CEREBRAL VENOUS THROMBOSIS

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CHAPTER 46 CEREBRAL VENOUS THROMBOSIS

Gian Luigi Lenzi, Alessio Mercurio, Marta Altieri

Cerebral vein and sinus thrombosis (CVST) is a rare event in comparison with arterial stroke, accounting for less than 1% of all strokes. CVST occurs in all age groups, peaking in incidence among neonates and young adults. Clinical diagnosis is difficult, because of the wide spectrum of clinical symptoms of CVST. The achievements of neuroimaging since the 1970s have been fundamental for diagnosing and treating CVST and for a better understanding of its pathogenesis. Early diagnosis of CVST is crucial, because therapy, based mainly on anticoagulation, reduces the risk of fatal outcome and severe disability.1,2

ANATOMY OF THE INTRACRANIAL VENOUS SYSTEM

Cortical Cerebral Veins

These veins drain blood from the superficial part of the brain (cortex and the adjacent white matter) and are composed of three systems:

1. The dorsomedial system drains into the superior sagittal sinus (SSS) and the inferior sagittal sinus (ISS), receiving blood from the convexity and the midline of the brain.
2. The posteroinferior system drains into the lateral sinus, receiving blood from the temporo-occipital areas.
3. The anterior system drains into the cavernous or the pterygoid venous plexus through sylvian veins, receiving blood from the frontal pole, the inferior part of the frontal lobe, and the anterior part of the temporal lobe.

These systems show variations among the population: Any of the three major components may be missing or hypoplastic. In these cases, the other components are hypertrophic. Cortical veins are connected to the dural sinuses by the so-called bridging veins.

Deep Cerebral Veins

These veins drain the deepest parts of the white matter, the basal ganglia, and the diencephalon. The septal and thalamostriate veins, called the subependymal veins, are the most important and drain into the internal cerebral vein.

1. The septal veins receive blood from the genu of the corpus callosum, from the septum pellucidum, and from the anterior part of the caudate nucleus, and they drain into the thalamostriate veins.
2. The thalamostriate veins receive blood from the basal ganglia and from the internal and external capsules; they pass through the roof of the third ventricle, cross in the interventricular foramen of Monro, and end in the internal cerebral veins.
3. The posterior choroidal veins drain blood from the pineal gland and from the choroid plexus of the lateral ventricles and end in the thalamostriate veins.
4. The internal cerebral veins run parallel beneath the choroidal vein of the third ventricle to join their counterpart and form the vein of Galen.
5. The vein of Galen, unique and median, runs from the posterior part of the diencephalon up to the straight sinus, between the cerebellum and the splenium of the corpus callosum; early in its course, it receives the paired basal veins of Rosenthal.
6. The basal veins of Rosenthal drain the bottom parts of the basal ganglia; the bottom parts of the temporal, frontal, and occipital lobes; and the medial parts of the insula and the temporal lobe. These veins originate in correspondence to the anterior perforated substance near the confluence of two vessels—the anterior limbic vein and the deep middle cerebral vein (or insular vein)—and then they “tie” into a bow around the mesencephalon before ending in the vein of Galen. Sometimes they receive the posterior limbic veins, the hippocampal veins, and the middle superior cerebellar veins.
7. The anterior limbic veins drain the cingulate circumvolution. In correspondence with the genu and the rostrum of the corpus callosum, they bend to reach the basis of the brain, in order to join the deep middle cerebral vein on the same side and to form the homolateral basal vein of Rosenthal.

Posterior Fossa Veins

The venous drainage of the posterior fossa is highly variable. Four main systems can be outlined:

1. The posterosuperior system drains the dorsal cerebellum, vermis, and the upper portion of the brainstem into the vein of Galen. The most important vessels of this group are the superior cerebellar hemispheric veins and the superior vermian veins.
2. The anteromedial system is formed by the anterior pontomesencephalic vein, which drains into the basal vein of Rosenthal on both sides.
3. The anterolateral system is formed by the petrosal veins, which drain the ventral cerebellum and the upper part of the brainstem, and by the choroidal vein of the fourth ventricle, which drains the lower part of the brainstem.
4. The posteroinferior system is formed by the inferior cerebellar hemispheric veins, which are tributaries of the transverse sinus, and by the bilateral posterior spinal vein, which ends in the inferior retrotonsillar vein; this vein and the superior retrotonsillar vein form the inferior vermian vein. This vessel is finally a tributary of the ISS.

Dural Sinuses

The dural sinuses are situated between the leaves of the falx and the tentorium and are triangular in section. They drain blood from the cortex, the meninges, and the scalp (through the calvarian veins) and deliver it to the internal jugular veins. They are connected with the extracranial veins in the scalp by the emissary veins. This may explain dural involvement after cutaneous contusions or infections (Fig. 46-1).

