Diagnosis and Treatment of Cerebral Venous.10

Diagnosis and Treatment REVIEW ARTICLE

of Cerebral Venous C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
Thrombosis
Downloaded from http://journals.lww.com/continuum by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCyw
By Ava L. Liberman, MD
CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 06/03/2023
ABSTRACT
OBJECTIVE: Cerebral venous thrombosis (CVT), thrombosis of the dural sinus,
cerebral veins, or both, is a rare cerebrovascular disease. Although
mortality rates after CVT have declined over time, this condition can result
in devastating neurologic outcomes. This article reviews the latest
literature regarding CVT epidemiology, details new factors associated with
the development of CVT, and describes advances in CVT treatment. It also
contains a discussion of future directions in the field, including novel
diagnostic imaging modalities, and potential strategies to reduce the risks
associated with CVT.
LATEST DEVELOPMENTS: The incidence of CVT may be as high as 2 per 100,000

adults per year. It remains a difficult condition to diagnose given its
variable clinical manifestations and the necessity of neuroimaging for
confirmation. The COVID-19 pandemic has revealed a novel CVT trigger,
vaccine-induced immune thrombotic thrombocytopenia (VITT), as well as
an association between COVID-19 infection and CVT. Although VITT is a
very rare event, timely diagnosis and treatment of CVT due to VITT likely
improves patient outcomes. Direct oral anticoagulants are currently being
used to treat CVT and emerging data suggest that these agents are as safe
CITE AS:
and effective as vitamin K antagonists. The role of endovascular therapy to CONTINUUM (MINNEAP MINN)
treat CVT, despite a recent clinical trial, remains unproven. 2023;29(2, CEREBROVASCULAR
DISEASE):519–539.
ESSENTIAL POINTS: Theincidence of CVT has increased, outcomes have Address correspondence to
improved, and the use of direct oral anticoagulants to treat CVT represents Dr Ava L. Liberman, 520 East 70th
an important advance in the clinical care of these patients. Rates of CVT as St, Starr 607, New York, NY
10021, all9188@med.cornell.edu.
a complication of COVID-19 vaccines using adenoviral vectors are very low
(<5 per million vaccine doses administered), with the benefits of COVID-19 RELATIONSHIP DISCLOSURE:
vaccination far outweighing the risks. The institution of Dr Liberman

has received research support
from the National Institutes of
Health.
INTRODUCTION UNLABELED USE OF
C
erebral venous thrombosis (CVT) is estimated to account for less PRODUCTS/INVESTIGATIONAL
than 1% of all strokes.1,2 Unlike arterial strokes, CVT tends to affect USE DISCLOSURE:
Dr Liberman reports no
young patients with a female predominance, is often nonapoplectic disclosure.
in onset, and has a wide spectrum of clinical presentations.3 These
and other features make CVT a challenging disease to diagnose © 2023 American Academy
without an understanding of its evolving epidemiology, clinical features, of Neurology.
CONTINUUMJOURNAL.COM 519
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

CEREBRAL VENOUS THROMBOSIS
associated conditions, and the neuroimaging findings typically needed to

confirm the diagnosis.
ANATOMY AND PATHOPHYSIOLOGY

The condition of CVT includes clots in both the large dural sinuses and cortical
veins.4 The most prominent superficial sinus is the superior sagittal sinus, which
drains into the transverse (lateral) sinuses and then out of the skull via the sigmoid
sinuses into the internal jugular veins on each side. The superior sagittal sinus is the
most frequent CVT location.5 The largest of the many tributary cortical veins that
drain into the superior and transverse sinuses are the bilateral veins of Trolard
(veins draped vertically over the parietal lobe, which drain into the superior
sagittal sinus) and Labbé (veins situated horizontally over the temporal lobe,
which drain into the transverse sinus). The deep venous system includes the
straight sinus, vein of Galen, inferior sagittal sinus, internal cerebral veins that
drain the thalami, and basal veins of Rosenthal (FIGURE 7-16).7 It is thought that
venous clots often originate in dural sinuses and then propagate to smaller veins
resulting in venous infarction, increased intracranial pressure, or both.4
EPIDEMIOLOGY
Recent population-based studies have shown a higher incidence of CVT than
previously reported. The latest annual CVT incidence ranges from 1.32 to 2 per
100,000 adults based primarily on data from high-income countries.1,2,8-10 Rising
CVT incidence over time is likely partially due to better disease ascertainment
with increasing availability of neuroimaging, although it is also possible that
FIGURE 7-1
Dural sinus and venous anatomy. Three-dimensional contrast-enhanced magnetic
resonance venography (MRV) using time-resolved imaging contrast kinetics shows the
sagittal view (A) and coronal view (B) of the same patient. Arrows indicate named sinuses
and veins. In this patient, the right transverse sinus is dominant. Asymmetric transverse
sinuses are a frequent finding on MRV in unselected patients with one study reporting that
61% of patients had a greater caliber right transverse sinus as compared with the left.6
520 APRIL 2023

changes in the prevalence of known, emerging, or as yet unknown CVT- KEY POINTS
predisposing conditions may be a contributing factor.11 In one of the recent
● Unlike arterial strokes,
studies using US data from two states, 0.66% of all stroke admissions from 2005 cerebral venous thrombosis
to 2016 were for CVT, with an estimated annual CVT incidence of 1.4 to 2 per (CVT) has a wide spectrum
100,000 people.1 In this study, the authors found that the proportion of stroke of clinical presentations,
admissions due to CVT had increased by 70%, from 0.47% in 2005 to 0.80% in tends to affect younger
patients with a female

