Autism spectrum disorder (asd) 3

Autism spectrumAutism spectrum
disorder (ASD)disorder (ASD)
Dr Jagan mohan varakalaDr Jagan mohan varakala

a b s t r a c t
On April 2013 experts in the field of autism from Italy and Israel convened in Jerusalem
to discuss and finalize clinical recommendations for early diagnosis and intervention in
Autism Spectrum Disorders (ASDs). In this paper, we summarize the results of this
Italian eIsraeli consensus conference.
ASDs constitute a class of severe and heterogeneous neurodevelopmental conditions
caused by atypical brain development beginning during early prenatal life, reflecting
many genetic, neurobiological and environmental influences. The first clinical signs of
ASDs begin to be evident in children between 12 and 18 months of age, often after a
period of relatively typical postnatal development. Recent longitudinal studies reveal
substantial diversity in developmental trajectories through childhood and adolescence.
Some intervention approaches have been demonstrated to be effective in improving
core symptoms of ASDs, even if the heterogeneity and developmental nature of the
disorder make it implausible that only one specific treatment will be best for all children
with ASDs.

1. Introduction1. Introduction
 Autism spectrum disorder (ASD) manifests inAutism spectrum disorder (ASD) manifests in
early childhood and is characterized byearly childhood and is characterized by
qualitative abnormalities in social interactions,qualitative abnormalities in social interactions,
markedly aberrant communication skills, andmarkedly aberrant communication skills, and
restricted repetitive behaviors, interests, andrestricted repetitive behaviors, interests, and
activities .activities .

Autism spectrum disorders (ASDs) constitute a class of
severe neurodevelopmental conditions caused by atypical
brain development beginning during prenatal or early
postnatal life and are considered to be life-long conditions,
with core symptoms being permanent across the lifespan.
In the last years, significant progress has been made in
understanding the causes of ASDs and converging links of
evidence strongly point towards altered developmentally
regulated brain connectivity.. Studies of genetic and
environmentally modulated epigenetic factors have
highlighted the polygenic nature of these conditions.

Etiologic causes of ASDs remain elusive in more than 80%
of cases; only in 10-20% of the patients neuro-imaging and
neurogenetic techniques have allowed to identify a specific
medical and genetic syndromes as a cause of ASD These
disorders affect today up to one in 88-110 children,being
therefore a major public health concern.The increase in
diagnosis rates is probably related to changing diagnostic
criteria and to the development and use of new
standardized autism-specific diagnostic tools. However,
taking into account the possibility of modifications in
environmental or epigenetic factors, an actual increase of
the prevalence of ASDs cannot be completely excluded

Signs and symptomsSigns and symptoms
 Developmental regressionDevelopmental regression
 Absence of protodeclarative pointingAbsence of protodeclarative pointing
 Abnormal reactions to environmental stimuliAbnormal reactions to environmental stimuli
 Abnormal social interactionsAbnormal social interactions
 Absence of smiling when greeted by parents and otherAbsence of smiling when greeted by parents and other
familiar peoplefamiliar people
 Absence of typical responses to pain and physical injuryAbsence of typical responses to pain and physical injury
 Language delays and deviationsLanguage delays and deviations
 Susceptibility to infections and febrile illnessesSusceptibility to infections and febrile illnesses
 Absence of symbolic playAbsence of symbolic play
 Repetitive and stereotyped behaviourRepetitive and stereotyped behaviour

Developmental regressionDevelopmental regression
 Between 13% and 48% of people with autismBetween 13% and 48% of people with autism
have apparently normal development until agehave apparently normal development until age
15-30 months, when they lose verbal and15-30 months, when they lose verbal and
nonverbal communication skills. Thesenonverbal communication skills. These
individuals may have an innate vulnerability toindividuals may have an innate vulnerability to
develop autism. Although regression may bedevelop autism. Although regression may be
precipitated by an environmental event (eg,precipitated by an environmental event (eg,
immune or toxic exposures), more likely it isimmune or toxic exposures), more likely it is
coincidental with other environmental events.coincidental with other environmental events.

Protodeclarative pointingProtodeclarative pointing
 Protodeclarative pointing is the use of the index fingerProtodeclarative pointing is the use of the index finger
to indicate an item of interest to another person.to indicate an item of interest to another person.
Toddlers typically learn to use protodeclarative pointing toToddlers typically learn to use protodeclarative pointing to
communicate their concern for an object to others. Thecommunicate their concern for an object to others. The
absence of this behavior is predictive of a later diagnosis ofabsence of this behavior is predictive of a later diagnosis of
autism.autism.
 The presence of protodeclarative pointing can be assessedThe presence of protodeclarative pointing can be assessed
by interview of the parent or caregiver. Screening questionsby interview of the parent or caregiver. Screening questions
include "Does your child ever use his or her index finger toinclude "Does your child ever use his or her index finger to
point, to indicate interest in something?" A negativepoint, to indicate interest in something?" A negative
response to this question suggests the need for a specializedresponse to this question suggests the need for a specialized
assessment for possible pervasive developmental disorder.assessment for possible pervasive developmental disorder.

