[Research progress of acupuncture for cerebral ischemia reperfusion injury in recent 10 years].

By searching relevant data from the PubMed database, Chinese National Knowledge Infrastructure (CNKI) database and Wanfang database, a comprehensive analysis and review regarding acupuncture for cerebral ischemia reperfusion injury (CIRI) in recent 10 years were performed. The results showed that acupuncture could inhibit the inflammatory reaction, reduce oxidative stress injury, restrain brain edema formation, inhibit apoptosis, promote neural and vascular regeneration, etc. Acupuncture methods used included electroacupuncture, scalp acupuncture, eye acupuncture and "consciousness-restoring resuscitation needling", etc. The existing problem was that the intervention action of acupuncture was mainly focused on inhibiting inflammatory reaction and oxidative stress injury, and the study on apoptosis and neural and vascular regeneration was needed. It is suggested that from the aspect of multiple target points, the intervention mechanism of acupuncture for CIRI should be systemically studied in the future, which could provide new idea for clinical diagnosis and treatment on ischemic cerebrovascular diseases.

Vasospasm: my first 25 years-what worked? what didn't? what next?

Angiographic vasospasm as a complication of aneurysmal and other types of subarachnoid hemorrhage (SAH) was identified about 62 years ago. It is now hypothesized that angiographic vasospasm contributes to delayed cerebral ischemia (DCI) by multiple pathways, including reduced blood flow from angiographic vasospasm as well as microcirculatory constriction, microthrombosis, cortical spreading ischemia, and delayed effects of early brain injury. It is likely that other factors, such as systemic complications, effects of the subarachnoid blood, brain collateral and anastomotic blood flow, and the genetic and epigenetic makeup of the patient, contribute to the individual's response to SAH. Treatment of aneurysmal SAH and DCI includes neurocritical care management, early aneurysm repair, prophylactic administration of nimodipine, and rescue therapies (induced hypertension and balloon or pharmacologic angioplasty) if the patient develops DCI. Well-designed clinical trials of tirilazad, clasozentan, antiplatelet drugs, and magnesium have been conducted using more than a 1,000 patients each. Some of these drugs have almost purely vascular effects; other drugs are theoretically neuroprotective as well, but they share in common the ability to reduce angiographic vasospasm and, in many cases, DCI, but have no effect on clinical outcome. Experimental research in SAH continues to identify new targets for therapy. Challenges for the future will be to identify the most promising drugs to advance from preclinical studies and to understand why clinical trials have so frequently failed to show drug benefit on clinical outcome. Similar issues with treatment of ischemic stroke are being addressed by suggestions for improving the quality of experimental studies, collaborative preclinical trials, and multinational, multicenter clinical studies that can rapidly include many patients and be large enough to account for numerous factors that conspire to disrupt clinical trials.

Thrombolytics in acute ischaemic stroke: historical perspective and future opportunities.

The discovery of thrombolytic agents goes back to the 1930s, when it was shown that substances derived from bacteria (streptokinase, staphylokinase), tissue (fibrinokinase), urine (urokinase) or bat saliva could activate the fibrinolytic system. The potential to treat arterial thrombosis with plasmin was recognized, but it was not until 1958 that its first use in acute ischaemic stroke (AIS) was described. However, since computer tomography (CT) was not available until the mid 1970s, optimal selection of patients was not possible. Early studies with streptokinase in AIS showed an increased risk of intracranial haemorrhage and lack of efficacy, which was associated with low fibrin specificity. The search for new agents with a better risk-benefit profile continued until 1979 when tissue plasminogen activator (t-PA) was discovered. In 1983 it became possible to produce recombinant t-PA (rt-PA) by expression of a cloned gene which enabled clinical trials to be started, mainly for coronary thrombolysis. In 1995, the National Institute of Neurological Disorders and Stroke study showed that rt-PA was an effective treatment for AIS, nowadays for use up to 4.5 h after onset. However, rt-PA still often fails in achieving rapid reperfusion, has relatively low recanalization rates and is associated with an increased bleeding risk. Several attempts have been made to develop thrombolytics with a better risk-benefit profile than rt-PA, but no real impact on clinical practice was observed. In 1994, it was shown that tenecteplase (rt-PA-TNK) had a higher fibrin specificity than rt-PA, but its clinical use in AIS was described only in 2005. The recently reported results of a small phase 2B trial showed significantly better reperfusion and clinical outcome with rt-PA-TNK compared to rt-PA; patients were selected by CT perfusion and angiography, and treated within 6 h after stroke onset. Currently, a phase 3 trial of rt-PA-TNK versus rt-PA is being planned in patients at an onset up to 4.5 h. The most fibrin-specific recombinant plasminogen activator desmoteplase originates from 1991, and its clinical development in AIS started in 2005. Desmoteplase is in phase 3 development for the treatment of AIS between 3 and 9 h after onset in AIS patients presenting with occlusion or high-grade stenosis.

