bluuebunny/crossref_metadata_2025 huggingface dataset:
Hemorrhage After an Acute Ischemic Stroke
Authors: Motto Cristina , Ciccone Alfonso , Aritzu Elisabetta , Boccardi Edoardo , De Grandi Carlo , Piana Alessandra , Candelise Livia
Published: June 2011

Background and Purpose
—Hemorrhagic transformation is frequently seen on CT scans obtained in the subacute phase of ischemic stroke. Its prognostic value is controversial.

Methods
—We analyzed 554 patients with acute ischemic stroke enrolled in the Multicenter Acute Stroke Trial–Italy (MAST-I) study in whom a second CT scan was performed on day 5. Presence of 1) intraparenchymal hemorrhages (hematoma or hemorrhagic infarction), 2) extraparenchymal bleeding (intraventricular or subarachnoid) and 3) cerebral edema (shift of midline structure, sulcal effacement or ventricular compression) alone or in association were evaluated. Death or disability at 6 months were considered as “unfavorable outcome.”

Results
—Patients who developed intraparenchymal hemorrhages, extraparenchymal bleeding, or cerebral edema had unfavorable outcome (83%, 100%, and 80%, respectively), but multivariate analysis demonstrated that only extraparenchymal bleeding (collinearity) and cerebral edema (OR=6.8; 95% CI, 4.5 to 10.4) were significant independent prognostic findings. Unfavorable outcome correlated with size of intraparenchymal hemorrhage (χ
2
for trend=30.5,
P
<0.0001). Nevertheless, when a large hematoma was present the negative effect was mostly due to concomitant extraparenchymal bleeding (χ
2
=51.6,
P
<0.0001), and when hemorrhagic infarction was detected the negative effect was mostly explained by the association with cerebral edema (χ
2
=36.6,
P
<0.0001).

Conclusions
—Extraparenchymal bleeding and cerebral edema are the main prognostic CT scan findings in the subacute phase of ischemic stroke. Stroke patients with a high risk for developing these 2 types of brain damage should be identified. Measures to prevent and adequately treat their development should be implemented.
Extracorporeal Rheopheresis in the Treatment of Acute Ischemic Stroke
Authors: Berrouschot Jörg , Barthel Henryk , Köster Johannes , Hesse Swen , Rössler Annegret , Knapp Wolfram H. , Schneider Dietmar
Published: June 2011

Background and Purpose
—Extracorporeal rheopheresis is a safe method to optimize hemorheology. Our aim was to determine whether treatment with extracorporeal rheopheresis in patients with acute ischemic hemispheric stroke improves cerebral perfusion as assessed with serial
99m
Tc–ethyl-cysteinate-dimer single-photon emission CT (
99m
Tc-ECD SPECT). We also investigated how clinical outcome is associated with treatment and imaging results.

Methods
—Thirty-three patients (mean age, 64±10 years) with acute ischemic hemispheric stroke were included in a prospective, randomized, parallel group pilot study. First treatment with or without extracorporeal rheopheresis took place within 12 hours after the onset of symptoms and was repeated 3 times at intervals of 24 hours. Hemorheological parameters were measured before and after each session. Each patient underwent
99m
Tc-ECD SPECT immediately before treatment, 6 to 8 hours after treatment, and after 5 days. A semiquantitative SPECT graded scale was used to measure depth and extent of activity deficits and thus to quantify the perfusion deficit.

Results
—Seventeen patients were actively treated with extracorporeal rheopheresis, and 16 patients did not receive extracorporeal rheopheresis. After 3 months, no differences were found in the functional or neurological outcome. Despite a rapid, sustained decrease of plasma viscosity and erythrocyte aggregation in the rheopheresis group, there was no significant difference in the SPECT graded scale after therapy between the 2 groups. Patients with early reperfusion (decrease in the SPECT graded scale >25% 6 to 8 hours after therapy compared with the baseline examination) experienced a better functional outcome (Modified Rankin Scale) after 3 months compared with patients without reperfusion (
P
=0.04).

Conclusions
—Since quantitative flow mapping and clinical follow-up did not reveal any differences between patients who were treated with extracorporeal rheopheresis and controls, it appears very unlikely that extracorporeal rheopheresis enhances reperfusion after acute cerebral ischemia.
Cerebral Blood Volume in Acute Brain Infarction
Authors: Hatazawa Jun , Shimosegawa Eku , Toyoshima Hideto , Ardekani Babak A. , Suzuki Akifumi , Okudera Toshio , Miura Yuko
Published: June 2011

Background and Purpose
—The aim of this study was to correlate the abnormality in cerebral blood volume (CBV) measured by dynamic susceptibility contrast-enhanced MRI with that in cerebral blood flow (CBF) estimated by single-photon emission CT with [
99m
Tc]hexamethylpropylenamine-oxime in patients with acute ischemic stroke.

Methods
—Nine patients with unilateral occlusion of either the middle cerebral artery or the internal carotid artery (4 men and 5 women; mean±SD age, 74.4±11.6 years) were studied within 6 hours after stroke onset. The relative CBV (relCBV) and CBF (relCBF) in the lesions were defined relative to the contralateral mirror regions.

Results
—In the brain regions with mild (relCBF ≥0.60), moderate (0.40≤relCBF<0.60), and severe (relCBF <0.40) hypoperfusion, the mean relCBV values were 1.29±0.31, 0.94±0.49, and 0.30±0.22, respectively. The relCBV was significantly elevated in the brain areas with mild hypoperfusion (
P
<0.001) and significantly reduced in the brain areas with severe hypoperfusion (
P
<0.001). The relCBF was significantly better than the relCBV in predicting the evolution of infarction (
P
<0.02). The probability of evolving infarction for the hypervolemic (relCBV >1.0) regions was significantly lower than that for hypovolemic (relCBV <1.0) regions in the relCBF range between 0.40 and 0.50 (
P
<0.02).

