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Platelet aggregation is intimately associated with vascular inflammation and is commonly seen on routine histology studies of cerebral aneurysms. Platelets, when activated, have been shown to augment neutrophil response and the pro-inflammatory cascade. Platelet-neutrophil complexes have been found to aggravate atherosclerosis through a positive feedback loop. We hypothesized that targeting platelet aggregation and downstream inflammation could be used to prevent aneurysm formation and progression. First, we induced cerebral aneurysm formation in a previously described intracranial aneurysm model via carotid artery ligation, hypertension, and stereotactic elastase injection in C57BL/6 mice and analyzed vessels for lesion and thrombus formation. Raybiotech cytokine arrays were used to analyze 96 cytokines in induced murine aneurysms and 120 cytokines in human tissue samples. Cerebral aneurysm formation and inflammatory pathway were then studied in animals treated with IgG2 antibody (control), anti-GpIb antibody (platelet depletion), 1:10 DMSO:PBS (control), clopidogrel, anti-CXCR1/2 small molecule inhibitor, or anti-CXCL7 antibody. Bleeding assays and flow cytometry were used to evaluate platelet function in treated groups. CD31 + platelet aggregates are a common feature in human and mouse cerebral aneurysm specimens. Platelet ablation in mice prevents cerebral aneurysm formation (20% vs 100% in control antibody-treated mice, n = 5 each, p = 0.0476). Mice treated with 1 mg/kg clopidogrel develop significantly less aneurysms than controls (18% vs 73%, n = 11 and 11, respectively, p = 0.03). Semi-quantitative analysis of 96 different cytokines using Raybiotech arrays shows increased protein expression of CXCL7 in murine cerebral aneurysms when compared to controls. Treatment with clopidogrel results in reciprocal decrease in detected CXCL7. Targeting CXCL7-CXCR1/2 axis with 10 mg/kg reparixin (CXCR1/2 antagonist) significantly decreases cerebral aneurysm formation (11% vs 73%, n = 9 and 11, p = 0.0098) while treatment with 10 mg/kg SB225002 tends to decrease aneurysm formation (36% vs 73%, n = 11 vs n = 7, p = 0.11). Lastly, specific antibody blockade against CXCL7 using anti-CXCL7 antibody at 100 ug/mL significantly decreases cerebral aneurysm formation (29% vs 75%, n = 7 vs n = 8, p = 0.046). Platelet inflammation has an important role in cerebral aneurysm formation. Small molecule inhibitors targeting platelet CXCL7-CXCR1/2 inflammatory axis could be used to prevent cerebral aneurysm formation or progression., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Cranial nerve (CN) palsies are rare presenting symptoms of intracranial aneurysms. Our objectives were to report our institutional outcomes and study-level meta-analysis summarizing rates of improvement and identifying factors associated with recovery from CN symptoms after flow diversion., Methods: We conducted a retrospective review of our institutional database for patients with intracranial aneurysms presenting with CN palsies who underwent treatment with flow diversion between 2015 and 2023. Systematic review of the literature was performed using Medline, EMBASE, Cochrane, as well as manual citation searches. Random effects meta-analysis was used., Results: Thirteen of 136 studies were included in the meta-analysis and were combined with our institutional data. The pooled rate of improvement in any CN palsies following flow diversion was 71 % (95 %CI, 60 %-82 %, n=322). Patients presenting with CN II deficits were less likely to improve following treatment compared to other CN deficits (pooled OR [pOR] 0.32, 95 %CI, 0.16-0.63, n=224). The pooled rate of clinical improvement was 53 % in CNII deficits (95 %CI, 42 %-65 %, n=80) and 80 % in other CN deficits (95 %CI, 71 %-88 %, n=106). An increased rate of improvement was associated with acute intervention (pOR 9.12, 95 % CI, 2.26-36.73, n = 71) and radiographic aneurysm occlusion (pOR 5.29, 95 %CI, 1.66-16.90, n=118)., Conclusions: Flow diversion improves CN palsy outcomes in patients with symptomatic intracranial aneurysms. The lower rate of improvement in visual acuity compared to other CN deficits may point to a different mechanism of injury or potential recoverability in these patients., Competing Interests: Declaration of Competing Interest The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article., (Copyright © 2024. Published by Elsevier B.V.)

