Autism spectrum disorders: a pediatric overview and update - Alexis

14 Pages·2013·0.41 MB·English

REVIEW
CURRENT Autism spectrum disorders: a pediatric overview
O
PINION
and update
Alexis Tchaconasa and Andrew Adesmanb
Purposeofreview
To provide anupdated overviewof autismspectrum disorders (ASDs), withparticular attention to the
pediatrician’s role inassessing andmanaging patients withASDs.
Recent findings
Clinical perspectives on ASDscontinue toevolve. The prevalence ofASDs inthe UnitedStates continues to
rise, and pediatricians arebeing tasked withthe responsibility foruniversal screening. Further changesin
its epidemiology willundoubtedly result from anticipated changes inthe diagnosticcriteria put forth inthe
upcoming revision to the Diagnostic and Statistical Manual (5th edition). Although there havebeen
considerable advances inidentifying ageneticcause inmanymore cases, the cause remains elusivein
most cases. Recent studies ofconcordant twins suggest there isa stronger environmental component than
previously believed. Research suggests earlier diagnosismaybe feasible insome cases, and anew
treatment approachhas been shownto be effectiveinvery youngchildren. Although there havenot been
any large-scale advances inthemedical treatment,some isolated successes havebeen reported and other
promising therapies are now being investigated.
Summary
Clinical guidelines forASDs areevolving, withupdated diagnostic criteria expected and revised
recommendations forevaluation also imminent.This articleprovides pediatricians witha clinicaloverview
of ASD – withanemphasis onthe clinical considerations relating to screening, evaluation, and
management.
Keywords
autism spectrum disorders, cause, diagnosis, pervasive developmental disorders
INTRODUCTION PREVALENCE
Twenty-six years ago, a colleague wrote: ‘In recent ASDs are one of the most prevalent neurodevelop-
years, no other childhood disorder has received as mental disorders among children today. More
muchattention,generatedmorecontroversy,orleft children are diagnosed with ASDs each year in the
educators and parents in more confusion about United States than AIDS, cancer, and diabetes
what to do than the condition known as hyper- combined [2]. ASDs, synonymous with pervasive
activity. The vagueness of the term has resulted in developmental disorders (PDDs), encompass a
an ‘‘epidemic’’ of cases, causes, and cures’ [1]. group of neurodevelopmental disorders along a
Although this observation might well still apply
to attention deficit hyperactivity disorder (ADHD),
aColumbia University, New York, New York and bDevelopmental and
otherscouldreasonablyarguethatitappliesequally
BehavioralPediatrics,StevenandAlexandraCohenChildren’sMedical
welltothefieldofautismspectrumdisorders(ASDs).
CenterofNewYork,NewHydePark,NewYork,USA
Although welackanswersforfartoomanyimport-
CorrespondencetoAndrewAdesman,MD,DevelopmentalandBehav-
ant questions and controversy swirls around every
ioral Pediatrics, Cohen Children’s Medical Center of New York, 1983
aspect of this diagnostic category, it is important MarcusAvenue,Suite130,LakeSuccess,NewYork,USA.Tel:+1516
thatpediatriciansfullyunderstandtheissuesrelated 8026112;e-mail:[email protected]
to early identification, evaluation, treatment, and CurrOpinPediatr2013,25:130–143
outcome of ASDs. DOI:10.1097/MOP.0b013e32835c2b70
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Autism spectrumdisorders Tchaconas and Adesman
The current DSM-4 criteria have been criticized
KEY POINTS
from both a clinical and an epidemiologic
standpoint. Inconsistent diagnoses over time and
(cid:2) Pediatricians playanessential roleinthe early
amongphysicianshaveinfluencedDSM-5develop-
identification and management ofchildren withautism
spectrum disorders. ers to minimize diagnostic ambiguities by consol-
idatingtheconstituentdisorders.WhentheDSM-5
(cid:2) Earlyidentification ofASDs isimportant becauseit may
isreleasedinMay2013,autisticdisorder,PDD-NOS,
reduce ASDseverity, though thisis morechallenging
CODD, and Asperger’s disorder will no longer be
formilder forms ofASD.
distinctconditions;instead,theywillcollectivelybe
(cid:2) Imminent release ofthe newest edition of the Diagnostic defined as ‘Autism Spectrum Disorder’ – formally
and Statistical Manual (DSM-5) willprovide arevised recognizing what has been the de-facto umbrella
nosology withstricter criteria forASDdiagnosis.
term in recent years.
(cid:2) Advances inmolecular genetictesting haveidentified a Asproposed,thediagnosticcriteriafor‘ASD’will
genetic causeinmore casesof ASD;however, there is reflect several other major changes. The three
agrowing body ofresearch supporting anepigenetic domainsdefiningASDsintheDSM-4arecondensed
cause ofASDinmany cases. Currentrecommendations intotwodomains:‘socialandcommunicationdefi-
forlaboratory testing are summarized.
cits’and‘fixedinterestsandrepetitivebehaviors’[7].
