Does the use of oral contraceptives or hormone replacement therapy offer protection against the formation or rupture of intracranial aneurysms in women?: a systematic review and meta-analysis.

OBJECTIVE: The aim of this study was to carry out a systematic review of the literature with meta-analysis to evaluate the effect of using oral contraceptive and hormone replacement therapy as a protective factor in the formation of intracranial aneurysms and subarachnoid hemorrhage. METHODS: This is a systematic review of the literature with meta-analysis, using PubMed and Embase as databases and the PRISMA method. Case-control and cohort studies published until December 2022 were included in this review. RESULTS: Four studies were included in this review; three of which were eligible for meta-analysis. Regarding the use of oral contraceptive and the development of subarachnoid hemorrhage, there was a lower risk of aneurysm rupture with an odds ratio 0.65 (confidence interval 0.5-0.85). In the analysis of patients using hormone replacement therapy and developing subarachnoid hemorrhage, there was also a lower risk of aneurysm rupture with an OR 0.54 (CI 0.39-0.74). Only one article analyzed the formation of intracranial aneurysm and the use of hormone replacement therapy and oral contraceptive, and there was a protective effect with the use of these medications. oral contraceptive: OR 2.1 (CI 1.2-3.8) and hormone replacement therapy: OR 3.1 (CI 1.5-6.2). CONCLUSION: The use of hormone replacement therapy and oral contraceptive has a protective effect in intracranial aneurysm rupture and formation.

Effects of Supplemental Dexmedetomidine Anesthesia on Intracranial Aneurysm Patients Undergoing Intracranial Interventional Embolization.

BACKGROUND: Intracranial aneurysm (IA) has been identified in approximately 0.4%-3% of the population and associated with 3%-10% mortality. IA is the major factor attributing to spontaneous subarachnoid hemorrhage. We aim to investigate that whether employing dexmedetomidine (DEX), an α2 adrenergic receptor agonist, as a supplementation could impact the outcomes of patients with intracranial interventional embolization. METHODS: Patients were randomly divided into a control group (n = 48 cases) and a DEX (0.6 µg/kg) supplement group (n = 48 cases). Patients' outcomes were evaluated using the Glasgow Outcome Scale. Serum levels of norepinephrine, cortisol, interleukin-6, C-reactive protein, neuron-specific enolase, and S100ß were determined using enzyme-linked immunoassay. The cognitive function of patients was assessed using the Mini-Mental State Exam and Montreal Cognitive Assessment tests. RESULTS: DEX supplementation during anesthesia reduced adverse reaction, surgical stress, and attenuated cognitive impairment after extubation in IA patients' postintracranial interventional embolization. CONCLUSIONS: Our study demonstrated that employing DEX as supplementation during anesthesia could effectively reduce surgical stress and improve cognitive function, ultimately improving patients' recovery from intracranial interventional embolization.

Single-Cell Transcriptome Analysis of the Circle of Willis in a Mouse Cerebral Aneurysm Model.

BACKGROUND: The circle of Willis (CoW) is the most common location for aneurysms to form in humans. Although the major cell types of the intracranial vasculature are well known, the heterogeneity and relative contributions of the different cells in healthy and aneurysmal vessels have not been well characterized. Here, we present the first comprehensive analysis of the lineage heterogeneity and altered transcriptomic profiles of vascular cells from healthy and aneurysmal mouse CoW using single-cell RNA sequencing. METHODS: Cerebral aneurysms (CAs) were induced in adult male mice using an elastase model. Single-cell RNA sequencing was then performed on CoW samples obtained from animals that either had aneurysms form or rupture 14 days post-induction. Sham-operated animals served as controls. RESULTS: Unbiased clustering analysis of the transcriptional profiles from >3900 CoW cells identified 19 clusters representing ten cell lineages: vascular smooth muscle cells, endothelial cells fibroblasts, pericytes and immune cells (macrophages, T and B lymphocytes, dendritic cells, mast cells, and neutrophils). The 5 vascular smooth muscle cell subpopulations had distinct transcriptional profiles and were classified as proliferative, stress-induced senescent, quiescent, inflammatory-like, or hyperproliferative. The transcriptional signature of the metabolic pathways of ATP generation was found to be downregulated in 2 major vascular smooth muscle cell clusters when CA was induced. Aneurysm induction led to significant expansion of the total macrophage population, and this expansion was further increased with rupture. Both inflammatory and resolution-phase macrophages were identified, and a massive spike of neutrophils was seen with CA rupture. Additionally, the neutrophil-to-lymphocyte ratio (NLR), which originated from CA induction mirrored what happens in humans. CONCLUSIONS: Our data identify CA disease-relevant transcriptional signatures of vascular cells in the CoW and is searchable via a web-based R/shiny interface.

