Abstract: BACKGROUND: Emergency Clinical Pathways (ECP) for stroke have never been tested in randomized controlled trials (RCTs). OBJECTIVE: To evaluate the effectiveness of an ECP for stroke patients in Latium (Italy) emergency system. METHODS: cluster-RCT designed to compare stroke patient referrals by Emergency Medical Service (EMS) and Emergency Room (ER) health professionals trained in the ECP, with those of non-trained EMS and ER controls. Primary outcome measure was the proportion of eligible (aged </= 80 and symptom onset </= 6 hours) stroke patients referred to a stroke unit (SU). Intention to treat (ITT) and per-protocol (PP) analyses were performed, and risk ratios (RR) adjusted by age, gender and area, were calculated. RESULTS: 2656 patients in the intervention arm and 2239 in the control arm required assistance; 78.3% of the former and 80.6% of the latter were admitted to hospitals, and respectively 74.8% and 78.3% were confirmed strokes. Of the eligible confirmed strokes, 106/434 (24.4%) in the intervention arm and 43/328 (13.1%) in the control arm were referred to the SU in the ITT analysis (RR = 2.01; 95% CI: 0.79-4.00), and respectively 105/243 (43.2%) and 43/311 (13.8%) in the PP analysis (RR = 3.21; 95%CI: 1.62-4.98). Of patients suitable for i.v. thrombolysis, 15/175 (8.6%) in the intervention arm and 2/115 (1.7%) in the control arm received thrombolysis (p = 0.02) in the ITT analysis, and respectively 15/99 (15.1%) and 2/107 (1.9%)(p = 0.001) in the PP analysis. CONCLUSION: Our data suggest potenti efficiency and feasibility of an ECP. The integration of EMS and ERs with SU networks for organised acute stroke care is feasible and may ameliorate the quality of care for stroke patients. TRIAL REGISTRATION: Current Controlled Trials (ISRCTN41456865).
Abstract: BACKGROUND/AIMS: We have described VMP1 as a new protein which expression triggers autophagy in mammalian cells. Here we show that experimental diabetes activates VMP1 expression and autophagy in pancreas beta cells as a direct response to streptozotocin (STZ). METHODS: Male Wistar rats were treated with 65 mg/kg STZ and pancreas islets from untreated rats were incubated with 1 mM STZ. RESULTS: RT-PCR analysis shows early VMP1 induction after STZ treatment. In situ hybridization reveals VMP1 mRNA in islet beta cells. Electron microscopy shows chromatin aggregation and autophagy morphology that was confirmed by LC3 expression and LC3-VMP1 co-localization. Apoptotic cell death and the reduction of beta cell pool are evident after 24 h treatment, while VMP1 is still expressed in the remaining cells. VMP1-Beclin1 colocalization in pancreas tissue from STZ-treated rats suggests that VMP1-Beclin1 interaction is involved in the autophagic process activation during experimental diabetes. Results were confirmed using pancreas islets, showing VMP1 expression and autophagy in beta cells as a direct effect of STZ treatment. CONCLUSION: Pancreas beta cells trigger VMP1 expression and autophagy during the early cellular events in response to experimental diabetes.
Abstract: Plasma levels of brain natriuretic peptide (BNP) are frequently elevated after an acute stroke and have been shown to be an independent predictor of mortality. However, the relationships between stroke and BNP concentrations have not yet been systematically investigated. Plasma BNP assay and echocardiography were performed in 48 patients with ischemic stroke or TIA with a mean delay of 12.7 h after onset. Median BNP concentration was 88.6 pg/mL (range 5-1270). Older age, chronic heart failure, atrial fibrillation, stroke severity, lower hemoglobin levels, lower left ventricular ejection fraction, and abnormalities of left atrium or appendage (LA/LAA) were univariately associated with increased BNP levels. At multivariable analysis, the presence of at least one LA/LAA abnormality (atrial dilatation, low flow velocity, spontaneous echocontrast or thrombus) had the strongest association with BNP, explaining 38.9% of the variance in the whole sample and 28.5% in patients without atrial fibrillation. In acute ischemic stroke patients, elevated plasma BNP levels have multiple determinants, among which left atrial disease appears to be the stronger, even in patients without atrial fibrillation. These results encourage further investigation of plasma BNP concentration as a potential marker of the presence of left atrial sources of emboli.