2016, with the largest increases in CVT incidence noted among men and older
predominance, and is often
women. Epidemiologic data from lower- and middle-income countries are nonapoplectic in onset.
lacking and represent an important area for future CVT research.1
Rates of CVT among women of reproductive age are consistently 3 times higher ● The latest annual CVT
than those for similarly aged men.2,8,12,13 The incidence of CVT among women age incidence ranges from 1.32
to 2 per 100,000 adults
18 to 44 years in the aforementioned US study remained virtually unchanged over based primarily on data from
the study time period at 2.9 to 3.3 cases per 100,000 people.1 Higher CVT rates high-income countries.
among young women are consistent with known sex-specific factors (eg, oral
contraceptive use, pregnancy, and the puerperium) associated with CVT.12 To ● Conditions associated
with CVT can be classified
date, racial differences in CVT incidence have been underexplored. Data from a as either predisposing (eg,
2020 study suggest that the incidence of CVT may be disproportionately higher in genetic prothrombotic
Black people compared with people of other races in the United States.1 Prevalence diseases, antiphospholipid
rates of systemic venous thromboembolism, deep venous thrombosis, and syndrome, cancer) or
precipitating (eg, oral
pulmonary embolism are generally higher in African Americans compared to other
contraceptives, infections).
racial and ethnic groups, but the reasons for these differences as well as whether or
not they are similar in patients with CVT require additional study.14
ASSOCIATED CONDITIONS
Conditions associated with CVT can be classified as either predisposing
(eg, genetic prothrombotic diseases, antiphospholipid syndrome, cancer) or
precipitating (eg, oral contraceptives, infections). In 80% of patients with CVT at
least one associated condition is found, and in nearly half of patients with CVT
more than a single condition is identified.5 Thus, the identification of one
condition known to be associated with CVT should not deter clinicians from
looking for additional conditions, particularly inherited thrombophilias.15
Indeed, the American Heart Association/American Stroke Association (AHA/
ASA) CVT guidelines note that testing for prothrombotic conditions, including
protein C, protein S, or antithrombin deficiencies antiphospholipid syndrome,
and prothrombin G20210A and factor V Leiden mutations, can be beneficial for
the management of patients with a first CVT (class 2a; level of evidence B).16
The more recently published European Stroke Organization (ESO) guidelines,
however, note that good clinical practice includes performing thrombophilia
testing in patients with a high probability of carrying severe thrombophilia (eg,
those with a personal or family history of venous thrombosis, or those with CVT
without a transient or permanent risk factor) to prevent recurrence based on the
existing low-quality evidence surrounding thrombophilia testing.17 Conditions
associated with CVT have been previously detailed in a comprehensive
meta-analysis of case-control and cohort studies from 201818; TABLE 7-118-25
summarizes and expands upon these findings. In the future, genetic and lifestyle
data may identify additional conditions associated with CVT and, perhaps,
facilitate precision medicine in this space. For example, a recent genome-wide
association study using genetic data from 11 European and 1 US research center
identified a locus on chromosome 9 that was strongly associated with a nearly
threefold increased CVT susceptibility.26 The single-nucleotide polymorphisms

TABLE 7-1 Conditions Associated With Cerebral Venous Thrombosisa
Predisposing
◆ Alcohol consumption
◆ Hypercholesterolemia
◆ Hyperhomocysteinemia
◆ Antiphospholipid antibodies present and antiphospholipid syndrome
◆ Autoimmune disease
◆ Anemia
◆ Malignancy (particularly within the first year of cancer diagnosis as well as among patients
with hematologic malignancies)19
◆ Pregnancy and the puerperium (a 2019 case-control study found a nearly 11-fold adjusted
increased risk of cerebral venous thrombosis [CVT] with higher risk during the first 6 weeks
postpartum as compared to 7 to 14 weeks)20
◆ Factor V G1691A polymorphism
◆ Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism
◆ Prothrombin G20210A polymorphism
◆ Protein C deficiency
◆ Protein S deficiency
◆ Antithrombin III deficiency
◆ Obesity (in women who used oral contraceptives, being overweight or obese was
associated with an increased risk of CVT in a dose-dependent manner)21
◆ Elevated factor VIII serum levels22
◆ Behçet disease23
Precipitating
◆ Glucocorticosteroids
◆ Trauma
◆ Infection (particularly central nervous system or ear and face)
◆ Surgical procedures
◆ Combined oral contraception pill treatment
◆ Vaccine-induced immune thrombotic thrombocytopenia
◆ L-asparaginase therapy
◆ All-transretinoic acid in acute promyelocytic leukemia24
◆ Lumbar puncture25
a
Data from Green M, et al, Thromb Res18 unless noted otherwise.
522 APRIL 2023

with the largest associations were in the coding regions of the ABO blood type KEY POINTS
gene and, after determining the blood group distribution of cases and controls,
● Data from a 2021 study
these researchers found that a non-O blood group was more prevalent in suggest that a rare but
CVT cases.26 demonstrable association
between CVT and COVID-19
COVID-19 AND CEREBRAL VENOUS THROMBOSIS infection exists, although
the underlying mechanisms

The COVID-19 pandemic has led to the identification of additional conditions
of this association are
associated with CVT. uncertain.
COVID-19 Infection ● In patients with

Infection as a precipitant of CVT (pyogenic CVT) has been well described.27,28 neurologic symptoms and
COVID-19 infection, a high
Data from a 2021 study suggest that a rare but demonstrable association between index of suspicion for CVT
CVT and COVID-19 infection exists, although the underlying mechanism of this should be encouraged, and
association is uncertain.29 Several thromboembolic pathways have been treatment of CVT should be
implicated in the pathophysiology of COVID-19 infection and cerebrovascular initiated as soon as possible.
disease as well as systemic venous thromboembolism that may also play a role in
CVT formation.30,31 The true prevalence of CVT in patients with COVID-19
infection is not known. A recent systematic review of existing case reports and
retrospective cohort studies using data from 34,331 patients hospitalized with
COVID-19 estimated the frequency of CVT at 0.08%. Signs, symptoms, and
diagnosis of CVT followed the onset of respiratory or systemic COVID-19
symptoms by 1 to 8 weeks in nearly all 54 patients with CVT included in this
study.32 Patients with CVT were often noted to have altered mental status, with
thrombosis of the deep cerebral venous system or involvement of multiple
sinuses.32 Only one of the identified patients with CVT and COVID-19 had an
isolated headache which may reflect the fact that patients with CVT without
severe neurologic deficits were underdiagnosed during the pandemic (ie,
selection bias) or that, among patients with active COVID-19 infection, CVT is
clinically more severe.33 Inpatient mortality was reported in nearly half of
patients with CVT and COVID-19 infection, much higher than that of patients
with CVT without COVID-19.34 It is unclear if this high mortality rate is related to
neurologic complications, care quality, or the severity of COVID-19 infection
itself.32 Based on these limited data, in patients with neurologic symptoms and
COVID-19 infection, a high index of suspicion for CVT should be encouraged,
and treatment of CVT should be initiated as soon as possible.
COVID-19 Vaccination
Another CVT precipitant was identified during postauthorization surveillance of
people who had received COVID-19 vaccines using adenoviral vectors (human
Ad26.COV2.S and chimpanzee ChAdOx1 nCov-19) to encode the spike
glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
In February 2021, reports emerged of patients with thrombocytopenia and
venous thromboembolism in unusual locations following administration of the
ChAdOx1 nCov-19 vaccine. Within months, three independent descriptions
were published of 39 people with thrombosis, frequently CVT, and
thrombocytopenia that developed 5 to 24 days after initial vaccination with
ChAdOx1 nCov-19.35-37 Shortly thereafter, 12 women aged 18 to 60 years who
presented with CVT and thrombocytopenia 6 to 15 days postvaccination with
Ad26.COV2.S were reported.38 To date, no independent predictors for CVT
development postvaccine have been identified, although vaccine recipients with