Environmental stimuliEnvironmental stimuli
 In contrast to toddlers with delayed or normal development,In contrast to toddlers with delayed or normal development,
toddlers withtoddlers with autism spectrum disorder are much moreautism spectrum disorder are much more
interested in geometric patternsinterested in geometric patterns..
 Parents of children with autism report unusual responses toParents of children with autism report unusual responses to
environmental stimuli, including excessive reaction or anenvironmental stimuli, including excessive reaction or an
unexpected lack of reaction to sensory input. Certain soundsunexpected lack of reaction to sensory input. Certain sounds
(eg, vacuum cleaners or motorcycles) may elicit incessant(eg, vacuum cleaners or motorcycles) may elicit incessant
screaming. Playing a radio, stereo, or television at a loud levelscreaming. Playing a radio, stereo, or television at a loud level
may appear to producemay appear to produce hyperacusishyperacusis
 Children with autistic disorder may also display exaggeratedChildren with autistic disorder may also display exaggerated
responses or rage to everyday sensory stimuli, such as brightresponses or rage to everyday sensory stimuli, such as bright
lights or touching.lights or touching.

Social interactionsSocial interactions
 Individuals with autism may display a lack ofIndividuals with autism may display a lack of
appropriate interaction with family members.appropriate interaction with family members.
Moreover, difficulties in social interactions are common.Moreover, difficulties in social interactions are common.
Children may have problemsChildren may have problems makingmaking friends andfriends and
understanding the social intentions of other children andunderstanding the social intentions of other children and
may instead show attachments to objects not normallymay instead show attachments to objects not normally
considered child oriented.considered child oriented. Although children withAlthough children with
autistic disorder may want to have friendships with otherautistic disorder may want to have friendships with other
children, their actions may actually drive away thesechildren, their actions may actually drive away these
potential companions. They may also exhibit inappropriatepotential companions. They may also exhibit inappropriate
friendliness and lack of awareness of personal space.friendliness and lack of awareness of personal space.
 Isolation likely increases in adolescence and youngIsolation likely increases in adolescence and young
adulthood.adulthood.

High pain thresholdHigh pain threshold
 An absence of typical responses to pain andAn absence of typical responses to pain and
physical injury may also be noted. Rather thanphysical injury may also be noted. Rather than
crying and running to a parent when cut orcrying and running to a parent when cut or
bruised, the child may display no change inbruised, the child may display no change in
behavior. Sometimes, parents do not realize thatbehavior. Sometimes, parents do not realize that
a child with autistic disorder is hurt until theya child with autistic disorder is hurt until they
observe the lesion. Parents often report that theyobserve the lesion. Parents often report that they
need to ask the child if something is wrongneed to ask the child if something is wrong
when the child's mood changes, and may needwhen the child's mood changes, and may need
to examine the child's body to detect injury.to examine the child's body to detect injury.

LanguageLanguage
 Speech abnormalities are common. They takeSpeech abnormalities are common. They take
the form of language delays and deviations.the form of language delays and deviations.
Pronominal reversals are common, includingPronominal reversals are common, including
saying "you" instead of "I." Some speech habits,saying "you" instead of "I." Some speech habits,
such as repeating words and sentences aftersuch as repeating words and sentences after
someone else says them, using language only thesomeone else says them, using language only the
child understands, or saying things whosechild understands, or saying things whose
meaning is not clear, may occur not only inmeaning is not clear, may occur not only in
autism but in other disorders as well.autism but in other disorders as well.

 PlayPlay
 Baron-Cohen and colleagues demonstrated that the absenceBaron-Cohen and colleagues demonstrated that the absence
of symbolic play in infants and toddlers is highly predictive ofof symbolic play in infants and toddlers is highly predictive of
a later diagnosis of autism.Therefore, screening for thea later diagnosis of autism.Therefore, screening for the
presence of symbolic play is a key component of the routinepresence of symbolic play is a key component of the routine
assessment of well babiesassessment of well babies. The absence of normal pretend play. The absence of normal pretend play
indicates the need for referral for specialized developmentalindicates the need for referral for specialized developmental
assessmentassessment for autism and other developmental disabilities.for autism and other developmental disabilities.
 Odd play may take the form of interest in parts of objectsOdd play may take the form of interest in parts of objects
instead of functional uses of the whole object. For example, ainstead of functional uses of the whole object. For example, a
child with autistic disorder may enjoy repeatedly spinning achild with autistic disorder may enjoy repeatedly spinning a
wheel of a car instead of moving the entire car on the groundwheel of a car instead of moving the entire car on the ground
in a functional manner.in a functional manner.

