Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial.

BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality. METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual. FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059). INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis. FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.

ExtendeD computed tomogrAphy angiographY for the successfuL DIaGnosis of cardioaortic tHrombus in Acute Ischemic stroke and TIA (DAYLIGHT): Study Protocol for a Randomized Controlled Trial.

INTRODUCTION: Cardiac imaging is one of the main components of the etiological investigation of ischemic strokes. However, basic and advanced cardiac imaging remain underused in most stroke centers globally. Computed tomography angiography (CTA) of the supra-aortic and intracranial arteries is the most frequent imaging modality applied during the evaluation of patients with acute ischemic stroke to identify the presence of a large vessel occlusion. Recent evidence from retrospective observational studies has shown a high detection of cardiac thrombi, ranging from 6.6 to 17.4%, by extending the CTA a few cm below the carina to capture cardiac images. However, this approach has never been prospectively compared against usual care in a randomized controlled trial. The DAYLIGHT (ExtendeD computed tomogrAphy angiographY for the successfuL DIaGnosis of cardioaortic tHrombus in Acute Ischemic stroke and TIA) prospective, randomized, controlled trial will evaluate whether an extended CTA (eCTA) + standard of care stroke workup results in higher detection rates of cardiac and aortic source of embolism compared to standard CTA (sCTA) + standard of care stroke workup. METHODS: DAYLIGHT is a single-center, prospective, randomized, open blinded end-point trial, aiming to recruit 830 patients with suspected acute ischemic stroke or transient ischemic attack (TIA) being assessed under acute code stroke at the Emergency Department or at a dedicated urgent stroke prevention clinic. Patients will be randomized 1:1 to eCTA vs sCTA. The eCTA will expand image acquisition caudally, 6 cm below the carina. All patients will receive standard of care cardiac imaging and diagnostic stroke workup. The primary efficacy endpoint will be the diagnosis of a cardioaortic thrombus after at least 30 days of follow-up. The primary safety endpoint will be door-to-CTA completion. The diagnosis of a qualifying ischemic stroke or TIA will be independently adjudicated by a stroke neurologist, blinded to the study arm allocation. Patients without an adjudicated ischemic stroke or TIA will be excluded from the analysis. The primary outcome events will be adjudicated by a board-certified radiologist with subspecialty training in cardio-thoracic radiology and a cardiologist with formal training in cardiac imaging. The primary analysis will be performed according to the intention-to-diagnose principle and without adjustment by logistic regression models. Results will be presented with odds ratios and 95% confidence intervals Conclusion. The DAYLIGHT trial will provide evidence on whether extending a CTA 6 cm below the carina results in an increased detection of cardio-aortic thrombi compared to standard of care stroke workup. CLINICALTRIALS: gov registration: NCT05522244.

Differences in Stroke Recurrence Risk Between Atrial Fibrillation Detected on ECG and 14-Day Cardiac Monitoring.

BACKGROUND: Ischemic stroke and transient ischemic attack (TIA) standard-of-care etiological investigations include an ECG and prolonged cardiac monitoring (PCM). Atrial fibrillation (AF) detected after stroke has been generally considered a single entity, regardless of how it is diagnosed. We hypothesized that ECG-detected AF is associated with a higher risk of stroke recurrence than AF detected on 14-day Holter (PCM-detected AF). METHODS: We conducted a retrospective, registry-based, cohort study of consecutive patients with ischemic stroke and TIA included in the London Ontario Stroke Registry between 2018 and 2020, with ECG-detected and PCM-detected AF lasting ≥30 seconds. We quantified PCM-detected AF burden. The primary outcome was recurrent ischemic stroke, ascertained by systematically reviewing all medical records until November 2022. We applied marginal cause-specific Cox proportional hazards models adjusted for qualifying event type (ischemic stroke versus TIA), CHA2DS2-VASc score, anticoagulation, left ventricular ejection fraction, left atrial size, and high-sensitivity troponin T to estimate adjusted hazard ratios for recurrent ischemic stroke. RESULTS: We included 366 patients with ischemic stroke and TIA with AF, 218 ECG-detected, and 148 PCM-detected. Median PCM duration was 12 (interquartile range, 8.8-14.0) days. Median PCM-detected AF duration was 5.2 (interquartile range, 0.3-33.0) hours, with a burden (total AF duration/total net monitoring duration) of 2.23% (interquartile range, 0.13%-12.25%). Anticoagulation rate at the end of follow-up or at the first event was 83.1%. After a median follow-up of 17 (interquartile range, 5-34) months, recurrent ischemic strokes occurred in 16 patients with ECG-detected AF (13 on anticoagulants) and 2 with PCM-detected AF (both on anticoagulants). Recurrent ischemic stroke rates for ECG-detected and PCM-detected AF groups were 4.05 and 0.72 per 100 patient-years (adjusted hazard ratio, 5.06 [95% CI, 1.13-22.7]; P=0.034). CONCLUSIONS: ECG-detected AF was associated with 5-fold higher adjusted recurrent ischemic stroke risk than PCM-detected AF in a cohort of ischemic stroke and TIA with >80% anticoagulation rate.

