[Show abstract][Hide abstract] ABSTRACT: Infections occur in 30% of stroke patients and are associated with unfavorable outcomes. Preventive antibiotic therapy lowers the infection rate after stroke, but the effect of preventive antibiotic treatment on functional outcome in patients with stroke is unknown. The PASS is a multicenter, prospective, phase three, randomized, open-label, blinded end-point (PROBE) trial of preventive antibiotic therapy in acute stroke. Patients are randomly assigned to either ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to standard stroke-unit care, or standard stroke-unit care without preventive antibiotic therapy. The aim of this study is to assess whether preventive antibiotic treatment improves functional outcome at 3 months by preventing infections. This paper presents in detail the statistical analysis plan (SAP) of the Preventive Antibiotics in Stroke Study (PASS) and was submitted while the investigators were still blinded for all outcomes.
[Show abstract][Hide abstract] ABSTRACT: In patients with mild to moderate symptomatic carotid artery stenosis, intraplaque hemorrhage (IPH) and a thin/ruptured fibrous cap (FC) as evaluated with MRI, and the presence of microembolic signals (MESs) as detected with transcranial Doppler, are associated with an increased risk of a (recurrent) stroke. The objective of the present study is to determine whether the prevalence of MES differs in patients with and without IPH and thin/ruptured FC, and patients with only a thin/ruptured FC without IPH.
[Show abstract][Hide abstract] ABSTRACT: Background
In the last couple of years, genome-wide association studies have largely altered the scope in genetic research in diseases in which both environmental and genetic risk factors contribute to the disease. To date, the genetic risk loci identified in stroke have lagged behind those in other complex diseases, possibly because of the heterogeneity of stroke phenotypes. Sufficiently large cohorts with well-defined and detailed phenotyping of stroke patients are needed to identify additional genetic risk loci.DesignThe String-of-Pearls Institute is a unique partnership between all eight University Medical Centers in the Netherlands. It was established in 2007 by the Netherlands Federation of University Medical Centers, and it conducts a large prospective cohort study in which comprehensive clinical data, detailed phenotyping of stroke, imaging data, and biomaterials are collected in a large cohort of stroke patients.AimsThe study aims (1) to collect a sufficiently large prospective cohort of stroke patients, with well-defined phenotypes; (2) to collect blood samples and DNA in a standardized infrastructure, allowing for storing and analyzing the samples in a uniform way; (3) to investigate associations between genetic risk loci and stroke; (4) to create possibilities to perform epidemiological studies in a well-defined hospital-based cohort of stroke patients; and (5) to allow for pooling data with other large ongoing genetic stroke studies.
International Journal of Stroke 09/2014; · 4.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and PurposeIn patients with space-occupying middle cerebral artery infarction, surgical decompression strongly reduces risk of death and increases the chance of a favorable outcome. This comes at the expense of an increase in the risk of survival with (moderately) severe disability. We assessed quality of life, depression, and caregiver burden in these patients.Summary of ReviewWe systematically reviewed the literature by searching MEDLINE, EMBASE, and PsycINFO up to March 2014. We included randomized controlled trials, cohort studies, case–control studies, and case series with quality of life, depression, or caregiver burden as primary or secondary outcome. Seventeen articles reporting on 459 patients were included. At final follow-up at 7 to 51 months, 1344 patients (30%) had died, and 34 (11%) were lost to follow up. Data on 291 patients were available, of whom 81 of 213 survivors (39%) achieved good functional outcome at final follow-up (modified Rankin Scale ≤3). Mean quality of life was 46% to 67% of the best possible score when based on questionnaires or visual analogue scales. At final follow-up, 143 of 189 patients (76%) would in retrospect again choose for surgical decompression. Severe depressive symptoms were present in 14 of 113 patients (16%). Three studies investigated caregiver burden and reported substantial burden. Patients more than 60 years old had a lower quality of life in comparison with younger patients.Conclusions
Most patients treated with surgical decompression for space-occupying infarction have a reasonable quality of life at long-term follow-up and are satisfied with the treatment received. Severe depressive symptoms are uncommon.
