Therapeutic hypothermia in experimental models of focal and global cerebral ischemia and intracerebral hemorrhage

Experimental evidence shows that therapeutic hypothermia (TH) protects the brain from cerebral injury in multiple ways. In different models of focal and global cerebral ischemia, mild-to-moderate hypothermia reduces mortality and neuronal injury and improves neurological outcome. In models of experimental intracerebral hemorrhage (ICH), TH reduces edema formation but does not show consistent benefi cial effects on functional outcome parameters. However, the number of studies of hypothermia on ICH is still limited. TH is most effective when applied before or during the ischemic event, and its neuroprotective properties vary according to species, strains and the model of ischemia used. Intrinsic changes in body and brain temperature frequently occur in experimental models of focal and global cerebral ischemia, and may have infl uenced studies on other neuroprotectants. This might be one explanation for the failure of a large amount of translational clinical neuroprotective trials. Hypothermia is the only neuroprotective therapeutic agent for cerebral ischemia that has successfully managed the transfer from bench to bedside, and it is an approved therapy for patients after cardiac arrest and children with hypoxic-ischemic encephalopathy. However, the implementation of hypothermia in the treatment of stroke patients is still far from routine clinical practice. In this article, the authors describe the development of TH in different models of focal and global cerebral ischemia, point out why hypothermia is so efficient in experimental cerebral ischemia, explain why temperature regulation is essential for further neuroprotective studies and discuss why TH for acute ischemic stroke still remains a promising but controversial therapeutic option.     

Glibenclamide in Cerebral Ischemia and Stroke

The sulfonylurea receptor 1 (Sur1)–transient receptor potential 4 (Trpm4) channel is an important molecular element in focal cerebral ischemia. The channel is upregulated in all cells of the neurovascular unit following ischemia, and is linked to microvascular dysfunction that manifests as edema formation and secondary hemorrhage, which cause brain swelling. Activation of the channel is a major molecular mechanism of cytotoxic edema and “accidental necrotic cell death.” Blockade of Sur1 using glibenclamide has been studied in different types of rat models of stroke: (i) in conventional non-lethal models (thromboembolic, 1–2 h temporary, or permanent middle cerebral artery occlusion), glibenclamide reduces brain swelling and infarct volume and improves neurological function; (ii) in lethal models of malignant cerebral edema, glibenclamide reduces edema, brain swelling, and mortality; (iii) in models with rtPA, glibenclamide reduces swelling, hemorrhagic transformation, and death. Retrospective studies of diabetic patients who present with stroke have shown that those whose diabetes is managed with a sulfonylurea drug and who are maintained on the sulfonylurea drug during hospitalization for stroke have better outcomes at discharge and are less likely to suffer hemorrhagic transformation. Here, we provide a comprehensive review of the basic science, preclinical experiments, and retrospective clinical studies on glibenclamide in focal cerebral ischemia and stroke. We also compare the preclinical work in stroke models to the updated recommendations of the Stroke Therapy Academic Industry Roundtable (STAIR). The findings reviewed here provide a strong foundation for a translational research program to study glibenclamide in patients with ischemic stroke.     

SMTP-7, a novel small-molecule thrombolytic for ischemic stroke: a study in rodents and primates

SMTP-7 (Stachybotrys microspora triprenyl phenol-7), a small molecule that promotes plasminogen activation through the modulation of plasminogen conformation, has excellent therapeutic activity against cerebral infarction in several rodent models. Detailed evaluations of SMTP-7 in a primate stroke model are needed for effective, safe drug development. Here we evaluated SMTP-7 in a monkey photochemical-induced thrombotic middle cerebral artery (MCA) occlusion model (n=6), in which MCA occlusion was followed by recanalization/reocclusion. SMTP-7 (10 mg/kg, intravenous infusion) significantly increased the postinfusion MCA recanalization rate (32.5-fold, P=0.043) and ameliorated the post-24-h neurologic deficit (by 29%, P=0.02), cerebral infarct (by 46%, P=0.033), and cerebral hemorrhage (by 51%, P=0.013) compared with the vehicle control animals. In normal monkeys, SMTP-7 did not affect general physiologic or hemostatic variables, including coagulation and platelet parameters. Investigations in rodent models of transient and permanent focal cerebral ischemia, as well as arterial thrombosis and bleeding tests, suggest a role for SMTP-7''s regulated profibrinolytic action and neuroprotective properties in the monkey MCA occlusion model. In conclusion, SMTP-7 is effective in treating thrombotic stroke in monkeys. SMTP-7 is thus a promising candidate for the development of alternative therapy for ischemic stroke.     

