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1.  Ischemic Brain Lesions After Carotid Artery Stenting Increase Future Cerebrovascular Risk 
Background
Brain lesions on diffusion-weighted imaging (DWI) are frequently found after carotid artery stenting (CAS), but their clinical relevance remains unclear.
Objectives
This study sought to investigate whether periprocedural ischemic DWI lesions after CAS or carotid endarterectomy (CEA) are associated with an increased risk of recurrent cerebrovascular events.
Methods
In the magnetic resonance imaging (MRI) substudy of ICSS (International Carotid Stenting Study), 231 patients with symptomatic carotid stenosis were randomized to undergo CAS (n = 124) or CEA (n = 107). MRIs were performed 1 to 7 days before and 1 to 3 days after treatment. The primary outcome event was stroke or transient ischemic attack in any territory occurring between the post-treatment MRI and the end of follow-up. Time to occurrence of the primary outcome event was compared between patients with (DWI+) and without (DWI–) new DWI lesions on the post-treatment scan in the CAS and CEA groups separately.
Results
Median time of follow-up was 4.1 years (interquartile range: 3.0 to 5.2). In the CAS group, recurrent stroke or transient ischemic attack occurred more often among DWI+ patients (12 of 62) than among DWI– patients (6 of 62), with a cumulative 5-year incidence of 22.8% (standard error [SE]: 7.1%) and 8.8% (SE: 3.8%), respectively (unadjusted hazard ratio: 2.85; 95% confidence interval: 1.05 to 7.72; p = 0.04). In DWI+ and DWI– patients, 8 and 2 events, respectively, occurred within 6 months after treatment. In the CEA group, there was no difference in recurrent cerebrovascular events between DWI+ and DWI– patients.
Conclusions
Ischemic brain lesions discovered on DWI after CAS seem to be a marker of increased risk for recurrent cerebrovascular events. Patients with periprocedural DWI lesions might benefit from more aggressive and prolonged antiplatelet therapy after CAS. (A Randomised Comparison of the Risks, Benefits and Cost Effectiveness of Primary Carotid Stenting With Carotid Endarterectomy: International Carotid Stenting Study; ISRCTN25337470)
doi:10.1016/j.jacc.2014.11.038
PMCID: PMC4323145  PMID: 25677309
carotid stenosis; DWI lesions; endarterectomy; long-term outcome; stenting; ARWMC, age-related white matter changes; CAS, carotid artery stenting; CEA, carotid endarterectomy; DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging; TIA, transient ischemic attack
2.  Long-term outcomes after stenting versus endarterectomy for treatment of symptomatic carotid stenosis: the International Carotid Stenting Study (ICSS) randomised trial 
Lancet  2015;385(9967):529-538.
Summary
Background
Stenting is an alternative to endarterectomy for treatment of carotid artery stenosis, but long-term efficacy is uncertain. We report long-term data from the randomised International Carotid Stenting Study comparison of these treatments.
Methods
Patients with symptomatic carotid stenosis were randomly assigned 1:1 to open treatment with stenting or endarterectomy at 50 centres worldwide. Randomisation was computer generated centrally and allocated by telephone call or fax. Major outcomes were assessed by an independent endpoint committee unaware of treatment assignment. The primary endpoint was fatal or disabling stroke in any territory after randomisation to the end of follow-up. Analysis was by intention to treat ([ITT] all patients) and per protocol from 31 days after treatment (all patients in whom assigned treatment was completed). Functional ability was rated with the modified Rankin scale. This study is registered, number ISRCTN25337470.
