Download Psychiatric Clinics of North America

Psychiatric Clinics of North America
Volume 25 • Number 4 • December 2002
Copyright © 2002 W. B. Saunders Company
Review article
The autistic spectrum: subgroups, boundaries, and
treatment
Sophie H.N. Willemsen-Swinkels, PhD *
Jan K. Buitelaar, MD, PhD
Department of Child and Adolescent Psychiatry
University Medical Center
PO Box 85500
3508 GA
Utrecht, The Netherlands
*
Corresponding author
E-mail address: [email protected]
PII S0193-953X(02)00020-5
Leo Kanner posited in 1943 [1] the existence of a syndrome called “early infantile
autism.” In 1956, Kanner and Eisenberg laid down two criteria for the definition of the
disorder: (1) profound lack of affective contact at least up to age 5 and (2) elaborate
repetitive routines [2] . At that time there was a general belief that Kanner's classic autism
was a unique and discrete condition. The concept of autism was found to be useful in
clinical practice in which many practitioners who had lived or worked with autistic
children were sure they could instantly identify any other child with the same type of
handicap [3] . In the decades that followed, however, it proved to be difficult to reach
consensus about the definition and validity of autism. Specifying and operationalizing
the essential characteristics necessary for a diagnosis took a much longer time than
originally anticipated.
We have come to realize that the boundaries of autism are not that clear. Many behaviors
commonly observed in autism (eg, stereotypies) also can be seen in non-autistic
individuals. Second, there is a complex influence of developmental level or intelligence
on symptom expression. Finally, there is a considerable amount of clinical and etiologic
heterogeneity in people with autism.
Over the past decades this has led to an inconsistent use of various diagnostic labels,
which is illustrated by the results of prevalence studies. Early studies reported prevalence
rates of 2 to 5 in 10,000 for autism. Recently, prevalence rates up to 60 in 10,000 were
reported [4] [5] . These differences in prevalence rates are believed to be caused mainly by
improved detection and recognition through systematic population approaches in later
prevalence studies together with a broadening of the diagnostic concept rather than to a
secular increase in the incidence of the disorder [6] .
Successive editions of the World Health Organization's “International Classification of
Diseases” (ICD) and the American Psychiatric Association's “Diagnostic and Statistical
Manual of the Mental Disorders” (DSM) have reflected changing ideas of autism and
related disorders. Almost 50 years after Kanner's first description, the latest versions of
ICD [7] and DSM-IV [8] provided virtually identical definitions of autism and autistic-like
disorders [9] .
In both systems the overall construct of autistic and autistic-like behavior problems has
been given the name pervasive developmental disorders (PDD). The term “pervasive”
was meant to emphasize that in autism development was disturbed over a range of
different domains, in contrast to the relatively more delineated difficulties of the specific
developmental disorders and the centrality of cognitive problems in mental retardation.
The term “developmental” implies that individuals with these conditions suffer from
disturbances in the normative unfolding of multiple developmental competencies,
including social relations and communication [10] . These disorders have their onset in the
first years of life, and developmental correlates have important implications throughout
the life span.
The latest versions of the systems—ICD-10 and DSM-IV—largely agree on the disorders
that fall under this construct of PDD. To be diagnosed as autistic disorder in the DSMIV, a child must meet a minimum of six criteria among the following three areas of
impairment: qualitative impairments in social interaction, qualitative impairments in
verbal and nonverbal communication, and restricted repetitive and stereotyped patterns of
behavior, interest, and activities. An additional requirement is that delays or abnormal
functioning in at least one of the areas of social interaction, language, and symbolic or
imaginative play have been noted before the age of 3 years.
The category PDD-Not Otherwise Specified (including atypical autism) (PDD-NOS) is
used for conditions that are characterized by pervasive impairments in reciprocal social
interaction, verbal and nonverbal communication, or rigid and stereotyped behavior
patterns but fail to meet the full set of criteria for autistic disorder. A classification of
PDD-NOS may be given in the following instances: (1) the case fails to have an onset
before age 3 years; (2) the case presents with atypical symptoms that do not fit with the
12 criteria of autistic disorder of DSM-IV; (3) the case is a subthreshold variant of
autistic disorder and has less than the cut-off point of six symptoms listed under autism;
or (4) the case fails to meet the pattern of criteria of autism (eg, less than two social
symptoms or no symptoms in either the communication or activity/interest domain). A
category similar to PDD-NOS is included in ICD-10 under the label of atypical autism.
As a result of being a residual category, positive or explicit diagnostic criteria were not
provided [11] .
One of the intriguing aspects of autism is the marked clinical heterogeneity. Lack of
responsiveness to people can express itself as a total avoidance of social interactions.
Lack of responsiveness also can be found, however, in patients who do show an interest
in other people and friendships. In these patients, lack of responsiveness is expressed as a
deficit in the understanding of conventions of social interaction. Communicative
impairments can range from total lack of expressive language to reasonably fluent speech
with abnormalities in pitch, intonation, rate, rhythm, or stress. Finally, the criterion of
bizarre responses to the environment includes behaviors as diverse as self-mutilation,
obsessive insistence on sameness, and preservative, stereotyped preoccupations. The
course of autism also varies. Some children seem to develop normally for several months
to several years and then show deterioration, whereas other children show an abnormal
course of development from birth onward. Some children with autism can have a stable
course with only minimal fluctuations in symptoms, whereas other children show either a
deterioration or improvement with age. There are also major individual differences in
responsivity to behavioral interventions.
Another source of clinical heterogeneity is the wide variation in level of intellectual
functioning among individuals with autism. Recent reports indicate a rate of mental
retardation between 26% and 55%, which is lower than the approximate 75% rate of
studies of older date [4] . Individuals with autism may have a range of other behavioral
symptoms, including hyperactivity, short attention span, impulsivity, aggressiveness, and
temper tantrums. There also may be abnormalities in eating, sleeping, or mood.
Heterogeneity in nonspecific neurologic symptoms or signs also may be noted. 10% to
15% of cases of autism are observed in association with various neurologic or other
medical conditions. Approximately 25% of the subjects with autism develop seizures.
Despite this marked heterogeneity, the DSM-IV field trial has established that autism is
one of the most robust diagnoses in the system [9] . In this trial, information was obtained
from 21 sites on 977 children, adolescents, and adults with severe developmental
disturbances. A standard coding system, which included basic demographic information,
the rater's clinical diagnosis, and explicit ratings of diagnostic criteria derived from the
various “official” diagnostic systems, was used by each of the 125 raters. For
inexperienced raters, a revised ICD-10 definition was found to have excellent sensitivity
(0.82) and specificity (0.87). The DSM-IV criteria were modeled on these revised ICD10 criteria.
Although the definition of autistic disorder in the latest versions of the classification
systems is one of the most reliable and valid diagnoses in psychiatric research, the
diagnosis of PDD-NOS is still problematic. The validity of autistic-like conditions such
as Asperger's disorder requires more clarification [12] . A diagnostic category must meet
two criteria to fulfill taxonomic validity [13] : (1) internal validity (ie, it should be possible
to measure or operationalize the category) and (2) external validity (ie, it should differ
from related disorders on attributes other than the behavioral descriptors by which the
disorder was originally defined). Examples of possible attributes are associated
nondiagnostic behaviors;, possible markers of etiology, such as pregnancy and birth
complications, family history, associated neurologic diseases, and epidemiologic
correlates, such as sex ratio and socioeconomic status; clinical course or outcome; and
response to treatment [13] . The following section discusses the many issues that relate to
the internal and external validity of the classification of the various PDDs.
Autistic disorder and pervasive developmental disorder
Autistic core group together with other pervasive developmental disorder remainder
groups
The formal diagnostic systems of ICD and DSM are organized around dichotomous
categories (ie, an individual either has or does not have a disorder). These diagnostic
systems are intended to divide populations into categories that share a common symptom
presentation and maybe common etiology and course that is distinct from those of other
categories. Within the domain of PDD there is a wide range of severity of symptoms. To
incorporate some indication of severity of symptoms, the ICD-10 and DSM-IV make a
distinction between individuals with many severe behavior problems and individuals with
fewer or less severe behavior problems. The result is a classification system that assumes
the existence of a core syndrome—autistic disorder—and other PDD remainder groups.
In essence, this distinction is based on the number or severity of autistic symptoms. This
leaves the question of where the boundary should be drawn. Justification for a particular
set or number of criteria can be based on the historical precedent for criteria such as
Kanner's original description [14] , pragmatics (eg, selection of the system with the greatest
coverage) [15] , or the best fit with current clinical practice on the basis of consensus by
clinical experts [16] .
An example of an attribute that has a clear danger of circularity is age of onset. The term
“age of recognition” is probably more appropriate than “age of onset” because parents
may not detect the early signs of abnormal development. An earlier age of recognition
(onset) is found to coincide with more profound disruption of normal developmental
processes [17] . Age of recognition (onset) may be an indicator of severity and
pervasiveness, but on its own it cannot be considered a specific characteristic that
discriminates between discrete disorders. In DSM-III, types of PDD were distinguished
in terms of age of onset. Dahl et al [17] addressed the question of whether children who
suffer from autism and children who suffer from what was called childhood-onset PDD
in DSM-III form homogeneous and discrete diagnostic categories. They concluded that
age of onset did not emerge as a differentiating characteristic for either PDD group.
Based on a study of 274 case records, Rescorla et al [18] also concluded that the DSM-III
concept of distinguishing types of PDD in terms of age of onset lacks firm empirical
validity.
