bluuebunny/crossref_metadata_2025 huggingface dataset:
The ICH Score
Authors: Hemphill J. Claude , Bonovich David C. , Besmertis Lavrentios , Manley Geoffrey T. , Johnston S. Claiborne
Published: June 2011

Background and Purpose
—Intracerebral hemorrhage (ICH) constitutes 10% to 15% of all strokes and remains without a treatment of proven benefit. Despite several existing outcome prediction models for ICH, there is no standard clinical grading scale for ICH analogous to those for traumatic brain injury, subarachnoid hemorrhage, or ischemic stroke.

Methods
—Records of all patients with acute ICH presenting to the University of California, San Francisco during 1997–1998 were reviewed. Independent predictors of 30-day mortality were identified by logistic regression. A risk stratification scale (the ICH Score) was developed with weighting of independent predictors based on strength of association.

Results
—Factors independently associated with 30-day mortality were Glasgow Coma Scale score (
P
<0.001), age ≥80 years (
P
=0.001), infratentorial origin of ICH (
P
=0.03), ICH volume (
P
=0.047), and presence of intraventricular hemorrhage (
P
=0.052). The ICH Score was the sum of individual points assigned as follows: GCS score 3 to 4 (=2 points), 5 to 12 (=1), 13 to 15 (=0); age ≥80 years yes (=1), no (=0); infratentorial origin yes (=1), no (=0); ICH volume ≥30 cm
3
(=1), <30 cm
3
(=0); and intraventricular hemorrhage yes (=1), no (=0). All 26 patients with an ICH Score of 0 survived, and all 6 patients with an ICH Score of 5 died. Thirty-day mortality increased steadily with ICH Score (
P
<0.005).

Conclusions
—The ICH Score is a simple clinical grading scale that allows risk stratification on presentation with ICH. The use of a scale such as the ICH Score could improve standardization of clinical treatment protocols and clinical research studies in ICH.
A Model for Multiparametric MRI Tissue Characterization in Experimental Cerebral Ischemia With Histological Validation in Rat
Authors: Jacobs Michael A. , Zhang Zheng G. , Knight Robert A. , Soltanian-Zadeh Hamid , Goussev Anton V. , Peck Donald J. , Chopp Michael
Published: June 2011

Background and Purpose
—After stroke, brain tissue undergoes time-dependent heterogeneous histopathological change. These tissue alterations have MRI characteristics that allow segmentation of ischemic from nonischemic tissue. Moreover, MRI segmentation generates different zones within the lesion that may reflect heterogeneity of tissue damage.

Methods
—A vector tissue signature model is presented that uses multiparametric MRI for segmentation and characterization of tissue. An objective (unsupervised) computer segmentation algorithm was incorporated into this model with the use of a modified version of the Iterative Self-Organizing Data Analysis Technique (ISODATA). The ability of the model to characterize ischemic tissue after permanent middle cerebral ischemia occlusion in the rat was tested. Multiparametric ISODATA measurements of the ischemic tissue were compared with quantitative histological characterization of the tissue from 4 hours to 1 week after stroke.

Results
—The ISODATA segmentation of tissue identified a gradation of cerebral tissue damage at all time points after stroke. The histological scoring of ischemic tissue from 4 hours to 1 week after stroke on all the animals was significantly correlated with ISODATA segmentation (
r
=0.78,
P
<0.001; n=20) when a multiparametric (T2-, T1-, diffusion-weighted imaging) data set was used, less correlated (
r
=0.70,
P
<0.01; n=20) when a T2- and T1-weighted data set was used, and not correlated (
r
=−0.12,
P
>0.47; n=20) when only a diffusion-weighted imaging data set was used.

Conclusions
—Our data indicate that an integrated set of MRI parameters can distinguish and stage ischemic tissue damage in an objective manner.
Correlation of Cerebral Hypoxic-Ischemic T2 Changes With Tissue Alterations in Water Content and Protein Extravasation
Authors: Qiao Min , Malisza Krisztina L. , Del Bigio Marc R. , Tuor Ursula I.
Published: June 2011

Background and Purpose
—Age-dependent changes in T2-weighted MR images have been reported in cerebral hypoxia-ischemia. However, the biophysical mechanisms responsible for the image changes remain poorly defined. We investigated whether cerebral hypoxia-ischemia–induced T2 changes correlate with alterations in either water content or protein extravasation.

Methods
—One- and 4-week-old rats were subjected to unilateral carotid artery occlusion plus hypoxia in 8% oxygen. T2 images were acquired before, during, and 1 or 24 hours after hypoxia-ischemia. Blood-brain barrier disruption and brain edema were evaluated by immunohistological detection of IgG extravasation and measurement of water content by dry-wet weight and specific gravity methods.

Results
—In 1-week-old rats, T2 values, areas of hyperintensity on T2-weighted images, and water content in the ipsilateral hemisphere increased during hypoxia-ischemia, recovered at 1 hour after hypoxia-ischemia, and increased again at 24 hours after hypoxia-ischemia. Extravasation of IgG occurred during hypoxia-ischemia and remained detectable 24 hours after hypoxia-ischemia. In 4-week-old rats, an increase in T2 or extravasation of IgG did not occur until 24 hours after hypoxia-ischemia despite a comparable elevation in water content during and soon after hypoxia-ischemia.

