Manuel Quintana

Effects of Admission Hyperglycemia on Stroke Outcome in Reperfused Tissue Plasminogen Activator-Treated Patients

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 <3 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 >140 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. Results— Median NIHSS score was 17. At baseline, 31 patients (42.5%) were hyperglycemic and 42 (57.5%) normoglycemic. Early reperfusion (<6 hours) occurred in 43 patients (58.9%). Admission blood glucose correlated negatively with the degree of neurological improvement at 24 hours in reperfused (r =−0.43;P =0.019) but not in nonreperfused (r =−0.20;P =0.21) tPA-treated patients. Increased age (P =0.014), history of diabetes mellitus (P =0.043), admission glucose >140 mg/dL (P =0.002), and early reocclusion (P =0.004) were factors associated with poor outcome among reperfused patients. A logistic regression modeling revealed that only admission glucose value >140 mg/dL (odds ratio, 8.4; 95% CI, 1.76 to 40.02;P =0.005) emerged as an independent predictor of poor outcome despite tPA-induced recanalization. In patients with 6-hour persistent MCA occlusion, baseline NIHSS score >15 points (P =0.011) and proximal MCA occlusion (P =0.039) were variables associated with poor outcome on univariate analysis. In a logistic regression model, only NIHSS score >15 points (odds ratio, 11.9; 95% CI, 1.48 to 97.1;P =0.032) remained as an independent predictor of poor outcome and functional dependence at 3 months in nonreperfused tPA-treated patients. Conclusions— Hyperglycemia before reperfusion may in part counterbalance the beneficial effect of early restoration of blood flow, which translates into a worse outcome in hyperglycemic patients despite tPA-induced recanalization.

Higher Risk of Further Vascular Events Among Transient Ischemic Attack Patients With Diffusion-Weighted Imaging Acute Ischemic Lesions

Background and Purpose— Recently, a new definition of transient ischemic attack (TIA) has been proposed based on the duration of symptoms and diffusion-weighted imaging (DWI) findings. We investigate the value of temporal and neuroimaging data on the prognoses of TIA patients. Methods— Clinical data, symptom duration, DWI, and ultrasonographic findings were collected in 83 consecutive classical TIA patients attended in the emergency department. Stroke recurrence, myocardial infarction, or any vascular event was recorded at follow-up (mean of 389 days). Results— A total of 27 (32.5%) patients revealed focal abnormalities on DWI, whereas 37(44.6%) had symptoms lasting >1 hour. Large-artery disease was detected in 37 (44.6%) patients. Twenty (24.1%) patients experienced an endpoint: 2 (2.4%) myocardial infarctions, 16 (19.3%) cerebral ischemic events, and 2 cases (2.4%) of peripheral arterial disease. Cox proportional hazards multivariate analyses identified the association of symptoms >1 hour with DWI abnormalities as independent predictors of further cerebral ischemic events or any vascular event (hazard ratio [HR], 5.02; CI, 1.37 to 18.30; P=0.015; and HR, 3.77; CI, 1.09 to 13.00; P=0.029). Large-artery occlusive disease also remained an independent predictor of both endpoints (HR, 4.22; CI, 1.17 to 15.22; P=0.028; and HR, 3.60; CI, 1.14 to 11.39; P=0.0293). Conclusions— TIA patients with DWI abnormalities associated with duration of symptoms >1 hour and those with large-artery occlusive disease have a higher risk of further vascular events. Routine use of DWI and Doppler ultrasonographic examinations will be useful for identifying TIA patients at high risk to plan aggressive prevention therapies.

Acute Hyperglycemia State Is Associated With Lower tPA-Induced Recanalization Rates in Stroke Patients

