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

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

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

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

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

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

Myeloperoxidase is increased in human cerebral aneurysms and increases formation and rupture of cerebral aneurysms in mice.

BACKGROUND AND PURPOSE: Cerebral aneurysm (CA) affects 3% of the population and is associated with hemodynamic stress and inflammation. Myeloperoxidase, a major oxidative enzyme associated with inflammation, is increased in patients with CA, but whether myeloperoxidase contributes to CA is not known. We tested the hypotheses that myeloperoxidase is increased within human CA and is critical for formation and rupture of CA in mice. METHODS: Blood was drawn from the lumen of CAs and femoral arteries of 25 patients who underwent endovascular coiling of CA, and plasma myeloperoxidase concentrations were measured with ELISA. Effects of endogenous myeloperoxidase on CA formation and rupture were studied in myeloperoxidase knockout mice and wild-type (WT) mice using an angiotensin II-elastase induction model of CA. In addition, effects of myeloperoxidase on inflammatory gene expression in endothelial cells were analyzed. RESULTS: Plasma concentrations of myeloperoxidase were 2.7-fold higher within CA than in femoral arterial blood in patients with CA. myeloperoxidase-positive cells were increased in aneurysm tissue compared with superficial temporal artery of patients with CA. Incidence of aneurysms and subarachnoid hemorrhage was significantly lower in myeloperoxidase knockout than in WT mice. In cerebral arteries, proinflammatory molecules, including tumor necrosis factor-α, cyclooxygenase-2 (COX2), chemokine (C-X-C motif) ligand 1 (CXCL1), chemokine (C motif) ligand (XCL1), matrix metalloproteinase (MMP) 8, cluster of differentiation 68 (CD68), and matrix metalloproteinase 13, and leukocytes were increased, and α-smooth muscle actin was decreased, in WT but not in myeloperoxidase knockout mice after induction of CA. Myeloperoxidase per se increased expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in endothelial cells. CONCLUSIONS: These findings suggest that myeloperoxidase may contribute importantly to formation and rupture of CA.

ApoB-100-related peptide vaccine protects against angiotensin II-induced aortic aneurysm formation and rupture.

BACKGROUND: T cells and macrophages are implicated in the pathogenesis of aortic aneurysm (AA) and atherosclerosis. We recently demonstrated that a vaccine using an apoB-100-related peptide p210 reduces atherosclerosis with favorable modulation of CD8+ T cells in apolipoprotein E-deficient (apoE-/-) mice. OBJECTIVES: This study hypothesized that a p210 vaccine could reduce AA formation in the angiotensin II (Ang II)-induced AA model. METHODS: Male apoE-/- mice were immunized with p210 vaccine and implanted with an Ang II-releasing pump for 4 weeks. Flow cytometry assessed T cell activation and phenotype. Interleukin-6 (IL-6) and monocyte chemotactic protein 1 (MCP-1) expression were assessed using reverse transcription polymerase chain reaction. We used ex vivo aortic explants to test monocyte adhesion and in vitro cocultures to evaluate CD8+ T cell function. RESULTS: The p210 vaccine activated CD8+ T cells and reduced AA formation and mortality due to AA rupture, which was attenuated by CD8+ T cell depletion. Vaccination decreased expression of IL-6 and MCP-1 and reduced macrophage infiltration in the aorta. Cytotoxic T-lymphocyte assay showed that CD8+ T cells from p210-immunized mice had higher lytic activity against Ang II-stimulated macrophages. The p210 vaccine decreased splenic Th17 cells, and in vitro coculture of CD4+ and CD8+ T cells showed that CD8+ T cells from p210-immunized mice inhibited the polarization of CD4+ T cells into Th17 cells. IL-17A-/- mice infused with a higher dose of Ang II did not develop AA rupture. CONCLUSIONS: A p210 vaccine protected against Ang II-induced AA formation and mortality by reducing macrophage infiltration in the aorta and decreasing Th17 cell polarization. Our findings provide a potentially novel immunomodulating approach against AA.

Two cases of rupture of esophagogastric varices during the course of oxaliplatin-based chemotherapy for colorectal cancer.

