Induced Hypertension for Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: A Randomized Clinical Trial.

BACKGROUND AND PURPOSE: Induced hypertension is widely used to treat delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage, but a literature review shows that its presumed effectiveness is based on uncontrolled case-series only. We here report clinical outcome of aneurysmal subarachnoid hemorrhage patients with DCI included in a randomized trial on the effectiveness of induced hypertension. METHODS: Aneurysmal subarachnoid hemorrhage patients with clinical symptoms of DCI were randomized to induced hypertension or no induced hypertension. Risk ratios for poor outcome (modified Rankin Scale score >3) at 3 months, with 95% confidence intervals, were calculated and adjusted for age, clinical condition at admission and at time of DCI, and amount of blood on initial computed tomographic scan with Poisson regression analysis. RESULTS: The trial aiming to include 240 patients was ended, based on lack of effect on cerebral perfusion and slow recruitment, when 21 patients had been randomized to induced hypertension, and 20 patients to no hypertension. With induced hypertension, the adjusted risk ratio for poor outcome was 1.0 (95% confidence interval, 0.6-1.8) and the risk ratio for serious adverse events 2.1 (95% confidence interval, 0.9-5.0). CONCLUSIONS: Before this trial, the effectiveness of induced hypertension for DCI in aneurysmal subarachnoid hemorrhage patients was unknown because current literature consists only of uncontrolled case series. The results from our premature halted trial do not add any evidence to support induced hypertension and show that this treatment can lead to serious adverse events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01613235.

RNA Sequencing Analysis of Intracranial Aneurysm Walls Reveals Involvement of Lysosomes and Immunoglobulins in Rupture.

BACKGROUND AND PURPOSE: Analyzing genes involved in development and rupture of intracranial aneurysms can enhance knowledge about the pathogenesis of aneurysms, and identify new treatment strategies. We compared gene expression between ruptured and unruptured aneurysms and control intracranial arteries. METHODS: We determined expression levels with RNA sequencing. Applying a multivariate negative binomial model, we identified genes that were differentially expressed between 44 aneurysms and 16 control arteries, and between 22 ruptured and 21 unruptured aneurysms. The differential expression of 8 relevant and highly significant genes was validated using digital polymerase chain reaction. Pathway analysis was used to identify enriched pathways. We also analyzed genes with an extreme pattern of differential expression: only expressed in 1 condition without any expression in the other. RESULTS: We found 229 differentially expressed genes in aneurysms versus controls and 1489 in ruptured versus unruptured aneurysms. The differential expression of all 8 genes selected for digital polymerase chain reaction validation was confirmed. Extracellular matrix pathways were enriched in aneurysms versus controls, whereas pathways involved in immune response and the lysosome pathway were enriched in ruptured versus unruptured aneurysms. Immunoglobulin genes were expressed in aneurysms, but showed no expression in controls. CONCLUSIONS: For rupture of intracranial aneurysms, we identified the lysosome pathway as a new pathway and found further evidence for the role of the immune response. Our results also point toward a role for immunoglobulins in the pathogenesis of aneurysms. Immune-modifying drugs are, therefore, interesting candidate treatment strategies in the prevention of aneurysm development and rupture.

Vessel wall perforation mechanism of the excimer laser-assisted non-occlusive anastomosis technique.

The excimer laser assisted non-occlusive anastomosis (ELANA) technique is used to make anastomoses on intracerebral arteries. This end-to-side anastomosis is created without temporary occlusion of the recipient artery using a 308-nm excimer laser with a ring-shaped multi-fiber catheter to punch an opening in the arterial wall. Over 500 patients have received an ELANA bypass. However, the vessel wall perforation mechanism of the laser catheter is not known exactly and not 100 % successful. In this study, we aimed to understand the mechanism of ELANA vessel perforation using specialized imaging techniques to ultimately improve its effectiveness. High-speed imaging, high-contrast imaging, and high-sensitivity thermal imaging were used to study the laser wall perforation mechanism and reveal the mechanical and thermal effects involved. In vitro, rabbit arteries were exposed with the special designed laser catheter in a setup representative for the clinical setting, in which blood was replaced with a transparent UV absorbing liquid for visualization. We observed that laser vessel wall perforation was caused by explosive vapor bubbles tearing through the vessel wall, mostly within the first 20 of the total 200 pulses. Thermal effects were minimal. Unsymmetrical tension in the vessel wall inducing migration of the flap during laser exposure was observed in case of unsuccessful wall perforations. The laser wall perforation mechanism in the ELANA technique is primarily mechanical. Symmetric tension in the recipient vessel wall is essential and should be trained by neurosurgeons.

