Jaume Roquer

Sex Differences in First-Ever Acute Stroke

Background and Purpose— There are few studies analyzing stroke in women, taking into account the vascular risk factors, cause of stroke, clinical picture, and outcome. The purpose of this study was to analyze possible sex differences in patients suffering first-ever acute stroke. Methods— From December 1995 to January 2002, 1581 patients with first-ever acute stroke were analyzed, taking into account sex, age, risk factors, clinical presentation, stroke subtype, treatment, and outcome data. Results— Mean age was higher in women than in men (P <0.001). Hypertension (P =0.0027) and cardioembolic disease (P =0.0035) were independent factors related to women. Alcohol overuse (P <0.001), smoking (P <0.001), and vascular peripheral disease (P =0.031) were related to the male sex. Women more often suffered aphasic disorders (P <0.001), visual field disturbances (P <0.05), and dysphagia (P <0.01) than men. There were no differences in hemorrhagic and ischemic strokes according to sex. Women suffered more cardioembolic strokes (P <0.001); men suffered more atherothrombotic (P <0.001) and lacunar strokes (P <0.05). Women who survived remained more disabled than men (P <0.001). Conclusions— Sex determines some clear differences in patients suffering a first-ever stroke. Women were, on average, 6 years older than men and had a different profile of vascular risk factors and a different distribution of stroke subtypes. Women had a longer hospital stay and remained more disabled than men. The amelioration of hypertension control and increase in anticoagulant treatment in patients with atrial fibrillation would be the best options for preventing stroke, especially in women.

Lipoprotein and apolipoprotein profile in men with ischemic stroke. Role of lipoprotein(a), triglyceride-rich lipoproteins, and apolipoprotein E polymorphism.

Background and Purpose: The role of lipoprotein abnormalities in the development of ischemic cerebrovascular disease has not been sufficiently clarified. The aim of this study was to identify the lipoprotein profile in ischemic cerebrovascular disease and the possible role of apolipoprotein E polymorphism. Methods: The relation between the concentrations of lipoprotein(a), intermediate density lipoproteins, apolipoprotein A-I, apolipoprotein B, apolipoprotein E, and other lipoproteins was studied in 100 men with ischemic cerebrovascular disease (48 atherothrombotic, 28 lacunar, and 24 of unknown type) and in 100 healthy age-matched men as a control group. Results: Patients with ischemic cerebrovascular disease had significantly higher levels of lipoprotein (a), lipids carried by intermediate density lipoproteins, and low density lipoprotein cholesterol and lower levels of high density lipoproteins than control subjects. Patients with atherothrombotic infarction had higher total serum cholesterol and low density lipoprotein cholesterol concentrations than patients with lacunar infarction. To assess lipoprotein abnormalities in normolipidemic subjects, a subgroup of 38 patients with ischemic cerebrovascular disease and 53 control subjects, both with serum cholesterol levels <5.2 mmol/1 (200 mg/dl) and triglycerides <2.3 mmol/1 (200 mg/dl), was analyzed. Serum lipoprotein (a), lipids carried by very low density lipoproteins and intermediate density lipoproteins, and low density lipoprotein triglycerides were significantly higher in normolipidemic patients compared with normolipidemic control subjects, whereas high density lipoprotein cholesterol levels were lower. Apolipoprotein E polymorphism in our ischemic cerebrovascular patients differed from that of the control group, with the ϵ4 allele being more prevalent. Conclusions: Increased serum lipoprotein (a) levels and intermediate density lipoprotein abnormalities together with decreased high density lipoprotein levels are major risk factors for ischemic cerebrovascular disease, even in normocholesterolemic and normotriglyceridemic subjects. Finally, the ϵ4 allele could probably be a predisposing genetic marker for ischemic cerebrovascular disease.

