CONTENTS

• Pathophysiology
• Clinical features
  • Epidemiology
  • Signs & symptoms
  • Relationship between thrombus location & clinical features
• Investigations
  • Laboratory studies
  • Imaging
• Treatment
  • Neurologic deterioration despite treatment
• Prognosis
• Podcast
• Questions & discussion
• Pitfalls

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pathophysiology

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anatomy

• The superior sagittal and transverse sinuses are most frequently involved (in 60% of patients).  The internal jugular and cortical veins are involved less often.
• Venous thrombosis may cause involvement of multiple areas of the brain that extend across numerous different arterial circulations.  This may help differentiate a venous thrombosis from an arterial occlusion.

physiology

• Dural venous sinuses lack valves, allowing the flow of blood in various directions.  Along with some anastomotic venous connections, this may allow for re-routing of venous blood to overcome thromboses (to a certain extent).
• If blood backs up enough, the following consequences may occur:
  • (#1) Cerebral edema due to elevated capillary pressures.  This may impair brain function, but it is reversible (e.g., if the occlusion can resolve).
  • (#2) Blood stasis in the tissues may eventually lead to ischemic infarction, which may become irreversible.  The combination of infarcted tissue plus elevated venous pressure may lead to hemorrhagic transformation of the infarction.
• Normally, the venous sinuses play a role in draining cerebrospinal fluid (especially through arachnoid granulations which drain into the superior sagittal sinus).  Sinus thrombosis may therefore lead to communicating hydrocephalus (excessive CSF causes dilation of the ventricles and elevated intracranial pressure).
  • Communicating hydrocephalus is most problematic if the superior sagittal sinus is thrombosed.

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epidemiology

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overall epidemiology

• Venous thrombosis accounts for ~1% of all strokes.
• This typically affects young patients (most commonly between 20-50 years old).(29752489)
• There is a 3-fold female predominance.(Louis 2021)
• Its overall incidence is comparable to that of bacterial meningitis.  Although this disease is uncommon, it will be encountered on a regular basis.(29752489)

risk factors

• Thrombophilia (suggested by prior venous thromboembolic disease):
  • Oral contraceptive use (increases risk six-fold, or 30-fold when combined with obesity); hormone replacement therapy; tamoxifen.(29923367)
  • Pregnancy (usually late in pregnancy or in the first postpartum months, the period of maximal hypercoagulability).(32487899)
  • Antiphospholipid syndrome (~6% of patients).(34192432)
  • Malignancy (chemotherapy with L-asparaginase, intrathecal methotrexate, malignant invasion of a venous sinus, hypercoagulable state due to malignancy).(Louis 2021)
  • Sickle cell disease.
  • Autoimmune disorders (e.g., lupus, vasculitis, antiphospholipid syndrome, inflammatory bowel disease).
  • Nephrotic syndrome.
  • Dehydration.
  • Heparin Induced Thrombocytopenia (HIT).
  • Inherited thrombophilias.
  • Intracranial hypotension.
• Head and neck infections, including:
  • Mastoiditis, sinusitis, otitis media.
  • Meningitis, cerebral abscess/empyema.
• Mechanical causes:
  • Traumatic brain injury (especially skull base fractures that cross venous sinuses).📖
  • Post neurosurgical procedures, external ventricular drain, lumbar puncture.
  • Jugular vein catheterization (causing thrombosis with intracranial extension).

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signs and symptoms

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overview:  diagnosis is difficult

• The manifestations are variable and nonspecific.  This reflects the varying location of thrombosis and its evolution over time (clots may extend or recanalize).
• There is a median of one week's delay between initial presentation and diagnosis.  Evolution may occur acutely, subacutely (over several days), or chronically (over more than a month).
• Different patients can present with a variety of chief complaints, including:
  • Headache.
  • Focal neurologic findings.
  • Seizure.
  • Encephalopathy.
• Thromboses in various vessels may cause specific clinical symptoms (table below).  However, reality may be a bit more confusing than this, because patients can have multiple sites of thrombosis simultaneously.

