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 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