Autism Spectrum Disorder - UCSF CMEucsfcme.com/.../syllabus/spring2016/MLL16022/2016.05-26.ASD.pdf · Autism Spectrum Disorder Bennett L. Leventhal, MD Professor Department of Psychiatry

05/26/2016

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Autism Spectrum Disorder

Bennett L. Leventhal, MDProfessor

Department of PsychiatryUniversity of California, San Francisco

Osher Mini‐Med SchoolUCSF

San Francisco, CA26 May 2016

STAR.ucsf.edu

DISCLOSURE of INTERESTSBennett L. Leventhal, MD

Sources of Research Support

NIH

Simons Foundation

Roche ‐ ended

Speaker Bureaus

None

Consulting Relationships

Janssen/J&J

Off Label Meds

Yes, of course

Stock and Investments

Sadly, no

Other Financial Interests

Regrettably, none

Family Financial Interest

All my children are employed

Honorarium

No

Travel

Too much; no conflict

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ASDAutism Spectrum Disorder

The Paradigmatic

Neurodevelopmental Disorder

What is a Neurodevelopmental Disorder?(1)

–Usually Syndromal

–Pediatric Onset–Affecting Brain Function–Clinical Effects on 

• Emotion

•Cognition•Behavior

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What is a Neurodevelopmental Disorder? (2)

• Etiology

– Usually a genetic component

– Often Familial

– Sometimes heritable 

– May be related to de novo events

– Role for epigenetics

– Role for Gene‐Environment Interactions (GEX)

What is a Neurodevelopmental Disorder? (3)

1. Intellectual Disability (ID)

(Intellectual Development Disorder)

2. Global Development Delay

3. Unspecified Intellectual Disability

(Intellectual Developmental Disorder)

4. Language Disorder

5. Speech Sound Disorder

6. Childhood‐Onset Fluency Disorder

(Stuttering)

7. Social Pragmatic Communication

Disorder (SCD)

8. Unspecified Communication Disorder

9. Autism Spectrum Disorder(ASD)

10. Attention Deficit Hyperactivity Disorder

(ADHD)

11. Other Specified Attention‐Deficit Hyperactivity Disorder

12. Unspecified Attention‐Deficit Hyperactivity Disorder

13. Specific Learning Disorder

14. Developmental Coordination Disorder

15. Stereotypic Movement Disorder

16. Tic Disorder

17. Other Specified Tic Disorder

18. Unspecified Tic Disorder

19. Other Specified Neurodevelopmental Disorder

20. Unspecified Neurodevelopmental Disorder

per DSM5

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What is a Neurodevelopmental Disorder? (4)

Consider Other Neurodevelopmental Disorders:OCDEating DisordersMood DisordersBipolar DisorderMajor Depressive Disorder

Substance  AbuseSchizophreniaTrauma related disordersEpilepsyAlzheimer’s Disease

Autism/ASD – A syndrome

• Syndrome– Group of symptoms that tend to cluster together and share a common natural history/course

• Disease– A syndrome for which there is either:

• A known etiology (or cause)

• A known pathophysiological process

• Both

• ASD is not so unusual because:– Like the most medical conditions, ASD is a syndrome

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New Yorker 12/27/93Oliver Sacks. Anthropologist from Mars

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Wild Boy of AveyronJean Marc Gaspard Itard (1774‐1838)

(1801 Memoire, 1806 Rapport Sur Victor de l’Aveyron)

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Leo Kanner(1894‐1981)

“Autistic Disturbances of Affective Contact”

The Nervous Child, 1943

Hans Asperger (1906 – 1980)

1943 Thesis

4 cases of “Autistic Psychopathy”

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Kanner Follow‐Up  (J. Aut Child Schiz, 1971)

1. 36 y/o Bachelor; bank teller; lives with parents; Pres Kiwanis; golfer

2. 34 y/o male; Devereux x23yrs; lives with mother;sheltered workshop‐duplicating maching

3. 33 y/o male; instituttionalized; basic care

4. 33 y/o male; no follow‐up.

5. 37 y/o female; state hospital;stereotypies & echolalia

6. 40 y/o female; state hospital; basic care; little language or social contact

7. 34 y/o male; foster family in country; no special ed; basic self‐help

8. 38 y/o male; various institutions; 

9. 32 y/o male; various institutions; volatile, social isolation, no language

10. Male; died in 1966; seizures

11. 39 y/o female; state hospitals; seizures; volatile behavior

Donald Gray Triplett (1933‐)Forest, MS

Kanner Case #1

The Atlantic, October 2010

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Psychological Theorists

• Manfred Bleuler

• Bruno Bettelheim

• Anna Freud

• Margaret Mahler

• Donald Meltzer

• Others

Early Advances in ASD

• 1961 – Biological Studies – 5HT– Schain & Freedman

• 1961 (1966) – Applied Learning Theory to Treatment– Ferster and Lovaas

• 1964 – Challenges to Psychological Etiology– Bernard Rimland

• 1966 –First Epidemiologic Study– Victor Lotter

• 1968 – Perceptual Problems in ASD– Ornitz and Ritvo

• 1968 – Integration of disparate research into a model– Michael Rutter

• 1971  ‐ Parents as co‐therapists in community setting (TEACCH)– Shopler and Reichler

