Methods— This clinical trial enrolled 522 patients with acute ischemic stroke in the middle cerebral artery territory (intent-to-treat population) with 460 patients treated as planned (per-protocol population). Within 6 hours of symptom onset, at 24 and 48 hours, EPO was infused intravenously (40 000 IU each). Systemic thrombolysis with recombinant tissue plasminogen activator was allowed and stratified for.

Results— Unexpectedly, a very high number of patients received recombinant tissue plasminogen activator (63.4%). On analysis of total intent-to-treat and per-protocol populations, neither primary outcome Barthel Index on Day 90 (P=0.45) nor any of the other outcome parameters showed favorable effects of EPO. There was an overall death rate of 16.4% (n=42 of 256) in the EPO and 9.0% (n=24 of 266) in the placebo group (OR, 1.98; 95% CI, 1.16 to 3.38; P=0.01) without any particular mechanism of death unexpected after stroke.

Conclusions— Based on analysis of total intent-to-treat and per-protocol populations only, this is a negative trial that also raises safety concerns, particularly in patients receiving systemic thrombolysis.

Methods— This study was a prospective, randomized, controlled trial with a blinded neurologic outcome evaluation comparison between prophylactic, catheter-based normothermia (CoolGard; ie, body core temperature 36.5°C) and conventional, stepwise fever management with anti-inflammatory drugs and surface cooling. Patients admitted to 1 of the 2 neurointensive care units were eligible for study inclusion when they had a (1) spontaneous subarachnoid hemorrhage with Hunt & Hess grade between 3 and 5, (2) spontaneous intracerebral hemorrhage with a Glasgow Coma Scale score ≤10, or (3) complicated cerebral infarction requiring intensive care unit treatment with a National Institutes of Health Stroke Scale score ≥15.

Results— A total of 102 patients (56 female) were enrolled during a 3.5-year period. Fifty percent had a spontaneous subarachnoid hemorrhage, 40% had a spontaneous intracerebral hemorrhage, and 10% had a complicated cerebral infarction. Overall median total fever burden during the course of treatment was 0.0°C hour and 4.3°C hours in the catheter and conventional groups, respectively (P<0.0001). Prophylactic normothermia did not lead to an increase in the number of patients who experienced a major adverse event. No significant difference was found in mortality and neurologic long-term follow-up.

Conclusions— Long-term, catheter-based, prophylactic normothermia significantly reduces fever burden in neurointensive care unit patients with severe cerebrovascular disease and is not associated with increased major adverse events.

Methods— Severe vascular disruption and ischemic injury was produced in adult Sprague Dawley rats by transient occlusion of the middle cerebral artery for 1, 2, 4, or 8 hours, followed by 30 minutes of reperfusion. Fluorescein isothiocyanate-dextran (2 MDa) was injected intravenously before occlusion. After perfusion-fixation, brain sections were processed for ultrastructure or fluorescence imaging. We identified early evidence of tissue damage with Fluoro-Jade staining of dying cells.

Results— With increasing ischemia duration, greater quantities of high molecular weight dextran-fluorescein isothiocyanate invaded and marked ischemic regions in a characteristic pattern, appearing first in the medial striatum, spreading to the lateral striatum, and finally involving cortex; maximal injury was seen in the mid-parietal areas, consistent with the known ischemic zone in this model. The regional distribution of the severe vascular disruption correlated with the distribution of 24-hour 2,3,5-triphenyltetrazolium chloride pallor (r=0.75; P<0.05) and the cell death marker Fluoro-Jade (r=0.86; P<0.05). Ultrastructural examination showed significantly increased areas of swollen astrocytic foot process and swollen mitochondria in regions of high compared to low leakage, and compared to contralateral homologous regions (ANOVA P<0.01). Dextran extravasation into the basement membrane and surrounding tissue increased significantly from 2 to 8 hours of occlusion duration (Independent samples t test, P<0.05).

Conclusion— Severe vascular disruption, as labeled with high-molecular-weight dextran-fluorescein isothiocyanate leakage, is associated with severe tissue injury. This marker of severe vascular disruption may be useful in further studies of the pathoanatomic mechanisms of vascular disruption-mediated tissue injury.

Summary of Case— We present a patient with cerebral microbleeds and likely amyloid angiopathy with evolving ischemic lesions visualized on diffusion-weighted imaging.

Conclusions— This case captures with serial MRI the evolving and dynamic nature of cerebral amyloid angiopathy and particularly illustrates the subclinical, yet progressive, ischemic aspects of this vasculopathic process.

Summary of Review— Possible mechanisms linking baroreflex impairment with unfavorable outcome in stroke may include increased cardiovascular morbidity and mortality, promotion of secondary brain injury due to local inflammation, hyperglycemia, or altered cerebral perfusion.

Conclusions— We suggest therefore that the modifying of autonomic functions may have important therapeutic implications in acute ischemic as well as in hemorrhagic stroke.

Methods— We sought articles published between January 1990 and June 2008 by using MEDLINE, EMBASE, the COCHRANE databases, hand-searching, abstract books from conferences, and official websites. Two reviewers independently and in duplicate selected articles on the risks of CAS, irrespective of the type of treatment, study design, setting, or language. The 2 reviewers abstracted data and assessed the quality of the studies.

Results— Two hundred six independent studies (with 54 713 patients) were included. The overall 30-day risk of stroke or death was 4.7% (95% CI, 4.1 to 5.2) with substantial heterogeneity across studies. Symptomatic patients were about twice as likely as those with asymptomatic stenoses to have complications. The 30-day risk of stroke or death was 7.6% (3.6 to 9.1) in symptomatic and 3.3% (2.6 to 4.1) in asymptomatic patients. Risks increased with age, hypertension, and history of coronary artery disease; were unrelated to sex and the presence of contralateral carotid occlusion; and were lower in patients who had carotid restenosis after CEA and in those treated with the use of a cerebral protection device. Risks have also decreased over time.

Conclusions— Risks of CAS vary substantially across studies. Risks are overall higher than those of CEA in symptomatic patients. Some factors are likely to help select good candidates for CAS.

Summary of Review— The identification of gene mutations and genetic risk factors associated with cerebral cavernous malformation, hereditary hemorrhagic telangiectasia, and sporadic arteriovenous malformation has enabled the development of animal models for these diseases and provided new insights into their etiology. All of the genes associated with VMBs to date have known or plausible roles in angiogenesis and vascular remodeling. Recent work suggests that the angiogenic process most severely disrupted by VMB gene mutation is that of vascular stabilization, the process whereby vascular endothelial cells form capillary tubes, strengthen their intercellular junctions, and recruit smooth muscle cells to the vessel wall. In addition, there is now good evidence that in some cases, cerebral cavernous malformation lesion formation involves a genetic 2-hit mechanism in which a germline mutation in one copy of a cerebral cavernous malformation gene is followed by a somatic mutation in the other copy. There is also increasing evidence that environmental second hits can produce lesions when there is a mutation to a single allele of a VMB gene.

Conclusions— Recent findings begin to explain how mutations in VMB genes render vessels vulnerable to rupture when challenged with other inauspicious genetic or environmental factors and have suggested candidate therapeutics. Understanding of the cellular mechanisms of VMB formation and progression in humans has lagged behind that in animal models. New knowledge of lesion biology will spur new translational work. Several well-established clinical and genetic database efforts are already in place, and further progress will be facilitated by collaborative expansion and standardization of these.

Methods— We prospectively followed a hospital-based cohort of 809 first-ever ischemic stroke patients for 1 to 4 years. We compared risks of death, recurrent stroke, and MI in patients with lacunar versus nonlacunar stroke, and performed an updated meta-analysis of recurrent stroke subtype patterns.

Results— During 1725 person-years of follow-up, 109 patients had a recurrent stroke and 31 had MI. All patients at baseline, and 93% with recurrent stroke, had brain imaging and more than half with recurrent stroke had diffusion-weighted MRI. Overall, there was no difference in recurrence risk after lacunar vs nonlacunar stroke, although there was a trend toward a lower recurrence risk in the early weeks after lacunar stroke. Lacunar recurrence was more likely after lacunar than nonlacunar stroke (OR, 6.5; 95% CI, 2.4–17.5; updated meta-analysis OR, 6.8; 95% CI, 4.2–11.2). MI risk was nonsignificantly lower after lacunar than nonlacunar stroke (rate ratio, 0.5; 95% CI, 0.2–1.1; rate ratio after excluding patients with previous ischemic heart disease: 0.3; 95% CI, 0.1–0.9).

Conclusions— Our finding of a trend toward a lower MI risk after lacunar vs nonlacunar stroke and confirmation of both a lower early recurrence risk after lacunar stroke and a tendency of recurrent stroke subtypes to "breed true" support the notion of a distinct nonatherothrombotic lacunar arteriopathy.

Methods— The volumes of subcortical and ependymal HWM regions were measured from high-resolution (1 mm³), 3-dimensional fluid-attenuated inversion recovery images acquired for 459 (283 females, 176 males) active participants in the San Antonio Family Heart Study. Subjects ranged in age from 19 to 85 years of age (47.9±13.5 years) and were part of 49 families (9.4±8.5 individuals per family).

Results— The volumes of whole-brain, subcortical, and ependymal HWM were highly heritable (h²=0.72, 0.66, and 0.73, respectively). The subcortical and ependymal HWM volumes shared 21% of genetic variability indicating significant pleiotropy. Genomewide linkage analysis showed only a suggestive bivariate linkage for subcortical and ependymal HWM volumes (log of odds=2.12) on chromosome 1 at 288 cM.

Conclusion— We replicated previous findings of high heritability for the whole-brain HWM volume. We also showed that subcortical and ependymal volume shared a significant portion of genetic variability and the bivarate linkage analysis produced a suggestive linkage near the locus previously identified in a study of whole-brain HWM volume and arterial pulse pressure.

Methods— We performed a case-control study with 101 consecutive stroke patients and 100 consecutive acute coronary syndrome patients admitted to an emergency hospital. CD was investigated in all patients and was confirmed when both immunofluorescence and hemagglutination tests were positive. Clinical, laboratory, and ECG findings were analyzed.

Results— We found that age (P=0.006), female sex (P=0.01), systolic blood pressure (P=0.001), diastolic blood pressure (P=0.03), previous stroke/transient ischemic attack history (P<0.001), atrial fibrillation (P=0.005), other arrhythmias (P=0.05), and CD-positive serology (P=0.002) were more frequent among stroke patients than among patients with acute coronary syndromes. After a multivariable analysis with a backward elimination procedure, previous stroke/transient ischemic attack history (odds ratio=6.98; 95% CI, 2.99 to 16.29), atrial fibrillation (odds ratio=4.52; 95% CI, 1.45 to 14.04), and CD-positive serology (odds ratio=7.17; 95% CI, 1.50 to 34.19) remained independently associated with stroke.

Conclusions— CD seems to be an independent risk factor for ischemic stroke. For patients in or coming from endemic regions, CD should be considered an etiologic or contributing factor for stroke.

Methods— We conducted a cross-sectional study of patients with acute ischemic stroke recruited from 3 centers (Melbourne, Sydney, Singapore). The caliber of retinal arterioles and venules was measured from digital retinal photographs. Severe extracranial carotid disease was defined as stenosis ≥75% or occlusion determined by carotid Doppler using North American Symptomatic Carotid Endarterectomy Trial-based criteria.

Results— Among the 1029 patients with acute stroke studied, 7% of the population had severe extracranial carotid disease. Retinal venular caliber was associated with ipsilateral severe carotid disease (P<0.001 in multivariate models). Patients with wider retinal venular caliber were more likely to have severe ipsilateral carotid disease (multivariable-adjusted OR, 3.81; 95% CI, 1.80 to 8.07, comparing the largest and smallest venular caliber quartiles). The retinal venular caliber–carotid disease association remained significant in patients with large artery stroke.

Conclusions— In patients with acute stroke, retinal venular widening was strongly associated with ipsilateral severe extracranial carotid disease. Our findings suggest concomitant retinal and cerebral microvascular disease may be present in patients with carotid stenosis or occlusion disease. The pathogenesis of stroke due to carotid disease may thus be partially mediated by microvascular disease.

Methods— An inception cohort of 204 patients with acute ischemic stroke or TIA was followed up for a mean of 2.3 years. At baseline, patients underwent ABI measurement and were assessed for risk factors, cardiovascular comorbidities, and cervical or intracranial artery stenosis. The association between low ABI (≤0.9) and the risk of the composite outcome of stroke, myocardial infarction, or death was examined by Kaplan-Meier and Cox regression analyses.

Results— A low ABI was found in 63 patients (31%) and was associated with older age, current smoking, hypertension, peripheral arterial disease, and cervical or intracranial stenosis. During a total of 453.0 person-years of follow-up, 37 patients experienced outcome events (8.2% per person-year), with a higher outcome rate per person-year in patients with low ABI (12.8% vs 6.3%, P=0.03). In survival analysis adjusted for age and stroke etiology, patients with a low ABI had a 2 times higher risk of stroke, myocardial infarction, or death than those with a normal ABI (hazard ratio=2.2; 95% CI, 1.1 to 4.5). Additional adjustment for risk factors and cardiovascular comorbidities did not attenuate the association.

Conclusions— A low ABI independently predicted subsequent cardiovascular risk and mortality in patients with acute stroke or TIA. ABI measurement may help to identify high-risk patients for targeted secondary stroke prevention.

Methods— We compared the prevalence of self-reported history of stroke or TIA in the REasons for Geographic And Racial Differences in Stroke (REGARDS) participants with HF (as defined by current digoxin use) and without HF. We excluded participants with atrial fibrillation or missing data. We examined the relationship between HF and history of stroke/TIA within tertiles of systolic blood pressure (SBP) adjusting for patient demographic and health characteristics.

Results— Prevalent stroke/TIA were reported by 66 (26.3%) of 251 participants with and 1805 (8.5%) of 21 202 participants without HF (P<0.0001). Within each tertile of SBP, the unadjusted OR (95% CI) for prior stroke/TIA among those with HF compared with those without HF (the reference group) was, 4.0 (2.8 to 5.8) for SBP <119.5 mm Hg, 2.7 (1.8 to 3.9) for SBP ≥119.5 but <131.5 mm Hg, and 2.3 (1.6 to 3.2) for SBP ≥131.5 mm Hg. After adjustment, the relationship between prior stroke/TIA and HF remained significant only within the lowest tertile of SBP (<119.5 mm Hg; 3.0; 1.5 to 6.1).

Conclusions— The odds of prevalent self-reported stroke/TIA are increased in participants with HF and most markedly increased in participants with low SBP. Longitudinal data are needed to determine whether this reflects stroke/TIA secondary to thromboembolism from poor cardiac function or secondary to cerebral hypoperfusion.

Methods— A systematic review and meta-analysis was performed to determine the prognostic value of ES in different potential cerebral embolic sources. Studies were identified that used transcranial Doppler to detect ES and included prospective stroke/TIA follow-up. Numbers of ES-positive and ES-negative patients were extracted with stroke/TIA and stroke alone outcomes.

Results— ES are most frequent in large artery disease, less frequent in cardioembolic stroke, and infrequent in lacunar stroke. Data relating ES to future stroke risk were available for acute stroke, large artery disease, and the perioperative period of carotid endarterectomy. For symptomatic carotid stenosis, ES predicted stroke alone (OR, 9.57; 95%CI, 1.54 to 59.38; P=0.02) and stroke/TIA (OR, 6.36; 95% CI, 2.90–13.96; P<0.00001). For asymptomatic carotid stenosis, ES predicted stroke alone (OR, 7.46; 95% CI, 2.24–24.89; P=0.001) and stroke/TIA (OR, 12.00; 95% CI, 2.43–59.34; P=0.002) but with heterogeneity (P=0.004). In acute stroke ES predicted stroke alone (OR, 2.44; 95% CI, 1.17–5.08; P=0.02) and stroke/TIA (OR, 3.71; 95% CI, 1.64–8.38; P=0.002). A high frequency of ES immediately after carotid endarterectomy predicted stroke alone (OR, 24.54; 95% CI, 7.88–76.43; P<0.00001) and stroke/TIA (OR, 32.04; 95% CI, 11.36–90.39; P<0.00001).

Conclusion— ES predict stroke risk in acute stroke, symptomatic carotid stenosis, and postoperatively after carotid endarterectomy; in asymptomatic carotid stenosis, data are less robust. In these conditions ES may be useful in risk stratification and in assessing therapeutic efficacy. For other embolic sources, further prospective data are required.

Materials and Methods— Fifty patients with symptomatic carotid atherosclerosis underwent ¹⁸F-FDG PET/CT and MRI. Correlations and agreement between imaging findings were assessed by Spearman and Pearson rank correlation tests, t tests, and Bland-Altman plots.

Results— Spearman between plaque ¹⁸F-FDG standard uptake values and CT/MRI findings varied from –0.088 to 0.385. Maximum standard uptake value was significantly larger in plaques with intraplaque hemorrhage (1.56 vs 1.47; P=0.032). Standard uptake values did not significantly differ between plaques with an intact and thick fibrous cap and plaques with a thin or ruptured fibrous cap on MRI. (1.21 vs 1.23; P=0.323; and 1.45 vs 1.54; P=0.727). Pearson between CT and MRI measurements varied from 0.554 to 0.794 (P<0.001). For lipid-rich necrotic core volume, the CT–MRI correlation was stronger in mildly (≤10%) than in severely (>10%) calcified plaques (Pearson 0.730 vs 0.475). Mean difference in measurement ±95% limits of agreement between CT and MRI for minimum lumen area, volumes of vessel wall, lipid-rich necrotic core, calcifications, and fibrous tissue were 0.4±18.1 mm² (P=0.744), –41.9 ±761.7 mm³ (P=0.450), 78.4±305.0 mm³ (P<0.001), 180.5±625.7 mm³ (P=0.001), and –296.0±415.8 mm³ (P<0.001), respectively.

Conclusions— Overall, correlations between ¹⁸F-FDG PET and CT/MRI findings are weak. Correlations between CT and MRI measurements are moderate to strong, but there is considerable variation in absolute differences.

Methods— Case series.

Results— We describe 4 elderly patients presenting with a cluster of stereotyped somatosensory migraine auras, initially referred for "crescendo transient ischemic attacks". Neuroimaging in each patient revealed an unexpected finding of spontaneous focal subarachnoid hemorrhage conforming to a cortical sulcus in the contralateral hemisphere. We postulate that the episodic aura symptoms corresponded to recurrent cortical spreading depression triggered by the presence of subarachnoid blood, and speculate that such episodes could be a presenting feature of cerebral amyloid angiopathy in the absence of typical cerebral microbleeds or history of cognitive impairment.

Conclusions— Focal subarachnoid hemorrhage can present clinically with transient repetitive migraine auras. Awareness of this entity is important because misdiagnosis as cerebral ischemic events could lead to incorrect treatment. We recommend that elderly patients presenting with a cluster of new unexplained migraine auras should be investigated ideally with MRI to detect focal subarachnoid hemorrhage.

Methods— We measured the OEF by using positron emission tomography and ¹⁵O gas in 100 nondisabled patients with atherosclerotic MCA disease in the chronic stage. On MRI, the infarcts were categorized as territorial, border-zone (external or internal), deep perforator, and superior perforator infarcts. In 62 patients, BZRs were measured using ¹¹C-flumazenil. By using 3-dimensional stereotactic surface projections, the abnormally decreased BZR index ("BZR index") [(the extent of the pixels with Z score more than 2 compared with controls)x(average Z score in those pixels)] was calculated. In the hemisphere affected by MCA disease, the type of infarcts was correlated with the value of OEF or BZR index in the cerebral cortex of the MCA distribution.

Results— Compared with patients without internal border-zone infarcts, those with these infarcts (n=18) had significantly increased OEF and significantly high BZR index. Multivariate analysis revealed that internal border-zone infarction was independently associated with increased OEF and high BZR index.

Conclusions— In atherosclerotic MCA disease, internal border-zone infarction is associated with increased OEF and a decrease in BZRs in the overlying cerebral cortex, suggesting that hemodynamic compromise may induce internal border-zone infarction and cortical neuronal damage.

Methods— This is a retrospective study of consecutive patients with large middle cerebral artery infarction admitted to our neurocritical care unit from January 2007 to October 2008. Medical records, laboratory data, and imaging of cerebral edema and cranial venous sinuses were analyzed.

Results— Of the 14 patients identified to have large middle cerebral artery infarction and images of cranial venous drainages, 5 (35.7%) had fatal edema with clinical signs of transtentorial herniation. Four of the 5 patients developed fatal edema within 48 hours of ictus and were found to have abnormal ipsilateral cranial venous drainage, including atresia of the transverse sinus (one), occlusion of the internal jugular vein (one), and hypoplasia of the transverse sinus and internal jugular vein (2). The fifth patient had symmetrical bilateral cranial venous drainages and fatal edema at Day 5. Of the 9 patients with nonmalignant middle cerebral artery infarction, all had ipsilateral dominant or symmetrical bilateral venous drainages.

Conclusions— In this small case series, we demonstrated that only the patients with hypoplasia or occlusion of the ipsilateral cranial venous drainage developed early fatal edema after large middle cerebral artery infarction. Our results suggest a role of cranial venous outflow abnormalities in the development of brain edema after arterial ischemic stroke.

