Antithrombotic Therapy in Cerebral Cavernous Malformations: A Systematic Review, Meta-Analysis, and Network Meta-Analysis.

BACKGROUND: Cerebral cavernous malformations are complex vascular anomalies in the central nervous system associated with a risk of intracranial hemorrhage. Traditional guidelines have been cautious about the use of antithrombotic therapy in this patient group, citing concerns about potential bleeding risk. However, recent research posits that antithrombotic therapy may actually be beneficial. This study aims to clarify the association between antithrombotic therapy, including antiplatelet and anticoagulant medications, and the risk of intracranial hemorrhage in patients with cerebral cavernous malformations. METHODS AND RESULTS: A comprehensive literature search was conducted in PubMed, Web of Science, and Scopus databases, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Nine single-center, nonrandomized cohort studies involving 2709 patients were included. Outcomes were analyzed using random-effects model, and a network meta-analysis was conducted for further insight. Of the 2709 patients studied, 388 were on antithrombotic therapy. Patients on antithrombotic therapy had a lower risk of presenting with intracranial hemorrhage (odds ratio [OR], 0.56 [95% CI, 0.45-0.7]; P<0.0001). In addition, the use of antithrombotic therapy was associated with lower risk of intracranial hemorrhage from a cerebral cavernous malformation on follow-up (OR, 0.21 [95% CI, 0.13-0.35]; P<0.0001). A network meta-analysis revealed a nonsignificant OR of 0.73 (95% CI, 0.23-2.56) when antiplatelet therapy was compared with anticoagulant therapy. CONCLUSIONS: Our study explores the potential benefits of antithrombotic therapy in cerebral cavernous malformations. Although the analysis suggests a possible role for antithrombotic agents, it is critical to note that the evidence remains preliminary. Fundamental biases in study design, such as ascertainment and assignment bias, limit the weight of our conclusions. Therefore, our findings should be considered hypothesis-generating and not definitive for clinical practice change.

Serum Interleukin-1 Levels Are Associated with Intracranial Aneurysm Instability.

Serum interleukin-1 (IL-1) are possibly indicative of the inflammation in the intracranial aneurysm (IA) wall. This study aimed to investigate whether IL-1 could discriminate the unstable IAs (ruptured intracranial aneurysms (RIAs) and symptomatic unruptured intracranial aneurysms (UIAs)) from stable, asymptomatic UIAs. IA tissues and blood samples from 35 RIA patients and 35 UIA patients were collected between January 2017 and June 2020 as the derivation cohort. Blood samples from 211 patients with UIAs were collected between January 2021 and June 2022 as the validation cohort (including 63 symptomatic UIAs). Blood samples from 35 non-cerebral-edema meningioma patients (non-inflammatory control) and 19 patients with unknown-cause subarachnoid hemorrhage (hemorrhagic control) were also collected. IL-1ß and IL-1.ra (IL-1 receptor antagonist) were measured in serum and IA tissues, and the IL-1 ratio was calculated as log10 (IL-1.ra/IL-1ß). Based on the derivation cohort, multivariate logistic analysis showed that IL-1ß (odds ratio, 1.48, P = 0.001) and IL-1.ra (odds ratio, 0.74, P = 0.005) were associated with RIAs. The IL-1 ratio showed an excellent diagnostic accuracy for RIAs (c-statistic, 0.91). Histological analysis confirmed the significant correlation of IL-1 between serum and aneurysm tissues. IL-1 ratio could discriminate UIAs from non-inflammatory controls (c-statistic, 0.84), and RIAs from hemorrhagic controls (c-statistic, 0.95). Based on the validation cohort, the combination of IL-1 ratio and PHASES score had better diagnostic accuracy for symptomatic UIAs than PHASES score alone (c-statistic, 0.88 vs 0.80, P < 0.001). Serum IL-1 levels correlate with aneurysm tissue IL-1 levels and unstable aneurysm status, and could serve as a potential biomarker for IA instability.

Direct Versus Indirect Revascularization for Moyamoya: a Large Multicenter Study.

