Advances and challenges in treatment and prevention of ischemic stroke

We review recent advances in the treatment and prevention of acute ischemic stroke, including the current state of endovascular therapy, in light of 5 randomized controlled trials published this past year. Although no benefit of endovascular therapy over intravenous (IV) recombinant tissue plasminogen activator (rt‐PA) has been demonstrated, endovascular therapy is an appropriate treatment for acute ischemic stroke patients within the t‐PA window who are ineligible for IV t‐PA but have a large vascular occlusion. These trials reveal promises and current limitations of endovascular therapy, and comparison of reperfusion therapies remains an important area of research. One common theme is the strong association between a faster time to reperfusion, improved outcome, and reduced mortality. Primary and secondary stroke prevention trials emphasize the importance of aggressive management of medical risk factors as part of any preventative strategy. New oral anticoagulants, for example, offer cost‐effective risk reduction in patients with atrial fibrillation, and may represent an opportunity for those with cryptogenic stroke. We highlight areas of unmet need and promising research in stroke, including the need to deliver proven therapies to more patients, and the need to recruit patients into clinical trials that better define the role of endovascular and other stroke therapies. Finally, improvement in strategies to recover speech, cognition, and motor function has the potential to benefit far more stroke patients than any acute stroke therapy, and represents the greatest opportunity for research in the coming century. Ann Neurol 2013;74:363–372     

Current status and perspectives of neuroprotection in ischemic stroke treatment

In developed countries, ischemic stroke is one of the leading causes of death and neurological impairment. The two most important therapeutic approaches in patients with acute cerebral ischemia consist of improving cerebral blood flow and blocking the biochemical and metabolic changes at the ischemic cascade level. The significant advances made in the past decade in the knowledge of the physiopathological mechanisms of cerebral ischemia, and the development of new drugs have given rise to true expectations regarding treatment and the rejection of nihilist attitudes. In the past 15 years, based on the excellent results obtained in experimental models of ischemia, many clinical trials have been conducted with different neuroprotective drugs. The results obtained in most studies have been negative, or the studies were terminated early owing to side effects. However, some drugs (citicoline, clomethiazole, piracetam and ebselen) have shown a certain degree of clinical efficacy, limited to subgroups of patients, and with a narrow therapeutic window, longer-lasting in the case of citicoline. The design of new clinical trials with neuroprotective drugs requires adequate preclinical assessment and the use of the new magnetic resonance techniques for the selection of patients and the assessment of the efficacy of treatment. The new trends in neuroprotection in focal cerebral ischemia and the results of the clinical trials published to date are reviewed.     

Neuroprotective agents for the treatment of acute ischemic stroke

Neuroprotective treatments are therapies designed to interrupt the cellular, biochemical, and metabolic elaboration of injury during or following exposure to ischemia; they encompass a rapidly expanding array of pharmacologic interventions. Various classes of neuroprotective agents have reached phase III efficacy trials in focal ischemic stroke, but none has proven effective, despite successful preceding animal studies. This notwithstanding, recent favorable results of hypothermia in human cardiac arrest trials have validated the general concept of neuroprotection. In addition, the promise of neuroprotective therapy for focal acute ischemic stroke has been renewed by innovations in strategies of preclinical drug development and clinical trial design that rectify past defects, including trial testing of combination therapies rather than single agents and novel approaches to accelerating time to initiation of experimental treatment.     

Endovascular management of acute ischemic stroke: advances in patient and treatment selection

Selection of patients for acute-stroke therapy has traditionally been based on rigid time criteria in clinical trials. Recent advances in radiographic imaging have allowed clinicians to estimate brain physiology and thus utilize radiographic parameters to select patients for acute-stroke therapies. Both a better understanding and the quantification methods of salvageable tissue versus irreversibly injured tissue can help guide clinicians to which treatment modality to utilize. The evolution of endovascular techniques to treat acute stroke has resulted in treatment modalities that include mechanical and chemical methods to revascularize occluded cerebral arteries. Prior technical limitations to accessing distal-cerebral arteries have been partially overcome by modifications in technology. Patient and treatment-modality selection can help reduce hemorrhagic complication rates and also potentially increase revascularization rates, which may translate into improved clinical outcomes. We review the recent advances in radiographic imaging that have advanced patient selection in treating acute ischemic stroke and also consider current endovascular treatment options that are available to interventionalists performing these procedures.     

