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Background and ObjectivesThrombosis is central to the pathogenesis of acute ischemic stroke, with higher thrombin generation being associated with increased stroke risk. The immune system may contribute to thrombin generation in stroke and thus may offer novel strategies for stroke prevention. This study addresses the research question regarding the relationship of thrombin generation to leukocyte gene expression in patients with acute ischemic stroke.MethodsWe isolated RNA from whole blood and examined the relationship to thrombin generation capacity in patients with acute ischemic stroke. Due to its effects on thrombin generation, patients on anticoagulants were excluded from the study. The relationship of gene expression with peak thrombin was evaluated by analysis of covariance across peak thrombin quartiles adjusted for sex and age.ResultsIn 97 patients with acute ischemic stroke, peak thrombin was variable, ranging from 252.0 to 752.4 nM. Increased peak thrombin was associated with differences in thromboinflammatory leukocyte gene expression, including a decrease in ADAM metallopeptidase with thrombospondin type 1 motif 13 and an increase in nuclear factor κB (NF-κB)–activating protein, protein disulfide isomerase family A member 5, and tissue factor pathway inhibitor 2. Pathways associated with peak thrombin included interleukin 6 signaling, thrombin signaling, and NF-κB signaling. A linear discriminant analysis model summarizing the immune activation associated with peak thrombin in a first cohort of stroke could distinguish patients with low peak thrombin from high peak thrombin in a second cohort of 112 patients with acute ischemic stroke.DiscussionThe identified genes and pathways support a role of the immune system contributing to thrombus formation in patients with stroke. These may have relevance to antithrombotic strategies for stroke prevention.

Atrial fibrillation (AF) is a major cause of adverse cardiovascular outcomes, and its prevalence is fast rising in Africa. The advent of direct oral anticoagulants (DOACs) has been a major revolution for the prevention of AF-related stroke and systemic embolism given the significant advantage over vitamin K antagonists in terms of both efficacy, safety, and adherence. However, due to their high cost, equitable access to DOACs has been a challenge, especially in low- and middle-income countries. Therefore, the recent addition of DOACs to the 21st WHO list of essential medicines comes as good news. African governments should take this opportunity to scale up the accessibility to DOACs for African patients with AF. This could be achieved through advocacy, appropriate training of health professionals, task shifting, patient education, strategic partnership to increase availability and quality of low-cost generic drugs, and appropriate medico-economic studies.

Thrombosis is central to the pathogenesis of acute ischemic stroke, with higher thrombin generation being associated with increased stroke risk. The immune system may contribute to thrombin generation in stroke and thus may offer novel strategies for stroke prevention. This study addresses the research question regarding the relationship of thrombin generation to leukocyte gene expression in patients with acute ischemic stroke. We isolated RNA from whole blood and examined the relationship to thrombin generation capacity in patients with acute ischemic stroke. Due to its effects on thrombin generation, patients on anticoagulants were excluded from the study. The relationship of gene expression with peak thrombin was evaluated by analysis of covariance across peak thrombin quartiles adjusted for sex and age. In 97 patients with acute ischemic stroke, peak thrombin was variable, ranging from 252.0 to 752.4 nM. Increased thrombin generation was associated with differences in thromboinflammatory leukocyte gene expression, including a decrease in ADAM metallopeptidase with thrombospondin type 1 motif 13 and an increase in nuclear factor B (NF-kB)-activating protein, protein disulfde isomerase family A member 5, and tissue factor pathway inhibitor 2. Pathways associated with peak thrombin included interleukin 6 signaling, thrombin signaling, and NF-kB signaling. A linear discriminant analysis model summarizing the immune activation associated with peak thrombin in a first cohort of stroke could distinguish patients with low peak thrombin from high peak thrombin in a second cohort of 112 patients with acute ischemic stroke.The identified genes and pathways support a role of the immune system contributing to thrombus formation in patients with stroke. These may have relevance to antithrombotic strategies for stroke prevention.

Background: IL-6 (interleukin-6) has important roles in atherosclerosis pathophysiology. To determine if anti-IL-6 therapy warrants evaluation as an adjuvant stroke prevention strategy in patients with carotid atherosclerosis, we tested whether circulating IL-6 levels predict carotid plaque severity, vulnerability, and progression in the prospective population-based CHS (Cardiovascular Health Study). Methods: Duplex carotid ultrasound was performed at baseline and 5 years. Baseline plaque severity was scored 0 to 5 based on North American Symptomatic Carotid Endarterectomy Trial grade of stenosis. Plaque vulnerability at baseline was the presence of markedly irregular, ulcerated, or echolucent plaques. Plaque progression at 5 years was a ≥1 point increase in stenosis severity. The relationship of baseline plasma IL-6 levels with plaque characteristics was modeled using multivariable linear (severity) or logistic (vulnerability and progression) regression. Risk factors of atherosclerosis were included as independent variables. Stepwise backward elimination was used with P >0.05 for variable removal. To assess model stability, we computed the E -value or minimum strength of association (odds ratio scale) that unmeasured confounders must have with log IL-6 and the outcome to suppress the association. We performed internal validation with 100 bootstrap samples. Results: There were 4334 participants with complete data (58.9% women, mean age: 72.7±5.1 years), including 1267 (29.2%) with vulnerable plaque and 1474 (34.0%) with plaque progression. Log IL-6 predicted plaque severity (β=0.09, P =1.3×10 −3 ), vulnerability (OR, 1.21 [95% CI, 1.05–1.40]; P =7.4×10 −3 , E -value=1.71), and progression (OR, 1.44 [95% CI, 1.23-1.69], P =9.1×10 −6 , E -value 2.24). In participants with >50% predicted probability of progression, mean log IL-6 was 0.54 corresponding to 2.0 pg/mL. Dichotomizing IL-6 levels did not affect the performance of prediction models. Conclusions: Circulating IL-6 predicts carotid plaque severity, vulnerability, and progression. The 2.0 pg/mL cutoff could facilitate the selection of individuals that would benefit from anti-IL-6 drugs for stroke prevention.

