Subarachnoid hemorrhage (SAH) comprises 7% of all stroke cases, and is associated with a disproportionately high morbidity and mortality with few therapeutic options available. The goal of this project was to understand the mechanism of neurological deterioration after experimental SAH, with a focus on cerebral vasospasm and brain injury after SAH. We tested the hypothesis that endothelial nitric oxide synthase (eNOS) is upregulated and uncoupled after SA, resulting in exacerbated neurological injury in a mouse model of SAH. The project entailed the investigation of eNOS-dimer uncoupling, its association with oxidative and nitrosative stress in the brain parenchyma and finally its association with secondary complications after SAH. In our studies we demonstrated the crucial role eNOS plays in anti-microthromboembolism, anti-apoptosis and maintenance of physiological superoxide (O2-)/NO balance. This study suggests that SAH up-regulates and disrupts eNOS, producing peroxynitrite (OONO-) and other radicals that further exacerbate the oxidative insult and neurological injury.

Subarachnoid hemorrhage (SAH) comprises 7% of all stroke cases, and is associated with a disproportionately high morbidity and mortality with few therapeutic options available. The goal of this project was to understand the mechanism of neurological deterioration after experimental SAH, with a focus on cerebral vasospasm and brain injury after SAH. We tested the hypothesis that endothelial nitric oxide synthase (eNOS) is upregulated and uncoupled after SA, resulting in exacerbated neurological injury in a mouse model of SAH. The project entailed the investigation of eNOS-dimer uncoupling, its association with oxidative and nitrosative stress in the brain parenchyma and finally its association with secondary complications after SAH. In our studies we demonstrated the crucial role eNOS plays in anti-microthromboembolism, anti-apoptosis and maintenance of physiological superoxide (O2-)/NO balance. This study suggests that SAH up-regulates and disrupts eNOS, producing peroxynitrite (OONO-) and other radicals that further exacerbate the oxidative insult and neurological injury.

Cerebral vasospasm following subarachnoid hemorrhage has high morbidity and mortality. Mathematical modeling of the progression of the condition provides insight to improve clinical treatment of patients post subarachnoid hemorrhage. An existing model of the clotting cascade is expanded to include the theoretical conditions of cerebral vasospasm. We consider clotting factor XIIIa, which has been implicated as a primary cause of the entrenchment of the smaller diameter. Solutions for clotting are used as boundary conditions to solve the concentration of diffusible clotting factors in the vessel wall and cerebrospinal fluid (CSF). Each domain (clot, vessel wall, CSF) is described by a separate initial-boundary value problem, requiring unique conditions, reaction-diffusion equations, and diffusion coefficients. Additionally, the results from the first domain (the clot) provide a subset of the boundary conditions for the second and third domains (arterial wall and CSF, respectively). Although this approach captures many detailed components of the clotting process, a simpler method for investigating the formation and dissolution of a clot post subarachnoid hemorrhage is to neglect the bulk of the clot cascade to focus on the most salient features, namely, the formation of cross-linked fibrin and the degradation of fibrin by plasmin. By assuming first order kinetics in the initial hours following hemorrhage, we find a simplified expression with kinetic rates that may be adjusted depending on experimental conditions.

A retrospective review was made of the case records, angiograms and computed tomography (CT) relating to a total of 263 patients with subarachnoid haemorrhage (SAH) due to ruptured berry aneurysms who were admitted to the Department of Neurosurgery, Wentworth Hospital during the four years 1983-1986. The part of the thesis concerning vasospasm (VS) includes two independent studies on calcium blocker Nimodipine (NO) in the prevention and treatment of VS done by the author. The aim of the thesis is to analyse the management problems of aneurysmal SAH, and investigate factors influencing outcome in order to establish the best possible management policy. The results are discussed and related to the recent data from literature. The main factors influencing outcome were: clinical condition of the patient, the timing of admission and surgery, hypertension and hyperglycaemia on admission, presence of vasospasm and related CT appearance of a thick layer of blood or clot in subarachnoid haemorrhage (CT-Fisher 3). The systemic administration of the calcium blocker nimodipine did not reverse or prevent delayed vasospasm and caused serious adverse effects i.e. hypotension and hyperglycaemia. The results of the thesis suggest a change in management policy and timing of surgery should depend. on clinical condition of the patient on admission (Hunt & Hess grading)(HH I/II grade (HH as possible regardless of timing of admission and results of radiological investigations (CT, angiography). Early surgery (1-3 days) should be the aim of the effort including referral, transport and hospital organisation. III grade (HH surgery should be performed soon after day 10 post-SAH. Particular attention should be paid to the careful preparation and selection of patients for angiography. IV/V grade (HH in specialised units as s000n as possible, preferably neurological or neurosurgical wards, and operated on as soon as their grade improves or, in selected (by surgeon, radiologist and anaesthetist) cases by delayed surgery ( after day 10 post-SAH). / Thesis (M.Med.)-University of Natal, Durban, 1988.

