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Autistic Spectrum Disorders: Current Perspectives April 8, 2011 Kathryn A. McVicar, MD Assistant Professor Pediatrics and Neurology UTHSC-Memphis Pediatric.

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Presentation on theme: "Autistic Spectrum Disorders: Current Perspectives April 8, 2011 Kathryn A. McVicar, MD Assistant Professor Pediatrics and Neurology UTHSC-Memphis Pediatric."— Presentation transcript:

1 Autistic Spectrum Disorders: Current Perspectives April 8, 2011 Kathryn A. McVicar, MD Assistant Professor Pediatrics and Neurology UTHSC-Memphis Pediatric Neuroscience Institute Le Bonheur Children’s Medical Center

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

4 Epidemiology  Prevalence Initially thought to be 1/1,000 Initially thought to be 1/1,000 Reevaluation/Change in definitions Reevaluation/Change in definitions DSM IVDSM IV International Classification of Diseases (ICD-10)International Classification of Diseases (ICD-10) Current estimates 1/99 (CDC 2010) Current estimates 1/99 (CDC 2010) 3-4:1 boys to girls 3-4:1 boys to girls

5 History  Kanner in US/Asperger in Austria 1943 Simultaneously described autism phenotype Simultaneously described autism phenotype Kanner- “autistic disturbances of affective contact”Kanner- “autistic disturbances of affective contact” 11 children-Mental retardation 11 children-Mental retardation Asperger-”autistic phsychosis”Asperger-”autistic phsychosis” 4 boys-No mental retardation 4 boys-No mental retardation BehaviorsBehaviors Social remoteness Social remoteness Obsessiveness Obsessiveness Stereotypy Stereotypy Echolalia Echolalia

6 History  DSM 1952, 1968 Autism as psychosis Autism as psychosis  Concept of ‘refrigerator Mom’ Child left untreated Child left untreated Mother given psychotherapy to improve ‘bonding’ with child Mother given psychotherapy to improve ‘bonding’ with child Above a clue to genetic component Above a clue to genetic component

7 History  DSM III 1980 First use of term pervasive developmental disorders 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.” …”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.”

8 History  Lorna Wing 1988 Concept of the “Autistic Continuum” Concept of the “Autistic Continuum” No clear cut offsNo clear cut offs Term “Autistic Spectrum” (Autistic Spectrum Disorders, ASD) came into use increasingly after this Term “Autistic Spectrum” (Autistic Spectrum Disorders, ASD) came into use increasingly after this

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11 Clinical presentation  Core deficits: Reciprocal social interactions Reciprocal social interactions Verbal and nonverbal communication Verbal and nonverbal communication Restricted and repetitive behaviors and interests Restricted and repetitive behaviors and interests

12 Examples of reciprocal attention

13 Lack of reciprocal attention

14 Easily overwhelmed

15 Pointing with eye contact

16 Gestures, but NOT communicating

17 Clinical presentation  Receptive language Pragmatics absent or diminished Pragmatics absent or diminished Lacks comprehension of communicative intent of othersLacks comprehension of communicative intent of others  Expressive language Semantics absent or diminished Semantics absent or diminished Lacks use of language/gestures with intent to communicateLacks use of language/gestures with intent to communicate

18 Clinical presentation  Motor apraxia ‘Clumsy’ ‘Clumsy’ ‘Stiff’ ‘Stiff’  Abnormal play No imagination No imagination No pretending No pretending Prefers to play alone Prefers to play alone

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

20 Regression  Up to 1/3 with ASD will regress Mean age at regression Mean age at regression months18-24 months Shinnar et al, 2001 McVicar et, months41.4 months Jones LA and Campbell JM, 2010

21 Epilepsy  Comorbid epilespy 5-38% Rossi PG et al. Brain Develop. 1995;17: Tuchman and Rapin. Lancet Neurol. 2002;1: Danielsson S et al. Epilepsia. 2005;46:  Bimodal incidence of epilepsy Infancy to age 5 Infancy to age 5 Adolescence (>10 years) Adolescence (>10 years) Volkmar and Nelson. J Am Acad Child Adolesc Psychiatry. 1990;29:127-29

22 Epilepsy  Cumulative probability of epilepsy Autism alone Autism alone 2% at 5 years2% at 5 years 8% at 10 years8% at 10 years Autism with severe mental retardation (MR) Autism with severe mental retardation (MR) 7% at 1 year7% at 1 year 16% at 5 years16% at 5 years 27% at 10 years27% at 10 years Autism with MR and cerebral palsy (CP) Autism with MR and cerebral palsy (CP) 20% at 1 year20% at 1 year 35% at 5 years35% at 5 years 67% at 10 years67% at 10 years Tuchman and Rapin. Lancet Neurol. 2002;1:352-58

