Autism Spectrum Disorders (Medical Psychiatry Series)

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Autism Spectrum Disorders edited by

Eric Hollander Mount Sinai School of Medicine New York, New York, U.S.A.

MARCEL

MARCEL DEKKER, INC.

NEW YORK • BASEL

Although great care has been taken to provide accurate and current information, neither the author(s) nor the publisher, nor anyone else associated with this publication, shall be liable for any loss, damage, or liability directly or indirectly caused or alleged to be caused by this book. The material in this publication is not intended to provide speciﬁc advice or recommendations for any speciﬁc situation. Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identiﬁcation and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN: 0-8247-0715-X This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc., 270 Madison Avenue, New York, NY 10016, U.S.A. tel: 212-696-9000; fax: 212-685-4540 Distribution and Customer Service Marcel Dekker, Inc., Cimarron Road, Monticello, New York 12701, U.S.A. tel: 800-228-1160; fax: 845-796-1772 Eastern Hemisphere Distribution Marcel Dekker AG, Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-260-6300; fax: 41-61-260-6333 World Wide Web http:/ /www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright  2003 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microﬁlming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA

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. Massachusetts General Hospital and Harvard University School of Medicine Boston, Massachusetts, USA

Siegfried Kasper, M.D. University Hospital for Psychiatry and University of Vienna Vienna, Austria

Bennett Leventhal, M.D. University of Chicago School of Medicine Chicago, Illinois, USA

Mark H. Rapaport, M.D. Cedars-Sinai Medical Center Los Angeles, California, USA

1 2 3

4. 5 6 7 8.

9. 10. 11 12

Handbook of Depression and Anxiety: A Biological Approach, edited by Johan A den Boer and J. M. Ad Sitsen Anticonvulsants in Mood Disorders, edited by Russell T. Joffe and Joseph R Calabrese Serotonin in Antipsychotic Treatment: Mechanisms and Clinical Practice, edited by John M Kane, H.-J. Moller, and Frans Awouters Handbook of Functional Gastrointestinal Disorders, edited by Kevin W. Olden Clinical Management of Anxiety, edited by Johan A den Boer Obsessive-Compulsive Disorders1 Diagnosis • Etiology • Treatment, edited by Eric Hollander and Dan J. Stein Bipolar Disorder: Biological Models and Their Clinical Application, edited by L. Trevor Young and Russell T. Joffe Dual Diagnosis and Treatment' Substance Abuse and Comorbid Medical and Psychiatric Disorders, edited by Henry R. Kranzlerand Bruce J. Rounsaville Geriatric Psychopharmacology, edited by J. Craig Nelson Panic Disorder and Its Treatment, edited by Jerrold F. Rosenbaum and Mark H Pollack Comorbidity in Affective Disorders, edited by Mauricio Tohen Practical Management of the Side Effects of Psychotropic Drugs, edited by Richard Baton

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 Implications, 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 Management, 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 English in the 1980s), and Kanner’s unfortunate formulation was rather widely accepted 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 communicational 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 volume). There were repetitive and compulsive behaviors; there could be impulsivity, explosiveness, aggressiveness; there were sometimes speciﬁc language disorders. Sometimes there were seizures or EEG abnormalities. And a large proportion of the autistic—at least, those with classical infantile 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 syndrome, 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 mysterious, 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 biological 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 fascinating 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 behaviors—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 target these speciﬁc areas of abnormality are now possible, along with more sophisticated 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 spectrum 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 convergence 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 pharmacological 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 scientiﬁc guidance Eric Hollander

Contents

Autism: A Historical Perspective Preface Contributors

Oliver Sacks

iii vii xiii

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

1

2. Core Symptoms, Related Disorders, and Course of Autism Eric Hollander and Caralynn V. Nowinski

15

Assessment 3. Autism Screening and Neurodevelopmental Assessment Sarah J. Spence and Daniel H. Geschwind 4. Assessment and Early Identiﬁcation of Autism Spectrum and Other Disorders of Relating and Communicating Stanley I. Greenspan and Serena Wieder

39

57 ix

x

5.

6.

Contents

Cognitive and Neuropsychological Assessment of Children with Autism Spectrum Disorders Audrey F. King, Ronald R. Rawitt, Katherine C. Barboza, and Eric Hollander Assessment and Diagnosis of Pervasive Developmental Disorder Cecelia McCarton

87

101

The Neurobiology of Autism

7.

Molecular Genetics of Autism Jennifer G. Reichert, Mario Kilifarski, Irina Bespalova, Nicolas Ramoz, and Joseph D. Buxbaum

133

8.

Immune Dysfunction in Autism Gina DelGiudice and Eric Hollander

153

9.

Autism and Environmental Toxins Martin Evers, Sherie Novotny, and Eric Hollander

175

10.

Neurobioloy of Serotonin Function in Autism Christopher J. McDougle, David J. Posey, and Marc N. Potenza

11.

Autism, Serotonin, and the Cerebellum: A New, Comprehensive Hypothesis Donatella Marazziti

199

221

Psychopharmacological Treatments

12.

13.

Antidepressants and Anticonvulsants/Mood Stabilizers in the Treatment of Autism Sherie Novotny and Eric Hollander Use of Atypical Antipsychotics in Autism David J. Posey and Christopher J. McDougle

231

247

Contents

xi

14. Treatment of Seizures in Children with Autism Spectrum Disorders Roberto Tuchman

265

15. Treatment of Movement Disorders in Autism Spectrum Disorders James Robert Brasic

273

16. Alternative Biological Treatments for Autism Charles Cartwright and Rachael Power

347

Other Treatment Approaches 17. Behavioral Assessment and Treatment Tristram Smith and Caroline Magyar

369

18. Educational Intervention: Inclusion vs. Self-Contained Classes Audrey F. King

383

19. Consumer Advocacy and Autism John Maltby

393

20. Autism: A Personal Perspective Temple Grandin

409

21. Future Trends Eric Hollander and Ronald R. Rawitt

419

Index

423

Contributors

Katherine C. Barboza, B.A. New York, U.S.A.

Mount Sinai School of Medicine, New York,

Irina Bespalova Seaver Autism Research Center and Laboratory of Molecular Neuropsychiatry, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, U.S.A. James Robert Brasˇic´, 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 Psychiatry, New York University School of Medicine, New York, New York, U.S.A. Joseph D. Buxbaum, M.D. Laboratory of Molecular Neuropsychiatry, Departments 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 Neurogenetics, 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 Medicine, New York, New York, U.S.A. Audrey F. King, Ph.D. Department of Psychiatry and Seaver Autism Research Center, Mount Sinai School of Medicine, New York, New York, U.S.A. Kathleen Koenig, M.S.N. Yale University, New Haven, Connecticut, U.S.A. Caroline Magyar, Ph.D. Strong Center for Developmental Disabilities, University 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 Center, Mount Sinai School of Medicine, New York, New York, U.S.A. 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 Adolescent 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 Medicine 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, New York, New York, U.S.A. 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 Medicine, New York, New York, U.S.A. Tristram Smith, Ph.D. Strong Center for Developmental Disabilities, University 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. ami, Florida, U.S.A.

Dan Marino Center, Miami Children’s Hospital, Mi-

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 contact,” 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 selfcontained 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 problems 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 sensitivity 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 condition and in some instances continue to complicate interpretation of the early research literature. Some of these controversies arose as a result of aspects of Kanner’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 syndrome 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 predominance 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 parents (4). Kanner initially speculated that autism was not related to other medical conditions, but subsequent research has shown that various conditions are associated with autism, including fragile X syndrome, tuberous sclerosis, and seizure disorders (5). An additional source of confusion arose because of Kanner’s original speculation that children with autism were not mentally retarded. This impression 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 complicated psychological phenomena such as hallucinations and delusions were attributed 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 autism. 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 treatment? In 1978 Rutter (8) synthesized Kanner’s original report and subsequent research in what later became a highly inﬂuential deﬁnition of autism. This deﬁnition 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 environment, and motor mannerisms. These criteria largely comprised the basis for the deﬁnition of autism in the third edition of the Diagnostic and Statistical Manual 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 (DSMIII-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 considerations, 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 deﬁnition 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 deﬁnition 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 communication (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, adherence 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 problems—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 formalize and standardize these criteria; in other cases instruments have been developed 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 answering the most pressing question posed in the last two decades regarding these disorders: is the incidence of autism and pervasive developmental disorders increasing? 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

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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 ﬁnergrained 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 syndrome, 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 identiﬁcation, 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 referred samples. The latter are biased toward those who need services at a particular 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 epidemiological 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-

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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 contrast, 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 diagnosis, 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 traditionally classiﬁed within the autistic spectrum. Fombonne (20) conducted a comprehensive meta-analysis of 23 epidemiological studies of autism that encompassed over 4 million children. Consideration of sample size and the associated conﬁdence intervals helped to gauge the accuracy 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 diagnosed 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 information 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 retarded 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 individuals are in the mild and moderate range of mental retardation. When syndrome deﬁnitions are broadened, a greater proportion of high-IQ individuals are identiﬁed. 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-

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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 families 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 techniques that speciﬁcally evaluate the reality of the cluster phenomenon while eliminating 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 speciﬁc 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, serving 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

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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 frequently, 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 observed 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 conditions 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 typical 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 disorders 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-

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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 affective responses, as well as anxiety and depression. Clinical depression and bipolar disorders have been reported and may respond to pharmacological intervention (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 disorder; 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 investigators have noted a sizable subgroup with major attentional problems (16,52). DIFFERENTIAL DIAGNOSIS An alternative way of conceptualizing the PDDs is through a dimensional approach, 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 disorder, 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 deceleration 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-

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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 generally 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 stereotypies 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 personality disorders (57). Associated medical conditions may, in an apparent minority of cases (estimated between 10% and 25%) underlie autistic-like presentations (58,59). Speciﬁcally, fragile X syndrome and tuberous sclerosis are seen with greater-thanchance frequency in the autistic population. Associations with congenital rubella, cerebral palsy, phenylketonuria, neuroﬁbromatosis, and Down’s syndrome appear 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 mechanisms, the diagnosis of PDD-NOS will beneﬁt from further reﬁnement: dimensional 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.

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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 neurobiological mechanisms and designing appropriate intervention. Family genetic studies are a useful methodology for identifying the presence of comorbid conditions. Data supporting whether associations arise by chance or at a greater-thanchance rate are critical as well. The current nosology will be enhanced by greater certainty regarding associated conditions combined with more precise conceptualization 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. REFERENCES 1. 2. 3.

4.

5.

6.

7.

Kanner L. Autistic disturbances of affective contact. Nerv Child 1943; 2:217–250. Rutter M. Diagnostic validity in child psychiatry. Adv Biol Psychiatry 1978; 2:2–22. Wing L, Gould J. Severe impairments of social interactions and associated abnormalities in children: epidemiology and classiﬁcation. J Autism Dev Disord 1979; 9(1):11–29. Volkmar FR, Carter A, Grossman J, Klin A. Social development in autism. In: Cohen DJ, Volkmar FR, eds. Handbook of Autism and Pervasive Developmental Disorders. 2nd ed. New York: Wiley, 1997:173–194. Dykens EM, Volkmar FR. Medical conditions associated with autism. In: Cohen DJ, Volkmar FR, eds. Handbook of Autism and Pervasive Developmental Disorders. 2nd ed. New York: Wiley, 1997:388–410. Sparrow S. Developmentally based assessments. In: Cohen DJ, Volkmar FR, eds. Handbook of Autism and Pervasive Developmental Disorders. 2nd ed. New York: Wiley, 1997:411–447. Volkmar FR, Klin A, Cohen DJ. Diagnosis and classiﬁcation of autism and related conditions: consensus and issues. In: Cohen DJ, Volkmar, FR, eds. Handbook of Autism and Pervasive Developmental Disorders. 2nd ed. New York: Wiley, 1997:5–40.

12 8. 9. 10. 11.

12. 13.

14. 15. 16.

17.

18. 19.

20. 21.

22.

23. 24. 25.

Volkmar et al. Rutter M. Diagnosis and deﬁnition of childhood autism. J Autism Child Schizophr 1978; 8(2):139–161. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC: American Psychiatric Publishing, 1980. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed revised. Washington, DC: American Psychiatric Publishing, 1987. Volkmar FR, Cicchetti DV, Bregman J, Cohen DJ. Three diagnostic systems for autism: DSM-III, DSM-III-R, and ICD-10. Special issue: classiﬁcation and diagnosis. J Autism Dev Disord 1992; 22(4):483–492. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Publishing, 1994. Volkmar FR, Klin A, Seigel B, Szatmari P, Campbell M, Freeman BJ, Cicchetti DV, Rutter M, Kline W, Buitelaar J, Hattab Y, Frombonne E, Fuentes J, Werry J, Stone W, Kerveshian J, Hoshino Y, Bregman J, Loveland K, Szymanski L, Towbin K. Field trial for autistic disorder in DSM-IV. Am J Psychiatry 1994; 151(9):1361– 1367. Volkmar FR, Rutter M. Childhood disintegrative disorder: results of the DSM-IV autism ﬁeld trial. J Am Acad Child Adolesc Psychiatry 1995; 34(8):1092–1095. Miller JN, Ozonoff S. Did Asperger’s cases have Asperger’s disorder? A research note. J Child Psychol Psychiatry 1997; 38(2):247–251. Towbin KE. Pervasive developmental disorder not otherwise speciﬁed. In: Cohen DJ, Volkmar FR, eds. Handbook of Autism and Pervasive Developmental Disorders. 2nd ed. New York: Wiley, 1997:123–147. Lord C. Diagnostic instruments in autism spectrum disorders. In: Cohen DJ, Volkmar FR, eds. Handbook of Autism and Pervasive Developmental Disorders. 2nd ed. New York: Wiley, 1997:460–483. Le Couteur A, Rutter M, Lord C, Rios P. Autism Diagnostic Interview: a standardized investigator-based instrument. J Autism Dev Disord 1989; 19(3):363–387. Lord C, Rutter ML, Goode S, Heemsbergen J, et al. Autism Diagnostic Observation Schedule: a standardized observation of communicative and social behavior. J Autism Dev Disord 1989; 19(2):185–212. Fombonne E. The epidemiology of autism: a review. Psychol Med 1999; 29:769– 786. Bryson SE. Epidemiology of autism: overview and issues outstanding. In: Cohen DJ, Volkmar FR, eds. Handbook of Autism and Pervasive Developmental Disorders. New York: Wiley, 1997:41–46. Fombonne E. Epidemiological ﬁndings on autism and related developmental disorders. Early Educational Interventions in Autism: Report from the National Academy of Sciences. Washington, DC, 2001. Lotter V. Epidemiology of autistic conditions in young children: I. Prevalence. Soc Psychiatry 1966; 1:124–137. McCarthy P, Fitzgerald M, Smith M. Prevalence of childhood autism in Ireland. Irish Med J 1984; 77:129–130. Burd L, Fisher W, Kerbeshan J. A prevalence study of pervasive developmental disorders in North Dakota. J Am Acad Child Adolesc Psychiatry 1987; 26:700– 703.

Diagnosis and Epidemiology 26. 27. 28. 29. 30. 31. 32. 33.

34. 35. 36.

37.

38. 39.

40.

41. 42. 43.

44.

13

Treffert DA. Epidemiology of infantile autism. Arch Gen Psychiatry 1970; 22:431– 438. Steinhausen H-C, Gobel D, Breinlinger M, Wohlloben B. A community survey of infantile autism. J Am Acad Child Psychiatry 1986; 25:186–189. Bryson SE, Clark BS, Smith IM. First report of a Canadian epidemiological study of autistic syndromes. J Child Psychol Psychiatry 1988; 4:433–445. Wing L. The deﬁnition and prevalence of autism: a review. Eur Child Adolesc Psychiatry 1993; 2:61–74. Baron-Cohen S, Saunders K, Chakrabarti S. Does autism cluster geographically? A research note. Autism 1999; 3:39–43. Fombonne E. Is the prevalence of autism increasing? J Autism Dev Disord 1996; 6:673–676. Reiss S, Levitan GW, Szyszko J. Emotional disturbance and mental retardation: Diagnostic overshadowing. Am J Ment Retard 1982; 86:567–574. White MJ, Nichols CN, Cook RS, Spengler PM, Walker BS, Look KK. Diagnostic overshadowing and mental retardation: a meta-analysis. Am J Ment Retard 1995; 100:293–298. Volkmar FR, Cohen DJ. Comorbid association of autism and schizophrenia. Am J Child Psychiatry 1991; 148(12):1705–1707. Tsai LY. Brief report: comorbid psychiatric disorders of autistic disorder. J Autism Dev Disord 1996; 26(2):159–163. Prior M, Ozonoff S. Psychological factors in autism. In: Volkmar FR, ed. Autism and Pervasive Developmental Disorders. Cambridge: Cambridge University Press, 1998:64–108. Rutter M, Bailey A, Simonoff E, Pickles A. Genetic inﬂuences in autism. In: Cohen DJ, Volkmar FR, eds. Handbook of Autism and Pervasive Developmental Disorders. 2nd ed. New York: Wiley, 1997:370–387. Poustka F, Lisch S. Autistic behaviour domains and their relation to self-injurious behaviour. Acta Paedopsychiatry 1993; 56(2):69–73. Jaselskis CA, Cook EH, Fletcher KE, Leventhal BL. Clonidine treatment of hyperactive and impulsive children with autistic disorder. J Clin Psychopharmacol 1992; 2(5):322–327. Quintana H, Birmaher B, Stedge D, Lennon S, Freed J, Bridge J, Greenhill L. Use of methylphenidate in the treatment of children with autistic disorder. J Autism Dev Disord 1995; 25(3):283–294. Realmuto GM, Main B. Coincidence of Tourette’s disorder and infantile autism. J Autism Dev Disord 1982; 12(4):367–372. Ghaziuddin M, Tsai L, Ghaziuddin N. Comorbidity of autistic disorder in children and adolescents. Eur Child Adolesc Psychiatry 1992; 1(4):209–213. Nelson EC, Pribor EF. A calendar savant with autism and Tourette syndrome: response to treatment and thoughts on the interrelationships of these conditions. Ann Clin Psychiatry 1993; 5(2):135–140. McDougle CJ, Kresch LE, Goodman WK, Naylor ST, Volkmar FR, Cohen DJ, Price LH. A case-controlled study of repetitive thoughts and behavior in adults with autistic disorder and obsessive-compulsive disorder. Am J Psychiatry 1995; 152(5): 772–777.

14 45. 46.

47. 48.

49. 50.

51. 52.

53.

54. 55.

56. 57.

58. 59.

Volkmar et al. Rumsey JM, Rapoport JL, Sceery WR. Autistic children as adults: psychiatric, social, and behavioral. J Am Acad Child Psychiatry 1985; 24(4): 465–473. McDougle, CJ, Naylor ST, Cohen DJ, Volkmar FR, Henninger GR, Price LH. A double-blind, placebo controlled study of ﬂuvoxamine in adults with autistic disorders. Arch Gen Psychiatry 1996; 53(11):1001–1008. Baron-Cohen S. Do autistic children have obsessions and compulsions? Br J Clin Psychol 1989; 28(Pt 3):193–200. Burd L, Fisher WW, Kerbeshian J, Arnold ME. Is development of Tourette’s disorder a marker for improvement in patients with autism and other pervasive developmental disorders? J Am Acad Child Adolesc Psychiatry 1987; 26(2):162–165. Lainhart JE, Folstein SE. Affective disorders in people with autism: a review of published cases. J Autism Dev Disord 1994; 24(5):587–601. Steingard R, Biederman J. Lithium responsive manic-like symptoms in two individuals with autism and mental retardation. J Am Acad Child Adolesc Psychiatry 1987; 26(6):932–935. Handen BL. Pharmacotherapy in mental retardation and autism. School Psychol Rev 1993; 22(2):163–183. Hellgren L, Gillberg IC. Children with deﬁcits in attention, motor control and perception (damp) almost grown up: at age 16 years. Eur Child Adolesc Psychiatry 1994; 3(1):11–15. Hollander E, Cartwright C, Wong CM, DeCaria CM, DelGiudice-Asch G, Buchsbaum MS, Aronowitz BR. A dimensional approach to the autism spectrum. Curr Trends Autism 1999; 103–114. Rett A. Uber ein eigenartiges hirntophisces syndroem bei hyperammonie im kindersalter. Wein Medizinische Wochenschrift 1966; 118:723–726. Volkmar FR, Klin A, et al. Childhood disintegrative disorder. In: Cohen DJ, Volkmar FR, eds. Handbook of Autism and Pervasive Developmental Disorders. 2nd ed. New York: Wiley, 1997:47–59. Asperger H. Die “autistichen psychopathen” im kindersalter. Archive fu¨r Psychiatrie und Nervenkrankheiten 1944; 117:76–136. Volkmar F, Cook E Jr, Pomeroy J, Realmuto G, Tanguay P. Summary of the practice parameters for the assessment and treatment of children, adolescents and adults with autism and other pervasive developmental disorders. J Am Acad Child Adolesc Psychiatry 1999; 38(12):1611–1615. Rutter M, Bailey A, Bolton P, Le Couter A. Autism and known medical conditions: myth and substance. J Child Psychol Psychiatry 1994; 35:311–322. Gilberg C, Coleman M. Autism and medical disorders: a review of the literature. Dev Med Child Neurol 1996; 38:191–202.

2 Core Symptoms, Related Disorders, and Course of Autism Eric Hollander and Caralynn V. Nowinski Mount Sinai School of Medicine New York, New York, U.S.A.

INTRODUCTION Autism, originally described by Kanner in 1943, is among the most severe of all neurodevelopmental disorders. It is a pervasive disorder associated with substantial 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 estimated 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

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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 disorders 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 Classiﬁcation 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 developmental 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 separately 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 DSMIV 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 disorder, 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

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involves social deﬁcits and repetitive, restricted interests but no delay in the development of language, cognition or age-appropriate self-help skills. Thus, it is difﬁcult to clinically distinguish it from high-functioning autism, i.e., an individual with autism who also has average intellectual functioning and no language delay. Differences among autism spectrum disorders seem to be linked to intelligence, 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 involvement 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 resulting from a variety of genetic and/or environmental factors (e.g., birth complications, 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 autismrelated symptoms into population samples (8,9). By using larger samples in research, scientists can increase the level of conﬁdence that their ﬁndings are accurate 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 symptoms 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,

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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 collection of more homogeneous, or similar, study populations. Nevertheless, the above issues of heterogeneity, developmental variation, neurological comorbidity, 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 speciﬁc genes may be linked to speciﬁc behavioral dimensions. It is the complex interaction of these genes that gives rise to the overall clinical picture. Environmental 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 involves better characterizing speciﬁc core symptom domains and associated symptom 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 DSMIV 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). Furthermore, 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 patients to better deﬁne the population. A recent review of approaches to subtyping autism (15) describes four methods: 1) social interaction/communication subtyping, 2) intellectual/developmental level and adaptive functioning subtyping, 3)

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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, neuroﬁbromatosis, 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, genetic studies have applied a dimensional approach to identify potential chromosomal 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 risperidone (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 severity. The effects of these drugs on different core dimensions were evident. Fluvoxamine targeted all three dimensions, causing improvements in repetitive thoughts/behaviors, social relatedness, and language usage, while risperidone targeted 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 (attentional difﬁculties, self-injurious behavior, mental retardation, self-stimulation, affective instability, EEG abnormalities), but the three core symptom domains appear 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 dimensions. 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

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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 treatments 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 independent such that elemental behaviors are nonoverlapping, an interdependence exists such that symptoms present within a single domain are insufﬁcient in differentiating autism from other developmental disorders. Lord et al. (28) demonstrated this phenomenon by showing that correlations exist between the domains as measured 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.

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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 dimension 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 highlight 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 phenomenological standpoint, consist of failure to develop reciprocal social interactions 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-

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odd children were more spontaneous in their social approaches, but these were odd and idiosyncratic. They were more aware of other people’s emotional reactions. 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 autistic patients exhibit only selected symptoms of these disorders and do so in combination 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 detachment 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 differentiating 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 autism (33). Using a dimensional approach in autism research has been useful in characterizing 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 development of autism (35). Decreased levels of plasma oxytocin have been found in

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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 exhibited a positive association (36). To better clarify the role of oxytocin, Green and colleagues (37) investigated precursor peptide forms of oxytocin. They found elevated oxytocin precursor peptide levels in contrast with reduced plasma oxytocin levels, which may indicate incomplete processing of oxytocin prohormone in autism (37). A processing 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 contribute to the development of targeted treatment approaches for individuals with autism. The Communication Domain The speech and communication deﬁcits in autism include mutism, echolalia, idiosyncratic 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 communication 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 language have an impaired ability to initiate and sustain a conversation and demonstrate 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

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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 deﬁcits 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 impairment 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 evidence 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 relative 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 ADIR, 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.

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The Repetitive Behaviors/Compulsivity Domain Compulsive and repetitive behaviors have also been studied in light of core dimensions 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 exploring the environment and may rather repetitively examine or handle particular objects. Compulsive symptoms often persist into adulthood and can include stereotypic 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 autism 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, rubbing, 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 compulsive symptoms associated with OCD, research has investigated systems implicated 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 individuals from singleton families (108). Studies that alter levels of peripheral and central 5-HT suggest that disturbing the serotonin system exacerbates repetitive and OCD-like behaviors, and a net deﬁciency in serotonergic function has been proposed as being responsible for autistic symptomatology in this domain (45).

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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 sumatriptan study, Hollander et al. (47) found that the sensitivity of the 5-HT1D receptor—measured by growth hormone (GH) response to sumatriptan—was positively correlated with the severity of the repetitive behavior domain rather than the severity of the overall autistic symptom complex or the other symptom domains. 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 inhibitors, 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 improvements in other domains, have been observed (26,48–53). Interestingly, the oxytocin system has also been associated with obsessivecompulsive 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 autism 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 hippocampus 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

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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 phenomenon 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, complex partial seizures, absence seizures (typical and atypical), generalized tonic clonic seizures, and myoclonic seizures (64,71). The most common types of epilepsy in autistic populations are generalized tonic-clonic, and atypical absence,

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followed by myoclonic and partial seizures, followed by atonic seizures and infantile 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 centroparietal 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 syndrome, 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; symptoms 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). Estimates 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., unpublished data). There is also evidence of increased expression of an impulsivity trait in relatives of autistic probands (91).

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The variety of associated features and comorbid disorders undoubtedly contributes 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 deﬁciency within the core domains tends to remain constant over time and development, 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 inappropriate means. As a teenager, this person may inadvertently resort to aggressive behavior 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 frequently 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. Stereotypic 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 special-needs classrooms or integrated within the normal system with a one-to-one aide. School education is frequently supplemented with aggressive therapy programs, including behavioral therapy, speech and language therapy, occupational

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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 increased 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 disorders and associated features pose difﬁculty in predicting developmental course as they often contribute to the degree of impairment. For example, mental retardation 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 eventually 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 speciﬁc 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 science, 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 different 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 neurobiological and genetic factors modulating core symptom domains in autism speaks to the explanatory power of the conceptualization. It is clear that no single gene

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accounts for the transmission of autism, but rather that several genes may contribute, 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 provide more homogeneous populations with which to elucidate genes that mediate the core domain phenotype. Various neurotransmitters, neuropeptide abnormalities, 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 receptor subsystem, oxytocin function, autoimmune markers, and regional metabolic 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 improve 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 domains may not be completely independent or orthogonal dimensions. For example, 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 abnormalities 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 repetitive 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 features 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

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autism, we may better understand the causes, features, and course of this disorder and provide viable treatment options for individuals with autism. In the meantime, 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 Institute of Neurological Diseases and Stroke grant NS43979. REFERENCES 1. 2. 3. 4. 5.

6.

7. 8.

9.

10.

11.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Publishing, 1994:886. Fombonne E. The epidemiology of autism: a review. Psychol Med 1999; 29:769– 786. Chakrabarti S, Fombonne E. Pervasive developmental disorders in preschool children. JAMA 2001; 285:3093–3099. Gillberg C, Wing L. Autism: not an extremely rare disorder. Acta Psychiatr Scand 1999; 99:399–406. Department of Developmental Services. Changes in the Population of Persons with Autism and Pervasive Developmental Disorders in California’s Developmental Services System: 1987 through 1998. Report to the Legislature, March 1, 1999. Available at http:/ /www.dds.ca.gov. World Health Organization. The ICD-10 Classiﬁcation of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva: World Health Organization, 1992:xii, 362. Myhr G. Autism and other pervasive developmental disorders: exploring the dimensional view. Can J Psychiatry 1998; 43:589–595. Le Couteur A, Bailey A, Goode S, Pickles A, Robertson S, Gottesman I, Rutter M. A broader phenotype of autism: the clinical spectrum in twins. J Child Psychol Psychiatry 1996; 37:785–801. Piven J, Palmer P, Jacobi D, Childress D, Arndt S. Broader autism phenotype: evidence from a family history study of multiple-incidence autism families. Am J Psychiatry 1997; 154:185–190. Buxbaum JD, Silverman JM, Smith CJ, Kilifarski M, Reichert J, Hollander E, Lawlor BA, Fitzgerald M, Greenberg DA, Davis KL. Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity. Am J Hum Genet 2001; 68:1514–1520. Lord C, Rutter M, Le Couteur A. Autism Diagnostic Interview–Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 1994; 24:659–685.

Symptoms, Related Disorders, and Course 12. 13.

14.

15. 16.

17.

18.

19. 20. 21. 22. 23.

24. 25.

26.

27.

28.

33

Cook EH Jr. Genetics of autism. Child Adolesc Psychiatr Clin N Am 2001; 10: 333–350. Bailey A, Phillips W, Rutter M. Autism: towards an integration of clinical, genetic, neuropsychological, and neurobiological perspectives. J Child Psychol Psychiatry 1996; 37:89–126. Volkmar FR, Klin A, Siegel B, Szatmari P, Lord C, Campbell M, Freeman BJ, Cicchetti DV, Rutter M, Kline W, et al. Field trial for autistic disorder in DSMIV. Am J Psychiatry 1994; 151:1361–1367. Beglinger LJ, Smith TH. A review of subtyping in autism and proposed dimensional classiﬁcation model. J Autism Dev Disord 2001; 31:411–422. Wing L, Gould J. Severe impairments of social interaction and associated abnormalities in children: epidemiology and classiﬁcation. J Autism Dev Disord 1979; 9:11–29. Tanguay PE, Robertson J, Derrick A. A dimensional classiﬁcation of autism spectrum disorder by social communication domains. J Am Acad Child Adolesc Psychiatry 1998; 37:271–277. Stevens MC, Fein DA, Dunn M, Allen D, Waterhouse LH, Feinstein C, Rapin I. Subgroups of children with autism by cluster analysis: a longitudinal examination. J Am Acad Child Adolesc Psychiatry 2000; 39:346–352. Rapin I. Practitioner review—developmental language disorders: a clinical update. J Child Psychol Psychiatry 1996; 37:643–655. Waterhouse L, Fein D, Modahl C. Neurofunctional mechanisms in autism. Psychol Rev 1996; 103:457–489. Rutter M, Bailey A, Bolton P, Le Couteur A. Autism and known medical conditions: myth and substance. J Child Psychol Psychiatry 1994; 35:311–322. Gillberg C. Subgroups in autism: are there behavioural phenotypes typical of underlying medical conditions? J Intellect Disabil Res 1992; 36(Pt 3):201–214. Bradford Y, Haines J, Hutcheson H, Gardiner M, Braun T, Shefﬁeld V, Cassavant T, Huang W, Wang K, Vieland V, Folstein S, Santangelo S, Piven J. Incorporating language phenotypes strengthens evidence of linkage to autism. Am J Med Genet 2001; 105:539–547. Hollander E, King A, Delaney K, Smith CJ, Silverman JM. Obsessive compulsive behaviors in parents of multiplex autism families. Psychiatry Res. In Press. Silverman JM, Smith CJ, Schmeidler J, Hollander E, Lawlor BA, Fitzgerald M, Buxbaum JD, Delaney K, Galvin P. Symptom domains in autism and related conditions: evidence for familiality. Am J Med Genet 2002; 114:64–73. McDougle CJ, Naylor ST, Cohen DJ, Volkmar FR, Heninger GR, Price LH. A double-blind, placebo-controlled study of ﬂuvoxamine in adults with autistic disorder. Arch Gen Psychiatry 1996; 53:1001–1008. McDougle CJ, Holmes JP, Carlson DC, Pelton GH, Cohen DJ, Price LH. A doubleblind, placebo-controlled study of risperidone in adults with autistic disorder and other pervasive developmental disorders. Arch Gen Psychiatry 1998; 55:633–641. Lord C, Risi S, Lambrecht L, Cook EH, Jr., Leventhal BL, DiLavore PC, Pickles A, Rutter M. The autism diagnostic observation schedule-generic: a standard measure of social and communication deﬁcits associated with the spectrum of autism. J Autism Dev Disord 2000; 30:205–223.

34 29. 30. 31. 32. 33. 34.

35. 36. 37. 38.

39.

40. 41.

42.

43.

44. 45. 46.

47.

Hollander and Nowinski Baron-Cohen S. Do people with autism understand what causes emotion? Child Dev 1991; 62:385–395. Rutter M. The treatment of autistic children. J Child Psychol Psychiatry 1985; 26: 193–214. Sigman M, Mundy P. Social attachments in autistic children. J Am Acad Child Adolesc Psychiatry 1989; 28:74–81. Wolff S, Chick J. Schizoid personality in childhood: a controlled follow-up study. Psychol Med 1980; 10:85–100. Smalley SL, McCracken J, Tanguay P. Autism, affective disorders, and social phobia. Am J Med Genet 1995; 60:19–26. Insel TR, Shapiro LE. Oxytocin receptor distribution reﬂects social organization in monogamous and polygamous voles. Proc Natl Acad Sci USA 1992; 89:5981– 5985. Panksepp J. Commentary on the possible role of oxytocin in autism. J Autism Dev Disord 1993; 23:567–569. Modahl C, Green L, Fein D, Morris M, Waterhouse L, Feinstein C, Levin H. Plasma oxytocin levels in autistic children. Biol Psychiatry 1998; 43:270–277. Green L, Fein D, Modahl C, Feinstein C, Waterhouse L, Morris M. Oxytocin and autistic disorder: alterations in peptide forms. Biol Psychiatry 2001; 50:609–613. MacLean JE, Szatmari P, Jones MB, Bryson SE, Mahoney WJ, Bartolucci G, Tuff L. Familial factors inﬂuence level of functioning in pervasive developmental disorder. J Am Acad Child Adolesc Psychiatry 1999; 38:746–753. Folstein SE, Santangelo SL, Gilman SE, Piven J, Landa R, Lainhart J, Hein J, Wzorek M. Predictors of cognitive test patterns in autism families. J Child Psychol Psychiatry 1999; 40:1117–1128. Piven J. The broad autism phenotype: a complementary strategy for molecular genetic studies of autism. Am J Med Genet 2001; 105:34–35. International Molecular Genetic Study of Autism Consortium. A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Hum Mol Genet 1998; 7:571–578. Rumsey JM, Duara R, Grady C, Rapoport JL, Margolin RA, Rapoport SI, Cutler NR. Brain metabolism in autism: resting cerebral glucose utilization rates as measured with positron emission tomography. Arch Gen Psychiatry 1985; 42:448– 455. McDougle CJ, Kresch LE, Goodman WK, Naylor ST, Volkmar FR, Cohen DJ, Price LH. A case-controlled study of repetitive thoughts and behavior in adults with autistic disorder and obsessive-compulsive disorder. Am J Psychiatry 1995; 152:772–777. Schain RJ, Freedman DX. Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children. J Pediatr 1961; 58:315–320. Cook EH, Leventhal BL. The serotonin system in autism. Curr Opin Pediatr 1996; 8:348–354. McDougle CJ, Naylor ST, Cohen DJ, Aghajanian GK, Heninger GR, Price LH. Effects of tryptophan depletion in drug-free adults with autistic disorder. Arch Gen Psychiatry 1996b; 53:993–1000. Hollander E, Novotny S, Allen A, Aronowitz B, Cartwright C, DeCaria C. The

Symptoms, Related Disorders, and Course

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59. 60. 61.

35

relationship between repetitive behaviors and growth hormone response to sumatriptan challenge in adult autistic disorder. Neuropsychopharmacology 2000; 22: 163–167. Gordon CT, State RC, Nelson JE, Hamburger SD, Rapoport JL. A double-blind comparison of clomipramine, desipramine, and placebo in the treatment of autistic disorder. Arch Gen Psychiatry 1993; 50:441–447. Sanchez LE, Campbell M, Small AM, Cueva JE, Armenteros JL, Adams PB. A pilot study of clomipramine in young autistic children. J Am Acad Child Adolesc Psychiatry 1996; 35:537–544. Brasic JR, Barnett JY, Kaplan D, Sheitman BB, Aisemberg P, Lafargue RT, Kowalik S, Clark A, Tsaltas MO, Young JG. Clomipramine ameliorates adventitious movements and compulsions in prepubertal boys with autistic disorder and severe mental retardation. Neurology 1994; 44:1309–1312. Cook EH Jr, Rowlett R, Jaselskis C, Leventhal BL. Fluoxetine treatment of children and adults with autistic disorder and mental retardation. J Am Acad Child Adolesc Psychiatry 1992; 31:739–745. Buchsbaum MS, Hollander E, Haznedar MM, Tang C, Spiegel-Cohen J, Wei TC, Solimando A, Buchsbaum BR, Robins D, Bienstock C, Cartwright C, Mosovich S. Effect of ﬂuoxetine on regional cerebral metabolism in autistic spectrum disorders: a pilot study. Int J Neuropsychopharmacol 2001; 4:119–125. Hollander E, Cartwright C, Wong CM, DeCaria CM, DelGiudice-Asch G, Buchsbaum MS, Aronowitz B. A dimensional approach to the autistic spectrum. CNS Spectrums 1998; 3:22–39. Swedo SE, Leonard HL, Kruesi MJ, Rettew DC, Listwak SJ, Berrettini W, Stipetic M, Hamburger S, Gold PW, Potter WZ, et al. Cerebrospinal ﬂuid neurochemistry in children and adolescents with obsessive-compulsive disorder. Arch Gen Psychiatry 1992; 49:29–36. Leckman JF, Goodman WK, North WG, Chappell PB, Price LH, Pauls DL, Anderson GM, Riddle MA, McSwiggan-Hardin M, McDougle CJ, et al. Elevated cerebrospinal ﬂuid levels of oxytocin in obsessive-compulsive disorder: comparison with Tourette’s syndrome and healthy controls. Arch Gen Psychiatry 1994; 51: 782–792. Hollander E, Novotny S, Hanratty M, Allen A, Yaffe R, DeCaria C, Aronowitz B, Mosovich S. Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’s disorders. Neuropsychopharmacology. In press. Haznedar MM, Buchsbaum MS, Metzger M, Solimando A, Spiegel-Cohen J, Hollander E. Anterior cingulate gyrus volume and glucose metabolism in autistic disorder. Am J Psychiatry 1997; 154:1047–1050. Haznedar MM, Buchsbaum MS, Wei TC, Hof PR, Cartwright C, Bienstock CA, Hollander E. Limbic circuitry in patients with autism spectrum disorders studied with positron emission tomography and magnetic resonance imaging. Am J Psychiatry 2000; 157:1994–2001. Rapin I. Autism. N Engl J Med 1997; 337:97–104. Freeman BJ. Guidelines for evaluating intervention programs for children with autism. J Autism Dev Disord 1997; 27:641–651. Filipek PA, Accardo PJ, Baranek GT, Cook EH Jr, Dawson G, Gordon B, Gravel

36

62. 63.

64. 65. 66. 67. 68. 69. 70. 71.

72. 73. 74. 75.

76. 77. 78. 79.

80. 81.

Hollander and Nowinski JS, Johnson CP, Kallen RJ, Levy SE, Minshew NJ, Ozonoff S, Prizant BM, Rapin I, Rogers SJ, Stone WL, Teplin S, Tuchman RF, Volkmar FR. The screening and diagnosis of autistic spectrum disorders. J Autism Dev Disord 1999; 29:439–484. Nordin V, Gillberg C. The long-term course of autistic disorders: update on followup studies. Acta Psychiatr Scand 1998; 97:99–108. Gillberg C, Steffenburg S. Outcome and prognostic factors in infantile autism and similar conditions: a population-based study of 46 cases followed through puberty. J Autism Dev Disord 1987; 17:273–287. Volkmar FR, Nelson DS. Seizure disorders in autism. J Am Acad Child Adolesc Psychiatry 1990; 29:127–129. Giovanardi Rossi P, Posar A, Parmeggiani A. Epilepsy in adolescents and young adults with autistic disorder. Brain Dev 2000; 22:102–106. Rossi PG, Parmeggiani A, Bach V, Santucci M, Visconti P. EEG features and epilepsy in patients with autism. Brain Dev 1995; 17:169–174. Tuchman RF, Rapin I, Shinnar S. Autistic and dysphasic children. II: Epilepsy. Pediatrics 1991; 88:1219–1225. Deykin EY, MacMahon B. The incidence of seizures among children with autistic symptoms. Am J Psychiatry 1979; 136:1310–1312. Olsson I, Steffenburg S, Gillberg C. Epilepsy in autism and autisticlike conditions: a population-based study. Arch Neurol 1988; 45:666–668. Rutter M. Autistic children growing up. Dev Med Child Neurol 1984; 26:122– 129. Gillberg CL. The Emanuel Miller Memorial Lecture 1991. Autism and autisticlike conditions: subclasses among disorders of empathy. J Child Psychol Psychiatry 1992; 33:813–842. Tuchman RF, Jayakar P, Yaylai I, Villalobos R. Seizures and EEG ﬁndings in children with autism spectrum disorder. CNS Spectrums 1998; 3:61–70. Hutt SJ, Hutt C, Lee D, Ounsted C. A behavioural and electroencephalographic study of autistic children. J Psychiatr Res 1965; 3:181–197. Lainhart JE, Folstein SE. Affective disorders in people with autism: a review of published cases. J Autism Dev Disord 1994; 24:587–601. Matson JL, Manikam R, Coe D, Raymond K, Taras M, Long N. Training social skills to severely mentally retarded multiply handicapped adolescents. Res Dev Disabil 1988; 9:195–208. Chung SY, Luk SL, Lee PW. A follow-up study of infantile autism in Hong Kong. J Autism Dev Disord 1990; 20:221–232. Ghaziuddin M, Tsai L. Depression in autistic disorder. Br J Psychiatry 1991; 159: 721–723. DeLong GR, Teague LA, McSwain Kamran M. Effects of ﬂuoxetine treatment in young children with idiopathic autism. Dev Med Child Neurol 1998; 40:551–562. Piven J, Palmer P. Psychiatric disorder and the broad autism phenotype: evidence from a family study of multiple-incidence autism families. Am J Psychiatry 1999; 156:557–563. Bolton PF, Pickles A, Murphy M, Rutter M. Autism, affective and other psychiatric disorders: patterns of familial aggregation. Psychol Med 1998; 28:385–395. Ghaziuddin M, Greden J. Depression in children with autism/pervasive develop-

Symptoms, Related Disorders, and Course

82.

83.

84. 85. 86.

87.

88.

89.

90. 91. 92.

93.

94.

95. 96.

97. 98.

37

mental disorders: a case-control family history study. J Autism Dev Disord 1998; 28:111–115. Weller EB, Rowan A, Elia J, Weller RA. Aggressive behavior in patients with attention-deﬁcit/hyperactivity disorder, conduct disorder, and pervasive developmental disorders. J Clin Psychiatry 1999; 60(suppl 15):5–11. Jaselskis CA, Cook EH Jr, Fletcher KE, Leventhal BL. Clonidine treatment of hyperactive and impulsive children with autistic disorder. J Clin Psychopharmacol 1992; 12:322–327. Tsai LY. Brief report: comorbid psychiatric disorders of autistic disorder. J Autism Dev Disord 1996; 26:159–163. Simons JM. Observations on compulsive behavior in autism. J Autism Child Schizophr 1974; 4:1–10. Grifﬁn JC, Ricketts RW, Williams DE, Locke BJ, Altmeyer BK, Stark MT. A community survey of self-injurious behavior among developmentally disabled children and adolescents. Hosp Commun Psychiatry 1987; 38:959–963. Grifﬁn JC, Williams DE, Stark MT, Altmeyer BK, Mason M. Self-injurious behavior: a state-wide prevalence survey of the extent and circumstances. Appl Res Ment Retard 1986; 7:105–116. Gardner W, Cole C. Aggression and related conduct disorders: deﬁnition, assessment and treatment. In: Matson JL, Barrett RP, eds. Psychopathology in the Mentally Retarded. Needham Heights, MA: Allyn and Bacon, 1993:213–245. Jacobson J. Problem behavior and psychiatric impairment within a developmentally disabled population: I. Behavior frequency. Appl Res Ment Retard 1982; 3: 121–139. Eyman RK, Call T. Maladaptive behavior and community placement of mentally retarded persons. Am J Ment Deﬁc 1977; 82:137–144. Murphy M, Bolton PF, Pickles A, Fombonne E, Piven J, Rutter M. Personality traits of the relatives of autistic probands. Psychol Med 2000; 30:1411–1424. Piven J, Harper J, Palmer P, Arndt S. Course of behavioral change in autism: a retrospective study of high-IQ adolescents and adults. J Am Acad Child Adolesc Psychiatry 1996; 35:523–529. Howlin P, Mawhood L, Rutter M. Autism and developmental receptive language disorder—a follow-up comparison in early adult life. II: Social, behavioural, and psychiatric outcomes. J Child Psychol Psychiatry 2000; 41:561–578. Mawhood L, Howlin P, Rutter M. Autism and developmental receptive language disorder—a comparative follow-up in early adult life. I: Cognitive and language outcomes. J Child Psychol Psychiatry 2000; 41:547–559. Bagley C, McGeein V. The taxonomy and course of childhood autism. Percept Mot Skills 1989; 69:1264–1266. Goldstein G, Minshew NJ, Siegel DJ. Age differences in academic achievement in high-functioning autistic individuals. J Clin Exp Neuropsychol 1994; 16:671– 680. Minshew NJ, Goldstein G, Taylor HG, Siegel DJ. Academic achievement in high functioning autistic individuals. J Clin Exp Neuropsychol 1994; 16:261–270. Rutter M. Autistic children: infancy to adulthood. Semin Psychiatry 1970; 2:435– 450.

38 99. 100. 101. 102. 103. 104.

105.

106. 107.

108.

Hollander and Nowinski Szatmari P, Bartolucci G, Bremner R, Bond S, Rich S. A follow-up study of highfunctioning autistic children. J Autism Dev Disord 1989; 19:213–225. Rumsey JM, Rapoport JL, Sceery WR. Autistic children as adults: psychiatric, social, and behavioral outcomes. J Am Acad Child Psychiatry 1985; 24:465–473. Osterling J, Dawson G. Early recognition of children with autism: a study of ﬁrst birthday home videotapes. J Autism Dev Disord 1994; 24:247–257. Baron-Cohen S, Allen J, Gillberg C. Can autism be detected at 18 months? The needle, the haystack, and the CHAT. Br J Psychiatry 1992; 161:839–843. Lord C. Follow-up of two-year-olds referred for possible autism. J Child Psychol Psychiatry 1995; 36:1365–1382. Gillberg C, Ehlers S, Schaumann H, Jakobsson G, Dahlgren SO, Lindblom R, Bagenholm A, Tjuus T, Blidner E. Autism under age 3 years: a clinical study of 28 cases referred for autistic symptoms in infancy. J Child Psychol Psychiatry 1990; 31:921–934. Kobayashi R, Murata T, Yoshinaga K. A follow-up study of 201 children with autism in Kyushu and Yamaguchi areas, Japan. J Autism Dev Disord 1992; 22: 395–411. Szatmari P, Bartolucci G, Bremner R. Asperger’s syndrome and autism: comparison of early history and outcome. Dev Med Child Neurol 1989; 31:709–720. Rutter M, Greenfeld D, Lockyer L. A ﬁve to ﬁfteen year follow-up study of infantile psychosis. II. Social and behavioural outcome. Br J Psychiatry 1967; 113: 1183–1199. Piven J, Tsai GC, Nehme E, Coyle JT, Chase GA, Folstein SE. Platelet serotonin, a possible marker for familial autism. J Autism Dev Disord 1991; 21:51–59.

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 neuropsychiatric syndromes characterized by abnormalities in social relatedness, verbal and nonverbal communication deﬁcits, and the presence of restricted and stereotyped 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 workup 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 children 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 Spec39

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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 expertise 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 acknowledge 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 developmental issues (11). Thus, the AAN/CNS committee (12) made strong recommendations about basic developmental screening at all well-child visits. Their approach 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 providers 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-

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II) or the Revised Denver Pre-Screening Developmental Questionnaire (RDPSQ) 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 abnormalities. They further propose the following absolute indications for immediate evaluation: 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.

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The AAN/CNS guidelines also emphasize that parents’ concerns about their child’s development are almost always valid (17–20) and must not be ignored. So, a parallel step in the screening process should be to listen to the speciﬁcs 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 screening 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 language 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 measurable 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 18month 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

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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) questionnaire 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 Vineland Adaptive Behavior Scale could be reliably used to differentiate autism from nonautistic developmental delay (40).

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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 testing—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, frequencyspeciﬁc testing or tone-evoked responses rather than clicks should be used because 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 mouthing 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 substantially prolonged lead-level elevations, and were at increased risk of re-exposure 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 guidelines 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 evaluation of autism. These might include a child psychiatrist, a child psychologist, a child neuropsychologist, a pediatric neurologist, and/or a developmental pedia-

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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, occupational therapists, physical therapists, and behavioral therapists. This not only enables the proper diagnosis but also facilitates treatment planning (11). Unfortunately, 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 covered 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 family 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. Information can be obtained from the family history, medical history, and physical exam. There are signiﬁcant epidemiological data to support the increased prevalence (50- to 100-fold) in ﬁrst-degree relatives of autistic children (47–49). Other psychiatric disorders (especially affective disorder, obsessive compulsive disorder, 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-

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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 neurocutaneous 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 retardation 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 maintenance 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 sensorimotor deﬁcits. The most common motor problems are hypotonia, limb apraxia, and motor stereotypies (e.g., rocking, hand or ﬁnger mannerisms, unusual posturing) (70). The most common sensory difﬁculties are over- or undersensitivity 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 surrounding the indications for most of this testing and that no standard of care has been set deﬁning a routine battery for every patient.

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Genetic Testing Currently the area that has drawn the most interest is genetic testing. As mentioned above, many practitioners are testing for fragile X, but most do not perform routine chromosomal analyses. With the rapidly evolving tools of molecular genetics 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 studying a large number of multiplex families in the United States, through the AGRE. The project entails collection of DNA, family histories, and neurological, psychiatric, 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 emerging 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 karyotyping 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 children 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 adolescence (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 abnormalities associated with complex partial seizures (e.g., staring, being unresponsive to one’s name, repetitive motor behaviors) can all be attributed to the

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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 ﬁndings, but most do not consider an abnormal EEG in the absence of clinical seizures 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 epileptic aphasia clinically described as the occurrence of auditory agnosia (the inability 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 deepest 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 isolated EEG abnormalities in children with autism spectrum disorders (91).

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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 presents 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 recommends 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 expectations 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 researchers 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 neuroimaging 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 neuroimaging techniques, such as magnetoencephalography (MEG) and other functional 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-

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gestive of a metabolic disease such as episodic vomiting or lethargy or encephalopathic 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 studies 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 infections (especially otitis media) (102), allergies (especially to food) and/or altered 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 ailments and the occurrence of autism, but also of intense debate. If and when any causal connections are identiﬁed, they could aid in understanding the pathophysiology 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 especially 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 cognitive 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 autistic 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 problems and controversies regarding screening and diagnosing autism and PDD. The

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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 regarding early intervention and outcomes. Comprehensive reporting of associations with other diseases, abnormal laboratory values, genetic evaluations, and other ancillary testing will ultimately shed light on what is certain to be the multifactorial 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 1.

2.

3.

4. 5. 6. 7. 8. 9. 10.

11.

12.

Harris SL, Handleman JS, Gordon R, Kristoff B, Fuentes F. Changes in cognitive and language functioning of preschool children with autism. J Autism Dev Disord 1991; 21:281–290. Harris SL, Handleman JS. Age and IQ at intake as predictors of placement for young children with autism: a four- to six-year follow-up. J Autism Dev Disord 2000; 30:137–142. McEachin JJ, Smith T, Lovaas OI. Long-term outcome for children with autism who received early intensive behavioral treatment. Am J Ment Retard 1993; 97: 359–372; discussion 373–391. Ozonoff S, Cathcart K. Effectiveness of a home program intervention for young children with autism. J Autism Dev Disord 1998; 28:25–32. Rapin I. Autism [comments]. N Engl J Med 1997; 337:97–104. Rogers SJ. Brief report: early intervention in autism. J Autism Dev Disord 1996; 26:243–246. Rogers SJ. Empirically supported comprehensive treatments for young children with autism [comments]. J Clin Child Psychol 1998; 27:168–179. Sheinkopf SJ, Siegel B. Home-based behavioral treatment of young children with autism [comments]. J Autism Dev Disord 1998; 28:15–23. Geschwind DH, Cummings JL, Hollander E, et al. Autism screening and diagnostic evaluation: CAN consensus statement. CNS Spectrums 1998; 3:40–49. Volkmar F, Cook EH Jr, Pomeroy J, Realmuto G, Tanguay P. American Academy of Child and Adolescent Psychiatry Working Group on Quality Issues. Practice parameters for the assessment and treatment of children, adolescents, and adults with autism and other pervasive developmental disorders [erratum appears in J Am Acad Child Adolesc Psychiatry 2000; 39(7):938]. J Am Acad Child Adolesc Psychiatry 1999; 38:32S–54S. Filipek PA, Accardo PJ, Baranek GT, et al. The screening and diagnosis of autistic spectrum disorders [published erratum appears in J Autism Dev Disord 2000; 30(1):81]. J Autism Dev Disord 1999; 29(6):439–484. Filipek PA, Accardo PJ, Ashwal S, et al. Practice parameter: screening and diagnosis of autism: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society. Neurology 2000; 55: 468–479.

52 13. 14. 15. 16.

17. 18. 19. 20. 21. 22. 23.

24.

25.

26.

27. 28. 29.

30.

31. 32.

Spence and Geschwind Bricker D, Squires J. The ages and stages questionnaires. Baltimore: Paul H. Brookes, 1999. Brigance A. The BRIGANCE-R screens. North Billerica, MA: Curriculum Associates, 1986. Ireton H. Child development inventories. Minneapolis: Behavior Science Systems, 1992. Glascoe HP. Collaborating with parents: using parents’ evaluation of developmental status to detect and address developmental and behavioral problems. Nashville: Ellsworth & Vandermeer, 1998. Glascoe FP. Using parents’ concerns to detect and address developmental and behavioral problems. J Soc Pediatr Nurs 1999; 4:24–35. Glascoe FP. Parents’ concerns about children’s development: prescreening technique or screening test? [comments]. Pediatrics 1997; 99:522–528. Glascoe FP, Dworkin PH. The role of parents in the detection of developmental and behavioral problems. Pediatrics 1995; 95:829–836. Glascoe FP. It’s not what it seems: the relationship between parents’ concerns and children with global delays. Clin Pediatr (Phila) 1994; 33:292–296. Stone WL, Lee EB, Ashford L, et al. Can autism be diagnosed accurately in children under 3 years? J Child Psychol Psychiatry 1999; 40:219–226. Lord C. Follow-up of two-year-olds referred for possible autism. J Child Psychol Psychiatry 1995; 36:1365–1382. Cox A, Klein K, Charman T, et al. Autism spectrum disorders at 20 and 42 months of age: stability of clinical and ADI-R diagnosis. J Child Psychol Psychiatry 1999; 40:719–732. Charman T, Swettenham J, Baron-Cohen S, Cox A, Baird G, Drew A. Infants with autism: an investigation of empathy, pretend play, joint attention, and imitation. Dev Psychol 1997; 33:781–789. Charman T, Swettenham J, Baron-Cohen S, Cox A, Baird G, Drew A. An experimental investigation of social-cognitive abilities in infants with autism: clinical implications. Infant Ment Health J 1998; 19:260–275. Mars AE, Mauk JE, Dowrick PW. Symptoms of pervasive developmental disorders as observed in prediagnostic home videos of infants and toddlers. J Pediatr 1998; 132:500–504. Osterling J, Dawson G. Early recognition of children with autism: a study of ﬁrst birthday home videotapes. J Autism Dev Disord 1994; 24:247–257. Baron-Cohen S, Allen J, Gillberg C. Can autism be detected at 18 months? The needle, the haystack, and the CHAT. Br J Psychiatry 1992; 161:839–843. Baron-Cohen S, Cox A, Baird G, et al. Psychological markers in the detection of autism in infancy in a large population. Br J Psychiatry 1996; 168:158– 163. Baird G, Charman T, Baron-Cohen S, et al. A screening instrument for autism at 18 months of age: a 6-year follow-up study. J Am Acad Child Adolesc Psychiatry 2000; 39:694–702. Berument SK, Rutter M, Lord C, Pickles A, Bailey A. Autism screening questionnaire: diagnostic validity. Br J Psychiatry 1999; 175:444–451. Garnett MS, Attwood AJ. The Australian Scale for Asperger’s Syndrome. In: Att-

Screening and Neurodevelopment Assessment

33.

34.

35.

36. 37. 38.

39.

40. 41. 42.

43. 44. 45. 46. 47.

48. 49. 50.

53

wood T, ed. Asperger’s Syndrome: A Guide for Parents and Professionals. London: Kingsley, 1998:17–19. Siegel B. Early screening and diagnosis in autistic spectrum disorders: the Pervasive Developmental Disorders Screening Test (PDDST). NIH State of the Science in Autism: Screening and Diagnosis Working Conference, Bethesda, MD, June 15–17, 1998. Gillberg C, Ehlers S, Schaumann H, et al. Autism under age 3 years: a clinical study of 28 cases referred for autistic symptoms in infancy [comments]. J Child Psychol Psychiatry 1990; 31:921–934. Dahlgren SO, Gillberg C. Symptoms in the ﬁrst two years of life: a preliminary population study of infantile autism. Eur Arch Psychiatry Neurol Sci 1989; 238: 169–174. Gillberg C, Coleman M. Diagnosis in Infancy: The Biology of the Autistic Syndromes. Vol 153/4. London: MacKeith Press, 2000. Stone WL, Hogan KL. A structured parent interview for identifying young children with autism. J Autism Dev Disord 1993; 23:639–652. Stone WL. STAT manual: Screening Tool for Autism in Two-Year-Olds. NIH State of the Science in Autism: Screening and Diagnosis Working Conference, Bethesda, MD, June 15–17, 1998. Stone WL. Descriptive information about the Screening Tool for Autism in TwoYear-Olds (STAT). NIH State of the Science in Autism: Screening and Diagnosis Working Conference, Bethesda, MD, June 15–17, 1998. Stone WL, Ousley OY, Hepburn SL, Hogan KL, Brown CS. Patterns of adaptive behavior in very young children with autism. Am J Ment Retard 1999; 104:187–199. Stapells DR, Oates P. Estimation of the pure-tone audiogram by the auditory brainstem response: a review. Audiol Neurootol 1997; 2:257–280. Grewe TS, Danhauer JL, Danhauer KJ, Thornton AR. Clinical use of otoacoustic emissions in children with autism. Int J Pediatr Otorhinolaryngol 1994; 30:123– 132. Cohen DJ, Johnson WT, Caparulo BK. Pica and elevated blood lead level in autistic and atypical children. Am J Dis Child 1976; 130:47–48. Shannon M, Graef JW. Lead intoxication in children with pervasive developmental disorders. J Toxicol Clin Toxicol 1996; 34:177–181. Rutter M, Bailey A, Bolton P, Le Couteur A. Autism and known medical conditions: myth and substance. J Child Psychol Psychiatry 1994; 35:311–322. Gillberg C, Coleman M. Autism and medical disorders: a review of the literature. Dev Med Child Neurol 1996; 38:191–202. Rutter M, Bailey A, Simonoff E, Pickles A. Genetic inﬂuences and autism. In: Cohen DJ, Volkmar FR, eds. Handbook of Autism and Pervasive Developmental Disorders. 2nd ed. New York: Wiley, 1997:370–387. Simonoff E. Genetic counseling in autism and pervasive developmental disorders. J Autism Dev Disord 1998; 28:447–456. Szatmari P, Jones MB, Zwaigenbaum L, MacLean JE. Genetics of autism: overview and new directions. J Autism Dev Disord 1998; 28:351–368. Bolton PF, Pickles A, Murphy M, Rutter M. Autism, affective and other psychiatric disorders: patterns of familial aggregation. Psychol Med 1998; 28:385–395.