Embolic stroke of unknown source (ESUS) represents one in five ischemic strokes. Ipsilateral non-stenotic carotid plaques are identified in 40% of all ESUS. In this narrative review, we summarize the evidence supporting the potential causal relationship between ESUS and non-stenotic carotid plaques; discuss the remaining challenges in establishing the causal link between non-stenotic plaques and ESUS and describe biomarkers of potential interest for future research. In support of the causal relationship between ESUS and non-stenotic carotid plaques, studies have shown that plaques with high-risk features are five times more prevalent in the ipsilateral vs. the contralateral carotid and there is a lower incidence of atrial fibrillation during follow-up in patients with ipsilateral non-stenotic carotid plaques. However, non-stenotic carotid plaques with or without high-risk features often coexist with other potential etiologies of stroke, notably atrial fibrillation (8.5%), intracranial atherosclerosis (8.4%), patent foramen ovale (5–9%), and atrial cardiopathy (2.4%). Such puzzling clinical associations make it challenging to confirm the causal link between non-stenotic plaques and ESUS. There are several ongoing studies exploring whether select protein and RNA biomarkers of plaque progression or vulnerability could facilitate the reclassification of some ESUS as large vessel strokes or help to optimize secondary prevention strategies.

Malawi is a country in Southern Africa (figures 1 and 2) and gained its independence from the British Colony in 1964. Currently 17.5 million people live in Malawi, and about 85% reside in rural areas and depend on farming for survival.1 Although one of the poorest countries in the world (with a gross domestic product of $338.48 per capita), it is blessed with a dramatic landscape, offering a variety of unique experiences and boasting some of Africa’s best safaris and bird watching. Tourist hot spots include Mount Mulanje and Lake Malawi (figure 3). Malawians are characteristically known for their warm smiles, and deservedly the country is nicknamed ‘the warm heart of Africa’. Figure 1 The map of Africa showing the location of Malawi and its neighbours. DRC, Democratic Republic of the Congo. Source: B Chiepa, 2018. Figure 2 Flag of Malawi (http://flagpedia.net/malawi; accessed on 20 February 2018). Figure 3 Some of Malawi's tourist destinations: Mulanje Mountain, Cape Maclear and Liwonde National Park. Source: B Chiepa, 2018. Malawi has an acute shortage of health workers, with approximately 0.12 available for every 1000 people. This contrasts with ratios in neighbouring countries such as Kenya (1.1 per 1000) and South Africa (2.1 per 1000).2 3 The life expectancy at birth in Malawi is 63 years, and the population is slowly ageing. Despite the WHO recommending one neurologist for every 50 000 people, Malawi has only one permanent paediatric neurologist (last author) and relies on visiting adult neurologists, usually on a voluntary basis and rarely continuous. Patients are referred to the Queen Elizabeth Central Hospital paediatric neurology services …

Hemorrhagic transformation (HT) is a common complication in patients with acute ischemic stroke. It occurs when peripheral blood extravasates across a disrupted blood brain barrier (BBB) into the brain following ischemic stroke. Preventing HT is important as it worsens stroke outcome and increases mortality. Factors associated with increased risk of HT include stroke severity, reperfusion therapy (thrombolysis and thrombectomy), hypertension, hyperglycemia, and age. Inflammation and the immune system are important contributors to BBB disruption and HT and are associated with many of the risk factors for HT. In this review, we present the relationship of inflammation and immune activation to HT in the context of reperfusion therapy, hypertension, hyperglycemia, and age. Differences in inflammatory pathways relating to HT are discussed. The role of inflammation to stratify the risk of HT and therapies targeting the immune system to reduce the risk of HT are presented.

Background and ObjectivesThe rate of infarct core progression in patients with acute ischemic stroke is variable and affects outcome of reperfusion therapy. We evaluated the hypoperfusion index (HI) to estimate the initial rate of core progression in patients with medium vessel occlusion (MeVO) compared to large vessel occlusion (LVO) stroke and within a larger time frame since stroke onset.MethodsCore progression was assessed in 106 patients with acute stroke and CT perfusion. Using reperfusion trial core time criteria, fast progressors had core >70 mL within 6 hours of stroke onset and slow progressors had core ≤70 mL, mismatch ≥15 mL, and mismatch to core ratio ≥1.8 within 6 to 24 hours. The relationship between HI and infarct core progression (core/time) was examined using receiver operating characteristics to determine optimal HI cutoff. The HI cutoff was then tested in the overall cohort, compared between MeVO and LVO, and evaluated in patients up to 24 hours from stroke onset to differentiate fast from slow rate of core progression. HI threshold was assessed in a second independent cohort of 110 patients with acute ischemic stroke.ResultsIn 106 patients with acute stroke, 6.6% were fast progressors, 27.4% were slow progressors, and 66% were not classified as fast or slow progressor by reperfusion trial core time criteria. HI >0.5 was associated with fast progression and able to distinguish fast from slow progressors (area under the curve [AUC] 0.94; 95% confidence interval [CI] 0.80–0.99). In MeVO (n = 26) HI >0.5 had a core progression of 0.30 mL/min compared to 0.03 mL/min for HI ≤0.5 (p < 0.001). In LVO (n = 80), HI >0.5 had a core progression of 0.26 mL/min compared to 0.02 mL/min for HI ≤0.5 (p < 0.001). In patients not classified as fast or slow progressor by reperfusion trial criteria, those with HI >0.5 had progression rate of 0.21 mL/min compared to 0.03 mL/min for those with HI ≤0.5 (p < 0.001). Validation in a second cohort of patients with acute ischemic stroke (n = 110; MeVO = 42, LVO = 68) yielded similar results for HI >0.5 to distinguish fast and slow core progression with an AUC of 0.84 (95% CI 0.72–0.97).DiscussionHI can differentiate fast from slow core progression in MeVO and LVO within the first 24 hours of acute ischemic stroke. Consideration of core progression rate at time of stroke evaluation may have implications in the selection of patients with MeVO and LVO stroke for reperfusion therapy that warrant further study.

