Jordi Jimenez-Conde

Variants at APOE influence risk of deep and lobar intracerebral hemorrhage.

Prior studies investigating the association between APOE alleles ε2/ε4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied.

High Risk of Early Neurological Recurrence in Symptomatic Carotid Stenosis

Background and Purpose— Few data are available on very early stroke recurrence evaluated within the first hours after onset of symptoms and outcome for unselected patients with first-ever mild stroke or TIA and symptomatic carotid stenosis ≥50%. Methods— One hundred sixty-three patients with symptomatic carotid stenosis and initial mild stroke (121) or TIA (42) were evaluated within 6 hours from onset of symptoms in a single tertiary hospital. Neurological recurrence (NR) was defined as a clearly defined new neurological event (TIA or stroke) or an increase of 4 points in the initial NIHSS. The NR rate was determined at 72 hours, 7 days, and 14 days. Disability was defined as a score of 3 to 6 on the modified Rankin scale at 14 days. Results— Forty-five patients (27.6%) had NR, including 6 patients with 2 episodes in different time periods: 34 (20.9%) within the first 72 hours; 11 (6.7%) between 72 hours and 7 days; and 6 (3.7%) at 14 days. Only carotid stenosis ≥70% was associated with NR; diabetes was marginally associated. At 2 weeks, 19 patients (11.7%) had disability; 14 of them experienced NR in the first 72 hours. Conclusions— Patients with first-ever mild stroke or TIA and symptomatic carotid stenosis are at high risk for NR, especially within the first 72 hours. Our results suggest the necessity of testing pharmacological or interventional strategies for use during the hyperacute stroke phase in these patients.

APOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage: a genetic association study

BACKGROUND Carriers of APOE ε2 and ε4 have an increased risk of intracerebral haemorrhage (ICH) in lobar regions, presumably because of the effects of these gene variants on risk of cerebral amyloid angiopathy. We aimed to assess whether these variants also associate with severity of ICH, in terms of haematoma volume at presentation and subsequent outcome. METHODS We investigated the association of APOE ε2 and ε4 with ICH volume and outcomes in patients with primary ICH in three phases: a discovery phase of 865 individuals of European ancestry from the Genetics of Cerebral Hemorrhage on Anticoagulation study, and replication phases of 946 Europeans (replication 1) and 214 African-Americans (replication 2) from an additional six studies. We also assessed the association of APOE variants with ICH volume and outcomes in meta-analyses of results from all three phases, and the association of APOE ε4 with mortality in a further meta-analysis including data from previous reports. Admission ICH volume was quantified on CT scan. We assessed functional outcome (modified Rankin scale score 3-6) and mortality at 90 days. We used linear regression to establish the effect of genotype on haematoma volume and logistic regression to assess the effect on outcome from ICH. FINDINGS For patients with lobar ICH, carriers of the APOE ε2 allele had larger ICH volumes than did non-carriers in the discovery phase (p=2·5×10(-5)), in both replication phases (p=0·008 in Europeans and p=0·016 in African-Americans), and in the meta-analysis (p=3·2×10(-8)). In the meta-analysis, each copy of APOE ε2 increased haematoma size by a mean of 5·3 mL (95% CI 4·7-5·9; p=0·004). Carriers of APOE ε2 had increased mortality (odds ratio [OR] 1·50, 95% CI 1·23-1·82; p=2·45×10(-5)) and poorer functional outcomes (modified Rankin scale score 3-6; 1·52, 1·25-1·85; p=1·74×10(-5)) compared with non-carriers after lobar ICH. APOE ε4 was not associated with lobar ICH volume, functional outcome, or mortality in the discovery phase, replication phases, or meta-analysis of these three phases; in our further meta-analysis of 2194 patients, this variant did not increase risk of mortality (1·08, 0·86-1·36; p=0·52). APOE allele variants were not associated with deep ICH volume, functional outcome, or mortality. INTERPRETATION Vasculopathic changes associated with the APOE ε2 allele might have a role in the severity and clinical course of lobar ICH. Screening of patients who have ICH to identify the ε2 variant might allow identification of those at increased risk of mortality and poor functional outcomes. FUNDING US National Institutes of Health-National Institute of Neurological Disorders and Stroke, Keane Stroke Genetics Research Fund, Edward and Maybeth Sonn Research Fund, and US National Center for Research Resources.