Effects of Induced Hypertension on Cerebral Perfusion in Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: A Randomized Clinical Trial.

BACKGROUND AND PURPOSE: The presumed effectiveness of induced hypertension for treating delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage is based on uncontrolled case-series only. We assessed the effect of induced hypertension on cerebral blood flow (CBF) in aneurysmal subarachnoid hemorrhage patients with delayed cerebral ischemia in a randomized clinical trial. METHODS: Aneurysmal subarachnoid hemorrhage patients were randomized to induced or no induced hypertension (control group) at delayed cerebral ischemia onset. CBF was assessed, blinded for treatment allocation, with computed tomographic perfusion in standardized predefined regions at delayed cerebral ischemia onset and after 24 to 36 hours of study treatment. Mean arterial blood pressure was compared between groups (linear mixed model). The primary outcome measure was the difference in change in overall CBF (Mann-Whitney U test). RESULTS: Mean arterial blood pressure was, on average, 12 mm Hg (95% confidence interval, 8.6-14.5) higher in the hypertension group (n=12) than in the control group (n=13). Change in overall CBF (mL/100g per s) was -8.5 (range, -42 to 30) in the control group and 0.1 (range, -31-43) in the hypertension group (P=0.25). CONCLUSIONS: Change in overall CBF did not differ to a statistically significant extent between the groups. Based on our results, 225 to 250 patients per group are needed to find a statistically significant difference in change in overall CBF between induced hypertension and no hypertension. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT0161323.

Recovery to Preinterventional Functioning, Return-to-Work, and Life Satisfaction After Treatment of Unruptured Aneurysms.

BACKGROUND AND PURPOSE: The eventual goal of preventive treatment of unruptured intracranial aneurysms is to increase the number of life years with high life satisfaction. Insight in the time with reduced functioning, working capacity, and life satisfaction after aneurysm treatment is pivotal to balance the pros and cons of preventive aneurysm occlusion. METHODS: We sent a questionnaire on time-to-recovery to preintervention functioning and return-to-work and life satisfaction to patients treated for an unruptured aneurysm between 2000 and 2013. Changes in life satisfaction before treatment, during recovery, and at follow-up were assessed with Wilcoxon signed-rank tests. RESULTS: The questionnaire was sent to 159 patients of whom 110 (69%) responded. The mean follow-up time after aneurysm treatment was 6 years (SD 4). Fifty-four patients had endovascular and 56 had microsurgical occlusion. Complete recovery to preintervention functioning was reported by 81% (95% confidence interval [CI], 74-88) of patients, with a median time-to-recovery of 3 months (range 0-48). Complete work recovery was reported by 78% (95% CI, 66-87) of patients. The proportion of patients with high life satisfaction reduced from 76% (95% CI, 67-84) before treatment to 52% (95% CI, 43-61) during the period of recovery (P<0.01) and restored largely at long-term follow-up (67% [95% CI, 59-76], P=0.08). CONCLUSION: Life satisfaction is significantly reduced during the period of recovery after treatment of unruptured aneurysms. In the long-term, ≈1 out of 5 patients reports incomplete recovery. These treatment effects should be kept in mind when considering preventive aneurysm treatment. Prospective studies are needed to better compare these losses in patients treated for unruptured aneurysms with those who had subarachnoid hemorrhage.

