ARTICLE IN PRESS Case Studies Cerebral Infarcts by Nonbacterial Thrombotic Endocarditis Associated with Adenomyosis: A Case Report Byungseok Kim, MD,* Seong-hoon Kim, MD,† and Taewon Kim, MD, PhD* We report a case of multiple embolic cerebral infarcts associated with nonbacterial thrombotic endocarditis (NBTE) in a patient with adenomyosis. The patient presented with dysarthria, left perioral sensory change, and left-hand weakness. Magnetic resonance imaging revealed multiple vascular territory infarctions involving the bilateral cerebellum and the right precentral gyrus. Magnetic resonance angiography was normal. D-Dimer, carbohydrate antigen (CA) 19-9, and CA125 levels were elevated. Abdominal and pelvic computed tomography with iodine contrast enhancement revealed a huge adenomyosis with left ovarian cyst. Transesophageal echocardiography (TEE) with agitated saline injection test demonstrated shaggy vegetation at the coapting edge of both mitral leaflets and mitral regurgitation. A diagnosis of NBTE was established and treatment with anticoagulation was initiated. Two weeks later, the thrombi reduced significantly on follow-up TEE and transthoracic echocardiography. The patient underwent an abdominal hysterectomy with bilateral salpingo-oophorectomy, and pathological specimens confirmed adenomyosis. The possibility that adenomyosis can be associated with NBTE suggests one of the underlying thromboembolic mechanisms in adenomyosis. Clinicians should be aware of the potential thromboembolic risk of adenomyosis. Further reporting of similar cases is needed to confirm the thromboembolic mechanism. Key Words: Adenomyosis—ischemic stroke—nonbacterial thrombotic endocarditis—anticoagulation. © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved. Introduction Adenomyosis is a condition in which heterotopic endometrial glands and stroma are present in the myometrium accompanied by adjacent smooth muscle hyperplasia. From the *Department of Neurology, College of Medicine, Incheon St Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea; and †Department of Neurology, College of Medicine, Uijeongbu St Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea. Received July 18, 2017; revision received September 29, 2017; accepted October 8, 2017. Address correspondence to Taewon Kim, MD, PhD, Department of Neurology, Incheon St’s Mary’s Hospital, Catholic University of Korea, 665 Bupyeong-6-dong, Bupyeong-gu, Incheon, 403-720, Republic of Korea. E-mail: kimtaewon@catholic.ac.kr. 1052-3057/$ - see front matter © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.10.005 Arterial thromboembolisms, including cerebral arterial infarcts and thrombi in the brachiocephalic trunk and the subclavian artery have been reported in adenomyosis patients.1 In addition to arterial thromboembolism, venous thrombosis manifesting in the cerebral dural venous sinus has also been identified in a patient with adenomyosis.2 Given the widespread systemic thromboembolism with consistent negative results of echocardiography in previous reports, the authors speculate that the underlying mechanism of thromboembolism in adenomyosis is hypercoagulability rather than cardiogenic embolism.1,2 Nonbacterial thrombotic endocarditis (NBTE) is characterized by sterile vegetations composed of platelets and fibrin that adhere to the heart valves and are susceptible to embolization.3,4 Patients with advanced malignancy and patients with systemic lupus erythematosus are the most common populations affected by NBTE,5 but an association with adenomyosis has been reported very rarely.6 Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2017: pp ■■–■■ 1 ARTICLE IN PRESS B. KIM ET AL. 2 Figure 1. Multiple vascular territory infarctions involving the bilateral cerebellum (A, arrows) and the right precentral gyrus (B, arrow) on diffusionweighted brain magnetic resonance imaging. We report a rare case of multiple embolic cerebral infarcts caused by NBTE in a patient with adenomyosis. Case Presentation A 49-year-old woman presented to our hospital with a sudden onset of dysarthria, left perioral sensory change, and