Search

Ischaemic penumbra is defined as the area of brain tissue that maintains some blood flow following ischaemic accident. This zone may be rescued by both neuroprotection and arterial revascularization. Early thrombolysis has been used with encouraging results since 1995 in several trials testing both streptokinase and recombinant tissue plasminogen activator (r-TPA): the r-TPA results are definitely more positive than those of streptokinase, despite an increased incidence of symptomatic haemorrhagic transformation, r-TPA significantly reducing death or dependency at the end of follow-up. Despite the fact that some experimental periods of application of these therapeutic strategies demonstrated real cost-effective benefits, only 1% of patients reaching hospital in time for thrombolysis are currently treated. This is because the profile of patients at risk of haemorrhagic transformation, which is definitely the most feared side-effect of thrombolysis in stroke, is yet to be clearly defined. Extended computerized tomography (CT) signs of the index stroke have been repeatedly indicated as reliable predictors of haemorrhagic transformation even if currently there are significant discrepancies in the criteria adopted by different researchers to define early CT signs. Based on experimental ischaemia, strategies for protecting the basal lamina during thrombolysis are suggested: neuroprotection is the second approach to stroke therapy; pharmacological reperfusion and brain protection are probably mutually dependent.

The growing body of clinical and instrumental information that can be gathered from the earliest phases of stroke has radically modified the way in which neurologists tackle the treatment of stroke patients. It is now theoretically possible to tailor therapeutic choices on the basis of prognostic estimates made within a few hours of stroke onset, that is at a time when numerous options to limit the ischemic insult are still open. However, once many hours or even days have passed, all one can do is witness the effects of a natural course which by then is virtually unmodifiable. This applies not only to stroke patients being treated within the context of pharmacological trials, but also to those in daily clinical management, since some choices, such as when and how to treat brain oedema and give thrombolytics, may now be made earlier and more accurately than in the past. Emergency CT in particular discloses important indices of subsequent clinical evolution and outcome, thus adding to already well-known predictors such as age and severity of neurological status at hospital admission [20]. CT does have the aforementioned limitations regarding inter-observer agreement, which may, however, be minimised by an appropriate training of observers. Moreover it has intrinsic limitations regarding the visualisation of the actual brain tissue damage, since up to one fifth of patients with no or very limited early CT signs may present symptomatic hemorrhagic transformation after thrombolysis [23] and approximately one sixth of early deteriorating patients do not show early CT signs [52]. Other techniques, such as positron and single photon emission tomography and in particular MR imaging, which may shed light on tissue viability and perfusion as well as arterial patency simultaneously, might be able to provide more accurate information [19] Nevertheless, CT is still the most widely used tool in clinical centres which hospitalise stroke patients, and is unlikely to be routinely replaced by the other imaging devices in the foreseeable future. Consequently, there is an urgent need both for a general consensus on the identification criteria of early CT signs and for the widest possible awareness of knowledge regarding CT capabilities among neurologists [47], waiting for the wide applicability of newer technologies.