(cid:2) Although developmental therapies are the backboneof Social and communication deficits are combined
treatment (with recentresearch supporting a refined because they are seen as being clinically linked
developmental approach), there will likely be an (if not inseparable) and to improve diagnostic
expanded role formedical treatments inthe specificity without compromising sensitivity. It is
years ahead.
hoped that numerical severity levels will enhance
specificity. Data analyses suggest the revised
criteria will have the highest kappa coefficient
spectrum,witheach ASDsubtypecharacterizedby yet of 0.69 [7,8].
varying degrees of difficulties with social interac- ASD diagnosis will now require children to
tion, communication (verbal and nonverbal), and exhibitallthreesymptomsinsocialcommunication
unusual, repetitive behaviors [3]. Currently, ASDs and interaction (a) and two of four symptoms in
affect1in88childrenintheUnitedStatesandare repetitivebehaviordomain(b);thesymptomsmust
four times more prevalent in males than females present in early childhood (c) and limit everyday
(1in54boysaffectedcomparedwith1in252girls functioning (d). Experts disagree about the impact
affected) [4]. While prevalence estimates of ASDs ofthesechangesonprevalence.Someproponentsof
have increased significantly in the recent years, the new changes believe it will reduce the over-
from1in150intheyear2000to1in88intheyear diagnosisofASDs;ontheotherhand,some(includ-
2008, it is unclear to what extent this is a true ing advocacy groups) are concerned the DSM-5
increase or a product of expanded diagnostic criteria will lead to a decrease in cases, and that
criteria [5]. high-functioning individuals with a ‘mild ASD’
(e.g.,PDD-NOSorAsperger’sdisorder)willnolonger
meetthecriteriaandpotentiallylosesomeservices,
DEFINITION AND NOSOLOGY
accommodation,and supports.The mostthorough
‘Autism’ received its own classification in the case analysis to date examining the effect of the
DiagnosticandStatisticalManualofMentalDisorders, proposed DSM-5 criteria on patients currently
ThirdEdition(DSM-3)in1980[6].WhentheDSM-4 diagnosed with ASD suggests that 91% of these
was updated in 1994, ‘autistic disorder’ was sub- patients will retain their diagnosis under the pro-
sumedunderanewumbrellacategoryof‘Pervasive posed DSM-5 criteria [9].
Developmental Disorders’ (PDDs), which included
four other disorders: Asperger’s disorder, child-
CAUSE
hood-onset disintegrative disorder (CODD), Rett
syndrome, and PDD-Not Otherwise Specified The most perplexing aspect of ASDs remains their
(PDD-NOS). Although each of these conditions cause.ThesuspectedcausesofASDsareasdiverseas
had some shared elements, the DSM-4 tried to thespectrumitself,andpresumablyreflectachild’s
delineate these different conditions with respect early life environment and genetic endowment. In
to age of onset, symptom severity, prognosis, and some cases, identifying a cause can not only allay
associated features [3]. While these disorders are familial guilt and anxiety, but also allow more
now generally known as ASDs, they were never meaningful family counseling, medical evaluation
labeled as such in the DSM-4. or monitoring, and treatment [10].
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Genetics implications of these different associations are
Advancesingenetictesting – forexample,compara- not well understood. While some studies suggest
tivegenomichybridizationandothernew,sophisti- maternal immune response to prenatal infection
cated techniques – have enabled researchers to may be responsible for many cases of ASDs, other
identify numerous candidate genes and loci on studieshaveidentifiedalteredimmuneresponsesin
nearly every chromosome [11–14]. Fernandez childrenwithASDs.
et al.’s [15] initial implication of copy number vari- Prenatal immune influences have been
ations (CNVs – an abnormal number of copies of a suggested by large-scale epidemiologic studies
DNAsegment)onthecontactin(CNTN)4genehas that demonstrate an increased risk of ASD in the
ledtoresearchlinkingotherCNTNfamilycandidate offspring of women who had a viral or bacterial
genes involved in central nervous system function infection during pregnancy. Researchers believe
(e.g.,CNTNAP2)tosmallpopulationswithASDs[16]. thatASDisnotaconsequenceoftheinfectionitself,
InterestinthegeneticheritabilityofASDsorigi- but rather the maternal immune response to that
nated with Folstein and Rutter’s first twin study infection.Thishypothesiswassupportedbyarecent
reporting a striking difference between monozy- animal study. When pregnant mice were injected
gotic and dizygotic twins [17]; their subsequent with a viral mimic that initiated the same type of
studies reported increasingly higher monozygotic immune response as a viral infection, the offspring
concordanceratesandnearly0%dizygoticconcord- demonstratedtheequivalentofcorebehavioraland
ance [18]. In the past decade, genetic susceptibility neuropathological symptoms associated with ASD.
to ASDs has been a main focus of research, with Moreover, the ‘ASD mice’ no longer exhibited
studies reporting concordance rates as high as 90% stereotyped/repetitive and anxiety-like behaviors
inmonozygotictwinsandaslowas10%indizygotic when irradiated and given an immunologically
twins[19].Geneticresearchhadcollectivelyimplied normal bone-marrow transplant. Such immune
a strong genetic component to ASDs – attributing system dysregulation could be a promising target
almost all variances in phenotypic expression to for ASD treatment in at least one-third of the ASD
heritable factors [18]. population. Further testing in mice models is
Lastyear,theresultsofthelargesteverASDtwin needed before considering immunological treat-
study,theCaliforniaAutismTwinStudy,foundASD ments in humans [21].
concordanceratestobemuchlowerthanpreviously Other recent studies have suggested that the
expected [20&]. A total of 192 twin pairs born immunesystemofchildrenwithASDismorehighly
between 1987 and 2004 were identified where at activated. For example, several investigators have
leastonetwinhadeitherautisticdisorderoramilder demonstrated increased cytokine levels in children
ASD. For autistic disorder (and not other ASDs), withASD,withonerecentstudyfindingthegreatest
probandwise concordance for male twins was 0.58 elevation in children with a history of regressive
for 40 monozygotic pairs and 0.21 for 31 dizygotic autism [22,23]. These findings, if replicated, have
pairs, and for female twins 0.60 for seven monozy- implications not only for the clinical diagnosis of
gotic pairs and 0.27 for 10 dizygotic pairs. Much ASD,butalsoforitstreatment.Webelieveitislikely
higher concordance was observed when the entire that researchers will make rapid and substantial
spectrum of ASDs was included. Probandwise con- gainsinteasingoutprenatalandpostnatalimmune
cordance for male twins was 0.77 for 45 monozy- influences in the next few years.
