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Post-stroke cognitive impairment can affect up to one third of stroke survivors. Since cognitive function greatly contributes to patients’ quality of life, an objective quantitative biomarker for early prediction of dementia after stroke is required. We developed a deep-learning (DL)-based signature using positron emission tomography (PET) to objectively evaluate cognitive decline in patients with stroke. We built a DL model that differentiated Alzheimer’s disease (AD) from normal controls (NC) using brain fluorodeoxyglucose (FDG) PET from the Alzheimer’s Disease Neuroimaging Initiative database. The model was directly transferred to a prospectively enrolled cohort of patients with stroke to differentiate patients with dementia from those without dementia. The accuracy of the model was evaluated by the area under the curve values of receiver operating characteristic curves (AUC-ROC). We visualized the distribution of DL-based features and brain regions that the model weighted for classification. Correlations between cognitive signature from the DL model and clinical variables were evaluated, and survival analysis for post-stroke dementia was performed in patients with stroke. The classification of AD vs. NC subjects was performed with AUC-ROC of 0.94 (95% confidence interval [CI], 0.89–0.98). The transferred model discriminated stroke patients with dementia (AUC-ROC = 0.75). The score of cognitive decline signature using FDG PET was positively correlated with age, neutrophil–lymphocyte ratio and platelet-lymphocyte ratio and negatively correlated with body mass index in patients with stroke. We found that the cognitive decline score was an independent risk factor for dementia following stroke (hazard ratio, 10.90; 95% CI, 3.59–33.09; P

The expected growth of stroke burden in Korea in early 2000s led to the initiation of a government-funded clinical research project with the goal of development and implementation of national stroke guidelines. The CRCS-K (Clinical Research Collaboration for Stroke in Korea) began as a part of this project. For stroke epidemiology and quality of care research, the CRCS-K developed a multicenter, prospective, stroke registry and began collection of data in 2008. Now, about 100 000 cases have been registered at 17 university hospitals or regional stroke centers and about 200 articles have been published based on the registry experience. The analysis of the 10-year secular trends showed overall improvement of stroke care and outcomes and areas for improvement. This large-scale, high-quality dataset provides opportunities to explore and compare treatment disparities using the comparative effectiveness research methods, design and conduct a registry-based randomized clinical trial, connect the registry data with other data sources including the national claims data and neuroimaging or genetic data, and collaborate with other international researchers. An international stroke registry consortium may be a viable future direction.

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 3–4). 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 CHA 2 DS 2 -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, 1.00–1.56) for ASVD 1, 1.34 (95% CI, 1.02–1.76) for ASVD 2, and 1.93 (95% CI, 1.24–2.99) for ASVD 3–4. The adjusted hazard ratio for all-cause death versus no ASVD was 1.32 (1.01–1.74), 1.47 (1.06–2.03), and 2.39 (1.47–3.89), respectively. Among ASVD components, the presence of symptomatic or asymptomatic extracranial atherosclerosis was a more potent predictor of major adverse cardiovascular events (1.27 [1.05–1.54]) and all-cause death (1.45 [1.17–1.81]). 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.

Background Unlike patients with stroke caused by other mechanisms, the effect of elevated plasma total homocysteine (tHcy) on the prognosis of patients with both ischemic stroke and atrial fibrillation (AF) is unknown. This study aimed to evaluate the association between tHcy level and the functional outcome of patients with AF‐related stroke. Methods and Results We included consecutive patients with AF‐related stroke between 2013 and 2015 from the registry of a real‐world prospective cohort from 11 large centers in South Korea. A 3‐month modified Rankin Scale score ≥3 was considered an unfavorable outcome. Since tHcy is strongly affected by renal function, we performed a subgroup analysis according to the presence of renal dysfunction. A total of 910 patients with AF‐related stroke were evaluated (mean age, 73 years; male sex, 56.0%). The mean tHcy level was 11.98±8.81 μmol/L. In multivariable analysis, the tHcy level (adjusted odds ratio, 1.04; 95% CI, 1.01–1.07, per 1 μmol/L) remained significantly associated with unfavorable outcomes. In the subgroup analysis based on renal function, tHcy values above the cutoff point (≥14.60 μmol/L) showed a close association with the unfavorable outcome only in the normal renal function group (adjusted odds ratio, 3.10; 95% CI, 1.60–6.01). In patients with renal dysfunction, tHcy was not significantly associated with the prognosis of AF‐related stroke. Conclusions A higher plasma tHcy level was associated with unfavorable outcomes in patients with AF‐related stroke. This positive association may vary according to renal function but needs to be verified in further studies.

Serum cardiac troponin I (cTnI) is often elevated in patients with ischemic stroke, and is associated with their prognosis. Since cTnI is also closely related to atrial fibrillation (AF), cTnI may be a sensitive prognostic indicator in patients with AF-related stroke. This study aimed to evaluate the association between serum cTnI and early neurological deterioration (END) in patients with AF-related stroke. We included consecutive AF-related stroke patients between 2013 and 2015. END was defined as an increase ≥ 2 in the total NIHSS score or ≥ 1 in the motor NIHSS score within the first 72 h of admission. A total of 1,133 patients with AF-related stroke were evaluated. In multivariable analysis, cTnI [adjusted odds ratio (aOR) = 1.16, 95% confidence interval (CI) 1.00–1.34; P = 0.047] remained significant after adjusting for confounders. Initial NIHSS score (aOR = 1.03, 95% CI 1.00–1.06; P = 0.043) was also positively associated with END; meanwhile, the use of anticoagulants was negatively associated in both vitamin K antagonists (aOR = 0.35, 95% CI 0.23–0.54; P P = 0.024). In conclusion, higher serum cTnI was associated with END in patients with AF-related stroke.

BACKGROUND Some researchers have reported that applying compression closer to the maximum diameter of the left ventricle (Point_max.LV) is associated with worse clinical outcomes, challenging its traditional position as optimum compression point (Point_optimum). By locating the mid-sternum (the actual compression site) in terms of Point_max.LV and its right ventricular equivalent (Point_max.RV), we aimed to determine its optimum horizontal position associated with increased chances of return of spontaneous circulation (ROSC). METHODS A retrospective, cross-sectional study was performed at a university hospital from 2014 to 2019 on non-traumatic out-of-hospital cardiac arrest (OHCA) victims who underwent chest computed tomography. On absolute x-axis, we designated the x-coordinate of the mid-sternum (x_mid-sternum) as 0 and leftward direction as positive. Re-defining the x-coordinate of Point_max.RV and Point_max.LV as 0 and 1 interventricular unit (IVU), respectively, we could convert x_mid-sternum to "-x_max.RV/(x_max.LV - x_max.RV) (IVU)." Using multiple logistic regression analysis, we investigated whether this converted x_mid-sternum was associated with clinical outcomes, adjusting core elements of the Utstein template. RESULTS Among 887 non-traumatic OHCA victims, 124 [64.4 ± 16.7 years, 43 women (34.7%)] were enrolled. Of these, 80 (64.5%) exhibited ROSC. X_mid-sternum ranging from -1.71 to 0.58 (-0.36 ± 0.38) IVU was categorised into quintiles

Amlodipine belongs to a class of calcium channel blockers that relax blood vessels to allow easier flow of blood. Higher blood pressure (BP) is associated with cerebrovascular disease and is an important contributor to cognitive decline and dementia.This study aimed to evaluate the effect of 24 weeks of S-amlodipine besylate therapy on cognitive function in patients with hypertension and cerebrovascular disease.The data were obtained from a study of post-market surveillance of S-amlodipine besylate.A total of 545 subjects (mean age 67 ± 9.68 years) with hypertension and ischemic cerebrovascular disease were enrolled. Patients with a baseline Mini-Mental State Examination (MMSE) score above 26 were assigned to the cognitive normal (CN) (n = 294) group, and those with MMSE score less than 26 were in the cognitive decline (CD) (n = 251) group. After 24 weeks of treatment with S-amlodipine besylate 5 mg, MMSE and Global Deterioration Scale (GDS) were evaluated again. Changes in MMSE were compared in the target BP reached (TBPR) and non-reached (NTBPR) groups and for CN and CD groups. Treatment with 5 mg of S-amlodipine besylate for 24 weeks improved MMSE and GDS scores (p 0.001). The CD group showed improvement in MMSE score regardless of whether target BP was obtained (TBPR: p 0.001, NTBPR: p 0.01). However, the CN classification was not significant for either TBPR or NTBPR groups.S-amlodipine besylate improved cognition of the CD group with hypertension and cerebrovascular disease regardless of obtaining target BP.