Conclusions
—In acute ischemic stroke within 6 hours of onset the CBV can be either increased, normal, or decreased, depending on the severity of hypoperfusion. The increased CBV has a protective effect on evolving infarction. Although the CBF is a better predictor of tissue outcome, the CBV measurement may help detect potentially salvageable brain tissue in the penumbra with compromised blood flow.
Amelioration of Vasospasm After Subarachnoid Hemorrhage in Transgenic Mice Overexpressing CuZn–Superoxide Dismutase
Authors: Kamii Hideyuki , Kato Ichiro , Kinouchi Hiroyuki , Chan Pak H. , Epstein Charles J. , Akabane Atsushi , Okamoto Hiroshi , Yoshimoto Takashi
Published: June 2011

Background and Purpose
—To clarify the effect of superoxide dismutase (SOD) on vasospasm after subarachnoid hemorrhage (SAH), we investigated sequential changes in arterial diameter after SAH in transgenic mice overexpressing CuZn-SOD (SOD-1).

Methods
—SOD-transgenic mice and nontransgenic littermates (35 to 40 g) were subjected to SAH produced by endovascular perforation of left anterior cerebral artery. At 4 hours and 1, 3, 7, and 14 days after SAH, the mice were perfused with 10% formalin and consequently with a mixture of carbon black and 10% gelatin to cast all vessels. Vasospasm was evaluated by measuring the diameter of the left middle cerebral artery (MCA) with a microscope.

Results
—In nontransgenic mice, the diameter of the MCA on day 3 after SAH (110.5±20.5 μm [mean±SD]; n=16) was significantly reduced compared with that without SAH (138.5±14.5 μm; n=12) (
P
<0.01). Moreover, on day 3 after SAH, the diameter of the MCA in SOD-transgenic mice (127.9±20.2 μm; n=20) was significantly larger than that in nontransgenic mice (110.5±20.5 μm; n=16) (
P
<0.05).

Conclusions
—These results suggest that SOD is effective on the amelioration of vasospasm after SAH and that oxygen free radicals, particularly superoxide, play an important role in the pathogenesis of vasospasm after SAH.
Familial Subarachnoid Hemorrhage
Authors: Ronkainen Antti , Niskanen Minna , Piironen Riitta , Hernesniemi Juha
Published: June 2011

Background and Purpose
—The aim of our study was to compare outcome and its determinants in familial subarachnoid hemorrhage and in sporadic subarachnoid hemorrhage in a large and well-documented patient population.

Methods
—Patients with aneurysmal subarachnoid hemorrhage (SAH) treated at the Department of Neurosurgery, Kuopio University Hospital, from 1977 to 1995 were included. Patients with polycystic kidney disease were excluded. The Glasgow Outcome Scale (GOS) score at 12 months was studied.

Results
—There were 120 patients (97 first-, 15 second-, and 8 third-degree family connections) in 96 different families with familial SAH and 1237 patients with sporadic SAH. Age, gender, and admission grade on the Hunt and Hess scale did not differ between these 2 groups. In both groups >80% of patients were in relatively good condition at admission. The outcome was good (GOS score of 1 to 2) in 87 patients (73%) with familial SAH and in 874 patients (71%) with sporadic SAH. Analysis of 20 variables, including presence of coexisting diseases, aneurysm site and size, amount of blood shown on CT scan, intraventricular bleeding, preoperative intracerebral hematoma and hydrocephalus, as well as postoperative bleeding and vasospasm, revealed no significant differences between study groups. The degree of family connection (first-, second-, and third-degree) did not have any statistically important effect on outcome in the familial group in the Finnish study population. In multivariate analysis the knowledge of familial SAH was not an independent prognostic factor.

Conclusions
—Admission status, postoperative course, and outcome were similar in the familial and sporadic SAH groups in this Finnish population, in contrast to previous results. Familial SAH may not be a significant risk factor for poor outcome.
Apolipoprotein E Deficiency Worsens Outcome From Global Cerebral Ischemia in the Mouse
Authors: Sheng Huaxin , Laskowitz Daniel T. , Mackensen G. Burkhard , Kudo Masaya , Pearlstein Robert D. , Warner David S.
Published: June 2011

Background and Purpose
—Apolipoprotein E (apoE) has been found relevant in a variety of central nervous system disorders. This experiment examined the effect of endogenous murine apoE on selective neuronal necrosis resulting from a transient forebrain ischemia insult.

Methods
—ApoE deficient (n=16) and wild type (n=17) halothane-anesthetized mice were subjected to severe forebrain ischemia (10 minutes of bilateral carotid occlusion and systemic hypotension). After 3 days’ recovery, brain injury was determined histologically. In other apoE-deficient and wild-type mice, regional cerebral blood flow (CBF) was determined by
14
C-iodoantipyrine autoradiography 10 minutes before, 5 minutes after onset of, and 30 minutes after reperfusion from 10 minutes of forebrain ischemia.

Results
—The percentage of dead hippocampal CA1 neurons (mean±SD) was greater in the apoE-deficient group (apoE deficient=67±30%; wild type=37±33%;
P
=0.011). A similar pattern was observed in the caudoputamen (
P
=0.002) and neocortex (
P
=0.014). Cerebral blood flow was similar between groups at each measurement interval. Marked hypoperfusion persisted in both groups at 30 minutes after ischemia.

