Cerebral venous sinus thrombosis

Cerebral venous sinus thrombosis is a rare form of thrombosis (a blood clot) affecting the dural venous sinuses which drain blood from the brain. Symptoms may include headaches, any of the symptoms of stroke, seizures, abnormal vision and raised intracranial pressure. Treatment is with anticoagulants (medication that suppresses blood clotting). Complications include raised intracranial pressure, which may warrant specialist interventions.^[1] There are several other terms for the condition, such as cerebral venous and sinus thrombosis, (superior) sagittal sinus thrombosis, dural sinus thrombosis and intracranial venous thrombosis.

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Signs and symptoms

Clinical presentation

Headache is a common presentation (present in 90% of cases); it tends to worsen over a period of several days, but may also develop suddenly (thunderclap headache).^[1] The headache may be the only symptom of cerebral venous sinus thrombosis.^[2] Many patients have symptoms of stroke: inability to move one or more limbs, weakness on one side of the face or difficulty speaking. This does not necessarily affect one side of the body as in "arterial" stroke.^[1] 40% of all patients have seizures (more in women before and after birth^[3]), mostly focal but often generalised and sometimes leading to status epilepticus.^[1] In the elderly, many of the aforementioned symptoms may not occur. Common symptoms in the elderly with this condition are a depressed level of consciousness and otherwise unexplained changes in mental status.^[4]

The intracranial pressure (pressure around the brain) may rise, causing papilloedema (swelling of the optic disc, leading to visual obscurations). In severely raised intracranial pressure, there may be signs of depressed level of consciousness, rising blood pressure, falling heart rate and abnormal posturing.^[1]

Risk factors

Cerebral venous sinus thrombosis is more common in particular situations. 85% of patients have at least one of these risk factors:^[1]

• Thrombophilia (a tendency to develop blood clots due to abnormalities in coagulation, e.g. deficiency of protein C, protein S, antithrombin or related problems)
• Nephrotic syndrome (a kidney problem causing protein loss in the urine)
• Chronic inflammatory diseases (inflammatory bowel disease, lupus, Behçet's disease)
• Pregnancy and puerperium (the period after giving birth)
• Particular blood disorders, especially polycythemia vera and paroxysmal nocturnal hemoglobinuria
• Use of the contraceptive pill
• Meningitis and infections of the ear, nose and throat area (mastoiditis, sinusitis)
• Direct injury to the venous sinuses, and medical procedures in the area

Other less well understood situations that increase the risk for cerebral sinus thrombosis are hyperthyroidism^[5] and myelodysplastic syndrome.^[6]

Diagnosis

Investigations

The diagnosis may be suspected on the basis of the symptoms (e.g. the combination of headache, signs of raised intercranial pressure and focal neurological abnormalities), or when alternative causes of headache and neurological abnormalities (such as a subarachnoid hemorrhage) have been excluded.^[1]

CT, MRI and angiography

There are various investigations that may detect cerebral sinus thrombosis. Cerebral oedema and venous infarction may be apparent on any modality, but for the detection of the thrombus itself, the most commonly used tests are computed tomography (CT) and magnetic resonance imaging (MRI), both using various types of radiocontrast to perform a venogram. Cerebral angiography may demonstrate smaller clots, and obstructed veins may give the "corkscrew appearance".^[1]

Computed tomography, with radiocontrast in the venous phase (CT venography or CTV), has a detection rate that in some regards exceeds that of MRI. The test involves injection into a vein (usually in the arm) of a radioopaque substance, and time is allowed for the bloodstream to carry it to the cerebral veins - at which point the scan is performed. It has a sensitivity of 75-100% (it detects 75-100% of all clots present), and a specificity of 81-100% (it would be incorrectly positive in 0-19%). In the first two weeks, the "empty delta sign" may be observed (in later stages, this sign may disappear).^[7]

Magnetic resonance venography employs the same principles, but uses MRI as a scanning modality. MRI has the advantage of being better at detecting damage to the brain itself as a result of the increased pressure on the obstructed veins, but it is not readily available in many hospitals and the interpretation may be difficult.^[7]

D-dimer

A 2004 German study suggested that the D-dimer blood test, already in use for the diagnosis of other forms of thrombosis, was abnormal (above 500 μg/l) in 34 out of 35 patients with cerebral sinus thrombosis, giving it a sensitivity of 97.1%, a negative predictive value of 99.6%, a specificity of 91.2%, and a positive predictive value of 55.7%. Furthermore, the level of the D-dimer correlated with the extent of the thrombosis.^[8] A subsequent 2005 study performed in France showed that 10% of patients with confirmed thrombosis had a normal D-dimer, and in those who had presented with only a headache 26% had a normal D-dimer. The study concludes that D-dimer is not useful in the situations where it would make the most difference (low-probability settings).^[9]