PathophysiologyPathophysiology Neural anomaliesNeural anomalies
 In patients with autism, neuroanatomic andIn patients with autism, neuroanatomic and
neuroimaging studiesneuroimaging studies reveal abnormalities of cellularreveal abnormalities of cellular
configurations in several regions of the brain,configurations in several regions of the brain,
including the frontal and temporal lobes and theincluding the frontal and temporal lobes and the
cerebellum. Enlargements of the amygdala and thecerebellum. Enlargements of the amygdala and the
hippocampushippocampus are common in childhood. Markedlyare common in childhood. Markedly
more neurons are present in select divisions of themore neurons are present in select divisions of the
prefrontal cortex of autopsy specimens of someprefrontal cortex of autopsy specimens of some
children with autism, compared with those withoutchildren with autism, compared with those without
autism.autism.
 Studies have suggested evidence for differences inStudies have suggested evidence for differences in
neuroanatomy and connectivity in people with autismneuroanatomy and connectivity in people with autism
compared with normal controls. Specifically, thesecompared with normal controls. Specifically, these
studies have found reduced or atypical connectivity instudies have found reduced or atypical connectivity in
frontal brain regions, as well as thinning of the corpusfrontal brain regions, as well as thinning of the corpus
callosum in children and adults with autism and relatedcallosum in children and adults with autism and related
conditions.conditions.

 Importantly, some of the regional differences in neuroanatomyImportantly, some of the regional differences in neuroanatomy
correlate significantly with the severity of specific autisticcorrelate significantly with the severity of specific autistic
symptoms.symptoms. For example, social and language deficits ofFor example, social and language deficits of
people with autism likely are related to dysfunction of thepeople with autism likely are related to dysfunction of the
frontal and temporal lobes.frontal and temporal lobes.
 The patches of abnormal neurons were found in the frontalThe patches of abnormal neurons were found in the frontal
and temporal lobes, regions involved in social, emotional,and temporal lobes, regions involved in social, emotional,
communication, and language functions. Since the changescommunication, and language functions. Since the changes
were in the form of patches, the researchers believe that earlywere in the form of patches, the researchers believe that early
treatment could rewire the brain and improve ASD symptoms.treatment could rewire the brain and improve ASD symptoms.
 Postmortem specimens of the brains of people with autismPostmortem specimens of the brains of people with autism
demonstrated reductions for gamma-aminobutyric acid–Bdemonstrated reductions for gamma-aminobutyric acid–B
(GABA B) receptors in the cingulate cortex, a key region for(GABA B) receptors in the cingulate cortex, a key region for
the evaluation of social relationships, emotions,the evaluation of social relationships, emotions, and cognition,and cognition,
and in the fusiform gyrus, a crucial region to evaluate faces andand in the fusiform gyrus, a crucial region to evaluate faces and
facial expressions. These findings provide the basis for furtherfacial expressions. These findings provide the basis for further
investigation of autism and other pervasive developmentalinvestigation of autism and other pervasive developmental
disorders.disorders.

 Metabolic anomaliesMetabolic anomalies
 DDysfunction of serotonin and the neuropeptides oxytocinysfunction of serotonin and the neuropeptides oxytocin
and vasopressinand vasopressin has been associated with abnormalities inhas been associated with abnormalities in
affiliative behaviors. Elevations of blood serotonin levels occuraffiliative behaviors. Elevations of blood serotonin levels occur
in approximately one third of individuals with autistic disorderin approximately one third of individuals with autistic disorder
and are also reported in the parents and siblings of patients.and are also reported in the parents and siblings of patients.
Functional anomalies in other neurotransmitters (eg,Functional anomalies in other neurotransmitters (eg,
acetylcholine, glutamate) have also been identified in someacetylcholine, glutamate) have also been identified in some
people with autism spectrum disorder.people with autism spectrum disorder.
 Serum biotinidaseSerum biotinidase is reduced in some people with autisticis reduced in some people with autistic
disorder. This enzyme is required for the use and recycling of thedisorder. This enzyme is required for the use and recycling of the
B vitamin biotin. Deficiency of biotin has been linked withB vitamin biotin. Deficiency of biotin has been linked with
behavioral disorders.behavioral disorders.
 Immunologic studies have identified abnormalities such asImmunologic studies have identified abnormalities such as
decreased plasma concentrations of thedecreased plasma concentrations of the C4B complementC4B complement
protein.protein.

