Cerebral Venous Thrombosis

Introduction

Cerebral vein and dural sinus thrombosis (CVT) is less frequent than other types of strokes and has a quite different clinical presentation and etiologic investigation. It rarely presents as a stroke syndrome, i.e., as the sudden onset of focal symptoms and signs in a patient with classical vascular risk factors. The clinical features of CVT are rather diverse, hence CVT is more challenging to diagnose than other types of stroke. Once considered a rare, often fatal disease, related to the puerperium and to infections of the central nervous system (CNS), sinuses, and mastoid, CVT is now recognized with increasing frequency. The clinical spectrum of CVT and associated conditions has widened considerably. The apparent rise in the frequency of CVT is related to increasing awareness for its diagnosis among neurologists and emergency physicians and to the use of magnetic resonance (MR) for the investigation of patients with headache, seizures, and unclear neurologic pictures. As CVT can be the initial manifestation or complicate several systemic conditions, CVT is a disease of interest not only for neurologists but also for neurosurgeons; ear, nose, and throat (ENT) specialists; ophthalmologists; internists; rheumatologists; oncologists; hematologists; and obstetricians.

Epidemiology

There are few epidemiologic studies of CVT that meet the current standards for a good quality epidemiologic stroke study, particularly in low-middle income countries, where CVT incidence appears to be higher, probably due to higher pregnancy rates, infections, and nutritional deficits. Older studies probably missed the mild, self-limited forms of CVT and underestimate the true incidence of CVT. A mortality study performed in the UK from 1952 to 1961 reported an average of 22 cases of fatal CVT annually, resulting in a death rate due to CVT of 0.39 per million. In a nationwide hospital-based series in Portugal, including patients admitted to all Neurology services in the country, 91 new cases of CVT were identified, corresponding to an incidence of 0.22/100,000/year. In Isfahan, Iran, the annual frequency of CVT based on hospital admission was 1.23 per 100,000/year. A hospital discharge registry in the USA gave an incidence of CVT during pregnancy of 11.6 per 100,000 deliveries. The incidence in the multicenter Canadian registry of CVT in infants and children aged less than 18 years was 0.67/100,000. In a cross-sectional study in two provinces in the Netherlands, the overall incidence of CVT was 1.32/100,000/year. Among women between the ages of 31 and 50 years, the incidence was 2.78/100,000/year. A retrospective study in Adelaide, Australia, using International Classification of Disease codes for CVT and neuroimaging reports, found an incidence of 1.57/100,000, with a nonsignificant higher relative risk (RR; 1.18) in females of reproductive age. These figures are higher than those of the incidence of bacterial meningitis in adults and indicate that the incidence of CVT among adults is probably higher than previously believed.

In hospital-based series, CVT is more common in children than in adults. Among children, CVT is more common in neonates than in older children. In adults, CVT affects patients younger than those with other types of strokes, and the incidence apparently decreases in older subjects. The median age in the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) cohort was 37 years, with only 8% of the patients older than 65. CVT was more common in females than in males (female:male ratio 2.9:1). A systematic review including 8829 CVT patients, from 74 case series with more than 40 subjects, found an average age of 32.9 years and female:male ratio of 3:2. This review also showed a clear trend in declining frequency of CVT patients presenting with focal deficits or in coma and a decrease in mortality over time. This decline in mortality can be due to better management or a decrease in septic CVT, but is probably mainly due to the identification of less severe cases by MRI. Over time there was also a shift in sex ratio with an increase in the proportion of women affected, possibly associated with an increase in the use of oral contraceptives.

A few studies addressed the chronobiology of CVT, and their results are inconclusive. In Portugal, CVT was more frequent in autumn and winter, raising the hypothesis of upper respiratory infections being the trigger of CVT in prone individuals. However, in Germany, CVT was more frequent in winter and summer. In Iran the seasonal CVT rate was higher in autumn and lower in summer in one study from Isfahan, but higher during high-temperature months in a larger study from Tehran. However, a recent study using Danish registries showed a peak of incidence in winter and fall.

