Multimodal CT Imaging in Acute Ischemic Stroke Dr Ferghal McVerry BA, MB, MRCP.

267 Pages·2014·2.69 MB·English

McVerry, Ferghal (2014) Multimodal CT imaging in acute ischemic
stroke. MD thesis.

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Glasgow Theses Service
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Multimodal CT Imaging in Acute
Ischemic Stroke

Dr Ferghal McVerry
BA, MB, MRCP.

A thesis which fulfills the requirements of the University of
Glasgow for the degree of Doctorate of Medicine

Institute of Neuroscience and Psychology
University of Glasgow
January 2014
2
Introduction
Options for imaging in acute stroke are expanding with the potential to select
therapy based on imaging targets, as well as providing additional diagnostic and
prognostic information. Multimodal CT has been used to image the ischemic
penumbra, infarct core, and to detect leptomeningeal collateral flow although
the optimum way to image these variables is not clear.
Methods
In addition to a systematic literature review of imaging for leptomeningeal
collaterals, Data from observational studies of acute stroke which employed
multimodal CT imaging on admission and follow up was used to evaluate
feasibility of acute stroke imaging with CT and MRI, Perfusion thresholds for core
and ischemic penumbra, methods to quantify leptomeningeal collateral flow and
sensitivity of non contrast CT for detecting infarct core pixels.
Results
Advanced imaging in acute stroke and at follow up was more feasible with CT
compared to MRI with the possible suggestion that imaging with MRI alone could
introduce a bias regarding age and clinical severity for patients entered into
clinical studies
Heterogeneity in grading and detecting collateral flow was found in the
literature providing an opportunity to devise a novel assessment method.
Well developed collaterals were associated with imaging and clinical markers for
good outcome as well as some potential biomarkers including atrial fibrillation
and blood fibrinogen level.
Relative cerebral blood flow and delay time were found to be the best
predictors on infarct core and ischemic penumbra after derivation of optimum
perfusion thresholds and subsequent validation in independent patient groups.
3
Pixel based comparison of infarct core on CT perfusion and non contrast CT
highlighted the lack of sensitivity of CT for detecting infarct core based on
Hounsfield unit value alone.
Conclusion
Multimodal CT for acute stroke assessment offers the potential for measuring
infarct core, ischemic penumbra and leptomeningeal collateral flow status
rapidly according to novel grading scales and thresholds and provides
information on tissue viability which cannot be detected on non-contrast CT.
Further evaluation on the impact additional imaging should have in clinical
practice is needed.
4
Table of Contents
Table of Contents .......................................................................... 4
Publications and Presentations.......................................................11
Author's declaration.......................................................................13
Chapter 1. Introduction ..................................................................16
1.1 Ischemic Stroke Pathophysiology.............................................17
1.1.1 The Ischemic Cascade ....................................................17
1.1.2 Evidence for Reversible and Permanent Ischemic Damage .........20
1.1.3 Normal Response to Ischemia ...........................................21
1.1.4 Identification of Penumbra in Humans with PET .....................22
1.1.5 Factors Affecting the Fate of the Penumbra..........................24
1.2 Treatment Options in Acute Ischemic Stroke...............................27
1.3 CT Imaging for Acute Stroke..................................................31
1.3.1 Non Contrast CT...........................................................31
1.3.2 CT Angiography............................................................33
1.3.3 CT Perfusion ...............................................................37
1.4 Magnetic resonance Imaging in Stroke ......................................45
1.4.1 DWI..........................................................................45
1.4.2 FLAIR........................................................................45
1.4.3 Gradient Echo Imaging ...................................................46
1.4.4 Magnetic Resonance Angiography.......................................47
1.4.5 Perfusion Weighted Imaging.............................................47
1.5 Conclusion.......................................................................48
Chapter 2. Collateral Circulation .......................................................49
2.1 Introduction .....................................................................49
2.2 The Cerebral Blood Supply....................................................49
2.3 The Circle of Willis.............................................................52
2.4 Leptomeningeal vessels........................................................54
2.4.1 Historical Context.........................................................54
2.4.2 Collateral Circulation in Animal Models of Stroke....................55
2.4.3 Collateral Therapeutics in Animal Stroke Models.....................59
2.4.4 Collateral Therapeutics in Human Stroke..............................60
2.5 Systematic Review of Methods for Assessing Leptomeningeal Collateral
Flow........................................................................................62
2.5.1 Methods.....................................................................63
2.5.2 Results......................................................................64
2.5.3 Discussion...................................................................84
2.5.4 Conclusion..................................................................90
Chapter 3. Materials and Methods ......................................................92
3.1 Introduction .....................................................................92
3.2 The Multicentre Acute Stroke Imaging Study (MASIS) .....................92