Conclusions
—T2 imaging appears reliable for detecting edema associated with disruption of the blood-brain barrier but not necessarily an increase in cerebral water or plasma proteins alone. The different hypoxic-ischemic changes in T2 in immature and older brain are associated with differences in alterations in water content plus extravasation of protein, consistent with age-dependent differences in hypoxic-ischemic alterations in vascular permeability.
Enoxaparin in Experimental Stroke
Authors: Mary Véronique , Wahl Florence , Uzan André , Stutzmann Jean-Marie
Published: June 2011

Background and Purpose
—Heparin and heparinoids have long been proposed for stroke treatment. This study investigates the effect of enoxaparin (Lovenox, Clexane), a low-molecular-weight heparin, on functional outcome (neuroscore) and lesion size in stroke models with reversible and irreversible cerebral ischemia using middle cerebral artery occlusion (MCAO) in the rat.

Methods
—Ischemia was induced in rats by transient occlusion for 2 hours or by permanent electrocoagulation of the left MCA. Forty-eight hours after ischemia, neurological deficit was evaluated by scoring sensorimotor functions and ischemic damage was quantified by histological evaluation of lesion volumes.

Results
—After transient MCAO, enoxaparin at 2×1.5 mg/kg IV (2 and 24 hours after insult) significantly reduced lesion size by 30% (
P
<0.05) and improved neuroscore (
P
<0.01). This significant effect on lesion size and neuroscore was still evident when treatment was started 5 hours after insult. Administered under the same protocol with a 5 hours delay post permanent MCAO, enoxaparin reduced lesion size by 49% (
P
<0.05) and improved neuroscore (
P
<0.01).

Conclusions
—This study indicates that standard nonhemorrhagic doses of enoxaparin reduce ischemic damage with a wide therapeutic window. In addition to its anticoagulant properties, other properties of enoxaparin could act in synergy to explain its neuroprotective profile in ischemia. Thus clinical application of enoxaparin treatment in stroke warrants serious consideration.
Timing of Spontaneous Recanalization and Risk of Hemorrhagic Transformation in Acute Cardioembolic Stroke
Authors: Molina Carlos A. , Montaner Joan , Abilleira Sonia , Ibarra Bernardo , Romero Francisco , Arenillas Juan F. , Alvarez-Sabín José
Published: June 2011

Background and Purpose
—The relationship between reperfusion and hemorrhagic transformation (HT) remains uncertain. Therefore, we aimed to clarify the relationship between the time course of recanalization and the risk of HT in patients with cardioembolic stroke studied within 6 hours of symptom onset.

Methods
—Fifty-three patients with atrial fibrillation and nonlacunar stroke in the middle cerebral artery (MCA) territory admitted within the first 6 hours after symptom onset were prospectively studied. Serial TCD examinations were performed on admission and at 6, 12, 24, and 48 hours. CT was performed within 6 hours after stroke onset and again at 36 to 48 hours.

Results
—Proximal and distal MCA occlusions were detected in 32 patients (60.4%) and 18 patients (34%), respectively. Early spontaneous recanalization occurring within 6 hours was identified in 10 patients (18.8%). Delayed recanalization (>6 hours) occurred in 28 patients (52.8%). HT on CT scan was detected in 17 patients (32%) within the first 48 hours. Only large parenchymal hemorrhage (PH2) was significantly associated with an increase (
P
=0.038, Kruskal-Wallis test) in the National Institutes of Health Stroke Scale (NIHSS) score compared with the other subtypes of HT. Univariate analysis revealed that an NIHSS score of >14 on baseline (
P
=0.001), proximal MCA occlusion (
P
=0.004), hypodensity >33% of the MCA territory (
P
=0.012), and delayed recanalization occurring >6 hours of stroke onset (
P
=0.003) were significantly associated with HT. With a multiple logistic regression model, delayed recanalization (OR 8.9; 95% CI 2.1 to 33.3) emerged as independent predictor of HT.

Conclusions
—Delayed recanalization occurring >6 hours after acute cardioembolic stroke is an independent predictor of HT.
Viability Thresholds of Ischemic Penumbra of Hyperacute Stroke Defined by Perfusion-Weighted MRI and Apparent Diffusion Coefficient
Authors: Røhl L. , Østergaard L. , Simonsen C. Z. , Vestergaard-Poulsen P. , Andersen G. , Sakoh M. , Le Bihan D. , Gyldensted C.
Published: June 2011

Background and Purpose
—The penumbra of ischemic stroke consists of hypoperfused, but not irreversibly damaged, tissue surrounding the ischemic core. The purpose of this study was to determine viability thresholds in the ischemic penumbra, defined as the perfusion/diffusion mismatch in hyperacute stroke, by the use of diffusion- and perfusion-weighted MRI (DWI and PWI, respectively).

Methods
—DWI and PWI were performed in 11 patients ≤6 hours after the onset of symptoms of acute ischemic stroke. Regions of interest (ROIs) were placed covering the ischemic core (ROI 1), the penumbra that progressed to infarction on the basis of follow-up scans (ROI 2), and the penumbra that recovered (ROI 3). The ratios of relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), mean transit time (MTT), and apparent diffusion coefficient were calculated as lesion ROIs relative to the contralateral mirror ROIs.

Results
—The post hoc analysis showed that the penumbra progressed to infarction at the following cutoff values: rCBF <0.59 and MTT >1.63. Higher sensitivity and accuracy in predicting outcome of the penumbra were obtained from the rCBF maps compared with the rCBV and MTT maps. The initial rCBV and apparent diffusion coefficient ratios did not differentiate between the part of the penumbra that recovered and the part that progressed to infarction. The mean rCBF ratio was optimal in distinguishing the parts of the penumbra recovering or progressing to infarction.

