Journal of Thrombosis and Haemostasis, 13 (Suppl. 1): S238–S244 DOI: 10.1111/jth.

12945

INVITED REVIEW

Cerebral venous thrombosis

J. M. COUTINHO
Department of Neurology, Academic Medical Center, Amsterdam, the Netherlands

To cite this article: Coutinho JM. Cerebral venous thrombosis. J Thromb Haemost 2015; 13 (Suppl. 1): S238–S44.

give an overview of the epidemiology, diagnosis, and

Summary. Cerebral venous thrombosis (CVT) is an treatment of CVT in adults.
uncommon cause of stroke that mainly affects young
adults and children. In contrast to venous thromboembo-
Historical perspective
lism, women are affected three times more often than
men. Baseline symptoms can vary considerably between The first description of CVT is attributed to the French
patients, but most present with headache, seizures, or physician Ribes, who, in 1825, described a patient with
focal neurological deficits. Patients can be diagnosed with severe headache and epilepsy due to thrombosis of the
magnetic resonance imaging, computerized tomography- superior sagittal and lateral sinuses [1,2]. The first case of
venography, or catheter angiography, although the latter puerperal CVT dates back to 1828, when John Abercrom-
is rarely required anymore. Approximately 30–50% of bie, physician to King George IV of England, published a
patients have an intracerebral hemorrhage, which can detailed report of a 24-year-old woman who developed
range from a small juxtacortical hemorrhage to large headaches and seizures 2 weeks after an otherwise unre-
space-occupying lesions. Based on limited evidence from markable delivery. She died of a status epilepticus
clinical trials, the primary therapy for CVT is anticoagu- (despite treatment with repeated bloodletting). At post-
lation with heparin. Uncontrolled studies have shown mortal examination, Abercrombie identified a thrombosis
promising results for the use of endovascular treatment in of the superior sagittal sinus and cortical veins [3]. Larger
severely affected patients, but these studies require confir- single-center studies were published in the second half of
mation in prospective clinical trials. In patients who the 20th century, which provided a broader insight into
develop clinical and radiological signs of impending her- the variable clinical manifestations and risk factors associ-
niation decompressive surgery can be both life saving and ated with CVT [1,4]. Multi-center studies with data of
result in a good functional outcome. more than 100 patients have been published in the last
25 years, the largest of which are the ‘international study
Keywords: cerebral thrombosis; decompressive on cerebral vein and dural sinus thrombosis’ (ISCVT, 624
craniectomy; hemorrhage; heparin; sinus thrombosis; patients) and an Italian (706 patients) registry [5,6].
stroke.
Epidemiology
The first calculations of the incidence of CVT were
Introduction extrapolated from autopsy series and provided estimates
of 0.1–0.2 cases per 100 000 [7]. A recent population-
The cerebral veins are an unusual site of thrombosis, and
based study found a 5- to 10-fold higher incidence among
cerebral venous thrombosis (CVT) is a distinct cause of
adults (1.3 per 100 000) [8]. In developing countries, the
stroke. In contrast to both venous thromboembolism
incidence is probably even higher [9]. The increase in inci-
(VTE) and arterial stroke, CVT predominantly affects
dence is most likely explained by the improvement in
young adults and children. Patients can present with a
imaging techniques, which enabled identification of less
range of signs and symptoms. Due to this variability in
severe cases. The higher incidence rates also suggest that,
clinical manifestations, and the rarity of the condition,
unlike previously believed, CVT may be more common in
CVT can be difficult to diagnose. In this review, I will
adults than in children, although direct comparisons have
not been performed [10].
Correspondence: Jonathan M. Coutinho, Department of Neurology,
Academic Medical Center – University of Amsterdam, Meibergdreef Risk factors
9, 1105 AZ Amsterdam, the Netherlands.
Tel.: +31 20 566 45 91; fax: +31 20 566 93 74. Most adult patients with CVT are between the ages of 20
E-mail: [email protected] and 50, and < 10% are older than 65 [11]. In young and

