Cerebral venous thrombosis: A comprehensive narrative review

Abstract

Cerebral venous thrombosis (CVT) is a rare cause of cerebral infarction, accounting for <1% of stroke cases worldwide. The pathophysiology of CVT is multifactorial, encompassing the direct effects of thrombosis, interference with the blood–brain barrier and development of cerebral edema. Several genetic and acquired risk factors of CVT have been identified, more recently this includes the pro-thrombotic effects of coronavirus disease of 2019 infection. CVT can present with wide variation of clinical characteristics, with headache being the most common clinical manifestation. Diagnosis is based on radiological imaging. The mainstay of CVT management is prompt initiation of anti-coagulation. Failure to recognize insidious symptoms of CVT, will lead to a delay in diagnosis and consequently treatment which eventually lead to significant complications, including neurological disability and death. The aim of this narrative review is to consolidate the existing knowledge on CVT, a rare condition with a challenging diagnosis and treatment.

Introduction

Cerebral venous thrombosis (CVT) is defined as clot formation in the cerebral veins and dural venous sinuses.[1] It is a rare disorder that is associated with considerable morbidity and mortality. CVT is responsible for approximately 0.5% of all cases of stroke.[2] The purpose of this narrative review is to provide a comprehensive outlook encompassing the latest findings related to the epidemiology, pathophysiology, etiology, clinical features, diagnosis, treatment and prognosis of CVT in adults.

Epidemiology

Globally, the epidemiology of CVT has been investigated in various studies. Previously, the incidence of CVT in adults was approximately around 3–4 cases per 1 million people.[3] In 1995, Daif et al. found a frequency of 7 CVT cases per 100,000 people in Saudi Arabia.[4] Another report from the Netherlands found the rate of CVT to be 1.32 per 100,000 person-years.[5]

However, in the last decade, many studies have shown a gradual increase in the number of patients with CVT worldwide. A population-based study from 2021 conducted in Italy reported that the overall incidence of CVT was 11.6 cases per 1 million people.[6] The same study also reported gender specific incidence rates of 15.1 and 7.8 per 1 million individuals in females and males, respectively. Thus, the occurrence of CVT was greater in women and also progressively increased over time.[6] Similarly, another recent study published in 2016 found an incidence of 15.7 cases per million people per year.[7] In India, the Vellore CVT registry recorded the number of CVT cases over a period of 26 years from 1995 to 2021. The authors reported an incidence of 49 cases per 100,000 hospitalizations before 2010, which dramatically increased to 96 cases per 100,000 hospitalizations after 2010.[8] Additionally, it has been observed in several reports that the overall incidence of CVT increased worldwide during the coronavirus disease of 2019 (COVID-19) pandemic.[9]

Otite et al. found that incidence of CVT also varied according to race, with the black population being affected significantly more than Caucasians or Asians.[10] Furthermore, a clinical review on CVT by Kristoffersen et al. suggested that the geographical distribution of CVT is in parallel with the local prevalence of risk factors of CVT such as infections, inflammatory conditions, multiple pregnancies, etc.[11]

Pathophysiology

The pathogenesis of CVT is multifactorial, depending on patient risk factors, environmental risk factors, site and size of venous occlusion in the brain. Clot formation occurs based on the following factors of Virchow’s triad: endothelial injury, stasis and hypercoagulability.[12] Subsequently, the effects of thrombus formation are based on whether there is partial or complete occlusion of the venous channels, as well as the location of the occlusion. For instance, blockage of a major venous sinus would result in intracranial hypertension, whereas thrombosis of the deep, cortical venous sinuses lead to cerebral edema and stroke like symptoms.[13]

Thrombosis of the cerebral veins results in increased capillary and venous pressure that is initially compensated by the collateral circulation but eventually leads to cerebral edema. CVT can cause cerebral edema through two mechanisms – cytotoxic edema occurring as a consequence of ischemic injury and vasogenic edema due to disruption of the blood–brain barrier.[14] This cerebral edema can lead to parenchymal damage and hemorrhagic infarction.[14]

