Online newspaper of professor Yasser Metwally

The author:Professor Yasser Metwally

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INTRODUCTION

Background: Thrombosis of the venous channels in the brain is an uncommon cause of cerebral infarction relative to arterial disease but is an important consideration because of its potential morbidity. Venous thrombosis may present with headache and cranial nerve palsies. Newer imaging procedures have led to easier recognition of venous sinus thrombosis, offering the opportunity for early therapeutic measures. Venous thrombosis also may be associated with other medical complications that require therapeutic intervention.

Pathophysiology: Knowledge of the anatomy of the venous system is essential in evaluating patients with venous thrombosis, since symptoms associated with the condition are related to the area of thrombosis. Cerebral infarction may occur with cortical vein or sagittal sinus thrombosis secondary to tissue congestion with obstruction. Lateral sinus thrombosis may be associated with headache and a pseudotumor cerebri–like picture. Extension into the jugular bulb may cause jugular foramen syndrome; cranial nerve palsies may be seen in cavernous sinus thrombosis as a compressive phenomenon. Cerebral hemorrhage also may be a presenting feature in patients with venous sinus thrombosis.

Frequency:

• Internationally: Incidence of cerebral venous thrombosis (CVT) is difficult to determine. Generally, it is believed to be an uncommon cause of stroke. However, with the advent of newer imaging techniques, the reported incidence is likely to increase as less severe cases are found. Towbin in 1973 reported CVT in 9% of 182 autopsies. Daif in a 1995 paper reported a frequency in Saudi Arabia of 7 per 100,000 hospital patients. The ratio of venous to arterial strokes has been found to be 1:62.5.

Mortality/Morbidity: Mortality in untreated cases of venous thrombosis is reported to range from 13.8-48%; this high mortality rate may be a reflection of clinical severity at entrance into the study. Between 25% and 30% of patients have full recovery.

Race: No racial predilection has been observed.

Sex: CVT is believed to be more common in women than men. Ameri in a series of 110 cases found a female-to-male ratio of 1.29:1.

Age: Ameri reported a uniform age distribution in men with CVT, while 61% of women with CVT were aged 20-35 years. This may be related to pregnancy or the use of oral contraceptives.

CLINICAL PICTURE

History:

• Patients may present with headache. Although thunderclap headache usually indicates subarachnoid hemorrhage, it also may be seen in sinus thrombosis.

• Nausea and vomiting may be associated.

• Patients with lateral sinus thrombosis may present with a pseudotumor cerebri–like syndrome.

• Patients may develop seizures that can be recurrent.

• Patients may have a decreased level of consciousness that progresses to coma.

• Focal neurological deficit may occur depending on the area involved.

  • Hemiparesis may occur, and in some cases of sagittal sinus thrombosis, weakness in the lower extremity. This also may develop as bilateral lower extremity involvement.

  • Aphasia, ataxia, dizziness, chorea, and hemianopia all have been described.

• Cranial nerve syndromes are seen with venous sinus thrombosis. These include the following:

  • Vestibular neuronopathy

  • Pulsatile tinnitus

  • Unilateral deafness

  • Double vision

  • Facial weakness

  • Obscuration of vision

Physical:

• Mental status may be quite variable, with patients showing no change in alertness, developing mild confusion, or progressing to coma.

• Cranial nerve findings may include papilledema, hemianopia, oculomotor and abducens palsies, facial weakness, and deafness. If the thrombosis extends to the jugular vein, the patient may develop involvement of cranial nerves IX, X, XI, and XII with the jugular foramen syndrome.

• Thrombosis of the superior sagittal (longitudinal) sinus may present with unilateral paralysis that then extends to the other side secondary to extension of the clot into the cerebral veins. Because of the location, this may present as a unilateral lower extremity weakness or paraplegia.

• Cavernous sinus thrombosis with obstruction of the ophthalmic veins may be associated with proptosis and ipsilateral periorbital edema. Retinal hemorrhages and papilledema may be present. Paralysis of extraocular movements, ptosis, and decreased sensation in the first division of the trigeminal nerve often are observed.