Some cases of portal hypertension developing during the course of oxaliplatin-based chemotherapy have been reported. However, there have been no reports of rupture of esophagogastric varices (EGV) in Japan. We present two cases of rupture of EGV during the course of oxaliplatin-based chemotherapy. One case was treated via balloon-occluded retrograde transvenous obliteration, and the other case was treated by using endoscopic variceal ligation and endoscopic injection sclerotherapy. On the basis of our results, we recommend careful monitoring for the occurrence of EGV during the course of oxaliplatin-based chemotherapy.

Posterior spinal artery aneurysm rupture after 'Ecstasy' abuse.

Posterior spinal artery (PSA) aneurysms are a rare cause of subarachnoid hemorrhage (SAH). The commonly abused street drug 3,4-methylenedioxymethamphetamine (MDMA) or 'Ecstasy' has been linked to both systemic and neurological complications. A teenager presented with neck stiffness, headaches and nausea after ingesting 'Ecstasy'. A brain CT was negative for SAH but a CT angiogram suggested cerebral vasculitis. A lumbar puncture showed SAH but a cerebral angiogram was negative. After a spinal MR angiogram identified abnormalities on the dorsal surface of the cervical spinal cord, a spinal angiogram demonstrated a left PSA 2 mm fusiform aneurysm. The patient underwent surgery and the aneurysmal portion of the PSA was excised without postoperative neurological sequelae. 'Ecstasy' can lead to neurovascular inflammation, intracranial hemorrhage, SAH and potentially even de novo aneurysm formation and subsequent rupture. PSA aneurysms may be treated by endovascular proximal vessel occlusion or open surgical excision.

Roles of hypertension in the rupture of intracranial aneurysms.

BACKGROUND AND PURPOSE: Systemic hypertension has long been considered a risk factor of aneurysmal rupture. However, a causal link between systemic hypertension and the development of aneurysmal rupture has not been established. In this study, using a mouse model of intracranial aneurysm rupture, we examined the roles of systemic hypertension in the development of aneurysmal rupture. METHODS: Aneurysms were induced by a combination of deoxycorticosterone acetate (DOCA)-salt and a single injection of elastase into the cerebrospinal fluid in mice. Antihypertensive treatment was started 6 days after aneurysm induction. Aneurysmal rupture was detected by neurological symptoms and confirmed by the presence of intracranial aneurysm with subarachnoid hemorrhage. Hydralazine (direct vasodilator) or discontinuation of DOCA-salt treatment was used to assess the roles of systemic hypertension. Captopril (angiotensin-converting enzyme inhibitor) or losartan (angiotensin II type 1 receptor antagonist) was used to assess the roles of the local renin-angiotensin system in the vascular wall. RESULTS: Normalization of blood pressure by hydralazine significantly reduced the incidence of ruptured aneurysms and the rupture rate. There was a dose-dependent relationship between reduction of blood pressure and prevention of aneurysmal rupture. Captopril and losartan were able to reduce rupture rate without affecting systemic hypertension induced by DOCA-salt treatment. CONCLUSIONS: Normalization of blood pressure after aneurysm formation prevented aneurysmal rupture in mice. In addition, we found that the inhibition of the local renin-angiotensin system independent from the reduction of blood pressure can prevent aneurysmal rupture.

[Two cases of esophageal variceal rupture associated with chemotherapy for liver metastasis of breast cancer].

A morphological change resembling liver cirrhosis called pseudocirrhosis may be observed following chemotherapy for liver metastasis of breast cancer. Pseudocirrhosis is hypothesized to be caused by retraction of the hepatic capsule along with tumor shrinkage and subsequent scar formation around the metastatic lesion, as a response to the infiltrating tumor or chemotherapy-induced hepatic injury. The progression of cirrhotic changes may result in portal hypertension and esophageal varices. We managed two cases of esophageal variceal rupture during chemotherapy for breast cancer with liver metastasis. Hemostasis was successfully achieved by the endoscopic variceal ligation technique in both cases. We conclude that clinicians should be aware of the risk of pseudocirrhosis during chemotherapy for liver metastasis, and a periodic endoscopic follow-up is recommended along with appropriate management of esophageal varices.