Methods— We used ³¹P-MRS to study patients with a diagnosis of either migrainous infarction or migraine with persistent aura without infarction (aura duration >7 days) according to International Headache Society criteria. We compared clinical presentation and metabolite ratios between patient groups. We also studied healthy controls with no history of migraine.

Results— Patients with persistent aura without infarction had lower phosphocreatine-phosphate (PCr/Pi) ratios (mean±SD, 1.61±0.10) compared with controls (1.94±0.35, P=0.011) and with patients with migrainous stroke (1.96±0.16, P<0.0001). These differences were present in cortical tissue only. In migrainous stroke patients, the metabolite ratios did not differ significantly from those of controls without migraine.

Conclusions— The differences in cortical energy reserves between patients with migrainous stroke and in those with migraine with persistent aura suggest that the pathomechanisms of these conditions differ and that migrainous infarction does not simply represent a particularly severe form of migrainous aura. This finding supports the revised International Headache Society criteria, which now distinguish between migrainous infarction and migraine with persistent aura without infarction.

Methods— Over 8.5 years, we prospectively identified 82 consecutive patients with anterior inferior cerebellar artery territory infarction diagnosed by MRI. Each patient completed a standardized audiovestibular questionnaire and underwent a neuro-otologic evaluation, including bithermal caloric tests and pure tone audiogram.

Results— All but 2 (80 of 82 [98%]) patients had acute prolonged vertigo and vestibular dysfunction of peripheral, central, or combined origin. The most common pattern of audiovestibular dysfunction was the combined loss of auditory and vestibular function (n=49 [60%]). A selective loss of vestibular (n=4 [5%]) or cochlear (n=3 [4%]) function was rarely observed. We could classify anterior inferior cerebellar artery territory infarction into 7 subgroups according to the patterns of neuro-otological presentations: (1) acute prolonged vertigo with audiovestibular loss (n=35); (2) acute prolonged vertigo with audiovestibular loss preceded by an episode(s) of transient vertigo/auditory disturbance within 1 month before the infarction (n=13); (3) acute prolonged vertigo and isolated auditory loss without vestibular loss (n=3); (4) acute prolonged vertigo and isolated vestibular loss without auditory loss (n=4); (5) acute prolonged vertigo but without documented audiovestibular loss (n=24); (6) acute prolonged vertigo and isolated audiovestibular loss without any other neurological symptoms/signs (n=1); and (7) nonvestibular symptoms with normal audiovestibular function (n=2).

Conclusions— Infarction in the anterior inferior cerebellar artery territory can present with a broad spectrum of audiovestibular dysfunctions. Unlike a viral cause, labyrinthine dysfunction of a vascular cause usually leads to combined loss of both auditory and vestibular functions.

Methods— Patients were recruited with MR studies performed within 48 hours of ischemic stroke. Mismatch patterns based on diffusion-weighted/perfusion-weighted images were categorized as classical (majority of the diffusion-weighted image within the perfusion-weighted image lesion) or nonclassical (fragmented) patterns. The proportion of patterns was assessed with reference to time, vessel patency, mismatch volume, and infarct core location.

Results— Sixty-seven patients (33 classical [49.3%] and 34 nonclassical patterns [50.7%]) were studied within 48 hours (median age, 74.0 years). Compared to the nonclassical pattern, the classical pattern had a shorter time to MR (3.4 hours vs 10.4 hours; P=0.004) and a larger mismatch volume (62.0 mL vs 3.5 mL; P<0.0001). The positive predictors for the classical pattern were earlier time, vessel occlusion, superficial core location, and larger mismatch volume.

Conclusion— The classical mismatch pattern may fragment with time. Over 48 hours the classical pattern is seen earlier after stroke onset, with higher rates of vessel occlusion and larger mismatch volumes.

Methods— We used diffusion-weighted MRI in patients hospitalized for a pulmonary embolism to assess cerebral embolic events. Sixty consecutive patients were evaluated at diffusion-weighted MRI. All patients underwent neurological assessment before diffusion-weighted MRI and a contrast echocardiography to detect PFO the next day.

Results— Diffusion-weighted MRI showed bright lesions in 6 patients among the 60 consecutive patients with pulmonary embolism in a pattern consistent with embolic events. There was only one patient with a neurological deficit. After contrast echocardiography, a PFO was diagnosed in 15 patients (25%). The frequency of silent brain infarcts in patients with a PFO was significantly higher than in patients without PFO (5 [33.3%] of 15 versus one [2.2%] of 45 patients, P=0.003). By logistic regression analysis, PFO was identified as an independent predictor of silent brain infarcts (OR, 34.9 [3.1 to 394.3]; P=0.004).

Conclusions— In pulmonary embolism, cerebral embolic events are more frequent than the apparent neurological complication rate. The prevalence of silent brain infarcts is closely related to the presence of a PFO suggesting a high incidence of unsuspected paradoxical emboli in those patients.

Methods— Initial CT scans with intraparenchymal hematoma from the first 1000 patients with stroke in the Oxford Vascular Study were independently categorized as intracerebral hemorrhage or hemorrhagic transformation of infarction by 5 neuroradiologists, both blinded and unblinded to clinical history. Thirty scans were reviewed twice. Agreement was quantified by the statistic.

Results— Seventy-eight scans showed intraparenchymal hematoma. Blinded pairwise interrater agreements for a diagnosis of intracerebral hemorrhage ranged from =0.15 to 0.48 with poor overall agreement (=0.35; 95% CI, 0.15 to 0.54) even after unblinding (=0.41; 0.21 to 0.60). Blinded intrarater agreements ranged from =0.21 to 0.92. Lack of consensus after unblinding was greatest in patients scanned ≥24 hours after stroke onset (67% versus 25%, P=0.001) and in minor stroke (National Institutes of Health Stroke Scale ≤5: 56% versus 29%, P=0.04) with disagreement in 75% of patients scanned ≥24 hours after minor stroke and in 48% of all 30-day stroke survivors in whom reliable diagnosis would be expected to influence long-term management.

Conclusion— Reliability of diagnosis of intraparenchymal hematoma on CT brain scan in minor stroke is poor, particularly if scanning is delayed. Immediate brain imaging is justified in patients with minor stroke.

Methods— In a retrospective study of 14 patients, lesions on 90-day follow-up FLAIR and T2 fast spin echo MRI were outlined by 9 independent, blinded, experienced neuroradiologists. Voxel-wise interrater agreement was measured as (1) the volume of the intersection of individual rater’s lesion outlines relative to the mean lesion volume (overlap ratio) and (2) the Hausdorff distance between the lesion markings.

Results— Mean patient age was 64.4 years (range, 45 to 79). Lesion volumes on FLAIR were, on average, 2.5 mL greater than were T2 volumes (median; P<0.001). We found considerable differences between raters’ lesion markings, but interrater agreement was consistently better on FLAIR than on T2 images, as measured by a greater overlap ratio (P<0.0001) and a smaller Hausdorff distance (P<0.0001) on FLAIR than on T2.

Conclusions— FLAIR should be used to quantify follow-up infarct size to minimize interrater variability. Our study suggests that imaging analysis performed by 1 or a few trained readers may be preferred. Future studies should address objective and preferably automated criteria for final lesion delineation.

Methods— We used the Swiss IVT databank to compare outcome and complications of IVT-treated patients with CAD with IVT-treated patients with other etiologies (non-CAD patients). Main outcome and complication measures were favorable 3-month outcome, intracranial cerebral hemorrhage, and recurrent ischemic stroke. Modified Rankin Scale score ≤1 at 3 months was considered favorable.

Results— Fifty-five (5.2%) of 1062 IVT-treated patients had CAD. Patients with CAD were younger (median age 50 versus 70 years) but had similar median National Institutes of Health Stroke Scale scores (14 versus 13) and time to treatment (152.5 versus 156 minutes) as non-CAD patients. In the CAD group, 36% (20 of 55) had a favorable 3-month outcome compared with 44% (447 of 1007) non-CAD patients (OR, 0.72; 95% CI, 0.41 to 1.26), which was less favorable after adjustment for age, gender, and National Institutes of Health Stroke Scale score (OR, 0.50; 95% CI, 0.27 to 0.95; P=0.03). Intracranial cerebral hemorrhages (asymptomatic, symptomatic, fatal) were equally frequent in CAD (14% [7%, 7%, 2%]) and non-CAD patients (14% [9%, 5%, 2%]; P=0.99). Recurrent ischemic stroke occurred in 1.8% of patients with CAD and in 3.7% of non-CAD-patients (P=0.71).

Conclusion— IVT-treated patients with CAD do not recover as well as IVT-treated non-CAD patients. However, intracranial bleedings and recurrent ischemic strokes were equally frequent in both groups. They do not account for different outcomes and indicate that IVT should not be excluded in patients who may have CAD. Hemodynamic compromise or frequent tandem occlusions might explain the less favorable outcome of patients with CAD.

Methods— The trial cohorts were combined in a data set of 305 patients. Twenty-eight baseline variables were included in univariate and multivariate analyses to define the independent predictors of good outcomes (modified Rankin Scale score ≤2), mortality, and successful revascularization (Thrombolysis In Myocardial Ischemia 2 to 3 flow).

Results— In the univariate analysis, final revascularization, baseline National Institutes of Health Stroke Scale, age, and systolic blood pressure were associated with both good outcomes and mortality at 90 days (P<0.0018 for all). In the multivariate analysis, final revascularization (OR, 20.4; 95% CI, 7.7 to 53.9; P<0.0001), baseline National Institutes of Health Stroke Scale (OR, 0.86; 95% CI, 0.81 to 0.92; P<0.0001), and age (OR, 0.96; 95% CI, 0.95 to 0.98; P=0.0004) were independent predictors of good outcome. Final revascularization (OR, 0.28; 95% CI, 0.16 to 0.50; P<0.0001), baseline National Institutes of Health Stroke Scale score (odds ratio, 1.09; 95% CI, 1.04 to 1.14; P=0.0001), age (OR, 1.05; 95% CI, 1.03 to 1.07; P<0.0001), and internal carotid artery occlusion (OR, 2.17; 95% CI, 1.22 to 3.86; P=0.0084) were the strongest predictors of mortality. Systolic blood pressure (<150 versus ≥150 mm Hg; OR, 0.42; 95% CI, 0.26 to 0.70; P=0.0007) and M2 occlusion (OR, 3.86; 95% CI, 1.28 to 11.67; P=0.0168) were independent predictors of revascularization.

Conclusion— Final recanalization status represents the strongest predictor of clinical outcomes in patients undergoing thrombectomy. The ability to remove the clot is negatively influenced by systolic blood pressure on presentation perhaps because of the hydraulic forces imposed by higher blood pressures. Although internal carotid artery occlusions are associated with increased mortality, they do not appear to influence the chances of good outcomes. This finding supports the inclusion of internal carotid artery occlusions in future efficacy trials.

Methods— Seven patients with acute ischemic stroke (aged 31 to 88 years) who underwent intra-arterial therapy with the Alligator retrieval device at our center are presented.

Results— The Alligator retrieval device was able to retrieve the thrombus in 5 of 7 cases with good to excellent recanalization seen and was unsuccessful in 2 of 7 patients. Complete recanalization was obtained in one of 7 patients and near complete recanalization obtained in 4 of 7 patients. Three of the 7 patients had good outcome at 3 months and 3 of 7 patients died within 30 days of treatment.

Conclusion— The Alligator retrieval device was successfully able to remove thrombus in the majority of cases. It appears to have increased success in proximal occlusions in relatively straight segments. In properly selected cases, it may be a useful device in intra-arterial stroke management.

Methods— In a multicenter, double-blind, randomized, placebo-controlled Phase II trial, 40 patients with ischemic stroke were treated with either placebo or active drug between 3 and 12 hours after symptom onset in a dose-finding design. Ten patients received placebo, 6 patients received a total dose of 2 mg/kg, 12 patients received a total dose of 3 mg/kg, and 12 patients received a total dose of 4 mg/kg. We studied the pharmacodynamics of microplasmin and its effect on the clinical and hemodynamic parameters of the patients. MRI was used as a surrogate marker and matrix metalloproteinases serum concentrations were used as markers of neurovascular integrity. The study was underpowered to detect clinical efficacy.

Results— Microplasmin induced reversible effects on markers of systemic thrombolysis and neutralized ₂-antiplasmin by up to 80%. It was well tolerated with one of 30 treated patients developing a fatal symptomatic intracerebral hemorrhage. No significant effect on reperfusion rate or on clinical outcome was observed. Matrix metalloproteinase-2 levels were reduced in microplasmin-treated patients.

Conclusions— Microplasmin was well tolerated and achieved neutralization of ₂-antiplasmin. Further studies are warranted to determine whether microplasmin is an effective therapeutic agent for ischemic stroke.

Methods— Five hundred subjects with acute ischemic stroke who could begin receiving study material within 6 hours of symptom onset were infused intravenously with either ancrod (0.167 IU/kg per hour) or placebo over 2 or 3 hours. The primary efficacy outcome was a dichotomized, modified Rankin score at 90 days with less stringent cut-points for higher prestroke modified Rankin score and pretreatment NIHSS total score ("responder analysis"). Safety variables included mortality, major bleeding, and intracranial hemorrhage.

Results— Although the desired changes in fibrinogen level were seen in >90% of ancrod subjects, interim analysis for futility led to the study being halted for lack of efficacy. Positive responder status in the interim dataset was seen in 39.6% of ancrod subjects and 37.2% of placebo subjects (P=0.47). Ninety-day mortality did not differ between the 2 groups (ancrod, 15.6%; placebo, 14.1%; P=0.32), and the incidence of symptomatic intracranial hemorrhage within the first 72 hours, although not significantly different in ancrod compared to placebo subjects (P=0.19), was approximately twice as high (3.9% vs 2.0%; P=0.19).

Conclusion— These results demonstrate that intravenous ancrod starting within 6 hours after symptom onset in a broad selection of subjects with ischemic stroke did not improve their outcome and revealed a trend to increased bleeding despite successful efforts to achieve rapid initial defibrinogenation and avoid prolonged hypofibrinogenemia.

Methods— We conducted a prospective, randomized, multicenter, 3-arm trial (tight control [target 70 to 110 mg/dL], loose control [target 70 to 200 mg/dL], and control usual care [70 to 300 mg/dL]) to assess the feasibility and safety of 2 insulin infusion protocol targets in patients with acute ischemic stroke. The planned sample was 72 subjects.

Results— A total of 74 subjects were enrolled. Seventy-two (97%) had data available for the primary analyses and 73 (99%) had 3-month clinical outcome data. Median age was 67 years, median National Institutes of Health Stroke Scale score was 8, median glucose was 163 mg/dL, and median time to randomization was 10.7 hours. Fifty-nine percent of patients were diabetic, 35% received thrombolysis, and 14% of subjects died within 3 months. The loose control and usual care groups had median glucose concentrations of 151 mg/dL. The tight control group had a median glucose concentration of 111 mg/dL. The loose control group spent 90% of the first 24 hours in target and the tight group 44% of time in target. There was only one symptomatic patient with hypoglycemia in the loose control group (4%) and zero in the tight control group. The overall rates of hypoglycemia (<55 mg/dL) were 4% in control, 4% in loose, and 30% in tight. Exploratory efficacy analysis was conducted.

Conclusions— Insulin infusion for patients with acute ischemic stroke is feasible and safe using the insulin infusion protocol in the Glucose Regulation in Acute Stroke Patients (GRASP) trial. Exploratory efficacy analysis supports further comparative study.

Methods— We prospectively enrolled 98 patients with intracerebral hemorrhage and recorded antiepileptic drug use as either prophylactic or therapeutic along with clinical characteristics. Antiepileptic drug administration and free phenytoin serum levels were retrieved from the electronic medical records. Patients with depressed mental status underwent continuous electroencephalographic monitoring. Outcomes were measured with the National Institutes of Health Stroke Scale and modified Rankin Scale at 14 days or discharge and the modified Rankin Scale at 28 days and 3 months. We constructed logistic regression models for poor outcome at 3 months with a forward conditional model.

Results— Seven (7%) patients had a clinical seizure, 5 on the day of intracerebral hemorrhage. Phenytoin was associated with more fever (P=0.03), worse National Institutes of Health Stroke Scale at 14 days (23 [9 to 42] versus 11 [4 to 23], P=0.003), and worse modified Rankin Scale at 14 days, 28 days, and 3 months. In a forward conditional logistic regression model, phenytoin prophylaxis was associated with an increased risk of poor outcome (OR, 9.8; 1.4 to 68.6; P=0.02), entering after admission National Institutes of Health Stroke Scale and age. Excluding patients with a seizure did not change the results. Levetiracetam was not associated with demographics, seizures, complications, or outcomes.

Conclusions— Phenytoin was associated with more fever and worse outcomes after intracerebral hemorrhage.

Methods— One hundred seventy-three participants of a community-dwelling elderly cohort had neurological and neuropsychological examinations and brain MRI. Gait function was measured by Tinetti gait (0 to 12), balance (0 to 16) and total (0 to 28) scores. DTI assessed fractional anisotropy in the genu and splenium of the corpus callosum. Conventional MRI was used to evaluate for brain infarcts and white matter hyperintensity volume.

Results— Participants with abnormal gait had low fractional anisotropy in the genu of the corpus callosum but not the splenium. Multiple regressions analyses showed an independent association between these genu abnormalities and all 3 Tinetti scores (P<0.001). This association remained significant after adding MRI infarcts and white matter hyperintensity volume to the analysis.

Conclusions— The independent association between quantitative measures of gait function and DTI findings shows that white matter integrity in the genu of corpus callosum is an important marker of gait in the elderly. DTI analyses of white matter tracts in the brain and spinal cord may improve knowledge about the pathophysiology of gait impairment and help target clinical interventions.

Methods— Gait analysis was performed as subjects (N=13) with chronic poststroke hemiparesis walked at their self-selected walking speeds during walking with and without FES.

Results— Compared with delivering FES to only the ankle dorsiflexor muscles during the swing phase, delivering FES to both the paretic ankle plantarflexors during terminal stance and dorsiflexors during the swing phase provided the advantage of greater swing-phase knee flexion, greater ankle plantarflexion angle at toe-off, and greater forward propulsion. Although FES of both the dorsiflexor and plantarflexor muscles improved swing-phase ankle dorsiflexion compared with noFES, the improvement was less than that observed by stimulating the dorsiflexors alone, suggesting the need to further optimize stimulation parameters and timing for the dorsiflexor muscles during gait.

Conclusions— In contrast to the typical FES approach of stimulating ankle dorsiflexor muscles only during the swing phase, delivering FES to both the plantarflexor and dorsiflexor muscles can help to correct poststroke gait deficits at multiple joints (ankle and knee) during both the swing and stance phases of gait. Our study shows the feasibility and advantages of stimulating the ankle plantarflexors during FES for poststroke gait.

Methods— We used the person trade-off procedure developed by the World Health Organization Global Burden of Disease Project (WHO-GBDP) to generate disability weights (DWs) ranging from 0 (normal) to 1 (dead) for each of 7 mRS grades. The ratings of an international, 9-member panel of stroke experts were combined by a modified Delphi process.

Results— DWs (95% CI) were 0 for mRS 0, 0.046 (0.004 to 0.088) for mRS 1, 0.212 (0.175 to 0.250) for mRS 2, 0.331 (0.292 to 0.371) for mRS 3, 0.652 (0.625 to 0.678) for mRS 4, 0.944 (0.873 to 1.015) for mRS 5, and 1.0 for mRS 6. DWs of adjacent mRS levels were significantly different (P<0.001 for all). Coefficients of variation showed a high degree of consensus for DWs among panel members. DWs placed each of the 5 intermediate mRS states in different disability class levels of the WHO-GBDP anchor conditions and identified natural clusters to use when reducing the mRS to fewer categories.

Conclusions— Formal DW assignment confirms that the mRS is an ordered but unequally spaced scale. The availability of DWs for each mRS level now permits direct comparison of each poststroke outcome state with the outcomes of hundreds of other diseases in the WHO-GBDP and the expression of stroke burden in different populations by using the uniform metric of disability-adjusted life-years lost.

Methods— The Screening Technology and Outcome Project in Stroke Study is a prospective imaging-based study of stroke outcomes performed at 2 academic medical centers. Patients with suspected acute stroke who presented within 24 hours of symptom onset and who underwent multimodality CT/CT angiography were approached for consent for collection of clinical data and 6-month assessment of outcome. Demographic and clinical variables and 6-month modified Rankin Scale scores were collected and combined with blinded interpretation of the CT angiography data. The OR of each variable, including occlusion of intracranial vascular segment in predicting good outcome and 6-month mortality, was calculated using univariate and multivariate logistic regression.

Results— Over a 33-month period, 735 patients with suspected stroke were enrolled. Of these, 578 were adjudicated as stroke and 97 as transient ischemic attack. Among patients with stroke, 267 (46%) had LVO accounting for the stroke and 13 (13%) of patients with transient ischemic attack had LVO accounting for transient ischemic attack symptoms. LVO predicted 6-month mortality (OR, 4.5; 95% CI, 2.7 to 7.3; P<0.001). Six-month good outcome (modified Rankin Scale score ≤2) was negatively predicted by LVO (0.33; 0.24 to 0.45; P<0.001). Based on multivariate analysis, the presence of basilar and internal carotid terminus occlusions, in addition to National Institutes of Health Stroke Scale and age, independently predicted outcome.