An arachnoid web is a pathological formation of the arachnoid membrane. It is a rare phenomenon but is known to lead to syrinx formation in the spinal cord along with pain and neurological deficits. On imaging, the 'scalpel sign' is pathognomonic for an arachnoid web. The etiology of syrinx formation from an arachnoid web is currently unknown. This report documents the only two cases of arachnoid webs with an extensive syrinx in which a likely pathophysiologic mechanism is identified. Both cases presented with motor deficits. The patients had no history of trauma or infection. After extensive workup in both patients and observation of the scalpel sign an arachnoid web was suspected. In both cases, the patients were treated surgically after an arachnoid web was suspected. Intra-operative ultrasound visualized in both cases demonstrates a fenestration in the web that allowed passage of cerebrospinal fluid in a rostral-caudal direction due to a ball-valve effect.

Maladaptive inflammation underlies the formation and rupture of human intracranial aneurysms. There is a growing body of evidence that anti-inflammatory pharmaceuticals may beneficially modulate this process. Clopidogrel (Plavix) is a commonly used irreversible P2Y12 receptor antagonist with anti-inflammatory activity. In this paper, we investigate whether clopidogrel is associated with the likelihood of aneurysm rupture in a multi-institutional propensity-matched cohort analysis. Patients presenting for endovascular treatment of their unruptured intracranial aneurysms and those presenting with aneurysm rupture between 2015 and 2019 were prospectively identified at two quaternary referral centers. Patient demographics, comorbidities, and medication usage at the time of presentation were collected. Patients taking clopidogrel or not taking clopidogrel were matched in a 1:1 fashion with respect to location, age, smoking status, aneurysm size, aspirin usage, and hypertension. A total of 1048 patients with electively treated aneurysms or subarachnoid hemorrhages were prospectively identified. Nine hundred twenty-one patients were confirmed to harbor aneurysms during catheter-based diagnostic angiography. A total of 172/921 (19%) patients were actively taking clopidogrel at the time of presentation. Three hundred thirty-two patients were matched in a 1:1 fashion. A smaller proportion of patients taking clopidogrel at presentation had ruptured aneurysms than those who were not taking clopidogrel (6.6% vs 23.5%, p < .0001). Estimated treatment effect analysis demonstrated that clopidogrel usage decreased aneurysm rupture risk by 15%. We present, to the best of our knowledge, the first large-scale multi-institutional analysis suggesting clopidogrel use is protective against intracranial aneurysm rupture. It is our hope that these data will guide future investigation, revealing the pathophysiologic underpinning of this association., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cerebral aneurysms are a source of neurological morbidity and mortality, most often as a result of rupture. The most common approach for treating aneurysms involves endovascular embolization using nonbiodegradable medical devices, such as platinum coils. However, the need for retreatment due to the recanalization of coil-treated aneurysms highlights the importance of exploring alternative solutions. In this study, we propose an injectable extracellular matrix-derived embolic formed in situ by Michael addition of gelatin-thiol (Gel-SH) and hyaluronic acid vinyl sulfone (HA-VS) that may be delivered with a therapeutic agent (here, RADA-SP) to fill and remodel aneurysmal tissue without leaving behind permanent foreign bodies. The injectable embolic material demonstrated rapid gelation under physiological conditions, forming a highly porous structure and allowing for cellular infiltration. The injectable embolic exhibited thrombogenic behavior in vitro that was comparable to that of alginate injectables. Furthermore, in vivo studies in a murine carotid aneurysm model demonstrated the successful embolization of a saccular aneurysm and extensive cellular infiltration both with and without RADA-SP at 3 weeks, with some evidence of increased vascular or fibrosis markers with RADA-SP incorporation. The results indicate that the developed embolic has inherent potential for acutely filling cerebrovascular aneurysms and encouraging the cellular infiltration that would be necessary for stable, chronic remodeling.

