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Background and Purpose: Argatroban is a direct thrombin inhibitor that safely augments recanalization achieved by tissue-type plasminogen activator (tPA) in animal stroke models. The Argatroban tPA Stroke Study was an open-label, pilot safety study of tPA plus Argatroban in patients with ischemic stroke due to proximal intracranial occlusion., Methods: During standard-dose intravenous tPA, a 100-μg/kg bolus of Argatroban and infusion for 48 hours was adjusted to a target partial thromboplastin time of 1.75× baseline. The primary outcome was incidence of significant intracerebral hemorrhage defined as either symptomatic intracerebral hemorrhage or Parenchymal Hematoma Type 2. Recanalization was measured at 2 and 24 hours by transcranial Doppler or CT angiography., Results: Sixty-five patients were enrolled (45% men, mean age 63±14 years, median National Institutes of Health Stroke Scale=13). The median (interquartile range) time tPA to Argatroban bolus was 51 (38-60) minutes. Target anticoagulation was reached at a median (interquartile range) of 3 (2-7) hours. Significant intracerebral hemorrhage occurred in 4 patients (6.2%; 95% CI, 1.7-15.0). Of these, 3 were symptomatic (4.6%; 95% CI, 0.9-12.9). Seven patients (10%) died in the first 7 days. Within the 2-hour monitoring period, transcranial Doppler recanalization (n=47) occurred in 29 (61%) patients: complete in 19 (40%) and partial in another 10 (21%)., Conclusions: The combination of Argatroban and intravenous tPA is potentially safe in patients with moderate neurological deficits due to proximal intracranial arterial occlusions and may produce more complete recanalization than tPA alone. Continued evaluation of this treatment combination is warranted., Clinical Trial Registration: URL: www.clinicaltrials.gov. Unique identifier: NCT00268762.

Decompressive surgery <48 h from stroke onset reduces the prevalence of mortality and morbidity from malignant supratentorial infarction. We investigated if utilization of decompressive surgery changed in the Czech Republic (CZ) after the release of new guidelines regarding treatment of malignant brain infarction. The volume of decompressive surgery in 2009 in all centers in the CZ was assessed using the same methodology as in 2006. All neurosurgery departments in the CZ were asked to complete a questionnaire and asked to identify all cases of decompressive surgery for malignant brain infarction through a combination of discharge codes for "brain infarction" and "decompressive surgery" from electronic hospital charts. Data for 56 patients were obtained from 15 of the 16 neurosurgery departments in the CZ. The average age was 53 ± 13; number of males 20; median time to surgery was 48 h (range 24-62); median NIHSS score was 25 (IQR, 20-30); median infarct volume was 300 cm(3) [interquartile (IQR, 250-350)]; mean shift on CT was 10.6 ± 3.6 mm and size of hemicraniectomy was 125 cm(2) (IQR, 110-154). A favorable outcome was achieved in 45% of the patients. The number of procedures increased from 39 in 2,006 to 2,056 in 2009. Based on data from one stroke center, 10% suffered from malignant supratentorial infarction and 2.3% met the criteria for decompressive surgery. In 2009, as compared to 2006, the volume of decompressive surgery carried out moderately increased. However, procedures remained underutilized because only ~10% of those who needed decompressive surgery underwent surgery.