International Journal of Stroke 08/2014; · 4.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We aimed to quantify the effects of white matter hyperintensities (WMHs) on specific cognitive functions with particular attention to WMH progression and localization.
PubMed (January 1990-July 2013) and bibliographies from included articles were used. Studies that were included (1) used MRI; (2) had a population-based or case-control design with a healthy control group that could be used for analysis; (3) matched/adjusted for age, sex, and education; and (4) addressed ≥1 predefined cognitive domains with ≥1 validated neuropsychological tests. Data were independently extracted by 2 investigators. Pearson r was extracted/calculated and used as the common metric for the effect size across studies.
Twenty-three cross-sectional and 14 longitudinal studies were included with a total of 8,685 and 7,731 participants. Presence of WMHs was significantly associated with concurrent cognitive deficits in all examined domains: general intelligence (Fisher z -0.10, 95% confidence interval [CI] -0.19 to -0.04), memory (-0.08, -0.13 to -0.06), processing speed (-0.11, -0.17 to -0.07), attention and executive functions (-0.11, -0.16 to -0.07), and perception/construction (-0.15, -0.21 to -0.07). Similar effect sizes were observed for cognitive decline over time. WMH progression was associated with greater cognitive decline, particularly for general intelligence (Fisher z -0.31, 95% CI -0.5 to -0.02) and attention and executive functions (-0.32, -0.34 to -0.28).
The small but robust and consistent effects of WMHs on all cognitive domains suggest a more global effect on cognition than previously thought. Progression of WMHs was associated with even worse cognitive functioning, most pronounced in attention and executive functioning.
[Show abstract][Hide abstract] ABSTRACT: Stroke is a leading cause of death worldwide. Infections after stroke occur in 30% of stroke patients and are strongly associated with unfavourable outcome. Preventive antibiotic therapy lowers infection rate in patients after stroke, however, the effect of preventive antibiotic treatment on functional outcome after stroke has not yet been investigated.The Preventive Antibiotics in Stroke Study (PASS) is an ongoing, multicentre, prospective, randomised, open-label, blinded end point trial of preventive antibiotic therapy in acute stroke. Patients are randomly assigned to either ceftriaxone at a dose of 2 g, given every 24 hours intravenously for four-days, in addition to stroke-unit care, or standard stroke-unit care without preventive antibiotic therapy. Aim of the study is to assess whether preventive antibiotic treatment improves functional outcome at three months by preventing infections.
To date, 2,470 patients have been included in PASS. Median stroke severity of the first 2,133 patients (second interim analysis) is 5 (IQR 3 to 9) on the National Institutes of Health Stroke Scale (NIHSS). Due to the PROBE design, no outcome data are available yet. In the initial trial protocol we proposed a dichotomisation of the mRS as primary analysis of outcome and ordinal regression analysis as secondary analysis of primary outcome, requiring a sample size of 3,200 patients. However, ordinal analysis of outcome data is becoming increasingly more common in acute stroke trials, as it increases statistical power. For PASS, funding is insufficient for inclusion of 3,200 patients with the overall inclusion rate of 15 patients per week. Therefore we change the analysis of our primary outcome from dichotomisation to ordinal regression analysis on the mRS. Power analysis showed that with similar assumptions, 2,550 patients are needed using ordinal regression analysis. . We expect to complete follow-up in June 2014. A full statistical analysis plan will be submitted for publication before treatment allocation will be unblinded.
The data from PASS will establish whether preventive antibiotic therapy in acute stroke improves functional outcome by preventing infection. In this update, we changed our primary outcome analysis from dichotomisation to ordinal regression analysis.Trial registration: Current controlled trials; ISRCTN66140176. Date of registration: 6 April 2010.
[Show abstract][Hide abstract] ABSTRACT: Assuming the involvement of homocysteine in a generalized small-vessel disease, we investigated the association of homocysteine levels with progression of white matter lesions, lacunar infarcts, and kidney disease.
Within the SMART-MR (Second Manifestations of ARTerial disease-Magnetic Resonance) Study, a prospective cohort study on brain aging in patients with symptomatic atherosclerotic disease, 663 patients (aged 57 ± 9 years) had vascular screening and 1.5-tesla MRI at baseline and after a mean follow-up of 3.9 years. Multiple regression analysis was used to estimate the longitudinal association between total homocysteine level, defined as a continuous variable and as hyperhomocysteinemia (the highest quintile of homocysteine), and progression of white matter lesion volume, lacunar infarcts, and estimated glomerular filtration rate.
