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Although ischemic stroke is a major cause of death worldwide and the predominant cause of acquired disability, the only effective drug therapy that has been developed thus far is reperfusion by tissue plasminogen activator. Since most patients do not qualify for this treatment, new methods have to be developed. It is well known that estradiol (E 2 ) exerts neuroprotective effects in different models of cerebral ischemia, but post-stroke treatment after an acute stroke has hardly been investigated. As many patients with an acute ischemic stroke have arterial hypertension, it is also of interest to evaluate the influence of this co-morbidity on the treatment efficacy of E 2 . The effects of E 2 administered 30min after a transient middle cerebral artery occlusion (tMCAO) induced by an intracerebral injection of endothelin-1 were assessed in male normotensive Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). Treatment with E 2 reduced infarct size in both WKY and SHRs and decreased the number of degenerating neurons, indicating that acute treatment with E 2 is indeed neuroprotective. To address the role of glia in neuroprotection, the effects of E 2 on the activation of microglia and astrocytes was determined. It appeared that E 2 had no effect on microglial activation, but reduced the activation of astrocytes in SHRs but not in the normotensive controls. We conclude that post-stroke E 2 treatment in both normotensive and hypertensive rats is neuroprotective. Although the presence of hypertension changed the astrocytic response to E 2 , it did not affect treatment efficacy., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: There are conflicting results regarding the effect of intravenous (IV) recombinant tissue plasminogen activator (rtPA) stroke treatment between men and women. Studies evaluating the impact of sex differences on functional outcome in relation to different age groups are nonexistent., Aim: The objective of the study is to examine the influence of sex differences in relation to age on the prognosis after IV rtPA treatment in acute stroke patients., Methods: In this cohort study, 887 patients with acute ischemic stroke were treated with rtPA. Functional outcome after 3 months was determined with the modified Rankin Scale (mRS). Good outcome was defined as an mRS score of 2 or lower. Age was stratified in decades (41-50, 51-60, 61-70, 71-80, and >80 years). Multivariable analyses were performed with adjustment for age, sex, stroke severity (National Institutes of Health Stroke Scale [NIHSS]), and stroke subtype (Trial of Org 10172 in Acute Stroke Treatment)., Results: Fifty-five percent of the patients were men. The mean age was 67.4 (men) and 72.0 (women) years. Fifty-six percent of the men and 45% of the women had a favorable outcome (P = .001). After adjustment for NIHSS score and stroke subtype, the women had a better outcome in the age group 51-60 years compared with men (odds ratio [OR] .38, 95% confidence interval [CI] .15-.96). In the age group >80 years, men had a better outcome than women (OR 2.69, 95% CI 1.21-5.96). There were no significant differences in the other age groups., Conclusion: Men and women have different prognoses after IV rtPA treatment for acute ischemic stroke, which also depends on age. Women in middle age appear to have a better outcome than men, whereas at a more advanced age men appear to have a better outcome than women., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

The exact pathogenesis of multiple sclerosis (MS) is incompletely understood. Although auto-immune responses have an important role in the development of hallmark focal demyelinating lesions, the underlying mechanism of axonal degeneration, the other key player in MS pathology and main determinant of long-term disability, remains unclear and corresponds poorly with inflammatory disease activity. Perfusion-weighted imaging studies have demonstrated that there is a widespread cerebral hypoperfusion in patients with MS, which is present from the early beginning to more advanced disease stages. This reduced cerebral blood flow (CBF) does not seems to be secondary to loss of axonal integrity with decreased metabolic demands but appears to be mediated by elevated levels of the potent vasospastic peptide endothelin-1 in the cerebral circulation. Evidence is evolving that cerebral hypoperfusion in MS is associated with chronic hypoxia, focal lesion formation, diffuse axonal degeneration, cognitive dysfunction, and fatigue. Restoring CBF may therefore emerge as a new therapeutic target in MS.

