Comparison of patients with biopsy positive and negative primary angiitis of the central nervous system.

OBJECTIVE: There is limited evidence on when to obtain a central nervous system (CNS) biopsy in suspected primary angiitis of the central nervous system (PACNS). Our objective was to identify which clinical and radiological characteristics were associated with a positive biopsy in PACNS. METHODS: From the multicenter retrospective Cohort of Patients with Primary Vasculitis of the CNS (COVAC), we included adults with PACNS based on a positive CNS biopsy or otherwise unexplained intracranial stenoses with additional findings supportive of vasculitis. Baseline findings were compared between patients with a positive and negative biopsy using logistic regression models. RESULTS: 200 patients with PACNS were included, among which a biopsy was obtained in 100 (50%) and was positive in 61 (31%). Patients with a positive biopsy were more frequently female (OR 2.90, 95% CI 1.25-7.10, p = 0.01) and more often presented with seizures (OR 8.31, 95% CI 2.77-33.04, p < 0.001) or cognitive impairment (OR 2.58, 95% CI 1.11-6.10, p = 0.03). On imaging, biopsy positive patients more often had non-ischemic parenchymal or leptomeningeal gadolinium enhancement (OR 52.80, 95% CI 15.72-233.06, p < 0.001) or ≥ 1 cerebral microbleed (OR 8.08, 95% CI 3.03-25.13, p < 0.001), and less often had ≥ 1 acute brain infarct (OR 0.02, 95% CI 0.004-0.08, p < 0.001). In the multivariable model, non-ischemic parenchymal or leptomeningeal gadolinium enhancement (aOR 8.27, 95% CI 1.78-38.46), p < 0.01) and absence of ≥ 1 acute brain infarct (aOR 0.13, 95% CI 0.03-0.65, p = 0.01) were significantly associated with a positive biopsy. CONCLUSIONS: Baseline clinical and radiological characteristics differed between biopsy positive and negative PACNS. These results may help physicians individualize the decision to obtain a CNS biopsy in suspected PACNS.

Cerebrovascular Events in Older Patients With Patent Foramen Ovale: Current Status and Future Perspectives.

Patent foramen ovale (PFO) closure, along with medical therapy, has emerged as the therapeutic gold standard in younger (<60-year-old) patients with a PFO-related stroke for preventing recurrent events. However, PFO management guidelines lack definite recommendations for older (>60 years) patients with a PFO-related cerebrovascular event, a complex group of patients who were mostly excluded from PFO closure clinical trials. Nevertheless, several studies have shown a higher prevalence of PFO among older patients with cryptogenic stroke, and its presence has been associated with an increased risk of recurrent events. Furthermore, older patients exhibit a higher prevalence of high-risk PFO anatomical features, present inherent age-related risk factors that might increase the risk of paradoxical embolism through a PFO, and have a higher incidence of ischemic events after a PFO-related event. Additionally, observational studies have shown the safety and preliminary efficacy of PFO closure in older PFO-related stroke patients. Yet, higher rates of recurrent cerebrovascular events and new-onset atrial fibrillation were observed in some studies among older patients compared to their younger counterparts. After careful case-by-case evaluation, including the assessment of hidden potential cardioembolic sources of a cryptogenic stroke other than PFO, transcatheter PFO closure might be a safe and effective therapeutic option for preventing recurrent thromboembolic events in patients >60 years with a high-risk PFO-associated stroke. Ongoing trials will provide important insights into the role of PFO closure in the elderly population.

Study of Rivaroxaban for Cerebral Venous Thrombosis: A Randomized Controlled Feasibility Trial Comparing Anticoagulation With Rivaroxaban to Standard-of-Care in Symptomatic Cerebral Venous Thrombosis.

