Microvascular reperfusion during endovascular therapy: the balance of supply and demand.

BACKGROUND: Endovascular therapy (EVT) has revolutionized the treatment of acute stroke, but large vessel recanalization does not always result in tissue-level reperfusion. Cerebral blood flow (CBF) is not routinely monitored during EVT. We aimed to leverage diffuse correlation spectroscopy (DCS), a novel transcranial optical imaging technique, to assess the relationship between microvascular CBF and post-EVT outcomes. METHODS: Frontal lobe CBF was monitored by DCS in 40 patients undergoing EVT. Baseline CBF deficit was calculated as the percentage of CBF impairment on pre-EVT CT perfusion. Microvascular reperfusion was calculated as the percentage increase in DCS-derived CBF that occurred with recanalization. The adequacy of reperfusion was defined by persistent CBF deficit, calculated as: baseline CBF deficit - microvascular reperfusion. A good functional outcome was defined as 90-day modified Rankin Scale score ≤2. RESULTS: Thirty-six of 40 patients achieved successful recanalization, in whom microvascular reperfusion in itself was not associated with infarct volume or functional outcome. However, patients with good functional outcomes had a smaller persistent CBF deficit (median 1% (IQR -11%-16%)) than patients with poor outcomes (median 28% (IQR 2-50%)) (p=0.02). Smaller persistent CBF deficit was also associated with smaller infarct volume (p=0.004). Multivariate models confirmed that persistent CBF deficit was independently associated with infarct volume and functional outcome. CONCLUSIONS: CBF augmentation alone does not predict post-EVT outcomes, but when microvascular reperfusion closely matches the baseline CBF deficit, patients experience favorable clinical and radiographic outcomes. By recognizing inadequate reperfusion, bedside CBF monitoring may provide opportunities to personalize post-EVT care aimed at CBF optimization.

Cell Therapy for Stroke: A Mechanistic Analysis.

Cell therapy has been widely recognized as a promising strategy to enhance recovery in stroke survivors. However, despite an abundance of encouraging preclinical data, successful clinical translation remains elusive. As the field continues to advance, it is important to reexamine prior clinical trials in the context of their intended mechanisms, as this can inform future preclinical and translational efforts. In the present work, we review the major clinical trials of cell therapy for stroke and highlight a mechanistic shift between the earliest studies, which aimed to replace dead and damaged neurons, and later ones that focused on exploiting the various neuromodulatory effects afforded by stem cells. We discuss why both mechanisms are worth pursuing and emphasize the means through which cell replacement can still be achieved.

Decreased contrast enhancement on high-resolution vessel wall imaging of unruptured intracranial aneurysms in patients taking aspirin.

OBJECTIVE: Inflammation plays an integral role in the formation, growth, and progression to rupture of unruptured intracranial aneurysms (UIAs). Animal and human studies have suggested that, due to its antiinflammatory effect, aspirin (ASA) may decrease the risks of growth and rupture of UIAs. High-resolution vessel wall imaging (HR-VWI) has emerged as a noninvasive method to assess vessel wall inflammation and UIA instability. To the authors' knowledge, to date no studies have found a significant correlation between patient use of ASA and contrast enhancement of UIAs on HR-VWI. METHODS: The University of Iowa HR-VWI Project database was analyzed. This database is a compilation of data on patients with UIAs who prospectively underwent HR-VWI on a 3T Siemens MRI scanner. The presence of aneurysmal wall enhancement was objectively defined using the aneurysm-to-pituitary stalk contrast ratio (CRstalk). This ratio was calculated by measuring the maximal signal intensity in the aneurysmal wall and the pituitary stalk on postcontrast T1-weighted images. Data on aneurysm size, morphology, and location and patient demographics and comorbidities were collected. Use of ASA was defined as daily intake of ≥ 81 mg during the previous 6 months or longer. Univariate and multivariate logistic regression analyses were performed to determine factors independently associated with increased contrast enhancement of UIAs on HR-VWI. RESULTS: In total, 74 patients harboring 96 UIAs were included in the study. The mean patient age was 64.7 ± 12.4 years, and 60 patients (81%) were women. Multivariate analysis showed that age (OR 1.12, 95% CI 1.05-1.19), aneurysm size ≥ 7 mm (OR 21.3, 95% CI 4.88-92.8), and location in the anterior communicating, posterior communicating, and basilar arteries (OR 10.7, 95% CI 2.45-46.5) were significantly associated with increased wall enhancement on HR-VWI. On the other hand, use of ASA was significantly associated with decreased aneurysmal wall enhancement on HR-VWI (OR 0.22, 95% CI 0.06-0.83, p = 0.026). CONCLUSIONS: The study results establish a correlation between use of ASA daily for ≥ 6 months and significant decreases in wall enhancement of UIAs on HR-VWI. The findings also demonstrate that detection of wall enhancement using HR-MRI may be a valuable noninvasive method for assessing aneurysmal wall inflammation and UIA instability.

