Risk factors for aneurysmal subarachnoid hemorrhage - BMI and serum lipids: 11-year follow-up of the HUNT and the Tromsø Study in Norway.

OBJECTIVES: Life-style factors have been associated with the risk for aneurysmal subarachnoid hemorrhage (aSAH), but it is not clear whether body mass index (BMI) and serum lipids are associated with risk. We prospectively assessed these associations in two large population studies. METHODS: A total of 65,526 participants in the Nord-Trøndelag Health Study (1995-1997) and 26,882 participants in the Tromsø Study (1994-1995) were included. Studies included measurements of body weight and height, serum lipids, and self-administered questionnaires. Participants who experienced aSAH were identified, and hazard ratios (HRs) were estimated using Cox regression analysis. RESULTS: During 11 years of follow-up, aSAH was diagnosed in 122 participants. Overweight (BMI 25-29.9) was negatively associated with the risk of aSAH (HR 0.7, 95% CI 0.4-1.0). There was no over all association of total serum cholesterol, HDL cholesterol, or triglycerides with the risk of aSAH, but in participants younger than 50 years, HDL cholesterol was inversely associated with the risk (HR per standard deviation increase 0.6, 95% CI 0.4-0.9). CONCLUSIONS: Overweight may be associated with reduced risk of aSAH, but there was no over all association of total serum cholesterol, HDL cholesterol, or triglycerides with the risk of aSAH in this prospective study.

Incidence and mortality of aneurysmal subarachnoid hemorrhage in two Norwegian cohorts, 1984-2007.

OBJECTIVE: The incidence of aneurysmal subarachnoid hemorrhage (aSAH) ranges from 4 to 10 per 100,000 person-years in most countries, and 30-day case fatality is high. The aim of this study was to estimate the incidence and case fatality of aSAH and to assess preictal predictors of survival in 2 large Norwegian population-based cohort studies. METHODS: A total of 94,976 adults (≥20 years) in the Nord-Trøndelag Health Study and 31,753 participants (aged ≥20 years) in the Tromsø Study were included. During follow-up, aSAHs were identified, incidence rates were estimated, and predictors of survival were assessed using Cox and Poisson regression analysis. RESULTS: A total of 214 patients with aSAH were identified during 2,077,927 person-years of follow-up from 1984 to 2007. The incidence rate was 10.3 per 100,000 person-years: 13.3 for women and 7.1 for men. The incidence increased by 2% (95% confidence interval [CI] 0-4) per 5-year time period. Case fatality at 3, 7, and 30 days was 20%, 24%, and 36%. Thirty-day case fatality remained stable during follow-up (odds ratio 1.01, 95% CI 0.97-1.06 per year). Never smokers had poorer survival after aSAH than current and former smokers combined (hazard ratio 1.6, 95% CI 0.9-2.9). CONCLUSIONS: The slight increase in incidence of aSAH over time may be explained by differences in diagnostic procedures. Case fatality remained stable during 23 years of follow-up.

Quality of life after treatment for incidental, unruptured intracranial aneurysms.

BACKGROUND: Discovering an intracranial aneurysm may profoundly affect the patient's quality of life. Patients living with unruptured and untreated aneurysms often report symptoms of anxiety and depression. There are few trials studying the quality of life after treatment of unruptured intracranial aneurysms. We aimed to compare the quality of life and symptoms of anxiety or depression after endovascular coiling or open surgery clipping of unruptured intracranial aneurysms, in patients with no prior subarachnoid haemorrhage. METHOD: 73 living patients were included. 44 had undergone open surgery clipping and 31 had undergone endovascular coiling within the last 5.5 years. We registered a number of parameters from medical records and the patients' current quality of life was assessed by a questionnaire. 63 of 73 (86.3%) returned our questionnaire, which included the Norwegian version of SF-36 and the Hospital Anxiety and Depression Scale (HAD). FINDINGS: Many patients treated for unruptured intracranial aneurysms have a relatively low quality of life. The low scores indicate that the patients experience limitations in their ability to work or accomplish desired activities due to perceived physical or mental handicaps. There were no significant differences between the open surgery group and the endovascular group when comparing quality of life parameters after treatment. A subgroup analysis of patients with a favourable functional outcome also showed reduced quality of life without any differences in the two treatment groups. There were no signs of improvement in quality of life over time. CONCLUSION: Quality of life after treatment does not seem to be a strong argument for choosing one modality of treatment over the other in patients with unruptured intracranial aneurysms. There are no significant differences in the quality of life of patients successfully treated using endovascular technique and patients who underwent craniotomy and clipping. We speculate that the low quality of life scores are due to factors unrelated to the aneurysms. The scores possibly reflect characteristics of a patient group where incidental aneurysms are more frequently diagnosed while undergoing extensive imaging procedures due to unrelated symptoms.