After adjusting for age, sex, follow-up time, and vascular risk factors, hyperhomocysteinemia was significantly associated with increased risk of white matter lesion progression (odds ratio 2.4, 95% confidence interval [CI] 1.5-4.1) and lower estimated glomerular filtration rate at follow-up (B = -3.4 mL/min, 95% CI -5.9 to -0.9) and borderline significantly associated with new lacunar infarcts (odds ratio 1.8, 95% CI 0.9-3.4).
Our findings implicate a role for homocysteine in the development of a generalized small-vessel disease in which both brain and kidney are affected.
[Show abstract][Hide abstract] ABSTRACT: To investigate the association of renal impairment on functional outcome and complications in stroke patients treated with IV thrombolysis (IVT).
In this observational study, we compared the estimated glomerular filtration rate (GFR) with poor 3-month outcome (modified Rankin Scale scores 3-6), death, and symptomatic intracranial hemorrhage (sICH) based on the criteria of the European Cooperative Acute Stroke Study II trial. Unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Patients without IVT treatment served as a comparison group.
Among 4,780 IVT-treated patients, 1,217 (25.5%) had a low GFR (<60 mL/min/1.73 m(2)). A GFR decrease by 10 mL/min/1.73 m(2) increased the risk of poor outcome (OR [95% CI]): (ORunadjusted 1.20 [1.17-1.24]; ORadjusted 1.05 [1.01-1.09]), death (ORunadjusted 1.33 [1.28-1.38]; ORadjusted 1.18 [1.11-1.249]), and sICH (ORunadjusted 1.15 [1.01-1.22]; ORadjusted 1.11 [1.04-1.20]). Low GFR was independently associated with poor 3-month outcome (ORadjusted 1.32 [1.10-1.58]), death (ORadjusted 1.73 [1.39-2.14]), and sICH (ORadjusted 1.64 [1.21-2.23]) compared with normal GFR (60-120 mL/min/1.73 m(2)). Low GFR (ORadjusted 1.64 [1.21-2.23]) and stroke severity (ORadjusted 1.05 [1.03-1.07]) independently determined sICH. Compared with patients who did not receive IVT, treatment with IVT in patients with low GFR was associated with poor outcome (ORadjusted 1.79 [1.41-2.25]), and with favorable outcome in those with normal GFR (ORadjusted 0.77 [0.63-0.94]).
Renal function significantly modified outcome and complication rates in IVT-treated stroke patients. Lower GFR might be a better risk indicator for sICH than age. A decrease of GFR by 10 mL/min/1.73 m(2) seems to have a similar impact on the risk of death or sICH as a 1-point-higher NIH Stroke Scale score measuring stroke severity.
[Show abstract][Hide abstract] ABSTRACT: Cerebral white matter lesions (WML) are associated with cognitive impairment, and carotid revascularization with cognitive worsening or improvement. We assessed the relation between WML severity and changes in cognition after carotid endarterectomy or stenting.
Patients with symptomatic carotid artery stenosis, enrolled in the International Carotid Stenting Study (ISRCTN25337470), underwent detailed neuropsychological examinations (NPEs) before and after 6months. Cognitive results were standardized into z-scores, from which a sum score was calculated. The primary outcome was the mean difference (MD) in sum score between baseline and follow-up. Changes in sum score were related to WML severity with the 'age-related white matter changes' score, assessed on baseline MRI-FLAIR. Three groups were formed based on this score.
Eighty-nine patients had both baseline MRI and NPE, of these 77 had a calculable cognitive difference score. The cognitive sum score at six months was worse than at baseline: MD, -0.21; 95% CI, -0.32 to -0.09. The change in sum score did not depend on WML load: MD for no-to-mild WML, -0.15; 95% CI, -0.39 to 0.09, for moderate WML, -0.27; 95% CI, -0.48 to -0.06; and for severe WML, -0.21; 95% CI, -0.40 to -0.04. This did not change essentially after adjustment for baseline factors.
