Total small vessel disease score and functional outcomes following acute intracerebral hemorrhage.

BACKGROUND: Individual cerebral small vessel disease (SVD) markers are independent predictors for poor prognosis following intracerebral hemorrhage (ICH), however, the impact of the cumulative SVD burden on outcomes remains unclear. We aimed to investigate the association between the global SVD burden and functional outcomes following ICH. METHODS: We retrospectively evaluated a consecutive cohort of patients with ICH who underwent brain magnetic resonance imaging and magnetic resonance angiography, from a prospective registry. We identified the presence and severity of the SVD markers (cerebral microbleeds, lacunar infarctions, periventricular hyperintensities, and deep white matter hyperintensities) and summed them to obtain the modified total SVD score (0-4). Poor functional outcomes were defined as a modified Rankin Scale score at discharge ≥ 3. A multivariate logistic regression model was used to assess the association between patient outcomes and the SVD score. RESULTS: A total of 144 patients were included (65.0 ± 12.2 years, 67.4% male). The modified total SVD score was potentially associated with poor functional outcomes (odds ratio [OR] 1.72, 95% confidence interval [CI] 0.97-3.03) after adjustment for age, sex, history of stroke, chronic kidney disease, prior use of antithrombotic agents, the National Institutes of Health Stroke Scale score on admission, the non-lobar location of ICH, and hematoma volume on admission. Moreover, among older patients (≥ 65 years), the SVD score was associated with poor outcomes (OR 3.11, 95% CI 1.01-9.55). Among those with supratentorial ICH, the score remained significant (OR 2.06, 95% CI 1.11-3.83). CONCLUSIONS: The modified total SVD score may have predictive value for poor functional outcomes following ICH.

Cortical Cerebral Microinfarcts on 3T Magnetic Resonance Imaging in Patients With Carotid Artery Stenosis.

Background and Purpose- Carotid artery stenosis is common in the elderly and contributes to cognitive impairment and dementia. Cortical cerebral microinfarcts (CMIs) play an important role in vascular cognitive impairment and dementia. We aimed to investigate the association between CMIs on 3T magnetic resonance imaging and clinical and radiological features, including plaque morphology, and cognitive function in patients with carotid stenosis. Methods- Eighty-nine patients with >30% carotid stenosis on ultrasound were prospectively enrolled, and underwent brain and carotid artery magnetic resonance imaging. CMIs were rated according to predetermined criteria based on 3D-double inversion recovery and fluid-attenuated inversion recovery images. Results- CMIs were identified in 26 patients (29%; median number 0, range 0-9). Poisson regression models adjusted for age and sex revealed that CMIs were associated with intraplaque hemorrhage (rate ratio, 1.95; 95% CI, 1.26-3.18), lacunar infarcts (rate ratio, 1.54; 95% CI, 1.00-2.44), and cortical infarcts (rate ratio, 3.22; 95% CI, 2.20-5.00). These associations were also observed in asymptomatic patients (n=64). Of 81 patients with unilateral carotid stenosis, the prevalence and number of CMIs were significantly higher in the hemisphere ipsilateral to the carotid stenosis than in the contralateral hemisphere ( P=0.005 and P<0.001, respectively). The presence of CMIs was associated with poor cognitive function. Conclusions- Our results indicate that vulnerable carotid plaque increases the risk of CMIs and subsequent cognitive impairment. Carotid atherosclerosis could be a potential therapeutic target for cognitive impairment.

Anterior Cerebral Artery Dissection in a Patient With Autosomal Dominant Polycystic Kidney Disease.

