https://orcid.org/0000-0002-4131-7990
Abstract
The evolution of the Coronavirus Disease-2019 pandemic and its vaccination raised more attention to cerebral venous thrombosis (CVT). Although CVT is less prevalent than arterial stroke, it results in larger years of life lost. CVT is more common in women and young patients. Predisposing factors are categorized as transient factors such as pregnancy, puerperium, oral contraceptive pills, trauma, and dehydration; and permanent factors such as neoplastic, vasculitic, thrombophilic, hematologic conditions, infectious causes such as severe acute respiratory syndrome coronavirus-2 infection and HIV. The most common manifestations are headache, seizures, focal neurologic deficits, altered level of consciousness, and cranial nerve palsies. The most common syndromes are stroke-like, raised-intracranial-pressure (ICP), isolated-headache, and encephalopathy, which may have overlaps. Diagnosis is mostly based on computed tomography, magnetic resonance imaging, and their respective venous sequences, supported by blood results abnormalities such as D-dimer elevation. Treatment includes the prevention of propagation of current thrombus with anticoagulation (heparin, or low molecular weight heparinoids and then warfarin, or direct oral anticoagulants), decreasing ICP (even by decompressive craniotomy), and treatment of specific underlying diseases.
Introduction
The evolution of the Coronavirus Disease-2019 (COVID-19) pandemic and its vaccination raised more attention to cerebral venous thrombosis (CVT). Here, we aim to provide an update regarding these emerging risk factors, new imaging modalities, and recent changes in the management of CVT with stress on the role of direct oral anticoagulants (DOACs) and endovascular treatment.
CVT is a clot formation in dural venous sinuses or cerebral veins, which can be due to pyogenic phlebitis or nonpyogenic thrombosis. Thrombosis of superficial cerebral sinuses and veins is more common than deep ones. Superior sagittal sinus (SSS) and TS are considered the most common locations for CVT. CVT of the deep system is defined as the involvement of the straight sinus, the vein of Galen, the basal vein of Rosenthal, internal cerebral veins, and all attributed veins.
Cortical vein thrombosis usually occurs in association with sinus thrombosis, but isolated cortical vein thrombosis has characteristic clinic-radiological presentations. Cavernous sinus thrombosis is the most frequent type of pyogenic CVT. It is an uncommon complication of infection in the face and/or paranasal sinuses, particularly sphenoid and ethmoid sinusitis [1]. All abbreviations are defined in Box 4.
Anatomy
Venous drainage of the skull and brain is done by a network of extracranial veins, diploic veins, dural venous sinuses, and superficial and deep cerebral veins. Cerebral venous sinuses are endothelium-lined venous channels between the two layers of dura. They drain the venous blood from superficial and deep cerebral veins and communicate with the extracranial venous system through diploic veins. The superficial sinus venous system is defined as superior, and inferior sagittal, transverse, sigmoid, occipital, and cavernous sinuses and all attributed superficial veins (superficial middle cerebral vein, etc.). The deep system is defined as a straight sinus, the vein of Galen, the basal vein of Rosenthal, internal cerebral veins, and all attributed veins (septal, thalamostriate, etc.) (Fig. 1).
Normal venous anatomy in different axial (a and b), sagittal (c), and coronal views (d).
Pathophysiology and pathogenesis
Thrombus formation in cerebral sinuses and/or veins may lead to increased intracranial pressure (ICP) and/or venous infarction. Blood–brain barrier (BBB) disruptions and vasogenic/cytotoxic edema are the major pathophysiologic mechanisms of CVT. The cortical veins have thin walls, no valves, and no muscular layer. Accordingly, occlusion of major sinuses causes blood reflux in cortical veins, which drain into them. This results in increased postcapillary venular pressure and opening of tight junctions and consequently leakage of fluid into the interstitial space (vasogenic edema) and disruption of the BBB. Simultaneously, obstruction of the cerebral sinuses may hinder cerebral spinal fluid (CSF) absorption by arachnoid granulations.
Initially, compensatory mechanisms such as vasodilatation and recruitment of adjacent outflow keep ICP maintained; however, when they fail ICP rises. Meanwhile, brain autoregulatory mechanisms compensate for the detrimental effect of raised intracranial pressure (RICP) on cerebral perfusion pressure (CPP). However, after a critical threshold, CPP diminishes. Decreased CPP impairs brain tissue oxygen and glucose supply, impairing the function of energy-dependent cellular membrane pumps. Consequent cytotoxic edema is due to water regression from the extracellular to the intracellular space.
Raised ICP and venous infarction with or without hemorrhagic transformation are the end-stage result of all these phenomena. Meanwhile, due to the presence of collateral channels and recanalization, all venous occlusions do not necessarily end up in neuronal injury or infarction. This sequence of events, seen in animal models of CVT [2], was corroborated in diffusion- and perfusion-weighted studies that showed vasogenic edema was the initial phase in the pathogenesis of CVT that might or might not be followed by cytotoxic edema as the underlying cause of irreversible damage [3, 4] (Fig. 2).
Illustrative physiopathology of CVST.
Epidemiology
Population-based studies about CVT are rare. The incidence was 1.32 and 0.25 per 100 000 per year in Finnish adults [5] and the Danish pediatric-age group [6], respectively.
Table 1 [5, 7–10] shows the demographics, clinic-radiological characteristics, and prognostic factors of some large studies of CVT. CVT seems more common in the Middle East and southern Asia [8]. For instance, the annual frequency of CVST was 12.3 per million in Iran [11]. Both genetic variations, especially in thrombotic factors, and environmental factors such as dehydration due to fasting [12], dehydration in the postpartum period due to following traditional beliefs [13], and nutritional deficiencies due to lower economic status [8] might be contributing to this difference.
Demographic, clinical, radiological, and prognostic characteristics of CVT series with >500 patients.
| Ferro et al. [7] | Wasay et al. [8] | Borhani-Haghighi et al. [9] | Ruuskanen et al. [5] | Duman et al. [10] | |
|---|---|---|---|---|---|
| Date of recruitment | 1998–2001 | 2009–2012 | 2000–2007 | 2005–2014 | 2000–2015 |
| Number of patients | 624 | 812 | 568 | 563 | 1144 |
| Ethnicity | Mostly European and American | Asian | American | European | European |
| Mean age (years) | 39.1 | 31 | 46.9 | Median age 55 for men and 42.5 for women | NM (80% below 50 years) |
| Female/male ratio | 2.9 | 1.4 | 1.8 | 1.3 | 2.1 |
| The most common predisposing factors | Thrombophilia: 34.1%, gender-related causes: 28% | Gender-related causes: 25%, infection:10% | Malignancy in 14% of nonpyogenic CVT | Malignancy: 7.5% | Gender-related causes: 42%, thrombophilia: 26% |
| Most common symptoms | Headache: 89%, seizure: 39%, FND: 46% mental status disorder: 22% cranial nerve palsy: NM | Headache: 90%, seizure: 44%, FND (motor): 40% GCS < 10: 13% cranial nerve palsy: 13% | NM | NM | Headache: 87%, seizure: 24%, FND: 18%, altered consciousness: 18% cranial nerve palsy: 11% |
| Tempo | Acute: 37%, Subacute: 56% Chronic: 7% | NM | NM | NM | Acute: 47% Subacute: 34% Chronic: 19% |
| Venous infarction | 46.5 | 71% | NM | NM | 19.1% |
| Hemorrhagic transformation | 39.3% | 26.7% (MRI), 9.6% (CT) | NM | NM | 17.3% |
| In-hospital mortality | 8.3% | 3.3% (in hospital) | 3.5% | 2.1% | NM |
| Poor prognostic factor | Age > 37 years, male sex, coma, mental status disorder, hemorrhage on admission CT scan, deep CVT, CNS infection, malignancy | Motor weakness, GCS ≤ 9, mental status disorder | Older age, intracerebral hemorrhage, hematologic disorders, systemic malignancy, CNS infection | Male sex, older age | Age > 50 years, parenchymal involvement, malignancy |
| Ferro et al. [7] | Wasay et al. [8] | Borhani-Haghighi et al. [9] | Ruuskanen et al. [5] | Duman et al. [10] | |
|---|---|---|---|---|---|
| Date of recruitment | 1998–2001 | 2009–2012 | 2000–2007 | 2005–2014 | 2000–2015 |
| Number of patients | 624 | 812 | 568 | 563 | 1144 |
| Ethnicity | Mostly European and American | Asian | American | European | European |
| Mean age (years) | 39.1 | 31 | 46.9 | Median age 55 for men and 42.5 for women | NM (80% below 50 years) |
| Female/male ratio | 2.9 | 1.4 | 1.8 | 1.3 | 2.1 |
| The most common predisposing factors | Thrombophilia: 34.1%, gender-related causes: 28% | Gender-related causes: 25%, infection:10% | Malignancy in 14% of nonpyogenic CVT | Malignancy: 7.5% | Gender-related causes: 42%, thrombophilia: 26% |
| Most common symptoms | Headache: 89%, seizure: 39%, FND: 46% mental status disorder: 22% cranial nerve palsy: NM | Headache: 90%, seizure: 44%, FND (motor): 40% GCS < 10: 13% cranial nerve palsy: 13% | NM | NM | Headache: 87%, seizure: 24%, FND: 18%, altered consciousness: 18% cranial nerve palsy: 11% |
| Tempo | Acute: 37%, Subacute: 56% Chronic: 7% | NM | NM | NM | Acute: 47% Subacute: 34% Chronic: 19% |
| Venous infarction | 46.5 | 71% | NM | NM | 19.1% |
| Hemorrhagic transformation | 39.3% | 26.7% (MRI), 9.6% (CT) | NM | NM | 17.3% |
| In-hospital mortality | 8.3% | 3.3% (in hospital) | 3.5% | 2.1% | NM |
| Poor prognostic factor | Age > 37 years, male sex, coma, mental status disorder, hemorrhage on admission CT scan, deep CVT, CNS infection, malignancy | Motor weakness, GCS ≤ 9, mental status disorder | Older age, intracerebral hemorrhage, hematologic disorders, systemic malignancy, CNS infection | Male sex, older age | Age > 50 years, parenchymal involvement, malignancy |
NM: not mentioned.