Pulmonary edema and blood volume after aneurysmal subarachnoid hemorrhage: a prospective observational study.

INTRODUCTION: Pulmonary edema (PED) is a severe complication after aneurysmal subarachnoid hemorrhage (SAH). PED is often treated with diuretics and a reduction in fluid intake, but this may cause intravascular volume depletion, which is associated with secondary ischemia after SAH. We prospectively studied intravascular volume in SAH patients with and without PED. METHODS: Circulating blood volume (CBV) was determined daily during the first 10 days after SAH by means of pulse dye densitometry. CBV of 60-80 ml/kg was considered normal. PED was diagnosed from clinical signs and characteristic bilateral pulmonary infiltrates on the chest radiograph. We compared CBV, cardiac index, and fluid balance between patients with and without PED with weighted linear regression, taking into account only measurements from the first day after SAH through to the day on which PED was diagnosed. Differences were adjusted for age, bodyweight, and clinical condition. RESULTS: In total, 102 patients were included, 17 of whom developed PED after a mean of 4 days after SAH. Patients developing PED had lower mean CBV (56.6 ml/kg) than did those without PED (66.8 ml/kg). The mean difference in CBV was -11.3 ml/kg (95% CI, -16.5 to -6.1); adjusted mean difference, -8.0 ml/kg (95% CI, -14.0 to -2.0). After adjusting, no differences were found in cardiac index or fluid balance between patients with and without PED. CONCLUSIONS: SAH patients developing pulmonary edema have a lower blood volume than do those without PED and are hypovolemic. Measures taken to counteract pulmonary edema must be balanced against the risk of worsening hypovolemia. TRIAL REGISTRATION: NTR1255.

Optimization of the excimer laser assisted non-occlusive anastomosis (ELANA) flap retrieval rate.

BACKGROUND AND OBJECTIVES: A key element in the Excimer Laser Assisted Non-occlusive Anastomosis (ELANA) technique is the retrieval of a disc ("flap") of artery wall from the anastomosis by the laser catheter tip. We assessed if the flap retrieval rate could be optimized. METHODS: We used a specially designed in vitro model using rabbit aortas. We tested three essential elements of the technique: (1) laser energy (10, 13, 15, or 18 mJ), (2) pressure on the catheter (0, 0.1, 0.2, or 0.4 N), and (3) number of lasing episodes (1 or 2). We made 2,280 anastomoses using different combinations of settings. With a logistic regression model we assessed the influence of each parameter. Current clinical settings (10 mJ, 0.2 N, 1 episode) were reference categories. RESULTS: Flap retrieval rate using conventional settings was 86.7%, equivalent to earlier reported clinical data. A significantly higher flap retrieval appeared when laser energy was increased to 13 mJ (OR 3.0, 95% CI 1.8-4.8), 15 mJ (OR 3.2, 95% CI 1.9-5.3), and 18 mJ (OR 3.7, 95% CI 2.2-6.2). A second lasing episode also significantly increased flap retrieval (OR 2.1, 95% CI 1.4-3.0). However, if we increased energy to 15 or 18 mJ, the effect of a second laser episode was insignificant. When the catheter was pushed down with 0.4 N, flap retrieval decreased significantly in all subgroups (OR 0.07, 95% CI 0.04-0.14). CONCLUSION: The flap retrieval of the ELANA anastomosis technique can be optimized to 100% by setting the laser energy at 15 mJ. However, safety studies are necessary before clinical application. A second lasing episode of 10 mJ is a good alternative to increase the flap retrieval. Moreover, the surgeon should be trained to apply not more than 0.2 N on the catheter.

Anosmia after endovascular and open surgical treatment of intracranial aneurysms.

