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1.  Disruption of the Cerebral White Matter Network Is Related to Slowing of Information Processing Speed in Patients With Type 2 Diabetes 
Diabetes  2013;62(6):2112-2115.
Patients with type 2 diabetes often show slowing of information processing. Disruptions in the brain white matter network, possibly secondary to vascular damage, may underlie these cognitive disturbances. The current study reconstructed the white matter network of 55 nondemented individuals with type 2 diabetes (mean age, 71 ± 4 years) and 50 age-, sex-, and education-matched controls using diffusion magnetic resonance imaging–based fiber tractography. Graph theoretical analysis was then applied to quantify the efficiency of these networks. Patients with type 2 diabetes showed alterations in local and global network properties compared with controls (P < 0.05). These structural network abnormalities were related to slowing of information processing speed in patients. This relation was partly independent of cerebrovascular lesion load. This study shows that the approach of characterizing the brain as a network using diffusion magnetic resonance imaging and graph theory can provide new insights into how abnormalities in the white matter affect cognitive function in patients with diabetes.
PMCID: PMC3661620  PMID: 23349494
2.  Ipsilateral foetal-type posterior cerebral artery is associated with cognitive decline after carotid revascularisation 
BMC Neurology  2014;14:84.
Stenosis of the internal carotid artery has been associated with cognitive impairment and decline. However, studies testing the effect of carotid revascularisation on cognition have had conflicting results. This may in part be explained by variation in the flow territory of the carotid artery. In 12 to 36% of the patients, the posterior cerebral artery is mainly or exclusively supplied by the internal carotid artery via a foetal-type posterior cerebral artery. In these patients, ipsilateral carotid artery stenosis is likely to result in a larger area with hypoperfusion than in case of a normal posterior cerebral artery. Patients with a foetal-type posterior cerebral artery could therefore benefit more from revascularisation. We compared the effects of carotid revascularisation on cognition between patients with a foetal-type and those with a normal posterior cerebral artery.
Patients with symptomatic internal carotid artery stenosis ≥ 50%, enrolled in the International Carotid Stenting Study (ICSS) at a single centre, underwent detailed neuropsychological examinations before and 6 months after revascularisation. Cognitive test results were standardized into z-scores, from which a cognitive sumscore was calculated. The primary outcome was the change in cognitive sumscore between baseline and follow-up. Changes in cognitive sumscore were compared between patients with an ipsilateral foetal-type and those with a normal posterior cerebral artery, as assessed with CT or MR angiography.
Of 145 patients enrolled in ICSS at the centre during the study period, 98 had both angiography at baseline and neuropsychological examination at baseline and at 6-months follow-up. The cognitive sum score decreased by 0.28 (95% confidence interval, 0.10 to 0.45) in 13 patients with an ipsilateral foetal-type posterior cerebral artery and by 0.07 (95% CI, 0.002 to 0.15) in 85 patients with a normal posterior cerebral artery (mean difference, -0.20; 95% CI, -0.40 to -0.01). This did not change essentially after adjustment for baseline factors.
An ipsilateral foetal-type posterior cerebral artery appears to increase cognitive decline after carotid revascularisation. Our findings have to be reproduced in an independent study before further implications can be made.
PMCID: PMC4021499  PMID: 24739135
Angioplasty and stenting; Carotid endarterectomy; Symptomatic carotid stenosis; Cognition; Circle of Willis
3.  Prediction of outcome in patients with suspected acute ischaemic stroke with CT perfusion and CT angiography: the Dutch acute stroke trial (DUST) study protocol 
BMC Neurology  2014;14:37.
Prediction of clinical outcome in the acute stage of ischaemic stroke can be difficult when based on patient characteristics, clinical findings and on non-contrast CT. CT perfusion and CT angiography may provide additional prognostic information and guide treatment in the early stage. We present the study protocol of the Dutch acute Stroke Trial (DUST). The DUST aims to assess the prognostic value of CT perfusion and CT angiography in predicting stroke outcome, in addition to patient characteristics and non-contrast CT. For this purpose, individualised prediction models for clinical outcome after stroke based on the best predictors from patient characteristics and CT imaging will be developed and validated.