BACKGROUND: Moyamoya is a chronic occlusive cerebrovascular disease of unknown etiology causing neovascularization of the lenticulostriate collaterals at the base of the brain. Although revascularization surgery is the most effective treatment for moyamoya, there is still no consensus on the best surgical treatment modality as different studies provide different outcomes. OBJECTIVE: In this large case series, we compare the outcomes of direct (DR) and indirect revascularisation (IR) and compare our results to the literature in order to reflect on the best revascularization modality for moyamoya. METHODS: We conducted a multicenter retrospective study in accordance with the Strengthening the Reporting of Observational studies in Epidemiology guidelines of moyamoya affected hemispheres treated with DR and IR surgeries across 13 academic institutions predominantly in North America. All patients who underwent surgical revascularization of their moyamoya-affected hemispheres were included in the study. The primary outcome of the study was the rate of symptomatic strokes. RESULTS: The rates of symptomatic strokes across 515 disease-affected hemispheres were comparable between the two cohorts (11.6% in the DR cohort vs 9.6% in the IR cohort, OR 1.238 (95% CI 0.651 to 2.354), p=0.514). The rate of total perioperative strokes was slightly higher in the DR cohort (6.1% for DR vs 2.0% for IR, OR 3.129 (95% CI 0.991 to 9.875), p=0.052). The rate of total follow-up strokes was slightly higher in the IR cohort (8.1% vs 6.6%, OR 0.799 (95% CI 0.374 to 1.709) p=0.563). CONCLUSION: Since both modalities showed comparable rates of overall total strokes, both modalities of revascularization can be performed depending on the patient's risk assessment.

Clopidogrel Is Associated with Reduced Likelihood of Aneurysmal Subarachnoid Hemorrhage: a Multi-Center Matched Retrospective Analysis.

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.

Postoperative cognitive dysfunction after endovascular treatments for unruptured intracranial aneurysms: A pilot study.

OBJECTIVE: Post operative cognitive dysfunction (POCD) has been widely observed after major surgery, particularly in elderly patients with general anesthesia (GA). However, a specific unanswered question is whether different approaches to anesthetic managements are associated with different cognitive outcomes after endovascular treatments for unruptured intracranial aneurysms (UIAs). The purpose of this study is to assess the correlation of POCD with GA versus monitored anesthesia care (MAC). METHODS: We performed a pragmatic, prospective study to assess the association between different anesthetic approaches and POCD. We compared the pre- and post-procedural Montreal Cognitive Assessment (MoCA) scores in patients with normal cognition who underwent treatments of UIAs with various endovascular methods, using either GA or MAC. RESULTS: A total of 23 patients with UIAs were enrolled in the study. Seven (30.4%) and sixteen (69.6%) UIAs were treated without perioperative complications under GA or MAC, respectively. There was a significant decline in the post-procedural MoCA score under GA (mean difference = 1.14; 95% confidence interval = [0.42-1.87], P < 0.01). By contrast, there was no significant difference of MoCA score between pre- and post-procedure under MAC (mean difference = 0.19; 95% confidence interval = [-0.29-0.67], P = 0.59). CONCLUSIONS: Treating UIAs using MAC was associated with a decrease in POCD as compared to GA in patients undergoing endovascular treatments for UIAs with normal cognition. Larger randomized studies are needed to confirm these findings.

Metastatic Renal Cell Carcinoma to the Spine: Outcomes and Morbidity: Single-Center Experience.

