Remote Ischemic Conditioning With Medical Management or Reperfusion Therapy for Acute Ischemic Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Remote ischemic conditioning (RIC) is a low-cost, accessible, and noninvasive neuroprotective treatment strategy, but its efficacy and safety in acute ischemic stroke are controversial. With the publication of several randomized controlled trials (RCTs) and the recent results of the RESIST trial, it may be possible to identify the patient population that may (or may not) benefit from RIC. This systematic review and meta-analysis aims to evaluate the effectiveness and safety of RIC in patients with ischemic stroke receiving different treatments by pooling data of all randomized controlled studies to date. METHODS: We searched the PubMed, Embase, Cochrane, Elsevier, and Web of Science databases to obtain articles in all languages from inception until May 25, 2023. The primary outcome was the modified Rankin Scale (mRS) score at the specified endpoint time in the trial. The secondary outcomes were change in NIH Stroke Scale (NIHSS) and recurrence of stroke events. The safety outcomes were cardiovascular events, cerebral hemorrhage, and mortality. The quality of articles was evaluated through the Cochrane risk assessment tool. This study was registered in PROSPERO (CRD42023430073). RESULTS: There were 7,657 patients from 22 RCTs included. Compared with the control group, patients who received RIC did not have improved mRS functional outcomes, regardless of whether they received medical management, reperfusion therapy with intravenous thrombolysis (IVT), or mechanical thrombectomy (MT). In the medical management group, patients who received RIC had decreased incidence of stroke recurrence (risk ratio 0.63, 95% CI 0.43-0.92, p = 0.02) and lower follow-up NIHSS score by 1.72 points compared with the control group (p < 0.00001). There was no increased risk of adverse events including death or cerebral hemorrhage in the IVT or medical management group. DISCUSSION: In patients with ischemic stroke who are not eligible for reperfusion therapy, RIC did not affect mRS functional outcomes but significantly improved the NIHSS score at the follow-up endpoint and reduced stroke recurrence, without increasing the risk of cerebral hemorrhage or death. In patients who received IVT or MT, the benefit of RIC was not observed.

Inter-hospital transfer for thrombectomy: transfer time is brain.

BACKGROUND AND PURPOSE: Patients with acute ischaemic stroke and a large vessel occlusion who present to a non-endovascular-capable centre often require inter-hospital transfer for thrombectomy. Whether the inter-hospital transfer time is associated with 3-month functional outcome is poorly known. METHODS: Acute stroke patients enrolled between January 2015 and December 2022 in the prospective French multicentre Endovascular Treatment of Ischaemic Stroke registry were retrospectively analysed. Patients with an anterior circulation large vessel occlusion transferred from a non-endovascular to a comprehensive stroke centre for thrombectomy were eligible. Inter-hospital transfer time was defined as the time between imaging in the referring hospital and groin puncture for thrombectomy. The relationship between transfer time and favourable 3-month functional outcome (modified Rankin Scale 0-2) was assessed through a mixed logistic regression model adjusting for centre and symptom-onset-to-referring-hospital imaging time, age, sex, diabetes, referring hospital National Institutes of Health Stroke Scale score, Alberta Stroke Programme Early Computed Tomography Score, occlusion site and intravenous thrombolysis use. RESULTS: Overall, 3769 patients were included (median inter-hospital transfer time 161 min, interquartile range 128-195; 46% with favourable outcome). A longer transfer time was independently associated with lower rates of favourable outcome (p < 0.001). Compared to patients with transfer time below 120 min, there was a 15% reduction in the odds of achieving favourable outcome for transfer times between 120 and 180 min (adjusted odds ratio 0.85; 95% confidence interval 0.67-1.07), and a 36% reduction for transfer times beyond 180 min (adjusted odds ratio 0.64; 95% confidence interval 0.50-0.81). CONCLUSIONS: A shorter inter-hospital transfer time is strongly associated with favourable 3-month functional outcome. A speedier inter-hospital transfer is of critical importance to improve outcome.

Endovascular therapy of acute vertebrobasilar occlusions: influence of first-line strategy in the Endovascular Treatment in Ischemic Stroke (ETIS) Registry.