The DUST is a prospective multi-centre cohort study in 1500 patients with suspected acute ischaemic stroke. All patients undergo non-contrast CT, CT perfusion and CT angiography within 9 hours after onset of the neurological deficits, and, if possible, follow-up imaging after 3 days. The primary outcome is a dichotomised score on the modified Rankin Scale, assessed at 90 days. A score of 0–2 represents good outcome, and a score of 3–6 represents poor outcome. Three logistic regression models will be developed, including patient characteristics and non-contrast CT (model A), with addition of CT angiography (model B), and CT perfusion parameters (model C). Model derivation will be performed in 60% of the study population, and model validation in the remaining 40% of the patients. Additional prognostic value of the models will be determined with the area under the curve (AUC) from the receiver operating characteristic (ROC) curve, calibration plots, assessment of goodness-of-fit, and likelihood ratio tests.
This study will provide insight in the added prognostic value of CTP and CTA parameters in outcome prediction of acute stroke patients. The prediction models that will be developed in this study may help guide future treatment decisions in the acute stage of ischaemic stroke.
PMCID: PMC3939816  PMID: 24568540
Stroke; Ischaemia; Infarct; Prediction; CT perfusion; CT angiography
4.  Extracellular vesicle protein levels are related to brain atrophy and cerebral white matter lesions in patients with manifest vascular disease: the SMART-MR study 
BMJ Open  2014;4(1):e003824.
Extracellular vesicles (EVs) and their protein levels have been identified as a potential risk marker for the development of vascular disease. In the present study, we assessed whether levels of four previously identified EV proteins (cystatin C, serpin G1, serpin F2 and CD14) are associated with cerebral white matter lesions (WMLs) and brain atrophy.
Cohort study; cross-sectional and prospective.
Single centre, secondary and tertiary setting.
1309 patients with manifest vascular disease from the Second Manifestations of ARTerial disease-MR (SMART-MR) study, of which 994 had successful brain MRI and EV protein level measurements.
WML and brain parenchymal fraction (BPF), as parameter for brain atrophy, at baseline and follow-up.
Statistical methods
The relationship between EV protein levels and WML volume (expressed as log transformed percentage of intracranial volume) and BPF (expressed percentage of intracranial volume) on 1.5 T brain MRI was assessed with multivariable linear regression modelling. Subsequently, the relationship between baseline EV protein levels and progression of atrophy and WML was analysed in 534 patients, in whom a follow-up MRI was obtained after 4 years.
Higher EV-cystatin C and EV-CD14 were significantly associated with larger WML volume (linear regression coefficient (95% CI) 0.10 log %/SD (0.04 to 0.17) and 0.14 log %/SD (0.07 to 0.20), respectively. Higher EV-CD14 was associated with more brain atrophy (–0.14%/SD; –0.27 to –0.01). Baseline EV-CD14 was significantly associated with increase of WMLs (0.11 log %/SD (0.04 to 0.18)). No relationship with EV-serpins was observed at baseline or at follow-up.
EV proteins cystatin C and CD14 are related to cerebral WMLs and the progression of brain atrophy in patients with manifest vascular disease, potentially identifying EVs in the aetiology of structural brain changes.
PMCID: PMC3902438  PMID: 24430876
extracellular vesicles; White matter lesion; Brain atrophy
5.  Microstructural White Matter Abnormalities and Cognitive Functioning in Type 2 Diabetes 
Diabetes Care  2012;36(1):137-144.
To examine whether type 2 diabetes is associated with microstructural abnormalities in specific cerebral white matter tracts and to relate these microstructural abnormalities to cognitive functioning.
Thirty-five nondemented older individuals with type 2 diabetes (mean age 71 ± 5 years) and 35 age-, sex-, and education-matched control subjects underwent a 3 Tesla diffusion-weighted MRI scan and a detailed cognitive assessment. Tractography was performed to reconstruct several white matter tracts. Diffusion tensor imaging measures, including fractional anisotropy (FA) and mean diffusivity (MD), were compared between groups and related to cognitive performance.