不同年龄阶段脑卒中患者同型半胱氨酸的初步研究

目的研究不同年龄阶段脑卒中患者血浆同型半胱氨酸(Hcy)水平,为预防及治疗脑卒中提供资料。方法观察不同年龄阶段健康者血浆Hcy水平,比较脑梗死以及脑出血患者与相应年龄阶段的健康者血浆Hcy的差异。结果健康对照组以及脑卒中患者Hcy水平均与年龄呈正相关,且脑梗死以及脑出血患者血浆Hcy水平均较相应年龄阶段的健康对照者血浆Hcy水平升高,有显著差异(P<0.05或P<001),脑梗死与脑出血患者血浆Hcy浓度比较差异无统计学意义(P>0.05)。结论血浆Hcy水平随年龄增长而增加,血浆Hcy水平是脑梗死与脑出血的独立危险因素。     

The evolving role of acute stroke imaging in intravenous thrombolytic therapy: patient selection and outcomes assessment

In early trials of thrombolysis, unenhanced CT was used to exclude patients with brain hemorrhage or large infarctions but was insensitive to stroke pathophysiology or early signs of cerebral ischemia or infarction. Currently, CT angiography, CT perfusion, and MR imaging can provide information about stroke mechanisms and prognosis, quantify penumbral tissue, and support risk stratification and patient selection. This article reviews the role of neuroimaging in the original intravenous thrombolytic trials, current application of these technologies, and the potential future role of imaging to extend the time window for thrombolysis and to augment therapeutic success.     

脑微出血的影像学与脑卒中临床研究

目的：探讨脑微出血（CMBs）与脑卒中发生和发展之间的关系。方法：对脑出血50例（脑出血组）、腩梗死50例（脑梗死组）和非腩血管病患者30例（对照组）行常规磁共振序列加梯度回波T2^＊加权（GRE—T2^＊）检查，分别记录CMBs的发生例数、部位、数日，脑卒中部位，脑白质疏松情况和患者高血压、高血脂、糖尿病等资料。结果：CMBs发生率在腩出血组为76％，脑梗死组为36％，对照组为10％。CMBs的发生与高血压、脑卒中病史、年龄和脑白质疏松有关；与血脂和血糖无关。结论：CMBs在脑卒中患者中有较高的发生率，加强对CMBs的充分认识，对于提高脑卒中的防治有重要意义。     

缺血性卒中患者静脉溶栓后不良预后危险因素的研究现状

急性缺血性卒中静脉溶栓的患者临床预后可受疾病严重程度、发病到溶栓的时间、脑小 血管病、血糖水平、中性粒细胞计数、血小板计数、溶栓后再灌注损伤及出血转化等多种因素的影响。 本文从流行病学、溶栓前后影响缺血性卒中静脉溶栓预后的危险因素及相关预测模型进行文献复习, 旨在加强对缺血性卒中患者静脉溶栓后不良预后危险因素及相关预测模型的认识,为其防治提供理 论依据和临床指导。     

Hyperacute Cerebral Enhancement: The Earliest Predictor of Hemorrhage by MR Imaging?

