Distribution of risk factors of ischemic stroke in Chinese young adults and its correlation with prognosis

Background The risk factors for ischemic stroke in young people are complex, varied and closely related to prognosis. This study aims to analyze the risk factors for ischemic stroke in Chinese young people and to explore the main factors influencing the prognosis. Method A total of 444 patients aged 16 to 45 years with ischemic stroke admitted to Suzhou tertiary hospital from 2011 to 2019 were retrospectively analyzed. Risk factors were identified according to the IPSS definition of pediatric stroke and the TOAST classification. All patients were followed up, and the modified Rankin score was used to evaluate the prognosis. Logistic regression analysis was used to explore the influencing factors of poor prognosis. Results Among the patients, 12 risk factors were found according to the IPSS definition of pediatric stroke, and 5 types of stroke were found according to the TOAST classification. A total of 299 patients had a good prognosis. Anemia, venous sinus thrombosis, isolated large-vessel occlusion, and high baseline NIHSS score were significant risk factors. Conclusion The IPSS definition enables patients to be classified on the basis of more risk factors than other classification methods. The prognosis of ischemic stroke in young people is generally good in the 5 years following the event. Anemia, venous sinus thrombosis, isolated large-vessel occlusion and high baseline NIHSS score were associated with poor prognosis.

Large Vessel Occlusion in Patients With Minor Ischemic Stroke in a Population-Based Study. The Dijon Stroke Registry

Introduction:Strategy for the acute management of minor ischemic stroke (IS) with large vessel occlusion (LVO) is under debate, especially the benefits of mechanical thrombectomy. The frequency of minor IS with LVO among overall patients is not well established. This study aimed to assess the proportion of minor IS and to depict characteristics of patients according to the presence of LVO in a comprehensive population-based setting.Methods:Patients with acute IS were prospectively identified among residents of Dijon, France, using a population-based registry (2013–2017). All arterial imaging exams were reviewed to assess arterial occlusion. Minor stroke was defined as that with a National Institutes of Health Stroke Scale (NIHSS) score of <6. Proportion of patients with LVO was estimated in the minor IS population. The clinical presentation of patients was compared according to the presence of an LVO.Results:Nine hundred seventy-one patients were registered, including 582 (59.9%) patients with a minor IS. Of these patients, 23 (4.0%) had a LVO. Patients with minor IS and LVO had more severe presentation [median 3 (IQR 2–5) vs. 2 (IQR 1–3), p = 0.001] with decreased consciousness (13.0 vs. 1.6%, p<0.001) and cortical signs (56.5 vs. 30.8%, p = 0.009), especially aphasia (34.8 vs. 15.4%, p = 0.013) and altered item level of consciousness (LOC) questions (26.1 vs. 11.6%, p = 0.037). In multivariable analyses, only NIHSS score (OR = 1.45 per point; 95% CI: 1.11–1.91, p = 0.007) was associated with proximal LVO in patients with minor IS.Conclusion:Large vessel occlusion (LVO) in minor stroke is non-exceptional, and our findings highlight the need for emergency arterial imaging in any patients suspected of acute stroke, including those with minor symptoms because of the absence of obvious predictors of proximal LVO.

Cost-effectiveness of thrombectomy in patients with minor stroke and large vessel occlusion: effect of thrombus location on cost-effectiveness and outcomes

BackgroundTo evaluate the cost-effectiveness of endovascular thrombectomy (EVT) to treat large vessel occlusion (LVO) in patients with acute, minor stroke (National Institute of Health Stroke Scale (NIHSS) <6) and impact of occlusion site.MethodsA Markov decision-analytic model was constructed accounting for both costs and outcomes from a societal perspective. Two different management strategies were evaluated: EVT and medical management. Base case analysis was done for three different sites of occlusion: proximal M1, distal M1 and M2 occlusions. One-way, two-way and probabilistic sensitivity analyses were performed.ResultsBase-case calculation showed EVT to be the dominant strategy in 65-year-old patients with proximal M1 occlusion and NIHSS <6, with lower cost (US$37 229 per patient) and higher effectiveness (1.47 quality-adjusted life years (QALYs)), equivalent to 537 days in perfect health or 603 days in modified Rankin score (mRS) 0–2 health state. EVT is the cost-effective strategy in 92.7% of iterations for patients with proximal M1 occlusion using a willingness-to-pay threshold of US$100 000/QALY. EVT was cost-effective if it had better outcomes in 2%–3% more patients than intravenous thrombolysis (IVT) in absolute numbers (base case difference −16%). EVT was cost-effective when the proportion of M2 occlusions was less than 37.1%.ConclusionsEVT is cost-effective in patients with minor stroke and LVO in the long term (lifetime horizon), considering the poor outcomes and significant disability associated with non-reperfusion. Our study emphasizes the need for caution in interpreting previous observational studies which concluded similar results in EVT versus medical management in patients with minor stroke due to a high proportion of patients with M2 occlusions in the two strategies.