Findings
1713 patients were assigned to stenting (n=855) or endarterectomy (n=858) and followed up for a median of 4·2 years (IQR 3·0–5·2, maximum 10·0). Three patients withdrew immediately and, therefore, the ITT population comprised 1710 patients. The number of fatal or disabling strokes (52 vs 49) and cumulative 5-year risk did not differ significantly between the stenting and endarterectomy groups (6·4% vs 6·5%; hazard ratio [HR] 1·06, 95% CI 0·72–1·57, p=0·77). Any stroke was more frequent in the stenting group than in the endarterectomy group (119 vs 72 events; ITT population, 5-year cumulative risk 15·2% vs 9·4%, HR 1·71, 95% CI 1·28–2·30, p<0·001; per-protocol population, 5-year cumulative risk 8·9% vs 5·8%, 1·53, 1·02–2·31, p=0·04), but were mainly non-disabling strokes. The distribution of modified Rankin scale scores at 1 year, 5 years, or final follow-up did not differ significantly between treatment groups.
Interpretation
Long-term functional outcome and risk of fatal or disabling stroke are similar for stenting and endarterectomy for symptomatic carotid stenosis.
Funding
Medical Research Council, Stroke Association, Sanofi-Synthélabo, European Union.
doi:10.1016/S0140-6736(14)61184-3
PMCID: PMC4322188  PMID: 25453443
3.  Ipsilateral foetal-type posterior cerebral artery is associated with cognitive decline after carotid revascularisation 
BMC Neurology  2014;14:84.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1471-2377-14-84
PMCID: PMC4021499  PMID: 24739135
Angioplasty and stenting; Carotid endarterectomy; Symptomatic carotid stenosis; Cognition; Circle of Willis
4.  Effect of white-matter lesions on the risk of periprocedural stroke after carotid artery stenting versus endarterectomy in the International Carotid Stenting Study (ICSS): a prespecified analysis of data from a randomised trial 
Lancet Neurology  2013;12(9):866-872.
Summary
Background
Findings from randomised trials have shown a higher early risk of stroke after carotid artery stenting than after carotid endarterectomy. We assessed whether white-matter lesions affect the perioperative risk of stroke in patients treated with carotid artery stenting versus carotid endarterectomy.
Methods
Patients with symptomatic carotid artery stenosis included in the International Carotid Stenting Study (ICSS) were randomly allocated to receive carotid artery stenting or carotid endarterectomy. Copies of baseline brain imaging were analysed by two investigators, who were masked to treatment, for the severity of white-matter lesions using the age-related white-matter changes (ARWMC) score. Randomisation was done with a computer-generated sequence (1:1). Patients were divided into two groups using the median ARWMC. We analysed the risk of stroke within 30 days of revascularisation using a per-protocol analysis. ICSS is registered with controlled-trials.com, number ISRCTN 25337470.
Findings
1036 patients (536 randomly allocated to carotid artery stenting, 500 to carotid endarterectomy) had baseline imaging available. Median ARWMC score was 7, and patients were dichotomised into those with a score of 7 or more and those with a score of less than 7. In patients treated with carotid artery stenting, those with an ARWMC score of 7 or more had an increased risk of stroke compared with those with a score of less than 7 (HR for any stroke 2·76, 95% CI 1·17–6·51; p=0·021; HR for non-disabling stroke 3·00, 1·10–8·36; p=0·031), but we did not see a similar association in patients treated with carotid endarterectomy (HR for any stroke 1·18, 0·40–3·55; p=0·76; HR for disabling or fatal stroke 1·41, 0·38–5·26; p=0·607). Carotid artery stenting was associated with a higher risk of stroke compared with carotid endarterectomy in patients with an ARWMC score of 7 or more (HR for any stroke 2·98, 1·29–6·93; p=0·011; HR for non-disabling stroke 6·34, 1·45–27·71; p=0·014), but there was no risk difference in patients with an ARWMC score of less than 7.
Interpretation
The presence of white-matter lesions on brain imaging should be taken into account when selecting patients for carotid revascularisation. Carotid artery stenting should be avoided in patients with more extensive white-matter lesions, but might be an acceptable alternative to carotid endarterectomy in patients with less extensive lesions.