Levels of cognitive or language development are other discriminators that easily suffer
from a circularity when severity of autistic symptoms was the differentiating descriptor
from the beginning. The validation of the distinction between a core group and other
remainder groups preferably must come from features such as prognosis and course,
etiology, and response to treatment. Regarding prognosis, follow-up studies [19] often have
been limited to cases with autistic disorder. Results suggest that outcome at adult age is
unrelated to the presence of individual symptoms (other than lack of speech) but seems to
be related to the total number of autistic symptoms. The crucial question that remains to
be addressed, however, is which number of autistic symptoms is associated with an
increased risk to poor long-term outcome.
Knowledge regarding the origin of autism so far does not support such a distinction.
Autistic disorder and PDD-NOS may be associated with other medical conditions,
although there is some suggestion that this holds more for cases with atypical
phenomenology (PDD-NOS) than for typical cases. A uniquely and pathognomonic
neural deficit has not (yet) been found for either autistic sisorder or PDD-NOS. There is a
widespread agreement that the PDDs are caused largely by genetic factors. The genes for
autistic disorder also confer susceptibility to the lesser variant, as is indicated by the fact
that the lesser variant occurs more commonly than expected in relatives of autistic
probands. This finding suggests that autistic disorder and the lesser variant PDD share
common genetic mechanisms [20] .
There are several suggestions for cognitive functional deficits that might be responsible
for several or all of the autistic features, such as deficits in theory of mind, central
coherence, or executive functioning. There is no suggestion that any one of them can be
considered specific for autistic disorder, however. On the contrary, most of these
deficits have been found not only in children with PDD-NOS but also to some degree in
children with other non-autistic conditions, such as mental retardation or attention deficit
hyperactivity disorder.
In clinical practice, the distinction between core autism and remainder PDD groups has
no real meaning with respect to treatment. The level of language development and the
overall level of cognitive functioning are of much greater importance for the choice of
treatment.
In summary, many discriminators between autistic disorder and PDD-NOS suffer from
a danger of circularity and cannot be considered conclusive with respect to the external
validity of the distinction between core autism and PDD-NOS. Currently no clear
nonbehavioral marker discriminates people with core autism from other people. The
current state of knowledge is that the remainder PDD group overall expresses a pattern of
autistic characteristics that is nearly identical to the pattern found for “core autism” [16] ,
with the only difference being the severity of symptoms.
Several autistic groups
One approach to limit the heterogeneity of the PDDs is to look for more homogeneous
behavioral subgroups. The identification of behaviorally similar subtypes of children with
autism may lead to clarifications regarding the cause because behaviorally similar
children may share specific pathologic etiologic conditions. Second, membership in
specific, behaviorally defined subcategories of PDD might have prognostic significance.
Third, subtypes of children with autism might respond differently to various treatments.
For example, autistic children with certain behavioral characteristics might respond more
favorably to particular pharmacologic or behavioral interventions [21] . For these reasons,
various investigators have attempted to subcategorize children based on, for example,
putative etiology, behavior or symptom clusters, cognitive profile, and differential
outcome.
By putative etiology
In some cases, PDDs are associated with, and presumably caused by, some medical
condition, of which infantile spasms, congenital rubella, tuberous sclerosis, cerebral
lipidosis, and the fragile X chromosome anomaly are among the most common. Efforts to
limit heterogeneity have included the creation of subgroups by presence of organic
features. Some controversy exists with respect to the frequency with which the basis of
autism is accounted for by a known diagnosable medical condition. Scandinavian (and
some other) studies reported high rates of associated medical conditions; for example,
Gillberg [22] mentioned a rate of 37%. Other investigators found approximately 8% to 10%
of the PDD cases to be associated with medical conditions [23] [24] . Part of the explanation
lies in the IQ distribution of the different samples [25] . Known medical conditions are
much more common when autism is accompanied by severe or profound mental
retardation.
Comparisons of the clinical pictures in PDDs that occur with and without associated
biologic syndromes are scarce and have not, as yet, reliably identified any specific
differences, apart from the fact that individuals with an associated biologic syndrome
tend more often to be severely or profoundly mentally retarded [25] . An exception is the
association of fragile X syndrome with gaze avoidance [26] .
By social functioning
A subgroup classification system proposed by Wing and Gould [27] emphasized
differences in the social behavior of children with autism. Three subgroups were
distinguished: (1) “Aloof” children are characterized by a failure to approach others and a
tendency to ignore or withdraw from others when approached. (2) “Passive” children, on
the other hand, are responsive when approached and remain socially engaged (albeit in a
limited manner) as long as the other person maintains the interaction. (3) “Active-butodd” children actively seek interaction with others but do so in an odd, awkward, and
overly persistent manner.
Initially, the social subtyping scheme forwarded by Wing and Gould was well received
and described as heuristically and clinically useful. The findings of Volkmar et al [28] with
regard to the validity of the social subtypes were somewhat disappointing, however,
because subtype assignment was not strongly related to independent measures of either
social interaction or development. A second problem was the interobserver reliability for
assignment to the passive group. Several studies reported difficulties with the assignment
to the passive group and failed to validate the division in three groups [28] [29] . Finally, a
strong relationship was found between Wing and Gould subtype assignment and level of
intellectual functioning [28] [29] . Volkmar et al [28] found that IQ was actually a slightly
better predictor of Wing subgroup assignment (based on clinician's ratings) than the
summary score of items drawn from the description of the Wing and Gould subtypes.
By level of functioning
The apparent relationship between IQ and prognosis suggests that autistic subjects might
be subclassified according to level of intellectual functioning. Level of intellectual
functioning has been found to correlate significantly with severity of symptoms in all
three domains of autistic impairment. A subclassification according to level of
intellectual functioning is, however, fundamentally different from a division between
autism and PDD-NOS, because the subcategory of PDD-NOS includes high-functioning
and low-functioning atypical groups of children.
Table 1 presents
results from studies that have addressed this issue by using cluster
analytic techniques to determine whether natural homogeneous subtypes emerge from the
data. A major constraint of cluster analytic techniques is that the clustering algorithm can
operate only on variables that the researcher has entered into the analysis. Selection of
variables to be clustered reflects the researcher's best guess as to the most important
dimensions that differentiate subgroups within the sample [30] , and clustering techniques
identify groups in any dataset. Further study is needed to investigate whether these
groups represent internally or externally valid PDD subtypes with distinctive and unique
patterns of symptomatology for which criteria could be specified [31] .
Table 1. Studies since 1990 that have used cluster analysis to find subgroups in
children with PDD
Subjects
Naam
n
Diagnosis
Age in Description of clusters
years
Eaves et al
1994 [97]
166 AD, PDD-NOS, or 3–12
autistic spectrum
disorder
1: typical autistic group
2: low-functioning group
3: high-functioning group
Table 1. Studies since 1990 that have used cluster analysis to find subgroups in
children with PDD
(Asperger/schizoid)
4: hard-to-diagnose group with mildmoderate retardation and a family history
of learning difficulties
Sevin et al
1995 [21]
34 Austism (27) and
PDD-NOS (7)
(DSM-III-R)
2–22
1: high functioning/atypical PDD
2: mild autism
3: moderate autism
4: low functioning/severe autism
Waterhouse
et al 1996 [14]
194 Some form of
PDD
3–7
A: other-PDD/active but odd/higher
cognitive and adaptive
functioning/relatively fewer autistic
behaviors
B: autistic/aloof/lower cognitive and
adaptive functioning/relatively more
autistic behaviors
Prior et al
1998 [32]
135 High functioning
with autistic
behaviors (DSMIII-R)
3–21
A: autistic-like
B: Asperger-like
C: mild PDD or PDD-NOS–like
Authors suggested: clusters based on
severity of symptoms and level of
cognitive functioning rather than
distinctive symptom patterns
Stevens et al
2000 [34]
138 Autistic disorder 7 or 9 – High-functioning subgroup
(DSM-III-R)
– Low-functioning subgroup
Differentiated at school age by
behavioral measures of social
abnormality, language ability, and
cognitive level
In most studies summarized in Table 1 , differences found are related to severity of
impairment—especially level of cognitive and adaptive functioning—rather than to
distinctive diagnostic patterns of behavior [32] . Even studies that explored developmental
level along with other variables support the role of intellectual functioning as one of the
strongest indicators of subtype [33] .
In a longitudinal study with autistic children, the lower functioning preschool subgroup
children overwhelmingly remained in the lower functioning school-age group, whereas
the higher functioning preschool group split into a poor outcome and a less good outcome
group [34] . Several recent pharmacologic studies have indicated a differential response to
pharmacologic therapy as a function of IQ [35] [36] [37] [38] , which suggests the presence of
biochemical differences in low- versus high-functioning autistic children.
In a review of the genetic epidemiology of autism and other PDDs, it was suggested that
higher and lower functioning PDDs do arise from nonidentical genetic mechanisms [20] .
This was based on two findings. First, IQ and measures of adaptive functioning seem to
run true within families. Higher functioning autistic people tend to have higher
functioning affected siblings, and lower functioning autistic people have similarly
affected siblings [39] . Second, for relatives of autistic people the risk of having the lesser
variant of autism varies by level of functioning of the person with autism [20] [40] .
Table 2 summarizes
reports on the differences between high- and low-functioning people
with autism. In conclusion, a subclassification by developmental level may offer clinical
utility. Two aspects must be kept in mind, however. First, apart from the differences
between high- and low-functioning people with autism, the two groups also show a
significant behavioral overlap. Second, in the current state of knowledge, the choice for a
particular IQ cut-off score that sets the boundary between high and low functioning is
arbitrary.
