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AutismAutism

Paul Glaser MD, PhDPaul Glaser MD, PhD

November 3, 2008November 3, 2008

Disease OverviewDisease Overview

Pervasive Developmental Disorders (PDDs)Pervasive Developmental Disorders (PDDs)

Autism Spectrum Autism Spectrum Disorders* (ASDs)Disorders* (ASDs)

Childhood Childhood Disintegrative Disintegrative

Disorder (CDD)Disorder (CDD)

Rett’s Rett’s DisorderDisorder

Tidmarsh L et al. Can J Psychiatry. 2003;48:517-525; DSM-IV TR. Washington, DC: American Psychiatric Association; 2000.

Autistic Autistic DisorderDisorder

Pervasive Pervasive Developmental Developmental

Disorder Not Otherwise Disorder Not Otherwise Specified (PDDSpecified (PDD--NOS)NOS)

Asperger’s Asperger’s DisorderDisorder

*ASD is not a DSM-IV TR definition but reflects categorization in the general public.

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EpidemiologyEpidemiology PrevalencePrevalence

•• 1 in 2000 (1966, 1 in 2000 (1966, LotterLotter))1 i 5001 i 500 1000 (19791000 (1979 1996)1996)•• 1 in 5001 in 500--1000 (19791000 (1979--1996)1996)

•• 1 in 500 (1999, 1 in 500 (1999, OsbahrOsbahr))•• 1 in 250 (2004, CDC)1 in 250 (2004, CDC)•• 1 in 150 (2007, CDC1 in 150 (2007, CDC))

Increased Increased detectiondetection??Wider Wider range being diagnosed? range being diagnosed? Wider Wider range being diagnosed? range being diagnosed?

Male:FemaleMale:Female RatioRatio•• 2:1 with severe dysfunction2:1 with severe dysfunction•• 4:1 with average IQ4:1 with average IQ

http://www.cdc.gov/ncbddd/autism/http://www.cdc.gov/ncbddd/autism/

GeneticsGenetics

A HIGHLY Genetic disorderA HIGHLY Genetic disorder•• 90% concordance (identical twins)90% concordance (identical twins)•• 33--4% in fraternal twins4% in fraternal twins

MultifactorialMultifactorial•• 44––20 20 genes estimated to be involvedgenes estimated to be involved•• Multiple “hot spots” identifiedMultiple “hot spots” identified•• Multiple hot spots identifiedMultiple hot spots identified

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Criteria For Autistic DisorderCriteria For Autistic Disorder

DSMDSM--IV IV -- A Categorical SystemA Categorical System DSMDSM IV IV A Categorical SystemA Categorical System Three DomainsThree Domains

•• (1) Social Communication(1) Social Communication•• (2) Verbal and Non(2) Verbal and Non--Verbal Verbal

CommunicationCommunication•• (3) Restrictive, Repetitive, (3) Restrictive, Repetitive,

Stereotypic BehaviorsStereotypic Behaviors

All or Nothing DiagnosisAll or Nothing Diagnosis

Autistic Disorder (1): Autistic Disorder (1): Impairment In Social InteractionImpairment In Social Interaction

Impairment in eye contact, facial Impairment in eye contact, facial i b d t ti b d t texpression, body posture, gestureexpression, body posture, gesture

Fails to develop peer relationships at a Fails to develop peer relationships at a developmentally appropriate leveldevelopmentally appropriate level

Not seeking to share enjoyment or Not seeking to share enjoyment or interestsinterests•• Oblivious to needs or interests of Oblivious to needs or interests of

othersothersothersothers Lack of social and emotional Lack of social and emotional

reciprocityreciprocity

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Autistic Disorder (2Autistic Disorder (2):):Impaired Impaired CommunicationCommunication

Delay or lack of spoken languageDelay or lack of spoken language Marked impairment in ability to Marked impairment in ability to

initiate or sustain conversation initiate or sustain conversation Stereotyped and repetitive use Stereotyped and repetitive use

of languageof language Lack of varied, spontaneous Lack of varied, spontaneous

makemake--believe or sociallybelieve or socially--makemake--believe or sociallybelieve or socially--imitative playimitative play

