Axel J. Rosengart

Prognostic Factors for Outcome in Patients With Aneurysmal Subarachnoid Hemorrhage

Background and Purpose— The purpose of this study was to describe prognostic factors for outcome in a large series of patients undergoing neurosurgical clipping of aneurysms after subarachnoid hemorrhage (SAH). Methods— Data were analyzed from 3567 patients with aneurysmal SAH enrolled in 4 randomized clinical trials between 1991 and 1997. The primary outcome measure was the Glasgow outcome scale 3 months after SAH. Multivariable logistic regression with backwards selection and Cox proportional hazards regression models were derived to define independent predictors of unfavorable outcome. Results— In multivariable analysis, unfavorable outcome was associated with increasing age, worsening neurological grade, ruptured posterior circulation aneurysm, larger aneurysm size, more SAH on admission computed tomography, intracerebral hematoma or intraventricular hemorrhage, elevated systolic blood pressure on admission, and previous diagnosis of hypertension, myocardial infarction, liver disease, or SAH. Variables present during hospitalization associated with poor outcome were temperature >38°C 8 days after SAH, use of anticonvulsants, symptomatic vasospasm, and cerebral infarction. Use of prophylactic or therapeutic hypervolemia or prophylactic-induced hypertension were associated with a lower risk of unfavorable outcome. Time from admission to surgery was significant in some models. Factors that contributed most to variation in outcome, in descending order of importance, were cerebral infarction, neurological grade, age, temperature on day 8, intraventricular hemorrhage, vasospasm, SAH, intracerebral hematoma, and history of hypertension. Conclusions— Although most prognostic factors for outcome after SAH are present on admission and are not modifiable, a substantial contribution to outcome is made by factors developing after admission and which may be more easily influenced by treatment.

Embolism from vertebral artery origin occlusive disease

We report 10 patients with severe occlusive disease of the vertebral artery (VA) origin in the neck with intra-arterial embolism to the posterior circulation. The VA lesions in seven patients were complete occlusions, and three patients had severe atherostenosis. All patients had strokes in the vertebrobasilar territory. The most frequent recipient sites of intra-arterial embolism were the intracranial VA-posterior inferior cerebellar artery region (8), and the distal basilar artery (BA) and its superior cerebellar and posterior cerebral artery branches (7). Two patients had pontine infarction due to BA embolism. The most common clinical signs were due to cerebellar infarction. Atherosclerotic disease of the VA origin has features in common with disease of the internal carotid artery origin. Both have similar risk factors and demography, and each can cause strokes by intracranial intra-arterial embolism.

Outcome in patients with subarachnoid hemorrhage treated with antiepileptic drugs.

OBJECT Prophylactic use of antiepileptic drugs (AEDs) in patients admitted with aneurysmal subarachnoid hemorrhage (SAH) is common practice; however, the impact of this treatment strategy on in-hospital complications and outcome has not been systematically studied. The goal in this study was twofold: first, to describe the prescribing pattern for AEDs in an international study population; and second, to delineate the impact of AEDs on in-hospital complications and outcome in patients with SAH. METHODS The authors examined data collected in 3552 patients with SAH who were entered into four prospective, randomized, double-blind, placebo-controlled trials conducted in 162 neurosurgical centers and 21 countries between 1991 and 1997. The prevalence of AED use was assessed by study country and center. The impact of AEDs on in-hospital complications and outcome was evaluated using conditional logistic regressions comparing treated and untreated patients within the same study center. RESULTS Antiepileptic drugs were used in 65.1% of patients and the prescribing pattern was mainly dependent on the treating physicians: the prevalence of AED use varied dramatically across study country and center (intraclass correlation coefficients 0.22 and 0.66, respectively [p < 0.001]). Other predictors included younger age, worse neurological grade, and lower systolic blood pressure on admission. After adjustment, patients treated with AEDs had odds ratios of 1.56 (95% confidence interval [CI] 1.16-2.10; p = 0.003) for worse outcome based on the Glasgow Outcome Scale; 1.87 (95% CI 1.43-2.44; p < 0.001) for cerebral vasospasm; 1.61 (95% CI 1.25-2.06; p < 0.001) for neurological deterioration; 1.33 (95% CI 1.01-1.74; p = 0.04) for cerebral infarction; and 1.36 (95% CI 1.03-1.80; p = 0.03) for elevated temperature during hospitalization. CONCLUSIONS Prophylactic AED treatment in patients with aneurysmal SAH is common, follows an arbitrary prescribing pattern, and is associated with increased in-hospital complications and worse outcome.

