Improving Acute Stroke Management with CT Perfusion Imaging

285 Pages·2017·5.78 MB·English

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Christopher D. d'Esterre, The University of Western Ontario
Supervisor: Dr. Ting-Yim Lee, The University of Western Ontario
A thesis submitted in partial fulfillment of the requirements for the Doctor of Philosophy degree
in Medical Biophysics
© Christopher D. d'Esterre 2013
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d'Esterre, Christopher D., "Improving Acute Stroke Management with CT Perfusion Imaging: Approaches
to Treatment Guidance and Brain Tissue Salvage" (2013). Electronic Thesis and Dissertation Repository.
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IMPROVING ACUTE STROKE MANAGEMENT WITH
CT PERFUSION IMAGING:
APPROACHES TO TREATMENT GUIDANCE AND BRAIN TISSUE SALVAGE

(Thesis format: Integrated-Article)

by

Christopher D. d’Esterre

Graduate Program in
Medical Biophysics

A thesis submitted in partial fulfilment
of the requirements for the degree of
Doctor of Philosophy

The School of Graduate and Postdoctoral Studies
The University of Western Ontario
London, Ontario, Canada

 Christopher D. d’Esterre 2013
ABSTRACT

CT Perfusion (CTP) provides measurement of perfusion at the capillary level which can
be used to characterize tissue viability, and blood-brain-barrier (BBB) compromise. Using
CTP, the goals of this research are to: 1) select patients that will benefit from acute stroke
treatment, and 2) determine if pre-stroke neuroprotection reduces stroke severity.
Chapter two investigates the cerebral blood volume (CBV) parameter in a small
acute ischemic stroke (AIS) patient set. Overestimation of the acute CBV defect is caused
by incomplete wash-out of the CT contrast due to a shortened CTP acquisition time
(“truncation artifact”).
In chapter three we examine the prognostic reliability of the acute CBV defect to
predict infarct core and penumbra in AIS. We determine that hypervolemia, the
“truncation artifact” and recanalization are all important variables which affect the
relationship between the acute CBV defect volume and the final infarct volume.
Chapter four implements a novel porcine model of ischemic stroke using the
transient vasoconstrictor, endothelin-1. Using this model, we show that the CTP-cerebral
blood flow (CBF) parameter is as good as MR-DWI for acute infarct core delineation,
and the CBF/CBV mismatch may not indicate penumbral tissue in the acute stroke
setting.
In Chapter five, it we show that vascular integrity measured with the CTP-BBB
permeability surface area product (PS) is a strong predictor of sub-acute bleeding in the
brain (hemorrhagic transformation).
Chapter six shows that different rates of CT contrast extravasation exist for
primary intracerebral hemorrhage (ICH) patients with/without the CTA-Spot Sign and/or
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post-contrast leakage. Furthermore, early rates of extravasation are correlated with sub-
acute hematoma expansion.
Chapter seven describes the development of an improved, reproducible and
survivable rabbit large clot embolic model (RLCEM) of cerebral ischemia for testing
treatment options for AIS. We demonstrate that pre-stroke treatment with dipyridamole
provides a neurovascular advantage post stroke onset.
In summary, the current uses of CTP imaging in acute stroke include: 1)
quantifying ischemia to define infarct core and penumbra in AIS, 2) predicting
hemorrhagic transformation of AIS, 3) predicting hematoma expansion in primary ICH,
and 4) assessing treatment response in animal models of stroke to facilitate new drug
development.

Keywords:
Stroke, CT Perfusion, cerebral ischemia, primary cerebral hemorrhage, secondary
hemorrhagic transformation, cerebral blood flow, cerebral blood volume, infarction,
hematoma expansion, animal stroke model, primary stroke treatment, tPA