Venous Anatomy

Blood of the brain is drained by the cerebral venous system, which consists of the cerebral veins and dural venous sinuses. Cerebral veins comprise the superficial venous system, deep venous system, and posterior fossa veins. The cerebral venous drainage pattern does not correspond to cerebral arterial territories and is often asymmetric. Brain parenchyma is drained mainly by cortical and medullary veins, which empty either into veins on the cortical surface or into the deep venous system. Superficial cerebral veins course over the surface of the brain, draining the major part of cerebral cortex, with the exception of the inner face of temporal and occipital lobes, and a portion of the subjacent white matter. They are quite variable in number and location. They have no valves and are linked by several anastomoses, allowing the development of collateral circulation in case of vein or sinus occlusion. Ascending superficial veins are named according to the area of cortex they drain. Anastomotic Trolard and Labbé veins connect the sylvian or superficial middle cerebral veins with the superior sagittal sinus and the lateral sinus, respectively.

The deep venous system drains the inferior frontal lobe, most of the deep white matter of cerebral hemispheres, the corpus callosum, the basal ganglia, and the upper brainstem. It includes the internal cerebral and basal veins of Rosenthal that join to form the great cerebral vein of Galen, which drains into the straight sinus. With the exception of the anatomic variations of the basal veins, the deep venous system is relatively constant compared to the superficial cortical venous system. Posterior fossa veins are variable in their number and course, and three groups of veins may be recognized: superior veins draining into the great vein of Galen, anterior veins draining into the petrosal sinus, and posterior veins draining into the torcula, the straight or lateral sinuses.

Cerebral veins drain the blood into the dural sinuses, which are endothelial-lined channels without valves, enclosed in the leaves of the dura mater. There are two groups of dural sinuses: (1) The superior group includes the superior and inferior sagittal sinus, and the straight, transverse, and sigmoid sinuses ( Fig. 45.1 ). Superficial veins run centrifugally, draining the cortex and the subcortical white matter into the superior sagittal and transverse sinuses, and the deep cerebral veins into the straight and transverse sinuses. The confluence of the sinuses (torcula Herophili) results from the junction of superior sagittal, straight, and transverse sinuses and is often asymmetric; (2) The inferior group drains the basal and medial part of the undersurface of the brain, the orbits, and the sphenoparietal sinus, and collects at the cavernous sinus. Cavernous sinuses connect with the lateral sinuses via superior and inferior petrosal sinuses and with the pterygoid plexus.

Most of the cerebral venous blood flows posteriorly, from the superior sagittal sinus or the straight sinus via the lateral sinuses into the internal jugular veins. A smaller proportion flows to the cavernous sinuses.

There are several anatomic variations of the dural sinuses. The most important are atresia of the anterior part of the superior sagittal sinus; duplication of the superior sagittal sinus, mainly in its posterior part; and asymmetry of the transverse sinus with dominance of the right transverse sinus in the majority of cases. Aplasia or hypoplasia of the posteromedial segment of the left transverse sinus. The straight sinus may join the torcula, the right transverse sinus, the left transverse sinus, or both.

Pathophysiology

Studies conducted using experimental models of CVT and technical developments on imaging modalities, such as diffusion- (DWI) and perfusion-weighted (PWI) MR, have improved our knowledge of cerebral venous thrombosis pathophysiology and identified differences between venous and arterial occlusion and infarction. Nevertheless, there are still conflicting results provided by these studies, and ultimately the pathogenesis of parenchymal lesion due to venous occlusion remains insufficiently understood.

There are at least two different mechanisms that may contribute to the clinical features of CVT: (1) increase of venous and capillary pressure due to the thrombosis of cerebral veins or dural sinus, which may lead to subsequent cerebral lesions, and (2) cerebrospinal fluid (CSF) absorption disturbance due to the occlusion of dural sinuses, resulting in an increase of intracranial pressure (ICP) and hydrocephalus.

