Clinical manifestations

Article section 3 of 14. Previous Next

By Caroline DiBattisto MD
Autism disorder, also referred to as autism, is a neurodevelopmental disorder that
overlaps with other disorders in the pervasive developmental disorder spectrum as well
as with psychiatric disorders indicative of social impairment, communication impairment,
and restricted interests and impulsivity. Symptoms and behavior change over time, and
this process parallels changes in brain development (Hollander et al 1998). The
Diagnostic and Statistical Manual of Mental Disorders-IV TR (2000) diagnostic criteria
for autistic disorder include: (1) qualitative impairment in social interaction, (2)
qualitative impairment in communication, and (3) restricted, repetitive, and stereotyped
patterns of behavior, interest, and activities. Additionally, there is a delay or abnormal
functioning in at least 1 of the following areas prior to 3 years of age: (1) social
interaction, (2) language as used in social conversation, or (3) symbolic or imaginative
play. The disturbance is not due to Rett disorder or to childhood disintegrative disorder
(American Psychiatric Association 2000).
The diagnostic criteria for Asperger disorder include: (1) qualitative impairment in social
interaction, (2) restricted, repetitive, and stereotyped patterns of behavior, interest, and
activities, (3) no clinically significant general delay in language (eg, single words by age
2 years, communicative phrases used by age 3 years), (4) no clinically significant delay
in cognitive development or in the development of age-appropriate self-help skills,
adaptive behavior (except social interaction), and curiosity about the environment in
childhood. In addition, there is clinically significant impairment in social, occupational, or
other important areas of functioning (American Psychiatric Association 2000).
Pervasive developmental disorder - not otherwise specified (PDD NOS) is diagnosed
when severe and pervasive difficulties occur in the above areas, but criteria are not met
for autistic disorder or Asperger disorder.
Although symptoms of autistic disorder may not become apparent until 18 months of
age or older, abnormalities in development may be observed as early as 6 months
(Zwaigenbaum et al 2005). A prospective study found that children who were later
diagnosed with an autism spectrum disorder were comparable at 6 months of age to a
control group, but after 6 months of age, they had a rapid decline in eye contact, social
smiling, and examiner responsiveness (Ozonoff et al 2010). The frequency of gaze to
faces and shared smiles were significantly different by 12 months of age; however, the
majority of the parents did not report any loss of skills during this period. Early indicators
(prior to 2 years of age) include lack of appropriate gaze; lack of warm, joyful
expressions with gaze; lack of sharing enjoyment or interest; lack of response to name;
lack of coordination of gaze, facial expression, gesture, and sound; lack of showing;
unusual prosody; repetitive movements or posturing of body, arms, hands, or fingers;
and repetitive movements with objects (Wetherby et al 2004)

The most important clinical manifestation of autistic disorder is markedly abnormal or

impaired development in social interaction and communication evident prior to 3 years
of age. These symptoms may be manifested differently at various chronological ages.
During infancy, children with autistic disorder may not show much interest in being
picked up, or they may not be comforted by physical closeness with their caregivers. As
toddlers, they may not follow (shadow) the parents in the house, preferring instead to
play by themselves. They may not show anxiety related to separation from their parents.
As they grow older they show a lack of interest in sharing enjoyment or achievements
with other people. They often fail to form close relationships with peers and show poor
social or emotional reciprocity. They may have difficulty recognizing the feelings,
perspective, and needs of others and may not be aware of others' feelings or distress.
Development of theory of mind, the understanding that others have viewpoints,
desires, and beliefs of their own, is believed to be impaired. Often, a lack of joint
attention exists in that the child may fail to initiate attention-sharing behaviors. They
may treat others as objects, tools, or mechanical aids in their activities. For example, a
child might try to use her mothers hand as a tool to turn on a toy rather than handing
the toy to her mother and indicating her desire. In addition, children with autism
spectrum disorders may show impairment in the use of nonverbal social behaviors (eg,
lack of eye-to-eye gaze, reciprocal smiling, and affectionate contact). Contrary to many
of the myths about autism spectrum disorders, individuals may be affectionate and may
desire social attention, but may lack the skills needed to effectively interact with others.
Children with autistic disorder typically have impairment in both verbal and nonverbal
communication skills. There may be a total lack of, or delay in, the development of
spoken language and deficits in receptive language. Their babble lacks the quality of
social communication. Nonverbal communication such as pointing with the index finger,
gesturing, and miming is absent or is markedly limited. If speech develops, persons with
autistic disorder may not engage in meaningful pragmatic communication and may lack
reciprocity, resulting in an impaired ability to sustain conversation. Spoken language
may be stereotyped in form and marked by immediate and delayed echolalia,
pronominal reversal, and idiosyncratic word usage. For example, a 6-year-old child's
spoken language consisted of repeating television cartoon dialogues verbatim for hours.
The speech of individuals with autistic disorder may be abnormal in pitch, intonation,
rate, and rhythm.
The play of young children with autism is often atypical. Many young children with
autism spectrum disorders fail to play with toys in the intended manner (eg, lining up
cars or examining a nonsignificant part of the toy). They may fail to engage in pretend
play such as playing with dolls, action figures, or stuffed animals. They may not be
interested in reciprocal social play such as peek-a-boo.
Children with autism spectrum disorders often exhibit restricted, repetitive, and
stereotyped patterns of behavior, interests, and activities. They may spend inordinate
amounts of time on 1 activity (eg, whirling strings, collecting items like sticks or cans,
lining up toys, clapping, hand-flapping, rocking, or twirling). For example, a 19-year-old
adult with autistic disorder would sneak out of his house to buy magazines so he could

tear out the subscription cards. He had many suitcases full of subscription cards and
spent several hours daily rearranging and sorting the cards. Individuals with autism may
also spend inordinate amounts of time on nonfunctional activities such as lining up
certain toys or arranging objects. Some individuals develop intense interests in topics
that may be age-appropriate (eg, trains) or not (eg, vacuum cleaners).
Stereotyped, self-stimulating movements may include finger flicking, hand flapping,
clapping, or complex whole-body movements. A 4-year-old child with autistic disorder
swayed on all 4 extremities for hours. Individuals with autism spectrum disorders may
show an intense preoccupation with parts of an object. They may show fascination with
movements like spinning wheels of a toy car or the motion of an electric fan. These
children often insist on sameness and may show catastrophic reaction (fear, panic,
anger, tantrums) to minor changes in their environment, routine, or rituals. Some
children with autism spectrum disorders may develop intense attachment to objects
such as a piece of string.
Associated features.
Intellectual impairment. The Autism and Developmental Disabilities Monitoring (ADDM)
Network published data from the 2006 surveillance year, which revealed that an
average of 41% of children with autism spectrum disorders had cognitive impairment
(IQ < 70) (Autism and Developmental Disabilities Monitoring Network Surveillance Year
2006 Principal Investigators 2009). A previous review of epidemiological evidence found
that about 70% of children with autism have intellectual impairments (Fombonne 2003).
About a third (30%) fall in the mild range of intellectual disability, and more than a third
(40%) fall in the severe to profound range of intellectual disability. In addition, cognitive
skills in individuals with autism may show uneven development. Deficits are sometimes
more marked in verbal skills, whereas spatial or visual motor skills may be average or
even superior. The diagnosis of autism in children with severe intellectual disability must
be made with care because some behaviors associated with autism (eg, stereotyped
behaviors) are also common in children with mental retardation but do not necessarily
indicate the presence of an autistic spectrum disorder.
Attention, mood, and behavioral disorders. Individuals with autism spectrum disorders
may show hyperactivity, impulsivity, and short attention span. There may be
abnormalities of mood or affect, especially if individuals develop insight of their
differences. Anxiety can be prominently manifested by excessive fears, transitionrelated stress, excessive startle, or obsessions and compulsions. They may
demonstrate inappropriate (excessive or lack of) reaction to perceived dangers. Some
parents of children with autism spectrum disorders have reported that their child does
not appear to react to pain or seems to be oversensitive to sound or touch. Often
individuals with autism spectrum disorders are keenly and exceptionally sensitive to
sensory stimuli. Loud noises may be overwhelming, smells may result in feeling sick,
and itchy clothing or sheets may produce significant discomfort. Textures of certain
foods may be so noxious that those foods are not tolerated. They may show increased
temper tantrums, aggressiveness, and a variety of self-injurious behaviors including

head banging, self-biting, or poking of various body orifices and it may appear these
occur without evident precipitating factors. However, evidence suggests that in many
cases self-injurious or aggressive behavior is functional for the individual and serves to
either communicate intent (escape, avoidance, or attention), or to provide sensory
stimulation to the individual.
Seizures. The prevalence of epilepsy is higher in children with autism than in the
general population. Approximately 25% of individuals with autism spectrum disorders
have major motor seizures, and 45% have EEG abnormalities (Parmeggiani et al 2010).
Children with comorbid severe global developmental delay/intellectual disability and
motor deficits tend to have a higher prevalence of seizures (42%) (Tuchman et al 1991).
The onset of epilepsy in individuals peaks twice: before 5 years of age and then again in
adolescence (Volkmar and Nelson 1990). Routine EEG evaluation in individuals with
autistic disorder is not recommended without clinical signs of seizures, but clinicians
should have a high index of suspicion and consider EEG for clinical spells that might be
seizures (Myers 2007).
Gastrointestinal problems. A review of the literature surrounding speculative
gastrointestinal factors in autism spectrum disorders found very few scientifically
rigorous studies in this area (Erickson et al 2005). The authors concluded that there is
little evidence to suggest that individuals with autism spectrum disorders are prone to
gastrointestinal symptoms such as diarrhea, constipation, or food intolerance. A
comparison of the incidence of gastrointestinal symptoms between 124 children with
autism and age- and gender-matched controls using a population-based cohort found
that the autism case group had a significantly higher incidence of constipation and
feeding issues/food selectivity (Ibrahim et al 2009).
Sleep problems. Disturbed sleep is commonly seen in children with autistic disorder. In
a study of 68 children with autism, 57 children with developmental delay, and 69
children with typical development, the children with autism had less total sleep time than
the other 2 groups on actigraphy (Goodlin-Jones et al 2008). Parents reported more
sleep problems in both the autism and developmental delay groups compared to the
typical development group.

