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Werner Hacke

Publications and source records attributed to Werner Hacke.

At least 37 records · Page 2Linked to original sources
PubMed2004

Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials.

BACKGROUND: Quick administration of intravenous recombinant tissue plasminogen activator (rt-PA) after stroke improved outcomes in previous trials. We aimed to analyse combined data for individual patients to confirm the importance of rapid treatment. METHODS: We pooled common data elements from six randomised placebo-controlled trials of intravenous rt-PA. Using multivariable logistic regression we assessed the relation of the interval from stroke onset to start of treatment (OTT) on favourable 3-month outcome and on the occurrence of clinically relevant parenchymal haemorrhage. FINDINGS: Treatment was started within 360 min of onset of stroke in 2775 patients randomly allocated to rt-PA or placebo. Median age was 68 years, median baseline National Institute of Health Stroke Scale (NIHSS) 11, and median OTT 243 min. Odds of a favourable 3-month outcome increased as OTT decreased (p=0.005). Odds were 2.8 (95% CI 1.8-4.5) for 0-90 min, 1.6 (1.1-2.2) for 91-180 min, 1.4 (1.1-1.9) for 181-270 min, and 1.2 (0.9-1.5) for 271-360 min in favour of the rt-PA group. The hazard ratio for death adjusted for baseline NIHSS was not different from 1.0 for the 0-90, 91-180, and 181-270 min intervals; for 271-360 min it was 1.45 (1.02-2.07). Haemorrhage was seen in 82 (5.9%) rt-PA patients and 15 (1.1%) controls (p<0.0001). Haemorrhage was not associated with OTT but was with rt-PA treatment (p=0.0001) and age (p=0.0002). INTERPRETATION: The sooner that rt-PA is given to stroke patients, the greater the benefit, especially if started within 90 min. Our results suggest a potential benefit beyond 3 h, but this potential might come with some risks.

Aged↗
PubMed2004

Benefit of clopidogrel over aspirin is amplified in patients with a history of ischemic events.

BACKGROUND AND PURPOSE: The goal of this study was to examine the influence of preexisting symptomatic atherosclerotic disease on subsequent ischemic event rates and compare the efficacy of clopidogrel versus aspirin (acetylsalicylic acid, ASA) in patients with such disease. METHODS: Using the CAPRIE database, we performed multivariate analyses for patients who had symptomatic atherosclerotic disease (ischemic stroke [IS] or myocardial infarction [MI]) in their medical history before enrollment in the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial. Two composite end points were used: (1) IS, MI, or vascular death and (2) IS, MI, or rehospitalization for ischemia. RESULTS: In the CAPRIE population, prior IS and MI each were statistically significant predictors of subsequent ischemic events. Compared with the overall population, patients with preexisting symptomatic atherosclerotic disease had elevated event rates for the end point of IS, MI, or vascular death; 3-year rates were 20.4% with clopidogrel and 23.8% with ASA (absolute risk reduction, 3.4%; 95% CI, -0.2 to 7.0; number needed to treat, 29; relative risk reduction, 14.9%; P=0.045). Similar results were obtained for the end point of IS, MI, or rehospitalization for ischemia; 3-year event rates were 32.7% with clopidogrel and 36.6% with ASA (absolute risk reduction, 3.9%; 95% CI, -0.4 to 8.1; number needed to treat, 26; relative risk reduction, 12.0%; P=0.039). CONCLUSIONS: CAPRIE patients with a history of prior symptomatic atherosclerotic disease had a high rate of subsequent ischemic events. The absolute benefit of clopidogrel over ASA seemed to be amplified in such high-risk patients.

Aged↗
PubMed2004

Stroke magnetic resonance imaging is accurate in hyperacute intracerebral hemorrhage: a multicenter study on the validity of stroke imaging.