Conclusions
—ApoE deficiency worsens ischemic outcome. This is not attributable to effects on CBF. A role of apoE in the cerebral response to global ischemia is consistent with prior reports that murine apoE deficiency increases infarct size resulting from focal cerebral ischemia.
Treatment and Rehabilitation on a Stroke Unit Improves 5-Year Survival
Authors: Jørgensen Henrik Stig , Kammersgaard Lars Peter , Nakayama Hirofumi , Raaschou Hans Otto , Larsen Kim , Hübbe Per , Olsen Tom Skyhøj
Published: June 2011

Background and Purpose
—We have previously reported a marked reduction in mortality up to 1 year after treatment and rehabilitation on a stroke unit versus on general neurological and medical wards in unselected stroke patients. In the present study we wanted to test the hypothesis that this mortality-reducing effect is not temporary but is long lasting.

Methods
—We performed a community-based comparison of outcome in 1241 stroke patients from 2 adjacent communities in Copenhagen: in one (Frederiksberg), treatment and rehabilitation were provided on general neurological and medical wards, and in the other (Bispebjerg), treatment and rehabilitation were provided on a single large stroke unit.

Results
—The 2 stroke populations were comparable regarding age, sex, initial stroke severity, lesion diameter on CT, and stroke subtype (hemorrhage/infarct), but patients treated on the stroke unit had a higher frequency of comorbidity and lower incomes. One-year mortality was 39% (general wards) versus 32% (stroke unit) (
P
=0.01). This difference was still present 5 years after stroke (71% versus 64%;
P
=0.02). In a multiple logistic regression model of 5-year mortality, treatment on a stroke unit reduced the relative risk of death by 40% (odds ratio, 0.60; 95% CI, 0.42 to 0.85;
P
<0.01), independent of age, sex, stroke severity, and comorbidity.

Conclusions
—The mortality-reducing effect of treatment and rehabilitation on a dedicated stroke unit is long lasting rather than temporary. Stroke unit treatment reduced the relative risk of death within 5 years after stroke by 40% in an unselected, community-based stroke population. These results emphasize the need for organization of treatment and rehabilitation of unselected stroke patients on dedicated stroke units.
Determination of Cognitive Hemispheric Lateralization by “Functional” Transcranial Doppler Cross-Validated by Functional MRI
Authors: Schmidt Peter , Krings Timo , Willmes Klaus , Roessler Florian , Reul Jürgen , Thron Armin
Published: June 2011

Background and Purpose
—Changes of blood flow velocity in the right and left middle cerebral artery (MCA) induced by cognitive demands are detectable by means of “functional” transcranial Doppler sonography (fTCD). Functional MRI (fMRI) is an alternative method for mapping brain activity. The purpose of this study was to determine whether fTCD can detect hemispheric lateralization and to cross-validate fTCD with fMRI.

Methods
—Bilateral continuous MCA monitoring of 14 healthy, right-handed subjects with TCD was performed while the subjects underwent a visuospatial task, and the hemispheric blood flow velocity shift was calculated. Identical stimulus and response patterns were used in fMRI. Blood oxygenation level–dependent fMRI was performed with the use of a gradient-echo echo-planar sequence on a 1.5-T scanner. Statistical maps were computed on a voxel-by-voxel basis, hemispheric ratios for activated pixels were computed, and a group study was performed separately for the male and female subgroups.

Results
—Statistical analyses (
t
test) showed a significantly higher mean peak blood flow velocity increase (
P
<0.05) of the right MCA (111.3±7.0%) compared with the left MCA (107.1±6.1%). fMRI demonstrated bilateral activation in the superior parietal lobulus (Brodmann area 7) with a right/left ratio of 1.95. Concordant differences between the female and male subgroups could be visualized with both methods.

Conclusions
—Both methods succeeded in discriminating a blood flow shift to the right hemisphere induced by a complex cognitive visuospatial task. fMRI cross-validates the findings of fTCD. Our study suggests that fTCD can investigate the close relationship between brain activity and blood flow and lateralize higher cognitive functions reliably.
Neglect After Right Insular Cortex Infarction
Authors: Manes F. , Paradiso S. , Springer J. A. , Lamberty G. , Robinson R. G.
Published: June 2011

Background and Purpose
—Case reports have shown an association between right insular damage and neglect. The aim of this study was to examine the incidence of neglect among patient groups with right or left insular infarction.

Methods
—We examined neglect in 9 right-handed subjects with insular stroke as evidenced by CT and/or MRI scans (4 with right insular and 5 with left insular cerebrovascular accident) between 4 and 8 weeks after acute stroke with tests of visual, tactile, and auditory perception.

Results
—Compared with patients with left insular lesions, patients with right insular lesions showed significant neglect in the tactile, auditory, and visual modalities.

Conclusions
—The right insular cortex seems to have a role in awareness of external stimuli, and infarction in this area may lead to neglect in multisensory modalities.
C-Reactive Protein and Outcome After Ischemic Stroke
Authors: Muir Keith W. , Weir Christopher J. , Alwan Wafa , Squire Iain B. , Lees Kennedy R.
Published: June 2011

Background and Purpose
—Elevated concentrations of the acute-phase reactant C-reactive protein (CRP) predict ischemic cardiac events in both hospital- and population-based studies and may signify a role for inflammation in the destabilization of cardiovascular disease. We examined the relationship between CRP and outcome after acute ischemic stroke.

Methods
—This was a subgroup analysis from a prospective observational study based in a University Hospital Acute Stroke Unit serving a population of ≈260 000. Survival time and cause of death for up to 4 years after the index stroke were determined and related to CRP concentration within 72 hours of stroke and known prognostic variables by a Cox proportional hazards regression model.

Results
—Ischemic stroke was diagnosed in 228 of 283 consecutive admissions. Median follow-up was 959 days. Geometric mean CRP concentration was 10.1 mg/L. Survival in those with CRP >10.1 mg/L was significantly worse than in those with CRP ≤10.1 mg/L (
P
=0.00009, log-rank test). Higher CRP concentration was an independent predictor of mortality (hazard ratio, 1.23 per additional natural log unit; 95% CI, 1.13 to 1.35;
P
=0.02), together with age and stroke severity on the National Institutes of Health Stroke Scale. Cardiovascular disease accounted for 76% of deaths in those with CRP >10.1 mg/L and 63% of deaths in those with CRP ≤10.1 mg/L.