Intra-operative 3D ultrasound in neurosurgery.

In recent years there has been a considerable improvement in the quality of ultrasound (US) imaging. The integration of 3D US with neuronavigation technology has created an efficient and inexpensive tool for intra-operative imaging in neurosurgery. In this review we present the technological background and an overview of the wide range of different applications. The technology has so far mostly been applied to improve surgery of tumours in brain tissue, but it has also been found to be useful in other procedures such as operations for cavernous haemangiomas, skull base tumours, syringomyelia, medulla tumours, aneurysms, AVMs and endoscopy guidance.

Serological responses to Cryptosporidium antigens among users of surface- vs. ground-water sources.

Cryptosporidium oocysts are commonly detected in surface-derived drinking water. However, the public health significance of these findings is unclear. This study compared serological responses to two Cryptosporidium antigen groups for blood donors and college students using chlorinated and filtered river water vs. ground-water sources. The surface water received agricultural and domestic sewage discharges upstream. Participants from the surface-water city had a higher relative prevalence (RP) of a serological response to the 15/17-kDa antigen group (72.3 vs. 52.4%, RP = 1.36, P < 0.001) and to the 27-kDa antigen group (82.6 vs. 72.5%, RP = 1.14, P < 0.02). Multivariate logistic regression analysis found that the people with a shorter duration of residence or drinking bottled water also had a lower seropositivity for each marker. Use of private wells was associated with a higher prevalence of response to the 15/17-kDa markers. Seroconversion to the 15/17-kDa antigen group was more common in the residents of the city using surface water. These findings are consistent with an increased risk of Cryptosporidium infection for users of surface-derived drinking water compared with users of municipal ground-water-derived drinking water. Users of private well water may also have an increased risk of infection.

A two-year follow-up survey of antibody to Cryptosporidium in Jackson County, Oregon following an outbreak of waterborne disease.

To estimate the duration of Cryptosporidium-specific antibody, a Western blot assay measured antibody in paired sera from 124 residents of Jackson County, Oregon collected 0.5 and 2.5 years after the end of an outbreak in Talent, Jackson County. The outcome measure was the intensity of antibody responses, (which may approximate to a titre), to 27-kDa and 15/17-kDa antigens. Intensity of response to the 27-kDa antigen(s) declined to 54% of the 1992 value while responses to a 15/17-kDa antigen(s) remained close to the initial values. Increasing age of the donor predicted higher intensity of antibody to the 15/17-kDa antigen(s) in both the initial (P = 0.004) and follow-up (P = 0.038) surveys. No relationship was observed between age and antibody intensity for the 27-kDa antigen(s) during either survey (P > 0.10). Both the initial and follow-up surveys showed significant elevations in antibody intensity for Talent residents, possibly indicating a high endemic rate of infection/re-infection or high levels of chronic infection.

A study of the contribution of changes in the cerebral blood volume to the haemodynamic response to anoxia in rat brain.

A susceptibility contrast agent which does not pass into the extra-cellular space was used to study the effect of changes in the relative cerebral blood volume (CBV) on the haemodynamic response to anoxia, for both normal and ischaemic brain tissue, in a rat model of acute focal ischaemia. In non-ischaemic tissue a strong CBV component was observed in the haemodynamic response, both during and after anoxia. During anoxia the change in the CBV of the non-ischaemic tissue was estimated to be 40% in the caudate putamen and 70% in the frontal-parietal cortex. For severely ischaemic tissue (ischaemic caudate putamen) there was no change in the CBV during anoxia while in areas of moderate ischaemia (ischaemic frontal parietal cortex) a change of 20% was observed. The effect of the contrast agent on spin-echo images was consistent with a small reduction in the microvascular blood volume of the ischaemic tissue.

