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Autism Spectrum Disorders

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Title: Autism Spectrum Disorders


1
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

2
Autism Spectrum Disorders
  • Learning Objectives
  • Symptomology
  • Likely/Unlikely Causes
  • genetic environmental
  • Neuropathology
  • Screening/Diagnostic Tools
  • Treatments
  • educational
  • medical
  • CAM

3
Autism Spectrum Disorders
  • ASDs differ by
  • when the symptoms started
  • symptom severity
  • nature of the symptoms
  • ASDs include
  • Autism Disorder (AD)
  • Aspergers syndrome (AS)
  • Pervasive developmental disorder, not otherwise
    specified (PDD-NOS)

4
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 aloofness
  • elaborate repetitive routines
  • Greek wordautos.meaning self,
  • extrapolated to mean alone, pre-occupied with
    self, a withdrawal into private world

5
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)

6
Autism -- DSM IV-TR
  • B. Delay or abnormal functioning in at least 1
    of the following with onset before 3yo
  • 1. Social interaction
  • 2. Language used in social communication
  • 3. Symbolic or imaginative play
  • C. Disturbance not better accounted for by
    Retts disorder or Childhood Disintegrative
    disorder

7
Autism -- Symptoms
8
Autistic Disorder -- DSM V
  • Autistic Disorder now to include the previous
    separate diagnoses
  • Autism
  • Asperger Syndrome
  • PDD-NOS
  • Child 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.

9
Autistic Disorder -- DSM V
  • Must meet criteria 1, 2, and 3
  • 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

10
Autistic Disorder -- DSM V
  • Must meet criteria 1, 2, and 3
  • 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
  • Symptoms must be present in early childhood (but
    may not become fully manifest until social
    demands exceed limited capacities)

11
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

12
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
    Oct38(5)1234-8
  • ? parental age (11)
  • ? awareness by parents (social influence)

13
ASD -- Causes
  • Multifactoral
  • Genetic (primarily)
  • Environmental factors (lesser extent)

Pardo, C.A and Eberhart, C.G. Brain Pathol.
200717434-447.
14
ASD -- Causes
  • Comorbidity -- Medical condition or syndrome
  • Epilepsy ? 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)

10-15
15
ASD -- Causes
  • GENETICS -- Family studies ... if one is AD
  • Identical twins ? 60-96 chance the other has AD
  • Fraternal twins ? up to 24 chance the other has
    AD
  • Siblings ? 5-10 chance the others have AD

16
ASD -- Causes
  • GENETICS -- Chromosomal studies
  • Chromosome 1 ATP1A2 (seizure susceptibility
    locus) 1q21.1 deletion, RIMS3
  • Chromosome 2 NRXN1 DLX12 (control early
    growth development), GAD1 (2q31), terminal
    deletion 2q37
  • Chromosome 3 CNTN4, OXTR
  • Chromosome 4 GABRA4, GABRB1

17
ASD -- Causes
  • GENETICS -- Chromosomal studies
  • Chromosome 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 GRIK2
  • Chromosome 7 RELN, CNTNAP2 (language), MET, EN2
  • Chromosome 8 MCPH1 (speech delay, LD)

18
ASD -- Causes
  • GENETICS -- Chromosomal studies
  • Chromosome 9 TSC1
  • Chromosome 10 PTEN (may account for 4.2 ASD),
    LRRTM3
  • Chromosome 11 DHCR7
  • Chromosome 12 CACNA1C, AVPR1A
  • Chromosome 13 NBea (important in brain
    development)
  • Chromosome 14 MDGA2

19
ASD -- Causes
  • GENETICS -- Chromosomal studies
  • Chromosome 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. 14358(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, DSC2
  • Chromosome 19 TLE2, TLE6

20
ASD -- Causes
  • GENETICS -- Chromosomal studies
  • Chromosome 20 ADA
  • Chromosome 21 NCAM2, GRIK1
  • Chromosome 22 deletion _at_ 22q13.3 (SHANK3)
  • Chromosome X originally thought because of 41
    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

21
ASD -- Causes
  • GENETICS -- Chromosomal studies
  • unbalanced chromosome rearrangements and or
    translocations
  • duplications or deletions
  • copy number variants of genes

22
ASD -- Causes
  • Maternal Factors
  • Autoimmune factors
  • Maternal auto-antibodies interact with fetal CNS
    proteins Brain Behav. Immun. 2007. 21351-357
    Neurotoxicology. 2008. 29226-31
  • 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.
    14388-394
  • More family members greater risk of ASD
  • rheumatoid arthritis (70), celiac disease (3x),
    type 1 diabetes (1.8x)