Familial and genetic factorsFamilial and genetic factors
 Familial factors influence the risk for autism spectrumFamilial factors influence the risk for autism spectrum
disorders. The rate of autism spectrum disorder in childrendisorders. The rate of autism spectrum disorder in children
born into families that already have a child with an autismborn into families that already have a child with an autism
spectrum disorder is as high as 8.7 %, and the risk is twice asspectrum disorder is as high as 8.7 %, and the risk is twice as
high in children born to families with 2 or more childrenhigh in children born to families with 2 or more children
with an autism spectrum disorder. Girls born to a family thatwith an autism spectrum disorder. Girls born to a family that
has a child with an autism spectrum disorder have 2.8 timeshas a child with an autism spectrum disorder have 2.8 times
the risk of having such a disorder.the risk of having such a disorder.
 Finding genetic bases for autism is a promising researchFinding genetic bases for autism is a promising research
goal. Factor analysis of datasets from the Autism Genomegoal. Factor analysis of datasets from the Autism Genome
Project has suggested linkage of a joint attention factor withProject has suggested linkage of a joint attention factor with
11q23 and of a repetitive sensory-motor behavior factor11q23 and of a repetitive sensory-motor behavior factor
with 19q13.with 19q13.

 While a third of monozygotic twins are concordant forWhile a third of monozygotic twins are concordant for
autism, dizygotic twins are concordant for autism at ratesautism, dizygotic twins are concordant for autism at rates
of 4-8%,which is comparable to siblings. A focusedof 4-8%,which is comparable to siblings. A focused
neurogenetic evaluation of children with autism spectrumneurogenetic evaluation of children with autism spectrum
disorder yields a genetic disorder in two fifths of thedisorder yields a genetic disorder in two fifths of the
children . mutations in the genechildren . mutations in the gene SHANK3SHANK3 are associatedare associated
with autism spectrum disorders.with autism spectrum disorders.
 Fragile X syndromeFragile X syndrome, a condition associated with autism,, a condition associated with autism,
can be identified through genetic testing.Antagonists tocan be identified through genetic testing.Antagonists to
metabotropic glutamate receptors can reverse themetabotropic glutamate receptors can reverse the
symptoms in mouse models of fragile Xsymptoms in mouse models of fragile X
syndrome.Autism has also been associated withsyndrome.Autism has also been associated with
tuberous sclerosistuberous sclerosis, a disorder with specific genetic, a disorder with specific genetic
mutations.mutations.

 Toxic exposureToxic exposure
 Roberts et al and Samson have reported an association betweenRoberts et al and Samson have reported an association between
exposure to the organochlorine pesticides dicofol andexposure to the organochlorine pesticides dicofol and
endosulfan during the first trimester of pregnancy and theendosulfan during the first trimester of pregnancy and the
subsequent development of autism spectrum disorder insubsequent development of autism spectrum disorder in
children. Potential mothers can wisely be advised to avoidchildren. Potential mothers can wisely be advised to avoid
exposure to organochlorine pesticides.exposure to organochlorine pesticides.
 In certain parts of the world, exposure to specific toxins mayIn certain parts of the world, exposure to specific toxins may
influence local autism rates. For example, the high incidence ofinfluence local autism rates. For example, the high incidence of
autism in portions of Japan has been hypothesized to be due toautism in portions of Japan has been hypothesized to be due to
a toxic effect of certain fish.a toxic effect of certain fish.

Parental ageParental age
 Meta-analyses of epidemiologic studies have shown thatMeta-analyses of epidemiologic studies have shown that
autism risk in offspring increases with advancing age ofautism risk in offspring increases with advancing age of
either parent.either parent.
 Sandin et al reported that, after controlling for paternalSandin et al reported that, after controlling for paternal
age, the adjusted relative risk for autism was 1.52 in theage, the adjusted relative risk for autism was 1.52 in the
offspring of mothers aged 35 years or older compared withoffspring of mothers aged 35 years or older compared with
mothers aged 25-29 years.mothers aged 25-29 years.
 Hultman et al found that, after controlling for maternalHultman et al found that, after controlling for maternal
age, offspring of men aged 50 years or older were 2.2 timesage, offspring of men aged 50 years or older were 2.2 times
more likely to have autism than offspring of men aged 29more likely to have autism than offspring of men aged 29
years or younger.years or younger.