Demographic, clinical, radiological, and prognostic characteristics of CVT series with >500 patients.
| Ferro et al. [7] | Wasay et al. [8] | Borhani-Haghighi et al. [9] | Ruuskanen et al. [5] | Duman et al. [10] | |
|---|---|---|---|---|---|
| Date of recruitment | 1998–2001 | 2009–2012 | 2000–2007 | 2005–2014 | 2000–2015 |
| Number of patients | 624 | 812 | 568 | 563 | 1144 |
| Ethnicity | Mostly European and American | Asian | American | European | European |
| Mean age (years) | 39.1 | 31 | 46.9 | Median age 55 for men and 42.5 for women | NM (80% below 50 years) |
| Female/male ratio | 2.9 | 1.4 | 1.8 | 1.3 | 2.1 |
| The most common predisposing factors | Thrombophilia: 34.1%, gender-related causes: 28% | Gender-related causes: 25%, infection:10% | Malignancy in 14% of nonpyogenic CVT | Malignancy: 7.5% | Gender-related causes: 42%, thrombophilia: 26% |
| Most common symptoms | Headache: 89%, seizure: 39%, FND: 46% mental status disorder: 22% cranial nerve palsy: NM | Headache: 90%, seizure: 44%, FND (motor): 40% GCS < 10: 13% cranial nerve palsy: 13% | NM | NM | Headache: 87%, seizure: 24%, FND: 18%, altered consciousness: 18% cranial nerve palsy: 11% |
| Tempo | Acute: 37%, Subacute: 56% Chronic: 7% | NM | NM | NM | Acute: 47% Subacute: 34% Chronic: 19% |
| Venous infarction | 46.5 | 71% | NM | NM | 19.1% |
| Hemorrhagic transformation | 39.3% | 26.7% (MRI), 9.6% (CT) | NM | NM | 17.3% |
| In-hospital mortality | 8.3% | 3.3% (in hospital) | 3.5% | 2.1% | NM |
| Poor prognostic factor | Age > 37 years, male sex, coma, mental status disorder, hemorrhage on admission CT scan, deep CVT, CNS infection, malignancy | Motor weakness, GCS ≤ 9, mental status disorder | Older age, intracerebral hemorrhage, hematologic disorders, systemic malignancy, CNS infection | Male sex, older age | Age > 50 years, parenchymal involvement, malignancy |
| Ferro et al. [7] | Wasay et al. [8] | Borhani-Haghighi et al. [9] | Ruuskanen et al. [5] | Duman et al. [10] | |
|---|---|---|---|---|---|
| Date of recruitment | 1998–2001 | 2009–2012 | 2000–2007 | 2005–2014 | 2000–2015 |
| Number of patients | 624 | 812 | 568 | 563 | 1144 |
| Ethnicity | Mostly European and American | Asian | American | European | European |
| Mean age (years) | 39.1 | 31 | 46.9 | Median age 55 for men and 42.5 for women | NM (80% below 50 years) |
| Female/male ratio | 2.9 | 1.4 | 1.8 | 1.3 | 2.1 |
| The most common predisposing factors | Thrombophilia: 34.1%, gender-related causes: 28% | Gender-related causes: 25%, infection:10% | Malignancy in 14% of nonpyogenic CVT | Malignancy: 7.5% | Gender-related causes: 42%, thrombophilia: 26% |
| Most common symptoms | Headache: 89%, seizure: 39%, FND: 46% mental status disorder: 22% cranial nerve palsy: NM | Headache: 90%, seizure: 44%, FND (motor): 40% GCS < 10: 13% cranial nerve palsy: 13% | NM | NM | Headache: 87%, seizure: 24%, FND: 18%, altered consciousness: 18% cranial nerve palsy: 11% |
| Tempo | Acute: 37%, Subacute: 56% Chronic: 7% | NM | NM | NM | Acute: 47% Subacute: 34% Chronic: 19% |
| Venous infarction | 46.5 | 71% | NM | NM | 19.1% |
| Hemorrhagic transformation | 39.3% | 26.7% (MRI), 9.6% (CT) | NM | NM | 17.3% |
| In-hospital mortality | 8.3% | 3.3% (in hospital) | 3.5% | 2.1% | NM |
| Poor prognostic factor | Age > 37 years, male sex, coma, mental status disorder, hemorrhage on admission CT scan, deep CVT, CNS infection, malignancy | Motor weakness, GCS ≤ 9, mental status disorder | Older age, intracerebral hemorrhage, hematologic disorders, systemic malignancy, CNS infection | Male sex, older age | Age > 50 years, parenchymal involvement, malignancy |
NM: not mentioned.
Predisposing factors
CVT is a multifactorial disorder. Predisposing factors can be categorized as provocative (transient) and nonprovocative (permanent) factors (Box 1). However, multiple or no predisposing factors can be found in a patient. The distribution of predisposing factors depends on age (malignancy is more common in older age), gender (pregnancy, puerperium, and OCP in women), and geographic area [gender-related causes, more frequent in Turkish [10], Iranian [14], Pakistani, and Indian populations [8].
Emerging predisposing factors
COVID-19
Based on available data, it is hard to claim whether a true association between CVT and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is present or not. Several studies support this association. In a large population-based study of 48 million English and Welsh adults, the frequency of CVT among hospitalized and nonhospitalized COVID-19 patients was <10/118 879 (<84 per million) and 21/1 248 180 (16 per million). Meanwhile, there were 671/46 632 841 (14 per million) CVT among the non-COVID population [15]. In a pool analysis of hospitalized COVID-19 patients (n = 292 080), the frequency of CVT was 353 per million [16].
These figures are more than the incidence of CVT in population-based studies in the pre-COVID era [13.2, 15.7, and 19.9 per million per year in the Finnish population [5], Australians [17], and Iranian women [11], respectively].
However, it cannot be easily concluded that the COVID pandemic has increased the frequency of CVT. For instance, there were no differences in CVT hospitalization rate between the first year of the COVID-19 epidemic and the year before in the same study [16, 18].
Population-based studies that cover both nonadmitted COVID-19 patients and nonadmitted CVT due to fear of an overwhelmed system may be better to investigate this association. Effects of the COVID-19 pandemic on predisposing factors of CVT such as head and neck bacterial infections should also be evaluated.
In the condition of the presence of an association, it is unclear whether SARS-CoV-2 infection “causes” CVT or only “triggers” the coagulation cascade in individuals with predisposing factors. In a meta-analysis, predisposing factors other than SARS-CoV-2 infection were present in 31% [19]. If any true association is present, it can be justified by a hypercoagulable state following SARS-CoV-2 infection mediated by increasing unopposed angiotensin-converting enzyme 1 [20], inflammatory cascades triggered by viral particles and damage-associated molecular patterns [21], and/or antiphospholipid antibodies and lupus anticoagulants [22].
Predisposing factors of CVT.
| Transient factors | Permanent factors |
|---|---|
Female gender-related causes
| Hematologic diseases
More common hypercoagulable states
|
| Transient factors | Permanent factors |
|---|---|
Female gender-related causes
| Hematologic diseases
More common hypercoagulable states
|
Predisposing factors of CVT.
| Transient factors | Permanent factors |
|---|---|
Female gender-related causes
| Hematologic diseases
More common hypercoagulable states
|
| Transient factors | Permanent factors |
|---|---|
Female gender-related causes
| Hematologic diseases
More common hypercoagulable states
|
Although the COVID-19 pandemic may be receding in many countries, high suspicion is required because it can be difficult to diagnose CVT in COVID-19 patients, or victims of apparently inevitable future viral epidemics.
COVID-19 vaccines
The evolution of CVT and other thromboembolic events after COVID-19 vaccines raised major health issues in the pandemic era since it affected younger patients without conventional predisposing factors of CVT and had higher morbi-mortality [23]. The incidence of CVT-vaccine-induced immune thrombotic thrombocytopenia (VITT) was as low as 0.7 to 4.4 per million administered adenovirus-based COVID-19 vaccines in Europe and the United States [24, 25].
