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Autism

Autism
Author:JamesRobertBrasic,MD,MPHChiefEditor:CarolyPataki,MDmore...
Updated:Dec15,2014

PracticeEssentials
Autismspectrumdisorder(ASD)manifestsinearlychildhoodandischaracterizedbyqualitativeabnormalitiesin
socialinteractions,markedlyaberrantcommunicationskills,andrestrictedrepetitivebehaviors,interests,and
activities(RRBs).

Essentialupdate:Studysuggestsimagingofneuralrepresentationsofsocialinteractionscan
identifyautism
Inastudythatincluded17adultswithhighfunctioningautismand17ageandIQmatchedcontrolsubjects,
functionalmagneticresonanceimaging(fMRI)ofthebrainthatshowedneuralrepresentationsofsocialinteractions
wasabletoaccuratelyidentifyindividualswithautism.Scanswereperformedasstudysubjectsthoughtaboutaset
ofsocialinteractionverbsfrombothanactionandarecipientperspective. [1,2]
Individualswithautismwereshowntolackasubcomponentofneuralactivityintheposteriorcingulate/precuneusin
responsetoconceptssuchashugandadore,whereasthisneuralactivitywasstronglypresentincontrolsubjects. [2]
Machinelearninganalysisautomaticallyidentifiedindividualswithautismandcontrolsonthebasisofthesethought
markerpatternswithanaccuracyof97%.
Anindividual'sneuralrepresentationofaparticularsocialinteractioncouldbereliablyidentifiedbyamachine
learningclassifiertrainedonactivitypatternsfromeitherthesameoranotherindividual,suggestingthata
systematicrelationbetweenbrainactivityandthoughtsonsocialinteractionsissharedacrossindividuals,including
thosewithautism. [2]Thedegreetowhichtheneuralrepresentationoftheselfinsubjectswithautismwasaltered
correlatedwithboththequalityofthecingulumbundleandwithbehavioralmeasures,suchasfaceprocessing
ability.

Signsandsymptoms
Behavioralanddevelopmentalfeaturesthatsuggestautismincludethefollowing:
Developmentalregression
Absenceofprotodeclarativepointing
Abnormalreactionstoenvironmentalstimuli
Abnormalsocialinteractions
Absenceofsmilingwhengreetedbyparentsandotherfamiliarpeople
Absenceoftypicalresponsestopainandphysicalinjury
Languagedelaysanddeviations
Susceptibilitytoinfectionsandfebrileillnesses
Absenceofsymbolicplay
Repetitiveandstereotypedbehavior
Regularscreeningofinfantsandtoddlersforsymptomsandsignsofautisticdisorderiscrucialbecauseitallowsfor
earlyreferralofpatientsforfurtherevaluationandtreatment.Siblingsofchildrenwithautismareatriskfor
developingtraitsofautismandevenafullblowndiagnosisofautism.Therefore,siblingsshouldalsoundergo
screeningnotonlyforautismrelatedsymptomsbutalsoforlanguagedelays,learningdifficulties,socialproblems,
andanxietyordepressivesymptoms. [3]
HavingparentsfillouttheAutismScreeningChecklistcanidentifychildrenwhomeritfurtherassessmentfor
possibleautism.Seetheimagebelowforaprintableversionofthechecklist.

ThesignificanceofanswerstoindividualAutismScreeningChecklistitemsisasfollows:Item1A"yes"occursinhealthychildren
andchildrenwithsomepervasivedevelopmentaldisordersa"no"occursinchildrenwithautism,Rettsyndrome,andother
developmentaldisorders.Item2A"yes"occursinhealthychildren,notchildrenwithautism.Item3A"yes"occursinhealthy
childrenandchildrenwithAspergersyndrome(ie,highfunctioningautism)a"no"occursinchildrenwithRettsyndromechildren
withautismmayelicita"yes"ora"no"somechildrenwithautismneverspeaksomechildrenwithautismmaydevelopspeech
normallyandthenexperiencearegressionwiththelossofspeech.Item4A"yes"occursinhealthychildrenandchildrenwith
Aspergersyndromeandsomeotherpervasivedevelopmentaldisordersa"no"occursinchildrenwithdevelopmentaldisorders
childrenwithautismmayelicita"yes"ora"no."Items510Scoresof"yes"occurinsomechildrenwithautismandinchildrenwith
otherdisorders.Item11A"yes"occursinhealthychildrena"no"occursinsomechildrenwithautismandinchildrenwithother
disorders.Items12,13Scoresof"yes"occurinsomechildrenwithautismandinchildrenwithotherdisorders.Items1419
Scoresof"yes"occurinchildrenwithschizophreniaandotherdisorders,notinchildrenwithautism,Aspergersyndrome,orother
autismspectrumdisorders.Thehigherthetotalscoreforitems510,12,and13ontheAutismScreeningChecklist,themorelikely
thepresenceofanautismspectrumdisorder.

SeeClinicalPresentationformoredetail.

Diagnosis
Examinationforpatientswithsuspectedautisticspectrumdisordermayincludethefollowingfindings:
Abnormalmotormovements(eg,clumsiness,awkwardwalk,handflapping,tics)

