der) and narrower (autism only) diagnosis schemes. Under the broad diagnosis,
the most significant region was at marker D5S2494 (MLS ⫽ 2.55). Other signifi-
cant results under this scheme were DXS10437 (MLS ⫽ 2.56), D5S2488 (MLS
⫽ 1.90), and D19S714 (MLS ⫽ 1.72). Under the narrower diagnosis, the most
significant region was on chromosome 19, near D19S714 (MLS ⫽ 2.53). Other
significant findings with the narrow scheme include DSX1047 (MLS ⫽ 2.67),
D16S2619 (MLS ⫽ 1.93), D5S2488 (MLS ⫽ 1.63), and D5S2494 (MLS ⫽ 1.41).
Initially they found no evidence for linkage on chromosome 7, but because
of overlapping findings of positive linkage for this chromosome in previous ge-
nome-wide screenings, a follow-up study was performed. Six microsatellite
markers from the original scan were included, as well as 28 additional markers
to densely cover the region on chromosome 7. These markers were genotyped
in 160 families, including the 110 from the original study. A peak LOD score
of 2.13 was found at D7S483, and another peak of 1.02 at D7S523.
A combination of the results from these studies implicates a locus on chro-
mosome 7q for autism etiology. However, the different studies report positive
peaks for loci on 7q that can be more than 20 cM apart.
A study from Duke University (31) focused the scope of their genome scan
based on the findings of the previously mentioned groups, and their own results
from a study of a family with a paracentric inversion on 7q. They genotyped 76
multiplex families, with nine markers, to this region. Their most significant results
were for the region between D7S2527 and D7S495. A multipoint HLOD score of
1.47 and an MLS of 1.03 were obtained for marker D7S495. They also observed a
peak NPL score of 2.01 for D7S640, and a peak MLS of 1.77 for D7S2527. This
group also noted an increased rate of recombination between autistic families vs.
CEPH controls. TDT analysis suggested transmission distortion at D7S495 ( p
⫽ 0.03), mostly with paternal contribution. Additionally, significant paternal con-
tribution to linkage disequilibrium was observed at D7S1824 ( p ⫽ 0.02), and to
IBD sharing at D7S640 ( p ⫽ 0.007). This increase in paternal contribution sup-
144 Reichert et al.
ports an imprinting effect. Overall, the results provide further supporting evidence
for an autism-susceptibility locus on 7q.
This group also conducted a follow-up study, genotyping 14 markers in
the chromosome 15q11–q13 region to 63 multiplex families (47). They found
evidence for linkage in this region, along with increased rates of recombination
near GABRB3 and D15S217, in autism families. For marker D15S217, they
found a maximum LOD score of 1.37 ( p ⫽ 0.03), under a recessive model, and
a Z-score of 1.78.
The Duke group’s recent genome-wide screening was performed in two
stages (65). In the first stage, 52 multiplex families were genotyped for 352 satel-
lite markers. Markers in eight regions on seven chromosomes (2, 3, 7, 15, 18,
19, and X) met a threshold MLS of ⱖ1.00, and were genotyped with their flanking
markers in the second stage, in 47 additional families. Other regions reported in
previous screenings (2, 7q, 13, and 15q11–q13) were also genotyped to these 99
families. Their peak linkage results were on chromosome X with a multipoint
MLS of 2.49. They also found that their peak at D3S3680, a unique finding,
remained strong with a pairwise MLS of 2.02. Two markers on chromosome
2, D2S2215 and D2S116, previously below the cutoff for inclusion in the sec-
ond stage, now both had MLOD ⱖ1.0, and overlapped with findings from other
studies (50,67). Their results for chromosome 7q (multipoint MLS ⫽ 1.66) also
overlapped with the IMGSAC findings (50), and their peaks on chromosome
15q11–q13 (MLOD ⱖ1.0) overlap with results from the PARISS group (46). The
regions on chromosome X and 19 also overlapped with the findings of IMGSAC,
PARISS, and Columbia (64).
Studies of both developmental language disorder, or specific language im-
pairment (SLI), and autism have had significant linkage results on chromosome
7q31. Although the two syndromes are diagnostically distinct, they overlap phe-
notypically (69). The prevalence of autism in families of children with SLI is
greater than expected, and the prevalence of SLI in families of children with
autism is also greater than expected. The two disorders appear to be genetically
related and may have some genes in common (70).
Alarcon et al. (71) performed nonparametric multipoint linkage analyses
of 152 nuclear families, with at least two children with an ASD, to search for
quantitative trait loci (QTLs). Nine ADI-R items were examined for familiality
and sibling correlations, and three had significant intersib correlations [age at
first word (WORD), age at onset of phrase speech (PHRASE), and repetitive
or stereotyped behavior (RSB)]. These three significant items were chosen as
endophenotypes. Previous family and linkage studies in autism have shown these
phenotypes to be relevant to genetic studies of autism. Two methods of linkage
analysis (nonparametric QTL and HE nonparametric) were used, and peaks with
Z-scores ⬎1.65 and LOD scores ⬎1.0, respectively, that were found in both
analyses, were reported. The highest Z-score was 2.98 on chromosome 7, between
D7S1824 and D7S3058, for WORD, with a corresponding HE LOD score of

1.14, close to the previously reported region of possible autism-susceptibility loci
(31,45,48,67). They found no evidence for linkage for a PHRASE QTL on 7q,
but did find peaks on three other chromosomes (10, 11, and 20) with Z-scores
ⱖ2.1, and HE LODs ⬎1.2. Another Z-score peak for WORD was also found on
chromosome 11 (Z ⫽ 2.22; HE LOD 0.96), 21 cM away from the PHRASE
linked region. In the initial scan, no evidence was found for an RSB QTL. The
peak Z-score (1.84) for RSB on chromosome 7q did exceed the threshold, but
the HE LOD score (0.16) did not support it. Twenty-eight fine-mapping markers
were then typed for the region between D7S1799 and D7S3058. The highest peak
for WORD remained, with a Z-score of 2.85 (HE LOD 0.84), as did the peak
RSB Z-score on 7q (2.48), although the HE LOD of 0.05 still did not support
an RSB peak in this region. Ten markers, between D7S1824 and D7S3058, were
then tested for association. Two (D7S1824 and D7S2462) showed evidence for
association with WORD. Additionally, D7S2462 showed association with RSB
and PHRASE. The distance (10.19 cM) between the two markers associated with
WORD suggests that there may be two language-related QTLs in this region.
In our first study (67), 95 multiplex families were screened in a two-stage
genome-wide scan. In the first stage, 35 families were genotyped, and the strong-
est evidence for linkage was on chromosome 2q. The second-stage analysis, with
additional families, generated maximal multipoint HLOD scores of 1.41 on 2q
in the whole sample, and an NPL score of 2.39, with evidence for genetic hetero-
geneity. The analysis was then restricted to a subset of families in which two or
more individuals had a narrow diagnosis of autism and in which the affected
individuals had onset of phrase speech occurring after 36 months of age. This
generated maximal multipoint HLOD scores of 2.89 on 2q, and an NPL score
of 3.32. There was significantly less evidence for heterogeneity in this restricted
sample. This indicates that restricting the sample to families with at least two
affecteds with delayed onset of phrase speech yields a population that is more
genetically homogeneous. The likelihood of positional cloning of susceptibility
loci is profoundly increased by this increased genetic homogeneity. The use of
a restricted sample set, using narrower diagnostic criteria to increase homogene-
ity, could be a way to increase the power of other linkage studies. Note that the
IMGSAC (30) used similar language criteria, and had their highest peak at the
same locus on chromosome 2q.
The Duke group conducted an additional study of their 99 families based
on these findings (72). They identified a subset of 45 families with delayed onset
(⬎36 months) of phrase speech. When this subset was analyzed, there was in-
creased support for linkage to 2q. The MLS for marker D2S2116 increased to
2.86 and the HLOD to 2.12. These data further support evidence for a gene on
chromosome 2, and support phenotypic homogeneity as a means of finding sus-
ceptibility loci by increasing power.
146 Reichert et al.
DISCUSSION
With several genome-wide linkage screens for autism having been completed,
the differing results are consistent with a disease model of genetic heterogeneity,
and multiple loci of weak effect. However, it is not altogether straightforward
to compare results, because of differences in methodology such as varying mark-
ers and marker maps, as well as different statistical analyses. Also, the criteria
for inclusion and diagnosis differ somewhat from study to study. It may be useful
to examine different subsets of affected probands, based on varying diagnostic
criteria, such as the recent study of language deficit and chromosome 2. Using
the three domains of autism disease (stereotyped or repetitive behaviors, language
deficits, and social deficits) to create subphenotypes may increase the power of
linkage and association findings for susceptibility loci for these subsets of af-
fected probands. These subphenotypes could be used to narrow down which loci
could relate to each domain of the disease. The subsets could also include subjects
who may not have autism but some diagnosis in the broader autism phenotype,
with high scores in one particular domain. Further study will help to distinguish
true susceptibility loci from false positives.
In summary, evidence from genome-wide scans, and analysis of dele-
tions and translocations, indicates a susceptibility gene for autism on chromo-
some 7q. Other loci are also concordant between screens, including chromosome
2. Using diagnostic criteria to restrict the families in further studies may decrease
heterogeneity, and thereby increase power to detect genes. In addition, broaden-
ing the definition of affected to include subthreshold cases may also increase
power.
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8
Immune Dysfunction in Autism
Gina DelGiudice
and Hospital for Special Surgery
Eric Hollander
INTRODUCTION
Cellular and humoral immune dysfunction, complement deficiencies, abnormal
antibody production, and abnormal cytokine levels have been documented in au-
tistic individuals. Complex interactions and links between the immune system,
the endocrine system, and the central nervous system have been well established,
and have relevance for the pathophysiology of autism. We review the literature
of the last 25 years pertaining to the relationship between autism and altered
immune response; propose three hypotheses of immunopathogenesis; and review
preliminary immunomodulatory treatment strategies. Additional research is
needed to determine the role of autoimmune and neuroendocrine factors in autism
since most findings are preliminary and the implications of the findings need to
be determined to see whether specific therapeutic agents targeting these systems
might ameliorate or cure symptoms of autism.
PATHOPHYSIOLOGY OF AUTISM
Autism is a severe neuropsychiatric and developmental disorder characterized by
social difficulties (e.g., lack of social reciprocity), language abnormalities (e.g.,
a delay in language development), and stereotyped patterns of behavior (e.g.,
153
154 DelGiudice and Hollander
obsessive routines and rituals, abnormal preoccupations, motor stereotypies, and

abnormal attachments to objects). Symptoms may manifest shortly after birth,
although in some cases one or two years of relatively normal development has
been reported. The disturbance, by definition, must be manifested by delays prior
to age 3 (1). The profile of cognitive skills is usually uneven regardless of the
general level of intelligence, with nonverbal skills superior to verbal skills and
75% of children with autism disorder functioning at a retarded level (2).
Although the syndrome was described over 50 years ago, the pathogenesis
remains unknown. Epidemiological studies suggest rates of autistic disorder of
two to five cases per 10,000 individuals (2). This includes a phenotype in nonau-
tistic individuals that is milder but qualitatively similar to the defining behaviors
of autism (the broader phenotype). Rates of the disorder are four to five times
higher in males that in females. The strong genetic component is supported by
a concordance rate of greater than 50% in monozygotic twins compared with 0%
in dizygotic twins, and greater than 90% in monozygotic twins compared with
approximately 10% in dizygotic twins (3,4). The recurrence risk for autistic disor-
ders in siblings is between 4.5% and 8.9% (5,6). Relatives of an autistic individual
are at greater risk for other disorders, including a lesser variant of autistic disor-
der, affective disorders, and substance-abuse disorders (7–9). Candidate gene
studies have suggested an association between the serotonin transporter gene
(HTT) and autistic disorder (10) and between autism and the GABA receptor
beta 3 subunit gene (GABRB3) (11). Chromosomal disorders have been found
in patients with autism. The most common are disorders of the proximal long
arm of chromosome 15 (15q11–q13) that are maternally inherited duplications
(12). Another area of research screened the genome of large samples of affected
sib pairs for susceptibility loci. This technique has identified several chromosome
regions that may contain predisposing genes to autism (13).
Postmortem brain studies of fewer than 35 brains of patients with autism
are available. Preliminary findings include a paucity of Purkinje cells and granular
cells in parts of the cerebellar cortex, and smaller than normal, more tightly
packed cells in some cerebellar nuclei and limbic structures including the hippo-
campus and the amygdala. On average, the studied brains tended to be large
(14). Several studies have recently been published using different neuroimaging
techniques to assess both brain function and structure in autism. These studies
use magnetic resonance imaging (MRI), single-photon emission computed to-
mography (SPECT), positron-emission tomography (PET), and functional MRI
(fMRI). MRIs of 15 high-functioning young adults with autism were compared
with 15 age- and IQ-matched control subjects (15). They documented decreased
gray matter in the right paracentral sulcus, left inferior frontal gyrus, and left
occipitotemporal cortex. Gray matter was increased in the left amygdala/peri-
amygdaloid cortex, left middle temporal gyrus, and cerebelleum. Levitt et al.
(16) found that the area of cerebellar vermis lobules VIII–X was smaller in
Immune Dysfunction 155
eight autistic children compared with 21 healthy children. A study using high-
resolution MRI scanning to examine the basal ganglia of 35 autistic individuals
in comparison with control subjects found increased caudate nuclei volume that
was proportional to increased total brain volume in subjects with autism (17).
They reported an association between caudate volume and compulsions. Reviews
of SPECT scans in autistic children have found focal areas of decreased cerebral
blood perfusion (18,19). PET studies have demonstrated asymmetrical 5-HT syn-
thesis in autistic boys (20,21). Functional MRI studies of individuals with autism
have demonstrated abnormal activation of certain brain regions during neuropsy-
chological tasks (22,23).
Serotonin (5-HT) continues to be the focus of neurochemical studies in
autism. Double-blind studies of the serotonin-reuptake inhibitors clomipramine
(24), fluvoxamine (25), and fluoxetine (26), as well as open-label studies of flu-
oxetine (27) and sertraline (28) have documented efficacy in treating both global
autistic symptoms and symptoms of repetitive behaviors and restricted interests
in up to 60% of patients treated.
Several biological studies have also suggested 5-HT dysregulation in autis-
tic patients. McBride et al. (29) measured platelet 5-HT in 77 autistic subjects
compared with normal controls and prepubertal children with mental retardation.
Prepubertal autistic subjects had significant elevation in platelet 5-HT compared
with controls, but this was not statistically significant in postpubertal subjects.
Previous studies have shown that hyperserotonemia in autistic subjects is familial
(30). Leboyer et al. (31) replicated these results and demonstrated that whole-
blood serotonin levels in autistic subjects were age-independent, whereas the
whole-blood serotonin levels decreased with age in controls.
AUTOIMMUNE DISORDERS AND AUTISM

The etiology of prototypical autoimmune disorders such as systemic lupus erythe-
matosus, multiple sclerosis, and myasthenia gravis is unknown. It is hypothesized
that a combination of infectious, environmental, hormonal, and genetic factors
stimulate host inflammatory and immune defenses. It is the ongoing host response
that causes inflammation and tissue damage, leading to the various clinical syn-
dromes. Whether similar events are associated with autism is not known since
most studies to date provide preliminary evidence of a possible autoimmune
mechanism.
THE IMMUNE SYSTEM

Immune Function
An effective immune system must be able to differentiate self from nonself. Im-
mune cells have evolved to provide a specialized and efficient defense mechanism
to react and adapt to environmental changes, to develop a memory to improve

efficiency of responses, and to regulate responses once mounted (32).
The cells of the immune system are organized into lymphoid organs. The
central or primary lymphoid organs—the thymus and bone marrow—provide
the environment for lymphopoesis and differentiation and maturation. The pe-
ripheral or secondary lymphoid organs—spleen, lymph nodes, and diffuse areas
of lymphoid tissue associated with the mucosal surfaces in the body—provide
an environment required for an effective immune response. There is continuing
communication between the lymphoid tissues by the pool of recirculating cells
present in the blood and lymph (32).
Cellular and Hormonal Systems

The cells of the immune system include lymphocytes and different types of
phagocytic cells organized in the lymphoid tissues. These lymphoid tissues are
in constant communication by virtue of lymphocyte traffic. Such traffic is possible
through the blood and lymphatic networks of the body (32).
The phagocytic cells are the more primitive cellular elements of the im-
mune system. One of these cells, the mononuclear phagocyte, also acts as an
antigen-presenting cell (APC). These cells ingest and partially degrade foreign
substances and then express constituent parts (antigenic determinants) of phago-
cytized antigens on their membrane so they can be recognized by lymphocytes.
There are two major types of lymphocytes (32).
The principal effectors of the cellular immune system are the T lympho-
cytes. Their specificity is controlled by antigen receptors on their surface, the T-
cell receptors (TCRs). The response of an individual T cell is initiated when it
encounters an antigenic determinant (on the surface of the APC) for which its
receptor is specific. T lymphocytes produce several types of molecules known
as lymphokines. Lymphokines, also known as cytokines, have various functions
that stimulate and amplify the responses of other lymphocytes, and regulate the
immune response. Cytokines are primarily produced by a functional subset of T
cells, the CD4⫹ (T-helper) cells. Analysis of lymphocyte production by many
T-cell clones in response to antigen reveals that some CD4⫹ clones secrete large
amounts of proinflammatory lymphokines interleukin-2 (IL-2) and interferon-
gamma (IFN-γ), whereas others secrete down-regulating cytokines such as in-
terleukin-10 (IL-10). The former are termed TH1 cells and the latter TH2 cells.
Other proinflammatory cytokines, tumor necrosis factor (TNF), and interleukins
1, 6, and 8 exhibit both systemic and local biological effects in inflammatory
disease such as fever, muscle breakdown, and tissue damage. Cytotoxic T cells
have the capacity to lyse specific cellular targets such as virally infected cells or
tumor cells. Another T lymphocyte, the suppressor T cell, performs an immuno-
regulatory role. When appropriately stimulated, suppressor T cells negatively in-
fluence the responses of other lymphocytes and “turn off ” the immune response.
A cytotoxic response requiring no induction with antigen is termed natural cyto-
toxicity. This spontaneous cytotoxicity arises from natural killer (NK) cells and
serves as an initial response before the induction of antigen-specific cytotoxic T
lymphocytes (32).
Other lymphocytes, B cells, are responsible for humoral immunity. Their
surface receptors for antigen are immunoglobulin (Ig) molecules. The five distinct
immunoglobulins are referred to as classes: M, D, E, G, and A. IgG is the main
immunoglobulin class produced. When a B cell encounters a specific antigenic
determinant it can recognize through its Ig surface receptor, it is stimulated to
divide and produces more Ig molecules. These secreted Ig molecules (also known
as antibodies) bind onto their specific Fc receptor and initiate phagocytosis, anti-
body-dependent cell-mediated cytotoxicity (ADCC), and the release of inflam-
matory mediators. IgM is the initial isotype elaborated in response to primary
antigen exposure and represents the first antibody class synthesized by the neo-
nate. IgG is the predominant antibody class in serum, accounting for approxi-
mately 75% of total serum immunoglobulin. IgG also accounts for the antibody
activity in serum and is the reservoir of immunological memory for previously
encountered antigens. Immunoglobulins can trigger secondary mechanisms in-
volving other plasma proteins, such as the complement components. The comple-
ment system consists of at least 30 proteins and following activation results in
cell lysis, increased vascular permeability, leukocyte chemotaxis, and viral neu-
tralization (33). The human immune response is composed of specific elements
that trigger the recruitment of cells and secretion of factors that nonspecifically
cause inflammation or tissue damage. This process should clear the host of patho-
genic organisms. However, dysregulation at any of the described steps can lead
to autoimmune disease.
Genetic Regulation of the Immune Response

The determinants of the immune system reside in the human leukocyte antigen
(HLA) complex on chromosome 6. There are two basic classes of MHC mole-
cules. Class I MHC molecules are expressed on the surface of nearly every nucle-
ated cell. There are three different polymorphic class I MHC molecules, called
HLA-A, HLA-B, and HLA-C. Class II molecules are found only on some cells,
such as macrophages and monocytes, B cells, activated T cells, and dendritic
cells. There are three polymorphic class II MHC molecules: HLA-DR, HLA-
DQ, and HLA-DP. Class II molecules are essential for presentation of antigenic
peptides to CD4⫹T cells and therefore cells that bear class II MHC are referred
to as antigen-presenting cells, described above. Specific HLA alleles have been
found to be associated with certain diseases, and contribute to the susceptibility
of over 70 autoimmune illnesses (32).
IMMUNOLOGICAL TOLERANCE
The concept of immunological tolerance explains the numerous strategies that the
immune system has evolved to ensure that an immune response against self does
not occur (34). These mechanisms can be broadly classified as central and periph-
eral tolerance. One of their roles is to delete autoreactive lymphocytes. Apoptosis,
a form of programmed cell death, regulates tolerance induction of self-reactive T
cells in the thymus and B cells in the bone marrow (35). There are many regulators
of apoptosis. Bc1-2, a 25 kDa membrane-bound protein, is a potent antiapoptotic
regulatory protein (34). A recent report interestingly documents a significant in-
crease in Bc1-2 levels in the temporal cortex of patients with schizophrenia (36).
We present four hypotheses with regard to an autoimmune cause of autism:
an infectious hypothesis, an autoimmune hypothesis, an immunological intoler-
ance hypothesis, and a neuropeptide hypothesis. In addition, we examine prelimi-
nary efforts using immunomodulatory therapies to threat autism.
Infectious Hypothesis
In clinical reports, autism has been linked to numerous fetal infections: rubella,
cytomegalovirus, varicella zoster, herpes simplex, and toxoplasmosis (37–41).
Best documented is the relationship between autism and damage caused by fetal
rubella infections. In a longitudinal study of 243 children with congenital rubella,
a high rate of autism and “autism-like” disorders were found, suggesting that, at
least in a subset of patients, fetal viral infections produce an autism syndrome.
However, there was no differentiation to distinguish between autism and mental
retardation in the study subjects, and there was a lack of control subjects as well.
Deykin and MacMahon (42) found no significant association between childhood
autism and maternal viral infections during pregnancy. While some studies on
seasonal variation in the births of autistic children (arguing for a seasonal expo-
sure to an environmental pathogen) have not found any correlation, others have
found a significantly higher incidence among children born in March and August
(43). Geographical areas may also differ in their influence on seasonal exposure
to chemicals or climate, and this was not considered.
So far, there have been few studies of viral agents in the serum or cerebro-
spinal fluid in autistic patients. Investigators have postulated that immunopatho-
logical sequelae of infections may not be direct but rather due to cross-reacting
antibodies; this is known as molecular mimicry. A classic example is rheumatic
fever and Sydenham’s chorea following a group A beta-hemolytic streptococcal
infection (GABHS). Husby et al. (44) documented immunofluorescent antibodies
reacting with the cytoplasm of neurons in the caudate and subthalamic nuclei of
the brain (44).
The monoclonal antibody D8/17 reacts with an antigen on at least 20% of
the B cells of all rheumatic fever patients (45). Two independent laboratory
groups have identified more peripheral B cells expressing D8/17 in children with
obsessive-compulsive disorder (OCD) (46,47). The results suggest that mono-
clonal D8/17 may serve as a marker to susceptibility in subsets of children who
develop childhood-onset OCD. Hollander et al. (48) hypothesized that D8/17
might serve as a marker for susceptibility to autism, and data demonstrate sig-
nificantly greater expression of monoclonal antibody D8/17 in a subgroup of
autistic children than in matched medically ill children. Severity of repetitive
behaviors as assessed by the compulsion score on the Yale-Brown Obsessive
Compulsive Scale strongly positively correlated with D8/17 expression. This
suggests that D8/17 antigen expression may represent both a genetic vulnerability
and an environmental susceptibility to autism.
Autoimmune Hypothesis
Pathogenic autoimmunity occurs when the immune system becomes autoaggres-
sive. Studies have focused on cellular elements of the immune system:
1. Phagocytic cells
2. Cytokines and complement system
3. T cells
4. Humoral antibodies
Studies of Phagocytic Cells
Warren et al. (49) investigated the possibility that altered NK-cell activity may
play a role in the development of autism. In a study of autistic subjects and
healthy controls, 40% of the autistic subjects demonstrated reduced NK cytotox-
icity that was not correlated with a decrease in the number of NK cells (49). This
was subsequently replicated in a later study (50). Since the NK cell is part of
the basic defense mechanism against viral infection, the authors hypothesize that
a predisposition to a relative NK-cell deficiency could subject a developing cen-
tral nervous system to increased risk of damage. However, the authors do not
take into account the bidirectional chemical messengers connecting the immune
system and the central nervous system. In fact, an initial CNS defect could alter
immune system function.
Cytokine and Complement Studies
The importance of complement in immune defense is demonstrated by the sus-
ceptibility of individuals with a deficiency of complement components to infec-
tious and autoimmune illnesses because of defective clearance of antigen–anti-
body complexes. Patients with C4, C2, and C3 deficiencies have a high incidence
of systemic lupus erythematosus (SLE) or other vasculitic syndromes. Patients
with C5, C6, C7, or C8 deficiency more commonly suffer from recurrent infec-
tions (32).
In a study of 19 autistic subjects and family members, Warren et al. (51)

documented that the null allele (no protein produced) for C4B occurred with
greater frequency in 58% of autistic subjects and their mothers, compared with
27% in control subjects. They did not report on a predisposition to infections or
other autoimmune illnesses.
Cytokines influence the growth, differentiation, and function of specific
cells and may explain the pathogenesis of many diseases. For example, in SLE,
B cells are more sensitized to IL-6 than normal B cells; levels of soluble interleu-
kin-2 (s1L-2) and of sIL-2 receptor are increased and correlate with clinical lupus
disease activity. Quantitation of sIL-2, sIL-2R, and sIL-1 in the serum of autistic
children has been performed (52). The serum concentration of sIL-2 was signifi-
cantly higher in autistic children than in healthy or mentally retarded control
subjects. Whether the increased serum concentration of sIL-2 indicates immune
deviation is unclear, and it has never been replicated. Studies have been per-
formed assaying bound and sIL-2R in unstimulated blood samples of autistic
subjects and in cell culture following 72-hour stimulation with a mitogen. No
differences were found between bound or soluble IL-2 receptors in the unstimu-
lated blood samples. A percentage of lymphocytes from autistic subjects ex-
pressed bound IL-2 receptor following mitogenic stimulation. The authors hy-
pothesize that defective signal transduction via IL-2 receptors results in
impairment of lymphocyte transformation in autism (52). Mitogen responses in
vitro, however, are not measures of antigen specificity and indirectly reflect im-
munoregulatory mechanisms on a cellular level.
Elevated plasma concentrations of IL-12 and IFN-γ have been demon-
strated in autistic patients when compared with normal controls (53). Levels of
IFN-α, IL-6, and TNF-α did not did not differ between the two groups. It was
suggested that the IL-12 and IFN-γ increases may be relevant to autoimmunity
in autism. However, the significance of this in vitro finding is uncertain even
though in vivo IL-12 and IFN-K increases may indicate antigenic stimulation of
TH1 cells that initiate the pathogenesis of autoimmune diseases. This study pro-
vides indirect immune evidence of a pathogenic factor in autism.
T-Cell Studies
Selective defects in T-cell function have been studied in autism. To test the hy-
pothesis that the presence of relative T-cell-mediated deficiency may be of impor-
tance in the etiology of autism, mitogen-induced proliferation of T lymphocytes
was studied in 12 autistic subjects and 13 healthy controls (52). Phytohemaggluti-
nin (PHA), a mitogen, induced proliferation and was significantly lower in the
12 autistic subjects studied than in the 13 healthy controls. Warren et al. (53)
confirmed these findings in 31 autistic subjects and also documented that autistic
lymphocytes demonstrate a decreased response to the T-cell mitogens. Both stud-
ies suggest a relative T-cell defect in a subgroup of autistic subjects. In contrast,
Ferrari et al. (54) reported an increased lymphocyte response to a T-cell mitogen

in 16 autistic children when compared with controls. The explanation for these
conflicting results may be due partly to differences in the composition of patients
and control groups in the studies. For example, little attention has been paid to
whether immune changes occur in relation to the ages of studied subjects, and
data on reference values, which change over time during normal development,
are as yet lacking.
Quantitative abnormalities in T-cell populations of autistic subjects have
been reported (53). A reduced total number of T cells was found, whereas the
proportion of B cells did not differ between patients and controls. The reduced
number of total T cells appeared to be related to depression of the CD4⫹/CD8⫹
ratio rather than due to a selective decrease of CD4⫹ cells. A positive correlation
was observed between the reduced T-cell numbers and the severity of psychiatric
symptoms exhibited in the patients (53). Yonk et al. (55) extended these findings
by demonstrating a depression of CD4⫹ lymphocytes in 25 autistic subjects as
compared with nonautistic controls (55). Denney et al. (52) examined lymphocyte
subsets in children with autism compared with age- and sex-matched healthy
controls. Children with autism in this study had a lower percentage of helper-
inducer cells and a lower helper-suppressor ratio. These decreases were shown
to be related to the severity of autistic symptoms as measured by a behavioral
questionnaire. Nonspecific stressors, such as medication or psychological stress,
were not taken into account in these studies, all of which could alter cellular
responses.
The T lymphocyte is the principal effector cell of the cellular immune sys-
tem. Overall, T-cell abnormalities described in autistic subjects are both quantita-
tive and qualitative. Both suggest T-cell defects in at least a subgroup of autistic
subjects, which provides preliminary evidence of an autoimmune abnormality in
autism.
Humoral Immunity
Studies of total immunoglobulin levels in autistic patients have yielded contradic-
tory results. Some studies have found no increase in immunoglobulin levels in
serum or cerebrospinal fluid of autistic subjects (56,57), while others have docu-
mented elevated immunoglobulin levels in the sera of autistic patients (55). War-
ren et al. (58) measured mean serum IgA levels in autistics and controls. Of the
40 autistics studied, 20% had a lower mean IgA level than controls. IgA is the
primary immunoglobulin defending the respiratory, gastrointestinal, and genito-
urinary barriers. This suggests that IgA deficiency might dictate a different re-
sponse to an offending organism when encountered.
Hyperserotonemia is seen in 30–66% of autistic children (59,60). Todd
and Ciaranello (61) investigated the possibility that antibrain antibodies are in-
volved in the pathogenesis of autism. They described circulating antibodies di-
rected at a subclass of human cortical serotonin (5-HT1A) receptors in the blood

and cerebrospinal fluid of a girl with autism as well as 7 of 13 other children
with autism but not in 13 normal children. In a subsequent study (62), antibrain
antibody titers (IgG) were determined against human frontal cortex membranes
in autistics, nonautistic mentally retarded (MR), depressed, and laboratory control
subjects. There were no differences in total antibrain antibody titers for autistic,
depressed, or normal subjects, although the MR group did have significantly
elevated titers. These results do not suggest a generalized, ongoing antibody-
mediated, antibrain response in autism. Only the frontal cortex was used as a
source of antigens; other brain areas might provide different results. Also, anti-
body titers were measured after the syndrome was established and does not elimi-
nate the role of antibodies during development or prior to the expression of autis-
tic symptoms.
Blocking antibodies to brain serotonin receptors were demonstrated in the
IgG fraction of sera from autistic children (63). The inhibitory IgG did not appear
to be specific to the 5-HT1A receptors and was not confined to IgG fractions
obtained from autistic subjects. Binding inhibition was also demonstrated in con-
trol subjects diagnosed with OCD and multiple sclerosis.
In a second group of studies, the possibility that antibrain antibodies are
involved in autism was further investigated. Singh et al. (64) identified serum
antibodies to myelin basic protein in 58% of sera from autistic children com-
pared with 9% of controls. These antibodies might represent an epiphenome-
non or an immunological assault that could result in abnormal function of the
neuron.
In a study by Plioplys (56), autistic children were reported to have in in-
creased incidence of serum IgG and IgM antibodies directed to cerebellar neuro-
filaments, although abnormal IgG or IgM reactivity against frontal cortex could
not be detected. Interestingly, structural abnormalites of the cerebellum have been
reported, such as loss of Purkinje cells and hypoplasia of cerebellar vermal lob-
ules VI and VII (65).
Singh et al. (64) originally described antibodies to neuron-axon filament
proteins (NAFP) in the serum of autistic children. Recently, this result was repli-
cated with IgG antibodies detected to NAFP and glial fibrillary acidic protein
(GFAP) in autistic subjects. Autoantibodies to NAFP are prevalent in pathologi-
cal states: Jakob-Creutzfeldt disease, Alzheimer’s disease, and amyotrophic lat-
eral sclerosis (66). GFAP, a biological marker of astrocytes, increases during
astrocyte activation, and its increase has been detected in the CSF of autistic
children (67). It is suggestive that reactive gliosis through anti-GFAP may con-
tribute to the pathophysiology of autism.
Connolly et al. (68) examined sera of 11 children with autism spectrum
disorder (ASD), two with Landau-Kaeffner syndrome (LKS), and 11 others with
LKS variant compared with controls. IgG and IgM antibrain antibodies were
elevated in three of 11 and four of 11 autistic subjects, respectively. Only one

of 51 controls demonstrated an elevation of IgG antibrain antibodies.
In summary, the above studies cite the presence of antibodies in autism.
This information raises the possibility that autoimmunity plays a role in the patho-
genesis of language, social development, and structural and behavioral abnormal-
ities in a subset of children.
Autism and Immunological Intolerance

Autism has been associated with a higher incidence of obstetric complications,
for example, miscarriages, infertility, and preeclampsia (69). It has been sug-
gested that the immune mechanisms responsible for these disorders of pregnancy
could result in immunological damage to neural tissue of the fetus.
Stubbs et al. (69) studied HLA antigen expression in parents of autistic
children. In this study 52 pairs of parents of autistic children were compared with
83 pairs of parents of normally developing children. Seventy-five percent of the
experimental group was found to share at least one HLA antigen as compared
with 22% of the control group. This suggests that parental sharing of HLA anti-
gens may underlie immune abnormalities in autism through a mechanism of im-
munological intolerance between mother and father. Other researchers have failed
to find support for such an association (70).
Warren et al. (71) investigated the connection between autism and an aber-
rant maternal immune response to fetal antigens also expressed on the father’s
lymphocytes. Six of 11 mothers (54%) with an autistic child exhibited a signifi-
cantly elevated complement-dependent cytotoxic reaction to the lymphocytes of
their child. Only two of the 20 control mothers with a healthy child demonstrated
the same reaction. In all cases in which maternal plasma reacted to the lympho-
cytes of the autistic child, the plasma also reacted to lymphocytes of the father.
The antibodies studied were IgM immunoglobulins directed against membranes
on lymphocytes of both father and child. Five of the six immune-reactive mothers
had experienced previous obstetric complications. In contrast, such complications
had occurred in only one of the mothers with an autistic child who were not
reactive. This suggests that aberrant maternal-fetal immune reactivity may be
correlated with autism and obstetrical complications. In all cases in which reactiv-
ity to lymphocytes was reported, the autistic child had a normally developing
older sibling. In this study, family composition, birth order, and other demograph-
ics were not provided.
Bcl-2, an important inhibitor of apoptosis, has been found to be reduced
in the cerebellum of autistic subjects (36). The pathophysiological implications
of this finding are important. The authors suggest that a reduction in Bc1 may
explain Purkinje-cell atrophy and could explain other cellular abnormalities in
other CNS sites that are manifested as developmental arrest in an autistic child.
A Neuropeptide Hypothesis
Nelson et al. (72) examined biological regulators of cerebral development in au-
tism from archived neonatal blood samples of autistic and MR children, children
with cerebral palsy (CP), and controls. Neuropeptides substance P, vasoactive
intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), and neuro-
trophin nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF),
neurotrophic 3 (NT3), and neurotrophin 415 (NT415) were measured using im-
munoaffinity chromatography. Concentrations of VIP, CGRP, BDNF, and NT415
were significantly higher in autistic and MR (without autism) children than in
controls. These findings provide evidence of the complex interaction of biological
molecules and relate the neurobiological and cognitive disorders to key proteins
involved in brain development. Whether clinical symptoms of autism such as GI
disturbances or sleep disorders are related to these abnormal values warrants fur-
ther study.
AUTISM AND IMMUNOMODULATORY THERAPY

The current treatment of choice for autism is early psychoeducational interven-
tion, to address behavioral and communication deficits, as well as social-skills
training (73). Autism tends to improve as children start to acquire language and
use it to communicate their needs. No drug or treatment cures autism; however,
psychotropic drugs targeting specific symptoms may aid substantially. Serotoner-
gic antidepressants are often prescribed to control stereotypies and perseverative
behavior; dopamine-receptor blockers are prescribed to treat self-injurious and
aggressive behaviors; and mood stabilizers are used to treat destructiveness and
mood swings (73). Immunomodulatory therapies, which can alter the host im-
mune and inflammatory response, have been cited in the literature. Intravenous
immunoglobulin (IVIG) has been used to treat antibody-deficient states and in-
flammatory disorders (e.g., Guillain-Barré, multiple sclerosis) (74). Immunoglob-
ulins, as described earlier, are the products of mature B cells. Immunoglobulin
products for intravenous use are prepared so they contain few molecules of immu-
noglobulin other than IgG. The manipulative effects of IgG on the immune sys-
tem most likely occur because of immunomodulatory antibodies directed against
pathogenic antibodies and blockade of the IgG receptor (FcR) in the mononuclear
phagocytic system. Thus, if receptors for the Fc portion of IgG on reticuloendothe-
lial cells were satiated by intravenously administered immunoglobulin, vulnera-
ble cells coated with an autoantibody would be less likely to be attached and
destroyed (74).
Several groups have investigated whether IVIG would improve autistic
symptoms. Gupta et al. (75) documented immune-system abnormalities in 10
autistic children who received monthly infusions of IVIG for 6 months. They
reported marked improvements in communication and autistic behaviors based

on clinical observation (75). No attention was paid to whether patients were re-
ceiving behavioral modification therapy, nutritional therapy, medications, or
megavitamins, or whether alterations in these therapies occurred during the study
period. DelGiudice-Asch et al. (76) conducted a pilot study performing bimonthly
behavioral assessments on a small group of children receiving monthly IVIG
infusions over a six month period. Using the same infusion protocol as Gupta,
they noted no statistically significant changes as measured by several outcome
measures: the Ritvo-Freeman Real Life Rating Scale (77), the Children’s Yale-
Brown Obsessive Compulsive Scale (C-YBOCS) (78,79), the Clinical Global
Impression Scale for Autistic Disorder (CGI-AD) (80), and the Autism Modifica-
tion of the NIMH Global Obsessive-Compulsive Scale (A-NIMH) (81). Given
the inconvenience, the inconclusive data, and the high economic costs of these
infusions, the use of IVIG in treating autistic children cannot be advocated on a
clinical basis.
Pentoxifylline, a phosphodiesterase inhibitor approved for the treatment of
intermittent claudication, is known to be an inhibitor of TNF, a potent proin-
flammatory cytokine, in vitro and in vivo (82,83). Pentoxifylline-treated rats with
experimental allergic encephalomyelitis (EAE), the animal model of multiple
sclerosis, showed a significantly lower incidence of clinical signs and less histo-
logical inflammation than saline-injected rats (84). Treatment with pentoxifylline
has been shown to slow the progression of dementia in patients with clinical
and neurological evidence of cerebrovascular disease (85). Japanese investigators
have documented beneficial effects of pentoxifylline treatment in autistic sub-
jects. Pentoxifylline was first used experimentally in a patient with autism sus-
pected of brain damage due to head injury. The autistic symptoms, which had
been resistant to previous therapies, improved (86). Numerous studies followed,
with a large number of patients showing improvement in autistic symptoms and
electroencephalogram (EEG) recordings (87–89). Systematic behavioral mea-
sures of outcome were not collected, and thus reports of behavioral improvement
must be regarded with caution.
Transfer factors are families of small peptides that have the property of
transferring the ability to express antigen-specific cell-mediated immunity from
immunized donors to nonimmunized recipients. Several clinical trials have shown
that transfer factors have application in clinical medicine. For instance, the herpes
simplex virus can cause chronic and recurrent skin, mucous membrane, and geni-
tal infections. Independently conducted clinical trials have shown that a transfer
factor from herpes simplex–immune donors dramatically reduces the frequency
and severity of infection exacerbations. Transfer factors from household contacts
have been implicated in correcting immunodeficiencies in Alzheimer’s disease
(90). Anecdotal reports of intramuscular transfer-factor administration in autism
have been published as well (91,92), documenting improvements in socialization,
attention span, and sleep duration. Systematic behavioral assessments were not
conducted, and no control group was studied.
Secretin, a gastrointestinal polypeptide, was reported to improve social re-
latedness and language skills in three children with autism (93). Three double-
blind placebo-controlled studies of single-dose intravenous secretin have been
conducted. Owley et al. (94) studied 20 children with autistic disorder in a cross-
over of secretin and placebo administered 4 weeks apart. There was no significant
difference between the treatment groups. Sandler et al. (95) found no significant
difference between secretin and placebo. Chez et al. (96) also found no difference
between secretin and placebo in a double-blind crossover study in autistic chil-
dren. These studies do not provide support for the use of secretin in treating
autism.
OTHER DRUG STUDIES

Studies of other drugs have reported efficacious results in treating autistic sub-
jects. Chez et al. (97) reported that aricept at doses of 2.5–5.0 mg appeared to
increase speech production and improved socialization skills in 25 boys with
autism. Rossi et al. (98) found niaprazine (an antihistamine) helpful in treating
insomnia and behavioral problems in 25 autistic subjects. King et al. (99) reported
results of a double-blind, placebo-controlled study of amantadine in which 39
subjects received amantadine (2.5 mg/kg) or placebo for 3 weeks. Amantadine,
an antagonist of the N-methyl-D-aspartate subtype of a glutamate receptor, is
used as prophylaxis and treatment of influenza A infections and to treat parkin-
sonism and drug-induced extrapyramidal reaction. Clinician-rated behavioral
scores were significantly superior for amantadine over placebo. Further studies
of these drugs may be useful in further understanding their role in treating autism.
Recently, theories have linked autism to clostridial infections (100). Results
of a 12-week open-label study of vancomycin in children with autism have been
reported (101). Subjects were less than 8 years of age and had a history of antibi-
otic exposure resulting in diarrhea prior to being diagnosed with autism. The
authors hypothesized that a disruption of gastrointestinal flora would allow for
colonization by a clostridial organism. This organism produces a neurotoxin and
could be responsible for autistic symptoms. Parental ratings noted improvement
in eight of 10 children, with behavioral worsening in 2 weeks. While this study
suggests a gut-peptide brain association, the use of vancomycin for prolonged
time periods has many negative side effects, including the development of antibi-
otic resistance.
CONCLUSIONS
Only in the past decade has it become accepted that autism is a biological disor-
der. Recent research in the areas of genetics, neuroimaging, neurochemistry, and
pharmacological treatment of autism has advanced the knowledge about the

pathophysiology of autism. There is reason to believe that an immune pathogene-
sis occurs in autism, and, at the least, immune aberrancies, in a subgroup of
patients. The bidirectional communication between the CNS and the immune
system compels attention to this field. With the availability of increasingly sensi-
tive and specific immunological techniques, neuroimmunological research may
yield more meaningful results for understanding developmental psychopathol-
ogy. As for future research, linking immune abnormalities to particular symptoms
of autism, rather than the syndrome itself, could provide a more precise descrip-
tion. It is quite obvious that autism is not one disease but rather a combination
of multiple pathophysiological mechanisms resulting in the autistic phenotype.
ACKNOWLEDGMENTS
This work was supported by the Seaver Foundation, a National Alliance for Re-
search on Schizophrenia and Depression (NARSAD) Distinguished Investigator
Award (Eric Hollander), Cure Autism Now (CAN) pilot project funding (Gina
DelGiudice and Eric Hollander), and in part by a grant (5 MOI RR00071) from
the Mount Sinai General Clinical Research Center via the National Center for
Research Resources, National Institutes of Health.
We would like to acknowledge the intellectual contributions of Dr. John
B. Zabriskie.
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9
Autism and Environmental Toxins
Martin Evers, Sherie Novotny, and Eric Hollander

INTRODUCTION
The etiology of autism is not well understood, and most cases are of unknown
etiology. Autism is most likely a multifactorial disease in which genetics and
environmental factors combine to yield a wide range of phenotypes. As such,
heterogeneity is a hallmark of both the origins and clinical manifestations of
autism.
Numerous studies have implicated various environmental factors as etio-
logical agents for autism. In addition, the apparent rise in the global prevalence
of the disorder (if it is a real increase rather than a reflection of better ascertain-
ment) could indicate a significant role for nongenetic factors in disease pathogen-
esis (1). Reports of geographic clustering (1) and an observed seasonality of the
births of autistic children may similarly point to the importance of environmental
influences.
THE SUPPORT FOR AN ENVIRONMENTAL PATHOGENESIS

Research Study Results
Numerous studies have implicated a multitude of environmental factors in au-
tism’s pathogenesis. No single etiological agent has been put forth to explain all,
or even a majority, of autism cases. Research on the different proposed pathogens
has often been marked by small sample sizes and limited numbers of case studies.
175
176 Evers et al.
However, the toxins and viruses under study may individually account for distinct
subsets of the disorder.
Much of the evidence concerning specific environmental factors is some-
what circumstantial. Although association is often established, firm causation is
more difficult to prove. Temporality, and therefore causality, are by nature diffi-
cult to deduce when examining prenatal and early postnatal influences in a syn-
drome typically diagnosed at 2 to 4 years of age. In addition, the detailed mecha-
nisms by which environmental factors alter brain development are largely
unknown. Despite such experimental difficulties, there is a compelling body of
research on the role of environmental pathogens in autism.
Specific proposed etiological factors are discussed later in this chapter.
Prevalence of Autism
The global prevalence of autism may be increasing. Nearly all epidemiological
studies done before the mid-1980s pointed to a prevalence of approximately 0.2–
.05 in 1000 (1). However, since 1985, 10 of 11 non-U.S. studies have indicated
rates at or in excess of 0.9 per 1000 (1). A prevalence of 1 or 2 per 1000 is
currently commonly cited (2). Some studies, however, have shown prevalence
in excess of 20 per 10,000 (1). Repeated surveys of Goteborg, Sweden, indicated
an autism prevalence of 4 per 10,000 in 1980, 7.6 per 10,000 in 1984, and 11.5
per 10,000 in 1988 (1)—nearly a threefold increase in less than a decade. It has
been estimated that the worldwide prevalence of autism is increasing by 3.8%
annually (1); this increase is not seen in U.S. data (2).
In the United States, the state of California reported an increase of 210%
in the autistic population accessing services of regional centers for the develop-
mentally disabled between 1987 and 1998 (2). This contrasts with an increase
of 60% in total population served by the centers over the same time period, and
an increase of 35-40% for disorders such as cerebral palsy and epilepsy.
Without comprehensive surveillance for the disorder, it is impossible to
state with a high degree of certainty the national or international prevalence of
autism. There appears to be a lower prevalence in the United States than the rest
of the world (3). However, we do not know whether the disorder’s occurrence
is uniform or varies markedly across regions or locales.
It is possible that the apparent rise in prevalence is actually a function of
better diagnosis and ascertainment rather than a true increase in cases of autism.
There is now greater recognition of a broader range of autism spectrum disorders;
current epidemiological studies may reflect only better physician diagnosis of a
complex heterogeneous syndrome. Such changes in diagnostic criteria hinder ef-
forts to track changes in prevalence over time. In addition, the consumption of
California mental health resources described above may be merely the increased
utilization of proffered services by a more aware and empowered public.
Environmental Toxins 177
However, if the prevalence of autism is truly increasing—at the sort of

rate indicated by the above studies—this may be evidence for the role of environ-
mental influences in disorder etiology. It would certainly seem to argue against
a solely genetic explanation.
Geographic Clustering of Autism

A geographic clustering of autism cases (that is not related to familial clustering
within the geographic area) could indicate the pathogenic effect of an environ-
mental toxin (or toxins). It has been suggested that such clustering may be oc-
curring in Brick Township, New Jersey. Parental concerns over the seemingly
large number of autistic children in the township led the Centers for Disease
Control and Prevention (CDC) and the Agency for Toxic Substances and Disease
Registry (ATSDR) to investigate township autism cases and environmental con-
ditions.
The CDC reported a township prevalence of 4 per 1000 for narrowly de-
fined autism and 6.7 per 1000 for broadly defined autism (1). These figures are
significantly higher than the currently accepted 1 per 1000 prevalence. The
ATSDR found that town drinking water had at various times been contaminated
with tetrachloroethylene, trichloroethylene, and trihalomethanes (THMs) (1).
THMs have been linked to neural tube defects, which have in turn been linked
to autism (1). However, in the Brick Township study no association was made
between the locations and timing of contamination and specific cases of autism.
Seasonality and Autism

A seasonal variation in the births of autistic children, if observed, would offer
indirect evidence for the effect of a seasonal environmental pathogen. Suggested
environmental factors may include: viruses or other infectious agents, tempera-
ture, nutritional factors, vitamin deficiencies, and obstetric complications (4). Re-
search to date has yielded conflicting results. Four studies have noted a marked
increase in autism for children born in March (with results differing for other
months implicated), although other studies have found no correlation (4). It is
worth noting that March was significantly associated with a higher frequency of
autistic births across climates, from Israel to Sweden and North America (4). An
Israeli study noted the overrepresentation of a 7-year period among the autistic
population, suggesting an epidemic effect. Such an effect is supportive of the
environmental-pathogen hypothesis (4). A Japanese study noted a correlation be-
tween frequency of autistic births and hospitalizations for pneumonia and bron-
chiolitis (5). In addition, in Sweden (one of the sites noting more frequent March
autism births), influenza epidemics tend to culminate between late January and
early March (6). This raises the possibility of influenza-mediated damage to the
autistic child’s brain in late fetal or early postnatal life (6).
178 Evers et al.
This is an area of ongoing research. At present, seasonality data seem to

be a possible indicator of environmental pathogenesis, but probably fall short of
being “strong evidence.” An absence of seasonality does not rule out an environ-
mental role in pathogenesis. Many of the proposed mechanisms by which envi-
ronmental influences lead to autism involve the interaction of common xenobiotic
agents, viruses, etc., with genetically predisposed individuals. Others involve expo-
sure (in the predisposed) to fairly ubiquitous substances during key developmental
windows. Interestingly, many neuropsychiatric conditions—including schizophre-
nia, schizoaffective disorder, Alzheimer’s disease, childhood psychosis, major de-
pression and bipolar disorder—display a seasonal birth distribution (4).
PROPOSED ETIOLOGICAL AGENTS AND MECHANISMS

Retinoids and Defective Neural Tube Closure
The retinoids are being examined as an etiological factor in autism based on their
ability to induce neural tube defects. Vitamin A has been strongly associated,
through its excess and deficiency, with these abnormalities. In animal models,
retinoids have also been associated with several brain lesions found in autism,
including cerebellar defects, cranial nerve abnormalities, and dopaminergic sys-
tem malfunction (1).
Retinoic acid exists in various forms. Vitamin A is an important element
of the diet. Numerous retinoid-based medications are currently available for treat-
ment of skin conditions and cancers. Over 10,000 retinoids have been synthesized
for potential use as medications. They are also present as direct environmental
pollutants.
Valproic acid, a moderator of retinoid metabolism, has produced in rats a
diminished number of neurons in cranial nerve nuclei, as well as a reduced num-
ber of Purkinje cells in the cerebellum (7). These anatomical phenomena parallel
findings in human autism. Other substances influencing retinoid metabolism in-
clude thyroid hormone and chemicals such as polychlorinated biphenyls.
Thalidomide, a retinoid derivative once administered to pregnant women
for amelioration of morning sickness, is perhaps the environmental agent most
firmly associated with autism. A study of Swedish thalidomide survivors found
that four of 15 people who had had early exposure to the drug (between days 20
and 24 of gestation) were autistic (8). No cases of autism were related to thalido-
mide exposure beyond that early window.
The association of thalidomide with autism inspired the concept that defec-
tive neural tube closure could be an etiological factor for the disorder. Thalido-
mide-related autism was seen only in connection with exposures between days
20 and 24 of gestation—the same window in which neural tube closure occurs.
Postmortem analysis of autistic tissue has also shown abnormalities in brainstem
structures formed during that window, as well as an increase in cranial nerve

abnormalities. In addition, autistic children have a higher rate of minor malforma-
tions of the ear (which would occur in this same time period) than normal children
and children with other developmental disorders (9). The brain dysfunction caus-
ative of autism, therefore, may relate to a defect in neural tube closure induced
by retinoids or retinoid-influencing substances as an environmental factor.
Retinoids are known modifiers of the Hox genes, a 38-gene family active
in embryonic development (including nervous system patterning). Certain aspects
of these genes point to a potential involvement in autism. Knockout mice lacking
certain Hox genes have some of the same abnormalities that are seen in clinical
autism cases and other animal models (e.g., rats exposed to valproic acid). Allelic
variants of HoxA1 seem to occur at a higher rate among autistic subjects than
among controls (1).
It has been suggested that the Hox family constitute “susceptibility genes”
for autism. Under this theory, autism develops based on the presence of two
elements: a genetic predisposition to the disorder (derived from specific allelic
variants of the Hox genes) and some environmental exposure to further moderate
Hox functioning. This exposure may come directly from one of the many forms
of retinoids or retinoid derivatives (e.g., thalidomide) discussed above. Alterna-
tively, it could result from a fluctuation in a chemical that influences retinoid
metabolism—valproic acid, thyroid hormone, polychlorinated biphenyls, etc.
Chronic Exposure to Xenobiotic Agents

Several studies have shown that chronic exposure to xenobiotics (toxic environ-
mental chemicals) is a statistically significant characteristic of a high proportion
of the families of autistic probands (10). Chronic exposure to neurotoxic xenobi-
otics such as polychlorinated biphenyls (PCBs) has been strongly associated with
certain pathological changes in neuroanatomy (10). Postmortem analysis of the
autistic brain has commonly shown a variety of neuroanatomical abnormalities
indicative of very early in utero insult. These include reduced production of Pur-
kinje and granule cells (1); abnormal neuronal migration in the brainstem, cere-
bellum, and cortex; stunting and abnormal branching of dendrites; nuclear abnor-
malities; and shortening of the brainstem (2,10).
This led to the hypothesis that xenobiotic agents, inducing certain of the
brain abnormalities characteristic of autism, may play a pathogenic role in the
disorder. According to this theory, the developing central nervous system (CNS)
of certain individuals is damaged both by xenobiotic agents and by the immune
response to these agents. For the toxins to have this effect, the liver must be
deficient in its detoxification abilities. This dysfunction is probably the result of
a genetic abnormality. Thus, this hypothesis rests on the interaction of genetic
predisposition and environmental influence.
180 Evers et al.
One study assessed liver function in autistic subjects and controls using
three measures. Glucaric acid levels, a biomarker for liver stress brought on by
xenobiotic contamination or liver disease, were analyzed as an index of both liver
function and significance of xenobiotic exposure. Second, specific blood analyses
were conducted to detect toxins in the blood. Lastly, comprehensive liver detoxi-
fication evaluation was conducted to assess the ability of the liver to process
toxins without accumulation of free radical metabolites or a back-up of unpro-
cessed chemicals that would be stored in fatty tissue.
The results of this study were supportive of liver dysfunction in autism.
All autistic subjects displayed elevated glucaric acid levels and abnormal liver
detoxification profiles. In addition, all but two subjects showed blood levels of
a variety of toxic agents in excess of maximum adult tolerance levels. Interest-
ingly, the subjects all had different combinations of elevated toxins. The results
therefore implicated the inability of the liver to process a range of different xeno-
biotics, rather than the deleterious effect of a particular agent. However, most
subjects did exhibit elevated trimethylbenzenes (10).
A different study found that 90% of autistic subjects lacked phenosulfo-
transferase, an enzyme central to the detoxication process (11).
The developing CNS is most vulnerable to xenobiotic agents during the
fetal period, when it lacks a formed blood–brain barrier. Therefore, it is likely
that neurotoxicity to the forming brain would begin in utero. The autistic individ-
ual’s fetal liver is unable to detoxify ordinary environmental chemicals. Not prop-
erly processed, these lipophilic chemicals would then damage the individual in
two ways.
First, they could pass directly into the brain, causing direct injury to struc-
tures such as neurons, dendritic processes, and receptors. Mitochondrial DNA
could be damaged as well. Xenobiotics may also activate 2′5 A-synthetase and
protein kinase R (PKR); this would decrease the production of mRNA and, subse-
quently, proteins critical to neuronal function, such as axial fibrillary proteins
and dendrites. Dysfunction of neuronal proteins could lead to the brain pathology
and dysfunction seen in autism.
Xenobiotic agents could also trigger indirect brain injury via the provoca-
tion of an immune response. Toxic insult to the brain could lead to the release
of a variety of brain antigens into the peripheral circulation. These antigens would
then stimulate an autoimmune response, creating autoantibodies to a variety of
nervous system components. Different neuronal proteins, myelin, glial fibrillary
proteins, Purkinje cells, etc., could all be targeted. The autoimmune aspects of
autism are discussed elsewhere. It should be noted here that autoantibodies to
certain of the above nervous system components (e.g., myelin basic protein, neu-
ron-axon filament proteins) have been detected in autistic individuals (12).
This view of autistic pathogenesis is characterized by a great variety of
possible pathological outcomes. Pathology will vary based on numerous factors,
including the severity of liver dysfunction; the specific chemicals involved; the
times, duration, and frequency of prenatal exposure to those factors; and the vigor
with which an autoimmune response is mounted to brain antigen. The variety of
pathological anomalies may relate to the variety of clinical manifestations of
autistic spectrum disorder.
Viral Infections of the Central Nervous System

A number of viral infections of the brain have been proposed and/or documented
as pathogenic for autism, or at least associated with the disorder. These viruses
are discussed below. Most documented viral infections related to autism are pre-
natal, with a few early postnatal exposures. Interesting exceptions include certain
herpes simplex cases, discussed below. Lending support to a viral hypothesis, an
increased incidence of bleeding, flulike symptoms, and medication use—possible
indications of prenatal maternal infection—has been noted during pregnancy in
single-case (but not multiplex) autism families (13). However, results have been
conflicting, with some studies showing no association between maternal viral
infection during pregnancy and the occurrence of childhood autism (14).
We discuss possible mechanisms of pathogenesis in virally induced autism.
We then review the evidence for each of the specific viruses implicated to date.
Viral Infection and Autism: Potential Mechanisms of

Pathogenesis
Autoimmune Response to Viral Infection
Autistic individuals display a wide range of immune abnormalities and have a
high incidence of autoimmune disorders (15). Autoimmune conditions are often
triggered by viral or microbial infection. In these cases, one proposed mechanism
is that antibodies to the virus or microbe made as part of the host immune re-
sponse are cross-reactive with some aspect of self. These antibodies persist in
circulation, injuring the host well after the initial infection has been resolved. It
should be noted, however, that there are also noninfectious causes of autoimmune
disorders.
A large percentage of autistic individuals have anti-MBP and anti-NAFP
antibodies in their sera (15,16). These antibodies clearly have the potential to
cause myelination defect and neuronal dysfunction. Very little myelin is present
in the brain at birth, and myelination is not completed until the age of 10 or later
(16). A virally provoked antimyelin immune response could result in generally
poor myelination or specific neuron axon defects and, subsequently, neurobehav-
ioral dysfunction (16). Studies have also found a greater frequency of antibodies
to brain endothelial cells and nuclei in autistic children than in normal controls
(17). No autoantibodies have been found that are exclusive to autism; for instance,
182 Evers et al.
anti-MBP antibodies are expressed in individuals with multiple sclerosis (17).