MD was significantly increased in all tracts in both hemispheres in patients compared with control subjects (P < 0.05), reflecting microstructural white matter abnormalities in the diabetes group. Increased MD was associated with slowing of information-processing speed and worse memory performance in the diabetes but not in the control group after adjustment for age, sex, and estimated IQ (group × MD interaction, all P < 0.05). These associations were independent of total white matter hyperintensity load and presence of cerebral infarcts.
Individuals with type 2 diabetes showed microstructural abnormalities in various white matter pathways. These abnormalities were related to worse cognitive functioning.
PMCID: PMC3526236  PMID: 22961577
6.  Intervention versus standard medical treatment in patients with symptomatic occlusion of the internal carotid artery: a randomised oxygen-15 PET study 
EJNMMI Research  2013;3:79.
The aim of this randomised pilot study was to investigate the haemodynamic effects measured by oxygen-15 positron emission tomography (PET) of interventional treatment consisting of either endarterectomy or endovascular treatment of stenosed cerebropetal arteries, or tapering of antihypertensive medication in comparison with standard medical treatment alone in patients with symptomatic internal carotid artery (ICA) occlusion.
Twenty-three patients with symptomatic ICA occlusion underwent PET scanning at baseline and after 3 months. Twelve patients were randomised to intervention (either endarterectomy or endovascular treatment of stenosed cerebropetal arteries, or tapering of antihypertensive medication) and 11 to standard medical treatment alone. Primary outcome was a change in cerebral blood flow (CBF), cerebral blood volume (CBV) and/or oxygen extraction fraction (OEF) after 3 months measured by PET.
There were no differences in changes in CBF, CBV or OEF between the two groups. Only patients with compromised perfusion at presentation showed a borderline significant increase in CBF of 2.8 mL/min/100 mL (95% confidence interval 0.0 to 5.7) after intervention (n = 7).
This pilot study shows that in patients with symptomatic ICA occlusion, oxygen-15 PET did not detect differences in improvement of CBF, CBV or OEF between interventional and standard treatment.
PMCID: PMC4029781  PMID: 24308868
Carotid artery diseases; Haemodynamics; Other cerebrovascular disease/stroke; PET
7.  Reliability of Visual Assessment of Non-Contrast CT, CT Angiography Source Images and CT Perfusion in Patients with Suspected Ischemic Stroke 
PLoS ONE  2013;8(10):e75615.
Background and Purpose
Good reliability of methods to assess the extent of ischemia in acute stroke is important for implementation in clinical practice, especially between observers with varying experience. Our aim was to determine inter- and intra-observer reliability of the 1/3 middle cerebral artery (MCA) rule and the Alberta Stroke Program Early CT Score (ASPECTS) for different CT modalities in patients suspected of acute ischemic stroke.
We prospectively included 105 patients with acute neurological deficit due to suspected acute ischemic stroke within 9 hours after symptom onset. All patients underwent non-contrast CT, CT perfusion and CT angiography on admission. All images were evaluated twice for presence of ischemia, ischemia with >1/3 MCA involvement, and ASPECTS. Four observers evaluated twenty scans twice for intra-observer agreement. We used kappa statistics and intraclass correlation coefficient to calculate agreement.
Inter-observer agreement for the 1/3 MCA rule and ASPECTS was fair to good for non-contrast CT, poor to good for CT angiography source images, but excellent for all CT perfusion maps (cerebral blood volume, mean transit time, and predicted penumbra and infarct maps). Intra-observer agreement for the 1/3 MCA rule and ASPECTS was poor to good for non-contrast CT, fair to moderate for CT angiography source images, and good to excellent for all CT perfusion maps.
Between observers with a different level of experience, agreement on the radiological diagnosis of cerebral ischemia is much better for CT perfusion than for non-contrast CT and CT angiography source images, and therefore CT perfusion is a very reliable addition to standard stroke imaging.