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Dermatologicanomalies(eg,aberrantpalmarcreases)
Abnormalheadcircumference(eg,smallatbirth,increasedfromage6monthsto2years, [4]normalin
adolescence [5])
Orofacial,extremity,andhead/trunkstereotypies(eg,purposeless,repetitive,patternedmotions,postures,
andsounds)
Selfinjuriousbehaviors(eg,pickingattheskin,selfbiting,headpunching/slapping)
Physicalabuseinflictedbyothers(eg,parents,teachers)
Sexualabuse:Externalexaminationofgenitaliaisappropriateifbruisesandotherevidenceoftraumaare
present,pelvicandrectalexaminationsmaybeindicated
Diagnosticcriteria
ThedefinitionofASDintheDiagnosticandStatisticalManualofMentalDisorders,FifthEdition(DSM5)
encompassesthepreviousmanual'sautisticdisorder(autism),Asperger'sdisorder,childhooddisintegrativedisorder,
andpervasivedevelopmentaldisordernototherwisespecified.ASDischaracterizedbythefollowing[6]:
Deficitsinsocialcommunicationandsocialinteraction
Restrictedrepetitivebehaviors,interests,andactivities(RRBs)
Thesesymptomsarepresentfromearlychildhoodandlimitorimpaireverydayfunctioning.Bothcomponentsare
requiredfordiagnosisofASD.
Testing
TherearenobloodstudiesrecommendedfortheroutineassessmentofASD.Althoughseveralmetabolic
abnormalitieshavebeenidentifiedininvestigationsofpeoplewithautism(eg,elevated5HT,reducedserum
biotinidase,abnormalneurotransmitterfunctions,impairedphenolicaminesmetabolism),ametabolicworkupshould
beconsideredonanindividualbasis.Nobiologicmarkersforautismcurrentlyexist.
Studiesthatmaybehelpfulintheevaluationofautisticdisorderincludethefollowing:
EEG:Toexcludeseizuredisorder,acquiredaphasiawithconvulsivedisorder(LandauKleffnersyndrome),
biotinresponsiveinfantileencephalopathy,relatedconditions
Psychophysiologicassessment:Toshowlackofresponsehabituationtorepeatedlypresentedstimuli(in
respiratoryperiod,electrodermalactivity,vasoconstrictiveperipheralpulseamplituderesponse)auditory
overselectivitymaybeseen
Polysomnography:Toidentifysleepdisordersandtodemonstrateseizuredischarges
Neuroimagingstudies
Thereiscurrentlynoclinicalevidencetosupporttheroleofroutineclinicalneuroimaginginthediagnosticevaluation
ofautism,eveninthepresenceofmegalencephaly. [3]Althoughcharacteristicabnormalitieshavebeenidentified,no
singlefindingisdiagnostic.
Thefollowingimagingtechniqueshaveyieldedinconsistentresultsinevaluatingautism:
MRIwithorwithoutdiffusiontensorimaging
CTscanning
PETscanning
SPECTscanning
SeeWorkupformoredetail.

Management
Theestablishedtherapiesforautisticdisorderarenonpharmacologicandmayincludeindividualintensive
interventions.Individualswithautismspectrumdisorderandunspecifiedpervasivedevelopmentaldisordertypically
benefitfrombehaviorallyorientedtherapeuticprogramsdevelopedspecificallyforthispopulation.Autisticchildren
shouldbeplacedinthesespecializedprogramsassoonasthediagnosisissuspected.
Nonpharmacologictherapy
Intensiveindividualspecialeducation
Speech,behavioral,occupational,andphysicaltherapies(eg,assistedcommunication,auditoryintegration
training,sensoryintegrationtherapy,exercise/physicaltherapy)
Socialskillstraininginsomechildrenwithautismspectrumdisorder,includingthosewithcomorbidanxiety
disorders [7]childrenwithautismspectrumdisorderandcomorbidADHDmaybenefitlessfromsocialskills
training [7]
Pharmacotherapy
Nopharmacologicagentiseffectiveinthetreatmentofthecorebehavioralmanifestationsofautisticdisorder,but
drugsmaybeeffectiveintreatingassociatedbehavioralproblemsandcomorbiddisorders(eg,selfinjurious
behaviors,movementdisorders).Thepossiblebenefitsfrompharmacotherapymustbebalancedagainstthelikely
adverseeffectsonacasebycasebasis(eg,venlafaxinemayincreasehighintensityaggressioninsome
adolescentswithautism[8])
Medicationsusedinmanagingrelatedbehavioralproblemsandcomorbidconditionsinchildrenwithautisminclude
thefollowing:
Secondgenerationantipsychotics(eg,risperidone,aripiprazole,ziprasidone)
SSRIantidepressants(eg,fluoxetine,citalopram,escitalopram)
Stimulants(eg,methylphenidate)
SeeTreatmentandMedicationformoredetail.

Background
Autismisaconditionthatmanifestsinearlychildhoodandischaracterizedbyqualitativeabnormalitiesinsocial
interactions,markedlyaberrantcommunicationskills,andrestrictedrepetitiveandstereotypedbehaviors.A
heterogeneousgroupofdisordersincludesthetraitofautism.

Motionanomalies
Motionanomaliesareaprominentfeatureinasubsetofindividualsandhavebeenreportedatbirthinsome
personswithautism.Motionanalysismayprovideevidenceofautisminearlyinfancy,beforeothermanifestations

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occur. [9]
Themotionanomaliesdemonstratedbychildrenwithautismareoftenhighlycharacteristicandnoticeable.An
exampleofamotiontypicalinautismoccurswhenthechildplacesahandwithfingersseparatelyoutstretched
beforetheeyesandrapidlymovesthehandbackandforth.Asimilarexperienceresultsfrommovingupanddown
whilegazingthroughtheslatsofVenetianblinds.Thisactionisdescribedasselfstimulationbecauseitproducesa
visualsensationofmovement.(SeePresentation.)
Manyofthemotionsofchildrenwithautismappeartobeattemptstoprovidethemselveswithsensoryinputina
barrenenvironment.Throughspecialeducation,childrenmaylearntosuppressthemovements,althoughthesemay
subsequentlybeexhibitedattimesofparticularstressorexcitement.