Genetics. Consensus is that autistic disorder is a complex heritable disorder involving

multiple genes. Evidence from various lines of research (twin studies, familial
aggregation, and chromosomal abnormalities) indicates that autism has a heritable
component (Newschaffer et al 2002) and most likely this involves a non-Mendelian
process that possibly involves 1 or more regulator genes that are activated during brain
development
Certain cognitive deficits (reading, spelling, executive function, and intellectual
disability), specific language abnormalities (especially social use of pragmatic language
and narrative discourse), personality characteristics (eg, social deficits), and psychiatric

disorders (eg, anxiety and affective disorder) are found more commonly in family
members of patients compared to individuals with other developmental disabilities
(Wolff et al 1988; Landa et al 1991; 1992; Ozonoff et al 1991; Abramson et al 1992;
Gillberg et al 1992; Smalley et al 1992b; Bolton 1998).
Strong evidence supporting genetic factors comes from twin studies (Bailey et al 1995;
Hallmayer et al 2002; Ho et al 2005). A 60% concordance for autism was found in
monozygotic twin pairs versus 0% in dizygotic twins, with an estimated heritability of
over 90%. Ninety-two percent of monozygotic twins were concordant for a broader
spectrum of cognitive or social abnormalities versus 10% in the dizygotic twins. This
marked fall off in concordance from monozygotic to dizygotic twins is most consistent
with multiple interacting genes (Piven 1997).
The known genetic causes of autism include visible chromosomal abnormalities (about
5% of cases), copy number variants (10% to 20%), and single gene disorders (about
5%). The most commonly observed chromosomal abnormality in autism is maternally
derived duplication of the Prader-Willi/Angelman syndrome critical region 15q11-q13
(Miles et al 2010). The minimum prevalence of Down syndrome in autism is 5%, greater
than in the general population (DiGuiseppi et al 2010). The aCGH test has identified
clinically significant copy number variants, such as 16p11.2 and 15q13.3 deletion
syndromes, which are associated with intellectual disability and autism spectrum
disorders (Miles et al 2010). Certain single gene disorders, including fragile X
syndrome, tuberous sclerosis complex (Hunt and Dennis 1987; Smalley et al 1992a;
Aicardi 1993), PTEN macrocephaly syndrome (McBride et al 2010), untreated
phenylketonuria (Lowe et al 1980), and possibly neurofibromatosis (Gillberg and Forsell
1984), have been reported to be associated with autism or autistic behavior. Fragile X
syndrome is an X-linked semidominant condition caused by a mutation in the FMR-1
gene that has neuropsychiatric symptoms similar to features of autistic disorder (Reiss
and Freund 1992). A study of 68 males with fragile X syndrome found that 30% met
criteria for autistic disorder and 30% met criteria for pervasive developmental disorder
not otherwise specified (PDD-NOS) (Harris et al 2008).
Other genetic disorders linked to autism include De Lange syndrome (Johnson et al
1976), Leber hereditary optic neuropathy (McKusick 1992), histidinemia (Kotsopoulos
and Kutty 1979), Joubert syndrome (Ozonoff et al 1999), and Williams syndrome
(Gillberg and Rasmussen 1994). Linkage disequilibrium in the 5 end of the Angelman
syndrome gene has been found (Nurmi et al 2001). Gene linkage studies have revealed
inconsistent results, and most studies have failed to identify loci with the classical
threshold for evidence of linkage (logarithm of odds greater than 3.6). Except for Rett
syndrome, generally attributable to mutations of the methyl-CpG-binding protein 2
(MeCP2) gene, the other pervasive developmental disorder subtypesautistic disorder,
Asperger disorder, childhood disintegrative disorder, and pervasive developmental
disorder - not otherwise specifiedare not linked to any particular genetic or nongenetic
cause, yet multiple interacting genes, each with moderate genetic effect, play a role as
the main causative determinants of autism (Risch et al 1999).

Structural abnormalities. Neuroanatomical studies involving autopsied brain samples

from patients with autistic disorder have revealed structural alterations including a loss
of Purkinje cells in the hippocampus, amygdala, and cerebellum. Inconsistency in
structural MRI studies reflects the heterogeneity of the illness (Palmen and van
Engeland 2004). It is thought that many alterations of the brain occur before symptoms
become obvious (Arndt et al 2005).
Abnormal functioning of the brain areas that participate in face processing and social
cognition has been consistently demonstrated in persons with autism and reflects
hypoactivation in the amygdala and fusiform gyrus (Grelotti et al 2004). The fMRI
studies of individuals with autism judging expressions from another persons eyes did
not activate the amygdala, whereas people without autism did show amygdala
activation. Research with newborn rhesus monkeys supports the hypothesis that early
damage to the amygdala-hippocampal complex may result in autistic-like behavior
(Bachevalier and Merjanian 1994). Because autism involves deficits in social
intelligence it is plausible that an amygdala deficit could be involved (Baron-Cohen et al
2000).
The relatively consistent cellular cerebellar pathologic findings in autism spectrum
disorders have resulted in increased interest in the contribution of the cerebellum to
language, attention, and other higher cerebral functions (Rapin 1999).
There is recognition that the cerebellum may have a modulatory role in a wide array of
neurobehavioral functions including learning, communication, attention, and
socialization in addition to motor behavior (Schmahmann 1991; Leiner et al 1993).
Evidence of hyperplasia of cerebellar lobules VI-VII has been found as well as
hippocampal enlargements in fragile X (Kaufmann et al 2003). One study revealed
decreased complexity and extent of the dendritic arbors in some pyramidal neurons of
the hippocampus (Raymond et al 1989), although hippocampus volume by MRI is the
same in controls as in autistic individuals (Piven et al 1998).
Research by Piven has found the volume of the total cerebellum to be significantly
increased (Piven et al 1997c). This may reflect hypoplasia (Courchesne et al 1988) as
autopsy studies have reported 25% to 30% evenly distributed Purkinje neuron loss in
the vermis (Arin et al 1991) with varying degrees of cell loss throughout the cerebellum,
and without significant gliosis. The absence of glial cell hyperplasia suggests that the
lesion is acquired early in development (Arin et al 1991). In addition, dysregulation of
Reelin (secretary glycoprotein responsible for normal layering of the brain) and Bc1-2
(regulatory protein responsible for control of programmed cell death in the brain) has
been found (Fatemi et al 2001).
Multiple brain areas are thought to be involved as neuroimaging findings have included
increased brain size, smaller body, and posterior subregions of the corpus callosum in
autistic individuals as well as Purkinje cell atrophy (Piven et al 1997a; Bauman and
Kemper 2005).