• Although unusual, cortical vein thrombosis may be seen in the absence of dural sinus involvement. These cases are associated with varied focal deficits including aphasia, hemiparesis, hemisensory loss, and hemianopia.

Causes: Many causative conditions have been described in CVT. These may be seen alone or in combination. For example, the prothrombin gene mutation in association with oral contraceptive use raises the odds ratio for developing CVT.

• Infection may occur by extension from the paranasal sinuses. These cases also may be associated with subdural empyema. Bacterial meningitis as a coexistent condition should be considered in these cases. Frontal sinuses are the most common source of infection, with spread through the emissary veins between the posterior sinus mucosa and the meninges. Rarely, sphenoid sinusitis may be associated with cavernous sinus thrombosis. Multiple organisms are to be considered, Staphylococcus aureus being the most common. In chronic infections, gram-negative organisms and fungi such as Aspergillus species may be found.

• Trauma may be an etiologic event. Cerebral sinus thrombosis easily may be overlooked in cases of minor head trauma. Neurosurgical procedures such as dural taps and infusions into the internal jugular vein also have been implicated.

• Many medical conditions have been associated with venous sinus thrombosis.

  • Pregnancy and puerperium are important considerations in women of childbearing age.

  • Inflammatory bowel diseases such as Crohn disease and ulcerative colitis are described as risk factors for venous thrombosis. Corticosteroids used in treatment of these conditions may play a causative role.

  • Hypercoagulable states associated with the antiphospholipid syndrome, protein S and C deficiencies, antithrombin III deficiency, lupus anticoagulant, and the Leiden factor V mutation may result in CVT. Pregnancy also is associated with a hypercoagulable tendency.

  • Hematologic conditions, including paroxysmal nocturnal hemoglobinuria, thrombotic thrombocytopenic purpura, sickle cell disease, and polycythemia, are to be considered. Malignancies may be associated with hypercoagulable states and therefore may be risk factors.

  • Collagen vascular diseases such as systemic lupus erythematosus, Wegener granulomatosis, and Behcet syndrome have been reported to be associated with CVT.

  • Nephrotic syndrome, dehydration, hepatic cirrhosis, and sarcoidosis all have been described as increasing the risk of CVT.

• Several medications are reported to increase the risk of CVT. Among these are oral contraceptives, including the third-generation formulations; corticosteroids; epsilon-aminocaproic acid; and L-asparaginase. Heparin therapy has been reported to produce thrombotic thrombocytopenia with associated venous sinus thrombosis.

INVESTIGATIONS

Lab Studies:

• Clinical laboratory studies are useful for determining the possible causes of CVT. Diagnosis of the condition is made on the basis of clinical presentation and imaging studies.

• CBC is done to look for polycythemia as an etiologic factor. Decreased platelet count would support thrombotic thrombocytopenic purpura; leukocytosis might be seen in sepsis. In addition, if heparin is used as treatment, platelet counts should be monitored for thrombocytopenia.

• Antiphospholipid and anticardiolipin antibodies should be obtained to evaluate for antiphospholipid syndrome. Other tests that may indicate hypercoagulable states include protein S, protein C, antithrombin III, lupus anticoagulant, and Leiden factor V mutation. These evaluations should not be made while the patient is on anticoagulant therapy.

• Sickle cell preparation or hemoglobin electrophoresis should be obtained in individuals of African decent.

• Erythrocyte sedimentation rate and antinuclear antibody should be performed for screening of systemic lupus erythematosus, Wegener granulomatosis, and temporal arteritis. If elevated, further evaluation including complement levels, anti-DNA antibodies, and neutrophil cytoplasmic antibodies (ANCA) could be considered.

• Urine protein should be checked and, if elevated, nephrotic syndrome considered.

• Liver function studies should be performed to rule out cirrhosis.

Imaging Studies:

• MRI

  • MRI shows the pattern of an infarct that does not follow the distribution of an expected arterial occlusion. It may show absence of flow void in the normal venous channels.

  • MR venography (MRV) is an excellent method of visualizing the dural venous sinuses and larger cerebral veins.