Conclusion— Large vessel intracranial occlusion accounted for nearly half of acute ischemic strokes in unselected patients presenting to academic medical centers. In addition to age and baseline stroke severity, occlusion of either the basilar or internal carotid terminus segment is an independent predictor of outcome at 6 months.

Methods— We compared consecutive patients with stroke arriving to our stroke center during the first 4 months of this new triage protocol (February 14 to June 14, 2005) versus the same 4-month period in 2004.

Results— The protocol resulted in an immediate doubling in the number of patients with acute stroke arriving to our regional stroke center within 2.5 hours of symptom onset. We observed a 4-fold increase in patients who were eligible for and treated with tissue plasminogen activator. The tissue plasminogen activator treatment rate for ischemic stroke patients increased from 9.5% to 23.4% (P=0.01), and one in 2 patients with ischemic stroke arriving within 2.5 hours received thrombolysis during this period (one in 5 of patients with ischemic stroke overall). The median onset-to-needle time for tissue plasminogen activator-treated patients was significantly reduced. Many implementation challenges were identified and addressed.

Conclusions— This prehospital triage was immediately successful in improving tissue plasminogen activator access for patients with ischemic stroke, enabling our center to achieve one of the highest tissue plasminogen activator treatment rates in North America and underscoring the need for coordinated systems of acute stroke care. Sustainability of such an initiative will be dependent on interdisciplinary teamwork, ongoing paramedic training, adequate hospital staffing, bed availability, and repatriation agreements with community hospitals.

Methods— Medical records were abstracted for consecutive ischemic stroke patients admitted from the Emergency Department within 48 hours of symptom onset at 35 academic medical centers participating in the University HealthSystem Consortium Ischemic Stroke Benchmarking Project between January 1, 2001 and March 31, 2001, and 32 centers between January 1, 2004 and June 30, 2004. Demographic and clinical characteristics of patients who presented within and after 2 hours of symptom onset were compared. Multivariate logistic regression was used to compare time to arrival by year and to identify patient characteristics associated with earlier hospital arrival.

Results— The study included 428 patients from 2001 and 481 from 2004. Although there was no difference in the percentage of patients who arrived within 2 hours between the 2 periods (37% in 2001 vs 38% in 2004, P=0.63), the percentage of these patients treated with IV t-PA increased (14.0% to 37.5%, P<0.0001). In risk-adjusted analysis, black patients had a lower odds of arriving within 2 hours (odds ratio=0.55; 95% CI, 0.39 to 0.78), whereas those with severe strokes were more likely to arrive promptly (odds ratio=2.17; 95% CI, 1.49 to 3.15).

Conclusions— There was no change in the proportion of stroke patients arriving at hospitals within 2 hours of symptom onset between 2001 and 2004; however, the rate of IV t-PA use increased, indicating system-level improvements of in-hospital care.

Methods— All 79 hospitals in Sweden admitting acute stroke patients participate in Riks-Stroke. During 2001 to 2007, 104 876 patients (87% of survivors) responded to a follow-up questionnaire 3 months after acute stroke; this included questions on satisfaction with various aspects of stroke care.

Results— The majority (>90%) were satisfied with acute in-hospital stroke care. Dissatisfaction was closely associated with outcome at 3 months. Patient who were dependent regarding activities of daily living, felt depressed, or had poor self-perceived general health were more likely to be dissatisfied. Dissatisfaction with global acute stroke care was linked to dissatisfaction with other aspects of care, including rehabilitation and support by community services. Patients treated in stroke units were less often dissatisfied than patients in general wards, as were patients who had been treated in a small hospital (vs medium or large hospitals) and patient who had participated in discharge planning. In multivariate analyses, the strongest predictor of dissatisfaction with acute care was poor outcome (dependency regarding activities of daily living, depressed mood, poor self-perceived health).

Conclusions— Dissatisfaction with in-hospital acute stroke care is part of a more extensive complex comprising poor functional outcome, depressive mood, poor self-perceived general health, and dissatisfaction not only with acute care but also with health care and social services at large. Several aspects of stroke care organization are associated with a lower risk of dissatisfaction.

Methods— This was a single blinded, randomized, pretest, posttest study using 2 age cohorts: younger (18 to 30 years) and older (50+ years). Stroke knowledge was measured by the 28-item Stroke Action Test taken before and after viewing either an Extended Parallel Process modified poster or a standard educational poster in widespread use and again 6 weeks later.

Results— Overall, there were 274 participants (222 younger and 52 older) with 139 randomly assigned to view the Extended Parallel Process poster and 135 assigned to view the standard poster. There was no significant difference (P>0.05) in the average Stroke Action Test score change between poster groups at all 3 testing intervals, although there was a nonsignificant greater drop in Stroke Action Test scores observed in the control group at the 6-week follow-up (–3.52 versus –2.60; P=0.46). The observed power for this difference was only 11% due to attrition of study participants (total 6-week follow-up, n=170). The younger group did significantly better on the Stroke Action Test from baseline to immediate posttest when viewing either poster (P<0.05).

Conclusions— A common stroke education poster modified according to the Extended Parallel Process model did not significantly increase stroke knowledge compared with a standard control. However, the Extended Parallel Process model may promote long-term stroke knowledge retention, although further studies are needed due to insufficient power from subject attrition.

Methods— Permanent middle cerebral artery occlusion was induced with an intraluminal filament. Diffusion- (DWI) and perfusion- (PWI) weighted magnetic resonance imaging was performed from 1 to 6 hours after stroke, with the PWI-DWI mismatch used to define the penumbra and thresholded apparent diffusion coefficient (ADC) maps used to define ischemic damage.

Results— There was significantly more ischemic damage in SHRSP than in WKY from 1 to 6 hours after stroke. The perfusion deficit remained unchanged in WKY (39.9±6 mm² at 1 hour, 39.6±5.3 mm² at 6 hours) but surprisingly increased in SHRSP (43.9±9.2 mm² at 1 hour, 48.5±7.4 mm² at 6 hours; P=0.01). One hour after stroke, SHRSP had a significantly smaller penumbra (3.4±5.8 mm²) than did WKY (9.7±3.8, P=0.03). In WKY, 56% of the 1-hour penumbra area was incorporated into the ADC lesion by 6 hours, whereas in SHRSP, the small penumbra remained static owing to the temporal increase in both ADC lesion size and perfusion deficit.

Conclusions— First, SHRSP have significantly more ischemic damage and a smaller penumbra than do WKY within 1 hour of stroke; second, the penumbra is recruited into the ADC abnormality over time in both strains; and third, the expanding perfusion deficit in SHRSP predicts more tissue at risk of infarction. These results have important implications for management of stroke patients with preexisting hypertension and suggest ischemic damage could progress at a faster rate and over a longer time frame in the presence of hypertension.

Methods— MD and fractional anisotropy were measured in 6 regions of interest in normal-appearing white matter. Visible white matter lesions were quantified using the Fazekas scale. Both were correlated with systolic and diastolic BP.

Results— Systolic BP was positively and significantly correlated with MD in all 6 regions (r=0.31 to 0.45; P=0.037 to 0.002). MD was also correlated with diastolic BP in the genu of the corpus callosum (r=0.34, P=0.018). A summary factor derived from principal component analysis of the MD measurements accounted for 53.8% of the variance and correlated at r=0.51 (P<0.001) with systolic BP and r=0.33 (P=0.028) with diastolic BP. Fractional anisotropy did not correlate significantly with BP. Deep white matter Fazekas scores correlated with diastolic BP (=0.35, P=0.019).

Conclusions— The increase in MD without change in fractional anisotropy indicates that, in normal-appearing white matter, higher BP may be associated with increased extracellular fluid before any cytoarchitectural damage occurs.

Methods— Ninety-seven mice were assigned to sham, SAH+vehicle, SAH+Ac-YVAD-CMK (6 or 10 mg/kg), and SAH+Z-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK, 6 mg/kg) groups. Drugs were intraperitoneally injected 1 hour post-SAH. Pulmonary edema measurements, Western blot for interleukin-1β, interleukin-18, myeloperoxidase, matrix metalloproteinase (MMP)-2, MMP-9, cleaved caspase-3 and zona occludens-1, MMP zymography, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining, and immunostaining were performed on the lung at 24 hours post-SAH.

Results— Ten- but not 6-mg/kg of Ac-YVAD-CMK significantly inhibited a post-SAH increase in the activation of interleukin-1β and caspase-3 and the number of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-positive pulmonary endothelial cells, preventing neurogenic pulmonary edema. Another antiapoptotic drug, Z-VAD-FMK, also reduced neurogenic pulmonary edema. SAH did not change interleukin-18, myeloperoxidase, MMP-2, MMP-9, zona occludens-1 levels, or MMP activity.

Conclusions— We report for the first time that Ac-YVAD-CMK prevents lung cell apoptosis and neurogenic pulmonary edema after SAH in mice.

Methods— Electronic searches of MEDLINE, EMBASE, and the Cochrane central register of controlled trials were performed. A total of 20 randomized clinical trials with 108 286 patients reporting stroke were available for this clinical outcome analysis.

Results— Angiotensin receptor blockers were associated with a significant reduction in the risk of stroke than placebo with an OR of 0.91 (0.84 to 0.98). Angiotensin receptor blockers were associated with no significant reduction in the risk of stroke compared with angiotensin-converting enzyme inhibitors (OR, 0.93; 0.84 to 1.03) and calcium antagonists (OR, 1.16; 0.91 to 1.48).

Conclusions— Evidence of the benefit of angiotensin receptor blockers on the risk of stroke is provided when compared with placebo. There was no evidence of the benefit when comparing angiotensin receptor blockers with angiotensin-converting enzyme inhibitors and with calcium antagonists.

Summary of Report— Clinically, the continuum of stroke research and care can be divided into primary prevention, acute interventions, secondary prevention, and poststroke recovery. From a technical/methodological standpoint, fundamental laboratory studies yield insights into basic disease mechanisms and applied laboratory studies further explore the biological basis of disease and evaluate possible therapeutic interventions. The results of these laboratory-based observations can inform clinical study design whereas questions raised by clinical observations can be explored in laboratory experiments (ie, "translational" research). Additional information is gained through observational, interventional, and synthetic (eg, meta-analytic) clinical studies. Outcomes/effectiveness research determines how well interventions perform in different "real-world" settings. The discussion provides examples of how several of these approaches can be used to address various research questions. The importance for stroke investigators to contribute to related public policy issues is also reviewed.

Conclusions— This is an exciting era for clinical investigators studying stroke and for those at the beginning stages of their careers. Whether taking a broad-based research approach or working on a specific, focused question, our combined efforts are leading to improved outcomes for patients with stroke, the very goal of Bill Feinberg’s career.

Methods— Adult Wistar rats weighing 200 to 250 g received occlusion of the right middle cerebral artery for 90 minutes. At 1 hour after reperfusion, electrodes were implanted to rats on the right frontal epidural space. Electric stimulation, at preset current (0 to 200 µA) and frequency (0 to 50 Hz), was performed for 1 week. Stroke animals were subjected to behavioral tests at 3 days and 1 week postmiddle cerebral artery and then immediately euthanized for protein and immunohistochemical assays. After demonstration of behavioral and histological benefits, subsequent experiments pursued the mechanistic hypothesis that electric stimulation exerted antiapoptotic effects through the phosphoinositide 3-kinase-dependent pathway; thus, cortical stimulation was performed in the presence or absence of specific inhibitors of phosphoinositide 3-kinase (LY294002) in stroke rats.

Results— Cortical stimulation abrogated the ischemia-associated increase in apoptotic cells in the injured cortex by activating antiapoptotic cascades, which was reversed by the phosphoinositide 3-kinase inhibitor LY294002 as reflected behaviorally and immunohistochemically. Furthermore, brain levels of neurotrophic factors (glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, vascular endothelial growth factor) were upregulated, which coincided with enhanced angiogenesis and suppressed proliferation of inflammatory cells in the ischemic cortex.

Conclusions— These results suggest that electric stimulation prevents apoptosis through the phosphoinositide 3-kinase pathway. Consequently, the ischemic brain might have been rendered as a nurturing microenvironment characterized by robust angiogenesis and diminished microglial/astrocytic proliferation, resulting in the reduction of infarct volumes and behavioral recovery. Electric stimulation is a novel and potent therapeutic tool for cerebral ischemia.

Methods— We examined the expression of endogenous markers of mitotic activity, proliferating cell nuclear antigen, and vimentin as a marker for neuronal progenitor cells, if any, in the adult rat cortex after spreading depression stimulation. Immunohistochemical analysis was also performed using antibodies for proliferating cell nuclear antigen, for vimentin, and for nestin. Nestin is a marker for activity dividing neural precursors.

Results— At the end of spreading depression (Day 0), glial fibrillary acidic protein-positive cells in the subpial zone and cortical Layer I demonstrated increased mitotic activity, expressing vimentin and nestin. On Day 1, nestin⁺ cells were found spreading in deeper cortical layers. On Day 3, vimentin^–/nestin⁺, neural precursor-like cells appeared in cortical Layers V to VI. On Day 6, new immature neurons appeared in cortical Layers V to VI. Induced spreading depression evokes cell division of astrocytes residing in the subpial zone, generating neural precursor-like cells.

Conclusions— Although neural precursor-like cells found in cortical Layers V to VI might have been transferred from the germinative zone rather than the cortical subpial zone, astrocytic cells in the subpial zone may be potent neural progenitors that can help to reconstruct impaired central nervous system tissue. Special caution is required when observing or treating spreading depression waves accompanying pathological conditions in the brain.

Methods— A comprehensive literature search was performed as per the Cochrane group guidelines. Only randomized controlled trials that compared overground physical therapy gait training to a placebo intervention or no treatment for chronic stroke patients with mobility deficits were included.

Results— Nine studies involving 499 participants matched the inclusion criteria and had moderate methodological quality. Results were mixed with no significant effect on the primary variable, gait function. Small effects for several performance variables were found: gait speed increased by 0.07 meters per second (95% confidence interval [CI]=0.05 to 0.10) based on 7 studies with 396 participants, timed up-and-go (TUG) test improved by 1.81 seconds (95% CI=–2.29 to –1.33) based on 3 studies and 118 participants, and 6-minute-walk test (6MWT) increased by 26.06 meters (95% CI=7.14 to 44.97) based on 4 studies with 181 participants. No significant differences in adverse events were found.

Conclusions— There is insufficient evidence to determine whether overground gait training directly benefits broad measures of gait function. Results from recent studies, however, suggest that specific training protocols may provide limited benefits for more uni-dimensional performance variables like gait speed, TUG test, and 6MWT.

Methods— Using the population of 2.3 million children (<20 years old) enrolled in a Northern Californian managed care plan (1993 to 2003), we performed electronic searches of (1) inpatient and outpatient diagnoses for International Classification of Diseases, 9th Revision codes suggestive of stroke and cerebral palsy; and (2) radiology reports for key words suggestive of infarction. Cases were confirmed through chart review. We calculated sensitivities and positive predictive values for the 2 search strategies.

Results— We identified 1307 potential cases from the International Classification of Diseases, 9th Revision code search and 510 from the radiology search. A total of 205 ischemic stroke cases were confirmed, yielding an ischemic stroke incidence of 2.4 per 100 000 person-years. The radiology search had a higher sensitivity (83%) than the International Classification of Diseases, 9th Revision code search (39%), although both had low positive predictive values. For perinatal stroke, the sensitivity of the stroke International Classification of Diseases, 9th Revision codes alone was 12% versus 57% for stroke and cerebral palsy codes combined; the radiology search was again the most sensitive (87%).

Conclusions— Our incidence estimate doubles that of prior US reports, a difference at least partially explained by our use of radiology searches for case identification. Studies relying purely on International Classification of Diseases, 9th Revision code searches may underestimate childhood ischemic stroke rates, particularly for neonates.

Methods— Serum bilirubin concentrations were measured in 78 724 health examinees (41 054 men, aged 30–89 years) from 1994 to 2001. The subjects with potential hepatobiliary diseases or Gilbert syndrome were excluded from analysis. Stroke incidence outcome was collected from hospital records of admission attributable to stroke from 1994 to 2007.

Results— Serum bilirubin measurements were divided into 4 levels: 0 to 10.2, 10.3 to 15.3, 15.4 to 22.1, and 22.2 to 34.2 µmol/L. The number of stroke cases was 1137 in men and 827 in women. In Cox proportional hazard models, participants with a higher level of bilirubin showed lower hazard ratios in men with ischemic stroke after adjustment for multiple confounding factors compared to the lowest level of bilirubin (hazard ratio [HR], 0.72; 95% CI, 0.58–0.90 in level 3; HR, 0.66; 95% CI, 0.49–0.89 in level 4; P for trend=0.016). The risk of all stroke types also decreased as bilirubin levels increased (HR, 0.81; 95% CI, 0.68–0.97 in level 3; HR, 0.74; 95% CI, 0.58–0.94 in level 4; P for trend=0.0071). However, these associations were not seen in hemorrhagic stroke or in women.

Conclusions— These findings suggest that serum bilirubin might have some protective function against stroke risk in men.

Methods— The data were derived from a cohort study of 3321 with 17.8 years of follow-up (1985 to 2002). Hazard ratios (HRs) and 95% CIs for strokes as related to body mass index were estimated by Cox proportional hazard models adjusted for age, hypertension, smoking, drinking, occupation, education, self-reported health, and age at menopause. A stratified analysis was conducted by age at menopause and smoking status.

Results— The obese group (body mass index ≥27.5 kg/m²) had higher risks of total stroke mortality (HR, 1.59; 95% CI, 1.05 to 2.42) and hemorrhagic stroke mortality (HR, 2.91; 95% CI, 1.37 to 6.19) than the normal weight group (18.5≤ body mass index <23.0). Among ever smokers, the obese group showed significantly increased risks of total stroke mortality (HR, 2.33; 95% CI, 1.00 to 5.43) and ischemic stroke mortality (HR, 7.21; 95% CI, 1.18 to 44.3). Obesity had more effect on stroke mortality among women who experienced menopause at age <50 than women with age ≥50. For the obese group of the former, the HR of total stroke was 2.04 (95% CI, 1.25 to 3.34) and that of hemorrhagic stroke 6.46 (95% CI, 2.42 to 17.25).

Conclusions— In this prospective study, obesity raised the risks of total stroke mortality and hemorrhagic stroke mortality among Korean menopausal women. It was more evident with women who experienced menopause at age <50. The obese group of ever smokers was at an increased risk of ischemic stroke mortality.

Methods— Two independent studies were performed. In the first, 342 SNPs from 52 candidate genes were genotyped in 307 IS cases and 324 control subjects. The SNPs significantly associated with IS were tested for replication in another cohort of 583 IS cases and 270 control subjects. In the second study, 212 SNPs from 62 candidate genes were analyzed in 710 IS cases with subtyping available and 3751 control subjects.

Results— None of the candidate genes (SNPs) were significantly associated with IS risk independent of known stroke risk factors after correction for multiple hypotheses testing.

Conclusion— These results are consistent with previous meta-analyses that demonstrate an absence of genetic association of variants in plausible candidate genes with IS risk. Our study suggests that the effect of the investigated SNPs may be weak or restricted to specific populations or IS subtypes.

Method— A total of 7760 patients who had received treatment for herpes zoster between 1997 and 2001 were included and matched with 23 280 randomly selected subjects. A 1-year stroke-free survival rate was then estimated using the Kaplan-Meier method. After adjusting for potential confounders, Cox proportional hazard regressions were carried out to compute the adjusted 1-year survival rate.

Results— Of the sampled patients, 439 patients (1.41%) developed strokes within the 1-year follow-up period, that is, 133 individuals (1.71% of the patients with herpes zoster) from the study cohort and 306 individuals (1.31% of patients in the comparison cohort) from the comparison cohort. The log rank test indicated that patients with herpes zoster had significantly lower 1-year stroke-free survival rates than the control (P<0.001). The adjusted hazard ratios of stroke after herpes zoster and herpes zoster ophthalmicus during the 1-year follow-up period were 1.31 and 4.28, respectively.

Conclusion— The risk for stroke increased after a zoster attack. Although varicella zoster virus vasculopathy is a well-documented complication that may induce a stroke postherpes zoster attack, it does not fully account for the unexpectedly high risk of stroke in these patients.

Methods— Consecutive patients with TIA were identified within a prospective population-based cohort study of stroke and TIA. The cohort was expanded by inclusion of patients with MIS and noncerebrovascular events referred to a daily TIA clinic serving the population. Diagnosis was assigned by a trained stroke physician independent of ABCD² score.

Results— Five hundred ninety-four patients were included (292 [49.2%] TIA, 45 [7.6%] MIS, and 257 [43.3%] noncerebrovascular). The mean ABCD² score showed a graded increase across diagnostic groups (MIS mean 4.8 [SD 1.4] versus TIA mean 3.9 [SD 1.5] versus noncerebrovascular mean 2.9 [SD 1.5]; P<0.00001). The ABCD² score discriminated well between noncerebrovascular and cerebrovascular events—TIA (c-statistic 0.68; 95% CI, 0.64 to 0.72), any vascular event (TIA+MIS; c-statistic 0.7; 95% CI, 0.66 to 0.74), and MIS (c-statistic 0.81; 95% CI, 0.75 to 0.87)—from noncerebrovascular events. Of ABCD² items, unilateral weakness (OR, 4.5; 95% CI, 3.1 to 6.6) and speech disturbance (OR, 2.5; 95% CI, 1.6, 4.1) were most likely overrepresented in TIA compared with noncerebrovascular groups.