Vaccine-induced CVT has been mostly reported with recombinant adenoviral-vector-based vaccines; however, CVT after other COVID-19 vaccines has also been reported [26]. COVID-19-vaccines-induced CVT could be associated with thrombocytopenia (VITT) or not. In a pool analysis of two eligible studies, 70% of patients with CVTs after COVID vaccination had VITT [23].
The following criteria must be met for a definitive diagnosis of CVT-VITT:(i) the date of COVID-19 vaccination: COVID-19 vaccination should be 4–42 days before symptom onset; (ii) all venous or arterial thrombosis, often cerebral or abdominal; (iii) thrombocytopenia (platelet count <150 000/μl); however, thrombosis with a normal platelet count after vaccination may occur in the early stages of VITT; (iv) positive anti-PF4 antibodies testing by ELISA; (v) raised D-dimer >4 times the upper limit of normal.
The pathogenesis of VITT is to some extent similar to heparin-induced thrombocytopenia and thrombosis (HITT). The hallmark of the pathogenesis of VITT is venous endotheliopathy triggered by an adjuvant conjugated with a vaccine which results in microthrombosis and platelet consumption [27]. A two-step mechanism underlying the VITT process is suggested: the “early” step (1–2 days after vaccination) is characterized by the formation of a complex of vaccine components with Platelet factor 4 (PF4) and pro-inflammatory immune responses. In the “late” step, between the 5th and the 20th day following vaccination, antibodies against PF4 activate platelets in a PF4- and polyanion-dependent manner [28]. This two-step mechanism underlies the development of thrombotic events in VITT patients. The mechanism behind thrombotic events after mRNA vaccination differs from the mechanism of VITT pathology after recombinant adenoviral vector vaccination [29–31]. Interestingly, it seems that the number of CVT associated with VITT patients in low-to-middle-income countries is lower than in high-income countries [32].
The European Medicines Agency and the World Health Organization have both stated that the benefits of the recombinant adenoviral-vector-based vaccines outweigh the very small risk of CVT and that the vaccine should continue to be used. However, these adverse effects are still being monitored by the respective authorities and if any new evidence is published the guidelines may change.
Symptoms
Headache
Headache is a milestone in CVT, even though the absence of headache does not exclude CVT. Ten per cent of the patients may have no headache at the presentation time [33].
Although CVT headache may resemble a primary headache, hyperacute evolution (thunderclap headache) [34]; severity (the worst headache ever experienced) [35]; being constant (lasted >6 days) [35], aggravation by the Valsalva maneuver and lying down [36]; and association with FNDs, altered level of consciousness, seizure, and papilledema should raise an index of suspicion [35]. About 15%–25% of CVT patients reported it as the sole presenting symptom [10, 37]. CVT patients with isolated headaches have a better prognosis than others. However, in the presence of isolated headaches without more severe neurological signs, there may be a delay in medical care and diagnosis [10, 37]. The presence of headache and papilledema with and without cranial nerve palsy (particularly VI), pulsatile tinnitus, or altered vision is indicated for RICP syndrome. This syndrome mostly presents in patients without parenchymal damage. Box 2 shows the red flags for the presence of CVT in patients who present with headache which necessitate appropriate imaging studies [38].
Suggested indications for urgent neuro-imaging for CVT in patients with headache (red flags) [38].
| Headache characteristics | Hyperacute onset |
|---|---|
| Progressive course | |
| Pattern change | |
| Precipitated by valsalva maneuver | |
| Aggravated by lying down or exertions | |
| Refractory to routine analgesics | |
| Associated symptoms | Seizure |
| Focal neurologic deficits | |
| Altered level of consciousness, abnormal behavior | |
| Diplopia, blurred vision | |
| Past medical history | History of CVT or DVT |
| Presence of predisposing factors (Box 1) | |
| Family history | History of CVT or DVT |
| Physical examination | Fever |
| Sign of dehydration | |
| Neck rigidity | |
| Papilledema | |
| Cranial nerve palsy | |
| Proptosis, conjunctival injection(in cavernous sinus thrombosis) | |
| Results of basic tests (Box 3) | High ESR, CRP |
| Polycythemia or anemia, leukocytosis, thrombocytosis | |
| Abnormal renal, liver or thyroid function tests |
| Headache characteristics | Hyperacute onset |
|---|---|
| Progressive course | |
| Pattern change | |
| Precipitated by valsalva maneuver | |
| Aggravated by lying down or exertions | |
| Refractory to routine analgesics | |
| Associated symptoms | Seizure |
| Focal neurologic deficits | |
| Altered level of consciousness, abnormal behavior | |
| Diplopia, blurred vision | |
| Past medical history | History of CVT or DVT |
| Presence of predisposing factors (Box 1) | |
| Family history | History of CVT or DVT |
| Physical examination | Fever |
| Sign of dehydration | |
| Neck rigidity | |
| Papilledema | |
| Cranial nerve palsy | |
| Proptosis, conjunctival injection(in cavernous sinus thrombosis) | |
| Results of basic tests (Box 3) | High ESR, CRP |
| Polycythemia or anemia, leukocytosis, thrombocytosis | |
| Abnormal renal, liver or thyroid function tests |
Suggested indications for urgent neuro-imaging for CVT in patients with headache (red flags) [38].
| Headache characteristics | Hyperacute onset |
|---|---|
| Progressive course | |
| Pattern change | |
| Precipitated by valsalva maneuver | |
| Aggravated by lying down or exertions | |
| Refractory to routine analgesics | |
| Associated symptoms | Seizure |
| Focal neurologic deficits | |
| Altered level of consciousness, abnormal behavior | |
| Diplopia, blurred vision | |
| Past medical history | History of CVT or DVT |
| Presence of predisposing factors (Box 1) | |
| Family history | History of CVT or DVT |
| Physical examination | Fever |
| Sign of dehydration | |
| Neck rigidity | |
| Papilledema | |
| Cranial nerve palsy | |
| Proptosis, conjunctival injection(in cavernous sinus thrombosis) | |
| Results of basic tests (Box 3) | High ESR, CRP |
| Polycythemia or anemia, leukocytosis, thrombocytosis | |
| Abnormal renal, liver or thyroid function tests |
| Headache characteristics | Hyperacute onset |
|---|---|
| Progressive course | |
| Pattern change | |
| Precipitated by valsalva maneuver | |
| Aggravated by lying down or exertions | |
| Refractory to routine analgesics | |
| Associated symptoms | Seizure |
| Focal neurologic deficits | |
| Altered level of consciousness, abnormal behavior | |
| Diplopia, blurred vision | |
| Past medical history | History of CVT or DVT |
| Presence of predisposing factors (Box 1) | |
| Family history | History of CVT or DVT |
| Physical examination | Fever |
| Sign of dehydration | |
| Neck rigidity | |
| Papilledema | |
| Cranial nerve palsy | |
| Proptosis, conjunctival injection(in cavernous sinus thrombosis) | |
| Results of basic tests (Box 3) | High ESR, CRP |
| Polycythemia or anemia, leukocytosis, thrombocytosis | |
| Abnormal renal, liver or thyroid function tests |
Seizure
Generalized or focal seizures are the second most common clinical presentation for CVT. Status epilepticus may evolve in patients with severe CVT with hemorrhagic supratentorial lesions. Primary predictors for acute symptomatic seizure are intracerebral hemorrhage, cerebral edema or infarction without ICH, thrombosis in the cortical vein and SSS, sulcal subarachnoid hemorrhage, and women-related risk factors [39]. Acute symptomatic seizure particularly status epilepticus, intracranial hemorrhage, subdural hematoma, and the need for hemicraniectomy are poor prognostic factors for late seizure [40].
Focal neurologic deficits
In any patient whose hyperacute or acute evolution of focal neurologic deficits suggests the possibility of arterial stroke, CVT should also be considered, particularly for patients with infarctions not compatible with arterial territories, bilateral infarctions, and more cephalad infarctions near SSS. Motor weakness (monoparesis, hemiparesis, or paraparesis) is the most common type of focal neurologic deficit. Visual symptoms or other manifestations can also be seen. Hemispheric manifestations are more common than brainstem and cerebellar presentations. Venous infarction with and without hemorrhagic transformation is most probably the cause of these symptoms.
Altered level of consciousness
An altered level of consciousness may present with confusion, delirium, drowsiness, obtundation, or coma. The involvement of deep cerebral veins/sinuses may explain this syndrome [41]. Pure encephalopathy may present in elderly patients.
Cranial nerve palsy
Single or multiple cranial nerve palsies (III–VIII) in association, or rarely without other signs and symptoms, can be a rare manifestation of CVT. It can be attributed to direct pressure of the clot on the nerves or stasis in posterior fossa veins draining into the venous sinuses [42]. Cavernous sinus thrombosis presents headache and III, IV, V, and/or VI cranial nerve palsies and/or ocular symptoms proptosis, conjunctival injection [1]. The inferior petrosal syndrome presents with headache and VII and/or VIII cranial nerve palsies [43].
Course
The course could be hyperacute (seconds to minutes), acute (≤48 h), subacute (>48 h–≤30 days), and chronic (≥1 month) [41], as thunderclap headaches, acute stroke-like manifestations, subacute presentations, and chronic pseudotumor-cerebri-like manifestations. The subacute course is the most common tempo [5, 7–10].