Cerebrospinal fluid (CSF) is absorbed through the arachnoid granulations that present in the cerebral venous sinuses. Thrombosis of the sinuses causes decreased absorption of CSF, resulting in intracranial hypertension.[15] Certain sinuses are more prone to thrombosis due to their anatomical features. For example, the superior sagittal sinus is frequently involved due to drainage of superficial cortical veins into this sinus against the direction of blood flow, as well as due to the presence of fibrous septa at its inferior angle. These factors lead to increased turbulence of blood flow in this region and greater susceptibility to thrombus formation.[16]

Figure 1 summarizes the pathophysiology of CVT based on the mechanisms described above.

Figure 1.

Pathophysiology of cerebral venous thrombosis

Etiology

Different risk factors may lead to the development of CVT, which are further classified as genetic and acquired causes.

Genetic causes

Genetic causes of CVT are those inherited mutations which predispose patients to the occurance of thrombosis. A retrospective study by Pai et al. conducted in India found that approximately one-fifth of their CVT cases were attributed to a state of heritable thrombophilia.[17] Among thrombophilic mutations, the prothrombin gene variant G20210A was detected in 29% of patients with CVT in a study from Italy.[18] Resistance to the effects of activated Protein C is conferred by Factor V Leiden mutation is also frequently implicated, while other genetic causes include inherited insufficiencies in the natural anticoagulants Protein C, Protein S and Antithrombin.[19] Rarely, a mutation in the methylene tetrahydrofolate reductase gene that leads to hyperhomocysteinemia has also been found to carry a four-fold increase in the risk of developing CVT.[20]

Most recently, a genome wide association study on a large cohort of patients with CVT from Europe has identified the first chromosomal region associated with a two-fold risk increase of CVT.[21] This genetic locus is also related to the genes that code for the ABO blood group system. Thus, the investigators reported a lower prevalence of CVT in blood group O individuals as compared to people with blood group A, B, or AB.[21]

Acquired causes

Among the acquired causes of CVT, pregnancy and puerperium are very frequently involved in occurrence of CVT. Pregnancy induced hypertension and undergoing cesarean section are significantly associated with CVT.[22] In a Saudi study of patients with CVT comprising predominantly of women, development of CVT was related to the use of oral contraceptive pills (OCPs) and hormone replacement therapy in up to 40% of total patients.[23] A study by Zuurbier et al. reported that the risk of CVT while on OCPs is further accentuated in obese women, especially those with a body mass index ≥ 30 (adjusted odds ratio: 29.26; 95% confidence interval: 13.47–63.60).[24]

Malignancy is a significant risk of CVT, especially in the 1^st year of getting a diagnosis of cancer. Hematological malignancies are a more common cause of CVT than solid organ tumors.[25] A study from Italy identified the JAK2V617F mutation – an acquired mutation leading to myeloproliferative neoplasms, in 6.6% of their cases.[26] Infections involving the nervous system (meningitis), head and neck (mastoiditis, otitis externa, periorbital cellulitis) as well as severe systemic infections (gastroenteritis with dehydration, respiratory tract infections) can all trigger an episode of CVT.[27]

Rarely, mechanical injury such as head trauma, neurosurgery and jugular catheterization may cause CVT due to damage to the venous walls, with subsequent endothelial injury triggering thrombosis.[14] Furthermore, approximately 1%–3% of CVT cases can be attributed to autoimmune disorders such as Systemic Lupus Erythematosus, Antiphospholipid antibodies syndrome and Behcet’s disease.[28,29]

