David K. Kung

Risk of ventriculostomy-related hemorrhage in patients with acutely ruptured aneurysms treated using stent-assisted coiling.

OBJECT Intracranial stenting has improved the ability to treat wide-neck aneurysms via endovascular techniques. However, stent placement necessitates the use of antiplatelet agents, and the latter may complicate the treatment of patients with acutely ruptured aneurysms who demonstrate hydrocephalus and require ventriculostomy. Antiplatelet agents in this setting could increase the incidence of ventriculostomy-related hemorrhagic complications, but there are insufficient data in the medical literature to quantify this potential risk. The aim of this study was to directly quantify the risk of ventriculostomy-related hemorrhage in patients with acute aneurysmal subarachnoid hemorrhage treated with stent-assisted coiling. METHODS The authors retrospectively identified 131 patients who underwent endovascular treatment for an acutely ruptured aneurysm as well as ventriculostomy or ventriculoperitoneal (VP) shunt placement. The rate of hemorrhagic complications associated with ventriculostomy or VP shunt insertion was compared between patients who underwent coiling without a stent (Group 1) and those who underwent stent-assisted coiling and dual antiplatelet therapy (Group 2). RESULTS One hundred nine ventriculostomies or VP shunt placement procedures were performed in 91 patients in Group 1, and 50 procedures were undertaken in 40 patients in Group 2. The rates of radiographic hemorrhage and symptomatic hemorrhage were significantly higher in Group 2 (32% vs 14.7%, p = 0.02; and 8% vs 0.9%, p = 0.03, respectively). On multivariate analyses, Group 2 had 3.42 times the odds of a radiographic hemorrhage (95% CI 1.46-8.04, p = 0.0048) after adjusting for antiplatelet use prior to admission. CONCLUSIONS The application of dual antiplatelet therapy in stent-assisted coiling of acutely ruptured aneurysms is associated with an increase in the risk of hemorrhagic complications following ventriculostomy or VP shunt placement, as compared with its use in a coiling procedure without a stent.

Macrophage Imaging Within Human Cerebral Aneurysms Wall Using Ferumoxytol-Enhanced MRI: A Pilot Study

Objective—Macrophages play a critical role in cerebral aneurysm formation and rupture. The purpose of this study is to demonstrate the feasibility and optimal parameters of imaging macrophages within human cerebral aneurysm wall using ferumoxytol-enhanced MRI. Methods and Results—Nineteen unruptured aneurysms in 11 patients were imaged using T2*-GE–MRI sequence. Two protocols were used. Protocol A was an infusion of 2.5 mg/kg of ferumoxytol and imaging at day 0 and 1. Protocol B was an infusion of 5 mg/kg of ferumoxytol and imaging at day 0 and 3. All images were reviewed independently by 2 neuroradiologists to assess for ferumoxytol-associated loss of MRI signal intensity within aneurysm wall. Aneurysm tissue was harvested for histological analysis. Fifty percent (5/10) of aneurysms in protocol A showed ferumoxytol-associated signal changes in aneurysm walls compared to 78% (7/9) of aneurysms in protocol B. Aneurysm tissue harvested from patients infused with ferumoxytol stained positive for both CD68+, demonstrating macrophage infiltration, and Prussian blue, demonstrating uptake of iron particles. Tissue harvested from controls stained positive for CD68 but not Prussian blue. Conclusion—Imaging with T2*-GE–MRI at 72 hours postinfusion of 5 mg/kg of ferumoxytol establishes a valid and useful approximation of optimal dose and timing parameters for macrophages imaging within aneurysm wall. Further studies are needed to correlate these imaging findings with risk of intracranial aneurysm rupture.

Stent-assisted coiling of wide-necked aneurysms in the setting of acute subarachnoid hemorrhage: experience in 65 patients.