We aimed to develop a novel prediction model for early neurological deterioration (END) based on an interpretable machine learning (ML) algorithm for atrial fibrillation (AF)-related stroke and to evaluate the prediction accuracy and feature importance of ML models. Data from multi-center prospective stroke registries in South Korea were collected. After stepwise data preprocessing, we utilized logistic regression, support vector machine, extreme gradient boosting, light gradient boosting machine (LightGBM), and multilayer perceptron models. We used the Shapley additive explanations (SHAP) method to evaluate feature importance. Of the 3,623 stroke patients, the 2,363 who had arrived at the hospital within 24 hours of symptom onset and had available information regarding END were included. Of these, 318 (13.5%) had END. The LightGBM model showed the highest area under the receiver operating characteristic curve (0.778, 95% CI, 0.726 - 0.830). The feature importance analysis revealed that fasting glucose level and the National Institute of Health Stroke Scale score were the most influential factors. Among ML algorithms, the LightGBM model was particularly useful for predicting END, as it revealed new and diverse predictors. Additionally, the SHAP method can be adjusted to individualize the features’ effects on the predictive power of the model.

Cardiovascular disease (CVD) is becoming more prevalent worldwide and is one of the leading causes of death [1]. To lower CVD mortality, aggressive and comprehensive management of its risk factors, including dyslipidemia, hypertension, diabetes mellitus, and smoking, are crucial [2]. The incidence of coronary artery disease (CAD) is rising in South Korea and although cerebral hemorrhage has declined since 2002, cerebral infarction is on the rise [3]. This is speculated to be due to the elevated prevalence of dyslipidemia and diabetes mellitus with the growing obesity population, while hypertension is well-managed and smoking rate has reached a plateau [4]. Thus, aggressive diagnosis and treatment of dyslipidemia, the most important risk factor for atherosclerosis, are critical for lowering the incidence and mortality of CAD and cerebral infarction. To promote appropriate treatment of dyslipidemia, the Korean Society of Lipid and Atherosclerosis (KSo-LA) published the first guidelines for the management of hyperlipidemia in 1996, the second guideline in 2003, the second revision in 2009, and the third guidelines for treatment of dyslipidemia with added contents in 2015, in collaboration with 18 other relevant academic societies and organizations [5]. However, new guidelines were published in Europe in 2016 and in the United States in 2017 based on new study findings, and new drugs, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been launched [6-8]. Therefore, the KSoLA Treatment Guideline Committee developed the fourth guidelines for treatment and management of dyslipidemia specific to Koreans based on evidence and expert opinions on the dynamically changing treatment modalities for dyslipidemia. The fourth guideline consists of information about the epidemiology of dyslipidemia, diagnosis and treatment criteria, lifestyle interventions, drug therapy, and dyslipidemia in specific patient groups. Finally, we present currently available data and the need to develop and validate scales to assess the risk of CVD specific to Koreans and CVD biomarkers appropriate for the Korean population. The level of evidence and strength of recommendations used in the fourth guideline are shown in Table 1. The fourth guideline is available in full text and an abstract form including tables and figures in Korean. This paper is an English summary of the full text. We hope the fourth guidelines for the treatment of dyslipidemia will be useful for health professionals treating dyslipidemia. Table 1. Levels of evidence: classes of recommendation

Objective To investigate suicidality related to cluster headache and factors associated with increased suicidality in cluster headache patients. Methods In this multicenter study, 193 cluster headache patients were recruited between September 2016 and August 2018. Patients were asked about their suicidality during and between attacks, specifically about passive suicidal ideation, active suicidal ideation, suicide plan, and suicide attempt. Univariable and multivariable logistic regression analyses were performed to evaluate the factors associated with high ictal suicidality (sum of positive response ≥ 2). Patients were followed up when they were in the between-bouts period. Results A total of 175 cluster headache patients in the in-bout period were included in this study. Passive suicidal ideation, active suicidal ideation, suicidal planning, and suicidal attempt were reported by 111 (64.2%), 62 (35.8%), 10 (5.8%), and four (2.3%) patients during attacks; seven (4.0%), six (3.5%), five (2.9%) and two (1.2%) patients interictally; and none (0%), one (1.9%), one (1.9%), and none (0%) among patients in the between-bouts period. Factors associated with high ictal suicidality were longer disease duration, the Headache Impact Test score, and the Patient Health Question-9 score (multivariable OR = 1.90 per 10-year increase in disease duration, 95% CI = 1.18–3.05, p = 0.008; multivariable OR = 3.19 per 10-point increase in HIT-6, 95% CI = 1.73–5.87, p Conclusions Cluster headache attack carries a high suicidality compared to the interictal or between-bouts state. An intensive treatment to reduce cluster headache burden may be helpful to alleviate suicide risk in cluster headache patients.

Cutaneous allodynia (CA) is an abnormal pain in response to non-painful stimuli. In the present study, we sought to investigate the presence of CA, its associated factors, and its clinical implications in patients with cluster headache (CH). In this cross-sectional study, we analysed data from a prospective multicentre registry enrolling consecutive patients with CH. We identified CA during and between headache attacks using the 12-item Allodynia Symptom Checklist (ASC) administered during the CH bout period. Comorbid depression and anxiety were ascertained using the Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorder (GAD-7) scales. Headache impact was evaluated using the Headache Impact Test-6 (HIT-6). Of 119 eligible patients, 48 and two (40.3% and 1.7%) had CA during and between headache attacks, respectively. In univariable analyses, total CH duration, major depressive disorder (MDD), and generalized anxiety disorder (GAD) were associated with CA during headache attack. They remained significantly associated with CA during headache attack in multivariable analyses. Patients with CA during headache attack had higher headache impact (P = 0.002). A “50% responder” analysis showed no difference in outcome of acute and preventive treatment between patients with and without CA during headache attack. Patients with CH commonly experienced CA during headache attack, but not between headache attacks. CA during headache attack was associated with disease duration, depression, and anxiety.

Objective Although blood pressure (BP) variability has been regarded as a risk factor for hemorrhagic transformation (HTF) after intravenous thrombolysis, its effect on HTF after endovascular recanalization therapy (ERT) remains to be elucidated. We aimed to study the relationship between BP variability and symptomatic intracerebral hemorrhage (sICH) after successful recanalization with ERT. Methods A total of 211 patients with acute ischemic stroke and successful recanalization (thrombolysis in cerebral infarction 2b or 3) after ERT were included between January 2013 and May 2017. The BP data following ERT was obtained over the first 24 hours using parameters including mean, maximum, minimum, difference between maximum and minimum, standard deviation, coefficient of variation, successive variations, and time rate (TR) of BP variation for systolic BP (SBP) and diastolic BP. sICH was defined as parenchymal hemorrhage type 2 with neurological deterioration of 4 points of more on the National Institute of Health Stroke Scale. Results Among the included patients, 20 (9.5%) developed sICH after successful ERT. The parameters linked with BP fluctuation over time were significantly related to sICH. After adjusting for confounders, the TR of SBP (per 0.1 mmHg/min increase) variation was independently associated with sICH (odds ratio = 1.71, 95% confidence interval = 1.013-2.886). Interpretation Time-related BP variability in the first 24 hours following successful ERT was more correlated with sICH than other absolute BP levels. This suggests that maintaining a stable BP may be an important factor in preventing sICH after successful ERT. Ann Neurol 2019;85:574-581.

BackgroundWe investigated the microRNA expression pattern from thrombus retrieved by mechanical thrombectomy in acute stroke patients to understand the stroke mechanism.MethodsThis study included acute ischemic stroke patients who had undergone intra-arterial thrombectomy at Chung-Ang University Hospital in Seoul, Korea between February 2016 and March 2019. The thrombus was retrieved and stored at −70℃ after obtaining informed consent. MicroRNA microarray analysis was performed for the patients with identified stroke mechanisms including (1) large artery atherosclerosis, (2) cardioembolism with atrial fibrillation, and (3) cardioembolism with valvular heart disease. The microRNAs derived from microarray analysis were validated by quantitative real-time polymerase chain reaction (qRT-PCR) from different patient populations. The correlation analysis was performed between microRNA levels and laboratory data to understand the functional relevance of the altered microRNA.ResultsIn total, 55 thrombi were obtained from 74 patients, and the microRNAs were analyzed in 45 samples. Microarray analysis of 2578 microRNAs revealed that 50 microRNAs were significantly altered among the three groups. Validation using qRT-PCR showed that miR-378f and miR-450b-5p were significantly elevated among the cardioembolic thrombi; both microRNAs were inversely correlated with the ejection fraction from echocardiography. Thrombi from patients with early neurological deterioration exhibited higher levels of miR-93-5p and lower levels of miR-629-5p than those from neurologically stable patients.ConclusionsThe microRNA expression pattern can provide information regarding the mechanism of stroke by reflecting the underlying pathological status of the organ from which the thrombus was derived.