Novel Treatment of Cerebral Vasospasm Using Solitaire Stent Retriever-Assisted Angioplasty: Case Series.

BACKGROUND: Endovascular procedures such as intraarterial (IA) vasodilator injection and balloon angioplasty are used to treat medically refractory cerebral vasospasm. The effects of IA therapy may be short lived and thus require multiple treatments. Balloon angioplasty also has limitations including transient occlusion of the spastic blood vessel, possible endothelial injury, and limited access to proximal vessels. We aim to demonstrate a novel technique using a stent retriever for the management of medically refractory vasospasm, especially in distal vessels. Compared with balloon angioplasty, stent retrievers provide a passive, self-limiting expansion of blood vessels. Other benefits over balloon angioplasty include 1) ability to simultaneously inject IA vasodilators, 2) limited contact and damage to vessel wall, 3) nonocclusive expansion, and 4) technical ease. METHODS: Fourteen blood vessels from 6 patients with symptomatic vasospasm after subarachnoid hemorrhage were identified. We injected 5 mg of IA vasodilator medication into the vasospastic segments without radiographic improvement in vessel diameter and blood flow. The stent retriever was deployed for 2-5 minutes in each vasospastic segment. RESULTS: Distal anterior and posterior circulation segments were easily accessible with the stent retriever system. It resulted in improved vessel diameter and blood flow with subsequent improvement in neurologic examination. All patients demonstrated radiographic resolution of vasospasm. No procedural-related complications were noted. CONCLUSIONS: We demonstrate the safety and efficacy of a novel technique for the treatment of medically refractory cerebral vasospasm using stent retriever angioplasty in distal vessels. Stent angioplasty can be used as an additional tool in the management of subarachnoid hemorrhage-induced cerebral vasospasm.

The Safety and Efficacy of Continuous Tirofiban as a Monoantiplatelet Therapy in the Management of Ruptured Aneurysms Treated Using Stent-Assisted Coiling or Flow Diversion and Requiring Ventricular Drainage.

BACKGROUND: Hemorrhagic complications are a major concern for aneurysmal subarachnoid hemorrhage patients treated with stenting or stent-assisted coiling and undergoing additional procedures such as shunting, ventriculostomy placement, and craniotomies/craniectomies. OBJECTIVE: To assess the safety and efficacy of using a continuous infusion of tirofiban as a monoantiplatelet therapy in the management of ruptured aneurysms in the setting of either stent-assisted coiling (SAC) or flow diversion devices (FDD) in patients requiring either an external ventricular drain (EVD) or ventriculoperitoneal shunt (VPS). METHODS: Aneurysmal subarachnoid hemorrhage (aSAH) patients between July 2017 and September 2018 who were treated with SAC or FDD were started on a continuous tirofiban infusion protocol (0.10 µg/kg/min) with no preceding loading dose as a monoantiplatelet therapy. Safety analysis was performed retrospectively to assess the complication rate, hemorrhagic rate, and rate of ischemic events. There were no hemorrhages related to the VPS surgery. RESULTS: Nineteen subjects were included in the series. The patients received a total of 25 procedures that included 19 EVDs and 6 VPSs. Two patients (8.3%) developed small asymptomatic track hemorrhages after EVD placement. One patient developed a large retroperitoneal hemorrhage due to renal artery branch injury during procedure, and another patient developed an idiosyncratic transient thrombocytopenia which resolved after stopping the medication. One patient (4%) developed a transient ischemic attack, which resolved after a bolus of tirofiban. CONCLUSION: Our study suggests that long-term use of intravenous tirofiban monotherapy in aSAH subjects for endovascular SAC or FDD is safe in the perioperative setting.

Risk of Vertebral Artery Injury and Stroke Following Blunt and Penetrating Cervical Spine Trauma: A Retrospective Review of 729 Patients.