• 1977 – Twin Studies– Folstein

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NSAC Criteria1978

A. Disturbed rate &/or sequence of development

B. Disturbed response to sensory stimuli

C. Disturbed speech/language, cognitive development

D. Disturbed Quality to relate appropriately to people, events and objects

DSM‐IV Pervasive Developmental Disorders 

(PDD)

299.0  Autistic Disorder

299.8  Asperger’s Disorder

299.9  Rett’s Syndrome

299.1  Childhood Disintegrative Disorder

299.8  Pervasive Developmental Disorder, Not Otherwise Specified (PDD‐NOS)

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DSM‐IV/ICD 10Autistic Disorder

A. Delay and/or abnormal patterns of development before age 3

B. Qualitative impairment in reciprocal social interactions

C. Qualitative impairments in communication

D. Restricted, repetitive and stereotyped patterns of behavior, interests and activities

DSM‐IVAutism Spectrum Disorders

Deficits

Dx

ReciprocalSocial

Language Cognitive Repetitive,

Restricted

Autism + + +/- +

Aspergers + - - +

PDD-NOS + +/- +/- +

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DSM 5: ASD

A. Persistent deficits in social communication and social interaction across contexts, not accounted for by general developmental delays 

B. Restricted, repetitive patterns of behavior, interests, or activities

C. Symptoms must be present in early childhood

D. Symptoms together limit and impair everyday functioning.

DSM‐IV  >>  DSM‐5 Summary

A. Delay and/or abnormal patterns of development before age 3

B. Qualitative impairment in reciprocal social interactions

C. Qualitative impairments in communication

D. Restricted, repetitive and stereotyped patterns of behavior, interests and activities

A. Persistent deficits in social communication and social interaction across contexts, not accounted for by general developmental delays 

B. Restricted, repetitive patterns of behavior, interests, or activities

C. Symptoms must be present in early childhood

D. Symptoms together limit and impair everyday functioning.

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DSM‐IV/DSM‐5 Asperger Comparison

Similar cross‐over, for example:A. Qualitative Impairments in Social Interaction >>>AB. Restricted, repetitive, and stereotyped patterns of behavior, interests, and activities, as manifested by at least one of the following:

• encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus >>>B1

• apparently inflexible adherence to specific, nonfunctional routines or rituals >>>B2

• stereotyped and repetitive motor mannerisms (e.g., hand or finger flapping or twisting, or complex whole‐body movements)>>>>B1

• persistent preoccupation with parts of objects >>>B3

DSM 5 Social Communication Disorder

A. Social Communication Disorder (SCD)is – an impairment of pragmatics

– diagnosed based on difficulty in the social uses of verbal and nonverbal communication

B. Low social communication abilities – result in functional limitations

C. Rule out Autism Spectrum Disorder

D. Symptoms must be present in early childhood

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ASDBack to Basics

Autism Spectrum Disorders (ASD)

A Syndrome

The 2 “D’s” = Delay & Deviations

Domains of Impairmenta. Social Development

• Joint Attention• Theory of Mind• Reciprocity 

b. Communication Developmentc. Restricted/Repetitive & Stereotyped Patterns of 

Interests and Activities (including IS)

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Autism & Autistic Spectrum Disorders (ASD)

• Coursea. Consistent over time

b. Some symptoms decreasea. Stereotypies

b. Visual regard

c. Some symptoms persist‐ Lack of social reciprocity

‐ Language abnormalities

‐ Restrictive and repetitive behaviors/IS

Dimensional Phenotyping

• Social Responsiveness

• Repetitive behaviors

• Compulsivity

• Theory of Mind

• Joint Attention

& many others

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VisualRegard

IMITATION

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POINTINGTo Share

POINTING(to ask)

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POINTING(to comment)

SYMBOLIC PLAYBy self

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SYMBOLIC PLAYReciprocal

Joint Attention

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Theory of Mind

What are the Spectra or Axes in

Autism Spectrum Disorders (ASD)?

Poor/No Language

Fluent Language

Few Autism Symptoms

Many Autism Symptoms

Good Social Skills

Lower Cognitive Function

Poor Social Skills

Higher  Cognitive Function

ASD

HIGH  Functioning> > > > > > > > > > > > > > > > > > > > > > > > > > > LOW Functioning

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The ASD EpidemicTerminology

• Prevalence– the proportion of a given population having a particular condition or characteristic; 

– number of cases present 

– “point prevalence” or “period prevalence”

• Incidence– the number of new cases in a specific time period divided by the size of the population at risk

• Epidemic – a dramatic rise in incidence

California CDER data: 1961 ‐ 1991

Department of Developmental Services, California 1999

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Trends in Minnesota

Gurney et al., 2003

DSM‐III‐RICD‐10

DSM‐IV

Individual  with Disabilities Educational Act (IDEA)

Prevalence:What once was rare…

• Old U.S. estimate for autism:– ~ 1/2500 (1985)

• Recent U.S. estimates for autism:– ~ 1/500   (1995)

• Newest U.S. estimates for ASD: – 1/150 (CDC, 2007)– 1/110 (CDC, 2009)– 1/91   (NSCH, 2009)– 1/88 (CDC, 2012)– 1/38 (Kim, 2011)– 1/45 (Zablotsky, 2015)

• Why are the numbers increasing?