Comparison of dysprosium DTPA BMA and superparamagnetic iron oxide particles as susceptibility contrast agents for perfusion imaging of regional cerebral ischemia in the rat.

The aim of the study was to compare the first-passage profiles of dysprosium diethylenetriamine penta-acetic acid bis(methylamide) (DTPA BMA) and the superparamagnetic iron oxide particles NSR 0430 in regions with severe and moderate cerebral ischemia. In seven rats subjected to middle cerebral artery occlusion, two dynamic MR perfusion imaging series were acquired after intravenous bolus injections of .5 mmol/kg dysprosium DTPA BMA and .06 mmolFe/kg iron oxide particles, respectively. The doses were chosen to obtain similar maximum signal change in normally perfused brain. The first-passage profiles were compared in a region of interest (ROI) in the core area with severe ischemia and in a ROI in the penumbra area of moderate ischemia. The results were compared both as the calculated mean signal intensity versus time curves for all seven rats and statistically for an estimated mean transit time (MTT) after gamma variate fitting of the calculated concentration versus time curves. The first-passage profiles for the two contrast agents were similar, both in the core area of severe ischemia and in the penumbra area of moderate ischemia. In this rat stroke model, dysprosium DTPA BMA and the superparamagnetic iron oxide particles NSR 0430 were found to be equally efficacious for the diagnosis of the perfusion deficit, but if safe for human investigations, iron oxide particles would have an advantage as equal susceptibility effect may be achieved with smaller injection volumes.

A study of the contribution of changes in the cerebral blood volume to the haemodynamic response to anoxia in rat brain.

A susceptibility contrast agent which does not pass into the extra-cellular space was used to study the effect of changes in the relative cerebral blood volume (CBV) on the haemodynamic response to anoxia, for both normal and ischaemic brain tissue, in a rat model of acute focal ischaemia. In non-ischaemic tissue a strong CBV component was observed in the haemodynamic response, both during and after anoxia. During anoxia the change in the CBV of the non-ischaemic tissue was estimated to be 40% in the caudate putamen and 70% in the frontal-parietal cortex. For severely ischaemic tissue (ischaemic caudate putamen) there was no change in the CBV during anoxia while in areas of moderate ischaemia (ischaemic frontal parietal cortex) a change of 20% was observed. The effect of the contrast agent on spin-echo images was consistent with a small reduction in the microvascular blood volume of the ischaemic tissue.

Cerebrovascular changes in rats during ischemia and reperfusion: a comparison of BOLD and first pass bolus tracking techniques.

Both first pass bolus tracking of a susceptibility contrast agent and blood oxygenation level dependent (BOLD) sequences provide information on the tissue perfusion and the cerebral blood volume, but each sequence has its own particular limitations. In this article, both techniques were used to assess the cerebrovascular changes occurring in a rat model of focal cerebral ischemia with reperfusion after 2 h of ischemia. The blood oxygenation level dependent studies were performed before, during, and after 60 s of anoxia to observe the response of the tissue to a respiratory challenge. Both techniques were able to detect ischemia and reperfusion; however, first pass bolus tracking provided better sensitivity and was easier to interpret. Because the blood oxygenation level dependent sequence did not provide any additional information, bolus tracking would appear to be the method of choice for studies of cerebral ischemia with reperfusion.

Analysis of dynamic magnetic resonance images.

Dynamic magnetic resonance (MR) imaging with contrast agents is a very promising technique for studying tissue perfusion in vivo. A temporal series of magnetic resonance images of the same slice are acquired following the injection of a contrast agent into the blood stream. The image intensity depends on the local concentration of the contrast agent, so that tissue perfusion can be studied by the image series. A new method of analyzing such series is described here. Nonparametric linear regression is used for modeling the image intensity along the series on a pixel by pixel basis. After modeling, some relevant quantities describing the time series are obtained and displayed as images. Due to its flexibility, this approach is preferred to parametric modeling when pathology is present since this can induce a wide spread of patterns for the pixel image intensity along time. Results of the application of the method to series of dynamic magnetic resonance images from ischaemic rat brains after the injection of the susceptibility agent Sprodiamide Inj. (Dy-DTPA-BMA) are shown and compared to results from a related known method.