Safety and Efficacy of Tenecteplase in Older Patients With Large Vessel Occlusion: A Pooled Analysis of the EXTEND-IA TNK Trials

Background and Objectives:Detailed study of tenecteplase (TNK) in patients greater than 80 years of age is limited. The objective of our study was to assess the safety and efficacy of TNK at 0.25 and 0.40 mg/kg doses in patients greater than 80 years with large vessel occlusion.Methods:A pooled analysis of the EXTEND-IA TNK randomized controlled trials (n=502). Patients were adults presenting with ischemic stroke due to occlusion of the intracranial internal carotid, middle cerebral, or basilar artery presenting within 4.5 hours of symptom onset. We compared the treatment effect of TNK 0.25mg/kg, TNK 0.40mg/kg, and alteplase 0.90mg/kg, stratifying for patient age (>80 years). Outcomes evaluated include 90-day modified Rankin scale (mRS), all-cause mortality, and symptomatic ICH. Treatment effect was adjusted for baseline NIHSS, age, and time from symptom onset to puncture via mixed effects proportional odds and logistic regression models.Results:In patients >80 years (n=137), TNK 0.25 mg/kg was associated with improved 90-day mRS (median 3 vs. 4, adjusted common OR=2.70, 95% CI: 1.23-5.94) and reduced mortality (aOR=0.34, 95% CI: 0.13-0.91) versus 0.40 mg/kg. TNK 0.25 mg/kg was associated with improved 90-day mRS (median 3 vs. 4, acOR=2.28, 95% CI: 1.03-5.05) versus alteplase. No difference in 90-day mRS or mortality was detected between alteplase and TNK 0.40 mg/kg. Symptomatic ICH was observed in 4 patients treated with TNK 0.40 mg/kg, one patient treated with alteplase and zero patients treated with TNK 0.25 mg/kg. In patients ≤ 80 years, no differences in 90-day mRS, mortality, or symptomatic ICH was observed between TNK 0.25 mg/kg, alteplase, and TNK 0.40 mg/kg.Conclusions:TNK 0.25 mg/kg was associated with improved 90-day mRS and lower mortality in patients greater than 80 years of age. No differences between the doses were observed in younger patients.Classification of Evidence:This study provides Class II evidence that tenecteplase 0.25 mg/kg given before endovascular therapy in patients >80 years old with large vessel occlusion stroke is associated with better functional outcomes at 90 days and reduced mortality when compared to tenecteplase 0.40 mg/kg or alteplase 0.90 mg/kg.Trial Registration:ClinicalTrials.gov Identifiers: NCT02388061, NCT03340493https://www.clinicaltrials.gov/ct2/show/NCT02388061https://www.clinicaltrials.gov/ct2/show/NCT03340493

Effect of stroke etiology on endovascular thrombectomy with or without intravenous alteplase: a subgroup analysis of DIRECT-MT

