Gene-Gene Interaction Between Factor-XI and ABO Genes in Cerebral Venous Thrombosis: The BEAST Study.

BACKGROUND AND OBJECTIVES: Gene-gene interactions likely contribute to the etiology of multifactorial diseases such as cerebral venous thrombosis (CVT) and could be one of the main sources of known missing heritability. We explored Factor XI (F11) and ABO gene interactions among patients with CVT. METHODS: Patients with CVT of European ancestry from the large Bio-Repository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) international collaboration were recruited. Codominant modelling was used to determine interactions between genome-wide identified F11 and ABO genes with CVT status. RESULTS: We studied 882 patients with CVT and 1,205 ethnically matched control participants (age: 42 ± 15 vs 43 ± 12 years, p = 0.08: sex: 71% male vs 68% female, p = 0.09, respectively). Individuals heterozygous (AT) for the risk allele (T) at both loci (rs56810541/F11 and rs8176645/ABO) had a 3.9 (95% CI 2.74-5.71, p = 2.75e-13) increase in risk of CVT. Individuals homozygous (TT) for the risk allele at both loci had a 13.9 (95% CI 7.64-26.17, p = 2.0e-15) increase in risk of CVT. The presence of a non-O blood group (A, B, AB) combined with TT/rs56810541/F11 increased CVT risk by OR = 6.8 (95% CI 4.54-10.33, p = 2.00e15), compared with blood group-O combined with AA. DISCUSSION: Interactions between factor XI and ABO genes increase risk of CVT by 4- to 14-fold.

Association of Time to Thrombolysis With Early Reperfusion After Alteplase and Tenecteplase in Patients With Large Vessel Occlusion.

BACKGROUND AND OBJECTIVES: Early treatment with intravenous alteplase increases the probability of lytic-induced reperfusion in large vessel occlusion (LVO) patients. The relationship of tenecteplase-induced reperfusion and the timing of thrombolytic administration has not been explored. In this study, we performed a comparative analysis of tenecteplase and alteplase reperfusion rates and assessed their relationship to the time of thrombolytic administration. METHODS: Patients who were initially treated with a thrombolytic within 4.5 hours of symptom onset were pooled from the Royal Melbourne Stroke Registry, EXTEND-IA, EXTEND-IA TNK, and EXTEND-IA TNK part 2 trials. The primary outcome, thrombolytic-induced reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion at initial angiographic assessment (or repeat CT perfusion/angiography). We compared the treatment effect of tenecteplase and alteplase through fixed-effects Poisson regression modelling. RESULTS: Among 846 patients included in the primary analysis, early reperfusion was observed in 173 (20%) patients (tenecteplase: 98/470 [21%], onset-to-thrombolytic time: 132 minutes [interquartile range (IQR): 99-170], and thrombolytic-to-assessment time: 61 minutes [IQR: 39-96]; alteplase: 75/376 [19%], onset-to-thrombolytic time: 143 minutes [IQR: 105-180], thrombolytic-to-assessment time: 92 minutes [IQR: 63-144]). Earlier onset-to-thrombolytic administration times were associated with an increased probability of thrombolytic-induced reperfusion in patients treated with either tenecteplase (adjusted risk ratio [aRR] 1.05 per 15 minutes [95% confidence interval (CI) 1.00-1.12] or alteplase (aRR 1.06 per 15 minutes [95% CI 1.00-1.13]). Tenecteplase remained associated with higher rates of reperfusion vs alteplase after adjustment for onset-to-thrombolytic time, occlusion site, thrombolytic-to-assessment time, and study as a fixed effect, (adjusted incidence rate ratio: 1.41 [95% CI 1.02-1.93]). No significant treatment-by-time interaction was observed (p = 0.87). DISCUSSION: In patients with LVO presenting within 4.5 hours of symptom onset, earlier thrombolytic administration increased successful reperfusion rates. Compared with alteplase, tenecteplase was associated with a higher probability of lytic-induced reperfusion, independent of onset-to-lytic administration times. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifiers: NCT02388061, NCT03340493. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among patients with LVO receiving a thrombolytic, reperfusion was more likely with tenecteplase than alteplase.

Stroke population-specific neuroanatomical CT-MRI brain atlas.