Management of intracranial aneurysms (IAs) is determined by patient age, risk of rupture, and comorbid conditions. While endovascular and microsurgical interventions offer solutions to mitigate the risk of rupture, pharmacological management strategies may complement these approaches or serve as alternatives in appropriate cases. The pathophysiology of IAs allows for the targeting of inflammation to prevent the development and rupture of IAs. The aim of this review is to provide an updated summary of different pharmaceutical management strategies for IAs. Acetylsalicylic acid and renin-angiotensin-aldosterone system (RAAS) inhibitor antihypertensives have some evidence supporting their protective effect. Studies of selective cyclooxygenase-2 (COX-2) inhibitors, statins, ADP inhibitors, and other metabolism-affecting drugs have demonstrated inconclusive findings regarding their association with aneurysm growth or rupture. In this manuscript, we highlight the evidence supporting each drug's effectiveness.

Background: Central venous catheters (CVCs) play an indispensable role in clinical practice. Catheter malposition and tip migration can lead to severe complications. The authors present a case illustrating the endovascular management of inadvertent marginal sinus cannulation after an internal jugular vein (IJV) catheter tip migration., Observations: A triple-lumen CVC was inserted without complications into the right IJV of a patient undergoing a repeat sternotomy for aortic valve replacement. Two weeks postinsertion, it was discovered that the tip had migrated superiorly, terminating below the torcula in the posterior fossa. In the interventional suite, a three-dimensional venogram confirmed the inadvertent marginal sinus cannulation. The catheter was carefully retracted to the sigmoid sinus to preserve the option of catheter exchange if embolization became necessary. After a subsequent venogram, which displayed an absence of contrast extravasation, the entire catheter was safely removed. The patient tolerated the procedure well., Lessons: Clinicians must be vigilant of catheter tip migration and malposition risks. Relying solely on postinsertion radiographs is insufficient. Once identified, prompt management of the malpositioned catheter is paramount in reducing morbidity and mortality and improving patient outcomes. Removing a malpositioned catheter constitutes a critical step, best performed by a specialized team under angiographic visualization.

Objective: Cerebral vasospasm and the resultant delayed cerebral infarction is a significant source of mortality following aneurysmal SAH. Vasospasm is currently detected using invasive or expensive imaging at regular intervals in patients following SAH, thus posing a risk of complications following the procedure and financial burden on these patients. Currently, there is no blood-based test to detect vasospasm., Methods: PubMed, Web of Science, and Embase databases were systematically searched to retrieve studies related to cerebral vasospasm, aneurysm rupture, and biomarkers. The study search dated from 1997 to 2022. Data from eligible studies was extracted and then summarized., Results: Out of the 632 citations screened, only 217 abstracts were selected for further review. Out of those, only 59 full text articles met eligibility and another 13 were excluded., Conclusions: We summarize the current literature on the mechanism of cerebral vasospasm and delayed cerebral ischemia, specifically studies relating to inflammation, and provide a rationale and commentary on a hypothetical future bloodbased test to detect vasospasm. Efforts should be focused on clinical-translational approaches to create such a test to improve treatment timing and prediction of vasospasm to reduce the incidence of delayed cerebral infarction., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Inc.)

