autistic spectrum disorders: current perspectives april 8, 2011 kathryn a. mcvicar, md assistant...
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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
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
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
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
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 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
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