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PubMed1999

Effects of citicoline combined with thrombolytic therapy in a rat embolic stroke model.

BACKGROUND AND PURPOSE: We sought to evaluate the effects of the combination of cytidine-5'-diphosphocholine (citicoline) and thrombolysis on infarct size, clinical outcome, and mortality in a rat embolic stroke model. METHODS: Eighty-three Sprague-Dawley rats were embolized in the carotid territory with a single fibrin embolus and randomly assigned to the following treatment groups: (1) control (saline), (2) citicoline 250 mg/kg, (3) citicoline 500 mg/kg, (4) recombinant tissue plasminogen activator (rtPA) 5 mg/kg, (5) rtPA 5 mg/kg plus citicoline 250 mg/kg, and (6) rtPA 5 mg/kg plus citicoline 500 mg/kg. rtPA was administered as a continuous intravenous infusion over 45 minutes starting 45 minutes after embolization; citicoline was given intraperitoneally 30 minutes and 24, 48, and 72 hours after embolization. At 96 hours, the brains were fixed and stained by hematoxylin-eosin, and infarct volumes were measured. Neurological scores were determined daily. RESULTS: The median infarct size, measured as percentage of the affected hemisphere, in the control group was 37% (interquartile range, 26% to 69%) compared with 22% (5% to 52%; P=NS) in group 2, 11% (5% to 34%; P=NS) in group 3, 24% (12% to 31%; P=NS) in group 4, 11% (3% to 22%; P=0.02) in the combined group 5, and 19% (9% to 51%; P=NS) in group 6. The infarct size was significantly reduced in the combined citicoline+rtPA-treated groups to a median of 13% (5% to 30%; P<0.01). Citicoline 500 mg/kg and citicoline combined with rtPA also promoted functional recovery. CONCLUSIONS: These results demonstrate that the combination of low-dose citicoline and rtPA significantly reduced infarct size in this focal ischemia model.

Animals↗
PubMed2003

Left atrial appendage aneurysm presenting with recurrent embolic strokes.

A case of left atrial appendage aneurysm is described in a 40-year-old man, who presented with recurrent embolic strokes and was asymptomatic until the last 6 months. Chest X-ray revealed a slightly prominent upper left heart border. The diagnosis was made by transthoracic two-dimensional echocardiography and confirmed by transesophageal echocardiography, magnetic resonance imaging and also by surgery.

Adult↗
PubMed2003

Reappraisal of early CT signs to predict the arterial occlusion site in acute embolic stroke.

OBJECTIVE: To elucidate the value of early computed tomographic (CT) signs of stroke in predicting the occlusion site in the cerebral arteries. PATIENTS: 105 consecutive patients with acute embolic stroke affecting the anterior circulation. METHODS: Four early signs were evaluated on cranial CT within six hours of stroke onset: loss of the insular ribbon (LIR); attenuation of the lentiform nucleus (ALN); hemispherical sulcus effacement (HSE); and the hyperdense middle cerebral artery sign (HMCAS). The arterial occlusion site was definitively identified on cerebral angiography within two hours of the CT examination. RESULTS: LIR was present in 55% of patients with internal carotid artery occlusion. ALN was present in 65% of patients with occlusion of the sphenoidal portion (M1) of the middle cerebral artery. HSE was present in 47% of patients with middle cerebral artery branch occlusion. LIR was related independently to internal carotid artery occlusion (odds ratio (OR) 2.8 (95% confidence interval, 1.2 to 6.8)), ALN to M1 occlusion (OR 2.9 (1.2 to 7.4)), and isolated HSE without ALN or LIR to branch occlusion (OR 12.8 (3.2 to 51.5)). The combined presence of the three signs was indicative of internal carotid artery occlusion (p < 0.05), and the presence of ALN and LIR without HSE was indicative of M1 occlusion (p < 0.05) by univariate analysis. HMCAS bore no relation to either arterial occlusion site. CONCLUSIONS: LIR, ALS, HSE, and combinations of these were useful predictors of the arterial occlusion site.