Background and Purpose: The purpose of our study was to investigate whether emergency transcranial Doppler (TCD) findings and their modifications over the first 48 hours are related to early neurological changes in acute ischemic stroke patients., Methods: Ninety-three patients underwent CT scan within 5 hours of a first-ever ischemic hemispheric stroke, and TCD serial examinations at 6, 24, and 48 hours after stroke onset. We classified TCD findings as follows: normal; middle cerebral artery (MCA) asymmetry (asymmetry index between affected and contralateral MCAs below -21%); and MCA no-flow (absence of flow signal from the affected MCA in the presence of ipsilateral anterior and posterior cerebral artery signals through the same acoustic window). We considered early deterioration and early improvement to be a decrease or an increase of 1 or more points, respectively, in the Canadian Neurological Scale score over the same period., Results: At 6-hour TCD examination, MCA asymmetry and MCA no-flow were present in 6 (22%) and 2 (7%), respectively, of 27 improving patients; in 20 (43%) and 10 (22%) of 46 stable patients, and in 9 (45%) and 8 (40%) of 20 deteriorating patients. TCD findings were normal in the remaining patients (P = 0.001). At serial TCD, we detected early (within 24 hours) recanalization (from no-flow to asymmetry or normal and from asymmetry to normal) in 2 (25%) improving patients, in 7 (23%) stable patients, and in 5 (29%) deteriorating patients and late (between 24 and 48 hours) recanalization in 4 (50%) improving patients, in 6 (20%) stable patients, and in none of the deteriorating patients (P = 0.03, chi 2 for trend, improving versus nonimproving irrespective of the timing of recanalization). One deteriorating patient (5%) developed a non-flow from an initial MCA asymmetry. Logistic regression selected normal TCD (odds ratio [OR], 0.17; 95% confidence interval [CI], 0.06 to 0.46) as an independent predictor of early improvement and abnormal TCD (asymmetry plus no-flow) (OR, 5.02; 95% CI, 1.31 to 19.3) as an independent predictor of early deterioration., Conclusions: TCD examination within 6 hours after stroke can help to predict both early deterioration and early improvement. Serial TCD shows that propagation of arterial occlusion is rarely related to early deterioration, whereas the fact that it can detect early recanalization (within 24 hours) in deteriorating patients and both early and late recanalization (after 24 hours) in improving patients suggests the existence of individual time frames for tissue recovery.

Two treatments, based on either ticlopidine or indobufen at their optimal individual daily dose (median dose: 250 and 200 mg/day, respectively), were compared in an open randomized multicenter trial in patients at risk of cerebral ischemia (men and women, aged 39 to 80 years, who had experienced in the month before entry into the study transient ischemic attack or amaurosis fugax or minor stroke). The total number of patients screened was 4033; 1632 were enrolled, 821 randomized to ticlopidine, 811 to indobufen. The overall frequency of the composite primary end-point (stroke, myocardial infarction, and death from any cause) was 4.4%. The ticlopidine-based regimen proved significantly better than the indobufen one in preventing the composite of fatal and non fatal events (49.6% relative risk reduction), or death alone (54.4% relative risk reduction). The two groups had similar percentages of adverse events (5.5% and 6.4% for ticlopidine and indobufen group, respectively) with withdrawals because of adverse events in 3.4% and 2.5%; gastrointestinal disorders and bleeding were more frequent in the indobufen group, whereas rash and abnormal liver function were more frequent in the ticlopidine one.

Objective: To evaluate the efficacy and safety of intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) in patients with acute ischemic stroke., Design: Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial., Setting: A total of 75 hospitals in 14 European countries., Patients: A total of 620 patients with acute ischemic hemispheric stroke and moderate to severe neurologic deficit and without major early infarct signs on initial computed tomography (CT)., Intervention: Patients were randomized to treatment with 1.1 mg per kilogram of body weight of rt-PA (alteplase) or placebo within 6 hours from the onset of symptoms., Outcome Measures: Primary end points included Barthel Index (BI) and modified Rankin Scale (RS) at 90 days. Secondary end points included combined BI and RS, Scandinavian Stroke Scale (SSS) at 90 days, and 30-day mortality. Tertiary end points included early neurologic recovery (SSS) and duration of in-hospital stay. Safety parameters included mortality and incidence of intracranial or extracranial hemorrhage., Results: The distribution of demographic variables was similar among patients in the rt-PA and placebo treatment arms in both the intention-to-treat (ITT) analysis and the explanatory analysis for the target population (TP). A total of 109 patients (17.4%) were included in the trial despite major protocol violations but excluded from the TP. There was no difference in the primary end points in the ITT analysis, while the TP analysis revealed a significant difference in the RS in favor of rt-PA-treated patients (P = .035). Of the secondary end points, the combined BI and RS showed a difference in favor of rt-PA-treated patients in both analyses (P < .001). Neurologic recovery at 90 days was significantly better for rt-PA-treated patients in the TP (P = .03). The speed of neurologic recovery assessed by the SSS was significantly better up to 7 days in the ITT analysis and up to 30 days for the TP in the rt-PA treatment arm. In-hospital stay was significantly shorter in the rt-PA treatment arm in both analyses. There were no statistically significant differences in the mortality rate at 30 days or in the overall incidence of intracerebral hemorrhages among the rt-PA and placebo treatment arms in either analysis. However, the occurrence of large parenchymal hemorrhages was significantly more frequent in the rt-PA-treated patients., Conclusions: Intravenous thrombolysis in acute ischemic stroke is effective in improving some functional measures and neurologic outcome in a defined subgroup of stroke patients with moderate to severe neurologic deficit and without extended infarct signs on the initial CT scan. However, the identification of this subgroup is difficult and depends on recognition of early major CT signs of early infarction. Therefore, since treating ineligible patients is associated with an unacceptable increase of hemorrhagic complications and death, intravenous thrombolysis cannot currently be recommended for use in an unselected population of acute ischemic stroke patients.

