Early Arterial Recanalization Research Articles

Pharmacological Modulation of Neutrophil Extracellular Traps Reverses Thrombotic Stroke tPA (Tissue-Type Plasminogen Activator) Resistance.

Background and Purpose- Recanalization of the occluded artery is a primary goal in stroke treatment. Unfortunately, endovascular treatment is not always available, and tPA (tissue-type plasminogen activator) therapy is limited by its narrow therapeutic window; importantly, the rate of early arterial recanalization after tPA administration is low, especially for platelet-rich thrombi. The mechanisms for this tPA resistance are not well known. Since neutrophil extracellular traps (NETs) have been implicated in this setting, our aim was to study whether NET pharmacological modulation can reverse tPA resistance and the role of TLR4 (Toll-like receptor 4), previously related to NET formation, in thrombosis. Methods- To this goal, we have used a mouse photothrombotic stroke model, which produces a fibrin-free thrombus composed primarily of aggregated platelets and thrombi obtained from human stroke patients. Results- Our results demonstrate that (1) administration of DNase-I, which promotes NETs lysis, but not of tPA, recanalizes the occluded vessel improving photothrombotic stroke outcome; (2) a preventive treatment with Cl-amidine, impeding NET formation, completely precludes thrombotic occlusion; (3) platelet TLR4 mediates NET formation after photothrombotic stroke; and (4) ex vivo fresh platelet-rich thrombi from ischemic stroke patients are effectively lysed by DNase-I. Conclusions- Hence, our data open new avenues for recanalization of platelet-rich thrombi after stroke, especially to overcome tPA resistance.

Associated Factors and Long-Term Prognosis of 24-Hour Worsening of Arterial Patency After Ischemic Stroke.

Background and Purpose- Early arterial recanalization in acute ischemic stroke is strongly associated with better outcomes. However, early worsening of arterial patency was seldom studied. We investigated potential predictors and long-term prognosis of worsening of arterial patency at 24 hours after stroke onset. Methods- Patients from the Acute Stroke Registry and Analysis of Lausanne registry including admission and 24-hour vascular imaging (computed tomography or magnetic resonance angiography) were included. Worsening of arterial patency was defined as a new occlusion and significant stenosis in any extracranial or intracranial artery, comparing 24 hours with admission imaging. Variables associated with worsening of arterial patency were assessed by stepwise multiple logistic regression. The impact of arterial worsening on 3-month outcome was investigated with an adjusted modified Rankin Scale shift analysis. Results- Among 2152 included patients, 1387 (64.5%) received intravenous thrombolysis and endovascular treatment, and 65 (3.0%) experienced 24-hour worsening of arterial patency. In multivariable analysis, history of hypertension seemed protective (adjusted odds ratio [aOR], 0.45; 95% CI, 0.27-0.75) while higher admission National Institutes of Health Stroke Scale (aOR, 1.06; 95% CI, 1.02-1.10), intracranial (aOR, 4.78; 95% CI, 2.03-11.25) and extracranial stenosis (aOR, 3.67; 95% CI, 1.95-6.93), and good collaterals (aOR, 3.71; 95% CI, 1.54-8.95) were independent predictors of worsening of arterial patency. Its occurrence was associated with a major unfavorable shift in the distribution of the modified Rankin Scale at 3 months (aOR, 5.97; 95% CI, 3.64-9.79). Conclusions- Stroke severity and admission vascular imaging findings may help to identify patients at a higher risk of developing worsening of arterial patency at 24 hours. The impact of worsening of arterial patency on long-term outcome warrants better methods to detect and prevent this early complication.

Twenty-Four-Hour Reocclusion After Successful Mechanical Thrombectomy: Associated Factors and Long-Term Prognosis.