BACKGROUND AND PURPOSE: Although modern multisequence stroke MRI protocols are an emerging imaging routine for the diagnostic assessment of acute ischemic stroke, their sensitivity for intracerebral hemorrhage (ICH), the most important differential diagnosis, is still a matter of debate. We hypothesized that stroke MRI is accurate in the detection of ICH. To evaluate our hypotheses, we conducted a prospective multicenter trial. METHODS: Stroke MRI protocols of 6 university hospitals were standardized. Images from 62 ICH patients and 62 nonhemorrhagic stroke patients, all imaged within the first 6 hours after symptom onset (mean, 3 hours 18 minutes), were analyzed. For diagnosis of hemorrhage, CT served as the "gold standard." Three readers experienced in stroke imaging and 3 final-year medical students, unaware of clinical details, separately evaluated sets of diffusion-, T2-, and T2*-weighted images. The extent and phenomenology of the hemorrhage on MRI were assessed separately. RESULTS: Mean patient age was 65.5 years; median National Institutes of Health Stroke Scale score was 10. The experienced readers identified ICH with 100% sensitivity (confidence interval, 97.1 to 100) and 100% overall accuracy. Mean ICH size was 17.3 mL (range, 1 to 101.5 mL). The students reached a mean sensitivity of 95.16% (confidence interval, 90.32 to 98.39). CONCLUSIONS: Hyperacute ICH causes a characteristic imaging pattern on stroke MRI and is detectable with excellent accuracy. Even raters with limited film-reading experience reached good accuracy. Stroke MRI alone can rule out ICH and demonstrate the underlying pathology in hyperacute stroke.

Acute Disease↗
PubMed2004

Critical illness myopathy serum fractions affect membrane excitability and intracellular calcium release in mammalian skeletal muscle.

The pathogenesis of myopathies occurring in critically ill patients (critical illness myopathy, CIM) is poorly understood. Both local and systemic responses to sepsis and other severe insults to the body are presumed to be involved but the precise mechanisms by which muscle function is impaired are far from clear. To elucidate such mechanisms we investigated the effects of blood serum fractions (5 kDa to 100 kDa molecular weight cut-off, MWCO) from patients with CIM and from control persons on membrane and contractile functions in intact mammalian single skeletal muscle fibres and chemically skinned fibre bundles. In intact fibres, resting membrane potentials were less negative when exposed to CIM serum fractions compared with control serum fractions. Half-width and maximum rise time of action potentials (AP) were smaller in CIM serum low MWCO fractions vs. control serum. Peak amplitudes of fast inward sodium currents (I(Na)) were increased by low MWCO-CIM fractions compared with control sera fractions. Additionally, voltage dependent inactivation of I(Na) was shifted towards more positive potentials by high MWCO fractions of CIM sera. In skinned fibres, pCa-force relations were similar in CIM and control serum fractions but peak force of Ca2+ induced force transients was decreased by low MWCO-CIM vs. control serum fractions. Our results (i) provide the first evidence that serum from CIM patients affects membrane excitability and the excitation-contraction coupling process at the level of the sarcoplasmic reticulum Ca2+ release of mammalian muscle fibres and (ii) also show that even control serum fractions "per se" alter the response to important physiological membrane and contractility parameters compared with physiological saline.

Animals↗
PubMed2004

Lack of association between polymorphisms of the toll-like receptor 4 gene and cerebral ischemia.

Toll-like receptor-4 (TLR4), an important mediator of the innate immune response, is expressed in atherosclerotic lesions. The common single nucleotide exchange (Asp299Gly) of the TLR4 gene has been previously reported to impair TLR4 function and to be associated with a decreased risk of carotid atherosclerosis. Therefore, we aimed to detect the potential impact of TLR4 genotypes on the risk of cerebral ischemia. We studied the prevalence of two common polymorphisms of the TLR4 gene (Asp299Gly and Thr399Ile) in 3 independent study populations: (1.) in a cross-sectional study including 769 patients either with type 1 or type 2 diabetes mellitus, of whom 56 (7.2%) had a history of cerebral ischemia (study 1), (2.) a case-control study (study 2) including 128 consecutive patients with cerebral ischemia, mean age 60 +/- 10.9 years and 139 control subjects, and (3.) a case-control study (study 3) including 171 young adults aged < 50 years with cerebral ischemia and 204 control individuals. In all subjects, Asp299Gly and Thr399Ile were detected by restriction length analysis. The prevalence of the TLR4 genotypes was essentially the same between patients with cerebral ischemia and control subjects in all 3 study populations. Furthermore, there was also no association with the subgroup of atherosclerotic stroke in both case-control studies populations. Although TLR4 polymorphisms are associated with a decreased risk of carotid atherosclerotic lesions, our findings indicate that they do not influence the prevalence of cerebral ischemia. This implies that the Asp299Gly TLR4-allele might have a protective role in carotid atherosclerosis, but not in cerebral ischemia.

Adult↗
PubMed2004

In vivo monitoring of acute flavivirus (Modoc) encephalitis with regional and whole-brain quantitative diffusion magnetic resonance imaging.