Further tests

In most patients, the direct cause for the cerebral sinus thrombosis is not readily apparent. Identifying a source of infection is crucial, but it is common practice to screen for various forms of thrombophilia (a propensity to form blood clots).^[1]

Pathogenesis

The veins of the brain, both the superficial veins and the deep venous system, empty into the dural venous sinuses, which carry blood back to the jugular vein. In cerebral venous sinus thrombosis, blood clots usually form both in the veins of the brain and the venous sinuses. The thrombosis of the veins themselves causes cerebral oedema (both vasogenic and cytotoxic oedema) through back pressure, and small petechial haemorrhages that may merge into large haematomas. Thrombosis of the sinuses is the main mechanism behind the increase in intracranial pressure due to decreased resorption of cerebrospinal fluid (CSF). Because this process is generalised, the condition does not lead to hydrocephalus.^[1]

Any blood clot forms due to an imbalance between coagulation (the formation of the insoluble blood protein fibrin) and fibrinolysis. The three major mechanisms for such an imbalance are enumerated in Virchow's triad: alterations in normal blood flow, injury to the blood vessel wall, and alterations in the constitution of blood (hypercoagulability). Most cases of cerebral venous sinus thrombosis are due to hypercoagulability.^[1]

It is possible for the clot to break off and migrate (embolism) to the lungs, causing a pulmonary embolism.^[1][3] An analysis of previous case reports concludes that this occurs in about 10% of cases, but has a very poor prognosis.^[10]

Treatment

Various studies have investigated the use of anticoagulation (suppression of blood clot formation) in cerebral venous sinus thrombosis. Before these trials, there was a concern that small areas of hemorrhage would bleed further as a result of treatment. The European Federation of Neurological Societies (EFNS) recommends heparin or low molecular weight heparin in the initial treatment, followed by warfarin, provided there are no other bleeding risks that would make these treatments unsuitable.^[3] The duration of warfarin treatment depends on the circumstances and underlying causes of the condition. If the thrombosis developed under temporary circumstances (e.g. pregnancy), three months are regarded as sufficient. If the condition was unprovoked but there are no clear causes or a "mild" form of thrombophilia, 6 to 12 months is advised. If there is a severe underlying thrombosis disorder, warfarin treatment may need to continue indefinitely.^[3]

Thrombolysis (removal of the blood clot with "clot buster" medication) has been described, either systemically by injection into a vein or directly into the clot during angiography. The 2006 EFNS guideline recommends that thrombolysis is only used in patients who deteriorate despite adequate treatment, and other causes of deterioration have been eliminated. It is unclear which drug and which mode of administration is the most effective. Bleeding into the brain and in other sites of the body is a major concern in the use of thrombolysis.^[3]

Raised intracranial pressure, if severe or threatening vision, may require therapeutic lumbar puncture (removal of excessive cerebrospinal fluid), medication (acetazolamide), or surgical treatment (optic nerve sheath fenestration or shunting).^[1] In certain situations, anticonvulsants may be used prophylactically (i.e. to prevent seizures); these are focal neurological problems (e.g. inability to move a limb) and/or focal changes of the brain tissue on CT or MRI scan.^[3]

Prognosis

In 2004 the first adequately large scale study on the natural history and long-term prognosis of this condition was reported and showed that at 16 months followup: 57.1% of patients had full recovery, 29.5%/2.9%/2.2% had respectively minor/moderate/severe symptoms or impairments, and 8.3% had died. Severe impairment or death were more likely in those aged over 37 years, male, affected by coma, mental status disorder, intracerebral hemorrhage, thrombosis of the deep cerebral venous system, central nervous system infection and cancer.^[11] A subsequent systematic review of nineteen studies in 2006 showed that mortality is about 5.6% during hospitalisation and 9.4% in total, while of the survivors 88% make a total or near-total recovery. After several months, two thirds of the cases has resolution ("recanalisation") of the clot. The rate of recurrence was low (2.8%).^[12]

Epidemiology

Cerebral venous sinus thrombosis is rare, with 3-4 per million annual incidence in adults and 7 per million incidence in children (predominantly in the newborn^[3]). 75% of cases are in women; some historical evidence suggests that the use of oral contraceptives in women is behind the disparity between the sexes.^[1] In adults, the disease occurs most often in the third decade.^[3]

References