Etiology, clinical features, and diagnosis of cerebral venous thrombosis

AuthorsJos M Ferro, MD, PhDPatrcia Canho, MD, PhDSection EditorScott E Kasner, MDDeputy EditorJohn F Dashe, MD, PhDDisclosures:Jos M Ferro, MD, PhDNothing to disclose.Patrcia Canho, MD, PhDNothing to disclose.Scott E Kasner, MDGrant/Research Support: WL Gore (patent foramen ovale and stroke); Acorda (Clinical trial of ampyra for stroke recovery). Consultant/Advisory Boards: Novartis (Stroke endpoint adjudication committee); Pfizer ( Stroke endpoint adjudication committee); Reata (Stroke endpoint adjudication committee; Merck (Stroke endpoint adjudication committee); Medtronic (DSMB for atrial fibrillation and aortic valve trials); Brainsgate (DSMB for acute stroke treatment trial); Photothera (Acute stroke trial steering committee); AstraZeneca (stroke prevention trial steering committee); Boehringer Ingelheim (stroke prevention trial steering committee); Cardionet (Advisory board for mobile cardiac telemetry). Employment: University of Pennsylvania.John F Dashe, MD, PhDEmployee of UpToDate, Inc.Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.Conflict of interest policyAll topics are updated as new evidence becomes available and ourpeer review processis complete.Literature review current through:Apr 2014.|This topic last updated:Jan 02, 2013.INTRODUCTIONCerebral vein and dural sinus thrombosis (CVT) is less common than most other types of stroke but can be more challenging to diagnose. Due to the widespread use of magnetic resonance imaging (MRI) and rising clinical awareness, CVT is recognized with increasing frequency. In addition, it is now known to have a more varied clinical spectrum than previously realized. Because of its myriad causes and presentations, CVT is a disease that may be encountered not only by neurologists and neurosurgeons, but also by internists, oncologists, hematologists, obstetricians, pediatricians, and family practitioners.This topic will review the epidemiology, pathogenesis, clinical features, and diagnosis of CVT. Prognosis and treatment are discussed separately. (See"Treatment and prognosis of cerebral venous thrombosis".)EPIDEMIOLOGYWhile high-quality epidemiologic studies of CVT are lacking, the available data suggest that CVT is uncommon [1]. This conclusion is supported by the following observations: In large teaching hospitals, only 5 to 10 patients with CVT are admitted yearly [2] A nationwide hospital-based series in Portugal that included patients admitted to all neurology services in the country identified 91 new cases of CVT, corresponding to an incidence of0.22/100,000annually (95% CI, 0-0.47) [3] A hospital-based population study from two provinces in the Netherlands identified 94 CVT adult cases over a three-year period, corresponding to an overall CVT incidence among adults of 1.32 per 100,000 population (95% CI, 1.06-1.61) [4]. The annual incidence of CVT was higher for women compared with men (1.86 versus 0.75 per 100,000 population, respectively). In Isfahan, Iran, the incidence based upon hospital admissions was estimated to be1.23/100,000per year [5] The incidence of CVT in the multicenter Canadian registry in infants and children aged less than 18 years was0.67/100,000per year [6] A hospital discharge registry in the United States reported that the incidence of CVT during pregnancy was11.6/100,000deliveries [7]In contrast, an autopsy study performed in the 1970s found a relatively high prevalence of CVT (9 percent) [8]. However, this is likely an overestimate, as autopsy studies are biased to severe, fatal cases.Cerebral venous thrombosis is more common in women than men, with a female to male ratio of 3:1 [9,10]. The imbalance may be due to the increased risk of CVT associated with pregnancy and puerperium and with oral contraceptives [11]. The female predominance in CVT is found in young adults, but not in children or older adults [6,9]. (See'Etiology'below.)In the prospective International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) cohort of 624 adults with CVT, women comprised 465 (75 percent) [10]. Compared with men, women were significantly younger (mean age 34 years, versus 42 years for men). Furthermore, a gender specific risk factor oral contraceptives, pregnancy, puerperium, and hormone replacement therapy was identified in 65 percent of women. Women also had a better