headache due to elevated ICP

• Perhaps the most common chief complaint, with headache reported in ~88% of patients.(31440838, 35028817)
• This is often the first symptom.  If untreated, the thrombus may extend and patients will accrue additional symptoms.
• Pain may be exacerbated by lying down or by performing the Valsalva maneuver.
• Pain usually starts gradually (although it may occasionally cause a thunderclap headache, especially if CVT leads to a secondary subarachnoid hemorrhage).(32958591)
• There may be associated features of intracranial pressure elevation:
  • Vision changes, diplopia.
  • Nausea, vomiting.
  • Papilledema (30%).
  • Cranial nerve 6 palsy (inability to abduct the eye).
  • Encephalopathy.
• Focal symptoms:
  • Sigmoid sinus involvement may cause occipital or neck pain.
  • Lateral sinus involvement may resemble an ear infection (fever, ear discharge, headache, pain over the mastoid region).(32877892)

focal neurological deficits

• General comments on focal neurologic deficits:
  • Onset is usually not as abrupt as a typical stroke due to arterial occlusion.
  • Focal deficits may reflect venous infarction and/or intracerebral hemorrhage.
• Hemiparesis is the most frequent (37% of patients).
• Dysarthria, aphasia.
• Visual impairment and aphasia.

seizures (~30% of patients)

• Usually focal, or focal with secondary generalization.(34192432) 
• Usually occur secondary to a venous infarct.(Nelson, 2020)

diffuse encephalopathy (22%)

• Causes may include:
  • (1) Communicating hydrocephalus.
  • (2) Occlusion of the deep venous system causing bilateral thalamic dysfunction (may cause some unusual findings such as mutism, amnesia).(32877892)
  • (3) Intracranial hemorrhage or edema, causing herniation.

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relationship between thrombus location & clinical features

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Some patients may have thrombosis in several locations, which may complicate the presentation.  Nevertheless, some relationships are discernable between thrombus location and clinical presentation:(32958591)

superior sagittal sinus (~60%)

• Elevation of intracranial pressure (e.g., headache with papilledema).
• Seizures.
• Focal symptoms which may include:
  • Aphasia.
  • Hemianopsia.
  • Hemisensory loss.
  • Motor deficits (often bilateral).
  • Psychiatric symptoms (when affecting the frontal lobe).(Louis 2021)

transverse sinus (~50%)

• Seizure.
• Headache, elevated intracranial pressure.
• Contralateral pyramidal signs/symptoms.
• Dominant hemisphere: Aphasia.
• Pulsating tinnitus.
• Extension into cerebellum: emesis, limb/gait ataxia.

sigmoid sinus (~45%)

• Pain in the mastoid region (thrombosis may also result from mastoiditis).
• CN VI-VII-VIII palsies.

deep venous system (~10%)

• Loss of consciousness, fluctuating consciousness.
• Motor deficits (bilateral, or fluctuating alternating paresis).
• Gaze palsy.

cortical veins (~10%)

• Focal deficits depending on location (e.g., sensorimotor deficits).
• Seizures.
• Headache (but without papilledema).

cavernous sinus (~1%)

• Oculomotor palsies (due to dysfunction of CN3, CN4, CN6).
• Facial numbness (due to involvement of V1-V2 divisions of CN5).
• Headache.
• Ocular findings: pain, redness, proptosis, loss of visual acuity.
• Fever may occur in patients with septic thrombophlebitis of the cavernous sinus.
• Causes of cavernous sinus thrombosis:(Louis 2021)
  • Usually infection.
  • Tolosa-Hunt syndrome (granulomatous inflammation of the cavernous sinus and superior orbital vein).
  • Cogan syndrome (polyarteritis nodosa with cerebral venous thrombosis).
  • Trauma.
  • Meningioma, nasopharyngeal tumor.

 

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laboratory studies

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D-dimer

• Sensitivity varies between 82-94%.  The sensitivity is higher for more acute and extensive thrombosis, and lower with more subacute or focal thromboses.
• Specificity will vary depending on clinical context.  For example:
  • In a population of outpatients presenting with isolated headache, D-dimer may be more specific for venous thrombosis.
  • In a population of patients with meningitis, D-dimer will be wholly nonspecific.
• The utility of D-dimer is dubious.  For example:  if there is a moderate or high suspicion for cerebral vein thrombosis, then imaging will be required regardless of the D-dimer value.

labs to guide management

• Baseline coagulation panel is important, prior to initiation of anticoagulation (e.g., INR, PTT, complete blood count).
• Blood cultures if signs of infection (e.g., cavernous sinus thrombosis).

lumbar puncture

• This isn't indicated as part of the evaluation for suspected cerebral vein thrombosis.  However, lumbar puncture may be performed as part of a broader evaluation to exclude infection.
• The opening pressure will be elevated in patients with elevated intracranial pressure.
• Cerebrospinal fluid may reveal nonspecific abnormalities (elevated lymphocytes, erythrocytes, and/or elevated protein).
  • ⚠️ Mild abnormalities in the cerebrospinal fluid shouldn't lead to premature diagnostic closure with a diagnosis of “lymphocytic meningitis.”