Background and Purpose- Early arterial recanalization is a strong determinant of prognosis in acute ischemic stroke. Nevertheless, reocclusion can occur after initial recanalization. We assessed associated factors and long-term prognosis of reocclusion after successful mechanical thrombectomy (MT). Methods- From the prospectively constructed Acute Stroke Registry and Analysis of Lausanne cohort, we included consecutive patients with anterior and posterior circulation strokes treated by successful MT (modified treatment in cerebral infarction 2b-3) and with 24-hour vascular imaging available. Reocclusion at this time-point was defined as new intracranial occlusion within an arterial segment recanalized at the end of MT. Through multivariate logistic regression, we investigated associated factors and 3-months outcome. In a 4:1 matched-cohort, we also assessed the role of residual thrombus or stenosis on post-recanalization angiographic images as potential predictor of reocclusion. Results- Among 473 patients with successful recanalization, 423 (89%) were included. Of these, 28 (6.6%) had 24-hour reocclusion. Preadmission statin therapy (aOR [adjusted odds ratio], 0.27; 95% CI, 0.08-0.94), intracranial internal carotid artery occlusion (aOR, 3.53; 95% CI, 1.50-8.32), number of passes (aOR, 1.31; 95% CI, 1.06-1.62), transient reocclusion during MT (aOR, 8.55; 95% CI, 2.14-34.09), and atherosclerotic cause (aOR, 3.14; 95% CI, 1.34-7.37) were independently associated with reocclusion. In the matched-cohort analysis, residual thrombus or stenosis was associated with reocclusion (aOR, 15.6; 95% CI, 4.6-52.8). Patients experiencing reocclusion had worse outcome (aOR, 5.0; 95% CI, 1.2-20.0). Conclusions- Reocclusion within 24-hours of successful MT was independently associated with statin pretreatment, occlusion site, more complex procedures, atherosclerotic cause, and residual thrombus or stenosis after recanalization. Reocclusion impact on long-term outcome highlights the need to monitor and prevent this early complication.

Prediction of Early Arterial Recanalization and Tissue Fate in the Selection of Patients With the Greatest Potential to Benefit From Intravenous Tissue-Type Plasminogen Activator.

Our objective is to determine the performance of the combination of likelihood of arterial recanalization and tissue fate to predict functional clinical outcome in patients with acute stroke. Clinical, imaging, and outcome data were collected in 173 patients with acute ischemic stroke who presented within 4.5 hours from symptom onset, in the time window eligible for intravenous tissue-type plasminogen activator. Imaging data included Alberta Score Program Early Computed Tomographic Score (ASPECTS), site of occlusion, volume of ischemic core and penumbra, and recanalization. Outcome data consisted of modified Rankin Scale score at 90 days. We classified patients based on their baseline imaging characteristics and treatment with intravenous tissue-type plasminogen activator (yes/no) according to 5 different hypothetical prognostic algorithms: (1) based on whether patients received intravenous tissue-type plasminogen activator, (2) based on ASPECTS, (3) based on the site of occlusion, (4) based on volume of ischemic core and penumbra, and (5) based on a matrix of predicted recanalization and volume of ischemic core and penumbra. We compared the performance of such algorithms to predict good clinical outcome, defined as modified Rankin Scale score of ≤2 at 90 days. One hundred and twenty-four patients received intravenous tissue-type plasminogen activator; 49 did not. In the group that was treated, 46 (37%) had good outcome as opposed to 38.7% in the nontreated. The algorithm that combined the prediction of recanalization with the volume of ischemic core and penumbra showed the highest accuracy to predict good outcome (77.7%) as opposed to others (range, 43.9%-57.2%) The combination of predicted recanalization and tissue fate proved superior to prognosticate good clinical outcome when compared with other usual predictors.

Prestroke Physical Activity Is Associated with Good Functional Outcome and Arterial Recanalization after Stroke due to a Large Vessel Occlusion

