Patent Foramen Ovale Closure in Older Patients With Stroke: Patient Selection for Trial Feasibility.

BACKGROUND AND OBJECTIVES: Whether patent foramen ovale (PFO) closure benefits older patients with PFO and cryptogenic stroke is unknown because randomized controlled trials (RCTs) have predominantly enrolled patients younger than 60 years of age. Our objective was to estimate anticipated effects of PFO closure in older patients to predict the numbers needed to plan an RCT. METHODS: Effectiveness estimates are derived from major observational studies (Risk of Paradoxical Embolism [RoPE] Study and Oxford Vascular Study, together referred to as the "RoPE-Ox" database) and all 6 major RCTs (Systematic, Collaborative, PFO Closure Evaluation [SCOPE] Consortium). To estimate stroke recurrence risk, observed outcomes were calculated for patients older than 60 years in the age-inclusive observational databases (n = 549). To estimate the reduction in the rate of recurrent stroke associated with PFO closure vs medical therapy based on the RoPE score and the presence of high-risk PFO features, a Cox proportional hazards regression model was developed on the RCT data in the SCOPE database (n = 3,740). These estimates were used to calculate sample sizes required for a future RCT. RESULTS: Five-year risk of stroke recurrence using Kaplan-Meier estimates was 13.7 (95% CI 10.5-17.9) overall, 14.9% (95% CI 10.2-21.6) in those with high-risk PFO features. Predicted relative reduction in the event rate with PFO closure was 12.9% overall, 48.8% in those with a high-risk PFO feature. Using these estimates, enrolling all older patients with cryptogenic stroke and PFO would require much larger samples than those used for prior PFO closure trials, but selectively enrolling patients with high-risk PFO features would require totals of 630 patients for 90% power and 471 patients for 80% power, with an average of 5 years of follow-up. DISCUSSION: Based on our projections, anticipated effect sizes in older patients with high-risk features make a trial in these subjects feasible. With lengthening life expectancy in almost all regions of the world, the utility of PFO closure in older adults is increasingly important to explore.

Angiographic Characteristics of Hemorrhagic and Ischemic Phases of Reversible Cerebral Vasoconstriction Syndrome.

PURPOSE: This study aimed to assess the evolution of imaging patterns over time in patients with neurological complications caused by reversible cerebral vasoconstriction syndrome. METHODS: A total of 24 consecutive patients with reversible cerebral vasoconstriction syndrome presenting between 2009 and 2016 were included, whose disease course was complicated by intracranial hemorrhage and/or ischemic events. In total 55 angiographic studies were carried out. The nature of the intracranial complication and location of vasoconstriction on the angiograms in relation to the time interval since symptom-onset were assessed. RESULTS: Complications included subarachnoid hemorrhage (n = 19, 79%), intracerebral hemorrhage (n = 7, 29%), ischemic stroke (n = 6, 25%), and transient ischemic attack (n = 4, 17%). Hemorrhagic complications mainly occurred within 7 days after symptom onset (18/19 patients, 95%), whereas ischemic events only occurred after the first week (10/10 patients, 100%, p < 0.00001). Distal vasospasm was predominantly observed within 7 days (26/28 angiograms, 93%) and proximal vasospasm ≥7 days (23/27 angiograms, 85%, p < 0.00001). CONCLUSION: In reversible cerebral vasoconstriction syndrome causing neurological complications, an early hemorrhagic phase with distal vasospasm and a delayed ischemic phase with proximal vasospasm can be discriminated.

Recurrent stroke predictors differ in medically treated patients with pathogenic vs. other PFOs.

OBJECTIVE: To examine predictors of stroke recurrence in patients with a high vs a low likelihood of having an incidental patent foramen ovale (PFO) as defined by the Risk of Paradoxical Embolism (RoPE) score. METHODS: Patients in the RoPE database with cryptogenic stroke (CS) and PFO were classified as having a probable PFO-related stroke (RoPE score of >6, n = 647) and others (RoPE score of ≤6 points, n = 677). We tested 15 clinical, 5 radiologic, and 3 echocardiographic variables for associations with stroke recurrence using Cox survival models with component database as a stratification factor. An interaction with RoPE score was checked for the variables that were significant. RESULTS: Follow-up was available for 92%, 79%, and 57% at 1, 2, and 3 years. Overall, a higher recurrence risk was associated with an index TIA. For all other predictors, effects were significantly different in the 2 RoPE score categories. For the low RoPE score group, but not the high RoPE score group, older age and antiplatelet (vs warfarin) treatment predicted recurrence. Conversely, echocardiographic features (septal hypermobility and a small shunt) and a prior (clinical) stroke/TIA were significant predictors in the high but not low RoPE score group. CONCLUSION: Predictors of recurrence differ when PFO relatedness is classified by the RoPE score, suggesting that patients with CS and PFO form a heterogeneous group with different stroke mechanisms. Echocardiographic features were only associated with recurrence in the high RoPE score group.

