Synonyms: cerebral vein thrombosis, CVT, intracranial sinus thrombosis

Thrombosis of cerebral veins or venous sinuses is a much less common cause of cerebral infarction than that caused by arterial disease. Clinically the diagnosis can be very difficult but modern imaging techniques allow earlier diagnosis and the possibility of early treatment. It is possible that many cases formerly labelled as benign intracranial hypertension were cases of intracranial venous thrombosis.^1,2 It is more likely to occur in patients with a prothrombotic tendency (for example in pregnancy) who also have local infection (for example sinusitis) and are either dehydrated, or have widespread malignancy.³ Headache and seizures are common.³

Knowledge of the anatomy of venous drainage is as important for making a clinical diagnosis as it is for arterial obstruction.
There may often be associated medical problems that require treatment.

Pathophysiology

Cerebral infarction can result from tissue congestion and obstruction. Cerebral haemorrhage may occur with the venous thrombosis and may even be a presenting feature.⁴
Symptoms are related to the area of thrombosis. Examples include:

• Lateral sinus thrombosis, which can cause headache (similar picture to pseudotumour cerebri).
• Involvement of the jugular bulb, which may cause jugular foramen syndrome.
• Cavernous sinus thrombosis, which may cause compressive symptoms with cranial nerve palsies.

Epidemiology

• Intracranial venous thrombosis appears to have become more common in recent years. However, this has occurred as modern imaging techniques have improved diagnosis.⁴
• Of all patients with stroke, intracranial venous thrombosis probably accounts for no more than 1 or 2%.¹
• Incidence is difficult to determine. Early studies were based on postmortem examinations but modern imaging gives much higher figures for incidence.
• Whereas arterial stroke tends to be a condition of the elderly (or at least become much more common with advancing age), intracranial venous thrombosis affects a much wider range of patients, including even the newborn.
• The age distribution is fairly uniform except that women are affected slightly more than men and mostly between the ages of 20 and 35. This is probably related to pregnancy and oral contraceptives.⁵
• The fact that there is often other serious disease also present may result in the condition being overlooked. In cases that are not associated with infection the mortality is less than 10% with 70% achieving full recovery.⁶

Aetiology

In about 20 to 30% of cases no predisposing cause is found.⁷ There are many possible contributory factors and more than one may be present:

• Infection is well recognised with spread from sinuses. The frontal sinuses are the most common source. Subdural empyema is another possibility. Many different organisms may cause infection but Staphylococcus aureus is the most common pathogen.
• Trauma can result in cerebral sinus thrombosis, as can some neurosurgical procedures.
• Pregnancy and the puerperium are associated with a predisposition to venous thrombosis, including intracranial venous thrombosis.
• Hypercoagulable states associated with the antiphospholipid syndrome and thrombophilia, including protein S and C deficiencies, antithrombin III deficiency, lupus anticoagulant, and the Leiden factor V mutation increase risk.⁷ Congenital varieties of thrombophilia account for around 15% of cases.⁷
• Crohn's disease and ulcerative colitis increase the risk, as does the use of steroids to treat them.
• Haematological conditions include paroxysmal nocturnal haemoglobinuria, thrombotic thrombocytopenia purpura, sickle cell disease and polycythaemia rubra vera. Some malignancies are associated with increased risk.
• Vascular diseases include systemic lupus erythematosus (SLE), Wegener's granulomatosis and Behçet's disease. A survey from Saudi Arabia found Behçet's syndrome to be a common aetiological factor.¹
• Risk is also increased by nephrotic syndrome, dehydration, cirrhosis and sarcoidosis.
• Infection, trauma and tumour account for about 10% of cases and the importance of infection appears to be declining.

Presentation

• Headache is a common presenting symptom and around 30% of cases present with episodic headache.⁴ It may be sudden like a blow to the head as in subarachnoid haemorrhage. There may be nausea and vomiting too. Headache can be the only feature with no neurological deficit. Headache can also be a feature that precedes stroke by a matter of weeks.
• There may be seizures and even status epilepticus. Guidance from the Royal College of Physicians (RCP) indicates that convulsions are common.
• Impaired level of consciousness is common but it may be normal, there may be confusion or it may progress to coma.
• Possible neurological signs include hemiparesis, weakness of the lower limbs, sometimes bilaterally, aphasia, ataxia, chorea and hemianopia.
• Specific cranial nerve lesions can include vestibular neuropathy, pulsatile tinnitus, unilateral deafness, diplopia, facial weakness and obscuration of vision. If the thrombosis involves the jugular vein, the IX, X, XI and XII nerves may be involved.
• Papilloedema may be seen.
• Guidelines on stroke from the RCP state:³ Occlusion of the cerebral veins or dural venous sinuses may present as a stroke syndrome, subarachnoid haemorrhage or as isolated raised intracranial pressure.² The condition should be considered in patients who may have a prothrombotic tendency (particularly during pregnancy or the puerperium), in those with intracranial, nasal sinus or ear infections, and in those who have been dehydrated or have disseminated malignancy. Headache is usually a prominent feature which may precede the stroke syndrome by several weeks. Seizures are common. Intracranial haemorrhage may occur and areas of infarction frequently show haemorrhagic change.