Intracranial aneurysms are reported to affect 2-5% of the population. Despite advances in the surgical management of this disease, diagnostic technologies have marginally improved and still rely on expensive or invasive imaging procedures. Currently, there is no blood-based test to detect cerebral aneurysm formation or quantify the risk of rupture. The aim of this review is to summarize current literature on the mechanism of aneurysm formation, specifically studies relating to inflammation, and provide a rationale and commentary on a hypothetical future blood-based test. Efforts should be focused on clinical-translational approaches to create an assay to screen for cerebral aneurysm presence and risk-stratify patients to allow for superior treatment timing and management. Cerebral Aneurysm Blood Test Considerations: There are multiple caveats to development of a putative blood test to detect cerebral aneurysm presence., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background  Stereotactic radiosurgical rhizolysis of the trigeminal nerve is an established modality increasingly employed to alleviate the symptoms of refractory trigeminal neuralgia. This study analyzes the academic impact of the top 100 cited articles on the radiosurgical management of trigeminal neuralgia. Methods  The Scopus database was searched for articles containing "radiosurgery" and one or more of "trigeminal neuralgia," "trigeminus neuralgia," and "tic douloureux." The top 100 articles written in English were arranged in descending order by citation count. Documents were evaluated for authors, publication year, journal and impact factor, total citations, nationality, study type, radiosurgical modality, and the affiliated institution. Quantitative and qualitative analyses were performed on the data. Results  The most cited articles were published between 1971 and 2019. The average citation per year was 4.3. The most targeted anatomic area was the "root entry zone" or proximal portion of the cisternal segment of the trigeminal nerve. The most utilized modality was Gamma Knife radiosurgery. The country with the highest number of publications was the United States. Thirty-six percent of the articles were published in the Journal of Neurosurgery . Lunsford, Kondziolka, Flickinger, and Régis, respectively, were the most frequently listed co-authors. The most prolific institute was the University of Pittsburgh Medical Center. Conclusion  Stereotactic radiosurgery is an important modality in the management of medically or surgically refractory trigeminal neuralgia. This analysis assesses its contributions over the past five decades to identify trends in treatment practices for neurosurgeons and to highlight areas where further study is needed., Competing Interests: Conflict of Interest None declared., (Asian Congress of Neurological Surgeons. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Background: Recent literature suggests that spinal infections are increasing in prevalence. Any compartment can be infected in the spine; however, multicompartmental infections are rare., Observations: To the authors' knowledge, this report is the only reported case of a tetra-compartmental spinal infection consisting of epidural, subdural, subarachnoid, and intramedullary components with a contiguous lumbar spondylodiscitis resulting in conus medullaris syndrome requiring surgical intervention., Lessons: This case highlights the importance of surgical intervention in severe cases such as the one illustrated in this report. Second, magnetic resonance imaging with and without contrast is required to check for spreading of the infection as these findings may change the surgical approach. Last, the use of intraoperative ultrasound is paramount to evaluate the subdural and intramedullary compartments in severe cases.

Introduction: Gram-negative rod (GNR) bacterial ventriculitis is a rare complication of shunt-dependent hydrocephalus, often requiring an extended and invasive treatment course. Accumulation of purulent material, as well as empyema and septation formation, limits circulation of antibiotics and infection clearance. Supplementation of standard care with neuroendoscopic-guided intraventricular lavage with lactated Ringer solution and fenestration of septations may facilitate infection clearance and simplify the eventual shunt construct required. Here, the utility of serial lavage for ventriculitis is described in a population of shunt-dependent neonates and infants at high risk for morbidity and mortality., Methods: Five infants with shunt-dependent hydrocephalus and subsequent GNR ventriculitis were treated with standard care measures with the addition of serial neuroendoscopic lavage. A retrospective chart review was performed to collect patient characteristics, shunt dependency, and shunt revisions within a year of ventriculitis resolution., Results: Patients demonstrated a mean 74% decrease in cerebrospinal fluid (CSF) protein following each neuroendoscopic lavage and trended toward a shorter time to infection clearance in comparison to previously published literature. Patients required 0-2 shunt revisions at 1-year follow-up following hospitalization for shunt-related ventriculitis (mean 0.8 +/- 0.8)., Conclusions: Serial neuroendoscopic lavage is an effective technique, used alone or in combination with fenestration of septations, to reduce the CSF protein and bacterial load in the treatment of ventriculitis, decreasing time until eradication of infection. Serial lavage may reduce the risk of future shunt malfunction, simplify the future shunt construct, and decrease duration of infection., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Cerebral aneurysm embolization is a therapeutic approach to prevent rupture and resultant clinical sequelae. Current, non-biodegradable metallic coils (platinum or tungsten) are the first-line choice to secure cerebral aneurysms. However, clinical studies report that up to 17% of aneurysms recur within 1 year after coiling, leading to retreatment and additional surgery. It would be ideal for the aneurysm coiling material to induce acute thrombotic occlusion, contribute to a tissue development process to fortify the degenerated vessel wall, and ultimately resorb to avoid leaving a permanent foreign body. With these properties in