Impaired autonomic function, characterized by a predominance of sympathetic activity, is common in patients with acute ischemic stroke. This review describes methods to measure autonomic dysfunction in stroke patients. It summarizes a potential relationship between ischemic stroke-associated autonomic dysfunction and factors that have been associated with worse outcome, including cardiac complications, blood pressure variability changes, hyperglycemia, immune depression, sleep disordered breathing, thrombotic effects, and malignant edema. Involvement of the insular cortex has been suspected to play an important role in causing sympathovagal imbalance, but its exact role and that of other brain regions remain unclear. Although sympathetic overactivity in patients with ischemic stroke appears to be a negative prognostic factor, it remains to be seen whether therapeutic strategies that reduce sympathetic activity or increase parasympathetic activity might improve outcome., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The aim of this study was to test the insulin-like growth factor-I (IGF-I) as a neuroprotective agent in a rat model for ischemic stroke and to compare its neuroprotective effects in conscious normotensive and spontaneously hypertensive rats. The effects of subcutaneous IGF-I injection were investigated in both rat strains using the endothelin-1 rat model for ischemic stroke. Motor-sensory functions were measured using the Neurological Deficit Score. Infarct size was assessed by Cresyl Violet staining. Subcutaneous administration of IGF-I resulted in significantly reduced infarct volumes and an increase in motor-sensory functions in normotensive rats. In these rats, IGF-I did not modulate blood flow in the striatum and had no effect on the activation of astrocytes as assessed by GFAP staining. In hypertensive rats, the protective effects of IGF-I were smaller and not always significant. Furthermore, IGF-I significantly reduced microglial activation in the cortex of hypertensive rats, but not in normotensive rats. More detailed studies are required to find out whether the reduction by IGF-I of microglial activation contributes to an impairment IGF-I treatment efficacy. Indeed, we have shown before that microglia in hypertensive rats have different properties compared to those in control rats, as they exhibit a reduced responsiveness to ischemic stroke and lipopolysaccharide., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: The prognostic value of serum uric acid (UA) in acute ischemic stroke is controversial. The aim of this study is to further analyse the relation between UA and outcome after acute ischemic stroke., Methods: We analysed UA levels in blood samples collected within 6h of stroke onset from patients included in the placebo arm of the US and Canadian Lubeluzole Ischemic Stroke Study (LUB-INT-9). We compared mean serum UA levels in patients with and without early neurological improvement (≥ 4 versus <4 points improvement on NIHSS after 5 days) and in patients with good functional and poor functional outcome (mRS 0-2 versus mRS 3-6). Multivariable logistic regression analyses were performed to adjust for possible confounders., Results: UA levels of 226 patients were available for analysis. Mean serum UA levels were not significantly higher in patients with than without early neurological improvement (0.33 mmol/L versus 0.30 mmol/L, p=0.070). The difference between patients with good and patients with poor functional outcome was borderline statistically significant (0.34 mmol/L versus 0.31 mmol/L, p=0.050). After adjustment for confounders, higher serum UA levels were neither associated with early neurological improvement OR (1.30, 95% CI 0.98-1.73, p=0.069), nor with a good functional outcome (OR 1.09, 95% CI 0.72-1.65, p=0.690)., Conclusion: We found no association between admission serum UA levels and both short- and long-term outcome in acute ischemic stroke., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: For successful translation to clinical stroke studies, the Stroke Therapy Academic Industry Round Table criteria have been proposed. Two important criteria are testing of therapeutic interventions in conscious animals and the presence of a co-morbidity factor. We chose to work with hypertensive rats since hypertension is an important modifiable risk factor for stroke and influences the clinical outcome. We aimed to compare the susceptibility to ischemia in hypertensive rats with those in normotensive controls in a rat model for induction of ischemic stroke in conscious animals., Methods: The vasoconstrictor endothelin-1 was stereotactically applied in the vicinity of the middle cerebral artery of control Wistar Kyoto rats (WKYRs) and spontaneously hypertensive rats (SHRs) to induce a transient decrease in striatal blood flow, which was measured by the laser Doppler technique. Infarct size was assessed histologically by cresyl violet staining. Sensory-motor functions were measured at several time points using the neurological deficit score. Activation of microglia and astrocytes in the striatum and cortex was investigated by immunohistochemistry using antibodies against CD68/Iba-1 and glial fibrillary acidic protein., Results and Conclusions: The SHRs showed significantly larger infarct volumes and more pronounced sensory-motor deficits, compared to the WKYRs at 24 h after the insult. However, both differences disappeared between 24 and 72 h. In SHRs, microglia were less susceptible to activation by lipopolysaccharide and there was a reduced microglial activation after induction of ischemic stroke. These quantitative and qualitative differences may be relevant for studying the efficacy of new treatments for stroke in accordance to the Stroke Therapy Academic Industry Round Table criteria.