OBJECT: Patients treated for aneurysmal subarachnoid hemorrhage (SAH) often report a loss of smell. To discriminate between the effects of aneurysmal rupture and treatment, the authors assessed the occurrence of anosmia after clipping and coiling of unruptured aneurysms as well as after the coiling of ruptured aneurysms. METHODS: The authors interviewed patients in whom an unruptured aneurysm was treated by clipping (32 cases) or endovascular coiling (26 cases) as well as patients with SAH who underwent coil therapy (32 cases). A geographically defined subset of 20 patients per group was invited to undergo olfactory testing. RESULTS: Nine clip-treated patients (28% [95% CI 14-47%]) in the unruptured group reported having anosmia, and no coil-treated patient in the unruptured group (95% [CI 0-13%]) reported having anosmia; in the SAH group, 7 patients (22% [95% CI 9-40%]) reported having anosmia. Anosmia had improved over time in 3 of the clip-treated patients and in all but 1 of the patients with SAH. Examination revealed olfactory disturbance in 13 (65% [95% CI 41-85%]) of the clip-treated and 8 (42% [95% CI 20-67%]) of the coil-treated patients with unruptured aneurysms, and also in 7 (35% [95% CI 15-59%]) coil-treated patients with SAH. In 20 patients who underwent clip therapy for unruptured aneurysms, 19 (95% [95% CI 75-100%]) had olfactory dysfunction on the side ipsilateral to surgery (anosmia reported by 8 of them). CONCLUSIONS: Both clip treatment and SAH contribute to the occurrence of anosmia, with different chances of improvement. Olfactory dysfunction occurs in almost all patients on the side of surgery and can occur subclinically after coil deployment.

Predictors of patency of excimer laser-assisted nonocclusive extracranial-to-intracranial bypasses.

OBJECT: Excimer laser-assisted nonocclusive anastomosis (ELANA) is a technique that can be used for extracranial-to-intracranial (EC-IC) bypasses, without the necessity of temporary occlusion of the donor or recipient artery. Information on predictors of patency of EC-IC bypasses in general and the ELANA bypass in particular is sparse. The authors studied 159 ELANA EC-IC bypasses to find predictors of patency. METHODS: From a prospective database of patients who underwent EC-IC bypass surgery, 143 consecutive patients who underwent a total of 159 ELANA bypasses were studied. The associations of patient characteristics, surgical aspects, and technical aspects specific to the ELANA technique with intraoperative and postoperative bypass patency were studied using logistic regression analysis. RESULTS: At the end of the operation, 146 (92%) of the 159 bypasses were patent. A first attempt to create a bypass was almost 8 times more likely (OR 7.6, 95% CI 2.1-27.5; p = 0.02) to result in a patent bypass than a second attempt. Administration of a small amount of heparin during the operation was also associated with bypass patency (OR 5.2, 95% CI 1.1-24.9; p = 0.04). One hundred twenty-three (77%) of the 159 bypasses were functional at patency assessments during the 1st month after the operation. Older age (OR 1.043 for every year of increase in age, 95% CI 1.010-1.076; p = 0.01), male sex (OR 2.9, 95% CI 1.3-6.5; p = 0.01), and high intraoperative bypass flow (OR 1.017 for every milliliter per minute increase in flow, 95% CI 1.004-1.030; p = 0.01) were associated with postoperative bypass patency. CONCLUSIONS: Attempts to create a second EC-IC ELANA bypass after the first one are more likely to fail, whereas administration of heparin to the patient during the procedure increases the intraoperative bypass patency rate. Postoperative patency results are better in male and in older patients. Intraoperative bypass flow measurements are essential because high bypass flow is an important determinant of postoperative patency.

Nurses' prediction of volume status after aneurysmal subarachnoid haemorrhage: a prospective cohort study.