Feasibility of deconvolution-based multiphase CT angiography perfusion maps in acute ischemic stroke: Simulation and concordance with CT perfusion.

OBJECTIVES: Integration of CT perfusion (CTP) with requisite non-contrast CT and CT angiography (CTA) stroke imaging may allow efficient stroke lesion volume measurement. Using surrogate images from CTP, we simulated the feasibility of using multiphase CTA (mCTA) to generate perfusion maps and assess target mismatch profiles. MATERIALS AND METHODS: Patients with acute ischemic stroke who received admission CTP were included in this study. Four CTP images (surrogate mCTA, one pre-contrast and three post-contrast, starting at the arterial peak then at 8 s intervals) were selected according to the CTP arterial time-density curve to simulate non-contrast CT and mCTA images. Cerebral blood flow (CBF) and Tmax maps were calculated using the same model-based deconvolution algorithm for the standard CTP and surrogate mCTA studies. Infarct and penumbra were delineated with CBF < 20% and Tmax > 6 s threshold, respectively. Classification accuracy of surrogate mCTA target mismatch (infarct <70 ml; penumbra ≥15 ml; mismatch ratio ≥1.8) with respect to standard CTP was assessed. Agreement between infarct and penumbra volumes from standard CTP and surrogate mCTA maps were evaluated by Bland-Altman analysis. RESULTS: Of 34 included patients, 28 had target mismatch and 6 did not by standard CTP. Accuracy of classifying target mismatch profiles with surrogate mCTA was 79% with respect to that from standard CTP. Mean  ±  standard deviation of differences (standard CTP minus surrogate mCTA) of infarct and penumbra volumes were 9.8 ± 14.8 ml and 20.1 ± 45.4 ml, respectively. CONCLUSIONS: Surrogate mCTA ischemic lesion volumes agreed with those from standard CTP and may be an efficient alternative when CTP is not practical.

Health-Related Quality of Life Among Patients With Acute Ischemic Stroke and Large Vessel Occlusion in the ESCAPE Trial.

Background and Purpose: Endovascular thrombectomy (EVT) reduces 90-day disability in patients following acute ischemic stroke due to large vessel occlusion. Patient-reported outcome measures after EVT, such as health-related quality of life and specific functional domains, are less well described. Methods: We report outcomes on the EuroQol-5D (EQ-5D) from the ESCAPE (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times) randomized controlled trial at 90 days after stroke. Death was assigned an index value of 0 for EQ-5D. We used quantile regression to evaluate the association between EVT and EQ-5D index scores and logistic regression for the association between EVT and symptom-free status among 90-day survivors for each EQ-5D dimension (self-care, usual activities, mobility, pain/discomfort, and anxiety/depression), assessing for modification by age or sex and adjusting for baseline factors including stroke severity, affected hemisphere, and receipt of alteplase. Lastly, the association between severe disability at 90 days and EQ-5D was evaluated with assessment for modification by EVT, age, and sex. Results: There were 165 patients randomized to EVT and 150 patients randomized to control. Median EQ-5D was significantly higher for those who received EVT compared with best medical management (0.80 versus 0.60; P<0.001). After accounting for the greater number of deaths in the elderly, there was evidence of modification of treatment effect by age, with older age associated with a larger effect size difference in EQ-5D with EVT. Those receiving EVT had higher odds of symptom-free status in self-care, usual activities, mobility for those aged 60 to 79 years, and pain/discomfort for women, but there was no association with anxiety/depression. Severe disability at 90 days was associated with lower EQ-5D in older compared with younger individuals, and the association was not modified by EVT. Conclusions: Patients treated with EVT report substantially improved health-related quality of life, with relatively greater impact in older individuals and observed benefit across multiple dimensions.

Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke. METHODS: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018. FINDINGS: Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups. INTERPRETATION: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. FUNDING: Canadian Institutes for Health Research, Alberta Innovates, and NoNO.

COVID-19: Stroke Admissions, Emergency Department Visits, and Prevention Clinic Referrals.

We assessed the impact of the coronavirus disease 19 (COVID-19) pandemic on code stroke activations in the emergency department, stroke unit admissions, and referrals to the stroke prevention clinic at London's regional stroke center, serving a population of 1.8 million in Ontario, Canada. We found a 20% drop in the number of code strokes in 2020 compared to 2019, immediately after the first cases of COVID-19 were officially confirmed. There were no changes in the number of stroke admissions and there was a 22% decrease in the number of clinic referrals, only after the provincial lockdown. Our findings suggest that the decrease in code strokes was mainly driven by patient-related factors such as fear to be exposed to the SARS-CoV-2, while the reduction in clinic referrals was largely explained by hospital policies and the Government lockdown.

Rare Bilateral Caudate Infarction in a Patient with a Common Circle of Willis Variant.

A 62-year-old male presented to hospital with acute aphasia. His past medical history was significant for a previous left middle cerebral artery stroke, from which he fully recovered, hypertension, dyslipidemia, coronary artery disease, one episode of atrial fibrillation postoperatively, and thalidomide exposure in utero. Although initially he was thought to be aphasic, on further examination, he demonstrated significant abulia. His level of consciousness was normal, and neurological examination was otherwise unremarkable. A CT angiogram of the head and neck was performed. The patient was not a candidate for acute therapy, as he had established stroke on imaging, and the time of onset was unclear.

Randomized assessment of rapid endovascular treatment of ischemic stroke.

BACKGROUND: Among patients with a proximal vessel occlusion in the anterior circulation, 60 to 80% of patients die within 90 days after stroke onset or do not regain functional independence despite alteplase treatment. We evaluated rapid endovascular treatment in addition to standard care in patients with acute ischemic stroke with a small infarct core, a proximal intracranial arterial occlusion, and moderate-to-good collateral circulation. METHODS: We randomly assigned participants to receive standard care (control group) or standard care plus endovascular treatment with the use of available thrombectomy devices (intervention group). Patients with a proximal intracranial occlusion in the anterior circulation were included up to 12 hours after symptom onset. Patients with a large infarct core or poor collateral circulation on computed tomography (CT) and CT angiography were excluded. Workflow times were measured against predetermined targets. The primary outcome was the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. A proportional odds model was used to calculate the common odds ratio as a measure of the likelihood that the intervention would lead to lower scores on the modified Rankin scale than would control care (shift analysis). RESULTS: The trial was stopped early because of efficacy. At 22 centers worldwide, 316 participants were enrolled, of whom 238 received intravenous alteplase (120 in the intervention group and 118 in the control group). In the intervention group, the median time from study CT of the head to first reperfusion was 84 minutes. The rate of functional independence (90-day modified Rankin score of 0 to 2) was increased with the intervention (53.0%, vs. 29.3% in the control group; P<0.001). The primary outcome favored the intervention (common odds ratio, 2.6; 95% confidence interval, 1.7 to 3.8; P<0.001), and the intervention was associated with reduced mortality (10.4%, vs. 19.0% in the control group; P=0.04). Symptomatic intracerebral hemorrhage occurred in 3.6% of participants in intervention group and 2.7% of participants in control group (P=0.75). CONCLUSIONS: Among patients with acute ischemic stroke with a proximal vessel occlusion, a small infarct core, and moderate-to-good collateral circulation, rapid endovascular treatment improved functional outcomes and reduced mortality. (Funded by Covidien and others; ESCAPE ClinicalTrials.gov number, NCT01778335.).