BACKGROUND: The choice of the first-line technique in vertebrobasilar occlusions (VBOs) remains challenging. We aimed to report outcomes in a large cohort of patients and to compare the efficacy and safety of contact aspiration (CA) and combined technique (CoT) as a first-line endovascular technique in patients with acute VBOs. METHODS: We retrospectively analyzed clinical and neuroradiological data of patients with VBOs from the prospective, multicenter, observational Endovascular Treatment in Ischemic Stroke (ETIS) Registry in France between January 2015 and August 2023. The primary outcome was the first pass effect (FPE) rate, whereas modified Thrombolysis In Cerebral Infarction (mTICI) 2b-3 and 2c-3, number of passes, need for rescue strategy, modified Rankin Scale (mRS) 0-2, mortality, and symptomatic intracranial hemorrhage (sICH) were secondary outcomes. We performed univariate and multivariate analyses to investigate differences between the two groups. RESULTS: Among the 583 included patients (mean age 66.2 years, median National Institutes of Health Stroke Scale (NIHSS) 13, median posterior circulation Alberta Stroke Program Early CT Score (pc-ASPECTS) 8), 393 were treated with CA alone and 190 with CoT. Procedures performed with CA were shorter compared with CoT (28 vs 47 min, P<0.0001); however, no differences were observed in terms of FPE (CA 43.3% vs CoT 38.4%, P=0.99), and successful final recanalization (mTICI 2b-3, CA 92.4% vs CoT 91.8%, P=0.74) did not differ between the two groups. Functional independence and sICH rates were also similar, whereas mortality was significantly lower in the CA group (34.5% vs 42.9%; OR 1.79, 95% CI 1.03 to 3.11). CONCLUSIONS: We observed no differences in FPE, mTICI 2b-3, sICH, and functional independence between the two study groups. First-line CA was associated with shorter procedures and lower mortality rates than CoT.

Evaluation of mechanical thrombectomy in acute ischemic stroke related to a distal arterial occlusion: A randomized controlled trial.

RATIONALE: Mechanical thrombectomy (MT) associated with the best medical treatment (BMT) has recently shown efficacy for the management of acute ischemic stroke (AIS) secondary to a large vessel occlusion. However, evidence is lacking regarding the benefit of MT for more distal occlusions. AIM: To evaluate the efficacy in terms of good clinical outcome at 3 months of MT associated with the BMT over the BMT alone in AIS related to a distal occlusion. METHODS: The DISCOUNT trial is a multicenter open-label randomized controlled trial involving French University hospitals. Adult patients (⩾18 years) with an AIS involving the anterior or posterior circulation secondary to a distal vessel occlusion within 6 h of symptom onset or within 24 h if no hyperintense signal on fluid attenuation inversion recovery acquisition will be randomized 1:1 to receive either MT associated with the BMT (experimental group) or BMT alone (control group). The number of patients to be included is 488. STUDY OUTCOMES: The primary outcome is the rate of good clinical outcome at 3 months defined as a modified Rankin scale (mRS) ⩽2 and evaluated by an independent assessor blinded to the intervention arm. Secondary outcomes include recanalization of the occluded vessel within 48 h, angiographic reperfusion in the experimental group, 3-month excellent clinical outcome (mRS ⩽ 1), all adverse events, and death. A cost utility analysis will estimate the incremental cost per quality-adjusted life year (QALY) gained. DISCUSSION: If positive, this study will open new insights in the management of AISs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05030142 registered on 1 September 2021.

Clinical, imaging, and management features of symptomatic carotid web: Insight from CAROWEB registry.