Conclusion— The ABCD² score had significant diagnostic usefulness for discrimination of true TIA and MIS from noncerebrovascular events, which may contribute to its predictive usefulness.

Methods— Patients with Alzheimer disease with multiple (≥8) MBs on T2*-weighted MRI were matched for age, sex, and field strength with patients with Alzheimer disease without MBs on a 1:2 basis. We included 21 patients with multiple MBs (73±7 years, 33% female) and 42 patients without MBs (72±7 years, 38% female). Mini-Mental State Examination was used to assess dementia severity. Cognitive functions were assessed using neuropsychological tests. Medial temporal lobe atrophy (0 to 4), global cortical atrophy (0 to 3), and white matter hyperintensities (0 to 30) were assessed using visual rating scales. In a subset, apolipoprotein E genotype and cerebrospinal fluid amyloid β 1-42, total and phosphorylated at threonine 181 were determined.

Results— Patients with multiple MBs performed worse on Mini-Mental State Examination (multiple MB: 17±7; no MB: 22±4, P<0.05) despite similar disease duration. Atrophy was not related to presence of MBs, but patients with multiple MBs had more white matter hyperintensities (multiple MB: 8.8±4.8; no MB: 3.2±3.6, P<0.05). Adjusted for age, sex, white matter hyperintensities, and medial temporal lobe atrophy, the multiple MB group additionally performed worse on Visual Association Test object naming and animal fluency. Patients with multiple MBs had lower cerebrospinal fluid amyloid β 1-42 levels (307±61) than patients without MBs (505±201, P<0.05). Adjusted for the same covariates, total , and phosphorylated at threonine 181 were higher in the multiple MB group.

Conclusion— Microbleeds are associated with the clinical manifestation and biochemical hallmarks of Alzheimer disease, suggesting possible involvement of MBs in the pathogenesis of Alzheimer disease.

Methods— A case-control imaging study in a referral institutional tertiary care center was conducted. Systematic brain MRIs, including T2*-weighted sequences, were performed in 60 patients with IE within 7 days of hospital admission and in 120 age- and gender-matched control subjects without IE. Two neuroradiologists, who were blinded to patient characteristics, independently assessed the presence, location, and size of CMBs using a standardized form.

Results— The interobserver agreement level on the presence of CMBs was high with a coefficient range (95% CI) of 0.70 (0.42 to 0.98) for subcortical regions to 0.91 (0.82 to 0.99) for cortical areas. CMBs were more prevalent in patients with IE (57% [n=34]) than in control subjects (15% [n=18]; matched OR, 10.06; 95% CI, 3.88 to 26.07). Moreover, the OR of IE increased gradually with CMBs number with an OR of 6.12 (95% CI, 2.09 to 17.94) for one to 3 CMBs and of 20.12 (95% CI, 5.20 to 77.80) for >3 CMBs.

Conclusion— CMBs are highly frequent in patients with IE. The strong association found between IE and CMBs supports the need for further evaluation of CMBs as additional diagnostic criteria of IE.

Methods— The Northern Manhattan Study includes a stroke-free community-based sample of Hispanic, black, and white participants with quantitative measurement of WMH volume (WMHV) and inflammatory biomarkers. We measured the association between Lp-PLA2, MPO, and hsCRP levels, and log-transformed WMHV after adjusting for sociodemographic and vascular risk factors.

Results— The hsCRP (median, 2.42 mg/L; IQR, 1.04, 5.19), Lp-PLA2 (median, 220.97 ng/mL; IQR, 185.77, 268.05), and MPO (median, 15.14 ng/mL; IQR, 12.32, 19.69) levels were available in 527 The Northern Manhattan Study participants with WMHV data but no subclinical infarcts. Those with hsCRP in the upper quartile (Q4 >4.92 mg/L or >3 mg/L), Lp-PLA2 in Q4 (≥264.9 ng/mL), or MPO levels in Q3 (15.04–19.39 ng/mL) or Q4 (>19.39 ng/mL) each had greater WMHV, adjusting for sociodemographic and vascular risk factors. Adjusting for all biomarkers simultaneously, WMHV was 1.3-fold greater for Lp-PLA2 levels in Q4 compared to Q1 (β=0.28; P=0.008) and 1.25-fold greater for MPO levels above the median compared to below (β=0.22; P=0.02), but hsCRP was not associated with WMHV.

Conclusions— Relative elevations of the inflammatory markers Lp-PLA2 and MPO were associated with a greater burden of WMH independent of hsCRP.

Methods— In this prospective longitudinal hospital-based cohort study, asymptomatic PAD was detected by ankle brachial index measurement in consecutive patients with stroke and patients with TIA. They were assessed for stroke risk factors, ankle brachial index measurement, and laboratory parameters known to be associated with stroke risk. These patients were followed for composite vascular events, including stroke, TIA, myocardial infarction, and vascular death.

Results— In a 1-year period, 102 patients were evaluated, of whom 26% had asymptomatic PAD. All patients were followed for a median period of 2.1 years from the index stroke/TIA (range, 1.0 to 2.7 years) for vascular events. Kaplan–Meier curve showed fewer patients with asymptomatic PAD remained free of composite vascular events (48% compared with 84% in the no-PAD group; log rank, P=0.0001). Asymptomatic PAD was significantly associated with composite vascular events before (hazard ratio, 4.2; 95% CI, 1.9 to 9.3; P=0.0003) and after adjustment for confounders (hazard ratio, from Model 1, 2.8; 95% CI, 1.1 to 7.2; P=0.03 and Model 2, 3.4; 95% CI, 1.4 to 8.2, P=0.006). Asymptomatic PAD was also significantly associated with stroke before (hazard ratio, 6.5; 95% CI, 2.1 to 19.9; P=0.001) and after adjustment for confounders (hazard ratio from Model 1, 4.8; 95% CI, 1.5 to 15.3; P=0.009 and Model 2, 5.2; 95% CI, 1.5 to 17.6; P=0.008).

Conclusions— In patients with stroke or TIA, asymptomatic PAD is independently associated with recurrent vascular events and stroke.

Methods— Prospective longitudinal study was conducted of patients with aSAH with Fisher grade ≥2 and/or Hunt/Hess grade ≥3. Serum cTnI was collected on Days 1 to 5; cohort dichotomized into peak cTnI ≥0.3 ng/mL (elevated) or cTnI <0.3 ng/mL. Relationships among cTnI and aSAH severity, 12-lead electrocardiography early (≤4 days) and late (≥7 days), Holter monitoring on Days 1 to 5, and transthoracic echocardiogram (left ventricular ejection fraction and regional wall motion abnormalities) early (Days 0 to 5) and late (Days 5 to 12) were evaluated.

Results— Of 204 subjects, 31% had cTnI ≥0.3 ng/mL. cTnI ≥0.3 ng/mL was incrementally related to aSAH severity by admission symptoms (Hunt/Hess P=0.001) and blood load (Fisher P=0.028). More patients with cTnI ≥0.3 ng/mL had prolonged QTc on early (63% versus 30%, P<0.0001) and late electrocardiography (24% versus 7%, P=0.024). On Holter monitoring, more patients with cTnI ≥0.3 ng/mL had ventricular tachycardia/fibrillation (22% versus 9%, P=0.018) but not atrial fibrillation/flutter (P=0.241). Cardiac troponin I ≥0.3 ng/mL was associated with both early ejection fraction <50% (44% versus 5%, P<0.0001) and regional wall motion abnormalities (44% versus 4%, P<0.0001). Regional wall motion abnormalities predominated in basal and midventricular segments and persisted to some degree in 73% of patients affected, whereas ejection fraction <50% persisted in 59% of patients affected.

Conclusions— Cardiac injury is incrementally worse with increasing aSAH severity and associated with persistent QTc prolongation and ventricular arrhythmias. Regional wall motion abnormalities and depressed ejection fraction persist to some degree in the majority of those affected.

Methods— Patients with CT-confirmed stroke were randomized to 3 g/day encapsulated fish oil containing approximately 1.2 g total omega-3 (0.7 g docosahexaenoic acid; 0.3 g eicosapentaenoic acid) or placebo oil (combination palm and soy) taken daily over 12 weeks. Serum triglycerides, total cholesterol and associated lipoproteins, selected inflammatory and hemostatic markers, mood, and health-related quality of life were assessed at baseline and follow-up. The primary outcome was change in triglycerides. Compliance was assessed by capsule count and serum phospholipid omega-3 levels (Australian Clinical Trials Registration: ACTRN12605000207617).

Results— One hundred two patients were randomized to fish oil or placebo. Intention-to-treat and per-protocol (>85% compliance) analyses showed no significant effect of fish oil treatment on any lipid, inflammatory, hemostatic, or composite mood parameters measured. Adherence to treatment based on pill count was good (89%) reflected by increased serum docosahexanoic acid (P<0.001) and eicosapentaenoic acid (P=0.0006) in the fish oil group. Analysis of oil composition, however, showed some degradation and potentially adverse oxidation products at the end of the study.

Conclusions— There was no effect of 12 weeks of treatment with moderate-dose fish oil supplements on cardiovascular biomarkers or mood in patients with ischemic stroke. It is possible that insufficient dose, short duration of treatment, and/or oxidation of the fish oils may have influenced these outcomes.

Methods— We prospectively enrolled 42 patients with subarachnoid hemorrhage with clinical deterioration suspect for DCI (new focal deficit or Glasgow Coma Scale decrease ≥2 points) within 21 days after hemorrhage. All patients underwent NCT, CTP, and CTA scans on admission and directly after clinical deterioration. The gold standard was the clinical diagnosis DCI made retrospectively by 2 neurologists who interpreted all clinical data, except CTP and CTA, to rule out other causes for the deterioration. Radiologists interpreted NCT and CTP images for signs of ischemia (NCT) or hypoperfusion (CTP) not localized in the neurosurgical trajectory or around intracerebral hematomas, and CTA images for presence of vasospasm. Diagnostic values for DCI of NCT, CTP, and CTA were assessed by calculating sensitivities, specificities, positive predictive values, and negative predictive values with 95% CIs.

Results— In 3 patients with clinical deterioration, imaging failed due to motion artifacts. Of the remaining 39 patients, 25 had DCI and 14 did not. NCT had a sensitivity of 0.56 (95% CI, 0.37 to 0.73), specificity=0.71 (0.57 to 0.77), positive predictive value=0.78 (0.55 to 0.91), negative predictive value=0.48 (0.28 to 0.68); CTP: sensitivity=0.84 (0.65 to 0.94), specificity=0.79 (0.52 to 0.92), positive predictive value=0.88 (0.69 to 0.96), negative predictive value=0.73 (0.48 to 0.89); CTA: sensitivity=0.64 (0.45 to 0.80), specificity=0.50 (0.27 to 0.73), positive predictive value=0.70 (0.49 to 0.84), negative predictive value=0.44 (0.23 to 0.67).

Conclusion— As a diagnostic tool for DCI, qualitative assessment of CTP is overall superior to NCT and CTA and could be useful for fast decision-making and guiding treatment.

Methods— Forty-six patients were prospectively recruited in whom intra-arterial angiography was being performed. Contrast-enhanced MR angiography, CT angiography, and duplex ultrasound were also performed. Angiographic images were analyzed blinded to patient identity by 2 experienced neuroradiologists.

Results— Contrast-enhanced MR angiography had the highest sensitivity and specificity (Radiologist 1, 0.83 and 0.91, respectively; Radiologist 2, 0.89 and 0.87) for detecting ≥50% stenosis. CT angiography had good sensitivity (Radiologist 1, 0.68; Radiologist 2, 0.58) and excellent specificity (Radiologist 1, 0.92; Radiologist 2, 0.93), whereas duplex had low sensitivity (0.44) but excellent specificity (0.95). For vertebral origin stenosis ≥50%, sensitivities were similar for contrast-enhanced MR angiography (Radiologist 1, 0.91; Radiologist 2, 0.82) but relatively higher for CT angiography (Radiologist 1, 0.82; Radiologist 2, 0.82) and duplex (0.67).

Conclusions— Contrast-enhanced MR angiography is the most sensitive noninvasive technique to detect vertebral artery stenosis and also has high specificity. CT angiography has good sensitivity and high specificity. In contrast, ultrasound has low sensitivity and will miss many vertebral stenoses.

Methods— The authors conducted a prospective, cross-sectional study at an academic hospital. Consecutive patients with AVS (vertigo, nystagmus, nausea/vomiting, head-motion intolerance, unsteady gait) with ≥1 stroke risk factor underwent structured examination, including horizontal head impulse test of vestibulo-ocular reflex function, observation of nystagmus in different gaze positions, and prism cross-cover test of ocular alignment. All underwent neuroimaging and admission (generally <72 hours after symptom onset). Strokes were diagnosed by MRI or CT. Peripheral lesions were diagnosed by normal MRI and clinical follow-up.

Results— One hundred one high-risk patients with AVS included 25 peripheral and 76 central lesions (69 ischemic strokes, 4 hemorrhages, 3 other). The presence of normal horizontal head impulse test, direction-changing nystagmus in eccentric gaze, or skew deviation (vertical ocular misalignment) was 100% sensitive and 96% specific for stroke. Skew was present in 17% and associated with brainstem lesions (4% peripheral, 4% pure cerebellar, 30% brainstem involvement; ², P=0.003). Skew correctly predicted lateral pontine stroke in 2 of 3 cases in which an abnormal horizontal head impulse test erroneously suggested peripheral localization. Initial MRI diffusion-weighted imaging was falsely negative in 12% (all <48 hours after symptom onset).

Conclusions— Skew predicts brainstem involvement in AVS and can identify stroke when an abnormal horizontal head impulse test falsely suggests a peripheral lesion. A 3-step bedside oculomotor examination (HINTS: Head-Impulse—Nystagmus—Test-of-Skew) appears more sensitive for stroke than early MRI in AVS.

Methods— We modeled the effect of different carotid imaging strategies and timing on endarterectomy workload, stroke, and death at 1 and 5 years. We used all available data on stroke prevention after transient ischemic attack from systematic reviews (carotid imaging, medical and surgical interventions), population-based transient ischemic attack/stroke studies, government statistics, and stroke prevention clinics.

Results— Choice of imaging strategy affected speed of assessment, strokes prevented, and endarterectomy workload. The number of strokes prevented at 5 years varied by up to 22 per 1000 patients between imaging strategies for a given time to assessment. Delaying endarterectomy from 14 to approximately 30 days would fail to prevent up to 11 strokes per 1000 patients depending on the imaging strategy. Sensitive fast imaging (eg, ultrasound) was best for patients seen early; specific imaging (eg, CT angiography or contrast-enhanced MR angiography) was best for patients seen late after transient ischemic attack. Intra-arterial angiography conferred no advantage over noninvasive imaging.

Conclusions— Rapid access to sensitive noninvasive carotid imaging prevents most strokes. However, imaging strategies differ in their effect on stroke prevention by as much as 22 per 1000 patients and optimal imaging varies with time after transient ischemic attack TIA. Routine intra-arterial angiography should be avoided.

Methods— This was a double-blind, placebo-controlled, parallel-group, multicenter study of 681 patients stratified according to whether or not tissue plasminogen activator was administered and then randomly assigned to treatment with repinotan or placebo. A continuous 72-hour intravenous infusion of repinotan or placebo was to be started within 4.5 hours from the onset of ischemic symptoms. A Point-of-Care test was used to adjust the infusion rate if appropriate. The goal of Modified Randomized Exposure Controlled Trial (mRECT) was to show whether repinotan is statistically superior to placebo (≤0.10) as measured by the response rate on the primary efficacy variable, Barthel Index (≥85) at 3 months, using a Cochran-Mantel-Haenszel test.

Results— For the intention-to-treat population at 3 months, the response rate on the Barthel Index was 37.1% (127 of 342) for patients on repinotan and 42.4% (143 of 337) for patients taking the placebo (Cochran-Mantel-Haenszel probability value=0.149). No apparent safety concerns were identified.

Conclusions— mRECT demonstrated the feasibility of conducting a rigorous trial using a short therapeutic window demanding clinical and radiographic criteria to optimize patient selection and a Point-of-Care test to achieve a targeted exposure to repinotan. The study failed to demonstrate a clinical benefit of repinotan. The development of repinotan in acute ischemic stroke was discontinued.

Methods— Severity was assessed with the National Institutes of Health Stroke Scale, Barthel Index, and modified Rankin Scale score at enrollment (1 to 6 months after the index event) and 90 days poststroke in subjects having a stroke during the trial.

Results— Over 4.9 years, strokes occurred in 576 subjects. There were reductions in fatal, severe (modified Rankin Scale score 5 or 4), moderate (modified Rankin Scale score 3 or 2), and mild (modified Rankin Scale score 1 or 0) outcome ischemic strokes and transient ischemic attacks and an increase in the proportion of event-free subjects randomized to atorvastatin (P<0.001 unadjusted and adjusted). Results were similar for all outcome events (ischemic and hemorrhagic, P<0.001 unadjusted and adjusted) with no effect on outcome hemorrhagic stroke severity (P=0.174 unadjusted, P=0.218 adjusted). If the analysis is restricted to those having an outcome ischemic stroke (ie, excluding those having a transient ischemic attack or no event), there was only a trend toward lesser severity with treatment based on the modified Rankin Scale score (P=0.0647) with no difference based on the National Institutes of Health Stroke Scale or Barthel Index.

Conclusion— The present exploratory analysis suggests that the outcome of recurrent ischemic cerebrovascular events might be improved among statin users as compared with nonusers.

Methods— Acute ischemic stroke patients aged ≥18 years, who could not walk unassisted, were randomized to receive enoxaparin (40 mg once daily) or UFH (5000 U every 12 hours) for 10 days. Patients were stratified according to baseline stroke severity using the National Institutes of Health Stroke Scale score. End points for this analysis included stroke progression (≥4-point increase in National Institutes of Health Stroke Scale score), neurological outcomes up to 3 months postrandomization (assessed using National Institutes of Health Stroke Scale score and modified Rankin Scale score), and incidence of intracranial hemorrhage.

Results— Stroke progression occurred in 45 of 877 (5.1%) patients in the enoxaparin group and 42 of 872 (4.8%) of those receiving UFH. Similar improvements in National Institutes of Health Stroke Scale and modified Rankin Scale scores were observed in both groups over the 90-day follow-up period. Incidence of intracranial hemorrhage was comparable between groups (20 of 877 [2.3%] and 22 of 872 [2.5%] in enoxaparin and UFH groups, respectively). Baseline National Institutes of Health Stroke Scale score, hyperlipidemia, and Hispanic ethnicity were independent predictors of stroke progression.

Conclusions— The clinical benefits associated with use of enoxaparin for venous thromboembolism prophylaxis in patients with acute ischemic stroke are not associated with poorer long-term neurological outcomes or increased rates of symptomatic intracranial hemorrhage compared with UFH.

Methods— The factorial PRoFESS secondary stroke prevention trial assessed BP-lowering and antiplatelet strategies in 20 332 patients; 1360 were enrolled within 72 hours of ischemic stroke, with telmisartan (angiotensin receptor antagonist, 80 mg/d, n=647) vs placebo (n=713). For this nonprespecified subgroup analysis, the primary outcome was functional outcome at 30 days; secondary outcomes included death, recurrence, and hemodynamic measures at up to 90 days. Analyses were adjusted for baseline prognostic variables and antiplatelet assignment.

Results— Patients were representative of the whole trial (age 67 years, male 65%, baseline BP 147/84 mm Hg, small artery disease 60%, NIHSS 3) and baseline variables were similar between treatment groups. The mean time from stroke to recruitment was 58 hours. Combined death or dependency (modified Rankin scale: OR, 1.03; 95% CI, 0.84–1.26; P=0.81; death: OR, 1.05; 95% CI, 0.27–4.04; and stroke recurrence: OR, 1.40; 95% CI, 0.68–2.89; P=0.36) did not differ between the treatment groups. In comparison with placebo, telmisartan lowered BP (141/82 vs 135/78 mm Hg, difference 6 to 7 mm Hg and 2 to 4 mm Hg; P<0.001), pulse pressure (3 to 4 mm Hg; P<0.002), and rate-pressure product (466 mm Hg.bpm; P=0.0004).

Conclusion— Treatment with telmisartan in 1360 patients with acute mild ischemic stroke and mildly elevated BP appeared to be safe with no excess in adverse events, was not associated with a significant effect on functional dependency, death, or recurrence, and modestly lowered BP.

Methods— In phase 1, the reliability of emergency INR POC measurements in comparison to CL was determined. In phase 2, patients with ischemic stroke admitted within the time frame for systemic thrombolysis and who were either using OAC or for whom information on OAC status was not available were enrolled. Patients received thrombolysis if POC INR was ≤1.5. Precision and time gain was recorded for INR as measured by POC vs CL.

Results— In phase 1 (n=113), Bland-Altman analysis showed close agreement between POC and CL, and Pearson correlation was highly significant (r=0.98; P<0.01). In phase 2, 48 patients were included, of whom 70.8% were using OAC; 23 patients received thrombolysis. After subtracting the time needed for the diagnostic work-up, the net time gain was 28±12 minutes (mean±SD).

Conclusions— Measuring INR by POC in an emergency setting is sufficiently precise in OAC acute stroke patients and substantially reduces the time interval until INR values are available and therefore may hasten the initiation of thrombolysis.

