Geoffrey Cloud

Evaluating the Genetic Component of Ischemic Stroke Subtypes: A Family History Study

Background and Purpose— Twin and family history studies support a role for genetic factors in stroke risk. Because the etiology of ischemic stroke is heterogeneous, genetic factors may vary by etiologic subtype. We determined the familial aggregation of stroke risk in different stroke phenotypes and used the results to model estimated sample size requirements for case-control studies. Methods— One thousand consecutive white subjects with ischemic stroke and 800 white controls matched for age and sex were recruited. A first-degree family history of stroke and myocardial infarction was obtained by structured interview. Stroke subtype was determined with the use of modified Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Results— A family history of stroke at ≤65 years was a significant risk factor for large-vessel disease (odds ratio [OR], 2.24; 95% CI, 1.49 to 3.36;P <0.001) and for small-vessel disease (OR, 1.93; 95% CI, 1.25 to 2.97;P =0.003). When only cases aged ≤65 years were considered, these ORs increased to 2.93 (95% CI, 1.68 to 5.13) (P <0.001) and 3.15 (95% CI, 1.81 to 5.50) (P <0.001), respectively. No significant associations were seen for cardioembolic stroke or stroke of undetermined etiology. Conclusions— A family history of vascular disease is an independent risk factor for both large-vessel atherosclerosis and small-vessel disease, especially in cases presenting before age 65 years. The estimated sample sizes for case-control studies illustrate how candidate gene studies for ischemic stroke might be made more effective by focusing on these specific phenotypes, in which the genetic component of the disease appears to be strongest.

Informal carers of stroke survivors–factors influencing carers: A systematic review of quantitative studies

Purpose. Despite increasing evidence of adverse effects on informal carers of caring for stroke survivors, little is known about the characteristics of carers and survivors that influence carer outcomes. The purpose of this review is to summarize factors influencing outcomes in carers of stroke survivors. Methods. A systematic review of studies identified from English language medicine, nursing and psychology databases from 1996 – 2006 was carried out. Results. Thirty-nine studies were identified. Studies from Europe and the USA investigating negative carer outcomes dominated. Carer psychological characteristics and survivor disability were shown to influence carer outcomes. However, the diversity of carers and outcomes investigated and differences in study timing post-stroke make generalizations difficult. Conclusions. Despite improvements in study design over the last two decades, atheoretical studies employing overlapping concepts and poorly defined participants still dominate. Future studies should have theoretical underpinning and should acknowledge the diversity of carers, survivors and their situations. In addition, future emphasis on positive carer outcomes may improve understanding of protective carer factors.

Imaging of vertebral artery stenosis: a systematic review.

Background and purpose: Posterior circulation stroke accounts for 20% of ischaemic strokes. Recent data suggest that the early stroke recurrence risk is high and comparable with carotid artery disease. Vertebral artery stenosis accounts for approximately 20% of posterior circulation stroke, and with endovascular treatment available accurate diagnostic imaging is important. We performed a systematic literature review to validate the accuracy of the non-invasive imaging techniques Duplex ultrasound (DUS), magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) in detecting severe vertebral artery stenosis, with intra-arterial angiography (IAA) as the reference standard. Methods: We identified studies that used non-invasive imaging and IAA as the reference standard to determine vertebral artery stenosis and provided adequate data to calculate sensitivity and specificity. We analysed the quality of these studies, looked for evidence of heterogeneity and performed subgroup analysis for different degrees of stenosis. Results: 11 studies categorised stenosis into 50–99%. The sensitivity of CTA (single study) and pooled sensitivities of contrast enhanced MRA (CE-MRA) and colour duplex were 100% (95% CI 15.8 to 100), 93.9% (79.8 to 99.3) and 70.2% (54.2 to 83.3), respectively. The specificities for CTA, CE-MRA and colour duplex were 95.2% (83.8 to 99.4), 94.8% (91.1 to 97.3) and 97.7% (95.2 to 99.1). However, specificities for CE-MRA and colour duplex demonstrated significant heterogeneity (p = 0.003 and p = 0.002, respectively). Conclusions: CE-MRA and possibly CTA may be more sensitive in diagnosing vertebral artery stenosis than DUS. However, data are limited and further high quality studies comparing DUS, MRA and CTA with IAA are required.

