Cerebral venous thrombosis (CVT)

Cerebral Venous Thrombosis (CVT) is much rarer than arterial strokes and has a better prognosis, but it must be recognized because it is amenable to effective treatment. Its incidence is 5 per million inhabitants per year, and it accounts for 0.5 to 1% of strokes. However, it is potentially underdiagnosed, as it has been found in up to 10% of autopsies.

It typically affects one or more venous sinuses, rarely a cortical vein. It may or may not cause a cerebral infarction, which is often secondarily hemorrhagic, and whose topography does not correspond to arterial territories (due to high individual variability in the venous network, rapid development of collateral circulation, and the frequent multiplicity of thrombosis sites).

CVT is a medical emergency.

Emergency management of strokes is addressed in a separate chapter.

Etiologies and Risk Factors

There is a slight predominance in women (specific risk factors: oral contraception, pregnancy, childbirth) and those under 50 years old, but it can occur at any age. In 20 to 40% of cases, no etiology or risk factor is identified. In other cases, the following are found:

Hypercoagulable States (~30 to 80%)

• Hormonal Changes in Women (20 to 50%): oral contraception (present in up to 55% of women with CVT, though this risk factor should be considered relative to the prevalence of this type of contraception), postpartum (10 to 15% of women with CVT), pregnancy (5 to 10% of women with CVT), hormone replacement therapy.
• Thrombophilia (7 to 35%):
  • Genetic (up to 22% of patients depending on the series): protein C resistance due to factor V mutation, factor II mutation, deficiencies in proteins C/S and antithrombin III, prothrombin mutation (20210A allele), etc.
  • Acquired (up to 15% of patients): antiphospholipid syndrome, hyperhomocysteinemia (controversial), nephrotic syndrome, polycythemia vera, thrombocytosis, hemoglobinopathies, etc. (rarely: DIC, aminocaproic acid treatment, paroxysmal nocturnal hemoglobinuria).
• Paraneoplastic conditions.
• Toxic and Iatrogenic Causes: androgens, danazol, lithium, vitamin A, IV immunoglobulins, ecstasy.

Infections (~5 to 15%)

• Local (most common): central nervous system infections (meningitis, encephalitis, brain abscess, empyema), oral-pharyngeal infections, inner ear infections, mastoiditis, sinusitis, facial infections.
• Systemic: sepsis, endocarditis, typhoid fever, tuberculosis, measles, hepatitis, cytomegalovirus, HIV, malaria, hookworm disease, trichinosis, aspergillosis, etc.
• Any CVT involving the cavernous sinus or occurring in an immunocompromised or diabetic patient should suggest an infection.

Malignant Hematologic Disorders and Other Neoplasms (4-8%)

Due to local inflammation, compression, sinus invasion (brain tumors), superior vena cava syndrome (extension to sigmoid sinus thrombosis), or systemic hypercoagulability.

Chronic Inflammatory Diseases (~5%)

Systemic lupus erythematosus, sarcoidosis, Crohn’s disease, ulcerative colitis, vasculitis (Behçet's disease, Wegener’s granulomatosis, etc.), thyroiditis, etc.

Rare Etiologies

Lumbar puncture, blood-patch, head trauma, neurosurgery, postoperative, jugular catheter occlusion, corticosteroid therapy, (arterio)venous malformations, severe dehydration, heart failure, diabetes, anemia, nephropathies, thyroid disorders, antifibrinolytic treatments, chemotherapy (L-asparaginase, tamoxifen), erythropoietin, corticosteroids, myelography, intrathecal injections, superior vena cava or jugular vein ligation, paroxysmal nocturnal hemoglobinuria, spontaneous intracranial hypotension, thrombotic thrombocytopenic purpura, recent major surgery, etc.

Clinical Presentations

Clinical manifestations of CVT are variable. It can have a subacute course (~50%, from 48 hours to 30 days), an acute course (30%, < 48 hours, rarely "thunderclap" onset), or a chronic course (20%, > 30 days).