VaccinationVaccination
 Some children have developed autism after immunizations,Some children have developed autism after immunizations,
including inoculations for measles, mumps, and rubella.including inoculations for measles, mumps, and rubella.
 Thompson and colleagues detected no causal associationThompson and colleagues detected no causal association
between exposure to vaccines that contain thimerosal andbetween exposure to vaccines that contain thimerosal and
neuropsychological deficits at age 7-10 years. In fact, in earlyneuropsychological deficits at age 7-10 years. In fact, in early
2010, the2010, the LancetLancet retracted the 1998 article by Wakefield et al thatretracted the 1998 article by Wakefield et al that
originally linked autism with measles-mumps-rubella (MMR)originally linked autism with measles-mumps-rubella (MMR)
vaccination.vaccination.
 Parents can permit the recommended childhood immunizationsParents can permit the recommended childhood immunizations
without fear of causing autism and related conditions. Adherencewithout fear of causing autism and related conditions. Adherence
to recommended immunization schedules, includingto recommended immunization schedules, including
immunization for measles, mumps, and rubella, is highlyimmunization for measles, mumps, and rubella, is highly
recommended.recommended.

Early signs and follow-up surveillance
The clinical diagnosis of autism is generally performed
in children between 18 and 30 months of age, but
autistic features, such as limitations in joint attention,
eye contact, reciprocal smiling, imitation, response to
name, gestures (i. pointing), and pretend and
imaginative play skills begin to be evident already in
children between 12 and 18 months of age,often after a
period of relatively typical postnatal development.

 DiagnosisDiagnosis
 Examination for patients with suspected autistic spectrum disorderExamination for patients with suspected autistic spectrum disorder
may include the following findings:may include the following findings:
 Abnormal motor movements (eg, clumsiness, awkward walk, handAbnormal motor movements (eg, clumsiness, awkward walk, hand
flapping, tics)flapping, tics)
 Dermatologic anomalies (eg, aberrant palmar creases)Dermatologic anomalies (eg, aberrant palmar creases)
 Abnormal head circumference (eg, small at birth, increased from age 6Abnormal head circumference (eg, small at birth, increased from age 6
months to 2 years,[4] normal in adolescence[5] )months to 2 years,[4] normal in adolescence[5] )
 Orofacial, extremity, and head/trunk stereotypies (eg, purposeless,Orofacial, extremity, and head/trunk stereotypies (eg, purposeless,
repetitive, patterned motions, postures, and sounds)repetitive, patterned motions, postures, and sounds)
 Self-injurious behaviors (eg, picking at the skin, self-biting, headSelf-injurious behaviors (eg, picking at the skin, self-biting, head
punching/slapping)punching/slapping)
 Physical abuse inflicted by others (eg, parents, teachers)Physical abuse inflicted by others (eg, parents, teachers)
 Sexual abuse: External examination of genitalia is appropriate; ifSexual abuse: External examination of genitalia is appropriate; if
bruises and other evidence of trauma are present, pelvic and rectalbruises and other evidence of trauma are present, pelvic and rectal
examinations may be indicatedexaminations may be indicated

 Age of onsetAge of onset
 Autistic disorder manifests in early childhood.Autistic disorder manifests in early childhood.
By contemporary criteria, the absence ofBy contemporary criteria, the absence of
abnormalities in the first 30 months of life rulesabnormalities in the first 30 months of life rules
out autistic disorder. Many parents reportout autistic disorder. Many parents report
normal development in their child until age 2normal development in their child until age 2
years before noticing the deficits in social andyears before noticing the deficits in social and
communicative skills.communicative skills.

Genetic Testing
Practice guidelines from the American Academy of Neurology
and the Child Neurology Society recommend genetic testing in
autistic children who meet any of the following criteria
The child has mental retardation
Mental retardation cannot be excluded
There is a family history of fragile X or
undiagnosed mental retardation
Dysmorphic features are present

NeuroimagingNeuroimaging
 MRIMRI
 Magnetic resonance imaging (MRI) studies in patients with autism yieldMagnetic resonance imaging (MRI) studies in patients with autism yield
inconsistent results.inconsistent results. However, typical findings include enlargement ofHowever, typical findings include enlargement of
the total brain, the total brain tissue, and the lateral and fourth ventricles,the total brain, the total brain tissue, and the lateral and fourth ventricles,
along with reductions in the size of the midbrain, the medulla oblongata,along with reductions in the size of the midbrain, the medulla oblongata,
the cerebellar hemispheres, and vermal lobules VI and VIIthe cerebellar hemispheres, and vermal lobules VI and VII. Although. Although
vermal hypoplasia is found in some individuals with autism, vermalvermal hypoplasia is found in some individuals with autism, vermal
hyperplasia is identified in others.hyperplasia is identified in others.
 The volume of the gray matter is bilaterally decreased in the amygdala,The volume of the gray matter is bilaterally decreased in the amygdala,
the precuneus, and the hippocampus of people with autism spectrumthe precuneus, and the hippocampus of people with autism spectrum
disorder.disorder.