prognosis. (See"Treatment and prognosis of cerebral venous thrombosis", section on 'Prognosis'.)In hospital-based series, CVT is more common in neonates and children than in adults [9,12]. In addition, CVT is more common in neonates than it is in infants and children [6]. In adults, CVT affects patients who are younger on average than those with arterial types of stroke. In the ISCVT, the mean age of patients with CVT was 39 years [9], and only 8 percent of the patients were older than 65 [13].PATHOGENESISThe pathogenesis of CVT remains incompletely understood because of the high variability in the anatomy of the venous system, and the paucity of experiments in animal models of CVT [14]. However, there are at least two different mechanisms that may contribute to the clinical features of CVT (figure 1): Thrombosis of cerebral veins or dural sinus leading to cerebral parenchymal lesions or dysfunction Occlusion of dural sinus resulting in decreased cerebrospinal fluid (CSF) absorption and elevated intracranial pressureObstruction of the venous structures (figure 2) results in increased venous pressure, decreased capillary perfusion pressure, and increased cerebral blood volume. Dilatation of cerebral veins and recruitment of collateral pathways play an important role in the early phases of CVT and may initially compensate for changes in pressure.The increase in venous and capillary pressure leads to blood-brain barrier disruption, causing vasogenic edema, with leakage of blood plasma into the interstitial space. As intravenous pressure continues to increase, mild parenchymal changes, severe cerebral edema, and venous hemorrhage may occur due to venous or capillary rupture. The increased intravenous pressure may lead to an increase in intravascular pressure and a lowering of cerebral perfusion pressure, resulting in decreased cerebral blood flow (CBF) and failure of energy metabolism. In turn, this allows intracellular entry of water from failure of theNa+/K+ATPase pump, and consequent cytotoxic edema [15].Advances in understanding the pathophysiology of venous occlusion have been aided by the use of newer magnetic resonance imaging (MRI) methods, mainly diffusion-weighted MRI (DWI) and perfusion-weighted MRI (PWI) [16-19]. These techniques have demonstrated the coexistence of both cytotoxic and vasogenic edema in patients with CVT [16,18-20].The other effect of venous thrombosis is impairment of CSF absorption. Normally, CSF absorption occurs in the arachnoid granulations, which drain CSF into the superior sagittal sinus. Thrombosis of the dural sinuses leads to increased venous pressure, impaired CSF absorption, and consequently elevated intracranial pressure. Elevated intracranial pressure is more frequent if superior sagittal sinus thrombosis is present, but it may also occur with thrombosis of the jugular or lateral sinus, producing a rise of pressure in the superior sagittal sinus.ETIOLOGYMany causes or predisposing conditions are associated with CVT. The major risk factors for CVT in adults can be grouped as transient or permanent (table 1) [1,9]. The most frequent are: Prothrombotic conditions, either genetic or acquired (table 2) Oral contraceptives Pregnancy and the puerperium Malignancy Infection Head injury and mechanical precipitantsIn more than 85 percent of adult patients, at least one risk factor for CVT can be identified, most often a prothrombotic condition [9]. In the ISCVT cohort, a prothrombotic condition was found in 34 percent of all patients, and a genetic prothrombotic condition was found in 22 percent of all patients [9]. Although infectious causes of CVT were frequently reported in the past, they are responsible for only 6 to 12 percent of cases in modern-era studies of adults with CVT [9,21].As with venous thrombosis in other parts of the body, multiple risk factors may be found in about half of adult patients with CVT [9]. In light of this, a thorough search for additional causes should be carried out even when a specific risk factor is identified in a given patient. (See"Overview of the causes of venous thrombosis".)