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									                               MAKING SENSE                           OF AUTISM
                             JOSEPH        J. HALLETT,      MD, AND VIREN              D'SA,   MD
     Autistic disorder      (AD) is a       PODs are Rett's disorder, childhood          to define with quantitative, objective
disorder of brain development.      Its     disintegrative disorder, Asperger's          diagnostic criteria and to associate the
neuropathogenesis and etiology are          disorder and PDD not otherwise               phenotype with a biological marker.
thought to be heterogeneous and are         specified (PDD NOS). POD NOS                 At present neither is available although
know in only a small fraction of cases.     was included to allow clinicians to          the Autistic Diagnostic Observation
Genes have a complex indirect and,          indicate that a child had a behavioral       Schedule (ADOS) offers a meaningful
to date, undefined role in AD. This         phenotype that was similarto one of the      advancement. Diagnostic criteria are
chronic neurologic disorder leaves          defined PODs but did not meet the full       based on a qualitative determination of
affected individuals dependent on their     criteria for that disorder. In the next      the severity of behavioral impairments,
families for life.                          revision of the DSM III infantile autism     and demonstrating that a child has
                                            was changed to autistic disorder(AD),        the DSM IV prescribed number
                                            the term used in subsequent editions,        of impairments.       This qualitative
   Autism, autistic      disorder   and     including the DSM IV.                        determination       is subject to the
autistic spec'trum disorder need                  With the explosion of research         confounding of observer bias and
definitions. They are best understood       in the past 25 years, the concept            marked rater-to-rater variance. This
from a historical perspective.              has emerged that the behavioral              confounding      variance has been a
      In 1943 Leo Kanner, a child           characteristics observed in children         recurring source of considerable
psychiatrist, described 11 children,        with AD are not unique to AD but             disagreement      among physicians,
most from prosperous and well-              are distributed in lesser forms and in       a disagreement that no doubt has
educated     parents    (several were       different combinations throughout a          perplexed the PCP who is caring for
physicians) with "autistic disturbances                                                  the child and supporting the family.
of affected contact.'" He borrowed the                                                   The ADOS offers an observational
                                                   "AD      AND      THE
word autistic from the schizophrenia                                                     instrument to reduce the influence of
literature, where it denoted the self-         OTHER         PDDs        ARE             these confounding variables.
centered thinking, detached behaviors            BEHAVIORALLY
and resulting isolation observed in                                                      AUTISTIC DISORDER
schizophrenia. Following his report,        DEFINED          SYNDROMES                        AD is a behaviorally defined
the term infantile autism emerged.               THAT        MEDICINE                    syndrome characterized by severe
      Kanner's report received little                                                    impairments in social interaction, the
                                             AND       THE     SCIENCES
attention in part because the behavioral                                                 social components of language and
phenotype was already subsumed                 ARE       STRUGGLING                      inflexible and restricted behaviors or
under the diagnosis of childhood                TO DEFINE            WITH                interests. A diagnosis is made based
schizophrenia. However, in the 1950s                                                     on a behavior phenotype defined in
the psychodynamic theorists resurrected          QUANTITATIVE,                           DSM IV.' Since the diagnosis is based
his work and hypothesized that children              OBJECTIVE                           on behaviors, the AD phenotype can
became autistic because they were not                                                    overlap with other disorders.     For
given appropriate emotional nurturing                                                    example, a large percent of children
by their "refrigerator" mothers. 2.3This           CRITERIA           ..."               with tuberous sclerosis have the AD
approach to autism was the antithesis                                                    phenotype. Similarly, approximately
of Kanner's speculation that infantile      population; AD behaviors represent           1% of children     with AD have
autism had a biologic cause. Infantile      a portion of this distribution. In the       tuberous sclerosis. This overlap of
autism was formalized as a disorder         1990s the descriptive term, autistic         phenotype is also seen with congenital
in 1980 when it was included in the         spectrum disorder (ASD), was coined          brain malformations and untreated
Diagnostic Statistic Manual, third          in the experimental literature. The          phenylketonuria. However, most cases
edition (DMS 111).4It was categorized       term migrated into clinical literature       of AD are idiopathic.
as a pervasive developmental disorder       where it is often used as a diagnostic
(PPD),      a group of behaviorally                                                      AUTISTIC SPECTRUM DISORDER
                                            term even though a common clinical
defined syndromes that share the                                                            The basic behavioral traits that
                                            definition has not been agreed upon.