left-hand weakness. The woman’s medical history included hypertension currently treated with a calcium channel blocker. She had a history of severe menorrhagia and dysmenorrhea 10 days before admission, which lasted for 4 days. At admission, the patient was not actively menstruating. On admission, the patient’s vital signs were stable without fever. Brain diffusion-weighted magnetic resonance image revealed multiple vascular territory infarctions involving the bilateral cerebellum and the right precentral gyrus (Fig 1, A,B). Magnetic resonance angiography of intracranial and extracranial vessels from the common carotid artery to the circle of Willis demonstrated unremarkable findings. Chest computed tomography angiography with iodine contrast enhancement revealed no abnormal findings such as cancer, pulmonary artery fistula, or thrombus on the aortic arch, the subclavian artery, or the brachiocephalic artery. Abdominal and pelvic computed tomography with contrast enhancement showed a huge adenomyosis with left ovarian cyst (Fig 2), without any filling defect lesion reflecting a venous thrombus in the inferior vena cava or common iliac veins. Hemoglobin level was 9.9 g/dL and the hematocrit level was 30.2%. The D-dimer level was 3.99 µg/mL (normal <1.0 µg/mL). Carbohydrate antigen (CA) 19-9 level was 69.2 U/mL (normal 0-35 U/mL) and CA125 level was 379 U/mL (normal 0-35 U/mL). Other laboratory studies were all normal, including platelet count, prothrombin time, partial thrombin time, antithrombin III level, fluorescent antinuclear antibody (FANA), rheumatoid factor, lupus anticoagulant antibody, anticardiolipin antibody, antineutrophil cytoplasmic antibodies, anti-Sjogren syndrome-related antigen type A or B, human leukocyte antigen (HLA) B27 and HLA B51, complement 3 and C4, C-reactive protein, factors V, VII, and VIII levels, factor Figure 2. Abdominal and pelvic computed tomography with contrast enhancement showed a huge adenomyosis with left ovarian cyst. V, Leiden gene, protein C activity, protein S activity, peripheral blood morphology, and blood culture. Continuous 24-hour electrocardiography Holter monitoring showed unremarkable findings. Transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) with agitated saline injection test demonstrated shaggy vegetation at the coapting edge of both mitral leaflets and mitral regurgitation with no shunts, or patent foramen ovale (PFO) (Fig 3). TEE revealed no thrombus in the left atrium, left atrial appendage, right atrium, or descending thoracic aorta. Based on vegetation ARTICLE IN PRESS NBTE IN ADENOMYOSIS 3 Figure 3. Transesophageal echocardiography demonstrated nodular echodensity indicative of shaggy vegetation (arrows) at the coapting edge of both mitral leaflets at its closed phase (A) and open phase (B). Parasternal short axis views of the transthoracic echocardiography at the level of the mitral valve at its open phase (C), and the M mode of the mitral valve (D). morphology and the clinical context, including lack of fever, negative blood culture, and a huge adenomyosis with elevated D-dimer, CA125, and CA19-9 levels, the diagnosis of NBTE was established. The patient was anticoagulated with enoxaparin and thrombi reduced significantly with improved mitral regurgitation on follow-up TTE and TEE performed 2 weeks later (Fig 4). The D-dimer level also decreased from 3.99 to 1.19 µg/mL. After the confirmation of the significant reduction of thrombi on follow-up TTE and TEE, the patient underwent an abdominal hysterectomy with bilateral salpingo-oophorectomy. Pathological specimens Figure 4. Initial transthoracic echocardiography (A and B) and follow-up transthoracic echocardiography performed 2 weeks later (C and D) demonstrated significantly reduced thrombi (arrows) with improved mitral regurgitation. ARTICLE IN PRESS B. KIM ET AL. 4 confirmed adenomyosis and no malignant findings were observed. The parenteral anticoagulation with enoxaparin was used for 1 month and switched to an oral vitamin K antagonist, which has hitherto been maintained for 3 months without any recurrence of cardioembolic