Causes
Althoughtheetiologyofautismisunknown,hypothesesincludegeneticabnormalities,obstetriccomplications,
exposuretotoxicagents,andprenatal,perinatal,andpostnatalinfections. [10,11,12,13]Maternalrubellais
associatedwithsignificantlyhigherratesofautismandotherconditionsinchildren.Additionally,tuberoussclerosis
isassociatedwithautismasacomorbiddisorder. [14]Approximately10%ofchildrenwithapervasivedevelopmental
disorderexhibitaknownmedicalcondition.(SeeEtiology.)
Ontheotherhand,anecdotalreportsthatautismmaybelinkedwithvaccinations(eg,formeasles,mumps,and
rubella)havenotbeensupportedbybroaderresearch. [15]ResearchfromtheCDCindicatesthatthenumberof
childhoodvaccinesadministered,eitherinasingledayorduringachild'sfirst2years,hasnoeffectontheriskof
developinganautismspectrumdisorder(ASD).Accordingtoresultsofacasecontrolstudyofmorethan1000
childrenbornbetweenJanuary1994andDecember1999,exposuretoantibodystimulatingproteinsor
polysaccharidesfromvaccinesbetweentheagesof3monthsand2yearswasnotassociatedwithanincreasedrisk
ofdevelopinganASD.Thestudyincluded256childrenwithanASDand752healthycontrols. [16,17]Parentsshould
beencouragedtofullyimmunizetheirchildren. [18](SeeEtiology.)
Effectivetreatmentofassociatedbehavioralproblemsincludesintensivebehavioral,educational,andpsychological
components.Interventionsinitiatedatthetimeofdiagnosisincreasethelikelihoodofafavorableoutcome. [19]
Regularscreeningofinfantsandtoddlersforsymptomsandsignsofautisticdisorderiscrucialbecauseitallowsfor
earlyreferralofpatientsforfurtherevaluationandtreatment.(SeeTreatment.)
Theinitialclinicaldescriptionsofautismsuggestedthatcold,rejectingparents("refrigeratormothers")caused
autisminoffspringhowever,carefulstudyofchildrenwithautismandtheirparentshasdisprovedthishypothesis.
Autismisnotcausedbyalackofwarmthandaffectioninparents,norbyanyotheremotionalorpsychological
parentaldeficits.Blamingparentsforthedevelopmentofautismintheirchildrenisinappropriate.

Diagnosis
Severalinstrumentshavebeendevelopedtodiagnoseautismandotherpervasivedevelopmentaldisorders.
Administeringthesetoolsinareliableandvalidmannerrequiresextensivetrainingandexperience.Therefore,
unlesstheyhavewideexperiencewithchildrenwithautismandunderstandtheconceptsimplicitinthediagnostic
criteriaandratingscales,pediatriciansandothercliniciansareadvisedtoreferpatientswithpossibleautismto
experiencedcliniciansfordefinitivediagnosticevaluations.(Seethescreeningchecklistbelow.)

ThesignificanceofanswerstoindividualAutismScreeningChecklistitemsisasfollows:Item1A"yes"occursinhealthychildren
andchildrenwithsomepervasivedevelopmentaldisordersa"no"occursinchildrenwithautism,Rettsyndrome,andother
developmentaldisorders.Item2A"yes"occursinhealthychildren,notchildrenwithautism.Item3A"yes"occursinhealthy
childrenandchildrenwithAspergersyndrome(ie,highfunctioningautism)a"no"occursinchildrenwithRettsyndromechildren
withautismmayelicita"yes"ora"no"somechildrenwithautismneverspeaksomechildrenwithautismmaydevelopspeech
normallyandthenexperiencearegressionwiththelossofspeech.Item4A"yes"occursinhealthychildrenandchildrenwith
Aspergersyndromeandsomeotherpervasivedevelopmentaldisordersa"no"occursinchildrenwithdevelopmentaldisorders
childrenwithautismmayelicita"yes"ora"no."Items510Scoresof"yes"occurinsomechildrenwithautismandinchildrenwith
otherdisorders.Item11A"yes"occursinhealthychildrena"no"occursinsomechildrenwithautismandinchildrenwithother
disorders.Items12,13Scoresof"yes"occurinsomechildrenwithautismandinchildrenwithotherdisorders.Items1419
Scoresof"yes"occurinchildrenwithschizophreniaandotherdisorders,notinchildrenwithautism,Aspergersyndrome,orother
autismspectrumdisorders.Thehigherthetotalscoreforitems510,12,and13ontheAutismScreeningChecklist,themorelikely
thepresenceofanautismspectrumdisorder.

Onegoalofthisarticleistoconveyfundamentalconceptsrelatedtoautismandrelatedconditions.Readersofthis
articlemustobtainconsiderableadditionaltrainingbeforetheycanreliablyandvalidlyapplydiagnosticcriteriaand
ratingtools.

Treatment
Individualized,intensivebehavioralandpsychologicalinterventionsmustbeinstitutedimmediatelyafterthe
diagnosisofautisminorderforthepatienttoachieveanoptimaloutcome.Althoughcontroversysurroundsthe
appropriateformofspecialeducation,someevidencesuggeststhatanindividualeducationalprogrammustbe
developedbyaspecialeducatorfamiliarwithautisticdisorderandrelatedconditions.
Becausedeficitsinlanguageandcommunicationareoftenmajorimpedimentstoprogressineducational,work,and
personalsettings,patientsoftenbenefitfromspecializedcommunicationdevicesandtraining.Personsexperienced
intheneedsandtreatmentofindividualswithseriouscommunicationhandicaps(ie,speechandlanguage
specialists)mayhelpthepatienttomaximizecommunicationskills.
Althoughpsychoanalyticapproachestotreatmentofchildrenwithautismwerecommoninthemid20thcentury,
theseapproacheswerenotfoundtobeeffectiveandarenolongerused.Pharmacotherapyisineffectiveintreating
thecoredeficitsofautismbutmaybeeffectiveintreatingassociatedbehavioralproblemsandcomorbiddisorders.
Thepossiblebenefitsfrompharmacotherapymustbebalancedagainstthelikelyadverseeffectsonacasebycase
basis.(SeeTreatment.)

Practiceguidelines
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TheAmericanAcademyofChildandAdolescentPsychiatryhasreleasednewpracticeguidelinesforthe
assessmentandtreatmentofchildrenandadolescentswithASD. [20,21]Recommendationsincludethefollowing:
QuestionsaboutcoresymptomsofASDshouldbearoutinepartofpsychiatricanddevelopmental
assessmentsofyoungchildren.
IfscreeningrevealssignificantASDsymptomatology,athoroughevaluationshouldbeperformedand
possiblecomorbiddiagnosesshouldbeconsidered.
ChildrenwithASDshouldundergoamultidisciplinaryassessment,includingaphysicalexamination,a
hearingscreen,communicationandpsychologicaltests,andgenetictesting.
Cliniciansshouldhelpfamiliesobtaineducationalandbehavioralinterventions,suchasappliedbehavioral
analysis(ABA)programs.
Pharmacotherapyshouldbeofferedforspecifictargetsymptomsorcomorbidconditions.
Cliniciansshouldmaintainanactiveroleintheplanningoflongtermtreatment.
Familiesshouldbeaskedabouttheuseofalternative/complementarytreatments.