Table 2. Differences between low-functioning and high-functioning people with
PDD
Low functioning relative to high functioning
Reported
by
Developmentally lower and more severe manifestations of the symptoms,
greater adaptive behavior impairment
[98] [99]
Poorer outcome, more behavioral and cognitive decline over time
[34] [100] [101]
Higher association with known medical conditions, more neurologic signs,
higher proportion of organic pathology, structural brain abnormalities,
epilepsy
[13] [14] [25] [103]
Higher proportion of female subjects
[105]
Siblings have greater risk of the lesser variant of PDD
[20] [40]
Lower prevalence of family psychiatric history
[103]
[102]
[104]
An autistic continuum without a bounded core or discrete clinical groups
Clinical intuition and studies [27] [41] suggest that autistic-like symptoms better fit to a
multivariately distributed dimensional trait than to categorical entities. Many researchers
have argued for an autistic continuum without sharp boundaries between an autistic core
group and other PDD remainder groups rather than for a sharp cut-off between these
groups [3] [31] [42] [43] . In this continuum, multiple and interacting biologic and environmental
influences are believed to determine the severity of impairment [44] .
The results of an epidemiologic study of children with special educational needs in one
area in London suggested that the autistic continuum is characterized by a set of three
features with a strong tendency to cluster together [27] : impairments of reciprocal social
interaction, verbal and nonverbal communication, and imagination (identified as being
closely related to the narrow, rigid, repetitive pattern of behavior). This cluster has been
referred to as the triad of impairments. Within this concept of an autistic continuum it is
uncertain as to where the cut-off from normality actually falls. There is evidence from
family studies of an elevated risk for social, communication, and repetitive impairments
among the relatives of probands with autism. The social difficulties are qualitatively
similar to, although milder, than those who typify autism and are sometimes apparent in
childhood [45] . Should the boundaries of the autistic continuum be extended to include
these relatives? This question poses a risk of the diagnosis of autism being extended to
include anyone whose odd and troublesome personality does not readily fit some other
category. Such overinclusion is likely to devalue the diagnosis to a meaningless label [43] .
The current versions of the two leading classification systems give no suggestions for the
cut-off of PDDs from normality. Within these classification systems, cases at the less
severe end of the continuum (mild phenotype expression) are likely to be classified as
PDD-NOS, the residual category; however, PDD-NOS is defined by what it is not (ie,
autistic-like but not autistic) rather than by explicit criteria. No threshold is given in the
differentiation between PDD-NOS and non-PDD conditions. In two independent datasets,
a scoring rule for the differentiation between PDD-NOS and non-PDD conditions has
been derived and tested [46] [47] . The best separation between PDD-NOS and non-PDD
conditions could be obtained with a cut-off point of at least four or five items of the full
set of DSM-IV criteria for autistic disorder, and with one of the social interaction
criteria set as mandatory. This diagnostic rule was found to be the best estimate for the
diagnostic rules that underlie the attribution of a clinical diagnosis of PDD-NOS in
current clinical practice.
An autistic spectrum
Many researchers have argued for the existence of an autistic spectrum rather than for an
autistic continuum. The term “continuum” suggests a simple straight line from severe to
mild (Fig. 1 ). With respect to the autistic disorders, the situation is believed to be much
more complex. The manifestations of the social and other problems vary widely in type
and severity, and all kinds of combinations of impairments are seen in clinical practice.
Some of these combinations have been named as syndromes. These syndromes are
discussed in the next section. Many other combinations of impairments have not (yet)
been assigned a separate identity. The term “spectrum” is used to indicate the fact that
although there is a common denominator, different types of children with a PDD present
with their own pattern of symptoms. These types of children differ by nature and not
merely by degree. This is reminiscent, metaphorically speaking, of the spectrum of
distinct colors after refraction of light by a prism [48] .
Fig. 1. (A) Autistic core with other PDD remainder groups. (B) Several autistic groups. (C) An
autistic continuum without a bounded core or discrete clinical groups. (D) An autistic spectrum.
Measurement issues
To advance our knowledge about the nosology of the autistic spectrum disorders and
facilitate further work on defining valid subgroups, several measurement issues should be
resolved. The first and most important issue is the establishment of biologic or
psychological markers of autism. The second issue involves introducing developmentally
sensitive criteria for autism and related disorders that enable researchers to arrive at
developmental age-corrected severity scores of the social, communicative, and rigidity
and other symptom domains. Third, attempts should be made to calibrate severity of
symptoms against levels of language ability and nonverbal skills. Fourth, the further
operationalization and specification of the as-yet abstract and complex diagnostic criteria
of autistic spectrum disorders, as listed in DSM-IV and ICD-10, will improve
possibilities to obtain reliable ratings about autistic symptoms in various contexts and
according to different informants, such as parents and teachers. Fifth, the development of
diagnostic instruments that quantify the symptom domains of social interaction,
communication, and rigidity and other symptoms is necessary. Commonly used standard
diagnostic instruments, such as the Autism Diagnostic Interview-Revised and the
Autism Diagnostic Observation Schedule, have been developed particularly to measure
the extreme manifestations of autistic symptoms and are less sensitive to the range of
more subtle manifestations that lie between normality and extreme pathology.
Consequently, the distances between values of these scales are uneven. Resolution of
these measurement issues gives new impetus to multivariate model fitting of subgroups
of autistic spectrum disorders.
Other pervasive developmental disorders
Several researchers and clinicians have searched for disorders that may be delineated
within the broad and heterogeneous class of PDDs. The ICD-10 and DSM-IV provide
tentative diagnostic descriptions of some other disorders in the PDD class in addition to
autistic disorder as the most nuclear type of PDD and PDD-NOS as the residual
category. These disorders include Asperger's disorder, Rett's disorder, childhood
disintegrative disorder, and overactivity disorder associated with mental retardation and
stereotyped movements (the latest one only in the ICD-10).
Asperger's disorder
One year after Kanner's first description of autism, the Austrian physician Asperger
described several cases whose clinical features largely resembled Kanner's. Asperger's
description differed from Kanner's, however, in that speech was less commonly delayed,
motor deficits were more common, the onset appeared somewhat later, and all the initial
cases occurred in boys [49] . Currently, Asperger's disorder is included in the DSM-IV and
the ICD-10. In DSM-IV, the criteria for Asperger's disorder on the domains “qualitative
impairment in social interaction” and “restricted, repetitive and stereotyped patterns of
behavior, interests, and activities” are identical to those for autistic disorder. Asperger's
disorder contrasts to autistic disorder in that there are no clinically significant delays in
the early development of language around age 1 to 2 years. There are also no clinically
significant delays in cognitive development or the development of age-appropriate selfhelp skills, adaptive behavior (other than social interaction), and curiosity about the
environment in childhood.
Clumsiness also has been proposed as a diagnostic feature of Asperger's disorder. Of 23
children with Asperger's disorder subjected to a clinical study, 83% were found to have
motor coordination problems [50] . The clinical description of Asperger's disorder in the
ICD-10 mentions a marked clumsiness as a common feature. Subsequent studies have
shown that clumsiness is not specific to Asperger's disorder, however, but is a feature that
is common in all PDDs and that patients with autism may even be more clumsy than
individuals with Asperger's disorder [51] .
Data on the prevalence of Asperger's disorder are inconclusive. Two surveys conducted
in Sweden [52] [53] reported high prevalence estimates (28.5 and 48.4 per 10,000,
respectively). These studies reported wide confidence intervals, however, which indicates
an extreme lack of precision of these estimates because of small studies [5] . On the other
hand, six epidemiologic surveys that have simultaneously assessed the presence of
autistic disorder and Asperger's disorder all reported a rate of Asperger's disorder
consistently lower than that of autistic disorder. A pooled analysis of these six studies
suggests a prevalence of 2 per 10,000 for Asperger's disorder [5] .
The validity of Asperger's disorder as distinct from other PDDs remains controversial, as
is explicitly noted in the ICD-10 [7] . The key question is whether Asperger's disorder is
qualitatively different from autism unaccompanied by mental retardation. The alternative
interpretation would be that Asperger's disorder is just a variant expression of “high
functioning autism” (HFA) [12] .
Several studies have attempted to identify discriminating criteria between Asperger's
disorder and high functioning autism, with mixed results [9] [54] [55] [56] . The differences
between the results of the studies can be explained by the differences in nosologic
approach. The use of a less systematic and stringent diagnostic assignment (eg, broader
definitions of Asperger's disorder) may explain the failure of finding significant
differences between Asperger's disorder and HFA groups in some studies [56] . On the
other hand, these studies suffer from the danger of circularity because findings of
differences often reflect the criteria adopted in the assignment of the diagnosis Asperger's
disorder and HFA in the first place.
The DSM-IV autism/PDD field trial compared individuals with Asperger's disorder with
individuals with HFA (full scale IQ > 85). Individuals with Asperger's disorder were
found to be less likely to have exhibited delays in the development of spoken language or
currently exhibit language/communication deviance; motor delays and “clumsiness” were
more variable; isolated special skills (often related to abnormal preoccupations) were
more frequent; and social, communicative, and “resistance to change” symptoms were
less frequent. Individuals with Asperger's disorder were more likely to exhibit verbal IQ
scores greater than performance IQ scores, whereas the opposite trend was obtained for
individuals with HFA [9] .