CVT and thrombocytopenia were often younger than age 60 years and were
women who lacked prothrombotic risk factors.39 In a comprehensive study using
data from postauthorization safety reports and official data from 30 European
countries and the United Kingdom, the calculated risk of CVT with
thrombocytopenia within 28 days of the first ChAdOx1 nCov-19 dose was 4.4
(95% confidence interval, 3.9 to 4.9) per million doses and 0.7 (95% confidence
interval, 0.2 to 2.4) after Ad26.COV2.S vaccination. In this analysis, the risk of
CVT with thrombocytopenia after ChAdOx1 nCov-19 vaccination was highest
among people aged 18 to 24 years (7.3 per million first doses) and lowest in those
aged 70 years or older (0.2 per million doses).40 On a population level, these
absolute numbers are small and, although data collection is ongoing as
vaccination continues, findings continue to overwhelmingly support the safety
and efficacy of vaccination with respect to reducing COVID-19 risk and reducing
death due to COVID-19.39,41 Additionally, the prevalence of CVT among
hospitalized patients with COVID-19, as noted above, is far higher (60-fold to
230-fold) than that of people who received adenovirus-based COVID-19
vaccines.4,29,42 However, given the link between adenoviral vector–based
vaccines and CVT, mRNA vaccines (BNT162b2 and mRNA-1273) may be
preferred for certain patient subgroups (eg, younger) since the risk of CVT with
thrombocytopenia following administration of mRNA vaccines is nearly zero.40
The entity implicated in these rare but potentially devastating cases of CVT
and thrombocytopenia following adenovirus-based COVID-19 vaccine
administration is now called vaccine-induced immune thrombotic
thrombocytopenia (VITT) or thrombosis with thrombocytopenia syndrome.
VITT is one of three rare but pathophysiologically related hypercoagulable states
associated with thrombosis, low platelet counts, and disseminated intravascular
coagulation. The other two hypercoagulable states are heparin-induced
thrombocytopenia (HIT), which occurs after heparin exposure and autoimmune
heparin-induced thrombocytopenia (aHIT), which refers to a condition where
antibodies activate platelets in the absence of heparin.4 These three
hypercoagulable states (VITT, HIT, and aHIT) are all mediated by
platelet-activating antibodies to platelet factor 4 (PF4). In HIT, exposure to
unfractionated heparin, a polyanion, causes complexes of PF4 and heparin to
form, resulting in the development of IgG autoantibodies against this complex
and eventually leading to platelet activation, aggregation, and release of
procoagulant molecules. Similarly, in VITT, autoantibodies are thought to be
generated from a not-yet-identified polyanion in the adenoviral vaccines or
expressed by the cells infected by the vaccine that binds to PF4.43 Why the
cerebral veins and sinuses, as opposed to other sites, are a frequent location of
thromboses in VITT, occurring in approximately half of patients with VITT at
presentation, is not well understood44; rates of CVT in VITT differ substantially
from rates of CVT in HIT (1.6%) and aHIT (2.5%).45,46 Prior to the COVID-19
era, thrombocytopenia at CVT presentation was very uncommon.47
In a multicenter UK cohort study, patients with VITT-associated CVT had
similar presenting features to those with non–VITT-associated CVT, including
84% presenting with headache.48 Those with VITT-associated CVT had more
intracranial veins thrombosed, more frequent extracranial thromboses, and
higher rates of death or dependency as compared to other patients with CVT
despite aggressive treatment.48 Fortunately, mortality for patients with
VITT-associated CVT has significantly decreased from nearly 50% in March 2021
524 APRIL 2023

to around 22% for cases diagnosed thereafter, likely due to the beneficial effect of KEY POINTS
earlier recognition and improved treatments, especially the avoidance of heparin
● The entity implicated in
anticoagulation to treat CVT in VITT.49 Therefore, in patients with CVT with the rare but potentially
symptom onset within 4 to 42 days of having received a COVID-19 vaccine using devastating cases of CVT
adenoviral vectors, following an algorithmic approach to evaluate and treat VITT and thrombocytopenia
is advised (FIGURE 7-243,50).43,50,51 following adenovirus-
based COVID-19 vaccine

administration is now
CLINICAL PRESENTATION OF CEREBRAL VENOUS THROMBOSIS called vaccine-induced
The signs and symptoms of CVT are diverse and may mimic other neurologic immune thrombotic
disorders, complicating diagnosis. Symptoms of CVT reflect the location of the thrombocytopenia (VITT), or
thrombosis with
vein or sinus affected and, in some cases, multiple locations may be affected
thrombocytopenia
simultaneously. Presentations of CVT can be roughly divided into four syndromes: syndrome.
(1) isolated headache or increased intracranial pressure, (2) focal neurologic
presentations, (3) subacute encephalopathy, and (4) cavernous sinus syndrome ● In patients with CVT with
with multiple cranial neuropathies.5 In ISCVT (International Study on Cerebral symptom onset within 4 to
42 days after having
Vein and Dural Sinus Thrombosis), a multicenter registry, the median time from received a COVID-19 vaccine
CVT symptom onset to diagnosis was 7 days (interquartile range 3 to 16 days), using adenoviral vectors,
suggesting considerable diagnostic delay.52 More recently, a multicenter following an algorithmic
retrospective US study found that a probable CVT misdiagnosis occurred in 3.6% approach to evaluate and
treat VITT is advised.
of patients who presented emergently mostly with headache symptoms.53
Detecting CVT in patients with isolated headache presentations, particularly those ● Presentations of CVT can
with a prior headache history, remains a significant clinical challenge.54,55 be roughly divided into four
Headaches are present in approximately 90% of patients with CVT.5,28,56 syndromes: (1) isolated
headache or increased
Failure of blood to drain properly from the brain can lead to increased
intracranial pressure, (2)
intracranial pressure manifesting with headache, vomiting, and papilledema focal neurologic
presentations, (3) subacute
encephalopathy, and (4)
cavernous sinus syndrome
with multiple cranial
neuropathies.
FIGURE 7-2
Algorithm for diagnosing vaccine-induced immune thrombotic thrombocytopenia.
aPTT = activated partial thromboplastin time; CBC = complete blood cell count; ELISA = enzyme-linked
immunosorbent assay; PF4 = platelet factor 4; PT = prothrombin time ; VITT = vaccine-induced immune
thrombotic thrombocytopenia.
a
Patients with thrombosis and a normal platelet count might be in the early stage of VITT; continued
assessment for development of thrombocytopenia/VITT is required.
Data from Rizk JE, et al, JAMA Cardiol43 and the American Society of Hematology.50