Venous or dural sinus occlusion may lead to different consequences in the brain, from no detectable lesions to venous infarction or hemorrhage. Although the understanding of the hemodynamic changes underlying the clinical and brain tissue manifestations of CVT remains incomplete, it is known that thrombosis of cerebral veins and dural sinus causes an obstruction of the drainage from brain tissue, forcing blood back into small venules and capillaries. At an early stage, the collateral pathways of venous drainage allow for significant compensation, and parenchymal lesions may not develop. However, when the collateral circulation through venous anastomoses is no longer able to compensate, venous and capillary pressure will increase and lead to dilatation of veins and capillaries and blood-brain barrier disruption, with leakage of blood plasma into the interstitial space, resulting in vasogenic edema. This pattern is often confirmed by DWI MR imaging, which may show increased ADC values compared to unaffected regions. ^{, ,} A pattern with increase in relative cerebral blood volume (rCBV) and mean transit time (MTT), with preserved relative cerebral blood flow (rCBF), has also been shown in brain lesions of patients with CVT. ^21,30. However, elevation of intravenous pressure may also result in lowering of cerebral perfusion pressure, leading to decreased CBF and failure of energy metabolism with consequent cytotoxic edema. ^{, , ,}

Experimental animal data suggest that vasogenic edema occurs earlier in venous than in arterial stroke. At this stage, if collateral pathways are efficacious or recanalization occurs, tissue perfusion may be possible, and swollen brain cells are potentially recoverable. Finally, further increase of intravenous pressure may also lead to venous or capillary rupture causing brain hemorrhage. Likewise, several of these pathophysiologic processes have been documented in cohorts of patients with CVT. The severity of the brain parenchymal changes was associated with increased venous sinus pressure measurements in a retrospective study of patients evaluated with conventional angiography. Venous occlusion involving collecting veins is associated with a higher risk of brain parenchymal lesion compared with sinus thrombosis, which is also in accordance with findings from animal models. ^, Still, there is a significant association between the extension of thrombosis and the development of brain lesions. Prior studies failed to show an association between the extent of baseline intracranial venous collaterals and the clinical severity or prognosis in patients with CVT. In summary, the pathogenesis of venous lesions is very different from that of arterial infarcts. Based on observation, increased reversibility is another distinctive feature of venous lesions.

As previously summarized, dural sinus thrombosis may also impair CSF circulation, further contributing to increased intracranial hypertension. CSF absorption mainly occurs in the arachnoid villi and granulations (Pacchionian bodies) contained in the superior sagittal sinus and other sinuses. Increased venous pressure due to sinus thrombosis with lead to impaired CSF absorption and consequently increased ICP. This is more frequent with superior sagittal sinus occlusion, but it may also result from rise in sinus pressure without thrombosis of the superior sagittal sinus, such as in lateral sinus or jugular vein thrombosis.

Etiology

A large number of conditions have been reported as causes, risk factors, or predisposing and precipitant conditions to CVT. These conditions can be classified as predisposing or permanent (e.g., genetic prothrombotic diseases, antiphospholipid syndrome, cancer) or precipitant or transient (e.g., oral contraceptives, infections, drugs with prothrombotic action), depending on the duration of the exposure ( Box 45.1 ). Most of these associated conditions cannot be named risk factors or causes of CVT because they do not fulfill the causality principles. Associations were described mostly in case reports or case series, and only a few were investigated in case-control studies. In more than 85% of patients, at least one associated condition can be identified, and multiple associated conditions are found in about half of patients.