mind, a new fatty amide-based polyurethane urea (PHEUU) elastomer was synthesized and coated on biodegradable metallic (Mg alloy) coils to prepare a bioabsorbable cerebral saccular aneurysm embolization device. The chemical structure of PHEUU was confirmed using two-dimensional nuclear magnetic resonance spectroscopy. PHEUU showed comparable physical properties to elastomeric biodegradable polyurethanes lacking fatty amide immobilization, modest enzymatic degradation profiles in the first 8 wks, inherent antioxidant activity (>70% at 48 h), no cytotoxicity, and better protection for the underlying Mg alloy than poly(lactic-co-glycolic acid) (PLGA) against surface corrosion and cracking. Rat aortic smooth muscle cell attachment and platelet deposition were higher with the PHEUUs compared to bare or PLGA coated Mg alloy in vitro. PHEUU-coated Mg alloy coils showed the potential to design a fully bioabsorbable embolization coil amenable to clinical placement conditions based on computational mechanics modeling and blood-contacting test using an in vitro aneurysm model. In vivo studies using a mouse aneurysm model elicited comparable inflammatory cytokine expression to a commercially available platinum coil., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: William R Wagner reports financial support was provided by National Science Foundation. William R Wagner has patent BIOABSORBABLE METALLIC ALLOY COILS COATED WITH A POLYURETHANE FOR TREATING INTRACRANIAL ANEURYSMS (IAs) AND RENAL ARTERY ANEURYSMS (RAAs) pending to University of Pittsburgh., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Establishing central venous access is important to provide fluid resuscitation or medications intravenously to patients., Observations: Although accidental cannulation of the internal carotid artery has been reported in the literature, to our knowledge this report is the first documented intraoperative ultrasound video demonstrating accidental and simultaneous common carotid artery and internal jugular cannulation during central line placement in the internal jugular vein., Lessons: Ultrasound use minimizes accidental carotid cannulation during central line placement in the internal jugular vein. Carotid artery puncture can be managed by external application of pressure or surgical reexploration.

Cerebral aneurysms are vascular lesions caused by the biomechanical failure of the vessel wall due to hemodynamic stress and inflammation. Aneurysmal rupture results in subarachnoid hemorrhage often leading to death or disability. Current treatment options include open surgery and minimally invasive endovascular options aimed at secluding the aneurysm from the circulation. Cerebral aneurysm embolization with appropriate materials is a therapeutic approach to prevent rupture and the resultant clinical sequelae. Metallic platinum coils are a typical, practical option to embolize cerebral aneurysms. However, the development of an alternative treatment modality is of interest because of poor occlusion permanence, coil migration, and coil compaction. Moreover, minimizing the implanted foreign materials during therapy is of importance not just to patients, but also to clinicians in the event an open surgical approach has to be pursued in the future. Polymeric injectable hydrogels have been investigated for transcatheter embolization and cell therapy with the potential for permanent aneurysm repair. This review focuses on how the combination of injectable embolic biomaterials and cell therapy may achieve minimally invasive remodeling of a degenerated cerebral artery with promise for superior outcomes in treatment of this devastating disease., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Preoperative chronic narcotic use has been linked to poor outcomes after surgery for degenerative spinal disorders in the form of lower health-related quality of life scores, higher revision rates, increased infections, lower likelihood of return to work, and higher 90-day readmission rates. This study evaluated the impact of preoperative chronic narcotic use on patient reported outcome measures following adult spinal reconstructive surgery., Methods: Patients who underwent adult spinal reconstructive surgery over 2 years at our institution were identified from a prospectively maintained spine registry. These patients were grouped into chronic opiate users as defined by a 6-month duration of use with a minimum morphine equivalent dose of 30 mg/day. Patient reported outcome measures were collected prospectively., Results: Of 140 patients included for analysis, 30 (21.4%) patients were categorized as chronic opiate users. No differences were identified in mean preoperative patient reported outcome measures, including Oswestry Disability Index, health state, visual analog scale, and EQ-5D indices. At both 6 weeks and 6 months postoperatively, patients in the opiate group demonstrated significantly worse mean visual analog scale back pain scores relative to the nonopiate group. At 6 months postoperatively and at the last known clinical follow-up, Oswestry Disability Index scores were higher in the opiate group., Conclusions: Chronic opiate use before adult spinal reconstructive surgery was associated with worse pain and disability following intervention. Further work is needed to understand the role of opiate weaning as part of a larger prehabilitation strategy for adult spinal reconstructive surgery., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Complete aneurysm obliteration is the goal of aneurysm treatment. In selected cases, a neck remnant may be left to preserve a critical branch. Literature on ophthalmic artery sacrifice in the treatment of cerebral aneurysms and subsequent risk of vision loss is limited., Case Description: Herein, we describe 2 cases where the ophthalmic artery originated from the aneurysm dome, resulting in a situation where we either incompletely obliterate the aneurysm or sacrifice the ophthalmic artery in order to completely clip the lesion, risking visual function., Conclusions: We report for the first time the use of visual evoked potential monitoring and intraoperative awakening to test visual function following intentional ophthalmic artery sacrifice to demonstrate gross vision preservation., (Copyright © 2020. Published by Elsevier Inc.)

