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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
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