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1. Diagnostic changesa. Broadening of Criteria

2. Better tools and methods for identification

3. Awarenessa. Mental health providers, primary 

care, schoolsb. Media, parents

4. More services5. Wider age range6. Diagnostic Substitution

Why are numbers increasing? Many reasons

• Standard diagnostic measures– Autism Diagnostic Interview‐Revised– Autism Diagnostic Observation Schedule ‐2

• Screening tools/algorithms/instruments in wide use:– MCHAT / AAP guidelines– SCQ– SRS– ASSQ

• Other factors: 1. Previous underestimates2. Methodology for obtaining epidemiological data3. What else???

– Increased incidence?

Why are numbers increasing: More reasons: Better tools?

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Variations in Prevalence of ASD in UK

Study LocationSize of 

PopulationAge

Prevalence (/10,000)

Baron‐Cohen (2009)Cambridge‐

shire11,635 5‐9 157

Baird (2007)South East Thames

56,946 9‐10 116.1

Chakarabarti & Fombonne (2001)

Staffordshire 15,500 2.5‐6.5 62.6

Fombonne (2001)England & Wales

10,438 5‐15 26.1

Baird (2000)South East Thames

16,235 7 57.9

Taylor (1999)North Thames

490,000 0‐16 10.1

x16 Increase

Korean ASD Prevalence Study

• Total Population Study

– Screening of All Children in a Target Area (N=23,400)

– Multi‐Informant Screening with Autism Spectrum Screening Questionnaire (ASSQ)

– Confirmative Diagnoses of ASD with ADOS and ADI‐R

Inclusion of CLINICAL & NON‐CLINICAL ASD POPULATION

• Total ASD Prevalence: 2.6%

– Clinical Population = 0.8%

– Non‐Clinical Population = 1.8%

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Clinical Characteristic between ASD Groups

ASD w/Services ASD w/o Services

ASD Subtype Diagnoses

3/4 AD1/4 Other ASD

1/4 AD3/4 Other ASD

SRS T‐Score 84 ± 17 64 ± 14

Sex Ratio 5:1 2.5:1

Performance IQ 75 98

ID Percentage 59% 16%

Adaptability T‐Scores

38 ± 9 43 ± 10

Awareness

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More Services

• More studies leading to evidence‐based treatments

– Medication

– Behavioral

– Other

• State and Federal laws requiring coverage by

– Schools

– Insurance companies

Age Range

• Previously a diagnosis of ages 6‐16

• Now

– Earlier Detection 12‐18 months

– Retained life time diagnoses

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CDC, Center for Health StatisticsZablotsky et al 2015

CDC, Center for Health StatisticsZablotsky et al 2015

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Prevalence Estimates: DSMIV PDD, DSM5 ASD, DSM5 SCD

% DSMIV PDD % DSM5 ASD % DSM5 SCD %DSM5 ASD+SCD

Population

Total 2.64 2.20 0.49 2.69

GPS 1.89 1.46 0.49 1.95

HPG 0.75 0.75 0.00 0.76

DSMIV PDDSubtype

Austistic Dis 1.04 1.03 0.001 1.04

Asperger 0.60 0.55 0.05 0.59

PDD‐NOS 1.00 0.63 0.32 0.94

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DSMIV cases not meeting DSM5 Criteria

Divergent Group, n=22 (7.5%)

% of Divergent

% Total

Other Diagnoses

SCD 14 64 4.8

SCD+other PsychDisorder

4 14 1.4

Other Psych Disorder

5 22 1.7

No Diagnosis 0 0 0

So, will people be left out?

• Will patients with DSM‐IV Pervasive Developmental Disorder not meet DSM‐5 criteria?– YES

• A few  ~ 3%• Rett’s Syndrome ‐ All• Autistic Disorder ‐ None• Aspergers ‐ very few

– > SCD 

• PDD‐NOS– > SCD (most) – > Other Psychiatric Disorder ‐ ? did not have PDD in the first place

» ADHD & Anxiety Disorder

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Autism EtiologyWhat Causes ASD?

• Chromosomal (syndromic) – fragile‐ X syndrome, tuberous sclerosis

• Genetic ‐ increased risk in twins, siblings– small chromosomal deletions or duplications (i.e., copy 

number variation or CNV.)

• Structural – anatomic, cellular

• Others – Environmental/toxic– Immunologic– gastrointestinal, – etc

Genetics • Genetic complexity matches clinical complexity

• Hints of future findings:

– Syndromes that include ASD

– Copy number variants

– Rare, de novo variants

– Synaptic development genes

• Molecular work is just beginning

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ASD Genetics Summary

• May not be entirely Genetic– gene‐gene interactions

– gene‐environment 

– Range in contribution of genetics vs. environment across disorders and individuals.

– epigenetic

• Most cases due to large number of smaller effect genetic and small to large environmental effects.

