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Papers by CARLOS ALBERTO Molina

Stroke, 2007

Background and Purpose-The objective of this study was to examine clinical outcomes and recanaliz... more Background and Purpose-The objective of this study was to examine clinical outcomes and recanalization rates in a multicenter cohort of stroke patients receiving intravenous tissue plasminogen activator by site of occlusion localized with bedside transcranial Doppler. Angiographic studies with intraarterial thrombolysis suggest more proximal occlusions carry greater thrombus burden and benefit less from local therapy. Methods-Using validated transcranial Doppler criteria for specific arterial occlusion (Thrombolysis in Brain Ischemia flow grades), we compared the rate of dramatic recovery (National Institutes of Health Stroke Scale score Յ2 at 24 hours) and favorable outcomes at 3 months (modified Rankin Scale Յ1) for each occlusion site. We determined the likelihood of recanalization at various occlusion sites and its predictors. Then, stepwise logistic regression was used to determine predictors of complete recanalization.

Background and Purpose-Although early recanalization is a powerful predictor of stroke outcome af... more Background and Purpose-Although early recanalization is a powerful predictor of stroke outcome after thrombolysis, some stroke patients remain disabled despite tissue plasminogen activator (tPA)-induced recanalization. Therefore, we sought to investigate whether the predictive accuracy of early recanalization on stroke outcome is improved when combined with clinical and radiological information. Methods-We evaluated 177 patients with nonlacunar strokes in the middle cerebral artery (MCA) treated with intravenous tPA who were followed up during 3 months. Transcranial Doppler monitoring of recanalization was conducted during the first hours after tPA administration. The relative contribution of clinical, transcranial Doppler, and radiological information on stroke outcome was evaluated. We used logistic regression to derive a predictive model for good outcome (modified Rankin Scale score Յ2) after thrombolysis. Results-Median National Institutes of Health Stroke Scale (NIHSS) score before tPA was 16. At 3 months, 87 patients (49.2%) became functionally independent (modified Rankin Scale score Յ2). In a logistic regression model, degree of recanalization within 300 minutes (PϽ0.001), proximal MCA occlusion (PϽ0.001), baseline NIHSS score (Pϭ0.0013), systolic blood pressure (Pϭ0.0116), and early ischemic changes on CT (Pϭ0.0253) independently predicted outcome at 3 months. A 5-item score was developed on the basis of the factors significantly associated with stroke outcome in the logistic regression (total score range, 0 to 7). The likelihood of good outcome at 3 months was 0.82 (95% CI, 0.72 to 0.92) in patients who scored 0 to 2, 0.51 (95% CI, 0.36 to 0.66) in those who scored 3 to 4, and 0.15 (95% CI, 0.05 to 0.25) in those who scored 5 to 7 points. Conclusions-The combination of clinical, radiological, and hemodynamic information predicts with a high accuracy long-term stroke outcome during or shortly after intravenous tPA administration. (Stroke. 2004;35:151-157.)

Stroke, 2007

Background and Purpose-The use of intravenous thrombolysis is restricted to a minority of patient... more Background and Purpose-The use of intravenous thrombolysis is restricted to a minority of patients by the rigid 3-hour time window. This window may be extended by using modern imaging-based selection algorithms. We assessed safety and efficacy of MRI-based thrombolysis within and beyond 3 hours compared with standard CT-based thrombolysis. Methods-Five European stroke centers pooled the core data of their CT-and MRI-based prospective thrombolysis databases. Safety outcomes were predefined as symptomatic intracranial hemorrhage and mortality. Primary efficacy outcome was a favorable outcome (modified Rankin Scale 0 to 1). We performed univariate and multivariate analyses for all end points, including age, National Institutes of Health Stroke Scale, treatment group (CT Ͻ3 hours, MRI Ͻ3 hours and Ͼ3 hours), and onset to treatment time as variables. Results-A total of 1210 patients were included (CT Ͻ3 hours: Nϭ714; MRI Ͻ3 hours: Nϭ316; MRI Ͼ3 hours: Nϭ180). Median age, National Institutes of Health Stroke Scale, and onset to treatment time were 69, 67, and 68.5 years (Pϭ0.66); 12, 13, and 14 points (Pϭ0.019); and 130, 135, and 240 minutes (PϽ0.001). Symptomatic intracranial hemorrhage rates were 5.3%, 2.8%, and 4.4% (Pϭ0.213); mortality was 13.7%, 11.7%, and 13.3% (Pϭ0.68). Favorable outcome occurred in 35.4%, 37.0%, and 40% (Pϭ0.51). Age and National Institutes of Health Stroke Scale were independent predictors for all safety and efficacy outcomes. The overall use of MRI significantly reduced symptomatic intracranial hemorrhage (OR: 0.520, 95% CI: 0.270 to 0.999, Pϭ0.05). Beyond 3 hours, the use of MRI significantly predicted a favorable outcome (OR: 1.467; 95% CI: 1.017 to 2.117, Pϭ0.040). Within 3 hours and for all secondary end points, there was a trend in favor of MRI-based selection over standard Ͻ3-hour CT-based treatment. Conclusion-Despite significantly longer time windows and significantly higher baseline National Institutes of Health Stroke Scale scores, MRI-based thrombolysis is safer and potentially more efficacious than standard CT-based thrombolysis. (Stroke. 2007;38:2640-2645.)

Background and Purpose-The relationship between reperfusion and hemorrhagic transformation (HT) r... more Background and Purpose-The relationship between reperfusion and hemorrhagic transformation (HT) remains uncertain.