54 51. 52. 53.

54.

55.

56.

57. 58.

59.

60.

61.

62. 63. 64. 65. 66. 67. 68. 69.

Spence and Geschwind DeLong R, Nohria C. Psychiatric family history and neurological disease in autistic spectrum disorders. Dev Med Child Neurol 1994; 36:441–448. Piven J, Chase GA, Landa R, et al. Psychiatric disorders in the parents of autistic individuals [comments]. J Am Acad Child Adolesc Psychiatry 1991; 30:471–478. Piven J, Palmer P. Psychiatric disorder and the broad autism phenotype: evidence from a family study of multiple-incidence autism families. Am J Psychiatry 1999; 156:557–563. Piven J, Gayle J, Chase GA, et al. A family history study of neuropsychiatric disorders in the adult siblings of autistic individuals [comments]. J Am Acad Child Adolesc Psychiatry 1990; 29:177–183. Piven J, Gayle J, Landa R, Wzorek M, Folstein S. The prevalence of fragile X in a sample of autistic individuals diagnosed using a standardized interview. J Am Acad Child Adolesc Psychiatry 1991; 30:825–830. Hashimoto O, Shimizu Y, Kawasaki Y. Brief report: low frequency of the fragile X syndrome among Japanese autistic subjects. J Autism Dev Disord 1993; 23: 201–209. Bailey A, Bolton P, Butler L, et al. Prevalence of the fragile X anomaly amongst autistic twins and singletons. J Child Psychol Psychiatry 1993; 34:673–688. Geschwind DH, Sowinski J, Jones P, et al. and the AGRE Scientiﬁc Steering Committee. The Autism Genetic Resource Exchange (AGRE): a resource for the study of autism and related neuropsychiatric conditions. Am J Hum Genet 2001; 69: 463–466. Hallmayer J, Pintado E, Lotspeich L, et al. Molecular analysis and test of linkage between the FMR-1 gene and infantile autism in multiplex families. Am J Hum Genet 1994; 55:951–959. Klauck SM, Munstermann E, Bieber-Martig B, et al. Molecular genetic analysis of the FMR-1 gene in a large collection of autistic patients. Hum Genet 1997; 100:224–229. Meyer GA, Blum NJ, Hitchcock W, Fortina P. Absence of the fragile X CGG trinucleotide repeat expansion in girls diagnosed with a pervasive developmental disorder. J Pediatr 1998; 133:363–365. Baker P, Piven J, Sato Y. Autism and tuberous sclerosis complex: prevalence and clinical features. J Autism Dev Disord 1998; 28:279–285. Hunt A, Shepherd C. A prevalence study of autism in tuberous sclerosis. J Autism Dev Disord 1993; 23:323–339. Gillberg IC, Gillberg C, Ahlsen G. Autistic behaviour and attention deﬁcits in tuberous sclerosis: a population-based study. Dev Med Child Neurol 1994; 36:50–56. Smalley SL, Tanguay PE, Smith M, Gutierrez G. Autism and tuberous sclerosis. J Autism Dev Disord 1992; 22:339–355. Gutierrez GC, Smalley SL, Tanguay PE. Autism in tuberous sclerosis complex. J Autism Dev Disord 1998; 28:97–103. Smalley SL. Autism and tuberous sclerosis. J Autism Dev Disord 1998; 28:407–414. Lainhart JE, Piven J, Wzorek M, et al. Macrocephaly in children and adults with autism. J Am Acad Child Adolesc Psychiatry 1997; 36:282–290. Filipek PA. The autistic spectrum disorders. In: Swaiman KF, Ashwal S, eds. Pediatric Neurology: Principles and Practice. St. Louis: Mosby, 1999:606–628.

Screening and Neurodevelopment Assessment 70.

71. 72. 73. 74.

75.

76. 77.

78. 79.

80. 81.

82.

83. 84. 85. 86.

87. 88.

55

Rapin I. Neurological examination. In: Rapin I, ed. Preschool Children with Inadequate Communication: Developmental Language Disorder, Autism, Low IQ. London: MacKeith, 1996:98–122. Kientz MA, Dunn W. A comparison of the performance of children with and without autism on the Sensory Proﬁle. Am J Occup Ther 1997; 51:530–537. Barrett S, Beck JC, Bernier R, et al. An autosomal genomic screen for autism: collaborative linkage study of autism. Am J Med Genet 1999; 88:609–615. Risch N, Spiker D, Lotspeich L, et al. A genomic screen of autism: evidence for a multilocus etiology. Am J Hum Genet 1999; 65:493–507. Philippe A, Martinez M, Guilloud-Bataille M, et al. Genome-wide scan for autism susceptibility genes: Paris Autism Research International Sibpair Study [erratum appears in Hum Mol Genet 1999; 8(7):1353]. Hum Mol Genet 1999; 8(5):805–812. IMGSAC. A full genome screen for autism with evidence for linkage to a region on chromosome 7q. International Molecular Genetic Study of Autism Consortium. Hum Mol Genet 1998; 7:571–578. Rutter M. Genetic studies of autism: from the 1970s into the millennium. J Abnorm Child Psychol 2000; 28:3–14. Lamb JA, Moore J, Bailey A, Monaco AP. Autism: Recent molecular genetic advances [erratum appears in Hum Mol Genet 2000; 9(9):1461]. Hum Mol Genet 2000; 9(6):861–868. Gillberg C. Chromosomal disorders and autism. J Autism Dev Disord 1998; 28: 415–425. Cook EH Jr, Lindgren V, Leventhal BL, et al. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet 1997; 60:928–934. Volkmar FR, Nelson DS. Seizure disorders in autism. J Am Acad Child Adolesc Psychiatry 1990; 29:127–129. Tuchman RF, Rapin I, Shinnar S. Autistic and dysphasic children. II. Epilepsy [erratum appears in Pediatrics 1992; 90(2 Pt 1):264]. Pediatrics 1991; 88(6):1219– 1225. Minshew N, Sweeney JA, Bauman ML. Neurologic aspects of autism. In: Cohen DJ, Volkmar FR, eds. Handbook of Autism and Pervasive Developmental Disorders. 2nd ed. New York: Wiley, 1997:344–369. Olsson I, Steffenburg S, Gillberg C. Epilepsy in autism and autisticlike conditions: a population-based study. Arch Neurol 1988; 45:666–668. Tuchman RF, Rapin I. Regression in pervasive developmental disorders: seizures and epileptiform electroencephalogram correlates. Pediatrics 1997; 99:560–566. Landau WM, Kleffner F. Syndrome of acquired aphasia with convulsive disorder in children. Neurology 1957; 7:523–530. Landau WM, Kleffner FR. Syndrome of acquired aphasia with convulsive disorder in children [1957—classical article]. Neurology 1998; 51:1241, 8 pp following 1241. Deonna TW. Acquired epileptiform aphasia in children (Landau-Kleffner syndrome). J Clin Neurophysiol 1991; 8:288–298. Lerman P, Kivity S. The benign partial nonrolandic epilepsies. J Clin Neurophysiol 1991; 8:275–287.

56 89. 90. 91. 92.

93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103.

104. 105. 106. 107.

108. 109.

Spence and Geschwind Mikati MA, Saab R. Successful use of intravenous immunoglobulin as initial monotherapy in Landau-Kleffner syndrome. Epilepsia 2000; 41:880–886. Morrell F, Whisler WW, Smith MC, et al. Landau-Kleffner syndrome: treatment with subpial intracortical transection. Brain 1995; 118:1529–1546. Tuchman R. Treatment of seizure disorders and EEG abnormalities in children with autism spectrum disorders. J Autism Dev Disord 2000; 30:485–489. Kanner AM. Commentary: the treatment of seizure disorders and EEG abnormalities in children with autistic spectrum disorders—are we getting ahead of ourselves? J Autism Dev Disord 2000; 30:491–495. Mantovani JF. Autistic regression and Landau-Kleffner syndrome: progress or confusion? Dev Med Child Neurol 2000; 42:349–353. Nass R, Devinsky O. Autistic regression with rolandic spikes. Neuropsychiatry Neuropsychol Behav Neurol 1999; 12:193–197. Prasad AN, Stafstrom CF, Holmes GL. Alternative epilepsy therapies: the ketogenic diet, immunoglobulins, and steroids. Epilepsia 1996; 37:S81–95. Filipek PA. Brief report: neuroimaging in autism—the state of the science 1995. J Autism Dev Disord 1996; 26:211–215. Filipek PA. Neuroimaging in the developmental disorders: the state of the science. J Child Psychol Psychiatry Allied Disc 1999; 40:113–128. Rumsey JM, Ernst M. Functional neuroimaging of autistic disorders. Ment Retard Dev Disabil Res Rev 2000; 6:171–179. Page T. Metabolic approaches to the treatment of autism spectrum disorders. J Autism Dev Disord 2000; 30:463–469. Gillberg IC, Gillberg C, Kopp S. Hypothyroidism and autism spectrum disorders. J Child Psychol Psychiatry 1992; 33:531–542. Page T, Coleman M. Purine metabolism abnormalities in a hyperuricosuric subclass of autism. Biochim Biophys Acta 2000; 1500:291–296. Konstantareas MM, Homatidis S. Ear infections in autistic and normal children. J Autism Dev Disord 1987; 17:585–594. Comi AM, Zimmerman AW, Frye VH, Law PA, Peeden JN. Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J Child Neurol 1999; 14:388–394. van Gent T, Heijnen CJ, Treffers PD. Autism and the immune system. J Child Psychol Psychiatry 1997; 38:337–349. Warren RP, Singh VK, Averett RE, et al. Immunogenetic studies in autism and related disorders. Mol Chem Neuropathol 1996; 28:77–81. D’Eufemia P, Celli M, Finocchiaro R, et al. Abnormal intestinal permeability in children with autism. Acta Paediatr 1996; 85:1076–1079. Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C, Tildon JT. Gastrointestinal abnormalities in children with autistic disorder [comments]. J Pediatr 1999; 135:559–563. Quigley EM, Hurley D. Autism and the gastrointestinal tract [comment; editorial]. Am J Gastroenterol 2000; 95:2154–2156. Wakeﬁeld AJ, Murch SH, Anthony A, et al. Ileal-lymphoid-nodular hyperplasia, non-speciﬁc colitis, and pervasive developmental disorder in children [comments]. Lancet 1998; 351:637–641.

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 pathophysiology. Nonprogressive developmental disorders are, therefore, best characterized in terms of types and degrees of limitations in fundamental developmental areas of functioning such as auditory processing and engaging with others purposefully, as well as symptoms (e.g., echolalia). Yet, both historically and recently, we have focused on symptoms and groups of symptoms comprising syndromes and very speciﬁc behaviors, such as saying “hello,” with only partial emphasis on identifying and working with functional developmental capacities that often underlie symptoms and determine overall adaptation. By functional 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 mechanism or well-described pathophysiological pathway for autism, we must be modest in our assumptions and base assessments and interventions on what is clearly 57

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observable and known. What is observable and known are the functional developmental limitations in critical areas, including emotional and social functioning, language, motor planning and sequencing, and sensory processing and modulation. In fact, as most clinicians recognize, there are huge differences among children 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 syndrome 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 functional 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 relationships 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 developmental 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 deﬁcit model, results are typically presented from the point of view of deﬁcits in each domain with general recommendations. Crucial areas of interactive relationships 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 evaluations 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.

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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–caregiver 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 infant–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 developmental level they relate to. The inﬂuencing variables are thus best understood, not as they might be traditionally, as general inﬂuences on development or behavior, 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 relationship (engaging), his mother’s tendency to be very intellectual and prefer talking 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 organize a calm, regulated state and experience pleasure. 2. Engage with and evince affective preference and pleasure for a caregiver. 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, functional 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 conceptual bridges among these categories. This ability creates the foundation for such basic personality functions as reality testing, impulse con-

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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 visualspatial 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 Adaptation (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 communication 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 closeness 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-limitsetting (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-

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Table 1 Sample Assessment Form Based on the Functional Emotional Developmental Scale Developmental level

Defect constriction

Instability

1. 2. 3. 4.

Regulation and interest in the world Attachment Intentional communication 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: ConstitutionalMaturational 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 processing differences: Sensory reactivity, including hypo- and hyperreactivity in each sensory modality (tactile, auditory, visual, vestibular, olfactory) Sensory processing in each sensory modality (e.g., the capacity to decode sequences, conﬁgurations, or abstract patterns), including auditory processing 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 capacities) (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 observed clinically. Is the child hyper- or hyposensitive to touch or sound? The

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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 information input or only a simple one? Does the 41/2-year-old have a receptive language (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 patterns 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 intensiﬁed 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 differences based on constitutional and maturational factors, it is important to describe 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

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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 confused, 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 meanings, 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 visa`-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 symbolic 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 children 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 fantasy, 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.

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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 compromised 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.

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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.

II. III.

IV.

V.

VI. VII.

VIII. IX.

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) History, including history of the above, beginning with prenatal development 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. 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). 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. Speech and language evaluation Evaluation of motor and sensory processing, including: Motor planning Sensory modulation Perceptual motor capacities Visual-spatial capacities Evaluation of cognitive functions, including neuropsychological and educational assessments 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–caregiver interaction patterns and family functioning.

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THE PROCESS OF CLINICAL ASSESSMENT Each clinician may develop his own way of doing an evaluation. A comprehensive assessment usually involves the following elements: the presenting “complaints” 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 family’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 communication, 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 ageappropriate developmental level and, if so, the full range of emotional inclinations. 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 functioning. 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, wordretrieval 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. (However, sometimes marital or other family problems erupt during the ﬁrst session.

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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 individual 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 different 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

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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 joining 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 aimless 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 engagement—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, aggression 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 developing the history or observing further. One then asks oneself a number of questions. How high up in the developmental progression has the child gone, in terms of 1) attending, 2) regulating and

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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 experience. 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 aggressive 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 dependency needs. One also looks at the range of experience organized at a particular developmental 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 developmental level, the stage may be narrow. In other words, he might be at that developmental stage only when it comes to assertiveness, but when it comes to dependency 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 patterns (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 developed 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

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on underlying processing dysfunctions and affective interactions with caregivers and family members. In addition, in the major outcome study on intensive behavioral 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 deﬁcits 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 perseverative 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 interactions going. These affective interactions are tailored to the child’s individual differences: 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 therapeutic work with the child. It also includes regular family consultations and team meetings, which include reviewing the overall therapeutic and educational program and coordination of relevant biomedical interventions.

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The home-based program of developmentally appropriate interactions is especially important. It is related to the recommendation by the National Association for the Education of Young Children (NAEYC) of developmentally appropriate 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 requires 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 developmental 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 typically 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 communication, 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 developmental 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 interactions (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.

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One of the most important components of a functional approach to intervention 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 disorders began evidencing a subtle deﬁcit in affective reciprocity and complex, preverbal, 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 milestones, provide the basis for delineating essential functional developmental landmarks (1,43). Therefore, just as a child’s physical growth can be charted, functional 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 parents use for clinical observations and/or questions about an infant and young child’s development. This involves using the functional developmental milestones outlined earlier. These milestones incorporate the well-known motor, language, 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 developmental 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).

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Historically, clinicians have approached children’s development in terms of isolated areas, such as motor development, the functioning of the senses, aspects 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 aspects 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 together. 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 interactions (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 communication, 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 intent), 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 components 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

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these doors provides an important picture of his adaptive and maladaptive development and the need for further evaluation and, possibly, intervention. If observing and/or asking about a child’s functional developmental capacities 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 clinical observations and questions, then a third level should be considered: a comprehensive developmental evaluation to determine the nature and extent of a suspected 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 milestones to be observed or asked about. The growth chart and questionnaire must provide straightforward, clear descriptions that can readily be observed by parents, health-care providers, and educators. It must cover all the areas of developmental functioning—emotional, social, cognitive, language, motor, and sensory—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 abilities. 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 accomplishments can be charted in relation to the age at which the accomplishment is expected 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 milestones) will have a curve that parallels the typical curve but may fall just below

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Figure 2

The Functional Development Growth Chart.

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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 increasing 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 running parallel to the typical curve but is signiﬁcantly below it. This developmental chart can be used by parents, educators (including daycare staff), and other child-care facilitators to monitor a child’s functional capacities. 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 Developmental Growth Chart Questionnaire following the chart will help in determining 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 patterns, 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 relating 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

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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 intervention 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 dysfunction, perseverative, and intermittently symbolic. Type I children can be perseverative and self-stimulatory, with scripted and echolalic language, but are also able to intermittently relate to caregivers, use gestures purposefully, and form problemsolving 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 capable of great warmth, a sense of humor, appropriate peer relationships, and progressing 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, visualspatial capacities, and hypersensitive to sensation. Type IB: Relatively strong auditory processing, weaker visual-spatial capacities, weaker motor planning and mixed reactivity to sensation. Type IC: Relatively stronger visual-spatial capacities and motor planning and weaker auditory processing, with underreactivity to sensation. Type ID: Relatively strong auditory memory, but relatively weak auditory 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-

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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 comprehensive 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 processing 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 intermittently engaged. Self-absorbed or avoidant, type III children evidence only intermittent 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, isolated words and intermittent use of phrases are possible. Processing proﬁle: type III is characterized by severe motor planning dysfunction (one- to two-step sequences), weaker auditory and visual-spatial processing 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 underor mixed reactivity) than in type III.

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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 affective, 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 children with autistic disorders are unable to progress to complex functional interactions and pragmatic language. In our chart review, we observed that children characterized as type II, while engaging and speaking, were still having signiﬁcant 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 relating 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-

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ber, the growth chart is simply a visual tool to draw attention to the developmental 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 smiling, making sounds or some other gesture, such as moving arms, that indicates 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 interaction 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) (Ask the questions from all prior categories plus the new ones for this category.) Does your toddler (by 24 months) ever respond to people talking with or playing

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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) (Ask the questions from all prior categories plus the new ones for this category.) 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

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or more give-and-take sequences about a variety of topics, ranging from negotiating foods and bedtimes to talking about friends or school? REFERENCES 1.

2. 3.

4.

5.

6.

7. 8. 9. 10.

11. 12. 13.

14. 15.

Greenspan SI. Infancy and Early Childhood: The Practice of Clinical Assessment and Intervention with Emotional and Developmental Challenges. Madison, CT: International Universities Press, 1992. Greenspan SI, Wieder S. The Child with Special Needs: Intellectual and Emotional Growth. Reading, MA: Addison Wesley Longman, 1998. Greenspan SI. The Development of the Ego: Implications for Personality Theory, Psychopathology, and the Psychotherapeutic Process. Madison, CT: International Universities Press, 1989. Greenspan SI. Intelligence and Adaptation: An Integration of Psychoanalytic and Piagetian Developmental Psychology. Psychological Issues, Monograph 47/68. New York: International Universities Press, 1979. Greenspan S, DeGangi G, Wieder S. The Functional Emotional Assessment Scale (FEAS) for Infancy and Early Childhood: Clinical and Research Applications. Bethesda, MD: Interdisciplinary Council on Developmental and Learning Disorders, 2001. Greenspan S. The affect diathesis hypothesis: the role of emotions in core deﬁcit in autism and the development of intelligence and social skills. J Dev Learning Disord 2001; 5:1–46. DeGangi G, Greenspan SI. The development of sensory functioning in infants. J Phys Occup Ther Pediatr 1988; 8(4):21–33. DeGangi G, Greenspan SI. The assessment of sensory functioning in infants. J Phys Occup Ther Pediatr 1989; 9:21–33. DeGangi G, Greenspan SI. Test of sensory functions in infants. Los Angeles: Western Psychology Services, 1989. Bristol M, Cohen D, Costello J, Denckla M, Eckberg T, Kallen R, Kraemer H, Lord C, Maurer R, McIllvane W, Minshew N, Sigman M, Spence A. State of the science in autism: Report to the National Institutes of Health. J Autism Dev Disord 1996; 26:121–154. Rogers S. Brief report: early intervention in autism. J Autism Dev Disord 1996; 26:243–246. Lovaas OI. Behavioral treatment and normal educational and intellectual functioning in young autistic children. J Consult Clin Psychol 1987; 55:3–9. McEachin JJ, Smith T, Lovaas OI. Long-term outcome for children with autism who received early intensive behavioral treatment. Am J Ment Retard 1993; 97: 359–372. Gresham FM, MacMillan DL. Early intervention project: can its claims be substantiated and its effects replicated? J Autism Dev Disord 1998; 28(1):5–12. Greenspan SI. Commentary—guidance for constructing clinical practice guidelines for developmental and learning disorders: knowledge vs. evidence-based approaches. J Dev Learn Disord 1998; 2(2):171–192.

Assessment and Early Identiﬁcation 16. 17.

18. 19.

20. 21.

22.

23.

24. 25.

26.

27. 28. 29.

30.

31. 32. 33.

83

Schopler E. Speciﬁc and non-speciﬁc factors in the effectiveness of a treatment system. Am Psychol 1987; 42:262–267. Smith T, Eikeseth S, Morten K, Lovaas I. Intensive behavioral treatment for preschoolers with severe mental retardation and pervasive developmental disorders. Am J Ment Retard 1997; 102:238–249. Smith T, Buch GA, Evslin T. Parent-directed, intensive early intervention for children with pervasive developmental disorder. Res Dev Disabil 2000; 21: 297–309. Smith T, Groen AD, Wynn JW . Randomized trial of intensive early intervention for children with pervasive developmental disorder. Am J Ment Retardation 2000; 105:265–285. Carew JV. Experience and the development of intelligence in young children at home and in day care. Monogr Soc Res Child Dev 1980; 45(607):1–115. Feuerstein R, Rand Y, Hoffman M, Miller, R. Cognitive modiﬁability in retarded adolescents: effects of instrumental enrichment. Am J Ment Deﬁc 1979; 83(6):539– 550. Feuerstein R, Miller R, Hoffman M, Rand Y, Mintsker Y, Morgens R, Jensen MR. Cognitive modiﬁability in adolescence: cognitive structure and the effects of intervention. J Spec Educ 1981; 150(2):269–287. Greenspan SI. Psychopathology and adaptation in infancy and early childhood: principles of clinical diagnosis and preventive intervention. Clinical Infant Reports., No. 1. New York: International Universities Press, 1979. Greenspan SI. The Growth of the Mind and the Endangered Origins of Intelligence. Reading, MA: Addison Wesley Longman, 1997. Klein PS, Wieder S, Greenspan SI. A theoretical overview and empirical study of mediated learning experience: prediction of preschool performance from mother– infant interaction patterns. Infant Ment Health J 1987; 89(2):110–129. Rogers SJ, Lewis H. An effective day treatment model for young children with pervasive developmental disorders. J Am Acad Child Adolesc Psychiatry 1989; 28: 207–214. Bredekamp S, Copple C, eds. Developmentally Appropriate Practices in Early Childhood Programs. Washington, DC: NAEYC, 1997. Greenspan SI, Wieder S. A functional developmental approach to autism spectrum disorders. J Assoc Pers Sev Handicaps (JASH), 1999; 24(3):147–161. ICDL Clinical Practice Workgroup. Interdisciplinary Council on Developmental and Learning Disorders’ Clinical Practice Guidelines: Redeﬁning the Standards of Care for Infants, Children, and Families with Special Needs. Bethesda, MD: Interdisciplinary Council on Developmental and Learning Disorders, 2000. Greenspan SI, Wieder S. Developmental patterns and outcomes in infants and children with disorders in relating and communicating: a chart review of 200 cases of children with autistic spectrum diagnoses. J Dev Learn Disord 1997; 1:87–141. Baron-Cohen S, Frith U, Leslie AM. Autistic children’s understanding of seeing, knowing, and believing. Br J Dev Psychol 1988; 4:315–324. Mundy P, Sigman M, Kasari C. A longitudinal study of joint attention and language development in autistic children. J Autism Dev Disord 1990; 20(1):115–128. Lewy AL, Dawson G. Social stimulation and joint attention in young autistic children. J Abnorm Child Psychol 1992; 20 (6):555–566.

84 34.

35.

36.

37. 38.

39. 40.

41.

42.

43.

44.

45. 46. 47. 48.

49.

Greenspan and Wieder Dawson G, Galpert I. Mother’s use of imitative play for facilitating social responsiveness and toy play in young autistic children. Dev Psychopathol 1990; 2:151– 162. Tanguay PE, Robertson J, Derrick A. A dimensional classiﬁcation of autism spectrum disorder by social communication domains. J Am Acad Child Adolesc Psychiatry 1998; 37(3):271–277. Tanguay PE. The diagnostic assessment of autism using social communication domains. Presented at the Interdisciplinary Council on Developmental and Learning Disorders’ Third Annual International Conference, Autism and Disorders of Relating and Communicating, McLean, VA, Nov 12–14, 1999. Osterling J, Dawson G. Early recognition of children with autism: a study of ﬁrst birthday home videotapes. J Autism Dev Disord 1994; 24(3): 247–257. Baranek GT. Autism during infancy: a retrospective video analysis of sensory-motor and social behaviors at 9–12 months of age. J Autism Dev Disord 1999; 29(3): 213–224. Wetherby AM, Prizant BM. Proﬁling communication and symbolic abilities in young children. J Child Commun Disord 1993; 15:23–32. Teitelbaum P, Teitelbaum O. Motor indicators of autism in the ﬁrst year. Presented at the Interdisciplinary Council on Developmental and Learning Disorders’ Third Annual International Conference on Autism and Disorders of Relating and Communicating, McLean, VA, Nov 12–14, 1999. Williamson GG, Anzalone ME. Sensory integration: a key component of the evaluation and treatment of young children with severe difﬁculties in relating and communicating. ZERO TO THREE 1997; 17:29–36. Baron-Cohen S. The early detection of autism. Presented at the Interdisciplinary Council on Developmental and Learning Disorders’ Third Annual International Conference on Autism and Disorders of Relating and Communicating, McLean, VA, Nov 12–14, 1999. Greenspan SI, Lourie RS. Developmental structuralist approach to the classiﬁcation of adaptive and pathologic personality organizations: application to infancy and early childhood. Am J Psychiatry 1981; 138 (6):725–735. Fillipek P, Accardo P, Baranek G, Cook E, Dawson G, Gordon B, Gravel J, Johnson C, Kallen R, Levy S, Minshew N, Prizant B, Rapin I, Rogers S, Stone W, Teplin S, Tuchman R, Volkmar F. The screening and diagnosis of autistic spectrum disorders. J Autism Dev Disord 1999; 29(6):439–484. Wetherby A, Prizant B. Communication and Symbolic Behavior Scales Developmental Proﬁle–Research Edition. Chicago: Applied Symbolix, 1998. Bricker D, Squires J. Ages and Stages Questionnaires: A Parent-Completed, ChildMonitoring System. 2nd ed. Baltimore: Paul H. Brookes, 1999. Volkmar FR, Schwab-Stone M. Annotation: childhood disorders in DSM-IV. J Child Psychol Psychiatry 1996; 37(7):779–784. Lord C, Rutter M, Goode S, Heemsbergen J, Jordan H, Mauhood. Autism Diagnostic Observation Schedule: a standardized observation of communicative and social behavior. J Autism Ment Disord 1989; 19(2):185–212. Tordjman S, Anderson GM, McBride PA, Hertzig ME, Snow ME, Hall LM,

Assessment and Early Identiﬁcation

50.

51.

85

Thompson, SM, Ferrari P, Cohen DJ. Plasma beta-endorphin, adrenocorticotropin hormone, and cortisol in autism. J Child Psychol Psychiatry 1996; 38(6):705–715. Diagnostic Classiﬁcation Task Force, Stanley Greenspan, M.D., Chair. Diagnostic Classiﬁcation: 0–3: Diagnostic Classiﬁcation of Mental Health and Developmental Disorders of Infancy and Early Childhood. ZERO TO THREE/National Center for Clinical Infant Programs. Arlington, VA, 1994. Greenspan SI, Wieder S. The assessment and diagnosis of infant disorders: developmental level, individual differences and relationship based interactions. In: Osofsky J, Fitzgerald H, eds. World Association for Infant Mental Health Handbook of Infant Mental Health. Vol 2. Intervention, Evaluation, and Treatment. New York: Wiley & Sons, 1999.

5 Cognitive and Neuropsychological Assessment of Children with Autism Spectrum Disorders Audrey F. King, Ronald R. Rawitt, Katherine C. Barboza, and Eric Hollander Mount Sinai School of Medicine New York, New York, U.S.A.

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 particularly crucial. The diagnosis of ASD is a multistep process, beginning with screening 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 educational planning. Full evaluations include, in addition to diagnosis, cognitive assessment, 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 behavioral disorders, and by ruling out/in mental retardation. Cognitive and neuropsychological evaluations are essential for school personnel in developing Individual Education Plans (IEP), and are important in supporting educational 87

Visual and sensory perception Rey-Osterrieth Com plex Figure

Adaptive functioning Vineland Adaptive Behavior Scale

Leiter International Performance Scale–R Raven’s Coloured Progressive Matrices

Tests of general intellectual functioning Wechsler Intelligence Scale for Children, 3rd (WISC-III)

Scale

Osterrieth PA (1944)

Sparrow S, Balla D, Cicchetti DV (1984)

Roid GH, Miller JN (1997) Raven JC (1947)

Wechsler D (1991)

Authors, year

Perceptual organization and visual memory. Children and adults.

Performance of daily activities required for personal and social sufﬁciency of individuals from birth to adulthood

Performance IQ in children ages 2–18 Reasoning. Child through adult.

IQ in children aged 6–16

Assesses

Table 1 Generally Used Cognitive, Adaptive, and Neuropsychological Tests

Timed test; measures visual perception/long-term visual memory; the order and accuracy with which the ﬁgure is copied and drawn from recall provides useful information concerning the location and extent of any brain damage.

Semistructured interview for caregiver; four domains: communication, daily living skills, socialization, and motor skills; can be used with all populations to determine levels of adaptive behavior and the extent to which handicaps affect daily functioning

Untimed intelligence test intended for the entire range of intellectual development; does not require verbalization, skilled manipulation ability, or subtle differentiation of visual-spatial information.

Individually administered; 12 subtests: picture completion, information, coding, similarities, picture arrangement, arithmetic, block design, vocabulary, object assembly, comprehension, digit span, and mazes and a symbol search subtest Nonverbal, culturally fair measure; visual matching test

Description

88 King et al.

Reitan RM (1969)

For Thought, Ltd. (1996)

Kagan J, et al. (1964)

Heaton RK, Chelune GJ, Talley JL, Kay GG, Curtiss G (1993)

VIGIL Continuous Performance Test

Matching Familiar Figures Test (MFFT)

Wisconsin Card Sorting Test (WCST)

Buschke H (1973)

Buschke Selective Reminding Test Tests of attention and executive function Trail Making Test

Learning and memory tests Wide Range AssessSheslow D, Adams ment of Memory and W (1990) Learning (WRAML)

Cognitive set-shifting and maintenance ability in response to reinforcement contingencies and nonverbal abstract concept formation. All ages.

Reﬂection versus impulsivity in children, adolescents, and adults

Speed for attention, sequencing, ﬂexibility, visual search and motor function; child and adult versions Brain damage, in subjects aged 6 to adulthood

Ability to actively learn and memorize a variety of information in children aged 5–17 Verbal memory deﬁcits

Computerized ﬂash task requiring the execution of one response with simultaneous inhibition of another of stimuli presented visually, auditorally, or in both modalities. Measures vigilance or the maintenance of concentration on a simple or relatively complex task over time. Timed with two practice and 12 experimental items; measures delay of decision making in situations where a correct response is not obvious (reﬂection) vs. the quick choice of an alternative without adequate consideration of options (impulsivity). Measure requires the ability to develop and maintain an appropriate problem-solving strategy across changing stimulus conditions in order to achieve a future goal

Subject draws a line through 25 stimuli in numerical order (part A) and of 25 encircled numbers and letters in alternating order (part B)

Measures the acquisition and retention of eight unrelated, common words across 10 trials

Three domains tested: verbal memory scale, visual memory scale, and learning scale

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Colarusso RP, Hammill DD (1996)

Tifﬁn J (1968)

Denckla MB (1985)

Purdue Pegboard Test

Denckla Motor Performance Battery

Golden CJ (1978)

Authors, year

Motor and graphomotor function Motor-Free Visual Perception Test

Stroop Color and Word Test

Scale

Table 1 Continued

Soft neurological signs in children with motor coordination problems in the absence of diagnosable neurological conditions

Finger dexterity and hand–eye coordination

Visual-perceptual abilities without involving motor skills of children ages 4–12

Cognitive ﬂexibility, resistance to interference from outside stimuli, and reaction to cognitive stress. Ages 17 to adult.

Assesses

Assess visual perception in children; especially useful for those who may have learning, cognitive, motor, or physical disabilities. Measures ﬁve areas of perception: spatial relationship, visual discrimination, ﬁgure-ground, visual closure, and visual memory. Tests individual’s ability to move right, left, and both hands, ﬁngers and arms (gross movement), and to control movements of small objects (ﬁngertip dexterity) Looks for signs of adventitious movements as child focuses on a delicate or difﬁcult task (e.g., sticking out the tongue while attempting to write, or grimacing, or moving the mouth to the side while focusing on a delicate activity), simultaneous movements of another part of the 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 the counterpart on the other side of the body

Used in diagnosis of brain dysfunction in the evaluation of stress, personality, cognition, and psychopathology

Description

90 King et al.

Ability to recognize faces

Benton AL, et al. (1994)

Ekman P, Friesen WV (1976)

Rosenzweig S (1978)

Pictures of Facial Affect Test

Rosenzweig Picture Frustration Test

Patterns of frustration and aggressive response to everyday stress

Ability to recognize facial affect

Visual-motor integration in children, adolescents, and adults

Beery KE, Buktenica NA (1989)

Developmental Test of Visual-Motor Integration (VMI) Facial recognition, emotional labeling, and empathy Benton Facial Recognition Test A three-part standardized measure of the ability to match unfamiliar faces; contains a 27-item short form and a 54-item long form; provides additional substantive data in the evaluation of brain-damaged patients Consists of 110 black-and-white photographs of 14 models; six emotions are represented in the set of photographs: “happiness,” “sadness,” “fear,” “anger,” “disgust,” and “surprise”; used to determine treatment effects of social skills training with persons with mental retardation Consists of 24 cartoon-like pictures, each depicting two people in a mildly frustrating situation of common occurrences. The task is to provide a reply for the anonymous frustrated person in the picture; three types of aggression (extrapunitive, intropunitive, impunitive) and three directions of aggression (obstacle-dominance, ego-defense, need-persistence) are assessed, yielding a total of nine scored factors.

Screens for visual-motor deﬁcits that can lead to learning and behavioral problems

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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, complex 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 information gathered from these tests reveals functioning in attention, memory, visual-spatial problem solving, abstract thinking, processing speed, fund of information, and comprehension. Another verbal test of intelligence is the StanfordBinet 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 assessed 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

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WPPSI-R, WISC-III, and SBIS have no normative data for children with developmental 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 Assessment Battery for Children (K-ABC) (9). This test battery assesses simultaneous and sequential mental processing. Six of these 10 subtests are considered nonverbal and are well suited for children with communication deﬁcits. However, although 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 cognitive 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, noncompliance, attentional deﬁcits, and over- or underactivity will compromise the validity of the proﬁle. Nonverbal measures of intelligence assess cognitive skills and aptitudes such as reasoning, spatial visualization, memory, attention, and speed of processing. These concepts are evaluated through the use of pictures, ﬁgural illustrations, 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., attentiondeﬁcit/hyperactivity disorder), and may thus be especially useful for use in ASD populations. Other nonverbal measures of intelligence include Raven’s Progressive Matrices (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 Matrices (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.

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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 belowaverage 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 available scales of adaptive behavior, the VABS are rated as having excellent psychometric properties and usefulness because of the availability of supplementary groups (ambulatory and nonambulatory mentally retarded institutionalized individuals, 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 neuropsychological impairments in explicit and working memory, establishing rules, planning, 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 processing while the presence of negative behaviors (self- and other-directed aggression), 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 California Verbal Learning Test–Children are two of the tests most often used for memory research in an autistic population.

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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 modest test–retest reliability while showing good validity. The CVLT-C has demonstrated utility in characterizing memory deﬁcits in individuals with head injury; epilepsy; Alzheimer’s, Parkinson’s, and Huntington’s diseases; vascular dementia; depression; and schizophrenia (8). The CVLT-C has also been used with autistic populations to study visual and auditory memory (37), prediction of adaptive 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 wellnormed test that has been used in autistic populations in testing working memory (32) in addition to other executive functions such as planning, organization, cognitive 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, decision 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

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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 information, 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 children 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 (responding to a nontarget), Hit rate (mean response time), Hit Rate Standard Error (consistency of response times), Attentiveness, and Risk Taking (response tendency 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 comprehensive 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 Functions, Visuospatial Processing, and Memory and Learning. The NEPSY provides a percentile rank score based on comparison with a nonclinical child population.

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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 coefﬁcients 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 diagnosis by ruling out other disorders, developing and supporting educational placement 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 determining the speciﬁc cognitive and neuropsychological deﬁcits in lower-functioning 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 ability 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. REFERENCES 1. 2.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Publishing, 1994. Filipek PA, Accardo PJ, Baranek GT, et al. The screening and diagnosing of autistic spectrum disorders. J Autism Dev Disord 1999; 29(6):439–484.

98 3.

4. 5. 6. 7. 8. 9. 10. 11. 12.

13. 14. 15. 16. 17. 18.

19.

20. 21.

22.

23.

King et al. Minshew NJ, Goldstein G, Siegel DJ. Neuropsychologic functioning autism: proﬁle of a complex information processing disorder. J Int Neuropsychol Soc 1997; 3 (4): 303–316. Siegel DJ, Minshew NJ, Goldstein G. Wechsler IQ proﬁles in diagnosis of highfunctioning autism. J Autism Dev Disord 1996; 26(4):389–406. Wechsler D. Wechsler Preschool and Primary Scale of Intelligence. San Antonio, TX: Psychological Corporation, 1989. Wechsler D. Wechsler Intelligence Scale for Children. 3rd ed. San Antonio, TX: Psychological Corporation, 1991. Thorndike RL, Hagen EP, Sattler JM. Guide for Administering and Scoring the Stanford-Binet Intelligence Scale. 4th ed. Chicago: Riverside, 1986. Spreen O, Strauss E. A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary. 2nd ed. New York: Oxford University Press, 1998. Kaufman AS, Kaufman NL. K-ABC: Kaufman—Assessment Battery for Children. Circle Pines, MN: American Guidance Service, 1983. Roid GH, Miller JN. Leiter International Test of Intelligence–Revised. Dale, IL: Stoeling, 1997. Raven JC. Progressive Matrices: A Perceptual Test of Intelligence. London: HK Lewis, 1938. Raven JC. Raven’s Coloured Progressive Matrices–“Japanese”. In: Iishiai S, Okiyama R, Koyama Y, Seki K, eds. Unilateral Spatial Neglect in Alzheimer’s Disease: A Line Bisection Study. Acta Neurologica Scandinavica 1996; 93:219– 224. Raven JC. Coloured Progressive Matrices Sets A, Ab, B. London: HK Lewis, 1947. Raven JC, Court JH, Raven J. Coloured Progressive Matrices. Oxford: Oxford Psychologists Press, 1995. Raven JC. Advanced Progressive Matrices. Sets I and II. London: HK Lewis, 1965. Raven JC. Advanced Progressive Matrices Sets I and II. Oxford: Oxford Psychologists Press Ltd, 1965, 1994. Sparrow SS, Balla DA, Cicchetti DV. Vineland Adaptive Behavior Scales. Expanded Edition. Circle Pines, MN: American Guidance Service, 1984. Carter AS, Volkmar FR, Sparrow SS, Wang JJ, et al. The Vineland Adaptive Behavior Scales: supplementary norms for individuals with autism. J Autism Dev Disord 1998; 28(4):287–302. Loveland KA, Kelley ML. Development of adaptive behavior in adolescents and young adults with autism and Down syndrome. Am J Ment Retard 1988; 93 (1): 84–92. Loveland KA, Kelley ML. Development of adaptive behavior in preschoolers with autism or Down syndrome. Am J Ment Retard 1991; 96(1):13–20. Rodrigue JR, Morgan SB, Geffken GR. A comparative evaluation of adaptive behavior in children and adolescents with autism, Down syndrome, and normal development. J Autism Dev Disord 1991; 21(2):187–196. Freeman BJ, Ritvo ER, Yokota A, Childs J, Pollard J. WISC-R and Vineland Adaptive Behavior Scale scores in autistic children. J Am Acad Child Adolesc Psychiatry 1988; 27 (4):428–429. Aman, M. Assessing psychopathology and behavior problems in persons with men-

Assessment of Children

24. 25.

26. 27.

28. 29. 30. 31.

32. 33.

34. 35. 36. 37.

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tal retardation: a review of available instruments. Rockville, MD: U.S. Department of Health and Human Services, 1991. Dawson G. Brief report—neuropsychology of autism: a report on the state of science. J Autism Dev Disord 1996; 26(2):179–184. Dawson G, Meltzoff AN, Osterling J, Rinaldi J, Brown E. Children with autism fail to orient to naturally occurring social stimuli. J Autism Dev Disord 1998; 28(6): 479–485. Delis DC, Massman PJ, Kaplan E, Ober BA. CVLT-C: California Verbal Learning Test–Children’s Version. San Antonio, TX: The Psychological Corporation, 1994. Liss M, Fein D, Allen D, Dunn M, Feinstein C, Morris R, Waterhouse L, Rapin I. Executive functioning in high-functioning children with autism. J Child Psychol Psychiatry Allied Disc 2001; 42(2):261–270. Farrant A, Blades M, Boucher J. Recall readiness in children with autism. J Autism Dev Disord 1999; 29(5):359–366. Renner P, Klinger L, Klinger M. Implicit and explicit memory in autism: is autism an amnesic disorder? J Autism Dev Disord 2000; 30(1):3–14. Berg EA A simple objective technique for measuring ﬂexibility in thinking. J Gen Psychol 1948; 39:15–22. Grant DA, Berg EA. A behavioral analysis of degree of impairment and ease of shifting to new responses in a Weigl-type card sorting problem. J Exp Psychol 1948; 39:404–411. Reed T. Visual perspective taking as a measure of working memory in participants with autism. J Dev Phys Disabil 2002; 14(1):63–76. Heaton RK, Chelune GJ, Talley JL, Kay GG, Curtis G. Wisconsin Card Sorting Test (WCST) Manual Revised and Expanded. Odessa, FL: Psychological Assessment Resources, 1993. Goldstein G, Johnson C, Minshew N. Attentional process in autism. J Autism Dev Disord 2001; 31(4):433–440. Conners CK and Multi-Health Systems Staff. Conners’ Continuous Performance Test. Toronto: MHS, 1995. Korkman AS, Kirk U, Kemp S. NEPSY, A Developmental Neuropsychological Assessment. The Psychological Corporation, San Antonio, 1998. Minshew NJ, Goldstein G. The pattern of intact and impaired memory functions in autism. J Child Psychol Psychiatry 2001; 42:1095–1101.

6 Assessment and Diagnosis of Pervasive Developmental Disorder Cecelia McCarton Albert Einstein College of Medicine and McCarton Center for Developmental Pediatrics New York, New York, U.S.A.

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 disturbance: “an inability to relate themselves in an ordinary way to people and situations 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. Language—in terms of prosody, content, and usage—was impaired, with echolalia, pronoun reversal, and a language-processing deﬁcit. Play was repetitive and stereotypic, 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

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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 autism). The study and research of this complex disorder over the past three decades have eventually brought these behaviors under the heading of pervasive developmental 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 restricted or repetitive patterns of behavior (2). Under the heading of pervasive developmental disorder, there are ﬁve speciﬁc diagnoses: 1. 2. 3. 4. 5.

Autistic disorder Pervasive developmental disorder–not otherwise speciﬁed Asperger’s syndrome Rett’s syndrome 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. 2. 3.

Impairment in communication and imaginative activity Impairment in reciprocal social interaction 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

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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 echolalia, 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. Comprehension of language is often poor; the child, at best, may understand simple commands 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 monotone 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 instead 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

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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 moderate (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 textures 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. Besides 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.

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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 pervasive 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 communication 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, PDDNOS 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 delays 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. However, 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 usually unable to form friendships. Tragically, they often desire to form these social

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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 movements, 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 childhood, 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, perseverative 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 prevalence rates range from 10 to 20 per 10,000 or one in every 500 to 1000 children

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(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 Services found a 273% increase between 1987 and 1998 in the number of new children 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 Maryland 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: Alabama, 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 evaluation 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-

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nally thought of in the 1950s and 1960s as an emotional or psychological disturbance 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 perinatal period as somehow putting a child at risk of developing PDD/ASD. However, 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 identical twins and 24% for fraternal twins (44–46). Recurrent risks of autism in subsequent 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 neuroﬁbromatosis and tuberous sclerosis (TS) also have strong associations with autism. 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 cytomegalovirus (61). Children with severe mental retardation also have a high incidence 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. Abnormalities 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 studies, the etiology of PDD/ASD remains unknown. Recently, considerable interest has focused on other possible causes of PDD/ASD. All of these remain speculative. Wakeﬁeld and his colleagues (74) generated intense controversy in the medical world when they reported evidence that the measles-mumps-rubella

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(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 vaccinations. 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 properties, to pass through the intestinal walls. These particles may disrupt normal brain function and development. In addition, most subjects had elevated urinary concentrations of methylmalonic acid, which is indicative of a functional vitamin B12 deﬁciency often seen in other gastrointestinal disorders. Vitamin B12 is essential 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. Thimerosal-free vaccines are available, but parents must request them. Abnormalities in the breakdown of peptides, especially those found in gluten 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 system in children with autism, including abnormalities of T cells, B cells, and natural killer (NK) cells, as well as various immunoglobulin classes. This deregulation may account for the autoimmune and allergic reactions common in autistic children 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

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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 autoantibodies. 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 language 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. Characteristically, 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 children, 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 presentation with autism. Often, these children exhibit an expressive and/or a receptive language delay. Lack of verbal communication or understanding of language often 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,

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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-ofsync” 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 children 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 communicative 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 interventions 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 growing, 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 diagnosis of PDD/ASD, although tests can rule out or identify other underlying problems. In order to determine a diagnosis of PDD/ASD, professionals depend on

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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 characterized 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 district 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 clinician 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 pediatrician, 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 developmental history. Parental input is important, and all professionals should investigate 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).

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Speciﬁc Evaluations to Determine PDD/ASD The diagnosis of PDD/ASD requires a comprehensive multidisciplinary approach. Evaluations may include all or some of the following. Detailed History (Medical, Developmental, Family) Information should be gathered about the pregnancy, labor, delivery, and immediate newborn period, along with achievement of developmental milestones. Medical complications such as seizures, head trauma, brain infections or injuries, and lead exposure should be noted. A family history of affective disorders (depression, 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, pretendplay, 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 selfdirected 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 decreased 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 repetitively 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 observation instrument that can be used in any child over 2 years old. It is widely recognized and used as a reliable instrument for the diagnosis of autism.

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The Autism Diagnostic Interview–Revised (ADI-R) (84,100,101) is a comprehensive 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 assessment 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 determining his overall level of functioning. It is important for both parents and practitioner 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, psychological 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 Primary 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 diagnosis 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, socialization, 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

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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 hearing loss. In any event, a hearing evaluation consisting of a behavioral evaluation (visual-reinforcement audiometry) or an electrophysiological assessment (brainstem auditory evoked responses) and tympanometry are the usual methods employed. 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, organization of materials, and increased sensitivity to tactile and auditory environmental stimuli (113,114). These behaviors are usually evaluated by an occupational therapist and physical therapist. Assessment of these skills utilizes a variety of standardized tools appropriate to the developmental level of the child. Once again, the most important aspect is that the evaluator be experienced in assessing children 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, pragmatic, and prosody (voice and speech production)—should be evaluated. Wetherby and Prizant (115) and Crais (116) recommend that all evaluations do the following: 1. 2. 3. 4. 5. 6. 7.

Focus on functions of communication Analyze preverbal communication (gaze, gestures, vocalizations) Assess social-affective signaling Proﬁle social, communicative, and symbolic abilities Directly assess the child Make observations of spontaneous and initiated communication 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-

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tion and Language Fundamentals–3 (CELF-3) (119), the Expressive One-Word Picture Vocabulary Test–Revised (EOWPVT-R ) (120), and the Receptive OneWord 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, carbohydrate, 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 suggests 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).

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BEYOND THE DIAGNOSIS Treatment of PDD/ASD Rutter (127) has outlined ﬁve main goals for the treatment of autism: 1. 2. 3. 4. 5.

Fostering of development Promotion of learning Reduction of rigidity and stereotypy Elimination of nonspeciﬁc maladaptive behaviors 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 teaching 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 concepts; 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 reported in a group of PDD/ASD children. Recently, Smith (129) compared two groups of children who began treatment 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 conducted most of the training, with parents assisting for several hours per week.

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2.

Seven children with autism and six with PDD received therapy provided by parents who were trained by professional therapists. In addition, 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 intensivetreatment group outperformed the parent-trained group on measures of intelligence, visual-spatial skills, language, and academics. IQ gains in the intensiveintervention 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 behavioral 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 pragmatic 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 weakness. 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 exposure to have interactive and meaningful conversations. This is often best accomplished 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

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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. Medication 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 physician 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 (disinhibition) is a rare event and may occur in a child who has a manic-depressive tendency. Hyperactivity and attentional disorders: Decreased attention, increased activity, and impulsivity are common ﬁndings in PDD/ASD. Some individuals 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 neuroleptics, 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 (Tegretol) and valporic acid (Depakene, Depakote), lithium, and serotonin-reuptake inhibitors.

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Seizure disorder: Seizures are a common ﬁnding in PDD/ASD. Anticonvulsants used include valporic acid (Depakene, Depakote) and carbamazepine (Tegretol). Because common drugs such as phenytoxin (Dilantin) and phenobarbital 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 medications—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 individuals 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 normal 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 normally 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 chronically 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., Nystatin) 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 vitamin 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 vitamin B6 and magnesium in improving autistic behavior (140). Dimethylglycine (DMG) is a food substance that resembles in its makeup vitamin B15. Anecdotal reports from parents claim improvements in speech, eye contact, social behavior, and attention span.

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Auditory Integration Training (AIT): Pioneered in France by Dr. Alfred 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 Electronic 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 connective 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 behavior and hyperactivity as well as an increase in communication. Intravenous immunoglobulin therapy: Gupta and coworkers (80) reported 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, dolphin 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

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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 unexpected, 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 provide information to parents through books and other reading material and meetings, 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

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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 professional 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 treatment. Parents of children who exhibit PDD/ASD behaviors may be utterly confused 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 realities 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 communicative 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

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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 abilities. Often, the ﬁgure of 70% retardation is cited with this diagnosis. However, no primary reference has ever been found that documents that ﬁgure. The hallmark 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 comprehensive, intense, consistent program of intervention. Various individuals and intervention 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

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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 deﬁnitions 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 observations. 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 history; physical and neurological examinations; a diagnostic parental questionnaire; cognitive measures; adaptive behavioral evaluation; a hearing test; speech/language evaluation; assessment of ﬁne and gross motor skills and sensory integration; and a social family history. The treatments most often used include Applied Behavioral Analysis therapy, 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 intervention are bringing about substantial—and in some cases remarkable—changes in the behavioral manifestations of PDD/ASD.

REFERENCES 1. 2. 3.

4.

5.

6. 7. 8.

Kanner L. Autistic disturbances of affective contact. Nerv Child 1943; 2:217–250. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Publishing, 1994. Rapin I. Neurological examination. In: Rapin I, ed. Preschool Children with Inadequate Communication: Developmental Language Disorder, Autism, Low IQ. London: MacKeith, 1996:98–122. Towbin KE. Pervasive developmental disorder not otherwise speciﬁed. In: Cohen DJ, Volkmar FR, eds. Handbook of Autism and Pervasive Developmental Disorders. 2nd ed. New York: Wiley, 1997:123–147. Asperger H. “Autistic psychopathy” in childhood. Translated and annotated by Frith U. In: Frith U, ed. Autism and Asperger Syndrome. New York: Cambridge University Press, 1991/1944:37–92. Bonnet A, Gao XK. Asperger syndrome in neurologic perspective. J Child Neurol 1996; 11:483–489. Klin A, Volkmar FR, Sparrow SS, eds. Asperger Syndrome. New York: Guilford Press, 2000. Armstrong DD. Review of Rett syndrome. J Neuropathol Exp Neurol 1997; 56: 843–849.

126 9. 10.

11. 12. 13. 14.

15. 16. 17. 18. 19. 20. 21.

22. 23. 24. 25. 26. 27.

28. 29.

McCarton Naidu S. Rett syndrome: a disorder affecting early brain growth. Ann Neurol 1997; 42:3–10. Hagberg B, Aicardi J, Dias K, Ramos O. A progressive syndrome of autism, dementia, ataxia and loss of purposeful hand use in girls: Rett’s syndrome: report of cases. Ann Neurol 1983; 14:471–479. Hagberg B. Rett syndrome: clinical peculiarities and biological mysteries. Acta Paediatrica 1995; 84:971–976. Percy A, Gillberg C, Hagberg B, Witt-Engerstrom I. Rett syndrome and the autistic disorders. Neurol Clin N Am 1990; 8:659–676. Volkmar FR, Rutter M. Childhood disintegrative disorder: results of the DSM-IV autism ﬁeld trial. J Am Acad Child Adolesc Psychiatry 1995; 34:1092–1095. Volkmar FR, Kiln A, Marans W, Cohen DJ. Childhood disintegrative disorder. In: Cohen DJ, Volkmar FR, eds. Handbook of Autism and Pervasive Developmental Disorders. 2nd ed. New York: Wiley, 1997. Malhotra S, Gupta N. Childhood disintegrative disorder. J Autism Dev Disord 1999; 29(6):491–498. Tuchman R. Pervasive developmental disorder: neurologic perspective. Acta Neuropaediatrica 1996; 2:82–93. Lotter V. Epidemiology of autistic conditions in young children. I. Prevalence. Soc Psychiatry 1966; 1:124–137. Brask BH. A prevalence investigation of childhood psychoses. In: Nordic Symposium on the Care of Psychotic Children. Oslo: Barnepsychiatrist Forening, 1970. Wing L, Gould J. Severe impairments of social interactions and associated abnormalities in children: epidemiology and classiﬁcation. J Autism Dev Disord 1979; 9:11–29. Bryson SE. Brief report: epidemiology of autism. J Autism Dev Disord1996; 26: 165–167. Bryson SE. Epidemiology of autism: overview and issues outstanding. In: Cohen DJ, Volkmar FR, eds. Handbook of Autism and Pervasive Developmental Disorders. 2nd ed. New York: Wiley, 1997:41–46. Bryson SE, Clark, BS, Smith IM. First report of a Canadian epidemiological study of autistic syndromes. J Child Psychol Psychiatry 1988; 4:433–445. Gillberg C, Steffenburg S, Schaumann H. Is autism more common now than ten years ago? Br J Psychiatry 1991; 158:403–409. Ishii T, Takahashi O. The epidemiology of autistic children in Toyota, Japan: prevalence. Jpn J Child Adolesc Psychiatry 1983; 24:311–321. Sugiyama T, Abe T. The prevalence of autism in Nagoya, Japan: a total population study. J Autism Dev Disord 1989; 19:87–96. Wing L. The deﬁnition and prevalence of autism: a review of the literature. Adolesc Psychiatry 1993; 2:61–74. Tanoue Y, Oda S, Asano F, Kawashima K. Epidemiology of infantile autism in Southern Ibaraki, Japan: differences in prevalence in birth cohorts. J Autism Dev Disord 1988; 18:155–166. Matsuishi T, Shiotsuki M, Yoshimura K, Shoji H, Imuta F, Yamashita F. High prevalence of infantile autism in Kurume City, Japan. J Child Neurol 1987; 2:268–271. Fombonne E. Epidemiological surveys of autism. Autism Pervasive Devel Disord 1998; 2:32–63.

Pervasive Developmental Disorder 30. 31. 32.

33.

34. 35. 36. 37.

38. 39.

40.

41. 42.

43. 44. 45. 46. 47. 48.

127

Ehlers S, Gillberg C. The epidemiology of Asperger’s syndrome: a total population study. J Child Psychol Psychiatry 1993; 34:1327–1350. Fisher BL, ed. Vaccine Reaction Bulletin 2000; 1–15. Bristol MM, Cohen DJ, Costello EJ, Denckla M, Eckberg TJ, Kallen R, Kraemer HC, Lord C, Maurer R, McIlvane WJ, Minshew N, Sigman M, Spence MA. State of the science in autism: report to the National Institutes of Health. J Autism Dev Disord 1996; 26:121–154. Filipek PA, Accardo PJ, Baranek GT, Cook EH., Dawson G, Gordon B, Gravel JS, Johnson CR, Kallen RJ, Levy SE, Minshew NJ, Prizant BM, Rapin I, Rodgers SJ, Stone WL, Teplin S, Tuchman RF, Volkmar FR. The screening and diagnosis of autistic spectrum disorders. J Autism Dev Disord 1999; 29(6):439–484. Bauman ML, Kemper TL, eds. The Neurobiology of Autism. Baltimore: Johns Hopkins University Press, 1994. Nelson KB. Prenatal and perinatal factors in the etiology of autism. Pediatrics 1991; 87(suppl 5):761–766. Cryan E, Bryne M, O’Donovan A. Brief report: a case control study of obstetric complications and later autistic disorder. J Autism Dev Disord 1996; 26(4):453–460. Bolton P, Macdonald H, Pickles A, Rios P, Goode S, Crowson M, Bailey A, Rutter M. A case-control family history study of autism. J Child Psychol Psychiatry 1994; 35:877–900. Ghaziuddin M, Shakal J, Tsai L. Obstetric factors in Asperger syndrome: comparison with high-functioning autism. J Intell Dis Res 1995; 39:538–543. Piven J, Simon J, Chase GA, Wzorek M, Landa R, Gayle J, Folstein S. The etiology of autism: pre-, peri- and neonatal factors. J Am Acad Child Adolesc Psychiatry 1993; 32:1256–1263. Rapin I. Historical data. In: Rapin I, ed. Preschool Children with Inadequate Communication: Developmental Language Disorder, Autism, Low IQ. London: MacKeith, 1996:58–97. Fein D, Allen D, Dunn M, Feinstein C, Green L, Morris R, Rapin I, Waterhouse L. Pitocin induction and autism. Am J Psychiatry 1997; 154:438–439. Rutter M, Bailey A, Simonoff E, Pickles A. Genetic inﬂuences and autism. In: Cohen DJ, . Volkmar FR, eds. Handbook of Autism and Pervasive Developmental Disorders. 2nd ed. New York: Wiley, 1997:370–387. Simonoff E. Genetic counseling in autism and pervasive developmental disorders. J Autism Dev Disord 1998; 28:447–456. Ritvo, ER, Freeman BJ, Mason-Brothers A. Concordance for the syndrome of autism in 40 pairs of afﬂicted twins. Am J Psychiatry 1985; 142:74–77. Folstein, SE, Piven J. Etiology of autism: genetic inﬂuences. Pediatrics 1991; 87: 767–773. Smalley, SL, Asarnow RF, Spence MA. Autism and genetics: a decade of research. Arch Gen Psychiatry 1988; 45:953–961. Ritvo ER, Freeman BJ, Pingree C. The UCLA–University of Utah epidemiological survey of autism: prevalence. Am J Psychiatry 1989; 146(2):194–199. Jorde LB, Mason-Brothers A, Waldmann R. The UCLA–University of Utah epidemiologic survey of autism. Genealogical analysis of familial aggregation. Am J Med Genet 1990; 36:85–88.