Conclusions
—The thresholds found in this study by combined DWI/PWI might aid in the selection of patients suitable for therapeutic intervention within 6 hours. However, these hypothesized thresholds need to be prospectively tested at the voxel level on a larger patient sample before they can be applied clinically.
White Matter Damage Is Associated With Matrix Metalloproteinases in Vascular Dementia
Authors: Rosenberg Gary A. , Sullivan Niky , Esiri Margaret M.
Published: June 2011

Background and Purpose
—Vascular disease causes multi-infarct dementia (MID) or Binswanger’s disease (BD), the latter of which is a progressive form of vascular dementia (VaD) associated pathologically with fibrinoid and hyaline changes in brain arterioles with injury to the white matter. Clinically, BD patients have long-standing hypertension with disturbances of gait and intellect. Because matrix metalloproteinases (MMPs) are important in cerebral infarction, we hypothesized that disturbances in the MMPs may be involved in VaD.

Methods
—Brain tissues from 5 patients with VaD of the BD or multi-infarct type (MID) were immunostained with antibodies to glial fibrillary acidic protein (GFAP), a microglial/macrophage cell marker (PG-M1), gelatinase A (MMP-2), stromelysin-1 (MMP-3), and gelatinase B (MMP-9). Control tissues were from 8 elderly patients: 4 with strokes without dementia and 4 without neurological diseases.

Results
—PG-M1+ cells appeared around infarcts in patients with strokes without dementia and in patients with VaD. In 2 of the 3 BD patients, PG-M1 cells were prominent near damaged arterioles and scattered diffusely in white matter. MMP-2 was seen normally in perivascular macrophages and in astrocytic processes near blood vessels and was present in patients with strokes in reactive astrocytes. MMP-9 was rarely seen. MMP-3 was seen in PG-M1+ microglial/macrophage cells around the acute infarctions. In BD, MMP-3 persisted in tissue macrophages and disappeared in long-standing white matter gliosis.

Conclusions
—These observations suggest that MMPs may participate in the damage to the white matter associated with VaD. Microglia/macrophage-induced damage, which is amenable to treatment, may be a factor in the progressive forms of VaD.
Cortical Neurogenesis in Adult Rats After Transient Middle Cerebral Artery Occlusion
Authors: Jiang Wei , Gu WeiGang , Brännström Thomas , Rosqvist Roland , Wester Per
Published: June 2011

Background and Purpose
—This study explored the possible occurrence of newly generated nerve cells in the ischemic cortex of adult rats after middle cerebral artery occlusion and reperfusion.

Methods
—Nine- to 10-week-old male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion by the monofilament method. Rats received repeated intraperitoneal injections of the cell proliferation–specific marker 5-bromodeoxyuridine (BrdU) after stroke induction. Brain sections were processed for immunohistochemistry with an avidin-biotin complex–alkaline phosphatase and/or –peroxidase method. Brain sections processed with double-immunofluorescent staining were further scanned by confocal microscopy.

Results
—Interspersed among the predominantly newly formed glial cells, some cells were double labeled by BrdU and 1 of the neuron-specific markers, Map-2, β-tubulin III, and Neu N, at 30 and 60 days after stroke onset. These cells were randomly distributed throughout cortical layers II through VI, occurring with highest density in the ischemic boundary zone. Three-dimensional confocal analyses of BrdU and the neuron-specific marker Neu N confirmed their colocalization within the same cortical cells.

Conclusions
—This study suggests that new neurons can be generated in the cerebral cortex of adult rats after transient focal cerebral ischemia. Cortical neurogenesis may be a potential pathway for brain repair after stroke.
Bradykinin Mediates the Acute Effect of an Angiotensin-Converting Enzyme Inhibitor on Cerebral Autoregulation in Rats
Authors: Takada Junichi , Ibayashi Setsuro , Nagao Tetsuhiko , Ooboshi Hiroaki , Kitazono Takanari , Fujishima Masatoshi
Published: June 2011

Background and Purpose
—In patients with stroke and long-standing hypertension, the autoregulation curve of cerebral blood flow (CBF) shifts toward higher blood pressure levels. Angiotensin-converting enzyme (ACE) inhibitors reduce blood pressure and shift the autoregulation curve back to normal in hypertensive patients. ACE inhibitors have 2 major pharmacological properties: they inhibit both the production of angiotensin II and the breakdown of kinins. Hence, we investigated whether the effect of an ACE inhibitor on the lower limit of CBF autoregulation is mediated by the potentiation of bradykinin-mediated vasodilatation.

Methods
—In 28 male Sprague-Dawley rats, CBF was measured by laser-Doppler flowmetry during stepwise controlled hypotension. The lower limit of CBF autoregulation was defined as the mean arterial pressure at which CBF decreased by 20% of the baseline value. The rats were treated with an ACE inhibitor, captopril, in the captopril group; a bradykinin BK2-receptor antagonist, Hoe140, in the Hoe140 group; and both agents in the captopril+Hoe140 group. Other rats served as a control group. The lower limits of CBF autoregulation were compared among the 4 groups.

Results
—In the captopril group, the lower limit of CBF autoregulation was 43±8 mm Hg (mean±SD), which was significantly lower than that in the control group (57±14 mm Hg). Inhibition of bradykinin abolished the effect of captopril on the lower limit of CBF autoregulation. Hoe140 alone had no significant effect on the lower limit of CBF autoregulation.

Conclusions
—These results suggest that the shift of the lower limit of CBF autoregulation by captopril is mediated, at least in part, by bradykinin.
Neuroprotection by the Selective Cyclooxygenase-2 Inhibitor SC-236 Results in Improvements in Behavioral Deficits Induced by Reversible Spinal Cord Ischemia
Authors: Lapchak Paul A. , Araujo Dalia M. , Song Donhuang , Zivin Justin A.
Published: June 2011

Background and Purpose
—Cyclooxygenase-2 (COX-2), an enzyme that is induced in the central nervous system after various insults, has been localized to neurons and in cells associated with the cerebral vasculature, where it may be involved in the inflammatory component of the ischemic cascade. COX-2 is part of the initial reaction that involves the arachidonic acid cascade, which produces molecules that support an inflammatory response. The present study evaluated the pharmacological effects of a specific long-acting COX-2 inhibitor, SC-236, in a reversible rabbit spinal cord ischemia model using clinical rating scores (behavioral analysis) as the primary end point.