Objective: To develop a model for predicting outcome in the first few hours after the onset of an ischemic stroke on the basis of the clinical findings obtained during a rapid bedside examination., Design: Clinical records were retrieved from the data bank of a randomized multicenter trial. The resulting case series was split into two subgroups that served as a "training set" and a "test set." Logistic regression was applied to the training set to select the prognostic predictors among baseline clinical findings. The performances of the model based on independent prognostic predictors were then validated in the test set., Setting: Eleven primary care institutions (either hospitals or university clinics) participating in the Italian Acute Stroke Study on the efficacy of hemodilution and monosialoganglioside in acute ischemic stroke., Patients: Consecutive noncomatose patients (N = 300) observed within the first 6 hours after the onset of a first supratentorial ischemic stroke., Main Outcome Measure: Death or disablement 4 months after the index stroke. Disablement was defined as a score of 3 or higher on the Rankin Scale., Results: Age and CNS score defined six risk groups with a predicted 4-month poor outcome rate ranging from 10% (patients aged 70 years or younger and with an initial CNS score of 7 or higher) to 89% (patients older than 70 years and with a CNS score of 4.5 or lower). When a risk of poor outcome of 60% was taken as a cutoff, the accuracy of the prediction was 78% +/- 6% in the training set and 72% +/- 9% in the test set., Conclusion: Long-term outcome can be predicted in the first few hours following an acute ischemic stroke by means of a simple model based on age and CNS score.

Background and Purpose: The etiology of stroke in the young is different from that in older patients and remains unknown in almost one third of the cases. To gain further insight into both pathogenic and etiologic determinants, we prospectively studied a large number of consecutive young adults with focal cerebral ischemia., Methods: Three hundred thirty-three patients aged 15-44 years with transient ischemic attack or ischemic stroke within the 8 weeks before hospital admission were recruited and investigated by using a standardized protocol of clinical evaluation, blood tests, electrocardiography, echocardiography, chest roentgenography, and brain computed tomography. Presumed etiology was diagnosed by prospectively applied criteria., Results: Women predominated (61%) among patients under 35 years of age, mainly due to the frequency of cerebral ischemia related to oral contraceptive use, while men outnumbered women (60%) among patients over that age because of a higher prevalence of atherothrombotic disease. Potential cerebral embolism of cardiac origin was the presumed cause of stroke in 23.7%, but conventional sources of emboli were found only in 7.5% of cases. There was a low prevalence of atrial fibrillation among young patients with cerebral ischemia. Mitral valve prolapse was found in 8.4%, as expected, predominantly (71.4%) among the younger patients. The prevalence of stroke over transient ischemic attack was proportional to the likelihood of cardiac embolism. Acute alcohol intoxication was considered a precipitating factor in only three patients. The percentages of cerebral ischemia attributed to arterial dissection (0.3%), oral contraceptive use in women (8.1%), migraine (1.2%), and other associated medical diseases (1.5%) were lower than reported in recent clinical series., Conclusions: Two different groups of pathogenic determinants predominate in younger women and in older men, supporting public health measures aimed at strict medical control of the recognized cerebrovascular risk factors.