gotic pairs and 0.31 for 45 dizygotic pairs, and for
female twins 0.50 for nine monozygotic pairs and
Environmental
0.36 for 13 dizygotic pairs. Results indicated that
ASD was 55% attributable to the environmental One of the most contentious environmental con-
factors shared by twins, a much greater percentage cerns centers on childhood vaccines. Dr Andrew
than predicted by earlier twin studies [20&]. Given Wakefield stirred this fear in parents when he
the California twin population was ethnically, released an article implying a link between the
demographically, and socioeconomically diverse, measles, mumps, and rubella (MMR) vaccine and
these results were interpreted as convincing evi- ‘a new syndrome of autism and bowel disease’
dence for environmental influences on ASDs. [24]. While the study was retracted for methodo-
logical concerns of sample bias, it was later
revealed that Wakefield falsified the data [25].
Immunological
Despite public renouncement of this study, many
Several different lines of recent research suggest parents were influenced by this putative ‘connec-
an association between ASDs and the immuno- tion’ between childhood vaccines and the devel-
logical response; unfortunately, the relevance and opment of ASDs.
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Autism spectrumdisorders Tchaconas and Adesman
Once the MMR vaccine was dismissed as a for the underlying cause of a child’s ASD. Clinical
cause of ASDs, thimerosal, the mercury-containing guidelines exist for highlighting the key behaviors
preservativeinvaccines,becamethenewtarget.To andsignsthatshouldalertapediatriciantoanASD.
ease concerns over potential neurotoxic effects of The American Academy of Pediatrics (AAP)’s most
the mercury, essentially all vaccinations for young recent guidelines [35] provide pediatricians with a
children are now thimerosal-free [26]. Unfortu- ‘toolbox’ of recommended tests to screen for ASDs
nately,ASDincidencehasnotdropped – validating and guidelines for the medical evaluation of
the opinion of experts that thimerosal was not children for whom there are clinical concerns.
responsible for the increased incidence of ASDs Specifically, the AAP developed an ‘Algorithm for
[27,28]. Developmental Surveillance and Screening’, with
InOctober2007,DrRobertSearspublishedThe the expectation that pediatricians screen with
VaccineBook:MakingtheRightDecisionforYourChild, standardized developmental tools at the 9, 18,
encouraging alternative and selective vaccine and24or30monthvisits,andthatanASD-specific
schedules for concerned parents. Sears proposed screening tool be used at the 18 and 24 month
giving a child the ‘bare minimum’ and increasing visits to maximize the early detection of ASDs
vaccinationintervals.DrSearsraisedconcernsabout [35].TheModifiedChecklistforAutisminToddlers
many vaccine ingredients – namely fetal bovine (M-CHAT)isahelpful(butimperfect)screeningtool
serum and human blood products (presumably thatcanbeadministeredtoallchildreninaprimary
albumin). However, his fears are generally predi- care setting at no cost to the practitioner [36].
cated on faulty logic and misinformation. For Toinsurethemostfavorableoutcome,increased
example, his rationale for spacing out vaccinations emphasis is being placed on early identification
istoavoidexposure tohighlevels ofaluminum.In of ASDs. As signs are sometimes present before
fact,by6monthsofage,infantstypicallyingestfar 12 months of age, pediatricians may wish to more
greater amounts of aluminum from breast milk or formally assess older infants. The AAP’s Autism
formulathaniscontainedinvaccines[29].Referto Toolkit includes a copy of the Communication
OffitandMoser’sbroadercritiqueofSears’ideology and Symbolic Behavior Scales Developmental Pro-
for more information [28]. file (CSBS DP), a 24-item parent checklist with
Although valid scientific evidence linking norms extending down to 6 months of age.
vaccinations to ASDs has yet to be produced, Researchers just reported on the positive-predictive
anxiousparentscontinuetoexpressconcernsabout valueofanotherscreeningtool,theFirstYearInven-
vaccine safety. Unfortunately, each time research tory (FYI) – a parent-report measure designed to
dispels concerns about one aspect of the vaccine identify 12-month-old infants at risk for ASDs
regimen, fears are raised about another theoretical [37&]. A longitudinal follow-up study found that
risk.Atthistime,manyinthescientificcommunity 31% of children classified as at risk for ASD on
are frustrated that limited resources continue to be theFYIat12monthsreceivedaconfirmeddiagnosis
expended refuting scientifically tenuous or falla- by 3 years old, with 85% of the at-risk children
cious reasoning; on the other hand, it is important having a developmental disability or concern by
tomaintainpublicconfidenceintherecommended 3yearsold.AsmostASD-specificscreeningbypedia-
vaccine regimen. triciansiscurrentlydonebetween18and24months
Given the recent reportsthat ASD concordance old, instruments like the FYI or the CSBS DP may
rates were severely underestimated for dizygotic allow children at high risk for ASD to receive early
twins in the past, research is now focused on the intervention even sooner.
potential prenatal and postnatal environmental
triggers [30]. Future research will likely analyze
MEDICAL EVALUATION
the shared environment, or experiences common
to both twins, prior to the second year of life [30]. Diagnostic medical testing of children with ASD or
Suspect environmental factors include parental age an intellectual disability (formerly mental retar-
[31], maternal infections during pregnancy [32], dation) has focused on four main areas – genetic
multiple births [33], and low birth weight [34]. testing, neuroimaging, EEG, and metabolic screen-
ing. In recent years, there have been significant
changes in the recommended diagnostic approach
EARLY IDENTIFICATION OF AUTISM
to evaluating children with ASD or intellectual dis-
SPECTRUM DISORDER
ability. Someconventional tests havebeen deemed
As most ASDs are diagnosed in early childhood, unnecessary because of their very low diagnostic
the pediatrician plays a crucial role in identifying yieldandothershavebeenrendered‘obsolete’with
toddlersatriskforanASD,andultimatelysearching thedevelopmentofmoresophisticatedalternatives.