128 49. 50. 51. 52. 53.

54. 55.

56. 57.

58. 59. 60. 61. 62.

63. 64. 65. 66. 67. 68. 69.

McCarton DeLong R. Children with autistic spectrum disorder and a family history of affective disorder. Dev Med Child Neurol 1994; 36:674–687. DeLong R, Nohria C. Psychiatric family history and neurological disease in autistic spectrum disorders. Dev Med Child Neurol 1994; 36:441–448. DeLong GR, Teague L, Kamran MM. Effects of ﬂuoxetine treatment in young children with idiopathic autism. Dev Med Child Neurol 1998; 40:551–562. Bailey A, Palferman S, Heavey L, LeCouteur A. Autism: the phenotype in relatives. J Autism Dev Disord 1998; 28:369–392. Brown WT, Jenkins EC, Cohen IL, Fisch GS, Wolf-Schein EG, Gross A, Waterhouse L, Fein D, Mason-Brothers A, Ritvo E. Fragile X and autism: a multicenter survey. Am J Med Genet 1986; 23:341–352. Wahlstrom J, Gillberg C, Gustavson KH, Holmgren G. Infantile autism and the fragile X: a Swedish multicenter study. Am J Med Genet 1986; 23:403–408. Bailey A, Bolton P, Butler L, LeCouteur A, Murphy M, Scott S, Webb T, Rutter M. Prevalence of the fragile X anomaly amongst autistic twins and singletons. J Child Psychol Psychiatry 1993; 34:673–688. Feinstein C, Reiss AL. Autism: the point of view from fragile X studies. J Autism Dev Disord 1998; 28:393–405. Dykens EM, Volkmar FR. Medical conditions associated with autism. In: Cohen DJ, Volkmar FR, eds. Handbook of Autism and Pervasive Developmental Disorders. 2nd ed. New York: Wiley, 1997:388–410. Harrison JE, Bolton PF. Annotation: tuberous sclerosis. J Child Psychol Psychiatry 1997; 38:603–614. Smalley S, Smith M, Tanguay P. Autism and psychiatric disorders in tuberous sclerosis. Ann NY Acad Sci 1991; 615:382–383. Gillberg IC, Gillberg C, Kopp S. Hypothyroidism and autism spectrum disorders. J Child Psychol Psychiatry Allied Disc 1992; 33:531–542. Stromland K, Nordin V, Miller M. Autism in thalidomide embryopathy: a population study. Dev Med Child Neurol 1994; 36:351–356. Nordin V, Gillberg C. Autism spectrum disorders in children with physical or mental disability or both. I. Clinical and epidemiological aspects. Dev Med Child Neurol 1996; 38:297–313. Courchesne E, Townsend J, Saitoh, O. The brain in infantile autism: posterior fossa structures are abnormal. Neurology 1994; 44:214–223. Filipek PA. Quantitative magnetic resonance in autism: the cerebellar vermis. Curr Opin Neurol 1995; 8:134–138. Piven J, Arndt S, Bailey J. An MRI study of brain size in autism. Am J Psychiatry 1995; 152(8):1145–1149. Bachevalier J. Medial temporal lobe structures and autism: a review of clinical and experimental ﬁndings. Neuropsychologia 1994; 32:627–648. Haas RH, Townsend J, Courchesne E. Neurological abnormalities in infant autism. J Child Neurol 1996; 11:84–92. Volkmar FR, Cohen DJ. Neurobiologic aspects of autism. N Engl J Med 1988; 318:1390–1392. Panksepp J, Sahley TL. Possible brain opioid involvement in disrupted social in-

Pervasive Developmental Disorder

70.

71. 72.

73.

74.

75. 76. 77. 78. 79. 80.

81.

82. 83.

84. 85. 86. 87. 88.

129

tent and language development of autism. In: Schopler E, Mesibov GB, eds. Neurobiological Issues in Autism. New York: Plenum, 1987. Bailey A, Phillips W, Rutter M. Autism: towards an integration of clinical, genetic, neuropsychological, and neurobiological perspectives. J Child Psychol Psychiatry 1996; 37:89–126. Lotspeich LJ, Ciaranello RD. The neurobiology and genetics of infantile autism. Int Rev Neurobiol 1993; 35:87–129. Chugani DC, Muzik O, Behen M, Rothermel R, Janisse JJ, Lee J, Chugani HT. Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol 1999; 45(3):287–295. Chugani DC, Muzik O, Rothermel R, Behen M, Chakraborty P, Mangmer T, daSilva EA, Chugani HT. Altered serotonin synthesis in the denta to thalamocortical pathway in autistic boys. Ann Neurol 1997; 42(4):666–669. Wakeﬁeld AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malek M, Berelowitz M, Drillon AP, Thomson MA, Harvey P, Valentine A, Davies SE, Walker-Smith JA. Ideal lymphoid-nodular dysplasia, non-speciﬁc colitis, and pervasive developmental disorder in children. Lancet 1998; 351:637–641. Gillberg C, Heijbel H. MMR and autism. Autism 1998; 2(4):423–424. Shattock P, Lowdon G. Proteins, peptides and autism. Part 2. Brain Dysfunct 1991; 4:323–334. Serussi K. Unraveling the Mysteries of Autism and PDD. NewYork: Simon & Schuster, 2000. Shaw W. Biological Treatments for Autism. 1998. Lewis L. Special Diets for Special Children. Texas: Future Horizons, 1998. Gupta S, Aggarwal S, Heads C. Brief report: dysregulated immune system in children with autism: beneﬁcial effects of intravenous immune globulin on autistic characteristics. J Autism Dev Disord 1996; 26:439–452. Singh VK, Lin, SX, Yang VC. Raid communication: serological association of measles virus and human herpisvirus-6 with brain autoantibodies in autism. Clin Immuol Immunopathol 1998; 89(1):105–108. Kranowitz C. The Out-of-Sync Child. New York: Perigree Books, 1999. Volkmar FR, Kiln A, Siegel B, Szatmari P, Lord C, Campbell M, Freeman BJ, Cicchetti DV, Rutter M, Kline W. Field trial for autistic disorder in DSM-IV. Am J Psychiatry 1994; 151:1361–1367. Lord C, Storoschuk S, Rutter M, Pickles A. Using the ADI-R to diagnose autism in preschool children. Infant Mental Health J 1993; 14:234–252. Gillberg C. Infantile autism: diagnosis and treatment. Acta Psychiatrica Scandinavica 1990; 81:209–215. Glascoe FP. It’s not what it seems: the relationship between parents’ concerns and children with global delays. Clin Pediatr 1994; 33:292–296. Glascoe FP. Parents’ concerns about children’s development: prescreening technique or screening test? Pediatrics 1997; 99:522–528. Glascoe FP. Collaborating with parents: using parental evaluation of developmental status to detect and address developmental and behavioral problems. Nashville: Ellsworth & Vandermeer, 1998.

130 89. 90.

91. 92.

93.

94. 95.

96.

97. 98. 99. 100.

101.

102. 103.

104. 105. 106. 107.

McCarton Glascoe FP, Dworkin PH. The role of parents in the detection of development and behavioral problems. Pediatrics 1995; 95:829–836. Piven J, Gayle J, Chase GA, Fink B, Landa R, Wzorek MM, Folstein SE. A family history study of neuropsychiatric disorders in the adult siblings of autistic individuals. J Am Acad Child Adolesc Psychiatry 1990; 29:177–183. Piven J, Wzorek M, Landa R, Lainhart J, Bolton P, Chase GA, Folstein S. Personality characteristics of the parents of autistic individuals. Psychol Med 1994; 24:783–795. Bolton PF, Murphy M, Macdonald H, Whitlock B, Pickles A, Rutter M. Obstetric complications in autism: consequences or causes of the condition? J Am Acad Child Adolesc Psychiatry 1997; 36:272–281. Fombonne E, Bolton P, Prior J, Jordan H, Rutter M. A family study of autism: cognitive patterns and levels in parents and siblings. J Child Psychol Psychiatry 1997; 38:667–683. Davidovitch M, Patterson B, Gartside P. Head circumference measurements in children with autism. J Child Neurol 1996; 11:389–393. Woodhouse W, Bailey A, Rutter M, Bolton P, Baird G, Couteur A. Head circumference in autism and other invasive developmental disorders. J Child Psychol Psychiatry 1996; 37:665–671. Lainhart JE, Piven J, Wzorek M, Landa R, Santangelo SL, Coon H, Folstein SE. Macrocephaly in children and adults with autism. J Am Acad Child Adolesc Psychiatry 1997; 36:282–290. Fiedler DJ, Bailey JN, Smalley SL. Macrocephaly in autism and other pervasive developmental disorders. Dev Med Child Neurol 2000; 42:737–740. Fombonne E, Roge B, Claverie J, Courty S, Fremolle J. Microcephaly and macrocephaly in Autism. J Autism Dev Disord 1999; 29(2):113–119. Schopler E, Reichler R, Rochen-Renner B. The Childhood Autism Rating Scale (CARS). Los Angeles: Western Psychological Services, 1988. Lord C, Rutter M, Le Couteur A. Autism Diagnostic Interview–Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 1994; 24:659–685. Lord C, Pickles A, McLennan J, Rutter M, Bregman J, Folstein S, Fombonne E, Leboyer M, Minshew N. Diagnosing autism: analyses of data from the Autism Diagnostic Interview. J Autism Dev Disord 1997; 27:501–517. DiLavore PC, Lord C, Rutter M. The pre-linguistic autism diagnostic observation schedule. J Autism Dev Disord 1995; 25:355–379. Lord C. The Autism Diagnostic Observation Schedule–Generic (ADOS-G). Presented at the NIH State of the Science in Autism: Screening and Diagnosis Working Conference, Bethesda, MD, 1998. Minshew NJ, Goldstein G. Autism as a disorder of complex information processing. Ment Retard Dev Disord Res Rev 1998; 4:129–136. Bayley N. Bayley Scales of Infant Development. 2nd ed. San Antonio, TX: Psychological Corp., 1993. Thorndike RL, Hagen EP, Sattler JM. The Stanford-Binet Intelligence Scale. 4th ed. Guide for Administering and Scoring. Chicago: Riverside, 1986. Wechsler Preschool and Primary Scale of Intelligence–Revised (WPPSI). San Antonio, TX: Psychological Corp., 1989.

Pervasive Developmental Disorder 108. 109. 110.

111. 112. 113. 114. 115.

116. 117. 118. 119. 120. 121. 122.

123.

124. 125. 126. 127.

131

Wechsler D. Wechsler Intelligence Scale for Children (WISC-III). San Antonio, TX: Psychological Corp., 1991. Sparrow SS, Balla DA, Cicchetti DV. Adaptive Behavior Scales (Survey Edition). Circle Pines, MN: American Guidance Service, 1984. Klin A, Carter A, Volkmar FR, Cohen DJ, Marans WD, Sparrow S. Developmentally based assessments. In: Cohen DJ, Volkmar FR, eds. Handbook of Autism and Pervasive Developmental Disorders. 2nd ed. New York: Wiley, 1997:411–447. Jure R, Rapin I, Tuchman RF. Hearing-impaired autistic children. Dev Med Child Neurol 1991; 33:1062–1072. Klin A. Auditory brainstem responses in autism: brainstem dysfunction or peripheral hearing loss? J Autism Dev Disord 1993; 23:15–35. Stone WL, Lemanek KL. Parental report of social behaviors in autistic preschoolers. J Autism Dev Disord 1990; 20:513–522. Kientz MA., Dunn W. A comparison of the performance of children with and without autism on the Sensory Proﬁle. Am J Occup Ther 1997; 51:530–537. Wetherby AM, Prizant BM. Proﬁling young children’s communicative competence. In: Warren S, Reichle J, eds. Causes and Affects in Communication and Language Intervention. Baltimore: Paul H. Brookes, 1992. Crais ER. Expanding the repertoire of tools and techniques for assessing the communication skills of infants and toddlers. Am J Speech-Lang Disord 1995; 4:47–59. Rossetti L. Infant-Toddler Language Scale. East Moline, IL: Lingui Systems, 1990. Zimmerman IL, Steiner VG, Pond RE. Preschool Language Scale–3. San Antonio, TX: Psychological Corp., 1992. Semel E, Wiig EH, Secord WA. Clinical Evaluation of Language Fundamentals– 3 Examiner’s Manual. New York: New York Psychological Corp., 1995. Gardner MF. Expressive One-Word Picture Vocabulary Test–Revised. Novato, CA: Academic Therapy Publications, 1990. Gardner MF. Receptive One-Word Picture Vocabulary Test–Revised. Novato, CA: Academic Therapy Publications, 1990. Curry CJ, Stevenson RE, Aughton D, Byrne J, Carey JC, Cassidy S, Cunniff C, Graham JM Jr, Jones MC, Kaback MM, Moeschler J, Schaefer GB, Schwartz S, Tarleton J, Opitz J. Evaluation of mental retardation: recommendations of a Consensus Conference: American College of Medical Genetics. Am J Med Genetics 1997; 72:468–477. Minshew NJ, Sweeney, JA, Bauman ML. Neurologic aspects of autism. In: Cohen DJ, Volkmar FR, eds. Handbook of Autism and Pervasive Developmental Disorders. 2d ed. New York: Wiley, 1997:344–369. Tuchman RF, Rapin I. Regression in pervasive developmental disorders: seizures and epileptiform electroencephalogram correlates. Pediatrics 1997; 99:560–566. Rapin I. Physicians’ testing of children with developmental disabilities. J Child Neurol 1995; 10(suppl):S11–15. Tuchman R, Jayakar P, Yaylali I, Villalobos R. Seizures and EEG ﬁndings in children with autism spectrum disorders. CNS Spectrums 1997; 3:61–70. Rutter M. The treatment of autistic children. J Child Psych Psychiatry Allied Disc 1985; 26:193–214.

132 128. 129.

130. 131. 132. 133.

134.

135.

136. 137. 138. 139. 140.

141. 142. 143. 144. 145. 146. 147.

McCarton Lovaas OI. The development of a treatment-research project for developmentally disabled and autistic children. J Applied Behav Analysis 1993; 26(4):617–630. Smith T, Groen AD, Wynn JW. Randomized trial of intensive early intervention for children with pervasive developmental disorder. Am J Ment Retard 2000; 105(4):269–285. Sheinkopf SJ, Siegel B. Home-based behavioral treatment of young children with autism. J Autism Dev Disord 1998; 28(1):15–23. Ayres J. Sensory integration and the child. Los Angeles: Western Psychological Services,1979. Trot M, Laurel M, Windeck S. Sense Abilities. San Antonio, TX: Therapy Skills, 1993. Handen BL, Johnson CR, Lubetsky M. Efﬁcacy of methylphenidate among children with autism and symptoms of attention deﬁcit-hyperactivity disorder. J Autism Dev Disord 2000; 30(3):245–255. Quintana H, Birmaher B, Stedge D, Lennon S, Freed J, Bridge J, Greenhill L. Use of methylphenidate in the treatment of children with autistic disorder. J Autism Dev Disord 1995; 25:283–294. Aman MG, Marks RE, Turbott S. Methylphenidate and thioridazine in the treatment of intellectually subaverage children: effects on cognitive-motor performance. J Am Acad Child Adolesc Psychiatry 1991; 30(5):816–824. Hering E, Epstein R, Elroy S, Iancu DR, Zelnik N. Sleep patterns in autistic children. J Autism Dev Disord 1999; 29(2):143–147. Horrigan JP, Barnhill LJ. Risperidone and explosive aggressive autism. J Autism Dev Disord 1997; 27(3):313–323. Schreier HA. Risperidone for young children with mood disorders and aggressive behavior. J Child Adolesc Psychopharmacol 1998; 8(1):49–59. Reichelt K, Knivsberg AM, Lind G, Nodland M. Probable etiology and possible treatment of childhood autism. Brain Dysfunct 1991; 4:308–319. Findling RL, Maxwell K, Szotese-Wojtila L, Huang J, Yamashita T, Wiznitzer M. High dose pyroxidene and magnesium administration in children with autistic disorder: an absence of salutary effects in a double-blind, placebo-controlled study. J Autism Dev Disord 1997; 27 (4):467–478. Stehli A. The Sound of a Miracle: A Child’s Triumph over Autism. New York: Doubleday, 1991. Edelson S, Rimland B. The effects of auditory integration training on autism. Am J Speech-Lang Pathol 1994; 3(2):16–24. Betteson S. The long-term effects of auditory training on children with autism. J Autism Dev Disord 1996; 26(3):361–374. Alvin J, Warwick A. Music Therapy for the Autistic Child. New York: Oxford University Press, 1991. Upledger JE. Craniosacral function in brain dysfunction. Osteopath Ann 1983; 11(7):318–324. Upledger JE, Vredevoogd JD. Craniosacral Therapy. Seattle: Eastland Press, 1983. DelGiudice-Ash, G, Simon L, Schneidler J, Cunningham-Rundles C, Hollander E. Brief report: a pilot open clinical trial of intravenous immunoglobulin in childhood autism. J Autism Dev Disord 1999; 29(2):157–160.

7 Molecular Genetics of Autism Jennifer G. Reichert, Mario Kilifarski, Irina Bespalova, Nicolas Ramoz, and Joseph D. Buxbaum Mount Sinai School of Medicine New York, New York, U.S.A.

INTRODUCTION Autism is a pervasive developmental disorder (PDD) characterized by communication 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 features of autism. Concordance for the broader phenotype of autism for DZ twins 133

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is considerably lower than the concordance for MZ twins: 10% and 92%, respectively (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 modeling 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 abnormalities 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, translocations, inversions, and aneuploidies, account for a small, but signiﬁcant, percent of the total incidence of autism. However, studying the location of these abnormalities 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 microdeletion, 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 duplicated 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 syndromes, 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 maternally inherited duplications, either pseudodicentric 15 or other atypical marker

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chromosomes with one or two extra copies of the area corresponding to the Angelman/Prader-Willi critical region. These patients usually have mental retardation (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 phenotypespeciﬁc variants in a mutation screening of 27 unrelated autistic individuals suggested 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 disorder, 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-

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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 (GABAA) receptor cluster—which has been implicated in epilepsy, as well as PraderWilli 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 linkage 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, although 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 autism. They tested a set of 80 families using ﬁve markers (69CA, 155CA-1, 155CA2, 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

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Table 1 Summary of Published Results for GABRB3 155CA-2 Study (Ref.) Cook et al., 1998 (45) Maestrini et al., 1999 (51) (transmissions to all affected) Maestrini et al., 1999 (51) (transmissions to a single affected) Salmon et al., 1999 (52) Martin et al., 2000 (54) Nurmi et al., 2001 (27) Buxbaum et al., 2001 (53)

Number of families

MTDT

df

p

138 99

28.63 17.21 a

10 10 a

0.0014 0.070a

99

13.79 b

9b

139 123 94 80

17.57 d — — 27.67

11 d — — 9

0.13b 0.092c 0.73d 0.71e 0.0011

a

Derived from Ref. 51, Table 2, pooling alleles 3 and 11. 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. b

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 suggested 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 singleton 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.

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A recent genome scan indicated 6q21 as a candidate region for an autismsusceptibility 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, performed with one affected proband per family, showed signiﬁcant maternal transmission 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 cortex, hippocampus, and several brainstem nuclei. Persico et al. (59) performed family-based analyses and case-control studies, which showed a signiﬁcant association 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 between 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 hindbrain development, exhibit phenotypic features that are often observed in autism. Sequencing of these two genes in patients with autism and autism spectrum disorders (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

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expectation. Analysis of the HOXB1 locus did not reveal any statistically signiﬁcant 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, identiﬁed 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

Chromosome

Position (cM)

Nearest marker

MSL

1p 2q 3 4p 4q 4q 5p 6q 7p 7q 7q 8q 9 10p 10q 11q 13q 14q 15q 15q 16p 16q 17p 18q 19q 22q Xq

4.8

D4S412

D7S2533 D7S530

3.63 2.53

51.9

D10S197

1.36

85.0 32.2

D13S193 D14S70

0.59 0.99

17.3

D16S407

1.51

D19S49 D22S264

Position (cM)

Nearest marker

Stanford (139 families)c

MLS

192

D2S364

0.64

199

D4S1535

0.88

5 109

D5S417 D6S283

0.84 2.23

Position (cM)

Nearest marker

MLS

149

D1S1675

2.15

42 147.2 138

D7S2564 D7S684 D7S1804

1.01 0.62 0.93

55

D13S800

0.68

11 100

D17S1876 D18S878

1.21 1.00

1.55

140.5 144.7

48.2 5.0

PARISS (51 families)b

0.99 1.39

125

D7S486

0.83

167

D10S217

0.84

32 21

D15S118 D16S3075

1.10 0.74

94 41

D18S68 D19S226

0.62 1.37

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Table 2 (Continued) CLSA (75 families)d

Chromosome 1p 2q 2q 3 4p 4q 4q 5p 6q 7p 7q 7q 8q 9 10p 10q 11q 13q 14q 15q 15q 16p 16q 17p 18q 19q 22q Xq

Position

Nearest

(cM)

marker

SARC (35 families)e

IMGSAC 2001 (152 sib-pairs)f

Position Nearest Multipoint HLOD HLOD Position MLS

72.5 167.6

D4S3248 D4S2368

1.33 1.52

104 150 60.3

D7S1813 D7S1824 D8S1477

2.20 0.80 1.02

147.8 55

D11S968 D13S800

1.22 3.00

13.1 32

D15S975 ACTC

0.50 0.54

100.4

D16S516

1.03

Nearest

Multipoint

(cM)

marker

NPL

(dom)

(rec)

(cM)

marker

MLS

186.2 204.5

D2S364 D2S325

2.45 1.52

2.25 0.67

1.65 0.65

206.4

D2S2188

3.74

119.6

D7S477

3.2

D16S3102

2.93

23.1

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.

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Table 2 (Continued) Columbia (110 families)g

Chromosome

Duke 2002 (99 families)h

Alarcon et al. (152 families)I

Position

Nearest

Multipoint

Position

Nearest

Multipoint

Position

Nearest

Z-score

(cM)

marker

MLS

(cM)

marker

MLS

(cM)

marker

(HE LOD)

198 36

D2S116 D3S3680

2.86 1.51

145

D7S495

1.66

152

D7S1824

2.85 (0.84)

1p 2q 3 4p 4q 4q 5p 6q 7p 7q 7q 8q 9 10p 10q 11q 13q 14q 15q 15q 16q 16q 17p 18q 19q 22q Xq

45

D5S2494

2.55 Broad

123 165 134

D7S523 D7S483 D8S1179

1.02 2.13 1.66 Broad

28

D16S2619

1.91 Narrow

52

D19S433

2.46 Narrow

60

D19S425

1.21

82

DXS1047

2.67 Narrow

63

DXS6789

2.49

a

IMGSAC, 1998 (50). 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). b

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

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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 5cM marker grid. Two regions of association were identiﬁed using linkage disequilibrium mapping. One region underlies the peak of linkage and the other is 27 cM distal. Recently, IMGSAC completed another linkage analysis study with additional 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) reported 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 regions 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-

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stage genome-wide screen. In the ﬁrst stage, 416 microsatellite markers were genotyped to 75 families. Their most signiﬁcant results were for regions on chromosomes 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 chromosomes 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 disorder) and narrower (autism only) diagnosis schemes. Under the broad diagnosis, the most signiﬁcant region was at marker D5S2494 (MLS ⫽ 2.55). Other signiﬁcant 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 genome-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 chromosome 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 contribution 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-

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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 satellite 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 second 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 impairment (SLI), and autism have had signiﬁcant linkage results on chromosome 7q31. Although the two syndromes are diagnostically distinct, they overlap phenotypically (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

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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 strongest 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 heterogeneity. 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 homogeneity, 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 increased 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 susceptibility loci by increasing power.

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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 markers 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 affected 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 deletions and translocations, indicates a susceptibility gene for autism on chromosome 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, broadening the deﬁnition of affected to include subthreshold cases may also increase power. REFERENCES 1. 2.

3. 4.

5.

6.

Rutter M. Routes from research to clinical practice in child psychiatry: retrospect and prospect. J Child Psychol Psychiatry 1998; 39(6):805–816. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, Rutter M. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995; 25(1):63–77. Folstein S, Rutter M. Infantile autism: a genetic study of 21 twin pairs. J Child Psychol Psychiatry Allied Disc 1977; 18:297–321. Ritvo ER, Freeman BJ, Mason-Brotheres A, Mo A, Ritvo AM. Concordance for the syndrome of autism in 40 pairs of afﬂicted twins. Am J Psychiatry 1985; 142: 74–77. Steffenburg S, Gillberg C, Hellgren L, Andersson L, Gillberg IC, Jakobsson G, Bohman M. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry 1989; 30:405–416. Bolton P, Macdonald H, Pickles A, Rios P, Goode S, Crowson M, Bailey A, Rutter M. A case-control family history study of autism. J Child Psychol Psychiatry Allied Disc 1994; 35(5):877–900.

Molecular Genetics 7. 8. 9. 10. 11. 12.

13. 14.

15.

16.

17.

18.

19. 20.

21.

22. 23.

147

Szatmari P, Jones MB, Zwaigenbaum L, MacLean JE. Genetics of autism: overview and new directions. J Autism Dev Disord 1998; 28(5):351–368. Rutter M, Silberg J, O’Connor T, Simonoff E. Genetics and child psychiatry. II. Empirical research ﬁndings. J Child Psychol Psychiatry 1999; 40(1):19–55. Fombonne E. The epidemiology of autism: a review. Psychol Med 1999; 29:769– 786. Folstein S. Twin and adoption studies in child and adolescent psychiatric disorders. Curr Opin Pediatr 1996; 8:339–347. Bailey A, Palferman S, Heavey L, Le Couteur A. Autism: the phenotype in relatives. J Autism Dev Disord 1998; 28(5):369–392. Pickles A, Bolton P, Macdonald H, Bailey A, Le Couteur A, Sim CH, Rutter M. Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism. Am J Hum Genet 1995; 57:717–726. Pritchard JK. Are rare variants responsible for susceptibility to complex diseases? Am J Hum Genet. 2001 Jul;69(1):124–37. Flejter WL, Bennett-Baker PE, Ghaziuddin M, McDonald M, Sheldon S, Gorski JL. Cytogenetic and molecular analysis of inv dup(15) chromosomes observed in two patients with autistic disorder and mental retardation. Am J Hum Genet 1996; 61:182–187. Cook EH Jr, Lindgren V, Leventhal BL, Courchesne R, Lincoln A, Shulman C, Lord C, Courchesne E. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet 1997; 60:928–934. Gurrieri F, Battaglia A, Torrisi L, Tancredi R, Cavallaro C, Sangiorgi E, Neri G. Pervasive developmental disorder and epilepsy due to maternally derived duplication of 15q11-q13. Neurology 1999; 52(8):1694–1697. Repetto GM, White LM, Bader PJ, Johnson D, Knoll JH. Interstitial duplications of chromosome region 15q11q13: clinical and molecular characterization. Am J Med Genet 1998; 79(2):82–89. Schroer RJ, Phelan MC, Michaelis RC, Crawford EC, Skinner SA, Cuccaro M, Simensen RJ, Bishop J, Skinner C, Fender D, Stevenson RE. Autism and maternally derived aberrations of chromosome 15q. Am J Med Genet 1998; 76(4):327–336. Wassink TH, Piven J, Shefﬁeld VC, Folstein SE, Haines JL, Patil SR. Chromosomal abnormalities in autism. Am J Hum Genet 1999; 65(suppl):A362. Sutcliffe JS, Nurmi EL, Haines JL, Piven J, Folstein SE. A potential autism susceptibility marker on chromosome 15 includes a genomic deletion at D15S822. Am J Hum Genet 1999; 65(suppl):A107. Christian SL, Fantes JA, Mewborn SK, Huang B, Ledbetter DH. Large genomic duplicons map to sites of instability in the PraderWilli/Angelman syndrome chromosome region (15q11-q13). Hum Mol Genet 1999; 8:1025–1037. Steffenburg S, Gillberg CL, Steffenburg U, Kyllerman M. Autism in Angelman syndrome: a population-based study. Pediatr Neurol 1996; 14(2):131–136. Wolpert CM, Menold MM, Bass MP, Qumsiyeh MB, Donnelly SL, Ravan SA, Vance JM, Gilbert JR, Abramson RK, Wright HH, Cuccaro ML, Pericak-Vance MA. Three probands with autistic disorder and isodicentric chromosome 15. Am J Med Genet 2000; 96(3):365–372.

148

Reichert et al.

24.

Weidmer-Mikhail E, Sheldon S, Ghaziuddin M. Chromosomes in autism and related pervasive developmental disorders: a cytogenetic study. J Intellect Disabil Res 1998; 42(Pt 1):8–12. Webb T. Inv dup(15) supernumerary marker chromosomes. J Med Genet 1994; 31: 585–594. Smith M, Filipek PA, Wu C, Bocian M, Hakim S, Modahl C, Spence MA. Analysis of a 1-megabase deletion in 15q22-q23 in an autistic patient: identiﬁcation of candidate genes for autism and of homologous DNA segments in 15q22q23 and 15q11q13. Am J Med Genet 2000; 96(6):765–770. Nurmi EL, Bradford Y, Chen Y, Hall J, Arnone B, Gardiner MB, Hutcheson HB, Gilbert JR, Pericak-Vance MA, Copeland-Yates SA, Michaelis RC, Wassink TH, Santangelo SL, Shefﬁeld VC, Piven J, Folstein SE, Haines JL, Sutcliffe JS. Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families. Genomics 2001; 77(1–2):105–113. Yu CE, Dawson G, Munson J, D’Souza I, Osterling J, Estes A, Leutenegger AL, Flodman P, Smith M, Raskind WH, Spence MA, McMahon W, Wijsman EM, Schellenberg GD. Presence of large deletions in kindreds with autism. Am J Hum Genet 2002; 71(1):100–115. Barrett S, Beck JC, Bernier R, Bisson E, Braun TA, Casavant TL, Childress D, Folstein SE, Garcia M, Gardiner MB, Gilman S, Haines JL, Hopkins K, Landa R, Meyer NH, Mullane JA, Nishimura DY, Palmer P, Piven J, Purdy J, Santangelo SL, Searby C, Shefﬁeld V, Singleton J, Slager S, et al. An autosomal genomic screen for autism: collaborative linkage study of autism. Am J Med Genet 1999; 88(6):609–615. IMGSAC. A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet 2001; 69(3):570–581. Ashley-Koch A, Wolpert CM, Menold MM, Zaeem L, Basu S, Donnelly SL, Ravan SA, Powell CM, Qumsiyeh MB, Aylsworth AS, Vance JM, Gilbert JR, Wright HH, Abramson RK, DeLong GR, Cuccaro ML, Pericak-Vance MA. Genetic studies of autistic disorder and chromosome 7. Genomics 1999; 61(3):227–236. Yan WL, Guan XY, Green ED, Nicolson R, Yap TK, Zhang J, Jacobsen LK, Krasnewich DM, Kumra S, Lenane MC, Gochman P, Damschroder-Williams PJ, Esterling LE, Long RT, Martin BM, Sidransky E, Rapoport JL, Ginns EI. Childhoodonset schizophrenia/autistic disorder and t(1;7) reciprocal translocation: identiﬁcation of a BAC contig spanning the translocation breakpoint at 7q21. Am J Med Genet 2000; 96(6):749–753. Tentler D, Brandberg G, Betancur C, Gillberg C, Anneren G, Orsmark C, Green ED, Carlsson B, Dahl N. A balanced reciprocal translocation t(5;7)(q14;q32) associated with autistic disorder: molecular analysis of the chromosome 7 breakpoint. Am J Med Genet 2001; 105(8):729–736. Warburton P, Baird G, Chen W, Morris K, Jacobs BW, Hodgson S, Docherty Z. Support for linkage of autism and speciﬁc language impairment to 7q3 from two chromosome rearrangements involving band 7q31. Am J Med Genet 2000; 96(2): 228–234. Vincent JB, Herbrick J, Gurling HMD, Bolton PF, Roberts W, Scherer SW. Identiﬁcation of a novel gene on chromosome 7q31 that is interrupted by a translocation breakpoint in an autistic individual. Am J Hum Genet 2000; 7:510–514.

25. 26.

27.

28.

29.

30. 31.

32.

33.

34.

35.

Molecular Genetics 36.

37.

38.

39.

40.

41. 42.

43.

44. 45.

46.

47.

48.

149

Lai CSL, Fisher SE, Hurst JA, Levy ER, Hodgson S, Fox M, Jeremiah S, Povey S, Jamison C, Green ED, Vargha-Khadem F, Monaco AP. The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder. Am J Hum Genet 2000; 67:357–368. Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 2001; 413(6855): 519–523. Newbury DF, Bonora E, Lamb JA, Fisher SE, Lai CS, Baird G, Jannoun L, Slonims V, Stott CM, Merricks MJ, Bolton PF, Bailey AJ, Monaco AP. FOXP2 is not a major susceptibility gene for autism or speciﬁc language impairment. Am J Hum Genet 2002; 70(5):1318–1327. Goizet C, Excofﬁer E, Taine L, Taupiac E, El Moneim AA, Arveiler B, Bouvard M, Lacombe D. Case with autistic syndrome and chromosome 22q13.3 deletion detected by FISH. Am J Med Genet 2000; 96(6):839–844. Sukumar S, Wang S, Hoang K, Vanchiere CM, England K, Fick R, Pagon B, Reddy KS. Subtle overlapping deletions in the terminal region of chromosome 6q24.2q26: three cases studied using FISH. Am J Med Genet 1999; 87(1):17–22. Thomas NS, Sharp AJ, Browne CE, Skuse D, Hardie C, Dennis NR. Xp deletions associated with autism in three females. Hum Genet 1999; 104(1):43–48. Monaghan KG, Van Dyke DL, Wiktor A, Feldman GL. Cytogenetic and clinical ﬁndings in a patient with a deletion of 16q23.1: ﬁrst report of bilateral cataracts and a 16q deletion. Am J Med Genet 1997; 73(2):180–183. Smith M, Escamilla JR, Filipek P, Bocian ME, Modahl C, Flodman P, Spence MA. Molecular genetic delineation of 2q37.3 deletion in autism and osteodystrophy: report of a case and of new markers for deletion screening by PCR. Cytogenet Cell Genet 2001; 94(1–2):15–22. Ghaziuddin M, Burmeister M. Deletion of chromosome 2q37 and autism: a distinct subtype? J Autism Dev Disord. 1999; 29(3):259–263. Cook EH Jr, Courchesne RY, Cox NJ, Lord C, Gonen D, Guter SJ, Lincoln A, Nix K, Haas R, Leventhal BL, Courchesne E. Linkage-disequilibrium mapping of autistic disorder, with 15q11-13 markers. Am J Hum Genet 1998; 62:1077–1083. Philippe A, Martinez M, Guilloud-Bataille M, Gillberg C, Rastam M, Sponheim E, Coleman M, Zappella M, Aschauer H, Van Maldergem L, Penet C, Feingold J, Brice A, Leboyer M, van Malldergerme L. Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study. Hum Mol Genet 1999; 8:805–812. Bass MP, Menold MM, Wolpert CM, Donnelly SL, Ravan SA, Hauser ER, Maddox LO, Vance JM, Abramson RK, Wright HH, Gilbert JR, Cuccaro ML, DeLong GR, Pericak-Vance MA. Genetic studies in autistic disorder and chromosome 15. Neurogenetics 2000; 2(4):219–226. Martin ER, Menold MM, Wolpert CM, Bass MP, Donnelly SL, Ravan SA, Zimmerman A, Gilbert JR, Vance JM, Maddox LO, Wright HH, Abramson RK, Delong GR, Cuccaro ML, Pericak-Vance MA. Analysis of linkage disequilibrium in gammaaminobutyric acid receptor subunit genes in autistic disorder. Am J Med Genet 2000; 96:43–48.

150

Reichert et al.

49.

Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J, Kalaydjieva L, McCague P, Dimiceli S, Pitts T, Nguyen L, Yang J, Harper C, Thorpe D, Vermeer S, Young H, Hebert J, Lin A, Ferguson J, Chiotti C, Wiese-Slater S, Rogers T, Salmon B, Nicholas P, Myers RM, et al. A genomic screen of autism: evidence for a multilocus etiology. Am J Hum Genet 1999; 65(2):493–507. International Molecular Genetic Study of Autism Consortium (IMGSAC). A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Hum Mol Genet 1998; 7:571–578. Maestrini E, Lai C, Marlow A, Matthews N, Wallace S, Bailey A, Cook EH, Weeks DE, Monaco AP. International Molecular Genetic Study of Autism Consortium (IMGSAC). Serotonin transporter (5-HTT) and gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSAC families. Am J Med Genet 1999; 88:492–496. Salmon B, Hallmeyer J, Rogers T, Kalaydjieva L, Peterson PB, Nicholas P, Pingree C, McMahon W, Spiker D, Lotspeich, L, Kraemer H, McCague P, Dimiceli S, Nouri N, Pitts T, Yang J, Hinds D, Myers RM, Risch N. Absence of linkage and linkage disequilibrium to chromosome 15q11-q13 markers in 139 multiplex families with autism. Am J Med Genet (Neuropsych Genet) 1999; 88:551–556. Buxbaum JD, Silverman JM, Smith CJ, Greenberg DA, Kilifarski M, Reichert J, Cook EH Jr, Fang Y, Song CY, Vitale R. Association between a GABRB3 polymorphism and autism. Mol Psychiatry 2002; 7(3):311–316. Martin ER, Kaplan NL, Weir BS. Tests for linkage and association in nuclear families. Am J Hum Genet 1997; 61:439–448. Cook EH Jr, Courchesne R, Lord C, Cox NJ, Yan S, Lincoln A, Haas R, Courchesne E, Leventhal BL. Evidence of linkage between the serotonin transporter and autistic disorder. Mol Psychiatry 1997; 2:247–250. Klauck SM, Poustka F, Benner A, Lesch KP, Poustka A. Serotonin transporter (5-HTT) gene variants associated with autism? Hum Mol Genet 1997; 6:2233– 2238. Kim SJ, Cox N, Courchesne R, Lord C, Corsello C, Akshoomoff N, Guter S, Leventhal BL, Courchesne E, Cook Jr EH. Transmission disequilibrium mapping at the serotonin transporter gene (SLC6A4) region in autistic disorder. Mol Psychiatry 2002; 7(3):278–288. Jamain S, Betancur C, Quach H, Philippe A, Fellous M, Giros B, Gillberg C, Leboyer M, Bourgeron T. Linkage and association of the glutamate receptor 6 gene with autism. Mol Psychiatry 2002; 7(3):302–310. Persico AM, D’Agruma L, Maiorano N, Totaro A, Militerni R, Bravaccio C, Wassink TH, Schneider C, Melmed R, Trillo S, Montecchi F, Palermo M, Pascucci T, Puglisi-Allegra S, Reichelt KL, Conciatori M, Marino R, Quattrocchi CC, Baldi A, Zelante L, Gasparini P, Keller F. Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol Psychiatry 2001; 6(2):150–159. Wassink TH, Piven J, Vieland VJ, Huang J, Swiderski RE, Pietila J, Braun T, Beck G, Folstein SE, Haines JL, Shefﬁeld VC. Evidence supporting WNT2 as an autism susceptibility gene. Am J Med Genet 2001; 105(5):406–413. McCoy PA, Shao Y, Wolpert CM, Donnelly SL, Ashley-Koch A, Abel HL, Ravan SA, Abramson RK, Wright HH, DeLong GR, Cuccaro ML, Gilbert JR, Pericak-

50.

51.

52.

53.

54. 55.

56.

57.

58.

59.

60.

61.

Molecular Genetics

62.

63.

64.

65.

66.

67.

68. 69. 70. 71.

72.

151

Vance MA. No association between the WNT2 gene and autistic disorder. Am J Med Genet 2002; 114(1):106–109. Ingram JL, Stodgell CJ, Hyman SL, Figlewicz DA, Weitkamp LR, Rodier PM. Discovery of allelic variants of HOXA1 and HOXB1: genetic susceptibility to autism spectrum disorders. Teratology 2000; 62(6):393–405. Li J, Tabor HK, Nguyen L, Gleason C, Lotspeich LJ, Spiker D, Risch N, Myers RM. Lack of association between HoxA1 and HoxB1 gene variants and autism in 110 multiplex families. Am J Med Genet 2002; 114(1):24–30. Liu J, Nyholt DR, Magnussen P, Parano E, Pavone P, Geschwind D, Lord C, Iversen P, Hoh J, Ott J, Gilliam TC. A genomewide screen for autism susceptibility loci. Am J Hum Genet 2001; 69(2):327–340. Shao Y, Wolpert CM, Raiford KL, Menold MM, Donnelly SL, Ravan SA, Bass MP, McClain C, von Wendt L, Vance JM, Abramson RH, Wright HH, AshleyKoch A, Gilbert JR, DeLong RG, Cuccaro ML, Pericak-Vance MA. Genomic screen and follow-up analysis for autistic disorder. Am J Med Genet 2002; 114(1):99– 105. IMGSAC. Search for autism susceptibility loci: genome screen follow-up and ﬁne mapping of a candidate region on chromosome 7q [abstr]. Am J Hum Genet 1999; 65(suppl):A106 (560). Buxbaum JD, Silverman JM, Smith CJ, Kilifarski M, Reichert J, Hollander E, Lawlor BA, Fitzgerald M, Greenberg DA, Davis KL. Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity. Am J Hum Genet 2001; 68(6):1514–1520. IMGSAC. Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q. Hum Mol Genet 2001; 10(9):973–982. Folstein S, Mankoski R. Chromosome 7q: where autism meets language disorder? Am J Hum Genet 2000; 67:278–281. Folstein S. Autism. Int Rev Psychiatry 1999; 11:269–277. Alarcon M, Cantor RM, Liu J, Gilliam TC, Geschwind DH. Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families. Am J Hum Genet 2002; 70(1):60–71. Shao Y, Raiford KL, Wolpert CM, Cope HA, Ravan SA, Ashley-Koch AA, Abramson RK, Wright HH, DeLong RG, Gilbert JR, Cuccaro ML, Pericak-Vance MA. Phenotypic homogeneity provides increased support for linkage on chromosome 2 in autistic disorder. Am J Hum Genet 2002; 70(4):1058–1061.

8 Immune Dysfunction in Autism Gina DelGiudice Mount Sinai School of Medicine and Hospital for Special Surgery New York, New York, U.S.A.

Eric Hollander Mount Sinai School of Medicine New York, New York, U.S.A.

INTRODUCTION Cellular and humoral immune dysfunction, complement deﬁciencies, abnormal antibody production, and abnormal cytokine levels have been documented in autistic 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

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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 nonautistic 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 disorders 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 disorder, 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 hippocampus 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 tomography (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/periamygdaloid cortex, left middle temporal gyrus, and cerebelleum. Levitt et al. (16) found that the area of cerebellar vermis lobules VIII–X was smaller in

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eight autistic children compared with 21 healthy children. A study using highresolution 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 synthesis in autistic boys (20,21). Functional MRI studies of individuals with autism have demonstrated abnormal activation of certain brain regions during neuropsychological 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 ﬂuoxetine (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 autistic 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 wholeblood 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 erythematosus, 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 syndromes. 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. Immune cells have evolved to provide a specialized and efﬁcient defense mechanism

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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 peripheral 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 immune 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 phagocytized 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 lymphocytes. Their speciﬁcity is controlled by antigen receptors on their surface, the Tcell 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 interferongamma (IFN-γ), whereas others secrete down-regulating cytokines such as interleukin-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 immunoregulatory role. When appropriately stimulated, suppressor T cells negatively in-

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ﬂuence the responses of other lymphocytes and “turn off ” the immune response. A cytotoxic response requiring no induction with antigen is termed natural cytotoxicity. 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, antibody-dependent cell-mediated cytotoxicity (ADCC), and the release of inﬂammatory mediators. IgM is the initial isotype elaborated in response to primary antigen exposure and represents the ﬁrst antibody class synthesized by the neonate. IgG is the predominant antibody class in serum, accounting for approximately 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 involving other plasma proteins, such as the complement components. The complement system consists of at least 30 proteins and following activation results in cell lysis, increased vascular permeability, leukocyte chemotaxis, and viral neutralization (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 pathogenic 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 molecules. Class I MHC molecules are expressed on the surface of nearly every nucleated 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, HLADQ, 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).

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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 peripheral 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 increase 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 intolerance hypothesis, and a neuropeptide hypothesis. In addition, we examine preliminary 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 exposure 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 cerebrospinal ﬂuid in autistic patients. Investigators have postulated that immunopathological 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

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groups have identiﬁed more peripheral B cells expressing D8/17 in children with obsessive-compulsive disorder (OCD) (46,47). The results suggest that monoclonal 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 signiﬁcantly 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 autoaggressive. Studies have focused on cellular elements of the immune system: 1. 2. 3. 4.

Phagocytic cells Cytokines and complement system T cells 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 cytotoxicity 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 central 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 susceptibility of individuals with a deﬁciency of complement components to infectious and autoimmune illnesses because of defective clearance of antigen–antibody 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 infections (32).

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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 interleukin-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 signiﬁcantly 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 performed 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 unstimulated blood samples. A percentage of lymphocytes from autistic subjects expressed bound IL-2 receptor following mitogenic stimulation. The authors hypothesize 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 immunoregulatory mechanisms on a cellular level. Elevated plasma concentrations of IL-12 and IFN-γ have been demonstrated 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 provides 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 hypothesis that the presence of relative T-cell-mediated deﬁciency may be of importance in the etiology of autism, mitogen-induced proliferation of T lymphocytes was studied in 12 autistic subjects and 13 healthy controls (52). Phytohemagglutinin (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 studies suggest a relative T-cell defect in a subgroup of autistic subjects. In contrast,

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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 helperinducer 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 system. Overall, T-cell abnormalities described in autistic subjects are both quantitative 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 contradictory results. Some studies have found no increase in immunoglobulin levels in serum or cerebrospinal ﬂuid of autistic subjects (56,57), while others have documented elevated immunoglobulin levels in the sera of autistic patients (55). Warren 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 genitourinary barriers. This suggests that IgA deﬁciency might dictate a different response 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 involved in the pathogenesis of autism. They described circulating antibodies di-

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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 antibodymediated, antibrain response in autism. Only the frontal cortex was used as a source of antigens; other brain areas might provide different results. Also, antibody titers were measured after the syndrome was established and does not eliminate the role of antibodies during development or prior to the expression of autistic 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 control 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 compared with 9% of controls. These antibodies might represent an epiphenomenon 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 increased incidence of serum IgG and IgM antibodies directed to cerebellar neuroﬁlaments, 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 lobules 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 replicated with IgG antibodies detected to NAFP and glial ﬁbrillary acidic protein (GFAP) in autistic subjects. Autoantibodies to NAFP are prevalent in pathological states: Jakob-Creutzfeldt disease, Alzheimer’s disease, and amyotrophic lateral 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 contribute 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

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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 pathogenesis of language, social development, and structural and behavioral abnormalities 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 suggested 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 antigens may underlie immune abnormalities in autism through a mechanism of immunological 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 aberrant maternal immune response to fetal antigens also expressed on the father’s lymphocytes. Six of 11 mothers (54%) with an autistic child exhibited a signiﬁcantly 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 lymphocytes 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 reactivity to lymphocytes was reported, the autistic child had a normally developing older sibling. In this study, family composition, birth order, and other demographics 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.

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A Neuropeptide Hypothesis Nelson et al. (72) examined biological regulators of cerebral development in autism 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 neurotrophin nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophic 3 (NT3), and neurotrophin 415 (NT415) were measured using immunoafﬁnity 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 further study.

AUTISM AND IMMUNOMODULATORY THERAPY The current treatment of choice for autism is early psychoeducational intervention, 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. Serotonergic 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 immune and inﬂammatory response, have been cited in the literature. Intravenous immunoglobulin (IVIG) has been used to treat antibody-deﬁcient states and inﬂammatory disorders (e.g., Guillain-Barre´, multiple sclerosis) (74). Immunoglobulins, as described earlier, are the products of mature B cells. Immunoglobulin products for intravenous use are prepared so they contain few molecules of immunoglobulin other than IgG. The manipulative effects of IgG on the immune system 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 reticuloendothelial cells were satiated by intravenously administered immunoglobulin, vulnerable 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

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reported marked improvements in communication and autistic behaviors based on clinical observation (75). No attention was paid to whether patients were receiving 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 YaleBrown Obsessive Compulsive Scale (C-YBOCS) (78,79), the Clinical Global Impression Scale for Autistic Disorder (CGI-AD) (80), and the Autism Modiﬁcation 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 proinﬂammatory 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 histological 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 subjects. Pentoxifylline was ﬁrst used experimentally in a patient with autism suspected 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 measures 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 genital 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,

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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 relatedness and language skills in three children with autism (93). Three doubleblind placebo-controlled studies of single-dose intravenous secretin have been conducted. Owley et al. (94) studied 20 children with autistic disorder in a crossover 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 children. 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 subjects. 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 parkinsonism 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 antibiotic 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 antibiotic resistance. CONCLUSIONS Only in the past decade has it become accepted that autism is a biological disorder. Recent research in the areas of genetics, neuroimaging, neurochemistry, and

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pharmacological treatment of autism has advanced the knowledge about the pathophysiology of autism. There is reason to believe that an immune pathogenesis 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 sensitive and speciﬁc immunological techniques, neuroimmunological research may yield more meaningful results for understanding developmental psychopathology. As for future research, linking immune abnormalities to particular symptoms of autism, rather than the syndrome itself, could provide a more precise description. 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 Research 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. REFERENCES 1. 2.

3.

4.

5.

6.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Press, 1994. Dunn M. Neurophysiologic observations in autism and implications for neurologic dysfunction. In: Bauman ML, Kemper TL, eds. The Neurobiology of Autism. Baltimore: Johns Hopkins University Press, 1994:45–65. Spiker D, Lotspeich L, Kraemer HC, Hallmayer J, McMahon W, Petersen PB, Nicholas P, Pingree C, Wiese-Slater S, Chiotti C, Wong DL, Dimicelli S, Ritvo E, Cavalli-Sforza LL, Ciananello RD. Genetics of autism: characteristics of affected and unaffected children from 37 multiplex families. Am J Med Genet 1994; 54:27–35. Bailey A, LeCouteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, Rutter M. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995; 2S:63–78. Jorde L, Hasstedt S, Ritvo E, Mason-Brothers A, Freeman B, Pongree C, McMahon W, Peterson B, Jenson W, Moll A. Complex segregation analysis of autism. Am J Hum Genet 1991; 49:932–938. Ritvo E, Jorde L, Mason-Brothers A, Freeman B, Pingree C, Johes M, McMahon W, Petersen P, Jenson W, Mo A. The UCLA–University of Utah epidemiologic survey of autism: recurrence risk estimates and genetic counseling. Am J Psychiatry 1989; 146:1032–1036.

168 7.

8.

9.

10.

11.

12.

13. 14. 15.

16.

17. 18.

19.

20.

21.

22.

DelGiudice and Hollander Piven J, Palmer P, Jacobi D, Childess D, Arndt S. Broader autism phenotype: evidence from a family history study of multiple incidence autistic families. Am J Psychiatry 1997; 154:185–190. Fornbonne E, Bolton P, Prior J, Jordan H, Rutter M. A family study of autism: cognitive patterns and levels in parents and siblings. J Child Psychol Psychiatry 1997; 38:667–683. Piven J, Gayle J, Chase GA, Fink B, Lauda R, Wzoreck MM, Folstein SE. A family history study of neuropsychiatric disorders in the adult siblings of autistic individuals. J Am Acad Child Adolesc Psychiatry 1990; 29:177–183. Cook E, Courchesne R, Lord C, Cox N, Yan S, Lincoln A, Haas R, Courchesne E, Leventhal BH. Evidence of linkage between the serotonin transporter and autistic disorder. Mol Psychiatry 1997; 2:247–250. Cook EH, Courchesne R, Cox NJ, Lord C, Gonen D, Guter SJ, Lincoln A, Haas R, Leventhal BL, Courchesne E. Linkage disequilibrium mapping with 15q11– 13 markers in autistic disorder. Am J Hum Genet 1998; 62:1077–1083. Schroer RJ, Phelan MC, Michaelis RC, Crawford EC, Skinner SA, Cuccaro M, Simensen RJ, Bishop J, Skinner C, Fender D, Stevenson RE. Autism and maternally derived aberrations of chromosome 15q. Am J Med Genet 1998; 76:327–36. Wassink TH, Piven J. The molecular genetics of autism. Curr Psychiatry Rep 2000; 2:170–175. Bauman ML, Kemper TL, eds. The Neurobiology of Autism. Baltimore: Johns Hopkins University Press, 1994. Abell F, Krams M, Ashburner J, Passingham R, Friston K, Frackowiak R, Happe F, Frith C, Frith U. The neuroanatomy of autism: a voxel-based whole brain analysis of structural scales. Neuroreport 1999; 10:1647–1651. Levitt JG, Blanton R, Capetillo-Cunliffe L, Guthrie D, Toga A, McCracken JT. Cerebellar vermis lobules VIII–X in autism. Prog Neuropsychopharmacol Biol Psychiatry 1999; 23:625–633. Sears LL. An MRI study of the basal ganglia in autism. Prog Neuropsychopharmacol Biol Psychiatry 1999; 23:613–624. Ohnishi T, Matsuda H, Hashimoto T, Kunihiro T, Nishikawa M, Uema T, Sasaki M. Abnormal regional cerebral blood ﬂow in childhood autism. Brain 2000; 123: 1838–1844. Ryu YH, Lee JD, Yoon PH, Kim DI, Lee HB, Shin YJ. Perfusion impairments in infantile autism on technetium-99m ethyl cysteinate dimer brain single-photon emission tomography: comparison with ﬁndings on magnetic resonance imaging. Eur J Nucl Med 1999; 26:253–259. Chugani DC, Muzik O, Behen M, Rothermel R, Janisse JJ, Lee J, Chugani HT. Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol 1999; 45, 287–295. Chugani DC, Muzik O, Rothermel R, Behen M, Chakraborty P, Mangner T, de Silva EA, Chugani HT. Altered serotonin synthesis in the dentatothalamocortical pathway in autistic boys. Ann Neurol 1997; 14:666–669. Baron-Cohen S, Ring HA, Wheelwright S, Bullmore ET, Brammer MJ, Simmons A, Williams SCR. Social intelligence in the normal and autistic brain: an fMRI study. Eur J Neurosci 1999; 11:1891–1898.

Immune Dysfunction 23.

24.

25.

26. 27. 28.

29.

30.

31.

32.

33. 34. 35.

36.

37. 38.

169

Ring HA, Baron-Cohen S, Wheelwright S, Williams SCR, Brammer M, Andrew C, Bullmore ET. Cerebral correlates of preserved cognitive skills in autism: a functional MRI study of embedded ﬁgures task performance. Brain 1999; 122:1305– 1315. Gordon CT, State RC, Nelson JE, Hamburger SD, Rapoport JL. A double-blind comparison of clomipramine, desipramine, and placebo in the treatment of autistic disorder. Arch Gen Psychiatry 1993; 50:441–447. McDougle CJ, Naylor ST, Cohen DJ, Volkman FR, Heninger GR, Price LH. A double-blind placebo-controlled study of ﬂuvoxamine in adults with autistic disorder. Arch Gen Psychiatry 1996; 53:1001–1008. Hollander ES, et al. Unpublished data. Mehlinger R, Scheftner WA, Pozanski E. Fluoxetine and autism. J Am Acad Child Adolesc Psychiatry 1990; 29:985. Steingard RJ, Ziminitzky B, DeMaso DR, Bauman ML, Bucci JP. Sertraline treatment of transition-associated anxiety and agitation in children with autistic disorder. J Am Acad Child Adolesc Psychiatry 1997; 7:9–15. McBride PA, Anderson GM, Hertzig ME, Snow ME, Thompson SM, Khait VD, Shapiro T, Cohen DJ. Effects of diagnosis, race, and puberty on platelet serotonin levels in autism and mental retardation. J Am Acad Child Adolesc Psychiatry 1998; 37:767–776. Cook EH Jr, Leventhal BL, Heller W, Metz J, Wainwright M, Freedman DX. Autistic children and their ﬁrst-degree relatives: relationships between serotonin and norepinephrine levels and intelligence. J Neuropsychiatry Clin Neurosci 1990; 2:268–274. Leboyer M, Philippe A, Bouvard M, Guilloud-Bataille M, Bondoux D, Tabuteau F, Feingold J, Mouren-Simeoni MC, Launay JM. Whole blood serotonin and plasma beta-endorphin in autistic probands and their ﬁrst-degree relatives. Biol Psychiatry 1999; 45:158–163. Kelly W, Ruddy S, Harris E, Sledge CB, eds. Textbook of Rheumatology. 5th ed. Philadelphia: Harcourt Brace, 1997:1015–1054, 851–966, 210–214, 805–807, 101–105, 267–282, 232–235. Salmon JE, Pricop L. Human receptors for immunoglobulin G. Arthritis Rheum 2001; 44:739–750. Elkon KB. Apopotosis. In: Wallace DJ, Hahn BH, eds. Dubois’ Lupus Erythematosus. 5th ed. Baltimore: Williams & Wilkins, 1997:133–142. Mepler E, Bini P, Drappa J, Ramos P, Friedman SM, Krammer PH, Elkon KB. The APO-a/Fas protein in human systemic lupus erythematosus. J Clin Invest 1994; 93:1029–1034. Fatemi SH, Haet AR, Stary JM, Realmuto GM, Jalali-Mousavi M. Reduction in anti-apoptotic protein Bcl-2 in autistic cerebellum. Neuroreport 2001;12:929– 933. Ghaziuddin M, Tsai LY, Eilevs Y, Ghaziuddin N. Brief report: autism and herpes simplex encephalitis. J Autism Dev Disord 1992; 22:107–113. Desmond MM, Montgomery JR, Melnick JL, Cochran GG, Verniaud W. Congenital rubella encephalitis: effects on growth and early development. Am J Dis Child 1969; 118(1):30–31.