Background: It is uncertain whether thrombolytic therapy is safe in patients with acute ischaemic stroke who are treated with warfarin and have a subtherapeutic international normalised ratio (INR) at stroke onset., Methods: The authors performed a systematic review of the literature and included studies that assessed the relation between prior warfarin use with subtherapeutic INR and outcome after intravenous or intra-arterial thrombolytic therapy in acute ischaemic stroke. Outcome measures were symptomatic intracranial haemorrhage (SICH), modified Rankin scale score 0-2 and mortality. Second, the authors performed a meta-analysis of the included studies., Results: Seven studies with 3631 patients were included. 240 (6.6%) patients used warfarin before stroke onset. The risk of SICH was increased in the warfarin group (OR 2.6; 95% CI 1.1 to 5.9. p=0.02). There was no significant difference, however, in functional outcome (OR 0.9; 95% CI 0.6 to 1.2, p=0.32) or death from all causes (OR 1.2; 95% CI 0.9 to 1.8)., Discussion: The risk of SICH after thrombolytic therapy is increased in patients using warfarin with subtherapeutic INR levels. The authors found no evidence of an increase in death from all causes or worsening of functional outcome in warfarin treated patients.

Background and Purpose: It is unclear whether pre-stroke beta-blockers use may influence stroke outcome. This study evaluates the independent effect of pre-stroke use of beta-blockers on ischaemic stroke severity and 3 months functional outcome., Methods: Pre-stroke use of beta-blockers was investigated in 1375 ischaemic stroke patients who had been included in two placebo-controlled trials with lubeluzole. Stroke severity was assessed by either the National Institute of Health Stroke Scale (NIHSS) or the European Stroke Scale (ESS). A modified Rankin scale (mRS) score of >3 at 3 months was used as measure for the poor functional outcome., Results: Two hundred and sixty four patients were on beta-blockers prior to stroke onset, and 105 patients continued treatment after their stroke. Pretreatment with beta-blockers did not influence baseline stroke severity. There was no difference in stroke severity between nonusers and those on either a selective beta(1)-blocker or a non-selective beta-blocker. The likelihood of a poor outcome at 3 months was not influenced by pre-stroke beta-blocker use or beta-blocker use before and continued after stroke onset., Conclusions:   Pre-stroke use of beta-blockers does not appear to influence stroke severity and functional outcome at 3 months., (© 2011 The Author(s). European Journal of Neurology © 2011 EFNS.)

Background and Purpose: The effects of early upright positioning in the acute phase of ischemic stroke on both blood pressure and functional outcome have not been previously examined., Methods: Prospective investigation of mean arterial pressure, heart rate, and peripheral oxygen saturation in the supine, sitting, and (if achievable) active standing position 1, 2, and 3 days after an acute stroke was performed. Also investigated was the presence of a significant postural blood pressure rise and fall using orthostatic definitions and the relation to functional outcome after 3 months., Results: One hundred sixty-seven patients were included (mean age, 68.5±15.2 years; median National Institutes of Health Stroke Scale, 7). Approximately 60% of the patients were able to stand. On average the mean arterial pressure increased when patients moved from the supine to sitting (Day 1: Δ 3.9 mm Hg; P<0.001) and from sitting to an active standing position (Day 1: Δ 4.6 mm Hg; P<0.001). Changes were most pronounced within the first 24 hours after a stroke. Blood pressure decreased significantly (fall) on standing in 13% of patients and increased significantly (rise) in 20% of the patients. The latter was independently associated with a favorable outcome (P=0.003). Moving to the standing position was accompanied by an increase of heart rate. No difference in oxygen saturation was observed in the various positions over the period of investigation., Conclusions: We found that a significant blood pressure rise during early upright positioning in patients with acute stroke was independently associated with a favorable outcome. No contraindication to early mobilization was found in this study.