Background: Although multiple studies and meta-analyses have consistently suggested that regular physical activity (PhA) is associated with a decreased stroke risk and recurrence, there is limited data on the possible preconditioning effect of prestroke PhA on stroke severity and prognosis. We aimed to study the association of prestroke PhA with different outcome variables in patients with acute ischemic stroke due to an anterior large vessel occlusion. Methods: The Prestroke Physical Activity and Functional Recovery in Patients with Ischemic Stroke and Arterial Occlusion trial is an observational and longitudinal study that included consecutive patients with acute ischemic stroke admitted to a single tertiary stroke center. Main inclusion criteria were: anterior circulation ischemic stroke within 12 h from symptom onset; presence of a confirmed anterior large vessel occlusion, and functional independence previous to stroke. Prestroke PhA was evaluated with the International Physical Activity Questionnaire and categorized into mild, moderate and high levels by means of metabolic equivalent (MET) minutes per week thresholds. The primary outcome measure was good functional outcome at 3 months (modified Rankin scale ≤2). Secondary outcomes were severity of stroke at admission, complete early recanalization, early dramatic neurological improvement and final infarct volume. Results: During the study period, 159 patients fulfilled the above criteria. The mean age was 68 years, 62% were men and the baseline NIHSS score was 17. Patients with high levels of prestroke PhA were younger, had more frequently distal occlusions and had lower levels of blood glucose and fibrinogen at admission. After multivariate analysis, a high level of prestroke PhA was associated with a good functional outcome at 3 months. Regarding secondary outcome variables and after adjustment for relevant factors, a high level of prestroke PhA was independently associated with milder stroke severity at admission, early dramatic improvement, early arterial recanalization after intravenous thrombolysis and lower final infarct volume. The beneficial association of prestroke PhA with stroke outcomes was already present with a cutoff point of 1,000 MET min/week, a level of PhA easily achieved by walking 1 h/day during 5 days or by doing a vigorous aerobic activity 1 h/day twice a week. Conclusions: Prestroke PhA is independently associated with favorable stroke outcomes after a large vessel occlusion. Future research on the underlying mechanisms is needed to understand this neuroprotective effect of PhA.

The ischemic penumbra

The clinical efficiency of thrombolysis is explained by the rescue of ischemic penumbra areas resulting from early arterial recanalization. The perfusion-diffusion weighted imaging mismatch is a commonly used MRI surrogate of the ischemic penumbra. However, the randomized trials testing the mismatch hypothesis have been negative. We will review the 'mismatch concept' and the recent studies that aim to localize the clinically eloquent areas of penumbra in middle cerebral artery (MCA) infarcts. New methods of image analysis have shown that poor outcomes after MCA stroke are related to infarction of an extremely well localized area of the periventricular white matter and adjacent internal capsule, where projections and association tracts are crossing and converging. This area almost colocalizes with the area salvaged by early arterial recanalization and is located extremely close to the initial ischemic core. The location of the area that correlates with disability in MCA stroke patients and that is salvaged by early arterial recanalization is in the same specific region of the deep white matter, close to the initial ischemic core. These findings may have important implications for designing new recanalization trials and support the importance of basic research on white-matter neuroprotection.

Abstract 74: Early Arterial Recanalization After Intra-venous Tissue-Plasminogen-Activator Treatment in the Interventional Management of Stroke-3 Study

Background: Data on arterial recanalization after IV t-PA treatment are rare. IMS-3 allows the study of variables affecting arterial recanalization after IV t-PA in acute ischemic stroke patients with CTA-proved major artery occlusions. Methods: Of 656 acute ischemic stroke patients in IMS-3, 306 were examined with baseline CTA and randomized either to IV t-PA (N=95) or to IV t-PA followed by digital subtraction angiography (DSA) and endovascular therapy (EVT) (N=211). Comparison of baseline CTA to DSA within 5 hours of stroke onset assessed early arterial recanalization after IV t-PA. A central core lab categorized DSA vessel occlusion as “no, partial, or complete”. We studied the association between arterial occlusion sites on baseline CTA with early recanalization for the endovascular group and analyzed its impact on clinical outcome at 90 days. Results: In the EVT group, 22 patients (10.4%) had no CTA intracranial occlusions, but 1 extracranial occlusion; 42 patients (19.9%) had occlusions of intracranial internal carotid artery (ic-ICA); 10 patients (4.7%) had tandem occlusions of the cervical ICA and middle cerebral artery (MCA); 95 patients (45.0%) had MCA-trunk (M1) occlusions, 33 patients (15.6%) had M2 occlusions, 3 patients (1.4%) had M3/4 occlusions, and 6 patients (2.8%) occlusions within posterior circulation. Partial or complete recanalization occurred in 28.6% of patients before DSA and was marginally associated with occlusion site (p=0.0525) (8 patients (19.0%) with ic-ICA occlusion, 0 patients with tandem ICA/MCA occlusions, 34 patients (35.8%) with M1 occlusions, 11 patients (33.3%) with M2 occlusions, 0 patients with M3/4 occlusions, and 1 patient (16.7%) with occlusion within posterior circulation). Three CTA negative patients had intracranial occlusions on DSA. Thirty-two patients (59.3%) with early recanalization achieved mRS of 0-2 at 90 days compared to 51 patients (38.4%) without early recanalization (p=0.0099). There was no relationship between early recanalization and time to IV t-PA or mean t-PA dose. Conclusion: Before EVT, IV rt-PA may facilitate arterial recanalization and better clinical outcome in about one third of patients.