Background and Purpose: Early neurological improvement (ENI) after thrombolytic therapy of acute stroke has been linked with recanalization and favorable outcome, although its definition shows considerable variation. We tested the ability of ENI, as defined in previous publications, to predict vessel recanalization and 3-month functional outcome after intravenous thrombolysis recorded in an extensive patient cohort in the Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR)., Methods: Of 21,534 patients registered between December 2002 and December 2008, 798 patients (3.7%) had CT- or MR angiography-documented baseline vessel occlusion and also angiography data at 22 to 36 hours post-treatment. ENI definitions assessed at 2 hours and 24 hours post-treatment were (1) National Institutes of Health Stroke Scale (NIHSS) score improvement ≥4 points from baseline; (2) NIHSS 0, 1, or improvement ≥8; (3) NIHSS ≤3 or improvement ≥10; (4) improvement by 20%; (5) 40% from baseline; or (6) NIHSS score 0 to 1. Receiver operating curve analysis and multiple logistic regression were performed to evaluate the association of ENI with vessel recanalization and favorable functional outcome (modified Rankin Scale score 0 to 2 at 3 months)., Results: ENI at 2 hours had fair accuracy to diagnose recanalization as derived from receiver operating curve analysis. Definitions of improvement based on percent of NIHSS score change from baseline demonstrate better accuracy to diagnose recanalization at 2 hours and 24 hours than the definitions based on NIHSS cutoffs (the best performance at 2 hours was area under the curve 0.633, sensitivity 58%, specificity 69%, positive predictive value 68%, and negative predictive value 59% for 20% improvement; and area under the curve 0.692, sensitivity 69%, specificity 70%, positive predictive value 70%, and negative predictive value 62% for 40% improvement at 24 hours). ENI-predicted functional outcome with OR 2.8 to 6.0 independently from recanalization in the angiography cohort (n=695) and with OR of 6.9 to 9.7 in the whole cohort (n=18 181)., Conclusions: Early 20% neurological improvement at 2 hours was the best predictor of 3-month functional outcome and recanalization after thrombolysis, although fairly accurate, and may serve as a surrogate marker of recanalization if only imaging evaluation of vessel status is not available. If recanalization status is required after intravenous thrombolysis, vascular imaging is recommended despite ENI.

Object: Decompressive surgery within 48 hours in patients younger than 60 years of age reduces mortality and morbidity from malignant supratentorial infarction. The goal of this study was to characterize the utilization of decompressive surgery in the Czech Republic in 2006., Methods: This nationwide study was undertaken from September to December 2007 using a questionnaire sent to all neurosurgery departments in the Czech Republic. Diagnosis of brain infarction and decompressive surgery was based on discharge codes. Patient data were retrieved from hospital charts. Favorable outcome was defined as a modified Rankin scale score ≤4 on the day of discharge from the hospital., Results: Data were obtained from 15 of the 16 neurosurgery departments in the Czech Republic (94%) and from 39 patients (11 female [28%]). The average patient age was 52 +/-14 years (11 patients > 60), median time to surgery was 48 hours (interquartile range [IQR] 26-67 hours; 15 patients > 48 hours), median National Institutes of Health Stroke Scale score was 22 (IQR 16-30), median infarct volume was 341 cm³ (IQR 243-375 cm³), mean shift from the midline was 9.9 +/- 4.1 mm, median duration of hospitalization was 19 days (IQR 13-30 days), and mean bone flap surface area was 75 cm² (IQR 70-97 cm²). A favorable outcome was achieved in 19 patients (49%). The median number of procedures per site in 2006 was 1.5 (range 0-13 procedures). Five sites (31%) serving one-third of the entire population did not perform any decompressive surgery. No variable was a significant predictor of outcome in a multiple regression model., Conclusions: In 2006 decompressive surgery was underutilized and occurred late in the clinical course in the Czech Republic. Revision of national guidelines is necessary to incorporate the latest data and ensure that the patients who can benefit most receive treatment.

Objective: To determine the association between admission blood glucose and outcome in ischemic stroke patients treated with thrombolysis., Design: A prospective, open, multinational, observational study., Setting: An ongoing Internet-based, academic-driven, interactive thrombolysis register., Patients: Between 2002 and 2007, 16 049 patients were recorded in the SITS-ISTR., Main Outcome Measure: Blood glucose was recorded at admission. Blood glucose was divided into the following categories: less than 80, 80-120 (reference range), 121-140, 141-160, 161-180, 181-200, and greater than 200 mg/dL. Outcomes were mortality and independence (modified Rankin Scale score of 0-2) at 3 months and symptomatic intracerebral hemorrhage (SICH) (National Institutes of Health Stroke Scale deterioration ≥4 points within 24 hours and type 2 parenchymal hemorrhage)., Results: In multivariable analysis, blood glucose as a continuous variable was independently associated with a higher mortality (P < .001), lower independence (P < .001), and an increased risk of SICH (P = .005). Blood glucose greater than 120 mg/dL as a categorical variable was associated with a significantly higher odds for mortality (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.07-1.44; P = .004) and a lower odds for independence (OR, 0.58; 95% CI, 0.48-0.70; P < .001), and blood glucose from 181 to 200 mg/dL was associated with an increased risk of SICH (OR, 2.86; 95% CI, 1.69-4.83; P < .001) compared with the reference level. The trends of associations between blood glucose and outcomes were similar in patients with diabetes (17%) or without such history, except for mortality (P = .23) and SICH (P = .06) in which the association was not statistically significant in patients with diabetes., Conclusions: Admission hyperglycemia was an independent predictor for poor outcome after stroke/thrombolysis, though SICH rates did not increase significantly until reaching 180 mg/dL. These results suggest that tight control of blood glucose may be indicated in the hyperacute phase following thrombolysis. Randomized trial data are needed.