BACKGROUND: Cervical spine trauma (CST) may result in vertebral artery injury (VAI), increasing the risk of developing stroke. Stroke risk following CST is poorly reported. METHODS: In total, 729 patients with CST were retrospectively analyzed, including rates of VAI, age at injury, cause of injury, cardiovascular history, smoking history, substance abuse history, embolization therapy, and antiplatelet or anticoagulant therapy prior or after injury. VAIs were identified and graded following the Modified Denver Criteria for Blunt Cerebrovascular Injury using magnetic resonance angiography and computed tomography angiography. Brain scans were reviewed for stroke rates and statistically significant variations. RESULTS: Thirty-three patients suffered penetrating trauma, whereas 696 patients experienced blunt trauma. In total, 81 patients met the criteria for analysis with confirmed VAI. VAI was more common in penetrating injury group compared with blunt injury group (64% vs. 9%, P < 0.0005). However, low-grade VAI (less than grade III) was more common in blunt injury group versus penetrating group (37% vs. 14%, P < 0.05). The frequency of posterior circulation strokes did not vary significantly between groups (26.3% vs. 13.8%, P = 0.21). Cardiovascular comorbidities were significantly more common in the blunt group (50%, P = 0.0001) compared with the penetrating group (0%). CONCLUSIONS: VAI occurs with a high incidence in penetrating CST. Although stroke risk following penetrating and blunt CST did not vary significantly, they resulted in serious complications in a group of patients. Further study of this patient population is required to provide high-level, evidence-based preventions for VAI complications.

Assessing variability in surgical decision making among attending neurosurgeons at an academic center.

OBJECTIVE: Although it is known that intersurgeon variability in offering elective surgery can have major consequences for patient morbidity and healthcare spending, data addressing variability within neurosurgery are scarce. The authors performed a prospective peer review study of randomly selected neurosurgery cases in order to assess the extent of consensus regarding the decision to offer elective surgery among attending neurosurgeons across one large academic institution. METHODS: All consecutive patients who had undergone standard inpatient surgical interventions of 1 of 4 types (craniotomy for tumor [CFT], nonacute redo CFT, first-time spine surgery with/without instrumentation, and nonacute redo spine surgery with/without instrumentation) during the period 2015-2017 were retrospectively enrolled (n = 9156 patient surgeries, n = 80 randomly selected individual cases, n = 20 index cases of each type randomly selected for review). The selected cases were scored by attending neurosurgeons using a need for surgery (NFS) score based on clinical data (patient demographics, preoperative notes, radiology reports, and operative notes; n = 616 independent case reviews). Attending neurosurgeon reviewers were blinded as to performing provider and surgical outcome. Aggregate NFS scores across various categories were measured. The authors employed a repeated-measures mixed ANOVA model with autoregressive variance structure to compute omnibus statistical tests across the various surgery types. Interrater reliability (IRR) was measured using Cohen's kappa based on binary NFS scores. RESULTS: Overall, the authors found that most of the neurosurgical procedures studied were rated as "indicated" by blinded attending neurosurgeons (mean NFS = 88.3, all p values < 0.001) with greater agreement among neurosurgeon raters than expected by chance (IRR = 81.78%, p = 0.016). Redo surgery had lower NFS scores and IRR scores than first-time surgery, both for craniotomy and spine surgery (ANOVA, all p values < 0.01). Spine surgeries with fusion had lower NFS scores than spine surgeries without fusion procedures (p < 0.01). CONCLUSIONS: There was general agreement among neurosurgeons in terms of indication for surgery; however, revision surgery of all types and spine surgery with fusion procedures had the lowest amount of decision consensus. These results should guide efforts aimed at reducing unnecessary variability in surgical practice with the goal of effective allocation of healthcare resources to advance the value paradigm in neurosurgery.

Cognitive and cerebral hemodynamic effects of endovascular recanalization of chronically occluded cervical internal carotid artery: single-center study and review of the literature.