© 2015 International Society on Thrombosis and Haemostasis

 Cerebral venous thrombosis S239

middle-aged adults – but not in children or elderly – CVT pying lesions or generalized cerebral edema [18]. Delayed
is three times more common among women than men. death is more frequently caused by an underlying condi-
This skewed sex ratio is the result of gender-specific risk tion – especially cancer – or recurrent thrombotic events.
factors: oral contraceptives, pregnancy or (more fre- Approximately 80% of patients recover without func-
quently) puerperium, and hormonal replacement therapy tional disability, although many do suffer from chronic
[12]. Interestingly, these factors are also associated with symptoms such as headache, fatigue, and concentration
VTE, but in this condition, the sex ratio is evenly distrib- difficulties, which often negatively impact their life
uted [13]. A possible explanation is that men intrinsically [5,6,19]. Based on baseline variables that are associated
have a higher risk of VTE, as supported by the observa- with poor outcome, a risk score has been developed
tion that, compared to women without reproductive risk which can be used to predict clinical outcome at follow-
factors, VTE is twice as common in men [14]. In contrast, up [20]. Estimates of the risk of a recurrent thrombotic
if the same type of analysis is performed in patients with event vary between 0% and 10%, although the number
CVT, the sex ratio is 1 : 1 [12]. of adequately sized cohort studies with a long follow-up
Many other risk factors have been associated with is small [6,21].
CVT, and an overview is provided in Table 1. One should
bear in mind that this list is not complete and that the
Pathophysiology
level of certainty of the association varies per risk factor.
Some, like sarcoidosis, have only been reported in case To explain the symptomatology of CVT, it is helpful to
reports, and the presumed relationship could be coinci- distinguish two separate pathophysiological mechanisms:
dental, or due to a confounding variable, like steroid thrombosis of the major cerebral sinuses and thrombosis
treatment. Most of the risk factors for CVT coincide with of the cortical veins. The cerebral sinuses, besides drain-
those for VTE, such as genetic thrombophilia, antiphosp- ing blood, are essential for the transportation of cerebro-
holipid syndrome, inflammatory bowel disease, and spinal fluid, a process mediated by the arachnoid villi,
malignancies [5,15]. Risk factors specific for CVT are which are also known by their eponym Pacchioni’s granu-
local conditions of the head and neck, such as head lations [22]. These villi are small protrusions of the arach-
trauma, neurosurgical interventions, and regional infec- noid mater into the cerebral sinuses and facilitate
tions. Although the absolute number of patients is low, transport of cerebrospinal fluid from the subarachnoid
acute lymphoblastic leukemia is infamous for being asso- space to the blood. Occlusion of the cerebral sinuses
ciated with CVT, most likely related to asparaginase ther- blocks transport of cerebrospinal fluid, which results in
apy [16]. intracranial hypertension. The second mechanism, occlu-
sion of a cortical vein, obstructs the drainage of blood
from the adjacent brain tissue. Depending on the extent
Prognosis
of the thrombus and the availability of venous collaterals,
The mortality of CVT has decreased steadily over the last occlusion of a cortical vein causes an increase in venous
decades and is currently between 5% and 10% [17]. The and capillary pressure and breakdown of the blood–brain
most important explanation for this decline is the same as barrier [23]. This process can result brain tissue damage,
the reason for the increase in incidence: the identification which is described in more detail below.
of less severe cases. Early mortality is usually caused by
transtentorial cerebral herniation due to large space-occu-
Clinical manifestations and diagnosis
Table 1 Causes and risk factors for cerebral venous thrombosis Headache is the most common presenting symptom of
Genetic thrombophilia Systemic diseases CVT and the intensity is usually severe. In a subset of
Gender-specific risk factors Cancer (especially hematological patients, the onset of headache is acute, similar to a sub-
Oral contraceptives malignancies) arachnoid hemorrhage. A minority of patients (10%) do
Pregnancy/puerperium Inflammatory bowel disease
not report headache at baseline. The absence of headache
Hormone replacement therapy Thyroid disease
Infections (Neuro)sarcoidosis is more common in men, elderly, patients with cancer,
Meningitis Behcßet disease and in isolated cortical vein thrombosis [24]. Seizures and
Otitis/mastoiditis Systemic lupus erythematosus focal neurological deficits, such as hemiparesis and apha-
Systemic Antiphospholipid syndrome sia, can occur in the presence of a brain parenchymal
Iatrogenic causes Miscellaneous causes
lesion. Approximately 40% of patients suffer from one or
Intracranial hypotension Dural arteriovenous fistula
after lumbar puncture Arteriovenous malformation more seizures in the acute phase, which is much higher
Neurosurgical operation Head trauma than in arterial stroke. While any combination of signs
Catheterization jugular vein Dehydration and symptoms is possible, most patients with CVT pres-
Medications (e.g. asparaginase Anemia ent with one of the following clinical syndromes: isolated
and steroids) Spontaneous intracranial
intracranial hypertension (headache, decreased visual
hypotension
acuity, and papilledema), focal symptoms (deficits or