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imaging

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overall performance of various modalities

• Nonenhanced CT or MRI scans will miss CVT in ~30% of patients.(Torbey, 2019)  
• If there is a concern regarding CVT, either MR venography or CT venography is needed.

noncontrast CT scan – indirect signs

• Imaging findings may be divided between direct signs (visualizing the clot itself) and indirect signs (hemorrhage or edema as a consequence of the clot).  Indirect signs may be more dramatic, ideally leading to further evaluation for an underlying clot.  
• (1) Hemorrhage (~1/3 of patients):  This is typically parenchymal, but less often may be subarachnoid or even subdural in location.  Rarely, subarachnoid hemorrhage may be the only imaging manifestation of CVT.(34192432)  Some unusual hemorrhage patterns may suggest the possibility of CVT:(26046515)
  • (a) Bilateral hemorrhages, for example:
    • Bilateral frontoparietal lobar hemorrhages due to superior sagittal sinus thrombosis.
    • Bilateral thalamic hemorrhages due to thrombosis of the vein of Galen or straight sinus.
  • (b) Gyriform hemorrhage.(28865528)
  • (c) Combination of hemorrhage plus disproportionate edema.
• (2) Cerebral edema may be seen.
• (3) Venous infarction:  hypodense tissue may reflect ischemia.  Features that may suggest venous infarction:
  • (a) Infarct spans multiple different arterial territories.
  • (b) Infarct involves deeper tissue, while sparing the cortex.
  • (c) Bilateral infarcts.
  • (d) Disproportionate cerebral edema and/or hemorrhagic transformation.

noncontrast CT scan – direct signs 

• May see a hyperdensity in vessel lumen acutely (which becomes isodense and later hypodense after the first week).
• This is visible in only about a third of cases.
  • Dense triangle sign, when thrombosis is within the superior sagittal sinus.
  • Dense cord sign, when thrombosis is in a cortical or deep vein.

CT venogram (CT-V)

• A CT venogram is in essence the same thing as a CT arteriogram, except that there is more delay between the time that the contrast is administered, and the time that the sequences are acquired.
• CT venogram increases performance to sensitivity of ~99% and specificity of 88%.  It is considered as accurate as MR venography to detect cerebral venous thrombosis.(28833980)
  • Contrasted head CT has only ~70% sensitivity, so a dedicated CT-venogram is needed.(29752489)
  • CT angiography (CTA) may not be able to pick up a venogram if there was incomplete venous filling at the time the sequences were obtained, so always ensure obtaining the CT venogram specific delayed filling sequences.
• A filling defect can be seen (e.g., empty delta sign in a dural sinus).
• Acute clot can appear dense (similar to contrast material).  Comparison of pre- versus post-contrast images may be needed to detect this.

MRI 

• MRI is superior to noncontrast CT scan, but is more expensive and may not be cost or time effective when CTV is readily accessible and is extremely quickly performed.
• Direct signs:
  • Normally, dural sinus can be seen as flow voids (e.g., on T2/FLAIR).  Absence of these flow voids may suggest thrombosis.  Flow voids are best visualized in an imaging plane perpendicular to the vessel.
  • The appearance of the clot itself will vary over time, as shown below.  GRE/SWI sequences may be helpful, because susceptibility blooming artefact can cause the thrombus to be especially prominent.
• Indirect signs:
  • Vasogenic edema may manifest as hyperintensity on T2 sequences.  This can be accompanied by frank parenchymal swelling.
  • MRI allows for cytotoxic edema (due to venous infarction) to be differentiated from vasogenic edema.
  • Hemorrhagic conversion of a venous infarct will have specific signal characteristics on T1 and T2 sequences.
  • Enhancement is variable and mostly involves the gyri.(26046515)