BACKGROUND: Emerging data suggest that direct oral anticoagulants may be a suitable choice for anticoagulation for cerebral venous thrombosis (CVT). However, conducting high-quality trials in CVT is challenging as it is a rare disease with low rates of adverse outcomes such as major bleeding and functional dependence. To facilitate the design of future CVT trials, SECRET (Study of Rivaroxaban for Cerebral Venous Thrombosis) assessed (1) the feasibility of recruitment, (2) the safety of rivaroxaban compared with standard-of-care anticoagulation, and (3) patient-centered functional outcomes. METHODS: This was a phase II, prospective, open-label blinded-end point 1:1 randomized trial conducted at 12 Canadian centers. Participants were aged ≥18 years, within 14 days of a new diagnosis of symptomatic CVT, and suitable for oral anticoagulation; they were randomized to receive rivaroxaban 20 mg daily, or standard-of-care anticoagulation (warfarin, target international normalized ratio, 2.0-3.0, or low-molecular-weight heparin) for 180 days, with optional extension up to 365 days. Primary outcomes were annual rate of recruitment (feasibility); and a composite of symptomatic intracranial hemorrhage, major extracranial hemorrhage, or mortality at 180 days (safety). Secondary outcomes included recurrent venous thromboembolism, recanalization, clinically relevant nonmajor bleeding, and functional and patient-reported outcomes (modified Rankin Scale, quality of life, headache, mood, fatigue, and cognition) at days 180 and 365. RESULTS: Fifty-five participants were randomized. The rate of recruitment was 21.3 participants/year; 57% of eligible candidates consented. Median age was 48.0 years (interquartile range, 38.5-73.2); 66% were female. There was 1 primary event (symptomatic intracranial hemorrhage), 2 clinically relevant nonmajor bleeding events, and 1 recurrent CVT by day 180, all in the rivaroxaban group. All participants in both arms had at least partial recanalization by day 180. At enrollment, both groups on average reported reduced quality of life, low mood, fatigue, and headache with impaired cognitive performance. All metrics improved markedly by day 180. CONCLUSIONS: Recruitment targets were reached, but many eligible participants declined randomization. There were numerically more bleeding events in patients taking rivaroxaban compared with control, but rates of bleeding and recurrent venous thromboembolism were low overall and in keeping with previous studies. Participants had symptoms affecting their well-being at enrollment but improved over time. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03178864.

Diagnosis and management of adult primary angiitis of the central nervous system: an international survey on current practices.

BACKGROUND: Primary angiitis of the central nervous system (PACNS) is a rare disease, for which no validated guidelines exist. We report the findings of a survey on the clinical practice of physicians who manage adults with PACNS. METHODS: An online survey was distributed through neurology, internal medicine, and rheumatology societies in Canada and Europe. Participants who were directly involved as treating physicians for at least two adult patients with PACNS were eligible for the survey. RESULTS: Ninety-six physicians completed the survey. Most participants were neurologists (n = 38, 40%), internists (n = 34, 35%) or rheumatologists (n = 22, 23%). Participants obtained a CNS biopsy in a median of 25% (IQR: 5-50%) of suspected PACNS cases. When determining the degree to which eight scenarios justified a CNS biopsy, participants achieved fair inter-rater agreement (Gwet's AC2 0.30, 95% CI 0.23-0.41). For induction therapy, 81 (84%) participants reported using glucocorticoids and cyclophosphamide in > 50% of patients. After obtaining remission, 85 (89%) participants systematically introduced or maintained immunosuppressive therapy. Glucocorticoids were prescribed for a median of 12 months. Maintenance therapy with another immunosuppressant was continued for a median of 24 months. In patients who achieved remission, we explored how eight scenarios with different imaging and CSF results supported an increase in treatment. Inter-rater agreement was substantial if the patient was symptomatic (0.66, 95% CI 0.58-0.80) and moderate (0.50, 95% CI 0.45-0.60) if asymptomatic. CONCLUSION: This survey illustrates current real-world management of PACNS and emphasizes several areas for which physicians still lack study-based evidence and/or clinical practice guidelines.

Ischemic stroke is a potential complication of uncontrolled inflammation in mevalonate kinase deficiency - A case report.