Pathophysiology
Neuralanomalies
Inpatientswithautism,neuroanatomicandneuroimagingstudiesrevealabnormalitiesofcellularconfigurationsin
severalregionsofthebrain,includingthefrontalandtemporallobesandthecerebellum.Enlargementsofthe
amygdalaandthehippocampusarecommoninchildhood.Markedlymoreneuronsarepresentinselectdivisionsof
theprefrontalcortexofautopsyspecimensofsomechildrenwithautism,comparedwiththosewithoutautism. [22]
Magneticresonanceimaging(MRI)studieshavesuggestedevidencefordifferencesinneuroanatomyand
connectivityinpeoplewithautismcomparedwithnormalcontrols.Specifically,thesestudieshavefoundreducedor
atypicalconnectivityinfrontalbrainregions,aswellasthinningofthecorpuscallosuminchildrenandadultswith
autismandrelatedconditions.
Importantly,someoftheregionaldifferencesinneuroanatomycorrelatesignificantlywiththeseverityofspecific
autisticsymptoms. [23,24]Forexample,socialandlanguagedeficitsofpeoplewithautismlikelyarerelatedto
dysfunctionofthefrontalandtemporallobes. [25]
Inastudyofpostmortembraintissuefrom11childrenwithautismand11unaffectedcontrols,researchersfound
focaldisruptionofcorticallaminararchitectureinthecortexesof10ofthechildrenwithautismand1ofthecontrols,
suggestingthatbrainirregularitiesinautismmayhaveprenatalorigins.Thepatchesofabnormalneuronswere
foundinthefrontalandtemporallobes,regionsinvolvedinsocial,emotional,communication,andlanguage
functions.Sincethechangeswereintheformofpatches,theresearchersbelievethatearlytreatmentcouldrewire
thebrainandimproveASDsymptoms. [26,27]
OnMRIscans,thebrainsofchildrenwithautismspectrumdisorderdemonstrategreatermyelinationinbilateral
medialfrontalcorticesandlessmyelinationinthelefttemporoparietaljunction. [28]Similarly,regionspecific
differencesintheconcentrationsofgraymatter,madeupofneuronalcellbodies,dendrites,unmyelinatedaxons
andglialcells,arealsofoundinthebrainsofpeoplewithautism. [29]
Postmortemspecimensofthebrainsofpeoplewithautismdemonstratedreductionsforgammaaminobutyricacid
B(GABA B)receptorsinthecingulatecortex,akeyregionfortheevaluationofsocialrelationships,emotions,and
cognition,andinthefusiformgyrus,acrucialregiontoevaluatefacesandfacialexpressions. [30]Thesefindings
providethebasisforfurtherinvestigationofautismandotherpervasivedevelopmentaldisorders.

Metabolicanomalies
Inanimalstudies,dysfunctionofserotoninandtheneuropeptidesoxytocinandvasopressinhasbeenassociated
withabnormalitiesinaffiliativebehaviors.Neurophysiologicdysfunctioninvolving1ormoreofthesesubstancesmay
alsobepresentinhumanswithautism.
Elevationsofbloodserotoninlevelsoccurinapproximatelyonethirdofindividualswithautisticdisorderandarealso
reportedintheparentsandsiblingsofpatients.Functionalanomaliesinotherneurotransmitters(eg,acetylcholine,
glutamate)havealsobeenidentifiedinsomepeoplewithautismspectrumdisorder. [25,31]
Serumbiotinidaseisreducedinsomepeoplewithautisticdisorder.Thisenzymeisrequiredfortheuseand
recyclingoftheBvitaminbiotin.Deficiencyofbiotinhasbeenlinkedwithbehavioraldisorders.
ImmunologicstudieshaveidentifiedabnormalitiessuchasdecreasedplasmaconcentrationsoftheC4B
complementprotein.Suchabnormalitiesmaybethesourceoftheincreasedsusceptibilitytoinfectionseeninsome
peoplewithautism.
Dietisacontroversialaspectofautism.Thegreatestattentionhasbeengiventoglutenandcaseinfreediets
anecdotalinformationsuggeststhatthesedietshelpsomechildrenwithautism. [32]Testfindingssuggestthatlow
functioningchildrenwithautismmayhaveimpairmentinthemetabolismofphenolicamines. [33]Therefore,
symptomsofautisticdisorderarepossiblyaggravatedbytheconsumptionofdairyproducts,chocolates,corn,sugar,
apples,andbananashowever,nolargepopulationstudieshaveconfirmedthis.
Oxidativestressmayplayaroleinthepathogenesisandthepathophysiologyofautism. [34]Comparedwithnormal
children,childrenwithautismhavedecrementsinthefollowing[34]:
Plasmalevelsofcysteine,glutathione,andmethionine
TheratioofSadenosylLmethionine(SAM)toSadenosylLhomocysteine(SAH)
Theratioofreducedtooxidizedglutathione
Somechildrenwithautismdisplayhyperlacticacidemia[35]aswellasevidenceofmitochondrialdisorders[35]
includingcarnitinedeficiency. [36]Theseabnormalitiesmayreflectdisturbedneuronalenergymetabolism.

Etiology
Inthe1940s,inhisseminalpapersthatfirstidentifiedautism,thechildpsychiatristLeoKannerconjecturedthat
infantileautismresultedfromrejectionoftheinfantbyemotionallycoldparents("refrigeratormothers").Inthe
1950sand1960s,BrunoBettelheimpopularizedthisidea.Sincethen,carefulfamilystudieshavedisprovedthe
hypothesisthatthedevelopmentofautisticdisorderinchildreniscausedbyfaultyparenting.Sensitiveclinicians
communicatetoparentsthattheirparentingskillsdidnotcausetheirchild'sautism.Repeatedcommunicationof
thisfactwillhelptominimizetheguiltoftenexperiencedbyparentsofautisticchildren.
Thecausesofautisticdisorderareunknown.Hypothesesincludeobstetriccomplications,infection,genetics,and
toxicexposures. [37,38,39]Noneofthese,however,hasbeenestablishedasadefiniteetiology.