170 39. 40. 41. 42. 43. 44.

45.

46.

47.

48.

49. 50.

51.

52. 53. 54. 55. 56.

DelGiudice and Hollander Stubbs EG, Ash E, Williams CP. Autism and congenital cytomegalovirus. J Autism Dev Disord 1984; 14:183–189. Peterson MR, Torrey EF. Viruses and other infectious agents as behavioral teratogens. In: Coleman M, ed. The Autistic Syndromes. New York: Elsevier, 1976:23–42. Knobloch H, Pasamarrick B. Gesell and Amatruda’s Developmental Diagnosis. 3rd ed. New York: Harper & Row, 1974:320–339. Deykin EY, MacMahon B. Viral exposure and autism. Am J Epidemiol 1979; 109: 628–638. Barak Y, Ring A, Sulkes J, Gabbay U, Elizur A. Season of birth and autistic disorder in Israel. Am J Psychiatry 1995; 152:798–800. Husby G, Van de Rijn E, Zabriskie JB, Abdin ZH, Williams RC. Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever. J Expt Med 1976; 144:1094–1110. Zabriskie JB, Lavenchy D, Williams RC Jr, Fu SM, Yeadon CA, Fotino M, Braun DG. Rheumatic fever-associated B cell alloantigens as identiﬁed by monoclonal antibodies. Arthritis Rheum 1985; 28:1047–1051. Murphy TK, Goodman WK, Fudge MW, et al. B lymphocyte antigen D8/17: a peripheral marker for childhood-onset obsessive-compulsive disorder and Tourette’s syndrome? Am J Psychiatry 1997; 154:402–407. Swedo SE, Leonard HL, Mittleman BB, Allen AJ, Rapoport JL, Dow SP, Kanter ME, Chapman F, Zabriskie J. Identiﬁcation of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever. Am J Psychiatry 1997; 154:110–112. Hollander E, DelGiudice-Asch G, Simon L, Schmeidler J, Cartwright C, DeCaria CM, Kwon J, Cunningham-Rundles C, Chapman F, Zabriskie J. B lymphocyte antigen D8/17 and repetitive behaviors in autism. Am J Psychiatry 1999; 156(2): 317–320. Warren RP, Foster A, Margaretten NC. Reduced natural killer cell activity in autism. J Am Acad Child Adolesc Psychiatry 1987; 26:333–335. Warren RP, Cole P, Odell JB, Pingree CB, Warren W, White E, Yonk LJ, Singh VK. Detection of maternal antibodies in infantile autism. J Am Acad Child Adolesc Psychiatry 1990; 29:873–877. Warren RP, Singh VK, Cole P, Odell JD, Pingree CB, Warren WL, White E. Increased frequency of the null allele at the complement C4B locus in autism. Clin Exp Immunol 1991; 83:438–440. Denney DR, Frei BW, Gaffney GR. Lymphocyte subsets and interleukin-2 receptors in autistic children. J Autism Dev Disord 1996; 26:87–97. Warren RP, Foster A, Margaretterinc, Pace NC. Immune abnormalities in patients with autism. J Autism Dev Disord 1986; 16:189–197. Ferrari P, Mavescot M, Moulias R, et al. Immunitaire dans l’autisme infantile. Encephale 1988; 14:339–344. Yonk LJ, Warren RP, Burger RA. CD4 and helper T cell depression in autism. Immunol Lett 1990; 25:341–346. Plioplys AV. Autism: immunological investigations. Proceedings of the State of the Art Conference on Autism: Diagnosis and Treatment, Goteborg, Sweden, May 8–10, 1989, pp. 133–138.

Immune Dysfunction 57.

58. 59.

60. 61.

62. 63.

64. 65.

66.

67.

68.

69. 70.

71.

72.

73. 74.

171

Young JG, Capanilo BK, Shaywitz BA, Johnson WT, Cohen DJ. Childhood autism: cerebrospinal ﬂuid examination and immunoglobulin levels. J Am Acad Child Psychiatry 1977; 16:174–179. Warren RP, Odell JD, Warren WL. Brief report: immunoglobulin A deﬁciency in a subset of autistic subjects. J Autism Dev Disord 1997; 27:187–192. Yuwiler A, Shih JC, Chen CH, Ritvo ER, Hauna G, Ellison GW, King BH. Hyperserotoninemia and antiserotonin antibodies in autism and other disorders. J Autism Dev Disord 1992; 22:33–45. Laszlo A, Horvath E, Eck E, Fekete M. Serum serotonin, lactate and pyruvate levels in infantile autistic children. Clin Chim Acta 1994; 229(1–2):205–207. Todd RD, Ciaranello RD. Demonstration of inter and intraspecies differences in serotonin binding sites by antibodies from an autistic child. Neurobiology 1985; 82:612–616. Todd RD. Pervasive developmental disorders and immunological tolerance. Psychiatr Dev 1986; 2:147–165. Cook EH Jr, Perry BD, Dawson G. Receptor inhibition by immunoglobulins: speciﬁc inhibition by autistic children, their relatives, and control subjects. J Autism Dev Disord 1993; 23(1):67–78. Singh VK, Fudenberg HH, Emerson D, Coleman M. Immunodiagnosis and immunotherapy in autistic children. Ann NY Acad Sci 1988; 540:602–604. Courchesne E, Lueng-Courchesne R, Piess GA, Uesselink JR, Jennigan TL. Hypoplasia of cerebellar vermal lobules VI and VII in autism. N Engl J Med 1988; 318:1349–1354. Toh BH, Gibbs CJ Jr, Gajdusek DC. The 200- and 150-Kda neuroﬁlament proteins react with IgG autoantibodies from patients with Kuru, Creutzfeldt-Jakob disease, and other neurologic diseases. Proc Natl Acad Sci USA 1985; 82(10):3485–3489. Rosengren LE, Ahlsen G, Belfrage M, Gillberg C, Haglid KG, Hamberger A. A sensitive ELISA for glial ﬁbrillary acidic protein: application in CSF of children. J Neurosci Meth 1992; 44(2–3):113–119. Connolly AM, Chez MG, Pestnonk A, et al. Serum antibodies to brain in LandauKleffner variant, autism, and other neurologic disorders. J Pediatr 1999; 134:607– 613. Stubbs EG, Ritvo ER, Mason-Brothers A. Autism and shared parental HLA antigens. J Am Acad Child Psychiatry 1985; 24:182–185. McConnachie PR, McIntryre JA. Maternal antipaternal immunity in couples predisposed to repeated pregnancy losses. Am J Reprod Immunol 1984; 5(4):145– 150. Warren RP, Yonk LJ, Burger RA, Cole P, Odell JD, Warren WL, White E, Singh VK. Suppressor-inducer (CD4⫹ CD45RA⫹) T cells in autism. Immunol Invest 1990; 19:245–251. Nelson KB, Grether JK, Croen LA, Dambrosia JM, Dickens BF, Jelliffe LL, Hanson RL, Phillips TM. Neuropeptides and neurotrophins in neonatal blood of children with Autism or mental retardation. Ann Neurol 2001; 49:597–606. Rapin I. Autism. N Engl J Med 1997; 337:97–104. Dwyer JM. Manipulating the immune system with immunoglobulin. N Engl J Med 1992; 326:4104–4109.

172 75.

76.

77.

78.

79.

80. 81.

82. 83.

84. 85. 86. 87. 88. 89. 90. 91. 92. 93.

DelGiudice and Hollander Gupta S, Agganual S, Heads C. Brief report: dysregulated immune system in children with autism; beneﬁcial effects of intravenous immune globulin on autistic characteristics. J Autism Dev Disord 1996; 26:439–452. DelGiudice-Asch G, Simon L, Schmeidler J, Cunningham-Rundles C, Hollander E. A pilot open clinical trial of intravenous immunoglobulin in childhood autism. J Autism Dev Disord 1998; 29(2): 157–160 Freeman BJ, Ritvo ER, Yokota A, Ritvo A. A scale for rating symptoms of patients with the syndrome of autism in real life settings. J Am Acad Child Psychiatry 1986; 25:130-136. Goodman W, Price L, Ramussen S, Mazure C. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Part I. Development, use, and reliability. Arch Gen Psychiatry 1989; 46:1006–1011. Goodman W, Price L, Ramusssen S, Mazure C. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Part II. Validity. Arch Gen Psychiatry 1989; 46:1012– 1016. Guy W. E.C.D.E.U. Assessment Manual for Psychopharmacology. DHEW Publication 76-338. Washington, DC: U.S. Government Printing Ofﬁce, 1976. Rapoport J, Elkins R, Mikkelsen E. Clinical controlled trial of clomipramine in adolescents with obsessive compulsive disorder. Psychopharm Bull 1980; 16:61– 63. Selman K, Reine CS. Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann Neurol 1988; 23:339–346. Han J, Thompson P, Beutler B. Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin: tumor necrosis factor synthesis at separate points in the signaling pathway. J Exp Med 1990; 172:391–394. Natal S, Louboutin J, Chabannes D. Pentoxifylline inhibits experimental allergic encephalitis. Acta Neurol Scand 1993; 88:97–99. Black RS, Barday LL, Nolan KA. Pentoxifylline in cerebrovascular dementia. J Am Geriatr Soc 1992; 40:237–244. Soganie S. On our experience in using pentoxifylline for abnormal behavior and the autistic syndrome. Jap J Child Psychiatry 1978; 19:134–144. Nakane A. Effect of pentoxifylline on autistic children. Tokepto Eisei Gakkashi 1980; 64:104–105. Shimode M. Effect of pentoxifylline on infantile autism. Clin Exp Med 1981; 58: 285–288. Turek S. Treatment of psychotic and autistic children with pentoxifylline. ASANA 1981; 1:51–60. Fudenberg HH, Singh VK. Implications of immunomodulant therapy in Alzheimer’s disease. Prog Drug Res 1988; 32:21–42. Dawson CA, Lineham JH. Biogenic amines. In: Massaro E, ed. Lung Cell Biology. New York: Marcel Dekker, 1989:1091. Fudenberg HH. Dialysable lymphocyte extract (DLyE) in infantile onset autism: a pilot study. Biotherapy 1996; 9:143–147. Horvath K, Stefanatos G, Sokolski KN, Wachtel R, Nabors L, Tildon JT. Improved social and language skills after secretin administration in patients with autistic spectrum disorders. Assoc Acad Minor Phys 1998; 9:9–15.

Immune Dysfunction 94.

95.

96.

97. 98. 99.

100. 101.

173

Owley T, Steele E, Corsello C, Risi S, McKaig K, Lord C, Leventhal BL, Cook EH Jr. A double-blind placebo-controlled trial of secretin for the treatment of autistic disorder. Medscape Gen Med 1999; 1:10. Sandler AD, Sutton KA, DeWeese J, Girardi MA, Sheppard V, Bodﬁsh JW. Lack of beneﬁt of a single dose of synthetic human secretin in the treatment of autism and pervasive developmental disorder. N Engl J Med 1999; 341:1801–1806. Chez MG, Buchanan CP, Bagan BT, Hammer MS, McCarthy KS, Ovrutskaya I, Nowinski CV, Cohen ZS. Secretin and autism: a two part clinical investigation. J Autism Dev Disord 2000; 30:87–94. Chez MG, Nowinski CV, Panchanan CP, Jones C. Donepezil (aricept) use in children with autism spectrum disorders. Ann Neurol 2000; 48:541. Rossi PG, Posar A, Parmeggiani A, Pipitone E, D’Agata M. Niaprazine in the treatment of autistic disorder. J Child Neurol 1999; 14:547–550. King BH, Cook EH, Sikich L, et al. A controlled trial of amantadine in the treatment of autistic children. 46th Annual Meeting of the American Academy of Child and Adolescent Psychiatry. Chicago, Oct 19–24, 2000. Bolter ER. Autism and Clostridium tebani. Med Hypoth 1998, 51:133–144. Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Vaisanen ML, Nelson MN, Wexler HM . Short-term beneﬁt from oral vancomycin treatment of regressive-onset autism. J Child Neurol 2000; 15:429–435.

9 Autism and Environmental Toxins Martin Evers, Sherie Novotny, and Eric Hollander Mount Sinai School of Medicine New York, New York, U.S.A.

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 etiological 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 ascertainment) could indicate a signiﬁcant role for nongenetic factors in disease pathogenesis (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 autism’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

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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 somewhat circumstantial. Although association is often established, ﬁrm causation is more difﬁcult to prove. Temporality, and therefore causality, are by nature difﬁcult to deduce when examining prenatal and early postnatal inﬂuences in a syndrome typically diagnosed at 2 to 4 years of age. In addition, the detailed mechanisms 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 developmentally 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 efforts 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.

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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 environmental 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 environmental toxin (or toxins). It has been suggested that such clustering may be occurring 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 conditions. The CDC reported a township prevalence of 4 per 1000 for narrowly deﬁned 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, temperature, nutritional factors, vitamin deﬁciencies, and obstetric complications (4). Research 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 between frequency of autistic births and hospitalizations for pneumonia and bronchiolitis (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).

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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 environmental role in pathogenesis. Many of the proposed mechanisms by which environmental inﬂuences lead to autism involve the interaction of common xenobiotic agents, viruses, etc., with genetically predisposed individuals. Others involve exposure (in the predisposed) to fairly ubiquitous substances during key developmental windows. Interestingly, many neuropsychiatric conditions—including schizophrenia, schizoaffective disorder, Alzheimer’s disease, childhood psychosis, major depression 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 system 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 treatment 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 number of Purkinje cells in the cerebellum (7). These anatomical phenomena parallel ﬁndings in human autism. Other substances inﬂuencing retinoid metabolism include 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 thalidomide exposure beyond that early window. The association of thalidomide with autism inspired the concept that defective neural tube closure could be an etiological factor for the disorder. Thalidomide-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

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structures formed during that window, as well as an increase in cranial nerve abnormalities. In addition, autistic children have a higher rate of minor malformations of the ear (which would occur in this same time period) than normal children and children with other developmental disorders (9). The brain dysfunction causative 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. Alternatively, 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 environmental chemicals) is a statistically signiﬁcant characteristic of a high proportion of the families of autistic probands (10). Chronic exposure to neurotoxic xenobiotics 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 Purkinje and granule cells (1); abnormal neuronal migration in the brainstem, cerebellum, and cortex; stunting and abnormal branching of dendrites; nuclear abnormalities; 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.

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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 detoxiﬁcation evaluation was conducted to assess the ability of the liver to process toxins without accumulation of free radical metabolites or a back-up of unprocessed 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. Interestingly, the subjects all had different combinations of elevated toxins. The results therefore implicated the inability of the liver to process a range of different xenobiotics, 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 phenosulfotransferase, 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 individual’s fetal liver is unable to detoxify ordinary environmental chemicals. Not properly processed, these lipophilic chemicals would then damage the individual in two ways. First, they could pass directly into the brain, causing direct injury to structures 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, subsequently, 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 provocation 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, neuron-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,

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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 prenatal, 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 response 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, neurobehavioral 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,

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anti-MBP antibodies are expressed in individuals with multiple sclerosis (17). The potential signiﬁcance is in the frequency with which autoantibodies are expressed in the autistic population. Research has established that autoantibodies are a common ﬁnding in autistic 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 cycle—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 cytopathic effect (CPE) in conjunction with inﬂammatory activation of cytokines, autoimmune response, free radical insult from improper processing of metabolites, 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 associated 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 handicaps, while most nonvirally infected autistic children are not multihandicapped. Interestingly, a large proportion of the autistic children with rubella studied recovered, relatively quickly, from their autistic symptoms (20). These symptoms included 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 natural recovery from other rubella consequences such as blindness, deafness, and

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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 established a strong association between maternal rubella infection and autism. Beyond proving association, studies on this population strongly suggested a pathogenic 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 inference 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 dysfunction in conjunction with viral infection of CNS and panencephalitis due to congenital rubella (20). Observed damage has ranged from mild cognitive disability to severe retardation and neuronal death, gliosis, and vasculitis (23). A study of

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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, parenchymal and perivascular necrosis in six, and subarachnoid hemorrhage in one case. Subclinical maternal rubella infection has also produced neurological damage 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 reduced 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 mental 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 levels due to diminishing antigenic stimulus. On the other hand, since CMV is a

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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 congenital 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 mimicry, 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 antibodymediated insult to the brain would then produce autistic pathology and symptomatology. 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

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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 identiﬁed two other children with reversible autistic syndrome secondary to encephalitis; 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 infection 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 individual. 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

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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 incidence of the presence of brain autoantibodies. Measles virus has been demonstrated to have neurological sequelae: measles 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 pathogenic 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 deletion of genes coding components that would normally provoke a host inﬂammatory 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 noninﬂammatory neurological disease in animals. It has therefore been suggested that persistent stealth virus infection may be responsible for a broad spectrum of neuropsychiatric 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.

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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 prenatal. 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 zidovudine (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 deﬁcits 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 etiological 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 intrauterine 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 possibility of prenatal parvovirus infection could not be ruled out on the basis of childhood 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 phenomena observed in human autism.

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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 activity leads to loss of neurons. Glial activation is seen throughout the brain. In addition, there are increased levels of proinﬂammatory cytokine mRNA (IL-1α, 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 unknown. 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, including 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.

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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 parents may lead to immunological intolerance and prevent the development of maternal 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 ultimately 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, including 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 Sydenham’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 chorea, 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 documented (39). Autism and other repetitive-movement disorders would, under this

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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 susceptible individuals (in which susceptibility is indicated by elevated D8/17 expression). 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 important for social learning and the development of social behavior, communication, and rituals. It has been hypothesized that abnormalities in the oxytocin system 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-

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sures than autistic children with lower oxytocin levels; this was the opposite of ﬁndings for normal subjects. Oxytocin levels increased with age in normal controls 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 certainty. 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 primarily 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 regression was not clustered in the months after vaccination. The weight of epidemiological 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).

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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 approximately 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 children, 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 FASrelated 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 autism that are generally not characteristic of, or do not overlap with, mental retardation. 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 surprising given the prevalence indicated by the study at hand. Since FAS is a syndrome presenting with a range of (often severe) physical and behavioral characteristics, 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 language, 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 echolalic speech lacking communicative intent, and did not engage in interactive activities. The autistic children frequently displayed hyperactivity in acts of perseverance. 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

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of a general conclusion concerning cocaine-speciﬁc etiology of autism. The research 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 degrees in the majority of the cocaine-exposed children. Thus, cocaine-speciﬁc effects 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 improved 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 environmental 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 variables: medical history, medication use, environment, demographics, diagnostic criteria, control group composition, etc. Research has also been limited by small

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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 environmental factors is somewhat circumstantial. While association is often established, 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 activities is to improve the lives of children with autism and their families. Identiﬁcation 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. REFERENCES 1. 2.

3. 4. 5.

6. 7.

8.

London E, Etzel R. The environment as an etiologic factor in autism: a new direction for research. Environ Health Perspect 2000; 108(suppl 3):401–404. Goldman L, Koduru S. Chemicals in the environment and developmental toxicity to children: a public health and policy perspective. Environ Health Perspect 2000; 108(suppl 3):443–448. Center for Children’s Health and the Environment. Autism and Environmental Exposures. 2000. Barak Y, Ring A, Sulkes J, Gabbay U, Elizur A. Season of birth and autistic disorder in Israel. Am J Psychiatry 1995; 152(5):798–800. Bolton P, Pickles A, Harrington R, Macdonald H, Rutter M. Season of birth: issues, approaches and ﬁndings for autism. J Child Psychol Psychiatry 1992; 33(3):509– 530. Gillberg C. Do children with autism have March birthdays? Acta Psychiatr Scand 1990; 82:152–156. Rodier P, Ingram J, Tisdale B, Nelson S, Romano J. Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei. J Compr Neurol 1996; 370:247–261. Stromland K, Nordin V, Miller M, Akerstrom B, Gillberg C. Autism in thalidomide embryopathy: a population study. Dev Med Child Neurol 1994; 36:351–356.

196

Evers et al.

9.

Rodier P, Bryson S, Welch J. Minor malformations and physical measurements in autism: data from Nova Scotia. Teratology 1997; 55:319–325. Edelson S, Cantor D. Autism: xenobiotic inﬂuences. Toxicol Ind Health 1998; 14(4):553–563. O’Reilly B, Waring R. Enzyme and sulfur oxidation deﬁciencies in autistic children with known food and chemical intolerances. J Ortho Med 1993; 8(4) Singh V, Lin S, Yang V. Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism. Clin Immunol Immunopathol 1998; 89(1):105–108. Mason-Brothers A, Ritvo E, Guze B, Mo A, Freeman B, Funderburk S, Schroth P. Pre-, peri-, and postnatal factors in 181 autistic patients from single and multiple incidence families. J Am Acad Child Adolesc Psychiatry 1987; 26:39–42. Deykin E, MacMahon B. Viral exposure and autism. Am J Epidemiol 1979; 109: 628–638. Trottier G, Srivastava L, Walker C. Etiology of infantile autism: a review of recent advances in genetic and neurobiological research. J Psychiatry Neurosci 1999; 24(2):103–115. Singh V, Warren R, O’Dell J, Warren W, Cole P. Antibodies to myelin basic protein in children with autistic behavior. Brain Behav Immun 1993; 7:97–103. Connolly A, Chez M, Pestronk A, Arnold S, Mehta S, Deuel R. Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. J Pediatrics 1999; 134(5):607–613. Chess S. Autism in children with congenital rubella. J Autism Child Schizophr 1971; 1(1):33–47. Nelson K. Prenatal and perinatal factors in the etiology of autism. Pediatrics 1991; 87(5 Pt 2):761–766. Chess S. Follow-up report on autism in congenital rubella. J Autism Child Schizophr 1977; 7(1):69–81. Markowitz P. Autism in a child with congenital cytomegalovirus infection. J Autism Dev Disord 1983; 13(3):249–253. Ritvo E, Mason-Brothers A, Freeman B, Pingree C, Jenson W, McMahon W, Petersen P, Jorde L, Mo A, Ritvo A. The UCLA–University of Utah epidemiologic survey of autism: the etiologic role of rare diseases. Am J Psychiatry 1990; 147(12): 1614–1621. Ciaranello A, Ciaranello R. The neurobiology of infantile autism. Annu Rev Neurosci 1995; 18:101–128. Desmond M, Montgomery JR, Melnick JL, Cochran GG, Verniaud W. Congenital rubella encephalitis—effects on growth and early development. Am J Dis Child 1969; 118:30–31. Ahlfors K, Ivarsson S, Harris S, Svanberg L, Holmqvist R, Lernmark B, Theander G. Congenital cytomegalovirus infection and disease in Sweden and the relative importance of primary and secondary maternal infections. Scand J Infect Dis 1984; 16:129–137. Stubbs E, Ash E, Williams C. Autism and congenital cytomegalovirus. J Autism Dev Disord 1984; 14(2):183–189. Warren R. An immunologic theory for the development of some cases of autism. CNS Spectrums 1998; 3(3):71–79.

10. 11. 12.

13.

14. 15.

16. 17.

18. 19. 20. 21. 22.

23. 24.

25.

26. 27.

Environmental Toxins 28.

29. 30. 31.

32. 33. 34.

35.

36. 37. 38.

39.

40.

41.

42.

43.

44. 45.

197

Jorgensen O, Goldschmidt V, Vestergaard B. Herpes simplex virus (HSV) antibodies in child psychiatric patients and normal children. Acta Psychiatr Scand 1982; 66:42–49. DeLong G, Bean S, Brown F. Acquired reversible autistic syndrome in acute encephalopathic illness in children. Arch Neurol 1981; 38(3):191–194. Ghaziuddin M, Tsai L, Eilers L, Ghaziuddin N. Brief report: autism and herpes simplex encephalitis. J Autism Dev Disord 1992; 22(1):107–113. Schmitt B, Seeger J, Kreuz W, Enenkel S, Jacobi G. Central nervous system involvement of children with HIV infection. Dev Med Child Neurol 1991; 33:535– 540. Anlar B, Oktem F, Torok T. Human parvovirus B19 antibodies in infantile autism. J Child Neurol 1994; 9(1):104–105. Hornig M, Weissenbock H, Horscroft N, Lipkin W. An infection-based model of neurodevelopmental damage. Proc Natl Acad Sci USA 1999; 96(21):12102–12107. Pletnikov M, Rubin S, Vasudevan K, Moran T, Carbone K. Developmental brain injury associated with abnormal play behavior in neonatally Borna disease virusinfected Lewis rats: a model of autism. Behav Brain Res 1999; 100(1–2):43–50. Waltrip R II, Buchanan R, Summerfelt A, Breier A, Carpenter W Jr, Bryant N, Rubin S, Carbone K. Borna disease virus and schizophrenia. Psychiatry Res 1995; 56:33–44. Stubbs E, Magenis R. HLA and autism. J Autism Dev Disord 1980; 10(1):15–19. Stubbs E, Ritvo E, Mason-Brothers A. Autism and shared parental HLA antigens. J Am Acad Child Psychiatry 1985; 24(2):182–185. Triﬁletti RR, Packard AM. Immune mechanisms in pediatric neuropsychiatric disorders: Tourette’s syndrome, OCD and PANDAS. Child Adolesc Psychiatr Clin N Am 1999; 8(4):767–775. Husby G, Van de Rijn I, Zabriskie J, Abdin Z, Williams R Jr. Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever. J Exp Med 1976; 144:1094–1110. Zabriskie JB, Lavenchy D, Williams RC Jr, Fu SM, Yeadon CA, Fotino M, Braun DG. Rheumatic fever–associated B cell alloantigens as identiﬁed by monoclonal antibodies. Arthritis Rheum 1985; 28:1047–1051. Murphy T, Goodman W, Fudge N. B lymphocyte antigen D8/17: a peripheral marker for childhood-onset obsessive-compulsive disorder and Tourette’s syndrome? Am J Psychiatry 1997; 154:402–407. Swedo S, Leonard H, Mittleman B, Allen A, Rapoport J, Dow S, Kanter M, Chapman F, Zabriskie J. Identiﬁcation of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever. Am J Psychiatry 1997; 154:110–112. Hollander E, DelGiudice-Asch G, Simon L, Schmeidler J, Cartwright C, DeCaria C, Kwon J, Cunningham-Rundles C, Chapman F, Zabriskie J. B lymphocyte antigen D8/17 and repetitive behaviors in autism. Am J Psychiatry 1999; 156(2):317–320. Rutter M, Bartak L. Causes of infantile autism: some considerations from recent research. J Autism Child Schizophr 1971; 1(1):20–32. Modahl C, Green L, Fein D, Morris M, Waterhouse L, Feinstein C, Levin H. Plasma oxytocin levels in autistic children. J Biol Psychiatry 1998; 43(4):270–277.

198

Evers et al.

46.

Insel T, O’Brien J, Leckman J. Oxytocin, vasopressin, and autism: is there a connection? Biol Psychiatry 1999; 45(2):145–157. Insel T. A neurobiological basis of social attachment. Am J Psychiatry 1997; 154(6): 726–735. Hollander E, Cartwright C, Wong C, et al. A dimensional approach to the autism spectrum. CNS Spectrums: Int J Neuropsychiatr Med 1998; 3:22–40. Fein D, Allen D, Dunn D. Pitocin induction and autism. Am J Psychiatry 1997; 154(3):438–439. Wakeﬁeld A, Murch S, Anthony A, Linnell J, Casson D, Malik M, Berelowitz M, Dhillon A, Thomson M, Harvey P, Valentine A, Davies S, Walker-Smith J. Ileallymphoid-nodular hyperplasia, non-speciﬁc colitis, and pervasive developmental disorder in children. Lancet 1998; 351:637–641. Taylor B, Miller E, Farrington C, Petropoulos M, Favot-Mayaud I, Li J, Waight P. Autism and measles, mumps and rubella vaccine: no epidemiological evidence for a causal association. Lancet 1999; 353:2026–2029. Measles, MMR, and autism: the confusion continues [editorial]. Lancet 2000; 355: 1379. Nanson J. Autism in fetal alcohol syndrome: a report of six cases. Alcohol Clin Exp Res 1992; 16(3):558–565. Davis E, Fennoy I, Laraque D. Autism and developmental abnormalities in children with perinatal cocaine exposure. J Natl Med Assoc 1992; 84(4):315–319. Ferriero D, Partridge J, Wong D. Congenital defects and stroke in cocaine exposed neonates. Ann Neurol 1988; 24:348. Ferriero D, Wong D, Townsend R, et al. Neurological complications in infants of cocaine abusing mothers. Neurology 1988; 38(suppl 1):163. Bidet B, Leboyer M, Descours B, Bouvard M, Benveniste J. Allergic sensitization in infantile autism [letter]. J Autism Dev Disord 1993; 23(2):419–420. Renzoni E, Beltrami V, Sestini P, Pompella A, Menchetti G, Zappella M. Brief report: allergological evaluation of children with autism. J Autism Dev Disord 1995; 25(3):327–333.

47. 48. 49. 50.

51.

52. 53. 54. 55. 56. 57. 58.

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 throughout 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 information (2–4). We ﬁrst recount the historical developments that led, in part, to studies of 5-HT function in autism.

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HISTORICAL PERSPECTIVE The landmark publication by Schain and Freedman in 1961 (5) is often acknowledged as the ﬁrst paper to describe an abnormality in 5-HT function in autism. Although 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 regarding 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 phenylketonuria (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 quotient (IQ) of subjects with PKU and their serum 5-HT and urinary 5-HIAA excretion. The investigators suggested that the decreased levels of serum 5-HT and urinary 5-HIAA might be due to competition between phenylalanine and tryptophan, 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; Armstrong 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, Sandler, 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-

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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 (5HTP) decarboxylase, which converts 5-HTP to 5-HT, by phenylacetic acid, phenylpyruvic 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 appreciably lower peaks for the urinary excretion of 5-HT and 5-HIAA. Unchanged 5HTP 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 between 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 perceptual 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 affected 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 surprising.” 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

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Figure 1 Serum 5-hydroxytryptamine (5-HT) (ng/ml) and urinary 5-hydroxyindoleacetic acid (5-HIAA) (mg/g creatinine) values in 49 phenylketonurics (∆) and 31 nonphenylketonuric 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 tryptophan. 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 indolelactic 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

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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. Multiple determinations of WBS were made in all the children. The subjects studied were divided into three groups. One (group A) included mildly retarded children with IQs of 60 to 80 described as “familial ‘subcultural’ 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 children. The third (group C) consisted of severely retarded children without a diagnosis of autism (IQ less than 20). These children had diagnoses including “congenital 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 children (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 concentration 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 phenobarbital, 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.

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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 replicated 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

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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 autism to that date (Table 1) (15). WBS and tryptophan were measured in 87 normal children and young adults and in 40 autistic subjects with a similar age distribution. WBS concentrations were signiﬁcantly higher in the drug-free autistic 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 remained 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 assessed. Prepubertal autistic children (n ⫽ 58) had signiﬁcantly higher 5-HT concentrations than prepubertal controls (n ⫽ 38), although the elevation (25%) was less than typically reported. Twenty-two mentally retarded or otherwise cognitively 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 relatively 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

Acid ﬂuorescence

Acid ﬂuorescence

1970

1971

1974

1975

Ritvo, Yuwiler, Geller, Ornitz, Saeger, and Plotkin

Yuwiler, Ritvo, Bald, Kyper, and Kopen

Campbell, Friedman, DeVito, Greenspan, and Collins Yuwiler, Ritvo, Geller, Ornitz, and Saeger

Acid ﬂuorescence

Acid ﬂuorescence

Bioassay

1961

Schain and Freedman

Technique

Year

Author

Whole blood

Platelet-rich plasma

Whole blood

Whole blood

Whole blood

Sample type

Table 1 Studies of Blood Serotonin in Autism

183 ⫾ 28 ng/ml, N ⫽ 4 494 ⫾ 42 ng/10 platelets, N⫽4 170 ng/ml, N ⫽ 6

205 ⫾ 17 ng/ml, N ⫽ 12 650 ⫾ 48 ng/10 9 platelets, N ⫽ 12

272 ⫾ 53 ng/ml, N ⫽ 7 760 ⫾ 113 ng/10 platelets, N⫽7 280 ng/ml, N ⫽ 11

273 ⫾ 30 ng/ml, N ⫽ 12 911 ⫾ 106 ng/10 9 platelets, N ⫽ 12

263 ⫾ 63 ng/ml, N ⫽ 23

65 ⫾ 17 ng/ml, N ⫽ 4 normals 72 ⫾ 33 ng/ml, N ⫽ 12 (mildly retarded) 216 ⫾ ng/ml, N ⫽ 36

Controls

141 ⫾ 78 ng/ml, N ⫽ 23

Autistic subjects

Mean values (mean ⫾ SD)

Platelet 5-HT uptake, efﬂux similar in both groups. Mean autistic and normal ages 5 and 8 yrs, respectively.

3–8-yr-old subjects; levels declined with age; no group differences when expressed as per platelet. 8 a.m. samples; similar group differences seen at noon. No circadian rhythm seen. Mean age autistics 5; mean age normals 6.

Mean autistic age 10.8.

Notes

206 McDougle et al.

Acid ﬂuorescence

HPLC ﬂuorometric

1984

1987

Source: Ref. 15.

Acid ﬂuorescence

1979

Hoshino, Kumashiro, and Kaneko Hoshino, Yamamoto, Kaneko, Tachibana, Watanabe, Ono, and Kumashiro Anderson et al.

Ninhydrin ﬂuorescence

1976

Takahashi, Kanai, and Miyamoto

Acid ﬂuorescence Acid ﬂuorescence

1976 1976

Goldstein and Coleman Hanley, Stahl, and Freedman

Whole blood

Whole blood

Serum

Platelet pellet

Whole blood Whole blood

73 ⫾ 23 ng/ml, N ⫽ 71 57 ⫾ 49 ng/ml, N ⫽ 6 normals 97 ⫾ 38 ng/ml, N ⫽ 23 (mildly retarded) 807 ⫾ 202 ng/mg, N ⫽ 30

175 ⫾ 60 ng/ml, N ⫽ 320 124 ⫾ 44 ng/ml, N ⫽ 67

136 ⫾ 50 ng/ml, N ⫽ 87 522 ⫾ 213 ng/10 9 platelets, N ⫽ 67

980 ⫾ 357 ng/mg, N ⫽ 30

218 ⫾ 79 ng/ml, N ⫽ 42 173 ⫾ 62 ng/ml, N ⫽ 37

205 ⫾ 73 ng/ml, N ⫽ 21 776 ⫾ 348 ng/10 9 platelets, N ⫽ 16

86 ⫾ 36 ng/ml, N ⫽ 72 135 ⫾ 57 ng/ml, N ⫽ 27

Mean age autistics 14.5; mean age normals 14.6; drugs reduced 5-HT levels; 5-HT elevated in young males.

Age-matched children. 7–23-yr-old subjects; no age effect seen; urinary 5-HIAA also higher in autistics. Expressed as ng/mg platelet protein; mean age 5 yrs; no age effect from 2–12 yrs. Mean age autistics 5.7; mean age normals 9.3. Tryptophan elevated in autistic subjects.

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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 collected 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 afﬁnity) 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 correlations between those peripheral markers and the [3H]-paroxetine Kd values, suggested 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 measurement 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 remains 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 measurements 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

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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 affected 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 brothers), and a group of healthy subjects (n ⫽ 118) age-matched for ﬁrst-degree

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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 investigators 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 decline 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 medication. 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 nonautistic 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 conducted 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 central 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-

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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 signiﬁcant change in clinical status from baseline following sham depletion (Figure 4).

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A signiﬁcant increase in sensory motor behaviors, including whirling, ﬂapping, pacing, banging, hitting self, rocking, and toe walking, was observed with tryptophan 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, sumatriptan, 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 hypothesized that this difference may be due to 5-HT dysfunction and, speciﬁcally, hypersensitivity of the 5-HT1D receptor. In a related study (36), the severity of repetitive 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 system (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 function 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 children (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 decreased 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 accumulation 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

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asymmetry scores between the autistic boys and siblings was statistically signiﬁcant. 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 aberrant innervation by 5-HT terminals or altered function in anatomically normal pathways. The second study on neuroimaging, also by Chugani et al. (38), was designed 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 differences 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 disrupted 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 transporter (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 promoter region (HTTLPR) (39) and a variable-number tandem repeat in the second 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

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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 transmission 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 ﬁndings concerning the preferentially transmitted alleles of 5-HTT between the German 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 subjects, 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

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autistics (12.5%) and autistic fragile X (9.1%) subjects than in the controls (21.7%). These differences, however, were not statistically different. The distribution 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 5HTT 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 genetics 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 system 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 differences in measures of 5-HT function between autistic subjects and controls. However, results from behavioral/neuroendocrine challenge studies have suggested

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that central 5-HT responsivity may be reduced in autistic subjects, particularly adults. Brain imaging studies utilizing tracers for measuring 5-HT synthesis capacity 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 neuroimaging studies of 5-HT-synthesis capacity in autistic subjects, clear developmental 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 randomized to ﬂuvoxamine responded in this study; none of the 16 placebo-treated subjects improved. In addition, the drug was very poorly tolerated and resulted in frequent and interfering adverse effects, including insomnia, agitation, motor hyperactivity, 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 response 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 characterizing aspects of 5-HT dysfunction in autism. Pharmacological treatments that effect changes in this system are beginning to prove helpful in a number of individuals with the disorder. Expanded research into 5-HT function in autism (e.g.,

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5-HT–immune interactions) appears warranted. Such effort should bring the ﬁeld closer to a better understanding of the pathophysiology of autism, the development of safer and more effective treatment interventions, and, ultimately, advances in identifying etiological aspects of the disorder. ACKNOWLEDGMENTS We thank Ms. Robbie Smith for preparing the manuscript. This work was supported in part by an Independent Investigator Award–Seaver Foundation Investigator award from the National Alliance for Research in Schizophrenia and Depression (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 Fellowship Award (Dr. Posey), the State of Indiana Division of Mental Health, and Department of Housing and Urban Development Grant B-01-SP-IN-0200 (Representative Dan Burton). REFERENCES 1.

2. 3.

4. 5. 6. 7. 8. 9.

10.

Whitaker-Azmitia PM. The role of serotonin and serotonin receptors in development of the mammalian nervous system. In: Zagon IS, McLaughlin PJ, eds. Receptors in the Developing Nervous System. Vol 2. Neurotransmitters. London: Chapman & Hall, 1993:43–53. Cook EH Jr, Leventhal BL. The serotonin system in autism. Curr Opin Pediatr 1996; 8:348–354. Anderson GM, Hoshino Y. Neurochemical studies of autism. In: Cohen DJ, Volkmar FR, eds. Handbook of Autism and Pervasive Developmental Disorders. Toronto: John Wiley & Sons, 1997:325–343. Potenza MN, McDougle CJ. The role of serotonin in autism-spectrum disorders. CNS Spectrums 1997; 2(5):25–42. Schain RJ, Freedman DX. Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children. J Pediatr 1961; 58:315–320. Sutton HE, Read JH. Abnormal amino acid metabolism in a case suggesting autism. Am J Dis Child 1958; 96:23–28. Pare CM, Sandler M, Stacey RS. 5-Hydroxytryptamine deﬁciency in phenylketonuria. Lancet 1957; i:551–553. Pare CM, Sandler M, Stacey RS. Decreased 5-hydroxytryptophan decarboxylase activity in phenylketonuria. Lancet 1958; ii:1099–1101. Pare CM, Sandler M, Stacey RS. The relationship between decreased 5-hydroxyindole metabolism and mental defect in phenylketonuria. Arch Dis Child 1959; 34: 422–425. Woolley DW. Manipulation of cerebral serotonin and its relationship to mental disorders. Science 1957; 125:752.

218

McDougle et al.

11.

Armstrong MD, Robinson KS. Abnormal metabolites in phenylketonuria. Fed Proc 1954; 13:175. Armstrong MD, Robinson KS. On the excretion of indole derivatives in phenylketonuria. Arch Biochem 1954; 52:287. Marrazzi AS. The action of psychotogens and a neurophysiological theory of hallucination. Am J Psychiatry 1960; 116:911. Ritvo ER, Yuwiler A, Geller E, Ornitz EM, Saeger K, Plotkin S. Increased blood serotonin and platelets in early infantile autism. Arch Gen Psychiatry 1970; 23: 566–572. Anderson GM, Freedman DX, Cohen DJ, Volkmar FR, Hoder EL, McPhedran P, Minderaa RB, Hansen CR, Young JG. Whole blood serotonin in autistic and normal subjects. J Child Psychol Psychiatry 1987; 28:885–900. McBride PA, Anderson GM, Hertzig ME, Snow ME, Thompson SM, Khait VD, Shapiro T, Cohen DJ. Effects of diagnosis, race, and puberty on platelet serotonin levels in autism and mental retardation. J Am Acad Child Adolesc Psychiatry 1998; 37(7):767–776. Croonenberghs J, Delmeire L, Verkerk R, Lin AH, Meskal A, Neels H, Van der Planken M, Schcarpe S, Deboutte D, Maes M. Peripheral markers of serotonergic and noradrenergic function in post-pubertal, caucasian males with autistic disorder. Neuropsychopharmacology 2000; 22(3):275–283. Leboyer M, Philippe A, Bouvard M, Guilloud-Bataille M, Dondoux D, Tabuteau F, Feingold J, Mouren-Simeoni M-C, and Launay J-M. Whole blood serotonin and plasma beta-endorphin in autistic probands and their ﬁrst-degree relatives. Biol Psychiatry 1999; 45:158–163. Kuperman S, Beeghly JH, Burns TL, Tsai LY. Serotonin relationships of autistic probands and their ﬁrst-degree relatives. J Am Acad Child Adolesc Psychiatry 1985; 24(2):186–190. Abramson RK, Wright HH, Carpenter R, Brennan W, Lumpuy O, Cole E, Young SR. Elevated blood serotonin in autistic probands and their ﬁrst-degree relatives. J Autism Dev Disord 1989; 19(3):397–407. Cook EH, Leventhal BL, Heller W, Metz J, Wainwright M, Freedman DX. Autistic children and their ﬁrst-degree relatives: relationships between serotonin and norepinephrine levels and intelligence. J Neuropsychiatry Clin Neurosci 1990; 2(3):268– 274. Leventhal BL, Cook EH, Morford M, Ravitz A. Relationships of whole blood serotonin and plasma norepinephrine within families. J Autism Dev Disord 1990; 20: 499–511. Piven J, Tsai GC, Nehme E, Coyle JT, Chase GA, Folstein SE. Platelet serotonin, a possible marker for familial autism. J Autism Dev Disord 1991; 21:51–59. Minderaa RB, Anderson GM, Volkmar FR, Akkerhuis GW, Cohen DJ. Urinary 5hydroxyindoleacetic acid and whole blood serotonin and tryptophan in autistic and normal subjects. Biol Psychiatry 1987; 22(8):933–940. Gillberg C, Svennerholm L, Hamilton-Hellberg C. Childhood psychosis and monoamine metabolites in spinal ﬂuid. J Autism Dev Disord 1983; 13:383–396. Gillberg C, Svennerholm L. CSF monoamines in autistic syndromes and other pervasive developmental disorders of early childhood. Br J Psychiatry 1987; 151:89–94.

12. 13. 14.

15.

16.

17.

18.

19.

20.

21.

22.

23. 24.

25. 26.

Neurobiology of Serotonin Function 27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

219

Narayan M, Srinath S, Anderson GM, Meundi DB. Cerebrospinal ﬂuid levels of homovanillic acid and 5-hydroxyindoleacetic acid in autism. Biol Psychiatry 1993; 33:630–635. Cohen DJ, Shaywitz BA, Johnson WT, Bowers MB. Biogenic amines in autistic and atypical children: Cerebrospinal ﬂuid measures of homovanillic acid and 5hydroxyindoleacetic acid. Arch Gen Psychiatry 1974; 31:845–853. Cohen DJ, Caparulo BK, Shaywitz BA, Bowers MB. Dopamine and serotonin metabolism in neuropsychiatrically disturbed children: CSF homovanillic acid and 5hydroxyindoleacetic acid. Arch Gen Psychiatry 1977; 34:545–550. Hoshino Y, Watanabe M, Tachibana R, Murata S, Kancko M, Yashima Y, Kumoshiro H. A study of the hypothalamus-pituitary function in autistic children by the loading test of 5HTP, TRH and LH-RH. Jpn J Brain Res 1983; 9:94–95. Hoshino Y, Tachibana JR, Watanabe M, Murata S, Yokoyama F, Kaneko M, Yashima Y, Kumoshiro H. Serotonin metabolism and hypothalamic-pituitary function in children with infantile autism and minimal brain dysfunction. Jpn J Psychiatry Neurol 1984; 26:937–945. McBride PA, Anderson GM, Hertzig ME, Sweeney JA, Kream J, Cohen DJ, Mann JJ. Serotonergic responsivity in male young adults with autistic disorder: results of a pilot study. Arch Gen Psychiatry 1989; 46:213–221. McDougle CJ, Naylor ST, Cohen DJ, Aghajanian GK, Heninger GR, Price LH. Effects of tryptophan depletion in drug-free adults with autistic disorder. Arch Gen Psychiatry 1996; 53:993–1000. Carpenter LL, Anderson GM, Pelton GH, Gudin JA, Kirwin PDS, Price LH, Heninger GR, McDougle CJ. Tryptophan depletion during continuous CSF sampling in healthy human subjects. Neuropsychopharmacology 1998; 19:26–35. Novotny S, Hollander E, Allen A, Mosovich S, Aronowitz B, Cartwright C, DeCaria C, Dolgoff-Kaspar R. Increased growth hormone response to sumatriptan challenge in adult autistic disorders. Psychiatry Res 2000; 94:173–177. Hollander E, Novotny S, Allen A, Aronowitz B, Cartwright C, DeCaria C. The relationship between repetitive behaviors and growth hormone response to sumatriptan challenge in adult autistic disorder. Neuropsychopharmacology 2000; 22:163–167. Chugani DC, Muzik O, Rothermel R, Behen M, Chakraborty P, Mangner T, da Silva EA, Chugani HT. Altered serotonin synthesis in the dentatothalamocortical pathway in autistic boys. Ann Neurol 1997; 42:666–669. Chugani DC, Muzik O, Behen M, Rothermel R, Janisse JJ, Lee J, Chugani HT. Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol 1999; 45:287–295. Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D, Lesch KP. Allelic variation of human serotonin transporter gene expression. J Neurochem 1996; 66: 2621–2624. Lesch KP, Balling U, Gross J, Strauss K, Wolozin BL, Murphy DL, Riederer P. Organization of the human serotonin transporter gene. J Neural Transmission 1994; 95:157–162. Cook EH, Courchesne R, Lord C, Cox NJ, Yan S, Lincoln A, Haas R, Courchesne E. Evidence of linkage between the serotonin transporter and autistic disorder. Mol Psychiatry 1997; 2:247–250.

220

McDougle et al.

42.

Spielman RS, Ewens WJ. The TDT and other family-based tests for linkage disequilibrium and association. Am J Hum Genet 1996; 59:983–989. Klauck SM, Poustka F, Benner A, Lesch KP, Poustka A. Serotonin transporter (5HTT) gene variants associated with autism? Hum Mol Genet 1997; 6(13):2233– 2238. Zhong N, Ye L, Ju W, Tsiouris J, Cohen I, Brown WT. 5-HTTLPR variants not associated with autistic spectrum disorders. Neurogenetics 1999; 2:129–131. International Molecular Genetic Study of Autism (IMGSA) Consortium. A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Hum Mol Genet 1998; 7(3):571–578. Maestrini E, Lai C, Marlow A, Matthews N, Wallace S, Bailey A, Cook EH, Weeks DE, Monaco AP, International Molecular Genetic Study of Autism (IMGSA) Consortium. Serotonin transporter (5-HTT) and K-aminobutyric acid receptor subunit 3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families. Am J Med Genet (Neuropsychiatric Genetics) 1999; 88:492–496. Persico AM, Militerni B, Bravaccio C, Schneider C, Melmed R, Conciatori M, Damiani V, Baldi A, Keller F. Lack of association between serotonin transporter gene promoter variants and autistic disorder in two ethnically distinct samples. Am J Med Genet 2000; 96:123–127. Lassig JP, Vachirasomtoon K, Hartzell K, Leventhal M, Courchesne E, Courchesne R, Lord C, Leventhal BL, Cook EH Jr. Physical mapping of the serotonin 5-HT7 receptor gene (HTR7) to chromosome 10 and pseudogene (HTR7P) to chromosome 12, and testing of linkage disequilibrium between HTR7 and autistic disorder. Am J Med Genet 1999; 88:472–475. McDougle CJ, Naylor ST, Cohen DJ, Volkmar FR, Heninger GR, Price LH. A double- blind, placebo-controlled study of ﬂuvoxamine in adults with autistic disorder. Arch Gen Psychiatry 1996; 53:1001–1008. McDougle CJ, Kresch L, Posey DJ. Repetitive thoughts and behavior in pervasive developmental disorders: treatment with serotonin reuptake inhibitors. J Autism Dev Disord 2000; 30(5):427–435.

43.

44. 45.

46.

47.

48.

49.

50.

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 development 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 heterogeneous. 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 abnormalities have been described in autistic patients, the most congruent ﬁndings 221

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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 TRPfree 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 pathogenetic 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-thalamocortical 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 between 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 transporter 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

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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 regulating 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 insitu hybridization in lymphocytes in which the 5-HT transporter has been detected by means of binding techniques (27), should aim to determine whether the increased [3H]-Par binding is due to an overexpression of the transporter protein. AUTISM AND THE CEREBELLUM Besides neurochemistry, neuroanatomical studies involving autoptic brain samples from autistic patients have produced evidence of alterations in the hippocampus, amygdala, and cerebellum; in particular at this level, a loss in Purkinje cells has been detected. These abnormalities have been conﬁrmed by magnetic resonance 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 occurring 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. According 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 neocerebellar 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 indeed 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–

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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 retroviral tracer (38). Its general architecture is quite simple, consisting of the primary outputs, represented by inhibitory Purkinje cells, which receive inputs from only one climbing ﬁbre, while mossy ﬁbers make excitatory synapses in the nuclei 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 cerebellar 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 5HT5A 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 receptor 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

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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 perikarya.

as the hippocampus and the ventrolateral region of the amygdala, while it is poorly represented in basal ganglia and absent from substantia nigra, areas involved in motor-function control. When the motor-control function of the cerebellum is impaired, the resulting and known effect is ataxia; similarly, when cerebellar control of cognitive and emotional functions is impaired, the result might be a sort of “cognitive”

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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 selective 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 autistic 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.

REFERENCES 1. 2. 3. 4. 5.

6.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Publishing, 1994. Schain RJ, Freedman DX. Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children. J Pediatr 1961; 58:315–320. Schmahmann JD. In: Bauman ML, Kemper TL, eds. The Neurobiology of Autism. Baltimore: John Hopkins University Press, 1994:195–226. Hoshino Y, Yamamoto T, Kaneko M. Blood serotonin and free tryptophan concentration in autistic children. Neuropsychobiology 1984; 11:22–27. Todd RD, Ciaranello RD. Demonstration of inter- and intraspecies differences in serotonin binding sites by antibodies from an autistic child. Proc Natl Acad Sci USA 1985; 82:612–616. Singh VKK, Singh EA, Warren RP. Hyperserotonemia and serotonin receptor antibodies in children with autism but not mental retardation. Biol Psychiatry 1997; 41:753–755.

Autism, Serotonin, and the Cerebellum 7. 8. 9. 10.

11. 12. 13.

14.

15. 16.

17.

18.

19. 20. 21. 22.

23.

24. 25.

227

Mc Dougle CJ, Naylor ST, Cohen CJ. Effect of tryptophan depletion in drug-free adults with autistic disorder. Arch Gen Psychiatry 1996; 53:993–1000. Potenza MC, C.J. Dougle CJ. The role of serotonin in autism-spectrum disorders. CNS Spectrum 1997; 2:25–42. Chugani DC, Muzik O., Rothermel R. Altered serotonin synthesis in the dentatothalamo-cortical pathway in autistic boys. Ann Neurol 1997; 42:666–669. Wennogle LP, Meyerson LR. Serotonin uptake inhibitors differentially modulate high-afﬁnity imipramine dissociation in human platelet membranes. Eur J Pharmacol 1985; 86:303–307. Marcusson JO, Ross SB. Binding of some antidepressants to the 5-hydroxytryptamine transporter in brain and platelets. Psychopharmacology 1991; 102:145–155. Hoffman BJ, Mezey E, Brownstein MJ. Cloning of a serotonin transporter affected by antidepressants. Science 1991; 254:579–580. Lesch KP, Wolozin BL, Murphy DL, Riederer A. Primary structure of the human platelet serotonin uptake: identity with the brain serotonin transporter. J Neurochem 1993; 60:2319–2322. Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS, Ganapathy V, Blakely RD. Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression and chromosomal localization. Proc Natl Acad Sci USA 1993; 90:2542–2546. Rausch JJ, Hutchinson J, Li X. Correlations of drug action between human platelets and human brain 5HT. Biol Psychiatry 1995; 137(suppl):600. Mellerup ET, Plenge P, Engelstoft M. High-afﬁnity binding of 3H-paroxetine and 3H-imipramine to human platelet membranes. Eur J Pharmacol 1983; 96:303– 309. Laruelle M, Vanisberg MA, Maloteaux JM. Regional and subcellular localization in human brain of 3H-paroxetine binding, a marker of serotonin uptake sites. Biol Psychiatry 1988; 24:299–309. Cook EH, Courchesne R, Lord C, Cox NJ, Yan S, Lincoln A. Evidence of linkage between the serotonin transporter and autistic disorder. Mol Psychiatry 1997; 2: 247–250. Klauch S, Poustka F, Benner A, Lesch KP, Poustka A. Serotonin transporter (5HTT) gene variants associated with autism? Hum Mol Genet 1997; 6:2233–2238. Boullin D, Freeman BJ, Geller E, Ritvo E, M. Rutter, Yuwiler A. Toward the resolution of conﬂicting ﬁndings. J Autism Dev Disord 1982; 12:97–103. Anderson GM, Minderaa RB, van Benthem PG, Volkmar FR, Cohen DJ. Platelet imipramine binding in autistic subjects. Psychiatry Res 1984; 11:133–141. Cook EH, Arora RC, Anderson GM, Berry-Kravis EM, Yan S, Yeoh HC. Platelet serotonin studies in hyperserotonemic relatives of children with autistic disorder. Life Sci 1993; 52:20006–20015. Marazziti D, Muratori F, Cesari A, Masala I, Baroni S, Giannaccini G, Dell’Osso L, Cosenza A, Pfanner P, Cassano GB. Autism and serotonin: new supportive ﬁndings from a platelet study. Pharmacopsychiatry 2000; 33:165–168. Lauder JM. Neurotransmitters as growth regulatory signals: role of receptors and second messengers. Trends Neurosci 1993; 16:233–240. Azmitia EC, Whitaker-Azmitia PM. Development and adult plasticity of serotoner-

228

26. 27.

28.

29.

30.

31.

32. 33. 34. 35. 36.

37. 38. 39. 40. 41. 42.

43.

Marazziti gic neurons and their target cells. In: Baumgartner HG, Goethert M, eds. Serotonergic Neurons and 5-HT Receptors in the CNS. New York: Springer, 1997:1–39. Bruening G, Liangos O, Baumgartner HG. Prenatal development of the serotonin transporter in mouse brain. Cell Tissue Res 1997; 289:211–221. Marazziti D, Rossi A, Giannaccini G, Baroni S, Lucacchini A, Cassano GB. Presence and characterization of the serotonin transporter in human resting lymphocytes. Neuropsychopharmacology 1998; 19:154–159. Courchesne E, Yeung-Courchesne R, Press GA, Hesselink JR, Jemigan TL. Hypoplasia of cerebellar vermal lobules VI and VII in autism. N Engl J Med 1988; 318: 1349–1354. Ritvo ER, Freeman BJ, Scheibel AB, Mason-Brothers A, Jenson WR, McMahon WM, Petersen BD, Jorde LB, Mo A, Ritvo A. Lower Purkinje cell counts in the cerebella of four autistic subjects: initial ﬁndings. Am J Psychiatry 1986; 143:862– 866. Hashimoto T, Tayama M, Murakawa K, Myazaki M, Kuroda Y. Development of the brain stem and cerebellum in autistic patients. J Autism Dev Disord 1995; 25: 1–18. Courchesne E, Saitoh O, Yeung-Courchesne R, Press GA, Haas RH, Schreibman L. Abnormality of cerebellar vermian lobules VI and VII in patients with infantile autism: identiﬁcation of hypoplastic and hyperplastic subgroups with MR imaging. Am J Roentgenol 1994; 162:123–130. Pivet J, Sabila K, Bailey J, Arnd S. An MRI study of autism: the cerebellum revisited. Neurology 1997; 49:546–551. Westman JC. Handbook of Learning Disabilities: A Multisystem Approach. Boston: Allyn & Bacon, 1990. Berntson GG, Torello MW. The paleocerebellum and the integration of behavioral function. Physiol Psychol 1982; 10:2–12 Schmahmann JD. In: Bauman ML, Kemper TL, eds. The Neurobiology of Autism. Baltimore: John Hopkins University Press, 1994:195–226. Parsons LM, Fox PT, Downs J, Glass T, Hirsch TB, Martin CC, Jerabek PA, Lancaster JL. Use of implicit motor imagery for visual shape discrimination as revealed by PET. Nature 1995; 375:54–58. Leiner HC, Leiner AL, Dow RS. Does the cerebellum contribute to mental skills? Behav Neurosci 1986; 100:443–454. Middleton FA, Strick PL. Anatomical evidence for the cerebellar and basal ganglia involvement in higher cognitive function. Science 1994; 266:458–461. Fiez JA. Cerebellar contributions to cognition. Neuron 1996; 16:13–15. Petersen SE. The processing of simple words studies with positron emission tomography. Ann Rev Neurosci 1993; 16:509–530. Pasqualetti M, Ori M, Nardi I, Cassano GB, Castagna A, Marazziti D. Distribution of serotonin 5A receptors in human brain. Mol Brain Res 1998; 56:1–8. Plassat JL, Boschert U, Amlaiky N, Hen R. The mouse 5HT5 receptor reveals a remarkable heterogeneity within the 5HT1D receptor family. EMBO J 1992; 11: 4779–4786. Hartig PR, Brancheck TA., Weinshank RL. A sub-family of 5-HT1D receptor genes. Trends Pharmacol 1992; 13:152–159.

Autism, Serotonin, and the Cerebellum 44.

45.

229

Matthew H, Boschert U, Amlaiky N, et al. Mouse 5-hydroxytryptamine5A and hydroxytryptamine5B receptors deﬁne a new family of serotonin receptors: cloning, functional expression, and chromosomal localization. Mol Pharmacol 1993; 43: 313–319. Marazziti D, Nardi I, Cassano GB. Autism, serotonin and cerebellum: might there be a connection? CNS Spectrum 1998; 3:80–82.

12 Antidepressants and Anticonvulsants/ Mood Stabilizers in the Treatment of Autism Sherie Novotny and Eric Hollander Mount Sinai School of Medicine New York, New York, U.S.A.