Early Vasospasm on Admission Angiography in Patients with Aneurysmal Subarachnoid Hemorrhage Is a Predictor for In-Hospital Complications and Poor Outcome

Background and Purpose— Early vasospasm (EVSP), defined here as arterial narrowing seen on diagnostic angiography within the first 48 hours of aneurysmal rupture, is a rarely reported and poorly defined phenomenon in patients with subarachnoid hemorrhage (SAH). The purpose of this study was to characterize EVSP in a large database of such patients. Methods— We analyzed the relationship of EVSP to clinical characteristics, in-hospital complications, and outcome at 3 months among 3478 patients entered into 4 prospective, randomized, double-blind, placebo-controlled trials of tirilazad conducted in neurosurgical centers around the world between 1991 and 1997. Results— Three hundred thirty-nine (10%) of 3478 patients had EVSP. EVSP was significantly more likely in patients with poor neurological grade on admission, history of SAH, intracerebral hematoma, larger aneurysm, thick SAH on cranial computed tomography, and intraventricular hemorrhage. EVSP was not associated with delayed cerebral vasospasm. After adjustment for differences in admission characteristics, EVSP was associated with cerebral infarction (adjusted odds ratios [OR]=1.51; 95% CI, 1.18 to 1.94; P=0.001), neurological worsening (OR=1.41; 95% CI, 1.10 to 1.81; P=0.007), and unfavorable outcome (OR=1.51; 95% CI, 1.15 to 2.00; P=0.003). In addition, there was a trend for patients with increasingly severe EVSP to have unfavorable outcome (OR=1.84 for mild and OR=2.66 for moderate/severe EVSP). Conclusions— EVSP was seen in 10% of SAH patients and was predictive of cerebral infarction and neurological worsening as well as unfavorable outcome at 3 months. EVSP was not associated with late vasospasm. EVSP may be as important as delayed vasospasm in predicting complications and long-term morbidity in SAH patients.

Cerebellar infarcts in the New England Medical Center Posterior Circulation Stroke Registry

We report the clinical findings and stroke mechanisms of 63 patients with cerebellar infarcts. We divided the intracranial vertebrobasilar circulation into the proximal territory (P), fed by the intracranial vertebral arteries and their branches; the middle territory (M), fed by the proximal and middle basilar artery and its branches; and the distal territory (D), fed by the rostral basilar artery and its branches. Cerebellar infarcts were classified by vascular territories P, M, D, P&D, and middle-plus (P&M, M&D, and P&M&D). Patients with P infarcts (11 patients) frequently had vertigo, gait instability, limb ataxia, and headache, whereas patients with D infarcts (15 patients) most often had limb ataxia, gait instability, and dysarthria. Patients with P&D infarcts (17 patients) had signs and symptoms of both groups combined. Infarcts in which the middle territory was involved, either alone (three patients) or combined with other territories (17 patients) were dominated by brainstem signs and symptoms. The predominant stroke mechanisms in the P, D, and P&D groups were embolic due to intra-arterial or cardiac embolism. When the M territory was involved, either alone or with P, D, or P&D territories, stroke mechanisms were more varied, and there was often large-artery occlusion with hemodynamic ischemia.

Encapsulation and release of plasminogen activator from biodegradable magnetic microcarriers.

There are a number of therapies available to recanalize occluded arteries. However, even though proven beneficial, these approaches are not without significant shortcomings. Previous research showed that by encapsulating therapeutic thrombolytic enzymes in liposomic formulations, the reperfusion times in vivo were significantly lower than for administration of free thrombolytic. Like liposomes, biodegradable, diblock polymers of poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) have been shown to have therapeutic benefit as delivery vehicles for a variety of drug delivery concepts. We report on new formulations based on tissue plasminogen activator (tPA) encapsulated in magnetic, PLA-PEG microcarriers. We studied the tPA encapsulation efficiency, loading, and release after varying the molecular weight of polymer, carrier size, tPA solution composition, and use of ultrasound to enhance release. We loaded 3.3-9.4wt% tPA and 12-17wt% magnetite into the carriers, depending on the exact formulation. The release of tPA was complete 20min after reconstitution. Ultrasound insonation failed to enhance tPA release rates in smaller carriers but significantly enhanced release in larger carriers. With these formulations, we should be able to achieve lytic concentrations if we can magnetically concentrate 5mg of carrier within about 11ml of blood volume near the clot.