Conclusions
—CRP concentration is an independent predictor of survival after ischemic stroke. These findings are consistent with a role for inflammation in acute ischemic stroke, as well as with the hypothesis that elevated CRP may predict future cardiovascular mortality.
Safety and Tolerability of GV150526 (a Glycine Site Antagonist at the
N
-Methyl-
d
-Aspartate Receptor) in Patients With Acute Stroke
Authors: Dyker Alexander G. , Lees Kennedy R.
Published: June 2011

Background and Purpose
—
GV150526
is a novel glycine site antagonist at the
N
-methyl-
d
-aspartate receptor complex. It is a potent neuroprotective agent in animal models of stroke, including permanent middle cerebral artery occlusion in the rat. Unlike antagonists at the glutamate ligand binding site,
GV150526
appears to be free of hemodynamic and central nervous system adverse effects. The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of loading and maintenance infusions of
GV150526
in patients with acute stroke.

Methods
—This was a randomized, placebo-controlled, parallel-group, ascending-dose study conducted in 2 phases. In part A of the study, loading doses of 50, 100, 200, 400, or 800 mg were administered. In part B, the maximum loading dose from part A was followed by maintenance infusions (5 infusions at 12-hour intervals), aiming to maintain neuroprotective levels. Safety data were collected throughout. The study was not designed to test efficacy, but outcome data (Barthel Index and National Institutes of Health Stroke Scale) were collected.

Results
—Sixty-six patients were recruited to the study over 11 months; 18 patients received placebo.
GV150526
was well tolerated by the 48 patients who received it. There was no excess of central nervous system or hemodynamic adverse events compared with placebo. Minor abnormalities in liver function tests were observed in association with the higher maintenance doses tested. Four of 7 patients receiving the 800-mg loading dose followed by 400 mg BID and 1 of 6 patients who received the 200-mg BID maintenance dose showed a small rise in bilirubin, and 3 patients had increases in transaminases; the mean values at 72 hours remained under twice the upper limit of normal. These changes were asymptomatic and resolved within 10 days.

Conclusions
—
GV150526
is an emerging neuroprotective agent, with no apparent significant central nervous system or hemodynamic effects. Dose-limiting effects appear to be restricted to mild transient and asymptomatic rises in bilirubin and/or transaminases, primarily observed at high maintenance doses, and there were no findings that should preclude further clinical development.
Progression of Mass Effect After Intracerebral Hemorrhage
Authors: Zazulia Allyson R. , Diringer Michael N. , Derdeyn Colin P. , Powers William J.
Published: June 2011

Background and Purpose
—While the evolution of mass effect after cerebral infarction is well characterized, similar data regarding intracerebral hemorrhage (ICH) are scant. Our goal was to determine the time course and cause for progression of mass effect after ICH.

Methods
—Patients with spontaneous supratentorial ICH who underwent ≥2 CT scans were identified in our prospectively collected database. CT lesion size and midline shift of the pineal and septum pellucidum were retrospectively measured and correlated with clinical and CT characteristics. Causes for increased midline shift were determined by 2 independent observers.

Results
—Seventy-six patients underwent 235 scans (3.1±1.3 per patient). Initial CT was obtained within 24 hours of ICH in 66. Twenty-five scans were repeated on day 1, 80 on days 2 through 7, 31 on days 8 through 14, and 24 >14 days after ICH. Midline shift was present on 88% of the initial scans. There were 17 instances of midline shift progression: 10 occurred early (0.2 to 1.7 days) and were associated with hematoma enlargement, and 7 occurred late (9 to 21 days) and were associated with edema progression. Progression of mass effect due to edema occurred with larger hemorrhages (
P
<0.05). Of 65 scans repeated for clinical deterioration, only 10 were associated with increased mass effect.

Conclusions
—Progression of mass effect after ICH occurred at 2 distinct time points: within 2 days, associated with hematoma enlargement, and in the second and third weeks, associated with increase in edema. The clinical significance of later-developing edema is unclear.
Diffusion MRI in Patients With Transient Ischemic Attacks
Authors: Kidwell Chelsea S. , Alger Jeffry R. , Di Salle Francesco , Starkman Sidney , Villablanca Pablo , Bentson John , Saver Jeffrey L.
Published: June 2011

Background and Purpose
—Diffusion MRI has established value in patients with ischemic stroke but has not been systematically investigated in patients with transient ischemic attack (TIA).

Methods
—Clinical, conventional MRI, and diffusion MRI data were collected on 42 consecutive patients with symptoms of cerebral TIA. TIA imaging data were compared with those from a contemporaneous group of 23 completed stroke patients.

Results
—Twenty of the 42 TIA patients (48%) demonstrated neuroanatomically relevant focal abnormalities on diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) imaging. When present, DWI/ADC signal changes in TIA patients were less pronounced and smaller in volume than those in completed stroke patients. TIA symptom duration was significantly longer for DWI-positive than for DWI-negative patients, 7.3 versus 3.2 hours. Diffusion MRI information changed the suspected anatomic and vascular TIA localization and the suspected etiologic mechanism in over one third of patients with diffusion MRI abnormalities. Of the 20 TIA patients with identifiable lesions on diffusion MRI, 9 had follow-up imaging studies; of these, 4 did not show a relevant infarct on follow-up imaging.

