Overview and Future Direction of Embolic Stroke of Undetermined Source from the Insights of CHALLENGE ESUS/CS Registry.

Cryptogenic stroke (CS) accounts for approximately one-fourth of acute ischemic strokes, with most cases derived from embolic etiologies. In 2014, embolic stroke of undetermined source (ESUS) was advocated and the efficacy of anticoagulant therapy was anticipated. However, 3 large-scale clinical trials failed to demonstrate the superiority of direct oral anticoagulants (DOACs) over aspirin, potentially due to the heterogeneous and diverse pathologies of ESUS, including paroxysmal atrial fibrillation (AF), arteriogenic sources such as nonstenotic carotid plaque and aortic complicated lesion (ACL), patent foramen oval (PFO), and nonbacterial thrombotic endocarditis (NBTE) related to active cancer.Transesophageal echocardiography (TEE) is one of the most effective imaging modalities for assessing embolic sources in ESUS and CS. The Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for Embolic Stroke of Undetermined Source/Cryptogenic Stroke (CHALLENGE ESUS/CS) registry is a multicenter registry that enrolled consecutive patients with CS who underwent TEE at 8 hospitals in Japan between April 2014 and December 2016. Their mean age was 68.7±12.8 years, and 455 patients (67.2%) were male. The median National Institutes of Health Stroke Scale (NIHSS) score was 2. Since 7 analyses have been conducted from each institution to date, novel and significant insights regarding embolic origins and pathophysiologies of ESUS and CS were elucidated from this multicenter registry. This review discusses the diagnosis and treatment of ESUS and CS, tracing their past and future directions. Meaningful insights from the CHALLENGE ESUS/CS registry are also referenced and analyzed.

A Cerebral Embolism Caused by a Malignant Peripheral Nerve Sheath Tumor in a Patient with Neurofibromatosis Type 1.

A 31-year-old man with neurofibromatosis type 1 (NF-1) had undergone resection of a malignant peripheral nerve sheath tumor (MPNST) on the buttock 3 months previously. He subsequently underwent mechanical thrombectomy for a hyperacute left middle cerebral artery embolism. Histopathologically, the emboli comprised neurofilament-positive pleomorphic tumor cells with geographic necrosis and conspicuous mitosis and were identified as MPNST. The patient died of respiratory failure due to lung MPNST metastasis on day 15 of hospitalization. To our knowledge, this is the first report of a spontaneous cerebral embolism due to MPNST in a NF-1 patient.

High-risk patent foramen ovale and elderly in cryptogenic stroke.

BACKGROUND: High-risk patent foramen ovale (PFO) could be pathological in cryptogenic stroke (CS), but its clinical characteristics have not been fully studied, especially in elderly patients. METHODS: Patients with CS were enrolled in the CHALLENGE ESUS/CS registry, a multicenter registry of CS patients undergoing transesophageal echocardiography. Clinical characteristics were compared among three groups: high-risk PFO group, large shunt PFO (≥25 microbubbles) or PFO with atrial septal aneurysm (ASA); right-to-left shunt (RLS) group, RLS including PFO with <25 microbubbles or without ASA; and no-RLS group. RESULTS: In total, 654 patients were analyzed: 91, 221, and 342 in the high-risk PFO, RLS, and no-RLS groups, respectively. In multinomial logistic regression analysis, the male sex (odds ratio [OR] 1.825 [1.067-3.122]) was independently associated with high-risk PFO, but hypertension (OR, 0.562 [0.327-0.967]), multiple infarctions (OR, 0.601 [0.435-0.830]), and other cardioaortic embologenic risks (OR, 0.514 [0.294-0.897]) were inversely associated with high-risk PFO compared with non-RLS. In 517 patients aged ≥60 years, multiple infarctions (OR, 0.549 [0.382-0.788]) and other cardioaortic embologenic risks (OR, 0.523 [0.286-0.959]) were inversely associated with high-risk PFO. CONCLUSIONS: High-risk PFO had specific clinical characteristics and possible mechanistic associations, and this trend was consistent among CS patients aged ≥60 years. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.umin.ac.jp/ctr/ (UMIN000032957).

