Secular Trends in Outcomes and Impact of Novel Oral Anticoagulants in Atrial Fibrillation-Related Acute Ischemic Stroke.

BACKGROUND: Novel oral anticoagulants (NOACs) are currently recommended for the secondary prevention of stroke in patients with acute ischemic stroke (AIS) accompanied by atrial fibrillation (AF). However, the impact of NOACs on clinical outcomes in real-world practice remains ambiguous. This study analyzes the trend of clinical events in patients with AF-related AIS and determines how much the introduction of NOACs has mediated this trend. METHODS: We identified patients with AIS and AF between January 2011 and December 2019 using a multicenter stroke registry. Annual rates of NOAC prescriptions and clinical events within 1 year were evaluated. The primary outcome was a composite of recurrent stroke, myocardial infarction, and all-cause mortality. To assess the mediation effect of NOACs on the relationship between the calendar year and these outcomes, we used natural effect models and conducted exposure-mediator, exposure-outcome, and mediator-outcome analyses using multivariable regression models or accelerated failure time models, adjusting for potential confounders. RESULTS: Among the 12 977 patients with AF-related AIS, 12 500 (average age: 74.4 years; 51.3% male) were analyzed after excluding cases of valvular AF. Between 2011 and 2019, there was a significant decrease in the 1-year incidence of the primary composite outcome from 28.3% to 21.7%, while the NOAC prescription rate increased from 0% to 75.6%. A 1-year increase in the calendar year was independently associated with delayed occurrence of the primary outcome (adjusted time ratio, 1.10 [95% CI, 1.07-1.14]) and increased NOAC prescription (adjusted odds ratio, 2.20 [95% CI, 2.14-2.27]). Increased NOAC prescription was associated with delayed occurrence of the primary outcome (adjusted time ratio, 3.82 [95% CI, 3.17 to 4.61]). Upon controlling for NOAC prescription (mediator), the calendar year no longer influenced the primary outcome (adjusted time ratio, 0.97 [95% CI, 0.94-1.00]). This suggests that NOAC prescription mediates the association between the calendar year and the primary outcome. CONCLUSIONS: Our study highlights a temporal reduction in major clinical events or death in Korean patients with AF-related AIS, mediated by increased NOAC prescription, emphasizing NOAC use in this population.

Prevalence of Mutations in Mendelian Stroke Genes in Early Onset Stroke Patients.

OBJECTIVE: Heritability of stroke is assumed not to be low, especially in the young stroke population. However, most genetic studies have been performed in highly selected patients with typical clinical or neuroimaging characteristics. We investigated the prevalence of 15 Mendelian stroke genes and explored the relationships between variants and the clinical and neuroimaging characteristics in a large, unselected, young stroke population. METHODS: We enrolled patients aged ≤55 years with stroke or transient ischemic attack from a prospective, nationwide, multicenter stroke registry. We identified clinically relevant genetic variants (CRGVs) in 15 Mendelian stroke genes (GLA, NOTCH3, HTRA1, RNF213, ACVRL1, ENG, CBS, TREX1, ABCC6, COL4A1, FBN1, NF1, COL3A1, MT-TL1, and APP) using a customized, targeted next generation sequencing panel. RESULTS: Among 1,033 patients, 131 (12.7%) had 28 CRGVs, most frequently in RNF213 (n = 59), followed by ABCC6 (n = 53) and NOTCH3 (n = 15). The frequency of CRGVs differed by ischemic stroke subtypes (p < 0.01): the highest in other determined etiology (20.1%), followed by large artery atherosclerosis (13.6%). It also differed between patients aged ≤35 years and those aged 51 to 55 years (17.1% vs 9.3%, p = 0.02). Only 27.1% and 26.7% of patients with RNF213 and NOTCH3 variants had typical neuroimaging features of the corresponding disorders, respectively. Variants of uncertain significance (VUSs) were found in 15.4% patients. INTERPRETATION: CRGVs in 15 Mendelian stroke genes may not be uncommon in the young stroke population. The majority of patients with CRGVs did not have typical features of the corresponding monogenic disorders. Clinical implications of having CRGVs or VUSs should be explored. ANN NEUROL 2023;93:768-782.

Covert Brain Infarction as a Risk Factor for Stroke Recurrence in Patients With Atrial Fibrillation.