3.2.1 Data Recording and Transfer ............................................98
3.3 POSH- POst Stroke Hyperglycaemia..........................................99
3.4 Combined Studies Image Analysis...........................................103
3.4.1 Image Transfer, Anonymization and Storage.........................104
3.4.2 Image Analysis............................................................104
3.5 Conclusion......................................................................107
Chapter 4. Feasibility of Imaging Based Study Recruitment .......................109
4.1 Introduction ....................................................................109
4.2 Methods.........................................................................113
4.3 Results...........................................................................114
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4.3.1 Acute Imaging.............................................................118
4.3.2 Subacute Imaging.........................................................121
4.3.3 Day 30 Imaging............................................................121
4.4 Discussion.......................................................................122
4.4.1 Conclusion.................................................................127
Chapter 5. Quantifying Collateral Flow Extent in Acute Ischemic Stroke........128
5.1 Introduction ....................................................................128
5.2 Quantifying Collateral Flow Using Multimodal CT Imaging. .............130
5.3 Inclusion Criteria ..............................................................131
5.3.1 Clinical Data ..............................................................132
5.3.2 Image Analysis............................................................132
5.3.3 Collateral Flow Grade ...................................................138
5.3.4 Statistical Analysis .......................................................142
5.4 Results...........................................................................142
5.4.1 Collateral Flow and Outcome ..........................................153
5.5 Discussion.......................................................................163
5.6 Conclusion......................................................................169
Chapter 6. Derivation and Evaluation of Thresholds for Core and Tissue at Risk of
Infarction Using CT Perfusion...........................................................171
6.1 Introduction ....................................................................171
6.2 Materials and methods........................................................172
6.2.1 Patient selection.........................................................172
6.2.2 Image Acquisition ........................................................175
6.2.3 Image analysis ............................................................175
6.2.4 Derivation dataset image analysis.....................................177
6.2.5 Validation datasets image analysis ....................................181
6.2.6 Statistical analysis .......................................................182
6.3 Results...........................................................................183
6.4 Discussion.......................................................................193
6.5 Conclusion......................................................................197
Chapter 7. Pixel Based Identification of Infarct Core on Non-Contrast CT ......199
7.1 Introduction ....................................................................199
7.2 Materials and methods........................................................200
7.3 Results...........................................................................205
7.4 Discussion.......................................................................211
Chapter 8. Conclusion ...................................................................215
8.1 Summary........................................................................215
8.2 Clinical Importance and Future Research Considerations ...............215
8.3 Concluding remarks ...........................................................217
Appendices ................................................................................218
Gradient Echo.............................................................................219
DWI.........................................................................................220
Circle of Willis MRA ......................................................................220
Perfusion...................................................................................221
Post Contrast FLAIR ......................................................................222
List of References........................................................................223
6
List of Tables
Table 2-1 Assessment Methods for Measuring Collateral Flow Using Different
Modalities...................................................................................65
Table 2-2 Angiographically Defined Collaterals.......................................71
Table 2-3CT based Collateral Grading Methods CT based Collateral Grading
Methods.....................................................................................79
Table 2-4MRI Based Collateral Assessments...........................................83
Table 2-5 Original and Modified TIMI and TICI Scales................................87
Table 3-1 MASIS Study Calendar.........................................................98
Table 3-2 POSH Study Calendar ........................................................103
Table 4-1 Recruitment Rates of Trials and Observational Studies of Thrombolysis
using CT or MRI ...........................................................................111
Table 4-2 Screening Failures for Study Participation in MASIS.....................117
Table 4-3 Comparison of Clinical Characteristics Between Patients Imaged Using
CT or MRI on Admission for MASIS......................................................120
