Maurizio Paciaroni

Effect of a Novel Free Radical Scavenger, Edaravone (MCI-186), on Acute Brain Infarction

Edaravone, a novel free radical scavenger, demonstrates neuroprotective effects by inhibiting vascular endothelial cell injury and ameliorating neuronal damage in ischemic brain models. The present study was undertaken to verify its therapeutic efficacy following acute ischemic stroke. We performed a multicenter, randomized, placebo-controlled, double-blind study on acute ischemic stroke patients commencing within 72 h of onset. Edaravone was infused at a dose of 30 mg, twice a day, for 14 days. At discharge within 3 months or at 3 months after onset, the functional outcome was evaluated using the modified Rankin Scale. Two hundred and fifty-two patients were initially enrolled. Of these, 125 were allocated to the edaravone group and 125 to the placebo group for analysis. Two patients were excluded because of subarachnoid hemorrhage and disseminated intravascular coagulation. A significant improvement in functional outcome was observed in the edaravone group as evaluated by the modified Rankin Scale (p = 0.0382). Edaravone represents a neuroprotective agent which is potentially useful for treating acute ischemic stroke, since it can exert significant effects on functional outcome as compared with placebo.

Early Hemorrhagic Transformation of Brain Infarction: Rate, Predictive Factors, and Influence on Clinical Outcome Results of a Prospective Multicenter Study

Background and Purpose— Early hemorrhagic transformation (HT) is a complication of ischemic stroke but its effect on patient outcome is unclear. The aims of this study were to assess: (1) the rate of early HT in patients admitted for ischemic stroke, (2) the correlation between early HT and functional outcome at 3 months, and (3) the risk factors for early HT. Methods— Consecutive patients with ischemic stroke were included in this prospective study in 4 study centers. Early HT was assessed by CT examination performed at day 5±2 after stroke onset. Study outcomes were 3-month mortality or disability. Disability was assessed using a modified Rankin score (≥3 indicating disabling stroke) by neurologists unaware of the occurrence of HT in the individual cases. Outcomes in patients with and without early HT were compared by &khgr;2 test. Multiple logistic regression analysis was used to identify predictors for HT. Results— Among 1125 consecutive patients (median age 76.00 years), 98 (8.7%) had HT, 62 (5.5%) had hemorrhagic infarction, and 36 (3.2%) parenchymal hematoma. At 3 months, 455 patients (40.7%) were disabled or died. Death or disability was seen in 33 patients with parenchymal hematoma (91.7%), in 35 patients with hemorrhagic infarction (57.4%) as compared with 387 of the 1021 patients without HT (37.9%). At logistic regression analysis, parenchymal hematoma, but not hemorrhagic infarction, was independently associated with an increased risk for death or disability (OR 15.29; 95% CI 2.35 to 99.35). At logistic regression analysis, parenchymal hematoma was predicted by large lesions (OR 12.20, 95% CI 5.58 to 26.67), stroke attributable to cardioembolism (OR 5.25; 95% CI 2.27 to 12.14) or to other causes (OR 6.77; 95% CI 1.75 to 26.18), high levels of blood glucose (OR 1.01; 95% CI 1.00 to 1.01), and thrombolytic treatment (OR 3.54, 95% CI 1.04 to 11.95). Conclusions— Early HT occurs in about 9% of patients. Parenchymal hematoma, seen in about 3% of patients, is associated with an adverse outcome. Parenchymal hematoma was predicted by large lesions attributable to cardioembolism or other causes, high blood glucose, and treatment with thrombolysis.

Efficacy and Safety of Anticoagulant Treatment in Acute Cardioembolic Stroke A Meta-Analysis of Randomized Controlled Trials