Imaging and Baseline Predictors of Cognitive Performance in Minor Ischemic Stroke and Patients With Transient Ischemic Attack at 90 Days.

BACKGROUND AND PURPOSE: Few studies have examined predictors of cognitive impairment after minor ischemic stroke and transient ischemic attack (TIA). We examined clinical and imaging features associated with worse cognitive performance at 90 days. METHODS: TIA or patients with minor stroke underwent neuropsychological testing 90 days post event. Z scores were calculated for cognitive tests, and then grouped into domains of executive function (EF), psychomotor processing speed (PS), and memory. White matter hyperintensity and diffusion-weighted imaging volumes were measured on baseline magnetic resonance imaging. Ninety-day outcomes included modified Rankin Scale (mRS) and Centre for Epidemiological Studies Depression Scale (CES-D) score. RESULTS: Ninety-two patients were included, 76% male, 54% TIA, and mean age 65.1±12.0. Sixty-four percent were diffusion-weighted imaging positive. Median domain z scores were not significantly different from published norms (P>0.05): memory -0.03, EF -0.12, and PS -0.05. Patient performance ≥1 SD below normal was 20% on memory, 16% on PS, and 17% on EF. Cognitive scores did not differ by diagnosis (stroke versus TIA), stroke pathogenesis, presence of obstructive sleep apnea, and diffusion-weighted imaging or white matter hyperintensity volumes. In multivariable analyses, lower EF was associated with previous cortical infarct on magnetic resonance imaging (P=0.03), mRS score of >1; P=0.0003 and depressive symptoms (CES-D ≥16; P=0.03). Lower PS scores were associated with previous cortical infarct (P=0.02), acute bilateral positive diffusion-weighted imaging (P=0.02), mRS score of >1 (P=0.003), and CES-D ≥16 (P=0.03). CONCLUSIONS: Despite average-range cognitive performance in this TIA and population with minor stroke, we found associations of EF and PS with evidence of previous stroke, postevent disability, and depression.

Men Are at Higher Risk of Screening Positive for Vascular Cognitive Impairment Compared to Women after Stroke and Transient Ischemic Attack.

While women have greater incidence of dementia, men have higher prevalence of vascular risk factors. This study examined sex differences in risk of screening positive for cognitive impairment after stroke. Ischemic stroke/TIA patients (N = 5969) participated in this prospective, multi-centered study, which screened for cognitive impairment using a validated brief screen. Men showed a higher risk of screening positive for cognitive impairment after adjusting for age, education, stroke severity, and vascular risk factors, suggesting that other factors may be contributing to increased risk among men (OR = 1.34, CI 95% [1.16, 1.55], p < 0.001). The effect of sex on cognitive impairment after stroke warrants further attention.

Cognitive correlates of antisaccade behaviour across multiple neurodegenerative diseases.

