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PubMed2003

Neuroprotective effects of YM872 coadministered with t-PA in a rat embolic stroke model.

YM872, an AMPA receptor antagonist, was administered together with t-PA to investigate the effects of coadministration on neuroprotection in a rat embolic stroke model, when administered 2 h after embolism. T-PA or YM872 alone decreased infarct volume and improved the neurological deficit score. Coadministration of YM872 and t-PA resulted in a further decrease in infarct volume and improvement of the neurological score as compared with single administration of t-PA. These data demonstrate that coadministration of YM872 and t-PA produces more potent neuroprotective effects than when t-PA is administered alone.

Animals↗

PubMed1987

Results of open heart surgery in patients with recent cardiogenic embolic stroke and central nervous system dysfunction.

Patients undergoing open heart surgery who have had recent cardiogenic embolic stroke or have central nervous system dysfunction pose a difficult management problem. There is always the risk that cardiopulmonary bypass and heparinization may exacerbate the neurologic injury. There is no clear data indicating what is a safe interval of time from the onset of neurologic symptoms to the time of surgery. Since 1982 we have operated on 15 patients with recent (2 to 28 days, mean 12.7 +/- 7.9 days) neurologic injury. Indications for surgery included recurrent embolization, sepsis, and hemodynamic deterioration. Three patients were comatose with no focal neurologic signs at the time of surgery, and 12 patients had focal neurologic deficits. All patients had preoperative computed tomographic scans. Embolic cerebral infarctions were documented in 12 patients, one patient had evidence of intracranial hemorrhage, and one patient had a subdural hematoma. Fourteen patients had native or prosthetic valvular endocarditis and one patient had a left atrial myxoma. All patients underwent corrective cardiac surgery. One patient died in the postoperative period from multisystem failure; all other patients have been followed since discharge (6 months to 4 years). All surviving patients demonstrated improvement in their neurologic symptoms and eight patients had complete neurologic recovery. The results of this study indicate that open heart surgery can be safely performed in patients with recent neurologic injury.

Adolescent↗

PubMed1988

A new model of embolic stroke produced by photochemical injury to the carotid artery in the rat.

We report a new model of embolic stroke in the rat, based on endothelial disruption and platelet aggregation in the carotid artery, which leads to distal embolization and focal brain infarction. The common carotid artery was irradiated for 6.5 minutes with the focused beam of an argon laser operated at a wavelength of 514.5 nm with a peak power of 2 W and an average power of 400 mw. Ipsilateral cerebral infarcts, ranging in size from 0.1 to 1.7 mm, were produced by platelet emboli in 12 of 13 rats. A total of 44 infarcts were observed in the 12 rats: 29 in the cortex, 6 in the hippocampus, 5 in the thalamus, and 4 in the basal ganglia. Scanning electron microscopy identified platelet aggregates in the carotid artery and in a deep cortical arteriole 50 minutes after the photochemical lesion. Twenty-four hours after the experiment, scanning electron microscopy of the carotid artery revealed damaged endothelium but few remaining adherent platelets. More intense laser irradiation in 8 rats, leading to carotid occlusion, produced an infarct in only 1. This new model can be used to study the acute and chronic pathological changes in the brain associated with platelet embolism.

Animals↗

PubMed2003

North American clinical experience with the EKOS MicroLysUS infusion catheter for the treatment of embolic stroke.