Background: Estrogen deficiency is associated with the development of cerebral aneurysms; however, the mechanism remains unknown. We explored the pathway of cerebral aneurysm development by investigating the potential link between estrogen deficiency and inflammatory factors., Methods and Results: First, we established the role of interleukin-17 (IL-17)A. We performed a cytokine screen demonstrating that IL-17A is significantly expressed in mouse and human aneurysms ( P =0.03). Likewise, IL-17A inhibition was shown to prevent aneurysm formation by 42% ( P =0.02) and rupture by 34% ( P <0.05). Second, we found that estrogen deficiency upregulates T helper 17 cells and IL-17A and promotes aneurysm rupture. Estrogen-deficient mice had more ruptures than control mice (47% versus 7%; P =0.04). Estradiol supplementation or IL-17A inhibition decreased the number of ruptures in estrogen-deficient mice (estradiol 6% versus 37%; P =0.04; IL-17A inhibition 18% versus 47%; P =0.018). Third, we found that IL-17A-blockade protects against aneurysm formation and rupture by increased E-cadherin expression. IL-17-inhibited mice had increased E-cadherin expression ( P =0.003). E-cadherin inhibition reversed the protective effect of IL-17A inhibition and increased the rate of aneurysm formation (65% versus 28%; P =0.04) and rupture (12% versus 0%; P =0.22). However, E-cadherin inhibition alone does not significantly increase aneurysm formation in normal mice or in estrogen-deficient mice. In cell migration assays, E-cadherin inhibition promoted macrophage infiltration across endothelial cells ( P <0.05), which may be the mechanism for the estrogen deficiency/IL-17/E-cadherin aneurysm pathway., Conclusions: Our data suggest that estrogen deficiency promotes cerebral aneurysm rupture by upregulating IL-17A, which downregulates E-cadherin, encouraging macrophage infiltration in the aneurysm vessel wall., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Introduction: Macrophages and neutrophils have been separately implicated in cerebral aneurysm formation. The interactions between different myeloid subsets and the contributions of macrophage phenotypes in these lesions over time are not known. The purpose of the study was to examine macrophage phenotypic changes in cerebral aneurysms., Methods: We induced aneurysm formation in C57BL/6 mice and quantified contributions of M1 and M2 macrophages in aneurysm specimens with or without neutrophil blockade. In our aneurysm model, the left common carotid and right renal arteries were ligated, and mice were placed on a hypertensive high fat diet. One week later, stereotactic injection with elastase solution into the basal cisterns was performed. An angiotensin II secreting osmotic pump was implanted. The mice were then treated with anti-CXCL1 antibody or IgG control antibody. Animals were euthanized at 3 days, or 1 or 2 weeks. The circle of Willis was analyzed using immunohistochemistry for M1 and M2 macrophage phenotype contributions., Results: Proinflammatory M1/M2 ratio increased in cerebral aneurysm formation over time, from 0.56 at 3 days to 1.75 at 2 weeks (p<0.0001). In contrast, anti-CXCL1 antibody blockade led to polarization towards an anti-inflammatory phenotype with an M1/M2 ratio of 0.95 at 2 weeks compared with IgG treated mice (p=0.0007)., Conclusions: CXCL1 dependent neutrophil inflammation appears to have an important role in macrophage polarization to M1 phenotype in cerebral aneurysm development., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Cerebral aneurysms are thought to develop at locations of hemodynamic shear stress, via an inflammatory process. The molecular mechanism that links shear stress to inflammation, however, is not completely understood. Progress in studying this disease is limited by a lack of a suitable in vitro model. To address this, we designed novel in vitro parallel-plate flow chamber models of a straight artery, a bifurcation, and a bifurcation aneurysm. We compared endothelial cell phenotypes across the 3 different models and among microenvironments within each flow model by cytokine array, ELISA, and