Conclusions
—Diffusion MRI demonstrates ischemic abnormalities in nearly half of clinically defined TIA patients. The percentage of patients with a DWI lesion increases with increasing total symptom duration. In nearly half, the diffusion MRI changes may be fully reversible, while in the remainder the diffusion MRI findings herald the development of a parenchymal infarct despite transient clinical symptoms. Finally, diffusion imaging results have significant clinical utility, frequently changing the presumed localization and etiologic mechanism.
Ischemic Preconditioning in 18- to 20-Month-Old Gerbils
Authors: Dowden Jennifer , Corbett Dale
Published: June 2011

Background and Purpose
—In young animals, ischemic preconditioning protects CA1 hippocampal neurons against global ischemia. However, cerebral ischemia occurs most frequently in individuals aged ≥65 years. This study examined the protection provided by ischemic preconditioning in a population of aged (18- to 20-month-old) gerbils.

Methods
—One group of animals was exposed to two 1.5-minute episodes of global ischemia separated by 24 hours and followed 72 hours later by a 5-minute occlusion of both carotid arteries. A second group was given 2 episodes of preconditioning only. Two other groups were exposed to 5 minutes of ischemia or sham surgery. The animals survived 10, 30, or 60 days. Functional and histological assessments were used to determine the extent of protection.

Results
—Ten days after ischemia there was >80% protection of CA1 neurons in ischemic preconditioned animals compared with 6% in ischemic gerbils. Nevertheless, these preconditioned animals were impaired in open-field tests of habituation. In addition, CA1 dendritic field potentials were smaller in amplitude compared with those in sham animals. While there was a complete loss of staining for CA1 microtubule-associated protein-2 in ischemic animals, staining in ischemic preconditioned animals was normal. This suggests that dendritic abnormalities per se were not responsible for the observed functional deficits. CA1 cell survival declined to ≈75% of sham values (
P
<0.05) at 60 days after ischemia.

Conclusions
—Ischemic preconditioning provided substantial neuroprotection in aged gerbils. Nonetheless, the striking dissociation between histological and functional protection provided by ischemic preconditioning in aged animals emphasizes the need to use functional end points and long-term survival when assessing neuroprotection. Although functional recovery was evident with increasing survival time, CA1 cell death continued, thereby raising the possibility that the level of neuroprotection attained was not permanent.
Neuroprotective FK506 Does Not Alter In Vivo Nitric Oxide Production During Ischemia and Early Reperfusion in Rats
Authors: Toung Thomas J. , Bhardwaj Anish , Dawson Valina L. , Dawson Ted M. , Traystman Richard J. , Hurn Patricia D.
Published: June 2011

Background and Purpose
—Previous studies have demonstrated that the immunosuppressant FK506 provides neuroprotection in experimental brain injury and suggest that this action may be mediated by suppression of neuronal nitric oxide synthase activation that occurs after ischemic depolarization. We sought to determine whether FK506 reduces histological injury after middle cerebral artery occlusion (MCAO) in the rat and whether the neuroprotective effect is mediated via suppression of in vivo nitric oxide (NO) production during ischemia or early reperfusion
.

Methods
—Under controlled conditions of normoxia, normocarbia, and normothermia, halothane-anesthetized male Wistar rats were subjected to 2 hours of MCAO by the intraluminal occlusion technique in a blinded, randomized experimental trial. Ipsilateral parietal cortical laser-Doppler flowmetry was monitored throughout ischemia. Animals were randomly assigned to 4 pretreatment groups: intravenous FK506 0.3 mg/kg or 1.0 mg/kg, vehicle (cremaphor), or an equivalent volume of saline administered 30 minutes before MCAO. Infarction volume was assessed by a triphenyltetrazolium chloride staining at 22 hours of reperfusion. In separate experiments, microdialysis probes were placed bilaterally into the striatum. Rats were perfused with artificial cerebrospinal fluid containing 3 μmol/L [
14
C]-
l
-arginine for 3 hours and then subjected to 2 hours of right MCAO. Intravenous 0.3 mg/kg FK506 or cremaphor was given 30 minutes before right MCAO. Right-left differences between [
14
C]-
l
-citrulline in the effluent were assumed to reflect differences in NO production.

Results
—All values are mean±SE. FK506 at 0.3 mg/kg reduced infarction volume in cortex: 40±12 mm
3
compared with saline (109±15 mm
3
) and cremaphor vehicle (148±23) (
P
<0.05). Striatal infarction was also reduced by low-dose FK506: 16±4 mm
3
versus 36±4 mm
3
and 34±4 mm
3
in saline and vehicle groups, respectively (
P
<0.05). High-dose treatment reduced infarction volume in cortex (61±14 mm
3
,
P
<0.05 from saline and vehicle groups) and in striatum (22±5 mm
3
,
P
<0.05 from saline and vehicle groups). [
14
C]-
l
-citrulline recovery via microdialysis was markedly enhanced in ischemic compared with nonischemic striatum. However, ischemia-evoked [
14
C]-
l
-citrulline recovery was not different in FK506-treated rats compared with vehicle-treated animals.

Conclusions
—These data demonstrate that FK506 provides robust neuroprotection against transient focal cerebral ischemia in the rat. The mechanism of protection in vivo is not through attenuation of ischemia-evoked NO production during MCAO and early reperfusion
.
Recently Occluded Intracranial and Extracranial Carotid Arteries
Authors: Lammie G. Alistair , Sandercock Peter A. G. , Dennis Martin S.
Published: June 2011

Background and Purpose
—It is now widely accepted that thrombotic coronary artery occlusion usually follows rupture of an unstable atherosclerotic plaque. The significance of such instability in arteries supplying the brain is less well appreciated. We therefore describe the clinical and pathological features of recent, symptomatic internal carotid artery occlusion to examine the pathogenetic role of plaque instability at both extracranial and intracranial sites.

