Alexander Dyker

The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument

BACKGROUND In patients with acute stroke, rapid intervention is crucial to maximise early treatment benefits. Stroke patients commonly have their first contact with medical staff in the emergency room (ER). We designed and validated a stroke recognition tool-the Recognition of Stroke in the Emergency Room (ROSIER) scale-for use by ER physicians. METHODS We prospectively collected data for 1 year (development phase) on the clinical characteristics of patients with suspected acute stroke who were admitted to hospital from the ER. We used logistic regression analysis and clinical reasoning to develop a stroke recognition instrument for application in this setting. Patients with suspected transient ischaemic attack (TIA) with no symptoms or signs when assessed in the ER were excluded from the analysis. The instrument was assessed using the baseline 1-year dataset and then prospectively validated in a new cohort of ER patients admitted over a 9-month period. FINDINGS In the development phase, 343 suspected stroke patients were assessed (159 stroke, 167 non-stroke, 32 with TIA [17 with symptoms when seen in ER]). Common stroke mimics were seizures (23%), syncope (23%), and sepsis (10%). A seven-item (total score from -2 to +5) stroke recognition instrument was constructed on the basis of clinical history (loss of consciousness, convulsive fits) and neurological signs (face, arm, or leg weakness, speech disturbance, visual field defect). When internally validated at a cut-off score greater than zero, the instrument showed a diagnostic sensitivity of 92%, specificity of 86%, positive predictive value (PPV) of 88%, and negative predictive value (NPV) of 91%. Prospective validation in 173 consecutive suspected stroke referrals (88 stroke, 59 non-stroke, 26 with TIA [13 with symptoms]) showed sensitivity of 93% (95% CI 89-97), specificity 83% (77-89), PPV 90% (85-95), and NPV 88% (83-93). The ROSIER scale had greater sensitivity than existing stroke recognition instruments in this population. INTERPRETATION The ROSIER scale was effective in the initial differentiation of acute stroke from stroke mimics in the ER. Introduction of the instrument improved the appropriateness of referrals to the stroke team.

Agreement Between Ambulance Paramedic- and Physician-Recorded Neurological Signs With Face Arm Speech Test (FAST) in Acute Stroke Patients

Background and Purpose— Patients with suspected stroke first assessed by ambulance paramedics require early recognition to facilitate appropriate triage and early treatment. We determined paramedics accuracy in detecting acute stroke signs by comparing agreement between neurological signs recorded in the Face Arm Speech Test (FAST), a stroke recognition instrument, by paramedics on the scene and by stroke physicians after admission. Methods— Suspected stroke patients admitted by ambulance paramedics directly to an acute stroke unit through a rapid ambulance protocol were examined by a trainee stroke neurologist or admitting stroke physician over a 1-year period. Recorded neurological signs (facial weakness, arm weakness, speech disturbance) in confirmed acute stroke/transient ischemic attack (TIA) cases were compared between paramedics and the stroke neurologist/physician. Results— Ambulance crews referred 278 suspected stroke patients of whom 217 (78%) had confirmed stroke (n=189) or TIA (n=28); 95% were examined by the stroke neurologist (median 18 hours after paramedic assessment). Recorded signs and agreement between paramedics and stroke physicians in confirmed stroke group were: facial weakness, 68% versus 70% (κ=0.49; 95% CI: 0.36 to 0.62); arm weakness, 96% versus 95% (κ=0.77; 95% CI: 0.55 to 0.99); and speech disturbance, 79% versus 77% (κ=0.69; 95% CI: 0.56 to 0.82). Interrater agreement was complete for arm weakness in 98% cases. Conclusions— Recognition of neurological deficits by ambulance paramedics using FAST shows good agreement with physician assessment, even allowing for temporal evolution of deficits. The high prevalence and good agreement for arm weakness suggest that this sign may have the greatest usefulness for prehospital ambulance triage and paramedic-based neuroprotective trials.