with or without visual loss or sixth nerve paresis. When any combination of these
features without other neurologic signs is present, the syndrome is referred to as
isolated intracranial hypertension and is estimated to occur in nearly one-third of
patients with CVT.5,57 Up to one-quarter of patients with CVT can present with
isolated headache without any additional stigmata of raised intracranial
pressure.56,58 Headache presentations in CVT are notoriously diverse. Among
patients with new headache, obtaining a detailed neurologic examination,

assessing for features known to be associated with CVT, and including secondary
causes of headache in the differential may help to improve diagnostic accuracy in
CVT. The International Classification of Headache Disorders, 3rd Edition,

explicitly notes that headaches attributed to CVT have no specific characteristics.
Evidence of a causal relationship between CVT and headache per the
International Classification of Headache Disorders, 3rd Edition, simply requires
that the headache developed in close temporal relation to the CVT and either
headache has significantly worsened in parallel with clinical or radiological signs
of extension of the CVT or headache has significantly improved or resolved after
improvement of the CVT.59 Some key clinical features of CVT-associated
headache include being exacerbated by Valsalva maneuver and recumbency,
subacute onset of pain, and more often diffuse than unilateral headache
location.60 However, acute presentations consistent with migraine or
thunderclap headache may also occur.58 The transverse sinus is frequently a site
of thrombosis among patients with CVT and isolated headache.58,61 Interestingly,
a prospective study from 2020 where all patients with CVT were treated with
anticoagulation acutely found no significant difference in the frequency of
headache of any type or headache with features of intracranial hypertension in
patients achieving full recanalization as compared with those who did not fully
recanalize.62 The relationship between venous recanalization and
CVT-associated headache as well as the mechanism by which CVT causes
headache pain require further investigation.
Alternatively, patients with CVT may present with focal deficits, seizures, or
both. Symptoms depend on the area of the brain affected. Common focal
symptoms in CVT include hemiparesis, aphasia, and loss of vision.5 A key feature
of focal neurologic deficits due to CVT is that they are frequently progressive in
contrast with arterial strokes, which tend to be maximal at onset.63 The duration
of CVT symptoms prior to presentation was greater than 48 hours in 53% of
patients in the VENOST study,56 another large CVT registry, and, in ISCVT,
symptom onset of between 48 hours and 30 days was seen in slightly more than
half of patients.5 Another feature that may distinguish the focal deficits of CVT
from those of more commonly encountered arterial strokes is their bilateral
nature, particularly when the superior sagittal sinus is affected.28,52 Seizures, both
generalized and focal, are far more common in CVT than with arterial
cerebrovascular events, occurring in nearly 40% of patients with CVT at
initial presentation.52
Finally, patients with thrombosis of the deep venous system may develop a
subacute encephalopathy with confusion and lethargy or experience a rapid
neurologic deterioration progressing to coma due to edema of bilateral thalami,
basal ganglia, or other deep structures typically drained by these veins.64,65
Approximately 10% of patients with CVT have thrombosis of the deep cerebral
venous system.52,64 Timely neurologic imaging is an essential component of the
diagnostic evaluation for patients who present in coma to distinguish deep
526 APRIL 2023

cerebral vein thrombosis from other neurologic causes. Cortical vein thrombosis KEY POINTS
is thought to be even more rare than deep venous system thrombosis, occurring
● A key feature of focal
in only 116 patients in the published literature.66 However, since most of the neurologic deficits due to
published cases of isolated cortical vein thrombosis have associated venous CVT is that they are
infarct, underreporting and potentially underdiagnosis of nonsevere isolated frequently progressive in
cortical vein thrombosis cases may occur. nature in contrast to arterial
strokes which tend to be

maximal at onset.
RADIOGRAPHIC FINDINGS
Given the broad spectrum of presentations seen in CVT, recognizing the ● Contrast-enhanced brain
presence of CVT on clinical grounds requires a high degree of suspicion. MRI provides detailed
Radiologic studies are crucial to establish the definitive diagnosis of CVT. In the information about the brain
parenchyma and is probably
emergency setting, CT is often the imaging test of choice for patients presenting more accurate for
with acute focal neurologic symptoms. However, ruling out CVT is difficult to do diagnosing CVT than non-
using CT alone.67 Both direct visualization of a thrombus in a cerebral vein or contrast-enhanced
sinus, often called the “dense clot sign” or “cord sign,” as well as visualization of a magnetic resonance
venography sequences.
filling defect within a dural sinus after contrast administration, the “empty delta
sign,” have high specificity but low sensitivity.68 Intracerebral hemorrhage,
which is well seen on head CT, is present in approximately one-third of patients
with CVT.5 Increased suspicion for hemorrhagic venous infarcts from CVT
should occur when multiple intraparenchymal hemorrhages are present; infarcts
are ill-defined or in a nonarterial territory; or involve the bilateral thalami or
bilateral basal ganglia, or are juxtacortical (CASE 7-1).69,70
Advanced imaging is generally required to diagnose and rule out CVT with
certainty, and noninvasive imaging is typically favored over cerebral
angiography, which is the gold standard.72 CT venography, a contrast-enhanced
helical CT examination performed with a time-optimized contrast bolus, allows
direct visualization of a thrombosed cerebral vein, and is a fairly reliable
alternative to angiography with high sensitivity but low specificity.73 Magnetic
resonance venography (MRV) can also be used to detect CVT without ionizing
radiation exposure. Both CT venography and contrast-enhanced MRV are
superior to time-of-flight MRV techniques since complex flow can produce
artifacts in the latter. Contrast-enhanced MRV allows for a direct assessment of
luminal filling similar to that of CT venography, with comparable sensitivity and
specificity to CT venography.74,75 Contrast-enhanced brain MRI provides
detailed information about the brain parenchyma and is probably more accurate
for diagnosing CVT than noncontrast-enhanced MRV sequences.68 On brain
MRI, the most common finding is visualization of the thrombus in the
T1-weighted images. However, the timing of the CVT is an important
consideration for thrombosis visualization on MRI: in the acute phase (first
5 days after CVT) thrombus is isointense on T1-weighted images and
hypointense on T2*-weighted images; from 5 to 15 days the thrombus becomes
hyperintense on T1-weighted and T2*-weighted images; finally, after 15 days it
becomes homogeneous and hypointense in all image sequences. T2*-weighted
and susceptibility-weighted imaging sequences can be useful to assist in the
diagnosis of isolated cortical venous thrombosis on brain MRI.16,76
Using MRI black-blood thrombus imaging, a noncontrast-enhanced
T1-weighted imaging method that allows for direct visualization of the thrombus
itself, to detect CVT has very high sensitivity and excellent specificity compared
to combined CT and MRI modalities in small studies.77,78 Since a similar native
contrast thrombus MRI technique is highly accurate for the diagnosis of new and

