Assessment of the Most Optimal Control Tissue for Intracranial Aneurysm Gene Expression Studies.

Background and Purpose- Finding adequate control tissue for intracranial aneurysm (IA) pathophysiological studies, including gene expression studies, can be challenging. We compared gene expression profiles of superficial temporal, cortical, and circle of Willis (CoW) arteries and IA in search of the most optimal control tissue for future experiments. Methods- We compared RNA-sequencing data of IA samples and of superficial temporal, cortical, and CoW artery samples using Pearson correlation, Euclidean distance, and principal component analysis. We used the Mann-Whitney U test for comparison of Pearson correlation coefficients and Euclidean distances, to assess which control tissue is most similar to IA in terms of gene expression. Other unrelated tissues were used as negative controls. Results- The cortical and the CoW arteries were more similar to IA in terms of gene expression than the superficial temporal artery. This was based on Pearson correlation (+0.023 [90% CI, 0.017/0.029; P=1.9E-09] for the cortical artery and +0.034 [90% CI, 0.028/0.040; P=6.0E-15] for the CoW artery compared with the superficial temporal artery), Euclidean distance (-25.71 [90% CI, -31.54/-20.02; P=1.9E-11] for the cortical artery and -38.09 [90% CI, -44.08/-32.19; P<2.2E-16] for the CoW artery compared with the superficial temporal artery) and principal component analysis. In all analyses, the unrelated tissues formed separate groups compared with IA and the 3 control arteries. Conclusions- The cortical arteries and the CoW arteries are better controls for gene expression studies on IA than the superficial temporal artery. This probably relates to differences in anatomy of these tissues, such as the presence of an external elastic lamina in the extracranial vasculature and absence in the intracranial vasculature, because IAs, cortical arteries, and CoW arteries are all intracranial while the superficial temporal artery is extracranial. Since CoW arteries can only be obtained postmortem, cortical arteries are preferred over CoW arteries.

Effectiveness of diagnostic strategies in suspected delayed cerebral ischemia: a decision analysis.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) is a serious complication after aneurysmal subarachnoid hemorrhage. If DCI is suspected clinically, imaging methods designed to detect angiographic vasospasm or regional hypoperfusion are often used before instituting therapy. Uncertainty in the strength of the relationship between imaged vasospasm or perfusion deficits and DCI-related outcomes raises the question of whether imaging to select patients for therapy improves outcomes in clinical DCI. METHODS: Decision analysis was performed using Markov models. Strategies were either to treat all patients immediately or to first undergo diagnostic testing by digital subtraction angiography or computed tomography angiography to assess for angiographic vasospasm, or computed tomography perfusion to assess for perfusion deficits. According to current practice guidelines, treatment consisted of induced hypertension. Outcomes were survival in terms of life-years and quality-adjusted life-years. RESULTS: When treatment was assumed to be ineffective in nonvasospasm patients, Treat All and digital subtraction angiography were equivalent strategies; when a moderate treatment effect was assumed in nonvasospasm patients, Treat All became the superior strategy. Treating all patients was also superior to selecting patients for treatment via computed tomography perfusion. One-way sensitivity analyses demonstrated that the models were robust; 2- and 3-way sensitivity analyses with variation of disease and treatment parameters reinforced dominance of the Treat All strategy. CONCLUSIONS: Imaging studies to test for the presence of angiographic vasospasm or perfusion deficits in patients with clinical DCI do not seem helpful in selecting which patients should undergo treatment and may not improve outcomes. Future directions include validating these results in prospective cohort studies.

Multidisciplinary consensus on assessment of unruptured intracranial aneurysms: proposal of an international research group.

BACKGROUND AND PURPOSE: To address the increasing need to counsel patients about treatment indications for unruptured intracranial aneurysms (UIA), we endeavored to develop a consensus on assessment of UIAs among a group of specialists from diverse fields involved in research and treatment of UIAs. METHODS: After composition of the research group, a Delphi consensus was initiated to identify and rate all features, which may be relevant to assess UIAs and their treatment by using ranking scales and analysis of inter-rater agreement (IRA) for each factor. IRA was categorized as very high, high, moderate, or low. RESULTS: Ultimately, 39 specialists from 4 specialties agreed (high or very high IRAs) on the following key factors for or against UIA treatment decisions: (1) patient age, life expectancy, and comorbid diseases; (2) previous subarachnoid hemorrhage from a different aneurysm, family history for UIA or subarachnoid hemorrhage, nicotine use; (3) UIA size, location, and lobulation; (4) UIA growth or de novo formation on serial imaging; (5) clinical symptoms (cranial nerve deficit, mass effect, and thromboembolic events from UIAs); and (6) risk factors for UIA treatment (patient age and life expectancy, UIA size, and estimated risk of treatment). However, IRAs for features rated with low relevance were also generally low, which underlined the existing controversy about the natural history of UIAs. CONCLUSIONS: Our results highlight that neurovascular specialists currently consider many features as important when evaluating UIAs but also highlight that the appreciation of natural history of UIAs remains uncertain, even within a group of highly informed individuals.

