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

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

doi:https://doi.org/10.1155/2020/8610903

Stroke Research and Treatment

On this page

Abstract Introduction Materials and Methods Results Discussion Conclusions Data Availability Conflicts of Interest Authors’ Contributions References Copyright Related Articles

Research Article | Open Access

Volume 2020 | Article ID 8610903 | https://doi.org/10.1155/2020/8610903

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

Derya Uluduz,¹Sevki Sahin,²Taskin Duman,³Serefnur Ozturk,⁴Vildan Yayla,⁵Nazire Afsar,⁶Nevzat Uzuner,⁷Ipek Midi,⁸Nilgun Cinar,²Mehmet Ali Sungur,⁹Fusun Mayda Domac,¹⁰and Birsen Ince¹ et al.

Academic Editor: Francisco Campos

Received30 Nov 2019

Accepted15 May 2020

Published01 Sept 2020

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 ( 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 ( 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 [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% () of the total 777 female cases were classified as RHRF (-) and 42% () of them as RHRF (+). The mean ages of the RHRF (+) group and the RHRF (-) group were and , 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 (). Parenchimal lesion involvement, especially hemorrhagic transformation (, 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 (, 73%), within the RHRF (+) group (, 75%), and within the RHRF (-) group (, 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.

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.

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.

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.

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.

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.

