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1.  Intravenous thrombolysis in acute ischaemic stroke: from trial exclusion criteria to clinical contraindications. An international Delphi study 
Several studies indicate that only a small proportion of patients with acute ischaemic stroke are treated with intravenous thrombolysis. Indications and contraindications for this treatment are usually based on the inclusion and exclusion criteria of randomised clinical trials. The trial context of these criteria hampers implementation in real life settings. We therefore aimed to obtain specialist opinion in a Delphi consensus on these contraindications.
We used the Delphi approach on an international group of specialists in the field of thrombolysis. Inclusion and exclusion criteria were reworded into 18 quantitatively phrased propositions. Feedback consisted of the median score, interquartile range and the panellist's own score in the previous round. For each item, we defined consensus as the achievement of an interdecile range within two prespecified clinically relevant units.
Thirty‐one specialists participated in the first round and 30 completed all three rounds. Consensus was reached on 12 of the 18 propositions: previous ischaemic stroke, head trauma and gastrointestinal tract bleeding should not have taken place earlier than 1.5 months, 2 months and 14 days, respectively; the severity of the neurological deficit is defined as a National Institutes of Health Stroke Scale (NIHSS) score of 2–3 or more, and blood pressure level should not be >185/110 mmHg; platelet count should be >90×1012/l, glucose levels 2.7–22 mmol/l, international normalised ratio <1.5 and activated partial thromboplastin time <50 s. No consensus was reached on propositions concerning the stroke onset to treatment time, patient's age, recent medical procedures, spontaneous improvement rate and blood pressure treatment.
We present specialists' opinion on contraindications for intravenous thrombolysis in ischaemic stroke. The results of this study may be relevant for routine clinical practice as they may help to increase the number of treated patients.
PMCID: PMC2117697  PMID: 17332052
2.  Update of the Preventive Antibiotics in Stroke Study (PASS): statistical analysis plan 
Trials  2014;15:382.
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.
The primary outcome is the score on the modified Rankin Scale (mRS), assessed by ordinal logistic regression analysis according to a proportional odds model. Secondary analysis of the primary outcome is the score on the mRS dichotomized as a favorable outcome (mRS 0 to 2) versus unfavorable outcome (mRS 3 to 6). Secondary outcome measures are death rate at discharge and 3 months, infection rate during hospital admission, length of hospital admission, volume of post-stroke care, use of antibiotics during hospital stay, quality-adjusted life years and costs. Complications of treatment, serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs) are reported as safety outcomes.
The data from PASS will establish whether preventive antibiotic therapy in acute stroke improves functional outcome by preventing infection and will be analyzed according to this pre-specified SAP.
Trial registration
Current controlled trials; ISRCTN66140176. Date of registration: 6 April 2010.
PMCID: PMC4195873  PMID: 25269598
stroke; infection; antibiotics; randomized clinical trial; statistical analysis plan
3.  Measuring Quality Improvement in Acute Ischemic Stroke Care: Interrupted Time Series Analysis of Door-to-Needle Time 
Cerebrovascular Diseases Extra  2014;4(2):149-155.
In patients with acute ischemic stroke, early treatment with recombinant tissue plasminogen activator (rtPA) improves functional outcome by effectively reducing disability and dependency. Timely thrombolysis, within 1 h, is a vital aspect of acute stroke treatment, and is reflected in the widely used performance indicator ‘door-to-needle time’ (DNT). DNT measures the time from the moment the patient enters the emergency department until he/she receives intravenous rtPA. The purpose of the study was to measure quality improvement from the first implementation of thrombolysis in stroke patients in a university hospital in the Netherlands. We further aimed to identify specific interventions that affect DNT.
We included all patients with acute ischemic stroke consecutively admitted to a large university hospital in the Netherlands between January 2006 and December 2012, and focused on those treated with thrombolytic therapy on admission. Data were collected routinely for research purposes and internal quality measurement (the Erasmus Stroke Study). We used a retrospective interrupted time series design to study the trend in DNT, analyzed by means of segmented regression.
Between January 2006 and December 2012, 1,703 patients with ischemic stroke were admitted and 262 (17%) were treated with rtPA. Patients treated with thrombolysis were on average 63 years old at the time of the stroke and 52% were male. Mean age (p = 0.58) and sex distribution (p = 0.98) did not change over the years. The proportion treated with thrombolysis increased from 5% in 2006 to 22% in 2012. In 2006, none of the patients were treated within 1 h. In 2012, this had increased to 81%. In a logistic regression analysis, this trend was significant (OR 1.6 per year, CI 1.4-1.8). The median DNT was reduced from 75 min in 2006 to 45 min in 2012 (p < 0.001 in a linear regression model). In this period, a 12% annual decrease in DNT was achieved (CI from 16 to 8%). We could not find a significant association between any specific intervention and the trend in DNT.
Conclusion and Implications
The DNT steadily improved from the first implementation of thrombolysis. Specific explanations for this improvement require further study, and may relate to the combined impact of a series of structural and logistic interventions. Our results support the use of performance measures for internal communication. Median DNT should be used on a monthly or quarterly basis to inform all professionals treating stroke patient of their achievements.
