Min Uk Jang

Grading and Interpretation of White Matter Hyperintensities Using Statistical Maps

Background and Purpose— We aimed to generate rigorous graphical and statistical reference data based on volumetric measurements for assessing the relative severity of white matter hyperintensities (WMHs) in patients with stroke. Methods— We prospectively mapped WMHs from 2699 patients with first-ever ischemic stroke (mean age=66.8±13.0 years) enrolled consecutively from 11 nationwide stroke centers, from patient (fluid-attenuated-inversion-recovery) MRIs onto a standard brain template set. Using multivariable analyses, we assessed the impact of major (age/hypertension) and minor risk factors on WMH variability. Results— We have produced a large reference data library showing the location and quantity of WMHs as topographical frequency-volume maps. This easy-to-use graphical reference data set allows the quantitative estimation of the severity of WMH as a percentile rank score. For all patients (median age=69 years), multivariable analysis showed that age, hypertension, atrial fibrillation, and left ventricular hypertrophy were independently associated with increasing WMH (0–9.4%, median=0.6%, of the measured brain volume). For younger (⩽69) hypertensives (n=819), age and left ventricular hypertrophy were positively associated with WMH. For older (≥70) hypertensives (n=944), age and cholesterol had positive relationships with WMH, whereas diabetes mellitus, hyperlipidemia, and atrial fibrillation had negative relationships with WMH. For younger nonhypertensives (n=578), age and diabetes mellitus were positively related to WMH. For older nonhypertensives (n=328), only age was positively associated with WMH. Conclusions— We have generated a novel graphical WMH grading (Kim statistical WMH scoring) system, correlated to risk factors and adjusted for age/hypertension. Further studies are required to confirm whether the combined data set allows grading of WMH burden in individual patients and a tailored patient-specific interpretation in ischemic stroke-related clinical practice.

Cortical Hubs and Subcortical Cholinergic Pathways as Neural Substrates of Poststroke Dementia

Background and Purpose— A role of neural networks in the development of poststroke dementia has not been clearly established. We hypothesized that stroke-mediated disruption of subcortical cholinergic pathway or large-scale neural networks contributes to poststroke dementia. Methods— A matched case–control study was conducted in a predetermined cohort with acute ischemic stroke. Cases were defined as newly developed dementia diagnosed >3 months after stroke using the Korean Vascular Cognitive Impairment Harmonization Standards. Each case was matched to 2 controls for age, education, and initial stroke severity. The Cholinergic Pathways HyperIntensities Scale was applied with some modifications to characterize disruption of cholinergic pathways by acute stroke lesions. Involvement of major cortical hub locations of the default mode network, central executive network, and salience network was also investigated. Results— After matching, 38 cases and 66 matched controls were included. Cholinergic Pathways HyperIntensities Scale scores were significantly higher in cases than in controls (2.2±2.9 versus 0.9±1.4). Acute ischemic lesions affecting the default mode and central executive networks were more frequently observed in cases compared with controls (36.8% versus 7.6% and 26.3% versus 6.1%, respectively). These findings remained significant in the multiple logistic regression models adjusted for various sets of potential confounders. Lesion location analysis revealed that cases were more likely to have acute lesions in the left corona radiata, hippocampal formation, and posterior parietal cortex. Conclusions— Disruption of cholinergic pathways and major hubs of large-scale neural networks might contribute to newly developed dementia after acute ischemic stroke.

Association between Visit-to-Visit Glucose Variability and Cognitive Function in Aged Type 2 Diabetic Patients: A Cross-Sectional Study

Background and Purpose Diabetes is associated with cognitive decline as well as the development of dementia. Although mean blood glucose levels are typically used to assess the status of diabetic patients, glucose variability is also involved in the manifestation of macro- and microvascular complications in this population. Thus, the present study sought to determine whether visit-to-visit glucose variability contributes to cognitive decline in patients with type 2 diabetes. Methods The present study assessed 68 patients with type 2 diabetes using several validated neuropsychological measures. All patients had no cerebrovascular disease, history of hypoglycemia, psychiatric conditions, or other medical illnesses. Standard deviations (SDs) and coefficients of variance (CVs) of the patients’ blood glucose (after fasting and 2 hours postprandial; FBS and PP2), and glycated hemoglobin (HbA1c) values were used as indices of glucose variability. The cognitive outcome parameters were transformed with z-scores and entered into a multiple linear regression model that included educational status, age, sex, vascular risk factors, and mean glucose parameters as covariates. Results The mean age of the total patient population was 70.9 years; 46 (67.6%) of the patients were men, and the median follow-up duration at our endocrinology outpatient clinic was 4.8 years. The mean FBS and PP2 glucose levels of the patients were 132 mg/dL and 199 mg/dL, respectively, and the mean HbA1c level was 8.0%. A univariable analysis revealed that only the PP2 value was associated with the Mini-Mental State Examination (MMSE) score, and multivariable analysis revealed that a high SD and/or CV for PP2 glucose were associated with low scores on the Rey Complex Figure Copy test and/or the Verbal Learning Test. Additionally, a high SD and a higher CV for HbA1c level were significantly associated with low MMSE and Digit Span test scores even after adjusting for mean HbA1c values. Conclusions The present data indicate that a greater degree of visit-to-visit glucose variability influenced specific types of cognitive function in type 2 diabetic patients independently of mean blood glucose levels. Future studies should focus on whether reductions in glycemic variability will improve the cognitive decline observed in type 2 diabetic patients.