• Headaches of varying characteristics (80 to 90%) but generally diffuse and gradually increasing in intensity, with or without other signs of intracranial hypertension: vomiting, visual impairment (papilledema), VI or III cranial nerve palsies.
• Focal or generalized seizures (more frequent than in arterial ischemia) in up to 40% of cases.
• Variable focal deficits (present in ~50% of cases, inaugural in 15%, often sensory-motor disturbances) often not corresponding to arterial territories due to venous ischemia or reversible vasogenic edema. Sixth nerve palsy is very suggestive.
• Rare, but the combination of chemosis (conjunctival edema), eyelid edema, ptosis, and painful ophthalmoplegia ("cavernous sinus syndrome") should systematically suggest a cavernous sinus thrombosis, often septic and with severe prognosis.
• Paucisymptomatic Forms (~25%, possibly underdiagnosed): isolated headaches, isolated seizures, transient symptoms, migraine-like aura, psychiatric-like symptoms as a primary presentation, tinnitus, isolated consciousness disturbances (especially deep CVT with bithalamic involvement in elderly patients), confusion.

In the case of post-lumbar puncture headaches, any disappearance of orthostatic characteristics should suggest CVT.

CVT should always be suspected in cases of headache associated with seizures, poorly localized or bilateral neurological deficits, altered consciousness, or cavernous sinus syndrome.

Up to 40% of CVTs present with secondary ischemic and/or hemorrhagic lesions → the finding of ischemic areas not corresponding to an arterial territory or intracerebral hemorrhage in an unusual location for hypertensive hemorrhage, in the absence of known or recurrent hypertension, should always prompt an MR venography to exclude CVT.

Lesional Locations (isolated or with another location) and Suggestive Signs:

• Superior Sagittal Sinus (62%): headache, signs of intracranial hypertension, papilledema, with or without unilateral or bilateral motor deficit, seizures, scalp vein dilation, scalp edema.
• Transverse Sinuses (= lateral sinuses) (45%): symptoms of ipsilateral middle ear or mastoid infection, signs of intracranial hypertension, scalp vein dilation, (hemianopsia, contralateral motor deficit, aphasia).
• Deep Cerebral Veins (internal veins, vein of Galen) (11%) and Straight Sinus (18%): rapid neurological deterioration, thalamic or basal ganglia ischemic involvement, bilateral neurological deficits.
• Cortical Veins (17%): secondary lobar hemorrhages.
• Cavernous Sinus: painful ophthalmoplegia (of any type), ptosis, chemosis.

Early Complications

• Seizures:
  • Occur in ≈40% of cases (70% in newborns), early or late (at >2 weeks). They increase the risk of anoxia but do not worsen the 1-year prognosis.
• Hydrocephalus:
  • Communicating hydrocephalus (< defect in resorption by arachnoid granulations) 6.6%.
  • Obstructive hydrocephalus (< intraventricular hemorrhage) very rare.
  • Surgical intervention (ventriculostomy or ventriculoperitoneal shunt) is faster than for other etiologies due to already compromised perfusion from venous ischemia!
• Intracranial Hypertension - up to 40%:
  • Due to venous return defect with or without hydrocephalus.
• Venous Infarction → worsens the prognosis.
• Secondary Hemorrhage → worsens the prognosis.

Diagnosis

The initial emergency examination is often a CT scan, but MRI remains the gold standard. In cases of low clinical suspicion or when MRI is unavailable, a negative contrast-enhanced CT scan and D-dimers < 500 μg/L are usually sufficient to rule out the diagnosis (a lumbar puncture with pressure measurement may be useful if symptoms have been present for several weeks).

CT Scan with and without Contrast

It is mainly used to exclude major differential diagnoses and is strictly normal in about 20% of CVT cases.

Without contrast, it may show secondary hemorrhagic infarction, and rarely, the thrombus (hyperdense). Secondary subarachnoid hemorrhages (SAH) are rare (< 1%, usually located in the convexity).