In vivo imaging of structural changes in the brain of patients with encephalitis has become an important aid in diagnostic and therapeutic procedures. Diffusion-weighted magnetic resonance imaging (DWI) was employed to quantitate regional and whole-brain diffusion-weighted MRI changes in a hamster model for acute flavivirus encephalitis. The regional apparent diffusion coefficient (ADC) was determined in hyperintense regions seen on T2-weighted images (i.e., the thalamic area and the temporal lobe), but anatomical variation and structural heterogeneity of encephalitic lesions severely impeded the placement of regions of interest (ROI). Therefore, quantitative whole-brain diffusion-weighted imaging was carried out and revealed a significantly reduced ADC (P = .02) in the brain of hamsters with acute encephalitis (n = 7) as compared to that of healthy, uninfected controls (n = 3). Furthermore, the ADC histogram demonstrated a reduced peak height and center of gravity during the acute encephalitis. Our findings could further support the use of diffusion-weighted imaging for in vivo monitoring of acute flavivirus encephalitis and for the study of therapeutic approaches.

Animals↗
PubMed2004

An update on thrombolytic therapy for acute stroke.

PURPOSE OF REVIEW: Stroke is the third leading cause of death after myocardial infarction and cancer, and is the leading cause of permanent disability and disability-adjusted loss of independent life-years in western countries. Thrombolysis is the treatment of choice for acute stroke within 3 h after the onset of symptoms. We present an overview of a diagnostic approach to acute stroke management that allows the individualization of patient management based on pathophysiological reasoning and not rigid time windows established by randomized controlled trials. RECENT FINDINGS: This review concentrates in the first part on giving the reader an integrated knowledge of the current status of thrombolytic therapy in stroke, and in the second part develops a treatment algorithm based on pathophysiological information rendered by a multiparametric stroke magnetic resonance imaging protocol. SUMMARY: Thrombolysis is an effective therapy for ischemic stroke, whether performed intravenously within 3 h or intra-arterially within 3-6 h. Meta-analyses have provided evidence of an effect of intravenous thrombolysis beyond the 3 h time window, especially when improved selection criteria such as modern magnetic resonance imaging protocols are applied. Sadly, thrombolysis is still underused. Positive results from studies currently underway may encourage more centers to offer this therapy to an increasing number of stroke patients, and thereby reduce the considerable socioeconomic burden of stroke.

Cerebral Infarction↗
PubMed2003

Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): an adaptive dose-response study of UK-279,276 in acute ischemic stroke.

BACKGROUND AND PURPOSE: UK-279,276 (neutrophil inhibitory factor) reduced infarct volume in a rat middle cerebral artery occlusion reperfusion model. ASTIN (Acute Stroke Therapy by Inhibition of Neutrophils) was an adaptive phase 2 dose-response-finding, proof-of-concept study to establish whether UK-279,276 improves recovery in acute ischemic stroke. The prime objective was to determine the dose that gave a clinically relevant effect in patients. METHODS: A Bayesian sequential design with real-time efficacy data capture and continuous reassessment of the dose response allowed double-blind, randomized, adaptive allocation to 1 of 15 doses (dose range, 10 to 120 mg) or placebo and early termination for efficacy or futility. The primary end point was change from baseline to day 90 on the Scandinavian Stroke Scale (DeltaSSS), adjusted for baseline SSS, aiming for a 3-point additional mean recovery above placebo. RESULTS: Nine hundred sixty-six acute stroke patients (887 ischemic, 204 cotreated with intravenous tissue plasminogen activator; mean baseline SSS score, 28; range, 10 to 40) were treated within 6 hours of symptom onset. Mean DeltaSSS was approximately +17 points of improvement on SSS for the overall evaluable population. There was no treatment effect for UK-279,276 (posterior probability of futility, 0.89). The trial was stopped early for futility. Post hoc analysis indicated a mean 1.6-point additional improvement on DeltaSSS in the tissue plasminogen activator-treated subset (credible interval=0.5, 2.6). UK-279,276 was generally well tolerated, with no increased incidence of infections. CONCLUSIONS: UK-279,276 did not improve recovery in acute ischemic stroke patients but was devoid of serious side effects. The adaptive design facilitated early termination for futility.

Acute Disease↗
PubMed2003

Topographically graded postischemic presence of metalloproteinases is inhibited by hypothermia.