Cortical and intracerebral abnormalities. Various abnormal cortical findings have

been reported in individuals with autism: cortical gyral malformations suggesting
developmental errors in neuronal migration (Piven et al 1990); an increase in cerebral
cortex volume (Filipek et al 1992); corpus callosum abnormalities (Piven et al 1997a); a
decrease in parietal lobe volume (Courchesne et al 1992); and cytoarchitectonic
abnormalities consisting of increased cell-packing density in the hippocampus,
amygdala, entorhinal cortex, mammillary body, and septum bilaterally (Bauman and
Kemper 1994). Research has also demonstrated that the working memory network
maybe shifted toward the right posterior part of the brain (Koshino et al 2005).
Approximately 30% of persons with autistic spectrum disorders have increased head
size and brain volume. One study found that birth occipitofrontal circumference was
significantly smaller in autistic spectrum disorder patients compared with controls.
However, children with autism had greater increase in occipitofrontal circumference
between birth and 6 to 14 months. This increase in occipitofrontal circumference was
strongly correlated with greater cerebral and cerebellar volumes on MRI by 2 to 5 years
of age, suggesting growth dysregulation in these areas (Courchesne et al 2003). One
study found that the rate of macrocephaly quadrupled in the first year of life (Lainhart
2006). The largest study evaluating age-related changes in brain size in autistic and
typical subjects from 12 months to 50 years of age, based on analyses of 586
longitudinal and cross-sectional MRI scans, showed early brain overgrowth during
infancy and the toddler years in children with autistic disorder, followed by an
accelerated rate of decline in size and perhaps degeneration with age (Courchesne et al
2011).
In summary, the available neuropsychological, neuroanatomic, and neuroimaging
studies suggest there is no obvious single brain structure or system that is abnormal in
autism. Findings associated with autism have been reported in various brain regions.
This neuroanatomic heterogeneity most likely reflects etiologic heterogeneity. The
underlying defect may be a distributed abnormality at the level of dendritic architecture
leading to a complex information processing deficit (Minshew et al 1997).
Electrophysiology abnormalities. In a Japanese study, epilepsy was diagnosed in
37% (375 of 1014) of children with autism spectrum disorders (Yasuhara 2010).
Epileptic EEG discharges occurred in 85.8% (870 of 1014) of the patients. There was
also a very high incidence of spike discharges in participants whose intellectual quotient
was very low or low. Epileptic seizure waves most frequently developed from the frontal
lobe (65.6%). Magnetoencephalography, a noninvasive method for identifying zones of
abnormal brain electrophysiology, has been used to evaluate patterns of epileptiform
activity during stage 3 sleep in 50 children with regressive autism spectrum disorders
(symptom onset between 20 and 36 months) and in 6 children with classic LandauKleffner syndrome. MEG data were compared with simultaneously recorded EEG data.
Magnetoencephalography identified epileptiform activity in 41 out of 50 (82%) children
with autism spectrum disorders; simultaneous EEG revealed epileptiform activity in only
68%; only 30% had previously been diagnosed with a clinical seizure disorder. This
study demonstrates that there may be clinically relevant epileptiform activity during

slow-wave sleep and magnetoencephalography may have significantly greater

sensitivity to this epileptiform activity than simultaneous EEG, 1-hour clinical EEG, or
24-hour clinical EEG (Lewine et al 1999).
Neurotransmitters. Given all the neurobiological investigations in autism, serotonin
dysfunction has the most empirical evidence. Elevated levels of whole-blood serotonin
have consistently been found in 25% to 40% of autistic patients (Anderson et al 1987a;
Anderson 2002). No significant associations have been found between serotonin level
and behavioral outcomes, except for an inverse relationship between serotonin level
and self-injury (Kolevzon et al 2010). Also elevated serotonin levels are not specific to
autism (Piven 1991).
Preliminary data suggest that acute depletion of the 5-hydroxytryptamine precursor,
tryptophan, can exacerbate many behavioral symptoms of autistic disorder. Twenty
drug-free adults with autistic disorder underwent short-term tryptophan depletion with
65% of the 17 patients having significant global worsening of behavioral symptoms
(McDougle et al 1993). Low urine tryptophan levels have been found in children with
autism spectrum disorders (both with a gluten-free casein-free diet, and regular diet)
compared to controls (Kalunza-Czaplinska et al 2010).
The indirect dopamine agonist, amphetamine, has been shown to exacerbate
stereotypic motor symptoms and hyperactivity in some autistic children, whereas
dopamine antagonists have been found to be effective in improving some of the
behavioral symptoms associated with autistic disorder. Increased dopamine functioning
has been suggested in autism based on the finding of elevated mean basal CSF levels
of the primary metabolite of brain dopamine, homovanillic acid, in medication-free
autistic children in comparison to matched controls (Gillberg and Svennerholm 1987).
However, other studies have found normal CSF homovanillic acid levels in autistic
individuals (Narayan et al 1993).
A literature review of the neurochemical correlates of autistic disorder found little
support for the idea that a dysfunction of norepinephrine or the endogenous opioids is
related to autism (Lam et al 2006). Elevated levels of plasma norepinephrine have been
reported in autistic individuals (Leventhal et al 1990), but these studies have
methodological limitations. Other studies have found no group differences in plasma
levels and urinary excretion of 3-methoxy-4-hyroxyphenylglycol or in urinary exertion
rates of norepinephrine, epinephrine, and vanillylmandelic acid between autistic and
control subjects (Minderaa et al 1994). In addition, there are reports of normal CSF
levels of 3-methoxy-4-hyroxyphenylglycol in autistic individuals (Gillberg and
Svennerholm 1987), which most accurately reflects the problems with measuring
peripheral neurotransmitters that may not accurately reflect brain levels of
neurotransmitters.
Some of the effects of opiates, such as decreased pain sensitivity, self-injurious
behavior, and poor social relations, resemble symptoms of autism (Panksepp 1979).
Reports of elevated CSF endorphin levels in autistic children have led to the speculation

that a defect in a maturation of the brain endorphin system may underlie some of the
symptoms of autism (Ross et al 1987). On the other hand, several studies have failed to
reveal consistent differences in beta-endorphin and adrenocorticotropic hormone levels
between autistic and control groups (Herman 1990; Gillberg et al 1992; Sandman
1992). The reasons for self-injurious behavior are poorly understood.
Glutamate, an excitatory neurotransmitter, is important in neuronal plasticity and
cognitive functioning. High levels of glutamate can be neurotoxic. Studies have shown
that people with autism have higher levels of plasma glutamate than controls. Because
plasma glutamate levels are correlated with CSF glutamate levels, there is potential for
a screening or diagnostic tool (Fatemi et al 2002; Shimmura et al 2011).
Hormones. High fetal testosterone levels have been associated with autistic traits in
toddlers and older children. This supports the extreme male brain theory of autism
advanced by Baron-Cohen (Auyeung et al 2010). Hypothalamic pituitary adrenal
dysregulation in persons with autism have been explored and identified through cortisol,
adrenocorticotropic hormone, and dehydroepiandrosterone measurements. The 11
human studies completed that measured cortisol found few differences in subjects and
controls, but the largest study (N= 48) found higher cortisol levels in subjects with
severe autistic spectrum disorder indicating a mechanism of possible neurotoxic effect
of cortisol (Lam et al 2006). Corbett found statistically significant cortisol elevations to a
nonsocial stimulus (Corbett 2006). Additional hypothalamic pituitary adrenal dysfunction
has been found in a study measuring levels of DHEA and DHEA-S (which may have
some neuroprotective effects) between 15 adult drug-free patients with autism and 13
healthy controls. Despite the small number of subjects, lower DHEA-S levels were
observed in the group with autistic spectrum disorders as compared to controls (p<
0.05) (Strous et al 2005). The ratio of these hormones may influence the deleterious
effects of cortisol on brain development and play a role in the etiopathophysiology of the
disorder (Colborn 2003; Rasmusson et al 2004).
Immunology. The relationship between the immune system and autism has been
studied since at least the 1970s. However, several controlled studies have not
supported this hypothesis (Krause et al 2002). More recently, significant increases in
plasma levels of a number of cytokines, including IL-1, IL-6, IL-8, and IL-12p40, in an
autism spectrum disorder group compared with typically developing controls were
found. It was noted that the increased cytokine levels were predominantly in children
who had a regressive form of autism spectrum disorder, and increasing cytokine levels
were associated with more impaired communication and aberrant behaviors (Ashwood
et al 2011b). A study of dynamic adaptive cellular immune function conducted with 66
children with autism spectrum disorder and 73 control subjects showed altered T-cell
function in the autism spectrum disorder group. Further longitudinal analyses are
needed to understand the relationship between immune function and developmentalbehavioral progression (Ashwood et al 2011a).
Prenatal and perinatal factors. A linked database cohort study of infants born between
1990 and 2002 was performed in Canada (Dodds et al 2011). Among 129,733 children,

