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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. Autism Spectrum Disorders. Learning Objectives Symptomology

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autism spectrum disorders
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

autism spectrum disorders1
Autism Spectrum Disorders

Learning Objectives

  • Symptomology
  • Likely/Unlikely Causes
    • genetic & environmental
  • Neuropathology
  • Screening/Diagnostic Tools
  • Treatments
    • educational
    • medical
    • CAM
autism spectrum disorders2
Autism Spectrum Disorders
  • ASDs differ by:
    • when the symptoms started
    • symptom severity
    • nature of the symptoms
  • ASDs include:
    • Autism Disorder (AD)
    • Asperger’s syndrome (AS)
    • Pervasive developmental disorder, not otherwise specified (PDD-NOS)
autism
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 word…autos….meaning “self”,
    • extrapolated to mean “alone, pre-occupied with self, a withdrawal into private [world]”
autism dsm iv tr
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 tr1
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 Rett’s disorder or Childhood Disintegrative disorder

autistic disorder dsm v
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.”

autistic disorder dsm v1
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
autistic disorder dsm v2
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)
asd prevalence
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 prevalence1
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
ASD -- Causes
  • Multifactoral
    • Genetic (primarily)
    • Environmental factors (lesser extent)

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

asd causes1
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%

asd causes2
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

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 causes3
ASD -- Causes
  • GENETICS -- Chromosomal studies
    • Chromosome 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, OXTR
    • Chromosome 4 – GABRA4, GABRB1
asd causes4
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)
asd causes5
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
asd causes6
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. 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, DSC2
    • Chromosome 19 – TLE2, TLE6
asd causes7
ASD -- Causes
  • GENETICS -- Chromosomal studies
    • Chromosome 20 – ADA
    • Chromosome 21 – NCAM2, GRIK1
    • Chromosome 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 causes8
ASD -- Causes
  • GENETICS -- Chromosomal studies
    • unbalanced chromosome rearrangements and or translocations
    • duplications or deletions
    • copy number variants of genes
asd causes9
ASD -- Causes
  • Maternal Factors
    • Autoimmune 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 causes10
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)
asd causes11
ASD -- Causes
  • Neuroimmunological
    • Up 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. NeurosciLett. 2006. 410:169–173.
asd causes12
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 (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 causes13
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 causes14
ASD -- Causes
  • MMR vaccine (no association)
    • Larger studies found no relationship between MMR vaccine and autism.

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

asd causes15
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.
asd causes16
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 causes18
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)
asd causes19
ASD -- Causes
  • Toxins
    • Mercury 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 autismJAMA. 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 causes20
ASD -- Causes
  • Toxins
    • Mercury in vaccines (thimerosal) – no association

Thimerosal removed from vaccines

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

asd causes21
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.
asd risk factors
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 ??
asd neuropathology1
ASD -- Neuropathology
  • Morphometric – brain size (measured by head circumference) is  ~10% initially

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

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

asd neuropathology2
ASD -- Neuropathology
  • Brain Bank
    • Brain size is still 1-3% increased in adulthood. Redcay E and Courchesne E. 2005; Biol. Psychiatry 58, 1–9.
asd neuropathology3
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. 2005;64(11):925-935

asd neuropathology4
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)
asd neuropathology5
ASD -- Neuropathology
  • Brain Bank
    • GAD67 mRNA expression is  40% in cerebellar Purkinje cells of autistic individuals compared to controls

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

asd neuropathology6
ASD -- Neuropathology
  • 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

asd neuropathology7
ASD -- Neuropathology
  • MRI
    • Regional gray & white matter volumetric differences in frontal, parietal & temporal lobes.

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

asd neuropathology8
ASD -- Neuropathology
  • MRI
    • Regional gray & white matter volumetric differences in cerebellum (Vermis )

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

asd neuropathology9
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. 2006;26:6897-6906

asd neuropathology10
ASD -- Neuropathology
  • PET
    • Developmental changes in brain serotonin synthesis capacity is dramatically different

Autistic

Normal

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

asd screening diagnosis
ASD – Screening & Diagnosis

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

asd screening diagnosis1
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) 18-24+mo
      • Modified CHAT (M-CHAT) 16-48mo
      • Screening Tool for Autism in Two-Year-Olds (STAT) 24-36mo
      • Social Communication Questionnaire 4yo
asd screening diagnosis2
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?
asd screening diagnosis3
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
asd screening diagnosis4
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”
asd screening diagnosis5
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
asd screening diagnosis6
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
asd screening diagnosis7
ASD – Screening & Diagnosis
  • 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
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 treatment1
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
asd treatment2
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 treatment3
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%)
asd treatment4
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)

asd treatment5
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
asd treatment6
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/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 treatment7
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 treatment8
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 treatment9
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
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
asd take home points1
ASD – Take Home Points
  • Research is ongoing (and needs to continue) with regards to cause:
    • multifactoral
    • genetic > environmental
    • NOT vaccine induced
  • Research is ongoing (and needs to continue) with regards to neuropathology:
    • Key areas:
      • frontal lobe, temporal lobe (amygdala), cerebellum
asd take home points2
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