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Didier Leys - Top 30 Publications

Cervical artery dissection in patients ≥60 years: Often painless, few mechanical triggers.

In a cohort of patients diagnosed with cervical artery dissection (CeAD), to determine the proportion of patients aged ≥60 years and compare the frequency of characteristics (presenting symptoms, risk factors, and outcome) in patients aged <60 vs ≥60 years.

Stroke occurring in patients with cognitive impairment or dementia.

To determine how pre-stroke cognitive impairment can be detected, its mechanism, and influence on outcome and management.

The management of acute cerebral ischaemia is now just a matter of organization. For spontaneous intracerebral hemorrhage, all has still to be done….

Vascular Cognitive Impairment.

Cerebrovascular disease typically manifests with stroke, cognitive impairment, or both. Vascular cognitive impairment refers to all forms of cognitive disorder associated with cerebrovascular disease, regardless of the specific mechanisms involved. It encompasses the full range of cognitive deficits from mild cognitive impairment to dementia. In principle, any of the multiple causes of clinical stroke can cause vascular cognitive impairment. Recent work further highlights a role of microinfarcts, microhemorrhages, strategic white matter tracts, loss of microstructural tissue integrity, and secondary neurodegeneration. Vascular brain injury results in loss of structural and functional connectivity and, hence, compromise of functional networks within the brain. Vascular cognitive impairment is common both after stroke and in stroke-free individuals presenting to dementia clinics, and vascular pathology frequently coexists with neurodegenerative pathology, resulting in mixed forms of mild cognitive impairment or dementia. Vascular dementia is now recognized as the second most common form of dementia after Alzheimer's disease, and there is increasing awareness that targeting vascular risk may help to prevent dementia, even of the Alzheimer type. Recent advances in neuroimaging, neuropathology, epidemiology, and genetics have led to a deeper understanding of how vascular disease affects cognition. These new findings provide an opportunity for the present reappraisal of vascular cognitive impairment. We further briefly address current therapeutic concepts.

Sex Differences and Functional Outcome After Intravenous Thrombolysis.

Women have a worse outcome after stroke compared with men, although in intravenous thrombolysis (IVT)-treated patients, women seem to benefit more. Besides sex differences, age has also a possible effect on functional outcome. The interaction of sex on the functional outcome in IVT-treated patients in relation to age remains complex. The purpose of this study was to compare outcome after IVT between women and men with regard to age in a large multicenter European cohort reflecting daily clinical practice of acute stroke care.

STROKOG (stroke and cognition consortium): An international consortium to examine the epidemiology, diagnosis, and treatment of neurocognitive disorders in relation to cerebrovascular disease.

The Stroke and Cognition consortium (STROKOG) aims to facilitate a better understanding of the determinants of vascular contributions to cognitive disorders and help improve the diagnosis and treatment of vascular cognitive disorders (VCD).

Post-stroke dementia - a comprehensive review.

Post-stroke dementia (PSD) or post-stroke cognitive impairment (PSCI) may affect up to one third of stroke survivors. Various definitions of PSCI and PSD have been described. We propose PSD as a label for any dementia following stroke in temporal relation. Various tools are available to screen and assess cognition, with few PSD-specific instruments. Choice will depend on purpose of assessment, with differing instruments needed for brief screening (e.g., Montreal Cognitive Assessment) or diagnostic formulation (e.g., NINDS VCI battery). A comprehensive evaluation should include assessment of pre-stroke cognition (e.g., using Informant Questionnaire for Cognitive Decline in the Elderly), mood (e.g., using Hospital Anxiety and Depression Scale), and functional consequences of cognitive impairments (e.g., using modified Rankin Scale). A large number of biomarkers for PSD, including indicators for genetic polymorphisms, biomarkers in the cerebrospinal fluid and in the serum, inflammatory mediators, and peripheral microRNA profiles have been proposed. Currently, no specific biomarkers have been proven to robustly discriminate vulnerable patients ('at risk brains') from those with better prognosis or to discriminate Alzheimer's disease dementia from PSD. Further, neuroimaging is an important diagnostic tool in PSD. The role of computerized tomography is limited to demonstrating type and location of the underlying primary lesion and indicating atrophy and severe white matter changes. Magnetic resonance imaging is the key neuroimaging modality and has high sensitivity and specificity for detecting pathological changes, including small vessel disease. Advanced multi-modal imaging includes diffusion tensor imaging for fiber tracking, by which changes in networks can be detected. Quantitative imaging of cerebral blood flow and metabolism by positron emission tomography can differentiate between vascular dementia and degenerative dementia and show the interaction between vascular and metabolic changes. Additionally, inflammatory changes after ischemia in the brain can be detected, which may play a role together with amyloid deposition in the development of PSD. Prevention of PSD can be achieved by prevention of stroke. As treatment strategies to inhibit the development and mitigate the course of PSD, lowering of blood pressure, statins, neuroprotective drugs, and anti-inflammatory agents have all been studied without convincing evidence of efficacy. Lifestyle interventions, physical activity, and cognitive training have been recently tested, but large controlled trials are still missing.