The more frequent risk factors are prothrombotic conditions, either genetic or acquired, oral contraceptives, puerperium or pregnancy, infection, and malignancy. The genetic background most likely determines the inherent individual risk of venous thrombosis. In the presence of some identified prothrombotic conditions patients are at increased risk of developing a CVT when exposed to CVT precipitants. Thrombophilic disorders are leading risk factors of CVT ( Box 45.2 ). In the ISCVT cohort, a prothrombotic condition was identified in 34% of the patients and was genetically determined in 22% of the patients. The most frequent are G20210A prothrombin mutation, identified in 6%–20% of patients, factor V Leiden, found in 10%–24% of CVT patients, and antiphospholipid syndrome (6%–8%). ^, Less often, protein C, S, or antithrombin III deficiencies are identified (0%–9% of patients). Two systematic reviews confirmed the increased risk of CVT in patients with G20210A prothrombin mutation (odds ratio [OR] 5.5), factor V Leiden (OR 2.5), protein C (OR 10.7), S (OR 5.7), and antithrombin III (OR 3.8) deficiencies, antiphospholipid syndrome and hyperhomocysteinemia (OR 3.1). ^, There are insufficient data to support the independent contribution of MTHFR mutation as a risk factor for CVT. Elevated factor VIII is also a risk factor for CVT.

Infective causes have declined and are responsible for 6%–12% in large series of adults with CVT. ^, In low-income countries, systemic and nervous system infections remain an important cause of CVT (18%). Although uncommon, cavernous sinus thrombosis is predominantly caused by facial infections of the face and oropharynx.

Cancer accounts for 7.4% of all CVT. Of these, 2.2% were associated with CNS malignancy, 3.2% with solid tumors outside the CNS, and 2.9% with hematologic disorders. Sinus or venous thrombosis can result from local compression or invasion by the tumor; can be caused by a hypercoagulable state; or less commonly are associated with local or systemic infections, are therapy-related, or are paraneoplastic. Many of the reported precipitants of CVT are systemic diseases or conditions known to predispose to venous thrombosis in other parts of the body, but others are peculiar to CVT. Among the latter are local causes such as brain tumors or arteriovenous malformations, major or minor head trauma, spontaneous intracranial hypotension, and some invasive procedures (e.g., neurosurgery, jugular catheter, radiation, and lumbar puncture with or without drugs infusion) (see Box 45.1 ).

The risk of CVT varies throughout life. In the Canadian Pediatric Ischemic Stroke Study Group, a risk factor was identified in 98% of the children. In neonates, acute systemic illness such as perinatal complications and dehydration were frequent, occurring in 84% of patients. Head and neck disorders, mostly infections, and chronic systemic diseases (e.g., connective-tissue disease, hematologic disorder, and cancer) were common in older children. A prothrombotic state was found in 41% of the patients, most often in non-neonates.

The most frequent risk factor in young women is oral contraceptive use. Two case-control studies have shown an increased risk of sinus thrombosis in women who use oral contraceptives. ^, The meta-analysis by Dentali et al. pointed out the risk of women taking oral contraceptives being almost six times higher compared with nonusers (OR 5.59; 95% confidence interval [CI], 3.95–7.91). The risk for women using oral contraceptives and carrying a prothrombotic defect is increased compared with women without such risk factors. Another frequent setting related to CVT in women is pregnancy and puerperium, ^{, ,} more common in less-developed world regions with higher pregnancy rates. In Western countries the risk is higher during the first 6 weeks postpartum. CVT was also diagnosed associated with the rare ovarian hyperstimulation syndrome resulting from in vitro fertilization. Obesity is an emerging risk factor for CVT in women (OR 2.63). In women who use oral contraceptives, overweight and obesity are associated with an increased risk of CVT in a dose-dependent manner.

In the ISCVT study, genetic or acquired thrombophilia, malignancies, and hematologic disorders such as polycythemia were the most common risk factors in elderly patients. In 37% of elderly patients no risk factors could be identified.

In almost 13% of adult CVT patients no underlying risk factor is found, despite extensive search. At times, the cause is revealed weeks or months after the acute phase. Therefore, in CVT cases without known cause it is recommended to follow up the patients and to continue searching for a cause (antiphospholipid syndrome, myeloproliferative syndromes, cancer).