Diagnosis
Timely diagnosis is the most critical factor for the prevention of thrombus propagation. However, there are still delayed diagnoses for CVT, which cause the dismal outcome. In one study, an average delay of 7 days between the onset of the symptoms and diagnosis was seen [44].
Imaging
Routine imaging
Noncontrast computed tomography and contrast-enhanced computed tomography of brain
Noncontrast computed tomography (NCCT) is the first step for screening acute CVT and ruling out other entities. A brain NCCT scan also shows venous infarct, hemorrhage, hydrocephalus, or sign of herniation. In other patients, a cortical vein or dural sinus hyperdensity can be seen in an unenhanced brain CT scan [45]. Elongated cord-like hyperdensity in the transverse sinus, known as the “cord sign,” is observed in 20% of cases (Fig. 3a). In subacute or chronic CVT, thrombosis may be hypodense, isodense, or mixed density. Polycythemia and anemia may cause false positive and false results for cord signs, respectively [46]. A thrombosed vein is relatively hyperdense compared to an artery. However, in the condition of polycythemia, there is no difference between the densities of arteries and veins [47].
(a) Cord sign in left transverse sinus in nonenhanced brain CT scan; (b) empty delta sign in Torcular Herrophili (confluence of sinuses) in contrast-enhanced brain MRI; (c) blooming artifact in the SSS and superficial cortical veins in gradient-enhanced echo (GRE); (d) TOF MRV showing absence of SSS and increased collateral veins.
Infarct areas that are incompatible with arterial territories spare the cortex but involve the subcortical white matter, particularly in multiple and bilateral ones, which should also raise suspicion of a venous origin.
Brain contrast-enhanced CT (CECT) may show an empty delta sign, a triangular defect visualized particularly in the torcular herophili, as a consequence of enhancement of the dural lining with a filling defect within the vein or sinus [48–50]. Even in CECT, direct and indirect signs of CVT cannot be seen in ~30% of the patients [46]. Accordingly, logistics suggests performing CECT or MRI depending on availability.
Laboratory investigations for patients with suspected/confirmed CVT.
| Basic investigations | CBC, urine analysis, uremic, and hepatic function tests, ESR, CRP | ||
|---|---|---|---|
| Complementary investigations | Inflammatory panel | p-ANCA, c-ANCA, anti dsDNA, ANA, antiphospholipid antibodies, lupus anticoagulants, ACLA, Antiß2GPI, HLA-B51 | |
| Thrombophilia panel | Level 1 | Activated protein C resistance, protein C and S, antithrombin III, homocysteine | |
| Level 2 | Factor V Leiden, prothrombin gene mutation (20210), factor VIII, MTHFR mutation, tissue plasminogen activator level, JAK-2 mutations, PAI-1, and other thrombophilia based on local prevalence | ||
| Hematologic panel | Serum iron, CD 55 and CD 59, JAK2 V617F mutation, Hb electrophoresis for HbS, antiplatelet factor 1 and 2 | ||
| Infectious panel | Systemic infections: investigations for HIV, COVID-19 or other causes of sepsis-induced coagulopathy | ||
| Localized infection: investigations for suspected microorganism based on clinico-radiological presentations | |||
| Basic investigations | CBC, urine analysis, uremic, and hepatic function tests, ESR, CRP | ||
|---|---|---|---|
| Complementary investigations | Inflammatory panel | p-ANCA, c-ANCA, anti dsDNA, ANA, antiphospholipid antibodies, lupus anticoagulants, ACLA, Antiß2GPI, HLA-B51 | |
| Thrombophilia panel | Level 1 | Activated protein C resistance, protein C and S, antithrombin III, homocysteine | |
| Level 2 | Factor V Leiden, prothrombin gene mutation (20210), factor VIII, MTHFR mutation, tissue plasminogen activator level, JAK-2 mutations, PAI-1, and other thrombophilia based on local prevalence | ||
| Hematologic panel | Serum iron, CD 55 and CD 59, JAK2 V617F mutation, Hb electrophoresis for HbS, antiplatelet factor 1 and 2 | ||
| Infectious panel | Systemic infections: investigations for HIV, COVID-19 or other causes of sepsis-induced coagulopathy | ||
| Localized infection: investigations for suspected microorganism based on clinico-radiological presentations | |||
Laboratory investigations for patients with suspected/confirmed CVT.
| Basic investigations | CBC, urine analysis, uremic, and hepatic function tests, ESR, CRP | ||
|---|---|---|---|
| Complementary investigations | Inflammatory panel | p-ANCA, c-ANCA, anti dsDNA, ANA, antiphospholipid antibodies, lupus anticoagulants, ACLA, Antiß2GPI, HLA-B51 | |
| Thrombophilia panel | Level 1 | Activated protein C resistance, protein C and S, antithrombin III, homocysteine | |
| Level 2 | Factor V Leiden, prothrombin gene mutation (20210), factor VIII, MTHFR mutation, tissue plasminogen activator level, JAK-2 mutations, PAI-1, and other thrombophilia based on local prevalence | ||
| Hematologic panel | Serum iron, CD 55 and CD 59, JAK2 V617F mutation, Hb electrophoresis for HbS, antiplatelet factor 1 and 2 | ||
| Infectious panel | Systemic infections: investigations for HIV, COVID-19 or other causes of sepsis-induced coagulopathy | ||
| Localized infection: investigations for suspected microorganism based on clinico-radiological presentations | |||
| Basic investigations | CBC, urine analysis, uremic, and hepatic function tests, ESR, CRP | ||
|---|---|---|---|
| Complementary investigations | Inflammatory panel | p-ANCA, c-ANCA, anti dsDNA, ANA, antiphospholipid antibodies, lupus anticoagulants, ACLA, Antiß2GPI, HLA-B51 | |
| Thrombophilia panel | Level 1 | Activated protein C resistance, protein C and S, antithrombin III, homocysteine | |
| Level 2 | Factor V Leiden, prothrombin gene mutation (20210), factor VIII, MTHFR mutation, tissue plasminogen activator level, JAK-2 mutations, PAI-1, and other thrombophilia based on local prevalence | ||
| Hematologic panel | Serum iron, CD 55 and CD 59, JAK2 V617F mutation, Hb electrophoresis for HbS, antiplatelet factor 1 and 2 | ||
| Infectious panel | Systemic infections: investigations for HIV, COVID-19 or other causes of sepsis-induced coagulopathy | ||
| Localized infection: investigations for suspected microorganism based on clinico-radiological presentations | |||
Non-contrast magnetic resonance imaging and contrast-enhanced magnetic resonance imaging
In unenhanced brain MRI, direct signs of thrombus formation and indirect signs of loss of flow void should be investigated. The signal intensity of thrombosis can be very different and dependent on the age of the thrombus. The signal intensity of the clot shows the same evolving signal changes to hematoma related to the paramagnetic proprieties of the hemoglobin and hemoglobin products. In the acute stages, the clot seems isointense on T1-WI and hypo-intense on T2-WI and FLAIR, which are similar to venous flow signals and cause a diagnostic dilemma. A rule of thumb may tackle this issue. Normal venous flow in dural sinuses has an opposite intensity on FLAIR and T2*-WI; however, thrombus shows the same signal intensity on these techniques, irrespective of the timing [51]. Clots are hyperintense both on T1-WI and T2-WI in the subacute stage. Clot intensities are variable in chronic stages and this also results in diagnostic difficulties [48–50].
In MRI with gadolinium, a central isodense lesion in a venous sinus with surrounding enhancement is the counterpart of the empty delta sign in CT (Fig. 3b) [48–50].
Susceptibility-weighted images (SWIs) can particularly assist with showing thrombosis as a low signal lesion in the area of dural sinuses or cortical veins (Fig. 3c) [48–50, 52]. However, hyperacute thrombus, which contains higher oxyhemoglobin, may not reveal this “blooming” effect [53]. Brush sign is the hypo-intense subependymal and deep medullary veins in paramagnetic-sensitive MR sequences which were seen in about one-sixth of CVT patients [54].
If CVT causes venous infarction, different MRI sequences, especially Diffusion-weighted images (DWIs), can show infarction with or without hemorrhagic transformations. Deep cerebral vein thrombosis may cause bilateral (rarely unilateral) thalamic, basal ganglionic, and/or deep temporal infarctions. The artery of Percheron infarction is a rare differential diagnosis that is distinct due to infarction of bilateral paramedian and/or anterior nuclei with or without midbrain involvement. Artery of Percheron is a rare anatomical variation in which a single arterial trunk arises from the posterior cerebral artery to supply both sides of the thalamus and midbrain.
MRI, particularly SWI, seems more sensitive in detecting isolated cortical vein thrombosis [48–50]. Confined edema, hemorrhagic infarction, or intraparenchymal hemorrhage is more common in isolated cortical vein thrombosis than in general CVT [55].
Sulcal effacement and reduced CSF spaces indicate brain edema, particularly in patients with raised ICP without focal neurologic deficits.