Evaluating the Potential Pathology and Short-Term Outcomes of Cryptogenic Stroke Using the Etiological Classification System.

AIM: Various embolic sources and pathogenetic mechanisms underlie cryptogenic stroke (CS). We investigated the association of etiological diversity with short-term outcomes in patients with CS using a modified atherosclerosis (A), small-vessel disease (S), cardiac pathology (C), other causes (O), and dissection (D) (ASCOD) system. METHODS: Patients with CS who underwent transesophageal echocardiography were registered in this multicenter, observational study. In the modified classification system, O and D were inapplicable and thus excluded. Instead, atherosclerosis, small-vessel disease, cardiac pathology-CS classification was specifically constructed for the etiological diagnosis of CS. We utilized this system to explore the mechanism of CS by grading each pathology and evaluated its association with poorer modified Rankin Scale scores of 3-6 at hospital discharge. RESULTS: A total of 672 patients (68.7±12.8 years, 220 females) were analyzed. In the multiple logistic regression model, female sex (odds ratio [OR], 1.87 [1.15-3.04]; P =0.012), body mass index (OR, 0.93 [0.88-0.99]; P =0.025), National Institute of Health Stroke Scale score (OR, 1.16 [1.12-1.21]; P＜0.001), CHADS2 score (OR, 1.56 [1.30-1.86]; P＜0.001), D-dimer (OR, 1.04 [1.01-1.08]; P =0.015), diffusion-weighted image (DWI) lesion size (OR, 1.44 [1.10-1.89]; P =0.009), and S＋C score (OR, 1.26 [1.03-1.56]; P =0.029) were associated with poor functional outcome at discharge whereas the S＋C score was marginally associated with poor functional outcome after excluding 137 patients with a premorbid modified Rankin Scale score of ≥ 3. CONCLUSIONS: The coexistence of small-vessel disease and cardiac pathology might be associated with poor in-hospital functional outcome in CS.

Distinction in Prevalence of Atherosclerotic Embolic Sources in Cryptogenic Stroke With Cancer Status.

Background Cerebrovascular diseases are common comorbidities in patients with cancer. Although active cancer causes ischemic stroke by multiple pathological conditions, including thromboembolism attributable to Trousseau syndrome, the relationship between stroke and inactive cancer is poorly known. The aim of this study was to elucidate the different underlying pathogeneses of cryptogenic stroke in active and inactive patients with cancer, with detailed investigation by transesophageal echocardiography. Methods and Results CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for Embolic Stroke of Undetermined Source/Cryptogenic Stroke) registry is a multicenter registry including data of patients initially diagnosed as having cryptogenic stroke and undergoing transesophageal echocardiography. Patients were divided into active cancer, inactive cancer, and noncancer groups, and their clinical features were compared. Of the total 667 enrolled patients (age, 68.7±12.8 years; 455 men), 41 (6.1%) had active cancer, and 51 (7.5%) had a history of inactive cancer. On multinomial logistic regression analysis, infarctions in multiple vascular territories (odds ratio [OR], 2.73; 95% CI, 1.39-5.40) and CRP (C-reactive protein) (OR, 1.10; 95% CI, 1.01-1.19) were independently associated with active cancer, whereas age (OR, 1.05; 95% CI, 1.01-1.08), contralateral carotid stenosis from the index stroke lesion (OR, 4.05; 95% CI, 1.60-10.27), calcification of the aortic valve (OR, 2.10; 95% CI, 1.09-4.05), and complicated lesion of the aortic arch (OR, 2.13; 95% CI, 1.11-4.10) were significantly associated with inactive cancer. Conclusions Patients with cancer were not rare in cryptogenic stroke. Although patients with active cancer had more multiple infarctions, patients with inactive cancer had more atherosclerotic embolic sources potentially causing arteriogenic strokes. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000032957.