Abstract 73: Resistance to Iv Thrombolysis and Prognostic Impact of Metabolic Syndrome in Middle Cerebral Artery Ischemic Stroke

Background: Metabolic Syndrome (MetS) may confer higher resistance to early arterial recanalization after intravenous (IV) thrombolysis and a poor impact in other prognostic variables after stroke. We aimed to test this hypothesis evaluating not only the clinical syndrome but also some relevant biomarkers associated with MetS and insulin resistance. Methods: Prospective, observational study in consecutive stroke patients with MCA occlusion and who received IV tPA in a single tertiary-care center. MetS was diagnosed following the unified criteria of the last Joint Interim Statement 2009. We measured PAI-1, adiponectin and CRP levels at admission (before treatment). Primary outcome variable was resistance to thrombolysis defined as the absence of complete MCA recanalization at 2 hours after tPA infusion assessed by transcranial color-coded duplex or when rescue mechanical thrombectomy after IV tPA was needed. Secondary outcome variables were dramatic neurological improvement (decrease in ≥10 points in the NIHSS score in the first 24 hours), poor outcome (mRS score >2 at 3 months), symptomatic intracerebral hemorrhage (SICH) following ECASS II criteria and infarct volume (AXBXC/2). Results: A total of 234 patients (55.6% men, mean age 69.5±13.3 years, median baseline NIHSS 16 [10-20]) were included and 146 (62.4%) fulfilled MetS criteria. After multivariate analysis MetS was an independent predictor of resistance to thrombolysis (OR 2.2 [1.3-4.2] p=0.01) and absence of early neurological recovery (OR 0.5 [0.28-0.97] p=0.04). In addition, MetS conferred poorer functional outcome at three months, higher SICH rate and increased infarct volume although these associations disappeared after adjustment for covariates. Adiponectin levels in women and CRP and PAI-1 levels in the whole sample were significantly associated with MetS but we found no influence of those biomarkers in resistance to thrombolysis, SICH, infarct volume or early neurological improvement. However, CRP levels were higher in patients with poor functional outcome. Conclusions: MetS is an independent predictor of resistance to clot dissolution after tPA administration in patients with acute MCA occlusions and it is associated with poorer neurologic outcome.

Intravenous Thrombolysis for Acute Ischemic Stroke Occurring during Hospitalization for Transient Ischemic Attack

There are limited data regarding the use of intravenous thrombolysis in patients who experienced acute ischemic symptoms during their hospitalization for prior transient ischemic attack. We sought to prospectively evaluate the safety and efficacy of intravenous thrombolysis for the treatment of acute ischemic stroke occurring during hospitalization for transient ischemic attack in an international, multicenter study. Consecutive patients with acute ischemic stroke that occurred during hospitalization for prior transient ischemic attack were treated with intravenous thrombolysis in five tertiary-care stroke centers. Early arterial recanalization was determined by transcranial Doppler at the end of recombinant tissue plasminogen activator infusion using previously validated criteria. Symptomatic intracranial hemorrhage complicating intravenous thrombolysis was evaluated using the National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study definition. Functional independence at three-months was defined as Modified Rankin Scale score of 0-2. Systemic recombinant tissue plasminogen activator infusion (median onset-to-treatment time 70 mins, interquartile range 50-150) was given in 25 consecutive patients (mean age 66 ± 10 years) who developed acute ischemic stroke symptoms (median National Institutes of Health Stroke Scale score 10 points; interquartile range 8-14) during hospitalization for prior transient ischemic attack (median ABCD(2) score 5 points; median time-to-symptom recurrence 24 h, interquartile range 24-48). No symptomatic intracranial hemorrhage (0%; 95% confidence interval 0-12%) was documented. Early complete recanalization occurred in 64% of patients (95% confidence interval 44-80%), and 84% (95% confidence interval 65-94%) achieved three-month functional independence. The rate of three-month functional independence was higher in patients treated with intravenous tissue plasminogen activator within 90 mins from symptom onset compared with those with onset-to-treatment time>90 mins (81% vs. 33%; P = 0.031). Intravenous thrombolysis for symptoms of acute ischemic stroke occurring after hospitalization for transient ischemic attack appears to be safe. These pilot data support resetting the clock if new symptoms recur shortly after transient ischemic attack.