OBJECTIVES: Mevalonate kinase deficiency (MKD) is an autosomal recessive autoinflammatory disease characterized by recurrent systemic inflammation attacks. Despite interconnections with inflammation, thrombosis is rare or underreported in MKD. Our goal is to report evidence of uncontrolled inflammation as the cause of ischemic stroke. MATERIALS AND METHODS: Case report. RESULTS: A 39-year-old French-Canadian patient consulted for stroke. He reported a previous diagnosis of familial Mediterranean fever and hospitalizations nearly monthly since birth for recurrent inflammatory attacks despite colchicine prophylaxis. Attacks were triggered by infections or stress, lasted 3-7 days, and included fever up to 41°C, painful lymphadenopathies, abdominal pain, polyarthralgia and maculopapular rash. Stroke culminated his most recent inflammatory attack. Brain MRI confirmed an acute infarct, without chronic ischemic damage. Blood tests documented increased C-reactive protein, amyloid A and immunoglobulin-D. Prothrombotic and autoantibody tests, cervicocephalic CT-angiography, echocardiography, cardiac monitoring, and toxic screen were unremarkable. Infections were excluded. His only sister had similar attacks. In both cases, sequencing of 32 autoinflammatory-associated genes identified two pathogenic mevalonate kinase mutations. Their non-consanguineous parents, half-brother and four children were asymptomatic. Following treatment with anti-interleukin-1beta monoclonal antibodies, he no longer had inflammatory attacks or stroke in >4 years. CONCLUSION: This MKD patient experienced an ischemic stroke during an attack, attributed to uncontrolled inflammation. Investigations excluded other stroke etiologies. Recurrent febrile attacks starting before age 1 and lasting >3 days, gastrointestinal symptoms, painful lymphadenopathies, maculopapular rash, triggers, aphthous stomatitis, non-Mediterranean ancestry, and ineffectiveness of colchicine prophylaxis are consistent with MKD. Anti-interleukin-1 therapy prevents recurrent autoinflammatory attacks.

Differential Effects of Speech and Language Therapy and rTMS in Chronic Versus Subacute Post-stroke Aphasia: Results of the NORTHSTAR-CA Trial.

BACKGROUND & OBJECTIVE: Contralesional 1-Hz repetitive transcranial magnetic stimulation (rTMS) over the right pars triangularis combined with speech-language therapy (SLT) has shown positive results on the recovery of naming in subacute (5-45 days) post-stroke aphasia. NORTHSTAR-CA is an extension of the previously reported NORTHSTAR trial to chronic aphasia (>6 months post-stroke) designed to compare the effectiveness of the same rTMS protocol in both phases. METHODS: Sixty-seven patients with left middle cerebral artery infarcts (28 chronic, 39 subacute) were recruited (01-2014 to 07-2019) and randomized to receive rTMS (N = 34) or sham stimulation (N = 33) with SLT for 10 days. Primary outcome variables were Z-score changes in naming, semantic fluency and comprehension tests and adverse event frequency. Intention-to-treat analyses tested between-group effects at days 1 and 30 post-treatment. Chronic and subacute results were compared. RESULTS: Adverse events were rare, mild, and did not differ between groups. Language outcomes improved significantly in all groups irrespective of treatment and recovery phase. At 30-day follow-up, there was a significant interaction of stimulation and recovery phase on naming recovery (P <.001). Naming recovery with rTMS was larger in subacute (Mdn = 1.91/IQR = .77) than chronic patients (Mdn = .15/IQR = 1.68/P = .015). There was no significant rTMS effect in the chronic aphasia group. CONCLUSIONS: The addition of rTMS to SLT led to significant supplemental gains in naming recovery in the subacute phase only. While this needs confirmation in larger studies, our results clarify neuromodulatory vs training-induced effects and indicate a possible window of opportunity for contralesional inhibitory stimulation interventions in post-stroke aphasia. NORTHSTAR TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02020421.

Hyperacute multi-organ thromboembolic storm in COVID-19: a case report.

