Review of Cerebral Aneurysm Formation, Growth, and Rupture
TL;DR: The data supporting a major role for inflammation in CA pathogenesis are summarized, which show that the inflammatory process is initiated by a hemodynamic insult and leads to matrix metalloproteinases–mediated degradation of the extracellular matrix and apoptosis of smooth muscle cells, which are the predominant matrix-synthesizing cells of the vascular wall.
Abstract: Cerebral aneurysms (CAs) occur in 3% to 5% of the general population and are characterized by localized structural deterioration of the arterial wall, with loss of the internal elastic lamina and disruption of the media.1 The most dreaded complication of CAs is rupture, the likelihood of which is related to several modifiable and nonmodifiable risk factors. Despite advances in surgical techniques and perioperative management, the mortality and morbidity associated with aneurysm rupture remain high.2 Current therapeutic options are limited to invasive therapies, namely microsurgical clipping and endovascular treatment, both of which carry a non-negligible risk of procedural morbidity.
In recent years, it has become obvious that CAs are not passively enlarging vascular structures but exhibit prominent features of inflammation and tissue degeneration. Other factors mainly hemodynamic, genetic, hormonal, and environmental may also play an important role. Knowledge of the pathogenic pathways of CAs may pave the way for the development of noninvasive therapies. The purpose of this review is to summarize the most relevant data on the molecular mechanisms, genetics, and risk factors for aneurysm formation, growth, and rupture. Although there are different forms of CAs, the present discussion focuses on saccular aneurysms, which represent the most common type of CAs and are also the most common cause of subarachnoid hemorrhage (SAH).
### Cerebral Aneurysms: an Inflammatory Disease
Increasing evidence points to inflammation as the leading factor in the pathogenesis of CAs. The inflammatory process is initiated by a hemodynamic insult and leads to matrix metalloproteinases (MMPs)–mediated degradation of the extracellular matrix and apoptosis of smooth muscle cells (SMCs), which are the predominant matrix-synthesizing cells of the vascular wall. These processes act in concert to weaken the arterial wall progressively, resulting in dilatation, aneurysm formation, and ultimately rupture (Figure; Table 1). The data supporting a major role for inflammation in CA pathogenesis are …
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TL;DR: In this article, a deep neural network (DNN) is used to enforce the initial and boundary conditions, and the governing partial differential equations (i.e., Navier-Stokes equations) are incorporated into the loss of the DNN to drive the training.
341 citations
TL;DR: The latest human data on the formation, progression and rupture of intracranial aneurysms, as well as risks associated with preventive treatment, are highlighted and the implication for clinical management is discussed.
Abstract: Saccular unruptured intracranial aneurysms (UIAs) have a prevalence of 3% in the adult population, and are being increasingly detected because of improved quality and higher frequency of cranial imaging. Large amounts of data, providing varying levels of evidence, have been published on aneurysm development, progression and rupture, but less information is available on the risks and efficacy of preventive treatment. When deciding how to best manage UIAs, clinicians must consider the age and life expectancy of the patient, the estimated risk of rupture, the risk of complications attributed to preventive treatment, and the level of anxiety caused by the awareness of having an aneurysm. This Review highlights the latest human data on the formation, progression and rupture of intracranial aneurysms, as well as risks associated with preventive treatment. Considering these we discuss the implication for clinical management. Furthermore, we highlight pivotal questions arising from current data on intracranial aneurysms and the implications the data have for future experimental or clinical research. We also discuss data on novel radiological surrogates for rupture for those aneurysms that do not require preventive occlusion. Finally, we provide guidance for clinicians who are confronted with patients with incidentally detected UIAs.
322 citations
TL;DR: CAWE was more frequently observed in unstable intracranial aneurysms and may be used as a surrogate of inflammatory activity in the aneurYSmal wall.
Abstract: Background and Purpose—Arterial wall enhancement on vessel wall MRI was described in intracranial inflammatory arterial disease. We hypothesized that circumferential aneurysmal wall enhancement (CAWE) could be an indirect marker of aneurysmal wall inflammation and, therefore, would be more frequent in unstable (ruptured, symptomatic, or undergoing morphological modification) than in stable (incidental and nonevolving) intracranial aneurysms. Methods—We prospectively performed vessel wall MRI in patients with stable or unstable intracranial aneurysms. Two readers independently had to determine whether a CAWE was present. Results—We included 87 patients harboring 108 aneurysms. Interreader and intrareader agreement for CAWE was excellent (κ=0.85; 95% confidence interval, 0.75–0.95 and κ=0.90; 95% confidence interval, 0.83–0.98, respectively). A CAWE was significantly more frequently seen in unstable than in stable aneurysms (27/31, 87% versus 22/77, 28.5%, respectively; P<0.0001). Multivariate logistic regr...
189 citations
TL;DR: It is likely that both genetic and environmental factors contribute to the variability of patients' post-SAH inflammatory response and that this confounds trials of anti-inflammatory therapies.
