autism spectrum disorders neurodevelopmental disorders characterized by qualitative abnormalities in...

Autism Spectrum Disorders

Neurodevelopmental disorders characterized by qualitative abnormalities in social/emotional behavior and communication as well as restricted, stereotyped and repetitive interests or activities


Learning Objectives Symptomology Likely/Unlikely Causes

genetic & environmental Neuropathology Screening/Diagnostic Tools Treatments

educationalmedicalCAM


ASDs differ by:when the symptoms startedsymptom severitynature of the symptoms

ASDs include:Autism Disorder (AD)Asperger’s syndrome (AS)Pervasive developmental disorder, not

otherwise specified (PDD-NOS)

Autism

Descriptions of “autistic-like” behavior date back to the 18th century.

Was first identified as autism by Leo Kanner (1943).describing 11 children social aloofnesselaborate repetitive routines

Greek word…autos….meaning “self”, extrapolated to mean “alone, pre-

occupied with self, a withdrawal into private [world]”

Autism -- DSM IV-TR

A. Six or more items from the following :

1. Qualitative impairment in social interaction (at least 2)2. Qualitative impairment in communication (at least 1)

3. Restricted, repetitive & stereotyped patterns of behavior, interests, & activities (at least 1)

Autism -- DSM IV-TR

B. Delay or abnormal functioning in at least 1 of the following with onset before 3yo:1. Social interaction2. Language used in social communication3. Symbolic or imaginative play

C. Disturbance not better accounted for by Rett’s disorder or Childhood Disintegrative disorder

Autism -- Symptoms

Autistic Disorder -- DSM V

“Autistic Disorder” … now to include the previous separate diagnoses:AutismAsperger SyndromePDD-NOSChild disintegrative disorder

To ensure that etiology is indicated, where known, clinicians will be encouraged to utilize the specifier: “associated with known medical disorder or genetic condition.”


Must meet criteria 1, 2, and 3:1. Clinically significant, persistent deficits

in social communication and interactions, as manifest by all of the following:•Marked deficits in nonverbal and verbal

communication used for social interaction:

•Lack of social reciprocity;•Failure to develop and maintain peer

relationships appropriate to developmental level


Must meet criteria 1, 2, and 3:2. Restricted, repetitive patterns of behavior,

interests, and activities, as manifested by at least TWO of the following: •Stereotyped motor or verbal behaviors, or

unusual sensory behaviors•Excessive adherence to routines and

ritualized patterns of behavior•Restricted, fixated interests

3. Symptoms must be present in early childhood (but may not become fully manifest until social demands exceed limited capacities)

ASD -- Prevalence

Four times more likely in males

CDC estimates 1 in 110 (0.9%) individuals have an ASD (using data from 2006)

Every hour in the United States, three children are diagnosed with autism

ASD -- Prevalence

Increased prevalence can be partially accounted for by: broadening of diagnostic criteria

(~40%)•Charman et al. report that “our

prevalence estimates varied by up to 4.5 times from the strictest to the least demanding set of diagnostic criteria.” Int J Epidemiol. 2009 Oct;38(5):1234-8

parental age (~11%) awareness by parents (social

influence)

ASD -- Causes

Multifactoral Genetic (primarily)Environmental factors (lesser extent)

Pardo, C.A and Eberhart, C.G. Brain Pathol. 2007;17:434-447.

ASD -- Causes

Comorbidity -- Medical condition or syndromeEpilepsy 30%Fragile X syndrome 2-5% (25-37% have ASD)Tuberous sclerosis 3-4% (16-65% have ASD)Angelman syndrome 1-4% (42% have ASD)Metabolic diseases ~5% (46-75% SLO have

ASD)ADHD 2.7% (41% have ASD)Prader-Willi (25% have ASD)DiGeorge/velocardiofacial syndrome (34-50%)

ASD -- Causes

GENETICS -- Family studies ... if one is ADIdentical twins 60-96% chance the

other has ADFraternal twins up to 24% chance the

other has ADSiblings 5-10% chance the others have

AD

Boyle C, Van Naarden Braun K, Yeargin-Allsopp M. The Prevalence and the Genetic Epidemiology of Developmental Disabilities. In: Genetics of Developmental Disabilities. Merlin Butler and John Meany eds. 2005