OBJECTIVE: Revascularization of a symptomatic, medically refractory, cervical chronically occluded internal carotid artery (COICA) using endovascular techniques (ETs) has surfaced as a viable alternative to extracranial-intracranial bypass. The authors aimed to assess the safety, success, and neurocognitive outcomes of recanalization of COICA using ETs or hybrid treatment (ET plus carotid endarterectomy) and to identify candidate radiological markers that could predict success. METHODS: The authors performed a retrospective analysis of their prospectively collected institutional database and used their previously published COICA classification to assess the potential benefits of ETs or hybrid surgery to revascularize symptomatic patients with COICA. Subjects who had undergone CT perfusion (CTP) imaging and Montreal Cognitive Assessment (MoCA) testing, both pre- and postprocedure, were included. The authors then performed a review of the literature on patients with COICA to further evaluate the success and safety of these treatment alternatives. RESULTS: The single-center study revealed 28 subjects who had undergone revascularization of symptomatic COICA. Five subjects had CTP imaging and MoCA testing pre- and postrevascularization and thus were included in the study. All 5 patients had very large penumbra involving the entire hemisphere supplied by the ipsilateral COICA, which resolved postoperatively. Significant improvement in neurocognitive outcome was demonstrated by MoCA testing after treatment (preprocedure: 19.8 ± 2.4, postprocedure: 27 ± 1.6; p = 0.0038). Moreover, successful revascularization of COICA led to full restoration of cerebral hemodynamics in all cases. Review of the literature identified a total of 333 patients with COICA. Of these, 232 (70%) showed successful recanalization after ETs or hybrid surgery, with low major and minor complication rates (3.9% and 2.7%, respectively). CONCLUSIONS: ETs and hybrid surgery are safe and effective alternatives to revascularize patients with symptomatic COICA. CTP imaging could be used as a radiological marker to assess cerebral hemodynamics and predict the success of revascularization. Improvement in CTP parameters is associated with significant improvement in neurocognitive functions.

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.

Complete spontaneous regression of cerebral arteriovenous malformation: a case report and review of the literature.

Spontaneous regression of an arteriovenous malformation (AVM) is the phenomenon of partial or complete obliteration of the vascular anomaly without any therapeutic intervention. Complete spontaneous regression is a rare event with limited previously reported cases in the literature. We present a new case of complete spontaneous regression of a right frontal AVM and report findings from the imaging studies. Furthermore, we present the findings of a detailed literature review and discuss hypotheses regarding the pathophysiology of this rare occurrence.

Complications Predicting Perioperative Mortality in Patients Undergoing Elective Craniotomy: A Population-Based Study.

OBJECTIVE: The objective of this study was to assess the independent effect of complications on 30-day mortality in 32,695 patients undergoing elective craniotomy. METHODS: The American College of Surgeons National Surgical Quality Improvement Program was queried for patients undergoing elective craniotomy from 2006 to 2015. Multivariate logistic regression was used to examine the effect of complications on mortality independent of preoperative risk and other postoperative complications. This effect was further assessed in risk-stratified patient subgroups using the American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator. RESULTS: Of 13 complications analyzed, the 5 most strongly associated with mortality independent of preoperative risk factors were unplanned intubation (odds ratio [OR], 12.1; 95% confidence interval [CI], 9.5-15.4; P < 0.001), stroke (OR, 11.1; 95% CI, 8.3-14.9; P < 0.001), ventilator requirement >48 hours after surgery (OR, 9.9; 95% CI, 7.9-12.6; P < 0.001), and renal failure (OR, 8.5; 95% CI, 4.4-16.2; P < 0.001). These same complications were also the 5 most associated with mortality independent of other postoperative complications. They were also associated with mortality across all risk-stratified patient subgroups. On the contrary, venous thromboembolism (OR, 1.3; 95% CI, 0.98-1.7; P = 0.06), urinary tract infection (OR, 1.1; 95% CI, 0.76-1.6; P = 0.61), unplanned reoperation (OR, 1.1; 95% CI, 0.83-1.4; P = 0.55), and surgical site infection (OR, 0.35; 95% CI, 0.18-0.71; P = 0.004) showed no significant link with increased mortality independent of other complications. CONCLUSIONS: Of 13 complications analyzed, myocardial infarction, unplanned intubation, prolonged ventilator requirement, stroke, and renal failure showed the strongest association with mortality independent of preoperative risk, independent of other complications, and across all risk-stratified subgroups. These findings help identify causes of perioperative mortality after elective craniotomy. Dedicating additional resources toward preventing and treating these complications postoperatively may help reduce rates of failure-to-rescue in the neurosurgical population.

The Effect of Underlying Liver Disease on Perioperative Outcomes Following Craniotomy for Tumor: An American College of Surgeons National Quality Improvement Program Analysis.