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Genetic testing commercially available and will supplant all other
Advances in molecular genetic testing have radi- genetic tests in the evaluation of children with
cally transformed the clinicalapproachtoetiologic severedevelopmentaldisability.Aproof-of-concept
evaluation of children with autism and intellectual study showed that whole-genome sequencing can
disability. Chromosomal karyotypes – routine be done in a clinical setting [44].
G-banding or when testing for fragility of the X Although CMA testing is quite sensitive for
chromosome – havenowbeenreplacedbymolecu- some genetic defects, it does not detect Fragile X
lar genetic techniques that have a higher yield. syndromeorRettsyndrome.TheAAP recommends
Chromosomal microarray analysis (CMA), other- thatDNAtestingforFragileXshouldalsobeoffered
wiseknownascomparativegenomichybridization, toallpatientswith ASD.The indexofsuspicion for
is the most robust test available to clinicians for Fragile X will be heightened if phenotypic features
identifying a genetic basis for ASD or intellectual or a positive family history are present; however,
disability [38–40]. Whereas G-banded karyotype Fragile X testing is indicated even if the family
would identify agenetic abnormalityinfewer than history is negative or if the patient – especially a
3% of cases, CMA – with its ability to detect clin- woman– isnonstigmatized.GenetictestingforRett
ically significant copy-number variants with 100 syndrome – MECP2 gene mutation and sequence
timesgreaterresolutionthanstandardkaryotyping analysis – should generally be limited to girls with
– has identified clinically significant abnormalities microcephaly or deceleration of head growth and
in 8% or more of ASD cases. Although the AAP’s otherfeaturesofRettsyndrome,orwhopresentwith
2007 guidelines did not recommend routine CMA stereotypicalhand-wringingmovementsanddevel-
testing,arecentAAPpublicationdetailedtheadvan- opmental regression [41].
tagesof CMA over karyotypes[38]. The AAP’s most Even though chromosomal karyotypes should
recent recommendations to physicians regarding no longer be routinely ordered, a karyotype is
the initial medical evaluation of a child with ASD indicated if a balanced translocation is suspected,
are outlined in the newly revised Autism Toolkit. as these will not be detected with CMA. Clinicians
There, the AAP recommends in its ‘Physician Fact shouldsuspectabalancedtranslocationifthereisa
Sheet’thatCMAbeofferedtoallpatientswithASD history of more than two miscarriages. In children
[41]. with ASD and macrocephaly (head circumference
Many commercial laboratories offer CMA test >2standarddeviationsabovethemean),PTENgene
batteries that focus on the genetic anomalies most mutation and sequence analysis should be con-
commonly associated with ASD. Interestingly, sidered, as affected patients (and some family
researchers recently reported on the findings of a members) are at increased risk for certain malig-
proprietary genetic test battery intended to predict nancies. This mutation should be considered
ASDs. Focusing on the 237 genetic markers on especially in men with penile macules. Clinical
146 genes and related cellular pathways linked to consultation with a geneticist may be helpful
ASDs,thistesttakesthenovelapproachofexamin- regarding further evaluation or counseling. For
ing multiple genetic mutations and their additive example, if Angelman syndrome is suspected in
contribution, while considering protective versus a child with intellectual disability, happy affect,
vulnerability single-nucleotide polymorphisms and hand waving and clapping, CMA may be
(SNPs) and the genetic differences between ethnic- negative in some cases and more sophisticated
ities. Investigators reported that the test correctly testing would be indicated [41].
predictedASDsin72%ofcasesintwoindependent
sets of central European-descending populations
Neuroimaging
[42&&]. The outcome of ongoing evaluations among
otherethnicgroupswillfurtherdeterminethetest’s Neuroimaging technologies have likewise become
accuracy and specificity. Nonetheless, like some of more sophisticated, with functional magnetic
the early screening parent questionnaires, this test resonance imaging (fMRI) emerging as an effec-
may aid early detection of ASDs in some cases. tive research tool for isolating frequently dis-
Though not yet clinically available through com- rupted neural systems that may underlie ASDs
merciallaboratories,exomesequencinghasrecently [41]. It is suspected that brain abnormalities
beenreportedtoidentifyde-novogeneticmutations found consistently among patients with ASDs
in about 15% of children with severe intellectual are a product of underlying genetic mutations
disability,someofwhomalsohadautism[43].This that influence the expression of key proteins in
investigational technique will likely be available in the brain, and thus result in inefficient neuronal
the not-too-distant future. Ultimately, it is anticip- migration, cortex organization, and overall neural
ated that whole-genome sequencing will become circuitry [45&].