Clinical Aspects

The clinical presentation of CVT is highly variable. In more than half of the patients the onset is subacute, with symptoms increasing in intensity and severity over several days. In about 1/3 of the patients the onset is acute, with the full clinical picture established within 24 hours, but onset is rarely apoplectic. A few cases have a protracted, chronic presentation. Symptoms and signs can be grouped in three more frequent syndromes: (1) isolated intracranial hypertension syndrome, consisting of headache with or without vomiting, papilledema, and visual disorders, including isolated headache; (2) focal syndrome, including focal deficits, seizures, or both; and (3) encephalopathy, when bilateral or multifocal signs, delirium, or dysexecutive or consciousness disturbances occur. ^, Less frequent presentation syndromes include the (4) cavernous sinus syndrome, consisting of orbital pain, oculomotor palsies, proptosis, and chemosis, (5) syndromes of multiple palsies of the lower cranial nerves, and (6) subarachnoid hemorrhage, either generalized or localized at a single or few cortical sulci of the hemispheric convexity or even to the perimesencephalic cisterns. However, subarachnoid hemorrhage in the absence of venous infarct is reported as rare.

Seizures can be focal or described as generalized from onset, and may evolve to status epilepticus. Acute symptomatic seizures occur more often in CVT patients with supratentorial lesions, especially if hemorrhagic, in those with motor and sensory deficits, and in patients with thrombosis of the superior sagittal sinus or cortical veins. CVT patients can also present as status epilepticus, or status epilepticus may develop in patients with severe forms of CVT with supratentorial lesions, especially if multiple and hemorrhagic. Status may be refractory in about 1/6 of the patients, with refractoriness being related to the pretreatment duration of status.

Some patients have a severe presentation with decreased consciousness, altered mental status, bilateral or multifocal signs, and/or seizures or status epilepticus. They usually have multiple sinus occlusions, in particular combining the superior sagittal sinus and the deep cerebral vein system and show bilateral parenchymal lesions, diffuse brain edema, or a large herniating lesion. Intense care is often needed in these cases.

Several factors have been associated with clinical presentation, including (1) gender, (2) age, ^, (3) interval from onset to presentation, ^, (4) presence of parenchymal lesions, (5) site and number of occluded sinus and veins, and (6) the underlying disease, if any. As in the general population, headaches are more frequent in women than in men with CVT.

Concerning pediatric CVT, symptoms are also different in neonates when compared to older children. In neonates, presentation is often nonspecific, with seizures in more than ½ of the babies, respiratory distress syndrome or apnea, poor feeding, lethargy, and hypo or hypertonia. Diffuse signs of brain damage, with coma and seizures, are also the main manifestations in younger children. Clinical manifestations in older children featuring headache with or without vomiting, papilledema, VI nerve palsy, motor deficits, focal or generalized seizures, and disturbances of consciousness are more similar to the adult presentation. ^,

When compared to younger adults, the most common pattern of clinical presentation is also distinct in elderly patients, in which encephalopathy is more frequent while headache is less often reported. ^{, ,}

The clinical picture is also associated with the time elapsed from onset to presentation. Patients with more severe clinical features such as disturbance of consciousness or mental status, seizures, or motor deficits tend to present earlier. On the other hand, isolated intracranial hypertension and papilledema are more frequent in patients with a chronic presentation. As expected, if the admission neuroimaging shows either a hemorrhage or a venous infarct, the clinical picture is more severe. Coma and consciousness disturbances, paresis, aphasia, and seizures are more common in these patients than in subjects without brain lesions. Conversely, patients with brain lesions are less likely to present with isolated headache.

