Wi-Sun Ryu

Cerebral microbleeds are a risk factor for warfarin-related intracerebral hemorrhage

Background: Cerebral microbleeds are known to be indicative of bleeding-prone microangiopathy and may predict incident intracerebral hemorrhage (ICH). In this study, we investigated whether microbleeds are associated with the incidence of warfarin-related ICH. Methods: Twenty-four patients with ICH while on outpatient treatment with warfarin were selected from a consecutive cohort. Control, warfarin-using subjects with no history of ICH were randomly selected during the same time period (n = 48). We compared demographic factors, vascular risk factors, laboratory findings, and radiologic findings including microbleeds between the groups. Result: There were more cases of patients with microbleeds in the ICH than control group (79.2% vs 22.9%: p < 0.001), and the number of microbleeds was much higher for the ICH group (9.0 ± 26.8 vs 0.5 ± 1.03: p < 0.001). Moreover, the number of microbleeds was significantly correlated with the presence of warfarin-related ICH (r = 0.299; p < 0.001). Conditional logistic regression analysis showed that increased prothrombin time and the presence of microbleeds were independently related to the incidence of warfarin-related ICH (microbleeds: adjusted OR, 83.12). Conclusion: This study suggests that underlying microbleeds are independently associated with an incidence of warfarin-related intracerebral hemorrhage. Future research should focus on elucidating the risks and benefits of warfarin medication in patients with microbleeds.

Pentraxin 3: A novel and independent prognostic marker in ischemic stroke

OBJECTIVE Pentraxin 3 (PTX3) is one of the pattern-recognition receptors related to the initial step of the immune response with C-reactive protein, but the physiologic and pathologic functions are not fully understood. The purpose of the current study was to determine the impact of PTX3 levels on mortality after ischemic stroke. METHODS We consecutively enrolled 376 patients who had ischemic stroke between September 2004 and September 2006. The patients were divided into tertiles according to PTX3 levels. Cox regression analysis was used to determine hazard ratios (HRs) and 95% confidence intervals (CIs) of the PTX3 tertiles for all-cause mortality with adjustment for traditional risk factors and laboratory variables, including C-reactive protein. RESULTS During the follow-up, 19.4% of the patients were deceased. The median PTX3 levels were higher in the deceased patients (18.0 vs. 6.4 ng/mL, p<0.001). Based on Cox regression analysis, compared with the first tertile of PTX3, the adjusted HRs of the second and third tertiles for all-cause mortality were 1.24 (95% CI, 0.52-2.98) and 2.64 (95% CI, 1.19-5.85), respectively. When the log-transformed levels of PTX3 were incorporated as continuous variables, higher levels of PTX3 were also associated with an increased mortality (increase per log unit; HR, 1.60; 95% CI, 1.19-2.16). CONCLUSIONS We showed that higher levels of PTX3 are independently associated with increased mortality after ischemic stroke. Our results suggest that PTX3 may be used as a new powerful prognostic biomarker in patients with ischemic stroke.

White matter lesions and poor outcome after intracerebral hemorrhage A nationwide cohort study

Background: The ability to predict poor outcome is important for patient care and treatment decision-making in cases of intracerebral hemorrhage (ICH). Previous studies have included relatively brief follow-up periods and small numbers of patients, and are limited in terms of considerations regarding individual brain vulnerabilities. Methods: The authors prospectively enrolled 1,321 ICH patients nationwide from 33 hospitals. Clinical, laboratory, and imaging variables, including white matter lesions (WMLs), were collected at admission. Immediate outcome after ICH was measured using total Glasgow Coma Scale (GCS) score at admission, early outcome using 30-day mortality, and long-term outcome using relative risk for mortality. The vital status of included patients was ascertained on December 31, 2006, using Korean National Death Certificates (mean follow-up, 32.6 months). Results: Of the 1,321 ICH patients included, 352 (27.8%) presented with a moderate GCS score (8.5–12.4) and 249 (19.7%) with a severe GCS score (≤8.4). The mortality rate was 9.1% at day 30 post-ICH and 381 patients (29.8%) had died up to the end of December 2006. Extensive WMLs were associated with severe GCS scores at admission (odds ratio [OR] 2.45, 95% confidence interval [CI] 1.73–3.46), 30-day mortality (OR 2.52, 95% CI 1.33–4.75), and the relative risk for mortality (RR 2.61, 95% CI 1.79–3.82) after adjusting for relevant covariates. Conclusions: These findings suggest that white matter lesions, which may reflect the vulnerability of individual brains to pathologic insults, should be considered when assessing immediate, early, and long-term outcomes after intracerebral hemorrhage.