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 CVT, as some patients may have a condition such as the antiphospholipid syndrome, polycythemia, thrombocythemia, or malignancy that is discovered weeks or months after the acute phase.The risk for CVT is influenced by the individual's genetic background [22]. In the presence of some prothrombotic conditions, patients are at an increased risk of developing a CVT when exposed to a precipitant such a head trauma, lumbar puncture, jugular catheter placement, pregnancy, surgery, infection, and drugs. These prothrombotic conditions include the following: Antithrombindeficiency [21] Protein C deficiency or protein S deficiency [6,23,24] Factor V Leiden mutation [25-27] G20210 A prothrombin gene mutation [26-29]The association of CVT with hyperhomocysteinemia due to gene mutations in methylene tetrahydrofolate reductase (MTHFR) is controversial [22,30,31]The risk factors associated with CVT vary throughout life. In the Canadian pediatric ischemic stroke registry, a risk factor was identified in 98 percent of the children [6]. In neonates, acute systemic illness, such as perinatal complications and dehydration, occurred in 84 percent of patients [6]. (See"Stroke in the newborn", section on 'Cerebral sinovenous thrombosis'.) A prothrombotic state was found in 41 percent of the patients, most often in infants older than four weeks of age and children. In infants older than four weeks of age and in children, head and neck disorders, mostly infections and chronic systemic diseases (eg, connective tissue disease, hematologic disorder, and cancer) were common. In a meta-analysis of case-control studies, with over 200 neonatal and pediatric cases of sinovenous thrombosis (ie, CVT), and 1200 control subjects, the prevalence of factor V Leiden (FVL) mutation among cases and controls was 12.8 and 3.6 percent respectively, and carriers of the FVL mutation were significantly more likely to develop CVT (odds ratio [OR] 3.1, 95% CI 1.8-5.5) [32]. Similarly, the prevalence of the prothrombin gene mutation among cases and controls was 5.2 and 2.5 percent, respective, and carriers were significantly more likely to develop CVT (OR 3.1, 95% CI 1.4-6.8). A 2010 meta-analysis of case-control studies found that the frequency of the MTHFR 677C>T polymorphism in adults was similar for 382 patients with CVT compared with 1217 controls (15.7 versus 14.6 percent; OR 1.12, 95% CI 0.8-1.58), suggesting that the MTHFR 677C>T polymorphism isnota risk factor for CVT [33]. In contrast, a 2011 meta-analysis, after controlling for heterogeneity among studies, found that the MTHFR 677C>T polymorphism was associated with CVT (OR 2.30, 95% CI 1.20-4.42) [22]. The most frequent risk factor in young women is the use of oral contraceptives. Two case-control studies have shown an increased risk of sinus thrombosis in women who use oral contraceptives [26,34]. Furthermore, the risk for CVT in women using oral contraceptives is increased if they have a prothrombotic defect [34]. In elderly CVT patients, the proportion of cases without identified risk factors is higher (37 percent) than it is in adults under age 65. The most common risk factors in those 65 years old are genetic or acquired thrombophilia, malignancy, and hematologic disorders such as polycythemia [13].CLINICAL ASPECTSCerebral vein and dural sinus thrombosis (CVT) has a highly variable clinical presentation [21,35]. The onset can be acute, subacute, or chronic. A case of CVT mimicking a transient ischemic attack has also been reported [36].Symptoms and signsSymptoms and signs of CVT can be grouped in three major syndromes: Isolated intracranial hypertension syndrome (headache with or without vomiting, papilledema, and visual problems) [37] Focal syndrome (focal deficits, seizures, or both) Encephalopathy (multifocal signs, mental status changes, stupor, or coma) [3,21]HeadacheHeadache is the most frequent symptom of CVT. In the ISCVT cohort, headache was present in 89 percent of patients [9]. Headaches associated with CVT are more frequent in women and young patients than in men or older adults. Headache is usually the first symptom of CVT, and can be the only symptom [38], or can precede other symptoms and signs by days or weeks [39].The features of CVT-related headache are quite variable: Head pain is more often localized than diffuse [39]. However, the site of the headache has no relationship with the localization of the occluded sinus or the parenchymal lesions [40,41]. Headache onset is usually gradual, increasing over several days [11]. However, some patients with CVT have sudden explosive onset of severe head pain (ie, thunderclap