This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: • This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. • A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. • This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. • The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. • When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. PATHOPHYSIOLOGY OF LACUNAR STROKE: ISCHAEMIC STROKE OR BLOOD BRAIN BARRIER DYSFUNCTION? EMMA LOUISE BAILEY BSc Hons Doctor of Philosophy University of Edinburgh 2011 CONTENTS Acknowledgements .....................................................................................................i Declaration ...............................................................................................................iii Publications ………………………………………………………………………..iv List of figures ………………………………………………………………………v List of tables …………………………………………………………………….....xi Abstract ……………………………………………………………………………xiv List of abbreviations ………………………………………………………………xvi CHAPTER 1 :GENERAL INTRODUCTION........................................................ 1 1.1 Stroke – why is it important?.............................................................................. 1 1.1.1 Disability and recurrence ............................................................................ 1 1.1.2 What constitutes a stroke?........................................................................... 1 1.2 Anatomy of stroke................................................................................................ 2 1.2.1 The cerebral blood supply........................................................................... 2 1.2.2 Autoregulation............................................................................................. 3 1.3 The effect of ischaemia on different vascular territories determines the clinical classification of stroke subtypes................................................................... 4 1.4 Lacunar Stroke..................................................................................................... 6 1.4.1 Clinical Syndromes ..................................................................................... 6 1.4.2 Prognosis..................................................................................................... 7 1.4.3 Risk Factors................................................................................................. 7 1.4.4 Brain and vascular territory......................................................................... 7 1.5 The appearance of acute lacunar lesions on imaging (see figure 1.4). .......... 10 Doctor of Philosophy University of Edinburgh 1.5.1 Cavitation of lacunar lesions..................................................................... 11 1.6 The wider implications and features of disease in the small deep perforating arterioles.................................................................................................................... 12 1.7 General Pathophysiology................................................................................... 13 1.7.1 Parenchymal lesions.................................................................................. 13 1.7.2 Vascular pathology.................................................................................... 14 1.8 What causes lacunar stroke? Evidence for a distinct arteriopathy............... 16 1.9 The problems of studying lacunar stroke pathology. ..................................... 17 1.9.1 Why would an animal model be useful?................................................... 18 1.10 Systematic Reviews – the value of and design ............................................... 19 1.11 Aims of the thesis.............................................................................................. 20 CHAPTER 2 : HUMAN LACUNAR STROKE PATHOLOGY – A SYSTEMATIC REVIEW........................................................................................ 21 2.1 Background......................................................................................................... 21 2.2 Materials and methods ...................................................................................... 21 2.2.1 Search strategy .......................................................................................... 21 2.2.2 Inclusion/Exclusion criteria ...................................................................... 22 2.2.3 Data extraction .......................................................................................... 22 2.2.4 Study quality ............................................................................................. 23 2.2.5 Data analysis ............................................................................................. 24 2.3 Results ................................................................................................................. 25 2.3.1 Search results ............................................................................................ 25 2.3.2 Study characteristics.................................................................................. 25 Doctor of Philosophy University of Edinburgh 2.3.3 Pathological assessments .......................................................................... 32 2.3.4 Terminology and definitions..................................................................... 32 2.3.5 Study quality score.................................................................................... 32 2.3.6 Pathological findings................................................................................ 33 2.3.7 Vascular lesions ....................................................................................... 36 2.4 Discussion............................................................................................................ 39 2.4.1 Strengths & weaknesses of the review and primary studies: .................... 40 2.4.2 Interpretation............................................................................................. 41 2.5 Conclusion........................................................................................................... 42 CHAPTER 3 : A SYSTEMATIC REVIEW OF POTENTIAL ANIMAL MODELS OF LACUNAR STROKE. .................................................................... 43 3.1 Background......................................................................................................... 43 3.2 Materials and Methods...................................................................................... 43 3.2.1 Study Identification................................................................................... 43 3.2.2 Search Strategy.......................................................................................... 44 3.2.3 Inclusion and Exclusion Criteria............................................................... 44 3.2.4 Data Extraction.......................................................................................... 45 3.2.5 Study Quality Assessment ........................................................................ 45 3.3 Results ................................................................................................................. 46 3.3.1 Methodological characteristics of included studies .................................. 46 3.3.2 Lesion induction methods ......................................................................... 49 3.4 Discussion............................................................................................................ 55 3.5 Conclusion........................................................................................................... 58 Doctor of Philosophy University of Edinburgh CHAPTER 4 : THE SPONTANEOUSLY HYPERTENSIVE STROKE PRONE RAT AS A MODEL OF SUBCORTICAL ISCHAEMIC STROKE. A SYSTEMATIC REVIEW........................................................................................ 59 4.1 Background......................................................................................................... 59 4.2 Materials and Methods...................................................................................... 60 4.2.1 Search strategy .......................................................................................... 60 4.2.2 Data extraction .......................................................................................... 60 4.2.3 Study quality ............................................................................................. 60 4.3 Results ................................................................................................................. 61 4.3.1 The available literature.............................................................................. 61 4.3.2 Study methodology ................................................................................... 63 4.3.3 Structural Pathological Findings - Brain parenchyma (Figure. 4.4):........ 65 4.3.4 Structural findings: Vessels (Figure 4.5.) ................................................