Cardiac and Echocardiographic Markers in Cryptogenic Stroke with Incidental Patent Foramen Ovale.

OBJECTIVE: Some cardiac abnormalities could be a substrate for potential embolic source in cryptogenic stroke (CS). We evaluated whether cardiac and echocardiographic markers were associated with CS in patients with incidental patent foramen ovale (PFO) as defined using the Risk of Paradoxical Embolism (RoPE) score. MATERIALS AND METHODS: Among 677 patients enrolled in a multicenter observational CS registry, 300 patients (44%) had PFOs detected by transesophageal echocardiography. They were classified into probable PFO-related stroke (RoPE score>6, n = 32) and stroke with incidental PFO (RoPE score≤6, n = 268) groups, and clinical characteristics, laboratory findings, cardiac and echocardiographic markers (i.e. brain natriuretic peptide, left atrial [LA] diameter, ejection fraction, early transmitral flow velocity/early diastolic tissue Doppler imaging velocity [E/e'], LA appendage flow velocity, spontaneous echo contrast, atrial septal aneurysm, substantial PFO, and aortic arch plaques), stroke recurrence, and excellent outcome (modified Rankin scale score <2) at discharge were compared. Risk factors for low RoPE scores were determined using multiple logistic regression analysis. RESULTS: Higher brain natriuretic peptide levels (p = 0.032), LA enlargement (p < 0.001), higher E/e' (p = 0.001), lower LA appendage flow velocity (p < 0.001), non-substantial PFO (p = 0.021), and aortic arch plaques (p = 0.002) were associated with the low RoPE score group. Patients with high RoPE scores had excellent outcomes (58% versus 78%, p = 0.035). LA enlargement (age- and sex-adjusted odds ratio, 1.15; 95 % confidence interval, 1.00-1.32; p = 0.039) was an independent predictor of low RoPE scores. CONCLUSIONS: Abnormal cardiac substrate could be associated with CS occurrence in a subset of patients with PFO. Patients with CS who had incidental PFO may be at risk of cardioembolism.

Different aspects of early and late development of atrial fibrillation during hospitalization in cryptogenic stroke.

The detection of underlying atrial fibrillation (AF) has become increasingly possible by insertable cardiac monitoring (ICM). During hospitalization for cryptogenic stroke, factors related to the early and late development of AF have not been studied. CHALLENGE ESUS/CS is a multicenter registry of cryptogenic stroke patients undergoing transesophageal echocardiography. Twelve-lead electrocardiogram, continuous cardiac monitoring, and 24-h Holter electrocardiogram were all used for the detection of AF. Early and late detection of AF was determined with an allocation ratio of 1:1 among patients with AF. A total of 677 patients (68.7 ± 12.8 years; 455 men) were enrolled, and 64 patients developed AF during hospitalization. Four days after admission was identified as the approximate median day to classify early and late phases to detect AF: ≤ 4 days, 37 patients; > 4 days, 27 patients. Multiple logistic regression analysis showed that spontaneous echo contrast (SEC) (OR 5.91; 95% CI 2.19-15.97; p < 0.001) was associated with AF ≤ 4 days, whereas a large infarction > 3 cm in diameter (OR 3.28; 95% CI 1.35-7.97; p = 0.009) was associated with AF > 4 days. SEC and large infarctions were important predictors of in-hospital AF detection, particularly in the early and late stages, respectively; thus, they could serve as indications for recommending ICM.

Atrial Fibrillation After Ischemic Stroke Detected by Chest Strap-Style 7-Day Holter Monitoring and the Risk Predictors: EDUCATE-ESUS.

