Albert Y. Jin

Atrial Fibrillation in Patients with Cryptogenic Stroke

BACKGROUND Atrial fibrillation is a leading preventable cause of recurrent stroke for which early detection and treatment are critical. However, paroxysmal atrial fibrillation is often asymptomatic and likely to go undetected and untreated in the routine care of patients with ischemic stroke or transient ischemic attack (TIA). METHODS We randomly assigned 572 patients 55 years of age or older, without known atrial fibrillation, who had had a cryptogenic ischemic stroke or TIA within the previous 6 months (cause undetermined after standard tests, including 24-hour electrocardiography [ECG]), to undergo additional noninvasive ambulatory ECG monitoring with either a 30-day event-triggered recorder (intervention group) or a conventional 24-hour monitor (control group). The primary outcome was newly detected atrial fibrillation lasting 30 seconds or longer within 90 days after randomization. Secondary outcomes included episodes of atrial fibrillation lasting 2.5 minutes or longer and anticoagulation status at 90 days. RESULTS Atrial fibrillation lasting 30 seconds or longer was detected in 45 of 280 patients (16.1%) in the intervention group, as compared with 9 of 277 (3.2%) in the control group (absolute difference, 12.9 percentage points; 95% confidence interval [CI], 8.0 to 17.6; P<0.001; number needed to screen, 8). Atrial fibrillation lasting 2.5 minutes or longer was present in 28 of 284 patients (9.9%) in the intervention group, as compared with 7 of 277 (2.5%) in the control group (absolute difference, 7.4 percentage points; 95% CI, 3.4 to 11.3; P<0.001). By 90 days, oral anticoagulant therapy had been prescribed for more patients in the intervention group than in the control group (52 of 280 patients [18.6%] vs. 31 of 279 [11.1%]; absolute difference, 7.5 percentage points; 95% CI, 1.6 to 13.3; P=0.01). CONCLUSIONS Among patients with a recent cryptogenic stroke or TIA who were 55 years of age or older, paroxysmal atrial fibrillation was common. Noninvasive ambulatory ECG monitoring for a target of 30 days significantly improved the detection of atrial fibrillation by a factor of more than five and nearly doubled the rate of anticoagulant treatment, as compared with the standard practice of short-duration ECG monitoring. (Funded by the Canadian Stroke Network and others; EMBRACE ClinicalTrials.gov number, NCT00846924.).

Prospective validation of the ABCD2 score for patients in the emergency department with transient ischemic attack

Background: The ABCD2 score (Age, Blood pressure, Clinical features, Duration of symptoms and Diabetes) is used to identify patients having a transient ischemic attack who are at high risk for imminent stroke. However, despite its widespread implementation, the ABCD2 score has not yet been prospectively validated. We assessed the accuracy of the ABCD2 score for predicting stroke at 7 (primary outcome) and 90 days. Methods: This prospective cohort study enrolled adults from eight Canadian emergency departments who had received a diagnosis of transient ischemic attack. Physicians completed data forms with the ABCD2 score before disposition. The outcome criterion, stroke, was established by a treating neurologist or by an Adjudication Committee. We calculated the sensitivity and specificity for predicting stroke 7 and 90 days after visiting the emergency department using the original “high-risk” cutpoint of an ABCD2 score of more than 5, and the American Heart Association recommendation of a score of more than 2. Results: We enrolled 2056 patients (mean age 68.0 yr, 1046 (50.9%) women) who had a rate of stroke of 1.8% at 7 days and 3.2% at 90 days. An ABCD2 score of more than 5 had a sensitivity of 31.6% (95% confidence interval [CI] 19.1–47.5) for stroke at 7 days and 29.2% (95% CI 19.6–41.2) for stroke at 90 days. An ABCD2 score of more than 2 resulted in sensitivity of 94.7% (95% CI 82.7–98.5) for stroke at 7 days with a specificity of 12.5% (95% CI 11.2–14.1). The accuracy of the ABCD2 score as calculated by either the enrolling physician (area under the curve 0.56; 95% CI 0.47–0.65) or the coordinating centre (area under the curve 0.65; 95% CI 0.57–0.73) was poor. Interpretation: This multicentre prospective study involving patients in emergency departments with transient ischemic attack found the ABCD2 score to be inaccurate, at any cut-point, as a predictor of imminent stroke. Furthermore, the ABCD2 score of more than 2 that is recommended by the American Heart Association is nonspecific.

