Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.

Background and Purpose-Because there is no biologic marker offering precise information about stroke etiology, many patients receive a diagnosis of undetermined stroke even after all available diagnostic tests are done, precluding correct treatment. Methods-To examine the diagnostic value of a panel of biochemical markers to differentiate stroke etiologies, consecutive acute stroke patients were prospectively evaluated. Brain computed tomography, ultrasonography, cardiac evaluations, and other tests were done to identify an etiologic diagnosis according to TOAST classification. Blood samples were drawn on Emergency Department arrival (Ͻ24 hours) to test selected biomarkers: C-reactive protein, D-dimer, soluble receptor for advanced glycation end products, matrix metalloproteinase-9, S-100b, brain natriuretic peptide (BNP), neurotrophin-3, caspase-3, chimerin, and secretagogin (assayed by ELISA). 6.7, PϽ0.001). A model combining clinical and biochemical data had a sensitivity of 66.5% and a specificity of 91.3% for predicting cardioembolism. Conclusions-Using a combination of biomarkers may be a feasible strategy to improve the diagnosis of cardioembolic stroke in the acute phase, thus rapidly guiding other diagnostic tests and accelerating the start of optimal secondary prevention. Results-Of

Background and Purpose-The risk of recurrent stroke is highest within the first few weeks after a transient ischemic attack (TIA), and it is likely to be related to the underlying pathology. We sought to study the early risk of recurrent stroke by etiologic subtype. Methods-We prospectively studied 388 TIA patients. The cause of TIA was classified according to the Trial of ORG 10172 criteria: large-artery atherosclerosis (LAA, nϭ90), cardioembolism (nϭ87), small-vessel disease (nϭ68), undetermined (nϭ127), and other determined cause (nϭ16). Patients were followed up at 3 months. Risk factors and clinical symptoms for each subtype were recorded. Results-The duration of symptoms and clinical symptoms varied significantly among the different subtypes. LAA was associated with recurrent short episodes of weakness, whereas speech impairment and cortical symptoms were associated with cardioembolism (PϽ0.05).

Background and Purpose-We aimed to determine clinical and hemodynamic predictors of early reocclusion (RO) in stroke patients treated with intravenous tissue plasminogen activator (tPA). Methods-We studied 142 consecutive stroke patients with a documented middle cerebral artery (MCA) occlusion treated with intravenous tPA. All patients underwent carotid ultrasound and transcranial Doppler (TCD) examination before tPA bolus. National Institutes of Health Stroke Scale (NIHSS) scores were performed at baseline and serially for Ͻ24 hours. TCD monitoring of MCA recanalization (RE) and RO was performed during the first 2 hours after tPA bolus and repeated when clinical deterioration occurred Ͻ24 hours after documented RE in absence of intracranial hemorrhage. Results-After 1 hour of tPA administration, RE occurred in 84 (61%) patients (53 partial, 31 complete). Of these, 21 (25%) patients worsened after an initial improvement and 17 (12%) of them showed RO on TCD. RO was identified at a mean time of 65Ϯ55 minutes after documented RE. RO was associated (Pϭ0.034) with a lower degree of 24-hour NIHSS score improvement than sustained RE, and a higher modified Rankin scale score at 3 months (Pϭ0.002). Age older than 75 years (Pϭ0.012), previous antiplatelet treatment (Pϭ0.048), baseline NIHSS score Ͼ16 points (Pϭ0.009), higher leukocytes count (Pϭ0.042), beginning of RE Ͻ60 minutes after tPA bolus (Pϭ0.039), and ipsilateral severe carotid stenosis/occlusion (Pϭ0.001) were significantly associated with RO. In a logistic regression model, NIHSS score Ͼ16 at baseline (odds ratio [OR], 7.1; 95% CI, 1.3 to 32) and severe ipsilateral carotid disease (OR, 13.3; 95% CI, 3.2 to 54) remained as independent predictors of RO. Conclusions-Stroke severity and ipsilateral severe carotid artery disease independently predict RO after tPA-induced MCA RE.