BACKGROUND: We aimed to evaluate covert brain infarction (CBI), frequently encountered during the diagnostic work-up of acute ischemic stroke, as a risk factor for stroke recurrence in patients with atrial fibrillation (AF). METHODS: For this prospective cohort study, from patients with acute ischemic stroke hospitalized at 14 centers between 2017 and 2019, we enrolled AF patients without history of stroke or transient ischemic attack and divided them into the CBI (+) and CBI (-) groups. The 2 groups were compared regarding the 1-year cumulative incidence of recurrent ischemic stroke and all-cause mortality using the Fine and Gray subdistribution hazard model with nonstroke death as a competing risk and the Cox frailty model, respectively. Each CBI lesion was also categorized into either embolic-appearing (EA) or non-EA pattern CBI. Adjusted hazard ratios and 95% CIs of any CBI, EA pattern CBI only, non-EA pattern CBI only, and both CBIs were estimated. RESULTS: Among 1383 first-ever stroke patients with AF, 578 patients (41.8%) had CBI. Of these 578 with CBI, EA pattern CBI only, non-EA pattern CBI only, and both CBIs were 61.8% (n=357), 21.8% (n=126), and 16.4% (n=95), respectively. The estimated 1-year cumulative incidence of recurrent ischemic stroke was 5.2% and 1.9% in the CBI (+) and CBI (-) groups, respectively (P=0.001 by Gray test). CBI increased the risk of recurrent ischemic stroke (adjusted hazard ratio [95% CI], 2.91 [1.44-5.88]) but did not the risk of all-cause mortality (1.32 [0.97-1.80]). The EA pattern CBI only and both CBIs elevated the risk of recurrent ischemic stroke (2.76 [1.32-5.77] and 5.39 [2.25-12.91], respectively), while the non-EA pattern only did not (1.44 [0.40-5.16]). CONCLUSIONS: Our study suggests that AF patients with CBI might have increased risk of recurrent stroke. CBI could be considered when estimating the stroke risk in patients with AF.

Improvement in Delivery of Ischemic Stroke Treatments but Stagnation of Clinical Outcomes in Young Adults in South Korea.

BACKGROUND: There is limited information on the delivery of acute stroke therapies and secondary preventive measures and clinical outcomes over time in young adults with acute ischemic stroke. This study investigated whether advances in these treatments improved outcomes in this population. METHODS: Using a prospective multicenter stroke registry in Korea, young adults (aged 18-50 years) with acute ischemic stroke hospitalized between 2008 and 2019 were identified. The observation period was divided into 4 epochs: 2008 to 2010, 2011 to 2013, 2014 to 2016, and 2017 to 2019. Secular trends for patient characteristics, treatments, and outcomes were analyzed. RESULTS: A total of 7050 eligible patients (mean age, 43.1; men, 71.9%) were registered. The mean age decreased from 43.6 to 42.9 years (Ptrend=0.01). Current smoking decreased, whereas obesity increased. Other risk factors remained unchanged. Intravenous thrombolysis and mechanical thrombectomy rates increased over time from 2008 to 2010 to 2017 to 2019 (9.5%-13.8% and 3.2%-9.2%, respectively; Ptrend<0.01). Door-to-needle time improved (Ptrend <.001), but onset-to-door and door-to-puncture times remained constant. Secondary prevention, including dual antiplatelets for noncardioembolic minor stroke (26.7%-47.0%), direct oral anticoagulants for atrial fibrillation (0.0%-56.2%), and statins for large artery atherosclerosis (76.1%-95.3%) increased (Ptrend<0.01). Outcome data were available from 2011. One-year mortality (2.5% in 2011-2013 and 2.3% in 2017-2019) and 3-month modified Rankin Scale scores 0 to 1 (68.3%-69.1%) and 0 to 2 (87.6%-86.2%) remained unchanged. The 1-year stroke recurrence rate increased (4.1%-5.5%; Ptrend=0.04), although the difference was not significant after adjusting for sex and age. CONCLUSIONS: Improvements in the delivery of acute stroke treatments did not necessarily lead to better outcomes in young adults with acute ischemic stroke over the past decade, indicating a need for further progress.

Deep learning-based personalised outcome prediction after acute ischaemic stroke.