PURPOSE: Development of a freely available stroke population-specific anatomical CT/MRI atlas with a reliable normalisation pipeline for clinical CT. METHODS: By reviewing CT scans in suspected stroke patients and filtering the AIBL MRI database, respectively, we collected 50 normal-for-age CT and MRI scans to build a standard-resolution CT template and a high-resolution MRI template. The latter was manually segmented into anatomical brain regions. We then developed and validated a MRI to CT registration pipeline to align the MRI atlas onto the CT template. Finally, we developed a CT-to-CT-normalisation pipeline and tested its reliability by calculating Dice coefficient (Dice) and Average Hausdorff Distance (AHD) for predefined areas in 100 CT scans from ischaemic stroke patients. RESULTS: The resulting CT/MRI templates were age and sex matched to a general stroke population (median age 71.9 years (62.1-80.2), 60% male). Specifically, this accounts for relevant structural changes related to aging, which may affect registration. Applying the validated MRI to CT alignment (Dice > 0.78, Average Hausdorff Distance < 0.59 mm) resulted in our final CT-MRI atlas. The atlas has 52 manually segmented regions and covers the whole brain. The alignment of four cortical and subcortical brain regions with our CT-normalisation pipeline was reliable for small/medium/large infarct lesions (Dice coefficient > 0.5). CONCLUSION: The newly created CT-MRI brain atlas has the potential to standardise stroke lesion segmentation. Together with the automated normalisation pipeline, it allows analysis of existing and new datasets to improve prediction tools for stroke patients (free download at https://forms.office.com/r/v4t3sWfbKs ).

Ambulatory activity in stroke survivors associated with functional outcome and quality of life: An observational cohort study.

BACKGROUND: Physical activity is beneficial in stroke prevention and recovery. Understanding activity dynamics and its effect on outcome after stroke is important to improve recommendations and develop interventions. OBJECTIVES: We examined serial changes in daily ambulatory activity (AA) averaged over 1 week in people with subacute to chronic stroke and its association with functional outcome (modified Rankin scale [mRS]) and quality of life (EQ-5D-3L). METHODS: This observational study examined AA in stroke survivors with no to moderate disability (US National Institute of Stroke Scale [NIHSS] score) who were mostly community dwelling and had cryptogenic stroke based on data from the Continuous Cardiac Monitoring to Assess Atrial Fibrillation After Cryptogenic Stroke study. The participants underwent long-term AA monitoring by accelerometric activity data obtained from an insertable cardiac monitor without receiving any specific encouragement regarding physical activity. We analysed AA changes and assessed the association between baseline AA and mRS/EQ-5D-3L scores. A small group of participants had follow-up data for 2 years, which allowed for analysing long-term serial changes. RESULTS: We included 186 participants (mean [SD] age 61.3 [11.2] years, 67% male, mean 39 [28] days after stroke). AA increased during the subacute phase in individuals with mild (NIHSS score 1-4, P<0.001) and moderate (NIHSS score 5-10, P=0.013) disability but not in the non-impaired group. Baseline AA was inversely associated with NIHSS score (P<0.001) and was associated with mRS score (P=0.001) and weakly correlated with EQ-5D-3L score at 6 months (P=0.032, r=0.22). For the 45 participants with follow-up data (mean age 64.5 [9.7] years, 80% male, mean 34 [21] days after stroke), AA remained stable. CONCLUSION: AA increased in stroke survivors with impairments but remained stable in those whose symptoms had resolved. AA during the early subacute period was associated with mRS and EQ-5D-3L scores at 6 months. Insertable cardiac monitoring offers a feasible method for monitoring activity over prolonged periods in people after stroke. Its increased use may offer an opportunity to overcome the limited reliability and validity of many existing measures. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00924638).

Presence of Atrial Fibrillation in Stroke Patients With Patent Foramen Ovale: Systematic Review and Meta-Analysis.