With contrast (to be performed if there is a history, clinical or biological suspicion), it can indirectly show the thrombus (delta sign, present in about 20% of CVT cases and appearing only after approximately 5 days of evolution: contrast uptake of the richly vascularized wall around the thrombotic lumen).

Many nonspecific indirect signs may be present: abnormal contrast enhancement at the falx cerebri or cerebellar tentorium, abnormal contrast enhancement (extensive and blurry) of the sinuses, dilation of intracerebral medullary veins, signs of cerebral edema (hypodensity, cortical sulcal effacement, increased cortico-subcortical differentiation, ventricular compression, etc.), secondary hemorrhages (from simple petechiae to a subdural hematoma or SAH).

The presence of an infarction not corresponding to an arterial territory, near a venous sinus, especially when it has a hemorrhagic component, or an atypical intraparenchymal hemorrhage for hypertensive origin, should always prompt an MRI (at minimum, a contrast-enhanced CT scan).

MRI + MRV (Gold Standard)

Beyond the common signs seen on CT, the T1-T2 evolution is typical in the absence of treatment:

• Up to 3 weeks: T1 and T2 → intravascular hypersignal (within the first 5 days: possible false negatives with T1 isosignal and T2 hyposignal).
• After 3 weeks: FLAIR hypersignal >> T2, possible T1 isosignal.

MR venography (mandatory if MRI is negative) → absence of flow. The contribution of diffusion is debated.

Conventional Angiography

Rarely necessary, in cases of strong clinical suspicion and inconclusive MRI, or when endovascular treatment is considered.

Laboratory Tests

Complete blood count (CBC), C-reactive protein (CRP), D-dimers, erythrocyte sedimentation rate (ESR), and coagulation studies. Possible increases in D-dimers, ESR, and leukocytosis, coagulation disorders, signs of causal infection.

A 2004 study (Stroke) → D-dimer with a threshold of 500 μg/L: Sensitivity 97.1%, Specificity 91.2%, Positive Predictive Value 55.7%, Negative Predictive Value 99.6%. Thus, negative D-dimers can reasonably rule out CVT if symptoms have been present for < 2 weeks and CVT suspicion is low to moderate.

Collect 2 pairs of blood cultures in case of septic, febrile, or inflammatory syndrome.

Lumbar Puncture with Pressure Measurement

Cerebrospinal fluid (CSF) is strictly normal in 10% of cases. Possible mild hyperproteinorachia < 1 g/L, RBC > 20/mm³, pleocytosis usually lymphocytic. Mandatory in febrile forms (to exclude meningitis).

Opening pressure will be abnormally high in approximately 80% of cases (more so in subacute or chronic forms) → Systematic MRV before concluding possible idiopathic intracranial hypertension in case of negativity.

Electroencephalogram

Abnormal in ~75% of cases (often diffuse and nonspecific abnormalities) but not useful for a positive diagnosis. Limited indication in cases with confusion or psychiatric symptoms to rule out non-convulsive status epilepticus.

Transcranial Doppler Ultrasound

Its only true indication is the daily monitoring of extensive superior sagittal sinus thromboses; otherwise, of little use. Transfontanellar ultrasound is useful for the rare pediatric cases.

Etiological Workup

In Emergency

Suspicion of infection or fever → blood cultures + lumbar puncture +- specialized opinion depending on suspected site + echocardiography if an unknown murmur or infectious syndrome without an obvious source is present.

Non-Urgent

A systematic workup should include:

• Blood tests: Complete blood count, thrombophilia (protein C and S deficiency, antithrombin deficiency, antiphospholipid and lupus anticoagulant antibodies, prothrombin mutation, Factor V Leiden) 2 to 4 weeks after diagnosis, ANA, ANCA, renal and liver function tests, TSH, serologies (CMV, HIV, Borrelia, syphilis), HbA1c.
• ENT and dental examination.
• Echocardiography.