BACKGROUND: Whether deep learning models using clinical data and brain imaging can predict the long-term risk of major adverse cerebro/cardiovascular events (MACE) after acute ischaemic stroke (AIS) at the individual level has not yet been studied. METHODS: A total of 8590 patients with AIS admitted within 5 days of symptom onset were enrolled. The primary outcome was the occurrence of MACEs (a composite of stroke, acute myocardial infarction or death) over 12 months. The performance of deep learning models (DeepSurv and Deep-Survival-Machines (DeepSM)) and traditional survival models (Cox proportional hazards (CoxPH) and random survival forest (RSF)) were compared using the time-dependent concordance index ([Formula: see text] index). RESULTS: Given the top 1 to all 60 clinical factors according to feature importance, CoxPH and RSF yielded [Formula: see text] index of 0.7236-0.8222 and 0.7279-0.8335, respectively. Adding image features improved the performance of deep learning models and traditional models assisted by deep learning models. DeepSurv and DeepSM yielded the best [Formula: see text] index of 0.8496 and 0.8531 when images were added to all 39 relevant clinical factors, respectively. In feature importance, brain image was consistently ranked highly. Deep learning models automatically extracted the image features directly from personalised brain images and predicted the risk and date of future MACEs at the individual level. CONCLUSIONS: Deep learning models using clinical data and brain images could improve the prediction of MACEs and provide personalised outcome prediction for patients with AIS. Deep learning models will allow us to develop more accurate and tailored prognostic prediction systems that outperform traditional models.

Predictors of long-term medication adherence in stroke survivors: A multicentre, prospective, longitudinal study.

BACKGROUND: Although the optimal use of prescribed medications for stroke survivors is critical for preventing secondary stroke, longitudinal observations of the natural course of medication persistence and adherence in Korean stroke survivors are rare. Furthermore, studies are needed to identify strong predictors influencing medication adherence and to determine whether these predictors change over time. AIMS AND OBJECTIVES: To evaluate the longitudinal medication persistence and adherence at 3 months and 1 year after discharge in all stroke patients and to identify predictors of long-term medication adherence in patients who can self-medicate. DESIGN: A multicentre, prospective, longitudinal descriptive study. METHODS: A total of 600 consecutive ischaemic stroke patients were recruited from three stroke centres across Korea, from 1 September, 2017 to 28 February, 2019. Various factors related to medication adherence suggested by the World Health Organisation were investigated through face-to-face interviews at each centre during hospitalisation. Medication persistence and adherence were assessed at 3 months and 1 year after discharge using the eight-item Morisky Medication Adherence Scale through telephone interviews. RESULTS: Of 537 survivors at 3 months, 526 (98.0%) were persistent and 472 (89.7%) were adherent. Of 493 survivors at 1 year, 477 (96.8%) were persistent and 392 (82.2%) were adherent. Medication belief, income and health literacy were statistically significant predictors of three-month medication adherence, which predicted one-year medication adherence with older age and low income. CONCLUSIONS: Among Korean stroke survivors, three-month and one-year medication persistence and adherence were relatively good. Medication beliefs and three-month medication adherence were important and modifiable factors predicting three-month adherence and one-year adherence, respectively. RELEVANCE TO CLINICAL PRACTICE: To increase long-term adherence to medication, various strategies are needed to improve beliefs about medication, taking into account the patient's age and level of knowledge. These interventions need to be initiated during hospitalisation to form early medication habits after discharge.

Frequency, management, and outcomes of early neurologic deterioration due to stroke progression or recurrence.

OBJECTIVE: The frequency, management, and outcomes of early neurologic deterioration (END) after ischemic stroke specifically due to stroke progression or stroke recurrence have not been well delineated. MATERIALS AND METHODS: In a multicenter, nationwide registry, data on END due to stroke progression or recurrence confirmed by imaging were collected prospectively between January 2019 and July 2020. Patient characteristics, management strategies, and clinical outcomes were analyzed. RESULTS: Among 14,828 consecutive ischemic stroke patients, 1717 (11.6%) experienced END, including 1221 (8.2%) with END due to stroke progression (SP) or stroke recurrence (SR). Active management after END was implemented in 64.2% of patients. Active management strategies included volume expansion (29.2%), change in antithrombotic regimen (26.1%), induced hypertension (8.6%), rescue reperfusion therapy (6.8%), intracranial pressure lowering with hyperosmolar agents (1.5%), bypass surgery (0.6%), and hypothermia (0.1%). Active management strategies that varied with patient features included volume expansion and induced hypertension, used more often in large artery atherosclerosis and small vessel occlusion, and rescue endovascular thrombectomy, more common in other (dissection), cardioembolism, and large artery atherosclerosis. Active management was associated with higher rates of freedom from disability (modified Rankin Scale, mRS, 0-1; 24.3% vs. 16.6%) and functional independence (mRS, 0-2; 41.6% vs. 27.7%) at 3 months. CONCLUSION: END specifically due to stroke progression or recurrence occurs in 1 in 12 acute ischemic stroke patients. In this observational study, active management, undertaken in two-thirds of patients, was most often hemodynamic or antithrombotic and was associated with improved functional outcomes.