• Genetic component to etiology doesn’t reduce need for therapy, habilitation, education, non‐genetic treatment

• Main goal of genetics is to understand mechanisms to develop novel treatments.

Non‐GeneticASD Etiology

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Structural Imaging

• 25% or fewer have nonspecific abnormal structural neuroimaging scans.

• Cerebellar hypoplasia seen in some.

• Mean increase in brain size is proportional to head circumference.

• Clinical MRI is not worth risk of sedation unless:– Indication beyond diagnosis of ASD.

Developmental macrocephaly

• Increased head circumference during first year of life then levels off

• ~ 5% elevated in adulthood

• Lack of pruning?

Courchesne, JAMA, 2003

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Abnormal Mirror Neuron System During Imitation?

• But…

– Hasn’t replicated well

– Unclear if specific to emotional expression

Dapretto et al., Nat Neurosci, 2006

Functional neuroimaging

• Fusiform face area underactive

– Inversely correlated with gaze

– Active with cartoon characters

Schultz, Int J Dev Neurosci, 2005

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Abnormal Amygdala Habituation to Faces?

• Correlates with symptom severity

• Equivalent identification of repeat faces

– But slower in autism group

Aylward et al., Am J Psychiatry, 2009

Visual scanning of faces

• Typical subjects concentrate on eyes

• Patients with autism focus on mouth

– ? Difficulty in speech comprehension

– Also focus more on background

Klin, Am J Psychiatry, 2002

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Autopsy Studies

• Decreased Purkinje cells in cerebellum– Most replicated neuropathological finding

• Neuronal migration abnormalities and dysplasia– No consistent locations

• Many of the highly penetrant genetic variants are related to activity‐dependent synaptic plasticity which may contribute to neuronal migration abnormalities.

Neuropathology

• Scarce resource

• Clouded by comorbidity: MR, seizures

• Decreased cerebellar Purkinje cells

• Signs of cortical dysgenesis

• Findings do not explain macrocephaly

– But brains are almost exclusively of adults

– Increased neuronal number in only small study of child brains

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Minshew, N. J. et al. Arch Neurol 2007;64:945‐950.

Micrographs of Brodmann area 4, lamina III, from a patient with autism (A) and from an age‐matched control (B)

But not yet replicated independently…

Other Risk Factors

• Parental age– Paternal > maternal?

– Likely to be genetically mediated

• Birth complications– Extreme low birth weight

– Extreme preterm birth

• Prenatal exposures– Thalidomide, valproic acid during end of first trimester

– Rubella during first trimester

• Other prenatal risk factors– Short interpregnancy interval?

– Maternal obesity / diabetes?

– Assisted reproductive technology?

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HYPERSEROTONEMIA present in ~25-30% of individuals with ASD; it is not seen in children with other developmental disorders

As heritable as height 0.99

SCHAIN AND FREEDMAN, 1961

2016: 55th Anniversary of First and Most Stable ASD Biomarker

Prenatal androgen exposure?

Amniocentesis between 11‐21 weeks

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Environmental Factors in ASD

• Twin Studies– MZ >> DZ Concordance Rate

– Not 100% Concordance Rate in MZ Twin

• Association between ASD and prenatal exposures:– thalidomide, valproate, rubella, etc.

• Exploration of environmental risks in ASD:– Prenatal/perinatal risks, infections, vaccines, pesticides, heavy metals, precipitation, proximity to power plants, geographic location, etc.   

Perinatal Risks in ASD

• Biological Plausibility: – Timing of Exposure– Animal model

(+) /Total Studies

Risk Ratios

Prenatal Smoking 2/3 1.4‐3.5

Threatened Abortion 2/4 1.3‐2.1

Abnormal Fetal Position 3/4 1.3‐2.1

High Parity 4/6 0.3‐0.5

Prematurity 5/7 1.2‐5.4

C‐section 5/7 1.2‐1.8

Low Birth Weight 7/10 1.3‐2.3

Limitations1. Small sample size2. Non Representative 

Sample3. Clinically drive sample4. Phenotype 

Heterogeneity5. Comorbid Condition

• Relative accuracy in retrospective data collection

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Challenges in ASD Environmental Studies(1) What To Study?

• Autism prevalence and precipitation rates in CA, Oregon & Washington Counties (Waldman et al, Arch Pediatr Adolesc Med 2008)

–At County Level, ASD prevalence ∝mean annual precipitation rates

•Other–Early TV, video viewing, Vitamin D deficiency, indoor activity related pathogens increase risks for ASD in genetically vulnerable individuals

Challenges in ASD Environmental Studies:Whom To Study? 