Cerebral venous thrombosis and coronavirus disease 2019

One of the most recent updates on CVT include the role of COVID-19 infection as a predisposing factor. A retrospective cohort study from Iran published in 2022 compared the hospitalization rates of patients with CVT before and during the COVID-19 pandemic. They reported a crude hospitalization rate of 14.3 patients with CVT per 1 million population in the pre-COVID era. This figure increased dramatically to 21.7 cases per million population during the COVID-19 pandemic.[30]

It is postulated that the mechanism of CVT in COVID-19 is related to the prothrombotic state created due to COVID-19 infection. Hypercoagulability in the context of COVID-19 arises due to a complex interplay between several factors which include vascular endothelial dysfunction, altered blood flow, complement activation, cytokine storm, platelet dysfunction and the development of antiphospholipid antibodies.[31] COVID-19-related CVT is encountered more frequently in old age, with a high risk of mortality.[32] Currently, the link between COVID-19 vaccination and occurrence of CVT is also under investigation, in light of few recent reports suggesting this association.[33]

Table 1 shows genetic and acquired causes of CVT.

Table 1.

Risk factors of cerebral venous thrombosis in adults

Risk factors of CVT
Genetic	Acquired
Factor V Leiden mutation	Oral contraceptive use
Prothrombin gene mutation	Smoking
Protein C deficiency	Obesity
Protein S deficiency	Infections
Antithrombin deficiency	Pregnancy and puerperium
MTHFR mutation	Antiphospholipid syndrome
	Autoimmune disorders
	Malignancy
	Head trauma
	Neurosurgery
	Drug induced

CVT: Cerebral venous thrombosis, MTHFR: Methylene tetrahydrofolate reductase

Cases where the root cause of CVT [such as the causes mentioned in Table 1] cannot be identified are labelled as “unprovoked,” also known as “cryptogenic” CVT, seen in 27%–49% of patients.[34,35]

Clinical Presentation

CVT can manifest with a diversity of clinical characteristics. Headache is the most common symptom at the time of presentation, seen in almost 80% of patients with CVT.[24,36] A study by Petrović et al. reported the characteristics of this headache to be unilateral, severe and throbbing in nature.[37] The same study also found that while majority of CVT cases presented with headache, those patients who did not have headache has more serious signs and symptoms such as seizures and altered mental status, including coma.[37]

Results of the VENOST study, a multi-center cohort of 1,144 patients with CVT, also reported headache as the most frequent presenting complaint.[38] Furthermore, the authors found that almost one-third of their cohort reported visual field defects. Seizures and focal neurological deficits were seen more commonly in women in this cohort. A minority of their population also presented with speech problems such as aphasia and dysarthria.[38]

Another large international multi-center cohort, the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT), included 624 adult patients with CVT. This study also reported headache as the prominent symptom, and there was a stark gender predominance with 74.5% of the patients being female.[39] 143 (22.9%) of their patients had isolated intracranial hypertension on presentation around 5% were comatose on arrival with a Glasgow coma scale score of <9.[39]

Patients with CVT commonly present with focal neurological deficits such as hemiparesis, paraparesis, ataxia, diplopia, dysarthria and aphasia.[40] The occurrence of these deficits are influenced by the site of CVT involvement. A study from Saudi Arabia also identified that approximately half of the patients with CVT may present with clinical features of pseudotumor cerebri.[4]

As infections of the central nervous system, head and neck are well-established causes of CVT, around 20% of cases will present with fever.[41] Furthermore, up to third of patients may present with vomiting, as a sign of increased intracranial pressure.[42] Therefore, CVT can also present insidiously, with non-specific signs as symptoms like fever and vomiting masking the true disorder. Such clinical features can lead to a delay in diagnosis and consequently treatment. These patients require a high index of suspicion in order to be properly diagnosed.

