Anti-platelet and anticoagulant therapy in acute cerebral ischemia]

Therapeutical trials in the acute phase of stroke have showed a moderate benefit of administration of aspirin in prevention of death or recurrent cerebral events. This benefit was obtained despite a small increase in systemic and cerebral haemorrhages. Heparin used at high dosage, without any control of coagulation test, induces an excess of cerebral and systemic haemorrhage which overset its benefit in prevention of recurrent cerebral events. Similar results have been observed with heparinoid and nadroparine used at high dosage. The only benefit of anticoagulation is the prevention of total and fatal pulmonary embolism which has been observed in all recent studies. The antithrombotic treatment which offers the best ratio benefit-risk in the acute phase of stroke is aspirin at a minimum dosage of 160 mg by day and, if risk factors are present, heparin at an adequate dosage to prevent venous thrombo-embolism. Explicative studies are required to explore the potential benefit of heparin in patients with a high risk of recurrent cerebral ischemic events.     

Angiopoietin-2 is vasoprotective in the acute phase of cerebral ischemia

Most forms of cerebral ischemia are characterized by damage to the entire neurovascular unit, which leads to an increase in the permeability of the blood–brain barrier (BBB). In response to permanent focal cerebral ischemia in mice, we detected an early concomitant increase in the expression of the vascular endothelial growth factor (VEGF), a key inducer of vascular leakage and pathological blood vessel growth, and of angiopoietin-2 (Ang2), which is closely associated with VEGF in vascular remodeling. Thus, the aim of this study was to evaluate the role of Ang2 alone, or in combination with VEGF, in the acute phase of cerebral ischemia. The effect of these angiogenic factors on the ischemic lesion volume was evaluated by magnetic resonance imaging. We observed that timely administration of VEGF exacerbates ischemic damage. In contrast, Ang2 decreases the ischemic volume and this beneficial effect is maintained in the presence of VEGF. This investigation reports, for the first time, a protective role of Ang2 following cerebral ischemia, an action associated with a reduced BBB permeability. We propose that Ang2 represents a pertinent molecular target for the treatment of cerebral ischemia since acute brain damage may be limited by a pharmacological protection of the vascular compartment.     

脑静脉系统疾病诊断与治疗进展

脑静脉系统疾病包括脑静脉系统血栓形成、静脉窦狭窄、颈内动脉海绵窦瘘和颅内动-静脉畸形等。近年来由于神经影像学和脑血管介入技术的快速发展,越来越多的脑静脉系统疾病得到及时诊断与治疗,如磁共振黑血血栓成像诊断脑静脉系统血栓形成、支架植入术治疗静脉窦狭窄、微弹簧圈联合Onyx胶栓塞术和覆膜支架植入术治疗颈内动脉海绵窦瘘等,使得对脑静脉系统疾病的研究更加深入。本文重点阐述常见脑静脉系统疾病的最新诊断与治疗进展。     

Perfusion imaging in the diagnosis of acute cerebral infarction]

There is no doubt that CT and MRI play a major role in the diagnosis and selection of optimal therapeutic strategies in cases of acute cerebral infarction. However, it is true that there is a wide variation in the scanning protocols as well as data analysis procedures; these differences in imaging studies could translate into a lack of control over therapeutic strategies, thereby undermining the quality of clinical practice. It is obvious that standardization of imaging procedures is mandatory; however, so far, no such project has been conducted either at home or abroad. With this background, a couple of multi-institutional working groups dedicated to the standardization and development of practical guideline for imaging procedures in the setting of acute cerebral stroke, are now in operation in Japan.     

Vertebrobasilar ischemia. Value of Doppler ultrasound in the acute phase]

We prospectively studied patients with acute vertebrobasilar ischaemia to assess the value of Doppler ultrasound compared to cerebral angiography during initial evaluation. Doppler ultrasound was diagnostic in 11 of 14 patients (79%). Transcranial ultrasonic examination yielded important information in addition to extracranial findings in 8 of 11 patients. Depending on the underlying vascular pathology, Doppler ultrasound proved to be a useful screening instrument to support acute management of vertebrobasilar ischaemia. With regard to clinical symptoms and ultrasonic findings, practical consequences for diagnostic evaluation are proposed.     

Hemodilution in the treatment of acute cerebral thrombosis]

11 cases of acute cerebral thrombosis were treated with a combination of venesection (400-800 ml of blood being let out at a time) and administration of an equal volume of low-molecular weight dextran solution Thereafter 500 ml of the dextran solution was given to each patient every day for 15 days. A comparison was made between this group and another group of patients who received just dextran. In the venesection group the mean value of hemoglobin was reduced from 15 g% to 13 g%, that of hematocrit from 44.6% to 40%, and that of the whole blood viscosity from 5.15 to 4.40. The neurological scores showed marked changes after three days of venesection. On the 21st day the scores in the venesection group increased by 31.6% (20.1 points) and that in the control group increased by 12.6% (7.7 points). Evidently the venesection group resulted in much better recovery (P less than 0.001).     