CASE 7-1 A 60-year-old right-handed man with no known past medical history
presented with a mixed aphasia. Initial imaging in the emergency
department revealed a left temporal lobe intraparenchymal hemorrhage
with subarachnoid extension (FIGURE 7-3A). On arrival, he was afebrile,
tachycardic, and had a severely elevated blood pressure of 210/103 mm
Hg. The etiology of this hemorrhage was initially thought to be

hypertensive vasculopathy; evidence of dense cord sign on head CT
(FIGURE 7-3B) was not appreciated. Two days later, he had a brief transient
episode of gaze deviation to the right and unresponsiveness.

CT venography was
performed and demonstrated
thrombosis of the left
transverse sinus, sigmoid
sinus, internal jugular vein,
and the vein of Labbé
(FIGURE 7-3C). He was started
on therapeutic IV
anticoagulation as well as
antiseizure medication.
Thrombosis of the left vein of
Labbé was confirmed on
T1-weighted brain MRI
(FIGURE 7-3D).
The patient’s hospital stay
was fairly uncomplicated. He
was diagnosed with type II
hypertension and started on FIGURE 7-3
oral antihypertensive agents Imaging of the patient in CASE 7-1. A, Initial
in addition to therapeutic emergency department imaging revealing a left
temporal lobe intraparenchymal hemorrhage with
anticoagulation and
subarachnoid extension on axial noncontrast CT
antiseizure medications prior (arrow). B, Evidence of dense cord sign on axial
to discharge. Despite noncontrast CT (arrow). C, CT venography
extensive laboratory testing, demonstrating thrombosis of the left transverse
no precipitating or sinus (arrow), sigmoid sinus, internal jugular vein,
and the vein of Labbé. D, Coronal T1-weighted MRI
predisposing factors sequence confirming thrombosis of the left vein of
associated with his left-sided Labbé; the arrow indicates thrombosis of the
cerebral venous thrombosis transverse sinus extending into the vein of Labbé.
(CVT) were found.
COMMENT This case illustrates the challenges in acute CVT diagnosis as well as the
relevant vascular anatomy and imaging findings of CVT. Antiseizure
medication treatment for CVT is only recommended for patients who have
had a seizure, as in the case presented; prophylactic use of antiseizure
medication is not recommended.16,17 Patients with CVT with supratentorial
lesions have a higher risk for both presenting with and having early
seizures.71
528 APRIL 2023

recurrent lower-extremity deep venous thrombosis,79,80 black-blood thrombus KEY POINT
imaging may be of value for CVT detection if current findings are supported by
● Both the American Heart
additional data.68 An interesting radiographic finding seen on brain MRI, the Association/American
brush sign, has recently been described in CVT. This sign is an abnormal Stroke Association (AHA/
hypointensity of the subependymal and deep medullary veins in paramagnetic- ASA) and the more recently
sensitive MRI brain sequences that has been reported in patients with CVT, published European Stroke
Organization (ESO)
particularly those with thrombosis of the deep venous system (FIGURE 7-481). The
guidelines recommend
deep medullary veins are small-caliber vessels located adjacent to the atrium and initiation of parenteral
posterior body of the lateral ventricle, draining the white matter of the cerebral anticoagulation with
hemispheres to the subependymal veins of the lateral ventricles. The brush sign unfractionated or low-
molecular-weight heparin
was associated with higher thrombus load as well as ipsilateral parenchymal
prior to transitioning to oral
lesions in one small study; this sign may be a marker of CVT severity and should anticoagulants for CVT
prompt close monitoring during the acute phase.81 treatment.
TREATMENT
Medical, endovascular, and surgical treatments can be used to treat CVT.
Acute Anticoagulation
Anticoagulation remains the first-line treatment of choice for CVT in the acute
setting, even when concurrent intracerebral hemorrhage is present.16,17,82 Both
the AHA/ASA and the ESO guidelines recommend initiation of parenteral
anticoagulation with unfractionated or low-molecular-weight heparin (LMWH)
prior to transitioning to oral anticoagulants for CVT treatment.16,17 The ESO
guidelines have a weak recommendation for LMWH over unfractionated heparin
based on a meta-analysis suggesting a nonsignificant trend toward improved
functional outcomes and mortality with LMWH without a difference in rates
of bleeding.17,83 This trend is in keeping with an analysis from ISCVT that
suggested LMWH might be safer and perhaps more efficacious than
unfractionated heparin.84
FIGURE 7-4
The brush sign in cerebral venous thrombosis. Axial T2*-weighted MRI shows bilateral brush
sign (A, arrows) in a patient with acute thrombosis of the superior sagittal sinus, bilateral
transverse sinus, jugular vein, vein of Galen, straight sinus, and internal cerebral veins; this
extensive CVT is well seen on magnetic resonance venography (MRV) (B).
Reprinted with permission from Aguiar de Sousa D et al, Stroke.81 © 2019 Wolters Kluwer Health.