Rabbit Elastase Aneurysm Model Mimics the Recurrence Rate of Human Intracranial Aneurysms following Platinum Coil Embolization.

BACKGROUND AND PURPOSE: Intracranial aneurysms treated with coils have been associated with incomplete occlusion, particularly in large or wide-neck aneurysms. This study aimed to validate the accuracy of the rabbit elastase model in predicting aneurysm recurrence in humans treated with platinum coils. MATERIALS AND METHODS: Elastase-induced saccular aneurysms were induced in rabbits and embolized with conventional platinum coils. The recurrence rates of aneurysms were retrospectively analyzed. Morphologic characteristics of aneurysms, angiographic outcomes, and histologic healing were evaluated. RESULTS: A total of 28 (15.3%) of 183 aneurysms recurred. The aneurysm recurrence rate observed in this study (15.3%) is similar to those reported in multiple analyses of aneurysm recurrence rates in humans (7%-27%). The rate of recurrence was higher in aneurysms treated without balloon assistance (19/66, 28.8%) compared with those treated with balloon assistance (9/117, 7.7%). Aneurysms treated with balloon-assisted coiling had a lower recurrence rate (OR = 0.17; 95% CI, 0.05-0.47; P = .001) and higher occlusion rate (OR = 6.88; 95% CI, 2.58-20.37; P < .001) compared with those treated without balloon-assisted coiling. In this rabbit elastase-induced aneurysm model, packing density and aneurysm volume were weak predictors of aneurysm recurrence; however, the packing density was a good predictor of the occlusion rate (OR = 1.05; 95% CI, 1.02-1.10; P = .008). CONCLUSIONS: The rabbit elastase aneurysm model may mimic aneurysm recurrence rates observed in humans after platinum coil embolization. Moreover, balloon assistance and high packing densities were significant predictors of aneurysm recurrence and occlusion.

Induction of large cerebral aneurysms by intraperitoneal administration of ß-aminopropionitrile fumarate in male rats.

BACKGROUND: It is necessary and useful to obtain an experimental model which steadily and rapidly induces aneurysms for investigation of the pathogenesis of cerebral aneurysm. We attempted to examine whether intraperitoneal administration of ß-aminopropionitrile fumarate (BAPN-F) with additional treatments of induced hypertension and hemodynamic stress could steadily and rapidly induce aneurysms in male rats. METHODS: Seven-week-old male Sprague-Dawley rats pretreated with ligation of left common carotid and bilateral posterior renal arteries were administrated BAPN-F intraperitoneally. Induction rate and size of aneurysms was investigated with varying dose and duration of BAPN-F administration (low dose; 400 mg/kg/week for 4 or 8 weeks and high dose; 2800 mg/kg/week for 8 or 12 weeks). RESULTS: Induction rate in the high-dose groups was significantly higher (P<0.01) than that in the low-dose groups. Making comparisons between 8 and 12 weeks of the high-dose groups, while there was no difference in induction rate (8 weeks; 85.2% vs. 12 weeks; 76.9%), aneurysmal size was larger in 12 weeks (8 weeks; 127.5 µm, vs. 12 weeks; 181.7 µm in terms of median) but lethal intrathoracic hemorrhage was increased in 12 weeks (8 weeks; 7.4% vs. 12 weeks; 30.8%). Induction rate of large aneurysm was 22.2% and 30.8% in 8 and 12 weeks of the high-dose groups, respectively. CONCLUSIONS: High-dose BAPN-F administration can cause high-frequency aneurysmal induction. Although there was the difference in size and mortality rate based on administration duration, intraperitoneal administration of 2800 mg/kg/week BAPN-F for 8 weeks would be suitable for aneurysmal induction.

