Risk factors associated with progressive lacunar strokes and benefit from dual antiplatelet therapy.

BACKGROUND AND PURPOSE: Early neurological deterioration (END) occurs in 20%-30% of patients with lacunar stroke and challenges their clinical management. This retrospective cohort study analyzed clinical and neuroimaging risk factors predicting the occurrence of END, the functional outcome after END and potential benefit from dual antiplatelet therapy (DAPT) in patients with lacunar strokes. METHODS: Factors associated with END and benefit from DAPT were retrospectively analyzed in 308 patients with lacunar stroke symptoms and detected lacunar infarction by magnetic resonance imaging. END was defined by deterioration of ≥3 total National Institutes of Health Stroke Scale (NIHSS) points, ≥2 NIHSS points for limb paresis or documented deterioration within 5 days after admission. Patients were treated with DAPT according to in-house standards. The primary efficacy end-point for functional outcome was fulfilled if NIHSS at discharge improved after END at least to the score at admission. RESULTS: Male gender [odds ratio (OR) 2.08; 95% confidence interval (CI) 1.09-4.00], higher age (OR = 1.65 per 10 years; 95% CI 1.18-2.31), motor paresis (OR = 18.89, 95% CI 4.66-76.57) and infarction of the internal capsule or basal ganglia (OR = 3.58, 95% CI 1.26-10.14) were associated with an increased risk for END. A larger diameter of infarction (OR = 0.85, 95% CI 0.76-0.95), more microangiopathic lesions (OR = 0.75, 95% CI 0.57-0.99) and pontine localization (OR = 0.29, 95% CI 0.12-0.65) were factors associated with unfavorable functional outcome after END occurred. Localization in the internal capsule or basal ganglia was identified as a significant predictive factor for a benefit from DAPT after END. CONCLUSIONS: Identified clinical and neuroimaging factors predicting END occurrence, functional outcome after END and potential benefit from DAPT might improve the clinical management of patients with lacunar strokes.

Angioplasty in asymptomatic carotid artery stenosis vs. endarterectomy compared to best medical treatment: One-year interim results of SPACE-2.

BACKGROUND: Treatment of individuals with asymptomatic carotid artery stenosis is still handled controversially. Recommendations for treatment of asymptomatic carotid stenosis with carotid endarterectomy (CEA) are based on trials having recruited patients more than 15 years ago. Registry data indicate that advances in best medical treatment (BMT) may lead to a markedly decreasing risk of stroke in asymptomatic carotid stenosis. The aim of the SPACE-2 trial (ISRCTN78592017) was to compare the stroke preventive effects of BMT alone with that of BMT in combination with CEA or carotid artery stenting (CAS), respectively, in patients with asymptomatic carotid artery stenosis of ≥70% European Carotid Surgery Trial (ECST) criteria. METHODS: SPACE-2 is a randomized, controlled, multicenter, open study. A major secondary endpoint was the cumulative rate of any stroke (ischemic or hemorrhagic) or death from any cause within 30 days plus an ipsilateral ischemic stroke within one year of follow-up. Safety was assessed as the rate of any stroke and death from any cause within 30 days after CEA or CAS. Protocol changes had to be implemented. The results on the one-year period after treatment are reported. FINDINGS: It was planned to enroll 3550 patients. Due to low recruitment, the enrollment of patients was stopped prematurely after randomization of 513 patients in 36 centers to CEA (n = 203), CAS (n = 197), or BMT (n = 113). The one-year rate of the major secondary endpoint did not significantly differ between groups (CEA 2.5%, CAS 3.0%, BMT 0.9%; p = 0.530) as well as rates of any stroke (CEA 3.9%, CAS 4.1%, BMT 0.9%; p = 0.256) and all-cause mortality (CEA 2.5%, CAS 1.0%, BMT 3.5%; p = 0.304). About half of all strokes occurred in the peri-interventional period. Higher albeit statistically non-significant rates of restenosis occurred in the stenting group (CEA 2.0% vs. CAS 5.6%; p = 0.068) without evidence of increased stroke rates. INTERPRETATION: The low sample size of this prematurely stopped trial of 513 patients implies that its power is not sufficient to show that CEA or CAS is superior to a modern medical therapy (BMT) in the primary prevention of ischemic stroke in patients with an asymptomatic carotid stenosis up to one year after treatment. Also, no evidence for differences in safety between CAS and CEA during the first year after treatment could be derived. Follow-up will be performed up to five years. Data may be used for pooled analysis with ongoing trials.