INTRODUCTION Many medications have been used to ameliorate autistic symptoms and behaviors in individuals with autism. Currently, there are no pharmacological treatments with established indications for autism (1). However, psychotropic medications have been used in autistic individuals to target core symptoms, behavioral dyscontrol, treatment of concurrent psychiatric disorders, and management of associated medical conditions such as seizures. Antidepressant medications, 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 (Prozac), sertraline (Zoloft), paroxetine (Paxil), ﬂuvoxamine (Luvox), and venlafaxine (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 carbamazepine, 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

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retrospective studies suggesting the efﬁcacy of these medications in autistic individuals.

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 autistic 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 individuals with affected relatives, 5-HT blood levels were signiﬁcantly higher than in those without affected relatives (10,11). In addition, relatives of autistic individuals 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 tryptophan 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 autoreceptor sensitivity in adult autistic patients (20,21), since these receptors are prevalent in frontal and thalamic, but not cerebellar, regions. These studies provide

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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-chlorophenylpiperazine (m-CPP) and sumatriptan have demonstrated that altered neuroendocrine responses to challenges with these agents signiﬁcantly correlate with severity 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 difﬁculties 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 females). 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 tachycardia, 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 insomnia, 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 autistic patients in whom there is already a predisposition to the development of seizures 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 33year-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. Brasˇic´ et al. (26), in an open-label clinical trial,

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found that clomipramine reduced adventitious movements and compulsions in ﬁve outpatient prepubertal males, aged 6–12, with autism and severe mental retardation, 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, behavioral 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 anticholinergic 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 antidepressants, 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 effects, changes in blood pressure, laboratory or electrocardiographic changes, seizures, or dyskinesias. Preliminary trials and observations have demonstrated alleviation of symptoms of autism with ﬂuoxetine (29–33). Most of these studies have reported a positive response to ﬂuoxetine in autistic patients, including improved social interaction and communication, a decrease in obsessive-compulsive behaviors 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 treatment 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, demonstrated signiﬁcant reduction in ritualistic behavior, such as snifﬁng, ﬁnger ﬂicking, and arm ﬂapping, and in frequency of temper outbursts, and increased tolerance 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 ﬂuoxetine. Treatment duration in responders was 14–16 months, and no side effects 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

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Global Impression (CGI) severity scale scores in 15 of 23 (65.22%) autistic patients 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 concomitant medications (neuroleptics, anticonvulsants, lithium, clonidine, benzodiazepines, 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 maximum dosage of 80 mg/day is high, and the dose was rapidly escalated. In addition, 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 effective 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-yearold 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 beneﬁt 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 treatment 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 sterotypy. Increases were noted on the hyperactivity subscale. Side effects included

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agitation and decreased appetite. Two patients discontinued treatment due to agitation. 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/compulsive and social behavior, problem behavior, stereotypies, and depression, but has also been shown to have some side effects, such as gastrointestinal disturbances 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 doubleblind, 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 improvement in ratings of social relatedness and language usage. Side effects included 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 maximum dose of 300 mg/day. Fluvoxamine blood levels were not obtained. In a

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blinded placebo-controlled crossover study of ﬂuvoxamine in children with autism (42), an improvement was seen in several behaviors, including social behaviors such as eye gaze, and language use during the medication phase. Approximately half of the children showed improvement in their CGI scores on ﬂuvoxamine. In another open-label study of ﬂuvoxamine in ﬁve aggressive children (43), two showed signiﬁcant decreases in aggressive behavior on ﬂuvoxamine, and another child showed a partial decrease in these behaviors. Another study (44) examined the relationship between dose and brain levels of both ﬂuvoxamine 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 treatment 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 generally 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 severalmonth follow-up period. Hellings and colleagues’ study (46) comprised nine adult inpatients. Other comorbid psychiatric conditions in these patients included OCD, intermittent explosive 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 carbamazepine 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 medication on obsessive-compulsive symptoms, language and communication dimensions, and social skills were not studied. In a recently published 12-week openlabel 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 subjects were found to be much or very much improved globally, with speciﬁc reductions noted in repetitive behaviors and levels of aggression. In addition, the SSRI

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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 associated 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. Trazodone has been shown to be effective in decreasing the aggressive and self-injurious 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 clomipramine, an SRI (23). Venlafaxine treatment, examined in a small group of individuals with autism spectrum disorders ranging in age from 3 to 21, was found to be effective in decreasing repetitive behaviors and hyperactivity, and improving social deﬁcits, attention, communication, and language function. Side effects included 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 determined 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 developing children develop verbal auditory agnosia at the same time as seizure disorder. 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,

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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 stabilization. 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 language 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. Improvements in associated symptoms of autism were also seen, including decreased 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

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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 refractory 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 effective in reducing aggressive behavior in this population. One report (69) in young children aged 3–6 with severe behavioral disorders, including autism and “childhood schizophrenia,” failed to show improvement with either lithium or chlorpromazine, with the exception of a marked reduction of aggressive and self-

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injurious behavior in one of 10 children. The patient was described as having childhood schizophrenia but may have met criteria for autism or pervasive developmental 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, ﬂuvoxamine, 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 instability, as well as for treating clinical and subclinical seizure disorders. All these medications, however, will need to be further examined using double-blind, placebo-controlled methods to validate their efﬁcacy and safety in treating the comorbid 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 Research on Schizophrenia and Depression, Eli Lilly and Company, and Abbott Laboratories. REFERENCES 1.

2.

3.

4.

Aman M, Van Bourgondien ME, Wolford P, et al. Psychotropic and anticonvulsant drugs in subjects with autism: prevalence and patterns of use. J Am Acad Child Adolesc Psychiatry 1995; 34(12):1672–1680. Ciarenello RD, Vanderberg SR, Anders TF. Intrinsic and extrinsic determinants of neuronal development: relevance to infantile autism. J Autism Dev Disord 1982; 12:115–145. Anderson GM, Freedman DX, Cohen DJ, Volkmar FR, Hoder EL, McPhedran P, Minderaa RB, Hansen CR, Young JG. Whole blood serotonin in autistic and normal subjects. J Child Psychol Psychiatry 1987; 28:885–900. Hoshino Y, Yamamoto T, Kaneko M, Tachibana R, Wantabe M, Ono Y, Kumashiro H. Blood serotonin and free tryptophan concentration in autistic children. Neuropsychobiology 1984; 11:22–27.

242

Novotny and Hollander

5.

Ritvo ER, Yuwiler A, Geller E, Ornitz EM, Saeger K, Plotkin S. Increased blood serotonin and platelets in early infantile autism. Arch Gen Psychiatry 1970; 23(6): 566–572. Campbell M, Plij M. Behavioral and cognitive measures used in psychopharmacological studies of infantile autism. Psychopharmacol Bull 1985; 21:1047–1053. Ritvo ER, Freeman BJ, Yuwiler A, et al. Fenﬂuramine therapy for autism: promise and precaution. Psychopharmacol Bull 1986; 22:133–140. Young JG, Level LI, Newcorn JH, Knott PJ. Genetic and neurobiological approaches to the pathophysiology of autism and the pervasive developmental disorders. In: Meltzer HY, ed. Psychopharmacology: The Third Generation of Progress. New York: Raven Press, 1987:825–836. Schain RJ, Freedman DX. Studies on 5-hydroxyindoleamine metabolism in autistic and other mentally retarded children. J Pediatr 1961; 58:315–320. Kuperman S, Beeghly JH, Burns TL, Tsai LY. Serotonin relationships of autistic probands and their ﬁrst-degree relatives. J Am Acad Child Adolesc Psychiatry 1985; 24:186–190. Piven J, Chase GA, Landa R, Wzorek M, Gayle J, Cloud D, Folstein S. Psychiatric disorders in the parents of autistic individuals. J Am Acad Child Adolesc Psychiatry 1991; 30:471–478. Abrahamson RK, Wright HH, Carpenter R, et al. Elevated blood serotonin in autistic probands and their ﬁrst-degree relatives. J Autism Dev Disord 1989; 19:397–407. Cook EH, Leventhal BL, Hellar W, et al. Relationships between serotonin and norepinephrine levels and intelligence. J Neuropsychiatry Clin Neurosci 1990; 2:268– 274. Marazziti D, Muratori F, Cesari A, Masala I, Baroni S, Giannaccini G, Dell’Osso L, Cosenza A, Pfanner P, Cassano GB. Increased density of platelet serotonin transporter in autism. Pharmacopsychiatry 2000; 33(5):165–168. Croonenberghs J, Delmeire L, Verkerk R, Lin AH, Meskal A, Neels H, Van der Planken M, Scharpe S, Deboutte D, Pison G, Maes M. Peripheral markers of serotonin and noradrenergic function in post-pubertal, caucasian males with autistic disorder. Neuropsychopharmacology 2000; 22(3):275–283. McDougle C, Naylor S, Cohen D, Aghajanian G, Heninger G, Price L. Effects of tryptophan depletion in drug-free adults with autistic disorder. Arch Gen Psychiatry 1996; 53(11):993–1000. McBride PA, Anderson GM, Hertzig ME, et al. Serotonergic response in male young adults with autistic disorder. Arch Gen Psychiatry 1989; 46:205–212. Todd RD, Ciaranello RD. Demonstration of inter- and intraspecies differences in serotonin binding sites by antibodies from an autistic child. Proc Natl Acad Sci USA 1985; 82:612–616. Chugani DC, Muzik O, Rothermel R, Behen M, Chakraborty P, Mangner T, da Silva EA, Chugani HT. Altered serotonin synthesis in the dentathalamocortical pathway in autistic boys. Ann Neurol 1997; 42:666–669. Hollander E, Novotny S, Allen A, Aronowitz B, DeCaria C. The relationship between repetitive behaviors and growth hormone response to sumatriptan challenge in adult autistic disorder. Neuropsychopharmacology 2000; 22(2):163–167. Novotny S, Hollander E, Allen A Mosovich S, Aronowitz B, Cartwright C, DeCaria

6. 7. 8.

9. 10.

11.

12. 13.

14.

15.

16.

17. 18.

19.

20.

21.

Antidepressants and Anticonvulsants

22. 23.

24. 25.

26.

27. 28.

29. 30. 31.

32. 33. 34. 35.

36. 37. 38. 39.

40.

243

C, Dolgoff-Kaspar R. Increased growth hormone response to sumatriptan challenge in adult autistic disorders. Psychiatry Res 2000; 44(2):173–177. Gordon C, Rapaport J, Hamburger S, et al. Differential response of autistic disorder to clomipramine. J Am Acad Child Adolesc Psychiatry 1991; 30:164. Gordon C, State R, Nelson J, Hamburger S, Rapoport J. A double-blind comparison of clomipramine, desipramine, and placebo in the treatment of autistic disorder. Arch Gen Psychiatry 1993; 50:441–447. McDougle CJ, Price LH, Volkmar FR, et al. Clomipramine in autism: preliminary evidence of efﬁcacy. J Am Acad Child Adolesc Psychiatry 1992; 31:746–750. Barger HJ, Megonige JJ, Slomka GT, Monieverde E. Clomipramine treatment of stereotypic behaviors and self-injury in patients with developmental disabilities. J Am Acad Child Adolesc Psychiatry 1992; 31:1157–1160. Brasˇic´ JR, Barnett JY, Kaplan D, et al. Clomipramine ameliorates adventitious movements and compulsions in prepubertal boys with autistic disorder and severe mental retardation. Neurology 1994; 44:1309–1312. Sanchez LE, Campbell M, Small AM, et al. A pilot study of clomipramine in young autistic children. J Am Acad Child Adolesc Psychiatry 1996; 35(4):537–544. McDougle CJ, Naylor ST, Cohen DJ, Volkmar FR, Heninger GR, Price LH. A double-blind placebo-controlled study of ﬂuvoxamine in adults with autistic disorder. Arch Gen Psychiatry 1996; 53:1001–1008. Mehlinger R, Scheftner WA, Poznanski E. Fluoxetine and autism [letter]. J Am Acad Child Adolesc Psychiatry 1990, 29:985. Todd RD. Fluoxetine in autism [letter]. Am J Psychiatry 1991; 148:1089. Cook E, Rowlett R, Jaselskis C, Leventhal B. Fluoxetine treatment of patients with autism and mental retardation. J Am Acad Child Adolesc Psychiatry 1992; 31:739745. Ghaziuddin M, Tsai L, Ghaziuddin N. Fluoxetine in autism with depression [letter]. J Am Acad Child Adolesc Psychiatry 1991; 30(3):508–509. Markowitz PI. Effect of ﬂuoxetine on self-injurious behavior in the developmentally disabled: a preliminary study. J Clin Psychopharmacol 1992; 12:27–31. Koshes RJ. Use of ﬂuoxetine for obsessive-compulsive behavior in adults with autism. Am J Psychiatry 1997; 154(4):578. Awad G. The use of selective serotonin reuptake inhibitors in young children with pervasive developmental disorders: some clinical observations. Can J Psychiatry 1996; 41:361-366. Fatemi SH, et al. Fluoxetine in treatment of adolescent patients with autism: a longitudinal open trial. J Autism Dev Disord 1998; 28(4):303–307. DeLong GR, Teague LA, Kamran MM. Effects of ﬂuoxetine treatment in young children with idiopathic autism. Dev Med Child Neurol 1998; 40:551–562. Peral M, Alcami M, Gilaberte I. Fluoxetine in children with autism. J Am Acad Child Adolesc Psychiatry 1999; 38(12):1472–1473. Hollander E, Cartwright C, Wong CM, DeCaria CM, DelGiudice-Asch G, Buchsbaum MS, Aronowitz BR. A dimensional approach to the autism spectrum. CNS Spectrum 1998; 3:22–39. Buchsbaum MS, Hollander E, Haznedar MM, Tang C, Spiegel-Cohen J, Wei TC, Solimando A, Buchsbaum BR, Robins D, Bienstock, C, Cartwright C, Mosovich S.

244

41.

42.

43.

44.

45.

46.

47.

48. 49. 50. 51.

52. 53. 54. 55. 56. 57.

Novotny and Hollander Effect of ﬂuoxetine on regional cerebral metabolism in autistic spectrum disorders: a pilot study. Int J Neuropsychopharmacol 2001; 4(2):119–125. McDougle CJ, Price LH, Goodman WK. Fluvoxamine treatment of coincident autistic disorder and obsessive-compulsive disorder: a case report. J Autism Dev Disord 1990; 20(4):537–543. Fukada T, Sugie H, Ito M, Sugie Y. [Clinical evaluation of treatment with ﬂuvoxamine, a selective serotonin reuptake inhibitor in children with autistic disorder.] No To Hattasu 2001; 33(4):314–318. Yokoyama H, Hirose M, Haginoya K, Munakata M, Iinuma K. [Treatment with ﬂuvoxamine against self-injury and aggressive behavior in autistic children.] No To Hattasu 2001; 34(3):249–253. Strauss WL, Unis AS, Cowan C, Dawson G, Dager SR. Flourine magnetic resonance spectroscopy measurement of brain ﬂuvoxamine and ﬂuoxetine in pediatric patients treated for pervasive developmental disorders. Am J Psychiatry 2002; 159(5):755–760. Steingard RJ, Zimmitsky B, DeMaso DR, Bauman ML, Bucci JP. Sertraline treatment of transition-anxiety and agitation in children with autistic disorder. J Child Adolesc Psychopharmacol 1997; 7(1):9–15. Hellings JA, Kelley LA, Gabrielli WF, Kilgore E, Shah P. Sertraline response in adults with mental retardation and autistic disorder. J Clin Psychiatry 1996; 57: 333–336. McDougle CJ, Brodkin ES, Naylor ST, Carlson DC, Cohen DJ, Price LH. Sertraline in adults with pervasive developmental disorders: a prospective open label investigation. J Clin Psychopharmacol 1998; 18:62–66. Snead RW, Boon F, Presberg J. Paroxetine for self-injurious behavior. J Am Acad Child Adolesc Psychiatry 1994; 33(6):909–910. Posey DJ, Litwiller M, Koburn A, McDougle CJ. Paroxetine in autism. J Am Acad Child Adolesc Psychiatry 1999; 38(2):111–112. Gedye A. Trazodone reduced aggressive and self-injurious movements in a mentally handicapped male patient with autism. J Clin Psychopharmacol 1991; 11(4):275–276. Hollander E, Kaplan A, Cartwright C, Reichman D. Venlafaxine in children, adolescents, and young adults with autism spectrum disorders: an open retrospective clinical report. J Child Neurol 2000; 15(2):32–135. Volkmar FR, Nelson DS. Seizure disorders in autism. J Am Acad Child Adolesc Psychiatry 1990; 29:127–129. Gillberg C, Coleman M. The Biology of the Autistic Syndromes. 2nd ed. London: MacKeith Press, 1992:74–81. Tharpe AM, Olson BJ. Landau-Kleffner syndrome: acquired epileptic aphasia in children. J Am Acad Audiol 1994; 5(2):146–150. Plioplys A. Autism: electroencephalogram abnormalities and clinical improvement with valproic acid. Arch Ped Adolesc Med 1994; 148:220–222. Childs JA, Blair JL. Valproic acid treatment of epilepsy in autistic twins. J Neurol Nursing 1997; 29:244–248. Hollander E, Dolgoff-Kaspar R, Cartwright C, Rawitt R, Novotny S. An open trial of divalproex sodium in autism spectrum disorders. J Clin Psychiatry 2001; 62: 530–534.

Antidepressants and Anticonvulsants 58.

59. 60. 61.

62.

63.

64.

65. 66. 67.

68.

69.

245

Hellings JA, Chibber S, Kilgore ER, Nickel J. Valproate response as a function of blood levels in adolescents with autistic disorder and PDD NOS. Proceedings of the 150th Annual American Psychiatric Association Meeting, San Diego, CA, 1997: 260. Sovner R. The use of valproate in the treatment of mentally retarded persons with typical and atypical bipolar disorders. J Clin Psychiatry 1989; 50(3):40–43. Komoto J, Usui S. Infantile autism and affective disorder. J Autism Dev Disord 1984; 14(1):81–84. Uvebrant P, Bauziene R. Intractable epilepsy in children: the efﬁcacy of lamotrigine treatment, including non-seizure related beneﬁts. Neuropediatrics 1994; 25:284– 289. Belsito KM, Law PA, Kirk KS, Landa RJ, Zimmerman AW. Lamotrigine therapy for autistic disorder: a randomized, double-blind, placebo controlled trial. J Autism Dev Disord 2001; 31(2):175–181. Kerbeshian J, Burd L, Fisher W. Lithium carbonate in the treatment of two patients with infantile autism and atypical bipolar symptomatology. J Clin Psychopharmacol 1987; 7(6):401–405. Steingard R, Biederman J. Lithium responsive manic-like symptoms in two individuals with autism and mental retardation. J Am Acad Child Adolesc Psychiatry 1987; 26(6):932–935. Dostal T, Zvolsky P. Antiaggressive effect of lithium salts in the treatment of severe mentally retarded adolescents. Int Pharmacopsychiatry 1970; 5:203–207. Micev V, Lynch DM. Effects of lithium on disturbed severely mentally retarded patients [letter]. Br J Psychiatry 1974; 125(0):110. Craft M, Ismail IA, Krishnamurti D, Mathews J, Regan A, Seth RV, North PM. Lithium in the treatment of aggression in mentally handicapped patients: a double blind trial. Br J Psychiatry 1987; 150:685–689. Tyrer SP, Walsh A, Edwards DE, Berney TP, Stephens DA. Factors associated with a good response to lithium in aggressive mentally handicapped subjects. Prog Neuropsychopharmacol Biol Psychiatry 1984; 8(4-6):751–755. Campbell M, Fish B, Korein J, Shapiro T, Collins P, Koh C. Lithium and chlorpromazine: a controlled crossover study of hyperactive severely disturbed young children. J Autism Child Schizophr 1972; 2(3):234–263.

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 autistic individuals, especially when treating severe symptoms such as physical aggression 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 recommendations for their practical use in the treatment of PDDs. Finally, future directions 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 extrapyram247

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Table 1 Relative Receptor Afﬁnities of Atypical Antipsychotics Receptor

Clozapine

D1 D2 D3 D4 D6 D7 5-HT1A 5-HT1D 5-HT2A 5-HT2C 5-HT3 5-HT6 5-HT7 Alpha1 Alpha2 Histamine1 Muscarinic1

High Low High

Risperidone Low High High High Mod High

Olanzapine

Quetiapine

High High High High

Low/mod. Low/mod. None

Low/mod. High High High High Mod./high Mod. High High

High

High

Low/mod.

High High High High High High Low

Mod./high Low High High

Mod./high Mod./high High None

Ziprasidone Low High High Mod.

High High High High Very low High High Mod. Very low Mod. 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 disorder. 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

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in a large minority of autistic children (2). This ﬁnding has been consistently replicated (3), although not yet fully explained. Most recently, McBride and colleagues (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 control group, although the 25% elevation was less than that typically reported. African-American and Latino children had signiﬁcantly lower levels of WBS than Caucasian children, regardless of diagnosis. The postpubertal subjects had consistently 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 increase in maladaptive behaviors in drug-free autistic adults. Hollander and associates (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. Fenﬂuramine, an indirect 5-HT agonist, was extensively studied following an inﬂuential report suggesting that it improved symptoms in three boys with autism (9). However, 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), ﬂuvoxamine (12), ﬂuoxetine (13), sertraline (14), and paroxetine (15), have been reported to reduce several maladaptive behaviors associated with autism. In contrast to fenﬂuramine, double-blind, placebo-controlled studies have supported the use of clomipramine in children, adolescents, and young adults with autistic disorder (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 enhance DA transmission) often worsen clinical symptoms and stereotypies in autistic children (17) and that typical antipsychotics (DA receptor antagonists) reduce certain symptoms associated with autism (18), studies of DA metabolism increased. Cerebrospinal ﬂuid levels of homovanillic acid (HVA), the primary me-

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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 autism 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 withdrawal dyskinesias (WDs) may be more frequent in this clinical population. In a large, prospective study of 118 children with autistic disorder treated with haloperidol, 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 (affective ﬂattening, alogia, and avolition) and the social withdrawal often seen in autistic disorder. This similarity led others to hypothesize that atypical antipsychotics 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 published describing beneﬁcial effects of the atypical antispychotics in treating maladaptive 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 children (ages 8 to 12 years) with autistic disorder who had not responded to haloperidol. All three subjects showed initial improvement improving in hyperactivity, negativism, aggression, and communication at doses of clozapine ranging from

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100 to 200 mg. One subject relapsed at 5 months. Adverse effects included transient 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 participants. 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). Aggression 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 autism, 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 efﬁcacious 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.

3 AD (5–10) 4 AD, 9 AS, 1 PDDNOS (9–17) 5 AD, 6 PDDNOS (8–17) 13 PDDNOS (25–49) 6 AD (5–9) 1 AD (12) 11 AD (6–34) 11 AD, 3 AS, 1 CDD, 3 PDDNOS (5–18) 6 PDD

Demb, 1996 (35)

Fisman, 1996 (28)

Lott, 1996 (37) Findling, 1997 (38)

Frischauf, 1997 (39)

Horrigan, 1997 (40) McDougle, 1997 (41)

Perry, 1997 (42)

Hardan, 1996 (36)

Simeon, 1995 (34)

2 PDD (29–30) 2 AD, 1 PDDNOS (20–44) 1 PDDNOS (13)

37 MR ⫾ autistic features (15–58)

Risperidone Vanden Borre, 1993 (31)

Purdon, 1994 (32) McDougle, 1995 (33)

3 AD (8–12)

No. subjects/ age range ( years)

Clozapine Zuddas, 1996 (30)

Medication/ﬁrst author

Open-label

Open-label Open-label

Case report

Case series Open-label

Open-label

Case series

Case series

Case report

DBPC (crossover; on concomitant drugs) Case series Case series

Case series

Methodology

5/6 improved

11/11 improved 12/18 improved

Improved

10/13 improved 6/6 improved

8/11 improved

14/14 improved

3/3 improved

Improved

2/2 improved 3/3 improved

Risperidone ⬎ placebo

2/3 sustained improvement

Results

Agitation, anxiety, repetitive behavior, social awareness Aggression, hyperactivity, impulsivity, oppositionality, self-injury Aggression, self-injury Aggression, fearfulness, irritability, restlessness, tantrums Aggression, concentration, depression, language Aggression, self-injury, sleep Aggression, impulsivity, repetitive behavior, social relatedness Anger, mood lability, sociability

Behavior, cognition, stereotypes Aggression, repetitive behavior, social relatedness Apathy, deﬁance, irritability, social withdrawal Aggression, hyperactivity, self-injury

Not stated

Aggression, communication, hyperactivity, negativism

Areas of improvement

Side effects

Hepatotoxicity, weight gain, withdrawal dyskinesia

Weight gain Weight gain

EPS, sedation, weight gain Weight gain, sedation

Galactorrhea, weight gain

EPS, transient sedation, weight gain Transient sedation

Transient sedation

Sedation

Enuresis, transient sedation

Table 2 Studies of Atypical Antipsychotics in Autistic Disorder and Related Pervasive Developmental Disorders

252 Posey and McDougle

Open-label Open-label

23 PDD (children) 6 AD

2/6 improved

Improved

Improved at 40 mg/day 6/8 improved

Improved Improved Improved

10/11 improved; 7/7 maintained improvement for 1 year

Improved Risperidone (8/14 improved) ⬎ placebo (0/ 16 improved) 8/10 improved Improved Maintained improvement for 2 years 2/2 improved

3/4 improved

2/2 improved

Irritability, self-injury

Psychosis Aggression, anxiety, depression, hyperactivity, irritability, self-injury, social behavior Accessibility

Aggression, hyperactivity, sleep Aggression, mood Aggression, hyperactivity

Aggression, irritability, social relatedness Anger, autistic symptoms, hyperactivity, uncooperativeness

Aggression, autistic symptoms Food refusal Aggression, noncompliance, self-injury

Insomnia Aggression, anxiety, depression, irritability, repetitive behavior

Aggression, disruptiveness, self-injury

Aggression, hyperactivity, self-injury

Behavioral activation, sedation, seizure, weight gain

Weight gain

None Weight gain, sedation

None

Tachycardia, QTc prolongation Weight gain, facial dystonia, amenorrhea

Weight gain, gynecomastia

Weight gain

None Transient sedation

Akathisia, sedation

None

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.

Kemner, 2000 (55) Quetiapine Martin, 1999 (56)

Case report Open-label

1 AD (14) 5 AD, 3 PDD-NOS (5–42)

Open-label

Case report Case report Case report

9 AD, 2 PDD-NOS (7–17)

Zuddas, 2000 (50)

Case series

Open-label Case report Case series

Case report DBPC

Case series

Case series

1 AD (10) 1 AD (17) 1 AD (8)

2 AD (2)

Posey, 1999 (49)

Olanzapine Horrigan, 1997 (51) Rubin, 1997 (43) Malek-Ahmadi, 1998 (52) Heimann, 1999 (53) Potenza, 1999 (54)

10 AD (4–10) 1 AD (3) 2 AD (27–33)

1 AD, 1 PDDNOS (3–5) 3 AD, 1 PDDNOS (31–48) 1 AD (3) 17 AD, 14 PDD-NOS (18–43)

Nicolson, 1998 (46) Schwam, 1998 (47) Dartnall, 1999 (48)

Doan, 1998 (45) McDougle, 1998 (29)

Cohen, 1998 (44)

Rubin, 1997 (43)

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There have not yet been any published placebo-controlled studies of risperidone in children and adolescents with autistic disorder. In 1997, the National Institute of Mental Health contracted with ﬁve university-afﬁliated medical centers (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 colleagues (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 improvement item. Improvement was seen in overall symptoms of autism, hyperactivity, social relatedness, affectual reactions, sensory responses, language usage, selfinjury, 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 disorder (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-

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pine (dose range 1.25–20 mg daily) was efﬁcacious on several measures including 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 because 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 population, 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 addition, 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 observed with haloperidol treatment in children with autistic disorder (25). Fortunately, 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.

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Early reports of risperidone treatment of children and adolescents with various 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 haloperidol 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 hepatotoxicity resolved after risperidone discontinuation and weight loss. Subsequent to this, Szigethy and colleagues (74) reviewed the charts of 38 children and adolescents treated with risperidone (mean dose 2.5 mg daily; mean duration of treatment 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 incidence of this may be lower with olanzapine. The signiﬁcance of an elevated prolactin level in the absence of clinically signiﬁcant symptoms is unclear.

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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 documented, and weekly to biweekly WBC counts are required during treatment. Possible 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 antipsychotics (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 carefully 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 antipsychotics 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

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Table 3 Recommended Atypical Antipsychotic Dosages in Pervasive Developmental Disorders Medication Clozapine Risperidone Olanzapine Quetiapine a b

Suggested starting dose (mg/day)a 25 0.5 2.5 50

(12.5) (0.25) (1.25) (25)

Usual effective dose (mg/day) 100–300b 0.5–6 2.5–20 75–400

Dosages in parentheses are those suggested for young children. 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 repetitive 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 pharmacotherapy of interfering symptoms of autism. Clozapine, because of its potential to cause seizures and agranulocytosis, should be reserved for the most severely 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 caregivers 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 glucose 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-

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tions with cardiac effects. Finally, clozapine treatment requires regular monitoring 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 olanzapine, quetiapine, and ziprasidone would be welcome, especially to better determine 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 improvement 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 development 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 Depression (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 Psychiatric Research Fellowship Award (Dr. Posey), a NARSAD Young Investigator Award (Dr. Posey), the State of Indiana Division of Mental Health, and Department of Housing and Urban Development Grant B-01-SP-IN-0200 (Representative Dan Burton). REFERENCES 1.

Janicak PG, Davis JM, Preskorn SH, Ayd FJ Jr. Principles and Practice of Psychopharmacotherapy. Philadelphia: Lippincott Williams & Wilkins, 2001.

260

Posey and McDougle

2.

Schain RJ, Freedman DX. Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children. J Pediatr 1961; 58:315–320. Anderson GM, Hoshino Y. Neurochemical studies of autism. In: Handbook of Autism and Pervasive Developmental Disorders. Cohen DJ, Hoshino Y, eds. New York: John Wiley & Sons, 1997:325–343. McBride PA, Anderson GM, Hertzig ME, Snow ME, Thompson SM, Khait VD, Shapiro T, Cohen DJ. Effects of diagnosis, race, and puberty on platelet serotonin levels in autism and mental retardation. J Am Acad Child Adolesc Psychiatry 1998; 37(7):767–776. Hoshino Y, Tachibana JR, Watanabe M, Murata S, Yokoyama F, Kaneko M, Yashima Y, Kumoshiro H. Serotonin metabolism and hypothalamic-pituitary function in children with infantile autism and minimal brain dysfunction. Jpn J Psychiatry Neurol 1984; 26:937–945. McBride PA, Anderson GM, Hertzig ME, Sweeney JA, Kream J, Cohen DJ, Mann JJ. Serotonergic responsivity in male young adults with autistic disorder: results of a pilot study. Arch Gen Psychiatry 1989; 46:213–221. McDougle CJ, Naylor ST, Cohen DJ, Aghajanian GK, Heninger GR, Price LH. Effects of tryptophan depletion in drugfree adults with autistic disorder. Arch Gen Psychiatry 1996; 53:993–1000. Hollander E, Novotny S, Allen A, Aronowitz B, Cartwright C, DeCaria C. The relationship between repetitive behaviors and growth hormone response to sumatriptan challenge in adult autistic disorder. Neuropsychopharmacology 2000; 22(2): 163–167. Geller E, Ritvo E, Freeman B, Yuwiler A. Preliminary observations on the effect of fenﬂuramine on blood serotonin and symptoms in three autistic boys. N Engl J Med 1982; 307:165–169. Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV. Valvular heart disease associated with fenﬂuramine-phentermine. N Engl J Med 1997; 337:581–588. Gordon CT, State RC, Nelson JE, Hamburger SD, Rapoport JL. A double-blind comparison of clomipramine, desipramine, and placebo in the treatment of autistic disorder. Arch Gen Psychiatry 1993; 50:441–447. McDougle CJ, Naylor ST, Cohen DJ, Volkmar FR, Heninger GR, Price LH. A double-blind, placebo-controlled study of ﬂuvoxamine in adults with autistic disorder. Arch Gen Psychiatry 1996; 53:1001–1008. Cook EH, Rowlett R, Jaselskis C, Leventhal BL. Fluoxetine treatment of children and adults with autistic disorder and mental retardation. J Am Acad Child Adolesc Psychiatry 1992; 31(4):739–745. McDougle CJ, Brodkin ES, Naylor ST, Carlson DC, Cohen DJ, Price LH. Sertraline in adults with pervasive developmental disorders: a prospective open-label investigation. J Clin Psychopharmacol 1998; 18(1):62–66. Posey DJ, Litwiller M, Koburn A, McDougle CJ. Paroxetine in autism. J Am Acad Child Adolesc Psychiatry 1999; 38(2):111–112. Posey DJ, McDougle CJ. The pharmacotherapy of target symptoms associated with autistic disorder and other pervasive developmental disorders. Harvard Rev Psychiatry 2000; 8(2):45–63.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15. 16.

Atypical Antipsychotics 17.

18.

19. 20.

21.

22.

23.

24.

25.

26.

27. 28. 29.

30. 31.

32. 33.

261

Campbell M, Small AM, Collins PJ, Friedman E, David R, Genieser N. Levodopa and levoamphetamine: a crossover study in young schizophrenic children. Curr Ther Res 1976; 19:70–83. Campbell M, Anderson L, Meier M, Cohen I, Small A, Samit C, Sachar E. A comparison of haloperidol and behavior therapy and their interaction in autistic children. J Am Acad Child Adolesc Psychiatry 1978; 17(4):640–655. Gillberg C, Svennerholm L, Hamilton-Hellberg C. Childhood psychosis and monoamine metabolites in spinal ﬂuid. J Autism Dev Disord 1983; 13:383–396. Narayan M, Srinath S, Anderson GM, Meundi DB. Cerebrospinal ﬂuid levels of homovanillic acid and 5-hydroxyindoleacetic acid in autism. Biol Psychiatry 1993; 33:630–635. Minderaa RB, Anderson GM, Volkmar F, Harcherik D, Akkerhuis CW, Cohen DJ. Neurochemical study of dopamine functioning in autistic and normal subjects. J Am Acad Child Adolesc Psychiatry 1989; 28:200–206. Anderson L, Campbell M, Grega D, Perry R, Small A, Green W. Haloperidol in the treatment of infantile autism: effects on learning and behavioral symptoms. Am J Psychiatry 1984; 141:1195–1202. Anderson LT, Campbell M, Adams P, Small AM, Perry R, Shell J. The effects of haloperidol on discrimination learning and behavioral symptoms in autistic children. J Autism Dev Disord 1989; 19:227–239. Perry R, Campbell M, Adams P, Lynch N, Spencer EK, Curren EL, Overall JE. Long-term efﬁcacy of haloperidol in autistic children: continuous versus discontinuous drug administration. J Am Acad Child Adolesc Psychiatry 1989; 28:87–92. Campbell M, Armenteros JL, Malone RP, Adams PB, Eisenberg ZW, Overall JE. Neuroleptic-related dyskinesias in autistic children: a prospective, longitudinal study. J Am Acad Child Adolesc Psychiatry 1997; 36:835–843. Chouinard G, Jones B, Remington G, Bloom D, Addington D, MacEwan GW, Labelle A, Beauclair L, Arnott W. A Canadian multicenter placebo-controlled study of ﬁxed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 1993; 13:25–40. Volkmar FR, Cohen DJ. Comorbid association of autism and schizophrenia. Am J Psychiatry 1991; 148:1705–1707. Fisman S, Steele M. Use of risperidone in pervasive developmental disorders: a case series. J Child Adolesc Psychopharmacol 1996; 6:177–190. McDougle CJ, Holmes JP, Carlson DC, Pelton GH, Cohen DJ, Price LH. A doubleblind placebo-controlled study of risperidone in adults with autistic disorder and other pervasive developmental disorders. Arch Gen Psychiatry 1998; 55:633–641. Zuddas A, Ledda MG, Fratta A, Muglia P, Cianchetti C. Clinical effects of clozapine on autistic disorder. Am J Psychiatry 1996; 153:738. Vanden Borre R, Vermote R, Buttiens M, Thiry P, Dierick G, Geutjens J, Sieben G, Heylen S. Risperidone as add-on therapy in behavioural disturbances in mental retardation: a double-blind placebo-controlled cross-over study. Acta Psychiatr Scand 1993; 87:167–171. Purdon SE, Lit W, Labelle A, Jones DW. Risperidone in the treatment of pervasive developmental disorder. Can J Psychiatry 1994; 39:400–405. McDougle CJ, Brodkin ES, Yeung PP, Naylor ST, Cohen DJ, Price LH. Risperidone

262

34.

35.

36.

37.

38.

39. 40. 41.

42.

43. 44.

45. 46. 47. 48.

49.

50.

Posey and McDougle in adults with autism or pervasive developmental disorder. J Child Adolesc Psychopharmacol 1995; 5(4):273–282. Simeon JB, Carrey NJ, Wiggins DM, Milin RP, Hosenbocus SN. Risperidone effects in treatment-resistant adolescents: preliminary case reports. J Child Adolesc Psychopharmacol 1995; 5(1):69–79. Demb HB. Risperidone in young children with pervasive developmental disorders and other developmental disabilities. J Child Adolesc Psychopharmacol 1996; 6(1): 79–80. Hardan A, Johnson K, Johnson C, Hrecznyj B. Risperidone treatment of children and adolescents with developmental disorders. J Am Acad Child Adolesc Psychiatry 1996; 35:1551–1556. Lott RS, Kerrick JM, Cohen SA. Clinical and economic aspects of risperidone treatment in adults with mental retardation and behavioral disturbance. Psychopharmacol Bull 1996; 32:721–729. Findling RL, Maxwell K, Wiznitzer M. An open clinical trial of risperidone monotherapy in young children with autistic disorder. Psychopharmacol Bull 1997; 33: 155–159. Frischauf E. Drug therapy in autism. J Am Acad Child Adolesc Psychiatry 1997; 36(5):577. Horrigan JP, Barnhill LJ. Risperidone and explosive aggressive autism. J Autism Dev Disord 1997; 27:313–323. McDougle CJ, Holmes JP, Bronson MR, Anderson GM, Volkmar FR, Price LH, Cohen DJ. Risperidone treatment of children and adolescents with pervasive developmental disorders: a prospective open-label investigation. J Am Acad Child Adolesc Psychiatry 1997; 36(5):685–693. Perry R, Pataki C, Munoz-Silva DM, Armenteros J, Silva RR. Risperidone in children and adolescents with pervasive developmental disorder: pilot trial and followup. J Child Adolesc Psychopharmacol 1997; 7:167–179. Rubin M. Use of atypical antipsychotics in children with mental retardation, autism, and other developmental disabilities. Psychiatry Ann 1997; 27:219–221. Cohen SA, Ihrig K, Lott RS, Kerrick JM. Risperidone for aggression and self-injurious behavior in adults with mental retardation. J Autism Dev Disord 1998; 28(3): 229–233. Doan RJ. Risperidone for insomnia in PDDs. Can J Psychiatry 1998; 43(10):1050– 1051. Nicolson R, Awad G, Sloman L. An open label trial of risperidone in young autistic children. J Am Acad Child Adolesc Psychiatry 1998; 37:372–376. Schwam JS, Klass E, Alonso C, Perry R. Risperidone and refusal to eat. J Am Acad Child Adolesc Psychiatry 1998; 37(6):572–573. Dartnall NA, Holmes JP, Morgan SN, McDougle CJ. Brief report: two-year control of behavioral symptoms with risperidone in two profoundly retarded adults with autism. J Autism Dev Disord 1999; 29(1):87–91. Posey DJ, Walsh KH, Wilson GA, McDougle CJ. Risperidone in the treatment of two very young children with autism. J Child Adolesc Psychopharmacol 1999; 9: 273–276. Zuddas A, Di Martino A, Muglia P, Cianchetti C. Long-term risperidone for perva-

Atypical Antipsychotics

51. 52. 53. 54.

55. 56.

57.

58.

59.

60.

61. 62.

63.

64. 65.

263

sive developmental disorder: efﬁcacy, tolerability, and discontinuation. J Child Adolesc Psychopharmacol 2000; 10(2):79–90. Horrigan JP, Barnhill LJ, Courvoisie HE. Olanzapine in PDD. J Am Acad Child Adolesc Psychiatry 1997; 36:1166–1167. Malek-Ahmadi P, Simonds JF. Olanzapine for autistic disorder with hyperactivity. J Am Acad Child Adolesc Psychiatry 1998; 37:902. Heimann SW. High-dose olanzapine in an adolescent. J Am Acad Child Adolesc Psychiatry 1999; 38(5):496–497. Potenza MN, Holmes JP, Kanes SJ, McDougle CJ. Olanzapine treatment of children, adolscents, and adults with pervasive developmental disorders: an open-label pilot study. J Clin Psychopharmacol 1999; 19:37–44. Kemner C, van Engeland H, Tuynman-Qua H. An open-label study of olanzapine in children with PDD. Schizophr Res 2000; 41(1):194. Martin A., Koenig K, Scahill L, Bregman J. Open-label quetiapine in the treatment of children and adolescents with autistic disorder. J Child Adolesc Psychopharmacol 1999; 9:99–107. Guy W. ECDEU Assessment Manual for Psychopharmacology. Publication 76-338. Washington, DC: National Institute of Mental Health, U.S. Department of Health, Education and Welfare, 1976. McDougle CJ, Scahill L, McCracken JT, Aman MG, Tierney E, Arnold LE, Freeman BJ, Martin A, McGough JJ, Cronin P, Posey DJ, Riddle MA, Ritz L, Swiezy NB, Vitiello B, Volkmar F, Votolato NA, Walson P. Research Units on Pediatric Psychopharmacology (RUPP) Autism Network: background and rationale for an initial controlled study of risperidone. Psychopharmacology 2000; 9(1):201–224. Arnold LE, Aman MG, Martin A, Collier-Crespin A, Vitiello B, Tierney E, Asarnow R, Bell-Bradshaw F, Freeman BJ, Gates-Ulanet P, Klin A, McCracken JT, McDougle CJ, McGough JJ, Posey DJ, Scahill L, Swiezy NB, Ritz L, Volkmar F. Assessment in multisite randomized clinical trials of patients with autistic disorder: the autism RUPP network. J Autism Dev Disord 2000; 30(2):99–111. Bymaster FP, Calliguro DO, Falcone JF, Marsh RD, Moore NA, Tye NC, Seeman P, Wang DT. Radioreceptor binding proﬁle of the atypical antipsychotic olanzapine. Neuropsychopharmacology 1996; 14:87–96. Heuring RE, Peroutka SJ. Characterization of a novel 3H-5-hydroxytryptamine binding site subtype in bovine brain membranes. J Neurosci 1987; 7:894–903. Baxter LR, Phelps ME, Mazziotta JC, Guze BH, Schwartz JM, Selin CE. Local cerebral glucose metabolic rates in obsessive-compulsive disorder: a comparison with rates in unipolar depression and in normal controls. Arch Gen Psychiatry 1987; 44(3):211–218. Aman MG, Singh NN, Stewart AW, Field CJ. The Aberrant Behavior Checklist: a behavior rating scale for the assessment of treatment effects. Am J Ment Deﬁc 1985; 89:485–491. Findling RL, McNamara NK, Gracious BL. Paediatric uses of atypical antipsychotics. Exp Opin Pharmacother 2000; 1(5):935–945. Sallee FR, Kurlan R, Goetz CG, Singer H, Scahill L, Law G, Dittman VM, Chappell PB. Ziprasidone treatment of children and adolescents with Tourette’s syndrome: a pilot study. J Am Acad Child Adolesc Psychiatry 2000; 39(3):292–299.

264

Posey and McDougle

66.

McDougle CJ, Kem DL, Posey DJ. Use of ziprasidone for maladaptive symptoms in youths with autism. J Am Acad Child Adolesc Psychiatry 2002; 41(8):921–927. Moller HJ, Pelzer E, Kissling W, Riehl T, Wernicke T. Efﬁcacy and tolerability of a new antipsychotic compound (risperidone): results of a pilot study. Pharmacopsychiatry 1991; 24(6):185–189. Feeney DJ, Klykylo W. Risperidone and tardive dyskinesia. J Am Acad Child Adolesc Psychiatry 1996; 35(11):1421–1422. Campbell M. Risperidone-induced tardive dyskinesia in ﬁrst-episode psychotic patients. J Clin Psychopharmacol 1999; 19(3):276–277. Mandoki MW. Risperidone treatment of children and adolescents: increased risk of extrapyramidal side effects? J Child Adolesc Psychopharmacol 1995; 5(1):49– 67. Kelly DL, Conley RR, Love RC, Horn DS, Ushchak CM. Weight gain in adolescents treated with risperidone and convential antipsychotics over six months. J Child Adolesc Psychopharmacol 1998; 8(3):151–159. Fuller M, Simon M, Freedman L. Risperidone-associated hepatoxicity. J Clin Psychopharmacol 1996; 16:84–85. Kumra S, Herion D, Jacobsen LK, Briguglia C, Grothe D. Case study: risperidoneinduced hepatotoxicity in pediatric patients. J Am Acad Child Adolesc Psychiatry 1997; 36(5):701–705. Szigethy E, Wiznitzer M, Branicky LA, Maxwell K, Findling RL. Risperidoneinduced hepatotoxicity in children and adolescents? A chart review study. J Child Adolesc Psychopharmacol 1999; 9(2):93–98. Ravin DS, Leverson JW. Fatal cardiac event following initiation of risperidone therapy. Ann Pharmacother 1997; 31:867–869. Edleman RJ. Risperidone side effects. J Am Acad Child Adolesc Psychiatry 1996; 35:4–5. Devinsky O, Honigfeld G, Patin J. Clozapine-related seizures. Neurology 1991; 41: 396–371. Lane H-L, Chang W-H, Chou JC-W. Seizure during risperidone treatment in an elderly woman treated with concomitant medications. J Clin Psychiatry 1998; 59(2): 81–82. Hudson RG, Cain MP. Risperidone associated hemorrhagic cystitis. J Urol 1998; 160(1):159. Emborg C. Neuroleptic malignant syndrome after treatment with olanzapine. Ugeskr Laeger 1999; 161(10):1424–1425. Research Units on Pediatric Psychopharmacology Autism Network. Risperidone in children with autism and serious behavioral problems. N Engl J Med 2002; 347: 314–321.

67.

68. 69. 70.

71.

72. 73.

74.

75. 76. 77. 78.

79. 80. 81.

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 nonverbal communication skills, sociocommunicative function, and repetitive behaviors. 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 historical support that has led to the now accepted concept of ASD as a neurobiological 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

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that occurs in adolescence may be associated with the degree of cognitive dysfunction, 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 combination of cognitive and motor deﬁcit. The combination of severe mental deﬁciency 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 deﬁciency, 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, cognitive 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 comprehension of language: verbal auditory agnosia (VAA) (8). VAA is a severe receptive and expressive language disorder believed to arise from inadequate auditory 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 diagnosis. It is deﬁned by having an acquired aphasia in association with an epileptiform 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 regression (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

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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 language 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 variables such as regression and seizures but also type and degree of language dysfunction 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 epilepsy. In both their 1991 and 1997 studies, Tuchman and colleagues found epileptiform abnormalities in 8% of autistic, nonepileptic children (3,14). In the 1997 study, when only those youngsters with EEG data were considered, the percentage 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 analysis, there was a statistically signiﬁcant increased risk of epileptiform abnormalities 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 epileptiform 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 differences between AER and LKS (19). Some of these differences include:

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1.

2.

3.

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. 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 qualitative social deﬁcits and repetitive behaviors present in ASD. EEG ﬁndings: in ASD the epileptiform activity associated with regression of language is a predominantly centrotemporal spike that can be infrequent and intermittent. In LKS the EEG ﬁndings are predominantly 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 dyspraxia, dysphagia, and transient isolated deterioration of speech production in association with epileptic discharges without clinical seizures (24). Similar correlations have recently been made with respect to electrical status epilepticus dur-

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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 location 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 controversial. 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 corticosteroids 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 epilepsy (clinical seizures) that suggest that aggressive treatment such as epilepsy surgery is associated with positive outcomes (35,36). It is important to re-emphasize 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 children 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 language, multifocal epileptiform EEGs, and symptoms of possible subclinical seizures (staring episodes, rapid eye blinking) without clinical seizures who underwent 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 interventions 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 controversial 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 anticonvulsants 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 treatment option in children with ASD. In addition, the evidence to suggest that treat-

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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. REFERENCES 1.

2. 3.

4. 5. 6. 7.

8. 9.

10. 11. 12.

13. 14. 15. 16.

17.

Gillberg C, Steffenburg S. Outcome and prognostic factors in infantile autism and similar conditions: a population-based study of 46 cases followed through puberty. J Autism Dev Disord 1987; 17(2):273–287. Volkmar FR, Nelson DS. Seizure disorders in autism. J Am Acad Child Adolesc Psychiatry 1990; 29(1):127–129. Tuchman RF, Rapin I, Shinnar S. Autistic and dysphasic children. II. Epilepsy [published erratum appears in Pediatrics 1992; 90(2 Pt 1):264]. Pediatrics 1991; 88(6): 1219–1225. Schain R, Yannet H. Infantile autism. J Pediatr 1960; 57(4):560–567. Deykin EY, MacMahon B. The incidence of seizures among children with autistic symptoms. Am J Psychiatry 1979; 136(10):1310–1312. Olson I, Steffenburg S, Gillberg C. Epilepsy in autism and austiclike conditions. Arch Neurol 1988; 45:666–668. Rapin I, Allen DA. Syndromes in developmental dysphasia and adult aphasia. In: Plum F, ed. Language, Communication, and the Brain. New York: Raven Press, 1988:57–75. Tuchman R, Rapin I, Shinnar S. Autistic and dysphasic children. I. Clinical characteristics. Pediatrics 1991; 88(6):1211–1218. Klein S, Kurtzberg D, Brattson A, Kreuzer J, Stapells D, Dunn M, et al. Electrophysiologic manifestations of impaired temporal lobe auditory processing in verbal auditory agnosia. Brain Lang 1995; 51:383–405. Mantovani JF, Landau WM. Acquired aphasia with convulsive disorder: course and prognosis. Neurology 1980; 30:524–529. Rapin I, Mattis S, Rowan JA, Golden G. Verbal auditory agnosia in children. Dev Med Child Neurol 1977; 19(2):192–207. Beaumanoir A. The Landau-Kleffner syndrome. In: Roger J, Dravet C, Bureau M, Dreifuss FE, Wolf P, eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. London: John Libbey Eurotext, 1985:181–191. Tuchman RF. Acquired epileptiform aphasia. Semin Pediatr Neurol 1997; 4(2):93– 101. Tuchman RF, Rapin I. Regression in pervasive developmental disorders: seizures and epileptiform electroencephalogram correlates. Pediatrics 1997; 99(4):560–566. Kobayashi R, Murata T. Setback phenomenon in autism and long-term prognosis. Acta Psychiatr Scand 1998; 98(4):296–303. Klein SK, Tuchman RF, Rapin I. The inﬂuence of premorbid language skills and behavior on language recovery in children with verbal auditory agnosia. J Child Neurol 2000; 15(1):36–43. Kawasaki Y, Yokota K, Shinomiya M, Shimizu Y, Niwa S. Brief report: electroen-

Treatment of Seizures

18.

19. 20. 21. 22. 23. 24.

25.

26.

27. 28. 29. 30.

31. 32. 33. 34.

35.

271

cephalographic paroxysmal activities in the frontal area emerged in middle childhood and during adolescence in a follow-up study of autism. J Autism Dev Disord 1997; 27(5):605–620. Lewine JD, Andrews R, Chez M, Patil AA, Devinsky O, Smith M, et al. Magnetoencephalographic patterns of epileptiform activity in children with regressive autism spectrum disorders [see comments]. Pediatrics 1999; 104(3 Pt 1):405–418. Mantovani JF. Autistic regression and Landau-Kleffner syndrome: progress or confusion? Dev Med Child Neurol 2000; 42(5):349–353. Tuchman R, Jayakar P, Yaylali I, Villalobos R. Seizures and EEG ﬁndings in children with autism spectrum disorders. CNS Spectrum 1997; 3(3):61–70. Gillberg C. The treatment of epilepsy in autism. J Autism Dev Disord 1991; 21(1): 61–77. Binnie CD, Marston D. Cognitive correlates of interictal discharges. Epilepsia 1992; 33(suppl 6):S11–117. Deonna T. Annotation: cognitive and behavioural correlates of epileptic activity in children. J Child Psychol Psychiatry 1993; 34(5):611–620. Roulet E, Deonna T, Despland P. Prolonged intermittent drooling and oromotor dyspraxia in bening childhood epilepsy with centrotemporal spikes. Epilepsia 1989; 30(5):564–568. Shafrir Y, Prensky AL. Acquired epileptiform opercular syndrome: a second case report, review of the literature, and comparison to the Landau-Kleffner syndrome. Epilepsia 1995; 36(10):1050–1057. Galanopoulou AS, Bojko A, Lado F, Moshe SL. The spectrum of neuropsychiatric abnormalities associated with electrical status epilepticus in sleep. Brain Dev 2000; 22(5):279–295. Yan Liu X, Wong V. Spectrum of epileptic syndromes with electrical status epilepticus during sleep in children. Pediatr Neurol 2000; 22(5):371–379. Schwab R. A method of measuring consciousness in petit mal epilepsy. J Nerv Ment Dis 1939; 89:690–691. Aarts J, Binnie C, Smith A, Wilkins A. Selective cognitive impairment during focal and generalized epileptiform EEG activity. Brain 1984; 107:293–308. Shewmon DA, Erwin RJ. The effect of focal interictal spikes on perception and reaction time. I. General considerations. Electroencephalogr Clin Neurophysiol 1988; 69(4):319–337. Shewmon DA, Erwin RJ. Focal spike-induced cerebral dysfunction is related to the after-coming slow wave. Ann Neurol 1988; 23(2):131–137. Nass R, Petrucha D. Acquired aphasia with convulsive disorder: a pervasive developmental disorder variant. J Child Neurol 1990; 5:327–328. Plioplys AV. Autism: electroencephalogram abnormalities and clinical improvement with valproic acid. Arch Pediatr Adolesc Med 1994; 148(2):220–222. Stefanatos GA, Grover W, Geller E. Case study: corticosteroid treatment of language regression in pervasive developmental disorder [see comments]. J Am Acad Child Adolesc Psychiatry 1995; 34(8):1107–1111. Neville BG, Harkness WF, Cross JH, Cass HC, Burch VC, Lees JA, et al. Surgical treatment of severe autistic regression in childhood epilepsy. Pediatr Neurol 1997; 16(2):137–140.

272

Tuchman

36.

Nass R, Gross A, Wisoff J, Devinsky O. Outcome of multiple subpial transections for autistic epileptiform regression. Pediatr Neurol 1999; 21(1):464–470. Szabo CA, Wyllie E, Dolske M, Stanford LD, Kotagal P, Comair YG. Epilepsy surgery in children with pervasive developmental disorder. Pediatr Neurol 1999; 20(5):349–353. Neville BG. Magnetoencephalographic patterns of epileptiform activity in children with regressive autism spectrum disorders [comment]. Pediatrics 1999; 104(3 Pt 1): 558–559.

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15 Treatment of Movement Disorders in Autism Spectrum Disorders James Robert Braˇsic´ The Johns Hopkins University School of Medicine Baltimore, Maryland Bellevue Hospital Center and New York University School of Medicine New York, New York, U.S.A.

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). Movement disorders occur in people with autism spectrum disorders both as manifestations of the underlying conditions and as adverse effects of therapeutic interventions (9). This chapter reviews the treatment of movement disorders in autism spectrum 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 mean273

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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 clinical 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 treatment of movement disorder commonly appearing as adverse effects of pharmacological therapy for autism spectrum disorders, namely, acute dystonia (acute dystonic 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 selfinjury, self-injurious behaviors merit inclusion in this chapter because of the resultant 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 concomitantly 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 individuals exhibit occasional unusual movements that do not interfere with social, occupational, recreational, or educational performance. For example, people may occasionally 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).

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A. Classiﬁcation of Movement Disorders as Hyperkinesias and Bradykinesias Movement disorders can be dichotomously subdivided into hyperkinesias, characterized by faster, more frequent, and more intense movements, and bradykinesias, characterized by slower, less frequent, and less intense movements. Bradykinesias 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 disorder, 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 motionless 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 spectrum disorders and 2) movement-disorder manifestations of autism spectrum disorders. 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-

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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 identiﬁcation 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 pharmacotherapy, 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 pathognomonic 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-

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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 disorders classiﬁed as self-injurious behaviors may cause serious morbidity and mortality 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 information about the diagnosis and treatment of tardive dyskinesia and associated conditions 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 medication. Individuals with autism appear prone to develop tardive dyskinesia— abnormal movements occurring after the causative medication has been discontinued—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 movement disorders in people with autism spectrum disorders by the dearth of published 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 pharmacological 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 clinicians 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 Checklist (FCC) (Table 4) (13,14), the Hillside Akathisia Scale (HAS) (Table 6) (11,15), the Movement Disorders Checklist (MDC) (Table 7) (11), the Myoclo-

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nus Versus Tic Checklist (MVTC) (Table 8) (17), the Psychoactive Medication Quality Assurance Rating Survey (PQRS) (Table 9) (11,18), the Timed SelfInjurious Behavior Scale (TSIBS) (Table 10) (24), and the Timed Stereotypies Rating Scale (TSRS) (Table 11) (11,25) to substantiate clinical trials of therapeutic 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 presynaptic 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 postsynaptic 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. Postsynaptic 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 effects. There are three common adverse effects of dopamine antagonists manifested by movement disorders in people with autism spectrum disorders: 1) acute dystonia (acute dystonic reaction), 2) acute akathisia, and 3) withdrawal and tardive dyskinesias (Table 12). The best public-health approach to all three movement disorders is the prevention of the occurrence of the conditions. This can be accomplished by avoiding the use of dopamine antagonists altogether. Before prescribing psychoactive medications including dopamine antagonists, prudent clinicians verify that treatment with psychoactive medications is appropriate for the patient. Since multiple 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.

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If the administration of dopamine antagonists is mandated by the clinical condition of the patient, then the use of newer agents—such as atypical neuroleptics, e.g., clozapine (Clozaril), risperidone (Risperdal) (46,47), and olanzapine (Zyprexa) (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 functioning, such as the CGAS (Table 3) (12) is a useful approach to regularly determine 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 administered. 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 example, the eye muscles may be affected, causing the eyes to deviate upward, downward, 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 speaking. Lastly, arm and leg muscles may be affected. The occurrence of acute dysto-

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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 experience, 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 experiencing pain from muscular contraction. There may be no localizing neurological signs. Therefore, experienced clinicians have a particularly high level of suspicion 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 (Benadryl) 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 anticholinergic medications. Oral doses of anticholinerigic agents usually cause the dystonia 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, unnecessary 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

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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 restlessness 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 verbalization of inner restlessness fosters precision in the diagnosis of akathisia. Therefore, 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 appropriate. 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 dopamine antagonists, akathisia may be present. Institution of treatment for that possible 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 objective 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, including 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-headedness, they are advised to sit or lie down immediately to abort a syncopal episode. Before commencing therapy with β-blockers, experienced clinicians con-

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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 (Table 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 neuroleptic 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 instrument to assess the propriety of treatment with psychoactive medication such as the PQRS (Table 9) (11,18,50). If treatment with neuroleptic medication is indicated, then administration of an atypical neuroleptic may be an appropriate therapeutic 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 manifestation is described as “rabbit syndrome”—small, quick movements of the nose, lips, and mouth. There may be associated choreic movements of the extremities. 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).

