One-year morbidity and mortality in patients treated with standard-dose and low-dose apixaban after acute large vessel occlusion stroke.

Although low-dose direct oral anticoagulants (DOACs) are recommended for patients at high risk of bleeding complications, it remains unclear whether the dose reduction in real-world setting is also appropriate in patients after large-vessel occlusion (LVO) stroke. This study hypothesized that patients with atrial fibrillation (AF) and LVO receiving low-dose DOACs have an increased risk of ischemic and hemorrhagic events. The study aimed to assess 1 year morbidity and mortality in patients treated with standard-dose and low-dose apixaban after LVO stroke. A post hoc analysis was performed using the acute LVO registry data, which enrolled patients with AF and LVO who received apixaban within 14 days of stroke onset. The incidences of ischemic events (ischemic stroke, acute coronary syndrome, acute myocardial infarction, and systemic embolism), major bleeding events, and death from any cause were compared between patients receiving standard- and low-dose apixaban. Of 643 patients diagnosed with LVO, 307 (47.7%) received low-dose apixaban. After adjustment for clinically relevant variables, no significant differences were observed in the incidence of ischemic events (adjusted hazard ratio [aHR]: 2.12, 95% confidence interval [CI] 0.75-6.02), major bleeding events (aHR: 1.17, 95% CI 0.50-2.73), and death from any cause (aHR: 1.95, 95% CI 0.78-4.89) between patients receiving standard- and low-dose apixaban. No significant differences were observed in the incidence of ischemic events, major bleeding events, or death from any cause between patients with AF and LVO receiving standard- and low-dose apixaban.

Higher Frequency of Premature Atrial Contractions Correlates With Atrial Fibrillation Detection after Cryptogenic Stroke.

BACKGROUND: Covert atrial fibrillation (AF) is a major cause of cryptogenic stroke. This study investigated whether a dose-dependent relationship exists between the frequency of premature atrial contractions (PACs) and AF detection in patients with cryptogenic stroke using an insertable cardiac monitor (ICM). METHODS: We enrolled consecutive patients with cryptogenic stroke who underwent ICM implantation between October 2016 and September 2020 at 8 stroke centers in Japan. Patients were divided into 3 groups according to the PAC count on 24-hour Holter ECG: ≤200 (group L), >200 to ≤500 (group M), and >500 (group H). We defined a high AF burden as above the median of the cumulative duration of AF episodes during the entire monitoring period. We evaluated the association of the frequency of PACs with AF detection using log-rank trend test and Cox proportional hazard model and with high AF burden using logistic regression model, adjusting for age, sex, CHADS2 score. RESULTS: Of 417 patients, we analyzed 381 patients with Holter ECG and ICM data. The median age was 70 (interquartile range, 59.5-76.5), 246 patients (65%) were males, and the median duration of ICM recording was 605 days (interquartile range, 397-827 days). The rate of new AF detected by ICM was higher in groups with more frequent PAC (15.5%/y in group L [n=277] versus 44.0%/y in group M [n=42] versus 71.4%/y in group H [n=62]; log-rank trend P<0.01). Compared with group L, the adjusted hazard ratios for AF detection in groups M and H were 2.11 (95% CI, 1.24-3.58) and 3.23 (95% CI, 2.07-5.04), respectively, and the adjusted odds ratio for high AF burden in groups M and H were 2.57 (95% CI, 1.14-5.74) and 4.25 (2.14-8.47), respectively. CONCLUSIONS: The frequency of PACs was dose-dependently associated with AF detection in patients with cryptogenic stroke.

Atrial Fibrillation Detection and Ischemic Stroke Recurrence in Cryptogenic Stroke: A Retrospective, Multicenter, Observational Study.