Computerized tomographic venography and magnetic resonance venography
On computerized tomographic venography (CTV), filling defects can reveal thrombosed sinuses; however, CTV can miss isolated cortical vein thrombosis [46]. Vascular imaging studies for CVT include CTV, magnetic resonance venography (MRV), and rarely digital subtraction angiography. CTV has been demonstrated to be a reliable screening modality for diagnosing CVT.
Time-of-flight (TOF) MRV (Fig. 3d) and contrast-enhanced magnetic resonance are the most often employed MRV techniques [52]. Venous flow with parallel or complex directions with the acquisition plane of TOF may falsely mimic CVT. Contrast-enhanced MRV improved visualization of cerebral venous structures.
The presence of a hypoplas1ic venous sinus (usually a transverse sinus, left more than right), slow flow, large arachnoid granulations, and dural calcifications are major pitfalls in imaging diagnosis of CVT [48–50]. Venous hypoplasia can be differentiated by lack of blooming in SWI, lack of filling defect in noncontrast magnetic resonance imaging (CEMRI), and smaller correspondent sigmoid notches on NCCT. Arachnoid granulations are relatively round and adhere to one side of the wall of the dural venous sinuses and may show central and inhomogeneous contrast enhancement in contrast-enhanced imaging.
An amalgam of routine MR techniques, blood-specific MR techniques (SWI or T2*), and particularly contrast-enhanced MRI/MRV are advocated for the most accurate diagnosis [52]. Evaluation of source rather than volume-rendered images is recommended.
New imaging modalities
New CT techniques that may improve diagnosis accuracy include mask-subtraction, dual-energy, and photo-counting CT [46]. Combo 4D MRV (combination of static contrast-enhanced 3D MRV and dynamic (1.5 s per dataset) analyses may enhance the sensitivity and specificity of MRV, particularly in patients with chronic CVT [56]. MR black-blood technique using a T1-weighted 3D variable-flip angle TSE sequence, particularly with delay alternating with nutation for tailored excitation (DANTE) preparation, improves diagnosis of CVT with lower thrombus volume [57].
Fibrin-specific MR contrasts have been used in animal studies for better thrombus detection, but they have not been utilized conventionally yet [58].
MR perfusion using the arterial spin labeling technique can show a hyperintense lesion in venous sinuses proximal to the clot. It is of significant importance that this method precludes the usage of Gadolinium contrast [59].
Laboratory investigation
There is controversy about the core laboratory investigations for patients with CVT. Obviously, if any clinical hint was taken in history and physical examination, attributed laboratories should be requested. Box 3 includes both basic and complementary laboratory investigations for the CVT diagnosis. Basic tests are necessary for all CVT patients. However, vasculitic tests, thrombophilic tests, hematologic tests, and infectious tests are suggested based on relevant symptoms, family history, results of neuroimaging, and basic studies. The different levels of thrombophilia panel are considered based on their prevalence and can be variable in different geographic areas [60]. Level-1 tests can be tested in patients with first-ever CVT. However, level-2 tests are better ordered for patients with recurrent CVT/DVT if only other basic and complementary tests fail.
List of abbreviation.
| Abbr. | Definition |
|---|---|
| CVT SSS OCP ICP LMWH CSF FND ICH CBC ESR CRP p-ANCA c-ANCA anti dsDNA ANA ACLA Antiβ2GPI HLA-B51 JAK2 PAI-1 Hb HbS NCCT CECT CEMRI SWI CTV MRV TOF AHA/ASA ESO UFH MT HITT VITT | Cerebral venous thrombosis Superior sagittal sinus Oral contraceptive pills Intracranial pressure Low molecular weight heparinoids Cerebral spinal fluid Focal neurologic deficit Intracerebral hemorrhage Complete blood count Erythrocyte sedimentation rate C-reactive protein Perinuclear antineutrophil cytoplasmic antibodies Cytoplasmic, antineutrophil cytoplasmic autoantibody anti-double stranded DNA Antinuclear antibodies Anticardiolipin antibodies Anti-β2-glycoprotein I antibodies human leukocyte antigens- B 51 Janus kinase 2 gene Plasminogen activator inhibitor-1 Hemoglobin Hemoglobin S Non-contrast computerized tomography Contrast-enhanced computed tomography Contrast-enhanced magnetic resonance imaging Susceptibility-weighted images Computerized tomographic venography Magnetic resonance venography Time-of-flight American Heart Association/American Stroke Association European Stroke Organization Unfractionated heparin Mechanical thrombectomy Heparin-induced thrombosis and thrombocytopenia Vaccine-induced immune thrombotic thrombocytopenia |
| Abbr. | Definition |
|---|---|
| CVT SSS OCP ICP LMWH CSF FND ICH CBC ESR CRP p-ANCA c-ANCA anti dsDNA ANA ACLA Antiβ2GPI HLA-B51 JAK2 PAI-1 Hb HbS NCCT CECT CEMRI SWI CTV MRV TOF AHA/ASA ESO UFH MT HITT VITT | Cerebral venous thrombosis Superior sagittal sinus Oral contraceptive pills Intracranial pressure Low molecular weight heparinoids Cerebral spinal fluid Focal neurologic deficit Intracerebral hemorrhage Complete blood count Erythrocyte sedimentation rate C-reactive protein Perinuclear antineutrophil cytoplasmic antibodies Cytoplasmic, antineutrophil cytoplasmic autoantibody anti-double stranded DNA Antinuclear antibodies Anticardiolipin antibodies Anti-β2-glycoprotein I antibodies human leukocyte antigens- B 51 Janus kinase 2 gene Plasminogen activator inhibitor-1 Hemoglobin Hemoglobin S Non-contrast computerized tomography Contrast-enhanced computed tomography Contrast-enhanced magnetic resonance imaging Susceptibility-weighted images Computerized tomographic venography Magnetic resonance venography Time-of-flight American Heart Association/American Stroke Association European Stroke Organization Unfractionated heparin Mechanical thrombectomy Heparin-induced thrombosis and thrombocytopenia Vaccine-induced immune thrombotic thrombocytopenia |
List of abbreviation.
| Abbr. | Definition |
|---|---|
| CVT SSS OCP ICP LMWH CSF FND ICH CBC ESR CRP p-ANCA c-ANCA anti dsDNA ANA ACLA Antiβ2GPI HLA-B51 JAK2 PAI-1 Hb HbS NCCT CECT CEMRI SWI CTV MRV TOF AHA/ASA ESO UFH MT HITT VITT | Cerebral venous thrombosis Superior sagittal sinus Oral contraceptive pills Intracranial pressure Low molecular weight heparinoids Cerebral spinal fluid Focal neurologic deficit Intracerebral hemorrhage Complete blood count Erythrocyte sedimentation rate C-reactive protein Perinuclear antineutrophil cytoplasmic antibodies Cytoplasmic, antineutrophil cytoplasmic autoantibody anti-double stranded DNA Antinuclear antibodies Anticardiolipin antibodies Anti-β2-glycoprotein I antibodies human leukocyte antigens- B 51 Janus kinase 2 gene Plasminogen activator inhibitor-1 Hemoglobin Hemoglobin S Non-contrast computerized tomography Contrast-enhanced computed tomography Contrast-enhanced magnetic resonance imaging Susceptibility-weighted images Computerized tomographic venography Magnetic resonance venography Time-of-flight American Heart Association/American Stroke Association European Stroke Organization Unfractionated heparin Mechanical thrombectomy Heparin-induced thrombosis and thrombocytopenia Vaccine-induced immune thrombotic thrombocytopenia |
| Abbr. | Definition |
|---|---|
| CVT SSS OCP ICP LMWH CSF FND ICH CBC ESR CRP p-ANCA c-ANCA anti dsDNA ANA ACLA Antiβ2GPI HLA-B51 JAK2 PAI-1 Hb HbS NCCT CECT CEMRI SWI CTV MRV TOF AHA/ASA ESO UFH MT HITT VITT | Cerebral venous thrombosis Superior sagittal sinus Oral contraceptive pills Intracranial pressure Low molecular weight heparinoids Cerebral spinal fluid Focal neurologic deficit Intracerebral hemorrhage Complete blood count Erythrocyte sedimentation rate C-reactive protein Perinuclear antineutrophil cytoplasmic antibodies Cytoplasmic, antineutrophil cytoplasmic autoantibody anti-double stranded DNA Antinuclear antibodies Anticardiolipin antibodies Anti-β2-glycoprotein I antibodies human leukocyte antigens- B 51 Janus kinase 2 gene Plasminogen activator inhibitor-1 Hemoglobin Hemoglobin S Non-contrast computerized tomography Contrast-enhanced computed tomography Contrast-enhanced magnetic resonance imaging Susceptibility-weighted images Computerized tomographic venography Magnetic resonance venography Time-of-flight American Heart Association/American Stroke Association European Stroke Organization Unfractionated heparin Mechanical thrombectomy Heparin-induced thrombosis and thrombocytopenia Vaccine-induced immune thrombotic thrombocytopenia |
Although the cost-effectiveness of a comprehensive panel of these tests remains to be elucidated, confirming predisposing diseases with the above tests may determine the duration of anticoagulation. As Protein C and protein S should not be measured during the acute phase of thrombus formation, they are better to be investigated after the discontinuation of warfarin.