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Autistic (3Autistic (3):):RestrictiveRestrictive, Repetitive, , Repetitive, StereotypedStereotyped

Patterns Patterns of Behaviorof Behavior

Preoccupation with restricted Preoccupation with restricted patterns of interestpatterns of interest

Inflexible adherence to Inflexible adherence to nonfunctional routine or ritualnonfunctional routine or ritual

Stereotyped and repetitive Stereotyped and repetitive motor mannerismsmotor mannerismsPersistent preoccupation with Persistent preoccupation with Persistent preoccupation with Persistent preoccupation with parts of objectsparts of objects

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Autistic Disorder DiagnosisAutistic Disorder Diagnosis

Onset prior to 3 years of ageOnset prior to 3 years of ageO p o o 3 y a o agO p o o 3 y a o ag Not better accounted for by Not better accounted for by

Rett’sRett’s Disorder or Childhood Disorder or Childhood Disintegrative DisorderDisintegrative Disorder

Differential DiagnosisDifferential Diagnosis

Mental RetardationMental Retardation Specific Developmental DisordersSpecific Developmental Disorders

•• Particularly language disordersParticularly language disorders

Selective Selective MutismMutism Reactive Attachment DisorderReactive Attachment Disorder Obsessive Compulsive DisorderObsessive Compulsive Disorder Childhood SchizophreniaChildhood Schizophrenia

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www.autism-society.org

Asperger’s DisorderAsperger’s Disorder

Similar criteria as Autistic Similar criteria as Autistic Di d ith li i ll i ifi t Di d ith li i ll i ifi t Disorder with clinically significant Disorder with clinically significant deficits in social interaction and deficits in social interaction and repetitive or stereotyped repetitive or stereotyped behaviorsbehaviors

But no clinically significant delay But no clinically significant delay But no clinically significant delay But no clinically significant delay in language, cognitive in language, cognitive delay delay or or curiosity about the environmentcuriosity about the environment

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DiagnosisDiagnosis

HowlinHowlin and Moore (1997) described the and Moore (1997) described the diagnostic experiences of 1,300 families diagnostic experiences of 1,300 families with children with autism in the with children with autism in the UKUK•• Average age at diagnosis: 6 years oldAverage age at diagnosis: 6 years old

US US average: 3average: 3--4 years old4 years old

•• Most parents sensed something was wrong Most parents sensed something was wrong at 18 monthsat 18 monthsat 18 monthsat 18 months

•• Most parents sought medical attention by 2 Most parents sought medical attention by 2 years of ageyears of age

Advantages of Early DiagnosisAdvantages of Early Diagnosis

R d ti f F il StR d ti f F il St Reduction of Family StressReduction of Family Stress Earlier Educational PlanningEarlier Educational Planning Appropriate Delivery of Appropriate Delivery of

Medical CareMedical Care

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Advantages of Early DiagnosisAdvantages of Early Diagnosis

10 years worth of outcome 10 years worth of outcome 10 years worth of outcome 10 years worth of outcome based studies have shown based studies have shown 75% or more increase in rates 75% or more increase in rates of developmentof development

Especially if 2 years or Especially if 2 years or more of intervention in more of intervention in preschool years*preschool years*

*Dawson & Osterling, 1997; Rogers, 1996,1998

The AnswerThe Answer

SCREENING Early screening and early diagnosis Early screening and early diagnosis

are crucial to improving outcomes are crucial to improving outcomes in children with autismin children with autism

SCREENING

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The 18The 18--month Well Child Visitmonth Well Child Visit

Check ImmunizationsCheck Immunizations Check Physical Check Physical ExamExam Counsel on Preventative Health TopicsCounsel on Preventative Health Topics Check Check DevelopmentDevelopment Physician concernsPhysician concerns Parental concernsParental concerns

When to referWhen to refer?? When When to reassure?to reassure?