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S240 J. M. Coutinho

seizures), a diffuse encephalopathy, or a cavernous sinus used although contrast enhanced MR-venography allows
syndrome. better depiction of the venous system [28]. CT-venography
There are three imaging techniques to diagnose CVT: is a decent and less expensive alternative to MRI for the
magnetic resonance imaging (MRI) with MR-venography, diagnosis of CVT, but it is inferior for the visualization of
computerized tomography (CT)-venography and catheter brain parenchymal lesions [29]. Unenhanced CT is gener-
angiography [25]. MRI is the most widely used technique ally insufficient for the diagnosis, although a recent small
and diagnosis requires visualization of the thrombus within study reported promising results on the diagnostic
the vessel in combination with absent flow on MR-venog- accuracy of CT density measurement of the dural sinuses
raphy (Fig. 1A,B). Depending on the age of the thrombus, in acute CVT [30].
the MRI signal can vary on different sequences [26]. Sus- Besides the absence of flow in the cerebral venous sys-
ceptibility weighted sequences are particularly useful to tem, a variety of lesions of the brain parenchyma can be
demonstrate a thrombus within a cortical vein [27]. For seen on imaging. Most common is an intracerebral hem-
MR-venography time-of-flight sequences are most often orrhage (ICH), which is found in about 30–50% of all

A C
B

D E F

Fig. 1. Imaging findings in patients with cerebral venous thrombosis (CVT). (A, B) Magnetic resonance imaging (MRI) of a 20-year-old male
with thrombosis of the superior sagittal sinus. The sagittal T1 sequence (A) shows a hyperintense signal in the superior sagittal sinus, due to
methemoglobin in the thrombus (arrows). On the corresponding contrast enhanced MR-venography (B), there is no filling visible of the supe-
rior sagittal sinus (arrows). (C) Axial MRI (fluid-attenuated inversion recovery [FLAIR] sequence) of a 43-year-old patient with thrombosis of
the deep venous system. A hyperintense signal is present in both thalami (arrows) indicating edema. Clinically, the patient had a mildly
decreased consciousness (E4M6V4). (D) Axial non-contrast enhanced computerized tomography (CT) scan of a patient with CVT showing a
parenchymal lesion in the right hemisphere. Within the large hypodense area (dark; edema), patchy hyperdense (white) areas are visible, which
are hemorrhages. Such lesions are generally termed venous hemorrhagic infarct. (E) Small juxtacortical hemorrhage (JCH) in the left hemi-
sphere of a patient with CVT. Note how the hemorrhage is located just below the cortex and how it follows its curvature. There also is a small
amount of edema (darker areas) surrounding the hemorrhage, although this can be hard to visualize on CT. These JCHs are almost exclusively
seen in patients with thrombosis of the superior sagittal sinus. (F) Large intracerebral hemorrhage (ICH) in the left temporal lobe in a 52-year-
old patient. She had a global aphasia and a right-sided hemiparesis. This patient had an occlusion of Labbe’s vein. Sometimes, these ICHs are
mistaken for an arterial bleed.