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Autism spectrumdisorders Tchaconas and Adesman
Current studies are using neuroimaging to iso- permeability studies, stool analyses, urinary pepti-
late these problem regions in the brains of people des, or mercury levels are helpful [41,48].
with and without ASDs, noting differences in gene
expression,brainarchitecture,anddisplayedbehav-
TREATMENT
iorsthatcharacterizeASD[46,47&&].Carefulanalysis
of the structural and volumetric measures derived Educational therapy focusing on behavior, com-
from brain MRIs has failed to identify a consistent munication, and social responsiveness remains
patternofearlybraindevelopmentinchildrenwith the mainstay of treatment for ASDs. Medications,
ASDs.Recentstudiesusingdiffusiontensorimaging though not indicated for the treatment of ASDs
(DTI, a technique that measures water diffusion themselves, are occasionally helpful in addressing
within a tissue) suggest that there is a distinct different symptoms, including hyperactivity and
white-matterfibertractmaturationpatterndiscern- irritability. A range of alternative therapies exist,
ableinhigh-riskinfantswhoeventuallydevelopan though they generally have very little research to
ASD or ASD-like symptoms [41]. It is hoped that support their use.
identification of ASD brain biomarkers will soon
allow earlier and enhanced ASD-risk detection and
Educational therapies
that,withtime,neuroimagingwillprovideanobjec-
tive diagnostic test. At this time, ‘isolated, stable Educational therapies are the primary form of
macrocephaly’isnotanindicationforanMRIorCT interventionforASDsinchildren.Althoughmany
scan. The AAP recommends that MRIs should only different techniques are available, only some of
be considered in children with acute regression, these approaches are considered ‘evidence based’.
microcephaly, midline facial defects, neurocutane- Appliedbehavioranalysis(ABA)andtheEarlyStart
ouslesions(withorwithoutWoodlamp),orabnor- Denver Model (ESDM) are best supported by well-
malities on neurologic examination [41]. designed research; however, pediatricians should
be familiar with other, widely known treatment
approaches.
Electroencephalogram
Guidelines suggest that a sleep-deprived EEG with Applied behavior analysis
adequate sampling of slow-wave sleep should only ABA encourages socially significant behaviors
be performed if there is a history of acute develop- through a reinforcement learning technique that
mental regression, unexplained behavior change, trains children with autism to engage in activities
clinicalseizures,orsuspicionofsubclinicalseizures ofdailyliving.ABAhasbeenconsideredasuccessful
[41,48]. behavioral intervention for the past five decades,
yielding substantial gains for children with autism
in intelligence quotient, language, academic per-
Metabolic testing
formance,andadaptivebehavior,withsignificantly
Metabolicdisorders,resultingfrombiologicalerrors bettersocialbehaviorcomparedwithchildrenwith
in amino acid, carbohydrate, purine, peptide, or autistic disorder in control groups [49].
mitochondrial metabolism, are the cause of an The success of ABA has led to many different
ASDinfewerthan5%ofallcases.Metabolictesting forms. In Lovaas’ Young Autism Project, a discrete
shouldnotberoutinelyperformed.TheAAPrecom- trial training (DTT) methodology was employed
mends that testing be limited to ‘children with [50]. DTT is now the most widely recognized form
cyclic vomiting, hypotonia, lethargy (especially of ABA. DTT fosters learning readiness by teaching
when associated with mild illnesses), poor growth, fundamental skills such as attention, compliance,
unusual odors, multiple organ involvement, ataxia imitation, and discrimination learning as small,
or other movement disorder, or evidence of a stor- individually acquired tasks [49].
age disease (e.g., coarse features). Testing should Like other forms of ABA, DTT has been ques-
include lactate, pyruvate, carnitine, acylcarnitine tionedforitsapplicabilityinnaturalsituationsasit
profile,liverandrenalfunction,aminoacidsinclud- is conducted entirely in a structured teaching
ing testing for phenylketonuria, and urine organic environment.Toaddresstheseconcerns,traditional
acids’. Lead levels should be monitored in children ABAtechniqueshavebeenmodifiedinrecentyears
with ASD and a history of pica, especially those vianaturalizationofthesebehavioralinterventions
living in a high-risk environment. Serum ferritin [51]. Whereas traditional ABA has long been recog-
level may also be indicated to assess iron stores. nized as the educational treatment of choice for
According to the AAP, there is no evidence that young childrenwith autism, it isless clear whether
hair analysis, micronutrient levels, intestinal this treatment paradigm is the optimal approach
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for less severely affected, higher functioning indi- their children to display pivotal developmental
viduals. behaviors: attention, persistence, interest, initia-
tion, cooperation, joint attention, and affect [49].
PRTreinforcespositivesocialcommunicationwith-
Early Start Denver Model
out disruptive self-stimulatory behaviors; it is
The ESDM is a novel developmental–behavioral
mainly used withpreschooland elementaryschool
intervention rooted in ABA that is designed for
children, but also helps adolescents and young
young children (toddlers) with signs of an ASD
adults [59,60]. PRT is a fundamental component
[52].TheESDMwaseffectiveinrandomizedclinical
of the ESDM.
trialsforchildrenasyoungas12–18monthsacross
all ASDs by teaching child-specific goals through
Relationship development intervention
playactivities [53].TheESDMmodelhasnowbeen
Relationship development intervention (RDI)
adaptedforexperimentaluseininfantsasyoungas
emphasizes the value of positive interaction by
6 months with signs of ASD [54].
engaging the child in a social relationship that
motivates the child to acquire the social skills to
‘Floortime’/developmental individual-
maintain such relationships [61]. RDI allows indi-
difference relationship-based model
vidualswithASDstodevelop‘dynamicintelligence’,
The developmental individual-difference relation-
orflexiblethinking,whichallowsthemtocopewith
ship-based (DIR) model is a relationship-focused
changesandnewinformation.RDIisbuiltfromthe
intervention often integrated with floortime play,
perspective that ASDs are a deviation from typical
in which adults engage with children by playing
development of social relationships because of an
withthemonthefloor[55].Byallowingthechildto
inability to think flexibly. RDI addresses this dys-
leadfloortimeplayactivities,thechildischallenged
function by helping parents gradually build their
to work toward achieving social and emotional
relationship with their child. Although Greenspan
milestones. An independent pilot study training
founda positiveresultina smallsampleofindivid-
parents to use the Floortime/DIR model at home
ualswithASDreceivingRDI[62],RDIefficacyhasyet
for 15h/week over 8–12 months reported that
tobeevaluatedbyindependentempiricalstudies.