PMCID: PMC3792960  PMID: 24116061
8.  Cerebral microinfarcts: a systematic review of neuropathological studies 
Vascular cognitive impairment is an umbrella term for cognitive dysfunction associated with and presumed to be caused by vascular brain damage. Autopsy studies have identified microinfarcts as an important neuropathological correlate of vascular cognitive impairment that escapes detection by conventional magnetic resonance imaging (MRI). As a frame of reference for future high-resolution MRI studies, we systematically reviewed the literature on neuropathological studies on cerebral microinfarcts in the context of vascular disease, vascular risk factors, cognitive decline and dementia. We identified 32 original patient studies involving 10,515 people. The overall picture is that microinfarcts are common, particularly in patients with vascular dementia (weighted average 62%), Alzheimer's disease (43%), and demented patients with both Alzheimer-type and cerebrovascular pathology (33%) compared with nondemented older individuals (24%). In many patients, multiple microinfarcts were detected. Microinfarcts are described as minute foci with neuronal loss, gliosis, pallor, or more cystic lesions. They are found in all brain regions, possibly more so in the cerebral cortex, particularly in watershed areas. Reported sizes vary from 50 μm to a few mm, which is within the detection limit of current high-resolution MRI. Detection of these lesions in vivo would have a high potential for future pathophysiological studies in vascular cognitive impairment.
PMCID: PMC3293128  PMID: 22234334
cerebral microinfarct; cerebrovascular disease; dementia; MRI; neuropathology
9.  Comparison of oxygen-15 PET and transcranial Doppler CO2-reactivity measurements in identifying haemodynamic compromise in patients with symptomatic occlusion of the internal carotid artery 
EJNMMI Research  2012;2:30.
Transcranial Doppler (TCD) CO2-reactivity and oxygen-15 positron emission tomography (PET) have both been used to measure the cerebral haemodynamic state in patients who may have a compromised blood flow. Our purpose was to investigate whether PET and TCD identify the same patients with an impaired flow state of the brain in patients with internal carotid artery (ICA) occlusion.
Patients with recent transient ischaemic attack or minor ischaemic stroke associated with ICA occlusion underwent TCD with measurement of CO2-reactivity and oxygen-15 PET within a median time interval of 6 days.
We included 24 patients (mean age 64 ± 10 years). Seventeen (71%) patients had impaired CO2-reactivity (≤20%), of whom six had absent reactivity (0%) or steal (<0%) in the hemisphere ipsilateral to the ICA occlusion. PET of the perfusion state of the hemisphere ipsilateral to the ICA occlusion demonstrated stage 1 haemodynamic compromise (decreased cerebral blood flow (CBF) or increased cerebral blood volume (CBV) without increased oxygen extraction fraction (OEF)) in 13 patients and stage 2 (increased OEF) in 2 patients. In 12 patients (50%), there was agreement between TCD and PET, indicating haemodynamic compromise in 10 and a normal flow state of the brain in 2 patients. There was no significant correlation between CO2-reactivity and CBF ipsilateral/contralateral hemispheric ratio (r = 0.168, p value = 0.432), OEF ratio (r = −0.242, p value = 0.255), or CBV/CBF ratio (r = −0.368, p value = 0.077).
In patients with symptomatic ICA occlusion, identification of an impaired flow state of the brain by PET and TCD CO2-reactivity shows concordance in only half of the patients.
PMCID: PMC3444322  PMID: 22682265
carotid artery disease; haemodynamic; PET; transcranial Doppler; stroke
10.  Preventing Deep Vein Thrombosis After Stroke: Strategies and Recommendations 
Opinion statement
The risk of deep vein thrombosis (DVT) after stroke is increased in patients with restricted mobility, a previous history of DVT, dehydration, or comorbidities such as malignant diseases or clotting disorders. Patients with an increased risk of DVT should receive prophylactic treatment. To reduce the chance of DVT, patients should be mobilized as soon as possible and should be kept well hydrated. Anti-embolism stockings cannot be recommended, because they have been demonstrated not useful for preventing DVT or pulmonary embolism in patients with stroke, and they are associated with a significantly increased risk of skin breaks. The usefulness of intermittent pneumatic compression is currently under study in a randomized clinical trial. Treatment with subcutaneously administered low-dose unfractionated heparin is preferred to unfractionated heparin and may be considered in patients with ischemic stroke if the risk of DVT is estimated to be higher than the risk of hemorrhagic complications. Aspirin may also be effective for patients with ischemic stroke who have contraindications to anticoagulants, although direct comparisons with anticoagulants are not available. In patients with intracerebral hemorrhage, low-dose subcutaneous low-molecular-weight heparin is probably safe after documentation of cessation of active bleeding, and may be considered on an individual basis after 3 to 4 days from stroke onset.
