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1.  Influence of stroke subtype on quality of care in the Get With The Guidelines–Stroke Program 
Neurology  2009;73(9):709-716.
Little is known about in-hospital care for hemorrhagic stroke. We examined quality of care in intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) admissions in the national Get With The Guidelines–Stroke (GWTG-Stroke) database, and compared them to ischemic stroke (IS) or TIA admissions.
Between April 1, 2003, and December 30, 2007, 905 hospitals contributed 479,284 consecutive stroke and TIA admissions. The proportions receiving each quality of care measure were calculated by dividing the total number of patients receiving the intervention by the total number of patients eligible for the intervention, excluding ineligible patients or those with contraindications to treatment. Logistic regression models were used to determine associations between measure compliance and stroke subtype, controlling for patient and hospital characteristics.
Stroke subtypes were 61.7% IS, 23.8% TIA, 11.1% ICH, and 3.5% SAH. Performance on care measures was generally lower in ICH and SAH compared to IS/TIA, including guideline-recommended measures for deep venous thrombosis (DVT) prevention (for ICH) and smoking cessation (for SAH) (multivariable-adjusted p < 0.001 for all comparisons). Exceptions were that ICH patients were more likely than IS/TIA to have door-to-CT times <25 minutes (multivariable-adjusted p < 0.001) and to undergo dysphagia screening (multivariable-adjusted p < 0.001). Time spent in the GWTG-Stroke program was associated with improvements in many measures of care for ICH and SAH patients, including DVT prevention and smoking cessation therapy (multivariable-adjusted p < 0.001).
Many hospital-based acute care and prevention measures are underutilized in intracerebral hemorrhage and subarachnoid hemorrhage compared to ischemic stroke /TIA. Duration of Get With The Guidelines–Stroke participation is associated with improving quality of care for hemorrhagic stroke.
= American Heart Association;
= deep venous thrombosis;
= generalized estimating equation;
= Get With The Guidelines–Stroke;
= intracerebral hemorrhage;
= ischemic stroke;
= Patient Management Tool;
= subarachnoid hemorrhage.
PMCID: PMC2734292  PMID: 19720978
2.  Intracerebral Hemorrhage in the Oldest Old: A Population-Based Study (Vantaa 85+) 
Aims: Very elderly subjects represent the fastest growing population in the world. Most of the recent studies on intracerebral hemorrhage (ICH) have been carried out on younger patients and/or preferably using novel radiological techniques. We investigated the prevalence, risk factors, and histopathological characteristics of the ICH in the oldest old. Materials and methods: The brains of 300 autopsied individuals (248 females, 52 males, mean age at death 92.4 ± 3.7 years) were investigated as part of the prospective population-based Vantaa 85+ study. After macroscopic investigation, the presence and extent of microscopic brain hemorrhages (MH) were analyzed by counting the number of iron containing macrophages (siderophages) by Prussian blue staining. Deposits with >5 siderophages were defined as MH+, forming a subgroup of MH. Genotyping of apolipoprotein E (APOE) and the analysis of microscopic (MI) or larger infarctions and cerebral amyloid angiopathy (CAA) were performed using standardized methods. Regression analysis was used to predict the presence of ICH, with and without co-localized CAA, and was adjusted for age at death and gender. Results: The prevalence of macroscopic ICH was 2.3% in total; consisting of 1% large lobar hemorrhage (LH), 1% deep hemorrhage (DH), and 0.3% of subarachnoid hemorrhage (SAH). 62% had MH and 15.3% MH+. All MH+ lesions were found to be >2 mm wide. 55.9% of subjects with MH and 81.2% of those with MH+ showed MH/MH+ and CAA in the same brain region (MHCAA and MH+CAA, respectively). MH was associated with none of the neuropathological or clinical conditions, nor with the APOE carrier status. The subjects with MH+, MHCAA or MH+CAA carried the APOE ε4 allele more frequently than controls (OR 3.681, 3.291, 7.522, respectively). Siderophages in MH+CAA co-localized with CAA and with two-thirds of the MI in the tissue sections. Conclusion: Macroscopic ICH was rare in the very elderly. MH was frequent and clinically insignificant. MH+ was rare but closely related with the APOE ε4 genotype and the presence of severe CAA and infarction.
PMCID: PMC3449495  PMID: 23015796
intracerebral hemorrhage; cerebral amyloid angiopathy; microinfarction; apolipoprotein E ε4 allele
3.  Apolipoprotein E, Statins and Risk of Intracerebral Hemorrhage 
Stroke; a journal of cerebral circulation  2013;44(11):10.1161/STROKEAHA.113.001304.
Background and Purpose
Apolipoprotein E (ApoE) genotypes have been associated with lobar intracerebral hemorrhage (ICH). Although HMG-CoA reductase inhibitors (statins) have been associated with an increased risk of ICH, meta-analyses have not consistently shown a statin-induced risk of ICH. Here, we test whether hypercholesterolemia and ApoE polymorphisms affect the risk with ICH by statin use.
The Genetic and Environmental Risk Factors for Hemorrhagic Stroke study is a prospective, demographically-matched case-control study of ICH. A similar study of ICH, Genetic Risks for Medication-Related Hemorrhagic Stroke study, was used as a replication cohort. Subjects were classified as normocholesterolemia (NC), hypercholesterolemia without statin (HC-NS), and hypercholesterolemia with statin use (HC-S). Statistical comparisons were performed using Fisher’s Exact Test, chi-square tests, and the Breslow-Day test.
The discovery cohort consisted of 558 ICH cases and 1,444 controls, and the replication cohort consisted of 1,020 ICH cases and 382 controls. The association of lower risk for hypercholesterolemia was not attenuated by statin use. Statin use was observed to confer a higher risk for lobar ICH in those carrying ApoE4/E4 and ApoE2/E4 genotypes in both discovery and replication cohorts and combined, showed a trend towards significance (p=0.11 for Statin vs. ApoE4/E4).