Investigations

• The diagnosis is usually made with the aid of CT or MRI scanning. The picture shows an area of infarction that is not compatible with arterial occlusion.⁸ If available, magnetic resonance venography provides excellent pictures but there are pitfalls in interpretation.^9,10 This is recommended with isolated intracranial hypertension, as the diagnosis of intracranial thrombosis is often otherwise missed.² Improved techniques have been evaluated.¹¹ Diffusion-weighted MRI is being evaluated and looks promising.^10,12
• FBC may show elevated Hb or platelets and white cell count is raised in infection. Platelets are low in thrombotic thrombocytopenia and they have to be monitored if heparin is used in treatment.
• Autoantibody screen includes antiphospholipid and anticardiolipin antibodies.⁷
• A thrombophilia screen should be performed.
• Other tests include albuminuria for nephrotic syndrome and LFTs for cirrhosis.
• D-dimer testing may be of value in people who present with a typical headache.¹³ They seem to have good negative predictive value¹⁴ but normal values do not completely exclude the condition.^14,15 It is less useful in the elderly.¹⁶
• Lumbar puncture may be performed if infection is suspected but it is contra-indicated if the intracranial pressure is raised.

Differential diagnosis

This depends upon the presentation but is usually with arterial stroke, infection and space-occupying lesions. Care should be taken, in cases of isolated intracranial hypertension, not to miss venous thrombosis.²

• Other causes of stroke.
• HIV associated infections (including cytomegalovirus encephalitis).
• Head injury.
• Intracranial abscess (epidural).
• Pseudotumour cerebri.
• Sarcoidosis.
• Meningitis (particularly staphylococcal).
• SLE.

Management

This will be determined by many factors. The neurological complications, the cause and any associated diseases need to be considered.

• General measures appropriate to the rehabilitation of stroke patients. Elevation of the head at 30-40º helps to reduce intracranial pressure.
• Seizures should be treated with anticonvulsants.
• Specific treatment involves anticoagulation or thrombolytic treatments. This has been a much debated topic. Concern over the risk of haemorrhage is an important consideration. Most evidence shows improved outcome with anticoagulation.
  • The potential for thrombolytic treatment of acute ischaemic stroke is well recognised but not so much so for venous occlusion. It has been performed but the evidence base is much smaller with what is a much rarer condition. It is undertaken only in specialist centres, on patients with significant deficit. Local infusion of thrombolytic agents has shown benefit but it involves a microcatheter being inserted into the dural venous sinus.⁴ It is thus much more demanding than the intravenous infusion used in stroke or acute myocardial infarction.¹⁷
  • Most studies report better outcomes with anticoagulation. Heparin is used and later converted to warfarin. Heparin appears to be a safe and effective treatment although it fails to facilitate recanalisation of the sinuses.¹⁸ The RCP now recommends full-dose anticoagulation (unless comorbidities preclude use).³ Long-term anticoagulants are generally not indicated and are reserved for recurrent intracranial venous thrombosis which occurs in only about 20% of cases.¹⁹
• Surgery may very rarely be required when there is marked neurological deterioration. The thrombus is removed and thrombolysis locally is also used. Reports of good outcomes are encouraging.⁴

Complications

It is important not to miss the diagnosis of intracranial venous thrombosis as it can result in death and disability. Complications can arise from both the neurological consequences and also from the associated contributory diseases.

Prognosis

Long-term follow-up suggests a generally good prognosis but there may be residual pyramidal symptoms, epilepsy, visual field defects and depression.^19,20 Mortality ranges from 5-30% but it is a diverse disease. Studies have shown much improved outcomes with use of anticoagulation with about twice as many making a full recovery when compared with no treatment.⁴

Practice tips

Failure to diagnose intracranial venous thrombosis is the major medicolegal pitfall associated with this condition in the USA.⁴Failures cited include:

• Inadequate treatment of frontal sinusitis leading to subdural empyema.
• Missed lateral sinus thrombosis in patients with pseudotumour cerebri.
• Missed diagnosis in thunderclap headache when subarachnoid haemorrhage but not intracranial venous thrombosis has been excluded.
• Not diagnosing associated medical conditions (for example, nephrotic syndrome, pregnancy, liver disease, and inflammatory bowel disease) in patients with intracranial venous thrombosis.

