Elevated C-reactive protein and long-term mortality after ischaemic stroke: relationship with markers of endothelial cell and platelet activation.

BACKGROUND AND PURPOSE: Inflammatory biomarkers predict development of atherothrombotic events. In the present study we examined the relationships between C-reactive protein (CRP), complement C3, and long-term mortality after acute ischemic stroke. METHODS: CRP and C3 were analyzed by in-house enzyme-linked immunosorbent assay in 394 subjects with acute ischemic stroke who survived for >30 days, followed-up for a median of 7.4 years. RESULTS: CRP was higher in subjects who died (10.8 mg/L; 95% CI, 9.1-12.8) compared with survivors (3.8 mg/L; 95% CI, 3.1-4.7), whereas C3 was similar in both groups (P=0.26). CRP remained predictive for mortality after adjusting for conventional clinical and demographic risk factors (the adjusted hazard ratio for those with CRP in the highest compared with the lowest quartile was 2.0; 95% CI, 1.3-3.1). However, CRP was no longer independently predictive of mortality after additionally adjusting for beta-thromboglobulin or von Willebrand factor. CONCLUSIONS: Our data suggest that the relationship between CRP and poststroke mortality may in part reflect inflammation-induced endothelial cell dysfunction and platelet activation.

Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK).

BACKGROUND: Hyperglycaemia after acute stroke is a common finding that has been associated with an increased risk of death. We sought to determine whether treatment with glucose-potassium-insulin (GKI) infusions to maintain euglycaemia immediately after the acute event reduces death at 90 days. METHODS: Patients presenting within 24 h of stroke onset and with admission plasma glucose concentration between 6.0-17.0 mmol/L were randomly assigned to receive variable-dose-insulin GKI (intervention) or saline (control) as a continuous intravenous infusion for 24 h. The purpose of GKI infusion was to maintain capillary glucose at 4-7 mmol/L, with no glucose intervention in the control group. The primary outcome was death at 90 days, and the secondary endpoint was avoidance of death or severe disability at 90 days. Additional planned analyses were done to determine any differences in residual disability or neurological and functional recovery. The trial was powered to detect a mortality difference of 6% (sample size 2355), with 83% power, at the 5% two-sided significance level. This study is registered as an International Standard Randomised Controlled Trial (number ISRCTN 31118803) FINDINGS: The trial was stopped due to slow enrolment after 933 patients were recruited. For the intention-to-treat data, there was no significant reduction in mortality at 90 days (GKI vs control: odds ratio 1.14, 95% CI 0.86-1.51, p=0.37). There were no significant differences for secondary outcomes. In the GKI group, overall mean plasma glucose and mean systolic blood pressure were significantly lower than in the control group (mean difference in glucose 0.57 mmol/L, p<0.001; mean difference in blood pressure 9.0 mmHg, p<0.0001). INTERPRETATION: GKI infusions significantly reduced plasma glucose concentrations and blood pressure. Treatment within the trial protocol was not associated with significant clinical benefit, although the study was underpowered and alternative results cannot be excluded.

Predictive variables for mortality after acute ischemic stroke.

BACKGROUND AND PURPOSE: Stroke is a major healthcare issue worldwide with an incidence comparable to coronary events, highlighting the importance of understanding risk factors for stroke and subsequent mortality. METHODS: In the present study, we determined long-term (all-cause) mortality in 545 patients with ischemic stroke compared with a cohort of 330 age-matched healthy control subjects followed up for a median of 7.4 years. We assessed the effect of selected demographic, clinical, biochemical, hematologic, and hemostatic factors on mortality in patients with ischemic stroke. Stroke subtype was classified according to the Oxfordshire Community Stroke Project criteria. Patients who died 30 days or less after the acute event (n=32) were excluded from analyses because this outcome is considered to be directly attributable to the acute event. RESULTS: Patients with ischemic stroke were at more than 3-fold increased risk of death compared with the age-matched control cohort. In multivariate analyses, age, stroke subtype, atrial fibrillation, and previous stroke/transient ischemic attack were predictive of mortality in patients with ischemic stroke. Albumin and creatinine and the hemostatic factors von Willebrand factor and beta-thromboglobulin were also predictive of mortality in patients with ischemic stroke after accounting for demographic and clinical variables. CONCLUSIONS: The results indicate that subjects with acute ischemic stroke are at increased risk of all-cause mortality. Advancing age, large-vessel stroke, atrial fibrillation, and previous stroke/transient ischemic attack predict mortality; and analysis of albumin, creatinine, von Willebrand factor, and beta-thromboglobulin will aid in the identification of patients at increased risk of death after stroke.

A patient with neuro-Behçet's disease is successfully treated with etanercept: further evidence for the value of TNFalpha blockade.

Behçet's disease is a chronic relapsing multisystem vasculitis with 49% of cases involving the CNS. Recently there have been two reports of neuro-Behçet's disease (NB) successfully treated with the tumour necrosis factor alpha (TNFalpha) monoclonal antibody infliximab. We describe a patient with longstanding NB who was poorly responsive to azathioprine, cyclosporin, thalidomide and methotrexate. She showed a remarkable response when treated with the recombinant human TNFalpha receptor protein, etanercept. To the best of our knowledge this is the first report of NB successfully treated with etanercept.

Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction.