Creating Clinically Relevant Aneurysm Sizes in the Rabbit Surgical Elastase Model.

BACKGROUND: Creating aneurysm sizes in animal models that resemble human aneurysms is essential to study and test neuroendovascular devices. The commonly used rabbit surgical elastase model, however, produces saccular aneurysms that are smaller than those typically treated in humans. The goal of this study was to determine whether an increased vessel stump length and the addition of calcium chloride to the incubation solution has an effect on the resulting aneurysm size. METHODS: Using a modified aneurysm creation method, 32 female New Zealand White rabbits underwent aneurysm creation procedures. Subjects were equally allocated into 4 different groups based on vessel stump length (2 cm controls vs. 3 cm) and incubation solution (elastase alone controls vs. a 1:1 mixture of elastase and calcium chloride). At 4 weeks, all animals underwent angiography to determine the resulting aneurysm size by a neurointerventionalist who was blinded to treatment group. RESULTS: An increase in stump length from 2 cm to 3 cm resulted in a significant increase in the height of aneurysm (P < 0.05). Compared with control animals, the combination of a 3-cm stump length and the addition of calcium chloride to the incubation solution resulted in a significant increase in aneurysm height, width, and volume (P < 0.05). CONCLUSIONS: Creating larger aneurysms is necessary for the rabbit model to be more clinically relevant. Our study demonstrated that the utilization of a 3-cm vessel stump as well as both calcium chloride and elastase in the incubation solution results in aneurysm sizes that more closely resemble the population of aneurysms treated in humans.

Rabbit Elastase Aneurysm: Imaging and Histology Correlates for Inflammation and Healing.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage remains a devastating event with poorly understood pathophysiology. Previous studies have suggested that aneurysm wall inflammation may play a part in the development and potential rupture of aneurysms. The rabbit elastase aneurysm model is a well-established model, which produces aneurysms closely mimicking human cerebral aneurysms in flow dynamics and histopathology. The primary aim of this study was to correlate inflammatory changes after aneurysm formation using sequential vessel wall imaging with histopathologic analysis. A secondary aim was to evaluate the potential effect of gender and anti-inflammatory treatment with aspirin on this inflammatory response. METHODS: Twenty-seven New Zealand rabbits underwent surgery to create an aneurysm using elastase infusion at the right common carotid artery origin. Vessel wall imaging and histopathologic analysis was obtained at different time points after aneurysm creation. The rabbits were also randomized by gender and to treatment groups with or without aspirin. RESULTS: Histopathologic analysis revealed 3 distinct phases after aneurysm formation. These phases were an initial inflammatory phase, followed by a regeneration phase, and finally a connective tissue deposition phase. Vessel wall imaging demonstrated 2 distinct imaging patterns. No appreciable differences were seen in histology or imaging when comparing gender or treatment with aspirin. CONCLUSIONS: Inflammatory changes induced by the rabbit elastase aneurysm model can be correlated with histopathologic findings and observed on noninvasive vessel wall imaging. This may provide a method to study the inflammatory pathway as it pertains to aneurysmal development and subsequent rupture.

High-resolution image-guided WEB aneurysm embolization by high-frequency optical coherence tomography.

