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A major problem facing ischemic stroke therapy is the lack of treatments that directly restore the anatomy and physiology of the injured neurovascular unit. Therapeutic angiogenesis emerged as a potential treatment for ischemic stroke after preclinical studies demonstrated that neovascularization induced by angiogenic pharmacological agents is associated with neuroprotection. This chapter discusses the: (1) epidemiology of ischemic stroke and the limitations of current treatments, (2) neuroprotection and therapeutic angiogenesis as new treatments for ischemic stroke, (3) biology of vascular endothelial cell growth factor (VEGF) and how VEGF has become a prime candidate for therapeutic angiogenesis, (4) potential clinical benefits and adverse effects of VEGF-based therapeutic angiogenesis for ischemic stroke, and (5) gaps in knowledge requiring further preclinical investigations before VEGF-based therapeutic angiogenesis can be considered safe and effective to begin clinical trials for ischemic stroke patients. The unresolved issues in the preclinical trials are whether: (A) VEGF-based therapeutic angiogenesis promotes or hinders neuroprotection, (B) doses of VEGF not demonstrating adverse effects at the light microscopy level associated with clinically-significant ultrastructural alterations of the neurovascular unit, (C) VEGF combination therapy provide greater neuroprotection over VEGF monotherapy without additional adverse effects, (D) different isoforms of VEGF produce different therapeutic outcomes, and how the most beneficial isoform affects the anatomy and physiology of other organs, (E) VEGF-based therapeutic angiogenesis affects systemic hemodynamics, (F) different animal models of ischemic stroke produce similar favorable or adverse outcomes, including the influences of age, gender and coexisting chronic diseases, (G) gene therapy and stem cells are beneficial for VEGF-based therapeutic angiogenesis for stroke. [ABSTRACT FROM AUTHOR]

The purpose of this chapter is to introduce physicians to the concept of a combined intravenous/intra-arterial (IA) approach to vascular recanalization. Current experience is limited but the concept is attractive and worthy of further study. To understand the potential advantages of a combined approach, it is helpful to first examine the known advantages and limitations of intravenous and IA delivery of thrombolytic agents. The basic rationale for IA thrombolysis is presented in Chapter 10. Here we discuss some of the limitations of IA therapy. [ABSTRACT FROM AUTHOR]

To successfully identify, triage, diagnose, and treat an acute stroke victim in time requires a coordinated, multidisciplinary effort that is organized around a predefined protocol. The protocol assures that all needed action will occur in a timely fashion. Also, the ratio of stroke to stroke-mimics may be one to four or five, which mandates the presence of an efficient, skilled procedure for eliminating the mimics (e.g., Todd's paralysis, transient ischemic attack, hysteria, migraine, and carpal tunnel syndrome). Stroke patients must be stabilized according to basic protocols (Airway, Breathing, Circulation) before the neurological evaluation begins; this process should require no more than 1 or 2 min. Stroke management then includes diagnosis and possibly treatment. All of the above is best accomplished with a institutionalized stroke team, comparable to a code blue team that rehearses, monitors performance, and uses feedback to continually improve care. [ABSTRACT FROM AUTHOR]

Thrombolysis is the treatment of choice for eligible acute stroke within 3 h after symptom onset. However, in the United States, only 2-5% of acute stroke patients receive this therapy, and among those patients who are treated there remains a risk of developing a symptomatic intracerebral hemorrhage (ICH) (1-3). Moreover, no treatment beyond 3 h has been approved by regulatory agencies. Thus, there is an urgent need to optimize safety and efficacy of thrombolytic therapy in the early time window (<3 h from onset), and identify selection criteria for therapies that can be safely extended into later time windows. Multimodal neuroimaging techniques are now available in the clinical setting and may provide an opportunity to meet both these needs. [ABSTRACT FROM AUTHOR]

Computed tomography (CT) was the first modality to image the brain and its pathology in vivo. Before the invention of CT in the early 1970s, brain diseases were categorized according to their clinical phenotype. The term "stroke" originates from these old days of medicine, when brain hemorrhages could not be differentiated from ischemic brain diseases. It is unfortunate that we still use the term "stroke" for different diseases like subarachnoid hemorrhage (SAH), cerebral venous thrombosis, spontaneous intracerebral hemorrhages (ICH), and focal brain ischemia, which should be distinguished even though each may present as "brain attack." [ABSTRACT FROM AUTHOR]

The demonstration that early thrombolytic therapy for acute cerebral infarction improves outcomes and the Food and Drug Administration (FDA) approval of intravenous recombinant tissue plasminogen activator (rt-PA) for acute cerebral infarction (seeChapter 7) stimulated establishment of rapid response stroke teams and certified stroke centers in the United States. The positive results from thrombolytic acute stroke clinical trials were exciting and not surprising given the known pathophysiology of acute cerebral infarction, the similarity of acute stroke to acute myocardial infarction (MI), and the demonstrated benefits of early myocardial reperfusion in acute MI. The need for rapid response teams in acute stroke is based on the evidence that thrombolysis with intravenous rt-PA is effective only within 3 h after stroke onset (1,2). The main risk in thrombolytic therapy for acute stroke is cerebral hemorrhage transformation of an infarct. Fortunately, the benefits of thrombolytic therapy in acute cerebral infarction overshadow the risks and the bleeding can be minimized by careful patient selection according to guidelines (seeChapter 18). [ABSTRACT FROM AUTHOR]