A subsequent study compared groups of Asperger's disorder and HFA individuals whose
diagnostic assignment was made after stringent criteria [56] . A comparison of
neuropsychological profiles revealed that 11 areas discriminated between the two
conditions. The neuropsychological differences between Asperger's disorder and HFA
were captured in the discrepancy between verbal IQ and performance IQ, with verbal IQ
being universally higher than performance IQ for individuals with Asperger's disorder,
whereas no verbal IQ-performance IQ discrepancy was found for individuals with HFA.
The Asperger's disorder and HFA groups did not differ in terms of full scale IQ.
In a comparative study of the cognitive profiles of 120 children with Asperger's disorder,
autistic disorder, and attention disorders, the intergroup discrimination overall was
found to be far from perfect [57] . The overall rate of correct diagnostic classification using
stepwise logistic regression analysis was found to be only 63%. The results indicated that
Asperger's disorder and autism share certain cognitive deficits on the Wechsler
Intelligence Scale for Children-Revised. Differences between Asperger's disorder and
autistic disorder were found on IQ level and verbal ability, with Asperger's disorder
characterized by a significantly better verbal ability.
Klin et al [56] argued that Asperger's disorder and HFA still could share the same origin or
other pathogenetic processes while having phenotypic differences solely accounted for by
neuropsychological differences. In this sense, Asperger's disorder and HFA could be seen
as the same diagnostic entity expressed differently because of different
neuropsychological endowment, which is similar, to some extent, to the phenomenologic
differences between lower functioning and higher functioning autism. Whether
Asperger's disorder and HFA are truly different diagnostic entities will be clarified only
with additional knowledge on the developmental, behavioral genetics, and neuroanatomic
aspects of the two conditions. Concerning developmental trajectories, children with
Asperger's disorder had less severe early behavioral abnormalities than children with
HFA. At follow-up in adolescence, however, the Asperger's disorder and the HFA groups
had similar behavioral manifestations [58] .
Few data are available on the cause of Asperger's syndrome as distinct from autism. One
study compared 23 children with Asperger's disorder to 23 age- and IQ-matched children
with infantile autism (DSM-III). Children with autism were found to have more
prenatal, perinatal, and neonatal problems [50] . Overall, the differences reported between
Asperger's syndrome and autism on etiologic parameters are relatively small and of
uncertain clinical significance. There is a high incidence of Asperger's syndrome in
family members of high-functioning autistic subjects [59] . Currently, it seems best to
conclude that the two syndromes are variable expressions of the same underlying disorder
and share a common etiology [60] .
Childhood disintegrative disorder
The general guidelines to the diagnosis of childhood disintegrative disorder (CDD) are
(1) onset of the condition after a fairly prolonged period of normal development and (2)
marked deterioration in multiple developmental areas accompanied by development of
various “autistic-like” features. Once the disorder is established, children with CDD
clearly resemble autistic children of the same intellectual level in terms of their behavior,
limited communication skills, pattern of long-term outcome, and the need for various
special services. CDD is included in the DSM-IV as part of the PDDs. The DSM-IV
criteria describe the period of normal development to have been at least 2 years but less
than 10 years. Volkmar and Rutter [61] mentioned a child who appeared to develop
normally for 18 months and then had a marked regression. Although good epidemiologic
data are lacking, it is undoubtedly true that CDD is a relatively uncommon condition,
much less frequent than autism [62] .
Some controversy still exists as to whether CDD should be regarded as a diagnostic
category separate from other variants of autistic disorder. The main question is whether
autism that seems to have been preceded by a period of definitely normal development
differs in any fundamental way from autism in which development has been abnormal
from the outset. Another problem is the fact that for the differentiation between autistic
disorder and CDD, clinicians must rely on information from the parents about the child's
behavior in the first years of life.
An argument in favor of a distinction is the finding that CDD seems to have an even
worse prognosis than autism in multiple respects. Volkmar et al [63] compared 10 children
with CDD to 165 individuals with autism. The children with CDD were found to be
significantly more likely to be mute and significantly more likely to be in residential
placement than children with autism. As a group, the 10 children with CDD had a
significantly lower mean IQ than the children with autism. Similar results were found
with the data of the DSM-IV Autism Field Trial [61] . In this study, 26 children with CDD
were compared with a group of children with autism. The children with CDD were found
to be more likely to be mute, have IQ scores of less than 40, and more often be in a
residential placement than children with autism. The median age of onset in the CDD
group was 36 months; the latest age at onset was 70 months.
Mouridsen et al [64] further contributed to the validation of CDD with their finding that
CDD and autistic disorder could be distinguished with reference to epilepsy. Thirteen
children who had normal or near-normal development for several years followed by a
loss of skills and speech were compared to 39 matched cases with autism. Significantly
more children with disintegrative disorders had developed seizures (77% versus 33%).
Although this finding suggests that CDD is caused by a significant neuropathologic
process, extensive evaluations usually fail to reveal identifiable medical conditions.
Rett's disorder
Just like CDD, Rett's disorder also starts with an initial period of normal development,
including normal perinatal head circumference. In contrast with CDD, the period of
normal development is usually short (ie, typically a matter of months) [65] . Then there is a
deceleration of head growth followed by a loss of hand skills and the appearance of
stereotypic hand-wringing movements. Social skills and expressive and receptive
language development also deteriorate at 2 to 3 years of age. Ataxia and apraxia become
prominent, and gait becomes broad-based and jerky, with stiff legs and side-to-side
swaying. Breathing dysfunctions may be severe [66] .
Once established, the disorder contains autistic features, such as impairments in social
interaction, impairments in communication, and stereotyped behaviors. Rett's disorder
has enough distinguishing features to warrant a distinct diagnostic entity, however. For
instance, the course of the disorder is different, with Rett's disorder progressing to various
forms of neurologic impairment that are not seen in autism. Overall, the prognosis of
Rett's disorder is much worse than that of autism, with marked motor impairment and the
development of scoliosis [65] .
The prevalence of Rett's disorder was studied in a part of southwestern Sweden. In a
population of 315,469 children aged 6 to 17 years, 10 cases were detected, all of whom
were girls. The corresponding prevalence was 0.65 per 10,000 girls [67] . Recently it has
been shown that familial cases are an X-linked dominant disorder and the disease locus
maps to Xq28. A candidate gene called methyl-CpG-binding protein 2 (MeCP2) was
identified from the Xq28 region and was shown to contain mutations in approximately
77% of Rett's disorder patients [68] .
Multiple complex developmental disorder/multidimensionally impaired
Several cluster analytic studies on children with severe developmental problems have
identified a group of children characterized by social problems, bizarre and disorganized
thinking, recurrent anxieties, inappropriate affect, and mood lability [17] [69] [70] . The
childhood-onset PDD category included in DSM-III was defined by, among others,
unexplained panic attacks, rage reactions, and lack of appropriate affective responses.
This led to an alternative operationalization of a severe developmental disorder under the
label of multiple complex developmental disorder (MCDD) [71] [72] [73] . In the MCDD
concept, emphasis is put on the presence of an impaired regulation of affective state,
primitive anxieties and thought disorders, and impairments in social interaction and social
sensitivity.
As a first-cut test of the clinical usefulness of MCDD, children with MCDD were
compared to children with dysthymia and conduct disordered children. A retrospective
chart review indicated that children with MCDD had earlier symptom onset, earlier age
of first hospitalization, higher psychopathology scores on the Child Behavior Checklist,
poorer peer relationships, and greater psychopathology than comparison groups of
children [73] .
Another chart review study [48] compared 105 children with MCDD with 32 children with
autism, 56 children with disruptive disorder, and 51 children with emotional disorder.
Multivariate analyses were performed on characteristics extracted from the charts. The
outcome of a cluster analysis indicated that MCDD subjects were similar to each other in
their symptom profile, whereas they seemed to be dissimilar to children with autistic
disorder, disruptive disorder, or emotional disorder. MCDD children proved to be less
disturbed in social interaction, communication, and stereotyped and rigid behavior than
children with autism. In contrast, MCDD children were found to be more impaired than
children with autism in thought disorders, primitive anxieties, and aggression. Children
with MCDD and autistic behavior were significantly different on factors that reflected
developmental and environmental background variables. Compared to non-PDD children,
children with MCDD were marked by more severe abnormalities in all symptoms areas,
including social interaction and communication and rigid behavior patterns. These data
did suggest that MCDD is not so much a subthreshold variant or an atypical expression of
autism as a representation of a PDD subcategory in its own right. The suggestion has
been raised that MCDD represents an early manifestation of major affective disorder or
schizophrenia [66] .
In a study of early-onset schizophrenia, approximately 30% of the cases screened for
childhood-onset schizophrenia had complex developmental disorders and brief psychotic
symptoms. The impression of a consistent clinical picture led to the proposal of a
subgroup of children with atypical psychosis, which was provisionally labeled
“multidimensionally impaired.” The characteristics were described as (1) poor ability to
distinguish fantasy from reality, as evidenced by ideas of reference and brief perceptual
disturbances during stressful periods or while falling asleep, (2) nearly daily periods of
emotional lability disproportionate to the precipitants, (3) impaired interpersonal skills
despite desire to initiate social interaction with peers, (4) cognitive deficits indicated by
multiple deficits in information processing, and (5) absence of formal thought disorder.
Similarities between subjects who were multidimensionally impaired and subjects with
early-onset schizophrenia were found in the pattern of premorbid developmental
difficulties, a discrepancy between word-reading ability and IQ and the increased rate of
schizophrenic-spectrum disorders in first-degree relatives. On the other hand, subjects
who were multidimensionally impaired were found to differ from subjects with earlyonset schizophrenia in that they had earlier cognitive and behavioral difficulties, earlier
age of onset of psychotic symptoms, and a less deviant pattern of autonomic activity.