The CBF was assessed in seven patients before and after rehabilitation for visuospatial neglect. Two months of treatment produced an increased perfusion both in the right posterior and left anterior areas of the brain. However, only the left anterior CBF increase was correlated with the neglect disorders. The left anterior improvement in CBF was inversely correlated with right-left cerebellum asymmetry in pre- and post-treatment. The present data suggest the role of the frontal eye-fields in the mechanism of recovery of visual exploration in patients with severe neglect.

Hypertensive vascular lesions in the brain include increased formation of atheroma, lacunae and lacunar infarctions, atherothrombotic brain infarction and vascular dementias such as multi-infarct dementia and Binswanger's disease. Hypertension is also associated with an increased risk of intracerebral and subarachnoid hemorrhage. Reduction of arterial pressure with antihypertensive agents can prevent the occurrence and limit the extent of stroke.

Reasons for the unsatisfactory number and reliability of most trials on the pharmacological treatment of acute cerebral ischemia are reviewed, focusing mainly on the clinical aspects of the issue. The opportunity of early intervention, supported by current pathophysiological hypotheses, is recognized. Past and recent Italian trials on ischemic stroke patients evaluated and treated within the first 6 h from onset are reported, also mentioning the results of a study including early cerebral angiography and SPECT (Single Photon Emission Computed Tomography). Early fibrinolytics associated to brain protecting agents are regarded as the future choice in clinical trials of acute cerebral ischemia.

Clinical management of patients affected by subarachnoid hemorrhage has been modified by the use of nimodipine. Although no differences in overall neurologic outcome and rates of symptomatic spasm have been observed between nimodipine and control patients, severity of permanent neurologic deficits consequent to cerebral vasospasm is reduced in the former. On the other hand, clinical trials with nimodipine in ischemic stroke did not substantiate the expected neurologic benefits. A meta-analysis of the two phase IV studies published thus far shows that of 350 patients examined, mortality rate was 11.5% and 19% in subjects given nimodipine and placebo, respectively (n.s.). Cerebral death accounted for 30% of cases in both groups, whereas a lower percentage of cardiac and pulmonary fatal events were observed among nimodipine-treated subjects. Moreover, neurologic outcome of survivors was not significantly different. These results may be associated with the notion that the voltage-operated channel blockade exerted by calcium antagonists is only a part of the complex events leading to the enhancement of calcium ion intracellular concentration as a "common final pathway." However, difficulties encountered in planning clinical trials in acute ischemic stroke also might explain the lack of conclusive results. The feasibility of randomization of an adequate sample of patients and of very early therapeutic intervention after stroke onset are discussed.

The frequency of myocardial infarction and sudden death is increased between 6 AM and noon. To determine whether the same is true for the onset of ischemic stroke, we studied 426 consecutive patients within 12 hours after the onset of their first hemispheric stroke. The frequency of onset of hemispheric stroke was significantly (p = 0.0001) higher from 6:01 AM to noon (56.1%) than from 12:01 PM to 6 PM (20.2%), from 6:01 PM to midnight (8.2%), and from 12:01 AM to 6 AM (15.5%). The identification of periods of high risk for vascular events may have important therapeutic implications, such as matching drug effects with vulnerability.

Blood levels of triglycerides, total cholesterol, isolated lipoprotein fractions (VLDL-LDL- and HDL-cholesterol) and apoproteins (Apo-A1 and Apo-B) were examined in multi-infarct dementia, senile dementia of the Alzheimer type, ischemic stroke associated with carotid atherosclerosis and in control subjects. Forty patients divided into 10 consecutive patients for each group were studied. Alzheimer patients showed mean total cholesterol and Apo-B values significantly higher than control subjects. Apo-B was significantly higher in stroke patients than in controls. The mean lowest HDL-cholesterol (HDL-c) value was observed in stroke patients. No significant differences in mean HDL-c levels were found between patients with multi-infarct and Alzheimer dementia.