Estimation of central aortic pressure by SphygmoCor ® requires intra-arterial peripheral pressures

Central arterial pressure, measured close to the heart, may be of more patho-physiological importance than conventional non-invasive cuff blood pressure. The technique of applanation tonometry using SphygmoCor® has been proposed as a non-invasive method of estimating central pressure. This relies on mathematically derived generalized transfer functions, which have been previously validated using invasive peripheral pressure measurements. We compared simultaneous estimates of central aortic pressure using this technique with those measured directly during the routine diagnostic cardiac catheterization of 30 subjects (age range 27–84 years), half of whom were aged 65 years or more. This was done by applanating the left radial artery and recording the non-invasive brachial cuff blood pressure to generate a central aortic pressure estimate, using the SphygmoCor® radial transfer function. The comparative results were analysed using Bland—Altman plots of mean difference. SphygmoCor®, on average, underestimated systolic central arterial pressure by 13.3 mmHg and overestimated diastolic pressure by 11.5 mmHg. The results were similar in patients aged under and above 65 years. Furthermore, non-invasively measured brachial pressures were seen to give an overall closer estimate of the central arterial pressure than the SphygmoCor® system. The transfer function has been validated from invasively measured arterial pressures and the current use by the system of non-invasive measures may explain the discrepancies. However, age, drugs and arterial disease would also be expected to play a role.

Family carers of stroke survivors: needs, knowledge, satisfaction and competence in caring

Purpose. To examine the support required by family carers for stroke survivors. Methods. Forty-two family carers were recruited for surveys of needs, knowledge, satisfaction, and competence in caring before and 4 – 6 weeks after discharge from an Acute Stroke Unit (ASU). Results. Information deficits about dealing with psychological, emotional, and behavioural problems and local service information were priorities before and after discharge. Younger female carers (under 56 years) were least satisfied with communication with ASU staff. Face to face contact was valued. After discharge younger female carers, particularly of non-White ethnic groups, reported lower levels of competence in caring and higher burden. Knowledge of stroke risk factors was low in all groups. High satisfaction with treatment and therapy in the ASU, was not transferred to the community. Carers reported feeling alone and described uncoordinated services. Conclusions. Carers are able to anticipate and prioritise their needs, value communication with staff and involvement with discharge-planning, but particular difficulties were experienced by younger female carers and those from non-White ethnic groups. This requires particular attention when developing targeted interventions for family carers from a mixed ethnic community. In-depth and longitudinal studies are needed to detail psychosocial needs and guide practice particularly amongst non-White family carers.

Theta Burst Stimulation in the Rehabilitation of the Upper Limb: A Semirandomized, Placebo-Controlled Trial in Chronic Stroke Patients

Background. Noninvasive cortical stimulation could represent an add-on treatment to enhance motor recovery after stroke. However, its clinical value, including anticipated size and duration of the treatment effects, remains largely unknown. Objective. The authors designed a small semi-randomized clinical trial to explore whether long-lasting clinically important gains can be achieved by adding theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation (TMS), to a rehabilitation program for the hand. Methods. A total of 41 chronic stroke patients received excitatory TBS to the ipsilesional hemisphere or inhibitory TBS to the contralesional hemisphere in 2 centers; each active group was compared with a group receiving sham TBS. TBS was followed by physical therapy for 10 working days. Patients and therapists were blinded to the type of TBS. Primary outcome measures (9-hole Peg Test [9HPT], Jebsen Taylor Test [JTT], and grip and pinch-grip dynamometry) were assessed 4, 30, and 90 days post treatment. The clinically important difference was defined as 10% of the maximum score. Results. There were no differences between the active treatment and sham groups in any of the outcome measures. All patients achieved small sustainable improvements—9HPT, 5% of maximum (confidence interval [CI] = 3%-7%); JTT, 5.7% (CI = 3%-8%); and grip strength, 6% (CI = 2%-10%)—all below the defined clinically important level. Conclusions. Cortical stimulation did not augment the gains from a late rehabilitation program. The effect size anticipated by the authors was overestimated. These results can improve the design of future work on therapeutic uses of TMS.