Statin use does not appear to attenuate the association of hypercholesterolemia with decreased risk for non-lobar ICH. Our data support a gene-by-drug effect for lobar ICH, but larger sample sizes are needed to confirm the association before any clinical change is warranted.
PMCID: PMC3873717  PMID: 24008570
Intracerebral hemorrhage [7]; Apolipoprotein E; Hypercholesterolemia; Statins; Case control studies [53]; Risk factors in epidemiology [59]
4.  Effects of apolipoprotein E genotype on outcome after ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage 
Rodent models of acute ischaemic stroke and head injury suggest that apolipoprotein E (APOE) genotype influences neuronal repair, regeneration and survival after brain injury. Possession of an APOE ε4 allele is associated with poor outcome after head injury in clinical studies. APOE might therefore influence outcome after acute stroke in humans.
Objective and methods
To comprehensively search, identify, assess and carry out meta‐analyses of studies reporting on the association between APOE and the combined outcome of death or dependency, or death alone, several months after ischaemic stroke, intracerebral haemorrhage (ICH) or subarachnoid haemorrhage (SAH).
Main analyses included data from nine studies on 2262 patients (1453 with ischaemic stroke, 199 with ICH and 610 with SAH). Overall, ε4+ genotypes were not significantly associated with risk of death or dependency several months after stroke. However, there was significant heterogeneity between studies, and between the three pathological types of stroke. ε4+ genotypes were associated with increased death or dependency after SAH (relative risk (RR) 1.40, 95% confidence interval (CI) 1.06 to 1.84), with a trend towards a similar association with ICH (RR 1.38, 95% CI 0.99 to 1.92), but not with ischaemic stroke (RR 0.98, 95% CI 0.85 to 1.12). Results were similar for death alone.
APOE may differentially affect outcome after the three main pathological types of stroke. Further, large studies are needed to confirm or refute these findings, and to assess the possibility of an interaction between the effects of APOE and age.
PMCID: PMC2077401  PMID: 16926234
5.  Effects of apolipoprotein E genotype on outcome after ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage 
Rodent models of acute ischaemic stroke and head injury suggest that apolipoprotein E genotype (APOE) influences neuronal repair, regeneration and survival after brain injury. Possession of an APOE ε4 allele is associated with poor outcome after head injury in clinical studies. APOE might therefore influence outcome after acute stroke in humans.
We comprehensively sought, identified, assessed and performed meta-analyses of studies reporting on the association between APOE and the combined outcome of death or dependency, or death alone, several months after ischaemic stroke (IS), intracerebral haemorrhage (ICH) or subarachnoid haemorrhage (SAH).
Our main analyses included data from 9 studies in a total of 2262 patients (1453 IS, 199 ICH, 610 SAH). Overall, ε4+ genotypes were not significantly associated with risk of death or dependency several months after stroke. However, there was significant heterogeneity between studies, and between the three pathological types of stroke. ε4+ genotypes were associated with increased death or dependency after SAH (RR 1.40, 95% CI 1.06 to 1.84), with a trend toward a similar association with ICH (RR 1.38, 95% CI 0.99 to 1.92), but not IS (RR 0.98, 95% CI 0.85 to 1.12). Results were similar for death alone.
APOE may differentially affect outcome after the three main pathological types of stroke. Further, large studies are needed to confirm or refute these findings, and to assess the possibility of an interaction between the effects of APOE and age.
PMCID: PMC2077401  PMID: 16926234
6.  Risk factors for intracerebral hemorrhage differ according to hemorrhage location 
Neurology  2012;79(23):2275-2282.
Risk factors have been described for spontaneous intracerebral hemorrhage (ICH); their relative contribution to lobar vs nonlobar hemorrhage location is less clear. Our purpose here was to investigate risk factors by hemorrhage location.
This case-control study prospectively enrolled subjects with first-ever spontaneous ICH and matched each with up to 3 controls by age, race, and gender. Conditional stepwise logistic regression modeling was used to determine significant independent risk factors for lobar and nonlobar ICH.
From December 1997 through December 2006, 597 cases and 1,548 controls qualified for the analysis. Hypertension, warfarin use, first-degree relative with ICH, personal history of ischemic stroke, less than a high school education, and APOE ε2 or ε4 genotype were more common in ICH cases. Hypercholesterolemia and moderate alcohol consumption (≤2 drinks per day) were less common in ICH cases. The associations of hypertension and hypercholesterolemia were specific for nonlobar ICH. Conversely, the association of APOE ε2 or ε4 genotype was specific for lobar ICH.
APOE ε2 or ε4 genotype was associated specifically with lobar ICH. Hypertension was associated specifically with nonlobar ICH. A protective association was seen between hypercholesterolemia and nonlobar ICH; no such association was identified for lobar ICH.
PMCID: PMC3542348  PMID: 23175721
7.  30-Day Mortality and Readmission after Hemorrhagic Stroke among Medicare Beneficiaries in Joint Commission Primary Stroke Center Certified and Non-Certified Hospitals 
Background and Purpose
Ischemic stroke patients treated at Joint Commission Primary Stroke Center (JC-PSC) certified hospitals have better outcomes. Data reflecting the impact of JC-PSC status on outcomes after hemorrhagic stroke are limited. We determined whether 30-day mortality and readmission rates after hemorrhagic stroke differed for patients treated at JC-PSC certified versus non-certified hospitals.
The study included all fee-for-service Medicare beneficiaries ≥65 years old with a primary discharge diagnosis of subarachnoid hemorrhage (SAH) or intracerebral hemorrhage (ICH) in 2006. Covariate-adjusted logistic and Cox proportional hazards regression assessed the effect of care at a JC-PSC certified hospital on 30-day mortality and readmission.