BACKGROUND AND PURPOSE: We present early experience with the EKOS MicroLysUS infusion catheter for acute embolic stroke treatment in North America. This study was designed to demonstrate the safety of the device and to determine if sonography accelerates thrombolysis and improves clinical outcomes. METHODS: Fourteen patients aged 40-77 years with anterior- or posterior-circulation occlusion presented with cerebral ischemia 3-6 or 4-13 hours after symptom onset, respectively. Patients were treated with the catheter and simultaneous intraarterial thrombolysis. Procedural and clinical information, including time to lysis, degree of recanalization, National Institute of Health Stroke Scale (NIHSS) score, and modified Rankin Scale (mRS) score was recorded before treatment and afterward (immediately and at 24 hours, 1 week, 1 month, and 3 months). RESULTS: Ten patients presented with acute anterior-circulation emboli; four patients, with posterior-circulation emboli (NIHSS score, 9-23 [mean. 18.2] and 11-27 [mean, 18.75], respectively). Three deaths occurred at 24 hours: two from hemorrhage and one from cerebral swelling. Deaths also occurred at 1 week and 1 month after treatment. Thrombolysis in Myocardial Ischemia grade 2-3 flow was achieved in eight patients in the first hour. Average time to recanalization was 46 minutes. Mean NIHSS scores in eight of nine survivors at 90 days were 5 in the anterior-circulation group and 3 in the posterior-circulation group; mean mRS scores at 90 days were 2 and 3, respectively. No catheter-related adverse events occurred. CONCLUSION: Use of the EKOS MicroLysUS infusion catheter is feasible in the treatment of acute ischemic stroke. Further studies to evaluate its efficacy are warranted.

Adult↗

PubMed1993

Neuroprotection with NBQX and thrombolysis with rt-PA in rat embolic stroke.

The efficacy of delayed thrombolysis with recombinant tissue plasminogen activator was tested in combination with the ischaemic protecting drug NBQX in an embolic stroke model. In 113 rats the carotid territory was embolized with a fibrin-rich clot formed in polyethylene tube. Hemispheric cerebral blood flow (CBF) was measured by intra-arterial 133Xenon injection method before and after embolization. Two hours after embolization 67 animals were treated with tissue plasminogen activator 20 mg kg-1, 46 control animals with saline. NBQX was given to 53 animals, of which 41 animals also received thrombolytic therapy and 12 were saline controls. Carotid angiography displayed the rate of occlusion of the cerebral arterial supply before and after treatment. Brains were fixed after two days, evaluated neuropathologically, and infarct volume was measured. Embolization caused a 60-78% reduction of median CBF. The comparison of post-treatment angiography of thrombolytic treated animals to controls showed significant (p < 0.01) reperfusion in thrombolytic treated animals, while NBQX alone did not enhance reperfusion. Thrombolytic therapy significantly reduced the total infarct volume from 19.5% to 4.5% of embolized hemisphere volume (p = 0.006). NBQX alone reduced total infarct volume from 19.5% to 6.5% and cortical infarct volume from 7.9% to 0.3% (p = 0.03). In thrombolytic treated animals NBQX reduced total infarct volume from 4.5% to 2.1%. The more than 50% reduction of total infarction volume caused by NBQX was not statistically significant due to the variation of infarct size in this model. Small haemorrhagic lesions in infarcts were observed in thrombolytic treated animals. The clinical outcome correlated well with infarct volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Influence of a 'brain protector' drug 21-amino steroid on the effects of experimental embolic stroke treated by thrombolysis.

This study was designed to evaluate the effects of tissue-type plasminogen activator (tPA) and 21- amino steroid (U74006F) in experimental embolic stroke in rabbits. The size of infarction from embolism was compared to controls with tPA alone, 21-amino steroid alone, and in combination. The middle cerebral artery of the rabbit was embolized by injecting an arterial ('white') thrombus in the right internal carotid artery. The rabbit treatment was 2 mg kg-1 of tissue-type plasminogen activator and/or 3 mg kg-1 of 21 amino steroid started at 2 h post-embolization. The animals were terminated 4 h post-treatment and brains were examined for evidence of ischemia and/or hemorrhage. Administration of tissue-type plasminogen activator and/or 21-amino steroid in the raw data show that there is a tendency for all treatments to reduce the ischemic volume when compared to the control group, also it is evident the standard deviation of these estimates is rather large when compared to the differences between treatments. The results of the analysis of variance shows that the differences expressed are not statistically significant. (No statistical differences were found between the treatment groups and the control group.) The results show that administration of tissue-type plasminogen activator and/or 21 amino steroid at 2 h post-embolization alone or in simultaneous administration does not significantly reduce the volume of infarction. Further studies need to be addressed in regards to the region of viable brain in the peri-infarct area, in reducing the time to treatment.

