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. 2020 Sep 1;2020:8610903. doi: 10.1155/2020/8610903

Cerebral Venous Sinus Thrombosis in Women: Subgroup Analysis of the VENOST Study

Derya Uluduz 1, Sevki Sahin 2,, Taskin Duman 3,, Serefnur Ozturk 4, Vildan Yayla 5, Nazire Afsar 6, Nevzat Uzuner 7, Ipek Midi 8, Nilgun Cinar 2, Mehmet Ali Sungur 9, Fusun Mayda Domac 10, Birsen Ince 1, Baki Goksan 1, Cemile Handan Misirli 11, Mustafa Bakar 12, Hasan Huseyin Kozak 13, Sena Colakoglu 3, Ali Yavuz Karahan 14, Eylem Ozaydin Goksu 15, Fatih Ozdag 16, Mehmet Guney Senol 16, Vedat Ali Yurekli 17, Ufuk Aluclu 18, Serkan Demir 19, Hayriye Kucukoglu 20, Serdar Oruc 21, Nilufer Yesilot 22, Ozge Yimaz Kusbeci 23, Bijen Nazliel 24, Firdevs Ezgi Ucan Tokuc 15, Hesna Bektas 25, Fatma Nida Tascilar 26, Emrah Aytac 27, Mustafa Gokce 28, Hale Zeynep Batur Caglayan 24, Ahmet Tufekci 29, Gulnur Uzuner 7, Dilek Necioglu Orken 30, Osman Ozgur Yalin 31, Uygar Utku 28, Arda Yilmaz 32, Hamit Genc 32, Murat Cabalar 33, Aysel Milanlioglu 34, Hakan Ekmekci 4, Burcu Zeydan 35, Sevim Baybas 36, Yuksel Kablan 37, Basak Karakurum Goksel 38, Mustafa Acikgoz 26, Hatice Kurucu 1, Seden Demirci 39, Taskin Gunes 40
PMCID: PMC7481993  PMID: 32953038

Abstract

Background

Early diagnosis of cerebral venous sinus thrombosis (CVST) associated with reproductive health-related risk factors (RHRF) including pregnancy, puerperium, and oral contraceptive (OC) use can prevent severe neurological sequelae; thus, the symptoms must be documented in detail for each group.

Methods

Out of 1144 patients with CVST, a total of 777 women were enrolled from a multicenter for the study of cerebral venous sinus thrombosis (VENOST). Demographic, biochemical, clinical, and radiological aspects were compared for 324 cases with RHRF and 453 cases without RHRF.

Results

The mean age of the RHRF (-) group (43.2 ± 13 years) was significantly higher than of the RHRF (+) group (34 ± 9 years). A previous history of deep venous thrombosis (3%), isolated cavernous sinus involvement (1%), cranial neuropathy (13%), comorbid malignancy (7%), and its disability scores after 12 months (9%) were significantly higher in the RHRF (-) group. The RHRF (+) group consisted of 44% cases of puerperium, 33% cases of OC users and 23% of pregnant women. The mean age was found to be higher in OC users (38 ± 9 years). A previous history of deep venous thrombosis was slightly higher in the pregnancy subgroup (4%). Epileptic seizures were more common in the puerperium group (44%).

Conclusion

The results of our study indicate that the risk of CSVT increases parallel to age, OC use, and puerperium period. In addition, when considering the frequency of findings and symptoms, epileptic seizures in the puerperium subgroup of the RHRF (+) group and malignancies in the RHRF (-) group may accompany the CSVT. In daily practice, predicting these risks for the CSVT and early recognition of the symptoms will provide significant benefits to patients.

1. Introduction

Cerebral venous sinus thrombosis (CVST) is an uncommon form of stroke [1]. Several risk factors for CVST have been recognized including pregnancy, puerperium, oral contraceptive (OC) use, infections, inflammatory diseases, and thrombophilia. CVST is believed to be more common in women than in men [1, 2]. In addition, there is uniform age distribution in men, while 60% of women with CVST are clustered at 20-35 years old [14]. In some studies, one of third cases was clustered in periods of pregnancy and puerperium [5].