INTRODUCTION: Patients who have suffered aneurysmal subarachnoid haemorrhage (SAH) often have derangements in blood volume, contributing to poor outcome. To guide fluid management, regular assessments of volume status must be conducted. We studied the ability of nursing staff to predict hypovolaemia or hypervolaemia, based on their interpretation of available haemodynamic data. METHODS: In a prospective cohort study, intensive care unit and medium care unit nurses, currently treating patients with recent SAH, were asked to predict present volume status. For their assessment they could use all available haemodynamic parameters (for example, heart rate, blood pressure, fluid balance). The nurses' assessments were compared with the actual circulating blood volume (CBV), as measured daily with pulse dye densitometry during the first 10 days after SAH. Normovolaemia was defined as a CBV of 60 to 80 ml/kg body weight; hypovolaemia as CBV under 60 ml/kg; severe hypovolaemia as CBV under 50 ml/kg and hypervolaemia as CBV above 80 ml/kg. RESULTS: A total of 350 combinations of volume predictions and CBV measurements were obtained in 43 patients. Prediction of hypovolaemia had a sensitivity of 0.10 (95% confidence interval [CI] = 0.06 to 0.16) and a positive predictive value of 0.37 (95% CI = 0.23 to 0.53) for actual hypovolaemia. The prediction of hypervolaemia had a sensitivity of 0.06 (95% CI = 0.01 to 0.16) and a positive predictive value of 0.06 (95% CI = 0.02 to 0.19) for actual hypervolaemia. Mean CBV was significantly lower in instances considered hypervolaemic than in instances considered normovolaemic. CONCLUSIONS: Assessment of haemodynamic condition in patients with SAH by intensive care unit or medium care unit nurses does not adequately predict hypovolaemia or hypervolaemia, as measured using pulse dye densitometry. Fluid therapy after SAH may require guidance with more advanced techniques than interpretation of usual haemodynamic parameters.

Risk Factors for Intracranial Aneurysm Rupture: A Systematic Review.

BACKGROUND: Intracranial aneurysm rupture prediction is poor, with only a few risk factors for rupture identified and used in clinical practice. OBJECTIVE: To provide an overview of all the risk factors (including genetic, molecular, morphological, and hemodynamic factors) that have potential for use in clinical practice. METHODS: We systematically searched PubMed and EMBASE and focused on factors that can be easily assessed in clinical practice, might be used for rupture prediction in clinical practice, and/or are potential targets for further research. Studies were categorized according to methodological quality, and a meta-analysis was performed, if possible. RESULTS: We included 102 studies describing 144 risk factors that fulfilled predefined criteria. There was strong evidence for the morphological factors irregular shape (studied in 4 prospective cohort studies of high-quality, pooled odds ratio [OR] of 4.8 [95% confidence interval 2.7-8.7]), aspect ratio (pooled OR 10.2 [4.3-24.6]), size ratio, bottleneck factor, and height-to-width ratio to increase rupture risk. Moderate level of evidence was found for presence of contact with the perianeurysmal environment (pooled OR 3.5 [1.4-8.4]), unbalanced nature of this contact (pooled OR 17.8 [8.3-38.5]), volume-to-ostium ratio, and direction of the aneurysm dome (pooled OR 1.5 [1.2-1.9]). CONCLUSION: Irregular aneurysm shape was identified as a risk factor with potential for use in clinical practice. The risk factors aspect ratio, size ratio, bottleneck factor, height-to-width ratio, contact with the perianeurysmal environment, volume-to-ostium ratio, and dome-direction should first be confirmed in multivariate analysis and incorporated in prediction models.

Determinants of Gadolinium-Enhancement of the Aneurysm Wall in Unruptured Intracranial Aneurysms.