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Tardive dyskinesias are frequently refractory to all therapeutic attempts. They may remain as permanent manifestations of treatment with traditional neuroleptics throughout a person’s life. The oral, buccal, lingual, and facial movements 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. Additionally, 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 diagnosis 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 assess 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 exacerbation 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 dyskinesias 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 psychoactive agents, particularly neuroleptics. The need for treatment with psychoactive agents should be veriﬁed before and throughout the course of treatment, for example, by administration of the PQRS (Table 9) (11,18,50). Since family compliance

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with recommended treatment, including pharmacotherapy, is crucial to the success 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 treatments—including no treatment—to the patient and family (6). The risk of tardive dyskinesia may remain a permanent disﬁguring manifestation 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 childhood 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 develop severe psychomotor retardation (2). Stereotyped hand movements are common (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 Xlinked 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 nervous 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

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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 pathogenesis of Rett’s disorder by the abnormalities in the densities of N-methyl-Daspartate (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 hypothesized to contribute to the hand movements of Rett’s disorder (77). Altered dopaminergic 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 interventions 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 Syndrome Association (IRSA) at www.rettsyndrome.org. 2. Movements of Autistic Disorder A wide variety of movements have been associated with autism spectrum disorders. Some, such as tics (81–84), may represent other disorders, such as Tourette’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.

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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, repeatedly ﬂushing the toilet while watching the water go down the drain, and repeatedly 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 appropriately 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 neuropsychiatric disorders (95). However, stereotypies occur spontaneously in humans (97,98) and animals (99). Table 13 contains additional information about stereotypies. 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 individual. 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 venlafaxine (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 serotonergic dysfunction characterizes a group of individuals with autism spectrum disorders, caution must be exercised in the administration of selective serotoninreuptake 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.

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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. Because any medication is associated with possible adverse effects, expected beneﬁts 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 disorders—early intervention (116) with individualized special education incorporating 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). Additionally, 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 pharmacotherapy 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 behaviors 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 morbidity and mortality. Fortunately, most individuals with autism spectrum disorders 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-

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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 epilepsy (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-stimulation 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 prevalence 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 common 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 regurgitated 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 deprived 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 despite a myriad of attempted therapeutic interventions. Despite various hypotheses (151) and clinical observations (152–154), the etiology of self-injurious behaviors in people with autism spectrum disorders and other neuropsychiatric disorders 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) syndromes. 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 metabolize purine, a product of normal metabolism, to uric acid (136,152,153). Hall-

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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 etiologies of the self-mutilation that is characteristic of the syndrome include dysfunction 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 selfinjurious behavior targeted toward body parts manifesting neuropathic pain in humans of normal intelligence has been hypothesized to be equivalent to autotomy in animals. Marked improvement has been obtained through successful treatment 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 movements 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 subsensitive. Therefore, self-injury may raise receptor input to a normal level to relieve a sense of dysphoria and to produce normal feelings of pleasure regulation. 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 activities 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 overall impairment (2,12,173–176), and assessments of surface damage (177) developed 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.

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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 information after a thorough interview and examination of the patient and an interview with the caregivers, guardians, teachers, neighbors, and all others who have contact 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 behavior in people with autism spectrum disorders (132,186). However, poor methodology hinders the objective assessment of many reports (187). Psychiatric inpatient units may be reluctant to admit patients with selfinjurious 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 prevent injury. Fifth, many staff members lack training in the management of selfinjurious 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 desperation, 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. Attempting 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 selfinjurious 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-

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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 consequences may then reduce or eliminate the occurrence of self-injury. Since behavioral programs may require considerable staff intervention, a Staff Intensity Scale has been developed (194). Behavioral intervention applied consistently at home and at school by persons experienced in the application of techniques for people with pervasive developmental disorders is probably the most generally effective therapeutic approach for autism spectrum disorders (195). By consistently applying behavioral interventions 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 spectrum 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 difﬁcult 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 according 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 treatment of autism spectrum disorders. Since self-injurious behaviors demand immediate cessation, behavioral therapy may not be effective for acute intervention. Behavioral methods have been classiﬁed as reduction or enhancement approaches (132). Behavior-reduction approaches: These techniques are negative consequences following the occurrence of self-injurious behaviors.

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Aversion therapy. While behavioral interventions (see Chapter 17) typically 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 aversive techniques may result in cessation of behavior that could injure the person. Although unavailable at the Kennedy-Krieger Institute, the Johns Hopkins Hospital, the Johns Hopkins Medical Institutions, the Johns Hopkins University, Bellevue 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 restraints 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 respiratory rate or temperature, requires immediate assessment and intervention. Since cardiac arrest may result from the utilization of physical restraints, the cardiovascular 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.

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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 mental retardation and other developmental disabilities. In such regions alternative strategies, including behavioral interventions (Section IV.B.1) and pharmacotherapy (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 outcomes 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 rehearsed 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 selfdestructive actions of persons with autism spectrum disorders (132). Speciﬁc self-injurious behaviors can often be effectively handled by physical 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 selfinjurious 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 incompatible (DRI) behaviors (201,226,229) are common forms of behavior-enhancement techniques employed for people with autism spectrum disorders. For example,

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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 activities 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 attempt 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 effective 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. Although 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. Guidelines for the utilization of psychoactive agents for self-injury in people with autism spectrum disorders and other developmental disabilities are being developed (247,248). Animal studies suggest that compulsive biting in monkeys with ventromedial thalamic lesions might result from stimulation of supersensitive dopamine

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type 1 (D1) receptors by dopamine agonists. This theory is substantiated in animals by the beneﬁcial effect of ﬂuphenazine (249). Control may be obtained by administering potent neuroleptics, such as ﬂuphenazine (250), and benzodiazepines. For example, adults with acute self-injurious 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 neuroleptic risperidone has been reported to relieve self-mutilation in rats (251) and men with autism disorder (252) and in adults with mental retardation (253). Risperidone 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 disorder is present, the self-injurious behavior may be a manifestation of partial seizures 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, including 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 electroconvulsive 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 administration 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 administration 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

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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 reported 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 behaviors (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, including 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 stereotypies 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 tapping an object may cause it to break. Because such movements can quickly cause severe damage, immediate intervention is needed. The discussions of self-injurious behavior (Section IV.B) and aggression toward others (Section IV.C) also apply to stereotypies causing property damage.

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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 battery is performed and recorded at baseline before the administration of any therapeutic intervention, clinicians may be unable to differentiate movement-disorder adverse effects of treatment from movement-disorder manifestations of the autism spectrum disorders. Acute dystonia (acute dystonic reaction), acute akathisia, 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 autistic disorder, have characteristic movements called stereotypies. Since most stereotypies 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 intervention to prevent morbidity and mortality. Although many interventions are reported to help treat movement disorders in speciﬁc individuals with autism spectrum disorders, no therapy is uniformly effective. All treatments for autism spectrum disorders carry the risk of adverse events. Potential beneﬁts of interventions must be weighed against likely risks of unfavorable outcomes (304,305). Published reports of treatments of movement disorders in autism are often anecdotal documents that are difﬁcult to generalize to other individuals (306). Welldesigned 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 cooperation 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-

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opmental Disabilities (CMEDD) of the Ofﬁce of Mental Retardation and Developmental 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 AMPA CGAS D1 D2 DRI DRO FCC GABA GSIBS HAS HGPRT MDC META MVTC NMDA PQRS SIB SSRI TSIBS TSRS

Abnormal Involuntary Movement Scale (Table 2) (10,11) alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid Children’s Global Assessment Scale (Table 3) (12) dopamine type 1 dopamine type 2 differential reinforcement of incompatible differential reinforcement of other Family Compliance Checklist (Table 4) (13,14) gamma-aminobutyric acid Global Self-Injurious Behavior Scale (Table 5) Hillside Akathisia Scale (Table 6) (11,15) hypoxanthineguanine phosphoribosyltransferase Movement Disorders Checklist (Table 7) (11) Medical Editors’ Trial Amnesty (16) Myoclonus Versus Tic Checklist (Table 8) (17) N-methyl-D-aspartate Psychoactive Medication Quality Assurance Rating Survey (Table 9) (11,18–21) self-injurious behavior selective serotonin-reuptake inhibitor Timed Self-Injurious Behavior Scale (Table 10) (24) Timed Stereotypies Rating Scale (Table 11) (11,25)

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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 unobtrusively 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. 2. 3. 4.

5. 6. 7. 8. 9. 10. 11. 12. 13.

Ask the subject to remove shoes and socks. Ask the subject if there is anything in his or her mouth (e.g., candy or gum) and, if there is, to remove it. 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? 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. 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. 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. Ask the subject to open the mouth. Observe the tongue at rest in the mouth. Do this twice. Ask the subject to protrude the tongue. Observe abnormalities of tongue movement. Do this twice. 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. Flex and extend the subject’s left and right arms one at a time. Note any rigidity. Ask the subject to stand up. Observe the subject in proﬁle. Observe all body areas including the hips. Ask the subject to extend both arms outstretched in front with palms down. Observe the trunk, the legs, and the mouth. 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.

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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, eyebrows, periorbital area, cheeks; including frowning, blinking, smiling, grimacing 2. Lips and perioral area—e.g., puckering, pouting, smacking 3. Jaw—e.g., biting, clenching, chewing, mouth opening, lateral movement 4. Tongue—rate only increases in movement both in and out of mouth, not the inability to sustain movement

0 1 2 3 4

0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

Extremity Movements 5. Upper (arms, wrists, hands, ﬁngers)—include choreic movements (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, foot tapping, heel dropping, foot squirming, and inversion and eversion of the foot

0 1 2 3 4

0 1 2 3 4

Trunk Movements 7. Neck, shoulders, hips—e.g., rocking, twisting, squirming, pelvic gyrations

0 1 2 3 4

Global Judgments 8. Severity of abnormal movements 9. Incapacitation due to abnormal movements 10. Subject’s awareness of abnormal movements—rate only the subject’s report.

0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

Dental Status 11. Current problems with teeth and/or dentures 12. Does the subject usually wear dentures? Source: Refs. 10, 11.

0 1 0 1

No Yes No Yes

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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 functioning 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 participates 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 minimally 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., sporadic 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; selfdoubts); 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.

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Table 3 Continued 50–41

40–31

30–21

20–11

10–1

Moderate degree of interference in functioning in most social areas or severe impairment of functioning in one area, such as might result from suicidal preoccupations and ruminations, school refusal and other forms of anxiety, obsessive rituals, major conversion symptoms, frequent anxiety attacks, poor or inappropriate social skills, or frequent episodes of aggressive or other antisocial behavior with some preservation of meaningful social relationships. 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 attempts with clear lethal intent; such children are likely to require special schooling and/or hospitalization or withdrawal from school (but this is not a sufﬁcient criterion for inclusion in this category). 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). 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. Needs constant supervision (24-hour care) due to severely aggressive or selfdestructive behavior or gross impairment in reality testing, communication, cognition, affect, or personal hygiene.

Source: Ref. 12.

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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. 2. Subject has two or more diagnoses.

Yes Yes

No* No

Yes

No

Yes* Yes*

No No

Yes*

No

Yes

No*

Lack of engagement (of the subject) 3. The subject has expressed a desire for treatment to reduce his or her symptoms. Family factors 4. 5. 6. 7.

The family has refused to permit the use of medication(s). Family members have refused to make appointments. Number of appointments missed over the last 6 months. The family has refused to sign the treatment plan.

Practitioner factors 8. Number of sessions with primary therapist over the past 6 months. 9. Team member or primary therapist has appropriate contact with 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 effectiveness of current psychopharmacotherapy and to consider alternative treatment plans. Source: Adapted from Ref. 13. 1998 Psychological Reports.

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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 Single self-injurious behavior Two self-injurious behaviors Three self-injurious behaviors Four self-injurious behaviors Five or more self-injurious behaviors

0 1 2 3 4 5

Frequency None Rarely Occasionally

Frequently Almost always

Always

There is no evidence of self-injurious behaviors. Self-injurious behaviors occur rarely. Bouts of self-injurious behaviors are brief and uncommon. There are occasional durations without any self-injurious behaviors. Brief bouts of self-injurious behaviors occasionally occur. Bouts of single self-injurious behaviors occur regularly. Periods of sustained self-injurious behaviors occur regularly. Bouts of two or more self-injurious behaviors are common. Self-injurious behaviors are present constantly. There are no observed waking intervals free of self-injurious behaviors.

0 1

2 3

4

5

Intensity Absent Minimal

Self-injurious behaviors are absent. 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.

0

1

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Table 5 Continued Mild

Moderate

Severe

Extreme

Self-injurious behaviors are no more forceful than comparable voluntary actions. Although there is no acute tissue damage, tissue damage could occur if speciﬁc selfinjurious behaviors persisted for more than a day. 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. 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. Self-injurious behaviors are extremely forceful and exaggerated in expression. They call immediate attention to the individual. There may be major tissue damage of lifethreatening proportions, including fractures, rupture of internal organs, loss of teeth, and impairments of hearing and vision.

2

3

4

5

Complexity None Borderline Mild

Moderate

Marked

Severe

If present, speciﬁc self-injurious behaviors are clearly “simple” (sudden, brief, purposeless) in character. Some self-injurious behaviors are not clearly simple in character. Some self-injurious behaviors are clearly complex (purposive in appearance) and mimic brief automatic behaviors that can be readily camouﬂaged. 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. 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. 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.

0 1

2

3

4

5

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Table 5 Continued Interference None Minimal Mild Moderate Marked

Severe

No self-injurious behaviors are present. Speciﬁc self-injurious behaviors do not interrupt the ﬂow of behavior or speech. Speciﬁc self-injurious behaviors occasionally interrupt the ﬂow of behavior or speech. Speciﬁc self-injurious behaviors frequently interrupt the ﬂow of behavior or speech. Speciﬁc self-injurious behaviors frequently interrupt the ﬂow of behavior or speech and occasionally disrupt the intended action or communication. Speciﬁc self-injurious behaviors constantly disrupt intended action or communication.

0 1 2 3

4 5

Impairment None Minimal

Mild

Moderate

Severe

There is no impairment in social, occupational, or educational functioning. 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 selfinjurious 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). Self-injurious behaviors are associated with minor difﬁculties in self-esteem, family life, social acceptance, school and job functioning, activities of daily living, daily chores, and vocational planning. 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). Self-injurious behaviors are associated with major difﬁculties in self-esteem, family life, social acceptance, school and job functioning, activities of daily living, daily chores, and vocational training.

0

1

2

3

4

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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).

Global Self-Injurious Behavior Scale (GSIBS) Score (sum of Number, Frequency, Intensity, Complexity, Interference, and Impairment Scores)

5

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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 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.

Sitting

Standing

Lying

Total

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

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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 Source: Refs. 11, 15.

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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

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Abnormal posture Abrupt Brief Can be suppressed Continuous Coordinated Feeling of restlessness Intermittent Movement ﬂows randomly Oscillatory Patterned Present at rest Present when maintaining a posture Purposeless Regular Repetitive Ritualistic Shock-like Squeezing movement Sudden Sustained Twisting movement Urge to move

Source: Ref. 11.

No

Yes

Don’t know

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

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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.

1. 2. 3. 4. 5. 6. 7. 8.

Simple jerks Random, unpredictable body distribution Wide range of amplitude Wide range of forcefulness Movements can be voluntarily suppressed Movements increase with intentional acts Sustained dystonic movements Complex movements

No

Yes

Don’t know

0 0 0 0 0 0 0 0

1 ⫺1 1 1 1 ⫺1 1 1

9 9 9 9 9 9 9 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. Source: Adapted from Ref. 17. 2000 Psychological Reports.

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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 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

Y

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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 25. Clinician 2 managed medications for subject 26. Clinician 3 managed medications for subject Past history 27. Record of previous diagnostic evaluation requested* 28. Record of previous diagnostic evaluation obtained*

Y Y

Current medical evaluation 29. Comprehensive nonpsychiatric medical evaluation is initiated* 30. Comprehensive nonpsychiatric medical evaluation is completed* 31. Relevant nonpsychiatric medical assessment components are completed*

Y Y Y

Current psychiatric evaluation 32. Comprehensive psychiatric evaluation is initiated* 33. Comprehensive psychiatric evaluation is completed* 34. Relevant psychiatric assessment components are completed* 35. Psychiatric diagnoses other than mental retardation, if applicable, by DSM-IV-TR diagnostic classiﬁcation (2)* 36. Psychiatric diagnoses other than mental retardation, if applicable, by 1998 ICD-9-CM (22) classiﬁcation*

Y Y Y Y Y

Current intellectual evaluation 37. Level of mental retardation is documented by IQ derived from individual formal testing* 38. Level of retardation is documented by adaptive functioning*

Y Y

Current behavioral evaluation 39. Focused behavioral evaluation is initiated* 40. Focused behavioral evaluation is adequate for initiating treatment* 41. Behavioral symptoms related to psychiatric diagnoses are speciﬁed*

Y Y Y

314

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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 45. Cardiovascular disease is diagnosed 46. Cataracts are diagnosed 47. The subject is hepatitis A antigen–positive 48. The subject is hepatitis B antigen–positive 49. Constipation is diagnosed 50. Toe infection is present 51. Ear/nose/throat disease is present 52. Respiratory infection is diagnosed 53. Central nervous system disease is diagnosed 54. Seizures are diagnosed 55. Endocrine disease is diagnosed 56. The subject ambulates with assistance 57. Mental retardation due to disorders of metabolism and nutrition is diagnosed 58. Mental retardation due to infection (e.g., rubella) or head trauma is diagnosed 59. Cerebral malformations are diagnosed 60. Down’s syndrome is diagnosed 61. Fragile X syndrome is diagnosed 62. Other chromosomal disorders are diagnosed 63. One or more seizures are recorded in the past 12 months 64. Stereotypies are diagnosed 65. Neuroleptic-related tardive or withdrawal dyskinesias are diagnosed 66. Additional medical diagnoses are given 67. It is speciﬁed if medical diagnoses contribute to target symptoms 68. Another nonpsychiatric medical condition, other than mental retardation, is diagnosed If yes, please list: 69. Other informal clinical symptom diagnoses, e.g., self-injurious behavior, are given 70. Hierarchy of severity of medical diagnoses is evident Speciﬁc psychiatric diagnoses 71. Autistic disorder is diagnosed 72. Other pervasive developmental disorder is diagnosed 73. Schizophrenia is diagnosed 74. Depression is diagnosed 75. Mania is diagnosed 76. Self-injurious behavior has been recorded 77. Aggression toward others has been recorded 78. Suicide has been attempted in the past year 79. Hyperactivity has been recorded in the past year

Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y

Y Y Y Y Y Y Y Y Y Y Y

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Table 9 Continued 80. Another nonmedical psychiatric diagnosis, other than mental retardation, is diagnosed If yes, please list: 81. Hierarchy of severity of psychiatric diagnoses is evident Target symptoms 82. More than one staff member has recorded each signiﬁcant symptom* 83. There is an obvious environmental cause for each symptom† 84. There is obvious bias by the observer; others do not agree† 85. More than one signiﬁcant symptom is observed 86. A hierarchy of symptom priorities for treatment is listed* 87. Target symptom(s) for treatment are established* 88. Baseline ratings of symptoms are obtained by rating scales 89. Baseline ratings of symptoms are obtained by informal observation* 90. Other target behavior symptoms are identiﬁed If yes, please list: 91. There is a hierarchy of severity of target behavioral symptoms* Treatment selection 92. Only one available psychoactive treatment is considered and reviewed† 93. More than one available psychoactive treatment is considered and reviewed* 94. Beneﬁcial and side effects of each psychoactive treatment are reviewed* 95. Sequence of psychoactive treatments is established* 96. Caution to do no harm to subject in treatment selection* 97. Informed consent is obtained prior to starting psychoactive medication* 98. Class of psychoactive medication selected in relation to psychiatric diagnoses* 99. Class of psychoactive medication selected in relation to target behavioral symptom(s)* 100. Class of psychoactive medication selected in relation to concurrent medical illnesses* 101. Class of psychoactive medication selected in relation to drug interactions* 102. Contraindicated and ineffective psychoactive medication(s) were excluded 103. Alternative psychoactive medication(s) are recorded* Treatment monitoring protocols 104. A behavioral treatment plan is speciﬁed* 105. A pharmacological treatment plan is speciﬁed* 106. The duration of psychoactive treatments is speciﬁed, other than monthly renewals* 107. After the monthly review of the symptoms of the subject, medication renewals are completed* 108. Outcome criteria are speciﬁed to determine continuation of therapy* 109. The time and the method to determine long-term side effects are recorded 110. Psychoactive medication review by preset schedule, other than monthly medication renewals

Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y

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316

Table 9 Continued 111. 112. 113. 114. 115. 116.

Psychoactive medication review by original protocol schedule Psychoactive medication review by number of drugs* Psychoactive medication review by long-term side effects* Nonmedication inﬂuences reviewed: baseline variation* Nonmedication inﬂuences reviewed: environmental* Nonmedication inﬂuences reviewed: concurrent treatments*

Medication dosage range 117. Psychoactive drug dosage Reference (23)* 118. Psychoactive drug dosage 119. Psychoactive drug dosage 120. Psychoactive drug dosage

Y Y Y Y Y Y

in usual range according to Physicians’ Desk in usual range according to state manual* in usual range according to standard texts* in usual range according to scientiﬁc journals*

Y Y Y Y

Monitoring medication dosage and treatment effects 121. Psychoactive drug dosage is monitored by formal protocol schedule 122. Psychoactive drug dosage is monitored by open drug trial 123. Psychoactive drug dosage is monitored by plasma drug levels 124. Psychoactive drug dosage is monitored by consideration of other drugs currently taken* 125. Appropriate beneﬁcial behavioral effects are monitored* 126. Appropriate medication side effects are monitored* 127. Monitoring by staff observation, with chart notes, at one site (day program or living unit)* 128. Monitoring by staff, with chart notes, at two or more sites (including both day program and living unit) 129. Monitoring by appropriate speciﬁc rating scales ﬁlled out by assigned raters 130. Monitoring by appropriate speciﬁc rating scales, with raters by convenience 131. Monitoring by open format 132. Monitoring by single-blind format 133. Monitoring by double-blind format 134. Monitoring includes use of placebo 135. Monitoring includes crossover of treatment components

Y Y Y Y Y Y Y Y

Drug 136. 137. 138. 139. 140.

Y Y Y Y Y

holidays Drug holiday of at least 4 weeks each year planned Drug holiday of at least 4 weeks this year attempted Drug holiday of at least 4 weeks this year completed No drug holiday, with documentation supporting this decision Attempt at drug holiday was discontinued, with justiﬁcation

Y Y Y Y Y Y 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. Source: Refs. 11, 18.

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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 10minute rating session.

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

1. 2. 3. 4. 5. 6. 7. 8.

0:00

0:10

0:20

0:30

0:40

0:50

1:00

1:10

1:20

1:30

1:40

1:50

Skin picking Self biting Head punching Head slapping Head-to-object banging Body-to-object banging Body punching Body slapping Eye poking Anal poking Other poking Please describe: Lip chewing Hair removal Nail removal Teeth banging Other self-injurious behavior Please describe:

Skin picking Self biting Head punching Head slapping Head-to-object banging Body-to-object banging Body punching Body slapping

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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 16. Other self-injurious behavior Please describe:

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

2:00

2:10

2:20

2:30

2:40

2:50

3:00

3:10

3:20

3:30

3:40

3:50

Skin picking Self biting Head punching Head slapping Head-to-object banging Body-to-object banging Body punching Body slapping Eye poking Anal poking Other poking Please describe: Lip chewing Hair removal Nail removal Teeth banging Other self-injurious behavior Please describe:

Skin picking Self biting Head punching Head slapping Head-to-object banging Body-to-object banging Body punching Body slapping Eye poking Anal poking Other poking Please describe:

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Table 10 Continued 12. 13. 14. 15. 16.

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Lip chewing Hair removal Nail removal Teeth banging Other self-injurious behavior Please describe: 4:00

4:10

4:20

4:30

4:40

4:50

5:00

5:10

5:20

5:30

5:40

5:50

Skin picking Self biting Head punching Head slapping Head-to-object banging Body-to-object banging Body punching Body slapping Eye poking Anal poking Other poking Please describe: Lip chewing Hair removal Nail removal Teeth banging Other self-injurious behavior Please describe:

Skin picking Self biting Head punching Head slapping Head-to-object banging Body-to-object banging Body punching Body slapping Eye poking Anal poking Other poking Please describe: 12. Lip chewing 13. Hair removal 14. Nail removal

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Table 10 Continued 15. Teeth banging 16. Other self-injurious behavior Please describe:

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

6:00

6:10

6:20

6:30

6:40

6:50

7:00

7:10

7:20

7:30

7:40

7:50

Skin picking Self biting Head punching Head slapping Head-to-object banging Body-to-object banging Body punching Body slapping Eye poking Anal poking Other poking Please describe: Lip chewing Hair removal Nail removal Teeth banging Other self-injurious behavior Please describe:

Skin picking Self biting Head punching Head slapping Head-to-object banging Body-to-object banging Body punching Body slapping Eye poking Anal poking Other poking Please describe: Lip chewing Hair removal Nail removal Teeth banging Other self-injurious behavior Please describe:

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321

Table 10 Continued

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

8:00

8:10

8:20

8:30

8:40

8:50

9:00

9:10

9:20

9:30

9:40

9:50

Skin picking Self biting Head punching Head slapping Head-to-object banging Body-to-object banging Body punching Body slapping Eye poking Anal poking Other poking Please describe: Lip chewing Hair removal Nail removal Teeth banging Other self-injurious behavior Please describe:

Skin picking Self biting Head punching Head slapping Head-to-object banging Body-to-object banging Body punching Body slapping Eye poking Anal poking Other poking Please describe: Lip chewing Hair removal Nail removal Teeth banging Other self-injurious behavior Please describe:

Source: Adapted from Ref. 24. 1997 Psychological Reports.

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.

Place of Rating

Time of Rating

Date of Rating

Rater Name

Subject Number

Subject Name

Table 11 Timed Stereotypies Rating Scale (TSRS)

322 Braˇsic´

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323

324

Braˇsic´

Source: Adapted from Refs. 11, 25.

Movement Disorders 325

326

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Table 12 Deﬁnitions and Examples of Common Subclasses of Hyperkinesias in Autism Spectrum Disorders 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.

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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

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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.

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Table 14 Medical Complications of Self-injurious Behaviors (SIB) Type of self-injurious behavior Aerophagia Eye poking Hair removal Head banging Self-biting Pica Rectal poking

Possible medical complication Constipation, diarrhea, indigestion Corneal ulcer, infection, lens dislocation, retinal detachment Alopecia Contusion, disﬁgurement, infection, laceration, seizure disorder, subdural hematoma Autoamputation, infection, laceration, ulceration Constipation, diarrhea, gastroenteritis, indigestion, intestinal obstruction, intestinal perforation, lead poisoning Abscess, ﬁssure, ﬁstula

REFERENCES 1. 2.

3.

4. 5. 6. 7. 8. 9. 10.

11. 12.

Dobbinson S, Perkins MR, Boucher J. Structural patterns in conversations with a woman who has autism. J Commun Disord 1998; 31:113–134. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed., text revision. Washington, DC: American Psychiatric Publishing, 2000. Teitelbaum P, Teitelbaum O, Nye J, Fryman J, Maurer RG. Movement analysis in infancy may be useful for early diagnosis of autism. Proc Natl Acad Sci USA 1998; 95:13982–13987. Brasˇic´ JR. Movements in autistic disorder. Med Hypotheses 1999; 53(1):48–49. Brasˇic´ JR. Pervasive developmental disorder: Asperger syndrome. eMedicine Journal Jan 7, 2002; 3(1). Brasˇic´ JR: Pervasive developmental disorder: autism. eMedicine Journal Feb 19, 2002; 3(2). Brasˇic´ JR, Gianutsos JG. Neuromotor assessment and autistic disorder. Autism Int J Res Pract 2000; 4(3):287–298. Gillberg C, Coleman M. The Biology of the Autistic Syndromes. 3rd ed. London: MacKeith Press, 2000. Brasˇic´ JR, Barnett JY. Hyperkinesias in a prepubertal boy with autistic disorder treated with haloperidol and valproic acid. Psychol Rep 1997; 80:163–170. National Institute of Mental Health (NIMH), Alcohol, Drug Abuse, and Mental Health Administration, Public Health Service, Department of Health, Education, and Welfare. Abnormal Involuntary Movement Scale (AIMS). Psychopharmacol Bull 1988; 24(4):781–783. Brasˇic´ JR, Bronson B: Tardive dyskinesia. eMedicine Journal May 20, 2002; 3(5). Shaffer D, Gould MS, Brasic J, Ambrosini P, Fisher P, Bird H, Aluwahlia S. A Children’s Global Assessment Scale (CGAS) (for children 4 to 16 years of age). Psychopharmacol Bull 1985; 21(4):747–748.

330 13.

14.

15.

16. 17. 18.

19.

20.

21. 22. 23. 24. 25. 26.

27.

28.

29. 30.

31.

Braˇsic´ Brasˇic´ JR, Will MV, Ahn SC, Nadrich RH, McNally G. A review of the literature and a preliminary study of family compliance in a developmental disabilities clinic. Psychol Rep 1998; 82:275–286. Brasˇic´ JR, Nadrich RH, Kleinrock S, Brathwaite C. Do families comply with child and adolescent psychopharmacology? Child Adolesc Psychopharmacol News 2001; 6(2):6, 7, 10. Fleischhacker WW, Bergmann KJ, Perovich R, Pestreich LK, Borenstein M, Lieberman J, Kane J. The Hillside Akathisia Scale: a new rating instrument for neuroleptic-induced akathisia. Psychopharmacol Bull 1989; 25:222–226. Medical Editors’ Trial Amnesty (META). J Neurol 1998; 245:563–564. Brasˇic´ JR. Differentiating myoclonus from tics. Psychol Rep 2000; 86:155–156. Brasˇic´ JR, Young JG, Furman J, Conte RM, Baisley WE, Jaslow RI. Psychoactive Medication Quality Assurance Rating Survey (PQRS). J Dev Phys Disabil 1997; 9:311–336. Brasˇic´ JR, Furman J, Conte RM, Baisley WE, Nadrich RH, Kaplan D, Ahmad R, Rodriguez M, Mendonc¸a MF, Will MV. Quality assurance of treatments for Tourette syndrome and other tic disorders [abstr]. 3rd International Scientiﬁc Symposium on Tourette Syndrome, New York, June 4–6, 1999, p 20. Brasˇic´ JR, Furman J, Conte RM, Baisley WE, Jaslow RI. Psychoactive Medication Quality Assurance Rating Survey (PQRS) screening criteria. J Dev Phys Disabil. In press. Brasˇic´ JR, Furman J, Conte RM, Baisley WE, Jaslow RI. Improving the quality of the utilization of psychoactive medication. J Dev Phys Disabil. In press. 1998 International Classiﬁcation of Diseases. Ninth Revision, Clinical Modiﬁcation, Fifth Edition. Salt Lake City: Medicode Publications, 1997. Physicians’ Desk Reference. 56th ed. Montvale, NJ: Medical Economics, 2002. www.PDR.net. Brasic JR, Barnett JY, Ahn SC, Nadrich RH, Will MV, Clair A. Clinical assessment of self-injurious behavior. Psychol Rep 1997; 80:155–160. Campbell M. Timed Stereotypies Rating Scale. Psychopharmacol Bull 1985; 21(3):1082. Steffenburg S, Gillberg C, Steffenburg U. Psychiatric disorders in children and adolescents with mental retardation and active epilepsy. Arch Neurol 1996; 53: 904–912. Brasˇic´ JR, Zagzag D, Kowalik S, Prichep L, John ER, Liang HG, Kutchko B, Cancro R, Sheitman BB, Buchsbaum M, Brathwaite C. Progressive catatonia. Psychol Rep 1999; 84:239–246. Brasˇic´ JR, Zagzag D, Kowalik S, Prichep L, John ER, Barnett JY, Bronson B, Nadrich RH, Cancro R, Buchsbaum M, Brathwaite C. Clinical manifestations of progressive catatonia. Ger J Psychiatry 2000; 3:13–24. Brasˇic´ JR. Catatonia. eMedicine Journal Sept 27, 2002; 3(9). Brasˇic´ JR, Barnett JY, Kowalik S, Prichep L, John ER, Nadrich RH, Will MV, Bronson B, Ahmad R, Kurz L, Brathwaite C, Cancro R. Catatonia in pervasive developmental disorders [abstr]. Mov Disord 2001; 16(suppl 1):S46–S47. Brasˇic´ JR, Zagzag D, Kowalik S, Prichep L, John ER, Buchsbaum M, Barnett JY, Nadrich RH, Kaplan D, Ahmad R, Mendonc¸a MF, Rodriguez M, Bronson B, Can-

Movement Disorders

32. 33. 34. 35.

36.

37. 38. 39.

40. 41.

42. 43. 44. 45. 46. 47.

48.

49.

331

cro R, Kurz L, Brathwaite C. Chronic motor tics are a manifestation of progressive catatonia [abstr]. 3rd International Scientiﬁc Symposium on Tourette Syndrome, New York, June 4–6, 1999, p 21. Brasˇic´ JR. Conversion disorder in childhood. Ger J Psychiatry 2002; 5(2):54–61. Barnes TRE. A rating scale for drug-induced akathisia. Br J Psychiatry 1989; 154: 672–676. Brasˇic´ JR, Barnett JY. Hyperkinesias in a prepubertal boy with autistic disorder treated with haloperidol and valproic acid. Psychol Rep 1997; 80:163–170. Brasˇic´ JR, Barnett JY, Aisemberg P, Ahn SC, Nadrich RH, Kaplan D, Ahmad R, Mendonc¸a MF. Dyskinesias subside off all medication in a boy with autistic disorder and severe mental retardation. Psychol Rep 1997; 81:755–767. Fleischhacker WW, Bergmann KJ, Perovich R, Pestreich LK, Borenstein M, Lieberman J, Kane J. The Hillside Akathisia Scale: a new rating instrument for neuroleptic-induced akathisia. Psychopharmacol Bull 1989; 25:222–226. Brasˇic´ JR, Barnett JY, Sheitman BB, Lafargue RT, Ahn SC. Clinical assessment of adventitious movements. Psychol Rep 1998; 83:739–750. Brasˇic´ JR. Should people with nocturnal leg cramps drink tonic water and bitter lemon? Psychol Rep 1999; 84:355–367. Brasˇic´ JR. Quinine-induced thrombocytopenia in a 64-year-old man who consumed tonic water to relieve nocturnal leg cramps [letter]. Mayo Clinic Proc 2001; 76:863–864. Jankovic J. Stereotypies. In: Marsden CD, Fahn S, eds. Movement Disorders 3. Oxford, England: Butterworth-Heinemann, 1994:503–517. Bodﬁsh JW, Symons FJ, Parker DE, Lewis MH. Varieties of repetitive behavior in autism: comparisons to mental retardation. J Autism Dev Disord 2000; 30:237– 243. Brasˇic´ JR.Clinical assessment of tics. Psychol Rep 2001; 89:48–50. Blakeslee S. Movement may offer early clue to autism. New York Times, Jan 26, 1999, p F3. Goffman E. Stigma: Notes on the Management of Spoiled Identity. Englewood Cliffs, NJ: Prentice-Hall, 1963. Brasˇic´ JR. Autistic disorder and intentional aggression. Phillips J, interviewer. New York: WPIX news, Dec 19 and 20, 1994. Nicolson R, Awad G, Sloman L. An open trial of risperidone in young autistic children. J Am Acad Child Adolesc Psychiatry 1998; 37:372–376. McDougle CJ, Scahill L, McCracken JT, Aman MG, Tierney E, Arnold LE, Freeman BJ, Martin A, McGough JJ, Cronin P, Posey DJ, Riddle MA, Ritz L, Swiezy NB, Vitiello B, Volkmar FR, Votolato NA, Walson P. Research Units on Pediatric Psychopharmacology (RUPP) autism network: background and rationale for an initial controlled study of risperidone. Child Adolesc Psychiatr Clin North Am 2000; 9: 201–224. Williams H, Clarke R, Bouras N, Martin J, Holt G. Use of the atypical antipsychotics olanzapine and risperidone in adults with intellectual disability. J Intellect Disabil Res 2000; 44:164–169. Haut F, Clos S. Acute akathisia and sodium valproate. Int J Psychiatry Clin Pract 2001; 5:219–222.

332 50.

51.

52.

53.

54.

55.

56. 57.

58.

59. 60. 61.

62.

63.

64.

65.

Braˇsic´ Brasˇic´ JR, Furman JW, Conte RM, Baisley WE. Continuous quality improvement in child and adolescent psychopharmacology. Child Adolesc Psychopharmacol News 1999; 4(3):9–10. Brasˇic´ JR, Furman J, Conte RM, Baisley WE, Jaslow RI. Assuring the quality of the utilization of psychoactive medication by people with mental retardation and developmental disabilities by assessing dosages. Ger J Psychiatry 2000; 3(3): 7– 12. www.gjpsy.uni-goettingen.de/gjp-article-brasic2.pdf. Campbell M, Armenteros JL, Malone RP, Adams PB, Eisenberg ZW, Overall JE. Neuroleptic-related dyskinesias in autistic children: a prospective, longitudinal study. J Am Acad Child Adolesc Psychiatry 1997; 36:835–843. Locascio JJ, Malone RP, Small AM, Kafantaris V, Ernst M, Lynch NS, Overall JE, Campbell M. Factors related to haloperidol response and dyskinesias in autistic children. Psychopharmacol Bull 1991; 27(2):119–126. Armenteros JL, Adams PB, Campbell M, Eisenberg ZW. Haloperidol-related dyskinesias and prenatal and perinatal complications in autistic-children. Psychopharmacol Bull 1995; 31:363–369. Advokat CD, Mayville EA, Matson JL. Side effect proﬁles of atypical antipsychotics, typical antipsychotics, or no psychotropic medications in persons with mental retardation. Res Dev Disabil 2000; 21:75–84. Simonic I, Gericke GS, Lippert M, Schoeman JF. Additional clinical and cytogenetic ﬁndings associated with Rett syndrome. Am J Med Genet 1997; 74:331–337. Berger-Sweeney J, Hohmann CF. Behavioral consequences of abnormal cortical development: insights into developmental disabilities. Behav Brain Res 1997; 86: 121–142. Hohmann CF, Berger-Sweeney J. Cholinergic regulation of cortical development and plasticity: new twists to an old story. Perspect Dev Neurobiol 1998; 5:401– 425. Wan M, Zhao K, Lee SSJ, Francke U. MECP2 truncating mutations cause histone H4 hyperacetylation in Rett syndrome. Hum Molec Genet 2001; 10:1085–1092. Lee SSJ, Wan M, Francke U. Spectrum of MECP2 mutations in Rett syndrome. Brain Dev 2001; 23(suppl 1):S138–S143. Francke U. Understanding Rett Syndrome: where are we? [abstr]. 3rd Annual Rett Syndrome Symposium, Baltimore, June 17–19, 2002. Cincinnati: Rett Syndrome Research Foundation (RSRF), 2002:1. Bailey MES, Mash V, Hever AM, Boxer M, Ørstavik KH, Reilly S, Kerr AM, Cass H, Charman T. A detailed genotype-phenotype correlation study in Rett syndrome [abstr]. 3rd Annual Rett Syndrome Symposium, Baltimore, June 17–19, 2002. Cincinnati: Rett Syndrome Research Foundation (RSRF), 2002:35. Vaudry D, Stork PJS, Lazarovici P, Eiden LE. Signaling pathways for PC12 cell differentiation: making the right connections. Science 2002; 296:1648–1649. www.sciencemag.org. Stearns NA, Floerke-Nashner L, Berger-Sweeney J. Behavioral characterization of a mouse model of Rett syndrome [abstr]. 3rd Annual Rett Syndrome Symposium, Baltimore, June 17–19, 2002. Cincinnati: Rett Syndrome Research Foundation (RSRF), 2002:33. Chen RZ, Akbarian S, Tudor M, Jaenisch R. Deﬁciency of methyl-CpG binding

Movement Disorders

66.

67.

68.

69.

70.

71.

72. 73. 74.

75. 76.

77.

78.

79.

333

protein-2 in CNS neurons results in a Rett-like phenotype in mice [letter]. Nat Genet 2001; 27:327–331. Shahbazian MD, Antalffy B, Armstrong DL, Zoghbi HY. Insight into Rett syndrome: MeCP2 levels display tissue- and cell-speciﬁc differences and correlate with neuronal maturation. Hum Mol Genet 2002; 11:115–124. Akbarian S, Chen RZ, Gribnau J, Rasmussen TP, Fong H-f, Jaenisch R, Jones EG. Expression pattern of the Rett syndrome gene MeCP2 in primate prefrontal cortex. Neurobiol Dis 2001; 8:784–791. Guy J, Hendrich B, Holmes M, Martin JE, Bird A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome [letter]. Nat Genet 2001; 27:322–327. Christodoulou J, Grimm A, Maher T, Bennetts B. RettBASE—the IRSA MECP2 variation database: a new mutation database offering enhanced capabilities [abstr]. 3rd Annual Rett Syndrome Symposium, Baltimore, June 17–19, 2002. Cincinnati: Rett Syndrome Research Foundation (RSRF), 2002:38–39. Kriaucionis S, Coenraads M, Hendrich B. The MeCP2 Mutation Database: http:/ / homepages.ed.ac.uk/skirmis [abstr]. 3rd Annual Rett Syndrome Symposium, Baltimore, June 17–19, 2002. Cincinnati: Rett Syndrome Research Foundation (RSRF), 2002:40. Leonard H, Colvin L, Fyfe S, Christodoulou J, Raffaele L, Leonard S, Schiavello T, Ellaway C, Davis M, De Kierk N. Now that the gene has been found: describing the phenotype in Rett syndrome using a national database [abstr]. 3rd Annual Rett Syndrome Symposium, Baltimore, June 17–19, 2002. Cincinnati: Rett Syndrome Research Foundation (RSRF), 2002:41–42. Blue ME, Naidu S, Johnston MV. Development of amino acid receptors in frontal cortex from girls with Rett sydrome. Ann Neurol 1999; 45:541–545. Wenk GL, Hauss-Wegrzyniak B. Altered cholinergic function in the basal forebrain of girls with Rett syndrome. Neuropediatrics 1999; 30:125–129. Horska´ A, Naidu S, Herskovits EH, Wang PY, Kaufmann WE, Barker PB. Quantitative 1H MR spectroscopic imaging in early Rett syndrome. Neurology 2000; 54: 715–722. Narbona J. Rett syndrome as a hodogenetic neural disorder. Revista de Neurologia 1999; 28:97–101. Burroni L, Aucone AM, Volterrani D, Hayek Y, Bertelli P, Vella A, Zappella M, Vattimo A. Brain perfusion abnormalities in Rett syndrome: a qualitative and quantitative SPET study with 99Tcm-ECD. Nucl Med Commun 1997; 18:527– 534. Blue ME, Naidu S, Johnston MV. Altered development of glutamate and GABA receptors in the basal ganglia of girls with Rett syndrome. Exp Neurol 1999; 156: 345–352. Chiron C, Bulteau C, Loc’h C, Raynaud C, Garreau B, Syrota A, Mazie`re B. Dopaminergic D2 receptor SPECT imaging in Rett syndrome: increase of speciﬁc binding in striatum. J Nucl Med 1993; 34:1717–1721. Stoessl AJ, Dobko T, Morrison KS, Oakes T, Ho HH, Snow BJ, Poskitt KJ, Dunn HG. Positron emission tomography studies of the dopamine system in Rett syndrome [abstr]. Neurology 1998; 50:A7.

334 80. 81.

82.

83. 84. 85.

86.

87.

88.

89.

90.

91.

92.

93. 94. 95.

Braˇsic´ Maguire D, Bachman C. Anaesthesia and Rett syndrome: a case report. Can J Anaesth 1989; 36:478–481. Brasˇic´ JR, Barnett JY, Nadrich RH, Kaplan D, Ahmad R, Rodriguez M, Mendonc¸a MF. Evaluation of self-injurious tics [abstr]. 3rd International Scientiﬁc Symposium on Tourette Syndrome, New York, June 4–6, 1999, p 19. Brasˇic´ JR, Zagzag D, Kowalik S, Prichep L, John ER, Buchsbaum M, Barnett JY, Nadrich RH, Kaplan D, Ahmad R, Mendonc¸a MF, Rodriguez M, Bronson B, Cancro R, Kurz L, Brathwaite C. Chronic motor tics are a manifestation of progressive catatonia [abstr]. 3rd International Scientiﬁc Symposium on Tourette Syndrome, New York, June 4–6, 1999, p 19. Ringman JM, Jankovic J. Occurrence of tics in Asperger’s syndrome and autistic disorder. J Child Neurol 2000; 15:394–400. Kadesjo B, Gillberg C. Tourette’s disorder: epidemiology and comorbidity in primary school children. J Am Acad Child Adolesc Psychiatry 2000; 39:548–555. Baron-Cohen S, Scahill VL, Izaguirre J, Hornsey H, Robertson MM. The prevalence of Gilles de la Tourette syndrome in children and adolescents with autism: a large scale study. Psychol Med 1999; 29:1151–1159. Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, Heninger GR, Charney DS. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry 1989; 46:1006–1011. Goodman W, Price LH, Rasmussen SA, Mazure C, Delgado P, Heninger GR, Charney DS. The Yale-Brown Obsessive Compulsive Scale. II. Validity. Arch Gen Psychiatry 1989; 46:1012–1016. Leckman JF, Riddle MA, Hardin MT, Ort SI, Swartz KL, Stevenson J, Cohen DJ. The Yale Global Tic Severity Scale: initial testing of a clinician-rated scale of tic severity. J Am Acad Child Adolesc Psychiatry 1989; 28:566–573. Leckman JF, Towbin KE, Ort SI, Cohen DJ. Clinical assessment of tic disorder severity. In: Cohen DJ, Bruun RD, Leckman JF, eds. Tourette’s Syndrome and Tic Disorders. New York: John Wiley & Sons, 1988:55–78. Arnold LE, Aman MG, Martin A, Collier-Crespin A, Vitiello B, Tierney E, Asarnow R, Bell-Bradshaw F, Freeman BJ, Gates-Ulanet P, Klin A, McCracken JT, McDougle CJ, McGough JJ, Posey DJ, Scahill L, Swiezy NB, Ritz L, Volkmar F. Assessment in multisite randomized clinical trials of patients with autistic disorder: the Autism RUPP Network. J Autism Dev Disord 2000; 30:99–111. Brasic JR, Barnett JY, Ahn SC, Roncoli M, Nadrich RH, Ahmad R. Characterization of movement disorders in prepubertal boys with autistic disorder [abstr]. Mov Disord 1996; 11(suppl 1):59. Wu¨rbel H, Freire R, Nicol CJ. Prevention of stereotypic wire-gnawing in laboratory mice: effects on behaviour and implications for stereotypy as a coping response. Behav Proc 1998; 42:61–72. Brown DW. Autism, Asperger’s syndrome and the Crick-Mitchison theory of the biological function of REM sleep. Med Hypotheses 1996; 47:399–403. Ross LL, Yu D, Kropla WC. Stereotyped behavior in developmentally delayed or autistic populations: rhythmic or nonrhythmic? Behav Modif 1998; 22:321–334. Ridley RM. The psychology of perseverative and stereotyped behaviour. Prog Neurobiol 1994; 44:221–231.

Movement Disorders 96. 97. 98.

99.

100.

101. 102. 103.

104.

105.

106.

107.

108.

109. 110.

111.

335

Lewis MH, Bodﬁsh JW. Repetitive behavior disorders in autism. Ment Retard Dev Disabil Res Rev 1998; 4(2):80–89. Nijhof G, Joha D, Pekelharing H. Aspects of stereotypic behaviour among autistic persons: a study of the literature. Br J Dev Disabil 1998; 44:3–13. Magulac M, Landsverk J, Golshan S, Jeste DV. Abnormal involuntary movements in neuroleptic-naı¨ve children and adolescents. Can J Psychiatry 1999; 44:368– 373. Powell SB, Newman HA, Pendergast JF, Lewis MH. A rodent model of spontaneous stereotypy: initial characterization of developmental, environmental, and neurobiological factors. Physiol Behav 1999; 66:355–363. Antoniou K, Kafetzopoulos E, Papadopoulou-Daifoti Z, Hyphantis T, Marselos M. d-amphetamine, cocaine and caffeine: a comparative study of acute effects on locomotor activity and behavioural patterns in rats. Neurosci Biobehav Rev 1998; 23:189–196. Barik S, de Beaurepaire R. Evidence for a functional role of the dopamine D3 receptors in the cerebellum. Brain Res 1996; 737:347–350. Chabrol H, Bonnet D, Roge B. Psychopharmacologie de l’autisme [the psychopharmacology of autism]. Ence´phale 1996; 22:197–203. Buitelaar JK, Dekker MEM, van Ree JM, van Engeland H. A controlled trial with ORG 2766, an ACTH-(4-9) analog, in 50 relatively able children with autism. Eur Neuropharmacol 1996; 6:13–19. Cazzullo AG, Musetti MC, Musetti L, Bajo S, Sacerdote P, Panerai A. β-Endophin levels in peripheral blood mononuclear cells and long-term naltrexone treatment in autistic children. Eur Neuropsychopharmacol 1999; 9:361–366. Hollander E, Kaplan A, Cartwright C, Reichman D. Venlafaxine in children, adolescents, and young adults with autism spectrum disorders: an open retrospective clinical report. J Child Neurol 2000; 15:132–135. Posey DJ, McDougle CJ. The pharmacotherapy of target symptoms associated with autistic disorder and other pervasive developmental disorders. Harv Rev Psychiatry 2000; 8:45–63. Brasic JR, Barnett JY, Kaplan D, Sheitman BB, Aisemberg P, Lafargue RT, Kowalik S, Clark A, Tsaltas MO, Young JG. Clomipramine ameliorates adventitious movements and compulsions in prepubertal boys with autistic disorder and severe mental retardation. Neurology 1994; 44:1309–1312. Brasˇic´ JR, Barnett JY, Sheitman BB, Lafargue RT, Kowalik S, Kaplan D, Tsaltas MO, Ahmad R, Nadrich RH, Mendonc¸a MF. Behavioral effects of clomipramine on prepubertal boys with autistic disorder and severe mental retardation. CNS Spectrums: Int J Neuropsychiatr Med 1998; 3(10):39–46. Brasˇic´ JR, Barnett JY, Sheitman BB, Tsaltas MO. Adverse effects of clomipramine [letter]. J Am Acad Child Adolesc Psychiatry 1997; 36:1165–1166. Sanchez LE, Campbell M, Small AM, Cueva JE, Armenteros JL, Adams PB. A pilot study of clomipramine in young autistic children. J Am Acad Child Adolesc Psychiatry 1996; 35:537–544. McDougle CJ, Kresch LE, Posey DJ. Repetitive thoughts and behavior in pervasive developmental disorders: treatment with serotonin reuptake inhibitors. J Autism Dev Disord 2000; 30:427–435.

336 112.

113.

114.

115. 116. 117.

118.

119. 120.

121. 122. 123.

124. 125.

126. 127. 128.

129.

Braˇsic´ Remington G, Sloman L, Konstantareas M, Parker K, Gow R. Clomipramine versus haloperidol in the treatment of autistic disorder: a double-blind, placebocontrolled, crossover study. J Clin Psychopharmacol 2001; 21:440–444. McDougle CJ, Naylor ST, Cohen DJ, Volkmar FR, Heninger GR, Price LH. A double-blind, placebo-controlled study of ﬂuvoxamine in adults with autistic disorder. Arch Gen Psychiatry 1996; 53:1001–1008. Harvey RJ. Cooray SE. The effective treatment of severe repetitive behaviour with ﬂuvoxamine in a 20 year old autistic female. Int Clin Psychopharmacol 1995; 10: 201–203. Kutcher SP. Child and Adolescent Psychopharmacology. Philadelphia: WB Saunders, 1997. Simpson RL. Early intervention with children with autism: the search for best practices. J Assoc Pers Sev Handicaps 1999; 24:218–221. Smith T, Antolovich M. Parental perceptions of supplemental interventions received by young children with autism in intensive behavior analytic treatment. Behav Interv 2000; 15:83–97. Saunders MD, Saunders RR, Marquis JG. Comparison of reinforcement schedules in the reduction of stereotypy with supported routines. Res Dev Disabil 1998; 19: 99–122. Morrison K, Rosales-Ruiz J. The effect of object preferences on task performance and stereotypy in a child with autism. Res Dev Disabil 1997; 18:127–137. Celiberti DA, Bobo HE, Kelly KS, Harris SL, Handelman JS. The differential and temporal effects of antecedent exercise on the self-stimulatory behavior of a child with autism. Res Dev Disabil 1997; 18:139–150. Symons F, Davis M. Instructional conditions and stereotyped behavior: the function of prompts. J Behav Ther Exp Psychiatry 1994 25:317–324. Duker PC, Schaapveld M. Increasing on-task behaviour through interruption prompting. J Intellect Disabil Res 1996; 40:291–297. Sweeney HM, LeBlanc JM. Effects of task size on work-related and aberrant behaviors of youths with autism and mental retardation. Res Dev Disabil 1995; 16: 97–115. Trepagnier CG. Virtual environments for the investigation and rehabilitation of cognitive and perceptual impairments. Neurorehabilitation 1999; 12:63–72. Willenberg H. Probleme der Klassiﬁkation heimlicher Selbstscha¨digung und Entwicklung eines Alternativvorschlages [problems of classifying secret self-injurious behaviors and development of an alternative proposal]. Psychother Psychosom Med Psychol 1994; 44:331–336. Szymanski L, Kedesdy J, Sulkes S, Cutler A, Stevens-Our P. Naltrexone in treatment of self injurious behavior: a clinical study. Res Dev Disabil 1987; 8:179–190. Wieseler NA, Hanson RH, Chamberlain TP, Thompson T. Functional taxonomy of stereotypic and self-injurious behavior. Ment Retard 1985; 23:230–234. Schroeder SR, Schroeder CS, Smith B, Dalldorf J. Prevalence of self-injurious behaviors in a large state facility for the retarded: a three-year follow-up study. J Autism Child Schizophr 1978; 8:261–269. Rapin I. Appropriate investigations for clinical care versus research in children with autism. Brain Dev 1999; 21:152–156.

Movement Disorders 130.

131. 132.

133.

134. 135.

136.

137. 138. 139.

140.

141.

142. 143. 144. 145.

146. 147.

337

Matson JL, Hamilton M, Duncan D, Bamburg J, Smiroldo B, Anderson S, Baglio C, Williams D, Kirkpatrick-Sanchez S. Characteristics of stereotypic movement disorder and self-injurious behavior assessed with the Diagnostic Assessment for the Severely Handicapped (DASH-II). Res Dev Disabil 1997; 18:457–469. King BH, Lynn D. Self-injurious behavior in mental retardation. Curr Opin Psychiatry 1998; 11:523–526. Ofﬁce of Medical Applications of Research, National Institutes of Health. Treatment of destructive behaviors in persons with developmental disabilities. Conn Med 1990; 54:65–74. Russo DC, Carr EG, Lovaas OI. Self-injury in pediatric populations. In: Ferguson JM, Taylor CB, eds. The Comprehensive Handbook of Behavioral Medicine. Vol 3. New York: Spectrum Publications, 1980:23–41. Eisenhauer GL, Woody RC. Self-mutilation and Tourette’s disorder. J Child Neurol 1987; 2:265–267. Jankovic J. Orofacial and other self-mutilations. In: Jankovic J, Tolosa E, eds. Facial Dyskinesias. Advances in Neurology, Vol 49. New York: Raven Press, 1988:365–381. Stodgell CJ, Loupe PS, Schroeder SR, Tessel RE. Cross-sensitization between footshock stress and apomorphine on self-injurious behavior and neostriatal catecholamines in a rat model of Lesch-Nyhan syndrome. Brain Res 1998; 783:10–18. Gualtieri CT. The measurement of self-injurious behavior. J Neuropsychiatry Clin Neurosci 1991; 3:S30–S34. Gedye A. Extreme self-injury attributed to frontal lobe seizures. Am J Ment Retard 1989; 94:20–26. Dura JR, Mulick JA, Rasnake LK. Prevalence of stereotypy among institutionalized nonambulatory profoundly mentally retarded people. Am J Ment Deﬁc 1987; 91:548–549. Fovel JT, Lash PS, Barron DA, Jr., Roberts MS. A survey of self-restraint, selfinjury, and other maladaptive behaviors in an institutionalized retarded population. Res Dev Disabil 1989; 10:377–382. Grifﬁn JC, Ricketts RW, Williams DE, Locke BJ, Altmeyer BK, Stark MT. A community survey of self-injurious behavior among developmentally disabled children and adolescents. Hosp Commun Psychiatry 1987; 38:959–963. Hill RK, Bruininks RH. Maladaptive behavior of mentally retarded individuals in residential facilities. Am J Ment Deﬁc 1984; 88:380–387. Oliver C, Murphy GH, Corbett JA. Self-injurious behaviour in people with mental handicap: a total population study. J Ment Deﬁc Res 1987; 31:147–162. Putnam N, Stein M. Self-inﬂicted injuries in childhood: a review and diagnostic approach. Clin Pediatr 1985; 24:514–518. Rojahn J. Self-injurious and stereotypic behavior of noninstitutionalized mentally retarded people: prevalence and classiﬁcation. Am J Ment Deﬁc 1986; 91:268– 276. Matson JL, Bamburg JW. A descriptive study of pica behavior in persons with mental retardation. J Dev Phys Disabil 1999; 11:353–361. Holburn CS. Aerophagia: an uncommon form of self-injury. Am J Ment Deﬁc 1986; 91:201–203.

338 148. 149. 150. 151. 152.

153. 154. 155. 156. 157.

158.

159.

160. 161.

162.

163. 164. 165. 166.

