Class of 2013 Abstract / Specific Aims: The purpose of this study was to assess the clinical and economic predictors associated with rural emergency department visits in stroke patients. Methods: The current research was a retrospective, observational, cohort study. Multivariate regression was used to assess data from the Agency for Healthcare Research and Quality (AHRQ) 2009 Nationwide Emergency Department Sample (NEDS). Inclusion criteria were at least 18 years of age and rural ED admission with principle diagnoses of stroke. Main Results: Significant results for risks included: Intubation for increased mortality (OR = 17.432, p = 0.001), increased length of stay (IRR = 1.643, p = 0.018) and increased charges (exp β = 2.289, p = < 0.001); myocardial infarction for increased mortality (OR = 1.969, p = 0.006), decreased charges (exp β = 0.862, p = 0.013) and decreased length of stay (IRR = 0.853, p = 0.001); moderate to severe liver disease for increased mortality (OR = 62.691, p = 0.001) and reduced length of stay (IRR = 0.517, p = 0.025); congestive heart failure for increased mortality (OR 1.978, p = 0.003) and increased charges (exp β = 1.118, p = 0.039); non-specific cancer (OR = 2.447, p = 0.017) and metastatic cancer (OR = 4.799, p = 0.016) for mortality; hemiplegia/paraplegia for increased charges (exp β = 1.173, p = < 0.001). Conclusion: The current study found a better understanding of national estimates of burden of illness to further define clinical decision rules for stroke in rural emergency departments.

Cerebral ischaemia, or stroke, is a leading cause of death and disability worldwide. Ischaemic stroke, as a result of arterial occlusion, and subarachnoid haemorrhage (SAH), as a consequence of arterial rupture in the subarachnoid space, are major subtypes of stroke. Treatment options for both are limited, and many therapeutic strategies have failed. In ischaemic stroke, lack of evidence of brain penetration of treatments has been cited as a major weakness and contributing factor to failed clinical trials. In SAH, animal models do not always mimic key pathophysiological hallmarks of the disease, hindering development of new therapeutics. Inflammation is strongly associated with brain injury after cerebral ischaemia and inhibition of the pro-inflammatory cytokine interleukin-1 (IL-1) represents apossible therapeutic target. Therefore, the key objectives of this thesis were; (1) to improve preclinical data on a promising stroke treatment, interleukin-1 receptor antagonist (IL-1Ra), by investigating its pharmacokinetic profile and brain penetration in a rat model of ischaemic stroke, (2) to investigate the endovascular perforation model of SAH in rat, as a tool for the investigation of neuroprotectants, and (3) to examine the role of the inflammatory response in the SAH model and the effects of IL-1Ra. The neuroprotective effect, pharmacokinetic profile and brain penetration of IL-1Ra were assessed after a single subcutaneous (s.c.) dose (100mg/kg) in rats, after transient (90 min) middle cerebral artery occlusion (MCAo). A single s.c. dose of IL-1Ra reduced neuronal damage, resulted in sustained, high concentrations of IL-1Ra in plasma and cerebrospinal fluid and also penetrated brain tissue exclusively in areas of blood brain-barrier (BBB) breakdown. An endovascular perforation model of SAH in rat was investigated and produced widespread multifocal infarcts. In this model, administration of IL-1Ra (s.c.) reduced BBB breakdown, which correlated with injury at 48 h. IL-1_ was expressed in the brain early after SAH in areas associated with haem oxygenase-1 (HO-1) expression, indicating the presence of free haem. Stimulation of primary mouse mixed glial cells in vitro with haem induced expression and release of IL-1 alpha but not IL-1 beta. These data, after MCAo in rat, are the first to show that a single s.c. dose of IL-1Ra rapidly reaches salvageable brain tissue and is neuroprotective. This allows confidence that IL-1Ra is able to confer its protective actions both peripherally and centrally. After experimental SAH, we suggest that haem, a breakdown product of haemoglobin, released from lysed red blood cells in the subarachnoid space, acts as a danger associated molecular pattern (DAMP) driving IL-1- dependent inflammation. These data provide new insights into inflammation after SAH-induced brain injury and suggest IL-1Ra as a candidate treatment for the disease. Overall, these findings strengthen preclinical data supporting IL-1Ra as a neuroprotective therapy for ischaemic stroke, and identify SAH as a new indication for treatment with IL-1Ra.