Stroke of Other Determined Etiology: Results From the Nationwide Multicenter Stroke Registry.

BACKGROUND: Stroke of other determined etiology (OE) includes patients with an uncommon cause of stroke. We described the general characteristics, management, and outcomes of stroke in OE and its subgroups. METHODS: This study is a retrospective analysis of a prospective, multicenter, nationwide registry, the Clinical Research Center for Stroke-Korea-National Institutes of Health registry. We classified OE strokes into 10 subgroups according to the literature and their properties. Each OE subgroup was compared according to clinical characteristics, sex, age strata, lesion locations, and management. Moreover, 1-year composites of stroke and all-cause mortality were investigated according to the OE subgroups. RESULTS: In total, 2119 patients with ischemic stroke with OE types (mean age, 55.6±16.2 years; male, 58%) were analyzed. In the Clinical Research Center for Stroke-Korea-National Institutes of Health registry, patients with OE accounted for 2.8% of all patients with stroke. The most common subtypes were arterial dissection (39.1%), cancer-related coagulopathy (17.3%), and intrinsic diseases of the arterial wall (16.7%). Overall, strokes of OE were more common in men than in women (58% versus 42%). Arterial dissection, intrinsic diseases of the arterial wall and stroke associated with migraine and drugs were more likely to occur at a young age, while disorders of platelets and the hemostatic system, cancer-related coagulopathy, infectious diseases, and hypoperfusion syndromes were more frequent at an old age. The composite of stroke and all-cause mortality within 1 year most frequently occurred in cancer-related coagulopathy, with an event rate of 71.8%, but least frequently occurred in stroke associated with migraine and drugs and arterial dissection, with event rates of 0% and 7.2%, respectively. CONCLUSIONS: This study presents the different characteristics, demographic findings, lesion locations, and outcomes of OE and its subtypes. It is characterized by a high proportion of arterial dissection, high mortality risk in cancer-related coagulopathy and an increasing annual frequency of cancer-related coagulopathy in patients with stroke of OE.

Association of ischemic stroke onset time with presenting severity, acute progression, and long-term outcome: A cohort study.

BACKGROUND: Preclinical data suggest circadian variation in ischemic stroke progression, with more active cell death and infarct growth in rodent models with inactive phase (daytime) than active phase (nighttime) stroke onset. We aimed to examine the association of stroke onset time with presenting severity, early neurological deterioration (END), and long-term functional outcome in human ischemic stroke. METHODS AND FINDINGS: In a Korean nationwide multicenter observational cohort study from May 2011 to July 2020, we assessed circadian effects on initial stroke severity (National Institutes of Health Stroke Scale [NIHSS] score at admission), END, and favorable functional outcome (3-month modified Rankin Scale [mRS] score 0 to 2 versus 3 to 6). We included 17,461 consecutive patients with witnessed ischemic stroke within 6 hours of onset. Stroke onset time was divided into 2 groups (day-onset [06:00 to 18:00] versus night-onset [18:00 to 06:00]) and into 6 groups by 4-hour intervals. We used mixed-effects ordered or logistic regression models while accounting for clustering by hospitals. Mean age was 66.9 (SD 13.4) years, and 6,900 (39.5%) were women. END occurred in 2,219 (12.7%) patients. After adjusting for covariates including age, sex, previous stroke, prestroke mRS score, admission NIHSS score, hypertension, diabetes, hyperlipidemia, smoking, atrial fibrillation, prestroke antiplatelet use, prestroke statin use, revascularization, season of stroke onset, and time from onset to hospital arrival, night-onset stroke was more prone to END (adjusted incidence 14.4% versus 12.8%, p = 0.006) and had a lower likelihood of favorable outcome (adjusted odds ratio, 0.88 [95% CI, 0.79 to 0.98]; p = 0.03) compared with day-onset stroke. When stroke onset times were grouped by 4-hour intervals, a monotonic gradient in presenting NIHSS score was noted, rising from a nadir in 06:00 to 10:00 to a peak in 02:00 to 06:00. The 18:00 to 22:00 and 22:00 to 02:00 onset stroke patients were more likely to experience END than the 06:00 to 10:00 onset stroke patients. At 3 months, there was a monotonic gradient in the rate of favorable functional outcome, falling from a peak at 06:00 to 10:00 to a nadir at 22:00 to 02:00. Study limitations include the lack of information on sleep disorders and patient work/activity schedules. CONCLUSIONS: Night-onset strokes, compared with day-onset strokes, are associated with higher presenting neurologic severity, more frequent END, and worse 3-month functional outcome. These findings suggest that circadian time of onset is an important additional variable for inclusion in epidemiologic natural history studies and in treatment trials of neuroprotective and reperfusion agents for acute ischemic stroke.