Intracranial artery dissection secondary to autosomal dominant polycystic kidney disease is far less common than cerebral aneurysm. A 55-year-old man presented a sudden onset of headache and disturbed consciousness caused by ischemic stroke in the bilateral frontal lobes with minor subarachnoid hemorrhage. The bilateral anterior cerebral arteries were firstly occluded and re-perfused with irregular narrowing and dilation in 3 days after stroke onset, indicating dissection. He was diagnosed with autosomal dominant polycystic kidney disease by abdominal CT findings and by his family history though his renal function was almost normal. Dissection in the anterior cerebral artery has not been reported previously, while some cases with dissection in the vertebral and extracranial arteries were reported in autosomal dominant polycystic kidney disease. His family also had a history of aortic dissection and subarachnoid hemorrhage. Intracranial artery dissection may be a manifestation of systemic arteriopathy with familial clustering in autosomal dominant polycystic kidney disease. Strict antihypertensive treatment is needed in these cases.

Associations between Pre-Admission Risk Scores and Two-Year Clinical Outcomes in Ischemic Stroke or Transient Ischemic Attack Patients with Non-Valvular Atrial Fibrillation.

BACKGROUND: We aimed to clarify associations between pre-admission risk scores (CHADS2, CHA2DS2-VASc, and HAS-BLED) and 2-year clinical outcomes in ischemic stroke or transient ischemic attack (TIA) patients with non-valvular atrial fibrillation (NVAF) using a prospective, multicenter, observational registry. METHODS: From 18 Japanese stroke centers, ischemic stroke or TIA patients with NVAF hospitalized within 7 days after onset were enrolled. Outcome measures were defined as death/disability (modified Rankin Scale score ≥3) at 2 years, 2-year mortality, and ischemic or hemorrhagic events within 2 years. RESULTS: A total of 1,192 patients with NVAF (527 women; mean age, 78 ± 10 years), including 1,141 ischemic stroke and 51 TIA, were analyzed. Rates of death/disability, mortality, and ischemic or hemorrhagic events increased significantly with increasing pre-admission CHADS2 (p for trend <0.001 for death/disability and mortality, p for trend = 0.024 for events), CHA2DS2-VASc (p for trend <0.001 for all), and HAS-BLED (p for trend = 0.004 for death/disability, p for trend <0.001 for mortality, p for trend = 0.024 for events) scores. Pre-admission CHADS2 (OR per 1 point, 1.52; 95% CI 1.35-1.71; p <0.001 for death/disability; hazard ratio (HR) per 1 point, 1.23; 95% CI 1.12-1.35; p <0.001 for mortality; HR per 1 point, 1.14; 95% CI 1.02-1.26; p = 0.016 for events), CHA2DS2-VASc (1.55, 1.41-1.72, p < 0.001; 1.21, 1.12-1.30, p < 0.001; 1.17, 1.07-1.27, p < 0.001; respectively), and HAS-BLED (1.33, 1.17-1.52, p < 0.001; 1.23, 1.10-1.38, p < 0.001; 1.18, 1.05-1.34, p = 0.008; respectively) scores were independently associated with all outcome measures. CONCLUSIONS: In ischemic stroke or TIA patients with NVAF, all pre-admission risk scores were independently associated with death/disability at 2 years and 2-year mortality, as well as ischemic or hemorrhagic events within 2 years.

Two-Year Outcomes of Anticoagulation for Acute Ischemic Stroke With Nonvalvular Atrial Fibrillation　- SAMURAI-NVAF Study.

BACKGROUND: We determined the 2-year long-term risk-benefit profile in patients with stroke or transient ischemic attack (TIA) receiving warfarin or direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF) using a prospective, multicenter, observational registry in Japan.Methods and Results:NVAF patients within 7 days after onset of ischemic stroke/TIA were enrolled in 18 stroke centers. Outcome measures included ischemic and bleeding events and death in the 2-year follow-up period. We enrolled 1,116 patients taking either warfarin (650 patients) or DOACs (466 patients) at acute hospital discharge. DOAC users were younger and had lower National Institutes of Health Stroke Scale, CHADS2and discharge modified Rankin Scale scores than warfarin users (P<0.0001 each). Incidences of stroke/systemic embolism (adjusted hazard ratio, 1.07; 95% CI, 0.66-1.72), all ischemic events (1.13; 0.72-1.75), and ischemic stroke/TIA (1.58; 0.95-2.62) were similar between groups. Risks of intracranial hemorrhage (0.32; 0.09-0.97) and death (0.41; 0.26-0.63) were significantly lower for DOAC users. Infection was the leading cause of death, accounting for 40% of deaths among warfarin users. CONCLUSIONS: Stroke/TIA patients receiving DOACs for secondary prevention were younger and had lower stroke severity and risk indices than those receiving warfarin. Estimated cumulative incidences of stroke and systemic embolism within 2 years were similar between warfarin and DOACs users, but those of death and intracranial hemorrhage were significantly lower among DOAC users.