Animals↗

PubMed2006

Cardiac papillary fibroelastoma presents as an acute embolic stroke in a 35-year-old African American male.

This is an interesting case of a young patient suffering an acute embolic stroke in the middle cerebral artery distribution, who was later found to have a papillary fibroelastoma on the mitral valve. The mass was first recognized by transesophageal echocardiography and eventually resected surgically. The retrieved specimen had classic histologic findings of a papillary fibroelastoma. A thrombus was noted on the tip of the specimen, supporting the theory that these masses are risks for strokes secondary to damage along the endothelial lining predisposing to subsequent fibrin deposition and mural thrombus formation.

Adult↗

PubMed2001

Embolic stroke and cardiac papillary fibroelastoma.

Papillary fibroelastomas are rare, benign, primary cardiac tumors. They are, however, the most common primary tumor of the cardiac valves and may cause great morbidity risk from embolization. This paper reports the case of a healthy 34-year-old man who presented with symptoms of a right occipital embolic stroke. Transesophageal echocardiography revealed a papillary fibroelastoma on the anterior leaflet of the mitral valve. The papillary fibroelastoma was surgically excised and he has had no recurrent symptoms. This case illustrates the importance of obtaining a transesophageal echocardiogram to investigate a possible embolic source in patients with ischemic stroke.

Adult↗

PubMed2001

[Atherosclerotic aortic plaques and risk of embolic stroke].

There is mounting evidence to implicate complex atherosclerotic aortic plaques as a significant independent risk factor for embolic stroke. Ulcerated plaques at autopsy, plaques thicker than 4 to 5mm at transesophageal echocardiography and those with mobile components are more likely to be associated with stroke. Mobile thrombus in the lumen may be a source of cerebral emboli. Among patients with ischemic stroke, those with plaques thicker than 4mm in the aortic arch have the highest risk of recurrent stroke, myocardial infarction, other vascular event including vascular death. However, since no randomized trials have been conducted to evaluate the role of any antithrombotic therapies in patients with aortic atheroma, no recommendation can be made regarding the best treatment strategies. Antiplatelet agents, oral anticoagulant, thrombolytic therapy, and elective surgical endarterectomy or graft replacement are all reasonable options that have been proposed and that must be evaluated in term of benefit/risks ratio in specific randomized controlled trials. Meanwhile, antiplatelet agents and aggressive risk factor management appear to be the first line treatment. No recommendation can be made to use oral anticoagulation in these patients nor for a target INR. Concerns also exist on the possibility of anticoagulation driven cholesterol embolism in these patients.

Aorta, Thoracic↗

PubMed1992

Dose-response of rt-PA and its combination with aspirin in a rat embolic stroke model.

The efficacy and safety of thrombolysis with different dose regimens of recombinant tissue plasminogen activator (rt-PA) and its combination with aspirin was tested in an embolic stroke model. In rats the carotid territory was embolized with a single clot formed in a polyethylene tube and washed with saline. Fifteen minutes after embolization 10 animals were treated with rt-PA 10 mg kg-1; 11 with 15 mg kg-1; 12 with 20 mg kg-1 and 9 with 10 mg kg-1 + 20 mg kg-1 aspirin and 34 animals with saline. Rt-PA 10 mg kg-1 reduced median infarct volume (in percent of the ipsilateral hemisphere volume) from 19.5 to 4.8; rt-PA 15 mg kg-1 to 2.0; rt-PA 20 mg kg-1 to 0.0, while rt-PA 10 mg kg-1 + aspirin resulted in a median infarct volume of 9.5%. Thrombolytic therapy significantly and dose dependently (p = 0.001) reduced the infarct volume, improved the presacrifice clinical score and increased (p = 0.02) angiographically verified reperfusion. There was no additional benefit of coadministration of aspirin.