The CHAT The CHAT is. . .is. . .

. . .The . . .The Checklist for Autism in Checklist for Autism in ToddlersToddlers Can be administered at 18, 24, Can be administered at 18, 24, 30 30

and 36 months of ageand 36 months of age Designed to take 5 minutesDesigned to take 5 minutes 9 questions to ask the parent, 4 9 questions to ask the parent, 4

points of observationpoints of observation Requires doll and toy cupRequires doll and toy cup depts.washington.edu/depts.washington.edu/dataprojdataproj/chat./chat.

htmlhtml

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CHATCHAT

Deficits predictive of autismDeficits predictive of autism••ProtodeclarativeProtodeclarative pointing pointing -- “look “look

at something”at something”••Gaze Gaze monitoring monitoring -- looking where looking where

someone indicatessomeone indicates••Pretend Pretend play play -- using an object to using an object to

represent something elserepresent something else

Types Of PointingTypes Of Pointing

ProtoimperativeProtoimperativepp••To To attempt to obtain an attempt to obtain an objectobject

ProtodeclarativeProtodeclarative••To To show something show something of of ••To To show something show something of of interestinterest

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CHAT ScoringCHAT Scoring

A child who fails at any item should A child who fails at any item should b b d i th ( d i th ( be rebe re--screened in one month (or screened in one month (or context of failure explained) context of failure explained)

Any child who fails the CHAT a Any child who fails the CHAT a second time should be referred to a second time should be referred to a specialist clinic for diagnosisspecialist clinic for diagnosisTh CHAT i t di ti t l Th CHAT i t di ti t l The CHAT is not a diagnostic tool The CHAT is not a diagnostic tool

CHAT ScoringCHAT Scoring

If a child fails five key items (s)he is at If a child fails five key items (s)he is at risk for a severe social communication risk for a severe social communication risk for a severe social communication risk for a severe social communication disorderdisorder Pretend playPretend play ProtodeclarativeProtodeclarative pointingpointing Following a pointFollowing a point PretendingPretending PretendingPretending Producing a pointProducing a point

BaronBaron--Cohen Brit J Cohen Brit J PsychiatrPsychiatr (1992) (1992) 161:839161:839

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Policy StatementPolicy Statement

http://www aap org/policy/re060018 html

Established by Study Group of Established by Study Group of AAP, AAN, AACAP, AAA, AOTAAAP, AAN, AACAP, AAA, AOTA

AAFP adopted and rewordedAAFP adopted and rewordedhttp://www aafp org/afp/20021http://www aafp org/afp/20021

http://www.aap.org/policy/re060018.html

http://www.aafp.org/afp/20021http://www.aafp.org/afp/20021101/1667.html101/1667.html

From the AAFP WebsiteFrom the AAFP Website

1) Ask the 1) Ask the parentparent•• Does your child ever pretend (for example, to make a cup of tea using Does your child ever pretend (for example, to make a cup of tea using

a toy cup and teapot) or pretend with other things? a toy cup and teapot) or pretend with other things? a toy cup a d teapot) o p ete d t ot e t gsa toy cup a d teapot) o p ete d t ot e t gs 2) Does your child ever use an index finger to point, to 2) Does your child ever use an index finger to point, to

indicate interest in something? indicate interest in something? Health practitioner Health practitioner observationobservation 3) Gain child's attention, then point across the room at an 3) Gain child's attention, then point across the room at an

interesting object and say "Oh look! There's a (name of interesting object and say "Oh look! There's a (name of toy)!" Watch child's face. Does the child look across to see toy)!" Watch child's face. Does the child look across to see at what at what you are you are pointing? pointing?

4) Gain child's attention, then give child a toy cup and 4) Gain child's attention, then give child a toy cup and teapot and teapot and ask ask "Can o make me a c p of tea?" Does the "Can o make me a c p of tea?" Does the teapot and teapot and ask ask "Can you make me a cup of tea?" Does the "Can you make me a cup of tea?" Does the child pretend to pour out tea, drink it, etc.? child pretend to pour out tea, drink it, etc.?