BACKGROUND: High-frequency optical coherence tomography (HF-OCT) is an intra-vascular imaging technique capable of assessing device-vessel interactions at spatial resolution approaching 10 µm. We tested the hypothesis that adequately deployed Woven EndoBridge (WEB) devices as visualized by HF-OCT lead to higher aneurysm occlusion rates. METHODS: In a leporine model, elastase-induced aneurysms (n=24) were treated with the WEB device. HF-OCT and digital subtraction angiography (DSA) were performed following WEB deployment and repeated at 4, 8, and 12 weeks. Protrusion (0-present, 1-absent) and malapposition (0-malapposed, 1-neck apposition >50%) were binary coded. A device was considered 'adequately deployed' by HF-OCT and DSA if apposed and non-protruding. Aneurysm healing on DSA was reported using the 4-point WEB occlusion score: A or B grades were considered positive outcome. Neointimal coverage was quantified on HF-OCT images at 12 weeks and compared with scanning electron microscopy (SEM). RESULTS: Adequate deployment on HF-OCT correlated with positive outcome (P=0.007), but no statistically significant relationship was found between good outcome and adequate deployment on DSA (P=0.289). Absence of protrusion on HF-OCT correlated with a positive outcome (P=0.006); however, malapposition alone had no significant relationship (P=0.19). HF-OCT showed a strong correlation with SEM for the assessment of areas of neointimal tissue (R²=0.96; P<0.001). More neointimal coverage of 78%±32% was found on 'adequate deployment' cases versus 31%±24% for the 'inadequate deployment' cases (P=0.001). CONCLUSION: HF-OCT visualizes features that can determine adequate device deployment to prognosticate early aneurysm occlusion following WEB implantation and can be used to longitudinally monitor aneurysm healing progression.

WEB Device Shape Changes in Elastase-Induced Aneurysms in Rabbits.

BACKGROUND AND PURPOSE: While WEB devices have been shown to be safe and effective for aneurysm treatment, WEB-shape modification compression has been associated with incomplete aneurysm occlusion. We explored the relationship between occlusion rates and WEB-shape modification in different WEB device types in an experimental aneurysm model. MATERIALS AND METHODS: Elastase-induced aneurysms were created in rabbits and treated with dual-layer (n = 12), single-layer (n = 12), or single-layer sphere (n = 12) WEB devices. Aneurysms were followed up either at 3 or 12 months. Angiographic occlusion was graded using the WEB Occlusion Scale: grade I, complete; grade II, complete but recess filling; grade III, residual neck; or grade IV, residual aneurysm. WEB-shape modification and histologic features were also analyzed. RESULTS: Grade I or II occlusion was seen in 16 (44%) aneurysms, and grade I, II, or III ("adequate") occlusion was observed in 22 (61.1%) aneurysms at follow-up. WEB-shape modification was observed in 22 (61.1%) aneurysms. WEB-shape modification was higher in single-layer (9/12) and dual-layer (10/12) devices compared with single-layer sphere devices (3/12). Aneurysms with WEB-shape modification had a higher level of thrombus organization in the dome compared with those without WEB-shape modification (68% [15/22] versus 50% [7/14]). WEB-shape modification was not correlated with angiographic or histologic outcomes but was significantly correlated with levels of fibrosis and smooth muscle cells in the aneurysm. CONCLUSIONS: WEB-shape modification is not associated with incomplete aneurysm occlusion of WEB devices in the rabbit model but may be related to connective tissue formation and the healing response to WEB device implantation.

Sex and Genetic Background Effects on the Outcome of Experimental Intracranial Aneurysms.