The complexities of acute stroke decision-making: a survey of neurologists.

OBJECTIVE: We hypothesized that low rates of tissue plasminogen activator (tPA) use are only partially explained by medical considerations, and that biases, beliefs, systems, and uncertainty affect acute stroke decision-making. METHODS: We generated a list of factors potentially influential in acute stroke decision-making: uncertainty, patient demographics that may predispose to bias (age, sex, comorbidities), physician experiences and beliefs, and systems factors. An online survey was distributed to neurologists in the province of Ontario, Canada, to assess the influence of these elements. A response rate of 69% was achieved. RESULTS: Seventy-nine percent (79%) of respondents were less likely to administer IV tPA to patients with dementia, and many were less likely to treat patients from nursing homes, with more severe strokes, or over age 80. All respondents recognized the presence of diagnostic uncertainty, and 87% believed that uncertainty in interpreting advanced imaging affected their use of tPA. The majority of respondents (70%) believed that a large left middle cerebral artery territory stroke was a fate worse than death. Four percent did not believe that IV tPA is an effective treatment for stroke. CONCLUSIONS: This study provides evidence for the presence of uncertainty, beliefs, and biases in acute stroke decision-making. This survey should be considered a preliminary investigation of the multiple factors implicit in IV tPA administration.

An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke.

OBJECTIVE: We aimed to create an index to stratify cryptogenic stroke (CS) patients with patent foramen ovale (PFO) by their likelihood that the stroke was related to their PFO. METHODS: Using data from 12 component studies, we used generalized linear mixed models to predict the presence of PFO among patients with CS, and derive a simple index to stratify patients with CS. We estimated the stratum-specific PFO-attributable fraction and stratum-specific stroke/TIA recurrence rates. RESULTS: Variables associated with a PFO in CS patients included younger age, the presence of a cortical stroke on neuroimaging, and the absence of these factors: diabetes, hypertension, smoking, and prior stroke or TIA. The 10-point Risk of Paradoxical Embolism score is calculated from these variables so that the youngest patients with superficial strokes and without vascular risk factors have the highest score. PFO prevalence increased from 23% (95% confidence interval [CI]: 19%-26%) in those with 0 to 3 points to 73% (95% CI: 66%-79%) in those with 9 or 10 points, corresponding to attributable fraction estimates of approximately 0% to 90%. Kaplan-Meier estimated stroke/TIA 2-year recurrence rates decreased from 20% (95% CI: 12%-28%) in the lowest Risk of Paradoxical Embolism score stratum to 2% (95% CI: 0%-4%) in the highest. CONCLUSION: Clinical characteristics identify CS patients who vary markedly in PFO prevalence, reflecting clinically important variation in the probability that a discovered PFO is likely to be stroke-related vs incidental. Patients in strata more likely to have stroke-related PFOs have lower recurrence risk.

Neuroimaging findings in cryptogenic stroke patients with and without patent foramen ovale.

BACKGROUND AND PURPOSE: Patent foramen ovale (PFO) and cryptogenic stroke are commonly associated but some PFOs are incidental. Specific radiological findings associated with PFO may be more likely to indicate a PFO-related cause. We examined whether specific radiological findings are associated with PFO among subjects with cryptogenic stroke and known PFO status. METHODS: We analyzed the Risk of Paradoxical Embolism(RoPE) Study database of subjects with cryptogenic stroke and known PFO status, for associations between PFO and: (1) index stroke seen on imaging, (2) index stroke size, (3) index stroke location, (4) multiple index strokes, and (5) prior stroke on baseline imaging. We also compared imaging with purported high-risk echocardiographic features. RESULTS: Subjects (N=2680) were significantly more likely to have a PFO if their index stroke was large (odds ratio [OR], 1.36; P=0.0025), seen on index imaging (OR, 1.53; P=0.003), and superficially located (OR, 1.54; P<0.0001). A prior stroke on baseline imaging was associated with not having a PFO (OR, 0.66; P<0.0001). Finding multiple index strokes was unrelated to PFO status (OR, 1.21; P=0.161). No echocardiographic variables were related to PFO status. CONCLUSIONS: This is the largest study to report the radiological characteristics of patients with cryptogenic stroke and known PFO status. Strokes that were large, radiologically apparent, superficially located, or unassociated with prior radiological infarcts were more likely to be PFO-associated than were unapparent, smaller, or deep strokes, and those accompanied by chronic infarcts. There was no association between PFO and multiple acute strokes nor between specific echocardiographic PFO features with neuroimaging findings.

The risk of paradoxical embolism (RoPE) study: initial description of the completed database.