Oculomotor tasks generate a potential wealth of behavioural biomarkers for neurodegenerative diseases. Overlap between oculomotor and disease-impaired circuitry reveals the location and severity of disease processes via saccade parameters measured from eye movement tasks such as prosaccade and antisaccade. Existing studies typically examine few saccade parameters in single diseases, using multiple separate neuropsychological test scores to relate oculomotor behaviour to cognition; however, this approach produces inconsistent, ungeneralizable results and fails to consider the cognitive heterogeneity of these diseases. Comprehensive cognitive assessment and direct inter-disease comparison are crucial to accurately reveal potential saccade biomarkers. We remediate these issues by characterizing 12 behavioural parameters, selected to robustly describe saccade behaviour, derived from an interleaved prosaccade and antisaccade task in a large cross-sectional data set comprising five disease cohorts (Alzheimer's disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease, and cerebrovascular disease; n = 391, age 40-87) and healthy controls (n = 149, age 42-87). These participants additionally completed an extensive neuropsychological test battery. We further subdivided each cohort by diagnostic subgroup (for Alzheimer's disease/mild cognitive impairment and frontotemporal dementia) or degree of cognitive impairment based on neuropsychological testing (all other cohorts). We sought to understand links between oculomotor parameters, their relationships to robust cognitive measures, and their alterations in disease. We performed a factor analysis evaluating interrelationships among the 12 oculomotor parameters and examined correlations of the four resultant factors to five neuropsychology-based cognitive domain scores. We then compared behaviour between the abovementioned disease subgroups and controls at the individual parameter level. We theorized that each underlying factor measured the integrity of a distinct task-relevant brain process. Notably, Factor 3 (voluntary saccade generation) and Factor 1 (task disengagements) significantly correlated with attention/working memory and executive function scores. Factor 3 also correlated with memory and visuospatial function scores. Factor 2 (pre-emptive global inhibition) correlated only with attention/working memory scores, and Factor 4 (saccade metrics) correlated with no cognitive domain scores. Impairment on several mostly antisaccade-related individual parameters scaled with cognitive impairment across disease cohorts, while few subgroups differed from controls on prosaccade parameters. The interleaved prosaccade and antisaccade task detects cognitive impairment, and subsets of parameters likely index disparate underlying processes related to different cognitive domains. This suggests that the task represents a sensitive paradigm that can simultaneously evaluate a variety of clinically relevant cognitive constructs in neurodegenerative and cerebrovascular diseases and could be developed into a screening tool applicable to multiple diagnoses.

Network interactions explain effective encoding in the context of medial temporal damage in MCI.

Selective dysfunction in the medial temporal lobe (MTL) in amnestic mild cognitive impairment (MCI) results in a relatively circumscribed impairment in episodic memory. Previously, we found that activation extent in MTL during encoding correlated with subsequent recognition (hit rate) in controls but not in MCI patients (Mandzia et al. [2009]: Neurobiol Aging 30:717-730). Here, we examined whether functional connectivity amongst MTL and cortical regions might better explain differences in subsequent recognition success. Participants underwent fMRI scanning during picture encoding, and multivariate analysis was used to characterize the relationship between network activations and recognition. Both patients and controls activated a canonical MTL encoding network. However, this network correlated with hit rate only for controls. In MCI patients, recognition variability was best explained by the engagement of an additional network including BA 20. We propose that this pattern represents functional reorganization caused by reduced efficiency in the MTL network. Our findings suggest that understanding brain-behavior relationships in neurological disorders requires examination of large-scale networks, even when dysfunction is relatively focal as in MCI.

Primary CNS vasculitis: A systematic review on clinical characteristics associated with abnormal biopsy and angiography.

BACKGROUND: Primary Central Nervous System Vasculitis (PCNSV) remains a diagnostic challenge due to its variable and non-specific clinical manifestations. In part, the clinical heterogeneity of PCNSV may be a consequence of the modalities used for diagnosis; accordingly, there may be different subtypes of PCNSV based on whether the diagnosis was attained by biopsy or cerebral angiography. OBJECTIVE: To examine the frequency of symptoms, laboratory, and radiological features associated with PCNSV, and to identify distinct clinical features between biopsy and angiography defined PCNSV. METHODS: We conducted a systematic review of articles published in the English language from 1991 to 2019 that met all diagnostic criteria of PCNSV. RESULTS: We identified 55 studies, reporting on 907 PCNSV cases. Median age was 45 (IQR 50-36), and 53% were women. Biopsy compared to angiography defined PCNSV had a higher percentage of cognitive impairment, and seizures on initial presentation, and were more likely to have a subacute or progressive onset, abnormal CSF profile, small vessel involvement on angiography, and tumor-like lesions and gadolinium enhancement on MRI. Angiography defined PCNSV were more likely to have an acute onset, focal weakness and visual impairment on initial presentation, medium vessel involvement on angiography, and infarcts on MRI. Brain biopsy was diagnostic of PCNSV in 71% of cases, and demonstrated an alternative diagnosis in 37% of cases, the most common being infection (19%) and lymphoproliferative disease (18%). CONCLUSIONS: This study provides further evidence that there are distinct clinical features between biopsy and angiography defined PCNSV, which may aid in selecting patients for appropriate invasive tests.

