Piero Verro

Gene expression in blood changes rapidly in neutrophils and monocytes after ischemic stroke in humans: a microarray study.

Ischemic brain and peripheral white blood cells release cytokines, chemokines and other molecules that activate the peripheral white blood cells after stroke. To assess gene expression in these peripheral white blood cells, whole blood was examined using oligonucleotide microarrays in 15 patients at 2.4 ± 0.5, 5 and 24 h after onset of ischemic stroke and compared with control blood samples. The 2.4 h blood samples were drawn before patients were treated either with tissue-type plasminogen activator (tPA) alone or with tPA plus Eptifibatide (the Combination approach to Lysis utilizing Eptifibatide And Recombinant tPA trial). Most genes induced in whole blood at 2 to 3 h were also induced at 5 and 24 h. Separate studies showed that the genes induced at 2 to 24 h after stroke were expressed mainly by polymorphonuclear leukocytes and to a lesser degree by monocytes. These genes included: matrix metalloproteinase 9; S100 calcium-binding proteins P, A12 and A9; coagulation factor V; arginase I; carbonic anhydrase IV; lymphocyte antigen 96 (cluster of differentiation (CD)96); monocarboxylic acid transporter (6); ets-2 (erythroblastosis virus E26 oncogene homolog 2); homeobox gene Hox 1.11; cytoskeleton-associated protein 4; N-formylpeptide receptor; ribonuclease-2; N-acetylneuraminate pyruvate lyase; BCL6; glycogen phosphorylase. The fold change of these genes varied from 1.6 to 6.8 and these 18 genes correctly classified 10/15 patients at 2.4 h, 13/15 patients at 5h and 15/15 patients at 24 h after stroke. These data provide insights into the inflammatory responses after stroke in humans, and should be helpful in diagnosis, understanding etiology and pathogenesis, and guiding acute treatment and development of new treatments for stroke.

Initial clinical experience with IV tissue plasminogen activator for acute ischemic stroke: A multicenter survey

Article abstract We assessed initial clinical experience with IV tissue plasminogen activator (t-PA) treatment of acute ischemic stroke in a standardized retrospective survey of hospitals with experienced acute stroke treatment systems. The incidence of symptomatic intracerebral hemorrhage (ICH) was 6% (11 of 189 patients; 95% CI 3 to 11%), similar to that in the National Institute of Neurological Disorders and Stroke (NINDS) t-PA Stroke Study. Deviations from the NINDS protocol guidelines were identified in 30% of patients (56 of 189). The incidence of symptomatic ICH was 11% among patients with protocol deviations as compared with 4% in patients who were treated according to the NINDS protocol guidelines, suggesting that strict adherence to protocol guidelines is prudent.

Intravenous tissue plasminogen activator for acute ischemic stroke in patients aged 80 years and older: The tPA stroke survey experience

BACKGROUND AND PURPOSE Intravenous tissue plasminogen activator (tPA) administered within 3 hours of symptom onset is the first available effective therapy for acute ischemic stroke (AIS). Few data exist, however, on its use in very elderly patients. We examined the characteristics, complications, and short-term outcome of AIS patients aged >/=80 years treated with tPA. METHODS Patients aged >/=80 years (n=30) were compared with counterparts aged <80 years (n=159) included in the tPA Stroke Survey, a US retrospective survey of 189 consecutive AIS patients treated with intravenous tPA at 13 hospitals. RESULTS Risk of intracerebral hemorrhage (fatal, symptomatic, and total) was 3%, 3%, and 7% in the elderly age group and 2%, 6%, and 9%, respectively, in their younger counterparts (P=NS for all comparisons). Likelihood of favorable outcome, defined as modified Rankin score 0 to 1, National Institutes of Health Stroke Scale score </=5, or marked improvement by hospital discharge, was comparable between groups (37%, 54%, and 43% versus 30%, 54%, and 43%, respectively; P=NS for all comparisons). Elderly patients were more likely to be treated by stroke specialists (87% versus 60%; P=0.005) and less likely to have an identified protocol deviation (13% versus 33%; P=0.03). Elderly patients were discharged more often to nursing care facilities (17% versus 5%; P=0.003). In logistic regression models there were no differences in odds ratio for favorable or poor outcome, other than tendency for higher in-hospital mortality in elderly patients (odds ratio, 2.8; 95% CI, 0.81 to 9.62; P=0.10). CONCLUSIONS Among AIS patients treated with intravenous tPA, age-related differences in characteristics and disposition were identified. No evidence for withholding tPA treatment for AIS in appropriately selected patients aged >/=80 years was identified.