Stroke, 2001

Background and Purpose-Patients with symptomatic intracranial atherosclerotic stenosis have a hig... more Background and Purpose-Patients with symptomatic intracranial atherosclerotic stenosis have a high rate of recurrence.

Background and Purpose-The role of early and delayed recanalization after thrombolysis in the dev... more Background and Purpose-The role of early and delayed recanalization after thrombolysis in the development of hemorrhagic transformation (HT) subtypes remains uncertain. We sought to explore the association between the timing of recanalization and HT risk in patients with proximal middle cerebral artery (MCA) occlusion treated with intravenous recombinant tissue plasminogen activator (rtPA) Ͻ3 hours of stroke onset and to investigate the relationship between HT subtypes, infarct volume, and outcome. Methods-Thirty-two patients with acute stroke caused by proximal MCA occlusion treated with rtPA Ͻ3 hours of symptom onset were prospectively studied. Serial transcranial Doppler examinations were performed on admission and at 6, 12, 24, and 48 hours. Presence and type of HT were assessed on CT at 36 to 48 hours. Modified Rankin scale was used to assess outcome at 3 months. Results-Early and delayed recanalization was identified in 17 patients (53.1%) and 8 patients (25%), respectively. HT was detected in 14 patients (43.7%): 4 (12.5%) with hemorrhagic infarction (HI 1 ), 5 (15.6%) with HI 2 , 3 (9.3%) with parenchymal hematoma (PH 1 ), and 2 (6.8%) with PH 2 . Distribution of HT subtypes differed significantly (Pϭ0.025), depending on the time to artery reopening. Eight of 9 (89%), 1 of 5 (20%), and 8 of 18 (44.4%) with HI 1 -HI 2 , with PH 1 -PH 2 , and without HT, respectively, recanalized in Ͻ6 hours. Delayed recanalization was observed in 1 patient with HI 1 -HI 2 (11%), 4 with PH 1 -PH 2 (80%), and 3 without HT (16.6%). Neurological improvement was significantly (PϽ0.001) more frequent in patients with HI 1 -HI 2 (88%) than in those without HT (39%). Infarct volume was significantly (PϽ0.031) lower in patients with HI 1 -HI 2 (51.4Ϯ42 cm 3 ) than in patients with PH 1 -PH 2 (83.8Ϯ48 cm 3 ) and those without HT (98.4Ϯ84 cm 3 , Pϭ0.021). The modified Rankin scale score was significantly lower in HI 1 -HI 2 compared with PH 1 -PH 2 patients (1.9Ϯ1.1 versus 4.6Ϯ1.2, PϽ0.001) and with those without HT (1.9Ϯ1.1 versus 3.5Ϯ2.0, Pϭ0.009.). Conclusions-Thrombolysis-related HI (HI 1 -HI 2 ) represents a marker of early successful recanalization, which leads to a reduced infarct size and improved clinical outcome. (Stroke. 2002;33:1551-1556.)

New England Journal of Medicine, 2004

Background and Purpose-We sought to investigate the impact of hyperglycemia before reperfusion on... more Background and Purpose-We sought to investigate the impact of hyperglycemia before reperfusion on long-term outcome in patients treated with intravenous tissue plasminogen activator (tPA). Methods-Of 268 consecutive patients with a nonlacunar middle cerebral artery (MCA) stroke evaluated at Ͻ3 hours after onset, 73 (27.2%) received intravenous tPA. Serum glucose was determined at baseline before tPA administration. Hyperglycemia was defined as a glucose level Ͼ140 mg/dL. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and 24 hours. Transcranial Doppler monitoring of recanalization and reocclusion was conducted during the first 24 hours. Total infarct volume was measured on CT at day 5 to 7. Modified Rankin Scale was used to assess outcome at 3 months.

Background and Purpose-The use of intravenous thrombolysis is restricted to a minority of patient... more Background and Purpose-The use of intravenous thrombolysis is restricted to a minority of patients by the rigid 3-hour time window. This window may be extended by using modern imaging-based selection algorithms. We assessed safety and efficacy of MRI-based thrombolysis within and beyond 3 hours compared with standard CT-based thrombolysis. Methods-Five European stroke centers pooled the core data of their CT-and MRI-based prospective thrombolysis databases. Safety outcomes were predefined as symptomatic intracranial hemorrhage and mortality. Primary efficacy outcome was a favorable outcome (modified Rankin Scale 0 to 1). We performed univariate and multivariate analyses for all end points, including age, National Institutes of Health Stroke Scale, treatment group (CT Ͻ3 hours, MRI Ͻ3 hours and Ͼ3 hours), and onset to treatment time as variables. Results-A total of 1210 patients were included (CT Ͻ3 hours: Nϭ714; MRI Ͻ3 hours: Nϭ316; MRI Ͼ3 hours: Nϭ180). Median age, National Institutes of Health Stroke Scale, and onset to treatment time were 69, 67, and 68.5 years (Pϭ0.66); 12, 13, and 14 points (Pϭ0.019); and 130, 135, and 240 minutes (PϽ0.001). Symptomatic intracranial hemorrhage rates were 5.3%, 2.8%, and 4.4% (Pϭ0.213); mortality was 13.7%, 11.7%, and 13.3% (Pϭ0.68). Favorable outcome occurred in 35.4%, 37.0%, and 40% (Pϭ0.51). Age and National Institutes of Health Stroke Scale were independent predictors for all safety and efficacy outcomes. The overall use of MRI significantly reduced symptomatic intracranial hemorrhage (OR: 0.520, 95% CI: 0.270 to 0.999, Pϭ0.05). Beyond 3 hours, the use of MRI significantly predicted a favorable outcome (OR: 1.467; 95% CI: 1.017 to 2.117, Pϭ0.040). Within 3 hours and for all secondary end points, there was a trend in favor of MRI-based selection over standard Ͻ3-hour CT-based treatment. Conclusion-Despite significantly longer time windows and significantly higher baseline National Institutes of Health Stroke Scale scores, MRI-based thrombolysis is safer and potentially more efficacious than standard CT-based thrombolysis. (Stroke. 2007;38:2640-2645.)