Background and Purpose: With advancing age, alterations occur to the immune system, including an increase in inflammation (inflammaging) and a reduced ability to respond to new immune challenges. The role of an aging immune system in patients with ischemic stroke remains unclear, although age is an important determinant of stroke risk and outcome. This study assessed the aging immune system in patients with acute ischemic stroke by differences in leukocyte gene expression in relationship to age. Methods: Peripheral blood RNA from 2 cohorts with acute ischemic stroke was measured by whole-genome microarray, and genes associated with advancing age were identified (false discovery rate-corrected P Results: There were 166 genes associated with age in cohort 1 (derivation cohort, n=94). Sixty-nine of these age-associated genes were verified in cohort 2 (validation cohort, n=79). Identified genes included a decrease in CR2 , CD27 , CCR7 , and NT5E . Genes were associated with altered B-cell receptor signaling, lymphocyte proliferation, and leukocyte homeostasis. Forty-three of the 69 age-associated genes in stroke were also associated with age in nonstroke studies. Conclusions: A relationship between leukocyte gene expression and age in patients with ischemic stroke was identified. The changes include alterations to the adaptive humoral immune system, which may influence age-related stroke risk and outcome.

Background: Advancing age is associated with changes to the immune system, which affect stroke outcome. We previously demonstrated an age-associated alteration in leukocyte gene expression in patients with ischemic stroke. The aim of this study is to validate these findings in an independent stroke cohort and assess the relationship to stroke outcome. Methods: Genes associated with age were identified in a cohort of 57 patients with acute ischemic stroke. Peripheral blood RNA was measured using whole genome microarrays and genes associated with advancing age identified (FDR-corrected p < 0.05, partial correlation coefficient r > |0.3|); age-associated gene expression differences in patients with poor 90-day outcome (mRS < 2) were also compared. Genes were functionally characterized by pathway and enrichment analysis and verified against age-associated genes from two additional stroke cohorts containing a total of 173 patients. Results: There were 536 genes associated with age in the new stroke cohort, of which 286 decreased and 253 increased with age. Thirty-nine (39) of the age-associated genes were present in previous stroke cohorts analyzed, including a decrease in CCR6, CXCR5, BLNK and NT5E. A decrease in CXCR5 and CD79B was also identified in patients with poor outcome. Pathways and enriched terms relating to the humoral adaptive system immune system, including B-cell and lymphocyte activation, were among those represented in age-associated genes. Conclusions: Age-related changes in leukocyte gene expression were validated in an independent cohort of patients with ischemic stroke. Verified changes include alterations to the humoral immune system and a relationship to stroke outcome. Further investigation of the aging immune system in stroke is warranted.

Background and purpose: Detection of atrial fibrillation (AF) after acute ischemic stroke is pivotal for the timely initiation of anticoagulation to prevent recurrence. Besides heart rhythm monitoring, various blood biomarkers have been suggested as complimentary diagnostic tools for AF. We aimed to summarize data on the performance of cardiac natriuretic peptides for the diagnosis of covert AF after acute ischemic stroke and to assess their potential clinical utility. Methods: We searched PubMed and Embase for prospective studies reporting the performance of B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) for the diagnosis of covert AF after acute ischemic stroke. Summary diagnostic performance measures were pooled using bivariate meta-analysis with random-effects model. Results: We included six studies focusing on BNP (n = 1930) and three studies focusing on NT-proBNP (n = 623). BNP had a sensitivity of 0.83 (95% CI: 0.64-0.93), a specificity of 0.74 (0.67-0.81), a positive likelihood ratio of 3.2 (2.6-4.0), and a negative likelihood ratio of 0.23 (0.11-0.49). NT-proBNP had a sensitivity of 0.91 (0.65-0.98), a specificity of 0.77 (0.52-0.91), a positive likelihood ratio of 3.9 (1.8-8.7), and a negative likelihood ratio of 0.12 (0.03-0.48). Considering a pre-test probability of 20%, BNP and NT-proBNP had post-test probabilities of 45% and 50%. Conclusions: NT-proBNP has a better performance than BNP for the diagnosis of covert AF after acute ischemic stroke. Both biomarkers have low post-test probabilities and may not be used as a stand-alone decision-making tool for the diagnosis of covert AF in patients with acute ischemic stroke. However, they may be useful for a screening strategy aiming to select patients for long-term monitoring of the heart rhythm.

Background and purposeDetection of atrial fibrillation (AF) after acute ischaemic stroke is pivotal for the timely initiation of anticoagulation to prevent recurrence. Besides heart rhythm monitoring, various blood biomarkers have been suggested as complimentary diagnostic tools for AF. We aimed to summarise data on the performance of cardiac natriuretic peptides for the diagnosis of covert AF after acute ischaemic stroke and to assess their potential clinical utility.MethodsWe searched PubMed and Embase for prospective studies reporting the performance of B-type natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) for the diagnosis of covert AF after acute ischaemic stroke. Summary diagnostic performance measures were pooled using bivariate meta-analysis with a random-effect model.ResultsWe included six studies focusing on BNP (n=1930) and three studies focusing on NT-proBNP (n=623). BNP had a sensitivity of 0.83 (95% CI 0.64 to 0.93), a specificity of 0.74 (0.67 to 0.81), a positive likelihood ratio of 3.2 (2.6 to 4.0) and a negative likelihood ratio of 0.23 (0.11 to 0.49). NT-proBNP had a sensitivity of 0.91 (0.65 to 0.98), a specificity of 0.77 (0.52 to 0.91), a positive likelihood ratio of 3.9 (1.8 to 8.7) and a negative likelihood ratio of 0.12 (0.03 to 0.48). Considering a pretest probability of 20%, BNP and NT-proBNP had post-test probabilities of 45% and 50%.ConclusionsNT-proBNP has a better performance than BNP for the diagnosis of covert AF after acute ischaemic stroke. Both biomarkers have low post-test probabilities and may not be used as a stand-alone decision-making tool for the diagnosis of covert AF in patients with acute ischaemic stroke. However, they may be useful for a screening strategy aiming to select patients for long-term monitoring of the heart rhythm.