Temperature management in stroke - an unsolved, but important topic

Clinical data clearly show that elevated body temperature contributes to an unfavorable outcome after ischemic and hemorrhagic stroke. Two promising therapeutic strategies arise from this observation: (1) treatment of fever aiming to sustain normothermia and (2) induced hypothermia, targeting core body temperatures below 36.5°C. A limited number of studies investigated antipyretic strategies after acute stroke and their results were rather disappointing in terms of clinical efficacy. For that reason, it remains unproven, whether sufficient fever treatment improves functional outcome. On the other hand, strong experimental evidence supports neuroprotective effects of induced hypothermia after stroke. Yet, clinical data on this topic remain preliminary and rely on a limited number of patients, mostly enrolled in nonrandomized trials. Therefore, induced hypothermia may be considered safe and feasible after ischemic stroke, but little can be said regarding efficacy. This review summarizes the data, both on fever treatment and induced hypothermia following stroke, starting with a synopsis of the most important experimental investigations, leading to the latest clinical trials. Given the promising data and the lack of successful acute neuroprotective therapies available thus far, suggestions are given for future investigation on both topics.     

Recent advances in stroke management

Major advances in stroke treatment and prevention have occurred over the last several years. Recent studies have documented that appropriate modification of stroke risk factors can lead to a substantial reduction in stroke incidence. In addition, a variety of new risk factors, such as elevated plasma homocysteine levels, antiphospholipid antibodies, and specific genetic factors, are being recognized. The most significant advance in acute stroke therapy is the use of intravenous tissue plasminogen activator (t-PA) for treatment of patients with ischemic stroke within 3 hours of symptom onset. T-PA is currently the only stroke treatment approved by the Federal Drug Administration. There continues to be uncertainty and misunderstanding regarding the risks and benefits of this therapy. A variety of neuroprotective agents have been highly successful for reducing ischemic brain injury in animal stroke models. Recent clinical trials with these agents, however, have not produced beneficial effects in humans. Newer neuroprotective agents with more favorable safety profiles and improvements in clinical trial design may lead to therapeutic successes in the near future. It is apparent that both thrombolytic and neuroprotective treatments for acute stroke must be administered very rapidly after stroke onset. Therefore, acute stroke teams are being developed to facilitate rapid diagnostic evaluation and treatment of stroke patients.     

Catheter-based recanalization techniques for acute ischemic stroke

Recent advances in endovascular interventional therapies have revolutionized the management of acute ischemic stroke. For patients who present with occluded circle of Willis vessels, timely and successful arterial recanalization is the best predictor of clinical improvement. Diagnostic neuroimaging has advanced noninvasive tools--namely, transcranial Doppler, CT angiography, and MR angiography--to screen individuals with acute neurologic syndromes rapidly for arterial occlusion, and hence to exclude from treatment those who are unlikely to benefit from or could be harmed by arterial recanalization strategies. Intra-arterial thrombolysis has been proven to be of benefit in large clinical trials. Moreover, the US Food and Drug Administration has recently approved the use of a mechanical clot retrieval device for acute embolic stroke, and a number of other similar strategies are under various stages of investigation. This article reviews the diagnostic and interventional approach to the management of large vessel embolic stroke.     

Applications of diffusion-perfusion magnetic resonance imaging in acute ischemic stroke.

Diffusion-weighted imaging (DWI) and perfusion imaging (PI) are two new magnetic resonance technologies that are becoming increasingly available for evaluation of acute ischemic stroke patients. DWI provides information about the location of acute focal ischemic brain injury at early time points and PI can document the presence of disturbances in microcirculatory perfusion. DWI and PI are now being used in clinical practice and in clinical trials of potential acute stroke therapies to assess their utility. In the future, DWI and PI may aid in the development of effective acute stroke therapies and help identify which stroke patients are most likely to benefit from specific agents.     

New perspectives on developing acute stroke therapy

The development of additional acute stroke therapies to complement and supplement intravenous recombinant tissue-type plasminogen activator within the first 3 hours after stroke onset remains an important and pressing need. Much has been learned about the presumed target of acute stroke therapy, the ischemic penumbra, and clinically available imaging modalities such as magnetic resonance imaging and computed tomography hold great promise for at least partially identifying this region of potentially salvageable ischemic tissue. Understanding the biology of ischemia-related cell injury has also evolved rapidly. New treatment approaches to improve outcome after focal brain ischemia will likely be derived by looking at naturally occurring adaptive mechanisms such as those related to ischemic preconditioning and hibernation. Many clinical trials previously performed with a variety of neuroprotective and thrombolytic drugs provide many lessons that will help to guide future acute stroke therapy trials and enhance the likelihood of success in future trials. Combining knowledge from these three areas provides optimism that additional acute stroke therapies can be developed to maximize beneficial functional outcome in the greatest proportion of acute stroke patients possible.     