Relation of Pre-Stroke Aspirin Use With Cerebral Infarct Volume and Functional Outcomes.

OBJECTIVE: We investigated (1) the associations of pre-stroke aspirin use with thrombus burden, infarct volume, hemorrhagic transformation, early neurological deterioration (END), and functional outcome, and (2) whether stroke subtypes modify these associations in first-ever ischemic stroke. METHODS: This multicenter magnetic resonance imaging (MRI)-based study included 5,700 consecutive patients with acute first-ever ischemic stroke, who did not undergo intravenous thrombolysis or endovascular thrombectomy, from May 2011 through February 2014. Propensity score-based augmented inverse probability weighting was performed to estimate adjusted effects of pre-stroke aspirin use. RESULTS: The mean age was 67 years (41% women), and 15.9% (n = 907) were taking aspirin before stroke. Pre-stroke aspirin use (vs nonuse) was significantly related to a reduced infarct volume (by 30%), particularly in large artery atherosclerosis stroke (by 45%). In cardioembolic stroke, pre-stroke aspirin use was associated with a ~50% lower incidence of END (adjusted difference = -5.4%, 95% confidence interval [CI] = -8.9 to -1.9). Thus, pre-stroke aspirin use was associated with ~30% higher likelihood of favorable outcome (3-month modified Rankin Scale score < 3), particularly in large artery atherosclerosis stroke and cardioembolic stroke (adjusted difference = 7.2%, 95% CI = 1.8 to 12.5 and adjusted difference = 6.4%, 95% CI = 1.7 to 11.1, respectively). Pre-stroke aspirin use (vs nonuse) was associated with 85% less frequent cerebral thrombus-related susceptibility vessel sign (SVS) in large artery atherosclerosis stroke (adjusted difference = -1.4%, 95% CI = -2.1 to -0.8, p < 0.001) and was associated with ~40% lower SVS volumes, particularly in cardioembolic stroke (adjusted difference = -0.16 cm3 , 95% CI = -0.29 to -0.02, p = 0.03). Moreover, pre-stroke aspirin use was not significantly associated with hemorrhagic transformation (adjusted difference = -1.1%, p = 0.09). INTERPRETATION: Pre-stroke aspirin use associates with improved functional independence in patients with first-ever ischemic large arterial stroke by reducing infarct volume and/or END, likely by decreasing thrombus burden, without increased risk of hemorrhagic transformation. ANN NEUROL 2021;90:763-776.

In Situ Spontaneous Fabrication of Tough and Stretchable Polyurethane-Polyethyleneimine Hydrogels Selectively Triggered by CO2.

CO2 -triggered in situ hydrogels is developed from waterborne poly(ε-caprolactone)-based polyurethane (PU) dispersion and aqueous polyethyleneimine (PEI) solution without any other chemicals and apparatus (e.g., UV light). In the approach, nontoxic CO2 in air is used as a selective trigger for the hydrogel formation. CO2 adsorption onto PEI results in the formation of ammonium cations in PEI and the subsequent multiple ionic crosslinking between PU and PEI chains. Besides the amount of CO2 in air, the rate of hydrogel formation can be controlled by NaHCO3 in the PU-PEI mixture, which serves as a CO2 supplier. The PU hydrogels exhibit tough and stretchable properties with high tensile strength (2.05 MPa) and elongation at break (438.24%), as well as biocompatibility and biodegradability. In addition, the PU hydrogels exhibit high adhesion strength on skin and injectability due to the in situ formation. It is believed that these PU hydrogels have the ideal features for various future applications, such as tissue adhesion barriers, wound dressing, artificial skin, and injectable fillers.

Risk of Subsequent Events in Patients With Minor Ischemic Stroke or High-Risk Transient Ischemic Attack.

This study aimed to present the prognosis after minor acute ischemic stroke (AIS) or transient ischemic attack (TIA), using a definition of subsequent stroke in accordance with recent clinical trials. In total, 9,506 patients with minor AIS (National Institutes of Health Stroke Scale ≤ 5) or high-risk TIA (acute lesions or ≥ 50% cerebral artery steno-occlusion) admitted between November 2010 and October 2013 were included. The primary outcome was the composite of stroke (progression of initial event or a subsequent event) and all-cause mortality. The cumulative incidence of stroke or death was 11.2% at 1 month, 13.3% at 3 months and 16.7% at 1 year. Incidence rate of stroke or death in the first month was 12.5 per 100 person-months: highest in patients with large artery atherosclerosis (17.0). The risk of subsequent events shortly after a minor AIS or high-risk TIA was substantial, particularly in patients with large artery atherosclerosis.