  • Single-slice phase-contrast angiography (SSPCA) takes less than 30 seconds and provides rapid and reliable information. Many neurologists now consider it to be the procedure of choice in diagnosing CVT. Adams, in a study of 21 patients, demonstrated a specificity and sensitivity of 100% for SSPCA when compared to alternative imaging techniques.

  • However, Ayanzen described transverse sinus flow gaps in 31% of patients with normal MRI findings. Ninety percent of these were in the nondominant transverse sinus and 10% in the codominant sinuses. None were seen in the dominant sinus. These should not be mistaken for thrombosis.

 Figure 1: R venogram – axial view [eft image]; A = Lateral (transverse) sinus; B = Sigmoid sinus; C = Confluence of sinuses; and D = Superior sagittal sinus. MR venogram – sagittal view [rght image]; A = Lateral (transverse) sinus; C = Confluence of sinuses; D = Superior sagittal sinus; and E = Straight sinus. (Click to magnify figure)

Figure 2: Case 1: Left lateral sinus thrombosis demonstrated on MR venography [left image]. This patient presented with sudden onset of headache. One week after treatment with heparin, [right image] the MR venogram of the patient displayed increased flow in the left lateral sinus consistent with early recanalization of the sinus; headache had resolved at this point. (Click to magnify figure)

• CT scan

  • CT scan is an important imaging technique, as it is often the first imaging study obtained. It may show evidence of infarction that does not correspond to an arterial distribution. However, in the absence of a hemorrhagic component, demonstration of the infarct may be delayed up to 48-72 hours. It is also useful in ruling out other conditions such as neoplasm and in evaluating coexistent lesions such as subdural empyema. CT of the sinuses is useful in evaluating sinusitis; CT of the mastoids may be helpful in lateral sinus thrombosis.

  • Empty delta sign appears on contrast scans as enhancement of the collateral veins in the superior sagittal sinus (SSS) walls surrounding a nonenhanced thrombus in the sinus. However, the sign is frequently absent. Early division of the SSS can give a false delta sign. The dense triangle sign formed by fresh coagulated blood in the SSS and the cord sign representing thrombosed cortical vein are extremely rare.

Figure 3: CT scan demonstrates a left posterior temporal hematoma in a 38-year-old woman on oral contraceptives (the only identified risk factor). Axial view of MR venogram demonstrating lack of flow in transverse sinus. Contrast-enhanced MRI showing lack of filling of left transverse sinus. Coronal view of MR venogram demonstrating lack of flow in the left transverse and sigmoid sinuses. (Click to magnify figure)

• Contrast studies

  • Carotid arteriography with delayed filming technique to visualize the venous system was the procedure of choice in the diagnosis of venous thrombosis prior to the advent of MRV. It is an invasive procedure and is therefore associated with a small risk.

  • If MR studies are not diagnostic, conventional angiography should be considered.

  • Direct venography can be performed by passing a catheter from the jugular vein into the transverse sinus with injection outlining the venous sinuses.

Other Tests:

• EEG may be normal, show mild generalized slowing, or show focal abnormalities if a unilateral infarct occurs. It is helpful in evaluating a seizure focus.

Procedures:

• Lumbar puncture is helpful in evaluating for meningitis as an associated infectious process. A large unilateral hemispheric lesion or posterior fossa lesion demonstrated on CT scan or MRI is a contraindication to the procedure. In the past, compression of the jugular vein unilaterally with pressure measurement has been utilized. Pressure may be elevated if thrombosis of the contralateral transverse sinus is present. However, collateral circulation or incomplete compression of the jugular vein may yield a false-negative result. Elevation of the intracranial venous pressure is a concern, as it may precipitate herniation. As the maneuver adds little to the diagnosis, it usually is not performed.

MANAGEMENT

Medical Care: Medical management of the patient with CVT is similar to that of patients with arterial stroke as far as stabilizing the patient is concerned.

• Patients with altered mental status or hemiplegia should be given nothing by mouth to prevent aspiration. Intravenous fluids should not be hypotonic solutions. Normal saline is recommended at a rate of approximately 1000 cc in 24 hours. To decrease intracranial pressure, the head should be elevated 30-40 degrees at all times. In the treatment of stroke patients, supplemental oxygen has not been shown to be beneficial unless level of consciousness is decreased.