relative immunofluorescence. Human aneurysms express interleukin-8 and chemokine (C-X-C motif) ligand 1 (CXCL1), whereas normal arteries do not. The bifurcation aneurysm model showed significantly higher interleukin-8 and CXCL1 levels than both the straight artery and bifurcation models. Within the bifurcation and bifurcation aneurysm models, endothelial cells near the bifurcation or within the aneurysm sac microenvironments have significantly higher expression of CXCL1, and interleukin-8 and CXCL1, respectively, than at the straight proximal segment or the limbs of the bifurcation. Murine aneurysms express CXCL1, and it is the primary ELR+ CXC chemokine expressed, whereas normal arteries do not. CXCL1 antibody blockade results in significantly fewer murine aneurysms (13.3 versus 66.7%; P=0.0078), decreased neutrophil infiltration, and vascular cell adhesion molecule 1 expression than an immunoglobulin G control. We successfully designed and validated a novel hemodynamic model of cerebral aneurysms in vitro. We also show that shear stress-induced CXCL1 plays a critical role in cerebral aneurysm formation., (© 2014 American Heart Association, Inc.)

Introduction: Cerebral aneurysms occur in up to 5% of the population. There are several murine models of aneurysms; however, all have limitations and none reproducibly model aneurysm rupture. To fulfill this need, we modified two current rodent aneurysm models to create a murine model which reproducibly produces intracranial aneurysms and rupture., Methods: The left common carotid arteries and the right renal arteries were ligated in C57BL/6 female mice with a hypertensive diet. One week later, small burr holes were created with a stereotactic frame using the following stereotactic measurements: 1.2 mm rostral and 0.7 mm lateral to the right of the bregma. A 26 G needle was gradually advanced via the burr hole until contact with the skull base, upon which the needle was pulled back 0.3 mm. Five, 10 and 20 μL of 10 U/mL elastase solution and 10 μL of 1 U/mL elastase solution were stereotactically injected into the basal cisterns. Angiotensin II was then continually infused at a dose of 1000 ng/kg/min via an osmotic pump placed subcutaneously. In the control mice, 20 μL bromophenol blue solution was injected. Three weeks later, or earlier if mice expired prior to 3 weeks, the circle of Willis was inspected by microscopy for aneurysm formation and/or signs of rupture. Histological analyses were then performed to evaluate elastic lamina destruction, inflammatory cell and macrophage infiltration, absence of intimal endothelial cells and thickening of the smooth muscle layer within the aneurysm wall. To compare with human aneurysms, human aneurysm specimens (n=35; 34 unruptured and 1 ruptured) and normal control superficial temporal arteries (STAs) (n=9) were examined., Results: All mice given 5, 10 and 20 μL of 10 U/mL elastase solution developed intracranial aneurysms within the circle of Willis; 40%, 60% and 50% of mice had ruptured aneurysms, respectively. In mice given 10 μL of 1.0 U/mL elastase solution, 90% developed intracranial aneurysms and 20% had ruptured aneurysms. Aneurysms were confirmed by examining the destruction of the elastic lamina. Aneurysms consistently demonstrated CD45 positive inflammatory cell and F4/80 positive macrophage infiltration within the aneurysm wall which was not present in the circle of Willis of normal sham-operated mice. These results were similar to those in human aneurysms and STA control arteries., Conclusions: We modified two current rodent aneurysm models to create a murine model that produces consistent aneurysms and rupture and can be used for studying cerebral aneurysm formation, rupture and treatment., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Object: A small percentage of cerebral aneurysms rupture, but when they do, the effects are devastating. Current management of unruptured aneurysms consists of surgery, endovascular treatment, or watchful waiting. If the biology of how aneurysms grow and rupture were better known, a novel drug could be developed to prevent unruptured aneurysms