History and definition of delayed cerebral ischemia.

A list of the vasospasm meetings is provided. The early descriptions of angiographic vasospasm and delayed cerebral ischemia are presented. Selected advances in knowledge in the field and some controversies are described. A proposal for definitions of neurological deterioration due to delayed cerebral ischemia, of cerebral infarction, and of vasospasm is reviewed.

Cerebral revascularization for ischemic disease in the 21st century.

Shortly after the first extracranial to intracranial (EC-IC) carotid artery bypass was performed by Yasargil in 1967 for internal carotid artery occlusion, cerebral revascularization became widely accepted in the neurosurgical field, and the procedures became increasingly used as practitioners began to master the technical aspects of the surgery. The procedures were performed for intracranial arterial stenosis and occlusion and used as an adjunct in the treatment of large aneurysms and skull base tumors. The results of the EC-IC bypass group trial in 1985 were surprising to many and sobering to all; EC-IC bypass for stenosis or occlusion of the high internal carotid artery or middle cerebral artery did not decrease the risk of subsequent stroke compared with medical management. Rather, the incidence of stroke increased, and the events were noted to occur sooner than with medical therapy alone. Despite the known limitations of this landmark study, the number of EC-IC bypass procedures fell precipitously over the ensuing decades. Despite this significant setback, cerebral revascularization is not obsolete. This article revisits the sequence of events leading to the rise of revascularization surgery and recaps the impact of the EC-IC bypass trial. The limitations of the trial are discussed, as are current studies evaluating the efficacy of cerebrovascular bypass procedures for symptomatic carotid occlusive disease. The authors review the accepted indications for bypass surgery in the early 21st century.

Past and recent BBB studies with particular emphasis on changes in ischemic brain edema: dedicated to the memory of Dr. Igor Klatzo.

The blood-brain barrier (BBB) functions to protect the environment of the brain through endothelial cells and their interactions with other cells and components of the cerebral vasculature and the brain parenchyma. Alterations in the BBB as a result of injuries (i.e., brain ischemia and traumatic brain injury) play a crucial role in the pathophysiological response.The following is a brief review of the BBB and the mechanisms by which its cellular elements participate in barrier disruptions such as those associated with ischemia and resulting brain edema formation.

Therapeutic hypothermia: past, present, and future.

Cardiac arrest causes devastating neurologic morbidity and mortality. The preservation of the brain function is the final goal of resuscitation. Therapeutic hypothermia (TH) has been considered as an effective method for reducing ischemic injury of the brain. The therapeutic use of hypothermia has been utilized for millennia, and over the last 50 years has been routinely employed in the operating room. TH gained recognition in the past 6 years as a neuroprotective agent in victims of cardiac arrest after two large, randomized, prospective clinical trials demonstrated its benefits in the postresuscitation setting. Extensive research has been done at the cellular and molecular levels and in animal models. There are a number of proposed applications of TH, including traumatic brain injury, acute encephalitis, stroke, neonatal hypoxemia, and near-drowning, among others. Several devices are being designed with the purpose of decreasing temperature at a fast and steady rate, and trying to avoid potential complications. This article reviews the historical development of TH, and its current indications, methods of induction, and potential future.