ASD -- Causes

GENETICS -- Chromosomal studiesChromosome 1 – ATP1A2 (seizure

susceptibility locus); 1q21.1 deletion, RIMS3

Chromosome 2 – NRXN1 & DLX1&2 (control early growth & development), GAD1 (2q31), terminal deletion 2q37

Chromosome 3 – CNTN4, OXTRChromosome 4 – GABRA4, GABRB1

ASD -- Causes

GENETICS -- Chromosomal studiesChromosome 5 – may account for up to

15%•5p14.1 -- between cadherin 10 and cadherin 9

(cell adhesion)

•5p15 -- SEMA5A (axonal guidance during development)

Chromosome 6 – GRIK2Chromosome 7 – RELN, CNTNAP2

(language), MET, EN2Chromosome 8 – MCPH1 (speech delay, LD)

ASD -- Causes

GENETICS -- Chromosomal studiesChromosome 9 – TSC1 Chromosome 10 – PTEN (may account for

~4.2% ASD), LRRTM3Chromosome 11 – DHCR7Chromosome 12 – CACNA1C, AVPR1AChromosome 13 – NBea (important in

brain development)Chromosome 14 – MDGA2

ASD -- Causes

GENETICS -- Chromosomal studiesChromosome 15 – maternal duplication of

q11-q13 – UBE3A gene (1-3% ASD), GABRB3

Chromosome 16 – duplication/deletion of a small area involving ~25 genes (1% ASD) N

Engl J Med. 2008. 14;358(7):737-9 however, see Eur J Med Genet. 2009

Chromosome 17 – duplication or deletion (resulting in language problems and obsessive traits) … maybe male only; BZRAP1

Chromosome 18 – DSC1, DSC2Chromosome 19 – TLE2, TLE6

ASD -- Causes

GENETICS -- Chromosomal studiesChromosome 20 – ADAChromosome 21 – NCAM2, GRIK1Chromosome 22 – deletion @ 22q13.3

(SHANK3)Chromosome X – originally thought because

of 4:1 male to female ASD occurrence •There is no major X-linked gene conferring

susceptibility to ASD Am J Med Genet B Neuropsychiatr Genet 2008; 147B(6):830-5

•NLGN3, NLGN4, MeCP2 (duplication),FMR1

ASD -- Causes

GENETICS -- Chromosomal studiesunbalanced chromosome rearrangements

and or translocationsduplications or deletionscopy number variants of genes

ASD -- Causes

Maternal FactorsAutoimmune factors

•Maternal auto-antibodies interact with fetal CNS proteins Brain Behav. Immun. 2007. 21:351-357; Neurotoxicology. 2008. 29:226-31

•16% of mothers of AD children have an autoimmune disorder (compared to 2% of the mothers of “normals”

• 46% ASD patients have 2 family members with autoimmune disorders J. Child Neurol. 1999. 14:388-394

• More family members = greater risk of ASD• rheumatoid arthritis (70%), celiac disease

(3x), type 1 diabetes (1.8x)

ASD -- Causes

Maternal Factors -- prenatal toxins/infectionThalidomide exposure (20-24d gestation …

around the time of the neural tube closure)Misoprostol exposure (6w gestation)Valproic acid exposure (probably 20-24d

gestationChlorpyrifos exposureEthanol exposure (possibly 3-5 weeks

gestation) … ~2% FAS children have ASDRubella exposure (first 8w)

ASD -- Causes

NeuroimmunologicalUp to 60% of ASD patients have some type

of systemic immune dysfunction. Brain Pathol.

2007;17:434-447.

Post-mortem brain tissues show active and ongoing neuroinflammatory processes •cerebral cortex, white matter and

cerebellum. Ann. Neurol. 2005. 57:67-81.

CSF exhibited a proinflammatory profile of cytokines. Ann. Neurol. 2005. 57:67-81.

Advanced glycation end products (AGEs) are elevated in both the brain tissue and serum of autistic patients. Neurosci Lett. 2006. 410:169–173.

ASD -- Causes

MMR vaccine1998, a study suggested a connection

between MMR vaccine and autism Lancet. 1998 .

351(9103):637-41.