characteristic of severe and pervasive                                                   comprise autism have not changed
disruption of development in "      PERVASIVE DEVELOPMENTAL DISORDERS            since Kanner reported them. However,
interaction skills, communication skills        AD and the other PODs           are      the interpretation of these traits has
or the presence of stereotyped behavior,    behaviorally defined syndromes that          changed and so has the type of child
interests and activities."4 The other       medicine and the sciences are struggling     receiving an autism diagnosis. The
                                                                                                             VOL. 88    NO.5   MAY 2005
   broadest interpretation is represented       disorders with shared neuropathological   Organic, behavioral and emotional
   by the term autistic spectrum disorder       parameters is a question awaiting         comorbidities are common. (Table 1)
   (ASD). It assumes that autism is not         clarifYing studies.                            AD has implications         for the
   a discreet disorder but should be            Although the utility of ASD is debated,   entire family. Mild language, social
   viewed as a spectrum of conditions           it has become a popular clinical term,    or psychiatric problems can be present
   or behaviors unified by impairments          used to define a behavioral phenotype                   1
                                                                                          in parents. 14. 5 Siblings have a greater,
   in social interactions, communication        without reference to pathogenesis or      albeit small, risk of AD, language
   and restricted behaviors or interests.       etiology. An understanding of this        disorder, learning disabilities, social
    Since ASD is defined by behaviors           is important because the use of ASD       problems and psychiatric disorders.
    and not by pathogenesis or causative        must be accompanied by a vigorous
    agent, a spectrum can include the           diagnostic evaluation for treatable       PREVALENCE
    Kanner-type AD in which there is            disorders.                                     A rise in the prevalence         of
    severe and profound impairments as                                                    children with an autistic diagnosis has
    well as mental retardation, to milder       EPIDEMIOLOGY                              been established although a specific
    cases such a POD NOS, to atypical                The epidemiology of AD has                                         Population
                                                                                          prevalence rate has not.12.16.17
    cases such as high functioning AD           not changed substantially from the        studies in the 1980s and early 1990s
    (AD with IQ> 70), to cases with no          findings reported in the 1980s and        found a prevalence ranging from 2 to
    impairment of language development          early 1990s. It is most often diagnosed   10 per 10,000 chiidren.13.17After 1994
    and only mild impairments in social         in males (male to female ratio of 4 to    prevalence increased annually with
    interaction and inflexibility such          1). Cases do not segregate by race,       recent estimates reaching as high as 67
    as in Asperger disorder, to children        level of education, socioeconomic         per 10,000 for ASD and 4 per 10,000
    whose impairments in the past were          status or geography. Behavioral signs     for ADY Since 1994 Rhode Island
    considered below diagnostic threshold       typically appear before the age of        has mirrored this trend in its special
    for POD. The dilemma present by             three.1o Delays in language (either       education population.18 In 2003, 605
    this approach is how to distinguish         absence or slow progression) are the      students with an autistic diagnosis
    between ASD behavior and behavior           most common presenting complaint. II      were educated in Rhode Island schools.
    that is eccentric, idiosyncratic or odd     A small portion have regression after     Understanding the factors behind this
    which are in general considered within      typical language development. Sixty       rise in prevalence is critical to our
    the range of normal.                        to seventy-five percent of the children   understanding of AD and ASD.
         Support for interpreting autism        with AD have mental retardation.12.13          Population-based incidence studies,
    as ASD comes from studies that find         Cognitive deficits may be more            using contemporary diagnostic criteria,
    AD behavioral traits, albeit with           severe in girls than boys although        are believed to more accurately reflect
    varying severity, distributed through       approximately 40% of boys will have       potential changes in the occurrence of
    families of children with AD and in         severe to profound mental retardation.    disorders across time periods. One such
    the general population.6. 7.8 Further
    support comes from functional brain           Table 1. Comorbidities in autistic disorder
    imaging studies (fMRI) that found
    similar activation patterns in adults           Mental retardation (60-75%)
    with high functioning autism and                Epilepsy (5% in children, 30% in adults)
    Asperger syndrome.9 On the other                Phenylketonuria if untreated (5%)
    hand, the term spectrum is most often           Tuberous sclerosis «1 %)
    used in the context of disorders that are       Neurofibromatosis
    clinically distinct and share a common          Congenital malformations
    etiology while varying in the severity of       Cerebral palsy
    symptoms. The validity of grouping              Down syndrome
    behaviorally defined phenotypes of              Hearing impairments
    potentially different etiologies has been       Vision impairments
    questioned.      AD and the disorders           Learning disabilities
    subsumed under ASD are postulated               Sleep disorder
    to have heterogeneous etiologies which          Self-injurious behaviors
    open the possibility that the autistic          Aggressive, angry or combative behaviors
    behavioral phenotype may represent              Oppositional behavior
    a final common pathway for a variety            Hyperkinetic behavior
    of disorders. Determining whether               Depression
    an autistic phenotype represents the            Anxiety
    final common expression of distinct             Obsessive compulsive disorder
    disorders or represents a spectrum of           Tics

study in Olmsted County Minnesota
(OC) found increases in the incidence          Table 2. Examples of disorders associated with
of AD from 0.55 per 10,000 children                     autistic disorder.