Background: In September, 2008, the European Acute Stroke Study III (ECASS III) randomised trial and the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR) observational study reported the efficacy and safety of the extension of the time window for intravenous alteplase treatment from within 3 h to within 4.5 h after stroke onset. We aimed to assess the implementation of the wider time window, its effect on the admission-to-treatment time, and safety and functional outcome in patients recorded in SITS-ISTR., Methods: Patients treated according to the criteria of the European Summary of Product Characteristics, except for the time window, were included. Patients were grouped according to whether they were registered into SITS-ISTR before or after October, 2008. We measured admission-to-treatment time and rates of symptomatic intracerebral haemorrhage, mortality, and functional independence at 3 months., Findings: 23 942 patients were included in SITS-ISTR between December, 2002, and February, 2010, of whom 2376 were treated 3-4.5 h after symptom onset. The proportion of patients treated within 3-4.5 h by the end of 2009 was three times higher than in the first three quarters of 2008 (282 of 1293 [22%] vs 67 of 1023 [7%]). The median admission-to-treatment time was 65 min both for patients registered before and after October, 2008 (p=0.94). 352 (2%) of 21 204 patients treated within 3 h and 52 (2%) of 2317 treated within 3-4.5 h of stroke had symptomatic intracerebral haemorrhage at 3 months (adjusted odds ratio [OR] 1.44, 95% CI 1.05-1.97; p=0.02). 2287 (12%) of 18 583 patients who were treated within 3 h and 218 (12%) of 1817 who were treated within 3-4.5 h had died by the 3-month follow-up (adjusted OR 1.26, 95% CI 1.07-1.49; p=0.005); 10 531 (57%) of 18 317 patients treated within 3 h of stroke and 1075 (60%) of 1784 who were treated within 3-4.5 h were functionally independent at 3 months (adjusted OR 0.84, 95% CI 0.75-0.95; p=0.005)., Interpretation: Since October, 2008, thrombolysis within 3-4.5 h after stroke has been implemented rapidly, with a simultaneous increase in the number of patients treated within 3 h; admission-to-treatment time has not increased. Safety and functional outcomes are less favourable after 3 h, but the wider time window now offers an opportunity for treatment of those patients who cannot be treated earlier. Thrombolysis should be initiated within 4.5 h after onset of ischaemic stroke, although every effort should be made to treat patients as early as possible after symptom onset., Funding: Boehringer Ingelheim, Ferrer, the European Union Public Health Executive Authority, and Medical Training and Research (ALF) from Stockholm County Council and Karolinska Institutet., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Opinion Statement: Ischemic stroke is most often caused by an acute extracranial or intracranial thromboembolic lesion obstructing an artery. It has been demonstrated that recanalization is the most important modifiable predictor of a good clinical outcome. Reperfusion strategies focus on early reopening of the vessel to reestablish antegrade flow within the penumbra.Current standard therapy within 4.5 h is intravenous thrombolysis (IVT) with tissue plasminogen activator (tPA, 0.9 mg/kg body weight, maximum dose 90 mg). Thrombolytic therapy appears to be safe and effective across various types of hospitals, if the treatment is conducted by a physician with stroke expertise.New imaging methods (MR diffusion/perfusion, CT perfusion) are being investigated in order to better select patients who are most likely to benefit from recanalization therapy based on current clinical evidence. Neither perfusion imaging with CT or MR nor the mismatch concept are recommended for routine treatment decisions within or beyond the 4.5 h available for IVT.If major vessel occlusion is proven but IVT is contraindicated, intra-arterial thrombolysis (IAT) with tPA or mechanical thrombectomy with the Merci Retriever or Penumbra System may be a treatment option. The availability of IAT generally should not preclude the intravenous administration of tPA in otherwise eligible patients. Intra-arterial treatment can be performed within 8 h after stroke onset. Combining intravenous tPA pretreatment with subsequent IAT or mechanical thrombectomy may improve the recanalization rate and may be used as a rescue therapy in cases of persistent major vessel occlusion after unsuccessful IVT.Despite testing, no thrombolytic agent other than tPA (e.g., IIb/IIIa antagonists, heparin, etc.) has yet been approved for routine practice for either intravenous or intra-arterial application, alone or in combination with tPA.Continuous transcranial Doppler (TCD) monitoring of an occluded vessel may increase the rate of early recanalization after tPA; this effect may be facilitated by the administration of microbubbles. This method is still considered experimental.