Acute viral pneumonia, hypoxemic respiratory failure and severe inflammatory response are hallmarks of severe coronavirus disease 2019 (COVID-19). The COVID-19-associated inflammatory state may further lead to symptomatic thromboembolic complications despite prophylaxis. We report a 66-year-old female patient with post-mortem diagnosis of COVID-19 who presented progressive livedo racemosa, acute renal failure and myocardial injury, as well as an absence of respiratory symptoms. Transthoracic echocardiography showed severe spontaneous echo contrast in the right cardiac chambers and right-sided cardiac overload presumed to result from pulmonary microvascular thrombosis or embolism. D-dimer levels were increased. The patient developed an acute ischemic stroke and died 2 days following presentation despite therapeutic anticoagulation. Her predominantly thromboembolic presentation supports the concept of coronavirus infection of endothelial cells and hypercoagulability, or COVID-19 endotheliitis. The case we report highlights that COVID-19-associated hyperacute multi-organ thromboembolic storm may precede or present disproportionately to respiratory involvement.

Non-invasive brain stimulation as add-on therapy for subacute post-stroke aphasia: a randomized trial (NORTHSTAR).

INTRODUCTION: Non-invasive brain stimulation (NIBS) with speech therapy might improve recovery from post-stroke aphasia. This three-armed sham-controlled blinded prospective proof-of-concept study tested 1 Hz subthreshold repetitive transcranial magnetic stimulation (rTMS) and 2-mA cathodal transcranial direct current stimulation (ctDCS) on the right pars triangularis in subacute post-stroke aphasia. PATIENTS AND METHODS: Sixty-three patients with left middle cerebral artery infarcts were recruited in five hospitals (Canada/United States/Germany, 01-2014/03-2018) and randomized to receive rTMS (N = 20), ctDCS (N = 24) or sham stimulation (N = 19) with ST for 10 days. Primary outcome variables were Z-score changes in naming, semantic fluency and comprehension tests and adverse event frequency. Secondary outcome variable was the percent change in the Unified Aphasia Score. Intention-to-treat analyses tested between-group effects at days 1 and 30 post-treatment with a pre-planned subgroup analysis for lesion location (affecting Broca's area or not). RESULTS: Naming was significantly improved by rTMS (median = 1.91/interquartile range = 0.77/p = .01) at 30 days versus ctDCS (median = 1.11/interquartile range = 1.51) and sham stimulation (median = 1.02/interquartile range = 1.71). All other primary results were non-significant. The rTMS effect was driven by the patient subgroup with intact Broca's area where NIBS tended to improve UnAS (median = 33.2%/interquartile range = 46.7%/p = .062) versus sham stimulation (median = 12.5%/interquartile range = 7.9%) at day 30. Conversely, in patients with infarcted Broca's area, UnAS tended to improve more with sham stimulation (median = 75.0%/interquartile range = 86.9%/p = .053) versus NIBS (median = 12.7%/interquartile range = 31.7).Conclusion: We found a delayed positive effect of low-frequency rTMS targeting the right pars triangularis on the recovery of naming performance in subacute post-stroke aphasia. This intervention may be beneficial only in patients with morphologically intact Broca's area.

Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in Atrial Fibrillation (BRAIN-AF): Methods and Design.

BACKGROUND: Compelling evidence showing a link between atrial fibrillation (AF) and cognitive decline and dementia is accumulating. METHODS: Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in Atrial Fibrillation (BRAIN-AF) is a prospective, multicentric, double-blind, randomized-controlled trial, recruiting patients with nonvalvular AF and a low risk of stroke. Patients with a high risk of bleeding will be excluded from the study. Participants will be randomized to receive either rivaroxaban (15 mg daily) or standard of care (placebo in patients without vascular disease or acetylsalicylic acid 100 mg daily in patients with vascular disease). RESULTS: The primary outcome is the composite of stroke, transient ischemic attack, and cognitive decline (defined by a decrease in the Montreal Cognitive Assessment score ≥ 3 at any follow-up visit after baseline). Approximately 3250 patients will be enrolled in approximately 130 clinical sites until 609 adjudicated primary outcome events have occurred. CONCLUSIONS: BRAIN-AF determines whether oral anticoagulation therapy with rivaroxaban compared with standard of care reduces the risk of stroke, transient ischemic attack, or cognitive decline in patients with nonvalvular AF and a low risk of stroke.

3T MRI study discloses high intrafamilial variability in CADASIL due to a novel NOTCH3 mutation.