Stroke, 2001

Background and Purpose-In animal models of cerebral ischemia, matrix metalloproteinase (MMP) expr... more Background and Purpose-In animal models of cerebral ischemia, matrix metalloproteinase (MMP) expression was significantly increased and related to blood-brain barrier disruption, edema formation, and hemorrhagic transformation (HT). MMP inhibitors reduce HT after embolic ischemia in tissue-type plasminogen activator-treated animals. We aimed to determine the relationship between MMPs and HT after human ischemic stroke. Methods-Serial MMP-2 and MMP-9 determinations were performed by means of ELISA in 39 cardioembolic strokes in the middle cerebral artery territory. Hemorrhagic events were classified according to clinical and CT criteria (hemorrhagic infarction [HI] and parenchymal hematoma [PH]). HT was evaluated on CT at 48 hours (early HT) and again between day 5 and 7 (late HT). Results-HT was present in 41% of the patients (43.75% early HI, 25% early PH and 31.25% late HI). MMP-2 values were within normal range and were unrelated to HT. Increased expression of MMP-9 (normal range Ͻ97 ng/mL) was found among patients with and without HT (159.3Ϯ82 versus 143.9Ϯ112.6 ng/mL; Pϭ0.64). According to HT subtypes, the highest baseline MMP-9 levels corresponded to patients with late HI (240.4Ϯ111.2 versus 102.5Ϯ76.7 ng/mL for all other patients, Pϭ0.002). Baseline MMP-9 was the only variable associated with late HI in the multiple logistic regression model (OR 9; CI 1.46, 55.24; Pϭ0.010). Peak of MMP-9 at the 24-hour time point (250.6 ng/mL) was found before appearance of PH. Conclusions-MMPs are involved in some subtypes of HT after human cardioembolic stroke. Baseline MMP-9 level predicts late HI and a 24-hour peak precedes early PH. (Stroke. 2001;32:2762-2767.)

Stroke, 2001

Background and Purpose-The relationship between arterial recanalization, infarct size, and outcom... more Background and Purpose-The relationship between arterial recanalization, infarct size, and outcome in patients treated with intravenous thrombolytics remains unclear. Therefore, we aimed to determine the time course of recombinant tissue plasminogen activator (rtPA)-induced recanalization in patients with cardioembolic stroke treated Ͻ3 hours from symptom onset and to investigate the relationship between arterial recanalization, infarct volume, and outcome. Methods-We prospectively studied 72 patients with an acute cardioembolic stroke in the middle cerebral artery territory: 24 treated with rtPA at Ͻ3 hours and 48 matched controls. Serial transcranial Doppler examinations were performed on admission and at 6,12, 24, and 48 hours. Infarct volume was measured by use of CT at day 5 to 7. Modified Rankin Scale score was used to assess outcome at 3 months. Results-Rate of 6-hour recanalization was higher (PϽ0.001) in the rtPA group (66%) than in the control group (15%).

Neuroscience Letters, 2006

Angiotensin converting enzyme (ACE) influences vessels tone and the coagulation/fibrinolysis syst... more Angiotensin converting enzyme (ACE) influences vessels tone and the coagulation/fibrinolysis system. The ACE gene I/D polymorphism has been linked with PAI-1 and fibrinogen levels and with Factors VII and X activities. Therefore, we aimed to test whether I/D polymorphism could be related to thrombolysis safety and efficacy. We studied strokes involving the middle cerebral artery (MCA) territory of patients who received t-PA <3 h of stroke onset. Blood samples were obtained before t-PA administration to measure fibrinogen, PAI-1, Factors VII and X. I/D polymorphism was determined by polymerase chain reaction and agarose electrophoresis. Recanalization rates were serially evaluated by Transcranial Doppler. Among 96 included patients the genotype frequency was: DD = 33.3%, ID = 57.3% and II = 9.4%. A strong association was found between DD homozygous and successful recanalization rates (DD = 69.2%, ID + II = 31.6%, p = 0.002 at 1 h; DD = 91.3%, ID + II = 51%, p = 0.001 at 6 h; DD = 100%, ID + II = 72.3%, p = 0.003 at 24 h post-t-PA administration). In fact, DD genotype was an independent predictor of recanalization (OR = 4.3 95% CI 1.35-13.49, p = 0.013). No relation was found between I/D polymorphism and symptomatic hemorrhagic complications (p = 0.237). No association between ACE genotypes and Factor VII or Factor X activities, neither with fibrinogen or PAI-1 levels was observed. DD homozygous is strongly associated with MCA recanalization following t-PA treatment. Mechanisms of benefit remain unknown since I/D polymorphism had similar FVII and X activities and PAI-1 and fibrinogen levels in our stroke population.