Adult↗
PubMed2005

Interatrial block as a predictor of embolic stroke.

Interatrial block (IAB), defined as a prolonged (>/=110 ms) P wave, is remarkably prevalent in general hospital populations and is associated with an enlarged, poorly contractile left atrium. The investigators sought to determine whether there is an increased incidence of IAB in patients with embolic strokes. Patients' medical records were reviewed for evidence of embolic cerebrovascular events and IAB. One hundred four patients were identified. In 61 patients in normal sinus rhythm, 49 (80%) had IAB. This was almost twice the prevalence of 2 previous studies (41% and 47%). Therefore, IAB may represent a new risk factor for stroke.

Adult↗
PubMed2000

A case of left atrial appendage thrombus with embolic stroke in association with aortic stenosis in sinus rhythm.

Although left atrial appendage (LAA) thrombus formation in the presence of sinus rhythm may potentially be the source for embolic events in various types of heart disease, no cases of LAA thrombus with embolic stroke in association with aortic stenosis in sinus rhythm have been reported. We present a case of valvular aortic stenosis with cerebral embolism in a person who was in sinus rhythm and had an LAA thrombus diagnosed by transesophageal echocardiography.

Aortic Valve Stenosis↗
PubMed1993

Optimized thrombolysis of cerebral clots with tissue-type plasminogen activator in a rabbit model of embolic stroke.

The dose-dependent effects of tissue-type plasminogen activator (t-PA) on the kinetics of cerebral clot lysis in a rabbit model of middle cerebral artery embolic stroke were investigated. The clots were formed in vitro and tagged with 99Tc for gamma-scintigraphic imaging. After embolization, groups of animals were treated with t-PA. Dose-response curves for the t-PA were generated, and in addition, long and short dosing schedules were assessed. The optimal doses for frequency and rate of cerebral clot lysis in this model are approximately 6.3 mg/kg given over 2 hr or 3.3 mg/kg given over 30 min. These dosing regimens for t-PA were accompanied by approximately 50% consumption of plasma plasminogen, fibrinogen and alpha 2-antiplasmin. Doses of t-PA on either side of this optimum caused attenuation in both the frequency and rate of cerebral clot lysis. Treatment with t-PA under either dosing regimen did not augment the frequency of hemorrhagic transformation, but the size of the resultant hemorrhage in those animals where intracranial bleeding occurred was reduced by 3.3 mg/kg t-PA given over 30 min.

Animals↗
PubMed2002

Effects of nonpeptide V(1) vasopressin receptor antagonist SR-49059 on infarction volume and recovery of function in a focal embolic stroke model.

BACKGROUND AND PURPOSE: Cerebral edema develops very early after the onset of focal cerebral ischemia and may be a major factor in early disability after an acute ischemic stroke. There have been very limited studies on the usefulness of antiedemic agents as neuroprotective agents in the setting of focal cerebral ischemia. We tested the neuroprotective effects of a new potent nonpeptide vasopressin receptor V(1) antagonist, SR-49059, in a focal embolic stroke model in rats. METHODS: Focal ischemic injury was induced by embolizing a preformed clot into the middle cerebral artery (MCA). Infarction volume was measured at 48 hours after the MCA occlusion. Neurological deficits, ischemic brain edema, seizure activity, and mortality and hemorrhage rates were also documented. RESULTS: Treatment with SR-49059 (2 mg/kg), initiated immediately after MCA occlusion, significantly reduced infarction volume (P<0.05) measured at 48 hours after the arterial occlusion. In animals in which the treatment was delayed for 1 hour after MCA occlusion, infarction volume was also reduced significantly (P<0.05). Infarction volume in the rats that received the drug at 3 or 6 hours after MCA occlusion was not different from that in the vehicle-treated group. Treatment with SR-49059, when started early after the arterial occlusion, also reduced neurological deficits and ischemic brain edema. Injection of drug at a higher dose (30 mg/kg) also reduced infarction volume and improved functional recovery but was not superior to the lower dose (2 mg/kg) when the drug was administrated at 1 hour after MCA occlusion. CONCLUSIONS: Our data show that the selective vasopressin receptor antagonist SR-49059 is a potent neuroprotective agent when used early after onset of arterial occlusion in an embolic focal ischemia model in rats. Further studies are needed in stroke models to better understand its neuroprotective properties when used alone or in combination with thrombolysis.