The potential significance is in the frequency with which autoantibodies are ex-
pressed in the autistic population.
Research has established that autoantibodies are a common finding in autis-
tic individuals. However, the origin of these autoantibodies as relating to a viral
or microbial infection has not been established. Similarly, the pathogenic role
of the autoantibodies observed in autism has not been confirmed. They may be
epiphenomena or an effect, rather than a cause, of autistic behavior.
Direct Viral Cytopathic Effect
Different viruses display a range of cytolytic effects in cells. The viral life cy-
cle—the amounts of time spent dormant, multiplying, lysing cells, etc.—varies
with both host- and virus-specific factors. Some of the damage to CNS structure
and function seen in viral infection may be the direct result of lytic viral action
on nervous tissue. Alternatively, insult may be the combined effect of viral cyto-
pathic effect (CPE) in conjunction with inflammatory activation of cytokines,
autoimmune response, free radical insult from improper processing of metabo-
lites, etc.
Viruses Implicated in the Pathogenesis of Autism

Congenital Rubella
Prenatal rubella infection is perhaps the best-documented infectious etiological
agent for autism. A high rate of autism and “partial syndrome of autism” was
identified in children infected in utero during a rubella epidemic in New York
City in 1964 (18). Ten “full autism” and eight partial-syndrome autism cases
were observed among 243 children with congenital rubella. This would translate
to 41.2 cases per 1000 for the complete syndrome and 32.9 per 1000 for the lesser
spectrum disorder, or a combined prevalence of 71.2 per 1000. Rubella was associ-
ated most strongly with cases of autism onset prior to the third birthday (19). A
follow-up study done 6 years later reported four additional cases of autism (one full
and three partial), for a final prevalence rate of 90.5 per 1000 (20). A similar study
on a different population of rubella-epidemic children found autism in eight of 64
children—an even higher prevalence than in the New York study (18).
The rubella-infected children with autism tended to have multiple handi-
caps, while most nonvirally infected autistic children are not multihandicapped.
Interestingly, a large proportion of the autistic children with rubella studied recov-
ered, relatively quickly, from their autistic symptoms (20). These symptoms in-
cluded a lack of relatedness to people and deficits in communicative language.
Recovery consisted of the development of affective relatedness to people and
communicative verbal or nonverbal language. These children did not display nat-
ural recovery from other rubella consequences such as blindness, deafness, and
cardiac and neuromuscular defect (20). Thus, autism associated with congenital
rubella is atypical in its prognosis, as well as the details of its attendant handicaps
and other clinical features.
The longitudinal studies following children with congenital rubella estab-
lished a strong association between maternal rubella infection and autism. Be-
yond proving association, studies on this population strongly suggested a patho-
genic role for rubella virus in autism via viral invasion of CNS and subsequent
brain damage. Rubella virus was recovered postmortem from the spinal fluid
and brain tissue of several of the rubella-infected children (18). The subsequent
recovery noted in many of the children, as well as the late onset of autism in
four other children, point to the disorder’s pathogenesis via chronic viral (CNS)
infection, in which recovery, worsening, and delayed effects may all take place.
Rubella may thus act as a “slow virus,” mediating chronic CNS damage, yielding
behavioral aberration as one of the ultimate results (21). Rubella has also been
implicated in chronic sclerosing panencephalitis, a chronic viral infection of the
CNS (21).
Prenatal rubella has also been associated with “partial autism,” or the broad
autistic phenotype. One study estimated that the virus was responsible for 13%
of partial autism cases, a very strong association, suggesting that partial autism
is a manifestation of congenital rubella (14). However, the 13% figure was
deemed an “unstable estimate” by the researchers, based on the small study size.
The same study indicated that the virus was also associated with “total” (classic)
autism. For the full phenotype the overall exposure rate of both the autism cases
and controls, and thus the percentage of autism cases attributable to the virus per
this study, was relatively low. Interestingly, rubella was the only virus in the
research in question to show an association with the partial autism phenotype;
the other virus looked at (pre- and postnatal mumps) was associated only with
the classic phenotype.
An epidemiological survey of autism in Utah revealed one autistic proband
with congenital rubella and one proband with possible congenital rubella (22).
The survey discovered 12 rare diseases (infectious and otherwise) with known
CNS pathology present in 233 autistic individuals (11% of those surveyed). The
presence of 12 different rare diseases in a relatively large proportion of those
with an additional rare disease (autism) caused the researchers to suggest or infer
that CNS pathology secondary to the rare conditions was an etiological factor
for autism in those individuals. Actual neuropathology was not assessed; the in-
ference was based on the high mathematical probability that such a convergence
of comorbidity would not occur in a random fashion.
Multiple studies have reported a wide range of CNS damage and dysfunc-
tion in conjunction with viral infection of CNS and panencephalitis due to con-
genital rubella (20). Observed damage has ranged from mild cognitive disability
to severe retardation and neuronal death, gliosis, and vasculitis (23). A study of
184 Evers et al.
neurological abnormality in 100 congenital rubella encephalitis patients noted

“autistic tendencies” in eight individuals, stereotyped behavior in 12 subjects and
delayed or absent language in 46 cases (24). Laboratory findings included virus
isolated from CNS in 28 individuals, increased spinal-fluid protein in 33 subjects,
and abnormal EEGs in 30 cases. Autopsy revealed leptomeningitis in 11, paren-
chymal and perivascular necrosis in six, and subarachnoid hemorrhage in one
case. Subclinical maternal rubella infection has also produced neurological dam-
age in children (14).
CNS damage via viral infection has been noted in numerous instances.
Enterovirus infection of the CNS in the first year of life has been associated with
lower intelligence quotient and diminished language comprehension, expression,
and articulation (14). Von Economo’s encephalitis is another example of a CNS
viral infection triggering severe (and sometimes delayed) behavioral disturbance
(20).
Rubella vaccination and prenatal screening programs have presumably re-
duced the proportion of autism cases attributable to congenital rubella.
Congenital Cytomegalovirus
Cytomegalovirus (CMV) is the most common congenital infection in humans. It
can cause a range of defects, including CNS abnormality, hepatosplenomegaly,
and extensive neurological sequelae, commonly including (but not limited to)
deafness (25). At least eight cases of congenital CMV infection associated with
autism have been reported (26,27). It has been observed that a large number of
autistic children with congenital viral infection (especially rubella and CMV)
display multiple handicaps, while the majority of non–virally infected autistic
children are not multihandicapped.
CMV-linked autism has been associated with primary maternal infection by
the 20th week of gestation (27). The observation that CMV mediates progressive
hearing loss has led to the suggestion that it acts through a “slow virus” effect,
with virus chronically mediating neurological sequelae (21).
Linkage of autism cases to congenital CMV infection is difficult, for several
reasons. For one, virtually all mothers infected with CMV are unaware of their
status, while from 0.5 to 1% of children are born with CMV infections (27). Only
5% of the children born CMV-infected are symptomatic, so the infection is often
overlooked. However, 10–15% of asymptomatic children (and perhaps a higher
proportion of symptomatic individuals) later develop complications such as men-
tal retardation and deafness (26). A similar manifestation of autism as a late
sequela of congenital CMV may be difficult to trace to its viral origins because
of this asymptomatic nature of infection. Autism is typically diagnosed at 3 years
of age or later; by this point, children congenitally infected with CMV have
stopped excreting virus in their urine and probably display reduced antibody lev-
els due to diminishing antigenic stimulus. On the other hand, since CMV is a
common infection of childhood, the presence of an elevated antibody titer in a

child does not confirm the presence of prenatally acquired virus.
The Utah epidemiological survey discussed above in the section on congen-
ital rubella identified one case of congenital CMV present in an autistic individual
(22). It was suggested that the CMV, via its known CNS pathology, had a causal
role in the subject’s autism.
Human Herpesvirus-6
Human herpesvirus-6 (HHV-6)–antibody-positive sera from autistic children has
been associated with the presence of two brain autoantibodies: anti–myelin basic
protein (anti-MBP) and anti–neuron-axon filament protein (anti-NAFP). These
are autoantibodies found by separate studies in autistic children (12). Nonautistic
HHV-6-antibody-positive controls showed no such association with anti-brain
antibodies. In addition, higher HHV-6-antibody titer levels correlated with a
greater likelihood of the presence of brain autoantibodies.
HHV-6 has been shown to have neurological sequelae (12). It has also
been linked to demyelination (in multiple sclerosis). Perhaps most importantly,
it displays “molecular mimicry” with MBP and NAFP, two common targets of
brain autoantibodies found in autistic individuals. Molecular mimicry occurs
when some aspect of a bacterial or viral pathogen resembles some part of the
host (such as a protein found in a particular tissue). Antibodies to the pathogen
made by the host may then mistakenly attack this aspect of self (as well as the
pathogen). This antibody-mediated assault on the self, caused by molecular mim-
icry, may be a pathogenic event in some autism cases. HHV-6 infection in certain
individuals could lead to the production of antibodies that are cross-reactive with
the aforementioned proteins (MBP and NAFP) in the brain. Subsequent antibody-
mediated insult to the brain would then produce autistic pathology and symptom-
atology. Alternatively, any pathogenesis could result from demyelination or some
yet unknown mechanism.
It should be noted that multiple studies have not shown a difference in
rates of herpes simplex virus or human herpesvirus infection between autism and
control populations (12,28).
Herpes Simplex
Several case studies have linked herpes simplex encephalitis to autism, albeit
with differing clinical features. DeLong et al. (29) reported on an 11-year old
girl who developed an autistic syndrome secondary to an acute encephalopathic
illness. The syndrome was characterized by such autistic features as stereotypies,
withdrawal, echolalia, diminution of spontaneous verbalization, perseveration,
global cognitive dysfunction and lack of imaginative play or gestures other than
pointing. The girl displayed elevated herpes simplex titers, supporting a diagnosis
186 Evers et al.
of herpes simplex encephalitis. CT revealed extensive lesion of the temporal lobes

(with the left being primarily affected). Herpesvirus has a tendency to attack the
temporal lobes; it has been suggested that these lobes have a role in the disease
mechanism of autism (30). The subject’s condition essentially reversed to normal
within 14 months; however, memory deficits did persist. The same study identi-
fied two other children with reversible autistic syndrome secondary to encephali-
tis; however, these children had normal CT scans and no etiological agent was
identified.
Whether, and the degree to which, autistic syndrome secondary to herpes
simplex encephalitis always resolves is unclear. The literature contains a report
of a 14-year old girl in this circumstance whose autistic symptoms continued
long after the fever and acute symptoms of the encephalitis had disappeared (30).
Of interest in the above cases is that the children, at 11 and 14 years old,
presumably were infected beyond the age range during which autism usually
develops. Most theories of viral and other environmental pathogenesis of autism
posit an insult to the developing CNS; these cases occurred at a later stage of
childhood.
Herpes simplex encephalitis has also been associated with autism via infec-
tion in the intrauterine or early postnatal period (30). Two cases reported in the
literature document elevated herpes titers, herpes antibodies, and/or direct culture
of virus from the subjects within the first 2 to 3 weeks of the postnatal period.
In addition, there was evidence of early postnatal CNS abnormality in each indi-
vidual. One subject had CT scan showing hypodense areas in the temporal regions
(primarily on the left), as well as slightly reduced brain volume and calcification
in the thalamus. The other patient exhibited tonic-clonic movements of the left
arm and leg, as well as deviation of eyes to the left.
The Utah epidemiological survey referred to previously also identified two
autistic individuals with congenital herpes and an additional proband who was
possibly infected (22). It was suggested that the herpes played an etiological role
in the autism.
Measles Virus
A study on the association of various prenatal and early postnatal viral exposures
with autism found an association between prenatal measles (i.e., maternal measles
infection) and autism (14). However, the exposure rate of both cases and controls
in the study was relatively low, and thus the “etiological fraction,” or percentage
of autism cases attributable to the prenatal exposures, was very small. This is a
common theme among the relationships of different viral agents and autism. Even
if one accepts a pathogenic mechanism underlying the various associations, the
total percentage of autism cases secondary to viral infections is rather low.
Measles-antibody-positive sera from autistic children has been associated
with the presence of two brain autoantibodies: anti-MBP and anti-NAFP. These
autoantibodies have elsewhere been found in autistic individuals (12). Nonautistic

measles-antibody-positive controls showed no such association with anti-brain
antibodies. Higher measles-antibody titer levels correlated with a greater inci-
dence of the presence of brain autoantibodies.
Measles virus has been demonstrated to have neurological sequelae: mea-
sles encephalomyelitis (12) and subacute sclerosing panencephalitis (14). It may
in some individuals act as a “slow virus,” marked by a long incubation period,
a slowly degenerative course of action on the CNS, and a lack of observable
inflammatory response (14). It has been linked to demyelination. In addition, it
displays molecular mimicry with MBP and NAFP. This mimicry may be patho-
genic for autism in certain individuals. Measles infection in these individuals
could lead to the production of antibodies cross-reactive with brain; subsequent
insult to the brain would then induce autistic pathology and manifestation of the
disorder. Alternatively, disorder etiology may be due to demyelination or some
still unknown insult to the CNS.
Stealth Virus
“Stealth viruses” are cytopathic viruses derived from herpesviruses via the dele-
tion of genes coding components that would normally provoke a host inflamma-
tory response. They do not show normal reactivity with antisera or conventional
assays such as PCR. Stealth virus has been isolated from patients with chronic
fatigue syndrome, acute encephalopathy, and other encephalopathies of varying
severity. Unpublished data have indicated that they cause chronic noninflamma-
tory neurological disease in animals. It has therefore been suggested that persis-
tent stealth virus infection may be responsible for a broad spectrum of neuropsy-
chiatric and neurological disorders. Stealth virus was repeatedly cultured from the
blood of a child with “a severe case of classical autism,” leading one researcher to
suggest that some cases of autism may be due to stealth virus encephalopathy.
Temporality is an issue here—the presence of virus in an autistic individual
does not establish any pathogenic role of that virus in the patient’s autism. The
question of causation rather than merely association is an issue seen repeatedly
when assessing the relationship between autism and viral infection. The stealth
virus bears mention because the diminished neurological function seen in autism
is theoretically consistent with chronic CNS viral infection. In addition, because
the stealth viruses are by their nature difficult to assay, they may have thus far
evaded conventional methods of detection in other autism cases.
Varicella
Clinical illness with varicella (chickenpox) in early infancy, or exposure at that
age to someone with the virus, has been associated with autism (14). However,
the association was based on a small number of cases. The overall significance
of varicella as an etiological agent for autism is probably not high.
188 Evers et al.
Mumps
A study of the relationship of viral exposures in prenatal and early postnatal life
found a positive association between both prenatal and postnatal mumps and
autism (14). The more novel finding was probably the association of postnatal
mumps and autism, as most viral associations with the disorder have been prena-
tal. However, the study estimated that the overall proportion of autism cases
attributable to such mumps exposures was likely very small. Mumps in animals
has been shown to block cerebrospinal fluid and lead to mild hydrocephalus (27).
Human Immunodeficiency Virus

A study of CNS abnormalities in children infected with human immunodeficiency
virus (HIV) noted autistic behavior, deterioration in play, and loss of language
skills in one child (31). The autistic behavior resolved after treatment with zido-
vudine (AZT). Somewhat similar “reversible autism” has been seen elsewhere as
secondary to encephalitis (e.g., the herpes simplex encephalitis discussed above).
Since classic autism is rarely reversed, such cases represent an atypical subset
of the disorder.
HIV infection of the brain can cause a progressive encephalopathy. This
encephalopathy is marked by developmental regression (loss of milestones) and
impaired brain development. The majority of HIV-infected children display defi-
cits in cognitive function and language, as well as developmental delays; one
study noted developmental abnormalities in 60% of HIV-infected children in the
first year of life (31).
Human Parvovirus B19
Several factors have led to speculation that parvovirus may have an etiologi-
cal role in autism (32). Parvoviruses cause cerebellar maldevelopment in
animals similar to the malformations seen in human autism. They also induce
transplacental infections in animals. In humans, parvovirus may cause intrauter-
ine infection.
A study on parvovirus infection in autistic and nonautistic children did not
support an association of the virus with autism (32). However, the duration of
antibody positivity after parvovirus infection is not well understood. The possibil-
ity of prenatal parvovirus infection could not be ruled out on the basis of child-
hood serologic examination.
Borna Disease Virus

Neonatal infection of male Lewis rats with Borna disease virus (BDV) leads to
a wide range of behavioral deficits and neuroanatomical abnormalities (33,34).
BDV infection produces behavioral deficits and CNS dysfunction similar to phe-
nomena observed in human autism.
In terms of behavior, deficits in play activities and other social interaction,

as well as learning, are observed (34). There is a reduction in the solicitation of
social play, as well an unwillingness to engage in play when solicited by others.
There is deficient information processing for ongoing events. In addition, deficits
in learning and long-term memory are observed. Infected rats do not realize the
emotional significance of stimuli—for instance, they do not show normal fear
responses. Stereotypic behavior is seen, as well as an inhibition of exploration
and inhibited response to novel stimuli. There is an abnormal unfolding of normal
developmental milestones. Hyperactivity is sometimes present. Abnormal
righting reflexes are also observed. All these behavior abnormalities mimic the
social deficits of autistic children.
BDV is trophic for limbic and cerebellar brain regions (33). Neonatally
infected rats display abnormalities of hippocampal and cerebellar development,
with diminished numbers of Purkinje cells and granules. Elevated apoptotic activ-
ity leads to loss of neurons. Glial activation is seen throughout the brain. In
addition, there are increased levels of proinflammatory cytokine mRNA (IL-1-
α, IL-1-β, IL-6, and TNF-α). Progressive cerebellar and hippocampal damage is
seen during this period of inflammation. This neurological dysfunction is similar
to the neurodevelopmental abnormalities sometimes seen in human autism.
The neurobehavioral disturbances seen in BDV rats correlate temporally
with shifts in cytokine expression and neuropathological events. These temporal
relationships are very important, providing a model for a virus as a pathogenic
factor in autism. Further research should establish the exact causal mechanisms
that underlie the observed temporal sequences. At present, it appears that elevated
proinflammatory cytokine expression is triggered by activated microglial cells or
reactive astrocytes indirectly infected by virus. Proposed triggers for the observed
neuronal apoptosis include the aforementioned up-regulated cytokine expression
and viral modulation of apoptosis-related products.
Whether BDV ultimately has a pathogenic role in human autism is un-
known. Testing of autistic sera to date has not revealed the presence of BDV
(33), although BDV antibodies have been detected elsewhere in humans.
Studies have associated BDV with a variety of neuropsychiatric illnesses
in humans, including schizophrenia (34,33) and affective disorders (35). BDV
has also been associated with alterations to specific brain structures (35). High
anti-BDV-antibody titers have been reported in those with brain pathology, in-
cluding HIV and multiple sclerosis patients; an autoimmune mechanism may be
at work in these individuals. However, these conclusions remain a matter of some
controversy. It is known that BDV infection in animals can cause the types of
socialization abnormalities seen in autism and numerous other human psychiatric
illnesses. A key aspect of BDV is the wide range of neurological disease caused
in animals; a similar range may be present in humans and ultimately extend to
autistic syndrome.
190 Evers et al.
Human Leukocyte Antigens and Viral Infection

Some of the viruses implicated in autism are quite common (e.g., an estimated
78% of the population possess antibodies to HHV-6) (12). In no instance does
a majority, or even a large number, of those infected with the virus develop
autism or even autistic traits. Clearly, there are factors moderating differential
responses of individuals to viral infection with regard to autism.
Certain human leukocyte antigens (HLAs) have been associated with viral
infection and the development of autoimmunity (36), although no specific HLA
has to date been implicated in susceptibility to autism. However, parental sharing
of HLA has been associated with autism (37). HLA-homozygosity between par-
ents may lead to immunological intolerance and prevent the development of ma-
ternal blocking antibodies which would normally protect the fetus from insult in
utero. The absence of said protection could lead to the brain pathology seen in
autism. Thus, shared parental HLA may facilitate damage to the fetal brain ulti-
mately caused by viral infection, autoantibodies, xenobiotics, etc.
Other Infectious Agents

Group A β-Hemolytic Streptococcus
Group A β-hemolytic streptococcus (GABHS) has been discussed as a potential
etiological agent for subsets of a number of repetitive movement disorders, in-
cluding autism, obsessive-compulsive disorder (OCD), Sydenham’s chorea, and
Tourette’s syndrome (TS). One estimate is that 10% of TS and OCD cases have
a clear streptococcal cause (38). The term PANDAS, for “pediatric autoimmune
neuropsychiatric disorders associated with streptococcal infection,” is a relatively
new diagnostic concept encompassing a spectrum of repetitive movement and
tic disorders and OCD secondary to (i.e., as a result of) GABHS infection. The
proposed pathogenic mechanism—autoimmune insult to the brain due to mimicry
(a concept discussed above in relation to HHV-6 infection) between GABHS and
CNS neurons—is discussed below.
GABHS is already a well-known causal agent for rheumatic fever and Sy-
denham’s chorea. In rheumatic fever, antibodies made in response to a GABHS
infection are cross-reactive with, and thus ultimately attack, myocardial cells.
This cross-reactivity is probably caused by mimicry between the group-specific
carbohydrate of GABHS and the glycoprotein of heart valves. Sydenham’s cho-
rea, seen in association with rheumatic fever in children, consists of rapid, jerky,
irregular movements, primarily in the face and limbs. It is caused by antibodies
targeted against the cytoplasm of neurons in the caudate and subthalamic nuclei
of the brain; the streptococcal-induced nature of these antibodies has been docu-
mented (39). Autism and other repetitive-movement disorders would, under this
theory, likewise be due to poststreptococcal antibodies cross-reactive with the

brain.
D8/17 is a monoclonal antibody that identifies a B-cell antigen indicative
of genetic susceptibility to rheumatic fever (40). Elevated D8/17 levels have been
documented in subsets of patients with OCD, TS, and autism (41–43). In one
set of autistic patients, D8/17 expression correlated positively with the severity
of one behavioral domain (repetitive behaviors) in autism (43).
The above findings have led to speculation that GABHS infection may
lead to a variety of neuropsychiatric disorders (autism, TS, OCD, tic disorders,
Sydenham’s chorea, etc.) through an autoimmune mechanism in genetically sus-
ceptible individuals (in which susceptibility is indicated by elevated D8/17 ex-
pression). The specific disorder caused may relate to the developmental stage at
which infection occurs. For instance, autism would probably be secondary to an
intrauterine infection, whereas Sydenham’s chorea is secondary to streptococcal
infection of children.
Toxoplasma gondii
Toxoplasmosis in pregnancy has been associated with autism (19). Specifically,
it has been associated with onset before the third birthday. A child with autism
was identified as having “probable brain damage” due to toxoplasmosis (44).
Haemophilus influenzae
Two individuals with autism and hemophilus influenza meningitis were identified
in the Utah epidemiological study described previously. Since meningitis results
in known CNS pathology, it was theorized that the meningitis was causal for the
autism. Previous research had also weakly associated a few cases of Haemophilus
influenzae with autism.
Syphilis
A case of syphilis in conjunction with autism has been identified in the literature.
Any causal relationship is currently unknown.
Other Environmental Insults

Pitocin (Synthetic Oxytocin)
Animal studies have shown that the hormones oxytocin and vasopressin are im-
portant for social learning and the development of social behavior, communica-
tion, and rituals. It has been hypothesized that abnormalities in the oxytocin sys-
tem have a causal role in autism. Autistic children have been found to have lower
plasma oxytocin levels than normal controls (45). Interestingly, autistic children
with higher oxytocin levels had lower scores on social and developmental mea-
192 Evers et al.
sures than autistic children with lower oxytocin levels; this was the opposite of
findings for normal subjects. Oxytocin levels increased with age in normal con-
trols but not in autistic subjects. The oxytocin system is different in males and
females, a significant fact given that autism is a disorder seen predominantly in
males. Further, oxytocin and vasopressin receptors are expressed more in the
developing brain (46); this is consistent with the developmental nature of autism.
Pitocin is a synthetic analog of the hormone oxytocin. It is routinely used
to induce labor or support uterine contraction during deliveries. While oxytocin
has a short plasma half-life and does not cross the blood–brain barrier in adults,
its distribution in, and consequences for, the neonate are unknown (47). There
has been speculation that induction of labor with pitocin somehow disrupts the
oxytocin system of genetically susceptible neonates, ultimately leading to the
social deficits of autism. A firm association of autism with this use of pitocin
has not been established. While a high incidence of pitocin-induced labor has
been observed in a clinical population of autistic patients (48), another survey
found no such relationship (49).
Analysis of more data is necessary to resolve this question with any cer-
tainty. Numerous potential confounding factors surround such surveys, such as
other medication use, difficulties in delivery, and maternal history. Even if an
association is ultimately discerned, causality may be more difficult to establish.
It is possible, for instance, that pitocin induction is necessitated by abnormalities
already present in an infant destined to develop autism.
Measles, Mumps, and Rubella Vaccine
There has been speculation that some cases of autism have been caused by the
measles-mumps-rubella (MMR) vaccine. This speculation was triggered primar-
ily by a case series study in the United Kingdom in which 12 children with a
history of normal development developed chronic enterocolitis and regressive
developmental disorder (50). The parents of eight of the children identified the
MMR vaccine to be the immediate precursor of developmental regression. This
seeming temporal association, widely reported in the media, led to a fear that
MMR administration is a causal agent for autism.
Large-scale epidemiological studies have since contradicted any causal link
between the MMR vaccine and autism. A study of all children with autism born
in eight U.K. health districts since 1979 found no change in trend in incidence
or age at diagnosis related to the introduction of MMR vaccination to the United
Kingdom in 1988 (51). The study found no temporal association between onset
of autism within 1 or 2 years after vaccination. In addition, developmental regres-
sion was not clustered in the months after vaccination. The weight of epidemio-
logical data to date thus supports the safety of MMR vaccination.
The British medical journal Lancet has further pointed out problems with
the presentation and quality of evidence presented by vaccination opponents (52).
Fetal Alcohol Syndrome

It has been suggested that prenatal exposure to excessive levels of alcohol may
be an etiological factor for autism. A review of the records of 326 children with
fetal alcohol syndrome (FAS) and other alcohol-related birth defects revealed
that six of the children had autism (53). This translates to a prevalence of approxi-
mately 18 cases per 1000 people—a very high rate. The six subjects had the
physical phenotypes necessary for FAS diagnosis, but the behavioral phenotypes
characteristic of autism. Compared to a control group of nonautistic FAS chil-
dren, the autistic individuals were significantly more retarded, displayed a greater
number of anomalies, had a 50% rate of cleft lip and/or palate, and probably
exhibited greater growth retardation. This greater number and severity of FAS-
related defects experienced by the autistic FAS children may point to a more
significant prenatal alcohol insult to this population. The autistic FAS children,
who were all classified as severely autistic, displayed behavioral features of au-
tism that are generally not characteristic of, or do not overlap with, mental retar-
dation.
As with most research associating autism with environmental factors, an
etiological role may be indicated by the data but is nonetheless difficult to prove.
Alcohol is a teratogen with a wide range of known and suspected effects on the
developing human. Specifically, animal models of FAS have displayed cerebellar
abnormalities, and such abnormalities are a consistent finding in autism (53).
Previous research had not associated autism with FAS, which is somewhat sur-
prising given the prevalence indicated by the study at hand. Since FAS is a syn-
drome presenting with a range of (often severe) physical and behavioral charac-
teristics, it is possible that the diagnosis of FAS often precludes the search for
other complex conditions.
Cocaine and Other Drugs

A prevalence of autism of 11.4% among children exposed to cocaine in utero
was indicated by a retrospective chart review of a New York City hospital (54).
A majority of children in the study experienced developmental delays in lan-
guage, social, and play skills (central to autistic behavior), as well as fine motor
skills. Language abnormalities were most commonly seen, affecting 94% of the
study population. Autistic subjects were nonverbal except for occasional echo-
lalic speech lacking communicative intent, and did not engage in interactive activ-
ities. The autistic children frequently displayed hyperactivity in acts of persever-
ance. Other studies of cocaine-exposed newborns have revealed infarctions,
atrophy, and other areas of CNS structural abnormality (55,56).
Of the mothers of the eight autistic children in the New York City study,
three had a history of alcohol use, one used phencyclidine, and one used heroin.
The issue of polydrug abuse is thus a potential confounder, hindering the drawing
194 Evers et al.
of a general conclusion concerning cocaine-specific etiology of autism. The re-

search in question (being retrospective) also did not quantify such variables as
duration of exposure and maternal cigarette smoking. However, the extremely
high prevalence of autism reported here has not been seen in studies of the other
abused substances. For instance, the FAS research discussed previously reported
six autistic children of a study of 326 individuals; the cocaine study showed a
frequency of eight autism cases of a total of 70 children. In addition, deficits in
areas central to autism (language, play, socialization) were seen to varying de-
grees in the majority of the cocaine-exposed children. Thus, cocaine-specific ef-
fects are suggested by the data.
Allergies
There is a high prevalence of allergic disorders among autistic individuals
(57,58). It has been suggested that food allergies and the toxicity of certain food
peptides may affect the CNS and be involved in the pathogenesis of autism.
Antibody reactivity to certain common foods is higher among autistic individuals
than among normal controls; the removal of these items from the diet has im-
proved behavioral symptoms.
SUMMARY
The etiology of autism is not well understood, and most cases are of unknown
etiology. Autism is most likely a multifactorial disease in which genetics and
environmental factors combine to yield a wide range of phenotypes.
There is a growing body of compelling evidence in support of an environ-
mental pathogenesis for some cases of autism. Numerous studies have implicated
various environmental factors as etiological agents for the disease. No single
agent has been put forth to explain all, or even most, of autism cases. However,
the toxins and viruses under study may individually account for distinct subsets
of the disorder.
An apparent rise in the global prevalence of autism, reports of geographic
clustering of the disease, and an observed seasonality of the births of autistic
children may similarly point to the importance of environmental influences.
FUTURE DIRECTIONS
Further research on the role of environmental agents in the pathogenesis of autism
is necessary.
Improving study quality—Some studies have not controlled for key vari-
ables: medical history, medication use, environment, demographics, diagnostic
criteria, control group composition, etc. Research has also been limited by small
sample sizes and limited numbers of case studies. Large-scale, well-controlled

studies are needed to validate results found to date.
Establishing causation—Much of the evidence concerning specific envi-
ronmental factors is somewhat circumstantial. While association is often estab-
lished, firm causation is more difficult to prove. Temporality and causality are
by nature difficult to deduce when examining pre-, peri-, and early postnatal
influences in a syndrome typically diagnosed at 2 to 4 years of age. However, a
causal link must be established for an association to be of true value.
Understanding the mechanisms of pathogenesis—The detailed mechanisms
by which environmental factors alter brain development must be explored.
Improving treatment—The ultimate goal of all research and clinical activi-
ties is to improve the lives of children with autism and their families. Identifica-
tion of subsets of autism caused by different environmental agents may lead to
better treatment for patients with these forms of the disease. Immunomodulatory
therapy may be useful for such patients, and some prophylaxis may be possible
to prevent occurrence of the disease in susceptible individuals.
Further efforts in this field may substantially improve the quality of life of
those with autism and their families.
ACKNOWLEDGMENT
This chapter was supported in part by a grant from the Seaver Foundation.
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10
Neurobiology of Serotonin Function
in Autism
Christopher J. McDougle and David J. Posey

Indiana University School of Medicine
Indianapolis, Indiana, U.S.A.
Marc N. Potenza
Yale University School of Medicine
and Connecticut Mental Health Center
New Haven, Connecticut, U.S.A.
INTRODUCTION
Serotonin [5-hydroxytryptamine (5-HT)] neurons are widely distributed through-
out the mammalian brain. This neuronal system is one of the earliest to develop,
and the turnover rate of 5-HT is higher in the immature mammalian brain than
at any other time in life. Serotonin plays a key role as a growth factor in the
immature brain, directing both proliferation and maturation (1). For these reasons
and others, 5-HT has been a target of investigation into the pathophysiology of
autistic disorder (autism) for nearly 50 years. This chapter reviews results from
studies of peripheral and central neurochemistry, behavioral/neuroendocrine
challenges, neuroimaging, and genetics related to 5-HT function in autism. The
reader is referred to other excellent reviews of this topic for additional informa-
tion (2–4). We first recount the historical developments that led, in part, to studies
of 5-HT function in autism.
199
200 McDougle et al.
HISTORICAL PERSPECTIVE
The landmark publication by Schain and Freedman in 1961 (5) is often acknowl-
edged as the first paper to describe an abnormality in 5-HT function in autism. Al-
though it was the first report of elevated whole-blood serotonin (WBS) levels in
subjects clearly defined as autistic, at least one prior study had been published regard-
ing dysregulation in other aspects of 5-HT function in this disorder (6) (see below).
In their classic paper (5), Schain and Freedman refer to four previously
published articles: three by Pare, Sandler, and Stacey (7–9), in which results
from studies of 5-HT function in “mental defectives” (in today’s terminology,
mental retardation) are described, and the other by Sutton and Read (6). It was
based on these data, in part, that Schain and Freedman pursued their studies of
5-hydroxyindole metabolism in children with autism. Because of the importance
of these early investigations to the subsequent work of Schain and Freedman,
we describe the results of these studies in some detail.
In their first study, Pare, Sandler, and Stacey (7) reported significantly lower
serum 5-HT levels (mean ⫾ SEM ⫽ 57 ⫾ 11 ng/ml) in subjects with phenylketo-
nuria (PKU) compared with children awaiting tonsillectomy (124 ⫾ 14 ng/ml)
and mentally defective controls (270 ⫾ 51 ng/ml). Similarly, mean values of
urinary 5-hydroxyindoleacetic acid (5-HIAA), the primary metabolite of 5-HT,
were significantly lower in the group with PKU (2.9 ⫾ 0.2 mg/g creatinine)
than in the mentally defective control group (4.9 ⫾ 0.7 mg/g creatinine), normal
children (6.6 ⫾ 0.9 mg/g creatinine), and children awaiting tonsillectomy (11.6
⫾ 1.3 mg/g creatinine). No correlation was found between the intelligence quo-
tient (IQ) of subjects with PKU and their serum 5-HT and urinary 5-HIAA excre-
tion. The investigators suggested that the decreased levels of serum 5-HT and
urinary 5-HIAA might be due to competition between phenylalanine and trypto-
phan, an essential amino acid and precursor of 5-HT, for the same hydroxylating
system. Furthermore, they hypothesized that, as a result, impaired 5-HT synthesis
may contribute to the causation of mental deficiency in subjects with PKU. This
hypothesis was based in part on the fact that 5-HT had recently been shown to
be normally present in the central nervous system (10). The investigators stated
that their studies were based on previous findings from Armstrong and Robinson
(11,12) that provided evidence of abnormal indole metabolism in PKU; Arm-
strong and Robinson had found indolelactic acid in the urine of affected subjects
and decreased urinary excretion of 5-HIAA in some of their subjects. Pare, San-
dler, and Stacey (7) thus hypothesized that the 5-HT pathway might be abnormal
in PKU and that such an anomaly might contribute to the nature of the mental
defect which remained unexplained and which had not been clearly linked to the
defective hydroxylation of phenylalanine to tyrosine.
In a subsequent study, Pare et al. (8) found that serum 5-HT levels increased
significantly, from 90 ng/ml to 142.3 ng/ml, in seven subjects with PKU adminis-
Neurobiology of Serotonin Function 201
tered a low-phenylalanine diet. The investigators stated that these results might
be explained by diminished competition between phenylalanine and tryptophan
for hydroxylation. In this same paper, the authors also described results from
a study designed to address the possibility that the decreased 5-hydroxyindole
production in PKU might be due to an inhibition of 5-hydroxytryptophan (5-
HTP) decarboxylase, which converts 5-HTP to 5-HT, by phenylacetic acid, phen-
ylpyruvic acid, and phenyl-lactic acid. This inhibition had been shown to occur
in vitro, and it had also been demonstrated that subjects with PKU excreted these
acids in excess. To test this hypothesis, the investigators administered 5-HTP 25
mg intravenously to four children with PKU and four age- and gender-matched
mentally defective children without PKU. The children with PKU gave apprecia-
bly lower peaks for the urinary excretion of 5-HT and 5-HIAA. Unchanged 5-
HTP was also found in postinjection samples. The investigators stated that these
results were in agreement with the postulated inhibition of 5-HTP decarboxylase
in PKU.
In the third paper from the series by Pare et al. (9) referenced by Schain
and Freedman (5), the group extended and replicated their original findings. In
49 subjects with PKU and 32 mentally defective controls, the investigators found
significantly lower values of urinary 5-HIAA in the subjects (2.2 mg/g creatinine)
compared with those of the controls (7.2 mg/g creatinine). Likewise, serum levels
of 5-HT were lower in the subjects (71.2 ng/ml) than the controls (283 ng/ml).
Contrary to their working hypothesis, there was no significant association be-
tween IQ and either 5-HT or 5-HIAA levels in the subjects with PKU. In this
report, it was pointed out that some of the mentally defective controls had values
for serum 5-HT that were as high as those found in patients with the carcinoid
syndrome (Figure 1). These data, in addition to observations of the potent percep-
tual effects of serotonergic hallucinogens, such as lysergic acid diethylamide
(LSD) (13), prompted Schain and Freedman’s early studies of WBS in autism.
Pare, Sandler, and Stacey summarized their studies by reporting that enzymes
from multiple other neurochemical systems, including catecholamine and
gamma-aminobutyric acid (GABA) systems, had recently been shown to be af-
fected by phenylalanine metabolites. Because of this multisystem involvement,
they stated that the failure to demonstrate any correlation between the degree of
5-hydroxyindole deficiency and IQ in the subjects with PKU was “hardly sur-
prising.”
PERIPHERAL MEASURES OF 5-HT FUNCTION IN AUTISM

In 1958, Sutton and Read (6) described the case of an 18-month-old female,
considered an autistic child, who demonstrated a deviation in the decarboxylation
pathways of tryptophan metabolism. At 9 months of age, the child developed a
seizure disorder. At 13 months, the parents began to note a gradual change in
202 McDougle et al.
Figure 1 Serum 5-hydroxytryptamine (5-HT) (ng/ml) and urinary 5-hydroxyindoleace-

tic acid (5-HIAA) (mg/g creatinine) values in 49 phenylketonurics (∆) and 31 nonphenyl-
ketonuric mentally defective controls (䊉). (From Ref. 9.)
her personality with an associated mental regression over the next 4 to 5 months.
As part of a metabolic assessment, urine samples were obtained from the subject,
her sibling, and each of their parents. In the children, but not the parents, a striking
departure from normal was observed on the amino acid chromatograms. The
pattern consisted of very low levels of glutamine and consistent excretion of
GABA along with a moderate increase in glutamic acid, but not in abnormal
amounts. The subject and a 20-month-old male control were given 0.25 g/kg of
L-tryptophan orally. In response to this challenge, the subject failed to excrete
detectable amounts of indoleacetic acid and idolelactic acid, and unchanged tryp-
tophan. The excretion of metabolites characteristic of the kynurenine pathway
(an alternative pathway of metabolism for tryptophan, rather than metabolism to
5-HT) were similar in the subject and control child. Subsequently, three more
control children were tested. The subject excreted the lowest amount of indolelac-
tic acid, indoleacetic acid, and 5-HIAA. The subject’s baseline levels of indole
metabolites were normal, but she was apparently limited in her ability to convert
large quantities of tryptophan to indolelactic acid, indoleacetic acid, and 5-HIAA.
The subject’s sibling continued to develop normally to the then present age of 16
months. It was not possible to test her ability to metabolize tryptophan. The authors
concluded that the subject’s mental aberration was the result of an altered ability
to maintain normal brain 5-HT levels. To our knowledge, this study by Sutton and
Read (6) was the first published assessment of 5-HT function in autism.
The study by Schain and Freedman (5) involved 23 children diagnosed
with “infantile autism,” ages 6 to 18 years (average age of 10.8 years), who were
institutionalized at the Southbury Training School in Connecticut. Blood and
urine were obtained for determination of 5-HT and 5-HIAA, respectively. Other
“defective” children, roughly matched for age and sex, were also studied. Multi-
ple determinations of WBS were made in all the children.
The subjects studied were divided into three groups. One (group A) in-
cluded mildly retarded children with IQs of 60 to 80 described as “familial ‘sub-
cultural’ defective children, high-grade Mongols.” The second (group B) included
children with the diagnosis of “infantile autism” who functioned on a severely
retarded level. These children were described as being usually not trainable, and
it was mentioned that they were segregated with other low-grade retarded chil-
dren. The third (group C) consisted of severely retarded children without a diag-
nosis of autism (IQ less than 20). These children had diagnoses including “con-
genital cerebral defect” and “diffuse encephalopathy.”
The mildly retarded children (group A) (n ⫽ 12) had WBS levels averaging
0.072 gamma/cc, with a range of 0.042 to 0.156 gamma/cc, which was similar
to the normal values obtained in the investigators’ laboratory. The autistic chil-
dren (group B) (n ⫽ 23) had average WBS levels of 0.141 gamma/cc, with a
range of 0.033 to 0.540 gamma/cc. Six of the 23 autistic children had mean levels
over 0.200 gamma/cc, a value significantly above the range of normal for the
investigators’ laboratory (0.02 to 0.15 gamma/cc) (Figure 2). By comparison,
the investigators stated that values for adult chronic schizophrenic patients tested
in their laboratory were within the normal range. A small group of nonautistic
low-grade defective children (group C) (n ⫽ 7) had an average WBS concentra-
tion of 0.128 gamma/cc, which was not significantly different from that of the
autistic group as a whole. Some of the children in the study were receiving pheno-
barbital, Dilantin, or chlorpromazine, although none of these drugs seemed to be
associated with any changes in WBS levels.
Urine 5-HIAA levels were higher in the autistic group (5.9) (n ⫽ 12) than
in the mildly retarded group (1.6) (n ⫽ 6) when expressed as gamma/mg of
creatinine. The absolute amount of 5-HIAA/ml of urine was similar in both
groups. Creatinine values, however, were much lower in the autistic children,
indicating greater dilution of urine. Urine 5-HIAA levels were not reported for
the children in group C. The investigators stated that none of the 5-HIAA results
could be considered significantly abnormal.
Tryptophan loads consisting of 1 g of L-tryptophan daily for 3 days were
given to four autistic children. This resulted in no consistent change in WBS
levels.
204 McDougle et al.
Figure 2 Mean blood 5-HT levels for individuals of each group. (From Ref. 5.)
In the discussion section of their paper (5), Schain and Freedman stated
that the results of their study confirmed the impressions of Pare et al. (9) that
mentally defective children have elevated levels of 5-HT in blood. In particular,
Schain and Freedman emphasized that the elevations of 5-HT in the blood of
their subjects tended to be present only in some of the more severely defective
children. They went on to say that consistent unusual elevations of WBS were
found only in the autistic children, although the mean WBS level of the other
severely retarded group was higher than that of the mildly retarded group. The
investigators could not find any differences in the presenting symptomatology
between the six autistic children with the highest WBS levels and those who had
normal levels. The only feature they found noteworthy was the absence of seizure
disorders in the six autistic children with elevated WBS levels.
In 1970, Ritvo and colleagues (14) published a study whose results repli-
cated those of Schain and Freedman. WBS levels were determined in 24 autistic
children, ages 33 to 91 months, and 82 controls consisting of hospital staff, their
children, children hospitalized for neurotic and behavior disorders, and paid adult
and child volunteers. The controls ranged in age from less than 23 months to
greater than 360 months. All subjects had been drug-free for at least 3 months.
An inverse relationship between age and both WBS levels and platelet values
was identified in the control group. A comparison of WBS levels between the
24 autistic children and 36 age-matched controls demonstrated significantly
higher values in the autistics (mean ⫾ SD ⫽ 0.263 ⫾ 0.063 µg/ml vs. 0.216 ⫾
0.061 µg/ml). Mean 5-HT per platelet values were not significantly different
between age-matched groups of autistics and controls.
In 1987, Anderson and other investigators from Yale published results
from their laboratory and reviewed and summarized data on WBS levels in au-
tism to that date (Table 1) (15). WBS and tryptophan were measured in 87 nor-
mal children and young adults and in 40 autistic subjects with a similar age
distribution. WBS concentrations were significantly higher in the drug-free autis-
tic subjects (mean ⫾ SE ⫽ 205 ⫾ 16 ng/ml) (n ⫽ 21) than in normal subjects
(136 ⫾ 5.4 ng/ml) (n ⫽ 87). When the 95th percentile of the normal group was
used to define “hyperserotonemia” (WBS greater than 220 ng/ml), 38% of the
autistic subjects were determined to be hyperserotonemic. The investigators did
not find that the elevation in WBS was due to a particular subgroup of autistic
subjects. The autistic subjects who were receiving anticonvulsants or typical
neuroleptics had significantly lower WBS levels than did the drug-free subjects.
An age effect was observed in young normal males only, as young boys had
higher WBS levels (181 ⫾ 15 ng/ml) (n ⫽ 9) than adult males (138 ⫾ 12 ng/
ml) (n ⫽ 17). Mean whole-blood tryptophan levels and platelet counts were no
different between the autistic and normal groups. The investigators concluded
that, while causal mechanisms for elevated WBS in autism remained elusive,
relative to other possibilities, it seemed more likely that an alteration in platelet
function accounted for the hyperserotonemia. They pointed out that the problem
of the link between central and peripheral regulation of 5-HT metabolism re-
mained to be clarified in order to deduce the functional “meaning” of deviant
peripheral measures.
In a subsequent study, McBride et al. (16) re-evaluated platelet 5-HT in
autism, measuring and controlling for effects of race and puberty. In addition,
the specificity of hyperserotonemia for autism vs. cognitive impairment was as-
sessed. Prepubertal autistic children (n ⫽ 58) had significantly higher 5-HT con-
centrations than prepubertal controls (n ⫽ 38), although the elevation (25%) was
less than typically reported. Twenty-two mentally retarded or otherwise cogni-
tively impaired prepubertal children without autistic features (n ⫽ 22) had levels
similar to those of the normal controls. White children had significantly lower
5-HT levels than black or Latino youngsters, regardless of diagnosis. Diagnosis
and race effects were nonsignificant in the postpubertal group. The investigators
emphasized, however, that the observed absence of a significant or substantial
elevation in platelet 5-HT in postpubertal autistic subjects was based on a rela-
tively small number of subjects. They stated that when 5-HT was expressed as
ng/ml blood, the postpubertal autistic group showed a modest (15%) elevation in
the mean level that might have proved statistically significant in a larger sample.
Postpubertal subjects had lower 5-HT concentrations than prepubertal subjects.
The investigators concluded that the prevalence of hyperserotonemia in autistic
206
Table 1 Studies of Blood Serotonin in Autism

Mean values (mean ⫾ SD)
Author Year Technique Sample type Autistic subjects Controls Notes
Schain and Freedman 1961 Bioassay Whole blood 141 ⫾ 78 ng/ml, N ⫽ 23 65 ⫾ 17 ng/ml, N ⫽ 4 normals Mean autistic age 10.8.
72 ⫾ 33 ng/ml, N ⫽ 12 (mildly
retarded)
Ritvo, Yuwiler, Geller, 1970 Acid fluorescence Whole blood 263 ⫾ 63 ng/ml, N ⫽ 23 216 ⫾ ng/ml, N ⫽ 36 3–8-yr-old subjects; levels de-
Ornitz, Saeger, and clined with age; no group differ-
Plotkin ences when expressed as per
platelet.
Yuwiler, Ritvo, Bald, 1971 Acid fluorescence Whole blood 272 ⫾ 53 ng/ml, N ⫽ 7 183 ⫾ 28 ng/ml, N ⫽ 4 8 a.m. samples; similar group dif-
Kyper, and Kopen 760 ⫾ 113 ng/10 platelets, 494 ⫾ 42 ng/10 platelets, ferences seen at noon. No circa-
N⫽7 N⫽4 dian rhythm seen.
Campbell, Friedman, 1974 Acid fluorescence Platelet-rich 280 ng/ml, N ⫽ 11 170 ng/ml, N ⫽ 6 Mean age autistics 5; mean age
DeVito, Greenspan, plasma normals 6.
and Collins
Yuwiler, Ritvo, Geller, 1975 Acid fluorescence Whole blood 273 ⫾ 30 ng/ml, N ⫽ 12 205 ⫾ 17 ng/ml, N ⫽ 12 Platelet 5-HT uptake, efflux similar
Ornitz, and Saeger 911 ⫾ 106 ng/10 9 platelets, 650 ⫾ 48 ng/10 9 platelets, in both groups. Mean autistic
N ⫽ 12 N ⫽ 12 and normal ages 5 and 8 yrs, re-
spectively.
McDougle et al.
Goldstein and Coleman 1976 Acid fluorescence Whole blood 86 ⫾ 36 ng/ml, N ⫽ 72 73 ⫾ 23 ng/ml, N ⫽ 71 Age-matched children.
Hanley, Stahl, and 1976 Acid fluorescence Whole blood 135 ⫾ 57 ng/ml, N ⫽ 27 57 ⫾ 49 ng/ml, N ⫽ 6 normals 7–23-yr-old subjects; no age effect
Freedman 97 ⫾ 38 ng/ml, N ⫽ 23 (mildly seen; urinary 5-HIAA also higher
retarded) in autistics.
Takahashi, Kanai, and 1976 Ninhydrin fluo- Platelet pellet 980 ⫾ 357 ng/mg, N ⫽ 30 807 ⫾ 202 ng/mg, N ⫽ 30 Expressed as ng/mg platelet pro-
Miyamoto rescence tein; mean age 5 yrs; no age effect
from 2–12 yrs.
Hoshino, Kumashiro, 1979 Acid fluorescence Serum 218 ⫾ 79 ng/ml, N ⫽ 42 175 ⫾ 60 ng/ml, N ⫽ 320 Mean age autistics 5.7; mean age
and Kaneko normals 9.3.
Hoshino, Yamamoto, 1984 Acid fluorescence Whole blood 173 ⫾ 62 ng/ml, N ⫽ 37 124 ⫾ 44 ng/ml, N ⫽ 67 Tryptophan elevated in autistic sub-
Kaneko, Tachibana, Wa- jects.
tanabe, Ono, and Ku-
mashiro
Anderson et al. 1987 HPLC fluoro- Whole blood 205 ⫾ 73 ng/ml, N ⫽ 21 136 ⫾ 50 ng/ml, N ⫽ 87 Mean age autistics 14.5; mean age
metric 776 ⫾ 348 ng/10 9 platelets, 522 ⫾ 213 ng/10 9 platelets, normals 14.6; drugs reduced 5-HT
Neurobiology of Serotonin Function
N ⫽ 16 N ⫽ 67 levels; 5-HT elevated in young

males.
Source: Ref. 15.

207
208 McDougle et al.
individuals may have been previously overestimated because of failure to control

for race and pubertal status.
A more recently published study, by Croonenberghs et al. (17), evaluated
a number of peripheral markers of 5-HT function in postpubertal caucasian males
with autism. Thirteen autistic males (mean ⫾ SD age ⫽ 14.5 ⫾ 1.8 years) and
13 male normal controls (15.1 ⫾ 1.5 years) who had passed the onset of puberty
participated in the study. The autistic group was somewhat atypical in that one
autistic subject had an IQ of between 55 and 60 whereas the others had borderline
or normal intellectual functioning. All subjects and controls were drug-free, and
subjects with an active seizure disorder were excluded. All samples were col-
lected over a 2-day period in the last week of September of 1997. The [3H]-
paroxetine binding Kd values on platelets were significantly higher (lower affin-
ity) in the autistic subjects than in the healthy controls. There were no significant
differences in [3H]-paroxetine binding Bmax values, 5-HT values in whole blood,
serum, or platelet-rich plasma, or 5-HIAA values in 24-hr urine between autistic
subjects and controls. The investigators stated that the findings that peripheral
5-HT and 5-HIAA values were normal, and that there were no significant correla-
tions between those peripheral markers and the [3H]-paroxetine Kd values, sug-
gested that the peripheral 5-HT transporter system in postpubertal, caucasian
autistic male subjects with an IQ greater than 55 is not altered. In the same
study, the investigators found significantly lower serum concentrations of total
tryptophan in the autistic group although the tryptophan/competing amino acid
(CAA) ratio was not significantly different. The investigators stated that the mea-
surement of free, in addition to total, tryptophan as a measure of the tryptophan
availability to the brain would have been more informative. In addition, they
stated that since the tryptophan/CAA ratio is not significantly decreased, it re-
mains unclear whether the availability of tryptophan to the brain is decreased in
autism.
In another recent study, by Leboyer et al. (18), WBS levels were determined
in 62 subjects with autism (42 boys, 20 girls), aged 3–23 years (mean ⫾ SD ⫽
9.2 ⫾ 4.2 years), 91 healthy controls aged 2–16 years, and 118 healthy subjects
over 16 years of age. Among the 60 autistic probands for whom 5-HT measure-
ments were performed, the 41 male subjects had a mean WBS level of 1.08 µmol/
L (range: 0.26–3.90) and the 19 female subjects had a mean WBS level of 0.90
µmol/L (range: 0.15–3.98). With WBS levels above 0.90 µmol/L defined as
hyperserotonemic, 29 (48%) of the 60 autistic subjects met this criterion. The
autistic subjects had significantly higher mean WBS levels (1.02 ⫾ 0.77 µmol/
L) than the 118 controls older than 16 years (0.42 ⫾ 0.14 µmol/L). While the
55 autistic subjects aged less than 16 years had WBS levels greater than those
of controls matched for age and gender (0.97 ⫾ 0.70 µmol/L vs. 0.86 ⫾ 0.30
µmol/L), the difference was not statistically significant. However, the distribution
of WBS levels remained very different in a comparison of aged-matched autistic
Figure 3 Whole-blood serotonin (5-HT) levels among autistic patients aged less than
16 years (n ⫽ 55) and controls (n ⫽ 91) according to age. (From Ref. 18, by permission
of Elsevier Science. Copyright 1999 by the Society of Biological Psychiatry.)
subjects and controls (Figure 3). This was due to the fact that among controls,
WBS values diminished with age, whereas WBS levels among autistic subjects
appeared to be age-independent.
Several studies have identified positive correlations between either platelet
5-HT (19) or WBS (20–22) levels of autistic children and WBS levels of their
parents and siblings. Autistic children with siblings affected with autism have
also been shown to have higher WBS levels than autistic probands without af-
fected siblings (23). As part of the study described above, Leboyer et al. (18)
sought to determine whether elevated WBS levels may be associated with genetic
liability to the development of autism. The sample included the 62 subjects with
autism, 122 first-degree relatives (61 mothers, 42 fathers, 11 sisters, and 8 broth-
ers), and a group of healthy subjects (n ⫽ 118) age-matched for first-degree
210 McDougle et al.
relatives over 16 years. As compared with the 118 controls above 16 years of
age (0.42 ⫾ 0.14 µmol/L), mean WBS levels were higher in the 42 fathers (0.79
⫾ 0.32 µmol/L), the 61 mothers (0.85 ⫾ 0.21 µmol/L), and the 8 siblings greater
than age 16 (1.04 ⫾ 0.14 µmol/L). In fact, only 12 mothers (20%) and 4 fathers
(9.5%) exhibited WBS levels below 0.70 µmol/L vs. 94% of the 118 controls
older than 16 years. Considering the whole population of first-degree relatives,
31/61 (51%) mothers, 19/42 (45%) fathers, and 7/8 siblings older than 16 years
(87%) had hyperserotonemia (WBS levels greater than 0.90 µmol/L). The inves-
tigators concluded that such familial aggregation of quantitative variables within
first-degree relatives of individuals with autism might enhance the search for
genetic vulnerability factors in autism.
In summarizing results from studies of WBS in autism, many but not all
investigations have found elevated WBS levels in younger autistic subjects that
tend to remain higher than those of normal controls across the age range. In
contrast, most studies of normal subjects have demonstrated an age-related de-
cline in WBS levels with increasing age. Some investigators have suggested that
these results could be explained, in part, by abnormal maturational processes of
the 5-HT system in autistic subjects (15,18). Additional factors that may affect
WBS levels include race, pubertal status, and treatment with psychotropic medi-
cation. Whether WBS levels will prove to be a useful quantitative measure in
the search for genetic susceptibility to autism remains to be determined.
In general, studies of urinary excretion of 5-HIAA (24) and whole-blood
tryptophan concentrations (15) have not found significant differences between
autistic subjects and controls.
CENTRAL MEASURES OF 5-HT FUNCTION IN AUTISM

Studies of baseline levels of cerebrospinal fluid (CSF) 5-HIAA have found no
significant difference between autistic children and controls (25–27). Two studies
that used probenecid to block the transport of 5-HIAA out of the CSF found
similar (28) or slightly lower (29) levels in autistic children compared with nonau-
tistic children with psychosis. To our knowledge, studies of CSF 5-HIAA have
not been conducted in postpubertal individuals with autism.
BEHAVIORAL/NEUROENDOCRINE CHALLENGE STUDIES

A small number of behavioral/neuroendocrine challenge studies have been con-
ducted in individuals with autism. The immediate precursor of 5-HT, 5-HTP, was
given to autistic children and adult normal controls (30,31). A reduced prolactin
response to 5-HTP was found in the autistic children, suggesting diminished cen-
tral 5-HT responsivity. Similarly, in a study involving seven male young adults
with autism and seven age- and gender-matched healthy controls, a blunted pro-
Figure 4 Clinician-rated global severity change scale scores at the ⫹300-minute period
(5 hours after the drink) after tryptophan depletion (11 of 17 patients significantly worse)
and sham depletion (none of 17 patients significantly worse) for 17 patients with autism
(p ⫽ 0.001, Fisher exact test). (From Ref. 33. Copyright 1996 by the American Medical
Association.)
lactin release was identified in the autistic subjects in response to a 60-mg oral
dose of the indirect 5-HT agonist fenfluramine (32).
As a follow-up to these studies, McDougle et al. (33) employed an acute
tryptophan-depletion paradigm in 17 drug-free adults with autism. Tryptophan
is the essential amino acid necessary for the production of 5-HT within the CNS.
Administration of tryptophan-free amino acid mixtures within this paradigm have
been shown to deplete plasma levels of tryptophan and CSF levels of tryptophan
and 5-HIAA within 5 hours in humans (34).
Administration of the tryptophan-free amino acid mixture led to a marked
and significant reduction in plasma levels of both free and total tryptophan at 5
hours postingestion. In contrast, administration of a similar amino acid mixture
containing tryptophan (sham depletion) led to a significant increase in plasma
free and total tryptophan, as one would expect following normal food intake.
Behavioral effects were observed and quantitated in a double-blind fashion using
standardized, validated rating scales. Eleven of the 17 subjects who completed
both test days showed a significant worsening in symptoms following short-term
tryptophan depletion. In contrast, none of the 17 subjects demonstrated a signifi-
cant change in clinical status from baseline following sham depletion (Figure 4).
212 McDougle et al.
A significant increase in sensory motor behaviors, including whirling, flapping,

pacing, banging, hitting self, rocking, and toe walking, was observed with trypto-
phan depletion. Because tryptophan depletion presumably transiently reduces
CNS 5-HT production and availability, the data from this study support a model
in which aspects of central 5-HT function may be reduced in some adult patients
with autism. To our knowledge, studies of acute tryptophan depletion have not
been conducted in children or adolescents with autism.
In the most recent set of serotonergic challenge studies in autism, sumatrip-
tan, a 5-HT1D receptor agonist that has been shown to increase growth hormone
release, and placebo were administered subcutaneously (separated by 1 week) to
11 adults with autism or Asperger’s disorder and nine matched controls (35).
The subjects with autism or Asperger’s disorder had a significantly greater growth
hormone response to sumatriptan than the controls. The investigators hypothe-
sized that this difference may be due to 5-HT dysfunction and, specifically, hyper-
sensitivity of the 5-HT1D receptor. In a related study (36), the severity of repeti-
tive behavior at baseline in adults with autism or Asperger’s disorder was
correlated with the growth hormone response to sumatriptan. The investigators
suggested that these results indicated that a specific component of the 5-HT sys-
tem (the 5-HT1D receptor) may play a role in mediating one specific behavioral
component of autism: repetitive behavior.
NEUROIMAGING STUDIES
To our knowledge, results from only two studies that assessed central 5-HT func-
tion in autism with neuroimaging techniques have been published. In the first of
these investigations, using alpha-[11C]methyl-L-tryptophan (AMT) as a tracer
for 5-HT synthesis with positron emission tomography (PET), eight autistic chil-
dren (seven boys, one girl; ages 4.1–11.1 years; mean age 6.6 years) and five of
their siblings (four boys, one girl; ages 8.2–14.4 years; mean age 9.9 years) were
studied (37). The investigators reported “gross” asymmetries of 5-HT synthesis
in frontal cortex, thalamus, and cerebellum in all seven autistic boys but not in
the one autistic girl. Decreased [11C]AMT accumulation was seen in the left
frontal cortex and thalamus in five of the seven boys. This was accompanied by
elevated [11C]AMT accumulation in the right dentate nucleus of the cerebellum,
confirmed through PET/magnetic resonance imaging image coregistration. The
investigators noted that the dentate nucleus is not visualized with [11C]AMT in
normal adults. In the other two autistic boys, [11C]AMT accumulation was de-
creased in the right frontal cortex and thalamus and elevated in the left dentate
nucleus. No gross asymmetries were seen in the frontal cortex or thalamus of
the sibling group; however, one sibling showed increased [11C]AMT accumula-
tion in the right dentate nucleus. Interestingly, this boy had a history of calendar
calculation and he ritualistically lined up his toys. The overall difference for
asymmetry scores between the autistic boys and siblings was statistically signifi-
cant. Differences for regional asymmetry scores in the frontal cortex and thalamus
were also statistically significant. The asymmetry scores for the dentate nucleus
approached but did not reach statistical significance. The investigators concluded
that these focal alterations in [11C]AMT accumulation may represent either aber-
rant innervation by 5-HT terminals or altered function in anatomically normal
pathways.
The second study on neuroimaging, also by Chugani et al. (38), was de-
signed to determine whether brain 5-HT synthesis capacity is higher in children
or adults and whether there are differences in 5-HT synthesis capacity between
autistic and nonautistic children. Serotonin-synthesis capacity was measured in
autistic and nonautistic children at different ages, using [11C]AMT and PET.
Global brain values for 5-HT synthesis capacity (K-complex) were obtained for
autistic children (24 boys and 6 girls; age range, 2.3–15.4 years; mean age, 6.41
⫾ 3.3 years), 8 of their nonautistic siblings (6 boys and 2 girls; age range, 2.1–
14.4 years; mean age, 9.18 ⫾ 3.4 years), and 16 children with epilepsy without
autism (9 boys and 7 girls; age range, 3 months to 13.4 years; mean age, 5.73
⫾ 3.6 years). K-complex values were plotted according to age and fitted to linear
and five-parameter functions, to determine developmental changes and differ-
ences in 5-HT synthesis between groups. For nonautistic children, 5-HT synthesis
capacity was more than 200% of adult values until the age of 5 years and then
declined toward adult values. Serotonin-synthesis capacity values declined at an
earlier age in girls than in boys. In autistic children, 5-HT synthesis capacity
increased gradually between the ages of 2 years and 15 years to values 1.5 times
adult normal values and showed no sex difference. Significant differences were
detected between the autistic and epileptic groups and between the autistic and
sibling groups for the change with age in 5-HT synthesis capacity (Figure 5).
The investigators concluded that humans undergo a period of high brain 5-HT
synthesis capacity during childhood, and that this developmental process is dis-
rupted in autistic children.
GENETIC STUDIES
Based on a number of abnormalities identified in various aspects of 5-HT function
in autism, as reviewed above, researchers have begun preliminary investigations
of genes involved in 5-HT neurotransmission in this disorder. The 5-HT trans-
porter (5-HTT), the site of action of serotonin-reuptake-inhibiting drugs, has been
considered a candidate gene for autism. Two polymorphisms have been described
for the 5-HTT gene: a functional insertion-deletion polymorphism in the pro-
moter region (HTTLPR) (39) and a variable-number tandem repeat in the sec-
ond intron (HTT-VNTR) (40). Cook et al. (41) were the first to describe results
from a study of the 5-HTT gene in autism. The results suggested the presence of
214 McDougle et al.
Figure 5 Serotonin synthesis capacity in children with autism (n ⫽ 30, 䊊), siblings of
children with autism (n ⫽ 8, 䉱), and children with epilepsy (n ⫽ 16, ■). Global brain
values for K complex (ml/g/min) were plotted as a function of age and linear fits were
obtained for each group. The slope parameter for the autism group was 0.000075 ⫾
0.000102 (⫾SD) (dashed line), for the sibling group was ⫺0.000565 ⫾ 0.000217 (thin
line), and for the epilepsy group was ⫺0.000315 ⫾ 0.000164 (thick line). The autistic
group was significantly different from both the sibling group (p ⫽ 0.007) and the epileptic
group (p ⫽ 0.044), whereas the sibling and epilepsy groups were not significantly different
( p ⫽ 0.358). (From Ref. 38, by permission of Wiley-Liss.)
association between the short variant of HTTLPR and autism using the transmis-
sion disequilibrium test (TDT) (42) in 86 singleton families from the United
States. In contrast, Klauck et al. (43) reported preferential transmission of the
long variant of HTTLPR in a sample of 65 singleton families from Germany
using the TDT test. These investigators suggested that these conflicting find-
ings concerning the preferentially transmitted alleles of 5-HTT between the Ger-
man and U.S. patient samples might reflect etiological heterogeneity, differences
in the selection of patients, or a low power of the tests due to a small sample
size.
A subsequent study, by Zhong et al. (44), was designed to determine the
distribution frequency of the HTTLPR long allele and short allele in 72 autistic
subjects, 11 fragile X syndrome subjects with autistic behavior, 43 normal sub-
jects, and 49 fragile X syndrome nonautistic subjects. The frequency of the long/
long genotype was somewhat higher in the autistics (44.4%) and autistic fragile X
individuals (54.5%) than in the controls (normals and fragile X syndrome without
autistic behaviors combined) (30.4%). The short/short genotype was lower in the
autistics (12.5%) and autistic fragile X (9.1%) subjects than in the controls
(21.7%). These differences, however, were not statistically different. The distri-
bution of the HTTLPR variant among the groups also showed no statistically
significant differences. This study used a simple case-control approach rather
than the more conservative TDT analysis.
In a recent study from the International Molecular Genetic Study of Autism
(IMGSA) Consortium (45), a two-stage genome search for susceptibility loci in
autism was performed on 87 affected sib pairs plus 12 non-sib affected relatives
from a total of 99 families. Regions on six chromosomes (4, 7, 10, 16, 19, and 22)
were identified that generated a multipoint maximum lod score ⬎1. No significant
increased allele sharing was detected in the 17q11.1–q12 region which contains
the 5-HTT gene. Because the presence of a locus with a small effect could not
be excluded, however, the investigators used the TDT to examine the two 5-HTT
gene polymorphisms in the IMGSA Consortium family data set (46). No evidence
for linkage or association was found at the HTTLPR locus, the HTT-VNTR locus,
or their haplotypes. The investigators concluded that polymorphisms at the 5-
HTT locus do not have a major effect on susceptibility to autism in their family
data set. Even more recently, Persico et al. (47) assessed linkage by both the
TDT and haplotype relative risk method in two new ethnically distinct samples
yielding a total sample of 98 trios and found no association between the HTTLPR
locus and autism.
Studies into other genes involved in 5-HT neurotransmission are ongoing.
Recently, Lassig and colleagues (48), using the TDT, found no evidence for an
association between polymorphisms in the gene encoding the 5-HT7 receptor
and autism.
CONCLUSION
This chapter has reviewed results from investigations of peripheral and central
neurochemistry, behavioral/neuroendocrine challenges, neuroimaging, and ge-
netics related to 5-HT function in autism. From peripheral neurochemical studies,
we have learned that WBS levels generally are higher in prepubertal autistic
subjects than in age-matched normal controls. Results from a number of studies
suggest that an age-related decline in WBS levels occurs normally in humans
and that this process may be altered in autism. These findings have led some
investigators to propose that an abnormal maturational process of the 5-HT sys-
tem may contribute to the pathophysiology of autism. Investigators are currently
attempting to determine whether WBS levels can serve as an objective measure
to assist in identifying individuals and families with a genetic vulnerability to
autism. Studies of basal central neurochemistry have not found significant differ-
ences in measures of 5-HT function between autistic subjects and controls. How-
ever, results from behavioral/neuroendocrine challenge studies have suggested
216 McDougle et al.
that central 5-HT responsivity may be reduced in autistic subjects, particularly

adults. Brain imaging studies utilizing tracers for measuring 5-HT synthesis ca-
pacity have found that humans undergo a period of high brain 5-HT synthesis
during childhood, and that this developmental process may be disrupted in autistic
children. These preliminary results are not unlike results from studies of WBS
in that they may represent an altered maturational process of the 5-HT system
in autism. To date, genetic studies of the 5-HT system in autism have yielded
inconsistent results. Due to recent efforts to create networks of multiple academic
sites focused on the genetics of autism, larger samples are being obtained, making
the identification of contributory genes more likely.
With the development of the selective serotonin-reuptake inhibitors
(SSRIs), researchers and clinicians now have access to drugs with potent effects
on the 5-HT system. Preliminary studies of this class of drugs in autism have
been conducted. Similar to results from investigations of WBS levels and neuro-
imaging studies of 5-HT-synthesis capacity in autistic subjects, clear develop-
mental differences have been identified in the efficacy and tolerability of SSRIs
in autism. To date, only one double-blind, placebo-controlled study of an SSRI
has been published in autism. Fluvoxamine was found to be significantly more
effective than placebo for reducing repetitive thoughts and behavior, maladaptive
behavior, and aggression in adults with autism (49). Eight of 15 subjects given
fluvoxamine vs. none who received placebo responded. Adverse effects were
mild and transient. In contrast to these encouraging results, a study of identical
design in children and adolescents with autism found fluvoxamine to be poorly
tolerated and with limited efficacy at best (50). Only one of 18 subjects random-
ized to fluvoxamine responded in this study; none of the 16 placebo-treated sub-
jects improved. In addition, the drug was very poorly tolerated and resulted in
frequent and interfering adverse effects, including insomnia, agitation, motor hy-
peractivity, impulsivity, and aggression. The marked difference in efficacy and
tolerability of fluvoxamine in children and adolescents with autism compared
with that of adults underscores the importance of developmental factors in the
pharmacotherapy of subjects with this disorder. This differential treatment re-
sponse is consistent with the hypothesis that ongoing brain development has a
significant impact on a subject’s ability to tolerate and respond to a drug, at least
with respect to fluvoxamine and possibly other SSRIs. Developmental changes
in brain 5-HT function may contribute to these widely varying clinical responses
between subjects with autism of different age groups. These observations, while
preliminary, may not be inconsistent with the developmental differences that have
been reported in studies of WBS and brain imaging described above.
Over the past five decades, significant progress has been made in character-
izing aspects of 5-HT dysfunction in autism. Pharmacological treatments that
effect changes in this system are beginning to prove helpful in a number of indi-
viduals with the disorder. Expanded research into 5-HT function in autism (e.g.,
5-HT–immune interactions) appears warranted. Such effort should bring the field
closer to a better understanding of the pathophysiology of autism, the develop-
ment of safer and more effective treatment interventions, and, ultimately, ad-
vances in identifying etiological aspects of the disorder.
ACKNOWLEDGMENTS
We thank Ms. Robbie Smith for preparing the manuscript. This work was sup-
ported in part by an Independent Investigator Award–Seaver Foundation Investi-
gator award from the National Alliance for Research in Schizophrenia and De-
pression (NARSAD) (Dr. McDougle), a NARSAD Young Investigator Award
(Dr. Posey), Research Unit on Pediatric Psychopharmacology (RUPP) Contract
NO1MH70001 from the National Institute of Mental Health to Indiana University
(Drs. McDougle and Posey), a Daniel X. Freedman Psychiatric Research Fellow-
ship Award (Dr. Posey), the State of Indiana Division of Mental Health, and
Department of Housing and Urban Development Grant B-01-SP-IN-0200 (Repre-
sentative Dan Burton).
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11
Autism, Serotonin and the Cerebellum
A New, Comprehensive Hypothesis
Donatella Marazziti
University of Pisa
Pisa, Italy
INTRODUCTION
Autism is a neuropsychiatric disorder characterized by disturbances in the devel-
opment of social interactions, imaginative activities, communication, and speech.
Associated features include resistance to change, ritualistic or compulsive
behaviors, stereotypies, self- and outwardly directed aggressive behaviors, mood
lability, and persistent preoccupation with parts of objects (1). In adolescence
the ritualistic behaviors may develop into obessional symptoms. Although its
onset occurs during childhood, it is a persistent and disabling disorder, severely
impairing the whole lifespan. Its prevalence in school-aged children is estimated
to be about 4 in 10,000 and four times higher in boys than in girls.
AUTISM AND SEROTONIN