Background and Purpose: Insulin-like growth factor I (IGF-I) is neuroprotective in animal models of stroke. We investigated whether serum IGF-I levels in patients with acute ischemic stroke influence stroke severity and outcome., Methods: Concentrations of IGF-I and IGF binding protein 3 were measured in serum samples obtained within 6 hours after stroke onset from 255 patients who took part in the placebo arm of the United States and Canadian Lubeluzole in Acute Ischemic Stroke Study. Stroke severity was assessed with the National Institutes of Health Stroke Scale. Multivariate analysis was performed to assess the overall shift in modified Rankin Scale score and changes in the National Institutes of Health Stroke Scale score at 3 months. Survival curves were plotted using the Kaplan-Meier method, and the Cox proportional hazard model was used for multivariate analysis to investigate factors influencing survival., Results: After controlling for statistically relevant risk factors, subjects with high IGF-I levels or IGF-I/IGF binding protein 3 ratios had a better neurological and functional outcome at 3 months. Baseline stroke severity was not different between high and low IGF-I groups. In contrast to the low IGF-I group, neurological symptoms gradually improved from Day 3 in the high IGF-I group., Conclusions: Our results suggest that high serum IGF-I levels just after ischemic stroke onset are associated with neurological recovery and a better functional outcome.

Background: Preliminary findings suggest that statins may have a neuroprotective effect in patients with acute ischaemic stroke. This study investigated whether patients on prior statin therapy and treated with tissue plasminogen activator (tPA) for acute ischaemic stroke have a better functional outcome than statin-naïve patients., Methods: In a prospective observational cohort study of 476 acute ischaemic stroke patients treated with tPA we investigated the relationship between prior statin use and functional outcome at 3 months, the occurrence of symptomatic intracerebral haemorrhage (SICH) and early in-hospital mortality. Ischaemic stroke subtypes were defined according to the TOAST classification. Favourable outcome was defined as a modified Rankin Scale score < or =2., Results: Of the 476 patients included, 98 (20.6%) used a statin at stroke presentation. In the entire cohort, 45.6% of patients had a favourable outcome with no difference between patients with or without statin therapy (45.9 vs. 45.5%, p = 0.94). In the multivariable analysis, statin use was not associated with favourable outcome (OR = 1.1, 95% CI = 0.6-1.9, p = 0.87). In none of the different stroke subtype groups was statin use associated with favourable outcome. Finally, statin use was not an independent risk factor of SICH or of early in-hospital mortality., Conclusion: Prior statin therapy in patients with acute ischaemic stroke treated with tPA is not associated with a more favourable outcome, and this is independent of stroke subtype., (Copyright 2010 S. Karger AG, Basel.)

Background and Purpose: Insulin-like growth factor I (IGF-I) exerts neuroprotective effects in both white and gray matter under different detrimental conditions. The purpose of this review is to collect the evidence whether IGF-I is a candidate neuroprotective drug in patients with acute ischemic stroke., Results: IGF-I was found to be neuroprotective in animal models of focal brain ischemia when given >or=2 hours after the insult. Different routes of administration (eg, cerebroventricular, intravenous, and intranasal) were found to be effective. In addition to inhibition of apoptosis and reduction of the infarct volume, IGF-I also improved neurological outcome. Furthermore, there are strong indications that IGF-I can also stimulate the regeneration of neural tissue., Conclusions: Additional studies are required to reveal the neuroprotective mechanisms of IGF-I in detail and to elucidate the role of IGF-binding proteins. Preclinical studies in relevant animal models for studying stroke (ie, hypertensive, diabetic, or aged animals) should be done testing different doses and routes of IGF-I administration and different combinations of IGF-I and IGF-binding proteins.

In the last decennium, thrombolytic therapy has changed the management of acute ischemic stroke. Randomized clinical studies have demonstrated that intravenous thrombolysis with tissue plasminogen activator improves functional outcomes. Recently the time window for intravenous thrombolysis has been extended from 3 to 4.5 hours after stroke onset, which will allow more stroke patients to benefit from this treatment. Currently several studies are investigating how to improve recanalization rates of thrombolytic therapy. In this review several aspects of intravenous and intra-arterial thrombolysis are discussed.