In order to evaluate the usefulness of presymptomatic MRI, we performed 3T brain MRI and Sanger gene sequencing in a proband with suspected but not confirmed CADASIL and her apparently asymptomatic father. The 35-year-old proband presented with migraine with visual aura. Brain MRI showed diffuse leukoencephalopathy, suggesting CADASIL. NOTCH3 gene sequencing (exons 3-6) was negative. Family history was unclear. The MRI study of the father documented severe, diffuse leukoencephalopathy, with involvement of the temporal poles and external capsules (not observed in the proband), and lacunar infarcts in the absence of cardiac disease or risk factors. The MRI findings were in favour of an autosomal dominant mode of transmission and reinforced the hypothesis of CADASIL. Full NOTCH3 gene sequencing uncovered a novel exon 8 mutation (c.1337G>A; p.Cys446Tyr) outside the most commonly mutated region of NOTCH3. The novel mutation leads to a typical MRI pattern but a variable overall phenotype. The study underlines the usefulness of combining full gene sequencing with familial MRI studies.

Carotid Plaque Vulnerability Assessment Using Ultrasound Elastography and Echogenicity Analysis.

OBJECTIVE: The purpose of this study was to evaluate ultrasound elastography and echogenicity analysis to discriminate between carotid plaques in patients with symptomatic internal carotid artery (ICA) stenosis versus patients with asymptomatic stenosis. SUBJECTS AND METHODS: Patients with symptomatic and asymptomatic ICA stenosis of more than 50% were recruited for the study. After both carotid arteries were scanned, plaque translation and elastography and echogenicity features were assessed. Parameters of index stenosis (i.e., symptomatic or more severe stenosis) were compared between populations. For further validation, parameters of index stenosis were also compared with those of the contralateral artery for segments with plaque. Segments without plaque on the index side were also evaluated between populations. ROC curve analyses were performed using a cross-validation method with bootstrapping to calculate sensitivity and specificity. RESULTS: Sixty-six patients with symptomatic (n = 26) or asymptomatic (n = 40) carotid stenoses were included. The maximum axial strain (p < 0.001), maximum axial shear strain magnitude (p = 0.03), and percentage of low-intensity of gray level (p = 0.01) of the index ICA were lower for patients with symptoms than for those without symptoms. In both groups, the contralateral ICA had translation and elastography and echogenicity parameters similar to those of the index ICA in patients with asymptomatic stenosis. The ROC curve for the detection of vulnerable plaques in patients with symptomatic stenosis was higher when ultrasound elastography and ultrasound echogenicity were used in combination than when each method was used alone (p < 0.001); a sensitivity of 71.6% and a specificity of 79.3% were obtained. CONCLUSION: This pilot study establishes the usefulness of combining elastography with echogenicity analysis to discriminate plaques in patients with symptomatic ICA stenosis versus asymptomatic stenosis.

Canadian Stroke Best Practice Consensus Statement: Acute Stroke Management during pregnancy.

The Canadian Stroke Best Practice Consensus Statement Acute Stroke Management during Pregnancy is the second of a two-part series devoted to stroke in pregnancy. The first part focused on the unique aspects of secondary stroke prevention in a woman with a prior history of stroke who is, or is planning to become, pregnant. This document focuses on the management of a woman who experiences an acute stroke during pregnancy. This consensus statement was developed in recognition of the need for a specifically tailored approach to the management of this group of patients in the absence of any broad-based, stroke-specific guidelines or consensus statements, which do not exist currently. The foundation for the development of this document was the concept that maternal health is vital for fetal well-being; therefore, management decisions should be based first on the confluence of two clinical considerations: (a) decisions that would be made if the patient wasn't pregnant and (b) decisions that would be made if the patient hadn't had a stroke, then nuanced as needed. While empirical research in this area is limited, this consensus document is based on the best available literature and guided by expert consensus. Issues addressed in this document include initial emergency management, diagnostic imaging, acute stroke treatment, the management of hemorrhagic stroke, anesthetic management, post stroke management for women with a stroke in pregnancy, intrapartum considerations, and postpartum management. These statements are appropriate for healthcare professionals across all disciplines and system planners to ensure pregnant women who experience a stroke have timely access to both expert neurological and obstetric care.

