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REVIEW ARTICLE
Year : 2022 | Volume
: 8
| Issue : 4 | Page : 180-187
Cerebral venous sinus thrombosis in pregnancy and puerperium: A comprehensive review
Hussein Algahtani1, Abdulrahman Bazaid2, Bader Shirah3, Raghad N Bouges4
1 Department of Medicine, Neurology Section, King Abdulaziz Medical City; King Abdullah International Medical Research Center; College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
2 Department of Obstetrics and Gynecology, King Salman Medical City, Madinah, Saudi Arabia
3 Department of Neuroscience, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia
4 College of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
Correspondence Address:
Hussein Algahtani
P.O. Box: 12723, Jeddah 21483
Saudi Arabia
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/bc.bc_50_22
Cerebral venous sinus thrombosis (CVST) is a distinct neurological emergency caused by occlusion, either partial or complete, of the dural venous sinus and/or the cerebral veins. It occurs more frequently in women during pregnancy and puerperium as compared to the general population. The clinical diagnosis is difficult in some cases due to its variable clinical presentation with numerous causes and risk factors. The diagnosis can be made at an early stage if clinical suspicion is high with the help of advanced neuroimaging techniques that were developed recently. Early therapeutic intervention using anticoagulants allows for preventing complications and improving outcomes. In this article, we review the topic of CVST in pregnancy and the postpartum period with an emphasis on its epidemiology, pathophysiology, clinical presentation, and treatment. We also elaborate on several practical points that are important to the treating team. This review will help obstetricians, neurologists, and emergency physicians diagnose affected pregnant women as early as possible to provide prompt treatment and avoid adverse outcomes.
Keywords: Cerebral venous sinus thrombosis, hypercoagulability, pregnancy, puerperium
Cerebral venous sinus thrombosis (CVST) is an uncommon and distinct neurological emergency that develops more frequently in women during pregnancy and puerperium as compared to the general population.[1] It is caused by occlusion, either partial or complete, of the dural venous sinus and/or the cerebral veins.[2] It has a highly variable clinical presentation with numerous causes and risk factors that make clinical diagnosis difficult.[3] Advances in neuroimaging techniques allow confirmation of diagnosis at an early stage if clinical suspicion are high.[4] Early diagnosis and therapeutic intervention with anticoagulants allow for a good outcome.[5] In this article, we review the topic of CVST in pregnancy and the postpartum period with an emphasis on its epidemiology, pathophysiology, clinical presentation, and treatment. We also elaborate on several practical points that are important to the treating team. This review will help obstetricians, neurologists, and emergency physicians diagnose affected pregnant women as early as possible to provide prompt treatment and avoid adverse outcomes.
HistoryDescriptions of patients who experienced symptoms indicating the puerperal CVST were first described in a Hippocratic manuscript [Figure 1]. It was not until two millennia later that the recognition of this clinical entity was established when autopsies became a part of clinical practice and medical education. The first postmortem description of CVST was reported in 1825 by the French physician Ribes,[6] who reported the history and postmortem examination of a 45-year-old male who passed away after a history of headache, delirium, and seizures for 6 months. He discovered widespread malignancy and thrombosis of the superior sagittal sinus, left lateral sinus, and the cortical vein in the parietal cortex. In 1828, John Abercrombie described a case of CVST during puerperium.[7] For more than a century, several names have been mistakenly given to this disorder, including puerperal hemiplegia, puerperal aphasia, and late postpartum eclampsia (proven on autopsy to be CVSTs). It was not until 1940 that Symonds defined this syndrome and outlined a basis for its diagnosis[8][Figure 2]. In 1942, Stansfield first used heparin to treat patients presenting with CVST.[9] Until 1968, postpartum strokes were mistakenly diagnosed as CVST, which was erroneous since most of these cases were demonstrated to be arterial in origin.[10] The first practical method for confirming the clinical diagnosis of CVST was X-ray contrast angiography. This was the standard method for diagnosis until it was replaced several years later by completely noninvasive magnetic resonance imaging (MRI) and computerized tomography techniques.[11]