Animals↗
PubMed2005

Embolic stroke with a patent foramen ovale and Behcet's disease.

We report a case of a 53-year-old man with Behcet's disease (BD) and paradoxical stroke. This patient suddenly developed sensory aphasia, right oculomotor palsy, nystagmus, and left ataxic hemiparesis. MR images showed fresh embolic infarcts in the midbrain and the left parietotemporal lobe. He presented with uveitis, oral aphthous ulcers and genital ulcers. An electrocardiogram revealed no abnormalities, and a transesophageal echocardiogram disclosed a patent foramen ovale. Since venous involvement is common in BD, we suspected the presence of smaller thrombi probable in this patient. We conclude that embolic stroke is a notable complication of BD with right-to-left shunting.

Anticoagulants↗
PubMed1987

Anticoagulants in the prevention of embolic stroke. Part I.

Cardiac lesions among those at high risk of cerebral emboli include: atrial fibrillation, rheumatic mitral valve disease, acute myocardial infarction, prosthetic heart valves, and idiopathic dilated cardiomyopathy. Many of these patients can be protected from cerebral infarction by anticoagulants. Following a cardiac embolic stroke, CT scans are critical in deciding for whom and at what time anticoagulation should be considered. From studies of CT and cerebrovascular pathology, it has become clear that it is the cerebral infarct rather than the arterial occlusion that provides the key piece of information in deciding whether and when anticoagulants should be considered for the secondary prevention of cardiac emboli among patients who present with a clinical stroke.

Aged↗
PubMed2002

Monteplase reduces infarct volume and hemorrhagic transformation in rat model of embolic stroke.

Monteplase, a modified recombinant tissue plasminogen activator (rt-PA), has a long half-life and reduces binding to plasminogen activator inhibitor. In this study we investigated whether its systemic administration reduces infarct volume without increasing the risk of intra-cerebral hemorrhage. The effect of the drug was tested on an embolic stroke rat model that uses white clots. Thirty minutes after clot embolization, rats were infused with 2.2 mg kg(-1) of monteplase or the same amount of saline, over 60 min. Relative regional cerebral blood flow had recovered 60 min after monteplase administration and infarct volume was significantly smaller 24 h after clot embolization in the monteplase-treated rats (47.0 mm3) than in the saline-treated rats (130.4 mm3). Also, the hemorrhagic transformation area was significantly smaller in monteplase-treated rats (0.8 mm2 vs. 18.0 mm2, respectively). These results indicate monteplase can be a promising thrombolytic agent for treatment of the acute stage of cerebral ischemia.

Animals↗
PubMed2002

Adjuvant treatment with neuroserpin increases the therapeutic window for tissue-type plasminogen activator administration in a rat model of embolic stroke.