• Seizures should be treated with appropriate anticonvulsants. Fosphenytoin is recommended for treatment of seizures in those patients who require a parenteral formulation. Alternatively, phenobarbital or sodium valproate injection may be utilized if the patient has allergy to phenytoin. Diazepam or lorazepam may be used to treat status epilepticus, but the patient also should be given an anticonvulsant with a longer duration of action to prevent recurrent seizures.

• Specific therapy for CVT involves anticoagulation or thrombolytic therapy. Use of anticoagulation in CVT has been a subject of some debate among neurologists. Concern has been expressed over the possibility of increasing hemorrhage in patients treated in this manner. Studies by De Bruijn and Stam in 1999 and by Einhaupl in 1991 indicated that anticoagulation could be used safely in this condition. The question of effectiveness of anticoagulation is not clear, but most articles tend to point toward improved outcome with utilization of anticoagulation.

  • Thrombolytic therapy has been described in several case reports as beneficial in cases of CVT. These patients were treated with infusion of a thrombolytic agent into the dural venous sinus utilizing microcatheter technique. This treatment at present is limited to specialized centers but should be considered for patients with significant deficit.

  • A recent report describes the use of a rheolytic catheter device in a patient who had not responded to microcatheter instillation of urokinase. The rheolytic catheter was designed for use in the coronary circulation and delivers 6 high-velocity saline jets through a halo device at the tip of the catheter. This leads to a Bernoulli effect that breaks up the thrombus. In addition, the particulate debris is directed into an effluent lumen for collection into a disposable bag. The catheter was advanced into the sagittal sinus, resulting in restoration of venous flow and reduction of intracranial pressure.

Surgical Care: In cases of severe neurological deterioration, open thrombectomy and local thrombolytic therapy have been described as beneficial. Patients selected for these procedures have progressed despite adequate anticoagulation and intensive medical care. Ekseth described 3 such patients who all returned to normal lives following this procedure.

Consultations:

• Neurosurgery consultation is indicated in patients with subdural empyema or brain abscess. Consultation should also be considered for patients who have severe deterioration despite aggressive medical management.

• Infectious disease opinion is to be considered for patients with CVT who have associated infection such as meningitis or sinusitis.

• Otolaryngology (ENT) opinion may be helpful in patients with associated sinusitis.

DRUGS

Heparin should be considered seriously in the management of CVT. Conversion to warfarin as maintenance therapy is then suggested. Subcutaneous low-molecular-weight heparin (Lovenox) also has been used in patients with venous sinus thrombosis.

Thrombolytic therapy may be useful, but all studies so far describe its use only with local instillation by microcatheter or direct instillation at the time of surgical thrombectomy.

Prognosis:

• Smith compared outcomes of patients treated with heparin and local infusion of urokinase with those of patients who received no treatment. Twelve patients received treatment and 21 patients received no treatment. Results are tabulated below.

Table 1. CVT Patients Treated with Heparin and Local Infusion of Urokinase vs Nontreated Group

Medical/Legal Pitfalls:

• Potential medical/legal pitfalls involve failure to properly diagnose associated conditions. Following are some examples:

  • Failure to aggressively treat frontal sinusitis leading to subdural empyema or CVT

  • Failure to consider MRI or MRV in patients with pseudotumor cerebri to look for lateral sinus thrombosis (unless other etiology is found)

  • Failure to consider CVT in patients with thunderclap headache; since such headache is not limited to subarachnoid hemorrhage (SAH) and may be seen with CVT, lack of evidence of SAH should prompt MRV

  • Failure to check patients with CVT for associated medical conditions such as hypercoagulable states, nephrotic syndrome, pregnancy, liver disease, and inflammatory bowel disease

  • Failure to consider medications that might lead to CVT, such as steroids and oral contraceptives

  • Failure to distinguish normal anatomic gaps in the dural sinuses from thrombosis on MRV.

References

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