Stroke is a pathological condition that causes extensive brain damage. During ischemic stroke, an excess of the excitatory neurotransmitter glutamate exerts many deleterious effects, which leads to cellular damage and cell death, a phenomenon appropriately termed excitotoxicity. Among the events triggered is the activation of the enzyme calpain, a protease whose action is dependent on the intracellular concentration of calcium, which is known to be elevated during excitotoxicity. In this thesis, I hypothesize that neuroprotective drugs can be better accumulated into stroke-affected regions by utilizing the actions of calpain. The extent of calpain activation was first investigated, and it was found to increase over time in both in vitro and in vivo models of stroke. Different amino acid sequences recognized and cleaved by calpain were then incorporated into the neuroprotective Tat-GluR2/3Y peptide. Although in vivo detection of modified Tat-GluR2/3Y peptides was unsuccessful due to technical difficulties, the accumulation of the therapeutic 3Y peptide fragments in neurons under excitotoxic conditions in vitro was found to increase with the CP-3 peptide, a peptide that is a modified version of the Tat-GluR2/3Y, with a sequence cleavable by calpain from the protein Collapsin Response Mediator Protein-3 (CRMP-3). These results suggest that it is possible to concentrate therapeutic agents into stroke-affected neurons, and this may translate into enhanced neuroprotective properties in both in vitro and in vivo animal stroke models. / Medicine, Faculty of / Graduate

Background: The majority of people living with the effects of stroke experience participation challenges. Occupational Performance Coaching for stroke survivors (OPC-Stroke) is designed to promote engagement in personally identified participation goals and develop the ability to address future participation goals. Purpose: This thesis explored the potential efficacy of OPC-Stroke, its mechanisms of action, and the feasibility and acceptability of the randomized controlled trial methods to inform the planning of a larger trial. Methods: A pilot randomized controlled trial with an embedded qualitative component. Twenty-one participants were randomly assigned to receive 10 sessions of OPC-Stroke or usual care. Participation, goal performance and satisfaction, goal self-efficacy, emotional well-being, and cognition were measured at pretest, posttest and six months follow-up. Qualitative interviews were conducted at posttest with individuals who were in the intervention group. Results: No significant between group differences were noted for any outcomes, although scores for cognition approached significance (p=0.065) and also showed a large effect size (partial eta squared =0.167). Examination of effect sizes indicated a moderate clinically significant benefit of OPC-Stroke for goal performance and satisfaction scores (partial eta squared = 0.075 and 0.078 respectively). Participation scores improved for both groups but the overall trajectory of participation seemed to be different between groups. Goal self-efficacy remained stable across time and groups, and emotional well-being declined in both groups. Qualitative findings confirmed that all components - emotional support, individualized education and goal-focused problem-solving - made important contributions to promote achievement of participant-selected participation goals. Recruitment, retention and outcome measure completion rates were satisfactory. Conclusion: Based on the effect sizes of goal performance and satisfaction, and cognition, a larger trial to examine the efficacy of OPC-Stroke is warranted. Further work to select the most appropriate tools to measure participation and goal self-efficacy is recommended prior to the next trial.

Following a stroke there is a significant increase in the number and migration of progenitor cells (PCs) to the infarct, and positive correlations between neurogenesis and recovery. Loss-of-function studies have conflicting findings on whether the ablation of PCs impedes motor or cognitive function post-stroke. This thesis examines if neurogenesis per se is required for motor recovery and spatial learning and memory. PCs were ablated in an adult GFAP-TK rat model that allows for the inducible deletion of GFAP-expressing PCs in the brain. An endothelin-1 (ET-1) stroke was produced and assessment of motor function and spatial learning and memory revealed no differences between control and GFAP-TK rats in which PCs were ablated. This study is the first to use a focal cortical stroke model in a rat to study PCs and stroke recovery, and suggest that PCs and their progeny are dispensable for motor recovery and spatial learning and memory post-stroke.

Ischemic stroke related brain damage causes loss of multiple cell types, including neural and vascular cells. The extent of post-stroke neurogenesis and angiogenesis predicts the level of functional regeneration/recovery after stroke. In this regard, my thesis was focused on defining the molecular process that modulates post-stroke functional recovery by co-ordinating post-stroke neurovascular remodeling. Since stroke-related brain damage releases enriched local microenvironmental cues, I examined the role of a signaling-induced epigenetic pathway, an atypical protein kinase C (aPKC)-mediated phosphorylation of CREB Binding Protein (CBP), in regulating post-stroke neurovascular remodeling and functional recovery. This pathway has previously been shown to be activated by metformin, an adenosine monophosphate kinase (AMPK) activator, to promote the differentiation of neural precursors in the developing and adult brain. Here, I first developed a murine focal cortical ischemic stroke model with persistent motor function deficits by combined intra-cortical injections of endothelin-1 (ET-1) and L-NAME into the sensorimotor cortex. Second, I applied the ET-1/L-Name-induced focal cortical stroke model in a knock-in mouse CBPS436A where the aPKC-CBP pathway is deficient, and showed that the aPKC-CBP pathway is involved in post-stroke functional recovery by coordinating neurovascular remodeling. Specifically, CBPS436A-KI mice displayed reduced motor recovery, correlated with reduced vascular remodeling and impaired post-stroke angiogenesis. Intriguingly, I also observed that CBPS436A-KI mice showed a reduction in the population of stroke-induced newborn pericytes but an increase in the population of perivascularly-derived neural precursors, implying that the aPKC-CBP pathway may be involved in the process that reprograms pericytes into neural precursors. Together, this study elucidates the novel role of the aPKC-CBP pathway in modulating neurovascular remodeling and functional recovery following focal ischemic cortical stroke.