BACKGROUND: Recent studies suggest that gadolinium-enhancement of the aneurysm wall may reflect aneurysm wall inflammation, which might increase the risk of aneurysm growth or rupture. OBJECTIVE: To determine the prevalence of gadolinium-enhancement and its determinants in patients with predominantly small (<7 mm) unruptured intracranial aneurysms. METHODS: We performed 3 T MRI aneurysm wall imaging in patients with ≥1 unruptured aneurysm. With Poisson regression analysis, we calculated crude and adjusted risk ratios (RRs) with 95% confidence intervals (CI) to assess determinants of gadolinium-enhancement. RESULTS: Gadolinium-enhancement was observed in 25/79 patients (32%; 95% CI: 21%-42%) and 26/89 aneurysms (29%; 95% CI: 20%-39%). With aneurysms 1.0-2.9 mm as reference, RRs were 4.6 (95% CI: 0.6-36.5) for 3.0 to 4.9 mm, 9.4 (95% CI: 1.3-67.2) for 5.0 to 6.9 mm, and 14.8 (95% CI: 2.1-104.6) for ≥7.0 mm. With internal carotid artery as reference, RRs adjusted for aneurysm size were 3.6 (95% CI: 1.1-11.4) for posterior communicating artery and 3.0 (95% CI: 1.0-8.6) for middle cerebral artery. RRs were 0.8 (95% CI: 0.4-1.8) for acetylsalicylic acid use, 0.9 (95% CI: 0.5-1.8) for statin use, 1.4 (95% CI: 0.7-2.8) for hypertension, 0.9 (95% CI: 0.4-1.8) for previous smoking, 0.9 (95% CI: 0.3-2.6) for never smoking, and 1.4 (95% CI: 0.7-2.7) for irregular aneurysm shape. CONCLUSION: Approximately one-third of patients had gadolinium-enhancement. Because aneurysm size is the strongest determinant of gadolinium-enhancement and also an established predictor for aneurysm growth and rupture, prospective studies with serial imaging need to investigate if gadolinium-enhancement predicts aneurysm growth and rupture.

Sutureless nonocclusive bypass surgery in combination with an expanded polytetrafluoroethylene graft. Laboratory investigation.

OBJECT: Cerebral aneurysms that cannot be treated by clip or coil placement can be treated with high-flow bypass surgery using techniques such as the excimer laser-assisted nonocclusive anastomosis (ELANA). To simplify the technique, a sutureless ELANA (SELANA) was developed in combination with an expanded polytetrafluoroethylene (ePTFE) graft. METHODS: In 18 rabbits a bypass was constructed on the abdominal aorta using the SELANA technique with an ePTFE graft, resulting in 18 bypasses and 36 anastomoses. Short-term effects were analyzed in the first 2 weeks and at 2 and 3 months after the procedure. Patency was evaluated using quantitative ultrasound flowmetry. The anastomotic sites were studied using scanning electron microscopy. RESULTS: Construction of the bypass using the SELANA technique was easier and faster (15-25 minutes) compared with bypasses made with the ELANA technique (> 90 minutes). At the end of follow-up, 16 of 18 bypasses were patent. Of 36 SELANA anastomoses, 32 could be completed without short temporary occlusion of the recipient vessel. Scanning electron microscopy showed complete coverage of all anastomoses with neointimal repair tissue after 10 days. CONCLUSIONS: The SELANA technique provides further advantages over the conventional ELANA technique in ease of use and shortening of procedure time. The patency rate in this series was 89% and neointima repair tissue at the anastomosis site was complete after 10 days. Further experimental studies of the long-term patency and safety of this technique are necessary before clinical application.

Comparative Ultrastructural and Stereological Analyses of Unruptured and Ruptured Saccular Intracranial Aneurysms.

Insight into processes leading to rupture of intracranial aneurysms (IAs) may identify biomarkers for rupture or lead to management strategies reducing the risk of rupture. We characterized and quantified (ultra)structural differences between unruptured and ruptured aneurysmal walls. Six unruptured and 6 ruptured IA fundi were resected after microsurgical clipping and analyzed by correlative light microscopy for quantitative analysis (proportion of the vessel wall area) and transmission electron microscopy for qualitative ultrastructural analysis. Quantitative analysis revealed extensive internal elastic lamina (IEL) thickening in ruptured IA (36.3% ± 15%), while thin and fragmented IEL were common in unruptured IA (5.6% ± 7.1%). Macrophages were increased in ruptured IA (28.3 ± 24%) versus unruptured IA (2.7% ± 5.5%), as were leukocytes (12.85% ± 10% vs 0%). Vasa vasorum in ruptured but not in unruptured IA contained vast numbers of inflammatory cells and extravasation of these cells into the vessel wall. In conclusion, detection of thickened IEL, leaky vasa vasorum, and heavy inflammation as seen in ruptured IA in comparison to unruptured IA may identify aneurysms at risk of rupture, and management strategies preventing development of vasa vasorum or inflammation may reduce the risk of aneurysmal rupture.

