Thrombolytic Treatment For Acute Stroke Research Articles

Progress in Intravenous Thrombolytic Therapy for Acute Stroke.

Intravenous recombinant tissue plasminogen activator (alteplase) was approved by the US Food and Drug Administration in 1996 for the treatment of acute ischemic stroke. Nearly 20 years later, it remains the only approved treatment, despite limitations in both efficacy and safety. With a growing capacity for stroke treatment worldwide, physicians need to understand where we have come from and what the future of stroke treatment might be. To present a historical prospective as well as current trends in thrombolytic therapy, focusing on characteristics of drugs that have worked and clinical trials that are moving the field forward. Sources are published pivotal clinical trials; seminal articles on physiology, pharmacology, and neuroimanging; and listings from clinical trial registries. The slow progress in thrombolysis for acute stroke has been multifactorial. A focus on extending the time window for alteplase beyond 4.5 hours has encumbered substantial resources in the field for many years, yet these efforts have been largely unsuccessful. New drug development has also been slow. Several drugs have failed in clinical trials and currently only tenecteplase remains to be tested as a potential alternative to alteplase. The parallel pursuit for catheter-based interventional revascularization in acute stroke, which appears to be successful, has shifted emphasis away from pharmacologically based studies. Although the field of acute thrombolysis has been making progress slowly for many years, advances in neuroimaging and new clinical trials that combine thrombolytics with other pharmacological and interventional techniques are beginning to gain momentum once again. The emergence of new approaches based largely on combination therapy strategies has reset a course to advance thrombolytic treatment for acute stroke and promises to improve outcomes in acute stroke in the near future.

A review of decision support, risk communication and patient information tools for thrombolytic treatment in acute stroke: lessons for tool developers.

BackgroundTools to support clinical or patient decision-making in the treatment/management of a health condition are used in a range of clinical settings for numerous preference-sensitive healthcare decisions. Their impact in clinical practice is largely dependent on their quality across a range of domains. We critically analysed currently available tools to support decision making or patient understanding in the treatment of acute ischaemic stroke with intravenous thrombolysis, as an exemplar to provide clinicians/researchers with practical guidance on development, evaluation and implementation of such tools for other preference-sensitive treatment options/decisions in different clinical contexts.MethodsTools were identified from bibliographic databases, Internet searches and a survey of UK and North American stroke networks. Two reviewers critically analysed tools to establish: information on benefits/risks of thrombolysis included in tools, and the methods used to convey probabilistic information (verbal descriptors, numerical and graphical); adherence to guidance on presenting outcome probabilities (IPDASi probabilities items) and information content (Picker Institute Checklist); readability (Fog Index); and the extent that tools had comprehensive development processes.ResultsNine tools of 26 identified included information on a full range of benefits/risks of thrombolysis. Verbal descriptors, frequencies and percentages were used to convey probabilistic information in 20, 19 and 18 tools respectively, whilst nine used graphical methods. Shortcomings in presentation of outcome probabilities (e.g. omitting outcomes without treatment) were identified. Patient information tools had an aggregate median Fog index score of 10. None of the tools had comprehensive development processes.ConclusionsTools to support decision making or patient understanding in the treatment of acute stroke with thrombolysis have been sub-optimally developed. Development of tools should utilise mixed methods and strategies to meaningfully involve clinicians, patients and their relatives in an iterative design process; include evidence-based methods to augment interpretability of textual and probabilistic information (e.g. graphical displays showing natural frequencies) on the full range of outcome states associated with available options; and address patients with different levels of health literacy. Implementation of tools will be enhanced when mechanisms are in place to periodically assess the relevance of tools and where necessary, update the mode of delivery, form and information content.