This study was performed to evaluate details about CVST among women and focused on reproductive health-related risk factors (RHRF) such as pregnancy, puerperium, and OC use.

2. Materials and Methods

This study includes 777 female CVST cases of the VENOST cohort. VENOST is a retrospective and multicenter observational study that includes 1144 patients with CVST diagnosed at 35 national neurology centers. In diagnosing CVST, the criteria defined in the VENOST study were used [1].

The patients were divided into two groups according to reproductive health-related risk factors (RHRF) such as oral contraceptive use, puerperium, and pregnancy as the RHRF (+) group and the RHRF (-) group. At the initial admission, both groups were evaluated according to demographics, clinical symptoms, and neurological signs. Radiological workup included brain computed tomography (CT), brain magnetic resonance imaging (MRI), MR venography, and/or digital subtraction angiography. Etiological factors, acute and maintenance treatment, and follow-up results were evaluated for each group. Then, the RHRF (+) group was divided into three subgroups according to risk factors such as oral contraceptive use, puerperium, and pregnancy, and these sub-groups were evaluated using the same risk factors. Putative etiological risk factors included the following: infections (systemic or paracranial infection—otitis media, mastoiditis, or sinusitis), systemic inflammatory diseases, rheumatologic or connective tissue disease, malignancies, and hematologic diseases; and other specified causes were recorded.

The type of onset was considered to be acute if the duration of symptoms was less than 48 hours on admission, subacute if the duration was between 48 hours and 1 month, and chronic if the symptom duration was longer than 1 month. The study was approved by the ethics committee of the coordinating center (Acceptance No. 83045809/604/02-12333).

3. Results

In this study, 58% (n = 453) of the total 777 female cases were classified as RHRF (-) and 42% (n = 324) of them as RHRF (+). The mean ages of the RHRF (+) group and the RHRF (-) group were 34 ± 9 and 43.2 ± 13, respectively, and were significantly different.

Acute onset is more frequent in the RHRF (+) group, whereas a subacute chronic mode of onset is more common in the RHRF (-) group. The most common symptoms were headache, visual field defects, and cranial neuropathies in the RHRF (-) group and headache and epileptic seizure in the RHRF (+) group. The comparison of these two groups according to clinical symptoms and signs: epileptic seizures (34%), nausea and vomiting (33%), and focal neurologic deficit (25%), was more common in the RHRF (+) group and visual field defect (29%) and cranial nerve palsies (13%) were more common in the RHRF (-) group.

In the total female group investigations, CVST was diagnosed with cranial MRI and MRV in 682 patients, with cranial MRI in 46 patients, with only cranial MRV in 31 patients, and with cranial CT and MRV in 14 patients. Parenchymal lesions were detected in 333 (42.8%) female patients including 160 (49.3%) in the RHRF (+) group and 173 (38.1%) in the RHRF (-) group (p = 0.003). Parenchimal lesion involvement, especially hemorrhagic transformation (n = 80, 25%), was more common in the RHRF (+) group. Venous involvement was found in 1 sinus in 373 (48%) female patients, in 2 sinuses in 274 (35%) patients, and in more than 2 sinuses in 130 (17%) patients. In the comparison of these two groups, there was no difference in intravenous involvement. Transverse sinus involvement was the most common site thrombosis within the total female group (n = 572, 73%), within the RHRF (+) group (n = 243, 75%), and within the RHRF (-) group (n = 329, 73%). The sigmoid sinus and sagittal sinus involvements were followed by transverse sinus in two groups.

Demographic aspects and comparative data of cases with RHRF (+) and RHRF (-) are displayed in Table 1.

Table 1.

Compared data of demographic and clinical aspects of groups.