Aspirin Plus Dipyridamole Versus Aspirin for Prevention of Vascular Events After Stroke or TIA: A Meta-Analysis

Background and Purpose— This meta-analysis systematically reviewed randomized controlled trials comparing aspirin plus dipyridamole with aspirin alone in patients with stroke and TIA to determine the efficacy of these agents in preventing recurrent cerebral and systemic vascular events. Methods— We performed separate analyses of the incidences of stroke alone and composite outcome of stroke, myocardial infarction, or vascular death. We also performed two subset analyses, planned a priori, to examine effect size based on trials using (1) exclusively immediate-release and (2) predominantly extended-release dipyridamole. Results— The summary results indicate a significant reduction in the overall risk ratio in favor of aspirin plus dipyridamole for stroke alone with relative risk 0.77 (0.67 to 0.89) and the composite end point with relative risk 0.85 (0.76 to 0.94). Studies using immediate-release dipyridamole showed a nonstatistically significant trend in favor of the combination for stroke alone with relative risk 0.83 (0.59 to 1.15) and for the composite outcome with relative risk 0.95 (0.75 to 1.19). Studies using predominantly extended-release dipyridamole showed a statistically significant difference in favor of the combination for stroke alone with relative risk 0.76 (0.65 to 0.89) and for the composite outcome with relative risk 0.82 (0.73 to 0.92). Conclusions— The combination of aspirin plus dipyridamole is more effective than aspirin alone in preventing stroke and other serious vascular events in patients with minor stroke and TIAs. The risk reduction was greater and statistically significant for studies using primarily extended release dipyridamole, which may reflect a true pharmacological effect or lack of statistical power in studies using immediate release dipyridamole.

Hyperdense middle cerebral artery sign: can it be used to select intra-arterial versus intravenous thrombolysis in acute ischemic stroke?

Background: Stroke patients with a hyperdense middle cerebral artery sign (HMCAS) may respond less favorably to intravenous (IV) thrombolysis. Objective: To compare outcomes of patients with and without early CT findings treated with IV versus intra-arterial (IA) recombinant tissue plasminogen activator (rtPA). Methods: Initial and 24-hour CT scans of the head were evaluated in 83 consecutive stroke patients (66 on IV rtPA, 17 on IA rtPA). Time permitting, a CT angiogram was performed immediately after the initial CT scan to ascertain major cerebral artery occlusion. Demographics and etiological stroke subtype, times to thrombolysis and CT scan, baseline (prethrombolysis) and 24-hour National Institutes of Health stroke scale (NIHSS) score, discharge NIHSS score and 90-day modified Rankin scale (mRS) were recorded. The initial CT of these patients was examined for early signs of stroke. The 24-hour scan was reviewed for the presence of infarct, hemorrhage and persistence of HCMAS. Results: A favorable outcome, indicated by a significant improvement in the discharge NIHSS score, was noted with IA rtPA, irrespective of the presence (p = 0.001) or absence (p = 0.01) of HCMAS. A less favorable outcome in discharge NIHSS score was noted with IV rtPA in patients with HCMAS (p = not significant) than those without the sign (p < 0.001). A similar proportion of patients with HCMAS exhibited a neurological improvement at 24 h as those without the sign in the IA rtPA group (p = 0.9). However, a smaller proportion of patients with HCMAS exhibited a neurological improvement at 24 h than those without the sign in the IV rtPA group (p = 0.005). The results were similar using 90-day mRS ≤1 as an indicator of significant persistent improvement (p = 1.0 for IA rtPA and 0.04 for IV rtPA group). Conclusions: In a small sample, patients with HMCAS appeared to respond better to IA than IV rtPA.