Hypertension and experimental stroke therapies

Hypertension is an established target for long-term stroke prevention but procedures for management of hypertension in acute stroke are less certain. Here, we analyze basic science data to examine the impact of hypertension on candidate stroke therapies and of anti-hypertensive treatments on stroke outcome. Methods: Data were pooled from 3,288 acute ischemic stroke experiments (47,899 animals) testing the effect of therapies on infarct size (published 1978–2010). Data were combined using meta-analysis and meta-regression, partitioned on the basis of hypertension, stroke model, and therapy. Results: Hypertensive animals were used in 10% of experiments testing 502 therapies. Hypertension was associated with lower treatment efficacy, especially in larger infarcts. Overall, anti-hypertensives did not provide greater benefit than other drugs, although benefits were evident in hypertensive animals even when given after stroke onset. Fifty-eight therapies were tested in both normotensive and hypertensive animals: some demonstrated superior efficacy in hypertensive animals (hypothermia) while others worked better in normotensive animals (tissue plasminogen activator, anesthetic agents). Discussion: Hypertension has a significant effect on the efficacy of candidate stroke drugs: standard basic science testing may overestimate the efficacy which could be reasonably expected from certain therapies and for hypertensive patients with large or temporary occlusions.     

Acute ischemic stroke management: medical management

The initial management of a patient with suspected stroke necessitates a rapid and focused evaluation. Establishing the time of symptom onset, performing a focused neurologic examination, and interpreting ancillary tests facilitates delivery of acute stroke therapies to eligible patients. This review emphasizes the fundamentals of urgent stroke evaluation and evidence-based acute ischemic stroke therapies. Results from randomized clinical trials of intravenous thrombolysis, glucose management, and blood pressure management in acute ischemic stroke patients will be highlighted. External ultrasound as an adjunct to intravenous thrombolysis and treatment of those patients that wake up with stroke symptoms will also be discussed.     

Misdiagnosis of stroke

Rapid diagnosis of stroke is necessary for the timely delivery of thrombolysis and evaluation of novel therapies such as neuroprotection. An accurate clinical history and competent examination are key to identifying which patients are likely to have had a stroke and arranging and interpreting neuroimaging. Stroke symptoms are typically acute in onset, but are highly variable depending on the vascular territory affected. Common presenting symptoms are limb weakness, and speech and visual disturbances. Common stroke mimics are seizures, space occupying lesions, syncope, somatization and delirium secondary to sepsis. Stroke recognition instruments can help nonspecialists in the early diagnosis of stroke, with studies reporting sensitivity of over 90% and specificity of approximately 85% for some instruments. In patients with a clinical diagnosis of stroke, brain computed tomography or MRI is required to exclude some stroke mimics and differentiate ischemic from hemorrhagic stroke, which is key to providing appropriate therapies such as thrombolysis. In the future, plasma biomarkers may improve clinical diagnosis of stroke, but prospective studies are required to establish their utility. Clinical trials of acute stroke therapies need to ensure rapid accurate diagnosis of stroke using structured clinical assessments and appropriate imaging to achieve early treatment and avoid entry of stroke mimics into trials.     

Hyperglycemia in acute ischemic stroke: physiopathological and therapeutic complexity

Diabetes mellitus and associated chronic hyperglycemia enhance the risk of acute ischemic stroke and lead to worsened clinical outcome and increased mortality. However, post-stroke hyperglycemia is also present in a number of non-diabetic patients after acute ischemic stroke, presumably as a stress response. The aim of this review is to summarize the main effects of hyperglycemia when associated to ischemic injury in acute stroke patients, highlighting the clinical and neurological outcomes in t...     

Glucagon-like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: a systematic scoping review

Stroke mortality and morbidity is expected to rise. Despite considerable recent advances within acute ischemic stroke treatment, scope remains for development of widely applicable neuroprotective agents. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally licensed for the management of Type 2 Diabetes Mellitus, have demonstrated pre-clinical neuroprotective efficacy in a range of neurodegenerative conditions. This systematic scoping review reports the pre-clinical basis of GLP-1RAs as neuroprotective agents in acute ischemic stroke and their translation into clinical trials. We included 35 pre-clinical studies, 11 retrospective database studies, 7 cardiovascular outcome trials and 4 prospective clinical studies. Pre-clinical neuroprotection was demonstrated in normoglycemic models when administration was delayed by up to 24 h following stroke induction. Outcomes included reduced infarct volume, apoptosis, oxidative stress and inflammation alongside increased neurogenesis, angiogenesis and cerebral blood flow. Improved neurological function and a trend towards increased survival were also reported. Cardiovascular outcomes trials reported a significant reduction in stroke incidence with semaglutide and dulaglutide. Retrospective database studies show a trend towards neuroprotection. Prospective interventional clinical trials are on-going, but initial indicators of safety and tolerability are favourable. Ultimately, we propose that repurposing GLP-1RAs is potentially advantageous but appropriately designed trials are needed to determine clinical efficacy and cost-effectiveness.     