Abstract: Autophagy is a degradation process of cytoplasmic cellular constituents, which serves as a survival mechanism in starving cells, and it is characterized by sequestration of bulk cytoplasm and organelles in double-membrane vesicles called autophagosomes. Autophagy has been linked to a variety of pathological processes such as neurodegenerative diseases and tumorigenesis, which highlights its biological and medical importance. We have previously characterized the vacuole membrane protein 1 (VMP1) gene, which is highly activated in acute pancreatitis, a disease associated with morphological changes resembling autophagy. Here we show that VMP1 expression triggers autophagy in mammalian cells. VMP1 expression induces the formation of ultrastructural features of autophagy and recruitment of the microtubule-associated protein 1 light-chain 3 (LC3), which is inhibited after treatment with the autophagy inhibitor 3-methiladenine. VMP1 is induced by starvation and rapamycin treatments. Its expression is necessary for autophagy, because VMP1 small interfering RNA inhibits autophagosome formation under both autophagic stimuli. VMP1 is a transmembrane protein that co-localizes with LC3, a marker of the autophagosomes. It interacts with Beclin 1, a mammalian autophagy initiator, through the VMP1-Atg domain, which is essential for autophagosome formation. VMP1 endogenous expression co-localizes with LC3 in pancreas tissue undergoing pancreatitis-induced autophagy. Finally, VMP1 stable expression targeted to pancreas acinar cell in transgenic mice induces autophagosome formation. Our results identify VMP1 as a novel autophagy-related membrane protein involved in the initial steps of the mammalian cell autophagic process.
Abstract: The increasing prevalence of cerebrovascular diseases has made urgent the need to develop timely and effective treatment strategies to tackle this health problem. Stroke units (SUs) appear to be the ideal setting where the management of acute stroke patients, including specific treatments as thrombolysis, may be optimized. Which model of SU gives the best results is still an unsettled issue. The more intensive and timely multidisciplinary approach to the acute phase of stroke, the management of medical complications, and the earlier and more focused rehabilitation, are likely the most qualifying aspects of our Neurovascular treatment unit.
Abstract: OBJECTIVES: Successful prediction of cardiac complications early in the course of acute ischaemic stroke could have an impact on the clinical management. Markers of myocardial injury on admission deserve investigation as potential predictors of poor outcome from stroke. METHODS: We prospectively investigated 330 consecutive patients with acute ischaemic stroke admitted to our emergency department based stroke unit. We analysed the association of baseline levels of cardiac troponin I (cTnI) with (a) all-cause mortality over a six month follow up, and (b) in-hospital death or major non-fatal cardiac event (angina, myocardial infarction, or heart failure). RESULTS: cTnI levels on admission were normal (lower than 0.10 ng/ml) in 277 patients (83.9%), low positive (0.10-0.39 ng/ml) in 35 (10.6%), and high positive (0.40 ng/ml or higher) in 18 (5.5%). Six month survival decreased significantly across the three groups (p<0.0001, log rank test for trend). On multivariate analysis, cTnI level was an independent predictor of mortality (low positive cTnI, hazard ratio (HR) 2.14; 95% CI 1.13 to 4.05; p = 0.01; and high positive cTnI, HR 2.47; 95% CI 1.22 to 5.02; p = 0.01), together with age and stroke severity. cTnI also predicted a higher risk of the combined endpoint "in-hospital death or non-fatal cardiac event". Neither the adjustment for other potential confounders nor the adjustment for ECG changes and levels of CK-MB and myoglobin on admission altered these results. CONCLUSIONS: cTnI positivity on admission is an independent prognostic predictor in acute ischaemic stroke. Whether further evaluation and treatment of cTnI positive patients can reduce cardiac morbidity and mortality should be the focus of future research.
Abstract: In the last few years there have been several important advances in the understanding of cerebrovascular disorder pathophysiology that have impacted on stroke management. The development of timely and effective treatment strategies was and is still considered a high priority issue. Therapeutic options dramatically increased both in the prevention and overall in the treatment of acute ischaemic stroke (AIS). At present, whereas neuroprotection remains experimental, intravenous (i.v.) thrombolysis is the only specific therapy effective in reducing mortality and disability associated with stroke. The efficacy and safety of the antithrombotic therapy in AIS treatment are not well established, and few issues in clinical stroke management are more controversial. However, some studies have brought new light and new doubts on the roles of these traditional therapies.
Abstract: Stroke is the third leading cause of death and the most important cause of long-term disability in Italy and other developed countries, heavily influencing quality of life and costs of health care. In spite of the widespread occurrence of the disease and its relevant impact in Italy, there is neither a national nor a regional surveillance system of cerebrovascular diseases. A regional surveillance system for stroke has two important aims: to help to interpret the geographical and temporal trends of the disease for health care planning and resource allocation and to allow close monitoring of the quality of stroke services. Age-standardized mortality rates for cerebrovascular diseases in the Lazio region (5,242,709 inhabitants) in the period 1998-99 were 69.4 for males and 59.4 for females per 100,000 inhabitants. In the year 2000, about 3% of all hospital discharges were for cerebrovascular diseases with a hospitalisation rate of 4.36 per 1000 inhabitants. The mean length of stay is 12 days (median of 9 days) and in-hospital death is 15.4%. The admission rate for cerebrovascular diseases to emergency departments is 3.40 per 1000 inhabitants. The goal of the Lazio Regional Health Authority is to implement a surveillance system for stroke based both on current data (mortality and discharge data) and on information collected in a registry for quality assessment of stroke care. The first step of the study is to develop a regional register of acute stroke using an 'ad hoc' data sheet integrated in the computer-based patient record system of clinical and administrative data (GIPSE) operating in all emergency departments in the region.