Compared data RHRF (-) RHRF (+) p
n = 453 n = 324
Age
 Years 43.2 ± 13 % 34 ± 9 % <0.001
Mode of onset
 Acute 187a 42 195b 62
 Subacute 150a 34 82b 26 <0.001
 Chronic 110a 25 38b 12
Clinical symptoms and signs
 Isolated headache 119 26 66 20 0.057
 Headache 387 85 282 87 0.523
 Nausea and vomiting 116 26 107 33 0.024
 Epileptic seizures 98 22 110 34 <0.001
 Visual field defect 131 29 66 20 0.007
 Focal neurological deficit 72 16 81 25 0.002
 Altered consciousness 78 17 67 21 0.222
 Cranial nerve palsies 59 13 24 7 0.012
Radiological work-up
 Cranial MRI 23 5 23 7 0.492
 Cranial MRV 19 4 12 4
 Cranial MRI+MRV 398 88 284 88
 Cranial CT+MRV 10 2 4 1
Number of sinuses involved
 1 sinus 230 51 143 44 0.281
 2 sinuses 148 33 126 39
 More than 2 sinuses 75 16 55 17
Involved sinuses
 Isolated transverse sinuses 122 27 78 24 0.369
 Isolated sagittal sinuses 66 15 44 14 0.697
 Isolated sigmoid sinuses 18 4 7 2 0.158
 Isolated cortical veins 8 2 11 3 0.147
 Isolated jugular sinuses 9 2 1 0 0.052
 Isolated cavernous sinuses 6 1 0 0 0.044
 Transverse sinuses 329 73 243 75 0.459
 Sigmoid sinuses 183 40 127 39 0.736
 Sagittal sinuses 157 35 134 41 0.057
 Internal jugular vein 71 16 47 15 0.655
 Cortical veins 13 3 16 5 0.134
 Cavernous sinuses 12 3 3 1 0.085
Parenchymal involvement
 No lesion 280a 62 164b 51 0.003
 Infarction 87a 19 66a 20
 Hemorrhagic infarction 68a 15 80b 25
 Intracerebral hemorrhage 18a 4 14a 4

MRI: magnetic resonance imaging; MRV: magnetic resonance venography; CT: computed tomography.

A positive previous history of venous thromboembolism and malignancy was detected in 6% and 7% in the RHRF (-) group. Hematological parameters were completed in 206 (26.5%) patients, and no differences were detected between the two groups. When the RHRF (+) group was investigated, it was found to be the largest group in the puerperium period (43.8%) but the smallest group in the pregnancy period (22.8%). Rankin scores, which suggested neurological disability after 12 months, were found significantly high in the RHRF (-) group. Etiological factors and outcome according to groups are presented in Table 2.

Table 2.

Comparison of etiological factors and outcome according to the RHRF (-) group or the RHRF (+) group.

Compared data RHRF (-) RHRF (+) p
n = 453% n = 324%
Infections
 Paracranial (focal) systemic 20 4 13 4 0.963
7 2 5 2
History of VTE
 Cerebral 11a 2 2a 0.6
 Deep venous thrombosis 14a 3 3b 1 0.024
 Other 6a 1 2a 0.6
 Malignancy 32 7 1 0.3 <0.001
 Family history VTE 5 1 1 0.3 0.409
 MTHFR mutation
 Heterozygote 19 7 9 4 0.120
 Homozygote 24 8 9 4
 Hyperhomocysteinemia 12 3 9 3 0.952
 Prothrombin mutation 5 2 7 3 0.249
 Protein C/S deficiency 25 7 13 5 0.302
 Factor V Leiden mutation 11 4 11 5 0.405
 Thrombocytosis 2 0.5 2 1 0.753
 Polycythemia vera 3 1 0 0 0.267
 Anticardiolipin Ab 2 0.5 1 0.4 0.752
 PAI mutation 4 1 2 1 0.681
 Antithrombin III deficiency 3 1 1 0.4 0.642
 Hyperfibrinogenemia 0 0 2 1 0.178
 Antiphospholipid Ab 7 2 4 2 0.767
 Activated protein C 5 1 4 2 0.892
 Resistance 13 4 4 2 0.114
 High ANA titers
First month Rankin
 0-1 304 80 236 81 0.276
 2 40 11 37 13
 >3 38 10 20 7
Third month Rankin
 0-1 287 89 227 91
 2 21 7 17 7 0.235
 >3 15 5 5 2
Sixth month Rankin
 0-1 262 90 215 96
 2 16 6 6 3 0.061
 >3 13 5 4 2
12th month Rankin
 0-1 239 91 185 97
 2 11 4 4 2 0.031
 >3 13 5 2 1