Comparison of MR perfusion imaging and microsphere measurements of regional cerebral blood flow in a rat model of middle cerebral artery occlusion.

The purpose of this investigation was to correlate magnetic resonance (MR) perfusion measurements with absolute regional cerebral blood flow (rCBF) in a rat model of focal ischemia. The MR perfusion measurements were made using dynamic first-pass bolus tracking of a susceptibility contrast agent, whereas rCBF was measured using radioactive microspheres. Two simple MR perfusion parameters, the maximum change in R2* (m delta R2*) and time delay to m delta R2* (t delta R2*), were derived from the signal intensity versus time curves on a pixel-to-pixel basis, without applying curve-fitting procedures or tracer kinetic theory. In each hemisphere, m delta R2* and t delta R2* were compared with the rCBF measurements in four selected regions of interest. Sixteen MR bolus tracking series were performed in 12 rats with occlusion of the middle cerebral artery. In all of the individual series there was a significant correlation (.0001 < or = p < or = .02) between m delta R2* and the microsphere rCBF measurements, with correlation coefficients ranging from .784 to .983. Pooling the m delta R2* data resulted in a correlation coefficient of .809 (p = .0001). There was a nonlinear correlation between the t delta R2* and rCBF. For both parameters there was considerable variation between different measurements regarding both the slope of the regression line and its intercept with the y-axis. Our results justify the use of m delta R2* as a relative measure of perfusion during acute cerebral ischemia. Because of the interindividual variation, calibration of MR perfusion measurements for the estimation of absolute flow values must be considered unreliable. The t delta R2* may have physiological relevance as a marker of collateral flow.

Perfusion and diffusion-weighted MR imaging for in vivo evaluation of treatment with U74389G in a rat stroke model.

BACKGROUND AND PURPOSE: The present study was performed to examine the potential of diffusion-weighted (DW) imaging and dynamic first-passage bolus tracking of susceptibility contrast agents (perfusion imaging) for early in vivo evaluation of the effects of treatment with the free radical scavenger U74389G in a rat model of temporary focal ischemia. METHODS: After 45 minutes of middle cerebral artery occlusion, the treatment group (n = 9) received an infusion of U74389G, and the control group (n = 9) received the identical volume of the vehicle. Reperfusion was instituted in both groups after 120 minutes of middle cerebral artery occlusion. The DW images were collected during middle cerebral artery occlusion and reperfusion and were compared with histologically assessed areas of tissue injury after 2 hours of reperfusion. The dynamic perfusion series were processed on a pixel-to-pixel basis to produce parametric maps reflecting the maximum reduction in the signal obtained during the first passage of the contrast agent and the time delay between the arrival of the bolus and the point of maximum contrast-agent effect. RESULTS: The area of ischemic injury, as assessed from the DW imaging at 60 minutes of reperfusion, was significantly smaller in the treatment group: 9 +/- 8% of ipsilateral hemisphere compared with 19 +/- 8% in the control group. The histological examination after 2 hours of reperfusion demonstrated an area of ischemic injury of 10 +/- 8% for the treatment group compared to 25 +/- 10% in the control group. In the treatment group, the perfusion imaging showed a reduction in time delay to maximum effect of the contrast agent in the ischemic hemisphere compared with the control group. CONCLUSIONS: The DW imaging during early reperfusion showed a protective effect of postocclusion treatment with the free radical scavenger U74389G. The improvement of time delay to maximum effect of the contrast agent observed in the perfusion imaging of the treatment group may reflect an improvement in the collateral flow to the ischemic tissue.

Combined perfusion and diffusion-weighted magnetic resonance imaging in a rat model of reversible middle cerebral artery occlusion.