Paradoxical longevity in obese patients with intracerebral hemorrhage

Background: The paradoxical phenomenon of relative longevity among obese patients with established diseases has been reported for various disease conditions. The authors sought to investigate whether the obesity paradox also applies to intracerebral hemorrhage (ICH) survivors. Methods: A total of 1,604 patients with ICH from 33 centers with nationwide coverage were prospectively enrolled to this cohort between October 2002 and March 2004. Baseline information including body mass index (BMI) was collected at admission, and mortality status was ascertained from the governmental mortality archive on December 2006. Associations between obesity and 30-day mortality or long-term risk of death were analyzed. Results: Among the 1,356 patients with ICH included, the 30-day mortality rate was 7.2% and the long-term mortality rate was 26.9% after a mean follow-up of 33.6 ± 15.5 months. Neither BMI nor obesity status were associated with 30-day mortality after ICH. However, BMI was independently associated with a lower risk of long-term mortality (hazard ratio [HR] 0.91 per 1-kg/m2 increase; 95% confidence interval [CI] 0.87–0.95). As compared with patients of normal weight, underweight subjects had a higher risk of death (HR 1.64; 95% CI 1.11–2.40), and conversely, overweight (HR 0.69; 95% CI 0.49–0.96) or obese (HR 0.61; 95% CI 0.43–0.88) subjects showed a lower risk of post-ICH death. Conclusion: In our study, obesity was associated with a lower risk of long-term death but not with 30-day mortality after ICH. Thus, it may be considered that an obesity status in a patient with ICH be treated as an indication of metabolic reservoir capacity and an increased likelihood of survival.

Adipocytokines and ischemic stroke: Differential associations between stroke subtypes

OBJECTIVE Experimental studies have indicated that adipocytokines are associated with vascular diseases with regard to the pathology of atherosclerotic plaque. We hypothesized that the strength of the associations between adipocytokines and stroke would differ between ischemic stroke subtypes. METHODS A total of 96 acute ischemic stroke patients (within 5 days from onset) and 48 non-stroke subjects were analyzed in this study. Stroke patients were comprised of 26 strokes due to large artery atherosclerosis (LAA) and 72 non-LAA strokes. Venous blood from all participants was drawn after an overnight fast, and serum levels of leptin, adiponectin and resistin were measured by multiple sandwich immunoassay techniques. RESULTS Compared with non-LAA strokes, patients with LAA strokes had lower levels of serum adiponectin (6.4 ± 3.1 vs. 8.5 ± 3.9 μg/mL; P=0.04), and a higher level of leptin-to-adiponectin ratio (L:A ratio; 1.6 ± 1.4 vs. 0.9 ± 0.9; P<0.01). Multinomial logistic regression analyses showed that, although none of the adipocytokines was associated with non-LAA strokes, lower adiponectin (adjusted OR, 0.79 per 1-μg/mL increase; 95% CI, 0.64-0.98), higher leptin (aOR, 1.12 per 1-ng/mL increase; 95% CI, 1.004-1.25) and higher L:A ratio (aOR, 2.93 per 1-quartile increase; 95% CI, 1.39-6.15) showed significant associations with increased odds of having LAA stroke, compared to non-stroke subjects. CONCLUSION From our study, we documented that leptin and adiponectin had differential association patterns with ischemic stroke according to the stroke subtype. Careful consideration of the heterogeneity of stroke subtypes would be warranted in studying the utility of biomarkers including adipocytokines.

Body mass index, initial neurological severity and long-term mortality in ischemic stroke.

