Autism Spectrum Disorders
Jess P. Shatkin, MD, MPH
Vice Chair for Education
NYU Child Study Center
New York University School of Medicine
Pervasive Developmental Disorders
• PDDs are characterized by severe and pervasive
impairment in several areas of development:
– Reciprocal social interaction skills
– Communication & language skills
– The presence of stereotyped behavior, interests and
activities
• Generally evident within the first few years of life
• Often associated with MR and/or a diverse group
of medical conditions (e.g., chromosomal
abnormalities, congenital infections, structural
abnormalities of the CNS, etc.)
Learning Objectives
Participants will be able to:
1. Name the 3 diagnostic domains of Pervasive
Developmental Disorders
2. Identify 2 major distinguishing factors between
Autistic Disorder and Asperger’s Disorder
3. Name 3 commonly comorbid psychiatric conditions
and 3 commonly comorbid general medical
conditions
4. Identify the key prognostic indicator for Autism
5. Describe 3 effective treatments for Autism
6. Describe the primary learning difficulties found in
children with pervasive developmental delays
The History of Autism
• Autistic children were historically believed to be
schizophrenic
• In 1943 Leo Kanner (Hopkins) described 11 cases of
what he termed “early infantile autism,” noting ways in
which it was distinctive from psychosis/schizophrenia
• Kanner’s (unfortunate) choice of the word “autism” was
meant to convey the unusual self-centered quality of
these children (following Bleuler)
• Although many of Kanner’s observations have lasted,
his speculations about certain aspects of the illness (e.g.,
normal IQ, lack of association with other medical
conditions, poor parenting/education) have been proven
incorrect
The History of Asperger’s Syndrome
• In 1944 Hans Asperger (in Austria) proposed a novel
concept, autistic psychopathy (coincidentally using the
same word as Kanner) based upon his observations of 4
children, which resembled Kanner’s concept in some
ways
• Now known as Asperger’s (a term coined by Lorna
Wing in England) to avoid the use of the word
psychopathy and to separate it from general autism
• Asperger’s Syndrome has been better described in the
European literature; these children in the U.S. have
generally been diagnosed with high functioning autism
Historical Myths about Autism
• Children with autism never make eye contact, show
affection, or smile
• Inside a child with autism is a normal child (or genius)
waiting to emerge
• Children with autism don’t speak, but they could if they
wanted to
• Children with autism don’t relate to peers & adults and
don’t want friends
• Children with autism are manipulative & selfish
• Autism is an emotional disorder
• Autism can be outgrown; or progress means a child is
not autistic
Autistic Disorder
• The best studied of the PDDs (DSM III in 1980)
• Better definitions have been hindered by
continuity w/other disorders, the broad range of
syndrome expression, changes in syndrome
expression w/age, high frequency of autistic-like
symptoms in those w/MR, & the relative
infrequency of this disorder
• In most cases there is no period of unequivocally
normal development (although 20% of parents
report normal development for first 1-2 yrs of life)
What We Know About Autism
• Autism is a biological disorder with multiple
etiologies
• No single cause, no single cure
• No biological marker
• No evidence of parenting defects or emotionally
induced autism (e.g., the “refrigerator mother”)
• Currently, the view is that some factor(s) act
through one or more mechanism to produced a
final common pathway of CNS insult that results
in the behavioral syndrome of autism
Current Research into Etiology
• Abnormalities in the genome
– Chromosome 15q11-q13 is implicated based upon
twin & family studies (re: PWS & Angelman)
• Mechanisms underlying the expression of these
abnormalities during brain development
• Resulting structural and functional abnormalities
in the brain
• Behavioral expressions of autism
The Autism Gene
• Numerous possible genes and chromosomal
regions have been identified:
–
–
–
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FXR1 (20 – 60% of affected kids are autistic)
15q11-13
17q11-21
SHANK3 (chromosome 22)
• Copy Number Variations (CNVs)
Mirror Neurons
• In monkeys, MNs are found in the inferior frontal
gyrus and inferior parietal lobule. These neurons are
active when monkeys perform a task or watch someone
perform a similar task. A similar system is theorized to
exist in the human brain.
• These neurons are theorized to be important for
understanding the actions of others and for learning
new skills by imitation.
• The most basic social brain system.
• The mirror system may simulate observed actions and
thus contribute to our Theory of Mind skills.
• fMRI studies have now demonstrated decreasing
activity (presumed MN activity) in the inferior frontal
gyrus (pars opercularis) in humans with autism
Mirror Neurons
Monkey See, Monkey Do…
Monkey Feel?
Amygdala
• The amygdala (“almond”) is thought to have many important
roles, including fear conditioning, memory consolidation, and in
the generation of important emotional responses, which help the
brain to process memories that are key to social learning
• The amygdala has long been suspected as a source of some
concern in autism
• More recently, David Amaral at the UC Davis MIND Institute
(Journal of Neuroscience, 2006) found that men and boys with
autism have fewer neurons in the amygdala
• One possibility is that there are always fewer neurons in the
amygdala of people with autism. Another possibility is that
autism is a degenerative process occurs later in life and leads to
neuron loss.
However: Prior Amygdala Research
• Prior research had demonstrated larger amygdala
structures among children with autism; larger right
amygdala volume has been associated with more
severe social and communicative impairments in
autistic 3 and 4 year olds.
• This is predictive of a more severe clinical course
and worse social/communicative outcome at the
age of 6. (Munson et al., 2006).