Canadian Stroke Best Practice Recommendations: secondary prevention of stroke guidelines, update 2014

Every year, approximately 62 000 people with stroke and transient ischemic attack are treated in Canadian hospitals. The 2014 update of the Canadian Secondary Prevention of Stroke guideline is a comprehensive summary of current evidence-based recommendations for clinicians in a range of settings, who provide care to patients following stroke. Notable changes in this 5th edition include an emphasis on treating the highest risk patients who present within 48 h of symptom onset with transient or persistent motor or speech symptoms, who need to be transported to the closest emergency department with capacity for advanced stroke care; a recommendation for brain and vascular imaging (of the intra- and extracranial vessels) to be completed urgently using computed tomography/computed tomography angiography; prolonged cardiac monitoring for patients with suspective cardioembolic stroke but without evidence for atrial fibrillation on electrocardiogram or holter monitoring; and de-emphasizing the need for routine echocardiogram. The Canadian Stroke Best Practice Recommendations include a range of supporting materials such as implementation resources to facilitate the adoption of evidence to practice, and related performance measures to enable monitoring of uptake and effectiveness of the recommendations using a standardized approach. The guidelines further emphasize the need for a systems approach to stroke care, involving an interprofessional team, with access to specialists regardless of patient location, and the need to overcome geographical barriers to ensure equity in access within a universal health-care system.

A prospective cohort study of patients with transient ischemic attack to identify high-risk clinical characteristics.

Background and Purpose— The occurrence of a transient ischemic attack (TIA) increases an individual’s risk for subsequent stroke. The objectives of this study were to determine clinical features of patients with TIA associated with impending (⩽7 days) stroke and to develop a clinical prediction score for impending stroke. Methods— We conducted a prospective cohort study at 8 Canadian emergency departments for 5 years. We enrolled patients with a new TIA. Our outcome was subsequent stroke within 7 days of TIA diagnosis. Results— We prospectively enrolled 3906 patients, of which 86 (2.2%) experienced a stroke within 7 days. Clinical features strongly correlated with having an impending stroke included first-ever TIA, language disturbance, longer duration, weakness, gait disturbance, elevated blood pressure, atrial fibrillation on ECG, infarction on computed tomography, and elevated blood glucose. Variables less associated with having an impending stroke included vertigo, lightheadedness, and visual loss. From this cohort, we derived the Canadian TIA Score which identifies the risk of subsequent stroke ⩽7 days and consists of 13 variables. This model has good discrimination with a c-statistic of 0.77 (95% confidence interval, 0.73–0.82). Conclusions— Patients with TIA with their first TIA, language disturbance, duration of symptoms ≥10 minutes, gait disturbance, atrial fibrillation, infarction on computed tomography, elevated platelets or glucose, unilateral weakness, history of carotid stenosis, and elevated diastolic blood pressure are at higher risk for an impending stroke. Patients with vertigo and no high-risk features are at low risk. The Canadian TIA Score quantifies the impending stroke risk following TIA.

Good is not Good Enough: The Benchmark Stroke Door-to-Needle Time Should be 30 Minutes.

Noreen Kamal, Oscar Benavente, Karl Boyle, Brian Buck, Ken Butcher, Leanne K. Casaubon,RobertCote,AndrewMDemchuk,YanDeschaintre,DarDowlatshahi,GordonJGubitz,GaryHunter,Tom Jeerakathil, Albert Jin, Eddy Lang, Sylvain Lanthier, Patrice Lindsay, Nancy Newcommon,Jennifer Mandzia, Colleen M. Norris, Wes Oczkowski, Celine Odier, Stephen Phillips,Alexandre Y Poppe, Gustavo Saposnik, Daniel Selchen, Ashfaq Shuaib, Frank Silver, Eric E Smith,Grant Stotts, Michael Suddes, Richard H. Swartz, Philip Teal, Tim Watson, Michael D. Hill

Functionalized amido ketones: new anticonvulsant agents.

We have reported that functionalized amino acids (FAA) are potent anticonvulsants. Replacing the N-terminal amide group in FAA with phenethyl, styryl, and phenylethynyl units provided a series of functionalized amido ketones (FAK). We show that select FAK exhibit significant anticonvulsant activities thereby providing information about the structural requirements for FAA and FAK bioactivity.

Brainstem neurons survive the identical ischemic stress that kills higher neurons: insight to the persistent vegetative state.

Global ischemia caused by heart attack, pulmonary failure, near-drowning or traumatic brain injury often damages the higher brain but not the brainstem, leading to a ‘persistent vegetative state’ where the patient is awake but not aware. Approximately 30,000 U.S. patients are held captive in this condition but not a single research study has addressed how the lower brain is preferentially protected in these people. In the higher brain, ischemia elicits a profound anoxic depolarization (AD) causing neuronal dysfunction and vasoconstriction within minutes. Might brainstem nuclei generate less damaging AD and so be more resilient? Here we compared resistance to acute injury induced from simulated ischemia by ‘higher’ hippocampal and striatal neurons versus brainstem neurons in live slices from rat and mouse. Light transmittance (LT) imaging in response to 10 minutes of oxygen/glucose deprivation (OGD) revealed immediate and acutely damaging AD propagating through gray matter of neocortex, hippocampus, striatum, thalamus and cerebellar cortex. In adjacent brainstem nuclei, OGD-evoked AD caused little tissue injury. Whole-cell patch recordings from hippocampal and striatal neurons under OGD revealed sudden membrane potential loss that did not recover. In contrast brainstem neurons from locus ceruleus and mesencephalic nucleus as well as from sensory and motor nuclei only slowly depolarized and then repolarized post-OGD. Two-photon microscopy confirmed non-recoverable swelling and dendritic beading of hippocampal neurons during OGD, while mesencephalic neurons in midbrain appeared uninjured. All of the above responses were mimicked by bath exposure to 100 µM ouabain which inhibits the Na+/K+ pump or to 1–10 nM palytoxin which converts the pump into an open cationic channel. Therefore during ischemia the Na+/K+ pump of higher neurons fails quickly and extensively compared to naturally resilient hypothalamic and brainstem neurons. The selective survival of lower brain regions that maintain vital functions will support the persistent vegetative state.