Stroke outcomes are worse with larger leukoaraiosis volumes

Leukoaraiosis or white matter hyperintensities are frequently observed on magnetic resonance imaging of stroke patients. We investigated how white matter hyperintensity volumes affect stroke outcomes, generally and by subtype. In total, 5035 acute ischaemic stroke patients were enrolled. Strokes were classified as large artery atherosclerosis, small vessel occlusion, or cardioembolism. White matter hyperintensity volumes were stratified into quintiles. Mean age (± standard deviation) was 66.3 ± 12.8, 59.6% male. Median (interquartile range) modified Rankin Scale score was 2 (1–3) at discharge and 1 (0–3) at 3 months; 16.5% experienced early neurological deterioration, and 3.3% recurrent stroke. The Cochran-Mantel-Haenszel test with adjustment for age, stroke severity, sex, and thrombolysis status showed that the distributions of 3-month modified Rankin Scale scores differed across white matter hyperintensity quintiles (P < 0.001). Multiple ordinal logistic regression analysis showed that higher white matter hyperintensity quintiles were independently associated with worse 3-month modified Rankin Scale scores; adjusted odds ratios (95% confidence interval) for the second to fifth quintiles versus the first quintile were 1.29 (1.10–1.52), 1.40 (1.18–1.66), 1.69 (1.42–2.02) and 2.03 (1.69–2.43), respectively. For large artery atherosclerosis (39.0%), outcomes varied by white matter hyperintensity volume (P = 0.01, Cochran-Mantel-Haenszel test), and the upper three white matter hyperintensity quintiles (versus the first quintile) had worse 3-month modified Rankin Scale scores; adjusted odds ratios were 1.45 (1.10–1.90), 1.86 (1.41–2.47), and 1.89 (1.41–2.54), respectively. Patients with large artery atherosclerosis were vulnerable to early neurological deterioration (19.4%), and the top two white matter hyperintensity quintiles were more vulnerable still: 23.5% and 22.3%. Moreover, higher white matter hyperintensities were associated with poor modified Rankin Scale improvement: adjusted odds ratios for the upper two quintiles versus the first quintile were 0.66 (0.47–0.94) and 0.62 (0.43–0.89), respectively. For small vessel occlusion (17.8%), outcomes tended to vary by white matter hyperintensitiy volume (P = 0.10, Cochran-Mantel-Haenszel test), and the highest quintile was associated with worse 3-month modified Rankin Scale scores: adjusted odds ratio for the fifth quintile versus first quintile, 1.98 (1.23–3.18). In this subtype, worse white matter hyperintensities were associated with worse National Institute of Health Stroke Scale scores at presentation. For cardioembolism (20.6%), outcomes did not vary significantly by white matter hyperintensity volume (P = 0.19, Cochran-Mantel-Haenszel test); however, the adjusted odds ratio for the highest versus lowest quintiles was 1.62 (1.09–2.40). Regardless of stroke subtype, white matter hyperintensities were not associated with stroke recurrence within 3 months of follow-up. In conclusion, white matter hyperintensity volume independently correlates with stroke outcomes in acute ischaemic stroke. There are some suggestions that stroke outcomes may be affected by leukoaraiosis differentially depending on stroke subtypes, to be confirmed in future investigations.