• Early studies of post-mortem evaluation among
adults with autism found higher cell density in
amygdala (Rapin & Katzman, 1998)
Implications of Amygdala Damage
• Subjects are non-autistic
individuals with unilateral or
bilateral amygdala damage
• Delivered questions about both
basic emotions (‘‘Is it happy, sad,
etc.?’’) and social emotions (‘‘Is
it flirtatious,guilty, etc.’’).
• Amygdala damage impairs
recognition of complex mental
states more than it does basic
emotions, though both are
affected
• The impairment was evident when
participants were presented with
both full faces and only the eyes,
an effect observed in autism
(Adolphs et al., 2002).
Implications of Amygdala Damage (2)
“Judging the mind in the eyes”
• Mentalizing task: participants had
to decide for each stimulus which
of two simultaneously presented
words best described what the
person in the photograph was
feeling or thinking
• Adults with HFA or AS with
intelligence in a normal range
show impairments in this task
(Baron-Cohen, et al, 1997).
• Cognitive Phenotype? Parents of
children with AS were
significantly less accurate at the
task, indicating that certain
cognitive qualities may be
inherited (Baron-Cohen &
Hammer, 1997).
Results: “Judging the mind in the eyes”
• Adults with HFA or AS showed
significantly less amygdala
activation during the task
• The autism group activated the
frontal lobes less extensively
than controls and did not
activate the amygdala at all
• Control group showed especially
powerful response in left
amygdala, which may be
extensively involved in
emotional processing
• Autistic group had more
processing activity in the
temporal lobe, which is
responsible for verbally labeling
complex visual stimuli and
processing faces and eyes
• Compensation? (Baron-Cohen et
al., 1999).
• Control group only activation: yellow
• Autistic group only activation: red
• Coincidental activation: blue
Amygdala: Putting It All Together
• Most recent theories suggest that social fear in autism may initially
trigger a hyperactive, abnormally enlarged amygdala, which
eventually gives way to a toxic adaptation that kills amygdala cells
and shrinks the structure (Davidson, 2006)
• In Davidson’s recent study, those in the autism group who had a
small amygdala were significantly slower at identifying happy, angry,
or sad facial expressions and spent the least time looking at eyes
relative to other facial regions. Autistic subjects with the smallest
amygdalae took 40 percent longer than those with the largest fear
hubs to recognize such emotional facial expressions, and those with
the largest amygdalae spent about four times longer looking at eyes
than those with the smallest. Eye fixation did not correlate with
amygdala volume among 24 control subjects.
• In a related study, another research team led by Davidson found that
well siblings of people with autism share some of the same
differences in amygdala volume, and in the way they look at faces
and activate social/emotional brain circuitry, particularly an area
critical for face processing
Cerebellar Findings
• Smaller number of Purkinje cells
• The cerebellum is one of the brain's busiest computational centers,
and the Purkinje cells are critical elements in its data-integration
system.
• At birth the brain of an autistic child is normal in size. But by the
time these children reach 2 to 3 years of age, their brains are much
larger than normal. This abnormal growth is not uniformly
distributed.
• Using MRI, Courchesne et al identified that both gray matter of the
cerebral cortex and white matter account for this mushrooming in
size.
• One theory: The proliferation of connections projecting to and
from the cerebral cortex and other areas of the brain, including the
cerebellum, may cause signal overload that injures the Purkinje
cells and ultimately kills them.
The Basal Ganglia
• “An obsessive desire for the maintenance of
sameness.” (Kanner, 1943)
• Stereotyped, ritualistic, repetitive motor behaviors and
difficulties with environmental changes are
phenomenologically similar to OCD and TS
– Contrast “passion” or “desire” with feeling compelled
• Functional and structural abnormalities of BG are
present in these disorders, specifically the caudate
(Hollander et al., 2005; Sears et al., 1999)
• Right caudate volume 10% greater in autistic individuals.
• Volume of the right caudate correlated with repetitive behaviors
as measured by the Autism Diagnostic Interview Repetitive
Behavior (ADI-C) domain total score (Hollander et al., 2005).
Oxytocin in Autism
• Oxytocin is synthesized in the hypothalamus and
released via the posterior pituitary
• It is released peripherally (milk letdown & uterine
contractions) and centrally (acts as a neuromodulator
along with arginine vasopressin)
• There is some data to suggest that oxytocin has a role in
social and repetitive behaviors (possibly involved in
Tourette’s, OCD, and autism)
•
Green & Hollander, 2010
Visual Research Data
• It has long been know that autistic individuals
have trouble with face recognition
• As the following photos show (from the movie
Who’s Afraid of Virginia Wolf?), autistic
individuals demonstrate difficulties in following
the salient facial features in others and the social
context of situations (Klin et al, 2002).
Who’s Afraid of Virginia
Woolf?