BackgroundStroke etiology might influence the clinical outcomes in patients with large vessel occlusion receiving endovascular treatment (EVT) with or without thrombolysis.ObjectiveTo examine whether stroke etiology resulted in different efficacy and safety in patients treated with EVT-alone or EVT preceded by intravenous alteplase (combined therapy).MethodsWe assessed the efficacy and safety of treatment strategy based on prespecified stroke etiology, cardioembolism (CE), large-artery atherosclerosis (LAA), and undetermined cause (UC) for patients enrolled in the DIRECT-MT trial. The primary outcome was the modified Rankin Scale (mRS) score at 90 days. Multivariate ordinal logistic regression analysis was used to calculate the adjusted common OR for a shift of better mRS score for EVT-alone versus combined therapy. A term was entered to test for interaction.ResultsIn this study, 656 patients were grouped into three prespecified stroke etiologic subgroups. The adjusted common ORs for improvement in the 90-day ordinal mRS score with EVT-alone were 1.2 (95% CI 0.8 to 1.8) for CE, 1.6 (95% CI 0.8 to 3.3) for LAA, and 0.8 (95% CI 0.5 to 1.3) for UC. Compared with CE, EVT-alone was more likely to result in an mRS score of 0–1 (pinteraction=0.047) and extended Thrombolysis in Cerebral Infarction ≥2b (pinteraction=0.041) in the LAA group. The differences in mortality and symptomatic intracranial hemorrhage within 90 days were not significant between the subgroups (p＞0.05).ConclusionsThe results did not support the hypothesis that a specific treatment strategy based on stroke etiology should be used for patients with large vessel occlusion (NCT03469206).

Selecting the Appropriate First-Line Strategy Based on Hyperdense Vessel Sign in Acute Ischemic Stroke Increases First Pass Recanalization: A Tertiary Center Experience

Background: The data pertaining to selecting an optimal first-line strategy (stent retriever [SR] vs. contact aspiration [CA]) based on noncontrast computed tomography (NCCT) in cases of acute ischemic stroke consequent to large vessel occlusion (LVO) is lacking. Aims: This article studies the influence of hyperdense vessel sign (HVS) in selecting optimal first-line strategy, with intention of increasing first-pass recanalization (FPR). Methods: Upfront approach at our center is SR technique with rescue therapy (CA) adoption consequent to three failed SR attempts to achieve successful recanalization. Data of patients with acute LVO who underwent mechanical thrombectomy from June 2017 to May 2020 was retrospectively analyzed. Patients were classified into HVS (+) and HVS (–) cohort. Rate of successful recanalization (first pass, early, and final) and efficacy of rescue therapy was assessed between the two cohorts. Results: Of 52 patients included, 28 and 24 were assigned to the HVS (+) and HVS (–) cohort, respectively. FPR was observed in 50% of HVS (+) and 20.9% of HVS (–) (p = 0.029). Early recanalization was documented in 64.2% of HVS (+) and 37.5% of HVS (–) (p = 0.054). Rescue therapy need was higher in patients not demonstrating HVS (p = 0.062). Successful recanalization was achieved with rescue therapy in 50% of HVS (–) group. Conclusion: A higher FPR is achievable following individualized first-pass strategy (based on NCCT appearance of clot), instead of a generalized SR first-pass approach. This CT imaging-based strategy is a step closer to achieving primary angiographic goal of FPR.

FSAP aggravated endothelial dysfunction and neurological deficits in acute ischemic stroke due to large vessel occlusion

Revascularization and angiogenesis, as substrates of sustained collateral circulation, play a crucial role in determining the severity and clinical outcome of acute ischemic stroke (AIS) due to large vessel occlusion (LVO). Developing an adjunct biomarker to help identify and monitor collateral status would aid stroke diagnosis and prognosis. To screen the potential biomarkers, proteomic analysis was performed in this study to identify those distinct plasma protein profiles in AIS due to LVO with different collateral status. Interestingly, we found that levels of Plasma Factor VII Activating Protease (FSAP) significantly increased in those AIS patients with poor collaterals, and were correlated with worse neurological outcome. Furtherly, both in vitro and in vivo models of ischemic stroke were used to explore pathological mechanisms of FSAP in endothelial dysfunction. We demonstrated that the FSAP inhibitor, high-molecular-weight hyaluronan (HMW-HA), enhanced the pro-angiogenic vascular factors, improved the integrity of brain blood barrier, and promoted newly formed cerebral microvessels in the ischemic penumbra, consequently improving neurological function. To elucidate the pathways that might contribute to revascularization during LVO, we applied transcriptomic analysis via unbiased RNA sequencing and showed that Wnt signaling was highly involved in FSAP mediated endothelial dysfunction. Notably, inhibition of Wnt5a largely reversed the protective effects from HMW-HA treatment, implying that FSAP might aggravate endothelial dysfunction and neurological deficits by regulating Wnt5a signaling. Therefore, FSAP may represent a potential biomarker for collateral status after LVO and a promising therapeutic target to be explored in the treatment of stroke.