BACKGROUND: Detecting a benefit from closure of patent foramen ovale in patients with cryptogenic stroke is hampered by low rates of stroke recurrence and uncertainty about the causal role of patent foramen ovale in the index event. A method to predict patent foramen ovale-attributable recurrence risk is needed. However, individual databases generally have too few stroke recurrences to support risk modeling. Prior studies of this population have been limited by low statistical power for examining factors related to recurrence. AIMS: The aim of this study was to develop a database to support modeling of patent foramen ovale-attributable recurrence risk by combining extant data sets. METHODS: We identified investigators with extant databases including subjects with cryptogenic stroke investigated for patent foramen ovale, determined the availability and characteristics of data in each database, collaboratively specified the variables to be included in the Risk of Paradoxical Embolism database, harmonized the variables across databases, and collected new primary data when necessary and feasible. RESULTS: The Risk of Paradoxical Embolism database has individual clinical, radiologic, and echocardiographic data from 12 component databases, including subjects with cryptogenic stroke both with (n = 1925) and without (n = 1749) patent foramen ovale. In the patent foramen ovale subjects, a total of 381 outcomes (stroke, transient ischemic attack, death) occurred (median follow-up 2·2 years). While there were substantial variations in data collection between studies, there was sufficient overlap to define a common set of variables suitable for risk modeling. CONCLUSION: While individual studies are inadequate for modeling patent foramen ovale-attributable recurrence risk, collaboration between investigators has yielded a database with sufficient power to identify those patients at highest risk for a patent foramen ovale-related stroke recurrence who may have the greatest potential benefit from patent foramen ovale closure.

Cryptogenic stroke and patent foramen ovale.

In patients with cryptogenic stroke and patent foramen ovale, options for stroke prevention include medical therapy (antiplatelet therapy or anticoagulation) and percutaneous device closure. In the only completed randomized controlled trial comparing medical therapy and percutaneous device closure, there was no difference in outcome between the two forms of treatment, and both are viable options for stroke prevention. The choice of therapy is made after careful weighing of potential risks and benefits associated with each form of therapy based on the limited evidence to date and the anticipated patient adherence with the planned treatment. Participation in a clinical trial is a third option for these patients.

BOLD-MRI cerebrovascular reactivity findings in cocaine-induced cerebral vasculitis.

BACKGROUND: An 18-year-old woman presented to a regional stroke center with dysphasia and right hemiparesis 2 days after consuming alcohol and inhaling cannabis and -- for the first time -- cocaine. INVESTIGATIONS: Physical examination, blood tests for inflammatory markers, vasculitis and toxicology screen, echocardiography, electrocardiography, CT scanning, brain MRI, magnetic resonance angiography, magnetic resonance vessel wall imaging, catheter angiography, and correlation of blood oxygen level-dependent (BOLD)-MRI signal intensity with changes in end-tidal partial pressure of carbon dioxide. DIAGNOSIS: Cocaine-induced cerebral vasculitis. MANAGEMENT: No specific therapy was initiated. The patient's vital signs and neurological status were monitored during her admission. Follow-up medical imaging was performed after the patient's discharge from hospital.

Recurrent stroke/TIA in cryptogenic stroke patients with patent foramen ovale.

BACKGROUND: Patent foramen ovale (PFO) is present in 40% of patients with cryptogenic stroke and may be associated with paradoxical emboli to the brain. Therapeutic options include antiplatelet agents, anticoagulation, percutaneous device and surgical closure. We assessed the hypothesis that there are differences in rates of recurrent TIA or stroke between patients in the four treatment groups. METHODS: Patients presenting from January 1997 with cryptogenic stroke or TIA and PFO were followed prospectively until June 2003. Treatment choice was made on an individual case basis. The primary outcome was recurrent stroke. The secondary outcome was a composite of stroke, TIA, and vascular death. RESULTS: Baseline. Our cohort consisted of 121 patients; 64 (53%) were men. Median age was 43 years. Sixty-nine percent presented with stroke and 31% with TIA. One or more vascular risk factor was present in 40%. Atrial septal aneurysm (ASA) was present in 24%. Treatment consisted of antiplatelet agents (34%), anticoagulation (17%), device (39%) and surgical closure (11%). Follow-up. Recurrent events occurred in 16 patients (9 antiplatelet, 3 anticoagulation, 4 device closure); 7 were strokes, 9 were TIA. Comparing individual treatments there was a trend toward more strokes in the antiplatelet arm (p = 0.072); a significant difference was seen for the composite endpoint (p = 0.012). Comparing closure versus combined medical therapy groups, a significant difference was seen for primary (p = 0.014) and secondary (p = 0.008) outcomes, favoring closure. Age and pre-study event predicted outcome. CONCLUSION: Patent foramen ovale closure was associated with fewer recurrent events. Complications of surgical and device closure were self-limited.