AIM: This study aimed to investigate the diagnostic yield of 7-day Holter monitoring for detecting covert atrial fibrillation (AF) in patients with recent embolic stroke of undetermined source (ESUS) and to identify the pre-entry screening biomarkers that had significant associations with later detection of AF (clinicaltrials.gov. NCT02801708). METHODS: A total of 206 patients who have recent ESUS without previously documented AF underwent Holter electrocardiography using a chest strap-style monitor. External validation of biomarkers predictive of AF was performed using 83 patients with ESUS who were implanted with insertable cardiac monitors. RESULTS: The 7-day Holter monitoring started at a median of 13 days after the onset of stroke. AF was detected in 14 patients, and three of these showed a single AF episode lasting ＜2 min. The median time delay to the first documented AF was 50 h. Each of serum brain natriuretic peptide ≥ 66.0 pg/mL (adjusted odds ratio 5.23), atrial premature contractions (APCs) ≥ 345 beats (3.80), and APC short runs ≥ 13 (5.74) on 24-h Holter prior to the 7-day Holter showed a significant association with detection of AF, independent of age and physiological findings in this derivation cohort, and all of these showed a significant association in the validation cohort (adjusted odds ratio 6.59, 7.87, and 6.16, respectively). CONCLUSIONS: In recent ESUS patients, the detection rate of AF using the 7-day Holter monitoring was 6.8% (95% CI 4.1%-11.1%). Brain natriuretic peptide, APC count, and APC short runs in the standard clinical workup seemed to be predictors of covert AF.

Atrial Septal Aneurysm may Cause In-Hospital Recurrence of Cryptogenic Stroke.

AIMS: Awareness of potentially embologenic diseases is critical to determining the prognosis of cryptogenic stroke. The clinical significance of atrial septal aneurysm (ASA) in cryptogenic stroke has not been fully studied. Therefore, we explored clinical characteristics and in-hospital recurrence in patients with ASA in cryptogenic stroke. METHODS: A multicenter observational registry of cryptogenic stroke patients was conducted. We obtained baseline characteristics, radiological and laboratory findings, and echocardiographic findings, especially of embolic sources on transesophageal echocardiography. The CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for embolic stroke of undetermined source/cryptogenic stroke) registry was recorded at http://www.umin.ac.jp/ctr/ (UMIN000032957). Patients' clinical characteristics were compared according to the presence of ASA, and factors associated with in-hospital stroke recurrence were assessed. RESULTS: The study included 671 patients (age, 68.7±12.7 years; 450 males; median National Institutes of Health Stroke Scale score, 2). ASA was detected in 92 patients (14%), displaying higher age (72.4±11.0 vs. 68.1 ±12.9 years, p=0.004), reduced frequency of diabetes mellitus (16% vs. 27%, p=0.030), higher frequency of right-to-left shunt (66% vs. 45%, p＜0.001), and in-hospital stroke recurrence (8% vs. 3%, p=0.034). ASA was relatively associated with in-hospital recurrence (odds ratio 2.497, 95% confidence interval 0.959-6.500, p= 0.061). CONCLUSIONS: The CHALLENGE ESUS/CS registry indicated that ASA was not rare in cryptogenic stroke, and ASA's clinical characteristics included higher age, reduced frequency of diabetes mellitus, and increased frequency of concomitant right-to-left shunt. ASA may be related to in-hospital stroke recurrence in cryptogenic stroke.

[A Rebleeding Case of Carotid Blowout Syndrome after Endovascular Treatment with Covered Stent].