924 had an administrative diagnosis of autism. They found that mothers with
prepregnancy weight of 90 kg or more and an 18 kg weight gain during pregnancy were
independent risk factors for autism. The authors proposed that leptin levels during
pregnancy may be involved. In addition, women who delivered less than 18 months
after a previous delivery and women with no previous deliveries were at increased risk
to have a child with autism. Teratogens that are known to increase the risk of autism
include maternal rubella infection, ethanol, thalidomide, valproic acid, and misoprostol
(Arndt et al 2005) and an association has been reported between cytomegalovirus
infection and autism (Chess 1971; Stubbs 1987; Ivarsson et al 1990).
A meta-analysis of perinatal and neonatal risk factors for autism was conducted. The
analysis included 40 studies, and over 60 perinatal and neonatal factors were
examined. Factors associated with autism risk in the meta-analysis were abnormal
presentation, umbilical-cord complications, fetal distress, birth injury or trauma, multiple
birth, maternal hemorrhage, summer birth, low birth weight, small for gestational age,
congenital malformation, low 5-minute Apgar score, feeding difficulties, meconium
aspiration, neonatal anemia, ABO or Rh incompatibility, and hyperbilirubinemia. Factors
not associated with autism risk included anesthesia, assisted vaginal delivery, postterm
birth, high birth weight, and head circumference (Gardener et al 2011).
There has been extensive speculation regarding non-heritable preconception and/or
prenatal risk factors such as obstetric complications, maternal infections, maternal
ingestion of pharmaceutical agents, and occupational exposure. There has also been
speculation regarding postnatal exposure to chemicals, infection, vaccines, and
mercury. However, at this time there is limited evidence regarding these risk factors
(Newschaffer et al 2002). A controversial study published in The Lancet in 1988 by
Wakefield suggested that toxic neuropeptides, which crossed the blood-brain barrier,
caused regressive signs (Wakefield 1998), and the report hypothesized that the MMR
(measles antigen) caused inflammation leading to absorption or symptoms of autism
(Elliman and Bedford 2001; Madsen et al 2002). Subsequent population-based studies
have revealed that although the subject has received a great deal of attention in the
media, the MMR vaccine has not been linked to autism in the empirical literature
(Madsen and Vestergaard 2004).
In summary, the proportion of patients with autism who have a known genetic etiology is
small. There is considerable evidence that genetic factors are important, even though
no single genetic mechanism has been identified as yet to identify the preponderance of
cases. Immunologic, prenatal, postnatal, and genetic factors are also thought to play a
role in the pathophysiologic mechanisms of autistic spectrum disorders (Hollander et al
1998). Individuals with congenital rubella, congenital cytomegalovirus infection, and
certain genetic disorders such as fragile X, tuberous sclerosis, untreated
phenylketonuria, and possibly neurofibromatosis are at increased risk to develop autism
or to have autistic behavior. Family members of autistic individuals are also at greater
risk for autism or other related cognitive or psychiatric disorders. Genetic counseling for
the family of the autistic patient and, in the case of phenylketonuria, dietary intervention,
is of potential value with respect to treatment and prevention (Ronald et al 2005).

Epidemiology
Article section 7 of 14. Previous Next
By Caroline DiBattisto MD
Autism spectrum disorders are one of the most common neurodevelopmental diseases
in children. Surveillance data were published in December 2009 from the Centers for
Disease Control and Prevention Autism and Developmental Disabilities Monitoring
Network, which revealed that the estimated prevalence of autism spectrum disorders in
the United States is 1 in 110 children (Autism and Developmental Disabilities Monitoring
Network Surveillance Year 2006 Principal Investigators 2009). This is significantly
higher than in previous surveillance estimates, with an average 57% increase from the
2002 to 2006 data collection years. Autism spectrum disorder prevalence was higher in
males, with a 4.5:1 male-to-female ratio. The average prevalence also varied by race
and ethnicity. Non-Hispanic white children had a higher prevalence than non-Hispanic
black children and Hispanic children.
Fombonne conducted a review of 43 studies published since 1966 investigating the
epidemiology of autism and other pervasive developmental disorders (Fombonne 2003).
Based on this review, prevalence of all pervasive developmental disorders (autistic
disorder, Asperger disorder, pervasive developmental disorder not otherwise
specified, and childhood disintegrative disorder) is estimated to be approximately 60 to
70 per 10,000. The prevalence of specific diagnoses is estimated to be: Autistic
disorder, 20 per 10,000; PDD-NOS, 30 per 10,000. Childhood disintegrative disorder is
rare (about 2 per 100,000 children). A number of studies have revealed a trend toward
increased referral and diagnosis of autism. Possible reasons for the steady rise in
prevalence include increased awareness of the disorder among front line professionals
such as primary care physicians and teachers, increased services, and a general
broadening of the diagnostic criteria used in more recent studies. Expertise has
improved in distinguishing autism from severe mental retardation, and some children
labeled in the past as mentally retarded are now being diagnosed as having autistic
spectrum disorder (Yeargin-Allsopp et al 2003). However, the possibility of a true
increase in incidence has not been conclusively ruled out.
There is no evidence that cases cluster in particular geographical regions. There is also
no evidence that the disorder clusters in terms of race, ethnicity, or social class
Differential diagnosis
Article section 9 of 14. Previous Next
By Caroline DiBattisto MD

A hearing test should be conducted because autism spectrum disorders can sometimes
be confused with hearing impairment. In some cases, behavioral problems may prevent
the child from participating in typical hearing assessments. Alternative methods such as
measuring auditory brainstem evoked responses can be employed in these cases (Klin
1993). Other pervasive developmental disorders should be distinguished from autistic
disorder. Rett syndrome may be identified through genetic testing. After a period of
normal development, head growth decelerates between the ages of 5 and 48 months;
there is a loss of previously acquired purposeful hand skills with subsequent midline
stereotypic wringing or hand washing movements, breath holding spells, and
development of loss of motor skills. Difficulties in social interaction develop with the skill
regression. Severe expressive and receptive language impairment and severe
psychomotor retardation may also be present (Volkmar et al 1996).
In childhood disintegrative disorder, autistic symptomatology appears after a period of
normal development until 2 to 4 years of age, and is accompanied by profound
developmental regression in language (both expressive and receptive), motor skills,
play, and social or adaptive skills (eg, bowel and bladder control). Childhood
disintegrative disorder has a very low incidence with only about 100 cases described in
the literature since Heller's report in 1908. In most cases, extensive evaluation reveals
no neuropathic process or associated medical condition (Volkmar et al 1996).
Asperger disorder can be distinguished from autistic disorder by a lack of significant
delay in language and cognitive development and by the development of ageappropriate self-help skills, curiosity about the environment, and adaptive behaviors
other than in social interaction. Verbal IQ is often significantly greater than performance
IQ. There is overlap with the neuropsychological concept of nonverbal learning disability
(Eisenmajer et al 1996; Volkmar et al 1996).
Schizophrenia, selective mutism, developmental language disorders, severe mental
retardation, stereotypic movement disorder, complex motor tics, and obsessive
compulsive disorder also fall under the differential diagnosis. Childhood schizophrenia
typically develops at a much later age and shows a regression from previous
functioning. These children show relatively good social relationships, but exhibit thought
disorder and active-phase symptoms including prominent delusions or hallucinations
that last for at least 1 month. In selective mutism, the child may be withdrawn, but
speaks normally in some situations and does not show severe impairment in social
interactions, interpersonal relationships, and play as seen in autistic disorder (Volkmar
et al 1996). In developmental language disorders, language impairment is not
associated with impairment in social interaction and behavior. Finally, an examination of
the social history and parent-child dyad must rule out reactive attachment difficulties as
the etiology of autistic like behavior.

It may be difficult to determine if the additional diagnosis of autistic disorder is warranted

in severe or profound intellectual disability. If there are qualitative deficits in social and
communication skills for level of cognitive functioning, and the specific behavioral
characteristics of autistic disorder are present, an additional diagnosis of autistic
disorder can be considered. The compulsive, perseverative, or self-stimulatory behavior
of a person with intellectual disability can look "autistic-like," yet the other impairments
typical of autism are absent. The ritualistic behavior of a person with intellectual
disability with obsessive-compulsive disorder may be confused with the repetitive and
stereotypic pattern of behavior of an autistic person. Typically, there is no qualitative
impairment in social interaction and communication in an individual with obsessivecompulsive disorder and intellectual disability.
As motor stereotypies are common in autistic disorder, an additional diagnosis of
stereotypic movement disorder is not appropriate. Motor stereotypies of autistic disorder
may be difficult to distinguish from complex motor tics present in various tic disorders,
such as Tourette syndrome and chronic motor or vocal tic disorder. This differential
diagnosis is further complicated by the presence of associated learning problems,
obsessive-compulsive behaviors, and overactivity sometimes associated with tic
disorders. The primary differentiating factor in these cases includes a history of social
deficits, communication problems, and unusual behaviors prior to 3 years of age in
autism versus repetitive movements, obsessive behaviors, and other difficulties arising
later in childhood in tic disorders (typically around 6 years of age)
Diagnostic workup
Article section 10 of 14. Previous Next
By Caroline DiBattisto MD
An interdisciplinary assessment is required for a comprehensive diagnostic evaluation
of individuals suspected of having autistic spectrum disorders. This includes an etiologic
workup, an assessment of strengths and weaknesses, and an individualized treatment
plan that includes educational, behavioral, pharmacological, social, and other indicated
medical interventions.
Screening instruments. Despite behavioral signs of autism being present in the first
year of life, the estimated age of diagnosis is 3 to 4 years of age (Autism and
Developmental Disabilities Monitoring Network Surveillance Year 2006 Principal
Investigators 2009; Barbaro and Dissanayake 2009). Early intervention is crucial, thus,
there has been a movement to develop brief screening instruments that can be used in
primary care settings to determine whether a child should be referred for a more
comprehensive evaluation. The American Academy of Pediatrics recommends that an
autism-specific standardized screening tool be administered at the 18- and 24-month