23 Epilepsy  Epilepsy persists into adult life  Remission in 16% Danielsson S et al. Epilepsia. 2005;46:918-23

24 Epilepsy  10 year follow up (n=30)  25% epileptic seizures 68% epileptiform EEG prior to seizure onset 68% epileptiform EEG prior to seizure onset  18% epileptiform EEG/NO SEIZURES  Epileptic group Lower IQ Lower IQ Lower social maturity score Lower social maturity score ↑ frequency of psychotropic medication tx ↑ frequency of psychotropic medication tx Hara H. Brain Dev. 2007;29:

25 Sleep  Sleep difficulties in children with autism 56%-68% 56%-68% Clements J et al. J Child Psychol Psychiat. 1986:27: Hoshino Y et al. Folia Psychiatrica et Neurologica Japonica. 1984:38:45-51 Wiggs L and Stores G. J Intell Dis Res. 1996;40: Up to 89% in high-functioning if ‘past’ included Up to 89% in high-functioning if ‘past’ included Richdale AL and Prior MF. Eur Child Adoles Psychiat. 1995;4:175-86

26 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

27 Sleep Disturbance and Intensity of ASD Symptoms  Parent report of sleep problems  Fewer hours of sleep predicted ↑ autism scores ↑ autism scores Social skills deficits Social skills deficits  Stereotypic behavior predicated by Fewer hours of sleep Fewer hours of sleep Screaming during night Screaming during night  Predicted communication problems ↑ sensitivity to environmental stimuli in bedroom ↑ sensitivity to environmental stimuli in bedroom Screaming at night Screaming at night Schreck KA et al. Research Dev Dis. 2004;255:57-66

28 Sleep Behaviors and Quality of Sleep  ASD Behavioral insomnia sleep-onset type Behavioral insomnia sleep-onset type Insomnia due to PDD 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 Dec 1;32(12):

29 Sleep Treatment  Melatonin (up to 6 mg) to treat insomnia Retrospective review of single pediatrician Retrospective review of single pediatrician n=107 childrenn=107 children 2-18 year-olds2-18 year-olds Parental report of change with tx Parental report of change with tx Melatonin dose range mg Melatonin dose range mg Andersen IM et al. J Child Neurol. 2008;23(5):482-5

30 Sleep Treatment  Results 25% no further sleep concerns 25% no further sleep concerns 60% improved sleep, continued concerns 60% improved sleep, continued concerns 13% sleep problems, major concern 13% sleep problems, major concern 1% worse sleep with melatonin 1% worse sleep with melatonin 1% undetermined response 1% undetermined response Andersen IM et al. J Child Neurol. 2008;23(5):482-5

31 Gastrointestinal symptoms in ASD  GI symptoms 52% of ASD 52% of ASD 7% TD age-matched healthy siblings (p<.001) 7% TD age-matched healthy siblings (p<.001)  ASD with irritability more likely with reflux eosphagitis 43% with GERD vs 17% without GERD 43% with GERD vs 17% without GERD Horvath K and Perman JA, 2002

32 Abdominal pain and discomfort in ASD  Vocal Behaviors Throat clearing, swallowing, tics, etc. Throat clearing, swallowing, tics, etc. Screaming, sobbing for unknown reason, sighing, whining, moaning, groaning Screaming, sobbing for unknown reason, sighing, whining, moaning, groaning Delayed echolalia-repeating what may have been asked of them in the past Delayed echolalia-repeating what may have been asked of them in the past Child saying “DOES YOUR TUMMY HURT?”Child saying “DOES YOUR TUMMY HURT?” Direct verbalizations Direct verbalizations Child saying “tummy hurts”, etc with/without pointingChild saying “tummy hurts”, etc with/without pointing Taken from Table 2 Pediatrics Vol 125, Supplement 1, January 2010:pg S4

33 Abdominal pain and discomfort in ASD  Motor Behaviors Grimacing, gritting teeth, wincing Grimacing, gritting teeth, wincing Constant eating/drinking/swallowing Constant eating/drinking/swallowing Mouthing behaviors/pica Mouthing behaviors/pica Pressure to abdomen Pressure to abdomen Taken from Table 2 Pediatrics Vol 125, Supplement 1, January 2010:pg S4

34 Abdominal pain and discomfort in ASD  Changes in overall state Sleep disturbance Sleep disturbance Increased irritability Increased irritability Oppositional behavior Oppositional behavior Taken from Table 2 Pediatrics Vol 125, Supplement 1, January 2010:pg S4