Intraventricular hemorrhage from ruptured aneurysm: clinical characteristics, complications, and outcomes in a large, prospective, multicenter study population

OBJECT In this study the authors analyzed the relationship of intraventricular hemorrhage (IVH) to in-hospital complications and clinical outcome in a large population of patients with aneurysmal subarachnoid hemorrhage (SAH). METHODS Data from 3539 patients with aneurysmal SAH were evaluated, and these data were obtained from four prospective, randomized, double-blind, placebo-controlled trials of tirilazad that had been conducted between 1991 and 1997. Clinical characteristics, in-hospital complications, and outcome at 3 months post-SAH (Glasgow Outcome Scale score) were analyzed with regard to the presence or absence of IVH. RESULTS Patients with SAH and IVH differ in demographic and admission characteristics from those with SAH but without IVH and are more likely to suffer in-hospital complications and a worse outcome at 3 months post-SAH. CONCLUSIONS The presence of IVH in patients with SAH has an important predictive value with regard to these aspects.

Quantitative real-time in vivo detection of magnetic nanoparticles by their nonlinear magnetization

A novel method of highly sensitive quantitative detection of magnetic nanoparticles (MP) in biological tissues and blood system has been realized and tested in real time in vivo experiments. The detection method is based on nonlinear magnetic properties of MP and the related device can record a very small relative variation of nonlinear magnetic susceptibility up to 10−8 at room temperature, providing sensitivity of several nanograms of MP in 0.1ml volume. Real-time quantitative in vivo measurements of dynamics of MP concentration in blood flow have been performed. A catheter that carried the blood flow of a rat passed through the measuring device. After an MP injection, the quantity of MP in the circulating blood was continuously recorded. The method has also been used to evaluate the MP distribution between rat’s organs. Its sensitivity was compared with detection of the radioactive MP based on isotope of Fe59. The comparison of magnetic and radioactive signals in the rat’s blood and organ samples demon...

Intermittent downbeat nystagmus due to vertebral artery compression

Downbeat nystagmus (DBN) uncommonly occurs as a transient phenomenon, and it rarely occurs in patients with cerebrovascular disease. We observed a patient with intermittent DBN and lightheadedness due to transient obstruction of his dominant vertebral artery when he turned his head to his left side. Surgical removal of an osteophyte at the site of the angiographically demonstrated lesion relieved his symptoms

Capture of magnetic carriers within large arteries using external magnetic fields

Our overall research goal is to advance the safety and effectiveness of acute ischemic stroke therapy by improving the benefit/risk ratio of thrombolysis and hence, the long-term outcome of acute ischemic stroke victims. Our approach is the development of a novel tissue plasminogen activator (t-PA) delivery system based on t-PA-loaded magnetic nano- and microcarriers guided directly to the site of vascular occlusion by external magnetic fields. Such a t-PA delivery system would conveniently combine the advantages of both intravenous (systemic) and intraarterial (catheter-facilitated) thrombolysis: non-invasiveness—the magnetic t-PA carriers can be injected intravenously and targeted, as drug delivery is magnetically guided to and t-PA focally released at and within the vascular clot to induce lysis. The focus of our discussion are the two necessary, fundamental and interrelated bioengineering steps: the research and development of well-characterized, biocompatible, functionally active and t-PA-loaded (encapsulated) magnetic nano- and microcarriers able to induce effective thrombolysis, and the design of magnetic guidance systems for targeted tPA-delivery allowing also the triggered release of the thrombolytic agent at the clot site. In this paper, we theoretically demonstrated magnetic trapping of blood borne magnetic nano- and microcarriers from human large vessels, especially arteries. Then, some preliminary experiments using primate models (monkeys) were done to identify successful in vivo sequestration of magnetic carriers in large and smaller arterial branches after arterial upstream and systemic venous injection. Histology (hematoxylin–eosin stain) verified intraarterial carrier concentration (identified as black carrier agglomerates on H and E staining) at the arterial region above the surface magnet. The results revealed the feasibility of magnetic drug-targeting at arteries and solidified the proposed t-PA delivery system.