Background and Purpose— Hyperglycemia (HG) has a deleterious effect in stroke patients by accelerating ischemic brain damage; moreover, its antifibrinolytic effect may also influence reperfusion. We aimed to study the effect of acute/chronic HG on tissue-type plasminogen activator (tPA)–induced recanalization. Methods— We studied 139 consecutive stroke patients with documented intracranial artery occlusion treated with intravenous tissue-type plasminogen activator (tPA). Admission glucose levels were recorded (in mg/dL). The existence of previous chronic HG was determined by plasma levels of glycosylated hemoglobin (HbA1c, %) and fructosamine (in &mgr;mol/L). Transcranial Doppler monitoring assessed complete recanalization 2 hours after tPA bolus. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and 48 hours. Results— On admission, the median NIHSS score was 18 and mean glucose value was140±63 mg/dL. At 2 hours, 32% of patients(n=44) achieved complete recanalization. Patients who recanalized showed lower admission glucose levels (127 vs 146 mg/dL; P=0.039) but no differences in HbA1c (6.3% vs 6.3%; P=0.896) or fructosamine (292 vs 293 &mgr;mol/L; P=0.957) were observed. Other variables associated with recanalization were initial distal middle cerebral artery occlusion (P=0.011) and platelet count (P=0.015). Patients with an admission glucose level >158 mg/dL had lower recanalization rates (16% vs 36.1%; P=0.035) and a higher NIHSS score at 48 hours (7 vs 14.5; P=0.04). After adjustment for stroke etiology, age, and risk factors, the only independent predictors on admission of no recanalization were glucose value >158 mg/dL (odds ratio [OR], 7.3; 95% confidence interval [CI], 1.3 to 42.3; P=0.027), proximal middle cerebral artery occlusion (OR, 2.6; 95% CI, 1.1 to 6.5; P=0.034), and platelet count <219 000/mL (OR, 2.6; 95% CI, 1.1 to 6.1; P=0.029). Conclusions— In tPA-treated patients, the acute but not chronic HG state may hamper the fibrinolytic process, delaying reperfusion of the ischemic penumbra. Early measures to reduce HG may favor early recanalization.

C-Reactive Protein Predicts Further Ischemic Events in First-Ever Transient Ischemic Attack or Stroke Patients With Intracranial Large-Artery Occlusive Disease

Background and Purpose— The role of inflammation in intracranial large-artery occlusive disease is unclear. We sought to investigate the relationship between high-sensitivity C-reactive protein (CRP) levels and the risk of further ischemic events in first-ever transient ischemic attack (TIA) or stroke patients with intracranial large-artery occlusive disease. Methods— Of a total of 127 consecutive first-ever TIA or ischemic stroke patients with intracranial stenoses detected by transcranial Doppler ultrasonography, 71 fulfilled all inclusion criteria, which included angiographic confirmation. Serum high-sensitivity CRP level was determined a minimum of 3 months after the qualifying event. Patients were followed up during 1 year after blood sampling. Results— Thirteen patients (18.3%) with intracranial large-artery occlusive disease experienced an end point event: 9 cerebral ischemic events, 7 of which were attributable to intracranial large-artery occlusive disease, and 4 myocardial infarctions. Patients in the highest quintile of high-sensitivity CRP level had a significantly higher adjusted odds ratio for new events compared with those in the first quintile (odds ratio, 8.66; 95% CI, 1.39 to 53.84; P =0.01). A high-sensitivity CRP level above the receiver operating characteristic curve cutoff value of 1.41 mg/dL emerged as an independent predictor of new end point events (hazard ratio, 7.14; 95% CI, 1.77 to 28.73; P =0.005) and of further intracranial large-artery occlusive disease-related ischemic events (hazard ratio, 30.67; 95% CI, 3.6 to 255.5; P =0.0015), after adjustment for age, sex, and risk factors. Kaplan-Meier curves showed that a significantly lower proportion of patients with a high-sensitivity CRP >1.41 mg/dL remained free of a new ischemic event (P <0.0001). Conclusions— High-sensitivity CRP serum level predicts further intracranial large-artery occlusive disease-related and any major ischemic events in patients with first-ever TIA or stroke with intracranial large-artery occlusive disease. These findings are consistent with the hypothesis that inflammation may be involved in the progression and complication of intracranial large-artery occlusive disease.

Safety and Efficacy of Intravenous Tissue Plasminogen Activator Stroke Treatment in the 3- to 6-Hour Window Using Multimodal Transcranial Doppler/MRI Selection Protocol