Abstract: During stroke trials local investigators have to face many practical problems and time consuming procedures (filling in huge case report forms, performing repeat blood sample drawings for pharmacokinetic studies etc.) which, however, simply require organizational structures which is understood to be necessary to be able to conduct such kind of studies. Other, and most worrisome problems, are indeed to be solved when a sponsored research may rise potential ethical issues, or when academic research proposals clash with the interest of pharmaceutical companies or find difficulties in being funded by public institutions. It is just a greater involvement of these latter, possibly free from bureaucratic laces, which might help a balance to be struck between academic and industrial aims.
Abstract: AIM: The appropriateness of early carotid endarterectomy (CEA) in patients with acute ischemic stroke is still unsettled. The aim of this study was to verify the safety and feasibility of early CEA in a consecutive series of patients with acute ischemic stroke observed in an emergency Department Stroke Unit. METHODS: During a 24-month study, out of 756 patients with acute ischemic stroke 33 (4.4%) were scheduled for early CEA. Endarterectomy procedures were distinguished according to the time between the onset of stroke and operation as emergency (within 8 hours), early CEA (1-18 days). Patients with impaired consciousness or an infarct larger than 2.5 cm on computed tomographic (CT) or magnetic resonance (MR) scans or both were excluded from surgery. All patients underwent spiral CT, echo-color-Doppler (ECD) sonography, transcranial Doppler (TCD) sonography and, when necessary, MR angiography within 6 hours of admission. No patient underwent conventional angiography. Most patients were operated on under cervical block (CB) anesthesia; general anesthesia (GA) was used only for those with an unstable neurological deficit. Selective shunting was used on the basis of intra-operative transcranial Doppler in patients under GA and the onset or worsening of neurological deficit under CB anesthesia. RESULTS: Of the 6 patients operated on within a median 6 hours after the onset of stroke, 1 (16.5%) had a fatal hemorrhagic transformation of the infarct, while the remaining 5 (83.5%) stopped fluctuating or progressing and had a favourable neurological outcome. Of the 16 patients operated on within a median 36 hours and of the 11 patients operated on within 7 days, none deteriorated after operation. CONCLUSION: Emergency CEA is feasible for acute ischaemic stroke provided that strict selection criteria are applied and the door-to-surgery interval is kept short (within 8 hours). Early CEA for secondary prevention is feasible and safe, confirming that a delayed operation is in most cases unwarranted. Large randomized trials are warranted before implementing emergent and early CEA in routine clinical practice.
Abstract: In order to evaluate the clinical usefulness of emergency computed tomography (CT) in acute ischemic stroke, we assessed whether CT findings within the first few hours of stroke onset reliably predict type, site and size of the index infarction, and risk of death or disability. For this reason we reviewed clinical and CT findings in a cohort of unselected consecutive patients referred to the stroke unit of a large urban hospital because of a presumed ischemic stroke in the anterior circulation (AC), and submitted to CT within 5 h from onset. Out of 158 total patients, emergency CT revealed parenchymal changes compatible with AC focal ischemia in 77 (49%) and a hyperdense middle cerebral artery (MCA) in 41 (26%). Parenchymal changes and hyperdense MCA predicted an AC territorial infarction respectively in 97% of cases (95% C.I. 93% to 100%) and in 95% of cases (95% C.I. 88% to 100%). Site and size of early changes coincided with those of final lesions in 79% of patients with cortical changes and in 95% of patients with cortico-subcortical changes, but only in 37% of patients with initial subcortical changes, the remainder of whom developed a cortico-subcortical infarction. At logistic regression parenchymal changes were the only independent predictor of an AC territorial infarction. Negative predictive power, however, was only 40% (95% C. I. 29% to 51%) for parenchymal changes, and 35% for hyperdense MCA (95% C.I. 26% to 44%). The odds for death or disability at 1 month associated with parenchymal changes were thrice as high as with negative CT, even after adjustment for clinical severity on admission. These results indicate that CT scan adds significantly to the prediction of outcome made on clinical grounds. The frequent development of a territorial infarction in patients with initially negative CT and the subsequent recruitment of the cortex in those initially exhibiting only subcortical changes suggest that the transition from ischemia to infarction often occurs after the first five h following stroke.
