Cerebral venous thrombosis (CVT), which includes thrombosis of the cerebral veins and the dural sinuses, is a rare disorder that can lead to significant morbidity and mortality. Cerebral venous thrombosis can present with variable signs and symptoms that include a headache, benign intracranial hypertension, subarachnoid hemorrhage, focal neurological deficit, seizures, unexplained altered sensorium, and meningoencephalitis. The diversity of risk factors and variable presentation present challenges in the diagnosis of cerebral vein thrombosis. Delay in diagnosis is common, as the median delay from symptom onset to hospital admission is 4 days and from symptom onset to diagnosis is 7 days. Thus, having a high index of suspicion for this disorder is crucial to ensure timely diagnosis and treatment.
Many risk factors contribute to the development of cerebral venous thrombosis. At least one risk factor was identified in more than 85% of patients with cerebral venous thrombosis, and multiple risk factors are found in more than 50% of patients with cerebral venous thrombosis. In general, cerebral venous thrombosis is common in any condition that leads to a prothrombotic state, including pregnancy, the post-partum state, or those on oral contraceptives. In the International Study on Cerebral Vein and Dural Sinus Thrombosis (ICSVT), genetic and acquired thrombophilia was present in 34% of patients with cerebral venous thrombosis. Inherited thrombophilia includes protein C and protein S deficiencies, antithrombin deficiency, factor V Leiden mutation, prothrombin gene mutation 20210, as well as hyperhomocysteinemia. Acquired thrombophilia should be suspected in a patient with a history of nephrotic syndrome (due to loss of antithrombin) or antiphospholipid antibodies. Additional causes and risk factors associated with cerebral venous thrombosis include chronic inflammatory disease states such as systemic lupus erythematosus, inflammatory bowel disease, malignancy, and vasculitides such as Wegener's granulomatosis. Local infections such as otitis, mastoiditis, which can lead to thrombosis of the adjacent sigmoid and transverse sinuses, have also been implicated in the development of cerebral venous thrombosis. Cerebral venous thrombosis may also be seen in a patient with a head injury, after certain neurosurgical procedures, direct injury to the sinuses or jugular veins, such as jugular vein catheterization, and even after a lumbar puncture.
Cerebral venous thrombosis is a rare disorder with an annual incidence estimated to be three to four cases per million. The frequency of peripartum and post-partum cerebral venous thrombosis is about 12 cases per 100,000 deliveries in pregnant women, which is only slightly lower than that of peripartum and postpartum arterial stroke. Cerebral venous thrombosis occurs three times as frequently in women as it does in men and this is thought to be due to gender-specific risk factors, for example, oral contraceptive use, and less frequently, pregnancy, puerperium, and hormone replacement therapy. More recently, there has been a significant female predominance among young adults, with the majority of cases (70% to 80%) being in women of childbearing age, but not among children or elderly persons.
There are two pathophysiologic mechanisms thought to contribute to the clinical manifestations of cerebral venous thrombosis. First, thrombosis of the cerebral veins leads to increased venous and capillary pressure, which leads to a decrease in cerebral perfusion. Decreased cerebral perfusion results in ischemic injury, manifested by cytotoxic edema, which damages the energy-dependent cellular membrane pumps and leads to intracellular swelling. Disruption of the blood-brain barrier leads to vasogenic edema and leakage into the interstitial space. The increased pressure in the venous system can lead to an intraparenchymal hemorrhage. The second pathophysiologic mechanism resulting in cerebral venous thrombosis is obstruction of the cerebral sinuses, particularly when thrombus does not resolve. Normally, the cerebrospinal fluid found in the cerebral ventricles is transported through the subarachnoid space to the arachnoid granulations and absorbed into the venous sinuses. Thrombosis of the venous sinuses results in impaired cerebrospinal fluid absorption and ultimately leads to increased intracranial pressure. Increased intracranial pressure leads to cytotoxic and vasogenic edema and ultimately may lead to parenchymal hemorrhage.
Physicians should highly suspect cerebral venous thrombosis given the variable presentation and low annual incidence. Signs and symptoms may be acute, subacute, or chronic, with the most common symptom in cerebral venous thrombosis being a headache. A headache presents in up to 90% of patients. Headaches may be generalized or diffuse and tend to mimic migraines, but may increase in severity slowly over days and weeks and are not relieved with sleep. In some instances, the headache may be thunderclap in nature, starting suddenly and maximal in intensity at onset, thereby mimicking the presentation of subarachnoid hemorrhage. A headache is often worsened with Valsalva or coughing, indicative of the increase in intracranial pressure. Papilledema and visual symptoms, such as diplopia caused by a sixth cranial nerve palsy when the intracranial pressure is too high, may also accompany a headache. The funduscopic examination will reveal papilledema, which, depending on the severity, can cause visual impairment and even permanent blindness if it is left untreated. However, an isolated headache without any other focal neurologic deficits or papilledema has been reported in up to a fourth of patients with cerebral venous thrombosis and further complicates the diagnostic picture. Focal neurologic signs are common and are seen in up to 44% of patients. Motor weakness, including hemiparesis, is the most common focal finding. However, unlike arterial thrombosis in the setting of cerebrovascular accident, localization to one vascular territory is often absent. Hemispheric symptoms, such as aphasia and hemiparesis, are a characteristic but rare finding. Seizures are seen in about 40% of patients with cerebral venous thrombosis, the most common of which are focal seizures. Focal seizures account for 50% of those who experience a seizure in the setting of cerebral venous thrombosis but have the potential to generalize to a status epilepticus. Thus, cerebral venous thrombosis should be considered in any patient who presents with a headache and some combination of either focal neurologic deficit and or new onset seizures. Thrombosis of the straight sinus, or in severe cases of venous infarction with hemorrhagic transformation can lead to compression of the diencephalon and brainstem, resulting in coma or death due to cerebral herniation.