BACKGROUND: Although carotid web (CaW) is increasingly diagnosed as a cause of cryptogenic stroke, data are still limited to monocentric small sample cohort. To broaden knowledge on symptomatic CaW, CAROWEB registry has been recently implemented. AIMS: In a large cohort of symptomatic CaW patients, we described epidemiologic characteristics, admission clinical and imaging features, and the current management including the secondary preventive strategy choice made in comprehensive French Stroke Units. METHODS: CAROWEB is an ongoing French observational multicenter registry enrolling consecutive CaW patients diagnosed after an ipsilateral ischemic stroke (IS) or transient ischemic attack (TIA). Submitted cases were validated by two experienced neurologist and neuroradiologist. Clinical, imaging, and management features were collected for this study. RESULTS: Between June 2019 and December 2021, 244 cases were submitted by 14 centers, 42 rejected, and 202 included (IS, 91.6%; TIA, 7.9%; retinal infarction, 0.5%; mean age, 50.8 ± 12.2 years; female, 62.9%; Caucasian, 47.5%; Afro-Caribbean, 20.3%). IS patients showed median (interquartile range (IQR)) admission National Institutes of Health Stroke Scale (NIHSS) score, 8 (2-15); intracranial artery occlusion, 71.8%; ipsilateral chronic cerebral infarction (CCI), 16.3%; and reperfusion treatment, 57.3%. CaW was not identified during the mechanical thrombectomy procedure in 30 of 85 (35.3%) patients. Secondary prevention was invasive in 55.6% (stenting, n = 80; surgery, n = 30). In multivariable analysis, the invasive therapeutic option was associated with ipsilateral CCI (odds ratio (OR): 4.24 (1.27-14.2), p = 0.019) and inversely associated with risk factors (OR: 0.47 (0.24-0.91), p = 0.025) and admission NIHSS score (OR: 0.93 (0.89-0.97), p = 0.001). CONCLUSION: CaW must be considered in all ethnic groups including Caucasians. Secondary prevention is heterogeneous in large French Stroke Centers. The absence of risk factors, milder severity strokes, and ipsilateral CCI were predictive variables of secondary invasive treatment. The high rate of invasive treatment suggests that medical treatment alone is deemed ineffective to avoid recurrence and emphasize the need of randomized trials.

C-reactive protein and D-dimer in cerebral vein thrombosis: Relation to clinical and imaging characteristics as well as outcomes in a French cohort study.

Introduction: Cerebral venous sinus thrombosis (CVST) is a rare disease with highly variable clinical presentation and outcomes. Clinical studies suggest a role of inflammation and coagulation in CVST outcomes. The aim of this study was to investigate the association of inflammation and hypercoagulability biomarkers with CVST clinical manifestations and prognosis. Methods: This prospective multicenter study was conducted from July 2011 to September 2016. Consecutive patients referred to 21 French stroke units and who had a diagnosis of symptomatic CVST were included. High-sensitivity C-reactive protein (hs-CRP), neutrophil-to-lymphocyte ratio (NLR), D-dimer, and thrombin generation using calibrated automated thrombogram system were measured at different time points until 1 month after anticoagulant therapy discontinuation. Results: Two hundred thirty-one patients were included. Eight patients died, of whom 5 during hospitalization. The day 0 hs-CRP levels, NLR, and D-dimer were higher in patients with initial consciousness disturbance than in those without (hs-CRP: 10.2 mg/L [3.6-25.5] vs 23.7 mg/L [4.8-60.0], respectively; NLR: 3.51 [2.15-5.88] vs 4.78 [3.10-9.59], respectively; D-dimer: 950 µg/L [520-2075] vs 1220 µg/L [950-2445], respectively). Patients with ischemic parenchymal lesions (n = 31) had a higher endogenous thrombin potential5pM than those with hemorrhagic parenchymal lesions (n = 31): 2025 nM min (1646-2441) vs 1629 nM min (1371-2090), respectively (P = .0082). Using unadjusted logistic regression with values >75th percentile, day 0 hs-CRP levels of >29.7 mg/L (odds ratio, 10.76 [1.55-140.4]; P = .037) and day 5 D-dimer levels of >1060 mg/L (odds ratio, 14.63 [2.28-179.9]; P = .010) were associated with death occurrence. Conclusion: Two widely available biomarkers measured upon admission, especially hs-CRP, could help predict bad prognosis in CVST in addition to patient characteristics. These results need to be validated in other cohorts.

Association between prolonged exposure to long working hours and stroke subtypes in the CONSTANCES cohort.

