John H. Wong

Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial

BACKGROUND Neuroprotection with NA-1 (Tat-NR2B9c), an inhibitor of postsynaptic density-95 protein, has been shown in a primate model of stroke. We assessed whether NA-1 could reduce ischaemic brain damage in human beings. METHODS For this double-blind, randomised, controlled study, we enrolled patients aged 18 years or older who had a ruptured or unruptured intracranial aneurysm amenable to endovascular repair from 14 hospitals in Canada and the USA. We used a computer-generated randomisation sequence to allocate patients to receive an intravenous infusion of either NA-1 or saline control at the end of their endovascular procedure (1:1; stratified by site, age, and aneurysm status). Both patients and investigators were masked to treatment allocation. The primary outcome was safety and primary clinical outcomes were the number and volume of new ischaemic strokes defined by MRI at 12-95 h after infusion. We used a modified intention-to-treat (mITT) analysis. This trial is registered with ClinicalTrials.gov, number NCT00728182. FINDINGS Between Sept 16, 2008, and March 30, 2011, we randomly allocated 197 patients to treatment-12 individuals did not receive treatment because they were found to be ineligible after randomisation, so the mITT population consisted of 185 individuals, 92 in the NA-1 group and 93 in the placebo group. Two minor adverse events were adjudged to be associated with NA-1; no serious adverse events were attributable to NA-1. We recorded no difference between groups in the volume of lesions by either diffusion-weighted MRI (adjusted p value=0·120) or fluid-attenuated inversion recovery MRI (adjusted p value=0·236). Patients in the NA-1 group sustained fewer ischaemic infarcts than did patients in the placebo group, as gauged by diffusion-weighted MRI (adjusted incidence rate ratio 0·53, 95% CI 0·38-0·74) and fluid-attenuated inversion recovery MRI (0·59, 0·42-0·83). INTERPRETATION Our findings suggest that neuroprotection in human ischaemic stroke is possible and that it should be investigated in larger trials. FUNDING NoNO Inc and Arbor Vita Corp.

Canadian Experience with the Pipeline Embolization Device for Repair of Unruptured Intracranial Aneurysms

BACKGROUND AND PURPOSE: Flow-diverting stents, such as the PED, have emerged as a novel means of treating complex intracranial aneurysms. This retrospective analysis of the initial Canadian experience provides insight into technical challenges, clinical and radiographic outcomes, and complication rates after the use of flow-diverting stents for unruptured aneurysms. MATERIALS AND METHODS: Cases were compiled from 7 Canadian centers between July 2008 and December 2010. Each center prospectively tracked their initial experience; these data were retrospectively updated and pooled for analysis. RESULTS: During the defined study period, 97 cases of unruptured aneurysm were treated with the PED, with successful stent deployment in 94 cases. The overall complete or near-complete occlusion rate was 83%, with a median follow-up at 1.25 years (range 0.25–2.5 years). Progressive occlusion was witnessed over time, with complete or near-complete occlusion in 65% of aneurysms followed through 6 months, and 90% of aneurysms followed through 1 year. Multivariate analysis found previous aneurysm treatment and female sex predictive of persistent aneurysm filling. Most patients were stable or improved (88%), with the most favorable outcomes observed in patients with cavernous carotid aneurysms. The overall mortality rate was 6%. Postprocedural aneurysm hemorrhage occurred in 3 patients (3%), while ipsilateral distal territory hemorrhage was observed in 4 patients (3.4%). CONCLUSIONS: Flow-diverting stents represent an important tool in the treatment of complex intracranial aneurysms. The relative efficacy and morbidity of this treatment must be considered in the context of available alternate interventions.