• 1966 adaptation of Edward Albee’s play, staring
Richard Burton and Elizabeth Taylor
• They play a New England academic couple, whose
marriage hangs by a thread
• George Segal and Sandy Dennis play a young, new to
campus unsuspecting couple, who come over for drinks
after a faculty party
• This movie was selected by Fred Volkmar and Ami
Klin at the Yale CSC to study visual tracking in autistic
individuals vs. non-autistic
The Fusiform Gyrus (1)
The Fusiform Gyrus (2)
• The fusiform gyrus lies under the temporal lobe
• There has long been a debate: Is the fusiform gyrus only a facial
recognition area, or is it a general recognition area? It turns out that the
FG is a general recognition area for things that people enjoy or like
– For me, it lights up for guitars
– For an autistic kid it might light up for whatever they’re passionate
about
• In the clips you’ve just seen of “Virginia Woolf,” effectively 90% of
information comes from the eyes (not the mouth where autistics tend to
look)
• Groups of autistic individuals viewing “Virginia Woolf” fall into three
groups: (1) The most impaired individuals look at everything/anything
and are highly disorganized; (2) the moderately impaired individuals
look at objects in the room; and (3) the higher functioning individuals
look at mouths
• Autistics tend to lack the facial inversion effect (that is, most individuals
by 6 months of age are better at recognizing faces when presented rightside up); but autistics never achieve it and thereby recognize faces
equally well right-side up or upside down
Visual Research Data (2)
• In non-autistic children the fusiform gyrus is
activated in response to a human face
– In autistic children this activation is normal when
shown pictures of their mothers but diminished when
shown pictures of strangers
– This may suggest that autistic individuals can be
trained to learn better face recognition, thereby
improving social skills
Brain Size and Growth
• The brains of autistic individuals have long been
suspected to be larger than non-autistic
• More recent work (Courchesne, 2003) has demonstrated
that at birth children with autism had smaller heads than
non-autistics but then showed sudden and excessive
growth from 1-2 months and 6-14 months
• By adolescence the brain size had normalized
• There appears to be an increase in the quantity of white
matter in the brains of autistic children along with growth
in the cerebellum (purkinje cells)
Vaccines
• Measles, Mumps, Rubella vaccine (MMR) is given at 1 year (1215 months) and booster at 4/5 years before school
• Wakefield in the UK suggested in 1998 that MMR might cause
autism b/c of a small number of cases (8 of 12) who had severe GI
problems along with autistic/behavioural symptoms
• Subsequent time trend analyses in the UK and California have
shown that while the number and percent of MMR vaccinations
have not changed, the number of cases of PDD/autism has grown
by 7+ fold.
• Numerous studies out of Japan have documented that even though
the MMR vaccine was used only between 1989 and 1993, there
has been no change in the number of cases of PDD/autism.
• A very large retrospective cohort study of all children born in
Denmark between 1991-98 (over ½ million) found no correlation
between autism/PDD and MMR
• A 2001 U.S. Institute of Medicine study confirmed no connection
between MMR and PDD.
Diet
• The theory is that some kids with PDD will show symptom
improvement when gluten (found in wheat products) and casein
(found in dairy products) are removed from their diet. The hypothesis
states that G and C may be difficult for these kids to digest and that
metabolites of this problematic digestion may include opioid like
substances (far in excess of what you would expect to find due to
CNS opioid production alone).
• Opioids can be tested for in the urine, and some PDD children with
self-injurious behavior have been found to have higher levels of
opioids in their urine.
• One problem with this theory is that naltrexone (an opioid blocker) is
not generally helpful for these kids
• 8 studies available for review, 6 of which were open, and 1 of which
used a single blind approach and 1 of which used a double blind (but
no placebo) approach (and only included 15 kids); all open and single
blind studies reported improvement; DB study demonstrated no group
effect, although some parents noted improvement. Need larger
randomized DBPC trials to determine real effect.
Autism is a spectrum disorder
• No good measure of “how autistic” someone is
• Usually related to cognitive skills (roughly ½ – ¾ are
MR; the relationship between cognitive and adaptive
function [as determined by a Vineland/AAMR inventory]
is vital & is often a useful starting point for interventions)
• Autism is usually a retrospective diagnosis
• Developmental history is vital to diagnosis
• Because the natural course of autism is toward
improvement, we may misdiagnose autistic adolescents
and adults b/c we don’t obtain an adequate retrospective
history (and they’ve shown some improvement)
Autism is a
Developmental Diagnosis
• Autism must be viewed developmentally:
– The greatest hallmark is “inconsistency in
development” (e.g., regressions, spurts, delays, greater
variation in transition from one stage of development
to the next)
– A common referral notes: “he began to speak and then
stopped”
Normal Developmental Oddities
•
•
•
•
•
•
Spinning
Toe Walking
Strobe Lighting
Odd/rigid food preferences
Dislike of labels and seams
Take Home Point: Many autistic
symptoms are developmentally “normal”
Autism is a
Developmental Diagnosis (2)
•
•
Signs and symptoms are related to chronological and
mental age
Two Types of Onset:
(1) Symptoms present in the first year of life (most cases)
*Many of these children will fail to initiate baby games with parents at
4-6 months (e.g., peek-a-boo, giggling interactions, etc.)
*These children may also not communicate common emotions well
(e.g., pain, hunger)
(2) Apparent normal development for the first 12 – 24 months of
life prior to the onset of symptoms
Epidemiology
• Autism is ubiquitous, occurring all over the world
• Current CDC estimates 1:100 (2009)
• Delays in diagnosis result in an average of at least 1.5 years
from the time parents first reported odd speech problems or
other social deficits, typically around the age of 3.
• Kogan et al reported 1:91 with a gender ratio of 4:1 male to
female
– Nearly 40% of those ever diagnosed did not currently have the
condition
– Parent survey of 78K, US children aged 3 – 17 years, a child was
considered to have ASD if parent reported that a doctor or other
health care provider had said the child had ASD and that the child
currently had the condition
• Are increasing numbers real or just the result of “switching”
diagnoses (e.g., reduced numbers of LD and MR)?