35 Diagnostic considerations for GI symptoms in ASD  Sleep disturbance GERD GERD  Self-injurious behavior, tantrums, aggression, oppositional behavior Constipation Constipation GERD GERD Gastritis Gastritis Intestinal inflammation Intestinal inflammation  Chronic diarrhea (≥3 loose stools daily for >2 weeks) Malabsorption Malabsorption Maldigestion Maldigestion Taken from Table 2 Pediatrics Vol 125, Supplement 1, January 2010:pg S4

36 Diagnostic considerations for GI symptoms in ASD  Flatulence and/or bloating Constipation Constipation Lactose intolerance Lactose intolerance Enteric infection Enteric infection GiardiaGiardia CryptosporidiumCryptosporidium Taken from Table 2 Pediatrics Vol 125, Supplement 1, January 2010:pg S4

37 How does this happen?

38 Structural brain differences  Cortical connectivity Impaired ability to integrate information Impaired ability to integrate information  Facial perception problems Impaired social interaction Impaired social interaction  Imitation problems/Mirror neurons Contributes to learning delay Contributes to learning delay Contributes to disorders of communication and contact Contributes to disorders of communication and contact

39 Cortical connectivity  Corpus callosum smaller volumes: 24 boys with autism (10.0 +/- 3.3 yr) 24 boys with autism (10.0 +/- 3.3 yr) 26 control boys (11.0 +/- 2.5 yrs) 26 control boys (11.0 +/- 2.5 yrs) 3 Tesla MRI 3 Tesla MRI Localize regions of callosal thinning in autism 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 Aug 1;60(3):218-25

40 Cortical Connectivity  Significant ↓ Total callosal area Total callosal area Anterior 1/3 of the CC Anterior 1/3 of the CC Splenium and genu 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 Aug 1;60(3):218-25

41 Corpus Callosum

42 Cortical Connectivity  DTI and volumetric measurements of the total CC and subregions  Results: Significant differences Significant differences volume,volume, fractional anisotropyfractional anisotropy mean diffusivitymean diffusivity radial diffusivityradial diffusivity Alexander AL, Lee JE, Lainhart JE. Diffusion tensor imaging of the corpus callosum in Autism. Neuroimage Jan 1;34(1):61-73

43 Cortical Connectivity Group differences driven by a subgroup of the autism group Group differences driven by a subgroup of the autism group small corpus callosum volumessmall corpus callosum volumes ↑ mean diffusivity↑ mean diffusivity ↓ anisotropy↓ anisotropy ↑ radial diffusivity↑ radial diffusivity Significantly ↓ performance IQ measuresSignificantly ↓ performance IQ measures Alexander AL, Lee JE, Lainhart JE. Diffusion tensor imaging of the corpus callosum in Autism. Neuroimage Jan 1;34(1): Epub 2006 Oct 4.

44 Facial Perception  Hypoactive in autism Fusiform gyrus (FG) Fusiform gyrus (FG) Cortical regions supporting face processing 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 Apr;131(Pt 4):987-99

45 Facial Perception Significant ↓ Neuron densities layer III Association cortex Total neuron numbers layers III, V and VI Association cortex Sensory in from thalamus Cortical 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 Apr;131(Pt 4):987-99

46 Inability to imitate/Mirror neurons  EEG activity during videos showing actions or still scenes 14 right-handed children with autism 14 right-handed children with autism Mean age 5 years 3 monthsMean age 5 years 3 months 14 right-handed, age- and gender-matched typical children 14 right-handed, age- and gender-matched typical children Mean age 7 years 11 monthsMean 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 Apr;68(1):35-40

47 Inability to imitate/Mirror neurons  Results: Typical children: Desynchronization of the EEG with observation of human actions Typical children: Desynchronization of the EEG with observation of human actions motor cerebral cortexmotor cerebral cortex frontal and temporal areasfrontal and temporal areas With autism: No desynchronization With autism: No desynchronization Inversion of the pattern of hemispheric activation was found in autistic childrenInversion of the pattern of hemispheric activation was found in autistic children ↑ cortical activity RT hemisphere posteriorly, including the centro-parietal and temporo-occipital sites↑ 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 Apr;68(1):35-40

48 EEG Sample

49 Brain

50 Clues from other diseases with an autism phenotype

51 Fragile X Genetics FMR1 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 plasticityAffects synaptic plasticity Peng et al. RNA and microRNAs in fragile X mental retardation Nature Cell Biology 6, (2004) doi: /ncb

52 Fragile X Genetics FMR1 gene  AMPA receptor trafficking →driving process for synaptic plasticity Normal system, process learning and memory Normal system, process learning and memory Abnormal system, Abnormal system, problems with learning and memoryproblems with learning and memory LTP disruptionLTP 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 Fulfilling the Promise of Molecular Medicine In Autism. M. Bear*, MIT Presented IMFAR 2009.