Stroke: historical perspectives.

The author gives a historical account of stroke, the devastating statistics that still plague Americans, what the future holds, the current research, and possible areas for improvement and growth. Now with specialized imaging, diffusion-weighted and perfusion-weighted magnetic resonance imagings may become the technique to rapidly diagnose brain attack. The cutting edge technology now involves balloons, coils, stents, angioplasty, and thrombolytics to save an ischemic penumbra. Of course, the overall goals remain early detection, intervention, and treatment, which today are individualized to each patient; community education of brain attack and what it looks like; and that time is brain survival. Therefore, a brain attack is a true 911 emergency.

Perfusion thresholds in human cerebral ischemia: historical perspective and therapeutic implications.

After middle cerebral artery occlusion (MCAO) in the laboratory animal, the ischemic penumbra has been documented as a severely hypoperfused, functionally impaired, but still viable cortex which can regain its function and escape infarction if it is reperfused before a certain time has elapsed. The penumbra surrounds the ischemic core of already irreversibly damaged tissue, and is progressively recruited into the core with increasing MCAO duration. In the animal, the threshold of cerebral blood flow (CBF) below which neuronal function is impaired and the tissue is at risk of infarction is around 22 ml/100 g/min (approximately 40% of normal) in the awake or lightly anesthetized monkey, and around 30--35 ml/100 g/min in the cat and the rat. The threshold of CBF below which the tissue becomes irreversibly damaged and will progress to infarction depends on the duration of ischemia, and is around 10 ml/100 g/min for 1--2 h (approximately 20% of normal) and around 18 ml/100 g/min for permanent ischemia in the monkey. Mildly reduced CBF down to the 40% threshold (termed 'oligemia') is normally well tolerated, and the affected tissue is not at risk of infarction under uncomplicated conditions (in the animal, however, selective neuronal death may occur even with only mildly reduced CBF values, but this sequela of stroke seems an exceptional encounter in man). Classic studies with carotid artery clamping in man have provided estimates for the penumbra threshold at around 20 ml/ 100 g/min for the whole brain, but only recently have imaging studies allowed to document the existence of the penumbra in acute stroke and given estimates of local CBF thresholds. With PET, the penumbra is characterized by a reduced CBF, an increased oxygen extraction fraction, and a relatively preserved oxygen consumption (CMRO(2)). In a series of PET studies performed 5--18 h after stroke onset, we have determined the threshold for penumbra to be around 20 ml/100 g/min, and documented that the extent of neurological recovery is proportional to the volume of penumbra that eventually escaped infarction. Within this time interval, the thresholds for irreversible damage were around 8 ml/ 100 g/min for CBF and around 0.9 ml/100 g/min for CMRO(2). Recent studies with diffusion-weighted and perfusion MR have reported similar relative thresholds for CBF of about 50 and 18% for penumbra and core, respectively. Although it is likely that the threshold for irreversibility will be lower with shorter duration since clinical onset, this has not been documented thus far. Because saving the penumbra will improve clinical outcome, it should constitute the main target of acute stroke therapy. We found evidence of penumbra in about one third of the cases studied between 5 and 18 h after onset, and as late as 16 h after symptom onset in occasional patients, suggesting the therapeutic window may be protracted in at least a fraction of the cases; similar experience has recently accrued from diffusion-weighted MR and perfusion MR. In the remaining patients, there was evidence of early extensive damage or early spontaneous reperfusion, which would make them inappropriate candidates for neuroprotective therapy. Recent evidence from PET studies of relative perfusion performed within 3 h of onset suggests that early thrombolysis indeed saves the tissue with CBF below a critical threshold of 12 ml/ 100 g/min, with a correlation between the volume of such tissue escaping infarction and subsequent neurological recovery. Thus, mapping the penumbra in the individual patient with physiologic imaging should allow to formulate a pathophysiological diagnosis, and in turn to design a rational management of the stroke patient and to increase the sensitivity of drug trials by appropriate patient selection.