Table 5-1 Baseline Clinical Characteristics of Subjects with Good and Reduced
Collaterals.................................................................................145
Table 5-2 Collateral Status and Associated Imaging Findings on Admission .....149
Table 5-3 Univariate Logistic Regression Summary..................................153
Table 5-4 Collateral Flow and Clinical Outcome.....................................155
Table 5-5 Clinical and Imaging Factors Associated with Clinical Outcome ......158
Table 5-6 Univariate Logistic Regression Analysis Summaries for Clinical Outcome
Prediction (Modified Rankin Scale ≤2 at one month.................................162
Table 6-1 Perfusion Parameter Ranges and Increments Evaluated for Tissue at
Risk.........................................................................................179
Table 6-2 Perfusion Parameter Range and Increments Evaluated for Core......179
Table 6-3 Characteristics of Tissue at Risk Evaluation Group......................184
Table 6-4 Clinical Characteristics of Infarct Core Groups..........................189
Table 7-1 Sensitivity and Specificity of HU Thresholds for Detecting Infarct Core
in Grey Matter ............................................................................210
Table 7-2 Sensitivity and Specificity of HU Thresholds for Detecting Infarct Core
in White Matter...........................................................................210
7
List of Figures
Figure 1-1 Cascade of Damaging Events in Cerebral Ischemia......................20
Figure 1-2 Consequences of Reduced Cerebral Perfusion Pressure ................22
Figure 1-3 Interaction Between CBF Threshold for Infarction and Time..........25
Figure 1-4 NCCT, CTA MIP and CTA-SI in patient with right MCA occlusion.......37
Figure 1-5 The Maximal Slopes Method.................................................40
Figure 1-6 The Impulse Residue Function..............................................41
Figure 2-1 Anatomy of the Middle Cerebral Artery...................................51
Figure 2-2 Illustration of Collateral Scoring Based on Catheter Angiography.....68
Figure 2-3 Hyperintense Vessels on FLAIR. ............................................81
Figure 3-1 MIStar Interface..............................................................107
Figure 4-1 Flowchart for Recruitment to MASIS Study ..............................116
Figure 4-2 Imaging Acquired at Each Study Timepoint..............................122
Figure 5-1 DT Summary Map with ROI Measuring Pixels with DT>2 Seconds.....134
Figure 5-2 Fusion Tool Before and After Co-registration ...........................136
Figure 5-3 Reformatted Structural Image After Co-Registration ..................137
Figure 5-4 4D Angiography Demonstrating Retrograde Collateral Flow ..........139
Figure 5-5 CTA After Application of High-Low HU Threshold ......................141
Figure 5-6 Flowchart for Inclusion in Collateral Flow Evaluation .................143
Figure 5-7 Collateral Status and NIHSS................................................146
Figure 5-8 Collateral Grade and Fibrinogen Level...................................146
Figure 5-9 Collateral Grade and Atrial Fibrillation..................................147
Figure 5-10 Collateral grade and Volume with DT ≥ 2 Seconds....................150
Figure 5-11 Collateral grade and Volume with DT≥ 4 seconds.....................150
Figure 5-12 Collateral grade and DT≥ 6 seconds.....................................151
Figure 5-13 Collateral grade and DT≥ 8 Seconds.....................................151
Figure 5-14 Collateral grade and Infarct Core Volume..............................152
Figure 5-15 Collateral Grade and Penumbra Volume................................152
Figure 5-16 Collateral Grade and Infarct Volume....................................156
Figure 5-17 Collateral Grade and Infarct Growth....................................156
Figure 5-18 Admission NIHSS and Outcome...........................................159
Figure 5-19 24hr NIHSS and Outcome..................................................159
Figure 5-20 Infarct Volume and Clinical Outcome..................................160
Figure 5-21 Proportion Penumbra Salvage and Clinical Outcome.................160
Figure 5-22 ASPECTS Score on CBV Maps and Clinical Outcome...................161
Figure 5-23 ASPECTS Score on NCCT and Clinical Outcome........................161
Figure 5-24 Collateral Flow and Clinical Outcome ..................................162
Figure 6-1 ROI Surrounding Final Infarct Volume....................................177
Figure 6-2 Penumbragram with Infarct ROI...........................................180
Figure 6-3 True & False Positive/Negative Pixels....................................181
Figure 6-4 Effect of Varying Perfusion Threshold on Sensitivity and Specificity183
Figure 6-5 Youden’s Index for Each Perfusion Threshold Evaluated for Tissue at
Risk.........................................................................................185
Figure 6-6 Frequency Distribution for Optimum DT, Relative MTT and Absolute
MTT Thresholds for Tissue at Risk......................................................186
Figure 6-7 Bland Altman Plot for DT >2 Seconds, Relative MTT 145 %, Relative
MTT 125 % and Absolute MTT 7 Seconds for Detecting Tissue at Risk ............187
Figure 6-8 Youden’s Index for Each Perfusion Threshold Evaluated for Core ...190
Figure 6-9 Frequency Distribution for Optimum Relative (A) and Absolute (B) MTT
Thresholds for Core ......................................................................191
Figure 6-10 Bland Altman Plot for Relative CBF ≤45%, Absolute CBV 2ml/100g,
Absolute MTT> 8 Seconds, and Relative MTT125%, for Detecting Infarct Core..192
Figure 7-1 Core Grey & White Matter Segmentation................................202
8
Figure 7-2 ROC Curve for Presence of Grey Matter Core Pixels on CT............206
Figure 7-3 ROC curve for presence of White Matter core pixels on CT...........207
Figure 7-4Frequency Distribution for Grey Matter Cut Points .....................208
Figure 7-5 Frequency Distribution for White Matter Cut Points ...................209
9
Acknowledgments