Epidemiology (2)
• Male to female ratio varies but is generally
somewhere between more than 1:1 and up to 4+:1
• Familial patterns are well established
– One study reports that each subsequent child born into
a family with an autistic child has a 8-9% chance of
having autism (100 – 200x greater risk than the general
population)
– Twin studies show 60 –85% concordance for identical
twins vs. 10% concordance for fraternal twins
Epidemiology (3)
• Population based study of all 7- to 12-year-old children (N=55,266) in a South
Korean community; the study used a high-probability group from special
education schools and a disability registry and a low-probability, generalpopulation sample from regular schools.
• Autism Spectrum Screening Questionnaire for systematic, multi-informant
screening; parents of children who screened positive were offered
comprehensive assessments using standardized diagnostic procedures.
• Prevalence of ASDs was estimated to be 2.64% (95% CI=1.91–3.37) or 1 in 38,
with 1.89% (95% CI=1.43–2.36) in the general-population sample and 0.75%
(95% CI=0.58–0.93) in the high-probability group; M:F ratios were 2.5:1 (gen
pop) and 5.1:1(high-prob); ratio of autistic disorders to other ASD subtypes were
1:2.6 (gen pop) and 2.6:1 (high-prob)
• 12% in the general-population sample had superior IQs, compared with 7% in
the high-probability group; and 16% in the general-population sample had
intellectual disability, compared with 59% in the high-probability group.
• Two-thirds of ASD cases in the overall sample were in the mainstream school
population, undiagnosed and untreated.
•
Kim et al, 2011
Associated Illnesses
• Autism frequently occurs in association with other
illnesses:
– MR (most common coexisting disorder; Fragile X is MCC [5 –
15%]; Downs not uncommon)
– Epilepsy
– Developmental Syndromes
• Turners, Tuberous Sclerosis
• Metabolic Disorders (e.g., PKU)
–
–
–
–
ADHD
Obsessive/Compulsive Disorder
Depression & Anxiety (esp in higher functioning)
Other psychiatric disorders (e.g., psychosis)
Phenotype: Social Interaction
• Younger children may have little or no interest in
establishing friendships
• Older individuals may have an interest in
friendship but lack an understanding of social
conventions and how to interact
• Often an individual’s awareness of others is
markedly impaired, demonstrating no concept of
the needs & interests of others (e.g., happiness,
distress, etc.), appearing oblivious to other
children (including siblings)
Phenotype: Communication
• When speech does develop, pitch, intonation, rate,
rhythm, or stress may be abnormal (e.g., monotonous,
inappropriate to context, or with question-like rises at the
end of sentences)
• Grammatical structure is often immature, stereotyped
(e.g., repeating jingles), or idiosyncratic
• Comprehension is often delayed
• Disturbance in pragmatic/social use of language is
evidenced by an inability to integrate words with gestures
or understand humor and non-literal speech/irony/implied
meanings
• Imaginative play is often absent or markedly impaired
Phenotype: Stereotyped
Behaviors and Activities
• “Insistence on sameness”
– Insistence on nonfunctional routines or rituals
– demonstrating resistance and/or distress over trivial
changes (e.g., a new driving route to school)
• A markedly restricted range of interests
• Stereotyped body movements & postural
abnormalities
• Preoccupation with parts of objects
• Fascination with movement
• Highly attached to inanimate objects
Assessment of the Autistic Child
• Motor Skills
• Communication
– Verbal, nonverbal, non-literal, prosody, pragmatics,
conversation
• Social Skills & Emotional Assessment
– Social interaction, family attachments, friendships,
self-concept, emotional development, presentation of
mood
• Cognitive/Academic Ability
• Behavioral Assessment
• Family Assessment
Current “Gold Standards” of
Evaluation
• ADOS (Autism Diagnostic Observation
System); done directly with child
• ADI (Autism Diagnostic Interview); done
with parent
• Others:
– Gilliam, CARS, Wing, Atwood, Ornitz, etc.
Medical Assessment
of the Autistic Child
• History & Physical
– Hearing & Visual screening
– Speech & Language Evaluation
– Occupational and Physical Therapy Evaluations
• Growth Milestones (e.g., head circumference)
• Imaging (?)
– CT or MRI to identify Tuberous Sclerosis,
leukodystrophy, etc.
• EEG (?)
• Psychoeducational Testing
Lab Assessment of the Autistic Child
• Cytogenetic/Molecular Screening may include:
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–
–
–
–
–
–
–
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Fragile X DNA Probe
DNA for MECP2 for Rett Syndrome
Chromosome/karyotype analysis
DiGeorge/VCF Syndrome (22q11)
Prader-Willi Syndrome (15q11q13)
Williams Syndrome/elastin gene (7q11.23)
Angelman Syndrome (15q11q13)
FISH Chromosomal analysis 15q11-13 for duplication
FISH for subtelomere probe
Lab Assessment of the
Autistic Child (2)
• ASO Titer & DNAse (DNAsb)
• Metabolic Screening (24 hour urine) may include:
–
–
–
–
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Uric Acid
Calcium & Phosphorus
Magnesium
Homovanillic Acid
Creatinine
Checklist for Autism in Toddlers
• CHAT involves a 5-item checklist for PCPs and a
9-item checklist for parents
• Recommended at 18-month pediatric evaluation
• On the PCP CHAT, children who fail items #2,
3,& 4 are at risk of autism and warrant further
evaluation
• On the Parent’s CHAT, items #5 & 7 are the
most important
• M-CHAT
PCP’s CHAT
1. Look for sustained eye-contact.
2. Get child’s attention; then point out an interesting
object in the room. The typical child should look to
where the physician points.
3. Ask the child to point out something in the room (e.g.,
“show me the light”). The absence of pointing by 18months is a cardinal sign of PDD.