45.5% of children made substantial functional
developmental progress, deeming it a potentially
Training and education of autistic and
cost-effective intervention for young children with
related communication handicapped
autism [56]. A recent study in Thailand found that
children
adding Floortime/DIR intervention for 15.2h/week
The training and education of autistic and related
for 3 months among preschool children with ASDs
communication handicapped children (TEACCH)
conferred on the intervention group significantly
method is structure based, often called ‘structured
greater gains on three measures: Functional
teaching’, including organization of the physical
Emotional Assessment Scale, Childhood Autism
environment, predictable sequences of activities,
Rating Scale, and the Functional Emotional Ques-
visual schedules, flexible routines, structured work
tionnaires [57]. Preliminary results of an ongoing
and activity systems, and visually structured acti-
randomized controlled Canadian trial of 51 pre-
vities[63].Emphasisliesonmodifyingtheenviron-
schoolagechildrenineitheraDIRtreatmentgroup
menttoaccommodateachild’sdeficitsandimprove
(2h/week of therapy and parent coaching) or a
the child’s individual skills [49]. Among children
community treatment group (3.9h/week) suggest
receivingTEACCHservices,improvementsinparent
that children in the DIR treatment group made
teaching skills and parent satisfaction have been
significantlygreatergainsinsocialinteractionskills
reported, though not based on controlled studies
compared with the community treatment group
of treatment outcomes. In a controlled study,
[58]. Although these two comparative studies from
children enrolled in a TEACCH-based home pro-
2011demonstratedthatDIR/Floortimesignificantly
gram for4 monthsalong with their local day treat-
improvedemotionaldevelopmentandreducedcore
ment programs improved significantly more than
ASDsymptoms,itisunclearwhetherthistreatment
those in the control group who only received local
approach would be as effective in settings where
day treatment services [64].
more extensive treatments are provided.
Pivotal response treatment Educational therapies in perspective
Pivotal response treatment (PRT) is another Given the expanded number of educational tech-
research-validated treatment for ASDs. PRT, also niquestotreatchildrenwithASD – somewithmore
derived from ABA, trains parents to encourage empirical support than others – it is likely difficult
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Autism spectrumdisorders Tchaconas and Adesman
for a primary care pediatrician to appreciate the Hyperactivity and impulsivity are not uncom-
differences among these treatment approaches mon in children with ASDs. Any of the FDA-
and make informed recommendations to families approved ADHD medications can be used in
about what constitutes an optimal treatment for a children with ASDs. When prescribed for children
specific child. Although it would be wonderful if with ASDs, stimulants typically have a somewhat
parents and professionals had an evidence-based smallereffectsize;inaddition,lowerdosesareoften
algorithm to clearly identify which treatment requiredand adverse eventsmay bemorecommon
method is best for each child on the autism spec- [66].ItmustberememberedthatchildrenwithASDs
trum, no such algorithm exists. Realistically, selec- maynotbeabletocommunicateside-effectssuchas
tionofaneducationalapproachforachildwithASD stomachaches or headaches, so parents and clini-
will be subject to clinical considerations as well as cians must be especially attentive to dosing and
nonclinicalfactors–suchasparentpreference,cost, clinicalresponse.AschildrenwithASDsoftenhave
and accessibility. difficulty with existing forms of long-acting stimu-
lants (caplets, capsules, sprinkled beads, or trans-
dermal patches), clinicians may find a newly
Pharmacotherapy: medical treatments
approved,extendedreleaseliquidmethylphenidate
currently available
formulation to be especially helpful in some
AlthoughnomedicationsareFDAapprovedtotreat children. Atomoxetine or alpha-2 agonists may be
thecoresymptomsofASDs,pharmacotherapymay usedtotreathyperactivityorimpulsivity,especially
be used in children with ASD to target commonly in children for whom stimulants are not effective
associated symptoms such as hyperactivity, impul- and well tolerated.
sivity, inattention, aggression, irritability, anxiety, In the past, selective serotoninreuptakeinhibi-
and withdrawal. The decision to prescribe medi- tors (SSRIs) such as fluoxetine have been used to
cationshouldbeonacase-by-casebasisafterreason- treatrepetitivebehaviorsorrigidityinchildrenwith
able nonpharmacologic interventions have been ASD; however, studies suggest these medications
attempted. Two atypical antipsychotics are may be effective in adults, but not children. Like-
approvedbytheFDAforthetreatmentofirritability wise, children with ASD are often very anxious,
in children with autism – risperidone (age 5 and which can then lead to significant behavior pro-
above) and aripiprazole (age 6 and above). These blems.Althoughtherearenostudiesdemonstrating
medications, though effective, often have side- that SSRIs are effective in reducing anxiety in
effects and require careful monitoring. Increased children with ASDs, these medications are some-
appetitewithsignificantweightgainisnotuncom- times prescribed based on their demonstrated
mon. Although monitoring abdominal girth (waist efficacy in the non-ASD population [67].