Background and Purpose: Thrombus formation is central to pathophysiology of stroke in patients with atrial fibrillation. Whether factors in plasma contribute to thrombus generation in patients with atrial fibrillation remains unclear. In this study we sought to determine whether plasma contributes to thrombin generation in patients with atrial fibrillation. Methods: There were 78 acute ischemic strokes with atrial fibrillation and 37 non-stroke controls. Plasma thrombin generation was measured by thrombin generation assay, resulting lag time, peak thrombin, time to peak and area under the curve was assessed. Thrombin generation capacity was compared in stroke patients with atrial fibrillation to non-stroke controls. The relationship to anticoagulation was assessed. In vitro, the effect of anticoagulation on plasma thrombin generation was determined. Results: Thrombin generation capacity was increased (shorter lag time and time to peak) in ischemic stroke patients with atrial fibrillation compared to non-stroke atrial-fibrillation controls (p Conclusions: Stroke patients with atrial fibrillation have a higher plasma induced thrombin generation compared to atrial fibrillation controls. Factors in plasma such as leukocyte derived tissue factor likely contribute to thrombus formation in patients with atrial fibrillation. As such, components in plasma may represent new targets to reduce thrombus formation and stroke risk in patients with atrial fibrillation.

Objective This review aimed to summarize the evidence on the risk of thromboembolism associated with carotid and aortic atherosclerosis in patients with AF, and the potential impact of their inclusion in current stroke risk stratification scores. Methods MEDLINE, Web of Science and EMBASE were systematically searched to identify all published studies providing relevant data through 28 February 2021. Results We identified 10 eligible studies. There was high heterogeneity across studies, precluding a meta-analysis. Carotid stenosis was not associated with incident ischemic stroke in three prospective studies, including the SPAF II trial and the ROCKET-AF trial. An association between carotid stenosis and thromboembolism was found in two studies, with a potential reporting bias due to their retrospective design. The evidence suggesting that carotid plaque predicts stroke or transient ischemic attack in AF patients were more consistent in the four studies evaluating this association. The inclusion of carotid plaque and carotid intima-media thickness (cIMT) into stroke risk stratification tools for AF patients improved their performance. Data on the association of aortic plaque with thromboembolism is scarce in patients with AF. The two studies reporting on this association suggest that aortic plaque alone does not predict incident ischemic stroke. Conclusion Available data suggest an association of carotid atherosclerosis with the risk of stroke and transient ischemic attack in patients with AF. Future studies should evaluate whether incorporating cIMT and characteristics of carotid and aortic plaques into scoring systems would improve stroke prediction and prevention in patients with AF.

Introduction Mechanisms driving neurodegeneration in Parkinson's disease (PD) are unclear and neurovascular dysfunction may be a contributing factor. White matter hyperintensities (WMH) are commonly found on brain MRI in patients with PD. It is controversial if they are more prevalent or more severe in PD compared with controls. This systematic review aims to answer this question. Methods A systematic search of electronic databases was conducted for studies of WMH in patients with PD. A qualitative synthesis was done for studies reporting WMH prevalence or WMH scores on a visual rating scale (VRS). In studies reporting total WMH volume, the difference between patients with PD and controls was pooled using random effects meta-analysis. Results Among 3860 subjects from 24 studies, 2360 were cases and 1500 controls. Fifteen studies reported WMH scores and four studies reported the prevalence of WMH. On VRS, five studies reported no difference in WMH scores, three found higher WMH scores in PD compared to controls, three reported increased WMH scores either in periventricular or deep white matter, and four reported higher scores only in PD with dementia. In studies reporting WMH volume, there was no difference between patients with PD and controls (pooled standardized mean difference = 0.1, 95%CI: −0.1–0.4, I2 = 81%). Conclusion WMH are not more prevalent or severe in patients with PD than in age-matched controls. PD dementia may have more severe WMH compared to controls and PD with normal cognition. Prospective studies using standardized methods of WMH assessment are needed.

Introduction: although the main manifestations of COVID-19 are respiratory, several neurological symptoms and complications have also been reported The pandemic seems to have some epidemiological specificities in sub-Saharan Africa, and this may be reflected in the type and frequency of neurological symptoms This study aimed to report neurological manifestations associated with symptomatic COVID-19 in a sub-Saharan African setting Methods: we conducted a retrospective review of symptomatic PCR-confirmed COVID-19 cases admitted to the Bafoussam Regional Hospital between March and September 2020 Patients’ files were reviewed at discharge by a consultant neurologist Socio-demographic characteristics, co-morbidities, symptoms on admission, neurological symptoms during hospitalization, management, and in-hospital outcome were recorded Comparisons between patients with and without neurological symptoms were performed using Fisher’s exact and Mann-Whitney U test Results: we enrolled 177 symptomatic patients (68% men) Mean age was 54 6 ± 17 8 years (range 2-99 years) Co-morbidities were present in 57 6% of patients, including hypertension (27 1%) and diabetes mellitus (25 4%) Neurological symptoms were found in 113 (63 8%) patients The most frequent were headache (39 0%), myalgia (35 6%), anosmia (11 9%), impaired consciousness (10 7%) and delirium (5 6%) Regarding the presenting symptoms, fever was more frequent in patients with neurological symptoms than in those without (81 4% versus 50 0%, p< 0 001), while digestive symptoms were less frequent in patients with neurological symptoms (0 9% versus 9 4%, p= 0 004) Conclusion: neurological manifestations are frequent and heterogeneous in patients with symptomatic COVID-19 Further studies are needed to clarify the pathophysiology of neurological symptoms in COVID-19 and their impact on patients’ long-term outcome © Yannick Fogoum Fogang et al