headache) that mimics subarachnoid hemorrhage [42,43]. (See"Thunderclap headache"and"Clinical manifestations and diagnosis of aneurysmal subarachnoid hemorrhage".) Headache caused by intracranial hypertension from CVT is typically characterized by severe, dull, generalized head pain that worsens with Valsalva maneuvers and with recumbency. Visual obscurations may occur, coinciding with bouts of increased headache intensity. Headache may resemble migraine with aura [44-46]. (See"Pathophysiology, clinical manifestations, and diagnosis of migraine in adults"and"Pathophysiology, clinical features, and diagnosis of migraine in children".)CVT must also be included as a possible cause of persisting headache following lumbar puncture, because lumbar puncture can rarely precipitate a CVT. (See"Post-lumbar puncture headache".)EncephalopathyDisturbances of consciousness and cognitive dysfunction, such as delirium, apathy, a frontal lobe syndrome, multifocal deficits, or seizures, can be present in severe cases of CVT.Focal symptoms and signsMotor weakness with monoparesis or hemiparesis, sometimes bilateral, is the most frequent focal deficit associated with CVT. In the ISCVT cohort, motor weakness was present in 37 percent of patients [9]. Aphasia, in particular of the fluent type, may follow sinus thrombosis, especially when the left lateral sinus is affected. Sensory deficits and visual field defects are less common.SeizuresFocal or generalized seizures, including status epilepticus, are more frequent in CVT than in other stroke types. In the ISCVT cohort of 624 patients, seizures at presentation occurred in 39 percent, and seizures after the diagnosis of CVT occurred in 7 percent [47]. In a retrospective cohort of 70 children (including 25 neonates) with CVT, seizures at presentation occurred in 20 of 45 non-neonates (44 percent) [48].Variables associated with seizures include supratentorial parenchymal brain lesions, sagittal sinus and cortical vein thrombosis, and motor deficits [47].Variables affecting presentation and courseClinical symptoms and signs in CVT depend on several factors: Site and number of occluded sinus and veins. Presence of parenchymal brain lesions Cerebral edema, venous infarction, and hemorrhagic venous infarctions are associated with a more severe syndrome. Patients are more likely to be comatose or to have motor deficits, aphasia, and seizures, and less likely to present with isolated headache. Patient age [6,9,13] In children, signs of diffuse brain injury, coma, and seizures are the main clinical manifestations, especially in neonates. In older children, the manifestations of CVT resemble those in adults, with headache and hemiparesis [12]. Elderly patients also have a distinctive presentation; vigilance and mental problems are more common while headaches and isolated intracranial hypertension are less frequent than in younger patients [13]. Gender Women are more likely than men to have a headache on presentation, and less likely to have a chronic onset of symptoms [10]. Interval from CVT onset to presentation [49] Isolated intracranial hypertension is more frequent in patients with a chronic presentation than in those who present acutely. In addition, patients with chronic course or delayed clinical presentation may show papilledema on funduscopy, a finding that is less frequent in acute cases. (See"Overview and differential diagnosis of papilledema".)Isolated sinus and vein thrombosisIsolated thrombosis of the different sinus and veins produces diverse clinical pictures. In cavernous sinus thrombosis, ocular signs dominate the clinical picture with orbital pain, chemosis, proptosis, and oculomotor palsies. Isolated cortical vein occlusion producesmotor/sensorydeficits and seizures [50-52]. With sagittal sinus occlusion, motor deficits, bilateral deficits, and seizures are frequent, while presentation as an isolated intracranial hypertension syndrome is infrequent. Patients with isolated lateral sinus thrombosis frequently present with isolated headache or isolated intracranial hypertension [53]. Less often, they may also present with focal deficits or seizures. Aphasia often follows if the left transverse sinus is occluded. Jugular vein or lateral sinus thrombosis may present as isolated pulsating tinnitus [54,55]. Multiple cranial nerve palsies may occur in thrombosis of the lateral sinus [56], jugular, or