Regional Performance of Carotid Endarterectomy Appropriateness, Outcomes, and Risk Factors for Complications

BACKGROUND AND PURPOSE Guided by the findings of randomized controlled trials evaluating carotid endarterectomy (CEA), we examined the appropriateness of CEAs performed in our city and determined the incidences and risk factors for postoperative stroke, death, and cardiac complications. METHODS Using health records, we retrospectively reviewed 291 consecutive CEAs performed in our region over 18 months. Based on randomized controlled trial results and standardized remeasurements of angiographic carotid stenoses, indications for CEA were considered appropriate for symptomatic carotid stenoses > or = 70%, uncertain for < 70% symptomatic or > or = 60% asymptomatic stenoses, or inappropriate for < 60% asymptomatic stenoses and for patients with preoperative neurological or medical instability. RESULTS We found that 41% of patients (118/291) were asymptomatic. Surgical indications were appropriate in 33% of cases (92/281), uncertain in 49% (138/281), and inappropriate in 18% (51/281). Stroke or death occurred within 30 days postoperatively in 5.2% (9/174) of symptomatic patients and 5.1% (6/117) of asymptomatic patients. At least one cardiac complication (angina, congestive heart failure, dysrhythmia, or myocardial infarction) developed in 8.9% (26/291). Independent preoperative risk factors for stroke or death were histories of angina or congestive heart failure and lack of antiplatelet medication; for cardiac complications, risk factors were age > 75 years and a history of congestive heart failure. CONCLUSIONS Almost 1 in 5 patients underwent CEA inappropriately, which was most commonly due to apparent over-estimation of stenosis severity, and half had uncertain indications. Our high complication rate possibly negated any overall surgical benefit in the large group of asymptomatic patients.

Hemodynamic Instability after Carotid Endarterectomy: Risk Factors and Associations with Operative Complications

OBJECTIVE To examine the incidences of hypertension, hypotension, and bradycardia after carotid endarterectomy (CEA) and to identify any hemodynamic variables predictive of postoperative stroke, death, or cardiac complications. METHODS Retrospective population-based cohort study of 291 consecutive patients undergoing CEA using hospital chart review. Hemodynamic data collected from time of arrival in the recovery room until the end of the 1st postoperative day. Primary and secondary outcome events were stroke or death within 30 days of surgery and any postoperative cardiac complication (angina, congestive heart failure, dysrhythmia, or myocardial infarction), respectively. RESULTS The incidences of postoperative hypertension (systolic blood pressure > 220 mm Hg), hypotension (systolic blood pressure < 90 mm Hg), and bradycardia (pulse < 60 beats/min) were 9% (26 of 290 cases), 12% (36 of 290 cases), and 55% (159 of 290 cases), respectively. The stroke or death rate was 5.2% (15 of 291 cases). Postoperative hypertension was associated significantly with stroke or death (P = 0.04) and by a statistical trend with cardiac complications (P = 0.07). Independent preoperative risk factors for postoperative hypertension by multivariate analysis included angiographic intracranial carotid stenosis greater than 50%, cardiac dysrhythmia, preoperative systolic blood pressure greater than 160 mm Hg, neurological instability, and renal insufficiency. Postoperative hypotension and bradycardia did not correlate with primary or secondary outcomes. CONCLUSION Hemodynamic instability was commonly observed after CEA, but only postoperative hypertension was associated with stroke or death and, possibly, with cardiac complications. Patients undergoing CEA, especially those at risk for postoperative hypertension, may be monitored best in settings suited to the expeditious management of neurological and cardiovascular emergencies.

The unruptured intracranial aneurysm treatment score A multidisciplinary consensus

Objective: We endeavored to develop an unruptured intracranial aneurysm (UIA) treatment score (UIATS) model that includes and quantifies key factors involved in clinical decision-making in the management of UIAs and to assess agreement for this model among specialists in UIA management and research. Methods: An international multidisciplinary (neurosurgery, neuroradiology, neurology, clinical epidemiology) group of 69 specialists was convened to develop and validate the UIATS model using a Delphi consensus. For internal (39 panel members involved in identification of relevant features) and external validation (30 independent external reviewers), 30 selected UIA cases were used to analyze agreement with UIATS management recommendations based on a 5-point Likert scale (5 indicating strong agreement). Interrater agreement (IRA) was assessed with standardized coefficients of dispersion (vr*) (vr* = 0 indicating excellent agreement and vr* = 1 indicating poor agreement). Results: The UIATS accounts for 29 key factors in UIA management. Agreement with UIATS (mean Likert scores) was 4.2 (95% confidence interval [CI] 4.1–4.3) per reviewer for both reviewer cohorts; agreement per case was 4.3 (95% CI 4.1–4.4) for panel members and 4.5 (95% CI 4.3–4.6) for external reviewers (p = 0.017). Mean Likert scores were 4.2 (95% CI 4.1–4.3) for interventional reviewers (n = 56) and 4.1 (95% CI 3.9–4.4) for noninterventional reviewers (n = 12) (p = 0.290). Overall IRA (vr*) for both cohorts was 0.026 (95% CI 0.019–0.033). Conclusions: This novel UIA decision guidance study captures an excellent consensus among highly informed individuals on UIA management, irrespective of their underlying specialty. Clinicians can use the UIATS as a comprehensive mechanism for indicating how a large group of specialists might manage an individual patient with a UIA.