Figure 2: A hand-drawn figure showing Sir Charles Putnam Symonds (1890–1978) Epidemiology CVST is a rare but serious neurological problem that accounts for 0.5%–1% of all cases of stroke.[12] Although CVST has a specific predilection for young female adults, it may affect patients of all ages, including neonates. Owing to the lack of a specific and well-designed epidemiological study devoted to addressing the exact incidence of CVST, the true incidence is unknown. The estimated annual incidence is 3–5 cases per 1,000,000 adults.[13] The incidence is possibly higher due to the improved awareness of the disease and the enhanced accessibility to better and more sensitive neuroimaging techniques. Pregnancy and puerperium are important risk factors that account for approximately 20% of CVST cases.[14] Venous strokes represent 6%–64% of all maternal strokes during pregnancy.[14] Up to 75% of CVST cases in adults are in women, which could be explained by the relationship between hormonal contraceptives, pregnancy, and puerperium.[14] Most cases associated with puerperium occur at 2 and 3 weeks postpartum.[14] The incidence of puerperal CVST in the United States of America and Europe varies from 1 to 2,500 deliveries to <1/10,000.[15],[16] In developing countries, such as India, the incidence of puerperal CVSTs is much higher (approximately 400–500/100,000 deliveries) due to delivery at home, fat and calorie-rich diets, occurrence during the third trimester, and water restriction during the 1st day after delivery.[17]
Mode of Onset and TimingThe mode of onset of CVST is highly variable which may result in difficulty in diagnosing this condition based on clinical grounds alone without a significant delay in disease management.[18] The onset may be acute (<2 days), subacute (between 2 days and 1 month), or chronic (more than 1 month). Acute presentation occurs in 20%–30%, subacute in 50%–60%, and chronic in 10%–20% of cases.[19] CVST often presents either in the postpartum period (75% of cases) or late pregnancy (third trimester) although it may occur at any time during normal pregnancy.[20] Interestingly, there is a spike in incidence during the first trimester, and several cases have been reported as early as 8 weeks of gestation. This uncommon occurrence is probably due to women who became pregnant while suffering from underlying thrombophilia or developing complications (e.g. spontaneous or therapeutic abortion).[21] The overall proportion estimates of pregnancy-related CVST in women with CVST is 25%.[22]
Physiological Hematological Changes during Pregnancy and PuerperiumPregnancy and the postpartum period are usually accompanied by several physiological alterations, including a predisposition of maternal cardiovascular circulation, hormonal variations in estrogen levels, and changes in the coagulation system.[23] To face the hemostatic challenges of delivery, physiological adaptations of the body occur in the form of enhancement of procoagulants and inhibition of anticoagulants. These changes in maternal coagulation include increased levels of coagulation factors (V, VII, VIII, IX, X, XII, and von Willebrand factor) and fibrinogen levels. In addition, alterations in intrinsic anticoagulation factors occur, such as a decrease in total Protein S and an increase in activated Protein C resistance. The risk of CVST is further exacerbated by the presence of prothrombotic conditions (e.g. factor V Leiden gene mutations).[24] Other changes include an increase in the aggregating ability of platelets and a reduction in the responsiveness to prostacyclin. These changes may also favor coagulation.[25] Other changes in hematological parameters include an increase in red blood cell volume, hemoglobin mass, oxygen-carrying capacity, white blood cell count, and humoral immunity.[26] Reduction in other parameters, including hematocrit, packed red blood cell volume, and viscosity of the blood may also contribute to increased coagulation.[27] During pregnancy, blood volume starts to increase at 10 weeks, with a maximum increase observed at 34 weeks, and an average increase in blood volume of 30%–60%.[28] In twin pregnancies, the increase in blood volume is 40%–80%.[29] Other hemodynamic and structural changes include an increase in nitric oxide and venous capacitance and a reduction in collagen and elastin content of systemic arteries. Such changes in the vessel wall result in greater hemodynamic stress and an increased risk of several hemorrhagic conditions in the brain[30][Figure 3].