Detection of Left Ventricular Thrombus by Cardiac Magnetic Resonance in Embolic Stroke of Undetermined Source.

BACKGROUND AND PURPOSE: We aimed to use contrast-enhanced cardiac magnetic resonance (CE-CMR) imaging to elucidate the prevalence of left ventricular (LV) thrombus in patients suspected of embolic stroke of undetermined source (ESUS) with previous myocardial infarction or LV dysfunction (LV ejection fraction [LVEF] <50%). METHODS: We prospectively investigated 797 consecutive patients who presented to our hospital with acute ischemic stroke between 2014 and 2015. Patients with myocardial infarction or LVEF<50% underwent CE-CMR imaging. ESUS was diagnosed according to proposal criteria based on transthoracic echocardiography findings. RESULTS: The prevalence of ESUS was 22% (178 of 797) on initial diagnosis. Among 60 patients with myocardial infarction or LVEF<50%, the stroke subtypes were as follows: small artery disease, 17% (10 of 60); large artery atherosclerosis, 5% (3 of 60); cardioembolic stroke, 49% (29 of 60); ESUS, 23% (14 of 60); and undetermined causes other than ESUS, 6% (4 of 60). Of 60 patients examined via CE-CMR, LV thrombus was confirmed in 12 patients, whereas only 1 had been detected on transthoracic echocardiography (P=0.04). Importantly, 29% (4 of 14) of patients with ESUS had LV thrombus. A prediction model based on CE-CMR findings showed higher performance in LV thrombus detection, permitting a net improvement of 0.46 (95% confidence interval, 0.08-0.82; P=0.016) in cardioembolic stroke reclassification. Compared with patients without LV thrombus, those with LV thrombus had lower LVEF (median: 26% versus 40%; P=0.003). Notably, 42% (5 of 12) of patients with LV thrombus had LVEF≥30%. CONCLUSIONS: When ESUS-suspected patients have myocardial infarction or LV dysfunction, CE-CMR may help improve detection of cardioembolic stroke and provide relevant information for anticoagulation therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02251665.

Recurrent Stroke Due to Metastatic Pulmonary Tumor Emboli as an Important Clinical Entity.

We present an autopsy case of repetitive stroke due to tumor emboli, indistinguishable from thromboembolism with a hypercoagulable state in its clinical course. A 72-year-old man diagnosed with stage IVA oropharyngeal squamous cell carcinoma received chemoradiotherapy. Follow-up imaging revealed mediastinal lymph nodes and pulmonary metastasis. One year later, the patient experienced right arm weakness, and brain magnetic resonance imaging showed acute ischemic lesions in multiple vascular territories. He was diagnosed with paradoxical cerebral embolism due to cancer-associated venous thrombosis and treated with rivaroxaban. However, newly developed cerebral infarcts were confirmed 1 month later. Then, rivaroxaban treatment was switched to subcutaneous unfractionated heparin injection. He was admitted again for stroke recurrence and died of respiratory failure 8 days after admission. Autopsy demonstrated pulmonary metastasis invading the veins and tumor emboli in the culprit cerebral arteries. D-dimer was kept constant at a slightly higher level, ranging from 1 to 3 µg/mL during the course of recurrence. We should consider tumor embolism in the differential diagnosis of recurrent stroke along with pulmonary tumor and resistance to heparin preparations with unchanged D-dimer levels.