Recanalization Therapy for Internal Carotid Artery Occlusion Presenting as Acute Ischemic Stroke

BACKGROUND We aimed to describe the current status and clinical outcomes of recanalization therapy for internal carotid artery occlusion (ICAO) presenting as acute ischemic stroke. METHODS Using a nationwide stroke registry database in Korea, we identified consecutive ischemic stroke patients with ICAO hospitalized within 12 hours of onset between March 2010 and November 2011. RESULTS ICAO accounted for 10.6% (322 of 3028) of acute ischemic strokes within 12 hours of onset. Among the 322 ICAO patients, 53% underwent recanalization therapy, 41% intravenous thrombolysis (IVT) alone, and 59% endovascular treatment (EVT). Twenty-two percent of those with mild deficits (National Institutes of Health Stroke Scale <4) and 50% of those 80 years of age or more received recanalization therapy. Compared with no treatment, recanalization therapy was not significantly associated with a favorable outcome (3-month modified Rankin scale, 0-2) (adjusted odds ratio [OR], 1.77; 95% confidence interval [CI], .80-3.91; P = .16). However, compared with IVT, EVT significantly improved the odds of favorable outcome (OR, 2.86; 95% CI, 1.19-6.88; P = .02) without significant increase of symptomatic intracranial hemorrhage (OR, 2.18; 95% CI, .42-11.43; P = .36) and 3-month mortality (OR, .53; 95% CI, .23-1.18; P = .12). Successful recanalization rate (Thrombolysis in Cerebral Infarction ≥2a) by EVT was 76%. CONCLUSIONS In Korea, one tenth of acute ischemic stroke was caused by ICAO, and about 50% were treated by recanalization therapy. EVT was widely used as a recanalization modality (about 60% of cases) despite lack of evidence. However, its effectiveness and safety were acceptable.

Recurrent Stroke, Myocardial Infarction, and Major Vascular Events during the First Year after Acute Ischemic Stroke: The Multicenter Prospective Observational Study about Recurrence and Its Determinants after Acute Ischemic Stroke I

BACKGROUND Patients with acute ischemic stroke (AIS) are at high risk of subsequent vascular events. The aim of this study was to estimate rates of recurrent stroke, myocardial infarction (MI), and major vascular events during the first year after AIS in Korea. METHODS Through a multicenter stroke registry in Korea, 12,227 consecutive cases of AIS were identified between November 2010 and May 2013 and were followed up for recurrent stroke, MI, and major vascular events up to 1 year after stroke. RESULTS Cumulative 30-day, 90-day and 1-year rates were 2.7%, 3.9%, and 5.7% for recurrent stroke; .1%, .3%, and .5% for MI; and 8.1%, 10.6%, and 13.7% for major vascular events, indicating that the early period is at high risk of recurrent stroke and major vascular events. The risk of recurrent stroke was substantially higher than the risk of MI: 13.0 times at 90 days and 11.4 times at 1 year. Compared to those with small-vessel occlusion (SVO), those with ischemic stroke subtypes other than SVO had a higher risk of recurrent stroke as well as major vascular events. Other common independent predictors for recurrent stroke and major vascular events were diabetes and prior stroke history. CONCLUSIONS During the first year after AIS, one in 18 had recurrent stroke and one in 7 major vascular events. More than two thirds of recurrent stroke and three quarters of major vascular events developed within 90 days in a Korean cohort of stroke patients. Better prevention strategies are required for high-risk patients during this high-risk period.

Preceding Intravenous Thrombolysis in Patients Receiving Endovascular Therapy

Background: The beneficial effects of endovascular therapy (EVT) in acute ischemic stroke have been demonstrated in recent clinical trials using new-generation thrombectomy devices. However, the comparative effectiveness and safety of preceding intravenous thrombolysis (IVT) in this population has rarely been evaluated. Methods: From a prospective multicenter stroke registry database in Korea, we identified patients with acute ischemic stroke who were treated with EVT within 8 h of onset and admitted to 14 participating centers during 2008-2013. The primary outcome was a modified Rankin Scale (mRS) score at 3 months. Major secondary outcomes were successful recanalization defined as a modified Treatment in Cerebral Ischemia score of 2b-3, functional independence (mRS score 0-2), mortality at 3 months, and symptomatic hemorrhagic transformation (SHT) during hospitalization. Multivariable logistic regression analyses using generalized linear mixed models were performed to estimate the adjusted odds ratios (ORs) of preceding IVT. Results: Of the 639 patients (male, 61%; age 69 ± 12; National Institutes of Health Stroke Scale score of 15 [11-19]) who met the eligibility criteria, 458 received preceding IVT. These patients showed lower mRS scores (adjusted common OR, 1.38 [95% CI 0.98-1.96]). Preceding IVT was associated with successful recanalization (1.96 [1.23-3.11]) and reduced 3-month mortality (0.58 [0.35-0.97]) but not with SHT (0.96 [0.48-1.93]). Conclusion: In patients treated with EVT within 8 of acute ischemic stroke onset, preceding IVT may enhance survival and successful recanalization without additional risk of SHT, and mitigate disability at 3 months.