•MMR bowel problems autism

•The study had limitations: • small sample size (n=12)• in some of the children symptoms of autism

appeared before symptoms of bowel disease• In 2004, 10 of 12 authors retracted. Lancet. 2004

363(9411):750.

ASD -- Causes

MMR vaccine (no association)Larger studies found no relationship

between MMR vaccine and autism. •One of the first population studies found:

Lancet. 1999. 353(9169):2026-9

• No in diagnosis with the intro of MMR• Age of diagnosis was the same in vaccinated

vs unvaccinated children • The onset of "regressive" symptoms did not

occur within 2 or 4 months of MMR

•Ecological studies found lack of association.• BMJ 2001. 322:460–463 (UK), J. Child Psychol. Psychiatry. 2005. 46:572–579 (Japan),

Pediatrics. 2006. 118(1):e139-50 (CAN), N. Engl. J. Med. 2002. 347:1477–1482 (Denmark), JAMA 2001. 285:1183–1185 (CA), Pediatrics. 2004. 113:259–266 (GA)

ASD -- Causes


between MMR vaccine and autism.

Fombonne, E. et al. Pediatrics 2006;118:e139-e150

ASD -- Causes


between MMR vaccine and autism.•2008 study replicated the original 1998

study with more subjects (25 ASD w GI problems, 13 controls w GI problems) and used one of the original labs for analysis

• No difference in presence of MV RNA between groups

• Found evidence AGAINST association of autism with MMR exposure. PLoS ONE 2008: 3(9):e3140.

ASD -- Causes

MMR vaccine (no association)2010 UK's General Medical Council on

Wakefield:•Behaved "dishonestly and irresponsibly" in his

research

•Unqualified to be carrying out some of the exp.• colonoscopies and lumbar punctures

•Unethical when he paid children £5 for their blood samples at his son's b-day party.

•“serious professional misconduct” when he filed for a patent on a "safer" vaccine that he was hoping to sell after he discredited the MMR vaccine.

ASD -- Causes

ASD -- Causes

ToxinsMercury in vaccines (thimerosal)

•Thimerosal is 49.6% ethylmercury by weight.

•1999 infants at 6mo were exposed to potentially unsafe cumulative doses of ethylmercury

• Due to addition of Hib and HepB vaccines (1991)

•2001 thimerosal was excluded from all vaccines (except some seasonal flu vaccines)

ASD -- Causes

ToxinsMercury in vaccines (thimerosal) – no

association•2006 an ecological study in Montreal

found that the prevalence AD (no thimerosal) was significantly > the prevalence AD (thimerosal) Pediatrics. 118: e139–e150

•Controlled observational studies have not found an association between thimerosal and autism JAMA. 2003. 290:1763–1766 (Denmark), Pediatrics. 2004. 114:584–591 (UK), Pediatrics. 2003. 112:1039–1048 & Arch Gen Psychiatry 2008;65:19-24 (US)

ASD -- Causes


association

Schechter, R. et al. Arch Gen Psychiatry 2008;65:19-24.

Thimerosal removed from vaccines

ASD -- Causes


association•Institute of Medicine (IOM) concluded

"the evidence favors rejection of a causal relationship between thimerosal-containing vaccines and autism." Immunization Safety Review: Vaccines and Autism, 2004.

ASD -- Risk Factors

Parental ageMothers … 10y increase 38% increaseFathers … 10y increase 22% increase

Low birth weight/gestational age Intrapartum hypoxia Maternal smoking Prenatal stress ??

ASD -- Neuropathology


Morphometric – brain size (measured by head circumference) is ~10% initially

Courchesne E., et al. Curr Opin Neurol. 2004;17(4):489-496

Courchesne E., et al. 2003; JAMA 290, 337–344.


Brain BankBrain size is still 1-3% increased in

adulthood. Redcay E and Courchesne E. 2005; Biol. Psychiatry 58, 1–9.