BACKGROUND: The association between underlying liver disease and poor surgical outcomes has been well documented across a wide variety of surgical disciplines. However, little is known about the importance of liver disease in neurosurgery. In this report, we assess the independent effect of liver disease on perioperative outcomes in patients undergoing craniotomy for tumor. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried for patients undergoing craniotomy for tumor from 2006 to 2015. Presence and severity of underlying liver disease was assessed with the aspartate aminotransferase-to-platelet ratio index and the Model for End-Stage Liver Disease-Sodium scores, computed from preoperative laboratory values. RESULTS: Among 11,897 patients, mild and advanced disease was identified in 2.4% and 1.9% of patients, respectively. Rates of 30-day mortality were 4.5% and 15.8% in these patients, compared with 3.1% in patients with healthy livers. The 30-day complication rate was 40.3%, 28.0%, and 19.8% in patients with advanced, mild, and no liver disease, respectively. In multivariate analysis, the presence of any liver disease (mild or advanced) was independently associated with mortality (OR = 2.46; 95% confidence interval [CI], 1.68-3.59; P < 0.001), morbidity (OR, 1.49; 95% CI, 1.18-1.87; P = 0.001), and length of hospital stay over 10 days (OR, 1.35; 95% CI, 1.07-1.70; P = 0.012), when compared with 13 covariates. Liver disease showed the strongest independent association with mortality of all risk factors analyzed. CONCLUSIONS: Liver disease is an independent predictor of poor 30-day outcomes following craniotomy for tumor. Consideration of underlying liver function can have a role in surgical decision making and postoperative care for these patients.

Pervasive within-Mitochondrion Single-Nucleotide Variant Heteroplasmy as Revealed by Single-Mitochondrion Sequencing.

A number of mitochondrial diseases arise from single-nucleotide variant (SNV) accumulation in multiple mitochondria. Here, we present a method for identification of variants present at the single-mitochondrion level in individual mouse and human neuronal cells, allowing for extremely high-resolution study of mitochondrial mutation dynamics. We identified extensive heteroplasmy between individual mitochondrion, along with three high-confidence variants in mouse and one in human that were present in multiple mitochondria across cells. The pattern of variation revealed by single-mitochondrion data shows surprisingly pervasive levels of heteroplasmy in inbred mice. Distribution of SNV loci suggests inheritance of variants across generations, resulting in Poisson jackpot lines with large SNV load. Comparison of human and mouse variants suggests that the two species might employ distinct modes of somatic segregation. Single-mitochondrion resolution revealed mitochondria mutational dynamics that we hypothesize to affect risk probabilities for mutations reaching disease thresholds.

Primary Cell Culture of Live Neurosurgically Resected Aged Adult Human Brain Cells and Single Cell Transcriptomics.

Investigation of human CNS disease and drug effects has been hampered by the lack of a system that enables single-cell analysis of live adult patient brain cells. We developed a culturing system, based on a papain-aided procedure, for resected adult human brain tissue removed during neurosurgery. We performed single-cell transcriptomics on over 300 cells, permitting identification of oligodendrocytes, microglia, neurons, endothelial cells, and astrocytes after 3 weeks in culture. Using deep sequencing, we detected over 12,000 expressed genes, including hundreds of cell-type-enriched mRNAs, lncRNAs and pri-miRNAs. We describe cell-type- and patient-specific transcriptional hierarchies. Single-cell transcriptomics on cultured live adult patient derived cells is a prime example of the promise of personalized precision medicine. Because these cells derive from subjects ranging in age into their sixties, this system permits human aging studies previously possible only in rodent systems.

Site-specific elevation of interleukin-1ß and matrix metalloproteinase-9 in the Willis circle by hemodynamic changes is associated with rupture in a novel rat cerebral aneurysm model.

The pathogenesis of subarachnoid hemorrhage remains unclear. No models of cerebral aneurysms elicited solely by surgical procedures and diet have been established. Elsewhere we reported that only few rats in our original rat aneurysm model manifested rupture at the anterior and posterior Willis circle and that many harbored unruptured aneurysms at the anterior cerebral artery-olfactory artery bifurcation. This suggests that rupture was site-specific. To test our hypothesis that a site-specific response to hemodynamic changes is associated with aneurysmal rupture, we modified our original aneurysm model by altering the hemodynamics. During 90-day observation, the incidence of ruptured aneurysms at the anterior and posterior Willis circle was significantly increased and the high incidence of unruptured aneurysms at the anterior cerebral artery-olfactory artery persisted. This phenomenon was associated with an increase in the blood flow volume. Notably, the level of matrix metalloproteinase-9 associated with interleukin-1ß was augmented by the increase in the blood flow volume, suggesting that these molecules exacerbated the vulnerability of the aneurysmal wall. The current study first demonstrates that a site-specific increase in interleukin-1ß and matrix metalloproteinase-9 elicited by hemodynamic changes is associated with rupture. Our novel rat model of rupture may help to develop pharmaceutical approaches to prevent rupture.