4. Show the child a doll and a cup and ask, “Can you give
the baby some juice?” An autistic child will have
difficulty engaging in pretend play.
5. Ask the child to build a tower of 3 blocks. (The
purpose of this task is to assess social interaction).
Parent’s CHAT
1. Does your child enjoy being swung or bounced
on your knee?
2. Does your child take interest in other children?
3. Does your child like climbing on things such as
stairs?
4. Does your child play peek-a-boo or hide-andseek?
5. Does your child ever pretend?
6. Does your child ever use his index finger to
point to or ask for something?
Parent’s CHAT (continued)
7. Does your child ever use your index finger to
point and indicate an interest in something?
8. Can your child play appropriately with small
toys without just mouthing, fiddling, or dropping
them?
9. Does your child ever bring objects to you to
show you something?
American Academy of Neurology
Warning Signs
• Any child with any of the following five symptoms
should be evaluated for autism:
1. No babbling by 12 months.
2. No gesturing, pointing, or waving goodbye by 12
months.
3. No single words by 16 months.
4. No two words spoken together spontaneously by 24
months (not echolalic)
5. Any loss of previously acquired language or social
skills at any time.
Prognosis and Course (1)
•
•
Prognosis is highly dependent upon the level of
functioning
By school age, autistic children can be divided into
three groups:
1.
Low Functioning
*Verbal and non-verbal IQ < 70
(about 50% of affected children)
2.
Mid-Functioning
*Non-verbal IQ > 70 but verbal IQ < 70
(about 25% of affected children)
3.
High Functioning
*Verbal and non-verbal IQ > 70
(about 25% of affected children)
Prognosis and Course (2)
•
Some children with autism show improvement in
adolescence which is related to good adult outcome:
–
–
–
–
–
–
•
Activity level usually decreases
Behavior becomes more manageable
Self-help skills improve
Communication continues to develop
IQ usually remains stable
Usually become more social
A large percentage (10 – 25%?) of children will
develop seizures (all types) as they age
Prognosis and Course (3)
•
•
Anxiety and depression are the most commonly
co-occurring psychiatric disorders in adults with
autism
Factors known to be related to outcome:
–
–
–
•
IQ by age 5 – 6 years
Communication skills by age 5 years
Early educational intervention
Factors not known to be related to outcome:
–
–
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Family history of neuropsychiatric disorders
Adequacy of parenting
Family atmosphere
DSM-IV Diagnoses
• DSM = Diagnostic and Statistical Manual
of the American Psychiatric Association
• “Statistical” because a given number of
symptoms are necessary to make a
diagnosis
• Diagnoses are phenomenological or
symptom driven and may be the result of
biological, psychological, and social factors
DSM-IV Diagnosis of Autistic Disorder
(1)
•
•
Must have six symptoms from the
following three domains
Three Domains:
1. Social Interaction
A.
B.
C.
D.
Impairment in non-verbal behaviors
Poor peer relations
Lack of spontaneous sharing
Lack of social or emotional reciprocity
DSM-IV Diagnosis of Autistic Disorder
(2)
2. Communication
A. Delay or lack of language development
B. Impairment in ability to initiate or sustain a
conversation
C. Stereotyped, repetitive or idiosyncratic use of
language
D. Lack of spontaneous make-believe or socially
imitative play
DSM-IV Diagnosis of Autistic Disorder
(3)
3. Behaviors, Interests & Activities
A. Preoccupation with stereotyped and restricted
patterns of interest
B. Inflexible adherence to specific and nonfunctional
rules, routines, or rituals
C. Stereotyped and repetitive motor mannerisms
D. Persistent preoccupation with parts of objects
Asperger’s Disorder…or
High Functioning Autism
• Researchers recognize the temporary status of
current DSM and ICD definitions of Asperger’s
Disorder
• Inclusion of Asperger’s Disorder was
“tentative”
• Clinicians have been less reserved about the use
of the diagnosis, often because they wish to
secure appropriate services for their patients
Alternative Diagnostic Concepts
• Schizoid Personality Disorder
– Social isolation, emotional detachment, unusual
communication style, rigidity of thought & behavior
• Nonverbal Learning Disorder
– Deficits in neuropsych skills (e.g., tactile perception, psychomotor coordination, visual-spatial organization, etc) occur in
the presence of preserved rote verbal abilities
• Developmental Learning Disability of the Right
Hemisphere
– The field of neurology’s take on these symptoms
• Semantic-Pragmatic Disorder
• Speech and language are adequate in form (syntax and phonology) but
impoverished in content and use (semantics and pragmatics)
• Sensory Integration Disorder
– Occupational Therapy
DSM-IV Diagnostic Criteria
•
Must have at least three symptoms from the following
two domains
1. Social Interaction (two or more symptoms)
A.
B.
C.
D.
Impairment in non-verbal behaviors
Poor peer relations
Lack of spontaneous sharing
Lack of social or emotional reciprocity
2. Behaviors, Interests & Activities (one or more symptoms)
A. Preoccupation with stereotyped and restricted patterns of interest
B. Inflexible adherence to specific and nonfunctional rules, routines, or
rituals
C. Stereotyped and repetitive motor mannerisms
D. Persistent preoccupation with parts of objects
What’s in a diagnosis?
• According to the DSM, Asperger’s looks like it
is simply autism without “communication”
problems.