Management of acute cerebral ischaemia.

Stroke is a major public health issue. Many are treatable in the acute stage, provided patients are admitted soon enough. The overall incidence of stroke in Western countries is approximately 2400 per year per million inhabitants, and 80% are due to cerebral ischaemia. The prevalence is approximately 12,000 per million inhabitants. Stroke is associated with increased long-term mortality, handicap, cognitive and behavioural impairments, recurrence, and an increased risk of other types of vascular events. There is strong evidence that stroke patients should be treated in dedicated stroke units; each time 24 patients are treated in a stroke unit, instead of a conventional ward, one death and one dependence are prevented. This effect does not depend on age, severity, and the stroke subtype. For this reason, stroke unit care is the cornerstone of the treatment of stroke, aiming at the detection and management of life-threatening emergencies, stabilization of most physiological parameters, and prevention of early complications. In cerebral ischaemia, besides this general management, specific therapies include intravenous recombinant tissue plasminogen activator, given as soon as possible and before 4.5hours, mechanical thrombectomy on top of rt-PA or alone in case of contra-indication to rt-PA, in patients with proximal large-vessel occlusion, aspirin 300mg, immediately or after 24hours in case of thrombolysis, and, in a few patients, decompressive surgery.

Proportion of single-chain recombinant tissue plasminogen activator and outcome after stroke.

To determine whether the ratio single chain (sc)/(sc + 2 chain [tc]) recombinant tissue plasminogen activator (rtPA) influences outcomes in patients with cerebral ischemia.

Cognitive status after intracerebral haemorrhage - Authors' reply.

Lobar intracerebral haematomas: Neuropathological and 7.0-tesla magnetic resonance imaging evaluation.

The Boston criteria for cerebral amyloid angiopathy (CAA) need validation by neuropathological examination in patients with lobar cerebral haematomas (LCHs). In "vivo" 1.5-tesla magnetic resonance imaging (MRI) is unreliable to detect the age-related signal changes in LCHs. This post-mortem study investigates the validity of the Boston criteria in brains with LCHs and the signal changes during their time course with 7.0-tesla MRI.

Author Response.

The Topography of Cortical Microinfarcts in Neurodegenerative Diseases and in Vascular Dementia: A Postmortem 7.0-Tesla Magnetic Resonance Imaging Study.

Cortical microinfarcts (CoMIs) are considered as barely visible lesions in clinical-neuroradiological correlation studies. On postmortem 7.0-tesla MRI, however, CoMIs of different size are easily detected.

The incidence of post-mortem neurodegenerative and cerebrovascular pathology in mixed dementia.

The clinical picture of dementia in most aged patients is due to a combination of different neurodegenerative processes and frequently associated to cerebrovascular lesions. They are called mixed dementia (MixD) cases, to be differentiated from those with pure vascular dementia (VaD) and those with Alzheimer's dementia (AD). The present study compares the frequency of different associated lesions in these disease groups.

Orolingual Angioedema During or After Thrombolysis for Cerebral Ischemia.

Orolingual angioedema (OLAE) is a life-threatening complication of intravenous thrombolysis. Our objective was to compare outcomes of patients with and without OLAE.

Dementia risk after spontaneous intracerebral haemorrhage: a prospective cohort study.

Dementia occurs in at least 10% of patients within 1 year after stroke. However, the risk of dementia after spontaneous intracerebral haemorrhage that accounts for about 15% of all strokes has not been investigated in prospective studies. We aimed to determine the incidence of dementia and risk factors after an intracerebral haemorrhage.

close: Closure of patent foramen ovale, oral anticoagulants or antiplatelet therapy to prevent stroke recurrence: Study design.

Currently available data do not provide definitive evidence on the comparative benefits of closure of patent foramen ovale, oral anticoagulants and antiplatelet therapy in patients with patent foramen ovale-associated cryptogenic stroke

Intravenous Thrombolysis in Patients Dependent on the Daily Help of Others Before Stroke.