BACKGROUND Stent-assisted coiling in the setting of subarachnoid hemorrhage remains controversial. Currently, there is a paucity of data regarding the utility of this procedure and the risks of hemorrhagic and ischemic complications. OBJECTIVE To assess the utility of stent-assisted coil embolization and pretreatment with antiplatelet agents in the management of ruptured wide-necked aneurysms. METHODS A retrospective study of 65 patients with ruptured wide-necked aneurysms treated with stent-assisted coiling. Patients with hydrocephalus or a Hunt and Hess grade ≥ III received a ventriculostomy before endovascular intervention. Patients were treated intraoperatively with 600 mg of clopidogrel and maintained on daily doses of 75 mg of clopidogrel and 81 mg of aspirin. The Glasgow outcome scale (GOS) score was recorded at the time of discharge. We identified major bleeding complications secondary to antiplatelet therapy and cases of in-stent thrombosis that required periprocedural thrombolysis. RESULTS Of the aneurysms, 66.2% arose within the anterior circulation; 69.2% of patients presented with hydrocephalus or a Hunt and Hess grade ≥ III and required a ventriculostomy. A good outcome (GOS of 4 or 5) was achieved in 63.1% of patients, and the overall mortality rate was 16.9%. There were 10 (15.38%) major complications associated with bleeding secondary to antiplatelet therapy (5 patients, 7.7%) or intraoperative in-stent thrombosis (5 patients, 7.7%). Three (4.6%) patients had a fatal hemorrhage. CONCLUSION Our findings suggest that stent-assisted coiling and routine treatment with antiplatelet agents is a viable option in the management of ruptured wide-necked aneurysms.

Evidence That Acetylsalicylic Acid Attenuates Inflammation in the Walls of Human Cerebral Aneurysms: Preliminary Results

Background Inflammatory cells and molecules may play a critical role in formation and rupture of cerebral aneurysms. Recently, an epidemiologic study reported that acetylsalicylic acid (ASA) decreases the risk of aneurysm rupture. The goal of this study was to determine the effects of ASA on inflammatory cells and molecules in the walls of human cerebral aneurysms, using radiographic and histological techniques. Methods and Results Eleven prospectively enrolled patients harboring unruptured intracranial aneurysms were randomized into an ASA‐treated (81 mg daily) group (n=6) and an untreated (control) group (n=5). Aneurysms were imaged at baseline using ferumoxytol‐enhanced MRI to estimate uptake by macrophages. After 3 months, patients were reimaged before undergoing microsurgical clipping. Aneurysm tissues were collected for immunostaining with monoclonal antibodies for cyclooxygenase‐1 (COX‐1), cyclooxygenase‐2 (COX‐2), microsomal prostaglandin E2 synthase‐1 (mPGES‐1), and macrophages. A decrease in signal intensity on ferumoxytol‐enhanced MRI was observed after 3 months of ASA treatment. Expression of COX‐2 (but not COX‐1), mPGES‐1, and macrophages was lower in the ASA group than in the control group. Conclusions This study provides preliminary radiographical and histological evidence that ASA may attenuate the inflammatory process in the walls of human cerebral aneurysms. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01710072.

Biology of Cerebral Arteriovenous Malformations with a Focus on Inflammation

Cerebral arteriovenous malformations (AVMs) entail a significant risk of intracerebral hemorrhage owing to the direct shunting of arterial blood into the venous vasculature without the dissipation of the arterial blood pressure. The mechanisms involved in the growth, progression and rupture of AVMs are not clearly understood, but a number of studies point to inflammation as a major contributor to their pathogenesis. The upregulation of proinflammatory cytokines induces the overexpression of cell adhesion molecules in AVM endothelial cells, resulting in enhanced recruitment of leukocytes. The increased leukocyte-derived release of metalloproteinase-9 is known to damage AVM walls and lead to rupture. Inflammation is also involved in altering the AVM angioarchitecture via the upregulation of angiogenic factors that affect endothelial cell proliferation, migration and apoptosis. The effects of inflammation on AVM pathogenesis are potentiated by certain single-nucleotide polymorphisms in the genes of proinflammatory cytokines, increasing their protein levels in the AVM tissue. Furthermore, studies on metalloproteinase-9 inhibitors and on the involvement of Notch signaling in AVMs provide promising data for a potential basis for pharmacological treatment of AVMs. Potential therapeutic targets and areas requiring further investigation are highlighted.