23
ASD -- Causes
  • Maternal Factors -- prenatal toxins/infection
  • Thalidomide exposure (20-24d gestation around
    the time of the neural tube closure)
  • Misoprostol exposure (6w gestation)
  • Valproic acid exposure (probably 20-24d gestation
  • Chlorpyrifos exposure
  • Ethanol exposure (possibly 3-5 weeks gestation)
    2 FAS children have ASD
  • Rubella exposure (first 8w)

24
ASD -- Causes
  • Neuroimmunological
  • Up to 60 of ASD patients have some type of
    systemic immune dysfunction. Brain Pathol.
    200717434-447.
  • Post-mortem brain tissues show active and ongoing
    neuroinflammatory processes
  • cerebral cortex, white matter and cerebellum.
    Ann. Neurol. 2005. 5767-81.
  • CSF exhibited a proinflammatory profile of
    cytokines. Ann. Neurol. 2005. 5767-81.
  • Advanced glycation end products (AGEs) are
    elevated in both the brain tissue and serum of
    autistic patients. Neurosci Lett. 2006.
    410169173.

25
ASD -- Causes
  • MMR vaccine
  • 1998, 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 (n12)
  • 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.

26
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. 322460463 (UK), J. Child Psychol.
    Psychiatry. 2005. 46572579 (Japan), Pediatrics.
    2006. 118(1)e139-50 (CAN), N. Engl. J. Med.
    2002. 34714771482 (Denmark), JAMA 2001.
    28511831185 (CA), Pediatrics. 2004. 113259266
    (GA)

27
ASD -- Causes
  • MMR vaccine (no association)
  • Larger studies found no relationship between MMR
    vaccine and autism.

Fombonne, E. et al. Pediatrics 2006118e139-e150
28
ASD -- Causes
  • MMR vaccine (no association)
  • Larger studies found no relationship 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.

29
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.

30
ASD -- Causes
31
ASD -- Causes
  • Toxins
  • Mercury 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)

32
ASD -- Causes
  • Toxins
  • Mercury in vaccines (thimerosal) no association
  • 2006 ? an ecological study in Montreal found that
    the prevalence AD (no thimerosal) was
    significantly gt the prevalence AD (thimerosal)
    Pediatrics. 118 e139e150
  • Controlled observational studies have not found
    an association between thimerosal and autism
    JAMA. 2003. 29017631766 (Denmark), Pediatrics.
    2004. 114584591 (UK), Pediatrics. 2003.
    11210391048 Arch Gen Psychiatry 20086519-24
    (US)

33
ASD -- Causes
  • Toxins
  • Mercury in vaccines (thimerosal) no association

Thimerosal removed from vaccines
Schechter, R. et al. Arch Gen Psychiatry
20086519-24.
34
ASD -- Causes
  • Toxins
  • Mercury in vaccines (thimerosal) no 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.

35
ASD -- Risk Factors
  • Parental age
  • Mothers 10y increase ? 38 increase
  • Fathers 10y increase ? 22 increase
  • Low birth weight/gestational age
  • Intrapartum hypoxia
  • Maternal smoking
  • Prenatal stress ??

36
ASD -- Neuropathology
37
ASD -- Neuropathology
  • Morphometric brain size (measured by head
    circumference) is ? 10 initially

Courchesne E., et al. 2003 JAMA 290, 337344.
Courchesne E., et al. Curr Opin Neurol.
200417(4)489-496
38
ASD -- Neuropathology
  • Brain Bank
  • Brain size is still 1-3 increased in adulthood.
    Redcay E and Courchesne E. 2005 Biol.
    Psychiatry 58, 19.

39
ASD -- Neuropathology
  • Brain Bank
  • Abnormalities 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)

CONTROL 10
AUTISTIC 12
Picket, J. and London, E. J. Neuropathol. Exp.
Neurol. 200564(11)925-935
40
ASD -- Neuropathology
  • Brain Bank
  • Abnormal 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)

41
ASD -- Neuropathology
  • Brain Bank
  • GAD67 mRNA expression is ? 40 in cerebellar
    Purkinje cells of autistic individuals compared
    to controls

Yip, J. et al. Acta Neuropathol.
2007113(5)559-568
42
ASD -- Neuropathology
  • MRI
  • ? brain volume (age related)
  • Abnormalities in sulcal and gyral anatomy
  • ? size of corpus callosum Biol Psychiatry. 2006.
    60 218225

Courchesne E., et al. Neurol. 200457(2)245-254
43
ASD -- Neuropathology
  • MRI
  • Regional gray white matter volumetric
    differences in frontal, parietal temporal lobes.