Background and Purpose— The role of anticoagulant treatment for acute cardioembolic stroke is uncertain. We performed an updated meta-analysis of all randomized trials to obtain the best estimates of the efficacy and safety of anticoagulants for the initial treatment of acute cardioembolic stroke. Methods— Using electronic and manual searches of the literature, we identified randomized trials comparing anticoagulants (unfractionated heparin or low-molecular-weight heparin or heparinoids), started within 48 hours, with other treatments (aspirin or placebo) in patients with acute ischemic cardioembolic stroke. Two reviewers independently selected studies and extracted data on study design, quality, and clinical outcomes, including death or disability, all strokes, recurrent ischemic stroke, and cerebral symptomatic bleeding. Odds ratios for individual outcomes were calculated for each trial and data from all the trials were pooled using the Mantel-Haenszel method. Results— Seven trials, involving 4624 patients with acute cardioembolic stroke, met the criteria for inclusion. Compared with other treatments, anticoagulants were associated with a nonsignificant reduction in recurrent ischemic stroke within 7 to 14 days (3.0% versus 4.9%, odds ratio 0.68, 95% CI: 0.44 to 1.06, P=0.09, number needed to treat=53), a significant increase in symptomatic intracranial bleeding (2.5% versus 0.7%, odds ratio 2.89; 95% CI: 1.19 to 7.01, P=0.02, number needed to harm=55), and a similar rate of death or disability at final follow up (73.5% versus 73.8%, odds ratio 1.01; 95% CI: 0.82 to 1.24, P=0.9). Conclusions— Our findings indicate that in patients with acute cardioembolic stroke, early anticoagulation is associated with a nonsignificant reduction in recurrence of ischemic stroke, no substantial reduction in death and disability, and an increased intracranial bleeding.

Dysphagia following Stroke

Background: Dysphagia is common after stroke. We aimed to study the prognosis of dysphagia (assessed clinically) over the first 3 months after acute stroke and to determine whether specific neurovascular-anatomical sites were associated with swallowing dysfunction. Methods: We prospectively examined consecutive patients with acute first-ever stroke. The assessment of dysphagia was made using standardized clinical methods. The arterial territories involved were determined on CT/MRI. All patients were followed up for 3 months. Results: 34.7% of 406 patients had dysphagia. Dysphagia was more frequent in patients with hemorrhagic stroke (31/63 vs. 110/343; p = 0.01). In patients with ischemic stroke, the involvement of the arterial territory of the total middle cerebral artery was more frequently associated with dysphagia (28.2 vs. 2.2%; p < 0.0001). Multivariate analysis revealed that stroke mortality and disability were independently associated with dysphagia (p < 0.0001). Conclusions: The frequency of dysphagia was relatively high. Regarding anatomical-clinical correlation, the most important factor was the size rather than the location of the lesion. Dysphagia assessed clinically was a significant variable predicting death and disability at 90 days.

Medical Complications Associated With Carotid Endarterectomy

Background and Purpose—Carotid endarterectomy (CE) has been shown to be beneficial in patients with symptomatic high-grade (70% to 99%) internal carotid artery stenosis. To achieve this benefit, complications must be kept to a minimum. Complications not associated with the procedure itself, but related to medical conditions, have received little attention. Methods—Medical complications that occurred within 30 days after CE were recorded in 1415 patients with symptomatic stenosis (30% to 99%) of the internal carotid artery. They were compared with 1433 patients who received medical care alone. All patients were in the North American Symptomatic Carotid Endarterectomy Trial (NASCET). Results—One hundred fifteen patients (8.1%) had 142 medical complications: 14 (1%) myocardial infarctions, 101 (7.1%) other cardiovascular disorders, 11 (0.8%) respiratory complications, 6 (0.4%) transient confusions, and 10 (0.7%) other complications. Of the 142 complications, 69.7% were of short duration, and only 26.8% prolo...

The role of carotid artery stenting and carotid endarterectomy in cognitive performance: a systematic review.

Background and Purpose— Change in cognition is being increasingly recognized as an important outcome measure; however, the role of carotid revascularization on this issue remains to be determined. It is still under debate whether carotid artery stenting and carotid endarterectomy have the same influence on neuropsychological functions. Summary of Review— This article systematically reviews recent literature in an attempt to clarify this issue. A total of 32 papers reporting on neurocognition after carotid endarterectomy (n=25), carotid artery stenting (n=4), or carotid artery stenting versus carotid endarterectomy (n=3) were identified. The studies were different for many methodological factors, eg, sample size, type of patients and control group, statistical measure, type of test, timing of assessment, and so on. There was a lack of consensus in defining the improvement or impairment after either carotid artery stenting or carotid endarterectomy. Furthermore, there were nonuneqivocal results regarding the same domain of assessment (memory, visuomotor, attention). Based on available evidence, it is probable that carotid endarterectomy as well as carotid artery stenting do not change neuropsychological function “per se.” Conclusions— Assessment of cognition after carotid revascularization is probably influenced by many confounding factors such as learning effect, type of test, type of patients, and control group, which are often minimized in their importance. The role of carotid revascularization is to prevent stroke in patients with severe carotid stenosis as highlighted by previous large randomized trials. Although an effect of carotid revascularization on cognition could be missed as a consequence of underpowered studies included in this review, at this time, no prediction can be done regarding its repercussions on higher intellectual functions. Larger studies appropriately designed and powered to assess cognition after carotid revascularization might change this view.