Monoamine metabolites in cerebrospinal fluid during and after acute cerebral ischemia

In order to understand the role of monoamines in cerebral ischemia, 3-methyoxy-4-hydroxyphenylglycol(MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid(HVA), the three major unconjugated monoamine metabolites in cerebrospinal fluid (CSF), of 33 patients and 18 controls were measured with high performance liquid chromatography. Results showed all three metabolites were raised in patients with severe ischemia, but only MHPG and 5-HIAA were elevated significantly, MHPG changes more quickly and regularly as a consequence of cerebral ischemia than the two others. A positive correlation between any pair of metabolites was found in controls and in patients in the first week after stroke, but not at the end of the second week. Computer assisted multivariate analysis indicated 5-HIAA and MHPG correlated more closely with the state of illness in the acute stage, whereas HVA correlated the least. Possible explanations for the changes of CSF levels of amine metabolites are discussed.     

慢性脑缺血的诊治现状与展望

慢性脑缺血是血管性痴呆、Alzheimer病(AD)和Binswanger病等多种疾病的共同病理过程,以持久或进展性认知功能障碍为主要表现[1].     

Antiplatelet therapy in acute cerebral ischemia

BACKGROUND: Improved recognition of stroke signs and symptoms has paralleled the development of pharmacological strategies that may be examined to reduce stroke mortality and morbidity. Presently, tissue plasminogen activator is the only therapy that significantly improves outcome in acute stroke, with no agent demonstrating a significant reduction in mortality. SUMMARY OF REVIEW: Antiplatelet agents are a heterogenous class of drugs that have been successfully used for more than 2 decades in secondary stroke prevention. These agents include aspirin, with or without dipyridamole, and more recently, the adenosine antagonists ticlopidine and clopidogrel. However, studies of the use of antiplatelet agents within 48 hours of the ictus have examined only aspirin. Only 1 study, the Multicentre Acute Stroke Trial-Italy (MAST-I), entered patients within 6 hours of the ictus. These data suggest that an improvement in mortality may be related to the speed of administration. No significant adverse events were noted with early antiplatelet monotherapy. However, MAST-I did note a significant increase in early mortality in patients receiving aspirin plus streptokinase, a finding not adequately explained by an increase in the intracranial hemorrhage rate. CONCLUSIONS: The use of antiplatelet therapy in acute stroke, clinical or experimental, has only recently received attention. It is likely that the use of antiplatelet agents for acute stroke therapy will be less restrictive than that currently seen for thrombolytics. Future studies should include an examination of those agents that have previously demonstrated efficacy in secondary stroke prevention, most notably, aspirin. The recognition that all platelet stimuli share a final common pathway that is dependent on the surface glycoprotein IIb/IIIa (fibrinogen) receptor has resulted in the development of various agents which block this receptor and are currently the focus for clinical trials. The role of nitric oxide in stroke therapy will depend on minimizing the hypotensive side effects of this agent. Stroke models are needed to provide preliminary data on the efficacy of antiplatelet therapy, especially as relates to the interaction of antiplatelet agents with thrombolytics.     

Peroxynitrite production in cerebral ischemia]

Peroxynitrite, generated by the reaction of nitric oxide and superoxide, has toxic effects including oxidation of sulfhydryls, lipid peroxidation and nitration of amino acid residues. So far peroxynitrite has not yet been detected in the ischemic brain because of its short half-life. Recently, we have succeeded in detecting 3-nitro-L-tyrosine, which is considered to be a footprint of peroxynitrite, in ischemic brain. Production of nitrotyrosine started during the ischemic period, increased after reperfusion, peaked at 48 hours, then declined up to 72 hours. Nitrotyrosine level was highest in the peri-infarct region, second highest in the core-of-infarct region, and lowest in the caudoputamen and the non-infarct region. Studies using pharmacological agents including MK-801, 7-nitroindazole and aminoguanidine suggest that peroxynitrite production originates from nNOS in the early phase of reperfusion, and from iNOS in the later phase of reperfusion. Further, the immunohistochemical study indicates that iNOS, located mainly in vascular cells, is predominantly responsible for nitrotyrosine production. Thus, peroxynitrite production depends on the stage of evolution of the ischemic process and on the cell type producing NO. These findings have important implications for the therapeutic time window and choice of NOS inhibitors in patients with cerebral infarction.     