Cases involving the deep cerebral veins, such as the basal vein of Rosenthal and the great cerebral vein of Galen, are known as deep cerebral vein thrombosis.[43] These patients tend to present with more severe symptoms, particularly a lesser degree of consciousness, more neurological disability and poor overall survival.[44]

Diagnosis

In clinically suspected cases of CVT, the diagnosis is confirmed radiologically. For this purpose, there are various imaging modalities available including computed tomography (CT) with or without the use of contrast, CT venography, magnetic resonance imaging (MRI), MR venography (MRV) and ultrasound (US).[45] Previously, CT angiography (CTA) was considered to be a highly specific and sensitive method of CVT diagnosis.[46] However, now due to practical constraints, CTA is now usually limited to those patients in whom thrombolysis is planned.

Each of these methods has their own pros and cons. CT techniques are usually preferred in the emergency setting as they provide rapid results and are cost-effective.[47] Whereas MRI and MRV provide higher sensitivity especially in the case of smaller lesions, no risk of radiation and minimal risk of side effects due to the use of contrast.[48] Ultrasound has very limited use in the context of CVT, usually reserved for suspected cases of CVT in neonates and infants.[49]

CVT can be visualized directly on CT imaging, referred to as a “dense clot sign” or “dense vessel sign” on non-contrast imaging, whereas a filling defect is noted on contrast CT.[50] The site of thrombosis also produces characteristic signs of imaging, for example, the classical “empty delta sign” refers to a triangular filling defect caused by thrombosis of the superior sagittal sinus.[51] Indirect signs of CVT include cerebral edema, cortical swelling and cerebral hemorrhage, which can be visualized on both CT and MRI techniques.[52] Another characteristic radiological feature is the “cashew nut sign,” a C-shaped appearance due to juxtacortical hemorrhages which are a highly specific finding in CVT.[53]

In a study by Sassi et al., radiological imaging showed that the superior sagittal sinus was the commonest site of CVT occurrence in approximately 70% of their patients, followed by the lateral sinus. Multiple venous sinuses were involved in over 70% patients.[41]

In addition to radiological imaging, D-dimer levels may be checked in suspected cases of CVT, similar to D-dimer testing in other conditions of thrombosis such as deep veinous thrombosis and pulmonary embolism. D-dimer testing in the context of CVT has proven to be of variable utility. A meta-analysis by Dentali et al. concluded that D-dimer testing had a sensitivity of 93.9% and specificity of 89.7% for CVT diagnosis.[54] However, another study reported false positive and false negative detection rates of 9% and 24% respectively.[55]

Furthermore, digital subtraction angiography remains the current gold standard for diagnosing CVT as it allows direct visualization of the clot.[56] However, due to its invasive nature, radiation exposure and a risk of neurological complications, its use is limited to rare circumstances which additionally require reperfusion therapy.[57] Practically, CT and MR venography remain the diagnostic modalities of choice for confirming CVT.[45]

Treatment

The purpose of treatment in CVT are to prevent clot propagation, minimize the risk of recurrent thrombosis, restore blood circulation in occluded veins and sinuses and to mitigate the effects of intracranial pressure changes, including cerebral edema, hemorrhage and brain herniation.[58] Prompt initiation of anticoagulation is considered the mainstay treatment for CVT. Surgical options are also available, as outlined below.

Medical management

While the results of considerable clinical trials on the role of anticoagulation in CVT have mostly been inconclusive, heparin has been the most widely studied drug since early 1990s.[59] Based on the initial trials and studies, heparin in either the unfractionated or low molecular weight forms has been the mainstay of management for acute CVT, regardless of the presence of cerebral hemorrhage.[60] A recent systematic review found that anticoagulation, particularly with LMWH, decrease the risk of mortality and neurological disability as compared to placebo in patients with CVT. The authors also reported that anticoagulation was beneficial in patients with CVT with or without concurrent intracranial hemorrhage (ICH), and that there were no new episodes of ICH while on anticoagulation.[61] A randomized controlled trial from India also reported that use of LMWH in patients with CVT resulted in significantly lower in-hospital mortality rates than patients who were treated with unfractionated heparin (UFH).[62] Coutinho et al. also recommended the use of LMWH as opposed to UFH in CVT,[63] whereas other reports have found LMWH and UFH to show similar results.[64,65]