BACKGROUND: Renal cell carcinoma with metastases to the spine (RCCMS) requires a multidisciplinary approach. We reviewed our institutional experience with RCCMS patients undergoing spinal surgery in order to identify factors that may affect clinical outcomes, survival, and complications. METHODS: Patients with RCCMS who underwent operative intervention from 2007 to 2020 were reviewed retrospectively. RESULTS: Forty-four patients with the diagnosis of RCCMS were identified. Pain was the most common symptom, and neurologic dysfunction was present in one third of cases. Thoracic spine was the most common location (N = 27), followed by the lumbar (N = 12) and cervical (N = 5) regions. The overall survival from diagnosis of renal cell carcinoma was 25 (2 - 194) months and 8 (0.3 - 92) months after spinal surgery. Gender, age, spinal level, postoperative radiation, and nephrectomy had no bearing on survival. Survival for patients with a Tokuhashi score of 0 - 8, 9 - 11, and 12 - 15 was 6.5 (1.5 - 23.5), 8.9 (0.3 - 91.6), and 23.4 (2.5 - 66) months, respectively (P = 0.03). The postoperative American Spinal Cord Injury Association score of E (hazard ratio 0.109 [95% confidence interval 0.022 - 0.534, P = 0.006) also bore a significant influence on survival. There was a total of 10 complications in 7 of 44 (16%) patients. CONCLUSIONS: Median postoperative survival of patients with RCCMS was 8 (0.3 - 92) months. Higher Tokuhashi score and ASIA E score at follow-up correlated with improved overall survival. Complication rate was 16%. Spinal surgery in RCCMS is indicated for the preservation of function and prevention of neurologic deterioration. Multimodality therapy with improved chemotherapy and stereotactic spinal radiation is expected to impact quality and length of survival positively.

Recanalization of the Chronically Occluded Internal Carotid Artery: Review of the Literature.

INTRODUCTION: We reviewed the literature on interventions for patients with medically refractory chronically occluded internal carotid artery (COICA) to assess the risks and/or benefits after recanalization via an endovascular technique (ET) or hybrid surgery (HS, i.e., ET plus carotid endarterectomy). METHODS: A systematic search of the electronic databases was performed. Patients with COICA were classified into 4 different categories according to Hasan et al classification. RESULTS: Eighteen studies satisfied the inclusion criteria. Only 6 studies involved an HS procedure. We identified 389 patients with COICA who underwent ET or HS; 91% were males. The overall perioperative complication rate was 10.1% (95% confidence interval [CI]: 7.4%-13.1%). For types A and B, the successful recanalization rate was 95.4% (95% CI: 86.5%-100%), with a 13.7% (95% CI: 2.3%-27.4%) complication rate. For type C, the success rate for ET was 45.7% (95% CI: 17.8%-70.7%), with a complication rate of 46.0% (95% CI: 20.0%-71.4%) for ET and for the HS technique 87.6% (95% CI: 80.9%-94.4%), with a complication rate of 14.0% (95% CI: 7.0%-21.8%). For type D, the success rate of recanalization was 29.8% (95% CI: 7.8%-52.8%), with a 29.8% (95% CI: 6.1%-56.3%) complication rate. Successful recanalization resulted in a symmetrical perfusion between both cerebral hemispheres, resolution of penumbra, normalization of the mean transit time, and improvement in Montreal Cognitive Assessment (MoCA) score (ΔMoCA = 9.80 points; P = 0.004). CONCLUSIONS: Type A and B occlusions benefit from ET, especially in the presence of a large penumbra. Type C occlusions can benefit from HS. Unfortunately, we did not identify an intervention to help patients with type D occlusions. A phase 2b randomized controlled trial is needed to confirm these findings.

A2, M2, P2 aneurysms and beyond: results of treatment with pipeline embolization device in 65 patients.