BACKGROUND: Atrial fibrillation (AF) is known to be a strong risk factor for stroke. However, the risk of stroke recurrence in patients with cryptogenic stroke with AF detected after stroke by an insertable cardiac monitor (ICM) is not well known. We sought to evaluate the risk of ischemic stroke recurrence in patients with cryptogenic stroke with and without ICM-detected AF. METHODS AND RESULTS: We retrospectively reviewed patients with cryptogenic stroke who underwent ICM implantation at 8 stroke centers in Japan. Cox regression models were developed using landmark analysis and time-dependent analysis. We set the target sample size at 300 patients based on our estimate of the annualized incidence of ischemic stroke recurrence to be 3% in patients without AF detection and 9% in patients with AF detection. Of the 370 patients, 121 were found to have AF, and 110 received anticoagulation therapy after AF detection. The incidence of ischemic stroke recurrence was 4.0% in 249 patients without AF detection and 5.8% in 121 patients with AF detection (P=0.45). In a landmark analysis, the risk of ischemic stroke recurrence was not higher in patients with AF detected ≤90 days than in those without (hazard ratio, 1.47 [95% CI, 0.41-5.28]). In a time-dependent analysis, the risk of ischemic stroke recurrence did not increase after AF detection (hazard ratio, 1.77 [95% CI, 0.70-4.47]). CONCLUSIONS: The risk of ischemic stroke recurrence in patients with cryptogenic stroke with ICM-detected AF, 90% of whom were subsequently anticoagulated, was not higher than in those without ICM-detected AF.

Von Willebrand Factor Antigen Levels Predict Poor Outcomes in Patients With Stroke and Cancer: Findings From the Multicenter, Prospective, Observational SCAN Study.

BACKGROUND: Patients with acute ischemic stroke and active cancer have more severe neurological symptoms, elevated risks of stroke recurrence, and death compared with the general population. We examined whether von Willebrand factor (vWF) antigen levels at stroke onset were associated with the poor outcomes of patients with stroke and cancer. METHODS AND RESULTS: Using data from 90 patients with acute ischemic stroke and active cancer who were registered in the SCAN (Ischemic Stroke in Patients With Cancer and Neoplasia) study, a prospective multicenter, observational study in Japan, we divided patients into 2 groups according to their median vWF antigen levels (high, n=46; or low, n=44). The high-vWF group had a significantly higher initial National Institutes of Health Stroke Scale score (median, 7 [interquartile range, 3-11.25] versus 3 [interquartile range, 1-8.5]; P<0.05) and a significantly higher incidence of cryptogenic stroke (32 [70%] versus 16 [36%]; P<0.01) and venous thromboembolism (7 [15%] versus 0 [0%]; P<0.01), as well as multiple lesions (28 [62%] versus 12 [27%]; P<0.001), than the low-vWF group. We observed no significant difference in the rate of stroke recurrence within 1 year between the groups. However, increased vWF levels were an independent predictor of death within 1 year of stroke onset, after adjusting for potential confounders (odds ratio, 6.77 [95% CI, 1.49-30.78]; P<0.05). CONCLUSIONS: Elevated vWF antigen levels were associated with adverse outcomes in patients with cancer-associated stroke and may represent a useful biomarker to guide future therapeutic interventions.

Association between the controlling nutritional status score and outcomes in ischemic stroke patients with active cancer.

BACKGROUND: The effect of nutritional status on survival in ischemic stroke patients with active cancer remains unclear. METHODS: This study retrospectively evaluated ischemic stroke patients with active cancer admitted to a university hospital in Japan between 2006 and 2016. Patients were followed for 2 years after stroke. The controlling nutritional status (CONUT) score was used to classify undernutrition degree into 4 groups: normal, light, moderate, and severe. Survival rates were compared using the Kaplan-Meier method. Hazard ratio (HR) and 95 % confidence intervals (CIs) for mortality were calculated using Cox regression models. RESULTS: A total of 158 patients (31 % women; median age: 71 years) were analyzed. Of these, 47 % had distant metastasis. The median (interquartile range) National Institute of Health Stroke Scale and CONUT scores were 4 (1-10) and 5 (3-7), respectively. Kaplan-Meier curve indicated that patients with poorer nutritional status had worse outcomes (overall log-rank test, p < 0.001). The univariable Cox regression analysis showed that the HR (95 % CI) for the light, moderate, and severe groups were 1.14 (0.45-2.86), 3.01 (1.27-7.12), and 2.94 (1.10-7.84), respectively. This statistical significance did not persist after adjustment for potential confounders (HR [95 % CI] for the light, moderate, and severe groups were 0.95 [0.36-2.49], 1.56 [0.57-4.28], and 1.34 [0.37-4.92], respectively). Past stroke, distant metastasis, and plasma D-dimer levels on admission were independent predictors of prognosis. CONCLUSIONS: This single-center, retrospective study suggests that nutritional status serves as a prognostic indicator for ischemic stroke patients with active cancer. However, the effect is not statistically independent.