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Obstetriccomplications
Manyindividualswithautismandrelatedconditionsexperienceduntowardeventsintheirprenatalandneonatal
periodsandduringdelivery. [10,11,12,40]Itisunclearwhethertheobstetriccomplicationscausedautisticdisorderor
whetherautismandobstetriccomplicationsresultedfromenvironmentalorotherproblems.
InalargeDanishstudypublishedinJAMA,maternaluseofvalproateduringpregnancywasassociatedwitha
significantlyincreasedriskforautisminoffspring.Thedrugisalreadynotrecommendedforuseinpregnantwomen
duetotheriskofcongenitalmalformationsanditspossibleassociationwithlowintelligenceinchildrenexposed
duringpregnancy.
ResearchersuseddataonallchildrenborninDenmarkbetween1996and2006.Ofthe655,615childrenborninthe
studyperiod,5437hadautismspectrumdisorder,including2067withchildhoodautism.Therewere2644children
exposedtoantiepilepticdrugsduringpregnancy,508ofwhomwereexposedtovalproate.Analysisshowedthatthe
childrenexposedtovalproatehada3foldincreasedriskforautismspectrumdisorderanda5foldincreasedriskfor
profoundchildhoodautismcomparedwithunexposedchildren,evenafteradjustmentforparentalpsychiatric
diseaseandepilepsy. [41,42]
Themanagementofwomenwithepilepsywhodesiretobearchildrencanbechallenging.Awomanwithan
ongoingseizuredisorderrequirestreatmentbecausematernalseizurescanresultinseriousmorbidityandmortality
forthemotherandthefetus.Tostopanticonvulsanttherapywhenawomanwithaseizuredisorderbecomes
pregnanttoavoidteratologiceffectsmayprecipitateuncontrolledseizuresthatmaybefataltothemotherandthe
fetus.Thereforephysicianstreatingwomenwithchildbearingpotentialcanappropriatelyinitiatefrankconversations
aboutfuturepregnancies.Juvenilemyoclonicepilepsyandotherseizuredisorderstypicallycauseseizures
throughoutadulthoodsopharmacotherapythroughoutadulthoodisareasonabletreatmentplan.Whilevalproateis
anexcellentagenttocontrolavastspectrumofseizuredisorders,itsuseinwomenofchildbearingpotentialis
fraughtwithdangerduetothegreatriskofproducingautismspectrumdisorders,spinabifida,andotherbirth
defects.Afrankconversationbetweenthephysicianandthewomanofchildbearingpotentialabouttherisksand
benefitsofspecificantiepilepticdrugsforthemotherandthefetusisindicated.Documentationofthese
conversationsisthemedicalrecordisneeded.Thisrecordmaybeusefulincourtiflegalactionisinitiatedifachild
hasbirthdefects.
Exposureofthemothertoselectiveserotoninreuptakeinhibitors,particularlyduringthefirsttrimester,mayincrease
theriskthatheroffspringwilldevelopanautismspectrumdisorder. [43]
Severe,earlygestationmaternalhypothyroxinemiaisassociatedwithanincreasedriskofhavingachildwith
autism,accordingtoanewstudythatinvolved5100womenand4039oftheirchildren.Severematernal
hypothyroxinemiaearlyingestationincreasedthelikelihoodofhavinganautisticchildbyalmost4fold.Byage6,
childrenofmotherswithseverehypothyroxinemiahadhigherautisticsymptomscoresonthePervasive
DevelopmentalProblemssubscaleoftheChildBehaviorChecklistandtheSocialResponsivenessScale. [44,45]

Infection
Aninfectiousbasisforsomecasesofautisticdisorderissuggestedbythelargenumberofchildrenwithautistic
disorderborntowomenwhocontractedrubelladuringpregnancy.Thisfindingsupportsthehypothesisthatthis
infectiontriggersavulnerabilitytothedevelopmentofautisticdisorderinthefetus.

Familialandgeneticfactors
Familialfactorsinfluencetheriskforautismspectrumdisorders.Therateofautismspectrumdisorderinchildren
bornintofamiliesthatalreadyhaveachildwithanautismspectrumdisorderisashighas18.7%,andtheriskis
twiceashighinchildrenborntofamilieswith2ormorechildrenwithanautismspectrumdisorder. [46]Girlsborntoa
familythathasachildwithanautismspectrumdisorderhave2.8timestheriskofhavingsuchadisorder. [46]
Twinstudieshavedemonstratedamoderatedegreeofgeneticheritabilityforautismandautismspectrum
disorders, [47,48,49]withenvironmentmakingasubstantialcontributiontothedevelopmentoftheseconditionsin
thestudysubjects. [49]
Multiplefamilystudieshavesuggestedgeneticcomponentsinmanycasesofautism. [50,40,51]Forexample,some
asymptomaticfirstdegreerelativesofsomeprobandswithautismhaveabnormalitiesinserotoninandother
chemicalssimilartotheprobands.
Findinggeneticbasesforautismisapromisingresearchgoal.FactoranalysisofdatasetsfromtheAutismGenome
Projecthassuggestedlinkageofajointattentionfactorwith11q23andofarepetitivesensorymotorbehaviorfactor
with19q13. [52]However,theclinicalusefulnessoftheassessmentoffamiliesofindividualswithautismhasnot
beenestablished.
Whileathirdofmonozygotictwinsareconcordantforautism,dizygotictwinsareconcordantforautismatratesof4
8%, [53]whichiscomparabletosiblings.Afocusedneurogeneticevaluationofchildrenwithautismspectrumdisorder
yieldsageneticdisorderintwofifthsofthechildren. [54]Forexample,mutationsinthegeneSHANK3are
associatedwithautismspectrumdisorders. [55]
FragileXsyndrome,aconditionassociatedwithautism,canbeidentifiedthroughgenetictesting. [56]Antagoniststo
metabotropicglutamatereceptorscanreversethesymptomsinmousemodelsoffragileXsyndrome. [57]Autismhas
alsobeenassociatedwithtuberoussclerosis,adisorderwithspecificgeneticmutations. [58,59]