BACKGROUND: Though there is increasing evidence on the effect of long working hours (LWH) and stroke, few studies have distinguished stroke subtypes. We examined the associations between LWH and ischaemic or haemorrhagic stroke after adjusting for cardiovascular risk factors. METHODS: From a national population-based cohort CONSTANCES, baseline questionnaires and initial health examinations were used to retrieve sociodemographic and cardiovascular risk factors from 2012 to 2018. LWH were defined as self-reported working time≥10 hours daily for at least 50 days per year. Incident cases of stroke were collected using International Classification of Disease codes recorded in the National Health Data System. Associations between LWH and stroke were investigated using multinomial models adjusted for cardiovascular risk factors. RESULTS: Among the 160 751 participants who were free from stroke at baseline, exposure to LWH≥10 years was reported by 20 723 participants, and 190 incident cases of stroke were identified, including 134 ischaemic and 56 haemorrhagic. Exposure to LWH was associated with an elevated odds of ischaemic stroke (OR=1.61 (1.04-2.49)) and haemorrhagic stroke (OR=2.50 (1.38-4.53)) in unadjusted models. In adjusted multivariable models, only the LWH association with haemorrhagic stroke remained significant (aOR=1.92 (1.01-3.09)). CONCLUSIONS: LWH were associated with stroke, though it remained significant for haemorrhagic stroke only after adjustments. Differences in direct and indirect biological pathways and lack of power in the ischaemic subgroup may explain these results and further studies on the impact of mediating and effect measure modifying factors are needed. Nevertheless, policies that attenuate effects of both LWH and cardiovascular risks factor are warranted.

Dual-layer carotid stenting for symptomatic carotid web: Results from the Caroweb study.

BACKGROUND & PURPOSE: Carotid Web (CaW) is a growingly recognized cause of ischemic stroke, associated with a high recurrence risk. Several therapeutic strategies have been proposed as a tertiary prevention including carotid stenting, endarterectomy and antithrombotic medications. Among these, carotid stenting with dual-layer stent may be promising to adequately cover the focal arterial dysplasia. Our aim was to investigate the safety and efficacy of the Casper stent in the treatment of symptomatic CaW. METHODS: We conducted a retrospective analysis of consecutive patients presenting with a symptomatic CaW and included in the ongoing prospective observational multicenter CAROWEB registry. The study period was January 2015 to December 2021. Inclusion criteria were CaW treated with dual-layer Casper stent. Patients treated with other types of carotid stent, endarterectomy or antithrombotic medication were excluded. Clinical and radiological initial data and outcomes were recorded. RESULTS: twenty-seven patients (with 28 caw) were included. median age was 52 (iqr: 46-68). median delay between index cerebrovascular event and cervical stenting was 9 days (IQR: 6-101). In all cases, the cervical carotid stenting was successfully performed. No major perioperative complication was recorded. No recurrent stroke or transient ischemic attack was observed during a median follow-up time of 272 days (IQR: 114-635). Long-term imaging follow-up was available in 25/28 (89.3%) stented CaW with a median imaging follow-up of 183 days (IQR: 107-676; range: 90-1542). No in-stent occlusion or stenosis was detected. CONCLUSION: In this study, carotid stenting with dual-layer Casper stent in the treatment of symptomatic CaW was effective regarding stroke recurrence prevention and safe, without procedural nor delayed detected adverse event. However, the optimal therapeutic approach of symptomatic CaW still needs to be explored through randomized trials.

Ipsilateral blooming of microbleeds after Hyperintense Acute Reperfusion Marker sign in an ischemic Stroke patient, a case report.

BACKGROUND: Hyperintense Acute Reperfusion Marker (HARM) is a hyperintense subarachnoid signal on FLAIR MRI sequence caused by gadolinium contrast leakage into the subpial space. While, on FLAIR, HARM may mimic subarachnoid hemorrhage, it is differentiated from it on computed tomography (CT) and SWAN MRI sequences. Cerebral microbleeds are black, rounded spots on SWAN caused by blood-products deposition following red blood cell leakage from small cerebral vessels brain. Both microbleeds and HARM carry important prognostic implication as they are associated with blood-brain barrier disruption and an increased risk of intracerebral hemorrhage. CASE PRESENTATION: A 79-year-old man presented with aphasia and right hemiparesis due to ischemic stroke with left middle cerebral artery occlusion. Admission NIHSS score was 7, and he was successfully treated by intravenous thrombolysis and mechanical thrombectomy. On day 1, his clinical condition worsened, and he had an urgent gadolinium-enhanced MRI. There was no evidence of early recurrence, nor of hemorrhage on SWAN or on FLAIR. Left middle cerebral artery was permeable. The patient was anticoagulated for newly diagnosed atrial fibrillation, and a second MRI following a generalized tonic-clonic seizure showed multiple left hemispheric diffusion-weighted imaging (DWI) hyperintense spots and a left hemispheric sub-arachnoid hyperintensity on FLAIR, compatible with a subarachnoid hemorrhage. This diagnosis was excluded by SWAN MRI sequence and a normal cerebral CT the same day. The diagnosis of HARM was retained. At day 9, patient's condition improved, and a control MRI did not show evidence of HARM. However, numerous microbleeds were detected in the left hemisphere only (ipsilateral with HARM and stroke). CONCLUSIONS: This case highlights first of all the importance of differentiating HARM and subarachnoid hemorrhage, especially in an anticoagulated patient with clinical aggravation. Secondly, it is crucial to identify microbleeds and understand their pathophysiology, as they are associated with higher risk of hemorrhage and stroke recurrence in ischemic stroke patients. Finally, the mono-hemispheric appearance of microbleeds in this case suggests for the first time that, in some acute ischemic stroke patients, a relationship between HARM and cerebral microbleeds may exist.