Importance There is an ongoing debate regarding the management of asymptomatic carotid stenosis. Previous studies have reported imaging features of high-risk plaques that could help to optimize the risk-benefit ratio of revascularization. However, such studies have not provided an accurate estimate of the prevalence of high-risk plaques and the associated annual incidence of ipsilateral ischemic cerebrovascular events to inform the design of clinical trials using a risk-oriented selection of patients before randomization. Objective To assess the relevance and feasibility of risk-oriented selection of patients for revascularization. Data Sources A systematic search of PubMed and Ovid Embase from database inception to July 31, 2019, was performed. Study Selection Prospective observational studies that reported prevalence of high-risk plaques and incidence of ipsilateral ischemic cerebrovascular events were included. Data Extraction and Synthesis Aggregated data were pooled using random-effects meta-analysis. Data were analyzed from December 16, 2019, to January 15, 2020. Main Outcomes and Measures Prevalence of high-risk plaques and annual incidence of ipsilateral ischemic events. Results Overall, 64 studies enrolling 20 751 participants aged 29 to 95 years (mean age range, 55.0-76.5 years; proportion of men, 45%-87%) were included in the meta-analysis. Among all participants, the pooled prevalence of high-risk plaques was 26.5% (95% CI, 22.9%-30.3%). The most prevalent high-risk plaque features were neovascularization (43.4%; 95% CI, 31.4%-55.8%) in 785 participants, echolucency (42.3%; 95% CI, 32.2%-52.8%) in 12 364 participants, and lipid-rich necrotic core (36.3%; 95% CI, 27.7%-45.2%) in 3728 participants. The overall incidence of ipsilateral ischemic cerebrovascular events was 3.2 events per 100 person-years (22 cohorts with 10 381 participants; mean follow-up period, 2.8 years; range, 0.7-6.5 years). The incidence of ipsilateral ischemic cerebrovascular events was higher in patients with high-risk plaques (4.3 events per 100 person-years; 95% CI, 2.5-6.5 events per 100 person-years) than in those without high-risk plaques (1.2 events per 100 person-years; 95% CI, 0.6-1.8 events per 100 person-years), with an odds ratio of 3.0 (95% CI, 2.1-4.3;I2 = 48.8%). In studies focusing on severe stenosis (9 cohorts with 2128 participants; mean follow-up period, 2.8 years; range, 1.4-6.5 years), the incidence of ipsilateral ischemic cerebrovascular events was 3.7 events per 100 person-years (95% CI, 1.9-6.0 events per 100 person-years). The incidence of ipsilateral ischemic cerebrovascular events was also higher in patients with high-risk plaques (7.3 events per 100 person-years; 95% CI, 2.0-15.0 events per 100 person-years) than in those without high-risk plaques (1.7 events per 100 person-years; 95% CI, 0.6-3.3 events per 100 person-years), with an odds ratio of 3.2 (95% CI, 1.7-5.9;I2 = 39.6%). Conclusions and Relevance High-risk plaques are common in patients with asymptomatic carotid stenosis, and the associated risk of an ipsilateral ischemic cerebrovascular event is higher than the currently accepted estimates. Extension of routine assessment of asymptomatic carotid stenosis beyond the grade of stenosis may help improve risk stratification and optimize therapy.

Objective To determine if pooled estimates of the prevalence of unexpected findings in patients with headache and normal neurologic examination support current expert opinion-based neuroimaging guidelines. Methods We searched PubMed and EMBASE for studies reporting neuroimaging findings in patients with headache and normal neurologic examination up to September 30, 2017. The overall and disease-specific prevalence of unexpected findings were pooled through random-effects meta-analysis. This study is registered with PROSPERO, registration number CRD42017079714. Results In forty-one studies including 15,760 participants, the overall prevalence of unexpected findings and normal variants was 17.5% (95% CI: 13.1–22.3). The prevalence was 26.6% (95% CI: 15.5–39.4) in studies using MRI only. The prevalence of vascular, neoplastic, and non-neoplastic findings was 6.6%, 1.4%, and 9.6%. The pooled disease-specific prevalence was 2.0% for stroke, 1.8% for aneurysms, 0.8% for subdural hematoma, 0.7% for hydrocephalus, 0.2% for glioma, and 0.1% for meningioma. In secondary analysis, there was 0.4% increase in the prevalence of vascular unexpected findings with each 1% increase in the proportion of migraine with aura (p-value for meta-regression = 0.005). Conclusions In patients with headache and normal neurologic examination, important vascular and neoplastic unexpected findings are rare and better detected with MRI. This supports current American College of Radiology and European Headache Federation recommendations to avoid systematic imaging in such patients and prefer MRI when imaging is needed.

Background and Purpose: An ipsilateral non-obstructive carotid atherosclerosis (NOCA), defined as carotid plaque with Methods: A search of Pubmed and Ovid-Embase identified observational studies reporting carotid plaque imaging features in patients with cryptogenic stroke, from inception to July 15, 2019. The prevalence of NOCA with high-risk features in ipsilateral and contralateral carotid was determined by pooling study-specific estimates using a random-effect meta-analysis. Results: Six prospective studies enrolling a total of 255 participants with unilateral ischemic stroke in the anterior circulation were included. Carotid arteries were imaged with ultrasound, computed tomography or MRI to identify echolucency, ulceration, intraplaque hemorrhage, thrombus, or thickness ≥ 3 mm. The pooled prevalence of NOCA with high-risk features in the ipsilateral carotid was 34.0% (95% CI: 25.7 – 42.9) compared to 7.3 % (95% CI: 0.8 – 18.1) in the contralateral carotid. The odds ratio of finding a plaque with high-risk features in the ipsilateral versus the contralateral carotid was 4.1 (95% CI: 2.0 – 8.7). Conclusion: Plaques with high-risk features are four times more prevalent in the ipsilateral compared to the contralateral carotid artery in patients with cryptogenic stroke, suggesting a relationship to stroke risk. These features may aid in etiologic classification of stroke and risk stratification for secondary prevention therapy.