Cognitive functioning deteriorated after carotid revascularization, regardless of baseline WML burden.
Journal of the neurological sciences 08/2013; · 2.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: Differentiation between an occluded and a patent extracranial internal carotid artery (ICA) is crucial in the diagnostic workup of patients with acute ischemic stroke; particularly in patients eligible for endovascular treatment. We report neurological and radiological findings of cases in which CTA in the acute phase incorrectly revealed an occlusion of the ICA. METHODS: In our image data base of 54 patients with acute ischemic stroke eligible for endovascular treatment, we searched for patients with an occluded extracranial ICA on CTA whereas DSA proved that this artery was patent. Of these patients, all available images were re-examined to investigate possible causes of these so-called pseudo-occlusions. RESULTS: We detected 6 patients (11%) with a pseudo-occlusion. The pseudo-occlusions on CTA were associated with reduced flow due to carotid T-occlusions (4 cases) or a combination of a high degree stenosis of the extracranial ICA and MCA occlusion (2 cases). CONCLUSION: CTA in the acute phase of ischemic stroke needs to be interpreted with severe caution, and in endovascular treatment decisions we should be aware that an extracranial ICA occlusion may be a false positive finding.
Clinical neurology and neurosurgery 02/2013; · 1.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND PURPOSE: Intravenous thrombolysis for acute ischemic stroke is beneficial within 4.5 hours of symptom onset, but the effect rapidly decreases over time, necessitating quick diagnostic in-hospital work-up. Initial time strain occasionally results in treatment of patients with an alternate diagnosis (stroke mimics). We investigated whether intravenous thrombolysis is safe in these patients. METHODS: In this multicenter observational cohort study containing 5581 consecutive patients treated with intravenous thrombolysis, we determined the frequency and the clinical characteristics of stroke mimics. For safety, we compared the symptomatic intracranial hemorrhage (European Cooperative Acute Stroke Study II [ECASS-II] definition) rate of stroke mimics with ischemic strokes. RESULTS: One hundred stroke mimics were identified, resulting in a frequency of 1.8% (95% confidence interval, 1.5-2.2). Patients with a stroke mimic were younger, more often female, and had fewer risk factors except smoking and previous stroke or transient ischemic attack. The symptomatic intracranial hemorrhage rate in stroke mimics was 1.0% (95% confidence interval, 0.0-5.0) compared with 7.9% (95% confidence interval, 7.2-8.7) in ischemic strokes. CONCLUSIONS: In experienced stroke centers, among patients treated with intravenous thrombolysis, only a few had a final diagnosis other than stroke. The complication rate in these stroke mimics was low.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND PURPOSE: In a substudy of the International Carotid Stenting Study (ICSS), more patients had new ischemic brain lesions on diffusion-weighted magnetic resonance imaging (MRI) after stenting (CAS) than after endarterectomy (CEA). In the present analysis, we compared characteristics of diffusion-weighted MRI lesions. METHODS: Number, individual and total volumes, and location of new diffusion-weighted MRI lesions were compared in patients with symptomatic carotid stenosis randomized to CAS (n=124) or CEA (n=107) in the ICSS-MRI substudy. RESULTS: CAS patients had higher lesion numbers than CEA patients (1 lesion, 15% vs 8%; 2-5 lesions, 19% vs 5%; >5 lesions, 16% vs 4%). The overall risk ratio for the expected lesion count with CAS versus CEA was 8.8 (95% confidence interval, 4.4-17.5; P<0.0001) and significantly increased among patients with lower blood pressure at randomization, diabetes mellitus, stroke as the qualifying event, left-side stenosis, and if patients were treated at centers routinely using filter-type protection devices during CAS. Individual lesions were smaller in the CAS group than in the CEA group (P<0.0001). Total lesion volume per patient did not differ significantly. Lesions in the CAS group were more likely to occur in cortical areas and subjacent white matter supplied by leptomeningeal arteries than lesions in the CEA group (odds ratio, 4.2; 95% confidence interval, 1.7-10.2; P=0.002). CONCLUSIONS: Compared with patients undergoing CEA, patients treated with CAS had higher numbers of periprocedural ischemic brain lesions, and lesions were smaller and more likely to occur in cortical areas and subjacent white matter. These findings may reflect differences in underlying mechanisms of cerebral ischemia.Clinical Trial Registration-URL: http://www.isrctn.org. Unique identifier: ISRCTN25337470.