from rupturing. Ruptured cerebral aneurysms are characterized by inflammation-mediated wall remodeling. The authors studied the role of stromal cell-derived factor-1 (SDF-1) in inflammation-mediated wall remodeling in cerebral aneurysms., Methods: Human aneurysms, murine carotid artery aneurysms, and murine intracranial aneurysms were studied using immunohistochemistry. Flow cytometry analysis was performed on blood from mice developing carotid or intracranial aneurysms. The effect of SDF-1 on endothelial cells and macrophages was studied by chemotaxis cell migration assay and capillary tube formation assay. Anti-SDF-1 blocking antibody was given to mice and compared with control (vehicle)-administered mice for its effects on the walls of carotid aneurysms and the development of intracranial aneurysms., Results: Human aneurysms, murine carotid aneurysms, and murine intracranial aneurysms all expressed SDF-1, and mice with developing carotid or intracranial aneurysms had increased progenitor cells expressing CXCR4, the receptor for SDF-1 (p < 0.01 and p < 0.001, respectively). Human aneurysms and murine carotid aneurysms had endothelial cells, macrophages, and capillaries in the walls of the aneurysms, and the presence of capillaries in the walls of human aneurysms was associated with the presence of macrophages (p = 0.01). Stromal cell-derived factor-1 promoted endothelial cell and macrophage migration (p < 0.01 for each), and promoted capillary tube formation (p < 0.001). When mice were given anti-SDF-1 blocking antibody, there was a significant reduction in endothelial cells (p < 0.05), capillaries (p < 0.05), and cell proliferation (p < 0.05) in the aneurysm wall. Mice given anti-SDF-1 blocking antibody developed significantly fewer intracranial aneurysms (33% vs 89% in mice given control immunoglobulin G, respectively; p < 0.05)., Conclusions: These data suggest SDF-1 is associated with angiogenesis and inflammatory cell migration and proliferation in the walls of aneurysms, and may have a role in the development of intracranial aneurysms.

Background: Up to 5% of the population may have a brain aneurysm. If the brain aneurysm ruptures, there is >50% mortality, and more than one third of survivors are dependent. Brain aneurysms detected before rupture can be treated to prevent rupture, or ruptured aneurysms can be treated to prevent rerupture. Endovascular coiling of brain aneurysms is the treatment of choice for some aneurysms; however, up to one quarter of aneurysms may recur. The coiled aneurysms that do not recur are characterized by inflammatory intra-aneurysmal tissue healing; therefore, we studied the biology of this process, specifically the role of monocyte chemotactic protein-1 (MCP-1), a cytokine known for tissue healing., Methods and Results: We created coils with a 50:50 poly-dl-lactic glycolic acid (PLGA) coating that released MCP-1 at 3 different doses (100 μg/mL, 1 mg/mL, and 10 mg/mL) and performed a dose-response study for effect on intra-aneurysmal tissue healing in a murine carotid aneurysm model. We then demonstrated that MCP-1 (100 μg/mL)-releasing coils promote significantly greater aneurysm tissue in-growth than bare platinum or PLGA-only coils. We show that MCP-1 recruits the migration of fibroblasts, macrophages, smooth muscle cells, and endothelial cells in vitro in cell migration assays and in vivo in murine carotid aneurysms. Using gfp(+) bone marrow-transplant chimeric mice, we demonstrate that the MCP-1-recruited fibroblasts and macrophages are derived from the bone marrow. We demonstrate that this MCP-1-mediated vascular inflammatory repair occurs via a macrophage inflammatory protein (MIP)-1α- and MIP-2-dependent pathway. MCP-1 released from coiled murine aneurysms causes significant upregulation of MIP-1α and MIP-2 expression by cytokine array assay. Blocking MIP-1α and MIP-2 with antagonist antibody causes a significant decrease in MCP-1-mediated intra-aneurysmal tissue healing., Conclusion: Our findings suggest that MCP-1 has a critical role in promoting inflammatory intra-aneurysmal tissue healing in an MIP-1α- and MIP-2-dependent pathway.