Background: The recommended treatment of asymptomatic carotid atherosclerosis is best medical therapy since the 1% annual risk of stroke is lower than the risk of stroke from revascularization. Specific imaging features may identify patients at increased risk of stroke and optimize the risk-benefit ratio of carotid surgery. To assess the relevance and feasibility of such approach, we aimed to summarize available data on the frequency of high-risk features and the related risk of stroke in patients with asymptomatic carotid atherosclerosis. Methods: A search of Pubmed and Ovid-Embase identified prospective studies reporting findings of carotid plaque imaging and incidence of stroke in patients with asymptomatic carotid atherosclerosis. Prevalence of high-risk features and incidence of ipsilateral ischemic events were pooled using random-effect meta-analysis. Results: Thirty-five studies enrolling 5808 participants with asymptomatic carotid atherosclerosis of various grades were included. The pooled prevalence (95% CI) of high-risk features on plaque imaging was 28.8 (18.8 - 38.7). The prevalence of neovascularization was 53.5% (45.2 - 61.8), echolucency 40.0% (30.8 - 49.6), lipid-rich necrotic core 35.7% (24.1 - 48.1), thin or ruptured fibrous cap 27.5% (14.2 - 43.3), silent brain infarcts 27.0% (15.3 - 40.5), impaired cerebrovascular reserve 25.9% (10.3 - 45.5), intraplaque hemorrhage 19.2% (13.9 - 25.1), microembolic signals 14.4% (8.9 - 20.8), and ulceration 13.5% (1.3 - 34.0). In 15 cohort studies enrolling 4215 participants, the mean duration of follow-up was 3.5 years (2.0 - 4.6). The pooled incidence of ipsilateral ischemic events was 2.7 per 100 person-years (1.6 - 4.0). This incidence was higher in patients with a high-risk feature (4.9%, 2.3 - 8.2) than in those without (0.9%, 0.2 - 1.8) with an odds ratio of 4.6 (2.3 - 9.3). Conclusion: High-risk features on imaging are frequent in asymptomatic carotid atherosclerosis and associated with a fourfold increase in the annual risk of ipsilateral ischemic events. A risk-oriented selection of patients with asymptomatic carotid atherosclerosis prior to randomization in revascularization trials appears relevant and may be a strategy to prevent stroke in asymptomatic carotid atherosclerosis.

Background\ud In sub-Saharan Africa, there is a dearth of epidemiologic data on the burden of cerebral ath-erosclerosis. This is explained by the limited availability and the high cost of standard vascu-\ud lar imaging techniques. Neurovascular ultrasound is portable, cheaper and non-invasive and could, therefore, represent a reasonable alternative to fill this knowledge gap. We explored the feasibility of neurovascular ultrasound in Malawian adults with acute stroke-like syndrome to inform the design of future large stroke studies comparing its diagnostic perfor-\ud mance to that of gold standard vascular imaging techniques in sub-Saharan Africa.\ud Methods\ud We enrolled consecutive patients diagnosed with acute stroke-like syndrome based on the World Health Organization definition. Clinical and demographic data were recorded, and a comprehensive neurovascular ultrasound was performed. Fisher’s exact and Kruskal-Wallis\ud tests were used to study the relationship between atherosclerosis and potential risk factors.\ud Results\ud Sixty-six patients were enrolled (mean age: 58.7 years). The frequency of extracranial ath-erosclerosis was 39.4% (n = 26, 95% CI: 28.6–52.2). There were 12 patients with abnormal carotid intima media thickness (18.2%, 95% CI: 9.8–29.6) and 14 patients with a carotid pla-que (21.2%, 95% CI: 12.1–33.0). The frequency of intracranial atherosclerosis was 19.2%(95%CI: 6.6–39.4) in 26 patients with successful transcranial insonation. Hypertension(80.8 versus 52.5%, p = 0.03) and hypercholesterolemia (11.5 versus 0.0%, p = 0.05) were more prevalent in patients with extracranial atherosclerosis.\ud Conclusions\ud This study demonstrates the feasibility of neurovascular ultrasound to assess cervical arter-ies in adults with stroke-like syndrome in sub-Saharan Africa. There is a high rate of tran-scranial insonation failure in this setting, highlighting the need for echocontrast agents.

Introduction: Immune system dysregulation occurs with age. This includes an increase in inflammation, and immunosenescence, the inability to efficiently respond to new immune challenges. These changes are evident in various diseases but have yet to be evaluated in a population with ischemic stroke. Age is an important factor in stroke, contributing to stroke risk, outcome and risk of hemorrhagic transformation. This study aimed to assess the changes that occur with age in the leukocyte gene expression of patients with ischemic stroke. Methods: Two cohorts of acute ischemic stroke patients were analyzed; cohort 1 (n=94) and cohort 2 (n=79). RNA was isolated from PAXgene tubes and processed on Affymetrix microarrays. Differentially expressed genes associated with age quartiles were identified by ANCOVA, adjusted for sex and batch. Functional analysis identified age-associated pathways. Differentially expressed genes were compared with previous non-stroke aging studies in whole blood. Results: There were 61 and 442 age-associated genes in cohorts 1 and 2 respectively (FDR-corrected pCR2, CCR6 and CXCR5 , were found in common and decreased with age among both cohorts (max-log10(p value) = 17). Functional analysis of the 61 and 442 genes revealed with advancing age there is a change in the humoral immune system, including antibody production and B cell proliferation. When compared to aging gene expression studies in controls, 52% of age-associated genes in cohort 1 and 31% of cohort 2 age-associated genes overlapped with those found in controls, and 16 of the 19 common genes to both cohorts overlapped in controls (max-log10(p value) = 15). Conclusion: In patients with acute stroke there is a change in leukocyte gene expression with advancing age. Changes included a shift in humoral immune response with a potentially impaired B cell response. While many of the age-associated alterations in gene expression present in stroke are similar to non-stroke controls, these changes warrant further investigation for their impact on stroke outcome and risk.

Cardiovascular disease (CVD) has become a major concern in low‐ and middle‐income countries, which bear about 80% of the cardiovascular mortality worldwide. Curbing the burden of CVD implies the management and control of many cardiovascular risk factors that act synergistically to increase cardiovascular mortality. Such actions may require expensive polymedications in a context of limited resources. Therefore, alternative solutions for CVD prevention in low‐ and middle‐income countries are urgently needed. In this context, the concept of a fixed‐dose combination therapy, a polypill composed of drugs known to effectively treat or prevent CVD, has been proposed as a scalable strategy to overcome nonadherence to polymedications and reduce costs. While this has recently been approved in more than 30 countries across America and Europe, there is a crucial need to analyze the potential benefits and challenges related to cardiovascular polypills implementation and vulgarization in low‐ and middle‐income countries, the epicenter of CVD.

The Cardio-Pad TM is a touchscreen tablet which enables to perform electrocardiograms (ECG) in remote underserved areas and transfer the test results via mobile phone connection to specialist physicians for interpretation and assistance in case management. As a telemedicine device, it is a potential solution to overcome the shortage of qualified health professionals and improve access to cardiovascular care in rural areas in low-income countries. After some improvements made on the prototype available in 2014, the commercialization of the Cardio-Pad TM started in early 2016. Despite its potential to help improve the care of patients with cardiovascular diseases (CVDs) in remote underserved areas in low-to-middle income countries, several questions remain unanswered, pertaining to its reliability and cost-effectiveness as a public health intervention. In this paper, we present updates on the Cardio-Pad TM initiative and some of its limitations and remaining challenges.