Objective: The goal of this study was to evaluate the utility of the stroke thrombolytic predictive instrument (s-TPI) in predicting clinical outcome in patients with acute ischaemic stroke treated with intravenous tissue plasminogen activator (t-PA)., Methods: The study assessed the external validity of the s-TPI in 301 consecutive stroke patients treated with intravenous t-PA. Clinical outcome was measured with the modified Rankin scale (mRs) at 3 months. The study used the s-TPI to calculate probabilities of a good outcome (mRs 0-1) and a poor outcome (mRs 5-6). We compared these probabilities with the observed outcome using receiver-operator characteristics (ROC) curves and calibration curves. Subgroup analyses for different onset-to-treatment time windows were performed., Results: According to the s-TPI, the mean predicted probability of a good and a poor outcome in the validation cohort were 0.45 and 0.17. The area under the ROC curves were 0.80 (4.5-hour time window), 0.82 (3-hour time window) and 0.77 (3-4.5 hours time window) for predicting good outcome, and 0.78 (4.5 hours), 0.80 (3 hours) and 0.74 (3-4.5 hours) for predicting poor outcome. Calibration curves revealed a slight overestimation of probabilities of a good outcome and underestimation of probabilities of a poor outcome., Conclusions: The s-TPI appears to be reasonably valid for predicting outcome after t-PA treatment in daily practice, although a slight overestimation of a good and underestimation of a poor outcome was observed.

Headache with neurologic deficits and cerebrospinal fluid lymphocytosis is a benign condition with a transient ischemic attack-like presentation. We present a case of a 22-year-old man with episodes of right-sided weakness, global dysphasia, and right-sided homonymous hemianopsia associated with frequent vomiting. Systemic thrombolytic therapy was considered. A subsequent magnetic resonance image with diffusion-weighted images revealed normal findings. A diagnosis of headache with neurologic deficits and cerebrospinal fluid lymphocytosis was made based mainly on clinical symptoms and cerebrospinal fluid analysis. With the current pressure on "door-to-needle" time for thrombolysis, it is important to keep an open eye to stroke mimics and exclude them if possible. We, therefore, strongly advise considering noninvasive magnetic resonance diffusion-weighted imaging in patients with unusual presentations (e.g., the vomiting in our patient) before thrombolysis.

Background: Low cholesterol levels have been associated with an increased risk of haemorrhagic stroke. This study investigated whether lipid levels or prior statin use influence outcome in patients with acute ischaemic stroke treated with IV thrombolysis., Methods: The relation between admission lipid levels or statin use and both the development of symptomatic intracerebral haemorrhage (sICH) and 3-months functional outcome was assessed in a prospective hospital-based stroke registry comprising 252 patients treated with IV tissue plasminogen activator (tPA). The fasting status of the patients was unknown. Favourable outcome at 3 months was defined as a modified Rankin scale score

Background: There is some uncertainty whether prior use of antiplatelet (AP) drugs increases the risk of symptomatic intracerebral hemorrhage (SICH) and influences functional outcome in patients with ischemic stroke treated with intravenous thrombolysis., Objective: To assess whether prior use of AP drugs is related to outcome following intravenous tissue plasminogen activator therapy in patients with ischemic stroke., Design, Setting, and Patients: A single-center prospective observational cohort study of the relation between prior AP therapy, occurrence of SICH, and functional outcome of consecutive patients with ischemic stroke undergoing intravenous thrombolysis with tissue plasminogen activator in a university hospital between April 1, 2002, and November 30, 2006., Main Outcome Measures: The occurrence of SICH and favorable outcome reflecting independence defined as a modified Rankin Scale score of 2 or lower at 3 months., Results: Of the 301 patients who received intravenous tissue plasminogen activator, 89 used AP drugs prior to thrombolysis. Symptomatic intracerebral hemorrhage occurred in 12 patients (13.5%; 95% confidence interval, 7.8%-22.3%) who had received AP drugs and in 6 patients (2.8%; 95% confidence interval, 1.2%-6.2%) without prior AP therapy (P = .001). Multivariate analysis revealed that prior AP therapy was an independent predictor of SICH (odds ratio, 6.0; 95% confidence interval, 2.0-17.1). Nonetheless, prior AP therapy was independently associated with a favorable outcome (odds ratio, 2.0; 95% confidence interval, 1.0-4.3)., Conclusion: Despite a higher incidence of SICH, the net benefit of intravenous tissue plasminogen activator therapy for acute ischemic stroke was greater in patients using AP drugs.