Canadian stroke best practice consensus statement: Secondary stroke prevention during pregnancy.

The Canadian Stroke Best Practice Consensus Statement: Secondary Stroke Prevention during Pregnancy, is the first of a two-part series devoted to stroke in pregnancy. This document focuses on unique aspects of secondary stroke prevention in a woman with a prior history of stroke or transient ischemic attack who is, or is planning to become, pregnant. Although stroke is relatively rare in this cohort, several aspects of pregnancy can increase stroke risk during or immediately after pregnancy. The rationale for the development of this consensus statement is based on the premise that stroke in this group requires a specifically-tailored management approach. No other broad-based, stroke-specific guidelines or consensus statements exist currently. Underpinning the development of this document was the concept that maternal health is vital for fetal wellbeing; therefore, management decisions should be based on the confluence of two clinical considerations: (a) decisions that would be made if the patient was not pregnant and (b) decisions that would be made if the patient had not had a stroke. While empirical research in this area is limited, this consensus document is based on the best available literature and guided by expert consensus. Issues addressed in this document include general management considerations for secondary stroke prevention, the use of antithrombotics, blood pressure management, lipid management, diabetes care, and management for specific ischemic stroke etiologies in pregnancy. The focus is on maternal and fetal health while minimizing risks of a recurrent stroke, through counseling, monitoring, and the safety of select pharmacotherapy. These statements are appropriate for health care professionals across all disciplines.

Prevalence of Fabry Disease and Outcomes in Young Canadian Patients With Cryptogenic Ischemic Cerebrovascular Events.

BACKGROUND AND PURPOSE: Previous studies reported Fabry disease in 0% to 4% of young patients with cryptogenic ischemic stroke (IS). We sought to determine the prevalence of Fabry and outcomes among young Canadians with cryptogenic IS or transient ischemic attack (TIA). METHODS: We prospectively enrolled individuals aged 18 to 55 with IS or speech or motor TIA, and no cause identified despite predetermined investigation. α-galactosidase-A gene was sequenced for Fabry diagnosis. National Institutes of Health Stroke Scale score was measured at presentation to quantify stroke severity. Modified Rankin Scale determined functional outcomes ≤7 days after presentation and 6 months later. RESULTS: We enrolled 365 patients with IS and 32 with TIA. α-galactosidase-A sequencing identified a single carrier of a genetic variant of unknown significance (p.R118C) and no well-recognized pathogenic variants. Mean National Institutes of Health Stroke Scale score was 3.1. Proportion of patients with modified Rankin Scale of 0 to 2 was 70.7% at ≤7 days and 87.4% at 6 months. National Institutes of Health Stroke Scale score at presentation and diabetes mellitus predicted 6-month modified Rankin Scale. Thirteen patients experienced 5 recurrent IS and 9 TIA during follow-up. No patient died. Most patients (98.7%) returned home. Among previous workers, 43% had residual working limitations. CONCLUSIONS: In this Canadian cohort of patients with cryptogenic IS or TIA, the prevalence of Fabry was 0.3% if p.R118C variant is considered as pathogenic. This suggests that more cost-effective methods should be applied for diagnosis of Fabry rather than systematic genetic screening in this population. Overall, cryptogenic IS in young adults is associated with favorable outcomes.

Endovascular thrombectomy and medical therapy versus medical therapy alone in acute stroke: A randomized care trial.