Defining an Acidosis-Based Ischemic Penumbra from pH-Weighted MRI

It has been proposed that the spatial mismatch between deficits on perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) in MRI can be used to decide regarding thrombolytic treatment in acute stroke. However, uncertainty remains about the meaning and reversibility of the perfusion deficit and even part of the diffusion deficit. Thus, there remains a need for continued development of imaging technology that can better define a potentially salvageable ischemic area at risk of infarction. Amide proton transfer (APT) imaging is a novel MRI method that can map tissue pH changes, thus providing the potential to separate the PWI/DWI mismatch into an acidosis-based penumbra and a zone of benign oligemia. In this totally noninvasive method, the pH dependence of the chemical exchange between amide protons in endogenous proteins and peptides and water protons is exploited. Early results in animal models of ischemia show promise to derive an acidosis penumbra. Possible translation to the clinic and hurdles standing in the way of achieving this are discussed.

Thrombolysis for Acute Stroke in Hemodialysis

Although data are absent, it has been stated that thrombolysis is probably not safe in the treatment of acute stroke in patients undergoing hemodialysis. The objective of this study was for stroke experts to define the range of management concerning thrombolytic treatment of acute stroke in hemodialysis. Sixty-five stroke experts in thrombolytic therapy of acute ischemic stroke were queried regarding their personal experience in the use of thrombolysis in hemodialysis patients. Hypothetical case scenarios were presented. Of the 65 stroke experts who were queried, 40 (62%) responded. One-third of the responders had previously treated hemodialysis patients with recombinant tissue-type plasminogen activator (rt-PA). Most favored use of intravenous rt-PA for hemodialysis patients with acute ischemic stroke. When presented with a case of a patient who had recently undergone dialysis with a mildly prolonged activated partial thromboplastin time (aPTT), 50% favored immediate intravenous thrombolysis. Seventy-eight percent of the experts would have considered an intra-arterial approach and would have preferred mechanical clot retrieval to thrombolysis. Despite the acknowledged absence of data and prevalent concerns about bleeding risk, most surveyed experts favored its use. One-third reported treating hemodialysis patients with this therapy. Although these results do not substitute for data, they usefully define the range of current practice of stroke experts.

Quantified T1 As An Adjunct To Apparent Diffusion Coefficient For Early Infarct Detection: A High-Field Magnetic Resonance Study in a Rat Stroke Model

Thrombolytic treatment for acute stroke has focused attention on accurate identification of injured vs. salvageable brain tissue, particularly if reperfusion occurs. However, our knowledge of differences in acute magnetic resonance imaging changes between transient and permanent ischemia and how they reflect permanently damaged tissue remain incomplete. Magnetic resonance imaging characteristics vary widely following ischemia and, at acute times, T1, T2 or apparent diffusion coefficient quantification may differentiate viable tissue from that destined to infarct. High-resolution magnetic resonance imaging was performed at 9.4 T following permanent or transient (90 min) middle cerebral artery occlusion in spontaneously hypertensive male rats or Wistar rats. Within 30 min, quantified maps of the apparent diffusion coefficient, T1, and T2 were performed and measures determined for sequences in the infarct and compared with that in the contralateral region. Lesion area for each magnetic resonance imaging sequence (T1, T2, apparent diffusion coefficient, and perfusion maps) was delineated for different time points using quantitative threshold measures and compared with final histological damage. Early extensive changes in T1 following both transient and permanent middle cerebral artery occlusion provided a sensitive early indicator of the final infarct area. Following reperfusion, small but measurable early T2 changes indicative of early development of vasogenic edema occurred in the transient but not permanent groups. In transient middle cerebral artery occlusion, at 70 min apparent diffusion coefficient decreased (P<0.001) and then pseudonormalized at 150 min. In permanent middle cerebral artery occlusion, apparent diffusion coefficient declined over time. Lesion area detected using T1 maps exceeded that with T2 and apparent diffusion coefficient at 70 and 150 min in both groups (P<0.001). The results indicate that, independent of reperfusion, quantified T1 is superior for detecting early ischemic changes that are not necessarily detected with T2 or apparent diffusion coefficient.