Toxicexposure
Exposurestotoxins,chemicals,poisons,andothersubstanceshavebeenhypothesizedtocauseautism.Although
anecdotalcasereportssuggestthatsuchexposuresmayplayaroleinisolatedcasesofautisticdisorder,a
causativerolefortoxinsinthedevelopmentofautismingeneralhasnotbeendemonstrated.
Robertsetal[60]andSamson[61]havereportedanassociationbetweenexposuretotheorganochlorinepesticides
dicofolandendosulfanduringthefirsttrimesterofpregnancyandthesubsequentdevelopmentofautismspectrum
disorderinchildren.Potentialmotherscanwiselybeadvisedtoavoidexposuretoorganochlorinepesticides.
Inpartsoftheworld,exposuretospecifictoxinsmayinfluencelocalautismrates.Forexample,thehighincidence
ofautisminareasofJapanhasbeenhypothesizedtobeduetoatoxiceffectofcertainfish.Althoughtoxinsmay
playaroleinthedevelopmentofisolatedcasesofautisminJapan,theyhavenotbeenprovedtobegenerally
causativeofautismthere.AnotherpossibleexplanationforthehighautismratesinJapanistheexcellenttrainingof
Japaneseclinicianslowrateselsewheremayreflectthelimitedabilitiesofclinicianstodiagnoseautism.
Somestudieshavedocumentedassociationsbetweenautismandairpollution.One,fromNorthCarolinafounda
linkbetweenexposuretotrafficrelatedairpollution,particularlyduringthethirdtrimester,tothedevelopmentof

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autisminoffspring.TheseresultsaddtotheevidencealreadyprovidedbypreviousstudiesconductedinCalifornia.
[62]

AnotherstudyofchildrenlivingincountiesinPennsylvaniafoundthatchildrenwithautismwere1.4totwotimes
morelikelytohavebeenexposedtohigherlevelsofairpollution,especiallythetoxinsstyreneandchromium,during
pregnancyandthefirst2yearsoflifethanchildrenwithoutthedisorder. [63]Cyanide,methylenechloride,methanol,
andarsenicwerealsolinkedtoincreasedriskofautism.

Parentalage
Metaanalysesofepidemiologicstudieshaveshownthatautismriskinoffspringincreaseswithadvancingageof
eitherparent.Sandinetalreportedthat,aftercontrollingforpaternalage,theadjustedrelativeriskforautismwas
1.52intheoffspringofmothersaged35yearsoroldercomparedwithmothersaged2529years. [64]Hultmanetal
foundthat,aftercontrollingformaternalage,offspringofmenaged50yearsorolderwere2.2timesmorelikelyto
haveautismthanoffspringofmenaged29yearsoryounger. [65]

Vaccination
Somechildrenhavedevelopedautismafterimmunizations,includinginoculationsformeasles,mumps,andrubella.
However,severalpopulationstudieshavedemonstratednoassociationbetweenchildhoodimmunizationandthe
developmentofautismandrelatedconditions. [66,67,68,69]}[70]}[71]
Thompsonandcolleaguesdetectednocausalassociationbetweenexposuretovaccinesthatcontainthimerosaland
neuropsychologicaldeficitsatage710years. [69]Infact,inearly2010,theLancetretractedthe1998articleby
Wakefieldetalthatoriginallylinkedautismwithmeaslesmumpsrubella(MMR)vaccination,citingflawsinthe
studyand2claimsinitthatwere"proventobefalse." [70]
Parentscanpermittherecommendedchildhoodimmunizationswithoutfearofcausingautismandrelated
conditions.Adherencetorecommendedimmunizationschedules,includingimmunizationformeasles,mumps,and
rubella,ishighlyrecommended. [71]

Epidemiology
Reportedratesofautismspectrumdisorderhavebeenrisinginmanycountriesoverthepast2decades. [72,73]It
remainsunclearhowmuchofthesedatarepresentanactualincreaseandhowmuchreflectchangesindiagnostic
definitionsandpractices,aswellasincreasingawarenessamongthegeneralpublicandwithinthemedical
profession. [74,75,76]Furtherepidemiologicstudiesareneeded.
However,suchstudiesofrelativelyuncommonconditionssuchasautismspectrumdisorderareexpensive.A
suitableresearchstrategyistheadministrationofmultiplescreeningsinapopulation,eachtimeidentifyingmore
likelysubjectsfordetailedinvestigation.
Forexample,areportingtool,suchastheAutismScreeningChecklist,canbedistributedtoallparentsand
guardiansinatargetpopulation.Seetheimagebelow.

ThesignificanceofanswerstoindividualAutismScreeningChecklistitemsisasfollows:Item1A"yes"occursinhealthychildren
andchildrenwithsomepervasivedevelopmentaldisordersa"no"occursinchildrenwithautism,Rettsyndrome,andother
developmentaldisorders.Item2A"yes"occursinhealthychildren,notchildrenwithautism.Item3A"yes"occursinhealthy
childrenandchildrenwithAspergersyndrome(ie,highfunctioningautism)a"no"occursinchildrenwithRettsyndromechildren
withautismmayelicita"yes"ora"no"somechildrenwithautismneverspeaksomechildrenwithautismmaydevelopspeech
normallyandthenexperiencearegressionwiththelossofspeech.Item4A"yes"occursinhealthychildrenandchildrenwith
Aspergersyndromeandsomeotherpervasivedevelopmentaldisordersa"no"occursinchildrenwithdevelopmentaldisorders
childrenwithautismmayelicita"yes"ora"no."Items510Scoresof"yes"occurinsomechildrenwithautismandinchildrenwith
otherdisorders.Item11A"yes"occursinhealthychildrena"no"occursinsomechildrenwithautismandinchildrenwithother
disorders.Items12,13Scoresof"yes"occurinsomechildrenwithautismandinchildrenwithotherdisorders.Items1419
Scoresof"yes"occurinchildrenwithschizophreniaandotherdisorders,notinchildrenwithautism,Aspergersyndrome,orother
autismspectrumdisorders.Thehigherthetotalscoreforitems510,12,and13ontheAutismScreeningChecklist,themorelikely
thepresenceofanautismspectrumdisorder.

Thechecklistidentifiesthosechildrenwithcharacteristicsofanautismspectrumdisorderanddifferentiatesthem
fromchildrenwithchildonsetschizophrenia.(SeeHistory).