• Yet perhaps the most conspicuous aspect of
presentation is the severe deficit in the social use
of language despite…
• Relative strengths in verbal ability (e.g.,
vocabulary, rote memorization) and…
• Weaknesses in nonverbal areas (e.g., visualmotor skills, pragmatics of language)
Communication
• Early speech development is not generally a concern
but significant problems in pragmatic or conversational
skills become evident with maturation
• Limited inflection and abnormalities in rate and volume
of speech are commonly seen
• Speech is often tangential and circumstantial, resulting
in a one-sided conversation; egocentric and unrelenting
monologues; every thought being verbalized; and
characterized by poorly organized sentences and
paragraphs
• Markedly verbose speech
Motor Function
• Motor milestones may be somewhat delayed
• Motor clumsiness and awkwardness are common
but are usually mild (and contribute to peer
rejection)
• Motor function may improve with age
• Less usual (than autism) to demonstrate motor
mannerisms or preoccupations with parts of
objects or nonfunctional elements of play
materials
Social Skills
• Individuals with AS are often interested in
having friends and intimate relationships
• They often approach others but in eccentric ways
• Repeated experiences of failures can lead to
clinical depression and anxiety
• The relatively preserved language skills (which
may manifest as a preoccupation with
definitions, rules, and facts) can be used to foster
strategies for learning, cognitive methods for
coping, and social skills
Associated Features
• May present differently at different ages but is often not evident
until school age
• Often the social disability is more striking w/time
• May experience feelings of victimization and social isolation
• Mental retardation is not usually observed
• ADHD is often a first diagnosis (given overactivity and
inattention)
• Questionable association with Tourette syndrome and OCD
• Increased rates of mood and anxiety disorders, as individuals
develop an increased capacity for self-awareness of their poor
social insight and repeatedly frustrated desire for social
relationships
• Diagnosed 5x more frequently in males
Asperger’s Disorder:
Natural History
• Lifelong disorder
• By adolescence some may learn to apply explicit verbal
rules or routines in stressful/social situations
• May make relationships with much older individuals b/c
of their lack of understanding the conventions of
establishing peer relations
• Better prognosis than with autism; adults are often
capable of gainful employment and self-sufficiency
• Increased frequency among first degree relatives; may
also be an increased risk of autism and general social
difficulties
Major Predictors of Improved Outcome
• Intellectual level
• Communicative speech
The Curious Incident of the Dog in
the Night-Time
• Published in 2003, this novel tells the story
of Christopher, who likely suffers from
Asperger’s Disorder or High Functioning
Autism
• This novel tells the improbable story of
Christopher’s quest to investigate the
suspicious death of a neighborhood dog
HFA vs. AS
• Individuals with AS are more likely to exhibit higher
verbal than performance IQs
• In contrast, individuals with HFA are more likely to
have higher performance IQ scores than verbal IQ
scores
• In DSM field trials, areas predictive of AS (vs. HFA)
included deficits in fine and gross motor skills, visual
motor integration, visual-spatial perception, nonverbal
concept formation, and visual memory
• AS individuals may have relatively fewer deficits in
“Theory of Mind” – that is, an ability to have a theory
of other people’s (and one’s own) subjectivity; the
ability to attribute mental states (such as beliefs, desires,
and intentions) to others
Characteristics That Interfere w/Learning
• A disproportionate reliance on language as a principle
means of socially relating, information gathering, and
relieving anxiety
• Number facts are learned through rote memorization;
number concepts are much more difficult to grasp (e.g.,
what is meant by “number,” “more & less,” “greater
than and less than,” “fraction,” etc.)
• Problems in the assessment of other’s emotional state
• Impaired assessment of social cause and effect
relationships
• Limited appreciation of humor and irony
• Misinterpretation of other’s behavior & intentions
Non-Verbal Learning Disorders (1)
• Asperger’s is often associated with NLD, but the
converse is not necessarily true
• Primary assets:
– Proficiency in most rote verbal skills
– Proficiency in some simple motor and psychomotor
skills
Non-Verbal Learning Disorders (2)
•
Major characteristics:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Bilateral tactile-perceptual deficits
Bilateral psychomotor coordination deficiencies
Visual-perceptual-organizational deficiencies
Poor adaptation to novel and otherwise complex situations
Deficits in nonverbal problem solving, concept formation, &
hypothesis testing
Distorted sense of time
Much verbosity in a repetitive, straightforward manner
Relative deficiencies in mechanical arithmetic as compared
to proficiencies in reading (word recognition) and spelling
Significant deficits in social perception, judgment, and
interaction
Well developed rote verbal capabilities
Educational Evaluation
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IQ Testing (verbal vs. performance)
Achievement Testing
Adaptive functioning (e.g., Vineland)
Neuropsychological Testing
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Laterality
Motor skills
Attention
Visual-spatial perception
Verbal and visual memory
Executive functioning
Pervasive Developmental Disorder NOS
• What is it?
• What does it mean?
• What good does it do?
Social Phobia versus Asperger’s
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Both are socially awkward
Both become anxious in social situations
Both may avoid social situations
Both generally profess to wanting social interaction
(albeit, Asperger’s in particular may profess this interest
oddly)
• Fear of being scrutinized by others (particularly
recognizing the fear as unreasonable) may be more
consonant with a diagnosis of Social Phobia
Treatment
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Family/caretaker education
Cognitive/academic interventions
Speech and Occupational Therapy
Social skills training
Applied Behavioral Analysis (aka Behavioral Mod)
Treat comorbid Axis I disorders
Stimulants and Strattera for ADHD
SSRIs for anxiety & depression
Antipsychotics for agitation, aggression, beligerance, &
stereotypies
Treatments w/Some Reasonable Data
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Antipsychotic Medication
Methylphenidate
Picture Exchange Communication (PECS)
Social Stories
Joint Attention Routines
Applied Behavioral Analysis/Discrete Trial
Training/Lovaas
• Treatment and Education of Autistic and related
Communication Handicapped Children (TEACH)
• Speech and Language Therapy
• Occupational Therapy
National Academy of
Sciences Recommendations
• 2001 Study of National Research Council
recommended six educational interventions:
1.