Methods— Eligibility criteria included presentation ≤8 hours after stroke onset, age 18 years or older, National Institutes of Health Stroke Scale score ≥8, angiographic demonstration of focal intracerebral artery occlusion ≤14 mm, and either contraindication to intravenous tissue plasminogen activator or failure to improve 1 hour after intravenous tissue plasminogen activator administration. Exclusion criteria included known hemorrhagic diathesis or coagulopathy, platelet count <100 000, intracranial hemorrhage, blood glucose level of <51 mg/100 mL, or CT perfusion imaging demonstrating more than one-third at-risk territory with nonsalvageable brain (low cerebral blood volume). Data are presented as mean±SD.

Results— Twenty patients were enrolled (mean age, 63±18 years;14 women). Mean presenting National Institutes of Health Stroke Scale was 14±3.8 (median 13). Presenting thrombolysis in myocardial infarction score was 0 (85% of patients) or 1 (15%). Recanalization to thrombolysis in myocardial infarction score of 3 (60% of patients) or 2 (40% of patients; P<0.0001) was achieved. One (5%) symptomatic and 2 (10%) asymptomatic intracranial hemorrhages occurred. At 1-month follow-up, a modified Rankin scale score of ≤3 was achieved in 12 of 20(60%) patients and a modified Rankin scale score of ≤1 was achieved in 9 of 20 (45%) patients.

Conclusion— This Food and Drug Administration-approved prospective study suggests primary intracranial stenting for acute stroke may be a valuable addition to the stroke treatment armamentarium.

Methods— Only cases with first-onset depression <2 years after stroke were considered as PSD in the present series. Diagnosis of depression was established prospectively using DSM-IV criteria for major depression. Neuropathological evaluation included bilateral semiquantitative assessment of microvascular ischemic pathology and lacunes; statistical analysis included Fisher exact test, Mann-Whitney U test, and regression models.

Results— Macroinfarct site was not related to the occurrence of PSD for any of the locations studied. Thalamic and basal ganglia lacunes occurred significantly more often in PSD cases. Higher lacune scores in basal ganglia, thalamus, and deep white matter were associated with an increased PSD risk. In contrast, microinfarct and diffuse or periventricular demyelination scores were not increased in PSD. The combined lacune score (thalamic plus basal ganglia plus deep white matter) explained 25% of the variability of PSD occurrence.

Conclusions— The cumulative vascular burden resulting from chronic accumulation of lacunar infarcts within the thalamus, basal ganglia, and deep white matter may be more important than single infarcts in the prediction of PSD.

Methods— We studied 137 patients within 24 hours of stroke onset with MR diffusion- and perfusion-weighted imaging and a test of hemispatial neglect that distinguishes between viewer-centered and stimulus-centered neglect. Using multivariable linear regression, we identified the independent contributions of severity of ischemia in specific locations, volume of ischemia, and age in accounting for severity of each neglect type.

Results— Severity of hypoperfusion in angular gyrus was the only variable that significantly and independently contributed to severity of viewer-centered neglect. Volume of dysfunctional tissue and hypoperfusion in posterior frontal cortex also accounted for some variability in severity of viewer-centered neglect. Severity of hypoperfusion of superior temporal cortex was the only variable that independently and significantly contributed to severity of stimulus-centered neglect.

Conclusions— Location, severity, and volume of ischemia together determine the type and severity of neglect after right hemisphere stroke. Results also show that perfusion-weighted MRI can be used as a semiquantitative measure of tissue dysfunction in acute stroke and can account for a substantial proportion of the variability in functional deficits in the acute stage.

Methods— We analyzed consecutive cases of first-ever primary intracerebral hemorrhages from 1993 to 2000 in a prospective stroke register covering the Malmö region, Sweden (population approximately 250 000). Mortality rates during 28 days and 3 years of follow-up and recurrence rates were analyzed.

Results— A total of 474 cases were identified (46% women). In patients <75 years of age, 20% of the women and 23% of the men died within 28 days (P=0.38). The corresponding figures in patients ≥75 years were 26% and 41%, respectively (P=0.02). Male sex was an independent risk factor both for 28-day (OR, 1.5; 95% CI, 1.008 to 2.2) and 3-year mortality (OR, 1.7; 95% CI, 1.3 to 2.3). Other independent predictors of death were high age, central and brain stem hemorrhage location, intraventricular hemorrhage, increased volume, and decreased consciousness level. The recurrence rate was 5.1 per 100 person-years, 2.3 per 100 person-years for intracerebral hemorrhage and 2.8 per 100 person-years for cerebral infarction. Only age >65 years was significantly related to recurrent stroke.

Conclusion— Women had better survival than men after primary intracerebral hemorrhages. The difference is largely explained by a higher 28-day mortality in male patients >75 years. However, the underlying reasons are yet to be explored.

Methods— The study sample included Medicare fee-for-service beneficiaries ≥65 years of age discharged with ischemic stroke in 2002 from 5070 hospitals, 317 of which were JC-certified by June 2007. Hierarchical logistic regression and Cox proportional hazards models were used to compare in-hospital mortality, 30-day mortality, and 30-day readmission for patients treated at future JC-certified versus noncertified hospitals.

Results— Among 366 551 patients, 18% (66 300) were treated at hospitals with centers that were JC-certified within the first few years of the program. These patients were younger, more likely to be white and male, and had fewer comorbidities and hospitalizations within the prior year. Unadjusted in-hospital mortality (4.7% versus 5.5%), 30-day mortality (9.8% versus 11.3%), and readmissions (13.8% versus 14.6%) were lower in the future JC-certified hospitals (all P<0.001). These differences remained after risk adjustment (in-hospital mortality: OR, 0.93; 95% CI, 0.90 to 0.96; 30-day mortality: OR, 0.92; 95% CI, 0.87 to 0.96; 30-day readmission: hazard ratio, 0.97; 95% CI, 0.95 to 0.99).

Conclusions— JC Primary Stroke Center-certified hospitals had better outcomes than noncertified hospitals even before the program began. Cross-sectional studies assessing the effects of stroke center certification need to account for these pre-existing differences.

Method— This analysis used the MEDPAR database, which is a claims-based dataset that contains every fee-for-service Medicare-eligible hospital discharge in the US. Cases potentially eligible for rt-PA treatment based on diagnosis were defined as those with a hospital DRG code of 14, 15, or 559, and that also had an ICD-9 code of 433, 434, or 436. Thrombolysis use was defined as an ICD-9 code of 99.1. Study interval was July 1, 2005 to June 30, 2007. Hospital locations were mapped using ArcView software; population densities and regions of the US are based on US Census 2000.

Results— There were 4750 hospitals in the MEDPAR database, which included 495 186 ischemic stroke admissions during the study period. Of these hospitals, 64% had no reported treatments with rt-PA for ischemic stroke, and 0.9% reported >10% treatment rates within the MEDPAR dataset. Bed size, rural or underserved designation, and population density were significantly associated with reported rt-PA treatment rates, and remained significant in the multivariable regression. Approximately 162 million US citizens reside in counties containing a hospital reporting a ≥2.4% treatment rate within the MEDPAR dataset.

Conclusion— We report the first description of US hospital rt-PA treatment rates by hospital. Unfortunately, we found that 64% of US hospitals did not report giving rt-PA at all within the MEDPAR database within a 2-year period. These tended to be hospitals that were smaller (average bed size of 95), located in less densely populated areas, or located in the South or Midwest. In addition, 40% of the US population resides in counties without a hospital that administered rt-PA to at least 2.4% of ischemic stroke patients, although distinguishing transferred patients is problematic within administrative datasets. Such national-based resource-utilization data is important for planning at the local and national level, especially for such initiatives as telemedicine, to reach underserved areas.

Methods— Three hundred ninety stroke survivors constituted the study population. Information on survival data during 5 years of follow-up, all hospital admissions since 1971, all outpatient and primary care consultations, and all municipal social service support during the year before and after the index stroke admission and patient interviews 1 week after discharge were obtained.

Results— The risk of death or a new stroke was high in the early phase after admission but then decreased rapidly during the next few months. Mortality during the first 5 years was influenced by age and functional ability, whereas the risk of stroke recurrence was influenced by number of previous strokes, hypertension diagnosis, and sex. On a day-by-day basis, 35% were dependent on municipal support before and 65% after the stroke. The corresponding proportions in outpatient care were 6% and 10%, and for hospital inpatient care 1% to 2% and 2% to 3%. Of the health care provided, nursing care dominated.

Conclusions— The risk of dying or having a new stroke event decreased sharply during the early postmorbid phase. Healthcare utilization increased after discharge but was still moderate on a day-by-day basis, except for municipal social service support, which was substantial.

Methods— Consecutive patients with stroke treated with recombinant tissue plasminogen activator in 10 Japanese stroke centers were included.

Results— A total of 600 patients (377 men, 72±12 years old) were studied. Median National Institutes of Health Stroke Scale scores decreased from 13 before recombinant tissue plasminogen activator to 8 at 24 hours later. Symptomatic intracerebral hemorrhage within 36 hours with a ≥1-point increase from the baseline National Institutes of Health Stroke Scale score developed in 23 patients (3.8%; 95% CI, 2.6% to 5.7%). At 3 months, 43 patients had died (7.2%; 5.4% to 9.5%), and 199 patients (33.2%; 29.5% to 37.0%) had a modified Rankin Scale score ≤1. Analysis of 399 patients with a premorbid modified Rankin Scale score ≤1 who met the criteria of the European license (≤80 years old, an initial National Institutes of Health Stroke Scale score ≤24, etc) showed that 40.6% (35.9% to 45.5%) had a 3-month modified Rankin Scale score ≤1. After multivariate adjustment, younger age, lower initial National Institutes of Health Stroke Scale score, absence of internal carotid artery occlusion, higher Alberta Stroke Program Early CT Score on CT, and absence of intravenous antihypertensives just before recombinant tissue plasminogen activator were independently related to a 3-month modified Rankin Scale score ≤1. Congestive heart failure and hyperglycemia were independently related to mortality.

Conclusions— Three-month outcomes of patients receiving low-dose intravenous recombinant tissue plasminogen activator therapy in the present study were similar to those from postmarketing surveys using 0.9 mg/kg alteplase.

Methods— Adeno-associated viral vector (AAV)-VEGF, an adeno-associated viral vector expressing VEGF, was injected into the brain of 3-, 12-, and 24-month-old mice. AAV-LacZ-injected mice were used as controls (n=6). Before euthanasia at 6 weeks after vector injection, the mice were intraperitoneally injected with 5-bromodeoxyuridine for 3 consecutive days. The vascular density and the number of neuroprogenitors were analyzed.

Results— Injection of AAV-VEGF increased the vascular density in the brain of 3-, 12-, and 24-month-old mice by 22%±7% (AAV-VEGF: 320±15 per 10x field versus AAV-LacZ: 263±8, P<0.05), 20%±8 (AAV-VEGF: 300±9 versus AAV-LacZ: 250±11, P<0.05), and 7%±16% (AAV-VEGF: 257±27 versus AAV-LacZ: 236±13, P=0.283), respectively. There were more VEGF receptor-positive neuroprogenitors in the subventricular zone of AAV-VEGF-injected 3- (22±2) and 12-month-old mice (21±5) than that of 24-month-old mice (7±1). More 5-bromodeoxyuridine-positive endothelial cells and neuroprogenitors were detected around the injection site and subventricular zone of 3- (13±4) and 12-month-old mice (14±5) than that of 24-month-old mice (1±1). VEGF receptor 2 was upregulated in AAV-VEGF-injected brains of 3- and 12-month-old mice, but not in 24-month-old mice.

Conclusion— The angiogenic and neurogenic response to VEGF stimulation is attenuated in the aged mouse brain, which may be due to reduced VEGF receptor activity.

Methods— In Experiment 1, mice were exposed to 3 weeks of daily restraint (3 hours) and then subjected to either 8 minutes of cardiac arrest/cardiopulmonary resuscitation (CA/CPR) or sham surgery. Anxiety-like behavior, microglial activation, and neuronal damage were assessed on postischemic Day 4. In Experiment 2, mice were infused intracerebroventricularly with minocycline (10 µg/day) to determine the effect of inhibiting post-CA/CPR microglial activation on the development of anxiety-like behavior and neuronal death.

Results— CA/CPR precipitated anxiety-like behavior and increased microglial activation and neuronal damage within the hippocampus relative to sham surgery. Prior exposure to stress exacerbated these measures among CA/CPR mice, but had no significant effect on sham-operated mice. Treatment with minocycline reduced both neuronal damage and anxiety-like behavior among CA/CPR animals. Anxiety-like behavior was significantly correlated with measures of microglial activation but not neuronal damage.

Conclusions— A history of stress exposure increases the pathophysiological response to ischemia and anxiety-like behavior, whereas inhibiting microglial activation reduces neuronal damage and mitigates the development of anxiety-like behavior after CA/CPR. Thus, modulating inflammatory signaling after cerebral ischemia may be beneficial in protecting the brain and preventing the development of affective disorders.

Methods— By means of Western blotting, patch-clamp electrophysiology, single-cell Fura-2 acetoxymethyl-ester microfluorometry, immunohistochemistry, and confocal microscopy, we investigated the regional and temporal changes of NCX1 protein in microglial cells of the peri-infarct and core regions after permanent middle cerebral artery occlusion. The exchanger expression and activity were measured in primary microglia isolated ex vivo from the core region of adult rat brains 7 days after permanent middle cerebral artery occlusion and in cultured microglia under in vitro hypoxia.

Results— One day after permanent middle cerebral artery occlusion, NCX1 protein expression was detected in some microglial cells adjacent to the soma of neurons in the infarct core. More interestingly, 3 and 7 days after permanent middle cerebral artery occlusion, NCX1 signal strongly increased in the round-shaped microglia invading the infarct core. Cultured microglial cells obtained from the core also displayed increased NCX1 expression as compared with contralateral cells and showed enhanced NCX activity in the reverse mode of operation. Similarly, NCX activity and NCX1 protein expression were significantly enhanced in BV2 microglia exposed to oxygen and glucose deprivation, whereas NCX2 and NCX3 were downregulated. Interestingly, in NCX1-silenced cells, [Ca²⁺]_i increase induced by hypoxia was completely prevented.

Conclusion– The upregulation of NCX1 expression and activity observed in microglia after permanent middle cerebral artery occlusion suggests a relevant role of NCX1 in modulating microglia functions in the postischemic brain.

Methods— Male SV129 mice were exposed to a 20-minute middle cerebral artery occlusion; hippocampi were then analyzed for Shh mRNA and protein expression by real-time polymerase chain reaction, immunoblot, and immunohistochemistry. Primary cell cultures of neurons, astrocytes, and NPCs were exposed to 16 hours of hypoxia (1% O₂) and analyzed by real-time polymerase chain reaction and immunoblot for Shh expression. Proliferation of NPCs, in vivo and in vitro, was measured by bromodeoxyuridine incorporation.

Results— Among the cell types examined in vitro, only NPC and neurons increased Shh mRNA under hypoxic conditions. Furthermore, hypoxia increased proliferation of NPCs and this proliferation was enhanced by the addition of recombinant Shh or blocked by the pathway-specific inhibitor, cyclopamine. Middle cerebral artery occlusion was associated with a transient 2-fold increase in the mRNA encoding both Shh and its transcription factor, Gli1, 0.5 days after ischemia. Within the hippocampus, Shh protein was increased approximately 3-fold 3 and 7 days after ischemia and was observed predominantly within cells in the CA3 and hilar regions. Shh was expressed only in mature neurons. In vivo, cyclopamine suppressed ischemia-induced proliferation of subgranular NPCs.

Conclusion— The Shh pathway plays a role in the proliferation of NPCs induced by ischemia/hypoxia and might participate in injury remodeling.

Methods— Clinical and radiological data from consecutive tpa-ineligible stroke patients with large anterior circulation infarcts involving either the entire internal carotid artery or the proximal middle cerebral artery territory were analyzed. Stroke subtypes were categorized according to TOAST criteria. Neurological deficits were assessed with the NIH stroke scale (NIHSS), and vessel recanalization was determined using the thrombolysis in myocardial infarction (TIMI) scale at the end of MRRT. Good outcome was defined as a modified Rankin score (mRS) ≤2.

Results— Fifty patients were included with a median age of 68. Thirteen patients died and 17 patients achieved an mRS ≤2 at 90 days. Variables associated with survival on multivariate analysis were admission NIHSS <20 (OR 15 95% CI 1 to 230) and postprocedure TIMI score 2 to 3 (OR 35.5 95% CI 2.3 to 603.9). Variables associated with good outcome included admission NIHSS <20 (OR 9.4 95% CI 1.3 to 71.3), day 1 NIHSS <15 (OR 6.4 95% CI 1.1 to 38.4), and postprocedure TIMI 3 (OR 7.4 95% CI 1.1 to 50.3).

Conclusions— MMRT resulted in high survival and good outcome rates in these critically ill patients. Lower baseline impairment and vessel recanalization increase the chances for good outcome. Our results suggest that the benefits of MMRT may merit further study and could be generalized to centers outside the United States and Europe.

Methods— We reviewed medical records of consecutive ischemic stroke admissions treated with intravenous thrombolysis over a 10-year period at our tertiary care hospital. The National Institutes of Health Stroke Scale score on admission was used to determine baseline stroke severity. The closest documented blood pressure values to the time of tissue plasminogen activator bolus (range, 0 to 10 minutes) were considered as pretreatment blood pressure. Pretreatment blood pressure protocol violations were identified as systolic blood pressure >185 or diastolic blood pressure >110 mm Hg prebolus. sICH was defined as brain imaging evidence of intracranial hemorrhage with clinical worsening by the National Institutes of Health Stroke Scale score increase of ≥4 points.

Results— Among 510 patients with ischemic stroke treated with intravenous tissue plasminogen activator (282 men; mean age, 65±15 years), sICH occurred in 31 patients (6.1%). Blood pressure protocol violations were present in 63 patients (12.4%) and they were more frequent in patients with sICH (26% versus 12%; P=0.019). After adjusting for demographic characteristics, onset-to-treatment time, baseline National Institutes of Health Stroke Scale, stroke risk factors and medications, pretreatment blood pressure protocol violations were independently associated with a higher likelihood of sICH (OR, 2.59; 95% CI, 1.07 to 6.25; P=0.034).

Conclusions— These data support current guidelines advising not to use intravenous tissue plasminogen activator when pretreatment blood pressure exceeds the prespecified thresholds by showing that blood pressure protocol violations are independently associated with a higher likelihood of sICH.

Methods— We conducted a retrospective review of patients with CIS who presented to our stroke center. Thrombolytic treatment was compared between cocaine-positive (n=29) and cocaine-negative (n=75) patients. We also compared patients with CIS treated with tissue plasminogen activator versus those who did not receive tissue plasminogen activator (n=58). Safety outcomes were determined by the incidence of symptomatic intracerebral hemorrhage, in-hospital mortality, and modified Rankin Scale at hospital discharge.

Results— There were no complications in tissue plasminogen activator-treated patients with CIS. Cocaine-positive and cocaine-negative treated patients had similar stroke severity and safety outcomes. Patients with CIS treated with tissue plasminogen activator had more severe strokes on baseline National Institutes of Health Stroke Scale but similar safety outcomes compared with nontreated patients with CIS.

Conclusion— Thrombolytic therapy for CIS appears to be safe in this small study. Further research is needed to more definitively assess safety and efficacy of tissue plasminogen activator for CIS.

Methods— A total of 141 ischemic stroke patients on warfarin therapy were enrolled in this study. One hundred five patients with similar demographic features who do not use warfarin were chosen as controls. We compared vascular risk factors and radiological findings including CMBs and leukoaraiosis between the groups.

Results— CMBs on gradient-echo MRI (GE-MRI) were found in 31 patients (22%) and 17 controls (16%) and there was not a significant difference between 2 groups (P=0.25). Study patients with CMBs were older than patients without CMBs (P=0.04) and frequency of leukoaraiosis was significantly higher (P=0.008). Mean duration of warfarin treatment was not different between the patients with and without CMBs (P=0.83).

Conclusion— Although patients with CMBs were older and had more leukoaraiosis the impact of warfarin treatment on CMBs is still controversial.

Methods— Using data from the Stroke Prevention in Young Women study, a population-based case-control study including 297 women aged 15 to 49 years with ischemic stroke and 422 women without stroke, we evaluated whether polymorphisms in genes regulating endothelial function, including endothelin-1 (EDN), endothelin receptor type B (EDNRB), and nitric oxide synthase-3 (NOS3), confer susceptibility to migraine and stroke.

Results— EDN SNP rs1800542 and rs10478723 were associated with increased stroke susceptibility in whites (OR, 2.1; 95% CI, 1.1–4.2 and OR, 2.2; 95% CI, 1.1–4.4; P=0.02 and 0.02, respectively), as were EDNRB SNP rs4885493 and rs10507875, (OR, 1.7; 95% CI, 1.1–2.7 and OR, 2.4; 95% CI, 1.4–4.3; P=0.01 and 0.002, respectively). Only 1 of the tested SNP (NOS3 rs3918166) was associated with both migraine and stroke.

Conclusions— In our study population, variants in EDN and EDNRB were associated with stroke susceptibility in white but not in black women. We found no evidence that these genes mediate the association between migraine and stroke.