OccurrenceintheUnitedStates
Autismspectrumdisorderisoneofthemostcommonchildhooddevelopmentaldisabilities.Autisticdisorderor
relatedconditionswerefoundtoaffect11.3in1,000(1in88)childrenaged8yearslivingin14communities
monitoredbytheUSCentersforDiseaseControlandPrevention(CDC). [77]However,overallprevalenceestimates
ofautisticspectrumdisordervariedwidelyacrossthe14monitoredcommunities(range,4.821.2in1,000children
aged8y).
Initsstudy,theCDCreporteda23%riseinprevalencefrom2006to2008inchildrenaged8years,oranincrease
from9in1,000to11in1,000forthe11sitesthatprovideddataforbothsurveillanceyears.From2002to2008,an
estimatedincreaseof78%occurredinchildrenaged8years. [77]Estimatesoftheprevalenceofautismsuggestthat
asmanyas400,000individualsintheUnitedStateshaveautismorarelatedcondition.

Internationaloccurrence
Autisticdisorderandrelatedconditionsareestimatedtoaffectupto1015peopleper10,000populationworldwide.
Inapopulationbasedstudyofall7to12yearoldchildren(N=55,266)inaSouthKoreancommunity,Kimetal
estimatedthattheprevalenceofautismspectrumdisorderswas2.64%[78]
StudiesinJapanreportmuchhigherratesthanarefoundinothercountries. [79]Japaneseinvestigatorssuggestthat
thesefindingsreflectthecarefulevaluationsperformedbyJapaneseclinicians,whichmayidentifycasesthatwould

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beoverlookedinothercountries.Alternatively,autismmaybemorecommoninJapanbecauseofgastrointestinal
andotherinfectionstransmittedthroughtheingestionofseafoodandotheraquaticallyderivedfoodsthatare
characteristicoftheJapanesediet.

Sexrelateddemographics
Estimatesoftheprevalenceofautismspectrumdisordervarywidelybysex.Approximately1in54boysand1in
252girlslivingintheAutismandDevelopmentalDisabilitiesMonitoring(ADDM)Networkcommunitieswere
identifiedashavingautismspectrumdisorders.Themaletofemaleratiorangedfrom2.7:1inUtahto7.2:1in
Alabama.Themaletofemaleratioforallsitescombinedwas4.6:1. [77]
Autisticdisorderismostcommoninboyswhohavethe46,XYkaryotype(ie,thenormalmalekaryotype).Insome
studies,fragileXisreportedinapproximately10%maleswithautisticdisorder. [80,81,82,83,84,85]

Prognosis
TheprognosisinpatientswithautismishighlycorrelatedwiththeirIQ.Lowfunctioningpatientsmayneverlive
independentlytheytypicallyneedhomeorresidentialcarefortherestoftheirlives.Highfunctioningpatientsmay
liveindependently,holdjobssuccessfully,andevenmarryandhavechildren.Remissionofautismhasbeen
describedinanecdotalcasereports.
HighfunctioningindividualswithautisticdisorderaresimilartopeoplewithAspergersyndrome.Pleaserefertothe
MedscapeReferencearticleAspergerSyndromeforfurtherinformationandtolearnmoreabouthighfunctioning
autism.

Comorbiddisorders
Gastrointestinaldisorders,particularlyconstipationandchronicdiarrhea,aremorecommoninchildrenwithautism
spectrumdisorder.Theriskofgastrointestinaldisordersincreaseswiththeseverityofautismsymptoms. [86]

PatientEducation
Becauselocalboardsofeducationmaybeignorantabouttheneedsofchildrenwithautisticspectrumdisorderand
relatedconditions,pediatriciansandparentsshouldseekadvicefromknowledgeablesourcessuchastheAutism
SocietyofAmerica,whichmaintainsaWebsiteandoffersatollfreehotlineat18003AUTISM,providing
informationandreferralservicestothepublic.Legalassistancemaybenecessarytoinfluenceaboardofeducation
tofundappropriateeducationforachildwithautisticdisorderandrelatedconditions.
Peoplewithdevelopmentaldisabilities,includingAspergersyndrome,arevulnerabletosexualabuse,withthemost
severelydisabledbeingathighestrisk.Parentsandcaregiversneedtobeawareofthisincreasedrisk.Additionally,
childrenwithAspergersyndromemustbetrainedtorecognizeimpendingsexualabuseandtodevelopplansof
actiontoabortit. [87]
Almosthalfofasampleofmorethan1000childrenwithautismspectrumdisordersexhibitedelopement,wandering
awayfromhome,school,andothersafeenvironments. [88]Parentsofchildrenwithautismspectrumdisordersneed
tobewarnedthatthereisafairchancethattheirchild,withoutwarning,maywalkawayfromhomeorschooltogo
toanenvironmentwherethereisariskforpotentialdanger.Additionally,parentsneedtobeadvisedtorequestthat
teachersandothercaregiversvigilantlywatchthechildtopreventelopement.
Forpatienteducationinformation,seetheBrainandNervousSystemCenter,aswellasAspergerSyndrome.

Obtaininginformedconsent
Peoplewithautismareidentifiedasahighlyvulnerablepopulationbecauseofthepresenceofcognitive,social,and
mentalimpairments.Regulatoryagencieshaveexpressedparticularconcernthattherightsofchildrenwithautistic
disorderandrelatedconditionsbecarefullyprotected.
Somehavesuggestedthatparentsmaynotbeimpartialguardiansandthatthirdpartiesbeusedinsteadofparents
toprovideinformedconsentforclinicalandresearchpurposes.However,parentsaregenerallyexcellentadvocates
seekingthebestfortheirchildren.Nevertheless,cliniciansmusttakeparticularcaretoensurethatinformedconsent
isobtainedinordertopreventmisinterpretationsandeventualmedicolegalproblems.
Exceptinemergencies,patients,parents,guardians,andsurrogatesmustbeawareofthediagnosticandtreatment
possibilitiesandmustprovidepermissionforpossibleinterventions.Bymakingavideorecordingoftheprocessof
explainingtotheparenttherecommendedprocedures,inadditiontothesigningofwrittenreleaseforms,the
clinicianestablishesevidencethathe/sheimpartedappropriateinformationtothecorrectparty.(Seethevideo
below.)
Cliniciansareadvisedtovideotapetheprocessofverballyexplainingtheprotocolandansweringquestions.Permissionmustbe
explicitlygiventoperformtheprocedureandcannotcontinueuntiltheparentsagree.Parentsareaskedtogivepermissionto
completethisprotocol.Theentireprocessisvideotaped.Inthissegment,themotherofahealthy,normalcontrolchildgives
informedconsenttoparticipateasavolunteerinaresearchstudyofautism.Occasionally,parentsdeclinetogiveconsent,andthe
proceduremustcease.AnearlierversionofthisvideotapeisintheNewYorkUniversityMedicalLibrary,NewYork,NewYork.