Intima-media thickness at the near or far wall of the common carotid artery in cardiovascular risk assessment.

Aims: Current guidelines recommend measuring carotid intima-media thickness (IMT) at the far wall of the common carotid artery (CCA). We aimed to precisely quantify associations of near vs. far wall CCA-IMT with the risk for atherosclerotic cardiovascular disease (CVD, defined as coronary heart disease or stroke) and their added predictive values. Methods and results: We analysed individual records of 41 941 participants from 16 prospective studies in the Proof-ATHERO consortium {mean age 61 years [standard deviation (SD) = 11]; 53% female; 16% prior CVD}. Mean baseline values of near and far wall CCA-IMT were 0.83 (SD = 0.28) and 0.82 (SD = 0.27) mm, differed by a mean of 0.02 mm (95% limits of agreement: -0.40 to 0.43), and were moderately correlated [r = 0.44; 95% confidence interval (CI): 0.39-0.49). Over a median follow-up of 9.3 years, we recorded 10 423 CVD events. We pooled study-specific hazard ratios for CVD using random-effects meta-analysis. Near and far wall CCA-IMT values were approximately linearly associated with CVD risk. The respective hazard ratios per SD higher value were 1.18 (95% CI: 1.14-1.22; I² = 30.7%) and 1.20 (1.18-1.23; I² = 5.3%) when adjusted for age, sex, and prior CVD and 1.09 (1.07-1.12; I² = 8.4%) and 1.14 (1.12-1.16; I²=1.3%) upon multivariable adjustment (all P < 0.001). Assessing CCA-IMT at both walls provided a greater C-index improvement than assessing CCA-IMT at one wall only [+0.0046 vs. +0.0023 for near (P < 0.001), +0.0037 for far wall (P = 0.006)]. Conclusions: The associations of near and far wall CCA-IMT with incident CVD were positive, approximately linear, and similarly strong. Improvement in risk discrimination was highest when CCA-IMT was measured at both walls.

Adult-onset botulism in a Japanese woman with prolonged spore excretion.

We report a case of an 80-year-old woman with botulism from 2020 in Osaka, Japan. The patient complained of dysarthria and dizziness. On the same day, the patient developed respiratory failure, and was intubated and placed on mechanical ventilation. Subsequently, ophthalmoparesis and quadriparesis progressed rapidly. Ten days after onset, the patient failed to respond to any external stimulation. Blood tests showed anemia, and computed tomography revealed undiagnosed cervical cancer. Initially, diagnosis of neuromuscular junction disorder and acute motor neuropathy, including paraneoplastic syndrome, were considered. However, intravenous immunoglobulin therapy and plasma exchange were ineffective. A fecal sample on day 30 showed a large number of C. botulinum spores. On day 34, a mouse bioassay revealed botulinum toxin type A in the patient's serum; therefore, a botulinum antitoxin was administered. Later, the patient's muscle strength was gradually improved. However, severe muscle paralysis persisted, and the patient died of cachexia owing to cervical cancer on day 196. The etiology of this case was unknown because no contaminated food was identified during an inspection of the patient's home. Fecal 16S rRNA gene sequencing revealed dysbiosis of the intestinal microbiota with abundant Enterococcus species. Long-lasting excretion of substantial botulinum spores even on day 30 indicated colonization of C. botulinum in the intestinal tract. This case suggests that C. botulinum colonization with co-existing intestinal dysbiosis may be associated with severe and prolonged symptoms of botulism.

Left atrial appendage flow velocity predicts occult atrial fibrillation in cryptogenic stroke: a CRYPTON-ICM registry.

