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
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 months
Shinnar 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;17:169-74
Tuchman and Rapin. Lancet Neurol. 2002;1:352-58
Danielsson 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



Stereotypic behavior predicated by



↑ autism scores
Social skills deficits
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


Self-injurious behavior, tantrums, aggression,
oppositional behavior





GERD
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

Impaired ability to integrate information
 Facial

connectivity
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 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. 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 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 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 Genetics
FMR1 gene

AMPA receptor trafficking →driving process for
synaptic plasticity


Normal system, process learning and memory
Abnormal system,
• problems with learning and memory
• LTP disruption
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.
↓ mGluR5 signaling can reverse fragile X sx
 Potential treatment with mGluR5 antagonists

Fulfilling the Promise of Molecular Medicine In Autism. M.
Bear*, MIT Presented IMFAR 2009.
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
• 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 1
Neurofibromin

Functions as a tumor suppressor
Kweh 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 1
Neurofibromin
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 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)


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




Role in early brain development.
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
Angelman
>50%
UBE3A (maternal)
Down syndrome >5%–15%
Chromosome 21
triplication
Fragile X
>45%–70%
FMR1
Neuro>4%A
NF1/NF2
fibromatosis
Macrocephaly >75%
PTEN
Potocki-Lupski >90%
17p duplications
Rett
>50%
MECP2
Smith-Lemli>50%–75%
DHCR7
Opitz
Tuberous
>40%–50%
Sclerosis
22q13 deletion >90% PDD-NOS
Timothy
>75%
Cell function References
Protein degradation
Multiple
RNA trafficking
PI3K signaling activity
TSC1/TSC2
PI3K signaling activity
Unknown
Transcriptional regulation
Cholesterol biosynthesis;
Ras-mediated ERK
signaling; PI3K
signaling
PI3K/mTOR signaling
Microdeletions
CACNA1C
Multiple
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
Other
Adapted 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