We present a case of a patient who survived carotid blowout syndrome(CBS)due to covered stent placement, but bled again 34 days later. A 67-year-old man with laryngeal cancer experienced cardiac arrest due to carotid blowout a day after he underwent the balloon occlusion test and abnormal feeder embolization of the tumor. After quick resuscitation, he was treated with endovascular therapy using a covered stent, since he had insufficient cerebral ischemic tolerance. We succeeded in stent placement and the bleeding stopped without any procedural complications. The patient survived after the procedure. However, bleeding recurred when a nasal endoscope was inserted 34 days later. The rupture point was immediately distal of the stent. We performed carotid artery occlusion with coils and n-butyl-cyanoacrylate. The patient survived, but his condition gradually weakened and died 97 days after stenting. Emergency hemostasis for carotid blowout using a covered stent is the only available treatment for patients who do not have sufficient cerebral ischemic tolerance. However, this procedure has a higher rate of re-bleeding than carotid artery occlusion. Moreover, it is an off-label treatment in Japan. Therefore, possible treatments for CBS including use of covered stent or treatments for non-ruptured CBS should be analyzed in the future.

Underlying embolic and pathologic differentiation by cerebral microbleeds in cryptogenic stroke.

BACKGROUND: Cryptogenic stroke encompasses diverse emboligenic mechanisms and pathogeneses. Cerebral microbleeds (CMBs) occur differently among stroke subtypes. The association of CMBs with cryptogenic stroke is essentially unknown. METHODS: CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for ESUS/CS) is a multicenter registry with comprehensive data including gradient-echo T2*-weighted magnetic resonance imaging of cryptogenic stroke patients who underwent transesophageal echocardiography. Patients' clinical characteristics were compared according to the presence and location of CMBs. RESULTS: A total of 661 patients (68.7 ± 12.7 years; 445 males) were enrolled, and 209 (32%) had CMBs. Age (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.00-1.04, p = 0.020), male sex (OR 1.85, 95% CI 1.18-2.91, p = 0.007), hypertension (OR 1.71, 95% CI 1.03-2.86, p = 0.039), chronic kidney disease (OR 1.64, 95% CI 1.11-2.43, p = 0.013), deep and subcortical white matter hyperintensity (OR 1.82, 95% CI 1.16-2.85, p = 0.009), and periventricular hyperintensity (OR 2.18, 95% CI 1.37-3.46, p = 0.001) were independently associated with the presence of CMBs. Aortic complicated lesions (OR 1.78, 95% CI 1.12-2.84, p = 0.015) were associated with deep and diffuse CMBs, whereas prior anticoagulant therapy (OR 7.88, 95% CI, 1.83-33.9, p = 0.006) was related to lobar CMBs. CONCLUSIONS: CMBs were common, and age, male sex, hypertension, chronic kidney disease, and cerebral white matter diseases were related to CMBs in cryptogenic stroke. Aortic complicated lesions were associated with deep and diffuse CMBs, while prior anticoagulant therapy was related to lobar CMBs.

Large aortic arch plaques correlate with CHADS2 and CHA2DS2-VASc scores in cryptogenic stroke.

BACKGROUND AND AIMS: Current trends have suggested covert atrial fibrillation as a mechanism of cryptogenic stroke. However, etiological heterogeneity regarding the underlying embolic sources remains a critical issue in cryptogenic stroke. METHODS: CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for Embolic Stroke of Undetermined Source/Cryptogenic Stroke) is a multicenter observational registry of cryptogenic stroke patients admitted to participating hospitals, who underwent transesophageal echocardiography between April 2014 and December 2016. We obtained baseline characteristics, radiological and laboratory data, and echocardiographic findings, especially for embolic sources demonstrated on transesophageal echocardiography, and conducted comparisons according to CHADS2 and CHA2DS2-VASc scores (0-1 vs. ≥2, respectively). This study was registered at http://www.umin.ac.jp/ctr/(UMIN000032957). RESULTS: The study comprised 677 patients (age, 68.7 ±â€¯12.8 years; 455 males; median National Institutes of Health Stroke Scale score, 2) with cryptogenic stroke. On multiple logistic regression analysis, large aortic arch plaque ≥4 mm (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.51-3.36; p < 0.001), with ulcerative or mobile components (OR, 2.37; 95%CI, 1.38-4.06; p = 0.002), was associated with CHADS2 score ≥2. Large aortic arch plaque ≥4 mm (OR, 3.88; 95%CI, 2.07-7.27; p < 0.001) and ulcerative or mobile components (OR, 3.25; 95%CI, 1.44-7.34; p = 0.005) were linked to CHA2DS2-VASc score ≥2. CONCLUSIONS: The CHALLENGE ESUS/CS registry is a large TEE registry, and clarifies potential embolic etiologies of cryptogenic stroke using TEE. Large aortic arch plaques were associated with high CHADS2 and CHA2DS2-VASc scores, and represented important embolic sources in cryptogenic stroke.