Transcranial Magnetic Stimulation and Muscle Contraction to Enhance Stroke Recovery: A Randomized Proof-of-Principle and Feasibility Investigation

Objective. To explore the efficacy of repetitive transcranial magnetic stimulation (rTMS) and voluntary muscle contraction (VMC) to improve corticospinal transmission, muscle function, and purposeful movement early after stroke. Methods. Factorial 2 × 2 randomized single-blind trial. Subjects: n = 27, mean age 75 years, mean 27 days after middle cerebral artery infarct (24 subjects completed outcome measures). Procedure: after baseline measurement (day 1), subjects were randomized to 1 of 4 groups. Treatment was given for the next 8 working days, and outcome was measured on day 10. Interventions: (a) Real-rTMS + RealVMC, (b) Real-rTMS + PlaceboVMC, (c) Placebo-rTMS + RealVMC, and (d) Placebo-rTMS + PlaceboVMC. Real-rTMS consisted of 200 1-Hz stimuli at 120% motor threshold in 5 blocks of 40 separated by 3 minutes delivered to the lesioned hemisphere. Placebo-rTMS used a dummy coil. In RealVMC, the paretic elbow was repeatedly flexed/extended for 5 minutes. In PlaceboVMC, subjects viewed pairs of drawings of upper limbs and reported their likeness. Outcomes: frequency of motor-evoked potentials in biceps and triceps, muscle function (torque about elbow), and purposeful movement (Action Research Arm Test). Analysis: group mean changes (outcome — baseline) were compared. Results. In the Real-rTMS + RealVMC group, motor-evoked potential frequency increased 14% for biceps and 20% for triceps, whereas in the Placebo-rTMS + PlaceboVMC group, it decreased 12% for biceps and 6% for triceps. For other groups, there were changes of intermediate values. No meaningful differences were found for secondary outcomes. Conclusions . A positive trend for motor-evoked potential frequency was found for Real-rTMS + RealVMC, whereas a negative trend for motor-evoked potential frequency was found for Placebo-rTMS + PlaceboVMC.

Vertebral artery origin angioplasty and primary stenting: safety and restenosis rates in a prospective series

Objectives: To report a single centre ongoing experience of endovascular treatment for atherosclerotic vertebral artery origin stenosis in a series of symptomatic patients, with follow up imaging to determine the incidence of restenosis. Methods: 14 patients with vertebral artery origin stenosis on catheter angiography were treated. Angioplasty without stenting was undertaken in the first four patients, all of whom had follow up catheter angiography at one year. Subsequently, patients were treated by primary stenting and followed up with colour Doppler ultrasound examination. Results: The procedure was technically successful in all treated arteries, with no immediate complications. The degree of stenosis was reduced from (mean (SD)) 73 (18)% before treatment to 21 (26)% immediately after treatment in the angioplasty alone group (p = 0.059). In the primary stenting patients, the severity of stenosis was reduced from 82 (8)% to 13 (13)% immediately after treatment (p < 0.001). Restenosis to 70% or greater occurred at one year in all four patients initially treated by angioplasty without stenting. One patient subsequently developed further symptoms and was retreated by stenting. One of the 10 patients treated by primary stenting developed restenosis. None of the remaining patients had further posterior circulation ischaemic symptoms during a mean follow up period of 33.6 months (range 1 to 72 months). Conclusions: Restenosis occurs often after vertebral artery origin balloon angioplasty without stenting but is uncommon after stenting. Primary stenting is therefore recommended to maintain patency at this site, and had a low complication rate in this series.