Favorable Outcome of Ischemic Stroke in Patients Pretreated with Statins

Background and Purpose— Statins may be beneficial for patients with acute ischemic stroke. We tested the hypothesis that patients pretreated with statins at the onset of stroke have less severe neurological effects and a better outcome. Methods— We prospectively included consecutive patients with ischemic stroke of <4-hour duration. We recorded demographic data, vascular risk factors, Oxfordshire Classification, National Institutes of Health Stroke Scale (NIHSS) score, admission blood glucose and body temperature, cause (Trial of Org 10172 in Acute Treatment [TOAST] criteria), neurological progression at day 3, previous statin treatment, and outcome at 3 months. We analyzed the data using univariate methods and a logistic regression with the dependent variable of good outcome (modified Rankin Scale [mRS] 0 to 1, Barthel Index [BI] 95 to 100). Results— We included 167 patients (mean age 70.7±12 years, 94 men). Thirty patients (18%) were using statins when admitted. In the statin group, the median NIHSS score was not significantly lower and the risk of progression was not significantly reduced. Favorable outcomes at 3 months were more frequent in the statin group (80% versus 61.3%, P =0.059 with the mRS; 76.7% versus 51.8%, P =0.015 with the BI). Predictors of favorable outcome with the BI were: NIHSS score at admission (OR: 0.72; CI: 0.65 to 0.80; P <0.0001), age (OR: 0.96; CI: 0.92 to 0.99; P =0.017), and statin group (OR: 5.55; CI: 1.42 to 17.8; P =0.012). Conclusions— Statins may provide benefits for the long-term functional outcome when administered before the onset of cerebral ischemia. However, randomized controlled trials will be required to evaluate the validity of our results.

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.

Valproate-induced hyperammonemic encephalopathy

Valproate‐induced hyperammonemic encephalopathy (VHE) is an unusual complication characterized by a decreasing level of consciousness, focal neurological deficits, cognitive slowing, vomiting, drowsiness, and lethargy. We have thoroughly reviewed the predisposing factors and their screening, the biochemical and physiopathological mechanisms involved, the different treatments described, and those that are being investigated. Etiopathogenesis is not completely understood, although hyperammonemia has been postulated as the main cause of the clinical syndrome. The increase in serum ammonium level is due to several mechanisms, the most important one appearing to be the inhibition of carbamoylphosphate synthetase‐I, the enzyme that begins the urea cycle. Polytherapy with several drugs, such as phenobarbital and topiramate, seems to contribute to hyperammonemia. Hyperammonemia leads to an increase in the glutamine level in the brain, which produces astrocyte swelling and cerebral edema. There are several studies that suggest that treatment with supplements of carnitine can lead to an early favorable clinical response due to the probable carnitine deficiency induced by a valproate (VPA) treatment. Development of the progressive confusional syndrome, associated with an increase in seizure frequency after VPA treatment onset, obliges us to rule out VHE by screening for blood ammonium levels and the existence of urea cycle enzyme deficiency, such as ornithine carbamoyltransferase deficiency. Electroencephalography (EEG) is characterized by signs of severe encephalopathy with continuous generalized slowing, a predominance of theta and delta activity, occasional bursts of frontal intermittent rhythmic delta activity, and triphasic waves. These EEG findings, as well as clinical manifestations and hyperammonemia, tend to normalize after VPA withdrawal.

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.

Reversal of apixaban induced alterations in hemostasis by different coagulation factor concentrates: significance of studies in vitro with circulating human blood.

Apixaban is a new oral anticoagulant with a specific inhibitory action on FXa. No information is available on the reversal of the antihemostatic action of apixaban in experimental or clinical settings. We have evaluated the effectiveness of different factor concentrates at reversing modifications of hemostatic mechanisms induced by moderately elevated concentrations of apixaban (200 ng/ml) added in vitro to blood from healthy donors (n = 10). Effects on thrombin generation (TG) and thromboelastometry (TEM) parameters were assessed. Modifications in platelet adhesive, aggregating and procoagulant activities were evaluated in studies with blood circulating through damaged vascular surfaces, at a shear rate of 600 s−1. The potential of prothrombin complex concentrates (PCCs; 50 IU/kg), activated prothrombin complex concentrates (aPCCs; 75 IU/kg), or activated recombinant factor VII (rFVIIa; 270 μg/kg), at reversing the antihemostatic actions of apixaban, were investigated. Apixaban interfered with TG kinetics. Delayed lag phase, prolonged time to peak and reduced peak values, were improved by the different concentrates, though modifications in TG patterns were diversely affected depending on the activating reagents. Apixaban significantly prolonged clotting times (CTs) in TEM studies. Prolongations in CTs were corrected by the different concentrates with variable efficacies (rFVIIa≥aPCC>PCC). Apixaban significantly reduced fibrin and platelet interactions with damaged vascular surfaces in perfusion studies (p<0.05 and p<0.01, respectively). Impairments in fibrin formation were normalized by the different concentrates. Only rFVIIa significantly restored levels of platelet deposition. Alterations in hemostasis induced by apixaban were variably compensated by the different factor concentrates investigated. However, effects of these concentrates were not homogeneous in all the tests, with PCCs showing more efficacy in TG, and rFVIIa being more effective on TEM and perfusion studies. Our results indicate that rFVIIa, PCCs and aPCCs have the potential to restore platelet and fibrin components of the hemostasis previously altered by apixaban.