Courchesne E., et al. Curr Opin Neurol.
200417(4)489-496
44
ASD -- Neuropathology
  • MRI
  • Regional gray white matter volumetric
    differences in cerebellum (Vermis ?)

Courchesne E., et al. Neurol. 200157(2)245-254
45
ASD -- Neuropathology
  • 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.
2006266897-6906
46
ASD -- Neuropathology
  • PET
  • Developmental changes in brain serotonin
    synthesis capacity is dramatically different

Autistic
Normal
Chugani, D.C. et al. Ann. Neurol. 199945287295
47
ASD Screening Diagnosis
Johnson, C. P. et al. Pediatrics
20071201183-1215
48
ASD Screening Diagnosis
  • 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) ?18-24mo
  • Modified CHAT (M-CHAT) ?16-48mo
  • Screening Tool for Autism in Two-Year-Olds (STAT)
    ?24-36mo
  • Social Communication Questionnaire ??4yo

49
ASD Screening Diagnosis
  • 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?

50
ASD Screening Diagnosis
  • 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

51
ASD Screening Diagnosis
  • 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

52
ASD Screening Diagnosis
  • Autism Diagnostic Observation Schedule -
    (ADOS)-Generic gold standard
  • 30- to 45-minute observation period
  • The 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

53
ASD Screening Diagnosis
  • 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

54
ASD Screening Diagnosis
  • Genetic testing??
  • Chromosomal microarray (CMA) should be considered
    as part of the initial diagnostic evaluation of
    patients with ASD. Pediatrics 2010125e727e735
  • 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

55
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

56
ASD Treatment
  • Educational interventions
  • Applied 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

57
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 2010125e17e23

58
ASD Treatment
  • Educational interventions
  • Structured 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)

59
ASD Treatment
  • Educational interventions
  • Social 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)

60
ASD Treatment
  • Educational interventions
  • Occupational 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

61
ASD Treatment
  • Medical management
  • Seizures 30 patients with ASD
  • GI problems upwards of 70 of patients
  • Sleep problems 44-83 of patients
  • Maladaptive behaviors 45 of children/adolescent
    s and 75 adults are treated with psychotropic
    medication
  • Risperidone is the 1st (and only) FDA approved
    treatment of irritability in children/adolescents
    with ASDs

62
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.
    911018-22
  • behavioral optometry
  • craniosacral manipulation
  • 16 music therapy ( short term) Child Care
    Health Dev. 2006. 32535-42
  • facilitated communication (-) J Autism Dev
    Disord. 2001. 31287-313

63
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. 27S162-S171

64
ASD Treatment
  • Medical management Complementary and
    Alternative Medicine
  • Biological therapies
  • dietary supplement regimens
  • 30.8 vitamin C (ps ) Prog Neuropsychopharmacol
    Biol Psychiatry. 1993. 17765-774
  • 30 vitamin B6 and magnesium (/-) Cochrane
    Database Syst Rev. 2005. 19CD003497
  • folinic acid, betaine B12 (ps ) Am J Clin
    Nutr. 2004 801611-7
  • vitamin B12 (-) AACAP 2006 33F47
  • 14 dimethylglycine (-) J Child Neurol. 2001.
    16169-73
  • 28.7 omega-3 fatty acids (ps improving
    hyperactivity stereotypy) Biol Psychiatry 2007.
    61551553

65
ASD Take Home Points
  • Autism is a neurodevelopmental disorder with
    three key abnormalities
  • social/emotional behavior
  • communication
  • restricted, stereotyped and repetitive behavior
  • ASDs are increasingly prevalent
  • broadening of diagnostic criteria
  • increased public awareness
  • increased parental age

66
ASD Take Home Points
  • Research is ongoing (and needs to continue) with
    regards to cause
  • multifactoral
  • genetic gt environmental
  • NOT vaccine induced
  • Research is ongoing (and needs to continue) with
    regards to neuropathology
  • Key areas
  • frontal lobe, temporal lobe (amygdala), cerebellum

67
ASD Take Home Points
  • There are an array of PCP and specialist
    screening tools available for use in diagnosis
  • There are an array of treatments available
  • educational
  • medical
  • CAM
  • but research on these methods needs to continue

68
ASD Take Home Points
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