BACKGROUND: An insertable cardiac monitor (ICM) and transesophageal echocardiography (TEE) are useful for investigating potential embolic sources in cryptogenic stroke, of which atrial fibrillation (AF) is a critical risk factor for stroke recurrence. The association of left atrial appendage flow velocity (LAA-FV) on TEE with ICM-detected AF is yet to be elucidated. METHODS: CRYPTON-ICM (CRYPTOgenic stroke evaluation in Nippon using ICM) is a multicenter registry of cryptogenic stroke with ICM implantation, and patients whose LAA-FV was evaluated on TEE were enrolled. The primary outcome was the detection of AF (> 2 min) on ICM. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-off of LAA-FV, and factors associated with ICM-detected AF were assessed. RESULTS: A total of 307 patients (age 66.6 ± 12.3 years; 199 males) with median follow-up of 440 (interquartile range 169-726) days were enrolled; AF was detected in 101 patients. The lower-tertile LAA-FV group had older age, more history of congestive heart failure, and higher levels of B-type natriuretic peptide (BNP) or N-terminal proBNP (all P < 0.05). On ROC analysis, LAA-FV < 37.5 cm/s predicted ICM-detected AF with sensitivity of 26.7% and specificity of 92.2%. After adjustment for covariates, the lower tertile of LAA-FV (hazard ratio [HR], 1.753 [1.017-3.021], P = 0.043) and LAA-FV < 37.5 cm/s (HR 1.987 [1.240-3.184], P = 0.004) predicted ICM-detected AF. CONCLUSIONS: LAA-FV < 37.5 cm/s predicts AF. TEE is useful not only to evaluate potential embolic sources, but also for long-term detection of AF on ICM by measuring LAA-FV in cryptogenic stroke. http://www.umin.ac.jp/ctr/ (UMIN000044366).

Predictors of Survival in Patients With Ischemic Stroke and Active Cancer: A Prospective, Multicenter, Observational Study.

Background Limited data exist on the prognostic factors for patients with ischemic stroke and active cancer. Methods and Results We conducted a prospective, multicenter, observational study in Japan, including patients with acute ischemic stroke and active cancer, to investigate the prognostic factors. We followed up the patients for 1 year after stroke onset. The patients were divided into 2 groups according to cryptogenic stroke and known causes (small-vessel occlusion, large-artery atherosclerosis, cardioembolism, and other determined cause), and survival was compared. The hazard ratios (HRs) and 95% CIs for mortality were calculated using Cox regression models. We identified 135 eligible patients (39% women; median age, 75 years). Of these patients, 51% had distant metastasis. A total of 65 (48%) and 70 (52%) patients had cryptogenic stroke and known causes, respectively. Patients with cryptogenic stroke had significantly shorter survival than those with known causes (HR [95% CI], 3.11 [1.82-5.32]). The multivariable Cox regression analysis revealed that distant metastasis, plasma D-dimer levels, venous thromboembolism (either deep venous thrombosis or pulmonary embolism) complications at stroke onset were independent predictors of mortality after adjusting for potential confounders. Cryptogenic stroke was associated with prognosis in univariable analysis but was not significant in multivariable analysis. The plasma D-dimer levels stratified the prognosis of patients with ischemic stroke and active cancer. Conclusions The prognosis of patients with acute ischemic stroke and active cancer varied considerably depending on stroke mechanism, distant metastasis, and coagulation abnormalities. The present study confirmed that coagulation abnormalities were crucial in determining the prognosis of such patients.

The tight junction protein occludin modulates blood-brain barrier integrity and neurological function after ischemic stroke in mice.

Blood-brain barrier (BBB) disruption contributes to brain injury and neurological impairment. Tight junctions (TJs) and cell-cell adhesion complexes develop between endothelial cells in the brain to establish and maintain the BBB. Occludin, the first transmembrane protein identified in TJs, has received intense research interest because numerous in vitro studies have suggested its importance in maintaining BBB integrity. However, its role in maintaining BBB integrity after ischemic stroke is less clear owing to the lack of in vivo evidence. This study aimed to investigate the dynamics and function of occludin across the acute and chronic phases after stroke using occludin-deficient mice. By photochemically induced thrombosis model, the expression of occludin was decreased in brain endothelial cells from ischemic lesions. The neurological function of occludin-deficient mice was continuously impaired compared to that of wild-type mice. BBB integrity evaluated by Evans blue and 0.5-kDa fluorescein in the acute phase and by 10-kDa fluorescein isothiocyanate-labeled dextran in the chronic phase was decreased to a greater extent after stroke in occludin-deficient mice. Furthermore, occludin-deficient mice showed decreased claudin-5 and neovascularization after stroke. Our study reveals that occludin plays an important role from the acute to the chronic phase after ischemic stroke in vivo.