1. The SSS begins at the foramen cecum, before the crista galli, and runs along the curve of the inner table of the skull to reach the torcular Herophili, where it converges with the straight sinus. Their combined flows drain into the transverse sinus. The SSS receives blood from frontal, parietal, and occipital superior regions of the cortex. The SSS, and other sinuses, contains the arachnoid villi and granulations in which the absorption of cerebrospinal fluid takes place. There is a direct dependency of cerebrospinal fluid pressure on the intracranial venous pressure, which explains the frequent increase in intracranial pressure in CVST. The dura mater adjacent to the sinus contains important venous plexuses, which represent a potential alternative drainage route when a sinus is occluded; this explains the “empty-delta” sign, which is visible on computed tomographic (CT) scan in occlusion of the SSS.
2. The straight sinus is formed by the junction of the tentorium, falx cerebri, and falx cerebelli and receives blood from the vein of Galen and from the ISS. It ends in the torcular Herophili or in the left transverse sinus.
3. The ISS runs parallel to the SSS in correspondence to the free margin of the cerebral falx, receiving blood from the middle regions of the brain that drains into the SSS through the venous vessels of the cerebral falx.
4. The lateral sinus connects the torcular Herophili with the internal jugular veins on both sides and is formed by two components: the transverse sinus, which lies in the peripheral margin of the tentorium cerebelli, and the sigmoid sinus. The transverse sinuses are frequently of unequal size; the left one, which receives blood from the SSS, is usually larger. Atresia or agenesis of the transverse sinus is related to alternative filling of the sigmoid sinus by the vein of Labbé. The sigmoid sinus starts at the end of the transverse sinus and reaches the jugular vein; agenesis and atresia of this sinus are very uncommon.
5. The cavernous sinuses are situated on the sphenoid bone, laterally to the sella turcica. Their walls contain the cranial nerves III, IV, V2, and V3 of both sides, whereas the cranial nerve V1, the intracavernous tract of the internal carotid artery, and the pericarotid sympathetic plexus are contained in their lumen. They drain the ophthalmic veins, the anterior and middle cranial fossa, and the sphenoparietal sinus (the medial extension of the superficial sylvian vein). Blood drains posterolaterally along petrosal sinuses to the lateral sinus and the jugular vein through the inferior petrosal sinus. The two cavernous sinuses are connected by the intracavernous sinus, which lies on the clivus behind the sella turcica: this strict anatomical connection explains their frequent simultaneous involvement (Fig. 46-2).
6. The petrosal sinuses are four in number, two for each side (superior and inferior). The first one is the anterior continuation of the transverse sinus and corresponds to the oblique insertion of the tentorium on the rocca petrosa, ending in the cavernous sinuses. The second begins at the inferior part of the intercavernous sinus to end, together with the sigmoid sinus, in the jugular vein.
7. The occipital sinus is located at the insertion of the falx cerebelli on the occipital bone, and it drains blood from the dorsal regions of the cerebellum vermis.
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Figure 46-1 A, Anatomy of the deep venous circulation of the brain. B, Anatomy of the superior sagittal sinus. C, Anatomy of the lateral sinus (divided into its components: transverse sinus and sigmoid sinus) and the straight sinus.

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Figure 46-2 Anatomy of the cavernous sinus.

Venous Anastomoses

The intracranial venous system has no valves and therefore allows reversals of the blood flow direction, following pressure gradients. The most important vessels of this system are (1) the great anastomotic vein of Trolard that runs from the sylvian fissure to the SSS, thus forming an anastomosis between the SSS and the petrosal sinuses, and (2) the little anastomotic vein of Labbé, which connects the superficial sylvian vein with the transverse sinus or connects the SSS with the transverse sinus (depending on interindividual variability). There are also other, less important links, such as those between the little cortical veins and the adjacent sinuses or those between the basal vein of Rosenthal and the cortical veins. Transcerebral veins are virtual vessels that, when necessary, connect superficial and deep veins, crossing the cerebral parenchyma. The dural sinuses also communicate with the meningeal, diploic, and calvarian veins through the emissary veins.1–5

EPIDEMIOLOGY

CVST may manifest with such a wide spectrum of clinical signs and symptoms that it goes unrecognized in quite a few patients. It follows that epidemiological studies are difficult to perform. On the basis of retrospective trials, CVST accounts for about 0.1% to 9% (mean, about 1%) of all deaths for stroke, with great geographic and ethnic variabilities.1,2,6–8 In industrialized countries, the incidence of CVST is estimated between 1.5 and 2.5 cases per 100,000 per year.6 Although these numbers, based on CT scan or magnetic resonance imaging (MRI) findings, are remarkably higher than those observed before the neuroimaging era, they still account for only patients who present with the more severe consequences of CVST: namely, hemorrhagic or ischemic venous strokes. As the frequency of venous stroke ranges from 30% to 80% of all cases, the prevalence of patients who develop symptoms related to intracranial hypertension might be considerably higher.6,9–12

