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Stroke is the third most common cause of death in the developed world.  Stroke results from cerebral ischaemia and leads to neuro-glial cell death.  Cell death is induced by a cascade of events and potently stimulates a potentially deleterious inflammatory response.  The inflammation is driven by cytokine release; one of the major cytokines involved being interleukin-1.  IL-1<span lang=EN-US style='font-family:Symbol'>b, which is implicated in ischaemic brain damage, is converted from its inactive form by caspase-1. In this study the IL-1 pathway in ischaemic brain damage was manipulated with the endogenous IL-1 antagonist, IL-1 receptor antagonist (IL-1ra) and with the caspase-1 inhibitor RU36384.  As a preliminary step the induction of transient cerebral ischaemia with the filament technique of middle cerebral artery occlusion (tMCAo) in rats was characterised, and found to be reproducible.  Administration of IL-1ra (10<span lang=EN-US style='font-family:Symbol'>mg) into the lateral cerebral ventricle (icv) at ischaemia and reperfusion resulted in a 43% reduction in total lesion volume.  This effect was also obtained by administering (20<span lang=EN-US style='font-family:Symbol'>mg) at later time points out to 3h after the initiation of ischaemia (41% reduction).  After independently confirming the effects of RU36384 on IL-1<span lang=EN-US style='font-family:Symbol'>b processing <i>in vitro.  </i>RU36384 was administered to rats icv after tMCAo and reduced ischaemic lesion volume when compared to control in a dose dependent fashion.  Administration of 5<i>, </i>10, 20 and 40<span lang=EN-US style='font-family:Symbol'>mg at ischaemia and reperfusion resulted in reductions of 37%, 46%, 65%<i> </i>and 40% respectively.  This effect was sustained out to 3h after the initiation of ischaemia but lost by 6h.  Administration of RU36384 did not alter cardiorespiratory variables or core body temperature when compared to control animals. These data implicate IL-1 as an important mediator of cell death after cerebral ischaemia and indicate that its therapeutic manipulation may have a role in the clinical arena.

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. 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.

Previous studies have highlighted the importance of understanding the subjective illness experience. Stroke, as the second highest cause of death and highest cause of adult morbidity internationally, is no exception. However, the research to date has significant gaps. Lay understandings of stroke in low and middle income countries remain poorly understood, and very few studies have explored the links between experience and the context in which they occur. These gaps in knowledge have resulted in insufficient attention being paid to the relevance of local contexts in the implementation of international and regional recommendations for stroke. The study presented in this thesis explores the experience of stroke in Central Aceh, Indonesia. It drew on phenomenology and ethnography and used a range of qualitative methods. People with stroke and their carers were involved in the examination of stroke understandings, its causation and mechanism, the impact of stroke on their lives, and actions taken to remediate the symptoms. This information was complemented with an in-depth study of healers, within the context of the health systems through which they operate. Further information on current social, religious and cultural practices was gathered through participant observation. The study revealed that lay understandings occurred within a range of explanatory models. Also highlighted was the complex relationship between the understanding of the condition, the impact on the family, and the health seeking behaviour. All were influenced by the specific context and an attempt to regain a homeostatic balance in life; within the person, with others, and with the supernatural. The results of this study demand critical interrogation of the international guidelines both for stroke and for policies to promote access to health personnel at the primary care level.

