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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.

Introduction: Nursing clinicians are primarily responsible for the monitoring and treatment of increased body temperature. The body temperature of patients during their acute care hospital stay is measured at regular repeated intervals. In the event a patient is assessed with an elevated temperature, a multitude of decisions are required. The action of instigating temperature reducing strategies is based upon the assumption that elevated temperature is harmful and that the strategy employed will have some beneficial effect. Background and Significance: The potential harmful effects of increased body temperature (fever, hyperthermia) following neurological insult are well recognised. Although few studies have investigated this phenomenon in the diagnostic population of non-traumatic subarachnoid haemorrhage, it has been demonstrated that increased body temperature occurs in 41 to 72% of patients with poor clinical outcome. However, in the Australian context the frequency, or other characteristics of increased body temperature, as well as the association between increased body temperature with poor clinical outcome has not been established. Design: This study used a correlational study design to: describe the frequency, duration and timing of increased body temperature; determine the association between increased body temperature and clinical outcome; and describe the clinical interventions used to manage increased body temperature in patients with non-traumatic subarachnoid haemorrhage. A retrospective clinical chart audit was conducted on 43 patients who met the inclusion criteria. Findings: The major findings of this study were: increased body temperature occurred frequently; persisted for a long time; and onset did not occur until 20 hours after primary insult; increased body temperature was associated with death or dependent outcome; and no intervention was recorded in many instances. Conclusion: This study has quantified in a non-traumatic subarachnoid haemorrhage patient population the characteristics of increased body temperature, established an association between increased body temperature with death or dependent outcome and described the current management of elevated temperatures in the Australian context to improve nursing practice, education and research.

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.

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 (<  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.

The trace elements zinc and copper are essential components of many enzymes, some of which are of importance for the development and function of the central nervous system. Deficiency of the metals has been shown to lead to malformations and to the loss of myelin in animals. Earlier reports of zinc concentrations in the cerebrospinal fluid are few and the results variable. In multiple sclerosis and in epilepsy therapy with phenytoin there are varying reports of changes in serum concentrations of zinc and copper. A method was developed for the determination of zinc in cerebrospinal fluid by flame atomic absorption spectrophotometry utilizing a pulse nebulizer technique. Zinc and copper in serum were determined by flame atomic absorption spectrophotometry with conti nous aspiration. The normal concentrations of zinc in cerebrospi nal fluid was 0.16_+0.03 micromoles per litre (mean +_ S.D.). The zinc concentrations were correlated with protein and albumin concentrations in the cerebrospinal fluid but not with the serum zinc levels. In the patients with increased protein concentrations in the cerebrospinal fluid or with subarachnoid haemorrhage increased zinc levels were found. In 50 patients with multiple sclerosis lower serum concentrations of zinc were found compared to age and sex matched controls. In younger patients low serum levels of copper were also observed. There was no correlation between zinc and protein parameters in the cerebrospinal fluid of multiple sclerosis patients. In untreated epileptic males low serum zinc concentrations were observed. During the first 72 hours of phenytoin therapy increased serum concentrations of zinc and copper were found. during long-term therapy with phenytoin alone or in combination with other antiepileptic drugs there was an increased serum concentration of copper and ceruloplasmin but no change in zinc concentration compared with controls. / <p>Diss. Umeå, Umeå universitet, 1982, härtill 4 uppsatser</p> / digitalisering@umu

Introduction. The glial cell water channel aquaporin-4 (AQP4) plays an important ro le in brain oedema, astrocyte migration and neuronal excitability. Current theories of AQP4 function are based largely on experiments using AQP4 -1- mice. These mice have only been partially characterized. I therefore undertook a detailed investigation of baseline brain properties in AQP4 -1- mice. In the second part of my experiments I investigated the role of AQP4 in brain oedema in a mouse model of subarachnoid haemorrhage. Method. Gross anatomical measurements included estimates of brain and ventricle size. Neurons, astrocytes and oligodendrocytes were assessed using the neuronal nuclear marker NeuN, the astrocyte marker GFAP, and the myelin stain Luxol Fast Blue. The blood brain barrier was studied by electron microscopy and the horseradish peroxidase extravasation technique. A mouse model in which 30~1 of autologous blood was injected into the basal cisterns was used to reproduce subarachnoid haemorrhage. Brain water content, intracranial pressure and neurological score were compared in wildtype and AQP4 -/- mice. I also measured blood brain barrier permeability and the osmotic permeability of the glia lim itans, one of the routes of oedema elimination.