Fast track — ArticlesAPOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage: a genetic association study

BACKGROUND Carriers of APOE ε2 and ε4 have an increased risk of intracerebral haemorrhage (ICH) in lobar regions, presumably because of the effects of these gene variants on risk of cerebral amyloid angiopathy. We aimed to assess whether these variants also associate with severity of ICH, in terms of haematoma volume at presentation and subsequent outcome. METHODS We investigated the association of APOE ε2 and ε4 with ICH volume and outcomes in patients with primary ICH in three phases: a discovery phase of 865 individuals of European ancestry from the Genetics of Cerebral Hemorrhage on Anticoagulation study, and replication phases of 946 Europeans (replication 1) and 214 African-Americans (replication 2) from an additional six studies. We also assessed the association of APOE variants with ICH volume and outcomes in meta-analyses of results from all three phases, and the association of APOE ε4 with mortality in a further meta-analysis including data from previous reports. Admission ICH volume was quantified on CT scan. We assessed functional outcome (modified Rankin scale score 3-6) and mortality at 90 days. We used linear regression to establish the effect of genotype on haematoma volume and logistic regression to assess the effect on outcome from ICH. FINDINGS For patients with lobar ICH, carriers of the APOE ε2 allele had larger ICH volumes than did non-carriers in the discovery phase (p=2·5×10(-5)), in both replication phases (p=0·008 in Europeans and p=0·016 in African-Americans), and in the meta-analysis (p=3·2×10(-8)). In the meta-analysis, each copy of APOE ε2 increased haematoma size by a mean of 5·3 mL (95% CI 4·7-5·9; p=0·004). Carriers of APOE ε2 had increased mortality (odds ratio [OR] 1·50, 95% CI 1·23-1·82; p=2·45×10(-5)) and poorer functional outcomes (modified Rankin scale score 3-6; 1·52, 1·25-1·85; p=1·74×10(-5)) compared with non-carriers after lobar ICH. APOE ε4 was not associated with lobar ICH volume, functional outcome, or mortality in the discovery phase, replication phases, or meta-analysis of these three phases; in our further meta-analysis of 2194 patients, this variant did not increase risk of mortality (1·08, 0·86-1·36; p=0·52). APOE allele variants were not associated with deep ICH volume, functional outcome, or mortality. INTERPRETATION Vasculopathic changes associated with the APOE ε2 allele might have a role in the severity and clinical course of lobar ICH. Screening of patients who have ICH to identify the ε2 variant might allow identification of those at increased risk of mortality and poor functional outcomes. FUNDING US National Institutes of Health-National Institute of Neurological Disorders and Stroke, Keane Stroke Genetics Research Fund, Edward and Maybeth Sonn Research Fund, and US National Center for Research Resources.

Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.

Weather as a Trigger of Stroke

Background: The conclusions of previous studies show little agreement concerning the relationship between weather and the incidence of stroke. We analyse the relationship between daily meteorological conditions and daily as well as seasonal stroke incidence. Methods: 1,286 consecutive strokes assessed during 3 years (2001–2003) from the reference area of Hospital del Mar were classified as intracerebral haemorrhage (ICH) (n = 243) or ischaemic stroke (IS) (n = 1,043). IS was divided in non-lacunar stroke (NLS) (n = 732) and lacunar stroke (LS) (n = 311). Daily meteorological data were obtained from ‘Observatori Fabra’ of Barcelona: atmospheric pressure (AP), relative humidity, maximum, minimum, and mean temperatures, and the variation of all these measures compared with the previous day. Results: Total stroke (TS) incidence showed little association with AP (coefficient of confidence, CC: –0.072; p = 0.022), but was higher with the AP variations (CC: 0.127; p < 0.001). NLS were related to AP falls (OR: 2.41; p < 0.001) whilst ICHs were associated with AP rises (OR: 2.07; p = 0.01). NLS and temperature showed an inverse correlation; however, it lost its significance after adjusting for AP variations. The daily incidences of NLS and ICH were higher in autumn and in winter, but depended strongly on the daily variations of AP. No other associations were found. Conclusions: The incidences of NLS and ICH are related to AP changes compared with the previous day. AP changes largely explain the seasonal and daily variations in the incidence of stroke. These data may help to explain the controversy in previous studies and to promote studies focused on the trigger mechanisms of stroke.

Hyperlipidemia and Reduced White Matter Hyperintensity Volume in Patients with Ischemic Stroke

Background and Purpose— White matter hyperintensity (WMH), or leukoaraiosis, is a radiologic finding generally assumed to reflect diseased small cerebral vasculature. WMH has significant functional impact through its relation to cognitive decline and risk of ischemic and hemorrhagic stroke. Accumulating evidence suggests that some manifestations of small-vessel disease such as intracerebral hemorrhage are associated with low levels of cholesterol. We sought to determine the relation between hyperlipidemia and WMH severity in patients with acute ischemic stroke (AIS). Methods— We analyzed 2 independent, hospital-based AIS cohorts. Demographic and clinical data were collected prospectively. WMH was measured using semiautomated volumetric image analysis and a semiquantitative visual grading scale. Univariate and multivariable regression analyses were used to assess the relation between WMH severity and study variables. Results— A total of 631 and 504 subjects in the first and second cohorts, respectively, were included. In univariate analyses, advancing age and hypertension were associated with severity of WMH (P<0.001) in both cohorts. In the multivariable analysis, after controlling for age, sex, and significant risk factors in the univariate and age-adjusted analyses, patients with a history of hyperlipidemia had less severe WMH in both cohorts (P<0.01). Conclusions— Results from 2 independent cohorts demonstrate that AIS patients with a history of hyperlipidemia have less severe WMH at the time of stroke. These data support the hypothesis that hyperlipidemia may play a relatively protective role in cerebral small-vessel disease.