A test to detect very early hemorrhage in acute cerebral infarct could offer a substantial increase in the safety and success of advanced stroke therapies, particularly when the use of thrombolytic therapies is contemplated. Currently, computed tomography is the standard test for the detection of cerebral hemorrhage but is not a valid predictor of potential areas of hemorrhagic transformation. A technique to evaluate the risk of hemorrhagic transformation in infarcted cerebral tissue has been conducted with contrast-enhanced magnetic resonance imaging in various animal stroke models. Knight demonstrated Gadolinium-DTPA enhancement in the territory of occluded vessels immediately in rats after reperfusion. Gadolinium enhancement was thought to predict areas of hemorrhagic transformation. Yenari and associates demonstrated in rabbit models that contrast-enhanced T1-weighted scans can reveal regions of blood-brain barrier disruption, characterized as hemorrhagic transformation in ischemic tissue. The authors report a clinical example in which hyperacute contrast-enhanced magnetic resonance imaging was the first indication of hemorrhagic transformation within 24 hours of onset of an acute cerebral infarct.     

Modeling Developmental Plasticity After Perinatal Stroke: Defining Central Therapeutic Targets in Cerebral Palsy

Perinatal stroke is presented as the ideal human model of developmental neuroplasticity. The precise timing, mechanisms, and locations of specific perinatal stroke diseases provide common examples of well defined, focal, perinatal brain injuries. Motor disability (hemiparetic cerebral palsy) constitutes the primary adverse outcome and the focus of models explaining how motor systems develop in health and after early injury. Combining basic science animal work with human applied technology (functional magnetic resonance imaging, diffusion tensor imaging, and transcranial magnetic stimulation), a model of plastic motor development after perinatal stroke is presented. Potential central therapeutic targets are revealed. The means to measure and modulate these targets, including evidence-based rehabilitation therapies and noninvasive brain stimulation, are suggested. Implications for clinical trials and future directions are discussed.     

缺血性卒中患者静脉溶栓后不良预后危险因素的研究现状

急性缺血性卒中静脉溶栓的患者临床预后可受疾病严重程度、发病到溶栓的时间、脑小
血管病、血糖水平、中性粒细胞计数、血小板计数、溶栓后再灌注损伤及出血转化等多种因素的影响。
本文从流行病学、溶栓前后影响缺血性卒中静脉溶栓预后的危险因素及相关预测模型进行文献复习,
旨在加强对缺血性卒中患者静脉溶栓后不良预后危险因素及相关预测模型的认识,为其防治提供理
论依据和临床指导。     

卒中类型、卒中部位与卒中后癫痫的多因素关系

目的探讨卒中类型、卒中部位与卒中后癫痫的多因素关系,为卒中后癫痫的防治提供参考。方法以1804例卒中患者为研究对象,收集其性别、年龄、卒中类型、卒中部位、卒中后癫痫发生的时间等资料,根据卒中后是否发生癫痫,将患者分为卒中后无癫痫组(n=1487)和卒中后癫痫组(n=317),分析卒中后癫痫发作的危险因素。结果共317例卒中后癫痫发作患者,其中早发性癫痫141例(44.48%),迟发性癫痫176例(55.52%)。不同卒中部位及卒中类型的癫痫发病率为17.57%。多因素logistic回归分析显示,卒中部位中的顶叶合并蛛网膜下腔、额叶合并颞叶、额叶合并颞叶和枕叶、单一颞叶是卒中后发生癫痫的危险因素(P<0.01),其中单一颞叶是卒中后早发性癫痫的危险因素(P<0.01)。脑梗死患者常见早发性癫痫(23.66%),脑出血患者常见迟发性癫痫(47.95%)。结论卒中类型中的脑梗死、脑出血、蛛网膜下腔出血与卒中后癫痫有关;卒中部位中顶叶合并蛛网膜下腔、额叶合并颞叶、额叶合并颞叶和枕叶、单一颞叶与卒中后癫痫有关。     

Intracerebral hemorrhage versus infarction: Stroke severity,risk factors,and prognosis