A 19-year-old man presented with a 1-year history of headache, generalised body weakness, progressive memory loss, and disorientation. One month prior to admission, there was aggravation of the weakness of the right upper limb, with new-onset difficulty with mastication, speech impairment, apathy, and urinary incontinence. On clinical examination, the patient had a motor aphasia and a right-sided hemiparesis with increased muscle tone and hyperreflexia. A noncontrast computed tomography (CT) scan of the brain revealed large ischaemic strokes extending beyond the classical vascular territories. Cerebrospinal fluid analysis showed a mildly increased protein level. The electrocardiogram revealed an irregular sinus bradycardia. The remainder of the cardiovascular and laboratory workup was unremarkable. Considering a working diagnosis of central nervous system vasculitis, the patient was treated with aspirin, prednisolone, and physiotherapy. However, he died suddenly a few weeks later. Based on this case, we discuss the challenges of stroke management in resource-limited settings, provide practical tips for general practitioners, reflect on the potential avenues for short- and long-term action, and introduce the budding collaboration platform between the University College London, the University of Liverpool, the Queen Elizabeth Central Hospital, and the Malawi-Liverpool-Wellcome Trust Clinical Research Programme.

Background\ud The Queen Elizabeth Central Hospital (QECH) is preparing to set up the first stroke unit in Blantyre, Malawi. We conducted this audit to assess current stroke management practices and outcomes at QECH and identify priority areas for intervention.\ud \ud Methods\ud From April to June 2018, we prospectively enrolled patients with acute stroke and collected data on clinical presentation, cardiovascular risk factors, investigations and interventions, in-hospital outcomes, and follow-up plans after discharge. The American Heart Association/American Stroke Association (AHA/ASA) guidelines were used as the standard of care for comparison.\ud \ud Results\ud Fifty patients with acute stroke were enrolled (46% women, 54% men). The mean age was 63.1 years (95% CI: 59.7-66.6). The diagnosis of stroke was based on the World Health Organization criteria. The diagnosis was made within 24 hours of admission in 19 patients (38%). Acute revascularisation therapy was not available. Forty-eight patients (96%) had their vital signs checked at baseline and 140/90 mmHg in 34 patients (68%), including 4 with values >220/120 mmHg. Nine patients had an RBS >10 mmol/L and four received insulin. Prophylaxis for deep venous thrombosis was offered to 12 patients (24%). Aspiration pneumonia was reported in 16 patients (32%) and was the most common hospital complication. The mean duration of hospitalisation was 10.4 days (95% CI: 5.6-15.2), and case fatality was 18%. The modified Rankin scale at discharge was ≤2 in 32% of patients. Only four patients (8%) were transferred to a rehabilitation centre. At the time of discharge, only 32% of patients received education on stroke.\ud \ud Conclusion\ud Acute stroke care is less than optimal in this setting. Simple interventions such as reducing the delay in making a stroke diagnosis, early swallow assessments, and closer monitoring of vital signs could make a significant difference in stroke outcome. Furthermore, treating cardiovascular risk factors and setting up health education programmes to improve secondary prevention represent key priorities.

Background and Purpose— An ipsilateral mild carotid stenosis, defined as plaque with Methods— We searched Pubmed and Ovid-Embase for studies reporting carotid plaque imaging features in embolic stroke of undetermined source. The prevalence of ipsilateral and contralateral mild carotid stenosis with high-risk features was pooled using random-effect meta-analysis. Results— Eight studies enrolling 323 participants were included. The prevalence of mild carotid stenosis with high-risk features in the ipsilateral carotid was 32.5% (95% CI, 25.3–40.2) compared with 4.6% (95% CI, 0.1–13.1) in the contralateral carotid. The odds ratio of finding a plaque with high-risk features in the ipsilateral versus the contralateral carotid was 5.5 (95% CI, 2.5–12.0). Conclusions— Plaques with high-risk features are 5 times more prevalent in the ipsilateral compared with the contralateral carotid in embolic stroke of undetermined source, suggesting a relationship to stroke risk.

IntroductionIn Sub-Saharan Africa, the rising rates of cerebrovascular and cardiovascular diseases (CBD/CVD) are intersecting with an ageing HIV-infected population. The widespread use of antiretroviral therapy (ART) may confer an additive risk and may not completely suppress the risk associated with HIV infection. High-quality prospective studies are needed to determine if HIV-infected patients in Africa are at increased risk of CBD/CVD and to identify factors associated with this risk. This study will test the hypothesis that immune activation and dysfunction, driven by HIV and reactivation of latent herpesvirus infections, lead to increased CBD/CVD risk in Malawian adults aged ≥35 years.Methods and analysisWe will conduct a single-centre, 36-month, prospective cohort study in 800 HIV-infected patients initiating ART and 190 HIV-uninfected controls in Blantyre, Malawi. Patients and controls will be recruited from government ART clinics and the community, respectively, and will be frequency-matched by 5-year age band and sex. At baseline and follow-up visits, we will measure carotid intima-media thickness and pulse wave velocity as surrogate markers of vasculopathy, and will be used to estimate CBD/CVD risk. Our primary exposures of interest are cytomegalovirus and varicella zoster reactivation, changes in HIV plasma viral load, and markers of systemic inflammation and endothelial function. Multivariable regression models will be developed to assess the study’s primary hypothesis. The occurrence of clinical CBD/CVD will be assessed as secondary study endpoints.Ethics and disseminationThe University of Malawi College of Medicine and Liverpool School of Tropical Medicine research ethics committees approved this work. Our goal is to understand the pathogenesis of CBD/CVD among HIV cohorts on ART, in Sub-Saharan Africa, and provide data to inform future interventional clinical trials. This study runs between May 2017 and August 2020. Results of the main trial will be submitted for publication in a peer-reviewed journal.Trial registration numberISRCTN42862937.