Abstract TMP24: Intravenous Thrombolysis For Acute Ischemic Stroke Occurring During Hospitalization For Transient Ischemic Attack: An International, Multicenter Study

Background&Purpose: There are limited data regarding the safety of intravenous thrombolysis (IVT) in patients who experienced acute ischemic stroke (AIS) during their hospitalization for Transient Ischemic Attack (TIA). We sought to prospectively evaluate the safety and efficacy of systemic thrombolysis in AIS occurring during hospitalization for TIA in an international, multi-center study Subjects&Methods: Consecutive patients with AIS that occurred during hospitalization for prior TIA were treated with standard intravenous tissue plasminogen activator (tPA) at five tertiary-care stroke centers. Early arterial recanalization was determined by transcranial Doppler at the end of tPA infusion using the previously validated Thrombolysis in Brain Ischemia flow-grading system. Symptomatic intracranial hemorrhage complicating systemic thrombolysis was evaluated using NINDS rtPA Stroke Study definition. Functional outcome at three months was evaluated using the modified Rankin Scale (mRS). Results: Systemic tPA (median onset-to-treatment time 70 min, interquartile range 50-150) was given in 25 consecutive patients (mean age 66±10years) who developed symptoms of acute stroke (median NIHSS-score 10 points; interquartile range 8-14) during hospitalization for prior TIA [(median ABCD2-score 5 points, median time-to-symptom recurrence 24 hrs, interquartile range 24-48). No symptomatic intracranial hemorrhage (0%; 95%CI:0-12%) was documented. Early complete recanalization occurred in 64% (95%CI:44%-80%) of the study population; 84% (95%CI:65%-94%) achieved three-month functional independence (mRS-score of 0-2). The rate of three-month functional independence was higher in patients treated with iv-tPA within 90 min from symptom onset compared to those with onset-to-treatment time>90 min (81% vs 33%; p=0.031) Conclusions: Intravenous thrombolysis for symptoms of ischemic stroke occurring after hospitalization for TIA appears to be safe. These pilot data support re-setting the clock if new symptoms recur shortly after TIA.

Temporal profile and prognostic value of Lp-PLA2 mass and activity in the acute stroke setting

Background Lp-PLA2 is a novel biomarker in cardiovascular diseases due to its ability to predict first-ever and recurrent stroke. Little information is known regarding its influence on early outcome after stroke. Objectives We aimed to investigate Lp-PLA2 in t-PA-treated stroke patients and to study its relationship with early outcome. Methods Lp-PLA2 mass and activity were measured in 135 healthy controls and also in stroke patients treated with t-PA at baseline ( n = 99) and serially thereafter ( n = 34) by means of the PLAC test at an automated Olympus analyzer and by a colorimetric activity method (diaDexus). NIHSS scores and TCD recordings were also obtained serially. Outcome was defined according to early neurological status, the presence of arterial recanalization and functional outcome at third month. Results Lp-PLA2 mass was increased as compared to controls, whereas Lp-PLA2 activity was significantly decreased at baseline as compared with controls and with 1 and 24 h determinations. Lp-PLA2 mass and activity were not related with early (48 h) neurological status. Regarding recanalization, higher mass and activity were found among patients who did not achieve complete recanalization by the end of t-PA treatment ( p = 0.029 for mass, p = 0.044 for activity). Lp-PLA2 mass and the existence of a proximal occlusion at baseline were the most powerful predictors for persistent occlusions (OR for proximal occlusion 6.8. p = 0.036, OR for Lp-PLA2 mass 7.2 per standard deviation increase, p = 0.008). Conclusions Significant changes in Lp-PLA2 concentrations occur early after stroke onset. Lp-PLA2 mass may add relevant information regarding early arterial recanalization in intravenous t-PA-treated stroke patients.

