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
educational medical CAM
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 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 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 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
Autism -- Symptoms
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 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 ď ş
Four times more likely in males
ď ş
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 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%)
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 -- 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 -- 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 -- 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 -- 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 -- 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 -- Causes
GENETICS -- Chromosomal studies unbalanced chromosome rearrangements and or translocations duplications or deletions copy number variants of genes
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 -- 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 -- 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. Neurosci Lett. 2006. 410:169–173.
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 -- 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 ď ş
MMR vaccine (no association) ď Ź
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
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 -- 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 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
Toxins
Mercury in vaccines (thimerosal) – no association
Thimerosal removed from vaccines
Schechter, R. et al. Arch Gen Psychiatry 2008;65:19-24.
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
Parental age Mothers … 10y increase 38% increase Fathers … 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. 2003; JAMA 290, 337–344.
Courchesne E., et al. Curr Opin Neurol. 2004;17(4):489-496
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 -- Neuropathology ď ş
Brain Bank ď Ź
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 -- 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 -- Neuropathology
Brain Bank
GAD67 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)
Courchesne E., et al. Neurol. 2004;57(2):245-254
Abnormalities in sulcal and gyral anatomy size of corpus callosum Biol Psychiatry. 2006. 60: 218–225
ASD -- Neuropathology ď ş
MRI ď Ź
Regional gray & white matter volumetric differences in frontal, parietal & temporal lobes.
Courchesne E., et al. Curr Opin Neurol. 2004;17(4):489-496
ASD -- Neuropathology
MRI
Regional 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
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
Johnson, C. P. et al. Pediatrics 2007;120:11831215
ASD – Screening & Diagnosis
2-level Screening Approach:
At well-baby check-up if fail routine developmental screening:
• Infant-Toddler Checklist (from CSBS-DP) 624mo • Checklist for Autism in Toddlers (CHAT) 1824+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 (MCHAT) 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 (MCHAT)
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 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 & 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 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 – 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 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 – 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 – 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 – 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 – 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 (-) • behavioral optometry • craniosacral manipulation • 16% music therapy (+ short term)
Arch Dis Child. 2006. 91:1018-22
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 +) • 30% vitamin B6 and magnesium (+/-) Cochrane Database Syst Prog Neuropsychopharmacol Biol Psychiatry. 1993. 17:765-774
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 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 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 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
ASD – Take Home Points