BACKGROUND: Intracranial aneurysms located in the distal vessels are rare and remain a challenge to treat through surgical or endovascular interventions. OBJECTIVE: To describe a multicenter approach with flow diversion using the pipeline embolization device (PED) for treatment of distal intracranial aneurysms. METHODS: Cases of distal intracranial aneurysms defined as starting on or beyond the A2 anterior cerebral artery, M2 middle cerebral artery, and P2 posterior cerebral artery segments were included in the final analysis. RESULTS: 65 patients with distal aneurysms treated with the PED were analyzed. Median aneurysm size at the largest diameter was 7.0 mm, 60% were of a saccular morphology, and 9/65 (13.8%) patients presented in the setting of acute rupture. Angiographic follow-up data were available for 53 patients, with a median follow-up time of 6 months: 44/53 (83%) aneurysms showed complete obliteration, 7/53 (13.2%) showed reduced filling, and 2/53 (3%) showed persistent filling. There was no association between patient characteristics, including aneurysm size (P=0.36), parent vessel diameter (P=0.27), location (P=0.81), morphology (P=0.63), ruptured status on admission (P=0.57), or evidence of angiographic occlusion at the end of the embolization procedure (P=0.49). Clinical outcome data were available for 60/65 patients: 95% (57/60) had good clinical outcome (modified Rankin Scale score of 0-2) at 3 months. CONCLUSIONS: This large multicenter study of patients with A2, M2, and P2 distal aneurysms treated with the PED showed that flow diversion may be an effective treatment approach for this rare type of vascular pathology. The procedural compilation rate of 7.7% indicates the need for further studies as the flow diversion technology constantly evolves.

Iron nanoparticle contrast enhanced microwave imaging for emergent stroke: A pilot study.

Emergent stroke is mostly evaluated using hospital based imaging. Quick imaging allows for rapid administration of IV thrombolysis and outcome improvement. Microwave imaging (MI) is an emerging portable imaging modality. Iron oxide nanoparticles are known to interact with microwave frequency electromagnetic radiation. In this manuscript, we provide proof of concept for a novel iron oxide nanoparticle enhanced microwave imaging device for differentiating emergent ischemic stroke from hemorrhagic stroke. A MI device was constructed. Attenuation of the microwave signal transmitted with or without iron oxide nanoparticles was measured over a 1-2 GHz frequency range in a silicone brain phantom, in New Zealand white rabbits, and in a human. Observed differences in signal attenuation were used to reconstruct an image following induction of a left sided anterior circulation stroke in a New Zealand white rabbit. An increase in microwave signal attenuation exists across a frequency range of 1.3-2 GHz when iron oxide nanoparticles are introduced into a silicone phantom model, in New Zealand white rabbits, and in a human volunteer. Using this increase in signal attenuation following nanoparticle administration, we localize induced ischemia in a New Zealand white rabbit. To the best of out knowledge, we provide the first evidence that superparamagnetic Iron oxide nanoparticles may be used as contrast in the setting of MI. Our data suggest infusion of intravenous iron oxide nanoparticles with follow on microwave imaging may ultimately allow for more timely administration of thrombolytic mediation in the setting of acute ischemic stroke.

Hybrid Surgery for Internal Carotid Artery Revascularization.

OBJECTIVE: The management of chronic complete internal carotid artery (ICA) occlusion (COICA) has been challenging. Endovascular procedures have been performed with variable success and risks, depending on the type of occlusion and distal revascularization. We present a novel hybrid procedure to recanalize the ICA when previous endovascular interventions have failed or been deemed too risky. METHODS: Two patients presented with symptomatic COICA after maximal medical management. They were deemed at high risk of endovascular intervention and/or previous endovascular attempts had failed. Thus, they had indications for a hybrid procedure. RESULTS: A hybrid technique was used to create a stump by surgical endarterectomy, followed by recanalization using an endovascular approach via femoral access. We have described the technique in detail. Postoperative computed tomography perfusion scanning showed normalization of the mean transient time, cerebral blood volume, and cerebral blood flow compared with the preoperative findings. Cerebral angiography showed successful recanalization of the ICA. Neither patient experienced any complications. CONCLUSION: A hybrid technique is feasible and should be considered for patients with COICA in whom maximal medical management has failed and who have a high-risk profile for endovascular intervention or in whom previous endovascular attempts have failed.

Cigarette Smoke Initiates Oxidative Stress-Induced Cellular Phenotypic Modulation Leading to Cerebral Aneurysm Pathogenesis.