Stroke is a global health concern, with a significant impact on mortality and disability. Motor impairment, including upper limb impairment is particularly common following stroke. Upper limb impairment impacts on an individual’s ability to complete activities of daily living and quality of life. Effective interventions targeted at upper limb recovery are therefore important and further research, within this area, has been identified as necessary. However, challenges researching such complex interventions have been recognised. To attempt to overcome such difficulties the Medical Research Council (MRC) proposed a framework for the development and evaluation of RCTs for complex interventions. In this thesis the MRC framework has been used, focusing on the processes of developing and feasibility/piloting, to provide information for a phase III randomised controlled trial (RCT) of a novel intervention targeted at upper limb recovery following stroke. A systematic review and meta-analysis was undertaken to investigate and clarify any possible association between predictive variables and upper limb recovery. Observational studies of stroke patients investigating at least one predictive variable and its relationship with a defined measure of upper limb recovery at a future time point were included. For this review data analysis combined several approaches. Fifty eight studies were included and 41 predictor variables identified. Initial measures of upper limb function and impairment were found to be the most significant predictors of upper limb recovery; odds ratio (OR) 38.62 (95% confidence interval (CI) 8.40-177.55) and OR 14.84 (95% CI 9.08-24.25) respectively. Neurophysiological factors (motor evoked potentials and somatosensory evoked potentials) were also consistently identified as strongly associated with upper limb recovery; OR 11.76 (95% CI 2.73-69.05) and OR 13.73 (95% CI 2.73-69.05) respectively. Moderate evidence of association was found for global disability and lower limb impairment. Interpretation of results is complicated by methodological factors, particularly relating to the heterogeneous nature of the included studies. In order to identify interventions which show potential for reducing impairment and/or improving upper limb function after stroke, an overview of the available evidence was completed. This systematic review and meta-analysis included Cochrane systematic reviews, other reviews and, where necessary, additional RCTs of interventions to promote upper limb recovery. Thirteen relevant interventions were found, covered by nine Cochrane systematic reviews (bilateral training, constraint-induced movement therapy (CIMT), electromyograhphic (EMG) biofeedback, electrostimulation, hands-on therapy interventions, mental practice, repetitive task training (RTT), electromechanical/robotic devices and virtual reality) and four other reviews (neurophysiological approaches, high-intensity therapy, mirror therapy and splinting). A statistically significant result, in terms of arm recovery, was found in favour of eight of the interventions: CIMT (standardised mean difference (SMD) 0.74 95% CI 0.44-1.03), EMG biofeedback (SMD 0.41 95% CI 0.05-0.77), electrostimulation (SMD 0.40 95% CI 0.02-0.77), mental practice (SMD 1.37 95% CI 0.60-2.15), mirror therapy (SMD 0.41 95%CI 0.05-0.77), RTT (SMD 0.23 95% CI 0.06-0.41), electromechanical/robotic devices (SMD 0.30 95% CI 0.02-0.58) and virtual reality (SMD 0.52 95% CI 0.25-0.78). Two out of the eleven interventions, which investigated hand function outcomes found a positive result (CIMT SMD 0.39 95% CI 0.11-0.68 and repetitive task training SMD 0.27 95% CI 0.06-0.47). Analyses were limited by a relatively small number of RCTs, which were also generally small in size. Heterogeneity of the available data and methodological limitations further impacts on the conclusions. Despite these limitations this overview provided a concise and informative summary of the available evidence. The interventions found to be beneficial, or showing promise tend to include elements of intensive, repetitive, task-specific practice. To build the evidence base for upper limb interventions, two Cochrane systematic reviews were undertaken. These reviews investigated the effects of bilateral training and home therapy programmes on upper limb recovery. Both included RCTs of stroke patients. Eighteen trials were included in the bilateral review, of which 14 were included in the analyses. Most of the included trials were considered to be at high risk of bias and the evidence was further limited by heterogeneity. No statistically significant results were found for any of the primary outcomes. One study found a statistically significant result in favour of another upper limb intervention for performance in extended ADL. No statistically significant differences were found for any of the other secondary outcomes. Four RCTs were included in the home-based therapy programmes review. No statistically significant result was found for any of the outcomes. There is currently insufficient good quality evidence to determine the effects of both the interventions studied. Following the evidence gained from the overview of interventions elements of intensive, repetitive and task-specific practice were to be included in a novel upper limb intervention. Robotic interventions, which incorporate these principles, were also found to have a positive effect on upper limb outcomes. Therefore a pilot, feasibility and acceptability study of a novel device (Armeo®Spring) that included these elements was completed. Medically stable adults with a clinical diagnosis of stroke and arm deficits admitted to an acute stroke unit were recruited. Participants were randomly allocated to experimental intervention (high or low intensity training with the Armeo®Spring arm orthosis) or usual stroke unit care. Primary outcomes were feasibility and acceptability of the experimental device recorded at postintervention. Secondary outcomes were; safety and three efficacy outcomes recorded at post-intervention, and 3 month follow-up. Patient recruitment was challenging; over eight months 393 consecutive stroke admissions were screened and 12 participants recruited. This study demonstrated that per-protocol levels of intensity were not feasible to provide in an acute stroke unit. However, higher levels of intensity could be achieved and this novel intervention was found to be acceptable to patients. This pilot trial also found higher change scores on the three efficacy outcomes within both intervention groups, compared to the control group. Due to small sample size and other possible confounding factors, these findings must be interpreted with caution. Using the MRC complex intervention framework as a guide I completed development and feasibility/piloting work surrounding an upper limb intervention, following stroke. Following the results of this research further development, feasibility/piloting work is suggested for the ArmeoSpring device prior to the undertaking of a phase III RCT. The information gained from this research could be used to inform phase III RCTs of other upper limb interventions.