Thrombolytic Treatment of Acute Stroke

Thrombolytic Treatment of Acute Stroke

Intracerebral haemorrhage revisited

Much evidence suggests that acute intracerebral haemorrhage usually starts to appear an hour or two after a thromboembolic brain infarct. Intravenous thrombolytic treatment is accepted treatment for acute ischaemic stroke; but all neurologists concur that brain imaging should be performed first, so that thrombolysis can be avoided if bleeding has already started. This article calls into question the current guidelines for the use of thrombolytic treatment in acute stroke. Are they too restrictive?

Increased Body Iron Stores Are Associated With Poor Outcome After Thrombolytic Treatment in Acute Stroke

Iron overload has been associated with greater oxidative stress and brain injury in experimental cerebral ischemia and reperfusion. This study investigates whether high serum ferritin levels, as an index of increased cellular iron stores, are associated with poor outcome, hemorrhagic transformation, and brain edema after treatment with tissue plasminogen activator in patients with acute ischemic stroke. A total of 134 consecutive patients treated with intravenous tissue plasminogen activator were prospectively studied in four centers. Serum ferritin levels were determined at baseline, 24 and 72 hours after treatment. Cranial computed tomography was performed on admission and at 24 to 36 hours after tissue plasminogen activator infusion. Stroke severity and outcome were evaluated by using the National Institute of Health Stroke Scale and the modified Rankin Scale. Computed tomography showed hemorrhagic transformation in 27 patients (hemorrhagic infarction in 15 and parenchymal hematoma in 12; symptomatic in four) and brain swelling with midline shift in 15. Poor outcome (modified Rankin Scale >2) at 90 days was observed in 54.5% of patients. Ferritin levels at baseline were higher in patients with poor outcome at 90 days (median [quartiles], 165 [98,307] versus 17 [12,37] ng/mL; P<0.001) and in those who developed parenchymal hematoma (P=0.006), symptomatic hemorrhagic transformation (P=0.008), and severe brain edema (P<0.001). Serum ferritin levels higher than 79 ng/mL before tissue plasminogen activator treatment were independently associated with poor outcome (OR, 117 [95% CI, 25 to 557]). Increased body iron stores are associated with poor outcome, symptomatic hemorrhagic transformation, and severe edema in patients treated with tissue plasminogen activator after ischemic stroke. These findings suggest that iron overload may offset the beneficial effect of thrombolytic therapies.

Leukoaraiosis Is a Risk Factor for Symptomatic Intracerebral Hemorrhage After Thrombolysis for Acute Stroke

The aim of the study was to evaluate whether leukoaraiosis (LA) is a risk factor for symptomatic intracerebral hemorrhage (sICH) in patients treated with thrombolysis for acute stroke. In this retrospective, multicenter analysis, we evaluated data from acute anterior circulation stroke patients (n=449; <6 hours after symptom onset) treated with thrombolysis. All patients had received standard magnetic resonance imaging evaluation before thrombolysis, including a high-quality T2-weighted sequence. For the analysis, LA in the deep white matter was dichotomized into absent or mild versus moderate or severe (corresponding to Fazekas scores of 0 to 1 versus 2 to 3). The rate of sICH was significantly more frequent in patients with moderate to severe LA of the deep white matter (n=12 of 114; 10.5%) than in patients without relevant LA (n=13 of 335; 3.8%), corresponding to an odds ratio of 2.9 (95% CI, 1.29 to 6.59; P=0.015). In a logistic-regression analysis (including age, National Institutes of Health Stroke Scale score at presentation, and type of thrombolytic treatment), LA remained a significant independent risk factor (odds ratio, 2.9; P=0.03). LA of the deep white matter is an independent risk factor for sICH after thrombolytic treatment for acute stroke.