Increased expression of the embryonic form of a developmentally regulated mRNA in Alzheimer's disease

There is increasing evidence that an aberrant sprouting response may contribute to some of the neuronal alterations observed in Alzheimers disease (AD). In this study, we demonstrate that in the rat CNS, sprouting results in the reinduction of the embryonic form of the mRNA for alpha-tubulin. The fetal form of alpha-tubulin mRNA was also elevated in the hippocampus obtained from five AD patients, as compared to five elderly controls. These results suggest that the reexpression of embryonic forms of cytoskeletal proteins, in association with an aberrant sprouting response, may contribute to the neuropathological alterations in AD.

Multidisciplinary consensus on assessment of unruptured intracranial aneurysms: proposal of an international research group.

Background and Purpose— To address the increasing need to counsel patients about treatment indications for unruptured intracranial aneurysms (UIA), we endeavored to develop a consensus on assessment of UIAs among a group of specialists from diverse fields involved in research and treatment of UIAs. Methods— After composition of the research group, a Delphi consensus was initiated to identify and rate all features, which may be relevant to assess UIAs and their treatment by using ranking scales and analysis of inter-rater agreement (IRA) for each factor. IRA was categorized as very high, high, moderate, or low. Results— Ultimately, 39 specialists from 4 specialties agreed (high or very high IRAs) on the following key factors for or against UIA treatment decisions: (1) patient age, life expectancy, and comorbid diseases; (2) previous subarachnoid hemorrhage from a different aneurysm, family history for UIA or subarachnoid hemorrhage, nicotine use; (3) UIA size, location, and lobulation; (4) UIA growth or de novo formation on serial imaging; (5) clinical symptoms (cranial nerve deficit, mass effect, and thromboembolic events from UIAs); and (6) risk factors for UIA treatment (patient age and life expectancy, UIA size, and estimated risk of treatment). However, IRAs for features rated with low relevance were also generally low, which underlined the existing controversy about the natural history of UIAs. Conclusions— Our results highlight that neurovascular specialists currently consider many features as important when evaluating UIAs but also highlight that the appreciation of natural history of UIAs remains uncertain, even within a group of highly informed individuals.

Carotid endarterectomy versus stenting: a meta-analysis of randomized trials

BACKGROUND A meta-analysis of randomized controlled trials (RCTs) was conducted to update the available evidence on the safety and efficacy of carotid endarterectomy (CEA) versus carotid artery stenting (CAS) in the treatment of carotid artery stenosis. METHODS A comprehensive search was performed of MEDLINE, EMBASE, CENTRAL, bibliographies of included articles and past systematic reviews, and abstract lists of recent scientific conferences. For each reported outcome, a Mantel-Haenszel random-effects model was used to calculate odds ratios (ORs) and 95% confidence intervals (CI). The I2 statistic was used as a measure of heterogeneity. RESULTS Twelve RCTs enrolling 6,973 patients were included in the meta-analysis. Carotid artery stenting was associated with a significantly greater odds of periprocedural stroke (OR 1.72, 95% CI 1.20 to 2.47) and a significantly lower odds of periprocedural myocardial infarction (OR 0.47, 95% CI 0.29 to 0.78) and cranial neuropathy (OR 0.08, 95% CI, 0.04 to 0.16). The odds of periprocedural death (OR 1.11, 95% CI 0.56 to 2.18), target vessel restenosis (OR 1.95, 95% CI 0.63 to 6.06), and access-related hematoma were similar following either intervention (OR 0.60, 95% CI 0.30 to 1.21). CONCLUSIONS In comparison with CEA, CAS is associated with a greater odds of stroke and a lower odds of myocardial infarction. While the results our meta-analysis support the continued use of CEA as the standard of care in the treatment of carotid artery stenosis, CAS is a viable alternative in patients at elevated risk of cardiac complications.

