<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.

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.

Subarachnoid hemorrhage (SAH) causes 5% of all strokes and is responsible for about 18,000 deaths per year in the United States (Aneurysmal Subarachnoid Hemorrhage, 2008). The incidence of SAH has been estimated at 6 to 8 per 100,000 persons per year (Linn, Rinkel, Algra, & van Gijn, 1996). In nearly 15% (range 5–34%) of patients with SAH, no source of hemorrhage can be identified via four-vessel cerebral angiography (Alen et al., 2003; Gupta et al., 2009), resulting in two major types of SAH: aneurysmal (ASAH) and nonaneurysmal (NASAH). Anecdotal evidence and contradictory research suggest that patients with NASAH experience some of the same health-related quality of life (HRQOL) issues as patients with ASAH. The purpose of this quantitative survey design study was to compare health-related quality of life (HRQOL) 1 to 3 years post-hemorrhage in patients who have experienced a NASAH to those who have experienced an ASAH. This is the first US study to specifically investigate HRQOL in NASAH and the second study comparing HRQOL outcomes between aneurysmal and nonaneurysmal subarachnoid hemorrhage patients. Our results are comparable to the first study by Hutter and Gilsbach, (1995), which also found that the two groups are much more similar than different. There were no significant differences between 28 of the 36 demographic and clinical characteristics examined in this study. Our study confirms previous findings that there is a significant impact on employment for both hemorrhage groups and an even greater inability to return to work for the NASAH patients. The nonaneurysmal group had more physical symptom complaints while the aneurysmal group had more emotional symptoms. Lastly, both groups had low levels of PTSD, and these levels did not differ significantly between groups. However, PTSD and social support were shown by regression analysis to impact HRQOL for both groups. We recommend that clinicians assess for PTSD in all subarachnoid hemorrhage patients and institute treatment early, which will decrease the negative effects on HRQOL. This may include offering psychological services or social work early in the hospital course to all SAH patients. Further research and policy changes are needed to assist in interventions that improve vocational reintegration after SAH. NASAH patients should no longer be referred to as having suffered a “benign hemorrhage.” They have had a life changing hemorrhage that may forever change their lives and impact their HRQOL.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24785号 / 医博第4977号 / 新制||医||1066(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 金子 新, 教授 YOUSSEFIAN Shohab, 教授 阪上 優 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

BACKGROUND A subarachnoid hemorrhage (SAH) is a bleed into the subarachnoid space surrounding the brain. This disease affects roughly 30,000 Americans each year and approximately one in six affected individuals die at the time of the ictal event. Individuals that do survive suffer from many complications including delayed cerebral vasospasm (DCV), cerebral edema, fever, and increased intracranial pressure (ICP) amongst others. These patients often suffer from brain damage due to neuronal apoptosis as a consequence of excess neuroinflammation. Microglia, the resident macrophage of the central nervous system, and Toll-like Receptor-4 (TLR4), a pro-inflammatory transmembrane receptor, have both been shown to play a role in the neuroinflammation seen in SAH. RBC components have been shown to activate microglial TLR4, and this event is suggested to trigger downstream mechanisms leading to neuronal apoptosis. The presented research takes a closer look at the role of microglial TLR4 in early neuronal apoptosis seen in an SAH model. METHODS All mice used were 10- to 12-week-old males on a C57BL/6 background: TLR4−/−, MyD88−/−, TRIF−/− and wild type (WT). To induce an SAH, a total of 60 ul of arterial blood from a donor WT mouse was injected for over 30 seconds into another mouse. For in vitro experiments, either primary microglia (PMG) or murine microglial BV2 cells were used. Microglia were separated from murine neuronal HT22 cells by 3um cell culture inserts or transwells, before being stimulated with lipopolysaccharide (LPS), red blood cells (RBCs), or RBC components including hemin (structurally similar to heme) and hemoglobin. In vivo samples were studied using either immunohistochemistry (IHC) or Fluorescence Activated Cell Sorting (FACS), and in vitro cells were studied using IHC and Light Microscopy. Neuronal cell death was measured using TUNEL and/or FloroJade C (FJC) assays. Cognitive function after SAH was measured using the Barnes Maze protocol. RESULTS In a 24-hour time course, more death occurred in the HT22 cells associated with BV2s treated with RBCs for 12-hour and 24-hour incubation time points as compared to 1-hour and 3-hour time points. Similar results were seen in the WT PMGs, as HT22 apoptosis increased in the RBC treated WT groups as the incubation time points increased. The WT PMG and MyD88−/− RBC treated PMGs showed significant death as compared to a WT untreated control (p<0.05) using a FJC assay, and both showed more death in a TUNEL assay as compared to an untreated control. WT mice treated with whole blood and hemoglobin had significantly more apoptosis as compared with a normal saline (NS)-treated control mouse (p<0.05). WT PMGs treated with whole blood and hemoglobin had more apoptosis as compared with an untreated control. MyD88-/- treated with RBC, hemoglobin, and hemin had more HT22 cell death compared with other genotypes treated with the same component. For the Barnes Maze, TLR4−/− mice performed significantly less total errors than WT mice on POD5 and 6 (p<0.01), and took significantly less time to reach the goal chamber on POD4, POD5 (p<0.05), and POD6 (p<0.01). CONCLUSION Our experimental results suggest that a microglial TLR4-dependent, MyD88-independent pathway is involved in neuronal apoptosis very early in an SAH model via RBC and hemoglobin activation, and that neuronal cell apoptosis due to TLR4 expression may be related to SAH-related cognitive and behavioral deficits. Our results suggest that TRIF may be the intracellular adaptor that is involved in this mechanism, but further experiments are needed to confirm this.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 6 uppsatser.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2004. / Härtill 5 uppsatser.

There is conflicting data on the effects of statins on cerebral vasospasm and clinical outcomes in aneurysmal subarachnoid hemorrhage (aSAH) patients. In this retrospective cohort study, patients were divided into those who received pravastatin (PRAV group) 40mg/d and those who did not (NP group). Data were analyzed using multivariate logistic regression. Eighty-one patients met inclusion criteria. There was a statistically significant decreased in the incidence of vasospasm in the PRAV group; however, this association did not retain significance after adjusting for WFNS, race, elevated WBC, and clipping (59% PRAV vs. 88% NP, p=0.08). There was no statistically significant difference in proportion of severe radiological vasospasm or mortality between groups. However, there was a trend towards a decreased mean length of stay (P=0.06) and a significantly higher proportion of survivors discharged to home in the PRAV group (P<0.0001). In conclusion, there was a trend towards a decrease in the incidence of vasospasm in the aSAH receiving pravastatin, but this trend did not achieve statistical significance after adjusting for potential confounders. Pravastatin was associated with other favorable clinical outcomes.