5) Say to the child "Where's the light?" or "Show me the 5) Say to the child "Where's the light?" or "Show me the light." Does the child point with an index finger at the light? light." Does the child point with an index finger at the light? To record "yes" on this item, the child must have looked up To record "yes" on this item, the child must have looked up at your face around the time of pointing. at your face around the time of pointing.

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Practice ParametersPractice Parameters

Establish a Establish a 22--step step process to process to ab aab a pp p o op o oevaluation and diagnosis of evaluation and diagnosis of autismautism

Level One: Level One: Routine Routine Developmental SurveillanceDevelopmental Surveillance

Level Two: Diagnosis and Level Two: Diagnosis and Evaluation of AutismEvaluation of Autism

Level OneLevel One

Routine Developmental Routine Developmental ppSurveillanceSurveillance•• AAP “stresses the importance of a AAP “stresses the importance of a

flexible, continual developmental flexible, continual developmental surveillance process at each wellsurveillance process at each well--child visit”child visit”c d s tc d s t Parental ConcernsParental ConcernsAge appropriate skillsAge appropriate skillsDenverDenver--IIII

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Absolute IndicationsAbsolute Indications

For Immediate Evaluation No No babbling babbling or pointing by 12 or pointing by 12

monthsmonths No single words by 16 monthsNo single words by 16 months No 2No 2--word spontaneous (not word spontaneous (not

echolalicecholalic) phrases by 24 months) phrases by 24 months ANY loss of ANY language or social ANY loss of ANY language or social

skills at ANY ageskills at ANY age

Immediate EvaluationImmediate Evaluation

AudiologicalAudiological AssessmentAssessment Lead Screen if PICALead Screen if PICA Optional: Blood Tests including Optional: Blood Tests including

chromosomes, Genetics referral chromosomes, Genetics referral if any dysmorphic featuresif any dysmorphic features

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Treatment of AutismTreatment of Autism

Parental Education StructureParental Education Structure Parental Education, StructureParental Education, Structure Multimodal TreatmentMultimodal Treatment

•• Speech TherapySpeech Therapy•• Occupational TherapyOccupational Therapy

Sensory Integration DisorderSensory Integration Disorder

•• Physical TherapyPhysical Therapy•• Developmental InterventionDevelopmental Intervention

Treatment of AutismTreatment of Autism

Appropriate Educational PlacementAppropriate Educational Placementpp ppp p Behavioral ManagementBehavioral Management

•• Massed, discreteMassed, discrete--trial learningtrial learning(e.g. (e.g. LovaasLovaas) )

•• SocialSocial--pragmatic teaching pragmatic teaching (e.g. Floor time Greenspan) (e.g. Floor time Greenspan)

Assistive TechnologyAssistive Technology

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Treatment of AutismTreatment of Autism

Medication ManagementMedication Managementgg•• Rarely neededRarely needed•• Only treats target symptomsOnly treats target symptoms•• High degree of variability in response High degree of variability in response

and side effects to medicationand side effects to medicationStart low go slowStart low go slow•• Start low, go slowStart low, go slow

Treat Treat comorbidcomorbid diagnoses e.g. diagnoses e.g. SeizuresSeizures

Treatment of AutismTreatment of Autism

Stimulants Stimulants •• Classically Classically –– idiosyncratic hyperactivityidiosyncratic hyperactivity•• For some we see improved concentrationFor some we see improved concentration•• Ritalin®, Ritalin®, ConcertaConcerta®®•• AdderallAdderall®, ®, AdderallAdderall XR®XR®•• Dexedrine® Dexedrine® , , VyvanseVyvanse®®

ClonidineClonidine, , TenexTenex® ® –– reduce impulsiveness, reduce impulsiveness, treat treat comorbidcomorbid tics/tics/Tourette’sTourette’s, also for sleep , also for sleep disturbancesdisturbances