Methods
—Cases were selected from a consecutive series of 188 adult neuropathology autopsies. In 90 of these, the principal neuropathological abnormality was cerebral infarction, in 14 cases due to recent occlusion of 1 or more segments of the internal carotid artery. In each case, a full systemic, cardiovascular, and neuropathological autopsy was performed. Plaque instability was assessed by the presence or absence of a large, necrotic, lipid core; a thin, fibrous cap; and superficial inflammation.

Results
—Of the 14 cases, 3 showed extracranial (carotid sinus), 7 intracranial, and 4 both extracranial and intracranial carotid artery occlusion. In 6 of the 7 occluded carotid sinuses, thrombus overlay an ulcerated, unstable, atherosclerotic plaque. In 1 extracranial and all 11 intracranial occlusions, there was either no atheroma or a mildly stenotic, stable, fibrous plaque, and in these cases, the cause of occlusion was embolism (8 cases), giant-cell arteritis (1 case), and unknown (3 cases).

Conclusions
—Coronary-type rupture of an unstable atherosclerotic plaque is the usual cause of fatal occlusion of the carotid sinus, but other causes usually underlie intracranial carotid occlusion. The nature and consequences of intracranial atherosclerosis require further study.
Race, Presenting Signs and Symptoms, Use of Carotid Artery Imaging, and Appropriateness of Carotid Endarterectomy
Authors: Oddone Eugene Z. , Horner Ronnie D. , Sloane Richard , McIntyre Lauren , Ward Aileen , Whittle Jeff , Passman Leigh J. , Kroupa Laura , Heaney Robert , Diem Susan , Matchar David
Published: June 2011

Background and Purpose
—We sought to determine whether there are racial differences in use of carotid artery imaging after controlling for clinical factors and to ascertain racial differences in presenting signs and symptoms and overall appropriateness for carotid endarterectomy (CE).

Methods
—We performed a retrospective cohort study of 803 patients older than 45 years, hospitalized between 1991 and 1994 at any of 4 Veterans Affairs Medical Centers, with a discharge diagnosis of transient ischemic attack or ischemic stroke. Clinical data were abstracted from the medical record, including presenting symptoms, diagnostic test results, and use of surgical procedures. Appropriateness for CE was determined according to RAND criteria.

Results
—Black patients were more likely than white patients to present with stroke (78% versus 55%) but less likely to present with transient ischemic attack (22% versus 45%;
P
=0.001). There was no racial difference in medical comorbidity or preoperative risk. Black patients were less likely to have an imaging study of their carotid arteries (67% versus 79%;
P
=0.001). Race remained an independent predictor of imaging after adjustment for clinical factors (odds ratio=1.50; 95% CI, 1.06 to 2.13). Because of higher prevalence of significant carotid artery stenosis, whites were significantly more likely than blacks to be assessed as appropriate candidates for surgery with the use of RAND criteria (18% versus 4%;
P
=0.001).

Conclusions
—Use of carotid artery imaging, a critical step in determining eligibility for CE, is influenced by the patient’s race after controlling for clinical presentation. Adjustment for appropriateness of CE reduces but does not eliminate the importance of race.
Development of a Stroke-Specific Quality of Life Scale
Authors: Williams Linda S. , Weinberger Morris , Harris Lisa E. , Clark Daniel O. , Biller José
Published: June 2011

Background and Purpose
—Clinical stroke trials are increasingly measuring patient-centered outcomes such as functional status and health-related quality of life (HRQOL). No stroke-specific HRQOL measure is currently available. This study presents the initial development of a valid, reliable, and responsive stroke-specific quality of life (SS-QOL) measure, for use in stroke trials.

Methods
—Domains and items for the SS-QOL were developed from patient interviews. The SS-QOL, Short Form 36, Beck Depression Inventory, National Institutes of Health Stroke Scale, and Barthel Index were administered to patients 1 and 3 months after ischemic stroke. Items were eliminated with the use of standard psychometric criteria. Construct validity was assessed by comparing domain scores with similar domains of established measures. Domain responsiveness was assessed with standardized effect sizes .

Results
—All 12 domains of the SS-QOL were unidimensional. In the final 49-item scale, all domains demonstrated excellent internal reliability (Cronbach’s α values for each domain ≥0.73). Most domains were moderately correlated with similar domains of established outcome measures (
r
2
range, 0.3 to 0.5). Most domains were responsive to change (standardized effect sizes >0.4). One- and 3-month SS-QOL scores were associated with patients’ self-report of HRQOL compared with before their stroke (
P
<0.001).

Conclusions
—The SS-QOL measures HRQOL, its primary underlying construct, in stroke patients. Preliminary results regarding the reliability, validity, and responsiveness of the SS-QOL are encouraging. Further studies in diverse stroke populations are needed.
Uncoupling of Oxygen and Glucose Metabolism in Persistent Crossed Cerebellar Diaschisis
Authors: Yamauchi Hiroshi , Fukuyama Hidenao , Nagahama Yasuhiro , Nishizawa Sadahiko , Konishi Junji
Published: June 2011

Background and Purpose
—The pathophysiology of deafferentation-induced changes after stroke remains unclear. Some supratentorial strokes cause persistent decreases in blood flow and metabolism in the contralateral cerebellum (persistent crossed cerebellar diaschisis[CCD]). Our previous study showed uncoupling of oxygen consumption and blood flow in this condition, which may reflect a characteristic change in brain metabolism caused by deafferentation. This uncoupling might be related to oxidation of some substrates other than blood-borne glucose, which could also lead to the uncoupling of oxygen consumption and glucose utilization. The purpose of this study was to investigate whether oxygen consumption is uncoupled from glucose utilization in persistent CCD.

Methods
—Using positron emission tomography in 10 unilateral supratentorial stroke patients, we evaluated regional blood flow, oxygen consumption, and glucose utilization in the cerebellar cortex in the chronic stage. Eight patients with a significant cerebellar blood flow asymmetry, defined as outside the 95% confidence limits predefined in 9 normal subjects, were selected as patients with persistent CCD.