Background— Growing data point toward intravenous tissue plasminogen activator (tPA) benefit after 3 hours in selected stroke patients. We aim to study safety and efficacy of tPA treatment in the 3- to 6-hour window using multimodal transcranial Doppler (TCD)/MRI selection criteria. Methods— We studied patients with acute middle cerebral artery (MCA) occlusion. Patients within 0 to 3 hours from symptom onset (A) were treated according to standard computed tomography criteria. Treatment within 3 to 6 hours (B) was decided according to TCD/MRI protocol. Continuous TCD assessed clot location and recanalization. National Institutes of Health Stroke Scale (NIHSS) at 24 hours assessed neurological improvement/worsening and modified Rankin score <3 functional independence at third month. Results— Of 135 patients, 56 were in the 3- to 6-hour window. Only 13 (23%) patients within 3 to 6 hours did not meet MRI inclusion criteria. Finally, 122 patients were treated with tPA: A, 79 (65%); B, 43 (35%). Median time to treatment was: A, 136 minutes (range 60 to 180); B, 223 (185 to 360). There were no differences in demographic parameters, baseline NIHSS (A, 17; B, 17; P=0.89), and occlusion location (proximal MCA A, 65.8%; B, 74.4%; P=0.28). Recanalization rates at 2 hours were similar (A, 49.3%; B, 55.2%; P=0.33), as were hemorrhagic transformation rates (asymptomatic: A, 18.7%, B, 26.6%, P=0.43; symptomatic: A, 3.75%, B, 2.38%, P=0.66). Improvement at discharge was similar in both groups (NIHSS dropped 6.3 points [A] versus 6.1 [B]; P=0.86). However, the number of patients who benefited from treatment was slightly higher in the 3- to 6-hour group (A, 58.2%; B, 76.2%; P=0.05), whereas the same rate of patients worsened (A, 11.4%; B, 7.1%; P=0.46). At 3 months, the rate of independent patients was: A, 42% versus B, 38% (P=0.74). Conclusions— tPA treatment can be safely and effectively extended to the 3- to 6-hour window using TCD/MRI selection criteria. Not using these criteria in the 3- to 6-hour window avoids potentially effective treatment in a high rate of patients.

Simvastatin in the acute phase of ischemic stroke: a safety and efficacy pilot trial

Although statins are being used for secondary prevention of ischemic stroke, recent experimental data have shown new pleiotropic effects of these drugs responsible for their role in neuroprotection. We conducted a pilot, double‐blind, randomized, multicenter clinical trial to study for the first time safety and efficacy of simvastatin in the acute phase of ischemic stroke. Simvastatin/placebo was given at 3–12 h from symptom onset to 60 patients with cortical strokes. Efficacy on the evolution of several inflammation markers [interleukin (IL)‐6, IL‐8, IL‐10, monocyte chemoattractant protein‐1, intercellular adhesion molecule‐1, vascular cell adhesion molecule‐1, C‐reactive protein, sApo/Fas, tumor necrosis factor‐α, E‐selectin, L‐selectin and nitrites+nitrates] and neurological outcome was evaluated at baseline, day 1, 3, 5, 7 and 90. No differences were found amongst the biomarkers studied regarding treatment allocation. Although simvastatin patients improved significantly by the third day (46.4% vs. 17.9%, P = 0.022), a non‐significant increase in mortality and greater proportion of infections (odds ratio 2.4, confidence interval 1.06–5.4) in the simvastatin group were the main safety concerns. Therefore, a larger clinical trial is needed to confirm the net benefit of this therapeutic approach.

Admission Fibrinolytic Profile Is Associated With Symptomatic Hemorrhagic Transformation in Stroke Patients Treated With Tissue Plasminogen Activator

Background and Purpose— Symptomatic intracranial hemorrhage (SICH) is the most feared complication after tissue plasminogen activator (tPA) stroke treatment. Endogenous fibrinolysis inhibitors play an essential role in the coagulation/fibrinolysis balance and may be involved in the bleeding process. We aim to determine the predictive value of pretreatment levels of fibrinolysis inhibitors (PAI-1, lipoprotein(a), TAFI, and homocysteine) on SICH. Methods— Consecutive tPA-treated stroke patients with middle cerebral artery occlusion were studied. Baseline blood samples were obtained just before tPA administration and fibrinolysis inhibitors were determined. A second computed tomography (CT) scan was obtained at 24 hours or when a neurological worsening occurred to rule out SICH. Results— Seventy-seven patients (40% women, age 75 years) were studied. Median admission National Institutes of Health Stroke Scale was 17 (range, 7 to 22) and mean time to treatment was 160 minutes. Six patients (7.9%) presented with a SICH. In analyses based on clinical and CT variables, no relation could be found with SICH. When laboratory data were analyzed, patients who experienced SICH showed lower baseline PAI-1 (21.7±3.5 ng/mL versus 31.8±12.1 ng/mL; P < 0.01) and higher TAFI (216.7±78.4% versus 162.1±54.2%; P = 0.03). Homocysteine and lipoprotein(a) were not related to SICH. The only factors associated with SICH were TAFI >180% (OR, 12.9; CI, 1.41 to 118.8; P = 0.02) and PAI-1 <21.4 ng/mL (OR, 12.75; CI, 1.17 to 139.2; P = 0.04). The combination of admission PAI-1 <21.4 ng/mL and TAFI >180% had a sensibility of 75% and a specificity of 97.6% (P <0.01) predicting SICH, with a positive predictive value of 75% and negative predictive value of 97.6%. Conclusions— Baseline PAI-1 and TAFI levels predict SICH after stroke tPA therapy. In the future, these biomarkers could be used to improve thrombolysis safety.