Age, sex, and setting in the etiology of stroke study (ASSESS): Study design and protocol.

RATIONALE: Stroke etiology and risk factors vary by age, sex, setting (hospital or community-based) and by region. Identifying these differences would improve our understanding of stroke etiology, diagnosis, and treatment. AIM: The Age, Sex and Setting in the Etiology of Stroke Study (ASSESS) is a multicenter cohort study to assess differences in stroke etiology. METHODS AND DESIGN: Data from all centers will be categorized according to age, sex, setting, stroke subtypes. Centers with extensive hospital- or community-based data regarding stroke from Argentina, Australia, Canada, India, Iran, Italy, Ghana, Nigeria, Thailand, the United Kingdom and the United States have agreed to participate so far. STUDY OUTCOMES: The primary outcome includes differences in stroke etiology in study centers. The secondary outcomes include stroke incidence, risk factors, preventive strategies, and short- and long-term outcomes. CONCLUSION: ASSESS will enable comparisons of data from different regions to determine the age and sex distribution of the most common causes of stroke in each setting. This will help clinicians to tailor the assessment and treatment of stroke patients on the basis of their specific local characteristics. It will also empower stroke epidemiologists to design preventive measures by targeting the specific characteristics of each population.

Severe Intracranial Involvement in Giant Cell Arteritis: 5 Cases and Literature Review.

OBJECTIVE: Involvement of intracranial arteries in giant cell arteritis (GCA) is rare. We describe the neurologic complications of intracranial GCA (IC GCA) and available treatment options. METHODS: We describe 5 IC GCA cases from 3 Canadian vasculitis centers and review the literature. We searched English-language publications reporting similar patients meeting American College of Rheumatology (ACR) criteria for GCA and having intracranial artery involvement diagnosed by autopsy, magnetic resonance angiography, computed tomography angiography, or conventional angiography. RESULTS: All 5 cases of IC GCA met ACR criteria for GCA; 4 cases had a temporal artery biopsy that was consistent with GCA. All cases experienced cerebrovascular accident(s). Arteritis involved the following vessels: intracranial internal carotid (n = 1), vertebrobasilar arteries (n = 1), or both (n = 3). All cases received aspirin and oral prednisone (preceded by intravenous methylprednisone in 3 cases), combined with an immunosuppressant in 4 cases. All patients survived; 2 had complete neurological recovery, 3 had residual neurologic sequelae. The literature review included 42 cases from 28 publications. The clinical features of the reported cases were similar to those of our 5 cases. However, mortality was 100% in untreated cases (n = 2), 58% in those treated with corticosteroid alone (n = 31), and 40% in those treated with corticosteroid and an immunosuppressant (n = 10). CONCLUSION: IC GCA appears to be associated with neurologic complications and mortality. In some cases corticosteroid alone was not sufficient to prevent neurologic complications. The role of additional immunosuppressive agents needs further investigation.

Post-stroke depression, obstructive sleep apnea, and cognitive impairment: Rationale for, and barriers to, routine screening.

Stroke can cause neurological impairment ranging from mild to severe, but the impact of stroke extends beyond the initial brain injury to include a complex interplay of devastating comorbidities including: post-stroke depression, obstructive sleep apnea, and cognitive impairment ("DOC"). We reviewed the frequency, impact, and treatment options for each DOC condition. We then used the Ottawa Model of Research Use to examine gaps in care, understand the barriers to knowledge translation, identification, and addressing these important post-stroke comorbidities. Each of the DOC conditions is common and result in poorer recovery, greater functional impairment, increased stroke recurrence and mortality, even after accounting for traditional vascular risk factors. Despite the strong relationships between DOC comorbidities and these negative outcomes as well as recommendations for screening based on best practice recommendations from several countries, they are frequently not assessed. Barriers related to the nature of the screening tools (e.g., time consuming in high-volume clinics), practice environment (e.g., lack of human resources or space), as well as potential adopters (e.g., equipoise surrounding the benefits of treatment for these conditions) pose challenges to routine screening implementation. Simple, feasible approaches to routine screening coupled with appropriate, evidence-based treatment protocols are required to better identify and manage depression, obstructive sleep apnea, and cognitive impairment symptoms in stroke prevention clinic patients to reduce the impact of these important post-stroke comorbidities. These tools may in turn facilitate large-scale randomized controlled treatment trials of interventions for DOC conditions that may help to improve cardiovascular outcomes after stroke or TIA.