Comparison of Factors Associated With Direct Versus Transferred-in Admission to Government-Designated Regional Centers Between Acute Ischemic Stroke and Myocardial Infarction in Korea.

BACKGROUND: There has been no comparison of the determinants of admission route between acute ischemic stroke (AIS) and acute myocardial infarction (AMI). We examined whether factors associated with direct versus transferred-in admission to regional cardiocerebrovascular centers (RCVCs) differed between AIS and AMI. METHODS: Using a nationwide RCVC registry, we identified consecutive patients presenting with AMI and AIS between July 2016 and December 2018. We explored factors associated with direct admission to RCVCs in patients with AIS and AMI and examined whether those associations differed between AIS and AMI, including interaction terms between each factor and disease type in multivariable models. To explore the influence of emergency medical service (EMS) paramedics on hospital selection, stratified analyses according to use of EMS were also performed. RESULTS: Among the 17,897 and 8,927 AIS and AMI patients, 66.6% and 48.2% were directly admitted to RCVCs, respectively. Multivariable analysis showed that previous coronary heart disease, prehospital awareness, higher education level, and EMS use increased the odds of direct admission to RCVCs, but the odds ratio (OR) was different between AIS and AMI (for the first 3 factors, AMI > AIS; for EMS use, AMI < AIS). EMS use was the single most important factor for both AIS and AMI (OR, 4.72 vs. 3.90). Hypertension and hyperlipidemia increased, while living alone decreased the odds of direct admission only in AMI; additionally, age (65-74 years), previous stroke, and presentation during non-working hours increased the odds only in AIS. EMS use weakened the associations between direct admission and most factors in both AIS and AMI. CONCLUSIONS: Various patient factors were differentially associated with direct admission to RCVCs between AIS and AMI. Public education for symptom awareness and use of EMS is essential in optimizing the transportation and hospitalization of patients with AMI and AIS.

d-dimer Level as a Predictor of Recurrent Stroke in Patients With Embolic Stroke of Undetermined Source.

Background and Purpose: This study aimed to investigate the value of d-dimer levels in predicting recurrent stroke in patients with embolic stroke of undetermined source. We also evaluated the underlying causes of recurrent stroke according to d-dimer levels. Methods: A total of 1431 patients with undetermined source were enrolled in this study and divided into quartiles according to their baseline plasma d-dimer levels. The primary outcome measure was the occurrence of recurrent stroke (ischemic or hemorrhagic) in the year following the stroke event. Results: The risk of recurrent stroke increased significantly with the increasing d-dimer quartile (log-rank P=0.001). Patients in the higher d-dimer quartiles had a higher probability of recurrent embolic stroke because of covert atrial fibrillation, hidden malignancy, or undetermined sources. Most recurrent strokes in Q3 and Q4 were embolic but not in Q1 or Q2. Multivariate analysis revealed that patients in Q3 and Q4 had a significantly increased risk of recurrent stroke compared with those in Q1 (hazard ratio, 3.12 [95% CI, 1.07−9.07], P=0.036; hazard ratio, 7.29 [95% CI, 2.59−20.52], P<0.001, respectively; Ptrend<0.001). Binary analyses showed a significant association between a high d-dimer level above normal range and the risk of recurrent stroke (hazard ratio, 2.48 [95% CI, 1.31−4.70], P=0.005). In subgroup analyses, a high d-dimer level was associated with a significantly higher risk of recurrent stroke in men than in women (P=0.039). Conclusions: Our findings suggest that d-dimer levels can be a useful risk assessment biomarker for predicting recurrent stroke, especially embolic ischemic stroke, in patients with undetermined source.

Atherosclerotic Burden and Vascular Risk in Stroke Patients With Atrial Fibrillation.