Purpose: Patent foramen ovale (PFO) is associated with ischemic stroke, especially in patients with embolic stroke of undetermined source. This study aims to evaluate the presence of atrial fibrillation (AF) in ischemic stroke patients with PFO. Methods: We systematically searched EMBASE and MEDLINE databases on May 21, 2020 for studies that analyzed the presence of AF in patients with PFO. The primary outcome was the presence of AF in patients with PFO compared with those without. Outcomes were pooled using a random-effects model using the method of DerSimonian and Laird. We recorded demographic characteristics and the methods used for AF detection in the studies included (unspecified, history/medical records review, ECG, Holter monitor, or loop recorder). Results: A total of 14 studies and 13,245 patients fulfilled the entry criteria. The average age was 61.2 years and 41.3% of the participants were female. There was a lower risk of AF in patients with PFO compared with those without (RR 0.52, 95% confidence interval, 0.41-0.63, p < 0.001). There was no evidence of heterogeneity. The lower risk of AF was found in cross-sectional and longitudinal studies and in studies stratified by average age (<60 or ≥60) and in cryptogenic stroke. Meta-regression by PFO detection technique suggested that studies using transoesophageal echocardiogram for PFO detection reported higher risk of AF (1.39, 95% confidence interval 1.14-1.70, p = 0.004). Conclusion: The presence of a PFO in patients with ischemic stroke/TIA may be associated with a lower risk of AF. Few studies have estimated the risk of future AF in patients with PFO.

Atrial Fibrillation Following Patent Foramen Ovale Closure: Systematic Review and Meta-Analysis of Observational Studies and Clinical Trials.

Background and Purpose: Multiple studies evaluated whether patent foramen ovale (PFO) closure reduces the risk of ischemic stroke. One commonly reported complication of PFO closure is the development of atrial fibrillation (AF), which is itself a powerful stroke risk factor that requires specific management. This study aims to evaluate the frequency of AF in patients post-percutaneous closure of PFO and the clinical factors that predict AF detection. Methods: Studies were identified by systematically searching EMBASE and MEDLINE databases on July 11, 2019. Meta-analysis of proportions was performed, assuming a random-effects model. Results: A total of 6 randomized controlled trials and 26 observational studies were included, comprising 3737 and 9126 patients, respectively. After PFO closure, the rate of AF development was 3.7 patients per 100 patient-years of follow-up (95% CI, 2.6­4.9). The risk of AF development is concentrated in the first 45 days post-procedure (27.2 patients per 100 patient-years [95% CI, 20.1­34.81], compared with 1.3 patients per 100 patient-years [95% CI, 0.3­2.7]) after 45 days. Meta-regression by age suggested that studies with older patients reported higher rate of AF (P=0.001).In medically treated patients, the rate of AF development was 0.1 per 100 patient-years of follow-up (95% CI, 0.0­0.4). Closure of PFO is associated with increased risk of AF compared with medical management (odds ratio, 5.3 [95% CI, 2.5­11.41]; P<0.001). Conclusions: AF is more common in PFO patients who had percutaneous closure compared with those who were medically treated. The risk of AF was higher in the first 45 days post-closure and in studies that included patients with increased age.

Automated DWI analysis can identify patients within the thrombolysis time window of 4.5 hours.

OBJECTIVE: To develop an automated model based on diffusion-weighted imaging (DWI) to detect patients within 4.5 hours after stroke onset and compare this method to the visual DWI-FLAIR (fluid-attenuated inversion recovery) mismatch. METHODS: We performed a subanalysis of the "DWI-FLAIR mismatch for the identification of patients with acute ischemic stroke within 4.5 hours of symptom onset" (PRE-FLAIR) and the "AX200 for ischemic stroke" (AXIS 2) trials. We developed a prediction model with data from the PRE-FLAIR study by backward logistic regression with the 4.5-hour time window as dependent variable and the following explanatory variables: age and median relative DWI (rDWI) signal intensity, interquartile range (IQR) rDWI signal intensity, and volume of the core. We obtained the accuracy of the model to predict the 4.5-hour time window and validated our findings in an independent cohort from the AXIS 2 trial. We compared the receiver operating characteristic curve to the visual DWI-FLAIR mismatch. RESULTS: In the derivation cohort of 118 patients, we retained the IQR rDWI as explanatory variable. A threshold of 0.39 was most optimal in selecting patients within 4.5 hours after stroke onset resulting in a sensitivity of 76% and specificity of 63%. The accuracy was validated in an independent cohort of 200 patients. The predictive value of the area under the curve of 0.72 (95% confidence interval 0.64-0.80) was similar to the visual DWI-FLAIR mismatch (area under the curve = 0.65; 95% confidence interval 0.58-0.72; p for difference = 0.18). CONCLUSIONS: An automated analysis of DWI performs at least as good as the visual DWI-FLAIR mismatch in selecting patients within the 4.5-hour time window.

University education and cervical artery dissection.