<strong>Aims:</strong> The purpose of the research presented in this thesis is to elucidate the mechanism of the stimulation of oxidative metabolism and contractile function that occurs in vascular smooth muscle during cerebral vasospasm (CV) after subarachnoid haemorrhage (SAH). The biochemical mechanisms leading to CV were investigated using an in vitro model of CV developed for this research. CSF (cerebrospinal fluid) from SAH patients at risk of vasospasm which stimulated oxygen consumption (CSF S ) was used to model vasospasm. The hypothesis is CSF_S contains a substance which stimulates tension generation over that of CSF_N ,(non-stimulatory cerebrospinal fluid) and also inhibits the myosin light chain phosphatase. <strong>Methods:</strong> The porcine carotid artery was used as a model for the human basilar artery. The rate of oxygen consumption (JO₂) was measured in response to CSF_S and tension generation was also examined. Various agents were used to treat or pretreat the tissue such as magnesium and andalpha;₁-adrenergic receptor agonists. Their effects on the CSF_S-induced stimulation were measured to study the mechanism of vasospasm. A myosin light chain phosphatase (MLCP) assay was developed to study the mechanisms leading to CV. <strong>Results and conclusion:</strong> Addition of CSF_S to the porcine carotid artery is a reliable and reproducible in vitro model of CV. Using this model, it was found that Mg⁺⁺ loading and andalpha;₁-adrenergic receptor agonists attenuated the vasospasm, but a non-specific endothelin antagonist had no effect. Acute addition of 12mM Mg⁺⁺ relaxed the tissue from a CSF_S induced contraction significantly and rendered the contraction rinsible. Okadaic acid (InM), a phosphatase inhibitor, had very similar effects to CSF_S because it stimulated JO₂ and slowed relaxation after a stretch. There was also significant inhibition of phosphatase caused by the CSF_S. Vasospasm appears to be caused by a combination of a contractile stimulus, and inhibition of MLCP activity.

Purpose: The principal aim of this project was to investigate the influence of clinical indices of injury severity and polymorphism of the apolipoprotein E gene upon the long-term physical, cognitive and emotional sequelae of traumatic brain injury and spontaneous subarachnoid haemorrhage. It was also intended to determine the extent to which changes occur in these sequelae beyond the initial six months post injury. Method: Sixty-two brain injury patients who had previously taken part in a neuropsychological assessment at six months post injury were traced and participated in a follow-up assessmens some 6-9 years subsequent to their injury. Separately, a group of 70 subarachnoid patients drawn from a consecutive series of neurosurgical admissions participated in a neuropsychological assessment at 14 months subsequent to their haemorrhage. In both studies, the assessment comprised a semi-structured interview and a battery of cognitive measures focusing principally upon memory and executive function tasks. A questionnaire including a range of standardised measures of anxiety, depression and quality of life was left with patients to be returned by post. Results: The ApoE e4 allele did not appear to influence recovery amongst these brain injury survivors, though there are suggestions that it may have an influence upon subgroups of patients. Amongst traumatic brain injury survivors, post-traumatic amnesia was a better predictor of functional or emotional outcome than consciousness based measures. However, consciousness based measures were more predictive of cognitive sequelae and low admission Glasgow Coma Scale was associated with continued improvement on information processing tasks. Other than on these tasks, there was little evidence of change between 6 months and 6-9 years post injury. Amongst the subarachnoid haemorrhage patients, Fisher Grade was found to be more predictive of subsequent Glasgow Outcome Scale and cognitive function than WFNS Grade or other clinical indices. Surviving aneurysmal patients had comparable levels of recovery to patients who had a negative angiogram. In both studies emotional sequelae, in particular anxiety-related difficulties, were found to be a principal factor in the functional outcome of some 40% of patients. Conclusions: Greater emphasis should be placed upon measures of post-traumatic amnesia as predictors of functional recovery in surviving patients. The use of an amnesia measure may also be warranted in studies of outcome following subarachnoid haemorrhage or other stroke. The ApoE e4 allele does not appear to have a strong influence upon functional recovery after brain injury across all patients, though it is possible that it interacts with other factors to influence recovery in subgroups. Greater emphasis should be placed upon the prevention and/or detection and treatment of mood disorders following brain injury. In the absence of intensive rehabilitative interventions, survivors of serious brain injury are more likely to deteriorate than to continue to recover beyond six months post injury.