Placental growth factor deficiency is associated with impaired cerebral vascular development in mice

STUDY HYPOTHESIS Placental growth factor (PGF) is expressed in the developing mouse brain and contributes to vascularization and vessel patterning. STUDY FINDING PGF is dynamically expressed in fetal mouse brain, particularly forebrain, and is essential for normal cerebrovascular development. WHAT IS KNOWN ALREADY PGF rises in maternal plasma over normal human and mouse pregnancy but is low in many women with the acute onset hypertensive syndrome, pre-eclampsia (PE). Little is known about the expression of PGF in the fetus during PE. Pgf  (-/-) mice appear normal but recently cerebral vascular defects were documented in adult Pgf  (-/-) mice. STUDY DESIGN, SAMPLES/MATERIALS, METHODS Here, temporal-spatial expression of PGF is mapped in normal fetal mouse brains and cerebral vasculature development is compared between normal and congenic Pgf  (-/-) fetuses to assess the actions of PGF during cerebrovascular development. Pgf/PGF, Vegfa/VEGF, Vegf receptor (Vegfr)1 and Vegfr2 expression were examined in the brains of embryonic day (E)12.5, 14.5, 16.5 and 18.5 C57BL/6 (B6) mice using quantitative PCR and immunohistochemistry. The cerebral vasculature was compared between Pgf  (-/-) and B6 embryonic and adult brains using whole mount techniques. Vulnerability to cerebral ischemia was investigated using a left common carotid ligation assay. MAIN RESULTS AND THE ROLE OF CHANCE Pgf/PGF and Vegfr1 are highly expressed in E12.5-14.5 forebrain relative to VEGF and Vegfr2. Vegfa/VEGF is relatively more abundant in hindbrain (HB). PGF and VEGF expression were similar in midbrain. Delayed HB vascularization was seen at E10.5 and 11.5 in Pgf  (-/-) brains. At E14.5, Pgf  (-/-) circle of Willis showed unilateral hypoplasia and fewer collateral vessels, defects that persisted post-natally. Functionally, adult Pgf  (-/-) mice experienced cerebral ischemia after left common carotid arterial occlusion while B6 mice did not. LIMITATIONS, REASONS FOR CAUTION Since Pgf  (-/-) mice were used, consequences of complete absence of maternal and fetal PGF were defined. Therefore, the effects of maternal versus fetal PGF deficiency on cerebrovascular development cannot be separated. However, as PGF was strongly expressed in the developing brain at all timepoints, we suggest that local PGF has a more important role than distant maternal or placental sources. Full PGF loss is not expected in PE pregnancies, predicting that the effects of PGF deficiency identified in this model will be more severe than any effects in PE-offspring. WIDER IMPLICATIONS OF THE FINDINGS These studies provoke the question of whether PGF expression is decreased and cerebral vascular maldevelopment occurs in fetuses who experience a preeclamptic gestation. These individuals have already been reported to have elevated risk for stroke and cognitive impairments. LARGE SCALE DATA N/A. STUDY FUNDING AND COMPETING INTERESTS This work was supported by awards from the Natural Sciences and Engineering Research Council, the Canada Research Chairs Program and the Canadian Foundation for Innovation to B.A.C. and by training awards from the Universidade Federal de Pernambuco and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazil to R.L.L.; Queens University to V.R.K. and the Canadian Institutes of Health Research to M.T.R. The work of P.C. is supported by the Belgian Science Policy BELSPO-IUAP7/03, Structural funding by the Flemish Government-Methusalem funding, and the Flemish Science Fund-FWO grants. There were no competing interests.

Rapid Assessment and Treatment of Transient Ischemic Attacks and Minor Stroke in Canadian Emergency Departments: Time for a Paradigm Shift.

A majority of acute cerebrovascular syndromes are transient ischemic attacks (TIA) or minor ischemic strokes. They are often thought of and managed as though benign, but are in fact a warning of impending disabling stroke. The risk of stroke progression or recurrence is highest in the first hours to days from initial symptom onset, with a 6.7% risk at 48 hours and a 10% risk by 7 days after a TIA.1,2 The highest risk period is early, with a median time to a recurrence or progression event of 1 day; many events occur overnight after the initial ictus.3 Many strokes are preventable after a TIA. Rapid diagnosis and treatment reduces the risk of stroke by as much as 80%4,5 and significantly reduces mortality, long-term disability, and costs.6,7 The estimated annual cost avoidance in Canada from the rapid assessment and treatment of TIA is

IV Thrombolysis in Stroke From a Cavernous Carotid Aneurysm to Artery Embolus

313.8 million (of which