Life satisfaction and return to work after aneurysmal subarachnoid hemorrhage.

This study was conducted to investigate life satisfaction and employment status after aneurysmal subarachnoid hemorrhage (SAH) and to explain the associations between life satisfaction and demographic, disease-related, psychological, and personality characteristics. Subjects with SAH (n = 141) living at home 2-4 years after the SAH responded to a mailed questionnaire. Outcomes were life satisfaction, as measured with the Life Satisfaction Questionnaire 9 (LiSat-9), and employment status. Determinants in multiple regression analysis were demographic and SAH characteristics, subjective complaints (eg, mood disorder, fatigue, cognitive complaints), and personality characteristics (eg, neuroticism, passive coping style). Of the 141 subjects, 64 (46.7%) had a Glasgow Outcome Scale score of V (good outcome) at discharge. Mean subject age was 51.4 ± 12.3 years, and mean time after SAH was 36.1 ± 7.9 months. Of the 88 subjects who were working at the time of the SAH, 54 (61.4%) returned to work, but only 31 (35.2%) resumed their work completely. The subjects were least satisfied with their vocational situation (51.9% satisfied) and sexual life (51.7%) and were most satisfied with their relationships (75.2%-88.7%) and self-care ability (88.6%). Age (ß value = 0.17), return to work after SAH (0.19), disability at hospital discharge (0.25), worsened mood (-0.37), and passive coping (-0.25) together accounted for 47.2% of the life satisfaction scores. Our data indicate that return to work is a major issue for individuals who survive an SAH. Not returning to work, disability, depression, and passive coping are associated with reduced life satisfaction. Thus, vocational reintegration after SAH merits more attention during rehabilitation.

Cost-effectiveness of magnetic resonance angiography versus intra-arterial digital subtraction angiography to follow-up patients with coiled intracranial aneurysms.

BACKGROUND AND PURPOSE: To follow up patients with coiled intracranial aneurysms, magnetic resonance angiography (MRA) is a promising noninvasive alternative to current standard intra-arterial digital subtraction angiography (IA-DSA). MRA test results do not always concord with those of IA-DSA, and the impact of discrepancies on health benefits and costs is unknown. We evaluated the cost-effectiveness of follow-up with MRA vs IA-DSA to assess whether in this setting MRA may replace IA-DSA. METHODS: We studied aneurysm occlusion on MRA in addition to follow-up IA-DSA in 310 patients with 341 coiled intracranial aneurysms. The observed sensitivity (82%) and specificity (89%) of MRA for detection of reopening with IA-DSA as a reference were used as input for a Markov decision-analytic model. Other determinants were derived from the literature. We compared life expectancy, quality-adjusted life-years (QALY), costs, and expected number of events for the two strategies. RESULTS: Follow-up with MRA yielded similar life expectancy (MRA, 26.66 years; IA-DSA, 26.63 years; difference, 0.03 years; 95% CI, -0.17-0.23) and QALY (MRA, 10.96; IA-DSA, 10.95; difference, 0.01 QALY; 95% CI, -0.05-0.08) at lower costs (MRA, $7003; IA-DSA, $8241 per patient; difference, -$1238; 95% CI, -2617--36). The expected number of events was comparable except for complications from IA-DSA. CONCLUSIONS: MRA provided equivalent health benefits as IA-DSA and was cost-saving. MRA dominates and should replace routine IA-DSA to follow-up patients with coiled aneurysms.

Optimal screening strategy for familial intracranial aneurysms: a cost-effectiveness analysis.