BACKGROUND AND PURPOSE: Diffusion-weighted imaging and dynamic first-pass bolus tracking of susceptibility contrast agents (perfusion imaging) are two new magnetic resonance imaging techniques that offer the possibility of early diagnosis of stroke. The present study was performed to evaluate the diagnostic information derived from these two methods in a rat model of temporary focal ischemia. METHODS: Fifteen male Wistar rats were assigned to 45 (n = 7) or 120 minutes (n = 8) of middle cerebral artery occlusion followed by reperfusion using the intraluminal filament technique. The diffusion-weighted images were collected, and areas of hyperintensity were compared with histologically assessed areas of ischemic injury. The magnetic resonance perfusion image series were postprocessed to produce topographic maps reflecting the maximum reduction in the signal obtained during the first passage of the contrast agent and the time delay between the arrival of the bolus and the point of maximum contrast-agent effect. RESULTS: Hyperintensity in diffusion-weighted images was demonstrated after 30 minutes of middle cerebral artery occlusion and was mainly expressed in the lateral caudoputamen and parts of the lower frontoparietal cortex. Reperfusion after 45 minutes of occlusion reduced the area of hyperintensity from 24.2% to 9.9% of hemispheric area. In the group with 120 minutes of occlusion, the hyperintense area increased from 24.4% to 29.1%. Relative to the nonischemic hemisphere, the changes in the topographic maps of maximum signal reduction occurred in the lateral caudoputamen and adjacent lower neocortical areas. Increased time delay to maximum effect, however, was seen also in the upper frontoparietal cortex. CONCLUSIONS: Hyperintensity in diffusion-weighted images was reversible after 45 minutes but not after 120 minutes of middle cerebral artery occlusion. Analysis of the signal-reduction and time-delay parametric maps demonstrated regions of different perfusion changes in the ischemic hemisphere.

Characterization of the microcirculation during ischemia and reperfusion in the penumbra of a rat model of temporary middle cerebral artery occlusion: a laser Doppler flowmetry study.

The dynamic changes in microcirculation were investigated with laser Doppler flowmetry in two selected regions of interest (ROI) of a stroke lesion during ischemia and early reperfusion using a rat model of temporary middle cerebral artery (MCA) occlusion. In each ROI measurements were made either during 30 min or 2 h of MCA occlusion followed by 1 h of reperfusion. On the periphery of the MCA territory, an area of mild ischemia with a mean reduction of flow to 38% (39.9% in the group with 30 min MCA occlusion and 35.9% in the group with 2 h MCA occlusion) of preischemic values was demonstrated. Closer to the center of the MCA territory, more severe ischemia with a mean reduction of flow to 21% (19.9% in the 30-min group and 22.9% in the 2-hour group) was seen. In the two groups with laser Doppler flowmetry in the ROI of mild ischemia, a compensatory increase in flow during the first 3-6 min after MCA occlusion could be seen. All rats displayed a peak hyperperfusion immediately after re-establishing of flow which then stabilized above, below, or equal to the preischemic level. This peak hyperemia was most abundant in the group in which flow was measured in the ROI of more severe ischemia after the 30-min MCA occlusion. In the same area a short hyperemic peak was followed by a significant hypoperfusion of 60% of preischemic flow after 2 h of MCA occlusion. In the groups with flow measurements in the ROI of mild ischemia, there was a return to preischemic flow after the 30-min ischemia and a tendency of preserved hyperemia after 2 h of MCA occlusion.

13C NMR spectroscopy study of cortical nerve cell cultures exposed to hypoxia.

Primary cultures of cerebral cortical GABA-ergic neurons growing on top of a preformed layer of astrocytes (co-cultures) were incubated with [1-13C]glucose and exposed to a low oxygen atmosphere (2% O2) for 17 hr. 13C, 1H, and 31P nuclear magnetic resonance (NMR) spectroscopy was performed on perchloric acid (PCA) extracts of cells and of media collected from these cultures. In the control groups incorporation of 13C label into glutamine, citrate, and lactate could be demonstrated in both cell extracts and culture media. Labeled GABA and glutamate were only observed in cell extracts. During hypoxia high energy phosphates decreased but lactate production and glucose consumption increased. There was a decreased amount of citrate and glutamine in cell extracts and media of the hypoxic co-cultures. There was a change in distribution of the 13C label within the GABA molecule, with an increase of labeling in the C-2 position. This change in 13C distribution was not found in glutamine present in the media where it is a precursor for GABA in neurons. Instead a decrease in the corresponding C-4 position was observed. These results suggest that energy depletion during hypoxia leads to reduced export from the astrocytic tricarboxylic acid (TCA) cycle as demonstrated by a decreased amount of citrate and changed distribution of 13C in glutamine. The change in the distribution of label in GABA from cell extracts as compared to glutamine in the medium may indicate that neurons are synthesizing GABA using precursors supplied from their own TCA cycle and not from precursors supplied by astrocytes.