Tenecteplase versus alteplase for large vessel occlusion recanalization (T-FLAVOR): Trial protocol

Background Tenecteplase has higher fibrin specificity with a longer half-life and the potential to achieve higher rates of recanalization than alteplase. A critical limitation of tenecteplase is no commercial use in Japan and no experience with its administration to Japanese patients. Hypothesis Tenecteplase is superior to alteplase in achieving recanalization on the initial angiogram when administered ≤4.5-hour of stroke onset in patients planned for mechanical thrombectomy (MT) in Japan where alteplase at the unique dose of 0.6mg/kg is officially used. Methods The Tenecteplase versus alteplase For LArge Vessel Occlusion Recanalization (T-FLAVOR) trial is an investigator-initiated, phase II, multicenter, prospective, randomized, open-label, masked-endpoint, superiority study. Eligibility criteria include acute ischemic stroke with pre-stroke modified Rankin Scale score ≤3 and large vessel occlusion (internal carotid artery, middle cerebral artery, or basilar artery) eligible for intravenous thrombolysis ≤4.5-hour and MT ≤6-hour of stroke onset. After completing the safety confirmation phase involving three patients who received non-masked tenecteplase (0.25 mg/kg), 220 patients will be randomized to two groups (1:1), intravenous alteplase (0.6mg/kg, n = 110) or tenecteplase (0.25mg/kg, n = 110), prior to MT. Outcomes In the safety confirmation phase, the primary outcome is symptomatic intracranial hemorrhage (sICH) ≤24-36-hour. In the randomized, comparative phase, the primary efficacy outcome is substantial angiographic reperfusion (mTICI grade 2b/2c/3) or absence of retrievable thrombus on the initial angiogram. The primary safety outcome is sICH ≤24-36-hour and 90-day mortality. Discussion T-FLAVOR may help determine if tenecteplase should be recommended as a routine clinical strategy before MT for Japanese stroke patients. Trial registration jRCTs051210055

Endogenous Deoxyribonuclease Activity and Cell-Free Deoxyribonucleic Acid in Acute Ischemic Stroke: A Cohort Study

Background and Purpose: Cell-free DNA (cfDNA) and endogenous deoxyribonuclease activity are opposing mediators and might influence the inflammatory response following acute ischemic stroke. In this cohort study, we investigated the relation between these markers, circulating inflammatory mediators and clinical course including occurrence of stroke-associated infections (SAI) in patients with acute stroke. Methods: Ninety-two patients with stroke due to large vessel occlusion undergoing mechanical thrombectomy were prospectively recruited at Hannover Medical School from March 2018 to August 2019. Deoxyribonuclease activity, cfDNA, damage-associated molecular patterns, and circulating cytokines were measured in venous blood collected immediately before mechanical thrombectomy and 7 days later. Reperfusion status was categorized (sufficient/insufficient). Clinical outcome was evaluated using the modified Rankin Scale after 90 days, where a score of 3 to 6 was considered unfavorable. To validate findings regarding SAI, another stroke cohort (n=92) was considered with blood taken within 24 hours after stroke onset. Results: Patients with unfavorable clinical outcome had higher cfDNA concentrations. After adjustment for confounders (Essen Stroke Risk Score, National Institutes of Health Stroke Scale, and sex), 7-day cfDNA was independently associated with clinical outcome and especially mortality (adjusted odds ratio: 3.485 [95% CI, 1.001–12.134] and adjusted odds ratio: 9.585 [95% CI, 2.006–45.790]). No association was found between reperfusion status and cfDNA or deoxyribonuclease activity. While cfDNA concentrations correlated positively, deoxyribonuclease activity inversely correlated with distinct biomarkers. Baseline deoxyribonuclease activity was lower in patients who developed SAI compared with patients without SAI. This association was confirmed after adjustment for confounding factors (adjusted odds ratio: 0.447 [95% CI, 0.237–0.844]). In cohort 2, differences of deoxyribonuclease activity between patients with and without SAI tended to be higher with higher stroke severity. Conclusions: The interplay of endogenous deoxyribonuclease activity and cfDNA in acute stroke entails interesting novel diagnostic and potential therapeutic approaches. We confirm an independent association of cfDNA with a detrimental clinical course after stroke due to large vessel occlusion. This study provides first evidence for lower endogenous deoxyribonuclease activity as risk factor for SAI after severe stroke.