{"paper_id":"3f5e3b07-90c6-41c8-88f3-d680d24431ce","body_text":"C A S E R E P O R T Open Access\nCerebral infarction associated with benign\nmucin-producing adenomyosis: report of\ntwo cases\nKoki Okazaki * , Fumiaki Oka, Hideyuki Ishihara and Michiyasu Suzuki\nAbstract\nBackground: Cerebral infarction associated with a malignant tumor is widely recognized as Trousseau syndrome. In\ncontrast, few cases of cerebral infarction associated with benign tumors have been reported. We present two cases\nof embolic stroke that seemed to be caused by mucin-producing adenomyosis.\nCase presentation: The patients were women aged 42 and 50 years old. Both patients developed right hemiparesis\nand aphasia, and cerebral infarctions were detected in the left cerebral hemisphere. There were no other abnormal\nfindings, except for elevation of CA125 and D-dimer. Trousseau syndrome was suspected in both cases, but whole\nbody examinations did not reveal any malignant tumors. However, uterine adenomyosis was detected in both patients.\nConclusions: From our findings and a review of the literature, both mucin-producing malignant tumors and mucin-\nproducing benign tumors such as adenomyosis may cause hypercoagulability and cerebral infarction. This mechanism\nshould be considered in a case of a young to middle-aged woman with embolic stroke of an undetermined origin.\nKeywords: Cerebral infarction, Adenomyosis, Trousseau’s syndrome, Benign tumor, Case report\nBackground\nMucin-producing malignant tumors may cause hyperco-\nagulability and associated cerebral infarction that is\nwidely referred to as Trousseau syndrome. Adenomyosis\nis also reported to produce mucin and to cause hyperco-\nagulability [ 1, 2]. Here, we present two cases of embolic\nstroke that developed in middle-aged women and\nseemed to be caused by benign mucin-producing\nadenomyosis.\nCase presentation\nPatient 1 (Fig. 1): A 42-year-old woman with no medical\nhistory of note presented with right hemiparesis and apha-\nsia, and was admitted to our hospital. The actual onset\ntime was unknown. On arrival, her National Institutes of\nHealth Score Scale (NIHSS) was 20. Diffusion-weighted\nbrain magnetic resonance imaging (MRI) showed a hyper-\nintense signal in the left middle cerebral artery (MCA) ter-\nritory, and MR angiography (MRA) indicated occlusion of\nthe left superior M2 (Fig. 1a, b). Because the infarct area\nseemed to match with the occluded artery territory, reper-\nfusion therapy was not performed. After admission, we\nperformed examinations to investigate the cause of cere-\nbral infarction. Transthoracic echocardiography (TTE)\nand transesophageal echocardiography (TEE) showed no\nremarkable findings. A 24-h Holter electrocardiogram\n(ECG) did not show atrial fibrillation or other arrhythmia.\nCarotid echography and carotid MRA did not show ath-\nerosclerotic changes at proximal arteries. Blood tests were\nconducted to investigate the possibility of coagulation dis-\norders, such as antiphospholipid antibody syndrome, colla-\ngen disease, protein S and C deficiency, antithrombin III\ndeficiency, and tumor markers. However, the results were\nunremarkable, except for elevation of D-dimer (1.4 μg/mL)\nand CA 125 (395 U/mL; normal, < 35 U/mL). Whole body\nenhanced computed tomography (CT) revealed no malig-\nnancy. Pelvic MRI showed uterine adenomyosis (Fig.1c).\nPatient 2 (Fig. 2): A 50-year-old woman with no med-\nical history of note presented with right hemiparesis and\nmixed aphasia, and was admitted to a local hospital. The\nonset time was unknown. Diffusion-weighted imaging\n(DWI) in brain MRI revealed a hyperintense area in the\n* Correspondence: kouki818@yamaguchi-u.ac.jp\nDepartment of Neurosurgery, Yamaguchi University School of Medicine,\n1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan\n© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0\nInternational License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and\nreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to\nthe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver\n(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.