Animals↗

PubMed1999

Reduction of intracerebral hemorrhaging in a rabbit embolic stroke model.

OBJECTIVE: To study the effects of a spin trap agent and a CD18 antibody administered after stroke induction on intracerebral hemorrhaging. The drugs can prevent leukocyte adhesion. METHODS: A rabbit embolic stroke model that produces intracerebral hemorrhage was used. RESULTS: A time course study showed that hemorrhaging was grossly apparent in approximately 50% of the subjects at 5 hours and in 75% at 24 hours after embolization. MDL 101,002, a spin trap agent, administered IV 5 minutes after embolization, significantly decreased the volume of hemorrhage. It also improved the behavior score relative to vehicle-treated rabbits. The CD18 antibody tended to decrease hemorrhage volume. CONCLUSION: The beneficial effect of MDL 101,002 may be caused by inhibition of free radical injury to brain tissue, thereby protecting brain microvessel integrity. Acute therapy for intracerebral hemorrhage may be feasible.

Animals↗

PubMed1993

Enhancing the efficacy of thrombolysis by AMPA receptor blockade with NBQX in a rat embolic stroke model.

Efficacy and safety of combined alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor blockade and thrombolytic therapy with human recombinant tissue plasminogen activator (TPA) was tested in a rat embolic stroke model. Sixty-three rats were embolized in the right internal carotid territory with a 200 microliters suspension of microclots formed by alternate moving of 150 microliters whole blood and 50 microliters of thrombin between two interconnected syringes for 4 min. Sixteen embolized rats served as controls, and 16 rats were treated with NBQX immediately after embolization. Thirty-one rats were treated with TPA 2 h following embolization, and in 16 of these rats additional NBQX treatments were initiated 90 min following embolization. Hemispheric cerebral blood flow (CBF) was measured by an intraarterial 133Xenon injection method before and after embolization. Carotid angiography displayed the rate of occlusion of the cerebral arterial supply before and after treatment. Brains were fixed after 2 days, evaluated neuropathologically, and infarct volumes were measured. Median CBF was reduced by 70-77% in the affected hemispheres following embolization. Significant recanalization occurred in all groups except those treated with NBQX. TPA-treated rats had significantly better reperfusion compared to controls judged by angiography 3 h following embolization (P = 0.04). NBQX alone and TPA alone caused insignificant reduction in infarct volume but, when combined, total infarct volume was reduced by 77% compared to controls (P = 0.02). Separate measurement of cortical infarct revealed significantly smaller infarcts (P = 0.05) in the combined treatment group compared to the TPA treatment group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1998

Embolic stroke in the territory of a cerebellar arteriovenous malformation--case report.

A 63-year-old male presented with an embolic stroke in the right medial inferior cerebellum. Angiography at 2 and 8 months after the stroke revealed arteriovenous shunts from the vermian branch of the right posterior inferior cerebellar artery of the right inferior vermian vein. The shunts mimicked the arteriovenous shunts of post-recanalization in acute ischemic stroke, but were finally diagnosed as a pre-existing congenital arteriovenous malformation based on their persistence. Arteriovenous shunts that persists more than 2 weeks after ictus should be differentiated from the post-recanalization arteriovenous shunts of ischemic stroke, as the different etiology may affect the ultimate prognosis and course of treatment.

Cerebellum↗

PubMed2002

Application of transesophageal echocardiography to aortic embolic stroke.

