The influence of baseline prognostic variables on outcome after thrombolysis

Thrombolysis increases case fatality but reduces the proportion of disabled survivors in recent trials in acute ischaemic stroke, although some trials show much higher mortality rates than others. One possible explanation for the different outcomes between trials is that the treatment effect with thrombolysis varies with baseline prognostic factors such as stroke severity. We examined the interaction between baseline risk and thrombolysis on outcome using individual patient data from the Multicentre Acute Stroke Trial–Italy (MAST-I). A multiple logistic regression of the MAST-I data was performed to identify which factors, identifiable at randomisation, most strongly predict a poor functional outcome. We then stratified the patients into those with severe strokes and those with mild strokes and examined the effect of thrombolysis on (a) case fatality and (b) dependency at 6 months after the stroke in the 157 patients who received streptokinase alone and the 156 controls. Streptokinase was found to cause an absolute increase of about 3% in case fatality in both “severe” and “mild” strokes; however, there was a 12% reduction in the number of dead or dependent “mild” strokes but a 6% increase in “severe” strokes. The number of patients was small, and therefore neither finding was statistically significant. In this exploratory analysis, the hazard with streptokinase appears similar in “severe” and “mild” strokes, but the benefit may be greater in “mild” strokes. Thrombolysis may be more effective in patients with “mild” strokes, but more information is required to confirm this hypothesis. Received: 29 January 1999 Received in revised form: 13 April 1999 Accepted: 5 May 1999     

Moyamoya病发生、发展及转归实验研究

目的研究Ｍｏｙａｍｏｙａ病的发生、发展及转归过程。方法建立Ｍｏｙａｍｏｙａ病的实验动物模型。结果颈动脉逐渐狭窄或闭塞的过程是内弹力纤维变性、断裂后,中膜平滑肌细胞沿断裂处向内膜游走、深入增生的过程。早期,因侧支循环血管建立不完善,脑组织缺血、缺氧出现多灶性脑软化坏死。随时间延长,脑内大量小动脉及毛细血管代偿性增生,其血管壁腔大壁薄,形成异网。同时５个粟粒状或囊状动脉瘤．蛛网膜下腔、脑室内及脑实质内有小的出血灶。结论Ｍｏｙａｍｏｙａ病临床表现早期以缺血性脑血管病为主,后期以出血性脑血管病为主,是由Ｍｏｙａｍｏｙａ病理的演变过程所决定的,是疾病的发展规律。     

大鼠脑局灶性预缺血对再次缺血的影响

目的研究不同时间单次缺血及重复缺血引起的脑组织病理变化。方法插线法阻塞大鼠大脑中动脉（ＭＣＡ）。单次缺血８、２８或９０ｍｉｎ,重复缺血８＋２８ｍｉｎ或２８＋９０ｍｉｎ。结果单次缺血组随缺血时间延长脑病变加重。８＋２８ｍｉｎ组ＭＣＡ供血区病变重于２８ｍｉｎ组;２８＋９０ｍｉｎ组ＭＣＡ供血区病变轻于９０ｍｉｎ组。结论不同时间的预缺血对再次缺血有导致积累性损伤或缺血耐受的双重效应。     

A photothrombotic ring stroke model in rats with or without late spontaneous reperfusion in the region at risk

This study aimed at developing a dual setup of the photothrombotic ring stroke model with or without late spontaneous reperfusion in the region at risk and to explore the morphological consequences. The exposed crania of adult male Wistar rats were subjected to a ring-shaped laser-irradiation beam (o.d. 5.0 mm, 0.35 mm thick) for 2 min simultaneously with intravenous erythrosin B (17 mg/kg) infusion. Transcardial carbon-black perfusion revealed that a laser intensity of 0.90 W/cm(2) resulted in late, that is, starting at 72 h, spontaneous reperfusion, whereas the lowest laser intensity that produced lack of reperfusion at 7 days post-irradiation was 1.84 W/cm(2). Laser-Doppler flowmetry showed prompt cortical cerebral blood flow (cCBF) reduction both in the ring lesion and region at risk (12% and 25% of control values) after high-intensity irradiation; these reduced flow values were more rapid and pronounced than in the low-intensity irradiation setup as previously shown. The high- compared with low-intensity irradiation setup produced more frequent occurrence of thrombi in the ring-lesion region and a larger ischemic cortical lesion with a more rapid pace of ischemic cellular changes in the ring-lesion region and the region at risk. The region at risk transformed into pannecrosis in the high-intensity, but recovered morphologically in the low-intensity irradiation setup. This dual photothrombotic setup with or without spontaneous reperfusion enables the study of events related to ischemic cell survival or death in an anatomically predefined region at risk.     

Receptor tyrosine kinase tie 1 mRNA is upregulated on cerebral microvessels after embolic middle cerebral artery occlusion in rat

Tie 1 is an endothelial specific transmembrane receptor tyrosine kinase and may be required during angiogenesis. Using in situ hybridization, we measured tie 1 mRNA in ischemic brain (n=15). Rats were subjected to middle cerebral artery (MCA) occlusion by a single fibrin rich clot. Expression of tie 1 was not detected in non ischemic brain. Cerebral microvessels expressed tie 1 in the ischemic lesion as early as 2 h after MCA occlusion. The number of microvessels containing tie 1 mRNA decreased in the ischemic lesion at 8 h after MCA occlusion. However, expression of tie 1 increased on microvessels at 24 h and 14 days after ischemia and tie 1 was primarily localized to the microvessels bordering pan necrotic tissue. Ninety-seven percent of cerebral vessels which expressed tie 1 mRNA had diameters of 3.7+/-0.17 microm. Our findings suggest a role for tie 1 in cerebral microvascular remodeling after embolic stroke.     