Acute stroke unit care and early neurological deterioration in ischemic stroke

ObjectiveTo evaluate the impact that monitored acute stroke unit care may have on the risk of early neurological deterioration (END), and 90-day mortality and mortality-disability.MethodsNon-randomized prospective study with consecutive patients with acute ischemic stroke (AIS) admitted to a conventional care stroke unit (CCSU), from May 2003 to April 2005, or to a monitored acute stroke unit (ASU) from May 2005 to April 2006. END was defined as an increase in the NIHSS score ≥ 4 points in the first 72 hours after admission.ResultsEND was detected in 19.6 % of patients (11.2 % of patients admitted to the ASU and 23.8 % to the CCSU; p < 0.0001). Patients admitted to the ASU received more treatment with intravenous rtPa (13.5 % versus 4.2 %; p < 0.0001), had a shorter length of stay (9.1 [11.0] d versus 13.1 [10.4] d; p < 0.0001), lower 90-day mortality (10.2 % versus 17.3 %; p = 0.02), and lower mortality-disability at 90-days (28.4 % versus 40.2 %; p = 0.004) than those admitted to the CCSU. Multivariable analysis showed that ASU admission was a protector for END (OR: 0.37; 95 % CI: 0.23–0.62). On admission, higher NIHSS (OR: 1.06; 95 % CI: 1.03–1.10), higher glycaemia (OR: 1.003; 95 % CI: 1.001–1.006), and higher systolic pressure (OR: 1.01; 95 % CI: 1.002–1.017) were independent predictors of END.ConclusionsEND prevention by ASU care might be a key factor contributing to better outcome and decrease of length of stay in patients admitted to monitored stroke units.

Early Arterial Study in the Prediction of Mortality After Acute Ischemic Stroke

Background and Purpose— The purpose of this study was to evaluate the value of the initial arterial study as a predictor of 90-day mortality in patients with acute ischemic stroke. Methods— A total of 1220 unselected patients assessed during the first 24 hours after stroke onset were prospectively studied. Initial stroke severity was evaluated by the National Institutes of Health Stroke Scale and dichotomized in mild (National Institutes of Health Stroke Scale ≤7) and severe (National Institutes of Health Stroke Scale >7). Severe arterial stenosis (≥70%) or arterial occlusion in the symptomatic territory was determined by a Doppler study and also by additional explorations (carotid duplex, MR or CT angiography) in the first 24 hours after admission. The following variables were also analyzed: age, gender, previous functional status, smoking, hypertension, hyperlipidemia, diabetes mellitus, peripheral arterial disease, ischemic heart disease, heart failure, atrial fibrillation, previous stroke, and prior use of antithrombotic or statins. Ninety-day mortality was the end point of the study. Results— Ninety-day mortality was 15.7%. A total of 25.5% of all deaths were in patients with mild stroke. In addition to well-known factors related to mortality (age, stroke severity, ischemic heart disease, heart failure, and previous disability), severe arterial stenosis/occlusion was the factor with the highest relationship with 90-day mortality (adjusted OR: stenosis 2.13, occlusion 4.42, both 3.36). Arterial stenosis/occlusion was a higher predictor of 90-day mortality in patients with mild (adjusted OR: 5.38) than severe stroke (adjusted OR: 3.05). Conclusions— Severe arterial stenosis/occlusion in the early arterial study was highly related with 90-day mortality in an unselected series of patients with stroke. These data achieve special relevance in patients with initial mild stroke.

Does sleep protect against ischemic stroke? Less frequent ischemic strokes but more severe ones.

Background and objectiveStroke occurrence follows a circadian curve, with a higher frequency in the morning. This curve changes if the hours of sleep also change. Our aim was to evaluate the characteristics, risk factors, and prognosis associated with sleep stroke.MethodsPatients with ischemic stroke (n = 813), consecutively assessed in our hospital for 2 years, were recorded with the time of clinical onset, pathological antecedents, severity (NIHSS), clinical classification, etiologic TOAST classification, and functional outcome at 3 months (modified Rankin scale). When clinical disturbance appeared during night sleep time it was considered as sleep stroke (SS). The rest were considered wakefulness stroke (WS). Differences SS–WS were analyzed with χ2, t-student, Mann-Whitney U, and logistic regression tests.ResultsFrom 813 patients included, 127 were SS (15.6%). The SS frequency was less than expected for the corresponding interval of hours. After the univariate analysis and posterior logistic regression, obesity was a factor associated with SS. Adjustment for age and gender revealed that atrial fibrillation (AF) was less frequent in the SS group. There were no differences for other risk factors or in the etiologic distribution. SS had a greater initial clinical severity and a worse functional outcome at 3 months. This functional outcome was dependent on the initial clinical severity.ConclusionsWhilst sleep could be associated with a lesser stroke occurrence, it could also be associated with a higher severity. Obesity appears as a factor related to SS whilst AF appears related to WS.