Sonothrombolysis for Proximal Occlusions

Early arterial recanalization with tissue plasminogen activator (t-PA) is associated with better neurological outcome in acute ischemic stroke (AIS). Research has suggested that microspheres — which can reach intracranial occlusions and transmit energy momentum from an ultrasound wave — can enhance recanalization in proximal occlusions, where thrombi are larger than distal thrombi and tend to be less responsive to systemic t-PA. This pilot safety study, funded by the manufacturer of microsphere technology, was a randomized, …

Ultrasound- and Microspheres-Enhanced Thrombolysis for Stroke Treatment: State of the Art

Intravenous administration of recombinant tissue-plasminogen activator (rt-PA) remains the fastest and widely feasible strategy to initiate treatment in acute ischemic stroke. Because it works by inducing recanalization of an occluded vessel, augmentation of this process is desirable and diagnostic transcranial Doppler (TCD) ultrasound can accomplish this safely. A 2-MHz pulsed-wave monitoring can at least double the chance of early complete arterial recanalization at no increase in the risk of symptomatic intracerebral hemorrhage. Gaseous microspheres, initially developed as ultrasound contrast agents, can further increase the effectiveness of rt-PA. A recent microsphere dose-escalation study called TUCSON showed sustained complete recanalization rates of 67% in patients receiving TCD monitoring with a 1.4-mL perflutren-lipid microsphere dose compared with controls receiving rt-PA alone with no increase in hemorrhage rate. In this article, we review the current and emerging applications of ultrasound and microspheres in stroke management including augmentation of systemic thrombolysis and implications for future reperfusion strategies.

Abstract: P739 ASSOCIATION OF LP-PLA2 WITH CORONARY ARTERY DISEASE IN AFRICAN AMERICANS AND CAUCASIANS

Lp-PLA2 is a novel biomarker in cardiovascular diseases due to its ability to predict first-ever and recurrent stroke. Little information is known regarding its influence on early outcome after stroke.We aimed to investigate Lp-PLA2 in t-PA-treated stroke patients and to study its relationship with early outcome.Lp-PLA2 mass and activity were measured in 135 healthy controls and also in stroke patients treated with t-PA at baseline (n = 99) and serially thereafter (n = 34) by means of the PLAC test at an automated Olympus analyzer and by a colorimetric activity method (diaDexus). NIHSS scores and TCD recordings were also obtained serially. Outcome was defined according to early neurological status, the presence of arterial recanalization and functional outcome at third month.Lp-PLA2 mass was increased as compared to controls, whereas Lp-PLA2 activity was significantly decreased at baseline as compared with controls and with 1 and 24 h determinations. Lp-PLA2 mass and activity were not related with early (48 h) neurological status. Regarding recanalization, higher mass and activity were found among patients who did not achieve complete recanalization by the end of t-PA treatment (p = 0.029 for mass, p = 0.044 for activity). Lp-PLA2 mass and the existence of a proximal occlusion at baseline were the most powerful predictors for persistent occlusions (OR for proximal occlusion 6.8. p = 0.036, OR for Lp-PLA2 mass 7.2 per standard deviation increase, p = 0.008).Significant changes in Lp-PLA2 concentrations occur early after stroke onset. Lp-PLA2 mass may add relevant information regarding early arterial recanalization in intravenous t-PA-treated stroke patients.