Cryptogenic stroke: time to determine aetiology

Summary.  Strokes that remain without a definite cause even after extensive work‐up are classified as cryptogenic. These constitute about 30–40% of all strokes. Stroke aetiology may remain undetermined for the following reasons: (i) the cause of stroke is transitory or reversible and the diagnostic work‐out is not therefore performed at the appropriate time; (ii) all known causes of stroke are not fully investigated; (iii) some causes of stroke remain unknown. Recent studies have challenged the previous view that cryptogenic stroke is a relatively benign cerebrovascular event, and have shown that cryptogenic stroke is associated with a higher rate of recurrence and adverse outcome at long‐term follow‐up. The determination of stroke aetiology is a valuable procedure to avoid the risk of stroke recurrence, especially in young patients. In this review, we discuss new evidence on the aetiology of cryptogenic stroke, specifically focusing on patients with patent foramen ovale and atheroma of the aortic arch.

Early seizures in patients with acute stroke: frequency, predictive factors, and effect on clinical outcome.

Background Early seizure (ES) may complicate the clinical course of patients with acute stroke. The aim of this study was to assess the rate of and the predictive factors for ES as well the effects of ES on the clinical outcome at hospital discharge in patients with first-ever stroke. Patients and methods A total of 638 consecutive patients with first-ever stroke (543 ischemic, 95 hemorrhagic), admitted to our Stroke Unit, were included in this prospective study. ES were defined as seizures occurring within 7 days from acute stroke. Patients with history of epilepsy were excluded. Results Thirty-one patients (4.8%) had ES. Seizures were significantly more common in patients with cortical involvement, severe and large stroke, and in patient with cortical hemorrhagic transformation of ischemic stroke. ES was not associated with an increase in adverse outcome (mortality and disability). After multivariate analysis, hemorrhagic transformation resulted as an independent predictive factor for ES (OR = 6.5; 95% CI: 1.95–22.61; p = 0.003). Conclusion ES occur in about 5% of patients with acute stroke. In these patients hemorrhagic transformation is a predictive factor for ES. ES does not seem to be associated with an adverse outcome at hospital discharge after acute stroke.

Genetics of ischemic stroke, stroke-related risk factors, stroke precursors and treatments

Stroke remains a leading cause of death worldwide and the first cause of disability in the western world. Ischemic stroke (IS) accounts for almost 80% of the total cases of strokes and is a complex and multifactorial disease caused by the combination of vascular risk factors, environment and genetic factors. Investigations of the genetics of atherosclerosis and IS has greatly enhanced our knowledge of this complex multifactorial disease. In this article we sought to review common single-gene disorders relevant to IS, summarize candidate gene and genome-wide studies aimed at discovering genetic stroke risk factors and subclinical phenotypes, and to briefly discuss pharmacogenetics related to stroke treatments. Genetics of IS is, in fact, one of the most promising research frontiers and genetic testing may be helpful for novel drug discoveries as well as for appropriate drug and dose selection for treatment of patients with cerebrovascular disease.

The Concept of Ischemic Penumbra in Acute Stroke and Therapeutic Opportunities

Ischemic penumbra was first defined by Astrup in 1981 as perfused brain tissue at a level within the thresholds of functional impairment and morphological integrity, which has the capacity to recover if perfusion is improved. It exists, even for a short period of time in the center of ischemia, from which irreversible necrosis propagates to the neighboring tissues over time. Penumbra has become the focus of intense imaging research to differentiate it from infarction. Accurate detection of this ‘tissue at risk’ could be used to identify patients who would benefit most from acute treatment. Currently, recombinant tissue plasminogen activator (rtPA) is the only approved drug that has shown significant benefits in acute stroke patients when administered intravenously less than 4.5 h after stroke. However, its use is limited. Discrimination between infarct core and the surrounding potentially salvageable tissue is useful to better identify patients suitable for treatment. This can be achieved by positron emission tomography, single-photon-emission computed tomography, computed tomography perfusion scan and perfusion-weighted and diffusion-weighted magnetic resonance imaging. Identification of the penumbra might enable selective rtPA use in patients with large penumbras and small infarct cores, even beyond the 4.5-hour time window, where the penumbra may persist for more than 12 h. The purpose of this review was to describe neuroimaging modalities capable of identifying penumbra tissue so as to provide surrogate markers for new trials in acute ischemic stroke patients.