Cerebral Venous Thrombosis: Clinical, Radiological, Biological, and Etiological Characteristics of a French Prospective Cohort (FPCCVT)-Comparison With ISCVT Cohort.

Introduction: Cerebral venous thrombosis (CVT) is a rare disease with highly variable clinical presentation and outcome. Etiological assessment may be negative. The clinical and radiological presentation and evolution can be highly variable. The mechanisms involved in this variability remain unknown. Objective: The aim of this multicenter French study registered on ClinicalTrials.gov (NCT02013635) was therefore to prospectively recruit a cohort of patients with cerebral venous thrombosis (FPCCVT) in order to study thrombin generation and clot degradation, and to evaluate their influence on clinical radiological characteristics. The first part of the study was to compare our cohort with a reference cohort. Methods: This prospective, multicenter, French study was conducted from July 2011 to September 2016. Consecutive patients (aged >15 years) referred to the stroke units of 21 French centers and who had a diagnosis of symptomatic CVT were included. All patients gave their written informed consent. The diagnosis of CVT had to be confirmed by imaging. Clinical, radiological, biological, and etiological characteristics were recorded at baseline, at acute phase, at 3 months and at last follow-up visit. Thrombophilia screening and the choice of treatment were performed by the attending physician. All data were compared with data from the International Study on CVT published by Ferro et al. Results: Two hundred thirty-one patients were included: 117 (50.6%) had isolated intracranial hypertension, 96 (41.5%) had focal syndrome. During hospitalization, 229 (99.1%) patients received anticoagulant treatment. Median length of hospital stay was 10 days. Five patients died during hospitalization (2.2%). At 3 months, 216 patients (97.0%) had follow-up with neurological data based on an outpatient visit. The mean duration of antithrombotic treatment was 9 months, and the mean time to last follow-up was 10.5 months. At the end of follow-up, eight patients had died, and 26 patients were lost to follow-up. At least one risk factor was identified in 200 patients. Conclusions: We demonstrated that the FPCCVT cohort had radiological, biological, and etiological characteristics similar to the historical ISCVT cohort. Nevertheless, the initial clinical presentation was less severe in our study probably due to an improvement in diagnostic methods between the two studies.

Remote Ischemic Conditioning in Ischemic Stroke and Myocardial Infarction: Similarities and Differences.

Acute myocardial infarction and ischemic stroke are leading causes of morbidity and mortality worldwide. Although reperfusion therapies have greatly improved the outcomes of patients with these conditions, many patients die or are severely disabled despite complete reperfusion. It is therefore important to identify interventions that can prevent progression to ischemic necrosis and limit ischemia-reperfusion injury. A possible strategy is ischemic conditioning, which consists of inducing ischemia - either in the ischemic organ or in another body site [i.e., remote ischemic conditioning (RIC), e.g., by inflating a cuff around the patient's arm or leg]. The effects of ischemic conditioning have been studied, alone or in combination with revascularization techniques. Based on the timing (before, during, or after ischemia), RIC is classified as pre-, per-/peri-, or post-conditioning, respectively. In this review, we first highlight some pathophysiological and clinical similarities and differences between cardiac and cerebral ischemia. We report evidence that RIC reduces circulating biomarkers of myocardial necrosis, infarct size, and edema, although this effect appears not to translate into a better prognosis. We then review cutting-edge applications of RIC for the treatment of ischemic stroke. We also highlight that, although RIC is a safe procedure that can easily be implemented in hospital and pre-hospital settings, its efficacy in patients with ischemic stroke remains to be proven. We then discuss possible methodological issues of previous studies. We finish by highlighting some perspectives for future research, aimed at increasing the efficacy of ischemic conditioning for improving tissue protection and clinical outcomes, and stratifying myocardial infarction and brain ischemia patients to enhance treatment feasibility.