Background: Although cranial autonomic symptoms are typical in cluster headache, some individuals with cluster headache show no cranial autonomic symptoms during their headache attacks. Probable cluster headache is a subtype of cluster headache that fulfils all but one of the five criteria for cluster headache. This study aimed to investigate the frequency and clinical features of cluster headache and probable cluster headache without cranial autonomic symptoms in comparison to those with cranial autonomic symptoms.Methods: We analysed data from the Korea Cluster Headache Registry, a prospective multicentre registry involving data from 16 hospitals.Results: Of the 216 participants with cluster headache and 26 with probable cluster headache, 19 (8.8%) and 7 (26.9%), respectively, did not have cranial autonomic symptoms. Participants with cluster headache without cranial autonomic symptoms exhibited less severe anxiety (General Anxiety Disorder-7 score, median [interquartile range], 2.0 [1.0-6.0] vs 8.0 [3.0-12.0], p = 0.001) and depression (Patient Health Questionnaire-9 score, 3.0 [1.0-7.0] vs 7.0 [3.0-11.0], p = 0.042) than those with cranial autonomic symptoms. Other clinical features, including headache intensity, daily headache frequency, attack duration, bout duration, and location of the pain, did not differ between participants with cluster headache with and without cranial autonomic symptoms. Headache intensity was less severe in participants with probable cluster headache without cranial autonomic symptoms than in those with cranial autonomic symptoms (numeric rating scale, 8.0 [7.0-8.0] vs 9.5 [8.0-10.0], p = 0.015).Conclusions: A significant proportion of participants with cluster headache and probable cluster headache did not have cranial autonomic symptoms. Some clinical features of cluster headache and probable cluster headache differed based on the presence of cranial autonomic symptoms.

Background The Clock Drawing Test (CDT) and Rey–Osterrieth Complex Figure Test (RCFT) are widely used as a part of neuropsychological test batteries to assess cognitive function. Our objective was to confirm the prediction accuracies of the RCFT-copy and CDT for cognitive impairment (CI) using convolutional neural network algorithms as a screening tool. Methods The CDT and RCFT-copy data were obtained from patients aged 60–80 years who had more than 6 years of education. In total, 747 CDT and 980 RCFT-copy figures were utilized. Convolutional neural network algorithms using TensorFlow (ver. 2.3.0) on the Colab cloud platform (www.colab.research.google.com) were used for preprocessing and modeling. We measured the prediction accuracy of each drawing test 10 times using this dataset with the following classes: normal cognition (NC) vs. mildly impaired cognition (MI), NC vs. severely impaired cognition (SI), and NC vs. CI (MI + SI). Results The accuracy of the CDT was better for differentiating MI (CDT, 78.04 ± 2.75; RCFT-copy, not being trained) and SI from NC (CDT, 91.45 ± 0.83; RCFT-copy, 90.27 ± 1.52); however, the RCFT-copy was better at predicting CI (CDT, 77.37 ± 1.77; RCFT, 83.52 ± 1.41). The accuracy for a 3-way classification (NC vs. MI vs. SI) was approximately 71% for both tests; no significant difference was found between them. Conclusions The two drawing tests showed good performance for predicting severe impairment of cognition; however, a drawing test alone is not enough to predict overall CI. There are some limitations to our study: the sample size was small, all the participants did not perform both the CDT and RCFT-copy, and only the copy condition of the RCFT was used. Algorithms involving memory performance and longitudinal changes are worth future exploration. These results may contribute to improved home-based healthcare delivery.

Objective We investigated the effect of arterial stiffness on the severity of enlarged perivascular spaces (EPVSs) and cerebral microbleeds (CMBs) at different brain locations. Methods A total of 854 stroke patients underwent both brachial‐ankle pulse wave velocity (baPWV) measurement and brain MRI. The extent of EPVS was separately rated at the levels of the basal ganglia (BG) and centrum semiovale (CS). The CMBs were categorized as strictly lobar CMB and deep CMB. The patients were categorized according to baPWV quartiles, and multivariable logistic regressions were performed to evaluate whether the baPWV increment was independently associated with each cerebral SVD marker at different locations. The odds ratio (OR) with 95% confidence interval (CI) was derived on the reference of the first quartile. Results Severe EPVSs at BG and CS were detected in 243 (28.5%) and 353 patients (41.3%), respectively. The increment of baPWV quartiles was associated with both severe BG EPVS burden (Q4: OR = 2.58, CI = 1.45–4.60) and severe CS EPVS burden (Q4: OR = 2.06, CI = 1.24–3.42). Deep CMBs were found in 259 patients (30.3%), and strictly lobar CMBs were found in 170 patients (19.9%). Multivariable logistic regression model revealed deep CMB was independently associated with the baPWV increment (Q4: OR = 2.52, CI = 1.62–3.94). However, strictly lobar CMB had a neutral relationship with baPWV. Conclusion Increased arterial stiffness is consistently associated with the presence of deep CMB and severe EPVS burden at the BG and CS, suggesting a common pathophysiologic mechanism., We investigated the effect of arterial stiffness on the severity of enlarged perivascular spaces (EPVSs) and cerebral microbleeds (CMBs) at different brain locations. A total of 854 stroke patients underwent both brachial‐ankle pulse wave velocity (baPWV) measurement and brain MRI. Increased arterial stiffness is consistently associated with the presence of deep CMB and severe EPVS burden at the BG and CS, suggesting a common pathophysiologic mechanism.

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.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.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.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.High CHA2DS2-VASc score was associated with END in ischemic stroke patients with AF. This close relationship is more pronounced in patients with ICAS.

Background Our aim was to investigate the relationship between coexisting cluster headache (CH) and migraine with anxiety and depression during active cluster bouts, and how symptoms change during remission. Methods We analyzed data from 222 consecutive CH patients and 99 age- and sex-matched controls using a prospective multicenter registry. Anxiety or depression was evaluated using the Generalized Anxiety Disorder-7 (GAD-7) or Patient Health Questionnaire-9 (PHQ-9), respectively. Moderate-to-severe anxiety or depression was defined as a score of ≥10 at baseline (during a cluster bout). We assessed for changes in anxiety and depression during CH remission periods. Results Among the CH patients, the prevalence of moderate-to-severe anxiety and depression was seen in 38.2% and 34.6%, respectively. Compared with controls, CH patients were associated with moderate-to-severe anxiety and depression (multivariable-adjusted odds ratio [aOR] = 7.32, 95% confidence intervals [CI] = 3.35–15.99 and aOR = 4.95, 95% CI = 2.32–10.57, respectively). CH patients with migraine were significantly more likely to have moderate-to-severe anxiety and depression (aOR = 32.53, 95% CI = 6.63–159.64 and aOR = 16.88, 95% CI = 4.16–68.38, respectively), compared to controls without migraine. The GAD-7 and PHQ-9 scores were significantly reduced between cluster bout and remission periods (from 6.8 ± 5.6 to 1.6 ± 2.8; P P Conclusions Our results indicate that CH patients are at increased risk of anxiety and depression, especially in the presence of coexisting migraine. However, the anxiety and depression can improve during remission periods.

Background This study aimed to describe the current status of acute stroke care in Korea and explore disparities among hospitals and regions. Methods The 2013 and 2014 national stroke audit data and the national health insurance claims data were linked and used for this study. Stroke patients hospitalized via emergency rooms within 7 days of stroke onset were selected. Results A total of 19,608 patients treated in 216 hospitals were analyzed. Among them 76% had ischemic stroke; 15%, intracerebral hemorrhage (ICH); and 9%, subarachnoid hemorrhage (SAH). Of the hospitals, 31% provided inpatient stroke unit care. Ambulances were used in 56% of cases, and the median interval from onset to arrival was 4.5 hours. One-quarter of patients were referred from other hospitals. Intravenous thrombolysis (IVT) and endovascular treatment (EVT) rates were 11% and 4%, respectively. Three-quarters of the analyzed hospitals provided IVT and/or EVT, whereas 47% of hospitals providing IVT and 67% of hospitals providing EVT had less than one case per month. Decompressive surgery was performed on 28% of ICH patients, and clipping and coiling were performed in 17.2% and 14.3% of SAH patients, respectively. There were noticeable regional disparities between the various interventions, ambulance use, arrival time, and stroke unit availability. Conclusion This study describes the current status of acute stroke care in Korea. Despite quite acceptable quality of stroke care, it suggests regional and hospital disparities. Expansion of stroke units, stroke center certification or accreditation, and connections between stroke centers and emergency medical services are highly recommended., Graphical Abstract

Background To track triage, routing, and treatment status regarding access to endovascular treatment (EVT) after acute ischemic stroke (AIS) at a national level. Methods From national stroke audit data, potential candidates for EVT arriving within 6 hours with National Institute of Health Stroke Scale score of ≥ 7 were identified. Acute care hospitals were classified as thrombectomy-capable hospitals (TCHs, ≥ 15 EVT cases/year) or primary stroke hospital (PSH, < 15 cases/year), and patients' initial routes and subsequent inter-hospital transfer were described. Impact of initial routing to TCHs vs. PSHs on EVT and clinical outcomes were analyzed using multilevel generalized mixed effect models. Results Out of 14,902 AIS patients, 2,180 (14.6%) were EVT candidates. Eighty-one percent of EVT candidates were transported by ambulance, but only one-third were taken initially to TCHs. Initial routing to TCHs was associated with greater chances of receiving EVT compared to initial routing to PSHs (33.3% vs 12.1%, P < 0.001; adjusted odds ratio [aOR], 2.21; 95% confidence interval [CI], 1.59–2.92) and favorable outcome (38.5% vs. 28.2%, P < 0.001; aOR, 1.52; 95% CI, 1.16–2.00). Inter-hospital transfers to TCHs occurred in 17.4% of those initially routed to a PSH and was associated with the greater chance of EVT compared to remaining at PSHs (34.8% vs. 7.5%, P < 0.001), but not with better outcomes. Conclusion Two-thirds of EVT candidates were initially routed to PSHs despite greater chance of receiving EVT and having favorable outcomes if routed to a TCH in Korea. Process improvement is needed to direct appropriate patients to TCHs., Graphical Abstract