Brain BankAbnormalities in frontal and temporal lobe

cortical minicolumns(neurons are arranged like beads on a string & believed to comprise the smallest level of functional organization in the cerebral cortex)

Picket, J. and London, E. J. Neuropathol. Exp. Neurol. 2005;64(11):925-935

CONTROL = 10 AUTISTIC = 12


Brain BankAbnormal maturation of the limbic system

( cell size, number and density and neuropil complexity)•hippocampus, subiculum and amygdala

number of Purkinje and granular cells in the cerebellum

Brainstem abnormalities and neocortical malformations (e.g. heterotopias)


Brain BankGAD67 mRNA expression is 40% in

cerebellar Purkinje cells of autistic individuals compared to controls

Yip, J. et al. Acta Neuropathol. 2007;113(5):559-568


MRI brain volume (age related)

Abnormalities in sulcal and gyral anatomy size of corpus callosum Biol Psychiatry. 2006. 60: 218–225

Courchesne E., et al. Neurol. 2004;57(2):245-254


MRIRegional gray & white matter volumetric

differences in frontal, parietal & temporal lobes.

Courchesne E., et al. Curr Opin Neurol. 2004;17(4):489-496


MRIRegional gray & white matter volumetric

differences in cerebellum (Vermis )

Courchesne E., et al. Neurol. 2001;57(2):245-254


fMRI Hypoactivation of

the fusiform gyrus in face-recognition tasks

Hypoactivation in “social” based cognitive and perceptual tasks

DiCicco-Bloom, E. et al. J. Neurosci. 2006;26:6897-6906


PETDevelopmental changes in brain serotonin

synthesis capacity is dramatically different

Chugani, D.C. et al. Ann. Neurol. 1999;45:287–295

Normal

Autistic

ASD – Screening & Diagnosis

Johnson, C. P. et al. Pediatrics 2007;120:1183-1215


2-level Screening Approach: At well-baby check-up if fail routine

developmental screening:•Infant-Toddler Checklist (from CSBS-DP) 6-24mo

•Checklist for Autism in Toddlers (CHAT) 18-24+mo

•Modified CHAT (M-CHAT) 16-48mo

•Screening Tool for Autism in Two-Year-Olds (STAT) 24-36mo

•Social Communication Questionnaire 4yo


Modified Checklist for Autism in Toddlers (M-CHAT)Parent questionnaire First 9 questions of CHAT plus 14 more:

•2. Does your child take an interest in other children?

•7. Does your child ever use his/her index finger to point, to indicate interest in something?

•9. Does your child ever bring objects over to you (parent) to show you something?


Modified Checklist for Autism in Toddlers (M-CHAT)First 9 questions of CHAT plus 14 more:

•13. Does your child imitate you? (e.g., you make a face-will your child imitate it?)

•14. Does your child respond to his/her name when you call?

•15. If you point at a toy across the room, does your child look at it?

Moderate sensitivity, high specificity


2-level Screening Approach: If fail specific autism screening, referral

for a formal evaluation by an experienced clinician is recommended:•Autism Diagnosis Interview-Revised (ADI-

R) 18mo

•Autism Diagnostic Observation Schedule-Generic (ADOS) 15mo+

•Childhood Autism Rating Scale (CARS) 2yrs

Generally by a pediatric “specialist”


Autism Diagnostic Observation Schedule - (ADOS)-Generic – “gold standard“30- to 45-minute observation periodThe examiner scores standard 'presses' for

communication and social interaction. •'Presses' planned social occasions in

which a predetermined behavior is likely to appear

There are 4 different modules … correspond to different age and language ability

High sensitivity and specificity


Other Screening Points: Referral is recommended immediately if:

•Child does not babble or point/use gestures by 12 months

•Child does not use single words by 16 months

•Child does not use spontaneous 2-word phrases by 24 months

•Child experiences any loss of language or social skills at any age


Genetic testing?? Chromosomal microarray (CMA) should

be considered as part of the initial diagnostic evaluation of patients with ASD. Pediatrics 2010;125:e727–e735

•In a cohort of 800 patients with ASD:• G-banded karyotyping for chromosomal

abnormalities detects ~2.5%• Fragile X testing detects ~0.5%• CMA detects ~10%

ASD – Treatment

Two prong approach:Educational interventions - fostering

acquisition of skills and knowledge for developing independence and personal responsibility•early intensive intervention may result in

substantially better outcomes Medical management – to address

medical problems associated with ASD

ASD – Treatment

Educational interventionsApplied behavior analysis (36.4%) - based

on triggers and reward system … often discrete trial teaching (DTT) … used to: and maintain desirable adaptive

behaviors interfering maladaptive behaviors (or

narrow the conditions under which they occur)