The etiology of autism is still unknown, but probably multifactorial and heteroge-
neous. The results obtained from neuropathological and brain imaging studies
strongly suggest that the cerebral defect in autism is microscopic or functional,
without major neuroanatomical pathology. Various descriptions of biochemical
and neuroanatomical correlates have accumulated in published research, but have
not yet been formed into a comprehensive picture. Although neurochemical ab-
normalities have been described in autistic patients, the most congruent findings
221
222 Marazziti
are those involving serotonin (5-HT). Since the first observations of Schain and
Freedman (2), who reported increased whole-blood 5-HT levels, this finding has
been replicated in a high percentage of autistic patients ranging from 30 to 40%
and even in patients’ relatives (for review, see Ref. 3). Subsequently, other indices
of altered serotonergic function have been observed, such as a decreased prolactin
response to L-tryptophan (TRP) and fenfluramine (4), the presence of antibodies
against serotonergic neurons (5,6), and the worsening of symptoms after a TRP-
free diet (7). There is also indirect evidence, based on preliminary observations,
of the potential effectiveness of clomipramine and of selective 5-HT-reuptake
inhibitors (SSRIs), mainly on obsessive-compulsive symptoms (8). The pathoge-
netic role of 5-HT is supported by a recent PET study (9) showing altered 5-HT
synthesis, while using alpha-(11C)methyl-L-tryptophan, in the dentato-thalamo-
cortical pathway of a small sample of autistic subjects.
The intrasynaptic availability of serotonin (5-HT) is regulated mainly by
an active transport or reuptake mechanism that removes the neurotransmitter
and returns it to the presynaptic terminal after its release. The 5-HT transporter
has become the subject of intensive interest in recent years, since it is the main
target of tricyclic antidepressants and SSRIs (10,11). Research in this area has
been assisted by the identity between brain and platelet 5-HT transporters, as
demonstrated by cloning studies (12–14) and by the significant correlation be-
tween the rates of inhibition of the 5-HT transporter in brain and platelets by
SSRIs (15). Apart from the direct evaluation of the reuptake rate, the 5-HT
transporter has been investigated in the brain and in platelets by means of the
specific binding first of [3H]-imipramine ([3H]-IMI) and then of [3H]-paroxetine
([3H]-Par), which appears to bind to a single site corresponding to the trans-
porter itself (16,17).
Recently, the role of the 5-HT transporter in autism has received some
support from genetic studies, but the results are still controversial: in fact, a higher
frequency of both the long and short alleles of the 5-HT transporter gene–linked
polymorphic region (5-HTTLPR) has been observed (18,19). However, the direct
measurement of the platelet 5-HT transporter has shown no difference between
autistic patients and healthy controls in platelet 5-HT uptake or [3H]-IMI binding.
In particular, autistic patients were not reported to differ from healthy controls
in terms of 5-HT reuptake (20) or [3H]-IMI binding sites (21). However, the
samples in the two studies were small and the age range was wide. In addition,
[3H]-Par is more specific than [3H]-IMI and might reveal changes that would
otherwise be undetectable. Cook et al. (22) evaluated [3H]-Par binding sites in
relatives of autistic subjects and reported a trend toward a lower dissociation
constant in hyperserotonemic than in normoserotonemic subjects. Recently, we
have observed an increased density of [3H]-Par binding sites, as compared with
matched healthy controls (23). It is interesting to underline that the function of
the 5-HT transporter is no longer considered to be restricted to the removal of
Autism, Serotonin, and the Cerebellum 223
the neurotransmitter once released in the synaptic cleft. Rather, different data
suggest that it plays a fundamental role in brain development, plasticity, and
neurodegeneration (24,25). While in adult life 5-HTT expression appears to be
restricted to raphe neurons, in postnatal development it has been detected in the
cingulate cortex and thalamus. Furthermore, the dense transient innervation of
somatosensory, visual, and auditory cortices has been shown to originate in the
thalamus, thus demonstrating a transient expression of the 5-HT transporter regu-
lating its maturation (26).
I propose that, perhaps, a disturbance in the normal process of expression
of the 5-HT transporter, such as an exaggerated persistence in postnatal life, has
profound effects on normal brain development that might lead to some disorders,
such as autism. However, currently, we cannot rule out that the increased density
of the platelet 5-HT transporter might represent a compensatory rather than a
primary phenomenon. Future studies, by means of brain-imaging studies or in-
situ hybridization in lymphocytes in which the 5-HT transporter has been detected
by means of binding techniques (27), should aim to determine whether the in-
creased [3H]-Par binding is due to an overexpression of the transporter protein.
AUTISM AND THE CEREBELLUM

Besides neurochemistry, neuroanatomical studies involving autoptic brain sam-
ples from autistic patients have produced evidence of alterations in the hippocam-
pus, amygdala, and cerebellum; in particular at this level, a loss in Purkinje cells
has been detected. These abnormalities have been confirmed by magnetic reso-
nance imaging (MRI), which has visualized a hypoplasia of the cerebellar vermal
lobules (28) and which has contributed to the description of alterations in other
areas, such as the cortex and cyngulate gyrus (29,30). Besides hypoplasia oc-
curring in about 87% of the patients, a subgroup of autistic patients (13%) seemed
to be characterized by hyperplasia of posterior vermal lobules VI and VII. Ac-
cording to the authors who described it after reanalyzing previously published
vermal area measures from different studies (31), this finding might explain the
negative data. However, criticisms have been raised on the specificity of neocere-
bellar abnormalities detectable on MRI in autism, as reviewed in a recent paper
(32) reporting enlarged volume of the cerebellum, which is consistent with a
similar finding in other brain regions and suggestive of a widespread distribution
of abnormalities throughout the brain. Alterations of specific brain areas are in-
deed suggested by the presence of neurological soft signs and dypraxia, recently
related not only to basal ganglia dysfunctions but also to cerebellar impairments
(33).
For decades, the cerebellum has been thought to contribute only to motor
coordination and control. In recent years, however, it has emerged that it may
have a role in cognition, emotional processes, and internal mental imaginery (34–
224 Marazziti
36). The observation that the cerebellum has more neurons than the whole brain
and that the development of the lateral hemispheres and dentate nuclei parallels
that of the neocortex in humans has led to the proposal that it might project to
associative regions of the brain (37). This hypothesis has recently been supported
by the demonstration of an anatomical network linking the cerebellum with the
nonmotor prefrontal cortex through a retrogradal transneural transport of a ret-
roviral tracer (38). Its general architecture is quite simple, consisting of the pri-
mary outputs, represented by inhibitory Purkinje cells, which receive inputs from
only one climbing fibre, while mossy fibers make excitatory synapses in the nu-
clei and branch to make excitatory synapses with a large number of granule and
Golgi cells in the cortex.
Therefore, it is currently believed that the cerebellum might play a role in
the control of some cognitive processes and, in this regard, nonmotor behavioral
deficits associated with cerebellar damage or abnormalities have been reported
by some investigators (39). Interestingly, Petersen (40) observed with PET an
increase in right lateral cerebellar blood flow during a language task.
Since the cerebellum receives diffuse serotonergic innervation by afferents
originating from the raphe nuclei, theoretically 5-HT might modulate such cere-
bellar functions through specific receptors that, to date, have never been described
in humans.
A NEW HYPOTHESIS LINKING SEROTONIN AND THE

CEREBELLUM IN AUTISM
Although both serotonergic and cerebellar abnormalities have been described in
autism, there is a gap in the chain. A possible link is indicated by the results of
one of our studies exploring the mRNA expression of specific 5-HT receptor
subtypes in human brain by means of in-situ hybridization.
In fact, my coworkers and I observed in the cerebellum a high level of 5-
HT5A mRNA expression, particularly in the Purkinje-cell perikarya but also in
the granule layer and in the dentate nucleus. This pattern of mRNA expression
was found in the cortex of both hemispheres and the vermis (41) (Figure 1).
To the best of our knowledge, this is the first report of a 5-HT receptor
localized in all the main cell types that control both cerebellar inputs and outputs.
In the mouse, the 5-HT5A mRNA seems to be expressed only in the granule cell
layer (42), with Purkinje cells representing one of the main sites of expression
of the 5-HT1B receptor, which is the rodent homolog of human 5-HT1Dβ (43).
The wide distribution of 5-HT5A mRNA in the cerebellum makes this recep-
tor a putative candidate, involved in different functions and, perhaps, in cognitive
and emotional processes. This hypothesis is in accordance with the observation
that the 5-HT5A mRNA is expressed in the cortex and in limbic structures such
Figure 1 Distribution of 5-HT5A receptor mRNA in the cerebellum. (Top left and right)
dark-field photomicrograph of a coronal section of the cerellar cortex; the Purkinje cells
are heavily labeled. High-magnification bright-field (bottom left) and dark-field (bottom
right) photomicrographs showing a high level of hybridization on the Purkinje-cell peri-
karya.
as the hippocampus and the ventrolateral region of the amygdala, while it is

poorly represented in basal ganglia and absent from substantia nigra, areas in-
volved in motor-function control.
When the motor-control function of the cerebellum is impaired, the re-
sulting and known effect is ataxia; similarly, when cerebellar control of cognitive
and emotional functions is impaired, the result might be a sort of “cognitive”
226 Marazziti
and “emotional” ataxia, as observed in autism, in which subjects appear unable

to coordinate these functions properly, even though their actual characteristics
have not necessarily changed.
It is noteworthy that, among the functions attributed to 5-HT5A, there is a
role in brain development and that reeler mutant rats exhibit abnormalities of
cerebellum, cerebral cortex, hippocampus, and olfactory bulbs consistent with
the pattern of 5-HT5A mRNA expression (44).
CONCLUSIONS
In conclusion, I suggest that autism (and perhaps autism-related disorders) might
be underlined by a specific disturbance in 5-HT5A receptors (45). This hypothesis
can currently be tested by comparing the level of expression of the specific
mRNA for 5-HT5A receptors in autoptic samples of cerebellum of autistic subjects
with those of healthy controls. Further studies could be carried out exploring the
possibility of structural changes at the level of the gene for 5-HT5A receptors in
autistic patients, and knockout techniques might also be employed for generating
animals lacking 5-HT5A receptors, whose (possible) behavioral abnormalities
might be used as models for some autistic symptoms. Future studies with selec-
tive agonists and antagonists for this receptor subtype, currently lacking, would
also be useful for supporting or rejecting our hypothesis, since they might permit
the comparison of the pharmacological characteristics of 5-HT5A receptors in au-
tistic subjects with those in healthy controls in autoptic brain samples or in vivo
by means of PET. Furthermore, such compounds might be of potential therapeutic
value for autism and related-disorders.
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12
Antidepressants and Anticonvulsants/
Mood Stabilizers in the Treatment
of Autism
Sherie Novotny and Eric Hollander

INTRODUCTION
Many medications have been used to ameliorate autistic symptoms and behav-
iors in individuals with autism. Currently, there are no pharmacological treat-
ments with established indications for autism (1). However, psychotropic medi-
cations have been used in autistic individuals to target core symptoms,
behavioral dyscontrol, treatment of concurrent psychiatric disorders, and man-
agement of associated medical conditions such as seizures. Antidepressant medi-
cations, particularly serotonin-reuptake inhibitors (SRIs), and anticonvulsant
medications are among the medications commonly used for autism spectrum
behaviors. The SRIs used include clomipramine (Ananfranil), fluoxetine (Pro-
zac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), and venlafax-
ine (Effexor). Some of these medications have been studied in an open-label as
well as double-blind manner. The results of these studies generally indicate that
these medications are efficacious in treating some of the symptoms of individuals
with autism spectrum disorder. Anticonvulsants, such as valproic acid and carba-
mazepine, are used particularly in individuals with comorbid seizure disorder,
as well as those with impulsive aggression and affective instability. However,
to date no placebo-controlled trials have been published examining the efficacy
of these medications. There have, however, been case reports and open-label
231
232 Novotny and Hollander
retrospective studies suggesting the efficacy of these medications in autistic indi-

viduals.
SRIs IN THE TREATMENT OF AUTISM

The Role of Serotonin in Autism Spectrum Disorders
The evidence supporting abnormal serotonin (5-HT) function in autism spectrum
disorders is substantial. This evidence provides the rationale for treatment with
antidepressants, particularly SRIs. Many studies of the neurobiology of autism
have focused on 5-HT, implicated in the regulation of many functions relevant
to autism spectrum disorders, such as learning, memory, repetitive behaviors,
sensory, and motor processes (2). Serotonin function also plays an important role
in modulating the symptoms of anxiety, depression, and obsessive-compulsive
disorders (OCDs).
Early studies suggested an elevation of whole blood serotonin in some au-
tistic individuals (3–5), and in some studies, an association was noted between
hyperserotonemia and greater cognitive impairment, increased stereotypies, and
more severe behavioral disturbance (6,7). However, other studies have not shown
serotonin levels to correlate with specific clinical features (8,9). In autistic indi-
viduals with affected relatives, 5-HT blood levels were significantly higher than
in those without affected relatives (10,11). In addition, relatives of autistic indi-
viduals with normal 5-HT levels were found to have normal 5-HT levels (12,13).
Thus, 5-HT blood levels may be familial and possibly associated with genetic
liability to specific subtypes of autism. In addition, an increased density of platelet
serotonin transporter has also been found in individuals with autistic disorder
(14,15). Croonenberghs and coworkers (15) also found decreased levels of trypto-
phan in autistic individuals.
Preliminary studies on the biology of the serotonergic system in autism
suggest that acute depletion of the 5-HT precursor tryptophan can exacerbate
many behavioral symptoms of autistic disorder (16). McBride et al. (17) showed
decreased central 5-HT responsiveness in autistic adults via blunted prolactin
response to fenfluramine, a 5-HT-releasing agent. Autoimmune factors possibly
affecting the 5-HT1A receptors in the blood of a subgroup of autistic patients have
also been reported (18).
A recent PET study, which utilized the radiolabeled serotonin precursor
alpha C11 methyl-tryptophan, provided empirical evidence of decreased serotonin
synthesis in frontal and thalamic regions and increased serotonin synthesis in
contralateral cerebellar dentate regions (19) in children with autistic disorders.
These findings are consistent with findings of increased 5HT1d inhibitory autore-
ceptor sensitivity in adult autistic patients (20,21), since these receptors are preva-
lent in frontal and thalamic, but not cerebellar, regions. These studies provide
Antidepressants and Anticonvulsants 233
important and consistent data to support the use of SRIs, which increase synaptic
serotonin availability in adult autistic subjects.
Additionally, our pilot studies with the 5-HT agonists meta-chlorophenylpi-
perazine (m-CPP) and sumatriptan have demonstrated that altered neuroendo-
crine responses to challenges with these agents significantly correlate with sever-
ity of repetitive behavior (20; Hollander et al., in preparation). As such, there is
substantial evidence that supports the involvement of 5-HT dysfunction in autism
(primarily decreased 5-HT function) and provides the rationale for a treatment
with SRIs such as fluoxetine that increase the availability of synaptic 5-HT and
down-regulate inhibitory 5-HT autoreceptors in autism.
Treatment Studies Using SRIs in Autism Spectrum Disorders

SRIs and selective serotonin-reuptake inhibitors (SSRIs) seem to be among the
most promising medications in treating autistic disorders at present. Compulsive/
repetitive behaviors, adventitious movements, and some social and language dif-
ficulties have been shown to respond to SRIs.
Clomipramine, a tricyclic antidepressant with potent effects on serotonin
reuptake—one of the medications most extensively studied in autism disorders—
has demonstrated efficacy in the treatment of these disorders (22–26). Gordon
et al. (23) conducted a double-blind comparison of clomipramine, desipramine,
and placebo in the treatment of 30 outpatient autistic patients (20 males, 10 fe-
males). Clomipramine was found to be superior to both placebo and desipramine
on ratings of autistic symptoms, anger, and compulsive, ritualized behavior. The
age range of patients was 6–23 (mean ⫽ 10.4; SD ⫽ 4.1 years). Dosage started
at 25 mg/day, increased every 4–5 days to a maximum of 250 mg/day or 5 mg/
kg/day. Adverse effects included QT prolongation on EKG and severe tachycar-
dia, both of which resolved with reduced dosage. One subject had a grand mal
seizure and had to be dropped from the study. Other side effects included insom-
nia, constipation, sedation, twitching, tremor, dry mouth, and decreased appetite,
and were minor for most patients. This highlights the side effects of tricyclics,
including clomipramine. In particular, a lowering of the seizure threshold in autis-
tic patients in whom there is already a predisposition to the development of sei-
zures can occur, as well as more severe cardiac adverse effects.
McDougle et al. (24) found that four of five outpatients with autism showed
significant improvement in social relatedness, obsessive-compulsive symptoms,
and aggressive and impulsive behavior with clomipramine treatment. These case
reports included a 13-year-old male, 24- and 27-year-old males, and 29- and 33-
year-old females. Dosages were 75 mg/day in the adolescent and 150–250 mg/
day in the adults. Side effects were not presented in this case study. Limitations
included its small sample size, open, nonblinded treatment design, and lack of
drug blood-level monitoring. Brašić et al. (26), in an open-label clinical trial,
found that clomipramine reduced adventitious movements and compulsions in

five outpatient prepubertal males, aged 6–12, with autism and severe mental retar-
dation, all of whom had been treated with neuroleptics in the past. They did not
assess the effect of clomipramine on other core symptoms of autism such as
social interaction and communication deficits. No side effects were reported in
the subjects. Limitations to this study were the open, nonblinded treatment design
and the lack of monitoring of drug blood levels. Sanchez et al. (27) found that
clomipramine was associated with side effects such as urinary retention, behav-
ioral toxicity, constipation, sedation, and insomnia in younger autistic children
aged 3.5–8.7. Limitations to the study include the rapid titration schedule, high
maximal dose, infrequent screening of clomipramine and metabolite blood levels,
and the open, nonblinded design of the study.
The use of SSRIs such as fluoxetine, which lack the tricyclic and anticholin-
ergic side effects of clomipramine, offers a distinct advantage in terms of side
effects and tolerability. Evidence suggests that fluoxetine and similar SSRIs are
associated with fewer side effects than other agents such as tricyclic antidepres-
sants, neuroleptics, and serotonin agonists (e.g., fenfluramine). Of 15 autistic
adults treated with fluvoxamine, McDougle (28) reported only mild sedation and
nausea, all of which self-resolved. There were no reports of anticholinergic ef-
fects, changes in blood pressure, laboratory or electrocardiographic changes, sei-
zures, or dyskinesias.
Preliminary trials and observations have demonstrated alleviation of
symptoms of autism with fluoxetine (29–33). Most of these studies have re-
ported a positive response to fluoxetine in autistic patients, including improved
social interaction and communication, a decrease in obsessive-compulsive be-
haviors and problem behaviors, and improvement in global severity. Mehlinger
et al. (29) reported that fluoxetine (20 mg every other day) reduced ritualistic
behavior such as ordering objects and stereotypies, temper outbursts, enuresis,
and depression in a 26-year-old female autistic patient. This patient had severely
impaired speech and marked perseveration, and had not responded to prior treat-
ment with imipramine 50 mg/day for 6 weeks. Todd (30) reported that three of
four autistic patients aged 8 to 19, of borderline to normal intelligence, demon-
strated significant reduction in ritualistic behavior, such as sniffing, finger flick-
ing, and arm flapping, and in frequency of temper outbursts, and increased toler-
ance of routine changes with fluoxetine treatment. The three responders were
treated with 20 mg/day and the nonresponder was on a 30-mg/day dose of flu-
oxetine. Treatment duration in responders was 14–16 months, and no side ef-
fects were reported. Koshes (34) reported on two adult autistic indivduals whose
obsessive-compulsive symptomatology improved significantly with fluoxetine
treatment.
In studies of autism and mental retardation, Cook et al. (31) found that 20–
80 mg per day of fluoxetine produced significant improvement in Clinician
Global Impression (CGI) severity scale scores in 15 of 23 (65.22%) autistic pa-

tients and 10 of 16 (62.5%) mentally retarded subjects in an open-label trial with
outpatients. The age range of the patients was 7 to 28 years, with mean ⫾SD ⫽
15.9 ⫾ 6.2 years. Five patients were female and 18 were male. Comorbid mental
retardation was found in 21 of 23 of the autistic patients. Oral fluoxetine ranging
from 20 mg q.o.d. to 80 mg q.d. was administered according to open titration.
Thirteen of 23 autistic and 12 of 16 mentally retarded patients were on concomi-
tant medications (neuroleptics, anticonvulsants, lithium, clonidine, benzodiaze-
pines, and methylphenidate). While six of 23 of the autistic patients experienced
side effects that interfered with function or outweighed therapeutic effects, only
one of 15 patients who showed improvement on CGI had significant side effects.
Side effects included agitation/hyperactivity, insomnia, elated affect, decreased
appetite, and increased screaming. No relationship was found between level of
mental retardation and response to fluoxetine in this study, which is limited by
being an open, nonblinded trial without a placebo control arm. Also, the maxi-
mum dosage of 80 mg/day is high, and the dose was rapidly escalated. In addi-
tion, many of the subjects were on concomitant medications that contributed to
side effects. Moreover, children and adolescent patients differ from adult patients
in treatment response, side-effect profile, and dosage scheduling, but this was
not adjusted for in this particular study.
Ghazziuddin et al. (32) found that 20–40 mg of fluoxetine per day in four
autistic adolescents with mental retardation and/or Down’s syndrome was effec-
tive in the reduction of depressive symptoms but not in the reduction of core
symptoms of autism such as stereotypies, temper outbursts and irritability, and
impaired social and communication skills. Subjects included 13- and 16-year-
old females with moderate mental retardation, and 17- and 21-year-old males
with Down’s syndrome, all of whom had comorbid depressive disorders. Both
females experienced increased irritability and anxiety—in one, after 2 weeks of
treatment with 20 mg/day, and in the other, after 4 weeks of treatment up to 40
mg/day. No definitive conclusion can be made from these case reports as they
were not blinded, placebo-controlled studies. Mixed samples of autistic patients
with mental retardation, Down’s syndrome, and attention-deficit/hyperactivity
disorder may be particularly sensitive to medication side effects, and might bene-
fit from smaller doses.
Awad (35) also reported on the efficacy of SSRIs in children with autism
spectrum disorders. Four of eight children benefited from treatment with SSRIs,
including fluoxetine, paroxetine, and sertraline. Four children discontinued treat-
ment due to adverse effects. Fatemi et al. (36) reported on seven adolescents with
autism who were treated with fluoxetine. All seven patients showed improvement
on four of the subscales of the Aberrant Behavior Checklist on fluoxetine. The
improved subscales included irritability, inappropriate speech, lethargy, and ster-
otypy. Increases were noted on the hyperactivity subscale. Side effects included
agitation and decreased appetite. Two patients discontinued treatment due to agi-
tation. DeLong et al. (37) studied 37 children aged 2–7 in an open-label study
of fluoxetine at doses of 0.2–1.4 mg/kg/day. Twenty-two of these children had
a beneficial treatment response sustained through several months of treatment
(13–33 months). Eleven of these children had an excellent response and were
able to be mainstreamed into regular classroom. The other 11 had a good response
but remained in special-education environments. Fifteen children had little or no
response to the medication. Side effects, which included hyperactivity, agitation,
and aggressiveness, were often the reason for discontinuation.
Peral et al. (38) reported on an open-label trial of fluoxetine in six children,
aged 4–7, with autistic disorder. Five of the six children improved markedly,
with decreased repetitive behavior and improved social interest. Side effects
noted included agitation, insomnia, and decreased appetite. In addition, pilot data
from a study by Hollander et al. (39) which examined the use of fluoxetine in
children, adolescents, and adults in a double-blind, placebo-controlled crossover
design, found fluoxetine to be superior to placebo in the acute treatment of global
autism severity. A recently published study examined metabloic activity in the
brain before and after fluoxetine treatment in six adult patients, three of whom
were responders. The study noted that metabolic activity increased in the right
frontal lobe, including the anterior cingulate gyrus, following treatment and that
individuals with increased activity in these areas prior to treatment had the most
response to the medication (40). In summary, fluoxetine has been a promising
treatment in several domains, including global autistic severity, repetitive/com-
pulsive and social behavior, problem behavior, stereotypies, and depression, but
has also been shown to have some side effects, such as gastrointestinal distur-
bances and agitation, particularly in younger patients.
Fluvoxamine, an SSRI, also appears promising. McDougle et al. (41) first
reported a single case of fluvoxamine treatment of coincident autism and OCD.
There was a marked improvement in the obsessive-compulsive symptoms and
in social interaction, and a decrease in temper tantrums. In a more recent double-
blind, placebo-controlled study of fluvoxamine treatment in adults with autism,
McDougle et al. (28) found that eight of 15 (53.33%) patients were responders
compared with none of 15 in the placebo group, with improvement in repetitive
thoughts and behavior, maladaptive behavior and aggression, and significant im-
provement in ratings of social relatedness and language usage. Side effects in-
cluded mild nausea and sedation in a minority of the patients, with no occurrence
of seizures, cardiovascular events, or dyskinesias. This study was 12 weeks in
duration in both inpatient (9) and outpatient (21) populations, and patient ages
ranged from 18 to 53 years. Only three of 30 patients were female. Dosage was
started at 50 mg/day and increased at a rate of 50 mg every 3–4 days to a maxi-
mum dose of 300 mg/day. Fluvoxamine blood levels were not obtained. In a
blinded placebo-controlled crossover study of fluvoxamine in children with au-

tism (42), an improvement was seen in several behaviors, including social behav-
iors such as eye gaze, and language use during the medication phase. Approxi-
mately half of the children showed improvement in their CGI scores on
fluvoxamine. In another open-label study of fluvoxamine in five aggressive chil-
dren (43), two showed significant decreases in aggressive behavior on fluvoxa-
mine, and another child showed a partial decrease in these behaviors. Another
study (44) examined the relationship between dose and brain levels of both flu-
voxamine and fluoxetine in children with autism spectrum disorders and found
the levels to be comparable with adult levels of the medication when adjusted
for dose and weight, suggesting that dosing can be extrapolated from adult data.
Sertraline, another SSRI, has also been found to be promising in the treat-
ment of transition-associated anxiety and agitation in children with autism (45),
and in self-injury and aggression in adult autistic patients with comorbid mental
retardation (46). Steingard et al. (45) studied nine children 6–12 years old in an
open-label sertraline trial with no placebo-controlled arm. Therapeutic doses of
sertraline were low in all cases (25–50 mg/day), with a clinical response gener-
ally appearing in 2–8 weeks. Adverse effects were minimal except for apparent
sertraline-induced worsening of behavior in two children when their doses were
increased to 75 mg/day. In three children, an initial satisfactory clinical response
appeared to diminish after 3–7 months of treatment, despite steady or increased
doses. In six patients, the beneficial effects persisted throughout the several-
month follow-up period.
Hellings and colleagues’ study (46) comprised nine adult inpatients. Other
comorbid psychiatric conditions in these patients included OCD, intermittent ex-
plosive disorder, stereotypy-habit disorder, impulse-control disorder, psychosis
not otherwise specified (NOS), and dysthymia. Total doses varied from 25 mg
to 100 mg/day, after starting at an initial dose of 25 mg/day. Most of the patients
were also on concomitant medications such as neuroleptics, lithium, propranolol,
methylphenidate, buspirone, and carbamazepine. The one patient on carbamaze-
pine also had comorbid seizure disorder. The rating scale used was the CGI.
Eight of the nine subjects experienced an overall improvement of severity, with
a mean improvement score of 2.44 ⫾ 1.67. Length of treatment ranged from 28
to 208 days, with a mean of 109.78 days. There was an overall lack of reported
untoward effects. The study was open and not placebo-controlled. Effects of med-
ication on obsessive-compulsive symptoms, language and communication dimen-
sions, and social skills were not studied. In a recently published 12-week open-
label study of sertraline (dosages 122 mg/day ⫾ 61) in 42 adult patients (age
range 18–39 years) with pervasive developmental disorders (47), 24 of the sub-
jects were found to be much or very much improved globally, with specific reduc-
tions noted in repetitive behaviors and levels of aggression. In addition, the SSRI
paroxetine has also been reported to decrease self-injurious behavior (48) and
improve irritability and temper tantrums (49) in case reports of children with
autism spectrum disorders.
Thus, SSRIs such as fluoxetine appear promising in treating global as well
as compulsive/repetitive and social symptoms of autism. Furthermore, they are
well tolerated in low doses, and do not have the seizure and cardiac risks associ-
ated with clomipramine. However, large-scale, controlled trials are needed to
establish their efficacy and safety.
Other antidepressants have also been used to treat autistic disorders. Trazo-
done has been shown to be effective in decreasing the aggressive and self-injuri-
ous behavior in one autistic patient; however, this medication has not yet been
studied in a group of individuals (50). Desipramine, a norepinephrine-reuptake
inhibitor, has also been studied but was found to be less effective than clomipra-
mine, an SRI (23). Venlafaxine treatment, examined in a small group of individu-
als with autism spectrum disorders ranging in age from 3 to 21, was found to be
effective in decreasing repetitive behaviors and hyperactivity, and improving so-
cial deficits, attention, communication, and language function. Side effects in-
cluded behavioral activation, nausea, and polyuria (51).
USE OF ANTICONVULSANTS AND MOOD STABILIZERS IN

AUTISM DISORDERS
Seizure Disorders in Autism
One frequent use of anticonvulsants in autism is in treating comorbid seizure
disorders. Seizure disorders are common in autism—approximately 20–35 % of
individuals with autism have epilepsy and up to 50% have EEG abnormalities.
The type of epilepsy varies among individuals and includes generalized, partial
complex, and absence seizures, as well as infantile spasms. Some children have
a combination of these disorders as well. Temporal-lobe focal points, as deter-
mined by EEG, are also common. There is a bimodal distribution of onset, with
peak occurrences before the age of 3 and once again at puberty. Treatment is
generally with traditional anticonvulsant medication and is discussed later in this
book. Of note, in some children with both autism and epilepsy, improvement in
both disorders is noted upon treatment of the epilepsy (52,53).
Landau-Kleffner Syndrome
Landau-Kleffner syndrome (LKS) is a rare syndrome in which normally devel-
oping children develop verbal auditory agnosia at the same time as seizure disor-
der. The sleep EEG is usually abnormal and is characterized by abnormalities
such as a continuous spike-and-slow-wave pattern, focal sharp waves with spikes,
or centrotemporal spikes. This disorder is sometimes responsive to treatment by

anticonvulsants (54).
Anticonvulsant Use in Autism Spectrum Disorders

In addition to a higher incidence of seizure disorder, individuals with autism
display a number of behaviors that could respond to anticonvulsant/mood stabili-
zation. Affective instability, tantrums, and impulsive and aggressive behavior are
quite common in both children and adults with autism spectrum disorders. A
review of case studies of individuals with autism suggested a rate of 35% with
affective disorders. In addition, there is a high rate of affective disorders among
first-degree relatives of individuals with autism, up to 35%. Traditionally these
symptoms have been addressed in other disorders by use of mood-stabilizing
medications such as divalproex sodium (Depakote) and lithium. Carbamazepine
(Tegretol) has also been used. Newer anticonvulsants such as lamotrigine and
topiramate have also been used in individual cases, but the results have not yet
been reported in the literature.
Of the mood-stabilizing medications noted above, the use of divalproex
sodium (DS) in autistic individuals has been the most extensively documented.
Several case studies have been reported in which children treated with DS for
their seizure disorder or abnormal EEGs showed improvement in their autistic
symptoms. Three cases have been described by Pliopys (55) in which autistic
children with epileptiform findings on their EEGs significantly improved when
treated with a form of valproic acid. Each child improved significantly in lan-
guage and social skills, and after treatment no longer met criteria for autism.
Childs and Blair (56) also describe dramatic improvement in 3-year-old autistic
twins who had comorbid seizure disorder. Both twins improved in language and
social skills and showed a decrease in difficult behavior.
A retrospective study of open-label treatment of DS in individuals with
autistic disorder (57) showed clinical improvement in 10 of 14 patients (71%)
5-40 years old. Of the 10 responders, four had seizure disorders or abnormal
EEGs. The improvements were seen primarily in social relatedness and repetitive
behavior, with one patient showing improvement in language skills as well. Im-
provements in associated symptoms of autism were also seen, including de-
creased impulsivity, aggression, and affective lability. Patients with seizures or
abnormal EEGs were more likely to be responders although patients without
these abnormalities also showed improvement. Side effects included weight gain,
sedation, and gastrointestinal upset. Elevated liver enzymes were seen in one
patient, otherwise no serious adverse events were reported. In addition, Hellings
et al. (58) reported on an open-label study of valproate as an add-on therapy in 10
adolescents with autistic disorders and symptoms of mania including irritability,
aggression, increased activity, and hypersexuality. The medication was found to
be safe and effective in this population at doses that produced blood levels of 75–
100 Tg/ml. Five of the patients were on other psychotropic medication, including
clonidine, lithium, thioridazine, sertraline, and methylphenidate. Sovner (59) also
reported on five cases of mentally challenged individuals with comorbid bipolar
disorder, two of whom had autism, who responded to valproate with a decrease
of their mood symptoms. No side effects are reported in this study.
Other anticonvulsants have been used to improve behavior in individuals
with autism. There is one case report (60) of two adolescent patients with autism
who received carbamazepine for treatment of “bipolar-like” affective disorders.
Both individuals evidenced decreased mood lability and a discontinuation of their
episodic mood symptoms after achieving a steady blood level of the medication.
No side effects were reported. There have been no follow-up studies examining
the efficacy of carbamazepine in ameliorating the symptoms of autism, or of
affective disorders in individuals with autism. One study of treatment of refrac-
tory seizures in children with lamotrigine showed improvement in both seizure
control and autistic symptoms in eight of the 13 autistic children in the study
(61). However a blinded, placebo-controlled 12-week study of lamotrigine did
not show any difference between lamotrigine and placebo on measures of autism
and aberrant behavior (62).
Other Mood Stabilizers in Autism

Although lithium is one of the most well-studied mood-stabilizing medications in
psychiatry, there are no placebo-controlled, blinded studies examining its efficacy
in the autistic population. Several case reports have suggested that lithium may be
effective in treating comorbid bipolar disorder in individuals with autism spectrum
disorders. Kerbeshian et al. (63) reported on two children, ages 4 and 5, with
autistic disorder and family histories positive for bipolar disorder, who responded
well to treatment with lithium at levels above 1.0 mEq/L. Both children evidenced
improvement in their language and social skills, along with a decrease in their
aggressive behavior and irritability. In addition, Steingard and Biederman (64)
reported on two autistic individuals with manic-like symptoms, one child and one
young adult, who responded to lithium by manifesting a stabilization in their mood
and improvement in their autistic symptoms. Side effects were not reported in
either study; however, the medication appeared to be well tolerated.
In addition to the above case reports, several studies on lithium use in
developmentally disordered, mentally retarded, or behaviorally disturbed children
have been published (65–68). Overall, these reports suggest that lithium is effec-
tive in reducing aggressive behavior in this population. One report (69) in young
children aged 3–6 with severe behavioral disorders, including autism and “child-
hood schizophrenia,” failed to show improvement with either lithium or chlor-
promazine, with the exception of a marked reduction of aggressive and self-
injurious behavior in one of 10 children. The patient was described as having

childhood schizophrenia but may have met criteria for autism or pervasive devel-
opmental disorder–NOS. Side effects reported in many of the children on lithium
included polyuria, polydipsia, lethargy, and tremor. Overall, lithium appears to be
effective in helping to control aggressive and self-injurious behavior in mentally
retarded individuals and in decreasing manic behavior in autistic individuals.
However, placebo-controlled, blinded studies are needed to further determine the
efficacy and safety of lithium in autistic individuals.
SUMMARY
In conclusion, although no medication is currently approved for the treatment
of autistic disorders, many medications show promise in treating the concurrent
symptoms of this disorder. In particular, the SRIs, especially fluoxetine, fluvox-
amine, and venlafaxine, have been shown to decrease repetitive and compulsive
behavior and to improve social and language abilities. Divalproex sodium seems
to be particularly useful in decreasing impulsive aggression and affective instabil-
ity, as well as for treating clinical and subclinical seizure disorders. All these
medications, however, will need to be further examined using double-blind, pla-
cebo-controlled methods to validate their efficacy and safety in treating the co-
morbid symptoms of autistic disorders.
ACKNOWLEDGMENTS
Supported in part by grants from the Seaver Foundation, the Food and Drug
Administration, the Cure Autism Now Foundation, the National Alliance for Re-
search on Schizophrenia and Depression, Eli Lilly and Company, and Abbott
Laboratories.
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13
Use of Atypical Antipsychotics
in Autism
David J. Posey and Christopher J. McDougle

Indiana University School of Medicine
Indianapolis, Indiana, U.S.A.
INTRODUCTION
The atypical antipsychotics have been very useful adjunctive treatments for autis-
tic individuals, especially when treating severe symptoms such as physical ag-
gression and self-injury. Clinical treatment, however, is sometimes complicated
by their propensity to cause weight gain and other adverse effects.
This chapter briefly reviews the pharmacology of atypical antipsychotics
and describes a rationale for their use in the treatment of autistic disorder (autism)
and related pervasive developmental disorders (PDDs). Clinical drug studies of
atypical antipsychotics in this population are reviewed in depth. Potential adverse
effects associated with atypical antipsychotics are discussed, along with recom-
mendations for their practical use in the treatment of PDDs. Finally, future direc-
tions for research are proposed.
PHARMACOLOGY OF ATYPICAL ANTIPSYCHOTICS

Atypical antipsychotics as a class are distinct from the conventional (or typical)
antipsychotics in several ways. In addition to dopamine (DA) antagonism, the
atypical antipsychotics also block serotonin (5-HT) 5-HT2 receptors. This 5-HT2
antagonism has been hypothesized to underlie the lower incidence of extrapyram-
247
248 Posey and McDougle
Table 1 Relative Receptor Affinities of Atypical Antipsychotics

Receptor Clozapine Risperidone Olanzapine Quetiapine Ziprasidone
D1 High Low High Low/mod. Low

D2 Low High High Low/mod. High
D3 High High High
D4 High High High None Mod.
D6 Mod
D7 High
5-HT1A Low/mod. High
5-HT1D High
5-HT2A High High High Low/mod. High
5-HT2C High High
5-HT3 High High Very low
5-HT6 High High High
5-HT7 High High
Alpha1 Mod./high High Mod./high Mod./high Mod.
Alpha2 Mod. High Low Mod./high Very low
Histamine1 High High High High Mod.
Muscarinic1 High Low High None Very low
D ⫽ dopamine; 5-HT ⫽ serotonin; alpha ⫽ alpha-adrenergic.

Source: Adapted from Table 5.3 in Ref. 1.
idal symptoms (EPS), as well as the increased efficacy in treating the “negative”
symptoms of schizophrenia (1, p. 105).
Clozapine, risperidone, olanzapine, quetiapine, and ziprasidone are atypical
antipsychotics that are United States Food and Drug Administration (FDA)–
approved treatments for schizophrenia. They differ in their affinities for subtypes
of receptors (see Table 1) and side-effect profile (discussed below).
RATIONALE FOR USE OF ATYPICAL ANTIPSYCHOTICS IN

AUTISM
Atypical antipsychotics are potent antagonists at 5-HT2 receptors, as well as DA
receptors. There is strong basic-science and clinical evidence of a role for both
5-HT and DA in the pathophysiology and symptom expression of autistic disor-
der. In addition, atypical antipsychotics may have certain advantages over the
typical antipsychotics for the treatment of individuals with PDDs.
Serotonin
A dysregulation in the 5-HT system has been known since Schain and Freedman’s
classic 1961 article reporting elevations in whole-blood serotonin (WBS) levels
Atypical Antipsychotics 249
in a large minority of autistic children (2). This finding has been consistently
replicated (3), although not yet fully explained. Most recently, McBride and col-
leagues (4) reported results from a study of 77 individuals with autistic disorder,
65 normal controls, and 22 prepubertal children with mental retardation (without
autistic features). In the prepubertal autistic children, significantly higher levels
of WBS were found compared with both normals and the mentally retarded con-
trol group, although the 25% elevation was less than that typically reported. Afri-
can-American and Latino children had significantly lower levels of WBS than
Caucasian children, regardless of diagnosis. The postpubertal subjects had consis-
tently lower levels of WBS than the prepubertal subjects, and this was not affected
by diagnosis or race.
Blunted neuroendocrine responses to pharmacological probes of the 5-HT
system have also been reported in children, using 5-hydroxytryptophan (5), and
in adults, using fenfluramine (6). In a placebo-controlled study, McDougle and
colleagues (7) reported that acute tryptophan depletion caused a significant in-
crease in maladaptive behaviors in drug-free autistic adults. Hollander and associ-
ates (8) also recently reported that the severity of repetitive behaviors in adults
with PDDs positively correlated with the magnitude of growth hormone response
to sumatriptan (a 5-HT1D agonist) challenge.
Several medications affecting the 5-HT system have been studied. Fenflur-
amine, an indirect 5-HT agonist, was extensively studied following an influential
report suggesting that it improved symptoms in three boys with autism (9). How-
ever, double-blind, placebo-controlled studies with parallel groups design failed
to demonstrate any significant difference between fenfluramine and placebo. It
was subsequently removed from the market over concerns about its contributions
to cardiac valve abnormalities (10).
Serotonin-reuptake inhibitors (SRIs), including clomipramine (11), flu-
voxamine (12), fluoxetine (13), sertraline (14), and paroxetine (15), have been
reported to reduce several maladaptive behaviors associated with autism. In con-
trast to fenfluramine, double-blind, placebo-controlled studies have supported the
use of clomipramine in children, adolescents, and young adults with autistic dis-
order (11) and fluvoxamine in adults (12). For a comprehensive review of these
medications in autistic disorder and related PDDs, the reader is referred to a
recent summary by Posey and McDougle (16).
Dopamine
Following demonstrations that psychostimulants (medications that in part en-
hance DA transmission) often worsen clinical symptoms and stereotypies in autis-
tic children (17) and that typical antipsychotics (DA receptor antagonists) reduce
certain symptoms associated with autism (18), studies of DA metabolism in-
creased. Cerebrospinal fluid levels of homovanillic acid (HVA), the primary me-
tabolite of central DA, were initially reported to be elevated in children with

autism (19), but these results have failed to be replicated (20). Plasma HVA was
not found to be different in autistic subjects compared with normals (21). Results
from measurements of urinary HVA have been inconsistent (3).
The typical antipsychotic medications have been extensively studied in au-
tism and appear to decrease a number of interfering and maladaptive symptoms.
Haloperidol, the best studied of these medications, has consistently been reported
to reduce hyperactivity, aggression, and stereotypical movements in controlled
studies of children with autistic disorder (18,22–24). The efficacy of haloperidol
may be due to its potent DA receptor antagonism and the positive effects that
these medications have on disorders of excessive motor movement.
Advantages
Atypical antipsychotics are associated with a lower incidence of tardive dyskinesia
(TD). This is especially important when treating PDDs because tardive and with-
drawal dyskinesias (WDs) may be more frequent in this clinical population. In a
large, prospective study of 118 children with autistic disorder treated with haloperi-
dol, Campbell and colleagues (25) found a 33.9% incidence of dyskinesias. The
majority of these were WDs and reversible; however, nine developed TD.
Atypical antipsychotics have also been reported to be better than typical
antipsychotics for the treatment of negative symptoms of schizophrenia (26).
While schizophrenia is thought to be a distinct syndrome from autistic disorder
(27), there are similarities between the negative symptoms of schizophrenia (af-
fective flattening, alogia, and avolition) and the social withdrawal often seen in
autistic disorder. This similarity led others to hypothesize that atypical antipsy-
chotics may have benefits in treating the core social impairment of autism (28).
STUDIES OF ATYPICAL ANTIPSYCHOTICS IN AUTISM AND

RELATED PDDS
Several open-label studies and one placebo-controlled study (29) have been pub-
lished describing beneficial effects of the atypical antispychotics in treating mal-
adaptive symptoms in children, adolescents, and adults with autism. These studies
are presented in Table 2. Important points are emphasized below.
Clozapine
There has been only one report of the use of clozapine to treat symptoms of
autistic disorder. Zuddas and colleagues (30) described treatment of three chil-
dren (ages 8 to 12 years) with autistic disorder who had not responded to haloperi-
dol. All three subjects showed initial improvement improving in hyperactivity,
negativism, aggression, and communication at doses of clozapine ranging from
100 to 200 mg. One subject relapsed at 5 months. Adverse effects included tran-
sient sedation and enuresis.
The side-effect profile of clozapine raises two concerns in the treatment of
individuals with autism. First, clozapine is associated with seizures at high doses.
This side effect could be important in treating autism since seizure disorders
are diagnosed in a substantial minority of these patients. Second, because of the
possibility of agranulocytosis, frequent venipuncture is needed to monitor white
blood cell (WBC) counts. This is less than desirable both in children and in those
with comorbid mental retardation because these populations are frequently unable
to fully comprehend the necessity for blood testing and are often reluctant partici-
pants. Because of this, clozapine is rarely used as an initial treatment option in
this population.
Risperidone
There have been multiple positive reports of risperidone treatment of children,
adolescents, and adults with autistic disorder and other PDDs (Table 2). Aggres-
sion is one common target symptom that improves with treatment. Others include
irritability, self-injury, sleep disturbance, repetitive behavior, and hyperactivity.
Interestingly, several studies have also reported improvements in some aspects
of social relatedness. It is unclear whether this was a direct effect of risperidone
treatment or an indirect effect due to a reduction in other maladaptive behaviors.
The most commonly reported adverse effect in these studies has been weight
gain.
Risperidone’s efficacy for treating the associated symptoms of autism has
been described in children as young as 2 years old (49), as well as adolescents
and adults. Doses of risperidone have usually been in the range of 1 to 3 mg
daily. The majority of these reports have been either retrospective or of short
duration. More recently, there has been increased interest in the efficacy and
safety of risperidone over longer durations of treatment (50).
In contrast to the large number of open-label studies of risperidone in au-
tism, there has been only one controlled study. In this 12-week, double-blind,
placebo-controlled study of adults with autistic disorder and PDD not otherwise
specified (NOS), McDougle and colleagues (29) found risperidone treatment ef-
ficacious in 8 of 14 subjects compared with none of the 16 subjects treated with
placebo. Responders were defined by a rating of “much improved” or “very much
improved” on the Clinical Global Impressions (CGI) scale (57). The mean dose
of risperidone was 2.9 mg daily. Improvement was seen in repetitive behavior,
aggression, anxiety, depression, irritability, and the overall behavioral symptoms
of autism. Risperidone was well tolerated, with mild, transient sedation being
the most frequently reported adverse effect. In contrast to studies of risperidone
in children and adolescents, weight gain was reported in only two subjects.
252
Table 2 Studies of Atypical Antipsychotics in Autistic Disorder and Related Pervasive Developmental Disorders
Medication/first No. subjects/
author age range ( years) Methodology Results Areas of improvement Side effects
Clozapine
Zuddas, 1996 (30) 3 AD (8–12) Case series 2/3 sustained improvement Aggression, communication, hyperactiv- Enuresis, transient sedation
ity, negativism
Risperidone
Vanden Borre, 1993 37 MR ⫾ autistic fea- DBPC (crossover; Risperidone ⬎ placebo Not stated Sedation
(31) tures (15–58) on concomi-
tant drugs)
Purdon, 1994 (32) 2 PDD (29–30) Case series 2/2 improved Behavior, cognition, stereotypes
McDougle, 1995 (33) 2 AD, 1 PDDNOS Case series 3/3 improved Aggression, repetitive behavior, social Transient sedation
(20–44) relatedness
Simeon, 1995 (34) 1 PDDNOS (13) Case report Improved Apathy, defiance, irritability, social
withdrawal
Demb, 1996 (35) 3 AD (5–10) Case series 3/3 improved Aggression, hyperactivity, self-injury EPS, transient sedation,
weight gain
Fisman, 1996 (28) 4 AD, 9 AS, 1 Case series 14/14 improved Agitation, anxiety, repetitive behavior, Transient sedation
PDDNOS (9–17) social awareness
Hardan, 1996 (36) 5 AD, 6 PDDNOS Open-label 8/11 improved Aggression, hyperactivity, impulsivity, Galactorrhea, weight gain
(8–17) oppositionality, self-injury
Lott, 1996 (37) 13 PDDNOS (25–49) Case series 10/13 improved Aggression, self-injury EPS, sedation, weight gain
Findling, 1997 (38) 6 AD (5–9) Open-label 6/6 improved Aggression, fearfulness, irritability, rest- Weight gain, sedation
lessness, tantrums
Frischauf, 1997 (39) 1 AD (12) Case report Improved Aggression, concentration, depression,
language
Horrigan, 1997 (40) 11 AD (6–34) Open-label 11/11 improved Aggression, self-injury, sleep Weight gain
McDougle, 1997 (41) 11 AD, 3 AS, 1 CDD, Open-label 12/18 improved Aggression, impulsivity, repetitive be- Weight gain
3 PDDNOS (5–18) havior, social relatedness
Perry, 1997 (42) 6 PDD Open-label 5/6 improved Anger, mood lability, sociability Hepatotoxicity, weight gain,
withdrawal dyskinesia
Posey and McDougle
Rubin, 1997 (43) 1 AD, 1 PDDNOS Case series 2/2 improved Aggression, hyperactivity, self-injury None
(3–5)
Cohen, 1998 (44) 3 AD, 1 PDDNOS Case series 3/4 improved Aggression, disruptiveness, self-injury Akathisia, sedation
(31–48)
Doan, 1998 (45) 1 AD (3) Case report Improved Insomnia None
McDougle, 1998 (29) 17 AD, 14 PDD-NOS DBPC Risperidone (8/14 im- Aggression, anxiety, depression, irrita- Transient sedation
(18–43) proved) ⬎ placebo (0/ bility, repetitive behavior
16 improved)
Nicolson, 1998 (46) 10 AD (4–10) Open-label 8/10 improved Aggression, autistic symptoms Weight gain
Schwam, 1998 (47) 1 AD (3) Case report Improved Food refusal
Atypical Antipsychotics
Dartnall, 1999 (48) 2 AD (27–33) Case series Maintained improvement Aggression, noncompliance, self-injury Weight gain, gynecomastia
for 2 years
Posey, 1999 (49) 2 AD (2) Case series 2/2 improved Aggression, irritability, social relat- Tachycardia, QTc prolonga-
edness tion
Zuddas, 2000 (50) 9 AD, 2 PDD-NOS Open-label 10/11 improved; 7/7 main- Anger, autistic symptoms, hyperactiv- Weight gain, facial dysto-
(7–17) tained improvement for ity, uncooperativeness nia, amenorrhea
1 year
Olanzapine
Horrigan, 1997 (51) 1 AD (10) Case report Improved Aggression, hyperactivity, sleep None
Rubin, 1997 (43) 1 AD (17) Case report Improved Aggression, mood
Malek-Ahmadi, 1998 1 AD (8) Case report Improved Aggression, hyperactivity
(52)
Heimann, 1999 (53) 1 AD (14) Case report Improved at 40 mg/day Psychosis None
Potenza, 1999 (54) 5 AD, 3 PDD-NOS Open-label 6/8 improved Aggression, anxiety, depression, hyper- Weight gain, sedation
(5–42) activity, irritability, self-injury, social
behavior
Kemner, 2000 (55) 23 PDD (children) Open-label Improved Accessibility Weight gain
Quetiapine
Martin, 1999 (56) 6 AD Open-label 2/6 improved Irritability, self-injury Behavioral activation, seda-
tion, seizure, weight gain
AD ⫽ autistic disorder; MR ⫽ mental retardation; DBPC ⫽ double-blind, placebo-controlled; PDD ⫽ pervasive developmental disorder; PDD-NOS ⫽ pervasive developmental
disorder not otherwise specified; EPS ⫽ extrapyramidal symptoms; AS ⫽ Asperger’s syndrome; CDD ⫽ childhood disintegrative disorder.
253
There have not yet been any published placebo-controlled studies of risperi-
done in children and adolescents with autistic disorder. In 1997, the National
Institute of Mental Health contracted with five university-affiliated medical cen-
ters (Indiana University, Ohio State University, the Kennedy-Krieger Institute/
Johns Hopkins University, Yale University, and the University of California at
Los Angeles) to create a Research Unit on Pediatric Psychopharmacology
(RUPP) network designed to investigate promising new drug treatments for the
maladaptive symptoms associated with autistic disorder (58). Risperidone was
chosen as the first drug to study through the RUPP network. In the first phase
of this double-blind study, 102 children and adolescents with autistic disorder
were randomized to 8 weeks of treatment with risperidone or placebo. Responders
to risperidone received an additional 4 months of treatment to examine the safety
and efficacy of risperidone over a longer duration. For a review of methodological
issues in the design of this study, the reader is referred to the article by Arnold and
colleagues (59). In this study, risperidone treatment led to significant response in
69.4% of subjects compared with the 11.5% response rate seen in placebo-treated
subjects (81).
Olanzapine
Several case reports have been published suggesting efficacy of olanzapine for
the treatment of aggression, hyperactivity, mood symptoms, sleep disturbance,
and psychosis occurring in autistic disorder (Table 2). In a 12-week, prospective,
open-label study of eight children, adolescents, and adults with PDDs (ages 5 to
42 years; five with autistic disorder, three with PDD-NOS), Potenza and col-
leagues (54) found that olanzapine (mean dose of 7.8 ⫹ 4.7 mg daily; range 5–
20 mg daily) led to significant improvement in six of the subjects based on a
rating of “much improved” or “very much improved” on the CGI global improve-
ment item. Improvement was seen in overall symptoms of autism, hyperactivity,
social relatedness, affectual reactions, sensory responses, language usage, self-
injury, aggression, irritability, anxiety, and depression. Olanzapine did not appear
to reduce interfering repetitive behavior. This is in contrast to studies showing
risperidone’s efficacy for this symptom cluster of autism (29,41). The authors
hypothesized that this may be due to risperidone’s greater affinity for the 5-HT1D
receptor (60). The 5-HT1D receptor is abundant in the basal ganglia (61), a brain
region strongly implicated in the pathophysiology of obsessive-compulsive disor-
der (62). Sedation and weight gain were the most frequent adverse effects in this
study. The weight gain was particularly concerning. The mean weight for the
group increased from 62.50 ⫹ 25.37 kg to 70.88 ⫹ 25.06 kg. Two of the six
responders (both children) discontinued olanzapine treatment following the study
due to weight gain.
In another study of 23 children with PDDs, 3 months of open-label olanza-
pine (dose range 1.25–20 mg daily) was efficacious on several measures includ-
ing the Aberrant Behavior Checklist (63) and the CGI (55). As in the above study,
weight gain was a significant adverse effect, with subjects gaining an average of
4.8 kg. To our knowledge, there have not yet been any placebo-controlled studies
of olanzapine in subjects with PDDs.
Quetiapine
Currently, there is only one report of the use of quetiapine in the treatment of
individuals with autism. Martin and colleagues (56) reported their results of a
16-week, open-label study of quetiapine (dose range 100 to 350 mg daily) in six
children and adolescents (ages 6 to 15 years) with autistic disorder. Only two
subjects were judged “responders” by the CGI global improvement item. The
other four subjects did not complete the trial of quetiapine; three dropped out
prematurely due to sedation and lack of response and another was removed be-
cause of a possible seizure. Other side effects included behavioral activation,
increased appetite, and weight gain. The investigators concluded that quetiapine
was poorly tolerated and associated with serious side effects in this clinical popu-
lation, although others have reported a different clinical impression (64). Further
studies are needed to better determine the safety and efficacy of quetiapine for
the treatment of individuals with PDDs.
Ziprasidone
Ziprasidone is the newest atypical antipsychotic to be marketed in the United
States. Studies of ziprasidone in Tourette’s syndrome are promising (65). In addi-
tion, ziprasidone may have a lower incidence of weight gain, possibly due to its
lower affinity for the Histamine1 receptor (see Table 1). Preliminary results from
a case series suggests that it may be efficacious in PDDs and not associated with
weight gain (66).
ADVERSE EFFECTS
Tardive Dyskinesia and Extrapyramidal Side Effects
Most antipsychotic medications have the potential to cause irreversible movement
disorders (e.g., tardive dyskinesia). These are especially important to recognize
in treating individuals with PDDs given the high incidence of TD and WD ob-
served with haloperidol treatment in children with autistic disorder (25). Fortu-
nately, the potent 5-HT2A antagonism of atypical antipsychotics may reduce the
risk of TD (67). However, there have been several reports of TD with risperidone
treatment (68,69), so it is important to remain vigilant in monitoring for this very
serious side effect.
Early reports of risperidone treatment of children and adolescents with vari-

ous psychiatric disorders reported a high incidence of acute EPS in contrast to
clinical experience in adults (70). This may have been due to the aggressive
dosing strategies used. Subsequent studies involving children, adolescents, and
adults with PDDs have not shown a high incidence of EPS. This is in contrast
to the rather frequent reports of acute dystonic reactions in the studies of haloperi-
dol in children with autistic disorder (22).
Weight Gain
As discussed above, weight gain has been a prominent and frequent adverse effect
associated with atypical antipsychotic treatment. The magnitude of this may be
greater in children and adolescents compared with adults. In a retrospective study
of 60 adolescent inpatients, those treated with risperidone (n ⫽ 18) gained a
mean of 8.64 kg over a 6-month observation period, compared with 3.03 kg for
those taking typical antipsychotics (n ⫽ 23) and a 1.04-kg weight loss for those
on no antipsychotic medication (n ⫽ 19) (71). Weight gain may also contribute
to the development of hyperglycemia and hepatotoxicity (see below). This is
especially concerning given that many autistic individuals treated with atypical
antipsychotics will require chronic treatment, thus predisposing the individual to
complications of obesity including hypertension, diabetes, and heart disease.
Hepatotoxicity
Concern about risperidone-induced hepatotoxicity followed a case report of two
adults with schizophrenia who developed this complication following risperidone
treatment (72). Kumra and colleagues (73) screened 13 schizophrenic children
and adolescents treated with risperidone and discovered two who had obesity,
elevated liver enzymes, and evidence of steatohepatitis. Both cases of hepatotox-
icity resolved after risperidone discontinuation and weight loss. Subsequent to
this, Szigethy and colleagues (74) reviewed the charts of 38 children and adoles-
cents treated with risperidone (mean dose 2.5 mg daily; mean duration of treat-
ment 15.2 months) and found only one subject who had an elevation in liver
enzymes (not clinically significant) in spite of significant weight gain occurring
in the group. The question as to whether to routinely monitor liver enzymes
during atypical antipsychotic treatment remains unanswered.
Prolactin Elevation
Risperidone has been reported to increase prolactin levels in some subjects and
has been associated with galactorrhea, amenorrhea, and gynecomastia. The inci-
dence of this may be lower with olanzapine. The significance of an elevated
prolactin level in the absence of clinically significant symptoms is unclear.
Cardiovascular Effects
Concerns about antipsychotics, such as thioridazine and pimozide, prolonging
the corrected QT interval and potentially leading to fatal cardiac arrhythmias have
been raised. Dose-related tachycardia and corrected QT-interval prolongation was
reported in a 2-year-old boy with autistic disorder treated with risperidone (49).
This resolved upon decreasing the dose. Finally, a case of cardiac-related sudden
death in a 34-year-old woman with schizophrenia treated with risperidone has
been reported (75). Electrocardiograms (EKGs) should be considered during the
course of treatment with risperidone, especially in the presence of tachycardia,
administration of concomitant medications with cardiac effects, or when treating
the very young.
Other Adverse Effects