PMCID: PMC3207135  PMID: 21909622
11.  Progression of Cerebral Atrophy and White Matter Hyperintensities in Patients With Type 2 Diabetes 
Diabetes Care  2010;33(6):1309-1314.
Type 2 diabetes is associated with a moderate degree of cerebral atrophy and a higher white matter hyperintensity (WMH) volume. How these brain-imaging abnormalities evolve over time is unknown. The present study aims to quantify cerebral atrophy and WMH progression over 4 years in type 2 diabetes.
A total of 55 patients with type 2 diabetes and 28 age-, sex-, and IQ-matched control participants had two 1.5T magnetic resonance imaging scans with a 4-year interval. Volumetric measurements of total brain, peripheral cerebrospinal fluid (CSF), lateral ventricles, and WMH were performed with k-nearest neighbor–based probabilistic segmentation. All volumes were expressed as percentage of intracranial volume. Linear regression analyses, adjusted for age and sex, were performed to compare brain volumes between the groups and to identify determinants of volumetric change within the type 2 diabetic group.
At baseline, patients with type 2 diabetes had a significantly smaller total brain volume and larger peripheral CSF volume than control participants. In both groups, all volumes showed a significant change over time. Patients with type 2 diabetes had a greater increase in lateral ventricular volume than control participants (mean adjusted between-group difference in change over time [95% CI]: 0.11% in 4 years [0.00 to 0.22], P = 0.047).
The greater increase in lateral ventricular volume over time in patients with type 2 diabetes compared with control participants shows that type 2 diabetes is associated with a slow increase of cerebral atrophy over the course of years.
PMCID: PMC2875445  PMID: 20299484
12.  Arterial spin labeling perfusion MRI at multiple delay times: a correlative study with H215O positron emission tomography in patients with symptomatic carotid artery occlusion 
Arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI) with image acquisition at multiple inversion times is a noninvasive ASL technique able to compensate for spatial heterogeneities in transit times caused by collateral blood flow in patients with severe stenosis of the cerebropetal blood vessels. Our aim was to compare ASL-MRI and H215O positron emission tomography (PET), the gold standard for cerebral blood flow (CBF) assessment, in patients with a symptomatic internal carotid artery (ICA) occlusion. Fourteen patients (63±14 years) with a symptomatic ICA occlusion underwent both ASL-MRI and H215O PET. The ASL-MRI was performed using a pulsed STAR labeling technique at multiple inversion times within 7 days of the PET. The CBF was measured in the gray-matter of the anterior, middle and posterior cerebral artery, and white-matter. Both PET and ASL-MRI showed a significantly decreased CBF in the gray-matter of the middle cerebral artery in the hemisphere ipsilateral to the ICA occlusion. The average gray-matter CBF measured with ASL-MRI (71.8±4.3 mL/min/100 g) was higher (P<0.01) than measured with H215O PET (43.1±1.0 mL/min/100 g). In conclusion, ASL-MRI at multiple TIs is capable of depicting areas of regions with low CBF in patients with an occlusion of the ICA, although a systematic overestimation of CBF relative to H215O PET was noted.
PMCID: PMC2949108  PMID: 19809464
carotid artery; magnetic resonance imaging (MRI); MRI comparison with PET; MRI perfusion; positron emission tomography (PET)
13.  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
14.  Distribution of cerebral blood flow in the caudate nucleus, lentiform nucleus and thalamus in patients with carotid artery stenosis 
European Radiology  2010;21(4):875-881.
To investigate the influence of internal carotid artery (ICA) stenosis on the distribution of blood flow to the caudate nucleus, lentiform nucleus, and thalamus.
We studied 18 healthy control subjects, 20 patients with a unilateral asymptomatic ICA stenosis, and 15 patients with a recently symptomatic unilateral ICA stenosis. The contribution of the ICAs and the basilar artery to the perfusion of the deep brain structures was assessed by perfusion territory selective arterial spin labeling (ASL) MRI. Differences were tested with a two-tailed Fishers’ exact test.