Thesis (Ph. D.)--University of Wisconsin, 1943. / Typescript (carbon copy). Some plates accompanied with leaf of explanatory text. Most ill. are laid in photographs. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaf [29]).

Abstract Subarachnoid haemorrhage (SAH) is a life-threatened disease with poor outcome. It is usually caused by an intracranial aneurysm (IA) rupture and rapid diagnosis and treatment are of great importance. Computed tomography (CT) is a reliable method to detect the blood in the subarachnoid (SA) spaces. Digital subtraction angiography (DSA) offers dynamic and morphological information of a ruptured IA. The treatment options for excluding an aneurysm from the main circulation are neurosurgical clipping and endovascular procedures. The purpose of the present study was to evaluate the risk factors of acute hydrocephalus (HC) and the reliability to localize the ruptured aneurysm based on non-contrast CT. The aim was also to compare the effect of neurosurgical and endovascular treatment on the development of chronic HC, and evaluate the incidence and the risk factors of early rebleeding (&lt;  30 days) after coiling. The data of 180 operated patients with a ruptured IA were checked. Two neuroradiologists separately located the IAs based on non-contrast CT. The analyses of blood amount and distribution was a reliable method for estimating the location of ruptured middle cerebral artery (MCA) aneurysms and anterior communicate artery (ACoA) aneurysms. Intracerebral haemorrhage (ICH) was a predictor for detecting the precise site. The results confirmed that intraventricular haemorrhage (IVH) was the most consistent single risk factor for the development of acute HC. Haemorrhage in the basal region and the large total blood amount in the SA spaces were strong predictors. The effect of early treatment modality for ruptured IAs on the development of chronic HC with 102 clipped and 107 coiled patients was compared. The treatment method used was not significantly associated with the occurrence of chronic HC or the need for shunt operation. The incidence and risk factors of early rebleeding after coiling were investigated in 194 consecutive acutely (within 3 days) coiled patients with ruptured IAs. The incidence of early rehaemorrhage was 3.6%. The presence of ICH at admission and poor clinical condition were significant predictors for rebleeding. An early rehaemorrhage appeared as an enlargement of the ICH in all of these patients. In conclusion, the non-contrast CT is a reliable method to detect the location of ruptured IA in patients with MCA and ACoA aneurysms. The risk factor for the development of acute HC is IVH. Other predictors are the total SA blood amount and blood in the basal regions. The treatment method used for acutely ruptured IA has no significant effect on the occurrence of chronic HC. The incidence of early rebleeding after coiling is low. The risk factors of rebleeding are the presence of ICH and poor clinical condition. Rehaemorrhage appears often as an enlargement of the ICH.