The potential for life-threatening agranulocytosis with clozapine is well docu-
mented, and weekly to biweekly WBC counts are required during treatment. Pos-
sible acute leukocytopenia was reported in a 15-year-old boy with schizoaffective
disorder treated with risperidone who had previously had similar reactions to
typical antipsychotics (76). Seizures can occur with high doses of clozapine (77),
but this has only rarely been reported for other atypical antipsychotics (78). A
single case report of hemorrhagic cystitis associated with risperidone has been
reported in an 11-year-old boy (79). Symptoms began one week after initiation of
risperidone treatment and resolved one week after its discontinuation. Neuroleptic
malignant syndrome has also been reported with atypical antispychotic treatment
(80).
The majority of other adverse effects associated with atypical antipsychot-
ics (sedation, enuresis, etc.) are mild, transient, or quickly reversible upon dose
decrease or discontinuation. In general, the atypical antipsychotics represent an
improvement over the typical antipsychotics with regard to adverse effects.
ROLE OF ATYPICAL ANTIPSYCHOTICS IN THE TREATMENT

OF AUTISM AND RELATED PDD
The decision to prescribe an atypical antipsychotic medication comes after care-
fully weighing the risks and potential benefits. Atypical antipsychotics can be
very effective medications in treating severe maladaptive behaviors in children,
adolescents, and adults with autism and other PDDs. The most clinically relevant
adverse effects are weight gain and the potential to cause TD. Atypical antipsy-
chotics are best used when symptoms are of at least moderate severity and when
behavioral therapy or medications with fewer side effects have not been effective.
Informed consent should include a discussion about potential adverse effects,
especially TD. In addition, it is important for caregivers to monitor weight closely
Table 3 Recommended Atypical Antipsychotic

Dosages in Pervasive Developmental Disorders
Suggested starting Usual effective

Medication dose (mg/day)a dose (mg/day)
Clozapine 25 (12.5) 100–300b

Risperidone 0.5 (0.25) 0.5–6
Olanzapine 2.5 (1.25) 2.5–20
Quetiapine 50 (25) 75–400
a
Dosages in parentheses are those suggested for young children.
b
Limited experience with clozapine in this population.
and intervene with appropriate diet modification if needed to prevent significant

weight gain.
One must also decide on which atypical antipsychotic to use. Risperidone
is the best studied of the atypical antipsychotics for the treatment of interfering
symptoms of autism. Several open-label studies and two controlled studies have
shown risperidone to be efficacious in improving associated symptoms of autism,
such as aggression, self-injury, irritability, anxiety, sleep disturbance, and repeti-
tive phenomena. An intriguing finding in some of these studies was the reported
improvement in some aspects of social relatedness. Olanzapine and quetiapine
have been studied to a lesser extent, but are appropriate alternatives in the phar-
macotherapy of interfering symptoms of autism. Clozapine, because of its poten-
tial to cause seizures and agranulocytosis, should be reserved for the most se-
verely ill and those who do not respond to other atypical antipsychotics.
In general, the doses of atypical antipsychotics used in the published studies
have been low. Table 3 presents recommended starting and maintenance doses
based on a review of the literature and our clinical practice. In general, atypical
antipsychotics are prescribed in divided doses (twice daily), but certain patients
do better with less or more frequent dosing.
Monitoring of adverse effects is important prior to and during treatment
with atypical antipsychotic medications. Abnormal involuntary movements
should be sought and asked about at each follow-up visit. Patients and their care-
givers should be warned about the potential for atypical antipsychotics to increase
appetite and cause weight gain. Any increase in weight should prompt further
discussion and diet modification. One should also consider measuring blood glu-
cose and liver enzymes in individuals gaining weight on atypical antipsychotics.
If bradycardia or tachycardia is present at baseline or follow-up, an EKG should
be done to rule out corrected QT-interval prolongation or any other cardiac
rhythm disturbance. EKG monitoring should also be considered in treating the
very young or when prescribing risperidone concomitantly with other medica-
tions with cardiac effects. Finally, clozapine treatment requires regular monitor-
ing of WBC counts throughout treatment.
FUTURE DIRECTIONS
In contrast to the large number of case reports and open-label studies of atypical
antipsychotics in autism, there is a paucity of controlled studies. There are two
placebo-controlled studies of risperidone in PDDs. Controlled studies of olanza-
pine, quetiapine, and ziprasidone would be welcome, especially to better deter-
mine whether there are significant differences in efficacy or side-effect profile
between the atypical antipsychotics in this population.
An intriguing result of some studies of atypical antipsychotics in subjects
with PDDs is an improvement in some aspects of social impairment. This im-
provement needs to be better characterized in a systematic manner to determine
whether this is a direct effect of the atypical antipsychotic or an indirect effect
mediated through the reduction of other maladaptive symptoms. The develop-
ment of rating scales that adequately track social impairment are needed.
One important limitation of the atypical antipsychotics is their potential to
cause weight gain, especially in children and adolescents. Ziprasidone, a new
atypical antispsychotic, may have a lower propensity to cause weight gain and
should be thoroughly studied in this population. Finally, more research is needed
to determine the mechanism underlying the weight gain associated with atypical
antipsychotics and to develop preventive strategies.
ACKNOWLEDGMENTS
We thank Ms. Teresa Sasher for assistance in preparing this chapter. This work
was supported in part by an Independent Investigator Award–Seaver Foundation
Investigator from the National Alliance for Research in Schizophrenia and De-
pression (NARSAD) (Dr. McDougle), the Theodore and Vada Stanley Research
Foundation (Dr. McDougle), Research Unit on Pediatric Psychopharmacology
(RUPP) Contract NO1MH70001 from the National Institute of Mental Health to
Indiana University (Drs. McDougle and Posey), a Daniel X. Freedman Psychiat-
ric Research Fellowship Award (Dr. Posey), a NARSAD Young Investigator
Award (Dr. Posey), the State of Indiana Division of Mental Health, and Depart-
ment of Housing and Urban Development Grant B-01-SP-IN-0200 (Representa-
tive Dan Burton).
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14
Treatment of Seizures in Children with
Autism Spectrum Disorders
Roberto Tuchman
Miami Children’s Hospital
Miami, Florida, U.S.A.
INTRODUCTION
Autism is a complex developmental disorder that is behaviorally defined. Autism
spectrum disorder (ASD) is an inclusive term that includes a heterogeneous group
of children with similar symptoms and multiple biological etiologies. As a group,
children with ASD are characterized by early onset of deficits in verbal and non-
verbal communication skills, sociocommunicative function, and repetitive behav-
iors. The behaviors characteristic of ASD are secondary to central nervous system
dysfunction. The well-documented increased frequency of seizures and abnormal
electroencephalographic (EEG) findings in ASD provided some of the initial his-
torical support that has led to the now accepted concept of ASD as a neurobiologi-
cal disorder.
EPILEPSY AND EEG ABNORMALITIES IN AUTISM SPECTRUM

DISORDERS
The association between autism and epilepsy is now well accepted. Numerous
investigators have documented that there is an increased frequency of seizures
in ASD. There appears to be a two-peak distribution to seizures in ASD. One
peak occurs in infancy prior to age 5 years and the other occurs in adolescence
after age 10 years (1,2). There is evidence to suggest that the secondary peak
265
266 Tuchman
that occurs in adolescence may be associated with the degree of cognitive dys-
function, but further research to answer this observation is needed (3).
The prevalence of epilepsy in ASD varies among studies, from a low of
7% to a high of 42% (4–6). The two major risk factors for epilepsy (defined as
more than one seizure) in ASD are level of cognitive functioning and the combi-
nation of cognitive and motor deficit. The combination of severe mental defi-
ciency and motor deficit is associated with epilepsy in 42% of individuals with
ASD (3). On the other hand, in children with ASD without severe mental defi-
ciency, motor deficit, associated perinatal or medical disorder, or a positive family
history of epilepsy, seizures occur in 6% of individuals, a figure analogous to
the 8% frequency of seizures in children with dysphasia without autism (3). It
is important to realize, then, that the same risk factors for epilepsy—that is, cogni-
tive and motor deficits—are also the risk factors for seizure occurrence in ASD.
In children with ASD and without severe cognitive or motor deficit, the
only other risk factor for seizures was the type of language dysfunction. In a
study that classified 197 autistic children without severe mental retardation or
hearing impairment into four language subtypes based on a modified clinical
classification scheme proposed by Rapin and Allen (7), the highest percentage
of epilepsy (41%) occurred in children with the most severe deficit in the compre-
hension of language: verbal auditory agnosia (VAA) (8). VAA is a severe re-
ceptive and expressive language disorder believed to arise from inadequate audi-
tory or phonological processing that engages activity in primary or secondary
auditory cortices (9,10). VAA can occur in a developmental or acquired form
(11). In the acquired form it is the language type associated with Landau-Kleffner
syndrome (LKS) and also known as acquired epileptic aphasia (12). LKS is a
rare epileptic syndrome, and clinical seizures are not a necessary part of the diag-
nosis. It is defined by having an acquired aphasia in association with an epilepti-
form EEG demonstrating spikes or spike-and-wave discharges over the temporal
and parietal head regions. It is important to point out that up to 25% of individuals
with this diagnosis do not have clinical seizures. This suggests that, at least in this
subgroup of individuals, it is the “subclinical seizures” as indexed by epileptiform
activity on the EEG and not the clinical seizures that are responsible for the
language and behavioral manifestations that occur in LKS (13). The importance
of LKS to epilepsy in ASD is that approximately 30% of individuals with autism
have a regression in language and an acquired aphasia (VAA) similar to that in
LKS. Some studies have shown no significant difference in the prevalence of
epilepsy between a group of youngsters with a history of regression and those
without regression (14). Other studies have reported that epilepsy is significantly
more frequent in those with a history of regression than in those without regres-
sion (31% in those with regression vs. 15% in those without) (15). VAA is an
important predictor of outcome in all children with language dysfunction and
Treatment of Seizures 267
seizures, and in a recent study the duration of language loss in a group of children
with developmental or acquired VAA was not influenced by the persistence of
clinical seizures. Premorbid language and behavior were more predictive of lan-
guage recovery in this group of children with VAA (16). Future studies will need
to look at children with language-epilepsy syndromes in terms of not only vari-
ables such as regression and seizures but also type and degree of language dys-
function and the behavioral profile.
To summarize, the variability in seizure frequency reported by different
investigators in ASD is likely due to three risk factors: 1) the age groups studied,
with the higher percent of seizures being found in studies that included adolescent
and young adults, 2) the level of cognitive function, with the higher percent of
seizures found in studies that include lower-functioning individuals, and 3) the
type and degree of language dysfunction, with the highest percent of seizures
occurring in individuals with VAA (3).
Epileptiform abnormalities on EEG (interictal spikes or spike-and-wave
complexes) are even more frequent in youngsters with ASD than clinical epi-
lepsy. In both their 1991 and 1997 studies, Tuchman and colleagues found epilep-
tiform abnormalities in 8% of autistic, nonepileptic children (3,14). In the 1997
study, when only those youngsters with EEG data were considered, the percent-
age of autistic, nonepileptic youngsters with epileptiform abnormalities rose to
15%. Furthermore, in that study there was an equal proportion of children with
epileptiform EEGs among those with a history of regression and those without.
However, when children with a history of epilepsy were excluded from the analy-
sis, there was a statistically significant increased risk of epileptiform abnormali-
ties in youngsters with a history of regression (19% in those with regression vs.
10% in those without). Kawasaki and colleagues, in a cohort of 158 individuals
with multiple sleep-recorded EEGs, found epileptiform EEG abnormalities in
60.8% (17). Lewine and colleagues found epileptiform EEG activity in 68% of
50 children with ASD and a history of regression. Utilizing the experimental,
relatively new technique of magnetoencephalography (MEG), they demonstrated
epileptiform activity in 82% of these 50 children (18). Although several studies
have documented a high frequency of epileptiform abnormalities in individuals
with ASD without seizures, especially with prolonged sleep studies, the role that
these interictal discharges have in accounting for the behavioral and language
dysfunction characteristic of ASD has not been elucidated.
Children with ASD, regression (an acquired VAA), and an abnormal epi-
leptiform EEG without clinical seizures have been described as having autistic
epileptiform regression (AER), and treatment strategies used in LKS have also
been tried in a limited number of studies in this subgroup of children. Although
there are clinical and electrophysiological similarities, there are important differ-
ences between AER and LKS (19). Some of these differences include:
268 Tuchman
1. Age of language regression: the mean age of language regression in

ASD is 21 months, and over 90% of children with ASD who undergo
a regression do so before age 3 years. In LKS the mean age is between
5 and 7 years, and only 12 to 14% of children regress before age 3
years. Because of the early onset of language loss in ASD, when it
does occur it usually entails the loss of single words only. In LKS the
regression of language may be more dramatic since children are usually
older and may have more developed vocabulary and communicative
use of language.
2. Behavioral profile: all children with ASD meet the behavioral profile
consistent with a diagnosis of ASD, while in LKS language is primarily
affected and the behavioral profile is less likely to include the qualita-
tive social deficits and repetitive behaviors present in ASD.
3. EEG findings: in ASD the epileptiform activity associated with re-
gression of language is a predominantly centrotemporal spike that
can be infrequent and intermittent. In LKS the EEG findings are pre-
dominantly temporal spikes that are usually frequent and less likely
to be intermittent (20). This differentiation of LKS and AER is an
important one to establish, because treatment strategies effective in
one of these disorders may not necessarily be appropriate for the other
disorder.
TREATMENT ISSUES
The treatment of children with autism and seizures or with autism and epileptiform
abnormalities on EEG recordings without seizures needs to be discussed within the
context of the limited knowledge presently available on the role that epilepsy, both
clinical and subclinical, has on the behavioral and language profile of children with
ASD. In general terms, all types of seizures are reported in children with ASD,
and the treatment of these seizures per se is not usually difficult or different from
treatment of seizures in the general non-ASD population (21).
The observation that epileptiform discharges on the EEG without clinical
seizures can cause behavioral, language, and cognitive impairments (22) raises
the question of whether this is occurring to some extent in complex behavioral
disorders such as autism. For example, children can have language impairment
secondary to an active epileptic focus in an area subserving language even in
the absence of clinical seizures (23). There are also well-documented reports of
patients with benign partial epilepsy of childhood with centrotemporal spikes
who have fluctuating disturbances such as intermittent drooling, oromotor dys-
praxia, dysphagia, and transient isolated deterioration of speech production in
association with epileptic discharges without clinical seizures (24). Similar corre-
lations have recently been made with respect to electrical status epilepticus dur-
ing slow-wave sleep (ESES) (25–27). The concept that transitory changes in
higher cortical functions can be secondary to EEG discharges not accompanied
by seizures is not new; it was proposed over 50 years ago (28). The term transient
cognitive impairment (TCI) is used to describe individuals with epileptiform
EEG discharges in association with a momentary disruption of adaptive cerebral
function (29). It has also been shown that focal interictal spikes may transiently
disrupt aspects of cortical functioning corresponding to the neuroanatomical lo-
cation in which they occur (30,31). It is important to emphasize that at present
we do not have scientific evidence to either refute or confirm the premise that
interictal epileptiform discharges play a role in the symptoms and signs that
occur in ASD.
Treatment studies in children with AER are preliminary, limited, and contro-
versial. Published studies have included the use of valproic acid in a total of four
case reports of children with ASD without clinical seizures but with epileptiform
abnormalities on the EEG (32,33). There is one published report of the use of corti-
costeroids in a child with autism, VAA, and regression but with a normal EEG (34).
There are numerous abstracts and anecdotal reports on the use of valproic acid and
the use of steroids in children with AER, but without controlled clinical trials on
the use of these interventions no definite recommendations can be made.
There are also a few studies on children with autistic regression and epi-
lepsy (clinical seizures) that suggest that aggressive treatment such as epilepsy
surgery is associated with positive outcomes (35,36). It is important to re-empha-
size that these case reports were of children with intractable epilepsy and, as
such, the surgery was being done for treatment of the seizures and not for the
symptoms of autism. One study suggests that after surgical intervention in chil-
dren with ASD and intractable seizures, the seizures may improve but the ASD
symptoms do not (37). A recent publication reported improvement in language
and behavior in 12 of 18 children with ASD and a history of regression in lan-
guage, multifocal epileptiform EEGs, and symptoms of possible subclinical sei-
zures (staring episodes, rapid eye blinking) without clinical seizures who under-
went multiple subpial transections (18). This latter study not only is controversial
but highlights how the lack of controlled clinical trials using good assessment
tools may lead to inappropriate irreversible and potentially life-threatening inter-
ventions in children with ASD. The use of surgery in children with LKS to treat
the symptoms associated with this disorder is still not well validated and contro-
versial in its own right (38), and its use in children with ASD without intractable
epilepsy is presently unacceptable.
Many clinicians believe that it is reasonable to consider a trial of anticon-
vulsants or steroids in a child with ASD and an epileptiform EEG who has a
history of regression of language and VAA. In the absence of intractable clinical
seizures there is no scientific evidence to suggest that epilepsy surgery is a treat-
ment option in children with ASD. In addition, the evidence to suggest that treat-
270 Tuchman
ment of epileptiform discharges thought to be producing specific dysfunction in

selected aspects of cognition, language, or behavior makes a positive difference
is limited and anecdotal, and a better understanding is needed of the role that
interictal epileptiform discharges play in cognition, behavior, and language.
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cephalographic paroxysmal activities in the frontal area emerged in middle child-

hood and during adolescence in a follow-up study of autism. J Autism Dev Disord
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fusion? Dev Med Child Neurol 2000; 42(5):349–353.
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61–77.
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30(5):564–568.
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Dis 1939; 89:690–691.
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558–559.
15
Treatment of Movement Disorders in
James Robert Brǎsić

The Johns Hopkins University School of Medicine
Baltimore, Maryland
Bellevue Hospital Center and
New York University School of Medicine
I. INTRODUCTION
Autism spectrum disorders are conditions usually presenting in early childhood
characterized by marked impairments in social interaction and communication
(1) and by extremely restricted and odd interests and activities (2). For at least
a subgroup of individuals, movement disorders are salient manifestations of the
condition. For example, anomalous motions are prominent presenting (3) and
persisting signs (4–7) in some persons with autism spectrum disorders (8). Move-
ment disorders occur in people with autism spectrum disorders both as manifesta-
tions of the underlying conditions and as adverse effects of therapeutic interven-
tions (9).
This chapter reviews the treatment of movement disorders in autism spec-
trum disorders. For information on the autism spectrum disorders, please refer
to chapters 1–6. This chapter concentrates on diagnostic and therapeutic aspects
of common movement disorders in autism spectrum disorders.
The goal of this chapter is to integrate the latest scientific findings on the
treatment of movement disorders in autism spectrum disorders in clinically mean-
273
274 Brǎsić
ingful ways. It is aimed at professionals who are treating individuals with autism
spectrum disorders, with an emphasis on effective strategies targeting specific
symptoms. The chapter provides clear empirical pharmacological, behavioral,
and language-based data from several related disciplines to support optimal clini-
cal care in the treatment of movement disorders in autism.
Section II discusses the characteristics of movement disorders commonly
seen in autism spectrum disorders. Section III addresses the diagnosis and treat-
ment of movement disorder commonly appearing as adverse effects of pharmaco-
logical therapy for autism spectrum disorders, namely, acute dystonia (acute dys-
tonic reactions), acute akathisia, and withdrawal and tardive dyskinesias. Section
IV begins with a discussion of the diagnosis and treatment of the movements
typically observed in Rett’s disorder and autistic disorder, and concludes with a
discussion of the diagnosis and treatment of self-injurious behavior. Although
only a minority of individuals with autism spectrum disorders experience self-
injury, self-injurious behaviors merit inclusion in this chapter because of the re-
sultant morbidity and mortality.
Please refer to Table 1 at the end of the chapter for abbreviations utilized
herein.
II. MOVEMENT DISORDERS: DEFINITIONS

Movement disorders are pathological conditions characterized by abnormalities
in motion, posture, sensation, and utterance. They are thus unwanted occurrences
that take place during waking hours when the individual is at rest as well as when
performing an activity. Typically, movement disorders subside with sleep. In
fact, the occurrence of motions, postures, sensations, or utterances during sleep
raises the likelihood of other conditions, such as seizure and sleep disorders.
Since seizure disorders are common in people with autism spectrum disorders
(26), both seizure disorders and movement disorders are likely to occur concomi-
tantly in these individuals. Therefore, people with autism spectrum disorders are
likely to have movement and seizure disorders together (refer to Chapter 14 for
further information).
Differentiating abnormal from normal movements in persons with autism
spectrum disorders may be challenging. Throughout their lifespan most individu-
als exhibit occasional unusual movements that do not interfere with social, occu-
pational, recreational, or educational performance. For example, people may oc-
casionally experience isolated forceful eye blinks, which could be classified as
tics if repetitive. Single nonrecurring movements are not classified as movement
disorders, which typically occur daily. Particularly at the start and the end of life,
most individuals may demonstrate motions, postures, and utterances that would
be abnormal in typical adults (7).
Movement Disorders 275
A. Classification of Movement Disorders as Hyperkinesias

and Bradykinesias
Movement disorders can be dichotomously subdivided into hyperkinesias, char-
acterized by faster, more frequent, and more intense movements, and bradykine-
sias, characterized by slower, less frequent, and less intense movements. Bradyki-
nesias may occur in individuals with autism spectrum disorders (5,6,27–31);
however, they are relatively less common than hyperkinesias. On the other hand,
hyperkinesias are common in people with autism spectrum disorders. Therefore,
this chapter reviews only hyperkinesias in Rett’s disorder, autistic disorder, other
pervasive developmental disorders, and related conditions. Thus, bradykinesias
are beyond the scope of this chapter. Additionally, movements associated with
other psychiatric, neurological, and medical disorders (11,27–31) are excluded
from this review. Also, movement disorders without an apparent physical basis—
e.g., psychogenic movement disorders, conversion disorders, somatization disor-
der, hypochondriasis, other somatoform disorders, malingering, and factitious
disorders (2,11,27–32)—are not discussed in this chapter.
B. Classification of Hyperkinesias
Hyperkinesias can be subdivided broadly into seven common subgroups (defined
in Table 12). While there is considerable overlap among some of the subgroups,
they can be separated by component descriptive terms (11). The relationships of
the common hyperkinetic movement disorders are represented in Figure 1 (11).
Some movement disorders, such as tics (11,17,42), may be temporarily
suppressed by the individual. This may happen when the person is concentrating
intensely on intellectual or physical activities. Although tics may be temporarily
suppressed, the person usually experiences an urge to perform the suppressed
tic. When the tic is eventually expressed, the individual then feels a sense of
relief. Additionally, a volley of intense tics is likely to occur when the suppressed
tic is finally expressed. On the other hand, akathisia is a movement disorder
characterized by the subjective experience of inner restlessness and an urge to
move. While individuals with akathisia typically also exhibit objective evidence
of the disorder, such as marching in place, akathisia may be present in a mo-
tionless individual (34,35,37).
Movement disorders in autism spectrum disorders can be broadly classified
into two types: 1) movement disorders resulting from treatments for autism spec-
trum disorders and 2) movement-disorder manifestations of autism spectrum dis-
orders. Because movement disorders occur frequently as adverse effects of the
pharmacotherapy of autism, this review includes this serious subgroup.
Motion analysis of home videotapes of infants facilitates the diagnosis of
autism. For example, Teitelbaum and colleagues (3) have suggested that anoma-
276 Brǎsić
Figure 1 Venn diagram of the relationships among hyperkinetic movement disorders

utilizing the defining traits of the Movement Disorders Checklist (MDC) (Table 7). (From
Ref. 11.)
lies in the motions of babies who later exhibit autism may be diagnostic of autism
in infancy (43). Although this report holds great promise for the early identifica-
tion of children at risk to develop autism, the number of reported cases is small.
Also, the methods utilized by Teitelbaum and colleagues are highly specialized.
Because therapy for autism spectrum disorders, particularly pharmacother-
apy, can cause many motions, postures, sensations, and utterances, it may be
difficult to distinguish movements caused by autism from movements caused
by treatment for autism spectrum disorders. Although the movement disorders
resulting from autism spectrum disorders are poorly described, they may be pa-
thognomonic for autism (4). While the movements resulting from autism cause
individuals to stand out in crowds, the movements typically do not bother the
individuals themselves. The movements resulting from autism may upset family
members because these movements identify the individuals as psychiatric patients
to the general public. These movements may constitute a stigma as a sign to the
community of the deviance of the person (44). Movements resulting from autism
may be embarrassing to the families and caregivers without harming the individ-
ual. On the other hand, some movement disorders resulting from autism can cause
serious tissue damage to the individual (24) (see Section IV.B), to others (45)
(Section IV.C), and to property (Section IV.D). In particular, the movement disor-
ders classified as self-injurious behaviors may cause serious morbidity and mor-
tality and therefore demand immediate intervention to prevent permanent tissue
damage (24) (Section IV.B).
The second group of movement disorders in autism is caused by treatments
for autism. Medications, particularly typical neuroleptics such as chlorpromazine
(Thorazine), haloperidol (Haldol), and thioridazine (Mellaril), are responsible for
many movement disorders that are difficult to treat. Pharmacological agents that
block postsynaptic dopamine type 2 (D2) receptors in the brain, such as the typical
neuroleptics, often result in tardive dyskinesia, a movement disorder that usually
occurs within 3 months of the discontinuation of the agent. Additional informa-
tion about the diagnosis and treatment of tardive dyskinesia and associated condi-
tions can be obtained in a recent review (11). A related group of movement
disorders includes withdrawal dyskinesias, movement disorders occurring as the
dose of the pharmacological agent is reduced or discontinued. People with autism
spectrum disorders appear to be exquisitely sensitive to adverse effects from med-
ication. Individuals with autism appear prone to develop tardive dyskinesia—
abnormal movements occurring after the causative medication has been discon-
tinued—when treated with medication, especially dopamine antagonists. Since
tardive dyskinesias can be painful and extremely troubling to the individual, they
often lead people with autism and their families and caregivers to seek treatment
(11).
Clinicians are hampered in their quest for effective treatments for move-
ment disorders in people with autism spectrum disorders by the dearth of pub-
lished reports. Therefore, there exists a need for publication of clinical trials of
therapeutic interventions for movement disorders in autism spectrum disorders.
Publication of even single case reports of negative clinical trials of pharmacologi-
cal and other interventions is justified and needed to advance knowledge about
beneficial and adverse effects of interventions for autism spectrum disorders (16).
The desperation of parents of children with Rett’s disorder, autistic disorder, and
other autism spectrum disorders may lead them to employ novel interventions
to attempt to help their children. Publication of the results of these efforts is
crucial to distinguish beneficial therapies from harmful ones. Publication of case
reports of adverse effects of treatment on these children is valuable to alert clini-
cians and parents about harmful effects of new agents. Clinicians and researchers
can benefit from the regular use of established rating scales (37), including the
Abnormal Involuntary Movement Scale (AIMS) (Table 2) (10,11), the Children’s
Global Assessment Scale (CGAS) (Table 3) (12), the Family Compliance Check-
list (FCC) (Table 4) (13,14), the Hillside Akathisia Scale (HAS) (Table 6)
(11,15), the Movement Disorders Checklist (MDC) (Table 7) (11), the Myoclo-
278 Brǎsić
nus Versus Tic Checklist (MVTC) (Table 8) (17), the Psychoactive Medication
Quality Assurance Rating Survey (PQRS) (Table 9) (11,18), the Timed Self-
Injurious Behavior Scale (TSIBS) (Table 10) (24), and the Timed Stereotypies
Rating Scale (TSRS) (Table 11) (11,25) to substantiate clinical trials of therapeu-
tic interventions.
III. MOVEMENT DISORDERS RESULTING FROM TREATMENT

OF PEOPLE WITH AUTISM SPECTRUM DISORDERS
The majority of treatment-related movement disorders in people with autism
spectrum disorders are caused by administration of dopamine antagonists. This
group of pharmacological agents acts by binding to the postsynaptic D2 receptor.
Dopamine is a neurotransmitter that carries messages from one neuron (nerve
cell) to another in the nervous system. The dopamine is released by the presynap-
tic membrane of the neuron to cross the synapse (the space between neurons) to
attach to receptors on the postsynaptic membrane of the neuron receiving the
nervous impulse. D2 antagonists act by binding to the D2 receptors on the postsyn-
aptic membrane. The endogenous dopamine released by the presynaptic neuron
into the synapse cannot attach to the postsynaptic D2 receptors already occupied
by the dopamine antagonist. Therefore, dopamine antagonists block the action
of endogenous dopamine on the postsynaptic neuron. Dopamine antagonists thus
act by blocking the postsynaptic D2 sites, thereby reducing stimulation of the
postsynaptic D2 receptors. In time, postsynaptic D2 receptors typically become
supersensitive to dopamine. In other words, after being blocked by D2 antagonists,
postsynaptic D2 receptors react excessively to small amounts of dopamine. Post-
synaptic D2 receptor hypersensitivity may therefore contribute to the development
of tardive dyskinesias (11) and other movement disorders.
Typical neuroleptics, however, have other effects besides the beneficial ef-
fects. There are three common adverse effects of dopamine antagonists mani-
fested by movement disorders in people with autism spectrum disorders: 1) acute
dystonia (acute dystonic reaction), 2) acute akathisia, and 3) withdrawal and tar-
dive dyskinesias (Table 12).
The best public-health approach to all three movement disorders is the pre-
vention of the occurrence of the conditions. This can be accomplished by
avoiding the use of dopamine antagonists altogether. Before prescribing psycho-
active medications including dopamine antagonists, prudent clinicians verify that
treatment with psychoactive medications is appropriate for the patient. Since mul-
tiple steps comprise the decision process to treat a patient with psychoactive
medication, confirmation of the need for psychopharmacotherapy is facilitated
by the utilization of a reliable protocol. For example, administration of the PQRS
(Table 9) (11,18) before the institution of treatment with dopamine antagonists
helps to determine whether treatment with psychoactive agents is truly indicated.
If the administration of dopamine antagonists is mandated by the clinical condi-

tion of the patient, then the use of newer agents—such as atypical neuroleptics,
e.g., clozapine (Clozaril), risperidone (Risperdal) (46,47), and olanzapine (Zy-
prexa) (48)—is desirable because these agents are associated with a much lower
risk of movement disorders than typical neuroleptics. However, the high cost and
limited availability of atypical neuroleptics may prohibit their administration in
some locations.
Gradual introduction of dopamine antagonists to the patient helps minimize
adverse effects. Additionally, utilization of the lowest dose to produce a beneficial
effect for the shortest period of time is a strategy to prevent adverse effects,
including movement disorders. Regular administration of a reliable procedure to
evaluate the suitability of treatment with psychoactive medications, e.g., the
PQRS (Table 9) (11,18), throughout the course of pharmacological treatment
helps assess whether continued treatment with dopamine antagonists is indicated.
Additionally, utilization of an overall evaluation of the individual’s level of func-
tioning, such as the CGAS (Table 3) (12) is a useful approach to regularly deter-
mine the usual psychological status of an individual. The CGAS is well suited
for individuals with autism spectrum disorders. It can be readily administered in a
few seconds by an experienced rater. Additionally, success of therapy frequently
depends on the participation of the family. Therefore, regular administration of
the FCC (Table 4) (13,14) before and during the course of treatment is helpful
to predict whether the therapy ordered by the physician will actually be adminis-
tered. Thus, regular use of the PQRS, the CGAS, and the FCC are helpful to
assess a child’s need for beginning and continuing treatment with psychoactive
medication.
A. Acute Dystonia
Acute dystonia (acute dystonic reaction) is characterized by the sudden forceful
contractions of muscle groups (Table 12). This may present within hours of the
first dose of a dopamine antagonist or at any moment in the course of neuroleptic
treatment.
Although rare, a dystonic contraction blocking respiration may occur. This
constitutes a medical emergency. A tracheostomy (insertion of a tube into the
windpipe, below the larynx) may be required to permit ventilation to prevent a
fatality.
Several muscle groups are commonly affected by acute dystonia. For exam-
ple, the eye muscles may be affected, causing the eyes to deviate upward, down-
ward, or to the side. The neck muscles may also be affected. The head may extend
backward (retrocollis) or to either side (torticollis). In addition, the tongue and
mouth muscles may be affected, preventing the person from swallowing or speak-
ing. Lastly, arm and leg muscles may be affected. The occurrence of acute dysto-
280 Brǎsić
nia can be extremely upsetting. The person may believe that an outside force is
causing contraction of the muscles, and may be unable to verbalize the experi-
ence, especially if speech is affected. The experience of acute dystonia may cause
severe distress, escalating anxiety and further increasing muscular contraction.
To minimize the discomfort and upset associated with the occurrence of
acute dystonia, people who are being treated with dopamine antagonists are
warned before the institution of treatment that dystonic reactions are common
side effects that can be effectively treated. They are educated about the nature
of acute dystonia and advised that they may experience sudden muscle spasms.
They are warned to immediately notify staff if they experience symptoms of
acute dystonia in order to receive appropriate interventions. Furthermore, when
it appears that patients are suffering from acute dystonia, they are educated that
they are likely experiencing a temporary side effect of medication that can be
quickly relieved. The need for medication is re-evaluated and, if possible, therapy
with the causative agent is reduced or discontinued.
Patients may be unable to accurately articulate the possibility that they are
experiencing an acute dystonic reaction. Instead, they may indicate that they are
having trouble talking, swallowing, breathing, or walking, or that they are experi-
encing pain from muscular contraction. There may be no localizing neurological
signs. Therefore, experienced clinicians have a particularly high level of suspi-
cion that acute dystonia may be occurring in patients who are being treated with
dopamine antagonists for the first time. Intramuscular administration of 2 mg
benztropine mesylate (Cogentin) or 25 mg diphenhydramine hydrochloride (Ben-
adryl) for sudden apparent subtle deficits in speech or walking often immediately
confirms the diagnosis of acute dystonia by relieving the symptoms. Usually the
patient reports immediate relief. If symptoms are not helped, then another cause
must be sought.
Acute dystonia can be effectively treated by the administration of anticho-
linergic medications. Oral doses of anticholinerigic agents usually cause the dys-
tonia to subside in an hour or so. Patients often prefer parenteral administration
of the anticholinergic to obtain the faster beneficial effect. Since anticholinergic
medications produce unpleasant adverse effects, they are not routinely prescribed
until the individual develops at least one dystonic reaction. Therefore, unneces-
sary administration of anticholinergics, and the risk of their adverse effects, can
be avoided for many.
B. Acute Akathisia
Akathisia is a sense of inner restlessness and an urge to move resulting from
treatment with medications, commonly dopamine antagonists. Unlike the other
common movement disorders discussed in this chapter, which are characterized
by motions of the patient, objective evidence of movement is not required to

diagnose akathisia. Instead, the subjective experience of restlessness inside and
the urge to move is the hallmark (2,11,33–36). Fidgeting movements, including
marching in place or walking back and forth, are common in these patients. The
requirement that the patient verbalize a sense of inner restlessness and an urge
to move to strictly diagnose akathisia cannot be met in persons who lack the
cognitive capacity to express those concepts in words. In such cases, probable
objective akathisia and pseudoakathisia can be diagnosed (11,33–36). Although
some clinicians treating clients with mental retardation have proposed broader
definitions of akathisia without the expression of the symptom of inner restless-
ness and the urge to move, these notions are not accepted by experts in movement
disorders. Utilization of strict criteria for akathisia requiring the subject’s verbal-
ization of inner restlessness fosters precision in the diagnosis of akathisia. There-
fore, clinicians benefit from the utilization of the rigorous diagnostic criteria for
akathisia to verify the presence of the condition.
However, in practice, a therapeutic trial for possible akathisia is often ap-
propriate. Seasoned clinicians have a particularly high level of suspicion for
akathisia among individuals newly treated with dopamine antagonists and other
psychoactive medications (49). If a person with an autism spectrum disorder or
other developmental disability begins to exhibit an increase in motor activity
level, including pacing and marching in place, after starting treatment with dopa-
mine antagonists, akathisia may be present. Institution of treatment for that possi-
ble condition may then be indicated. While marching in place may be a behavioral
gesture, prudence dictates ruling out the possibility of a treatable condition such
as akathisa.
β-blockers are a reasonable initial treatment for akathisia or probable objec-
tive akathisia. For example, 10 mg of propranolol (Inderal) by mouth four times
daily is a sensible starting dose. The dose may be gradually increased. Some
patients require a month or two or longer to demonstrate full beneficial effects
of treatment with β-blockers.
Patients must be warned about possible adverse effects of β-blockers, in-
cluding drowsiness and light-headedness. Specifically, patients are warned to
avoid driving or operating dangerous machinery (e.g., lawnmowers) when taking
β-blockers until they have adapted to a dose. Patients are also warned about the
possibility of postural hypotension. They are advised to avoid jumping out of
bed for fear of precipitating a faint. Rather, a cautious clinician recommends
slowly sitting from lying, then dangling the legs over the side of the bed briefly
while adjusting to the upright posture. Also, patients treated with β-blockers are
advised to slowly rise to standing from sitting. If they experience light-head-
edness, they are advised to sit or lie down immediately to abort a syncopal epi-
sode. Before commencing therapy with β-blockers, experienced clinicians con-
282 Brǎsić
sider both 1) the effects of β-blockers on concurrent medical conditions, such as

diabetes mellitus, congestive heart failure, and asthma, and 2) the interactions of
β-blockers with the pharmacotherapy of those concurrent medical conditions.
An effective long-term treatment strategy for acute akathisia is the gradual
reduction and eventual discontinuation of the causative pharmacological agent.
Administration of the PQRS (Table 9) (11,18,50) regularly during the course of
treatment with dopamine antagonists is helpful to determine whether continued
treatment is indicated.
C. Withdrawal and Tardive Dyskinesias

Withdrawal dyskinesias are hyperkinetic movement disorders (Table 12) that
emerge when the dose of a pharmacological agent, usually a dopamine antagonist,
is being reduced. Tardive dyskinesias are hyperkinetic movement disorders (Ta-
ble 12) that occur after treatment for at least 3 months with a pharmacological
agent, usually a dopamine antagonist, has been discontinued. Tardive dyskinesias
usually develop within 4 weeks of the cessation of drug treatment (11).
Although some individuals may require long-term treatment with neurolep-
tic medications to control behaviors that are potentially damaging to themselves,
other people, and property, and behaviors that are intolerable in the community,
every person receiving treatment with psychoactive medication merits careful
review of the need for continued medication therapy on a regular basis, at least
annually. This can be accomplished through administration of a reliable instru-
ment to assess the propriety of treatment with psychoactive medication such as
the PQRS (Table 9) (11,18,50). If treatment with neuroleptic medication is indi-
cated, then administration of an atypical neuroleptic may be an appropriate thera-
peutic intervention to avoid the risk of tardive dyskinesias (11) and other adverse
effects of typical neuroleptics.
Withdrawal and tardive dyskinesias are considered together because they
are related phenomena that occur at different points during the course of treatment
with psychoactive medications. For simplicity, the following discussion of tardive
dyskinesias applies also to withdrawal dyskinesias.
The classic manifestations of tardive dyskinesia are buccal, lingual, facial,
and masticatory movements. The person typically exhibits uncontrolled writhing
movements of the mouth, tongue, jaw, neck, and face. The buccal and lingual
movements display what has been called a “fly-catcher tongue.” A related mani-
festation is described as “rabbit syndrome”—small, quick movements of the
nose, lips, and mouth. There may be associated choreic movements of the extrem-
ities. The finger movements may resemble those of a pianist or guitarist (11).
In addition to the classic manifestations of tardive dyskinesia, the common
movement disorders (Table 12) can all occur as tardive effects of the withdrawal
and discontinuation of psychoactive medication (11).
Tardive dyskinesias are frequently refractory to all therapeutic attempts.

They may remain as permanent manifestations of treatment with traditional neu-
roleptics throughout a person’s life. The oral, buccal, lingual, and facial move-
ments are so characteristic that tardive dyskinesia can often be diagnosed by the
movements alone. In fact, tardive dyskinesia can be diagnosed in complete
strangers at a distance. Although one may not know the causative agent, the
syndrome of tardive dyskinesia may be blatant to an experienced observer. Addi-
tionally, the presence of tardive dyskinesia also leads to the likely diagnosis of
schizophrenia or other chronic mental disorder, such as schizoaffective disorder,
that requires long-term administration of neuroleptics. For years, people with
schizophrenia were treated with high doses of typical neuroleptics. Thus, the
presence of a tardive dyskinesia suggests that the individual received the diagno-
sis of schizophrenia and subsequent treatment with traditional neuroleptics for
an extended period of time. The tardive dyskinesia is often a bizarre posture that
causes the person to stand out in a crowd. While tardive dyskinesias may not
bother the individuals, they frequently bother family, friends, and neighbors (11).
Thus, a person with tardive dyskinesias may suffer the stigma of presumed mental
illness in the community (44).
Treatment of tardive dyskinesias is a challenging problem. Prevention is
desirable. Regular administration of the PQRS (Table 9) (11,18,50) helps to as-
sess the need for continued treatment with psychoactive medication. Necessary
medications should be prescribed at the minimal effective dosages (51). Care is
needed to avoid exceeding maximal recommended dosages of all medication (51).
If not needed, the causative agents should be gradually tapered in dose and finally
totally discontinued. Sudden discontinuation of psychoactive medication should
be avoided because abrupt cessation of neuroleptics may precipitate an exacerba-
tion of psychological symptoms, including hallucinations and delusions. Senior
citizens, particularly women, are at greater risk to develop tardive dyskinesia.
Children with autism, particularly girls (52), are prone to develop tardive dyskine-
sias after long-term administration of haloperidol (53). Prenatal and perinatal
complications predispose children with autism to develop tardive and withdrawal
complications when exposed to haloperidol (52,54), Young men are prone to
develop tardive blepharospasm and tardive dystonia. If neuroleptics are required,
then use of newer atypical neuroleptics, such as risperidone (46,47) and clozapine
should be considered (55). Care must be exercised—especially with clozapine,
which requires regular hematological monitoring to prevent fatal adverse effects,
including agranulocytosis (11).
To prevent medicolegal problems, patients and guardians provide written
informed consent before and throughout the course of treatment with psychoac-
tive agents, particularly neuroleptics. The need for treatment with psychoactive
agents should be verified before and throughout the course of treatment, for exam-
ple, by administration of the PQRS (Table 9) (11,18,50). Since family compliance
284 Brǎsić
with recommended treatment, including pharmacotherapy, is crucial to the suc-

cess of therapeutic interventions with people with autism spectrum disorders,
assessment of this parameter by administration of the FCC (Table 4) (13,14) at
the start, during the course, and at completion of therapy is indicated. In addition
to obtaining written informed consent before starting treatment with psychoactive
medication, cautious clinicians document on videotape the explanation of the
risks and benefits of treatment with psychoactive agents and alternative treat-
ments—including no treatment—to the patient and family (6).
The risk of tardive dyskinesia may remain a permanent disfiguring mani-
festation of typical neuroleptic treatment. Since reasonable alternatives exist in
the form of atypical neuroleptics, treatment with traditional neuroleptics may be
hard to justify unless expense or availability prohibit the use of alternative agents
(11).
IV. MOVEMENT-DISORDER MANIFESTATIONS OF AUTISM

SPECTRUM DISORDERS
A. Movements Without Property Destruction or Harm to Self
or Others
1. Movements of Rett’s Disorder
Rett’s disorder is a condition affecting primarily girls, with onset in early child-
hood characterized by the loss of developmental skills and a decrease in growth
of the head and brain. The disorder is characterized by the development in early
childhood of decrements in head growth, loss of purposeful hand movements,
lack of coordination in gait and trunk movements, and marked impairments in
social interactions and communication (2). Individuals with Rett’s disorder de-
velop severe psychomotor retardation (2). Stereotyped hand movements are com-
mon (2); patients typically have midline hand movements resembling washing
or wringing of hands. Some individuals may also manifest tics since families
manifest both Rett’s and Tourette’s disorders (56).
Dysfunction of cholinergic regulation of cerebral cortical development
(57), particularly in the forebrain, is hypothesized to result in the decreased
growth of the brain common in early childhood of those with Rett’s syndrome
(58). Diagnostic criteria recently proposed for the disorder and its variants can
be obtained through the IRSA at www.rettsyndrome.org. Mutations in the X-
linked gene that encodes the methyl-CpG binding protein 2 (MeCP2) resulting
in alterations of chromatin structure (59) are present in the majority of individuals
with Rett’s disorder (60–62). Impairments in signal transduction within the ner-
vous system (63) are likely to result from the MeCP2 mutations. Studies of mice
deficient in MeCP2 (64) suggest that MeCP2 is critical to the functioning of
mature neurons (65–67) and that MeCP2 deficiency results in instability of brain
functioning (68). Databases of MeCP2 mutations in Rett’s disorder (69–71) are
maintained at http://homepages.ed.ac.uk/skirmis and http://mecp2.chw.edu.au.
Dysfunction of excitatory neurotransmission is implicated in the pathogen-
esis of Rett’s disorder by the abnormalities in the densities of N-methyl-D-
aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA), and gamma-aminobutyric acid (GABA) in the superior frontal gyrus
of people with the disorder (72). Impaired cerebral metabolism, particularly in
the frontal (73) and parietal lobes and the insular cortex, likely play a role in the
pathogenesis (74). Dysfunction in dendritogenesis is hypothesized to occur in
Rett’s disorder (75). Reduced cerebral bloodflow in both hemispheres probably
also contributes to the stereotyped hand movements (76).
Reductions in 1) AMPA and NMDA receptor densities in the putamen and
2) kainate-type glutamate receptor densities in the caudate nucleus are hypothe-
sized to contribute to the hand movements of Rett’s disorder (77). Altered dopa-
minergic neurotransmission in the striatum is hypothesized to contribute to the
movement disorders (78,79). These typically do not bother the individual, but
they may cause the person to stand out in a crowd. In this sense, the movements
may be disfiguring mannerisms that contribute to the stigma of mental illness
(44). The hand movements may additionally bother family, friends, and teachers.
Since there is no danger to the individual from the hand movements, no treatment
for the patient is indicated. Instead, the family, friends, teachers, and neighbors
may benefit from counseling about the benign nature of the movements. They
may be helped to learn to accept the movements.
People with Rett’s disorder typically can receive medical and surgical inter-
ventions when indicated. For example, general anesthesia with halothane, nitrous
oxide, and isoflurane has been successfully performed on a subject with Rett’s
disorder (80). Patients with Rett’s disorder require supervision around the clock
because they are unable to care for themselves.
Further information about Rett’s disorder can be obtained from the Rett
Syndrome Research Foundation (RSRF), 4600 Devitt Drive, Cincinnati, OH
45246, (513) 874-3020, at www.rsrf.org, and from the International Rett Syn-
drome Association (IRSA) at www.rettsyndrome.org.
2. Movements of Autistic Disorder
A wide variety of movements have been associated with autism spectrum disor-
ders. Some, such as tics (81–84), may represent other disorders, such as Tou-
rette’s syndrome (42,85), that may coexist with autism spectrum disorders (Table
12). Further information about tics and Tourette’s syndrome may be obtained
from the Tourette Syndrome Association, Inc., 42-40 Bell Blvd., Bayside, NY
11361, (718) 224-2999, www.tsa-usa.org.
286 Brǎsić
Additionally, repetitive movements often are carried out over and over by
persons with autistic disorder. The movements are often conducted in a ritualistic
manner consistent with compulsions. Orchestrated sequences of coordinated
movements—such as repeatedly dropping rocks from a particular height, repeat-
edly flushing the toilet while watching the water go down the drain, and repeat-
edly touching walls or spinning objects—have been classified as compulsions or
complex tics. Administration of diagnostic procedures designed for obsessions,
compulsions (86,87), tics (42,88,89), and other adventitious movements (11,37)
can be modified for the limitations of people with autism spectrum disorders to
obtain assessments with a modicum of reliability (28,37,90). Tics (42), Tourette’s
disorder, obsessive-compulsive disorder, and other comorbid disorders can ap-
propriately be treated with the usual therapies for those conditions.
The most common movements in autistic disorder, however, are an array
of motions categorized as stereotypies (40,41,91–93). Several specific motions
have been identified in autism spectrum disorders (4,94–96) and other neuropsy-
chiatric disorders (95). However, stereotypies occur spontaneously in humans
(97,98) and animals (99). Table 13 contains additional information about stereo-
typies. Some stereotypies, especially those of a complicated nature, may be also
classified as compulsions and complex tics (42,88,89).
Stereotypies in autism spectrum disorders typically do not bother the indi-
vidual. Although they may cause the person to stand out and to be identified as
a mental patient, they usually do not cause injury to the person or others. Parents,
family, teachers, neighbors, and friends may object to the presence of stereotypies
in part due to the associated stigma of mental illness (44). However, stereotypies
that do not harm self or others can usually be ignored. While treatments such as
dopamine agonists (100), dopamine antagonists (101), serotonergic agents (102),
an analog of adrenocorticotrophic hormone (103), naltrexone (104), and venlafax-
ine (105) may at least temporarily ameliorate stereotypies, they are associated
with adverse effects themselves (106). Although often effective in alleviating
stereotypies in children with autistic disorder (107), clomipramine has serious
side effects (106,108–112), including seizures and cardiac events. Therefore, use
of newer serotonergic agents, such as fluoxetine and fluvoxamine (113,114), may
be an appropriate initial approach (102,106). (Refer to Chapter 12 for further
information about the administration of serotonergic medications.) Since seroton-
ergic dysfunction characterizes a group of individuals with autism spectrum dis-
orders, caution must be exercised in the administration of selective serotonin-
reuptake inhibitors (SSRIs) because dyscontrolled behaviors may result from
their use. Utilization of rating scales for adverse effects of SSRIs before starting
treatment and regularly throughout the course of treatment (108,115) facilitates
the early identification of adverse effects so that appropriate interventions can
be instituted.
Since stereotypies in autism spectrum disorders do not usually hurt the

individual or others, consideration in the preparation of a treatment plan and
individual educational plan should be given to therapy without medication. Be-
cause any medication is associated with possible adverse effects, expected bene-
fits of pharmacotherapy must be weighed against potential side effects. People
with autism spectrum disorders appear to be particularly sensitive to medication,
so the likelihood of the development of adverse effects may be an appropriate
consideration. The major effective treatment approach to autism spectrum disor-
ders—early intervention (116) with individualized special education incorporat-
ing intensive psychological and behavioral training (5,6,117)—is an appropriate
tool to utilize for the stereotypies that a person with autism spectrum disorders
may exhibit. Experienced teachers and workshop instructors can help people to
learn effective, constructive alternative behaviors to stereotypies (118,119). For
example, jogging has reduced stereotypies in a child with autism (120). Addition-
ally, the presentation of smaller tasks and the administration of instructional
prompts (121,122) may minimize the performance of stereotypies and maximize
the work productivity of persons with autism (123). Since behavioral strategies
lack the risk of medication side effects, they are often preferred to pharmacother-
apy to eliminate stereotypies (102). Virtual environments and other technological
developments offer promise in the treatment of stereotypies and other movements
in people with autism spectrum disorders (124).
Additionally, parents and friends may benefit from counseling to learn that
most stereotypies are not harmful to self or others and, therefore, can be tolerated
in some situations. Exceptions exist when the behaviors are not tolerated by the
community, such as masturbation in public, or when the behaviors may result in
damage to the self, such as self-injurious behaviors (Section IV.B), to others
(Section IV.C), or to property (Section IV.D).
B. Self-Injurious Behaviors
While self-injurious behaviors—chronic movements causing external or internal
trauma on a mechanical basis—present challenges to classification (125), a subset
of these activities meet the criteria for stereotypies. Therefore, stereotypical be-
haviors resulting in injury to self are discussed in this chapter. Self-injurious
behaviors are also classified as self-mutilative and self-abusive behaviors
(126,127). Unlike most stereotypies in autism spectrum disorder, self-injurious
behaviors are serious problems requiring immediate intervention to prevent mor-
bidity and mortality. Fortunately, most individuals with autism spectrum disor-
ders never exhibit self-injurious behaviors. Those who do, however, are likely
to have additional deficits, including seizure disorders, language disorders, visual
impairments, and profound mental retardation (128–131). Self-injurious behav-
288 Brǎsić
iors are among the most challenging manifestations of autism spectrum disorders,
consuming large amounts of human and fiscal resources while causing great
suffering and disfigurement (132). In addition to afflicting people with autism
spectrum disorders, self-injurious behaviors are serious public-health problems
affecting patients with mental retardation (133), Tourette’s disorder (134,135),
Lesch-Nyhan syndrome (136), Cornelia de Lange syndrome (154), frontal-lobe epi-
lepsy (138), and other neuropsychiatric disorders (135). Self-injurious behaviors
also consume enormous amount of caregiver time. The direct and indirect costs
of treatment and management of self-injurious behaviors amount to billions of
dollars annually (132). These behaviors must be differentiated from the self-stim-
ulation occasionally seen in infants and toddlers, which is time-limited and never
inflicts permanent harm.
Prevalence rates of self-injurious behaviors range from 8% to 40% among
persons with mental retardation and other developmental disabilities. The preva-
lence roughly correlates with the degree of mental retardation, a possible cause
of the discrepant findings in different settings (132,137,139–145).
Self-injurious behaviors involve most bodily parts and functions. The com-
mon forms include head banging, hand biting, self-scratching, self-hitting, eye
gouging, and rectal digging. Less common forms of self-injury include pica (the
ingestion of nonnutritive substances) (146), coprophagia (the ingestion of feces),
and aerophagia (the swallowing of air) (147). Rumination (the ingestion of regur-
gitated food) is also occasionally classified as a self-injurious behavior. Some of
the more common sequelae of self-injurious behaviors are listed in Table 14.
These behaviors are a major roadblock for successful community placement of
affected individuals.
Animal models have been developed for self-injurious behavior. Head
banging (148) and other forms of self-injury have been observed in socially de-
prived monkeys (149). By analogy, humans may respond to a socially isolated
environment by self-injurious behavior as a form of self-stimulation (150).
Some individuals exhibit the desire to perform self-injuring behaviors de-
spite a myriad of attempted therapeutic interventions. Despite various hypotheses
(151) and clinical observations (152–154), the etiology of self-injurious behav-
iors in people with autism spectrum disorders and other neuropsychiatric disor-
ders is poorly understood.
Understanding the biological etiologies (155) of self-injury in people with
autism spectrum disorders can be fostered by examination of other genetically
distinct syndromes with self-injury (156), including the Lesch-Nyhan (136,152,
153), Cornelia de Lange (154), and Riley-Day (familial dysautonomia) syn-
dromes. A striking condition with self-injury is the Lesch-Nyhan syndrome, an
X-linked recessive disorder of males resulting from an absence or deficiency of
hypoxanthineguanine phosphoribosyltransferase (HGPRT), an enzyme to metab-
olize purine, a product of normal metabolism, to uric acid (136,152,153). Hall-
marks of the Lesch-Nyhan syndrome include mental retardation, choreoathetoid

movements, hyperuricemia, and severe self-mutilation, such as lip, tongue, and
finger biting, eye gouging, and head banging. Hypothesized neurochemical etiol-
ogies of the self-mutilation that is characteristic of the syndrome include dysfunc-
tion of the metabolism of uric acid, dopamine (157–160), and serotonin (135,157,
158,161).
Dysesthesias are hypothesized to be present in some people with autism
spectrum disorders who manifest self-injurious behaviors. Compulsive self-
injurious behavior targeted toward body parts manifesting neuropathic pain in
humans of normal intelligence has been hypothesized to be equivalent to autot-
omy in animals. Marked improvement has been obtained through successful treat-
ment of the underlying painful dysesthesiae (162).
Another biological line of inquiry into the basis of self-injury in autism
spectrum disorders is the theory that vestibular stimulation by repetitive move-
ments reinforces the behavior (163). This may be a manifestation of an innate
neural basis for rhythmic behavior in animals (164) and may explain in part the
increased head banging seen in some with otitis media.
An alternative hypothesis to explain self-injurious behaviors in people with
autism spectrum disorders utilizes the endogenous opiate theory, which postulates
either an excess or a deficiency of these naturally occurring peptides (165). If
levels of endogenous opiates are low, then self-injurious behavior is hypothesized
to be reinforced by the production of normal levels. On the other hand, if the
levels of endogenous opiates are high, then receptors are hypothesized to be sub-
sensitive. Therefore, self-injury may raise receptor input to a normal level to
relieve a sense of dysphoria and to produce normal feelings of pleasure regula-
tion. This hypothesis is substantiated by the observation that children and animals
raised in isolation display self-injurious behaviors.
People with autism spectrum disorders may demonstrate a variety of activi-
ties that might cause themselves harm, including poking the eyes, the anus, and
other body parts, skin picking, self-biting, punching and slapping of the head
and other parts of the body, head-to-object banging, body-to-object banging, lip
chewing, removal of hair and nails, and teeth banging (24). Several strategies
have been employed to assess self-injury, including frequency counts (24,126,
143,166–169), symptom checklists (24,126,143,170–172), global scores of over-
all impairment (2,12,173–176), and assessments of surface damage (177) devel-
oped from methods of assessment of physical injury (178-184). To objectively
assess individuals with self-injurious behavior in clinical settings, practitioners
need both cross-sectional and longitudinal measurements. For this purpose, the
TSIBS (Table 10) (24,185) and the Global Self-Injurious Behavior Scale (GSIBS)
(Table 5) (12,88,175,177) are invaluable. The TSIBS gives a measure of the
extent of self-injury during a 10-minute observation period in the clinic, providing
an objective measure of the status of self-injurious behaviors at a point in time.
290 Brǎsić
The GSIBS gives a longitudinal picture of the self-injury exhibited by the patient
in the past week. It is completed by the clinician, utilizing all sources of informa-
tion after a thorough interview and examination of the patient and an interview
with the caregivers, guardians, teachers, neighbors, and all others who have con-
tact with the patient. Clinicians assessing and treating people with self-injurious
behaviors benefit from the administration of the TSIBS and the GSIBS before
treatment begins and regularly during the course of treatment to assess its effects
(24,185).
The occurrence of self-injurious behaviors requires immediate intervention
to prevent morbidity and mortality. However, the nature of optimal treatment is
moot. Several treatment modalities have been suggested for self-injurious behav-
ior in people with autism spectrum disorders (132,186). However, poor methodol-
ogy hinders the objective assessment of many reports (187).
Psychiatric inpatient units may be reluctant to admit patients with self-
injurious behavior for several reasons. First, observation of the behavior is likely
to upset other patients and visitors. Second, self-injurious behaviors can disrupt
scheduled ward activities. Third, the need for immediate intervention requires
the active participation of multiple staff members at a moment’s notice. Fourth,
these patients typically require one-to-one observation by a staff member to pre-
vent injury. Fifth, many staff members lack training in the management of self-
injurious behaviors. These concerns on the part of administration and staff at
psychiatric facilities are understandable.
Therefore, because of the dearth of psychiatric inpatient facilities available
to treat self-injurious behaviors in people with autism spectrum disorders, there
exists a need for specialized inpatient programs for their evaluation and treatment.
For example, the Kennedy-Krieger Institute in Baltimore, Maryland, has a unit
where patients stay for days, weeks, or longer for the evaluation and treatment of
self-injurious and other challenging behaviors. However, because many patients
cannot readily travel to specialized units, particularly for an inpatient stay of
weeks or months, alternative strategies are needed. The shortage of such treatment
facilities is a problem that remains to be adequately addressed and resolved by
the policy-makers and planners of health care in many locations. Out of despera-
tion, some parents are forced to improvise physical restraints, including tying
together a child’s hands to prevent face slapping and eye poking or wrapping a
child in a blanket to prevent head-to-object or body-to-object banging. At-
tempting to handle a child with self-injurious behavior is a tremendous burden
on parents who are typically already exhausted by the burden of caring for a
severely disturbed child. Family situations may be complicated by physical abuse
when a frustrated parent loses control in attempting to handle a child with self-
injurious behavior who appears recalcitrant to all therapeutic interventions (6).
Adequate inpatient treatment facilities are needed for these patients. Referral to
a specialized facility such as the Kennedy-Krieger Institute may be the appro-
priate action regardless of the distance involved. Although passive euthanasia is