Stroke, 2007

Background and Purpose-The use of intravenous thrombolysis is restricted to a minority of patient... more Background and Purpose-The use of intravenous thrombolysis is restricted to a minority of patients by the rigid 3-hour time window. This window may be extended by using modern imaging-based selection algorithms. We assessed safety and efficacy of MRI-based thrombolysis within and beyond 3 hours compared with standard CT-based thrombolysis. Methods-Five European stroke centers pooled the core data of their CT-and MRI-based prospective thrombolysis databases. Safety outcomes were predefined as symptomatic intracranial hemorrhage and mortality. Primary efficacy outcome was a favorable outcome (modified Rankin Scale 0 to 1). We performed univariate and multivariate analyses for all end points, including age, National Institutes of Health Stroke Scale, treatment group (CT Ͻ3 hours, MRI Ͻ3 hours and Ͼ3 hours), and onset to treatment time as variables. Results-A total of 1210 patients were included (CT Ͻ3 hours: Nϭ714; MRI Ͻ3 hours: Nϭ316; MRI Ͼ3 hours: Nϭ180). Median age, National Institutes of Health Stroke Scale, and onset to treatment time were 69, 67, and 68.5 years (Pϭ0.66); 12, 13, and 14 points (Pϭ0.019); and 130, 135, and 240 minutes (PϽ0.001). Symptomatic intracranial hemorrhage rates were 5.3%, 2.8%, and 4.4% (Pϭ0.213); mortality was 13.7%, 11.7%, and 13.3% (Pϭ0.68). Favorable outcome occurred in 35.4%, 37.0%, and 40% (Pϭ0.51). Age and National Institutes of Health Stroke Scale were independent predictors for all safety and efficacy outcomes. The overall use of MRI significantly reduced symptomatic intracranial hemorrhage (OR: 0.520, 95% CI: 0.270 to 0.999, Pϭ0.05). Beyond 3 hours, the use of MRI significantly predicted a favorable outcome (OR: 1.467; 95% CI: 1.017 to 2.117, Pϭ0.040). Within 3 hours and for all secondary end points, there was a trend in favor of MRI-based selection over standard Ͻ3-hour CT-based treatment. Conclusion-Despite significantly longer time windows and significantly higher baseline National Institutes of Health Stroke Scale scores, MRI-based thrombolysis is safer and potentially more efficacious than standard CT-based thrombolysis. (Stroke. 2007;38:2640-2645.)

Background and Purpose-The relationship between reperfusion and hemorrhagic transformation (HT) r... more Background and Purpose-The relationship between reperfusion and hemorrhagic transformation (HT) remains uncertain.

Stroke, 2001

Background and Purpose-Patients with symptomatic intracranial atherosclerotic stenosis have a hig... more Background and Purpose-Patients with symptomatic intracranial atherosclerotic stenosis have a high rate of recurrence.

Background and Purpose-The role of early and delayed recanalization after thrombolysis in the dev... more Background and Purpose-The role of early and delayed recanalization after thrombolysis in the development of hemorrhagic transformation (HT) subtypes remains uncertain. We sought to explore the association between the timing of recanalization and HT risk in patients with proximal middle cerebral artery (MCA) occlusion treated with intravenous recombinant tissue plasminogen activator (rtPA) Ͻ3 hours of stroke onset and to investigate the relationship between HT subtypes, infarct volume, and outcome. Methods-Thirty-two patients with acute stroke caused by proximal MCA occlusion treated with rtPA Ͻ3 hours of symptom onset were prospectively studied. Serial transcranial Doppler examinations were performed on admission and at 6, 12, 24, and 48 hours. Presence and type of HT were assessed on CT at 36 to 48 hours. Modified Rankin scale was used to assess outcome at 3 months. Results-Early and delayed recanalization was identified in 17 patients (53.1%) and 8 patients (25%), respectively. HT was detected in 14 patients (43.7%): 4 (12.5%) with hemorrhagic infarction (HI 1 ), 5 (15.6%) with HI 2 , 3 (9.3%) with parenchymal hematoma (PH 1 ), and 2 (6.8%) with PH 2 . Distribution of HT subtypes differed significantly (Pϭ0.025), depending on the time to artery reopening. Eight of 9 (89%), 1 of 5 (20%), and 8 of 18 (44.4%) with HI 1 -HI 2 , with PH 1 -PH 2 , and without HT, respectively, recanalized in Ͻ6 hours. Delayed recanalization was observed in 1 patient with HI 1 -HI 2 (11%), 4 with PH 1 -PH 2 (80%), and 3 without HT (16.6%). Neurological improvement was significantly (PϽ0.001) more frequent in patients with HI 1 -HI 2 (88%) than in those without HT (39%). Infarct volume was significantly (PϽ0.031) lower in patients with HI 1 -HI 2 (51.4Ϯ42 cm 3 ) than in patients with PH 1 -PH 2 (83.8Ϯ48 cm 3 ) and those without HT (98.4Ϯ84 cm 3 , Pϭ0.021). The modified Rankin scale score was significantly lower in HI 1 -HI 2 compared with PH 1 -PH 2 patients (1.9Ϯ1.1 versus 4.6Ϯ1.2, PϽ0.001) and with those without HT (1.9Ϯ1.1 versus 3.5Ϯ2.0, Pϭ0.009.). Conclusions-Thrombolysis-related HI (HI 1 -HI 2 ) represents a marker of early successful recanalization, which leads to a reduced infarct size and improved clinical outcome. (Stroke. 2002;33:1551-1556.)