Improving the Appropriateness of Carotid Endarterectomy Results of a Prospective City-Wide Study

BACKGROUND AND PURPOSE In light of previously reported concerns regarding carotid endarterectomy (CEA) use in our city, our goal was to determine the influence of a prospective audit and educational campaign on the performance of CEA with respect to surgical appropriateness and complication frequency. METHODS Results of our previous audit of 291 CEAs, along with CEA practice guidelines and notification of prospective surveillance, were supplied to surgeons performing CEA in our city. After this, 184 consecutive patients undergoing CEA from September 1996 to August 1997 were followed prospectively. On the basis of blinded standardized remeasurements of angiographic carotid stenoses, CEA was classified as appropriate for patients with symptomatic carotid stenoses >/=70%, uncertain for those with symptomatic stenoses <70% or asymptomatic stenoses >/=60%, and inappropriate for patients with asymptomatic carotid stenoses <60% or preoperative neurological or medical instability. RESULTS Forty percent of patients were asymptomatic. Compared with our prior audit, the rate of appropriate CEAs improved from 33% previously to 49% of cases in the present study (P=0.0005), uncertain indications did not change significantly (49% versus 47%; P=0.61), and inappropriate indications dropped from 18% to 4% (P=0. 00002). Perioperative stroke or death occurred in 6.4% of symptomatic patients but developed in only 2.7% of asymptomatic patients, which was improved from the 5.1% rate previously found. CONCLUSIONS In our city, the use of a surgical audit identified areas of concern regarding CEA, and subsequent education and ongoing surveillance significantly improved the use and performance of this procedure.

Auditing carotid endarterectomy: a regional experience.

BACKGROUND Proof from randomized controlled trials that carotid endarterectomy (CEA) is efficacious in stroke prevention has resulted in a large resurgence of its use in recent years. We wished to determine if patients in our region were being selected and treated with complication rates consistent with the randomized trials. METHODS We have completed four audits of CEAs performed in our region since 1994, each followed by feed-back of results to the participating surgeons. Operations for > 70% symptomatic stenosis were considered appropriate, those for 50%-69% symptomatic and > 60% asymptomatic stenosis were considered uncertain and all others, including those in medically or neurologically unstable patients, were designated inappropriate. In part 4, the referral source and nature of the patients was also determined. RESULTS Part 1 (April 1994-September 1995) found that of 291 CEAs performed 33% were appropriate, 48% were uncertain and 18% were inappropriate, and 40% of patients who underwent CEA were asymptomatic. In part 2 (September 1996-September 1997) appropriate indications significantly improved to 49% of 184 CEAs (P=0.005), uncertain indications remained nearly the same at 47%, inappropriate indications fell to 4% (P=.00002), and asymptomatic patients remained at 40%. The results of part 3 (October 1997-October 1998) remained nearly the same as part 2 (249 CEAs, 47% appropriate, 51% uncertain, 2% inappropriate, 45% asymptomatic). Part 4 (October 1999-October 2000) results were significantly better than part 3, appropriate indications increasing from 47% to 58% of 222 CEAs (P=0.02), and an elimination of inappropriate operations (P=0.03). Stroke and death complications declined over the study period from an overall rate of 5.2% in part 1 to 2.3% in part 4. In part 4 the majority of patients (69%) were referred to surgeons directly from general practitioners, including 58 (73%) of the 80 asymptomatic patients who underwent CEA. INTERPRETATION Regular auditing and feedback of results and information to surgeons has resulted in significant and continued improvements in the surgical performance of CEA in our region. Since the majority of patients are referred directly to surgeons by general practitioners, it is important that this group of physicians be familiar with current CEA guidelines.