Increased D-dimer levels may represent a high pathological level of fibrin degradation products associated with thrombus formation. In addition to its high negative predictive value for ruling CVT out in patients with isolated headache [61], new studies showed its specificity, sensitivity, and accuracy in ruling in CVT and the evolution of focal neurologic deficits [35, 62]. Some laboratory prognostic biomarkers such as neutrophil-to-lymphocyte ratio and the systemic immune-inflammatory index have also been proposed [63].
Differential diagnosis
The most important differential diagnoses of CVT include subarachnoid hemorrhage, acute angle closure glaucoma, internal carotid artery arterial dissection, acute ischemic stroke, primary or secondary intra-parenchymal hemorrhage, temporal arteritis, preeclampsia/eclampsia, reversible vasoconstriction syndrome, acute or subacute subdural hematoma, pituitary apoplexy, third ventricular colloid cyst, intracranial hypotension. Meningoencephalitis, orbital cellulitis, preseptal cellulitis, orbital apex syndrome, and all fall under the clinical differential diagnosis of cavernous sinus thrombosis. Table 2 summarizes the clinical and radiological characteristics of five major differential diagnoses of CVT [5, 7–10, 64–72].
The clinical and radiological characteristics of major differential diagnoses of CVT.
| Predisposing factors | Headache | Seizure | Focal Neurologic Deficit | Encephalopathy | CT +/−contrast Findings | MRI +/−Findings | CTA/CTV/ MRA/MRV Findings | |
|---|---|---|---|---|---|---|---|---|
| CVST [5, 7–10] | Pregnancy, OCP, thrombophilia, vasculitis, malignancy | 87%–90% | 24%–44% | 18%–46% | 13%–22% | Cord sign, Delta sign | Direct thrombosis, loss of flow void, restriction in DWI, Blooming in SWI | Loss of Flow in CTV/MRV |
| SAH [64, 65] | Aneurysm, AVM, trauma, | 70% | 6%–9% | 10% | 33% | Blood in sulci, parenchyma or ventricles | Blood in sulci, parenchyma or ventricle (FLAIR& SWI) | Aneurysm or AVMs |
| RVCS [66] | Migraine, vasoactive substances, dissection | 97% | 1%–17% | 8%–43% | Rare | Normal, rare infarct or hemorrhage | DWI: cortical and multifocal diffusion restriction, FLAIR: dot sign | Vasoconstriction |
| Arterial stroke [67–69] | HTN, DM, dyslipidemia, smoking | 6%–44% | 4% | Very common | 17% | Normal, infarction, hemorrhagic transformation | Diffusion restriction in DWI +/− hemorrhagic transformation in SWI | Normal or stenosis or occlusion |
| PRES [70] | Severe hypertension, medication, transplantation, preeclampsia/eclampsia | 50% | 60%–75% | 10%–15% | 50%–80% | Normal or vasogenic edema, hemorrhage in 10%–25% | Bilateral cortical subcortical occipito-parietal vasogenic edema | Vasoconstriction |
| Intracranial hypotension [71, 72] | Trauma, surgery | 99% | Very rare | Very rare | 3% | Mostly normal, subdural effusion | Pachymeningeal enhancement, engorgement of venous sinuses, effacement of suprasellar cistern, subdural fluid collection, effacement of the prepontine cisterns and reduced mamillopontine distance | Mostly normal |
| Predisposing factors | Headache | Seizure | Focal Neurologic Deficit | Encephalopathy | CT +/−contrast Findings | MRI +/−Findings | CTA/CTV/ MRA/MRV Findings | |
|---|---|---|---|---|---|---|---|---|
| CVST [5, 7–10] | Pregnancy, OCP, thrombophilia, vasculitis, malignancy | 87%–90% | 24%–44% | 18%–46% | 13%–22% | Cord sign, Delta sign | Direct thrombosis, loss of flow void, restriction in DWI, Blooming in SWI | Loss of Flow in CTV/MRV |
| SAH [64, 65] | Aneurysm, AVM, trauma, | 70% | 6%–9% | 10% | 33% | Blood in sulci, parenchyma or ventricles | Blood in sulci, parenchyma or ventricle (FLAIR& SWI) | Aneurysm or AVMs |
| RVCS [66] | Migraine, vasoactive substances, dissection | 97% | 1%–17% | 8%–43% | Rare | Normal, rare infarct or hemorrhage | DWI: cortical and multifocal diffusion restriction, FLAIR: dot sign | Vasoconstriction |
| Arterial stroke [67–69] | HTN, DM, dyslipidemia, smoking | 6%–44% | 4% | Very common | 17% | Normal, infarction, hemorrhagic transformation | Diffusion restriction in DWI +/− hemorrhagic transformation in SWI | Normal or stenosis or occlusion |
| PRES [70] | Severe hypertension, medication, transplantation, preeclampsia/eclampsia | 50% | 60%–75% | 10%–15% | 50%–80% | Normal or vasogenic edema, hemorrhage in 10%–25% | Bilateral cortical subcortical occipito-parietal vasogenic edema | Vasoconstriction |
| Intracranial hypotension [71, 72] | Trauma, surgery | 99% | Very rare | Very rare | 3% | Mostly normal, subdural effusion | Pachymeningeal enhancement, engorgement of venous sinuses, effacement of suprasellar cistern, subdural fluid collection, effacement of the prepontine cisterns and reduced mamillopontine distance | Mostly normal |
The clinical and radiological characteristics of major differential diagnoses of CVT.
| Predisposing factors | Headache | Seizure | Focal Neurologic Deficit | Encephalopathy | CT +/−contrast Findings | MRI +/−Findings | CTA/CTV/ MRA/MRV Findings | |
|---|---|---|---|---|---|---|---|---|
| CVST [5, 7–10] | Pregnancy, OCP, thrombophilia, vasculitis, malignancy | 87%–90% | 24%–44% | 18%–46% | 13%–22% | Cord sign, Delta sign | Direct thrombosis, loss of flow void, restriction in DWI, Blooming in SWI | Loss of Flow in CTV/MRV |
| SAH [64, 65] | Aneurysm, AVM, trauma, | 70% | 6%–9% | 10% | 33% | Blood in sulci, parenchyma or ventricles | Blood in sulci, parenchyma or ventricle (FLAIR& SWI) | Aneurysm or AVMs |
| RVCS [66] | Migraine, vasoactive substances, dissection | 97% | 1%–17% | 8%–43% | Rare | Normal, rare infarct or hemorrhage | DWI: cortical and multifocal diffusion restriction, FLAIR: dot sign | Vasoconstriction |
| Arterial stroke [67–69] | HTN, DM, dyslipidemia, smoking | 6%–44% | 4% | Very common | 17% | Normal, infarction, hemorrhagic transformation | Diffusion restriction in DWI +/− hemorrhagic transformation in SWI | Normal or stenosis or occlusion |
| PRES [70] | Severe hypertension, medication, transplantation, preeclampsia/eclampsia | 50% | 60%–75% | 10%–15% | 50%–80% | Normal or vasogenic edema, hemorrhage in 10%–25% | Bilateral cortical subcortical occipito-parietal vasogenic edema | Vasoconstriction |
| Intracranial hypotension [71, 72] | Trauma, surgery | 99% | Very rare | Very rare | 3% | Mostly normal, subdural effusion | Pachymeningeal enhancement, engorgement of venous sinuses, effacement of suprasellar cistern, subdural fluid collection, effacement of the prepontine cisterns and reduced mamillopontine distance | Mostly normal |
| Predisposing factors | Headache | Seizure | Focal Neurologic Deficit | Encephalopathy | CT +/−contrast Findings | MRI +/−Findings | CTA/CTV/ MRA/MRV Findings | |
|---|---|---|---|---|---|---|---|---|
| CVST [5, 7–10] | Pregnancy, OCP, thrombophilia, vasculitis, malignancy | 87%–90% | 24%–44% | 18%–46% | 13%–22% | Cord sign, Delta sign | Direct thrombosis, loss of flow void, restriction in DWI, Blooming in SWI | Loss of Flow in CTV/MRV |
| SAH [64, 65] | Aneurysm, AVM, trauma, | 70% | 6%–9% | 10% | 33% | Blood in sulci, parenchyma or ventricles | Blood in sulci, parenchyma or ventricle (FLAIR& SWI) | Aneurysm or AVMs |
| RVCS [66] | Migraine, vasoactive substances, dissection | 97% | 1%–17% | 8%–43% | Rare | Normal, rare infarct or hemorrhage | DWI: cortical and multifocal diffusion restriction, FLAIR: dot sign | Vasoconstriction |
| Arterial stroke [67–69] | HTN, DM, dyslipidemia, smoking | 6%–44% | 4% | Very common | 17% | Normal, infarction, hemorrhagic transformation | Diffusion restriction in DWI +/− hemorrhagic transformation in SWI | Normal or stenosis or occlusion |
| PRES [70] | Severe hypertension, medication, transplantation, preeclampsia/eclampsia | 50% | 60%–75% | 10%–15% | 50%–80% | Normal or vasogenic edema, hemorrhage in 10%–25% | Bilateral cortical subcortical occipito-parietal vasogenic edema | Vasoconstriction |
| Intracranial hypotension [71, 72] | Trauma, surgery | 99% | Very rare | Very rare | 3% | Mostly normal, subdural effusion | Pachymeningeal enhancement, engorgement of venous sinuses, effacement of suprasellar cistern, subdural fluid collection, effacement of the prepontine cisterns and reduced mamillopontine distance | Mostly normal |
Treatment
Acute treatment
Medical acute treatment
Destruction of current thrombosis including intravenous thrombolysis
Only a few case series have studied the administration of systemic thrombolysis for CVT. At present, the American Heart Association/American Stroke Association (AHA/ASA) and European Stroke Organization (ESO) guideline does not advocate for thrombolysis in patients with acute CVT with a pretreatment low risk of poor outcome [49, 73].