The clot in the venous system is the primary target of acute anticoagulation.
In a systematic review including data from 694 patients with CVT, vessel
recanalization occurred in roughly 85% at follow-up. This study found a
significant increase in the chance of favorable outcome (defined as a modified
Rankin Scale [mRS] score of 0 to 1) in patients with CVT with recanalization.85
New data suggest that vessel recanalization occurs early once anticoagulation is
initiated. In a prospective study of 68 patients with CVT all treated acutely with
anticoagulation who were imaged 0, 8, and 90 days from diagnosis, 43 (68%) had
partial recanalization and 4 (6%) had full recanalization at day 8.62 At 90 days,
41% had partial recanalization and 54% had full vessel recanalization. Patients
with early recanalization were at a lower risk of enlargement of nonhemorrhagic
lesions and showed early regression of venous infarcts. These findings support
the widely accepted hypothesis that recanalization improves regional
perfusion.62 An additional important aspect of early anticoagulation initiation in
CVT is prevention of other dangerous venous thromboembolisms in patients
with CVT, particularly pulmonary embolisms, at index hospitalization.86
Duration of Anticoagulation
The duration of anticoagulation following CVT has not been studied in any
randomized controlled trials; current recommendations are based on
extrapolation from venous thromboembolism data.16,17 This extrapolation from
venous thromboembolism to the CVT population, who are younger and likelier
to have had a provoked event, has been challenged. EXCOA-CVT (EXtending
oral antiCOAgulation treatment after acute Cerebral Vein Thrombosis) is a
cluster randomized trial designed to evaluate the efficacy and safety of
anticoagulation with vitamin K antagonists for 3 to 6 versus 12 months after CVT
to clarify the optimal duration of this therapy.87 Current AHA/ASA guidelines
note that for patients with provoked CVT (associated with a transient risk factor)
a 3- to 6-month duration of anticoagulation is reasonable but that for patients
with unprovoked CVT anticoagulation may be continued for 6 to 12 months.16
Patients who have recurrent venous thrombosis or an associated prothrombotic
condition with a high thrombotic risk may need permanent anticoagulation;
specific recommendations for the prevention of recurrent venous
thromboembolic events should be followed in those conditions.17
Use of Direct Oral Anticoagulants

Since the noninferiority of direct oral anticoagulants to prevent systemic venous
thromboembolism as compared to vitamin K antagonists has been shown,88 a
great deal of interest has been expressed in using these newer agents to reduce
the risk of venous thromboembolism after CVT. Direct oral anticoagulants have a
favorable safety profile, predictable pharmacokinetics, and are easier to
administer than vitamin K antagonists.89 Some support for the use of direct oral
anticoagulants after CVT comes from recent clinical trials. RESPECT-CVT
(Clinical Trial Comparing Efficacy and Safety of Dabigatran Etexilate with
Warfarin in Patients With Cerebral Venous and Dural Sinus Thrombosis) was a
prospective, randomized, open-label trial to evaluate the efficacy and safety of
dabigatran compared to dose-adjusted vitamin K antagonists to prevent
recurrent venous thromboembolism.90 In this trial, 120 adult patients with CVT
were randomized in a 1:1 fashion to dose-adjusted warfarin to maintain an
international normalized ratio (INR) of 2 to 3 or dabigatran 150 mg twice a day
530 APRIL 2023

for 24 weeks. Patients were eligible for inclusion if they were stable after 5 to
15 days of treatment with therapeutic heparin, able to swallow, did not have CVT
associated with either CNS infection or major trauma, and did not have any
surgical treatments planned. At the end of the study, no recurrent venous
thromboembolisms were observed in either treatment group, but three major
bleeding events occurred. These major bleeding events involved one patient with
intestinal bleeding in the dabigatran group and two patients with intracranial
(subdural) hemorrhages in the vitamin K antagonists group. The two treatment
groups had nearly identical rates of CVT recanalization on imaging. While
RESPECT-CVT could not detect a statistically significant difference between the

two treatments for recurrent venous thromboembolism, it did suggest that
dabigatran is a reasonable option to prevent recurrent venous thromboembolism
after CVT.
The safety and efficacy of rivaroxaban in CVT has also been studied.
EINSTEIN-Jr (Oral Rivaroxaban in Children With Venous Thrombosis), a
multicenter, parallel-group, open-label, randomized study, compared
rivaroxaban to dose-adjusted vitamin K antagonists in children (aged 0 to
17 years) with venous thromboembolism; a prespecified substudy of patients
enrolled with CVT was published in 2020.91 The main trial assigned patients in a
2:1 fashion to body weight–adjusted rivaroxaban in a 20 mg equivalent dose or
standard anticoagulation. Of the 114 children with confirmed CVT, symptomatic
recurrent venous thromboembolism occurred in none of the 73 children in the
rivaroxaban group versus one (2.4%) of the 41 children in the standard
anticoagulation group. Clinically relevant, nonmajor extracranial bleeding was
observed in five rivaroxaban recipients (6.8%) and one child (2.4%) in the
standard anticoagulation arm had a major bleeding event (subdural). No new
venous infarcts occurred in either group and repeat imaging demonstrated a
similar effect on clot resolution with rivaroxaban as compared to vitamin K
antagonists.91 Although it is challenging to apply the findings from a pediatric
trial (particularly one that was not powered for hypothesis testing) to an adult
population, the CVT substudy of EINSTEIN-Jr supports the overall trend that
direct oral anticoagulants are effective after CVT. Currently, SECRET (Study of
Rivaroxaban for CeREbral Venous Thrombosis), an open-label, randomized,
controlled, phase II clinical trial designed to evaluate the safety of rivaroxaban in
adults, is ongoing.92 Another trial called RWCVT (Rivaroxaban versus Warfarin
in CVT Treatment) has completed enrollment but has not yet published results.
An ongoing international observational study, DOAC-CVT (Direct Oral
Anticoagulants for the Treatment of Cerebral Venous Thrombosis,
NCT04660747), may also inform future practice.
Many practitioners have already started using direct oral anticoagulants to
treat CVT based on existing data. A systematic review of direct oral anticoagulant
use in CVT found a substantial increase in observational cohorts and case series
that included patients with CVT treated with apixaban, dabigatran, edoxaban, or
rivaroxaban since 2019. The observational cohorts included in the systematic
review reported a similar risk of death in direct oral anticoagulant versus
standard therapy arms and noted that favorable outcomes (mRS 0 to 2) were
more likely in direct oral anticoagulant–treated patients with CVT.93
ACTION-CVT (Direct Oral Anticoagulants Versus Warfarin in the Treatment of
Cerebral Venous Thrombosis), a large multicenter retrospective study, provides
additional reassurance to those who use direct oral anticoagulants after the acute