OBJECTIVE: Individuals with a family history of subarachnoid hemorrhage (SAH), defined as 2 or more affected first-degree relatives, have an increased risk of aneurysm formation and rupture. Screening such individuals for intracranial aneurysms is advocated, but its effectiveness and cost-effectiveness are unknown, as are the optimal age ranges and interval for screening. METHODS: With a Markov model and Monte Carlo simulations we compared screening with no screening in individuals with a family history of SAH. We varied age ranges (starting screening at 20, 30, or 40 years old, ending screening at 60, 70, or 80 years old) and screening intervals (2-, 3-, 5-, 7-, 10-, and 15-year interval), and analyzed the impact in costs and quality-adjusted life years (QALY). RESULTS: Screening individuals with a family history of SAH is cost-effective. The strategy with the lowest costs per QALY was to screen only twice, at 40 and 55 years old. Sequentially lengthening the screening period and decreasing the screening interval yielded additional health benefits at acceptable costs up to screening from age 20 to 80 every 7 years. More frequent screening within this age range still provided extra QALYs, with an incremental cost-effectiveness ratio more favorable than 26,308/QALY ($38,410/QALY). CONCLUSION: This study provides evidence for recommendations to screen individuals with 2 or more first-degree relatives with subarachnoid hemorrhage. The optimal screening strategy according to our model is screening from age 20 until 80 every 7 years given a cost-effectiveness threshold of 20,000/quality-adjusted life year (QALY) ($29,200/QALY).

Comparison of telephone and face-to-face assessment of the modified Rankin Scale.

BACKGROUND: A structured interview improves the reliability of the modified Rankin Scale (mRS), a commonly used functional outcome scale in stroke trials. Telephone interview is a fast and convenient way to assess the mRS grade, but its validity is unknown. We assessed the validity of a telephone interview in patients who had had an aneurysmal subarachnoid haemorrhage (SAH) by comparing it with a face-to-face assessment. METHODS: Eighty-three SAH patients were interviewed twice, once face-to-face and once by telephone, by 2 of 5 observers who used a structured interview to assess the mRS grade. Intermodality agreement was measured using weighted kappa statistics. To check for systematic differences between face-to-face and telephone assessment the Wilcoxon test for matched pairs was used. RESULTS: Agreement between telephone and face-to-face assessment was perfect in 47 (57%) patients. A difference of 1 level occurred in 31 (37%) patients and this was almost equally distributed over the grades of the mRS. Weighted kappa was 0.71 (95% CI 0.59-0.82). Telephone assessment did not result in a consistently more or less favourable grade than face-to-face assessment (Wilcoxon test for matched pairs, p = 0.33). CONCLUSIONS: Telephone assessment of the mRS with a structured interview has a good agreement with face-to-face assessment and can thus be used reliably in the setting of a clinical trial.

Decision analysis to complete diagnostic research by closing the gap between test characteristics and cost-effectiveness.

OBJECTIVE: The lack of a standard methodology in diagnostic research impedes adequate evaluation before implementation of constantly developing diagnostic techniques. We discuss the methodology of diagnostic research and underscore the relevance of decision analysis in the process of evaluation of diagnostic tests. STUDY DESIGN AND SETTING: Overview and conceptual discussion. RESULTS: Diagnostic research requires a stepwise approach comprising assessment of test characteristics followed by evaluation of added value, clinical outcome, and cost-effectiveness. These multiple goals are generally incompatible with a randomized design. Decision-analytic models provide an important alternative through integration of the best available evidence. Thus, critical assessment of clinical value and efficient use of resources can be achieved. CONCLUSION: Decision-analytic models should be considered part of the standard methodology in diagnostic research. They can serve as a valid alternative to diagnostic randomized clinical trials (RCTs).

Cost-effectiveness of preventive treatment of intracranial aneurysms: new data and uncertainties.

BACKGROUND: Previous modeling studies on treatment of unruptured intracranial aneurysms largely disregarded detailed data on treatment risks and omitted several factors that could influence cost-effectiveness. We performed a cost-effectiveness analysis of surgical and endovascular treatment of unruptured aneurysms for different rupture rates and life expectancies, and assessed the influence of excess mortality risks in these persons, de novo development of aneurysms, and utility of awareness of having an untreated aneurysm, and also identified important factors for which data are lacking. METHODS: We used a Markov model to compare surgical, endovascular, and no treatment of unruptured intracranial aneurysms. Inputs for the model were taken mainly from meta-analyses. Direct medical costs were derived from Dutch cost studies and expressed in 2005 Euros. We performed sensitivity analyses to evaluate model robustness. RESULTS: For 50-year-old patients, treatment of unruptured aneurysms is cost-effective for all rupture rate scenarios between 0.3% and 3.5%/year. In 70-year-old patients, treatment is not cost-effective in men with rupture rates < or =1%/year and women with rupture rates < or =0.5%/year. With lower utility of awareness of an untreated aneurysm, the cost-effectiveness of treatment strongly increased. The effect of excess mortality risks on the incremental cost-effectiveness ratios was modest. The risk of formation of new aneurysms had no relevant impact. CONCLUSIONS: Patients' life expectancy, risk of rupture, and utility of awareness of an untreated aneurysm mainly define cost-effectiveness. However, important uncertainties remain on the rupture risk according to size and location of the aneurysm and on the utility of awareness of untreated aneurysm. More data on these factors are needed to define and individualize cost-effectiveness analyses.

