Michael F. Waters

Stenting versus aggressive medical therapy for intracranial arterial stenosis

BACKGROUND Atherosclerotic intracranial arterial stenosis is an important cause of stroke that is increasingly being treated with percutaneous transluminal angioplasty and stenting (PTAS) to prevent recurrent stroke. However, PTAS has not been compared with medical management in a randomized trial. METHODS We randomly assigned patients who had a recent transient ischemic attack or stroke attributed to stenosis of 70 to 99% of the diameter of a major intracranial artery to aggressive medical management alone or aggressive medical management plus PTAS with the use of the Wingspan stent system. The primary end point was stroke or death within 30 days after enrollment or after a revascularization procedure for the qualifying lesion during the follow-up period or stroke in the territory of the qualifying artery beyond 30 days. RESULTS Enrollment was stopped after 451 patients underwent randomization, because the 30-day rate of stroke or death was 14.7% in the PTAS group (nonfatal stroke, 12.5%; fatal stroke, 2.2%) and 5.8% in the medical-management group (nonfatal stroke, 5.3%; non-stroke-related death, 0.4%) (P=0.002). Beyond 30 days, stroke in the same territory occurred in 13 patients in each group. Currently, the mean duration of follow-up, which is ongoing, is 11.9 months. The probability of the occurrence of a primary end-point event over time differed significantly between the two treatment groups (P=0.009), with 1-year rates of the primary end point of 20.0% in the PTAS group and 12.2% in the medical-management group. CONCLUSIONS In patients with intracranial arterial stenosis, aggressive medical management was superior to PTAS with the use of the Wingspan stent system, both because the risk of early stroke after PTAS was high and because the risk of stroke with aggressive medical therapy alone was lower than expected. (Funded by the National Institute of Neurological Disorders and Stroke and others; SAMMPRIS ClinicalTrials.gov number, NCT00576693.).

Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): The final results of a randomised trial

BACKGROUND Early results of the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial showed that, by 30 days, 33 (14·7%) of 224 patients in the stenting group and 13 (5·8%) of 227 patients in the medical group had died or had a stroke (percentages are product limit estimates), but provided insufficient data to establish whether stenting offered any longer-term benefit. Here we report the long-term outcome of patients in this trial. METHODS We randomly assigned (1:1, stratified by centre with randomly permuted block sizes) 451 patients with recent transient ischaemic attack or stroke related to 70-99% stenosis of a major intracranial artery to aggressive medical management (antiplatelet therapy, intensive management of vascular risk factors, and a lifestyle-modification programme) or aggressive medical management plus stenting with the Wingspan stent. The primary endpoint was any of the following: stroke or death within 30 days after enrolment, ischaemic stroke in the territory of the qualifying artery beyond 30 days of enrolment, or stroke or death within 30 days after a revascularisation procedure of the qualifying lesion during follow-up. Primary endpoint analysis of between-group differences with log-rank test was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00576693. FINDINGS During a median follow-up of 32·4 months, 34 (15%) of 227 patients in the medical group and 52 (23%) of 224 patients in the stenting group had a primary endpoint event. The cumulative probability of the primary endpoints was smaller in the medical group versus the percutaneous transluminal angioplasty and stenting (PTAS) group (p=0·0252). Beyond 30 days, 21 (10%) of 210 patients in the medical group and 19 (10%) of 191 patients in the stenting group had a primary endpoint. The absolute differences in the primary endpoint rates between the two groups were 7·1% at year 1 (95% CI 0·2 to 13·8%; p=0·0428), 6·5% at year 2 (-0·5 to 13·5%; p=0·07) and 9·0% at year 3 (1·5 to 16·5%; p=0·0193). The occurrence of the following adverse events was higher in the PTAS group than in the medical group: any stroke (59 [26%] of 224 patients vs 42 [19%] of 227 patients; p=0·0468) and major haemorrhage (29 [13%]of 224 patients vs 10 [4%] of 227 patients; p=0·0009). INTERPRETATION The early benefit of aggressive medical management over stenting with the Wingspan stent for high-risk patients with intracranial stenosis persists over extended follow-up. Our findings lend support to the use of aggressive medical management rather than PTAS with the Wingspan system in high-risk patients with atherosclerotic intracranial arterial stenosis. FUNDING National Institute of Neurological Disorders and Stroke (NINDS) and others.