Schizoaffective disorder was found to develop in 3 (27%) of 11 multidimensionally
impaired patients [74] . In these multidimensionally impaired patients, transient features of
PDD were reported. The relation of this construct of multidimensionally impaired to the
somewhat similar construct of MCDD is still unclear.
Overall, the nosologic status of the MCDD concept is unclear [75] . There are arguments
for and against including MCDD in the PDD category. A contra argument, for example,
is that the social relatedness of subjects with MCDD is variable, frequently ambivalent,
and different from the typical pattern found in autism. One also may object to including
MCDD in the category of personality disorders because no clear continuity between
MCDD and any of the personality disorders in adults has been demonstrated. Further
research, particularly including follow-up studies, is necessary to resolve these issues.
Overactive disorder associated with mental retardation and stereotyped movements
The ICD-10 describes a disorder whose diagnosis depends on the combination of
developmentally inappropriate severe overactivity, motor stereotypies, and severe mental
retardation. The ICD-10 acknowledges that this is an ill-defined disorder of uncertain
nosologic validity [7] .
Pathogenesis and treatment
Pathogenesis
Progress in understanding the cause, let alone developing new approaches to treatment,
has been painfully slow [71] . Research on the pathogenesis of PDD has focused almost
exclusively on autism.
Substantial evidence from twin and family-genetic studies exists that autism has strong
genetic components [76] [77] . The recurrence risk for autism after the birth of an autistic
child is 60 to 150 times the population base rate. Epidemiologically based same-gender
twin studies have reported higher concordance rates for autism among identical twins
than among nonidentical twins. The mode of genetic transmission is unclear. The marked
fall-off in rate of autism that occurs from identical to nonidentical twins or siblings
suggests that a small number of interacting genes rather than one single gene is involved,
with estimates of genes involved ranging from 2 to 20. The genetic loading seems to be
conferred to a broad phenotype that includes lesser variants of autism with subtle social,
communicative, and language problems. Several full genome searches for susceptibility
loci in autism using affected sibling pairs have been performed, as have a dozen
candidate genes studies. Although several areas of the genome (ie, on chromosome 7q, 1,
2, 6, 13 and 16) have been identified as regions of interest, currently no specific variation
in a specific gene has been firmly established as a susceptibility gene for autism [77] .
Postmortem studies on small case series report cellular abnormalities in the limbic system
and cerebellum. An in vivo MRI study on 59 autistic subjects also reported anatomic
abnormalities within the limbic system [78] . Another finding with respect to brain
morphology is that between 10% and 20% of individuals with autism have
macrocephalia, which is in accordance with MRI findings of an increased total brain
tissue volume and enlargement most prominent in the occipital and parietal lobes [79] [80] [81]
. An interesting study on 60 autistic boys aged 2 to 16 years concluded that abnormal
regulation of brain growth in autism results in early overgrowth with hyperplasia of
cerebral gray matter and cerebral and cerebellar white matter at approximately age 2 to 4
years followed by abnormally slowed growth and reduced cerebral gray and white matter
at an older age [82] . The area dentata, part of the hippocampus, was significantly smaller
in autism compared to normal children, particularly at approximately age 2 to 5 years [83] .
Another robust and well-replicated neurobiologic abnormality in autism is an elevation
of whole blood serotonin, which is found in more than 30% of patients [84] [85] .
These and other studies together present overwhelming evidence that abnormalities of
brain structure and function underlie the autistic syndrome. The following points are also
clear, however: reported abnormalities are heterogenous and based on studies of small
samples, most reported abnormalities have not been replicated, findings specific to the
core social and communicative deficits have not yet been demarcated from nonspecific
findings, and neurobiologic abnormalities have not been examined in a genetic
perspective, which leaves open the question as to whether, where, and to what extent
genetic influences on autism produce aberrant brain morphology or brain function.
Drug treatment
Given that the neurochemical basis of autism is unknown, there is as yet no place for
pharmacotherapy based on defined pathogenesis of the core social and communicative
deficits. The exception, perhaps, is intervention in the serotonin neurotransmitter system,
which may be based on evidence for abnormalities in whole blood serotonin in a
subgroup of individuals with autism.
Fenfluramine is a halogenated amphetamine that promotes the release and inhibits the
reuptake of serotonin and blocks dopamine receptors. Early studies reported dramatic
improvements, but subsequent large-scale and controlled trials could not support the
initial claims. Because of the potential neurotoxicity and reports of serious adverse
effects, fenfluramine is no longer recommended for clinical use [86] .
Clomipramine is a tricyclic antidepressant and a potent nonselective serotonin reuptake
inhibitor. Treatment with clomipramine led to improvements in—among other areas—
social behavior and aggression in two open-label studies, one with autistic patients [87] and
one with adults with PDD [88] . Clomipramine was found to be superior to desipramine, a
tricyclic noradrenergic uptake inhibitor, in a controlled study in autistic children and
adolescents [89] . Treatment with clomipramine may result in troublesome and serious
physical and behavioral side effects, however, and should be used judiciously. Three
selective serotonin reuptake inhibitors—fluvoxamine, fluoxetine, and sertraline—also
have been studied in autism. Overall, the results of the selective serotonin reuptake
inhibitors are encouraging in adults with autism who are characterized by strong
behavioral rigidity and obsessive-compulsive disorder-like symptoms. In contrast,
children and adolescents seem to be sensitive to the stimulating adverse effects of
selective serotonin reuptake inhibitors and have a much lower response rate [86] .
Buspirone, an agonist of the serotonin 5-HT1a receptor, has been reported to decrease
anxiety and affective lability [90] . So far only open studies have been reported.
Other interventions have been developed, not so much based on a defined pathogenesis of
autism but from a pragmatic perspective. Distressing or maladaptive symptoms, such as
hyperactivity, aggression, anxiety, negativism, ritualized repetitive behaviors, and selfinjurious behaviors, can be the target of (drug) intervention. Although treatment of these
symptoms does not cure autism, their effective treatment improves quality of life and
enhances opportunities for appropriate education and community independence [91] . For
these reasons an intervention with classic neuroleptic drugs, for example, the newer or
“atypical” neuroleptic drugs, or psychostimulants can be an option, depending on the
severity of symptoms such as motor stereotypies or hyperactivity (Table 3 ). Drug
treatment, however, is seldom considered as a single intervention and is mostly part of a
comprehensive, multidisciplinary treatment approach.
Table 3. Treatment options for distressing or maladaptive symptoms
Abbreviation: SSRIs = selective serotonin reuptake inhibitors.
Rigidity,
rituals
SSRIs
X
Atypical
antipsychotics
X
Hyperactivity,
impulsiveness
Aggression,
self-injury
Anxiety,
affective
symptoms
X
X
X
X
X
Stimulants
X
Naltrexone
X
Clonidine
X
Lithium
X
Beta-blockers
X
Anticonvulsants
X
Buspirone
X
Social and behavioral therapies
There are many treatments for autism, most of which demand a substantial sacrifice of
time, attention, and funds. The overall approach for PDD-NOS does not differ in a
substantial way from strategies used in autism. Overall, it is generally accepted that
behavior modification procedures can enable a child to develop better social and
emotional relationships, learn better communicative skills, and decrease the intensity of
stereotypic and bizarre behaviors. No single mode of treatment is ever likely to be
effective for all children and all families. Instead, intervention must be adapted to the
child's individual pattern of strengths and handicaps [92] [93] . Treatment should begin early
and may need to continue, in one form or another, into adulthood [94] .
Several specific treatments for autism are advocated with great enthusiasm. These
approaches are often based on reports of open, uncontrolled experiments that made little
allowance for natural developmental change and included only small sample sizes,
however [43] . There are hardly any comparison studies between methods of treatment and
few investigations designed to identify when and where a particular approach works best.
The approaches to modify behavior in autistic subjects can be divided roughly into two
different strategies: massed, discrete-trial learning (also called teacher- or therapistcentered learning or traditional behavioral learning) and social-pragmatic teaching (also
called child-centered therapy, pivotal-behavior therapy, or incidental teaching) [66] .
Eventually, many of the named therapies evolve to a point at which they include elements
of both strategies.
Summary
There is consensus about the disorders that comprise the autistic spectrum, with autistic
disorder, Asperger's disorder, and PDD-NOS as the most typical examples and Rett's
disorder and disintegrative disorder as the other components. Important controversies
regarding the precise definitions of autistic spectrum disorders and the boundaries
between the milder manifestations of those disorders, particularly PDD-NOS, and nonautistic conditions have not been and cannot be resolved fully as long as there is no
known biologic cause or consistent biologic or psychological marker. This includes
issues as basic as whether the autistic spectrum is a predominantly unitary entity or a
collection of more or less similar phenotypes with multiple, varying etiologies. This is
why the highest long-term priority in the area of definite diagnosis is the search for
biologic marker(s) for autism and related autism spectrum disorders [91] .
In the absence of a medical test to unequivocally diagnose autism, definitions of autism
and related conditions are based only on manifestations in overt behavior, with all the
unreliability this entails. In the future, the discovery of biologic correlates, causes, and
pathogenetic pathways will undoubtedly change the way in which autism is diagnosed
and lead to a new nosology [95] . Until that time the definitions in the current versions of
the classification systems should be considered in a state of evolution.