Acute stroke management in patients with known or suspected atrial fibrillation.

Atrial fibrillation (AF) is an important cause of ischemic stroke, especially in older individuals. Strokes attributed to AF are often large and result in a high rate of fatality. The new oral anticoagulants offer advantages over warfarin in terms of dosing, pharmacokinetic characteristics, and lower rates of intracranial hemorrhage, but pose new management questions for physicians treating these patients. The management of acute stroke is not modified by the presence of AF, but is unique with respect to management of anticoagulation in the hyperacute and acute phases. We will review and discuss acute treatment options in anticoagulated patients with ischemic stroke, anticoagulation discontinuation, and timing of initiation with old and new oral anticoagulants, and managing intracranial hemorrhage in anticoagulated patients. We will end by briefly discussing investigations of stroke patients with suspected cardioembolic stroke.

Neural correlates of incidental memory in mild cognitive impairment: an fMRI study.

Behaviour and fMRI brain activation patterns were compared during encoding and recognition tasks in mild cognitive impairment (MCI) (n=14) and normal controls (NC) (n=14). Deep (natural vs. man-made) and shallow (color vs. black and white) decisions were made at encoding and pictures from each condition were presented for yes/no recognition 20 min later. MCI showed less inferior frontal activation during deep (left only) and superficial encoding (bilaterally) and in both medial temporal lobes (MTL). When performance was equivalent (recognition of words encoded superficially), MTL activation was similar for the two groups, but during recognition testing of deeply encoded items NC showed more activation in both prefrontal and left MTL region. In a region of interest analysis, the extent of activation during deep encoding in the parahippocampi bilaterally and in left hippocampus correlated with subsequent recognition accuracy for those items in controls but not in MCI, which may reflect the heterogeneity of activation responses in conjunction with different degrees of pathology burden and progression status in the MCI group.

Migraines linked to intrapulmonary right-to-left shunt.

OBJECTIVE: To determine if there is an association between migraines and intrapulmonary right-to-left shunt. BACKGROUND: Several studies have described an association between migraines and intracardiac right-to-left shunt. METHODS: Patients with hereditary hemorrhagic telangiectasia (HHT) were retrospectively recruited from the Toronto Hereditary Hemorrhagic Telangiectasia Center Clinical Database. All patients had been prospectively, systematically asked about a history of migraines and systematically screened for pulmonary and cerebral arteriovenous malformations (AVMs). All patients with a definite diagnosis of HHT, assessed during a 2-year period (February 1997 to April 1999), were included. Univariate analyses and logistic regression were performed, for migraine as the dependent variable and the following independent variables: age, sex, pulmonary AVMs, and cerebral AVMs. RESULTS: Of the 200 patients assessed during the 2-year period, 124 (62%) had a definite diagnosis of HHT and were included in the analysis. Eighty (65%) were females. Forty-seven (38%) of the HHT patients had a history of migraine, of whom 38 (81%) had migraine with aura. The prevalence of migraine was greater in patients with pulmonary AVMs (46%) compared to patients without pulmonary AVMs (33%), OR = 1.7 (0.8 to 3.6), though this did not reach statistical significance (P = .14). Pulmonary AVMs were significantly associated with migraine (OR = 2.4, 95% CI = 1.1 to 5.5, P = .04), after adjustment for age and sex, using logistic regression. CONCLUSIONS: There is a significant association between intrapulmonary right-to-left shunt and migraine.