A DNA methylation imprint, determined by the sex of the parent, distinguishes the Angelman and Prader-Willi syndromes

The Angelman (AS) and Prader-Willi (PWS) syndromes are two clinically distinct disorders that are caused by a differential parental origin of chromosome 15q11-q13 deletions. Both also can result from uniparental disomy (the inheritance of both copies of chromosome 15 from only one parent). Loss of the paternal copy of 15q11-q13, whether by deletion or maternal uniparental disomy, leads to PWS, whereas a maternal deletion or paternal uniparental disomy leads to AS. The differential modification in expression of certain mammalian genes dependent upon parental origin is known as genomic imprinting, and AS and PWS represent the best examples of this phenomenon in humans. Although the molecular mechanisms of genomic imprinting are unknown, DNA methylation has been postulated to play a role in the imprinting process. Using restriction digests with the methyl-sensitive enzymes HpaII and HhaI and probing Southern blots with several genomic and cDNA probes, we have systematically scanned segments of 15q11-q13 for DNA methylation differences between patients with PWS (20 deletion, 20 uniparental disomy) and those with AS (26 deletion, 1 uniparental disomy). The highly evolutionarily conserved cDNA, DN34, identifies distinct differences in DNA methylation of the parental alleles at the D15S9 locus. Thus, DNA methylation may be used as a reliable, postnatal diagnostic tool in these syndromes. Furthermore, our findings demonstrate the first known epigenetic event, dependent on the sex of the parent, for a locus within 15q11-q13. We propose that expression of the gene detected by DN34 is regulated by genomic imprinting and, therefore, that it is a candidate gene for PWS and/or AS.

Detailed Analysis of Periprocedural Strokes in Patients Undergoing Intracranial Stenting in Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS)

Background and Purpose— Enrollment in the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial was halted due to the high risk of stroke or death within 30 days of enrollment in the percutaneous transluminal angioplasty and stenting arm relative to the medical arm. This analysis focuses on the patient and procedural factors that may have been associated with periprocedural cerebrovascular events in the trial. Methods— Bivariate and multivariate analyses were performed to evaluate whether patient and procedural variables were associated with cerebral ischemic or hemorrhagic events occurring within 30 days of enrollment (termed periprocedural) in the percutaneous transluminal angioplasty and stenting arm. Results— Of 224 patients randomized to percutaneous transluminal angioplasty and stenting, 213 underwent angioplasty alone (n=5) or with stenting (n=208). Of these, 13 had hemorrhagic strokes (7 parenchymal, 6 subarachnoid), 19 had ischemic stroke, and 2 had cerebral infarcts with temporary signs within the periprocedural period. Ischemic events were categorized as perforator occlusions (13), embolic (4), mixed perforator and embolic (2), and delayed stent occlusion (2). Multivariate analyses showed that higher percent stenosis, lower modified Rankin score, and clopidogrel load associated with an activated clotting time above the target range were associated (P⩽0.05) with hemorrhagic stroke. Nonsmoking, basilar artery stenosis, diabetes, and older age were associated (P⩽0.05) with ischemic events. Conclusions— Periprocedural strokes in SAMMPRIS had multiple causes with the most common being perforator occlusion. Although risk factors for periprocedural strokes could be identified, excluding patients with these features from undergoing percutaneous transluminal angioplasty and stenting to lower the procedural risk would limit percutaneous transluminal angioplasty and stenting to a small subset of patients. Moreover, given the small number of events, the present data should be used for hypothesis generation rather than to guide patient selection in clinical practice. Clinical Trial Registration Information— URL: http://clinicaltrials.gov. Unique Identifier: NCT00576693.

Effect of Weekend Compared With Weekday Stroke Admission on Thrombolytic Use, In-Hospital Mortality, Discharge Disposition, Hospital Charges, and Length of Stay in the Nationwide Inpatient Sample Database, 2002 to 2007

Background and Purpose— A stroke “weekend effect” on mortality has been demonstrated in other countries with a possible slight effect in the United States. We studied patients with stroke in the Nationwide Inpatient Sample database for a weekend effect on thrombolytic use, in-hospital mortality, discharge disposition, hospital charges, and length of stay. Methods— The Nationwide Inpatient Sample 2002 to 2007 was searched for all emergency room admissions for International Classification of Diseases, 9th Revision codes corresponding to ischemic stroke. Generalized estimated equations for generalized linear models were performed, adjusting for gender, age, race, season, median income level, payer, comorbidity score, hospital region, hospital location, teaching status, bed size, and hospital annual stroke case volume to compare weekend versus weekday stroke admission incidence of thrombolytic use, in-hospital mortality, discharge disposition, hospital charges, and length of stay. The same analysis was performed using the International Classification of Diseases, 9th Revision codes for ischemic stroke AND transient cerebral ischemia to check internal validity for coding irregularities that may occur in differentiating stroke from transient ischemic attack. Results— There were 599 087 emergency room admissions for ischemic stroke: 159 906 weekend admissions and 439 181 weekday admissions. Generalized estimated equation for generalized linear model analysis was performed and demonstrated weekend compared with weekday patients with stroke were slightly more likely to receive thrombolytics (OR=1.114; 95% CI=1.039 to 1.194; P=0.003); incur slightly higher total hospital charges (effect ratio=1.011; 95% CI=1.006 to 1.017; P<0.001); and have slightly longer lengths of stay (effect ratio=1.021; 95% CI=1.015 to 1.027; P<0.001). There was no difference in in-hospital mortality or discharge disposition. Conclusions— There is a slight stroke weekend effect on thrombolytic use, total hospital charges, and length of stay, but no difference in in-hospital mortality or discharge disposition.