The key problem of the current classification systems is the fact that the boundaries
between the various disorders are fuzzy. Instead of a categorical approach, a more useful
description might be that of “autistic spectrum disorder,” which reflects the range of
severity of symptoms. Such a dimensional understanding of PDD is useful to clinicians,
who may otherwise use nonspecific terms to avoid the categorical diagnosis of autism [31]
.
Rutter and Schopler [96] argued for separate clinical and research schemes because clinical
and research needs are different. For research purposes it is desirable to have as much
direct comparability across studies as possible. The focus is on a high degree of
homogeneity within diagnostic groupings. A price must be paid for this detailed
specification, and the main cost lies in the proportion of cases left undiagnosed. For
example, there may be good scientific reasons for a narrowly defined categorical
diagnosis that includes only individuals who definitely and clearly have a specifically
defined condition and excludes individuals who may have the condition. For clinicians
and educators, classification helps guide the selection of treatments for an individual.
From this point of view, broader diagnostic concepts may be most appropriate [95] .
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Review article
Autism
Roberto Tuchman, MD
Dan Marino Center
Department of Neurology
Miami Children's Hospital
2900 South Commerce Parkway
Weston, FL 33331, USA
E-mail address: [email protected]
PII S0733-8619(03)00011-2
Autism is a complex neurodevelopmental disorder that is behaviorally defined. The
behavioral manifestations that define autism include qualitative deficits in social
interaction and communication and restricted repetitive and stereotyped patterns of
behavior, activities, and interests [1] . Autism defines children at a behavioral level and is
associated with multiple etiologies. The phenotypic presentation of autism is influenced
by factors that are not part of the defining features of this disorder. One aspect of autism
that is not part of the diagnostic criteria but is an important prognostic indicator is
cognitive ability. The wide range of social skills, communication abilities, and patterns of
behavior that occur in autism are best captured by the term “autism spectrum disorders”
(ASDs) [2] [3] .
Autism is a prototype disorder of sociocognitive development that provides an important
opportunity to observe and delineate the regions of the brain that are responsible for
behaviors that define social cognition and communication. Recent reports indicate that
there is an explosion of children given the diagnosis of an ASD. Prevalence figures range
from 4 to 10 per 10,000 up to 2 to 5 per 1000 [4] . Reports disagree, however, on whether
or not prevalence truly has increased. One explanation for the increased diagnosis is that
there is a greater awareness of the ASDs, especially in mildly affected children and in
those with severe mental retardation [5] . The purpose of this article is to review the
current clinical and neurobiologic understanding of autism.
Clinical perspective
Impairment of social interaction in ASD may manifest as social isolation or inappropriate
social behavior. These deficits in social interaction are represented by gaze avoidance,
failure to respond when called, failure to participate within groups, lack of awareness of
others, indifference to affection or inappropriate affection, and a lack of social or
emotional empathy. As individuals enter adulthood, there is in general an amelioration of
the social isolation, but the poverty of social skills and the impaired ability to make peer
friendships persist. Adolescents and adults with autism have significant misperceptions
of how others perceive them, and the adult with autism and adequate cognitive skills is in
general a loner.
Impairment in communication affects verbal and nonverbal abilities to share information
with others. Deficits in communication are variable. In some children they are
characterized by failure to develop expressive and receptive language skills. In others,
language is immature and characterized by echolalia, pronoun reversals, unintelligible
jargon, and abnormal melody (sing-song prosody, monotonous tone, or abnormal tone).
In those who have adequate speech there may be an inability to initiate or sustain an
appropriate conversation. Language and communication deficits persist into adulthood
and a significant proportion of individuals with autism remains nonverbal. Those who do
acquire verbal skills demonstrate persistent deficits in conversational skills, such as
taking turns and understanding the subtleties of language including jokes or sarcasm.
Deficits in communication also manifest as an impaired ability to interpret body
language, intonation, and facial expressions.
Repetitive and stereotyped patterns of behavior characteristic of autism include
resistance to change, insistence on certain routines, attachments to objects, and
fascination with parts and movement of objects, such as the turning wheels of cars or
fans. Children may play with toys but are preoccupied with lining up or manipulating the
toys, as opposed to using them symbolically. Motor and verbal stereotypies, such as
flapping, humming, rocking, running around in circles, or repetition of certain words,
phrases, or songs, also are frequent manifestations of autism. In the adult with autism,
adaptation to change improves but the restricted interests persist and those with adequate
cognitive skills tend to focus on narrow topics, such as train schedules, maps, or
historical facts, which dominate their lives.
In the absence of a biologic marker, diagnosing autism and delineating its boundaries
remain somewhat arbitrary clinical decisions. The behavioral manifestations of
individuals with autism are not limited to this group of children and can be seen in the
larger population of individuals with social communication spectrum disorders [6] . The
DSM-IV criteria classify children under the terminology, “pervasive developmental
disorders,” and include five subgroups in this category (Table 1 ). The core clinical feature
that defines autism and related disorders is a disturbance of social interaction, but this
deficit in social interaction is not absolute and the social behaviors of individuals with
autism differ depending on their cognitive level, developmental stage, associated
disabilities, and the type of social structure in which they are observed [7] . It is reasonable
to postulate that the regions in the brain essential for social cognition and communication
are distributed widely and may be affected to different degrees in individuals with social
communication disorders. The degree to which these social brain regions are affected and
the degree to which other associated brain regions, such as those of language and motor
function, are involved account for the clinical heterogeneity of social communication
spectrum disorders.
Table 1. Pervasive developmental disorders
Subtypes of autistic Characteristics
spectrum disorders
Autistic disorder
Classic autism with deficits in sociability and language and with
repetitive behaviors and a restricted repertoire of interests.
Symptoms usually are present from infancy or the toddler years
(<3 years). Approximately 30% of children have unexplained
regression, usually between 18 and 24 months, of language and
sociability.
Asperger syndrome
(AS)
Language develops better than in classical autism and cognition is
better. Individuals with AS, however; have problems with the
semantic and pragmatic use of language. Many of these
individuals are misdiagnosed early on and in adulthood may be
described as odd or eccentric.
Pervasive
developmental
disorder, not
otherwise specified
These are individuals who do not meet full criteria for any other
subtype of pervasive developmental disorder. There is wide range
of cognitive and behavioral problems in this group of children, but
in general, the social, communicative, and behavioral deficits,
although similar to autism, are less severe.
Childhood
disintegrative
disorder
Children who between ages 2 and 10, after entirely normal early
development of language, sociability, and cognition, experience a
regression in at least two of the following areas: language, social
skills, bowel or bladder control, play or motor skills. Cognitive
skills usually are significantly impaired.
Rett syndrome
Specific X-linked genetic deficit strongly associated with
mutations of the MECP2 gene. It affects postnatal birth growth,
resulting in severe mental retardation and motor deficits. It is
associated with a specific “hand-washing” stereotypy. Although
there is loss of social interaction early, if often improves later in
the course of the disorder.
There is no biologic test to diagnose autism; as such, the goal of neurologic examination
is to assess which, if any, tests are needed depending of course on the history and
neurologic examination. The initial work-up (Table 2 ) of an individual with autism
should have a clear clinical purpose and should be differentiated from research goals.
There are evidence-based guidelines that have been established for the diagnosis of
autism and related disorders [8] . Autism may be associated with diverse etiologies and
with a variety of medical disorders including seizures. The role of the neurologist is to
determine if a specific etiology can be established in an individual with autism and to
determine how this information has an impact on prognosis, genetic counseling, and, in
the rare situation, a specific therapeutic intervention.
Table 2. Initial diagnostic evaluation of autistic spectrum disorder
From 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; with permission.
Work-up
Key points
Clinical history
(1) Parental report is usually better than what one observes in a
brief office visit. Gathering several sources of information
sometime may be essential for diagnosis.
(2) The use of standardized questionnaires is extremely helpful in
the screening and diagnosis of autism.
(3) A family history specifically probing for a history of other
family members with social deficits, manic-depression, obsessivecompulsive disorder, language disorders, or seizures.
Clinical examination (1) Observation of how a child plays, especially with
representational toys, is an important clinical tool and essential to
assess a young child's language, cognitive ability, sociability, and
affect.
(2) Look for physical abnormalities, usually minor, that may help
diagnose a genetic disorder.
(3) Examine for skin manifestations that may suggest a
neurocutaneous syndrome.
(4) Stereotypies are not diagnostic but are present in the majority of
children with autism.
(5) The head circumference in children with autism may be at
upper limit of normal.
Standarized tests and (1) Hearing test
evaluations
(2) Communication assessment by speech and language
pathologist.
(3) Assessment by occupational or physical therapist specifically in
those with motor deficits, motor planning, or sensory dysfunction.
(4) Neuropsychologic batteries are valuable for planning
individualized intervention programs.
Genetic and
metabolic studies
(1) Chromosome studies to detect a syndromic condition, fragile-X,
or some other possibly genetic etiology. Depending on the clinical
situation, genetic consultation may be appropriate.
(2) Metabolic tests are needed only if the history or examination
suggests (ie, family history of mental retardation or if the child has
not been screened at birth).
Neuroimaging
studies
(1) Imaging studies are indicated only if the neurologic
examination suggests it or if the child is a candidate for specific
intervention such as epilepsy surgery.
Table 2. Initial diagnostic evaluation of autistic spectrum disorder
Neurophysiology
studies
(1) A one-hour sleep EEG should be done if any suspicious
behavioral episode that might represent a seizure.
(2) In selective situations, such as children with a history of autistic
regression, no speech, and severe comprehension deficits, an
overnight EEG that captures slow-wave sleep is indicated.
