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PubMed2001

Comparison of TNK with wild-type tissue plasminogen activator in a rabbit embolic stroke model.

BACKGROUND AND PURPOSE: Tissue plasminogen activator (tPA) is an effective treatment for stroke, but its utility is limited by fear of cerebral hemorrhage. Tenecteplase (TNK), a genetically modified form of wild-type tPA, exhibits a longer biological half-life and greater fibrin specificity, features that could lead to fewer cerebral hemorrhages than wild-type tPA in stroke patients. METHODS: We injected radiolabeled blood clots into the cerebral circulation of New Zealand White rabbits. One hour later, we administered tPA (n=57), 0.6 mg/kg TNK (n=43), 1.5 mg/kg TNK (n=27), or vehicle control (n=37). A blinded observer examined the brains for macroscopic hemorrhage using a semiquantitative score. We estimated thrombolysis by assessing the amount of radiolabel remaining in the cerebral vessels postmortem. RESULTS: Both wild-type tPA and TNK caused thrombolysis in most subjects. Hemorrhage was detected in 26% (6/23) of the control group, 66% (27/41) of the wild-type tPA group, 55% (16/29) in the 0.6-mg/kg TNK group, and 53% (9/17) in the 1.5-mg/kg TNK group (P:<0.05, chi(2) test). The tPA group was statistically significantly different from the control group, but the TNK and tPA groups did not differ from each other. Neither TNK nor tPA affected the size of the hemorrhages. CONCLUSIONS: TNK shows comparable rates of recanalization compared with wild-type tPA in a model of embolic stroke. While tPA increases hemorrhage rate, the hemorrhage associated with TNK treatment is not statistically different compared with controls or the tPA group. These findings suggest that TNK shows promise as an alternative thrombolytic treatment for stroke, but we could not demonstrate improved safety compared with wild-type tPA.

Animals↗
PubMed1991

Tissue plasminogen activator plus glutamate antagonist improves outcome after embolic stroke.

Thrombolytic therapy is likely to be effective in some patients with stroke, but further improvements may require combination treatment with neuroprotective agents that can be given rapidly with relative safety. We tested the effects of tissue plasminogen activator (t-PA) with the glutamate antagonist MK-801 or the calcium channel blocker nimodipine in an embolic stroke model. We found that MK-801, followed by t-PA, was more effective than t-PA alone in reducing neurologic damage. Nimodipine plus t-PA was not better than t-PA alone. Combined glutamate antagonist and thrombolytic therapy may provide increased efficacy and safety for stroke treatment.

Animals↗
PubMed2005

Functional recovery in aged and young rats after embolic stroke: treatment with a phosphodiesterase type 5 inhibitor.

BACKGROUND AND PURPOSE: Advanced age is associated with a decrease in brain plasticity compared with the young adult. Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor promotes brain plasticity and improves functional outcome after stroke in the young animal. Here, we test the hypothesis that sildenafil provides restorative therapeutic benefit to the aged animal. METHODS: Male Wistar rats (aged, 18-month old; young, 3-month old) were subjected to embolic stroke. Saline or sildenafil was administered daily at a dose of 2 mg/kg orally or 10 mg/kg subcutaneously for 7 consecutive days starting 24 hour after stroke onset. RESULTS: Aged rats exhibited significant impairment of functional recovery and reductions of vascular density, and endothelial cell proliferation compared with young rats. Aged rats treated with sildenafil at a dose of 10 mg/kg but not 2 mg/kg, showed significant improvements of functional recovery and concomitant increases in cortical cyclic guanosine 3',5'-cyclic monophosphate (cGMP) level, vascular density, endothelial cell proliferation, and synaptogenesis compared with aged rats treated with saline. In young rats, treatment with sildenafil at a dose of 2 or 10 mg/kg significantly enhanced functional recovery and amplified brain plasticity compared with young rats treated with saline. CONCLUSIONS: Age is associated with reduction of angiogenesis, and poor neurological functional recovery after stroke. However, treatment of aged stroke rats with sildenafil improves functional recovery that is likely fostered by enhancement of angiogenesis and synaptogenesis.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2006

Memantine, an uncompetitive low affinity NMDA open-channel antagonist improves clinical rating scores in a multiple infarct embolic stroke model in rabbits.