There were 2,305 SAH and 8,708 ICH discharges from JC-PSC certified hospitals and 3,892 SAH and 22,564 ICH discharges from non-certified hospitals. Unadjusted in-hospital mortality (SAH: 27.5% vs. 33.2%, p<0.0001; ICH: 27.9% vs. 29.6%, p=0.003) and 30-day mortality (SAH: 35.1% vs. 44.0%, p<0.0001; ICH: 39.8% vs. 42.4%, p<0.0001) were lower in JC-PSC hospitals, but 30-day readmission rates were similar (SAH: 17.0% vs. 17.0%, p=0.97; ICH: 16.0% vs. 15.5%; p=0.29). Risk-adjusted 30-day mortality was 34% lower (OR 0.66, 95% CI 0.58–0.76) after SAH and 14% lower (OR 0.86, 95% CI 0.80–0.92) after ICH for patients discharged from JC-PSC certified hospitals. There was no difference in 30-day risk-adjusted readmission rates for SAH or ICH based on JC-PSC status.
Patients treated at JC-PSC certified hospitals had lower risk-adjusted mortality rates for both SAH and ICH but similar 30-day readmission rates as compared with non-certified hospitals.
PMCID: PMC3292255  PMID: 22033986
hemorrhagic stroke; certified stroke center; outcomes
8.  Recent Epidemiological Trends of Stroke 
Rapid increase in aged population and westernization of lifestyle have modified epidemiological status of stroke. The purpose of this study is to analyze changing trends of stroke epidemiology in South Korea.
We reviewed retrospectively medical records of 1,124 cases diagnosed as stroke among 54,534 patients who visited the Emergency Medical Center at our hospital from January 1994 to December 1996 (Group A). Also, we evaluated 1,705 cases diagnosed as stroke among 55,381 patients who visited to the same hospital from January 2003 to December 2005 (Group B). The variable features of stroke, such as age, sex, seasonal variation and distribution of stroke subtypes were studied by comparing group A with B.
In group A, hemorrhagic stroke (67.9%) was more prevalent than ischemic stroke (32.1%). However, group B showed that the ratio of hemorrhagic stroke (40.3%) to ischemic stroke (59.6%) has been reversed. The highest incidence of stroke was noted in their sixties and seventies of age in group B, which was older than that of group A. In group A, male ischemic stroke (IS) patients outnumbered female patients (1.26:1). Moreover, this gender disproportion became higher in group B (1.53:1). In group A, the number of male intracerebral hermorrhage (ICH) patients were similar to that of female patients (0.97:1). However, male ICH patients outnumbered female patients in group B (1.23:1). As for subarachnoid hemorrhage (SAH), female patients outnumbered male patients more than two-fold in both groups. Both groups showed that the occurrence of ischemic stroke was highest in summer, but that of hemorrhagic stroke was the highest in winter.
This study showed the changing trends of stroke in its distribution of subtypes. Multicenter prospective study using stroke registry would be required for the determination of national epidemiologic trends.
PMCID: PMC2588151  PMID: 19096539
Stroke; Epidemiology; Seasons; South Korea
9.  Relationship between C - Reactive Protein and Stroke: A Large Prospective Community Based Study 
PLoS ONE  2014;9(9):e107017.
Previous studies have suggested that C-reactive protein (CRP) was associated with risk of stroke. There were few studies in Asian population, or on stroke subtypes other than ischemic stroke. We thus investigated the relationship between CRP and the risks of all stroke and its subtypes in a Chinese adult population.
In the current study, we included 90,517 Chinese adults free of stroke and myocardial infarction at baseline (June 2006 to October 2007) in analyses. Strokes were classified as ischemic stroke (IS), intracranial heamorrhage (ICH) and subarachnoid heamorrhage (SAH). High-sensitivity CRP (hs-CRP) were categorized into three groups: <1 mg/L, 1 to 3 mg/L, and >3 mg/L. Cox proportional hazards regression was used to calculate the association between hs-CRP concentrations and all stroke, as well as its subtypes.
During a median follow-up time of 49 months, we documented 1,472 incident stroke cases. Of which 1,049 (71.3%) were IS, 383 (26.0%) were ICH, and 40 (2.7%) were SAH. After multivariate adjustment, hs-CRP concentrations ≥1 mg/L were associated with increased risks of all stroke (hs-CRP 1–3 mg/L: hazard ratio (HR) 1.17, 95% confidential interval (CI) 1.03–1.33; hs-CRP>3 mg/L: HR 1.25, 95% CI 1.07–1.46) and IS (hs-CRP 1–3 mg/L: HR 1.17, 95% CI 1.01–1.36; hs-CRP>3 mg/L: HR 1.33, 95% CI 1.11–1.60), but not with ICH and SAH. Subgroup analyses showed that higher hs-CRP concentration was more prone to be a risk factor for all stroke and IS in non-fatal stroke, male and hypertensive participants.
We found that higher hs-CRP concentrations were associated with a higher risk of IS, particularly for non-fatal stroke, male and hypertensive subjects. In contrast, we did not observe significant associations between hs-CRP and ICH/SAH.
PMCID: PMC4156395  PMID: 25191699
10.  Genetic Epidemiology of Intracerebral Hemorrhage 
We have previously reported that family history of ICH was associated with both lobar and non-lobar ICH. We sought to further examine this finding by analyzing differences by age and Apolipoprotein E genotype.
All cases of hemorrhagic stroke in the Greater Cincinnati area are identified through retrospective screening and a subset is invited to undergo a direct interview and genetic testing. Interviewed subjects are matched to two controls by age, race and gender. Conditional stepwise logistic regression modeling was used to determine if having a first-degree relative with an ICH (FHICH) was an independent risk factor for ICH.