circumference) may be helpful, BMI measurements Sleep problems are also common in children
at baseline and at follow-up provide a more precise with ASDs. Although nonpharmacologic interven-
metric.Insulinresistancewithbloodsugarelevation tions should always be the initial treatment
is also associated with the atypical antipsychotics. approach,melatoninhasbeenshowntobeeffective
Although monitoring protocols vary considerably, when given before bedtime at doses ranging from
manyexpertsrecommendbaselinetestingandthen 0.5 to 10mg. As alpha-2 agonists and atomoxetine
follow-up testing at 3 months, 6 months, and then arealsosomewhatsedatinginsomechildren,night-
every6monthsthereafter[65].Baseline blood tests time administration of these medications may be
shouldincludefastingplasmaglucose,hemoglobin helpful in children experiencing problems with
a1c,fastinglipids,liverfunctiontests,prolactin,and sleep onset [67].
thyroid stimulating hormone. Follow-up testing Although treatment with other medications
should include fasting glucose and lipids. Some (e.g., typical antipsychotics, mood stabilizers) is
guidelines also recommend monitoring insulin sometimes indicated, children with ASD needing
levels,thoughotherssuggestfollowinghigh-density more sophisticated or aggressive psychopharmaco-
lipoprotein/triglyceride ratios, as triglyceride eleva- logic management should likely be referred to a
tionisalmostalwayspresentwithinsulinresistance. pediatric subspecialist with expertise in this field
Prolactinlevelsshouldbemonitoredincaseswhere – either pediatric neurologist, child psychiatrist, or
symptomsorsignsofelevationareevident;likewise, developmental pediatrician [67].
acompletebloodcountmaybeincludedifthereare
concerns about neutropenia. Patients who have
Promising medical treatments
multipleriskfactorsfordiabetesmellitusorwhohave
gained at least 7% of their pretreatment weight GeneticinvestigationsofASDshaveledresearchers
shouldbemonitoredespeciallyclosely. to develop experimental medical treatments that
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Office pediatrics
target these genetic abnormalities. For example, found to improve core deficits of ASD in children
arbaclofen(aninvestigationaldrugforpatientswith and adolescents. Increased brain activity in
FragileXsyndrome)hasbeenshowntobeapoten- regions known to process social information was
tial disease-modifying drug in preclinical models observedfollowingoxytocintreatment,translating
[68&] and results in significant improvements in behaviorally to greater social engagement [74].
social impairment in clinical trial [69&&]. Given its Again, additional studies are needed to determine
preliminary success in treating a core symptom of whether these available medications are indeed
autism,arbaclofenwillbefurthertestedinongoing well tolerated and effective for use in children
clinical trials, and could be the first effective medi- with ASD.
cinetotreatFragileX.Ofcourse,itishopedthat,if
arbaclofen can improve the social function of
COMPLEMENTARY AND ALTERNATIVE
children with comorbid ASD and Fragile X, it may
MEDICINE THERAPIES
beeffectiveinotherASDpopulationsaswellorlead
to the development of other effective medications. Studiesindicatethat50–75%ofchildrenwithASDs
Enzyme replacement therapy is another inves- are treated with complementary and alternative
tigational treatment that has been fast-tracked for medicine(CAM)[75,76];thesepercentagesareeven
clinicaltestingintheUSA.Thistreatmentistargeted higher in children with severe autism or comorbid
at children with autism who are reported to have intellectual disability. Such therapies are easily
biomarkers suggesting enzyme deficiencies. These accessible and perhaps more psychologically com-
enzyme deficiencies then result in an inability to fortingforparentsgiventhattheyaregenerallyless
digestprotein,whichthencompromisesaminoacid invasive[76].Unfortunately,thescopeofthisarticle
production. A proprietary high-protease enzyme does not allow discussion of the dozens of CAM
replacementformulation(CM-AT)wasjustreported therapies for ASD; instead, we will briefly discuss
to be significantly more effective than placebo in some of the more popular, intriguing, and con-
treating core and noncore symptoms of children troversial interventions.
aged 3–8 years with autism in a randomized, Dietary changes are often made to enhance or
double-blind, Phase III clinical trial [70,71]. alleviatecommonsymptomsinchildrenwithASD.
Another potential therapeutic focuses on the Themostcommondietaryinterventionisagluten-
patients with autism, intellectual disability, and free/casein-free diet, which families pursue in the
seizuresbecauseofadefectofbranchedchainamino hope that it will alleviate suspect gastrointestinal
acid (BCAA) metabolism. Patients with this rare problemsthoughttoaggravateASDsymptoms[77].
mutationhavedecreasedlevelsofBCAAs.Novarino Althoughmanygluten-freefoodsarenowavailable,
et al. [72] demonstrated ina genetically engineered the gluten-free/casein-free elimination diet can be
‘knockout mice’ model that abnormal brain amino difficult to implement. More importantly, in a
acid profiles and neurobehavioral deficits respond methodologically rigorous, well-controlled study
to dietary supplementation. The researchers also ofchildrenwithASDsonthegluten-free/casein-free
took skin samples from patients with this gene diet for at least 1 month, there were no significant
defect and converted them into neural stem cells; changesinattention,activity,sleep,orbowelhabits
these neural cells functioned normally in the pres- [78]. Pediatricians should counsel families about
enceofanenvironmentrichinthedepletedamino thislatestresearchfinding–recognizingatthesame
acids – suggestingthatatleastoneveryrareformof time that many parents will be encouraged by
autism may be treatable. anecdotalreportsandtrythegluten-free/casein-free
New research suggests that other available diet nonetheless.