Cerebral small vessel disease (SVD) causes focal lacunar infarction and more diffuse ischaemia, referred to as leukoaraiosis. Endothelial dysfunction has been proposed as a causal mechanism in the disease. Homocysteine is toxic to endothelium. We determined whether elevated homocysteine levels and the methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism are risk factors for SVD as a whole, and for two different SVD subtypes: isolated lacunar infarction and ischaemic leukoaraiosis. We also determined whether any association was mediated by endothelial dysfunction, as assessed by circulating endothelial markers. One hundred and seventy-two Caucasian patients with SVD and 172 community controls of similar age and sex were studied. Serum homocysteine measurement and MTHFR genotyping was performed. Levels of intercellular adhesion molecule 1 (ICAM1) and thrombomodulin were measured in a subgroup. Mean homocysteine levels were higher in SVD than controls [14.55 micromol/l [95% confidence interval (CI) 13.78-15.35] versus 12.01 micromol/l (95% CI 11.42-12.64), P < 0.0005]. Homocysteine was a stronger risk factor in those with ischaemic leukoaraiosis [12.92 (95% CI 4.40-37.98), P < 0.0005) per micromol increase in log homocysteine concentration (P < 0.0005)] in comparison with isolated lacunar infarction [4.22 (95% CI 1.29-13.73), P = 0.02] after controlling for both conventional risk factors and age. The MTHFR 677T allele was a risk factor only in the ischaemic leukoaraiosis group [odds ratio (OR) 2.02 (95% CI 1.31-3.1), P = 0.001]. Inclusion of the endothelial markers ICAM1 and thrombomodulin in a logistic regression model resulted in the association between homocysteine and SVD no longer being significant. In conclusion, hyperhomocysteinaemia is an independent risk factor for SVD, particularly ischaemic leukoaraiosis, and this effect may be mediated via endothelial dysfunction. Homocysteine-lowering therapy may be particularly effective in this subgroup.

Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis.

Patients with cerebral small vessel disease (SVD) can present as isolated lacunar infarction or with diffuse white matter changes, with the imaging appearance of leukoaraiosis. Endothelial dysfunction, which can lead to breakdown of the blood-brain barrier, impaired cerebral autoregulation and prothrombotic changes, is believed to be important in mediating disease. Circulating levels of intercellular adhesion molecule 1 (ICAM1), thrombomodulin (TM), tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are markers of endothelial activation and damage, and may provide insights into disease pathogenesis or differences between phenotypes. We therefore measured these markers in a prospective series of patients with lacunar stroke. One hundred and ten white Caucasian patients with previous lacunar stroke and 50 community control subjects were studied. Markers of endothelial function were measured on venous blood samples. Patients were classified on brain imaging into two groups: isolated lacunar infarction (n = 47) and ischaemic leukoaraiosis, defined as a clinical lacunar stroke and leukoaraiosis on brain imaging (n = 63). The number of lacunes and severity of leukoaraiosis were also scored on MRI. ICAM1, TM and TFPI were elevated in cerebral SVD subjects compared with controls (P

How to undertake a clinically relevant systematic review in a rapidly evolving field. Magnetic resonance angiography.

OBJECTIVES: The aim was to determine which generations of the evolving technology of magnetic resonance angiography (MRA) are currently of clinical relevance in two clinical applications. Our purpose was to plan a systematic review that would be valuable both to purchasers driven by cost-effectiveness and to practicing clinicians. METHODS: Information was gathered from a search of major bibliographic databases, from a short questionnaire sent to 500 U.K. vascular radiologists and vascular surgeons, and from local clinical experts. We asked which of the MRA techniques were currently used and, assuming availability, what would be their technique of choice. RESULTS: There were 206 published articles that satisfied preliminary inclusion criteria: 69 discussed 2D time of flight (TOF); 47, 3D TOF; and 38, contrast-enhanced techniques. There were 162 questionnaires returned (60 radiologists, 102 surgeons). Of the total respondents, 77/162 (48%) used MRA in the assessment of carotid artery stenosis; 47/77 (61%) used 2D TOF; 32/77 (42%), 3D TOF; and 26/77 (34%), contrast-enhanced techniques. Thirty-five of 162 (22%) respondents used MRA in the assessment of peripheral vascular disease (PVD); 15/35 (43%) used 2D TOF, 4/35 (11%) used 3D TOF, and 22/35 (63%) used contrast-enhanced techniques. For those wishing to use MRA, contrast-enhanced techniques were the method of choice. CONCLUSIONS: The TOF methods that represent earlier generations of the technology remain clinically relevant, and will therefore be included in our systematic review. To ensure complete and relevant coverage in reviews of other evolving technologies, it would be advisable to obtain data for guidance in a similar way.

Use of magnetic resonance angiography to select candidates with recently symptomatic carotid stenosis for surgery: systematic review.

OBJECTIVE: To determine if sufficient evidence exists to support the use of magnetic resonance angiography as a means of selecting patients with recently symptomatic high grade carotid stenosis for surgery. DESIGN: Systematic review of published research on the diagnostic performance of magnetic resonance angiography, 1990-9. MAIN OUTCOME MEASURES: Performance characteristics of diagnostic test. RESULTS: 126 potentially relevant articles were identified, but many articles failed to examine the performance of magnetic resonance angiography as a diagnostic test at the surgical decision thresholds used in major clinical trials on endarterectomy. 26 articles were included in a meta-analysis that showed a maximal joint sensitivity and specificity of 99% (95% confidence interval 98% to 100%) for identifying 70-99% stenosis and 90% (81% to 99%) for identifying 50-99% stenosis. Only four articles evaluated contrast enhanced magnetic resonance angiography. CONCLUSIONS: Magnetic resonance angiography is accurate for selecting patients for carotid endarterectomy at the surgical decision thresholds established in the major endarterectomy trials, but the evidence is not very robust because of the heterogeneity of the studies included. Research is needed to determine the diagnostic performance of the most recent developments in magnetic resonance angiography, including contrast enhanced techniques, as well as to assess the impact of magnetic resonance angiography on surgical decision making and outcomes.