Background: The administration of tissue plasminogen activator (t-PA) has been proven effective for ischemic stroke within 3 h after onset. A pooled-analysis of six trials showed that intravenous t-PA still improves outcome when given between 3 to 4.5 h after stroke onset. On the basis of this pooled analysis, t-PA was also routinely offered to our patients between 3-4.5 h. We report the safety and clinical features of this group together with the features of the group given t-PA within 3 h., Methods: Prospectively patient characteristics, stroke severity, stroke subtype, incidence of symptomatic intracerebral hemorrhage (SICH), in-hospital mortality, and 3-months modified Rankin Scale scores (mRS) were registered. Data was analyzed separately for patients treated within 3 h (early group) and those treated between 3-4.5 h (late group)., Results: Among 176 patients who underwent intravenous thrombolysis, 101 were treated in the early group and 75 in the late group. Six (5.9%; 95% CI 2.8%-12.3%) patients in the early group and 4 (5.3%; 95% CI 2.2%-12.9%) in the late group developed SICH (p=1.0). In the early group 13 (12.9%; 95% CI 7.7%-20.8%) patients died within 7 days after admission, compared to 5 (6.7%; 95% CI 3.0%-14.7%) in the late group (p=0.179). In the early group 44 (43.6%; 95% CI 43.3%-53.3%) were independent (mRS< or =2) at three months, compared to 36 (48.0%; 95% CI 37.0%-59.1%) in the late group (p=0.559)., Conclusion: Our data show no trend of decreased safety of thrombolysis beyond 3 h. Due to a small sample size a harmful effect cannot be excluded but seems unlikely.

Background and Purpose: ZK 200775 is a selective competitive AMPA receptor antagonist. It has demonstrated neuroprotective efficacy in experimental models of stroke and tolerability in healthy volunteers. We tested the safety and tolerability of ZK 200775 in patients with acute ischaemic stroke., Methods: In a multicentre double-blind, randomised, placebo-controlled phase II trial, 61 ischaemic stroke patients were treated with either placebo or active drug in a dose finding design. Twenty-five patients received placebo, 12 patients received a total dose of 262.5 mg in 48 h (group 1) and 13 patients received a total dose of 525 mg in 48 h (group 2), and 11 patients received a total dose of 105 mg over a period of 6 h (group 3). We studied the pharmacokinetics of the compound and the effect of the infusion on the neurologic and haemodynamic parameters of the patients. The study was not powered to detect neuroprotective efficacy., Results: In group 2 there was a significant transient worsening in the mean NIH stroke scale score 14- 18 h after the start of treatment. This was due to reduction of consciousness (stupor and coma) in 8 out of 13 patients. Level of consciousness improved approximately 6 h after cessation of infusion. No significant haemodynamic responses were observed. Even after reduction of the administered dose and duration of infusion to 6 h (group 3), 2 patients experienced a reduction in level of consciousness. The effect of ZK 200775 on level of consciousness gave cause for concern and the trial was stopped prematurely for safety reasons., Conclusions: The AMPA antagonist ZK 200775 reversibly worsened the neurological condition in patients with acute ischaemic stroke. Our results suggest that ZK 200775 exerts significant sedative effects in patients with acute stroke which preclude its further development as a neuroprotective agent in this indication., (Copyright 2005 S. Karger AG, Basel.)