health maintenance visits (Johnson and Myers 2007). The Checklist of Autism in
Toddlers was developed to screen and identify toddlers as young as 18 months of age
for autism (Baron-Cohen et al 1992). Despite high specificity, its sensitivity has been
relatively low, and many children with the disorder are not identified by this instrument
(Baird et al 2000). To address these problems, the Modified Checklist for Autism in
Toddlers (M-CHAT) was developed for children ages 16 to 30 months. The M-CHAT is
a short parent checklist and appears to provide good discrimination between children
with and without autism (Robins et al 2001). For children over the age of 4 years, The
Social Communication Questionnaire has been found to be an effective screening
instrument (Eaves 2006). The Communication and Symbolic Behavior Scales
Developmental Profile (CSBS DP) is not autism-specific, but it is a useful parentcompleted screening tool to evaluate eye gaze, gestures, sounds, words,
understanding, and play in children 6 to 24 months of age (Wetherby and Prizant 2002).
The Screening Tool for Autism in Two-Year-Olds (STAT) is an interactive screening
measure for autism that assesses play, communication, and imitation skills.
Psychometric properties include acceptable levels of interrater agreement, test-retest
reliability, and agreement between STAT risk category and Autism Diagnostic
Observation Schedule (ADOS)-G classification (Stone et al 2004). The STAT has also
been studied in children younger than 2 years of age (Stone et al 2008). In this study,
71 children received the STAT between 12 and 23 months of age and a follow-up
diagnostic evaluation after 24 months. All had an older sibling with an autism spectrum
diagnosis (n=59) or had been referred for evaluation for concerns about autism (n=12).
Signal detection analysis resulted in a cut score of 2.75 for this sample, which yielded a
sensitivity of 0.95, specificity of 0.73, positive predictive value of 0.56, and negative
predictive value of 0.97. False positives were highest for the 12- to 13-month-old age
group.
History and examination. A detailed history should be obtained with particular
emphasis on specific symptoms typical of autism and on differential diagnosis,
associated features, early development, course of development, and progress.
Information should also be obtained regarding history of maternal infections during
pregnancy, perinatal or postnatal insult to the patient's brain, meningitis, encephalitis, or
seizures. An inquiry should be made into family history of autism and other genetic
disorders, related developmental disorders, or psychiatric disorders.
Physical examination should include assessment of any dysmorphic features or signs of
specific disorders such as fragile X syndrome, tuberous sclerosis, congenital rubella,
Rett syndrome, or other genetic disorders that may be responsible for the child's autistic
symptomatology. Neurologic examination may reveal associated soft neurologic signs
and sensorimotor deficits. Mental status examination should attempt to assess: (1) the
child's relatedness to and interest in the professionals, caregivers, siblings, peers, and

other people in the child's environment; (2) the quality of reciprocal social exchange in
verbal and nonverbal communication (eye contact, gestures, facial expression,
stereotyped speech, echolalia, pronominal reversal); (3) the child's ability to engage in
reciprocal imaginative play with representational toys; (4) the presence of perseverative,
stereotypic, and ritualistic behavior; and (5) the presence of problematic behaviors, such
as attentional difficulties, high activity level, aggression, and self-injurious behavior. Any
child presenting with self-injurious head banging should be evaluated for the presence
of otitis media, sinus infection, and pinworms, which are sometimes a causal factor in
this behavior.
Autism-specific assessment instruments. A comprehensive assessment should
include both parent interview and child observation. Many autism diagnostic instruments
of varying reliability and validity are available. Parent report instruments include
checklists, and parent interviews such as The Autism Diagnostic Interview-Revised
(Lord et al 1994). Standardized child observation instruments include The Childhood
Autism Rating Scales (Schopler et al 1988) and the Autism Diagnostic Observation
Schedule (Lord et al 1994; DiLavore et al 1995). The Childhood Autism Rating Scales is
intended to provide a measure of autism severity whereas the Autism Diagnostic
Observation Schedule is intended to serve as a diagnostic instrument. Training is
required to ensure reliability on both of these instruments.
Cognitive assessment. Assessment of the child's current level of cognitive functioning,
adaptive and maladaptive behaviors, language skills, and educational strengths and
weaknesses is crucial in treatment planning. Alternative test batteries like the
Differential Abilities Scale-II, the Mullen Scales of Early Learning, and the Leiter
International Performance Scale - Revised should be considered if a standard test
battery, such as the Wechsler scales (WPPSI-III and WISC-IV) and the Stanford-Binet:
5th Edition cannot be used due to limited linguistic and cognitive skills.
The Vineland Adaptive Behavior Scales, 2nd Edition is a commonly used measure of
adaptive functioning. Assessment of adaptive behavior can serve to monitor progress
over time and settings and as an outcome measure of interventions. Assessment of the
socialization domain helps to quantify social deficits characteristic of autism. A formal
speech and language evaluation should be done to assess the formal aspects of
language (eg, articulation, vocabulary, and syntax), as well as vocal intonation,
inflection of voice, use of linguistic skills for communication purposes, pragmatics,
narrative-discourse performance (in children with higher verbal functioning), and
nonverbal communication. For the nonverbal or primarily echolalic child, the
communication specialist will need to obtain information about the child's prelinguistic
skills and communicative resources.

A formal educational assessment should be obtained in the school-aged child utilizing

tests to measure both comprehension and rote learning, as children with autism often
lag behind in their understanding. This assessment will be helpful in planning an
individualized educational program for the child and in providing specific guidelines for
intervention to the classroom teacher. A formal behavioral assessment and consultation
by a behavioral specialist may be needed to recommend specific interventions and
strategies if the child presents with behavioral problems that interfere with learning or
adaptation to the classroom or the home, or presents a potentially dangerous situation
for the child or others, as assessment of behaviors potentially injurious to the patient
and others must be addressed.
Medical investigation. Hearing should be tested, especially if there is speech delay. If
the child is unable or unwilling to cooperate with audiometry, the initial test is suboptimal
or equivocal, or suggests CNS abnormality, hearing should be tested with brainstem
auditory evoked response.
Genetic testing is recommended for children diagnosed with an autism spectrum
disorder. Chromosome analysis and fragile X testing are recommended due to the
genetic implications for other family members. The diagnostic yield of chromosomal
microarray was compared with G-banded karyotype in a cohort of over 900 patients
(Shen et al 2010). Microarray identified deletions or duplications in 18.2% of patients,
with 7.0% considered abnormal, which includes variants associated with known
genomic disorders or variants of possible significance. Karyotype yielded abnormal
results in 2.23% of patients, and fragile X testing was abnormal in 0.46% of patients.
Wake and sleep EEG should be obtained if the history is suggestive of seizures,
behavioral regression, or loss of language. Metabolic screening, amino acid
chromatography, serological tests for evidence of intrauterine infections such as
toxoplasmosis or cytomegalic disease, and tests for phenylketonuria, serum copper,
and ceruloplasmin are indicated if autistic symptoms appeared after 3 years of age or
are progressive. Routine MRI, CT, and PET scanning may have some research
implications, but have limited clinical utility because information obtained is unlikely to
change management strategy (Hollander et al 1998).
Other consultations (eg, neurology, endocrinology, developmental pediatrics,
psychology, psychiatry, occupational therapy, and physical therapy) may be indicated
based on a particular patient's symptomatology.
Autism spectrum disorders
Prognosis and complications
Article section 11 of 14. Previous Next

By Caroline DiBattisto MD
Autism spectrum disorders are typically considered a disorder of childhood; however,
most persons have significant functional impairment throughout life. A long-term
outcome study of individuals with IQs above 50 revealed a range of outcomes, with
approximately 12% having a very good outcome and needing no support in daily
living, and an equal number having a very poor outcome requiring hospital-level support
(Howlin et al 2004). The remaining 76% required some level of support in daily living.
Not surprisingly, IQ above 70 was consistent with a more positive outcome than IQ
below 70. Language and nonverbal skills at 4 to 6 years of age appears to be a good
predictor of response to intervention (Szatmari et al 2003).
A broad range of syndrome expression is seen in autism spectrum disorders.
Symptoms can change over the course of development and in relation to associated
mental disabilities.
With treatment there may be improvement in social functioning. Patients may develop
improved social relatedness and communication, but it is rarely of normal quality or
quantity. Behavior problems often become more prominent during elementary school
years. There may be either a severe regression or a marked gain in skills and behavior
during adolescence. Deterioration reported during adolescence in 12% of autistic
subjects may be explained by the onset of major motor or complex partial seizures
(Lockyer and Rutter 1970).
Evidence suggests that intensive early intervention (ie, beginning by 3 years) is a key
factor in promoting positive outcomes for individuals with autism (Anderson and
Romanczyk 2000). Early intervention for children with autism began in the 1970s, but
did not become common until the last decade. Additionally, increased awareness about
autism has also aided in early identification so more children are now benefiting from
early intervention. Therefore, the prognosis of individuals diagnosed with autism today
may be more positive than suggested by earlier studies.
Management
Article section 12 of 14. Previous Next
By Caroline DiBattisto MD
Early intervention should begin early focus on teaching new skills and reducing problem
behaviors. In the following sections, we will review comprehensive treatment
approaches for autism, general curriculum planning, family support, pharmacological
interventions, and alternative treatment approaches.