SPECT (single-photon emission CT)SPECT (single-photon emission CT)
scanningscanning
 Chiron et al found that the normal asymmetry of regionalChiron et al found that the normal asymmetry of regional
cerebral blood flow (ie, higher in the left hemisphere in right-cerebral blood flow (ie, higher in the left hemisphere in right-
handed individuals) was lacking in some people with autism.handed individuals) was lacking in some people with autism.
Tests of regional cerebral blood flow with xenon-133 (133 Xe)Tests of regional cerebral blood flow with xenon-133 (133 Xe)
revealed left-hemispheric dysfunction, especially in the corticalrevealed left-hemispheric dysfunction, especially in the cortical
areas devoted to language and handedness.Regional cerebralareas devoted to language and handedness.Regional cerebral
blood flow assessed with technetium-99m (99m Tc) labeled toblood flow assessed with technetium-99m (99m Tc) labeled to
hexamethylpropyleneamine oxide (HMPAO), a lipophilichexamethylpropyleneamine oxide (HMPAO), a lipophilic
substance, in children with autistic disorder demonstratessubstance, in children with autistic disorder demonstrates
variable anomalies, including reductions in the vermis, thevariable anomalies, including reductions in the vermis, the
cerebellar hemispheres, the thalami, the basal ganglia, and thecerebellar hemispheres, the thalami, the basal ganglia, and the
parietal and temporal lobes. of regional cerebral blood flowparietal and temporal lobes. of regional cerebral blood flow
dysfunction.dysfunction. These findings suggest that no single abnormalityThese findings suggest that no single abnormality
characterizes all individuals with autistic disorder. Biologiccharacterizes all individuals with autistic disorder. Biologic
classes may have specific typesclasses may have specific types

 ElectroencephalographyElectroencephalography
 electroencephalography is useful for ruling out seizureelectroencephalography is useful for ruling out seizure
disorder (present in a third of children with autism), acquireddisorder (present in a third of children with autism), acquired
aphasia with convulsive disorder (Landau-Kleffner syndrome),aphasia with convulsive disorder (Landau-Kleffner syndrome),
biotin-responsive infantile encephalopathy, and relatedbiotin-responsive infantile encephalopathy, and related
conditions. The American Academy of Neurology and theconditions. The American Academy of Neurology and the
Child Neurology Society found inadequate evidence toChild Neurology Society found inadequate evidence to
recommend an electroencephalogram (EEG) in all individualsrecommend an electroencephalogram (EEG) in all individuals
with autism.with autism.
 Indications for performing a sleep-deprived EEG withIndications for performing a sleep-deprived EEG with
appropriate sampling of slow-wave sleep in patients withappropriate sampling of slow-wave sleep in patients with
autism are clinical seizures (or suspicion of subclinicalautism are clinical seizures (or suspicion of subclinical
seizures) and clinically significant loss of social andseizures) and clinically significant loss of social and
communicative function, especially in toddlers andcommunicative function, especially in toddlers and
preschoolers.

TREATMENTTREATMENT
 Non-pharmacological treatmentsNon-pharmacological treatments

 Special EducationSpecial Education
 Special education is central to the treatment of autisticSpecial education is central to the treatment of autistic
disorder. Although parents may choose to use variousdisorder. Although parents may choose to use various
experimental treatments, including medication, theyexperimental treatments, including medication, they
should concurrently use intensive individual specialshould concurrently use intensive individual special
education by an educator familiar with instructingeducation by an educator familiar with instructing
children who have autistic disorder or a relatedchildren who have autistic disorder or a related
condition. Intensive behavioral interventions, institutedcondition. Intensive behavioral interventions, instituted
as early as possible, are indicated for every child inas early as possible, are indicated for every child in
whom autistic disorder is suspected .whom autistic disorder is suspected .
 Pediatricians and parents cannot assume, however, thatPediatricians and parents cannot assume, however, that
their community’s school will provide satisfactorytheir community’s school will provide satisfactory
education for a child with autistic disorder or a relatededucation for a child with autistic disorder or a related
condition.condition.