Intravenous nicardipine dosing for blood pressure lowering in acute intracerebral hemorrhage: the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-Intracerebral Hemorrhage study.

BACKGROUND: Intravenous nicardipine is commonly used to reduce elevated blood pressure in acute intracerebral hemorrhage (ICH). We determined factors associated with nicardipine dosing and the association of dose with clinical outcomes in hyperacute ICH. METHODS: Hyperacute (<3 hours from onset) ICH patients with initial systolic blood pressure (SBP) greater than 180 mm Hg were included. All patients initially received 5 mg/hour of intravenous nicardipine. The dose was adjusted to maintain SBP between 120 and 160 mm Hg. Associations of maximum hourly and total doses with early neurologic deterioration (END), hematoma expansion (>33%), and modified Rankin Scale score 4-6 at 3 months were assessed. RESULTS: Two hundred six patients (81 women, 65.8 ± 11.8 years) were studied. Initial SBP was 201.9 ± 15.9 mm Hg. Maximum and total nicardipine doses were 9.1 ± 4.2 mg/hour and 123.7 ± 100.2 mg/day, respectively. Multivariate analyses revealed that men (standardized regression coefficient [ß] = .20, P = .0030 for maximum dose; ß = .25, P = .0002 for total dose), age (ß = -.28, P = .0002; ß = -.25, P = .0005), and initial SBP (ß = .19, P = .0018; ß = .18, P = .0021) were independently associated with both maximum and total doses. Body weight (ß = .20, P = .0084) was independently associated with total dose. After multivariate adjustment, maximum dose (per 1 mg/hour; odds ratio [OR], 1.25; 95% confidence interval [CI], 1.09-1.45) was independently, and total dose (per 10 mg/day; OR, 1.06; 95% CI, .998-1.132) tended to be independently, associated with END. Nicardipine dose was not associated with hematoma expansion or 3-month outcome. CONCLUSIONS: Nicardipine dose is roughly predictable with sex, age, body weight, and initial SBP in acute ICH. The maximum dose was associated with neurologic deterioration.

Low left atrial volume is an independent predictor of persistent hypotension after carotid artery stenting.

BACKGROUND: Persistent hypotension (PH) after carotid artery stenting (CAS) is a relatively common complication; however, it is unclear which patients are more likely to experience this phenomenon. Recently, lower left atrial (LA) volume was associated with vasovagal syncope, which has a similar neurological mechanism to hypotension after CAS. This study aimed to investigate whether LA volume can predict PH after CAS. METHODS: This single center retrospective analysis used data from 316 patients who had undergone CAS between March 2013 and February 2021. After the exclusion of urgent CAS, 212 procedures (202 patients) with transthoracic echocardiograms were included. The procedures were divided among two groups according to the presence or absence of PH for more than 1 hour after CAS. RESULTS: The mean age of the patients was 73.0±7.5 years. PH was observed during 52 (24.5%) procedures. The PH group exhibited a lower LA volume index (LAVI) than the no-PH group (29.7±9.1 vs 37.7±12.5 mL/m2, respectively; p<0.001). The area under the receiver operating characteristic curve was 0.716. The optimal cut-off value was 33.5 mL/m2 (sensitivity 0.750, specificity 0.625). Multiple logistic regression analysis showed that LAVI <33.5 mL/m2 was an independent predictor for PH after CAS (OR 4.950, 95% CI 2.190 to 11.200; p<0.001). Preoperative hydration was negatively associated with PH (OR 0.235, 95% CI, 0.070 to 0.794; p=0.020). CONCLUSIONS: A lower LA volume can predict PH after CAS, and preoperative hydration may prevent PH after CAS.

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

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

Paraneoplastic Cerebellar Degeneration and Lambert-Eaton Myasthenic Syndrome Associated with Neuroendocrine Carcinoma of the Oropharynx.

Paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome (PCD-LEMS) are usually associated with small-cell lung carcinoma (SCLC). PCD-LEMS with extrapulmonary non-SCLC tumors; however, has not been previously reported. A 78-year-old man presented with dysarthria, dysphagia, staggering gait, and lower extremity muscle fatigue. He was diagnosed with PCD-LEMS associated with neuroendocrine carcinoma of the oropharynx, based on the histological findings of the biopsy, the existence of antibodies against P/Q-type voltage-gated calcium channels, and an incremental response of the compound muscle action potentials during repetitive nerve stimulation tests. Thus, PCD-LEMS should be included in the differential diagnosis of neurological dysfunction, even in extrapulmonary non-SCLC patients.

Ischemic stroke in cancer patients treated with direct oral anticoagulants for venous thromboembolism.

Direct oral anticoagulants (DOACs) are at least as efficacious as conventional anticoagulation therapy for the initial and long-term treatment of cancer patients with venous thromboembolism (VTE). Whether DOACs are non-inferior to low-molecular-weight heparin for the management of cancer patients with VTE is under investigation. In addition, the efficacy of DOACs for the treatment of cancer patients with arterial thrombosis (e.g., ischemic stroke) remains unclear. Herein, we report on two cancer patients admitted to our hospital with Stage IV gastric adenocarcinoma who were being treated with DOACs due to a history of VTE and had developed their first ever ischemic stroke, which was diagnosed due to cancer-related hypercoagulation. Notably, neither patient had recurrence of VTE during the course of their disease. In cancer-related thrombosis, DOACs effectively reduce VTE, but may be insufficient for preventing ischemic stroke.

Three-month risk-benefit profile of anticoagulation after stroke with atrial fibrillation: The SAMURAI-Nonvalvular Atrial Fibrillation (NVAF) study.

AIMS: This study was performed to determine the short-term risk-benefit profiles of patients treated with oral anticoagulation for acute ischemic stroke or transient ischemic attack using a multicenter, prospective registry. METHODS: A total of 1137 patients (645 men, 77 ± 10 years old) with acute ischemic stroke/transient ischemic attack taking warfarin (662 patients) or non-vitamin K antagonist oral anticoagulants (dabigatran in 205, rivaroxaban in 245, apixaban in 25 patients) for nonvalvular atrial fibrillation who completed a three-month follow-up survey were studied. Choice of anticoagulants was not randomized. Primary outcome measures were stroke/systemic embolism and major bleeding. RESULTS: Both warfarin and non-vitamin K antagonist oral anticoagulants were initiated within four days after stroke/transient ischemic attack onset in the majority of cases. Non-vitamin K antagonist oral anticoagulant users had lower ischemia- and bleeding-risk indices (CHADS2, CHA2DS2-VASc, HAS-BLED) and milder strokes than warfarin users. The three-month cumulative rate of stroke/systemic embolism was 3.06% (95% CI 1.96%-4.74%) in warfarin users and 2.84% (1.65%-4.83%) in non-vitamin K antagonist oral anticoagulant users (adjusted HR 0.96, 95% CI 0.44-2.04). The rate of major bleeding was 2.61% (1.60%-4.22%) and 1.11% (0.14%-1.08%), respectively (HR 0.63, 0.19-1.78); that for intracranial hemorrhage was marginally significantly lower in non-vitamin K antagonist oral anticoagulant users (HR 0.17, 0.01-1.15). Major bleeding did not occur in non-vitamin K antagonist oral anticoagulant users with a CHADS2 score <4 or those with a discharge modified Rankin Scale score ≤2. CONCLUSIONS: Stroke or systemic embolism during the initial three-month anticoagulation period after stroke/transient ischemic attack was not frequent as compared to previous findings regardless of warfarin or non-vitamin K antagonist oral anticoagulants were used. Intracranial hemorrhage was relatively uncommon in non-vitamin K antagonist oral anticoagulant users, although treatment assignment was not randomized. Early initiation of non-vitamin K antagonist oral anticoagulants during the acute stage of stroke/transient ischemic attack in real-world clinical settings seems safe in bleeding-susceptible Japanese population.