Abstract: 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.
Abstract: BACKGROUND and PURPOSE: It is not yet known which end points are the most suitable for evaluation of the effects of acute stroke intervention. The European Cooperative Acute Stroke Study (ECASS) I study used 2 primary end points. The study was powered to detect a 15% improvement of the median of each primary end point. The study failed to show this effect and was negative in the intention-to-treat analysis. The National Institute of Neurological Disorders and Stroke (NINDS) study used 4 dichotomized end points and applied a global end-point analysis. This study was positive and led to FDA approval of thrombolytic therapy for acute ischemic stroke. This study was undertaken to answer the question of whether a different statistical design may have shown a positive results of the ECASS I trial. METHODS: We performed a retrospective analysis of the ECASS I intention-to-treat data set (615 randomized and treated patients, rtPA treatment versus placebo) and post hoc application of the NINDS trial statistical methodology (global end-point analysis). The scores of the modified Rankin Scale (mRS), Barthel Index (BI), and the National Institutes of Health Stroke Scale (NIHSS) were dichotomized according to the criteria used in the NINDS trial. Favorable outcome was defined as a score of 0 or 1 on mRS, a score of 95 or 100 on BI, and a score of 0 or 1 on NIHSS. RESULTS: The number of patients reaching favorable outcome were higher in all 3 end points in the rtPA-treated group. The effect sizes were 8% for mRS, 6% for BI, and 14% for NIHSS, respectively. The differences are statistically significant for the mRS (P=0.044; odds ratio [OR], 1. 4; 95% confidence interval [CI], 1.0 to 2.0) and the NIHSS (P=0.001; OR, 1.9; 95% CI, 1.4 to 2.8), while for the BI significance was missed (P=0.102; OR, 1.3; 95% CI, 0.9 to 1.8). The global end-point statistics, however, shows a significant increase (P=0.008; OR, 1.5; 95% CI, 1.1 to 2.0) of favorable outcome in the rtPA-treated patient group. CONCLUSIONS: Using the global end-point analysis, ECASS is positive in the intention-to-treat analysis. This may indicate that the time window for thrombolysis may be as long as 6 hours. Looking at the 3 dichotomized end points, the effect sizes for 2 end points, mRS and BI, are smaller in the ECASS 6-hour intention-to-treat population compared with the NINDS trial, whereas the effect size for the NIHSS is larger. While in the NINDS trial all 3 end points reveal statistically significant results, in ECASS only 2 of the 3 corresponding end points, mRS and NIHSS, were statistically significant. This finding underlines an important difference of a global end-point approach: it may show a positive overall result although one of the end points is not positive.
Abstract: BACKGROUND AND PURPOSE: Our aims were to identify predictors of early neurological improvement in acute ischemic stroke patients, to evaluate its impact on clinical outcome, and to investigate possible mechanisms. METHODS: A consecutive series of 152 first-ever ischemic hemispheric stroke patients hospitalized within 5 hours of onset underwent a first CT scan within 1 hour of hospitalization, and the initial subset of 80 patients also underwent angiography. During the first 48 hours of hospital stay, an increase or a decrease of 1 or more points in the admission Canadian Neurological Scale (CNS) score was defined as early improvement or early deterioration, respectively. Repeated CT scan or autopsy was performed 5 to 9 days after stroke. RESULTS: Thirty-four patients (22%) improved, 84 (56%) remained stable, and 34 (22%) deteriorated. Logistic regression, which took into account vascular risk factors, baseline clinical and CT data, and therapies administered, selected younger age, lower admission CNS score, and absence of early hypodensity at first CT as independent predictors of early improvement. Among the patients who underwent angiography, logistic regression selected arterial patency and presence of collateral blood supply as independent predictors of early improvement. At the repeated CT scan or autopsy, improving patients presented the highest frequency of small infarcts. Thirty-day case-fatality rate and disability were lower in improving patients. Variables independently associated with outcome at logistic regression were admission CNS score, early deterioration, and early improvement. CONCLUSIONS: Early improvement can be predicted by the absence of early CT hypodensity and is highly predictive of good outcome. Presence of collateral blood supply and presumably early spontaneous recanalization are likely to be the mechanisms underlying early improvement.