Abstract The purpose of the study was to analyze the angiographic and clinical results of endovascularly treated intracranial aneurysms in Oulu University Hospital, Finland. The study population consisted of 416 consecutive patients (467 aneurysms, 332 ruptured), who were referred for endovascular treatment of intracranial aneurysm(s) between December 1993 and July 2004. Technical failures were analyzed for an assesment of technical feasibility. Angiographic results were assessed using modified Raymond Classification. Clinical results were analyzed from patient files using the Glasgow Outcome Scale (GOS). Patient, aneurysm, and procedure related variables were tested with an intention to find the predictors of the angiographic and clinical outcome. The clinical effects on presenting symptoms were analyzed for a subgroup of patients with a symptomatic unruptured aneurysm (n = 30). The mean results on technical feasibility, complications, and angiographic results were separately assessed for three time periods (1993–1997, 1998–2000 and 2001–2004) to demonstrate potential significant changes in outcome. Endovascular treatment of saccular aneurysms was technically feasible in 91.4% of the treatments. Initially, 25.7% of the aneurysms were completely occluded, 57.9% had a neck remnant, and 16.3% remained incompletely occluded. In follow-up, the rates for complete occlusions, neck remnants and incomplete occlusions were 37.6%, 49.7% and 12.7%, respectively. Small aneurysm size predicted complete aneurysm occlusion, while a wide aneurysm neck and location in the posterior circulation predicted incomplete occlusion. In follow-up (mean 38.2 months), 78.1% of the patients with a ruptured aneurysm and 92.3% of the patients with an unruptured aneurysm had resumed independent life (GOS 4-5). The predictors of good outcome were young age, good preprocedural clinical condition, small amount of blood in CT scan, and uncomplicated procedure. Ten of the treated aneurysms involved intracranial bleeding in follow-up, and the annual risk for bleeding after endovascular treatment was 0.95% among the patients with ruptured aneurysms and 0.33% among those with unruptured aneurysms. The risk of bleeding was associated with larger aneurysm size and lower occlusion grade. In the subgroup of symptomatic unruptured aneurysms, 53.4% of the patients showed either resolution or improvement of the symptoms after treatment. The rates of procedural complications, morbidity, and mortality were 16.5%, 6.7%, and 1.7%, respectively. The risk for procedural complications was higher when the balloon remodeling technique was used and lower in retreatments. Technical feasibility (85.6%, 90.6%, and 95.7%, respectively) and the percentage of complete occlusions (initially 16.5%, 23.0%, and 32.9%, respectively) were significantly improved by increased experience, while no statistical difference was detected in the total procedural complication rates (15.4%, 15.7%, and 18.3%, respectively) or the combined procedural morbidity and mortality rates (8.0%, 8.3%, and 9.1%, respectively). All six dissecting aneurysms treated with parent artery occlusion or the stent remodeling technique resulted in complete occlusions. The present results confirmed endovascular treatment of intracranial aneurysms as a feasible, safe, and effective method in preventing further bleeding of aneurysms. Increased experience in a single center improved the feasibility of the treatment as well as the angiographic results.

Viele Studien haben sich bereits mit Nutzen und Risiken einer intensivierten Insulintherapie (IIT) intensivmedizinischer Patienten auseinandergesetzt. Die unterschiedlichen Ergebnisse gaben Anlass, die Auswirkungen einer Hyperglykämie auf Patienten mit einer Subarachnoidalblutung (SAB) weiter zu analysieren. In diesem Zusammenhang war der Stellenwert einer IIT von besonderem Interesse. Um den Einfluss des erhöhten Blutzuckers möglichst genau zu erfassen, wurde mittels Integralfunktion die Blutzuckerhöhe in Abhängigkeit der Zeit bestimmt. Es konnte ein negativer Einfluss einer hyperglykämen Stoffwechsellage auf den Krankheitsverlauf der Patienten dargestellt werden. Hervorzuheben sind hier vor allem Patienten, die sich initial in einem besseren Zustand befanden. Anschließend erfolgte die Einführung einer intensivierten Insulintherapie. In der IIT war es nicht immer möglich, den gewünschten Zielbereich des Blutzuckers zu erreichen, um einen signifikanten Unterschied beider Therapiegruppen bezüglich der Blutzuckereinstellung zu erhalten. Dennoch zeigte sich ein deutlicher Trend zugunsten der intensiviert therapierten Gruppe und dessen Krankheitsverlauf. Die Behandlung der Hyperglykämie durch eine IIT bleibt ein wichtiger Aspekt in der Intensivmedizin. Anzustreben ist eine moderate Insulintherapie, damit sowohl Hypo- als auch Hyperglykämien weitestgehend verhindert und so das Genesungspotential der Patienten unterstützt werden kann.