MR venography

• Gadolinium allows for direct visualization of luminal filling, similar to a CT venogram.  Thus, contrast MR venography is highly accurate, on par with CT venogram.  MR might be slightly superior for isolated cortical vein thrombosis or deep thromboses.(32958591)
• In patients unable to receive gadolinium, certain MRI sequences can be used to improve visualization of the venous system (e.g., TOF or phase contrast).  However, these sequences alone remain inferior to gadolinium-enhanced MR venography or to CT venography.
• As always, check with your local radiology department as a lot of the newer MRI contrast formulations no longer contain gadolinium and may no longer be contraindicated in patients with renal failure.

invasive catheter angiography

• This is rarely used for diagnostic purposes currently.
• Potential indications:
  • (1) Invasive angiography could be considered if CT and MRI are equivocal.
  • (2) Suspicion of a dural arteriovenous fistula.(32958591)

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treatment

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anticoagulation

• Heparin anticoagulation is generally the mainstay of therapy.
  • ⚠️ Patients with heparin-induced thrombocytopenia (HIT) or antiphospholipid antibody syndrome may require alternative anticoagulation strategies, directed at these disorders.📖
• Cerebral venous thrombosis may cause hemorrhage into an area of venous infarction and/or subarachnoid hemorrhage.  These are not contraindications to heparin anticoagulation.(32958591)  
  • An observational study found hemorrhage extension to be uncommon (11%) and unrelated to anticoagulation.(29923367)  On the contrary, extension of untreated thrombus due to a lack of anticoagulation seems to be the main risk for worsening hemorrhage.
  • Current guidelines strongly indicate that intracranial hemorrhage isn't a contraindication to anticoagulation. (28833980)
• Either unfractionated or low molecular-weight heparin may be used.
  • European guidelines weakly recommend low molecular weight heparin, based on one RCT with some methodological limitations.(28833980)  This is consistent with literature regarding DVT and PE, where low molecular-weight heparin may improve outcomes when compared to unfractionated heparin infusion.  
  • Low molecular-weight heparin might be preferable for patients with mild cerebral venous thrombosis, who are unlikely to require an emergent procedure (e.g., an external ventricular drain or decompressive craniectomy).  Alternatively, unfractionated heparin infusion is preferable for patients who are critically ill and more likely to require a procedure.
  • If unfractionated heparin is used, particular care should be taken to avoid either supratherapeutic or subtherapeutic drug levels.  Given the usual high clot burden associated with these types of clots, many centers now start the heparin drip with a bolus, despite the concerns for an acute hemorrhage.  Restoration of venous drainage will make the most difference in determining a patient’s outcome.

seizure management

• Seizures occur in 10-40% of all patients with CVT.
• Risk factors for seizure include:
  • Supratentorial lesions with involvement of the cortex.
  • Focal edema or infarcts (ischemic/hemorrhagic).
  • Focal neurological deficits (eg., focal sensory deficits).
• Seizure prophylaxis is generally not recommended, but it may be considered among individual patients at high risk for seizure.(32877892)  
• There should be a low threshold for EEG among patients with altered mental status or possible seizure.
• If seizures do occur, these should be treated aggressively.  Even a single seizure is an indication for antiepileptic therapy.  

communicating hydrocephalus

• Impaired drainage of CSF into the venous sinuses may lead to communicating hydrocephalus and thereby cause elevated intracranial pressure.
• Drainage of CSF may be necessary:
  • External ventricular drain (EVD) placement may rarely be necessary.
  • Lumbar puncture may also be used to reduce intracranial pressure in patients without any focal lesions on head CT.(29923367)  However, to be effective this probably requires serial lumbar puncture, which is difficult to balance with the need for ongoing anticoagulation.
    • Always review imaging prior to proceeding with lumbar puncture – avoid this in any cases with evidence of large areas of edema (as these patients may be at risk of developing brain herniation).
    • If lumbar puncture is effective at reducing ICP, consider placing a lumbar drain.
• Acetazolamide could be considered to reduce CSF production, in the absence of high-quality evidence (500-1000 mg/day).(Nelson, 2020)  European guidelines state: “In isolated intracranial hypertension secondary to cerebral vein thrombosis, causing severe headaches or threatening vision, acetazolamide may be considered if its safety profile is acceptable.” (28833980)  Acetazolamide will cause renal bicarbonate wasting, which may require administration of exogenous bicarbonate.📖  Acetazolamide is contraindicated in pregnancy due to a risk of teratogenicity.(33896537)