Epidemiology, Clinical Features, and Outcome in a Cohort of Adolescents With Cerebral Venous Thrombosis.

BACKGROUND AND OBJECTIVES: We aimed to analyze the epidemiologic, clinical, and paraclinical features of adolescents with cerebral venous thrombosis (CVT) and its therapeutic management and outcome. METHODS: This multicenter retrospective cohort included patients 10 to 18 years of age hospitalized for a first episode of CVT in 2 French regions between 1999 and 2019. The number of cases was compared to the number recorded by the French health insurance system. The CVT registry of the Lariboisière hospital allowed comparisons with adults. RESULTS: One hundred two patients were included (52.9% female; median age 15.1 years). Estimated incidence was 0.37 to 0.38 per 100,000 adolescents per year; 45.5% of patients presented with focal deficits or seizures or in a coma. Male patients were younger than female patients (14.2 vs 15.6 years; p < 0.01) and more often admitted to intensive care (52.1% vs 24.1%; p = 0.0,035). The lateral sinus was the most common CVT location (72.3%), and 29.4% of adolescents had associated venous infarction or hematoma. Most patients (94.1%) received anticoagulation. Treatment also included an endovascular procedure (2.9%), decompressive craniectomy (4.9%), and CSF shunt (6.9%). The most frequently identified CVT-associated condition was local infection in male (18.6%) and systemic disease in female (14.8%; p < 0.001) patients. The proportion of CVTs in adolescents without an identified associated condition or risk factor was low (1.9% vs 11.4% in adults; p < 0.002). Adverse outcome at 1 year was more frequent than in adults (33.3% vs 11.8%; p = 0.0,001). DISCUSSION: CVT in adolescents is rare and complex with specific epidemiology, including differences in clinical presentation and associated conditions between sexes, and more severe outcomes than in adults. Careful specialized management and follow-up are therefore recommended.

Use of ADAM-C and CHA2DS2-VASc scores to predict complex aortic atheroma after brain ischemia: A prospective observational study.

BACKGROUND AND AIMS: Complex aortic atheroma (CAA) is a common cause of acute brain ischemia (BI), including ischemic stroke (IS) and transient ischemic attack (TIA), and is associated with recurrence. The CHA2DS2-VASc score is a useful tool for predicting stroke in patients with atrial fibrillation (AF), and can also predict cardiovascular events in other populations, including non-AF populations. The ADAM-C score is a new risk score for predicting the diagnostic yield of transesophageal echocardiography (TEE) after BI. We aimed to evaluate the ability of CHA2DS2-VASc and ADAM-C scores to predict CAA after BI. METHODS: This prospective, multicenter, observational study included 1479 patients aged over 18 years who were hospitalized for BI. CAA was defined as the presence of one or more of the following criteria: thrombus, ulcerated plaque, or plaque thickening ≥ 4 mm. RESULTS: CAA was diagnosed in 216 patients (14.6%). CHA2DS2-VASc and ADAM-C scores were significantly higher in the CAA group versus the non-CAA group (P < .0001 for both). The CHA2DS2-VASc and ADAM-C scores appear to be good predictors of CAA (AUC 0.699 [0.635, 0.761] and 0.759 [0.702, 0.814], respectively). The sensitivity, specificity, predictive positive value (PPV), and negative predictive value (NPV) of the scores for detecting CAA were 94%, 22%, 17%, and 96%, respectively, for a CHA2DS2-VASc score < 2, and 90%, 46%, 22%, and 96%, respectively, for an ADAM-C score < 3 CONCLUSIONS: CHA2DS2-VASc and ADAM-C scores are able to predict CAA after BI. CHA2DS2-VASc < 2 and ADAM-C < 3 both have an interesting NPV of 96%.

Platelet, Plasma, Urinary Tryptophan-Serotonin-Kynurenine Axis Markers in Hyperacute Brain Ischemia Patients: A Prospective Study.