ANA: antinuclear antibody; MTHFR: methylenetetrahydrofolate reductase; PAI: plasminogen activator inhibitor; VTE: venous thromboembolism.

The mean age of OC users was higher than other groups. The mode of acute clinical onset was high in all subgroups of RHRF (+) cases. In addition, chronic onset and intracerebral hemorrhage ratio were found more frequently in the OC user group than in the other subgroups. Epileptic seizures were found to be significantly higher in the puerperium group. Demographic and clinical characteristics of subgroup analyses are shown in Table 3.

Table 3.

Comparison of demographic and clinical characteristics of subgroups according to reproductive health-related risks.

Compared data of reproductive health-related risk factors Pregnancy Puerperium Oral contraceptive use p
n = 74, 23% n = 142, 44% n = 108, 33%
Age
 Years 32.2 ± 6a 32 ± 7a 38 ± 9b <0.001
Mode of onset
 Acute 51a 70 85a 62 59a 56
 Subacute 14a 19 42a 31 26b 25 <0.030
 Chronic 8a,b 11 10b 7 20a 19
Clinical symptoms and signs
 Isolated headache 16 22 24 17 26 24 0.361
 Headache 69 93 117 82 96 89 0.062
 Nausea and vomiting 22 30 43 30 42 39 0.283
 Epileptic seizures 18a 24 63b 44 29a 27 0.002
 Visual field defect 17 23 28 20 21 19 0.817
 Focal neurological 11 15 41 29 29 27 0.068
 Deficit 16 22 34 24 17 16 0.277
 Altered consciousness 6 8 8 6 10 9 0.537
 Cranial nerve palsies
Radiological workup
 Cranial MRI 4 6 12 9 7 7 0.975
 Cranial MRV 3 4 6 4 3 3
 Cranial MRI+MRV 65 89 122 86 97 90
 Cranial CT+MRV 1 1 2 1 1 1
Number of sinuses involved
 1 sinus 35 47 68 48 40 37 0.490
 2 sinuses 26 35 51 36 49 45
 More than 2 sinuses 13 18 23 16 19 18
Involved sinuses
 Isolated transverse 21 28 34 24 23 21 0.547
 Sinuses 11 15 20 14 13 12 0.838
 Isolated sagittal 2 3 3 2 2 1 0.926
 Sinuses 1 1 9 6 1 1 0.051
 Isolated sigmoid 0 0 1 1 0 0 0.526
 Sinuses 0 0 0 0 0 0
 Isolated cortical veins 57 77 99 70 87 81 0.132
 Isolated jugular sinus 30 41 53 37 44 41 0.830
 Isolated cavernous 25 34 60 42 49 45 0.284
 Sinuses 13 18 17 12 17 16 0.490
 Transverse sinuses 2 3 11 8 3 3 0.120
 Sigmoid sinuses 0 0 2 1 1 1 0.798
 Sagittal sinuses
 Internal jugular vein
 Cortical veins
 Cavernous sinuses
Parenchymal involvement
 No lesion 48a 65 63b 44 53b 49 0.002
 Infarction 12a 16 37a 26 17a 16
 Hemorrhagic 12a 16 40a 28 28a 26
 Infarction 2a 3 2a 1 10b 9
 Intracerebral
 Hemorrhage

MRI: magnetic resonance imaging; MRV: magnetic resonance venography; CT: computed tomography.

