Clinical characteristics of cerebral venous sinus thrombosis patients with new-onset of headache

Objective This study aimed to assess the clinical characteristics of cerebral venous sinus thrombosis (CVT) patients with new-onset headache and to identify the risk factors for headache in this population. Methods We retrospectively reviewed the demographic and clinical data of 69 CVT patients recruited between September 2017 and September 2019. Patients were classified into two groups, the headache group and the non-headache group, according to the presence or absence of new-onset headache symptoms at admission. The following characteristics and parameters were measured and analyzed, including gender, age, amount of thromboembolic cerebral venous sinus(ATCVS), and other relevant indicators. Results The incidence of headache was 75% in this cohort. The proportion of female patients in the headache group was higher than that in the non-headache group. Patients in the headache group were younger than those without headache. CVT patients of headache group showed higher lymphocyte ratio (LR), blood urea nitrogen (BUN), and intracranial pressure (ICP) compared to the non-headache group, whereas mean corpuscular volume (MCV) and levels of protein (cerebrospinal fluid, CSF) and lactic dehydrogenase (LDH) in CSF were lower in headache patients. The data also revealed younger age and the increased level of chloride ion CI-(CSF) were the risk factors for the occurrence of headache in CVT patients. Conclusion Age, LR, MCV, BUN levels, ICP, protein (CSF), and LDH (CSF) in patients with headache were significantly different from those in the non-headache group at admission. Younger age and a level of CI- (CSF) were risk factors for headache in CVT patients. These findings may provide guidance for clinical diagnosis and treatment of CVT.


Introduction
Cerebral venous thrombosis (CVT) is an uncommon cerebrovascular disease that accounts for 0.5-2% of all stroke cases [1]. Patients with CVT often present with various symptoms including headache, dizziness, vomiting, nausea, seizures, unconsciousness, and unresponsiveness. CVT is also a rare, life-threatening disease that may cause sudden death [2]. It may occur in all age groups [3] and females are three times more likely to be diagnosed with CVT than males [4,5]. The risk factors for CVT include infectious diseases (e.g. head and face infection) and non-infectious factors, such as hypercoagulability, blood stasis, head and neck trauma, oral contraceptive drugs, hormone replacement therapy, pregnancy [6] and low intracranial pressure [2]. No underlying risk factor is found in approximately 13% of CVT patients [7]. Current treatments for CVT include anticoagulation therapy, symptomatic therapy, and etiological treatment. Intravascular intervention may be applied to patients with severe CVT [8]. With the improvement in imaging diagnostic techniques and early treatment with anticoagulation, the mortality rate of CVT has decreased over the past years [9].
Headache is a common manifestation present in over 85% of CVT patients. However, there are limited studies that investigate the association between clinical characteristics of CVT patients and the occurrence of headache. The pathological mechanism of CVT-related headache may involve the stretching and compression of occluded venous sinuses, which lead to increased ICP and eventually pain in the head.
Different types of headaches have been observed in CVT patients, including exploding headache, migraine-like headache, chronic tension headache, and chronic thunderclap headache [10,11]. In this study, we analyzed the clinical characteristics of CVT patients with or without headache and identified the risk factors for headache in this population. Our findings may provide guidance for the early diagnosis of headache in patients with CVT.

Study design
A total of 69 consecutive patients who were diagnosed with CVT between September 2017 and September 2019 in the First Affiliated Hospital of Soochow University were recruited. The inclusion criteria were as follows: 1) patients who were diagnosed with CVT based on clinical presentation and imaging examinations including magnetic resonance venography (MRV), computed tomographic venography (CTV), or conventional digital subtraction angiography (DSA). In CTV, MRV, and DSA, CVT patients showed filling defects in cerebral venous sinuses. 2) patients were admitted to Neurology clinic. 3) patients were conscious, cooperative, and able to provide all necessary information. Patients were excluded if 1) they were diagnosed without imaging examinations; 2) they had arterial systematic cranial vascular disease, head trauma, acute intracranial infection, renal or hepatic failure, acute myocardial infarction, or hematological malignancy; 3) they were unwilling to cooperate or unable to provide reliable information.
The patients were divided into two groups, the headache group and the non-headache group, according to the presence or absence of new-onset headache symptoms at admission. Headache was defined as a pain on the top of the head, in the forehead, or an occipital ache. Patients in each group were further classified into three subgroups based on the stage of CVT: 1) acute stage: ≤ 48 h; 2) subacute stage: between 48 h and 30 days; 3) chronic stage, ≥ 30 days [12]. All participants received formal anticoagulation therapy. Patients with severer CVT also received intravascular treatment. This study was approved by the ethics committee of the hospital. All patients provided written informed consent (Fig. 1).