BACKGROUND: Until recently, the benefits of endovascular treatment in stroke were not proven. Care trials have been designed to simultaneously offer yet-to-be validated interventions and verify treatment outcomes. Our aim was to implement a care trial for patients with acute ischemic stroke. METHODS: The study was offered to all patients considered for endovascular management of acute ischemic stroke in one Canadian hospital. Inclusion criteria were broad: onset of symptoms≤5h or at any time in the presence of clinical-imaging mismatch and suspected or demonstrated proximal large vessel occlusion. Exclusion criteria were few: established infarction or hemorrhagic transformation of the target symptomatic territory and poor 3-month prognosis. The primary outcome was mRS≤2 at 3 months. Patients were randomly allocated to standard care or standard care plus endovascular treatment. ClinicalTrials.gov: Identifier NCT02157532. RESULTS: Seventy-seven patients were recruited in 19 months (March 2013-October 2014) at a single center. Randomized allocation was interrupted when other trials showed the benefits of endovascular therapy. At 3 months, 20 of 40 patients (50.0%; 95% CI: 35%-65%) in the intervention group had reached the primary outcome, compared to 14 of 37 patients (37.8%; 95% CI: 24%-54%) in the control group (P=0.36). Eleven patients in the intervention group died within 3 months compared to 9 patients in the standard care group. CONCLUSION: A care trial was implemented to offer verifiable care to acute stroke patients. This approach offers a promising means to manage clinical dilemmas and guide uncertain practices.

Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Triggers, Causes, and Outcome (SECRETO): Rationale and design.

BACKGROUND: Worldwide, about 1.3 million annual ischaemic strokes (IS) occur in adults aged <50 years. Of these early-onset strokes, up to 50% can be regarded as cryptogenic or associated with conditions with poorly documented causality like patent foramen ovale and coagulopathies. KEY HYPOTHESES/AIMS: (1) Investigate transient triggers and clinical/sub-clinical chronic risk factors associated with cryptogenic IS in the young; (2) use cardiac imaging methods exceeding state-of-the-art to reveal novel sources for embolism; (3) search for covert thrombosis and haemostasis abnormalities; (4) discover new disease pathways using next-generation sequencing and RNA gene expression studies; (5) determine patient prognosis by use of phenotypic and genetic data; and (6) adapt systems medicine approach to investigate complex risk-factor interactions. DESIGN: Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO; NCT01934725) is a prospective multi-centre case-control study enrolling patients aged 18-49 years hospitalised due to first-ever imaging-proven IS of undetermined etiology. Patients are examined according to a standardised protocol and followed up for 10 years. Patients are 1:1 age- and sex-matched to stroke-free controls. Key study elements include centralised reading of echocardiography, electrocardiography, and neurovascular imaging, as well as blood samples for genetic, gene-expression, thrombosis and haemostasis and biomarker analysis. We aim to have 600 patient-control pairs enrolled by the end of 2018. SUMMARY: SECRETO is aiming to establish novel mechanisms and prognosis of cryptogenic IS in the young and will provide new directions for therapy development for these patients. First results are anticipated in 2019.

Early CT changes in patients admitted for thrombectomy: Intrarater and interrater agreement.

OBJECTIVE: To systematically review the literature and assess agreement on the Alberta Stroke Program Early CT Score (ASPECTS) among clinicians involved in the management of thrombectomy candidates. METHODS: Studies assessing agreement using ASPECTS published from 2000 to 2015 were reviewed. Fifteen raters reviewed and scored the anonymized CT scans of 30 patients recruited in a local thrombectomy trial during 2 independent sessions, in order to study intrarater and interrater agreement. Agreement was measured using intraclass correlation coefficients (ICCs) and Fleiss kappa statistics for ASPECTS and dichotomized ASPECTS at various cutoff values. RESULTS: The review yielded 30 articles reporting 40 measures of agreement. Populations, methods, analyses, and results were heterogeneous (slight to excellent agreement), precluding a meta-analysis. When analyzed as a categorical variable, intrarater agreement was slight to moderate (κ = 0.042-0.469); it reached a substantial level (κ > 0.6) in 11/15 raters when the score was dichotomized (0-5 vs 6-10). The interrater ICCs varied between 0.672 and 0.811, but agreement was slight to moderate (κ = 0.129-0.315). Even in the best of cases, when ASPECTS was dichotomized as 0-5 vs 6-10, interrater agreement did not reach a substantial level (κ = 0.561), which translates into at least 5 of 15 raters not giving the same dichotomized verdict in 15% of patients. CONCLUSIONS: In patients considered for thrombectomy, there may be insufficient agreement between clinicians for ASPECTS to be reliably used as a criterion for treatment decisions.