The blockade of NMDA receptors has been pursued as a strategy to reduce the consequences of acute ischemic stroke (AIS) and NMDA receptors remain a valid therapeutic target to treat AIS. Because the pharmacological and toxicity profile of memantine in Alzheimer's disease patients appears to be good, we determined whether memantine would be effective at improving behavioral performance following embolic strokes in rabbits. For these studies, we used a rabbit multiple infarct ischemia model with a well-defined behavioral endpoint. In this study, memantine dissolved in PBS was given intravenously either as a bolus injection (over 1 min) or infused over 60 min. The P(50) of the control groups measured 24 h after embolization were 1.12 +/- 0.18 mg and 1.08 +/- 0.23 mg for the bolus injected and infused groups, respectively. Bolus injections of memantine at 1 mg/kg and 10 mg/kg were not effective at altering the P(50) value and memantine at a dose of 25 mg/kg was lethal. However, slowly infused memantine (25 mg/kg) significantly increased the P(50) value to 2.31 +/- 0.48 mg and 3.13 +/- 1.13 mg when given 5 and 60 min following embolization, respectively. Memantine administered 180 min following embolization also increased the P(50) value to 2.69 +/- 2.21 mg, but the response was variable. These results suggest that uncompetitive NMDA antagonists, more specifically open channel blockers, which may be alternatives to high affinity NMDA antagonists, may have substantial therapeutic benefit for the treatment of AIS and memantine or new dual activity analogs of memantine should be further pursued as a useful therapy to treat the behavioral deficits associated with multiple-infarct ischemia.

Animals↗
PubMed1997

Diffusion-weighted magnetic resonance imaging characteristics of hemorrhagic transformation in experimental embolic stroke.

Diffusion-weighted magnetic resonance imaging (MRI) can detect ischemia within minutes of onset, but its ability to reliably detect hyperacute cerebral hemorrhage is unknown. The present study characterized diffusion-weighted, T2-weighted, and contrast-enhanced T1-weighted MRI appearances of hemorrhagic transformation within 5 hours of onset in experimental embolic stroke. Apparent diffusion coefficients and MRI signal characteristics were noted within corresponding regions of hemorrhage observed on gross pathology. Apparent diffusion coefficients were significantly increased within hemorrhagic lesions, but were still within the expected range for bland ischemia. The appearance of the hemorrhagic lesions on diffusion-weighted MRI was also very heterogeneous and not very useful for clinical screening. Other MRI modalities should be investigated, but computed tomography remains the only widely available clinical method of reliably detecting cerebral hemorrhage.

Analysis of Variance↗
PubMed1998

Severely reduced left atrial appendage function: a cause of embolic stroke in patients in sinus rhythm?

Recently, attention has been focused on transesophageal echocardiographic detection of left atrial appendage function to assess of risk of thrombus formation because of potential benefit of anticoagulation therapy. However, most of these studies have been conducted in patients with atrial fibrillation or mitral valve disease. In this article we review cases of 2 patients without valvular disease who had embolic stroke in sinus rhythm. Transesophageal echocardiography revealed thrombi in the left atrial appendage in both patients. The left atrial appendage function in these patients was compared with that in patients with chronic atrial fibrillation and a control group in sinus rhythm. Left atrial appendage function in the patients with stroke and sinus rhythm was significantly lower than that of patients in the control group in sinus rhythm (P < .001) and was similar to the appendage function in patients with chronic atrial fibrillation. These observations provide further evidence that the finding of reduced left atrial appendage function can be a cause of stroke in patients with sinus rhythm even in the absence of mitral valve disease. Reduced left atrial appendage function may identify patients with unexplained stroke who should receive anticoagulation therapy even in the absence of detectable appendage thrombi.

Adult↗
PubMed1986

Association of embolic stroke in pregnancy with the lupus anticoagulant. A case report.

Recently the association of recurrent spontaneous abortions and intrauterine fetal death was linked to the lupus anticoagulant (LA). LA is an immunoglobulin directed against phospholipid, causing characteristic changes in coagulation tests, and is associated with an increased risk of thrombosis. We treated a pregnant woman who presented with an embolic stroke and laboratory evidence of LA.

Adult↗
PubMed2003

Successful treatment of pacemaker related endocarditis with acute embolic stroke without device removal.

Pacemaker related endocarditis is a rare potentially fatal condition, most commonly acquired during manipulation of the pacemaker system. Most patients have involvement of the right heart. Only rarely has involvement of the left-heart been documented. In the absence of controlled studies regarding management of such cases, many recommend complete removal of the pacing system along with intravenous antibiotics. We present a patient with documented pacemaker related left-sided endocarditis associated with an acute embolic stroke who was treated with antibiotics with complete recovery and its two-year follow up.

Aged↗
PubMed1989

The effects of a new tissue plasminogen activator analogue, Fb-Fb-CF, on cerebral reperfusion in a rabbit embolic stroke model.