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 Cerebral venous thrombosis S241

patients [5,26,31]. Localized cerebral edema in the absence the introduction of anticoagulation [37], did not occur in
of ICH can also be present, especially in the basal ganglia any patient treated with heparin, while two patients in
and thalami if the deep venous system is occluded the placebo groups had a diagnosis of probable pulmo-
(Fig. 1C). The thrombus within the veins can often be nary embolism, one of which was fatal. Because of a bet-
seen on an unenhanced CT scan in these patients, in ter safety profile, low molecular weight heparin is
which case the diagnosis is almost certain. Less common generally preferable over unfractionated heparin, except
findings are subdural and subarachnoid hemorrhages. in patients where it is anticipated that rapid reversal of
The appearance of ICHs in patients with CVT is highly anticoagulation may be required, for instance because of
variable. Most common is an area of brain edema with a neurosurgical intervention [38,39].
patchy areas of hemorrhage in it (Fig. 1D). Such a lesion
is usually termed ‘venous hemorrhagic infarct’, although
pathologically, this is not an adequate descriptive term,
as the edema is often reversible [26]. A distinctive type of A
ICH in patients with CVT is a juxtacortical hemorrhage.
These are small hemorrhages with little or no surround-
ing edema, localized at the junction between the superfi-
cial and deep venous drainage system (Fig. 1E).
Juxtacortical hemorrhages are very specific for CVT and
almost exclusively occur if the superior sagittal sinus is
occluded [31]. Occlusion of Labbe’s vein may cause a
large ICH of the temporal lobe, which can sometimes be
confused with an aneurysmal or other arterial hemor-
rhage (Fig. 1F).
Routine blood studies including a chemistry panel,
complete blood count and prothrombin time, and acti-
vated partial thromboplastin time should be performed in
all patients with CVT. D-dimer measurements are not
used frequently in the diagnostic work-up of patients with
suspected CVT. Several studies have examined the sensi-
tivity of D-dimer in CVT and a recent meta-analysis
calculated a mean sensitivity of 94% [32]. Among patients B
with a chronic onset or isolated headache, however, the
sensitivity is much lower (83% and 82%, respectively). As
these are precisely the type of patients where D-dimer
values would be helpful – as there may be no other
reason to perform brain imaging in these patients – the
value of measuring D-dimers for excluding CVT is lim-
ited. Screening for thrombophilia is often performed,
although the results rarely change the management of
patients [15].

Treatment

Anticoagulation

Heparin is the mainstay therapy for CVT and is recom-

mended by international guidelines [25,33]. This recom-
mendation is based on the data of two small randomized Fig. 2. Decompressive surgery (DS). (A) Preoperative axial comput-
trials [34,35]. Patients treated with heparin had a better erized tomography (CT) scan showing a large venous hemorrhagic
clinical outcome, although the difference was not statisti- infarct in the right hemisphere of a patient with cerebral venous
cally significant in a meta-analysis (relative risk of death thrombosis (CVT). There is significant mass effect and a midline
0.33, 95% CI 0.08–1.21) [36]. Importantly, however, hep- shift of approximately 1.5 cm. The patient was comatose (E1M5V2)
and had a dilated and fixed pupil on the right side. (B) Postoperative
arin was not associated with hemorrhagic complications, CT scan of the same patient as in (A). After DS, there is a reduction
which was the main concern of opponents to anticoagula- in mass effect and almost normalization of the midline shift. Clini-
tion. In addition, pulmonary emboli, which used to be an cally, the patient also improved. After 12 months follow-up, she had
important cause of death in patients with CVT prior to a residual mild hemiparesis and hemianopia.