New England Journal of Medicine, 2004

Stroke, 2007

Background and Purpose-The objective of this study was to examine clinical outcomes and recanaliz... more Background and Purpose-The objective of this study was to examine clinical outcomes and recanalization rates in a multicenter cohort of stroke patients receiving intravenous tissue plasminogen activator by site of occlusion localized with bedside transcranial Doppler. Angiographic studies with intraarterial thrombolysis suggest more proximal occlusions carry greater thrombus burden and benefit less from local therapy. Methods-Using validated transcranial Doppler criteria for specific arterial occlusion (Thrombolysis in Brain Ischemia flow grades), we compared the rate of dramatic recovery (National Institutes of Health Stroke Scale score Յ2 at 24 hours) and favorable outcomes at 3 months (modified Rankin Scale Յ1) for each occlusion site. We determined the likelihood of recanalization at various occlusion sites and its predictors. Then, stepwise logistic regression was used to determine predictors of complete recanalization.

Background and Purpose-Although early recanalization is a powerful predictor of stroke outcome af... more Background and Purpose-Although early recanalization is a powerful predictor of stroke outcome after thrombolysis, some stroke patients remain disabled despite tissue plasminogen activator (tPA)-induced recanalization. Therefore, we sought to investigate whether the predictive accuracy of early recanalization on stroke outcome is improved when combined with clinical and radiological information. Methods-We evaluated 177 patients with nonlacunar strokes in the middle cerebral artery (MCA) treated with intravenous tPA who were followed up during 3 months. Transcranial Doppler monitoring of recanalization was conducted during the first hours after tPA administration. The relative contribution of clinical, transcranial Doppler, and radiological information on stroke outcome was evaluated. We used logistic regression to derive a predictive model for good outcome (modified Rankin Scale score Յ2) after thrombolysis. Results-Median National Institutes of Health Stroke Scale (NIHSS) score before tPA was 16. At 3 months, 87 patients (49.2%) became functionally independent (modified Rankin Scale score Յ2). In a logistic regression model, degree of recanalization within 300 minutes (PϽ0.001), proximal MCA occlusion (PϽ0.001), baseline NIHSS score (Pϭ0.0013), systolic blood pressure (Pϭ0.0116), and early ischemic changes on CT (Pϭ0.0253) independently predicted outcome at 3 months. A 5-item score was developed on the basis of the factors significantly associated with stroke outcome in the logistic regression (total score range, 0 to 7). The likelihood of good outcome at 3 months was 0.82 (95% CI, 0.72 to 0.92) in patients who scored 0 to 2, 0.51 (95% CI, 0.36 to 0.66) in those who scored 3 to 4, and 0.15 (95% CI, 0.05 to 0.25) in those who scored 5 to 7 points. Conclusions-The combination of clinical, radiological, and hemodynamic information predicts with a high accuracy long-term stroke outcome during or shortly after intravenous tPA administration. (Stroke. 2004;35:151-157.)

Stroke, 2007

Background and Purpose-The use of intravenous thrombolysis is restricted to a minority of patient... more Background and Purpose-The use of intravenous thrombolysis is restricted to a minority of patients by the rigid 3-hour time window. This window may be extended by using modern imaging-based selection algorithms. We assessed safety and efficacy of MRI-based thrombolysis within and beyond 3 hours compared with standard CT-based thrombolysis. Methods-Five European stroke centers pooled the core data of their CT-and MRI-based prospective thrombolysis databases. Safety outcomes were predefined as symptomatic intracranial hemorrhage and mortality. Primary efficacy outcome was a favorable outcome (modified Rankin Scale 0 to 1). We performed univariate and multivariate analyses for all end points, including age, National Institutes of Health Stroke Scale, treatment group (CT Ͻ3 hours, MRI Ͻ3 hours and Ͼ3 hours), and onset to treatment time as variables. Results-A total of 1210 patients were included (CT Ͻ3 hours: Nϭ714; MRI Ͻ3 hours: Nϭ316; MRI Ͼ3 hours: Nϭ180). Median age, National Institutes of Health Stroke Scale, and onset to treatment time were 69, 67, and 68.5 years (Pϭ0.66); 12, 13, and 14 points (Pϭ0.019); and 130, 135, and 240 minutes (PϽ0.001). Symptomatic intracranial hemorrhage rates were 5.3%, 2.8%, and 4.4% (Pϭ0.213); mortality was 13.7%, 11.7%, and 13.3% (Pϭ0.68). Favorable outcome occurred in 35.4%, 37.0%, and 40% (Pϭ0.51). Age and National Institutes of Health Stroke Scale were independent predictors for all safety and efficacy outcomes. The overall use of MRI significantly reduced symptomatic intracranial hemorrhage (OR: 0.520, 95% CI: 0.270 to 0.999, Pϭ0.05). Beyond 3 hours, the use of MRI significantly predicted a favorable outcome (OR: 1.467; 95% CI: 1.017 to 2.117, Pϭ0.040). Within 3 hours and for all secondary end points, there was a trend in favor of MRI-based selection over standard Ͻ3-hour CT-based treatment. Conclusion-Despite significantly longer time windows and significantly higher baseline National Institutes of Health Stroke Scale scores, MRI-based thrombolysis is safer and potentially more efficacious than standard CT-based thrombolysis. (Stroke. 2007;38:2640-2645.)

Background and Purpose-The relationship between reperfusion and hemorrhagic transformation (HT) r... more Background and Purpose-The relationship between reperfusion and hemorrhagic transformation (HT) remains uncertain.