practiced in some regions, active therapeutic interventions by specially trained
experts in autistic disorder and other developmental disabilities are preferable.
1. Behavioral Interventions
Behavior modification (188–193) employs the principle that the frequency of a
behavior will increase if it is rewarded and decrease if it is not rewarded. For
instance, a patient in a bleak environment may enjoy the staff attention that results
from self-injury. Alternatively, a patient may learn that onerous chores can be
avoided through self-injury. Program adjustment resulting in less desirable conse-
quences may then reduce or eliminate the occurrence of self-injury. Since behav-
ioral programs may require considerable staff intervention, a Staff Intensity Scale
has been developed (194).
Behavioral intervention applied consistently at home and at school by per-
sons experienced in the application of techniques for people with pervasive devel-
opmental disorders is probably the most generally effective therapeutic approach
for autism spectrum disorders (195). By consistently applying behavioral inter-
ventions on a regular basis at home, school, and work, and in other settings, the
onset of acute episodes of self-injurious behavior can frequently be aborted. Also,
the institution of behavioral techniques as soon as the diagnosis of autism spec-
trum disorder is made helps minimize the morbidity and mortality of the child
and the family. Since self-injury may represent an attempt to communicate basic
needs, an assessment of the possible intended communication may facilitate more
appropriate communication (196,197). Behavioral strategies may be more diffi-
cult to apply and less effective for older children and adults.
In higher-functioning persons with autism spectrum disorders, a token
economy is often helpful to lessen or abolish self-injurious behaviors. Patients
are given tangible rewards for on-task behaviors. That is, they are differentially
reinforced for behaviors other (DRO) than self-injury (198,199) and for behaviors
that are incompatible (DRI) with self-injury. The rewards take the form of items
that are intrinsically pleasurable, such as food and playing cards, or they may be
tokens for exchange for privileges or gifts. The form of the rewards varies ac-
cording to the developmental level of the subject. When self-injury occurs, the
subject is punished by forfeiting tokens or relinquishing rewards.
Refer to Chapter 17 for further information about this mainstay of the treat-
ment of autism spectrum disorders. Since self-injurious behaviors demand imme-
diate cessation, behavioral therapy may not be effective for acute intervention.
Behavioral methods have been classified as reduction or enhancement ap-
proaches (132).
Behavior-reduction approaches: These techniques are negative conse-

quences following the occurrence of self-injurious behaviors.
292 Brǎsić
Aversion therapy. While behavioral interventions (see Chapter 17) typi-

cally employ positive rewards to obtain the desired responses, the effects may
take weeks and months of training. Self-injurious behaviors may be refractory
to the usual behavioral interventions (Section IV.B.1), physical restraints (below),
and pharmacotherapy (Section IV.B.6.). In such situations, application of aver-
sive techniques may result in cessation of behavior that could injure the person.
Although unavailable at the Kennedy-Krieger Institute, the Johns Hopkins Hospi-
tal, the Johns Hopkins Medical Institutions, the Johns Hopkins University, Belle-
vue Hospital Center, and New York University, aversive therapy is reported to
be an effective intervention for challenging behaviors including self-injurious
behaviors. While aversive therapy is illegal in some locations and controversial
in others (200), a comprehensive discussion of self-injurious behavior includes
mention of this disputatious technique.
Punishment—the application of a noxious stimulus, such as an electric
shock, immediately after self-injury—is a quick, effective method of eliminating
the behavior (193,201,202). One aversive approach is the administration of a
spray of water from a water pistol to the nose or face (198,203). Other aversive
techniques include the application of a small current of electricity to the skin,
resulting in a small electric shock. Loud bursts of white noise have also been
employed as an aversive stimulus (204).
Aversive techniques are illegal in some locations, and clinicians must know
and follow local laws. While there is potential for abuse and misuse by untrained
individuals, aversive approaches, as noted above, are sometimes effective (205).
Referral of subjects to inpatient facilities experienced in the practice of aversive
therapy may be appropriate for people with autism who exhibit self-injurious
behaviors unresponsive to alternative treatments.
Physical restraints. Because of the risk of morbidity and mortality as a
result of a bout of self-injurious behavior, prompt, effective treatment is required.
Physical intervention by one or more adults may be needed, and use of a camisole,
straitjacket, or wrist and ankle restraints considered. The rules and regulations
of the relevant agency and the government must be followed when physical re-
straints are administered. Restraints should be applied for the shortest duration
possible, and must be removed immediately when the risk of self-damage has
subsided. Also, the subject must be assessed regularly while restraints are in place
to verify the absence of any serious physiological effects of the intervention.
Vital signs should be monitored closely while restraints are applied. Evidence
of a serious physiological consequence, such as an elevation of heart or respira-
tory rate or temperature, requires immediate assessment and intervention. Since
cardiac arrest may result from the utilization of physical restraints, the cardiovas-
cular status of an individual in restraints must be carefully monitored and the
restraints may need to be released. Training is needed to avoid accidental injury
in the application of physical restraints (206). Interventions must be individually
tailored to the needs of the person exhibiting the self-injurious behaviors.
As noted above, the local statutes must be obeyed in the application of

physical restraints; clinicians must be aware of the applicable legislation. For
example, some states prohibit the use of physical restraints for persons with men-
tal retardation and other developmental disabilities. In such regions alternative
strategies, including behavioral interventions (Section IV.B.1) and pharmacother-
apy (Section IV.B.6) may be considered. However, physical restraints may be the
only effective acute treatment for some individuals with self-injurious behavior.
Transfer of the patient to a facility experienced in the administration of physical
restraint to persons with autism spectrum disorders who exhibit self-injurious
behavior may be an appropriate plan of action to abort possible deleterious out-
comes such as blindness, permanent physical disability, and death.
Overcorrection: In this procedure, the “the environmental effects of the
undesirable behavior are corrected and desirable behaviors are thoroughly re-
hearsed or practiced (e.g., cleaning up their own clutter and the clutter made by
others)” (Ref. 132, p. 68). Patients may be physically forced to perform actions
opposite to the unwanted behaviors (207).
Protective intervention. Protective clothing (208), tubing (209), helmets
(210), gloves (211), and other devices have been employed to prevent the self-
destructive actions of persons with autism spectrum disorders (132).
Specific self-injurious behaviors can often be effectively handled by physi-
cal devices custom-made for the individual. For example, a patient with head
banging may be given a padded football helmet (210). Additionally, splints can
be manufactured to keep arms extended at the elbow for individuals who perform
self-injurious behaviors with their hands, including face slapping and eye poking.
In many cases the devices must be tailored to the physical dimensions of the
individual. The devices should be utilized for the shortest period of time required.
They can be removed at night when the subject sleeps as well as for meals. In
combination with behavioral therapy, physical devices may be effective strategies
for dealing with self-injurious behaviors. The use of the physical restraints can
usually be diminished and eliminated when the target self-injurious behaviors
subside. While the physical devices are being used, the person must be regularly
assessed to verify the absence of serious physiological effects.
Elimination of reinforcing sensory stimulation. In some individuals with
autism spectrum disorders, visual, tactile, and other sensations produced by self-
injurious actions and other self-stimulatory behaviors (212) appear to reinforce
the unwanted behaviors. For this reason, visual screening (203,213–215) and the
removal of other sensory input (216,217), such as extinction of other sensations
(218–220), have been utilized to eliminate the target behaviors (132).
Behavior-enhancement approaches: Differential reinforcement of

other (DRO) behavior (201,221–228) and differential reinforcement of incompat-
ible (DRI) behaviors (201,226,229) are common forms of behavior-enhancement
techniques employed for people with autism spectrum disorders. For example,
294 Brǎsić
participation in physical exercise is incompatible with self-injurious behaviors

and may diminish the return of self-injurious behaviors when the exercise stops
(230).
2. Educational and Training Techniques
The goal of educational approaches is to teach the individual constructive activi-
ties that will be valuable for daily functioning. Initially a functional analysis
(231) is performed to identify variables maintaining self-injury (189,232–234).
Classroom training with an individual educational program helps persons to learn
worthwhile activities (235). Since self-injurious behavior may represent an at-
tempt of persons with autism spectrum disorders to communicate (236), they
may be taught more effective ways of functionally communicating their needs
(234,237–243).
3. Ecological Approaches
Since particular environmental stimuli may trigger self-injurious behaviors in
some individuals with autism spectrum disorders, ecological approaches strive
to optimize the settings in which a person functions (132,244).
4. Surgery
Surgery as a form of treatment for self-injurious behavior is typically used when
all else has failed. For example, extraction of teeth is a treatment for intractable
self-biting (135).
5. Psychodynamic Psychotherapy
Psychodynamic theorists have viewed self-injury as an individual’s attempt to
alleviate guilt, displace anger and resentment of others, and establish body reality
or ego boundaries (245,246). However, these perspectives do not result in effec-
tive treatment techniques. On the contrary, substantial increases in self-injurious
behaviors have resulted from attempts to provide comfort and reassurance to such
individuals.
6. Pharmacotherapy
Self-injurious behaviors are an emergency demanding effective intervention. Al-
though possible short- and long-term adverse consequences of pharmacotherapy
need to be considered, the need to prevent damage to the individual justifies
consideration of interventions that may produce later unwanted effects. Guide-
lines for the utilization of psychoactive agents for self-injury in people with au-
tism spectrum disorders and other developmental disabilities are being developed
(247,248).
Animal studies suggest that compulsive biting in monkeys with ventrome-
dial thalamic lesions might result from stimulation of supersensitive dopamine
type 1 (D1) receptors by dopamine agonists. This theory is substantiated in ani-

mals by the beneficial effect of fluphenazine (249).
Control may be obtained by administering potent neuroleptics, such as flu-
phenazine (250), and benzodiazepines. For example, adults with acute self-injuri-
ous behavior may attain a remission after the administration of 5 mg haloperidol
and 2 mg lorazepam intramuscularly every 2 to 4 hours. Vital signs must be
closely monitored. Because cardiorespiratory arrest is a possible outcome, staff
must be trained in advanced cardiorespiratory life support. The atypical neurolep-
tic risperidone has been reported to relieve self-mutilation in rats (251) and men
with autism disorder (252) and in adults with mental retardation (253). Risperi-
done has also been found effective in reducing large-amplitude stereotypies in a
4-year-old boy with autism (254) and to safely lead to behavioral improvements
in young children with autistic disorder (46,47). Interactions of risperidone and
other agents must be considered by clinicians prescribing pharmacotherapy
(255,256). Treatment with clomipramine (257), other serotonergic agents (see
Chapter 12), olanzapine (258) and other atypical neuroleptics (259) (Chapter 13),
divalproex sodium (260,261) and other anticonvulsants (Chapter 12), and other
pharmacological treatments (Chapter 16) can reasonably be considered to abort
self-injurious behaviors. Interactions of SSRIs with concomitant medications
must be considered to determine appropriate dosages (262,263). If a seizure disor-
der is present, the self-injurious behavior may be a manifestation of partial sei-
zures with complex symptomatology, so assessment with simultaneous videotape
and electroencephalographic monitoring and treatment with anticonvulsants (see
Chapters 12 and 14) are appropriate.
Use of β-blockers, including propanolol (264), and opiate antagonists, in-
cluding naloxone hydrochloride (Narcan) and naltrexone hydrochloride (Trexan),
may be helpful for self-injurious behaviors. Both naloxone and naltrexone have
been reported to help prevent respiratory failure in adults with chronic obstructive
pulmonary disease, possibly through central endorphin pathways (265). Although
beneficial effects of naloxone on healthy adults (266,267) and on adults with
tardive dyskinesia (268) and with cognitive deficits secondary to electroconvul-
sive treatments (269) have not been demonstrated in anecdotal reports, parenteral
naloxone has been reported to prevent stereotypies in rats (270) as well in humans
(168) with mental retardation (168,169) and other developmental disabilities
(271). However, administration of naloxone has been reported to increase the
occurrence of self-injury in a girl with moderate mental retardation and autism
(272). Nevertheless, the self-injury was dramatically reduced with the administra-
tion of naltrexone in doses of 50 mg/day (1.2 mg/kg/day) (272).
Naltrexone, an oral opiate antagonist, has the advantage of route of admin-
istration over naloxone, an opiate antagonist requiring parenteral administration.
There is a risk of idiosyncratic reaction to naltrexone (273). Although apparently
ineffective for parkinsonian symptoms (274,275), naltrexone has been found
296 Brǎsić
helpful in anecdotal reports to treat human immunodeficiency virus (HIV) disease

(276) and secondary hypothalamic amenorrhea (277) and to control symptoms
of bulimia (278) and postconcussion syndrome (279). Naltrexone has been re-
ported to reduce self-injurious behavior (280) in people with mental retardation
(126,281–283) and autism (284). Additionally, naltrexone has been reported to
help many individuals with autistic disorder to reduce fidgety and hyperactive
behavior (285) and to control stereotypies (286), including self-injurious behav-
iors (173,287–292). Oral treatment of children may begin with 12.5 mg twice
daily, to be increased in 3 weeks to 25 mg twice daily if there is not a full clinical
response. Oral treatment of adolescents may begin with 25 mg twice daily, to
be increased in 3 weeks to 50 mg twice daily in the absence of a full remission
of symptoms (115).
Additionally, benzodiazepines (293), β-blockers, lithium (264), anxiolytics,
antihistamines, and other pharmacological agents (294–302) have been found to
be effective for the treatment of self-injurious behaviors in some individuals with
autism spectrum disorders.
C. Aggression Toward Others

Rarely do stereotypies in people with autism spectrum disorders appearing in the
form of behaviors—e.g., spitting, biting, and scratching—cause harm to others
(45). There are often behavioral signs to warn that violence toward others is
likely to occur (206). These resemble self-injurious behaviors (see Section IV.B)
because they require immediate intervention to prevent morbidity or mortality
to others. Another similarity to self-injurious behaviors is the refractory nature
of these stereotypies to therapeutic interventions. A variety of medications, in-
cluding dopamine antagonists, have been found to reduce aggression (303), at
least temporarily. Potential adverse effects of therapy must be weighed against
possible benefits. The above discussion of self-injurious behaviors applies to ste-
reotypies manifested by aggression toward others. Physical devices (IV.B.1) can
be manufactured to control aggressive behaviors. For example, helmets with
facemasks or biteplates interrupt attempts of the individual with autism to spit
on or bite others.
D. Property Destruction
Rarely, stereotypies exhibited by people with autism spectrum disorders result
in potential property destruction. For example, repeated touching, hitting, or tap-
ping an object may cause it to break. Because such movements can quickly cause
severe damage, immediate intervention is needed. The discussions of self-injuri-
ous behavior (Section IV.B) and aggression toward others (Section IV.C) also
apply to stereotypies causing property damage.
V. SUMMARY
Movement disorders are a prominent feature of autism spectrum disorders. They
constitute a manifestation of the underlying autism spectrum disorder as well as
an adverse effect of many pharmacological interventions commonly utilized for
autism spectrum disorders. Unless a comprehensive movement-assessment bat-
tery is performed and recorded at baseline before the administration of any thera-
peutic intervention, clinicians may be unable to differentiate movement-disorder
adverse effects of treatment from movement-disorder manifestations of the au-
tism spectrum disorders. Acute dystonia (acute dystonic reaction), acute aka-
thisia, and tardive dyskinesia are movement disorders commonly observed in
people with autism spectrum disorders following pharmacological interventions,
particularly with dopamine antagonists.
People with autism spectrum disorders, particularly Rett’s disorder and au-
tistic disorder, have characteristic movements called stereotypies. Since most ste-
reotypies do not harm the individual or others, they can usually be adequately
managed by behavioral treatment. On the other hand, self-injurious behaviors
constitute challenging stereotypies exhibited by a minority of individuals with
autism spectrum disorders. Self-injurious behaviors demand immediate interven-
tion to prevent morbidity and mortality. Although many interventions are re-
ported to help treat movement disorders in specific individuals with autism spec-
trum disorders, no therapy is uniformly effective. All treatments for autism
spectrum disorders carry the risk of adverse events. Potential benefits of interven-
tions must be weighed against likely risks of unfavorable outcomes (304,305).
Published reports of treatments of movement disorders in autism are often anec-
dotal documents that are difficult to generalize to other individuals (306). Well-
designed research (307) is needed to assess diagnostic and therapeutic procedures
for movement disorders in autism spectrum disorders (308–310). Carefully
planned assessments of even single cases are needed to yield meaningful results
(311–313). The beneficial and adverse effects of treatments for these disorders
must be established through controlled clinical trials.
ACKNOWLEDGMENTS
This work is sponsored by the Department of Psychiatry of Bellevue Hospital
Center and the New York University School of Medicine, The Essel Foundation,
Family and Friends of Chelsea Coenraads, the National Alliance for Research
on Schizophrenia and Depression (NARSAD), the Rett Syndrome Research
Foundation (RSRF), and the Tourette Syndrome Association, Inc. The coopera-
tion of Bellevue Hospital Center and the Health and Hospitals Corporation of
the City of New York is gratefully acknowledged. This work was supported by
the Medical Fellows Program of the Consortium for Medical Education in Devel-
298 Brǎsić
opmental Disabilities (CMEDD) of the Office of Mental Retardation and Devel-

opmental Disabilities (OMRDD) of the State of New York. Drs. Elaine Tierney
and Michael V. Will, Mr. Rodney A. Fisk, and Ms. Maryanne Martin are thanked
for their criticisms of earlier versions of this chapter. The author is a member of
the Medical Advisory Board of the Tourette Syndrome Association of Greater
Washington, Silver Spring, Maryland.
Table 1 Abbreviations Frequently Encountered in the Treatment of Movement

Disorders in Autism Spectrum Disorders
AIMS Abnormal Involuntary Movement Scale (Table 2) (10,11)

AMPA alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
CGAS Children’s Global Assessment Scale (Table 3) (12)
D1 dopamine type 1
D2 dopamine type 2
DRI differential reinforcement of incompatible
DRO differential reinforcement of other
FCC Family Compliance Checklist (Table 4) (13,14)
GABA gamma-aminobutyric acid
GSIBS Global Self-Injurious Behavior Scale (Table 5)
HAS Hillside Akathisia Scale (Table 6) (11,15)
HGPRT hypoxanthineguanine phosphoribosyltransferase
MDC Movement Disorders Checklist (Table 7) (11)
META Medical Editors’ Trial Amnesty (16)
MVTC Myoclonus Versus Tic Checklist (Table 8) (17)
NMDA N-methyl-D-aspartate
PQRS Psychoactive Medication Quality Assurance Rating Survey (Table 9)
(11,18–21)
SIB self-injurious behavior
SSRI selective serotonin-reuptake inhibitor
TSIBS Timed Self-Injurious Behavior Scale (Table 10) (24)
TSRS Timed Stereotypies Rating Scale (Table 11) (11,25)
Table 2 Abnormal Involuntary Movement Scale (AIMS)
Subject Name
Subject Number
Rater Name
Date of Rating
Time of Rating
Place of Rating
Examination Procedure
Either before or after completing the Examination Procedure, observe the subject unobtru-
sively at rest, e.g., in the waiting room. The chair to be used in this examination should
be a hard, firm one without arms.
1. Ask the subject to remove shoes and socks.

2. Ask the subject if there is anything in his or her mouth (e.g., candy or gum) and,
if there is, to remove it.
3. Ask the subject about the current condition of his or her teeth. Ask whether he or
she wears dentures. Do teeth or dentures bother the subject now?
4. Ask the subject whether he or she notices any movements in mouth, face, hands, or
feet. If yes, ask to describe and to what extent they currently bother the subject or
interfere with his or her activities.
5. Have the subject sit in the chair with hands on knees, legs slightly apart and feet
flat on the floor. Look at the entire body for movements while in this position.
6. Ask the subject to sit with hands hanging unsupported. If male, between legs. If female
and wearing a dress, hanging over knees. Observe the hands and other body areas.
7. Ask the subject to open the mouth. Observe the tongue at rest in the mouth. Do this twice.
8. Ask the subject to protrude the tongue. Observe abnormalities of tongue movement.
Do this twice.
9. Ask the subject to tap the thumb, with each finger, as rapidly as possible for 10 to 15
seconds; separately with right hand, then with left hand. Observe facial and leg movements.
10. Flex and extend the subject’s left and right arms one at a time. Note any rigidity.
11. Ask the subject to stand up. Observe the subject in profile. Observe all body areas
including the hips.
12. Ask the subject to extend both arms outstretched in front with palms down. Observe
the trunk, the legs, and the mouth.
13. Have the subject walk a few paces, turn, and walk back to the chair. Observe the
hands and the gait. Do this twice.
Instructions
Complete the above Examination Procedure before making ratings. For movement ratings,
circle the highest severity observed.
300 Brǎsić
Table 2 Continued
Code:
0 None
1 Minimal, may be extreme normal
2 Mild
3 Moderate
4 Severe
Facial and Oral Movements

1. Muscles of facial expression—e.g., movements of forehead, 0 1 2 3 4
eyebrows, periorbital area, cheeks; including frowning, blinking,
smiling, grimacing
2. Lips and perioral area—e.g., puckering, pouting, smacking 0 1 2 3 4
3. Jaw—e.g., biting, clenching, chewing, mouth opening, lateral 0 1 2 3 4
movement
4. Tongue—rate only increases in movement both in and out of 0 1 2 3 4
mouth, not the inability to sustain movement
Extremity Movements
5. Upper (arms, wrists, hands, fingers)—include choreic movements 0 1 2 3 4
(i.e., rapid, objectively purposeless, irregular, spontaneous),
athetoid movements (i.e., slow, irregular, complex, serpentine).
Do not include tremor (i.e., repetitive, regular, rhythmic).
6. Lower (legs, knees, ankles, toes)—e.g., lateral knee movement, 0 1 2 3 4
foot tapping, heel dropping, foot squirming, and inversion and
eversion of the foot
Trunk Movements
7. Neck, shoulders, hips—e.g., rocking, twisting, squirming, pelvic 0 1 2 3 4
gyrations
Global Judgments
8. Severity of abnormal movements 0 1 2 3 4
9. Incapacitation due to abnormal movements 0 1 2 3 4
10. Subject’s awareness of abnormal movements—rate only the 0 1 2 3 4
subject’s report.
Dental Status
11. Current problems with teeth and/or dentures 0 No
1 Yes
12. Does the subject usually wear dentures? 0 No
1 Yes
Source: Refs. 10, 11.

Table 3 Children’s Global Assessment Scale (CGAS) (for Children 4 to 16 Years

Old)
Subject Name
Subject Number
Rater Name
Date of Rating
Time of Rating
Place of Rating
Instructions to rater: Please rate the subject’s most impaired level of general functioning
for the specified time period by selecting the lowest level that describes his or her function-
ing on a hypothetical continuum of health–illness. Use the intermediary levels (e.g., 35,
58, 62). Rate actual functioning regardless of treatment or prognosis. The examples of
behavior provided are only illustrative and are not required for a particular rating.
Specified Time Period: 1 Month

100–91 Superior functioning in all areas (at home, at school, and with peers); involved
in a wide range of activities and has many interests (e.g., has hobbies or partici-
pates in extracurricular activities or belongs to an organized group such as
Scouts); likable, confident; “everyday” worries never get out of hand; doing
well in school; no symptoms.
90–81 Good functioning in all areas; secure in family, school, and with peers; there
may be transient difficulties and “everyday” worries that occasionally get out
of hand (e.g., mild anxiety associated with an important exam, occasional
“blowups” with siblings, parents, or peers).
80–71 No more than slight impairment in functioning at home, at school, or with peers;
some disturbance or behavior or emotional distress may be present in response
to life stresses (e.g., parental separations, deaths, birth of a sib), but these are
brief and interference with functioning is transient; such children are only mini-
mally disturbing to others and are not considered deviant by those who know
them.
70–61 Some difficulty in a single area, but generally functioning pretty well (e.g., spo-
radic or isolated antisocial acts, such as occasionally playing hooky or petty
theft; consistent minor difficulties with school work; mood changes of brief
duration; fears and anxieties that do not lead to gross avoidance behavior; self-
doubts); has meaningful interpersonal relationships; most people who do not
know the child well would not consider him or her deviant but those who do
know him or her well might express concern.
60–51 Variable functioning with sporadic difficulties or symptoms in several but not
all social areas; disturbance would be apparent to those who encounter the child
in a dysfunctional setting or time but not to those who see the child in other
settings.
302 Brǎsić
Table 3 Continued
50–41 Moderate degree of interference in functioning in most social areas or severe
impairment of functioning in one area, such as might result from suicidal preoc-
cupations and ruminations, school refusal and other forms of anxiety, obsessive
rituals, major conversion symptoms, frequent anxiety attacks, poor or inappro-
priate social skills, or frequent episodes of aggressive or other antisocial behav-
ior with some preservation of meaningful social relationships.
40–31 Major impairment in functioning in several areas and unable to function in one
of these areas, i.e., disturbed at home, at school, with peers, or in society at
large, e.g., persistent aggression without clear instigation; markedly withdrawn
and isolated behavior due to either mood or thought disturbance, suicidal at-
tempts with clear lethal intent; such children are likely to require special school-
ing and/or hospitalization or withdrawal from school (but this is not a sufficient
criterion for inclusion in this category).
30–21 Unable to function in almost all areas, e.g., stays at home, in ward, or in bed
all day without taking part in social activities or severe impairment in reality
testing or serious impairment in communications (e.g., sometimes incoherent
or inappropriate).
20–11 Needs considerable supervision to prevent hurting others or self (e.g., frequently
violent, repeated suicide attempts) or to maintain personal hygiene or gross
impairment in all forms of communication, e.g., severe abnormalities in verbal
and gestural communications, marked social aloofness, stupor.
10–1 Needs constant supervision (24-hour care) due to severely aggressive or self-
destructive behavior or gross impairment in reality testing, communication, cog-
nition, affect, or personal hygiene.
Source: Ref. 12.

Table 4 Family Compliance Checklist (FCC)
Subject Name
Subject Number
Rater Name
Date of Rating
Time of Rating
Place of Rating
Instructions to rater: Please circle the appropriate response or write in the appropriate
number based on all available sources of information.
Severity of subject’s illness

1. Subject has a documented history of illness over the past year. Yes No*
2. Subject has two or more diagnoses. Yes No
Lack of engagement (of the subject)

3. The subject has expressed a desire for treatment to reduce his Yes No
or her symptoms.
Family factors
4. The family has refused to permit the use of medication(s). Yes* No
5. Family members have refused to make appointments. Yes* No
6. Number of appointments missed over the last 6 months.
7. The family has refused to sign the treatment plan. Yes* No
Practitioner factors
8. Number of sessions with primary therapist over the past 6
months.
9. Team member or primary therapist has appropriate contact with Yes No*
other providers, e.g., school, group residence, foster care
agency.
* If this response is circled, then immediate review is needed to assess the need for and the effective-
ness of current psychopharmacotherapy and to consider alternative treatment plans.
Source: Adapted from Ref. 13. 1998 Psychological Reports.
304 Brǎsić
Table 5 Global Self-Injurious Behavioral Scale (GSIBS)
Subject Name
Subject Number
Rater Name
Date of Rating
Time of Rating
Place of Rating
Instructions to rater: Utilizing all available sources of information, please circle the
number corresponding to the most appropriate response for the past week.
Number
None 0
Single self-injurious behavior 1
Two self-injurious behaviors 2
Three self-injurious behaviors 3
Four self-injurious behaviors 4
Five or more self-injurious behaviors 5
Frequency
None There is no evidence of self-injurious behaviors. 0
Rarely Self-injurious behaviors occur rarely. Bouts of self-injurious
behaviors are brief and uncommon. 1
Occasionally There are occasional durations without any self-injurious
behaviors. Brief bouts of self-injurious behaviors
occasionally occur. 2
Frequently Bouts of single self-injurious behaviors occur regularly. 3
Almost always Periods of sustained self-injurious behaviors occur
regularly. Bouts of two or more self-injurious behaviors
are common. 4
Always Self-injurious behaviors are present constantly. There
are no observed waking intervals free of self-injurious
behaviors. 5
Intensity
Absent Self-injurious behaviors are absent. 0
Minimal Self-injurious behaviors are less forceful than comparable
voluntary actions. They may be masked by voluntary actions,
and may be overlooked unless the subject is observed
closely. There is no tissue damage. 1
Table 5 Continued
Mild Self-injurious behaviors are no more forceful than
comparable voluntary actions. Although there is no acute
tissue damage, tissue damage could occur if specific self-
injurious behaviors persisted for more than a day. 2
Moderate Self-injurious behaviors are more forceful than comparable
voluntary actions. They call attention to the individual
because of the intensity of the force. There may be minimal
tissue damage, such as bruises. 3
Severe Self-injurious behaviors are more forceful than comparable
voluntary actions. They call attention to the individual
because of their forceful and exaggerated character. Major
tissue damage requiring medical and surgical intervention,
such as laceration and hemorrhage, may occur. 4
Extreme Self-injurious behaviors are extremely forceful and
exaggerated in expression. They call immediate attention to
the individual. There may be major tissue damage of life-
threatening proportions, including fractures, rupture of
internal organs, loss of teeth, and impairments of hearing and
vision. 5
Complexity
None If present, specific self-injurious behaviors are clearly
“simple” (sudden, brief, purposeless) in character. 0
Borderline Some self-injurious behaviors are not clearly simple in
character. 1
Mild Some self-injurious behaviors are clearly complex (purposive
in appearance) and mimic brief automatic behaviors that can
be readily camouflaged. 2
Moderate Some self-injurious behaviors are more complex (more
purposive and sustained in appearance), and may occur in
orchestrated bouts that are difficult to camouflage but
resemble normal behavior or speech. 3
Marked Some self-injurious behaviors are highly complex in
character and tend to occur in sustained orchestrated bouts
that are difficult to camouflage and cannot be easily
rationalized as normal behavior because of the duration and
the unusual, inappropriate, or bizarre character, and the
severity of tissue damage. 4
Severe Some self-injurious behaviors involve lengthy bouts of
orchestrated behavior that are impossible to camouflage or
successfully rationalize as normal because of the duration
and extremely unusual, inappropriate, or bizarre character
(lengthy displays), and the severity of the tissue damage. 5
306 Brǎsić
Table 5 Continued
Interference
None No self-injurious behaviors are present. 0
Minimal Specific self-injurious behaviors do not interrupt the flow of
behavior or speech. 1
Mild Specific self-injurious behaviors occasionally interrupt the
flow of behavior or speech. 2
Moderate Specific self-injurious behaviors frequently interrupt the flow
of behavior or speech. 3
Marked Specific self-injurious behaviors frequently interrupt the flow
of behavior or speech and occasionally disrupt the intended
action or communication. 4
Severe Specific self-injurious behaviors constantly disrupt intended
action or communication. 5
Impairment
None There is no impairment in social, occupational, or
educational functioning. 0
Minimal Self-injurious behaviors are associated with subtle difficulties
in self-esteem, family life, social acceptance, school and job
functioning, activities of daily living, daily chores, and
vocational training (infrequent upset or concern about self-
injurious behaviors regarding the future; periodic or slight
increase in family tensions because of self-injurious
behaviors; friends or acquaintances may occasionally notice
or comment about self-injurious behaviors in an upsetting way). 1
Mild Self-injurious behaviors are associated with minor difficulties
vocational planning. 2
Moderate Self-injurious behaviors are associated with definite
difficulties in self-esteem, family life, social acceptance,
school and job functioning, activities of daily living, daily
chores, and vocational training (episodes of dysphoria;
periodic distress and upheaval in the family; frequent
tensions in caretaking staff; frequent teasing by peers or
episodic social avoidance; periodic interference in school or
job performance because of self-injurious behaviors; periodic
interference in activities of daily living and daily chores by
self-injurious behaviors). 3
Severe Self-injurious behaviors are associated with major difficulties
vocational training. 4
Table 5 Continued
Interference
Extreme Self-injurious behaviors are associated with extreme
difficulties in self-esteem, family life, social acceptance,
school and job functioning, activities of daily living, daily
chores, and vocational training (severe depression with
suicidal ideation and attempts; disruption of family including
separation, divorce, and residential placement; interference
with the routine functioning of caretaking staff; disruption of
social ties and peer interactions including severely restricted
life because of social stigma and social avoidance; removal
from school or vocational activity; extreme interference with
activities of daily living and daily chores). 5
Global Self-Injurious Behavior Scale (GSIBS) Score (sum of Number,

Frequency, Intensity, Complexity, Interference, and Impairment Scores)
308 Brǎsić
Table 6 Hillside Akathisia Scale (HAS)
Subject Name
Subject Number
Rater Name
Date of Rating
Time of Rating
Place of Rating
Subjective score
Objective score
Total score
Subjective Subscale (items 1 and 2)

0 Absent
1 Questionable
2 Present and easily controlled
3 Present and barely controlled
4 Present and not controlled
Subjective items Sitting Standing Lying Total

1. The subject has a sensation of inner
restlessness.
2. The subject has the urge to move.
Objective items
3. Akathisia is present in the head and
the trunk.
4. Akathisia is present in the hands and
the arms.
5. Akathisia is present in the feet and
the legs.
Objective subscale (items 3, 4, and 5)

0 No akathisia
1 Questionable
2 Small-amplitude movements, part of the time
3 Small-amplitude movements, all of the time, or large-amplitude movements, part
of the time
4 Large-amplitude movements, all of the time
Table 6 Continued
Clinical Global Impression
Severity of akathisia Score
Considering your total experience with this particular population, how akathisic is the
subject at this time?
0 Not assessed
1 Normal, not akathisic
2 Borderline akathisia
3 Mildly akathisic
4 Moderately akathisic
5 Markedly akathisic
6 Severely akathisic
7 Among the most akathisic of subjects
Global improvement Score
Rate total improvement whether or not, in your judgment, it is entirely due to drug
treatment. Compared with subject’s condition at admission to the study, how much has
he or she changed.
0 Not assessed
1 Very much improved
2 Much improved
3 Minimally improved
4 No change
5 Minimally worse
6 Much worse
7 Very much worse

310 Brǎsić
Table 7 Movement Disorders Checklist (MDC)
Subject Name
Subject Number
Rater Name
Date of Rating
Time of Rating
Place of Rating
Instructions for rater: Fill out separate checklists for each different movement, posture,
or utterance observed. Do not rate two or more particular movements, postures, or
utterances on the same sheet. Complete the following items based on all available
sources of information concerning each movement, posture, or utterance on the date of
the rating.
Item Characteristic No Yes Don’t know
1 Abnormal posture 0 1 9
2 Abrupt 0 1 9
3 Brief 0 1 9
4 Can be suppressed 0 1 9
5 Continuous 0 1 9
6 Coordinated 0 1 9
7 Feeling of restlessness 0 1 9
8 Intermittent 0 1 9
9 Movement flows randomly 0 1 9
10 Oscillatory 0 1 9
11 Patterned 0 1 9
12 Present at rest 0 1 9
13 Present when maintaining a posture 0 1 9
14 Purposeless 0 1 9
15 Regular 0 1 9
16 Repetitive 0 1 9
17 Ritualistic 0 1 9
18 Shock-like 0 1 9
19 Squeezing movement 0 1 9
20 Sudden 0 1 9
21 Sustained 0 1 9
22 Twisting movement 0 1 9
23 Urge to move 0 1 9
Source: Ref. 11.

Table 8 Myoclonus Versus Tic Checklist (MVTC)
Subject Name
Subject Number
Rater Name
Date of Rating
Time of Rating
Place of Rating
Instructions: Please complete the following items based on all available sources of
information for the past 7 days.
No Yes Don’t know
1. Simple jerks 0 1 9
2. Random, unpredictable body distribution 0 ⫺1 9
3. Wide range of amplitude 0 1 9
4. Wide range of forcefulness 0 1 9
5. Movements can be voluntarily suppressed 0 1 9
6. Movements increase with intentional acts 0 ⫺1 9
7. Sustained dystonic movements 0 1 9
8. Complex movements 0 1 9
To score, convert all 9s to 0s. If the total score is positive, tics are more likely. If the
total score is negative, myoclonus is more likely. If the total score is zero, myoclonus
and tics are equally likely.
312 Brǎsić
Table 9 Psychoactive Medication Quality Assurance Rating Survey (PQRS)
Subject Name
Subject Number
Rater Name
Date of Rating
Time of Rating
Place of Rating
Instructions to rater: These guidelines apply to all items unless indicated otherwise.
After reviewing the subject’s chart for the 12 months before the rating date, circle Y if
the stated item is true. For example, if the response to the item is no, not applicable,
none, don’t know, other, or any response other than yes for an item, leave it blank.
You may write any additional information on the backs of the pages.
Identifying personal information

1. Case number
2. Form number
3. Time number
4. Rater code number
5. Subject number
6. Rating date
7. Today’s date
8. Subject’s sex is male Y
9. Subject’s date of birth
10. Subject’s age in years
11. Subject’s street address
12. Subject’s apartment number
13. Subject’s city
14. Subject’s state, province, or region
15. Subject’s zip or postal code
16. Subject’s telephone number
17. Subject’s racial/ethnic origin
1 ⫽ Asian or Pacific Islander
2 ⫽ Black, African American, or Negro
3 ⫽ Hispanic or Latino
4 ⫽ American Indian, Eskimo, or Aleut
5 ⫽ White
6 ⫽ Other
9 ⫽ Don’t know
18. Subject’s living unit
19. Subject’s date of admission to this
institution
Table 9 Continued
20. Subject’s level of mental
retardation
1 ⫽ Profound (IQ below 20 or 25)
2 ⫽ Severe (IQ 20–25 to 35–40)
3 ⫽ Moderate (IQ 35–40 to 50–55)
4 ⫽ Mild (IQ 50–55 to approximately 70)
5 ⫽ Borderline (IQ 71 to 84)
6 ⫽ Not retarded
9 ⫽ Don’t know
21. Subject’s full-scale IQ, as
measured by standard individual
test
22. The subject is deceased. Y
Caregivers
23. Subject’s primary clinician
24. Clinician 1 managed medications for subject
Past history
27. Record of previous diagnostic evaluation requested* Y
28. Record of previous diagnostic evaluation obtained* Y
Current medical evaluation
29. Comprehensive nonpsychiatric medical evaluation is initiated* Y
30. Comprehensive nonpsychiatric medical evaluation is completed* Y
31. Relevant nonpsychiatric medical assessment components are completed* Y
Current psychiatric evaluation
32. Comprehensive psychiatric evaluation is initiated* Y
33. Comprehensive psychiatric evaluation is completed* Y
34. Relevant psychiatric assessment components are completed* Y
35. Psychiatric diagnoses other than mental retardation, if applicable, by
DSM-IV-TR diagnostic classification (2)* Y
36. Psychiatric diagnoses other than mental retardation, if applicable, by 1998
ICD-9-CM (22) classification* Y
Current intellectual evaluation
37. Level of mental retardation is documented by IQ derived from individual
formal testing* Y
38. Level of retardation is documented by adaptive functioning* Y
Current behavioral evaluation
39. Focused behavioral evaluation is initiated* Y
40. Focused behavioral evaluation is adequate for initiating treatment* Y
41. Behavioral symptoms related to psychiatric diagnoses are specified* Y
314 Brǎsić
Table 9 Continued
42. Behavioral symptoms related to medical diagnoses are specified* Y
43. Baseline behavioral symptoms similar to treatment side effects are specified* Y
Specific medical diagnoses
44. Pulmonary disease is diagnosed Y
45. Cardiovascular disease is diagnosed Y
46. Cataracts are diagnosed Y
47. The subject is hepatitis A antigen–positive Y
48. The subject is hepatitis B antigen–positive Y
49. Constipation is diagnosed Y
50. Toe infection is present Y
51. Ear/nose/throat disease is present Y
52. Respiratory infection is diagnosed Y
53. Central nervous system disease is diagnosed Y
54. Seizures are diagnosed Y
55. Endocrine disease is diagnosed Y
56. The subject ambulates with assistance Y
57. Mental retardation due to disorders of metabolism and nutrition is diagnosed Y
58. Mental retardation due to infection (e.g., rubella) or head trauma is diagnosed Y
59. Cerebral malformations are diagnosed Y
60. Down’s syndrome is diagnosed Y
61. Fragile X syndrome is diagnosed Y
62. Other chromosomal disorders are diagnosed Y
63. One or more seizures are recorded in the past 12 months Y
64. Stereotypies are diagnosed Y
65. Neuroleptic-related tardive or withdrawal dyskinesias are diagnosed Y
66. Additional medical diagnoses are given Y
67. It is specified if medical diagnoses contribute to target symptoms Y
68. Another nonpsychiatric medical condition, other than mental retardation,
is diagnosed Y
If yes, please list:
69. Other informal clinical symptom diagnoses, e.g., self-injurious behavior,
are given Y
70. Hierarchy of severity of medical diagnoses is evident Y
Specific psychiatric diagnoses
71. Autistic disorder is diagnosed Y
72. Other pervasive developmental disorder is diagnosed Y
73. Schizophrenia is diagnosed Y
74. Depression is diagnosed Y
75. Mania is diagnosed Y
76. Self-injurious behavior has been recorded Y
77. Aggression toward others has been recorded Y
78. Suicide has been attempted in the past year Y
79. Hyperactivity has been recorded in the past year Y
Table 9 Continued
80. Another nonmedical psychiatric diagnosis, other than mental retardation,
is diagnosed Y
81. Hierarchy of severity of psychiatric diagnoses is evident Y
Target symptoms
82. More than one staff member has recorded each significant symptom* Y
83. There is an obvious environmental cause for each symptom† Y
84. There is obvious bias by the observer; others do not agree† Y
85. More than one significant symptom is observed Y
86. A hierarchy of symptom priorities for treatment is listed* Y
87. Target symptom(s) for treatment are established* Y
88. Baseline ratings of symptoms are obtained by rating scales Y
89. Baseline ratings of symptoms are obtained by informal observation* Y
90. Other target behavior symptoms are identified Y
91. There is a hierarchy of severity of target behavioral symptoms* Y
Treatment selection
92. Only one available psychoactive treatment is considered and reviewed† Y
93. More than one available psychoactive treatment is considered and reviewed* Y
94. Beneficial and side effects of each psychoactive treatment are reviewed* Y
95. Sequence of psychoactive treatments is established* Y
96. Caution to do no harm to subject in treatment selection* Y
97. Informed consent is obtained prior to starting psychoactive medication* Y
98. Class of psychoactive medication selected in relation to psychiatric
diagnoses* Y
99. Class of psychoactive medication selected in relation to target behavioral
symptom(s)* Y
100. Class of psychoactive medication selected in relation to concurrent medical
illnesses* Y
101. Class of psychoactive medication selected in relation to drug interactions* Y
102. Contraindicated and ineffective psychoactive medication(s) were excluded Y
103. Alternative psychoactive medication(s) are recorded* Y
Treatment monitoring protocols
104. A behavioral treatment plan is specified* Y
105. A pharmacological treatment plan is specified* Y
106. The duration of psychoactive treatments is specified, other than monthly
renewals* Y
107. After the monthly review of the symptoms of the subject, medication
renewals are completed* Y
108. Outcome criteria are specified to determine continuation of therapy* Y
109. The time and the method to determine long-term side effects are recorded Y
110. Psychoactive medication review by preset schedule, other than monthly
medication renewals Y
316 Brǎsić
Table 9 Continued
111. Psychoactive medication review by original protocol schedule Y
112. Psychoactive medication review by number of drugs* Y
113. Psychoactive medication review by long-term side effects* Y
114. Nonmedication influences reviewed: baseline variation* Y
115. Nonmedication influences reviewed: environmental* Y
116. Nonmedication influences reviewed: concurrent treatments* Y
Medication dosage range
117. Psychoactive drug dosage in usual range according to Physicians’ Desk
Reference (23)* Y
118. Psychoactive drug dosage in usual range according to state manual* Y
119. Psychoactive drug dosage in usual range according to standard texts* Y
120. Psychoactive drug dosage in usual range according to scientific journals* Y
Monitoring medication dosage and treatment effects
121. Psychoactive drug dosage is monitored by formal protocol schedule Y
122. Psychoactive drug dosage is monitored by open drug trial Y
123. Psychoactive drug dosage is monitored by plasma drug levels Y
124. Psychoactive drug dosage is monitored by consideration of other drugs
currently taken* Y
125. Appropriate beneficial behavioral effects are monitored* Y
126. Appropriate medication side effects are monitored* Y
127. Monitoring by staff observation, with chart notes, at one site (day program
or living unit)* Y
128. Monitoring by staff, with chart notes, at two or more sites (including both
day program and living unit) Y
129. Monitoring by appropriate specific rating scales filled out by assigned raters Y
130. Monitoring by appropriate specific rating scales, with raters by convenience Y
131. Monitoring by open format Y
132. Monitoring by single-blind format Y
133. Monitoring by double-blind format Y
134. Monitoring includes use of placebo Y
135. Monitoring includes crossover of treatment components Y
Drug holidays
136. Drug holiday of at least 4 weeks each year planned Y
137. Drug holiday of at least 4 weeks this year attempted Y
138. Drug holiday of at least 4 weeks this year completed Y
139. No drug holiday, with documentation supporting this decision Y
140. Attempt at drug holiday was discontinued, with justification Y
* This criterion is required prior to treatment with psychoactive medication.

† This criterion indicates that further investigation is required prior to treatment with psychoactive
medication.
Table 10 Timed Self-Injurious Behavior Scale (TSIBS)
Subject Name
Subject Number
Rater Name
Date of Rating
Time of Rating
Place of Rating
Instructions: Please place a checkmark (⻫) on the appropriate line the first time the
indicated behavior occurs during each 10-second interval for each minute of the 10-
minute rating session.
0:00 0:10 0:20 0:30 0:40 0:50

1. Skin picking
2. Self biting
3. Head punching
4. Head slapping
5. Head-to-object banging
6. Body-to-object banging
7. Body punching
8. Body slapping
9. Eye poking
10. Anal poking
11. Other poking
Please describe:
12. Lip chewing
13. Hair removal
14. Nail removal
15. Teeth banging
16. Other self-injurious behavior
Please describe:
1:00 1:10 1:20 1:30 1:40 1:50

1. Skin picking
2. Self biting
3. Head punching
4. Head slapping
7. Body punching
8. Body slapping
318 Brǎsić
Table 10 Continued
9. Eye poking
10. Anal poking
11. Other poking
Please describe:
12. Lip chewing
13. Hair removal
14. Nail removal
15. Teeth banging
Please describe:
2:00 2:10 2:20 2:30 2:40 2:50

1. Skin picking
2. Self biting
3. Head punching
4. Head slapping
7. Body punching
8. Body slapping
9. Eye poking
10. Anal poking
11. Other poking
Please describe:
12. Lip chewing
13. Hair removal
14. Nail removal
15. Teeth banging
Please describe:
3:00 3:10 3:20 3:30 3:40 3:50

1. Skin picking
2. Self biting
3. Head punching
4. Head slapping
7. Body punching
8. Body slapping
9. Eye poking
10. Anal poking
11. Other poking
Please describe:
Table 10 Continued
12. Lip chewing
13. Hair removal
14. Nail removal
15. Teeth banging
Please describe:
4:00 4:10 4:20 4:30 4:40 4:50

1. Skin picking
2. Self biting
3. Head punching
4. Head slapping
7. Body punching
8. Body slapping
9. Eye poking
10. Anal poking
11. Other poking
Please describe:
12. Lip chewing
13. Hair removal
14. Nail removal
15. Teeth banging
Please describe:
5:00 5:10 5:20 5:30 5:40 5:50

1. Skin picking
2. Self biting
3. Head punching
4. Head slapping
7. Body punching
8. Body slapping
9. Eye poking
10. Anal poking
11. Other poking
Please describe:
12. Lip chewing
13. Hair removal
14. Nail removal
320 Brǎsić
Table 10 Continued
15. Teeth banging
Please describe:
6:00 6:10 6:20 6:30 6:40 6:50

1. Skin picking
2. Self biting
3. Head punching
4. Head slapping
7. Body punching
8. Body slapping
9. Eye poking
10. Anal poking
11. Other poking
Please describe:
12. Lip chewing
13. Hair removal
14. Nail removal
15. Teeth banging
Please describe:
7:00 7:10 7:20 7:30 7:40 7:50

1. Skin picking
2. Self biting
3. Head punching
4. Head slapping
7. Body punching
8. Body slapping
9. Eye poking
10. Anal poking
11. Other poking
Please describe:
12. Lip chewing
13. Hair removal
14. Nail removal
15. Teeth banging
Please describe:
Table 10 Continued
8:00 8:10 8:20 8:30 8:40 8:50
1. Skin picking
2. Self biting
3. Head punching
4. Head slapping
7. Body punching
8. Body slapping
9. Eye poking
10. Anal poking
11. Other poking
Please describe:
12. Lip chewing
13. Hair removal
14. Nail removal
15. Teeth banging
Please describe:
9:00 9:10 9:20 9:30 9:40 9:50

1. Skin picking
2. Self biting
3. Head punching
4. Head slapping
7. Body punching
8. Body slapping
9. Eye poking
10. Anal poking
11. Other poking
Please describe:
12. Lip chewing
13. Hair removal
14. Nail removal
15. Teeth banging
Please describe:
Table 11 Timed Stereotypies Rating Scale (TSRS)
322
Subject Name
Subject Number
Rater Name
Date of Rating
Time of Rating
Place of Rating
Instructions: Place a checkmark (⻫) in the appropriate box the first time the indicated stereotypy occurs during each 30-second interval.
Write a description of each “other” stereotypy, namely, items 19–24, 27–32, 46–51, 60–65, 68–73, and 77–89.
Brǎsić
324 Brǎsić
Movement Disorders
Source: Adapted from Refs. 11, 25.

325
326 Brǎsić
Table 12 Definitions and Examples of Common Subclasses of Hyperkinesias in

Akathisia—a subjective experience of a sense of inner restlessness and an urge to

move associated with the withdrawal and the discontinuation of medication,
particularly traditional neuroleptics (2,11,33–36). Akathisa is characterized by
continuous, coordinated, patterned, and repetitive movements that are typically
purposeless or ritualistic (11).
Although motions, such as marching in place, are common in people with
akathisia, they are not required to diagnose akathisia. Akathisia can be strictly defined
solely on the basis of the subjective report of symptoms by the subject without any
visible signs (2,11). Since the verbal expression of a sense of inner restlessness and an
urge to move is required to diagnose akathisia, akathisia cannot strictly be diagnosed in
individuals who cannot produce that clear verbal expression. Therefore, akathisia
cannot be rigorously identified in people who lack the cognitive ability to orally report
inner restlessness and an urge to move. In such situations, probable objective akathisia
or pseudoakathisia can be diagnosed (34,35,37).
Chorea—an abrupt, quick, brief, continuous, irregular movement that appears to flow
randomly from one body part to another (11).
Choreic movements have dancelike qualities. The movements of chorea may be
camouflaged to resemble intentional movement. For example, a choreic hand
movement may be followed by a movement to touch the head, giving the appearance
that the individual deliberately groomed his or her hair.
Dystonia—a patterned, forceful, sustained contraction of a muscle group. Dystonia is

characterized by abnormal postures and repetitive squeezing or twisting movements (11).
Dystonic movements are often writhing. Opisthotonus is the forceful arching of the
back with extension of the head. Retrocollis is the extension of the head backward.
Torticollis is the sustained twisting of the neck toward the shoulder.
Acute dystonia (acute dystonic reaction) is common after the administration of
dopamine antagonists, a class of medications often used to treat autism spectrum disorders,
tics, and other disorders. See Section III.A for information on the diagnosis and treatment
of acute dystonia.
Myoclonus—a brief, shock-like, and sudden contraction of a muscle group (11).

Contraction of muscles, particularly in the legs, frequently occurs during sleep. For
example, contraction of calf muscles—a “Charlie horse”—is common in senior citizens
(38,39).
The Myoclonus Versus Tic Checklist (MVTC) (Table 8) (17) assists in the
differentiation of myoclonus from tics.
Stereotypies—continuous, coordinated, patterned, and repetitive motions or utterances

that are purposeless or ritualistic (11,40,41).
The movements characteristic of children with autism are traditionally classified as
stereotypies (4,6). However, stereotypies occur in a wide variety of conditions in addition
to autism.
Table 12 Continued
Tic—an abrupt, brief, discontinuous, and intermittent motion, sound, sensation, or
utterance that can be suppressed temporarily (11,42).
Tics commonly present in childhood, affecting boys much more frequently than
girls (2). An individual may experience an urge to perform a tic, which subsides with a
feeling of relief when the tic is completed. Tics can typically be suppressed, especially
when the individual is concentrating intensely on a physical or mental activity. When
the tics are finally expressed, there may be an explosion of them, as if to make up for
the time during which the expression of the tics was suppressed.
Motor and phonic, or vocal, tics are frequently observed. Common motor tics
include eye blinks, mouth twitches, and shoulder shrugs. Copropraxia is the
performance of obscene gestures. Common phonic tics include heavy breathing, throat
clearing, sniffing, bird sounds, and animal sounds, including barking. Coprolalia is the
utterance of obscene and profane expressions. Copropraxia and coprolalia occur in a
minority of individuals with Tourette’s disorder, which is characterized by the presence
of both motor and phonic tics for at least a year (2).
The Myoclonus Versus Tic Checklist (MVTC) (Table 8) (17) assists in the
differentiation of tics from myoclonus.
Further information about tics may be obtained from the Tourette Syndrome
Association, Inc. See page 285 for contact information.
Tremor—an oscillatory movement present both at rest and when maintaining a

posture (11).
Tremors due to cerebellar lesions typically worsen with voluntary movement,
such as alternately touching the finger of the examiner and the nose of the subject.
Other tremors typically diminish with voluntary action. Tremors are often present at
rest. Parkinson’s disease is characterized by a pill-rolling tremor in which the thumb is
repetitively rubbed against the tips of the fingers back and forth from the pointer finger
to the little finger to the pointer finger. Familial tremors may affect the hands, the
neck, and other parts of the body, and are often relieved by consumption of an
alcoholic beverage.
328 Brǎsić
Table 13 Stereotypies Commonly Observed in People with Autistic Spectrum

Disorders
Bouncing—jumping up and down repeatedly. Often occurs when the person is happy
and excited.
Bronx cheer—forcefully blowing air through tightly closed lips to produce a sound
similar to a flatulent report.
Ear covering—placing the palms over the external ears as if to block hearing.
Eye covering—placing the palms over the eyes as if to block vision.
Finger wiggling—movements resembling piano playing.
Forceful breathing—heavy expiration and inspiration through an open mouth.
Hand flapping—flinging both hands up and down repeatedly with a limp wrist.
Typically occurs when the individual is excited or happy; may be associated with
bouncing and rotating.
Hand rubbing—moving the palm repeatedly over an item. Appears to be associated
with an intense sensory interest in the feeling of the texture and configuration of an
item of interest.
Head tilting—leaning the head to one side. Often associated with fixation of visual
focus on a specific item in the environment. The individual appears to be attempting
to obtain a better view of the object.
Rotating—moving around a vertical axis in the head and body. May also be seen with
bouncing and hand flapping. Rotating may be a manifestation of excitement and
pleasure.
Toe wiggling—movements resembling playing piano with one’s toes.
Source: Refs. 4, 11, 25.