Expanded polytetrafluoroethylene graft for bypass surgery using the excimer laser-assisted nonocclusive anastomosis technique.

OBJECT: Patients with complex craniocerebral pathophysiologies such as giant cerebral aneurysms, skull base tumors, and/or carotid artery occlusive disease are candidates for a revascularization procedure to augment or preserve cerebral blood flow. However, the brain is susceptible to ischemia, and therefore the excimer laser-assisted nonocclusive anastomosis (ELANA) technique has been developed to overcome temporary occlusion. Harvesting autologous vessels of reasonable quality, which is necessary for this technique, may at times be problematic or impossible due to the underlying systemic vascular disease. The use of artificial vessels is therefore an alternative graft for revascularization. Note, however, that it is unknown to what degree these grafts are subject to occlusion using the ELANA anastomosis technique. Therefore, the authors studied the ELANA technique in combination with an expanded polytetrafluoroethylene (ePTFE) graft. METHODS: The experimental surgeries involved bypassing the abdominal aorta in the rabbit. Ten rabbits were subjected to operations representing 20 ePTFE graft-ELANA end-to-side anastomoses. Intraoperative blood flow, followup angiograms, and long-term histological characteristics were assessed 75, 125, and 180 days postoperatively. Angiography results proved long-term patency of ePTFE grafts in all animals at all time points studied. Data from the histological analysis showed minimal intimal reaction at the anastomosis site up to 180 days postoperatively. Endothelialization of the ePTFE graft was progressive over time. CONCLUSIONS: The ELANA technique in combination with the ePTFE graft seems to have favorable attributes for end-to-side anastomoses and may be suitable for bypass procedures.

Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm.

Genetic risk factors for intracranial aneurysm (IA) are not yet fully understood. Genomewide association studies have been successful at identifying common variants; however, the role of rare variation in IA susceptibility has not been fully explored. In this study, we report the use of whole exome sequencing (WES) in seven densely-affected families (45 individuals) recruited as part of the Familial Intracranial Aneurysm study. WES variants were prioritized by functional prediction, frequency, predicted pathogenicity, and segregation within families. Using these criteria, 68 variants in 68 genes were prioritized across the seven families. Of the genes that were expressed in IA tissue, one gene (TMEM132B) was differentially expressed in aneurysmal samples (n=44) as compared to control samples (n=16) (false discovery rate adjusted p-value=0.023). We demonstrate that sequencing of densely affected families permits exploration of the role of rare variants in a relatively common disease such as IA, although there are important study design considerations for applying sequencing to complex disorders. In this study, we explore methods of WES variant prioritization, including the incorporation of unaffected individuals, multipoint linkage analysis, biological pathway information, and transcriptome profiling. Further studies are needed to validate and characterize the set of variants and genes identified in this study.

Visualization of the aneurysm wall: a 7.0-tesla magnetic resonance imaging study.

BACKGROUND: Risk prediction of rupture of intracranial aneurysms is poor and is based mainly on lumen characteristics. However, characteristics of the aneurysm wall may be more informative predictors. The limited resolution of currently available imaging techniques and the thin aneurysm wall make imaging of wall thickness challenging. OBJECTIVE: To introduce a novel protocol for imaging wall thickness variation using ultra--high-resolution 7.0-Tesla (7.0-T) magnetic resonance imaging (MRI). METHODS: We studied 33 unruptured intracranial aneurysms in 24 patients with a T1-weighted 3-dimensional magnetization-prepared inversion-recovery turbo-spin-echo whole-brain sequence with a resolution of 0.8 × 0.8 × 0.8 mm. We performed a validation study with a wedge phantom and with 2 aneurysm wall biopsies obtained during aneurysm treatment using ex vivo MRI and histological examination and correlating variations in MRI signal intensity with variations in actual thickness of the aneurysm wall. RESULTS: In vivo, the aneurysm wall was visible in 28 of the 33 aneurysms. Variation in signal intensity was observed in all visible aneurysm walls. Ex vivo MRI showed variation in signal intensity across the wall of the biopsies, similar to that observed on the in vivo images. Signal intensity and actual thickness in both biopsies had a linear correlation, with Pearson correlation coefficients of 0.85 and 0.86. CONCLUSION: Unruptured intracranial aneurysm wall and its variation in thickness can be visualized with 7.0-T MRI. Aneurysm wall thickness variation can now be further studied as a risk factor for rupture in prospective studies.