Effect of the RNF213 p.R4810K Variant on the Progression of Intracranial Artery Stenosis: A 15-Year Follow-up Study.

Background and Objectives: Intracranial artery stenosis is the predominant etiology of ischemic stroke in the Asian population. Furthermore, the presence of the RNF213 p.R4810K variant, which is a susceptibility gene for moyamoya disease, increases the risk of ischemic stroke attributable to large-artery atherosclerosis. Accordingly, we hypothesized that this genetic variant may affect the long-term outcome of intracranial artery stenosis in the East Asian population. We thus aimed to examine the effect of this variant on the long-term progression and prognosis of intracranial artery stenosis. Methods: Using a prospective database, we identified adult patients with intracranial artery stenosis who underwent periodic MRI examinations for >5 years. We evaluated stenosis progression using a validated visual grading system. We excluded patients diagnosed with moyamoya disease at the time of initial MRI. Genotyping of RNF213 p.R4810K was performed at the end of the follow-up period. Results: Among 52 eligible patients, 22 (42%) were carriers of the RNF213 p.R4810K variant. The median follow-up duration was 10.3 years. During the follow-up period, progression of intracranial artery stenosis was observed in 64% variant carriers and 27% noncarriers. There was a significant association of the variant with time to progression of intracranial artery stenosis (hazard ratio [HR] 3.31, 95% CI 1.38-7.90, p = 0.007), and time to the composite endpoint of symptomatic stroke and transient ischemic attack (HR 3.70, 95% CI 1.15-11.86, p = 0.028), but not to symptomatic stroke alone (HR 2.18, 95% CI 0.62-7.74, p = 0.23). Two variant carriers with progression were newly diagnosed with moyamoya disease. Discussion: Our findings indicated that the RNF213 p.R4810K variant increases the risk of intracranial artery stenosis progression.

Heterogeneity of Stroke in Patients with Systemic Lupus Erythematosus.

Objective The underlying pathophysiology varies according to stroke subtype. However, stroke heterogeneity among patients with systemic lupus erythematosus (SLE) remains unstudied. We hypothesized that the contribution of SLE to stroke might vary according to its subtype and investigated the associations of SLE and various stroke subtypes. Methods Diagnostic codes and electronic medical records were used to identify 70 patients with SLE who developed acute cerebral infarction or intracerebral hemorrhaging at four tertiary referral hospitals between 2008 and 2018. Intracerebral hemorrhaging was classified as lobar or deep, while cerebral infarction was classified according to the SSS-TOAST criteria. Physician notes were used to identify SLE activity, and their prevalences were compared among stroke subtypes. Outcomes were collected from the patients' medical records. Results The most common stroke subtype in patients with SLE was that of undetermined causes (31%), followed by small artery occlusion (16%), cardioaortic embolism (13%), other causes (11%), lobar hemorrhaging (10%), deep hemorrhaging (10%), and large artery atherosclerosis (9%). Stroke onset occurred during a period of high SLE activity in 21 patients (30%). The proportion of patients with high SLE activity varied according to stroke subtype (p=0.039) and was highest for cerebral infarction with undetermined causes. Stroke recurrence or death was observed in 40% of patients within 5 years after the initial stroke onset. Conclusion The contributions of SLE to stroke varied significantly according to the stroke subtype. Given the unfavorable prognosis, close stroke subtype-specific observation by rheumatologists and stroke specialists is recommended after stroke events.

Racial and Ethnic Differences in the Association Between Classical Cardiovascular Risk Factors and Common Carotid Intima-Media Thickness: An Individual Participant Data Meta-Analysis.