To test the hypothesis that presence of metalloproteases (MMPs), their inhibitors (TIMPs) and their substrate laminin-5 differs between the ischemic core and the surrounding tissue, we examined the impact of middle cerebral artery occlusion/reperfusion (MCA:O/R) on these molecules in different regions of the infarct. We also investigated the influence of hypothermia on the progression of the ischemic lesion and MMP activity. Brain sections from 64 Wistar rats subjected to MCA:O/R were examined by means of cytohistochemistry and zymography. The artery was occluded for 2 h followed by 3, 5, 8 and 12 h of reperfusion. Well characterized antibodies against laminin-5, MMPs and TIMP-2 were used. A total of 32 rats were treated with hypothermia. The presence of each antigen was related to the following regions of interest: ischemic core with BBB breakdown (I(c)), surrounding ischemic tissue without BBB breakdown (I(r)), and the contralateral non-ischemic region (N). Regions of interest were defined by MRI. The I(c) increased over time at the cost of the I(r). BBB breakdown occurred early in the ischemic core and increased over time. Hypothermia reduced the BBB breakdown at all time points. A graded decreased presence of laminin-5 was observed with 16.5+/-3.7(N)>10+/-2.8(I(r))>4+/-1.4(I(c)) immunopositive microvessels/mm(2) at 3 h of reperfusion. MMP-9 showed a reverse pattern with 0 (N)<4+/-0.8(I(r))<10+/-1.5(I(c)) immunopositive microvessels/mm(2). Hypothermia decreased the MMP activity measured by zymography. Laminin-5 and MMP presence relate directly to the degree of postischemic injury. Hypothermia reduces the conversion from the I(r) to ischemic core and the degree of BBB as well as MMP abundance.

Animals↗
PubMed2003

Stroke MRI in intracerebral hemorrhage: is there a perihemorrhagic penumbra?

BACKGROUND AND PURPOSE: Cerebral ischemia has been proposed as a contributing mechanism to secondary neuronal injury after intracerebral hemorrhage (ICH). The search for surrogate parameters that allow treatment stratification for spontaneous ICH continues. We sought to assess the presence and prognostic effect of perihemorrhagic ischemic changes and hypoperfusion in a prospective stroke MRI study. METHODS: We performed stroke MRI in 32 patients with hyperacute ICH (mean, 16.9+/-17.2 mL) within 6 hours after symptom onset (mean, 3.1+/-1.3 hours). Clinical data at baseline (National Institutes of Health Stroke Scale) and on day 90 (Barthel Index, modified Rankin Scale) were assessed. Perihemorrhagic perfusion- and diffusion-weighted imaging changes were assessed in a 1-cm-wide area around the clot. RESULTS: Despite a mild perihemorrhagic mean transit time prolongation of 0.7+/-1.1 second, there were no significant perihemorrhagic apparent diffusion coefficient or mean transit time changes indicating irreversible ischemia or hypoperfusion. ICH size, time to imaging, or clinical severity at baseline or outcome were not reflected by changes of relative apparent diffusion coefficient or perfusion-weighted imaging. ICH size correlated with baseline clinical severity (r=0.51, P=0.005). There was a significant association (P=0.0494) and a significant negative correlation (r=-0.468, P=0.0103) of perihemorrhagic perfusion change with time from symptom onset not associated with ICH size. CONCLUSIONS: Perihemorrhagic hypoperfusion probably is a consequence of reduced metabolic demand (diaschisis) rather than a sign of ischemia. We found no evidence for a perihemorrhagic and potentially salvageable ischemic penumbra in hyperacute ICH. Further studies should address metabolic, toxic, apoptotic, and microvascular aspects.

Acute Disease↗
PubMed2003

Arterial pulsations are present in one third of the human cranial vascular volume penetrated by near infrared light.

The percentage of cranial vascular volume that undergoes arterial pulsations is estimated by 18 paired measurements in nine healthy volunteers using near infrared spectroscopy (NIRS, 10 Hz sampling frequency, 769 nm). The NIR absorption is decomposed in pulsatile and non-pulsatile components by digital filtering. The time course of absorption changes of these components after sudden intravenous injection of indocyanine-green (ICG) is used to estimate the arterial fraction of vascular volume (f(art)). Approximately 28% of the vascular volume within the optical field of the NIR spectroscope was arterial. The range of values was 6-43%. Variance of f(art) was 4.8 times higher between subjects than within subjects, indicating that the variability observed is not due to imprecise estimation but to optode position and subject.

Blood Vessels↗