to very good for the left lateral sinus and straight sinus, and poor to good for the cortical veins [122]. The diagnosis of isolated cortical vein thrombosis can be difficult, but the use of T2* https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 12/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate susceptibility-weighted MRI may enable a diagnosis of isolated cortical vein thrombosis by demonstrating thrombus as an area of hypointensity [84,113,119]. MR venography MR venography, usually performed using the time-of-flight (TOF) technique, is useful for demonstrating absence of flow in cerebral venous sinuses, though interpretation can be confounded by normal anatomic variants such as sinus hypoplasia and asymmetric flow [1]. Other MR techniques may be useful to distinguish these variants from venous thrombosis. Contrast-enhanced MR venography can provide better visualization of cerebral venous channels, and gradient echo or susceptibility-weighted sequences will show normal signal in a hypoplastic sinus and abnormally low signal in the presence of thrombus. A chronically thrombosed hypoplastic sinus will show absence of flow on two-dimensional TOF MR venography and enhancement on contrast-enhanced MRI and MR venography. Conventional angiography Cerebral digital subtraction angiography is typically reserved for cases when the clinical suspicion for CVT is high but CT venography or MR venography are inconclusive [1]. Angiography may be helpful for making this diagnosis by showing the sudden termination of a cortical vein surrounded by dilated and tortuous collateral "corkscrew veins" or by the filling of a cortical vein that was not apparent on an earlier angiographic study during the acute phase of CVT. Other typical signs of CVT on angiography are nonvisualization of all or part of a venous sinus, delayed venous emptying with pathologically increased collaterals, and reversal of venous flow. As with MR and CT venography, conventional cerebral angiography may be limited by potential pitfalls. Anatomic variations, such as variability of number and location of cortical veins, hypoplasia of the anterior part of the superior sagittal sinus, duplication of the superior sagittal sinus, and hypoplasia or aplasia of the transverse sinuses, may make the diagnosis of CVT by all types of angiography difficult [59]. While the interobserver agreement for a diagnosis of CVT is not perfect, the combination of conventional contrast angiography plus brain MRI has a higher interobserver agreement than angiography alone (94 versus 62 percent) [123]. Laboratory tests Aside from neuroimaging, there is no simple confirmatory laboratory test that can confidently rule out CVT in the acute phase of the disease. We suggest routine blood studies consisting of a complete blood count, chemistry panel, prothrombin time, and activated partial thromboplastin time for patients with suspected CVT, in agreement with guidelines from the American Heart Association/American Stroke Association [1]. The findings from these tests may suggest the presence of conditions that contribute to the development of CVT such as an underlying hypercoagulable state, infection, or inflammatory process. The guidelines recommend screening for these and other potential prothrombotic conditions that may predispose to CVT, including use of contraceptives, at the initial clinical presentation. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 13/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate The utility of D-dimer testing and lumbar puncture is reviewed in the following sections. D-dimer An elevated plasma D-dimer level supports the diagnosis of CVT, but a normal D- dimer does not exclude the diagnosis in patients with suggestive symptoms and predisposing factors. The potential utility of D-dimer for the diagnosis of CVT is illustrated by the following observations: A 2012 meta-analysis included 14 studies that evaluated D-dimer in 1134 patients for the diagnosis of suspected or confirmed CVT [124]. In seven studies that evaluated patients with suspected CVT, D-dimer was elevated in 145 of 155 patients in whom CVT was confirmed and was normal in 692 of 771 patients in whom CVT was ruled out, yielding a sensitivity and specificity of 94 and 90 percent, respectively. D-dimer performed less well in seven studies that enrolled subjects with already-confirmed CVT; the sensitivity and specificity were 89 and 83 percent, respectively. The sensitivity of D-dimer for CVT was also lower in patients with isolated headache as the presenting symptom (82 percent), in those with subacute or chronic clinical presentations of CVT (83 percent), and in those with a single affected venous sinus (84 percent). In a subsequent study of 233 patients with suspected CVT and symptom onset of less than seven days, D-dimer demonstrated a sensitivity and specificity of 94 and 98 percent, respectively, for predicting CVT [125]. Thus, D-dimer measurement may have some value as a diagnostic screening tool for the assessment of patients with possible CVT. However, a normal D-dimer value cannot exclude CVT, especially in patients with isolated headache or with thrombosis of a single sinus. Individual assays used to measure D-dimer vary, but it is reasonable to use the same threshold levels as used in diagnostic protocols for deep venous thrombosis (eg, D-dimer >500 ng/mL of fibrinogen equivalent units). (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity", section on 'D-dimer'.) Lumbar puncture Lumbar puncture may be useful to exclude meningitis in patients with CVT who present with isolated intracranial hypertension, a syndrome that may account for up to 25 percent of all patients with CVT [5]. In addition, lumbar puncture is valuable in such patients to measure and decrease cerebrospinal fluid (CSF) pressure when vision is threatened. However, in the absence of suspicion for meningitis, CSF analysis is usually not helpful diagnostically for patients with focal neurologic findings and neuroimaging confirmation of CVT [1]. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 14/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate The CSF abnormalities in CVT are nonspecific and may include a lymphocytic pleocytosis, elevated red blood cell count, and elevated protein; these abnormalities are present in 30 to 50 percent of patients with CVT [60,61]. Performing a lumbar puncture is not harmful in patients with CVT, as suggested by the findings of a study that analyzed 624 patients with CVT and identified 224 who had lumbar puncture [126]. The groups with and without lumbar puncture did not differ on any of the outcome measures, which were neurologic worsening within 30 days of CVT onset, acute death, complete recovery at six months, or death or dependency at six months. Nevertheless, lumbar puncture is contraindicated in patients with large brain lesions because they have an increased risk of herniation. Evaluation for thrombophilic state Searching for a thrombophilic state, either genetic or acquired, should be done for patients with CVT who have a high pretest probability of severe thrombophilia, a category that includes those with a personal and/or family history of venous thrombosis, CVT at a young age, and CVT in the absence of a transient or permanent risk factor ( table 1) [104]. When appropriate, screening should include: Antithrombin Protein C Protein S Factor V Leiden Prothrombin G20210A pathologic variant Lupus anticoagulant, anticardiolipin, and anti-beta2 glycoprotein-I antibodies Homocysteine Acute thrombosis can transiently reduce levels of antithrombin, protein C, and protein S, so the utility of testing for these disorders in the acute phase of CVT is limited. In practice, it is preferable to test for protein C, protein S, and antithrombin at least two weeks after oral anticoagulation has been discontinued, since warfarin therapy reduces measurements of protein C and protein S and may raise plasma antithrombin concentrations into the normal range in patients with hereditary antithrombin deficiency. It is possible to test for protein C and protein S levels while receiving heparin therapy, which does not alter plasma protein C or protein S concentrations. However, testing for antithrombin should be performed when off heparin, which can lower antithrombin levels. (See "Antithrombin deficiency" and "Protein C deficiency" and "Protein S deficiency".) No underlying etiology or risk factor for CVT is found in approximately 13 percent of adult patients. However, it is important to continue searching for a cause even after the acute phase of https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 15/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate CVT, as some patients may have a condition such as the antiphospholipid syndrome, polycythemia, thrombocythemia, malignancy, or inflammatory bowel disease that is discovered weeks or months after the acute phase. (See 'Risk factors and associated conditions' above.) If abnormal results are found in assays for lupus anticoagulant, anticardiolipin, or anti-beta2 glycoprotein-I antibodies, testing should be repeated at least 12 weeks later, as the diagnosis of antiphospholipid syndrome requires two positive determinations of these biomarkers. (See "Diagnosis of antiphospholipid syndrome", section on 'Antiphospholipid antibody testing'.) An evaluation for paroxysmal nocturnal hemoglobinuria should be pursued if the complete blood count shows unexplained hemolytic anemia, iron deficiency, or pancytopenia. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria", section on 'Diagnosis and classification'.) In patients older than 40 years without identified etiology, we suggest searching for an occult malignancy. In patients with sepsis or with fever and no obvious cause of infection, we recommend performing a lumbar puncture. DIFFERENTIAL DIAGNOSIS The clinical presentation of CVT can be nonspecific (eg, headache, seizure, encephalopathy) and the cause may not be apparent on initial routine neuroimaging studies. For patients presenting with symptoms and signs of isolated intracranial hypertension syndrome (headache with or without vomiting, papilledema, and visual problems), the main considerations in the differential are idiopathic intracranial hypertension (pseudotumor cerebri) and meningitis. Other conditions associated with elevated intracranial pressure (eg, intracranial mass lesions from tumor or abscess) are usually apparent on neuroimaging with CT or MRI. If neuroimaging reveals no structural intracranial lesion responsible for intracranial hypertension, a lumbar puncture is indicated with measurement of opening pressure and cerebrospinal fluid for analysis. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis".) For patients presenting with a focal neurologic syndrome (eg, focal deficits, seizures, or both) the differential is broad and includes other vascular etiologies (eg, intracerebral hemorrhage from a variety of other causes, subdural hemorrhage, ischemic stroke), infection (eg, meningitis, abscess), and tumor. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 16/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate For patients presenting with encephalopathy (eg, multifocal signs, mental status changes, stupor, or coma), the differential includes infection (eg, bacterial and viral meningoencephalitis), inflammation (eg, paraneoplastic and autoimmune encephalitis), demyelination (eg, acute disseminated encephalomyelitis, neuromyelitis optica spectrum disorders), and toxic and metabolic disturbances. For patients presenting with thunderclap headache, which is rare in CVT, the differential ( table 2) includes subarachnoid hemorrhage, other types of intracranial hemorrhage, reversible cerebral vasoconstriction syndromes (RCVS), cervical artery dissection, viral and bacterial meningitis, acute complicated sinusitis, spontaneous intracranial hypotension, ischemic stroke, acute hypertensive crisis, third ventricular colloid cyst, and pituitary apoplexy. If initial neuroimaging is nondiagnostic, patients with thunderclap headache should have lumbar puncture with measurement of opening pressure and cerebrospinal fluid analysis to exclude subarachnoid hemorrhage and meningitis ( algorithm 1). If lumbar puncture is also nondiagnostic, imaging of the cerebral circulation is necessary, preferably with magnetic resonance angiography/venography. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis" and "Reversible cerebral vasoconstriction syndrome" and "Overview of thunderclap headache".) For patients during pregnancy or puerperium, preeclampsia or eclampsia are diagnostic considerations with any of the presentations listed above or otherwise when presenting with ischemic stroke or intracerebral hemorrhage. (See "Cerebrovascular disorders complicating pregnancy".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Stroke in children".) SUMMARY AND RECOMMENDATIONS Epidemiology and risk factors Cerebral venous thrombosis (CVT) is uncommon, with an estimated incidence of <2.5 per 100,000 annually. Among young adults, CVT is more common in females than males. The mean age of onset is 39 years old. (See 'Epidemiology' above.) https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 17/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate The major risk factors for CVT in adults ( table 1) are prothrombotic (hypercoagulable) conditions, oral contraceptives, pregnancy and the puerperium, malignancy, obesity, infection, head injury, and mechanical precipitants. (See 'Risk factors and associated conditions' above.) Clinical features The clinical presentation of CVT is highly variable. The onset can be acute, subacute, or chronic. Headache (of gradual, acute, or thunderclap onset) is the most frequent symptom, occurring in almost 90 percent of patients, and may occur as part of an isolated intracranial hypertension syndrome, with or without vomiting, papilledema, and visual problems. In other cases, headache may be accompanied by focal neurologic deficits, focal or generalized seizures, and encephalopathy with altered mental status or coma. (See 'Clinical aspects' above.) Neuroimaging features Parenchymal brain lesions, including brain swelling, edema, venous infarction, or hemorrhagic venous infarction, may occur secondary to venous occlusion. (See 'Neuroimaging' above.) Head CT scan is normal in up to 30 percent of CVT cases, and most of the findings with CVT are nonspecific. However, in about one-third of patients, CT demonstrates direct signs of CVT, which include the cord sign, the dense triangle sign, and the empty delta sign ( image 2 and image 3). CT venography may demonstrate filling defects, sinus wall enhancement, and increased collateral venous drainage and is an alternative to magnetic resonance (MR) venography ( image 4 and image 2). (See 'CT' above and 'CT venography' above.) Brain MRI along with MR venography is the most informative technique for demonstrating the presence of dural thrombus, cortical vein thrombosis, and the extent of brain injury ( image 6 and image 5). (See 'MRI' above and 'MR venography' above.) Diagnosis The combination of an abnormal signal in a venous sinus on brain MRI and the corresponding absence of flow on MR venography confirms the diagnosis of CVT. However, these findings are not always evident, and the diagnosis may rest on imaging features showing only absence of flow in a venous sinus or cortical vein. Other than neuroimaging, there is no simple confirmatory laboratory test that can confidently rule out CVT in the acute phase of the disease. (See 'Diagnosis' above.) 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Graphic 80911 Version 3.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 28/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Major cerebral veins and sinuses Graphic 72961 Version 2.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 29/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Systemic and local conditions increasing the risk of cerebral venous thrombosis