2.
3.
4.
Functional spontaneous communication
Social skills
Play skills
Cognitive development taught in a natural setting to
facilitate generalization
5. Reduction of problem behaviors
6. Functional academic skills
Applied Behavioral Analysis
• ABA focuses on teaching small, measurable units
of behavior in a systematic way
• Problematic target behaviors are chosen,
antecedents are identified, and corrective
behaviors are taught
• Typically a question or command is given; a clue
or hint is given as necessary
• Correct response earns immediate reward
• Incorrect responses are ignored or neutrally
corrected
Risperdal Approved by FDA
• On October 10, 2006, the FDA approved Risperdal to
treat irritability in children and adolescents (ages 5 – 16
years) with autism
• Risperdal was the first medication approved for use in
treating behavior-related problems associated with
autism in children (now Abilify also approved).
Classified under the general heading of irritability, these
behaviors include aggression, deliberate self-injury, and
temper tantrums.
• The approval for treating children with autism was based
on two eight-week clinical trials that evaluated the drug
vs. placebo in 156 children 5 to 16 years old (McCracken
et al, 2002; Shea et al, 2004).
Risperidone vs. Haloperidol
• R/DB/PC trial of 30 children and adolescents with Autistic
Disorder
• 12-weeks, ages 8 – 18 years
• Both treatments given once daily from 0.01 – 0.08 mg/kg/day.
• Reduction in baseline in the Ritvo-Freeman Real Life Rating Scale,
sensory motor and language subscales, were significant in the
risperidone group (p<0.5).
• Compared to haloperidol, risperidone led to a significantly greater
reduction in the Aberrant Behavior Checklist and Turgay DSM-IV
PDD scale scores
• Greater increase in prolactin with the risperidone group and a
greater increase in alanine amino transferase (ALT) with the
haloperidol group
Miral et al, 2008
Risperidone in Preschool Children
• A small handful of case and open label studies have reported
treatment efficacy in preschool children (Masi et al, 2001)
• The first two randomized DBPC studies of preschool children and
risperidone were reported in 2006 (Luby et al, 2006; Ngaraj et al,
2006).
• Luby: 24 children, ages 2.5 – 6 years, most of whom were also
undergoing intensive behavioral treatment, were treated with
Risperdal at 0.5 – 1.5 mg/day for 6 months. CARS & GARS were
the primary outcome measures. Weight gain and hypersalivation
were the most common side effects reported, and
hyperprolactinemia without lactation or related signs was observed.
Significant differences between groups found at baseline
complicated the analyses (randomization was not perfect).
• In general, preschoolers on risperidone demonstrated greater
improvements in autism severity. The change in autism severity
scores from baseline to 6-month follow up for the risperidone group
was 8% compared to 3% for the placebo group (on CARS).
Notably, both groups significantly improved over the 6-month
treatment period.
Risperidone in Preschool Children
• Nagaraj: This study looked at behavior (aggressiveness, hyperactivity,
irritability), social and emotional responsiveness, and communication
skills.
• A RDBPC trial with 40 consecutive children with autism, 2 - 9 years of
age, were treated with risperidone or placebo given orally at a dose of 1
mg/day for 6 months. The outcome variables were total scores on the
Childhood Autism Rating Scale (CARS) and the Children's Global
Assessment Scale (CGAS) after 6 months.
• 39 completed the trial over a period of 18 months; 19 received
risperidone, and 20 received placebo. In the risperidone group, 12 of 19
children showed improvement in the total CARS score and 17 of 19
children in the CGAS score compared with 0 of 20 children for the
CARS score and 2 of 20 children for the CGAS score in the placebo
group (P < .001 and P = .035, respectively).
• Risperidone also improved social responsiveness and nonverbal
communication and reduced the symptoms of hyperactivity and
aggression.
• Primary side effects included increased appetite and a mild weight gain,
mild sedation in 20%, and transient dyskinesias in three children.
Risperidone Long-Term Side Effects
• Review by Pandina et al (2006) of over 800 children
treated with risperidone for disruptive behavior disorders
found that weight stabilized after 6 months and initial
increases in prolactin came down after about 3 months
• The most common adverse effect with risperidone was
somnolence (74% vs. 7% with placebo).
Olanzapine
• Numerous case reports and open label studies with
generally positive findings in reducing disruptive and
repetitive behaviors in PDD, but difficulties with side
effects are common
• The only DBPC trial of Olanzapine in the treatment of
children with ASD (Hollander et al, 2006). Eleven
patients with a diagnosis of either autism, Asperger's
syndrome, or PDD NOS, aged 6-14 years were
randomized into an 8-week double-blind, placebocontrolled, parallel treatment study with olanzapine.
50% on olanzapine versus 20% on placebo were
responders per CGI. Olanzapine was associated with
significant weight gain (7.5 +/- 4.8 lbs vs. 1.5 +/- 1.5
lbs on placebo).
Aripiprazole
• 218 children and adolescents (6 – 17 years) with a diagnosis of autistic disorder,
and with behaviors such as tantrums, aggression, self-injurious behavior, or a
combination of these symptoms, were randomized to aripiprazole (5, 10, or 15
mg/day) or placebo in this 8-week randomized DB/PC study.
