Autistic Spectrum Disorders:

Current PerspectivesApril 8, 2011

Kathryn A. McVicar, MDAssistant Professor Pediatrics and NeurologyUTHSC-MemphisPediatric Neuroscience InstituteLe Bonheur Children’s Medical Center

Introduction Epidemiology History Clinical Presentation Epilepsy Sleep disturbance Structural brain differences Genetic work suggesting future treatments Current treatment Conclusions

Epidemiology

Prevalence

Initially thought to be 1/1,000

Reevaluation/Change in definitions• DSM IV• International Classification of Diseases (ICD-10)

Current estimates 1/99 (CDC 2010)

3-4:1 boys to girls

History

Kanner in US/Asperger in Austria 1943 Simultaneously described autism phenotype

• Kanner- “autistic disturbances of affective contact” 11 children-Mental retardation

• Asperger-”autistic phsychosis” 4 boys-No mental retardation

• Behaviors Social remoteness Obsessiveness Stereotypy Echolalia

History

DSM 1952, 1968 Autism as psychosis

Concept of ‘refrigerator Mom’ Child left untreated Mother given psychotherapy to improve

‘bonding’ with child Above a clue to genetic component

History

DSM III 1980 First use of term pervasive developmental

disorders …”distortions in the development of multiple

basic psychological functions that are involved in the development of social skills and language such as attention, perception, reality testing, and motor movements.”

History

Lorna Wing 1988 Concept of the “Autistic Continuum”

• No clear cut offs Term “Autistic Spectrum” (Autistic Spectrum

Disorders, ASD) came into use increasingly after this

Clinical presentation

Core deficits:

Reciprocal social interactions

Verbal and nonverbal communication

Restricted and repetitive behaviors and interests

Examples of reciprocal attention

Lack of reciprocal attention

Easily overwhelmed

Pointing with eye contact

Gestures, but NOT communicating

Clinical presentation

Receptive language Pragmatics absent or diminished

• Lacks comprehension of communicative intent of others

Expressive language Semantics absent or diminished

• Lacks use of language/gestures with intent to communicate

Clinical presentation

Motor apraxia ‘Clumsy’ ‘Stiff’

Abnormal play No imagination No pretending Prefers to play alone

Clinical presentation

Overlap and co-morbidity with Mental retardation Developmental dysphasia Obsessive Compulsive Disorder Schizoid personality Bi-polar Disorder ADHD Sleep disturbance Behavior disorder

Regression

Up to 1/3 with ASD will regress Mean age at regression

• 18-24 monthsShinnar et al, 2001

McVicar et, 2005

• 41.4 months

Jones LA and Campbell JM, 2010

Epilepsy

Comorbid epilespy 5-38%Rossi PG et al. Brain Develop. 1995;17:169-74Tuchman and Rapin. Lancet Neurol. 2002;1:352-58Danielsson S et al. Epilepsia. 2005;46:918-23

Bimodal incidence of epilepsy Infancy to age 5 Adolescence (>10 years)

Volkmar and Nelson. J Am Acad Child Adolesc Psychiatry. 1990;29:127-29

Epilepsy Cumulative probability of epilepsy

Autism alone• 2% at 5 years• 8% at 10 years

Autism with severe mental retardation (MR)• 7% at 1 year• 16% at 5 years• 27% at 10 years

Autism with MR and cerebral palsy (CP)• 20% at 1 year• 35% at 5 years• 67% at 10 years

Tuchman and Rapin. Lancet Neurol. 2002;1:352-58

Epilepsy

Epilepsy persists into adult life Remission in 16%

Danielsson S et al. Epilepsia. 2005;46:918-23

Epilepsy

10 year follow up (n=30) 25% epileptic seizures

68% epileptiform EEG prior to seizure onset 18% epileptiform EEG/NO SEIZURES

Epileptic group Lower IQ Lower social maturity score ↑ frequency of psychotropic medication tx

Hara H. Brain Dev. 2007;29:486-490

Sleep

Sleep difficulties in children with autism 56%-68%

Clements J et al. J Child Psychol Psychiat. 1986:27:399-407

Hoshino Y et al. Folia Psychiatrica et Neurologica Japonica. 1984:38:45-51

Wiggs L and Stores G. J Intell Dis Res. 1996;40:518-28

Up to 89% in high-functioning if ‘past’ included

Richdale AL and Prior MF. Eur Child Adoles Psychiat. 1995;4:175-86

Sleep Disturbances

More variable sleep patterns Sleep onset Sleep maintenance Irregular sleep-wake patterns