Braˇsic´ Levison CA. The development of head banging in a young rhesus monkey. Am J Ment Deﬁc 1970; 75:323–328. Allyn G, Deyme A, Be`gue I. Self-ﬁghting syndrome in macaques. I. A representative case study. Primates 1976; 17: 1–22. Jones IH, Barraclough BM. Auto-mutilation in animals and its relevance to selfinjury in man. Acta Psychiatr Scand 1978; 58:40–47. Cataldo MF, Harris J. The biological basis for self-injury in the mentally retarded. Anal Interv Dev Disabil 1982; 2:21–38. Kelley WM, Wyngaarden JB. Clinical syndromes associated with HGPRT deﬁciency. In: Stanbury JB, Wyngaarden JB, et al., eds. The Metabolic Basis of Inherited Disease. 5th ed. New York: McGraw-Hill, 1983:1115–1143. Lesch M, Nyhan WL. A familial disorder of uric acid metabolism and central nervous system function. Am J Med 1964; 36:561–570. Shear CS, Nyhan WL, Kirman BH, Stern J. Self-mutilative behavior as a feature of the de Lange syndrome. J Pediatr 1971; 78:506–509. Gualtieri CT. The differential diagnosis of self-injurious behavior in mentally retarded people. Psychopharmacol Bull 1989; 25(3):358–363. Jones IH. Self-injury: toward a biological basis. Perspect Biol Med 1982; 26:137– 150. Ciaranello RD, Anders TF, Barchas JD, Berger PA, Cann HM. The use of 5hydroxytryptophan in a child with Lesch-Nyhan syndrome. Child Psychiatry Hum Dev 1976; 7:127–133. Lloyd KG, Hornykiewicz O, Davidson L, Shannak K, Farley I, Goldstein M, Shibuya M, Kelley WN, Fox IH. Biochemical evidence of dysfunction of brain neurotransmitters in the Lesch-Nyhan syndrome. N Engl J Med 1981; 305:1106– 1111. Lake CR, Ziegler MG. Lesch-Nyhan syndrome: low dopamine-beta-hydroxylase activity and diminished sympathetic response to stress and posture. Science 1977; 196:905–906. Mizuno TI, Yugari Y. Self mutilation in Lesch-Nyhan syndrome [letter]. Lancet 1974; i(7860):761. Nyhan WL, Johnson HG, Kaufman IA, Jones KL. Serotonergic approaches to the modiﬁcation of behavior in the Lesch-Nyhan syndrome. Appl Res Ment Retard 1980; 1:25–40. Mailis A. Compulsive targeted self-injurious behaviour in humans with neuropathic pain: a counterpart of animal autotomy? Four case reports and literature review. Pain 1996; 64:569–578. Ritvo ER, Ornitz EM, La Franchi S. Frequency of repetitive behaviors in early infantile autism and its variants. Arch Gen Psychiatry 1968; 19:341–347. Delcomyn F. Neural basis of rhythmic behavior in animals. Science 1980; 210: 492–498. Olson GA, Olson RD, Vaccarino AL, Kastin AJ. Endogenous opiates:1997. Peptides 1998; 19:1791–1843. Beckwith BE, Couk DI, Schumacher K. Failure of naloxone to reduce self-injurious behavior in two developmentally disabled females. Appl Res Ment Retard 1986; 7:183–188.

Movement Disorders 167. 168.

169.

170.

171.

172.

173. 174. 175.

176.

177.

178.

179. 180. 181. 182. 183. 184. 185.

339

Davidson PW, Kleene BM, Carroll M, Rockowitz RJ. Effects of naloxone on selfinjurious behavior: a case study. Appl Res Ment Retard 1983; 4:1–4. Sandman CA, Barron JL, Crinella FM, Donnelly JF. Inﬂuence of naloxone on brain and behavior of a self-injurious woman. Biol Psychiatry 1987; 22:899– 906. Sandman CA, Datta PC, Barron J, Hoehler FK, Williams C, Swanson JM. Naloxone attenuates self-abusive behavior in developmentally disabled clients. Appl Res Ment Retard 1983; 4:5–11. Ballinger BR, Armstrong J, Presley AS, Reid AH. Use of a standardized psychiatric interview in mentally handicapped patients. Br J Psychiatry 1975; 127:540– 544. Goldberg DP, Cooper B, Eastwood MR, Kedward HB, Shepherd M. A standardized psychiatric interview for use in community surveys. Br J Prev Soc Med 1970; 24:18–23. Read SG, Batchelor DH. Violent and self-injurious behaviour in mentally handicapped patients—psychopharmacological control. Int Clin Psychopharmacol 1986; 1(suppl 1):63–74. Campbell M, Adams P, Small AM, Tesch LM, Curren EL. Naltrexone in infantile autism. Psychopharmacol Bull 1988; 24(1):135–139. Sandyk R. Naloxone abolishes self-injuring in a mentally retarded child. Ann Neurol 1985; 17:520. Spitzer RL, Williams JBW, Gibbon M, First MB. Structured Clinical Interview for DSM-III-R–Patient Edition (SCID-P, Version 1.0). Washington, DC: American Psychiatric Publishing, 1990. Bernstein GA, Hughes JR, Mitchell JE, Thompson T. Effects of narcotic antagonists on self-injurious behavior: a single case study. J Am Acad Child Adolesc Psychiatry 1987; 26:886–889. Iwata BA, Pace GM, Kissel RC, Nau PA, Farber JM. The Self-Injury Trauma (SIT) Scale: a method for quantifying surface tissue damage caused by self-injurious behavior. J Appl Behav Anal 1990; 23:99–110. Baker SP, O’Neill B, Haddon W, Jr., Long WB. The Injury Severity Score: a method for describing patients with multiple injuries and evaluating emergency care. J Trauma 1974; 14(3):187–196. Barancik JI, Chatterjee BF. Methodological considerations in the use of the Abbreviated Injury Scale in trauma epidemiology. J Trauma 1981; 21(8):627–631. Champion HR, Sacco WJ, Lepper RL, Atzinger EM, Copes WS, Prall RH. An anatomic index of injury severity. J Trauma 1980; 20(3):197–202. Committee on Medical Aspects of Automotive Safety. Rating the severity of tissue damage. I. The abbreviated scale. JAMA 1971; 215:277–280. Committee on Medical Aspects of Automotive Safety. Rating the severity of tissue damage. II. The comprehensive scale. JAMA 1972; 220:717–720. Greenspan L, McLellan BA, Greig H. Abbreviated Injury Scale and Injury Severity Score: a scoring chart. J Trauma 1985; 25:60–64. Mayer T, Matlak ME, Johnson DG, Walker ML. The modiﬁed injury severity scale in pediatric multiple trauma patients. J Pediatr Surg 1980; 15:719–726. Brasic JR, Kisnad HV, Barnett JY, Kowalik S, Ahn SC, Nadrich RH, Mendonca

340

186. 187. 188.

189.

190.

191. 192. 193. 194.

195. 196.

197.

198. 199.

200. 201.

202.

Braˇsic´ MF. Clinical assessment of self-injurious behaviors in people with movement disorders [abstr]. Mov Disord 2001; 16(suppl 1):S46. Gorman-Smith D, Matson JL. A review of treatment research for self-injurious and stereotyped responding. J Ment Deﬁc Res 1985; 29:295–308. Lundervold D, Bourland G. Quantitative analysis of treatment of aggression, selfinjury, and property destruction. Behav Modif 1988; 12:590–617. Durand VM, Carr EG. Operant learning methods with chronic schizophrenia and autism: aberrant behavior. In: Matson JL, ed. Chronic Schizophrenia and Adult Autism. New York: Springer, 1989:231–273. Durand VM, Crimmins DB, Caulﬁeld M, Taylor J. Reinforcer assessment. I. Using problem behavior to select reinforcers. J Assoc Pers Sev Handicaps 1989; 14:113– 126. Favell JE, Azrin NH, Baumeister AA, Carr EG, Dorsey MF, Forehand R, Foxx RM, Lovaas OI, Rincover A, Risley TR, Romanczyk RG, Russo CD, Schroeder SR, Solnick JV. The treatment of self-injurious behavior. Behav Ther 1983:13: 529–554. Iwata BA, Dorsey MF, Slifer KJ, et al. Toward a functional analysis of self injury. Anal Interv Dev Disabil 1982; 2:3–20. Repp AC, Felce D, Barton LE. Basing the treatment of stereotypic and self-injurious behaviors on hypotheses of their causes. J Appl Behav Anal 1988; 21:281–289. Rincover A. Behavioral research in self-injury and self-stimulation. Psychiatr Clin North Am 1986; 9:755–766. Silverstein BJ, Olvera DR. Schalock R. Allocating direct-care resources for treatment of maladaptive behavior: the Staff Intensity Scale. Ment Retard 1987; 25: 91–100. Gerdtz J. Evaluating behavioral treatment of disruptive classroom behaviors of an adolescent with autism. Res Soc Work Pract 2000; 10:98–110. Dawson JE, Matson JL, Cherry KE. An analysis of maladaptive behaviors in persons with autism, PPD-NOS, and mental retardation. Res Dev Disabil 1998; 19: 439–448. Martin NT, Gaffan EA, Williams T. Experimental functional analyses for challenging behavior: a study of validity and reliability. Res Dev Disabil 1999; 20: 125–146. Lockwood K, Williams DE. Treatment and extended follow-up of chronic hand mouthing. J Behav Ther Exp Psychiatry 1994; 25(2):161–169. Miller BY, Jones RSP. Reducing stereotyped behaviour: a comparison of two methods of programming differential reinforcement. Br J Clin Psychol 1997; 36(2):297–302. Corbett J. Aversion for the treatment of self-injurious behaviour. J Ment Deﬁc Res 1975; 19:79–95. Barrett RP, Matson JL, Shapiro ES, Ollendick TH. A comparison of punishment and DRO procedures for treating stereotypic behavior of mentally retarded children. Appl Res Ment Retard 1981; 2:247–256. Duker PC, Seys DM. A quasi-experimental study on the effect of electrical aversion treatment on imposed mechanical restraint for severe self-injurious behavior. Res Dev Disabil 2000; 21:235–242.

Movement Disorders 203. 204.

205. 206. 207. 208.

209.

210. 211. 212. 213. 214. 215. 216.

217.

218. 219. 220. 221. 222.

341

Singh NN, Watson JE, Winton ASW. Treating self-injury: water spray versus facial screening or forced arm exercise. J Appl Behav Anal 1986; 19:403–410. Peri T, Ben-Shakhar G, Orr, SP, Shalev AY. Psychophysiologic assessment of aversive conditioning in posttraumatic stress disorder. Biol Psychiatry 2000; 47: 512–519. Altmeyer BK, Williams DE, Sams V. Treatment of severe self-injurious and aggressive biting. J Behav Ther Exp Psychiatry 1985; 16:169–172. Brasˇic´ JR, Fogelman D. Clinician safety. Psychiatr Clin North Am 1999; 22:923– 940. Azrin NH, Kaplan SJ, Foxx RM. Autism reversal: eliminating stereotyped selfstimulation of retarded individuals. Am J Ment Deﬁc 1973; 78:241–248. Silverman K, Watanabe K, Marshall AM, Baer DM. Reducing self-injury and corresponding self-restraint through the strategic use of protective clothing. J Appl Behav Anal 1984; 17:545–552. Pace GM, Iwata BA, Edwards GL, McCosh KC. Stimulus fading and transfer in the treatment of self-restraint and self-injurious behavior. J Appl Behav Anal1986; 19:381–389. Luiselli JK. Modiﬁcation of self-injurious behavior: an analysis of the use of contingently applied protective equipment. Behav Modif 1986; 10:191–204. Luiselli JK. Contingent glove wearing for the treatment of self-excoriating behavior in a sensory-impaired adolescent. Behav Modif 1989; 13:65–73. Lovaas I, Newson C, Hickman C. Self-stimulatory behavior and perceptual reinforcement. J Appl Behav Anal 1987; 20:45–68. Clauser B, Gould K. Visual screening as a reductive procedure: an examination of generalization and duration. Behav Residential Treat 1988; 3:51–61. Watson J, Singh NN, Winton ASW. Suppressive effects of visual and facial screening on self-injurious ﬁnger-sucking. Am J Ment Deﬁc 1986; 90:526–534. Winton ASW, Singh NN, Dawson MJ. Effects of facial screening and blindfold on self-injurious behavior. Appl Res Ment Retard 1984; 5:29–42. Goodall E, Corbett J. Relationships between sensory stimulation and stereotyped behaviour in severely mentally retarded and autistic children. J Ment Deﬁc Res 1982; 26:163–175. Stroh G, Buick D. The effect of relative sensory isolation on the behaviour of two autistic children. In: Hutt SJ, Hutt C, eds. Behaviour Studies in Psychiatry. Oxford, England: Pergamon Press, 1970:161–174. Luiselli JK. Use of sensory extinction in treating self-injurious behavior: a cautionary note. The Behavior Therapist 1984; 7:142–160. Norton RS. Side effects of sensory extinction and an alternative procedure for high rates of self-injury. The Behavior Therapist 1985:8:86–87. Rincover A. Sensory extinction: some answers and questions. The Behavior Therapist 1985; 8:177–178. Azrin NH, Besalel VA, Jamner JP, Caputo JN. Comparative study of behavioral methods of treating severe self-injury. Behav Residential Treat 1988; 3:119–152. Haring TG, Breen CG, Pitts-Conway V, Gaylord-Ross R. Use of differential reinforcemnt of other behavior during dyadic instruction to reduce stereotyped behavior of autistic students. Am J Ment Deﬁc 1986; 90:694–702.

342 223.

224.

225.

226. 227.

228.

229.

230.

231.

232. 233.

234.

235.

236. 237.

238. 239.

Braˇsic´ Matson JL, Keyes JB. A comparison of DRO to movement suppression time-out and DRO with two self-injurious and aggressive mentally retarded adults. Res Dev Disabil 1990; 11:111–120. Parrish JM, Iwata BA, Dorsey MF, Bunck TJ, Slifer KJ. Behavior analysis, program development, and transfer of control in the treatment of self-injury. J Behav Ther Exp Psychiatry 1985; 16:159–167. Repp AC, Deitz SM, Speir NC. Reducing stereotypic responding of retarded persons by differential reinforcement of other behavior. Am J Ment Deﬁc 1974; 79: 279–284. Tarpley HD, Schroeder SR. Comparison of DRO and DRI on rate of suppression of self-injurious behavior. Am J Ment Deﬁc 1979; 84:188–194. Hegel MT, Ferguson RJ. Differential reinforcement of other behavior (DRO) to reduce aggressive behavior following traumatic brain injury. Behav Modif 2000; 24(1):94–101. Luiselli JK. Functional assessment and treatment of aggressive and destructive behaviors in a child victim of physical abuse. J Behav Ther Exp Psychiatry 1996; 27:41–49. Paisey TJH, Whitney RB, Moore J. Person-treatment interactions across nonaversive response-deceleration procedures for self-injury: a case study of effects and side effects. Behav Residential Treat 1989; 4:69–88. Lancioni GE, O’Reilly MF. A review of research on physical exercise with people with severe and profound developmental disabilities. Res Dev Disabil 1998; 19: 477–492. Repp AC, Singh NN, Olinger E, Olson DR. The use of functional analyses to test causes of self-injurious behaviour: rationale, current status and future directions. J Ment Deﬁc Res 1990; 34:95–105. Durand VM, Crimmins DB. Identifying the variables maintaining self-injurious behavior. J Autism Dev Disord 1988; 18:99–117. Iwata BA, Pace GM, Kalsher MJ, Cowdery GE, Cataldo MF. Experimental analysis and extinction of self-injurious escape behavior. J Appl Behav Anal 1990; 23: 11–27. Steege MW, Wacker DP, Cigrand KC, Berg WK, Novak CG, Reimers TM, Sasso GM, DeRaad A. Use of negative reinforcement in the treatment of self-injurious behavior. J Appl Behav Anal 1990; 23:459–467. Bourland G, Jablonski EM, Lockhart DL. Multiple-behavior comparison of group and individual instruction of persons with mental retardation. Ment Retard 1988; 26:39–46. Durand VM. Self-injurious behavior as intentional communication. Adv Learn Behav Disabil 1986; 5:141–155. Bird F, Dores PA, Moniz D, Robinson J. Reducing severe aggressive and selfinjurious behaviors with functional communication training. Am J Ment Retard 1989; 94:37–48. Carr EG, Durand VM. See me, help me. Psychol Today 1987; 21(11):62–64. Day RM, Johnson WL, Schussler NG. Determining the communicative properties of self-injury: research, assessment, and treatment implications. Adv Learn Behav Disabil 1986; 5:117–139.

Movement Disorders 240. 241.

242. 243. 244. 245. 246. 247. 248.

249.

250. 251.

252. 253.

254.

255. 256. 257.

258.

343

Day RM, Rea JA, Schussler NG, Larsen SE, Johnson WL. A functionally based approach to the treatment of self-injurious behavior. Behav Modif 1988; 12:565–589. Durand VM, Carr EG. Functional communication training to reduce challenging behavior: maintenance and application in new settings. J Appl Behav Anal 1991; 24:251–264. Durand VM, Carr EG. Self-injurious behavior: motivating conditions and guidelines for treatment. School Psychol Rev 1985; 14(2):171–176. Braithwaite KL, Richdale AL. Functional communication training to replace challenging behaviors across two behavioral outcomes. Behav Interv 2000; 15:21–36. Schroeder SR, Rojahn J, Mulick JA. Ecobehavioral organization of developmental day care for the chronically self-injurious. J Pediatr Psychol 1978; 3(2):81–88. Arnaud M. E´tude des ste´re´otypies dans l’autisme infantile [a study of stereotypies in infantile autism]. Psychiatr Enfant 1986; 29:387–420. Kennedy H, Moran GS. The developmental roots of self-injury and response to pain in a 4-year-old boy. Psychoanal Study Child 1984; 39:195–212. Kerbeshian J, Burd L, Avery K. Pharmacotherapy of autism: a review and clinical approach. J Dev Phys Disabil 2001; 13:199–228. Madrid AL, State MW, King BH. Pharmacologic management of psychiatric and behavioral symptoms in mental retardation. Child Adolesc Psychiatr Clin North Am 2000; 9:225–243. Goldstein M, Kuga S. Dopamine (DA) agonist induced compulsive biting (CB) behavior in monkeys: animal model for Lesch-Nyhan syndrome [abstr]. Soc Neurosci Abstracts 1984; 10(part 2):804. Gualtieri CT, Schroeder SR. Pharmacotherapy for self-injurious behavior: preliminary tests of the D1 hypothesis. Psychopharmacol Bull 1989; 25(3):364–371. Allen SM, Freeman JN, Davis WM. Evaluation of risperidone in the neonatal 6hydroxydopamine model of Lesch-Nyhan syndrome. Pharmacol Biochem Behav 1998; 59:327–330. Horrigan JP, Barnhill LJ. Risperidone and explosive aggressive autism. J Autism Dev Disord 1997; 27:313–323. Cohen SA, Ihrig K, Lott RS, Kerrick JM. Risperidone for aggression and selfinjurious behavior in adults with mental retardation. J Autism Dev Disord 1998; 28:229–233. Mendonca MF, Brasic JR, Perry R, Krigsman S, Lucien M, Petty CB. Risperidone ameliorates large amplitude complex stereotypies and high activity level in a boy with autistic disorder [abstr]. Mov Disord 2001; 16(suppl 1):S36. DeVane CL, Nemeroff CB. An evaluation of risperidone drug interactions. J Clin Psychopharmacol 2001; 21:408–416. Drug interactions of risperidone. Child Adolesc Psychopharmacol News 2002; 7(2):12. Aman MG, Arnold LE, Armstrong SC. Review of serotonergic agents and perseverative behavior in patients with developmental disabilities. Ment Retard Dev Disabil Res Rev 1999; 5:279–289. Potenza MN, Holmes JP, Kanes SJ, McDougle CJ. Olanzapine treatment of children, adolescents, and adults with pervasive developmental disorders: an openlabel pilot study. J Clin Psychopharmacol 1999; 19:37–44.

344 259. 260. 261. 262.

263. 264. 265. 266.

267. 268.

269.

270. 271. 272.

273. 274.

275. 276. 277. 278.

Braˇsic´ Aman MG, Madrid A. Atypical antipsychotics in persons with developmental disabilities. Ment Retard Dev Disabil Res Rev 1999; 5:253–263. Divalproex sodium in autism spectrum disorders. Child Adolesc Psychopharmacol News 2002; 7(2):10–11. Hollander E, Dolgoff-Kaspar R, et al. An open trial of divalproex sodium in autism spectrum disorders. J Clin Psychiatry 2001; 62:530–534. Ereshefsky L, Riesenman C, Lam YWF. Serotonin selective reuptake inhibitor drug interactions and the cytochrome P450 system. J Clin Psychiatry 1996; 57(suppl 8):17–25. Oesterheld JR, Shader RI. Cytochromes: a primer for child and adolescent psychiatrists. J Am Acad Child Adolesc Psychiatry 1998; 37:447–450. Luchins DJ, Dojka D. Lithium and propranolol in aggression and self-injurious behavior in the mentally retarded. Psychopharmacol Bull 1989; 25(3):372–375. Reents SB, Beck CA Jr. Naloxone and naltrexone: application in COPD. Chest 1988; 93:217–219. Cohen MR, Cohen RM, Pickar D, Murphy DL, Bunney WE Jr. Physiological effects of high dose naloxone administration to normal adults. Life Sci 1982; 30: 2025–2031. Grevert P, Albert LH, Inturrisi CE, Goldstein A. Effects of eight-hour naloxone infusions on human subjects. Biol Psychiatry 1983; 18:1375–1392. Newhouse PA, Tariot PN, Gross M, Murphy DL, Cohen RM. Failure of high dose naloxone to relieve tardive dyskinesia [letter]. J Clin Psychopharmacol 1987; 7: 364–365. Nasrallah HA, Varney N, Coffman JA, Bayless J, Chapman S. Effects of naloxone on cognitive deﬁcits following electroconvulsive therapy. Psychopharmacol Bull 1985; 21(1):89–90. Pollock J, Kornetsky C. Naloxone prevents and blocks the emergence of neurolepticmediated oral stereotypic behaviors. Neuropsychopharmacology 1991; 4:245–249. Richardson JS, Zaleski WA. Naloxone and self-mutilation. Biol Psychiatry 1983; 18:99–101. Barrett RP, Feinstein C, Hole WT. Effects of naloxone and naltrexone on selfinjury: a double-blind, placebo-controlled analysis. Am J Ment Retard 1989; 93: 644–651. Malcolm R, Gabel T, Morton A. More on idiosyncratic reaction to naltrexone [letter]. Am J Psychiatry 1989; 146:124–125. Rascol O, Fabre N, Blin O, Poulik J, Sabatini U, Senard J-M, Ane´ M, Montastruc J-L, Rascol A. Naltrexone, an opiate antagonist, fails to modify motor symptoms in patients with Parkinson’s disease. Mov Disord 1994; 9:437–440. Sandyk R, Iacono RP. Naltrexone attenuates the antiparkinsonian effects of picoTesla range magnetic ﬁelds. Int J Neurosci 1994; 78:111–122. Dennis K. Naltrexone. Treatment Issues: The GMHC Newsletter of Experimental AIDS Therapies 1990; 4(1):1–2. Wildt L, Leyendecker G. Induction of ovulation by the chronic administration of naltrexone in hypothalamic amenorrhea. J Clin Endocrinol Metab 1987; 64:1334–1335. Igoin-Apfelbaum L, Apfelbaum M. Naltrexone and bulimic symptoms [letter]. Lancet 1987; ii(8567):1087–1088.

Movement Disorders 279. 280. 281.

282. 283.

284.

285.

286.

287.

288. 289. 290. 291.

292.

293. 294. 295. 296. 297.

345

Tennant FS Jr, Wild J. Naltrexone treatment for postconcussional syndrome. Am J Psychiatry 1987; 144:813–814. Herman BH, Hammock MK, Arthur-Smith A, Egan J, Chatoor I, Werner A, Zelnik N. Naltrexone decreases self-injurious behavior. Ann Neurol 1987; 22:550–552. Herman BH, Hammock MK, Egan J, Feinstein C, Chatoor I, Boeckx R, Zelnick N, Jack R, Rosenquist J. Naltrexone induces dose-dependent decreases in selfinjurious behavior [abstr]. Abstr Soc Neurosci 1985; 11:468. Garcia D, Smith RG. Using analog baselines to assess the effects of naltrexone on self-injurious behavior. Res Dev Disabil 1999; 20:1–21. Sandman CA, Hetrick W, Taylor DV, Marion SD, Touchette P, Barron JL, Martinezzi V, Steinberg RM. Long-term effects of naltrexone on self-injurious behavior. Am J Ment Retard 2000; 105:103–117. Campbell M, Anderson LT, Small AM, Adams P, Gonzalez NM, Ernst M. Naltrexone in autistic children: behavioral symptoms and attentional learning. J Am Acad Child Adolesc Psychiatry 1993; 32:1283–1291. Campbell M, Anderson LT, Small AM, Locascio JJ, Lynch NS, Choroco MC. Naltrexone in autistic children: a double-blind and placebo-controlled study. Psychopharmacol Bull 1990; 26(1):130–135. Campbell M, Overall JE, Small AM, Sokol MS, Spencer EK, Adams P, Foltz RL, Monti KM, Perry R, Nobler M, Roberts E. Naltrexone in autistic children: an acute open dose range tolerance trial. J Am Acad Child Adolesc Psychiatry 1989; 28: 200–206. Campbell M. Resolved: autistic children should have a trial of naltrexone—afﬁrmative: Magda Campbell, MD. J Am Acad Child Adolesc Psychiatry 1996; 35: 246–247. Herman BH, Chatoor I. Naltrexone shown to decrease frequency of self-injurious behavior. The Psychiatric Times 1991; 8(8):32–39. Leboyer M, Bouvard MP, Dugas M. Effects of naltrexone on infantile autism [letter]. Lancet 1988; i(8587):715. Lienemann J, Walker F. Naltrexone for treatment of self-injury [letter]. Am J Psychiatry 1989; 146:1639–1640. Sandman CA, Hetrick WP, Taylor DV, Barron JL, Touchette P, Lott I, Crinella F, Martinazzi V. Naltrexone reduces self-injury and improves learning. Exp Clin Psychopharmacol 1993; 1:242–258. Walters AS, Barrett RP, Feinstein C, Mercurio A, Hole WT. A case report of naltrexone treatment of self-injury and social withdrawal in autism. J Autism Dev Disord 1990; 20:169–176. Chisholm T, Morehouse RL. Adult headbanging: sleep studies and treatment. Sleep 1996; 19:343–346. Durand VM. A behavioral/pharmacological intervention for the treatment of severe self-injurious behavior. J Autism Dev Disord 1982; 12:243–251. Farber JM. Psychopharmacology of self-injurious behavior in the mentally retarded. J Am Acad Child Adolesc Psychiatry 1987; 26:296–302. Luiselli JK. Behavior analysis of pharmacological and contingency management interventions for self-injury. J Behav Ther Exp Psychiatry 1986; 17:275–284. Luiselli JK, Evans TP, Boyce DA. Pharmacological assessment and comprehen-

346

298. 299. 300.

301. 302. 303.

304.

305. 306. 307.

308.

309.

310.

311.

312.

313.

Braˇsic´ sive behavioral intervention in a case of pediatric self-injury. J Clin Child Psychol 1986; 15:323–326. Singh NN, Winton ASW. Behavioral monitoring of pharmacological interventions for self-injury. Appl Res Ment Retard 1984; 5:161–170. Lapierre YD, Reesal R. Pharmacologic management of aggressivity and self-mutilation in the mentally retarded. Psychiatr Clin North Am 1986; 9:745–754. Singh NN, Millichamp CJ. Effects of medication on the self-injurious behavior of mentally retarded persons. Psychiatr Aspects Ment Retard Rev 1984; 3(4):13– 16. Singh NN, Millichamp CJ. Pharmacological treatment of self-injurious behavior in mentally retarded persons. J Autism Dev Disord 1985; 15:257–267. Swett C, Jr. Psychotropic medications used during mechanical restraint of patients. Curr Ther Res 1985:38(4):621–626. Brasˇic´ JR, Barnett JY, Zelhof R, Tarpley H. Dopamine antagonists ameliorate the dyskinesias, aggression, and inattention of persons with mental retardation referred to psychiatric clinics. Ger J Psychiatry 2001; 4(1):9–16. www.gjpsy.unigoettingen/gjp-article-brasic3.pdf. Practice parameters for the assessment and treatment of children, adolescents, and adults with autism and other pervasive developmental disorders. J Am Acad Child Adolesc Psychiatry 1999; 38(suppl):32S–54S. Tsai LY. Psychopharmacology in autism. Psychosom Med 1999; 61:651–665. Duchan JF. Describing the unusual behavior of children with autism. J Commun Disord 1998; 31:93–112. Brasˇic´ JR, Young JG. Research design, measures, and statistics. In: Robson KS, ed. Manual of Clinical Child and Adolescent Psychiatry. Revised ed. Washington, DC: American Psychiatric Press, 1994:435–463. Walkup JT, Labellarte MJ, Riddle MA. Commentary: unmasked and uncontrolled medication trials in child and adolescent psychiatry. J Am Acad Child Adolesc Psychiatry 1998; 37:360–363. Martin A, Patzer DK, Volkmar FR. Psychopharmacological treatment of higherfunctioning pervasive developmental disorders. In: Klin A, Volkmar FR, Sparrow SS, eds. Asperger Syndrome. New York: The Guilford Press, 2000:210–228. Matson JL, Bamburg JW, Mayville EA, Pinkston J, Bielecki J, Kuhn D, Smalls Y, Logan JR. Psychopharmacology and mental retardation: a 10 year review (1990–1999). Res Dev Disabil 2000; 21:263–296. Brasˇic´ JR, Kaplan D, Young JG: The design and analysis of single-patient randomized clinical trials for children and adolescents with developmental disorders [abstr]. Abstracts of the 12th International Congress of the International Association for Child and Adolescent Psychiatry and Allied Professions, Kyoto, Japan, July 16–20, 1990, Symposium S-84-2:192. Brasˇic´ JR, Kaplan D, Young JG: The design and analysis of experiments with N ⫽ 1 [abstr]. Abstracts of the Second International Conference on Industrial and Applied Mathematics, Washington, DC, July 8–12, 1991:27. Baving L, Schmidt MH. Evaluated treatment approaches in child and adolescent psychiatry. I. Z Kinder Jugendpsychiatr Psychother 2001; 29:189–205.

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 treatments 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 serotoninreuptake 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 summary, 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, families 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 pediatricians, will see many more (1). They will all undoubtedly hear of many alterna347

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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 caregivers. 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 deﬁnitive 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 attempted, as in any other type of pharmacotherapy it is paramount that parents and practitioners work together to monitor efﬁcacy, safety, and side effects. Parents should also be educated on guidelines for evaluating treatments and encouraged 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, promoted 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 nonFDA-approved treatment with claims of success. The excitement regarding secre-

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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 disservice 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 unrealistically 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 treatment for autism and related disorders. Biochemistry and Physiology of Secretin In 1981, secretin (in its puriﬁed porcine form, manufactured by Ferring Laboratories 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 secretin and no evidence documenting the safety of its use in children. Secretin is a 27-amino-acid peptide (ﬁrst sequenced in 1965) that was discovered 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 similar, 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.

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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 receptor (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 sensitivity 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

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addition, electrical stimulation of the amygdala led to an augmented acid-induced pancreatic secretion of water and bicarbonate. This effect was abolished by bilateral truncal vagotomy. These ﬁndings suggest that the peripheral secretory response 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 dysregulation of catecholamines (thought to play an important role in the modulation of reward mechanisms, attention, arousal, and impulse control) has been hypothesized to play a role in these functions, and autism is often accompanied by features of inattention, difﬁculty regulating impulsivity, and repetitive behaviors. Gastrointestinal Complaints in Autism Behaviors such as nighttime awakening, sudden episodes of irritability, and aggressive 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 allergies, and occult-positive stools. These children had been previously diagnosed as having autism spectrum disorders. Standard diagnostic gastrointestinal endoscopy 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 administration, 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 observations of therapists and teachers unaware of the medical procedure. Speciﬁcally,

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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 pervasive 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, nighttime awakening, and unexplained irritability. Of these children, 47% were on a gluten-free and/or casein-free diet. They underwent endoscopy under general anesthesia, including biopsies of esophagus, stomach, and duodenum for histology, measurement of digestive enzymes of the pancreas (before and after secretin infusion) and the small intestine, as well as bacterial and fungal cultures. Porcine secretin, 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 children 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. Twentytwo 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 children 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 majority 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 upregulation 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 privatepractice setting in New York, six children diagnosed with autism were treated with single secretin infusions. Only one was found to respond with a clinically

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signiﬁcant improvement in language and relatedness. Three others showed subtle changes in these areas of functioning, one child became more active and aggressive, and the last showed no change. Aman and Armstrong (15) posted a standardized questionnaire on the Internet 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 interest, 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 hyperactivity, 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

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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). Intravenous porcine secretin (Ferring Pharmaceuticals, Tarrytown, NY) was administered 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 socialcommunication 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 completed 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 behaviors was assessed using parent report, the ABC, and the Clinical Global Improvement Scale. In addition, the Vineland and the Treatment Emergent Symptoms Scale, a rating scale that measures medication side effects, were administered. Fifty-six subjects completed the study (28 in each group). The authors reported that there were no signiﬁcant improvements on any of the outcome measures 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.

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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 children’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 gastrointestinal symptoms and the outcome assessments that were used were insensitive 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, crossover 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 completed by physician or nurse (devised by the authors’ clinic). Parents also completed 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 expressive language, gastrointestinal function, eye contact, and receptive language. Despite this ﬁnding, the authors concluded that there were no signiﬁcant differences in CARS scores of children treated with secretin as compared with those treated

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with saline, and therefore that no obvious clinical beneﬁts were evident in children 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 instruments 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 sample being on some form of medication) and those who were receiving secretin alone. The study’s ﬁndings might therefore have been confounded by drug–secretin 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.

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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 validity. 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 conclusion that vitamin B6, or pyridoxine, was associated with signiﬁcant behavioral improvement by parental report in 30–40% of patients. A few children experienced 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 clinically 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 beneﬁcial 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-

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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 homovanillic 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 vitamin 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 physicians 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 perception, language processing, and attention. Natural vitamin A would repair the defective 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 abnormal 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 Neuroscience meeting in New Orleans, Louisiana. Entitled “A Required Role for Vitamin 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

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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 atypically developing brains. It should be remembered, though, that vitamin A toxicity is manifested by anorexia, hepatosplenomegaly, and increased intracranial pressure. A clinical trial using cod liver oil in autistic children has been approved by the American College for Advancement of Medicine, an organization dedicated to alternative and complementary medicine based in Laguna Hills, California, 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 RitvoFreeman 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. However, 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 ﬁrstline 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 revealed no statistically signiﬁcant differences. The major methodological weakness 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)

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on learning (35) and social interest (36). ORG 2766 had been reported to improve social and communicative behavior in autistic subjects. A controlled trial published 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 improvements 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 unprecedented 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. government’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 Psychiatry, a poster presented by Ozgur Yorbik and collaborators (unpublished) reported plasma copper levels of autistic children that were signiﬁcantly higher than normal. 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, cadmium, copper, lead, mercury, nickel and platinum. These are found in a multitude of sources, seemingly unavoidable in our postindustrial age. Low-level methylmercury has recently come under scrutiny because of increased recognition of its neurotoxicity to developing nervous systems (42). Of special concern is exposure 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-

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cognition, including language, attention, and memory. Another source of exposure 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 41/2year-old boy diagnosed with attention-deﬁcit/hyperactivity disorder and autism who had a high lead level. The child improved while being treated with the chelating 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 prospective 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 questionnaires frequent mention of thrush in infants later diagnosed with autism. This led to speculation of fungal-associated autism. In 1995, medical biochemist William 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

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his book Biological Treatments for Autism and PDD, he believes that these compounds 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 behavioral 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 videotapes scored by a clinical psychologist blinded to treatment status. The improvements 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, immunoglobulin 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 inquiry 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 dietary 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 neurological 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 collection. 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).

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Lay literature abounds promoting a casein-free, gluten-free diet as a treatment 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 characterized by social withdrawal, introversion, and decreased sensitivity to pain. Unfortunately, trials with opiate antagonists did not support this contention. But more recent studies do suggest a role for naltrexone in self-injurious behavior, as interacting 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 immunological 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 gluten- 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 antifungal 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

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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 describes the effects of parental expectation. The extra attention given unconsciously 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 highlight 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 research 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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REFERENCES 1.

2.

3. 4. 5.

6. 7. 8.

9.

10.

11. 12.

13. 14. 15. 16. 17.

18.

Powell JE, et al. Changes in the incidence of childhood autism and other autistic spectrum disorders in preschool children from two areas of the West Midlands, UK. Dev Med Child Neurol 2000; 42(9):624–628. Horvath K, Stefanatos G, et al. Improved social and language skills after secretin administration in patients with autistic spectrum disorders. J Assoc Acad Minor Phys 1998; 9(1):9–15. Lightdale JR, Heyman MB. Secretin: cure or snake oil for autism in the new millennium? J Pediatr Gastroenterol Nutr 1999; 29(2):114–115. Chez MG, Buchanan CP, et al. Secretin and autism: a two-part clinical investigation. J Autism Dev Disord 2000; 30(2):87–94. Holtmann MH, Hadac EM. Molecular basis and species speciﬁcity of high afﬁnity binding of vasoactive intestinal polypeptide by the rat secretin receptor. J Pharmacol Exp Ther 1996; 279(2):555–560. Li P, Lee KY, et al. Mechanism of acid-induced release of secretin in rats: presence of a secretin releasing peptide. J Clin Invest 1990; 86:1474–1479. Holst JJ. Neuronal control of pancreatic exocrine secretion. Eur J Clin Invest 1990; 20(suppl 1):33–39. Momany FA, Bowers CY. Speculations on the mechanism of hormone-receptor interactions of the secretin/glucagon family of polypeptide hormones derived from computational structural studies. Ann NY Acad Sci 1996; 26:172–181. de Bono M, Bargmann CI. Natural variation in a neuropeptide Y receptor homolog modiﬁes social behavior and food response in C. elegans. Cell 1998; 94(5):679– 689. Banks WA, Kastin AJ, et al. Passage of pituitary adenylate cyclase activating polypeptide1-27 and pituitary adenylate cyclase activating polypeptide1-38 across the blood-brain barrier. J Pharmacol Exp Ther 1993; 267(2):690–696. Conter RL, Hughes MT, et al. Intracerebroventricular secretin enhances pancreatic volume and bicarbonate response in rats. Surgery 1996; 119(2):208–213. Roskoski R Jr, White L, Knowlton R, Roskoski LM. Regulation of tyrosine hydroxylase activity in rat PC12 cells by neuropeptides of the secretin family. Mol Pharmacol 1989; 36(6):925–931. Horvath K, Papadimitriou JC, et al. Gastrointestinal abnormalities in children with autistic disorder. J Pediatr 1999; 135(5):559–563. Perry R, Bangaru BS. Secretin in autism. J Child Adolesc Psychopharmacol 1998; 8(4):247–248. Aman MG, Armstrong SA. Regarding secretin for treating autistic disorder. J Autism Dev Disord 2000; 30(1):71–72. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Publishing, 1994. Owley T, Steele E, Corsello C, Risi S, McKaig K, Lord C, Leventhal BL, Cook EH Jr. A double-blind, placebo-controlled trial of secretin for the treatment of autistic disorder. MedGenMed Oct 6, 1999; E2. Sandler AD, Sutton KA, et al. Lack of beneﬁt of a single dose of synthetic human secretin in the treatment of autism and pervasive developmental disorder. N Engl J Med 1999; 341(24):1801–1806.

366

Cartwright and Power

19.

Horvath K. Secretin treatment for autism. N Engl J Med 2000; 342(16):1216; discussion, 1218. Rimland B. Comments on: Chez MG, et al. Secretin and autism: a two-part clinical investigation. J Autism Dev Disord 2000; 30(2):95; discussion, 97–98. Rimland B. In: Shaw W, Rimland B, Semon B, Lewis L. Biological Treatments for Autism and PDD: What’s Going On? What Can You Do About It? Overland Park, KS: Great Plains Laboratory, 1998. Rimland B, Callaway E, Dreyfus P. The effect of high doses of vitamin B6 on autistic children: a double blind crossover study. Am J Psychiatry 1978;135:472– 475. Lelord G, Muh JP, Barthelemy C, Martineau J, Garreau B, Callaway E. Effects of pyridoxine and magnesium on autistic symptoms: initial observations. J Autism Dev Disord 1981; 11:219–230. Findling RL, Maxwell K, Scotese-Wotjila L, Huang J, Yamashita T, Wiznitzer M. High-dose pyridoxine and magnesium administration in children with autistic disorder: an absence of salutary effects in a double-blind, placebo-controlled study. J Autism Dev Disord 1997; 27:467–478. Pfeiffer SI, Norton J, Nelson L, Shott S. Efﬁcacy of vitamin B6 and magnesium in the treatment of autism: a methodology review and summary of outcomes. J Autism Dev Disord 1995; 25:481–493. Martineau J, Cheliakine C, Lelord G. Brief report: an open middle-term study of combined vitamin B6-magnesium in a subgroup of autistic children selected for their sensitivity to this treatment. J Autism Dev Discord 1988; 3:372–376. Lelord G, et al. Cited in Coleman M, Gillberg C, eds. The Biology of Autistic Syndromes. New York: Cambridge University Press, 2000:279. Megson MN. Is autism a G-alpha protein defect reversible with natural vitamin A? Med Hypotheses 2000; 54(6):979–983. Farfel Z, Bourne HR, Iiri T. The expanding spectrum of G protein diseases. N Eng J Med 1999; 340(13):1012–1020. Chung JJ, et al. Activation of retinoic acid receptor gamma induces proliferation of immortalized hippocampal progenitor cells. Brain Res Mol Brain Rev 2000; 83(1–2):52–62. Zetterstrom R, et al. Role of retinoids in the CNS: differential expression of retinoid binding proteins and receptors and evidence for presence of retinoic acid. Eur J Neurosci 1999; 11(2):407–416. Dolske MC, Spollen J, McKay S, Lancashire E, Tolbert L. A preliminary trial of ascorbic acid as supplemental therapy for autism. Prog Neuropsychopharmacol Biol Psychiatry 1993; 17(5):765–774. Bolman WM, Richmond JA. A double-blind, placebo-controlled, crossover pilot trial of low dose dimethylglycine in patients with autistic disorder. J Autism Dev Disord 1999; 29(3):191–194. van Rijzingen IM, Gispen WH, Spruijt BM. The ACTH(4-9) analog ORG 2766 and recovery after brain damage in animal models: a review. Behav Brain Res 1996; 74(1–2):1–15. Horvath KM, Meerlo P, Felszeghy K, Nyakas C, Luiten PG. Early postnatal treatment with ACTH4-9 analog ORG 2766 improves adult spatial learning but does

20. 21.

22.

23.

24.

25.

26.

27. 28. 29. 30.

31.

32.

33.

34.

35.

Alternative Biological Treatments

36.

37.

38.

39. 40. 41. 42. 43. 44.

45. 46.

47. 48. 49. 50.

51. 52.

367

not affect behavioural stress reactivity. Behav Brain Res 1999; 106(1–2):181– 188. Hol T, Ruven S, Van Ree JM, Spruijt BM. Chronic administration of Org2766 and morphine counteracts isolation-induced increase in social interest: implication of endogenous opioid systems. Neuropeptides 1996; 30(3):283–291. Buitelaar JK, Dekker ME, van Ree JM, van Engeland H. A controlled trial with ORG 2766, an ACTH-(4–9) analog in 50 relatively able children with autism. Eur Neuropsychopharmacol 1996; 6:13–19. Horvath KM, Abraham IM, Harkany T, Meerlo P, Bohus BG, Nyakas C, Luiten PG. Postnatal treatment with ACTH-(4–9) analog ORG 2766 attenuates N-methylD-aspartate-induced excitotoxicity in rat nucleus basalis in adulthood. Eur J Pharmacol 2000; 405(1–3):33–42. Shearer TR, Larson K, Neuschwander J, Gedney B. Minerals in the hair and nutrient intake of autistic children. J Autism Dev Disord 1982; 12:25–34. Jackson MJ, Garrod PJ. Plasma zinc, copper and amino acid levels in the blood of autistic children. J Autism Child Schizophr 1978; 8:203–208. Wiedel L, Coleman M. The autistic and control population of this study. In: Coleman M, ed. The Autistic Syndromes. Amsterdam: North-Holland, 1976:11–20. Mahaffey KR. Recent advances in recognition of low-level methylmercury poisoning. Curr Opin Neurol 2000; 13(6):699–707. Reich F, et al. Cytoxicity of dental composite components and mercury compounds in lung cells. Dent Mater 2001; 17(2):95–101. Eppright TD, Sanfacon JA, Horwitz EA. Attention deﬁcit hyperactivity disorder, infantile autism and elevated blood-lead: a possible relationship. Mol Med 1996; 93(3):136–138. Alberti A, et al. Sulphation deﬁcits in “low-functioning” autistic children: a pilot study. Biol Psychiatry 1999; 46:420–424. Shaw W, Kassen E, Chaves E. Increased urinary excretion of analogs of Krebs cycle metabolites and arabinose in two brothers with autistic features. Clin Chem 1995; 41:1094–1104. Sandler RH, Finegold SM, Bolte ER, et al. Short-term beneﬁt from oral vancomycin treatment of regressive-onset autism. J Child Neurol 2000; 15(7):429–435. Page T. Metabolic approaches to the treatment of autism spectrum disorders. J Autism Dev Disord 2000; 30(5):463–469. Coleman M, Gillberg C. The Biology of the Autistic Syndromes. 3rd ed. New York: Cambridge University Press, 2000. Lucarelli S, Frediani T, Zingoni AM, Ferruzzi F, Giardini O, Quintieri F, Barbato M, D’Eufemia P, Cardi E. Food allergy and infantile autism. Panminerva Med 1995; 37(3):137–141. Wolraich M. Attention deﬁcit hyperactivity disorder. Prof Care Mother Child 1998; 8(2):35–37. Dawson G, Watling R. Interventions to facilitate auditory, visual and motor integration in autism: a review of the evidence. J Autism Dev Disord 2000; 30(5):415– 421.

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 beststudied intervention for this disorder. Researchers have published more than 550 peer-refereed, data-based investigations on behavioral treatment (also called applied 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 impairments 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 reading 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 pro369

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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 paraprofessionals who work under the close supervision of professional behavior analysts. 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 behavioral 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 performs. 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 individual with autism performs too often or too intensely, such as tantrums or stereotypies) or behavioral deﬁcits (activities that the individual with autism performs too seldom or not at all, such as communicating or playing with toys). A functional analysis focuses on three kinds of events: 1) antecedents, which are events that occur immediately before the behavior and thus may trigger it, 2) consequences, 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 consequences. 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 immediately 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 systematically presented and removed. Data are usually graphed and interpreted by visual inspection (e.g., looking for consequences that reliably follow the behavior), but inferential statistics such as time series analyses may also be used.

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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 environment 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 ﬂapping 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 environmental 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 facilitate 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-

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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 determine 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 assessments serve as the basis for selecting interventions. Ongoing assessments of response to interventions may lead to revisions of the initial assessments and modiﬁcations 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. Collaboration with caregivers and involvement of peers are also emphasized. Intervention 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.

2.

Discrete trial training (DTT): DTT is a highly structured, precise instructional procedure characterized by a) one-to-one interaction between 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. Loosely structured training: for situations when individuals with autism do not need the tightly controlled learning situations provided in

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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 instructions 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 environments 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 provide cues for these behaviors. For example, teachers may aim to “catch children being good” (e.g., praise children when the children are playing 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 accepting a rough approximation of it and then reinforcing close and closer approximations (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

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interaction and identifying adults as consistent sources of positive and negative consequences. It also introduces the individual with autism to the basic framework (instruction–response–consequence) that many future teaching interactions will follow (2). The second stage of treatment emphasizes going from basic to more complex 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 functionally 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, understanding 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 individuals, 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 presents two objects simultaneously so that the individual learns to discriminate between requests for each object (e.g., selecting a book in response to “touch

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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 following 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 teaching how to combine sounds into syllables, words, and, eventually, phrases. Individuals 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 communication, 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 individuals 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 prerecorded 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 answering “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

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such as appropriate greetings and conversational statements (11). Peers often facilitate 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 implement skills-training methods to teach more advanced academic skills such as reading, mathematics, spelling, language arts, science, and social studies. Although 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’ learning 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, chaining 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 supervision, 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.

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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 individuals 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 behavior teachers also employ an intervention to reduce the problem behavior. Perhaps 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 consists 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 misbehavior. 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 appropriate 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 combination of reinforcement and reductive procedures. In response cost, the individual loses a previously acquired reinforcer when she displays the target behavior. Response 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 ontask behavior but taking away a token for every instance of yelling.

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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 autism 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 Exchange Communication System (PECS) learn to use such systems to communicate (19). Most also acquire skills for interacting with peers, playing with toys, and engaging in leisure activities, although many use these skills only when requested to do so (1). Success rates of 70–80% have been reported for toilettraining 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 intensively (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 placements in less restrictive educational settings than are typically offered to individuals 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 interventions 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 designed to accommodate the learning deﬁcits of autism. For example, because

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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 aversive, individuals with autism often work at their own workstations rather than with classmates, although some activities occur in small groups. Because transitions 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 comparable 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 individuals 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 relational 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 therapy 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 designed 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 complete 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,

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the most inﬂuential relational therapy is Greenspan’s Developmental IndividualDifference Relationship-Based Model (DIR) (27), a diathesis-stress model for autism. According to this model, individuals with autism are born with constitutional 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,” particularly 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 approaches 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 intervention. First, recent research on learning may suggest ways to enhance this intervention. 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 promise 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 appropriate 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

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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. REFERENCES 1.

2. 3. 4.

5. 6.

7.

8. 9. 10.

11. 12. 13. 14. 15.

16.

17.

Matson JL, Benavidez, DA, Compton LS, Paclawskyj T, Baglio C. Behavioral treatment of autistic persons: a review of research from 180 to the present. Res Dev Disabil 1996; 17:433–465. Newsom CB. Autistic Disorder. In: Mash EJ, Barkley RA, eds. Treatment of Childhood Disorders. 2nd ed. New York: Guilford, 1998:416–467. Jacobson JW, Mulick JA, Schwartz AA. A history of facilitated communication: science, pseudoscience, and antiscience. Am Psych 1995; 50:750–765. Autism Special Interest Group. Guidelines for Consumers of Applied Behavior Analytic Services to Individuals with Autism. Kalamazoo, MI: Association for Behavior Analysis, 1998. Haynes SN, O’Brien WH, Hayes W. Principles and Practice of Behavioral Assessment. New York: Plenum, 2000. Desrochers MN, Hile MG, Williams-Moseley TL. Survey of functional assessment procedures used with individuals who have severe mental retardation. Am J Ment Retard 1997; 101:535–546. Anderson SR, Taras M, Cannon BO. Teaching new skills to young children with autism. In: Maurice C, ed. Behavioral Intervention for Young Children with Autism. Austin, TX: PRO-ED, 1996:181–194. Skinner BF. Verbal Behavior. New York: Appleton-Century-Crofts, 1957. Salzinger K. Experimental manipulation of verbal behavior: a review. J Gen Psych 1959; 61:65–94. Taylor BA, McDonough KA. Selecting teaching programs. In: Maurice C, ed. Behavioral Intervention for Young Children with Autism. Austin, TX: PRO-ED, 1996: 63–180. Krantz PJ, McClannahan LE. Teaching children with autism to initiate to peers: effects of script fading procedure. J Appl Behav Anal 1993; 26:121–132. Kohler F, Strain P. Peer-assisted interventions: early promises, notable achievements, and future aspirations. Clin Psych Rev 1990; 10:441–452. Krantz PJ, McClannahan LE. Activity Schedules for Children with Autism: Teaching Independent Behavior. Bethesda, MD: Woodbine House, 1998. Lovaas OI, Ackerman AB, Alexander D, Firestone P, Perkins J, Young D. Teaching developmentally disabled children: the ME book. Austin, TX: PRO-ED, 1981. Etzel BC, Leblanc JM, Schillmoeller KJ, Stella ME. Behavior modiﬁcation contributions to education. In: Bijou SW, Ruiz R, eds. Stimulus Control Procedures in the Education of Young Children. Hillsdale, NJ: Lawrence Erlbaum, 1981:3–37. Rogers SJ, Bennetto L, McEvoy R, Pennington BF. Imitation and pantomime in high-functioning adolescents with autism spectrum disorders. Child Dev 1996, 67: 2060–2073. Reichle J, Wacker DP. Communicative Alternatives to Challenging Behavior: Inte-

382

18. 19.

20. 21. 22.

23.

24. 25. 26. 27. 28.

29.

30.

31.

Smith and Magyar grating Functional Assessment and Intervention Strategies. Baltimore: Paul H. Brookes, 1993. Howlin PA. The effectiveness of operant language training with autistic children. J Autism Dev Disord 1981; 21:281–290. Schwartz IS, Garﬁnkle AA, Bauer, J. The Picture Exchange Communication System: communicative outcomes for young children with disabilities. Top Early Child Spec Educ 1998; 18:144–159. Ando H. Training autistic children to urinate in the toilet through operant conditioning techniques. J Autism Child Schizophr 1977; 7:151–163. Smith T. Early intervention for children with autism. Clin Psych: Sci Pract 1999; 6:33–49. Marcus L, Schopler E, Lord C. TEACCH services for preschool children. In: Handleman JS, Harris SL, eds. Preschool Programs for Children with Autism. 2nd ed. Austin, TX: PRO-ED, 2000:215–232. Rogers SJ, Hall T, Osaki D, Reaven J, Herbison J. The Denver Model: a comprehensive, integrated educational approach to young children with autism and their families. In: Handleman JS, Harris SL, eds. Preschool Programs for Children with Autism. 2nd ed. Austin, TX: PRO-ED, 2000:95–134. Ayres AJ. Sensory Integration and the Child. Los Angeles: Western Psychological Association, 1972. Arendt RE, MacLean WE, Baumeister AA. Critique of Sensory Integration Therapy and its application in mental retardation. Am J Ment Retard 1988; 92:401–411. Mason SA, Iwata BA. Artifactual effects of sensory-integrative therapy on selfinjurious behavior. J Appl Behav Anal 1990; 23:361–370. Greenspan SI, Weider S. A functional developmental approach to autism spectrum disorders. J Assoc Pers Sev Handicaps 1999; 24:147–161. Greenspan SI. The Development of the Ego: Implications for Personality Theory, Psychopathology, and the Psychotherapeutic Process. Madison, CT: International Universities Press, 1989:318. Greenspan SI. Reconsidering the diagnosis and treatment of very young children with autism spectrum or pervasive developmental disorder. Zero to Three 1992; 3: 1–9. Wilkinson KM, McIlvane WJ. Contributions of stimulus control perspectives to psycholinguistic theories of vocabulary development and delay. In: Adamson LB, Romski MA, eds. Communication and Language Acquisition: Discoveries from Atypical Development. Baltimore: Paul H. Brookes, 1998:2548. 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 Mount Sinai School of Medicine New York, New York

INTRODUCTION The “normalization” movement has been integral in protecting civil rights, deinstitutionalizing and humanizing services for people with developmental handicaps (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 disabilities. 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

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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 underactivity, 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 education 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 inclusion 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 addressing target behaviors. Peer tutoring has been successfully used to increase reading ﬂuency in highfunctioning children with autism (12) and to improve imitation and play behaviors 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 strategies for teaching children with autism in small groups, including choral responding (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 discrepancies between the autism and mental-retardation (MR) groups. The autism group demonstrated higher gains that the MR group, suggesting that there is no general

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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 settings. 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 psychologists 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 decreasing 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 welldescribed 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 disabilities 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-

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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 studies 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 children 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 between 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 environments 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 successful 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 “mainstreamed” into a regular classroom (24,26,30,31). Mainstreaming and full inclusion are typically not considered until a child has participated in some form of behavioral treatment. Based on these ﬁndings, even special-education classrooms

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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 environments 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 intensive 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 social 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

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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, fullinclusion, 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 autistic 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 sophisticated understanding of the features of autism and treatment strategies, while mainstream teachers expressed a rudimentary understanding of the disorder, noting the behavioral difﬁculties and special abilities exhibited by some children with autism. Given the results of this survey, it is unclear whether teachers outside 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 besttrained 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 overloaded, general- and special-education teachers have gained a substantial amount of experience, training, and appreciation for teaching children with disabilities (37). But to what extent this experience and training are appropriate for teaching children with autism is unclear given the lack of empirical research in this area.

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Children with autism can experience seemingly unprovoked emotional or aggressive outbursts if their status quo is disturbed. These outbursts can be prolonged 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 educators, especially special educators, have signiﬁcant training in behavior management, teachers’ knowledge about autism and beliefs about managing the behaviors 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 problems require more intrusive teacher supervision to prevent inappropriate interactions with peers. However, the ﬁndings of this study, indicated that intrusive teacher supervision increased the rates of negative behaviors or were superﬂuous to how the disabled child’s interaction with a nondisabled peer. Educators without training in behavior management of children with autism may use inappropriate behavior management and may have much more difﬁculty teaching these children. Mesibov and Shea (11) suggest that children with milder handicaps and fewer behavioral problems tend to beneﬁt most from integrated classrooms. Full inclusion has been a successful educational environment for some children 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 environments 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.

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IQ, functional ability, age at initiation of behavioral intervention, and successful 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. Prospective, 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 presentation of the autistic children studied, an important shortcoming given the heterogeneity of the disorder. Clearly, there is a strong need for more research in this area. REFERENCES 1. 2. 3. 4. 5.

6.

7. 8.

9. 10. 11. 12.

Wolfensberger W. PASS: A Method of the Quantitative Evaluation of Human Services. Toronto: National Institute on Mental Retardation, 1973. Blau G. Autism—assessment and placement under the Education for All Handicapped Children Act: a case history. J Clin Psychol 1985; 41(3):440–447. Katsiyannis A, Reid R. Autism and section 504: rights and responsibilities. Focus Autism Other Dev Disabil 1999; 14(2):66–72. Powell S, Jordan R. A psychological perspective on identifying and meeting the needs of exceptional pupils. School Psychol Int 1991; 12(4):315–327. Kamps D, Leonard B., Vernon S, Dugan E, Delquadri J, Gershon B, Wade L, Louise F. Teaching social skills to students with autism to increase peer interactions in an integrated ﬁrst-grade classroom. J Appl Behav Anal 1992; 25:281–288. Ando H, Yosimura I, Shinichiro W. Effects of age on adaptive behavior levels and academic skill levels in autistic and mentally retarded children. J Autism Dev Disord 1980; 10(2):173–184. Mesibov G. Normalization and its relevance today. J Autism Dev Disord 1990; 20(3):379–390. Romanczyk R. Behavioral analysis and assessment: the cornerstone to effectiveness. In: Maurice C, Green G, eds. Behavioral Intervention for Young Children with Autism. Austin, TX: PRO-ED, 1996. Autism Society of America. 2001. http:/ /www.autism-society.org/society/ options.html. Silver A. Children with autistic behavior in a self-contained unit in the public schools. Dev Behav Pediatr 1986; 7(2):84–92. Mesibov G, Shea V. Full inclusion and students with autism. J Autism Dev Disord 1996; 26(3):337–346. Kamps D, Dugan E, Leonard B, Daoust P. Enhanced small group instruction using choral responding and student interaction for children with autism and developmental disabilities. Am J Ment Retard 1994; 99(1):60–73.

Educational Intervention 13. 14.

15. 16. 17. 18. 19.

20.

21.

22.

23. 24.

25.

26. 27. 28.

29.

30. 31.

