David Kung

Early change in ferumoxytol-enhanced magnetic resonance imaging signal suggests unstable human cerebral aneurysm: a pilot study.

Background and Purpose— The clinical significance of early (ie, within the first 24 hours) uptake of ferumoxytol by macrophages in the wall of human cerebral aneurysms is not clear. The purpose of this study was to determine whether early uptake of ferumoxytol suggests unstable cerebral aneurysm. Methods— Thirty unruptured aneurysms in 22 patients were imaged with magnetic resonance imaging 24 hours after infusion of ferumoxytol. Eighteen aneurysms were also imaged 72 hours after infusion of ferumoxytol. Aneurysm dome tissue was collected from 4 patients with early magnetic resonance imaging signal changes, 5 patients with late signal changes, and 5 other patients with ruptured aneurysms. The tissue was immunostained for expression of cyclooxygenase-1, cyclooxygenase-2, microsomal prostaglandin E2 synthase-1, and macrophages. Results— In 23% (7/30) of aneurysms, there was pronounced early uptake of ferumoxytol. Four aneurysms were clipped. The remaining 3 aneurysms were managed conservatively; all 3 ruptured within 6 months. In 53% (16 of 30) of aneurysms, there was pronounced uptake of ferumoxytol at 72 hours. Eight aneurysms were surgically clipped, and 8 were managed conservatively; none ruptured or increased in size after 6 months. Expression of cyclooxygenase-2, microsomal prostaglandin E2 synthase-1, and macrophages was similar in unruptured aneurysms with early uptake of ferumoxytol and ruptured aneurysms. Expression of these inflammatory molecules was significantly higher in aneurysms with early uptake of ferumoxytol versus aneurysms with late uptake. Conclusions— Uptake of ferumoxytol in aneurysm walls within the first 24 hours strongly suggests aneurysm instability and probability of rupture within 6 months, and may warrant urgent intervention.

Upregulation of Cyclooxygenase-2 (COX-2) and Microsomal Prostaglandin E2 Synthase-1 (mPGES-1) in Wall of Ruptured Human Cerebral Aneurysms : Preliminary Results

Background and Purpose— Cyclooxygenase-2 (COX-2) and Microsomal Prostaglandin E2 Synthase-1 (mPGES-1) catalyze isomerization of the cyclooxygenase product PGH2 into PGE2. Deletion of COX-2/mPGES-1 suppresses carotid artery atherogenesis and angiotensin II-induced aortic aneurysms formation, and attenuates neointimal hyperplasia after vascular injury in mice. The upregulation of COX-2/mPGES-1 in the wall of ruptured human cerebral aneurysms is not known. Methods— Ten patients with intracranial aneurysms (5 ruptured and 5 nonruptured) underwent microsurgical clipping. During the procedure, a segment of the aneurysm dome was resected and immunostained with monoclonal antibodies for COX-1, COX-2, and mPGES-1. A segment of the superficial temporal artery was also removed and immunostained with monoclonal antibodies for COX-1, COX-2, and mPGES-1. Results— All 10 aneurysm tissues stained positive for mPGES-1 monoclonal antibody. Expression of mPGES-1 was more abundant in ruptured aneurysm tissue than in nonruptured aneurysms, based on a semiquantitative grading. None of the superficial temporal artery specimens expressed mPGES-1. COX-2 was upregulated in the same distribution as was mPGES-1. COX-1 was present constitutively in all tissues. Conclusions— COX-2/mPGES-1 are expressed in the wall of human cerebral aneurysms and more abundantly so in ruptured aneurysms than in nonruptured. We speculate that the protective effect of aspirin against rupture of cerebral aneurysms may be mediated in part by inhibition of COX-2/mPGES-1.

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.

Stent-Assisted Coil Embolization of Complex Wide-Necked Bifurcation Cerebral Aneurysms Using the “Waffle Cone” Technique: A Review of Ten Consecutive Cases

Endovascular treatment of complex, wide-necked bifurcation cerebral aneurysms is challenging. Intra/extra-aneurysmal stent placement, the “waffle cone” technique, has the advantage of using a single stent to prevent coil herniation without the need to deliver the stent to the efferent vessel. The published data on the use of this technique is limited. We present our initial and follow-up experience with the waffle cone stent-assisted coiling (SAC) of aneurysms to evaluate the durability of the technique. We retrospectively identified ten consecutive patients who underwent SAC of an aneurysm using the waffle cone technique from July 2009 to March 2011. Clinical and angiographic outcomes after initial treatment and follow-up were evaluated. Raymond Class I or II occlusion of the aneurysm was achieved in all cases with the waffle cone technique. No intraoperative aneurysm rupture was noted. The parent arteries were patent at procedure completion. Clinical follow-up in nine patients (median 12.9 months) revealed no aneurysm rupture. Two patients had a transient embolic ischemic attack at 18 hours and three months after treatment, respectively. Catheter angiography or MRA at six-month follow-up demonstrated persistent occlusions of aneurysms in seven out of eight patients. Another patient had stable aneurysm occlusion at three-month follow-up study. Our experience in the small series suggests the waffle cone technique could be performed on complex, wide-necked aneurysms with relative safety, and it allowed satisfactory occlusions of the aneurysms at six months in most cases.