Metabolic and neuroanatomical correlates of barrel-rolling and oculoclonic convulsions induced by intraventricular endothelin-1: a novel peptidergic signaling mechanism in visuovestibular and oculomotor regulation?

The neuroactive peptide endothelin-1 has receptors distributed abundantly among subdivisions and nuclei of the visuovestibular and oculomotor systems. In previous work, we and others described the convulsive manifestations resulting from central injection of this neuropeptide, including nystagmus, oculoclonus, exophthalmos, tonic hindlimb extension, and a generalized repetitive motor disturbance called barrel-rolling. We applied the quantitative, autoradiographic [¹⁴C]deoxy-glucose method to examine the hypothesis that visuovestibular and oculomotor structures would become metabolically stimulated when endothelin was introduced into the brain via the ventricular system in conscious rats. Since previous work had demonstrated that hypermetabolic responses to endothelin in other neural systems were inhibited by an antagonist of neuronal calcium L-type channels, nimodipine, we further tested whether the increased function of vestibulooculomotor nuclei whose metabolic activity was sensitive to endothelin could be altered following nimodipine pretreatment via the ventricle. A single unilateral injection of endothelin (9 pmol in 3 l saline) into a lateral ventricle provoked significantly increased rates of glucose metabolism in 22 of 39 individual anatomical structures of the visuovestibular and oculomotor systems. Among those affected were the superficial stratum of the caudal superior colliculus (+25%), the optic tract bilaterally (+ 35 to 43%), the oculomotor cranial nerve nuclei (III, IV, VI; range of +21 to 47%), and the medial terminal nucleus of the accessory optic tract which harbors dense fields of endothelin binding sites (bilateral increase of +70 to 96%). Several other nuclei involved in the proprioceptive and visuovestibular disturbance caused by endothelin displayed increased metabolic activity, including the cuneate, gracile, sensory trigeminal, and prepositus hypoglossal nuclei, the vestibular subnuclear system, and the cerebellar flocculus. Identification of hypermetabolic responsivity to endothelin in these structures provides further information on the anatomical substrates mediating the behavioral phenomenology of endothelin-induced motor convulsions which involve the paroxysmal participation of the extraocular muscles and motor control systems producing barrel-rolling convulsions. Nimodipine pretreatment inhibited both the convulsive activity and the cerebral hypermetabolic responses to intraventricular endothelin. The results indicate that the neural systems sensitive to intraventricular endothelin become functionally active via a calcium-mediated process that may involve the neuropeptide as an intrinsic signaling molecule.     

Diagnosis of cardiac thrombosis in patients with atrial fibrillation in the absence of macroscopically visible thrombi

Summary Cardiac thrombosis due to atrial fibrillation (AF) has been recognized as the most common cause of cerebral embolism. However, sometimes no macroscopic thrombus is found at autopsy in the heart of a victim of this type of cerebral embolism. We investigated morphological changes in the left atrial endocardium of 31 patients (including 21 cases with AF) who had died of cerebral embolism. Rough endocardium (RE) seen macroscopically provided evidence for the existence of atrial thrombosis. The RE that appeared in AF cases was due to a granular and wrinkled appearance of the endocardium associated with oedematous and fibrous thickening. Fibrin-thread deposits were also always distinguishable. Mural thrombi and oedema with neutrophil infiltration in the subendocardium could be seen under the microscope. Small areas of endothelial denudation and thrombotic aggregations were commonly observed by scanning electron microscopy (SEM). These SEM lesions were significantly more frequent in cases with AF than in controls (P< 0.001). The diagnostic success rate for atrial thrombosis among cases with AF increased from 33.3% to 81% when thrombi proven by histological investigation of the areas with RE were added. Left atrial RE may be an anatomically relevant finding for the existence of atrial thrombosis with AF, when the thrombosis cannot be detected upon gross observation at autopsy.     

Doppler flow velocity measurements in patients with intracranial hypertension

Summary In patients with severe brain lesions monitoring of the intracranial pressure as well as monitoring of cerebral blood flow can be of clinical value. While at the moment there is no atraumatic method for measuring cerebral blood flow in man, it is recommended to measure blood flow velocity with the ultrasound Doppler technic in the common carotid artery. On theoretical grounds a positive correlation between cerebral blood flow and blood flow velocity can be expected and the observations presented show that such a correlation exists in normal controls and in neurological patients. In many neurological patients the flow velocity in the common carotid artery decreases with increasing intracranial pressure. This suggests that the autoregulation is disturbed. The demonstration of such a disturbance can have clinical implications.

---

Zusammenfassung Bei Patienten mit ernsten Läsionen im Gehirn kann Monitoring von sowohl intercraniellem Druck als auch der zerebralen Blutdurchströmung für die Klinik von Bedeutung sein. Da im Moment keine atraumatische Methode für die Messung der zerebralen Blutdurchströmung besteht, wird anempfohlen, die Durchströmungsgeschwindigkeit mit der Ultraschall-Doppler-Technik in der Arteria carotis communis zu messen. Theoretisch kann eine positive Korrelation zwischen der zerebralen Blutdurchströmung und der Strömungsgeschwindigkeit erwartet werden.Die beschriebenen Ergebnisse zeigen, daß tatsächlich ein solcher Zusammenhang besteht, sowohl bei gesunden Versuchspersonen als auch bei neurologischen Patienten.Bei vielen dieser Patienten nimmt die Durchströmungsgeschwindigkeit in der Arteria carotis communis ab bei einer Zunahme des intracraniellen Druckes. Dies suggeriert eine gestörte Autoregulation. Das Aufzeigen einer solchen Störung kann klinische Bedeutung haben.