Gene Expression in Peripheral Blood Differs after Cardioembolic Compared with Large-Vessel Atherosclerotic Stroke: Biomarkers for the Etiology of Ischemic Stroke

There are no biomarkers that differentiate cardioembolic from large-vessel atherosclerotic stroke, although the treatments differ for each and ~30% of strokes and transient ischemic attacks have undetermined etiologies using current clinical criteria. We aimed to define gene expression profiles in blood that differentiate cardioembolic from large-vessel atherosclerotic stroke. Peripheral blood samples were obtained from healthy controls and acute ischemic stroke patients (< 3, 5, and 24 h). RNA was purified, labeled, and applied to Affymetrix Human U133 Plus 2.0 Arrays. Expression profiles in the blood of cardioembolic stroke patients are distinctive from those of large-vessel atherosclerotic stroke patients. Seventy-seven genes differ at least 1.5-fold between them, and a minimum number of 23 genes differentiate the two types of stroke with at least 95.2% specificity and 95.2% sensitivity for each. Genes regulated in large-vessel atherosclerotic stroke are expressed in platelets and monocytes and modulate hemostasis. Genes regulated in cardioembolic stroke are expressed in neutrophils and modulate immune responses to infectious stimuli. This new method can be used to predict whether a stroke of unknown etiology was because of cardioembolism or large-vessel atherosclerosis that would lead to different therapy. These results have wide ranging implications for similar disorders.

Signatures of cardioembolic and large-vessel ischemic stroke.

The cause of stroke remains unknown or cryptogenic in many patients. We sought to determine whether gene expression signatures in blood can distinguish between cardioembolic and large‐vessel causes of stroke, and whether these profiles can predict stroke etiology in the cryptogenic group.

Prediction of Cardioembolic, Arterial, and Lacunar Causes of Cryptogenic Stroke by Gene Expression and Infarct Location

Background and Purpose— The cause of ischemic stroke remains unclear, or cryptogenic, in as many as 35% of patients with stroke. Not knowing the cause of stroke restricts optimal implementation of prevention therapy and limits stroke research. We demonstrate how gene expression profiles in blood can be used in conjunction with a measure of infarct location on neuroimaging to predict a probable cause in cryptogenic stroke. Methods— The cause of cryptogenic stroke was predicted using previously described profiles of differentially expressed genes characteristic of patients with cardioembolic, arterial, and lacunar stroke. RNA was isolated from peripheral blood of 131 cryptogenic strokes and compared with profiles derived from 149 strokes of known cause. Each sample was run on Affymetrix U133 Plus 2.0 microarrays. Cause of cryptogenic stroke was predicted using gene expression in blood and infarct location. Results— Cryptogenic strokes were predicted to be 58% cardioembolic, 18% arterial, 12% lacunar, and 12% unclear etiology. Cryptogenic stroke of predicted cardioembolic etiology had more prior myocardial infarction and higher CHA2DS2-VASc scores compared with stroke of predicted arterial etiology. Predicted lacunar strokes had higher systolic and diastolic blood pressures and lower National Institutes of Health Stroke Scale compared with predicted arterial and cardioembolic strokes. Cryptogenic strokes of unclear predicted etiology were less likely to have a prior transient ischemic attack or ischemic stroke. Conclusions— Gene expression in conjunction with a measure of infarct location can predict a probable cause in cryptogenic strokes. Predicted groups require further evaluation to determine whether relevant clinical, imaging, or therapeutic differences exist for each group.