We compared outcome and complications in patients with stroke treated with intravenous thrombolysis (IVT) who could not live alone without help of another person before stroke (dependent patients) versus independent ones.

European Cooperative Acute Stroke Study-4: Extending the time for thrombolysis in emergency neurological deficits ECASS-4: ExTEND.

Thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) is an effective and approved therapy for acute ischemic stroke within 4.5 h of onset except for USA, Canada, Croatia, and Moldovia with a current 3 h label. We hypothesized that ischemic stroke patients selected with significant penumbral mismatch on magnetic resonance imaging (MRI) at 4.5-9 h after onset of stroke will have improved clinical outcomes when given intravenous rt-PA (alteplase) compared to placebo.

Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2.

Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years.

Detection of Cortical Microbleeds in Postmortem Brains of Patients with Lewy Body Dementia: A 7.0-Tesla Magnetic Resonance Imaging Study with Neuropathological Correlates.

It is unclear whether associated cerebrovascular pathology contributes to the clinical spectrum of Lewy body dementia (LBD).

Higher neutrophil counts before thrombolysis for cerebral ischemia predict worse outcomes.

To determine whether higher neutrophil counts before IV recombinant tissue plasminogen activator (rtPA) administration in ischemic stroke (IS) patients are associated with symptomatic intracerebral hemorrhages (sICH) and worse outcomes at 3 months.

Individual patient data meta-analysis of antiplatelet regimens after noncardioembolic stroke or TIA: rationale and design.

The Cerebrovascular Antiplatelet Trialists' Collaborative Group was formed to obtain and analyze individual patient data from the major randomized trials of common antiplatelet regimens after cerebral ischemia. Although the risk of stroke can be reduced by antiplatelet drugs, there continues to be uncertainty about the balance of risk and benefits of different antiplatelet regimens for an individual patient.

Influence of previous physical activity on the outcome of patients treated by thrombolytic therapy for stroke.

Physical activity prevents stroke and is associated with less severe strokes. The neuroprotective effect in patients treated with intravenous (i.v.) recombinant tissue plasminogen activator (rt-PA), remains uncertain. We aimed at evaluating the relationship between previous physical activity and outcomes in stroke patients treated with i.v. rt-PA. OPHELIE-SPORT was a prospective observational multicenter study conducted in French and Japanese stroke patients treated with i.v. rt-PA. We evaluated the presence, weekly duration (<2, 2-5, >5 h) and intensity (light, moderate, heavy) of previous leisure-time physical activity according to standardized criteria. The primary end-point was an excellent outcome [modified Rankin Scale (mRS) 0-1 or similar to the pre-stroke mRS] after 3 months. Secondary end-points were good outcome (mRS 0-2 or similar to the pre-stroke mRS), and death. Of 519 patients, 74 (14.3 %) had regular physical activity before stroke. They were 14 years younger (p < 0.001), treated 25 min earlier (p = 0.004) and more likely to be men, free of pre-stroke handicap (mRS = 0), atrial fibrillation, arterial hypertension, and diabetes mellitus. National Institutes of Health Stroke Scale scores, at baseline (p = 0.183) and 24 h later (p = 0.203), did not differ between patients with and without physical activity. After adjustment on confounders, there was no association between previous leisure-time physical activity and outcome. Outcomes 3 months after treatment of cerebral ischaemia with i.v. rt-PA are not influenced by previous physical activity.

Influence of glycaemic control on the outcomes of patients treated by intravenous thrombolysis for cerebral ischaemia.

Whether the glycaemic control during the first hours of cerebral ischaemia treated by thrombolysis influences outcomes remains unsettled. We aimed at evaluating the quality of the glycaemic control and whether patients with well-controlled glycaemia after thrombolysis for acute cerebral ischaemia have better outcomes. We retrospectively analysed data prospectively collected in consecutive stroke patients who received i.v. thrombolysis at the Lille University Hospital. Patients with glycaemia >1.6 g/l (8.9 mmol/l) at any point during the first 48 h received insulin. We used 2 definitions of well controlled glycaemia: (i) "well controlled 100 %" when 100 % glycaemia were <1.6 g/l (8.9 mmol/l), and (ii) "well controlled 70 %" when at least 70 % glycaemia were <1.6 g/l (8.9 mmol/l). The outcome measures at 3 months were (1) independence [modified Rankin scale (mRS) score 0 or 1], (2) absence of handicap (mRS 0-2), (3) death, and (4) symptomatic intracerebral haemorrhage (sICH). Of 875 consecutive patients, 657 (75.2 %) were considered as well controlled with a threshold at 100 % and 736 (84.2 %) with a threshold at 70 %. The glycaemic control was not independently associated with any of the four outcome measures. In patients treated by insulin, hypoglycaemic events were rare (2.1 % of all patients) and of moderate intensity [>0.5 g/l (2.8 mmol/l)]. The quality of the glycaemic control was not associated with outcomes in patients treated by thrombolysis. A possible explanation is that the glycaemic control after thrombolysis has minor influence compared with glycaemic control before thrombolysis when the artery is not yet re-open and the penumbra area at maximum.

