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 ObjectivesParticipants 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 Autism5. 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:– 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).

• 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).

Results: “Judging the mind in the eyes”

• Control group only activation: yellowControl group only activation: yellow• Autistic group only activation: redAutistic group only activation: red• Coincidental activation: blueCoincidental 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 right-side 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 (12-

15 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 developmen

t” (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, general-population 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:– 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:– 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 18-months 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-and-

seek?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:– 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. Impairment in non-verbal behaviors

B. Poor peer relations

C. Lack of spontaneous sharing

D. Lack of social or emotional reciprocity

DSM-IV Diagnosis of Autistic Disorder (2)

2. CommunicationA. 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 & ActivitiesA. 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…orHigh 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, psycho-

motor 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. Impairment in non-verbal behaviors

B. Poor peer relations

C. Lack of spontaneous sharing

D. 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., visual-motor 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. Bilateral tactile-perceptual deficits2. Bilateral psychomotor coordination deficiencies3. Visual-perceptual-organizational deficiencies4. Poor adaptation to novel and otherwise complex situations5. Deficits in nonverbal problem solving, concept formation, &

hypothesis testing6. Distorted sense of time7. Much verbosity in a repetitive, straightforward manner8. Relative deficiencies in mechanical arithmetic as compared

to proficiencies in reading (word recognition) and spelling9. Significant deficits in social perception, judgment, and

interaction10. Well developed rote verbal capabilities

Educational Evaluation

• IQ Testing (verbal vs. performance)• Achievement Testing• Adaptive functioning (e.g., Vineland)• Neuropsychological Testing

– 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

• 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• 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

• 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. Functional spontaneous communication

2. Social skills

3. Play skills

4. 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

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, placebo-controlled, 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

• 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

• 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• 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 neuroinflammation3) Heavy metal chelation