Computed Tomographic Parameters Predicting Fatal Outcome in Large Middle Cerebral Artery Infarction

Background: Large middle cerebral artery (MCA) ischaemic stroke when associated with extensive mass effect can result in brain herniation and neurological death. As yet there are few guidelines to aid the selection of patients for aggressive interventional therapies, such as decompression hemicraniectomy and/or hypothermia. Methods: We studied a cohort of patients from seven centres with large MCA infarction requiring neurocritical care. The purpose of this analysis was to assess the use of early radiological signs on follow-up computed tomographic (CT) signs performed within 48 h of stroke onset for predicting mortality at 30 days. The CT parameters assessed included horizontal displacement of the septum pellucidum, pineal shift, complete or partial infarction of the temporal lobe, involvement of additional vascular territories, and the presence of hydrocephalus. The primary outcome measure was in-hospital death within 30 days. Results: One hundred and thirty-five patients who had follow-up CT scans within 48 h were identified from a total of 201 patients with large MCA infarction that received conventional medical therapy alone. The median age was 68 (range 29–99), 56% were female, and the median NIHSS category was 26–30 at 48 h. Among CT variables in univariable analysis, anteroseptal shift ≧5 mm, pineal shift ≧2 mm, complete temporal lobe infarction, involvement beyond the MCA territory, and moderate or severe hydrocephalus were equally predictive of death. Multivariable analysis adjusting for time to CT scan revealed the following predictors of fatal outcome: anteroseptal shift ≧5 mm (OR 10.9; 95% CI 3.2–37.6), NIHSS within 48 h >20 (OR 6.6; 95% CI 2.3–19.3), and infarction beyond the MCA territory (OR 4.9; 95% CI 1.6–15.0). Conclusions: We identified the role of early CT signs in predicting death following massive MCA infarction. The CT parameters anteroseptal shift (>5 versus ≤5 mm), pineal shift ≧2 mm, hydrocephalus, temporal lobe infarction, and other vascular territory infarction if present were predictive of fatal outcome. These CT parameters require prospective validation before they should be considered reliable markers for decision-making.

Hemicraniectomy and Durotomy Upon Deterioration From Infarction-Related Swelling Trial: Randomized Pilot Clinical Trial

Background and Purpose— Hemicraniectomy and Durotomy Upon Deterioration From Infarction-Related Swelling Trial (HeADDFIRST) was a randomized pilot study to obtain information necessary to design a Phase III trial to evaluate the benefit of surgical decompression for brain swelling from large supratentorial cerebral hemispheric infarction. Methods— All patients with stroke were screened for eligibility (age 18–75 years, National Institutes of Health Stroke Scale ≥18 with Item 1a<2 [responsive to minor stimulation], and CT demonstrating unilateral, complete middle cerebral artery territory infarction by specific imaging criteria). All enrolled patients were treated using a standardized medical treatment protocol. Those with both ≥4 mm of pineal shift and deterioration in level of arousal or ≥7.5 mm of anteroseptal shift within 96 hours of stroke onset were randomized to continued medical treatment only or medical treatment plus surgery. Death at 21 days was the primary outcome measure. Results— Among 4909 screened patients, only 66 (1.3%) patients were eligible for HeADDFIRST. Forty patients were enrolled, and 26 patients developed the requisite brain swelling for randomization. All who failed to meet randomization criteria were alive at 21 days. Mortality at 21 and 180 days was 40% (4/10) in the medical treatment only and 21% (3/14) and 36% (5/14) in the medical treatment plus surgery arms, respectively. Conclusions— HeADDFIRST randomization criteria effectively distinguished low from high risk of death from large supratentorial cerebral hemispheric infarction. Lower mortality in the medical treatment only group than in other published trials suggests a possible benefit to standardizing medical management. These results can inform the interpretation of recently completed European trials concerning patient selection and medical management. Clinical Trial Registration— This trial was not registered because enrollment began before July 1, 2005.