Methods
—SC-236 was administered (10 to 100 mg/kg SC) 5 minutes after the start of occlusion to groups of rabbits exposed to ischemia induced by temporary (10 to 40 minutes) occlusion of the infrarenal aorta. Behavioral analysis, which allowed for the calculation of an ET
50
value representing the duration of ischemia (minutes) associated with a 50% probability of resultant permanent paraplegia, was conducted 18 and 48 hours later. A drug was determined to be neuroprotective if it prolonged the ET
50
significantly compared with the appropriate control group.

Results
—Since SC-236 is not readily soluble in aqueous solutions, it was dissolved in 100% dimethyl sulfoxide (DMSO) for subcutaneous administration. Therefore, the vehicle-treated control group consisted of rabbits given an equal volume of DMSO without drug. In the DMSO-treated control group, the ET
50
assessed 18 hours after initiation of aortal occlusion was 18.84±3.19 minutes. In contrast, treatment with 100 mg/kg of SC-236 given 5 minutes after the start of occlusion prolonged the ET
50
of the group significantly to 30.04±3.55, an effect that was still evident 48 hours later. In addition, lower doses of the drug (10 and 50 mg/kg) also showed a trend for an increase in ET
50
. SC-236 (100 mg/kg) did not significantly alter body temperature after a subcutaneous injection.

Conclusions
—The present study suggests that COX-2 plays an important role in the ischemic cascade of events that translate into ischemia-induced behavioral deficits and furthermore that selective COX-2 inhibitors may be useful in the treatment of ischemic stroke to improve behavioral functions.
Ethical and Methodological Issues in Pedigree Stroke Research
Authors: Worrall Bradford Burke , Chen Donna T. , Meschia James F.
Published: June 2011

Background
—Stroke is a complex genetic disorder with a variable phenotype. Investigations of heritable factors in complex genetic disorders use pedigree and genetic techniques, which pose different ethical and methodological challenges than those routinely encountered in therapeutic research. Building consensus on acceptable research practices in this field is vital to the success of multicentered collaborations.

Summary of Review
—We review important ethical and methodological concerns related to the collection, storage, and release of pedigree research information. The human studies aspects of pedigree research are complicated methodologically because individuals can be active or passive participants and pedigrees can be proband derived, partially validated, or fully validated. Current research ethics frameworks do not work well outside of a dyadic researcher-subject relationship. Privacy and confidentiality for family members must be considered in pedigree research. Investigators should anticipate potential conflicts of interest among family members when designing a pedigree research protocol.

Conclusions
—We propose a “proband-initiated contact” methodology in which the proband or the proband’s designate allows identification of potential families without breaching the privacy of individuals in the family. In situations in which family history data are collected without direct contact between researchers and individuals in the proband’s family, an Institutional Review Board may waive consent by family members after appropriate review of the protocol and application of rules for granting waivers of consent. Certificates of Confidentiality should be considered.
Ipsilateral Motor Responses to Focal Transcranial Magnetic Stimulation in Healthy Subjects and Acute-Stroke Patients
Authors: Alagona Giovanna , Delvaux Valérie , Gérard Pascale , De Pasqua Victor , Pennisi Giovanni , Delwaide Paul J. , Nicoletti Francesco , Maertens de Noordhout Alain
Published: June 2011

Background and Purpose
—Prevalence and characteristics of ipsilateral upper limb motor-evoked potentials (MEPs) elicited by focal transcranial magnetic stimulation (TMS) were compared in healthy subjects and patients with acute stroke.

Methods
—Sixteen healthy subjects and 25 patients with acute stroke underwent focal TMS at maximum stimulator output over motor and premotor cortices. If present, MEPs evoked in muscles ipsilateral to TMS were analyzed for latency, amplitude, shape, and center of gravity (ie, preferential coil location to elicit them). In stroke patients, possible relationships between early ipsilateral responses and functional outcome at 6 months were sought.

Results
—With relaxed or slightly contracting target muscle, maximal TMS over the motor cortex failed to elicit ipsilateral MEPs in the first dorsal interosseous (FDI) or biceps of any of 16 normal subjects. In 5 of 8 healthy subjects tested, ipsilateral MEPs with latencies longer than contralateral MEPs were evoked in FDI muscle (in biceps, 6 of 8 subjects) during strong (>50% maximum) contraction of the target muscle. In 15 of 25 stroke patients, ipsilateral MEPs in the unaffected relaxed FDI (in biceps, 6 of 25 stroke patients) were evoked by stimulation of premotor areas of the affected hemisphere. Their latencies were shorter than those that MEPs evoked in the same muscle by stimulation of the motor cortex of the contralateral unaffected hemisphere. Such responses were never obtained in normal subjects and were mostly observed in patients with subcortical infarcts. Patients harboring these responses had slightly better bimanual dexterity after 6 months.

Conclusions
—Ipsilateral MEPs obtained in healthy individuals and stroke patients have different characteristics and probably different origins. In the former, they are probably conveyed via corticoreticulospinal or corticopropriospinal pathways, whereas in the latter, early ipsilateral MEPs could originate in hyperexcitable premotor areas.
Acute Stroke Patterns in Patients With Internal Carotid Artery Disease
Authors: Szabo Kristina , Kern Rolf , Gass Achim , Hirsch Jochen , Hennerici Michael
Published: June 2011

Background and Purpose
—Diffusion-weighted (DW) MRI is a sensitive method that facilitates early stroke pattern identification. There are limited data about the influence of stenosis grade on the development of particular stroke patterns in internal carotid artery (ICA) disease. We therefore investigated the lesion patterns on DW MRI in acute stroke patients with ICA disease.