BACKGROUND: After stroke, the thrombolytic effect of tissue-type plasminogen activator (tPA) in the intravascular space is beneficial, whereas its extravascular effect on ischemic neurons is deleterious. We tested the hypothesis that neuroserpin, a natural inhibitor of tPA, reduces tPA-induced neuronal toxicity and increases its therapeutic window for treatment of embolic stroke. METHODS AND RESULTS: Rats were subjected to embolic middle cerebral artery occlusion (MCAO). Ischemic brains were treated with neuroserpin in combination with recombinant human tPA (n=7), tPA alone (n=7), or saline (n=9). Neuroserpin (20 micro L of 16 micro mol/L active neuroserpin) was intracisternally injected 3 hours and tPA (10 mg/kg) was intravenously administered 4 hours after ischemia. MRI measurements were performed to study blood brain barrier (BBB) leakage and ischemic lesion volume. Administration of tPA alone 4 hours after ischemia significantly (P<0.05) increased BBB leakage in the ischemic core measured by Gd-DTPA-enhanced MRI compared with rats treated with saline. However, treatment with neuroserpin in combination with tPA significantly (P<0.05) reduced BBB leakage, brain edema, and ischemic lesion volume compared with rats treated with tPA alone, although ischemic lesion volumes were the same in both groups before the treatment. Immunostaining revealed that MCAO resulted in reduction of neuroserpin immunoreactivity in the ipsilateral hemisphere after 2 to 6 hours of ischemia. Zymographic assay showed increased plasminogen activity in areas with BBB leakage in rats treated with tPA. CONCLUSIONS: Administration of neuroserpin after stroke is neuroprotective, seemingly because it blocks the extravascular effect of tPA, leading to subsequent decrease in stroke volume and widening of the therapeutic window for the thrombolytic effect of tPA.

Adjuvants, Pharmaceutic↗
PubMed2004

Abciximab treatment for obstructive prosthetic aortic and mitral valve thrombosis in the presence of large thrombi, cardiogenic shock, and acute evolving embolic stroke.

Obstructive thrombosis of left-sided mechanical prosthetic valves is a life-threatening complication. Intravenous thrombolytic therapy is contraindicated due to risk of clot embolization and surgical treatment is often required for hemodynamically unstable patients. We report for the first time the successful use of abciximab in the management of a patient in cardiogenic shock with multiple prosthetic valve obstructive thrombosis and evolving embolic stroke. Serial Doppler echocardiography and cinefluoroscopy demonstrated resolution of thrombi, improvements in transvalvular gradients and improvement in leaflet motion. This observation suggests abciximab should be considered as a therapeutic option in the treatment of obstructed prosthetic heart valves.

Abciximab↗
PubMed1996

Embolic stroke in a pregnant patient with a mechanical heart valve on optimal heparin therapy.

A 28-year-old woman with a mechanical aortic heart valve experienced an embolic stroke in early pregnancy after her anticoagulation therapy was changed from warfarin to heparin. This occurred despite use of a subcutaneous heparin infusion pump and optimal anticoagulation. Thromboembolism can occur in pregnant patients with mechanical heart valves despite optimal heparin therapy.

Adult↗
PubMed2005

Analysis of combined treatment of embolic stroke in rat with r-tPA and a GPIIb/IIIa inhibitor.

Suppression of platelet activation improves the efficacy of thrombolytic therapy for stroke. Thus, combination treatment with recombinant tissue plasminogen activator (r-tPA) and 7E3 F(ab')2, a GPIIb/IIIa inhibitor that binds the platelet to fibrin, may improve the efficacy of thrombolytic therapy in embolic stroke. Magnetic resonance imaging (MRI) was used to monitor treatment response in rats subjected to embolic middle cerebral artery (MCA) occlusion (MCAo). Animals were randomized into treated (n=12) and control (n=10) groups and received intravenous combination therapy or saline, respectively, 4 hours after MCAo. Magnetic resonance imaging (MRI) measurements performed 1 hour after MCAo showed no difference between groups. However, an increased incidence (50%) of MCA recanalization was found in the treated group at 24 hours compared with 20% in the control group. The area of low cerebral blood flow at 24 and 48 hours was significantly smaller in the combination treatment group, and the lesion size, as indicated from the T2 and T1 maps, differed significantly between groups. Fluorescence microscopy measurements of cerebral microvessels perfused with fluorescein isothiocyanate-dextran and measurements of infarct volume revealed that the combination treatment significantly increased microvascular patency and reduced infarct volume, respectively, compared with the control rats. The efficacy of combination treatment 4 hours after ischemia is reflected by MRI indices of tissue perfusion, MCA recanalization, and reduction of lesion volume. The treatment also reduced secondary microvascular perfusion deficits.