Endothelial dysfunction, vascular disease and stroke: the ARTICO study.

Endothelial dysfunction is a fundamental step in the atherosclerotic disease process. Its presence is a risk factor for the development of clinical events, and may represent a marker of atherothrombotic burden. Also, endothelial dysfunction contributes to enhanced plaque vulnerability, may trigger plaque rupture, and favors thrombus formation. The assessment of endothelial vasomotion is a useful marker of atherosclerotic vascular disease. There are different methods to assess endothelial function: endothelium-dependent vasodilatation brachial flow-mediated dilation, cerebrovascular reactivity to L-arginine, and the determination of some biomarkers such as microalbuminuria, platelet function, and C-reactive protein. Endothelial dysfunction has been observed in stroke patients and has been related to stroke physiopathology, stroke subtypes, clinical severity and outcome. Resting ankle-brachial index (ABI) is also considered an indicator of generalized atherosclerosis, and a low ABI is associated with an increase in stroke incidence in the elderly. Despite all these data, there are no studies analyzing the predictive value of ABI for new cardiovascular events in patients after suffering an acute ischemic stroke. ARTICO is an ongoing prospective, observational, multicenter study being performed in 50 Spanish hospitals. The aim of the ARTICO study is to evaluate the prognostic value of a pathological ABI (≤0.9) in the presence of a major cardiovascular event during a 1-year follow-up after first-ever ischemic stroke. Secondary objectives include the evaluation of the predictive value for major cardiovascular events of the carotid intima-media thickness, carotid duplex findings, and certain biomarkers. Data from the ARTICO study will increase the knowledge of patient outcome after ischemic stroke and may help to improve our ability to detect patients at high risk of stroke recurrence or major cardiovascular events.

Previous antiplatelet therapy is an independent predictor of 30-day mortality after spontaneous supratentorial intracerebral hemorrhage.

AbstractBackgroundIntracerebral hemorrhage (ICH) constitutes 10% to 15% of all strokes. Despite several existing outcome prediction models for ICH, there are some factors with equivocal value as well as others that still have not been evaluated.Patients and methodsAll patients with first ever supratentorial ICH presenting to our institution between December 1995 and December 2002 were prospectively enrolled into the study. Patients with historic modified Rankin Scale > 2 and those under anticoagulant treatment or with multiple ICH were excluded. The following parameters were analyzed in 194 consecutive patients: age, gender, past history of hypertension, diabetes mellitus, hypercholesterolemia, past history of ischemic stroke, presence of ischemic heart disease or cardioembolic disease, current antiplatelet treatment, current alcohol overuse, smoking, Glasgow Coma Scale score (GSS) at admission, volume and location (deep or lobar) of ICH, ventricular extension, glycemia and temperature at admission, and leukoaraiosis. We correlated these data with the 30–day mortality identifying the independent predictors by logistic regression analysis.ResultsFactors independently associated with 30–day mortality were: age, Glasgow Coma Scale score at admission, ICH volume, ventricular extension, glucose level at admission, and previous antiplatelet use.ConclusionsApart from the classical outcome predictors, the previous use of antiplatelet agents and the glucose value at admission are independent predictors of 30–day mortality in patients suffering a supratentorial ICH.