Background Cluster headaches (CH) are recurrent severe headaches, which impose a major burden on the life of patients. We investigated the impact of CH on employment status and job burden. Methods The study was a sub-study of the Korean Cluster Headache Registry. Patients with CH were enrolled from September 2016 to February 2018 from 15 headache clinics in Korea. We also enrolled a headache control group with age-sex matched patients with migraine or tension-type headache. Moreover, a control group including individuals without headache complaints was recruited. All participants responded to a questionnaire that included questions on employment status, type of occupation, working time, sick leave, reductions in productivity, and satisfaction with current occupation. The questionnaire was administered to participants who were currently employed or had previous occupational experience. Results We recruited 143 patients with CH, 38 patients with other types of headache (migraine or tension-type headache), and 52 headache-free controls. The proportion of employees was lower in the CH group compared with the headache and headache-free control groups (CH: 67.6% vs. headache controls: 84.2% vs. headache-free controls: 96.2%; p = 0.001). The CH group more frequently experienced difficulties at work and required sick leave than the other groups (CH: 84.8% vs. headache controls: 63.9% vs. headache-free controls: 36.5%; p

Background There is insufficient evidence on the effect of statins, particularly high‐intensity statins, in patients with acute ischemic stroke and atrial fibrillation. We investigated the impact of statins on the outcomes in these patients, including those who might be vulnerable to statin therapy and those without clinical atherosclerotic cardiovascular diseases. Methods and Results A total of 2153 patients with acute ischemic stroke and atrial fibrillation were enrolled in the present nationwide, multicenter, cohort study. The primary composite end point was the occurrence of net adverse clinical and cerebral events ( NACCE ; death from any cause, stroke, acute coronary syndrome, or major bleeding) over a 3‐year period based on statin intensity. NACCE rates were lower in patients receiving low‐ to moderate‐intensity (adjusted hazard ratio 0.64; 95% CI : 0.52‐0.78) and high‐intensity statins (hazard ratio 0.51; 95% CI 0.40‐0.66) than in those not receiving statin therapy. High‐intensity statins were associated with a lower risk for NACCE than low‐ to moderate‐intensity statins (hazard ratio 0.76; 95% CI 0.59‐0.96). Subgroup analyses showed that the differences in hazard ratio for 3‐year NACCE favored statin use across all subgroups, including older patients, those with low cholesterol levels, patients receiving anticoagulants, and patients without clinical atherosclerotic cardiovascular diseases. Magnified benefits of high‐intensity statins compared with low‐ to moderate‐intensity statins were observed in patients who underwent revascularization therapy and those under 75 years of age. Conclusions Statins, particularly high‐intensity statins, could reduce the risk for NACCE in patients with acute ischemic stroke and atrial fibrillation; this needs to be further explored in randomized controlled trials.

Stroke severity of 1 hospital is a crucial information when assessing hospital performance. We aimed to determine the effect of stroke severity in the association between hospital patient volume and outcome after acute ischemic stroke.Data from National Acute Stroke Quality Assessment in 2013 and 2014 were analyzed. Hospital patient volume was defined as the annual number of acute ischemic stroke patients who admitted to each hospital. Comparisons among hospital patient volume quartiles before and after adjusting age, sex, onset to arrival and stroke severity were made to determine the associations between hospital patient volume and mortality at 30 days, 90 days and 1 year. Assessments for the nonlinear associations, with treating hospital patient volume as a continuous variable, and the associations between hospital patient volume and quality of care were also made.A total of 14,666 acute ischemic stroke patients admitted to 202 hospitals were analyzed. In the crude analysis, patients admitted to hospitals with lower patient volume showed higher mortality with a non-linear inverse association with a cut-off value of 227 patients/year. While the associations remained significant after adjusting age, sex and onset to arrival time (P's.05), they disappeared when stroke severity was further adjusted (P's.05). In contrary, hospital patient volume showed a nonlinear positive association with a plateau for summary measures of quality indicators even after adjustments for covariates including stroke severity (P.001).Our study implicates that stroke severity should be considered when assessing hospital performance regarding outcomes of acute stroke care.

Background Cluster headache is famous for attacks with seasonal and diurnal periodicity. This diurnal and seasonal variation might be related to sunlight and vitamin D metabolism. We investigated the serum vitamin D levels in patients with cluster headache. Methods We enrolled patients with cluster headache and age- and sex-matched migraineurs and normal controls. From October 2016 to March 2018, non-fasting serum 25(OH)D concentrations were measured using a chemiluminescent immunoassay. Vitamin D deficiency was defined as a concentration

Objective To investigate the temporal changes of circadian rhythmicity in relation to the disease course in patients with cluster headache. Methods In this multicenter study, patients with cluster headache were recruited between September 2016 and July 2018. We evaluated the patients for circadian rhythmicity and time of cluster headache attacks in the current bout and any experience of bout-to-bout change in circadian rhythmicity. We analyzed the patterns of circadian rhythmicity in relation to the disease progression (the number of total lifetime bouts, grouped into deciles). Results Of the 175 patients in their active, within-bout period, 86 (49.1%) had circadian rhythmicity in the current bout. The prevalence of circadian rhythmicity in the active period was overall similar regardless of disease progression. Sixty-three (46.3%) out of 136 patients with ≥2 bouts reported bout-to-bout changes in circadian rhythmicity. The most frequent time of cluster headache attacks was distributed evenly throughout the day earlier in the disease course and dichotomized into hypnic and midday as the number of lifetime bouts increased ( p = 0.037 for the homogeneity of variance). When grouped into nighttime and daytime, nighttime attacks were predominant early in the disease course, while daytime attacks increased with disease progression (up to 7th deciles of total lifetime bouts, p = 0.001) and decreased in patients with the most advanced disease course ( p = 0.013 for the non-linear association). Conclusions Circadian rhythmicity is not a fixed factor, and changes according to the disease course. Our findings will be valuable in providing a new insight into the stability of functional involvement of the suprachiasmatic nucleus in the pathophysiology of cluster headache.

Background Off‐hour presentation can affect treatment delay and clinical outcomes in endovascular therapy ( EVT ) for acute ischemic stroke. We aimed to examine the treatment delays and clinical outcomes of EVT between on‐ and off‐hour admission and to evaluate the effect of hospital procedure volume and the number of neurointerventionalists on off‐hour EVT . Methods and Results From a multicenter registry, we identified patients who were treated with EVT within 12 hours of symptom. Annual hospital procedure volume was divided as low (60). The effect of the number of neurointerventionalists and annual hospital procedure volume on clinical outcome was estimated by the generalized estimation equation. Of the 31 133 stroke patients, 1564 patients met the eligibility criteria (mean age: 69±12 years; median baseline National Institutes of Health stroke scale score, 15 [interquartile range, 10–19]). Of 1564 patients, 893 (57.1%) arrived during off‐hour. The off‐hour patients had greater median door‐to‐puncture time (110 versus 95 minutes; P P =0.90). The presence of three neurointerventionalists was significantly associated with favorable outcomes at 3 months during on‐ and off‐hour (2.07 [1.53–2.81]; P Conclusions The number of neurointerventionalists was more crucial to effective around‐the‐clock EVT for acute stroke patients than hospital procedural volume.

Background and aims Elevated serum homocysteine level is known to be associated with increased risk of vascular event due to endothelial senescence. We investigated the association between serum homocysteine level and cerebral arteriosclerosis status including intracranial vascular calcification and atherosclerosis burden. Methods We identified 1193 consecutive patients (mean age = 68.6 ± 12.7, 537 female patients) who were admitted with acute cerebral infarction or transient ischemic attack from a single university medical center. The patients were categorized into three groups according to their serum homocysteine level. Cerebral artery calcification was assessed from the cavernous portion of both internal carotid arteries, and cerebral atherosclerosis burden was derived as the sum of stenosis degree of major intracranial arteries from brain computed tomography angiography. Results The mean homocysteine level was 14.1 ± 6.2 μmol/L, and intracranial cerebral artery calcification was present in 974 patients (81.6%), with 339 cases of advanced calcification (28.4%). The prevalence of cerebral artery calcification, advanced cerebral artery calcification and cerebral atherosclerosis burden showed increasing tendency throughout the homocysteine tertiles. Multivariable logistic regression analysis including age, sex, vascular risk factors, serum C-reactive protein, estimated glomerular filtration rate and homocysteine tertile disclosed that the highest serum homocysteine tertile was an independent predictor of advanced cerebral artery calcification (odds ratio = 1.45, confidence interval = 1.02–2.05) and advanced cerebral atherosclerosis (odds ratio = 1.42, confidence interval = 1.01–1.99) compared to the lowest group. Conclusions An elevated serum homocysteine level was independently associated with intracranial arterial calcification and atherosclerosis burden. Future studies are warranted to test whether lowering serum homocysteine can delay cerebral arteriosclerotic changes.