Over the last decade, the direct oral anticoagulants (DOACs) have gained much popularity over the use of Vitamin K-antagonists (VKAs) such as warfarin for the management of thrombosis due to their ease of administration, few drug interactions and low risk of adverse effects.[66] A study by Hsu et al. showed that there is no significant difference in outcomes among patients with CVT treated with warfarin as compared to those receiving DOACs.[67] Another study published in 2023 reported that use of apixaban in the long term led to successful recanalization in all of their patients with CVT.[68]

In recent years, there is increasing evidence supporting DOACs use in CVT.[69,70] RE-SPECT CVT is a recent RCT which compared the use of warfarin and dabigatran in adult patients with CVT, reporting a low risk of recurrent thrombosis and hemorrhagic complications with either of the two anti-coagulant drugs.[71] Similarly, ACTION-CVT is an international, multi-center study which compared the use of warfarin with the DOACs rivaroxaban, dabigatran, and apixaban. The authors concluded that when compared with warfarin, the DOACs had similar chance of recurrent thrombosis, mortality and equal rates of recanalization, but a less risk of hemorrhagic complications.[72]

Surgical management

In terms of surgical management, endovascular treatment (EVT) options including mechanical thrombectomy may be considered to dislodge the thrombus and restore blood circulation.[73] A systematic review by Siddiqui et al. reported that mechanical thrombectomy in CVT led to favorable outcomes in 84% of study population with near total recanalization in 74% patients, with the complication of hemorrhage encountered in up to 10% patients.[74]

The Thrombolysis or Anticoagulation for CVT (TO-ACT) randomized controlled trial was an international study which enrolled patients with CVT three different countries.[75] When compared to standard anticoagulation therapies, they found that EVT did not have a significant impact on improving the functional outcome of these patients, nor was it associated with any difference in mortality rates.[75]

Brain herniation is one of the potentially fatal complications of CVT, which can be managed aggressively through decompressive craniectomy.[76] A meta-analysis of 483 CVT cases who underwent decompressive surgery reported that if the surgery is performed urgently within 2 days of hospital admission with a diagnosis of CVT, it will lead to decreased mortality with better functional outcomes.[77]

Additionally, supportive treatment is needed, based on the signs and symptoms that the patient presents with. Anticonvulsants must be initiated promptly in patients who present with seizures.[78]

Table 2 summarizes the evidence available on various treatment modalities for CVT.

Table 2.

Medical and surgical treatment modalities in cerebral venous thrombosis

Author	Year	Location	Study design	Sample size	Results
Misra et al.[62]	2012	India	RCT	66	Significant decrease in hospital mortality with LMWH treatment versus UFH
Coutinho et al.[63]	2010	Multi-National	Prospective cohort	421	LMWH has superior safety and efficacy compared to the use of UFH in patients with CVT
Koneru et al.[64]	2018	India	Observational	61	LMWH and UFH showed similar results on functional outcomes in CVT
Afshari et al.[65]	2015	Iran	RCT	52	LMWH and UFH had a similar impact on reduction of neurological disability after occurrence of CVT
Hsu et al.[67]	2020	USA	Retrospective cohort	46	Patients with CVT who received DOACs had similar outcomes compared to warfarin treated patients
Bharath et al.[68]	2023	USA	Retrospective cohort	9	All patients with CVT on long-term apixaban therapy achieved successful recanalization (78% complete and 22% partial recanalization)
Giles et al.[69]	2021	USA	Retrospective cohort	54	DOACs showed similar safety and efficacy as warfarin in CVT
Covut et al.[70]	2019	USA	Retrospective observational	9	Over a median follow-up of 1 year, patients with CVT treated with rivaroxaban or apixaban did not have any episode of thromboembolism or significant bleeding
Ferro et al.[71]	2019	International, multi-center	RCT	120	Dabigatran and warfarin showed similar safety and efficacy in patients with CVT in terms of risk of bleeding and recurrent thrombosis
Yaghi et al.[72]	2022	International, multi-center	Retrospective	845	DOACs showed similar risk of recurrent thrombosis and mortality as warfarin but less chances of hemorrhagic complications
Stam et al.[73]	2008	Netherlands	Prospective case series	20	Thrombolysis with urokinase followed by mechanical thrombus disruption might be beneficial in severe CVT cases however is associated with a higher risk of hemorrhage
Coutinho et al.[75]	2020	International, multi-center	RCT	67	EVT with standard anticoagulation did not improve functional outcomes
Alselisly et al.[76]	2021	Egypt	Retrospective case series	7	Decompressive craniectomy is indicated for emergent management of raised intracranial pressure in CVT