Abstract: BACKGROUND AND PURPOSE: Ischemic stroke patients whose initial clinical presentation suggests an involvement of the anterior circulation (AC) are sometimes found to have a posterior circulation (PC) infarct, a fact that may generate erroneous decisions in clinical management. We investigated the prevalence of this misdiagnosis in the first few hours after stroke onset. METHODS: We performed a cohort study of 158 patients hospitalized within 5 hours of onset of a presumed AC ischemic stroke, as diagnosed on clinical grounds. RESULTS: Final CT or pathology diagnosis was AC infarct in 128 patients (81%), a repeatedly negative CT in 14 (9%), PC infarct (5 pons, 1 midbrain and cerebellum, 6 supratentorial territory of the posterior cerebral artery) in 12 (8%), and other or undiagnosed lesions in 4 (3%). AC and PC stroke patients did not differ in terms of age, vascular risk factors, and initial severity, but the latter were more frequently men (83% versus 53%; P = .04), were hospitalized later (mean +/- SD, 168 +/- 86 versus 109 +/- 55 minutes; P = .001), and presented a pure motor hemiparesis or a sensorimotor stroke (50% versus 33%) more often than their counterparts. At baseline CT, PC stroke patients never exhibited an early parenchymal hypodensity in the carotid territory or a hyperdense middle cerebral artery, which were instead found in 59% (P = .0003) and 31% (P = .02) of AC stroke patients, respectively. Early neurological deterioration, 1 month case-fatality rate, and disablement in survivors were comparable in the two groups. CONCLUSIONS: Shortly after onset the clinical discrimination between AC and nontypical PC infarcts is not reliable, which explains the frequent occurrence of this misdiagnosis. Emergency CT scan helps in the differential diagnosis only when it demonstrates an early focal hypodensity within the carotid territory.
Abstract: Thrombolysis is an attractive but potentially dangerous they for cerebral ischemia: it is capable of dissolving an arterial thrombus, but can also transform a pale infarct into a hematoma and/or may cause severe oedema and herniation. The safety and efficacy of the treatment critically depend on the timing of intervention ad on patient selection. In recent studies on ischemic stroke, spontaneous hemorrhagic transformation of an infarct seems to be related to the size of the lesion, and can be reliably predicted as early as five hours from stroke onset by the presence of focal hypodensity in the CT scan. That is why in the European Co-operative Acute Stroke (ECASS), a randomised, double blind trial on intravenous rt-PA in hemispheric stroke, patients showing, on the admission CT scan, extended early hypodensity, involving more than one third of the territory of the middle cerebral artery, were excluded from the day. Other ongoing trials on thrombolytic agents are expected to provide further indications on how to identify those patients most likely to benefit and least likely to experience adverse effects from this treatment.
Abstract: OBJECTIVE: To identify, in the first 5 hours of acute brain infarct, clinical and radiologic predictors of subsequent hemorrhagic transformation (HT), and to evaluate its influence on the clinical course. BACKGROUND: The identification of early predictors of HT might be important to plan antithrombotic or thrombolytic treatments. PATIENTS: One hundred fifty consecutive patients with cerebral anterior circulation infarct systematically underwent a first CT within 5 hours of onset. During the first week after stroke, we performed a repeat CT or autopsy to look for HT. Outcome measures were early neurologic deterioration within the first week of onset and 30-day case fatality rate and disability. RESULTS: HT was observed in 65 patients (43%): 58 (89%) had a petechial HT and seven (11%) a hematoma. Among initial clinical an CT findings, the only independent predictor of HT was early focal hypodensity. Its presence was associated with subsequent HT in 77% of cases (95% CI, 68 to 86%), whereas its absence predicted the absence of subsequent HT in 94% of cases (95% CI, 89 to 99%). No baseline clinical or CT characteristic differentiated patients with petechial HT from those with hematoma. Antithrombotic and antiplatelet agents did not influence the occurrence of either type of HT. The frequency of early neurologic deterioration and of 30-day death or disability in HT patients was twice as high as in those without HT. However, a large-sized infarct and the presence of mass effect at the repeat CT or autopsy were the only factors independently linked to both the outcome events, irrespective of the development of HT. Clinical evolution of HT patients given antithrombotics was comparable with that of HT patients not receiving these drugs. CONCLUSIONS: HT of a brain infarct is a common event that occurs independently of anticoagulation and can be reliably predicted as early as 5 hours from stroke onset by the presence of focal hypodensity at CT. Apart from the infrequent cases of massive hematoma, HT does not influence prognosis, whereas a poor outcome in HT patients is correlated with a higher frequency of large edematous infarcts in this subgroup. The clinical course and final outcome of HT in anticoagulated patients does not differ from that of non-anticoagulated HT patients.
Abstract: 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.