PMCID: PMC4105950  PMID: 25076959
Acute ischemic stroke; Acute stroke care; Door-to-needle time; Recombinant tissue plasminogen activator; Performance indicator; Quality of care; Process indicators; Quality improvement
4.  Effect of genetic variations in Syntaxin Binding Protein-5 and Syntaxin-2 on Von Willebrand Factor concentration and cardiovascular risk 
Elevated von Willebrand Factor (VWF) plasma levels are associated with an increased risk of cardiovascular disease. A meta-analysis of genome wide association studies on VWF identified novel candidate genes, i.e. syntaxin-binding protein 5 (STXBP5) and syntaxin 2 (STX2), which are possibly involved in the secretion of VWF. We investigated whether VWF antigen levels (VWF:Ag), VWF collagen-binding activity (VWF:CB), and the risk of arterial thrombosis are affected by common genetic variations in these genes.
Methods and Results
In 463 young Caucasian subjects (males ≤ 45 years, females ≤ 55 years), who were included one to three months after a first event of arterial thrombosis, and 406 controls, we measured VWF:Ag and VWF:CB. Nine haplotype tagging SNPs of STXBP5 and STX2 were selected and subsequently analysed using linear regression with additive genetic models adjusted for age, sex and ABO blood group. The minor alleles of rs9399599 and rs1039084 in STXBP5 were associated with lower VWF plasma levels and activity, whereas the minor allele of rs7978987 in STX2 was associated with higher VWF plasma levels and activity. The minor alleles of the SNPs in STX2 were associated with a reduced risk of arterial thrombosis (rs1236:OR 0.73 [95%CI 0.59, 0.89], rs7978987:OR 0.81 [95%CI 0.65, 1.00], rs11061158:OR 0.69 [95%CI 0.55, 0.88]).
Genetic variability in STXBP5 and STX2 affects both VWF concentration and activity in young individuals with premature arterial thrombosis. Furthermore, in our study genetic variability in STX2 is associated with the risk of arterial thrombosis. However, at this point the underlying mechanism remains unclear.
PMCID: PMC3511837  PMID: 21156930
Von Willebrand Factor; genetics; STX2; STXBP5; cardiovascular diseases
5.  Prediction of intracranial findings on CT-scans by alternative modelling techniques 
Prediction rules for intracranial traumatic findings in patients with minor head injury are designed to reduce the use of computed tomography (CT) without missing patients at risk for complications. This study investigates whether alternative modelling techniques might improve the applicability and simplicity of such prediction rules.
We included 3181 patients with minor head injury who had received CT scans between February 2002 and August 2004. Of these patients 243 (7.6%) had intracranial traumatic findings and 17 (0.5%) underwent neurosurgical intervention. We analyzed sensitivity, specificity and area under the ROC curve (AUC-value) to compare the performance of various modelling techniques by 10 × 10 cross-validation. The techniques included logistic regression, Bayes network, Chi-squared Automatic Interaction Detection (CHAID), neural net, support vector machines, Classification And Regression Trees (CART) and "decision list" models.
The cross-validated performance was best for the logistic regression model (AUC 0.78), followed by the Bayes network model and the neural net model (both AUC 0.74). The other models performed poorly (AUC < 0.70). The advantage of the Bayes network model was that it provided a graphical representation of the relationships between the predictors and the outcome.
No alternative modelling technique outperformed the logistic regression model. However, the Bayes network model had a presentation format which provided more detailed insights into the structure of the prediction problem. The search for methods with good predictive performance and an attractive presentation format should continue.
PMCID: PMC3212831  PMID: 22026551
6.  Microstructural brain injury in post-concussion syndrome after minor head injury 
Neuroradiology  2010;53(8):553-563.
After minor head injury (MHI), post-concussive symptoms commonly occur. The purpose of this study was to correlate the severity of post-concussive symptoms in MHI patients with MRI measures of microstructural brain injury, namely mean diffusivity (MD) and fractional anisotropy (FA), as well as the presence of microhaemorrhages.
Twenty MHI patients and 12 healthy controls were scanned at 3 T using diffusion tensor imaging (DTI) and high-resolution gradient recalled echo (HRGRE) T2*-weighted sequences. One patient was excluded from the analysis because of bilateral subdural haematomas. DTI data were preprocessed using Tract Based Spatial Statistics. The resulting MD and FA images were correlated with the severity of post-concussive symptoms evaluated with the Rivermead Postconcussion Symptoms Questionnaire. The number and location of microhaemorrhages were assessed on the HRGRE T2*-weighted images.
Comparing patients with controls, there were no differences in MD. FA was decreased in the right temporal subcortical white matter. MD was increased in association with the severity of post-concussive symptoms in the inferior fronto-occipital fasciculus (IFO), the inferior longitudinal fasciculus and the superior longitudinal fasciculus. FA was reduced in association with the severity of post-concussive symptoms in the uncinate fasciculus, the IFO, the internal capsule and the corpus callosum, as well as in the parietal and frontal subcortical white matter. Microhaemorrhages were observed in one patient only.