Between 5/97 and 12/02, we recruited 333 cases of ICH. FHICH was found to be an independent risk factor for both lobar ICH (OR=3.9; p=0.04) and non-lobar ICH (OR=5.4; p=0.01) after controlling for the presence of numerous variables. Among non-lobar ICH cases the risk appeared to be predominately in those <70 years of age. The presence of apolipoprotein E4 was associated with lobar ICH = 70 years of age but not < 70 years of age.
Family history of ICH appears to be a significant risk factor for non-lobar ICH <70 years of age. Presence of Apolipoprotein E4 appears to be a risk factor for lobar ICH = 70 years of age but not < 70 years of age. Family history of ICH is a risk factor for lobar ICH after controlling for the presence of Apo E4.
PMCID: PMC1615714  PMID: 16557295
Genetics; Stroke; Intracerebral Hemorrhage; Family History; Apolipoprotein E
11.  APOE Genotype and Functional Outcome Following Aneurysmal Subarachnoid Hemorrhage 
Biological research for nursing  2008;10(3):205-212.
Apolipoprotein E (apoE), the major apolipoprotein in the central nervous system, has been shown to influence neurologic disease progression and response to neurologic injury in a gene-specific manner. Presence of the APOE4 allele is associated with poorer response to traumatic brain injury and ischemic stroke, but the association between APOE genotype and outcome following aneurysmal subarachnoid hemorrhage (SAH) remains unclear. The purpose of this project was to investigate the association between APOE genotype and outcome after SAH. We also explored the association of APOE4 genotype and cerebral vasospasm (CV) presence in a subsample of our population with available angiographic data. A sample of 206 aneurysmal SAH participants had APOE genotyping performed, Glasgow outcome scores (GOS) and modified Rankin scores (MRS) collected at 3 and 6 months after aneurysm rupture. No significant association was found between the presence of the APOE4 genotype and functional outcomes controlling for age, race, size of hemorrhage (Fisher grade), and severity of injury (Hunt & Hess grade). However when controlling for CV and the covariates listed above, individuals with the APOE4 allele had worse functional outcomes at both time points. The presence of the APOE2 allele was not associated with functional outcomes even when considering presence of CV. There was no difference in mortality associated with APOE4 presence, APOE2 presence, or presence of CV. These findings suggest APOE4 allele is associated with poor outcome after aneurysmal SAH.
PMCID: PMC2744368  PMID: 19017669
apolipoprotein E; subarachnoid hemorrhage; cerebral vasospasm; Modified Rankin Score; Glasgow Outcome Score
12.  Update in Intracerebral Hemorrhage 
The Neurohospitalist  2011;1(3):148-159.
Spontaneous, nontraumatic intracerebral hemorrhage (ICH) is defined as bleeding within the brain parenchyma. Intracranial hemorrhage includes bleeding within the cranial vault and encompasses ICH, subdural hematoma, epidural bleeds, and subarachnoid hemorrhage (SAH). This review will focus only on ICH. This stroke subtype accounts for about 10% of all strokes. The hematoma locations are deep or ganglionic, lobar, cerebellar, and brain stem in descending order of frequency. Intracerebral hemorrhage occurs twice as common as SAH and is equally as deadly. Risk factors for ICH include hypertension, cerebral amyloid angiopathy, advanced age, antithrombotic therapy and history of cerebrovascular disease. The clinical presentation is “stroke like” with sudden onset of focal neurological deficits. Noncontrast head computerized tomography (CT) scan is the standard diagnostic tool. However, newer neuroimaging techniques have improved the diagnostic yield in terms of underlying pathophysiology and may aid in prognosis. Intracerebral hemorrhage is a neurological emergency. Medical care begins with stabilization of airway, breathing function, and circulation (ABCs), followed by specific measures aimed to decrease secondary neurological damage and to prevent both medical and neurological complications. Reversal of coagulopathy when present is of the essence. Blood pressure management can be key and continues as an area of debate and ongoing research. Surgical evacuation of ICH is of unproven benefit though a subset of well-selected patients may have improved outcomes. Ventriculostomy and intracranial pressure (ICP) monitoring are interventions also used in this patient population. To date, hemostatic medications and neuroprotectants have failed to result in clinical improvement. A multidisciplinary approach is recommended, with participation of vascular neurology, vascular neurosurgery, critical care, and rehabilitation medicine as the main players.
PMCID: PMC3726132  PMID: 23983850
intracerebral hemorrhage; diagnosis; treatment; prognosis; surgery
13.  Study of clinical features of amyloid angiopathy hemorrhage and hypertensive intracerebral hemorrhage 
Objective: The purpose of this study was to differentiate between cerebral amyloid angiopathy (CAA) and hypertension (HTN) based on hemorrhage pattern interpretation. Methods: From June 1994 to Oct., 2000, 83 patients admitted to our service with acute intracerebral hemorrhage (ICH) were investigated retrospectively; 41 patients with histologically proven diagnosis of cerebral amyloid angiography and 42 patients with clear history of hypertension were investigated. Results: Patients with a CAA-related ICH were significantly older than patients with a HTN-related ICH (74.0 years vs 66.5 years, P<0.05). There was a significantly higher number of hematomas≥30 ml in CAA (85.3%) when compared with HTN (59.5%). No basal ganglional hemorrhage was seen in CAA, but in 40.5% in HTN. In CAA-related ICH, subarachnoid hemorrhage (SAH) was seen in 26 patients (63.4%) compared to only 11 patients (26.2%) in HTN-related ICH. Intraventricular hemorrhage was seen in 24.4% in CAA, and in 26.2% in HTN. Typical features of CAA-related ICH included lobar distribution affecting mainly the lobar superficial areas, lobulated appearance, rupture into the subarachnoid space, and secondary IVH from the lobar hemorrhage. More specifically, multiplicity of hemorrhage, bilaterality, and repeated episodes also strongly suggest the diagnosis of CAA. Multiple hemorrhages, defined as 2 or more separate hematomas in multiple lobes, accounted for 17.1% in CAA-related ICH. Conclusion: There are certain features in CAA on CT and MRI and in clinical settings. To some extent, these features may contribute to distinguishing CAA from HTN related ICH.