The caudate nucleus was predominantly supplied with blood by the ipsilateral ICA in all groups. In 4 of the 15 (27%) the symptomatic patients, the caudate nucleus partially received blood from the contralateral ICA, compared to none of the 18 healthy control subjects (p = 0.03). The lentiform nucleus and the thalamus were predominantly supplied with blood by the ipsilateral ICA and basilar artery respectively in all groups.
In patients with a symptomatic ICA stenosis, the caudate nucleus may be supplied with blood by the contralateral ICA more often than in healthy controls.
PMCID: PMC3047207  PMID: 20853001
Magnetic resonance imaging; Cerebral hemodynamics; Perfusion; Basal ganglia; Carotid artery stenosis
16.  Day-to-Day Test–Retest Variability of CBF, CMRO2, and OEF Measurements Using Dynamic 15O PET Studies 
Molecular Imaging and Biology  2010;13(4):759-768.
We assessed test–retest variability of cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO2), and oxygen extraction fraction (OEF) measurements derived from dynamic 15O positron emission tomography (PET) scans.
In seven healthy volunteers, complete test–retest 15O PET studies were obtained; test–retest variability and left-to-right ratios of CBF, CBV, OEF, and CMRO2 in arterial flow territories were calculated.
Whole-brain test–retest coefficients of variation for CBF, CBV, CMRO2, and OEF were 8.8%, 13.8%, 5.3%, and 9.3%, respectively. Test–retest variability of CBV left-to-right ratios was <7.4% across all territories. Corresponding values for CBF, CMRO2, and OEF were better, i.e., <4.5%, <4.0%, and <1.4%, respectively.
The test–retest variability of CMRO2 measurements derived from dynamic 15O PET scans is comparable to within-session test–retest variability derived from steady-state 15O PET scans. Excellent regional test–retest variability was observed for CBF, CMRO2, and OEF. Variability of absolute CBF and OEF measurements is probably affected by physiological day-to-day variability of CBF.
PMCID: PMC3128261  PMID: 20700768
Parametric; CBF; CMRO2; OEF; PET
17.  Cognition in the Early Stage of Type 2 Diabetes 
Diabetes Care  2009;32(7):1261-1265.
Type 2 diabetes is known to be associated with decrements in memory and executive functions and information-processing speed. It is less clear, however, at which stage of diabetes these cognitive decrements develop and how they progress over time. In this study, we investigated cognitive functioning of patients with recent screen-detected type 2 diabetes, thus providing insight into the nature and severity of cognitive decrements in the early stage of the disease. Possible risk factors were also addressed.
Included in this study were 183 diabetic patients from a previously established study cohort and 69 control subjects. A full neuropsychological assessment, addressing six cognitive domains, was made for each participant. Raw test scores were standardized into z scores per domain and compared between the groups. Possible risk factors for cognitive decrements were examined with multivariate linear regression.
Relative to scores for the control group, mean z scores were between 0.01 and 0.2 lower in the diabetic group across all domains, but after adjustment for differences in IQ between patients and control subjects, only memory performance was significantly reduced (mean difference −0.15 [95% CI −0.28 to −0.03]). A history of macrovascular disease and current smoking were significant determinants of slower information-processing speed in patients with diabetes.
This study shows that modest cognitive decrements are already present at the early stage of type 2 diabetes. A history of macrovascular disease and smoking are significant risk factors for some early decrements.
PMCID: PMC2699741  PMID: 19366968
18.  Bilateral carotid artery occlusion with transient or moderately disabling ischaemic stroke: clinical features and long-term outcome 
Journal of Neurology  2009;256(10):1728-1735.
