Clinical features of Trousseau’s syndrome with multiple acute ischemic strokes

Trousseau’s syndrome or migrating thrombophlebitis can cause venous or arterial thrombosis; however, multiple acute ischemic strokes (MAIS) caused by Trousseau’s syndrome are rare. The aim of this study was to analyse the clinical features of Trousseau’s syndrome with MAIS and to improve the awareness and the knowledge of this disease. Clinical data from fifteen patients who were diagnosed as Trousseau’s syndrome with MAIS in Rizhao People’s Hospital from January 2017 to April 2020 were collected and analysed. The clinical data included the following: patients’ basic information (including gender, age, underlying diseases, and tumour stage), laboratory results, imaging features, treatment regimens, and short-term prognoses were collected. The mean age was 65.5 years, with thirteen males and two females. Most patients (11/15) had a history of smoking and (or) drinking. The average score of NIHSS was 2.13. 6 of the 15 patients first presented with ischemic stroke and then found the primary tumour. Most common types of primary tumour was lung cancer (11/15), and other types of primary tumour were gastric adenocarcinoma, renal cell carcinoma, oesophageal adenosquamous carcinoma, and cholangiocarcinoma (one in each). All the 15 patients showed different levels of increase of D-dimer. The increase in CRP appears in 10 of the 15 patients. Various tumour markers were increased in the 15 patients, especially for CYFRA-211, all the patients of which were higher than normal. All of the 15 patients had multiple vascular territory lesions in DWI, and most lesions were near the cortex areas. Only 4 of the 15 patients (26.7%) occurred with peripheral venous thrombosis. Thirteen patients were given low molecular heparin for anticoagulant therapy, of which 9 patients were improved in short-term while 4 patients were not. Trousseau’s syndrome with MAIS was associated with old-age male, smoking and (or) drinking history, low NIHSS score, increased D-dimer, CRP and tumour markers, and lesions near the cortex areas with multiple vascular territories in DWI. Patients with these features should be alert of malignant tumour. Most common types of primary tumour were lung cancer. Treatment with low molecular heparin may be effective in short term.


Introduction
Trousseau's syndrome was first described in 1865 as the relationship between venous thromboembolisms and cancer [16]. Sack et al. extended this definition to include chronic disseminated intravascular coagulopathy associated with microangiopathy, verrucous endocarditis, and arterial embolism in patients with cancer [11]. Multiple acute ischemic stroke (MAIS) is a rare manifestation of Trousseau's syndrome, usually involving elevation of D-dimer levels and acute simultaneous multiple embolisms in multiple vascular territories. There have been few large series studies on clinical features of Trousseau's syndrome with MAIS. Here, we summarized and analysed the clinical manifestations, laboratory results, and brain magnetic resonance image (MRI) features of fifteen patients who were diagnosed with Trousseau's syndrome with MAIS in our hospital to improve the awareness and early diagnosis of this disease.

Methods
Clinical data from fifteen patients who were diagnosed with Trousseau's syndrome with MAIS in Rizhao People's Hospital from January 2017 to April 2020 were collected and analysed. The criteria of our study must have clinical symptoms of ischemic strokes and be confirmed by MRI diffusion-weighted imaging (DWI). The patients with large vessel disease, small vessel disease, and cardiogenic embolism were excluded. The diagnosis of cancer was based on pathological outcome in all the patients. The blood samples and other data were obtained as part of treatment. Clinical data included the following: patients' basic information (including gender, age, underlying diseases, and tumour stage), laboratory results (including blood counts, blood coagulation, tumour markers, details of tumour histological type and metastasis), imaging reports (including neck vascular ultrasound, echocardiogram, cranial MRI and MRA), National Institutes of Health Stroke Scale (NIHSS) score, treatment regimens, and short-term prognoses were collected.

Clinical characteristics
The clinical features of the patients are summarized in Table 1. The mean age was 65.5 years (range 47-75 years), including thirteen males and two females. Six patients first presented to hospital with ischemic stroke and then with primary tumour. The types of primary tumour were lung cancer in 11 patients (7 patients with adenocarcinoma, 2 patients with squamous carcinoma, and 2 with nonsmall cell carcinoma) and gastric adenocarcinoma, renal cell carcinoma, oesophageal adenosquamous carcinoma, and cholangiocarcinoma (one in each) (Fig. 1). Of the 15 patients, 7 had a history of smoking and drinking, 4 had only a history of smoking or drinking, and the remaining 4 had neither a history of smoking nor drinking. There was no history of any condition commonly associated with thrombosis, such as diabetes mellitus, hypertension, hyperlipidaemia, coronary heart disease, rheumatic heart disease, and atrial fibrillation. All 15 patients (100.0%) had neurological symptoms, including hemiplegia (n = 5), dysarthria (n = 3), dizziness (n = 3), dysphagia (n = 2), ataxia (n = 1), and disturbance of consciousness (n = 1). And the average score of NIHSS was 2.13 (range 0-4). In terms of treatment, 13 patients were given low molecular heparin for anticoagulant therapy for 2 weeks, of which 9 patients were improved while 4 patients were not, including 2 patients with worsening dizziness, 1 patient with worsening consciousness, and 1 patient with dysarthria. Two patients were treated with aspirin, one was improved, but another one developed consciousness and died within a short period of time (1 month).