PMCID: PMC1388732  PMID: 15362199
Intracerebral hemorrhage; Cerebral amyloid angiopathy; Hypertension; Diagnosis; Computed tomography; Magnetic resonance imaging
14.  Impact of a Neurointensivist on Outcomes in Critically Ill Stroke Patients 
Neurocritical Care  2012;16(1):63-71.
Current guidelines for management of critically ill stroke patients suggest that treatment in a neurocritical care unit (NCCU) and/or by a neurointensivist (NI) may be beneficial, but the contribution of each to outcome is unknown. The relative impact of a NCCU vs. NI on short- and long-term outcomes in patients with acute ischemic stroke (AIS), intracerebral hemorrhage (ICH) and aneurysmal subarachnoid hemorrhage (SAH) was assessed.
2,096 stroke patients admitted to a NCCU or non-neuro ICU at a tertiary stroke center were analyzed before the appointment of a NI, during the NI’s tenure, and after the NI departed and was not replaced. Data included admission ICU type, availability of a NI, age, NIHSS, ICH score and 3 and 12 month outcome.
For AIS, compared to the time interval with a NI, departure of the NI predicted a worse rate of return to pre-stroke function at 3 months. For ICH, NCCU treatment predicted shorter ICU and hospital LOS but had no effect on short or long term outcomes. No effect of a NI was seen. For SAH, availability of an NI (but not an NCCU) predicted improved outcomes but longer ICU LOS. Disposition and in-hospital mortality improved when a NI was present, but continued improvement did not occur after the NI’s departure.
Presence of an NI was associated with improved clinical outcomes. This effect was more evident in patients with SAH. Patients with ICH tend to have poor outcomes regardless of the presence of a NCCU or a NI.
PMCID: PMC3265609  PMID: 21847702
ischemic stroke; intracerebral hemorrhage; subarachnoid hemorrhage; neurointensivist; neurocritical care; outcomes
15.  Effects of Comprehensive Stroke Care Capabilities on In-Hospital Mortality of Patients with Ischemic and Hemorrhagic Stroke: J-ASPECT Study 
PLoS ONE  2014;9(5):e96819.
The effectiveness of comprehensive stroke center (CSC) capabilities on stroke mortality remains uncertain. We performed a nationwide study to examine whether CSC capabilities influenced in-hospital mortality of patients with ischemic and hemorrhagic stroke.
Methods and Results
Of the 1,369 certified training institutions in Japan, 749 hospitals responded to a questionnaire survey regarding CSC capabilities that queried the availability of personnel, diagnostic techniques, specific expertise, infrastructure, and educational components recommended for CSCs. Among the institutions that responded, data on patients hospitalized for stroke between April 1, 2010 and March 31, 2011 were obtained from the Japanese Diagnosis Procedure Combination database. In-hospital mortality was analyzed using hierarchical logistic regression analysis adjusted for age, sex, level of consciousness on admission, comorbidities, and the number of fulfilled CSC items in each component and in total. Data from 265 institutions and 53,170 emergency-hospitalized patients were analyzed. Mortality rates were 7.8% for patients with ischemic stroke, 16.8% for patients with intracerebral hemorrhage (ICH), and 28.1% for patients with subarachnoid hemorrhage (SAH). Mortality adjusted for age, sex, and level of consciousness was significantly correlated with personnel, infrastructural, educational, and total CSC scores in patients with ischemic stroke. Mortality was significantly correlated with diagnostic, educational, and total CSC scores in patients with ICH and with specific expertise, infrastructural, educational, and total CSC scores in patients with SAH.
CSC capabilities were associated with reduced in-hospital mortality rates, and relevant aspects of care were found to be dependent on stroke type.
PMCID: PMC4020787  PMID: 24828409
16.  Prognostic Value of Serum S100 Protein by Elecsys S100 Immunoassay in Patients with Spontaneous Subarachnoid and Intracerebral Hemorrhages 
The serum S100 protein has been known to reflect the severity of neuronal damage. The purpose of this study was to assess the prognostic value of the serum S100 protein by Elecsys S100 immunoassay in patients with subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH) and to establish reference value for this new method.
Serum S100 protein value was measured at admission, day 3 and 7 after bleeding in 42 consecutive patients (SAH : 20, ICH : 22) and 74 healthy controls, prospectively. Admission Glasgow coma scale (GCS) score, Hunt & Hess grade and Fisher grade for SAH, presence of intraventricular hemorrhage, ICH volume, and outcome at discharge were evaluated. Degrees of serum S100 elevation and their effect on outcomes were compared between two groups.
Median S100 levels in SAH and ICH groups were elevated at admission (0.092 versus 0.283 µg/L) and at day 3 (0.110 versus 0.099 µg/L) compared to healthy controls (0.05 µg/L; p<0001). At day 7, however, these levels were normalized in both groups. Time course of S100 level in SAH patient was relatively steady at least during the first 3 days, whereas in ICH patient it showed abrupt S100 surge on admission and then decreased rapidly during the next 7 days, suggesting severe brain damage at the time of bleeding. In ICH patient, S100 level on admission correlated well with GCS score (r=-0.859; p=0.0001) and ICH volume (r=0.663; p=0.001). A baseline S100 level more than 0.199 µg/L predicted poor outcome with 92% sensitivity and 90% specificity. Logistic regression analyses showed Ln (S100) on admission as the only independent predictor of poor outcome (odd ratio 36.1; 95% CI, 1.98 to 656.3).