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CO-AUTHORSHIP

Chapter two has been adapted from the original research manuscript entitled “The
evolution of the cerebral blood volume abnormality in patients with ischemic stroke: a CT
perfusion study”, published in Acta Radiologica 53(4):461-7, May 2012, by: C.D.
d’Esterre, R.I. Aviv, T.Y. Lee. I was responsible for the study design, analyzing and
interpreting the data, and writing the manuscript under the supervision of T.Y. Lee. R.I.
Aviv recruited the patients, collected data, and helped with editing the manuscript.
The contents of chapter three have been adapted from the original research
manuscript entitled “Reliability of the cerebral blood volume parameter in ischemic
stroke”, reviewed and re-submitted to the journal Neuroradiology by: C.D. d’Esterre,
T.Y. Lee, S. Ceruti, G. Roversi, A. Saletti, E. Fainardi. T.Y. Lee and E. Fainardi were
responsible for the study design and editing the manuscript. I was responsible for
analyzing and interpreting the data, and writing the manuscript under the supervision of
T.Y. Lee. The remaining authors helped with recruiting patients, collecting data, and
editing the manuscript.
Chapter four has been adapted from the original research manuscript submitted to
Stroke in April 2013. The manuscript is entitled “Multi-modality neuroimaging in a
porcine model of endothelin-1 induced cerebral ischemia: defining the acute infarct core”,
by: C.D. d’Esterre, U. Anazodo, K. St. Lawrence, L. Morrison, T.Y. Lee, E. Fainardi. I
designed the study with T.Y. Lee and E. Fainardi. I was responsible for performing the
experiments, with help from U. Anazodo, L. Morrison and K. St. Lawrence. I also
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collected and analyzed all data and wrote the manuscript under the supervision of T.Y.
Lee. T. Y. Lee and E. Fainardi reviewed and edited the manuscript.
Chapter five has been adapted from the original research manuscript entitled
“Hemorrhagic transformation of ischemic stroke: prediction with CT perfusion”
published in Radiology 250(3):867-77, in March 2009, by: R.I Aviv, C.D. d’Esterre, B.D.
Murphy, J.J. Hopyan B. Buck, G. Mallia, V. Li, L. Zhang, S.P. Symons, T.Y. Lee. T.Y.
R.I. Aviv and I contributed equally to this manuscript. Lee and R.I Aviv were responsible
for the study design and manuscript editing. I was responsible for analyzing all data,
under the supervision of R.I Aviv and T.Y. Lee. G. Mallia helped with the statistical
analysis and manuscript writing, while the remaining authors helped with patient
recruitment, collecting data, and provided assistance with manuscript preparation.
Chapter six has been adapted from the original research manuscript entitled “Early
rate of contrast extravasation in patients with intracerebral hemorrhage” published in the
American Journal of Neuroradiology, 32(10):1879-84, November 2011 by: C.D.
d'Esterre, T. Chia, A. Jairath, T.Y. Lee, S.P. Symons, R.I. Aviv. T.Y. Lee and R.I. Aviv
were responsible for the study design and manuscript editing. I was responsible for
analyzing the data and writing the manuscript, under the supervision of T.Y. Lee and R.I
Aviv. The remaining authors helped with the design of the study, recruited patients,
collected data, and provided assistance with the manuscript preparation.
Chapter seven has been adapted from the original research manuscript entitled
“Dipyridamole treatment prior to stroke onset: examining post-stroke cerebral circulation
and outcome in rabbits”, published in Translational Stroke Research, 2: 186-194, January
2011, by: C.D. d’Esterre, K.M. Tichauer, R.I. Aviv, L. Morrison, W. Eisert, T.Y.. Lee.
T.Y. Lee and W. Eisert were responsible for designing the study and reviewing the
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manuscript. I developed the experimental procedures for the stroke model and collected
all data, with the help from L. Morrison. I was responsible for data analysis and
interpretation and manuscript writing and editing. The remaining authors helped with the
design of the study and provided assistance with the manuscript preparation.

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EPIGRAPH

“Sometimes life's so much cooler when you just don't know any better and all the painful
lessons haven’t hammered your head open yet.”

-Anthony Kiedis

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DEDICATION

To my Mother,
I couldn’t have done this without you.
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ACKNOWLEDGEMENTS

The work contained within this thesis was accomplished with the help of a number of
individuals. I would like to thank my supervisor, Dr. Ting-Yim Lee, for his leadership,
support and friendship throughout my graduate school career. His passion for research and
experimental creativity and prowess has truly been an inspiration. I would also like to
thank the members of my advisory committee, Dr. Keith St. Lawrence and Dr. David
Cechetto.
I would like to thank my collaborators, Dr. Richard Aviv of Sunnybrook Health
Science Centre and Dr. Enrico Fainardi from the University of Ferrara. Despite their busy
clinical schedules, they were always available for valued discussions and guidance. Their
friendship, professional and personal, will have a lasting impression on my career.
My utmost gratitude goes out to Anne Leaist – her tireless work-ethic and
meticulous devotion to the group has truly been appreciated. Special thanks to the “Lee
Lab Ladies” – Jennifer Hadway, Laura Morrison, and Lise Desjardins. Their dedication
and enthusiasm was the key to my successful experiments.
I would like to thank my friends, especially my roommates at “The 172”, and also
my teammates from the UWO cross country and track teams. Finally, I would like to thank
my mother and brother for their encouragement.

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