Treatment of blister-like aneurysms with the pipeline embolization device.

BACKGROUND Endovascular vessel reconstruction with the pipeline embolization device (PED) has become common practice. Data on the safety and efficacy of the PED in blister-like aneurysms (BLAs) are limited. OBJECTIVE To retrospectively present our experience with use of the PED in BLAs. METHODS A total of 8 patients harboring 8 BLAs were treated with the PED at our institution between November 2011 and April 2013. RESULTS Aneurysm size was 2.5 mm on average. Five patients had sustained a subarachnoid hemorrhage (SAH), 1 patient presented with sentinel headaches, and in 2 patients the aneurysm was incidentally discovered. Seven aneurysms arose from the ICA and 1 from the basilar artery. Placement of the PED was successful in all 8 patients. There were no procedural or perioperative complications in any of the patients. At the latest follow-up, all 8 patients achieved a favorable outcome (mRS 0-2). Angiographic follow-up was available for 6 patients at a mean time point of 3.9 months. Follow-up angiography showed 100% aneurysm occlusion in 5 patients and marked decrease in aneurysm size in 1 patient. CONCLUSION The findings of this study suggest that the PED may be a safe and effective treatment for BLAs. Given the limitations of other treatment modalities and the challenging nature of BLAs, flow diversion may be a valuable option for these lesions.

Imaging aspirin effect on macrophages in the wall of human cerebral aneurysms using ferumoxytol-enhanced MRI: preliminary results.

BACKGROUND AND PURPOSE Daily intake of aspirin was shown to decrease human cerebral aneurysm rupture by 60%. The feasibility of imaging macrophages in human cerebral aneurysm walls using ferumoxytol-enhanced MRI has been demonstrated. The goal of the present study is to image aspirin effect on macrophages in the wall of human cerebral aneurysm using ferumoxytol-enhanced MRI. MATERIAL AND METHODS Five patients with known intracranial aneurysms underwent baseline imaging using T2(*) gradient-echo and T1 MRI sequences using ferumoxytol-enhanced MRI 72-hour post-ferumoxytol infusion. Patients then received 81 mg aspirin per os daily. After 3 months, imaging studies were repeated and analyzed by co-registration using a histogram and subtraction of follow-up images from baseline. RESULTS In all five patients, after 3 months of treatment with aspirin, the signal intensity corresponding to the uptake of ferumoxytol by macrophages in the aneurysm wall was less intense than in the baseline images. This was confirmed by co-registration of images using histogram and subtraction of follow-up images from baseline. CONCLUSION These preliminary results suggest the feasibility of imaging aspirin effect on macrophages localized in the wall of human cerebral aneurysm using ferumoxytol-enhanced MRI. The findings provide radiographic evidence of decreased inflammation in human cerebral aneurysms with daily intake of aspirin using macrophages as a surrogate marker for inflammation.

A Single Pipeline Embolization Device is Sufficient for Treatment of Intracranial Aneurysms

BACKGROUND AND PURPOSE: The Pipeline Embolization Device has emerged as an important treatment option for intracranial aneurysms. The number of devices needed to treat an aneurysm is uncertain and is the subject of vigorous debate. The purpose of this study was to compare rates of complications, aneurysm occlusion, and outcome in patients treated with a single-versus-multiple Pipeline Embolization Devices. MATERIAL AND METHODS: One hundred seventy-eight patients were treated with the Pipeline Embolization Device at our institution. Patients were divided into 2 groups: a single-device group (n = 126) and a multiple-device group (n = 52). RESULTS: There was no statistically significant difference between the 2 groups with respect to baseline characteristics except for age and aneurysm size (higher with multiple Pipeline Embolization Devices). Complications occurred more frequently with multiple (15%) versus a single device (5%, P = .03). In multivariate analysis, the use of multiple devices independently predicted complications. A similar proportion of patients achieved adequate aneurysm obliteration at follow-up in the single-device (84%) and the multiple-device groups (87%, P = .8). In multivariate analysis, age and follow-up time predicted obliteration. At follow-up, a significantly higher proportion of patients treated with a single device (97%) achieved a favorable outcome compared with those treated with multiple devices (89%, P = .03). In multivariate analysis, there was a strong trend for the use of a single device to predict favorable outcomes (P = .06). CONCLUSIONS: Treatment with a single Pipeline Embolization Device provides similar occlusion rates with less complications and better overall outcomes. These findings suggest that a single Pipeline Embolization Device is sufficient for treatment of most intracranial aneurysms.