Comprehensive treatment approaches. Dozens of treatment programs are available

that are designed specifically for individuals with autism, but few have had reliable
outcome studies reported. Whichever program is considered, it should be
comprehensive in nature and should address the child's difficulty with learning adaptive
skills, appropriate social behaviors, and communication. Currently, major treatment
approaches for autism include applied behavior analysis (McEachin et al 1993),
interactive approaches such as Floor Time (Greenspan and Wieder 1997), and the
environmentally structured TEACCH Program (Lord and Schopler 1994). The treatment
with the most research support is applied behavior analysis. Comprehensive behavioral
treatment has been described by Lovaas and Smith (Lovaas and Smith 1989). Briefly,
applied behavior analysis involves setting individualized goals for the child and teaching
skills by breaking them down into small steps. Teaching techniques are based on
scientifically derived principles of behavior. Applied behavior analysis can be
implemented in a variety of ways including discrete trial teaching, individualized
instruction, group interventions, and incidental teaching. Numerous studies have
investigated the use of intensive applied behavior analysis with children with autism
(Anderson et al 1987b; Lovaas 1987; Birnbrauer and Leach 1993; McEachin et al 1993;
Smith et al 1997; Sheinkopf and Siegel 1998) The outcomes of these studies showed
that the children receiving applied behavior analysis treatment made significant gains in
areas such as cognitive functioning, language, social interaction, and adaptive skill
development. Anderson and Romanczyk reviewed the existing research regarding
applied behavior analysis and concluded that a clear and considerable body of evidence
exists to support the use of applied behavior analysis with children with autism
(Anderson and Romanczyk 2000).
Floor Time is a child-directed therapy that aims to teach the 6 fundamental milestones
that are the basis of Greenspans Developmental-Individual Difference model. In order
to address the lack of communicative ability in children with autism, parents may be
asked to set aside regularly scheduled short periods of "floor time" to play with their
child, with emphasis on promoting purposeful and positive reciprocal social exchange
(Greenspan and Greenspan 1989). A chart review of 200 children with autism or
pervasive developmental disorder has been used as support for the floor time model
(Greenspan and Wieder 1997). However, the study lacked experiment control, did not
use a validated outcome measure, and was based on the progress evaluation of a
single clinician who was not blind to the hypotheses of the review.
The TEACCH (Treatment and Education of Autistic and Related Communication
Handicapped Children) Program was developed at the University of North Carolina at
Chapel Hill. The program is based on the use of a structured teaching curriculum and
extensive environmental modifications and supports. A number of studies have followed

young children receiving TEACCH services and have described good outcomes.
However, direct treatment outcome studies have not been reported.
Given the theoretical and practical differences in the major treatment approaches to
autism, some authors have attempted to identify common elements of successful
programs. Dawson and Osterling reviewed outcome studies for 8 comprehensive
treatment programs and found that comparison is difficult as the programs used
different tools to measure effectiveness (Dawson and Osterling 1997). Different
intelligence measures were used, and some programs only reported developmental
gains. Many reported post-preschool placement into regular education classes but did
not report on the extent or type of support required to maintain the child in that class.
The authors concluded that all of the programs were effective in improving
development, increasing IQ scores, and in placing a significant number of children in
regular education classes despite their wide philosophical differences. Successful
programs have common elements that address the "core" needs and deficits of persons
with autism, including:
(1) A structured curriculum teaching methods for paying attention to environmental
stimuli and other people, motor and verbal imitation, ability to comprehend and use
language, ability to play with toys appropriately, and ability to socially interact with
others.
(2) These skills need to be taught in a highly structured environment with a low staff-tochild
ratio
(1:2,
1:1).
(3) Children with autism become more open to learning and more attentive when
information is presented in a structured predictable routine. They can become disruptive
when the same information is presented in an unpredictable fashion.
(4) Inappropriate and disruptive behaviors should be evaluated by a functional
assessment of the problem behavior and by teaching alternative appropriate behaviors
that serve the same function for the child. Initially, a detailed record of the behavior is
made. Based on patterns of the behaviors, hypotheses are generated regarding the
function of the behaviors. Then, changes are made in the environment to support
appropriate behaviors, and the child is taught skills to cope with the situation with
emphasis
on
using
communication.
(5) Support with the transition from preschool to kindergarten or first grade. This move is
challenging for children with autism due to difficulty in making changes and generalizing
previously
acquired
skills
to
new
locations.
(6) The child's family is instrumental in the success of a curriculum and must be viewed
as a critical part of the intervention team (Dawson and Osterling 1997).
Curriculum development. Because individuals with autism present with differing
problems and needs, educational interventions must be individualized and must be
based on the childs unique pattern of strengths and weaknesses. A comprehensive and

appropriate educational plan for a child with autism should include assessment and
intervention in all of the following areas: communication, social skills, cognitive skills,
sensory and motor development, adaptive behaviors, and problem behaviors.
Direct speech training using discrete trials, natural language paradigms, or incidental
teaching is most effective when there is evidence of some limited language, gesturing,
or prelinguistic skills. Alternative modes of communication (sign language, augmented
communication) should be introduced if there is little or no progress in speech. One
popular approach to augmentative communication is the Picture Exchange
Communication System program (Bondy and Frost 1994). The program involves
teaching children to exchange pictures in order to fulfill wants and needs (eg, handing
an adult a picture of a toilet to indicate the need to use the restroom). Research
suggests that the use of augmentative communication systems (eg, Picture Exchange
Communication System, sign language) do not interfere with the development of
spoken language and can promote the use of speech in some children.
Children with autism typically need direct social skills training to help address social
deficits. Social skills interventions vary widely across intervention programs. Intervention
approaches include parent training, peer training, various forms of modeling, groups,
and direct instruction in social skills. Behaviorally based programs tend to begin by
teaching individual social behaviors such as eye contact and play skills and to progress
toward integration of the these skills over time. Greenspans floor time model focuses
on the improving the quality and positive balance of interactions between the child and
adult. The TEACCH program emphasizes participation in group activities to build skills.
Like all parts of the educational plan, cognitive goals must be individualized and must
be based on the individuals current level of functioning. Academic goals such as
reading and math skills are made based on assessment of the individuals ability level.
For teenagers and young adults, it is particularly important to provide vocational
counseling and training. Higher functioning individuals may be able to hold jobs or
attend college. Other individuals may do well in supported employment situations.
Children with autism may display unusual sensory responses and may have motor
planning and apraxia difficulties. For these children, the curriculum should include
focused intervention for gross and fine motor skills, balance, and use of gestures.
Children with these needs are often provided with physical or occupational therapy.
Sensory integration therapy is considered an alternative therapy, but anecdotally has
been reported to be beneficial in alleviating hypersensitivity to touch, sound, and smell.
However, no evidence-based outcome studies have been published supporting the use
of sensory integration with children with autism or related disorders such as mental
retardation, language disorders, and learning disabilities.

Most intervention programs focus on teaching adaptive behaviors such as toilet training,
dressing, and safety skills. The majority of the published research in this area has
focused on the use of behavioral strategies to teach and maintain adaptive behaviors.
When maladaptive behaviors are a concern, the childs educational curriculum should
include specific plans to remediate these behaviors. Behavioral approaches are the
mainstay of treatment to reduce rigidity, stereotypy, and perseveration and to eliminate
maladaptive behaviors such as tantrums, aggression, and self-injurious behavior.
Problem behaviors often viewed as maladaptive ways of communicating typical needs
for an individual with limited communication and social skills. Therefore, behavioral
treatment methods must be adapted to each child's specific circumstances. After a
functional analysis of the target behaviors, an intervention plan is developed that
typically includes changes in the antecedents and consequences to the behavior. For
example, antecedent visual cues can be used to help a child predict and manage
change (eg, use of a picture schedule). Similarly, positive consequences can occur
when the child makes an adaptive, alternative response to the problem behavior (eg,
holding up a break card rather than having a tantrum). Data are often gathered to
investigate whether a particular intervention is having the desired effect. Frequently,
negative behaviors cannot be completely eliminated, so a realistic goal might be a 75%
reduction from baseline (Coucouvanis 1997). Care must be taken to avoid premature
misuse and abuse of aversive procedures (Elder 1996). Stereotypies tend to increase in
unstimulating environments and unstructured situations; hence, structured stimulating
environments help to encourage more socially accepted behavior. The frequency and
duration of target behaviors must be specific and measurable with baseline
measurements.
Family support. It is important to alleviate family distress by helping the family gain an
understanding of their child's behavior. Myths and misplaced guilt regarding the etiology
of autism can contribute to marital, individual, and sibling stress. Family members need
to be engaged as co-therapists in the child's treatment and fully participate in the child's
education, language and socialization development, and behavior management.
Families need professional and personal support to help them deal with guilt and
frustration, and with slow or seeming lack of progress. They must advocate for their
child's educational needs, and for their financial needs for various therapeutic
interventions. They need respite care to enable them to attend to other members of the
family. There are many self-help and support groups available through the local
branches of the Autism Society of America.
Pharmacotherapy. Pharmacological interventions to reduce or eliminate maladaptive
and injurious behaviors have an important role in the treatment of autism, and now there
is a body of literature to guide clinical treatment (Aman et al 1995; Scahill 2006; Myers
2007). It is imperative that pharmacotherapy be instituted only in conjunction with a