Document references

1. Daif A, Awada A, al-Rajeh S, et al; Cerebral venous thrombosis in adults. A study of 40 cases from Saudi Arabia. Stroke. 1995 Jul;26(7):1193-5. [abstract]
2. Biousse V, Ameri A, Bousser MG; Isolated intracranial hypertension as the only sign of cerebral venous thrombosis. Neurology. 1999 Oct 22;53(7):1537-42. [abstract]
3. National clinical guideline for stroke (third edition), Royal College of Physicians (July 2008); Prepared by the Intercollegiate Stroke Working Party, incorporating the recommendations from NICE stroke guideline
4. McElveen WA, Gonzalez RF, Keegan AP; Cerebral Venous Thrombosis, eMedicine, Apr 2010
5. de Bruijn SF, Stam J, Vandenbroucke JP; Increased risk of cerebral venous sinus thrombosis with third-generation oral contraceptives. Cerebral Venous Sinus Thrombosis Study Group. Lancet. 1998 May 9;351(9113):1404.
6. Ameri A, Bousser MG; Cerebral venous thrombosis. Neurol Clin. 1992 Feb;10(1):87-111. [abstract]
7. Deschiens MA, Conard J, Horellou MH, et al; Coagulation studies, factor V Leiden, and anticardiolipin antibodies in 40 cases of cerebral venous thrombosis. Stroke. 1996 Oct;27(10):1724-30. [abstract]
8. Lee SK, terBrugge KG; Cerebral venous thrombosis in adults: the role of imaging evaluation and management. Neuroimaging Clin N Am. 2003 Feb;13(1):139-52. [abstract]
9. Ayanzen RH, Bird CR, Keller PJ, et al; Cerebral MR venography: normal anatomy and potential diagnostic pitfalls. AJNR Am J Neuroradiol. 2000 Jan;21(1):74-8. [abstract]
10. Wasay M, Azeemuddin M; Neuroimaging of cerebral venous thrombosis. J Neuroimaging. 2005 Apr;15(2):118-28. [abstract]
11. Rollins N, Ison C, Reyes T, et al; Cerebral MR venography in children: comparison of 2D time-of-flight and gadolinium-enhanced 3D gradient-echo techniques. Radiology. 2005 Jun;235(3):1011-7. Epub 2005 Apr 28. [abstract]
12. Lovblad KO, Bassetti C, Schneider J, et al; Diffusion-weighted mr in cerebral venous thrombosis. Cerebrovasc Dis. 2001;11(3):169-76. [abstract]
13. Lalive PH, de Moerloose P, Lovblad K, et al; Is measurement of D-dimer useful in the diagnosis of cerebral venous thrombosis? Neurology. 2003 Oct 28;61(8):1057-60. [abstract]
14. Kosinski CM, Mull M, Schwarz M, et al; Do normal D-dimer levels reliably exclude cerebral sinus thrombosis? Stroke. 2004 Dec;35(12):2820-5. Epub 2004 Oct 28. [abstract]
15. Crassard I, Soria C, Tzourio C, et al; A negative D-dimer assay does not rule out cerebral venous thrombosis: a series of seventy-three patients. Stroke. 2005 Aug;36(8):1716-9. Epub 2005 Jul 14. [abstract]
16. Harper PL, Theakston E, Ahmed J, et al; D-dimer concentration increases with age reducing the clinical value of the D-dimer assay in the elderly. Intern Med J. 2007 Sep;37(9):607-13. Epub 2007 Jun 2. [abstract]
17. Yamini B, Loch Macdonald R, Rosenblum J; Treatment of deep cerebral venous thrombosis by local infusion of tissue plasminogen activator. Surg Neurol. 2001 Jun;55(6):340-6. [abstract]
18. Cipri S, Gangemi A, Campolo C, et al; High-dose heparin plus warfarin administration in non-traumatic dural sinuses thrombosis. A clinical and neuroradiological study. J Neurosurg Sci. 1998 Mar;42(1):23-32. [abstract]
19. Preter M, Tzourio C, Ameri A, et al; Long-term prognosis in cerebral venous thrombosis. Follow-up of 77 patients. Stroke. 1996 Feb;27(2):243-6. [abstract]
20. Buccino G, Scoditti U, Patteri I, et al; Neurological and cognitive long-term outcome in patients with cerebral venous sinus thrombosis. Acta Neurol Scand. 2003 May;107(5):330-5. [abstract]

Internet and further reading

• Benamer HT, Bone I; Cerebral venous thrombosis: anticoagulants or thrombolyic therapy? J Neurol Neurosurg Psychiatry. 2000 Oct;69(4):427-30.

Acknowledgements