Hoshino Y et al. Folia Psychiatrica et Neurologica Japonica. 1984:38:45-51

Sleep Disturbance and Intensity of ASD Symptoms

Parent report of sleep problems Fewer hours of sleep predicted

↑ autism scores Social skills deficits

Stereotypic behavior predicated by Fewer hours of sleep Screaming during night

Predicted communication problems ↑ sensitivity to environmental stimuli in bedroom Screaming at night

Schreck KA et al. Research Dev Dis. 2004;255:57-66

Sleep Behaviors and Quality of Sleep

ASD Behavioral insomnia sleep-onset type Insomnia due to PDD

Picked up by questionnaire and actigraphy

Souders MC et al. Sleep behaviors and sleep quality in children with autism spectrum disorders. Sleep. 2009

Dec 1;32(12):1566-78

Sleep Treatment

Melatonin (up to 6 mg) to treat insomnia Retrospective review of single pediatrician

• n=107 children • 2-18 year-olds

Parental report of change with tx Melatonin dose range 0.75-6mg

Andersen IM et al. J Child Neurol. 2008;23(5):482-5

Sleep Treatment

Results 25% no further sleep concerns 60% improved sleep, continued concerns 13% sleep problems, major concern 1% worse sleep with melatonin 1% undetermined response

Andersen IM et al. J Child Neurol. 2008;23(5):482-5

Gastrointestinal symptoms in ASD

GI symptoms 52% of ASD 7% TD age-matched healthy siblings (p<.001)

ASD with irritability more likely with reflux eosphagitis 43% with GERD vs 17% without GERD

Horvath K and Perman JA, 2002

Abdominal pain and discomfort in ASD

Vocal Behaviors Throat clearing, swallowing, tics, etc. Screaming, sobbing for unknown reason,

sighing, whining, moaning, groaning Delayed echolalia-repeating what may have

been asked of them in the past• Child saying “DOES YOUR TUMMY HURT?”

Direct verbalizations• Child saying “tummy hurts”, etc with/without

pointing

Taken from Table 2 Pediatrics Vol 125, Supplement 1, January 2010:pg S4

Abdominal pain and discomfort in ASD

Motor Behaviors Grimacing, gritting teeth, wincing Constant eating/drinking/swallowing Mouthing behaviors/pica Pressure to abdomen

Taken from Table 2 Pediatrics Vol 125, Supplement 1, January 2010:pg S4

Abdominal pain and discomfort in ASD

Changes in overall state Sleep disturbance Increased irritability Oppositional behavior

Taken from Table 2 Pediatrics Vol 125, Supplement 1, January 2010:pg S4

Diagnostic considerations for GI symptoms in ASD

Sleep disturbance GERD

Self-injurious behavior, tantrums, aggression, oppositional behavior

Constipation GERD Gastritis Intestinal inflammation

Chronic diarrhea (≥3 loose stools daily for >2 weeks)

Malabsorption Maldigestion

Taken from Table 2 Pediatrics Vol 125, Supplement 1, January 2010:pg S4

Diagnostic considerations for GI symptoms in ASD

Flatulence and/or bloating Constipation Lactose intolerance Enteric infection

• Giardia• Cryptosporidium

Taken from Table 2 Pediatrics Vol 125, Supplement 1, January 2010:pg S4

How does this happen?

Structural brain differences

Cortical connectivity Impaired ability to integrate information

Facial perception problems Impaired social interaction

Imitation problems/Mirror neurons Contributes to learning delay Contributes to disorders of communication

and contact

Cortical connectivity Corpus callosum smaller volumes:

24 boys with autism (10.0 +/- 3.3 yr) 26 control boys (11.0 +/- 2.5 yrs) 3 Tesla MRI Localize regions of callosal thinning in autism

Vidal CN, Nicolson R, Thompson PM, et al. Mapping corpus callosum deficits in autism: an index of aberrant cortical connectivity. Biol Psychiatry. 2006 Aug 1;60(3):218-25

Cortical Connectivity

Significant ↓ Total callosal area Anterior 1/3 of the CC Splenium and genu of the CC

Suggest aberrant connections of cortical regions

Vidal CN, Nicolson R, Thompson PM, et al. Mapping corpus callosum deficits in autism: an index of aberrant cortical connectivity. Biol Psychiatry. 2006 Aug 1;60(3):218-25

Corpus Callosum

Cortical Connectivity

DTI and volumetric measurements of the total CC and subregions

Results: Significant differences

• volume,• fractional anisotropy• mean diffusivity• radial diffusivity Alexander AL, Lee JE, Lainhart JE. Diffusion tensor imaging of

the corpus callosum in Autism. Neuroimage. 2007 Jan 1;34(1):61-73

Cortical Connectivity

Group differences driven by a subgroup of the autism group• small corpus callosum volumes • ↑ mean diffusivity • ↓ anisotropy• ↑ radial diffusivity• Significantly ↓ performance IQ measures Alexander AL, Lee JE, Lainhart JE. Diffusion tensor imaging of

the corpus callosum in Autism. Neuroimage. 2007 Jan 1;34(1):61-73. Epub 2006 Oct 4.