We studied by angiography 80 patients within 6 hours from the onset of symptoms of supratentorial ischaemic stroke. Occlusion of the internal carotid artery in the extracranial segment was found in 19 patients, at the bifurcation in 11 and at the cervical level in 8. While in the chronic phase of stroke, internal carotid artery occlusion in the cervical segment is an uncommon angiographic finding, we found a high frequency of occlusion at this level (8 out of 19) in our patients. Cervical segment occlusion may be due to a dissecting aneurysm or to an intracranial carotid artery occlusion (embolic or atherothrombotic) with subsequent migration of the clot down to this level. A direct embolic occlusion may be postulated as well.

Positron emission tomography (PET) studies with 18F deoxyglucose were completed in 35 patients with acute ischemic strokes. Twelve cases were studied within 72 h, 23 between 4 and 14 days. Results indicate the functional and prognostic significance of early tomography studies of metabolism, and anticipate possible use of metabolic imaging in the evaluation of treatment.

Regional cerebral blood flow and its autoregulation after intravenous glycerol infusion have been studied in eight patients in the acute phase of cerebral infarction. Glycerol seems to improve the cerebral blood flow in the damaged region but does not seem to restore autoregulation.

The oxidation of adrenaline to adrenochrome has been shown to reflect the activation of leukocytes in vivo. We tested the in vivo activation of leukocytes by measuring plasma oxidation of adrenaline to adrenochrome in patients suffering from cerebral ischemia, cerebral hemorrhage, and transient ischemic attacks and in healthy subjects. Patients with cerebral ischemia and cerebral hemorrhage had significantly higher values than healthy subjects, while patients with transient ischemic attacks had values similar to those of healthy subjects. In some patients with cerebral ischemia, the test was repeated 4 and 15 days after the acute event, but the follow-up data did not differ from baseline values. Our study shows that leukocyte activation occurs in cerebral ischemia and cerebral hemorrhage.

Over the past ten years, several studies have outlined the importance of high blood viscosity as a pathogenetic factor in ischemic cerebrovascular diseases. Clinical studies have demonstrated that a high blood viscosity due to an elevated hematocrit (greater than 46%) increases the risk of cerebral infarction. Furthermore, in patients with high hematocrit, the cerebral blood flow seems to be lower than in controls and, by removing 200-250 ml of blood by venesection, the cerebral blood flow can be normalized. Several authors have therefore proposed that venesection may be used as a preventive measure in patients at risk for cerebral ischemia with high hematocrit. In addition, studies on experimental brain ischemia have shown that hemodilution reduces the size of the infarction. Therefore, hemodilution has been proposed as an effective measure in the treatment of acute cerebral ischemia. In conclusion, it seems that high blood viscosity is a risk factor in cerebral ischemia although its pathogenetic mechanisms and clinical importance are not yet completely clarified.

Clinical neurological examination, computed tomography (CT) scan, cerebral angiography, and cerebral blood flow-single photon emission computerized tomography (CBF-SPECT) study have been performed in 39 patients with acute ischemic stroke within 6 h from the onset of symptoms. Seven of these patients were submitted to a second CBF study after an intravenous infusion of nimodipine. A greater CBF impairment was observed in patients with severe neurological deficit at entry, poor outcome, cerebral arterial occlusion, and large hypodensity on the CT scan performed 1 week after admission. In patients treated with nimodipine, a significant increase of CBF was detected at the periphery of the ischemic zone, indicating a potential action of this Ca antagonist on the "ischemic penumbra."

From a consecutive series of 812 patients at risk of stroke we selected 100 who seemed to be at high risk (excessive stroke risk--ESR) on the following clinical criteria: either multiple reversible ischemic attacks in one carotid territory or multiple (or bilateral) severe stenotic carotid lesions. The patients of the first subgroup received medical therapy and those of the second were referred for surgery. The 100 patients were followed up for 12 months, during which 29 patients had cerebral ischemic events: 17 having stroke and 12 TIA. This study suggests that it is possible to identify beforehand subgroups of ESR patients, thereby facilitating the selection of patients for brain protection and avoiding huge trials of unselected cerebrovascular patients.