Brain damage in ICH patient seems to develop immediately after bleeding, whereas in SAH patients it seems to be sustained for few days. Degree of brain damage is more severe in ICH compared to SAH group based on the S100 level. S100 level is considered an independent predictor of poor outcome in patient with spontaneous ICH, but not in SAH. Further study with large population is required to confirm this result.
PMCID: PMC2612568  PMID: 19119467
S100 protein; Prognosis; Subarachnoid hemorrhage; Elecsys S100 immunoassay; Intracerebral hemorrhage
17.  Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy 
Neurology  2010;75(8):693-698.
To identify and compare clinical and neuroimaging predictors of primary lobar intracerebral hemorrhage (ICH) recurrence, assessing their relative contributions to recurrent ICH.
Subjects were consecutive survivors of primary ICH drawn from a single-center prospective cohort study. Baseline clinical, imaging, and laboratory data were collected. Survivors were followed prospectively for recurrent ICH and intercurrent aspirin and warfarin use, including duration of exposure. Cox proportional hazards models were used to identify predictors of recurrence stratified by ICH location, with aspirin and warfarin exposures as time-dependent variables adjusting for potential confounders.
A total of 104 primary lobar ICH survivors were enrolled. Recurrence of lobar ICH was associated with previous ICH before index event (hazard ratio [HR] 7.7, 95% confidence interval [CI] 1.4–15.7), number of lobar microbleeds (HR 2.93 with 2–4 microbleeds present, 95% CI 1.3–4.0; HR = 4.12 when ≥5 microbleeds present, 95% CI 1.6–9.3), and presence of CT-defined white matter hypodensity in the posterior region (HR 4.11, 95% CI 1.01–12.2). Although aspirin after ICH was not associated with lobar ICH recurrence in univariate analyses, in multivariate analyses adjusting for baseline clinical predictors, it independently increased the risk of ICH recurrence (HR 3.95, 95% CI 1.6–8.3, p = 0.021).
Recurrence of lobar ICH is associated with previous microbleeds or macrobleeds and posterior CT white matter hypodensity, which may be markers of severity for underlying cerebral amyloid angiopathy. Use of an antiplatelet agent following lobar ICH may also increase recurrence risk.
= cerebral amyloid angiopathy;
= confidence interval;
= CT-defined white matter hypodensity;
= hazard ratio;
= intracerebral hemorrhage;
= variance inflation factor.
PMCID: PMC2931649  PMID: 20733144
18.  Copeptin as a Marker for Severity and Prognosis of Aneurysmal Subarachnoid Hemorrhage 
PLoS ONE  2013;8(1):e53191.
Grading of patients with aneurysmal subarachnoid hemorrhage (aSAH) is often confounded by seizure, hydrocephalus or sedation and the prediction of prognosis remains difficult. Recently, copeptin has been identified as a serum marker for outcomes in acute ischemic stroke and intracerebral hemorrhage (ICH). We investigated whether copeptin might serve as a marker for severity and prognosis in aSAH.
Eighteen consecutive patients with aSAH had plasma copeptin levels measured with a validated chemiluminescence sandwich immunoassay. The primary endpoint was the association of copeptin levels at admission with the World Federation of Neurological Surgeons (WFNS) grade score after resuscitation. Levels of copeptin were compared across clinical and radiological scores as well as between patients with ICH, intraventricular hemorrhage, hydrocephalus, vasospasm and ischemia.
Copeptin levels were significantly associated with the severity of aSAH measured by WFNS grade (P = 0.006), the amount of subarachnoid blood (P = 0.03) and the occurrence of ICH (P = 0.02). There was also a trend between copeptin levels and functional clinical outcome at 6-months (P = 0.054). No other clinical outcomes showed any statistically significant association.
Copeptin may indicate clinical severity of the initial bleeding and may therefore help in guiding treatment decisions in the setting of aSAH. These initial results show that copeptin might also have prognostic value for clinical outcome in aSAH.
PMCID: PMC3543451  PMID: 23326397
19.  Clinical features of recurrent stroke after intracerebral hemorrhage 
Neurology International  2012;4(2):e10.
There have been many reports about the prognosis and risk factors of stroke recurrence following brain infarction (BI). However, little is known about the stroke recurrence after primary intracerebral hemorrhage (PICH). Therefore, we explored the recurrent stroke patients after initial PICH retrospectively, to reveal the critical factors of stroke recurrence. Acute BI (n=4013) and acute PICH patients (n=1067) admitted to the hospital between April 2000 and March 2009 were consecutively screened. PICH patients with a history of ICH and BI patients with a history of ICH were then classified into the ICH-ICH group (n=64, age 70.8±9.5 years) and ICH-BI group (n=52, age 72.8±9.7years), respectively. ICH lesions were categorized into ganglionic and lober types according to the brain magnetic resonance imaging. Subtypes of BI were classified into cardioembolism, large-artery atherosclerosis, small-artery occlusion and others. There was no difference in incidence of risk factors between ICH-ICH and ICH-BI groups. Distribution of initial PICH lesions was significantly abundant in the lobar type in the ICH-ICH group (P<0.01) and in ganglionic type in the ICH-BI group (P<0.02). Age of onset was significantly older in recurrent lobar ICH compared with recurrent ganglionic ICH (P<0.01: 73.6±10.0 and 59.1±9.0 years, respectively). In conclusion, ganglionic ICH patients may have a chance of recurrent stroke in both brain infarction and ganglionic ICH, suggesting the participation of atherosclerosis in intracranial arteries. Lobar ICH patients were older and prone to recurrent lobar ICH, suggesting the participation of cerebral amyloid angiopathy as a risk of stroke recurrence.