Ultrasound Enhancement of Fibrinolysis

Systemic administration of tissue plasminogen activator (tPA) remains the fastest way to initiate treatment for acute ischemic stroke. The presence of a proximal arterial occlusion should not be viewed as an insurmountable predictor of tPA failure. Because tPA works by induction of partial recanalization of large thrombi, early augmentation of fibrinolysis to improve recanalization is desirable. This augmentation is feasible and can be safely achieved at the bedside with diagnostic Doppler ultrasound. In the CLOTBUST trial, 83% of patients achieved any recanalization (46% complete, 27% partial) with tPA+transcranial Doppler vs 50% (17% complete, 33% partial) with tPA alone within 2 hours of treatment (P<0.001). Sustained, complete recanalization at 2 hours was 38% vs 13%, respectively (P=0.03). A recent meta-analysis of 6 randomized and 3 nonrandomized clinical studies of sonothrombolysis showed that any diagnostic ultrasound monitoring can at least double the chance of early complete arterial recanalization at no increase in the risk of symptomatic intracerebral hemorrhage. Because application in humans of frequencies below the diagnostic range resulted in increased symptomatic bleeding rates, mechanisms by which megahertz and kilohertz frequencies interact with the clot-residual flow interface and endothelium are currently under renewed investigations. Catheter-based ultrasound delivery to arterial thrombi and intraventricular clots is the subject of ongoing clinical trials. Addition of gaseous perflutren-lipid microspheres to tPA and transcranial Doppler can further facilitate early flow improvement, with a 50% rate of early, complete recanalization in a recent feasibility study. Transcranial ultrasound delivery in an operator-independent and dose-controlled manner is being tested in a clinical trial.

Reversible diffusion-weighted lesion in a TIA patient without arterial recanalization: A case report

A 70-year-old man with right hemiparesis (NIHSS score 15) was admitted to our hospital 1 h after onset. Diffusion-weighted imaging (DWI) revealed a hyperintense lesion in the left corona radiata and magnetic resonance angiography (MRA) revealed occlusion of the left middle cerebral artery (MCA). At 2.5 h after onset, his neurological deficits dramatically improved (with NIHSS score change from 15 to 2). Immediately thereafter, follow-up MRI revealed that the hyperintense lesion on DWI had disappeared, though the left MCA occlusion remained. By the end of follow-up MRI examination, his neurological deficits had completely disappeared. We report here the patient with transient ischemic attack with a reversible ischemic lesion on DWI without early arterial recanalization.

Saving the Ischemic Penumbra: Potential Role for Statins and Phosphodiesterase Inhibitors

Ischemic stroke is the third cause of death and the most common cause of neurological disability. A main target of treatment is the still salvageable tissue surrounding the core of infarction and called "ischemic penumbra". Up to now the only drug approved for the treatment of acute ischemic stroke is recombinant tissue plasminogen activator to achieve early arterial recanalization and hypoxic tissue reperfusion and improve neural function. However, thrombolytic therapy has to be administered soon after the event since its efficacy is time dependent. This intervention also carries an increased risk of hemorrhagic transformation. In the rescue of poorly perfused cerebral regions an important role is played by collateral blood supply through the circle of Willis and through small pial vessels surrounding the lesion. The extent of collateralization is variable and at least in part regulated by the modulation of arteriolar nitric oxide (NO)-dependent endothelial function. Drugs that can improve endothelial function and cerebrovascular reactivity could have a role in collateral formation and infarct volume limitation. Statins affect endothelial NO production demonstrating their potential to influence endothelial NO synthase (eNOS) and in treating stroke. Phosphodiesterase (PDE) inhibitors improve functional recovery after stroke in rats enhancing neuro and synapto genesis and increasing guanosine 3,5-cyclic monophosphate (cGMP). The aim of this review is to highlight the potential of these two classes of drugs in the treatment of acute ischemic stroke by analysing their pharmacological effects and involvement in the NO and cGMP pathways.

Association of Pretreatment Blood Pressure With Tissue Plasminogen Activator-Induced Arterial Recanalization in Acute Ischemic Stroke