Intra-Arterial Thrombolysis for Left Middle Cerebral Artery Embolic Stroke During Coronary Angiography

Cerebral thromboembolism is an uncommon but serious complication of cardiac catheterization. Early diagnosis and rapid treatment by reperfusion techniques have been shown to prevent long-term neurological morbidity. We report 2 consecutive cases of successful local intra-arterial thrombolysis (LIT) for embolic stroke of the middle cerebral artery (MCA) during diagnostic coronary angiography that resulted in complete neurological recovery. A 77-year-old woman with severe valvular aortic stenosis was admitted to our catheterization laboratory for a preoperative coronary angiography. Performed from the femoral approach, it showed a normal angiographic pattern. Immediately after the procedure, the patient became stuporous with right hemiplegia and global aphasia. She was hemodynamically stable. The left carotid digital subtraction angiography that was performed immediately revealed total occlusion of the M2 part of the left MCA. There was no extravasation of contrast (Figure 1). We decided to administer selective intra-arterial urokinase infusion. After systemic heparinization (bolus of 5000 UI), a 6F Amplatz Right Guide catheter was placed in the left internal …

Atorvastatin Downregulates Tissue Plasminogen Activator-Aggravated Genes Mediating Coagulation and Vascular Permeability in Single Cerebral Endothelial Cells Captured by Laser Microdissection

The effects of statins on gene expression of cerebral endothelial cells (ECs) in vivo have not been investigated after stroke. We developed a rapid double immunofluorescent staining protocol with antibodies against von Willebrand factor (a marker for endothelium) and glial fibrillary acidic protein (a marker for astrocytes) for laser capture microdissection to isolate single ECs in brain tissue of the rat. Using this protocol in combination with real-time PCR, we found that stroke significantly increased mRNA levels of protease-activated receptor 1 (PAR-1) and tissue factor (TF) in ECs isolated from ischemic cerebral microvessels compared with nonischemic vessels. Treatment of embolic stroke with recombinant human tissue plasminogen activator (rht-PA) 4 h after stroke further elevated PAR-1 mRNA levels nearly 1000-fold in the core and 500-fold in the boundary above the nonstroke group 30 h after stroke, while TF mRNA levels were elevated approximately 10 fold above the nonstroke group. Furthermore, stroke significantly increased matrix metalloproteinase (MMP) 2 and 9 mRNA levels in the ischemic core and boundary regions 6 and 30 h after stroke. Treatment with rht-PA-upregulated MMP2 expression in the ischemic boundary and core. Atorvastatin completely blocked rht-PA upregulation of the above genes, when atorvastatin in combination with rht-PA was administered 4 h after stroke. Monotherapy of atorvastatin 4 h after stroke did not significantly reduce expression of genes examined in the present study. These data provide evidence that atorvastatin reduces exogenous tPA-aggravated cerebral endothelial genes that mediate thrombosis and blood-brain barrier permeability, which could contribute to the beneficial effects of statins on thrombolytic treatment of acute stroke.

FUNCTIONAL NEUROIMAGING IN ACUTE STROKE

To the present day, the first and most widespread diagnostic approach in the assessment of acute stroke remains CT scan. Its sensitivity is very high (nearly 100%) in detecting intracerebral hemorrhage in the acute period, but its capability of revealing ischemic injury in the very first hours from symptom onset is relatively poor. Since the efficacy of thrombolytic treatment in acute stroke has been suggested by the ECASS and NINDS rt-PA trials, functional neuroimaging able to distinguish potentially salvageable tissue from irreversibly injured areas has acquired primary importance. The possibility to correctly identify the tissue of the ischemic penumbra within the first hours from symptom onset is essential for correct patient selection for thrombolitic treatment. Different imaging strategies are available for the definition of perfusion deficits within the acute time window; among these are positron emission tomography (PET), single photon emission computed tomography (SPECT), Xenon CT (XeCT), dynamic CT perfusion imaging (CTP), diffusion weighted magnetic resonance imaging (DW-MRI), and perfusion weighted magnetic resonance imaging (PW-MRI). Though each technique has its advantages and limitations to present day functional MRI remains the most widespread imaging technique in the assessment of acute stroke being more accessible than both SPECT and PET, and capable of giving information on both perfusion and tissue functional status in a single imaging session.In this paper we discuss the role of functional neuroimaging in acute stroke.