Background The major risk factors for atherosclerotic cardiovascular disease differ by race or ethnicity but have largely been defined using populations of European ancestry. Despite the rising prevalence of cardiovascular disease in Africa there are few related data from African populations. Therefore, we compared the association of established cardiovascular risk factors with carotid-intima media thickness (CIMT), a subclinical marker of atherosclerosis, between African, African American, Asian, European, and Hispanic populations. Methods and Results Cross-sectional analyses of 34 025 men and women drawn from 15 cohorts in Africa, Asia, Europe, and North America were undertaken. Classical cardiovascular risk factors were assessed and CIMT measured using B-mode ultrasound. Ethnic differences in the association of established cardiovascular risk factors with CIMT were determined using a 2-stage individual participant data meta-analysis with beta coefficients expressed as a percentage using the White population as the reference group. CIMT adjusted for risk factors was the greatest among African American populations followed by Asian, European, and Hispanic populations with African populations having the lowest mean CIMT. In all racial or ethnic groups, men had higher CIMT levels compared with women. Age, sex, body mass index, and systolic blood pressure had a significant positive association with CIMT in all races and ethnicities at varying magnitudes. When compared with European populations, the association of age, sex, and systolic blood pressure with CIMT was weaker in all races and ethnicities. Smoking (beta coefficient, 0.39; 95% CI, 0.09-0.70), body mass index (beta coefficient, 0.05; 95% CI, 0.01-0.08) and glucose (beta coefficient, 0.13; 95% CI, 0.06-0.19) had the strongest positive association with CIMT in the Asian population when compared with all other racial and ethnic groups. High-density lipoprotein-cholesterol had significant protective effects in African American (beta coefficient, -0.31; 95% CI, -0.42 to -0.21) and African (beta coefficient, -0.26; 95% CI, -0.31 to -0.19) populations only. Conclusions The strength of association between established cardiovascular risk factors and CIMT differed across the racial or ethnic groups and may be due to lifestyle risk factors and genetics. These differences have implications for race- ethnicity-specific primary prevention strategies and also give insights into the differential contribution of risk factors to the pathogenesis of cardiovascular disease. The greatest burden of subclinical atherosclerosis in African American individuals warrants further investigations.

Ischemic Stroke Due to Heparin-induced Thrombocytopenia during Severe COVID-19 Infection.

A 53-year-old woman with severe coronavirus disease 2019 (COVID-19) pneumonia was admitted and treated with intravenous unfractionated heparin for thromboprophylaxis under general anesthesia with mechanical ventilation. She developed right hemiparesis after hospitalization due to a large hemorrhagic infarction. Her platelet count decreased from 243,000/µL at administration to 121,000/µL. Anti-platelet factor 4-heparin antibody testing was positive according to a latex immunoturbidimetric assay. She was therefore diagnosed with heparin-induced thrombocytopenia. We immediately stopped the heparin and started argatroban; the platelet count recovered, and thrombosis did not relapse. Physicians should consider heparin-induced thrombocytopenia as a cause of ischemic stroke in patients with COVID-19 infection.

RNF213 p.R4810K Variant Carriers with Intracranial Arterial Stenosis Have a Low Atherosclerotic Burden.

AIM: The ring finger protein 213 gene (RNF213) p.R4810K variant is a major susceptibility gene for intracranial arterial stenosis in East Asia. We hypothesized that if intracranial arterial stenosis is induced by a non-atherosclerotic mechanism similar to moyamoya disease, the patients with RNF213 p.R4810K variant may have a lower cumulative atherosclerotic burden than the non-carriers. METHODS: A total of 112 participants with intracranial arterial stenosis were enrolled in this multicenter cross-sectional study. We compared the prevalence of atherosclerotic risk factors and three different cardiovascular risk scores (Essen Stroke Risk Score, Framingham Risk Score, and Suita Risk Score) between the RNF213 p.R4810K variant carriers and non-carriers. Patients with moyamoya disease were excluded from the study. RESULTS: The RNF213 p.R4810K variant carriers were younger than the non-carriers (P＜0.001). The prevalence of each atherosclerotic risk factor was not significant, but it tended to be lower in the variant carriers. The Essen Stroke Risk Score (carriers: 2.3±1.5 vs. non-carriers: 2.9±1.5, P=0.047), Framingham Risk Score (10.7±6.4 vs. 15.3±6.2, P=0.001), and Suita Risk Score (35.4±15.8 vs. 48.7±15.2, P＜0.001) were significantly lower in the variant carriers. Among the three risk scores, the Suita score showed the highest predictive accuracy for the variant carriers. CONCLUSIONS: RNF213 p.R4810K variant carriers have a lower cumulative atherosclerotic burden than non-carriers among patients with intracranial arterial stenosis. New therapeutic approaches beyond the standard management of atherosclerotic risk factors are required to prevent the development of intracranial arterial stenosis.

