Multiple Cerebral Infarctions Complicating Deep Vein Thrombosis Associated With Uterine Adenomyosis: A Case Report and Literature Review

We describe a 46-year-old woman who developed multiple cerebral infarctions in the left middle cerebral artery territory and deep vein thrombosis, presumably related to uterine adenomyosis. Uterine adenomyosis can cause coagulation abnormalities, as observed in Trousseau’s syndrome. Along with previous reports, our case experienced a stroke during menstruation and presented with increased cancer antigen 125 (CA125) levels. A hysterectomy was performed to prevent the recurrence of cerebral infarction. Our case also had complicated deep vein thrombosis, which is also known as a complication of uterine adenomyosis. We consider cerebral infarction and deep vein thrombosis with uterine adenomyosis might be caused by a common mechanism, hypercoagulation. Hysterectomy requires careful discussion before undergoing it because of fertility problems, but it might be the most effective approach for preventing the recurrence of brain infarction derived from adenomyosis and may be effective for both cerebral infarction and deep vein thrombosis.


Introduction
Uterine adenomyosis, a common disease in which endometrial-like tissue is formed in the myometrium, has been known to cause menstrual pain and menorrhagia, with reports showing a prevalence of approximately 20% among women. Uterine adenomyosis can induce venous thromboembolism in 12.2% of cases [1], during menstruation or hypercoagulation due to tissue factors [2], causing elevated levels of cancer antigen 125 (CA125) [3] associated with menstruation. It has been shown that hypercoagulability associated with uterine adenomyosis can cause cerebral infarction [4], or deep vein thrombosis [1]. Here, we report on a case of cerebral infarction and review the literature on cases of uterine adenomyosis-associated cerebral infarction.

Case Presentation
A 46-year-old Japanese woman with no medical history developed acute right hemiplegia and aphasia, for which she was admitted to a nearby hospital. According to the family, she had mild right paralysis a day before being transported to the emergency room. Brain magnetic resonance imaging (MRI) revealed acute cerebral infarctions in the left middle cerebral artery territory. Treatment with aspirin, ozagrel sodium, and heparin (5,000 units per day) was started. Given the presence of a pelvic tumor on computed tomography (CT) ( Figure 1A), she was transferred to our gynecological department on day four on suspicion of Trousseau's syndrome.
On admission, her blood pressure, pulse, and body temperature were 195/121 mmHg, 75/min, and 37.5°C, respectively. She had severe right hemiplegia with facial involvement and total aphasia, and was awakened but unable to communicate in the language. Blood tests revealed diabetes mellitus, anemia, and elevated Ddimer concentrations. Serum levels of CA125 and carbohydrate antigen 19-9 (CA19-9) were high ( Table 1). T2-weighted MRI of the pelvic tumor suggested no malignancy ( Figure 1B). Brain MRI revealed a fresh infarction in the left middle cerebral artery region, which included the cortex (Figure 2A), whereas magnetic resonance angiography revealed obstruction at the left internal carotid artery, with the development of collateral circulation ( Figure 2B). No arrhythmia, such as atrial fibrillation, was observed on electrocardiography. Transesophageal echocardiography was performed to determine the source of the embolism, although no abnormalities that could cause cerebral infarction were found, such as a patent foramen ovale or intracardiac thrombosis. Contrast-enhanced CT showed deep venous thrombosis in the right lower extremity and a pulmonary embolus. Needle biopsy of the uterus led to the diagnosis of adenomyosis.   Given that brain infarction emerged during menstruation, we considered coagulation disorder caused by adenomyosis to have been the main cause. The gradual progression of symptoms/signs generally suggests atherothrombotic infarction, but we interpreted such course can be occurred by embolic infarct associated with a hypercoagulation state. Additionally, MRI revealing an infarction in the caudate nucleus (striatocapsular infarction) and cerebral cortex suggested an embolic infarct.
The patient was then treated with heparin, which improved her aphasia over time. Her auditory comprehension improved significantly within a few days after treatment, but her motor aphasia remained. Based on previous reports [4][5][6][7][8][9][10][11][12][13][14], we considered hysterectomy to be effective in preventing the recurrence of cerebral infarction. Careful discussion (among her and her family, and the medical team) was made considering that she was not postmenopausal. Finally, she decided to have surgery in light of the risk of recurrence of cerebral infarction in the future. The patient underwent a total hysterectomy on day 20. We switched heparin to rivaroxaban (15 mg/day) on day 33 for the treatment of deep vein thrombosis. Subsequent blood tests confirmed normalization of tumor markers and D-dimer, and a follow-up MRI showed no new infarcts. Her severe right upper limb paralysis remained, but her right lower limb paralysis gradually improved. She was transferred to the rehabilitation hospital on day 56. Among 16 months since the onset of cerebral infarction, she has not experienced a recurrence of infarction or thrombotic events.
Our case experienced an onset of brain infarction during menstruation and markedly high levels of CA125, which was similar to those of the previous reports on the recurrence of cerebral infarction, and deep vein thrombosis, suggesting that coagulopathy may be present. Atherothrombotic cerebral infarction was also differentiated from the background of diabetes and the slowly progressive course, but when considering the association with deep vein thrombosis comorbidity from the early onset of cerebral infarction and elevated tumor markers, it was considered unlikely. In addition, screening blood tests for juvenile cerebral infarction such as hyperphospholipid antibody syndrome were also negative. The possibility of cardiogenic cerebral embolism or paradoxical cerebral embolism was not suspected more actively by the results of cardiac ultrasonography and electrocardiogram.
Although 17 cases of uterine adenomyosis with cerebral infarction have been reported, our case is the first reported case that complicated remarkable deep vein thrombosis. Based on the reported cases, hysterectomy might be the most effective approach for preventing the recurrence of brain infarction derived from adenomyosis, and our case suggests hysterectomy may be effective for both cerebral infarction and deep vein thrombosis.

Conclusions
We herein report a case of cerebral infarction and deep vein thrombosis that was thought to have been caused by coagulopathy due to uterine adenomyosis. Both of them might be caused by a common mechanism, hypercoagulation. The mechanism by which coagulopathy developed might be similar to that for Trousseau's syndrome, with evidence suggesting that hysterectomy may be the most effective therapy for preventing recurrence.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.