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

Authors: Derya Uluduz; Sevki Sahin; Taskin Duman; Serefnur Ozturk; Vildan Yayla; Nazire Afsar; Nevzat Uzuner; Ipek Midi; Nilgun Cinar; Mehmet Ali Sungur; Fusun Mayda Domac; Birsen Ince; Baki Goksan; Cemile Handan Misirli; Mustafa Bakar; Hasan Huseyin Kozak; Sena Colakoglu; Ali Yavuz Karahan; Eylem Ozaydin Goksu; Fatih Ozdag; Mehmet Guney Senol; Vedat Ali Yurekli; Ufuk Aluclu; Serkan Demir; Hayriye Kucukoglu; Serdar Oruc; Nilufer Yesilot; Ozge Yimaz Kusbeci; Bijen Nazliel; Firdevs Ezgi Ucan Tokuc; Hesna Bektas; Fatma Nida Tascilar; Emrah Aytac; Mustafa Gokce; Hale Zeynep Batur Caglayan; Ahmet Tufekci; Gulnur Uzuner; Dilek Necioglu Orken; Osman Ozgur Yalin; Uygar Utku; Arda Yilmaz; Hamit Genc; Murat Cabalar; Aysel Milanlioglu; Hakan Ekmekci; Burcu Zeydan; Sevim Baybas; Yuksel Kablan; Basak Karakurum Goksel; Mustafa Acikgoz; Hatice Kurucu; Seden Demirci; Taskin Gunes
Journal: Stroke Research and Treatment
 (2020)

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## 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.


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## Body

## 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 [1–4]. 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 Table1.Table 1
Compared data of demographic and clinical aspects of groups.
Compared dataRHRF (-)RHRF (+)pn=453n=324AgeYears43.2±13%34±9%<0.001Mode of onsetAcute187a42195b62Subacute150a3482b26<0.001Chronic110a2538b12Clinical symptoms and signsIsolated headache1192666200.057Headache38785282870.523Nausea and vomiting11626107330.024Epileptic seizures982211034<0.001Visual field defect1312966200.007Focal neurological deficit721681250.002Altered consciousness781767210.222Cranial nerve palsies59132470.012Radiological work-upCranial MRI2352370.492Cranial MRV194124Cranial MRI+MRV3988828488Cranial CT+MRV10241Number of sinuses involved1 sinus23051143440.2812 sinuses1483312639More than 2 sinuses75165517Involved sinusesIsolated transverse sinuses1222778240.369Isolated sagittal sinuses661544140.697Isolated sigmoid sinuses184720.158Isolated cortical veins821130.147Isolated jugular sinuses92100.052Isolated cavernous sinuses61000.044Transverse sinuses32973243750.459Sigmoid sinuses18340127390.736Sagittal sinuses15735134410.057Internal jugular vein711647150.655Cortical veins1331650.134Cavernous sinuses123310.085Parenchymal involvementNo lesion280a62164b510.003Infarction87a1966a20Hemorrhagic infarction68a1580b25Intracerebral hemorrhage18a414a4MRI: 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 Table2.Table 2
Comparison of etiological factors and outcome according to the RHRF (-) group or the RHRF (+) group.
Compared dataRHRF (-)RHRF (+)pn=453%n=324%InfectionsParacranial (focal) systemic2041340.9637252History of VTECerebral11a22a0.6Deep venous thrombosis14a33b10.024Other6a12a0.6Malignancy32710.3<0.001Family history VTE5110.30.409MTHFR mutationHeterozygote197940.120Homozygote24894Hyperhomocysteinemia123930.952Prothrombin mutation52730.249Protein C/S deficiency2571350.302Factor V Leiden mutation1141150.405Thrombocytosis20.5210.753Polycythemia vera31000.267Anticardiolipin Ab20.510.40.752PAI mutation41210.681Antithrombin III deficiency3110.40.642Hyperfibrinogenemia00210.178Antiphospholipid Ab72420.767Activated protein C51420.892Resistance134420.114High ANA titersFirst month Rankin0-130480236810.276240113713>33810207Third month Rankin0-1287892279122171770.235>315552Sixth month Rankin0-126290215962166630.061>31354212th month Rankin0-123991185972114420.031>313521ANA: 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 Table3.Table 3
Comparison of demographic and clinical characteristics of subgroups according to reproductive health-related risks.
Compared data of reproductive health-related risk factorsPregnancyPuerperiumOral contraceptive usepn=74, 23%n=142, 44%n=108, 33%AgeYears32.2±6a32±7a38±9b<0.001Mode of onsetAcute51a7085a6259a56Subacute14a1942a3126b25<0.030Chronic8a,b1110b720a19Clinical symptoms and signsIsolated headache1622241726240.361Headache69931178296890.062Nausea and vomiting2230433042390.283Epileptic seizures18a2463b4429a270.002Visual field defect1723282021190.817Focal neurological1115412929270.068Deficit1622342417160.277Altered consciousness68861090.537Cranial nerve palsiesRadiological workupCranial MRI46129770.975Cranial MRV346433Cranial MRI+MRV6589122869790Cranial CT+MRV112111Number of sinuses involved1 sinus3547684840370.4902 sinuses263551364945More than 2 sinuses131823161918Involved sinusesIsolated transverse2128342423210.547Sinuses1115201413120.838Isolated sagittal2332210.926Sinuses1196110.051Isolated sigmoid0011000.526Sinuses000000—Isolated cortical veins5777997087810.132Isolated jugular sinus3041533744410.830Isolated cavernous2534604249450.284Sinuses1318171217160.490Transverse sinuses23118330.120Sigmoid sinuses0021110.798Sagittal sinusesInternal jugular veinCortical veinsCavernous sinusesParenchymal involvementNo lesion48a6563b4453b490.002Infarction12a1637a2617a16Hemorrhagic12a1640a2828a26Infarction2a32a110b9IntracerebralHemorrhageMRI: 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 Table4.Table 4
Etiological factors and outcome of subgroups according to reproductive health-related risks.
Compared data of reproductive health-related risk factorsPregnancyPuerperiumOral contraceptive usepn=74%n=142%n=108%InfectionsParacranial (focal)2343770.589Systemic113211History of VTECerebral0a01a11a1Deep venous thrombosis3a40b00b00.030Other0a02a10a0Malignancy0011000.526Family history VTE1100000.228MTHFR mutationHeterozygote, homozygote1255350.385Hyperhomocysteinemia1277120.204Prothrombin mutation0054450.240Protein C/S deficiency0033460.361Factor V Leiden mutation3587220.335Thrombocytosis4933460.716Polycythemia vera1211000.241Anticardiolipin Ab000000—PAI mutation0011000.517Antithrombin III deficiency0011120.718Hyperfibrinogenemia0000110.568Antiphospholipid Ab2300000.057Activated protein C1233000.362Resistance1211220.821High ANA titers0044000.122First month Rankin0-149781027885860.177271118141212>371111822Third month Rankin0-14592103897994236109450.828>3123311Sixth month Rankin0-1449610094719721244110.937>312221112th month Rankin0-1349787956410021333000.409>3002200ANA: 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 [14–16].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.



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