BACKGROUND AND PURPOSE: We investigated whether university education is more likely in cervical artery dissection (CeAD)-patients than in age- and sex-matched patients with ischemic stroke (IS) due to other causes (non-CeAD-IS-patients). METHODS: Patients from the Cervical Artery Dissection and Ischemic Stroke Patients study with documented self-reported profession before onset of IS due to CeAD (n = 715) or non-CeAD causes (n = 631) were analyzed. In the reported profession, the absence or presence of university education was assessed. Professions could be rated as academic or non-academic in 518 CeAD and 456 non-CeAD patients. Clinical outcome at 3 months was defined as excellent if modified Rankin Scale was 0-1. RESULTS: University education was more frequent in CeAD-patients (100 of 518, 19.3%) than in non-CeAD-IS-patients (61 of 456, 13.4%, p = 0.008). CeAD-patients with and without university education differed significantly with regard to smoking (39 vs. 57%, p = 0.001) and excellent outcome (80 vs. 66%, p = 0.004). In logistic regression analysis, university education was associated with excellent outcome in CeAD-patients (OR 2.44, 95% CI 1.37-5.38) independent of other outcome predictors such as age (OR 0.97, 95% CI 0.84-0.99), NIHSS (OR 0.80, 95% CI 0.76-0.84) and local signs (OR 2.77, 95% CI 1.37-5.57). CONCLUSION: We observed a higher rate of university education in patients with CeAD compared with non-CeAD patients in our study population. University education was associated with favorable outcome in CeAD-patients. The mechanism behind this association remains unclear.

Predictors for atrial fibrillation detection after cryptogenic stroke: Results from CRYSTAL AF.

OBJECTIVE: We assessed predictors of atrial fibrillation (AF) in cryptogenic stroke (CS) or transient ischemic attack (TIA) patients who received an insertable cardiac monitor (ICM). METHODS: We studied patients with CS/TIA who were randomized to ICM within the CRYSTAL AF study. We assessed whether age, sex, race, body mass index, type and severity of index ischemic event, CHADS2 score, PR interval, and presence of diabetes, hypertension, congestive heart failure, or patent foramen ovale and premature atrial contractions predicted AF development within the initial 12 and 36 months of follow-up using Cox proportional hazards models. RESULTS: Among 221 patients randomized to ICM (age 61.6 ± 11.4 years, 64% male), AF episodes were detected in 29 patients within 12 months and 42 patients at 36 months. Significant univariate predictors of AF at 12 months included age (hazard ratio [HR] per decade 2.0 [95% confidence interval 1.4-2.8], p = 0.002), CHADS2 score (HR 1.9 per one point [1.3-2.8], p = 0.008), PR interval (HR 1.3 per 10 milliseconds [1.2-1.4], p < 0.0001), premature atrial contractions (HR 3.9 for >123 vs 0 [1.3-12.0], p = 0.009 across quartiles), and diabetes (HR 2.3 [1.0-5.2], p < 0.05). In multivariate analysis, age (HR per decade 1.9 [1.3-2.8], p = 0.0009) and PR interval (HR 1.3 [1.2-1.4], p < 0.0001) remained significant and together yielded an area under the receiver operating characteristic curve of 0.78 (0.70-0.85). The same predictors were found at 36 months. CONCLUSION: Increasing age and a prolonged PR interval at enrollment were independently associated with an increased AF incidence in CS patients. However, they offered only moderate predictive ability in determining which CS patients had AF detected by the ICM.

Association between the perfusion/diffusion and diffusion/FLAIR mismatch: data from the AXIS2 trial.

The perfusion-/diffusion-weighted imaging (PWI/DWI) mismatch and the diffusion/fluid attenuated inversion recovery (DWI/FLAIR) mismatch are magnetic resonance imaging (MRI) markers of evolving brain ischemia. We examined whether the DWI/FLAIR mismatch was independently associated with the PWI/DWI mismatch. Furthermore, we determined whether the presence of the DWI/FLAIR mismatch in patients with the PWI/DWI mismatch would provide additional information regarding last seen normal time (LTM). We used data from the 'AX200 for ischemic stroke' trial (AXIS 2 study NCT00927836). We studied the association between the presence of the DWI/FLAIR and PWI/DWI mismatch, baseline National Institute of Health Stroke Scale (NIHSS), age, ischemic-core volume, gender, intravenous (IV) tissue plasminogen activator (tPA), and perfusion-mismatch volume in univariate analysis. Significant variables (P<0.05) were added into the final multivariate model. We analyzed 197 patients. Seventy-two (37%) had both the PWI/DWI and the DWI/FLAIR mismatch. Patients with the double mismatch pattern had a shorter LTM than patients with the PWI/DWI mismatch alone (Median difference 90 minutes, P<0.01). Multivariate analysis confirmed the independent association between the two mismatch patterns (odds ratio (OR) 2.6, 95% confidence interval (CI) 1.2 to 5.4). Our study implies that the DWI/FLAIR mismatch and PWI/DWI mismatch are strongly associated, independent from LTM. Furthermore, in the presence of the PWI/DWI mismatch, the DWI/FLAIR pattern indicates a shorter LTM. This could have implications in selecting patients for reperfusion therapy.