Abstract: Subarachnoid hemorrhage (SAH) can lead to devastating neurological outcomes, and there are few pharmacologic treatments available for treating this condition. Both animal and human studies provide evidence of inflammation being a driving force behind the pathology of SAH, leading to both direct brain injury and vasospasm, which in turn leads to ischemic brain injury. Several inflammatory mediators that are elevated after SAH have been studied in detail. While there is promising data indicating that blocking these factors might benefit patients after SAH, there has been little success in clinical trials. One of the key factors that complicates clinical trials of SAH is the variability of the initial injury and subsequent inflammatory response. It is likely that both genetic and environmental factors contribute to the variability of patients' post-SAH inflammatory response and that this confounds trials of anti-inflammatory therapies. Additionally, systemic inflammation from other conditions that affect patients with SAH could contribute to brain injury and vasospasm after SAH. Continuing work on biomarkers of inflammation after SAH may lead to development of patient-specific anti-inflammatory therapies to improve outcome after SAH.
157 citations
Cites background from "Review of Cerebral Aneurysm Formati..."
...A detailed discussion of the contribution of inflammation to aneurysm formation is outside the scope of this review and was reviewed recently elsewhere [38]....
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TL;DR: Recent developments of biobased PUs for non-implantable devices as well as short- and long-term implants are described in detail in this review and compared to more conventional PU structures.
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References
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TL;DR: Patients' age was a strong predictor of surgical outcome, and the size and location of an aneurysm predict both surgical and endovascular outcomes.
3,287 citations
TL;DR: The prevalence of UIAs is higher in patients with ADPKD or a positive family history of intracranial aneurysm of subarachnoid haemorrhage than in people without comorbidity, implicating higher risks of rupture in Finland and Japan.
Abstract: Summary Background Unruptured intracranial aneurysms (UIAs) are increasingly detected and are an important health-care burden. We aimed to assess the prevalence of UIAs according to family history, comorbidity, sex, age, country, and time period. Methods Through searches of PubMed, Embase, and Web of Science we updated our 1998 systematic review up to March, 2011. We calculated prevalences and prevalence ratios (PRs) with random-effects binomial meta-analysis. We assessed time trends with year of study as a continuous variable. Findings We included 68 studies, which reported on 83 study populations and 1450 UIAs in 94 912 patients from 21 countries. The overall prevalence was estimated as 3·2% (95% CI 1·9–5·2) in a population without comorbidity, with a mean age of 50 years, and consisting of 50% men. Compared with populations without the comorbidity, PRs were 6·9 (95% CI 3·5–14) for autosomal dominant polycystic kidney disease (ADPKD), 3·4 (1·9–5·9) for a positive family history of intracranial aneurysm of subarachnoid haemorrhage, 3·6 (0·4–30) for brain tumour, 2·0 (0·9–4·6) for pituitary adenoma, and 1·7 (0·9–3·0) for atherosclerosis. The PR for women compared with men was 1·61 (1·02–2·54), with a ratio of 2·2 (1·3–3·6) in study populations with a mean age of more than 50 years. Compared with patients older than 80 years, we found no differences by age, except for patients younger than 30 years (0·01, 0·00–0·12). Compared with the USA, PRs were similar for other countries, including Japan (0·8, 0·4–1·7) and Finland (1·0, 0·4–2·4). There was no statistically significant time trend. Interpretation The prevalence of UIAs is higher in patients with ADPKD or a positive family history of intracranial aneurysm of subarachnoid haemorrhage than in people without comorbidity. In Finland and Japan, the higher incidence of subarachnoid haemorrhage is not explained by a higher prevalence of UIAs, implicating higher risks of rupture. Funding Julius Centre for Health Sciences and Primary Care and Department of Neurology and Neurosurgery, University Medical Centre, Utrecht.
1,302 citations
"Review of Cerebral Aneurysm Formati..." refers background in this paper
...A recent, large metaanalysis that included 1450 unruptured CAs in 94 912 patients from 21 countries identified autosomal dominant polycystic kidney disease, a positive family history of CA or SAH, female sex, and older age as significant risk factors for harboring CAs.(59) The meta-analysis did not find a higher prevalence of CAs in Finnish and Japanese populations, which suggests that the higher incidence of SAH in those countries(60) is related to higher risks of aneurysm rupture....
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TL;DR: It was shown that the natural course of unruptured cerebral aneurysms varies according to the size, location, and shape of theAneurysm.