KCNC3: Phenotype, mutations, channel biophysics – a study of 260 familial ataxia patients

We recently identified KCNC3, encoding the Kv3.3 voltage‐gated potassium channel, as the gene mutated in SCA13. One g.10684G>A (p.Arg420His) mutation caused late‐onset ataxia resulting in a nonfunctional channel subunit with dominant‐negative properties. A French early‐onset pedigree with mild mental retardation segregated a g.10767T>C (p.Phe448Leu) mutation. This mutation changed the relative stability of the channels open conformation. Coding exons were amplified and sequenced in 260 autosomal‐dominant ataxia index cases of European descent. Functional analyses were performed using expression in Xenopus oocytes. The previously identified p.Arg420His mutation occurred in three families with late‐onset ataxia. A novel mutation g.10693G>A (p.Arg423His) was identified in two families with early‐onset. In one pedigree, a novel g.10522G>A (p.Arg366His) sequence variant was seen in one index case but did not segregate with affected status in the respective family. In a heterologous expression system, the p.Arg423His mutation exhibited dominant‐negative properties. The p.Arg420His mutation, which results in a nonfunctional channel subunit, was recurrent and associated with late‐onset progressive ataxia. In two families the p.Arg423His mutation was associated with early‐onset slow‐progressive ataxia. Despite a phenotype reminiscent of the p.Phe448Leu mutation, segregating in a large early‐onset French pedigree, the p.Arg423His mutation resulted in a nonfunctional subunit with a strong dominant‐negative effect. Hum Mutat 31:191–196, 2010.

Prospective Quality Initiative to Maximize Dysphagia Screening Reduces Hospital-Acquired Pneumonia Prevalence in Patients With Stroke

Background and Purpose— Dysphagia can lead to pneumonia and subsequent death after acute stroke. However, no prospective study has demonstrated reduced pneumonia prevalence after implementation of a dysphagia screen. Methods— We performed a single-center prospective interrupted time series trial of a quality initiative to improve dysphagia screening. Subjects included all patients with ischemic or hemorrhagic stroke admitted to our institution over 42 months with a 31-month (n=1686) preintervention and an 11-month (n=648) postintervention period. The intervention consisted of a dysphagia protocol with a nurse-administered bedside dysphagia screen and a reflexive rapid clinical swallow evaluation by a speech pathologist. Results— The dysphagia initiative increased the percentage of patients with stroke screened from 39.3% to 74.2% (P<0.001). Furthermore, this initiative coincided with a drop in hospital-acquired pneumonia from 6.5% to 2.8% among patients with stroke (P<0.001). Patients admitted postinitiative had 57% lower odds of pneumonia, after controlling for multiple confounds (odds ratio=0.43; confidence interval, 0.255–0.711; P=0.0011). The best predictors of pneumonia were stroke type (P<0.0001), oral intake status (P<0.0001), dysphagia screening status (P=0.0037), and hospitalization before the beginning of the quality improvement initiative (P=0.0449). Conclusions— A quality improvement initiative using a nurse-administered bedside screen with rapid bedside swallow evaluation by a speech pathologist improves screening compliance and correlates with decreased prevalence of pneumonia among patients with stroke.