Background and Purpose: Sleep problems are commonly reported by stroke patients. Poor sleep quality can detrimentally impact upon multiple clinical variables, including mood, physical health, cognition and the rehabilitation process itself. However, the relationship between sleep and stroke is complex and not fully understood. Pre-sleep cognitions and pre-sleep arousal have been proposed as contributing factors in sleep disturbance within the general population and this novel study investigates these variables as potential factors associated with sleep post-stroke. Methods: Stroke rehabilitation inpatients (N=21) were classified as good or poor sleepers using the Pittsburgh Sleep Quality Index (PSQI) and compared using measures of pre-sleep cognitions and pre-sleep arousal; relevant factors including daytime sleepiness, fatigue, mood and environmental disturbance were also explored. Results: Poor sleepers reported a significantly higher level of pre-sleep cognitions, pre-sleep cognitive arousal, fatigue and mood disturbance than good sleepers. The level of daytime sleepiness and perceptions of environmental disturbance did not differ significantly between groups. Conclusions: This study revealed a high level of poor sleep within the current sample (48%) based on the PSQI and pre-sleep cognitions and cognitive arousal appear potentially important factors in sleep quality post-stroke. Theoretical and practical implications and future directions for research are discussed.

Introduction: Oxygen-glucose deprivation (OGD)±reperfusion and hyperglycaemia exacerbate the ischaemic cerebral injuries during or after a stroke. The key biochemical events associated with these pathologies include excessive cytoskeletal remodelling, modulation of tight junction proteins and the induction of oxidative stress. Recently, the overactivities of protein kinase C (PKC), RhoA/Rho-kinase, and pro-oxidant NADPH oxidase have been shown to account for the development of these events and the consequent disruption of human blood-brain barrier (BBB) integrity. Objectives: This thesis focused on the putative roles of RhoA/Rho-kinase signalling in OGD and OGD+reperfusion-evoked modulation of cytoskeletal remodelling, tight junction proteins and oxidative stress in human brain microvascular endothelial cells (HBMEC). The effects of hyperglycaemia-mediated PKC overactivities in modulating the RhoA/Rho-kinase pathway with reference to the aforementioned parameters i.e. cytoskeletal remodelling and tight junction protein expression and localisation have also been the focus of this thesis. Methods: For the OGD studies, the HBMEC were exposed to normoxia (controls), OGD (4, 20 hours) alone and followed by reperfusion (20 hours). The HBMEC-human astrocyte (HA) cocultures were established to mimic human BBB before exposing them to the experimental conditions. The integrity and function of HBMEC-HA cocultures were measured by transendothelial electrical resistance (TEER) and flux of permeability markers sodium fluorescein (NaF) and Evan’s blue-labelled albumin (EBA), respectively. For the hyperglycaemia studies, the HBMEC monolayers and the cocultures were exposed to normoglycaemia (5.5 mM D-glucose), hyperglycaemia (25 mM D-glucose), and hyperglycaemia with inhibitors of Rho-kinase, PKC, PKC-α, PKC-β, PKC-βII, PKC-δ; and the BBB integrity and function were measured by the TEER and flux studies, respectively. Fold differences in the protein expression or activity of RhoA, Rho-kinase-2, mono- and di-phosphorylated myosin light chain-2 (MLC2), total MLC2, gp91-phox (a pivotal NADPH oxidase subunit), catalase, occludin, claudin-5, zonula occludens-1 (ZO-1), β-catenin, and vinculin were either measured by in-cell or ordinary