phase of CVT. The ACTION-CVT study included 845 patients with CVT across
27 centers in four countries. It found that direct oral anticoagulant treatment was
associated with a similar rate of recurrent venous thromboembolism (5.26 versus
5.87 per 100 patient years), a lower risk of major hemorrhage (2.44 versus 4.70
per 100 patient years), and similar rates of death and recanalization as with
vitamin K antagonists.94 In ACTION-CVT, two-thirds of patients on direct oral
anticoagulants were treated with apixaban. Although ACTION-CVT and other

retrospective treatment studies are prone to confounding by indication, no major
safety issues have been found with the use of direct oral anticoagulants as
opposed to vitamin K antagonists in clinical practice.95 It is important to note that

patients with antiphospholipid antibody syndrome should not be treated with
direct oral anticoagulants based on two randomized trials showing an increase in
arterial thrombotic events when these patients were treated with rivaroxaban
instead of warfarin.96,97 Additionally, pregnant patients with CVT should likely
be continued on LMWH rather than any other agent due to potential
teratogenicity.98
Endovascular Therapy
Endovascular therapy, defined as mechanical thrombectomy with or without
thrombolysis, has long been used to rapidly recanalize occluded sinuses in
patients with severe CVT who worsen despite anticoagulation or who cannot
receive anticoagulation. The results of the TO-ACT (Thrombolysis or
Anticoagulation for Cerebral Venous Thrombosis) trial were recently
published.99 This multicenter, open-label, blinded-endpoint, randomized trial
was designed to assess the safety and efficacy of endovascular therapy. Patients
with CVT were randomized 1:1 to receive either endovascular therapy with
anticoagulation or anticoagulation alone. Adult patients with radiologically
confirmed CVT who had one or more prespecified features associated with poor
outcome (mental status disorder, coma state, intracerebral hemorrhage, or
thrombosis of the deep venous system) were included in the study. TO-ACT was
halted after the first interim analysis for futility. A total of 67 patients were
randomized into TO-ACT, accounting for approximately 16% of patients with
CVT (67 of 420) seen at the sites during the study period. The number of patients
with a favorable functional outcome (mRS 0 to 2) at 12 months was very similar
between treatment groups (85% versus 82%). The mortality rates at 6 and
12 months were numerically higher in the endovascular therapy group than the
medical management group but did not reach statistical significance. Because of
the small sample size, TO-ACT is somewhat difficult to interpret. It remains
possible that improved methods of patient selection or different endovascular
techniques (in TO-ACT, more modern stent retrievers and aspiration catheters
were not used) may increase the frequency of favorable outcomes after CVT.
Indeed, symptomatic hemorrhage was higher in the medical arm (9% versus 3%)
in TO-ACT, suggesting that EVT may be effective in reducing the risk of further
bleeding. Retrospective data, however, have suggested that the role of
endovascular therapy in CVT is limited. Using data from the Nationwide
Inpatient Sample from 2004 to 2014, researchers found that 3% of identified
patients with CVT were treated with endovascular therapy. These researchers
found that endovascular therapy was independently associated with an increased
risk of death (odds ratio 1.96) after adjustment to account for measured
confounders.100 Further data as to the role of endovascular therapy in select
532 APRIL 2023

patients with CVT are likely needed before treatment recommendations can KEY POINTS
be made.
● The ACTION-CVT study
and other retrospective
Treatment of Vaccine-Induced Immune Thrombotic Thrombocytopenia– treatment studies are prone
Associated Cerebral Venous Thrombosis to confounding by
Early recognition, diagnosis, and treatment of VITT has led to favorable patient indication; nevertheless,
there do not seem to be

outcomes.101 As in HIT, therapeutic anticoagulation with nonheparin
major safety issues with
anticoagulants is the primary treatment for VITT with or without CVT. Based on the use of direct oral
data from patients with aHIT, administration of IV immunoglobulin (IVIg) as anticoagulants as opposed
soon as VITT is diagnosed or under consideration is recommended by both the to vitamin K antagonists in
clinical practice.
American Society of Hematology (ASH) and the AHA/ASA at a recommend dose
of 1 g/kg for two days.50,51 In patients with severe VITT (extensive thrombosis ● As in heparin-induced
with platelets <50 103/μL) or resistant VITT (continued thrombosis despite thrombocytopenia,
medical therapy), treatment with IVIg as a sole immunotherapy might not be therapeutic anticoagulation
enough because of the high antibody burden.43 Although the 2020 AHA/ASA with non-heparin
anticoagulants is the primary
guidelines for VITT-associated CVT do not address plasma exchange as a treatment for VITT with or
treatment modality, the ASH notes that plasma exchange can be considered if without CVT.
thrombosis continues despite nonheparin anticoagulation and IVIg.102 Aspirin
should not be used in patients with VITT. Platelet transfusions should be avoided ● Despite the low quality of
evidence, the ESO
with careful risk and benefit assessments made in patients with bleeding, who
guidelines now strongly
require surgical intervention, or both.51 Some cases of VITT-associated CVT with recommend using
extensive clot burden treated with endovascular therapy have been reported decompressive surgery for
with mostly favorable outcomes.103 Given the rarity of thrombocytopenia and patients with acute CVT and
parenchymal lesions with
CVT, all care should be individualized for each patient.
impending herniation to
prevent death as a
Decompressive Surgery randomized controlled trial
Herniation attributable to unilateral mass effect produced by large edematous is unlikely for ethical and
venous infarctions or parenchymal hemorrhages is the major cause of acute death feasibility reasons.
in CVT.104 Although the vast majority of patients with CVT have a favorable
outcome, about 4% develop cerebral edema severe enough to cause brain
herniation. In these instances, decompressive craniectomy, hematoma
evacuation, or both have been used to prevent death.5 Although a potential
disadvantage of craniectomy is that it precludes anticoagulation for the
immediate postoperative period, support for decompressive surgery exists. In
a retrospective study that included a systematic review of the literature, a total
of 69 patients with CVT were identified.105 Of those, only 12 (17%) had a poor
outcome (mRS 5 to 6) at a median of 12 months of follow-up. Nearly one-third
of patients who were comatose prior to surgery recovered completely at
follow-up.105 An updated systematic review published in 2019 identified 169
patients with CVT who were treated with decompressive surgery, mostly
from low- to middle-income countries, and similarly found a low mortality
rate of 16% at follow-up.106 Despite the low quality of evidence, the ESO
guidelines now strongly recommend using decompressive surgery for patients
with acute CVT and parenchymal lesions with impending herniation to
prevent death as a randomized controlled trial is unlikely for ethical and
feasibility reasons.17
Chemical Prophylaxis
Whether individuals with a history of CVT would benefit from targeted
prophylaxis in scenarios associated with increased venous thromboembolism risk