BACKGROUND AND PURPOSE: Intracranial aneurysm formation and rupture risk are, in part, determined by genetic factors and sex. To examine their role, we compared 3 mouse strains commonly used in cerebrovascular studies in a model of intracranial aneurysm formation and rupture. METHODS: Intracranial aneurysms were induced in male CD1 (Crl:CD1[ICR]), male and female C57 (C57BL/6NCrl), and male 129Sv (129S2/SvPasCrl or 129S1/SvImJ) mice by stereotaxic injection of elastase at the skull base, combined with systemic deoxycorticosterone acetate-salt hypertension. Neurological deficits and mortality were recorded. Aneurysms and subarachnoid hemorrhage grades were quantified postmortem, either after spontaneous mortality or at 7 to 21 days if the animals survived. In separate cohorts, we examined proinflammatory mediators by quantitative reverse transcriptase-polymerase chain reaction, arterial blood pressure via the femoral artery, and the circle of Willis by intravascular latex casting. RESULTS: We found striking differences in aneurysm formation, rupture, and postrupture survival rates among the groups. 129Sv mice showed the highest rates of aneurysm rupture (80%), followed by C57 female (36%), C57 male (27%), and CD1 (21%). The risk of aneurysm rupture and the presence of unruptured aneurysms significantly differed among all 3 strains, as well as between male and female C57. The same hierarchy was observed upon Kaplan-Meier analysis of both overall survival and deficit-free survival. Subarachnoid hemorrhage grades were also more severe in 129Sv. CD1 mice showed the highest resistance to aneurysm rupture and the mildest outcomes. Higher mean blood pressures and the major phenotypic difference in the circle of Willis anatomy in 129Sv provided an explanation for the higher incidence of and more severe aneurysm ruptures. TNFα (tumor necrosis factor-alpha), IL-1ß (interleukin-1-beta), and CCL2 (chemokine C-C motif ligand 2) expressions did not differ among the groups. CONCLUSIONS: The outcome of elastase-induced intracranial aneurysm formation and rupture in mice depends on genetic background and shows sexual dimorphism.

Risk of Intracranial Aneurysm and Dissection and Fluoroquinolone Use: A Case-Time-Control Study.

Background and Purpose- Fluoroquinolone use is associated with an increased risk of aortic aneurysm and dissection. We investigated this risk of arterial wall injury on intracranial arteries, given the similar pathophysiological mechanisms for aneurysm and dissection in both types of arteries. Methods- A case-time-control study was conducted using French National Insurance databases covering >60 million inhabitants. Cases were aged ≥18 years with first ruptured intracranial aneurysm and dissection between 2010 and 2015. For each case, fluoroquinolone use was compared between the exposure-risk window (day 30-day 1 before the outcome) and matched control windows (day 120-day 91, day 150-day 121, and day 180-day 151) and adjusted for time-varying confounders; potential time-trend for exposure was controlled using an age- and sex-matched reference group. Amoxicillin use was studied similarly for indication bias controlling. The potential excess of risk conveyed by fluoroquinolones was assessed by the ratio of OR for fluoroquinolones to that for amoxicillin. Results- Of the 7443 identified cases, 75 had been exposed to fluoroquinolones in the prior 180 days, including 16 in the 30-day at-risk window (385/97 cases exposed to amoxicillin, respectively). The adjusted OR for fluoroquinolones was 1.26 (95%CI, 0.65-2.41) and that for amoxicillin of 1.36 (95% CI, 1.05-1.78). Ratio of OR for fluoroquinolones to that for amoxicillin was estimated at 0.92 (95% CI, 0.46-1.86). Result was similar when extending outcome definition to unruptured events (ratio of OR for fluoroquinolones to that for amoxicillin, 0.97 [95% CI, 0.61-1.53]). Conclusions- This study did not evidence an excess of risk of intracranial aneurysm or dissection with fluoroquinolone use.

Fatal intracranial aneurysm rupture after thrombolytic treatment for ischemic stroke: a case report and literature review.

Intravenous thrombolysis is a proven treatment of acute ischemic stroke. Its complications include intracranial hemorrhage; the risk may be increased in the presence of an unruptured aneurysm. We present a case report of a patient who suffered fatal subarachnoid hemorrhage after thrombolysis from a known aneurysm. A history of recent previously inexperienced headaches was revealed retrospectively, suggestive of sentinel bleedings. A similar patient was identified in the literature; we thus propose that this history should be excluded in patients harboring an aneurysm considered for thrombolytic treatment.

Prevention Effect of Antiplatelets on Aneurysm Rupture in a Mouse Intracranial Aneurysm Model.

BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) from intracranial aneurysm rupture results in significant morbidity and mortality. In the present study, we examined the effect of most widely used antiplatelet drugs, aspirin and cilostazol, on aneurysm rupture prevention using a mouse intracranial aneurysm model. MATERIALS AND METHODS: Intracranial aneurysms were induced by a combination of deoxycorticosterone acetate-salt and a single injection of elastase into the cerebrospinal fluid in mice. Treatment with aspirin or cilostazol was started 1 day after aneurysm induction. Aneurysm rupture was detected by neurological symptoms and the presence of intracranial aneurysm with SAH was confirmed by post-mortem examination. RESULTS: Aspirin (10 mg/kg) significantly reduced aneurysm rupture (control:aspirin = 80%:31%, p < 0.05) without affecting the overall incidence of aneurysm formation (60%:62%). Cilostazol (3 mg/kg, 30 mg/kg) did not reduce both rupture rate (control:3 mg/kg:30 mg/kg = 81%:67%:77%) and the overall incidence of aneurysm formation (control:3 mg/kg:30 mg/kg = 72%:71%:76%). Tail vein bleeding time prolonged significantly in both aspirin and cilostazol groups (p < 0.01). CONCLUSION: Aspirin prevented aneurysm rupture in a mouse intracranial aneurysm model, while cilostazol did not. Aspirin, the most frequently used drug for patients with ischemic myocardial and cerebral diseases, is also effective in preventing cerebral aneurysmal rupture.

Acute thrombus formation on phosphorilcholine surface modified flow diverters.

PURPOSE: Thromboembolic complications remain a limitation of flow diverting stents. We hypothesize that phosphorilcholine surface modified flow diverters (Pipeline Flex with Shield Technology, sPED) would have less acute thrombus formation on the device surface compared with the classic Pipeline Embolization device (cPED). METHODS: Elastase-induced aneurysms were created in 40 rabbits and randomly assigned to receive cPED or sPED devices with and without dual antiplatelet therapy (DAPT) (four groups, n=10/group). Angioplasty was performed to enhance apposition and create intimal injury for a pro-thrombotic environment. Both before and after angioplasty, the flow diverter was imaged with intravascular optical coherence tomography. The outcome measure was the number of predefined segments along the implant relative to the location of the aneurysm with a minimum of 0 (no clot formation) and maximum of 3 (all segments with thrombus). Clot formation over the device at ostia of branch arteries was assessed as either present or absent. RESULTS: Following angioplasty, the number of flow diverter segments with clots was significantly associated with the flow diverter (p<0.0001), but not with DAPT (p=0.3872) or aneurysm neck size (p=0.8555). The incidence rate for clots with cPED was 1.72 times more than with sPED. The clots on the flow diverter at the location corresponding to side branch ostia was significantly lower with sPED than with cPED (OR 0.180; 95% CI 0.044 to 0.734; p=0.0168), but was not associated with DAPT (p=0.3198). CONCLUSION: In the rabbit model, phosphorilcholine surface modified flow diverters are associated with less thrombus formation on the surface of the device.

Rabbit aneurysm models mimic histologic wall types identified in human intracranial aneurysms.

BACKGROUND: Semiquantitative scales correlate histopathologic findings in the walls of human aneurysms with rupture status. OBJECTIVE: To apply a semiquantitative scale to the rabbit elastase-induced aneurysm model to determine whether rabbit histologic types mimic the full range of histologic subtypes of humans. MATERIALS AND METHODS: Twenty-seven elastase-induced female rabbit aneurysms were studied, harvested at 2 weeks (n=5) and 12 weeks (n=22). Paraffin-embedded sections received hematoxylin-eosin and Verhoeff-Van Gieson staining. Immunohistochemistry was performed for α-smooth muscle actin and CD31 for endothelial cells. A semiquantitative scale was used for scoring based on human aneurysm tissue, divided into four subtypes according to cellular and extracellular matrix findings: type A, linear organized smooth muscle cells (SMCs) and intact endothelium; type B, thickened wall with disorganized, proliferating SMCs; type C, thick, collagenized and hypocellular wall with or without organizing thrombosis, and type D, extremely thin, hypocellular wall. Separate scoring was performed of the aneurysm neck and proximal and distal zones. RESULTS: Findings compatible with all subtypes of human aneurysm tissue were identified. Types A and C were found in 13 (48%) and 11 (41%) of 27 aneurysms and in the proximal and distal wall at both time points. Type B was found in 16 aneurysms (59%), exclusively at the neck at both time points; type D, in 14 aneurysms (52%), exclusively at proximal and distal zones of 12-week aneurysms. CONCLUSIONS: The wall of elastase-induced rabbit aneurysm demonstrates histologic findings similar to the four categories of human cerebral aneurysms based on cellular and extracellular wall content.