Analysis of laboratory results
All the 15 patients showed different degrees of increase of D-dimer. The mean D-dimer level was 12.39 μg/ml. The increase in CRP appears in 10 of the 15 patients. Various tumour markers were increased in the 15 patients. Especially for CYFRA-211, all the patients of which is higher than normal. Most patients showed an increase in NSE, CA125, CA153, and CA199. In the meantime, we found an increase in CA724 in only two patients, and AFP was normal in all patients ( Table 2).

MRI findings
All patients were confirmed with cerebral infarction in brain magnetic resonance imaging (MRI), and all of them had multiple vascular territory lesions in the diffusion-weighted

Complementary examinations
There was no evidence of atrial fibrillation on electrocardiography, and echocardiography showed no signs of congenital heart disease or valvular disease. Carotid artery ultrasonography in all patients did not show stenosis. Atherosclerosis was present in 6 patients. Of the 15 patients, 4(26.7%) included in this study occurred with peripheral venous thrombosis, including subclavian venous thrombosis (n = 2), deep left leg venous thrombosis (n = 2), and bilateral calf muscle vein thrombosis (n = 2).

Discussion
The aetiology of ischemic stroke is complicated and various. But in clinical work, malignant tumour is often neglected as the cause of ischemic stroke. In the present study, there were 11 (73.33%) cases of lung cancer, including 7 cases of lung adenocarcinoma. It could be seen that Trousseau's syndrome with MAIS was more common in lung cancer, which might be related to the high incidence of lung cancer in Chinese population. In addition, adenocarcinoma had a higher proportion of Trousseau's syndrome with MAIS in lung cancer. This is because the sialic acid moieties of mucin from adenocarcinoma can cause a direct nonenzymatic activation of factor X. On the side, carcinoma mucins interact with the selectin adhesion molecule, namely, L-selectin, which is expressed on leukocytes, and P-selectin, which is expressed on platelets and endothelial cells. It is more likely to cause ischemic stroke [4]. It is worth noting that in our study, 6 patients had an ischemic stroke first, and then found a tumour lesion. So, ischemic stroke might be the first manifestation of an undiagnosed cancer [2]. Another common mechanism in patients with Trousseau's syndrome is hypercoagulable state. Its potential mechanisms include hypercoagulability induced by cancer procoagulant, tissue factor, mucin secreted by carcinomas, hypoxia, and the MET oncogene, which upregulates plasminogen activator inhibitor-1 (PAI-1) and cyclooxygenase-2 (COX-2) associated with coagulopathy [18]. Previous literature has reported case of Trousseau's syndrome in squamous carcinoma, which is considered to be related to hypercoagulability [1]. It has been reported that the incidence of hypercoagulability in renal cell carcinoma is 40% [17], so we consider that the occurrence of Trousseau's syndrome in renal cell carcinoma is also related to hypercoagulability. In clinical practice, most patients are assessed for hypercoagulability by monitoring their D-dimer levels. Previous studies showed that plasma D-dimer levels were significantly elevated in patients with cancer-associated ischemic stroke compared to those suffering from non-cancer-associated ischemic stroke Table 2 D-dimer, the normal range is 0-1.5ug/ml; CRP, C-reactive protein, the normal range is 0-10 mg/L; CYFRA-211, cytokeratin 19 fragment, the normal range is 0-3.3 ng/ml; NSE, neuron-specific enolase, the normal range is 0-16.3 ng/ml; CEA, carcinoembryonic antigen, the normal range is 0-3.4 ng/ml; AFP, alpha fetoprotein, the normal range is 0-13.6 ng/ml; CA-125, carbohydrate antigen-125, the normal range is 0-35 u/ml; CA-153, carbohydrate antigen-153, the normal range is 0-25 u/ml; CA-199, carbohydrate antigen-199, the normal range is 0-27 u/ml; CA-724, carbohydrate antigen-724, the normal range is 0-6.9 u/ml  [9]. Therefore, most scholars believe that Trousseau syndrome is related to increased plasma D-dimer, and if there is no timely diagnosis and treatment, the plasma D-dimer will show persistent increase and recurrent cerebral infarction. Moreover, one research had shown that serial D-dimer levels of 10 patients who died within 90 days were significantly higher than those of the 11 patients who survived up to 90 days [6]. This suggests that serial D-dimer determinations may be a good biomarker and a useful prognostic indicator for Trousseau syndrome patients. In our study, all the 15 patients showed different degrees of increase of D-dimer. The mean D-dimer level was 12.39 μg/ml, significantly elevated than normal. So we found D-dimer is an important diagnostic biomarker of Trousseau's syndrome and confirmed with the previous studies. Further, nonbacterial thrombotic endocarditis (NBTE) can also cause Trousseau's syndrome, which is characterized by nonbacterial vegetation without valvular destruction [14]. But NBTE is diagnosed infrequently before death, but prevalence can increase up to 32% in postmortem series [13]. None of the 15 patients in this study underwent