Speech, Behavioral, Occupational,Speech, Behavioral, Occupational,
and Physical Therapiesand Physical Therapies
 Therapies that are reported to help some individuals with autismTherapies that are reported to help some individuals with autism
include the following:include the following:
 Assisted communicationAssisted communication --
 Using keyboards, letter boards, word boards, and other devicesUsing keyboards, letter boards, word boards, and other devices
(eg, the Picture Exchange Communication System, with the(eg, the Picture Exchange Communication System, with the
assistance of a therapistassistance of a therapist
 Auditory integration trainingAuditory integration training - A procedure in which the- A procedure in which the
individual listens to specially prepared sounds throughindividual listens to specially prepared sounds through
headphonesheadphones
 Sensory integration therapySensory integration therapy -- A treatment for motor andA treatment for motor and
sensory motor problems typically administered by occupationalsensory motor problems typically administered by occupational
therapiststherapists
 Exercise and physical therapyExercise and physical therapy - Exercise is often therapeutic- Exercise is often therapeutic
for individuals with autistic disorder; a regular program offor individuals with autistic disorder; a regular program of
activity prescribed by a physical therapist may be helpfulactivity prescribed by a physical therapist may be helpful

The treatment and education of autistic and related
communication handicapped children (TEACCH)
TEACCH emphasizes two basic principles:
structuring the environment to promote skill acquisition and
facilitating independence at all levels of functioning. The
underlying premise for structured teaching is to modify the
environmentin order to meet the needs of individuals with ASD.
Four main components are related to this process, i.e. physical
organization, visual schedules, work systems, and task
organization. TEACCH has been implemented in many
different countries and adapted to different situations
(home-based, mainstream schools, special schools, residential
centers).

Social skills training (SST)
Recent developments SST interventions have shown a shift from
focusing on the enhancement of specific social behaviors such as
listening, eye contact, conversational skills, or gestures to a
multidimensional perception of social functioning. This
multidimensional perception encompasses the child’s capacity to
integrate behavioral skills (e.g., socialinteraction), cognitive skills
(e.g., accurate processing of information, perspective taking, social
understanding), and affective skills (e.g., emotional regulation,
knowledge, and recognition) in order to adapt flexibly to diverse
social contexts and demands. Social interventions for children with
ASD are also shifting from skills-oriented SST programs based
mainly on social behaviors to more comprehensive, holistic
interventions based on modifications of classic cognitivebehavioral
treatment (CBT) models, to help these children

Second-Generation AntipsychoticsSecond-Generation Antipsychotics
 Risperidone (Risperdal, Risperdal Consta, Risperdal MRisperidone (Risperdal, Risperdal Consta, Risperdal M

 Risperidone is an atypical antipsychotic agent that isRisperidone is an atypical antipsychotic agent that is
indicated for irritability associated with autistic disorderindicated for irritability associated with autistic disorder
in children and adolescents aged 5-16 years.in children and adolescents aged 5-16 years.
Risperidone is a mixed serotonin-dopamine antagonistRisperidone is a mixed serotonin-dopamine antagonist
that binds to 5-HT2 with very high affinity and binds tothat binds to 5-HT2 with very high affinity and binds to
the dopamine D2 receptor with less affinity. Affinitythe dopamine D2 receptor with less affinity. Affinity
for the dopamine D2 receptor is 20 times lower thanfor the dopamine D2 receptor is 20 times lower than
that for the 5-HT2 receptor.that for the 5-HT2 receptor.

 Aripiprazole (Abilify, Abilify Discmelt)Aripiprazole (Abilify, Abilify Discmelt)

 Aripiprazole is indicated for irritability associated withAripiprazole is indicated for irritability associated with
autistic disorder in children and adolescents aged 6-17autistic disorder in children and adolescents aged 6-17
years. Aripiprazole is thought to be a partial dopamineyears. Aripiprazole is thought to be a partial dopamine
(D2) and serotonin (5-HT1A) agonist, and to(D2) and serotonin (5-HT1A) agonist, and to
antagonize serotonin (5-HT2A). Aripiprazole isantagonize serotonin (5-HT2A). Aripiprazole is
available as a tablet, an orally disintegrating tablet, or anavailable as a tablet, an orally disintegrating tablet, or an
oral solution.oral solution.