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

Abstract. 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.

Implementation of an Early Mobility Pathway in Neurointensive Care Unit Patients With External Ventricular Devices

ABSTRACT Background: Patients with an external ventricular drain (EVD) may not be readily mobilized because of concerns of catheter dislodgment and/or inappropriate cerebrospinal fluid drainage. Delayed mobilization may result in longer hospital stays and an increased risk for complications related to immobility. We aimed to determine the safety, feasibility, and outcome of an EVD mobilization protocol in patients with subarachnoid hemorrhage (SAH). Methods: A multidisciplinary group developed a formal algorithm for the mobilization of patients with SAH with EVDs. Outcome measures included intensive care unit (ICU) length of stay (LOS), day to first mobilization, and discharge disposition. Patients were prospectively enrolled during a 12-month period and compared with a historical control group of patients with SAH for the preceding 12-month period. Results: Thirty-nine of 45 (86.7%) patients were women. Mean age did not differ significantly between the preintervention (n = 19) and postintervention (n = 26) groups (59.6 vs 55.7). Number of EVD device days did not differ significantly between groups (16.3 vs 15, P = .422]. Of 101 attempted postintervention mobilization sessions, six were aborted for increased lethargy (1), pain (1), elevated intracranial pressure (1), drain malfunction (1), and hypotension (2). Twenty-four sessions were attempted but never initiated because of worsening neurologic examination (10), pulmonary instability (2), hemodynamic instability (2), medical instability (3), and provider request (1). No patient experienced catheter dislodgment. Mean ICU LOS was not different between groups (20.7 vs 18.2, P = .262). The day of first mobilization was significantly earlier in the postintervention group (18.7 vs 6.5, P < .0001). The percentage of patients discharged home or to acute rehabilitation was higher in the postintervention group (63.2% vs 88.5%, P = .018], when accounting for Hunt and Hess grade. Conclusions: The mobilization of patients with EVDs is safe and feasible; it may be associated with earlier mobilization, reduced ICU LOS, and better discharge disposition. No major complications were attributable to early mobilization.

Plasma ADAMTS13 activity and von Willebrand factor antigen and activity in patients with subarachnoid haemorrhage

Increased von Willebrand factor (VWF) and reduced ADAMTS13 activity are associated with arterial thrombosis. This may also be the culprit mechanism implicated in delayed cerebral ischaemia after aneurysmal subarachnoid haemorrhage (SAH). It was our objective to determine plasma VWF and ADAMTS13 in patients with SAH and healthy subjects; and to explore the levels of those markers and outcome after SAH. Forty consecutive patients were enrolled between September 2007 and April 2014 in a pilot study. Plasma samples were collected from SAH patients on post-bleed day (PBD) 0, 1, 3, 5, 7 and 10 and healthy controls. VWF antigen (VWFAg) and VWF activity (VWFAc) were determined by enzyme-linked immunoassay and collagen binding assay, respectively. ADAMTS13 activity was determined by the cleavage of a fluorescent substrate. Univariate descriptive statistics and cluster analyses were performed based on outcomes in the group with SAH only. Mean age of SAH patients was 52.4 years (26-84 years) and 30 (75 %) were women. 12/40 (30 %) had a high Hunt and Hess grade (IV-V) and 25 (62.5 %) were treated with coil embolisation. Plasma VWFAg and VWFAc were significantly higher in SAH patients than those in healthy subjects on each PBD (p<0.0001). Concurrently, plasma ADAMTS13 activity in SAH patients was significantly lower than that in healthy subjects (p<0.0001). Among those with SAH, cluster analysis demonstrated that patients with higher VWFAg and VWFAc and/or lower ADAMTS13 activity might be at risk of increased mortality. In conclusion, the relative deficiency of plasma ADAMTS13 activity in SAH patients may associate with worse outcome.

Site-specific elevation of interleukin-1β 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-1β 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-1β 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 hunters 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.

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.