(3) Prolonged video-EEG monitoring also may be indicated if
suspicious behavioral episodes persist despite a normal one-hour
sleep EEG and in those children with severe comprehension
deficits that are not improving.
Social, cognitive, and related disabilities
The defining features of the social communication deficits in children with autism
include deficits in joint attention (defined as the behaviors used to share the experience of
objects or events with others), disturbances in affect, impairments in imitation,
impairments in the capacity for pretend play with objects or people, and impairments in
the ability to attribute beliefs to the self and others (theory of mind) [9] [10] [11] [12] [13] [14] [15] .
In addition, cognitive level, language and communication skills, motor function, patterns
of behavior, interests, and activities all contribute to social functioning.
Assessment in autism requires a multidisciplinary approach and the use of objective
scales. One of the most widely used assessment tools in the United States is the
Childhood Autism Rating Scale (CARS) [16] . Evidence suggests that factor analysis–
based scores using the CARS is helpful in identifying subgroups of children with autism.
Five factors have emerged from this factor analysis, including social communication,
emotional reactivity, social orienting, cognitive and behavioral consistency, and odd
sensory exploration [17] . This study [17] suggests that even within the ASD population there
are distinguishing aspects of the social deficit that can be quantified objectively and used
to differentiate subgroups within the larger spectrum.
The most comprehensive systems available for the diagnosis of autism are the Autism
Diagnostic Observation System and the Autism Diagnostic Interview, which together
provide a structured detailed interview and an observation method to assess objectively
an individual's social ability, communication skills, and behavior [18] [19] [20] [21] [22] . Specific
“social communication” handicaps can be identified in ASD using the Autism Diagnostic
Observation Schedule, and three factors seem to play a crucial role: joint attention,
affective reciprocity, and theory of mind [23] . These three social communication domains
are central to social development in most children, and when they do not develop
appropriately they account for the core deficits seen in social communication spectrum
disorders.
Cognition is not part of the clinical criteria for autism but is an important variable that
influences diagnosis, is related to associated medical disabilities (such as rates of
epilepsy), and predicts outcome [24] [25] . Measures of nonverbal problem solving in highfunctioning individuals with autism correlate with outcome, and the severity of autistic
behaviors is a poor predictor of prognosis [26] . Children and adults with autism who have
severe cognitive deficits and those who have normal or above-average intelligence may
form distinct subgroups [27] . Symptoms or behaviors of autism represent a different
dimension from level of functioning, and these two factors largely are responsible for the
variability of the phenotype that occurs in autism [28] .
Cognitive deficits in autism are characterized by impairment in the processing of
information and the transfer of this information into symbolic representations [29] . There
is evidence suggesting that all persons with autism have a cognitive deficit affecting their
perception of the world, that they have an impaired capacity to see things from another
person's point of view, and that they have little awareness of the mental states of other
people (metacognition theory) [30] [31] [32] . This “theory of mind” has been proposed as
central to the cognitive dysfunction of the individual with autism; evidence suggests that
understanding of false belief and understanding of emotion may be distinct aspects of
social cognition in young children [33] .
Approximately one third of children fulfilling criteria for a diagnosis of autism are
reported to lose language and social skills in the second year of life [34] [35] [36] . There is no
accepted definition of regression and, despite reports by parents of single words or
phrases that drop out accompanied by decreased social play and increased irritability, this
phenomena frequently is overlooked. It often is difficult to ascertain if development truly
was normal before the regression [37] . Investigators who examined family videotapes
made before the identification of symptoms of autism often found evidence of preexisting developmental differences [38] [39] . There is some preliminary evidence that
cognitive impairment is more likely in people with ASD who experience regression [40] .
There also is controversy regarding whether or not disintegrative disorder and autistic
regression are discrete entities [41] . There are no prospective studies of autistic regression,
therefore the true nature and incidence of regression are not well understood.
Epilepsy is common in autism, but the rates of seizures vary, with the highest risk in
those with the greatest degree of cognitive and motor impairment and the most significant
deficits in receptive language deficit. There has been significant controversy regarding
the causal role of seizures in autism. The relationship of children who have autism,
regression of language, and an epileptiform EEG to those children with Landau-Kleffner
syndrome (LKS) is not presently understood. Specific age, behavioral, and EEG profile
differences between children with autistic regression and seizures or an epileptiform EEG
and those children with LKS do exist, and this may have important etiologic and
therapeutic implications. The complex and controversial relationship between autism and
epilepsy (clinical and subclinical) recently has been reviewed by Tuchman and Rapin [42] .
Neurobiologic overview
Earlier studies of autism suggested that cerebellar abnormalities in autism may account
for inability to execute rapid attentional shifts and that this impairment in shifting
attention, possibly in conjunction with abnormalities in other neuronal systems, impairs
social and cognitive development and produces the behavioral manifestations
characteristic of autism [43] . More recent studies have focused on specific cortical areas
and, at least in boys with autism, a significant asymmetry reversal in language-related
inferior-lateral-frontal and posterior-superior-temporal regions and in inferior temporal
regions involved in visual face processing has been identified [44] . One of the more
interesting and relevant areas to the understanding of a social cognition neuronal network
is the evidence that facial recognition is impaired early on in autism and that the
amygdala is crucial in the development of this facial recognition by providing emotional
valence to the fusiform face area [45] [46] [47] . It now can be reasonably stated that neuronal
networks dedicated to social cognition do exist and that specific regions of the brain
important for social cognition can be reliably identified and measured [48] .
Current understanding of the neuropathology of autism is limited. In the small number of
brains studied, investigators have found consistent neuropathologic changes in the limbic
system and in cerebellar circuits. Cells in the limbic system (hippocampus, amygdala,
mamillary body, anterior cingulate gyrus, and nuclei of the septum) are small in size and
increase in number per unit volume (increased cell packing density). In these studies, the
cerebellum showed a decreased number of Purkinje cells, especially in the posterolateral
neocerebellum and adjacent archicerebellar cortex (posterior and inferior portions of the
cerebellum) [49] [50] [51] . In addition to the developmental abnormalities of the brainstem,
cortical abnormalities have been found in the few number of brains that have been
studied [52] . Recently, a paradigm that emphasizes the role of circuits and information
processing within the brain, rather than single-cell pathology, has been introduced to
investigate the neuropathology of autism and other developmental disorders of the brain
[53]
. This paradigm is based on the finding that minicolumnar organization of the brain of
individuals with autism is abnormal and shows cell columns that are more numerous,
smaller, and less compact in their cellular configuration and have reduced neuropil space
in the periphery [54] .
MRI studies have demonstrated abnormalities of the posterior fossa structures in autism,
including hypoplasia of cerebellar vermal lobules VI and VII and diminished size of the
brainstem [55] [56] [57] . Findings of cerebellar abnormalities have not been consistently
reproduced and some investigators have stated that previous reports of posterior fossa
abnormalities may be related to technical and methodologic factors [58] . A meta-analysis
of data from separate laboratories suggests a bimodal distribution in the measurements of
the cerebellar vermis in subjects with autism. A subgroup with hypoplasia of vermal
lobules VI and VII and a subgroup with hyperplasia were found. The majority (>80%) of
patients fell into the hypoplasia group. Besides differing from each other, the groups
differed significantly from control patients [43] [59] . There is a discrepancy, however,
between neuropathologic and neuroradiologic studies. Neuropathologic studies have
shown that maximal anatomic abnormalities are in the posterior and inferior portions of
the cerebellar hemispheres and involve cell loss. The cell loss now has been found in the
entire cerebellum and affects the vermis evenly (it is not confined to lobules VI and VII).
Neuroimaging studies demonstrate a decrease in tissue area confined mostly to lobules VI
and VII. The vermis, however, may turn out to be the best in vivo indicator that the
cerebellum as a whole is abnormal in autism and the emphasis on MR imaging of vermal
lobules I-V and VI-VII in the autism literature may reflect merely the ease and reliability
with which these structures can be measured [60] . Other studies suggest that, in children
with cerebellar hypolasia and autism, the degree of cerebellar hypoplasia can be
correlated with slowed attentional responses to visual cues in a spatial attention paradigm
[61]
. This has become a timely topic of discussion, as the literature continues to suggest
that the cerebellum may have an important role not only in autism but also in other
disorders of higher cognitive function [50] . There also is some preliminary data suggesting
that deficits in procedural learning in autism may be important and that these deficits
may reflect dysfunction in the cerebellum [62] .
Morphometric analysis has demonstrated that male autistic subjects have enlarged brains
and that the enlargement of the brain is a result of greater brain tissue volume and greater
lateral ventricle volume [63] . Other morphometric studies did not find a larger brain in
autistic patients compared with control patients but did report reductions in volume in the
amygdala and in the hippocampus, particularly in relation to total brain volume [64] . These
studies suggest that the histopathology of autism and that the reductions of volume are
related to dendritic tree and neuropil underdevelopment and that this likely reflects the
lack of fully developed connections between limbic structures and cerebral cortex.
Structural MRI data in high-functioning individuals with autism has identified graymatter differences in an amygdala-centered system relative to age- and IQ-matched
control patients. Decreases in gray matter were found in anterior parts of this system
(right paracingulate sulcus and left inferior frontal gyrus) and increases were found in
posterior parts (amygdala/periamygdaloid cortex, middle temporal gyrus, and inferior
temporal gyrus) and in regions of the cerebellum [65] . Several studies have found that
brain development in autism follows an abnormal pattern [66] . These studies have found
accelerated brain growth during the first few years in children with autism resulting in
brain enlargement in early childhood [67] . In adolescents and adults with autism, brain
volume is normal secondary to a slight decrease in brain volume during late childhood,
the time when most children experience a slight increase in brain growth [68] [69] .