Safety and efficacy of tirofiban in stent-assisted coil embolization of intracranial aneurysms.

BACKGROUND Thromboembolic complications are a major concern in stent-assisted coiling of intracranial aneurysms that may be prevented with adequate antiplatelet therapy. OBJECTIVE To assess the safety and efficacy of tirofiban in stent-assisted coiling. METHODS Two protocols were used. In the initial protocol, tirofiban was administered intravenously as a 0.4 μg/kg per min bolus for 30 minutes followed by 0.10 μg·kg min maintenance infusion. The revised protocol consisted of a 0.10 μg·kg min maintenance infusion alone. RESULTS Sixty-seven patients received tirofiban, 16 under the initial protocol and 51 under the revised protocol. Thirty (44.8%) patients had sustained a subarachnoid hemorrhage (SAH). Tirofiban infusion was initiated after thromboembolic events in 9 (13.4%) patients and prophylactically in 58 (86.6%). Four (6.0%) intracranial hemorrhages were noted. Three (18.8%) intracranial hemorrhages occurred with the initial protocol in patients treated electively and were fatal in 2 (66.7%) cases. The only complication (1.9%) under the revised protocol was a subclinical worsening of the computed tomographic appearance of an SAH. There was no tirofiban-related morbidity or deaths with the revised protocol. Of 9 patients that received tirofiban as a rescue treatment, 7 (77.8%) had complete and 2 (22.2%) had partial arterial recanalization. No thromboembolic events occurred in patients receiving prophylactic tirofiban. CONCLUSION A bolus followed by a maintenance dose of tirofiban appears to have a high risk of cerebral hemorrhage. A maintenance infusion without an initial bolus, however, has an exceedingly low risk of hemorrhage and appears to be very safe and effective, even in the setting of SAH.

Fate of the Ophthalmic Artery After Treatment With the Pipeline Embolization Device.

BACKGROUND Flow diverters have emerged as a major tool in the treatment of cerebral aneurysms. A crucial issue with the use of flow diverters is the patency of side branches covered by the device, most importantly the ophthalmic artery (OA). OBJECTIVE To assess the patency of the OA after coverage with the pipeline embolization device (PED). METHODS All patients who had a PED covering the OA and in whom angiographic follow-up was available were included in the study. The patency of the OA at follow-up was systematically evaluated by 2 authors who were not involved in the procedure. RESULTS Of 95 treated patients, the OA was covered by 1 PED in 81 patients (85%) and by 2 PEDs in 14 patients (15%). Mean angiographic follow-up was 7.5 months, ranging from 3 to 24 months. At the latest follow-up, the OA remained patent in 85 patients (89%), showed diminished flow in 4 patients (4%), and was occluded in 6 patients (7%). Only 1 patient had clinical symptoms related to OA occlusion. In multivariable analysis, larger aneurysm size predicted OA occlusion (P = .04). There was also a strong trend for younger age (P = .06) and coverage by more than 1 device (P = .07). CONCLUSION Treatment of internal carotid artery aneurysms with the PED preserves the patency of the OA in most cases. The occlusion of the OA in the few cases where it occurs is usually a clinically irrelevant event. Minimizing the number of PEDs across the OA is crucial to preserve its patency.