Methods
—DW MRI was analyzed in 102 consecutive acute stroke patients with different degrees of ipsilateral ICA disease. Patients were assigned to 1 of 5 observed lesion patterns: (1) territorial ischemia, (2) subcortical ischemia without or (3) with embolus fragmentation, (4) disseminated lesions in distal cortical regions, and (5) multiple lesions in hemodynamic risk zones. In addition, perfusion-weighted (PW) MRI and MR angiography information was included in the assessment.

Results
—All patterns were observed in the different stages of ICA disease. Half of the patients with high-grade or subtotal stenosis had lesions in hemodynamic risk zones. Territorial stroke occurred in 47.6% of patients with ICA occlusion. Statistical analysis showed a significant relationship between the degree of stenosis and the observed stroke pattern (
P
=0.001). In 77.8% of patients exhibiting high-grade ICA stenosis, subtotal stenosis, or occlusion, the perfusion lesion was larger than the diffusion lesion (PW/DW mismatch).

Conclusions
—Although in the individual patient any of the infarct patterns may occur, in statistical terms the incidence of a particular stroke pattern is clearly dependent on the degree of stenosis.
Socioeconomic Status and Ischemic Stroke
Authors: Jakovljević Dimitrije , Sarti Cinzia , Sivenius Juhani , Torppa Jorma , Mähönen Markku , Immonen-Räihä Pirjo , Kaarsalo Esko , Alhainen Kari , Kuulasmaa Kari , Tuomilehto Jaakko , Puska Pekka , Salomaa Veikko
Published: June 2011

Background and Purpose
—It has been shown that low socioeconomic status is associated with death from stroke. More-detailed data have, however, remained scanty. The purpose of the present study was to examine the association of socioeconomic status with ischemic stroke. Besides mortality, we analyzed the incidence, case-fatality ratio, and prognosis of ischemic stroke events.

Methods
—Our population-based study included 6903 first stroke events registered by the FINMONICA Stroke Register in 3 areas of Finland during 1983 to 1992. Indicators of socioeconomic status, such as taxable income and education, were obtained by record linkage of the stroke register data with files of Statistics Finland.

Results
—Incidence, case-fatality ratio, and mortality rates for ischemic stroke were all inversely related to income. Furthermore, 28 days after the onset of symptoms, a greater proportion of patients with low income than of those with high income was still in institutionalized care and/or in need of help for their activities of daily living. Population-attributable risk of the incidence of first ischemic stroke due to low socioeconomic status was 36% for both sexes. For the death from first ischemic stroke, it was 56% for both sexes.

Conclusions
—Persons with low socioeconomic status have considerable excess rates of morbidity and mortality from ischemic stroke in Finland. A reduction in this excess could markedly decrease the burden of ischemic stroke to the society and thus constitute an important public health improvement.
Effect of Apolipoprotein E Genotype on Cerebral Autoregulation During Cardiopulmonary Bypass
Authors: Ti Lian K. , Mathew Joseph P. , Mackensen G. Burkhard , Grocott Hilary P. , White William D. , Reves J. G. , Newman Mark F.
Published: June 2011

Background and Purpose
—The presence of the apolipoprotein E ε4 (apoE4) allele has been associated with cognitive decline after cardiac surgery. We compared autoregulation of cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRO
2
), and arterial−venous oxygen content difference [C(A−V)O
2
], during cardiopulmonary bypass (CPB) in patients with and without the apoE4 allele to help define the mechanism of association with cognitive decline.

Methods
—One hundred fifty-four patients underwent coronary artery bypass grafting with CPB, nonpulsatile flow, and α-stat management. CBF was measured by using
133
Xe washout methods. C(A−V)O
2
, CMRO
2
, and oxygen delivery were calculated. Pressure-flow autoregulation was tested by using 2 CBF measurements at stable hypothermia: the first at stable mean arterial pressure (MAP) and the second 15 minutes later, when MAP had increased or decreased ≥20%. Metabolism-flow autoregulation was tested by varying the temperature and measuring the coupling of CBF and CMRO
2
.

Results
—In patients with (n=41) or without (n=113) the apoE4 allele, there were no differences in CBF, CMRO
2
, C(A−V)O
2
, pressure-flow and metabolism-flow autoregulation corrected for age, gender, non–insulin-dependent diabetes, hemoglobin, CPB time, and temperature.

Conclusions
—We conclude that apoE genotype does not affect global CBF and oxygen delivery/extraction during CPB, which suggests that other mechanisms are responsible for the apoE isoform–related neurocognitive dysfunction seen in patients undergoing CPB.
Vitamin D Deficiency and Risk of Hip Fractures Among Disabled Elderly Stroke Patients
Authors: Sato Yoshihiro , Asoh Takeshi , Kondo Izumi , Satoh Kei
Published: June 2011

Background and Purpose
—Risk of hip fracture after stroke is 2 to 4 times that in a reference population. Osteomalacia is present in some patients with hip fractures in the absence of stroke, while disabled elderly stroke patients occasionally have severe deficiency in serum concentrations of 25-hydroxyvitamin D (25-OHD) (≤5 ng/mL). To determine the effects of vitamin D status on hip fracture risk, we prospectively studied a cohort of patients with hemiplegia after stroke who were aged at least 65 years.