Figure 3: Physiological hematological changes during pregnancy and puerperium Pathogenesis The clinical neurological features are postulated to be caused by either increased venous pressure or intracranial hypertension due to decreased cerebrospinal fluid absorption. The presence of a thrombus within a sinus or a cortical vein causes sinus occlusion with subsequent backflow of blood into venules and capillaries, leading to increased local venous pressure. The increase in venous pressure causes a reduction in cerebral perfusion, ischemic injury, cytotoxic edema, disruption of the blood–brain barrier (causing vasogenic edema), and rupture of the vessel wall (causing parenchymal hemorrhage). Furthermore, sinus occlusion can result in dysfunction of arachnoid granulations with a subsequent decrease in cerebrospinal fluid absorption. Impaired cerebrospinal fluid absorption causes elevation of intracranial pressure with worsening of venular and capillary hypertension, as well as cytotoxic and vasogenic edema and parenchymal hemorrhage.[3]
Risk FactorsHypercoagulability has a key role in CVST development during pregnancy and puerperium. These alterations in the coagulation system are more pronounced in the third trimester. The prothrombotic state is worsened by dehydration, excessive vomiting, prolonged bed rest, pregnancy-induced hypertension, and local obstetric trauma during delivery (instrumental delivery and cesarean section). In addition, anemia, infection, and the younger age of pregnancy (14–25 years) are considered to be independent risk factors for the development of obstetric CVST.[31]
Clinical FeaturesThe most common presenting symptoms of CVST in pregnancy and the postpartum period include headache, obtundation, motor deficits, seizures, and visual changes[5][Table 1]. Headache is usually a gradual-onset high-pressure phenotype, i.e. progressive in nature and worsens with the Valsalva maneuver and while lying down (postural relationship). Headache in CVST is commonly described as diffuse, although thunderclap headaches may be the presenting feature.[32] The onset of symptoms is usually subacute, with a mean duration from symptom onset to diagnosis of 5.9 days. The erroneous attribution of symptoms to preeclampsia or postdural puncture headache is the main reason for delayed diagnosis.[33] Seizures are usually partial in onset with or without secondary generalization, and status epilepticus is a remarkably serious presentation. The incidence of seizures in CVST patients is far higher compared to patients with arterial stroke.[34] Approximately one-quarter of patients may present with a syndrome resembling benign intracranial hypertension, with headache, visual disturbance, and papilledema.[35] Physical examination may be remarkable for papilledema, signs of meningeal irritation from subarachnoid bleeding secondary to cortical infarction, and focal deficits.[36] Cerebrospinal fluid pressure is typically raised, and its analysis may reveal increased protein or cellular content.[37]
Table 1: Presenting symptoms of cerebral venous sinus thrombosis in pregnancy and postpartum period Neuroimaging Most patients with CVST require brain imaging to confirm the diagnosis and exclude conditions with similar presentations such as preeclampsia or eclampsia. The goals are to minimize ionizing radiation, avoid intravenous contrast exposure, and optimize the diagnostic yield by selecting the correct tool and sequence.[38] MRI and magnetic resonance venography (MRV) are reliable tools for detecting thrombosis in large cerebral veins and sinuses. MRV is mainly obtained with noncontrast techniques such as two-dimensional time of flight or three-dimensional phase contrast venography. Contrast-enhanced MRV techniques are also available. In pregnant patients, MRI is generally considered safe, despite the lack of conclusive data. It is better to avoid the use of gadolinium unless the information to be gained by its use exceeds its potential risk since repeated supraclinical doses of gadolinium were associated with fetal demise and malformation in animal studies. Radiological abnormalities on MRI include intraluminal thrombi and parenchymal lesions, including venous infarct and intracerebral hemorrhage[39][Figure 4]. A combination of MRI and MRV is essential for the diagnosis of CVST. Susceptibility-weighted sequences along with other standard MR sequences are essential to identify clots in the acute and subacute stages without the need for intravenous contrast. Diffusion-weighted image is very sensitive to identify late subacute clots. Susceptibility contrast also permits the identification of hemorrhagic venous infarcts and subarachnoid hemorrhage from CVST. Computed tomography (CT) venography can be used as a reliable alternative to MRV for confirming the diagnosis of obstetric CVST in patients with contraindications to MRV or in centers that lack MRI facilities [Figure 5]. CT venography is thought to be as accurate as MRV, although it has important limitations, including a reduced sensitivity for detecting parenchymal lesions and cortical vein thrombosis.[40] With advances in CT and MRI, digital subtraction angiography is mainly used nowadays, when there is a need to perform an endovascular intervention to remove sinus clots.[41]
Figure 4: MRI of the brain showing CVST involving the anterior two-thirds of the superior sagittal sinus extending into its bilateral frontal cortical tributaries, bilateral frontal hemorrhagic venous infarctions centered on the bilateral superior frontal and extending posteriorly on the left side to involve the precentral gyrus, surrounded by peri-hemorrhagic vasogenic edema. MRI: Magnetic resonance imaging, CVST: Cerebral venous sinus thrombosis