Data collection
The demographic and clinical data of 69 CVT patients were collected and retrospectively reviewed. The characteristics of patients with or without headache were compared, including demographic features, date of symptom onset, all symptoms presented from the onset of the headache at admission, the results from imaging examinations, and the National Institutes of Health Stroke Score (NIHSS) at admission and at discharge, Patient outcomes were assessed at discharge by NIHSS. The following parameters, which were measured within 24 h after admission.The patients systolic blood pressure(SBP), diastolic blood pressure(DBP) were measuered and analyzed in 24 h after admission. Amount of thromboembolic cerebral venous sinus were counted after have a MRV check. levels of D-dimer and hypersensitive C-reactive protein, white blood cell count, the number of lymphocytes(L), lymphocytes ratio(LR), Mean corpuscular volume (MCV), levels of hepatitis B surface antibody and blood urea nitrogen(BUN) in peripheral blood in 24 h after admission. the pressure of the cerebrospinal fluid (CSF), levels of protein, Lactic dehydrogenase(LDH), and adenosine deaminase(ADA)in the CSF were anayzed after undergoing a lumbar puncture in 48 h after admission. urine specific gravity (USG) was detected in 24 h after admission, Patient outcomes were assessed by two professional Physician of neurology at discharge by NIHSS. The severity of CVT was determined by amount of thromboembolic cerebral venous sinus. The severity of headache was evaluated using Visual Analogue Scale-100(VAS-100). An ICP of more than 200 mmH 2 O was defined as intracranial hypertension.

Statistical analysis
All data analyses were performed by SPSS (version 21, IBM). Quantitative variables that were normally distributed were expressed as mean ± standard deviation, whereas non-normally distributed data were shown as median with inter-quartile range (IQR). Categorical variables were presented as number and percentage (%). Student's t-test or Mann-Whitney test was used for the analysis of continuous data, while χ 2 or Fisher's exact test was used to compare categorical data. The independent variables associated with headache and the risk factors for CVT were analyzed by logistic regression analysis. A difference was considered significant if P < 0.05.
Among all CVT patients, 47.82% of them were at the acute stage; 33.33% were at the subacute stage; and 18.84% were at the chronic stage. The proportions of headache patients at acute, subacute, and chronic stages were 53.84% (28/52), 28.84% (15/52), and 17.30% (15/52), respectively. In the non-headache group, the percentage of patients at acute, subacute, and chronic stages were 64.70% (11/17), 29.41% (5/11), 9%(1/11), respectively.  The flowchart of recruitment and selection process, there are total 91patients information collected in our study, but 22 patients were excluded for loss clinical data and other reasons. Sixty-nine patients were into the research lastly 5000 IU, subcutaneous injection, b.i.d.) for two weeks. Two patients received intravascular treatment. At discharge, 92.75% of all patients had an NIHSS of 0, indicating that they were in relatively good condition; 7.25% of them were in a relatively poor condition (NHISS > 1); 4 patients were in coma. One patient from the head group died during hospitalization (  Fig. 2).

Discussion
Headache is one of the most common symptoms in CVT patients. In this cohort, 75% (52/69) of the patients reported headache at admission, which was consistent with a previous study showing that 80-90% of CVT patients presented with headache [13]. Previous evidence reveals that CVT is most prevalent among young women [14]. Here, we found that patients with headache were younger than those in the non-headache group. Also, 78.7% of our patients were females. It has been reported that headache is associated with papilledema in 25-75% of CVT patients [15]. The proportions of female patients in headache and non-headache groups were 55.67% and 29.42%, respectively. Headache may occur at the acute, subacute, or chronic stages of CVT. Botta et al. found that headache onset was acute in 51.1%, subacute in 42.6%, thunderclap in 4.3%, and chronic in 2.1% of the CVT patients and the mean VAS was 76.4 ± 18.8 [10], which was consistent with our findings.
Infection has been considered as one of the most common causes of CVT [16] and the neutrophil-tolymphocyte ratio is significantly associated with poor outcomes at discharge [16,17]. Our study showed that head and face infection or upper respiratory infection occurred in 27.68% (26/69) of the patients. Compared  to the non-headache group, patients with headache had a higher LR. However, no significant difference was observed in other inflammation markers, such as WBC and the number of lymphocytes. We also found that a high level of HBs-Ab in all CVT patients, but there was no significant difference between the headache and nonheadache groups. Previous studies reported that CVT patients had a higher HBs-Ag-positive rate compared to health controls [16,18], indicating HBV infection may be a risk factor for CVT [18]. Intracranial CSF pressure is an important sign of CVT [1,19]. In the current study, the ICP exceeded 200 mm H 2 O in both groups. Also, CVT patients with headache showed higher ICP compared to the non-headache group. Intracranial hypertension caused indirectly by a mass compressing part of the intracranial venous sinuses, resulting in obstruction of venous drainage [17].
CSF examination provides important information for the diagnosis of CVT. Most CVT patients have normal or increased cell counts and protein concentrations in the CSF [1]. In our cohort, the headache group showed significantly lower levels of protein (CSF), Cerebrospinal fluid protein content is increased in all patients with cerebral venous sinus thrombosis. Compared with nonheadache patients, cerebrospinal fluid protein content is relatively lower in headache patients, which may be related to increased protein catabolism or poor nutrition in headache patients. ADA (CSF), LDH (CSF), and CI-(CSF) also were lower compared to patients non-headache. The changes in CSF profile in headache patients may be related to the inflammation of sensory nerves. We also demonstrated that the MCV in the headache group was significantly lower than that in patients without headache. Anemia caused by iron deficiency is a common disorder in juvenile populations [20]. Iron-deficiency anemia has been identified as a contributor to the development of CVT [21]. Some patients have normal hemoglobin, and although the MCV is lower, we have found that red blood cells are small and prone to suffer CVT. Hypercoagulability and venous stasis have also been shown to play vital roles in the pathogenesis of thrombus [4]. Further investigations are needed to explore the relationships between these clinical parameters and headache in CVT patients.