Animals↗
PubMed2001

Protective effects of pamiteplase, a modified t-PA, in a rat model of embolic stroke.

The effects of alteplase (tissue plasminogen activator, t-PA) and pamiteplase (a modified t-PA with longer half-life and increased potency) were compared in a clinically relevant model of embolic stroke. Rats were treated with pamiteplase (0.5 mg/kg or 1 mg/kg bolus), alteplase (10 mg/kg infusion) or normal saline. Pamiteplase (1 mg/kg) was as effective as alteplase in reducing 24 h brain infarct volumes, neurological deficit scores and residual clot grades. Cerebral blood flow recovery at 30 min after thrombolytic treatment was partial and did not correlate with 24 h infarct volumes or neurological deficits. However, there was good correlation between 24 h residual clot grades and infarct volumes, suggesting a delayed timeframe for pamiteplase- and alteplase-induced reperfusion.

Animals↗
PubMed1994

Fibrin content of carotid thrombi alters the production of embolic stroke in the rat.

BACKGROUND AND PURPOSE: Mechanical denudation of the endothelium of the carotid artery in animals produces a nonocclusive thrombus, but the brains of these animals have not been examined for the presence of embolic stroke. METHODS: The endothelium of the right carotid artery of 16 Wistar rats was denuded using a balloon catheter. Phosphotungstic acid hematoxylin (PTAH) staining and scanning electron micrographs of the nonocclusive thrombi in the carotid arteries were compared with those produced by photochemical methods, and brains were examined for infarcts. RESULTS: Although nonocclusive thrombi were present in the carotid arteries of 4 of 4 rats killed at 4 hours and in 8 of 12 killed at 24 hours, neither cerebral infarcts nor emboli were seen in the 14 brains evaluated by light microscopy. PTAH demonstrated a high fibrin content in the thrombus produced by the endothelial denudation, with almost no fibrin seen in photochemically induced thrombi. Scanning electron microscopy confirmed dense networks of fibrin in the thrombi produced by balloon denudation. CONCLUSIONS: The composition of a nonocclusive thrombus may determine the embolic potential of this thrombus. A low fibrin content in a nonocclusive platelet thrombus may enhance the embolic potential. This suggests that platelet inhibition may also be indicated in patients with carotid artery disease who are being treated with anticoagulant.

Animals↗
PubMed1997

Correlation of diffusion MRI and heat shock protein in a rat embolic stroke model.

The expression of 70 kDa heat shock protein (HSP-70) in focal ischemia occurs in regions that sustain sub-lethal ischemic injury, and may therefore be considered as a biological marker of the ischemic penumbra. In a rat embolic stroke model, using fibrin-rich emboli, we correlated the expression of HSP-70 mRNA with diffusion magnetic resonance imaging (MRI) to determine if HSP-70 mRNA expression was associated with alterations in the apparent diffusion coefficient (ADC) of brain tissue water, a putative early marker of cytotoxic injury that is readily measured in vivo. Serial ADC measurements were made for 120 min following embolic infarction in the right carotid artery territory. HSP-70 mRNA expression was observed at the boundaries of the densely ischemic zone, as judged by diffusion imaging. ADC values observed in HSP-70 mRNA-positive regions were intermediate between those observed in the ischemic core or in control regions. In addition, the volume of HSP-70 mRNA-positive tissue correlated positively with the volume of tissue showing intermediate ADC values at 120 min. These findings suggest that intermediate ADC values occur in penumbral regions. Heterogeneity of ischemic cellular injury is suggested as the basis for the intermediate ADC values observed in these regions.

Animals↗