Abstract: Background The natural history of unruptured cerebral aneurysms has not been clearly defined. Methods From January 2001 through April 2004, we enrolled patients with newly identified, unruptured cerebral aneurysms in Japan. Information on the rupture of aneurysms, deaths, and the results of periodic follow-up examinations were recorded. We included 5720 patients 20 years of age or older (mean age, 62.5 years; 68% women) who had saccular aneurysms that were 3 mm or more in the largest dimension and who initially presented with no more than a slight disability. Results Of the 6697 aneurysms studied, 91% were discovered incidentally. Most aneurysms were in the middle cerebral arteries (36%) and the internal carotid arteries (34%). The mean (±SD) size of the aneurysms was 5.7±3.6 mm. During a follow-up period that included 11,660 aneurysm-years, ruptures were documented in 111 patients, with an annual rate of rupture of 0.95% (95% confidence interval [CI], 0.79 to 1.15). The risk of rupture increased with increasing size of the aneurysm. With aneurysms that were 3 to 4 mm in size as the reference, the hazard ratios for size categories were as follows: 5 to 6 mm, 1.13 (95% CI, 0.58 to 2.22); 7 to 9 mm, 3.35 (95% CI, 1.87 to 6.00); 10 to 24 mm, 9.09 (95% CI, 5.25 to 15.74); and 25 mm or larger, 76.26 (95% CI, 32.76 to 177.54). As compared with aneurysms in the middle cerebral arteries, those in the posterior and anterior communicating arteries were more likely to rupture (hazard ratio, 1.90 [95% CI, 1.12 to 3.21] and 2.02 [95% CI, 1.13 to 3.58], respectively). Aneurysms with a daughter sac (an irregular protrusion of the wall of the aneurysm) were also more likely to rupture (hazard ratio, 1.63; 95% CI, 1.08 to 2.48). Conclusions This study showed that the natural course of unruptured cerebral aneurysms varies according to the size, location, and shape of the aneurysm. (Funded by the Ministry of Health, Labor, and Welfare in Japan and others; UCAS Japan UMIN-CTR number, C000000418.).
1,147 citations
"Review of Cerebral Aneurysm Formati..." refers background in this paper
...95%, as identified by the recent well-designed Japanese cohort.(70) The same study...
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...90% for basilar artery aneurysms.(70) The annual rupture rate by size was 0....
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TL;DR: The overall incidence of SAH is approximately 9 per 100 000 person-years; rates are higher in Japan and Finland and increase with age, while the preponderance of women starts only in the sixth decade.
Abstract: Background and aim: To update our 1996 review on the incidence of subarachnoid haemorrhage (SAH) and assess the relation of incidence with region, age, gender and time period Methods: We searched for studies on the incidence of SAH published until October 2005 The overall incidences with corresponding 95% confidence intervals were calculated We determined the relationship between the incidence of SAH and determinants by means of univariate Poisson regression Results: We included 51 studies (33 new), describing 58 study populations in 21 countries, observing 45 821 896 person-years Incidences per 100 000 person-years were 227 (95% CI 219 to 235) in Japan, 197 (181 to 213) in Finland, 42 (31 to 57) in South and Central America, and 91 (88 to 95) in the other regions With age category 45–55 years as the reference, incidence ratios increased from 010 (008 to 014) for age groups younger than 25 years to 161 (124 to 207) for age groups older than 85 years The incidence in women was 124 (109 to 142) times higher than in men; this gender difference started at age 55 years and increased thereafter Between 1950 and 2005, the incidence decreased by 06% (13% decrease to 01% increase) per year Conclusions: The overall incidence of SAH is approximately 9 per 100 000 person-years Rates are higher in Japan and Finland and increase with age The preponderance of women starts only in the sixth decade The decline in incidence of SAH over the past 45 years is relatively moderate compared with that for stroke in general
1,028 citations
TL;DR: The results suggest that in contrast to the pathogenic effect of a high WSS in the initiating phase, a low WSS may facilitate the growing phase and may trigger the rupture of a cerebral aneurysm by causing degenerative changes in the aneurYSm wall.
Abstract: Background and Purpose—Wall shear stress (WSS) is one of the main pathogenic factors in the development of saccular cerebral aneurysms. The magnitude and distribution of the WSS in and around human middle cerebral artery (MCA) aneurysms were analyzed using the method of computed fluid dynamics (CFD). Methods—Twenty mathematical models of MCA vessels with aneurysms were created by 3-dimensional computed tomographic angiography. CFD calculations were performed by using our original finite-element solver with the assumption of Newtonian fluid property for blood and the rigid wall property for the vessel and the aneurysm. Results—The maximum WSS in the calculated region tended to occur near the neck of the aneurysm, not in its tip or bleb. The magnitude of the maximum WSS was 14.396.21 N/m 2 , which was 4-times higher than the average WSS in the vessel region (3.641.25 N/m 2 ). The average WSS of the aneurysm region (1.641.16 N/m 2 ) was significantly lower than that of the vessel region (P0.05). The WSSs at the tip of ruptured aneurysms were markedly low. Conclusions—These results suggest that in contrast to the pathogenic effect of a high WSS in the initiating phase, a low WSS may facilitate the growing phase and may trigger the rupture of a cerebral aneurysm by causing degenerative changes in the aneurysm wall. The WSS of the aneurysm region may be of some help for the prediction of rupture. (Stroke. 2004;35:2500-2505.)
765 citations
"Review of Cerebral Aneurysm Formati..." refers background in this paper
...Whereas Cebral et al(47) found that high and concentrated WSS was associated with aneurysm rupture, several computational fluid dynamic studies have shown that the WSS at the tip or bleb of an aneurysm, where rupture most commonly occurs, is in fact low.(48,49) It is thought that low WSS may induce apoptosis of endothelial cells, thus promoting the structural remodeling/fragility of the aneurysm wall and ultimately leading to CA rupture....
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