Summary of Review— This "neuroprotection strategy" has focused primarily on targets in the neurotoxic environment that occurs under ischemic conditions. In many cases, these agents were designed to tackle events that are known to start almost immediately after onset of ischemia, which is far before a realistic therapeutic time window opens for most, if not all, patients with stroke. In other instances, they were evaluated beyond a realistic timeframe in which one could expect significant salvageable tissue or penumbra to exist. Surprisingly, most of these agents were not evaluated in conjunction with strategies for improving perfusion to the affected tissue, indicating an overoptimistic assumption that neuroprotection alone could be sufficient to halt injury caused by an abrupt interruption of brain blood flow.

Conclusions— We provide a constructive translational medicine perspective about how one could improve the drug development process with the hope that the probability for success can increase in our quest to establish a novel therapy for stroke.

Methods— We performed a systematic review of all studies published from 1980 to 2008 inclusive that reported the risk of stroke and death due to CEA in relation to the time between presenting symptom and surgery. Pooled estimates of risk by the time since the last event were obtained by Mantel–Haenszel meta-analysis.

Results— Of 494 published operative series, only 47 stratified risk by timing of surgery. The pooled absolute risks of stroke and death after urgent CEA were high in patients with stroke-in-evolution (20.2%, 95% CI 12.0 to 28.4) and in patients with crescendo TIA (11.4%, 6.1 to 16.7), with no trends toward reduced risks in more recent studies. However, there was no significant difference between early and later CEA in neurologically stable patients with recent TIA or nondisabling stroke (<1 week versus ≥1 week, OR=1.2, 0.9 to 1.7, P=0.17; <2 weeks versus ≥2 weeks, OR=1.2, 0.9 to 1.6, P=0.13).

Conclusions— Emergency endarterectomy for stroke-in-evolution has a high operative risk, but the risk may be somewhat lower in patients with crescendo TIA. Surgery in the first week in neurologically stable patients with TIA or minor stroke is not associated with a substantially higher operative risk than delayed surgery. More data are required on the risk and benefit of more urgent surgery for TIA and minor stroke and for early versus delayed surgery in patients with major nondisabling stroke.

Methods— This cross-sectional study examined associations of hopelessness and depressive symptoms with carotid artery intimal-medial thickening (IMT) in 559 women (62% white, 38% black; mean±SD age, 50.2±2.8 years) without evidence of clinical CVD from the Study of Women’s Health Across the Nation (SWAN) Heart Study. Hopelessness was measured by 2 questionnaire items; depressive symptoms were measured with the 20-item Center for Epidemiological Studies Depression Scale. Mean and maximum IMT were assessed by B-mode ultrasonography of the carotid arteries.

Results— Increasing hopelessness was significantly related to higher mean (P=0.0139) and maximum (P=0.0297) IMT in regression models adjusted for age, race, site, income, and CVD risk factors. A weaker pattern of associations was noted for depressive symptoms and mean (P=0.1056) and maximum (P=0.0691) IMT. Modeled simultaneously in a risk factor-adjusted model, hopelessness was related to greater mean IMT (P=0.0217) and maximum IMT (P=0.0409), but depressive symptoms were unrelated to either outcome (P>0.4). No interactions with race or synergistic effects of depressive symptoms and hopelessness were observed.

Conclusions— Among middle-aged women, higher levels of hopelessness are associated with greater subclinical atherosclerosis independent of age, race, income, CVD risk factors, and depressive symptoms.

Methods— IMT was measured by B-mode ultrasound and DNA was collected from a population-based sample of South Asian (n=328), Chinese (n=302), and European Caucasian (n=268) participants. Genetic association was measured using multivariate linear regression including adjustment for covariates.

Results— The most robust association across all models tested was observed for a SNP (rs3791398) in histone deacetylase 4 (HDAC4; P=1.8e-5 to P=3.6e-5), while another strong association signal was observed with natriuretic peptide receptor a/guanylate cyclase A (NPR1) (rs10082235, P=5.4e-5). Seven of 13 previously reported functional candidate genes contained a SNP that was marginally associated (0.01<P≤0.05).

Conclusion— This initial multi-ethnic high-density association study of carotid IMT suggests some novel loci requiring further evaluation in follow-up studies.

Methods— We examined relations of carotid IMT to prospective trajectories of cognitive function among 538 (aged 20 to 93, 39% male, 66% white) participants in the Baltimore Longitudinal Study of Aging (BLSA) free of known cardiovascular, cerebrovascular, and neurological disease. Participants underwent initial carotid ultrasonography and repeat neuropsychological testing on up to 8 occasions over up to 11 years of follow-up. Mixed-effects regression analyses were adjusted for age, gender, race, education, mean arterial pressure, body mass index, total cholesterol, smoking, depressive symptoms, and cardiovascular medication use.

Results— Individuals with greater carotid IMT displayed accelerated decline in performance over time on multiple tests of verbal and nonverbal memory, as well as a test of semantic association fluency and executive function.

Conclusions— Carotid IMT predicts accelerated cognitive decline, particularly in the domain of memory, among community-dwelling individuals free of vascular and neurological disease.

Methods— The sample consisted of 3C-Dijon study participants who had 2 cerebral MRIs, at entry and at 4-year follow-up. WML volumes were estimated using a fully automatic procedure. We performed analysis of covariance to evaluate the relationship between apolipoprotein E genotype and WML load and progression.

Results— Multivariable analyses showed that 44 individuals had both significantly higher WML volume at baseline and higher WML increase over 4-year follow-up than noncarriers and heterozygous of the 4 allele for apolipoprotein E genotype.

Conclusion— These findings suggest it might be important to take into account WML severity when assessing the relationship between apolipoprotein E and dementia.

Methods— In 172 individuals, circulating EPC were defined by the surface markers CD31 and von Willebrand factor. ARWMC were rated on CT scan using the ARWMC scale and divided into 3 groups based on ARWMC scale score (ARWMC score 0 [none], score 1–10 [mild-to-moderate], score >10 [severe]). Severity of ARWMC was correlated with levels of EPC and vascular risk factors.

Results— On univariate analysis, EPC were found to be significantly lower in patients with severe ARWMC (P=0.01). ARWMC were also associated with hypertension (P<0.001), age (P<0.001), creatinine clearance (P=0.031), C-reactive protein (P<0.001), and use of angiotensin-converting enzyme or angiotensin receptor blocker (P=0.004). Multiple logistic regression analysis identified EPC level, age, hypertension, and hypertriglyceridemia as significant independent predictors of severe ARWMC.

Conclusions— Levels of circulating EPC were significantly lower in patients with severe ARWMC. Other variables significantly associated with severe ARWMC were age, hypertension, and hypertriglyceridemia. Further study is required to delineate the pathophysiological relationship between EPC, vascular risk factors, and ARWMC.

Methods— We studied 149 patients with acute ischemic stroke of SVD etiology according to Trial Of Org 10172 In Acute Stroke Treatment criteria and 25 age-matched control subjects. Patients were classified into focal-SVD: 39 patients with isolated lacunar infarct without leukoaraiosis and diffuse-SVD: 110 patients with an isolated lacunar infarct with leukoaraiosis or with multiple lacunar infarcts with or without leukoaraiosis. Baseline data included vascular risk factors and extensive laboratory tests, including plasma Aβ levels.

Results— Median [quartiles] Aβ_1-40 levels (40.4 [35.1, 50.5] versus 55.1 [42.3, 69.6] pg/mL), but not Aβ_1-42 levels, were significantly higher in the diffuse-SVD group than in focal-SVD group (P<0.001) and control subjects (P<0.001). No differences in Aβ_1-40 levels were found between focal-SVD and control subjects. Logistic regression analysis showed that age (OR, 1.06; 95% CI, 1.01 to 1.12), history of hypertension (OR, 3.5; 95% CI, 1.3 to 9.2), and plasma β-amyloid_1-40 levels over the median value (OR, 17.3; 95% CI, 3.0 to 99 for the third quartile and OR, 6.0; 95% CI, 1.6 to 23 for the fourth quartile) were independently associated with the diffuse-SVD subtype.

Conclusions— Plasma β-amyloid_1-40 levels are independently associated with the diffuse-SVD subtype. These results are consistent with the pathophysiological role of fraction Aβ_1-40 in disrupting endothelial vascular function.

Methods— We performed a retrospective cohort study for patients admitted from our emergency department with a new diagnosis of transient ischemic attack confirmed by a neurologist. ABCD² scores were calculated and patients with a score of ≥4 were placed in the high-risk cohort. Tests evaluated included electrocardiogram, CT, MRI, MR angiography, carotid ultrasonography, and echocardiography. Specific test findings considered to signify positive diagnostic tests were created a priori.

Results— We identified 256 patients with transient ischemic attack for inclusion; 167 (61%) were female, the median age was 60 years (interquartile range, 50 to 72), and 162 (63%) patients had an ABCD² score of ≥4. Rates of completion of diagnostic testing were electrocardiogram, 270 (100%); CT, 224 (88%); MRI, 89 (35%); MR angiography, 68 (27%); carotid ultrasonography, 125 (49%); and echocardiography, 135 (53%). Univariate analysis found a significant association only with elevated ABCD² score and carotid duplex testing (P<0.05).

Conclusion— An elevated ABCD² score may help predict patients with severe carotid occlusive disease but does not predict positive outcome in other commonly ordered tests for patients being evaluated for transient ischemic attack. An elevated ABCD² score cannot be recommended as a tool to guide diagnostic testing in patients presenting acutely with transient ischemic attack.

Methods— We assessed symptoms of chronic bronchitis, frequency of flu-like illnesses, and behavior during acute febrile infection in 370 consecutive patients with ischemic or hemorrhagic stroke or TIA and 370 age- and sex-matched control subjects randomly selected from the population.

Results— Cough with phlegm during ≥3 months per year (grade 2 symptoms of chronic bronchitis) was associated with stroke or TIA independent from smoking history, other risk factors, and school education (odds ratio [OR] 2.63, 95% confidence interval [CI] 1.17 to 5.94; P=0.021). There was also an independent association between frequent flu-like infections (>2 per yr) and stroke/TIA (OR 3.54; 95% CI 1.52 to 8.27; P=0.003). Simultaneous assessment of chronic bronchitis and frequent flu-like infections did not attenuate the effect of either factor. Patients reported more often than control subjects to continue to work despite febrile infection (OR 3.68, 95% CI 1.80 to 7.52, multivariate analysis).

Conclusions— Our results suggest that chronic bronchitis is among those chronic infections that increase the risk of stroke. Independent from chronic bronchitis, a high frequency of flu-like illnesses may also be a stroke risk factor. Infection-related behavior may differ between stroke patients and control subjects.

Methods— We conducted a cross-sectional cohort study in a university hospital from January 2002 to December 2003. Consecutive Chinese patients with acute ischemic stroke underwent CT brain, MRI brain (with MR angiography and diffusion-weighted imaging sequences), and carotid duplex.

Results— In total, 251 patients were included in the analysis. Of these, 109 (43%) had concurrent stenoses. Patients who had concurrent stenoses, as compared with those without concurrent stenoses, had more symptomatic stenoses (84% versus 58%; OR, 4.0; 95% CI, 2.1 to 7.3; P<0.001), more concomitant perforating artery infarct, pial infarct, and borderzone infarct (14% versus 4%; OR, 3.6; 95% CI, 1.4 to 9.7; P=0.007), more multiple diffusion-weighted imaging lesions (55% versus 37%; OR, 2.1; 95% CI, 1.3 to 3.4; P=0.005), and more infarcts in the territory of the leptomeningeal branches of middle cerebral artery (26% versus 13%; OR, 2.2; 95% CI, 1.2 to 4.3; P=0.01). In multivariate regression analysis, smoking; prior stroke; the presence of concomitant pial infarct, pial infarct, and borderzone infarcts; multiple diffusion-weighted imaging lesions; and symptomatic stenoses were significantly associated with concurrent stenoses. Among patients with concurrent stenoses, those who had tandem lesions, as compared with those who had nontandem lesions, had more perforating artery infarct and borderzone infarcts (27% versus 8%; OR, 4.3; 95% CI, 0.9 to 19.8; P=0.04); more concomitant pial infarct, pial infarct, and borderzone infarcts (18% versus 0%; P=0.02), and more multiple diffusion-weighted imaging lesions (65% versus 23%; OR, 6.2; 95% CI, 2.2 to 17.2; P<0.001). Infarcts in the territory of middle cerebral artery leptomeningeal branches and symptomatic stenoses were more common in patients with tandem lesions.

Conclusions— Concomitant perforating artery infarct, pial infarct, and borderzone infarcts; multiple diffusion-weighted imaging lesions, and infarcts in the leptomeningeal branches of the middle cerebral artery were more common in patients with concurrent stenoses, especially those with tandem lesions. This study suggested that the combination of hemodynamic compromise attributable to concurrent stenoses and artery-to-artery embolization is a common stroke mechanism in these patients.

Methods— Consecutive patients with ischemic stroke referred to a neurovascular ultrasound laboratory were evaluated from March 2007 to February 2008. PI was defined as (peak systolic velocity–end-diastolic velocity)/mean flow velocity as recommended. Transcranial Doppler was examined in both middle cerebral arteries and vertebral arteries, and basilar arteries. All patients with ischemic stroke were subdivided according to the presence of proximal internal carotid arterial steno-occlusion (ICS).

Results— The numbers of patients enrolled for the present analysis as ischemic stroke without and with ICS were 272 and 92, respectively. PIs measured in the cerebral arteries did not show a significant difference in the two groups, in spite of the fact that mean flow velocities of both basilar arteries and vertebral arteries were significantly elevated in the patients with ICS. Plasma tHcy was found to be independently associated with graded increases of PIs in all cerebral arteries in the patients without ICS, even adjusted for the potential confounders. However, there was no association between tHcy and PI in the patients with ICS.

Conclusion— Plasma tHcy was directly associated with increased cerebral arterial resistance. But in clinical situations when the cerebral arterial hemodynamics were altered as in the patients with ICS, the effect of tHcy on arterial remodeling could be obscured.

Methods— We studied clinical, MRI, and angiographic data of 86 consecutive MMI patients. The lesions were correlated with clinical findings, and long-term outcomes, divided into mild and severe (modified Rankin scale >3), were assessed by telephone interview. Central poststroke pain (CPSP) was defined as persistent pain with visual numeric scale ≥4.

Results— The lesions were located mostly in the rostral medulla (rostral 76%, rostral+middle 16%), while ventro-dorsal lesion patterns include ventral (V, 20%), ventral+middle (VM, 33%), and ventral+middle+dorsal (VMD, 41%). Clinical manifestations included motor dysfunction in 78 patients (91%), sensory dysfunction in 59 (73%), and vertigo/dizziness in 51 (59%), each closely related to involvement of ventral, middle, and dorsal portions, respectively (P<0.001, each). Vertebral artery (VA) atherosclerotic disease relevant to the infarction occurred in 53 (62%) patients, mostly producing atheromatous branch occlusion (ABO). Small vessel disease (SVD) occurred in 24 (28%) patients. ABO was more closely related to VMD (versus V+VM) than was SVD (P=0.035). During follow-up (mean 71 months), 11 patients died, and recurrent strokes occurred in 11. Old age (P=0.001) and severe motor dysfunction at admission (P=0.001) were factors predicting poor prognosis. CPSP, occurring in 21 patients, was closely (P=0.013) related to poor clinical outcome.

Conclusion— MMI usually presents with a rostral medullary lesion, with a good clinical ventro-dorsal imaging correlation, caused most frequently by ABO followed by SVD. A significant proportion of patients remain dependent or have CPSP.

Methods— Leukocyte/lymphocyte subsets were assessed serially by white blood cell count and fluorescence-activated cell sorter analysis in ischemic stroke patients (n=50) at baseline, day 1, and day 4 after stroke onset and compared to an age-matched control group (n=40). Concomitantly, monocytic human leukocyte antigen-DR expression and the in vitro function of blood monocytes measured by the production of tumor necrosis factor- upon stimulation with lipopolysaccharide were assessed. Associations of these immunologic parameters with stroke specific factors (National Institutes of Health Stroke Scale, infarct size) were explored. Multivariable logistic regression analysis was applied to identify early predictors for poststroke respiratory and urinary tract infections.

Results— Infarct volume was the main factor associated with lymphocytopenia on day 1 and day 4 poststroke. Particularly, blood natural killer cell counts were reduced after stroke. Monocyte counts increased after ischemia paralleled by a profound deactivation predominantly after extensive infarcts. Reduced T helper cell counts, monocytic human leukocyte antigen-DR expression, and monocytic in vitro production of tumor necrosis factor- were associated with infections in univariate analyses. However, only stroke volume prevailed as independent early predictor for respiratory infections (OR 1.03; CI 1.01 to 1.04).

Conclusions— Infarct volume determines the extent of lymphocytopenia, monocyte dysfunction, and is a main predictor for subsequent infections.

Methods— Serum samples were collected at 4 annual intervals in 52 stroke-free participants from the Northern Manhattan Study (NOMAS) and assayed for hsCRP and Lp-PLA₂ mass and activity levels using standard techniques. Log transformation of levels was performed as needed to stabilize the variance. Stability of marker levels over time was assessed using random effects models unadjusted and adjusted for demographics and other risk factors. In addition, samples from 37 initially stroke-free participants with stroke (n=17) or MI (n=20) were available for measurement before and after the vascular event (median 5 days, range 2 to 40 days). Levels before and after events were compared using nonparametric tests.

Results— HsCRP and Lp-PLA₂ activity levels were stable over time, whereas Lp-PLA₂ mass levels decreased on average 5% per year (P=0.0015). Using accepted thresholds to define risk categories of Lp-PLA₂ mass, there was no significant change over time. HsCRP increased after stroke (from median 2.2 mg/L prestroke to 6.5 mg/L poststroke; P=0.0067) and MI (from median 2.5 mg/L pre-MI to 13.5 mg/L post-MI; P<0.0001). Lp-PLA₂ mass and activity levels both decreased significantly after stroke and MI (for Lp-PLA₂ mass, from median 210.0 ng/mL to 169.4 ng/mL poststroke, P=0.0348, and from median 233.0 ng/mL to 153.9 post-MI, P<0.0001).

Conclusion— Lp-PLA₂ mass levels decrease modestly, whereas hsCRP and Lp-PLA₂ activity appear stable over time. Acutely after stroke and MI, hsCRP increases whereas Lp-PLA₂ mass and activity levels decrease. These changes imply that measurements made soon after stroke and MI are not reflective of prestroke levels and may be less reliable for long-term risk stratification.

Methods— Thirty-five experts participated in the consensus process. The presented recommendations were approved during a meeting of the consensus group in October 2008 in Giessen, Germany. The project was an initiative of the German Competence Network Stroke and performed under the auspices of the Neurosonology Research Group of the World Federation of Neurology.

Results— Recommendations are given on how examinations should be performed in the time-limited situation of acute stroke, including criteria to assess the quality of the acoustic bone window, the use of echo contrast agents, and the evaluation of intracranial vessel status. The important issues of the examiners’ training and experience, the documentation, and analysis of study results are addressed. One central aspect was the development of standardized criteria for diagnosis of arterial occlusion. A transcranial color-coded duplex sonography recanalization score based on objective hemodynamic criteria is introduced (consensus on grading intracranial flow obstruction [COGIF] score).

Conclusions— This work presents consensus statements in an attempt to standardize the application of transcranial color-coded duplex sonography in the setting of acute stroke research, aiming to improve the reliability and reproducibility of the results of future stroke studies.

Methods— Baseline and follow-up DWI and PWI lesions and 30-day fluid-attenuated inversion recovery scans of 32 patients were coregistered. Lesion geography was defined by the proportion of the DWI lesion superimposed by a T_max (time when the residue function reaches its maximum) >4 seconds PWI lesion; Type 1: >50% overlap and Type 2: ≤50% overlap. Three-dimensional structure was dichotomized into a single lesion (one DWI and one PWI lesion) versus multiple lesions. Lesion reversal was defined by the percentage of the baseline DWI or PWI lesion not superimposed by the early follow-up DWI or PWI lesion. Final infarct prediction was estimated by the proportion of the final infarct superimposed on the union of the DWI and PWI lesions.

Results— Single lesion structure with Type 1 geography was present in only 9 patients (28%) at baseline and 4 (12%) on early follow-up. In these patients, PWI and DWI lesions were more likely to correspond with the final infarcts. DWI reversal was greater among patients with Type 2 geography at baseline. Patients with multiple lesions and Type 2 geography at early follow-up were more likely to have early reperfusion.

Conclusion— Before thrombolytic therapy in the 3- to 6-hour time window, Type 2 geography is predominant and is associated with DWI reversal. After thrombolysis, both Type 2 geography and multiple lesion structure are associated with reperfusion.

Methods— At 15 North Carolina hospitals, we enrolled a prospective nonconsecutive sample of admitted TIA patients. We excluded patients not undergoing a DWMRI within 24 hours of admission and patients for whom a dichotomized (≤ or >3) ABCD² score could not be calculated. We conducted a medical record review to determine disabling ischemic stroke outcomes within 90 days.

Results— Over 35 months, 944 TIA patients met inclusion criteria, of whom 4% (n=41) had a disabling ischemic stroke within 90 days. In analyses stratified by low versus moderate/high ABCD² score, the combination of a low risk ABCD² score and a negative early DWMRI had excellent sensitivity (100%, 95% CI 34 to 100) for identifying low-risk patients. In patients classified as moderate to high risk, a negative early DWMRI predicted a low risk of disabling ischemic stroke within 90 days (sensitivity 92%, 95% CI 80 to 97; NLR 0.11, 95% CI 0.04 to 0.32).