Abstract: OBJECTIVES: To identify predictors and possible pathogenetic mechanisms of early neurological deterioration in patients with acute ischemic strokes and to evaluate their impact on clinical outcome. DESIGN: Case series. SETTING: University hospital's stroke unit. PATIENTS: A continuous series of 152 patients with first-ever ischemic hemispheric strokes were hospitalized within 5 hours of onset, evaluated with the Canadian Neurological Scale, and underwent a computed tomographic (CT) scan. The initial subset of 80 patients also underwent angiography. A repeated CT scan or autopsy was performed within 5 to 9 days of a patient's stroke. Progressing neurological deficit was defined as a decrease of one point or more in the global neurological scale score during hospitalization, when compared with that at entry. RESULTS: The conditions of 39 patients (26%) deteriorated during the initial 4 days; 20 patients (51%) had an impaired level of consciousness, and 19 patients (49%) had impaired limb strength and/or speech. They had been hospitalized earlier and had higher serum glucose levels at admission; the baseline CT scans of these patients showed an early focal hypodensity and initial mass effect more frequently. On the repeated CT scan (144 patients) or at autopsy (eight patients), patients with a progressing course more frequently had large infarcts, severe mass effect, and hemorrhagic infarction. We found no differences with regard to demographic data, medical history, and treatments that were given; only subcutaneous heparin calcium was more frequently administered to patients with a progressing course. Twenty-two (27%) of the 80 patients who underwent angiography had a progressing course, of whom 20 (91%) had an intracranial and/or extracranial arterial occlusion, with collateral blood supply in seven patients (35%). Logistic regression analysis showed that the independent predictors of progression were the serum glucose levels at admission and the early focal hypodensity with cortical and corticosubcortical locations, with the positive predictive values of the latter being 34% (95% confidence interval [CI], 26% to 42%) and 57% (95% CI, 47% to 67%), respectively. Among patients who underwent angiography, logistic regression analysis showed a significant correlation between carotid siphon occlusion and a progressing course. The 30-day case-fatality ratio and disability (Barthel index, < 60) were higher in patients with a progressing course (36% and 54% vs 12% and 35%, respectively). CONCLUSIONS: Early stroke deterioration is still an event that is difficult to predict; it is largely determined by cerebral edema following an arterial occlusion, as indicated by an early focal hypodensity and initial mass effect on the baseline CT scan. Since early deterioration anticipates a bad outcome in 90% of patients, it might be used as an early surrogate end point in therapeutic trials.
Abstract: BACKGROUND AND PURPOSE: Pure motor hemiparesis and sensorimotor stroke syndromes are not accurate predictors of lacunar infarct when described in the first 12 hours of stroke onset. We evaluate here whether this inaccuracy of clinical diagnosis might have influenced the planning of patient management either in routine practice or in therapeutic trials. METHODS: A consecutive hospital series of 517 first-ever ischemic hemispheric stroke patients presented lacunar or nonlacunar syndromes at the first examination within 12 hours of the event. A distinction was subsequently made, by means of a CT scan or autopsy performed within 15 +/- 2 days of stroke, between patients affected by lacunar or nonlacunar infarcts. We compared stroke risk factors, considered to be indicative of potential pathogenetic mechanisms, and the clinical outcome of lacunar infarct versus nonlacunar infarct patients and those of lacunar syndrome versus nonlacunar syndrome patients. RESULTS: Two hundred nineteen patients (42%) presented a lacunar syndrome and 298 (58%) a nonlacunar syndrome, while 170 (33%) had lacunar infarcts and 347 (67%) nonlacunar infarcts. Lacunar infarct patients were more frequently associated with hypertension and a previous transient ischemic attack and less frequently with atrial fibrillation when compared with their nonlacunar infarct counterparts, whereas no differences were apparent between lacunar syndrome and nonlacunar syndrome patients. Logistic regression analysis showed that hypertension and a previous transient ischemic attack on the one hand and atrial fibrillation on the other were strongly correlated with the diagnosis of lacunar infarct and nonlacunar infarct, respectively, while no risk factor was correlated with the diagnosis of lacunar syndrome. Twenty-two percent of lacunar infarct patients and 68% of nonlacunar infarct subjects had a poor outcome (death plus disability of survivors) as opposed to 40% of lacunar syndrome and 63% of nonlacunar syndrome patients. Logistic regression selected age, severity of neurological deficit at entry, cardiopathies, diabetes, and lacunar infarct, but not lacunar syndrome, as predictors of outcome. CONCLUSIONS: The inaccurate clinical diagnosis of lacunar infarct made in the first 12 hours of stroke might lead to no distinction being made between stroke subgroups with potentially different pathogenetic mechanisms and prognostic estimates, thus negatively influencing the planning of patient management.