Western analyses. Results from the OGD studies: OGD compromised the barrier integrity as observed by decreases in TEER values and concomitant increases in flux of EBA and NaF across the cocultures. Transfection of HBMEC with constitutively active RhoA also decreased the TEER and increased the NaF paracellular permeability, whereas inactivation of RhoA by anti-RhoA-IgG electroporation exerted barrier protective effects. Moreover, OGD alone and after constitutively active RhoA transfection introduced stress fibres in HBMEC, which were abrogated by inactivation of RhoA and the specific inhibition of its main effector Rho-kinase by Y-27632. In addition, dramatic increases in the protein expressions of RhoA-GTP, Rho-kinase-2, gp91-phox, and antioxidant catalase were observed in HBMEC exposed to OGD+reperfusion conditions. These along with increases in the NADPH oxidase activity and total superoxide anion levels confirmed the oxidative stress in HBMEC under these experimental conditions. A marked rise in the protein expressions of claudin-5 and β-catenin observed after OGD (20 hours) alone and followed by reperfusion may represent the effects of oxidative stress on tight and adherens junction proteins stability, respectively. These results also concurred with marked decreases in TEER and concomitant increases in the flux of EBA across the in vitro models of human BBB exposed to OGD±reperfusion conditions when compared with the controls. Cotreatment with Y-27632 under OGD±reperfusion normalised the protein expressions of RhoA, Rho-kinase-2, gp91-phox, claudin-5, catalase; activities of RhoA and NADPH oxidase; and total superoxide anions levels, alongside improving the expression of occludin and the coculture integrity under the OGD±reperfusion conditions. Results from the hyperglycaemia studies: Hyperglycaemia also increased RhoA-GTP, Rho-kinase-2, mono- and di-phosphorylated MLC2 protein levels and total PKC activity. These changes were consistent with the actin stress fibre formations, ZO-1 and occludin redistribution from HBMEC periphery. Hyperglycaemia-mediated endothelial-barrier dysfunction was further characterised by reduction in TEER and elevation in flux of EBA. Glucose normalisation, RhoA neutralisation by anti-RhoA-IgG electroporation and Rho-kinase-2 inhibition by Y-27632 normalised all abovementioned protein expressions, restored actin and tight junction protein localisations and barrier integrity. Cotreatment of HBMEC with hyperglycaemia and a general PKC inhibitor namely, bisindolylmaleimide-I normalised the Rho-kinase-2, mono- and di-phosphorylated MLC2 levels. Moreover, specific inhibitors of PKC-α (Ro-32-0432), PKC-β (LY333531), PKC-βII (CGP53353) attenuated the PKC overactivity, normalised all protein expressions, restored actin localisation and improved barrier integrity. In addition, the PKC-α and PKC-β siRNA transfections mimicked the effects of the specific inhibitors and attenuated the hyperglycaemia-evoked RhoA-GTP, mono- and di-phosphorylated MLC2 protein levels and stress fibre formations. Conclusions: The RhoA/Rho-kinase overactivities compromise the endothelial-barrier integrity, in part, by modulating the cytoskeletal remodelling and inducing the NADPH oxidase-evoked oxidative stress under OGD±reperfusion pathology. Moreover, hyperglycaemia-mediated increases in PKC-α and PKC-β activities exacerbate the endothelial-barrier dysfunction by modulating RhoA/Rho-kinase signalling pathway. Summary: These findings support the hypothesis that OGD±reperfusion and hyperglycaemia perturb BBB integrity through regulation of RhoA/Rho-kinase activity and modulation of cytoskeletal reorganisation, oxidative stress and tight junction protein expressions or localisations.