OBJECTIVE: Cigarette smoke exposure (CSE) is a risk factor for cerebral aneurysm (CA) formation, but the molecular mechanisms are unclear. Although CSE is known to contribute to excess reactive oxygen species generation, the role of oxidative stress on vascular smooth muscle cell (VSMC) phenotypic modulation and pathogenesis of CAs is unknown. The goal of this study was to investigate whether CSE activates a NOX (NADPH oxidase)-dependent pathway leading to VSMC phenotypic modulation and CA formation and rupture. APPROACH AND RESULTS: In cultured cerebral VSMCs, CSE increased expression of NOX1 and reactive oxygen species which preceded upregulation of proinflammatory/matrix remodeling genes (MCP-1, MMPs [matrix metalloproteinase], TNF-α, IL-1ß, NF-κB, KLF4 [Kruppel-like factor 4]) and downregulation of contractile genes (SM-α-actin [smooth muscle α actin], SM-22α [smooth muscle 22α], SM-MHC [smooth muscle myosin heavy chain]) and myocardin. Inhibition of reactive oxygen species production and knockdown of NOX1 with siRNA or antisense decreased CSE-induced upregulation of NOX1 and inflammatory genes and downregulation of VSMC contractile genes and myocardin. p47phox-/- NOX knockout mice, or pretreatment with the NOX inhibitor, apocynin, significantly decreased CA formation and rupture compared with controls. NOX1 protein and mRNA expression were similar in p47phox-/- mice and those pretreated with apocynin but were elevated in unruptured and ruptured CAs. CSE increased CA formation and rupture, which was diminished with apocynin pretreatment. Similarly, NOX1 protein and mRNA and reactive oxygen species were elevated by CSE, and in unruptured and ruptured CAs. CONCLUSIONS: CSE initiates oxidative stress-induced phenotypic modulation of VSMCs and CA formation and rupture. These molecular changes implicate oxidative stress in the pathogenesis of CAs and may provide a potential target for future therapeutic strategies.

Surgical Management of Tumors Involving Meckel's Cave and Cavernous Sinus: Role of an Extended Middle Fossa and Lateral Sphenoidectomy Approach.

OBJECTIVE: To study the indications and outcomes of lateral sphenoidectomy as part of a combined skull base approach in the treatment of tumors involving Meckel's cave (MC) and cavernous sinus (CS). STUDY DESIGN: Retrospective patient series. SETTING: Tertiary referral center. PATIENTS: Twenty-two consecutive patients (mean age: 45 yr, range: 16-76) who underwent transzygomatic, extended middle fossa approaches for tumors involving MC and CS. INTERVENTIONS: Surgical access to MC and CS was achieved via extended middle fossa, trans-clinoid approach. Lateral sphenoidectomy was defined as drill-out of the greater sphenoid wing lateral to foramen rotundum and ovale, decompression of superior orbital fissure, and removal of anterior clinoid process. Reconstruction was achieved using combination of autologous and synthetic materials. Eleven patients (50%) received adjuvant radiation. MAIN OUTCOME MEASURES AND RESULTS: Tumor pathologies included meningioma (16 patients), epidermoid cyst (2), trigeminal schwannoma (2), invasive pituitary adenoma (1), and chondrosarcoma (1). Mean (range) preoperative tumor size was 4.0 cm (1.3-9). Mean (range) length of follow-up was 4 years (range 0.1-10). Overall tumor control and gross total resection were achieved in 95 and 23% of patients, respectively. Lateral sphenoidectomy was performed in 16 patients (73%) for enhanced surgical access and/or tumor extension to the infratemporal fossa (6 patients). Postoperatively, cranial nerve deficits occurred in 12 (55%) patients (V-9 patients; III, IV, or VI-4; VII-2; VIII-2). Cerebrospinal fluid leak and hydrocephalus occurred in two and four patients, respectively. CONCLUSION: In combination with middle fossa-based approaches to tumors involving MC and CS, lateral sphenoidectomy may play a viable role in tumor access and control.

Treatment of Lateral Skull Base and Posterior Cranial Fossa Lesions Utilizing the Extended Middle Cranial Fossa Approach.