• Genetic Heritability and Shared Environmental Factors among Twin Pairs with Autism (Hayway et al., Arch Gen Psychiatry 2011)–192 Twin Pairs from 1156 Pairs in CA Department of Developmental Service (DDS)–ASD concordance rate 0.77 in MZ vs. 0.31 in DZ–Moderate genetic heritability and a substantial shared twin environmental component

• Problems– DDS Data administrative data– 192/1156 Potential  Study Pairs  (17% Participation Rate)

• No demographic difference between participants and non‐participants• Demographic factors did not predict concordance rates in twin  pairs

• Suggestions– Target Representative Population– Aim for Optimal Participation Rate– Methods to Examine Possibility of Sampling Bias

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Other Etiologic Issues

Ileal‐lymphoid‐nodular Hyperplasia, Non‐Specific Colitis and Pervasive Developmental Disorder in Children

Wakefield, Murch, Anthony et al

Lancet 1998:351:637‐641

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Andrew WakefieldWakefield et al. (1998)

12 children with PDD and gastrointestinal disease

Purpose was to look at relationship b/w these

Participants were selected b/c they had been referred to a pediatric gastroenterology dept for tx of intestinal problems (e.g., diarrhea, pain, bloating)

Onset appeared to be near time of MMR vaccination

Theory…MMR led to impaired intestinal functioning– Permeability of the intestines increased

– Resulted in excess absorption of peptides from food

– The peptides have opioid effects

– Opioid excess led to brain dysfunction, and…

– Concluded that ASD was caused by MMR vaccine

MMR coverage and autism riskGP RD data

0

20

40

60

80

100

0

10

20

30

40

1988 1989 1990 1991 1992 1993

Autism risk MMR prevalence

Aut

ism

ris

k pe

r 10

,000

MM

R p

reva

lenc

e (%

)

Year of birthKaye et al., 2001

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Is age of onset or autistic regression associated with 

MMR?

Age at first parental concernsADI-R data (item 2)

19.5 19.2 19.3

0

5

10

15

20

25

Family study all born <1980

N=89

Clinic sample born 1987-1996

N=68

Stafford survey born 1992-1995

N=96

Age in months

F2,250 = 0.02, NS

Pre-MMR Post-MMR

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Thimerosal and the Occurrence of Autism: Negative Ecological EvidenceFrom Danish Population‐Based Data

Kreesten M. Madsen, et al.

PEDIATRICS Vol. 112:3:604‐606 September 2003

Mercury (Hg)

• Methyl Mercury (MeHg)– Subject of EPS Toxicity Studies 

• Ball et al, 2001

– More potent

– Excretion ½ life = 50 days

• Ethyl Mercury (EtHg)– Excretion ½ life = 7‐10 days

– Renal excretion

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Meta‐analysis of MMR and autism

Smeeth et al. 2004

DeStefano et al 33

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ASD Assessment

ASD Early Warning Signs

• By 6 mos: No smile or expression of joy

• By 9 mos: No sharing of sounds, smiles or facial expression

• By 12 mos: no babbling, no reciprocal gestures (pointing, showing, reaching, waving)

• By 12 mos: no response to own name

• By 16 mos: no words

• By 24 mos: no meaningful 2‐word phrases       (not echoing)

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Sources of Informatiom

• Screening

• Clinical Interview

– History

– Direct Observation

• Standard Diagnostics

– ADI

– ADOS

– CARS

• Adaptive Function

– Vineland

– ABC

• Physical Examination

– Neurological

– Sensory Exam

• Laboratory

– Only as indicated

ASD Screening Instruments(1)

• Social Emotional Growth ChartStanley I. Greenspan, MD(for children 0‐42 months)35 items – 10 minutes – teacher/caregiver completed

• Modified Checklist for Autism in Toddlers (M‐CHAT)Diana Robins, M.A., Deborah Fein, Ph.D., et al.(for children 16‐30 months)

• Autism Spectrum Screening Questionnaire (ASSQ)Ehlers, Gillberg, and  Wing)(for children 7‐16)27 item checklist completed by lay informants

• Social Communication Questionnaire (SCQ) (Previously the ASQ‐ Autism Screening Questionnaire)Lord,  Rutter, Anthony (for children 4 and older)40 yes‐no items; 2 forms: Lifetime and Current; Parallels ADI‐R

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The Gold Standard:  ADOS‐2/ADI‐R

1. Autism Diagnostic Interview ‐ Revised– ADI‐R

– Lord, Rutter, LeCouter (1994)

2. Autism Diagnostic Observation Schedule ‐ 2– ADOS‐2

– Lord, Rutter, et al (2012)

3. New‐ Toddler ADOS

‐ Adapted ADOS

How Predictive is ADI/ADOS Diagnosis?

• Of 108 children referred for diagnosis of autism at 

age 2, diagnoses at 5 years were:

– 61% Autism

– 25% PDD‐NOS

– 14% Nonspectrum(language‐impaired or mentally retarded)

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• Many, many others

• Questionnaires for caregivers

– SCQ (Lord et al)

– CHAT (Baron‐Cohen et al., 1992)

– PDDST (Siegel)

– E2 (Rimland)

• Ratings from observation:

– GARS (Gilliam, 1995)

– CARS (Schopler et al., 1988)

– BRIACC (Ruttenberg et al., 1977)

More Diagnostic Instruments

Social Responsiveness Scale (SRS)‐2

• 65‐item parent or teacher rating scale • Used in both clinical and general populations• Scales:

– singular scale score: severity of social deficits – Subscales:  social awareness, social information processing, capacity for reciprocal social responses, social anxiety/avoidance and characteristic autisticpreoccupations/traits