This thesis, along with my training in stroke medicine was made possible by the
help of my supervisor Professor Keith W. Muir to whom I will be forever grateful. I
was given every opportunity during my fellowship to ask questions, explore areas
of particular interest and was given lots of encouragement and helpful advice. The
skills learnt during this time are invaluable both academically and clinically, and for
his role as a supervisor I owe Professor Muir a debt of gratitude.
In addition I acknowledge the support of the other members of the acute stroke
team based at the Southern General Hospital; Dr Tracey Baird, Dr Ian Reeves, Dr
George Duncan, Dr Phil Birschel, Dr Julie McManus, Dr Fozia Nazir, and Dr
Margaret Roberts from whom I learnt a great deal in acute stroke management
and who welcomed me into the acute stroke team. The radiography and Nursing
staff were excellent in facilitating the research projects. Dr Evelyn Teasdale and Dr
Celestine Santosh were sources encouragement and set an example for work
ethic and attention to detail in stroke imaging.
My research colleagues Dr Niall MacDougall and Dr Krishna Dani are good friends
and provided excellent insights into acute stroke research and imaging, and both
made me feel welcome in Glasgow. Christine Aiken, Sandra Greenshields, Angela
Welch, Sally Baird and Wilma Smith were always sources of assistance. Dr Mark
Parsons was a welcoming host during my visiting fellowship to the John Hunter
Hospital, Newcastle Australia and provided excellent training and insight into
image analysis in stroke.
I am grateful to both the Translational Medicine Research Collaboration and
Chest Heart and Stroke, Scotland for providing funding for my fellowship and
conference attendances.
I also wish to express thanks to Professor Jean-Claude Baron and Professor I
Mhairi Macrae for taking the time to examine the manuscript and for helpful
suggestions on how to improve it following the viva examination.
Finally I must acknowledge my family, my parents who were always at hand to
help out especially when travelling over and back from Glasgow, and in