Physical rehabilitation of individuals who are experiencing a disabling illness or have survived a traumatic injury (i.e. stroke) must seek to train the body’s structures and functions to reduce disability (activity limitations, participation restrictions) (Stucki, 2005). Figure 1 represents a modified version of the International Classification of Functioning (ICF), Disability and Health (World Health Organization, 2002). This figure illustrates how, for example, a stroke impacts the body structures and functions (e.g. muscle recruitment) which influences the ability to complete activities (e.g. gait) ultimately restricting participation in all areas of life (e.g. employment). The ICF model presents a framework for clinical practice and rehabilitation research studies. Although it has been shown to be strongly correlated (Schmid, Van Puymbroeck, et al., 2013) the concept of function cannot always be directly correlated with the concept of quality of life (Stucki, 2005) as the individual may not perceive, for example, impaired balance and mobility as detrimental to their quality of life. However, reduced function does put an individual at further risk of complications including falls and injuries from compensatory mechanisms and therefore must be addressed. The focus of this thesis is the study of the potential benefits of an exercise modality (virtual reality) to encourage restoration of the body’s structures and functions for individuals post-stroke. As the individuals engage in physical rehabilitation through exercise, there may be improvements on the individual’s abilities as seen through measurements of the control of posture and walking. The thesis comprises four studies, two of which have been published in peer reviewed journals. The progression of studies attempts to characterize outcomes following the use of virtual reality training in clinical populations (dementia and stroke) to address impairments to the body structures and functions (e.g. mobility) as measured by both clinical measures of activity and laboratory based measures of balance and to elucidate a possible mechanism (focus of attention) that makes training in a virtual environment effective.

Bakgrund: Stroke är en av de största folksjukdomarna i Sverige och årligen drabbas cirka 30 000 personer av stroke. Sjukdomen är en livshotande händelse och kan medföra funktionsnedsättningar i olika grad som påverkar på personers liv. Det kan även påverka på de anhörigas liv som tar hand om sin familjemedlem som har insjuknat. Syfte: Att beskriva patienters upplevelser av att leva med funktionsnedsättningar det första året efter en stroke. Metod: En systematisk litteraturstudie av vårdvetenskapliga artiklar med kvalitativ ansats enligt Evans beskrivande syntes. Resultat: Upplevelser som framkom i resultatet delades in i två teman: förlorad kontroll över kroppen och återfå kontroll över livet. Utifrån dessa teman framkom sex underteman: att bli instängd, att bli orkeslös, att leva med förlorad identitet, att leva med förändrad sinnesstämning, att anpassa sig till funktionsnedsättningar och att uppleva hopp. Slutsats: Att leva med funktionsnedsättningar efter en stroke påverkar på patienters kropp, själ och ande samt leder det till ett nytt och annorlunda liv. Sjuksköterskan bör uppmärksamma upplevelser som medförs av funktionsnedsättningar och anpassa vården efter detta. Att kunna lyssna, ge stöd och använda sin kunskap vid bemötande av patienter efter en stroke medför att kvalitén på omvårdnaden kan förbättras. / Background: Stroke is one of the most common widespread diseases in Sweden and approximately 30 000 people suffers each year. The disease is a life-threatening experience and can lead to disabilities and affect the patient’s lifestyle. It can also affect the lives of the relatives who take care of their family member who has been diagnosed with a stroke. Aim: To describe patient’s experiences of living with the disabilities the first year after a stroke. Method: A systematic literature study of nursing research articles with qualitative approach according to Evans descriptive synthesis. Results: Experiences, which were identified in the result, were divided into two themes: Lost control of the body and regain control of their life. Based on the themes six sub-themes appeared: To be trapped, to be decrepit, to live with lost identity, to live with altered mood, to adapt to the disabilities and to experience hope. Conclusion: Living with disabilities after a stroke affect a patient’s body, mind and spirit, and lead to a new and different life. Nurses should pay attention to victim’s experiences of the disabilities and adapt the nursing accordingly. Being able to listen, provide support and use their knowledge in the treatment of patients after a stroke can improve the quality of healthcare.