Aneurysms in neurofibromatosis type 2: Evidence for vasculopathy?

There have been anecdotal reports of vasculopathy associated with Neurofibromatosis Type 2 (NF2). Given the increasing use of bevacizumab, a vascular endothelial growth factor inhibitor which results in an increased risk of bleeding, it is important to ascertain if there is a predisposition to vascular abnormalities in NF2. In our unit NF2 patients undergo annual MRI brain and internal auditory meatus imaging. We noted incidental intracranial aneurysms in some patients and sought to determine the prevalence of intracranial aneurysms in our cohort of NF2 patients. We conducted a retrospective audit of the MRI images of 104 NF2 patients from 2014 to 2016. Axial T2 brain MRI images were assessed for vascular abnormalities by two neuroradiologists blinded to patient's clinical details. Intracranial aneurysms were detected in four patients and an aneurysm clip related to previous surgery was noted in one additional patient. Using standard MRI imaging sequences alone we provide evidence of intracranial aneurysms in 4.4% of our cohort. This compares with an estimated overall prevalence of 3% in the general population. We discuss these findings as well as other evidence for a vasculopathy associated with NF2.

Concomitant aneurysm detection in an intracranial dolichoectasia mouse model using a MicroFil polymer perfusion technique.

OBJECTIVE: To assess the feasibility of using MicroFil polymer perfusion to detect concomitant saccular aneurysms in an intracranial arterial dolichoectasia (IADE) model in mice, and to report detailed histomorphometric features of these aneurysms. MATERIALS AND METHODS: IADE models were created in C57/BL6 mice via microsurgical injection of 25 mU elastase into the cisterna magna. The cerebral vasculature was perfused with MicroFil polymer and harvested at 1, 3, and 7 days, and 2 and 4 weeks (n=8 for each group). IADE was defined by a tortuosity index >10 combined with a 25% increase in diameter of the A1 segment of the anterior cerebral artery (ACA), internal carotid artery (ICA), or basilar artery compared with the baseline of controls, which received heat-inactivated elastase. Saccular aneurysm occurrence rate, location, and morphological parameters were investigated using macroscopic and microscopic analysis. RESULTS: IADE was present in 95% (36/38) of the subjects, with a mortality rate of 5% (2/40). Fifteen concomitant saccular aneurysms were detected in 8 (21%) of the 38 surviving mice, including 6 at the posterior communicating artery, 1 along the ACA, 2 along the anterior communicating artery complex, 3 along the ICA, and 3 along the middle cerebral artery. Rupture was confirmed in two aneurysms. Histological examination indicated that the aneurysms develop via arterial-wall remodelling, which is characterized by internal elastic lamina disruptions and muscular layer discontinuity in the media. CONCLUSIONS: The proportion of subjects developing saccular aneurysms in addition to IADE in our mouse model is similar to the 15% of patients with IADE who have concomitant saccular aneurysms.

Testing Stenting and Flow Diversion Using a Surgical Elastase-Induced Complex Fusiform Aneurysm Model.