Telestroke: a multi-site, emergency-based telemedicine service in Ontario.

A telestroke service was established in Ontario in 2002. Six neurologists on four campuses of two academic health centres of the University of Toronto participated in the call roster to support emergency physicians in two northern cities, North Bay and Sudbury. Videoconferencing units were provided in the hospitals and in the homes of the neurologists. PC workstations were used to access computed tomography (CT) images. In the first 34 months' operation, a total of 88 patient consultations were conducted. Twenty-six patients received tissue plasminogen activator (t-PA). Although the number of consultations was relatively low, the feasibility of telemedicine for acute stroke care was demonstrated. The economics remain to be explored. The telestroke model is a viable alternative to the provision of acute stroke care for communities that have CT scanners, but no access to a resident neurologist.

Sex differences in stroke care and outcomes: results from the Registry of the Canadian Stroke Network.

BACKGROUND: Stroke is an important cause of death and disability in women as well as men. However, little is known about sex differences in stroke care and outcomes. METHODS: The Registry of the Canadian Stroke Network (RCSN) captured data on patients with stroke seen at acute care hospitals across Canada. We used data from phase 1 (July 2001 to February 2002) and phase 2 (June to December 2002) of the RCSN to compare stroke presentation, management, and 6-month outcomes in women and men using multivariable regression techniques to adjust for age and other factors. RESULTS: The study sample included 3323 patients, with 1527 women. Stroke symptoms at presentation were similar in women and men, except that women were more likely to present with headaches and were less likely to have brain stem or cerebellar symptoms. There were no sex differences in the use of neuroimaging, thrombolysis, antithrombotic therapy, or consultations. Women were less likely than men to receive care on an acute stroke unit, but this difference was no longer significant after adjustment for age and other factors. Women were more likely than men to be discharged to long-term care and had greater disability at 6 months. Mortality and quality of life at 6 months were similar in women and men. CONCLUSIONS: Among patients participating in the RCSN, there were no major sex differences in stroke presentation or management. Compared with men, women were more often institutionalized and had a slightly worse functional status at 6 months after stroke.

Clinical outcomes of patent foramen ovale closure for paradoxical emboli without echocardiographic guidance.

The objective of this study was to determine the feasibility of device closure of patent foramen ovale (PFO) for presumed paradoxical emboli without echocardiographic guidance or balloon sizing and the clinical outcome after device closure. Closure of the PFO has been proposed as an alternative to anticoagulation in patients with presumed paradoxical emboli. At present, most centers perform device closure with transesophageal echocardiographic guidance and balloon sizing of the defect. Between May 1998 and April 2002, 92 consecutive patients underwent device closure for a PFO using fluoroscopic monitoring only. Procedural success and major complications were recorded. Follow-up outcomes were recurrence rate and residual atrial shunting on transthoracic echocardiography. All patients (mean age, 45 +/- 13 years; 52% male) had successful device deployment using either the CardioSeal (n = 78) and Amplatzer (n = 14) PFO occluders with no major complications. Mean procedure time and fluoroscopy time was 27 +/- 13 and 6 +/- 4 min, respectively. One patient had a residual shunt on echocardiography at 1 year. Cumulative event-free survival for recurrence of paradoxical embolus at 1 year was 97.3% +/- 1.8%. This study provides a basis for device closure of PFO becoming a safe, day-case procedure, resulting in a low rate of residual shunting and recurrent thromboembolic events.

Neurological manifestations of West Nile virus infection.

BACKGROUND: Over the past four years, West Nile virus (WNV) has become a significant health issue in North America. In 2002, WNV infection made its first appearance in the human population in Canada. METHODS: Patients who presented to the University Health Network and Mount Sinai Hospital in Toronto with neurological disease attributed to WNV infection were identified and followed by the neurology service. Clinical features and results of laboratory, electrodiagnostic, radiological and pathological studies are presented. RESULTS: In August and September 2002, 26 patients were admitted with WNV infection; 14 presented with neurological illness. Encephalitis was the most common presentation (11 patients). Eleven patients developed neuromuscular disease; two at presentation and nine after encephalitis. While the majority had a motor process that localized to the anterior horn cell and/or motor neuron, two patients had evidence of a demyelinating neuropathy and one a sensorimotor axonal neuropathy. Less common manifestations included rhombencephalitis, ataxia, myelopathy and parkinsonism. Death occurred in four patients; two > 75 years of age, and two who were immunocompromised. CONCLUSIONS: The most common neurological manifestation of WNV infection was encephalitis with subsequent neuromuscular involvement. The diversity of clinical and pathological findings, however, suggests widespread involvement of the central and peripheral nervous system. A poorer prognosis for neurological recovery and overall survival was seen in older and immunocompromised patients.