The Apolipoprotein E ε4 Allele and Outcome in Cerebrovascular Disease

Background and Purpose —Polymorphism of the apolipoprotein E gene ( APOE ) may influence outcome after traumatic brain injury and intracerebral hemorrhage, with the e4 allele being associated with poorer prognosis. We investigated APOE allele distribution in acute stroke and the effect of the e4 allele on outcome. Methods — APOE genotypes were determined in 714 stroke patients: 640 ischemic stroke and 74 intracerebral hemorrhage patients. The survival effect of the e4 allele was assessed with the use of a stratified log-rank test. A Cox proportional hazards regression model was used to estimate the independent effect of e4 dose (0, 1, or 2) on survival, and logistic regression was used to determine the effect on 3-month outcome (good if alive at home, poor if in care or dead). Results —Allele distribution matched the general population with no difference between the ischemic and hemorrhagic groups. Survival in the entire cohort was unaffected by e4 dose. Improved survival with increasing e4 dose was found in the ischemic group (relative hazard=0.76 per allele; P =0.04). If transient ischemic attacks were excluded, a trend for improved survival persisted ( P =0.06). With intracerebral hemorrhage, a trend was seen toward reduced survival with e4 ( P =0.07, log-rank test). Three-month outcome in the ischemic group was unaffected by e4 dose, and a trend toward poorer outcome with e4 was seen for intracerebral hemorrhage ( P =0.10). Conclusions —The APOE e4 allele had divergent effects on survival and outcome in ischemic and hemorrhagic strokes in this population. The reported adverse effect on patients with intracerebral hemorrhage was supported. The favorable survival effect on ischemic stroke patients requires further study.

Thrombolytic therapy for acute stroke in the United Kingdom: experience from the safe implementation of thrombolysis in stroke (SITS) register

AIM To describe the United Kingdom (UK) experience with thrombolytic therapy with intravenous alteplase (rt-PA) for stroke, as captured by the Implementation of Thrombolysis in Stroke (SITS) project. METHODS The multinational Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) was an observational study to assess the safety and efficacy of thrombolytic therapy, when administered within the first 3 h after onset of ischaemic stroke. SITS-MOST was embedded within the Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR), an internet-based, international monitoring registry for auditing the safety and efficacy of routine therapeutic use of thrombolysis in acute ischaemic stroke. We performed an analysis of data contributed to SITS-MOST and SITS-ISTR from UK centres. RESULTS A total of 614 patients received thrombolysis for stroke between December 2002 and April 2006, 327 were registered to SITS-MOST and 287 to SITS-ISTR. Thirty-one centres treated patients in the UK, of which 23 registered patients in both SITS-MOST and SITS-ISTR and eight solely to SITS-ISTR. The median age from the UK SITS-MOST was identical to the non-UK SITS-MOST register: 68 years (IQR 59-75). The majority (96.1%) of patients from the UK were treated between 8.00 a.m. and 9.00 p.m., and only 18.4% were treated on weekend days, reflecting the difficulties of maintaining provision of a thrombolytic service out of hours. Median onset-to-treatment-time was 155 min (IQR 130-170 min) for the UK, compared to 140 min (IQR 114-165 min) for the non-UK SITS-MOST group (P < 0.001). UK SITS-MOST patients at baseline had more severe stroke in comparison with non-UK patients [median NIHSS 14.5 (IQR 9-19) vs. 12 (IQR 8-17) (P < 0.001)]. Forty-eight percent of UK patients achieved mRS of 0-2 (independence), compared to 55% of the non-UK SITS-MOST register. There was no significant difference in symptomatic intracerebral haemorrhage rate in the UK compared with the non-UK SITS-MOST patients [2.5% (95% CI 1.3-4.8) vs. 1.7% (95% CI 1.4-2.0) P = 0.28]. In the multivariate analysis, there was no statistically significant difference in any outcome between UK and non-UK SITS-MOST patients. CONCLUSION Thrombolytic therapy for stroke has been implemented successfully at a small number of UK stroke centres, with patchy provision throughout the country. The low frequency of treatment out with office hours suggests deficient infrastructure to support delivery. UK patients tended to be more severely affected at baseline and to be treated later. Outcomes are comparable to those seen at the non-UK SITS centres.