In cases of acquired thrombophilia, repeated unexplained thrombotic episodes, or in patients > 40 years old, consider a workup to rule out malignancy or hematological disorders (PET scan, etc.). Depending on the location and clinical presentation, perform a contrast-enhanced CT angiography to look for a tumor obstruction of the superior vena cava.

Therapeutic Management - Treatments

Refer to the dedicated chapter on the emergency management of strokes. Specific considerations compared to an arterial stroke:

• Etiological Treatment and Elimination of Risk Factors Upon Identification: Eradicate infectious foci (minimum of 3 weeks of antibiotic therapy, drainage, debridement, etc.), discontinue any contributing medication, and provide specific management if needed for neoplasms or hematological disorders, bloodletting in the case of polycythemia, etc.
  • Empirical Antibiotic Therapy: Vancomycin + ceftriaxone or cefepime, ± metronidazole (if a dental or sinus focus is suspected); antifungal treatment if the biopsy is positive or in immunocompromised patients (consider in diabetic patients).
    • If Septic Focus = Sinusitis: Systematic early surgical drainage.
    • If Septic Focus = Mastoiditis: Consider mastoidectomy if there is no improvement after 24 hours of antibiotic therapy.
• Systemic Anticoagulant Treatment: Therapeutic doses of heparin or LMWH in emergency, later transitioned to VKAs, to be continued for:
  • At least 3 to 6 months if a reversible etiological factor is found.
  • 1 year if no etiological factor is identified and in cases of mild hereditary thrombophilia (deficiencies in proteins C and S, heterozygosity for factor V mutation, G20210A prothrombin allele).
  • Lifetime in cases of recurrence or severe hereditary thrombophilia (AT deficiency, homozygous factor V mutation, antiphospholipid antibody syndrome, combination of two other causes of thrombophilia) or the presence of a non-reversible risk factor other than mild thrombophilia.
  • Always Consider: Benefit is still observed even in cases of secondary hemorrhagic infarction.
    • However, no EBM exists for septic TVC cases → recommended by consensus, but be more cautious about contraindications.
    • If Absolute Contraindication: Use antiplatelet therapy, no EBM other than expert consensus.
• Corticosteroid Therapy:
  • Not generally recommended except for a few etiologies: tumors with edema, septic cerebral venous thromboses of the cavernous sinus (dexamethasone IV 4 x 10 mg/day IV – after antibiotic coverage!).
• Symptomatic Treatment:
  • Seizures: Treat the crisis + prophylaxis (++ levetiracetam [Keppra]) for at least 1 year.
  • Intracranial Hypertension: Diamox 250 mg twice daily as first-line treatment. If progressive visual loss occurs despite treatment, consider lumbar puncture for decompression, ventriculoperitoneal shunt, or optic nerve fenestration. If neurological deterioration or risk of herniation, admit to intensive care, implement general measures for intracranial hypertension, use intracranial pressure monitoring, and consider decompressive craniectomy if there is deterioration despite optimal medical treatment.
• In Case of Worsening:
  • During the transition from heparin to VKAs → revert to heparin → consult between neurologists and vascular specialists.
  • Under heparin therapy:
    • Generally, the risk of fibrinolysis seems to far exceed its benefit and should be reserved for TVCs that worsen despite well-conducted IV heparin therapy. Example: urokinase via jugular or femoral route, local rt-PA in combination with heparin.
    • In case of severe mass effect or major secondary intraparenchymal hemorrhage → systematic neurosurgical consultation, consider decompressive craniectomy. In case of obstructive hydrocephalus → CSF diversion. If surgical indications are rejected, consider an endovascular approach.

Assessment and Secondary Prevention

• Elimination of risk factors.
• Search for occult infections and neoplasms in the presence of persistent inflammatory syndrome.
• Search for vasculitis and connective tissue diseases.
• Evaluation for congenital and acquired thrombophilia.