Background and Purpose: Pathophysiological considerations and observational studies indicate that elevated body temperature, hypoxia, hypotension, and cardiac arrhythmias in the acute phase of ischemic stroke may aggravate brain damage and worsen outcome., Methods: Both units were organized with the same standard care and multidisciplinary approach to nursing and rehabilitation. A blinded observer assessed functional outcome at 3 months with the modified Rankin scale (mRS) and Barthel Index (BI). End points were (1) poor outcome, defined as either mRS > or =4 or BI <60 or the need for institutional care and (2) mortality., Results: Fifty-four patients meeting the inclusion criteria were randomized. The groups were well matched for baseline characteristics, stroke subtype, stroke severity, vascular risk factors, and prognostic factors. Poor outcome was seen in 7 (25.9%) patients in the SCMU group and in 13 (48.1%) in the SU group (P=0.16). Mortality was lower in the SCMU group than in the SU group (1 [3.7%] vs 7 [25.9%]; odds ratio, 0.11 [95% CI, 0.02 to 0.96], P=0.05)., Conclusions: This pilot study suggests that admission of acute stroke patients to an SCMU may reduce mortality and poor outcome. A larger trial is required to confirm these findings.

Background and Purpose: S-100B and neuron-specific enolase (NSE) serum concentrations can be used as peripheral markers of glial cell and neuronal damage, respectively. We investigated these markers in a clinical trial with the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) antagonist ZK200775 in acute ischemic stroke patients., Methods: In a multicenter, double-blind, randomized, placebo-controlled phase 2 trial, 61 ischemic stroke patients were treated with either placebo or active drug in a dose-finding design. Twenty-five patients received placebo, 12 patients received a total dose of 262.5 mg in 48 hours (dose group 1), and 13 patients received a total dose of 525 mg in 48 hours (dose group 2). Eleven patients received a total dose of 105 mg over a period of 6 hours (dose group 3; reduction of total dose and infusion time because of adverse events in group 2). Serum concentrations of S-100B and NSE were analyzed with the use of a monoclonal sandwich immunoluminometric assay. Neurological outcome was assessed with the National Institutes of Health Stroke Scale (NIHSS)., Results: In group 2 there was a significant transient worsening in the mean NIHSS score 48 hours after the start of treatment. The mean increase was 11 points. This was due to reduction of consciousness (stupor and coma) in 8 of 13 patients. Neurological deterioration in group 2 was associated with a higher increase of S-100B concentrations, but not of NSE concentrations, than in the placebo group. The trial was stopped prematurely for safety reasons., Conclusions: The AMPA antagonist ZK200775 transiently worsened the neurological condition in patients with acute ischemic stroke. Our results suggest that in addition to neuronal dysfunction, glial cell toxicity may have occurred. It may be useful to introduce monitoring of serum markers of brain damage in phase 2 trials with glutamate receptor antagonists.

Ischaemic stroke is a leading cause of death and long-lasting disability. Several neuroprotective drugs have been developed that have the potential to limit ischaemic brain damage and improve outcome for patients. While promising results with these drugs have been achieved in animal stroke models, all Phase III trials conducted so far indicate that these drugs have failed to live up to their promise. Despite the limits of animal models, which cannot mimic the clinical situation, the disappointing results of neuroprotective trials might largely be due to methodological problems. Future trials with neuroprotective drugs should be performed in stroke (care) units, after sufficient information regarding therapeutic time window, dosage, duration of therapy and safety has been gathered from pilot studies, and a better selection of target patients has been made. Much of this information can now be obtained by techniques that visualize the penumbra, such as combined diffusion-weighted and perfusion MRI. Consideration should also be given to clinical trials with well-designed combinations of treatments.

Over the past few years there have been enormous changes in the management of stroke patients. General practitioners, ambulance personnel/paramedics and the general public need to be well informed that stroke is a medical emergency. Prevention of secondary brain damage by normalising vital parameters and combating fever should already start at the scene or in the ambulance. Early recognition of stroke symptoms, immediate transfer to a suitable treatment facility, and rapid in hospital triage protocols should bring thrombolysis to a larger number of stroke victims. Admission to a unit that is dedicated to the care of stroke patients helps to reduce mortality and morbidity.