Stroke is the first cause of disability and second most frequent cause of mortality after ischemic heart disease in adults worldwide. The influence of visual system impairment on the patient’s functional ability and quality of life are still largely neglected in neurological rehabilitation. Therapists are seldom concerned with the visual status and ability of their patients. Members of the rehabilitation team rarely assess, monitor or treat impairment of visual efficiency processes and visual information processing dysfunction that may be observed in patients after a stroke. In the absence of specific intervention visual deficits stabilise and become permanent due to poor or almost absent spontaneous recovery of the visual system in stroke patients. A matched-pair randomised controlled trial was conducted. Twenty-four (24) participants were screened based on their functional activity level as measured on the Stroke Activity Scale (SAS). When a participant’s SAS score matched a previously allocated participant’s score, that particular participant was placed in the opposite group from the existing matched participant. If the newly assessed participant’s SAS did not match another participant’s SAS, the participant was randomly allocated to either the experimental or the control group. The process was repeated until (24) patients had been allocated into two groups consisting of twelve (12) participants per group as they were admitted to Tshwane Rehabilitation Centre (TRC). Group 1 (Experimental Group) received saccadic eye movement training with visual scanning exercises integrated with task-specific activities and Group 2 (Control Group) received task-specific activities for four (4) consecutive weeks. Participants functional progress on body impairment and functional activity level were assessed and documented on a weekly basis during the intervention period of four (4) weeks. In order to determine whether the integration of visual scanning through saccadic eye movement training had a permanent or long-term effect on the participants’ functional ability and quality of life after rehabilitation had been terminated, functional progress on body impairment-, functional activity and participation levels as well as their perceived quality of life were assessed and documented eight (8), twelve (12), sixteen (16) and twenty (20) weeks after admission to the rehabilitation facility. A large number of participants were lost to follow-up following discharge from the TRC after the intervention period of four (4) weeks. As result of the small sample group at week eight (8), week twelve (12), week sixteen (16) and week twenty (20), these results were not discussed. Results of the matched-pair randomised controlled trial indicated that the effect of saccadic eye movement training with visual scanning exercises integrated with task specific activities as an intervention for participants that presented with unilateral spatial inattention, visual-spatial disorders and visual-constructive disorders poststroke resulted in significant improvement in impairment level. This improvement related to oculomotor visual performance, visual attention, depression as well as results on functional activity level with regard to the ability to independently complete ADL after four (4) weeks of rehabilitation. It may therefore be concluded that saccadic eye movement training with visual scanning exercises integrated with task-specific activities as an intervention tend to improve functional ability in participants that presented with unilateral spatial inattention, visual-spatial disorders and visual-constructive disorders post-stroke. / Dissertation (MPhysT)--University of Pretoria, 2013. / Physiotherapy / unrestricted

The burden of strokes on the healthcare system is tremendous. Strokes are one of the leading causes of long-term morbidity and mortality in the United States. In addition, strokes have a huge economic burden that lasts long after the actual stroke has occurred and has been medically stabilized. Thus, there is a desire to prevent strokes, as well as treat those who have experienced stroke. As technology has and continues to advance, there is the potential for the inclusion of new technologies to become integrated into the healthcare system. One such example is the inclusion of virtual reality in the rehabilitation of patients who have experienced a stroke. The current process of stroke rehabilitation focuses upon returning a patient as close as possible to their baseline level of function. This is generally through the use of repetitive activity to help the brain reroute neuro signaling pathways around damaged areas of the brain. With the inclusion of virtual reality into the process of rehab, it may be possible to better control the environment around a patient and create activities to help better simulate activities of daily life. Through the inclusion of current generation virtual reality into modern rehabilitation regiments it may be possible to better the outcomes of patients who have undergone a stroke with physical deficits. With the current burden of stroke on the medical system it is important to find ways to treat patients as efficiently as possible. By incorporating virtual reality into stroke rehabilitation, there may be better outcomes for patients which will allow them to live better and more capable lives. Much of the research that has been conducted on the matter has shown promise but has lacked large sample sizes and often uses outdated technology. More research must be conducted using more modern technologies and larger sample sizes to show a true benefit in its utilization. The proposed study in this thesis will be a two-armed randomized control trial to assess the efficacy of virtual reality in stroke rehabilitation. The Fugl-Meyer assessment of motor recovery after stroke will be used to evaluate the physical motor benefits of implementation of virtual reality in stroke rehab. The potential benefit of virtual reality into stroke rehab could profoundly impact how we take care of patients who have experienced a stroke. It can create an effective new means to help patients regain their pre-stroke level of function, thus better helping return individuals to their normal lives. This in turn can help decrease costs on the healthcare system by decreasing the number of people living with long term disability.