Prevention of propagation of current thrombus by anticoagulant therapy
AHA/ASA and ESO guidelines currently recommend unfractionated heparin (UFH) or low molecular weight heparinoids (LMWHs) in the acute phase of CVT [49, 73]. This advice is mostly supported by two RCTs with <100 patients. Nevertheless, several observational studies have shown the safety and efficacy of UFH or LMWH in acute CVT.
These guidelines do not view hemorrhagic transformation as a contraindication for using UFH or LMWH. Current ESO guideline makes a weak recommendation for LMWH over UFH. Most studies are in favor of anticoagulation in septic CVT as well [1].
Decreasing ICP
For patients with very high ICP, hyperventilation, intravenous mannitol, or 3% saline should be tried before decompressive craniotomy.
Symptomatic treatment
Symptomatic treatment for headache, seizure, and other presentations of CVT should be considered. The ESO guideline does not support prophylactic antiepileptic treatment for patients without an overt seizure [73].
Treatment of specific underlying diseases
In the case of drug-induced CVT, the culprit drug should be discontinued indefinitely. High-dose antibiotics are the backbone of treatment for infections related to CVT, especially mastoiditis or middle ear infections. Furthermore, local pus accumulation at these sites may need to be drained. Patients with nephrotic syndrome associated with CVT or CVT due to vasculitides should be treated with steroids [73].
Endovascular acute treatment
The efficacy and indications of catheter-based treatment options for CVT remain to be elucidated. Endovascular treatment includes both intrasinus thrombolysis and mechanical thrombectomy (MT). A bolus dose of 10 mg rTPA could be injected [74], and then it could be infused through the catheter for 1–2 mg/h [75]. Techniques for endovascular clot retrieval include rheolytic thrombectomy, balloon angioplasty and/or stenting, microsnare, suction thrombectomy, and manual aspiration [76].
Although clot retrieval has been mostly considered for patients with progressive course despite medical treatment (Class IIb, level of evidence C) [73], some argued that adopting this policy may deprive some patients of endovascular treatments and suggested other indications such as coma at the time of admission or predominant involvement of deep cerebral veins for endovascular interventions [77].
Nevertheless, if a patient has any signs of impending cerebral herniation, craniotomy should be prioritized to endovascular treatments. Posttraumatic CVT is also a contraindication for intrasinus thrombolysis [76].
In the only randomized clinical trial of MT for CVST, the TO-ACT trial [78], eligible patients included those with confirmed CVT radiologically, to have a poor outcome due to one or more risk factors, or if the physician was unsure whether endovascular thrombolysis or standard anticoagulant therapy was more appropriate. The TO-ACT was terminated due to premature vainness of the MT arm. This trial had several major limitations including very low sample volume, lack of evaluation of primary recanalization rate, lack of initial analysis for prognostic variables, and heterogeneity of interventions. In a recent analysis of patients recruited in the ACTION-CVT cohort, by using Propensity score matching and inverse probability treatment weighting techniques, it was shown that endovascular treatment could not improve the functional outcome of the patients in comparison to an artificial control group [79].
Despite these negative results, new trials with predefined and well-accepted indications for MT recruiting patients from high-volume centers should be designed and executed. Till that time, endovascular clot retrieval with or without thrombolysis should only be considered as an off-label alternative for patients whose condition is aggravated despite standard treatment in centers with experienced interventionists.
Surgical acute treatment
In acute patients with clinico-radiological signs of herniation, decompressive surgery is evidence-based and can be lifesaving. Anticoagulation can be started or resumed safely between 24 and 48 h after surgery [80].
Treatment beyond acute phase
Medical treatment for prevention of recurrent CVT
After the acute stage of CVT, heparin or LMWH is followed by oral anticoagulants. A bridging therapy, particularly warfarin, is recommended to provide an international normalizing ratio of 2.5–3. Although there are no RCTs, current AHA/ASA and ESO guidelines recommend commencing warfarin for secondary prevention [49].
Recently, two RCTs in the adults [81, 82] and children [83], and a large cohort study [84] have shown the safety and efficacy of DOACs in secondary prevention for CVT patients. The RESPECT-CVT trial revealed dabigatran and warfarin are equally safe and effective for the prevention of recurrent venous thrombotic events [81]. In the SECRET study, bleeding happened more in the rivaroxaban group, but the frequencies of hemorrhages and recurrent venous thromboembolism were generally low in both case and control groups [82]. In the EINSTEIN-Jr CVT study, pediatric CVTs treated with rivaroxaban had a low risk of recurrent venous thrombotic events and hemorrhage [83]. In the ACTION-CVT study, clinical and radiological results and safety measures were similar between DOACs and warfarin group [84]. In addition, several systematic reviews and metanalyses revealed similar efficacy and safety of DOCAs compared to warfarin [85–88]. Although ESO and AHA/ASO guidelines have yet to advocate for DOACS, future guidelines may consider them a reasonable alternative to warfarin.
The duration of anticoagulation is a matter of debate. It depends entirely on the risk of recurrence of VTE in general and CVT in particular. Meanwhile, the risk of hemorrhage should also be kept in mind. The general risk of recurrence was 2.03 for 100 person-years for all VTE and 0.53 for 100 person-years for CVT [89]. Malignancy, thrombophilia, hemoglobinopathies, antiphospholipid antibody syndrome, and previous VTE had the highest risk of recurrence and justified long-term or even lifelong anticoagulation. On the other hand, 3–6 months of anticoagulation in patients with provoked causes is recommended by most guidelines. The ongoing extension oral anticoagulation treatment (EXCOA) may provide better answers to the above questions [90]. Table 3 [81, 83, 91–94] summarizes the therapeutic considerations of anticoagulant drugs for CVT.
Level of evidence, strength recommendation, dose, duration and consideration of anticoagulants for CVT.
| Intervention | Recommendation of AHA/ASA guideline30 | Recommendation of ESO guideline52 | Dose | Duration | Monitoring | Major considerations | ||
|---|---|---|---|---|---|---|---|---|
| Size of treatment effect | Estimate of certainty of treatment effect | Quality of evidence | Strength of recommendation | |||||
| Unfractioned heparin [91] | Recommended | Recommended | 1000 IU/h | Acute stage until no indication for surgical or endovascular intervention | aPTT of 1.5–2.5 times the control values | -If thrombocytopenia develops consider HITT | ||
| Class IIa | Level of Evidence B | Moderate | Strong | |||||
| Low molecular weight heparinoids (92–94) | Recommended | Recommended | Enoxaparin 60 mg SC Q12h | Same as above | None | -Not appropriate for patients with renal failure or candidate for surgery | ||
| Class IIa | Level of Evidence B | Low | Weak | |||||
| Vitamin K antagonist (warfarin) | Recommended | Recommended | 2–5 mg qd to target INR | 3–6 months for provocative causes, longer for nonprovocative causes | Target INR of 2.0–3.0 | -Decreases Protein C and Protein S -needs bridging -Several food and drug interactions -Not recommended in pregnancy | ||
| Class IIb | Level of Evidence C | Very low | Weak | |||||
| Direct oral anticoagulants (DOACs) [81, 83] | Not mentioned | Not recommended | Rivaroxaban 20 mg po QD Apixaban 5 mg po Bid Dabigatran 150 mg po Bid | Generally as warfarin but scarce data | No commercial test | -High risk of recurrence of thrombosis with sudden discontinuation -Not recommended in pregnancy | ||
| Very low | Weak | |||||||
| Intervention | Recommendation of AHA/ASA guideline30 | Recommendation of ESO guideline52 | Dose | Duration | Monitoring | Major considerations | ||
|---|---|---|---|---|---|---|---|---|
| Size of treatment effect | Estimate of certainty of treatment effect | Quality of evidence | Strength of recommendation | |||||
| Unfractioned heparin [91] | Recommended | Recommended | 1000 IU/h | Acute stage until no indication for surgical or endovascular intervention | aPTT of 1.5–2.5 times the control values | -If thrombocytopenia develops consider HITT | ||
| Class IIa | Level of Evidence B | Moderate | Strong | |||||
| Low molecular weight heparinoids (92–94) | Recommended | Recommended | Enoxaparin 60 mg SC Q12h | Same as above | None | -Not appropriate for patients with renal failure or candidate for surgery | ||
| Class IIa | Level of Evidence B | Low | Weak | |||||
| Vitamin K antagonist (warfarin) | Recommended | Recommended | 2–5 mg qd to target INR | 3–6 months for provocative causes, longer for nonprovocative causes | Target INR of 2.0–3.0 | -Decreases Protein C and Protein S -needs bridging -Several food and drug interactions -Not recommended in pregnancy | ||
| Class IIb | Level of Evidence C | Very low | Weak | |||||
| Direct oral anticoagulants (DOACs) [81, 83] | Not mentioned | Not recommended | Rivaroxaban 20 mg po QD Apixaban 5 mg po Bid Dabigatran 150 mg po Bid | Generally as warfarin but scarce data | No commercial test | -High risk of recurrence of thrombosis with sudden discontinuation -Not recommended in pregnancy | ||
| Very low | Weak | |||||||
SC: subcutaneous; INR: international normalized ratio; PTT: partial thromboplastin time; HITT: heparin-induced thrombocytopenia.