Conclusions— After risk stratification by the ABCD² score, early DWMRI enhances the prediction of a low risk for disabling ischemic stroke within 90 days. Further study is warranted in a large, consecutive TIA population of early DWMRI as a sensitive negative predictor for disabling stroke within 90 days.

Methods— In vivo MRI data of carotid plaques from 12 patients scheduled for endarterectomy were acquired for model reconstruction. Histology confirmed that 5 of the 12 plaques had rupture. Plaque wall stress (PWS) and flow maximum shear stress were extracted from all nodal points on the lumen surface of each plaque for analysis. A critical PWS (maximum of PWS values from all possible vulnerable sites) was determined for each plaque.

Results— Mean PWS from all ulcer nodes in ruptured plaques was 86% higher than that from all nonulcer nodes (123.0 versus 66.3 kPa, P<0.0001). Mean flow maximum shear stress from all ulcer nodes in ruptured plaques was 170% higher than that from all nonulcer nodes (38.9 versus 14.4 dyn/cm2, P<0.0001). Mean critical PWS from the 5 ruptured plaques was 126% higher than that from the 7 nonruptured ones (247.3 versus 108 kPa, P=0.0016 using log transformation).

Conclusion— The results of this study show that plaques with prior ruptures are associated with higher critical stress conditions, both at ulcer sites and when compared with nonruptured plaques. With further validations, plaque stress analysis may provide additional stress indicators helpful for image-based plaque vulnerability assessment.

Methods— In 123 first-ever lacunar stroke patients we performed 24-hour ambulatory BP monitoring after the acute stroke-phase. We counted BMBs on T2*-weighted gradient-echo MR images. Because a different etiology for BMBs according to location has been suggested, we distinguished between BMBs in deep and lobar location.

Results— BMBs were seen in 36 (29.3%) patients. After adjusting for age, sex, number of antihypertensive drugs, asymptomatic lacunar infarcts, and white matter lesions, we found 24-hour, day, and night systolic and diastolic BP levels to be significantly associated with the presence and number of BMBs (odds ratios 1.6 to 2.3 per standard deviation increase in BP). Distinguishing between different locations, various BP characteristics were significantly associated with the presence of deep (or combined deep and lobar) BMBs, but not with purely lobar BMBs.

Conclusions— Our results underline the role of a high 24-hour BP load as an important risk factor for BMBs. The association of BP levels with deep but not purely lobar BMBs is in line with the idea that different vasculopathies might be involved. Deep BMBs may be a particular marker of BP-related small vessel disease, but longitudinal and larger studies are now warranted to substantiate these findings.

Methods— Thirty patients with a premorbid modified Rankin score ≤1 and NIHSS between 5 and 22 were included. All had admission CT, CTA, and CT perfusion scans to evaluate for salvageable brain tissue. Recanalization effectiveness was assessed by angiograms obtained within 30 hours after intervention. Patient, treatment characteristics, and immediate and 3-month outcomes were analyzed.

Results— Mean NIHSS at presentation was 13 (median=12). Mean interval between time last-seen well and angiogram was 12.75 hours (median=10). Twenty-six patients (86.7%) presented with complete-to-near-complete vessel occlusion (thrombolysis in myocardial infarction [TIMI] 0/1); 4 had partial vessel occlusion (TIMI 2). Interventions included intra-arterial pharmacological thrombolysis (n=10), mechanical thrombectomy(n=21; Merci, 16; intracranial stent, 9; extracranial stent, 3), angioplasty (n=14; intracranial, 11; extracranial, 3). Nine patients received GPIIb/IIIa inhibitors (eptifibatide); all received heparin. Partial-to-complete recanalization (TIMI 2/3) was achieved in 20 patients (66.7%). Procedure-related complications included vascular perforations (n=3) and femoral access site complication (n=1). One patient had an embolic anterior cerebral artery infarct during intervention; another had progression of brain stem infarct. Symptomatic intracerebral hemorrhage occurred in 3 patients (10%), with 2 being primarily subarachnoid in location. Total in-hospital mortality including procedural mortality, disease progression, or other comorbidities was 23.3% (n=7). Mean discharge NIHSS was 9.5, representing an overall NIHSS 3.5-point improvement. Overall, mean modified Rankin score at death or last follow-up (mean=10.6 months) was 4.2. At 3 months, total mortality was 33.3% (n=10), 20% had modified Rankin score ≤2, and 33% had modified Rankin score ≤3. Among survivors, mean modified Rankin score at 3-month follow-up was 3.

Conclusion— Our data show that delayed endovascular revascularization of carefully selected patients is safe, effective, and improves clinical outcome.

Methods— This prospective study included patients with spontaneous ganglionic intracerebral hemorrhage and severe intraventricular hemorrhage with acute obstructive posthemorrhagic hydrocephalus who received an EVD (n=32). The treatment algorithm started with IVF (4 mg recombinant tissue plasminogen activator every 12 hours) until clearance of the third and fourth ventricles from blood. Thereupon, EVD was clamped and if clamping was unsuccessful, communicating posthemorrhagic hydrocephalus was assumed and LD placed. EVD was removed if there was neither an increase of intracranial pressure nor ventricle enlargement on CT. A ventriculoperitoneal shunt was indicated if "LD weaning" was unsuccessful for >10 days. Outcome was assessed at 90 and 180 days using the modified Rankin Scale.

Results— IVF resulted in fast clearance of the third and fourth ventricles (73±50 hours). However, early EVD removal was only possible in 4 patients. The remaining 28 patients developed communicating posthemorrhagic hydrocephalus. In all of these patients, early LD was capable to replace EVD. EVD exchange was not necessary and EVD duration was 105±59 hours. Only one patient required a ventriculoperitoneal shunt. At 180 days, 20 (62.5%) patients had a good (modified Rankin Scale 0 to 3) outcome and 5 (15.6%) patients had died. One patient had asymptomatic ventricular rebleeding.

Conclusions— In patients with secondary intraventricular hemorrhage and posthemorrhagic hydrocephalus, the combined treatment approach of IVF and early LD is safe and feasible, avoids EVD exchange, and may markedly reduce the need for shunt surgery.

Methods— We conducted a case-control study using the Dutch PHARMO Record Linkage System database. Cases (n=6763) were patients with a first hip/femur fracture; controls were matched by age, sex, and region. Odds ratio (OR) for the risk of hip/femur fracture was derived using conditional logistic regression analysis, adjusted for disease and drug history.

Results— An increased risk of hip/femur fracture was observed in patients who experienced a stroke at any time before the index date (adjusted OR, 1.96; 95% CI, 1.65–2.33). The fracture risk was highest among patients who sustained a stroke within 3 months before the index date (adjusted OR, 3.35; 95% CI, 1.87–5.97) and among female patients (adjusted OR, 2.12; 95% CI, 1.73–2.59). The risk further increased among patients younger than 71 years (adjusted OR, 5.12; 95% CI, 3.00–8.75). Patients who had experienced a hemorrhagic stroke tended to be at a higher hip/femur fracture risk compared with those who had experienced an ischemic stroke.

Conclusions— Stroke is associated with a 2.0-fold increase in the risk of hip/femur fracture. The risk was highest among patients younger than 71 years, females, and those whose stroke was more recent. Fall prevention programs, bone mineral density measurements, and use of bisphosphonates may be necessary to reduce the occurrence of hip/femur fractures during and after stroke rehabilitation.

Methods— We used 5 biennial waves (1998–2006) from the Health and Retirement Study to assess risk factors associated with falling accidents and fall-related injuries among stroke survivors. We abstracted demographic data, living status, self-evaluated general health, and comorbid conditions. We analyzed the rate ratio (RR) of falling and the OR of injury within 2 follow-up years using a multivariate random effects model.

Results— We identified 1174 stroke survivors (mean age±SD, 74.4±7.2 years; 53% female). The 2-year risks of falling, subsequent injury, and broken hip attributable to fall were 46%, 15%, and 2.1% among the subjects, respectively. Factors associated with an increased frequency of falling were living with spouse as compared to living alone (RR, 1.4), poor general health (RR, 1.1), time from first stroke (RR, 1.2), psychiatric problems (RR, 1.7), urinary incontinence (RR, 1.4), pain (RR, 1.4), motor impairment (RR, 1.2), and past frequency of ≥3 falls (RR, 1.3). Risk factors associated with fall-related injury were female gender (OR, 1.5), poor general health (OR, 1.2), past injury from fall (OR, 3.2), past frequency of ≥3 falls (OR, 3.1), psychiatric problems (OR, 1.4), urinary incontinence (OR, 1.4), impaired hearing (OR, 1.6), pain (OR, 1.8), motor impairment (OR, 1.3), and presence of multiple strokes (OR, 3.2).

Conclusions— This study demonstrates the high prevalence of falls and fall-related injuries in stroke survivors, and identifies factors that increase the risk. Modifying these factors may prevent falls, which could lead to improved quality of life and less caregiver burden and cost in this population.

Methods— Participants in this prospective, single-blinded, randomized, clinical trial were 78 incident stroke survivors admitted over 18 months and identified via neuropsychological assessment as having attention deficit. Participants were randomly allocated to standard care plus up to 30 hours of APT or standard care alone. Both groups were impaired (z≤–2.0) across measures of attention at baseline, with the exception of Paced Auditory Serial Addition Test, which was below average (z≤–1.0). Outcome assessment occurred at 5 weeks and 6 months after randomization. The primary outcome was Integrated Visual Auditory Continuous Performance Test Full-Scale Attention Quotient.

Results— APT resulted in a significantly greater (P<0.01) improvement on the primary outcome than standard care. Difference in change on the Cognitive Failures Questionnaire approached significance (P=0.07). Differences on other measures of attention and broader outcomes were not significant.

Conclusion— APT is a viable and effective means of improving attention deficits after incident stroke.

Methods— The Apathy Assessed cohort was formed from stroke survivors participating in a longitudinal study of health-related quality of life after stroke. A family caregiver completed an apathy questionnaire by telephone at 1, 3, 6, and 12 months after stroke (n=408). Group-based trajectory modeling and ordinal regression were used to identify distinctive groups of individuals with similar trajectories of apathy over the first year after stroke and predictors of apathy trajectory.

Results— Both 3- and 5-group trajectory models fit the data. We used the 5-group model because of the potential to further explore the apathy construct. The largest group (50%) had low apathy and 33% had minor apathy that remained stable throughout the first year after stroke. A small proportion (3%) of the study sample had high apathy that remained high. Two other groups of almost equal size (7%) showed worsening and improving apathy. Poor cognitive status, low functional status, and high comorbidity predicted higher apathy. High apathy had a significant negative effect on physical function, participation, health perception, and physical health over the first 12 months after stroke.

Conclusion— Some degree of apathy was prevalent and persistent after stroke and was predicted by older age, poor cognitive status, and low functional status after stroke. Even a minor level of apathy had an important and statistically significant impact on stroke outcomes.

Methods— Stroke patients were prospectively assessed by means of the NIH Stroke Scale, Barthel index, and modified Rankin scale. Proxies and patients answered the Hospital Anxiety and Depression Scale and the SIS 3.0. Comparisons of patient-proxy mean scores (paired t test), effect size, and intraclass correlation coefficients (ICC) were calculated for each of the SIS domains, and weighted kappa for individual items.

Results— 180 proxy-patient pairs were assessed. Proxies were younger (mean age: 43.1 versus 57.9 years) and had a higher education level (P<0.0001). The bias between patient-proxy mean differences was low (from 5.3, Strength, to 0.1, Communication). Proxies significantly scored patients as more severally affected in Strength (41.7 versus 36.6; P<0.0001) and ADL (46.2 versus 43.1; P=0.01) domains, and Composite Physical Domain (CPD; 39.7 versus 34.9; P<0.0001). The magnitude of difference was small (size effect: 0.21). ICC values for the SIS domains ranged from 0.17 (Emotion) to 0.79 (Hand function). The ICC value for the CPD was 0.83. Memory, Communication, Emotion, and Social Participation domains had ICC lower values. The weighted kappa values for the SIS items ranged from 0.09 (item 4e) to 0.80 (item 7d). Highest values (moderate/high agreement) were observed for the SIS-16 and CPD (kappa values: 0.31 to 0.80).

Conclusions— Agreement between stroke patients and proxies was acceptable for most SIS domains and SIS-16. Proxy’s assessment of SIS subjective domains should be taken with caution.

Methods— We reviewed all Merci thrombectomy cases of either terminal ICA or M1 occlusions and classified them according to diffusion MRI patterns of (1) completed basal ganglia infarct (pure M1a), (2) near-completed basal ganglia infarct (incomplete M1a), and (3) relative sparing of deep MCA field (M1b). We compared the M1a and M1b patients with respect to neurological deficit on presentation, recanalization rates, hospital length of stay, and disability on discharge. We also determined whether deep MCA compromise predicted hematomal hemorrhagic transformation (HT) and whether this correlated with worse clinical outcome at discharge.

Results— The M1a group had worse pre-Merci NIHSS (21 versus 14, P=0.004), worse discharge NIHSS (12 versus 4, P<0.001), longer hospital length of stay (11.5 versus 6.4 days, P=0.003), and higher rates of discharge mRS ≥3 (OR 8.4, 95% CI 2.1 to 44.7) despite equivalent recanalization rates when compared to the M1b group. The M1a group had a higher rate of parenchymal hematomal HT (OR 6.7, 95% CI 1.02 to 183.3). Patients with such hematomal HT had higher rates of death or dependency discharge (100% versus 60%, OR=infinite).

Conclusions— Among patients with ICA and M1 occlusions, preintervention diffusion MRI evidence of advanced injury in the basal ganglia bodes worse dysfunction and disability at discharge, longer hospital stays, and higher rates of hemorrhage after intervention when compared to other diffusion patterns.

Methods— This was a case–cohort study of patients with acute ischemic stroke seen between July 2003 and March 2005 and captured in the Registry of the Canadian Stroke Network. After stratifying by age category, we assessed for evidence of effect modification by age on the reduction in stroke fatality associated with stroke unit/organized care.

Results— Among 3631 patients with ischemic stroke, stroke case-fatality at 30 days was lower for patients admitted to a stroke unit compared with those admitted to general medical wards (10.2% versus 14.8%; P<0.0001 with an absolute risk reduction=4.6%, number needed to treat=22). All age groups achieved a similar benefit of stroke unit care versus general medical ward care (absolute risk reduction for 30-day stroke fatality was 4.5% for <60 years; 3.4% for 60 to 69 years; 5.3% for 70 to 79 years; and 5.5% for those >80 years). Increasing levels of organized care were associated with lower stroke fatality or institutionalization. The beneficial effect of stroke units/organized care on survival was seen even after adjustment for multiple prognostic factors and after excluding patients on palliative approach. There was no evidence of effect modification by age in any analyses.

Conclusions— Stroke units and organized inpatient care reduce death or institutionalization with the same magnitude of effect across all age groups.

Methods— This was a prospective cohort study of patients with acute ischemic stroke in the province of Ontario, Canada, admitted to stroke centers participating in the Registry of the Canadian Stroke Network between July 1, 2003 and March 31, 2005. Primary outcomes were the following selected indicators of quality stroke care: (1) use of thrombolysis; (2) dysphagia screening; (3) admission to a stroke unit; (4) carotid imaging; (5) antithrombotic therapy; and (6) warfarin for atrial fibrillation at discharge. Secondary outcomes were risk-adjusted stroke fatality, discharge disposition, pneumonia, and length of hospital stay.

Results— Among 3631 patients with ischemic stroke, 1219 (33.6%) were older than 80 years. There were no significant differences in stroke care delivery by age group. Stroke fatality increased with age, with a 30-day risk adjusted fatality of 7.1%, 6.5%, 8.8%, and 14.8% for those aged 59 or younger, 60 to 69, 70 to 79, and 80 years or older, respectively. Those aged older than 80 years had a longer length of hospitalization, increased risk of pneumonia, and higher disability at discharge compared to those younger than 80. This group was also less likely to be discharged home.

Conclusions— In the context of a province-wide coordinated stroke care system, stroke care delivery was similar across all age groups with the exception of slightly lower rates of investigations in the very elderly. Increasing age was associated with stroke severity and stroke case-fatality.

Methods— Self-reported data from the 2005 and 2007 Behavioral Risk Factor Surveillance System were used (n=765 368). The potential contributors for self-reported stroke prevalence (n=27 962) were demographics (age, sex, geography, and race/ethnicity), socioeconomic status (education and income), common risk factors (smoking and obesity), and chronic diseases (hypertension, diabetes, and coronary heart disease). Multivariate logistic regression was used in the analysis.

Results— The age- and sex-adjusted OR comparing self-reported stroke prevalence in the 11-state Stroke Belt versus non-Stroke Belt region was 1.25 (95% CI, 1.19 to 1.31). Unequal black/white distribution by region accounted for 20% of the excess prevalence in the Stroke Belt (OR reduced to 1.20; 1.15 to 1.26). Approximately one third (32%) of the excess prevalence was accounted either by socioeconomic status alone or by risk factors and chronic disease alone (OR, 1.12). The OR was further reduced to 1.07 (1.02 to 1.13) in the fully adjusted logistic model, a 72% reduction.

Conclusions– Differences in socioeconomic status, risk factors, and prevalence of common chronic diseases account for most of the regional differences in stroke prevalence.

Methods— Temporal changes in microvascular SphK activity and expression were measured after HPC. The SphK inhibitor dimethylsphingosine or sphingosine analog FTY720 was administered to adult male Swiss-Webster ND4 mice before HPC. Two days later, mice underwent a 60-minute transient middle cerebral artery occlusion and at 24 hours of reperfusion, infarct volume, neurological deficit, and hemispheric edema were measured.

Results— HPC rapidly increased microvascular SphK2 protein expression (1.7±0.2-fold) and activity (2.5±0.6-fold), peaking at 2 hours, whereas SphK1 was unchanged. SphK inhibition during HPC abrogated reductions in infarct volume, neurological deficit, and ipsilateral edema in HPC-treated mice. FTY720 given 48 hours before stroke also promoted ischemic tolerance; when combined with HPC, even greater (and dimethylsphingosine-reversible) protection was noted.

Conclusions— These findings indicate hypoxia-sensitive increases in SphK2 activity may serve as a proximal trigger that ultimately leads to sphingosine-1-phosphate-mediated alterations in gene expression that promote the ischemia-tolerant phenotype. Thus, components of this bioactive lipid signaling pathway may be suitable therapeutic targets for protecting the neurovascular unit in stroke.

Methods— Adult mice subjected to transient middle cerebral artery occlusion underwent chronic intermittent hypoxia starting either 1 or 5 days after ischemia and brain damage was assessed by T2-weighted MRI at 43 days. In addition, we investigated the potential neuroprotective effect of hypoxia applied after oxygen glucose deprivation in primary neuronal cultures.

Results— The present study shows for the first time that a late application of hypoxia (5 days) after ischemia reduced delayed thalamic atrophy. Furthermore, hypoxia performed 14 hours after oxygen glucose deprivation induced neuroprotection in primary neuronal cultures. We found that hypoxia-inducible factor-1 expression as well as those of its target genes erythropoietin and adrenomedullin is increased by hypoxic postconditioning. Further studies with pharmacological inhibitors or recombinant proteins for erythropoietin and adrenomedullin revealed that these molecules participate in this hypoxia postconditioning-induced neuroprotection.

Conclusions— Altogether, this study demonstrates for the first time the existence of a delayed hypoxic postconditioning in cerebral ischemia and in vitro studies highlight hypoxia-inducible factor-1 and its target genes, erythropoietin and adrenomedullin, as potential effectors of postconditioning.

Methods— A unilateral infarction was induced in mouse brain by photoinduction after injection of Rose Bengal. The volume of the infarction was analyzed using the public domain National Institutes of Health image program. The level of protein-conjugated acrolein at the locus of infarction and in plasma was measured by Western blotting and enzyme-linked immunosorbent assay, respectively. The levels of polyamines at the locus of infarction and in plasma were measured by high-performance liquid chromatography.

Results— The level of protein-conjugated acrolein was greatly increased, and levels of spermine and spermidine were decreased at the locus of infarction at 24 hours after the induction of stroke. The size of infarction was significantly decreased by N-acetylcysteine, a scavenger of acrolein. It was also found that the increases in the protein-conjugated acrolein, polyamines, and polyamine oxidases in plasma were observed after the induction of stroke.

Conclusions— The results indicate that the induction of infarction is well correlated with the increase in protein-conjugated acrolein at the locus of infarction and in plasma.

Methods— Postnatal Day 7 rats were subjected to unilateral carotid artery occlusion and hypoxia. Rats were treated immediately after HI with TAT-NBD, the JNK inhibitor TAT-JBD, and/or the TNF- inhibitor etanercept. We determined brain damage, NF-B and AP-1 activity, Gadd45β, XIAP, (P-)TAK1, TNF-, and TNF receptor expression.

Results— Our data confirm that TAT-NBD treatment reduces brain damage without inhibiting TNF- production. We now show that TAT-NBD treatment increased HI-induced AP-1 activation concomitantly with reduced Gadd45β, XIAP, and increased (P)-TAK1 expression. Combined inhibition of NF-B and JNK/AP-1 abrogated HI-induced TNF- production. However, this treatment reduced the neuroprotective effect of NF-B inhibition alone. We show that etanercept was detectable in the HI brain after intraperitoneal administration and that etanercept treatment also reduced the neuroprotective effect of NF-B inhibition. Finally, NF-B inhibition decreased HI-induced upregulation of TNF-R1 and increased TNF-R2 expression.