events. Discussion NBTE associated with adenomyosis has been rarely reported. To the best of our knowledge, only 1 case has been reported.6 In the present study, we described another case of adenomyosis presenting with NBTE and multiple embolic infarction. In previous reports regarding adenomyosis and thromboembolism, most cases were arterial embolisms presenting with cerebral ischemic stroke. Some were accompanied by arterial infarcts in the fingers and kidney, as well as thrombi in the brachiocephalic trunk and the subclavian artery.1 Despite the widespread location of arterial embolic infarction and multiple cerebral infarcts in different vascular territories, no cardioembolic sources have been found on echocardiography in these cases. Therefore, the authors concluded that the underlying mechanism of thromboembolism in adenomyosis is hypercoagulability rather than cardiogenic embolism.1,2 The distinct feature of our patient compared with the most previously reported cases was the presence of definite cardioembolic sources presenting with NBTE. Only 1 adenomyosis case presenting with NBTE has been reported.6 In that report, thrombotic vegetation was located at the aortic valve and disappeared 2 weeks after the hysterectomy without any therapy. The possibility that adenomyosis is associated with NBTE suggests an underlying thromboembolic mechanism in adenomyosis that may provide a plausible mechanism for prior reports of stroke in the presence of adenomyosis. Hypercoagulability is not a distinct entity associated with NBTE. Hypercoagulability may be an essential prerequisite for NBTE, and NBTE may therefore be just 1 manifestation of hypercoagulability. We might have merely demonstrated a connecting link between hypercoagulability and multiple embolic infarctions. Our patient had an elevated D-dimer level and markedly elevated levels of CA125 and CA 19-9. These elevated mucinous proteins have been suggested to play a role in the development of cerebral infarcts and hypercoagulability in adenomyosis.7 Most NBTEs are discovered on autopsy and rarely found antemortem because of their small dot-like vegetation size under cardiac valves and also a potential possibility of vegetation to have already detached from the cardiac valve, resulting in cerebral infarction when evaluating with 8-11 echocardiography. A recent study reported that NBTE was detected with TEE in 18% of patients with cancer and stroke,10 although NBTE has been diagnosed in patients with cancer and stroke, with a prevalence as high as 32% in postmortem series.11 Therefore, it may be one of the reasons why echocardiography has consistently revealed no abnormal findings in many prior reports. In conclusion, we describe a rare case of an adenomyosis patient presenting with NBTE and multiple cerebral infarction. Adenomyosis is a rare condition associated with cerebral infarcts but is certainly a potential risk for thromboembolism. NBTE may represent a link between hypercoagulability and multiple embolic infarctions. Clinicians should be aware of the potential thromboembolic risk of adenomyosis. Further reporting of similar cases is needed to confirm the thromboembolic mechanism. References 1. Yamashiro K, Tanaka R, Nishioka K, et al. Cerebral infarcts associated with adenomyosis among middle-aged women. J Stroke Cerebrovasc Dis 2012;21:910.e911-915. 2. Nishioka K, Tanaka R, Tsutsumi S, et al. Cerebral dural sinus thrombosis associated with adenomyosis: a case report. J Stroke Cerebrovasc Dis 2014;23:1985-1987. 3. Bick RL. Cancer-associated thrombosis. N Engl J Med 2003;349:109-111. 4. Borowski A, Ghodsizad A, Cohnen M, et al. Recurrent embolism in the course of marantic endocarditis. Ann Thorac Surg 2005;79:2145-2147. 5. Liu J, Frishman WH. 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Yield of transesophageal echocardiography for nonbacterial thrombotic endocarditis and other cardiac sources of embolism in cancer patients with cerebral ischemia. Am J Cardiol 2006;97:894-898. 11. Graus F, Rogers LR, Posner JB. Cerebrovascular complications in patients with cancer. Medicine (Baltimore) 1985;64:16-35.