Stroke, 2001

Background and Purpose-Patients with symptomatic intracranial atherosclerotic stenosis have a hig... more Background and Purpose-Patients with symptomatic intracranial atherosclerotic stenosis have a high rate of recurrence.

Background and Purpose-The role of early and delayed recanalization after thrombolysis in the dev... more Background and Purpose-The role of early and delayed recanalization after thrombolysis in the development of hemorrhagic transformation (HT) subtypes remains uncertain. We sought to explore the association between the timing of recanalization and HT risk in patients with proximal middle cerebral artery (MCA) occlusion treated with intravenous recombinant tissue plasminogen activator (rtPA) Ͻ3 hours of stroke onset and to investigate the relationship between HT subtypes, infarct volume, and outcome. Methods-Thirty-two patients with acute stroke caused by proximal MCA occlusion treated with rtPA Ͻ3 hours of symptom onset were prospectively studied. Serial transcranial Doppler examinations were performed on admission and at 6, 12, 24, and 48 hours. Presence and type of HT were assessed on CT at 36 to 48 hours. Modified Rankin scale was used to assess outcome at 3 months. Results-Early and delayed recanalization was identified in 17 patients (53.1%) and 8 patients (25%), respectively. HT was detected in 14 patients (43.7%): 4 (12.5%) with hemorrhagic infarction (HI 1 ), 5 (15.6%) with HI 2 , 3 (9.3%) with parenchymal hematoma (PH 1 ), and 2 (6.8%) with PH 2 . Distribution of HT subtypes differed significantly (Pϭ0.025), depending on the time to artery reopening. Eight of 9 (89%), 1 of 5 (20%), and 8 of 18 (44.4%) with HI 1 -HI 2 , with PH 1 -PH 2 , and without HT, respectively, recanalized in Ͻ6 hours. Delayed recanalization was observed in 1 patient with HI 1 -HI 2 (11%), 4 with PH 1 -PH 2 (80%), and 3 without HT (16.6%). Neurological improvement was significantly (PϽ0.001) more frequent in patients with HI 1 -HI 2 (88%) than in those without HT (39%). Infarct volume was significantly (PϽ0.031) lower in patients with HI 1 -HI 2 (51.4Ϯ42 cm 3 ) than in patients with PH 1 -PH 2 (83.8Ϯ48 cm 3 ) and those without HT (98.4Ϯ84 cm 3 , Pϭ0.021). The modified Rankin scale score was significantly lower in HI 1 -HI 2 compared with PH 1 -PH 2 patients (1.9Ϯ1.1 versus 4.6Ϯ1.2, PϽ0.001) and with those without HT (1.9Ϯ1.1 versus 3.5Ϯ2.0, Pϭ0.009.). Conclusions-Thrombolysis-related HI (HI 1 -HI 2 ) represents a marker of early successful recanalization, which leads to a reduced infarct size and improved clinical outcome. (Stroke. 2002;33:1551-1556.)

New England Journal of Medicine, 2004

Background and Purpose-We sought to investigate the impact of hyperglycemia before reperfusion on... more Background and Purpose-We sought to investigate the impact of hyperglycemia before reperfusion on long-term outcome in patients treated with intravenous tissue plasminogen activator (tPA). Methods-Of 268 consecutive patients with a nonlacunar middle cerebral artery (MCA) stroke evaluated at Ͻ3 hours after onset, 73 (27.2%) received intravenous tPA. Serum glucose was determined at baseline before tPA administration. Hyperglycemia was defined as a glucose level Ͼ140 mg/dL. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and 24 hours. Transcranial Doppler monitoring of recanalization and reocclusion was conducted during the first 24 hours. Total infarct volume was measured on CT at day 5 to 7. Modified Rankin Scale was used to assess outcome at 3 months.

Background and Purpose-The use of intravenous thrombolysis is restricted to a minority of patient... more Background and Purpose-The use of intravenous thrombolysis is restricted to a minority of patients by the rigid 3-hour time window. This window may be extended by using modern imaging-based selection algorithms. We assessed safety and efficacy of MRI-based thrombolysis within and beyond 3 hours compared with standard CT-based thrombolysis. Methods-Five European stroke centers pooled the core data of their CT-and MRI-based prospective thrombolysis databases. Safety outcomes were predefined as symptomatic intracranial hemorrhage and mortality. Primary efficacy outcome was a favorable outcome (modified Rankin Scale 0 to 1). We performed univariate and multivariate analyses for all end points, including age, National Institutes of Health Stroke Scale, treatment group (CT Ͻ3 hours, MRI Ͻ3 hours and Ͼ3 hours), and onset to treatment time as variables. Results-A total of 1210 patients were included (CT Ͻ3 hours: Nϭ714; MRI Ͻ3 hours: Nϭ316; MRI Ͼ3 hours: Nϭ180). Median age, National Institutes of Health Stroke Scale, and onset to treatment time were 69, 67, and 68.5 years (Pϭ0.66); 12, 13, and 14 points (Pϭ0.019); and 130, 135, and 240 minutes (PϽ0.001). Symptomatic intracranial hemorrhage rates were 5.3%, 2.8%, and 4.4% (Pϭ0.213); mortality was 13.7%, 11.7%, and 13.3% (Pϭ0.68). Favorable outcome occurred in 35.4%, 37.0%, and 40% (Pϭ0.51). Age and National Institutes of Health Stroke Scale were independent predictors for all safety and efficacy outcomes. The overall use of MRI significantly reduced symptomatic intracranial hemorrhage (OR: 0.520, 95% CI: 0.270 to 0.999, Pϭ0.05). Beyond 3 hours, the use of MRI significantly predicted a favorable outcome (OR: 1.467; 95% CI: 1.017 to 2.117, Pϭ0.040). Within 3 hours and for all secondary end points, there was a trend in favor of MRI-based selection over standard Ͻ3-hour CT-based treatment. Conclusion-Despite significantly longer time windows and significantly higher baseline National Institutes of Health Stroke Scale scores, MRI-based thrombolysis is safer and potentially more efficacious than standard CT-based thrombolysis. (Stroke. 2007;38:2640-2645.)