Background and Purpose: The Barthel Index (BI) and the Modified Rankin Scale (MRS) are commonly used scales that measure disability or dependence in activities of daily living in stroke victims. The objective of this study was to investigate how these scales were used and interpreted in acute stroke trials., Methods: We identified from MEDLINE the major efficacy trials with neuroprotective drugs, thrombolytic drugs, and anticoagulants in acute ischemic stroke published between January 1995 and December 1998. We selected those trials that used the BI and/or MRS as outcome parameters., Results: Fifteen trials fulfilling the inclusion criteria were identified. The BI was used in 13 and the MRS in 8. In 4 trials mean and median scores of the BI were used, and in 1 trial median scores of the MRS were compared. Primary end points included the BI in 7, the MRS in 6, and both the BI and MRS in 3. With regard to the BI, a variety of sum scores between 50 and 95 were used as cutoff scores to define favorable outcome. Favorable outcome on the MRS was defined as either 3, or BI <60.

A detrimental effect of hyperglycemia in ischemic brain has been demonstrated in laboratory experiments and it has been found that hyperglycemia in ischemic stroke is a predictor of poor outcome. We determined serum neuron specific enolase (NSE) concentrations in 41 consecutive patients with a cerebral hemispheric stroke between 12 and 24 h after stroke onset. In cortical ischemic strokes complicated by hyperglycemia (blood glucose concentration > 7 mmol/l) we found significantly higher NSE levels than in normoglycemic patients. In lacunar ischemic strokes NSE levels were not significantly different between normoglycemic and hyperglycemic patients. Our findings support the concept that hyperglycemia during acute cortical ischemic stroke is associated with enhanced neuronal cell death.

Aspirin reduces the occurrence of ischemic strokes. In some prophylactic trials it was suggested that aspirin might also lessen stroke severity, and hence improve outcome in patients sustaining an ischemic stroke. We examined stroke severity (by using the Mathew scale) and early outcome (Barthel index and mortality on day 21) in 91 patients with an acute (< 24 h) ischemic stroke in the territory of the middle cerebral artery. Twenty-seven patients were taking low-dose aspirin (100 or 200 mg/day) prior to their stroke, and 64 were not using antiplatelet drugs. There were no significant differences in baseline stroke severity, early (21 days) mortality or early disability between the two groups. The results of this small study suggest that the use of low-dose aspirin prior to an ischemic stroke does not influence the severity of that stroke and early outcome.

Background and Purpose: We aimed to assess the safety and efficacy of lubeluzole in patients with a clinical diagnosis of acute (< 6 hours) ischemic stroke in the carotid artery territory., Methods: A randomized, double-blind, placebo-controlled multicenter trial was conducted in 232 patients. Because treatment was administered within 6 hours and a CT scan was not mandatory before the start of treatment, 39 patients with either an intracerebral hemorrhage or ischemic stroke in the vertebrobasilar circulation were excluded from the primary efficacy analysis as prespecified in the protocol. Of the 193 patients with acute ischemic stroke in the carotid artery territory (target population), 61 received placebo, 66 lubeluzole 7.5 mg over 1 hour followed by 10 mg/d for 5 days, and 66 lubeluzole 15 mg over 1 hour followed by 20 mg/d for 5 days., Results: The trial, initially aimed at a patient inclusion of 270, was terminated prematurely according to the advice of the Safety Committee because of an imbalance in mortality between the treatment groups. Mortality rates at the final follow-up of 28 days for placebo, lubeluzole 10 mg/d, and lubeluzole 20 mg/d were, respectively, 18%, 6%, and 35% in the target population, results that were confirmed in the intent-to-treat population. Multivariate logistic regression analysis showed that the lower mortality in the lubeluzole 10 mg/d group was significantly in favor of the 10 mg/d treatment (P = .019). The higher mortality rate in the 20 mg/d group could be explained, at least in part, by an imbalance at randomization that led to a higher number of patients in that group with severe ischemic stroke. A total of 26 of 66 patients (39%) who received lubeluzole 10 mg/d had a score on the Barthel Index of > 70 at day 28, indicating no or mild disability, compared with 21 of 61 (34%) in the placebo group and 19 of 66 (29%) in the lubeluzole 20 mg/d group (P = NS)., Conclusions: In patients with acute ischemic stroke, the dosage regimen of 7.5 mg over 1 hour followed by 10 mg/d of intravenous lubeluzole is safe and statistically significantly reduced mortality. Further clinical trials in a larger number of patients are ongoing to confirm efficacy.