Abstract: BACKGROUND AND PURPOSE: Clinical differentiation of lacunar from nonlacunar strokes in the very early phase could help to exclude patients with lacunar stroke from pharmacologic trials designed for nonlacunar strokes, namely, those with thrombolytic agents. In a continuous series of acute ischemic stroke patients, we evaluated how accurately a clinical diagnosis of pure motor hemiparesis or sensorimotor stroke formulated in the first hours from onset predicts a lacunar stroke documented by cerebral computed tomography or by autopsy. METHODS: We examined 517 patients (299 men, 218 women; mean +/- SD age, 67 +/- 10 years) within 12 hours (mean +/- SD, 6.1 +/- 3.2 hours) of the event. At hospital admission, we observed 151 (29%) patients with pure motor hemiparesis and 68 (13%) patients with sensorimotor stroke. RESULTS: Computed tomography or autopsy was compatible with a lacunar stroke (ie, detection of a lacune or permanently negative computed tomography) in 170 (33%) patients, of whom 123 (72%) had pure motor hemiparesis and 47 (28%) had sensorimotor stroke. This led to a sensitivity of 72%, a specificity of 72%, a positive predictive value of 56%, and a negative predictive value of 84%. Overall positive predictive value of pure motor hemiparesis was 58% (60% for two areas and 58% for three areas involved), and that of sensorimotor stroke was 51% (87% for two areas and 40% for three areas involved). By separately evaluating the sides of lesions, we found a positive predictive value of 46% for right-side infarcts and of 72% for left-side infarcts. Right-side lesions constituted 51% of lesions in lacunar syndrome patients with lacunar stroke, 76% in those with nonlacunar stroke, 19% in nonlacunar syndrome patients with lacunar stroke, and 31% in those with nonlacunar stroke (P < .0001). During the first days of hospital stay we observed a deterioration of 21% of lacunar syndrome patients with nonlacunar stroke and an improvement of 49% of nonlacunar syndrome patients with lacunar stroke, with appearance and disappearance of symptoms of cortical involvement, respectively. The examination of these patients after the occurrence of these clinical changes would have led to a daily increase of the positive predictive value up to a maximum of 66% at day 7. CONCLUSIONS: Pure motor hemiparesis and sensorimotor stroke diagnosed within 12 hours of the event are poorly predictive of lacunar strokes. Hence, the very early identification of these syndromes cannot be used for patient selection in therapeutic trials.
Abstract: We investigated the effects of hyperglycaemia on infarct size of 82 acute ischaemic stroke patients with angiographically diagnosed intracranial occlusion in middle cerebral artery territory. There were 9 diabetics, 40 non-diabetic hyperglycaemics and 33 non-diabetic normoglycaemics (mean age 67 +/- 8 SD years, male/female ratio 1:1). For each patient the infarct at CT was compared to that predicted from the location of the arterial occlusion. The extent of the infarct was then classified as equal to, smaller than and larger than estimated, taking a standard anatomical template of arterial territories as reference. The results were analysed separately according to the presence or absence of a collateral blood supply (CBS) at angiography. The clinical outcome at 30 days was also evaluated. The 35 patients lacking CBS had a high frequency of equal to estimated lesions (75%), without substantial differences among the three subgroups (72% of hyperglycaemics, 82% of normoglycaemics and 67% of diabetics; Fisher's exact test not significant for any of the pairwise comparisons). On the contrary, the 47 patients with CBS exhibited an overall predominance of smaller than estimated lesions (66%) but with a very uneven distribution among hyperglycaemics, normoglycaemics and diabetics (82%, 64% and 0%, respectively; p < 0.05 at Fisher's exact test for diabetics vs hyperglycaemics). Finally, the clinical outcome was bad (death and neurological impairment) in 89% of diabetics, 72% of hyperglycaemics and 54% of normoglycaemics (p < 0.05). These results suggest that in patients with intracranial arterial occlusion associated with CBS the effects of hyperglycaemia might be beneficial in non-diabetics and harmful in diabetics.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: A consecutive series of 327 patients (188 males, 139 females; mean age 68.4, SEM 1.33) were hospitalized within 12 h of the onset of their first-ever hemispheric infarct. Three groups of patients were identified: diabetics (n = 70), non-diabetic hyperglycaemics (n = 93) and normoglycaemics (n = 164). Case-fatality ratios at 30 days after stroke were 38.6%, 22.6% and 9.2% (P less than 0.001) respectively, whereas the causes of death and functional outcome of survivors were not significantly different between the groups. Mean admission serum glucose levels (SGLs) of decreased, impaired/unchanged and improved patients within each one of the three groups, were also not significantly different as opposed to their mean Canadian Neurological Scale (CNS) scores at entry (P less than 0.01). Among patients with less severe initial neurological deficit (i.e., CNS score greater than or equal to 7.0), 82.6% of non-diabetic hyperglycaemic subjects fared well, in comparison with 56.5% of diabetic and 70.1% of normoglycaemic individuals. The size of the infarcted areas at the second CT correlated with mean CNS scores (P less than 0.01) but not with mean SGLs on admission. The site of the ischaemic areas did not correlate with mean SGLs at entry. Therefore the influence of initial SGLs on the clinical course of the present series of patients is questionable or, alternatively, varied probably according to the pattern of residual cerebral blood flow after arterial occlusion.