Table 14 Medical Complications of Self-injurious Behaviors (SIB)

Type of self-injurious
behavior Possible medical complication
Aerophagia Constipation, diarrhea, indigestion

Eye poking Corneal ulcer, infection, lens dislocation, retinal detachment
Hair removal Alopecia
Head banging Contusion, disfigurement, infection, laceration, seizure disor-
der, subdural hematoma
Self-biting Autoamputation, infection, laceration, ulceration
Pica Constipation, diarrhea, gastroenteritis, indigestion, intestinal
obstruction, intestinal perforation, lead poisoning
Rectal poking Abscess, fissure, fistula
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16
Alternative Biological Treatments for
Autism
Charles Cartwright and Rachael Power

University of Medicine and Dentistry of New Jersey–New Jersey Medical
School
Newark, New Jersey, U.S.A.
INTRODUCTION
The primary treatment for autism is educational, an intensive behavioral approach
that has become widespread despite some lingering controversy. Biological treat-
ments are strictly adjunctive at present. These consist of primarily psychotropic
medications that address certain aspects of the core symptoms such as stimulants
for hyperactivity and inattention, clonidine for insomnia, selective serotonin-
reuptake inhibitors (SSRIs) for repetitive obsessive-compulsive-like behaviors
and antipsychotics for aggression. When these medications are effective they
often also have a beneficial effect on language and social relatedness. In sum-
mary, they have a limited impact on some autistic symptoms in some patients.
However, parents of an autistic child for the most part seek more than just a
partial fix. They are desperate to find a solution to the puzzle of their strangely
disordered child. They commonly feel that the “perfect” child who was born to
them has been made captive to an unknown process and they are willing to make
any sacrifice to rescue their beloved son or daughter. Until more is known about
the causes of autism spectrum disorders and effective treatments are available, fami-
lies and patients will remain vulnerable to speculative theories and treatments.
General pediatricians should expect to have at least one autistic patient;
other practitioners, including neurologists, psychiatrists, and developmental pedi-
atricians, will see many more (1). They will all undoubtedly hear of many alterna-
347
348 Cartwright and Power
tive treatments. It is important for the physician to keep an open mind in working
with patients and families, who need above all an ally and professional sounding
board they can trust on the long road of raising an autistic child. In addition to
trying to find a “cure” after the child has been diagnosed, and the search for
treatments to improve the core symptoms, there will be many associated problems
that may become a focus of attention. These can include problems with feeding,
sleep, toileting, hyperactivity, and aggression.
Practitioners should evaluate alternative treatments using sound scientific
principles, carefully weighing the risks and benefits with their patients and care-
givers. At the same time it is important to understand that parents who are dealing
with troubling behaviors on a daily basis may not be willing to wait until defini-
tive studies have been performed, and that their threshold for testing a substance
that offers some hope for improvement is much lower than what objectivity would
dictate. Practitioners should ensure that parents feel comfortable sharing with
them all aspects of the child’s management. When unproven treatments are at-
tempted, as in any other type of pharmacotherapy it is paramount that parents
and practitioners work together to monitor efficacy, safety, and side effects. Par-
ents should also be educated on guidelines for evaluating treatments and encour-
aged to initiate only one change at a time, to target specific symptoms, and to
identify measurable objectives—ideally, together with the practitioner. It is also
preferable to use blinded observers such as teachers and therapists to assess the
efficacy of a given intervention.
This chapter discusses some of the commonly used alternative treatments:
vitamin and nutritional therapies, antifungals and antibiotics, detoxification of
heavy metals, and auditory integrative training. Secretin and immunoglobulin
therapies are discussed elsewhere.
SECRETIN
On October 7, 1998, the national news program “Dateline NBC” aired a story
in which Bernard Rimland, Ph.D., along with a parent of an autistic child, pro-
moted the neuropeptide secretin as being highly effective in treating, and in some
cases “curing,” autistic disorders. This set off an outpouring of intense interest
from the public, with secretin being viewed as a major medical breakthrough. Dr.
Rimland based his report on a study by Horvath and Stefanatos (2) that reported
significant improvements in three children with autism following treatment with
secretin as well as anecdotal reports he was receiving from parents about the
successful use of secretin. Following the broadcasting of the story, clinicians in
the field of autism and related disorders were inundated with calls from parents
making desperate pleas for treatment with this hormone for their children. There
were postings on the Internet by physicians who were administering this non-
FDA-approved treatment with claims of success. The excitement regarding secre-
Alternative Biological Treatments 349
tin led to attempts by certain health-care professionals to profit financially from

the plight of parents and their willingness to try anything that might benefit their
children. By August 1999, autism interest groups were claiming that more than
4000 children with autism and related disorders had received secretin, and more
than 70% of all those who received this treatment had improved significantly,
particularly in the areas of eye contact, interest in the environment, sleeping habits
and language skills, tantrums, and gastrointestinal function (3).
Many important medical breakthroughs have been made serendipitously
and accompanied by much public attention and enthusiasm. As such, prematurely
dismissing undeveloped findings as “another false hope” can in fact be a disser-
vice to scientific progress and to interested parties. In the case of autism, among
the most severe of neuropsychiatric disorders, in which scientific progress is
slow-moving in contrast to the distress and suffering of the affected families,
leaving a potential resource untapped would be unwise. However, of concern
was the fact that there were no rigorous controlled research studies on the safety
and efficacy of secretin use in autism. The treatment was being used clinically,
and claims of dramatic progress following secretin infusion may have unrealisti-
cally raised the expectations and hopes of parents desperate for good news about
treatment options. Now, three years later, several studies have been published
and a more objective perspective gained on the limitations of secretin as a treat-
ment for autism and related disorders.
Biochemistry and Physiology of Secretin

In 1981, secretin (in its purified porcine form, manufactured by Ferring Labora-
tories of Suffern, New York) was approved by the Food and Drug Administration
for single-dose use in the diagnostic workup of gastrointestinal disorders in
adults. It has a drug half-life of only 2 minutes when given intravenously (4).
There have been no data regarding the safety of repeated administrations of secre-
tin and no evidence documenting the safety of its use in children.
Secretin is a 27-amino-acid peptide (first sequenced in 1965) that was dis-
covered by Bayless and Starling in 1902, and is the defining member of a family
of peptides that include vasoactive intestinal peptide (VIP), glucagon, pituitary
adenylate cyclase-activating polypeptide (PACAP), growth-hormone-releasing
hormone, and neuropeptide Y. These hormones have similar but not identical
ordered sequences of amino acids and their three-dimensional structures are simi-
lar, which leads to significant recognition and binding (with differing capacities)
of each other’s receptors (so called “crosstalk,” which is even more apparent
when exogenously administered high doses are given) (5). This makes it difficult
to assign specific functions to each member of the secretin family. In addition,
this makes it possible that benefits that have been attributed to secretin infusions
may in fact be due to activation of non-secretin receptors.
Secretin release is regulated by a local gastrointestinal mechanism (acid

contents in the stomach and duodenum) (6). Secretin is produced and released
by the S cells of the small intestine, and reaches the exocrine glands (e.g., the
pancreas) via the portal circulation, and has effects on the pancreas (leading to
bicarbonate and water secretion) and on bile ducts (choliretic). It inhibits gastric
acid secretion and motility via direct vagal effects. The release of secretin by the
S cells in the duodenum is in response to the presence of acidic contents in the
stomach and duodenum.
Exogenous secretin, given in physiological doses, has been found to induce
pancreatic secretions. This increase in secretions is caused by vagal stimulation
of the pancreas (7).
The human secretin receptor was found to have 440 amino acids and to be
a G-protein-coupled receptor (8). Human secretin receptors were found to have
the greatest density in the pancreas, with declining levels in the kidney, small
intestine, lung, and liver, and trace levels in the brain, heart, and ovary. The
human secretin receptor has been shown to bind VIP, PACAP, and glucagon but
with less potency (by up to three orders of magnitude) than secretin itself (8).
Animal Studies with Secretin

Most of the studies on secretin and related peptides have been conducted using
animal models. As such, the results have limited generalization to the human
population, and even less to a group with neurodevelopmental problems as in
autism. Nonetheless, these research findings are important to examine. A number
of studies shed light on secretin’s possible neurobiological mechanisms that could
potentially be involved in ameliorating the core behaviors in autism.
In an interesting study of the genetic mutation of the neuropeptide Y recep-
tor (member of the secretin family), the worms C. elegans with the defect were
found not to congregate for feeding. This mutation specifically altered the way
that they fed. The social pattern of their feeding disappeared. The study shows
how social behaviors may be under the control of peptides such as secretin (9).
An important issue regarding the use of secretin administered peripherally
is whether it crosses the blood–brain barrier. After an intravenous dose of a
closely related peptide (PACAP), the peptide was taken up into the brain tissue
in the range of 0.01–0.1% of the original dose (10). Whether this concentration
of a neuropeptide-like secretin affects brain function directly depends on the sen-
sitivity of the brain to the peptide. The PACAP that entered was found to be
intact and had entered the parenchymal compartment. Given the similarity in size
and amino acid sequence hemology between PACAP and secretin, it is possible
that secretin crosses the blood–brain barrier in a similar fashion.
Very small doses of secretin directly infused into the ventricles of rats were
found to give rise to an increase of pancreatic secretions of bicarbonate (11). In
addition, electrical stimulation of the amygdala led to an augmented acid-induced

pancreatic secretion of water and bicarbonate. This effect was abolished by bilat-
eral truncal vagotomy. These findings suggest that the peripheral secretory re-
sponse by the pancreas to secretin is mediated by a central neural mechanism.
Secretin was reported in animal studies to bring about the activation of
tyrosine hydroxylase (the rate-limiting enzyme in catecholamine biosynthesis)
through the stimulation of cyclic AMP–dependent protein kinase (12). The dys-
regulation of catecholamines (thought to play an important role in the modulation
of reward mechanisms, attention, arousal, and impulse control) has been hypothe-
sized to play a role in these functions, and autism is often accompanied by fea-
tures of inattention, difficulty regulating impulsivity, and repetitive behaviors.
Gastrointestinal Complaints in Autism

Behaviors such as nighttime awakening, sudden episodes of irritability, and ag-
gressive behavior are commonly observed in children with autism. It has been
suggested that these may be related to gastrointestinal symptoms (13). This is
one of a small number of studies reporting on the incidence of GI disturbance
in autism. The limited language abilities of the majority of children affected with
autism make it extremely difficult to link specific gastrointestinal symptoms to
behavioral problems.
Horvath et al. (2) described three children (ages 3–5) who presented with
gastrointestinal problems, including chronic diarrhea, food intolerance and aller-
gies, and occult-positive stools. These children had been previously diagnosed
as having autism spectrum disorders. Standard diagnostic gastrointestinal endos-
copy was performed on these children; this included an upper-gastrointestinal
endoscopy under general anesthesia, pancreaticobiliary fluid collection/analysis,
and the intravenous administration of secretin to assess the pancreaticobiliary
response. Basal collection of pancreatic fluid occurred at a rate of 1–2 ml within
2–5 minutes (in keeping with nonautistic control groups). After secretin adminis-
tration, a significantly increased pancreaticobiliary response (7.5–10 ml/min) was
noted (significantly above the normal rate of 1–2 ml/min). However, protein
content, pH, and enzyme activities were reported to be within the normal range.
Bacterial and fungal cultures of the collected duodenal fluid were also found to be
normal. One child was found to have abnormal lactase activity. Gastrointestinal
symptoms were found to be significantly improved or resolved up to 8 months
after the administration of secretin.
More notably, within 3–8 weeks of the intravenous infusion of secretin,
significant improvements were noted in the social and communication abilities
of these three patients. Behavioral evaluations, collected from various sources,
included structured assessments (Vineland, CBCL, CARS) and anecdotal obser-
vations of therapists and teachers unaware of the medical procedure. Specifically,
the children showed better eye contact, a greater level of alertness, and improved
language skills.
In a study of gastrointestinal function in 36 children with autism and perva-
sive developmental disorder not otherwise specified (PDD-NOS) ranging in age
from 21/2 to 10 years (13), subjects were referred for a gastrointestinal workup due
to the presence of abdominal pain, chronic diarrhea, gaseousness/bloating, night-
time awakening, and unexplained irritability. Of these children, 47% were on a
gluten-free and/or casein-free diet. They underwent endoscopy under general anes-
thesia, including biopsies of esophagus, stomach, and duodenum for histology,
measurement of digestive enzymes of the pancreas (before and after secretin infu-
sion) and the small intestine, as well as bacterial and fungal cultures. Porcine secre-
tin, in a dose of 2 CU/kg body weight, was given as an intravenous infusion over
1 minute.
Comparisons were made with specimens collected from nonautistic chil-
dren who had undergone a similar procedure in the same setting. Test results
showed the presence of reflux esophagitis in 25 of the 36 (69%) children. Twenty-
two of these 25 children had nighttime awakening, irritability, and abdominal
upset. Fifteen of the children had chronic inflammation of the gastric mucosa
and 24 had chronic nonspecific duodenal inflammation. In addition there was
evidence of Paneth cell hyperplasia and hypertrophy in the majority of the chil-
dren scoped. The significance of this is not known. There was reduced activity
of one or more of the disaccharidases and glucoamylase in 21 of the 36 children.
All the children with reduced levels also reported the presence of loose stools
and gaseousness. All subjects had normal levels of pancreatic enzymes. The ma-
jority had a significantly increased pancreaticobiliary fluid output in response to
the secretin infusion. Nineteen of the 21 with chronic diarrhea had a significantly
increased pancreatic output, and most responded to secretin in the weeks after
the infusion with improved stool consistency. The authors hypothesized that the
increased pancreaticobiliary response to secretin was due to the up-regulation of
secretin receptors in the ductal cells of the pancreas and bile ducts. This up-
regulation is due to the reduced availability of secretin in these children.
In summary, the study found evidence to support the connections between
certain behavioral problems and the presence of gastrointestinal dysfunction in
autism. The authors felt that secretin may have opened a window into discovering
how common gastrointestinal disturbance is in autism, thereby linking brain–gut
dysfunction.
Treatment Studies
Open-Label Studies
In a small, open-label study by Perry and Bangaru (14) conducted in a private-
practice setting in New York, six children diagnosed with autism were treated
with single secretin infusions. Only one was found to respond with a clinically
significant improvement in language and relatedness. Three others showed subtle

changes in these areas of functioning, one child became more active and aggres-
sive, and the last showed no change.
Aman and Armstrong (15) posted a standardized questionnaire on the In-
ternet for completion by parents of children with autism who had already received
secretin infusions. Parents of 24 children between the ages of 2 and 7 (secretin
dose of 2 CU/kg) responded, and reported improvements in the areas of eye
contact, communication, and play as well as in gastrointestinal function. Of inter-
est, almost 60% of the sample reported experiencing the side effects after secretin
of hyperactivity, irritability, and sleep problems.
Chez et al. (4) conducted an open-label treatment trial of secretin with 56
children (49 boys and 7 girls; mean age 6.4 and SD 2.7) who all received one
infusion of porcine secretin of 2 international units (IU) per kg. The subject group
included 34 children with a diagnosis of PDD-NOS and 22 with a diagnosis of
autistic disorder (on the basis of DSM-IV criteria). This was a heterogeneous
group in terms of comorbid disorders and the medications they were taking—37
children had abnormal EEGs; 33 children had a history of chronic gastrointestinal
symptoms including diarrhea, vomiting, and constipation. Forty-five children were
on one or more medications, mostly valproic acid and sometimes in combination
with steroids, SSRIs, atypical neuroleptics, and psychostimulant medication.
An outcome measure, the Childhood Autism Rating Scale (CARS), was
completed by parents at baseline and during follow-up visits that varied from
between 3 and 6 weeks after infusion. The authors noted a statistically significant
improvement in the group as a whole in the following areas from baseline to
follow-up (there was no control group): relating to people, imitation, emotional
response, use of objects, adaptation to change, visual response, listening response,
tase/touch/smell, activity level, and verbal communication. Thirty-four percent
of the sample had improvements in gastrointestinal function and eye contact.
Areas that did not show significant change included intellectual level, fear, body
use, and nonverbal communication. Although the change in average CARS score
was statistically significant pre- and postsecretin, this difference in rating was
less than the six-point improvement that the authors designated as being clinically
significant. Thirteen of the 56 children reached this clinically significant level
(23% of the total sample) and 10 of these 13 (77%) were severely autistic. Eleven
children had no change or were worse—for example, displaying increased hyper-
activity, agitation, and reduced responsiveness to others. There was no specific
clinical area that showed dramatic improvement. Rather, the overall change in
CARS ratings was caused by somewhat subtle improvements across the different
clinical categories as listed above. No anaphylactic reactions were observed.
Double-Blind Studies
Owley et al. (17), of the University of Chicago, published their study on the
Internet because of the demand for rapid access to information about the potential
use of secretin. It was a double-blind, placebo-controlled, crossover study, part

of a multisite study with a planned total subject number of 60. In this part of the
study, 20 subjects were included between the ages of 3 and 12 years with a
diagnosis of autistic disorder made by the Autism Diagnostic Interview–Revised
(ADI-R) and Autism Diagnostic Observation Schedule–Generic (ADOS-G). In-
travenous porcine secretin (Ferring Pharmaceuticals, Tarrytown, NY) was admin-
istered in a dosage of 2 CU/kg) either at baseline (secretin–placebo group) or
at the end of week 4 (placebo–secretin group). Outcome assessments included
the ADOS-G, a test of visual perception, fine motor skills, and vocabulary. The
Vineland Adaptive Behavior Scales were administered at baseline and weeks 4
and 8. The Gilliam Autism Rating (GAR) Scale and Aberrant Behavior Checklist
(ABC) were given at baseline and weeks 2, 4, 6, and 8. The Clinical Global
Improvement Scale was completed at baseline and weeks 4 and 8. They found
no significant differences in the primary outcome measure—the ADOS-G social-
communication scores—between the secretin and placebo groups. In addition,
the two groups showed no significant differences on the GAR or the ABC. There
were no anaphylactic reactions either during or after secretin infusion, and no
side effects were clearly linked to secretin. However, one 8-year-old child who
was also on fluoxetine (40 mg daily), and had no previous history of seizures,
developed a nonfebrile seizure during the third week of the study (the secretin
arm of the study) and another seizure a month after that. Limitations of the study
included the small sample size (that may have obscured small differences) and
the fact that only a single dose of secretin was administered. The strength of the
study was that each child served as his or her own control.
In a double-blind placebo-controlled trial that generated significant media
attention (18), a single dose of intravenous synthetic human secretin (0.4 µg per
kg) or a saline placebo was administered to a group of 60 children ages 3–14
diagnosed with autistic disorder and PDD-NOS. Diagnoses were made using
DSM-IV criteria (16), the CARS and the ABC Behavioral assessments were com-
pleted prior to the infusions and at regular intervals thereafter, up to the end of
4 weeks after treatment. Communication was assessed using the communication
subscale of the Vineland Adaptive Behavior Scales. The severity of autistic be-
haviors was assessed using parent report, the ABC, and the Clinical Global
Improvement Scale. In addition, the Vineland and the Treatment Emergent Symp-
toms Scale, a rating scale that measures medication side effects, were adminis-
tered.
Fifty-six subjects completed the study (28 in each group). The authors re-
ported that there were no significant improvements on any of the outcome mea-
sures in either group (secretin and placebo). In particular, there was no significant
change in overall severity of autistic symptoms and behaviors, nor was there any
significant change in communication skills. Subgroup analysis showed that the
children with autism and those with PDD-NOS showed a similar response to
secretin. No significant side effects to secretin were reported.
Despite these negative findings, 69% of all study parents reported that they
remained interested in pursuing the use of secretin as a treatment for their chil-
dren’s difficulties (63% of parents of children who received secretin and 76% of
parents of children who received placebo). It is apparent that parents are likely
to continue to advocate for the use of secretin as they have done with other
alternative treatment for autism (dietary manipulations, vitamin therapies, and
sensory integration techniques) despite the lack of empirical evidence.
This study was notable for its use of standardized outcome measures to
assess change as well as the attempt to differentiate the diagnostic categories of
autism and PDD-NOS. Shortcomings include the short-term nature of the study
in a disorder that is unlikely to show change in such a short period, the use of
only a single dose of secretin whereas multiple doses may be more effective,
and the use of synthetic secretin—past reports of positive effects were following
treatment with porcine secretin. A critique of this study by Horvath (19) cautioned
that the majority of children who show improvement on secretin do so gradually
and after repeated injections. It was noted that subjects did not have serious gas-
trointestinal symptoms and the outcome assessments that were used were insensi-
tive to change. In addition, Horvath suggested that children be given the secretin
in a fasting state because of the possible antagonism from other gastrointestinal
hormones.
Chez and colleagues (4), following on their open-label study, decided to
further test the benefits of secretin and assess whether the above changes were
due to rater bias or the real effects of the drug. They chose to study the subgroup
of children who had shown apparent progress in the first study and included
additional subjects as well. In the second double-blind, placebo-controlled, cross-
over clinical study, 25 children (22 boys, 3 girls) with an average age of 6.0
years (SD 2.4) were included. Nine of the subjects had gastrointestinal symptoms.
Group A received secretin followed by placebo 4 weeks later and group B had
placebo followed by secretin. Subjects were evaluated at baseline and, weeks 4
and 8 on the CARS and detailed neurological and symptom questionnaires com-
pleted by physician or nurse (devised by the authors’ clinic). Parents also com-
pleted diaries and noted changes in behavior. The study found no statistically
significant overall differences in CARS scores between the groups at weeks 4
and 8. No significant adverse events were reported at the time of infusion with
secretin.
Within group A there were no statistically significant group differences in
CARS scores from baseline to week 4 (secretin arm) and weeks 4 to 8 (placebo
arm), i.e., no difference between placebo and secretin. In group B, there were no
significant differences after the placebo infusion; however, after secretin, parents
perceived their children as having improved, particularly in the areas of expres-
sive language, gastrointestinal function, eye contact, and receptive language. De-
spite this finding, the authors concluded that there were no significant differences
in CARS scores of children treated with secretin as compared with those treated
with saline, and therefore that no obvious clinical benefits were evident in chil-
dren with varying degrees of severity of autism after receiving a single infusion
of secretin. No specific subgroup was identified who responded preferentially to
secretin. They suggested that the perceived improvements noted by parents (in
both the open-label and the controlled studies) may have been due to “expectancy
effects”—the trial led to an expectancy by parents of a positive response, which
was then reported to investigators. In a critique of the study, Dr. Bernard Rimland
(20) argued that the study design had a bias toward a negative outcome and that
the authors downplayed the positive findings in both their studies.
Chez et al. (4) acknowledged the limitations of their study. These included
the use of the CARS as an outcome measure, as this instrument was not designed
to be sufficiently sensitive to detect subtle changes in the course of a short-term
treatment trial. Future trials would need to use standardized assessment instru-
ments as well as a variety of standardized, well-validated parent, clinician, and
teacher outcome-assessment instruments. It would also be important to include
independent evaluators who could reliably assess behavioral change. Another
methodological weakness was that the children were not separated into those
who were receiving psychotropic medication (the majority, with 80% of the sam-
ple being on some form of medication) and those who were receiving secretin
alone. The study’s findings might therefore have been confounded by drug–secre-
tin interactions.
The authors suggested that future research should attempt to identify the
possible mechanisms of action of secretin as well as describe the neurobiology
of the effect of secretin on the brain, either directly (crossing the blood–brain
barrier) or indirectly through neural or humoral mechanisms.
In summary, as a single infusion, secretin has been found to be clinically
ineffective; however, cinical trials that investigate the efficacy of multiple doses
of secretin are in progress or nearing completion.
Conclusion
Researchers remain largely in the dark about the function of secretin and related
peptides and their respective receptors in the brain. It is not clear whether findings
from animal studies will be replicated among humans. It remains to be determined
whether peripheral neuropeptide dysfunction reflects central neuropeptide
changes. In cases where improvement has been noted, it is unclear whether the
therapeutic benefit is due to an improvement in gastrointestinal symptoms or
attributable to neurobiological changes in the brain.
Evidence from open-label and double-blind controlled treatment trials of
secretin in autism does not support any therapeutic benefit in the area of social
and communication deficits. Given the heterogeneity of autism, however, the
possibility remains that there is a small subgroup of children with autism who
may benefit from secretin treatment.
Secretin may not be harmless—the repeated use of porcine secretin may

lead to the development of antibodies to secretin (17). Of further concern is the
amount of time and money invested in a treatment that appears to have no va-
lidity.
Pressure from powerful autism advocacy groups directed toward federal
research and funding institutions enabled the scientific community to respond
rapidly in their investigation of the role of secretin in autism. The media played
an important role in bringing this alternative treatment to the public, with the
Internet rapidly providing detailed information (both positive and negative) to
thousands of parents of autistic children. The important lesson of this focus on
secretin as an alternative treatment for autism is that well-designed, double-blind,
placebo-controlled studies are essential for providing valid and reliable efficacy
data.
VITAMIN B6 (PYRIDOXINE) AND MAGNESIUM

In the 1960s Bernard Rimland, Ph.D., was instrumental in promoting the idea of
a biological etiology for autism. In 1967 he began distributing a questionnaire
to parents of autistic children that dealt with many aspects of each individual’s
history and treatment (21). Information gleaned from this survey pointed toward
the possible effectiveness of vitamin therapies. Dr. Rimland followed over 200
autistic children on megadoses of vitamins in the 1970s and came to the conclu-
sion that vitamin B6, or pyridoxine, was associated with significant behavioral
improvement by parental report in 30–40% of patients. A few children experi-
enced irritability, sound sensitivities, and bedwetting that appeared to clear with
the addition of magnesium. Further double-blind, controlled studies were done
by Rimland et al. (22) and Lelord et al. (23) with subjects who had responded
in the open trials, with improvement seen in up to 47%. Improvements were
noted in a wide range of symptoms, including improved eye contact, decreased
self-stimulatory behavior, increased curiosity, fewer tantrums, and increased
speech in the 16 and 15, respectively, pre-selected children. Noteworthy is the
worsening that was observed with the crossover design.
More recently, Findling et al. (24) raised doubts about the efficacy of this
treatment in a 10-week double-blinded study of 10 patients. However, no clini-
cally significant side effects have been reported in the literature, although the
possibility for magnesium toxicity exists as well as peripheral sensory neuropathy
with high doses of pyridoxine. Dr. Rimland anecdotally reports four cases of
mild paresthesias that resolved on decreasing or discontinuing the pyridoxine.
Used in the proprietary mixtures that are available and at the recommended dose
(on average 17 mg/kg of pyridoxine, 7–8 mg/kg of magnesium), however, it has
generally been considered safe. The majority of studies have shown some benefi-
cial effect, a fact acknowledged even by critics (25). Although definitely not a
cure, pyridoxine does play a role in tryptophan metabolic pathways, but the sup-
posed metabolic defect is unknown and currently there is no way to test for it.
Martineau et al. (26) suggested that it might decrease elevated levels of homova-
nillic acid in autistic subjects; the clinical significance of this is unknown. Others
have shown some evidence of changed in evoked potentials (27). Again, this is
an interesting finding whose significance is currently not understood.
In the case of metabolic, vitamin-responsive defects, high doses of a vita-
min will improve coenzyme binding of a mutant enzyme and partially improve
function. Whether this is the explanation for the apparent benefit of pyridoxine
in some autistic children has not been clarified.
VITAMIN A
At the 1999 conference of DAN! (Defeat Autism Now!, an organization of physi-
cians and scientists convened by the Autism Research Institute), pediatrician Dr.
Mary Megson hypothesized that autism may be due to a G-alpha protein defect
that is reversible with natural vitamin A (28). G-alpha protein diseases refer to
defects in the production or activity of G proteins, which are important signaling
molecules that are intermediaries for a host of chemical messengers. For the
most part these diseases have been limited to rare endocrine disorders. Recently,
however, they have been implicated in more common disease states, including
hypertension (29). According to Dr. Megson, the patients at risk for autism would
be those with a family history of at least one parent with a pre-existing G-alpha
protein defect, including night blindness, pseudohypoparathyroidism, or thyroid
or pituitary adenomas. She proposes that in these instances there may be a defect
in the hippocampal retinoid receptors that are essential for vision, sensory percep-
tion, language processing, and attention. Natural vitamin A would repair the de-
fective transmission. A review of the basic science literature certainly suggests
that retinoids are important in many brain structures, including the hippocampus,
where it promotes cell proliferation (30). It may also play an important role in
gene regulatory events postnatally (31).
This area of research is noteworthy, but it is not at all clear how it fits into
the autism puzzle. Dr. Megson reports encouraging results anecdotally in several
autistic patients, with disappearance of the common “sideways” glance, improved
eye contact being one of the first benefits, as well as immediate improvements
in language, attention, and social interaction, in addition to normalization of ab-
normal lipid profiles. She believes these changes are due to the stimulation of
blocked acetylcholine receptors by vitamin A in the form of cod liver oil in
association with urocholine, which purportedly acts as the “switch.”
An interesting study in mice was presented at the 2000 Society for Neuro-
science meeting in New Orleans, Louisiana. Entitled “A Required Role for Vita-
min A Signaling in Hippocampal Long-Term Synaptic Plasticity,” it was done
at the Salk Institute and funded in part by the National Institutes of Health. The
study suggested that withholding vitamin A from adult animals impairs learning
pathways, and that these changes are reversible with vitamin A administration.
Many questions remain as to the role of vitamin A in typically and atypi-
cally developing brains. It should be remembered, though, that vitamin A toxicity
is manifested by anorexia, hepatosplenomegaly, and increased intracranial pres-
sure. A clinical trial using cod liver oil in autistic children has been approved
by the American College for Advancement of Medicine, an organization dedi-
cated to alternative and complementary medicine based in Laguna Hills, Califor-
nia, and is now underway.
VITAMIN C
Vitamin C, found in high concentrations in the brain, fulfills vital functions
throughout the body. It has been proposed that high doses of vitamin C may
decrease stereotypic behaviors through a dopaminergic mechanism. In 1993
Dolske and collaborators (32) conducted a 30-week double-blind, controlled trial
with ascorbic acid as a supplemental pharmacological treatment in 18 autistic
children in a residential school. Behaviors were rated weekly using the Ritvo-
Freeman scale as well as sensory motor scores, and were found to be significantly
decreased in association with administration of ascorbic acid. The dose used was
8 g/70 kg/day. The only major concern in the possibility of kidney stones. How-
ever, further studies are necessary to delineate vitamin C’s efficacy and its place
in the pathogenesis and treatment of autistic individuals.
DIMETHYLGLYCINE
Dimethylglycine is classified as a nutritional supplement and has been proposed
by Bernard Rimland and others as a safe substance that should be used as a first-
line treatment of autistic symptoms. A recent double-blind, controlled pilot trial
was done in eight autistic males ranging from 41/2 to 30 years of age (33). Three
scales were used: the Campbell-NIMH rating scale, an experimental rating scale,
and an individualized rating scale for each subject. Analysis of the results re-
vealed no statistically significant differences. The major methodological weak-
ness was the low dose and small sample size. As with vitamin C, no conclusions
can be drawn based on such preliminary work.
ORG 2766
It has been demonstrated that ACTH (adrenocorticotropic hormone) plays a role
in recovery from brain damage, in part by modulating the activity of endogenous
opioids and the NMDA (N-methyl-D-aspartate) receptor (34). Other basic science
research has focused on the effect of ACTH (in the form of its analog ORG 2766)
on learning (35) and social interest (36). ORG 2766 had been reported to improve
social and communicative behavior in autistic subjects. A controlled trial pub-
lished in 1996 failed to replicate earlier findings (37). Outcome was assessed
using the Aberrant Behavior Checklist by parents and teachers as well as by
detailed observation of 30 of the 50 study subjects. Interestingly, significant im-
provements were noted outside the defining variables, in a subgroup of patients
who were more hyperactive with more stereotypies and abnormal speech, less
initial eye contact, and a lower performance IQ. The authors of this study wonder
whether ORG 2766 would be useful for certain subtypes of autism. Basic science
research on ORG 2766 by Horvath’s group continues (38) and may prove to be
particularly germane if an excitotoxic mechanism of neuronal death is found to
be important in the pathogenesis of autism.
CHELATION OF HEAVY METALS

Chelation treatment is based on the premise that exposure to heavy metals causes
or contributes to the brain dysfunction in autistic individuals. The current unprec-
edented human exposure to heavy metals is well established, and the toxicity of
heavy metals has been delineated in detail. See, for example, the U.S. govern-
ment’s own Environmental Health Information Service and its five publications
that deal with the many ramifications of this issue. However, a link between
heavy-metal exposure and autism spectrum disorders has not been established,
or even examined, with the possible exception of two studies done in the late
’70s and early ’80s that did not find any evidence of increased levels in the blood
and hair of autistic children (39,40). However, it has been noted that parents of
autistic children have more exposure to chemicals than matched controls (41).
At the 2000 meeting of the American Academy of Child and Adolescent Psychia-
try, a poster presented by Ozgur Yorbik and collaborators (unpublished) reported
plasma copper levels of autistic children that were significantly higher than nor-
mal. The significance of this finding is unknown. In theory, as explained by Maile
Pouls, Ph.D., on the Health Education Alliance for Life and Longevity (HEALL)
website, the heavy metals in question would include aluminum, arsenic, cad-
mium, copper, lead, mercury, nickel and platinum. These are found in a multitude
of sources, seemingly unavoidable in our postindustrial age. Low-level methyl-
mercury has recently come under scrutiny because of increased recognition of
its neurotoxicity to developing nervous systems (42). Of special concern is expo-
sure from fish consumption by pregnant and nursing women. Infants are exposed
to a disproportionate amount through consumption of human milk. As cited in
this report, a committee of the U.S. National Research Council determined that
0.1 µg/kg body weight per day is a scientifically justified level of methylmercury
exposure for maternal-fetal pairs. Autism has not been specifically mentioned;
however, exposure to the metal has been implicated in many domains of neuro-
cognition, including language, attention, and memory. Another source of expo-

sure that has come under fire, especially in the autism community, is the mercury
in thimerosol found in vaccines. Safe Minds is a parent organization that argues
on its website that 187.5 µg of mercury is given in vaccines from birth to
age 6 months, compared with, for example, 17 µg found in a can of tuna. This
is significantly in excess of federal guidelines, as the FDA warned in 1999.
Thimerosol-containing vaccines remain widely used despite the availability of
newer versions without thimerosol. Another possible source is the mercury
in dental amalgam fillings (43). Presumably exposure to the fetus would be
greatly increased when dental work is performed during pregnancy.
Effects of heavy-metal toxicity may appear after acute or, more frequently,
chronic low-level exposure to air, water, and food sources. The pathogenesis is
described by Dr. Pouls as stemming from free radicals, causing tissue damage
through unchecked oxidation. It is well established that this is the mechanism
that operates in most degenerative diseases. Diagnosis is done mainly by analysis
of hair samples by special laboratories. With the exception of those for lead and
iron, these tests are not commonly performed by mainstream labs, and there may
be problems with the validity of the results. Standard treatment of documented
heavy-metal toxicity is by intravenous chelation. Proponents indicate that oral
chelation may be just as effective, albeit slower. Oral preparations of mixtures
of vitamins, minerals, bioflavonoids, phytonutrients, amino acids, enzymes, and
miscellaneous other substances are commercially available, which may be more
appealing for parents combing through possible alternative medicine treatments
such as chelation for their disabled child. One case report (44) describes a 41/2-
year-old boy diagnosed with attention-deficit/hyperactivity disorder and autism
who had a high lead level. The child improved while being treated with the chelat-
ing agent succimer and then regressed when this was discontinued. Undoubtedly
more research in this area is needed. As Dr. Coleman proposed in the 2000 edition
of her book, to arrive at a more definitive conclusion as to the role of “chemicals”
or xenobiotics in the etiology of autism, it would be necessary to conduct prospec-
tive studies on people who are exposed to these substances and follow the health
of their children. Another area for further research would be the possibility of a
decreased ability to detoxify such substances in autistic subjects, leading to
greater cellular injury (45).
ANTIFUNGALS AND ANTIBIOTICS

In 1966, Bernard Rimland’s group noticed in the responses to their parental ques-
tionnaires frequent mention of thrush in infants later diagnosed with autism. This
led to speculation of fungal-associated autism. In 1995, medical biochemist Wil-
liam Shaw, Ph.D. found abnormal organic acids in the urine of two brothers who
had autism in addition to occasional muscle weakness (46). As he explains in
his book Biological Treatments for Autism and PDD, he believes that these com-
pounds are derived from intestinal bacteria and fungi. Laboratories such as his
own Great Plains Laboratory and the Great Smokies Laboratory test for these
metabolites in the urine of autistic children as well as for excessive amounts of
yeast and anaerobic bacteria in the stool. The typical scenario described is of a
child with frequent antibiotic treatments, usually for repeated ear infections, who
then develops chronic diarrhea and regresses into an autistic state. There are
anecdotal reports of improvement on antifungal treatments such as diflucan and
Nizoral, as well as with low-sugar, low-yeast diets.
Recently, in this same vein, Sandler et al. (47) reported unexpected behav-
ioral improvement on Vancomycin in eight of 10 autistic children. The subjects
all had a prior history of treatment with broad-spectrum antibiotics followed by
chronic diarrhea and a regressive type of onset in which prior developmental
gains prior to diagnosis had been lost. Behavior was evaluated by coded video-
tapes scored by a clinical psychologist blinded to treatment status. The improve-
ments did not persist at follow-up. However, the findings add to the hypothesis
of a “gut–brain connection” in autism. This idea is widely disseminated and is
cited in many alternative treatments, including diet for food allergies, immuno-
globulin therapy, antifungals, and secretin. It may have started with the clinical
observation of concomitant steatorrhea and autism, and continues with the MMR
controversy currently unfolding as its latest manifestation. Further scientific in-
quiry is necessary to understand whether the intestinal dysfunction leads to or
contributes to autistic symptoms, is coincidental, is a consequence of a primary
insult or is unrelated.
DIETARY INTERVENTION
Several metabolic defects have been described in association with autism (48).
These include phenylketonuria, histidinemia, adenylosuccinate lyase deficiency,
dihydropyrimidine dehydrogenase deficiency, 5″-nucleotidase superactivity, and
phosphoribosylpyrophosphate synthetase deficiency. It is clear that specific di-
etary interventions in these cases can often produce dramatic improvements. Most
of these defects have been described in a very small number of cases and have
associated abnormalities such as megaloblastic anemia, seizures, and other neuro-
logical abnormalities. In the case of hyperuricosuric, or “purine,” autism, as many
as 10–30% of the autistic populations are afflicted. Symptoms include cognitive
delays, poor muscle tone, hearing loss, seizures, poor social skills, and specific
dietary sensitivities. Plasma levels are usually within normal limits, but excretion
is increased. Diagnosis is done by the uricase method on a 24-hour urine collec-
tion. No effective treatment has been found, but a low-purine diet with or without
allopurinol has been helpful. It is unlikely that the elevated uric acid itself is
causing autism, as other disorders with much higher levels are not associated
with autistic symptoms (49).
Lay literature abounds promoting a casein-free, gluten-free diet as a treat-

ment for autism. Related to the gut–brain connection hypothesis, it is speculated
that food allergies—in this case, to dairy and common grain products—lead to
altered gastrointestinal function of a “leaky gut” that allows peptides to enter the
bloodstream and then the central nervous system, where these peptides have been
described as having properties similar to those of opiates. This related to a theory
popular in the 1980s that autism is akin to an opiate-intoxicated state character-
ized by social withdrawal, introversion, and decreased sensitivity to pain. Unfor-
tunately, trials with opiate antagonists did not support this contention. But more
recent studies do suggest a role for naltrexone in self-injurious behavior, as inter-
acting in some way with the immune system.
An interesting paper from Italy reports on 36 autistic children placed on
an elimination diet (50). Behavioral improvement was reported as well as immu-
nological abnormalities not found in 20 normal controls. These included high
IgA antigen-specific antibody for casein, lactalbumin, and β-lactoglobulin IgG
and IgM for casein. Another diet attempted by some parents is the Feingold
program, which eliminates synthetic colorings, flavorings, and preservatives as
well as medicinal and natural sources of salicylates (apples, oranges, tomatoes).
This diet was originally proposed for children with attention-deficit/hyperactivity
disorder and has produced uncertain results (51). With this diet, as with the glu-
ten- and casein-free diet mentioned above, supporters describe many nonspecific
symptoms as evidence of food allergy. The list includes catarrh, red cheeks and
ears, puffiness and dark circles under the eyes, frequent colds, and asthma as
well as a comprehensive set of behaviors found in autism. In a recent presentation
to the Allergy Research Foundation, pediatrician Dr. Michael Tettenborn reported
that 28 of 57 children with an autism diagnosis showed definite and sustained
improvement on a diet low in yeast and milk and gluten products and/or antifun-
gal treatment. This was a self-referred group, mostly with intestinal symptoms
coexisting with autism.
All elimination diets require significant effort by the family, but may be
worth trying, particularly when intestinal symptoms are also present. Attention
must be given to meeting nutritional needs. The abundance of lay literature and
support for these types of diets helps to fuel the hopes of many parents, despite
the paucity of hard data. Controlled studies of diet elimination therapies would
be very helpful in sorting out fact from fantasy.
AUDITORY INTEGRATION TRAINING

Auditory integration training was propelled into the autism whirlwind several
years back, when a book was written that described the miraculous recovery of
an autistic girl. The treatment consists of having the child listen via earphones to
a specified series of tones and frequencies in order to retrain the brain’s auditory
processing. A review of the literature includes five studies that have produced
discouraging results that are at best equivocal (52). In the latest study, done in
March of 2000, a crossover experimental design was provided for 16 autistic
children and again no differences were detected on teacher-rated measures, IQ,
or language comprehension. There was a decrease in adaptive/social behavior
scores and expressive language quotients. Fifty-six percent of the parents were
unable to identify in retrospect when their child received the treatment. Many
occupational therapists and schools for autistic children throughout the country
use techniques of sensory integration that are felt to often be helpful as part of
an overall educational program. Their benefits may be secondary to some other
mechanism. This is yet another area to be researched.
CONCLUSION
In evaluating unproven treatments for autism, it is important to be mindful of
the “Hawthorne phenomenon.” This is not simply a placebo effect; rather, it de-
scribes the effects of parental expectation. The extra attention given uncon-
sciously to the child has been shown to influence the results of a given treatment.
This awareness does not discount the possibility of a true effect, but it does high-
light the need to adhere to rigorous scientific standards in the research of this
still unfathomable and tragic disorder.
It is logical to presume that innovations in treatments for autism should
stem from breakthroughs in understanding the pathophysiological mechanisms
of the disorder. However, this is not always the path that scientific advancement
takes. Although some resources and hopes are diverted to alternative hypotheses
and treatments, there may be some benefit in having a free-for-all brainstorming
of ideas. In the literature—both mainstream and alternative—there are many
interesting hypotheses, especially in the area of a metabolic/immunological basis
for autism that is triggered by an environmental insult, whether it be an infection,
exposure to toxins, or vaccine-associated antigens. The increase in autism re-
search is encouraging; some definitive answers can be expected as well as many
more new questions.
SELECTED WEBSITES
Dr. Rimland, ARI, vitamin B6: www.autism.com/ari
Mercury and vaccines: www.safeminds.org
Dr. Megson, vitamin A: home.att.net/pediatricaac
Heavy metal detoxification: www.heall.com/healingnews/may/heavy
Purine autism: www2.dgsys.com/purine
Dr. William Shaw: www.greatplainslaboratory.com
Elimination diet: www.panix.com/donwiss/reichelt.html
Autism Society of America: www.autism-society.org/asa home.html
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17
Behavioral Assessment and Treatment
Tristram Smith and Caroline Magyar

University of Rochester Medical Center
Rochester, New York, U.S.A.
INTRODUCTION
Although autism is biological in origin, behavioral treatment is currently the best-
studied intervention for this disorder. Researchers have published more than 550
peer-refereed, data-based investigations on behavioral treatment (also called ap-
plied behavior analysis), and these investigations have shown that the treatment
confers a wide range of benefits (1). For example, it helps most individuals with
autism communicate with others, engage in play and leisure activities with peers
and caregivers, carry out self-care activities such as toileting and dressing, acquire
academic and vocational skills, and manage disruptive behaviors such as tantrums
or stereotypies (2).
From a behavioral perspective, individuals with autism have biological im-
pairments that reduce their ability and motivation to learn in ways that typically
developing children and adults do. In particular, individuals with autism have
little skill or interest in playing creatively, conversing, modeling other people’s
actions, exploring their environments, attending to teachers’ instructions, or read-
ing books on topics that are unfamiliar to them. As a result, a primary goal of
behavioral treatment is to provide learning situations that enable individuals with
autism to experience success and that motivate them to continue learning.
Because many interventions developed for individuals with autism have
proved ineffective or even harmful (3), behavioral practitioners believe that it is
essential to use interventions whose benefits have been documented in controlled
studies and that are derived from scientifically sound principles on how to pro-
369
370 Smith and Magyar
mote learning. Moreover, they believe that the effects of these interventions need
to be monitored carefully for each individual with autism who receives them.
Behavioral assessment and treatment are usually implemented by parapro-
fessionals who work under the close supervision of professional behavior ana-
lysts. Such professionals should have master’s, doctoral, or postdoctoral training
in behavior analysis from university departments of psychology, education, or
human development and a year or more of internship experience providing behav-
ioral assessment and treatment for individuals with autism (4).
ASSESSMENT
Prior to a behavioral assessment, individuals with autism should complete an
interdisciplinary evaluation to establish the diagnosis, rule out medical conditions
other than autism (e.g., hearing loss), and determine the individual’s current skill
level. The focus of behavioral assessment is on directly observing an individual
in order to obtain precise information on the activities that the individual per-
forms. The main purposes are: a) identifying behaviors to address in treatment
(target behaviors), b) examining how events influence these behaviors (functional
analysis), c) determining what skills an individual needs to acquire in order to
perform new behaviors (task analysis), and d) evaluating interventions (5).
Target behaviors are either behavioral excesses (activities that the individ-
ual with autism performs too often or too intensely, such as tantrums or stereoty-
pies) or behavioral deficits (activities that the individual with autism performs
too seldom or not at all, such as communicating or playing with toys). A func-
tional analysis focuses on three kinds of events: 1) antecedents, which are events
that occur immediately before the behavior and thus may trigger it, 2) conse-
quences, which are events that occur immediately after a behavior and thus may
increase or decrease the likelihood that the behavior recurs, and 3) establishing
operations, which are events that alter the effects of antecedents and conse-
quences.
Investigators have developed many methods for conducting a functional
analysis (6). Perhaps the simplest and most common approach is to set up an
antecedent–behavior–consequence (A-B-C) chart, on which each episode of the
behavior is recorded as it occurs, along with events that were observed immedi-
ately before and after the behavior. A more rigorous approach that is useful with
especially severe or complex behavior problems is to have trained raters observe
the individual with autism and score the antecedents, behavior, consequences,
and establishing operations on a standard rating form. Another approach is to set
up observation sessions during which antecedents and consequences are system-
atically presented and removed. Data are usually graphed and interpreted by vi-
sual inspection (e.g., looking for consequences that reliably follow the behavior),
but inferential statistics such as time series analyses may also be used.
Behavioral Assessment and Treatment 371
Teachers select interventions based on the results of the functional analysis.

For example, if a functional analysis indicates that an individual with autism
tantrums in response to requests and that the tantrums lead others to withdraw
the requests, the intervention may be composed of teaching appropriate responses
to requests and instructing others not to withdraw these requests. Teachers also
set a specific goal, tailored to the needs of the individual with autism, the environ-
ment in which the behavior occurs, and the target behavior. For example, if an
individual with autism is included in a class with typically developing children,
any episodes of aggression might jeopardize this placement; hence, the goal
would be to reduce aggression to zero. However, if an individual with autism
displays a stereotyped behavior such as hand flapping, eliminating this behavior
completely might be unnecessary. Hence, the goal might be to reduce hand flap-
ping during teaching situations (when it might interfere with learning), while
allowing it at other times.
Once teachers have specified an intervention and goal, they monitor the
frequency of the behavior to determine whether the intervention is effectively
reducing it. They may also continue to keep A-B-C charts, because the environ-
mental events that influence the behavior often change over time or turn out to
be more complex than the initial assessment indicated. If data indicate that the
behavior is decreasing, teachers continue the intervention. If not, they modify
the intervention.
Although the foregoing examples have focused on behavioral excesses,
functional analyses are also important for behavioral deficits because they facili-
tate the identification of antecedents, consequences, and establishing operations
that are associated with increased rates of behavior. For example, instructions
presented in a pictorial format may yield a higher rate of correct responding from
an individual with autism than instructions presented in words. Access to favorite
toys may be more reinforcing than hugs for one individual, while the reverse
may be true for another. Additionally, task analyses of the target behavior are
critical. Even a seemingly straightforward activity such as brushing one’s teeth
involves many skills (finding a toothbrush and toothpaste, putting the toothpaste
on the brush, turning on the water, etc.). Speaking a word to make a request (e.g.,
“cookie”) requires that the individual with autism utter several different sounds
accurately, blend these sounds together to form the word, and recognize when
the request is appropriate. Because individuals with autism may not learn skills
without special instruction, each skill involved in an activity may need to be
identified and taught individually. Task analyses of an activity are usually carried
out by carefully observing individuals who are proficient at the activity (7).
To benefit from learning a skill, individuals with autism need to use it
consistently. Hence, teachers set a criterion for mastery of the skill (e.g., correct
responding in 90% of opportunities for two consecutive days). Also, because the
rate at which individuals with autism use the skill may vary greatly across set-
tings, teachers usually specify the settings in which the behavior is to occur. They
may do so by outlining a sequence of goals. For example, the first goal might
be to enable the individual to respond accurately to instructions in a one-to-one
teaching situation. After this goal has been achieved, the next goal might be for
the individual to respond accurately to the same instructions when given in a
small-group teaching situation, then to do so on community outings. Data are
collected on the number of opportunities to perform the skill being taught, the
number of times the individual correctly used the skill, and the level of assistance
that the individual needed to perform the skill (e.g., did he need manual guidance
to perform the skill, or did he perform the skill in response to an instruction
without extra help?). These data are graphed, and the rate of correct responding
and need for assistance are analyzed by visual inspection of the graphs to deter-
mine whether the rate of correct, unassisted responses is increasing. If so, the
intervention is continued until the individual attains the criterion for mastery. If
not, the instructional format is altered in an effort to increase the rate of progress.
In sum, behavioral assessment and treatment are intertwined. Initial assess-
ments serve as the basis for selecting interventions. Ongoing assessments of re-
sponse to interventions may lead to revisions of the initial assessments and modi-
fications of interventions.
BEHAVIORAL TREATMENT
Principles
Behavioral treatment of children with autism involves systematically applying
principles derived from research on learning in order to increase adaptive and
functional behavioral repertoires (2). The treatment is comprehensive, targeting
skills in all domains of development. Developmental sequences and educational
models for typically developing children are used to guide the treatment plan.
Intervention occurs across settings and often involves multiple instructors. Col-
laboration with caregivers and involvement of peers are also emphasized. Inter-
vention methods are designed to create multiple learning opportunities and enable
high rates of success for individuals with autism during both skill-acquisition
and skill-application phases. The four main teaching formats are as follows:
1. Discrete trial training (DTT): DTT is a highly structured, precise in-
structional procedure characterized by a) one-to-one interaction be-
tween the teacher and the individual with autism, b) short and clear
instructions from the teacher, c) carefully planned procedures for
prompting the individual to follow instructions and for fading these
prompts, and d) immediate reinforcement for each correct response.
2. Loosely structured training: for situations when individuals with au-
tism do not need the tightly controlled learning situations provided in
DTT, investigators have developed a variety of “loosely structured”

skills-training approaches. In such approaches, teachers select teaching
materials and tasks but follow a more flexible format than in DTT. For
example, they may set up a schedule (often presented in a pictorial
format) for individuals with autism to follow, rather than giving in-
structions at each step. Also, they may have a peer model a skill rather
than demonstrate the skill themselves. In addition, they may conduct
behavioral skills training (BST), in which they give an instruction,
model an appropriate response, have individuals rehearse this response,
and give feedback and reinforcement for this response. Further, they
may provide instruction in small groups rather than to one individual.
3. Incidental teaching: in incidental teaching, the teacher sets up environ-
ments that encourage the child to initiate activities and then instructs
him in the context of the activities that he has chosen. For example,
the teacher may put toys in sight but out of reach and, whenever the
child attempts to gain access to one of the toys, the teacher may ask,
“What do you want?” and require that the child name the toy in order
to obtain access to it.
4. Free Operant Instruction: in free operant approaches, teachers reinforce
appropriate behaviors and discourage disruptive behaviors when they
occur, but they do not systematically arrange the environment or pro-
vide cues for these behaviors. For example, teachers may aim to “catch
children being good” (e.g., praise children when the children are play-
ing quietly and appropriately with toys).
Within each of these formats, teachers commonly simplify teaching situations
further. For example, they may work toward a target behavior by initially ac-
cepting a rough approximation of it and then reinforcing close and closer approxi-
mations (a procedure called shaping). Or they might break the behavior down
into smaller units, teach each unit individually, and then connect the units together
(chaining).
Overview
Treatment progresses in stages, each of which has specific objectives. Stages
vary greatly in length depending on the individual’s skill level and response to
treatment. The beginning stage has two interdependent goals: teaching behaviors
that promote learning (e.g., sitting in a chair, attending to the teacher, and looking
at the teaching materials) and reducing behaviors that interfere with learning (e.g.,
aggression, noncompliance, and self-injury). Teachers usually employ DTT to
teach and reinforce learning-readiness skills. During DTT, they also use reductive
procedures, described in “Maladaptive Behaviors” below, to decrease interfering
behaviors. This phase of treatment is crucial to establishing basic rules of social
interaction and identifying adults as consistent sources of positive and negative

consequences. It also introduces the individual with autism to the basic frame-
work (instruction–response–consequence) that many future teaching interactions
will follow (2).
The second stage of treatment emphasizes going from basic to more com-
plex skill repertoires. During this stage, individuals are taught how to respond
to instructions, follow directions, express their needs and ask questions, match
objects and pictures, identify numbers and letters, count, play with toys function-
ally and interact with peers, draw and write, eat independently, and assist with
dressing and bathing.
In the third stage, treatment focuses on advancing skill development and
application to include observational learning, problem solving and coping, under-
standing and following social rules, and participating in classroom activities. The
main objective of this stage is to prepare individuals with autism for placement
into community settings such as public-school classrooms.
Curriculum
Language and Communication
Behavioral training for establishing language and communication in individuals
with autism evolved out of the conceptual work of Skinner and the experimental
work of Salzinger and others who suggested that language, like many other
classes of behavior, could be conceptualized as operant behavior (i.e., behavior
influenced by contingencies of reinforcement) (8,9). Behavioral teachers have
developed curricula to enable individuals with autism to progress from being
preverbal to having extensive communication skills (10). For preverbal individu-
als, the teacher usually begins by using DTT to teach receptive language skills
such as following directions and selecting objects requested by the teacher. For
the latter, the teacher chooses objects that the individual prefers and that are
commonly found in the individual’s environment (e.g., favorite toys or foods).
In the first step of DTT, the teacher displays one object at a time, gives a verbal
cue (e.g., “touch book”), and may prompt the response (e.g., physically guiding
the individual’s hand to the object). The teacher immediately reinforces a correct
response (e.g., providing access to the object for a brief time) and corrects an
inaccurate response. At the end of this sequence, the teacher removes the object
briefly (1–3 seconds), then brings the object back and starts the sequence again.
Instruction continues until the individual reliably selects the object without a
prompt. Next, the teacher uses the same procedures to instruct the individual to
select a second object when that object is presented alone. Once the individual
reliably selects these two objects when either is presented alone, the teacher pre-
sents two objects simultaneously so that the individual learns to discriminate
between requests for each object (e.g., selecting a book in response to “touch
book” and selecting a doll in response to “touch doll”). After the individual has
mastered this discrimination, the selection of additional objects is taught in the
same manner as with the first two. Also, the individual is taught to generalize
the skill by responding to varied instructions (e.g., “show me the book” or “point
to the book”), across different settings (e.g., home vs. school), with different
instructors.
Receptive language training expands quickly to include such skills as fol-
lowing multistep directions and comprehending verbs, prepositions, adjectives,
and functions and classification of objects. Teachers use a combination of DTT,
loosely structured approaches, and incidental teaching methods to establish skills
and generalize these skills to the individual’s everyday environment.
Once the individual receptively identifies a small set of items (usually about
10), expressive language training begins. For those with minimal expressive
speech, teachers use DTT to teach imitation of sounds. Later, they focus on teach-
ing how to combine sounds into syllables, words, and, eventually, phrases. Indi-
viduals who have difficulty imitating oral motor movements needed to make
sounds may receive intensive training in making such movements and while this
training is ongoing may be taught to use alternative or augmentative communica-
tion, such as a picture symbol system. Whether focusing on vocal language or
augmentative communication, the next goal of expressive language instruction
is to teach the individual to request and label a variety of objects (usually ones
previously mastered in receptive language training). Subsequently, individuals
are taught to label pictures and actions that they or others perform. Teachers
apply incidental teaching methods concurrently with DTT in order to help indi-
viduals use their new language skills to communicate in everyday settings (e.g.,
placing objects in sight but out of reach so that individuals are likely to request
them). Teachers may also implement loosely structured approaches to expand
these skills. For example, they may teach individuals with autism to play prere-
corded social phrases that prompt them to converse with peers. Once such skills
have been mastered, expressive language instruction may proceed to advanced
skills such as speaking in sentences that include parts of speech (e.g., prepositions
and pronouns) and morphemes (e.g., verb tenses and plurals), asking and answer-
ing “wh-“ questions, making conversational statements on a topic, and joining
ongoing conversations.
Play and Social Interaction
Through DTT and loosely structured approaches—especially BST—individuals
with autism learn simple imitation skills that they can use in play and social
interactions, such as blowing a kiss, clapping hands, waving, building with
blocks, rocking a doll, rolling a truck, and stirring a spoon in a pot. These skills
are then combined to form longer behavior sequences and pretend-play activities.
Subsequently, with BST, individuals with autism may master other social skills
such as appropriate greetings and conversational statements (11). Peers often fa-
cilitate instruction, by serving either as models for new skills or as tutors who
direct individuals with autism to use their skills in everyday settings (12). To
help individuals play and engage in other leisure activities without supervision,
teachers can instruct them to follow picture activity schedules (13).
Cognitive and Academic Skills
Teachers employ DTT methods to teach preacademic skills such as matching,
counting, number and letter identification, and drawing (14). They then imple-
ment skills-training methods to teach more advanced academic skills such as
reading, mathematics, spelling, language arts, science, and social studies. Al-
though few studies have compared different BST approaches, clinical experience
suggests that the most effective ones include carefully planned sequences of skill
development and techniques for modifying instruction to suit individuals’ learn-
ing styles (e.g., relying on pictorial rather than verbal instruction and allowing
more time to complete tasks) (15).
Motor Skills and Independent Living Skills
Although fine and gross motor skills are often a strength for individuals with
autism, some exhibit delays in this area, particularly in their performance of
planned sequences of motor activities (16). Individuals with autism who are
skilled at imitation may learn a variety of activities when the teacher simply
models the activities and reinforces correct application. Others may also require
graduated guidance (i.e., providing physical assistance, which is systematically
reduced as the individual progresses) (13). In addition to these procedures, chain-
ing is useful for teaching activities that involve a sequence of behaviors. For
example, dressing is best taught using backward chaining: the last step in the
sequence is taught first, followed by the second-to-last step, and so on, until the
whole sequence is acquired. Thus, in teaching an individual with autism to put
on her pants, a parent might place the pants on the girl and zip up the front but
leave the top button undone. Using graduated guidance, the parent would assist
her to fasten the top button and then reinforce her. Once she had mastered this
step, the parent would leave the zipper down in addition to keeping the button
undone. This process would continue until the daughter learned to independently
step into her pants, pull them over her ankles, raise them up her legs, zip, and
button. In order to help individuals perform self-help activities without supervi-
sion, teachers often instruct them to follow picture schedules (13).
Maladaptive Behaviors
Individuals with autism often demonstrate behavior problems (e.g., aggression,
noncompliance, self-injury) that interfere with learning and overall functioning.
Treatment for behavior problems varies depending on the function or functions

the behavior serves for the individual, as determined from functional-analysis
procedures described above, under “Assessment.” In general, however, there are
two goals: reducing the problem behavior and strengthening alternative, more
adaptive behaviors (e.g., asking for a toy instead of climbing up shelves to get
it) (17). DTT and loosely structured instruction are used to enhance skills—
particularly in the areas of communication and play—and incidental teaching
and free operant procedures that involve reinforcement are used to strengthen
existing adaptive behavior. For example, teachers may reinforce behaviors that
are incompatible with the target behavior (e.g., clapping hands instead of flapping
them in front of the eyes) or reinforce behaviors only when they occur at a low
rate (e.g., asking to leave the teaching situation once every 15 minutes rather
than asking continually throughout the session). Another reinforcement strategy
is to follow the completion of a less-preferred or non-preferred task with the
opportunity to engage in a preferred activity. Token economies, in which individ-
uals accumulate stickers or pennies that they exchange for a larger reinforcement
such as the opportunity to watch a video, are often an effective way to administer
reinforcement.
Usually, when implementing an intervention to reinforce appropriate be-
havior teachers also employ an intervention to reduce the problem behavior. Per-
haps the most common reductive procedure is to withhold reinforcement for the
problem behavior (an intervention called extinction). For example, the teacher
may ignore an individual’s screaming but reinforce appropriate verbal requests
for attention (e.g., calling the teacher over). Extinction may also be used for
stereotyped behaviors. For example, the teacher may extinguish hand flapping
by covering the individual’s eyes, thereby cutting off visual feedback that may
reinforce the flapping. Another reductive procedure is overcorrection, which con-
sists of one or both of the following components: restitution and positive practice.
In restitutional overcorrection the individual is required to correct his misbehavior
by restoring the environment to a better state than it was in before the misbehav-
ior. For example, if a child throws her juice cup on the floor she may be required
not only to wipe up the spill but also to clean the surrounding floor area. In
positive practice overcorrection the individual repeatedly engages in an appro-
priate behavior that is similar in form to the target behavior. For example, in the
scenario described above, the child may be required to practice pouring her juice
down the drain. An additional reductive procedure, response cost, uses a combi-
nation of reinforcement and reductive procedures. In response cost, the individual
loses a previously acquired reinforcer when she displays the target behavior. Re-
sponse cost is often used as part of a token economy. For example, a token
economy may include giving a sticker for every 10 minutes of appropriate on-
task behavior but taking away a token for every instance of yelling.
It is inappropriate to implement reductive procedures in isolation. If they

are used, they should be part of a multicomponent treatment plan that includes
methods for increasing alternative, appropriate behaviors.
OUTCOMES OF BEHAVIORAL TREATMENT

Studies have indicated that with behavioral treatment most individuals with au-
tism acquire receptive and expressive spoken language skills and use these skills
to communicate with others (18). In addition, almost all individuals with autism
who receive training in visual communication systems such as the Picture Ex-
change Communication System (PECS) learn to use such systems to communi-
cate (19). Most also acquire skills for interacting with peers, playing with toys,
and engaging in leisure activities, although many use these skills only when re-
quested to do so (1). Success rates of 70–80% have been reported for toilet-
training interventions (e.g., Ref. 20). Several such interventions exist, and if more
than one is attempted success rates likely rise above 80%. Almost all individuals
with autism can be taught to put on clothes, close fasteners on clothing, and carry out
household tasks such as putting away belongings (13). Most also acquire academic
skills such as counting, identifying numbers, and reading words. In addition, most
learn vocational skills such as assembling objects or filing documents (15).
When implemented early in life (starting prior to 4 years of age) and inten-
sively (20 or more hours per week), behavioral treatment may greatly enhance
the functioning of individuals with autism. Several peer-reviewed studies have
indicated that early, intensive behavioral treatment yields average IQ gains of
approximately 20 points, similar gains on other standardized tests, and place-
ments in less restrictive educational settings than are typically offered to individu-
als with autism (21). However, the studies have had significant limitations, such
as small numbers of participants and nonrandom assignment of participants to
treatment groups. Thus, the results are highly encouraging but require replication
in large-scale, randomized clinical trials.
ALTERNATIVES AND SUPPLEMENTS TO BEHAVIORAL

TREATMENT
Apart from behavioral treatment, many other psychological and educational inter-
ventions are available for individuals with autism. Some of these interventions
are usually offered as alternatives to behavioral treatment, whereas others are
offered as supplements to it. Of the many alternatives to behavioral treatment,
only two have been evaluated in peer-reviewed studies: Project TEACCH and
the Denver Model.
In Project TEACCH (22), individuals receive classroom instruction de-
signed to accommodate the learning deficits of autism. For example, because
visual skills tend to be more advanced than verbal skills, instructions may be
presented in pictures rather than words, and tasks may have visual prompts
(grooves to indicate where to place items, pictures of each step of a task, etc.).
Because classroom noise and intrusions from peers may be distracting or aver-
sive, individuals with autism often work at their own workstations rather than
with classmates, although some activities occur in small groups. Because transi-
tions from one activity to another may be difficult, individuals with autism may
have a highly structured schedule displayed at their workstations. A number of
uncontrolled and quasiexperimental studies have suggested that Project TEACCH
is effective, and some investigators have suggested that its benefits may be com-
parable to those of behavioral treatment. However, because no controlled studies
have evaluated TEACCH, additional research is needed (21).
In the Denver Model (23), teachers aim to establish “warm, affectionate,
playful relationships” with individuals with autism. They also encourage individ-
uals with autism to exercise control in these relationships by choosing activities,
asking to finish activities, and taking turns in songs and games. Such relationships
are intended to facilitate teaching skills in the following areas: communication,
sensory activities (e.g., messy art projects or play at a water table), independent
living skills, social interaction, motor activities, and participation in classroom
routines. Uncontrolled studies have indicated that individuals with autism may
make gains on developmental tests after participating in the Denver Model, but
this finding has yet to be confirmed in controlled investigations (21).
The main supplements to behavioral treatment are sensorimotor and rela-
tional therapies. In sensorimotor therapies, individuals with autism are viewed
as having difficulty processing sensory input from the environment and/or
translating such input into effective action. The most common sensorimotor ther-
apy for individuals with autism is sensory integration therapy (SIT), which is
based on the observation that many individuals with autism respond too much
or too little to sounds or tactile stimulation and may seem unaware of their bodies
(24). To improve their responsiveness and awareness, SIT involves activities de-
signed to stimulate sensory systems such as brushing or squeezing parts of the
body, spinning on specially constructed equipment, or engaging in activities that
require balance. Although individuals with autism probably do have sensory
deficits, SIT and other sensorimotor therapies have fared poorly in research. More
fundamentally, investigators have pointed out that there is no basis in biology
or learning theory for expecting that activities such as brushing or spinning would
alleviate sensory deficits (25). However, these activities may help desensitize
individuals to sensory stimuli that are aversive or overly arousing. Also, they
may be reinforcing and thus may be useful when offered as an incentive to com-
plete other activities (26).
In relational therapies, autism is viewed as a disorder that primarily affects
individuals’ ability to enter into meaningful interactions with others. Currently,
the most influential relational therapy is Greenspan’s Developmental Individual-

Difference Relationship-Based Model (DIR) (27), a diathesis-stress model for
autism. According to this model, individuals with autism are born with constitu-
tional deficits that impede their attempts to integrate and regulate sensory input.
However, these deficits cause only minor problems until individuals regress in
development between 16 and 24 months of age. This regression is said to stem
from sensory overload resulting from “the individual’s own emerging capacities
for higher level presymbolic and symbolic functioning” (28). The main goal of
treatment is “establishing a relationship with two-way communication,” particu-
larly between individual and parent (29). This is accomplished by following the
lead of the individual with autism and participating in his or her activities (e.g.,
moving a toy that the child is playing with) so that the individual is likely to
interact (e.g., looking at the parent or moving the car back). Following the child’s
lead is often part of a comprehensive intervention that includes semistructured
teaching and sensorimotor therapies. DIR has not been evaluated in controlled
research. However, DIR treatment approaches resemble certain behavioral ap-
proaches that have been shown to be effective (particularly incidental teaching).
Hence, the utility of DIR warrants investigation.
FUTURE DIRECTIONS
In addition to the need to validate alternatives and supplements to behavioral
treatment, there are a number of directions for future development of this inter-
vention. First, recent research on learning may suggest ways to enhance this inter-
vention. For example, studies on stimulus equivalence may lead to improved
methods for promoting generalization of skills (30). Second, neuropsychological
investigations have identified areas that are particularly difficult for individuals
with autism yet have received little attention in behavioral treatment, such as
theory of mind (recognizing the mental states of others) and executive functioning
(planning, sequencing activities, and adjusting to changes in routines). Hence,
research on how to address these problems in behavioral treatment is likely to
be beneficial (21).
Finally—and perhaps most importantly—because autism is biological in
origin, behavioral interventions will need to be integrated with findings from
biomedical research. Two avenues for such integration may hold particular prom-
ise in the foreseeable future. First, nonresponders to treatment may constitute a
more homogeneous sample for studying associated biomedical problems than
would a general group of individuals with autism. For example, individuals who
remain nonverbal after treatment, who cannot give up routines for more appro-
priate leisure activities, or who do not learn to understand others’ mental states
may be especially informative about the neural basis of each of these deficits.
Second, the neural functioning of individuals who largely overcome such deficits
with treatment may differ from untreated individuals, as has been observed in
other clinical populations (31). Thus, the exploration of such differences may
yield important information about brain–behavior relationships.
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31. Schwartz JM, Stoessel PW, Baxter LR, Martin KM, Phelps ME. Systemic changes
in cerebral glucose metabolic rate after successful behavior modification treatment
of obsessive-compulsive disorder. Arch Gen Psychiatry 1996; 53:109–113.
18
Educational Intervention: Inclusion vs.
Self-Contained Classes
Audrey F. King
New York, New York
INTRODUCTION
The “normalization” movement has been integral in protecting civil rights, de-
institutionalizing and humanizing services for people with developmental handi-
caps (1). Section 504 of the Rehabilitation Act of 1973 and Public Law 94-142
(Education for All Handicapped Children Act of 1975) have had a tremendous
impact on providing quality services to individuals with developmental disabili-
ties. A key problem of service delivery, however, is that the needs of children
with mental retardation and children with autism are not well differentiated (2)
by the laws put in place. Additionally, issues pertaining to children with autism,
including medication, social-skills training, placement, and programming, are not
well addressed by this legislation (3), which is important because autism and
mental retardation are different in terms of developmental pattern and outcome
(4–6). In practice, the effort toward integration has sometimes led to a lack of
diversity of services, inappropriate practices, and a lack of responsiveness to
individuals’ needs (7). More recently, Public Law 106-310 (the Children’s Health
Act of 2000) has outlined plans to increase research and education on autism.
The passing of this law has been a substantial milestone in an effort to discover
the etiology of and effective treatments for autism.
Not only do the needs of children with autism differ from those of children
with mental retardation, but not all therapies for autism are appropriate for all
383
384 King
children with autism. Despite a general diagnosis of autism, the heterogeneity of

the expression of the disorder necessitates individualized treatment plans, based
on careful consideration of each child’s specific symptoms and abilities (8–10).
The need for individualization is supported by the Autism Society of America,
whose policy of parental choice states that no one program or service will be
appropriate for all children with autism.
Children with autism exhibit significant delays in expressive and receptive
language, verbal and nonverbal communication, and social interests and skills,
as well as nonadaptive—and sometimes negative—behaviors, such as repetitive
behaviors, restricted interests, compulsivity and impulsivity, serious over- or un-
deractivity, resistance to change, sensitivity to noises or textures, and self injury.
The provision of appropriate education curricula to children with autism is a
complex issue, with both proponents and opponents of mainstreaming and full
inclusion.
Similar in ideology to “integration,” “mainstreaming,” and the “regular ed-
ucation initiative,” full inclusion involves placing children with disabilities in
regular classrooms. Mainstreaming implies that students participate in selected
regular classes while maintaining a special-education home base, while full inclu-
sion suggests the elimination of a special-education home base, replacing it with
the regular class (11).
EDUCATION ENVIRONMENTS USED WITH AUTISTIC