• Aberrant Behavior Checklist Irritability subscale was the primary efficacy
measure, along with the clinician rated CGI.
• All aripiprazole doses produced significantly greater improvement than placebo
in mean ABC Irritability subscale scores (5 mg/day, -12.4; 10 mg/day, -13.2; 15
mg/day, -14.4; versus placebo, -8.4; all p < .05). All aripiprazole doses
demonstrated significantly greater improvements in mean CGI vs. placebo.
• Discontinuation rates due to adverse events were as follows: placebo 7.7%,
aripiprazole 5 mg/day 9.4%, 10 mg/day 13.6%, and 15 mg/day 7.4%.
• The most common adverse event leading to discontinuation was sedation. There
were two serious adverse events: presyncope (5 mg/d) & aggression (10 mg/d).
• At week 8, mean weight change (last observation carried forward) was as
follows: placebo +0.3 kg, aripiprazole 5 mg/day +1.3 kg, 10 mg/day +1.3 kg,
and 15 mg/day +1.5 kg; all p < .05 versus placebo.
Aripiprazole
• 98 subjects underwent an 8 week randomized DB/PC study of children and
adolescents (6 – 17 years) with Autistic Disorder, 51 received placebo and 47
received aripiprazole.
• Patients were randomly assigned (1:1) to flexibly dosed aripiprazole (target
dosage: 5, 10, or 15 mg/day) or placebo.
• Efficacy outcome measures included the Aberrant Behavior Checklist irritability
subscale and the Clinical Global Impression–Improvement score (CGI-I)
• Aripiprazole demonstrated significantly greater global improvements than
placebo, as assessed by the mean CGI-I score from week 1 through week 8;
however, clinically significant residual symptoms may still persist for some
patients.
• Discontinuation rates as a result of adverse events (AEs) were 10.6% for
aripiprazole and 5.9% for placebo. Extrapyramidal symptom-related AE rates
were 14.9% for aripiprazole and 8.0% for placebo. No serious AEs were reported.
Mean weight gain was 2.0 kg on aripiprazole and 0.8 kg on placebo at week 8.
Owen et al, 2009
Citalopram for Repetitive Behavior in
Children with ASD
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149 children and adolescents (5 – 17 years) with ASD were randomized to receive
citalopram (n = 73) or placebo (n = 76).
Subjects received 12 weeks of Citalopram (10 mg/5 mL) or placebo. The mean (SD)
maximum dosage of citalopram hydrobromide was 16.5 mg/d by mouth (maximum, 20
mg/d).
CGI and C-YBOCS were measures
There was no significant difference in the rate of positive response on the Clinical Global
Impressions, Improvement subscale between the citalopram-treated group (32.9%) and
the placebo group (34.2%) (relative risk, 0.96; 95% confidence interval, 0.61-1.51; P >
.99). There was no difference in score reduction on the Children's Yale-Brown Obsessive
Compulsive Scales modified for pervasive developmental disorders from baseline (mean
[SD], -2.0 [3.4] points for the citalopram-treated group and -1.9 [2.5] points for the
placebo group; P = .81).
Citalopram use was significantly more likely to be associated with adverse events,
particularly increased energy level, impulsiveness, decreased concentration,
hyperactivity, stereotypy, diarrhea, insomnia, and dry skin or pruritus.
• King et al, 2009
Alternative Treatments w/No Data
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Holding Therapy
Secretin
Vitamin/dietary regimens
Anti-yeast therapy
Brushing
Higashi Daily Life Therapy
So, how do we treat?
• Parents are desperate and will often try
anything (e.g., experimental therapies,
unproven medications, etc.)
• Absence of good research data has not
affected prescription patterns – physicians
are under pressure to treat in a mental health
system that requires fast therapeutic effects
Older parents
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Both mother’s and father’s age increase the risk of having a child with autism
Archives of Pediatrics & Adolescent Medicine, April 2007
Croen and colleagues analyzed the data of 132,844 single births at Kaiser Permanente
hospitals in Northern California from 1995 to 1999 and found 593 autism diagnoses.
Using data from birth certificates and Kaiser Permanente outpatient clinical databases,
researchers projected the risk of having a child with a diagnosis by age 10
Adjusting for the other parent's age, educational levels, race and ethnicity, the study
found the increasing risk with parental age statistically significant for both mothers and
fathers
Older parents do tend to bring children to the doctor more often, but when controlled for,
the increased risk was still noted
For new parents 40 and older, compared with peers ages 25 to 29, women had a 30%
greater risk and men a 50% greater risk of having a child diagnosed with autism. That
increased risk is still very small: Only 1 in 123 children born to women 40 and older
will have autism, compared with 1 in 156 children born to women 25 to 29 in this study
One of four major studies confirming this finding
The findings are fairly consistent and seem to suggest an association between maternal
age and severity of autism, although that's still somewhat speculative
Non-inherited mutations accumulating in the father's sperm or a woman's increased risk
of labor complications as they age could be factors. Or perhaps socially awkward
parents may marry and have children later in life.
Government Funding & NIMH Studies
•
•
Combating Autism Act (S. 843, now Public
Law 109-416), passed in December of 2006,
authorizes $945 million over 5 years for
research, screening, intervention, and education
on autism spectrum disorders (ASD) and
developmental disabilities
Major areas of study at NIMH:
1) Subtypes of Autism (regressive vs. non-regressive)
2) Minocycline for chronic neuroinflammation
3) Heavy metal chelation