Background: Obesity is believed to increase the risks of ischemic stroke or coronary heart disease; however, regarding outcome after established vascular diseases, recent unexpected evidence has suggested that an increased body mass index (BMI) might have beneficial effects (obesity paradox). The aim of this study was to evaluate the independent association between BMI and long-term mortality after ischemic stroke. Methods: A total of 1,592 consecutive patients with ischemic stroke were prospectively included through our stroke cohort. In this study, the levels of BMI were classified based on guidelines for the Asian-Pacific population. Initial neurological severity was estimated by the National Institutes of Health Stroke Scale (NIHSS) score. Information on mortality was collected until the end of 2009, and the median follow-up period was 4 years. To examine the association between BMI and long-term mortality, we used Cox’s proportional regression analysis. Results: During follow-up, 23% of patients died. Linear regression analysis showed that the level of BMI was inversely related to initial neurological severity (p = 0.002). In the model of adjustment of age and gender using Cox’s proportional regression analysis, this inverse trend was also significant (reference, normal weight; hazard ratio of underweight, 2.45; overweight, 0.77; obesity, 0.60). However, after adjustment of all covariates, including initial neurological severity, only the harmful effect of underweight remained significant (2.79; 95% CI, 1.92–4.05); however, beneficial effects of overweight and obesity did not. Conclusion: Our study showed that an independent association between BMI and long-term mortality after ischemic stroke was found only in underweight patients. The obesity paradox phenomenon seems to be limited, and might not be interpreted as a direct causal relationship due to a strong association with initial neurological severity.

Low level of low-density lipoprotein cholesterol increases hemorrhagic transformation in large artery atherothrombosis but not in cardioembolism.

BACKGROUND AND PURPOSE Low cholesterol level is known to be associated with increased cerebral hemorrhage. However, the associations of hemorrhagic transformation (HTf) after acute ischemic stroke and the low levels of total cholesterol (TC) or low-density lipoprotein cholesterol (LDLC) are largely undiscovered. METHODS Of the 1034 patients with acute ischemic stroke who were consecutively admitted to our hospital, 377 patients with stroke attributable to large artery atherothrombosis (LAA; n=210) or cardioembolism (n=167) were selected for this study. Demographic and clinical information was collected and HTf was evaluated through follow-up T2*-weighted gradient-echo MRI performed usually within 1 week after stroke. Measurement of lipid parameters included TC, LDLC, high-density lipoprotein cholesterol, and triglyceride. RESULTS Of the 377 patients, HTf was noted in 74 patients (19.6%). When patients were divided into 4 groups according to their TC and LDLC levels, the incidence of HTf was significantly elevated in the lowest quartile of each TC (P<0.01) and LDLC (P<0.01) level in LAA subgroup, but not in cardioembolism. After adjusting covariates, a low level of LDLC (OR, 0.46 per 1 mmol/L-increase; 95% CI, 0.22-0.98) was independently associated with HTf in LAA, but not in cardioembolism. There was no significant association between low levels of TC (OR, 0.63 per 1 mmol/L-increase; 95% CI, 0.35-1.15) and HTf in LAA. CONCLUSIONS Low levels of LDLC, and possibly TC, are associated with greater risk of hemorrhagic transformation after acute ischemic stroke attributable to LAA.

Increased serum alkaline phosphatase as a predictor of long-term mortality after stroke