Early fibrinolytic therapy with full molecular tissue plasminogen activator (t-PA) has been observed to be both angiographically and clinically effective when employed in animal stroke models. Preliminary clinical trials with t-PA are in progress. It is possible to refine t-PA by developing fragments or analogues of the drug. Using recombinant DNA technology in the Escherichia coli system, a t-PA analogue consisting of the catalytic fragment of t-PA and a dimer of the B fragment of staphylococcal protein A (Fb-Fb-CF) has been produced. Because this analogue has a long serum half-life of 90 minutes, we employed Fb-Fb-CF in a rabbit cerebral embolic stroke model to assess its efficacy as a reperfusion agent. When given as a bolus to 10 animals 15 minutes after embolization, Fb-Fb-CF produced angiographic cerebral reperfusion in 48 +/- 21 minutes (+/- SD), while in 8 saline-treated controls, reperfusion was not observed at 180 minutes in any animal (p less than 0.01). In another experiment reperfusion was demonstrated at 66 +/- 32 minutes in 11 animals treated with Fb-Fb-CF 90 minutes after embolization as compared with 100 +/- 25 minutes in 12 saline-treated controls (p less than 0.01). A small macroscopic hemorrhage within an infarct was seen in 1 Fb-Fb-CF-treated animal in the 15-minute experiment and in none of the controls. In the 90-minute experiment, macroscopic hemorrhagic infarction was seen in 4 Fb-Fb-CF-treated animals and in 3 controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Delayed treatment with a t-PA analogue and streptokinase in a rabbit embolic stroke model.

Fibrinolytic therapy may be effective in the treatment of ischemic stroke, and clinical trials are under way. We evaluated two fibrinolytic agents, an analogue of tissue plasminogen activator (Fb-Fb-CF, the catalytic fragment of the tissue plasminogen activator molecule with a prolonged serum half-life, n = 10) and streptokinase (n = 7), in a rabbit model of embolic stroke. Both agents were given 3 hours after stroke onset, a time relevant to the clinical setting. Fb-Fb-CF was significantly better (p less than 0.04) than saline (n = 7) in restoring blood flow to previously occluded intracranial arteries, but streptokinase was ineffective. Neither fibrinolytic agent was associated with a substantial risk for intracerebral hemorrhagic side effects. Our study demonstrates that Fb-Fb-CF can safely and effectively reperfuse rabbit intracranial arteries 3 hours after occlusion, while streptokinase does not.

Animals↗
PubMed2000

[A cardiac embolic stroke due to malposition of the pacemaker lead in the left ventricle. A case report].

Misplacement of a permanent pacemaker lead has been described in several locations but rarely in the left ventricle. Less commonly, as described in our report, malposition may occur when the lead perforates the interatrial septum and extends across the left atrium and through the mitral valve into the left ventricle. The actual incidence of this pacemaker complication is unknown. Consequences may include perforation and systemic or cerebral thromboembolic events. We report the case of a patient with unintentionally misplaced left heart pacemaker lead admitted for neurological symptoms consistent with embolic stroke. The patient was on aspirin when symptoms occurred. The lead misplacement was not recognized at the time of implantation. Pacing threshold was normal. A 12-lead electrocardiogram showed right bundle branch block configuration paced complexes. By two-dimensional and transesophageal echocardiography, the pacemaker lead was carefully evaluated. The pacemaker lead crossed the interatrial septum, the left atrium, the mitral valve to be implanted in the left ventricular endocardium. To avoid the risk of future embolization, it was felt that the lead should be removed and right ventricular pacing established, once anticoagulation treatment was initiated. Successful percutaneous lead replacement was accomplished without sequelae. Measures to avoid lead misplacement are suggested.

Electrodes↗
PubMed1991

Recurrent embolic stroke and cocaine-related cardiomyopathy.

Ischemic stroke temporally related to cocaine abuse has become increasingly common in young adults. Despite this relation, however, the pathogenesis of infarction in many of these patients remains obscure. I report the case of a 39-year-old man who developed occlusion of the frontopolar branches of the left middle cerebral artery 1 hour after intravenous cocaine use. Eleven days later he developed occlusion of the superior division of the right middle cerebral artery. In this case the mechanism of infarction was clearly cardiogenic embolization. Chest radiograph and echocardiogram revealed dilated cardiomyopathy with left ventricular thrombi. No cause other than cocaine abuse was found for his cardiomyopathy. This is the second reported case of cocaine-related cardiomyopathy presenting as embolic stroke and associated with intracavitary thrombus. Such an association may be more common than previously thought. Thorough cardiac evaluation in all patients with ischemic stroke related to cocaine abuse is appropriate.

Adult↗
PubMed1980

Experimental embolic stroke in the guinea pig (Cuvis cobaya).