Apolipoprotein E genotype, coagulation, and survival following acute stroke

Article abstract— The authors hypothesized that divergent influences of the APOE ε4 allele on ischemic and hemorrhagic stroke survival might result from differences in coagulation profiles. In 49 hemorrhagic stroke patients, ε4 carriers had higher partial thromboplastin time ratios (p < 0.01) than non-ε4 carriers. Among 529 ischemic stroke patients, increasing ε4 allele dose was associated with improved survival (p = 0.03) after adjusting for baseline NIH stroke scale (p = 0.00001) and partial thromboplastin time ratio (p = 0.01). Relative anticoagulation does not fully explain the survival advantage in ε4-carrying ischemic stroke patients.

Tolerability of the Low-Affinity, Use-Dependent NMDA Antagonist AR-R15896AR in Stroke Patients A Dose-Ranging Study

Background and Purpose — AR-R15896AR is a use-dependent, low-affinity blocker of the NMDA ion channel with neuroprotective effects in animal models of focal cerebral ischemia. This study aimed to establish the highest safe and tolerated loading and maintenance dosing regimen of AR-R15896AR in acute ischemic stroke patients and to determine the associated plasma concentrations of AR-R15896AR. Methods — This was a 4-part, multicenter, randomized, double-blind, placebo-controlled study in 175 patients (mean age, 69 years) within 24 hours of acute stroke symptom recognition. Ascending 60-minute intravenous infusion loading doses of AR-R15896AR were initially examined (100, 150, 200, 250, or 300 mg or placebo in 3:1 randomization, n=36 treated); in part 2, 250, 275, or 300 mg was compared with placebo (n=33). In part 3, a 250-mg loading dose was followed by 9 maintenance doses of 60, 75, 90, 105, or 120 mg every 8 hours versus placebo in 3:1 randomization (n=59); subsequently, in part 4, maintenance doses of 90, 105, and 120 mg after the 250-mg loading dose were directly randomized against placebo (n=42). Safety, tolerability, and pharmacokinetics were the primary end points; NIHSS at 1 week and Barthel and modified Rankin scores at 1 month were also recorded, but the study was neither designed nor powered to assess efficacy. Results — Rates for mortality and serious adverse events (SAE) were similar in active and placebo groups (9% mortality and 23% SAE for all active combined versus 11% mortality and 33% SAE for placebo). Adverse events associated with AR-R15896AR were dizziness, vomiting, nausea, stupor, and some agitation/hallucination. Withdrawal from treatment occurred only in response to loading doses with AR-R15896AR: placebo, 3 of 46 (7%); 250 mg, 11 of 89 (12%); 275 mg, 1 of 8 (12.5%); and 300 mg, 3 of 15 (20%). No significant difference in outcome was observed between groups. Plasma concentrations of AR-R15896AR were 1524±536 ng/mL at the end of the 250-mg loading infusion and were 1847±478 ng/mL at steady state after the 9 maintenance doses of 120 mg. Conclusions — The maximum tolerated loading infusion of AR-R15896AR in this study was 250 mg over a period of 1 hour. Subsequent maintenance infusions of 120 mg every 8 hours were well tolerated. With these doses, putative neuroprotective concentrations of 1240 ng/mL are attained by the loading dose and are satisfactorily maintained thereafter. The loading dose may be improved further by adjustment on an individual patient basis, but tolerability issues remain.