Background: Although the critical role of alkaline phosphatase in bone mineralization is clearly understood, the potentially adverse effect of high alkaline phosphatase levels on the cardiovascular system was only recently suggested. In this study, we hypothesized that increased levels of serum alkaline phosphatase may be associated with poor outcome after stroke in terms of mortality. Methods: We prospectively included patients with acute stroke admitted consecutively to our hospital, from October 2002 to September 2008. A total of 2,029 patients were selected for the analyses. In the analyses of mortality, the patients were divided by baseline measurements into quintiles of alkaline phosphatase levels (<57, 57–69, 70–81, 82–97, >97 IU/L). Results: In the Cox proportional hazard models, compared with the first alkaline phosphatase quintile, adjusted hazard ratios of the third, fourth, and fifth quintiles for all-cause death were 1.67 (95% confidence interval 1.12–2.49), 1.79 (1.20–2.67), and 2.83 (1.95–4.10). When we divided the patients into ischemic and hemorrhagic stroke, the association was also significant for both subtypes of stroke. In terms of vascular death, compared to the first alkaline phosphatase quintile, the adjusted hazard ratios of the fourth and fifth quintiles of alkaline phosphatase were 1.81 (95% confidence interval 1.14–2.86) and 2.78 (1.87–4.15). Conclusion: Our study demonstrated that increased serum levels of alkaline phosphatase are an independent predictor of all-cause and vascular death after either ischemic or hemorrhagic stroke.

Lithium pretreatment reduces brain injury after intracerebral hemorrhage in rats

Abstract Objective: In addition to the mood-stabilizing effects of lithium in patients with bipolar disorder, recent in vitro and in vivo studies in rodents increasingly implicate that lithium may be useful for treating acute cerebral ischemia, neuroinflammatory conditions, and chronic neurodegenerative diseases. However, whether lithium has a protective effect against hemorrhagic stroke is yet unknown. To test this possibility, we attempted to determine lithium’s effect on experimental intracerebral hemorrhage (ICH). Methods: We treated adult rats with either lithium (2 mEq/kg) or saline for 3 days before inducing ICH via a stereotaxic infusion of collagenase into the left basal ganglia. Hematoma volumes, hemispheric swelling, long-term hemispheric atrophy, microglial activation, cell death, cyclooxygenase-2 expression, and behavioral outcomes were assessed. Results: Per behavioral tests 2 days after ICH, the lithium-treated group recovered better than did the saline-treated group. Three days after ICH, the hematoma volumes did not differ between the groups, but hemispheric swelling was less in the lithium-treated group. Forty-two days after ICH, hemispheric atrophy was less in the lithium-treated group. Lithium reduced cell death, cyclooxygenase-2 expression, and reactive microglia in the perihematomal regions. Conclusion: The present study shows that lithium, via anti-inflammation, reduces the perihematomal cell death, which is associated with sensorimotor recovery after experimental ICH.

Ischemic Stroke During Sleep: Its Association With Worse Early Functional Outcome

Background and Purpose— Approximately one fourth of stroke occur during sleep. Despite the clinical and radiological similarities between wake-up stroke (WUS) and non-WUS, the functional outcomes of WUS are largely unknown. Methods— This retrospective analysis reviewed 2289 consecutive patients with acute ischemic stroke who were admitted between November 2002 and December 2009. We used 3 end-point analytic techniques to evaluate the association between WUS and functional outcomes: dichotomized analysis for “functional dependency” (a discharge modified Rankin Scale [mRS] score ≥2 regardless of initial stroke severity), severity-adjusted responder analysis for “unfavorable outcome” (a discharge mRS ≥1 for an admission National Institutes of Health Stroke Scale score 0 to 7; mRS ≥2 for National Institutes of Health Stroke Scale 8 to 14; or mRS ≥3 for National Institutes of Health Stroke Scale ≥15), and shift analysis for changes in overall distributions of discharge mRS scores. Results— The initial National Institutes of Health Stroke Scale score of patients with WUS was significantly higher than that of their non-WUS counterparts (median [interquartile range]; 4 [2 to 7] versus 3 [1 to 6]; P<0.01). The dichotomized analysis strategy failed to detect a significant association between WUS and functional dependency at discharge (adjusted OR, 0.99; 95% CI, 0.76 to 1.28). However, the responder analysis showed that patients with WUS were more likely to have “unfavorable outcomes” (adjusted OR, 1.33; 95% CI, 1.02 to 1.72), and the shift analysis also detected significant effect of WUS on the mRS score distributions toward increased dependency (adjusted OR, 1.22; 95% CI, 1.01 to 1.48). Conclusions— From our study, we documented that WUS was associated with worse short-term outcomes after ischemic stroke. Careful selection of appropriate analytic techniques may help to detect modest associations in observational studies.