Background and Purpose: Data on the effect on vascular outcomes of concomitant atherosclerotic vascular disease (ASVD) with atrial fibrillation (AF) after stroke are limited. This study evaluated the effect of ASVD with AF versus AF only on the risk of vascular events. Methods: We retrospectively analyzed a prospectively registered multicenter database involving 3213 stroke patients with AF. ASVD included extracranial atherosclerosis measured in the proximal portion of the internal carotid artery, intracranial atherosclerosis (all ≥50% stenosis), coronary artery disease, and peripheral artery disease and was categorized into 4 strata depending on the number of ASVDs (0, 1, 2, and 3­4). The independent associations of ASVD with major adverse cardiovascular events, stroke, and all-cause death were assessed. Results: A total of 2670 patients were included (mean age, 73.5±9.8 years; median CHA2DS2-VASc score, 5; interquartile range, 4−6). During the follow-up (mean, 1.7 years), a total of 672 (25.2%) major adverse cardiovascular events, 170 (6.4%) stroke events, and 501 (18.8%) all-cause deaths were noted. The adjusted hazard ratio for major adverse cardiovascular events versus no ASVD was 1.25 (95% CI, 1.00­1.56) for ASVD 1, 1.34 (95% CI, 1.02­1.76) for ASVD 2, and 1.93 (95% CI, 1.24­2.99) for ASVD 3­4. The adjusted hazard ratio for all-cause death versus no ASVD was 1.32 (1.01­1.74), 1.47 (1.06­2.03), and 2.39 (1.47­3.89), respectively. Among ASVD components, the presence of symptomatic or asymptomatic extracranial atherosclerosis was a more potent predictor of major adverse cardiovascular events (1.27 [1.05­1.54]) and all-cause death (1.45 [1.17­1.81]). Conclusions: ASVD burden with AF can be a cumulative marker of a high risk for untoward vascular outcomes. Among ASVD components, extracranial atherosclerosis seems to have a predominant effect.

Pre-Admission CHADS2 and CHA2DS2-VASc Scores on Early Neurological Worsening.

BACKGROUND: Stroke risk scores (CHADS2 and CHA2DS2-VASc) not only predict the risk of stroke in atrial fibrillation (AF) patients, but have also been associated with prognosis after stroke. OBJECTIVE: The aim of this study was to evaluate the relationship between stroke risk scores and early neurological deterioration (END) in ischemic stroke patients with AF. METHODS: We included consecutive ischemic stroke patients with AF admitted between January 2013 and December 2015. CHADS2 and CHA2DS2-VASc scores were calculated using the established scoring system. END was defined as an increase ≥2 on the total National Institutes of Health Stroke Scale (NIHSS) score or ≥1 on the motor NIHSS score within the first 72 h of admission. RESULTS: A total of 2,099 ischemic stroke patients with AF were included. In multivariable analysis, CHA2DS2-VASc score (adjusted odds ratio [aOR] = 1.17, 95% confidence interval [CI] = 1.04-1.31) was significantly associated with END after adjusting for confounders. Initial NIHSS score, use of anticoagulants, and intracranial atherosclerosis (ICAS) were also found to be closely associated with END, independent of the CHA2DS2-VASc score. Multivariable analysis stratified by the presence of ICAS demonstrated that both CHA2DS2-VASc (aOR = 1.20, 95% CI = 1.04-1.38) and CHADS2 scores (aOR = 1.24, 95% CI = 1.01-1.52) were closely related to END in only patients with ICAS. In patients without ICAS, neither of the risk scores were associated with END. CONCLUSIONS: High CHA2DS2-VASc score was associated with END in ischemic stroke patients with AF. This close relationship is more pronounced in patients with ICAS.

Cerebellar infarction presenting with isolated positional vertigo: differentiating factors for benign paroxysmal positional vertigo.

BACKGROUND: Isolated central positional vertigo (CPV) due to cerebellar infarction is often difficult to differentiate from benign paroxysmal positional vertigo (BPPV). Here, we aimed to evaluate whether vascular risk factors and serum vitamin D level can differentiate between positional vertigo types. METHODS: A total of 78 consecutive patients were consecutively enrolled from January 2017. All CPV patients had a National Institutes of Health Stroke Scale score of 0 and cerebellar infarctions confirmed by brain MR imaging. Vascular risk factors and serum 25-hydroxyvitamin D levels were compared between the two groups of patients. RESULTS: The proportion of men was higher in the CPV than in the BPPV group (p = 0.004). Atrial fibrillation was common in the CPV group on univariate analysis (p = 0.046). However, there were no independent differentiating factors between the two groups. The proportion of patients according to the number of risk factors was significantly different between the two groups (linear by linear association test, p = 0.02). The mean serum 25-hydroxyvitamin D level did not differ. Also, the proportions of vitamin D insufficiency and deficiency did not differ significantly between the two groups. CONCLUSIONS: Increased number of vascular risk factors including male sex suggested more CPV than BPPV. However, the serum vitamin D level was below the normal range in both groups. Our results demonstrate that serum vitamin D level has little value in the differential diagnosis of positional vertigo. Efforts to identify differentiating factors are warranted, and accumulating evidences including our research may lead to a diagnostic algorithm for isolated positional vertigo.