• High test‐retest reliability • Strong correlations with DSM‐IV & 5 criterion scores • Constantino, et al (2012 )

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Cognitive Measures

• Verbal

– Wechsler

• WPPSI, WISC, WAIS

– Stanford Binet

• Non‐Verbal 

– DAS (Differential Abilities Scale

– Mullens

– Raven’s

Measures of Adaptive Function

• Vineland Scales of Social Maturity

• Alpern Boll• DABS 

–Diagnostic Adaptive Behavior Scale• From AAIDD

• Other

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Language

• Full Spectrum of Communication– Expressive and Receptive– Reciprocal– Types

• Speech– Articulation– Vocabulary– Prosody– Inflection

• Gesture– Hands– Face– Body

– Written

Aberrant Behavior Checklist (ABC)

• A 58‐item standardized checklist comprising 5 subscales:– The 5 subscales are as follows:

• Irritability (15 items, range: 0 to 45 points)

• Lethargy and Social Withdrawal (16 items, range: 0 to 48 points)

• Stereotypic Behavior (7 items; range: 0 to 21 points)

• Hyperactivity/Non‐Compliance (16 items; range: 0 to 48 points)

• Inappropriate Speech (4 items; range: 0 to 12)

– Each of the 58 items have a possible score of 0 to 3 points: 

• 0=no problem; 3=severe problem

• Higher ABC subscale scores correlate with increased symptom severity

– The scale is observer‐rated and parent‐driven, and under the guidance of a clinical specialist.

Aman, MG, et al. Am J Mental Deficiency 1985;89(5):492-502

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Functional Behavior Analysis

• Analysis of problematic behaviors

– Interfere with learning

– Interfere with adaptation

– Interfere with participation in the environment

– Atypical and lead to social isolation

Assess for Comorbidity

• Other psychopathology– CBCL– BASC‐2– Other

• Intellectual Disability– 25‐50%

• Seizures– 25%– Atypical risk for adolescent onset– Risk inversely correlated with IQ

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Other Assessments

• Psychoeducational Testing

• Neuropsychological Testing

• Occupational Therapy

• Physical Therapy

• Vision

• Hearing

Laboratory Studies

• Genetics– FraX– SNP Microarray– WES – Whole Exome Sequencing– WGS – Whole Genome Sequencing

• Imaging– Only with focal findings

• EEG– Only with findings of possible epilepsy– PSG for unremitting sleep problems

• Heavy metals– Pica or other exposure

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Appropriate Assessment

is the

Starting Point for Treatment

of

Autism

The goal of the evaluation is:Develop and Effective Treatment Plan

• An effective treatment plan is

– Based on careful, comprehensive evaluation

– In a developmental context

– Builds on skills

– Works around limits and deficits

– Does no harm

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Factors That Predict Autism Outcome

1. Expressive Language 

‐ Communicative speech by age 5

2. Language Comprehension

‐ Spoken language by age 5

3. Intellectual Capacity

‐ Non‐verbal intelligence

4. Adaptive Function

5. Severity of Autism

a. Social 

b. Restricted, Repetitive Behaviors

c. Aggression

Environmental Interventions:How Early?  How Often?

• Speech & Language Therapy• Educational Programming• Behavior Therapy

– ABA– DTT– Pivotal Response Training– ESDM

• Family Interventions– Education– Parent Training

• Individual Psychotherapy• Pharmacotherapy

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SPEECH&

LANGUAGE

THERAPY

Educational Programming

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Social Skills Training

• Structured Curricula• Individual• Groups

• Sites• In home• Community• School• Public areas/programs

• Programs• Social Stories – Carole Gray• Floor Time – Greenspan• Social Thinking by Michelle Garcia‐Winner• Video modeling by Scott Bellini, • Relationship Development Intervention (RDI) ‐ Gutstein• Early Start Denver Model (ESDM) - Rogers

Behavior Management

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Behavioral Techniques

• General Behavior Therapy– ABA 

• Applied Behavior Analysis

– DTT• Discreet Trial Training

• Lovaas Model– Smith T, Eikeseth S, Klevstrand M, Lovaas OI, 1997

• Pivotal Response Training (PRT)

• Group Programs– Peers

Parent Training• Educational

• Behavioral

• Support

• All either in individual and/or groups

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So, What can we accomplish with Psychopharmacology?

1. Treat Specific Behaviors/Symptoms

2. Decrease problems that interfere with other treatments

3. Do no harm!

Change in the mean item score on the Children’s Psychiatric Rating Scale-14 (CPRS-14) with risperidone.

Each line represents an individual child’s score from baseline to the end of short-term treatment.