Results
—In patients with CCD, the cerebellar cortex contralateral to the stroke showed significant decreases in both oxygen consumption and glucose utilization compared with the ipsilateral cerebellar cortex. The decrease in oxygen consumption was less than the decrease in glucose utilization, resulting in a significant increase in the oxygen consumption/glucose utilization ratio.

Conclusions
—Persistent CCD caused by stroke may induce uncoupling of oxygen consumption and glucose utilization, which may reflect a characteristic change in brain metabolism caused by deafferentation.
Reliability and Validity of Noninvasive Imaging of Internal Carotid Artery Pseudo-Occlusion
Authors: Fürst Günter , Saleh Andreas , Wenserski Frank , Malms Jürgen , Cohnen Mathias , Aulich Albrecht , Neumann-Haefelin Tobias , Schroeter Michael , Steinmetz Helmuth , Sitzer Matthias
Published: June 2011

Background and Purpose
—Our study evaluated noninvasive tests for the diagnosis of atheromatous internal carotid artery (ICA) pseudo-occlusion.

Methods
—Twenty patients (17 men, 3 women; mean age ±SD, 64.3±11.6 years) with angiographically proven atheromatous ICA pseudo-occlusion (20 vessels) were prospectively examined with MR angiography (MRA; 2D and 3D time-of-flight techniques), color Doppler–assisted duplex imaging (CDDI) and power-flow imaging (PFI) with and without an intravenous ultrasonic contrast agent. As a control group, 13 patients (13 men; mean±SD age, 63.0±9.0 years) with angiographically proven ICA occlusion (13 vessels) were studied with the same techniques. For the determination of interobserver agreement (κ statistics), the findings of each diagnostic technique were read by 2 blinded and independent observers who were not involved in patient recruitment and initial data acquisition. Specificity and sensitivity were calculated for all noninvasive techniques (observer consensus) in comparison to the standard of reference (intra-arterial angiography).

Results
—Interobserver reliabilities were κ=0.86 for intra-arterial angiography, κ=0.90 for unenhanced CDDI, κ=0.93 for enhanced CDDI, κ=0.93 for unenhanced PFI, κ=1.0 for enhanced PFI, κ=0.93 for 2D MRA, and κ=0.77 for 3D MRA, respectively (
P
<0.0001). Specificities and sensitivities were 0.92 and 0.70 for unenhanced CDDI, 0.92 and 0.83 for enhanced CDDI, 0.92 and 0.95 for unenhanced PFI, 1.0 and 0.94 for enhanced PFI, 1.0 and 0.65 for 2D MRA, and 0.89 and 0.47 for 3D MRA, respectively.

Conclusions
—Advanced ultrasonographic techniques, especially PFI (with only 1 false-positive diagnosis of occlusion in the present series), can provide reliable and valid data to differentiate between ICA pseudo-occlusion and complete occlusion. In contrast, time-of-flight MRA at its present state is not capable of predicting minimal residual flow within a nearly occluded ICA.
Reorganization of Sensory and Motor Systems in Hemiplegic Stroke Patients
Authors: Nelles Gereon , Spiekermann Gregor , Jueptner Markus , Leonhardt Georg , Müller Stefan , Gerhard Horst , Diener H. Christoph
Published: June 2011

Background and Purpose
—Cortical reorganization of motor systems has been found in recovered stroke patients. Reorganization in nonrecovered hemiplegic stroke patients early after stroke, however, is less well described. We used positron emission tomography to study the functional reorganization of motor and sensory systems in hemiplegic stroke patients before motor recovery.

Methods
—Regional cerebral blood flow (rCBF) was measured in 6 hemiplegic stroke patients with a single, subcortical infarct and 3 normal subjects with the [
15
O]H
2
O injection technique. Brain activation was achieved by passive elbow movements driven by a torque motor. Increases of rCBF comparing passive movements and rest were assessed with statistical parametric mapping. Significant differences were defined at
P
<0.01.

Results
—In normal subjects, significant increases of rCBF were found in the contralateral sensorimotor cortex, supplementary motor area, cingulate cortex, and bilaterally in the inferior parietal cortex. In stroke patients, significant activation was observed bilaterally in the inferior parietal cortex and in the contralateral sensorimotor cortex, ipsilateral prefrontal cortex, supplementary motor area, and cingulate cortex. Significantly larger increases of rCBF in patients compared with normal subjects were found bilaterally in the sensorimotor cortex, stronger in the ipsilateral, unaffected hemisphere, and in both parietal lobes, including the ipsilateral precuneus.

Conclusions
—Passive movements in hemiplegic stroke patients before clinical recovery elicit some of the brain activation patterns that have been described during active movements after substantial motor recovery. Changes of cerebral activation in sensory and motor systems occur early after stroke and may be a first step toward restoration of motor function after stroke.
Increased Thromboxane Biosynthesis Is Associated With Poststroke Dementia
Authors: van Kooten F. , Ciabattoni G. , Koudstaal P. J. , Grobbee D. E. , Kluft C. , Patrono C.
Published: June 2011

Background and Purpose
—It has been suggested that daily intake of aspirin is associated with a reduction of cognitive decline, both in normal and in demented subjects, but the mechanism is unclear. We have therefore studied the relationship between thromboxane (TX) A
2
biosynthesis, as reflected by the urinary excretion of 11-dehydro-TXB
2
, and the presence of dementia in patients after acute stroke.

Methods
—Patients from the Rotterdam Stroke Databank were screened for dementia between 3 and 9 months after stroke. Patients had a full neurological examination, neuropsychological screening, and, if indicated, extensive neuropsychological examination. Criteria used for the diagnosis of dementia were from the
Diagnostic and Statistical Manual of Mental Disorders, Third Edition (Revised)
. Urine samples were taken at the time of screening. Urinary 11-dehydro-TXB
2
was measured by means of a previously validated radioimmunoassay.