PMCID: PMC3490469  PMID: 23139848
stroke; brain infarction; intracerebral hemorrhage; stroke prevention.
20.  An association between systolic blood pressure and stroke among patients with impaired consciousness in out-of-hospital emergency settings 
Stroke is difficult to diagnose when consciousness is disturbed. However few reports have discussed the clinical predictors of stroke in out-of-hospital emergency settings. This study aims to evaluate the association between initial systolic blood pressure (SBP) value measured by emergency medical service (EMS) and diagnosis of stroke among impaired consciousness patients.
We included all patients aged 18 years or older who were treated and transported by EMS, and had impaired consciousness (Japan Coma Scale ≧ 1) in Osaka City (2.7 million), Japan from January 1, 1998 through December 31, 2007. Data were prospectively collected by EMS personnel using a study-specific case report form. Multiple logistic regressions assessed the relationship between initial SBP and stroke and its subtypes adjusted for possible confounding factors.
During these 10 years, a total of 1,840,784 emergency patients who were treated and transported by EMS were documented during the study period in Osaka City. Out of 128,678 with impaired consciousness, 106,706 who had prehospital SBP measurements in the field were eligible for our analyses. The proportion of patients with severe impaired consciousness significantly increased from 14.5% in the <100 mmHg SBP group to 27.6% in the > =200 mmHg SBP group (P for trend <0.001). The occurrence of stroke significantly increased with increasing SBP (adjusted odd ratio [AOR] 1.34, 95% confidence interval [CI] 1.33 to 1.35), and the AOR of the SBP > =200 mmHg group versus the SBP 101-120 mmHg group was 5.26 (95% CI 4.93 to 5.60). The AOR of the SBP > =200 mmHg group versus the SBP 101-120 mmHg group was 9.76 in subarachnoid hemorrhage (SAH), 16.16 in intracranial hemorrhage (ICH), and 1.52 in ischemic stroke (IS), and the AOR of SAH and ICH was greater than that of IS.
Elevated SBP among emergency patients with impaired consciousness in the field was associated with increased diagnosis of stroke.
PMCID: PMC3878578  PMID: 24341562
Systolic blood pressure; Prehospital; Impaired consciousness
21.  White matter hyperintensity volume is increased in small vessel stroke subtypes 
Neurology  2010;75(19):1670-1677.
White matter hyperintensity (WMH) may be a marker of an underlying cerebral microangiopathy. Therefore, we hypothesized that WMH would be most severe in patients with lacunar stroke and intracerebral hemorrhage (ICH), 2 types of stroke in which cerebral small vessel (SV) changes are pathophysiologically relevant.
We determined WMH volume (WMHV) in cohorts of prospectively ascertained patients with acute ischemic stroke (AIS) (Massachusetts General Hospital [MGH], n = 628, and the Ischemic Stroke Genetics Study [ISGS], n = 263) and ICH (MGH, n = 122).
Median WMHV was 7.5 cm3 (interquartile range 3.4–14.7 cm3) in the MGH AIS cohort (mean age 65 ± 15 years). MGH patients with larger WMHV were more likely to have lacunar stroke compared with cardioembolic (odds ratio [OR] = 1.87 per SD normally transformed WMHV), large artery (OR = 2.25), undetermined (OR = 1.87), or other (OR = 1.85) stroke subtypes (p < 0.03). These associations were replicated in the ISGS cohort (p = 0.03). In a separate analysis, greater WMHV was seen in ICH compared with lacunar stroke (OR = 1.2, p < 0.02) and in ICH compared with all ischemic stroke subtypes combined (OR = 1.34, p < 0.007).
Greater WMH burden was associated with SV stroke compared with other ischemic stroke subtypes and, even more strongly, with ICH. These data, from 2 independent samples, support the model that increasing WMHV is a marker of more severe cerebral SV disease and provide further evidence for links between the biology of WMH and SV stroke.
= atrial fibrillation;
= acute ischemic stroke;
= coronary artery disease;
= confidence interval;
= diabetes mellitus;
= diffusion-weighted imaging;
= fluid-attenuated inversion recovery;
= hypertension;
= intracranial area;
= intraclass correlation coefficient;
= intracerebral hemorrhage;
= interquartile range;
= Ischemic Stroke Genetics Study;
= Massachusetts General Hospital;
= odds ratio;
= small vessel;
= Trial of Org 10172 in Acute Stroke Treatment;
= white matter hyperintensity;
= white matter hyperintensity volume.
PMCID: PMC3033608  PMID: 21060091
22.  Predicting Cerebral Amyloid Angiopathy-Related Intracerebral Hemorrhages and Other Cerebrovascular Disorders in Alzheimer’s Disease 
Cerebral amyloid angiopathy (CAA) of amyloid β-protein (Aβ) type is common in Alzheimer’s disease (AD). Aβ immunotherapies have been reported to induce CAA-related intracerebral hemorrhages (ICH) or vasogenic edema. For the purpose of developing a method to predict CAA-related ICH and other cerebrovascular disorders in AD, the biomarkers, and risk factors are reviewed. The biomarkers include (1) greater occipital uptake on amyloid positron emission tomography imaging and a decrease of cerebrospinal fluid Aβ40 levels as markers suggestive of CAA, and (2) symptomatic lobar ICH, lobar microhemorrhages, focal subarachnoidal hemorrhages/superficial siderosis, cortical microinfarcts, and subacute encephalopathy (caused by CAA-related inflammation or angiitis) as imaging findings of CAA-related ICH and other disorders. The risk factors include (1) old age and AD, (2) CAA-related gene mutations and apolipoprotein E genotype as genetic factors, (3) thrombolytic, anti-coagulation, and anti-platelet therapies, hypertension, and minor head trauma as hemorrhage-inducing factors, and (4) anti-amyloid therapies. Positive findings for one or more biomarkers plus one or more risk factors would be associated with a significant risk of CAA-related ICH and other cerebrovascular disorders. To establish a method to predict future occurrence of CAA-related ICH and other cerebrovascular disorders in AD, prospective studies with a large number of AD patients are necessary, which will allow us to statistically evaluate to what extent each biomarker or risk factor would increase the risk. In addition, further studies with progress of technologies are necessary to more precisely detect CAA and CAA-related cerebrovascular disorders.