Bilateral Cerebral Infarctions and Intracardiac Thrombus in a Young Duchenne Muscular Dystrophy Patient.

A 31-year-old man with Duchenne muscular dystrophy was admitted to our center, having infarctions in bilateral cerebral hemispheres and an occluded right middle cerebral artery. His right middle cerebral artery was spontaneous recanalization on the next day, and thrombus in the left ventricle vanished on the eighth day after giving warfarin.

[A case of cardiogenic embolism, which occurred under appropriate warfarin use, treated with thoracoscopic left atrial appendectomy].

A 74-year-old man with a past medical history of bradycardiac atrial fibrillation and an old cerebral infarction presented with dysarthria. He had been treated with warfarin and PT-INR on admission was 2.0. MRI of the head revealed an acute ischemic stroke involving the cerebellum and left occipital lobe. Because transesophageal cardiac echography showed a thrombus in the left atrial appendage, anticoagulant treatment with warfarin and heparin was initiated. The thrombus was enlarging; therefore, we changed the anticoagulant therapy to apixaban with heparin on day 11. On day 17, a hemorrhagic cerebral infarction occurred. After the hemorrhage diminished, we treated him with warfarin aiming for a PT-INR between 3 and 4. The thrombus gradually shrank and disappeared on day 110. Finally, a thoracoscopic left atrial appendectomy was performed as a secondary prevention, with no recurrence till date.

Comparison of Characteristics of Stroke-Associated Pneumonia in Stroke Care Units in Indonesia and Japan.

BACKGROUND: Pneumonia is one of the most common medical complications after stroke. Incidence and risk factor analyses of stroke-associated pneumonia (SAP) in stroke care units (SCUs) are limited. SAP incidence comparisons across countries can identify the most effective treatment to reduce this incidence. METHODS: This was a retrospective study including consecutive patients with acute stroke in SCUs in 2 hospitals: 105 patients (mean age 78.2 ± 5.8) from the National Cerebral and Cardiovascular Center (NCVC) in Osaka, Japan (from July to August 2015), and 105 patients (mean age 60 ± 5.8) from the National Brain Centre (NBC) Hospital in Jakarta, Indonesia (from May to September 2015). We used descriptive statistics and a logistic regression model for statistical analysis. RESULTS: The incidence of SAP in the SCU NBC Hospital was higher than that in the SCU NCVC (22.9% versus 12.4%, P = .0466). In the SCU NBC Hospital, dysphagia (odds ratio [OR] 15.20, 95% confidence interval [CI] 1.77-130.73) and severe neurological deficits on admission (OR 5.31, 95% CI 1.60-17.60) were significantly associated with SAP, whereas in the SCU NCVC, dysphagia (OR 14.42, 95% CI 2.34-88.98) and diabetes mellitus (OR 7.16, 95% CI 1.27-40.18) were the risk factors. When the patients of both hospitals were analyzed together, severe neurological deficits on admission (OR 3.36, 95% CI 1.31-8.64) and dysphagia (OR 12.62, 95% CI 3.75-42.45) were significant determinants for developing SAP. CONCLUSIONS: The incidence of SAP was higher in the Indonesian hospital than in the Japanese one. Our findings support other epidemiological data of a high incidence of SAP with severe neurological deficits on admission and dysphagia in an SCU setting.