Prognosis, Follow-up, and Late Complications

Data varies, but the outcome of venous ischemias appears more favorable than that of arterial ischemias and carries a lower risk of recurrence. Poor prognostic factors include septic thromboses (mortality up to 80%), young children or elderly individuals, focal signs, coma, the presence of a hemorrhagic infarct or a "delta sign" on CT scan, involvement of the deep system or the posterior fossa. Early mortality ranges from 3 to 15%. Late mortality is primarily related to the potential underlying etiology. Overall, approximately 80% of patients will achieve full recovery (with a median of 16 months). Around 10% of patients will remain dependent (GOS > 3) at 1 year.

Between 5 to 32% of patients will experience epileptic seizures more than 2 weeks after onset, usually within the first year (more common in cases with hemorrhagic lesions, motor deficits, or early seizures) → antiepileptic treatment is recommended for a minimum of 6 months to 1 year.

A decrease in visual acuity necessitates an MRI, ophthalmological examination with fundus, and lumbar puncture with pressure measurement (ensure hemostatic function is checked beforehand) → see above.

Some consider the possibility of dural arteriovenous fistulas as rare late complications.

A significant proportion (0 to 53% according to various studies) of patients will not achieve significant recanalization with anticoagulation alone. However, it has not been shown that radiological recanalization is linked to prognosis → consider other treatments (endovascular, fibrinolysis… significant iatrogenic morbidity and mortality!) only if symptoms persist or worsen after 1 year of well-conducted anticoagulation therapy.

There is no EBM (Evidence-Based Medicine) regarding radiological follow-up, but it seems reasonable to perform a follow-up MRI before discontinuing anticoagulation to rule out progression and at 6 months to 1 year after discontinuation to exclude recurrence. Approximately 50% of patients will subsequently complain of chronic headaches, usually unrelated to CVT (migraines, tension headaches, psychogenic). However, doubt warrants an MRI and fundus examination, ± a lumbar puncture (check hemostatic function beforehand) to rule out progression or intracranial hypertension (→ in such cases, consider the introduction of Diamox, decompressive lumbar punctures, a ventriculoperitoneal shunt, or stenting of residual stenosis).

Cerebral Venous Thrombosis in Pregnant Women

→ See the chapter dedicated to "Cerebrovascular Diseases and Pregnancy."

Pediatric Cerebral Venous Thrombosis

The incidence is 0.67/100,000 children/year, and 43% of these cases occur in newborns.

• Risk Factors in Newborns: Mechanical traction during delivery, neonatal thrombophilia, hemoconcentration due to dehydration, ± others: transplacental transfer of potential maternal antiphospholipid antibodies, maternal (pre-)eclampsia, infections, meningitis, congenital heart diseases. Etiologies to exclude in older children and adolescents include: systemic lupus erythematosus, nephrotic syndrome, malignant hematologic diseases, trauma, iron deficiency anemia, thrombophilia.
• Clinical presentation in newborns is often nonspecific and typically limited to seizures and/or poorly localized neurological deficits. MR venography remains the diagnostic gold standard, but trans-fontanellar ultrasound can be performed initially (less reliable for partial thromboses). Lesions are more often hemorrhagic than in adults, with frequent sub-tentorial or intraventricular hemorrhages.

Therapeutic management in children older than 28 days is similar to that in adults, but systematic follow-up imaging is recommended after 1 week of anticoagulation to rule out secondary hemorrhage.

For newborns younger than 28 days, anticoagulation should be discussed (low level of evidence). If started, it should be continued for 6 weeks to 3 months.

Blood cultures and imaging of the sinuses should be performed systematically. Continuous EEG monitoring is recommended in cases of suspected seizures, altered consciousness, or intubation.

The risks of pediatric endovascular treatments are not well known → these should be reserved for severe deterioration despite optimal medical-surgical management.

Bibliography

Caplan RL, Caplan's Stroke. A clinical approach, 4th ed, Saunders, 2009

EMC, Traité de Neurologie, 2018

Saponisk et al., Diagnosis and management of cerebral venous thrombosis: a scientific statement from the American Heart Association, Stroke, vol 55, nb 3, Jan 2024