PMCID: PMC3336108  PMID: 22539931
cerebral amyloid angiopathy; Alzheimer’s disease; intracerebral hemorrhage; cerebrovascular disorders; dementia; amyloid β-protein; biomarker; risk factor
23.  Subarachnoid hemorrhage: tests of association with apolipoprotein E and elastin genes 
BMC Medical Genetics  2007;8:49.
Apolipoprotein E (APOE) and elastin (ELN) are plausible candidate genes involved in the pathogenesis of stroke. We tested for association of variants in APOE and ELN with subarachnoid hemorrhage (SAH) in a population-based study. We genotyped 12 single nucleotide polymorphisms (SNPs) on APOE and 10 SNPs on ELN in a sample of 309 Caucasian individuals, of whom 107 are SAH cases and 202 are age-, race-, and gender-matched controls from the Greater Cincinnati/Northern Kentucky region. Associations were tested at genotype, allele, and haplotype levels. A genomic control analysis was performed to check for spurious associations resulting from population substructure.
At the APOE locus, no individual SNP was associated with SAH after correction for multiple comparisons. Haplotype analysis revealed significant association of the major haplotype (Hap1) in APOE with SAH (p = 0.001). The association stemmed from both the 5' promoter and the 3' region of the APOE gene. APOE ε2 and ε 4 were not significantly associated with SAH. No association was observed for ELN at genotype, allele, or haplotype level and our study failed to confirm previous reports of ELN association with aneurysmal SAH.
This study suggests a role of the APOE gene in the etiology of aneurysmal SAH.
PMCID: PMC1950089  PMID: 17672902
24.  Pharmacogenomic effects of Apolipoprotein E on Intracerebral Hemorrhage 
Background and Purpose
To evaluate the effect of APOE genotype and the feasibility of administering an apoE-mimetic therapeutic to modify outcomes in a murine model of intracerebral hemorrhage (ICH).
ICH was induced via stereotactic injection of 0.1 U Clostridial collagenase into the left basal ganglia of wild-type (WT) and apolipoprotein-E targeted-replacement (APOETR) mice, consisting of either homozygous 3/3 (APOE3TR) or 4/4 (APOE4TR) genotypes. Animals were randomized to receive either vehicle or apoE-mimetic peptide. Outcomes included functional neurological tests (21-point neuroseverity score and rotorod latency) over the initial 7 d after injury, radiographic and histological hemorrhage size at 3 and 7 d, brain water content for cerebral edema at 24 h, and q-PCR for inflammatory markers at 6, 24, and 48 h.
APOE3TR animals demonstrated superior neuroseverity scores and rotorod latencies over the first 3 d after ICH, decreased cerebral edema at 24 h, and reduced up-regulation of IL-6 and eNOS at 6 h when compared to their APOE4TR counterparts. Following intravenous administration of 1 mg/kg apoE-mimetic peptide, both WT and APOE4TR animals exhibited improved functional outcomes over 7 d after ICH, less edema at 24 h and reduced up-regulation of IL-6 and eNOS when compared to mice that did not receive the peptide.
Our data indicate that APOE genotype influences neurological outcome after ICH in a murine model. In particular APOE4 is associated with poor functional outcome and increased cerebral edema. Additionally, this outcome can be modified by the addition of an apoE mimetic-peptide, COG1410.
PMCID: PMC2699752  PMID: 19109539
Intracerebral hemorrhage; Apolipoprotein E; Mouse; Inflammation; Gene therapy
25.  APOE Genotype Is Associated With CT Angiography Spot Sign In Lobar Intracerebral Hemorrhage 
Background and Purpose
The CT angiography (CTA) spot sign predicts hematoma expansion and poor outcome in patients with primary intracerebral hemorrhage (ICH). The biological underpinnings of the spot sign remain poorly understood; it may be that the underlying vasculopathy influences its presence. Therefore, we conducted a study to identify genetic predictors of the spot sign.
In an ongoing prospective cohort study, we analyzed 371 patients with CTA and genetic data available. CTAs were reviewed for the spot sign by two experienced readers, blinded to clinical data, according to validated criteria. Analyses were stratified by ICH location.
In multivariate analysis, patients on warfarin were more likely to have a spot sign regardless of ICH location: OR 3.85 (95% CI 1.33 - 11.13) in deep ICH and OR 2.86 (95% CI 1.33 - 6.13) in lobar ICH. APOE ε2, but not ε4, was associated with presence of a spot sign in lobar ICH (OR 2.09; 95% CI 1.05 - 4.19). There was no effect for ε2 or ε4 in deep ICH.
ICH patients on warfarin are more likely to present with a spot sign, regardless of ICH location. Among patients with lobar ICH, those who possess the APOE ε2 allele are more likely to have a spot sign. Given the established relationship between APOE ε2 and vasculopathic changes in cerebral amyloid angiopathy, our findings suggest that both hemostatic factors and vessel pathology influence spot sign presence.
PMCID: PMC3426364  PMID: 22621984
Intracerebral Hemorrhage; Genetics; APOE; CTA Spot Sign; Hematoma Expansion

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