Malone et al. JAACAP, 41:(2):140-47.February 2002

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All Medications have

Side Effects

A special problem in treating ASD

Just because a small amount of medication works well,

it does not mean that a lot will work better

Another special problem in treating ASD

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RRB’sRestrictive and Repetitive 

Behaviors1. Stereotypies

2. Insistence on sameness

3. “Stimming”

4. Habits

5. Tics

SSRI’sSerotonin Reuptake Inhibitors*

• fluoxetine (Prozac)

• sertraline (Zoloft)

• paroxetine (Paxil)

• fluvoxamine (Luvox)

• citalopram (Celexa)

• escitalopram (Lexapro)

• clorimpramine (Anafranil)

*Note: FDA Warning about suicidality

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Hollander, et al. Neuropsychopharm (2004) pp1-8

ollander Fig 1‐YBOCS Compulsion Score

CY-BOCS Compulsion Score

Hollander, et al. Neuropsychopharm (2004) pp1-8

Hollander Fig 3 – CGI Global Improvement ‐Composite

CGI Global Improvement - Composite

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Hollander, et al. Neuropsychopharm (2004) pp1-8

Symptom Fluoxetine Placebo

Anxiety/Nervousness 15.9% [ 6/39] 33.3% [12/36]

Insomnia 35.9% [14/39] 47.2% [16/36]

Drowsiness/Fatigue/Sedation 17.9% [ 7/39] 11.1% [ 4/36]

Agitation 46.2% [18/39] 44.4% [16/36]

Diarrhea 5.1% [ 2/39] 19.4% [ 7/36]

Anorexia 15.4% [ 6/39] 11.1% [ 4/36]

URI 10.3% [ 4/39] 19.4% [ 7/36]

Weight Gain 0% [ 0/39] 2.8% [ 1/36]

Fluoxetine/Placebo Side Effects

Aggression & Irritability

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Traditional Neuroleptics

• haloperidol  (Haldol)

• trifluoperazine (Stelazine)

• fluphenazine  (Prolixin)

Atypical Neurolpeptics

• clozapine (clozaril)

• risperidone (Risperdal)

• olanzepine  (Zyprexa)

• quetiapine  (Seroquel)

• ziprasadone (Geodon)

• aripiperazole (Abilify)

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The RUPP Autism Study

Primary Endpoint Analysis 

Aberrant Behavior Checklist ‐ Irritability

LOCF analysis; *P<0.001 vs. PBO

BL (RIS)=26.2  BL (PBO)=25.5Week 8 (RIS)=11.3       Week 8 (PBO)=21.9

Risperidone (n=49) 

Placebo (n=52) 

*

Time in Weeks

0

5

10

15

20

25

30

0 2 4 6 8

Mean

 ABC Irritability Total Score

Improvemen

t

*

*

*

RUPP Autism Network. N Engl J Med. 2002;347:314‐321. 

After 8 weeks of treatment, the risperidone group had a 56.9% improvement compared to a 14.1% improvement in the placebo group.

Mean Daily Dose at Week 8 RIS = 1.8 mg

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Primary Endpoint Analysis Clinical Global Impression ‐ Improvement

“Much Improved” or “Very Much Improved” on CGI‐I by group

Time in Weeks

risperidone (n=49)

Placebo (n=52)

*P<0.001 vs. placebo at weeks 4 and 8

RUPP Autism Network. N Engl J Med. 2002;347:314‐321.

0

10

20

30

40

50

60

70

80

90

0 1 2 3 4 5 6 7 8Percentage of Subjects with CGI‐I < 3

75.5%

11.5%

*

*

Mean Daily Dose at Week 8 RIS= 1.8 mg

Secondary Endpoint Analysis Aberrant Behavior Checklist Subscales

Change in ABC‐Subscale scores from baseline to endpoint

Stereotypy

10.6

9.0

5.8

7.3

0

2

4

6

8

10

12

Risperidone Placebo

AB

C-S

tere

oty

py

Sco

re

P<0.001 vs placebo

RUPP Autism Network. N Engl J Med. 2002;347:314‐321.

Baseline

8‐weeks

31.8 32.3

17.0

27.6

0

5

10

15

20

25

30

35

Risperidone Placebo

AB

C-H

yper

acti

vity

Sco

re

Hyperactivity

P<0.001 vs placebo

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Change in ABC‐Subscale scores from baseline to endpoint

*Scores for Social Withdrawal and Inappropriate Speech did not differ significantly from placebo after the Bonferroni correction (NS indicates not significant)

RUPP Autism Network. N Engl J Med. 2002;347:314‐321.

Baseline

8‐weeks

4.8

6.5

3.0

5.9

0

1

2

3

4

5

6

7

Risperidone Placebo

AB

C-I

nap

pro

pri

ate

Sp

eech

Sco

re

Inappropriate Speech

NS vs. placebo*16.4 16.1

8.9

12.0

0

2

4

6

8

10

12

14

16

18

Risperidone Placebo

AB

C-S

oci

al W

ith

dra

wl S

core

Social WithdrawalNS vs. placebo*

RUPP Autism Secondary Endpoint AnalysisAberrant Behavior Checklist (ABC) Scales 

RUPP Autism Study: Adverse Events

Adverse event risperidone n = 49n (%)

Placebon = 52n (%)

P-value†

Increased appetite

Mild 24 (49) 13 (25) 0.03

Moderate 12 (24) 2 (4) 0.01

Fatigue 29 (59) 14 (27) 0.003

Drowsiness 24 (49) 6 (12) <0.001

Drooling 13 (27) 3 (6) 0.02

Tremor

Dizziness

Constipation

Tachycardia

7 (14)

8 (16)

14 (29)

6 (12)

1 (2)

2 (4)

6 (12)

1 (2)

0.06

0.05

0.06

0.06

Weight gain in kg 2.7 ± 2.9 0.8 ± 2.2 <0.001*

RUPP Autism Network. N Engl J Med. 2002;347:314‐321.