References

T. Duman, D. Uluduz, I. Midi et al., “A Multicenter Study of 1144 Patients with Cerebral Venous Thrombosis: The VENOST Study,” Journal of Stroke and Cerebrovascular Diseases, vol. 26, no. 8, pp. 1848–1857, 2017.
View at: Publisher Site | Google Scholar
A. Ameri and M.-G. Bousser, “Cerebral venous thrombosis,” Neurologic Clinics, vol. 10, no. 1, pp. 87–111, 1992.
View at: Publisher Site | Google Scholar
M. Galarza and R. Gazzeri, “Cerebral venous sinus thrombosis associated with oral contraceptives: the case for neurosurgery,” Neurosurgical Focus, vol. 27, no. 5, article E5, 2009.
View at: Publisher Site | Google Scholar
J. M. Coutinho, J. M. Ferro, P. Canhão et al., “Cerebral venous and sinus thrombosis in women,” Stroke, vol. 40, no. 7, pp. 2356–2361, 2009.
View at: Publisher Site | Google Scholar
C. Cantu and F. Barinagarrementeria, “Cerebral venous thrombosis associated with pregnancy and puerperium. Review of 67 cases,” Stroke, vol. 24, no. 12, pp. 1880–1884, 1993.
View at: Publisher Site | Google Scholar
J. Stam, “Thrombosis of the Cerebral Veins and Sinuses,” The New England Journal of Medicine, vol. 352, no. 17, pp. 1791–1798, 2005.
View at: Publisher Site | Google Scholar
J. M. Ferro, P. Canhao, J. Stam, M. G. Bousser, F. Barinagarrementeria, and ISCVT Investigators, “Prognosis of cerebral vein and dural sinus thrombosis: results of the international study on cerebral vein and dural sinus thrombosis (ISCVST),” Stroke, vol. 35, no. 3, pp. 664–670, 2004.
View at: Publisher Site | Google Scholar
J. M. Ferro, P. Canhao, M. G. Bousser, J. Stam, and F. Barinagarrementeria, “Cerebral vein and dural sinus thrombosis in elderly patients,” Stroke, vol. 36, no. 9, pp. 1927–1932, 2005.
View at: Publisher Site | Google Scholar
J. A. Heit, “Epidemiology of venous thromboembolism,” Nature Reviews Cardiology, vol. 12, no. 8, pp. 464–474, 2015.
View at: Google Scholar
E. Jackson, K. M. Curtis, and M. E. Gaffield, “Risk of venous thromboembolism during the postpartum period,” Obstetrics and Gynecology, vol. 117, no. 3, pp. 691–703, 2011.
View at: Publisher Site | Google Scholar
E. R. Pomp, A. M. Lenselink, F. R. Rosendaal, and C. J. M. Doggen, “Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study,” Journal of Thrombosis and Haemostasis, vol. 6, no. 4, pp. 632–637, 2008.
View at: Publisher Site | Google Scholar
C. Jaigobin and F. L. Silver, “Stroke and pregnancy,” Stroke, vol. 31, no. 12, pp. 2948–2951, 2000.
View at: Publisher Site | Google Scholar
D. J. Lanska and R. J. Kryscio, “Risk factors for peripartum and postpartum stroke and intracranial venous thrombosis,” Stroke, vol. 31, no. 6, pp. 1274–1282, 2000.
View at: Publisher Site | Google Scholar
C. L. Dennis, K. Fung, S. Grigoriadis, G. E. Robinson, S. Romans, and L. Ross, “Traditional postpartum practices and rituals: a qualitative systematic review,” Womens Health, vol. 3, no. 4, pp. 487–502, 2016.
View at: Publisher Site | Google Scholar
N. K. Tepper, S. L. Boulet, M. K. Whiteman et al., “Postpartum venous thromboembolism: incidence and risk factors,” Obstetrics and Gynecology, vol. 123, no. 5, pp. 987–996, 2014.
View at: Publisher Site | Google Scholar
J. A. Heit, C. E. Kobbervig, A. H. James, T. M. Petterson, K. R. Bailey, and L. J. Melton III, “Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study,” Annals of Internal Medicine, vol. 143, no. 10, pp. 697–706, 2005.
View at: Publisher Site | Google Scholar
A. I. Kashkoush, H. Ma, N. Agarwal et al., “Cerebral venous sinus thrombosis in pregnancy and puerperium: a pooled, systematic review,” Journal of Clinical Neuroscience, vol. 39, pp. 9–15, 2017.
View at: Publisher Site | Google Scholar
G. J. Hankey, J. W. Eikelboom, F. M. van Bockxmeer, E. Lofthouse, N. Staples, and R. I. Baker, “Inherited thrombophilia in ischemic stroke and its pathogenic subtypes,” Stroke, vol. 32, no. 8, pp. 1793–1799, 2001.
View at: Publisher Site | Google Scholar
W. H. W. Inman, M. P. Vessey, B. Westerholm, and A. Engelund, “Thromboembolic disease and the steroidal content of Oral Contraceptives. A report to the Committee on Safety of Drugs,” BMJ, vol. 2, no. 5703, pp. 203–209, 1970.
View at: Publisher Site | Google Scholar
C. Kolacki and V. Rocco, “The combined vaginal Contraceptive Ring, NuvaRing, and cerebral venous sinus thrombosis: a case report and review of the literature,” The Journal of Emergency Medicine, vol. 42, no. 4, pp. 413–416, 2012.
View at: Publisher Site | Google Scholar
A. McDaid, E. Logette, V. Buchillier et al., “Risk prediction of developing venous thrombosis in combined oral contraceptive users,” PLOS ONE, vol. 12, no. 7, p. e0182041, 2017.
View at: Publisher Site | Google Scholar
S. Mehraein, H. Ortwein, M. Busch, M. Weih, K. Einhäupl, and F. Masuhr, “Risk of recurrence of cerebral venous and sinus thrombosis during subsequent pregnancy and puerperium,” Journal of Neurology, Neurosurgery, and Psychiatry, vol. 74, no. 6, pp. 814–816, 2003.
View at: Publisher Site | Google Scholar
J. W. Blom, J. P. M. Vanderschoot, M. J. Oostindier, S. Osanto, F. J. M. van der Meer, and F. R. Rosendaal, “Incidence of venous thrombosis in a large cohort of 66 329 cancer patients: results of a record linkage study,” Journal of Thrombosis and Haemostasis, vol. 4, no. 3, pp. 529–535, 2006.
View at: Publisher Site | Google Scholar
D. J. Lee, A. Ahmadpour, T. Binyamin, B. C. Dahlin, K. Shahlaie, and B. Waldau, “Management and outcome of spontaneous cerebral venous sinus thrombosis in a 5-year consecutive single-institution cohort,” Journal of NeuroInterventional Surgery, vol. 9, no. 1, pp. 34–38, 2016.
View at: Publisher Site | Google Scholar
F. S. Southwick, E. P. Richardoson JR., and M. N. Swartz, “Septic thrombosis of the dural venous sinuses,” Medicine, vol. 65, no. 2, pp. 82–106, 1986.
View at: Publisher Site | Google Scholar
A. Razmara, K. Bakhadirov, A. Batra, and S. K. Feske, “Cerebrovascular complications of pregnancy and the postpartum period,” Current Cardiology Reports, vol. 16, no. 10, p. 532, 2014.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2020 Derya Uluduz et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

2308

Downloads

1207

Citations