Autism Spectrum Disorders Neurodevelopmental disorders characterized by qualitative abnormalities in...
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Transcript of 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
Autism Spectrum Disorders
Learning Objectives Symptomology Likely/Unlikely Causes
genetic & environmental Neuropathology Screening/Diagnostic Tools Treatments
educationalmedicalCAM
Autism Spectrum Disorders
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.”
Autistic Disorder -- DSM V
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
Autistic Disorder -- DSM V
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
MMR vaccine (no association)Larger studies found no relationship
between MMR vaccine and autism.
Fombonne, E. et al. Pediatrics 2006;118:e139-e150
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 -- 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
ToxinsMercury in vaccines (thimerosal) – no
association
Schechter, R. et al. Arch Gen Psychiatry 2008;65:19-24.
Thimerosal removed from vaccines
ASD -- Causes
ToxinsMercury 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
Parental ageMothers … 10y increase 38% increaseFathers … 10y increase 22% increase
Low birth weight/gestational age Intrapartum hypoxia Maternal smoking Prenatal stress ??
ASD -- Neuropathology
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.
ASD -- Neuropathology
Brain BankBrain size is still 1-3% increased in
adulthood. Redcay E and Courchesne E. 2005; Biol. Psychiatry 58, 1–9.
ASD -- Neuropathology
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
ASD -- Neuropathology
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)
ASD -- Neuropathology
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
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 -- Neuropathology
MRIRegional gray & white matter volumetric
differences in frontal, parietal & temporal lobes.
Courchesne E., et al. Curr Opin Neurol. 2004;17(4):489-496
ASD -- Neuropathology
MRIRegional gray & white matter volumetric
differences in cerebellum (Vermis )
Courchesne E., et al. Neurol. 2001;57(2):245-254
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 -- Neuropathology
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
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 & 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 & 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 & 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 & Diagnosis
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
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 & 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
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
ASD – Take Home Points
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
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:educationalmedicalCAM
but research on these methods needs to continue
ASD – Take Home Points