The role of the amygdala and related structures in autism also has been documented by
functional MRI (fMRI) studies in patients with autism or Asperger syndrome in whom
activation of the front temporal regions, but not the amygdala, occurs when making
mentalistic (theory of mind) inferences from the eyes [70] . This is in contrast to control
patients who did show activation of the superior temporal gyrus and amygdala, which is
the brain system proposed to be at the core of the “social brain network.” Positron
emission tomography (PET) findings in autistic subjects include modest and not always
significant global increase in resting cerebral glucose use, mostly in the basal ganglia,
frontal, temporal and parietal lobes, whereas others have found no significant differences
between autistic and control subjects [71] . The lack of consistent abnormalities in PET
studies of autism may be the result of the heterogeneous nature of the disorder that
makes comparisons of group differences unreliable. A PET study of a group of five highfunctioning autistic males (compared with a control group) showed (1) reversed
hemispheric dominance during verbal auditory stimulation; (2) a trend toward reduced
activation of auditory cortex during acoustic stimulation; and (3) reduced cerebellar
activation during nonverbal auditory perception [72] . PET using “theory of mind” tasks in
control subjects and in subjects with Asperger syndrome have demonstrated a lack of
normal activation of the left prefrontal area in those with Asperger syndrome. Instead,
children with Asperger syndrome activated neighboring areas of the brain, suggesting a
nonspecific reasoning mechanism for inferring mental states [73] .
The most consistent neurochemical finding in autism has been an elevation in platelet
serotonin levels [74] . Despite extensive research, neither the relationship of this finding to
concomitant mental retardation nor the mechanism of the hyperserotoninemia has been
elucidated. Cook has suggested that hyperserotoninemia in autism may be
heterogeneous, as one subgroup of subjects demonstrated increased 5-HT uptake and
another subgroup decreased 5-HT2 binding [75] . A role for other monoamine
neurotransmitters has been suggested, however; aside from serotonin, the only other
consistently replicated neurochemical finding in autism has been elevated
norepinephrine plasma levels [76] . In a series of studies using PET scans, altered serotonin
synthesis in the dentatothalamocortical pathway in autistic males has been demonstrated.
Furthermore, it has been documented that there is a lack of the normal high-brain
serotonin synthesis period in children with autism [77] [78] .
Electrophysiologic studies of autistic children have included clinical EEG studies and
evoked potential studies. Clinical EEG studies performed on autistic children have
revealed abnormal EEGs in 13% to 83% of cases [36] . The clinical diagnostic criteria used
for autism, the associated medical disorders that coexist, and the methods of recording
and interpreting clinical EEGs likely account for the variability in rates among studies.
Prolonged EEG studies are significantly more likely to identify abnormalities than
routine one-hour studies, at least in children with ASD and a history of regression. VideoEEG 23-hour overnight telemetry studies of children with ASD and regression, but
without seizures, have found that 46% have an epileptiform EEG [24] .
Magnetoelectroencephalography (MEG) studies of children with ASD and regression
(and suspected history of seizures) have found epileptiform activity in 82% [79] . The high
rate of seizures and epileptiform abnormalities in ASD are especially interesting in light
of emerging data on the role of the amygdala in autism, as the amygdala also is a known
to be a highly epileptogenic structure. It is likely, however, that the immunologic
abnormalities described previously and the EEG findings reported in autism represent
epiphenomena and are not a primary etiology in autism.
Evoked potential studies have shown no consistent abnormality in either the brainstem
auditory evoked potential (BAEP) or the middle latency responses (MLRs) of patients
with nonretarded autistic disorder [80] . Clinical reports and research, however, continue
to suggest the possibility of specific abnormalities [81] [82] [83] . In general, reviews of the
literature on auditory brainstem response in autism have found overall contradictory
results, with some studies finding prolongation but others shortening and no
abnormalities in central transmission latencies [84] . Evoked potential studies also have
been used to document abnormalities in face processing and attention in children with
autism [45] [85] .
Genetic studies have demonstrated an increased recurrence risk for autism of
approximately 3% to 8% in families with one autistic child [86] . The search for autism
genes is complicated and, although many chromosomes have been implicated in autism,
no definite answers are available [87] [88] [89] . One point learned from experience
determining genetic links in autism is that specific clinical characterization of the
language and social deficits of the individuals studied has to be performed [22] [90] . This
has been shown in work looking at the relationship between chromosome 2 and autism
[91] [92]
. Other chromosomes of interest in autism include chromosome 15 [93] [94] and
chromosome 7 [95] [96] [97] . Despite rare clinical reports documenting mutations in methylCpG-binding protein 2 (MECP2) gene, which is a known cause of Rett syndrome, this
gene does not play a major role in the majority of individuals with autism [98] . Other
possible genetic causes that have been investigated are the roles of the HOXA1 gene and
the reelin gene, but the data implicating these genes in the etiology of autism is
inconsistent [99] [100] [101] [102] [103] [104] . No genes or chromosomes involved in autism have
been definitely identified, but the heritability of autism is difficult to dispute.
Investigators have become increasingly aware of the importance of identifying and
quantifying the core social and communication deficits in the broader autism phenotype
to elucidate the specific contribution of genetics to this heterogeneous disorder [105] .
Overview of intervention
The data from neurobiologic investigations of autism suggest that specific networks in
the brain, such as the amygdala and related regions crucial for social communication, can
be identified [48] [106] . When these regions of the brain are dysfunctional, there are deficits
in joint attention, affective reciprocity, and theory of mind. If these deficits can be
identified early, then specific interventions can be implemented. Then understanding of
the plasticity of the brain can be used to maximize potential. To a limited extent, this is
currently ongoing in autism behavioral and educational intervention research in young
children with autism [107] [108] [109] [110] .
Management of individuals with autism requires a multidisciplinary approach.
Appropriate behavioral management techniques, educational or work programs, and
communication techniques form the basis of management. Working with a psychologist
or educators well versed in functional behavioral analysis and behavioral management
techniques is essential. In individuals with autism and deficits in motor function, such as
problems with motor planning, an occupational therapist is helpful. The role of the
neurologist is to coordinate these diverse interventions and guide the family in evidencebased interventions that take into account the findings of the neurologic examination and
assessment.
As understanding of the neurochemical basis of the social networks of the brain becomes
more sophisticated, specific pharmocotherapeutic interventions will be developed. At
present, there is emerging evidence to suggest that in autism, serotonergic
neurotransmission is dysfunctional [74] [111] . In light of these findings, specific
interventions that modulate the serotonergic system, such as the selective serotonin
reuptake inhibitors (SSRIs), may have a role in the treatment of autism and related
disorders of social communication [112] [113] .
The atypical antipsychotics that block postsynaptic dopamine and serotonin receptors
have attracted clinical and research interest as potential agents in the treatment of autism.
A multisite randomized double-blind trial found that specific symptoms significantly
improved with the use of risperidone compared with placebo [114] . McCracken et al
demonstrated that risperidone, over an eight-week period, was well tolerated and
effective for the treatment of tantrums, aggression, or self-injurious behavior in children
and adolescents with autism [114] . This study highlights many of the shortcomings of
clinical and research drug therapy for autism in that the core symptoms of autism (ie,
social communication and language) are not targeted. In general, improvement in core
symptoms is difficult to measure and in the vast majority of clinical situations
medications are treating the associated and not the core symptoms of autism.
The known increased risk of seizures in autism has led to clinical, but mostly anecdotal,
reports of treatment with antiepileptic drugs (AEDs) in individuals with autism. In the
absence of clinical trials, however, no definite recommendations can be made regarding
any specific AEDs treatment. The role of AEDs in the treatment of autism recently has
been reviewed [115] . The co-occurrence of autism, epilepsy, and affective disorders is
common, and these disorders may therefore share a common neurochemical substrate,
which is targeted by the psychotropic mechanism of action of several AEDs [116] .
There continues to be a great deal of interest regarding immunologic abnormalities in
autism and the possibility of a specific abnormality in the opioid system, which could
lead to specific types of interventions [117] [118] [119] . Several studies have attempted
treatment using immunoglobulins, steroids, diet, and specific opioid blockers such as
naltrexone [120] [121] [122] [123] [124] . This line of research, however, has been controversial and
the scientific evidence to suggest that interventions based on these theories are successful
has been inconsistent [125] [126] [127] [128] .
The use of medication in autism remains limited. Nevertheless, there are well
documented successful uses of medications in autism to treat symptoms such as anxiety,
obsessive-compulsive behaviors, aggression, impulsivity, and hyperactivity [129] [130] [131] [132]
. Intervention programs in autism emphasize an applied behavior analysis approach and
have in common key elements such as intensity, structure, and frequency, but there still is
significant controversy over the most effective types of intervention for maximizing an
individual's potential and leading to successful outcome [133] [134] [135] [136] . The types of
intervention and potential neurobiologic factors that predict successful outcome need to
be clarified further [137] [138] [139] .
Being social is a complex act that touches the essence of humanity. The networks in the
brain responsible for social cognition and communication are distributed widely and are
linked to many regions of brain function. These neuronal networks are specified by the
genome, but just as genetics dictate how these pathways develop, the experiences of
being social in turn sculpt these networks. As such, the importance of early intervention
for all children with developmental disorders of social communication cannot be
overemphasized [140] . Social, affective, and cognitive developmental research into ASDs
will continue to provide a window into the complexities of brain-behavior relationships
with practical implications for all members of society.
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