Most large acute stroke trials have shown no treatment effect. Functional outcome is routinely used as the primary outcome in stroke trials. This is usually analysed using a binary analysis, e.g. death or dependency versus independence. This project assessed which statistical approaches are most efficient in analysing functional outcome data from stroke trials. Fifty five data sets from 47 (54,173 patients) completed randomised trials were assessed. Re-analysing this data with a variety of statistical approaches showed that methods which retained the ordinal nature of functional outcome data were statistically more efficient than those which collapsed the data into two or more groups. Ordinal logistic regression, t-test, robust rank test, bootstrapping the difference in mean rank, or the Wilcoxon test are recommended. When assessing sample size, using ordinal logistic regression to analyse data instead of a binary outcome can reduce the sample size needed for a given power by 28%. Ordinal methods may not be appropriate for trials of treatments which not only increase the proportion of patients having a good outcome but also have an increase in hazard, such as thrombolytics. Adjusting the analysis performed for prognostic factors can have an additional effect on sample size. Re-analysing data from 23 stroke trials (25,674 patients), where covariate data was supplied, showed that ordinal logistic regression adjusted for age, sex and baseline stroke severity reduced the sample size needed for a given statistical power by around 37%. Alternatively trialists could increase the statistical power to find an effect for a given sample size, as it is argued that stroke trials have been too small and therefore underpowered. Stroke prevention trials also routinely collect binary data, e.g. stroke/no stroke. Converting this data into ordinal outcomes, e.g. fatal stroke/non-fatal stroke/no stroke and analysing these with a method which takes into account the ordered nature of the data also increases the statistical power to find a treatment effect. This method also provides additional information on the effect of treatment on the severity of events. Using ordinal methods of analysis may improve the design and statistical analysis of both acute and stroke prevention trials. Smaller trials would help stroke developments by reducing time to completion, study complexity, and financial expense.

Stroke is the principal cause of long-term disability. Hemiplegia affects up to 80% of people with stroke and a significant number will not recover use of the affected arm. People with profoundly-affected arm may experience pain, stiffness and difficulty with care activities. We cannot currently predict who is most at risk of these difficulties, and historically interventions have been designed without understanding the temporal evolution of impairment or disability. The International Classification of Functioning, Disability and Health (WHO, 2001) was used to develop a model of the consequences of the profoundly-affected arm on impairment, disability, and participation. A systematic review of thirty observational studies was undertaken and identified potential predictors of increased impairment in general populations of people with stroke. However, there was a paucity of evidence directed at people with profoundly-affected arm or regarding impact on passive care. The aim of this study was to test the feasibility of using an observational study design to develop a longitudinal profile of the profoundly-affected arm. Specific objectives of the feasibility study were to assess the processes of recruitment and follow-up, to review the sample characteristics, and to establish the acceptability and responsiveness of the predictor variables and outcome measures. Key tenets of the project were to involve people with cognitive and communication disability, and to use assessments that could be adopted by therapists working in a patient’s own home. Forty people with stroke and nine carers were recruited and followed up at three and six months post-stroke. Using enhanced communication techniques and personal consultees, it was possible to include people with severe cognitive and communication disability. The baseline demographic characteristics and the rate of loss to follow-up of participants reflect that expected in people more severely affected by stroke. Qualitative data suggest that participants affirmed the model of impairments and disabilities that had been developed. The predictor variables and outcome measures were considered acceptable to participants, and collected a range of data, generally performing in the manner expected. However, there were a number of exceptions. Cognitive and communication disability impacted on completion of the self-reported assessments, and may have affected performance on measures of mood and sensation/perception. In addition to this, measures of range of movement varied at each time point, in a manner not in accordance with expected change over time. The evidence from this thesis suggests the research design has potential to be used to develop a longitudinal profile of the profoundly-affected arm. Further work is required to improve carer recruitment, establish the best assessments for those with severest cognitive and communication disability, and review the method of measuring range of movement.