Facial Perception

Hypoactive in autism Fusiform gyrus (FG) Cortical regions supporting face processing

7 post-mortem autism brains 10 controls FG analyzed

van Kooten IA, Palmen SJ, Schmitz C. Neurons in the fusiform gyrus are fewer and smaller in autism. Brain. 2008 Apr;131(Pt 4):987-99

Facial Perception

Significant ↓Neuron densities layer III

Association cortex Total neuron numbers layers III, V and VI

Association cortexSensory in from thalamusCortical in to thalamus

Mean perikaryal volumes of neurons layers V and VI

van Kooten IA, Palmen SJ, Schmitz C. Neurons in the fusiform gyrus are fewer and smaller in autism. Brain. 2008 Apr;131(Pt 4):987-99

Inability to imitate/Mirror neurons

EEG activity during videos showing actions or still scenes 14 right-handed children with autism

• Mean age 5 years 3 months 14 right-handed, age- and gender-matched

typical children • Mean age 7 years 11 months

Martineau J, Cochin S, Barthelemy C, et al. Impaired cortical activation in autistic children: is the mirror neuron system involved? Int J Psychophysiol. 2008 Apr;68(1):35-40

Inability to imitate/Mirror neurons

Results: Typical children: Desynchronization of the

EEG with observation of human actions • motor cerebral cortex• frontal and temporal areas

With autism: No desynchronization • Inversion of the pattern of hemispheric activation

was found in autistic children• ↑ cortical activity RT hemisphere posteriorly,

including the centro-parietal and temporo-occipital sites

Martineau J, Cochin S, Barthelemy C, et al. Impaired cortical activation in autistic children: is the mirror neuron system involved? Int J Psychophysiol. 2008 Apr;68(1):35-40

EEG Sample

Brain

Clues from other diseases with an autism phenotype

Fragile X GeneticsFMR1 gene

FMR1 (fragile X mental retardation 1) X chromosome FMR1 CGG repeat Loss of RNA-binding protein Role in mRNA transport and translational

regulation• Affects synaptic plasticity

Peng et al. RNA and microRNAs in fragile X mental retardation Nature Cell Biology  6, 1048 - 1053 (2004) doi:10.1038/ncb1104-1048

Fragile X GeneticsFMR1 gene

AMPA receptor trafficking →driving process for synaptic plasticity

Normal system, process learning and memory Abnormal system,

• problems with learning and memory • LTP disruption

↓ mGluR5 signaling can reverse fragile X sx Potential treatment with mGluR5 antagonists

Nakamoto et al. Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptors. Proceedings of the National Academy of Sciences of the United States of America. August 2007.

Fulfilling the Promise of Molecular Medicine In Autism. M.Bear*, MIT Presented IMFAR 2009.

mGluR5 antagonistsSafety and efficacy in humans

Phase II trial of fenobam in adults with FXS N=12 adults (mean age 23.9 yrs)

• UC Davis MIND Institute• RUSH, University in Chicago

All tolerated single dose without significant SE 50% had ≥ 20% improvement in prepulse

inhibition (p = 0.03) Majority scored at ceiling on continuous

performance task Not helpful in assessing medication benefits

R. Hagerman et al. Trial of fenobam, an mGluR5 antagonist, in adults with Fragile X Syndrome. JIDR; Vol 52 (10):814.

Neurofibromatosis 1Neurofibromin

Functions as a tumor suppressorKweh F, Zheng M, Kurenova E, Wallace M, Golubovskaya V, Cance WG. Mol Carcinog. 2009 May 28

Neurofibromin deficiency Loss of regulation of signaling and intersecting

pathways Acts on

Actin cytoskeleton reorganization Cell motility and adhesion

Larizza et al. Developmental abnormalities and cancer predisposition in neurofibromatosis type 1. Curr Mol Med. 2009 Jul;9(5):634-53

NF 1Neurofibromin

NF 1Future Treatment

NF1-Malignant Peripheral Nerve Sheath Tumor (MPNST) explant grown subcutaneously in NOD-SCID mice

Rapamycin in low doses Inhibited human NF1-MPNST mTOR pathway

activation Inhibited explant growth in vivo Without systemic toxicities

Behavioral changes similar to ASD, improved

Bhola P et al. Preclinical in vivo evaluation of rapamycin in human malignant peripheral nerve sheath explant xenograft. Int J Cancer. 2009 Jul 24