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LithiumLithium Carbonate

propranolol

Inderal

[α‐adrenergic blocker]

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Attentional Deficits

Mean Parent & Teacher Rated ABC Hyperactivity Subscale Scores During Crossover & Open Label Phase

RUPP, Arch Gen Psychiatry, 62 (11) 1266-1274 (2005)

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Mood DisturbanceIrritability

Anticonvulsants(mood stabilizers)

• valproate (Depakote)

• carbamazepine (Tegretol)

• lamotragine (Lamictal)

• neurotonin (Neurontin)

• gabapentin  (Gabatril)

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SSRI’sSerotonin Reuptake Inhibitors*

• fluoxetine (Prozac)

• sertraline (Zoloft)

• paroxetine (Paxil)

• fluvoxamine (Luvox)

• citalopram (Celexa)

• escitalopram (Lexapro)

• clorimpramine (Anafranil)

*Note: FDA Warning about suicidality

Anxiety 

1. Anti‐anxiety medications2. Benzodiazepines3. SSRI’s*

– fluoxetine (Prozac)– sertraline (Zoloft)– paroxetine (Paxil)– fluvoxamine (Luvox)– citalopram (Celexa)– escitalopram (Lexapro)– clorimpramine (Anafranil)

*Note: FDA Warning about suicidality

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New Medications

• GABA – active agents

• mGluR5 agonists and antagonists

• Oxytocin

• Vasopressin 1A antogonist

• Others directed at evolving biology

Cognitive Enhancers?

Arricept (donepezil)

Exelon (rivastigmine)

Namenda (memantine)

Reminyl (galantamine)

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Complementary and Alternative/ Integrative Treatments ‐ “Off‐label”

• Sleep supplements (e.g., melatonin)

• Diets (e.g., gluten free/casein free)

• Supplements (e.g., omega 3 fatty acids)

• Vitamins (e.g., B6 and magnesium)

• Allergies (e.g., lactose)

• Anti‐oxidants (e.g.,Vit E)

• Neurotransmission Modulators (e.g., NAC)

Other Proposed Treatments

• Vitamins

• Minerals

• Dietary Supplements

• Dietary Restrictions

• Sugar

• Food Dyes

• Chelation

• Secretin

• Steroids

• Eye Tracking

• Sensory Diets

• Facilitated Communication

• Floor Time

• ?

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0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8Week

Sco

re

Secretin-Placebo ABC-C Placebo-Secretin ABC-C

Placebo

SecretinPlacebo

Secretin

CHELATION[The Removal of Heavy Metals]

•Benefits

‐Removes toxic heavy metals, when present‐Measured in blood, tissue, X‐Ray

‐NOT measured in hair

‐E.g., lead, strontium

•Risks

‐Chelating chemicals are toxic themselves

‐ Sickness & Death

‐ Takes a long time

‐ Remove toxin but likely will not reverse neural damage

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Special Challenges in ASD

Transition to Adulthood

• Transition planning should begin long before leaving school.

• Frequently a cliff moving from federally mandated appropriate educational services until the end of school age (e.g. 22 years‐old) to less well‐mandated adult services.

• With support many transition well to adult vocational and educational services (including up to graduate school).

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Transition to Older Adulthood

• Largely unstudied.

• Includes death of parent(s) with grief that may be more challenging with communication impairment.

• Requires transition to other guardians, typically siblings or cousins.

• Attention to difficulty in communicating physical symptoms such as angina.

Most children with ASD get better over time!

Our goals are: 

Search for etiologies that can be used to 

Enhance treatment

Prevent ASD

In the meantime:

Use treatments that improve the rate at which individuals with ASD acquire skills and the ability to use those skills for independent and semi‐independent living

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ASD Resources

Networking Resources

• ASA (Autism Society of America) www.autism‐society.org

• Autism Speaks  • www.autismspeaks.org• Organization for Autism Research (OAR) 

www.researchautism.org• Interactive Autism Network (IAN)   

www.ianproject.org

• Autism Science Foundation  www.autismsciencefoundation.org

• Simons Foundation Autism Research Initiativewww.sfari.org

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Networking Resources• American Association on Intellectual and Developmental Disabilities (previously AAMR) www.aaidd.org

• National Association for the Dually Diagnosed (NADD)  • www.thenadd.org• The ARC • www.thearc.org• American Academy of Child and Adolescent Psychiatry (AACAP)  

• www.aacap.org• National Alliance on Mental Illness (NAMI)  www.nami.org

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QUESTIONS?

THANK YOU

Autism Spectrum Disorder

Bennett L. Leventhal, MDProfessor

Department of PsychiatryUniversity of California, San Francisco

Osher Mini‐Med SchoolUCSF

San Francisco, CA26 May 2016

STAR.ucsf.edu