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Treatment of AutismTreatment of Autism

Antidepressants/Antidepressants/AntianxietyAntianxiety Antidepressants/Antidepressants/AntianxietyAntianxiety•• SSRI’s (SSRI’s (fluoxetinefluoxetine, , sertralinesertraline, ,

duloxetineduloxetine, , citalopramcitalopram))•• Treat rigidity of thought, reduce Treat rigidity of thought, reduce

obsessive behaviorsobsessive behaviorsAlso for depression in Also for depression in Asperger’sAsperger’s•• Also for depression in Also for depression in Asperger’sAsperger’s

Mood Stabilizers Mood Stabilizers –– comorbidcomorbid Bipolar Bipolar Affective DisorderAffective Disorder

Treatment of AutismTreatment of Autism

AntipsychoticsAntipsychoticsRi d lRi d l® ® ZZ ® ® S lS l® ® •• RisperdalRisperdal®, ®, ZyprexaZyprexa®, ®, SeroquelSeroquel®, ®, GeodonGeodon®, ®, AbilifyAbilify®, ®, InvegaInvega®®

•• Decrease aggression, selfDecrease aggression, self--mutilationmutilation•• Reduce obsessive preoccupationsReduce obsessive preoccupations•• Improve socialization (? decreased Improve socialization (? decreased

anxiety)anxiety)•• AtypicalsAtypicals rarely cause “Parkinson’s”rarely cause “Parkinson’s”--

like reactions (EPS), rare like reactions (EPS), rare tardivetardivedyskinesiadyskinesia (unlike (unlike HaldolHaldol®, ®, ThorazineThorazine®)®)

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TreatmentsTreatments

Clinical Trials have failed Clinical Trials have failed forforF fl iF fl i FenfluramineFenfluramine

Auditory integration training (AIT)Auditory integration training (AIT) Facilitated CommunicationFacilitated Communication SecretinSecretin Casein and glutenCasein and gluten--free diets (in free diets (in

most children with autistic most children with autistic disorder)disorder)

TreatmentsTreatments

Clinical Trials have failed for (or Clinical Trials have failed for (or have not been donehave not been done))have not been donehave not been done))

Oral Oral NystatinNystatin NaltrexoneNaltrexone Corticosteroids, IVIGCorticosteroids, IVIG

MM it i B6/ iit i B6/ i MegaMega--vitamins B6/magnesiumvitamins B6/magnesium ChelationChelation treatments (DMSA)treatments (DMSA)

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Etiology of AutismEtiology of Autism

Currently unknownCurrently unknown Not caused by MMR, Not caused by MMR, thiomerisolthiomerisol, ,

other vaccinesother vaccines Not due to cold or indifferent Not due to cold or indifferent

mothersmothers

A Neuropsychiatric DisorderA Neuropsychiatric Disorder

Developmental DelayDevelopmental DelayE ilE il EpilepsyEpilepsy

Large Head Size (with rapid growth Large Head Size (with rapid growth in first year)in first year)

Unequal sex ratioUnequal sex ratio Greater rate of obstetric Greater rate of obstetric Greater rate of obstetric Greater rate of obstetric

complicationscomplications

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Pathophysiology of AutismPathophysiology of Autism

Neurotransmitters abnormal, especially Neurotransmitters abnormal, especially glutamate receptor rich areasglutamate receptor rich areasglutamate receptor rich areasglutamate receptor rich areas

Seizures are common comorbiditySeizures are common comorbidity•• About 30About 30--40% of Autistic Disorder40% of Autistic Disorder•• Often first seizure in adolescent periodOften first seizure in adolescent period

Immune Disorders (abnormal shift Immune Disorders (abnormal shift between helper Tbetween helper THH1 and T1 and THH2 cells, changes 2 cells, changes in activation of IgM, IgE and interleukin 2)in activation of IgM, IgE and interleukin 2)

GI disorders GI disorders –– chronic diarrhea, chronic diarrhea, constipation in someconstipation in some