53 mGluR5 antagonists Safety 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 UC Davis MIND Institute RUSH, University in Chicago 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 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.

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56 Neurofibromatosis 1 Neurofibromin  Functions as a tumor suppressor Kweh F, Zheng M, Kurenova E, Wallace M, Golubovskaya V, Cance WG. Mol Carcinog May 28  Neurofibromin deficiency Loss of regulation of signaling and intersecting pathways Loss of regulation of signaling and intersecting pathways  Acts on Actin cytoskeleton reorganization Actin cytoskeleton reorganization Cell motility and adhesion Cell motility and adhesion Larizza et al. Developmental abnormalities and cancer predisposition in neurofibromatosis type 1. Curr Mol Med Jul;9(5):634-53

57 NF 1 Neurofibromin

58 NF 1 Future 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 human NF1-MPNST mTOR pathway activation Inhibited explant growth in vivo Inhibited explant growth in vivo Without systemic toxicities 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 Jul 24

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

60 Rett disease mouse model  ↑ brain weight  Partially restores Spine density Spine density Synaptic amplitude Synaptic amplitude ↑ PSD-95 ↑ PSD-95 Stabilizes cortical plasticity to wild-type levels 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):

61 IGF-1 in Autism  Insulin-like growth factor-I (IGF-I) Role in early brain development. Role in early brain development.  IGF-I levels measured in the CSF of 11 children with autism 4 girls 4 girls 7 boys 7 boys Mean age 3.8 years Mean age 3.8 years  Compared levels in 11 control children 6 girls 6 girls 5 boys 5 boys mean age 3.8 years 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

62 Rare syndromes with ASD co-occurrence Syndrome ASD co-diagnosis Gene mutationCell 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; OpitzRas-mediated ERK signaling; PI3K signaling   Tuberous >40%–50% TSC1/TSC2PI3K/mTOR signaling Sclerosis   22q13 deletion >90% PDD-NOS MicrodeletionsMultiple   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 Apr;119(4):747-54

63 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  Other Adapted from GeneReviews, Copyright, University of Washington, Seattle

64 Phenotypic variables that may define discrete (ASD) subgroups  Morphology and growth Generalized dysmorphology 15–20% Generalized dysmorphology 15–20% Macrocephaly 35% Macrocephaly 35% Microcephaly 5–15% Microcephaly 5–15%  Brain malformations 20%  Medical/neurologic Seizures 25% Seizures 25% EEG abn 50% EEG abn 50% Sleep disorder 65% Sleep disorder 65% Adapted from Miles JH. Autism spectrum disorders—A genetics review. Genetics in Medicine, April 2011.

65 Phenotypic variables that may define discrete (ASD) subgroups  Savant skills 5%  Clinical course Age of onset Age of onset Regressive onset 30% Regressive onset 30%  Adolescent/adult catatonic regression 17% Adapted from Miles JH. Autism spectrum disorders—A genetics review. Genetics in Medicine, April 2011.

66 Phenotypic variables that may define discrete (ASD) subgroups  Significant family history of related disorders ASD 25% ASD 25% Alcoholism 30% Alcoholism 30% ADHD 70% ADHD 70% Affective disorders Affective disorders Bipolar/major affective disorder 30% Bipolar/major affective disorder 30% Adapted fromMiles JH. Autism spectrum disorders—A genetics review. Genetics in Medicine, April 2011.

67 Phenotypic variables that may define discrete (ASD) subgroups  Functionally defined variables IQ IQ Response to therapy Response to therapy Adaptive behaviors (unclear) Adaptive behaviors (unclear) Outcome measures (poorly defined/unclear) Outcome measures (poorly defined/unclear) Adapted fromMiles JH. Autism spectrum disorders—A genetics review. Genetics in Medicine, April 2011.

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69 Treatment  Behavioral therapy  Medical treatment of symptoms Sleep Sleep ADHD ADHD Aggression Aggression Anxiety Anxiety Obsessive compulsive tendencies Obsessive compulsive tendencies Epilepsy Epilepsy Constipation Constipation GERD GERD

70 Behavioral therapy  Mainstay of therapy  Consistently proven benefit

71 Medication Therapies  Start LOW and go SLOW  Trial and error  Caregiver participation Choices Choices Permission to STOP Permission to STOP Frequent appointments Frequent appointments  WITH BEHAVIORAL THERAPY

72 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

73 Conclusions  Behavioral therapy is the BEST intervention  Definitive medical therapy based on nerve cell functioning may be close


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