Background and Purpose: Ischemic stroke is one of the most common causes of morbidity and mortality and has numerous clinical mimics. Previous studies have suggested a potential role of the tryptophan-serotonin (5-HT)-kynurenine (TSK) axis in ischemic stroke. Studies assessing this axis in the hyperacute phase of ischemic stroke (<4.5 h) are lacking. This prospective study thus evaluates the TSK axis in transient ischemic attack (TIA) and hyperacute ischemic stroke (AIS) patients. Methods: This study included 28 patients (24 AIS and 4 TIA) and 29 controls. The blood and urine samples of patient were collected within 4.5 h of symptoms onset (day 0, D0), then at 24 h and 3 months. Control blood and urine samples were collected once (D0). The TSK axis markers measured were platelet serotonin transporter (SERT) and 5-HT2A receptor (5-HT2AR) densities and platelet, plasma, and urinary 5-HT, plasma and urinary 5-hydroxyindole acetic acid (5-HIAA), and plasma kynurenine and tryptophan (TRP) levels. Results: At D0, patients exhibited a lower (p = 10-5) platelet SERT density, higher (p < 10-6) platelet 5-HT2AR density, higher (p = 10-5) plasma kynurenine/tryptophan (K/T) ratio, and higher urinary 5-HT (p = 0.011) and 5-HIAA (p = 0.003) levels than controls. Conclusions: We observed, for the first time, a hyperacute dysregulation of the serotonergic axis, and hyperacute and long-lasting activation of the tryptophan-kynurenine pathway in brain ischemia.

The effect of exposure to long working hours on stroke: A systematic review and meta-analysis from the WHO/ILO Joint Estimates of the Work-related Burden of Disease and Injury.