Background: Subarachnoid haemorrhage (SAH) is a severe stroke that in 85% of all cases is caused by the rupture of a cerebral aneurysm. The median age at onset is 50-55 years and the overall mortality is approximately 45%.Sufficient cortisol levels are important for survival. After SAH hypothalamic/pituitary blood flow may be hampered this could result in inadequate secretion of cortisol. SAH is also associated with a substantial inflammatory response. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, mediates vasoconstriction and increased ADMA levels may be involved in inflammation and endothelial dysfunction. Continuous electroencephalogram (EEG) monitoring can be used to detect non-convulsive seizures, leading to ischemic insults in sedated SAH patients. Elevated ADMA levels are risk factors for vascular diseases. Vascular disease has been linked to stress, inflammation and endothelial dysfunction. SAH possesses all those clinical features and theoretically SAH could thus induce vascular disease. Aims: 1. Assess cortisol levels after SAH, and evaluate associations between cortisol and clinical parameters. 2. Assess ADMA levels and arginine/ADMA ratios after SAH and evaluate associations between ADMA levels and arginine/ADMA ratios with severity of disease, co-morbidities, sex, age and clinical parameters. 3. Investigate occurrence of subclinical seizures in sedated SAH patients. 4. Evaluate if patients that survive a SAH ≥ one year have an increased risk of vascular causes of death compared to a normal population. Results: Continuous infusion of sedative drugs was the strongest predictor for a low (&lt;200 nmol/L) serum cortisol. The odds ratio for a sedated patient to have a serum cortisol &lt; 200 nmol/L was 18.0 times higher compared to an un-sedated patient (p &lt; 0.001). Compared to admission values, 0-48 hours after SAH, CRP increased significantly already in the time-interval 49-72 hours (p&lt;0.05), peaked in the time-interval 97-120 hours after SAH and thereafter decreased. ADMA started to increase in the time-interval 97-120 hours (p&lt;0.05). ADMA and CRP levels were significantly higher, and arginine/ADMA ratios were significantly lower in patients with a more severe condition (p&lt;0.05). Epileptic seizure activity, in sedated SAH patients, was recorded in 2/28 (7.1%) patients during 5/5468 (0.09%) hours of continuous EEG monitoring. Cerebrovascular disease was significantly more common as a cause of death in patients that had survived a SAH ≥ one year, compared to the population from the same area (p&lt;0.0001). Conclusions: Continuous infusion of sedative drugs was associated with low (&lt;200 nmol/L) cortisol levels. ADMA increased significantly after SAH, after CRP had peaked, indicating that endothelial dysfunction, with ADMA as a marker, is induced by a systemic inflammation. Patients with a more severe condition had significantly higher ADMA and CRP levels, and significantly lower arginine/ADMA ratio. Continuous sedation in sedated SAH patients seems to be beneficial in protecting from subclinical seizures. Cerebrovascular causes of death are more common in SAH survivors. / <p>Funding: The Swedish Society of Medicine, the Faculty of Medicine at Umeå University, The Kempe Foundations and The Stroke Foundation of Northern Sweden supported this study financially.</p>