A history of deep venous thrombosis ratio was found high in the pregnancy group. Hematologic and genetic tests and Ranking scales were similar among the groups. A comparison of etiological factors and outcomes of subgroups is seen in Table 4.

Table 4.

Etiological factors and outcome of subgroups according to reproductive health-related risks.

Compared data of reproductive health-related risk factors Pregnancy Puerperium Oral contraceptive use p
n = 74% n = 142% n = 108 %
Infections
 Paracranial (focal) 2 3 4 3 7 7 0.589
 Systemic 1 1 3 2 1 1
History of VTE
 Cerebral 0a 0 1a 1 1a 1
 Deep venous thrombosis 3a 4 0b 0 0b 0 0.030
 Other 0a 0 2a 1 0a 0
 Malignancy 0 0 1 1 0 0 0.526
 Family history VTE 1 1 0 0 0 0 0.228
 MTHFR mutation
 Heterozygote, homozygote 1 2 5 5 3 5 0.385
 Hyperhomocysteinemia 1 2 7 7 1 2 0.204
 Prothrombin mutation 0 0 5 4 4 5 0.240
 Protein C/S deficiency 0 0 3 3 4 6 0.361
 Factor V Leiden mutation 3 5 8 7 2 2 0.335
 Thrombocytosis 4 9 3 3 4 6 0.716
 Polycythemia vera 1 2 1 1 0 0 0.241
 Anticardiolipin Ab 0 0 0 0 0 0
 PAI mutation 0 0 1 1 0 0 0.517
 Antithrombin III deficiency 0 0 1 1 1 2 0.718
 Hyperfibrinogenemia 0 0 0 0 1 1 0.568
 Antiphospholipid Ab 2 3 0 0 0 0 0.057
 Activated protein C 1 2 3 3 0 0 0.362
 Resistance 1 2 1 1 2 2 0.821
 High ANA titers 0 0 4 4 0 0 0.122
First month Rankin
 0-1 49 78 102 78 85 86 0.177
 2 7 11 18 14 12 12
 >3 7 11 11 8 2 2
Third month Rankin
 0-1 45 92 103 89 79 94
 2 3 6 10 9 4 5 0.828
 >3 1 2 3 3 1 1
Sixth month Rankin
 0-1 44 96 100 94 71 97
 2 1 2 4 4 1 1 0.937
 >3 1 2 2 2 1 1
12th month Rankin
 0-1 34 97 87 95 64 100
 2 1 3 3 3 0 0 0.409
 >3 0 0 2 2 0 0

ANA: antinuclear antibody; MTHFR: methylenetetrahydrofolate reductase; PAI: plasminogen activator inhibitor; VTE: venous thromboembolism.

4. Discussion

Pregnancy, puerperium, and hormone replacement treatment increase the tendency to cerebral venous sinus thrombosis (CVST) in women. CVST is much more frequently seen in women than in men -a ratio of 3/1 [6]. In the study of Coutinho et al., female ratio was found to be 75% and female gender-specific risk factors at 65% [4]. In the International Study on Cerebral Venous and Dural Sinus Thrombosis (ISCVST), the female ratio was found to be 75% of patients. Gender-specific risk factors such as OCs, pregnancy, puerperium, and hormone replacement therapy were responsible [7]. The results of meta-analyses showed that gender-specific risk factors were only not effective in children and the elderly female groups and that the use of OCs increased venous thrombosis development in reproductive age females [8]. In our study, the female ratio was found to be 68% and gender-specific risks which were grouped as RHRF (+) by us were found in 41% of women. Our findings are similar to the results of previous studies.