comprehensive individualized behavioral and family treatment program and it is

suggested that behavioral interventions be implanted prior to the initiation of any
psychopharmacologic interventions. However, pharmacological intervention may
increase the ability of persons with autism to benefit from educational and other
interventions (McDougle et al 1997). It is important to note that medications are not
specific to autism and do not treat core aspects of the disorder. However, novel
pharmacotherapies to address the social impairment in autism spectrum disorders are
under investigation (Wink et al 2010).
For clinical purposes, target symptoms include attentional problems; aggression;
ritualistic, stereotypic, self-injurious behavior; and seizures. Extreme care should be
taken in the selection and administration of medications (American Academy of Child
and Adolescent Psychiatry 1999). Persons with autism are sometimes nonverbal, and,
therefore, reliance on reports and observations of specific behaviors is common. It is
essential to rule out coexisting medical problems, ie, head banging due to otitis media
versus self-stimulation related to autism. Close follow-up of targeted treatment
symptoms is recommended to evaluate the efficacy of medication, side effect profile,
safety, and continued need for medication. An Abnormal Involuntary Movement Scale
test is needed each visit if the patient is on a neuroleptic (Guy 1976). No clear end point
of medication administration exists because of the lifelong nature of the disorder.
Neuroleptics. Risperidone and aripiprazole have been approved by the FDA for the
treatment of irritability associated with autism spectrum disorders (Wink et al 2010).
Risperidone, an atypical antipsychotic that is a potent dopamine D2 or serotonin (5HT)
receptor antagonist with powerful antipsychotic properties, was approved for individuals
5 to 16 years of age with autism and disruptive behavior for the treatment of tantrums,
aggression, and self injury (United States Food and Drug Administration 2006). In a
multisite, randomized, double-blind trial by the Research Unit on Pediatric
Psychopharmacology Autism Network, 101 children were randomly assigned to receive
risperidone or placebo for an 8-week trial. Risperidone was found to be well tolerated for
the treatment of tantrums, aggression, and self-injurious behavior (McCracken et al
2002). A review of 4 double-blind, placebo-controlled studies and 24 open-label,
observational or retrospective trials regarding the efficacy of risperidone revealed that
risperidone is efficacious in treating irritability, aggression, hyperactivity, and stereotypy.
However, the medication does not improve social skill and communication deficits
(Chavez et al 2006). All studies identified weight gain to be the most significant side
effect with a few patients experiencing sedation. Risperidone was generally well
tolerated, extrapyramidal effects being relatively rare and occurring primarily at high
doses. In addition, retrospective chart reviews and an 8-week prospective study
demonstrated improvement in youth with bipolar illness (Frazier 1999; Biederman
2005).

Aripiprazole, an atypical antipsychotic agent with a relatively high affinity for dopamine
D2 and D3 receptors and serotonin 5-HT1A and 5-HT2A receptors, was approved by
the FDA in 2009 for the treatment of irritability associated with autism spectrum
disorders in children ages 6 to 17 years. The indication was based on data from two 8week, randomized, double-blind, placebo-controlled, multicenter Phase III studies in
which aripiprazole, compared to placebo, significantly improved scores on the Irritability
subscale of the caregiver-rated Aberrant Behavior Checklist and Clinical Global
Impressions-Improvement score (Marcus et al 2009; Owen et al 2009). In these studies,
dosing started at 2 mg and increased to a maximum of 15 mg, as tolerated. Aripiprazole
has a relatively lower risk for weight gain, but body mass index and metabolic profiles
should be monitored with both risperidone and aripiprazole (Wink et al 2010).
There are relatively few studies in this population of treatment with other atypical
antipsychotics. Olanzapine has been used in treating disruptive behavior in adolescents
(N=16) with subaverage intelligence during an 8-week label prospective trial (Handen et
al 2006). A 13-week open-label trial with olanzapine (N=40) in children 7 to 17 years of
age showed improvement from baseline on the Aberrant Behavior Checklist and the
Clinical Global Impressions-Severity score (Fido and Al-Saad 2008). A small, 8-week
placebo-controlled trial of olanzapine was conducted in children ages 6 to 14 years
(N=11) with an autism spectrum disorder (Hollander et al 2005). The authors concluded
olanzapine was promising for the treatment of autism spectrum disorders; however,
significant weight gain is a concern.
An open-label clinical trial of quetiapine, another atypical antipsychotic, was completed
in 6 children and adolescents with autism. After the 16-week trial, it was concluded that
the group as a whole displayed no statistically significant improvement between
baseline and endpoint; additionally, quetiapine was poorly tolerated and associated with
serious side effects (behavioral activation, hyperphagia, weight gain, and seizure in 1
participant) (Martin et al 1999). This medication is an antagonist of multiple
neurotransmitter receptor sites including serotonin, dopamine, D1 and D2 histamine,
and alpha1 and alpha2 receptors, but was not very useful in this study. A 16-week,
open label study of quetiapine (Martin et al 1999) and a 12-week study (Findling et al
2004) of youth with autism found it to be poorly tolerated and not particularly effective.
Ziprasidone is another atypical that may show promise. It is, however, associated with
increases in the QTc interval. A retrospective chart review by Staller and an open label
study by McDougle and colleagues of 12 subjects found it to be useful for aggression,
agitation, and irritability (McDougle et al 2002; Staller 2005). Twelve adolescents with
autism were treated in a 6-week open-label pilot study (Malone et al 2007). Ziprasidone
dosage ranged from 20 to 160 mg/day. Nine of the twelve (75%) patients responded to
treatment based on the Clinical Global Impressions-Improvement item. Ziprasidone was

weight neutral, and the QTc increased by a mean of 14.7 msec. Two of the subjects had
acute dystonic reactions; cholesterol decreased and prolactin remained the same.
Clozapine has a significant associated risk of agranulocytosis and seizures and is,
therefore, not recommended for routine use (Fisman 1997). It, however, has had no
reports of tardive dyskinesia, which is thought to be related to the pure dopamine
mechanisms of action.
Weight gain was a significant issue in all studies and olanzapine has been shown to
pose the greatest risk for this effect. In general, the newer atypical antipsychotic
medications appear to pose less long-term risk of undesired side effects and show
promise in treatment of autism. However, epidemiologic studies suggest an increased
risk of treatment-emergent hyperglycemia related to adverse events (ie, marked weight
gain) (Physicians Desk Reference 2006).
The D2 antagonists, haloperidol at 0.25 to 4 mg/day (Campbell et al 1978; Joshi et al
1988; Anderson et al 1989) and pimozide at 1 to 9 mg/day (Naruse et al 1982), have
been shown to decrease symptoms of withdrawal, stereotypies, hyperactivity,
fidgetiness, negativism, and angry affect. The typical neuroleptics are used less
frequently for autism spectrum disorder due to the higher risk of serious side effects.
Thioridazine is the most useful of the low-potency traditional neuroleptics in decreasing
aggression and agitation (Fisman 1997). These medications have also been shown to
increase relatedness and facilitate discrimination learning due to their effects on
attentional mechanisms (Frazier 2002). Moban is the only weight neutral traditional
neuroleptic and it has been found to be useful in this population (Frazier, personal
communication, 2000). However, traditional neuroleptics should be used with caution
and preferably limited to short-term acute management due to the increased risk for
many adverse and potentially irreversible long-term side effects such as tardive
dyskinesia and neuroleptic malignant syndrome. It appears that greater cumulative
haloperidol dose, or longer exposure to haloperidol, or both, may increase the risk of
dyskinesias (Campbell et al 1997).
Selective serotonin reuptake inhibitors. The selective serotonin reuptake inhibitors
(SSRIs) inhibit serotonin transport and were initially of interest because of the relatively
consistent finding of high peripheral serotonin levels in this population. An analysis of 7
randomized controlled trials of SSRIs in participants with autism spectrum disorders
was conducted by Williams and colleagues (Williams et al 2010). There were a total of
271 subjects and 4 different medications (fluoxetine, fluvoxamine, fenfluramine, and
citalopram. Five of the studies included only children. Due to different outcome
measures used in the studies, a meta-analysis could not be completed. A large,
randomized placebo-controlled study of citalopram in children with autism spectrum
disorders showed no benefit on the Clinical Global Impressions-Improvement subscale,

or on the Children's Yale-Brown Obsessive Compulsive Scales modified for pervasive