An Older Thrombus Delays Reperfusion after Mechanical Thrombectomy for Ischemic Stroke.

BACKGROUND: Thrombosis is a dynamic process, and a thrombus undergoes physical and biochemical changes that may alter its response to reperfusion therapy. This study assessed whether thrombus age influenced reperfusion quality and outcomes after mechanical thrombectomy for cerebral embolism. METHODS: We retrospectively evaluated 185 stroke patients and thrombi that were collected during mechanical thrombectomy at three stroke centers. Thrombi were pathologically classified as fresh or older based on their granulocytes' nuclear morphology and organization. Thrombus components were quantified, and the extent of NETosis (the process of neutrophil extracellular trap formation) was assessed using the density of citrullinated histone H3-positive cells. Baseline patient characteristics, thrombus features, endovascular procedures, and functional outcomes were compared according to thrombus age. RESULTS: Fresh thrombi were acquired from 43 patients, and older thrombi were acquired from 142 patients. Older thrombi had a lower erythrocyte content (p < 0.001) and higher extent of NETosis (p = 0.006). Restricted mean survival time analysis revealed that older thrombi were associated with longer puncture-to-reperfusion times (difference: 15.6 minutes longer for older thrombi, p = 0.002). This association remained significant even after adjustment for erythrocyte content and the extent of NETosis (adjusted difference: 10.8 minutes, 95% confidence interval [CI]: 0.6-21.1 minutes, p = 0.039). Compared with fresh thrombi, older thrombi required more device passes before reperfusion (p < 0.001) and were associated with poorer functional outcomes (adjusted common odds ratio: 0.49; 95% CI: 0.24-0.99). CONCLUSION: An older thrombus delays reperfusion after mechanical thrombectomy for ischemic stroke. Adding therapies targeting thrombus maturation may improve the efficacy of mechanical thrombectomy.

Chronobiology of transient global amnesia.

INTRODUCTION: The etiology of transient global amnesia (TGA) is still a matter of debate. Based, among others, on the observation of a close temporal relation between certain events and subsequent TGA episodes, recent proposals discuss the relevance of stress-associated processes impacting on hippocampal functioning. Circadian, infra- and ultradian rhythmicity has been found to play a relevant role in the multifactorial pathomechanisms of various disorders but has not been thoroughly studied in TGA. METHODS: Data of patients with a final diagnosis of TGA were collected in Mannheim, Germany (06/1999-01/2018, n = 404), and in the Kansai district, Japan (04/2006-03/2018, n = 261). Chronological patterns of TGA occurrence were determined. RESULTS: Significant circadian rhythmicity of TGA occurrence with bimodal peaks (mid-morning, late afternoon) was found for the entire population (p = 0.002) and for either sub-cohort (Mannheim: p = 0.003, Kansai: p = 0.007). This finding was confirmed for either sex (women: p = 0.004, men: p = 0.004) and different age groups (< 65 years: p = 0.0009, ≥ 65 years: p = 0.003). There was no variation according to day of the week, month or season, but the proportion of patients with a weekday episode was significantly higher in the Mannheim cohort (p = 0.002). DISCUSSION: We identified a robust circadian rhythm in TGA occurrence which remarkably applied to either of the two study sites located on different continents and which was independent of sex and age. In light of abundant evidence of circadian rhythmicity of both, components of the human stress response system and memory, chronobiological analyses may provide an opportunity to further uncover the mechanisms underlying TGA.