Stroke, 2001

Background and Purpose-In animal models of cerebral ischemia, matrix metalloproteinase (MMP) expr... more Background and Purpose-In animal models of cerebral ischemia, matrix metalloproteinase (MMP) expression was significantly increased and related to blood-brain barrier disruption, edema formation, and hemorrhagic transformation (HT). MMP inhibitors reduce HT after embolic ischemia in tissue-type plasminogen activator-treated animals. We aimed to determine the relationship between MMPs and HT after human ischemic stroke. Methods-Serial MMP-2 and MMP-9 determinations were performed by means of ELISA in 39 cardioembolic strokes in the middle cerebral artery territory. Hemorrhagic events were classified according to clinical and CT criteria (hemorrhagic infarction [HI] and parenchymal hematoma [PH]). HT was evaluated on CT at 48 hours (early HT) and again between day 5 and 7 (late HT). Results-HT was present in 41% of the patients (43.75% early HI, 25% early PH and 31.25% late HI). MMP-2 values were within normal range and were unrelated to HT. Increased expression of MMP-9 (normal range Ͻ97 ng/mL) was found among patients with and without HT (159.3Ϯ82 versus 143.9Ϯ112.6 ng/mL; Pϭ0.64). According to HT subtypes, the highest baseline MMP-9 levels corresponded to patients with late HI (240.4Ϯ111.2 versus 102.5Ϯ76.7 ng/mL for all other patients, Pϭ0.002). Baseline MMP-9 was the only variable associated with late HI in the multiple logistic regression model (OR 9; CI 1.46, 55.24; Pϭ0.010). Peak of MMP-9 at the 24-hour time point (250.6 ng/mL) was found before appearance of PH. Conclusions-MMPs are involved in some subtypes of HT after human cardioembolic stroke. Baseline MMP-9 level predicts late HI and a 24-hour peak precedes early PH. (Stroke. 2001;32:2762-2767.)

Stroke, 2001

Background and Purpose-The relationship between arterial recanalization, infarct size, and outcom... more Background and Purpose-The relationship between arterial recanalization, infarct size, and outcome in patients treated with intravenous thrombolytics remains unclear. Therefore, we aimed to determine the time course of recombinant tissue plasminogen activator (rtPA)-induced recanalization in patients with cardioembolic stroke treated Ͻ3 hours from symptom onset and to investigate the relationship between arterial recanalization, infarct volume, and outcome. Methods-We prospectively studied 72 patients with an acute cardioembolic stroke in the middle cerebral artery territory: 24 treated with rtPA at Ͻ3 hours and 48 matched controls. Serial transcranial Doppler examinations were performed on admission and at 6,12, 24, and 48 hours. Infarct volume was measured by use of CT at day 5 to 7. Modified Rankin Scale score was used to assess outcome at 3 months. Results-Rate of 6-hour recanalization was higher (PϽ0.001) in the rtPA group (66%) than in the control group (15%).

Neuroscience Letters, 2006

Angiotensin converting enzyme (ACE) influences vessels tone and the coagulation/fibrinolysis syst... more Angiotensin converting enzyme (ACE) influences vessels tone and the coagulation/fibrinolysis system. The ACE gene I/D polymorphism has been linked with PAI-1 and fibrinogen levels and with Factors VII and X activities. Therefore, we aimed to test whether I/D polymorphism could be related to thrombolysis safety and efficacy. We studied strokes involving the middle cerebral artery (MCA) territory of patients who received t-PA <3 h of stroke onset. Blood samples were obtained before t-PA administration to measure fibrinogen, PAI-1, Factors VII and X. I/D polymorphism was determined by polymerase chain reaction and agarose electrophoresis. Recanalization rates were serially evaluated by Transcranial Doppler. Among 96 included patients the genotype frequency was: DD = 33.3%, ID = 57.3% and II = 9.4%. A strong association was found between DD homozygous and successful recanalization rates (DD = 69.2%, ID + II = 31.6%, p = 0.002 at 1 h; DD = 91.3%, ID + II = 51%, p = 0.001 at 6 h; DD = 100%, ID + II = 72.3%, p = 0.003 at 24 h post-t-PA administration). In fact, DD genotype was an independent predictor of recanalization (OR = 4.3 95% CI 1.35-13.49, p = 0.013). No relation was found between I/D polymorphism and symptomatic hemorrhagic complications (p = 0.237). No association between ACE genotypes and Factor VII or Factor X activities, neither with fibrinogen or PAI-1 levels was observed. DD homozygous is strongly associated with MCA recanalization following t-PA treatment. Mechanisms of benefit remain unknown since I/D polymorphism had similar FVII and X activities and PAI-1 and fibrinogen levels in our stroke population.