Although many patients with cluster headaches (CH) are disabled by their condition, few studies have examined this in detail. This cross-sectional, multicenter observational study prospectively collected demographic and clinical questionnaire data from 224 consecutive patients with CH. We assessed headache impact using the six-item Headache Impact Test (HIT-6) and evaluated the factors associated with the impact of CH. Participants with a HIT-6 score ≥ 60 were classified into a severe impact group. The majority (190, 84.8%) of the participants were classified into the severe impact group. These patients were characterized by younger age, earlier onset of CH, longer duration of each headache attack, higher pain intensity, more cranial autonomic symptoms, a higher proportion of depression or anxiety, higher score of stress, and lower score of quality of life. The anxiety (OR = 1.19, 95% CI: 1.08–1.31, p = 0.006), greater pain intensity (OR = 1.06, 95% CI: 1.02–1.10, p = 0.002), and age (OR = 0.99, 95% CI: 0.99–1.00, p = 0.008) were significant predictors for a severe impact of CH patients. According to the HIT-6 results, most of the CH patients were significantly affected by CH. As well as pain intensity, anxiety and age modulated CH’s impact on their lives.

Background and purpose We analyzed the incidence and causes of oral anticoagulant (OAC) cessation and subsequent stroke after OAC withdrawal in a cohort of Korean stroke patients with atrial fibrillation. Methods The Korean Atrial Fibrillation Evaluation Registry in Ischemic Stroke patients (K-ATTENTION) is a multicenter cohort study, merging stroke registries from 11 tertiary centers in Korea. The number of OAC interruption episodes and the reasons were reviewed from hospital records. Stroke after OAC withdrawal was defined when a patient experienced ischaemic stroke within 31 days after OAC withdrawal. Clinical variables were compared between patients who experienced stroke recurrence during OAC interruption and those who did not experience recurrence. Results Among 3213 stroke patients with atrial fibrillation, a total of 329 episodes of OAC interruption were detected in 229 patients after index stroke (mean age 72.9 ± 8.3 years, 113 female patients). The most frequent reason for OAC withdrawal was poor compliance [103 episodes (31.3%)] followed by extracranial bleeding [96 episodes (29.2%)]. Stroke after OAC withdrawal was noted in 13 patients. Mean age, vascular risk factor profile and mean CHA2 DS2 -VASc score were not significantly different between patients with and without recurrent stroke. Conclusions A considerable number of stroke patients with atrial fibrillation experienced temporary interruption of OAC after index stroke, which was associated with stroke recurrence of 4.0 cases per 100 interruption episodes.

The criterion for the remission period of chronic cluster headache (CCH) was recently revised from < 1 month to < 3 months in the third edition of the International Classification of Headache Disorders (ICHD-3). However, information on the clinical features of CCH based on the ICHD-3 criteria is currently limited. The present study aimed to investigate the clinical features of CCH based on ICHD-3 using data from the Korean Cluster Headache Registry (KCHR). The KCHR is a multicentre prospective registry of patients with cluster headache (CH) from 15 hospitals. Among the 250 participants with CH, 12 and 176 participants were classified as having CCH and episodic cluster headache (ECH), respectively. Among 12 participants with CCH, 6 (50%) had remission periods of < 1 month, and the remaining 6 (50%) had a remission period of 1-3 months. Six participants had CCH from the time of onset of CH, and in the other 6 participants, CCH evolved from ECH. CCH subjects had later age of onset of CH, developed the condition after a longer interval after CH onset, and had more migraine and less nasal congestion and/or rhinorrhoea than ECH subjects. Clinical features of CCH with remission periods < 1 month were not significantly different from those of CCH with remission periods of 1-3 months, except for the total number of bouts. More current smoking and less diurnal rhythmicity were observed in participants with CCH evolved from ECH compared to those with ECH. In conclusion, the number of subjects with CCH doubled when the revised ICHD-3 criteria were used. Most of clinical characteristics of CCH did not differ when the previous and current version of ICHD was applied and compared. Some clinical features of CCH were different from those of ECH, and smoking may have a role in CH chronification.

We investigated the prevalence and mechanisms of neurological deterioration after endovascular thrombectomy. Between January 2011 and October 2017, acute ischemic stroke patients treated by endovascular thrombectomy in a tertiary university hospital were included. Early neurological deterioration (END) was defined as an increase of 2 or more National Institute of Health Stroke Scale (NIHSS) compared to the best neurological status after stroke within 7 days. The END mechanism was categorized into ischemia progression, symptomatic hemorrhage, and brain edema. A total of 125 acute ischemic stroke patients received endovascular thrombectomy. Neurological deterioration was detected in 44 patients, and 38 cases (86.4% of END) occurred within 72 h. The END mechanism included 20 ischemia progression, 16 brain edema and 8 hemorrhagic transformation cases. Multivariable logistic regression analysis revealed that the patients who experienced END were more likely to have poor functional outcome defined as modified Rankin scale 3–6 at 90 days than neurologically stable patients (odds ratio (OR) = 4.06, confidence interval (CI) = 1.39–11.9). The risk factor of END due to ischemia progression was stroke subtype of large artery atherosclerosis (OR = 6.28, CI = 1.79–22.0). Successful recanalization (OR = 0.11, CI = 0.03–0.39) and NIHSS after endovascular thrombectomy (OR = 1.15 per one-point increase, CI = 1.06–1.24) were significantly associated with END due to hemorrhage or brain edema. Neurological deterioration frequently occurs after endovascular thrombectomy, and the risk factors of END differ according to the mechanism of END.

Objective Restless legs syndrome (RLS) has been associated with vascular diseases, including cerebrovascular and cardiovascular diseases. Among the various mechanisms in RLS, peripheral vascular endothelial dysfunction in patients with RLS has recently been proposed as a vascular pathophysiology of RLS. This study investigated arterial stiffness related to RLS in acute ischemic stroke patients and its influence on stroke outcome. Methods RLS in patients with acute ischemic stroke was assessed based on the four essential criteria of the International Restless Legs Syndrome Study Group described in 2003. The patients’ clinical and laboratory characteristics, arterial stiffness, small vessel disease occurrence, and burden on brain MRI were recorded. Stroke severity was determined using the National Institute of Health Stroke Scale (NIHSS), and clinical outcomes were determined using the modified Rankin Scale. Results Of 296 patients with acute ischemic stroke, 16 (5.4%) were diagnosed with restless legs syndrome. Logistic regression analysis showed that a 1 m/s increase in brachial arterial pulse wave velocity was associated with the diagnosis of RLS (odds ratio, 1.092; 95% confidence interval, 1.019–1.170, p = 0.012). Diagnosis of RLS in patients with acute ischemic stroke was associated with poor clinical outcome three months after stroke (modified Rankin Scale 3–6) (odds ratio, 4.263; 95% confidence interval, 1.229–14.792, p = 0.022) along with initial NIHSS score. Conclusion RLS in patients with acute ischemic stroke is associated with increased arterial stiffness and poor clinical outcomes.

Vitamin D deficiency has been known to be associated with the aggressiveness and prognosis of several cancers. This study evaluated the effect of preoperative serum vitamin D levels on the aggressiveness and prognosis of papillary thyroid cancer (PTC).In total, 820 patients with PTC were enrolled. 25-hydroxyvitamin D levels were measured in blood samples before surgery. Clinical, pathologic, and recurrence data were accessed to examine the prognostic effects of vitamin D. Patients were categorized into four quartiles by preoperative serum vitamin D levels.Of the enrolled patients, 795 (97%) had insufficient vitamin D levels (30 ng/mL). Vitamin D levels showed positive correlations with age and body mass index (BMI), and negative correlations with serum thyrotropin levels and antithyroid peroxidase antibody titers. The association between vitamin D quartile and the risks of extrathyroidal invasion, lymph node metastasis, advanced cancer stages (III or IV), and risk of recurrence were not significant after adjusting for age, sex, BMI, preoperative ionized calcium, and parathyroid hormone. Additionally, serum vitamin D was not associated with recurrent or persistent PTC.Serum vitamin D levels are not associated with either disease aggressiveness or poor outcomes among patients with PTC and vitamin D insufficiency.