Although 8 yr have passed since the Food and Drug Administration (FDA) released tissue plasminogen activator (t-PA) for use in the United States to treat patients with acute ischemic stroke, thrombolysis is still very controversial. Clearly, thrombolysis is a step forward but there remain problems with its use, and with the guidelines and policies that direct its application. [ABSTRACT FROM AUTHOR]

The use of tissue plasminogen activators (t-PA) for acute stroke was proven safe and effective in the National Institutes of Neurologic Disorders and Stroke (NINDS) study of t-PA for acute stroke, published in 1995 (1). The therapy was approved by the US Food and Drug Administration (FDA) in 1996, and endorsed by the American Heart Association, American Academy of Neurology, and National Stroke Association in 1997 (2-4). Nevertheless, some authorities argued that thrombolytic therapy with t-PA for stroke was still not ready for general use, leaving the practitioner in an awkward position (5). Since the original approval, there have been several reports that bear on some of the questions raised by skeptics. What have we learned since the original study to answer remaining concerns about thrombolytic stroke therapy? Are data available now, that were not available previously, to reassure neurologists that it is now time to expand their use of thrombolytic therapy for stroke patients? The extension of thrombolytic therapy into the community—that is outside of specialized academic medical centers—is presented in Chapter 9. In the previous edition of this book, the case for limiting the use of thrombolytic therapy was eloquently made by Dr. Lou Caplan; for this edition, in Chapter 14, Dr. Caplan continues to point out the limitations of our understanding of thrombolysis, while making a case in favor of limiting thrombolytic use to specialized centers. Here, we will present the case in favor of thrombolytic therapy under the current guidelines. [ABSTRACT FROM AUTHOR]

Most experience with thrombolysis involves patients with cerebral hemisphere ischemia related to thromboembolic disease within the anterior (carotid arterial) territory (seeChapters 2 and 7). Although less experience has been gained in patients with posterior circulation (vertebrobasilar [VB] arterial) thromboembolism, most such data has concerned patients whose arterial lesions were documented before and after thrombolysis. [ABSTRACT FROM AUTHOR]

Intra-arterial (IA) thrombolysis provides an alternative to intravenous (iv) thrombolysis in selected patients with acute ischemic stroke. Recent advances in the field of neuro-interventional radiology, with the development of extremely soft, compliant microcatheters and steerable microguidewires, along with high-resolution fluoroscopy and digital imaging, and nonionic contrast agents, have made it feasible and safe to access the major intracranial blood vessels around the circle of Willis from a percutaneous transfemoral approach under local anesthesia. Rapid local delivery of fibrinolytic agents is now feasible using these techniques and is performed at many major medical centers in selected patients with acute cerebral ischemia. [ABSTRACT FROM AUTHOR]

The US Food and Drug Administration (FDA) approved intravenous tissue plasminogen activator (t-PA) as treatment for acute ischemic stroke in June 1996, based on the results of the National Institute of Neurological Disorders and Stroke (NINDS) study (seeChapter 7). The next important question was whether t-PA treatment could be applied in nonstudy community medical centers with a feasibility, safety, and efficacy comparable to that of NINDS trial. This question was answered by many community studies, which evaluated t-PA therapy in acute ischemic stroke. This chapter discusses community experience with intravenous t-PA in stroke treatment from 1996 to the present. Those studies are discussed in chronological order, highlighting the outcome and complication rates of each. Table 1 summarizes the results. [ABSTRACT FROM AUTHOR]

Following the initial publication of the National Institute of Neurological Disorders and Stroke (NINDS) tissue-plasminogen activator (t-PA) Stroke Trial results, the NINDS investigators published a series of additional data and analyses. These analyses were necessary because not all the relevant data could be included in the primary report, and to answer criticisms of the original article. Some of these analyses are summarized in other chapters, including Chapters 9 and 18. This chapter focuses on three important issues: cost effectiveness, subgroup selection, and long-term follow-up. The cost-effectiveness issue is critical because thrombolytic drugs are expensive. To show that the drug cost is worthwhile, the costs of stroke care absent treatment, including how costs might increase or decrease with successful treatment, were examined. Subgroup selection is addressed because some have advocated such analysis to help select patients at particular risk or susceptibility of benefit. Regression modeling was used to rigorously identify any subgroups that could be preferred for treatment. To ensure that the benefits of thrombolysis were sustained over the long term, the original cohort of patients up to 1 yr after stroke was followed. The essentials of these three follow-up analyses, cost effectiveness, subgroup selection, and longterm follow-up, have been published, so only brief descriptions of the methods are given here (1-3). The aim of this chapter is to put the results of these analyses into perspective for the practicing clinician. [ABSTRACT FROM AUTHOR]