Abstract: We studied polysomnographic recordings using an Oxford Medilog 9000 System in 18 patients with ischemic stroke in the middle cerebral artery territory. All patients underwent neurologic examination and brain CT scan within 5 h after the onset of symptoms. Polysomnographic recordings were started immediately thereafter and went on for three nights. Clinical and polysomnographic follow-up were performed 3 weeks after admission. The number and duration of REM phases were significantly reduced in the acute phase. This reduction correlated with the severity of neurological deficit at outcome and with the anatomical site of the lesion on CT scan. Our data provide evidence that polysomnographic recording is useful to detect symptoms of patients with different clinical outcomes during the acute phase of ischemic stroke.
Abstract: 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.
Abstract: In a continuous series of 80 acute ischemic hemispheric strokes, the onset of symptoms was between 6:01 a.m. and noon in 45% of cases, between noon and 6:00 p.m. in 22.5%, between 6:01 p.m. and midnight in 31.25%, and between midnight and 6:00 a.m. in 1.25% (p less than 0.0001). By means of angiography and computerized tomography, and by detection of arterial and cardiac sources of emboli, four stroke subtypes were identified. Embolic and thrombotic strokes had their most frequent onset between 6:01 a.m. and noon (45% and 71%, respectively), whereas strokes of unknown origin and lacunar strokes were randomly distributed between 6:01 p.m. and midnight. The morning activation of the catecholaminergic system can account for this pattern of circadian onset of ischemic stroke.
Abstract: We studied cerebrovascular anatomy using intra-arterial digital angiography, and blood flow velocity in the middle cerebral artery (MCA) using transcranial Doppler (TCD) ultrasonography in 42 patients with acute hemispheric ischemic brain infarction. We compared angiography with TCD and the clinical findings within 6 hours of the onset of symptoms. The location and extent of the chronic ischemic brain damage was assessed by CT performed 1 to 3 months after the ictus. Abnormal TCD, as manifested by either an unobtainable MCA flow signal or a significantly depressed MCA flow velocity, was highly associated with proximal MCA occlusions demonstrated by angiography. Abnormal TCD predicted both larger chronic CT lesions and more extensive ischemic change within the MCA territory. These data demonstrate that early TCD conveys useful information concerning cerebral tissue prognosis following hemispheric ischemia.
Abstract: 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.
Abstract: Eleven of 31 clinical centers participating in the Italian Acute Stroke Study--Hemodilution carried out a preliminary study on the effectiveness of ganglioside GM1 in acute stroke; 502 patients were randomized to GM1 (GM1, n = 121), GM1 plus hemodilution (GM1 + H, n = 128), placebo (P, n = 130), or placebo plus hemodilution (P + H, n = 123) groups less than or equal to 12 hours after onset of a hemispheric cerebral infarct. The patients were treated for 15 days and were evaluated on Days 21 and 120 after the onset of stroke. Intention-to-treat analysis failed to show any differences in neurologic deficit, mortality, or neurologic disability among the groups. Efficacy analysis showed a significantly higher degree of neurologic improvement in GM1 group patients compared with patients in the P group during the first 15 days. GM1-treated patients (GM1 and GM1 + H groups) showed a significantly higher degree of neurologic improvement during the first 10 days compared with the placebo-treated patients (P and P + H groups). These differences were no longer statistically significant at Day 120. Our results provide a rationale for the planning of a larger, multicenter trial of GM1 ganglioside in acute stroke.
Abstract: The development of fibrinolytic agents such as streptokinase and recombinant tissue type plasminogen activator (r-TPA) and other modalities of treatment in acute ischemic stroke, has raised the need for a more precise knowledge of the pathophysiology of the acute phases of ischemic stroke as it pertains to prediction of clinical outcome. In a prospective analysis, 80 patients were studied within less than 6 h from the onset of symptoms by means of a detailed protocol including clinical evaluation, cerebral computed tomography, digital angiography and ultrasound transcranial Doppler sonography. Early angiography revealed a complete arterial occlusion in 76% of cases, the majority of which were intracranial (66%). Seventy percent of the occlusions that were retested were removed within 1 week. Potential embolic sources were found in more than 80% of cases. Patients with documented intracranial occlusion and scarce or absent collateral filling at early angiography, had the worst clinical outcome (P less than 0.05), based on mortality data and the Canadian Neurological Scale. The 30-day mortality rate was 25%. Survival was significantly better (P less than 0.01) in patients with a Canadian Neurological Score on entry of greater than or equal to 6.5 than in patients with a less than 6.5 value. Our data indicate that early pathophysiological studies augment the clinical information and should be taken into account in the design and analysis of therapeutic trials of acute ischemic stroke.