The purpose of this study was to compare stroke severity, risk factors, and prognosis in patients with intracerebral hemorrhage versus infarction. We prospectively studied 1,000 unselected patients with acute stroke of a verified type in the Copenhagen Stroke Study. Neurological deficits and functional disabilities were evaluated weekly from the time of acute admission throughout the rehabilitation period. Eighty-eight (9%) had intracerebral hemorrhage. The relative frequency of intracerebral hemorrhage rose exponentially with increasing stroke severity. In multivariate analyses, stroke type had no influence on mortality, neurological outcome, functional outcome, or the time course of recovery. Initial stroke severity was the all-important prognostic factor. The relative importance of hypertension and blood pressure on admission was not greater for intracerebral hemorrhage than for infarction. No preponderance was found between type of stroke and sex, age, and smoking. Diabetes, ischemic heart disease, and elevated serum total cholesterol level all favored cerebral infarction as opposed to intracerebral hemorrhage. We conclude that the type of stroke per se has no influence on stroke prognosis in general; the extent of the injury is decisive. The poorer prognosis in patients with intracerebral hemorrhage is due to the increase in frequency of intracerebral hemorrhage with increasing stroke severity. The likelihood of cerebral infarction occuring as opposed to intracerebral hemorrhage seems increased fivefold in stroke patients with diabetes. Hypertension and blood pressure on admission were not predictors of stroke type.     

VEGF-A angiogenesis induces a stable neovasculature in adult murine brain

Angiogenesis is a critical component of stroke, head injury, cerebral vascular malformation development, and brain tumor growth. An understanding of the mechanisms of adult cerebral angiogenesis is fundamental to therapeutic vessel modulation for these diseases. To study angiogenesis in the central nervous system, we injected an adenoviral vector engineered to express vascular endothelial growth factor (VEGF-A164) into adult murine striatum. Vector-infected astrocytes expressed VEGF-A164 resulting in vascular permeability, hemorrhage, and the formation of greatly enlarged "mother" vessels. Subsequently, endothelial cells and pericytes lining mother vessels proliferated and assembled into glomeruloid bodies, complex cellular arrays interspersed by small vessel lumens. As VEGF-A164 expression declined, glomeruloid bodies involuted through apoptotic processes to engender numerous small daughter vessels. Characterized by modestly enlarged lumens with prominent pericyte coverage, daughter vessels were distributed with a density greater than normal cerebral vessels. Daughter vessels remained stable and patent to 16 months and represented the final stage of VEGF-A-induced cerebral angiogenesis. Together, these findings provide a mechanistic understanding of angiogenesis in cerebral disease processes. Furthermore, the long-term stability of daughter vessels in the absence of exogenous VEGF-A164 expression suggests that VEGF-A may enable therapeutic angiogenesis in brain.     

The Role of CT and MRI in the Emergency Evaluation of Persons with Suspected Stroke

As a growing number of therapeutic treatment options for acute stroke are being introduced, multimodal acute neuroimaging is assuming a growing role in the initial evaluation and management of patients. Multimodal neuroimaging, using either a CT or MRI approach, can identify the type, location, and severity of the lesion (ischemia or hemorrhage); the status of the cerebral vasculature; the status of cerebral perfusion; and the existence and extent of the ischemic penumbra. Both acute and long-term treatment decisions for stroke patients can then be optimally guided by this information.     

121例自发性颅内出血的病因和治疗方法探讨

目的:研究自发性颅内出血的病因诊断,并探讨其治疗方法。方法:病例经计算机体层摄影(CT)、磁共振成像(MRI)和腰穿等检查明确诊断及病因。74洲经手术治疗,21例经血管内治疗.9咧经伽玛刀(γ—刀)治疗,17例保守治疗。结果:121例自发性颅内出血中,动脉瘤46例,瞄血管畸形45例,动脉瘤合并血管畸形2例,颅内肿瘤卒中5例,烟雾病2例,21鲕J原因不明。结论:脑动脉瘤和血管畸形是自发性颅内出血最常见的病因(占74.4％),CT和MRI对出血的病因提供诊断线索,脑血管造影能明确病因诊断,根据病因不同、病变大小和部位不同选择合适的治疗方法,大型脑动静脉畸形(AVM)主张联合治疗。     