Information on the prognosis of patients with transient ischaemic attack or moderately disabling ischaemic stroke associated with bilateral internal carotid artery (ICA) occlusion is scarce. We prospectively studied 57 consecutive patients (46 men; mean age 60 ± 9 years) with bilateral ICA occlusion who had presented with unilateral transient or moderately disabling cerebral or retinal ischaemic symptoms. We determined the long-term risk of recurrent ischaemic stroke and the composite outcome of stroke, myocardial infarction or vascular death. Four patients had a recurrent ischaemic stroke during a mean follow-up of 5.9 years, resulting in an annual stroke rate of 1.2% (95% confidence interval (CI) 0.3–3.1). Risk factors for recurrent ischaemic stroke could not be identified. Eighteen patients suffered a stroke, myocardial infarction or vascular death, resulting in an annual rate for major vascular events of 5.3% (95% CI 3.1–8.3). Age and a history of ischaemic heart disease were significant risk factors for future vascular events. Patients with transient or moderately disabling symptoms of cerebral or retinal ischaemia associated with bilateral ICA occlusion have a relatively low risk of recurrent ischaemic stroke. Although this study was not designed to compare conservative treatment with surgical intervention, the favourable outcome suggests that a policy of medical therapy and control of risk factors may be justified in these patients.
PMCID: PMC2758212  PMID: 19488672
Carotid artery diseases; Stroke; Collateral circulation; Follow-up studies
19.  Correction: PAIS: paracetamol (acetaminophen) in stroke; protocol for a randomized, double blind clinical trial. [ISCRTN74418480] 
The Paracetamol (Acetaminophen) In Stroke (PAIS) study is a phase III multicenter, double blind, randomized, placebo-controlled clinical trial of high-dose acetaminophen in patients with acute stroke. The trial compares treatment with a daily dose of 6 g acetaminophen, started within 12 hours after the onset of symptoms, with matched placebo. The purpose of this study is to assess whether treatment with acetaminophen for 3 days will result in improved functional outcome through a modest reduction in body temperature and prevention of fever.
The previously planned statistical analysis based on a dichotomization of the scores on the modified Rankin Scale (mRS) may not make the most efficient use of the available baseline information. Therefore, the planned primary analysis of the PAIS study has been changed from fixed dichotomization of the mRS to a sliding dichotomy analysis.
Instead of taking a single definition of good outcome for all patients, the definition is tailored to each individual patient's baseline prognosis on entry into the trial.
The protocol change was initiated because of both advances in statistical approaches and to increase the efficiency of the trial by improving statistical power.
Trial Registration
Current Controlled Trials [ISCRTN74418480]
PMCID: PMC2600816  PMID: 18983661
20.  A pilot study of rivastigmine in the treatment of delirium after stroke: A safe alternative 
BMC Neurology  2008;8:34.
Delirium is a common disorder in the early phase of stroke. Given the presumed cholinergic deficiency in delirium, we tested treatment with the acetylcholinesterase inhibitor rivastigmine.
This pilot study was performed within an epidemiological study. In 527 consecutive stroke patients presence of delirium was assessed during the first week with the confusion assessment method. Severity was scored with the delirium rating scale (DRS). Sixty-two patients developed a delirium in the acute phase of stroke. Only patients with a severe and persistent delirium (defined as a DRS of 12 or more for more than 24 hours) were enrolled in the present study. In total 26 fulfilled these criteria of whom 17 were treated with orally administered rivastigmine with a total dose between 3 and 12 mg a day. Eight patients could not be treated because of dysphagia and one because of early discharge.
No major side effects were recorded. In 16 patients there was a considerable decrease in severity of delirium. The mean DRS declined from 14.8 on day one to 8.5 after therapy and 5.6 after tapering. The mean duration of delirium was 6.7 days (range; 2–17).
Rivastigmine is safe in stroke patients with delirium even after rapid titration. In the majority of patients the delirium improved after treatment. A randomized controlled trial is needed to establish the usefulness of rivastigmine in delirium after stroke.
Trial registration
Nederlands Trial Register NTR1395
PMCID: PMC2556687  PMID: 18803862
21.  Hemicraniectomy after middle cerebral artery infarction with life-threatening Edema trial (HAMLET). Protocol for a randomised controlled trial of decompressive surgery in space-occupying hemispheric infarction 
Trials  2006;7:29.