OBJECTIVES: To determine the relative value of transesophageal echocardiography (TEE) and transthoracic echocardiography (TTE) in exploring the potential embolic source (PES) in heart and aortic arch and to study the clinical significance of aortic arch atherosclerosis (AAA). METHODS: Forty-nine patients with cerebral embolism were included in this study. TEE and TTE were used to evaluate the potential source of emboli in aortic arch, heart and duplex in the carotid artery. An atherosclerotic lesion of the aortic arch was defined as normal, mild plaque, moderate plaque, and protruding plaque or mobile plaque. RESULTS: Of the 49 patients, 31 (63%) patients showed evidence of AAA: 7 (14.1%) patients were mild, 9 (18.4%) were moderate and 15 (30.6%) were severe. In those 15 patients, 11 had neither severe ICAA nor heart disease. Thirty-three patients had internal carotid arterial atherosclerosis (ICAA). The potential sources of embolization of heart and aortic arch is 48.98% by TEE, but only 18.4% by TTE; 9 patients had heart disease. Age and ICAA were significantly correlated with AAA. CONCLUSION: At present, TEE is a better method for exploring atherosclerotic lesions in the thoracic aorta. AAA is an important potential source of cerebral embolic stroke.

Adult↗

PubMed1993

Neuroprotection by excitatory amino acid antagonist augments the benefit of thrombolysis in embolic stroke in rats.

BACKGROUND AND PURPOSE: The effects of delayed thrombolysis with alteplase and neuroprotection with an excitatory amino acid receptor antagonist and their combination were tested in an embolic stroke model. METHODS: In 61 rats the carotid artery territory was embolized with arterial-like fibrin-rich clots. Hemispheric cerebral blood flow before and after embolization was measured by intra-arterial 133Xe injection method. The animals were assigned to one of the following treatments: (1) vehicle-treated controls (n = 15); (2) dizocilpine 1 mg/kg i.v. 5 minutes after embolization (n = 16); (3) alteplase 20 mg/kg as an intravenous continuous infusion starting 2 hours after embolization (n = 16); and (4) both agents (n = 14). Carotid angiography displayed the site of occlusion of the cerebral arterial tree immediately after and 3 hours after embolization, and the clinical neurological score was assessed after the rats recovered from anesthesia and before the rats were killed. Brains were fixed after 2 days and evaluated neuropathologically; infarct volume affecting cortical and deep brain structures was measured separately. RESULTS: Both alteplase and dizocilpine reduced the total infarct volume (P = .05 and P = .04, respectively, Mann-Whitney tests). Dizocilpine reduced the incidence of cortical infarctions by 48% (P < .001, Fisher's test). Only the combined treatment significantly reduced deep brain infarctions (P = .03, Mann-Whitney test). The combined treatment also improved the clinical score by 83% compared with controls, by 75% compared with the group treated by dizocilpine alone, and by 50% compared with the group treated by alteplase alone. Sixty-seven percent of thrombolytic-treated animals recanalized completely compared with 39% of those given no thrombolytics (P = .05, Fisher's test). The clinical outcome correlated with infarct size (P < .01, Spearman test). CONCLUSIONS: Our results document comparable efficacy of delayed thrombolysis and excitatory amino acid receptor antagonism in this model and suggest that combination of these two therapeutic approaches may yield additional benefit in treatment of thromboembolic stroke, particularly in cases where deep brain (end-artery-supplied) structures are affected.

Animals↗

PubMed2003

Thrombolytic and anticoagulation treatment in a rat embolic stroke model.

OBJECTIVES: The effects of pentasaccharide (PENTA), given alone or combined with thrombolysis using recombinant tissue plasminogen activator (rt-PA), on infarct size and clinical outcome were evaluated in a rat embolic stroke model. MATERIALS AND METHODS: Ninety-two rats were embolized unilaterally and assigned to: (i). controls, (ii). rt-PA 6 mg/kg, (iii). PENTA 0.5 mg/kg, (iv). PENTA 0.5 mg/kg and rt-PA 6 mg/kg. After 2 days animals were killed, the brains removed and evaluated microscopically. RESULTS: The median infarct size measured in percentage of the affected hemisphere was 25% in the control group, 4% (P < 0.01, Mann Whitney) in group 2, 19% (n.s.) in group 3, and 10% (P < 0.05) in group 4. rt-PA, and rt-PA combined with PENTA also promoted functional recovery. CONCLUSION: The present study found no effect of 0.5 mg/kg PENTA treatment. Compared with rt-PA treatment alone, 0.5 mg/kg PENTA alone or combined with rt-PA did not significantly increase mortality or tendency for hemorrhage.