Funding
Medical Research Council, the Stroke Association, Sanofi-Synthélabo, the European Union Research Framework Programme 5.
doi:10.1016/S1474-4422(13)70135-2
PMCID: PMC3744748  PMID: 23849948
5.  Different strokes for different folks: the rich diversity of animal models of focal cerebral ischemia 
No single animal model is able to encompass all of the variables known to affect human ischemic stroke. This review highlights the major strengths and weaknesses of the most commonly used animal models of acute ischemic stroke in the context of matching model and experimental aim. Particular emphasis is placed on the relationships between outcome and underlying vascular variability, physiologic control, and use of models of comorbidity. The aim is to provide, for novice and expert alike, an overview of the key controllable determinants of experimental stroke outcome to help ensure the most effective application of animal models to translational research.
doi:10.1038/jcbfm.2010.66
PMCID: PMC2949237  PMID: 20485296
animal models; diabetes; hypertension; physiologic control; stroke; vascular variability
6.  Different strokes for different folks: the rich diversity of animal models of focal cerebral ischemia 
No single animal model is able to encompass all of the variables known to affect human ischemic stroke. This review highlights the major strengths and weaknesses of the most commonly used animal models of acute ischemic stroke in the context of matching model and experimental aim. Particular emphasis is placed on the relationships between outcome and underlying vascular variability, physiologic control, and use of models of comorbidity. The aim is to provide, for novice and expert alike, an overview of the key controllable determinants of experimental stroke outcome to help ensure the most effective application of animal models to translational research.
doi:10.1038/jcbfm.2010.66
PMCID: PMC2949237  PMID: 20485296
animal models; diabetes; hypertension; physiologic control; stroke; vascular variability
7.  Therapeutic hypothermia for acute ischemic stroke: ready to start large randomized trials? 
Therapeutic hypothermia is a means of neuroprotection well established in the management of acute ischemic brain injuries such as anoxic encephalopathy after cardiac arrest and perinatal asphyxia. As such, it is the only neuroprotective strategy for which there is robust evidence for efficacy. Although there is overwhelming evidence from animal studies that cooling also improves outcome after focal cerebral ischemia, this has not been adequately tested in patients with acute ischemic stroke. There are still some uncertainties about crucial factors relating to the delivery of hypothermia, and the resolution of these would allow improvements in the design of phase III studies in these patients and improvements in the prospects for successful translation. In this study, we discuss critical issues relating first to the targets for therapy including the optimal depth and duration of cooling, second to practical issues including the methods of cooling and the management of shivering, and finally, of factors relating to the design of clinical trials. Consideration of these factors should inform the development of strategies to establish beyond doubt the place of hypothermia in the management of acute ischemic stroke.
doi:10.1038/jcbfm.2010.44
PMCID: PMC2949207  PMID: 20354545
acute stroke; animal models; clinical trials; hypothermia; shivering MR spectroscopy
8.  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.
doi:10.1007/s00415-010-5756-4
PMCID: PMC3036804  PMID: 20878419
Stroke; Body temperature; Clinical outcome
9.  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.
Objective
To investigate the influence of internal carotid artery (ICA) stenosis on the distribution of blood flow to the caudate nucleus, lentiform nucleus, and thalamus.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1007/s00330-010-1952-y
PMCID: PMC3047207  PMID: 20853001
Magnetic resonance imaging; Cerebral hemodynamics; Perfusion; Basal ganglia; Carotid artery stenosis
10.  Publication Bias in Reports of Animal Stroke Studies Leads to Major Overstatement of Efficacy 
PLoS Biology  2010;8(3):e1000344.
Publication bias confounds attempts to use systematic reviews to assess the efficacy of various interventions tested in experiments modelling acute ischaemic stroke, leading to a 30% overstatement of efficacy of interventions tested in animals.