脑卒中并发上消化道出血的临床研究

目的掌握急性脑卒中患者并发上消化道出血的临床特点。方法对763例急性脑卒中患者并发上消化道出血的情况进行调查研究。结果在763例患者中,急性脑出血并发上消化道出血的发生率明显高于急性脑梗死组,病变累及脑干时尤为突出。伴意识障碍的患者并发上消化道出血的发生率较高。脑卒中并发上消化道出血发生时间多在发病后24h内出现,亦可发生于病程10d左右。并发上消化道出血的脑卒中患者死亡率明显高于未并发上消化道出血者。结论脑卒中并发上消化道出血预后不良,早期应采取措施,积极预防。     

综合康复治疗对脑卒中偏瘫患者日常生活能力的疗效观察

目的观察早期综合康复治疗对脑梗死及脑出血偏瘫患者日常生活能力（ADL）的影响及其差异。方法急性脑卒中偏瘫患者42例分为脑梗死康复脑梗死组和脑出血康复脑出血组各21例。2组均接受神经内科常规药物治疗及配合康复治疗,1次／d,30rain／次,其余时间由家属协助训练;2组治疗30d后采用Barthel指数评分。结果脑梗死组和脑出血组治疗前ADL评分具有可比性（P〉0．05）;治疗后ADL评分分别增加135．69％和199．51％,且2组治疗前后ADL评分差异均显著（P〈0．01）;治疗后脑出血组增加的ADL评分与脑梗死组相比较多（17．52±3．62）分,且2组治疗后ADL评分差异明显（P〈0．05）。结论药物并配合康复治疗可提高2组的整体疗效和ADL指数,且脑出血康复组更显著。     

Transcranial doppler: Technique and common findings (Part 1)

Transcranial Doppler (TCD) can be aptly called as the doctor’s stethoscope of the brain. Since its introduction in 1982, by Rune Aaslid, TCD has evolved as a diagnostic, monitoring, and therapeutic tool. During evaluation of patients with acute ischemic stroke, TCD combined with cervical duplex ultrasonography provides physiological information on the cerebral hemodynamics, which is often complementary to structural imaging. Currently, TCD is the only diagnostic tool that can provide real time information about cerebral hemodynamics and can detect embolization to the cerebral vessels. TCD is a noninvasive, cost-effective, and bedside tool for obtaining information regarding the collateral flow across various branches of the circle of Willis in patients with cerebrovascular disorders. Advanced applications of TCD help in the detection of right-to-left shunts, vasomotor reactivity, diagnosis, and monitoring of vasospasm in subarachnoid hemorrhage and as a supplementary test for confirmation of brain death. This article describes the basic ultrasound physics pertaining to TCD insonation methods, for detecting the flow in intracranial vessels in addition to the normal and abnormal spectral flow patterns.     

Vascular plasticity in cerebrovascular disorders

Cerebral ischemia remains a major cause of morbidity and mortality with little advancement in subacute treatment options. This review aims to cover and discuss novel insight obtained during the last decade into plastic changes in the vasoconstrictor receptor profiles of cerebral arteries and microvessels that takes place after different types of stroke. Receptors like the endothelin type B, angiotensin type 1, and 5-hydroxytryptamine type 1B/1D receptors are upregulated in the smooth muscle layer of cerebral arteries after different types of ischemic stroke as well as after subarachnoid hemorrhage, yielding rather dramatic changes in the contractility of the vessels. Some of the signal transduction processes mediating this receptor upregulation have been elucidated. In particular the extracellular regulated kinase 1/2 pathway, which is activated early in the process, has proven to be a promising therapeutic target for prevention of vasoconstrictor receptor upregulation after stroke. Together, those findings provide new perspectives on the pathophysiology of ischemic stroke and point toward a novel way of reducing vasoconstriction, neuronal cell death, and thus neurologic deficits after stroke.