Stroke Genetics Network (SiGN) study: design and rationale for a genome-wide association study of ischemic stroke subtypes.

BACKGROUND AND PURPOSE: Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The National Institute of Neurological Disorders and Stroke SiGN (Stroke Genetics Network) contributes substantially to meta-analyses that focus on specific subtypes of stroke. METHODS: The National Institute of Neurological Disorders and Stroke SiGN includes ischemic stroke cases from 24 genetic research centers: 13 from the United States and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the Web-based causative classification of stroke system, with data entered by trained and certified adjudicators at participating genetic research centers. Through the Center for Inherited Diseases Research, the Network plans to genotype 10,296 carefully phenotyped stroke cases using genome-wide single nucleotide polymorphism arrays and adds to these another 4253 previously genotyped cases, for a total of 14,549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. Center for Inherited Diseases Research-generated genotypes and corresponding phenotypes will be shared with the scientific community through the US National Center for Biotechnology Information database of Genotypes and Phenotypes, and brain MRI studies will be centrally archived. CONCLUSIONS: The Stroke Genetics Network, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.

Thrombolytics in acute ischaemic stroke: historical perspective and future opportunities.

The discovery of thrombolytic agents goes back to the 1930s, when it was shown that substances derived from bacteria (streptokinase, staphylokinase), tissue (fibrinokinase), urine (urokinase) or bat saliva could activate the fibrinolytic system. The potential to treat arterial thrombosis with plasmin was recognized, but it was not until 1958 that its first use in acute ischaemic stroke (AIS) was described. However, since computer tomography (CT) was not available until the mid 1970s, optimal selection of patients was not possible. Early studies with streptokinase in AIS showed an increased risk of intracranial haemorrhage and lack of efficacy, which was associated with low fibrin specificity. The search for new agents with a better risk-benefit profile continued until 1979 when tissue plasminogen activator (t-PA) was discovered. In 1983 it became possible to produce recombinant t-PA (rt-PA) by expression of a cloned gene which enabled clinical trials to be started, mainly for coronary thrombolysis. In 1995, the National Institute of Neurological Disorders and Stroke study showed that rt-PA was an effective treatment for AIS, nowadays for use up to 4.5 h after onset. However, rt-PA still often fails in achieving rapid reperfusion, has relatively low recanalization rates and is associated with an increased bleeding risk. Several attempts have been made to develop thrombolytics with a better risk-benefit profile than rt-PA, but no real impact on clinical practice was observed. In 1994, it was shown that tenecteplase (rt-PA-TNK) had a higher fibrin specificity than rt-PA, but its clinical use in AIS was described only in 2005. The recently reported results of a small phase 2B trial showed significantly better reperfusion and clinical outcome with rt-PA-TNK compared to rt-PA; patients were selected by CT perfusion and angiography, and treated within 6 h after stroke onset. Currently, a phase 3 trial of rt-PA-TNK versus rt-PA is being planned in patients at an onset up to 4.5 h. The most fibrin-specific recombinant plasminogen activator desmoteplase originates from 1991, and its clinical development in AIS started in 2005. Desmoteplase is in phase 3 development for the treatment of AIS between 3 and 9 h after onset in AIS patients presenting with occlusion or high-grade stenosis.

Modifying expression of EphA4 and its downstream targets improves functional recovery after stroke.