•teach new skills

•generalize behaviors to new environments or situations

ASD – Treatment

Educational interventions•Early Start Denver Model - consistent

with the principles of ABA• interpersonal exchange and positive affect • shared engagement with real-life materials

and activities • adult responsivity and sensitivity to child cues• focus on verbal and nonverbal communication

•2yrs of ESDM therapy resulted in significant improvements in IQ, language, adaptive behavior, and reduced severity of autism diagnosis Pediatrics 2010;125:e17–e23

ASD – Treatment

Educational interventionsStructured teaching -- TEACCH (15.7%)

•organization of the physical environment

•predictable sequence of activities

•visual schedules

•routines with flexibility

•structured work/activity systems

•visually structured activities.Speech and language therapy (70%)

ASD – Treatment

Educational interventionsSocial story therapy (36.1%)

When we go to the shoe store,There will be many shoes to choose from. (Descriptive) I might not know which shoes I like. (Perspective)That is okay with everyone. (Affirmative)I can hold onto my string while I decide. (Control) When I decide about the shoes, I will tell the grown-up.

(Directive)The grown-up will go get the shoes for me. (Cooperative)

ASD – Treatment

Educational interventionsOccupational Therapy - promote

development of self-care skills … teach them to function in their environment

Sensory Integration Therapy (38.2%) - remediate the deficits in neurologic processing and sensory information integration to allow the child to interact with the environment in a more adaptive fashion

ASD – Treatment

Medical managementSeizures – ~30% patients with ASDGI problems – upwards of 70% of patientsSleep problems – 44-83% of patientsMaladaptive behaviors – 45% of

children/adolescents and 75% adults are treated with psychotropic medication•Risperidone is the 1st (and only) FDA

approved treatment of irritability in children/adolescents with ASDs

ASD – Treatment

Medical management – Complementary and Alternative Medicine 52% ASD patients are treated with at least

1 CAM (only 36-62% PCP were told)Nonbiological interventions:

•auditory integration (-) Arch Dis Child. 2006. 91:1018-22

•behavioral optometry

•craniosacral manipulation•16% music therapy (+ short term) Child Care Health

Dev. 2006. 32:535-42

•facilitated communication (-) J Autism Dev Disord. 2001. 31:287-313

ASD – Treatment

Medical management – Complementary and Alternative Medicine Biological therapies:

•immunoregulatory interventions: • administration of immunoglobulin (+/-) • 8% administration of antibiotics/antiviral/

antifungal agents (-)

•7% detox therapies (chelation) – DANGEROUS

•gastrointestinal treatments: • 20.5% probiotics• yeast-free diet • 23.1/26.8% gluten/casein-free diet (+/-) J Dev Behav

Pediatr. 2006. 27:S162-S171

ASD – Treatment

Medical management – Complementary and Alternative Medicine Biological therapies:

•dietary supplement regimens:• 30.8% vitamin C (ps +) Prog Neuropsychopharmacol Biol Psychiatry. 1993.

17:765-774

• 30% vitamin B6 and magnesium (+/-) Cochrane

Database Syst Rev. 2005. 19:CD003497 • folinic acid, betaine & B12 (ps +) Am J Clin Nutr.

2004 80:1611-7

• vitamin B12 (-) AACAP 2006; 33:F47 • 14% dimethylglycine (-) J Child Neurol. 2001. 16:169-73

• 28.7% omega-3 fatty acids (ps + improving hyperactivity & stereotypy) Biol Psychiatry 2007. 61:551–553

ASD – Take Home Points

Autism is a neurodevelopmental disorder with three key abnormalitiessocial/emotional behavior communication restricted, stereotyped and repetitive

behavior

ASDs are increasingly prevalent:broadening of diagnostic criteria increased public awarenessincreased parental age


Research is ongoing (and needs to continue) with regards to cause:multifactoralgenetic > environmentalNOT vaccine induced

Research is ongoing (and needs to continue) with regards to neuropathology:Key areas:

•frontal lobe, temporal lobe (amygdala), cerebellum


There are an array of PCP and “specialist” screening tools available for use in diagnosis

There are an array of treatments available:educationalmedicalCAM

but research on these methods needs to continue

autism spectrum disorders neurodevelopmental disorders characterized by qualitative abnormalities in...

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