Figure 5: CT venography showing CVST involving more than the anterior two-thirds of the superior sagittal sinus extending into the bilateral superior frontal cortical veins. CT: Computed tomography, CVST: Cerebral venous sinus thrombosis Treatment The management of obstetric CVST requires a multidisciplinary approach that includes supportive care, measures to lower intracranial pressure, treatment of seizures and any existing infection, and prevention of further thrombosis.[42] The standard treatment for obstetric CVST in the hyperacute phase involves subcutaneous low-molecular-weight heparin (LMWH). This treatment is also used in patients with CVST and intracranial hemorrhage.[43] The LMWH enoxaparin has a good safety profile, high bioavailability, long plasma half-life, does not cross the placenta and is not excreted in breast milk. In addition, it reduces the risk of occurrence and recurrence of preeclampsia and eclampsia.[44] The recommended initial dose of subcutaneous enoxaparin is 1 mg/kg every 12 h throughout pregnancy. It should be discontinued 24 h before the induction of labor or performing a cesarean section. It should be resumed 4–6 h after vaginal delivery or 6–12 h after cesarean section. It is recommended that LMWH be continued in pregnant women with CVST for at least 6 weeks' postpartum.[45]
Intravenous unfractionated heparin has the advantage of a short half-life, dose adjustment based on monitoring activated partial thromboplastin time and can be antagonized using protamine sulfate.[46] However, associations with an elevated risk of fetal bleeding and teratogenicity have led to the recommendation of LMWH instead of unfractionated heparin during the hyperacute phase in obstetric patients with CVST.[47]
Vitamin K antagonists and direct oral anticoagulants (e.g. apixaban, edoxaban, rivaroxaban, and dabigatran) are contraindicated during pregnancy due to their ability to cross the placenta and cause neurodevelopmental teratogenic disorders and fetal bleeding.[48] High-risk patients with recurrent venous thromboembolism or underlying thrombophilic conditions require lifelong oral anticoagulation therapy postpartum.[49]
Brain herniation due to a large hemorrhagic venous infarction in the acute setting of obstetric CVST can cause death.[50] Studies evaluating thrombolysis and mechanical thrombectomy during pregnancy and puerperium are limited.[51] Similarly, surgical intervention using decompressive surgery is scarcely described.[52] These interventions should not be withheld in potentially fatal or debilitating cases of obstetric CVST. Further evaluation of these interventions in pregnant and puerperal patients is warranted to establish the guidelines for endovascular or surgical therapy.
At present, anticoagulants are the standard treatment for CVST, but endovascular treatment has also been reported to be effective. Such treatments include mechanical thrombectomy, stent retrieval, aspiration technique, or microcatheter in combination with local urokinase thrombolytic treatment administered continuously. In a recent systematic review, the quality of the available data was limited, and only one randomized controlled trial was identified with a total sample size of 33 patients.[53],[54] The results of this showed that there is no difference between endovascular techniques and anticoagulation in terms of functional outcome. Most of the studies included in this systematic review were case reports, prospective case series, and retrospective analyses. Although there is a lack of sufficient evidence, endovascular treatment should be fully considered for the purpose of saving the mother's life. This is especially correct in patients with suspected poor outcomes as part of individual healing attempts. Such patients may include a patient with substantial thrombus material that is not responding to anticoagulation, those in need of intensive care, and those with vaccine-induced immune thrombotic thrombocytopenia. Further randomized controlled trials are warranted to investigate patient selection, treatment strategies, and timing of the intervention.[53]
PrognosisThe prognosis of obstetric CVST is variable, with a reported mortality rate ranging from 4% to 33%.[55] When a pregnant woman presents with an isolated headache with no motor deficit or change in the level of consciousness, the prognosis is good. Poor prognostic factors include an acute fulminant course, bilateral hemorrhagic venous infarction, and diffuse cerebral edema [Figure 6]. Other poor prognostic factors include a low Glasgow coma scale score (below 9), involvement of the deep cerebral venous system, and underlying systemic disease with poor prognosis (malignancy and cerebral or systemic infection). Neuropsychiatric manifestations and pseudotumor cerebri-like presentations have favorable prognoses.[56] The risk of CVST recurrence in subsequent pregnancies is low, and the rate of miscarriage is not significantly different from that estimated for the general population.[57] For women with a history of CVST, contraceptives containing estrogens should be avoided, and future pregnancy is not contraindicated as long as prophylactic LMWH is administered during pregnancy.[58]
Figure 6: MRI of the brain of a young pregnant woman showing CVST with intracerebral hemorrhage and cerebral edema (upper raw) and follow-up MRI 6 months after delivery showing encephalomalacia. MRI: Magnetic resonance imaging, CVST: Cerebral venous sinus thrombosisAlthough there are no data to suggest a difference in the fetal outcome between healthy pregnant women and pregnant women with CVST treated with anticoagulation, further studies are needed to determine the fetal outcome in pregnancy-related CVST. In addition, studies should evaluate the fetal outcome when prophylactic LMWH is administered during pregnancy for women with a history of CVST.
ConclusionCVST is an infrequent but serious and fatal cerebrovascular emergency that may occur during pregnancy or in the postpartum period. The high occurrence of CVST during pregnancy may be explained by several factors, including venous stasis, physiological hypercoagulability, and microtrauma of the venous wall. Immediate anticoagulation therapy with LMWH is recommended when CVST is suspected as it can significantly improve the outcome. Multidisciplinary care with different teams is highly recommended. Further research is needed to explore several aspects of CVST during pregnancy.
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