\nOkazaki et al. BMC Neurology  (2018) 18:166 \nhttps://doi.org/10.1186/s12883-018-1169-2\n\nleft MCA territory. MRA showed occlusion at M1\n(Fig. 2a, b). The patient was referred to our hospital\nfor further examination and treatment. On arrival,\nher NIHSS was 23. Emergent digital subtraction\nangiography (DSA) was performed and partial reper-\nfusion of the left MCA was found (Fig. 2c). We hesi-\ntated to perform endovascular treatment because of\nthe large infarction. After admission, we performed\nexaminations to investigate the cause of cerebral in-\nfarction. TTE and TEE showed no remarkable find-\nings, and a 24-h Holter ECG did not show atrial\nfibrillation or other arrhythmia. DSA and carotid echogra-\nphy did not show atherosclerotic changes at proximal ar-\nteries. Blood tests performed to investigate the presence of\ncoagulation disorders (as listed above for case 1) were un-\nremarkable, except for elevation of D-dimer (3.7 μg/mL)\nand CA125 (143 U/mL; normal, < 35 U/mL). Whole body\nenhanced CT revealed no malignancy. Pelvic MRI showed\nuterine adenomyosis (Fig. 2d). Her aphasia gradually im-\nproved, but motor aphasia remained.\nBased on the above findings, both cases were finally\ndiagnosed with cerebral infarction due to Trousseau\nsyndrome-like hypercoagulability associated with adeno-\nmyosis. For secondary prevention, the first patient was\ntreated with warfarin and the second patient was treated\nwith rivaroxaban, and there has been no recurrence for\n68 and 19 months and modified rankin scale is 1 and 4,\nrespectively.\nDiscussion\nThe risk of thrombotic complication is high in patients\nwith malignant tumor, and this condition is referred to as\nTrousseau syndrome [ 3]. Varki reported multiple mecha-\nnisms of hypercoagulability in patients with malignant\ntumor, involving tissue factor, mucin, cysteine protease,\nand various cytokines [ 4]. Especially, mucin promotes\nplatelet aggregation by interaction with platelet P-selectin\nand leukocyte L-selectin, with resulting hypercoagulability\n[5]. CA125 is a repeating peptide epitope of mucin\nMUC16 and a marker of mucin-producing malignant tu-\nmors such as ovarian cancer [ 6]. Elevation of CA125 in\npatients with a malignant tumor increases the risk of is-\nchemic stroke [ 7–9]. Hypercoagulability and elevation of\nCA125 in patients with adenomyosis has also been re-\nported [1, 2], and as for patients with cancer, hypercoagu-\nlability can occur in patients with adenomyosis due to\nincreased expression of tissue factor [ 2]. Indeed, as shown\nin T able 1, elevation of D-dimer at onset has been found\nin all except one of the reported cases of ischemic stroke\nrelated to adenomyosis. Elevation of CA125 was also\nAB C\nFig. 1 a Diffusion-weighted magnetic resonance imaging (MRI) revealed an infarct in the left middle cerebral artery territory.b Magnetic resonance\nangiography showed occlusion at left M2 (arrow). c T2-weighted pelvic MRI revealed enlargement of the uterus and obscure junctional zone,\nsuggesting adenomyosis\nFig. 2 a Diffusion-weighted MRI revealed an infarct in the left middle cerebral artery territory. b Magnetic resonance angiography at a previous\nhospital showed left M1 occlusion. c Angiography revealed partial recanalization of the left middle cerebral artery.d Pelvic MRI revealed adenomyosis\nOkazaki et al. BMC Neurology  (2018) 18:166 Page 2 of 4\n\ndetected in both of our cases. The previous and current\ncases indicate that adenomyosis itself seems to cause hy-\npercoagulability through a mechanism similar to that of\nTrousseau syndrome and may cause ischemic stroke. In\ncontrast to previous reports, both of our patients had large\nvessel occlusion with emboli and large infarction. As for\npatients with Trousseau syndrome, both multiple infarc-\ntion and large vessel occlusion can also occur in patients\nwith mucin-producing adenomyosis and could cause se-\nvere neurological deficits, as shown in our cases.\nThe primary approach to treatment of Trousseau syn-\ndrome is to eliminate the causative tumor. This approach\ncould be used for patients with cerebral infarction\nassociated with adenomyosis,but the benign characteristics\nof the lesion and limited evidence for the cause make it\nhard to choose surgery as first-line treatment. A\ngonadotropin-releasing hormone (GnRH) agonist may be a\ntreatment option, based on its effect of decreasing secretion\nof estrogen. However, side effects restrict the administration\nperiod of a GnRH agonist, and there is a report of a patient\n(Case No. 4 in Table 1) who had recurrent ischemic stroke\nafter discontinuation of a GnRH agonist [ 8, 9]. Antithrom-\nbotic drugs are another treatment option. In patients with\nTrousseau syndrome, heparin, warfarin and other direct\noral anticoagulants have been used to prevent thrombosis,\nalthough it is still unclear which drug is the most effective\n[10]. Anticoagulants and antiplatelet agents can also be\nused in patients with adenomyosis. In our patients, warfarin\nand rivaroxaban were administered and there have been no\nrecurrent attacks. Long-term hormone replacement therapy\nmay cause hypercoagulabilityin patients with adenomyosis,\nand discontinuation of this therapy in one reported case\n(Case No. 6, Table 1) did not lead to recurrence [ 11]. Over-\nall, further studies are needed to clarify the mechanisms of\ndevelopment of cerebral infarction in patients with adeno-\nmyosis or other mucin-producing benign.