Conclusions— When NF-B was inhibited after neonatal cerebral HI, JNK/AP-1 activity was increased and required for increased TNF- expression. Our data indicate that the switch to JNK/AP-1 activation preserves HI-induced TNF- expression and thereby might contribute to the neuroprotective effect of TAT-NBD possibly through a TNF-R2 dependent mechanism.

Methods— The premature rabbit pups, delivered by cesarean section, were treated with intraperitoneal glycerol at 2 hours postnatal age to induce IVH. The development of IVH was diagnosed by head ultrasound at 24 hours of age. Neurobehavioral, histological, and ultrastructural evaluation and diffusion tensor imaging studies were performed at 2 weeks of age.

Results— Although 25% of pups with IVH (IVH pups) developed motor impairment with hypertonia and 42% developed posthemorrhagic ventriculomegaly, pups without IVH (non-IVH) were unremarkable. Immunolabeling revealed reduced myelination in the white matter of IVH pups compared with saline- and glycerol-treated non-IVH controls. Reduced myelination was confirmed by Western blot analysis. There was evidence of gliosis in IVH pups. Ultrastructural studies in IVH pups showed that myelinated and unmyelinated fibers were relatively preserved except for focal axonal injury. Diffusion tensor imaging showed reduction in fractional anisotropy and white matter volume confirming white matter injury in IVH pups.

Conclusion— The rabbit pups with IVH displayed posthemorrhagic ventriculomegaly, gliosis, reduced myelination, and motor deficits, like humans. The study highlights an instructive animal model of the neurological consequences of IVH, which can be used to evaluate strategies in the prevention and treatment of posthemorrhagic complications.

Methods— Blood flow in AAAs was examined using fluorescein isothiocyanate–labeled red blood cells (RBCs) as a flow indicator in 16 anesthetized C57BL/6J mice before and after MCA occlusion up to 7 experimental days.

Results— We observed paradoxical flow in AAAs; labeled RBCs entered from both the MCA and anterior cerebral artery sides and the opposing flows met at a branching T-junction, where the flows combined and passed into a penetrating arteriole. The dually fed T-junction was not fixed in position, but functionally jumped to adjacent T-junctions in response to changing hemodynamic conditions. On MCA occlusion, RBC flow from the MCA side immediately stopped. After a period of "hesitation," blood started to move retrogradely in one of the MCA branches toward the MCA stem. The retrograde blood flow was statistically significantly (P<0.05), serving to feed blood to other MCA branches after a lag period. In capillaries, MCA occlusion induced immediate RBC disappearance in the ischemic core and to a lesser extent in the marginal zone near AAAs. At day 3 after ischemia, we recognized the beginning of remodeling with angiogenesis centering on AAAs.

Conclusions— AAAs appear to play a key role in local hemodynamic homeostasis, both in the normal state and in the development of collateral channels and revascularization during ischemia.

Methods— Primary ICH was induced in rats. Simvastatin (2 mg/kg), atorvastatin (2 mg/kg), or phosphate-buffered saline (n=6 per group) was given daily for 1 week. MRI studies were performed 2 to 3 days before ICH, and at 1 to 2 hours and 1, 2, 7, 14, and 28 days after ICH. The ICH evolution was assessed via hematoma volume measurements using susceptibility-weighted imaging (SWI) and tissue loss using T₂ maps and hematoxylin and eosin (H&E) histology. Neurobehavioral tests were done before ICH and at various time points post-ICH. Additional histological measures were performed with doublecortin neuronal nuclei and bromodeoxyuridine stainings.

Results— Initial ICH volumes determined by SWI were similar across all groups. Simvastatin significantly reduced hematoma volume at 4 weeks (P=0.002 versus control with acute volumes as baseline), whereas that for atorvastatin was marginal (P=0.09). MRI estimates of tissue loss (% of contralateral hemisphere) for treated rats were significantly lower (P=0.0003 and 0.001, respectively) than for control at 4 weeks. Similar results were obtained for H&E histology (P=0.0003 and 0.02, respectively). Tissue loss estimates between MRI and histology were well correlated (R²=0.764, P<0.0001). Significant improvement in neurological function was seen 2 to 4 weeks post-ICH with increased neurogenesis observed.

Conclusions— Simvastatin and atorvastatin significantly improved neurological recovery, decreased tissue loss, and increased neurogenesis when administered for 1 week after ICH.

Methods— A cohort study was done in 12 centers admitting 5515 consecutive patients with acute stroke in The Netherlands. A multilevel logistic regression model was used to relate the likelihood of treatment with thrombolysis to characteristics of the organizational culture of the centers. Organizational culture was defined by 10 characteristics and scored by a panel. A sum score was created by adding all scores and dividing by 10.

Results— Thrombolysis rates varied from 5.7% to 21.7%. We observed an association between thrombolysis and the availability of informal and formal feedback (OR, 1.18; 95% CI, 1.09 to 1.28); a learning culture (OR, 1.12; 95% CI, 1.02 to 1.23); uncompromising, individual clinical leadership (OR, 1.12; 95% CI, 1.03 to 1.23); explicit goals (OR, 1.08; 95% CI, 1.01 to 1.17); and with the sum score (OR, 1.12; 95% CI, 1.02 to 1.23).

Conclusions— Several cultural characteristics of the hospital organization are related to thrombolysis rate. Organizational culture may be an important target for interventions aimed at increasing rates of thrombolysis for acute ischemic stroke in hospitals.

Methods— Two researchers independently reviewed the literature. Crossdisciplinary electronic databases were interrogated using the following key words: Stroke*; Cerebrovasc*; Modified Rankin*; Rankin Scale*; Oxford Handicap*; Observer variation*. Data were extracted according to prespecified criteria with decisions on inclusion by consensus.

Results— From 3461 titles, 10 studies (587 patients) were included. Reliability of modified Rankin Scale varied from weighted =0.95 to =0.25. Overall reliability of mRS was =0.46; weighted =0.90 (traditional modified Rankin Scale) and =0.62; weighted =0.87 (structured interview).

Conclusion— There remains uncertainty regarding modified Rankin Scale reliability. Interobserver studies closest in design to large-scale clinical trials demonstrate potentially significant interobserver variability.

Methods— Stroke severity and dependency have been categorized as mild, moderate, or severe. We studied 2 acute stroke unit cohorts, measuring Scandinavian Stroke Scale (SSS), modified Rankin Scale (mRS), Barthel Index (BI), and modified National Institutes of Health Stroke Scale (mNIHSS). Receiver operating characteristic (ROC) curves were examined to determine the ability of full and categorized scales to predict death and dependency. A weighted kappa analysis assessed agreement between the categorized scales.

Results— When scales are categorized, the area under the ROC curve is significantly reduced; however, the differences are small and may not be practically important. BI, mRS, and SSS all have excellent agreement with each other when categorized, whereas mNIHSS has substantial agreement with mRS and BI.

Conclusions— Little predictive information is lost when stroke scales are categorized. There is substantial to almost perfect agreement among categorized scales. Therefore the use and categorization of a variety of stroke severity or dependency scales is acceptable in analyses.

Methods— From June 2007 to December 2008, patients with anterior circulation ischemic stroke were evaluated for a "total mismatch" profile. MRI was performed at admission and at day 1. The score was assessed at baseline and the modified Rankin scale score was assessed at day 30.

Results— Among 52 patients, 3 showed a total mismatch with arterial occlusion confirmed on magnetic resonance angiography. All had fluctuating symptoms (National Institutes of Health Stroke Scale scores, 0 to 10) and received intravenous tissue plasminogen activator. Day 1 DWI disclosed minimal changes in all patients. Outcome was favorable in all patients (day 30 modified Rankin scale, 0–1).

Conclusion— PWI may be helpful for treatment decisions in patients without DWI damage and fluctuating clinical course.

Methods— We performed a systematic review and meta-analysis of randomized controlled trials assessing the use of endothelin-receptor antagonists (ETRAs) in patients with SAH.

Results— Three studies met eligibility criteria, enrolling 867 patients. ETRAs significantly reduced the occurrence of DINDs (OR 0.68 [0.49 to 0.95]) and radiographic vasospasm (OR 0.31 [0.19 to 0.49]), but did not have any impact on mortality (OR 1.09 [0.69 to 1.72]) or poor neurological outcomes (OR 0.87 [0.63 to 1.20]). Any benefit of ETRAs may have been partially offset by adverse effects, including hypotension(OR 2.39 [1.37 to 4.17]) and pulmonary complications (OR 2.12 [1.51 to 2.98]).

Conclusions— Although ETRAs reduce radiographic vasospasm and DINDs, there is currently no evidence that they improve outcomes.

Methods— Following a guideline-based algorithm, we screened consecutive patients with ischemic stroke and patients with transient ischemic attack for asymptomatic coronary artery disease using the Framingham Heart Study Coronary Risk Score (FCRS) cutoff of high risk (≥20%) for experiencing a hard coronary artery disease event over a 10-year period. Patients with high FCRS received dobutamine stress echocardiogram outpatient screening, additional treatment (β-blocker), or further management (cardiologist referral).

Results— From July 2004 to September 2007, among 693 patients, 501 (72%) met study criteria, of which 80 (16%) had FCRS ≥20%. Elevated serum glucose, nonhigh-density lipoprotein, triglycerides, homocysteine, glycosylated hemoglobin as well as large vessel atherosclerotic stroke mechanism were more frequent in high versus low FCRS patients (P<0.05). Among high FCRS patients, 35 (44%) had dobutamine stress echocardiogram performed. Leading reasons for dobutamine stress echocardiogram nonperformance were patient noncompliance (42%) and primary care physician refusal (33%).

Conclusions— Screening for coronary artery disease risk using FCRS is feasible in hospitalized patients with stroke, but outpatient adherence to stress testing is challenging largely due to patient and primary care physician-related factors.

Methods— This study followed a cohort of 6291 residents in Kangwha County, aged ≥55 years in March 1985, for their cause-specific mortality for 20.8 years up to December 31, 2005. We calculated hazard ratio of mortality by experience or frequency of binge drinking using the Cox proportional hazard model. Binge drinking was defined as having ≥6 drinks on one occasion.

Results— In men, binge drinkers who drink daily had an increased risk of mortality from all causes (hazard ratio, 1.33; 95% CI, 1.11 to 1.60) as compared with nondrinkers. They showed much increased risks of mortality from total stroke (hazard ratio, 1.86; 95% CI, 1.16 to 2.99) and hemorrhagic stroke (hazard ratio, 3.39; 95% CI, 1.38 to 8.35). Female binge drinkers also showed an increased risk of mortality from cardiovascular disease as compared with female nondrinkers, but the outcome was not statistically significant.

Conclusions— The results of this study suggest that frequent binge drinking has a harmful effect on hemorrhagic stroke in Korean men. These findings need to be confirmed in further studies.

Methods— In 2013 stroke-free Framingham offspring (mean±SD age, 58±9.5 years; 53% women), we related baseline plasma ADMA levels (1995–1998) to subsequent brain magnetic resonance imaging measures (1999–2004) of subclinical vascular injury: presence of silent brain infarcts (SBIs) and large white-matter hyperintensity volumes (LWMHs; defined as >1 SD above the age-specific mean).

Results— Prevalences of SBIs and LWMHs were 10.7% and 12.6%, respectively. In multivariable analyses adjusting for age, sex and traditional stroke risk factors, higher ADMA levels were associated with an increased risk of prevalent SBIs (odds ratio [OR] per 1-SD increase in ADMA=1.16; 95% CI, 1.01 to 1.33; P=0.04). We observed that participants in the upper 3 age-specific quartiles (Qs) of plasma ADMA values had an increased prevalence of SBIs (OR for Q2–Q4 vs Q1=1.43; 95% CI, 1.00 to 2.04; P<0.05). The prevalence of SBIs in Q1and Q2–Q4 was 8.3% and 11.6%, respectively. The prevalence of LWMHs did not differ according to ADMA concentrations.

Conclusions— Higher plasma ADMA values were associated with an increased prevalence of SBIs, after adjustment for traditional stroke risk factors. Thus, ADMA may be a potentially useful new biomarker of subclinical vascular brain injury, which is an important correlate of vascular cognitive impairment and risk of stroke.

Methods— From a group of DNA samples collected at baseline in a prospective cohort of 14 916 initially healthy American men, we assessed 16 TRPM7 tag–single-nucleotide polymorphisms (SNPs) (dbSNP: rs11854949, rs4775899, rs11635825, rs12905120, rs16973487, rs7173321, rs7163283, rs17520378, rs17520350, rs4775892, rs7174839, rs17645523, rs3109894, rs616256, rs11070795, and rs313158) from 245 white men who subsequently had an incident ischemic stroke and from 245 age- and smoking habit–matched white men who remained free of reported vascular disease during follow-up (controls).

Results— All SNPs examined were in Hardy-Weinberg equilibrium. Overall allele, genotype, and haplotype distributions were similar between cases and controls. Marker-by-marker conditional logistic-regression analysis, adjusted for potential risk factors, showed no evidence for an association between any of the SNPs tested and ischemic stroke. Further investigation with an Entropy Blocker–defined, haplotype-based approach showed similar null findings. Prespecified analysis limited to participants without baseline diabetes and hypertension (ie, low-risk group) again showed similar null findings.

Conclusions— The present prospective investigation provides no evidence of a role for the TRPM7 gene in the risk of incident ischemic stroke.

Methods— One hundred twenty older adults with diagnosed cardiovascular disease were recruited from outpatient cardiology clinics. Each participant underwent a comprehensive neuropsychological test battery and a blood draw.

Results— Participants with the SELP 1087A allele performed more poorly on tests of attention (Trail Making Test A: t[116]=3.20, P=0.002), executive function (Trail Making Test B: t[116]=2.89, P=0.005), psychomotor speed (Digit–Symbol Coding: t[117]=2.54, P=0.012), and memory (California Verbal Learning Test Discrimination: t[116]=2.05, P=0.04). There were no significant differences between the SELP genotype groups on demographic/medical variables or C-reactive protein levels.

Conclusions— Contrary to expectations, the present analyses showed that older patients with cardiovascular disease with the SELP 1087A allele performed more poorly on neuropsychological testing. Findings from the present study were counter to previous research with coronary artery bypass graft candidates. Further work using neuroimaging and alternative measures of cardiovascular function is needed to clarify the mechanisms of this association.

Methods— A total of 1209 patients with stroke and 1174 controls were examined using a case–control methodology. The 1425G/A SNP in PRKCH was genotyped by allele-specific real-time PCR assay.

Results— The 1425G/A SNP in PRKCH was significantly associated with both ischemic stroke (odds ratio [OR]=1.31; 95% confidence interval [CI], 1.08 to 1.60; P=0.0058) and cerebral hemorrhage (OR=1.94; 95% CI, 1.21 to 3.10; P=0.0054) under a dominant model. Even after age- and sex-adjustment, the significant associations remained (in ischemic stroke, for AA+AG versus GG, OR=1.37, 95% CI, 1.12 to 1.67, P=0.0019; in cerebral hemorrhage, for AA+AG versus GG, OR=1.96, 95% CI, 1.21 to 3.19, P=0.0064).

Conclusions— The 1425G/A SNP in PRKCH increases the risk of both ischemic stroke and cerebral hemorrhage in the Chinese population.

Methods— Women (18 to 50 years) with and without migraine and free from cardiovascular disease were evaluated with tests of coagulation (von Willebrand factor activity, prothrombin fragment), fibrinolysis (tissue-type plasminogen activator antigen), inflammation (high-sensitivity C-reactive protein), and oxidative stress (homocysteine, total nitrate/nitrite concentrations, thiobarbituric acid–reactive substances).

Results— Sixty-one participants had migraine with aura (MA), 64 had migraine without aura (MO), and 50 were controls. Compared with controls, women with migraine had higher adjusted odds ratios for elevated von Willebrand factor activity of 6.51 (95% CI, 1.94 to 21.83) in those with MA and of 4.59 (95% CI, 1.37 to 15.38) in those with MO, elevated high-sensitivity C-reactive protein of 7.99 (95% CI, 2.32 to 27.61) in those with MA and of 2.63 (95% CI, 0.73 to 9.45) in those with MO, and for lower nitrate/nitrite levels of 6.60 (95% CI, 2.06 to 21.16) in those with MA and of 3.03 (95% CI, 0.90 to 10.15) in those with MO. Within the migraine group, von Willebrand factor activity was correlated with tissue-type plasminogen activator antigen (P=0.035) and nitrate/nitrite (P=0.024). There was a trend with high-sensitivity C-reactive protein (P=0.09).

Conclusions— In premenopausal women with migraine, particularly in those with MA, there is evidence of increased endothelial activation, a component of endothelial dysfunction.

Methods— Charts of all patients with symptomatic intracranial atherosclerotic disease from July 2004 to September 2007 were reviewed and assessed for history of transient ischemic attack or stroke. Patients were either treated with "best medical therapy" (Medical Therapy Group) or PTAS plus antiplatelet agents (PTAS Group) and followed prospectively. A favorable outcome was defined as the absence of transient ischemic attacks, strokes, or vascular death; modified Rankin Scale of ≤3; and no endovascular reintervention of symptomatic in-stent restenosis.

Results— One hundred eleven patients fulfilled entry criteria, with 58 (52.3%) and 53 patients (47.7%) enrolled in the Medical Therapy and PTAS Groups, respectively. Thirty-eight patients of the Medical Therapy Group (65.5%) had a favorable outcome compared with 37 patients of the PTAS Group (69.8%). Combined ischemic end point data for the occurrence of transient ischemic attack, stroke, and vascular death was similar with 14 (24%) events in the Medical Therapy Group versus 15 (28.3%) events in the PTAS Group.

Conclusion— Overall, the combined ischemic end point was the same in the Medical Therapy and PTAS Groups.

Methods— Six hundred ninety-nine patients enrolled in a prospective cohort study involving CT angiographic imaging in acute stroke were dichotomized according to the presence of a PO, including a subgroup of 177 subjects with middle cerebral artery M1 occlusion.

Results— The median NIHSS score of patients found to have a PO was higher than the overall median (9 versus 5, P<0.0001). The median NIHSS score of patients with middle cerebral artery M1 occlusion was 14. NIHSS score ≥10 had 81% positive predictive value for PO but only 48% sensitivity with the majority of subjects with PO presenting with lower NIHSS scores. All patients with NIHSS score ≥2 would need to undergo angiographic imaging to detect 90% of PO.

Conclusions— High NIHSS score correlates with the presence of a proximal arterial occlusion in patients presenting with acute cerebral ischemia. No NIHSS score threshold can be applied to select a subgroup of patients for angiographic imaging without failing to capture the majority of cases with clinically important occlusive lesions. The finding of minimal clinical deficits should not deter urgent angiographic imaging in otherwise appropriate patients suspected of acute stroke.

Methods— We retrospectively reviewed CT angiograms performed in all patients who presented to our emergency department over a 9-year period with primary intracerebral hemorrhage and had a follow-up noncontrast head CT within 48 hours of the baseline CT angiogram. Three neuroradiologists reviewed the CT angiograms and determined the presence and characteristics of spot signs according to strict radiological criteria. Baseline and follow-up intracerebral hemorrhage volumes were determined by computer-assisted volumetric analysis.

Results— We identified spot signs in 71 of 367 CT angiograms (19%), 6 of which were delayed spot signs (8%). The presence of any spot sign increased the risk of significant hematoma expansion (69%, OR=92, P<0.0001). Among the spot sign characteristics examined, the presence of ≥3 spot signs, a maximum axial dimension ≥5 mm, and maximum attenuation ≥180 Hounsfield units were independent predictors of significant hematoma expansion, and these were subsequently used to construct the spot sign score. In multivariate analysis, the spot sign score was the strongest predictor of significant hematoma expansion, independent of time from ictus to CT angiogram evaluation.

Conclusion— The spot sign score predicts significant hematoma expansion in primary intracerebral hemorrhage. If validated in other data sets, it could be used to select patients for early hemostatic therapy.

Methods— Among 741 patients enrolled in a prospective cohort study involving CT angiographic imaging in acute stroke, 134 cases with proximal middle cerebral artery occlusion and 235 control subjects with no occlusions were identified. CT angiography was used to identify occlusions and grade the extent of collateral vessels in the sylvian fissure and leptomeningeal convexity. History of symptom fluctuation or progressive worsening was obtained on admission.

Results— Prehospital symptoms were unrelated to occlusion or collateral status. In cases, 37.5% imaged within 1 hour were found to have diminished collaterals versus 12.1% imaged at 12 to 24 hours (P=0.047). No difference in worsening was seen between cases and control subjects with adequate collaterals, but cases with diminished sylvian and leptomeningeal collaterals experienced greater risk of worsening compared with control subjects measured either by admission to discharge National Institutes of Health Stroke Scale increase ≥1 (55.6% versus 16.6%, P=0.001) or ≥4 (44.4% versus 6.4%, P<0.001).

Conclusion— Most patients with proximal middle cerebral artery occlusion rapidly recruit sufficient collaterals and follow a clinical course similar to patients with no occlusions, but a subset with diminished collaterals is at high risk for worsening.