The aim of this study was to determine the association of brachial-ankle pulse wave velocity (baPWV) with both acute and chronic cerebral small vessel disease (SVD).We identified 1282 consecutive patients with acute ischemic stroke or transient ischemic attack. Neuroimaging correlates of chronic lacunes, white matter hyperintensity (WMH), and cerebral microbleed (CMB) were assessed using MR images. Combined SVD score was defined as the number of presence of SVD markers including chronic lacunes, WMH, deep CMB, and acute lacunar infarction. The association between baPWV and SVD was tested using linear and logistic regression analyses.Mean age of patients was 68 (± 12) years. Chronic lacunes were found in 675 patients (53%), WMH in 970 patients (77%), and deep CMB in 349 patients (30%). Among the 1145 patients with ischemic stroke, 292 patients (26%) were classified as having acute SVD. On multivariate analysis, a 1-SD increase in baPWV was associated with chronic lacunes [odds ratio, 1.24; 95% CI, 1.07-1.44; p0.01], WMH (1.38; 1.13-1.71; p0.01), deep CMB (1.29; 1.11-1.51; p0.01), acute SVD (1.19; 1.01-1.40; p = 0.04), combined SVD score1 (1.27; 1.06-1.53; p = 0.01), and combined SVD score2 (1.40; 1.19-1.65; p0.01).baPWV is associated with both acute and chronic SVD. Our findings suggest that arterial stiffness is linked to the pathogenesis of SVD. Also, baPWV could be used as a biomarker of SVD. In future trials, it should be tested whether arterial stiffness can be a therapeutic target for SVD.

Objectives This study aimed to determine the characteristics and significance of a probable diagnostic entity for primary headache disorder (PHD). Background A diagnosis of probable primary headache disorder (PPHD) is given when a patient's headache fulfills all but one criteria of the third beta edition of the international classification of headache disorder (ICHD-3β). Despite the uncertainty regarding this diagnosis, the inclusion of a probable diagnosis entity in this manual may aid in the accurate classification of headache disorders and allow effective treatment strategies to be started at the patient's initial visit. Methods This cross-sectional multicenter registry study assessed first-visit patients with complaints of headaches who presented at the outpatient clinics of 11 neurologists in Korea. The classification of a headache disorder was made according to the criteria of the ICHD-3β by each investigator based on the initial evaluation of the patient or by a consensus meeting for uncertain cases. The rates of a probable diagnosis among PPHD patients were assessed and the clinical characteristics of these patients were compared with those of patients with a diagnosis of definite primary headache disorder (DPHD). Results A total of 1429 patients were diagnosed with PHD, and 305 (21.3%) of these patients had PPHD. The proportions of PPHD differed among the subtypes of DPHD as follows: migraines (16.1%), tension-type headaches (TTH; 33%), trigeminal autonomic cephalalgia (TAC; 40.9%), and other PHD (14%, P

The purpose of this study was to test the feasibility and usefulness of the International Classification of Headache Disorders, third edition, beta version (ICHD-3β), and compare the differences with the International Classification of Headache Disorders, second edition (ICHD-2). Consecutive first-visit patients were recruited from 11 headache clinics in Korea. Headache classification was performed in accordance with ICHD-3β. The characteristics of headaches were analyzed and the feasibility and usefulness of this version was assessed by the proportion of unclassified headache disorders compared with ICHD-2. A total of 1,627 patients were enrolled (mean age, 47.4±14.7 yr; 62.8% female). Classification by ICHD-3β was achieved in 97.8% of headache patients, whereas 90.0% could be classified by ICHD-2. Primary headaches (n=1,429, 87.8%) were classified as follows: 697 migraines, 445 tension-type headaches, 22 cluster headaches, and 265 other primary headache disorders. Secondary headache or painful cranial neuropathies/other facial pains were diagnosed in 163 patients (10.0%). Only 2.2% were not classified by ICHD-3β. The main reasons for missing classifications were insufficient information (1.6%) or absence of suitable classification (0.6%). The diagnoses differed from those using ICHD-2 in 243 patients (14.9%). Among them, 165 patients were newly classified from unclassified with ICHD-2 because of the relaxation of the previous strict criteria or the introduction of a new diagnostic category. ICHD-3β would yield a higher classification rate than its previous version, ICHD-2. ICHD-3β is applicable in clinical practice for first-visit headache patients of a referral hospital., Graphical Abstract

Objective: Migraine, particularly with aura, is a risk factor for ischemic stroke. Recent data in migraine mutant mice suggest that cerebral hyperexcitability associated with migraine accelerates recruitment of ischemic penumbra into the core, resulting in faster infarct growth compared with wild type. We hypothesized that individuals with a history of migraine are more likely to exhibit increased recruitment of ischemic tissue into the infarct in acute stroke. Methods: In this retrospective case-control study, we identified participants with reliably documented migraine history, measured lesion volumes on diffusion-weighted and perfusion-weighted MRI obtained within 72 hours of symptom onset, calculated the proportion of ischemic tissue on perfusion-weighted imaging (PWI) hyperintense on diffusion-weighted imaging (DWI), and compared the proportion of patients with no-mismatch pattern defined as DWI lesion >83% of PWI lesion. Results: Migraineurs (n = 45) were younger, more often female, less likely to have vascular risk factors, and more often had cervical artery dissection, but otherwise did not differ from controls (n = 27). A significantly larger proportion of migraineurs had no-mismatch pattern, indicating that the entire perfusion defect was recruited into the infarct by the time of MRI (22% vs 4% of migraineurs and controls, respectively; p = 0.044). The difference was even more prominent in migraineurs with aura (36% vs 4%, p = 0.019). The association between migraine and no-mismatch pattern persisted after adjustment for time to MRI ( p = 0.041). Conclusions: This case-control study supports the hypothesis that a history of migraine, particularly with aura, is associated with a no-mismatch pattern during acute ischemic stroke, consistent with data obtained in migraine mutant mice.

Purpose Non-vitamin K antagonist oral anticoagulants (NOACs) are widely used in patients with atrial fibrillation (AF) because of their effectiveness in preventing stroke and their better safety, compared with warfarin. However, there are concerns for an increased risk of bleeding associated with concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) or selective serotonin reuptake inhibitors (SSRIs) with NOACs. In this study, we aimed to evaluate the risk of bleeding events in individuals taking concomitant NSAIDs or SSRIs with NOACs after being diagnosed with AF. Materials and methods A nested case-control analysis to assess the safety of NSAIDs and SSRIs among NOAC users with AF was performed using data from Korean National Health Insurance Service from January 2012 to December 2017. Among patients who were newly prescribed NOACs, 1233 cases hospitalized for bleeding events were selected, and 24660 controls were determined. Results The risk of bleeding events was higher in patients receiving concomitant NSAIDs [adjusted odds ratio (aOR) 1.41; 95% confidence interval (CI) 1.24-1.61] or SSRIs (aOR 1.92; 95% CI 1.52-2.42) with NOACs, compared to no use of either drug, respectively. The risk of upper gastrointestinal bleeding was higher in patients receiving concomitant NSAIDs or SSRIs without proton pump inhibitors (PPIs) (NSAIDs: aOR 2.47; 95% CI 1.26-4.83, SSRI: aOR 10.8; 95% CI 2.41-2.48) compared to no use. Conclusion When NSAIDs or SSRIs are required for NOAC users with AF, physicians need to monitor bleeding events and consider the use of PPIs, especially for combined use of both drugs or when initiating NOACs treatment.

Cerebral microinfarcts (CMI) are associated with intracerebral hemorrhage due to small vessel disease (SVD) in studies not including an ischemic etiologic workup. We aimed to determine their incidence and potential causes in a large ischemic stroke (IS) cohort.Consecutive patients with MRI-confirmed IS within 72 hours of onset were enrolled. Subjects had either single high-risk embolic source (cardioembolic or large vessel disease) or no embolic source. CMIs were classified by their relationship to the primary infarct as within or outside the same vascular territory. White matter hyperintensities (WMH) and microbleeds were markers SVD severity. Multivariable regression tested the association between CMIs and potential etiologies.We analyzed 946 IS patients, mean age 69 ± 15 years, 46% female. We detected CMI (≤5 mm) on diffusion-weighted imaging in 269 (28%) subjects, 190 (71%) within the vascular territory of the primary infarct. Large-vessel atherosclerosis (P.001), cardioembolic source (P.001), higher WMH (P = .032) and lower systolic blood pressure (SBP, P = .024) were independently associated with the presence of CMI. While SBP was associated with CMI in any location (P.05), WMH was only associated with CMI outside the territory of the primary infarct (P = .033), and large vessel atherosclerosis with CMI within the primary infarct territory (P = .004).CMIs occurring within the vascular territory of a larger infarct are more likely embolic, but those occurring outside are probably related to SVD. Our findings suggest a role for SVD in pathogenesis of CMIs and emphasize the importance of etiologic workup to identify alternate etiologies.