Angiography↗

PubMed1997

Improved perfusion with rt-PA and hirulog in a rabbit model of embolic stroke.

We conducted a study using diffusion-weighted (DWI) and perfusion-weighted (PWI) magnetic resonance imaging (MRI) to evaluate the efficacy of thrombolysis in an embolic stroke model with recombinant tissue plasminogen activator (rt-PA) and hirulog, a novel direct-acting antithrombin. DWI can identify areas of ischemia minutes from stroke onset, while PWI identifies regions of impaired blood flow. Right internal carotid arteries of 36 rabbits were embolized using aged heterologous thrombi. Baseline DWI and PWI scans were obtained to confirm successful embolization. Four animals with no observable DWI lesion on the initial scan were excluded; therefore, a total of 32 animals were randomized to one of three treatment groups: rt-PA (n = 11), rt-PA plus hirulog (n = 11), or placebo (n = 10). Treatment was begun 1 h after stroke induction. Intravenous doses were as follows: rt-PA, 5 mg/kg over 0.5 h with 20% of the total dose given as a bolus; hirulog, 1 mg/kg bolus followed by 5 mg/kg over 1 h. MRI was performed at 2, 3, and 5 h following embolization. Six hours after embolization, brains were harvested, examined for hemorrhage, then prepared for histologic analysis. The rt-PA decreased fibrinogen levels by 73%, and hirulog prolonged the aPTT to four times the control value. Posttreatment areas of diffusion abnormality and perfusion delay were expressed as a ratio of baseline values. Significantly improved perfusion was seen in the rt-PA plus hirulog group compared with placebo (normalized ratios of the perfusion delay areas were as follows: placebo, 1.58, 0.47-3.59; rt-PA, 1.12, 0.04-3.95; rt-PA and hirulog, 0.40, 0.02-1.08; p < 0.05). Comparison of diffusion abnormality ratios measured at 5 h showed trends favoring reduced lesion size in both groups given rt-PA (normalized ratios of diffusion abnormality areas were as follows: placebo, 3.69, 0.39-15.71; rt-PA, 2.57, 0.74-5.00; rt-PA and hirulog, 1.95, 0.33-6.80; p = 0.32). Significant cerebral hemorrhage was observed in one placebo, two rt-PA, and three rt-PA plus hirulog treated animals. One fatal systemic hemorrhage was observed in each of the rt-PA groups. We conclude that rt-PA plus hirulog improves cerebral perfusion but does not necessarily reduce cerebral injury. DWI and PWI are useful methods for monitoring thrombolysis.

Animals↗

PubMed2004

MRI evaluation of treatment of embolic stroke in rat with intra-arterial and intravenous rt-PA.

Using magnetic resonance imaging (MRI), we investigated treatment of a rat model of embolic stroke with rt-PA via intra-arterial (IA) and intravenous (IV) routes of administration. Rats were treated with rt-PA by either IA (n = 13) or IV (n = 13) routes at 3 h after stroke induction. Diffusion, perfusion, T2, and magnetization transfer MRI were performed prior to and at 1-3 and at 24 h after embolization. The IA treated group exhibited smaller lesion volumes than the IV treated group (p = 0.02). The relative areas with low ADCW and cerebral blood flow (CBF) after IA rt-PA intervention were significantly (p < or = 0.03) smaller than those in the IV treated group at 24 h after embolization. Significant differences (p < 0.02) between IA and IV treated groups in the relative area with high T2 and inverse of the apparent forward transfer rate of magnetization (kINV) in the ipsilateral hemisphere were also detected at 24 h after embolization. The IA treated group exhibited less intracerebral hemorrhage (27%) than the IV treated (64%) groups. Our data suggest that the beneficial effects of IA rt-PA treatment can be detected by changes in CBF, ADCW, T2, and kINV.

Animals↗