Lack of Evidence for Arterial Ischemia in Transient Global Amnesia

Background and Purpose— Lesions in diffusion-weighted imaging (DWI-L) have been commonly described in transient global amnesia (TGA). We investigated a possible relationship between brain ischemia and TGA. Methods— Twenty-eight patients underwent transcranial and carotid Doppler ultrasonography (including microembolus detection) and MRI within 24 hours of TGA onset (including DWI, perfusion-weighted imaging and angio-MRI). MRI was repeated at 48 to 96 hours (21 patients) and 30 days (18 patients). Results— Punctate DWI-L were observed in 16 patients (57%) and were not attributable to perfusion abnormalities, arterial stenoses or underlying cardioembolic disease. MRIs performed between 12 and 72 hours showed the highest frequency of DWI-L (88%; P<0.001). No pathological findings were observed at 30 days. Conclusions— These results suggest that TGA is not related to cerebral arterial ischemia.

Plasma S100B Level After Acute Spontaneous Intracerebral Hemorrhage

Background and Purpose— We sought to determine plasma S100B level after acute (<24 hours) spontaneous intracerebral hemorrhage (ICH) and to study its relation with neurological outcome. Methods— We determined S100B concentration on plasma samples from 78 ICH patients on admission. Clinical (Glasgow Coma Scale and National Institutes of Health Stroke Scale [NIHSS] scores) and radiological information (ICH and perihematomal edema volumes) were collected at baseline and follow-up visits. Early neurological deterioration, defined as the increase of ≥4 points in the NIHSS score at 48 hours, and unfavorable outcome (modified Rankin Scale >2) at 3 months were also recorded. Results— The median S100B level was higher than our laboratory reference values for healthy controls (103.6 versus 48.5 pg/mL; P<0.001) and a positive correlation was observed between S100B level and baseline ICH volume (r=0.45; P<0.0001). The median S100B level was higher in patients who deteriorated early (256.8 versus 89.7 pg/mL; P=0.001) and also in patients with an unfavorable outcome (136 versus 75.9 pg/mL; P=0.003). Multivariate analysis showed baseline ICH volume as the best predictor for both early neurological deterioration (odds ratio 15; 95% CI, 2.9 to 76.3) and unfavorable outcome at 3 months (odds ratio 17; 95% CI, 2.0 to 142). Conclusion— Increased S100B level is found after acute spontaneous ICH, in association with a worse early and late evolution, and closely related to initial hematoma volume.

Angiogenesis in Symptomatic Intracranial Atherosclerosis: Predominance of the Inhibitor Endostatin Is Related to a Greater Extent and Risk of Recurrence

Background and Purpose— Angiogenesis may be beneficial in chronic myocardial and limb ischemia, but its role in intracranial atherosclerosis remains unknown. We aimed to investigate the relationship between the pro-angiogenic vascular endothelial growth factor (VEGF) and the anti-angiogenic endostatin, and the extent and risk of recurrence of symptomatic intracranial atherosclerosis. Methods— Of a total of 94 consecutive patients with symptomatic intracranial stenoses, 40 fulfilled all inclusion criteria. Intracranial stenoses were confirmed by magnetic resonance angiography. Magnetic resonance imaging (MRI) including diffusion-weighted sequences was conducted. Plasmatic VEGF and endostatin were determined from blood samples obtained 3 months after stroke onset, and patients were followed-up thereafter. Results— A total of 144 intracranial stenoses were confirmed (median number per patient=3). Endostatin/VEGF ratio gradually augmented with the increasing number of intracranial stenoses (r=0.35, P=0.02). Diabetes mellitus (OR, 6.04; CI, 1.1 to 32.2; P=0.03) and a higher endostatin/VEGF ratio (OR, 15.7; CI, 2.2 to 112.3; P=0.006) were independently associated with a greater extent of intracranial atherosclerosis. During a median follow-up of 13 months, 8 patients (20%) experienced a new cerebral ischemic event. A higher baseline endostatin concentration was an independent predictor of new events (hazard ratio, 7.24; CI, 1.6 to 33.8; P=0.011) in a Cox regression model after adjustment for age, sex, number of stenotic vessels, and risk factors. Patients with a higher endostatin level had a lower survival free of new events (P=0.01, log-rank test). Conclusions— A predominance of the inhibitor endostatin within the endogenous angiogenic response is associated with a greater extent and risk of recurrence of symptomatic intracranial atherosclerosis, suggesting that angiogenesis may be beneficial in this condition.