Biomarkers are objective indicators used to assess normal or pathological processes, evaluate responses to treatment and predict outcomes. Many blood biomarkers already guide decision-making in clinical practice. In stroke, the number of candidate biomarkers is constantly increasing. These biomarkers include proteins, ribonucleic acids, lipids or metabolites. Although biomarkers have the potential to improve the diagnosis and the management of patients with stroke, there is currently no marker that has demonstrated sufficient sensitivity, specificity, rapidity, precision, and cost-effectiveness to be used in the routine management of stroke, thus highlighting the need for additional work. A better standardization of clinical, laboratory and statistical procedures between centers is indispensable to optimize biomarker performance. This review focuses on blood biomarkers that have shown promise for translation into clinical practice and describes some newly reported markers that could add to routine stroke care. Avenues for the discovery of new stroke biomarkers and future research are discussed. The description of the biomarkers is organized according to their expected application in clinical practice: diagnosis, treatment decision, and outcome prediction.

Background: Despite an abundance of studies and landmark clinical trials conducted in Africa, no systematic analysis of published data has been done to ascertain the true burden of cryptococcal meningitis (CM) in different regions and its aetiologies. We aimed to establish the prevalence, incidence and mortality associated with CM and its aetiological causes in Africa. Methods: We searched PubMed, Embase, ISI Web of Science, Africa Index Medicus, and CINAHL for studies involving adults and/or children published between 1st January 1950 and 31st December 2017 and reporting data on prevalence, incidence, mortality, and aetiology of CM in Africa, with no language restriction. Random-effect meta-analysis was used to derive pooled prevalence, mortality and incidence. Findings: In 111 studies included, 53 reported on prevalence, 63 on mortality, 5 on incidence and 14 on molecular data. The prevalence and mortality of CM in Africa were 10.3% (95%CI 7.7 - 13.2) in 37,072 participants and 47.7% (95%CI 41.0 - 54.5) in 6,011 cases respectively between 1990 and 2017. The incidence of CM was 4.8 per 100,000 person-years at risk. The recurrence rate of CM was 1.2% (95%CI 0.0 - 3.8). Prevalence and mortality were higher in individuals with mean age Interpretation: The prevalence and mortality of CM remain unacceptably high in Africa, stressing the need for stronger actions to improve access to diagnosis and treatment both for CM and HIV on the continent. Funding Statement: The authors state: "None." Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This study is registered with PROSPERO, number CRD42017081312.

Introduction Bien que les principales manifestations de la COVID-19 soient respiratoires, de plus en plus de donnees de la litterature rapportent de multiples symptomes et complications neurologiques liees au SARS-CoV-2. Objectifs Le but de ce travail etait de decrire le spectre des manifestations neurologiques de la COVID-19 dans un contexte sub-saharien. Patients et methodes Il s’agissait d’une etude transversale retrospective menee de mars a septembre 2020 a l’hopital regional de Bafoussam, dans l’Ouest Cameroun. Etaient inclus les patients symptomatiques avec un test RT-PCR positif au SARS-CoV-2. Les donnees sociodemographiques et cliniques notamment les manifestations neurologiques en relation temporelle avec le diagnostic etaient extraites des dossiers des patients a leur sortie. Resultats Nous avons inclus 177 patients. L’âge moyen etait de 54,60 ± 17,8 ans. Les manifestations neurologiques etaient retrouvees chez 113 (63,84 %) patients. Les plus frequentes etaient : les cephalees (58,41 %), les myalgies (50,44 %), l’anosmie (18,58 %), les troubles de la conscience (16,8 %), le delirium (15,04 %), une hemiplegie (4,42 %), l’agueusie (4,42 %). Une hypersialorrhee (2 cas) et un tremblement intentionnel (1 cas). Les diagnostics poses etaient la meningo-encephalite (11,50 %), l’encephalopathie (20,35 %) et l’AVC ischemique (4,42 %). Discussion Les manifestations neurologiques sont frequentes au cours de la COVID-19. Cette frequence varie en fonction de la methodologie employee et du site de l’etude. Nous rapportons deux cas d’hypersialorhee pouvant traduire une atteinte neurovegetative. Le caractere retrospectif et les difficultes de l’interrogatoire chez des patients en etat critique et contagieux sont des limites a cette etude. Conclusion Les manifestations neurologiques au cours de la COVID-19 sont frequentes et polymorphes, retrouvees chez environ 2/3 des patients. La prise en charge doit integrer des neurologues dans la mesure du possible.

IntroductionCryptococcal meningitis is a neglected disease and an AIDS-defining illness, responsible for 15% of all AIDS-related deaths globally. In 2014, the estimated number of incident cryptococcal meningitis cases was 223 100, with 73% of them occurring in Africa. Currently available data on the prevalence, incidence, aetiologies and mortality of cryptococcal meningitis across Africa are sparse and of limited quality. We propose to conduct the first systematic review to summarise the epidemiological data available on cryptococcal meningitis and its aetiological causes in Africa.Methods and analysisWe will search PubMed, MEDLINE, Excerpta Medica Database, ISI Web of Science, Africa Index Medicus, Cumulative Index to Nursing and Allied Health for studies on cryptococcal meningitis published between 1st January 1950 and 31st December 2017, involving adults and/or children residing in Africa. After study selection, full text paper acquisition and data extraction, we will use validated tools and checklists to assess the quality of reporting and risk of bias for each study. Heterogeneity across studies will be assessed using the χ2test on Cochrane’s Q statistic and a random effect meta-analysis will be used to estimate the overall prevalence, incidence density and mortality of cryptococcal meningitis across studies with similar characteristics. This protocol is prepared and presented in accordance with the 2015 Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines. Reporting of the results will be compliant with the Meta-Analysis Of Observational Studies in Epidemiology (MOOSE) guidelines.Ethics and disseminationThere is no requirement for ethical approval since we will be using data from published studies. The final report will be published in a peer-reviewed journal and further presented at conferences. This study is expected to provide useful contextual estimates needed to inform treatment policies on the African continent and assess the impact of diagnostic and prevention strategies on the burden of cryptococcal meningitis in the post antiretroviral therapy era.PROSPERO registration numberCRD42017081312.