Race and Income Disparity in Ischemic Stroke Care: Nationwide Inpatient Sample Database, 2002 to 2008

BACKGROUND Health care disparities exist between demographic groups with stroke. We examined whether patients of particular ethnicity or income levels experienced reduced access to or delays in receiving stroke care. METHODS We studied all admissions for ischemic stroke in the Nationwide Inpatient Sample (NIS) database between 2002 and 2008. We used statistical models to determine whether median income or race were associated with intravenous (i.v.) thrombolysis treatment, in-hospital mortality, discharge disposition, hospital charges, and LOS in high- or low-volume hospitals. RESULTS There were a total of 477,474 patients with ischemic stroke: 10,781 (2.3%) received i.v. thrombolysis, and 380,400 (79.7%) were treated in high-volume hospitals. Race (P < .0001) and median income (P < .001) were significant predictors of receiving i.v. thrombolysis, and minorities and low-income patients were less likely to receive i.v. thrombolysis. Median income was a predictor of access to high-volume hospitals (P < .0001), with wealthier patients more likely to be treated in high-volume hospitals, which had lower mortality rates (P = .0002). Patients in high-volume hospitals were 1.84 times more likely to receive i.v. thrombolysis (P < .0001). CONCLUSIONS African Americans, Hispanics, and low median income patients are less likely to receive i.v. thrombolysis for ischemic stroke. Low median income patients are less likely to be treated at high-volume hospitals. High-volume hospitals have lower mortality rates and a higher likelihood of treating patients with i.v. thrombolysis. There is evidence for an influence of socioeconomic status and racial disparity in the treatment of ischemic stroke.

Hemispheric Differences in Ischemic Stroke: Is Left-Hemisphere Stroke More Common?

Background and Purpose Understanding the mechanisms underlying stroke can aid the development of therapies and improve the final outcome. The purposes of this study were to establish whether there are characteristic mechanistic differences in the frequency, severity, functional outcome, and mortality between left- and right-hemisphere ischemic stroke and, given the velocity differences in the carotid circulation and direct branching of the left common carotid artery from the aorta, whether large-vessel ischemia (including cardioembolism) is more common in the territory of the left middle cerebral artery. Methods Trial cohorts were combined into a data set of 476 samples. Using Trial of Org 10172 in Acute Stroke Treatment criteria, ischemic strokes in a total 317 patients were included in the analysis. Hemorrhagic stroke, stroke of undetermined etiology, cryptogenic stroke, and bilateral ischemic strokes were excluded. Laterality and vascular distribution were correlated with outcomes using a logistic regression model. The etiologies of the large-vessel strokes were atherosclerosis and cardioembolism. Results The overall event frequency, mortality, National Institutes of Health Stroke Scale (NIHSS) score, Glasgow Coma Scale score, and rate of mechanical thrombectomy interventions differed significantly between the hemispheres. Left-hemispheric strokes (54%) were more common than right-hemispheric strokes (46%; p=0.0073), and had higher admission NIHSS scores (p=0.011), increased mortality (p=0.0339), and higher endovascular intervention rates (p≤0.0001). ischemic strokes were more frequent in the distribution of the left middle cerebral artery (122 vs. 97; p=0.0003) due to the higher incidence of large-vessel ischemic stroke in this area (p=0.0011). Conclusions Left-hemispheric ischemic strokes appear to be more frequent and often have a worse outcome than their right-hemispheric counterparts. The incidence of large-vessel ischemic strokes is higher in the left middle cerebral artery distribution, contributing to these hemispheric differences. The hemispheric differences exhibit a nonsignificant trend when strokes in the middle cerebral artery distribution are excluded from the analysis.

Frequency of KCNC3 DNA variants as causes of spinocerebellar ataxia 13 (SCA13)

Background Gain-of function or dominant-negative mutations in the voltage-gated potassium channel KCNC3 (Kv3.3) were recently identified as a cause of autosomal dominant spinocerebellar ataxia. Our objective was to describe the frequency of mutations associated with KCNC3 in a large cohort of index patients with sporadic or familial ataxia presenting to three US ataxia clinics at academic medical centers. Methodology DNA sequence analysis of the coding region of the KCNC3 gene was performed in 327 index cases with ataxia. Analysis of channel function was performed by expression of DNA variants in Xenopus oocytes. Principal Findings Sequence analysis revealed two non-synonymous substitutions in exon 2 and five intronic changes, which were not predicted to alter splicing. We identified another pedigree with the p.Arg423His mutation in the highly conserved S4 domain of this channel. This family had an early-onset of disease and associated seizures in one individual. The second coding change, p.Gly263Asp, subtly altered biophysical properties of the channel, but was unlikely to be disease-associated as it occurred in an individual with an expansion of the CAG repeat in the CACNA1A calcium channel. Conclusions Mutations in KCNC3 are a rare cause of spinocerebellar ataxia with a frequency of less than 1%. The p.Arg423His mutation is recurrent in different populations and associated with early onset. In contrast to previous p.Arg423His mutation carriers, we now observed seizures and mild mental retardation in one individual. This study confirms the wide phenotypic spectrum in SCA13.