© 2015 International Society on Thrombosis and Haemostasis

S242 J. M. Coutinho

come can be further improved will hopefully be revealed

Endovascular treatment
by future research. Three aspects of treatment of CVT
Endovascular treatment (ET) for CVT was first reported in are currently being examined in international studies.
the 1980s [40]. Since then, a myriad of case reports and The TO-ACT trial is a randomized trial in which the
small case series have described this approach, but no ran- efficacy and safety of ET for CVT is being assessed [47].
domized trials or large prospective studies. The two meth- At the time, this manuscript was written, 51 of the
ods of ET for patients with CVT are intrasinus required 164 patients had been included. The DECOM-
thrombolysis and mechanical thrombectomy. Judging from PRESS-2 study is an ongoing prospective registry of
the number of publications, thrombectomy appears to gain consecutive patients who undergo DS and will provide a
the overhand in recent years [41], possibly because it is more robust estimate of the outcome of these patients.
believed to carry a lower risk of hemorrhagic complica- Finally, EXCOA is a cluster-randomized trial of short-
tions. Because of the limited data on its efficacy and poten- vs. long-term treatment with oral anticoagulation after
tial risk of complications – especially ICHs – ET should CVT. This study was launched recently and the aim was
not be routinely used in patients with CVT at this stage. to recruit 900 patients in the coming years. Efforts are
also underway to identify new genes and biomarkers
that are associated with CVT and which may aid in the
Decompressive surgery
diagnosis [48].
A minority of patients develop large venous hemorrhagic One topic that will most likely be examined in the near
infarcts that result in brain displacement and transtentori- future is the role of new oral anticoagulants (NOACs) in
al or subfalcine herniation (Fig. 2A). These patients suffer the treatment of CVT. In patients with VTE and atrial
from a decreased consciousness and uni- or bilateral third fibrillation, NOACs are associated with an approximate
nerve palsy. Patients can deteriorate very quickly and 50% relative risk reduction in ICHs compared to warfarin
prompt action is required if there is any hope for sur- [49,50]. This observation makes NOACs an attractive can-
vival. During the last two decades, data have amassed didate drug for the treatment of CVT. With the exception
which suggest these patients are best treated with decom- of two small case series, however, no studies have examined
pressive surgery (DS). the efficacy and safety of NOACs for CVT [51,52]. If a ran-
During DS, part of the skull on the side of the lesion is domized trial is undertaken, one thing is for sure: given the
temporarily removed to decrease the mass effect and rarity of CVT, it will only succeed through collaboration of
reverse brain displacement (Fig. 2B). In 1999, Stefini large number of hospitals.
et al. [42] reported good outcomes after DS in two of
three patients with CVT and advanced stages of hernia- Acknowledgements
tion. Following this article, several studies with similar
results have been published [43–45]. All of the evidence Parts of this manuscript were included in my PhD thesis:
for the use of DS in CVT comes from uncontrolled stud- ‘epidemiology, diagnosis, and treatment of cerebral
ies. Of course, a randomized trial would offer the highest venous thrombosis’. I am grateful to Jan Stam for his
level of evidence, but most experts believe such a trial is comments on the manuscript and would like to thank
unlikely to be performed. First, only 5–10% of patients Susanna M. Zuurbier for her help with the figures.
with CVT would be eligible for randomization, which
makes recruitment of a sufficient number of patients
Disclosure of Conflict of Interests
almost impossible. More importantly, one may wonder if
a randomized study is even desirable. Transtentorial her- The author received a lecturing fee from Boehringer
niation is the most frequent cause of early death in Ingelheim, outside the submitted work.
patients with CVT [18] and the majority of patients with
clinical and radiological signs of herniation will die if they
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