Level of evidence, strength recommendation, dose, duration and consideration of anticoagulants for CVT.
| Intervention | Recommendation of AHA/ASA guideline30 | Recommendation of ESO guideline52 | Dose | Duration | Monitoring | Major considerations | ||
|---|---|---|---|---|---|---|---|---|
| Size of treatment effect | Estimate of certainty of treatment effect | Quality of evidence | Strength of recommendation | |||||
| Unfractioned heparin [91] | Recommended | Recommended | 1000 IU/h | Acute stage until no indication for surgical or endovascular intervention | aPTT of 1.5–2.5 times the control values | -If thrombocytopenia develops consider HITT | ||
| Class IIa | Level of Evidence B | Moderate | Strong | |||||
| Low molecular weight heparinoids (92–94) | Recommended | Recommended | Enoxaparin 60 mg SC Q12h | Same as above | None | -Not appropriate for patients with renal failure or candidate for surgery | ||
| Class IIa | Level of Evidence B | Low | Weak | |||||
| Vitamin K antagonist (warfarin) | Recommended | Recommended | 2–5 mg qd to target INR | 3–6 months for provocative causes, longer for nonprovocative causes | Target INR of 2.0–3.0 | -Decreases Protein C and Protein S -needs bridging -Several food and drug interactions -Not recommended in pregnancy | ||
| Class IIb | Level of Evidence C | Very low | Weak | |||||
| Direct oral anticoagulants (DOACs) [81, 83] | Not mentioned | Not recommended | Rivaroxaban 20 mg po QD Apixaban 5 mg po Bid Dabigatran 150 mg po Bid | Generally as warfarin but scarce data | No commercial test | -High risk of recurrence of thrombosis with sudden discontinuation -Not recommended in pregnancy | ||
| Very low | Weak | |||||||
| Intervention | Recommendation of AHA/ASA guideline30 | Recommendation of ESO guideline52 | Dose | Duration | Monitoring | Major considerations | ||
|---|---|---|---|---|---|---|---|---|
| Size of treatment effect | Estimate of certainty of treatment effect | Quality of evidence | Strength of recommendation | |||||
| Unfractioned heparin [91] | Recommended | Recommended | 1000 IU/h | Acute stage until no indication for surgical or endovascular intervention | aPTT of 1.5–2.5 times the control values | -If thrombocytopenia develops consider HITT | ||
| Class IIa | Level of Evidence B | Moderate | Strong | |||||
| Low molecular weight heparinoids (92–94) | Recommended | Recommended | Enoxaparin 60 mg SC Q12h | Same as above | None | -Not appropriate for patients with renal failure or candidate for surgery | ||
| Class IIa | Level of Evidence B | Low | Weak | |||||
| Vitamin K antagonist (warfarin) | Recommended | Recommended | 2–5 mg qd to target INR | 3–6 months for provocative causes, longer for nonprovocative causes | Target INR of 2.0–3.0 | -Decreases Protein C and Protein S -needs bridging -Several food and drug interactions -Not recommended in pregnancy | ||
| Class IIb | Level of Evidence C | Very low | Weak | |||||
| Direct oral anticoagulants (DOACs) [81, 83] | Not mentioned | Not recommended | Rivaroxaban 20 mg po QD Apixaban 5 mg po Bid Dabigatran 150 mg po Bid | Generally as warfarin but scarce data | No commercial test | -High risk of recurrence of thrombosis with sudden discontinuation -Not recommended in pregnancy | ||
| Very low | Weak | |||||||
SC: subcutaneous; INR: international normalized ratio; PTT: partial thromboplastin time; HITT: heparin-induced thrombocytopenia.
Outcome
Morbidity and mortality of CVT have diminished dramatically in recent decades [95]. This is most probably because of the advances in imaging techniques, which lead to more accurate and rapid diagnosis of CVT. In-hospital mortality was between 2.1% and 8.3% in large series [5, 7–10]. However, it is still high in low-income countries and low-to-middle-income countries. For example, the mortality was 10% in Sub-Saharan Africa [96]. The most important chronic complications of CVT are intracranial hypertension [97] and dural arteriovenous fistulas [98].
Prognosis
The overall prognosis of CVST is better than the outcome of the arterial stroke [99]. Older age [9], stupor or coma [100], intracerebral hemorrhage at the time of presentation [9], underlying hematological disorders [9], malignancy, or infection [101] are considered independent predictors of mortality in studies. In CVT patients, venous infarcts were linked to clinical worsening [102]. The prognosis of CVT is overall good in CVST with obstetric-gynecologic causes [99]. Recently, some laboratory prognostic biomarkers such as neutrophil-to-lymphocyte ratio and the systemic immune-inflammatory index have also been proposed [63].
Future directions
There are still many gray zones in diagnosing and managing CVT. Is CT-based diagnosis (CT/CTV/CTP) better than MR-based diagnosis (MRI/MRV/MRP)? Although decompressive surgery is well accepted, when is the exact time for discontinuation and reinstitution of anticoagulants? What are the indications, contraindications, and best methods for endovascular treatment of CVT? What is the rate of recurrence? What is the determinant of recurrence? What is the role of venous stenosis in CVT?
Multiple Choice Questions
The role of which mechanism is not fully established in the pathogenesis of CVT?
Blood–brain barrier disruption
Disruption of the glymphatic system
Vasogenic edema
Cytotoxic edema
Answer B
Which statement is true regarding the relationship between COVID-19, COVID-19 vaccines, and CVT?
COVID-associated CVT can evolve in patients without any known risk factor for CVT
Antiphospholipid antibodies have no role in COVID-associated CVT
CVT-VITT was more associated with mRNA COVID vaccines
The number of CVT associated with VITT patients in low-to-middle-income countries is higher than in high-income countries
Answer A
Which symptom/sign can be seen in cavernous sinus thrombosis rather than SSS thrombosis?
Seizure
Headache
Diplopia
Proptosis
Answer: D.
4. Very high levels of which laboratory test is helpful in ruling in CVT?
A. ESR.
B. CRP.
C. D-Dimer.
D. Fibrinogen.
Answer: C.
5. DOACs are efficacious and safe in the prevention of recurrent CVT?
A. True.
B. False.
Answer: A.
Main messages
The benefits of the recombinant adenoviral-vector-based vaccines outweigh the very small risk of CVT.
DOACs are safe and efficacious in secondary prevention of CVT.
A well-designed trial for the role of MT in the treatment of acute CVT is needed.
Current research questions
Is CT-based diagnosis (CT/CTV/CTP) better than MR-based diagnosis (MRI/MRV/MRP)?
What are the indications, contraindications, and best methods for endovascular treatment of CVT?
What is the role of venous stenosis in CVT?
Key references
Wasay M, Kaul S, Menon B, et al. Asian study of cerebral venous thrombosis. J Stroke Cerebrovasc Dis 2019;28:104247.
Borhani Haghighi A, Edgell RC, Cruz-Flores S, et al. Mortality of cerebral venous-sinus thrombosis in a large national sample. Stroke 2012;43:262–4.
Saposnik G, Barinagarrementeria F, Brown RD, et al. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42:1158–92.
Ghoneim A, Straiton J, Pollard C, et al. Imaging of cerebral venous thrombosis. Clin Radiol 2020;75:254–64.
Ferro JM, Bousser MG, Canhão P, et al. European Stroke Organization guideline for the diagnosis and treatment of cerebral venous thrombosis – endorsed by the European Academy of Neurology. Eur Stroke J 2017;2:195–221.
Acknowledgements
Prof. Christopher Levi, Prof. Neil Spratt, and Dr Carlos Garcia-Esperon read and commented on the first drafts of this manuscript. We thank them for their great mentorship. We also thank Dr Parimah Shahravan for drawing Figure 2 and Dr Arash Azimi-Tabrizi and Dr Alireza Rezvani for their help.
Conflict of interest statement
None declared.
Funding
None.
Authors’ Contributions
A.B.H. and E.H. contributed equally to the study conception, drafting, design, and critical revision of the manuscript.
References
Author notes
Contributing author: Etrat Hooshmandi, Tel/Fax: (+98)-713-6281572, E-mail: [email protected]