Growth rates of intracranial aneurysms: exploring constancy.

OBJECT: The annual rate of rupture of intracranial aneurysms is often assumed to be constant, but it is unknown whether this assumption is true. Recent case reports have suggested that aneurysms grow fast in a short period of time. The authors of the present report investigated the plausibility of a constant growth rate for intracranial aneurysms. METHODS: Assuming a constant aneurysm growth rate within an individual and varying rates between individuals, a hypothetical cohort was simulated. Individuals with high growth rates will display aneurysm formation and rupture at a young age; such persons disappear early from the hypothetical cohort. As a result the mean lesion growth rate varies over time. In hypothetical cohorts with different initial mean growth rates, the authors calculated age-specific incidence rates (per 100,000 person-years) of subarachnoid hemorrhage and compared these rates with population-based data on the incidence of subarachnoid hemorrhage (per 100,000 person-years). RESULTS: A hypothetical cohort with a mean initial growth rate of 0.18 mm/year reproduced most closely the incidence rates observed in the population. However, even for this most plausible hypothetical cohort, age-specific incidence rates in the model differed substantially and statistically significantly from those observed in the population. CONCLUSIONS: Based on the results of this study, it is unlikely that intracranial aneurysms in general grow at a constant time-independent rate. The authors hypothesized that the actual growth process is irregular and discontinuous, which results in periods with and without aneurysm growth and with high and low risks of rupture.

Life expectancy after perimesencephalic subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Patients with a perimesencephalic nonaneurysmal subarachnoid hemorrhage are not at risk for rebleeding in the initial years after the hemorrhage. Nevertheless, uncertainty remains on the long-term prognosis after perimesencephalic hemorrhage, and former patients are often considered high-risk cases for health insurance or are denied life insurance. We performed a very long-term follow-up study of a large consecutive series of such patients and compared mortality in this cohort with that in the general population. METHODS: All patients with a perimesencephalic hemorrhage (defined by pattern of hemorrhage on computed tomography within 72 hours after onset and absence of aneurysm) admitted between 1983 and 2005 to our service were followed-up by telephone. For patients who had died, we retrieved age and cause of death. We compared the age- and sex-specific mortality of this cohort with that of the general population by means of standardized mortality ratios with corresponding 95% confidence intervals. RESULTS: The cohort consisted of 160 patients, with a total number of patient-years of 1213. No new episodes of subarachnoid hemorrhage had occurred. During follow-up 11 patients had died; the expected number of deaths based on mortality rates in the general population (adjusted for age and gender) was 18.1. The standardized mortality ratio was 0.61 (95% confidence interval, 0.34 to 1.1). CONCLUSIONS: Patients with perimesencephalic hemorrhage have a normal life expectancy and are not at risk for rebleeding. No restrictions should be imposed on these patients by physicians or health or life insurance companies.

Direct costs of surgical clipping and endovascular coiling of unruptured intracranial aneurysms.

BACKGROUND: Unruptured intracranial aneurysms can be preventively treated by surgical clipping or endovascular coiling. We determined in detail the costs of these treatments. METHODS: We included patients who were treated for an unruptured aneurysm between 1997 and 2003. Patients coiled in this period were matched with clipped patients according to the year of treatment, age and gender. Considering clipping and coiling, we compared all pre-admission costs of diagnostic procedures, all costs of treatment, and costs during follow-up including standard angiographic control examinations at 6 and 18 months after coiling. Costs were calculated as the product of the used resources and the costs of these resources. RESULTS: The mean price for clipping was EUR 8,865.42 and that for coiling EUR 10,370.29. The difference was mainly determined by the higher material costs of coiling (EUR 5,300) compared with clipping (EUR 690). Costs of clipping were mainly determined by the need for intensive care facilities (1.2 days after clipping and 0 days after coiling) and the length of hospital stay (10.5 days after clipping and 3.4 days after coiling). After bootstrapping the data, costs of coiling were on average EUR 1,553 (95% confidence interval: EUR 1,539-1,569) higher than those of clipping. CONCLUSIONS: For unruptured intracranial aneurysms, direct in-hospital costs of coiling are on average higher than those of clipping, mostly because of the more expensive coils.