NMR spectroscopic study of cell cultures of astrocytes and neurons exposed to hypoxia: compartmentation of astrocyte metabolism.

Primary cultures of murine cerebral cortical astrocytes or cerebellar granule neurons were exposed to 7 h of hypoxia (3 h in some cases). The culture medium was analyzed at the end of the hypoxic or normoxic period by 1H NMR spectroscopy and intracellular components were analyzed as perchloric acid extracts by 31P and 1H NMR spectroscopy. Lactate production in astrocytes increased only marginally, whereas high energy phosphate concentrations were reduced, during 7 h of hypoxia and after 17 h of reoxygenation. After 3 h of hypoxia full recovery was possible during reoxygenation. Citrate and glutamine secretion was reduced or unchanged, respectively, during 7 h of hypoxia. Succinate secretion was only observed during normoxia, whereas pyruvate was secreted during hypoxia. Cerebellar granule neurons were more efficient in increasing glycolysis and were, therefore, more resistant to the effects of hypoxia than astrocytes. In the neurons lactate production was doubled and no effects on levels of high energy phosphates were seen after 7 h of hypoxia. Astrocytes were reoxygenated for 17 h after hypoxia or normoxia in a medium containing [2-13C]acetate in order to access if astrocytes were still capable of supplying neurons with essential precursors. The media were subsequently analyzed by 13C NMR spectroscopy. After shorter periods of hypoxia (3 h) full recovery was possible. Citrate and glutamine production remained however decreased during reoxygenation after 7 h of hypoxia. 13C incorporation into glutamine was greatly reduced but that into citrate was unchanged. These results suggest that under the present conditions, neurons are more efficient than astrocytes in switching the energy metabolism from aerobic to anaerobic glycolysis and that astrocytes may suffer long term damage to mitochondria from longer periods of hypoxia. Furthermore, evidence is presented for the existence of several TCA cycles within astrocytes based on labeling ratios. During normoxia the labeling ratios in the C-2/C-4 positions in glutamine and in the equivalent positions in citrate were 0.27 and 0.11, respectively.

NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline) did not affect recovery of high energy phosphates and pH in early reperfusion in a rat model of transient forebrain ischemia. Or: an in vivo 31P NMR spectroscopy study.

The new non-NMDA (N-methyl-D-aspartate) receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline) has previously been shown to exert a neuroprotective effect in animal models of cerebral ischemia when administered in the post-ischemic phase. In this investigation the effect of NBQX on acidosis and energy recovery in early reperfusion after 10 min of transient forebrain ischemia with the 2-vessel occlusion model in the rat was studied with 31P NMR spectroscopy. In the intervention group the animals received a bolus dose of NBQX 30 mg.kg-1 i.v. at the start of reperfusion. 31P NMR spectroscopy was used to measure intracellular pH, ATP and phosphocreatine continuously in-vivo during, and after, the ischemic event. The recovery of high energy phosphates and pH was followed during 30 min of reperfusion. Pre-ischemic levels of phosphocreatine were reached after approximately 9-10 min in both groups. Although a slight improvement could be seen in the intervention group there was no significant difference in the rate of recovery between the two groups. ATP reached 90% of preischemic levels after about 8 min without significant difference between the two groups. With respect to the recovery of intracellular pH, no difference could be shown. Our results do not contradict previously published results, but suggest that the potential protective effect of NBQX is not mediated through improved recovery of energy metabolism in early reperfusion.

K-space substitution: a novel dynamic imaging technique.

A rapid dynamic imaging sequence has been developed in which only the 32 phase encoding steps that encode low spatial frequencies are collected for each dynamic image. These are substituted into a previously acquired, 128 x 128 raw data set prior to image reconstruction. In this way the dynamic information is retained while the overall appearance is improved in comparison with images obtained by zero filling to 128 x 128, leading to better qualitative evaluation. The limited k-space sampling means that the technique is most effective for large homogeneous areas of signal change since fine changes in contrast are imperfectly recorded.