Methods
—We compared baseline serum indices of bone metabolism, bone mineral density, and hip fracture occurrence in stroke patients with serum 25-OHD ≤25 nmol/L (≤10 ng/mL; deficient group, n=88) with findings in patients from the same cohort who had 25-OHD levels 26 to 50 nmol/L (10 to 20 ng/mL; insufficient group, n=76) or ≥51 nmol/L (≥21 ng/mL; sufficient group, n=72).

Results
—Over a 2-year follow-up interval, hip fractures on the paretic side occurred in 7 patients in the deficient group and 1 patient in the insufficient group (
P
<0.05; hazard ratio=6.5), while no hip fractures occurred in the sufficient group. The 7 hip fracture patients in the deficient group had an osteomalacic 25-OHD level of <5 ng/mL. Higher age and severe immobilization were noted in the deficient group. Serum 25-OHD levels correlated positively with age, Barthel Index, and serum parathyroid hormone.

Conclusions
—Elderly disabled stroke patients with serum 25-OHD concentrations ≤12 nmol/L (≤5 ng/mL) have an increased risk of hip fracture. Immobilization and advanced age cause severe 25-OHD deficiency and consequent reduction of BMD.
Evolution of Cerebral Tumor Necrosis Factor-α Production During Human Ischemic Stroke
Authors: Sairanen Tiina , Carpén Olli , Karjalainen-Lindsberg Marja-Liisa , Paetau Anders , Turpeinen Ursula , Kaste Markku , Lindsberg Perttu J.
Published: June 2011

Background and Purpose

—

Tumor necrosis factor-α (TNF-α) is detected in ischemic brain cells in experimental animal models and is believed to play an important role in apoptosis. However, the natural expression of TNF-α during human stroke is not known.

Methods

—

We examined TNF-α immunohistochemistry and terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling (TUNEL) in brain samples of stroke victims (n=16) after variable survival (15 hours to 18 days). Systemic TNF-α content from a separate cohort including severe or lethal stroke cases (n=26) was also assayed.

Results

—

Neuronal TNF-α was demonstrated from 0.6 to 5.4 days after the onset of stroke symptoms, peaking bilaterally during days 2 and 3. Bilateral glial TNF-α immunoreactivity was detected during the acute phase, with the astrocytic TNF-α expression dominating in later phases and persisting contralaterally to the infarct in more matured phases (17 to 18 days). Invading inflammatory cells were TNF-α immunopositive beginning on the third day. Besides, vascular wall structures showed immunoreactivity sporadically. TNF-α levels were mostly nondetectable in peripheral blood. TUNEL labeling and TNF-α staining overlapped, although not completely, during the first days.

Conclusions

—

The data support the hypothesis that TNF-α may be involved both in the acute propagation of inflammatory processes and cell death and possibly in the more delayed reconstitutive processes of human ischemic stroke.
Phenotype of a Homozygous CADASIL Patient in Comparison to 9 Age-Matched Heterozygous Patients With the Same R133C

Notch3

Mutation
Authors: Tuominen Susanna , Juvonen Vesa , Amberla Kaarina , Jolma Tapani , Rinne Juha O. , Tuisku Seppo , Kurki Timo , Marttila Reijo , Pöyhönen Minna , Savontaus Marja-Liisa , Viitanen Matti , Kalimo Hannu
Published: June 2011

Background and Purpose

—

CADASIL is an autosomal dominant arteriopathy, characterized by multiple brain infarcts, cognitive decline, and finally dementia, which is caused by mutations in
Notch3
gene encoding a Notch3 receptor protein. We describe the clinical, neuropsychological, imaging, genetic, and skin biopsy findings in a CADASIL patient homozygous for the C475T mutation resulting in R133C amino acid substitution, in comparison to 9 age-matched heterozygous patients with the same mutation.

Methods

—

The patients were examined clinically and neuropsychologically and with MRI and positron emission tomography for assessment of cerebral blood flow. The gene defect was analyzed by sequencing the products of polymerase chain reaction of exons 3 and 4 of the
Notch3
gene. Dermal arteries were analyzed electron microscopically.

Results

—

The homozygous patient had his first-ever stroke at age 28 years. This is markedly earlier than the average, but the patient’s heterozygous son had his first transient ischemic attack–like episode at the same age and another heterozygous patient had his first-ever stroke when only 2 years older. He was neuropsychologically more severely deteriorated than all but 1 of the heterozygous patients. These 2 patients had the most severe (confluent grade D) white matter MRI changes. Positron emission tomography showed markedly reduced cerebral blood flow. Skin biopsy revealed profuse deposits of granular osmiophilic material. The progression of disease in the homozygous case was, however, slower than in the most severely affected heterozygous patient.

Conclusions

—

Our homozygous patient’s phenotype is within the clinical spectrum of CADASIL, although at its severe end. Thus, CADASIL may follow the classic definition of a dominant disease, according to which the heterozygous and homozygous patients are clinically indistinguishable.
Development of a Novel, Weighted, Quantifiable Stroke Scale
Authors: Gotoh Fumio , Terayama Yasuo , Amano Takahiro ,   for the Stroke Scale Committee of the Japan Stroke Society
Published: June 2011

Background and Purpose

—

Several stroke scales are available for estimation of the severity of stroke, but none of them provides information regarding the relative weights of the observed variables. To define an integrated severity of stroke, we developed a quantifiable stroke scale with weighted variables that apply conjoint analysis to calculate the relative weight of each item.

Methods

—

We selected 10 variables (consciousness, language, neglect, hemianopsia, gaze, pupillary abnormality, facial palsy, plantar reflex, sensation, and weakness) based on the multivariate analysis of the Keio Stroke Patient Database Battery. The variables were categorized and evaluated for their distribution and sensitivity. The categorizations were then modified and rechecked. The procedure was repeated until the appropriate categorization was obtained from 198 patients. A temporary stroke scale without weight was then formulated, and the reliability of the scale was examined and revised with 80 new stroke patients. As a next step, 150 neurologists were asked to rank a set of 27 virtual patients, each with a different combination of variables, according to severity. From these rankings, conjoint analysis was used to derive utility scores (weights) for each factor level.