CHILDREN
A variety of classroom enhancements have been developed and used with autistic
children in special-education, mainstream, and full-inclusion classrooms. These
include peer tutoring, small-group instruction, supportive intervention, and ad-
dressing target behaviors.
Peer tutoring has been successfully used to increase reading fluency in high-
functioning children with autism (12) and to improve imitation and play behav-
iors in low-functioning (13) and high-functioning children with autism (14).
These classwide interventions have been successful; however, the use of very
small sample sizes (one to three children with autism) and the lack of longitudinal
follow-up make these results difficult to generalize.
Studies of small-group instruction for children with autism have shown
positive results. A study by Kamps et al. (12) suggested several effective strate-
gies for teaching children with autism in small groups, including choral re-
sponding (response as a group to a question), student-to-student responding,
quick rotation of materials among the group, and random responding (students
were called on randomly). The results of the study were positive, with discrepan-
cies between the autism and mental-retardation (MR) groups. The autism group
demonstrated higher gains that the MR group, suggesting that there is no general
Educational Intervention 385
teaching model for all children with developmental disabilities. The idea of taking
into full account the specific needs and limitations of children with autism, along
with each child’s cognitive abilities, is an important consideration for education
(15).
Supportive interventions have also been studied as a way to increase the
academic potential of children with autism in full-inclusion or mainstream set-
tings. The practice of providing occupational therapy, speech therapy, and other
important services to children with autism in special-education, full-inclusion, or
mainstream educational settings is widely used and accepted as an important
aspect of service provision (16,17).
Koegel et al. (18,19) suggest that the identification by teachers and psychol-
ogists of “pivotal” target behaviors to be addressed in the classroom may impact
academic and social performance of these children. Such behaviors affect wide
areas of functioning and therefore have a global impact on the child’s functioning
(18).
Another environmental intervention used is the decrease of task size in
order to increase on-task behavior. Sweeney and LeBlanc (20) found that decreas-
ing the number of beads to string resulted in fewer negative or off-task behaviors
and increased the number of beads strung in five children diagnosed as severely
autistic and mentally retarded. This study was based on results using a well-
described but small group of subjects, and yielded some individual variability in
results. These results highlight the importance of decreasing sample heterogeneity
in autism studies by using a sample that not only is well defined but exhibits
homogeneous symptoms, or using a sample large enough to control for individual
differences.
Koegel et al. (21) assessed the effectiveness of teaching self-management
procedures to decrease disruptive behaviors of children with developmental disa-
bilities in full-inclusion classrooms. However, because of the small sample size
used, it is unclear whether this strategy could be generalized.
In summary, current research exploring classroom techniques helpful in
educating children with autism in mainstream, full-inclusion, or special-education
classes is plagued by several shortcomings. First, it may not be enough to classify
autistic children as “high-” or “low-” functioning. In order to determine which
children with autism will benefit from different educational environments, careful
description of their individual skills, deficits, and symptoms is crucial because
of the heterogeneity of the disorder. Therefore, the question is not only “will this
intervention work for autistic children?” but also “will this work for most, or
only a subgroup of, autistic children?” For example, Tjus et al. (22) found that
language age discriminated between the responses to treatment of a group of
autistic children with varying cognitive abilities. Second, the use of small sample
sizes makes generalizing results difficult. Especially because autism is such a
heterogeneous disorder, large-scale studies should be conducted in order to iden-
386 King
tify subgroups of children with autism who benefit from different educational
environments.
FULL INCLUSION VS. MAINSTREAMING VS. SPECIAL

EDUCATION
The discussion of full inclusion and mainstreaming has focused primarily on
children with handicaps and disabilities other than autism (11,12,23). These stud-
ies have not yielded results strongly supporting full inclusion, although slight
trends toward favoring full inclusion over segregation have been uncovered (11).
Few studies have examined the success of fully integrating children with
autism in regular classrooms (11,23). A review of the literature by Mesibov and
Shea (11) uncovered only two research studies evaluating the success of full
inclusion in an autistic population on academic or social outcomes. Harris and
Handleman (24) compared the effect of full inclusion on high-functioning chil-
dren with autism and their normally developing peers. Outcome was measured
as the change in the ratio of language age to chronological age using the Preschool
Language Scale (24). Both typical children and autistic children had significant
increases in rate and level of development, with nonsignificant differences be-
tween the two groups. Myles et al. (25) examined social interactions among and
between autistic children and normally developing peers as well as their regular
classroom teachers. The results of this study suggested that regular-classroom
teachers gave less praise, instruction, and neutral comments but more assistance
to the children with autism compared with normal peers. Socially, the children
with autism initiated few interactions with peers with or without autism. These
findings suggest that successful integration of children with autism should rely
on more than physical integration, and should focus on using more structure and
interventions in order to develop social and other skills. Based on these limited
findings, it is difficult to construct an empirically based argument for predicting
which educational placement will be successful.
Although no “cure” for autism exists, appropriately structured programs for
the education and management of children with autism can significantly enhance
outcomes (26), and this research may help match appropriate educational environ-
ments and subgroups of autistic children. Perhaps children who have responded
well to early intensive behavioral intervention will perform best in full-inclusion
classrooms. It is widely accepted among experts in the field of autism that suc-
cessful treatment requires interventions that are early (before age 5), intensive
(up to 40 hours per week), and sustained (for more than 1 year) (24,27,28,30).
Often, treatment outcome is judged successful if a child can be “main-
streamed” into a regular classroom (24,26,30,31). Mainstreaming and full inclu-
sion are typically not considered until a child has participated in some form of
behavioral treatment. Based on these findings, even special-education classrooms
without specific and individualized curricula for children with autism may not
be the appropriate first-line placement for some, as these classrooms may lack
the intensity and flexibility to modify the behaviors of young or low-functioning
children with autism (30). Thus, children who do not receive or benefit from
intensive behavioral treatment provided before the age of 5 or 6 may not do well
in special-education classrooms. These children may benefit more from schools
with programs that directly address autism and offer specific curricula and envi-
ronments for children with autism (2).
The question remains: what responses to early behavioral intervention
would indicate that mainstreaming, full-inclusion, or special education would be
most appropriate for a given child? Intellectual ability at time of admission to
an intensive treatment program has been determined to be an important predictor
for outcome (24), as have age at first treatment and autism severity (32). Full
inclusion may be a good fit for children who achieve near-grade-level language
acquisition by the age of 6 or earlier.
One concern of parents who desire mainstreaming or full inclusion for their
autistic child is the opportunity for interaction with typical peers (33). The hope
is that through observation and modeling of typical peers, the child with autism
may begin to use more typical or adaptive behaviors, and may become better
socialized. However, autistic children rarely initiate social interactions with peers,
either autistic or nonautistic (11,19,25). In studies that have examined the effect
of academic and social peer tutoring on the social behaviors of autistic children,
there is no evidence for long-term gains in social peer tutoring, although some
short-term gains have been evident (34–36).
Also at issue is to what extent typically developing peers would engage
children with autism. While some typically developing peers [39], but not all
(38), say they would interact with nontypical peers, they may not interact with
them given the opportunity (39). Therefore, it is unclear whether children with
autism would gain a social benefit from mainstreaming or full inclusion.
In summary, while few studies have empirically examined which children
would benefit from full inclusion and which would benefit from mainstreamed
classes, factors such as IQ, age at initiation of treatment, successful early inten-
sive behavioral intervention, and presence of negative behaviors may be related
to academic performance and may determine which subgroups of children with
autism may benefit from full inclusion, mainstreaming, or special education. An
additional factor may be pre-existing functional abilities, because full-inclusion
classes typically do not address these types of “real-world” skills (40).
The extent to which mainstreaming or full inclusion leads to increased so-
cial behaviors and social integration is unclear since studies have yielded mixed
results. As with academic achievement, it is possible that children with autism
with less social impairment may benefit most from social inclusion. However,
studies have not rated children in social dimensions, so there is no evidence for
388 King
this. What is clear is the need for studies using very well-defined samples of
children who are carefully described, and rated on all their symptoms.
PARENT AND TEACHER PERSPECTIVES

Kasari et al. (23) asked 113 parents of children with autism and 149 parents
of children with Down’s syndrome whether they preferred mainstreaming, full-
inclusion, or special-education classes for their child. The parents of children
with autism were less likely to endorse full inclusion. This finding reflects the
view of some parents and professionals that full inclusion for autistic children
would deny them the individualized and specialized services that are essential
(11). Indeed, the families of autistic children found specialized teachers very
important (41), overwhelmingly preferring teachers and teaching programs that
focused solely on treating children with autism (23).
Teachers also have preferences regarding educating children with autism.
A large-scale survey of teachers in Scotland asked about the advantages and
disadvantages of mainstreaming for autistic children, and their own ability to
cope with these children in mainstreamed classes, and what they considered might
be predictors of successful integration (33). A minority of mainstream teachers
supported integrating children with autism. Teachers who had more experience
with autism expressed more confidence in their ability to teach and manage autis-
tic children. Many teachers expressed concern over the effects on other students
of mainstreaming children with autism. A majority of the teachers were willing
to participate in more training (33).
A study by York et al. (42) of special-education and mainstream teachers
in the United Kingdom found that special-education teachers had a more sophisti-
cated understanding of the features of autism and treatment strategies, while
mainstream teachers expressed a rudimentary understanding of the disorder, not-
ing the behavioral difficulties and special abilities exhibited by some children
with autism. Given the results of this survey, it is unclear whether teachers out-
side a special-education setting would be prepared to undertake the special
demands of educating an autistic child. The extent to which these findings may
be generalized to teachers in the United States remains unclear, as studies are
lacking in this area. However, the anecdotal evidence suggests that even the best-
trained and most willing U.S. teachers experience difficulty meeting the needs
of already heterogeneous classes, let alone the special requirements of students
with moderate to severe disabilities (41). Nonetheless, despite being over-
loaded, general- and special-education teachers have gained a substantial amount
of experience, training, and appreciation for teaching children with disabili-
ties (37). But to what extent this experience and training are appropriate for teach-
ing children with autism is unclear given the lack of empirical research in this
area.
Children with autism can experience seemingly unprovoked emotional or

aggressive outbursts if their status quo is disturbed. These outbursts can be pro-
longed and difficult to manage. To effectively manage and extinguish the negative
behaviors associated with autism requires careful training of caregivers, as these
outbursts can result in injury of the child or others.
Children who exhibit behavioral problems—even after treatment—such
as self-injury, aggression, and tantrums, may prove difficult to mainstream, and
even difficult for a special education classroom, depending on the severity of
behavioral symptoms (32). In addition, inaccurate or inappropriate intervention
can actually increase the frequency and intensity of outbursts. Although educa-
tors, especially special educators, have significant training in behavior manage-
ment, teachers’ knowledge about autism and beliefs about managing the behav-
iors of developmentally disabled children are sometimes not supported
empirically (33,41). Meyer et al. (44) found that many teachers believe that
children with developmental disabilities and concomitant behavior prob-
lems require more intrusive teacher supervision to prevent inappropriate interac-
tions with peers. However, the findings of this study, indicated that intrusive
teacher supervision increased the rates of negative behaviors or were super-
fluous to how the disabled child’s interaction with a nondisabled peer. Educators
without training in behavior management of children with autism may use inap-
propriate behavior management and may have much more difficulty teaching
these children. Mesibov and Shea (11) suggest that children with milder handi-
caps and fewer behavioral problems tend to benefit most from integrated class-
rooms.
Full inclusion has been a successful educational environment for some chil-
dren with high-functioning autism (41) or Asperger’s disorder, or children who
respond well to early, intensive behavior-modification therapy (30). However,
research exploring the benefits of full-inclusion and mainstreaming for children
with autism has been limited. Literature on special-education classroom environ-
ments for children with autism has reported mixed outcomes in academic success.
Therefore, it remains unclear which children with autism will benefit from full
inclusion, which will benefit from special education, and which would benefit
from neither.
CONCLUSION
The goal of full inclusion for children with autism is a viable and important one.
While full-inclusion, mainstreaming, and special-education classrooms may not
be adequate or appropriate first-line interventions for children with autism, it may
be possible to identify subgroups of autistic children who will benefit from these
different environments, who will be fully integrated, and who will be placed in
special education. As yet, this question remains unanswered.
390 King
IQ, functional ability, age at initiation of behavioral intervention, and suc-

cessful response to behavioral intervention may all be good predictors of school
placement and achievement, and may be a starting point for predicting which
subgroups of autistic children are likely to benefit from, or be good candidates
for, special education and which will be good candidates for full inclusion. Pro-
spective, longitudinal studies are needed to support these clinical impressions
with empirical findings.
There have been few studies exploring factors contributing to successful full
inclusion or special education of children with autism. In addition, findings have
been mixed and limited by small subject numbers which make generalization of
findings difficult. Further studies have not adequately described the symptom pre-
sentation of the autistic children studied, an important shortcoming given the hetero-
geneity of the disorder. Clearly, there is a strong need for more research in this area.
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19
Consumer Advocacy and Autism
John Maltby
Sleepy Hollow, New York, U.S.A.
INTRODUCTION
In recent years there has been remarkable growth in the amount of attention paid
to autism. Only a generation ago, the syndrome was thought to be too rare, and
its expression too diverse, to warrant much scientific attention. The condition
was blamed on poor parenting, treatment was primitive to nonexistent, and diag-
nosis was delayed or often simply not made at all. In the past 35 years we have
seen enormous gains, many of them arising from the efforts of motivated individ-
uals with autism and their families.
Autism is often depicted in terms of its impact on children; indeed, it was
formerly diagnosed as “childhood schizophrenia.” For a syndrome that has few
treatments and no cure, it is obvious that most people with autism are likely to
be adults. For most individuals and their families, advocacy is a lifelong commit-
ment. Similarly, the public image of the caregiver is generally that of a highly
motivated parent, vigorously arguing for a particular kind of treatment or style
of education. However, a significant majority of caregivers are in fact profes-
sional, mostly low-paid, workers in group homes or workshops, as well as educa-
tors, psychologists, social workers, and medical professionals. These profession-
als constitute the largest body of potential advocates for people with autism.
Autism was once considered a rare disability, with a prevalence of 2–5 per
10,000. Prevalence rates are now generally understood to be much higher. Studies
presented at the 1997 Centers for Disease Control/National Alliance for Autism
Research conference on prevalence put the rate as high as 25 per 10,000. The
CDC-funded study of Brick Township, New Jersey, in 1999 concluded that local
393
394 Maltby
prevalence rates could be as high as 50 per 10,000. There is much discussion

about whether this increase in prevalence rate is due to better diagnosis, broader
diagnosis, or indeed to an actual increase in incidence, or a combination of all
three factors. What is clearly understood is that this is a much more common
syndrome than first thought, with as many as 500,000 people in the United States
affected. For every individual affected there are many more involved as family
members, direct-care workers, and ancillary professionals. The cost of the disabil-
ity is estimated to be in the range of $30 billion annually in the United States
alone.
Autism is no longer the concern of a few desperate parent advocates and
their children; it is a major health problem.
HISTORY OF CONSUMER ADVOCACY

Although Leo Kanner had postulated an organic as well as a psychogenic basis
for autism when he first isolated it as a syndrome in 1943, by the 1960s the
dominant interpretation of autism was that it was psychogenic in origin. This
theory was put forward by psychiatrists, notably Bruno Bettelheim. Bettelheim
maintained that the source of the symptoms was emotional neglect by parents,
principally by the mother, and that treatment required therapy for the family at
least, and possibly removal from the home of the individual with autism.
Parents of children with autism, under the stress of raising a child with
severe problems and labeled as emotionally cold and neglectful, knew that this
cruel theory was untrue. Many had raised other, perfectly healthy children. The
trials they went through soured the relationship between medical professionals
and people with autism and their families for many years.
The National Society for Autistic Children (NSAC), whose famous logo
of a child’s head in a jigsaw puzzle was later adopted by the Autism Society of
America (ASA), was formed in the United Kingdom in 1962. Consumer advo-
cacy for individuals with autism got a major boost with the 1964 publication of
Infantile Autism: The Syndrome and Its Implications for a Neural Theory of Be-
havior by Bernard Rimland, whose work was the first to highlight the neurologi-
cal and physical origin of autism. Dr. Rimland had been impelled to carry out
his research because his son had been diagnosed as autistic. In 1965, he and other
parents formed NSAC, the forerunner of today’s ASA. In The Siege (1967), Clara
Park tells the story of raising her daughter Jessy, then 8 years old. For many of
their fellow parents these two books—Rimland’s and Park’s—were their first
ray of hope. Over the years many parents have followed their example into print,
describing the unique stories of their children, touching a chord with their fellow
parents.
In 1967 Bettelheim published The Empty Fortress, which restated his view
that autism was psychogenic in origin. It was widely reviewed and acclaimed.
Consumer Advocacy 395
Bettelheim, although the most visible proponent of psychogenesis, was hardly

alone at that time in his views. Indeed, while totally discredited in the United
States, it is still the dominant view in some supposedly enlightened countries, and
continues to color relations between advocates and professional service providers.
An investigative study of Bettelheim, The Creation of Dr. B by Richard
Pollak (1997), exposed Bettelheim as having falsified his background, academic
record, and results. By then the damage was beginning to be repaired, but Bettel-
heim and his adherents probably set autism research back by a generation. The
cause of reason was kept alive by the ASA, a partnership of a few dedicated
researchers, individuals with autism, and their family members.
The ASA now has some 25,000 members, most of them individuals with
autism and their families, but with a strong professional contingent as well. To-
gether with its foundation its annual budget, raised mainly by fund raising from
its members, is $2.2 million. It is organized into some 200 chapters at the state
and local level. For many years it was the only advocacy organization in the
United States. In the 1970s, ASA took part in the passage of Public Law 94-142,
which entitled every child to a free and appropriate education. It is hard to remem-
ber that prior to that time children with severe disabilities could be actively denied
an education and forced to stay at home or be institutionalized. Today, in collabo-
ration with other disability groups, it still actively lobbies for the continuation
of the educational entitlement, now known as the Individuals with Disabilities
Education Act (IDEA). This act, from which so many gains have been made and
which is one of the cornerstones of the Applied Behavioral Analysis education
movement, was a great victory, but one that even today has to be defended every
year from attempts to water it down. Unfortunately, these efforts often arise from
well-meaning advocates, teachers’ unions, and school boards, and therefore indi-
rectly from some of the professionals who work every day with our children.
ASA has stepped up its advocacy for adults with autism, lobbying for im-
provement in work and living conditions. It has lobbied at the state and national
level for increase of Supplemental Security Income/Social Security Disability
Insurance (SSI/SSDI) benefits, expansion of Home and Community Based Med-
icaid Waiver services, Medicaid /Medicare coverage, and adult entitlements in
general.
Each year ASA has sponsored a national conference that highlights the
latest in treatment and scientific research. It publishes information packets on
autism-related subjects, both on its website and in print. Most of these packets
are available in both English and Spanish and some in other languages also. Its
chapters provide local support to people dealing with “the system,” and a place
to share their experiences with other families.
The history of autism advocacy is entwined with the history of autism treat-
ment and with the syndrome itself. In the early days there was not much applied
or basic research into the causes of autism and its effective treatment. In the
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vacuum this absence created, various treatment methods were promoted. Over
the years these have included the use of vitamins, hyperbaric chambers, holding
therapy, facilitated communication, electric shock, aversion treatment, auditory
integration, psychopharmacological “treatment,” and the use of high doses of
secretin. In many instances these were trumpeted as “cures,” sometimes on the
basis of very little evidence. None of them has been borne out when examined
in a rigorous scientific fashion. Some of them have lured families into spending
a great deal of money and time chasing rainbows. Some of them have posed
physical danger to the subjects. This problem is exacerbated by the public media,
which seize on touching stories and promising cures and ignore the slow and
steady process of developing real science. Despite the imperfections of the movie
“Rain Man,” it was fair to say that at that time any publicity was good publicity.
Colleagues would ask a parent whether their son could count cards, rather than
whether he was “artistic.” Ten years or so on, now that public awareness is higher,
the advocacy community needs to assert common sense and be more active in
refuting pseudo science.
Given the history of autism, it is not surprising that any research that points
to families with an autistic child as being in any way “different” treads a delicate
path. However, it is becoming clearer that in many instances there is evidence
of subclinical autistic-like symptoms in both the immediate and extended fami-
lies. With a disability with a potentially strong genetic component, this should
not be surprising. The advocacy community has tended to embody some of these
traits of obsessiveness and of difficulty in communication. Professionals are natu-
rally wary of alluding to these problems, but it is past time for all involved to
recognize this obstacle and find ways to work through it.
As a syndrome, autism covers a wide range of different levels of ability.
It is now hoped that eventually we will be able to better understand the different
disorders that the syndrome encompasses. When we hear a lecture by Temple
Grandin, Ph.D., inspiration for Oliver Sacks’ An Anthropologist on Mars (1995),
we are witness to a remarkably gifted person. Dr. Grandin eloquently describes
how she deals with life as a person with autism (see Chapter 20). Her insights
are an inspiration to other people who live and function with autism, and to the
families of those people with autism who have never spoken a word, appear
severely retarded, and demonstrate self-injurious behaviors, and whose lives are
an immense daily struggle. It is also clear, though, that what we are seeing across
the spectrum is a range of people with very different levels of functioning and
very different needs. Dr. Grandin’s insights are comforting but may not relate
to the situation of other, less able autistic individuals. Despite this diversity, the
diagnosis is likely to be the same. For example, a highly verbal yet profoundly
introverted individual lacking social skills might be given the same diagnostic
label as a nonverbal, self injurious person classified as severely retarded. On the
face of it, such a lumping together is nonsensical. The clinician making the diag-
nosis is typically not the professional who will be carrying out the treatment or
looking after the individual. Unfortunately, one label is taken to fit all.
The NIH treatment conference (1999) concluded that, while there is strong
support for applied behavior analysis as an education tool and indications that
some pharmacological treatments may reduce symptoms in some instances, we
are a long way from certainty for any particular regimen. Findings presented
there demonstrated that in many pharmacological studies the placebo effect was
much higher than that found in studies of other disabilities—often higher than
40%. This helps us understand the sincerity of the more vigorous proponents of
some of the fad treatments. It is hard to deny or oppose a “treatment” that may
seem to work.
Taken together, the lack of specificity of diagnosis, the fad treatments that
are promoted like wildfire, the natural fractiousness of the community, and the
wide range of ability and need that the spectrum presents make coordinated advo-
cacy very difficult. Over the years these factors have created periodic schisms
in the advocacy community. The worst of these arose in the mid-1980s. There
was violent disagreement over the use of “aversives,” ranging from the most
benign use of rewards to extremes such as the use of cattle prods, aggressive
bullying language, and severe physical restraints. In the absence of real treatment,
desperate measures were being attempted, and in some cases, as with almost all
autism treatments, were showing apparently positive results. This was also the
height of the “deinstitutionalization” movement, and some families were justifi-
ably afraid that in moving their sons or daughters “into the community” services
would be lost. Some of these fears have been shown to be unwarranted, especially
when there was a strong advocate for the individual. However, for many people
with autism, especially those with no family or advocate, there was a loss of
support, and they simply went from one expensive institutional setting to a
smaller, cheaper one–or worse.
These bitter ideological arguments of the mid-1980s wracked the autism
community. Despite the vocal extremists, most people found themselves some-
where in the middle, opposed to painful treatments but not opposed to rewards,
opposed to the worst of the institutional settings but not ready to throw their son
or daughter into an unfriendly society. One consequence of the arguments was
the creation of new advocacy groups, generally focused on a single issue. With
the progress being made in autism research these schisms are beginning to heal,
as the goals become clearer and, even more important, attainable.
In its history the ASA has been called on many times to endorse a treatment
that may have seemed to work for some people, or to come out against a particular
kind of aversive. It was advisedly reluctant to endorse one treatment over another,
or to endorse any at all, given the lack of hard science. It created the Options
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Policy, which states that individuals and families should be able to pursue treat-
ments that make sense to them, without an ASA endorsement. Naturally this
decision, in turn, disaffected many people.
RESEARCH ADVOCACY
The first major private funding initiative in basic autism research came with the
establishment of the Seaver Center in New York City in 1994. The Center is
primarily funded by the Seaver Foundation, which has strong links with local
advocacy groups in the New York area and has also reached out to the national
advocacy groups. Since its inception in 1994, the Foundation has invested over
$10 million in applied and basic autism research. In addition, the Center has
received funding from other voluntary groups and from the NIH.
After much lobbying by ASA and by the professional community, the NIH
held its first symposium on autism—“The State of the Science”—in 1995. For
the first time, this brought together leading researchers to summarize what is
known about causes and treatments for autism. The symposium highlighted the
need for increased research funding, for an organized effort to recruit consumer
research participants, This event and the growing body of substantive research
led to the creation of three national consumer-led research-funding organizations.
The National Alliance for Autism Research (NAAR), founded in 1995 in
Princeton, New Jersey, began funding researchers in 1997. NAAR’s focus has
been on funding basic science investigators, particularly those seeking to gather
initial data prior to submission for more substantial long-term grants to the NIH
and other funding sources. It assembled a stellar Scientific Advisory Board
(SAB), and its annual RFP process, which in 1997 attracted 27 proposals and
funded five grants, received 90 proposals and expected to fund 21 awards and
fellowships for a total of $1.5 million in 2000. In its first four years, NAAR has
funded 50 studies for a total of $3 million, in addition to its outreach work and its
Autism Tissue Program (ATP) joint venture with the ASA Foundation (ASAF).
In 1994, the ASA had provided significant funding to the Stanford autism
project when its program came under threat following the death of its leader, Dr.
Roland Ciaranello. This followed initial discussions at the Las Vegas Conference
of that year aimed at creating a biomedically based foundation. The Society de-
bated long and hard over whether to focus exclusively on biomedical research
or to add applied research to its mission. The ASAF was finally formed in 1996
and was tied very closely to the ASA governance process and to ASA’s member-
ship . In addition to funding basic research, the ASAF also funds applied research
to lead to better understanding and improved conditions in treatment, schooling,
work and housing, consumer rights, etc. In 2001, in addition to ASA’s funding
commitment to advocacy, services, and education, the ASAF funded five such
projects. These are projects of major interest and utility to its constituency that
focus on the lifelong need for support of the individual with autism. In a signifi-
cant change from the fractious history of autism advocacy the ASAF has created
close ties to other advocacy and research organizations. Rather than try to dupli-
cate the NAAR SAB, for example, ASAF directs the bulk of its basic science
funding through the NAAR SAB process, and has to date funded eight grants
this way. In addition, ASAF and NAAR created the ATP, which serves to recruit
potential brain-tissue donors from the ASA membership and to enable exchange
of existing tissue between researchers. This has been a very successful program,
doubling the limited amount of tissue available.
ASAF also created the Autism Research Registry (ARR), which enlists
ASA members and the broader community as potential research participants
through a clearinghouse designed to protect research subjects and researchers,
increase the number of research subjects, until now a very small pool, and reduce
the cost and time involved in recruitment. This registry currently includes 1500
people across the United States.
Cure Autism Now (CAN) was founded in 1995 in Los Angeles. CAN funds
basic and applied research, and has made commitments of $5.7 million in research
awards over the past five years. CAN created the Autism Genetic Research Ex-
change (AGRE), a collaborative gene bank for genetic research in autism, which
by the end of 2001 had created a bank of immortalized cell line DNA and frozen
serum samples from a total of 400 multiplex families.
None of this would be possible without the continuing sponsorship and
facilitation of the NIH. As recently as 10 years ago, some divisions of the NIH
felt that autism research would be futile because the syndrome was too diffuse
and too rare. Worse still, the autism advocacy community seemed to be bitterly
divided along numerous fault lines. They “couldn’t get their act together,” and
this turned the research community away from them. Thanks to the vigorous
activity of autism professionals in the NIH, these obstacles were gradually over-
come. In 1995, the year of the first State of the Science Conference, NIH funding
was $10 million. In 1999 NIH funded $26 million for autism research, and the
total for year 2000 was close to $47 million. Still modest in relation to the scope
of the disorder, but a vastly different profile and approach. Since the 1995 confer-
ence NIH has created an interdepartmental forum to exchange information from
all the different facets of NIH research, a forum that involves consumers.
The CDC and NAAR cosponsored a prevalence conference in 1997. Esti-
mates spanned the range from the historical estimate of 5 per 10,000 to as high as
30–40 per 10,000 in Japanese and Scandinavian studies. Recently after vigorous
consumer advocacy from families in Brick Township, New Jersey, a CDC study
concluded that the local prevalence was closer to 50 per 10,000. Whether in-
creased prevalence is based on improved or loosened diagnosis, driven by the
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fact that a diagnosis is the key to services, or whether there has been an actual
increase in incidence remains an open question. What is clear is that, as a result
of consumer activity, autism is recognized as a major public-health problem.
Applied behavior analysis (ABA) is sometimes identified with particular
practitioners but is a technique used to varying degrees in different educational
milieux. Although the number of large-scale controlled studies is limited, small-
scale studies demonstrate that individuals have had positive outcomes over an
extended period of time. Normally identified publicly as being most effective
with young children, it is also applicable to older individuals. The families of
young children with autism have been very vigorous in the past decade in pressur-
ing school districts to provide ABA-type learning environments for their children.
In some instances these have been incorporated into the public schools; in others,
families have been the driving force behind creating ABA-based classes and sepa-
rate schools. Obtaining these programs has often involved litigation, expensive
for both the families and the school district, in addition to the emotional toll that
the constant battle takes. To support this effort, many organizations have been
created at the local level, some with one purpose only—to create an ABA-based
program—and others that provide wider advocacy. The best known of these orga-
nizations is FEAT (Families for Early Autism Treatment). Founded in 1993 by
parents and professionals in Sacramento, California, FEAT sponsors a website
and workshops in conjunction with the UCLA Clinic for the Behavioral Treat-
ment of Children, promotes awareness of education issues, and provides support
on an ongoing basis to individuals with autism and their families.
ADVOCACY FOR THE INDIVIDUAL

Most of the families of individuals with autism do not expect to be thrust into
the role of advocate. The advocate is the one constant person in a life that will
include many different professionals—medical, educational, and social. It is a
role that lasts a lifetime, and, for parents, beyond their lifetime. For the first time
in history, developmentally disabled individuals are living to middle age and
older, and outliving their parents. The specter of what might become of their
adult children if they are not able to prepare adequately for the future haunts
most parents. There are some steps that the advocate for an individual with autism
can take, and that professional involvement can enhance.
The first step is to be as informed as possible about the science of the
disability. Today there are many resources; the various voluntary organizations
provide basic scientific information and there is a great deal of literature on the
subject. The more informed the advocate or self-advocate, the less likely they
are to be taken in by fads. They will feel less stigmatized. They are likely to
soon know as much or more about the disability than the majority of professionals
they encounter and, while tact is always helpful, can be more in charge of their
own treatment and support.
The second step is to join a local voluntary group—an ARC or ASA chap-
ter, for example. Obviously some function better than others, but it is the best
way to learn how to deal with the local bureaucracy and what programs and
benefits the individual is entitled to, and to share experiences with others with
similar concerns. For most people with autism, day-to-day difficulties are very
local, and very time-consuming, for example, ensuring that receive their food
stamps, SSI, SSDI, Medicaid funding—processes that take many hours of work.
When they go in to an Individualized Education Program (IEP) meeting, they
need to be properly prepared, and they may need help getting transportation and
access to work and leisure. An advocate who knows the science, supported by
the local experience of other advocates, is likely to encounter far better treatment
by the bureaucracy than a passive consumer, with consequently more beneficial
outcomes. While it may sometimes seem otherwise, most social-services bureau-
crats did not go into the field because they were indifferent to people. They fre-
quently enjoy meeting someone who is highly motivated and who has done his
or her homework, and they are more responsive to such advocates.
Third, as the individual with autism grows older, advocates should find a
way to replace themselves. They should put in place the Guardianship structures
that might be needed—Special Needs Trusts, if possible. Information on these
legal structures is available from the ASA and also from most ARCs and the
UJA. These organizations can help to design a long-term financial and service
plan that will survive the advocate. One effective way to create such a support
system is to form a Circle of Support, comprising family and friends and commu-
nity members to share the workload and ensure ongoing support.
All the services an individual will receive in his or her lifetime are provided
by systems. In recent years we have seen a welcome reduction in the size of
some of these service-delivery mechanisms, but virtually by definition they are
likely to be highly structured and not well geared to the needs of the individual.
Systems tend to standardize services and be reimbursed in a uniform fashion,
resulting in generic services delivery. The advocate must therefore be the oil in
the gears. The more vigorous and informed the advocate, the more responsive
the system will perforce be.
LOCAL ADVOCACY
Throughout their lifetime, individuals with autism and advocates for individuals
with autism will find support from local associations. Most parents, regardless
of prognosis, will wonder why this has happened to their child and why it has
happened to them. They will ask this question of themselves for the rest of their
402 Maltby
lives, and it doesn’t have an answer. One of the many assumptions we make of
autism—that it cuts across all social classes and ethnicities—actually seems to
be very true. Most consumer advocates lead very different lives from one another
but have one profound difficulty in common, and it is only with other people
who share the same difficulty that they can ever truly feel comfortable dealing
with it. This common emotional bond should not be the raison d’être of an advo-
cacy group, but it is a necessary part of the foundation.
An effective local group does not have to be one that encompasses the
entire range of needs and abilities—it doesn’t have to be solely about autism,
although the stronger ASA chapters will afford the greatest level of support. The
spectrum is wide-ranging. Some individuals function almost independently and
are verbal and literate, but have excruciating social difficulties at school and work
and are constantly aware of having to “fit in.” Elsewhere on the spectrum, the
focus may be on safety, treatment of self-injurious behaviors, protection from
abuse by group-home housemates, or coping when communication is almost ab-
sent. At the local level, it is hard to form a group that will include people with
experience in different parts of the spectrum, and especially hard to reflect such
diversity if a group was originally formed by a small cadre of families with
particular shared needs. However, the key to effectiveness is to focus on those
things that everyone will have in common, e.g., dealing as a group with local
education authorities, finding a pediatrician or a dentist who works well with
developmentally disabled patients, or determining which local government office
is least obstructive in obtaining benefits. At the same time, bringing in speakers
on a range of topics is one way to address the diversity of need and to better
understand each other’s priorities.
At a very practical level, local organizations around the country have cre-
ated “ombudsman” programs. An ombudsman is a member of the community—
possibly a relative of an individual with a disability—who, after some training,
undertakes to visit a group home or a work or school program. Their job is not
to ensure compliance with regulations; that is a whole industry by itself. Rather,
their function is to visit the programs, act as a friend and support to the individuals
in them, and be alert to the potential for neglect, sterility of content, and quality-
of-life issues that are not covered by the regulatory framework. Twenty five years
after Willowbrook, gross neglect and severe abuse still occur in the group-home
industry; with an active ombudsman program there is an extra level of safeguard.
In many cases, the ombudsman may after a few years become the longest-serving
“staff” member of a program, given the frequency of staff turnover. The people
participating in the program, however, have control over the extent to which they
join with the ombudsman; their friendship is not forced. The programs have been
successful in raising the quality of life for disabled individuals, at a very modest
cost, and without additional regulatory hierarchy. The program is also extremely
rewarding for the ombudsman.
No single organization is likely to fulfill all the needs of an individual with

autism, especially at the local level. An ASA chapter might help with school
lobbying or with support in an IEP hearing, an ARC with establishing residential
alternatives. There are times when organizations find it worthwhile to work to-
gether, for example, an ARC and an ASA chapter to raise awareness on a particu-
lar issue, or a parent organization with a teacher organization to press for better
classroom conditions. On the other hand, there is much to be said for advocacy
groups remaining independent. Provider unions do not have the same interest as
consumer groups. As well, ideologies of even the most well meaning can conflict.
One example relating to research occurred recently. Advocacy organiza-
tions that lobby for the protection of individuals with disabilities from abuse in
the course of scientific research are to be lauded. In some instances, though,
they have gone beyond the bioethical frontier to argue for no “unnecessary” or
“invasive” research with human subjects at all (BioEthics Board Hearings, Wash-
ington D.C., 1998, Harold Shapiro, Chair). People with autism have the right to
be protected from sloppy or unprofessional research. They also have the right to
advocate for and participate in research that will potentially better their lives and
the lives of others. The prospect of one consumer advocacy group opposed to
another is more common than an outsider would expect. In the autism world
there are advocates for different types of schooling, different housing conditions,
and research protocols. Unfortunately, and not unique to autism, their most vocal
adherents tend to have little charity toward one another. A good litmus test for
how much support a particular view might have is to see whether it literally
represents consumer views or, in contrast, is politically motivated
SUSTAINING ADVOCACY
People in the United States have formed countless community organizations over
the years, and it is not very hard to see why the successful ones work. In autism
it is important to have a “big tent” outlook. The spectrum is wide, the needs are
various, and, while not all of them can be met, they should all be considered.
Similarly, with treatment and living options, one size does not fit all. Successful
organizations stay mission-focused and have a structure that provides for succes-
sion and consensus. Fledgling organizations often benefit from a charismatic en-
trepreneur, but one doesn’t need to look far in the business news to see what
befalls organizations that do not learn how to move past that developmental stage.
Another aspect that some groups relegate to too minor a role is fund raising and
development. Organizations should be on a sound financial footing, and a board
should always consider this, along with changing the world, one of their primary
responsibilities. Often the best way to raise money at the local level is through
grants and government funding, a developmental process. The most successful
organizations work with their community, the local politicians, local and state
404 Maltby
government organizations, and other advocacy groups. It is important to build

consensus and hold in check the urge to seek an aggressive solution to every
problem. There are times when a little heat—for example, use of the media or
political pressure—will work to their advantage, but it is a weapon best used
sparingly.
Local media are generally enthusiastic seekers of “content” and are for the
most part genuinely interested in supporting their community. Many local papers
assign a reporter to disability issues, and a surprising number of people read local
newspapers with more attention than they give to national media. Like everyone
else, reporters don’t want to be called only when something is being asked of
them, and so it pays to take a long-term, educational view. A working relationship
with local newspapers, even the local newspaper of a big city, is a very effective
way to build long-term public awareness and to have access when a specific issue
arises.
Television is a very different medium from print. Everyone would love to
be on TV, and often the first question when media coverage is brought up is how
to get the local stations interested. However, TV coverage is difficult to arrange.
At the national level, autism usually gets a story only when a new fad comes
along. The work of serious practitioners, scientists, and advocacy groups that
have worked for years for their cause is not newsworthy. Even at the local level,
television access is very hard for an advocacy group to obtain. Stories are very
brief, mostly less than a minute long. Attention will be on the sound-bite and
the best “visual.” Coverage of a school-board meeting, say, will focus on the
loud and loutish, not on the articulate or deliberative. It is not a medium disposed
to examining a complex issue.
NATIONAL ADVOCACY
The growth of public awareness coupled with real scientific advances in the 1990s
has created steady growth in the size and effectiveness of the national autism
advocacy movement. At the same time, it can appear on the surface to be ever
more diffuse as new organizations spring up almost every month. Perhaps the
real story is that national autism advocacy is finally growing up. We are moving
from a nationwide support group, united against an uncaring public and a mis-
guided medical establishment, to a national disability advocacy movement, lob-
bying for legislation to get serious about research funding, raising money for
services and research, and working with the medical and education community
to increase public awareness at the national level.
Advocacy at the national level falls into four main categories.
Advocating for Research and Treatment

There has been some success here. In 1995, after the first NIH conference, the
total budget for autism research funding was $10 million. The next year that grew
to $14 million and by 1999 to $26 million. The budget for the Centers for Disease
Control was increased from zero to $10 million in the same period. Legislation
already approved by the Senate and now in the House would increase annual
funding to $60 million. The three major research foundations—NAAR, ASAF,
and CAN—have developed a more unified approach to lobbying and to working
with the NIH and CDC. As a result, the legislature and the administration get a
common message and focus. There is still a great deal of work to do. The current
level of funding is a great improvement and has drawn many new scientists to
the field, but the research funding does not yet approach the level of the problem.
We continue to advocate for better funding for basic and applied research, fund-
ing for centers of excellence. In 1999 the ASAF was instrumental in lobbying
the National Bioethics commission to modify its position on human-subject re-
search on individuals with developmental disabilities. The original position
would have so constrained research as to be a denial of the right to direct research
to find treatments and cures for autism.
Educational Rights
The battle to provide for a free and appropriate public education for all children
was not ended by PL 94-142 in 1979. Every year there are attempts to dilute the
act, most recently on the grounds of the need to prevent unruly children from
disrupting classes (this against a background fear of disturbed children bringing
guns to school). Primarily funded by teachers’ unions, this unfortunately has the
effect of pitting the parents of children with disabilities against the parents of
normal children. Advocates need to do a better job of informing the public of
the cost benefit of improved education access, as well as its clinical benefit. In
some ways this is a harder struggle than finding money for research. Most people,
albeit naively, equate funding research with finding a cure. Maintaining the right
to remain integrated in the educational system is asking for a long-term social
change, one that has moved far in the generation since PL 94-142 passed, but
that will need several more generations to reach fulfillment. This advocacy relies
heavily on an organized nationwide grass-roots movement that can be called on
to write and phone its congressional representatives on short notice when faced
with a late session “end run.” We are improving with practice.
The Right to Work and Recreation

One benefit of the recent prosperity in the United States is that as employment
rates have risen it has become somewhat more feasible for people with disabilities
to find meaningful work with meaningful compensation. The Work Incentives
Act, the result of efforts by a coalition of advocacy groups, allows people to
work without compromising their Medicaid benefits. A similar program run by
the Social Security Administration, PASS (Plan for Achieving Self-Support), was
the result of advocacy not only by consumers and their families but also by profes-
406 Maltby
sional social worker organizations. One of the long-term objectives of ASA’s

advocacy for adults is to move people from sheltered workshops into meaningful
compensated employment. This movement is not only about work and econom-
ics, it is also part of a long-term social change.
Poverty
In addition to the medical diagnosis, most individuals with autism have an addi-
tional handicap of poverty. People with developmental disabilities are the most
impoverished of all Americans. They might receive services that cost a great deal
of money, but remain personally impoverished and dependent. Allied with other
disability groups at the national level, autism organizations, principally the ASA,
have lobbied for the expansion and maintenance of SSI/SSDI, food stamps, heat-
ing and air conditioning grants, housing improvement grants, and transportation
subsidies. As we move further away from the long-term institutional model, these
programs will become a more important part of every individual’s support.
SERVICE STANDARDS
Nonprofit provider agencies still retain vestiges of the charitable institutions many
of them sprang from. However, most are small businesses to midsize corpora-
tions, distinguished only by tax treatment from their other private-sector brethren.
We still expect them to be caring and altruistic in purpose, and many are. How-
ever, the lingering aura of charity, and the low pay in the profession, allow for
deficiencies and variability in standards of care. The current euphemism for a
person with disabilities in this context is “consumer.” Most of our “consumers”
do not have much choice as to service provider, and are utterly in their power.
A long-term objective of the autism advocacy movement is to create national
standards for training and qualifications for people who work with individuals
with autism syndrome disorder (ASD). There are possibly as many as 500,000
people whose work is primarily involved with ASD individuals and who have
an interest in improving their professional qualifications, not only in the teaching
profession but, especially, in the human-services professions These professionals
should be the allies of the autism advocacy community.
“SUPRA-NATIONAL” AND VIRTUAL ORGANIZATIONS

One of the first uses the ASD advocacy movement made of the Internet was to
create a network of individuals with “high-functioning” autism who were intellec-
tually inclined to computer sciences as well as temperamentally disposed to the
anonymity of the Internet. They were able to communicate with other people
who faced hurdles similar to their own, without the awkwardness and frustration
of a social setting. This virtual networking has given a huge boost to the confi-
dence of individuals with high-functioning ASD, and has spurred the creation of
self-advocacy and support groups around the world. The ASA (assuring anonym-
ity) provides details on how to participate in several such groups.
In 1999 the Shirley Foundation and the NSAC in the United Kingdom
created and hosted the first Virtual Conference on Autism. There were over
23,000 delegates from 112 countries. While the ASA has for some time been in
touch with organizations in other countries, this was the first truly international
convocation. Because the knowledge available in this kind of forum can reach
people all over the world, the impact on the millions of people with autism will
be extremely powerful.
HOW CAN PROFESSIONALS HELP?

In the United States, at least, the schism between professional providers and the
families of people with ASD that had been created by the psychogenic fallacy
is history, and in many areas advocates and providers work very closely together.
For many years, there was little a physician could tell a person with ASD
or his family. Although we don’t yet have a great range of treatment, there is
now a substantial body of information that an informed physician or educator
can provide. The more that the individual and his or her family know, the more
power and independence they have, i.e., the more control over their own lives.
Professionals should not feel compelled to be polite about some of the junk sci-
ence that has plagued us; they should steer people away from miraculous cures
for autism with the same forthrightness they would use in talking about hocus-
pocus treatments for heart disease or cancer. While the headlines will always be
devoted to the more sensational treatments, long-term education of the public
pays off—we see it in more tolerant public attitudes and better understanding
by entry-level workers. Professionals should take an active role in this process.
Autism research, treatment, and support cross many disciplines. It is some-
times hard for professionals from different disciplines to talk to each other, or
to see what they have in common. Imagine how difficult that lack of communica-
tion is for the individual with autism to deal with. The psychiatrist who meets
quarterly with a patient in his office might be involved in creating an “individual-
ized” plan, the funding for which has to fit a particular regimen administered by
a fiscal worker, the implementation of which has to be supervised by a Certified
Social Worker (CSW), and its day-to-day operation by a direct-care person who
may work in a facility with a staff of two or three people “supervising” 10 or
more individuals.. By the time the plan gets to the individual, it is often unrecog-
nizable. There is very little vertical integration. Many line workers have very
little training in what clinical differences there might be between the people they
look after. Even more sophisticated workers would tend to view every autistic
person as being the same, and prescribe behavioral rules uniformly. There is a
408 Maltby
significant need for more in-service training, for greater understanding of what
the different branches of the system do.
ADVOCACY NOW
It is finally dawning on the medical and political establishment that autism is a
worldwide health problem. The autism advocacy community is beginning to
come together far more effectively as research offers greater hope for the future,
and as all the work done for so many years on educating the public and advocating
for better services and recognition bears fruit. We are at the beginning of a new
phase in advocacy at the national level, one that presents huge opportunity. At
this writing there are two research funding bills in the House of Representatives
and one that has just been passed in the Senate. Since the first NIH-sponsored
State of the Science conference in 1995, there has been a series of others, includ-
ing Diagnosis, Treatment, and the Development of an Animal Model. Dozens of
studies in basic research have been funded by NAAR, ASAF, and CAN. ASAF
has funded a series of applied research studies. The ATP is a national resource
for obtaining and distributing brain tissue for research. The AGRE has facilitated
the use of genetic material for researchers across the country. The ARR is a
national clearinghouse for researchers and research participants.
While the future for national-based organizations looks promising, and the
level of community support has grown, at the end of the day advocacy is most
effective when it is most focused. Each advocate should reflect on where he or
she can do the most good. Advocacy movements can be waylaid by organiza-
tional politics, multiple agendas, and all the ills that corporations are prone to.
Sometimes it is best to think about actually achieving the next step, no matter
how small—make one good thing happen.
FURTHER INFORMATION
The Autism Society of America
800-3-AUTISM
www.autism-society.org
National Alliance for Autism Research, 888-777-NAAR
www.Naar.org
Cure Autism Now, 323-549-0500
www.Canfoundation.org
The Organization for Autism Research (OAR)
703-351-5031
OAR@autism.org
20
Autism: A Personal Perspective
Temple Grandin
Colorado State University
Fort Collins, Colorado, U.S.A.
As an individual with autism, I have learned that, unfortunately, some therapists

and physicians are unaware of autistics’ overly acute senses, specifically hyper-
acute hearing [1,2] For example, the birthday party fun of noisemakers for a
normal child was torture for me. There are many first-person reports of people
with autism who, like me, find certain loud sounds intolerable (3–5).
Some children and adults with autism also have visual sensitivity problems.
I enjoyed visually stimulating things such as flags or automatic supermarket
doors, but individuals with severe visual sensitivities cannot tolerate even fluo-
rescent lights. In her book, Somebody Somewhere (6), autistic Donna Williams
describes how the flicker from fluorescent lights causes her visual overload. A
study conducted by Coleman et al. (7) indicates that fluorescent lights can in-
crease repetitive behavior in children with autism.
Autistic sensory problems are highly variable. When I was a child, I liked
to play with running water; however, another child with autism may not be able
to tolerate the same sound. I was attracted to automatic supermarket doors and
I liked to watch them move. Another autistic child or adult may scream and run
away from these same automatic doors because sudden movement hurts his or her
eyes. Maybe a small anomaly in my visual processing caused me to be attracted to
the movement of the doors. A greater anomaly may cause another individual to
avoid the same stimulus. Waterhouse et al. (8) found it puzzling that I was at-
Adapted with permission from CNS Spectrums 1997; 2(5):24.
409
410 Grandin
tracted to strong visual stimuli, yet high-pitched auditory stimuli hurt my ears.
I don’t think this is puzzling at all. Margaret Creedon (1992, unpublished) found
that I have a very slight jerkiness in my visual tracking although my vision is
otherwise normal. This slight defect may explain my attraction to things such as
flags, kites, and automatic doors.
My auditory processing problems are far greater than my visual processing
problems. When I was a small child I could understand what adults said when
they spoke directly to me, but when adults talked quickly to one another I could
not decipher what sounded to me like gibberish. As an adult, I still have difficulty
hearing hard consonant sounds. Often, I mix up similar sounding names such as
Crandell and Brandell. In such instances, I figure out words by the context cues.
For example, if one is talking about “fog” at the airport, I know from the context
that they are not saying “bog.” I was shocked at how badly I performed on a
series of central auditory processing tests although my pure tone hearing test was
normal. Nevertheless, a pure tone hearing test does not detect problems with
hearing hard consonants or other central auditory processing problems.
THE IMPORTANCE OF CUSTOMIZED THERAPY

When I was 21/2, I had all the classic symptoms of autism. I was placed in an
excellent early intervention program, which consisted of over 40 hours a week
of speech therapy, structured play with a nanny, and old-fashioned lessons on
table manners at every meal. My day consisted or 3 hours of speech therapy class
in the morning in a nursery school with five or six speech-handicapped children.
In the afternoons my nanny played structured games with me and my sister. My
entire day was strictly planned except for a 1-hour rest period after lunch. During
this time, I reverted back to autistic behavior. As in my therapy, the single most
important common denominator for a successful program is to begin when symp-
toms first appear and to structure many hours to keep the child connected to the
world. My therapy did not allow me to tune out and rock for hours, as I might
have been prone to do.
Both my mother and nanny recognized that I needed to be protected from
certain types of sounds such as noisemakers at loud birthday parties and other
noises such as the school bell. Autistic children will often be afraid to enter a
particular place because of a previously experienced hurtful stimulus. One little
boy was afraid of his church because he feared that the clergyman’s microphone
might screech as it had a time before.
My speech therapist used to force me to pay attention by gently grabbing
my chin, which, as long as the room was reasonably quiet, could “snap me out
of it.” She was gently insistent. If she pushed too hard I would have a tantrum
from sensory overload and if she pushed too little there was no progress. She
A Personal Perspective 411
had to push just hard enough to get me out of my world. Children who have
more severe sensory problems than I did may not respond well to intensive pro-
grams such as that of Lovaas (9). I had touch and sound sensitivity problems,
but my senses provided a more or less accurate picture of the world. Children with
more severe sensory problems than mine may be driven into sensory overload if
a teacher grabs their chin.
Williams (10), a woman living with autism whose sensory processing prob-
lems are different from mine, explains that she is what can be referred to as
“mono channel.” She cannot attend to simultaneous visual and auditory input.
In other words, she has to either listen to or look at something but she cannot
do both. In her new book she describes visual shutdown, wherein her visual
system ceases to function when overloaded.
It is clear that sensory function in autism can vary a great deal. Recently,
I talked to a Lovaas therapist who was currently a witness to such variation. She
informed me that she was having great success with two children, but that a third
child was making almost no progress. The third child was moving into sensory
shutdown. Therefore, from a clinical standpoint, there appears to be two basic
types of 2- to 3-year-old children with autism.
The first type of autistic child has relatively mild sensory processing prob-
lems and will probably respond well to a Lovaas-style program. The therapist
can gently pull such children out of their world and reach them through their,
“front door” (11). I also believe strongly that good programs should include sen-
sory treatments. Sensory treatments such as Agren (11) sensory integration as
well as auditory and visual training can help a child’s nervous system become
more receptive to a structured educational program. Vigorous exercise will also
help reduce repetitive stereotypic and maladaptive behavior and Rimland and
Edelson (12) also found that auditory integration training was helpful in reducing
sound sensitivity and improving behavior (13–15). Both my work (16) and Gil-
lingham’s (17) stress the need for awareness of sensory problems in autism.
The second type of child has very severe sensory processing problems. In
severe cases, vision and audition may jumble together.
Williams (6) and Joliffe et al. (18) describe problems autism may cause
with an individual’s kinesthetic sense, the ability to discern body boundaries. For
children of this type, the world is a profoundly confusing place of sensory over-
load, something like living inside a rock and roll speaker. To such a child, fluo-
rescent lights would be like flashing strobe lights. Intrusive methods such as the
Lovaas method often work poorly with these children. If parents report that their
autistic child has tantrums and cannot tolerate large supermarkets, shopping
malls, or similar environments, this is often an indication of very severe sensory
processing problems. Since my sensory processing problems were fairly mild I
could enjoy certain demanding sensory environments such as the supermarket.
412 Grandin
One must be consistently aware that sensory problems are highly variable.
Some children may have visual problems and others may not. One child will be
able to tolerate fluorescent lights and another will not. Therapists working with
autistic children must be able to understand that fluorescent lights or fear of a
phone ringing, problems that arise from sensory processing difficulties, may make
it hard for a child to learn. Therapists and parents should make understanding
such sensory problems and fears a priority and modify the child’s environment
accordingly.
With the first type of child, the therapist should be gently intrusive in order
to enter his or her “front door.” However, with the second type of child, the
therapist must carefully tiptoe through the child’s “back door.” Children with
severe sensory problems will likely respond better if the therapist talks very qui-
etly to them in a darkened room, which cuts down on total sensory stimulation
and therefore reduces possible overstimulation. This allows the child to concen-
trate on one sensory channel at a time.
VISUAL THINKING
Many people with autism are visual thinkers, including myself. All of my
thoughts are like videotapes playing in my imagination. Even my abstract thought
is in pictures. For example, I have no generalized concept of beauty in my mind.
Instead, there are only specific examples of beautiful things that I have come
into contact with, such as a slide of a rainbow in Hawaii or the Rocky Mountains
near my house.
It was through questioning many people that I discovered the true extent
of my thinking differences. I can best explain the differences by specific exam-
ples. When most people are asked to access their memory of church steeples,
they usually report seeing a rather vague picture of a generic steeple (19). If they
are asked to think about specific church steeples they can do it, but their mind
tends to drift back to the generic picture.
I have discovered that most people think by mentally surveying a concept
and then moving to specific examples. My thinking works in the opposite manner.
I form concepts by looking at many different specific examples and comparing
them.
As a child, I figured out that cats and dogs were different. Even though
dachshunds and golden retrievers were very different, I still knew that both of
these animals were dogs. Although both breeds were dissimilar, they had com-
mon characteristics that cats did not have. By comparing the specific cat and dog
pictures in my imagination I was able to differentiate between dogs and cats at
a young age. I figured out that all cats have silky fur and retractable claws and
all dogs have the same type of nose. It was easier for me to form concepts when I
had many specific examples. The bottom line is that my thoughts go from specific
examples to general principles and are devoid of language. They are just like a
video playing in my head.
Visual thinking is also associative and nonlinear. When I search my mem-
ory for information, it is something like surfing the Internet. My associative think-
ing goes from one video “web page” to the next. For example, if I think about
vacuum cleaners, the first picture that appears in my imagination is a giant vac-
uum cleaner used in my elementary school that terrified me. The next associative
picture is the electric broom in my closet, and the third picture is a video of me
walking through my house. The fourth associative picture is one of my first big
livestock design jobs. So how did I get from vacuum cleaners to livestock equip-
ment? After the image of the electric broom in my closet, my image changed to
me walking through my house and seeing a picture of a livestock project I have
on my wall. Associative thinking of this kind helps explain how an autistic child
can make connections that seem nonsensical.
MY MEDICATION VOYAGE
It was when I entered puberty that my anxiety attacks started (20). It felt like
being in a constant state of stage fright for absolutely no reason. My ner-
vous system was consistently activated and ready to fight in the absence of any
threat.
During this time, to help relieve my anxiety attacks, I built a device that
I could use to apply pressure to large areas of my body (21,22). Relief through
body pressure seems to be common in autism because many children and adults
with autism seek pressure by getting under mattresses and other objects. Agren
(11), McClure and Holz (21), and Zisserman (23) all report that pressure applied
to large areas of the body will reduce self-stimulatory behaviors and calm the
nervous system.
During my late teens and early 20s I was able to control my anxiety attacks
and calm my nerves by using my pressure machine and engaging in heavy physi-
cal exercise and work. When I reached my early 30s, however, the anxiety attacks
began to destroy me both physically and mentally. I would wake up abruptly at
3:00 a.m. with my heart pounding.
Approximately 20 years ago, when I was in my ealy 30s, fluoxetine was
not on the market. At this time I read a journal article by Sheean et al. (24) about
imipramine for anxiety and I asked my doctor to prescribe 50 mg/day. It worked
like magic and my anxiety attacks stopped. The 50 mg/day dose that controlled
my anxiety was much lower than the doses normally used to treat depression.
After taking imipramine for a few months I had a relapse. I resisted the
urge to increase the dose and, fortunately, after a few weeks my anxiety again
subsided. To help reduce my side effects I switched to desipramine and used it
for 10 years. A dosage of 50 mg/day successfully controlled my anxiety.
414 Grandin
Then I had a hysterectomy in which one ovary was removed along with
my uterus. Shortly after the hysterectomy I went on estrogen supplements to
relieve severe menopause symptoms. A dose of 0.66 mg/day of conjugated estro-
gen made me feel really good. I took the estrogen every day with no breaks. This
worked for about 2 years. After 2 years at 0.66 mg/day I started getting anxiety
attacks again. When I stopped taking the estrogen my anxiety diminished. I rea-
soned that I could control both, menopause symptoms and my anxiety by manipu-
lating the dose of estrogen. Depending on how I felt I switched back and forth
between 0.3 mg and 0.66 mg/day. This dosage strategy worked for about a year
and then I started having constant anxiety attacks and problems sleeping through
the night, so I reduced the dosage to 0.3 mg/day every day.
In the fall of 1996, during the book tour for Thinking in Pictures, my new
book, I had a severe anxiety attack. I really wanted to complete the book tour,
and I thought that my anxiety would probably lessen if I stopped taking estrogen.
I went off estrogen for 6 weeks, and my anxiety subsided during the first 4 weeks.
However, during the last 2 weeks without estrogen supplements, menopause
symptoms started and my anxiety increased. When I went back on the supple-
ments, I felt much better. Around Christmas of 1996 I started a new estrogen
strategy to mimic natural estrogen cycles. I took 0.3 mg every day from 10 days
to 2 weeks and then went off the medication from 10 days to 2 weeks. In other
words, I took daily doses of estrogen until I started to feel anxious and then
stopped until I felt aching joints or other menopause symptoms return.
One may wonder why I did not just take more trycyclics. The reasons are
fairly straightforward. I am already slightly overweight and I did not want to get
bigger—weight gain being a common side effect of tricyclics. Also, I have been
on tricyclics for over 20 years, and I was afraid that would have a bad reaction
if I tried to get off the tricyclic desipramine to switch to fluoxetine or one of the
other selective serotonin-reuptake inhibitors (SSRIs). My strategy of going on
and off estrogen is working, for the time being. At one point I tried buspirone,
and I had an awful experience. It felt like I had overdosed on allergy pills. My
mind was fuzzy and I could not think. It felt like I had taken too much cold
medicine!
UPDATE ON MY MEDICATION: MARCH 2000