in 1980-1983 to 4.49 per 10,000
children in 1995-1997.17 A rising              in utero exposure to rubella, CMV, valproate, thalidomide
incidence among young children was
responsible for most of the increased.         neonatal or early infant insults (e.g., hypoxia, infection, trauma,
During the same period the incidence              hypothyroidism)
among children older than 10 years of
                                               brain malformations
age remained stable. Several putative
environmental agents, such as mercury
and vaccines, have been intensely              chromosomal abnormalities (5%)
stUdied, but to date no environmental
agent has been identified to explain the       Gene mutations (1-2%)
rise in incidence. Genetic and genomic            15q11-13 (Prader Willi/Angelman region) most frequent
stUdies have also failed to explain the           fragile X mutation
nse.                                              tuberous sclerosis
      Prevalence stUdies assessing time           phenylketonuria (if untreated)
trends are subject to inaccuracies that
                                              in 1991. If this biased diagnosis,          in the past but is now rare. Other causes
result from changes in diagnostic
                                              stUdies ascertaining cases using school     of AD include prenatal agents such as
criteria, inability to validate diagnoses
and increased awareness of the disorder       data would be expected to identify          infection and hypoxia. Although
across time, all of which have occurred       a rise in prevalence.     Support for       several environmental agents have been
                                              this possibility would be evidence of       implicated as causative agents (e.g.,
in autism. I? 19.20 The broadening of
                                              diagnosis swapping. Croen20 found           mercury), stUdies have not provided
the diagnostic criteria can be seen in
the revisions of the DSM since infantile      evidence of diagnosis swapping in           supporting evidence.
autism was first included in 1980. The        California, a state that has reported             Current conceptUalization of the
use of ASD has broadened the criteria         a dramatic rise in autism. A period         role of genes in AD is that of imparting
                                              of rising prevalence in AD saw a            susceptibility but not causing AD.
still further. Public and physician
                                              corresponding drop in the prevalence of     Genetic heterogeneity is the operating
awareness has grown substantially.            mental retardation without autism.          hypothesis in studies with estimates
Validating the AD or ASD is short
                                                    The reasons for the disturbing rise   of the number of involved genes
coming in many prevalence stUdies. A
                                              in the prevalence of AD andASD do not       ranging from 10-15. Four candidate
second stUdy of Minnesota children
                                              suggest a meaningful rise in new cases      susceptibility genes are currently under
(MS) illustrates the problems. This
                                              but a rise due to diagnosis swapping,       stUdy.22 (Table 3) Linkage stUdies
study found a greater increase in
                                              an increased identification of cases        have identified chromosomes 2, 7, 17,
prevalence, to 52 per 10,000, than the
                                              and a broadening of diagnostic criteria     22 and X, but confirming stUdies have
OC stUdywhich measured incidence.21
                                              to include cases that were considered       given inconsistent results. Numerous
This difference can be explained in
                                              below the diagnostic threshold in the       candidate genes have been identified
part by the method of ascertaining
                                              past. However, the possibility that a       including most neurotransmitter
subjects and validation differences
between the two stUdies. In the OC            portion of the rising prevalence results    receptors and proteins for essential
                                              from a true increased incidence in          brain development (e.g., neuroligin,
study, investigators reviewed medical         autism has not been excluded.
and school records to determine the                                                       reelin), but no candidate gene has
                                                                                          been consistently found in children
diagnosis of each subject using DSM           ETIOLOGY                                    with AD. This lack of clarity is
criteria. The MS stUdy used student
                                                   AD is categorized       as either      not inconsistent with overlapping
data reported to the department of
education. Such data do not allow             idiopathic or secondary when the cause      gene effects. Genes can be epistatic
                                              is known. Approximately 90% of the          (several genes influencing a behavior)
diagnostic validation.