Diagnosis of cerebral venous thrombosis is one that is clinical and confirmed with neuroimaging. Given its varied presentation and myriad of symptoms, one must have a high index of suspicion to identify and diagnose this rare and potentially life-threatening condition correctly. It should be suspected in young and middle-aged patients, especially in patients with cerebral venous thrombosis risk factors, such as women who are postpartum, those with genetic or acquired thrombophilia, and patients with focal neurological findings. It should also be suspected in those:
Laboratory evaluation should include a complete blood count, coagulation panel, chemistry panel, as well as inflammatory markers such as a sedimentation rate and C-reactive protein to evaluate for proinflammatory states. Ideally, a screening test that could effectively rule out the diagnosis without subjecting patients to neuroimaging when it is not necessary, would be ideal, and prove helpful to clinical practice. The D-dimer assay has been evaluated in this regard, and unfortunately, it has been shown to have an unacceptable false negative rate of up to 26% in one study. This low sensitivity of the D-dimer assay is in contrast to the utility of the D-dimer in ruling out deep venous thrombosis, which may be due to the lower thrombotic burden of cerebral venous thrombosis in comparison to DVT. Based on recent guidelines by the American Heart Association/American Stroke Association, a negative D-dimer does not effectively rule out cerebral venous thrombosis and should not preclude neuroimaging if there is a clinical suspicion for cerebral venous thrombosis.
Management is initially focused on identifying and addressing life-threatening complications of cerebral venous thrombosis, including increased intracranial pressure (ICP), seizures, and coma. If a patient seizes and has a lesion such as a hemorrhage or infarction on neuroimaging, then specific anticonvulsant therapy, as well as seizure prophylaxis, should be initiated. If a seizure does not occur, then seizure prophylaxis is not indicated. In the case of increased ICP, the head of the bed should be elevated, and administration of dexamethasone and mannitol should be done promptly to reduce increased ICP. This is followed by admission to the intensive care unit or stroke unit for close ICP monitoring, with a neurosurgical consultation if the patient decompensates and requires surgical decompression. Next, attention should be shifted to specific therapy, including anticoagulation and in certain cases, catheter-directed fibrinolysis and surgical thrombectomy.
Anticoagulation has been a controversial topic due to the potential for hemorrhagic transformation of cerebral infarcts before the administration of anticoagulation. The goal of anticoagulation is to prevent the thrombus propagation, to help recanalize the lumen of occluded cerebral veins, and to prevent the complications of deep venous thrombosis and pulmonary embolism in patients who already have thrombus burden and are predisposed to forming additional thrombi. The results of two randomized controlled trials, which compared anticoagulation with placebo, although statistically insignificant, showed that anticoagulation had a favorable outcome more often than controls. They also showed that anticoagulation was safe and not contraindicated, even in patients with cerebral hemorrhage. Based on these randomized controlled trials, as well as other observational studies, anticoagulation is recommended as a safe and effective treatment of cerebral venous thrombosis and should be initiated immediately upon diagnosis of cerebral venous thrombosis. Anticoagulation with intravenous unfractionated heparin or with subcutaneously administered low-molecular-weight heparin as a bridge to oral anticoagulation with a vitamin K antagonist is recommended. The target goal of treatment is an international normalized ratio of 2.0 to 3.0 cerebral venous thrombosis 3 to 6 months in patients with provoked cerebral venous thrombosis and 6 to 12 months in patients with unprovoked cerebral venous thrombosis. Indefinite anticoagulation should be considered in patients with recurrent cerebral venous thrombosis, those who develop deep vein thrombosis and pulmonary embolism in addition to cerebral venous thrombosis, or those with first-time cerebral venous thrombosis in the setting of severe thrombophilia.
Although the majority of patients see clinical improvement with anticoagulation therapy, there is a small subset of patients who do not, and these individuals clinically deteriorate despite anticoagulation. In these cases, where prognosis is poor, systemic and catheter-directed thrombolysis is indicated in patients with large and extensive cerebral venous thrombi who clinically deteriorate despite treatment with anticoagulation. As is the case whenever fibrinolytics are used, there is an increased risk of intracranial hemorrhage. Based on a systemic review conducted in 2003 which looked at 72 studies and 169 patients with cerebral venous thrombosis there seems to be a possible clinical benefit due to the use of fibrinolytics in patients with a severe presentation. Intracranial hemorrhage occurred in 17% of patients treated with fibrinolytics and was associated with clinical deterioration in 5% of cases. Overall, the use of endovascular thrombolytics should be applied at centers with staff who are experienced in interventional radiology and should be reserved for patients who are clinically deteriorating and despite treatment with anticoagulation.
Surgical thrombectomy is reserved for cases of severe neurological deterioration despite maximal medical therapy. In the case of large venous infarcts and hemorrhages causing a mass effect with risk of herniation, decompressive surgery has been thought to improve clinical outcomes especially if done early, although this is level C evidence.
It is important to elucidate the underlying contributory factors of cerebral venous thrombosis and to devise a treatment strategy to correct them. Women who are on hormonal contraceptive therapy should seek non-estrogen based methods of contraception such as the levonorgestrel and copper intrauterine devices or progestin-only pill. Further testing to identify the etiology of all acquired and reversible thrombophilic states should be conducted and when possible, corrected. In addition to clinical follow-up, the American Heart Association and American Stroke Association recommend follow-up imaging 3 to 6 months after diagnosis to assess for recanalization.