During the last 40 years, management of patients with ischemic stroke has advanced (Table 1.2). Basic science research provides information about the causes of stroke and the vascular/cellular consequences from an arterial occlusion. We have learned that the course of acute brain ischemia evolves over a few hours and that dysfunctional brain tissue can be saved. Early treatment is crucial—time is brain. This knowledge serves as the foundation for therapies that treat stroke. The diagnosis of ischemic stroke and its underlying causes has been greatly expedited with advances in technology; in particular brain, vascular, and cardiac imaging. The introduction of computed tomography (CT) in the 1970s, which facilitated the differentiation of hemorrhagic or ischemic stroke and which was much more accurate than clinicians, was the first step in the revolution of acute stroke care. Magnetic resonance imaging followed. The development of promising pharmacological agents and new strategies to treat acute ischemic stroke were rapid during the last two decades of the twentieth century. Some interventions were aimed at limiting the neurological consequences (neuroprotective therapy) of the acute ischemic process while others focused on the restoration or improvement of the circulation. Subsequently, clinical research in treatment of acute ischemic stroke used an integrated series of projects to test for safety, to screen for potential efficacy, and to develop criteria for patient selection. The preliminary steps provided the bases for testing efficacy within larger Phase III clinical trials. Some trials demonstrated the non-utility of time-honored interventions such as emergency anticoagulation and, to date, the trials of neuroprotective agents are negative. Still, the results of large Phase III trials are used by regulatory bodies to approve new therapies for stroke. The first governmental approval for any treatment of acute ischemic stroke, intravenous thrombolysis, was by the US Food and Drug Administration (FDA) in 1996. The authors of evidence-based treatment guidelines also use the results of clinical trials as the basis of recommendations for patient care [1]. The guidelines in stroke, which first appeared in the USA, are replicated around the world and these statements are revised and updated with advances in knowledge of management of acute ischemic stroke.

As a result of these advances, the treatment of patients with ischemic stroke is vastly different than it was just 20 years ago.

In the 1960s, physicians tested the utility of thrombolytic therapy in patients with stroke with disappointing results. The studies, which were performed prior to the advent of CT, probably enrolled some patients with intracranial hemorrhages and the interval from onset of stroke until treatment (approximately 24 h) was exceedingly long [2]. Despite these negative studies, research continued. Experimental studies showed that rapid restoration of blood flow could limit the neurological consequences of a thromboembolic occlusion. The success of reperfusion therapy in improving outcomes among patients with acute coronary artery occlusions also provided an impetus for new research on intravenous thrombolysis for stroke. A number of agents were tested. In 1995, the investigators of the National Institute of Neurological Disorders and Stroke (NINDS) trial of intravenous administration of recombinant tissue plasminogen activator (rtPA) reported that early administration of the agent (<3 h of onset of stroke) was associated with an increased likelihood of a favorable outcome at 3 months [3]. For the first time, an intervention of proven utility was available to treat acute ischemic stroke.

While there is considerable enthusiasm about the success of intravenous thrombolysis, skeptics question the utility of treatment [4, 5]. These criticisms led to an independent review of the data; the result was the conclusion that intravenous thrombolysis was effective [6]. Additional trials were performed including one that showed efficacy of treatment up to 4.5 h after onset of stroke, and another which confirmed the efficacy of treatment in both younger and older patients [7, 8]. Although the FDA has not approved the use of rtPA in the 3–4.5 h time period, it is approved in Europe and American guidelines recommend its use [1, 9]. While some resistance to the use of intravenous thrombolysis in treatment of acute ischemic stroke persists, a meta-analysis of the clinical trials confirms the utility of intravenous thrombolysis [10]. Frankly, the debate about the utility of intravenous thrombolysis in the mainstream scientific medical community is over. Intravenous thrombolysis is efficacious; it should be administered to those patients who are eligible for treatment.

The results of the trials also provide additional safety and efficacy data that affects management decisions; for example, the sooner the patient is treated, the better are the chances for a good outcome [11]. The agent must be treated with respect; it is a potent thrombolytic agent that may be complicated by serious bleeding. Despite an increased risk of hemorrhagic complications and increased likelihood of death within the first days after stroke, long-term stroke mortality is not increased [10]. The patients at highest risk for bleeding complications with thrombolysis, including hemorrhagic transformation of the ischemic lesion, also have severe strokes that if left untreated have the highest risk for malignant cerebral infarction with herniation and death.

Intravenous thrombolysis has several advantages. It is relatively patient-, doctor- and health-care system friendly. The indications and contraindications for treatment are clearly described in the Guidelines for the Emergency Management of Acute Ischemic Stroke [1]. While not all patients recover following treatment with intravenous rtPA, many patients do have clinical improvement. The screening tests before treatment are limited and they can be performed rapidly. The latest version of the Guidelines for the Emergency Management of Acute Ischemic Stroke states that only the results of the blood glucose value and the brain imaging study are required to be known prior to treatment [1]. The medication may be ordered by any physician; it does not require special expertise. Instructions for the dosage and methods for administration are available and potential pitfalls for nursing and pharmacy personnel are known. While the cost of rtPA is considerable, it is much less expensive than long-term care or prolonged rehabilitation. Overall, it is a cost-effective therapy.

Unfortunately, some patients do not improve despite treatment. The likelihood of reestablishing perfusion is limited, particularly when a thrombosis is extensive and occludes a large-caliber artery. Thus, there is considerable room for improvement.

Endovascular treatment, an alternative reperfusion strategy, is a rapidly evolving field that involves intra-arterial administration of medications including rtPA or the use of mechanical interventions to remove or break up an arterial thrombosis. Endovascular therapy has many advantages. It administers the intervention at the site of the arterial occlusion. Recanalization, particularly with the newer clot extraction devices, can be achieved in a high percentage of patients [12]. Restoring adequate blood flow is associated with improved neurological outcomes. Treatment may be given to some patients who are not eligible for intravenous therapy, such as those with coagulation abnormalities. An endovascular intervention may complement intravenous treatment and it could be delivered as a rescue therapy to those patients who do not improve following thrombolysis. Conversely, endovascular therapy has limitations. It requires considerable physician expertise and expensive technology, which is not widely available; as a result, most patients with stroke likely cannot be treated. The costs of endovascular interventions, not including transport to a center where this service available, are considerably higher than those that accompany intravenous treatment. The current limitations imply that the overall impact of endovascular treatment on the public’s health may be small.

Evidence for success of endovascular treatment is currently lacking. Recent clinical trials were unable to demonstrate the superiority of: (1) endovascular administration of rtPA, (2) an advantage of combined intravenous and endovascular treatment, or (3) success of endovascular treatment selected on the basis of baseline brain imaging findings [13–15], as further described in Chap. 4. Given that the trials are negative, third-party payers may be reluctant to reimburse hospitals and physicians for these expensive procedures. This would be regrettable because many physicians involved in the care of patients with acute ischemic stroke believe that these interventions may be very helpful in treating carefully selected patients. In addition, the recent trials have limitations; in particular, the more advanced devices, which are associated with the greatest chances of reperfusion, were not employed. In effect, the recent trials may have been premature. Still, one conclusion that can be drawn from this research is that intravenous treatment should not be withheld from an eligible patient in order for the patient to receive an endovascular intervention.

While reperfusion therapy is effective, its utility is limited in that far too few patients are being treated [16, 17] (Fig. 1.1). Although approximately 20 years have passed since the FDA approved the use of rtPA, only approximately 5 % of American patients with acute ischemic stroke are receiving thrombolytic therapy. In addition, the impact of endovascular treatment is very small. These numbers are dismal.