Microbleed Status and 3-Month Outcome After Intravenous Thrombolysis in 717 Patients With Acute Ischemic Stroke.

Whether cerebral microbleeds (CMBs) detected on pretreatment magnetic resonance imaging increase the risks of symptomatic intracranial hemorrhage (sICH) and, most importantly, poor outcome in patients treated by intravenous thrombolysis for acute ischemic stroke is still debated. We assessed the effect of CMB presence and burden on 3-month modified Rankin Scale and sICH in a multicentric cohort.

The European Stroke Organisation Guidelines: a standard operating procedure.

In 2008, the recently founded European Stroke Organisation published its guidelines for the management of ischemic stroke and transient ischemic attack. This highly cited document was translated in several languages and was updated in 2009. Since then, the European Stroke Organisation has published guidelines for the management of intracranial aneurysms and subarachnoidal hemorrhage, for the establishment of stroke units and stroke centers, and recently for the management of intracerebral hemorrhage. In recent years, the methodology for the development of guidelines has evolved significantly. To keep pace with this progress and driven by the strong determination of the European Stroke Organisation to further promote stroke management, education, and research, the European Stroke Organisation decided to delineate a detailed standard operating procedure for its guidelines. There are two important cornerstones in this standard operating procedure: The first is the implementation of the Grading of Recommendations Assessment, Development, and Evaluation methodology for the development of its Guideline Documents. The second one is the decision of the European Stroke Organisation to move from the classical model of a single Guideline Document about a major topic (e.g. management of ischemic stroke) to focused modules (i.e. subdivisions of a major topic). This will enable the European Stroke Organisation to react faster when new developments in a specific stroke field occur and update its recommendations on the related module rather swiftly; with the previous approach of a single large Guideline Document, its entire revision had to be completed before an updated publication, delaying the production of up-to-date guidelines. After discussion within the European Stroke Organisation Guidelines Committee and significant input from European Stroke Organisation members as well as methodologists and analysts, this document presents the official standard operating procedure for the development of the Guideline Documents of the European Stroke Organisation.

Improvement of stroke management: The most important might still have to come.

Epidemiology, pathophysiology, diagnosis, and management of intracranial artery dissection.

Spontaneous intracranial artery dissection is an uncommon and probably underdiagnosed cause of stroke that is defined by the occurrence of a haematoma in the wall of an intracranial artery. Patients can present with headache, ischaemic stroke, subarachnoid haemorrhage, or symptoms associated with mass effect, mostly on the brainstem. Although intracranial artery dissection is less common than cervical artery dissection in adults of European ethnic origin, intracranial artery dissection is reportedly more common in children and in Asian populations. Risk factors and mechanisms are poorly understood, and diagnosis is challenging because characteristic imaging features can be difficult to detect in view of the small size of intracranial arteries. Therefore, multimodal follow-up imaging is often needed to confirm the diagnosis. Treatment of intracranial artery dissections is empirical in the absence of data from randomised controlled trials. Most patients with subarachnoid haemorrhage undergo surgical or endovascular treatment to prevent rebleeding, whereas patients with intracranial artery dissection and cerebral ischaemia are treated with antithrombotics. Prognosis seems worse in patients with subarachnoid haemorrhage than in those without.

Which factors influence the resort to surrogate consent in stroke trials, and what are the patient outcomes in this context?

The provision of informed consent is a prerequisite for inclusion of a patient in a clinical research project. In some countries, the legislation on clinical research authorizes a third person to provide informed consent if the patient is unable to do so directly (i.e. surrogate consent). This is the case during acute stroke, when the symptoms may prevent the patient from providing informed consent and thus require a third party to be approached. Identification of factors associated with the medical team's decision to resort to surrogate consent may (i) help the care team during the inclusion process and (ii) enable the patient's family circle to be better informed (and thus feel less guilty) about providing surrogate consent.