medications may be helpful in treating children Supplementation with omega-3 fatty acids is
with ASD. Oral administration of N-acetylcysteine also not uncommon. A randomized, double-blind,
(NAC), an antioxidant and a glutamatergic modu- placebo-controlled,6-weekpilottrial[79]examined
lator,displayedefficacyintreatingdisruptivesymp- theeffectsof1.5g/dayofomega-3fattyacids(0.84g/
toms in children with autistic disorder in a pilot dayeicosapentaenoicacidand0.7g/daydocosahex-
study [73&].Furtherstudies areneeded toassess the aenoic acid) supplementation on children with
feasibility of using NAC as a routine treatment ASDs. In this pilot study of 13 children (aged
option for disruptive behaviors from autistic dis- 5–17 years) with autistic disorders accompanied
order and for other disorders marked by repetition by severe tantrums, aggression, or self-injurious
and compulsion (i.e. obsessive compulsive disorder behavior, investigators noted decreased hyperacti-
andskinpicking).Similarly,preliminaryresultsofa vityandstereotypy(eachwithalargeeffectsize)and
large-scale, placebo-controlled, double-blind study no significant adverse effects. Although replicating
suggestthatnasallyadministeredoxytocinhasbeen these findings in larger samples is needed, there is
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Autism spectrumdisorders Tchaconas and Adesman
likelylittleharminfamiliesconsideringanempiric treatments. Pediatricians who want to practice
trial of fish oil supplementation. evidence-basedmedicinemustrememberthatnovel
Manyotherdietarysupplementshavebeenpro- therapies may be effective and that the absence of
moted, though few have credible research to sup- research does not necessarily mean absence
port theiruse. Inapairofcontrolled studies bythe of benefit. On the other hand, the benefits (if any)
investigators at Arizona State University, investi- ofmostCAMtreatmentsareoverstated,andthereare
gatorsnotedchildrenwithautisticdisordertohave considerable risks if families pursue each and every
various nutritional deficiencies [80] and that vita- CAM treatment available. A family’s decision to
minandmineralsupplementsledtoimprovements pursue CAM may be acceptable as long as it does
on nutritional, metabolic, and clinical outcome notpresenthealthriskstothechild,precludemore
measures [81]. Despite longstanding claims that effective therapies, or usurp limited family resour-
Vitamin B6 and magnesium supplementation is ces[86].Integrativemedicine,ablendoftraditional
helpful,arecentCochranereviewnotedtherewere andnontraditionaltreatments,isanemergingcom-
few studies available, the samples were small, and promisebetweenmainstreampediatricianswhoare
the results inconclusive. It concluded that research skeptical and hopeful parents desperate to help
doesnotsupportthisformoftreatment[82].Methyl their child.
B12 injections have been used toprevent oxidative
stress often linked to ASDs, with only anecdotal
Prognosis
reports of improvement [83]. Studies looking at
the nutritional status of children with ASD and Recentstudiessuggestthattheoutcomeforchildren
treatmentopportunitiesareactivelybeingpursued; with ASD can be highly variable. Children with
hopefully, research will soon clarify which dietary ASDs can differ considerably at baseline and at
and nutritional interventions can be considered follow-up not just in terms of severity, but also
well tolerated and effective. withregardtoassociateddevelopmentaldisabilities
Hyperbaric oxygen therapy (HBOT), which (e.g., intellectual disability), medical conditions,
uses pressurized oxygen to increase blood flow and andcomorbidpsychiatricdisorders.Effortstomodel
oxygentothebrainanddecreaseinflammation,has thediversecasesofASDshavegeneratedmathemat-
beensuggestedasatreatmentforASD.Atthispoint, ical representations of typical outcomes along a
there are very few well-controlled trials and the path of defined functional level. Through a longi-
resultsareinconsistent.Expertshaverecommended tudinal developmental surveillance study of a large
thatmethodologicallyrigorousstudiesbeconducted population of children with ASDs in California, six
with meticulous attention to sham control con- distinct trajectories in three functional domains
ditions.Pendingfurtherevidencetosuggestefficacy, (social, communication, and repetitive behavior)
HBOT is not recommended for children with ASD havebeenidentified[87&&].AscanbeseeninFig.1,
[84]. each of these trajectories – high, medium-high,
Chemicalchelationhasbeenapopularyetcon- bloomers, medium, low-medium, and low – begins
troversial intervention among families who believe withabaselineASDseverity,whichhasbeenassoci-
heavymetalpoisoning(e.g.,mercury)isresponsible atedwiththemostcommonfactorswithinthepopu-
for their child’s ASD symptoms. In two internet- lation. Socioeconomic status is implicated as a
based surveys, 7–8% of parents of children with significant factor in ASD developmental outcome,
ASDindicatedthattheyhadtriedchelationtherapy. as it encompasses variables inherent to home and
Although a few published studies provide weak evi- neighborhood environment, including quality of
dence for chelation, there are no well-controlled treatment and education, and access to services
studies to suggest it is either well tolerated or effec- andearlyinterventions[87&&].
tive. A 2013 review article concludes that research
does not support chelation as a treatment for ASD
CONCLUSION
[85]. Pediatricians should also discourage families
from pursuing craniosacral massage (most typically Years ago, Winston Churchill – in reference to the
proffered by chiropractors) or auditory integration Russian foreign policy – lamented: ‘It is a riddle,
therapy. wrappedinamystery,insideanenigma;butperhaps
thereisakey’.Undoubtedly,expertsinchilddevel-
opment would likely extend Churchill’s famous
Complementary and alternative medicine in
words to ASDs. Although gains in understanding
perspective
have been achieved, progress has been slow and
Fromanemotionalstandpoint,itisunderstandable researchers have far more questions than answers.
how families may feel compelled to explore CAM Whereas causes were once viewed as either genetic
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