Because of the demonstrated suitability of the guinea pig (Cuvis cobaya) for a large variety of laboratory investigations, we sought to develop a stroke model in this animal. Many ingenious stroke models in other animals exist; some depend on anomalous anatomy, others utilize methods of intracranial or extracranial vascular occlusion and yet others combine ischemia and anoxic damage (1-14). As one proposed application for this work was to study immune responses following experimental stroke, survival of several days after cerebral infarction was a requirement. Three to five days elapse before detection of a hymoral and cellular immune response is possible. The guinea pig is especially suited to immunological studies because of the enormous amount of accumulated data on the immunology of this animal. However, the guinea pig has proved relatively invulnerable to existing small animal techniques. Moreover the unacceptably short postoperative survival associated with the use of existing techniques necessitated the development of a new procedure. We have successfully pursued the development of an embolic stroke procedure applicable to this animal.

Animals↗
PubMed2003

Microvascular Basal lamina damage after embolic stroke in the rat: relationship to cerebral blood flow.

Microvascular basal lamina damage has been demonstrated after balloon occlusion of the middle cerebral artery in the nonhuman primate and after intravascular filament occlusion in the rat. The aim of the present study was to investigate in the rat whether microvascular damage can be found in the stroke model of intracarotid clot injection as early as 3 hours after clot injection and whether microvascular damage relates to the level of regional cerebral blood flow (rCBF). Microvascular densities and total stained microvascular areas were determined by immunohistochemistry of collagen type IV in cortex and basal ganglia and automatic video-imaging analysis. rCBF was measured by autoradiography in the same brain areas. Compared with the corresponding areas in the nonischemic hemisphere, a significant loss of microvascular density (-16%) and total stained microvascular areas (-10%) was observed in these areas. The reduction of microvascular basal lamina staining was comparable in all animals and was not related to the value of rCBF when measured 3 hours after onset of embolic stroke. In conclusion, microvascular damage occurs as soon as 3 hours after intracarotid clot injection, even in brain areas in which rCBF has returned to normal values.

Animals↗
PubMed2005

Recurrent embolic strokes and cardiac valvular disease in a patient with non-small cell adenocarcinoma of lung.

The etiology and mechanisms of stroke could differ in cancer compared to non-cancer patients due to altered blood coagulability and/or non-bacterial thrombotic endocarditis (NBTE). These conditions could be either missed by using inappropriate diagnostic methods or misinterpreted. For instance, certain techniques (transthoracic echocardiography, TTE) may provide false-negative results and delay appropriate therapy. On the other hand, these patients, by having atypical findings, may challenge the differential between bacterial and sterile valvular heart disease. Cerebrovascular disease in cancer patients is often aggressive with tendency to recurrent events and rapid neurological devastation. Timely diagnosis is crucial. Current treatment approach to NBTE includes anticoagulation. We report a case of multiple embolic strokes in a patient diagnosed with lung cancer. Primary and secondary stroke prevention is discussed with relevant review of the literature.

Aged↗
PubMed2001

Therapy of postoperative stroke: report of intra-arterial thrombolysis of a hyperacute embolic stroke 5 days following CABG.

Intra-arterial (IA) recombinant tissue plasminogen activator (rt-PA) is an investigational treatment for acute stroke. We report a case of IA thrombolysis of a hyperacute middle cerebral artery stroke 5 days after coronary artery bypass graft surgery. Despite a serious extracranial bleeding complication (hemothorax), immediate thrombolysis with IA rt-PA led to near complete resolution of the neurological deficit and a favorable outcome.

Aged↗
PubMed2001

[Thrombotic or embolic stroke?].

BACKGROUND: Transoesophageal echocardiography reveals a possible source of embolism in many patients who present with acute brain ischaemia. The aim of this study was to observe the prevalence of possible sources of embolism in a representative Norwegian stroke population in a county hospital with a defined reference population. METHODS: All 103 patients with ischaemic stroke or transient ischaemic attack admitted to our hospital during a five-month period were enrolled. We performed transthoracic echocardiography in 98 patients, transoesophageal echocardiography in 83, and Doppler examination of the precerebral arteries in 92. RESULTS: Mean patient age was 72 years; 19 patients had atrial fibrillation. Examinations revealed 70 potential sources of embolism in 55 patients. Twenty-eight findings were in the heart. Five patients had thrombi in left-sided heart chambers. Ten patients had patent foramen ovale; 11 had atrial septal aneurysm; four had both. Thirty-three had atheromas of the aorta with a protrusion of more than 4 mm, ten of them with mobile elements. Nine patients had carotid stenosis of high grade or carotid occlusion ipsilateral to a hemispheric stroke. INTERPRETATION: Potential precerebral sources of embolism are common in a representative population of patients with ischaemic stroke. Atheromas of the aorta may be an important contributor to brain ischaemia.

Aged↗