The consolidation of scientific knowledge proceeds through the interpretation and then distillation of data presented in research reports, first in review articles and then in textbooks and undergraduate courses, until truths become accepted as such both amongst “experts” and in the public understanding. Where data are collected but remain unpublished, they cannot contribute to this distillation of knowledge. If these unpublished data differ substantially from published work, conclusions may not reflect adequately the underlying biological effects being described. The existence and any impact of such “publication bias” in the laboratory sciences have not been described. Using the CAMARADES (Collaborative Approach to Meta-analysis and Review of Animal Data in Experimental Studies) database we identified 16 systematic reviews of interventions tested in animal studies of acute ischaemic stroke involving 525 unique publications. Only ten publications (2%) reported no significant effects on infarct volume and only six (1.2%) did not report at least one significant finding. Egger regression and trim-and-fill analysis suggested that publication bias was highly prevalent (present in the literature for 16 and ten interventions, respectively) in animal studies modelling stroke. Trim-and-fill analysis suggested that publication bias might account for around one-third of the efficacy reported in systematic reviews, with reported efficacy falling from 31.3% to 23.8% after adjustment for publication bias. We estimate that a further 214 experiments (in addition to the 1,359 identified through rigorous systematic review; non publication rate 14%) have been conducted but not reported. It is probable that publication bias has an important impact in other animal disease models, and more broadly in the life sciences.
Author Summary
Publication bias is known to be a major problem in the reporting of clinical trials, but its impact in basic research has not previously been quantified. Here we show that publication bias is prevalent in reports of laboratory-based research in animal models of stroke, such that data from as many as one in seven experiments remain unpublished. The result of this bias is that systematic reviews of the published results of interventions in animal models of stroke overstate their efficacy by around one third. Nonpublication of data raises ethical concerns, first because the animals used have not contributed to the sum of human knowledge, and second because participants in clinical trials may be put at unnecessary risk if efficacy in animals has been overstated. It is unlikely that this publication bias in the basic sciences is restricted to the area we have studied, the preclinical modelling of the efficacy of candidate drugs for stroke. A related article in PLoS Medicine (van der Worp et al., doi:10.1371/journal.pmed.1000245) discusses the controversies and possibilities of translating the results of animal experiments into human clinical trials.
doi:10.1371/journal.pbio.1000344
PMCID: PMC2846857  PMID: 20361022
11.  Can Animal Models of Disease Reliably Inform Human Studies? 
PLoS Medicine  2010;7(3):e1000245.
H. Bart van der Worp and colleagues discuss the controversies and possibilities of translating the results of animal experiments into human clinical trials.
doi:10.1371/journal.pmed.1000245
PMCID: PMC2846855  PMID: 20361020
12.  Reprint: Good laboratory practice: preventing introduction of bias at the bench 
As a research community, we have failed to show that drugs, which show substantial efficacy in animal models of cerebral ischemia, can also improve outcome in human stroke. Accumulating evidence suggests this may be due, at least in part, to problems in the design, conduct, and reporting of animal experiments which create a systematic bias resulting in the overstatement of neuroprotective efficacy. Here, we set out a series of measures to reduce bias in the design, conduct and reporting of animal experiments modeling human stroke.
doi:10.1161/STROKEAHA.108.525386
PMCID: PMC2729492  PMID: 18797473
animal models; drug trials; experimental; outcomes; preventing bias; translational research
13.  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.
Background
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
Methods
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.
doi:10.1186/1745-6215-7-29
PMCID: PMC1570365  PMID: 16965617
14.  PAIS: paracetamol (acetaminophen) in stroke; protocol for a randomized, double blind clinical trial. [ISCRTN 74418480] 
Background
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.
Methods/design
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.
Discussion
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.
doi:10.1186/1471-2261-5-24
PMCID: PMC1208871  PMID: 16109181
15.  Effect of paracetamol (acetaminophen) and ibuprofen on body temperature in acute ischemic stroke PISA, a phase II double-blind, randomized, placebo-controlled trial [ISRCTN98608690] 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1471-2261-3-2
PMCID: PMC152640  PMID: 12657165

Results 1-15 (15)