Imaging the future of stroke: I. Ischemia

Envisioning the future of stroke appears daunting considering the milestones already achieved in stroke imaging. A historical perspective on the developments in stroke care provides a striking narrative of how imaging has transformed diagnosis, therapy, and prognosis of cerebrovascular disorders. Multimodal imaging techniques such as CT and MRI, incorporating parenchymal depictions, illustration of the vasculature, and perfusion data, can provide a wealth of information regarding ischemic pathophysiology. Key elements of ischemic pathophysiology depicted with imaging include vascular occlusion, compensatory collateral flow, resultant hemodynamic conditions that reflect these sources of blood flow, and the neurovascular injury that ensues. The mantra of “time is brain” has been perpetuated, but this does not provide an entirely accurate reflection of ischemic pathophysiology and imaging insight shows far more than time alone. Maximizing the potential of perfusion imaging will continue to expand the nascent concept that cerebral ischemia may be completely reversible in certain scenarios. Novel modalities provide a fertile ground for discovery of therapeutic targets and the potential to assess effects of promising strategies. Beyond clinical trials, imaging has become a requisite component of the neurological examination enabling tailored stroke therapy with the use of detailed neuroimaging modalities. In this first article on ischemia, the focus is on the most recent imaging advances and exploring aspects of cerebral ischemia where imaging may yield additional therapeutic strategies. A subsequent article will review recent and anticipated imaging advances in hemorrhage. These thematic overviews underscore that imaging will undoubtedly continue to dramatically shape the future of stroke. Ann Neurol 2009;66:574–590     

急性缺血性卒中血管内治疗筛选病例的研究进展

急性缺血性卒中发病率呈逐年上升趋势,并且具有很高的致残率和致死率。由于静脉阿替普酶溶栓治疗急性缺血性卒中的局限性,2015年以来5大临床前瞻随机双盲多中心临床研究证实新一代血管再通策略（主要是可回收支架）在大血管闭塞导致的急性缺血性卒中明显优于单独内科治疗,各国脑卒中指南也相应进行更新。本文围绕5大临床研究及欧洲、美国最新指南中关于筛选合适卒中患者进行机械取栓的研究进展综述如下。     

Statins in hemorrhagic stroke

Statin therapy has a major impact on the treatment of coronary artery disease and also has an impact on the treatment of ischemic stroke. Both clinical and experimental studies support the concept of statin actions beyond those of lipid lowering per se (pleiotrophic effects). In this article, we briefly review the clinical, experimental and biological data on the actions of statins and then review the literature regarding the impact of statin use on the two major forms of hemorrhagic stroke: aneurysmal subarachnoid hemorrhage and intracranial hemorrhage (ICH). We make recommendations regarding acute statin therapy, statin withdrawal and chronic statin therapy, including a possibly negative impact - the increased incidence of ICH associated with the use of higher doses of statin in patients with a prior history of stroke. Epidemiological data on the association between low total cholesterol or low levels of low-density cholesterol, hypertension and the incidence of ICH appear relevant and are also discussed. We speculate on the relationship between data derived from randomized controlled trials employing statin and ICH epidemiology.     

Ischemic stroke: emergencies and management

The past 40 years have seen the evolution of acute ischemic stroke management from unproven therapies du jour, such as steroids, heparin for stroke in evolution, and hypervolemic-hemodilution, to more of a scientific basis for our decision-making process. This evolution is directly related to the advancements in imaging of stroke. It is also related to carefully designed, controlled clinical trials of potential therapies, which have led to the recognition of the benefits of thrombolytic therapy in the acute setting but have also caused confusion and frustration over the lack of benefit for potential neuroprotective agents that once seemed promising.     

Clinical Trials of Adult Stem Cell Therapy in Patients with Ischemic Stroke

Stem cell therapy is considered a potential regenerative strategy for patients with neurologic deficits. Studies involving animal models of ischemic stroke have shown that stem cells transplanted into the brain can lead to functional improvement. With current advances in the understanding regarding the effects of introducing stem cells and their mechanisms of action, several clinical trials of stem cell therapy have been conducted in patients with stroke since 2005, including studies using mesenchymal stem cells, bone marrow mononuclear cells, and neural stem/progenitor cells. In addition, several clinical trials of the use of adult stem cells to treat ischemic stroke are ongoing. This review presents the status of our understanding of adult stem cells and results from clinical trials, and introduces ongoing clinical studies of adult stem cell therapy in the field of stroke.