OBJECTIVE: Define the indications and outcomes for subjects undergoing treatment utilizing the extended middle cranial fossa approach (EMCF). STUDY DESIGN: Retrospective records review. SETTING: University-based tertiary referral center. PATIENTS: Subjects undergoing treatment of posterior cranial fossa (PCF) lesions. INTERVENTION(S): EMCF exposure and treatment of the indicating PCF lesion. MAIN OUTCOME MEASURE(S): Demographic, audiometric, and cranial nerve functioning variables were assessed. RESULTS: Thirty-five subjects who underwent an EMCF exposure were identified over a 12-year period. The most common indication was meningioma (18; 51%) followed by schwannomas (six, 17%), and vascular lesions (five, 14%). Preoperative cranial nerve complaints were common (32, 94%) as were objective cranial nerve abnormalities on physical examination (21; 60%). Preoperative audiometric data from subjects with hearing demonstrated good functioning including pure-tone average (PTA) (21.7 ±â€Š15.6 dB HL) and word understanding scores (95.1 ±â€Š7.4%). Most (34, 97%) subjects had intact facial nerve function. The average length of stay was 11.6 days (median = 9). Cranial neuropathies were common postoperatively with 27 (79%) subjects demonstrating some objective cranial nerve dysfunction, the most common of which was trigeminal nerve hypesthesia (21, 61.7%). Subjects with identifiable pre- and postoperative audiometric data and preoperative hearing demonstrated small declines in the four-tone average (16.2 dB) and word recognition scores (22.4%). Two subjects (6%) had new profound hearing loss postoperatively. CONCLUSIONS: The EMCF approach can provide safe and effective exposure of the anterior PCF.

Technology developments in endovascular treatment of intracranial aneurysms.

Advances in the management and endovascular treatment of intracranial aneurysms are progressing at a tremendous rate. Developments in novel imaging technology may improve diagnosis, risk stratification, treatment planning, intraprocedural assessment, and follow-up evaluation. Evolution of devices, including microwires, microcatheters, balloons, stents, and novel scaffolding devices, has greatly expanded the potential to treat difficult aneurysms. Although developments in technology have greatly improved the efficiency and efficacy of treatment of neurovascular disorders, novel devices do not always improve outcomes and may be associated with unique complications. As such, it is paramount to have an in-depth understanding of new devices and the implications of their introduction into clinical practice. This review provides an update on developments in endovascular treatment of intracranial aneurysms.

Endovascular Treatment of Venous Sinus Stenosis in Idiopathic Intracranial Hypertension: Complications, Neurological Outcomes, and Radiographic Results.

INTRODUCTION: Idiopathic intracranial hypertension (IIH) may result in a chronic debilitating disease. Dural venous sinus stenosis with a physiologic venous pressure gradient has been identified as a potential etiology in a number of IIH patients. Intracranial venous stenting has emerged as a potential treatment alternative. METHODS: A systematic review was carried out to identify studies employing venous stenting for IIH. RESULTS: From 2002 to 2014, 17 studies comprising 185 patients who underwent 221 stenting procedures were reported. Mean prestent pressure gradient was 20.1 mmHg (95% CI 19.4-20.7 mmHg) with a mean poststent gradient of 4.4 mmHg (95% CI 3.5-5.2 mmHg). Complications occurred in 10 patients (5.4%; 95% CI 4.7-5.4%) but were major in only 3 (1.6%). At a mean clinical follow-up of 22 months, clinical improvement was noted in 130 of 166 patients with headaches (78.3%; 95% CI 75.8-80.8%), 84 of 89 patients with papilledema (94.4%; 95% CI 92.1-96.6%), and 64 of 74 patients with visual symptoms (86.5%; 95% CI 83.0-89.9%). In-stent stenosis was noted in six patients (3.4%; 95% CI 2.5-4.3%) and stent-adjacent stenosis occurred in 19 patients (11.4%; 95% CI 10.4-12.4), resulting in restenting in 10 patients. CONCLUSION: In IIH patients with venous sinus stenosis and a physiologic pressure gradient, venous stenting appears to be a safe and effective therapeutic option. Further studies are necessary to determine the long-term outcomes and the optimal management of medically refractory IIH.