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: Novel postprocessing techniques have enabled accurate quantification of intracranial carotid atherosclerotic disease on CT Angiography (CTA). Our purpose was to estimate the prevalence of intracranial carotid artery disease, i.e., stenosis and calcium, on CTA in patients with recent neurological symptoms. METHODS: The degree of stenosis and calcium volume of 162 extracranial and intracranial internal carotid arteries (ICAs) was quantitatively measured on CTA images of 88 consecutive patients with recent neurological symptoms and extracranial ICA stenosis as screened by ultrasound. The prevalence of intracranial ICA stenosis and presence of calcium was estimated and correlated with extracranial ICA stenosis. RESULTS: Intracranial ICA stenosis was observed in 83 % (95 %CI: 77-89 %) and 39 % (95 %CI: 31-47 %) for a stenosis of ≥30 % and ≥50 %, respectively. Only on the symptomatic side, a statistical significant correlation between intracranial and extracranial stenoses was observed (Pearson's r 0.32, P = 0.006). In the 37 arteries with an extracranial ICA stenosis of ≥70 %, 89 % (95 %CI: 79-99 %) and 46 % (95 %CI: 30-62 %) of the intracranial ICA showed a stenosis of ≥30 % and ≥50 %, respectively. CONCLUSION: In our population of patients with recent neurological symptoms and extracranial stenosis as screened by ultrasound, CTA imaging resulted in a substantially higher prevalence of intracranial ICA disease than previously reported. This remarkably high prevalence of intracranial ICA disease on CTA may have important future implications for acute and preventive treatment strategies.
[Show abstract][Hide abstract] ABSTRACT: Stroke is the main cause of disability in high income countries and ranks second as a cause of death worldwide. Infections occur frequently after stroke and may adversely affect outcome. Preventive antibiotic therapy in the acute phase of stroke may reduce infections and improve outcome.
1. To assess whether preventive antibiotic therapy in patients with acute stroke reduces the risk of dependency and death at follow-up. 2. To assess whether preventive antibiotic therapy in patients with acute stroke reduces infection rate.
We searched the Cochrane Stroke Group's Trials Register (October 2010); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 3); MEDLINE (1950 to October 2010) and EMBASE (1980 to October 2010). In an effort to identify further published, unpublished and ongoing trials we searched trials and research registers, scanned reference lists and contacted authors, colleagues and researchers in the field.
Randomised controlled trials (RCTs) of preventive antibiotic therapy versus control (placebo or open control) in patients with acute ischaemic or haemorrhagic stroke.
Two authors independently selected articles and performed data extraction; we discussed and resolved discrepancies in a consensus meeting with a third observer. We contacted the study authors to obtain missing data when required. An independent observer assessed methodological quality. We calculated relative risks (RRs) for dichotomous outcomes, assessed heterogeneity amongst included studies and performed subgroup analyses on study quality.
We included five studies involving 506 patients. Study population, study design, type of antibiotic and definition of infection differed considerably. The number of patients who died in the preventive antibiotic group was non-significantly reduced (33/248 (13%) versus 38/258 (15%), RR 0.85, 95% confidence interval (CI) 0.47 to 1.51); the number of dependent patients in the preventive antibiotic therapy group was also non-significantly reduced (97/208 (47%) versus 127/208 (61%), RR 0.67, 95% CI 0.32 to 1.43). Preventive antibiotic therapy did reduce the incidence of infections in patients with acute stroke from 36% to 22% (36/166 (22%) versus 61/169 (36%), RR 0.58, 95% CI 0.43 to 0.79). No major side-effects of preventive antibiotic therapy were reported.
In this meta-analysis, preventive antibiotic therapy seemed to reduce the risk of infection, but did not reduce the number of dependent or deceased patients. However, the included studies were small and heterogeneous. Large randomised trials are urgently needed.