Rett disease

Most common basis of autism in girls X-linked MECP 2 Deficit in synaptic maturation in the brain MeCP2 mutant mice

Sparse dendritic spines ↓ PSD-95 in motor cortex pyramidal neurons ↓ synaptic amplitude in the same neurons Protracted cortical plasticity in vivo

Tropea et al. Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice. PNAS. Feb 2009; vol. 106 (6): 2029-2034

Rett disease mouse model

↑ brain weight Partially restores

Spine density Synaptic amplitude ↑ PSD-95 Stabilizes cortical plasticity to wild-type levels

IGF-1 a candidate for pharmacological treatment of Rett disease and other neurodevelopmental disorders

Tropea et al. Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice. PNAS. Feb 2009; vol. 106 (6): 2029-2034

IGF-1 in Autism Insulin-like growth factor-I (IGF-I)

Role in early brain development. IGF-I levels measured in the CSF of 11 children with

autism 4 girls 7 boys Mean age 3.8 years

Compared levels in 11 control children 6 girls 5 boys mean age 3.8 years

IGF-I in the CSF lower with autism (p=0.03)

Vanhala et al. Low levels of insulin-like growth factor-1 in cerebrospinal fluid in children with autism. Dev Med & Child Neuro. 2001, 43;9:614-16

Rare syndromes with ASD co-occurrence

Syndrome ASD co-diagnosis Gene mutation Cell function References

Angelman >50% UBE3A (maternal) Protein degradation Down syndrome >5%–15% Chromosome 21 Multiple

triplication Fragile X >45%–70% FMR1 RNA trafficking Neuro- >4%A NF1/NF2 PI3K signaling activity fibromatosis Macrocephaly >75% PTEN PI3K signaling activity Potocki-Lupski >90% 17p duplications Unknown Rett >50% MECP2 Transcriptional

regulation Smith-Lemli- >50%–75% DHCR7 Cholesterol

biosynthesis; Opitz Ras-mediated ERK

signaling; PI3K signaling

Tuberous >40%–50% TSC1/TSC2 PI3K/mTOR signaling Sclerosis 22q13 deletion >90% PDD-NOS Microdeletions Multiple Timothy >75% CACNA1C Calcium signaling Pat Levitt and Daniel B. Campbell. The genetic and neurobiologic compass points

toward common signaling dysfunctionsin autism spectrum disorders. J Clin Invest. 2009 Apr;119(4):747-54

Protein functions with known genes associated with ASD

Neuronal cell adhesion and/or synapse function Neuronal activity regulation Neurodevelopmental genes Sodium channel Calcium channel Neurotransmitter genes Mitochondrial OtherAdapted from GeneReviews, http://www.genetest.org. Copyright,

University of Washington, Seattle 1997-2010.

Phenotypic variables that may define discrete (ASD) subgroups

Morphology and growth Generalized dysmorphology 15–20% Macrocephaly 35% Microcephaly 5–15%

Brain malformations 20% Medical/neurologic

Seizures 25% EEG abn 50% Sleep disorder 65% Adapted from Miles JH. Autism spectrum disorders—A genetics

review. Genetics in Medicine, April 2011.

Phenotypic variables that may define discrete (ASD) subgroups

Savant skills 5% Clinical course

Age of onset Regressive onset 30%

Adolescent/adult catatonic regression 17%

Adapted from Miles JH. Autism spectrum disorders—A genetics review. Genetics in Medicine, April 2011.

Phenotypic variables that may define discrete (ASD) subgroups

Significant family history of related disorders ASD 25% Alcoholism 30% ADHD 70% Affective disorders Bipolar/major affective disorder 30%

Adapted fromMiles JH. Autism spectrum disorders—A genetics review. Genetics in Medicine, April 2011.

Phenotypic variables that may define discrete (ASD) subgroups

Functionally defined variables IQ Response to therapy Adaptive behaviors (unclear) Outcome measures (poorly defined/unclear)

Adapted fromMiles JH. Autism spectrum disorders—A genetics review. Genetics in Medicine, April 2011.

Treatment

Behavioral therapy Medical treatment of symptoms

Sleep ADHD Aggression Anxiety Obsessive compulsive tendencies Epilepsy Constipation GERD

Behavioral therapy

Mainstay of therapy

Consistently proven benefit

Medication Therapies

Start LOW and go SLOW Trial and error Caregiver participation

Choices Permission to STOP Frequent appointments

WITH BEHAVIORAL THERAPY

Conclusions

ASD often present as speech and language delay

Any loss of language or behavioral function needs to be evaluated promptly

ASD caused by abnormal /different brains with abnormal/different brain function

Treatment is symptomatic

Conclusions

Behavioral therapy is the BEST intervention

Definitive medical therapy based on nerve cell functioning may be close