The historical development, current practice, and the future of interventional neuroradiology are intricately linked to the advancements in the imaging and devices used for neuroendovascular treatments. This thesis explores the advanced imaging potential of the C-arm imaging systems used in the neurointerventional suite and investigates the initial clinical experience with a new flow diverter device to treat the intracranial aneurysms. A cohort of aneurysmal SAH patients who developed delayed cerebral ischaemia (DCI) were prospectively studied with a new parenchymal blood volume (PBV) research protocol C-arm CT examination concurrent with a magnetic resonance (MR) imaging examination that included perfusion and diffusion weighted sequences. Using a robust quantitative volume-of-interest analysis, it was demonstrated that C-arm CT PBV measurements are in agreement with MR-PWI CBV and CBF, and the PBV represents a composite perfusion parameter with both blood-flow (&asymp;60&percnt;) and blood-volume (&asymp;40&percnt;) weightings. Subsequently, using a voxel-wise ROC curve analysis and MR-DWI, it was shown that using optimal thresholds, C-arm CT PBV measurements allow reliable demarcation of the irreversibly infarcted parenchyma. For evaluation of ischaemic parenchyma, the PBV measurements were reliable for moderate-to-severe ischaemia but were prone to underestimate the mild-to-moderate ischaemia. A catalogue of reference mean PBV measurements was then created for various anatomical regions encompassing the whole brain after excluding any locations with ongoing ischaemia or infarction. Next, using an ROI-based analysis of the C-arm CT projection data, steady-state contrast concentration assumption underlying the PBV calculations was investigated. It was demonstrated that for clinical scans, the ideal steady-state assumption is not fully met, however, for a large majority of C-arm CT examinations the temporal characteristics of TDCs closely approximate the expected ideal steady-state. The degree to which the TDC of a C-arm CT scan approximates the ideal steady-state was found to influence the resulting PBV measurements and their agreement to MR-CBV. Moreover, the temporal characteristics of TDCs showed inter-subject variation. Finally, the C-arm CT cross-sectional soft tissue images were demonstrated to be of adequate quality for the assessment of ventricles and for the detection of procedural vessel rupture. These findings advance the understanding of the nature of PBV parameter, establish the optimal PBV thresholds for infarction, provide reference PBV measurements, and highlight the limitations of C-arm CT PBV imaging. The work is of considerable clinical significance and has implications for implementation of C-arm CT PBV imaging in the interventional suite for management of patients with acute brain ischaemia. In regards to the initial clinical experience with the flow diversion treatment of intracranial aneurysms, the procedural, angiographic, and clinical outcomes were studied. Several pertinent technical and clinical issues were highlighted for this new treatment approach. Based on the observations made during this work, a new grading schema was then developed to monitor the angiographic outcomes after flow diversion treatment. Using the angiographic data for patients treated with FD, the new grading schema was demonstrated to be sufficiently sensitive to register gradual aneurysm occlusion and evaluate parent artery patency, with an excellent inter-rater reliability and applicability to various aneurysm morphologies. This work (largest multi-centre series at the time of its publication) informed the interventional neuroradiology community about the safety, efficacy, and outcomes of flow diversion treatment. Additionally, it provided a sensitive and reliable scale to evaluate the angiographic outcomes after flow diversion treatment, in both research and clinical practice.

Many patients with an aneurysmal subarachnoid haemorrhage (SAH) exhibit difficulties in rehabilitation, even in cases of a good prognosis. The present project investigates this using qualitative methods and standardised outcome measures. Patients with SAH treated at Uppsala University Hospital between 2002 and 2005 with an expected good prognosis were consecutively included. In addition, nurses working with such patients were interviewed. Outcome was assessed in terms of perception of care, psychiatric health, coping and health related quality of life (HRQoL). Qualitative content analyses revealed eight categories, which were divided into two patterns, Confident or Pessimistic perception of recovery, largely on the basis of the presence or absence of depression. Eighty-three patients were assessed by The Structured Clinical Interview for DSM-IV, Axis I (SCID-I). Forty-one percent fulfilled criteria for any psychiatric disorder seven months after SAH and 45 % presented with a history of lifetime psychiatric morbidity. Logistic regressions indicated that a psychiatric history was related to a higher risk of psychiatric problems seven months after SAH, as well as a lower return to work. SAH patients had lower HRQoL than the general Swedish population; almost entirely in the subgroup with a psychiatric history prior to the SAH. Those with a psychiatric history used more evasive, fatalistic, emotive and palliative coping strategies associated with inability to handle illness. Multiple regressions revealed that a psychiatric history and use of coping were independently associated with HRQoL, albeit more in the mental than the physical domains. Qualitative content analyses revealed that nurses viewed patients’ support needs as a process ranging from technological to emotional care. Shortcomings in the communication between nurses in acute and rehabilitation settings on the subject of support were acknowledged. The results underline the importance of early diagnosis of coexisting psychiatric illness and the need for an intact health care chain.