急性期升高血压对大鼠局灶性脑缺血损伤的保护作用

目的　探讨升高血压对急性期局灶性脑缺血损伤的保护作用。方法　线栓法制作大鼠局灶性脑缺血模型 ,利用 TTC染色法测定脑梗死体积 ,尼氏染色光镜观察缺血中心边缘区脑组织病理改变 ,电镜观察该区脑组织的超微结构。结果　缺血后 3h内升压治疗能够明显缩小梗死体积 (P<0 .0 5 ) ,光镜观察发现缺血中心区周围存在神经元变性移行区 ,电镜观察发现缺血 4 h后缺血中心边缘区神经元明显固缩、毛细血管腔严重受压 ,而缺血 3h升压组上述部位神经元及毛细血管损伤明显减轻。结论　急性期升高血压对局灶性脑缺血损伤具有明显保护作用。     

Advances in cerebral ischemia: experimental approaches.

Drugs that dissolve clots, such as streptokinase and rTPA, and drugs that promote vasodilation are undergoing clinical testing for the treatment of hyperacute stroke, but an adjuvant therapy that either prolongs temporal thresholds before irreversible injury occurs or actually protects the brain from ischemia would transform these trials. Mild hypothermia, either intraischemically or at the onset of reperfusion, provides us with a gold standard for cytoprotection against which new pharmacologic strategies can be measured. The cytoprotective effects of the voltage-sensitive calcium channel blockers and the NMDA antagonists have been relatively less compelling than more recent findings with non-NMDA or AMPA antagonists. Their ability to inhibit SINN or reduce neocortical infarction is remarkable. Future randomized clinical trials for both resuscitated cardiac arrest victims and patients sustaining embolic stroke are predicted by this major advance in the field of stroke medicine.     

Physiology and pathology of cerebral ischemia]

In this article the pathophysiology of cerebral ischemia is reviewed. The concept of penumbra is explained, and a distinction is made between ischemic necrosis, which occurs in the severely ischemic regions and is associated with loss of calcium and glutamate homeostasis, and programmed cell death, or apoptosis, which is more likely to occur in the moderately ischemic regions, evolves more slowly and depends on the activation of a sequence of genes. Despite this knowledge, it is pointed out that currently only a small percentage of stroke patients can access therapies. Some thoughts are provided on future research directions and therapies.     

Quantitative EEG study in patients with cerebral ischemia during nimodipine treatment

In a group of 15 patients with chronic unilateral cerebral ischemia, a quantitative EEG study was performed before, during and after nimodipine (Bay e 9736) infusion (1 microgram/kg/min). The EEG was recorded bipolarly from the rolandic region. After computerized EEG analysis, a multiparametric asymmetry score (MAS) was calculated; this MAS provides a sensitive indicator for discrimination between neurologically normal subjects and patients with unilateral ischemia. A positive MAS is characteristic for healthy subjects, a negative one for ischemia patients. During nimodipine treatment, the MAS became more negative (increased EEG asymmetry) in 7 and less negative (decreased EEG asymmetry) in 8 patients. A correlation was found between the direction of the EEG asymmetry changes and the localization of the infarcted area as seen in the CT scan.     

缺血性脑卒中急性期IL-6、IL-8、IL-10变化的观察

目的观察IL-6、8、10在缺血性脑卒中急性期的变化及意义。方法采取双抗体夹心ELISA法对20例缺血性脑卒中患者分别在发病后第1、3、7d和15例健康体检者第1d的血清IL-6、IL-8、IL-10进行检测。结果急性缺血性脑卒中患者与正常健康体检者相比,IL-6、IL-8均在发病后第1、3d明显增高(P<0.05);第7d结果相差不大(P>0.05);IL-10在第1、3、7d逐渐增高(P<0.05)。结论白细胞介素的监测可以为早期临床治疗及康复干预提供试验指标,以便控制脑卒中的进展及复发。     

缺血性脑卒中急性期IL-6、IL-8、IL-10变化的观察

目的观察IL-6、8、10在缺血性脑卒中急性期的变化及意义。方法采取双抗体夹心ELISA法对20例缺血性脑卒中患者分别在发病后第1、3、7d和15例健康体检者第1d的血清IL-6、IL-8、IL-10进行检测。结果急性缺血性脑卒中患者与正常健康体检者相比，IL-6、IL-8均在发病后第1、3d明显增高（P〈0．05）；第7d结果相差不大（P〉0．05）；IL-10在第1、3、7d逐渐增高（P〈0．05）。结论白细胞介素的监测可以为早期临床治疗及康复干预提供试验指标，以便控制脑卒中的进展及复发。