Patients with a hemispheric infarct and massive space-occupying brain oedema have a poor prognosis. Despite maximal conservative treatment, the case fatality rate may be as high as 80%, and most survivors are left severely disabled. Non-randomised studies suggest that decompressive surgery reduces mortality substantially and improves functional outcome of survivors. This study is designed to compare the efficacy of decompressive surgery to improve functional outcome with that of conservative treatment in patients with space-occupying supratentorial infarction
The study design is that of a multi-centre, randomised clinical trial, which will include 112 patients aged between 18 and 60 years with a large hemispheric infarct with space-occupying oedema that leads to a decrease in consciousness. Patients will be randomised to receive either decompressive surgery in combination with medical treatment or best medical treatment alone. Randomisation will be stratified for the intended mode of conservative treatment (intensive care or stroke unit care). The primary outcome measure will be functional outcome, as determined by the score on the modified Rankin Scale, at one year.
PMCID: PMC1570365  PMID: 16965617
22.  PAIS: paracetamol (acetaminophen) in stroke; protocol for a randomized, double blind clinical trial. [ISCRTN 74418480] 
In patients with acute stroke, increased body temperature is associated with large lesion volumes, high case fatality, and poor functional outcome. A 1°C increase in body temperature may double the odds of poor outcome. Two randomized double-blind clinical trials in patients with acute ischemic stroke have shown that treatment with a daily dose of 6 g acetaminophen (paracetamol) results in a small but rapid and potentially worthwhile reduction of 0.3°C (95% CI: 0.1–0.5) in body temperature. We set out to test the hypothesis that early antipyretic therapy reduces the risk of death or dependency in patients with acute stroke, even if they are normothermic.
Paracetamol (Acetaminophen) In Stroke (PAIS) is a randomized, double-blind clinical trial, comparing high-dose acetaminophen with placebo in 2500 patients. Inclusion criteria are a clinical diagnosis of hemorrhagic or ischemic stroke and the possibility to start treatment within 12 hours from onset of symptoms. The study will have a power of 86% to detect an absolute difference of 6% in the risk of death or dependency at three months, and a power of 72% to detect an absolute difference of 5%, at a 5% significance level.
This is a simple trial, with a drug that only has a small effect on body temperature in normothermic patients. However, when lowering body temperature with acetaminophen does have the expected effectiveness, 20 patients will have to be treated to prevent dependency or death in one.
PMCID: PMC1208871  PMID: 16109181
23.  Effect of paracetamol (acetaminophen) and ibuprofen on body temperature in acute ischemic stroke PISA, a phase II double-blind, randomized, placebo-controlled trial [ISRCTN98608690] 
Body temperature is a strong predictor of outcome in acute stroke. In a previous randomized trial we observed that treatment with high-dose acetaminophen (paracetamol) led to a reduction of body temperature in patients with acute ischemic stroke, even when they had no fever. The purpose of the present trial was to study whether this effect of acetaminophen could be reproduced, and whether ibuprofen would have a similar, or even stronger effect.
Seventy-five patients with acute ischemic stroke confined to the anterior circulation were randomized to treatment with either 1000 mg acetaminophen, 400 mg ibuprofen, or placebo, given 6 times daily during 5 days. Treatment was started within 24 hours from the onset of symptoms. Body temperatures were measured at 2-hour intervals during the first 24 hours, and at 6-hour intervals thereafter.
No difference in body temperature at 24 hours was observed between the three treatment groups. However, treatment with high-dose acetaminophen resulted in a 0.3°C larger reduction in body temperature from baseline than placebo treatment (95% CI: 0.0 to 0.6 °C). Acetaminophen had no significant effect on body temperature during the subsequent four days compared to placebo, and ibuprofen had no statistically significant effect on body temperature during the entire study period.
Treatment with a daily dose of 6000 mg acetaminophen results in a small, but potentially worthwhile decrease in body temperature after acute ischemic stroke, even in normothermic and subfebrile patients. Further large randomized clinical trials are needed to study whether early reduction of body temperature leads to improved outcome.
PMCID: PMC152640  PMID: 12657165
24.  Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12 
Neurology  2014;83(8):678-685.
To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases.
Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico “look-up” of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls.
In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07–1.13], p = 7.12 × 10−11) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90–1.17], p = 0.695).
Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.
PMCID: PMC4150131  PMID: 25031287

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