Reasons and evolution of non-thrombolysis in acute ischaemic stroke.

INTRODUCTION: Despite increasing evidence of its efficacy in advanced age or in mild or severe strokes, intravenous thrombolysis remains underused for acute ischaemic stroke (AIS). Our aim was to obtain an updated view of reasons for non-thrombolysis and to identify its changing patterns over time. METHODS: This is a retrospective study of prospectively collected data from the Acute Stroke Registry and Analysis of Lausanne (ASTRAL) from the years 2003-2011. Patients admitted with acute stroke in the past 24 hours who had not had thrombolysis were identified; reasons for non-thrombolysis documented in the prospectively entered data were tabulated and analysed for the group as a whole. Data were analysed for the years 2003-2006 and 2007 forward because of changes in contraindications. A subgroup of patients who arrived within the treatment window ≤180 min was separately analysed for reasons for non-thrombolysis. Predictors of non-thrombolysis were investigated via multivariate regression analyses. RESULTS: In the 2019 non-thrombolysed patients the most frequent reasons for non-thrombolysis were admission delays (66.3%), stroke severity (mostly mild) (47.9%) and advanced age (14.1%); 55.9% had more than one exclusion criterion. Among patients arriving ≤180 min after onset, the main reasons were stroke severity and advanced age. After 2006, significantly fewer patients were excluded because of age (OR 2.65, p<0.001) or (mostly mild) stroke severity (OR 10.56, p=0.029). Retrospectively, 18.7% of all non-thrombolysed patients could have been treated because they only had relative contraindications. CONCLUSION: Onset-to-admission delays remain the main exclusion criterion for thrombolysis. Among early arrivals, relative contraindications such as minor stroke severity and advanced age were frequent. Thrombolysis rate increased with the reduction of thrombolysis restrictions (eg, age and stroke severity).

SPACE-2: A Missed Opportunity to Compare Carotid Endarterectomy, Carotid Stenting, and Best Medical Treatment in Patients with Asymptomatic Carotid Stenoses.

BACKGROUND: Because of recent advances in best medical treatment (BMT), it is currently unclear whether any additional surgical or endovascular interventions confer additional benefit, in terms of preventing late ipsilateral carotid territory ischemic stroke in asymptomatic patients with significant carotid stenoses. The aim was to compare the stroke-preventive effects of BMT alone, with that of BMT in combination with carotid endarterectomy (CEA) or carotid artery stenting (CAS) in patients with high grade asymptomatic extracranial carotid artery stenosis. METHODS: SPACE-2 was planned as a three-armed, randomized controlled trial (BMT alone vs. CEA plus BMT vs. CAS plus BMT, ISRCTN 78592017). However, because of slow patient recruitment, the three-arm study design was amended (July 2013) to become two parallel randomized studies (BMT alone vs. CEA plus BMT, and BMT alone vs. CAS plus BMT). RESULTS: The change in study design did not lead to any significant increase in patient recruitment, and trial recruitment ceased after recruiting 513 patients over a 5 year period (CEA vs. BMT (n = 203); CAS vs. BMT (n = 197), and BMT alone (n = 113)). The 30 day rate of death/stroke was 1.97% for patients undergoing CEA, and 2.54% for patients undergoing CAS. No strokes or deaths occurred in the first 30 days after randomization in patients randomized to BMT. There were several potential reasons for the low recruitment rates into SPACE-2, including the ability for referring doctors to refer their patients directly for CEA or CAS outwith the trial, an inability to convince patients (who had come "mentally prepared" that an intervention was necessary) to accept BMT, and other economic constraints. CONCLUSIONS: Because of slow recruitment rates, SPACE-2 had to be stopped after randomizing only 513 patients. The German Research Foundation will provide continued funding to enable follow up of all recruited patients, and it is also planned to include these data in any future meta-analysis prepared by the Carotid Stenosis Trialists Collaboration.