Functional recovery after stroke varies greatly between patients, potentially due to differences in gene expression. Several processes like angiogenesis, neurogenesis, axonal reorganization and synaptic plasticity act in concert to restore neurological functions. The ephrin family has known roles in all these processes. EphA4 is the most abundant ephrin receptor in the nervous system. Therefore, we investigated whether EphA4 affects functional recovery from stroke, and evaluated the potential of this receptor as a therapeutic target. Motor recovery after photothrombotic stroke was studied in transgenic mice in which expression of EphA4 was reduced. Furthermore, blocking a downstream target of EphA4, ROCK (Rho-associated kinase), by two different compounds was evaluated in the same model. Motor recovery after photothrombotic stroke was markedly enhanced in transgenic mice with reduced levels of EphA4, whereas infarct sizes were similar compared with non-transgenic controls. Pharmacological inhibition of the EphA4 signaling cascade using two ROCK inhibitors,Y-27632 and fasudil, improved motor function of mice after stroke. Infarct size was comparable in all groups studied, suggesting that the benefit obtained by EphA4 inhibition is not neuroprotective in nature but due to an effect on the mechanisms underlying recovery. Our findings show that reduction of EphA4 improves motor function after experimental stroke and demonstrate that ROCK inhibition is a promising therapeutic strategy to enhance recovery after ischemic stroke.

Novel COL4A1 mutations cause cerebral small vessel disease by haploinsufficiency.

Mutations in COL4A1 have been identified in families with hereditary small vessel disease of the brain presumably due to a dominant-negative mechanism. Here, we report on two novel mutations in COL4A1 in two families with porencephaly, intracerebral hemorrhage and severe white matter disease caused by haploinsufficiency. Two families with various clinical presentations of cerebral microangiopathy and autosomal dominant inheritance were examined. Clinical, neuroradiological and genetic investigations were performed. Electron microscopy of the skin was also performed. In one of the families, sequence analysis revealed a one base deletion, c.2085del, leading to a frameshift and a premature stopcodon, p.(Gly696fs). In the other family, a splice site mutation was identified, c.2194-1G>A, which most likely leads to skipping of an exon with a frameshift and premature termination as a result. In fibroblasts of affected individuals from both the families, nonsense-mediated decay (NMD) of the mutant COL4A1 messenger RNAs (mRNAs) and a clear reduction of COL4A1 protein expression were demonstrated, indicating haploinsufficiency of COL4A1. Moreover, thickening of the capillary basement membrane in the skin was documented, similar to reports in patients with COL4A1 missense mutations. These findings suggest haploinsufficiency, a different mechanism from the commonly assumed dominant-negative effect, for COL4A1 mutations as a cause of (antenatal) intracerebral hemorrhage and white matter disease.

Randomized, placebo-controlled, dose-ranging clinical trial of intravenous microplasmin in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Microplasmin is a recombinant truncated form of human plasmin. It has demonstrated efficacy in experimental animal models of stroke and tolerability in healthy volunteers. We tested the tolerability of microplasmin in patients with acute ischemic stroke. METHODS: In a multicenter, double-blind, randomized, placebo-controlled Phase II trial, 40 patients with ischemic stroke were treated with either placebo or active drug between 3 and 12 hours after symptom onset in a dose-finding design. Ten patients received placebo, 6 patients received a total dose of 2 mg/kg, 12 patients received a total dose of 3 mg/kg, and 12 patients received a total dose of 4 mg/kg. We studied the pharmacodynamics of microplasmin and its effect on the clinical and hemodynamic parameters of the patients. MRI was used as a surrogate marker and matrix metalloproteinases serum concentrations were used as markers of neurovascular integrity. The study was underpowered to detect clinical efficacy. RESULTS: Microplasmin induced reversible effects on markers of systemic thrombolysis and neutralized alpha(2)-antiplasmin by up to 80%. It was well tolerated with one of 30 treated patients developing a fatal symptomatic intracerebral hemorrhage. No significant effect on reperfusion rate or on clinical outcome was observed. Matrix metalloproteinase-2 levels were reduced in microplasmin-treated patients. CONCLUSIONS: Microplasmin was well tolerated and achieved neutralization of alpha(2)-antiplasmin. Further studies are warranted to determine whether microplasmin is an effective therapeutic agent for ischemic stroke.

Geography, structure, and evolution of diffusion and perfusion lesions in Diffusion and perfusion imaging Evaluation For Understanding Stroke Evolution (DEFUSE).

