Autism or Autisms?

9/30/2015
Conflict of Interest
AUTISM OT AUTISMS: WHAT SHOULD BE
OUR DEFAULT POSITION?
Autism Research Institute Webinar
September 30, 2015
Manuel F. Casanova, M.D.
SmartState Endowed Chair in Childhood
Neurotherapeutics
Greenville Health System
Autism of Autisms?
How many are there?
• Neuronetics (TMS platform), Neuronetrix
Incorporated, Clearly Present Foundation
• Pfizer, Eisai, Nycomed Amersham, Aventis
Pasteur Limited, Medvantis Medical Service
• Council of Health Care Advisors for the
Gerson Lehrman Goup
• Royalties: Springer, Nova, Taylor and Francis,
John Wiley
Autism or Autisms?
Robert Schultz has said “If you’ve seen one child with
autism, you’ve seen one child with autism. Autism’s like
a snowflake”
Diverging counts: Tanguay, Edelson, Amaral’s Phenome Project
Rethinking Autism
Researchers “should be hunting for what is similar, for the
unifying characteristic [of autism]” Margaret Bauman
• Autism should not be considered a set of
discrete disorders, but rather, a continuous
range of individually rare conditions. Holt
and Monaco, 2011
• The concept of autism as a unitary
disorder resulting from a common cause is
close to being abandoned. Boucher, 2011
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Autism or Autisms?
Falsifiability of Diagnosis
The Null Hypothesis: Pyramidal
Cells and Interneurons
Triple Hit Hypothesis
Autism is a severe pervasive
developmental disorder of
childhood characterized by:
Disturbances of social
interaction
A delay or failure to acquire
verbal and non-verbal
communicative skills, and
Restricted and/or stereotyped
patterns of interests, activities,
and behaviors.
Karl Popper (1902-1994)
Yokota et al., PLoS One, 2007
Autism or Autisms: What it is Not
Casanova, Brain Pathol, 2007
Purkinje Cell Counts
Boy with no CNS
pathology
Autistic boy
.
Coronal section through the human brain
Cerebellum in Autism
(A) control patient; (B–C) atrophic folia and marked loss of Purkinje and granular cells
in the cerebellum of an autistic patient (H&E stain); (D) microglia activation seen with
anti-MHC class II immunostaining
Ritvo et al., Am J Psychiatry, 1986
Autism Comorbidities
Some reported brain abnormalities in autism may reflect the effect of comorbidities.
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Gliotic (Repair) Reaction in Autism
Postmortem Brain Tissue
•
A recent survey (7/20/07) of material collected by the Autism Tissue Program
(ATP) showed 35 autistic patients. Eleven of these patients drowned (31.4% of
total, PMI 21.0+12hrs), 1 stated no cause of death, and 23 died from diverse
causes (PMI 23.7+16.7 hrs) including seizures, circulatory failure, sepsis, anoxic
encephalopathy, and acute respiratory distress. Of the eleven drowning victims 3
were missing medical history and autopsy findings, 2 received CPR and survived
for an indeterminate amount of time.
Vargas et al., Ann Neurol 2005; 57: 67-81
Patches of disorganized cortex in autism
Stoner et al.,
NEMJ, 2014
Some reported brain abnormalities in autism
may reflect the way an individual died.
Postmortem Brain Tissue
•
“…the possibility that the patches are mere artifacts arising focally in the
tissue after death is far from excluded. In fact, it is well known that RNA
degrades rapidly in postmortem tissue.” Robert Hevner, MD, 2014
The Null Hypothesis: Pyramidal
Cells and Interneurons
Triple Hit Hypothesis
“…it was very disappointing to discover that the majority of the brain
samples showed extensive degradation and that no meaningful
conclusions could be drawn from the experiments. If we had not decided
to perform the autoradiography and the hemalum staining after the
Western blot experiments, we would have not been aware that we were
working with degraded tissue samples. Several research groups received
the same brain samples that we got and because they did not perform
brain sections, they did not realize the problem with the tissue quality and
went on to publish their findings.” Catalina Betancur and Salah El
Mestikawy, Universite Pierre et Marie Curie, Paris France, ATP Report,
2010.
Yokota et al., PLoS One, 2007
Casanova, Brain Pathol, 2007
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Neuroarcheology
Heterotopias in Autism
Syndromic and Idiopathic Types
o “Heterotopias” are
malformative lesions
comprised of “normal” cells
in the wrong location.
o Studies in autism suggest a
defect in radial migration
involving: 1) its onset out of
their precursor field, and, 2)
ongoing migration through
the white matter
(intermediate zone).
Casanova, Handbook of Autism, 2013
Sarnat, 2006
Rakic, Cereb Cortex, 2003
Neuropathological and clinical manifestations
associated with subependymal and subcortical
heterotopias
• Cortical malformations, e.g.
schizencephaly
• Gyral malformations, e.g.
polymicrogyria
• Changes in brain size
• Enlarged ventricles
• Seizures, often intractable
• Mental retardation
• Developmental delays
• Dyslexia
•
•
•
•
•
Schizophrenia
Schizoaffective disorder
Major depression
Anxiety disorders
Attention deficit
hyperactivity disorder
(ADHD)
• Obsessive compulsive
disorder
• Self-injurious behaviors
• Autism spectrum disorders
The subplate in autism
Hutsler and Casanova, 2015
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Cortical Modularity in
History
Minicolumn Method
GLI Method
Brodmann, 1909
Schlapp, 1898
“All elements of the cortex are represented in it, and therefore it may
be called an elementary unit, in which, theoretically, the whole
process of transmission of impulses from the afferent fibers to the
efferent axon may be accomplished.” Lorente de Nȯ (1938)
Casanova, 2005
Wider minicolumns in autism: a neural basis for altered processing?
McKavanagh et al., Brain 138:2034-45, 2015
Casanova et al., Neurology, 2002
Casanova et al., J Child Neurol, 2002
Minicolumns in Autism
• The [minicolumnar] findings depend on the age of the individual.
In other words, when the data from studies are compared while
accounting for subject age, they suggest that minicolumns are
wider in youth in autism but then become narrower in later life.
This is interesting because it is consistent across the studies and
reinforces that autism as a developmental condition which changes
across the lifespan. It also makes sense in the light of other MRI
studies which have shown larger brains in ASD in early life,
followed by a loss of this enlargement later on.
Steven Chance, autismsciencefoundation.wordpress.com
Minicolumnar Width by Lamina in
Autism and Controls
Casanova, Brain Pathology 2008
Shower Curtain of Inhibition
Szentágothai & Arbib, Neurosci Res Program Bull, 1974
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Information (Neuronal Activity) and Background
The Null Hypothesis: Pyramidal
Cells and Interneurons
Yokota et al., PLoS One, 2007
Triple Hit Hypothesis
Casanova, Brain Pathol, 2007
Locus Minoris Resistentiae
The End
Brain findings in autism are highly suggestive of a migrational abnormality. This is a
medical condition that deserves more research and whose patients would benefit from
treatment when the same is necessary (e.g., seizures, mood disorders).
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