RettRett SyndromeSyndrome

Almost always affects girls Almost always affects girls Rare 1:10Rare 1:10--20,00020,000 Caused by mosaic expression of mutant Caused by mosaic expression of mutant

copies of the Xcopies of the X--linked MECP2 (methyllinked MECP2 (methyl--cytosine binding protein involved in cytosine binding protein involved in transcriptional transcriptional repression) repression)

Develop normally then regress (at about Develop normally then regress (at about 66--18 months)18 months)66 18 months)18 months)

Midline hand Midline hand ringingringing Head Growth decelerationHead Growth deceleration Loss of language, walking, IQLoss of language, walking, IQ Some survive into adulthoodSome survive into adulthood

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MMR NMMR Not Linked ot Linked with Autismwith Autism

“A population“A population--based study of measles, based study of measles, mumps mumps and rubella vaccination and autism.” Madsen et and rubella vaccination and autism.” Madsen et al. NEJM Nov.2002al. NEJM Nov.2002

537,303 children 537,303 children in in DenmarkDenmark•• 440,655 (82.0 percent) had received the MMR vaccine 440,655 (82.0 percent) had received the MMR vaccine •• Relative risk of autistic disorder Relative risk of autistic disorder -- 0.920.92•• Of any autism spectrum disorder Of any autism spectrum disorder -- 0.830.83

Other studies verify this in California and Other studies verify this in California and FinlandFinland

Vaccine Related IncidentsVaccine Related Incidents

PatjaPatja et al. et al. PedsPeds Inf.DisInf.Dis. Dec. 2000. Dec. 2000 Looked at 1 8 million MMR Looked at 1 8 million MMR immunizations immunizations Looked at 1.8 million MMR Looked at 1.8 million MMR immunizations immunizations

in Finland from 1982in Finland from 1982--19961996 5.3 per 100,000 serious adverse events5.3 per 100,000 serious adverse events

•• About 40% neurologic (mostly febrile seizure)About 40% neurologic (mostly febrile seizure)•• 40% allergic40% allergic•• Only one death, but not clearly related to Only one death, but not clearly related to

vaccinevaccine•• Is autoIs auto--immune phenomena possible?immune phenomena possible?

MMR, GI symptoms, Autism diagnosis not MMR, GI symptoms, Autism diagnosis not temporally connected, 2008, temporally connected, 2008, HornigHornig et al.et al.

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Autism Autism Not Linked Not Linked with with ThiomerisalThiomerisal

““ThimerosalThimerosal and the Occurrence of and the Occurrence of A ti N ti E l i l E idA ti N ti E l i l E idAutism: Negative Ecological Evidence Autism: Negative Ecological Evidence From Danish PopulationFrom Danish Population--Based Data” Based Data” Madsen et al. Madsen et al. PediatricsPediatrics, Sep, 2003, Sep, 2003

ThimerosalThimerosal discontinued in Denmark in discontinued in Denmark in 19911991 yet rate of Autism Spectrumyet rate of Autism Spectrum1991 1991 yet rate of Autism Spectrum yet rate of Autism Spectrum Disorders continue to riseDisorders continue to rise

Vaccinations Vaccinations Going DownGoing Down

New epidemics of measles New epidemics of measles increasingincreasing•• 9090% of affected have not received MMR % of affected have not received MMR

vaccinevaccine

http://www.immunize.org/ http://www.immunize.org/ •• Good Good source of education for doctors source of education for doctors

and familiesand families

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ConclusionsConclusions

Family Practitioners and other Family Practitioners and other Primary Care Providers Primary Care Providers are in a are in a Primary Care Providers Primary Care Providers are in a are in a critical position to improve critical position to improve developmental outcomes for developmental outcomes for children with pervasive children with pervasive developmental developmental disordersdisorders

Screening at the 18Screening at the 18--month month wellwell--hild hild i it d b t i it i i it d b t i it i child child visit and subsequent visits is visit and subsequent visits is

the key to early detection and early the key to early detection and early treatmenttreatment