focal cerebral edema

• Focal tissue infarction with subsequent edema may compress adjacent tissue.  This varies quite a bit:
  • Mild, focal swelling may improve over time with heparin therapy alone.
  • In extreme cases, edema may precipitate herniation and death.
• If there is substantive edema that seems to be causing deterioration, general supportive measures for cerebral edema may be utilized (e.g., bed elevation and osmotherapy).📖
• Decompressive craniectomy may occasionally be necessary to prevent herniation.
  • Decompressive craniectomy is strongly recommended in the European guidelines, albeit in the absence of RCT-level evidence.(28833980)
  • Among all patients with stroke, younger patients with venous thrombosis may be among the best candidates for decompressive craniectomy.
  • Potential radiological indications for decompressive craniectomy may include:(32958591)
    • Uncal herniation, or herniation-induced ischemia of the territory of the posterior cerebral artery.
    • Midline shift >5 mm.
    • Persistent, severe increase in intracranial pressure.
• (Steroid does not appear to be useful.)

treat any underlying problems, e.g.:

• (1) Infection
  • Cerebral venous thrombosis may occur as a consequence of underlying infection (e.g., mastoiditis, sinusitis, otitis media, meningitis, or cerebral abscess).  Cavernous sinus thrombosis in particular may tend to be associated with underlying infection that leads to septic thrombophlebitis.
  • Suspected or definite underlying infection may be an indication for obtaining cultures, starting antibiotics, and possibly obtaining additional imaging studies to evaluate for an underlying focus of infection.  Some foci of infection may require surgical intervention.
• (2) Vasculitis or autoimmune disorders may require steroid therapy.
• (3) Prothrombotic medications may need to be discontinued (e.g., hormonal therapy).

catheter-directed endovascular therapy

• This may include local administration of thrombolytics into the cerebral veins, and/or mechanical clot disruption.
• Available RCT-level evidence has not shown benefit from interventional therapy.
• Typically reserved as a rescue therapy, when all other therapies have failed.

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neurologic deterioration despite treatment

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potential causes of neuroworsening

1. Clot propagation, causing an increased amount of infarcted tissue.
2. Intracranial hemorrhage (or extension of hemorrhage).
3. Seizure (either convulsive or non-convulsive).
4. Enlarging hematoma or edema may cause compression of adjacent tissue, including herniation.
5. Communicating hydrocephalus due to impaired CSF reabsorption.

evaluation may include:

• (1) CT scan with CT venogram (to look for #1 & #2 above).
• (2) EEG if seizure is a concern
• (3) Evaluation of intracranial pressure (e.g., with ultrasonography to evaluate for papilledema).

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prognosis

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overall prognosis

• Mortality is ~5%.
• Risk of permanent disability or death is ~15-20%.

poor prognostic factors

• The most important factors appear to be:
  • Coma or mental status disturbance.
  • Thrombosis of the deep venous system.
  • Intracerebral hemorrhage (i.e., hemorrhagic venous transformation).
• Patients without these factors are at very low risk of poor outcome.(28833980)

cerebral venous thrombosis risk score

• This may be used as a rough tool to determine functional prognosis. 👇 (19420921)
• Some patients will do well, even if they accrue multiple indicators of poor prognosis:

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podcast

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Failure to consider the diagnosis of cerebral venous thrombosis, leading to a failure to perform adequate imaging and thereby missing the diagnosis.
• Incorrect belief that patients with cerebral venous thrombosis and hemorrhagic transformation cannot be anticoagulated.  In fact, most patients with controlled hemorrhagic transformation should be anticoagulated.

Acknowledgement:  Thanks to Dr. Richard Choi (@rkchoi) for thoughtful comments on this chapter.

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Going further

• Cerebral Venous Thrombosis:  Pearls & Pitfalls, in emDocs, by Brit Long and Alex Koyfman
• Cerebral Venous Thrombosis, on CoreEM, by Anand Swaminathan
• Cerebral Venous Thrombosis Imaging, in Radiopaedia, by Tee Yu Jin and Frank Gaillard
• EMCrit 304 – Cerebral Venous Thrombosis (CVT)