Summary Background The optimal treatment for patients with ischaemic stroke with a high risk of cerebral haemorrhage is unclear. We assessed the efficacy and safety of cilostazol versus aspirin, with and without probucol, in these patients. Methods In this randomised, controlled, 2 × 2 factorial trial, we enrolled patients with ischaemic stroke with a history of or imaging findings of intracerebral haemorrhage or two or more microbleeds from 67 centres in three Asian countries. Patients were randomly assigned (1:1:1:1) to receive oral cilostazol (100 mg twice a day), aspirin (100 mg once a day), cilostazol plus probucol (250 mg twice a day), or aspirin plus probucol with centralised blocks stratified by centre. Cilostazol versus aspirin was investigated double-blinded; probucol treatment was open-label, but the outcome assessor was masked to assignment. The co-primary outcomes were incidence of the composite of stroke, myocardial infarction, or vascular death (efficacy) and incidence of haemorrhagic stroke (safety), which were assessed in intention-to-treat and modified intention-to-treat populations. Efficacy was analysed with a non-inferiority test and a superiority test if non-inferiority was satisfied. Safety was assessed with a superiority test only. This trial is registered with ClinicalTrials.gov, NCT01013532. Findings Between Aug 1, 2009, and Aug 31, 2015, we randomly assigned 1534 patients to one of the four study groups, of whom 1512 were assessed for the co-primary endpoints. During a median follow-up of 1·9 years (IQR 1·0–3·0), the incidence of composite vascular events was 4·27 per 100 person-years in patients who received cilostazol and 5·33 per 100 person-years in patients who received aspirin (HR 0·80, 95% CI 0·57–1·11; non-inferiority p=0·0077; superiority p=0·18). Incidence of cerebral haemorrhage was 0·61 per 100 person-years in patients who received cilostazol and 1·20 per 100 person-years in those who received aspirin (HR 0·51, 97·5% CI 0·20–1·27; superiority p=0·18). The incidence of vascular events was 3·91 per 100 person-years in the probucol group compared with 5·75 per 100 person-years in the non-probucol group (HR 0·69, 95% CI 0·50–0·97; superiority p=0·0316). The incidence of cerebral haemorrhage was 0·72 per 100 person-years in the probucol group and 1·11 per 100 person-years in the non-probucol group (HR 0·65, 97·5% CI 0·27–1·57; p=0·55). Adverse events were similar across the four study groups; the most common events were dizziness, headache, diarrhoea, and constipation. Interpretation In patients with ischaemic stroke at high risk of cerebral haemorrhage, cilostazol was non-inferior to aspirin for the prevention of cardiovascular events, but did not reduce the risk of haemorrhagic stroke. Addition of probucol to aspirin or cilostazol could be beneficial for reducing the incidence of cardiovascular events. Funding Korea Otsuka Pharmaceutical.

Objective:To investigate whether prestroke antiplatelet agent (PA) use was associated with initial stroke severity.Methods:This was a retrospective, case-control study based on data from a prospectively collected hospital-based stroke registry (Korea University Stroke Registry). A total of 3,025 patients who were admitted with a diagnosis of first-ever ischemic stroke within 5 days of symptom onset were included. Stroke severity was measured with the NIH Stroke Scale (NIHSS). NIHSS score ≤4 at admission was categorized as mild stroke. Patients from the PA group were matched with those from the non-PA group using estimated propensity scores at a 1:1 ratio. Stepwise multivariable logistic regression analyses were performed on patients in the matched datasets with initial mild stroke.Results:Patients' mean age was 66.3 ± 13.0 years, and 1,850 were men (61.5%). A total of 748 patients had been taking antiplatelet agents prior to stroke onset; 644 patients (86.1%) were taking a single antiplatelet agent. Among these agents, aspirin (83.7%) was the most common. A total of 102 patients (13.6%) were taking 2 antiplatelet agents. Multivariable analysis after propensity score matching demonstrated that PA use was associated with initial mild stroke (odds ratio 1.344; 95% confidence interval 1.014–1.782).Conclusions:PA use was associated with decreased first-ever stroke severity, suggesting that it has a beneficial effect.Classification of evidence:This study provides Class II evidence that prestroke use of antiplatelet agents reduces stroke severity in patients with first-ever acute ischemic stroke.

Background and Purpose— The aim of this study was to determine the association between 25-hydroxyvitamin D (25(OH)D) and neuroimaging correlates of cerebral small vessel disease. Methods— We identified 759 consecutive patients with acute ischemic stroke or transient ischemic attack. Lacunes, white matter hyperintensity, and cerebral microbleed (CMB) were assessed using MR images. Deep CMB was defined as the presence of CMB in basal ganglia, thalamus, or brain stem. The association between 25(OH)D and small vessel disease was tested using linear and logistic regression analyses. Results— Mean age was 68 (±13) years. Mean level of 25(OH)D was 34.1±17.8 nmol/L. On bivariate analysis, a 25-nmol/L decrease in 25(OH)D was associated with lacunes (regression coefficient, 0.23; 95% confidence interval [CI], 0.02–0.45), severe white matter hyperintensity (odds ratio, 2.05; 95% CI, 1.41–3.08), and deep CMB (odds ratio, 1.28; 95% CI, 1.01–1.63). Also, 25(OH)D deficiency (≤25 nmol/L) was associated with lacunes (regression coefficient, 0.5; 95% CI, 0.04–0.95), severe white matter hyperintensity (odds ratio, 2.74; 95% CI, 1.31–6.45), and deep CMB (odds ratio, 1.68; 95% CI, 1.03–2.78). The association remained significant even after multivariable adjustment and in the subgroup of previously healthy patients. Conclusions— 25(OH)D is inversely associated with lacunes, white matter hyperintensity, and deep CMB. Our findings suggest that 25(OH)D is linked to small vessel disease, and in future trials it should be tested whether 25(OH)D supplementation can prevent small vessel disease.

We attempted to determine the propensity for sidedness of cardiogenic emboli associated with atrial fibrillation (AF) by comparing the sides on which microembolic signals (MES) were detected via transcranial Doppler (TCD) monitoring and the location of infarcts on magnetic resonance imaging.Patients with AF on Holter monitoring and MES on TCD monitoring were selected from an ischemic stroke registry. Patients with prosthetic valves or cerebral/carotid artery stenosis were excluded.By TCD monitoring of 30 patients, 78 MES were detected: 47 on the right and 31 on the left side (60.3% vs. 39.7%, p0.01, chi-square test). Among 21 patients who had middle or anterior cerebral artery (MCA/ACA) territory infarcts, 16 had right-side-dominant infarcts and 5 patients had left-side-dominant infarcts (76.2% vs. 23.8%, p0.01, chi-square test). The median infarct volume on the right side was 16.2 (3.18-75.4) ml, while that of left side was 1.2 (0.25-5.05) ml (p0.01, Mann-Whitney U test).This study demonstrated the existence of a right-side propensity of cardiogenic emboli and the larger infarct volume of right-side MCA/ACA stroke in patients with AF. These results can be attributed to anatomical differences between the innominate and the left common carotid artery.

BackgroundGlycogen phosphorylase is the key enzyme that breaks down glycogen to yield glucose-1-phosphate in order to restore depleted energy stores during cerebral ischaemia. We sought to determine whether plasma levels of glycogen phosphorylase BB (GPBB) isoform increased in patients with acute ischaemic stroke (AIS).MethodsWe studied plasma GPBB levels within 12 hours and again at 48±24 hours of symptom onset in 172 patients with imaging-confirmed AIS and 133 stroke-free individuals. We determined the ability of plasma GPBB to discriminate between cases and controls and examined the predictive value of plasma GPBB for 90-day functional outcome, 90-day survival and acute lesion volumes on neuroimaging.ResultsThe mean (SD) GPBB levels were higher in cases (46.3±38.6 ng/mL at first measurement and 38.6±36.5 ng/mL at second measurement) than in controls (4.1±7.6 ng/mL, pConclusionGPBB demonstrates robust response to acute ischaemia and high sensitivity for small infarcts. If confirmed in more diverse populations that also include stroke mimics, GPBB could find utility as a stand-alone marker for acute brain ischaemia.

Background and Purpose— Ischemic stroke patients often have intracranial atherosclerosis (ICAS), despite heterogeneity in the cause of stroke. We tested the hypothesis that ICAS burden can independently reflect the risk of long-term vascular outcome. Methods— This was a retrospective cohort study analyzing data from a prospective stroke registry enrolling consecutive patients with acute ischemic stroke or transient ischemic attack. A total of 1081 patients were categorized into no ICAS, single ICAS, and advanced ICAS (ICAS ≥2 different intracranial arteries) groups. Primary and secondary end points were time to occurrence of recurrent ischemic stroke and composite vascular outcome, respectively. Study end points by ICAS burden were compared using Cox proportional hazards models in overall and propensity-matched patients. Results— ICAS was present in 405 patients (37.3%). During a median 5-year follow-up, recurrent stroke and composite vascular outcome occurred in 6.8% and 16.8% of patients, respectively. As the number of ICAS increased, the risk for study end points increased after adjustment of potential covariates (hazard ratio per 1 increase in ICAS, 1.19; 95% confidence interval, 1.01–1.42 for recurrent ischemic stroke and hazard ratio, 1.18; 95% confidence interval, 1.05–1.33 for composite vascular outcome). The hazard ratios (95% confidence interval) for recurrent stroke and composite vascular outcome in patients with advanced ICAS compared with those without ICAS were 1.56 (0.88–2.74) and 1.72 (1.17–2.53), respectively, in the overall patients. The corresponding values in the propensity-matched patients were 1.28 (0.71–2.30) and 1.95 (1.27–2.99), respectively. Conclusions— ICAS burden was independently associated with the risk of subsequent composite vascular outcome in patients with ischemic stroke. These findings suggest that ICAS burden can reflect the risk of long-term vascular outcome.