developmental disorders (King et al 2009). In addition, the treatment group had
significantly more adverse effects, including increased energy level, impulsiveness,
decreased concentration, hyperactivity, and stereotypy. Simon and colleagues provided
an excellent review of the FDA black box warning for antidepressants (Simon et al
2006).
Other studies of SSRIs in this population have shown improvements in global
functioning, stereotypy, and anxiety reduction (Kolevzon et al 2006). Fluoxetine has
been evaluated in several open-label and case report studies, as well as a placebocontrolled double-blind crossover trial in children and adolescents with autism spectrum
disorders. Forty-five children were randomized into two 8-week trials of fluoxetine and
placebo. Low-dose liquid fluoxetine (mean final dose: 9.9+/-4.35 mg/day) was superior
to placebo in the treatment of repetitive behaviors by Childrens Yale-Brown Obsessive
Compulsive Scale (Hollander et al 2005). Cook and colleagues found that fluoxetine
was associated with an improved level of functioning for persons with autism or mental
retardation (Cook et al 1992). Fatemi and colleagues noted improvement in irritability,
lethargy, stereotypy, and inappropriate speech (Fatemi et al 1998). DeLong and
colleagues studied 37 children with autism; 22 of the 37 children had a beneficial
treatment response to fluoxetine in behavioral, language, cognitive, affective, and social
domains. It was also noted that response to fluoxetine strongly correlated with a family
history of affective disorder. On extension of the study, of 68 patients, 71% were found
to be positive responders (DeLong et al 1998).
Selective serotonin reuptake inhibitors have been used in attempts to reduce libido in
masturbating males (Levitsky and Owens 1999). A survey of 89 adults with autism living
in group homes in North Carolina found most were involved in masturbation with one
third being involved in person oriented behavior (Van Bourgondien et al 1997). Reports
of use of an injectable testosterone-suppressing agent, leuprolide, have been reported
to help decrease sexual behaviors that threatened placement (Realmuto and Ruble
1999). This followed behavioral and educational programs. One case report suggests
mirtazapine for decreasing excessive masturbation in an adolescent with autism
(Nguyen and Murphy 2001).
Obsessive-compulsive disorder-type features appear to be in a spectrum with features
of perseveration. Diagnostics of a specific disorder versus a need for sameness have
similar clinical features but it is unclear if the same corticostriatal-thalamocortical
circuitry explains the biological mechanisms of the behaviors (Towbin 2003).
Fluvoxamine and clomipramine are medications more specific to obsessive-compulsive
disorder-type behaviors. Fluvoxamine was administered to 30 adults with autistic
disorder in a 12-week, double-blind, placebo-controlled trial. Fifty-three percent were
categorized as responders with significant reduction in repetitive thoughts and behavior,

maladaptive behavior, aggression, and in improvement in some aspects of social

relatedness, especially language usage. Mild sedation and nausea were the only
reported side effects, suggesting it is well tolerated in children and adults with autism
(McDougle et al 1996). Preliminary impressions are that selective serotonin reuptake
inhibitors can be used to decrease repetitive behavior, or anxiety, or both, serious side
effects are rare and behavioral activation is common (Scahill 2006). Clomipramine is
also a potent inhibitor of the serotonin transporter but is a tricyclic medication. In a
randomized, crossover study of children with autism, clomipramine was found to be
superior to desipramine in decreasing overactivity and obsessive-compulsive
symptomatology (Gordon et al 1992). In a series of case reports, McDougle and
colleagues found that 4 out of 5 adolescents and young adults with autism showed
significant improvement in social relatedness, obsessive-compulsive symptoms, and
aggressive and impulsive behavior. Side effects include irritability, aggression, seizures,
and electrocardiographic changes (Gordon et al 1992; McDougle et al 1992). The
potential for seizure exacerbation is clearly a significant risk factor that needs to be
carefully considered (Gualtieri and Johnson 2006).
An open-label clinical study with low-dose venlafaxine (a potent inhibitor of serotonin,
norepinephrine and to a lesser extent, dopamine reuptake) helped to improve social
deficits (range 6.25 to 50 mg/day), repetitive behaviors, communication, inattention, and
hyperactivity in 6 of 10 autistic patients (Hollander et al 2000). Case reports of
venlafaxine in 2 adolescents and a young adult with autistic disorder appeared to
demonstrate improvement in attention deficit hyperactivity disorder-like symptoms
(Carminati et al 2006).
Mood stabilizers. There is some evidence that mania can co-occur with pervasive
developmental disorder (Wozniak et al 1997). However, minimal information and studies
are available concerning the use of lithium or other mood stabilizers. When there is
cyclic irritability and explosiveness, with or without aggression, a trial of lithium or the
anticonvulsant mood stabilizers (valproic acid, carbamazepine) can decrease
symptomatology (Fisman 1997). In general, no major therapeutic benefit has been
noted with lithium for autism per se (Campbell et al 1990) even though there is FDA
approval for use in youth 12 years of age. These are case studies supportive of use for
behavioral control but no empirical research studies. Anticonvulsants are used to treat
seizures, mood lability, and aggression in children with autism in the same way as in
children without autism. The disadvantage of these medications is the need for routine
serum level monitoring, as well as thyroid and renal function tests with lithium, white cell
counts with carbamazepine, and liver function tests and a risk for women of polycystic
ovary syndrome (Sussman and Ginsberg 1998) with valproic acid.
Stimulants. Stimulant medication use in persons with autism is frequent, despite few
studies that have systematically evaluated their efficacy in the autistic population (Aman

et al 1995; Campbell et al 1996). A population-based study found that approximately

50% of individuals with autistic disorder were treated with psychostimulants in Olmstead
County, Minnesota, from 1976 to 1997 (Nickels et al 2008). About 70% of the subjects
reported favorable outcomes, and at least 1 side effect was reported in 66% of the
subjects. Analysis of attention in individuals with high functioning autism found attention
deficit to actually be primary deficits in complex decision making or psychomotor
abilities. A double-blind, crossover study evaluating efficacy of methylphenidate in
children with autism found statistically significant improvement of methylphenidate over
placebo, but with more frequent adverse events. In another study, 8 of 13 children
demonstrated improvement on methylphenidate but adverse side effects of irritability
and social withdrawal were noted while on medication (Quintana et al 1995). Stimulants
can be helpful for short attention span, hyperactivity, and impulsivity in some individuals;
however, close follow-up is needed as stimulants may potentially worsen the behavior
and stereotypies in some individuals with autism. Stimulants can be useful, but less so
than in typically developing children, vulnerability to adverse effects is common, and low
doses may be most useful (Scahill 2006). Venlafaxine has shown early promise with
improvement in hyperactivity in an open study (Hollander et al 2000).
Atomoxetine. An open-label study of 12 children with autistic disorder was conducted
(Charnsil 2011). The participants received atomoxetine for 10 weeks. There was no
change to the hyperactivity subscale of the Aberrant Behavior Checklist compared to
baseline. However, a similar small study found a significant reduction of 21% in the
hyperactivity subscale of the Aberrant Behavior Checklist (Troost et al 2006).
Alpha adrenergic receptor agonists. The hyperarousal behaviors (eg, stereotyped body
movements, self-stimulation, hypervigilance, and hyperactivity) evident with many
individuals with autism have been successfully treated with clonidine, an alpha2
adrenergic receptor agonist, in 2 small, double-blind, placebo studies using oral and
transdermal clonidine. Sedation and fatigue were noted side effects (Fankhauser et al
1992; Jaselskis et al 1992). Tolerance may develop to the sedative but not the
therapeutic effects of clonidine. Guanfacine, another alpha2 agonist, has less sedative
side effects, and this medication has been studied in this population, with irritability
(30%) and sedation (24%) noted (Scahill 2006). A long-acting form of guanfacine has
become available, with an indication for attention deficit hyperactivity disorder. A longacting form of clonidine is available in patch form but dermatologic issues have often
been a concern contraindicating use.
Beta adrenergic blockers. Propranolol can be useful in the management of aggression
in developmental disorders, especially with coexisting agitation and anxiety. The half-life
of propranolol is short (about 4 hours) and, therefore, frequent administration is
necessary. Side effects include hypotension and bradycardia. It can also cause

increased airway resistance; therefore, propranolol is contraindicated in asthmatic

patients and is not frequently used (Fisman 1997).
Opiate blocking agents. Opiate blocking agents have been postulated to reduce selfinjurious behavior, stereotyped and aggressive behavior, and increase prosocial
behaviors. Several studies have explored the efficacy of naltrexone, an opiate blocker,
to address these symptoms (Campbell et al 1989; Kolmen et al 1995; WillemsenSwinkels et al 1996). A review of the literature evaluating the safety and efficacy of
naltrexone in the treatment of autism spectrum disorders found 3 case reports, 8 case
series, and 14 clinical studies. Studies reported doses of 0.5 to 2 mg/kg/day and found
efficacy in decreasing self-injurious behavior. Naltrexone may also help with
hyperactivity, agitation, irritability, temper tantrums, social withdrawal, and stereotyped
behaviors. Patients may also exhibit improved attention and eye contact. Sedation was
the most commonly reported adverse event, and no serious side effects have been
reported (Elchaar et al 2006).
Alternative treatments. The National Standards Project in 2009 sought to classify
treatments for autism into the following categories based on scientific evidence:
established, emerging, unestablished, and ineffective/harmful (National Autism Center
2009). Examples of established treatments include comprehensive behavioral treatment
for young children, schedules, and story-based intervention packages. Emerging
treatments include picture exchange communication system (known as PECS),
language therapy, music therapy, and social skills training. Unestablished treatments
include auditory integration training and the gluten-free casein-free diet. Often wellcontrolled studies have not been conducted, so a treatment continues to be viewed as
experimental due to lack of investigation. Healthcare professionals must communicate
objective findings to parents so they can make the most knowledgeable informed
decisions and avoid potentially costly but unproven treatment. The quest for a cure
can deplete a familys resources, both emotionally and financially.