posterior fossa veins thrombosis. When the deep cerebral venous system (ie, the straight sinus and its branches) is occluded, the signs and symptoms of CVT are generally severe, with coma, mental problems, and motor deficits, often bilateral [57-59]. However, more limited thrombosis of the deep venous system can produce relatively mild symptoms [60].NeuroimagingThe neuroimaging features of CVT include findings that suggest the primary underlying pathology of venous thrombosis and associated brain parenchymal lesions [1]. These may include focal areas of edema or venous infarction, hemorrhagic venous infarction, diffuse brain edema, or (rarely) isolated subarachnoid hemorrhage. In patients with CVT, the proportion who present with intracerebral hemorrhage is 30 to 40 percent [61,62].Guidelines from the American HeartAssociation/AmericanStroke Association(AHA/ASA)published in 2011 state that imaging of the cerebral venous system should be performed in patients with lobar intracerebral hemorrhage of otherwise unclear origin or with cerebral infarction that crosses typical arterial boundaries [1]. In addition, the guidelines conclude that imaging of the cerebral venous system should be performed for patients with the clinical features of idiopathic intracranial hypertension, and that imaging of the cerebral venous system is reasonable to exclude CVT in patients with headache associated with atypical features.MRIMRI using gradient echo T2* susceptibility-weighted sequences in combination with MR venography is the most sensitive imaging method for demonstrating the thrombus and the occluded dural sinus or vein (image 1) [20,63-68]. The characteristics of the MRI signal depend on the age of the thrombus [63,69]: In the first five days, the thrombosed sinuses appear isointense on T1-weighted images and hypointense on T2-weighted images Beyond five days, venous thrombus becomes more apparent because signal is increased on both T1 and T2-weighted images After the first month, thrombosed sinuses exhibit a variable pattern of signal, which may appear isointenseOn gradient echo T2*-weighted MRI sequences, the clot can be directly visualized as an area of hypointensity in the affected cortical veinand/orsinus [52,65,70]. However, a chronically thrombosed sinus may still demonstrate low signal on these sequences. Limited data from a series of 28 patients with CVT suggest that the presence of hyperintensities in the veins or sinuses on diffusion-weighted MRI sequences predicts a low recanalization rate [71].Parenchymal brain lesions secondary to venous occlusion, including brain swelling, edema, or venous infarction, appear as hypointense or isointense on T1-weighted MRI, and hyperintense on T2-weighted MRI (image 2). Hemorrhagic venous infarcts appear as hyperintense lesions on both MRI sequences (image 3).MR venographyMR 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 (see'Diagnosis'below) [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.Head CTHead CT is normal in up to 30 percent of CVT cases, and most of the findings are nonspecific [21]. However, CT is often the first investigation to be performed in clinical practice, and it is useful to rule out other acute or subacute cerebral disorders.In about one-third of cases, CT demonstrates direct signs of CVT, which are as follows (image 4) [21,72-74]: The dense triangle sign, seen on noncontrast head CT as a hyperdensity with a triangular or round shape in the posterior part of the superior sagittal sinus caused by the venous thrombus The empty delta sign (also called the empty triangle or negative delta sign), seen on head CT with contrast as a triangular pattern of contrast enhancement surrounding a central region lacking contrast enhancement in the posterior part of the superior sagittal sinus The cord sign, usually seen on head CT with contrast as a curvilinear or linear hyperdensity over the cerebral cortex caused by a thrombosed cortical veinIndirect signs of CVT on head CT are more frequent. These can include intense contrast enhancement of falx and tentorium, dilated transcerebral veins, small ventricles, and parenchyma abnormalities. In addition, associated brain lesions may be depicted in 60 to 80 percent of patients with CVT. These may be hemorrhagic or nonhemorrhagic: Hemorrhagic lesions include intracerebral hemorrhage, hemorrhagic infarcts, or rarely (