IMPORTANCE The ability of present-day etiologic stroke classification systems to generate subtypes with discrete stroke characteristics is not known. OBJECTIVE To test the hypothesis that etiologic stroke subtyping identifies different disease processes that can be recognized through their different clinical courses. DESIGN, SETTING, AND PARTICIPANTS We performed a head-to-head evaluation of the ability of the Causative Classification of Stroke (CCS), Trial of Org 10172 in Acute Stroke Treatment (TOAST), and ASCO (A for atherosclerosis, S for small-vessel disease, C for cardiac source, and O for other cause) classification systems to generate etiologic subtypes with different clinical, imaging, and prognostic characteristics in 1816 patients with ischemic stroke. This study included 2 cohorts recruited at separate periods; the first cohort was recruited between April 2003 and June 2006 and the second between June 2009 and December 2011. Data analysis was performed between June 2014 and May 2016. MAIN OUTCOMES AND MEASURES Separate teams of stroke-trained neurologists performed CCS, TOAST, and ASCO classifications based on information available at the time of hospital discharge. We assessed the association between etiologic subtypes and stroke characteristics by computing receiver operating characteristic curves for binary variables (90-day stroke recurrence and 90-day mortality) and by calculating the ratio of between-category to within-category variability from the analysis of variance for continuous variables (admission National Institutes of Health Stroke Scale score and acute infarct volume). RESULTS Among the 1816 patients included, the median age was 70 years (interquartile range, 58-80 years) (830 women [46%]). The classification systems differed in their ability to assign stroke etiologies into known subtypes; the size of the undetermined category was 33% by CCS, 53% by TOAST, and 42% by ASCO (P < .001 for all binary comparisons). All systems provided significant discrimination for the validation variables tested. For the primary validation variable (90-day recurrence), the area under the receiver operating characteristic curve was 0.71 (95% CI, 0.66-0.75) for CCS, 0.61 (95% CI, 0.56-0.67) for TOAST, and 0.66 (95% CI, 0.60-0.71) for ASCO (P = .01 for CCS vs ASCO; P < .001 for CCS vs TOAST; P = .13 for ASCO vs TOAST). The classification systems exhibited similar discrimination for 90-day mortality. For admission National Institutes of Health Stroke Scale score and acute infarct volume, CCS generated more distinct subtypes with higher between-category to within-category variability than TOAST and ASCO. CONCLUSIONS AND RELEVANCE Our findings suggest that the major etiologic stroke subtypes are distinct categories with different stroke characteristics irrespective of the classification system used to identify them. We further show that CCS generates discrete etiologic categories with more diverse clinical, imaging, and prognostic characteristics than either TOAST or ASCO.

Background Anticoagulation effectively prevents cardioembolic stroke in atrial fibrillation (AF) patients, whereas it is less effective than antiplatelet therapy (AT) in noncardioembolic stroke prevention. We hypothesized that the ischemic lesion pattern and vascular patency would differ according to the antithrombotic treatment status in AF patients. Methods The medical records of 1078 acute ischemic stroke patients with AF were retrospectively reviewed. Patients were classified according to medication at stroke onset: (1) optimal anticoagulation (OAC; international normalized ratio [INR] 1.7-3.0; n = 36); (2) suboptimal anticoagulation (SOAC; INR ≤1.7; n = 134); (3) AT (n = 285); and (4) control (no antithrombotic medication; n = 623). Imaging and clinical variables of each group were compared with that of controls. Results Small cortical or single subcortical infarctions were more common in the OAC group than in controls (6% vs. 1% and 22% vs. 8%, respectively; standardized residual, 2.4 and 2.8). Multicirculatory infarctions were less common in the OAC group than in controls (0% vs. 11%; standardized residual, −2.0). Obstruction of the corresponding artery was less common in the OAC group than in controls (26.5% vs. 46.5%, P = .02). Initial neurologic severity was lower in the OAC and AT groups than in controls (P = .01 and .03, respectively). OAC and AT were independently associated with favorable functional outcome at 3-months (P = .015 and Conclusions Ischemic stroke can occur during OAC in AF patients. Small cortical or single subcortical lesions were more common than typical cardioembolic lesion patterns. OAC and AT were protective against severe neurologic deficit and independently associated with favorable outcome, but SOAC was not.

Background and Purpose— The integrity of white matter tracts connecting different parts of the brain is important for rapid compensation for the lost function from ischemic stroke. Impaired white matter reserve capacity secondary to leukoaraiosis may facilitate detection of new symptomatic ischemic events that would otherwise remain inconspicuous after an initial ischemic stroke. We sought to identify whether the extent of leukoaraiosis was a predictor of risk of early stroke recurrence. Methods— We used Cox regression analysis in consecutive patients with ischemic stroke to determine the relationship between leukoaraiosis burden and symptomatic stroke recurrence within 90 days. We graded total leukoaraiosis, periventricular leukoaraiosis, and subcortical leukoaraiosis using the Fazekas scale as mild ( Results —There were 106 recurrent events in 2378 patients. The cumulative incidence of recurrence was 5.9% at 90 days. Kaplan–Meier estimate of recurrence-free survival rate was lower in patients with extensive leukoaraiosis ( P =0.04) and extensive periventricular leukoaraiosis ( P =0.02) but not in extensive subcortical leukoaraiosis ( P =0.09). Multivariable Cox regression analysis revealed a hazard ratio of 1.50 (95% confidence interval, 1.00–2.25) for extensive leukoaraiosis, 1.67 (95% confidence interval, 1.11–2.51) for extensive periventricular leukoaraiosis, and 1.42 (95% confidence interval, 0.94–2.12) for extensive subcortical leukoaraiosis. Conclusions— The extent of leukoaraiosis independently predicts 90-day recurrent stroke risk after ischemic stroke. This suggests that leukoaraiosis may be used for risk stratification in ischemic stroke.

Background/Aims: An increase in the pulsatility index (PI) has been suggested to reflect distal vascular resistance. The purpose of the present study was to investigate the association between intracranial arterial calcification and intracranial PIs. Methods: Consecutive patients with acute ischemic stroke or transient ischemic attack were included. The PIs of both middle cerebral arteries (MCAs) were measured by transcranial Doppler ultrasonography. Intracranial carotid artery calcification (ICAC) was assessed on computed tomography angiography, and then compared with the mean PI of both MCAs. Patients with internal carotid artery steno-occlusion were excluded from this study. Results: A total of 156 patients were finally enrolled. The prevalence of diabetes increased as the PI value increased (p for trends; p = 0.025). PI was correlated with ICAC score (r = 0.413, p < 0.001) and age (r = 0.507, p < 0.001). Multiple linear regression analysis indicated that aging and ICAC were independent determinants of the PI of MCA after adjusting for sex, systolic blood pressure, smoking, and the presence of diabetes. Conclusions: This study shows that an increase in PI was correlated with the severity of ICAC, which suggests calcification-related vascular resistance might have a role in the elevation of PI.

Background and Purpose— In patients with acute ischemic stroke caused by large artery atherosclerosis, clopidogrel plus aspirin versus aspirin alone might be more effective to prevent recurrent cerebral ischemia. However, there is no clear evidence. Methods— In this multicenter, double-blind, placebo-controlled trial, we randomized 358 patients with acute ischemic stroke of presumed large artery atherosclerosis origin within 48 hours of onset to clopidogrel (75 mg/d without loading dose) plus aspirin (300-mg loading followed by 100 mg/d) or to aspirin alone (300-mg loading followed by 100 mg/d) for 30 days. The primary outcome was new symptomatic or asymptomatic ischemic lesion on magnetic resonance imaging within 30 days. Secondary outcomes were 30-day functional disability, clinical stroke recurrence, and composite of major vascular events. Safety outcome was any bleeding. Results— Of 358 patients enrolled, 334 (167 in each group) completed follow-up magnetic resonance imaging. The 30-day new ischemic lesion recurrence rate was comparable between the clopidogrel plus aspirin and the aspirin monotherapy groups (36.5% versus 35.9%; relative risk, 1.02; 95% confidence interval, 0.77–1.35; P =0.91). Of the recurrent ischemic lesions, 94.2% were clinically asymptomatic. There were no differences in secondary outcomes between the 2 groups. Any bleeding were more frequent in the combination group than in the aspirin monotherapy group, but the difference was not significant (16.7% versus 10.7%; P =0.11). One hemorrhagic stroke occurred in the clopidogrel plus aspirin group. Conclusions— Clopidogrel plus aspirin might not be superior to aspirin alone for preventing new ischemic lesion and clinical vascular events in patients with acute ischemic stroke caused by large artery atherosclerosis. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00814268.