Results

—

The relative weights of each of the factors were as follows: consciousness 49.8%, language 9.9%, weakness of lower extremity 7.3%, pupillary abnormality 6.8%, gaze palsy 5.6%, weakness of arm 4.3%, weakness of hand 3.7%, neglect 3.7%, facial palsy 2.4%, plantar reflex 2.2%, hemianopsia 2.2%, and sensory impairment 2.1%. The total score for a patient could be calculated from the sum of the scores for each of the variables ranging from −0.38 to 27.86. Scoring of 100 patients with acute stroke was carried out, and the changes in scores were followed for validation. Longitudinal clinical monitoring of the patients correlated well with the scores in each patient. The interrater and intrarater reliabilities of the scale were excellent (weighted κ 0.83; Cronbach’s α 0.998).

Conclusions

—

The Japan Stroke Scale is a parametric stroke scale that provides a quantitative measure of the severity of stroke. Each of the variables of the scale has a relative weight according to the severity of stroke. Reliability and responsiveness were proved to be excellent. The present data revealed a potentiality for the Japan Stroke Scale to be a universally accepted and reliable standardized system from the clinimetrical point of view.
Cerebrovascular Reserve in Patients With Carotid Occlusive Disease Assessed by Stable Xenon-Enhanced CT Cerebral Blood Flow and Transcranial Doppler
Authors: Pindzola Ronda R. , Balzer Jeffrey R. , Nemoto Edwin M. , Goldstein Steven , Yonas Howard
Published: June 2011

Background and Purpose

—

Cerebrovascular reserve (CVR) by both transcranial Doppler ultrasonography (TCD) and quantitative cerebral blood flow (CBF) can identify subgroups of patients at increased risk for stroke. A direct comparison of CVR measurements obtained with both technologies in patients with cerebrovascular occlusive disease is lacking.

Methods

—

CVRs before and after acetazolamide administration (1 g IV) were measured by TCD insonation of the middle cerebral artery (MCA) and CBF obtained with stable xenon CT (Xe/CT) in 38 patients with carotid occlusive disease. Sensitivity/specificity calculations were based on 2 Xe/CT MCA values: an average over 4 levels and the level with the lowest percent change in CBF. Compromised CVR was defined as no reactivity or a decrease in reactivity.

Results

—

Using the analysis of the systolic TCD, we found that velocity changes compared with the average Xe/CT MCA CVR showed a sensitivity of 33%, specificity of 90.6%, positive predictive value of 54.5%, and negative predictive value of 80%. The sensitivity of TCD compared with the lowest Xe/CT CBF CVR was 35.5%, specificity and positive predictive values were 100%, and negative predictive value was 66.7%. The index of validity was between 72% and 76%.

Conclusions

—

TCD is much less sensitive than Xe/CT CBF in identifying patients with compromised CVR. This may be a result of the inability of TCD to identify patients with compromised reserves when their MCA blood flow comes from collateral sources. The lack of correlation between TCD and Xe/CT CBF for identifying patients with compromised CVR should be considered when stroke risk assessments are made by TCD.
Vasospasm After Subarachnoid Hemorrhage
Authors: Condette-Auliac S. , Bracard S. , Anxionnat R. , Schmitt E. , Lacour J.C. , Braun M. , Meloneto J. , Cordebar A. , Yin L. , Picard L.
Published: June 2011

Background and Purpose

—

Vasospasm secondary to subarachnoid hemorrhage (SAH) is responsible for severe ischemic complications. Although effective, angioplasty must be performed at a very early stage to produce any clinical recovery. Diagnostic investigations to assess arterial narrowing (transcranial Doppler, angiography) or cerebral perfusion (xenon CT, single-photon emission CT) do not provide evidence of the extent of parenchymal ischemia. In stroke, diffusion-weighted MR imaging (DWI) appears to be the most sensitive procedure to detect cerebral ischemia. We studied asymptomatic vasospasm in patients with aneurysmal SAH to assess whether DWI provides predictive markers of silent ischemic lesions and/or progression toward symptomatic ischemia.

Methods

—

Seven asymptomatic vasospasm patients (average blood velocity rates >120 cm/s), 3 patients with symptomatic vasospasm, and 4 patients with SAH but without vasospasm were studied at regular intervals by DWI, and their apparent diffusion coefficients (ADCs) were calculated.

Results

—

All patients with vasospasm including those without symptoms presented abnormalities on DWI with a reduction of the ADC prevalently in the white matter. No such abnormalities were observed in patients without vasospasm. The abnormalities on DWI resolved completely in 4 of the 7 patients, with no parenchymal lesion. Resolution was partial in 3 patients whose white matter still presented residual round, focal ischemic lesions.

Conclusions

—

Being able to correlate abnormalities on DWI with parenchymal involvement in asymptomatic patients would be of considerable clinical significance. It is hoped that larger studies will be undertaken to determine whether the ADC has a reversibility threshold, because this would facilitate patient management.
High-Resolution Turbo Magnetic Resonance Angiography for Diagnosis of Moyamoya Disease
Authors: Yamada Ichiro , Nakagawa Tsuneaki , Matsushima Yoshiharu , Shibuya Hitoshi
Published: June 2011

Background and Purpose

—

High-resolution turbo MR angiography with zero-filling interpolation (ZFI) technique is a new vascular imaging method with reduced scan time. The purpose of the present study was to evaluate high-resolution turbo MR angiography for the diagnosis and assessment of moyamoya disease.