Patency, flow, and endothelialization of the sutureless Excimer Laser Assisted Non-occlusive Anastomosis (ELANA) technique in a pig model.

OBJECT: The purpose of this study was to assess flow, patency, and endothelialization of bypasses created with the sutureless Excimer Laser Assisted Non-occlusive Anastomosis (SELANA) technique in a pig model. METHODS: In 38 pigs, a bypass was made on the left common carotid artery (CCA), using the right CCA as a graft, with 2 SELANAs. Bypass flow was measured using single-vessel flowmetry. The pigs were randomly assigned to 1 of 12 survival groups (1, 2, 3, 4, 5, 6, 7, and 10 days; 2 and 3 weeks; and 3 and 6 months). One extra animal underwent the procedure and then was killed after 1 hour of bypass patency to serve as a control. Angiography was performed just before the animals were killed, to assess bypass patency. Scanning electron microscopy and histological studies were used to evaluate the anastomoses after planned death. RESULTS: The mean SELANA bypass flow was not significantly different from the mean flow in the earlier ELANA (Excimer Laser Assisted Non-occlusive Anastomosis) pig study at opening and follow-up. Overall SELANA bypass patency (87%) was not significantly different from the ELANA patency of 86% in the earlier study. Complete SELANA endothelialization was observed after 2-3 weeks, compared with 2 weeks in the earlier ELANA study. CONCLUSIONS: The SELANA technique is not inferior to the current ELANA technique regarding flow, patency, and endothelialization. A pilot study in patients is a logical next step.

Massive intraventricular haemorrhage from aneurysmal rupture: patient proportions and eligibility for intraventricular fibrinolysis.

Massive intraventricular haemorrhage (IVH) complicating aneurysmal subarachnoid haemorrhage (SAH) is associated with a poor prognosis. Small observational studies suggest favourable results from fibrinolysis of the intraventricular blood. We performed an observational study on IVH in a large series of patients with SAH to assess the proportion of patients that may benefit from fibrinolytic treatment. From our prospective database we retrieved patients with aneurysmal SAH admitted between January 2000 and January 2005. We calculated the proportion of patients with massive IVH and the proportion of patients that are eligible for fibrinolysis on basis of clinical and CT-scan characteristics and assessed neurological outcome in a treatment strategy without fibrinolysis. Poor neurological condition was defined as World Federation of Neurological Surgeons scale 4 and 5, poor outcome as death or dependence 3 months after SAH. Of the 573 patients admitted with aneurysmal SAH, 59 (10%; 95% confidence interval CI 8-13%) had massive IVH, of which 55 were in poor clinical condition. For these 55 patients, the case-fatality rate was 78% (95% CI 66-88%) and the proportion with poor outcome 91% (95% CI 81-97%). Of the 55 patients, 31 (56%, and 5% of all patients SAH within the study period) fulfilled our eligibility criteria and were considered suitable for intraventricular fibrinolysis. At 3 months, 30 of these 31 eligible patients (97%; 95% CI 85-100%) had a poor outcome. Massive IVH occurs in 10% of patients with aneurysmal SAH. Half of these patients may benefit from intraventricular fibrinolysis. Without fibrinolysis outcome is almost invariably poor in these patients.