Background and Purpose-Although tandem internal carotid artery/middle cerebral artery (MCA; TIM) occlusion has been associated with low recanalization rate after IV tissue plasminogen activator (tPA), its independent contribution on stroke outcome remains unknown. Moreover, whether the relative resistance to thrombolysis in tandem lesions varies depending on the location of MCA clot remains uncertain. Methods-Two hundred and twenty-one consecutive stroke patients with an acute MCA occlusion treated with IV tPA were studied. Emergent carotid artery ultrasound and transcranial Doppler (TCD) examinations were performed in all patients before treatment. Recanalization was assessed on TCD at 2 hours of tPA bolus. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and after 24 hours. Modifed Rankin Scale score was used to assess outcome at 3 months. Results-Median prebolus NIHSS score was 16 points. On TCD, 156 (71.6%) patients had a proximal and 65 (29.4%) a distal MCA occlusion. TIM occlusion was identified in 44 (19.9%) patients. Eighteen (41.9%) patients with and 123 (69.5%) without TIM lesions achieved an MCA recanalization (Pϭ0.01). In a logistic regression model, hyperglycemia Ͼ140 mg/dL (odds ratio [OR] 3.3, 95% CI, 1.6 to 6.8) and the presence of TIM occlusion (OR 2.8, 95% CI, 1.1 to 6.9) emerged as independent predictors of absence of recanalization. However, the independent contribution of TIM lesions on poor response to thrombolysis varied depending on the location of MCA occlusion. TIM occlusion independently predicted resistance to thrombolysis in patients with proximal (OR 4.63, 95% CI, 1.79 to 11.96), but not in those with distal MCA occlusion. Patients with TIM occlusion had worse short-(PϽ0.0001) and long-term (PϽ0.0001) clinical outcome. Conclusions-TIM occlusion independently predicts poor outcome after IV thrombolysis. However, its impact varies depending on the location of MCA clot. Therefore, emergent carotid ultrasound plus TCD examinations may improve the selection of patients for more aggressive reperfusion strategies.

Background and Purpose-Matrix metalloproteinases (MMPs) are involved in tissue destruction produced by the neuroinflammatory response that follows ischemic stroke. In the present study we use an MMP array to investigate the blood levels of several MMPs in stroke patients and its relation with brain tissue damage and neurological outcome. Methods-Twenty-four patients with middle cerebral artery occlusion who received thrombolytic therapy were included.Blood samples were drawn before tissue plasminogen activator treatment and an MMP array (multiplex enzyme-linked immunosorbent assay [ELISA]) was performed including gelatinases (MMP-2 and MMP-9), collagenases (MMP-1, MMP-8, and MMP-13), stromelysines (MMP-3 and MMP-10), and MMP endogen inhibitors (TIMP-1 and TIMP-2). To assess tissue lesion a serial multimodal MRI study was performed (pretreatment and at 24 hours). Results-Neither initial diffusion lesion nor hypoperfused volume was associated with metalloproteinase expression within the first 3 hours after stroke onset. Nevertheless, a strong correlation was found between MMP-9 and MMP-13 with diffusion-weighted image (DWI) lesion expansion (rϭ0.54, Pϭ0.05 and rϭ0.60, Pϭ0.017, respectively). Baseline levels of both MMP-9 (OR, 14;95% CI, 1.5 to 131; Pϭ0.019) and MMP-13 (OR, 73; 95% CI, 3.9 to 1388; Pϭ0.004) were independent predictors of final increase in brain infarct volume at 24 hours. Conclusions-Our results demonstrate that within the neuroinflammatory response, high levels of MMP-9 and MMP-13 are involved in DWI lesion growth despite thrombolytic therapy, suggesting its ultra-early role in brain injury.

Blood pressure variability is associated with greater diffusion-weighted imaging lesion growth and worse clinical course in patients with stroke treated with IV tissue plasminogen activator. However, its impact varies depending on the occurrence of early recanalization after thrombolysis.

To evaluate impact of glucose burden on diffusion-weighted imaging (DWI)-lesion evolution according to ischemia duration in stroke. We studied 47 patients with transcranial Doppler (TCD)-documented artery occlusion treated with intravenous tissue plasminogen activator. Hyperglycemia (HG) was defined as glucose>140 mg/dL. A subcutaneous device continuously monitored glucose during 24 h. Magnetic resonance imaging was performed pretreatment (1) and at 24 to 36 h (2) in 30 patients. We measured initial PWI lesion (PW1) and DWI growth: DW2-DW1 (DWg). Serial TCD during 24 h determined occlusion time (OT). National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and 48 h. Poor short-term clinical course defined as <50% recovery of initial NIHSS. Baseline NIHSS was 18. On admission 10 patients (21.3%) were hyperglycemic and presented similar NIHSS, DW1, and PW1 lesion extension as those without HG. During monitoring 24 patients (51%) had HG, 21 (45%) of them during OT (median OT 12 h). Median 48 h-NIHSS was 10; 15 patients presented poor outcome. 48 h-NIHSS was higher in patients with HG during OT (15 versus 3; P<0.001). Patients with favorable outcome had shorter OT (8.4 versus 17.4 h; P<0.001). However, the only independent predictor of poor outcome was HG during OT (OR: 20.3; 95% CI: 3.77 to 108.8; P<0.001). At 24 h mean DWg was 52 cm(3). A receiver operating characteristic curve identified DWg>14 cm(3) best predictor of poor outcome (sensitivity, 85.7%; specificity, 75%). Total OT (P=0.007) and HG during OT (P=0.01) showed the strongest correlation with DWg. DWI lesion grew 2.7 times faster in patients with HG than without HG during OT (1.73 versus 4.63 cm(3)/h of occlusion; P=0.07). In a regression model the only independent predictor of DWg was HG during OT (OR: 10.83; 95% CI: 1.96 to 59.83; P=0.006). Hyperglycemia, especially during OT, has a powerful deleterious effect after stroke accelerating brain damage.