Smooth Muscle Peroxisome Proliferator-Activated Receptor γ Plays a Critical Role in Formation and Rupture of Cerebral Aneurysms in Mice In Vivo.

Vascular inflammation plays a critical role in the pathogenesis of cerebral aneurysms. Peroxisome proliferator-activated receptor γ (PPARγ) protects against vascular inflammation and atherosclerosis, whereas dominant-negative mutations in PPARγ promote atherosclerosis and vascular dysfunction. We tested the role of PPARγ in aneurysm formation and rupture. Aneurysms were induced with a combination of systemic infusion of angiotensin-II and local injection of elastase in (1) mice that received the PPARγ antagonist GW9662 or the PPARγ agonist pioglitazone, (2) mice carrying dominant-negative PPARγ mutations in endothelial or smooth muscle cells, and (3) mice that received the Cullin inhibitor MLN4924. Incidence of aneurysm formation, rupture, and mortality was quantified. Cerebral arteries were analyzed for expression of Cullin3, Kelch-like ECH-associated protein 1, nuclear factor (erythroid-derived 2)-like 2, NAD(P)H dehydrogenase (quinone)1 (NQO1), and inflammatory marker mRNAs. Neither pioglitazone nor GW9662 altered the incidence of aneurysm formation. GW9662 significantly increased the incidence of aneurysm rupture, whereas pioglitazone tended to decrease the incidence of rupture. Dominant-negative endothelial-specific PPARγ did not alter the incidence of aneurysm formation or rupture. In contrast, dominant-negative smooth muscle-specific PPARγ resulted in an increase in aneurysm formation (P<0.05) and rupture (P=0.05). Dominant-negative smooth muscle-specific PPARγ, but not dominant-negative endothelial-specific PPARγ, resulted in significant decreases in expression of genes encoding Cullin3, Kelch-like ECH-associated protein 1, and nuclear factor (erythroid-derived 2)-like 2, along with significant increases in tumor necrosis factor-α, monocyte chemoattractant protein-1, chemokine (C-X-C motif) ligand 1, CD68, matrix metalloproteinase-3, -9, and -13. MLN4924 did not alter incidence of aneurysm formation, but increased the incidence of rupture (P<0.05). In summary, endogenous PPARγ, specifically smooth muscle PPARγ, plays an important role in protecting from formation and rupture of experimental cerebral aneurysms in mice.

Elective endovascular treatment of unruptured intracranial aneurysms: a management case series of patient outcomes after institutional change to admit patients principally to postanesthesia care unit rather than to intensive care.

BACKGROUND: Our intention in this case series was to review the postoperative care and neurologic outcomes of patients who had undergone elective endovascular treatment of unruptured intracranial aneurysms. The case series is unique managerially in that a progressively increasing percentage of patients were admitted to the postanesthesia care unit (PACU; 1:2 nurse-to-patient ratio) and subsequently to the neurosurgical ward (1:3 nurse-to-patient ratio) instead of directly to the intensive care unit (ICU; 1:1 nurse-to-patient ratio). METHODS: A retrospective review was performed of 170 consecutive elective endovascular procedures to treat unruptured intracranial aneurysms between July 2009 and September 2012. Data included patient, aneurysm, procedural characteristics, and adverse events within 96 hours after the procedure. Rates of ICU admission and perioperative neurologic adverse events were compared over time. RESULTS: Although direct ICU admission rates decreased over time (P < 0.0001) from 100% to 15%, perioperative neurologic event rates did not change (P = 0.79). Sixteen of 170 patients experienced perioperative neurologic events. The percentages of patients with neurologic events who died or had deficits that did not resolve before discharge were 38% (3 of 8) among patients directly admitted to the ICU versus 38% (3 of 8) among those first admitted to the PACU. Although the duration of anesthesia was greater among patients admitted to the ICU, duration was not useful in predicting decisions on the day of surgery for individual patients. The duration of anesthesia also was not meaningfully associated with information available preoperatively (i.e., for use when scheduling the case). CONCLUSIONS: In centers in which PACU and ward care are comparable to those in this case series, in the absence of intraoperative events with the potential for ongoing cerebral ischemia, most patients undergoing elective endovascular treatment of unruptured cerebral aneurysms can be managed without direct ICU admission. Scheduling all these procedures by using the mean historical anesthesia duration is reasonable.