Objective: Microspheres (microS) reach intracranial occlusions and transmit energy momentum from an ultrasound wave to residual flow to promote recanalization. We report a randomized multicenter phase II trial of microS dose escalation with systemic thrombolysis., Methods: Stroke patients receiving 0.9mg/kg tissue plasminogen activator (tPA) with pretreatment proximal intracranial occlusions on transcranial Doppler (TCD) were randomized (2:1 ratio) to microS (MRX-801) infusion over 90 minutes (Cohort 1, 1.4ml; Cohort 2, 2.8ml) with continuous TCD insonation, whereas controls received tPA and brief TCD assessments. The primary endpoint was symptomatic intracerebral hemorrhage (sICH) within 36 hours after tPA., Results: Among 35 patients (Cohort 1 = 12, Cohort 2 = 11, controls = 12) no sICH occurred in Cohort 1 and controls, whereas 3 (27%, 2 fatal) sICHs occurred in Cohort 2 (p = 0.028). Sustained complete recanalization/clinical recovery rates (end of TCD monitoring/3 month) were 67%/75% for Cohort 1, 46%/50% for Cohort 2, and 33%/36% for controls (p = 0.255/0.167). The median time to any recanalization tended to be shorter in Cohort 1 (30 min; interquartile range [IQR], 6) and Cohort 2 (30 min; IQR, 69) compared to controls (60 min; IQR, 5; p = 0.054). Although patients with sICH had similar screening and pretreatment systolic blood pressure (SBP) levels in comparison to the rest, higher SBP levels were documented in sICH+ patients at 30 minutes, 60 minutes, 90 minutes, and 24-36 hours following tPA bolus., Interpretation: Perflutren lipid microS can be safely combined with systemic tPA and ultrasound at a dose of 1.4ml. Safety concerns in the second dose tier may necessitate extended enrollment and further experiments to determine the mechanisms by which microspheres interact with tissues. In both dose tiers, sonothrombolysis with microS and tPA shows a trend toward higher early recanalization and clinical recovery rates compared to standard intravenous tPA therapy. Ann Neurol 2009;66:28-38.

Background: The benefit of intravenous (i.v.) tissue plasminogen activator (tPA) in acute ischemic stroke (IS) is attributable to lysis of thrombus and restoration of perfusion to ischemic but not yet infarcted brain., Aims: Our multicentre collaborative group prospectively implemented a protocol for transcranial Doppler assessment of intracranial recanalization with tPA treatment based on the CLOTBUST clinical trial (CLOTBUST-PRO). We aim to determine whether early recanalization (within 1 h from tPA bolus) is independently associated with better 3-month outcome in patients with intracranial arterial occlusions and correlates to a shorter time interval elapsed from symptom onset to tPA bolus., Subjects and Methods: Consecutive patients with acute IS due to intracranial arterial occlusions will be treated with standard i.v.-tPA and continuously monitored with 2 MHz Transcranial Doppler for arterial recanalization. Early recanalization will be determined with the previously validated Thrombolysis in Brain Ischemia flow-grading system within 60 min after tPA bolus. Power calculations are based on the assumption of alpha=0.05 (two-sided test) and probabilities of functional independence at 3 months of 0.50 and 0.35 in patients with early complete recanalization and persisting occlusion, respectively. Detection of a 15% difference with a power of 0.824 requires an estimated sample of 480 patients of whom 25% are expected to achieve early recanalization while 75% will have persisting occlusion at 1 h after tPA bolus. We also plan to test prespecified secondary hypotheses within the projected study sample., Conclusions: CLOTBUST-PRO is designed to determine if the timing (within 1 h from tPA bolus) of tPA-induced arterial recanalization is an independent determinant of 3-month functional recovery. We also seek to demonstrate that the sooner the tPA is given to stroke patients, the earlier the recanalization occurs and the greater is the likelihood of functional independence at 3 months.