Predictors of Acute and Persisting Ischemic Brain Lesions in Patients Randomized to Carotid Stenting or Endarterectomy

Background and Purpose— We investigated predictors for acute and persisting periprocedural ischemic brain lesions among patients with symptomatic carotid stenosis randomized to stenting or endarterectomy in the International Carotid Stenting Study. Methods— We assessed acute lesions on diffusion-weighted imaging 1 to 3 days after treatment in 124 stenting and 107 endarterectomy patients and lesions persisting on fluid-attenuated inversion recovery after 1 month in 86 and 75 patients, respectively. Results— Stenting patients had more acute (relative risk, 8.8; 95% confidence interval, 4.4–17.5; P<0.001) and persisting lesions (relative risk, 4.2; 95% confidence interval, 1.6–11.1; P=0.005) than endarterectomy patients. Acute lesion count was associated with age (by trend), male sex, and stroke as the qualifying event in stenting; high systolic blood pressure in endarterectomy; and white matter disease in both groups. The rate of conversion from acute to persisting lesions was lower in the stenting group (relative risk, 0.4; 95% confidence interval, 0.2–0.8; P=0.007), and was only predicted by acute lesion volume. Conclusions— Stenting caused more acute and persisting ischemic brain lesions than endarterectomy. However, the rate of conversion from acute to persisting lesions was lower in the stenting group, most likely attributable to lower acute lesion volumes. Clinical Trial Registration —URL: www.isrctn.org. Unique identifier: ISRCTN25337470.

Platelet Function Following Acute Cerebral Ischemia

Background: Studies have previously identified increased levels of platelet activation following acute ischemic stroke. In order to evaluate new antiplatelet agents and their combinations, there is a need for accurate measures of platelet activation. Methods: Blood was taken from 17 patients within 24 hours of an acute ischemic stroke, and then at 3, 7, 14 and 42 days. For comparison, a group of 18 stable arteriopaths had identical tests performed. Platelet aggregation was measured using a free platelet counting technique, and platelet surface P-selectin and monocyte platelet aggregates (MPAs) were measured using flow cytometry. Soluble P-selectin and D-dimers were measured by an enzyme linked immune assay. Results: The initial level of MPAs was significantly raised in the stroke patients compared with the stable patients (p = 0.04, 14.2% vs. 9.3%); however, this difference was not significantly higher than later study points (14.2%, 10.1%, 9.3%, 11.9%, 11.3%; days 1, 3, 7, 14 and 42 respectively. Day 1 vs. day 7 p = 0.07 ANOVA). No changes in P-selectin or platelet aggregation were identified. D-dimer levels were significantly higher on day 7 than day 42 (p < 0.01), and fibrinogen levels were elevated on both days 3 and 14 compared with day 42. Fibrinogen levels were not elevated compared with stable patients. Conclusions: MPA levels are elevated following an acute ischemic stroke compared to stable patients, but no significant change was seen with other platelet markers. This study suggests MPAs are a more sensitive marker of platelet activation than either P-selectin or aggregation.

Soluble but not platelet P-selectin correlates with spontaneous platelet aggregation: a pilot study.

Background. P-selectin (PS) is a marker of platelet activation measured on the platelet surface as platelet PS (pPS) or in serum as soluble PS (sPS). Controversy remains over the exact relationship between sPS, pPS, and other markers such as spontaneous platelet aggregation (SPA). Objective. To investigate correlations between pPS, sPS, and SPA in patients with peripheral arterial disease. Methods. SPA, pPS, and sPS levels were measured in venous blood sampled from patients following intermittent claudication (n = 18) or an acute stroke (n = 18). Results. SPA and sPS correlated significantly in the claudicants (Pearson correlation coefficient, r = 0.661; P = .0020) and stroke patients (r = 0.514; P = .020). No significant correlation was identified between pPS and SPA, or sPS and pPS. Conclusions. The 2 methods of assessing PS are not comparable. Although pPS is accepted as a platelet activation marker, sPS may be a better indicator of aggregation represented by SPA.