                                              cases are idiopathic. A cause of the AS     or pleiotrophic (one gene influencing
     The possibility that school data
                                              can be identified in approximately 10%.     several behaviors).
may be biased towards categorizing            (Table 2) Chromosomal abnormalities
students as autistic is suggested by the      account for 5% of the secondary             INHERITANCE
timing of the initial rise in prevalence                                                       The inheritance of idiopathic AD
                                              AD. Duplication in the Prader Willi/
(between 1991 and 1994 in most
                                              Angelman region (15qll-13) is the           is complex and non-mendelian.        No
stUdies). Coincident with the initial
                                              most frequent gene mutation. Untreated      single inheritance pattern has been
rise was the inclusion of autism in the
                                              phenylketonuria      was responsible a      recognized. Inheritance is thought to be
list of disabilities eligible for federally                                               multifactoral involving the interaction
                                              considerable portion of secondary AD
mandated special education services

                                                                                                               VOL. 88 NO.5 MAY2(
                                                                                                     neuronal morphology and number,
            Table 3. Candidate autism susceptibility genes                                           synaptic abnormalities and dysfunctional
                                                                                                     pathways as a consequence.
                              chromosome locus
                AUTS1        7q11 (William syndrome region)                                          REFERENCES
                                                                                                     1. Kanner L. Nervous Child 1943;2:217-50.
                AUTS2        3q25                                                                    2. Bettelheim B. The Empty Fortress: Infantile
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                AUTS4       15q11 (Prader-Willi/Angelman syndrome region)                            Press; 1967.
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                                                         the ability to recognize, manipulate
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                                                         of language, another's behaviors or
                                                                                                     21. Gurney]G, Fritz MS, et aI. Arch Pediatr
           and language, social and psychiatric          expressions. An important pathway           Adolesc Med2003;157:622-7.
           problems, families with one child with        mediating social cognition involves         22. Online      Mendelian      Inheritance    in Man.
                                                         the amygdala, superior temporal        entrez/ query.
           AD are given an additional risk of 4-6%
                                                                                                     fcgi?db=OMIM (enter aurism)
           for one of these problems.                    sulcus and fusiform gyrus of the                                                       M
                                                                                                     23 Bailey A, Le Couteur A, et al. Psychol ed
                                                         orbitofrontal cortex. fMRI studies have     1995;25:63-78.
           NEUROPATHOGENESIS                             demonstrated the abnormal activation        24. Wassink TH, Brzustowicz L, et aI. MRDD
                                                                                                     Res Rev 2004;10:272-83.
                 Kanner was the first to speculate       of these structUres in high functioning     25. Brothers L. Concepts Neurosci 1990; 1:27-
           that AD had a biological cause. He            autistic individuals.                        51.
           supported his speculation by observing        Of particular interest is the serotonin
           that severalchildren had largeheads. His      system: 30% of children with AD have               Joseph H Hallett, MD, is Physician-
           observation of macrocephaly has been          elevated platelet serotonin. Whether this   in-Chief, Department of Pediatrics,
           confirmed by anthropomorphic and              contributes to the neuropathogenesis of     Memorial Hospital of Rhode Island, and
           neuroimaging studies. Macrocephaly is         AD or is an incidental finding will                          {Clinical}of Pediatrics,
           present in 20% of the children with AD,       require further stUdy.                      Brown Medical School.
           appears late in the first year and resolves        Studies of the autistic brain have             VirenD'Sa, MD, isa Developmental
           by five years old in most children. The       produced heterogeneous collections           Behavioral             Pediatric            Fellow,
           high incidence of seizures and mental         of findings most likely the result of        Neurodevelopmental            Center, Department
           retardation provides further evidence         its heterogeneous etiologies.     The        of Pediatrics, Memorial Hospital
           for a neuropathogenesis.                      picture that appears to be emerging is
                 StUdies to elucidate abnormal           disruption of early brain development        Correspondence:
            brain regions in AD have produced            with subsequent abnormalities       in       Joseph J. Hallett, MD

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