Anterior communicating artery aneurysm rupture after intravenous thrombolysis for acute middle cerebral artery thromboembolism: case report.

BACKGROUND AND IMPORTANCE: The use of intravenous recombinant tissue plasminogen activator (IV rtPA) has become an integral part of modern acute ischemic stroke management; however, its use has been associated with the development of intracranial hemorrhage in 6.4% of patients. It is possible that underlying and unsuspected vascular lesions, such as cerebral aneurysms, may lead to intracranial hemorrhage after IV rtPA thrombolysis. CLINICAL PRESENTATION: We present a previously unreported case of a 51-year-old woman who presented with subarachnoid hemorrhage from an acutely ruptured anterior communicating artery aneurysm after IV rtPA treatment for acute left middle cerebral artery thromboembolism. The patient underwent mechanical thromboembolectomy of the left middle cerebral artery occlusion with resultant TIMI (Thrombolysis In Myocardial Infarction) grade I recanalization, followed by coil embolization of the anterior communicating artery aneurysm. The patient never improved neurologically, and she ultimately died. CONCLUSION: Screening to identify patients at risk for development of hemorrhagic complications from underlying structural vascular lesions before the use of IV rtPA with computed tomography angiography should be considered.

Subarachnoid and intraventricular hemorrhage due to ruptured aneurysm after combined spinal-epidural anesthesia.

A patient received combined spinal-epidural anesthesia for a scheduled total knee arthroplasty. After an injection of spinal anesthetic and ephedrine due to a decrease in blood pressure, the patient developed a severe headache. The patient did not respond to verbal command at the completion of the operation. A brain CT scan revealed massive subarachnoid and intraventricular hemorrhages, and a CT angiogram showed a ruptured aneurysm. Severe headaches should not be overlooked in an uncontrolled hypertensive patient during spinal anesthesia because it may imply an intracranial and intraventricular hemorrhage due to the rupture of a hidden aneurysm.

Ruptured de novo thrombotic giant aneurysm induced by ethyl 2-cyanoacrylate: case report.

BACKGROUND: A very rare case of a ruptured aneurysm induced by ethyl 2-cyanoacrylate is reported. CASE DESCRIPTION: Six years earlier, this 68-year-old woman had undergone microvascular decompression for trigeminal neuralgia during which the left vertebral artery, which compressed the exit zone of the trigeminal nerve, had been detached and fixed to the dura mater of the petrous bone with ethyl 2-cyanoacrylate. Shortly thereafter she underwent microvascular decompression for left-side facial palsy; again ethyl 2-cyanoacrylate was used. Six years later, she suffered a subarachnoid hemorrhage because of rupture of a new aneurysm of the left vertebral artery. She was referred to our hospital where coil embolization was attempted on the day following the insult. However, the left vertebral artery and the aneurysm could not be occluded completely, and she suddenly died 20 days later from rerupture of the aneurysm. CONCLUSION: This is the first pathologic report of a ruptured de novo aneurysm induced by ethyl 2-cyanoacrylate. We suggest that arterial wall damage by ethyl 2-cyanoacrylate may have contributed to the development of the de novo aneurysm.

Delayed cerebrovascular complications of intrathecal colloidal gold.

OBJECTIVE: Therapy with intrathecal colloidal gold has been used in the past as an adjunct in the treatment of childhood neoplasms, including medulloblastoma and leukemia. We describe the long-term follow-up period of a series of patients treated with intrathecal colloidal gold and emphasize the high incidence of delayed cerebrovascular complications and their management. METHODS: Between 1967 and 1970, 14 children with posterior fossa medulloblastoma underwent treatment at the University of Minnesota. Treatment consisted of surgical resection, external beam radiotherapy, and intrathecal colloidal gold. All patients underwent long-term follow-up periods. RESULTS: Of the 14 original patients, 6 died within 2 years of treatment; all experienced persistent or recurrent disease. The eight surviving patients developed significant neurovascular complications 5 to 20 years after treatment. Three patients died as a result of aneurysmal subarachnoid hemorrhage, and five developed ischemic symptoms from severe vasculopathy that resembled moyamoya disease. CONCLUSION: Although therapy with colloidal gold resulted in long-term survival in a number of cases of childhood medulloblastoma, our experience suggests that the severe cerebrovascular side effects fail to justify its use. The unique complications associated with colloidal gold therapy, as well as the management of these complications, are presented. We recommend routine screening of any long-term survivors to exclude the presence of an intracranial aneurysm and to document the possibility of moyamoya syndrome.