Rotational vertebrobasilar insufficiency due to compression of a persistent first intersegmental vertebral artery variant: case report.

Rotational vertebrobasilar insufficiency, or bow hunter's syndrome, is a rare cause of posterior circulation ischemia, which, following rotation of the head, results in episodic vertigo, dizziness, nystagmus, or syncope. While typically caused by dynamic occlusion of the vertebral artery in its V2 and V3 segments, the authors here describe a patient with dynamic occlusion of the vertebral artery secondary to a persistent first intersegmental artery, a rare variant course of the vertebral artery. In this case the vertebral artery coursed under rather than over the posterior arch of the C-1. This patient was also found to have incomplete development of the posterior arch of C-1, as is often seen with this variant. The patient underwent dynamic digital subtraction angiography, which demonstrated occlusion at the variant vertebral artery with head turning. He was then taken for decompression of the vertebral artery through removal of the incomplete arch of C-1 that was causing the dynamic compression. After surgery the patient had a complete resolution of symptoms. In this report, the authors present the details of this case, describe the anatomical variants involved, and provide a discussion regarding the need for atlantoaxial fusion in these patients.

Pressure modulation algorithm to separate cerebral hemodynamic signals from extracerebral artifacts.

We introduce and validate a pressure measurement paradigm that reduces extracerebral contamination from superficial tissues in optical monitoring of cerebral blood flow with diffuse correlation spectroscopy (DCS). The scheme determines subject-specific contributions of extracerebral and cerebral tissues to the DCS signal by utilizing probe pressure modulation to induce variations in extracerebral blood flow. For analysis, the head is modeled as a two-layer medium and is probed with long and short source-detector separations. Then a combination of pressure modulation and a modified Beer-Lambert law for flow enables experimenters to linearly relate differential DCS signals to cerebral and extracerebral blood flow variation without a priori anatomical information. We demonstrate the algorithm's ability to isolate cerebral blood flow during a finger-tapping task and during graded scalp ischemia in healthy adults. Finally, we adapt the pressure modulation algorithm to ameliorate extracerebral contamination in monitoring of cerebral blood oxygenation and blood volume by near-infrared spectroscopy.

Paradoxical Increase in Mortality and Rupture of Intracranial Aneurysms in Microsomal Prostaglandin E2 Synthase Type 1-Deficient Mice: Attenuation by Aspirin.

BACKGROUND: Inflammation plays an important role in formation and rupture of intracranial aneurysms. Expression of microsomal prostaglandin E2 (PGE2) synthase type 1 (mPGES-1) is increased in the wall of intracranial aneurysms in humans. PGE2, a by-product of mPGES-1, is associated with inflammation and cerebrovascular dysfunction. OBJECTIVE: To test the hypothesis that deletion of mPGES-1 decreases the formation and rupture of intracranial aneurysms in a murine model. METHODS: Intracranial aneurysms were induced in wild-type and mPGES-1 knockout (mPGES-1 KO) mice by using a combination of deoxycorticosterone acetate-salt-induced hypertension and intracranial injection of elastase in the basal cistern. Prevalence of aneurysms, subarachnoid hemorrhage, and mortality were assessed. We also tested the effects of administration of aspirin (6 mg/kg/d) by gavage and PGE2 (1 mg/kg/d) by subcutaneous infusion. RESULTS: Systolic blood pressure and prevalence of aneurysm were similar in wild-type and mPGES-1 KO mice. However, mortality and the prevalence of subarachnoid hemorrhage were markedly increased in mPGES-1 KO mice (P < .05). Bone marrow reconstitution studies suggest that mPGES-1 derived from leukocytes does not appear to increase rupture of intracranial aneurysms. Aspirin, but not PGE2, attenuated the increased mortality in mPGES-1 KO mice (P < .05). CONCLUSION: Vascular mPGES-1 plays a protective role in blood vessels and attenuates rupture of cerebral aneurysms. In contrast to effects on abdominal aneurysms, mPGES-1 deficiency is associated with an increase in rupture of cerebral aneurysms and mortality, which are attenuated by low-dose aspirin.

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.