BACKGROUND AND PURPOSE: Rabbit elastase-induced saccular aneurysms have been commonly used for preclinical testing of endovascular devices, including flow diverters. However, all tested devices have been shown to be capable of aneurysm occlusion with this model. We aimed to create a more challenging model to test and discriminate among neurovascular devices of varying efficacies. MATERIALS AND METHODS: With a surgical approach that included elastase infusion and balloon dilation, we attempted the creation of complex fusiform aneurysms in 16 rabbits, with standard saccular carotid aneurysms created in 15 other animals. Aneurysms were randomly allocated to one of the following treatments: flow diversion (n = 8), high-porosity stent (n = 6), double high-porosity stent (n = 5), and control (n = 6). Angiographic assessment and pathologic analyses were performed at 3 months. RESULTS: Creation of complex fusiform and standard saccular aneurysms was successful in 12/16 and 13/15 attempts, respectively. All saccular (n = 4) or complex fusiform (n = 4) aneurysms treated with flow diverters were successfully occluded. Three of 3 saccular compared with 0/2 complex fusiform aneurysms were occluded by double high-porosity stents. One of 3 saccular and 0/3 complex fusiform aneurysms were occluded by a single high-porosity stent. Both aneurysm types shared the same pathologic findings when untreated: The aneurysm wall lacked an elastic layer and smooth muscle cells, while the lumen was lined with neointima of varying thickness. Neointimal coverage of the devices was complete when aneurysms were occluded, while leaks were always associated with aneurysm remnants. CONCLUSIONS: Challenging fusiform aneurysms can be created in rabbits by using a surgical modification of the elastase method.

A small animal model for early cerebral aneurysm pathology.

Prior studies, using systemic hypertension and elastase infusion, have induced cerebral aneurysm (CA) formation in mice. However, the CAs induced were rapidly formed, relatively large, and often ruptured. These features are not completely representative of human CAs. We set out to develop a mouse model representative of the early pathological features of human CA. Twenty male C57/BL6 mice were placed in a stereotactic frame. Low dose elastase solution (2µl/min) was manually injected into the right basal cistern. Human angiotensin II (0.11µl/h) was infused subcutaneously. Mice were observed for 2-3weeks prior to euthanasia. Early CA histopathological features including endothelial change (EC) and internal elastic lamina degeneration (IELD) were systematically sought at major cerebral arterial bifurcations. Brains were harvested from 11 of 15 mice, yielding 27 bifurcations. Sub-arachnoid haemorrhage (SAH) without CA formation was observed in one brain. Macroscopic CA without SAH was observed in another brain. Early CA features were observed in 8/11 (73%) brains. All bifurcations with IELD demonstrated EC: where EC was absent, IELD was also absent. EC severity appeared to correlate with IELD severity. EC and IELD were both severe within the CA. Using lower dose elastase solution than previously employed, we developed a model of early CA pathology. Our model demonstrated that the spectrum of known early CA pathology can be created at multiple bifurcations in mice, with EC severity appearing to correlate with IELD severity. This model permits the study of factors which potentially advance or retard the progression of CA formation.

Evaluation of occurring complications after flow diverter treatment of elastase-induced aneurysm in rabbits using micro-CT and MRI at 9.4 T.

INTRODUCTION: Flow diverters are increasingly being used to treat intracranial aneurysms. This study evaluates occurring complications of flow-diverting devices in the treatment of experimental aneurysms, involving the use of micro-CT and small animal MRI at 9.4 T, in correlation to angiographic and histological findings. METHODS: We previously published two preclinical studies, in which we assessed two different flow diverters in the treatment of elastase-induced aneurysms. Devices have been implanted across the aneurysm neck as well as in the abdominal aorta. From these studies, a total of 65 devices (prototype FD (n = 30) and Derivo embolization device (n = 35)) additionally underwent micro-CT and MRI after angiographic follow-up and before being histologically examined. RESULTS: The different architectures of both devices were precisely comparable due to high-resolution micro-CT imaging. Micro-CT revealed wire fractures in nine cases (30 %) only with the prototype FD. In three cases (10 %), severe wire fractures correlated with an in-stent stenosis due to intimal hyperplasia. Other complications, like distal stent occlusions and post-stent stenosis, were seen in both groups and verified with both imaging techniques. Osseous metaplasia were correlated to calcifications seen with micro-CT. MRI enabled visualization of the position of the implanted devices relative to the aneurysm and revealed incomplete aneurysm neck coverage with the prototype FD in two cases (6.7 %). CONCLUSION: Micro-CT and 9.4-T MRI are valid to discover and understand occurring complications of flow diverters in the preclinical phase and can serve as evaluation tools to minimize complication rates of endovascular devices in the future.