transesophageal echocardiography, so the presence of NBTE could not be completely excluded. In our study, various tumour markers had increased to varying degrees. Especially for CYFRA-211, all the 15 patients of which is higher than normal. We considered that this might be associated with a higher proportion of lung cancer. Therefore, patients with increased CYFRA-211 in multiple acute ischemic strokes should pay special attention to the possibility of lung cancer. According to previous reports, the serum tumour markers CA19-9 and CA125 were found to be markedly elevated, which may also had been involved in the formation of thromboembolism [8]. Another Fig. 2 Multiple acute ischemic lesions located in different vascular territories. On DWI images, these lesions show restricted diffusion. There was no significant stenosis of the brain arteries on MRA study had suggested that CA125 and CA15-3 expression were associated with the incidence of thromboembolism in cancer patients, and the significant increase of CA125 was associated with the recurrence of ischemic strokes in patients with metastatic cancer [7,15]. Most patients in our study showed an increase in NSE, CA125, CA153, and CA199. In the meantime, we found AFP was normal in all patients. This is related to the fact that it is a specific indicator of liver cancer. In conclusion, patients with Trousseau's syndrome may have elevated levels of tumour markers, which may also be associated with thromboembolic formation.
We found that the clinical manifestations of patients were hemiplegia, (or) dysarthria, and dizziness. The average score of NIHSS was 2.13. So the symptoms and signs of focal neurological deficits in patients with Trousseau's syndrome may be similar with traditional ischemic strokes, but not serious. Four(26.7%) of our patients had peripheral venous thrombosis, including subclavian venous thrombosis (n = 2), deep left leg venous thrombosis (n = 2), and bilateral calf muscle vein thrombosis (n = 2). Thus patients with Trousseau's syndrome with MAIS may have vein thrombosis at the same time, which is consistent with other literature reports [12]. This suggests that patients in this category should be alert to the possibility of peripheral venous thrombosis and perform peripheral vascular examination as soon as possible.
Imaging results in this study revealed that all patients had multiple infarction lesions in DWI, usually with no significant stenosis of the brain arteries on MRA (Fig. 2). Most of the infarct lesions had a characteristic appearance, being non-enhancing, non-ring appearing clusters or single areas of restricted diffusion of 0.5-2 cm with a peripheral location or larger vascular territories, uncommonly in a watershed distribution and with absence of diffuse cortical ribbon or deep grey nuclei involvement [3]. In our study, there were 13 patients with bilateral anterior and posterior circulation, 1 patient with unilateral anterior circulation plus posterior circulation, and 1 patient with bilateral anterior circulation. These results suggest that the anterior and posterior circulation is the most compelling MR imaging feature of Trousseau's syndrome with MAIS. In particular, DWI presented a higher proportion of bilateral anterior and bilateral posterior circulation. Some studies sought to highlight the "three territory sign" (TTS) (bilateral anterior and posterior circulation acute ischemic diffusionweighted imaging [DWI] lesions), as a radiographic marker of stroke due to malignancy [3,10]. Therefore, it is necessary to pay attention to the screening of the unknown neoplasia in patients with similar imaging characteristics.
The major approach for treating Trousseau's syndrome is to eliminate the causative tumour [5]. For Trousseau's syndrome with MAIS, early anticoagulant therapy is more important. At the present time, direct oral anticoagulants have not been recommended for such patients [18]. Moreover, most articles recommend anticoagulant therapy, but it is not clear whether anticoagulation is better than anti-platelet aggregation, which needs further research. Thirteen of the fifteen patients in the present study were given anticoagulation with low molecular heparin, and most of which were improved after treatment and 4 patients were not. So low molecular heparin may be effective in a short term for Trousseau's syndrome with MAIS.

Conclusions
The characteristic outcomes of the fifteen patients studied were old-age male, smoking and (or) drinking history, low NIHSS score, increased D-dimer, CRP and tumour markers, lesions near the cortex areas with multiple vascular territories in DWI. Patients with these features should be alert of malignant tumour. Most common types of primary tumours were lung cancer. Treatment with low molecular heparin may be effective in short term. This may facilitate to improve the awareness and early diagnosis of this disease.

Declarations
Ethics approval and consent to participate This study was approved by the ethics committee of Rizhao People`s Hospital. A written informed consent form was obtained from each study participant.

Competing interests
The authors declare no competing interests.