Results
—Dementia was diagnosed in 71 patients, and urine samples were available for 62. Median value (range) of 11-dehydro-TXB
2
was 399 (89 to 2105) pmol/mmol creatinine for demented patients versus 273 (80 to 1957) for 69 controls with stroke but without dementia (
P
=0.013). No difference was found between 44 patients with vascular dementia, 404 (89 to 2105) pmol/mmol creatinine, and 18 patients with Alzheimer’s disease plus cerebrovascular disease, 399 (96 to 1467) pmol/mmol creatinine (
P
=0.68). In a stepwise logistic regression analysis, in which possible confounders such as use of antiplatelet medication, cardiovascular risk factors, and type of stroke were taken into account, increased urinary excretion of 11-dehydro-TXB
2
remained independently related to the presence of dementia (OR 1.12, 95% CI 1.03 to 1.22 per 100 pmol/mmol creatinine). The difference in metabolite excretion rates between demented and nondemented patients was most prominent within the subgroup of ischemic stroke patients who received aspirin (
P
<0.01).

Conclusions
—Increased thromboxane biosynthesis in the chronic phase after stroke is associated with the presence of but not the type of poststroke dementia. It is particularly apparent in patients on aspirin, thereby suggesting the involvement of extraplatelet sources of TXA
2
production in this setting.
Impact of Apolipoprotein E ε4 and Vascular Disease on Brain Morphology in Men From the NHLBI Twin Study
Authors: DeCarli C. , Reed T. , Miller B. L. , Wolf P. A. , Swan G. E. , Carmelli D.
Published: June 2011

Background and Purpose
—Apolipoprotein E ε4 genotype (ApoE4) has been associated with increased risk for cardiovascular disease morbidity or mortality. This appears to be mediated by an ApoE4-related increase in cardiovascular atherosclerosis. Given the similarities between risk factors for heart disease and risk factors for stroke, a positive association between ApoE4 and stroke would be expected. Since age-related brain atrophy and the extent of white matter hyperintensities (WMH) share similar risk factors, we examined the combined effect of ApoE4 and history of vascular disease on brain volume, WMH, and MRI evidence of stroke.

Methods
—Subjects were the surviving members of the National Heart, Lung, and Blood Institute Twin Study. This is a longitudinal study of the effects of cardiovascular disease risk factors in community-dwelling male veterans. The fourth and final examination of this cohort included cerebral MRI and was completed in 1997. Apolipoprotein E (ApoE) genotype, quantitative measures of brain volume, WMH, and the presence of stroke on MRI were obtained from the 396 participants in the final examination. The presence or absence of a history of coronary heart disease, cerebrovascular disease, peripheral arterial disease, and ApoE genotype were determined for each subject.

Results
—Of the 396 men, 88 (22%) had at least 1 ApoE4 allele. ApoE4 was not associated with differences in age or education. While the prevalence of vascular disease was generally greater in the ApoE4 group, this was only significant for coronary heart disease (29.8% in subjects without ApoE4 versus 40.7% in subject with ApoE4;
P
=0.03). ApoE4 subjects had significantly smaller brain volumes (942.4±34.5 versus 952.2±40.1 cm
3
;
P
=0.02). MRI evidence of stroke was detected in 88 (22%) of the subjects. The distribution of ApoE genotype was marginally different between subjects with MRI-detected stroke compared with those without. Further analysis revealed that the co-occurrence of cerebrovascular disease and ApoE4 was associated with significantly greater brain atrophy and WMH than either ApoE4 or cerebrovascular disease alone. Similar relations were seen for coronary heart disease and peripheral arterial disease.

Conclusions
—We conclude that ApoE4 enhances the extent of brain abnormalities in the presence of various vascular diseases. We speculate that this effect may be mediated by an increased susceptibility to brain injury or impaired repair mechanisms associated with ApoE4.
Is QT Interval a Marker of Subclinical Atherosclerosis in Nondiabetic Subjects?
Authors: Festa Andreas , D’Agostino Ralph , Rautaharju Pentti , O’Leary Daniel H. , Rewers Marian , Mykkänen Leena , Haffner Steven M.
Published: June 2011

Background and Purpose
—We studied the relationship of heart rate–corrected QT interval with subclinical atherosclerosis, as determined by ultrasonographic measurement of carotid intima-media thickness (IMT) in nondiabetic subjects in the Insulin Resistance Atherosclerosis Study (IRAS). Prolonged heart rate–corrected QT interval is an unfavorable prognostic factor of cardiovascular morbidity and mortality, and QT interval prolongation may be the result of atherosclerosis.

Methods
—B-mode ultrasound imaging of the carotid artery IMT was performed in a large, triethnic, nondiabetic population free of clinical coronary artery disease (n=912). QT interval was measured on resting electrocardiograms with use of a computer program and corrected for heart rate with standard equations.

Results
—IMT of the common carotid artery correlated significantly with heart rate–corrected QT interval duration (
r
=0.15 for QT
60
and
r
=0.14 for QTc), whereas no relationship between IMT of the internal carotid artery and QT interval was found (
r
=−0.01). The association was somewhat stronger in women than in men. In a multiple regression analysis adjusting for demographic variables, the association of common carotid artery IMT to heart rate–corrected QT interval remained highly significant, but adjustment for cardiovascular risk factors weakened the relationship.

Conclusions
—We found a significant relation of heart rate–corrected QT interval to carotid atherosclerosis in nondiabetic subjects that was stronger in women and partly mediated by cardiovascular risk factors, including hypertension. QT interval may therefore serve as a marker for clinically undetected (“subclinical”) atherosclerotic disease.