Roles of estrogen in the formation of intracranial aneurysms in ovariectomized female mice.

BACKGROUND: Epidemiological studies have indicated that postmenopausal women have a higher incidence of intracranial aneurysms than men in the same age group. OBJECTIVE: To investigate whether estrogen or estrogen receptors (ERs) mediate protective effects against the formation of intracranial aneurysms. METHODS: Intracranial aneurysms were induced in mice by combining a single injection of elastase into the cerebrospinal fluid with deoxycorticosterone acetate salt hypertension. The mice were treated with estrogen (17ß-estradiol), an ERα agonist (propyl pyrazole triol), and an ERß agonist (diarylpropionitrile) with and without a nitric oxide synthase inhibitor. RESULTS: The ovariectomized female mice had a significantly higher incidence of aneurysms than the male mice, which was consistent with findings in previous epidemiological studies. In ovariectomized female mice, an ERß agonist, but not an ERα agonist or 17ß-estradiol, significantly reduced the incidence of aneurysms. The protective effect of the ERß agonist was absent in the ovariectomized ERß knockout mice. The protective effect of the ERß agonist was negated by treatment with a nitric oxide synthase inhibitor. CONCLUSION: The effects of sex, menopause, and estrogen treatment observed in this animal study were consistent with previous epidemiological findings. Stimulation of estrogen receptor-ß was protective against the formation of intracranial aneurysms in ovariectomized female mice.

Angiotensin 1-7 reduces mortality and rupture of intracranial aneurysms in mice.

Angiotensin II (Ang II) stimulates vascular inflammation, oxidative stress, and formation and rupture of intracranial aneurysms in mice. Because Ang 1-7 acts on Mas receptors and generally counteracts deleterious effects of Ang II, we tested the hypothesis that Ang 1-7 attenuates formation and rupture of intracranial aneurysms. Intracranial aneurysms were induced in wild-type and Mas receptor-deficient mice using a combination of Ang II-induced hypertension and intracranial injection of elastase in the basal cistern. Mice received elastase+Ang II alone or a combination of elastase+Ang II+Ang 1-7. Aneurysm formation, prevalence of subarachnoid hemorrhage, mortality, and expression of molecules involved in vascular injury were assessed. Systolic blood pressure was similar in mice receiving elastase+Ang II (mean±SE, 148±5 mm Hg) or elastase+Ang II+Ang 1-7 (144±5 mm Hg). Aneurysm formation was also similar in mice receiving elastase+Ang II (89%) or elastase+Ang II+Ang 1-7 (84%). However, mice that received elastase+Ang II+Ang 1-7 had reduced mortality (from 64% to 36%; P<0.05) and prevalence of subarachnoid hemorrhage (from 75% to 48%; P<0.05). In cerebral arteries, expression of the inflammatory markers, Nox2 and catalase increased similarly in elastase+Ang II or elastase+Ang II+Ang 1-7 groups. Ang 1-7 increased the expression of cyclooxygenase-2 and decreased the expression of matrix metalloproteinase-9 induced by elastase+Ang II (P<0.05). In Mas receptor-deficient mice, systolic blood pressure, mortality, and prevalence of subarachnoid hemorrhage were similar (P>0.05) in groups treated with elastase+Ang II or elastase+Ang II+Ang 1-7. The expression of Mas receptor was detected by immunohistochemistry in samples of human intracranial arteries and aneurysms. In conclusion, without attenuating Ang II-induced hypertension, Ang 1-7 decreased mortality and rupture of intracranial aneurysms in mice through a Mas receptor-dependent pathway.