Up to 90% of CVT patients complain of headache, which is the most frequent symptom of CVT and usually the initial one. In 9% of ISCVT patients, headache was the only symptom of CVT. As for other secondary headaches, headaches associated with CVT are more frequent in women and young patients. The localization of the headaches has no relationship with the site of venous occlusions or of the parenchymal lesions. ^, CVT-associated headaches are more severe and of more acute onset than other types of headaches requiring emergency care, with the exception of subarachnoid hemorrhage. Headache is more frequently localized and continuous, with an acute-subacute onset of pain and moderate to severe intensity. The most frequent type of headache is the intracranial hypertension type, a severe, generalized headache worsening with Valsalva maneuvers and when lying down. Transient loss of vision can occur in association with spells of more intense headache. In CVT manifesting only as headache, the onset of headache is usually progressive, and the pain is continuous. Headache is more often unilateral and ipsilateral to the occluded lateral sinus than diffuse. A few cases of CVT presenting with sudden, explosive headache and neck stiffness, ^, mimicking subarachnoid hemorrhage, have been reported. In a minority of those patients the CSF is bloody, but in the majority the headache meets the criteria of thunderclap headache. Migraine with aura has also been reported. Some of the conditions and precipitants associated with CVT also manifest with headache, thus increasing the challenge of the diagnosis of CVT complicating these conditions. This is the case of meningitis, meningiomas, dural arteriovenous fistulae, Behcet disease, other vasculitides, and also low ICP. CVT must also be included as a possible cause of persisting headache following lumbar puncture, in particular if the pattern of headache changes, losing its characteristic postural relief when lying down.

Some patients may complain of visual loss (13%) or show papilledema on fundoscopy (28%), a finding more frequent in chronic cases. Severe acute cases present disturbances of consciousness ranging from drowsiness to coma (14%) or mental troubles (22%), such as delirium, apathy, or a dysexecutive syndrome. Unilateral or less frequently bilateral motor deficits, in the form of mono- or hemiparesis, are the most frequent focal deficits (37%). Aphasia can also occur (19%). Fluent aphasia is often a manifestation of left lateral sinus with a posterior temporal lobe lesion. Sensory deficits (5%) and visual field defects are less common. Seizures are more frequent than in other stroke types. They can be focal (20%) or generalized (30%), and be complicated by status epilepticus, which can rarely occur from the onset. Seizures are more frequent in patients with brain lesions, motor or sensory deficits, and in sagittal sinus and cortical vein thrombosis. ^, Cerebellar signs are rare but can be found in posterior fossa CVT with cerebellar venous infarct or haemorrhage.

The clinical presentation of CVT also varies according to the location of the occluded sinus or vein. In cavernous sinus thrombosis, which is rare nowadays and usually has an infectious cause, ocular signs dominate the clinical picture with headache, orbital pain, chemosis, proptosis, ptosis, diplopia, and oculomotor palsies. Isolated cortical vein thrombosis is probably under-identified, and its diagnosis is difficult to confirm. Using traditional MR sequences and MR angio, the interobserver agreement for the diagnosis of cortical vein thrombosis is low. The diagnostic accuracy is much improved by the use of paramagnetic-sensitive sequences. Typically, cortical vein thrombosis produces headache, motor and/or sensory deficits, or seizures without papilledema. In the occlusion of the sagittal sinus motor deficits (46%), focal (35%) and generalized (47%) seizures are frequent while presentation as an isolated intracranial hypertension syndrome (17%) is infrequent. Bilateral motor deficits are not uncommon (7%). The opposite is found in patients with isolated thrombosis of the lateral sinus, who often present with isolated intracranial hypertension (31%–47%) but rarely have paresis (11%–15%) and focal (9%–12%) or generalized seizures (20%–24%). Aphasia is frequent in left transverse sinus occlusion (40%). Multiple cranial nerve palsies (Collet-Sicard syndrome) are a rare manifestation of lateral sinus, jugular, or posterior fossa veins thrombosis. A pulsating tinnitus may be the sole symptom of a jugular vein or lateral sinus thrombosis. ^, When the deep cerebral venous system is occluded, the clinical picture is often severe with coma (67%), mental deficits (87%), and paresis (56%) that can be bilateral (11%). Still, limited thrombosis of the deep venous system can produce relatively mild symptoms without disturbances of consciousness.

Diagnosis

Whenever CVT is suspected, urgent neuroimaging is required. The confirmation of the diagnosis of CVT depends on the demonstration of thrombi in the cerebral veins and/or sinuses by neuroimaging. The European guidelines recommend either computed tomographic (CT) venography or MRI with MR venography as reliable alternatives to digital subtraction angiography in the diagnosis of CVT.