In order to obtain functional images of brain perfusion, we exploited a new concept, which is to take advantage of the short half-life of a radioactive tracer. Under continuous intracarotid infusion of a solution of Kr-81m (T1/2 = 13 sec; produced from its parent, 4.6-hr Rb-81), this tracer will never reach equilibrium within the brain because of the rapid radioactive decay. Its distribution will therefore reflect regional arrival of the nuclide, indicating regional cerebral blood flow rather than volume. During continuous infusion of Kr-81m, perfusion images can be obtained by simply collecting counts with a gamma camera and recording on Polaroid film. The procedure is readily repeatable in order to get images in multiple veiws or to follow minute-by-minute changes of cerebral perfusion.

Eighty patients were studied by angiography within 6 h of an ischaemic stroke. Angiography was carried out with digital equipment and was usually limited to the vascular territory responsible for the neurological deficits. In 12 of 19 patients with internal carotid occlusion, the contralateral side was also studied. The angiographic abnormalities were classified as extracranial, intracranial, and combined extra and intracranial. The data show a high incidence (66%) of occlusive pathology of intracranial arteries, either isolated or associated with a significant presence of a potential embolic source (85%), and a high incidence of carotid occlusions located at the cervical segment (8 of 19). These observations suggest that most strokes are occlusive in origin.

The current neurological indications for calcium entry blockers list a potential usefulness in tissue protection against the effects of cerebral anoxia and ischemia. Experimental data support these indications. Clinical data are preliminary so far and suggest designs for larger trials. A possible alternative strategy is the study of particular subgroups of patients such as the patients at excessive risk of stroke.

It has long been established that hypertension is the major risk factor for stroke. Three Italian studies have been reviewed in order to examine different aspects of the problem. In the first study, the role played by the systolic, diastolic and systodiastolic components of hypertension in causing atherosclerotic damage of extracerebral and intracerebral arteries was examined. At the extracranial level, a significant correlation between systolic hypertension and atherosclerotic lesions was evident. The second study evaluated the risk of major stroke, myocardial infarction and death in patients with transient ischemic attacks and reversible ischemic neurologic deficits. Possible prognostic predictors of these events were thoroughly considered: Cumulative survival with the multivariate Kaplan-Meier analysis was significantly lower in hypertensive than in normotensive subjects, particularly for cerebral deaths and for all deaths. The third study was aimed at assessing the risk factors for transient ischemic attacks and stroke in young adults. Again, hypertension emerged as a fundamental risk factor, significantly more frequent in the subgroup of older patients than in the younger subgroup.

The rCBF was evaluated using I-123 HIPDM and single photon emission computed tomography (SPECT) on 14 patients undergoing extracranial-intracranial (EC-IC) bypass surgery because of internal carotid artery (ICA) occlusion. Before surgery, all patients showed cortical areas of hypoperfusion over the affected cerebral hemisphere. Shortly after EC-IC bypass a rCBF increase was observed in six patients. However, at the 6 and 12 month follow-ups, with angiographic control of bypass patency, rCBF studies did not show any significant rCBF change. Long-term noninvasive tomographic monitoring of perfusion changes occurring after EC-IC bypass surgery failed to show a long-lasting improvement in perfusion.

We compared digital intra-arterial angiography and transcranial Doppler sonography in acute cerebral ischemia as part of a wider study on a continuous series of 48 patients with acute focal cerebral ischemia in the carotid territory, observed within 4 hours of the onset of symptoms. The most significant Doppler findings of the middle cerebral artery included no detection of the artery when occlusion of the carotid siphon or the middle cerebral artery at its origin was shown by angiography and reduced flow velocities and asymmetry (symptomatic less than asymptomatic) when the occlusion was located in the terminal tract of the middle cerebral artery mainstem or in numerous terminal branches. Higher flow velocities in the anterior cerebral artery or posterior cerebral artery, mostly in the symptomatic hemisphere, often accompanied middle cerebral artery pathology, probably indicating collateral compensatory pathways.