\nConclusions\nIn conclusion, we have reported two cases of cerebral in-\nfarction that seemed to be caused by adenomyosis.\nThese cases suggest that cerebral infarction might de-\nvelop in patients with a benign mucin-producing tumor,\nin addition to cases with a malignant tumor. Cerebral\nembolism in patients with adenomyosis is not common,\nbut these patients may develop cerebral infarction due\nto hypercoagulability and elevated CA125. Therefore, we\nsuggest inclusion of adenomyosis as a differential diag-\nnosis in embolic stroke of an undetermined origin in\nmiddle-aged women.\nAbbreviations\nCT: Computed tomography; DSA: Digital subtraction angiography;\nDWI: Diffusion-weighted imaging; ECG: Electrocardiogram; GnRH: Gonadotropin-\nreleasing hormone; MCA: Middle cerebral artery; MRI: Magnetic resonance\nimaging; NIHSS: National Institutes of Health Score Scale; TEE: Transesophageal\nechocardiography; TTE: Transthoracic echocardiography\nFunding\nInstitutional sources only. No financial support was provided for this study.\nAvailability of data and materials\nThe dataset supporting the conclusion of this article is included within the\narticle.\nAuthors’ contributions\nKO and FO collected the clinical data and interpreted the data. HI and MS\ngave us important clinical opinions. KO drafted the manuscript. FO helped\nwrite and revise the manuscript. All authors read and approved the final\nmanuscript.\nEthics approval and consent to participate\nThe authors declare that ethics approval was not required for this case\nreport.\nConsent for publication\nWritten informed consents were obtained from both patients for publication\nof this case report and accompanying images.\nCompeting interests\nThe authors declare that they have no competing interests.\nPublisher’sN o t e\nSpringer Nature remains neutral with regard to jurisdictional claims in\npublished maps and institutional affiliations.\nTable 1 Summary of cases of ischemic stroke related to adenomyosis\nCase No. [Ref] Age (y.o) CA125 (U/mL) D-dimer ( μg/mL) Secondary prevention Recurrence\n1[ 9] 45 159 1.1 Antiplatelet, GnRH agonist ( −)\n2[ 9] 44 Not mentioned FDP 5.9 μg/mL Warfarin, GnRH agonist ( −)\n3[ 9] 55 42.6 0.57 (normal) Aspirin, GnRH agonist ( −)\n4[ 8]a 42 1750 6.0 Antiplatelet (6 m). GnRH agonist (6 m) (+)\n5[ 9]a 42 907 4.1 Warfarin, GnRH agonist ( −)\n6[ 11] 59 334.8 7.0 Discontinuation of hormone replacement therapy ( −)\n7b 42 395 1.4 Warfarin ( −)\n8b 50 143 3.7 Rivaroxaban ( −)\naCase Nos. 4 and 5 are the same patient\nbCase Nos. 7 and 8 are the present cases\nOkazaki et al. BMC Neurology  (2018) 18:166 Page 3 of 4\n\nReceived: 25 April 2018 Accepted: 28 September 2018\nReferences\n1. Babacan A, Kizilaslan C, Gun I, Muhcu M, Mungen E, Atay V. CA 125 and\nother tumor markers in uterine leiomyomas and their association with\nlesion characteristics. Int J Clin Exp Med. 2014;7:1078 –83.\n2. Liu X, Nie J, Guo SW. Elevated immunoreactivity to tissue factor and its\nassociation with dysmenorrhea severity and the amount of menses in\nadenomyosis. Hum Reprod. 2011;26:337 –45.\n3. Evans TR, Mansi JL, Bevan DH. Trousseau ’s syndrome in association with\novarian carcinoma. Cancer. 1996;77:2544 –9.\n4. Varki A. 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Yamashiro K, Tanaka R, Nishioka K, Ueno Y, Shimura H, Okuma Y, et al.\nCerebral infarcts associated with adenomyosis among middle-aged women.\nJ Stroke Cerebrovasc Dis. 2012;21:910.e1 –5.\n10. Ikushima S, Ono R, Fukuda K, Sakayori M, Awano N, Kondo K. Trousseau ’s\nsyndrome: cancer-associated thrombosis. Jpn J Clin Oncol. 2016;46:204 –8.\n11. Hijikata N, Sakamoto Y, Nito C, Matsumoto N, Abe A, Nogami A, et al.\nMultiple cerebral infarctions in a patient with adenomyosis on hormone\nreplacement therapy: a case report. J Stroke Cerebrovasc Dis. 2016;25:183 –4.\nOkazaki et al. BMC Neurology  (2018) 18:166 Page 4 of 4","source_license":"CC0","license_restricted":false}