Methods

—

Forty-six patients suspected of having moyamoya disease were examined with high-resolution turbo MR angiography with the ZFI technique, MRI, and conventional angiography. Moyamoya disease was diagnosed in 42 of these patients. Blind, separate interpretation of the images was performed.

Results

—

High-resolution turbo MR angiography and MRI accurately evaluated 349 (95%) and 325 (88%) of 368 arteries, respectively, but the degree of stenosis was overestimated in the other arteries. MR angiography and MRI depicted basal cerebral moyamoya vessels in 82 (98%) and 82 (98%) of 84 hemispheres, respectively. MR angiography also depicted leptomeningeal and transdural collateral vessels in 51 (100%) of 51 hemispheres and in 38 (88%) of 43 hemispheres, respectively. The sensitivity and specificity of high-resolution turbo MR angiography for the diagnosis of moyamoya disease were 98% and 100%, respectively.

Conclusions

—

High-resolution turbo MR angiography in reduced scan time is highly accurate in the assessment of both steno-occlusive lesions and collateral vessels in moyamoya disease, thus providing a highly accurate (98%) diagnosis and assessment of moyamoya disease.
Cooling for Acute Ischemic Brain Damage (COOL AID)
Authors: Krieger Derk W. , De Georgia Michael A. , Abou-Chebl Alex , Andrefsky John C. , Sila Cathy A. , Katzan Irene L. , Mayberg Marc R. , Furlan Anthony J.
Published: June 2011

Background and Purpose

—

Hypothermia is effective in improving outcome in experimental models of brain infarction. We studied the feasibility and safety of hypothermia in patients with acute ischemic stroke treated with thrombolysis.

Methods

—

An open study design was used. All patients presented with major ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score >15) within 6 hours of onset. After informed consent, patients with a persistent NIHSS score of >8 were treated with hypothermia to 32±1°C for 12 to 72 hours depending on vessel patency. All patients were monitored in the neurocritical care unit for complications. A modified Rankin Scale was measured at 90 days and compared with concurrent controls.

Results

—

Ten patients with a mean age of 71.1±14.3 years and an NIHSS score of 19.8±3.3 were treated with hypothermia. Nine patients served as concurrent controls. The mean time from symptom onset to thrombolysis was 3.1±1.4 hours and from symptom onset to initiation of hypothermia was 6.2±1.3 hours. The mean duration of hypothermia was 47.4±20.4 hours. Target temperature was achieved in 3.5±1.5 hours. Noncritical complications in hypothermia patients included bradycardia (n=5), ventricular ectopy (n=3), hypotension (n=3), melena (n=2), fever after rewarming (n=3), and infections (n=4). Four patients with chronic atrial fibrillation developed rapid ventricular rate, which was noncritical in 2 and critical in 2 patients. Three patients had myocardial infarctions without sequelae. There were 3 deaths in patients undergoing hypothermia. The mean modified Rankin Scale score at 3 months in hypothermia patients was 3.1±2.3.

Conclusion

—

Induced hypothermia appears feasible and safe in patients with acute ischemic stroke even after thrombolysis. Refinements of the cooling process, optimal target temperature, duration of therapy, and, most important, clinical efficacy, require further study.
Anesthetic Choice of Halothane Versus Propofol
Authors: Bhardwaj Anish , Castro III Alejandro F. , Alkayed Nabil J. , Hurn Patricia D. , Kirsch Jeffrey R.
Published: June 2011

Background and Purpose—

It is not known whether preischemic exposure to anesthetic agents affects the amount of damage from transient focal ischemia that occurs after cessation of the anesthetic. We compared the effect of prior exposure to halothane or propofol on infarction size after transient middle cerebral artery occlusion (MCAO) induced in the awakening animal to test the hypothesis that anesthetic type and exposure duration would independently affect the amount of brain injury.

Methods—

Male Wistar rats (weight, 200 to 300 g) were anesthetized briefly with halothane for placement of hemodynamic instrumentation. Twenty-four hours later, rats were treated with either a short (approximately 1 hour) or long (8 hours) duration of inhaled halothane (1% to 2%) or intravenous propofol (10 mg/kg bolus, 30 mg/kg per hour infusion). Each cohort (n=8 per group) was then subjected to 2-hour MCAO by the intraluminal suture technique. All anesthesia was discontinued once MCAO was achieved. Infarct volume was measured at 22 hours of reperfusion. In a second cohort, regional cerebral blood flow (CBF) was measured ([
14
C]iodoantipyrine autoradiography) at end-occlusion in short-duration halothane (n=5) or short-duration propofol (n=5) anesthesia groups and in corresponding surgical shams (n=3 each).

Results—

Pericranial temperature, Pa
o
2
, Pa
co
2
, and blood pressure were controlled and not different among groups before or during occlusion. MCAO resulted in a similar immediate reduction in laser-Doppler flow signal after discontinuation of anesthesia in the awakening animals. Infarct volume was smaller in rats exposed to short-duration halothane in cortex (87.5±16.6 mm
3
) (mean±SEM) and caudoputamen (38.3±13.7 mm
3
) compared with rats exposed to short-duration propofol (cortex, 177.5±16.9 mm
3
; caudoputamen, 47.8±2.9 mm
3
). Infarct volume was not different in long-duration halothane versus long-duration propofol treatment. Absolute cortical or caudoputamen intraischemic CBF was not different between short-duration halothane or short-duration propofol treatment.

Conclusions—

These data demonstrate that short-duration halothane exposure before MCAO in the awakening animal attenuates infarction volume compared with propofol. This protection by halothane is not mediated through preservation of intraischemic CBF. Longer durations of halothane exposure may activate secondary injury pathways, which negate the protective effects of short-term halothane preischemic treatment.