Intracranial aneurysms and cocaine abuse: analysis of prognostic indicators.

OBJECTIVE: The outcome of subarachnoid hemorrhage associated with cocaine abuse is reportedly poor. However, no study in the literature has reported the use of a statistical model to analyze the variables that influence outcome. METHODS: A review of admissions during a 6-year period revealed 14 patients with cocaine-related aneurysms. This group was compared with a control group of 135 patients with ruptured aneurysms and no history of cocaine abuse. Age at presentation, time of ictus after intoxication, Hunt and Hess grade of subarachnoid hemorrhage, size of the aneurysm, location of the aneurysm, and the Glasgow Outcome Scale score were assessed and compared. RESULTS: The patients in the study group were significantly younger than the patients in the control group (P < 0.002). In patients in the study group, all aneurysms were located in the anterior circulation. The majority of these aneurysms were smaller than those of the control group (8 +/- 6.08 mm versus 11 +/- 5.4 mm; P = 0.05). The differences in mortality and morbidity between the two groups were not significant. Hunt and Hess grade (P < 0.005) and age (P < 0.007) were significant predictors of outcome for the patients with cocaine-related aneurysms. CONCLUSION: Cocaine use predisposed aneurysmal rupture at a significantly earlier age and in much smaller aneurysms. Contrary to the published literature, this group did reasonably well with aggressive management.

Cerebral aneurysm rupture after r-TPA thrombolysis for acute myocardial infarction.

BACKGROUND: Intracranial hemorrhage is the most dreaded risk of thrombolytic therapy for acute myocardial infarction because of the high mortality and disability rates associated with this complication. Brain structural lesions may predispose a patient to bleeding. To date, aneurysm rupture has not been described as a complication of such therapy. CASE DESCRIPTION: A 66-year-old hypertensive woman was admitted because of chest pain. Myocardial infarction was diagnosed and fibrinolytic therapy with recombinant tissue plasminogen activator (r-TPA) was initiated. Eight hours after admission she became unconscious. Brain computed tomography scan showed subarachnoid hemorrhage, and a cerebral arteriography showed an anterior communicating artery aneurysm. Because of her poor clinical condition treatment was postponed. Death occurred 7 days later because of multiorgan failure. CONCLUSIONS: Cerebral aneurysms should be considered as a possible contributing factor to intracranial bleeding after thrombolytic therapy.

Ruptured de novo aneurysm induced by ethyl 2-cyanoacrylate: case report.

OBJECTIVE AND IMPORTANCE: We report a rare case of a ruptured de novo aneurysm induced by ethyl 2-cyanoacrylate. CLINICAL PRESENTATION: A 44-year-old woman had undergone microvascular decompression for a right-sided facial spasm. The preoperative vertebral angiogram did not show any aneurysmal dilation. The right anteroinferior cerebellar artery, which was compressing the exit zone of the facial nerve, was detached and fixed to the dura mater with ethyl 2-cyanoacrylate. Nine years later, the patient suffered a subarachnoid hemorrhage caused by the rupture of a newly developed aneurysm of the right anteroinferior cerebellar artery. INTERVENTION: The aneurysm was clipped 2 days after onset of the subarachnoid hemorrhage. It consisted of two bulges in the arterial wall on the proximal side of the meatal loop. One bulge was stuck to the dura mater of the pyramis by ethyl 2-cyanoacrylate, which had been used in the microvascular decompression 9 years previously. CONCLUSION: This is the first reported clinical case of a de novo aneurysm induced by a cyanoacrylate adhesive. Ethyl 2-cyanoacrylate can damage the arterial wall and induce a de novo aneurysm.