Elevated systolic blood pressure (SBP) and lack of early vessel recanalization are predictors of poor outcome among patients with stroke treated with systemic tissue plasminogen activator (tPA). We aimed to evaluate the potential relationship between pretreatment SBP and tPA-induced recanalization. Consecutive patients with acute ischemic stroke resulting from intracranial artery occlusion were treated with standard intravenous tPA and assessed with 2-MHz transcranial Doppler for arterial recanalization. Early arterial recanalization was determined with previously validated Thrombolysis in Brain Ischemia flow grading system at 120 minutes after tPA bolus. Functional outcome at 3 months was evaluated using the modified Rankin Scale. A total of 351 patients received intravenous tPA (mean age: 68.7+/-13.4 years, median National Institutes of Health Stroke Scale score 16.5). Patients with complete recanalization (n=94) had lower mean pretreatment SBP values (152+/-23 mm Hg) than patients with incomplete or absent recanalization (n=257, 160+/-22 mm Hg, P=0.010). Pretreatment SBP levels were inversely associated with complete recanalization (OR per 10-mm Hg increase: 0.85; 95% CI: 0.74 to 0.98, P=0.022) after adjustment for demographics, risk factors, stroke severity, pretreatment Thrombolysis in Brain Ischemia grades, and continuous versus intermittent exposure to transcranial Doppler. Although patients with poor functional 3-month outcomes (modified Rankin Scale >2) had higher pretreatment SBP values (160+/-25 mm Hg) than functionally independent patients (154+/-20 mm Hg, P=0.027), pretreatment SBP levels were not independently associated with functional outcome on multivariable analysis. Age, complete recanalization, baseline National Institutes of Health Stroke Scale score, and time from symptom onset to tPA bolus were independent (P<0.05) predictors of 3-month outcome. Higher pretreatment SBP levels are associated with poor recanalization in patients with acute stroke treated with intravenous tPA.

Tratamiento con alteplasa en el infarto cerebral agudo 2007: una opción terapéutica efectiva a nuestro alcance

The greatest progress has been made in the research field based on the early arterial recanalization strategy in cerebral ischemia. To carry out a revision of stroke treatment with intravenous thrombolysis during the therapeutic window period covering the first three hours of evolution. The revision focuses on information provided by clinical trials, meta-analysis and open-label reports studies. Clinical trials that study the use of alteplase in the acute stroke treatment, especially the two phase III clinical trials carried out by the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, are described. A great deal of useful information has been provided through systematic revisions that analyze data on these treatment clinical trials jointly. Meta-analysis studies are described: the Pooled Analysis of ATLANTIS, ECASS and NINDS t-PA Stroke Trials, Cochrane Meta-analysis: Thrombolysis for Acute Ischemic Stroke. Community based studies, especially the SITS-MOST study, were revised, and their findings were compared with other open-label t-PA studies. t-PA is effective when administered in the first three hours of evolution of stroke in selected patients and under ideal conditions, and it may be beneficial, using the same selection criteria, in a therapeutic window of four and a half hours. The treatment is effective when applied as part of the daily clinical practice in our environment. This effectiveness does not disappear when extending its use to a large number of qualified hospitals.

Ultrasound Enhanced Thrombolysis for Stroke

In the pivotal clinical trials of intravenous tissue plasminogen activator (TPA) therapy, a low rate of early arterial recanalization was suspected because only a few stroke patients may have had early dramatic clinical improvement. Tissue plasminogen activator activity can be enhanced with ultrasound, including 2 MHz transcranial Doppler (TCD). Transcranial Doppler identifies residual blood flow signals around thrombi, and, by delivering mechanical pressure waves, exposes more thrombus surface to circulating TPA. For the first time in clinical medicine, the international multicenter CLOTBUST trial showed that ultrasound enhances the thrombolytic activity of a drug in humans, thereby confirming multidisciplinary experimental research conducted worldwide for the past 30 years. In the CLOTBUST trial, the dramatic clinical recovery from stroke coupled with complete recanalization within 2 h after TPA bolus occurred in 25% of patients treated with TPA+TCD compared with 8% who received TPA alone (P=0.02). Complete clearance of a thrombus and dramatic recovery of brain functions during treatment are feasible goals for ultrasound-enhanced thrombolysis that can lead to sustained recovery. An early boost in brain perfusion seen in the target CLOTBUST group resulted in a trend of 13% more patients achieving favorable outcome at 3 months. To further enhance the ability of TPA to break up thrombi, current ongoing clinical trials include phase II studies of 2 MHz TCD with ultrasound contrast agents or (microbubbles): TCD+TPA+Levovist; TCD+TPA+MRX nano-platform (C(3)F(8)). Intra-arterial TPA delivery can be enhanced with 1 x 7-2 x 1 MHz pulsed wave ultrasound (EKOS catheter, IMS trial). Dose escalation studies of microbubbles, ultrasound exposure, and the development of an operator-independent ultrasound device are underway.