 Ziprasidone (Geodon)Ziprasidone (Geodon)

 Ziprasidone, a second-generation antipsychotic drug, isZiprasidone, a second-generation antipsychotic drug, is
used off-label to treat serious behavior disordersused off-label to treat serious behavior disorders
associated with autism, such as self-injurious behavior.associated with autism, such as self-injurious behavior.
It elicits its effects through antagonism of D2, D3, 5-It elicits its effects through antagonism of D2, D3, 5-
HT2A, 5-HT2C, 5-HT1A, 5-HT1D, and alpha1-HT2A, 5-HT2C, 5-HT1A, 5-HT1D, and alpha1-
adrenergic receptors. In addition, it has a moderateadrenergic receptors. In addition, it has a moderate
antagonistic effect for histamine H1. It moderatelyantagonistic effect for histamine H1. It moderately
inhibits the reuptake of serotonin and norepinephrine.inhibits the reuptake of serotonin and norepinephrine.

 Experimental ApproachesExperimental Approaches
 Secretin therapySecretin therapy
 Several anecdotal reports suggested that secretin, aSeveral anecdotal reports suggested that secretin, a
gastrointestinal hormone that may function as agastrointestinal hormone that may function as a
neurotransmitter, was an effective intervention for theneurotransmitter, was an effective intervention for the
symptoms of autism. This led to several scientificsymptoms of autism. This led to several scientific
studies of secretin for children with autism spectrumstudies of secretin for children with autism spectrum
Hyperbaric oxygen therapyHyperbaric oxygen therapy
 Beneficial effects from hyperbaric oxygen therapy haveBeneficial effects from hyperbaric oxygen therapy have
been reported in 6 patients with autism. The risks ofbeen reported in 6 patients with autism. The risks of
this procedure must be weighed against the benefits forthis procedure must be weighed against the benefits for
individual patients. Controlled clinical trials and otherindividual patients. Controlled clinical trials and other
studies are needed to confirm the potential value of thisstudies are needed to confirm the potential value of this
intervention.intervention.

 Intranasal oxytocinIntranasal oxytocin
 Research suggests that administration of a single intranasal doseResearch suggests that administration of a single intranasal dose
of the hormone oxytocin increases activity in brain regionsof the hormone oxytocin increases activity in brain regions
associated with reward, social perception, and emotionalassociated with reward, social perception, and emotional
awareness and temporarily improves social informationawareness and temporarily improves social information
processing in children with autism spectrum disorder (ASD).processing in children with autism spectrum disorder (ASD).
 Children and adolescents with ASD, brain centers associatedChildren and adolescents with ASD, brain centers associated
with reward and emotion recognition responded more duringwith reward and emotion recognition responded more during
social tasks when children received oxytocin instead of a placebo.social tasks when children received oxytocin instead of a placebo.
 Although behavioral studies in children and adults suggest that aAlthough behavioral studies in children and adults suggest that a
single dose of intranasal oxytocin improves social interaction andsingle dose of intranasal oxytocin improves social interaction and
comprehension of affective speech, results from clinical trialscomprehension of affective speech, results from clinical trials
examining the effect of daily administration of the drug haveexamining the effect of daily administration of the drug have
been mixed.been mixed.

Future directions
A major goal of the current interdisciplinary researches is to understand
specific and non-specific factors that influence variability both in the
relative risk of developing autism, and in the responsiveness to treatments.
The clinical heterogeneity of ASDs might be reduced when more
homogeneous subgroups, based on a specific genotype or epigenetic
mechanisms, are extracted from the overall genetically heterogeneous ASD
population. The existence of specific ASD genotypes also implies that these
could be rescued by specific, targeted molecular treatments. In the future,
animal models of monogenic diseases associated with autism, such as
Fragile X syndrome, Rett syndrome,or Tuberous Sclerosis, may provide a
better understanding of the pathogenetic mechanisms underlying ASDs and
could help in the development of more effective treatment strategies. More
randomized control trials (RCTs) on early intervention are needed to
identify the most effective strategies and provide the most efficient
allocation of resources during the critical early intervention time period.

Future research should focus on linking biological phenotypes with
specific genotypes, thus establishing a foundation for the
development of diagnostic screening tools and individualization of
treatments.A future goal will be to better understand whether very
early intervention may result not only in significant improvements
in behavior e including reduced autism symptoms and increased
cognitive, language, and social abilities but also in significant
changes in brain function and organization related to functional
recovery.This will help to identify the neurobiological mechanisms
responsible for effective outcome following intervention and
might, therefore, suggest the way to reduce or even prevent the
manifestations of the full syndrome.

With a better understanding of the biochemical alterations of ASDs
it will be possible to detect early biomarkers for the diagnosis of
ASDs, to improve our knowledge and ability to develop
pharmacological therapies, to elaborate more definite interventions
on the basis of the different clinical phenotypes, and thus bridge
the gap between scientific research and clinical applications.

Autism spectrum disorder (asd) 3

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