BACKGROUND AND PURPOSE: The classical representation of acute ischemic lesions on MRI is a central diffusion-weighted imaging (DWI) lesion embedded in a perfusion-weighted imaging (PWI) lesion. We investigated spatial relationships between final infarcts and early DWI/PWI lesions before and after intravenous thrombolysis in the Diffusion and perfusion imaging Evaluation For Understanding Stroke Evolution (DEFUSE) study. METHODS: Baseline and follow-up DWI and PWI lesions and 30-day fluid-attenuated inversion recovery scans of 32 patients were coregistered. Lesion geography was defined by the proportion of the DWI lesion superimposed by a Tmax (time when the residue function reaches its maximum) >4 seconds PWI lesion; Type 1: >50% overlap and Type 2: < or = 50% overlap. Three-dimensional structure was dichotomized into a single lesion (one DWI and one PWI lesion) versus multiple lesions. Lesion reversal was defined by the percentage of the baseline DWI or PWI lesion not superimposed by the early follow-up DWI or PWI lesion. Final infarct prediction was estimated by the proportion of the final infarct superimposed on the union of the DWI and PWI lesions. RESULTS: Single lesion structure with Type 1 geography was present in only 9 patients (28%) at baseline and 4 (12%) on early follow-up. In these patients, PWI and DWI lesions were more likely to correspond with the final infarcts. DWI reversal was greater among patients with Type 2 geography at baseline. Patients with multiple lesions and Type 2 geography at early follow-up were more likely to have early reperfusion. CONCLUSION: Before thrombolytic therapy in the 3- to 6-hour time window, Type 2 geography is predominant and is associated with DWI reversal. After thrombolysis, both Type 2 geography and multiple lesion structure are associated with reperfusion.

Efficacy and safety of tissue plasminogen activator 3 to 4.5 hours after acute ischemic stroke: a metaanalysis.

BACKGROUND AND PURPOSE: The Third European Cooperative Acute Stroke Study (ECASS-3) demonstrated a benefit of treatment with intravenous tissue plasminogen activator (tPA) for acute stroke in the 3- to 4.5-hour time-window. Prior studies, however, have failed to demonstrate a significant benefit of tPA for patients treated beyond 3 hours. The purpose of this study was to produce reliable and precise estimates of the treatment effect of tPA by pooling data from all relevant studies. METHODS: A metaanalysis was undertaken to determine the efficacy of tPA in the 3- to 4.5-hour time-window. The effect of tPA on favorable outcome and mortality was assessed. RESULTS: The metaanalysis included data from patients treated in the 3- to 4.5-hour time-window in ECASS-1 (n=234), ECASS-2 (n=265), ECASS-3 (n=821) and The Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) (n=302). tPA treatment was associated with an increased chance of favorable outcome (odds ratio 1.31; 95% CI: 1.10 to 1.56; P=0.002) and no significant difference in mortality (odds ratio 1.04; 95% CI: 0.75 to 1.43; P=0.83) compared to placebo treated patients. CONCLUSIONS: Treatment with tPA in the 3- to 4.5-hour time-window is beneficial. It results in an increased rate of favorable outcome without adversely affecting mortality.

Treatment time-specific number needed to treat estimates for tissue plasminogen activator therapy in acute stroke based on shifts over the entire range of the modified Rankin Scale.

BACKGROUND AND PURPOSE: To make informed treatment decisions, patients and physicians need to be aware of the benefits and risks of a proposed treatment. The number needed to treat (NNT) for benefit and harm are intuitive and statistically valid measures to describe a treatment effect. The aim of this study is to calculate treatment time-specific NNT estimates based on shifts over the entire spectrum of clinically relevant functional outcomes. METHODS: The pooled data set of the first 6 major randomized acute stroke trials of intravenous tissue plasminogen activator was used for this study. The data were stratified by 90-minute treatment time windows. NNT for benefit and NNT for harm estimates were determined based on expert generation of joint outcome distribution tables. NNT for benefit estimates were also calculated based on joint outcome distribution tables generated by a computer model. RESULTS: NNT for benefit estimates based on the expert panel were 3.6 for patients treated between 0 and 90 minutes, 4.3 with treatment between 91 and 180 minutes, 5.9 with treatment between 181 and 270 minutes, and 19.3 with treatment between 271 and 360 minutes. The computer simulation yielded very similar results. The NNT for harm estimates for the corresponding time intervals are 65, 38, 30, and 14. CONCLUSIONS: Up to 4(1/2) hours after symptom onset, tissue plasminogen activator therapy is associated with more benefit than harm, whereas there is no evidence of a net benefit in the 4(1/2)- to 6-hour time window. The NNT estimates for each 90-minute epoch provide useful and intuitive information based on which patients may be able to make better informed treatment decisions.