My strategy of going on and off the conjugated estrogen is no longer effective.
I am now 52 and I am becoming more and more nervous and have more difficulty
sleeping. About two years ago, a lady who had had a hysterectomy told me that
taking progesterone calmed her anxiety. I then started taking 2.5 mg of medroxy-
progesterone along with the estrogen. I felt a depressant effect, which made me
sleepy after taking one tablet. For about 6 months I took 0.3 mg of the conjugated
estrogen and 2.5 mg of the progesterone on a continuous basis. This worked well
for about 6 months and then the sleeping problems returned. I then thought to
myself “The female body is not designed for a steady-state dose of hormones”.
To more closely mimic the natural cycle, I started taking the combination of
estrogen and progesterone for 3 weeks and then going off all the hormones for
1 week. This 3-weeks-on-and-1-week-off cycle of both conjugated estrogen and
medroxyprogesterone worked well for about a year.
For the last 6 months of 1999 and up until the writing of this update I have
engaged in a program of vigorous exercise. I was very out of shape and my only
exercise had been walking through airports and walking around in meat plants
and feedlots. I now exercise for 15 to 20 minutes each day by jogging in place.
It took me 4 months to work up to jogging in place for 15 minutes without getting
winded. After I started to exercise it took about 2 weeks for my sleep to improve.
I had to find an exercise I could do easily in a hotel room or in front of the TV
at home. Going to a gym is too much trouble. At the present time, the combination
of exercise and the combination hormones of 3 weeks on and 1 week off is
working. My dose of desipramine is still 50 mg/day.
As I have gotten older, sleeping has become progressively more difficult.
I have more and more problems getting to sleep, and I would wake up in the
middle of the night and feel so “wired” that I could not get back to sleep. The
problem of lack of sleep was one of the main things that motivated me to do
further experiments with hormones. When I have a bad night I feel terrible, and
if I have too many bad nights I tend to get more colds and flu. When I sleep
well I function better.
CONCLUSION
Today, tricyclic antidepressants are not the first-choice medications for adults
with autism. Many of my autistic friends and associates are having good results
with fluoxetine or fluvoxamine. During my lectures at autism conferences I have
heard of many medication disasters. The most common is when too high a dose
of an SSRI is prescribed. People with autism often need much lower doses than
others (J. Ratey and E. Cook, personal communication). Too high a dose will
cause irritability, insomnia, and aggression. Discussions with hundreds of parents
and many people with autism indicate that low doses of fluoxetine, sertraline,
paroxetine, or fluvoxamine are often effective. Scientific studies also support the
use of fluoxetine or fluvoxamine for autistic adults (22,25). These are good first-
choice medications.
Epilepsy is common in people with autism [26]. During my travels I have
been told of three or four autistic cases in which grand mal seizures were triggered
by clomipramine. Clomipramine works well for autistic people with severe obses-
sive-compulsive disorder, but it is probably not the best first-choice medication
in autism due to the increased epilepsy hazard.
416 Grandin
REFERENCES
1. Grandin T, Scariano M. Emergence Labelled Autistic. New York: Warner Books,
1986.
2. Grandin T. Thinking in Pictures. New York: Vintage Books, 1995.
3. Bemporad ML. Adult recollections of a formerly autistic child. J Autism Dev Disord
1979; 9:179–197.
4. Stehli A. Sound of a Miracle. New York: Doubleday, 1991.
5. White DB, White MS. Autism from the inside. Medical Hypotheses 1987; 24:223–
229.
6. Williams D. Somebody Somewhere. New York: Time Books, 1994.
7. Coleman RS, Frankel F, Ritvoe E, Freeman BJ. The effects of fluorescent and incan-
descent illumination upon repetitive behaviors in autistic children. J Autism Dev
Disord 1976; 6:157–162.
8. Waterhouse L, Fein D, Modahl C. Neurofunctional mechanisms in autism. Psychol
Rev 1996; 103:457–489.
9. Lovaas I. Behavioral treatment and normal educational and intellectual functioning
in young autistic children. J Consult Clin Psychol 1987; 55:3–9:
10. Williams D. Autism: an Inside Outside Approach. Wiltshire, England: Cromwell
Press Melksham, 1996.
11. Agren JA. Sensory Integration and the Child. Los Angeles: Western Psychological
Services, 1979.
12. Rimland B, Edelson S. The effects of auditory integration training in autism. J
Speech Lang Pathol 1994; 5:16–24.
13. Elliot RO, Dobbin AR, Rose GD, Soper HV. Vigorous aerobic exercise versus gen-
eral motor training effects on maladaptive and stereotypic behavior of adults with
both autism and mental retardation. J Autism Dev Disord 1994; 24:565–576.
14. Walters RG, Walters WE. Decreasing self-stimulatory behavior with physical exer-
cise in a group of autistic boys. J Autism Dev Disord 1980; 10:379–387.
15. McGinsey JF, Favell JE. The effects or increased physical exercise on disruptive
behavior in retarded persons. J Autism Dev Disord 1988; 18:167–179.
16. Grandin T. Brief report: response to National Institutes of Health report. J Autism
Dev Disord 1996; 26:185–187.
17. Gillingham G. Autism—Fragile Handle with Care. Arlington, TX: Future Horizons,
1995.
18. Joliffe T. Lakesdown R, Robinson C. Autism, a personal account. Communication
1992: 26(3):12–19.
19. Grandin T. How people with autism think. In: Schopler E, Mesibov G, eds. Learning
and Cognition in Autism. New York: Plenum Press, 1995.
20. Grandin T. Calming effects of deep touch pressure on patients with autistic disor-
ders, college students and animals. J Child Adolesc Psychopharmacol 1992; 2:63–
70.
21. McClure MK, Holtz M. The effects of sensory stimulatory treatment on an autistic
child. Am J Occup Ther 1991; 45:1138–1142.
22. McDougal C, Sherman C. Fluvoxamine for obsessive-compulsive disorder. Med
Lett Drugs Ther 1995; 37:13–14.
23. Zisserman L. The effects of deep pressure on self stimulating behavior in a child
with autism and other disabilities. Am J Occup Ther 1992; 46:547–551.
24. Sheean DV, Beh MB, Basllanger J, Jacobson G. Treatment of endogenous anxiety
with phobic, hysterical and hypochondriacal symptoms. Arch Gen Psychiatry, 1980;
37:51–59.
25. Cook EH, Rowlett R, Jasiskis C, Levanthal B. Fluoxetine treatment of children
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61–77.
21
Future Trends
Eric Hollander and Ronald R. Rawitt

THE CLINICAL CONDITION

In the approximately 60 years since autism was first described, our understanding
of the disorder has grown exponentially in moving from naturalistic observation to a
more rigorously researched scientific study. In the future, our focus on this complex
disorder will bring us closer to an understanding of the basic mechanisms involved
so that prevention and/or cure of autism and related disorders will be possible.
The categorical definition of autism focusing on social abnormalities, im-
paired communication, and restricted range of interest and activities with onset of
illness before age 3 had been a useful prototype. Other disorders in the pervasive
developmental delay class such as Asperger’s disorder, Rett’s disorder, childhood
disintegrative disorder, and pervasive developmental disorder not otherwise spec-
ified in the Diagnostic and Statistical Manual of Mental Disorders (fourth edition,
text revision) need to be further developed. Dimensional approaches to diagnosis
and use of standard assessments of intelligence, adaptive skills, and more special-
ized assessments of communicative skills may be useful in exploring the neurobi-
ological underpinnings of specific symptom clusters. There is need to have di-
mensional instruments that have greater sensitivity and specificity.
ASSESSMENTS
Additional research toward standardized screening and diagnosis of autism spe-
cifically, and the pervasive developmental delay spectrum disorders, will aid indi-
419
420 Hollander and Rawitt
vidual children and families, as well as studies of early intervention and out-
comes. Rigorous data collection will help reveal the multifactorial etiology of
autism and pervasive developmental delays, especially associated with other dis-
eases, by analyzing abnormal lab values, genetic testing, and other ancillary
testing.
Emphasis on a child’s ability to use a capacity toward an emotional goal,
or to satisfy a need, is described in a functional developmental approach, which
needs further systemization and exploration but may improve assessments and
intervention based on what is observable and known.
THE NEUROBIOLOGY OF AUTISM

Genetic studies need to agree on shared methodology, diagnostic inclusion crite-
ria, markers and marker maps, and statistical analyses. Using the categorical
definition of autism, as well as dimensional approaches focusing on social abnor-
malities, impaired communication, and restricted interests and activities to create
subphenotypes, may increase the power of linkage and association findings for
susceptible gene loci. The study of large numbers of multiplex families with
autistic members and/or pervasive developmental delays may increase the ability
to find specific gene loci.
The role of environmental agents in the pathogenesis of autism needs fur-
ther investigation, including well-controlled studies of improved quality on a
larger scale. Establishing causation is difficult because the diagnosis is often made
at 2 to 3 years of age. Association is more often established. The mechanisms
of environmental factors in the pathogenesis and alteration of brain development
also need to be explored. Identifying subsets of autism associated with various
environmental agents might conceivably lead to appropriate therapy and, in some
cases, prophylaxis, making it possible to prevent the occurrence of the disease
in susceptible individuals.
Whole-blood serotonin levels have been investigated as a possible method
of stratifying individuals and families with a genetic vulnerability to autism. Re-
cent challenge studies suggest that central 5-HT responsivity may be altered in
adult autistic subjects. Studies have shown that alterations of brain 5-HT synthesis
during childhood may be disruptive in children with autism, but further studies
are needed to replicate and elucidate these mechanisms. The focus on serotonin
has led to double-blind, placebo-controlled study of selective serotonin-reuptake
inhibitors (SSRIs) such as fluvoxamine and fluoxetine in adults with autism, dem-
onstrating a reduction in repetitive thoughts and behaviors, maladaptive behav-
iors, and aggression. Better studies with SSRIs are needed in children and adoles-
cents with autism, as higher doses may be poorly tolerated in this population.
Children and adolescents with autism may differ in comparison with adults in
tolerability of SSRIs, consistent with the impact of ongoing brain development
Future Trends 421
on the tolerability and response to SSRIs. These findings warrant further research
on 5-HT functioning in autism and its impact on pathophysiology and symptom
domains of autism, and may result in safer and more effective treatments for
specific symptom domains.
The autism phenotype may be a final common pathway of various patho-
physiological mechanisms, one of which involves autoimmune and neuroendo-
crine factors. Findings in this area are clearly preliminary, but perhaps specific
immunomodulatory therapeutic agents may result in amelioration of symptoms
in some patients.
Investigators have examined the relationships between neurochemical dys-
function of specific subtypes of the serotonergic system and neuroanatomical
abnormalities, especially in the cerebellum. Further studies are needed to test this
hypothesis.
TREATMENTS
Pharmacological approaches have been a key element in managing specific symp-
toms in autistic individuals. Mood stabilizers, antiepileptic drugs, antidepressants
(particularly the SSRIs), atypical antipsychotics, stimulants, and cholinergic
agents are available on a clinical basis, but need further double-blind, placebo-
controlled studies to validate safety and efficacy. In particular, studies in children
and adolescents are important and needed. There is also a need for new, better,
safer, and more efficacious compounds to be characterized and tested with appro-
priate outcome measures and study designs.
Studies of children with autism spectrum disorders and either clinical or
subclinical seizures need to be undertaken to determine the effects of seizures
on behavior and language. Epileptiforme discharges on EEG recordings, without
clinical seizures, can cause behavioral, language, and cognitive impairments, and
this needs to be studied in autism spectrum disorders as well. Additionally, treat-
ment modalities need to be systematized and studied in controlled clinical trials
that employ double-blind methods and placebo controls.
The treatment of autism spectrum disorder individuals with movement dis-
orders has been hampered by a lack of published reports and a need for clinical
trials, which are crucial in order to better characterize and treat these individuals.
A variety of alternative treatments for autism have gained a great degree
of popularity but do not have systematic data to support widespread use. These
include secretin, peridoxin and magnesium, vitamin A, vitamin C, dimethylgly-
cine, ORG2766, chelation of heavy metals, antifungals and antibiotics, various
dietary interventions, and auditory integration training.
In the future, behavioral assessment and treatment may be enhanced by
research on learning and neuropsychological correlates of specific areas of diffi-
culty. Research on how to address specific areas of difficulty with behavioral
422 Hollander and Rawitt
treatments, and how to integrate behavioral treatments with new biomedical find-
ings, is also needed. Individuals nonresponsive to a treatment may comprise a
specific subgroup, further clarifying information on the neural basis of specific
deficit areas. Alternatively, individuals who improve with the help of specific
treatments may again reveal a subclass of individuals, which may enhance our
understanding of autism spectrum disorders.
ADVOCACY
Autism research has been greatly facilitated by advocacy groups such as Cure
Autism Now, the National Alliance for Autism Research, and the Autism Society
of America that have developed a more unified approach to lobbying and working
with the National Institute of Health and the Centers for Disease Control and
Prevention. This has led to a common message to legislative and administrative
bodies, resulting in better funding for basic and applied research. Nevertheless,
more work is needed to improve funding. Advocacy in education to inform the
public of the cost benefits of improved educational access and the clinical benefits
is also needed. Efforts to find appropriate work and housing for people with
autism spectrum disorders are crucial in moving individuals from sheltered work-
shops to meaningfully compensated employment and out of perpetual poverty
and dependency. A long-term objective of advocacy groups is the creation of
national standards for the training and qualifications for people who work with
individuals with autism spectrum disorders. Also, there is a need for in-service
training for people working with individuals with autism spectrum disorders. As
part of this advocacy approach, reports from people with autism spectrum disor-
ders and their families are helpful in educating professionals and the general
public about these disorders, and in helping individuals, families, and our society
as a whole to integrate people with autism spectrum disorders and help them
become useful and productive members of society.
Index
Tables are indicated by (t).
Abstract concepts, 412 [Adults]

Acetylcholine, 358 and SSRIs, 8, 234, 235, 237
Active-but-odd children, 21–22 support systems, 400–401
Acute dystonia, 279–280 symptoms in, 30
Adaptive functioning, 94, 114 relationships with, 21, 123–124
tests for, 88(t) Adventitious movements, 90(t), 233–234
Adderall, 119 Advocacy
Adenylosuccinate lyase, 362 educational rights, 405
Adolescents future directions, 422
and aggression, 29 history of, 394–398
and anxiety attacks, 413 for individuals, 400–401
and epilepsy, 27 local, 401–404
and fluoxetine, 235 national, 404–406
and herpes simplex, 186 research, 398–400, 403, 404–405
puberty effect, 30, 155 success factors, 403–404
and seizures, 30 work and recreation, 405–406
and serotonin, 155 Affection, 21
Adrenocorticotropic hormone (ACTH), Affective disorders, 28, 108, 113
286, 359–360 and virus, 189
Adults Affective symptoms, 28 (see also Emo-
autistic tions)
first person account, 413–415 African Americans, 205
medication for, 415, 420–421 Age factors
obsessive-compulsive, 8, 25 diagnosis timing, 29, 42, 111
oxytocin, 26 and medication, 216, 235
423
424 Index
[Age factors] Amphetamines, 119

for seizures, 30, 47, 265–266, 267– Amygdala, 26, 154
268 Angelman’s syndrome, 116, 134–135
and serotonin, 155, 210, 215, 222– Anger, 233
223 Animals, 21
and SSRIs, 420–421 Anterior cingulate gyrus, 26–27
Aggression Antibiotics, 120, 166, 361–362
and anxiety, 413 Antibodies (see also Immunoglobulins)
and EEG, 116 abnormalities, 161–163
medication for, 119, 295–296 auto-, 180, 181–182
antipsychotics, 251, 254 to brain, 109–110, 161–163, 181–
mood stabilizer, 240–241 182
SSRIs, 233, 236, 237 description, 157
in obsessions, 25 maternal, 163
physical devices, 296 for measles and herpes, 109
Agitation, 237 monoclonal D8/17, 158–159
Agnosia, 48, 266–267, 269 streptococcal-induced, 190–191
Akathisia, 280–282, 308–309, 326 Anticholinergics, 280
Alcohol, 193 Anticonvulsants
Allergies, 50, 194, 363 indications for, 269–270
Website, 364 and Landau-Kleffner, 238–240
Aloofness, 21 and language, 48
Alpha-blockers, 296 and self-injury, 295
Alternative therapies and serotonin, 205
antibiotics, 120, 166, 361–362 Antifungal agents, 120, 361–362
antifungals, 120, 361–362 Antihistamines, 166, 296
auditory integration training (AIT), Antipsychotics, 247–250, 252–253(t),
121, 363–364 257–259 (see also specific
behavioral, 378–380 agents)
chelation, 360–361 adverse effects, 255–257
craniosacral, 121 monitoring, 258–259
diet, 120, 359, 362–363 Anxiety
immunoglobulins, 121, 164–165 attacks of, 413–414
magnesium, 120, 357–358 in family, 108, 113
music, 121 medication, 237, 296, 413
nutritional supplements, 359 antipsychotics, 251, 254
ORG 2766, 359–360 Aphasia, 48, 266
secretin, 166, 348–357 Apoptosis, 163, 189
vitamins, 120, 357–359 Applied Behavioral Analysis (ABA),
Websites, 364 117–118, 400
Amantadine, 166 Apraxia, 46, 102–103, 116
American Academy of Child and Ado- Aricept, 166
lescent Psychiatry (AACAP), 40, Asperger’s disorder
44, 50 affective disorders, 28
American Academy of Neurology differential diagnosis, 9–10, 16–17,
(AAN), 40, 42, 45, 49, 50 24, 105–106
Index 425
[Asperger’s disorder] [Autism spectrum disorders (see also

and education, 389 DIR model)]
language development, 23–24, 105 and EEGs, 47–49
screening for, 42–43 etiology, 17, 107–110, 124
and serotonin, 212 genetic factors, 17, 18
symptoms, 105–106 heterogeneity, 16–18
ASQ, 42–43 medication effects, 277
Assessment, 370–372, 419–420 (see movements of, 285–291
also DIR model; Screening) prevalence, 106–107
Associated disorders (see Comorbidity) prognostic subtypes, 76–79
Astrocytes, 162 Autistic epileptiform regression, 267–
Ataxia, 106, 225–226 268
Attention Autoimmune response
and immune therapy, 165–166 and bacteria, 190
and intelligence testing, 93 to brain, 109–110, 181–182
joint, 103, 113 description, 159–163
management of, 410–411 future work, 421
and medication, 119 and viral infections, 190
questionnaire, 80 Aversion therapy, 292
shifting, 68 Avoidant personality disorder, 10
testing, 96 AZT, 188
Auditory integration training (AIT),
121, 363–364, 411 Bacteria, 190–191
Australian Scale, 43 intestinal, 120, 361–362
Autism B cells, 109, 157, 158–159
atypical, 4 Bcl-2, 163
course of, 29–30 Behavioral skills training, 373, 375–376
heterogeneity, 31, 384, 385, 396–397 Behavioral therapy, 373–378
prediction of, 276 alternatives, 378–380
purine, 362 and cognitive ability, 70
Autism Diagnostic Interview–Revised, controversies, 397
18, 114 enhancement approach, 293–296
Autism Diagnostic Observation Sched- extinction, 377
ule–Generic, 114 future work, 422
Autism Genetic Resource Exchange and mainstreaming, 386–387
(AGRE), 46 outcomes, 69–70, 117–118, 378
Autism Research Registry (ARR), 399 overcorrection, 293, 377
Autism Society of America (ASA), reduction techniques, 291–293, 377
394–395, 397–400, 406–407 reinforcement, 377
contact information, 408 for self-injury, 291–296
Autism spectrum disorders (see also Behaviors (see also Repetitive behav-
DIR model) iors; Self-injury; Stereotypies)
versus autism, 102 adaptive, 88(t), 94, 114
brain sites, 26–27 in Asperger’s syndrome, 105–106
core deficits, 17 assessment of, 370–372
and development deficits, 72 and Borna disease virus, 189
426 Index
[Behaviors (see also Repetitive behav- Brainstem auditory evoked response

iors; Self-injury; Stereotypies)] (BAER), 44
compulsive (see Compulsive be- Breathing, 328
havior) Broad autism phenotype, 17 (see also
descriptions, 25–27, 103–104 Phenotype)
and diagnosis, 8, 17 Bronchitis, 177
and diet, 120, 194
evaluation of, 50 Calcitonin gene-related peptide (CGRP),
and gastrointestinal disorders, 351– 164
352 California Verbal Learning Test, 95
impairment range, 17 Candida albicans, 120
maladaptive, 376–378 Carbamazepine, 240
purposeful, 80 Card sorting, 89(t), 95
target, 385 Caregivers
and test-taking, 93 and etiology, 107–108, 124
treatment, 372–378 relationship with, 63–65, 67–68, 77
and tryptophan, 212 and therapy, 70
Benzodiazepines, 295 Casein, 109, 120, 363
Beta-blockers, 281–282, 295 Caudate nuclei, 155, 158
Bettelheim, Bruno, 394–395 CD4⫹ cells, 156, 161
Bioethics, 403 Centers for Disease Control and Preven-
Bipolar disorder, 28, 108, 113 tion (CDC), 399–400
Birth Cerebellum (see also Purkinje cells)
complications of, 17, 163 and alcohol, 193
labor induction, 191–192 hypoplasticity, 108
and seasonality, 158, 177–178 and immune system, 162, 163
Biting, 294 and immunoglobulins, 162
Blepharospasm, 283 postmortem findings, 154
Body boundaries, 411 and RELN gene, 138
Body pressure, 413 and retinoids, 178
Books, 394 role of, 223–224
Borna disease virus, 188–189 and serotonin, 224–226, 421
Bouncing, 328 Cerebral cortex, 138, 164
Boundaries, 411 Cerebral palsy, 10
Bradykinesia, 275 Chaining, 373, 376
Brain antibodies, 109–110, 161–163, Change, resistance to, 1, 25, 103
181–182 Chart, of functional development, 74–76
Brain damage Chelation, 360–361
test for, 89 Website, 364
from virus, 189 Chickenpox, 187
Brain-derived neurotrophic factor Child Health Act of 2000, 15
(BDNF), 164 Childhood Autism Rating Scale, 113
Brain development, 138 Childhood disintegrative disorder, 9,
Brain metabolism, 236 106
Brain sites, 26–27, 108, 154–155 Child Neurology Society (CNS), 40, 42,
Brainstem, 108, 138, 178–179 45, 49, 50
Index 427
Children (see also Preschool age chil- [Communication]

dren; Toddlers) of diagnosis, 105, 111
nonverbal, 93 disorders of
school age, 43 DIR model, 59–60, 76–79
and serotonin, 155 symptoms, 23–24, 102–103
and SSRIs, 420–421 evaluation of, 50, 115–116
M-chlorophenylpiperazine, 233 test for, 88(t), 94
Chorea, 326 impairment range, 17, 23
Chromosomes, 134–145 nonverbal, 93
Cingulate gyrus, 26–27 parent with child, 380
Clapping, 106 with pictures, 78, 81, 378
Clomipramine and prognosis, 77–79
and anger, 233 and secretin, 351–352
and compulsive behavior, 222, 233–234 and SSRIs, 234, 236
double-blind study, 233–234 twin study, 24
and repetitive behavior, 26 Community resources, 112
and self-injury, 295 Comorbidity, 7–9
side effects, 286, 415 of affective disorders, 28
Clostridium, 166 epilepsy, 27–28, 47–48, 265–268
Clozapine of gastrointestinal disorders, 351–352
dosage, 258(t) of mental retardation, 27, 124
side effects, 252(t), 257, 258, 279, 283 metabolic defects, 362–363
symptom improvement, 250–251 miscellaneous, 50
Clusters obsessive-compulsive disorder, 8, 25
geographic, 4–5, 7, 158, 176–177 and subcategories, 19
of symptoms, 9 Compulsive behavior, 25–27
Cocaine, 193–194 brain site, 155
Cognitive ability genetic basis, 159
abstract concepts, 412 medication for, 222, 233–234, 236
and behavioral therapy, 70 types, 25
and cerebellum, 225–226 Consumer advocacy, 394–398, 406
and epilepsy, 266, 267, 269 Continuous Performance Test(CPT), 96
evaluation of, 50, 114 Conversation
testing, 88(t), 92–97 practicing, 118
nonverbal, 93 in questionnaire, 81–82
of nonverbal children, 93 as symptom, 23
and serotonin, 225–226 Coordination, 104, 118–119
task-specific strengths, 92 Coping, 122–123
visual, 412–413 Coprolalia, 327
Color, 104 Copropraxia, 327
Coloring agents, 363 Core symptoms
Communication course of, 29
and behavioral training, 378 description, 20–27
chromosomes, 24 in DSM-IV, 18
conversation, 23, 81–82, 118 influential factors, 31
curriculum for, 374–375 limitations, 31
428 Index
Corticosteroids, 269–270 [Diagnosis (see also Differential diagno-

Counting, 378 sis; Screening)]
Craniiosacral therapy, 121 laboratory tests, 46, 49–50, 116
Cuddling, 103 medical evaluation, 44–50
Cure Autism Now (CAN), 39–40, 44, metabolic testing, 49–50
50, 399 neuroimaging, 49
Curiosity, 357 neurological examination, 113
Cytokines, 156, 159–160, 189 presenting symptoms, 29, 66
Cytomegalovirus, 108, 184–185 synthesis, 68–69, 111–116
in toddlers, 105
Daily living skills, test for, 88(t), 94 Diagnostic and Statistic Manual of Men-
Dancing, 104 tal Disorders (DSM)
Deinstitutionalization, 397 autism in
Delusions, 110, 283 DSM-IV, 102, 16, 18
Dementia infantilism (see Childhood dis- initially, 3–4, 5, 6
integrative disorder) pervasive developmental disorders
Denver Model, 379–380 (PDD) 105, 16, 18
Depression, 28 Diarrhea, 351–352
in family members, 108, 113 Diet, 120, 194, 359, 362–363
medication for, 254 gluten- and casein-free, 109
Desensitization, 379 Differential diagnosis
Desipramine, 233, 238 core deficits, 17
Destructiveness, 296 frim sensory integration disorder, 111
Developmental levels, 59–61 hearing impairement, 110
Developmental Neuropsychological As- Landau-Kleffner syndrome, 267–268
sessment (NEPSY), 96–97 from language delay, 110
Diagnosis (see also Differential diagno- from mental retardation, 110
sis; Screening) from OCD, 25, 110–111
age at, 29, 42, 111 from PDDs, 9–10, 16–17
behavioral evaluation, 50, 111–112 Asperger’s, 9–10, 16–17, 24, 42,
cognitive evaluation, 50 105–106
communication of, 105, 111 childhood disintegrative disorder,
community resources, 112 106
coordinating, 112 Rett’s syndrome, 106
core symptoms, 16, 18, 20–27, 102–104 from schizophrenia, 110
dimensional approach, 4 Dihydropyrimidine dehydrogenase, 362
DSM inclusion, 2–7 Dimethylglycine (DMG), 120, 359
EEG role, 47–49 DIR model
euphemisms, 105 description, 58–59, 379–380
and family members, 50 evaluation process, 62–69, 71–79
genetic testing, 47 prognostic subtypes, 76–79
history, 66–67, 113 questionnaires, 74
ICD, 3, 16 therapeutic approach, 70–76
in infants, 21 Disaccharidases, 352
in initial sessions, 66–69 Discrete trial training (DTT), 372–377
instruments for, 18, 419 Disinhibition, 119
Index 429
Disintegrative psychosis (see Childhood Electroencephalograms

disintegrative disorder) abnormalities, 28
Divalproex sodium, 239–240 indications for, 116–117
Dolphin therapy, 121–122 and Landau-Kleffner syndrome, 268
Doors, 409 and seizures, 47–49, 265–268
Dopamine, 108, 249–250, 286 Emotions
antagonists, 278–280, 282 awareness of, 81
Down’s syndrome, 10 medication for, 254
Dressing, 376, 378 testing, 91(t)
Dysesthesias, 289 Empathy, 21, 79, 91(t)
Dyskinesias, 277 Employment, 30, 378, 405–406
tardive, 277, 282–284, 295 Encephalitis, 186, 188
Dysmorphic features, 50, 136 Endorphins, 295
Dyspraxia, 104, 118–119 Enjoyment, 3, 21
Dystonia, 279–280 Enuresis, 234
defined, 326 Environment
as cause, 7, 17, 420
Ears pathogens, 158, 175–178
covering, 104, 114–115, 328 response to, 3, 25, 46
infections, 50, 110, 120 and self-injury, 294
malformations of, 179 of therapy, 412
Echolalia, 1, 77 toxins, 17, 177, 179–181
immediate versus delayed, 103 Enzymes, 180
Edges, of objects, 104 Epidemiology, 4–7
Education Epilepsy, 27–28, 47–48, 265–268, 415
advocacy, 405 (see also Seizure disorders)
and Asperger’s disorder, 389 Esophagitis, 352
class size, 294, 384 Estrogen, 414–415
cognitive skills, 376 Etiology (see also Genetics)
and communication, 374–375 allergies, 194
diverse needs, 384, 385 bacteria, 190–191
elementary level, 29 brain abnormality, 108
full inclusion, 383–390 environmental, 7, 158, 179–181, 420
high school, 30 immune disorders, 109–110, 153–
for independent living, 376 164
legislation on, 383 parenting, 124
mainstreaming, 383–390 peptide metabolism, 109
and maladaptive behaviors, 376–378 pitocin, 191–192
for motor skills, 376 retinoids, 178–179
peer tutoring, 384, 387 serotonin, 25–26, 108, 215–217 (see
and self-injury, 294 also Serotonin)
for self-management, 385 substance abuse, 193–194
and social skills, 375–376 vaccines, 109
target behaviors, 385 viruses, 108–110, 158–159, 181–190
task size, 385 Executive function, 89(t), 95–96
types of, 372–373 Exercise, 411, 413, 415
430 Index
Eye contact Fantasies, 63

after rough-housing, 104 Fear, 410
and medication, 237 Fenfluramine, 249
myths about, 123 Fetal alcohol syndrome, 193
and secretin, 351–352 Fidgeting, 281, 295
and speech therapy, 118 Fingers, 25
as symptom, 21, 103, 113 Flavorings, synthetic, 363
and vitamin B6, 357 Fluoxetine, 26–27, 234–236, 286, 415
Eyes Fluphenazine, 295
blinking, 283 Fluvoxamine, 26, 216, 236–237, 286,
covering, 328 415
muscles of, 279, 283 Focusing, 80
squinting, 104 Foods
staring, 116 allergies to, 194, 363, 364
dietary therapy, 120
Facial dysmorphism, 136 texture of, 104
Facial expressions, 21, 91(t), 103 Fragile X syndrome
Facial writhing, 282 and boys, 116
Families comorbidity, 8, 10
assessing, 67, 303 karyotyping, 46–47
in assessment, 62–63, 67–68 prevalence, 19, 45–46, 108
coping, 122–123 Free operant instruction, 373
isolation in, 108 Free radicals, 361
multiplex, 25, 47 Fruits, 363
genetic studies, 135, 145 Full inclusion, 383–390
Families for Early Autism Treatment Functional assessment (see also Cogni-
(FEAT), 400 tive ability)
Family members (see also Parents) development milestones, 72–74
affective disorders in, 28, 45, 108, questionnaire, 79–82
113 in DIR model, 59–61, 73–79
anxiety disorders in, 45, 113 neuropsychological, 96–97
in diagnosis, 45–46, 62–65, 112–113 tests, 88–91(t)
in evaluation, 67–68 Functional development
impulsivity in, 28 charting, 74–76
intrusive and aloof, 62–63 and HIV, 188
with language impairment, 144 language delay, 110, 144–145
mental diseases, 108, 110–111, 113 mastery criteria, 76
and mental retardation, 8 Funding, 398–400
nonverbal communication, 24
OCD in, 45, 113 G-alpha proteins, 358
phrase speech, 24 Gamma-aminobutyric acid, receptor
prevalence in, 45–46, 108 gene, 136–137, 154, 201, 202
recurrence risk, 154 Gastrointestinal disorders
and serotonin, 25, 209–210, 232 after vaccine, 108–109, 192
social disorders in, 22, 28, 108 and behaviors, 351–352
and symptom domains, 31 causal relationship, 50
Index 431
[Gastrointestinal disorders] Glutamine, 202

clostridium, 166 Gluten, 109, 120
and neuropeptides, 164 Graphomotor function, 104
yeast overgrowth, 120 GRIK2 gene, 138
Gender Guardianship structures, 400–401 (see
and genetic testing, 116 also Families)
and prevalence, 154
and Rett’s syndrome, 106 Haemophilus influenzae, 191
sex ratio, 6 Hallucinations, 110, 283
and tardive dyskinesia, 283 Haloperidol, 119, 255, 283, 295
Genetic markers, 19, 159 Hands
Genetic origins, 17 and behavior training, 377
Genetics (see also Fragile X syndrome) clapping, 106
and brain development, 138 coordination, 104, 118–119
chromosomes, 24, 47, 134–145 finger wiggling, 328
and communication (phrase speech), flapping, 25, 103
24 in Rett’s syndrome, 106
and environment, 179 rubbing, 328
familial risk factors, 30–31, 108 staring at, 104
multiplex families, 135, 145, 420 washing, 106
FRM-1 gene, 46 Head
gene bank, 399 banging, 289
genome-wide screens, 139–145 size of, 46, 106, 113
and glutamate, 138 tilting, 328
heritability rate, 133 Health insurance, 405
and immune system, 109, 157, 163 Hearing
and language delay, 144–145 and diagnosis, 110
and mental retardation, 27 hyperacute, 409–411
phenotype, 17, 19, 24, 421 listening, 121
RELN gene, 138 monochannel, 411
of Rett’s disorder, 284–285 testing for, 44, 114–115
and serotonin, 213–215, 222–223 Heller’s syndrome (see Childhood disin-
specific genes, 136–139, 179 tegrative disorder)
susceptibility gene, 24 Hematological toxicity, 283
Genetic testing, 47, 116 Heroin, 193–194
Geographical areas, 4–5, 7, 158, 176– Herpes virus, 109–110, 185–186
177 Hippocampus
Gestures abnormalities, 26, 154
adventitious, 233–234 and genetics, 138
and prognosis, 78 metabolism, 26
as social cues, 103 and vitamin A, 358–359
Glial cells, 162, 189 Hispanics, 205
Glucaric acid, 180 Histidinemia, 362–363
Glucoamulases, 352 Hoarding, 25
GluR6 gene, 138 Holding, 123
Glutamate, 138, 166 Holding therapy, 121–122
432 Index
Home-based program, 71, 117–118 Immunoglobulins

Homovanillic acid, 358 abnormalities, 109, 161–163
Hormones, 414–415 description, 157
HOXA1 gene, 138–139 as therapy, 121, 164–165, 363
Hox genes, 179 Impulsivity, 28, 119
5-HTT gene, 137 Incidental teaching, 373
Hugging, 123 Independent living, 376
Human immunodeficiency virus (HIV), Infants
188 assessment of, 67–68
Human leukocyte antigen (HLA) com- functioning questionnaire, 80
plex, 157, 163, 190 attention development, 21
Human parvovirus, 188 diagnosis in, 29
5-hydroxytryptamine (see Serotonin) motion analysis, 276
Hyperactivity, 8 screening, 41–43
therapy for, 119, 254, 295 and serotonin, 222–223
Hyperbaric oxygen, 121–122 spasms in, 46
Hyperkinesia, 275–278 vaccinations, 108–109
Hyperlexia, 105 viral infections, 187–188
Hypersensitivity, 1, 46, 118–119, 409–411 Inflammation, 156, 165, 189
Hypomelanosis of Ito, 19 Influenza, 177
Hypopigmentation, 46 Insomnia, 415
Hypotension, 281 Institutionalization, and testing, 94
Hypothyroidism, 108 Instruments (see Questionnaires; Screen-
Hypotonia, 46, 50, 104, 113 ing; Testing)
Hypoxanthineguanine.... (HGPRT), 288 Insurance, 405
Intelligence
Illness, 60 and behavioral training, 378
Imagination, 3, 110 increase in, 117–118, 121
Imipramine, 413 nonverbal measures, 93
Imitation, 80, 81, 113 versus other factors, 2
Immigrants, 6–7 retardation, 6, 7–8
Immune system and seizures, 27
allergies, 194 testing, 88(t), 92–97
and autism etiology, 158–166 Interactions (see also Social interac-
and birth complications, 163 tions)
description, 155–157 chains of, 80
and environmental toxins, 180 conversation, 23, 81–82, 118
future studies, 421 and family coping, 122–123
genetic factors, 109, 157, 163 in functioning questionnaire, 80
genetic regulation, 157 in infancy, 80
maternal/fetal, 163 with parents (see Parents)
and obsessive-compulsive disorder, with peers (see Peers)
158–159 and test-taking, 93
and Purkinje cells, 163 therapeutic, 71
and therapy, 121, 164–166 Interests, 3, 25 (see also Attention)
and viruses, 109 Interferon-gamma (IFN-ã), 156, 160
Index 433
Interferon-K, 160 [Language disorders]

Interleukins, 156, 160, 189 developmental, 10
International Classification of Diseases differential diagnosis, 110
(ICD), 3, 16 in differential diagnosis, 10
Internet, 122, 406–407 echolalia, 1, 77, 103
Interruption, 116 in family members, 24
Intestinal flora, 120, 361–362 and prognosis, 77–79
Intrusiveness, 411 regression, 48, 269–270
Irritability, 237–238, 254 and social interaction, 18
Isolation, 108 sound production, 78
Language therapy, 118
Jargoning, 103 Latinos, 205
Jobs, 30, 378, 405–406 Lead, 44
Job training, 30, 378 Learning
occupational therapy, 50, 118–119, 385 instruction types, 372–373
Johns Hopkins University, 292 skill mastery, 371–372
Jumping, 104 tests for, 89(t)
Legislation, 15, 383, 405
Kanner, Leo, 1–2, 101 Leiter test, 93
Kaufman Assessment Battery (K-ABC), Lesch-Nyhan syndrome, 288–289
93 Licking, 104, 106
Kennedy-Krieger Institute, 290–291 Lights, 104, 409
Kinesthetic sense, 411 Limb apraxia, 46
Limb muscles, 279
Laboratory tests, 46, 49–50, 116 Lips, 282
Lactalbumin, 363 Listening, 121
β-lactoglobulin, 363 Lithium, 119, 240–241, 296
Lamotrigine, 240 Liver, 179–180
Landau-Kleffner syndrome, 48, 162– Local advocacy, 401–404
163, 238–239, 266 Lorazepam, 295
Language Lovaas method, 410–411
and Asperger’s disorder, 23–24, 105 Lymphocytes, of father, 163
behavioral therapy, 378 Lymphokines, 156, 159–160
curriculum, 374–375
in diagnosis, 113
and epilepsy, 266–267 Macrocephaly, 46
evaluation of, 115–116 Magnesium, 120, 357–358
and genetics, 144–145 Mainstreaming, 383–390
literalness, 1 Mannerisms, 3, 25, 103
medication for, 236, 239, 240, 254 adventitious, 90(t), 233–234
symptoms, 1, 102–103, 103 Manual dexterity, test for, 90(t)
in toddlers, 80–81 Marching, 281
and vitamin B6, 357 Marital problems, 63, 67
Language disorders Maturation variations, 61–62
and chromosomes, 135–136, 144 Measles, 108–110, 186–187, 192
and cocaine, 193 Medicaid, 405
434 Index
Medication (see also specific agents) Minerals, 120

adverse effects, 277 Moebius syndrome, 19
for aggression/self-injury, 119–120 Mood disorders, 28
antibiotics, 120, 166, 361–362 Mood stabilizers, 119, 239–241, 296
anticholinergic, 280 Motor-Free Visual Perception Test,
anticonvulsants (see Anticonvulsants) 90(t)
antifungal, 120, 361–362 Motor system
antihistamines, 166, 296 evaluation, 90(t)
antipsychotics, 247–250, 254, 257– evaluation of, 62, 90–91(t), 115
259 milestones, 73
side effects, 255–257 and prognosis, 78
aricept, 166 symptoms, 104
AZT, 188 therapy for, 118–119
beta-blockers, 281–282, 295 Movement disorders (see also Self-in-
corticosteroids, 269–270 jury)
dosage, 415 abbreviations, 298(t)
future studies, 421 adventitious movements, 90(t), 233–
glutamate antagonist, 166 234
hormones, 414–415 attitudes toward, 276–277, 279–280,
for hyperactivity, 254, 295 283, 286
and language, 236, 239, 240, 254 behavioral therapy, 291–296
opiate antagonists, 295–296 checklist, 310
psychotropic, 239–240 classification, 275–278
quality assurance rating, 312–316 definitions, 274, 326–327
serotonergic, 286 future work, 421
withdrawal, 282–284 hyperkinesia, 275–278
Memory, testing, 89(t), 94–95 rating, 277–278, 299–302
Meningitis, 191 in Rett’s disorder, 284–285
Mental retardation self-injurious, 287–296
in autistic persons, 6, 7 stereotypies, 286–287, 377 (see also
comorbid, 27, 124 Stereotypies)
differential diagnosis, 110 therapy-induced, 277–284
and fluoxetine, 235 tics, 285
genetic transmission, 7–8 training, 376
and intelligence tests, 92–93 Mumps, 108–109, 188
myths, 124 Music, 121
versus other factors, 2 Mutism, 10
and Rett’s syndrome, 106 Myelin, 162, 180, 181
and tuberous sclerosis, 46 and measles, 187
Mercury, 109, 360–361 Myoclonus, 326
Website, 364 Myoclonus venus, 311
Metabolism, 49–50, 120, 236 Myths, 123–124
Methylmalonic acid, 109
Methylphenidate, 240 Naloxone, 295
Milk, 120 Naltrexone, 286, 295–296, 363
Mimicry, 158, 190, 376 Name, response to, 113, 114–115
Index 435
National advocacy, 404–406 Obscenities, 327

National Alliance for Autism Research Obsessive compulsive disorder (OCD)
(NAAR), 398, 408 and B cells, 158–159
National Association for the Education of comorbidity, 8, 25
Young Children (NAEYC), 71 differential diagnosis, 10, 25, 110–
National Institutes of Health, 397, 398, 111
399 in family members, 108
National Society for Autistic Children and genetics, 159
(NSAC), 394 and immune system, 158–159
Natural killer cells, 109, 159 medication, 415
Neck, 279 Occupational therapy, 50, 118–119, 385
Neonates, infections in, 186 vocational skills, 30, 378
NEPSY (Developmental Neuropsycho- Occupations, 30, 378, 405–406
logical Asessment), 96–97 Olanzapine (see also Antipsychotics)
Neural tube, 178–179 dosage, 258
Neurobiology, 420–422 efficacy, 254–255
Neurofibromatosis, 10, 19 and self-injury, 295
Neuroimaging side effects, 279
of anterior cingulate gyrus, 26–27 Ombudsman programs, 402
for brain abnormalities, 154–155 Onset, 6, 15, 21, 29
diagnostic role, 49 of childhood disintegrative disorders,
EEGs, and seizures, 28 106
indications for, 46 of phrase speech, 144–145
and serotonin, 212–213, 232–233 of regression, 106
of temporal lobe, 186 of seizures, 30, 47, 50
Neurological examination, 113 of therapy, 117–118, 410
Neuron-axon filament, 162, 180, 181 Opioids, 108
and measles, 187 antagonists, 295–296, 363
Neurons, 162, 178–179, 189 and self-injury, 289, 295
Neuropeptides, 164 Orbitofrontal cortex, 26–27
Neuropsychiatric evaluation, 88–91(t), ORG 2766, 359–360
94–97 Organizations, 394–403 (see also Child
Neurotransmitters, 25–26, 108 (see also Neurology Society (CNS))
specific neurotransmitters) contact information, 408
Neurotrophin 415, 164 virtual, 406–407
Neurotrophin nerve growth factor Otitis media, 50
(NGF), 164 Overcorrection, 293, 377
Niaprazine, 166 Oxygen therapy, 121–122
Noise, 1, 409–411 Oxytocin, 22–23, 26, 191–192
Nonverbal intelligence tests, 93, 95
Nonverbal skills, 114 Pacing, 212, 281
Numbers, 378 Pain, 104, 109, 289
Pancreas, 351–352
Objects PANDAS, 190
preoccupation with, 21, 25, 103–104 Paneth cells, 352
toys, 67–68, 103 Panic attacks (see Anxiety)
436 Index
Parents (see also Family members) Phenylalanine, 200

and etiology, 107–108, 124, 163 Phenylketonuria
expectations of, 364 and diet, 362
and eye contact, 103 incidence of, 10
HLA in, 163, 190 as risk indicator, 108
myth about, 124 and serotonin, 200–201
presenting complaints, 112 Phrase speech, 24, 144–145
relationship with, 2, 60 Physical exercise, 411, 413, 415
assessment of, 62–65, 67–68 Physical restraints, 292–293
therapy for, 70 Phytohemagglutinin (PHA), 160
Paroxetine, 235, 415 Picture exchange, 378
Parvovirus, 188 Pictures
Passive children, 21 as communication, 78
PDD-NOS, 10, 42–43 in questionnaire, 81
Pedantic style, 105 Pimozide, 257
Pediatricians, 40–42, 112 Pitocin, 191–192
Peers, interactions with Planning, 95–96
and behavioral training, 378 motor, 118–119
description, 21, 29, 103 Play
and DIR model, 60 and behavioral training, 378
and therapy, 71, 375–376 in education, 375–376
in toddlers, 81 imaginative, 3
Peer tutoring, 384, 387 symbolic, 17
Pentoxifylline, 165 symptoms, 103–104
Peptides Play therapy, DIR approach, 71
and clostridium, 166 Pleasure, 3, 21
metabolism of, 120 and self-injury, 289
neuropeptides, 164 Pneumonia, 177
secretin, 166 Pointing, 113
transfer factors, 165–166 Polychlorinated biphenyls, 178, 179
and vaccines, 109, 120 Positive practice, 377
Perseveration, 71 Postmortem studies, 154–155, 178–179
Pervasive development disorders Posture, 21, 46
descriptions, 105–106 (see also Au- Poverty, 406
tism spectrum disorders) Prader-Willi syndrome, 116, 134
etiology, 107–110 Pregnancy
in ICD-10, 3 environmental toxins, 108, 179–181
prevalence, 106–107 immure response, 163
therapy, 117–122 infections during, 108
Phagocytes, 156, 157, 159 bacterial, 191
Phencyclidine, 193–194 viral, 158, 177, 182–185, 186, 188
Phenotype and retinoids, 178–179
broad autism (BAP), 17, 24 substance use, 193–194
and HOXA1 gene, 138–139 Preschool age children
and immune system, 421 education for, 71
and mental retardation, 27 evaluation resources
Index 437
[Preschool age children] [Purkinje cells]

cognitive testing, 92, 114 and serotonin, 224
functioning, 81–82 and virus, 189
language testing, 115–116 and xenobiotic agents, 179
rating scale, 113 Purposeful activity, 80, 106
self-referral resources, 112 Pyridoxine, 120, 357–358
Preschool Language Scale, 115
Pressure, 413 Questionnaires
Pretend-play, 77–79, 81, 113 for diagnoses, 74, 113–114
Prevalence functional development, 79–82
and advocacy, 393–394 Quetiapine, 253(t), 255, 258(t) (see also
conference on, 399–400 Antipsychotics)
and environment, 176–178
in family members, 45–46, 108 Rabbit syndrome, 282
siblings/twins, 24, 108, 133–134 Racial factors, 205
gender factor, 154 Raven’s Progressive Matrices, 93
overall, 6, 15, 133 Reactive attachment disorder, 10
of PDDs, 6 Reading, 105, 378
of pervasive development disorders, Reality, sense of, 63
106–107 Reciprocity, 3, 73
sex ratio, 6 and speech therapy, 118
trends, 7, 11 Registries, 399
Primary-care providers, 40–42, 43 Regression
Problem solving, 71, 80 after vaccine, 192
Progesterone, 414–415 autistic epileptiform, 267–268
Prognosis and EEGs, 116
indicators of, 76–79 and epilepsy, 266
myths versus reality, 124 and HIV, 188
Project TEACCH, 378–379 linguistic, 48, 269–270
PROMPT methodology, 118 onset of, 106
Pronoun reversal, 1, 103 and relational therapy, 379–380
Propranolol, 119, 281–282 Reinforcement strategies, 377
Prosody, 103 Relational therapy, 58–59, 379–380
Protective devices, 293 Relationships (see also Interactions; So-
Proteins, G-alpha, 358 cial interactions)
Psychotherapy, psychodynamic, 294 deficit types, 3
Puberty, 30 disorder subtypes (DIR model), 76–
Publicity, 394, 396, 404 79
Punishment, 292 evaluating, 60, 67–68
Purdue Pegboard Test, 90(t) with family member, 2, 62–65, 67–
Purine, 362, 364 68
Purkinje cells in functioning questionnaire, 80
abnormalities, 154, 162 in infancy, 80
and Bcl-2, 163 with new person, 68
postmortem findings, 154 Religion, 25
and retinoids, 178 RELN gene, 138
438 Index
Repetitive behaviors Rubella, 10, 182–184

in adults, 30 vaccine for, 108–109, 192
and Asperger’s syndrome, 105–106 Rule generation, 95–96
classification, 286
emergence of, 29 Salicylates, 363
genetic basis, 144, 159 Savants, 27
and immune system, 159 Schizoid personality disorder, 22
and intelligence tests, 93 Schizophrenia
medication for, 26, 236, 237, 239, as comorbid condition, 7
254 (see also Serotonin-reuptake differential diagnosis, 110
inhibitors (SSRIs)) in family members, 108
and neurotransmitters, 25–26 and medication, 250
and siblings, 24 and virus, 189
symptoms, 17, 25–27, 103–104 Screening
Research advocacy, 398–400, 403, ancillary, 44
404–405 for Asperger’s disorder, 42–43
Resititutional overcorrection, 377 autism-specific, 42–43
Response cost, 377 future trends, 420
Restlessness, 280–282, 308–309, 326 for general development, 40–42
Restraints, 292–293 genome-wide, 139–145
Retinoids, 178–179 instruments, 42, 74
Rett, Andreas, 9 school-age children, 43
Rett’s disorder, 9, 16 Seasons, 158, 177–178
genetics of, 284–285 Seaver Center, 398
movement disorders, 284–285 Secretin, 166, 348–357
Rett’s syndrome Seizure disorders, 8, 10, 27–28, 238–
description, 106 239 (see also Epilepsy)
prevalence, 19 therapy for, 120, 239–240, 268–270
Rewards, 377 Seizures
Rheumatic fever, 190–191 age factors, 30, 47, 265–266, 267–268
Risperidone and clomipramine, 415
and aggression, 119 and EEGs, 116
candidates for, 19 frequency, 267
clinical results, 251–254, 258 and metabolic disorders, 50
dosage, 258(t) and Rett’s syndrome, 106
interactions, 295 and self-injury, 295
side effects, 119, 255–256, 279 subclinical, 268–269, 421
and social relatedness, 258 and tuberous sclerosis, 46
for stereotypies, 119, 295 very early-onset, 50
Ritalin, 119 Selective mutism, 10
Rituals, 25 Selective serotonin-reuptake inhibitors
Rocking, 46, 103, 212 (SSRIs) (see also specific agents)
Rossetti Infant-Toddler Language Scale, age factors, 420
115 and behaviors, 8, 26, 31, 155
Rotating (see Spinning) dosage, 415
Rough-housing, 104 and interest, 155
Index 439
[Selective serotonin-reuptake inhibitors [Sensory processing]

(SSRIs) (see also specific agents)] medication for, 254
monitoring, 286 monochannel, 411
side effects, 119 and prognosis, 78
and social interaction, 31 symptoms, 104
for stereotypies, 234, 286 Serotonergics, 286
Self-absorption Serotonin (see also specific agents)
minimization of, 71 and age, 155, 215
and prognosis, 76–78 age factors, 210
Self-injury and antibodies, 161–162
autistic, versus OCD, 25 and Asperger’s disorder, 212
common forms, 288 and ataxia, 225–226
and education, 294 and autistic symptoms, 232–233, 248–249
etiology, 288–289 and cerebellum, 224–226, 421
interventions, 290–296 challenge studies, 210–212
and mainstreaming, 389 as etiology, 25–26, 108
medical complications, 329 and family members, 25, 209–210, 232
medication for, 119, 238, 240–241, future studies, 420–421
254, 294–296 genetic studies, 213–215, 222–223
and opiate antagonists, 295 historical perspective, 200–201
protective devices, 293 measurements, 201–210
rating, 289–290, 304–306, 317–321 neuroimaging studies, 212–213
and seizures, 295 racial factors, 205
stimuli, 289, 293 and repetitive behavior, 25–26
study of, 8 transporter genes, 137
and surgery, 294 Sertraline, 235, 237, 415
and tryptophan, 212 Sex, obsession with, 25
Self-management, 385 Sex ratio, 6
Self-perception Shaping, 373
and family system, 63 Siblings, 15
self referral, 103 and communication, 24
testing, 95–96 genetic studies, 142, 144
Self-stimulation, 71, 357 recurrence risk, 154
Senses, 94, 104, 409–410, 411 (see also and serotonin, 209
Hearing; Touch) Singsong, 103
Sensitivity (see also Stimuli) Skills, 371–376
description, 409–411 Skin, 46
to textures, 111 Sleep, 48–49, 165–166, 352, 415
therapy for, 118–119 Sleep disorders, 164
Sensorimotor deficits, 46, 212, 379 Smell, 104
Sensory integration disorder (SID), 111 Social awkwardness, in family, 108
Sensory integration therapy, 379, 411 Social interactions (see also Interac-
Sensory processing tions; Peers; Relationships)
evaluation of, 61–62, 115 in adults, 30
first person description, 409–411 and Asperger’s syndrome, 105–106
kinesthetic sense, 411 and Borna disease virus, 188–189
440 Index
[Social interactions (see also Interac- Squinting, 104

tions; Peers; Relationships)] SSRIs (see Selective serotonin-reuptake
deficit emergence, 29 inhibitors)
and differential diagnosis, 110 Stanford-Binet test, 92–93, 114
and family members, 28 Staring, 116
gene study, 138 Stealth viruses, 187
impairment range, 17 Stereotypies, 8, 25, 46
and language deficit, 218 and Borna disease virus, 189
and mainstreaming, 387–388 and comorbidity, 8
myths, 123–124 defined, 326
and secretin, 351 descriptions, 103, 104, 286–287, 328
and sensory integration disorder, 111 education for, 377
subtypes, 21–22 and exercise, 411
symptoms, 21–23, 103 genetic basis, 144
test for, 88(t), 94 medication, 286, 295, 296
therapy versus other therapy, 287
antipsychotic, 254, 258 SSRIs, 119, 234, 286
aricept, 166 prevalence, 25, 46
diet, 120 rating, 322–325
immunomodulation, 165–166 and vitamin C, 359
mood stabilizers, 239, 240 in young children, 29
music, 121 Stimuli (see also Sensitivity)
SSRIs, 31, 234, 236 desensitization to, 379
training for, 375–376 reaction to, 46, 104
Social phobia, 10, 22 for self-injury, 289, 293, 294
in relatives, 28 Streptococcus, 190–191
Socioeconomic class, 2, 5, 6–7 Stress, 60
Sounds Substance P, 164
production of, 78, 327, 328 Subtypes, 18–20, 31–32
reaction to, 104, 114–115 Sumatriptan, 26, 212
sensitivity to, 1, 409–411 Support groups, 401–403
Spatial awareness, 411 Surgery, 269–270, 294
Spatial orientation, 411 Swallowing, 279–280
Speaking, pedantic style, 105 Sydenham’s chorea, 190–191
Specific language impairment, 144 Symmetry, obsession with, 25
Speech therapy Syphilis, 191
attention techniques, 410–411
frequency of, 70–71 Tantrums
with mainstreaming, 385 and mainstreaming, 389
therapist qualifications, 118 medication for, 234, 236, 237–238
in toddlers, 111 triggers, 103
Spinning and vitamin B6, 357
after effects, 104 Tardive dyskinesia, 277, 282–284, 295
description, 328 Task-specific strengths, 92
toys, 103 Taste, 104
and tryptophan, 212 Teeth, 103
Index 441
Temporal lobes, 186 Thimerosal, 109, 361

Terminology, 102 Thioridazine, 240, 257
Testing Third person, 103
of cognitive ability, 88–91(t), 92–97, Thought patterns, 412–413
114 Thyroid, 108, 176
of handicapped children, 94 Tics, 8–9, 275, 285–286
of institutionalized persons, 94 checklist, 311
for language/speech, 115–116 defined, 327
of nonambulatory persons, 94 phonic, 327
performance, 2 Timing (see Onset)
prenatal, 116 T lymphocytes, 109, 156–157, 160–161
Tetrachloroethylene, 177 Toddlers
Textures, 104 diagnosis in, 29, 105
Thalidomide, 108, 178–179 and intelligence tests, 92
Therapist language in, 80–81
role of, 68, 123, 407–408 risperidone in, 251
standards for, 406 screening, 41–43, 80–81
Therapy (see also Alternative therapies; speech therapy in, 111
Medication) Toes, 212, 328
adverse effects, 277–284 Toilet-training, 378
for behaviors (see Behavioral therapy) Token economy, 377
consumer issues, 395–397 Tongue, 279, 282
dimensional approach, 19 Touch
environment of, 412 avoidance of, 111
for HIV, 188 body pressure, 413
home-based, 71, 117–118 craniosacral, 121
immune, 121, 164–166, 363 and speech therapy, 118
initial sessions, 66–68 textures, 104, 111
integration, 407–408 Tourette’s syndrome, 8–9, 285
intensity of, 386, 410 Toxins, 17, 177, 179–181
for language disorders, 236, 239, 240, Toxoplasmosis, 191
254 Toys, 67–68, 103, 378
NIH conference, 397 Training (see Education; Job training)
non-medicinal, 29–30, 120–123, 287 Transfer factors, 165–166
occupational, 118–119 Trazodone, 238
outcome predictors, 27 Tremors, 327
parent-child interaction in, 67–68 Trends, 11
program components, 70–71 Trichloroethylene, 177
relational, 58–59, 379–380 Tricyclic antidepressants, 413–414, 415
for seizures, 120, 239–240, 268–270 (see also specific agents)
standards for, 406 Trihalomethanes (THMs), 177
for stereotypies, 286–287 (see also Trimethylbenzenes, 180
under Stereotypies) Tryptophan
surgery, 269–270 depletion of, 26, 211
targeted, 31 and rocking, 212
in toddlers, 111 and serotonin, 200, 203, 232
442 Index
Tuberous sclerosis Vitamin B12, 109

comorbidity, 8 Vitamin B15, 120
diagnosis, 113 Vitamin C, 359
prevalence, 19, 46 Vocational skills, 30, 378
Tumor necrosis factor (TNF), 156, 165 Voice, tone of, 103
Twins, 24, 108, 133–134 Vomiting, 50
UCLA Young Autism Project, 117–118 Walking, 212

Urine, 109, 120 Water
contaminated, 177
Vaccines, 108–110, 192, 361 preoccupation with, 104, 409
Website, 364 Websites, 364, 395, 408
Valproic acid, 119, 178, 269 Wechsler scales, 88(t), 92–93, 114
Vancomycin, 166, 361–362 Weight gain, 119
Varicella, 187 Wheat, 120
Vasoactive intestinal peptide (VIP), 164 Wisconsin Card Sorting Test (WCST),
Venlafaxine, 238, 286 89(t), 95–96
Verbal auditory agnosia, 266–267, 269 WNT2 gene, 138
Vestibular stimulation, 289 Writhing, 282
Vineland Adaptive Behavior Scale, 94, Writing, 104
114
Viruses, 108–110, 158–159, 181–190 Yeast, 120
Vision, 409–410, 411
Visual thinking, 88(t), 412–413 Zero-to-Three programs, 112
Vitamin A, 178–179, 358–359 Zidovudine (AZT), 188
Website, 364 Ziprasidone, 255, 259 (see also Antipsy-
Vitamin B6, 120, 357–358 chotics)
About the Editor
Eric Hollander is Professor of Psychiatry; Clinical Director of the Seaver Autism

Research Center, and Director of Clinical Psychopharmacology and the Compul-
sive, Impulsive and Anxiety Disorders Program, Mount Sinai School of Medi-
cine, New York, New York. The editor or coeditor of 13 books, including Obses-
sive-Compulsive Disorders (Marcel Dekker, Inc.), he is the author or coauthor
of over 400 journal publications and book chapters and is founding editor of CNS
Spectrums. A Fellow of the American Psychiatric Association and the American
College of Neuropsychopharmacology, Dr. Hollander is the recipient of two na-
tional research awards from the American Psychiatric Association and a Distin-
guished Investigator Award from the National Alliance for Research in Schizo-
phrenia and Depression. Dr. Hollander received the B.A. degree (1978) from
Brandeis University, Waltham, Massachusetts, and the M.D. degree (1982) from
the State University of New York Downstate Medical College, Brooklyn. He
completed his residency in psychiatry at Mount Sinai School of Medicine, New
York, New York, and his fellowship in psychiatry research at Columbia Univer-
sity College of Physicians and Surgeons, New York, New York.

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Autism Spectrum

MARCEL DEKKER, INC. NEW YORK • BASEL

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PRINTED IN THE UNITED STATES OF AMERICA

Jonathan E. Alpert, M.D., Ph.D. Siegfried Kasper, M.D.

Bennett Leventhal, M.D. Mark H. Rapaport, M.D.

1 Handbook of Depression and Anxiety: A Biological Approach, edi-

ADDITIONAL VOLUMES IN PREPARATION

Handbook of Chronic Depression' Diagnosis and Therapeutic Man-

Then there is the assessment—the detailed dimensional evaluation of different

Oliver Sacks, M.D.

Autism, the third commonest developmental disorder, is a complex and fascinat-

role of oxytocin, immunization, and infections in the causation of autism spec-

Autism: A Historical Perspective Oliver Sacks iii

The Clinical Condition

1. Autism: Diagnosis and Epidemiology 1

2. Core Symptoms, Related Disorders, and Course of Autism 15

3. Autism Screening and Neurodevelopmental Assessment 39

4. Assessment and Early Identiﬁcation of Autism Spectrum and

5. Cognitive and Neuropsychological Assessment of Children with

6. Assessment and Diagnosis of Pervasive Developmental Disorder 101

The Neurobiology of Autism

7. Molecular Genetics of Autism 133

8. Immune Dysfunction in Autism 153

9. Autism and Environmental Toxins 175

10. Neurobioloy of Serotonin Function in Autism 199

11. Autism, Serotonin, and the Cerebellum: A New,

12. Antidepressants and Anticonvulsants/Mood Stabilizers in the

13. Use of Atypical Antipsychotics in Autism 247

14. Treatment of Seizures in Children with Autism Spectrum

15. Treatment of Movement Disorders in Autism Spectrum

16. Alternative Biological Treatments for Autism 347

Other Treatment Approaches

17. Behavioral Assessment and Treatment 369

18. Educational Intervention: Inclusion vs. Self-Contained Classes 383

19. Consumer Advocacy and Autism 393

20. Autism: A Personal Perspective 409

21. Future Trends 419

Katherine C. Barboza, B.A. Mount Sinai School of Medicine, New York,

Irina Bespalova Seaver Autism Research Center and Laboratory of Molecular

James Robert Brašić, M.D., M.P.H. Postdoctoral Fellow in PET/SPECT/

Joseph D. Buxbaum, M.D. Laboratory of Molecular Neuropsychiatry, Depart-

Charles Cartwright, M.D. Assistant Professor, Department of Psychiatry,

Gina DelGiudice, M.D. Seaver Autism Research Center and Department of

Psychiatry, Mount Sinai School of Medicine, and Department of Rheumatology,

Martin Evers, B.S. Department of Psychiatry and Seaver Autism Research

Daniel H. Geschwind, M.D., Ph.D. Assistant Professor, Program in Neurogen-

Temple Grandin, Ph.D. Assistant Professor, Department of Animal Sciences,

Stanley I. Greenspan, M.D. Bethesda, Maryland, U.S.A.

Eric Hollander, M.D. Professor, Department of Psychiatry; Clinical Director,

Mario Kilifarski Laboratory of Molecular Neuropsychiatry, Department of

Audrey F. King, Ph.D. Department of Psychiatry and Seaver Autism Research