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Carr E, Darcy M. Setting generality of peer modeling in children with autism. J Autism Dev Disord 1990; 20(1):45–49. Kamps D, Walker D, Maher J, Rotholz D. Academic and environmental effects of small group arrangements in classrooms for students with autism and other developmental disabilities. J Autism Dev Disord 1992; 22(2). Verheij F, Van Doorn E. Autism and mental retardation: the planning of a therapeutic environment. Int J Rehabil Res 1990; 13(2):127–136. Harrower J, Dunlap G. Including children with autism in general education classrooms: a review of effective strategies. Behav Modif 2001; 25(5):762–784. Rapin I. An 8-year-old boy with autism. JAMA 2001; 285(13):1749–1757. Koegel R, Koegel K, Carter C. Pivotal teaching interactions for children with autism. School Psychol Rev 1999; 28(4):576–594. Koegel L, Koegel R, Frea W, Fredeen R. Identifying early intervention targets for children with autism in inclusive school settings. Behav Modif 2001; 25(5):745– 761. Sweeney H, LeBlanc J. Effects of task size on work-related and aberrant behaviors of youths with autism and mental retardation. Res Dev Disabil 1995; 16(2):97– 115. Koegel L, Harrower J, Koegel R. Support for children with developmental disabilities in full inclusion classrooms through self-management. J Posit Behav Interv 1999; 1(1):26–34. Tjus T, Heimann M, Nelson K. Interaction patterns between children and their teachers when using a speciﬁc multimedia and communication strategy: observations from children with autism and mixed intellectual disabilities. Autism 2001; 5(2):175–187. Kasari C, Freeman S, Bauminger N, Alkin M. Parental perspectives in inclusion: effects of autism and down syndrome. J Autism Dev Disord 1999; 29(4):297–305. Harris S, Handleman J. Age and IQ at intake as predictors of placement for young children with autism: a four- to six-year follow-up. J Autism Dev Disord 2000; 30(2):137–142. Myles B, Simpson R, Ormsbee C, Erickson C. Integration preschool children with autism with their normally developing peers: research ﬁndings and best practices recommendations. Focus Autistic Behav 1993; 8:1–20. Howlin P. Practitioner review: psychological and educational treatments for autism. J Child Psychol Psychiatry 1998; 39(3):307–322. Green G, Brennan L, Fein D. Intensive behavioral treatment for a toddler at high risk for autism. Behav Modif 2002; 26(1):69–102. AACAP. Practice parameters for the assessment and treatment of children, adolescents, and adults with autism and other pervasive developmental disorders. J Am Acad Child Adolesc Psychiatry 1999; 38:32S–54S. Green G. Early behavioral intervention for autism. In: Maurince C, Green G, eds. Behavioral Intervention for Young Children with Autism. Austin, TX: PRO-ED, 1996. Lovaas I. Behavioral treatment and normal education and intellectual functioning in young autistic children. J Consult Clin Psychol 1987; 55(1):3–9. McClannahan L, Krantz P. The Princeton child development institute. In: Harris

392

32. 33. 34.

35.

36.

37. 38.

39.

40. 41.

42.

43. 44.

King SL, Handleman JS, eds. Preschool Education Programs for Children with Autism. Austin, TX: PRO-ED, 1994:107–126. Eaves L, Ho H. School placement and academic achievement in children with autistic spectrum disorders. J Dev Phys Disabil 1997; 9(4):277–291. McGregor E, Campbell E. The attitudes of teachers in Scotland to the integration of children with autism into mainstream schools. Autism 2001; 5(2):189–207. Dugan E, Kamps D, Leonard B. Effects of cooperative learning groups during social studies of students with autism and fourth-grade peers. J Appl Behav Anal 1995; 28(2):175–188. Roeyers H. The inﬂuence of nonhandicapped peers on the social interactions of children with a pervasive developmental disorder. J Autism Dev Disord 1996; 26(3): 303–320. Wolfberg P, Schuler A. Integrated play groups: a model for promoting social and cognitive dimensions of play in children with autism. J Intellect Disabil Res 1999; 43(4):314–324. Fisher D. According to their peers: inclusion as high school students see it. Ment Retard 1999; 37(6):458–467. Swaim K., Morgan S. Children’s attitudes and behavioral intentions toward a peer with autistic behaviors: does a brief educational intervention have an effect? J Autism Dev Disord 2001; 31(2):195–205. Schleien S, Mustonen T, Rynders J. Participation of children with autism and nondisabled peers in a cooperatively structured community art program. J Autism Dev Disord 1995; 25(4):397–413. Chesley G, Calaluce P. The deception of inclusion. Ment Retard 1997; 35(6):488– 490. Trillingsgaard A, Sorensen E. School integration of high-functioning children with autism: a qualitative clinical interview study. Eur Child Adolesc Psychiatry 1994; 3(3):187–196. York A, von Fruanhofer J, Turk P, Sedgwick P. Fragile X syndrome, Down’s syndrome and autism: awareness and knowledge amongst special educators. J Intellect Disabil Res 1999; 43(4):314–324. Helps S, Newsom-Davis I, Callias M. Autism: the teacher’s view. Autism 1999; 3(3):287–298. Meyer L, Fox A, Schermer A, Ketelson D, Montan N, Maley K, Cole D. The effects of teacher intrusion on social play interactions between children with autism and their nonhandicapped peers. J Autism Dev Disord 1987; 17(3).

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 diagnosis 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 individuals 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 commitment. 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 professional, mostly low-paid, workers in group homes or workshops, as well as educators, psychologists, social workers, and medical professionals. These professionals 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

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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 disability 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 advocacy 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 Behavior by Bernard Rimland, whose work was the ﬁrst to highlight the neurological 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.

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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 Bettelheim 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. Together 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 remember 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 collaboration 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 indirectly from some of the professionals who work every day with our children. ASA has stepped up its advocacy for adults with autism, lobbying for improvement 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 Medicaid 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 treatment 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 families. 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 naturally 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

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face of it, such a lumping together is nonsensical. The clinician making the diagnosis 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 advocacy 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 justiﬁably 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 somewhere 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 treatments 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 debated 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 membership . 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

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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 signiﬁcant change from the fractious history of autism advocacy the ASAF has created close ties to other advocacy and research organizations. Rather than try to duplicate 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 Exchange (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 overcome. 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 conference 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. Estimates 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 increased 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, smallscale 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 pressuring 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 separate 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 organizations 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 Treatment 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

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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 chapter, 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 bureaucrats did not go into the ﬁeld because they were indifferent to people. They frequently 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 community 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

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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’eˆtre of an advocacy 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 absent. 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 created “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 qualityof-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.

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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 together, for example, an ARC and an ASA chapter to raise awareness on a particular 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 organizations 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, Washington 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 succession and consensus. Fledgling organizations often beneﬁt from a charismatic entrepreneur, 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

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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 misguided medical establishment, to a national disability advocacy movement, lobbying 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

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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, funding for centers of excellence. In 1999 the ASAF was instrumental in lobbying the National Bioethics commission to modify its position on human-subject research 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-

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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 economics, it is also part of a long-term social change. Poverty In addition to the medical diagnosis, most individuals with autism have an additional 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, heating 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 corporations, 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. However, 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 intellectually 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-

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dence of individuals with high-functioning ASD, and has spurred the creation of self-advocacy and support groups around the world. The ASA (assuring anonymity) 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 science that has plagued us; they should steer people away from miraculous cures for autism with the same forthrightness they would use in talking about hocuspocus 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 sometimes 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 communication 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 “individualized” 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 unrecognizable. 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

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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, including 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 organizational 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 [email protected]

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 hyperacute 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 ﬂuorescent 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 increase 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.

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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 symptoms 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

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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 programs 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 problems 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 problems 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 sensory 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 Gillingham’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 overload, something like living inside a rock and roll speaker. To such a child, ﬂuorescent 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.

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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 quietly to them in a darkened room, which cuts down on total sensory stimulation and therefore reduces possible overstimulation. This allows the child to concentrate 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 examples. 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 common 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

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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 memory for information, it is something like surﬁng the Internet. My associative thinking 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 vacuum 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 equipment? 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 nervous 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 physical 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.

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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 estrogen 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 reasoned that I could control both, menopause symptoms and my anxiety by manipulating 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 supplements, 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 medroxyprogesterone 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

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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 ﬁrstchoice 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 obsessive-compulsive disorder, but it is probably not the best ﬁrst-choice medication in autism due to the increased epilepsy hazard.

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REFERENCES 1. 2. 3. 4. 5. 6. 7.

8. 9. 10. 11. 12. 13.

14. 15. 16. 17. 18. 19. 20.

21. 22.

Grandin T, Scariano M. Emergence Labelled Autistic. New York: Warner Books, 1986. Grandin T. Thinking in Pictures. New York: Vintage Books, 1995. Bemporad ML. Adult recollections of a formerly autistic child. J Autism Dev Disord 1979; 9:179–197. Stehli A. Sound of a Miracle. New York: Doubleday, 1991. White DB, White MS. Autism from the inside. Medical Hypotheses 1987; 24:223– 229. Williams D. Somebody Somewhere. New York: Time Books, 1994. Coleman RS, Frankel F, Ritvoe E, Freeman BJ. The effects of ﬂuorescent and incandescent illumination upon repetitive behaviors in autistic children. J Autism Dev Disord 1976; 6:157–162. Waterhouse L, Fein D, Modahl C. Neurofunctional mechanisms in autism. Psychol Rev 1996; 103:457–489. Lovaas I. Behavioral treatment and normal educational and intellectual functioning in young autistic children. J Consult Clin Psychol 1987; 55:3–9: Williams D. Autism: an Inside Outside Approach. Wiltshire, England: Cromwell Press Melksham, 1996. Agren JA. Sensory Integration and the Child. Los Angeles: Western Psychological Services, 1979. Rimland B, Edelson S. The effects of auditory integration training in autism. J Speech Lang Pathol 1994; 5:16–24. Elliot RO, Dobbin AR, Rose GD, Soper HV. Vigorous aerobic exercise versus general motor training effects on maladaptive and stereotypic behavior of adults with both autism and mental retardation. J Autism Dev Disord 1994; 24:565–576. Walters RG, Walters WE. Decreasing self-stimulatory behavior with physical exercise in a group of autistic boys. J Autism Dev Disord 1980; 10:379–387. McGinsey JF, Favell JE. The effects or increased physical exercise on disruptive behavior in retarded persons. J Autism Dev Disord 1988; 18:167–179. Grandin T. Brief report: response to National Institutes of Health report. J Autism Dev Disord 1996; 26:185–187. Gillingham G. Autism—Fragile Handle with Care. Arlington, TX: Future Horizons, 1995. Joliffe T. Lakesdown R, Robinson C. Autism, a personal account. Communication 1992: 26(3):12–19. Grandin T. How people with autism think. In: Schopler E, Mesibov G, eds. Learning and Cognition in Autism. New York: Plenum Press, 1995. Grandin T. Calming effects of deep touch pressure on patients with autistic disorders, college students and animals. J Child Adolesc Psychopharmacol 1992; 2:63– 70. McClure MK, Holtz M. The effects of sensory stimulatory treatment on an autistic child. Am J Occup Ther 1991; 45:1138–1142. McDougal C, Sherman C. Fluvoxamine for obsessive-compulsive disorder. Med Lett Drugs Ther 1995; 37:13–14.

A Personal Perspective 23. 24.

25.

26.

417

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. 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. Cook EH, Rowlett R, Jasiskis C, Levanthal B. Fluoxetine treatment of children and adults with autistic disorder and mental retardation. J Am Acad Child Adolesc Psychiatry 1992: 31:739–745. Gillberg C. The treatment of epilepsy in autism. J Autism Dev Disord 1991; 21: 61–77.

21 Future Trends Eric Hollander and Ronald R. Rawitt Mount Sinai School of Medicine New York, New York, U.S.A.

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, impaired 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 speciﬁed 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 specialized assessments of communicative skills may be useful in exploring the neurobiological underpinnings of speciﬁc symptom clusters. There is need to have dimensional instruments that have greater sensitivity and speciﬁcity. ASSESSMENTS Additional research toward standardized screening and diagnosis of autism speciﬁcally, and the pervasive developmental delay spectrum disorders, will aid indi419

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vidual children and families, as well as studies of early intervention and outcomes. Rigorous data collection will help reveal the multifactorial etiology of autism and pervasive developmental delays, especially associated with other diseases, 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 criteria, markers and marker maps, and statistical analyses. Using the categorical deﬁnition of autism, as well as dimensional approaches focusing on social abnormalities, 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 further 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. Recent 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, demonstrating a reduction in repetitive thoughts and behaviors, maladaptive behaviors, and aggression. Better studies with SSRIs are needed in children and adolescents 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

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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 pathophysiological mechanisms, one of which involves autoimmune and neuroendocrine 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 dysfunction 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 symptoms 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, placebocontrolled 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 appropriate 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, treatment 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 disorders 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, dimethylglycine, 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 difﬁculty. Research on how to address speciﬁc areas of difﬁculty with behavioral

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treatments, and how to integrate behavioral treatments with new biomedical ﬁndings, 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 workshops 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 disorders 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 Acetylcholine, 358 Active-but-odd children, 21–22 Acute dystonia, 279–280 Adaptive functioning, 94, 114 tests for, 88(t) Adderall, 119 Adenylosuccinate lyase, 362 Adolescents and aggression, 29 and anxiety attacks, 413 and epilepsy, 27 and ﬂuoxetine, 235 and herpes simplex, 186 puberty effect, 30, 155 and seizures, 30 and serotonin, 155 Adrenocorticotropic hormone (ACTH), 286, 359–360 Adults autistic ﬁrst person account, 413–415 medication for, 415, 420–421 obsessive-compulsive, 8, 25 oxytocin, 26

[Adults] and SSRIs, 8, 234, 235, 237 support systems, 400–401 symptoms in, 30 relationships with, 21, 123–124 Adventitious movements, 90(t), 233–234 Advocacy educational rights, 405 future directions, 422 history of, 394–398 for individuals, 400–401 local, 401–404 national, 404–406 research, 398–400, 403, 404–405 success factors, 403–404 work and recreation, 405–406 Affection, 21 Affective disorders, 28, 108, 113 and virus, 189 Affective symptoms, 28 (see also Emotions) African Americans, 205 Age factors diagnosis timing, 29, 42, 111 and medication, 216, 235 423

424 [Age factors] for seizures, 30, 47, 265–266, 267– 268 and serotonin, 155, 210, 215, 222– 223 and SSRIs, 420–421 Aggression and anxiety, 413 and EEG, 116 medication for, 119, 295–296 antipsychotics, 251, 254 mood stabilizer, 240–241 SSRIs, 233, 236, 237 in obsessions, 25 physical devices, 296 Agitation, 237 Agnosia, 48, 266–267, 269 Akathisia, 280–282, 308–309, 326 Alcohol, 193 Allergies, 50, 194, 363 Website, 364 Aloofness, 21 Alpha-blockers, 296 Alternative therapies antibiotics, 120, 166, 361–362 antifungals, 120, 361–362 auditory integration training (AIT), 121, 363–364 behavioral, 378–380 chelation, 360–361 craniosacral, 121 diet, 120, 359, 362–363 immunoglobulins, 121, 164–165 magnesium, 120, 357–358 music, 121 nutritional supplements, 359 ORG 2766, 359–360 secretin, 166, 348–357 vitamins, 120, 357–359 Websites, 364 Amantadine, 166 American Academy of Child and Adolescent Psychiatry (AACAP), 40, 44, 50 American Academy of Neurology (AAN), 40, 42, 45, 49, 50

Index Amphetamines, 119 Amygdala, 26, 154 Angelman’s syndrome, 116, 134–135 Anger, 233 Animals, 21 Anterior cingulate gyrus, 26–27 Antibiotics, 120, 166, 361–362 Antibodies (see also Immunoglobulins) abnormalities, 161–163 auto-, 180, 181–182 to brain, 109–110, 161–163, 181– 182 description, 157 maternal, 163 for measles and herpes, 109 monoclonal D8/17, 158–159 streptococcal-induced, 190–191 Anticholinergics, 280 Anticonvulsants indications for, 269–270 and Landau-Kleffner, 238–240 and language, 48 and self-injury, 295 and serotonin, 205 Antifungal agents, 120, 361–362 Antihistamines, 166, 296 Antipsychotics, 247–250, 252–253(t), 257–259 (see also speciﬁc agents) adverse effects, 255–257 monitoring, 258–259 Anxiety attacks of, 413–414 in family, 108, 113 medication, 237, 296, 413 antipsychotics, 251, 254 Aphasia, 48, 266 Apoptosis, 163, 189 Applied Behavioral Analysis (ABA), 117–118, 400 Apraxia, 46, 102–103, 116 Aricept, 166 Asperger’s disorder affective disorders, 28 differential diagnosis, 9–10, 16–17, 24, 105–106

Index [Asperger’s disorder] and education, 389 language development, 23–24, 105 screening for, 42–43 and serotonin, 212 symptoms, 105–106 ASQ, 42–43 Assessment, 370–372, 419–420 (see also DIR model; Screening) Associated disorders (see Comorbidity) Astrocytes, 162 Ataxia, 106, 225–226 Attention and immune therapy, 165–166 and intelligence testing, 93 joint, 103, 113 management of, 410–411 and medication, 119 questionnaire, 80 shifting, 68 testing, 96 Auditory integration training (AIT), 121, 363–364, 411 Australian Scale, 43 Autism atypical, 4 course of, 29–30 heterogeneity, 31, 384, 385, 396–397 prediction of, 276 purine, 362 Autism Diagnostic Interview–Revised, 18, 114 Autism Diagnostic Observation Schedule–Generic, 114 Autism Genetic Resource Exchange (AGRE), 46 Autism Research Registry (ARR), 399 Autism Society of America (ASA), 394–395, 397–400, 406–407 contact information, 408 Autism spectrum disorders (see also DIR model) versus autism, 102 brain sites, 26–27 core deﬁcits, 17 and development deﬁcits, 72

425 [Autism spectrum disorders (see also DIR model)] and EEGs, 47–49 etiology, 17, 107–110, 124 genetic factors, 17, 18 heterogeneity, 16–18 medication effects, 277 movements of, 285–291 prevalence, 106–107 prognostic subtypes, 76–79 Autistic epileptiform regression, 267– 268 Autoimmune response and bacteria, 190 to brain, 109–110, 181–182 description, 159–163 future work, 421 and viral infections, 190 Aversion therapy, 292 Avoidant personality disorder, 10 AZT, 188 Bacteria, 190–191 intestinal, 120, 361–362 B cells, 109, 157, 158–159 Bcl-2, 163 Behavioral skills training, 373, 375–376 Behavioral therapy, 373–378 alternatives, 378–380 and cognitive ability, 70 controversies, 397 enhancement approach, 293–296 extinction, 377 future work, 422 and mainstreaming, 386–387 outcomes, 69–70, 117–118, 378 overcorrection, 293, 377 reduction techniques, 291–293, 377 reinforcement, 377 for self-injury, 291–296 Behaviors (see also Repetitive behaviors; Self-injury; Stereotypies) adaptive, 88(t), 94, 114 in Asperger’s syndrome, 105–106 assessment of, 370–372 and Borna disease virus, 189

426 [Behaviors (see also Repetitive behaviors; Self-injury; Stereotypies)] compulsive (see Compulsive behavior) descriptions, 25–27, 103–104 and diagnosis, 8, 17 and diet, 120, 194 evaluation of, 50 and gastrointestinal disorders, 351– 352 impairment range, 17 maladaptive, 376–378 purposeful, 80 target, 385 and test-taking, 93 treatment, 372–378 and tryptophan, 212 Benzodiazepines, 295 Beta-blockers, 281–282, 295 Bettelheim, Bruno, 394–395 Bioethics, 403 Bipolar disorder, 28, 108, 113 Birth complications of, 17, 163 labor induction, 191–192 and seasonality, 158, 177–178 Biting, 294 Blepharospasm, 283 Body boundaries, 411 Body pressure, 413 Books, 394 Borna disease virus, 188–189 Bouncing, 328 Boundaries, 411 Bradykinesia, 275 Brain antibodies, 109–110, 161–163, 181–182 Brain damage test for, 89 from virus, 189 Brain-derived neurotrophic factor (BDNF), 164 Brain development, 138 Brain metabolism, 236 Brain sites, 26–27, 108, 154–155 Brainstem, 108, 138, 178–179

Index Brainstem auditory evoked response (BAER), 44 Breathing, 328 Broad autism phenotype, 17 (see also Phenotype) Bronchitis, 177 Calcitonin gene-related peptide (CGRP), 164 California Verbal Learning Test, 95 Candida albicans, 120 Carbamazepine, 240 Card sorting, 89(t), 95 Caregivers and etiology, 107–108, 124 relationship with, 63–65, 67–68, 77 and therapy, 70 Casein, 109, 120, 363 Caudate nuclei, 155, 158 CD4⫹ cells, 156, 161 Centers for Disease Control and Prevention (CDC), 399–400 Cerebellum (see also Purkinje cells) and alcohol, 193 hypoplasticity, 108 and immune system, 162, 163 and immunoglobulins, 162 postmortem ﬁndings, 154 and RELN gene, 138 and retinoids, 178 role of, 223–224 and serotonin, 224–226, 421 Cerebral cortex, 138, 164 Cerebral palsy, 10 Chaining, 373, 376 Change, resistance to, 1, 25, 103 Chart, of functional development, 74–76 Chelation, 360–361 Website, 364 Chickenpox, 187 Child Health Act of 2000, 15 Childhood Autism Rating Scale, 113 Childhood disintegrative disorder, 9, 106 Child Neurology Society (CNS), 40, 42, 45, 49, 50

Index Children (see also Preschool age children; Toddlers) nonverbal, 93 school age, 43 and serotonin, 155 and SSRIs, 420–421 M-chlorophenylpiperazine, 233 Chorea, 326 Chromosomes, 134–145 Cingulate gyrus, 26–27 Clapping, 106 Clomipramine and anger, 233 and compulsive behavior, 222, 233–234 double-blind study, 233–234 and repetitive behavior, 26 and self-injury, 295 side effects, 286, 415 Clostridium, 166 Clozapine dosage, 258(t) side effects, 252(t), 257, 258, 279, 283 symptom improvement, 250–251 Clusters geographic, 4–5, 7, 158, 176–177 of symptoms, 9 Cocaine, 193–194 Cognitive ability abstract concepts, 412 and behavioral therapy, 70 and cerebellum, 225–226 and epilepsy, 266, 267, 269 evaluation of, 50, 114 testing, 88(t), 92–97 nonverbal, 93 of nonverbal children, 93 and serotonin, 225–226 task-speciﬁc strengths, 92 visual, 412–413 Color, 104 Coloring agents, 363 Communication and behavioral training, 378 chromosomes, 24 conversation, 23, 81–82, 118 curriculum for, 374–375

427 [Communication] of diagnosis, 105, 111 disorders of DIR model, 59–60, 76–79 symptoms, 23–24, 102–103 evaluation of, 50, 115–116 test for, 88(t), 94 impairment range, 17, 23 nonverbal, 93 parent with child, 380 with pictures, 78, 81, 378 and prognosis, 77–79 and secretin, 351–352 and SSRIs, 234, 236 twin study, 24 Community resources, 112 Comorbidity, 7–9 of affective disorders, 28 epilepsy, 27–28, 47–48, 265–268 of gastrointestinal disorders, 351–352 of mental retardation, 27, 124 metabolic defects, 362–363 miscellaneous, 50 obsessive-compulsive disorder, 8, 25 and subcategories, 19 Compulsive behavior, 25–27 brain site, 155 genetic basis, 159 medication for, 222, 233–234, 236 types, 25 Consumer advocacy, 394–398, 406 Continuous Performance Test(CPT), 96 Conversation practicing, 118 in questionnaire, 81–82 as symptom, 23 Coordination, 104, 118–119 Coping, 122–123 Coprolalia, 327 Copropraxia, 327 Core symptoms course of, 29 description, 20–27 in DSM-IV, 18 inﬂuential factors, 31 limitations, 31

428 Corticosteroids, 269–270 Counting, 378 Craniiosacral therapy, 121 Cuddling, 103 Cure Autism Now (CAN), 39–40, 44, 50, 399 Curiosity, 357 Cytokines, 156, 159–160, 189 Cytomegalovirus, 108, 184–185 Daily living skills, test for, 88(t), 94 Dancing, 104 Deinstitutionalization, 397 Delusions, 110, 283 Dementia infantilism (see Childhood disintegrative disorder) Denver Model, 379–380 Depression, 28 in family members, 108, 113 medication for, 254 Desensitization, 379 Desipramine, 233, 238 Destructiveness, 296 Developmental levels, 59–61 Developmental Neuropsychological Assessment (NEPSY), 96–97 Diagnosis (see also Differential diagnosis; Screening) age at, 29, 42, 111 behavioral evaluation, 50, 111–112 cognitive evaluation, 50 communication of, 105, 111 community resources, 112 coordinating, 112 core symptoms, 16, 18, 20–27, 102–104 dimensional approach, 4 DSM inclusion, 2–7 EEG role, 47–49 euphemisms, 105 and family members, 50 genetic testing, 47 history, 66–67, 113 ICD, 3, 16 in infants, 21 in initial sessions, 66–69 instruments for, 18, 419

Index [Diagnosis (see also Differential diagnosis; Screening)] laboratory tests, 46, 49–50, 116 medical evaluation, 44–50 metabolic testing, 49–50 neuroimaging, 49 neurological examination, 113 presenting symptoms, 29, 66 synthesis, 68–69, 111–116 in toddlers, 105 Diagnostic and Statistic Manual of Mental Disorders (DSM) autism in DSM-IV, 102, 16, 18 initially, 3–4, 5, 6 pervasive developmental disorders (PDD) 105, 16, 18 Diarrhea, 351–352 Diet, 120, 194, 359, 362–363 gluten- and casein-free, 109 Differential diagnosis core deﬁcits, 17 frim sensory integration disorder, 111 hearing impairement, 110 Landau-Kleffner syndrome, 267–268 from language delay, 110 from mental retardation, 110 from OCD, 25, 110–111 from PDDs, 9–10, 16–17 Asperger’s, 9–10, 16–17, 24, 42, 105–106 childhood disintegrative disorder, 106 Rett’s syndrome, 106 from schizophrenia, 110 Dihydropyrimidine dehydrogenase, 362 Dimethylglycine (DMG), 120, 359 DIR model description, 58–59, 379–380 evaluation process, 62–69, 71–79 prognostic subtypes, 76–79 questionnaires, 74 therapeutic approach, 70–76 Disaccharidases, 352 Discrete trial training (DTT), 372–377 Disinhibition, 119

Index Disintegrative psychosis (see Childhood disintegrative disorder) Divalproex sodium, 239–240 Dolphin therapy, 121–122 Doors, 409 Dopamine, 108, 249–250, 286 antagonists, 278–280, 282 Down’s syndrome, 10 Dressing, 376, 378 Dysesthesias, 289 Dyskinesias, 277 tardive, 277, 282–284, 295 Dysmorphic features, 50, 136 Dyspraxia, 104, 118–119 Dystonia, 279–280 deﬁned, 326 Ears covering, 104, 114–115, 328 infections, 50, 110, 120 malformations of, 179 Echolalia, 1, 77 immediate versus delayed, 103 Edges, of objects, 104 Education advocacy, 405 and Asperger’s disorder, 389 class size, 294, 384 cognitive skills, 376 and communication, 374–375 diverse needs, 384, 385 elementary level, 29 full inclusion, 383–390 high school, 30 for independent living, 376 legislation on, 383 mainstreaming, 383–390 and maladaptive behaviors, 376–378 for motor skills, 376 peer tutoring, 384, 387 and self-injury, 294 for self-management, 385 and social skills, 375–376 target behaviors, 385 task size, 385 types of, 372–373

429 Electroencephalograms abnormalities, 28 indications for, 116–117 and Landau-Kleffner syndrome, 268 and seizures, 47–49, 265–268 Emotions awareness of, 81 medication for, 254 testing, 91(t) Empathy, 21, 79, 91(t) Employment, 30, 378, 405–406 Encephalitis, 186, 188 Endorphins, 295 Enjoyment, 3, 21 Enuresis, 234 Environment as cause, 7, 17, 420 pathogens, 158, 175–178 response to, 3, 25, 46 and self-injury, 294 of therapy, 412 toxins, 17, 177, 179–181 Enzymes, 180 Epidemiology, 4–7 Epilepsy, 27–28, 47–48, 265–268, 415 (see also Seizure disorders) Esophagitis, 352 Estrogen, 414–415 Etiology (see also Genetics) allergies, 194 bacteria, 190–191 brain abnormality, 108 environmental, 7, 158, 179–181, 420 immune disorders, 109–110, 153– 164 parenting, 124 peptide metabolism, 109 pitocin, 191–192 retinoids, 178–179 serotonin, 25–26, 108, 215–217 (see also Serotonin) substance abuse, 193–194 vaccines, 109 viruses, 108–110, 158–159, 181–190 Executive function, 89(t), 95–96 Exercise, 411, 413, 415

430 Eye contact after rough-housing, 104 and medication, 237 myths about, 123 and secretin, 351–352 and speech therapy, 118 as symptom, 21, 103, 113 and vitamin B6, 357 Eyes blinking, 283 covering, 328 muscles of, 279, 283 squinting, 104 staring, 116 Facial dysmorphism, 136 Facial expressions, 21, 91(t), 103 Facial writhing, 282 Families assessing, 67, 303 in assessment, 62–63, 67–68 coping, 122–123 isolation in, 108 multiplex, 25, 47 genetic studies, 135, 145 Families for Early Autism Treatment (FEAT), 400 Family members (see also Parents) affective disorders in, 28, 45, 108, 113 anxiety disorders in, 45, 113 in diagnosis, 45–46, 62–65, 112–113 in evaluation, 67–68 impulsivity in, 28 intrusive and aloof, 62–63 with language impairment, 144 mental diseases, 108, 110–111, 113 and mental retardation, 8 nonverbal communication, 24 OCD in, 45, 113 phrase speech, 24 prevalence in, 45–46, 108 recurrence risk, 154 and serotonin, 25, 209–210, 232 social disorders in, 22, 28, 108 and symptom domains, 31

Index Fantasies, 63 Fear, 410 Fenﬂuramine, 249 Fetal alcohol syndrome, 193 Fidgeting, 281, 295 Fingers, 25 Flavorings, synthetic, 363 Fluoxetine, 26–27, 234–236, 286, 415 Fluphenazine, 295 Fluvoxamine, 26, 216, 236–237, 286, 415 Focusing, 80 Foods allergies to, 194, 363, 364 dietary therapy, 120 texture of, 104 Fragile X syndrome and boys, 116 comorbidity, 8, 10 karyotyping, 46–47 prevalence, 19, 45–46, 108 Free operant instruction, 373 Free radicals, 361 Fruits, 363 Full inclusion, 383–390 Functional assessment (see also Cognitive ability) development milestones, 72–74 questionnaire, 79–82 in DIR model, 59–61, 73–79 neuropsychological, 96–97 tests, 88–91(t) Functional development charting, 74–76 and HIV, 188 language delay, 110, 144–145 mastery criteria, 76 Funding, 398–400 G-alpha proteins, 358 Gamma-aminobutyric acid, receptor gene, 136–137, 154, 201, 202 Gastrointestinal disorders after vaccine, 108–109, 192 and behaviors, 351–352 causal relationship, 50

Index [Gastrointestinal disorders] clostridium, 166 and neuropeptides, 164 yeast overgrowth, 120 Gender and genetic testing, 116 and prevalence, 154 and Rett’s syndrome, 106 sex ratio, 6 and tardive dyskinesia, 283 Genetic markers, 19, 159 Genetic origins, 17 Genetics (see also Fragile X syndrome) and brain development, 138 chromosomes, 24, 47, 134–145 and communication (phrase speech), 24 and environment, 179 familial risk factors, 30–31, 108 multiplex families, 135, 145, 420 FRM-1 gene, 46 gene bank, 399 genome-wide screens, 139–145 and glutamate, 138 heritability rate, 133 and immune system, 109, 157, 163 and language delay, 144–145 and mental retardation, 27 phenotype, 17, 19, 24, 421 RELN gene, 138 of Rett’s disorder, 284–285 and serotonin, 213–215, 222–223 speciﬁc genes, 136–139, 179 susceptibility gene, 24 Genetic testing, 47, 116 Geographical areas, 4–5, 7, 158, 176– 177 Gestures adventitious, 233–234 and prognosis, 78 as social cues, 103 Glial cells, 162, 189 Glucaric acid, 180 Glucoamulases, 352 GluR6 gene, 138 Glutamate, 138, 166

431 Glutamine, 202 Gluten, 109, 120 Graphomotor function, 104 GRIK2 gene, 138 Guardianship structures, 400–401 (see also Families) Haemophilus inﬂuenzae, 191 Hallucinations, 110, 283 Haloperidol, 119, 255, 283, 295 Hands and behavior training, 377 clapping, 106 coordination, 104, 118–119 ﬁnger wiggling, 328 ﬂapping, 25, 103 in Rett’s syndrome, 106 rubbing, 328 staring at, 104 washing, 106 Head banging, 289 size of, 46, 106, 113 tilting, 328 Health insurance, 405 Hearing and diagnosis, 110 hyperacute, 409–411 listening, 121 monochannel, 411 testing for, 44, 114–115 Heller’s syndrome (see Childhood disintegrative disorder) Hematological toxicity, 283 Heroin, 193–194 Herpes virus, 109–110, 185–186 Hippocampus abnormalities, 26, 154 and genetics, 138 metabolism, 26 and vitamin A, 358–359 Hispanics, 205 Histidinemia, 362–363 Hoarding, 25 Holding, 123 Holding therapy, 121–122

432 Home-based program, 71, 117–118 Homovanillic acid, 358 Hormones, 414–415 HOXA1 gene, 138–139 Hox genes, 179 5-HTT gene, 137 Hugging, 123 Human immunodeﬁciency virus (HIV), 188 Human leukocyte antigen (HLA) complex, 157, 163, 190 Human parvovirus, 188 5-hydroxytryptamine (see Serotonin) Hyperactivity, 8 therapy for, 119, 254, 295 Hyperbaric oxygen, 121–122 Hyperkinesia, 275–278 Hyperlexia, 105 Hypersensitivity, 1, 46, 118–119, 409–411 Hypomelanosis of Ito, 19 Hypopigmentation, 46 Hypotension, 281 Hypothyroidism, 108 Hypotonia, 46, 50, 104, 113 Hypoxanthineguanine.... (HGPRT), 288 Illness, 60 Imagination, 3, 110 Imipramine, 413 Imitation, 80, 81, 113 Immigrants, 6–7 Immune system allergies, 194 and autism etiology, 158–166 and birth complications, 163 description, 155–157 and environmental toxins, 180 future studies, 421 genetic factors, 109, 157, 163 genetic regulation, 157 maternal/fetal, 163 and obsessive-compulsive disorder, 158–159 and Purkinje cells, 163 and therapy, 121, 164–166 and viruses, 109

Index Immunoglobulins abnormalities, 109, 161–163 description, 157 as therapy, 121, 164–165, 363 Impulsivity, 28, 119 Incidental teaching, 373 Independent living, 376 Infants assessment of, 67–68 functioning questionnaire, 80 attention development, 21 diagnosis in, 29 motion analysis, 276 screening, 41–43 and serotonin, 222–223 spasms in, 46 vaccinations, 108–109 viral infections, 187–188 Inﬂammation, 156, 165, 189 Inﬂuenza, 177 Insomnia, 415 Institutionalization, and testing, 94 Instruments (see Questionnaires; Screening; Testing) Insurance, 405 Intelligence and behavioral training, 378 increase in, 117–118, 121 nonverbal measures, 93 versus other factors, 2 retardation, 6, 7–8 and seizures, 27 testing, 88(t), 92–97 Interactions (see also Social interactions) chains of, 80 conversation, 23, 81–82, 118 and family coping, 122–123 in functioning questionnaire, 80 in infancy, 80 with parents (see Parents) with peers (see Peers) and test-taking, 93 therapeutic, 71 Interests, 3, 25 (see also Attention) Interferon-gamma (IFN-a˜), 156, 160

Index Interferon-K, 160 Interleukins, 156, 160, 189 International Classiﬁcation of Diseases (ICD), 3, 16 Internet, 122, 406–407 Interruption, 116 Intestinal ﬂora, 120, 361–362 Intrusiveness, 411 Irritability, 237–238, 254 Isolation, 108 Jargoning, 103 Jobs, 30, 378, 405–406 Job training, 30, 378 occupational therapy, 50, 118–119, 385 Johns Hopkins University, 292 Jumping, 104 Kanner, Leo, 1–2, 101 Kaufman Assessment Battery (K-ABC), 93 Kennedy-Krieger Institute, 290–291 Kinesthetic sense, 411 Laboratory tests, 46, 49–50, 116 Lactalbumin, 363 β-lactoglobulin, 363 Lamotrigine, 240 Landau-Kleffner syndrome, 48, 162– 163, 238–239, 266 Language and Asperger’s disorder, 23–24, 105 behavioral therapy, 378 curriculum, 374–375 in diagnosis, 113 and epilepsy, 266–267 evaluation of, 115–116 and genetics, 144–145 literalness, 1 medication for, 236, 239, 240, 254 symptoms, 1, 102–103, 103 in toddlers, 80–81 and vitamin B6, 357 Language disorders and chromosomes, 135–136, 144 and cocaine, 193

433 [Language disorders] developmental, 10 differential diagnosis, 110 in differential diagnosis, 10 echolalia, 1, 77, 103 in family members, 24 and prognosis, 77–79 regression, 48, 269–270 and social interaction, 18 sound production, 78 Language therapy, 118 Latinos, 205 Lead, 44 Learning instruction types, 372–373 skill mastery, 371–372 tests for, 89(t) Legislation, 15, 383, 405 Leiter test, 93 Lesch-Nyhan syndrome, 288–289 Licking, 104, 106 Lights, 104, 409 Limb apraxia, 46 Limb muscles, 279 Lips, 282 Listening, 121 Lithium, 119, 240–241, 296 Liver, 179–180 Local advocacy, 401–404 Lorazepam, 295 Lovaas method, 410–411 Lymphocytes, of father, 163 Lymphokines, 156, 159–160

Macrocephaly, 46 Magnesium, 120, 357–358 Mainstreaming, 383–390 Mannerisms, 3, 25, 103 adventitious, 90(t), 233–234 Manual dexterity, test for, 90(t) Marching, 281 Marital problems, 63, 67 Maturation variations, 61–62 Measles, 108–110, 186–187, 192 Medicaid, 405

434 Medication (see also speciﬁc agents) adverse effects, 277 for aggression/self-injury, 119–120 antibiotics, 120, 166, 361–362 anticholinergic, 280 anticonvulsants (see Anticonvulsants) antifungal, 120, 361–362 antihistamines, 166, 296 antipsychotics, 247–250, 254, 257– 259 side effects, 255–257 aricept, 166 AZT, 188 beta-blockers, 281–282, 295 corticosteroids, 269–270 dosage, 415 future studies, 421 glutamate antagonist, 166 hormones, 414–415 for hyperactivity, 254, 295 and language, 236, 239, 240, 254 opiate antagonists, 295–296 psychotropic, 239–240 quality assurance rating, 312–316 serotonergic, 286 withdrawal, 282–284 Memory, testing, 89(t), 94–95 Meningitis, 191 Mental retardation in autistic persons, 6, 7 comorbid, 27, 124 differential diagnosis, 110 and ﬂuoxetine, 235 genetic transmission, 7–8 and intelligence tests, 92–93 myths, 124 versus other factors, 2 and Rett’s syndrome, 106 and tuberous sclerosis, 46 Mercury, 109, 360–361 Website, 364 Metabolism, 49–50, 120, 236 Methylmalonic acid, 109 Methylphenidate, 240 Milk, 120 Mimicry, 158, 190, 376

Index Minerals, 120 Moebius syndrome, 19 Mood disorders, 28 Mood stabilizers, 119, 239–241, 296 Motor-Free Visual Perception Test, 90(t) Motor system evaluation, 90(t) evaluation of, 62, 90–91(t), 115 milestones, 73 and prognosis, 78 symptoms, 104 therapy for, 118–119 Movement disorders (see also Self-injury) abbreviations, 298(t) adventitious movements, 90(t), 233– 234 attitudes toward, 276–277, 279–280, 283, 286 behavioral therapy, 291–296 checklist, 310 classiﬁcation, 275–278 deﬁnitions, 274, 326–327 future work, 421 hyperkinesia, 275–278 rating, 277–278, 299–302 in Rett’s disorder, 284–285 self-injurious, 287–296 stereotypies, 286–287, 377 (see also Stereotypies) therapy-induced, 277–284 tics, 285 training, 376 Mumps, 108–109, 188 Music, 121 Mutism, 10 Myelin, 162, 180, 181 and measles, 187 Myoclonus, 326 Myoclonus venus, 311 Myths, 123–124 Naloxone, 295 Naltrexone, 286, 295–296, 363 Name, response to, 113, 114–115

Index National advocacy, 404–406 National Alliance for Autism Research (NAAR), 398, 408 National Association for the Education of Young Children (NAEYC), 71 National Institutes of Health, 397, 398, 399 National Society for Autistic Children (NSAC), 394 Natural killer cells, 109, 159 Neck, 279 Neonates, infections in, 186 NEPSY (Developmental Neuropsychological Asessment), 96–97 Neural tube, 178–179 Neurobiology, 420–422 Neuroﬁbromatosis, 10, 19 Neuroimaging of anterior cingulate gyrus, 26–27 for brain abnormalities, 154–155 diagnostic role, 49 EEGs, and seizures, 28 indications for, 46 and serotonin, 212–213, 232–233 of temporal lobe, 186 Neurological examination, 113 Neuron-axon ﬁlament, 162, 180, 181 and measles, 187 Neurons, 162, 178–179, 189 Neuropeptides, 164 Neuropsychiatric evaluation, 88–91(t), 94–97 Neurotransmitters, 25–26, 108 (see also speciﬁc neurotransmitters) Neurotrophin 415, 164 Neurotrophin nerve growth factor (NGF), 164 Niaprazine, 166 Noise, 1, 409–411 Nonverbal intelligence tests, 93, 95 Nonverbal skills, 114 Numbers, 378 Objects preoccupation with, 21, 25, 103–104 toys, 67–68, 103

435 Obscenities, 327 Obsessive compulsive disorder (OCD) and B cells, 158–159 comorbidity, 8, 25 differential diagnosis, 10, 25, 110– 111 in family members, 108 and genetics, 159 and immune system, 158–159 medication, 415 Occupational therapy, 50, 118–119, 385 vocational skills, 30, 378 Occupations, 30, 378, 405–406 Olanzapine (see also Antipsychotics) dosage, 258 efﬁcacy, 254–255 and self-injury, 295 side effects, 279 Ombudsman programs, 402 Onset, 6, 15, 21, 29 of childhood disintegrative disorders, 106 of phrase speech, 144–145 of regression, 106 of seizures, 30, 47, 50 of therapy, 117–118, 410 Opioids, 108 antagonists, 295–296, 363 and self-injury, 289, 295 Orbitofrontal cortex, 26–27 ORG 2766, 359–360 Organizations, 394–403 (see also Child Neurology Society (CNS)) contact information, 408 virtual, 406–407 Otitis media, 50 Overcorrection, 293, 377 Oxygen therapy, 121–122 Oxytocin, 22–23, 26, 191–192 Pacing, 212, 281 Pain, 104, 109, 289 Pancreas, 351–352 PANDAS, 190 Paneth cells, 352 Panic attacks (see Anxiety)

436 Parents (see also Family members) and etiology, 107–108, 124, 163 expectations of, 364 and eye contact, 103 HLA in, 163, 190 myth about, 124 presenting complaints, 112 relationship with, 2, 60 assessment of, 62–65, 67–68 therapy for, 70 Paroxetine, 235, 415 Parvovirus, 188 Passive children, 21 PDD-NOS, 10, 42–43 Pedantic style, 105 Pediatricians, 40–42, 112 Peers, interactions with and behavioral training, 378 description, 21, 29, 103 and DIR model, 60 and therapy, 71, 375–376 in toddlers, 81 Peer tutoring, 384, 387 Pentoxifylline, 165 Peptides and clostridium, 166 metabolism of, 120 neuropeptides, 164 secretin, 166 transfer factors, 165–166 and vaccines, 109, 120 Perseveration, 71 Pervasive development disorders descriptions, 105–106 (see also Autism spectrum disorders) etiology, 107–110 in ICD-10, 3 prevalence, 106–107 therapy, 117–122 Phagocytes, 156, 157, 159 Phencyclidine, 193–194 Phenotype broad autism (BAP), 17, 24 and HOXA1 gene, 138–139 and immune system, 421 and mental retardation, 27

Index Phenylalanine, 200 Phenylketonuria and diet, 362 incidence of, 10 as risk indicator, 108 and serotonin, 200–201 Phrase speech, 24, 144–145 Physical exercise, 411, 413, 415 Physical restraints, 292–293 Phytohemagglutinin (PHA), 160 Picture exchange, 378 Pictures as communication, 78 in questionnaire, 81 Pimozide, 257 Pitocin, 191–192 Planning, 95–96 motor, 118–119 Play and behavioral training, 378 in education, 375–376 imaginative, 3 symbolic, 17 symptoms, 103–104 Play therapy, DIR approach, 71 Pleasure, 3, 21 and self-injury, 289 Pneumonia, 177 Pointing, 113 Polychlorinated biphenyls, 178, 179 Positive practice, 377 Postmortem studies, 154–155, 178–179 Posture, 21, 46 Poverty, 406 Prader-Willi syndrome, 116, 134 Pregnancy environmental toxins, 108, 179–181 immure response, 163 infections during, 108 bacterial, 191 viral, 158, 177, 182–185, 186, 188 and retinoids, 178–179 substance use, 193–194 Preschool age children education for, 71 evaluation resources

Index [Preschool age children] cognitive testing, 92, 114 functioning, 81–82 language testing, 115–116 rating scale, 113 self-referral resources, 112 Preschool Language Scale, 115 Pressure, 413 Pretend-play, 77–79, 81, 113 Prevalence and advocacy, 393–394 conference on, 399–400 and environment, 176–178 in family members, 45–46, 108 siblings/twins, 24, 108, 133–134 gender factor, 154 overall, 6, 15, 133 of PDDs, 6 of pervasive development disorders, 106–107 sex ratio, 6 trends, 7, 11 Primary-care providers, 40–42, 43 Problem solving, 71, 80 Progesterone, 414–415 Prognosis indicators of, 76–79 myths versus reality, 124 Project TEACCH, 378–379 PROMPT methodology, 118 Pronoun reversal, 1, 103 Propranolol, 119, 281–282 Prosody, 103 Protective devices, 293 Proteins, G-alpha, 358 Psychotherapy, psychodynamic, 294 Puberty, 30 Publicity, 394, 396, 404 Punishment, 292 Purdue Pegboard Test, 90(t) Purine, 362, 364 Purkinje cells abnormalities, 154, 162 and Bcl-2, 163 postmortem ﬁndings, 154 and retinoids, 178

437 [Purkinje cells] and serotonin, 224 and virus, 189 and xenobiotic agents, 179 Purposeful activity, 80, 106 Pyridoxine, 120, 357–358 Questionnaires for diagnoses, 74, 113–114 functional development, 79–82 Quetiapine, 253(t), 255, 258(t) (see also Antipsychotics) Rabbit syndrome, 282 Racial factors, 205 Raven’s Progressive Matrices, 93 Reactive attachment disorder, 10 Reading, 105, 378 Reality, sense of, 63 Reciprocity, 3, 73 and speech therapy, 118 Registries, 399 Regression after vaccine, 192 autistic epileptiform, 267–268 and EEGs, 116 and epilepsy, 266 and HIV, 188 linguistic, 48, 269–270 onset of, 106 and relational therapy, 379–380 Reinforcement strategies, 377 Relational therapy, 58–59, 379–380 Relationships (see also Interactions; Social interactions) deﬁcit types, 3 disorder subtypes (DIR model), 76– 79 evaluating, 60, 67–68 with family member, 2, 62–65, 67– 68 in functioning questionnaire, 80 in infancy, 80 with new person, 68 Religion, 25 RELN gene, 138

438 Repetitive behaviors in adults, 30 and Asperger’s syndrome, 105–106 classiﬁcation, 286 emergence of, 29 genetic basis, 144, 159 and immune system, 159 and intelligence tests, 93 medication for, 26, 236, 237, 239, 254 (see also Serotonin-reuptake inhibitors (SSRIs)) and neurotransmitters, 25–26 and siblings, 24 symptoms, 17, 25–27, 103–104 Research advocacy, 398–400, 403, 404–405 Resititutional overcorrection, 377 Response cost, 377 Restlessness, 280–282, 308–309, 326 Restraints, 292–293 Retinoids, 178–179 Rett, Andreas, 9 Rett’s disorder, 9, 16 genetics of, 284–285 movement disorders, 284–285 Rett’s syndrome description, 106 prevalence, 19 Rewards, 377 Rheumatic fever, 190–191 Risperidone and aggression, 119 candidates for, 19 clinical results, 251–254, 258 dosage, 258(t) interactions, 295 side effects, 119, 255–256, 279 and social relatedness, 258 for stereotypies, 119, 295 Ritalin, 119 Rituals, 25 Rocking, 46, 103, 212 Rossetti Infant-Toddler Language Scale, 115 Rotating (see Spinning) Rough-housing, 104

Index Rubella, 10, 182–184 vaccine for, 108–109, 192 Rule generation, 95–96 Salicylates, 363 Savants, 27 Schizoid personality disorder, 22 Schizophrenia as comorbid condition, 7 differential diagnosis, 110 in family members, 108 and medication, 250 and virus, 189 Screening ancillary, 44 for Asperger’s disorder, 42–43 autism-speciﬁc, 42–43 future trends, 420 for general development, 40–42 genome-wide, 139–145 instruments, 42, 74 school-age children, 43 Seasons, 158, 177–178 Seaver Center, 398 Secretin, 166, 348–357 Seizure disorders, 8, 10, 27–28, 238– 239 (see also Epilepsy) therapy for, 120, 239–240, 268–270 Seizures age factors, 30, 47, 265–266, 267–268 and clomipramine, 415 and EEGs, 116 frequency, 267 and metabolic disorders, 50 and Rett’s syndrome, 106 and self-injury, 295 subclinical, 268–269, 421 and tuberous sclerosis, 46 very early-onset, 50 Selective mutism, 10 Selective serotonin-reuptake inhibitors (SSRIs) (see also speciﬁc agents) age factors, 420 and behaviors, 8, 26, 31, 155 dosage, 415 and interest, 155

Index [Selective serotonin-reuptake inhibitors (SSRIs) (see also speciﬁc agents)] monitoring, 286 side effects, 119 and social interaction, 31 for stereotypies, 234, 286 Self-absorption minimization of, 71 and prognosis, 76–78 Self-injury autistic, versus OCD, 25 common forms, 288 and education, 294 etiology, 288–289 interventions, 290–296 and mainstreaming, 389 medical complications, 329 medication for, 119, 238, 240–241, 254, 294–296 and opiate antagonists, 295 protective devices, 293 rating, 289–290, 304–306, 317–321 and seizures, 295 stimuli, 289, 293 study of, 8 and surgery, 294 and tryptophan, 212 Self-management, 385 Self-perception and family system, 63 self referral, 103 testing, 95–96 Self-stimulation, 71, 357 Senses, 94, 104, 409–410, 411 (see also Hearing; Touch) Sensitivity (see also Stimuli) description, 409–411 to textures, 111 therapy for, 118–119 Sensorimotor deﬁcits, 46, 212, 379 Sensory integration disorder (SID), 111 Sensory integration therapy, 379, 411 Sensory processing evaluation of, 61–62, 115 ﬁrst person description, 409–411 kinesthetic sense, 411

439 [Sensory processing] medication for, 254 monochannel, 411 and prognosis, 78 symptoms, 104 Serotonergics, 286 Serotonin (see also speciﬁc agents) and age, 155, 215 age factors, 210 and antibodies, 161–162 and Asperger’s disorder, 212 and ataxia, 225–226 and autistic symptoms, 232–233, 248–249 and cerebellum, 224–226, 421 challenge studies, 210–212 as etiology, 25–26, 108 and family members, 25, 209–210, 232 future studies, 420–421 genetic studies, 213–215, 222–223 historical perspective, 200–201 measurements, 201–210 neuroimaging studies, 212–213 racial factors, 205 and repetitive behavior, 25–26 transporter genes, 137 Sertraline, 235, 237, 415 Sex, obsession with, 25 Sex ratio, 6 Shaping, 373 Siblings, 15 and communication, 24 genetic studies, 142, 144 recurrence risk, 154 and serotonin, 209 Singsong, 103 Skills, 371–376 Skin, 46 Sleep, 48–49, 165–166, 352, 415 Sleep disorders, 164 Smell, 104 Social awkwardness, in family, 108 Social interactions (see also Interactions; Peers; Relationships) in adults, 30 and Asperger’s syndrome, 105–106 and Borna disease virus, 188–189

440 [Social interactions (see also Interactions; Peers; Relationships)] deﬁcit emergence, 29 and differential diagnosis, 110 and family members, 28 gene study, 138 impairment range, 17 and language deﬁcit, 218 and mainstreaming, 387–388 myths, 123–124 and secretin, 351 and sensory integration disorder, 111 subtypes, 21–22 symptoms, 21–23, 103 test for, 88(t), 94 therapy antipsychotic, 254, 258 aricept, 166 diet, 120 immunomodulation, 165–166 mood stabilizers, 239, 240 music, 121 SSRIs, 31, 234, 236 training for, 375–376 Social phobia, 10, 22 in relatives, 28 Socioeconomic class, 2, 5, 6–7 Sounds production of, 78, 327, 328 reaction to, 104, 114–115 sensitivity to, 1, 409–411 Spatial awareness, 411 Spatial orientation, 411 Speaking, pedantic style, 105 Speciﬁc language impairment, 144 Speech therapy attention techniques, 410–411 frequency of, 70–71 with mainstreaming, 385 therapist qualiﬁcations, 118 in toddlers, 111 Spinning after effects, 104 description, 328 toys, 103 and tryptophan, 212

Index Squinting, 104 SSRIs (see Selective serotonin-reuptake inhibitors) Stanford-Binet test, 92–93, 114 Staring, 116 Stealth viruses, 187 Stereotypies, 8, 25, 46 and Borna disease virus, 189 and comorbidity, 8 deﬁned, 326 descriptions, 103, 104, 286–287, 328 education for, 377 and exercise, 411 genetic basis, 144 medication, 286, 295, 296 versus other therapy, 287 SSRIs, 119, 234, 286 prevalence, 25, 46 rating, 322–325 and vitamin C, 359 in young children, 29 Stimuli (see also Sensitivity) desensitization to, 379 reaction to, 46, 104 for self-injury, 289, 293, 294 Streptococcus, 190–191 Stress, 60 Substance P, 164 Subtypes, 18–20, 31–32 Sumatriptan, 26, 212 Support groups, 401–403 Surgery, 269–270, 294 Swallowing, 279–280 Sydenham’s chorea, 190–191 Symmetry, obsession with, 25 Syphilis, 191 Tantrums and mainstreaming, 389 medication for, 234, 236, 237–238 triggers, 103 and vitamin B6, 357 Tardive dyskinesia, 277, 282–284, 295 Task-speciﬁc strengths, 92 Taste, 104 Teeth, 103

Index Temporal lobes, 186 Terminology, 102 Testing of cognitive ability, 88–91(t), 92–97, 114 of handicapped children, 94 of institutionalized persons, 94 for language/speech, 115–116 of nonambulatory persons, 94 performance, 2 prenatal, 116 Tetrachloroethylene, 177 Textures, 104 Thalidomide, 108, 178–179 Therapist role of, 68, 123, 407–408 standards for, 406 Therapy (see also Alternative therapies; Medication) adverse effects, 277–284 for behaviors (see Behavioral therapy) consumer issues, 395–397 dimensional approach, 19 environment of, 412 for HIV, 188 home-based, 71, 117–118 immune, 121, 164–166, 363 initial sessions, 66–68 integration, 407–408 intensity of, 386, 410 for language disorders, 236, 239, 240, 254 NIH conference, 397 non-medicinal, 29–30, 120–123, 287 occupational, 118–119 outcome predictors, 27 parent-child interaction in, 67–68 program components, 70–71 relational, 58–59, 379–380 for seizures, 120, 239–240, 268–270 standards for, 406 for stereotypies, 286–287 (see also under Stereotypies) surgery, 269–270 targeted, 31 in toddlers, 111

441 Thimerosal, 109, 361 Thioridazine, 240, 257 Third person, 103 Thought patterns, 412–413 Thyroid, 108, 176 Tics, 8–9, 275, 285–286 checklist, 311 deﬁned, 327 phonic, 327 Timing (see Onset) T lymphocytes, 109, 156–157, 160–161 Toddlers diagnosis in, 29, 105 and intelligence tests, 92 language in, 80–81 risperidone in, 251 screening, 41–43, 80–81 speech therapy in, 111 Toes, 212, 328 Toilet-training, 378 Token economy, 377 Tongue, 279, 282 Touch avoidance of, 111 body pressure, 413 craniosacral, 121 and speech therapy, 118 textures, 104, 111 Tourette’s syndrome, 8–9, 285 Toxins, 17, 177, 179–181 Toxoplasmosis, 191 Toys, 67–68, 103, 378 Training (see Education; Job training) Transfer factors, 165–166 Trazodone, 238 Tremors, 327 Trends, 11 Trichloroethylene, 177 Tricyclic antidepressants, 413–414, 415 (see also speciﬁc agents) Trihalomethanes (THMs), 177 Trimethylbenzenes, 180 Tryptophan depletion of, 26, 211 and rocking, 212 and serotonin, 200, 203, 232

442

Index

Tuberous sclerosis comorbidity, 8 diagnosis, 113 prevalence, 19, 46 Tumor necrosis factor (TNF), 156, 165 Twins, 24, 108, 133–134

Vitamin B12, 109 Vitamin B15, 120 Vitamin C, 359 Vocational skills, 30, 378 Voice, tone of, 103 Vomiting, 50

UCLA Young Autism Project, 117–118 Urine, 109, 120

Walking, 212 Water contaminated, 177 preoccupation with, 104, 409 Websites, 364, 395, 408 Wechsler scales, 88(t), 92–93, 114 Weight gain, 119 Wheat, 120 Wisconsin Card Sorting Test (WCST), 89(t), 95–96 WNT2 gene, 138 Writhing, 282 Writing, 104

Vaccines, 108–110, 192, 361 Website, 364 Valproic acid, 119, 178, 269 Vancomycin, 166, 361–362 Varicella, 187 Vasoactive intestinal peptide (VIP), 164 Venlafaxine, 238, 286 Verbal auditory agnosia, 266–267, 269 Vestibular stimulation, 289 Vineland Adaptive Behavior Scale, 94, 114 Viruses, 108–110, 158–159, 181–190 Vision, 409–410, 411 Visual thinking, 88(t), 412–413 Vitamin A, 178–179, 358–359 Website, 364 Vitamin B6, 120, 357–358

Yeast, 120 Zero-to-Three programs, 112 Zidovudine (AZT), 188 Ziprasidone, 255, 259 (see also Antipsychotics)

About the Editor

Eric Hollander is Professor of Psychiatry; Clinical Director of the Seaver Autism Research Center, and Director of Clinical Psychopharmacology and the Compulsive, Impulsive and Anxiety Disorders Program, Mount Sinai School of Medicine, New York, New York. The editor or coeditor of 13 books, including Obsessive-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 national research awards from the American Psychiatric Association and a Distinguished Investigator Award from the National Alliance for Research in Schizophrenia 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 University College of Physicians and Surgeons, New York, New York.