The severity of post-concussive symptoms after MHI was significantly correlated with a reduction of white matter integrity, providing evidence of microstructural brain injury as a neuropathological substrate of the post-concussion syndrome.
PMCID: PMC3139069  PMID: 20924757
Craniocerebral trauma; Post-concussion syndrome; Diffusion tensor imaging; Magnetic resonance imaging; Cognition disorder
7.  An early rise in body temperature is related to unfavorable outcome after stroke: data from the PAIS study 
Journal of Neurology  2010;258(2):302-307.
Subfebrile temperature or fever is present in about a third of patients on the first day after stroke onset and is associated with poor outcome. However, the temporal profile of this association is not well established. We aimed to assess the relationship between body temperature on admission as well as the change in body temperature from admission to 24 h thereafter and functional outcome and death. We analyzed data of 1,332 patients admitted within 12 h of stroke onset. The relation between body temperature on admission or the change in body temperature from admission to 24 h thereafter (adjusted for body temperature on admission) on the one hand and unfavorable outcome (death, or a modified Rankin Scale score >2) at 3 months on the other were expressed as odds ratio per 1.0°C increase in body temperature. Adjustments for potential confounders were made with a multiple logistic regression model. No relation was found between admission body temperature and poor outcome (aOR 1.06; 95% CI 0.85–1.32) and death (aOR 1.23; 95% CI 0.95–1.60). In contrast, increased body temperature in the first 24 h after stroke onset was associated with poor outcome (aOR 1.30; 95% CI 1.05–1.63) and death (aOR 1.51; 95% CI 1.15–1.98). An early rise in body temperature rather than high body temperature on admission is a risk factor for unfavorable outcome in patients with acute stroke.
PMCID: PMC3036804  PMID: 20878419
Stroke; Body temperature; Clinical outcome
8.  Assessment of atherosclerotic carotid plaque volume with multidetector computed tomography angiography 
Purpose The amount of atherosclerotic plaque and its components (calcifications, fibrous tissue, and lipid core) could be better predictors of acute events than the now currently used degree of stenosis. Therefore, we evaluated a dedicated software tool for volume measurements of atherosclerotic carotid plaque and its components in multidetector computed tomography angiography (MDCTA) images. Materials and Methods Data acquisition was approved by the Institutional Review Board and all patients gave written informed consent. MDCTA images of 56 carotid arteries were analyzed by three observers. Plaque volumes were assessed by manual drawing of the outer vessel contour. The luminal boundary was determined based on a Hounsfield-Unit (HU) threshold. The contribution of different components was measured by the number of voxels within defined ranges of HU-values (calcification >130 HU, fibrous tissue 60–130 HU, lipid core <60 HU). Interobserver variability (IOV) was assessed. Results Plaque volume was 1,259 ± 621 mm3. The calcified, fibrous and lipid volumes were 238 ± 252 mm3, 647 ± 277 mm3 and 376 ± 283 mm3, respectively. IOV was moderate with interclass correlation coefficients (ICC) ranging from 0.76 to 0.99 and coefficients of variation (COV) ranging from 3% to 47%. Conclusion Atherosclerotic carotid plaque volume and plaque component volumes can be assessed with MDCTA with a reasonable observer variability.
Electronic supplementary material
The online version of this article (doi:10.1007/s10554-008-9309-1) contains supplementary material, which is available to authorized users.
PMCID: PMC2522292  PMID: 18373211
9.  PISA. The effect of paracetamol (acetaminophen) and ibuprofen on body temperature in acute stroke: Protocol for a phase II double-blind randomised placebo-controlled trial [ISRCTN98608690] 
During the first days after stroke, one to two fifths of the patients develop fever or subfebrile temperatures. Body temperature is a strong prognostic factor after stroke. Pharmacological reduction of temperature in patients with acute ischaemic stroke may improve their functional outcome. Previously, we studied the effect of high dose (6 g daily) and low dose (3 g daily) paracetamol (acetaminophen) in a randomised placebo-controlled trial of 75 patients with acute ischemic stroke. In the high-dose paracetamol group, mean body temperature at 12 and 24 hours after start of treatment was 0.4°C lower than in the placebo group. The effect of ibuprofen, another potent antipyretic drug, on body-core temperature in normothermic patients has not been studied.
The aim of the present trial is to study the effects of high-dose paracetamol and ibuprofen on body temperature in patients with acute ischaemic stroke, and to study the safety of these treatments.
Seventy-five (3 × 25) patients with acute ischaemic stroke confined to the anterior circulation will be randomised to treatment with either: 400 mg ibuprofen, 1000 mg acetaminophen, or with placebo 6 times daily during 5 days. Body-temperatures will be measured with a rectal electronic thermometer at the start of treatment and after 24 hours. An infrared tympanic thermometer will be used to monitor body temperature at 2-hour intervals during the first 24 hours and at 12-hour intervals thereafter. The primary outcome measure will be rectal temperature at 24 hours after the start of treatment. The study results will be analysed on an intent-to-treat basis, but an on-treatment analysis will also be performed. No formal interim analysis will be carried out.
PMCID: PMC101394  PMID: 11918829

Results 1-9 (9)