Statins reduce peri-procedural complications in carotid stenting.

BACKGROUND: In primary and secondary prevention, statins significantly reduce cardiovascular and cerebrovascular events. Pre-interventional statin medication shows a benefit in carotid artery stenosis patients treated with endarterectomy; however, there are few data available for patients treated with stent-angioplasty. The aim of this study was to investigate whether pre-interventional statin therapy is associated with decreased peri-interventional risk of stroke, myocardial infarction, and mortality in patients undergoing stent-angioplasty for internal carotid stenosis. METHODS: Data for 344 consecutively documented patients with internal carotid artery stenosis treated with stent-angioplasty in the years 2002-2012 at the same stroke center were collected in a prospectively defined database. Risk factors, medication, and indication for therapy were documented. Univariate and multivariate analysis was performed to investigate independent reduction of peri-interventional stroke, myocardial infarction, or death by statin medication prior to stent-angioplasty. RESULTS: The median age was 70 years (p25: 63, p75: 76), 75.5% of patients were male, and the median stenosis was 85% according to ECST criteria (p25: 80%, p75: 90%). 20.1% of patients had asymptomatic stenoses, and 60.2% had statin medication before stenting. As per multivariate analysis, pre-interventional statin medication was a predictor for significant peri-interventional risk reduction regarding primary endpoint ischemic stroke, myocardial infarction (MI), or death (odds ratio (OR) 0.31, p = .006). Statins also had a significant protective effect in secondary endpoint ischemic stroke, intracranial bleeding or death (OR 0.39, p = .014), and ischemic stroke or myocardial infarction (OR 0.20; p = .002). CONCLUSIONS: This study shows that pre-interventional statin medication has a protective effect against peri-interventional stroke, MI, or death in patients with internal carotid artery stenosis treated with stent-angioplasty. Accordingly, statins could be considered as a standard pre-interventional medical therapy in carotid stenting.

[Treatment of asymptomatic carotid artery stenosis: improvement of evidence with new SPACE-2 design necessary]. / Therapie asymptomatischer Karotisstenosen: Notwendige Klärung der Evidenz mit neuem SPACE-2-Design.

Asymptomatic carotid artery stenosis may be treated with carotid endarterectomy (CEA), carotid artery stenting (CAS) or with best medical treatment (BMT) only. Definitive and evidence-based treatment recommendations for one of these options are currently not possible. Studies showing an advantage of CEA over BMT alone do not meet current standards from a pharmacological point of view. On the other hand, more recent data point to a further stroke risk reduction using BMT according to current standards. Studies on carotid artery stenting as a third alternative treatment are partially insufficient, especially when comparing CAS with BMT. Initiated in 2009, the randomized, controlled, multicenter SPACE-2 trial is intended to answer the question about the best treatment option of asymptomatic carotid artery stenosis; however, to increase recruitment rates as a condition for the successful completion of this important study, the trial design had to be modified.

[Neurology and carotid artery interventions. What has to be done first?]. / Neurologie und Karotisinterventionen. Was soll wie organisiert sein?

Optimum therapy for patients with carotid stenosis requires the interdisciplinary cooperation of surgeons, neurologists and angiologists. Important diagnostic methods are ultrasound sonography, contrast-enhanced computed tomography, magnetic resonance tomography and digital subtraction angiography. Treatment of carotid artery stenosis depends on whether the stenosis is symptomatic or asymptomatic. The treatment of choice (medical therapy only vs. carotid artery stenting vs. carotid endarterectomy) depends on the characteristics of the stenosis, the presence of cerebral lesions and the general physical condition of the patient. After the intervention continuous monitoring and treatment of vascular risk factors are mandatory.

Stent-protected angioplasty in asymptomatic carotid artery stenosis vs. endarterectomy: SPACE2 - a three-arm randomised-controlled clinical trial.