Publishedresourcesforparents
Recommendedreadingsforparentsincludethefollowing:
AttwoodT.TheCompleteGuidetoAsperger'sSyndrome.London,UK:SKKingsleyPublishers2006
BaronCohenS,HowlinP.TeachingChildrenwithAutismtoMindread:aPracticalGuideforTeachersand
Parents.NewYork,NY:Wiley1998
CohenS.TargetingAutism.Berkeley,CA:UniversityofCaliforniaPress1998
GausVL.Cognitive/BehaviouralTherapyforAdultAsperger'sSyndrome.NewYork,NY:TheGuilfordPress
2007
HartCA.AParent'sGuidetoAutism.NewYork,NY:PocketBooks1993
HollanderE.AutismSpectrumDisorders.Volume24oftheMedicalPsychiatrySeries.NewYork,NY:
MarcelDekker2003
LovaasI.TheAutisticChild:LanguageDevelopmentthroughBehaviorModification.NewYork,NY:Irvington
Press1977
MatthewsP,MatthewsT.(2012)CharterofRightsforPeoplewithAutism:ReflectionsandPersonal
Experiences.Dublin,Ireland:Originalwriting2012
OffitPA.Autism'sfalseprophets.NewYork,NY:ColumbiaUniversityPress2008
PowersM.ChildrenwithAutism:AParents'Guide.Bethesda,Md:WoodbineHouse2000
QuillK.TeachingChildrenwithAutism:StrategiestoEnhanceCommunicationandSocialization.Albany,
NY:DelmarPublishers1995

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WingL.TheAutisticSpectrum:AParent'sGuidetoUnderstandingandHelpingYourChild.London,
England:UlyssesPress2001

Additionalresources
Individualswithautismandrelatedconditions,aswellastheiradvocates,canbenefitfromtheexperiencesofother
individualsandadvocateswhoaredealingwithautism.(Seetheorganizationsandresourceslistedbelow.)
AutismSocietyofAmerica
7910WoodmontAve,Suite650
Bethesda,MD208143015
Phone:18003288476
AutismSocietyofAmerica
ManhattanChapter
25West17thStGroundFloor
NewYork,NY10011
AutismSocietyofCanada
220CollegeSt
Toronto,Ontario
CanadaM5G1K2
NationalAllianceforAutismResearch
ResearchPark
414WallSt
Princeton,NJ08540
Phone:888777NAAR
TheNationalAutisticSociety
393CityRd
LondonEC1V1NG
UnitedKingdom
Phone:+44(0)2078332299
NationalInstitutesofHealth
http://www.nimh.nih.gov/health/topics/autismspectrumdisorderspervasivedevelopmentaldisorders/index.shtml
AspergerSyndromeCoalitionoftheUnitedStates(ASCUS)Inc
POBox49267
JacksonvilleFL322409267
LADDERS
65WalnutSt
WellesleyMA02481
Phone:7814496074
AutismResearchInstitute
4182AdamsAve
SanDiego,CA92116
Fax:6195636840
AutismSpeaks
5455WilshireBlvd,Suite715
LosAngeles,CA90036
Phone:3235490500

ContributorInformationandDisclosures
Author
JamesRobertBrasic,MD,MPHAssistantProfessor,RussellHMorganDepartmentofRadiologyand
RadiologicalScience,DivisionofNuclearMedicine,JohnsHopkinsUniversitySchoolofMedicineActiveStaff,
DepartmentofRadiologyandRadiologicalScience,DivisionofNuclearMedicine,JohnsHopkinsHospital
CourtesyStaff,DepartmentofRadiology,JohnsHopkinsBayviewMedicalCenter
JamesRobertBrasic,MD,MPHisamemberofthefollowingmedicalsocieties:AmericanAcademyofChildand
AdolescentPsychiatry,AmericanAcademyofNeurology,andMovementDisordersSociety
Disclosure:MedscapeRoyaltyOtherNeuroscienceNet,LLCRoyaltyOtherNationalInstitutesofHealth
Grant/researchfundsOther
ChiefEditor
CarolyPataki,MDHealthSciencesClinicalProfessorofPsychiatryandBiobehavioralSciences,Universityof
California,LosAngeles,DavidGeffenSchoolofMedicine

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CarolyPataki,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofChildandAdolescent
Psychiatry,NewYorkAcademyofSciences,andPhysiciansforSocialResponsibility
Disclosure:OtsukaPharmaceuticalConsultingfeeBoardmembership
AdditionalContributors
MaryLWindle,PharmDAdjunctAssociateProfessor,UniversityofNebraskaMedicalCenterCollegeof
PharmacyEditorinChief,MedscapeDrugReference
Disclosure:Nothingtodisclose.
Acknowledgments
ThisresearchissupportedbytheEsselFoundation,theBrainandBehaviorResearchFoundation(NARSAD),
theTouretteSyndromeAssociationInc,theNationalInstitutesofHealth,theDepartmentofPsychiatryof
BellevueHospitalCenter,andtheNewYorkUniversitySchoolofMedicine.ThecooperationoftheHealthand
HospitalsCorporationoftheCityofNewYorkisgratefullyacknowledged.
Theauthoralsogratefullyacknowledgesthetechnicalassistanceinthepreparationofthevideoportionsofthis
articleoftheDigitalMediaCenterattheSkirballInstituteofBiomolecularMedicineattheNewYorkUniversity
MedicalCenter.

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