In Vivo Quantitative Vasculature Segmentation and Assessment for Photodynamic Therapy Process Monitoring Using Photoacoustic Microscopy.

Vascular damage is one of the therapeutic mechanisms of photodynamic therapy (PDT). In particular, short-term PDT treatments can effectively destroy malignant lesions while minimizing damage to nonmalignant tissue. In this study, we investigate the feasibility of label-free quantitative photoacoustic microscopy (PAM) for monitoring the vasculature changes under the effect of PDT in mouse ear melanoma tumors. In particular, quantitative vasculature evaluation was conducted based on Hessian filter segmentation. Three-dimensional morphological PAM and depth-resolved images before and after PDT treatment were acquired. In addition, five quantitative vasculature parameters, including the PA signal, vessel diameter, vessel density, perfused vessel density, and vessel complexity, were analyzed to evaluate the influence of PDT on four different areas: Two melanoma tumors, and control and normal vessel areas. The quantitative and qualitative results successfully demonstrated the potential of the proposed PAM-based quantitative approach to evaluate the effectiveness of the PDT method.

Microbleeds and Outcome in Patients With Acute Ischemic Stroke and Atrial Fibrillation Taking Anticoagulants.

BACKGROUND AND PURPOSE: We investigated the impact of the presence, burden, and location of cerebral microbleeds (CMBs) on the risk of major adverse cerebrovascular and cardiovascular events (MACCE) in patients with acute ischemic stroke and atrial fibrillation treated with oral anticoagulants (OACs). We also examined whether the clinical effect of CMBs differs according to the type of OACs. METHODS: A total of 1742 patients with acute ischemic stroke and atrial fibrillation treated with OACs were enrolled in this cohort study. The primary composite outcome was the occurrence of MACCE (a composite of stroke, acute myocardial infarction, or vascular death) over a 2-year period according to CMB status. RESULTS: CMB presence was significantly associated with the risk of future MACCE (hazard ratio, 1.89 [95% CI, 1.23-2.88]; P=0.003) after adjustment for confounders in patients with acute ischemic stroke and atrial fibrillation taking OACs. Patients with exactly 1 CMB had a similar rate of MACCE compared with those without CMBs (P=0.461). However, patients with multiple CMBs (≥2), particularly high burden CMBs (≥5), had a significantly higher proportion of MACCE. Both CMB-positive groups with lobar and deep CMB had more frequent MACCE than the CMB-negative group, and the rate of MACCE was not different according to CMB location. In patients treated with warfarin, CMB was significantly associated with a risk of MACCE (P=0.002), but not in patients treated with direct OACs (P=0.517). CONCLUSIONS: The study results indicate that the risk of future MACCE increased with increasing CMB burden in patients with AIS and atrial fibrillation taking OACs, while the anatomic location of CMBs did not influence the risk of future MACCE. This risk seemed to be more apparent in patients taking warfarin.

Effect of Heart Rate on Stroke Recurrence and Mortality in Acute Ischemic Stroke With Atrial Fibrillation.

Background and Purpose- There is a paucity of information about the role of resting heart rate in the prediction of outcome events in patients with ischemic stroke with atrial fibrillation. We aimed to investigate the relationships between the level and variability of heart rate in the acute stroke period and stroke recurrence and mortality after acute ischemic stroke in patients with atrial fibrillation. Methods- Acute patients with ischemic stroke who had atrial fibrillation and were hospitalized within 48 hours of stroke onset were identified from a multicenter prospective stroke registry database. The acute stroke period was divided into early (within 24 hours of hospitalization) and late (72 hours to 7 days from onset) stages, and data on heart rate in both stages were collected. Moreover, the level and variability of heart rate were assessed using mean values and coefficients of variation. Outcome events were prospectively monitored up to 1 year after the index stroke. Results- Among 2046 patients eligible for the early acute stage analysis, 102 (5.0%) had a stroke recurrence, and 440 (21.5%) died during the first year after stroke. A statistically significant nonlinear J-shaped association was observed between mean heart rate and mortality (P<0.04 for quadratic and overall effect) but not between mean heart rate and stroke recurrence (P>0.1 for quadratic and overall effect). The nonlinear and overall effects of the coefficients of variation of heart rate were not significant for all outcome variables. The same results were observed in the late acute stage analysis (n=1576). Conclusions- In patients with atrial fibrillation hospitalized for acute ischemic stroke, the mean heart rate during the acute stroke period was not associated with stroke recurrence but was associated with mortality (nonlinear, J-shaped association). The relationships between heart rate and outcomes were not observed with respect to heart rate variability.