CVT: Cerebral venous thrombosis, EVT: Endovascular treatment, RCT: Randomized controlled trial, DOACs: Direct oral anticoagulants, LMWH: Low molecular weight heparin, UFH: Unfractionated heparin

The European Stroke Organization published their guidelines on the management of CVT in 2017.[79] According to their recommendations, acute CVT should be managed with parenteral anticoagulation, specifically LMWH, whereas DOACs are not preferred in the acute phase. Prompt initiation of anticoagulation in therapeutic doses is recommended, even if there is presence of any intracerebral hemorrhage. They prohibited the use of steroids and acetazolamide in CVT and advised for decompressive intervention as a life saving procedure in cases complicated by brain herniation.[79]

The most recent updates in CVT management have been provided by the American Heart Association in their Scientific Statement published in 2024.[57] They recommend initiating LMWH during the acute episode of CVT, followed by transition to either DOACs or VKAs for a period of 3-12 months, depending on individual risk factors. These guidelines also advocate for DOACs use in CVT as latest evidence shows them to be equally safe and efficacious as VKAs. While the authors found less substantial evidence for surgical management of CVT, they still advise endovascular therapy in case of clot propagation, worsening neurological function and having any contraindication to receiving anti-coagulation therapy. They also recommend decompressive intervention in patients with brain herniation.[57]

Complications and Prognosis

Complications of CVT include complications of the disease itself as well as adverse effects of anticoagulation therapy. Up to 50% patients can experience complications of CVT and its treatment, ranging from mild bleeding episodes to major hemorrhage and long term neurological dysfunction.[80] The prognosis of CVT is highly variable, often based on the size and site of the clot. A systematic review by Dentali et al. found that the fatality rates during acute and chronic phases of CVT are 5.6% and 9.4% respectively. They also reported that surviving patients had good functional outcomes with only mild neurological disability in the long term.[81] Similarly, the ISCVT found that more than half of their population had no residual neurological signs or symptoms after a median follow-up of 16 months.[39] In the ISCVT cohort, 14 patients (2.2%) had sinus thrombosis recurrence while 52 patients (8.3%) expired during the study period.[39]

According to the VENOST study, factors significantly associated with poor prognosis include occurrence of intracerebral hemorrhage, older age and malignancy related etiology of CVT.[38] The ISCVT identified transtentorial herniation as the prominent cause of death in patients with CVT.[39] Furthermore, pre-existing infections, particularly infections involving the nervous system, head and neck, also predict mortality in patients with CVT.[82]

Conclusion

CVT is an uncommon cause of stroke, associated with significant morbidity and mortality if not treated. Due to the highly variable and often insidious clinical presentation, the diagnosis requires a high index of suspicion. Prompt initiation of anticoagulation is necessary for restoration of blood flow and favorable neurological outcomes in these patients.

Ethical policy and institutional review board statement

Not applicable.

Data availability statement

Data sharing is not applicable to this article as no datasets were generated and/or analyzed during the current study.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.