Prior to the availability of computed tomography (CT) imaging, seven case series had reported the use of various thrombolytic agents for 249 patients with ischemic strokes(1-7). Mortality ranged from 20 to 50% and intracranial hemorrhage (ICH) rates from 11 to 35% in these studies (seeChapter 6). These discouraging results reflected the fact that patients were treated days to weeks after symptom onset and CT scanning was not yet available to appropriately exclude patients with hemorrhage. [ABSTRACT FROM AUTHOR]

The demonstration that tissue plasminogen activator (t-PA) is clinically effective for acute ischemic stroke was based on many important studies over the past two decades that then led to groundbreaking preliminary clinical trials. This chapter highlights and discusses these studies and their historical significance. Thrombolytic therapy is an inherently attractive treatment for ischemic stroke based on the known pathological and angiographic substrates of ischemic cerebrovascular disease (seeChapters 1-3). The majority of acute ischemic strokes are the direct consequences of atherothrombosis or thromboembolism of a cerebral or precerebral artery (seeChapter 2). The critical event is usually the formation of an acute thrombus, so the rationale for thrombolytic treatment is to achieve arterial recanalization with a relatively safe agent soon enough to improve patient outcome. [ABSTRACT FROM AUTHOR]

Thrombolysis is the first scientifically established treatment for acute ischemic stroke, but we now need to build on that success. One possible way this might be accomplished is by combining thrombolysis with neuroprotection (seeChapter 3). Such combination therapy might reduce complications of thrombolysis, especially hemorrhage, by protecting damaged endothelium or reducing the volume of tissue necrosis. It might also prevent secondary injury associated with reperfusion. Finally, it might augment the benefit of thrombolysis by extending the time window before irreversible damage occurs. This chapter explores the rationale behind combination therapy and describe laboratory and clinical results to date. [ABSTRACT FROM AUTHOR]

Prior to definitive human trials, considerable effort was expended in the laboratory perfecting thrombolytic therapy. The essential literature that provided the experimental impetus for proceeding to human trials is summarized in this chapter. From this experience, two important lessons emerged. First, thorough exploration of drug risks and benefits should be performed in relevant animal models prior to human trials. Second, animal models can predict human results accurately, but only if the correct models are chosen, and the results handled rigorously. For example, the experimental data clearly predicted the efficacy, and the side effects, of thrombolytic therapy with tissue plasminogen activator (t-PA). Furthermore, the excessive risk associated with streptokinase (SK) was predicted by the animal models. These data serve to illuminate an approach to studying putative stroke therapies in the future. [ABSTRACT FROM AUTHOR]

The majority of focal cerebral ischemic events result from arterial occlusion caused by embolism or in situ thrombosis. This interruption in blood flow, if severe and prolonged, leads to cerebral infarction. Brain infarction results from a disruption in blood flow, which causes a reduction in oxygen and glucose supplied to the tissue. Glucose and oxygen deprivation causes a metabolic shift toward the production of lactic acidic. Coincident with this impairment of the Na+/Ca++ exchange pump, excessive glutamate release causes an unregulated amount of calcium to enter the cells. Intracellular calcium increases trigger a variety of processes that result in the breakdown of membranes and nucleic acids. In addition, the release of free radicals, the breakdown of the blood-brain barrier and development of the inflammatory response all work together to promote further cellular injury. [ABSTRACT FROM AUTHOR]

Brain ischemia is caused by a heterogeneous array of different vascular disorders. The general categories of vascular disorders most often used are embolism, "thrombosis" (referring to a local in situ process that narrows and often occludes an artery or vein), and systemic hypoperfusion. Systemic disorders that lead to brain ischemia include cardiac disorders (cardiac arrest, arrythmias, low cardiac output), conditions that cause hypovolemia and lack of adequate oxygen-carrying blood (blood loss, severe anemia, shock, carbon monoxide poisoning, hypotension), and acute pulmonary conditions (i.e., pulmonary embolism). Because patients with systemic disorders are not candidates for thrombolysis and there are usually no associated intracranial vascular occlusions, this large category is not discussed here. This chapter, therefore, focuses entirely on embolic and thrombotic disorders. [ABSTRACT FROM AUTHOR]

The pharmacological use of plasminogen activators is associated with symptomatic improvement in patients with coronary artery thrombosis, peripheral arterial occlusions, and thrombosis of the venous system. Based on prospective angiographic studies and planned programs (1-5), thrombolysis is the only approved treatment of acute ischemic stroke (6-8) under limited circumstances. Currently, recombinant tissue plasminogen activator (rt-PA) is licensed in the United States and several other countries for the treatment of ischemic stroke within 3 h of onset (6). [ABSTRACT FROM AUTHOR]