KEY POINT is uncertain and represents an important area for future research. Pregnant
women have been the focus of some research regarding the use of chemical
● In general, CVT has a
favorable outcome with an
prophylaxis to prevent venous thromboembolism or CVT recurrence.107 In a
in-hospital mortality rate small retrospective study of 63 women who became pregnant after their
ranging from 1% to 4% and diagnosis of CVT and were treated with LMWH for the entire gestational
from 8% to 10% during period, two (3%) had venous thromboembolisms and none had bleeding
long-term follow-up.
complications.108 In an update of a systematic review published in 2017 that
included a total of 393 patients, an analysis stratified according to antithrombotic
prophylaxis showed a trend toward lower rates of recurrent CVT and
extracerebral venous thromboembolism in patients receiving antithrombotic

prophylaxis with heparin.109,110 Although limited, based on these and other data
both AHA/ASA and the ESO recommend LMWH prophylaxis in pregnant
patients with a previous history of CVT.16,17 The optimal dose of LMWH in
pregnant women with moderate to high risk of recurrence of venous
thromboembolism is the subject of substantial debate with an ongoing open-label
randomized controlled trial comparing two different doses of LMWH in
pregnant patients with a history of venous thromboembolism.111
CLINICAL OUTCOMES
In general, CVT has a favorable outcome with an in-hospital mortality rate ranging
from 1% to 4% and from 8% to 10% during long-term follow-up.2,5,10,13,104,112,113
Mortality rates after CVT have been declining. One systematic review found an
inverse correlation between mortality and the calendar year in which patients
with CVT were recruited into a particular study.114 The frequency of presenting
with focal neurologic deficits and coma also decreased significantly over time.
Possible explanations are improvements in treatment, a shift in risk factors, and
the identification of less severe cases by improved diagnostic methods.114 Most
studies reporting outcomes after CVT have reported mRS scores at follow-up
which may not accurately capture the morbidity that follows CVT. A
single-center study of 161 patients with CVT in Finland found that even though
82% of patients had an mRS of 0 to 1 at 6 months, as many as 68% of patients
reported residual symptoms which frequently included neuropsychological
difficulties and headache.115 Older, smaller-cohort studies have identified
cognitive impairments, headaches, and seizures after CVT, frequently resulting
in unemployment.116-118 Future research detailing functional outcome after CVT
and evaluating interventions to improve patients’ ability to return to the
workforce is warranted.
CONCLUSION
The epidemiology of CVT is changing, including more frequent detection among
older patients and increased reported incidence rates. The presentation of CVT
can be subtle and usually differs from that of other cerebrovascular diseases,
making detection of CVT on advanced neuroimaging an essential component of
diagnosis. The use of direct oral anticoagulants to treat CVT is an important
advance that has recently been shown to be safe and effective, and evidence
supports a shift toward their use in clinical practice. To date, the rates of CVT as
a complication of adenovirus-based COVID-19 vaccination are very low (<5 per
million vaccine doses) and essentially zero with mRNA-based vaccines, with
the benefits of COVID-19 vaccination far outweighing the risk of VITT.
534 APRIL 2023

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Diagnosis and Treatment of Cerebral Venous.10

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Diagnosis and Treatment REVIEW ARTICLE

LATEST DEVELOPMENTS: The incidence of CVT may be as high as 2 per 100,000

vaccination far outweighing the risks. The institution of Dr Liberman

INTRODUCTION UNLABELED USE OF

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associated conditions, and the neuroimaging findings typically needed to

ANATOMY AND PATHOPHYSIOLOGY

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patients with a female

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TABLE 7-1 Conditions Associated With Cerebral Venous Thrombosisa

522 APRIL 2023

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the underlying mechanisms

COVID-19 Infection ● In patients with

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524 APRIL 2023

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based COVID-19 vaccine

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patients with new headache, obtaining a detailed neurologic examination,

CVT. The International Classification of Headache Disorders, 3rd Edition,

526 APRIL 2023

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strokes which tend to be

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Hg. The etiology of this hemorrhage was initially thought to be

episode of gaze deviation to the right and unresponsiveness.

528 APRIL 2023

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Use of Direct Oral Anticoagulants

530 APRIL 2023

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RESPECT-CVT could not detect a statistically significant difference between the

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anticoagulants were treated with apixaban. Although ACTION-CVT and other

opposed to vitamin K antagonists in clinical practice.95 It is important to note that

532 APRIL 2023

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there do not seem to be

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extracerebral venous thromboembolism in patients receiving antithrombotic

534 APRIL 2023

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15 Bousser MG, Ferro JM. Cerebral venous

16 Saposnik G, Barinagarrementeria F, Brown RD,

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yhrombosis. Stroke 2016;47(5):1271-1277. Published January 3, 2022. Accessed July 25,

venous thrombosis: a descriptive multicenter 40 Krzywicka K, van de Munckhof A, Sánchez van

536 APRIL 2023

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9, 2022. Accessed July 25, 2022. https://www. STROKEAHA.119.028532

51 Furie KL, Cushman M, Elkind MSV, et al. Diagnosis 14(4):530-536. doi:10.1161/01.str.14.4.530

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Am Inc 2006;26 Suppl 1:S19-41; discussion S42-43. anticoagulants dabigatran, rivaroxaban,

thromboembolism: a systematic review and

538 APRIL 2023

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cerebral venous thrombosis: the TO-ACT

100 Siddiqui FM, Weber MW, Dandapat S, et al. 211-212. doi:10.1007/s00415-017-8666-x

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