Endovascular therapy for acute ischaemic stroke: the Pragmatic Ischaemic Stroke Thrombectomy Evaluation (PISTE) randomised, controlled trial

Objective The Pragmatic Ischaemic Thrombectomy Evaluation (PISTE) trial was a multicentre, randomised, controlled clinical trial comparing intravenous thrombolysis (IVT) alone with IVT and adjunctive intra-arterial mechanical thrombectomy (MT) in patients who had acute ischaemic stroke with large artery occlusive anterior circulation stroke confirmed on CT angiography (CTA). Design Eligible patients had IVT started within 4.5 hours of stroke symptom onset. Those randomised to additional MT underwent thrombectomy using any Conformité Européene (CE)-marked device, with target interval times for IVT start to arterial puncture of <90 min. The primary outcome was the proportion of patients achieving independence defined by a modified Rankin Scale (mRS) score of 0–2 at day 90. Results Ten UK centres enrolled 65 patients between April 2013 and April 2015. Median National Institutes of Health Stroke Scale score was 16 (IQR 13–21). Median stroke onset to IVT start was 120 min. In the intention-to-treat analysis, there was no significant difference in disability-free survival at day 90 with MT (absolute difference 11%, adjusted OR 2.12, 95% CI 0.65 to 6.94, p=0.20). Secondary analyses showed significantly greater likelihood of full neurological recovery (mRS 0–1) at day 90 (OR 7.6, 95% CI 1.6 to 37.2, p=0.010). In the per-protocol population (n=58), the primary and most secondary clinical outcomes significantly favoured MT (absolute difference in mRS 0–2 of 22% and adjusted OR 4.9, 95% CI 1.2 to 19.7, p=0.021). Conclusions The trial did not find a significant difference between treatment groups for the primary end point. However, the effect size was consistent with published data and across primary and secondary end points. Proceeding as fast as possible to MT after CTA confirmation of large artery occlusion on a background of intravenous alteplase is safe, improves excellent clinical outcomes and, in the per-protocol population, improves disability-free survival. Trial registration number NCT01745692; Results.

Weekly variation in health-care quality by day and time of admission: a nationwide, registry-based, prospective cohort study of acute stroke care.

BACKGROUND Studies in many health systems have shown evidence of poorer quality health care for patients admitted on weekends or overnight than for those admitted during the week (the so-called weekend effect). We postulated that variation in quality was dependent on not only day, but also time, of admission, and aimed to describe the pattern and magnitude of variation in the quality of acute stroke care across the entire week. METHODS We did this nationwide, registry-based, prospective cohort study using data from the Sentinel Stroke National Audit Programme. We included all adult patients (aged >16 years) admitted to hospital with acute stroke (ischaemic or primary intracerebral haemorrhage) in England and Wales between April 1, 2013, and March 31, 2014. Our outcome measure was 30 day post-admission survival. We estimated adjusted odds ratios for 13 indicators of acute stroke-care quality by fitting multilevel multivariable regression models across 42 4-h time periods per week. FINDINGS The study cohort comprised 74,307 patients with acute stroke admitted to 199 hospitals. Care quality varied across the entire week, not only between weekends and weekdays, with different quality measures showing different patterns and magnitudes of temporal variation. We identified four patterns of variation: a diurnal pattern (thrombolysis, brain scan within 12 h, brain scan within 1 h, dysphagia screening), a day of the week pattern (stroke physician assessment, nurse assessment, physiotherapy, occupational therapy, and assessment of communication and swallowing by a speech and language therapist), an off-hours pattern (door-to-needle time for thrombolysis), and a flow pattern whereby quality changed sequentially across days (stroke-unit admission within 4 h). The largest magnitude of variation was for door-to-needle time within 60 min (range in quality 35-66% [16/46-232/350]; coefficient of variation 18·2). There was no difference in 30 day survival between weekends and weekdays (adjusted odds ratio 1·03, 95% CI 0·95-1·13), but patients admitted overnight on weekdays had lower odds of survival (0·90, 0·82-0·99). INTERPRETATION The weekend effect is a simplification, and just one of several patterns of weekly variation occurring in the quality of stroke care. Weekly variation should be further investigated in other health-care settings, and quality improvement should focus on reducing temporal variation in quality and not only the weekend effect. FUNDING None.