BACKGROUND: The World Health Organization (WHO) and the International Labour Organization (ILO) are developing joint estimates of the work-related burden of disease and injury (WHO/ILO Joint Estimates), with contributions from a large network of individual experts. Evidence from mechanistic data and prior studies suggests that exposure to long working hours may cause stroke. In this paper, we present a systematic review and meta-analysis of parameters for estimating the number of deaths and disability-adjusted life years from stroke that are attributable to exposure to long working hours, for the development of the WHO/ILO Joint Estimates. OBJECTIVES: We aimed to systematically review and meta-analyse estimates of the effect of exposure to long working hours (three categories: 41-48, 49-54 and ≥55 h/week), compared with exposure to standard working hours (35-40 h/week), on stroke (three outcomes: prevalence, incidence, and mortality). DATA SOURCES: A protocol was developed and published, applying the Navigation Guide to systematic reviews as an organizing framework where feasible. We searched electronic databases for potentially relevant records from published and unpublished studies, including Ovid MEDLINE, PubMed, EMBASE, Scopus, Web of Science, CISDOC, PsycINFO, and WHO ICTRP. We also searched grey literature databases, Internet search engines, and organizational websites; hand-searched reference lists of previous systematic reviews; and consulted additional experts. STUDY ELIGIBILITY AND CRITERIA: We included working-age (≥15 years) individuals in the formal and informal economy in any WHO and/or ILO Member State but excluded children (aged < 15 years) and unpaid domestic workers. We included randomized controlled trials, cohort studies, case-control studies and other non-randomized intervention studies with an estimate of the effect of exposure to long working hours (41-48, 49-54 and ≥55 h/week), compared with exposure to standard working hours (35-40 h/week), on stroke (prevalence, incidence or mortality). STUDY APPRAISAL AND SYNTHESIS METHODS: At least two review authors independently screened titles and abstracts against the eligibility criteria at a first review stage and full texts of potentially eligible records at a second stage, followed by extraction of data from qualifying studies. Missing data were requested from principal study authors. We combined relative risks using random-effects meta-analysis. Two or more review authors assessed the risk of bias, quality of evidence and strength of evidence, using the Navigation Guide and GRADE tools and approaches adapted to this project. RESULTS: Twenty-two studies (20 cohort studies, 2 case-control studies) met the inclusion criteria, comprising a total of 839,680 participants (364,616 females) in eight countries from three WHO regions (Americas, Europe, and Western Pacific). The exposure was measured using self-reports in all studies, and the outcome was assessed with administrative health records (13 studies), self-reported physician diagnosis (7 studies), direct diagnosis by a physician (1 study) or during a medical interview (1 study). The outcome was defined as an incident non-fatal stroke event in nine studies (7 cohort studies, 2 case-control studies), incident fatal stroke event in one cohort study and incident non-fatal or fatal ("mixed") event in 12 studies (all cohort studies). Cohort studies were judged to have a relatively low risk of bias; therefore, we prioritized evidence from these studies, but synthesised evidence from case-control studies as supporting evidence. For the bodies of evidence for both outcomes with any eligible studies (i.e. stroke incidence and mortality), we did not have serious concerns for risk of bias (at least for the cohort studies). Eligible studies were found on the effects of long working hours on stroke incidence and mortality, but not prevalence. Compared with working 35-40 h/week, we were uncertain about the effect on incidence of stroke due to working 41-48 h/week (relative risk (RR) 1.04, 95% confidence interval (CI) 0.94-1.14, 18 studies, 277,202 participants, I2 0%, low quality of evidence). There may have been an increased risk for acquiring stroke when working 49-54 h/week compared with 35-40 h/week (RR 1.13, 95% CI 1.00-1.28, 17 studies, 275,181participants, I2 0%, p 0.04, moderate quality of evidence). Compared with working 35-40 h/week, working ≥55 h/week may have led to a moderate, clinically meaningful increase in the risk of acquiring stroke, when followed up between one year and 20 years (RR 1.35, 95% CI 1.13 to 1.61, 7 studies, 162,644 participants, I2 3%, moderate quality of evidence). Compared with working 35-40 h/week, we were very uncertain about the effect on dying (mortality) of stroke due to working 41-48 h/week (RR 1.01, 95% CI 0.91-1.12, 12 studies, 265,937 participants, I2 0%, low quality of evidence), 49-54 h/week (RR 1.13, 95% CI 0.99-1.29, 11 studies, 256,129 participants, I2 0%, low quality of evidence) and 55 h/week (RR 1.08, 95% CI 0.89-1.31, 10 studies, 664,647 participants, I2 20%, low quality of evidence). Subgroup analyses found no evidence for differences by WHO region, age, sex, socioeconomic status and type of stroke. Sensitivity analyses found no differences by outcome definition (exclusively non-fatal or fatal versus "mixed") except for the comparison working ≥55 h/week versus 35-40 h/week for stroke incidence (p for subgroup differences: 0.05), risk of bias ("high"/"probably high" ratings in any domain versus "low"/"probably low" in all domains), effect estimate measures (risk versus hazard versus odds ratios) and comparator (exact versus approximate definition). CONCLUSIONS: We judged the existing bodies of evidence for human evidence as "inadequate evidence for harmfulness" for all exposure categories for stroke prevalence and mortality and for exposure to 41-48 h/week for stroke incidence. Evidence on exposure to 48-54 h/week and ≥55 h/week was judged as "limited evidence for harmfulness" and "sufficient evidence for harmfulness" for stroke incidence, respectively. Producing estimates for the burden of stroke attributable to exposures to working 48-54 and ≥55 h/week appears evidence-based, and the pooled effect estimates presented in this systematic review could be used as input data for the WHO/ILO Joint Estimates. PROTOCOL IDENTIFIER: https://doi.org/10.1016/j.envint.2018.06.016. PROSPERO REGISTRATION NUMBER: CRD42017060124.

Posterior cerebral artery stroke by reverse flow embolism in thoracic outlet syndrome - a case report.

BACKGROUND: Arterial thoracic outlet syndrome is a rare condition characterized by a subclavian artery pathology associated with a bone abnormality. It is rarely associated with thromboembolic stroke. The mechanism of cerebral embolism associated with thoracic outlet syndrome have rarely been demonstrated. We present here a fully studied case with a high probability of reverse flow embolism. CASE PRESENTATION: A 24-year-old man with a known arterial thoracic outlet syndrome presented with a right cerebral posterior artery brain infarction. An ultrasound examination depicted the compression of the right subclavian artery in the scalene defile with a post stenotic aneurysm and the presence of a floating thrombus in this aneurysm. There was a reverse flow during diastole in this aneurysm. Anticoagulation was carried out with the disappearance of the floating thrombus with no new clinical or brain MRI event. Corrective surgery of this thoracic outlet syndrome was performed one month after stroke. CONCLUSION: Very few cases of stroke in arterial thoracic outlet syndrome have been described with thorough dynamic vascular imaging. To our knowledge, this is the fourth reported case that advocates for a reverse flow embolism mechanism in stroke associated with thoracic outlet syndrome, and the first to realize an extensive ultrasound and doppler workup.