Background: The benefit of intravenous recombinant tissue plasminogen activator (rtPA) in acute stroke is linked to clot lysis and artery recanalization. Argatroban is a direct thrombin inhibitor that safely augments the benefit of rtPA in animal stroke models. There are no human data on this combination., Design: We report the first phase of the Argatroban tPA Stroke Study, an ongoing prospective, open-label, dose-escalation, safety and activity study of argatroban and rtPA in patients with ischemic stroke. The primary outcome was incidence of intracerebral hemorrhage; secondary outcome, complete recanalization at 2 hours. After standard-dose intravenous rtPA administration, a 100-mug/kg bolus of argatroban followed by infusion of 1 mug/kg per minute for 48 hours was adjusted to a target partial thromboplastin time of 1.75 times that of the control group., Results: Fifteen patients (including 10 men) were enrolled, with a mean +/- SD age of 61 +/- 13 years. All patients had middle cerebral artery occlusions. Baseline median National Institute of Health Stroke Scale score was 14 (range, 4-25). The mean +/- SD time from symptom onset to argatroban bolus administration was 172 +/- 53 minutes. Symptomatic intracerebral hemorrhage occurred in 2 patients, including 1 with parenchymal hemorrhage type 2. Asymptomatic bleeding occurred in 1 patient and there was 1 death. Recanalization was complete in 6 patients and partial in another 4, and reocclusion occurred in 3 within 2 hours of rtPA bolus administration., Conclusion: The safety of low-dose argatroban combined with intravenous rtPA may be within acceptable limits, and its efficacy for producing fast and complete recanalization is promising, but a larger cohort of patients is required to confirm these preliminary observations.

Background: Patients with isolated middle cerebral artery (MCA) and tandem MCA/internal carotid artery (ICA) obstruction have similar presenting symptoms and stroke severity. We aimed to investigate early recanalization of MCA and clinical outcomes in patients with tandem ICA/MCA obstructions and isolated MCA occlusion., Methods: Patients with MCA occlusion on pretreatment transcranial Doppler were treated with intravenous tissue plasminogen activator. ICA lesions were detected with carotid duplex. Early neurological improvement (ENI) was defined by reduction of National Institutes of Health Stroke Scale (NIHSS) > or =10 points or total NIHSS < or =3 points. Good outcome at 3 months was a modified Rankin score of < or =2., Results: Among 104 patients, 31% had tandem lesions and 69% had isolated MCA occlusions. Complete recanalization rate was 39% in isolated MCA occlusion group and 9% in tandem group (P=0.002). ENI at 24 hours occurred in 46% of the isolated MCA occlusion group and in 25% of the tandem group (P=0.045). Good outcome was achieved by 30% and 39% respective patients (NS)., Conclusions: The tandem lesion group showed lower early recanalization rate and ENI rate than the isolated MCA occlusion group. Despite this, good outcomes were similar in both groups.

Background and Purpose: Transcranial Doppler (TCD) can detect intracranial stenoses and occlusions that can help in the diagnosis and management of ischemic stroke. The accuracy parameters for lesions located in the terminal internal carotid artery (TICA) are less known, unlike other basal cerebral vessels., Patients and Methods: The authors studied consecutive patients referred for TCD who underwent contrast angiography or magnetic resonance angiography. They calculated the sensitivity, specificity, positive and negative predictive values (PPV and NPV), and likelihood ratios., Results: Forty-three patients had TCD and angiography: mean age was 57 +/- 20 years, and 65% were men. Twenty-two patients were diagnosed with TICA stenosis or occlusion on TCD underwent angiography. Four patients had abnormal TCD findings that were not confirmed by angiography. Two of 21 patients with normal TCD showed moderate (< 50%) stenosis of the TICA and cavernous segment of the internal carotid artery at angiography. Accuracy parameters for TCD were as follows: sensitivity = 90% (confidence interval [CI], 63%-96%), specificity = 83% (CI, 61%-94%), PPV = 82%, NPV = 86%, positive likelihood ratio = 5, and negative likelihood ratio = 0.17., Conclusions: TCD is a sensitive screening tool for the lesions in the TICA. Specificity is likely affected by a wide spectrum of the stenosis severity shown at angiography and time lags between the studies.