In our study, the mean age of women with reproductive health-related risk factors (RHRF) was lower than that of the RHRF (-) group. In subgroup analyses of RHRF (+) cases, the mean age of OC users was higher than that of the other groups. This difference may be related to planning of the age of pregnancy [3].

Previous venous thrombosis history, thrombophilia, certain medical comorbidities, obesity, smoking, and postpartum hemorrhage increase the risk of CVST [9, 10]. In our study, the highest part of the RHRF (+) group consisted of cases of puerperium. Puerperium often occurs in the sixth to eighth week after delivery. In different population-based case-control studies on venous thrombosis, it was explained that risk increased 5-fold in the pregnancy period and a 60-fold in the puerperium [11]. Also, it has been reported that it occurs more commonly after a cesarean birth than a vaginal birth [12]. Infection, high maternal age and excessive vomiting during pregnancy increase the development of CVST [13]. All of the hormone levels, cardiovascular system, and pregnancy-related hematologic changes return to the baseline state within the slow process of puerperium. Human chorionic gonadotropin (hCG) and sex steroids are at low levels for the first 2-3 weeks. These changes may cause the tendency to thrombosis [1416].

In our study, headache was the most frequent symptom for all subgroups. However, epileptic seizures were higher in the puerperium group. In the study of Kashkoush et al., the highest frequencies of symptom were found to be headache (74%), seizure (50%), and an altered consciousness (45%) in puerperium [17].

The inherited mutations in anticoagulant or thrombolytic factors genes (the Factor V Leiden, the prothrombin Factor II) and mutations in genes coding for proteins C and S may increase the risk of developing venous thrombosis [18]. We did not find any relationship between inherited risk factors and CVST.

Venous thrombosis risk increases with OC use. Combined OCs containing estrogen and progesterone have higher risk [19]. When the patient has a history of previous CVST, the recurrence risk is increased by OC use [20, 21]. We did not determine the content of the OCs. In the RHRF (-) group, a previous history of CVST was high. In the subgroup analysis, a previous history of CVST was high in the “pregnancy group.” Very little is known about the relapse rate during pregnancy and puerperium in women with a history of CVST [22]. The results of our study suggest that physicians must keep in mind the possible recurrence of CVST in pregnancy.

In our study, malignancy was more frequent in the RHRF (-) group. It has been reported that cancer patients have an increased risk of tendency of venous thrombosis [23].

In the study by Lee et al., it has been reported that the transverse sinus is involved in the majority of cases (75.6%). Sigmoid sinus and superior sagittal sinus involvement followed it at ratios of 58.5% and 29.3%, respectively [24]. In our study, the “transverse sinus” was affected more than other venous sinuses. On the other hand, isolated cavernous sinus involvement was significantly high in RHRF (-) group. Cavernous sinus involvement is high in the presence of septicemia and malignancy [25]. Therefore, in our study, this result was expected to be more in the RHRF (-) group.

It has been reported that the prognosis in pregnant patients is better than in nonpregnant patients with CVST if they receive timely treatment [26]. In the VENOST main study, the prognosis of CVST was found to be better in women than men [1]. In our subgroup analysis, the prognosis was found to be worse in the RHRF (-) group.

5. Conclusions

Our results indicate that when CVST was detected in women with RHFR (-), the existence of malignancy should be investigated. The previous history of CVST may be related to recurrence in pregnancy. Clinical onset may present with chronic headache in CSVT cases related to OC use. Epileptic seizures may be a more frequent symptom in puerperal CSVT cases. Physicians must keep these situations in mind.

Contributor Information

Sevki Sahin, Email: drsahin@gmail.com.

Taskin Duman, Email: taskinduman@yahoo.com.

Data Availability

All data will be available on request.

Conflicts of Interest

The authors declared that they have no conflicts of interest for this article.

Authors' Contributions

Sevki Sahin and Taskin Duman have contributed equally.

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Data Availability Statement

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