Moderate to severe (> or =70%) asymptomatic stenosis of the extracranial carotid artery leads to an increased rate of stroke of approximately 11% in 5 years. Patients with asymptomatic carotid stenosis, however, are also at a higher risk of nonstroke vascular events. The estimated annual risks of such events in patients with asymptomatic stenosis are 7% for a coronary ischaemic event and 4-7% for overall mortality. The superiority of carotid endarterectomy compared with medical treatment in symptomatic carotid disease is established, provided that the surgical procedure can be performed with a perioperative morbidity and mortality of <6%. The advantage of carotid endarterectomy for asymptomatic patients is less established. An alternative treatment, carotid artery stenting, has been developed. This treatment is used frequently in both symptomatic and asymptomatic patients. In the last decade, major advantages in medical primary prevention of cerebrovascular and cardiovascular disease have been accomplished. The control groups in the large trials for asymptomatic carotid artery disease (ACAS and ACST) originate from more than a decade ago and, for the most part, have not received a medical primary prevention strategy that would now be considered the standard according to current national and international guidelines. For this reason, a three-arm trial (SPACE2; http://www.space-2.de) with a hierarchical design and a recruitment target of 3640 patients is chosen. Firstly, a superior trial of intervention (carotid artery stenting or carotid endarterectomy) vs. state-of-the-art conservative treatment is designed. In case of superiority of the interventions, a noninferiority end-point will be tested between carotid artery stenting and carotid endarterectomy. This trial is registered at Current Controlled Trials ISRCTN 78592017.

The role of the ocular lens in the regulation of intraocular pressure.

The relationship between lenticular colloid osmotic (oncotic) pressure and intraocular pressure is discussed, with particular reference to a postulated buffering reservoir action of the lens in protecting against acute changes in intraocular pressure. A hypothesis is developed regarding acute lenticular volume changes in those species manifesting change in lens shape during accommodation. The unusually high colloid osmotic pressure of fish lenses is discussed and related to their unique means of accommodation and their susceptibility to cataract formation.

Water loss in aging and its clinical significance.

Tissue water loss that occurs in aging has important implications for health status and treatment. This article discusses known mechanisms, physiologic examples, and clinical consequences of body-water changes with age, and suggests that careful monitoring of these changes can lead to better guiding of medication and fluid administration to avoid preventable complications.

Water and aging.

Having evolved from the sea and developed from an embryo, the species and the individual lose water--the medium and solvent wherein these processes occur--continually as they age. From an embryo, which is about 90% water, to a senescent individual in the tenth decade, there is a decline in body water to 60% or below. This loss in body water has profound effects on pathophysiology, making older persons susceptible to both under- and overhydration because they have a smaller volume of distribution for exogenous water. A colloid osmotic macromolecular aggregation model has been hypothesized to explain water loss in aging individuals.

A colloid osmotic model of macromolecular aggregation to explain tissue water loss in aging.

We have evolved from the sea, are composed mostly of water, the medium and solvent wherein most vital processes occur, and phylogenetically and ontogenetically lose water continually as we age. An embryo is about 90% water, a newborn child about 80% water, a mature adult about 70% water, an older adult about 60% water with recent work indicating that in senescence the percentage of body water is actually below 60%. The mechanisms of the water loss in aging have not been elucidated. From a theoretical point of view, there is good reason to believe that there may be profound changes in the chemical potential of intracellular and interstitial water with age due to increased macromolecular interaction or aggregation from cross linking, polymerization, insolubility, etc.; all of which are known to increase with aging. The resultant increased macromolecular solute-solute interaction would be accompanied by decreased macromolecular solute-solvent interaction, thereby causing a higher solvent (water) chemical potential. This would facilitate the loss of bound water, thereby explaining the observed losses in body water with age. The ocular lens is a microcosm of aging, in that from its nucleus to cortex, the oldest to youngest cells are concentrically arranged, as in a tree. We have developed a method to directly measure lens tissue oncotic pressure in an attempt to experimentally test the above cited hypothesis.