Cardioembolism and Involvement of the Insular Cortex in Patients with Ischemic Stroke

Background To evaluate whether topographical characteristics of insular involvement in ischemic stroke are associated with cardioembolism. Methods and Findings A consecutive series of patients hospitalized for ischemic stroke within 7 days of symptom onset were identified. Based on diffusion-weighted imaging, we included those who had ischemic lesions in the middle cerebral artery (MCA) territory. Each patient was assigned to one of two groups based on the presence or absence of insular involvement. The primary outcome was the frequency of cardioembolism, which was compared based on insular involvement. Of 1,311 patients with ischemic stroke in the MCA territory, 112 had insular involvement (8.5%). The frequency of cardioembolism in patients with insular involvement (52.7%) was significantly higher than that in patients without insular involvement (30.4%, P < 0.001). Although insular involvement was associated with a severe baseline National Institutes of Health Stroke Scale score (13 vs. 4), it did not independently affect the 3-month functional outcome. Conclusions In cases of stroke in the MCA territory, involvement of the insular cortex may be associated with a risk of cardioembolism.

Off-Hour Effect on 3-Month Functional Outcome after Acute Ischemic Stroke: A Prospective Multicenter Registry

Background and Purpose The time of hospital arrival may have an effect on prognosis of various vascular diseases. We examined whether off-hour admission would affect the 3-month functional outcome in acute ischemic stroke patients admitted to tertiary hospitals. Methods We analyzed the ‘off-hour effect’ in consecutive patients with acute ischemic stroke using multi-center prospective stroke registry. Work-hour admission was defined as when the patient arrived at the emergency department between 8 AM and 6 PM from Monday to Friday and between 8 AM and 1 PM on Saturday. Off-hour admission was defined as the rest of the work-hours and statutory holidays. Multivariable logistic regression was used to analyze the association between off-hour admission and 3-month unfavorable functional outcome defined as modified Rankin Scale (mRS) 3–6. Multivariable model included age, sex, risk factors, prehospital delay time, intravenous thrombolysis, stroke subtypes and severity as covariates. Results A total of 7075 patients with acute ischemic stroke were included in this analysis: mean age, 67.5 (±13.0) years; male, 58.6%. In multivariable analysis, off-hour admission was not associated with unfavorable functional outcome (OR, 0.89; 95% CI, 0.72–1.09) and mortality (OR, 1.09; 95% CI, 0.77–1.54) at 3 months. Moreover, off-hour admission did not affect a statistically significant shift of 3-month mRS distributions (OR, 0.90; 95% CI, 0.78–1.05). Conclusions ‘Off-hour’ admission is not associated with an unfavorable 3-month functional outcome in acute ischemic stroke patients admitted to tertiary hospitals in Korea. This finding indicates that the off-hour effects could be overcome with well-organized stroke management strategies.

Change in blood pressure variability in patients with acute ischemic stroke and its effect on early neurologic outcome

Background How short-term blood pressure variability (BPV) is affected in the acute stage of ischemic stroke and whether BPV is associated with early neurologic outcomes remains unclear. Methods Patients who admitted for ischemic stroke within 24 h of symptom onset were consecutively identified between January 2010 and January 2015. BP profiles measured in real-time were summarized into short-term, 24-h time intervals, based on standard deviation (SD) and mean of systolic BP (SBPSD) during the first 3 days. The primary outcome was daily assessment of early neurological deterioration (END). The associations between short-term SBPSD values and the secular trend for primary outcome were examined. Results A total of 2,545 subjects (mean age, 67.1 ± 13.5 years old and median baseline National Institutes of Health Stroke Scale score, 3) arrived at the hospital an average of 6.1 ± 6.6 h after symptom onset. SBPSD values at day 1 (SD#D1), SD#D2, and SD#D3 were 14.4 ± 5.0, 12.5 ± 4.5, and 12.2 ± 4.6 mmHg, respectively. Multivariable analyses showed that SD#D2 was independently associated with onset of END at day 2 (adjusted odds ratio, 1.08; 95% confidence interval, 1.03–1.13), and SD#D3 was independently associated with END#D3 (1.07, 1.01–1.14), with adjustments for predetermined covariates, SBPmean, and interactions with daily SBPSD. Conclusion Short-term BPV changed and stabilized from the first day of ischemic stroke. Daily high BPV may be associated with neurological deterioration independent of BPV on the previous day.