Stroke, 2007

Background and Purpose-The use of intravenous thrombolysis is restricted to a minority of patient... more Background and Purpose-The use of intravenous thrombolysis is restricted to a minority of patients by the rigid 3-hour time window. This window may be extended by using modern imaging-based selection algorithms. We assessed safety and efficacy of MRI-based thrombolysis within and beyond 3 hours compared with standard CT-based thrombolysis. Methods-Five European stroke centers pooled the core data of their CT-and MRI-based prospective thrombolysis databases. Safety outcomes were predefined as symptomatic intracranial hemorrhage and mortality. Primary efficacy outcome was a favorable outcome (modified Rankin Scale 0 to 1). We performed univariate and multivariate analyses for all end points, including age, National Institutes of Health Stroke Scale, treatment group (CT Ͻ3 hours, MRI Ͻ3 hours and Ͼ3 hours), and onset to treatment time as variables. Results-A total of 1210 patients were included (CT Ͻ3 hours: Nϭ714; MRI Ͻ3 hours: Nϭ316; MRI Ͼ3 hours: Nϭ180). Median age, National Institutes of Health Stroke Scale, and onset to treatment time were 69, 67, and 68.5 years (Pϭ0.66); 12, 13, and 14 points (Pϭ0.019); and 130, 135, and 240 minutes (PϽ0.001). Symptomatic intracranial hemorrhage rates were 5.3%, 2.8%, and 4.4% (Pϭ0.213); mortality was 13.7%, 11.7%, and 13.3% (Pϭ0.68). Favorable outcome occurred in 35.4%, 37.0%, and 40% (Pϭ0.51). Age and National Institutes of Health Stroke Scale were independent predictors for all safety and efficacy outcomes. The overall use of MRI significantly reduced symptomatic intracranial hemorrhage (OR: 0.520, 95% CI: 0.270 to 0.999, Pϭ0.05). Beyond 3 hours, the use of MRI significantly predicted a favorable outcome (OR: 1.467; 95% CI: 1.017 to 2.117, Pϭ0.040). Within 3 hours and for all secondary end points, there was a trend in favor of MRI-based selection over standard Ͻ3-hour CT-based treatment. Conclusion-Despite significantly longer time windows and significantly higher baseline National Institutes of Health Stroke Scale scores, MRI-based thrombolysis is safer and potentially more efficacious than standard CT-based thrombolysis. (Stroke. 2007;38:2640-2645.)

Background and Purpose-The relationship between reperfusion and hemorrhagic transformation (HT) r... more Background and Purpose-The relationship between reperfusion and hemorrhagic transformation (HT) remains uncertain.

Stroke, 2001

Background and Purpose-Patients with symptomatic intracranial atherosclerotic stenosis have a hig... more Background and Purpose-Patients with symptomatic intracranial atherosclerotic stenosis have a high rate of recurrence.

Background and Purpose-The role of early and delayed recanalization after thrombolysis in the dev... more Background and Purpose-The role of early and delayed recanalization after thrombolysis in the development of hemorrhagic transformation (HT) subtypes remains uncertain. We sought to explore the association between the timing of recanalization and HT risk in patients with proximal middle cerebral artery (MCA) occlusion treated with intravenous recombinant tissue plasminogen activator (rtPA) Ͻ3 hours of stroke onset and to investigate the relationship between HT subtypes, infarct volume, and outcome. Methods-Thirty-two patients with acute stroke caused by proximal MCA occlusion treated with rtPA Ͻ3 hours of symptom onset were prospectively studied. Serial transcranial Doppler examinations were performed on admission and at 6, 12, 24, and 48 hours. Presence and type of HT were assessed on CT at 36 to 48 hours. Modified Rankin scale was used to assess outcome at 3 months. Results-Early and delayed recanalization was identified in 17 patients (53.1%) and 8 patients (25%), respectively. HT was detected in 14 patients (43.7%): 4 (12.5%) with hemorrhagic infarction (HI 1 ), 5 (15.6%) with HI 2 , 3 (9.3%) with parenchymal hematoma (PH 1 ), and 2 (6.8%) with PH 2 . Distribution of HT subtypes differed significantly (Pϭ0.025), depending on the time to artery reopening. Eight of 9 (89%), 1 of 5 (20%), and 8 of 18 (44.4%) with HI 1 -HI 2 , with PH 1 -PH 2 , and without HT, respectively, recanalized in Ͻ6 hours. Delayed recanalization was observed in 1 patient with HI 1 -HI 2 (11%), 4 with PH 1 -PH 2 (80%), and 3 without HT (16.6%). Neurological improvement was significantly (PϽ0.001) more frequent in patients with HI 1 -HI 2 (88%) than in those without HT (39%). Infarct volume was significantly (PϽ0.031) lower in patients with HI 1 -HI 2 (51.4Ϯ42 cm 3 ) than in patients with PH 1 -PH 2 (83.8Ϯ48 cm 3 ) and those without HT (98.4Ϯ84 cm 3 , Pϭ0.021). The modified Rankin scale score was significantly lower in HI 1 -HI 2 compared with PH 1 -PH 2 patients (1.9Ϯ1.1 versus 4.6Ϯ1.2, PϽ0.001) and with those without HT (1.9Ϯ1.1 versus 3.5Ϯ2.0, Pϭ0.009.). Conclusions-Thrombolysis-related HI (HI 1 -HI 2 ) represents a marker of early successful recanalization, which leads to a reduced infarct size and improved clinical outcome. (Stroke. 2002;33:1551-1556.)

New England Journal of Medicine, 2004