In a multicenter prospective observational study, 624 patients with CVST were enrolled. Female gender was prevalent (74.5%); the mean age was 39 years. Patients were predominantly white (79.2% versus 9.3% Hispanic, 5% black, 3.4% Asian, and 3.1% other races). Ischemic venous infarction was present in 46.5% patients, and hemorrhagic lesions were detected in 39.3% patients. Ischemic and hemorrhagic infarcts coexisted in some patients; the cumulative rate of parenchymal lesions at neuroimaging was 62.9%. The SSS was the most frequently involved (62%), followed by the left lateral sinus (44.7%), the right transverse sinus (41.2%), the straight sinus (18%), the choroidal vein (17.1%), and the jugular veins (11.9%). The deep venous system was involved in 10.9% of patients, and the cavernous sinuses in 1.3%. A posterior fossa vein thrombosis was reported in only 0.3%.13

In one study, researchers have investigated the distribution of risk factors and clinical features of CVST among white and African-Brazilian patients. The female/male ratio was higher among the African-Brazilian patients than among the white patients (4.75 versus 1.36), whereas the mean ages were similar. African-Brazilian patients had higher rates of focal deficits (60.8% versus 46.1%) and decreased consciousness (47.8% versus 27%); however, these differences were not significant.7

A high incidence of CVST in young women, especially during pregnancy and the puerperium, has been reported in several studies.6,11,12 As a matter of fact, estimates of CVST associated with pregnancy and the puerperium range from 2 to 60 per 100,000 deliveries in western Europe and North America and from 200 to 500 per 100,000 in India.1,2 The use of oral contraceptives appears to be a risk factor for CVST.1,2,6,10–13

PATHOPHYSIOLOGY

The causal factors leading to CVST are essentially four: (1) prothrombotic state; (2) venous stasis; (3) direct involvement of the venous wall; and (4) abnormal blood viscosity.14 Symptoms of sinovenous occlusion may arise directly from the primary or underlying process, venous obstruction, vascular inflammation, or secondary complications. Venous obstruction causes a rise of venous and parenchymal pressure in its competence territory, which leads to venous distension and edema. Many of the clinical consequences of CVST arise from brain swelling and increased intracranial pressure caused both by venous engorgement and by decreased cerebrospinal fluid absorption secondary to venous hypertension. Furthermore, in the majority of cases, thrombosis involves multiple dural sinuses or both sinuses and veins.1,2,13,15

Experimental studies have contributed to a better definition of the pathological features of CVST. A subacute occlusion of SSS provokes clinical manifestations only when the occlusion spreads to cortical or bridging veins.16–20 SSS occlusion is usually associated with brain swelling, an increase in intracranial pressure, and diffuse cellular damage.16–21 On the other hand, occlusion of bridging and cortical veins produces a localized well-shaped venous infarction, with both ischemic and hemorrhagic features, surrounded by brain swelling and edema.19–23 In cats, the ligature of SSS provokes a stroke only when located after the confluence between this sinus and the rolandic vein, because the anterior third of the sinus is well compensated by collateral vessels. What is remarkable is that ischemic/hemorrhagic lesions are absent at 2 hours but present at 24 hours; this demonstrates that the acute occlusion of a dural sinus, at least in experimental conditions, is related not to an acute infarction but only to a subacute one.19 This observation could also apply to humans, inasmuch as the majority of patients with dural sinus involvement exhibit a subacute onset of the CVST signs and symptoms. Also remarkable is that neither the site nor the extent of a sinus occlusion is indicative of the final site and size of the corresponding ischemic lesion. On the contrary: The thrombosis of a cortical vein produces a definite area of infarction in the gray and superficial white matter. As a consequence, patients with cortical and deep vein thrombosis show the worst clinical outcome,22 because the deep vein thrombosis produces a widespread lesion that involves the thalamus, the deep white matter, and the upper parts of the brainstem.1,2,24

DIAGNOSIS AND CLINICAL FEATURES

CVSTs manifest with a wide spectrum of signs and symptoms; therefore, the differential diagnosis should account for a number of possible conditions. The variability of clinical features of CVST is high in relation to the site and extent of thrombosis, the rate of propagation of the occlusion, the age of the patient, and the underlying pathology. Spinal cord venous involvement in these thrombotic processes is also possible, but it is very rare and related mostly to the propagation of an infectious thrombophlebitis of the pelvic veins.

Headache is the most frequent presenting symptom and the most common complaint (75% of cases).1,2,12,25 The headache is usually diffuse and progressive, with no typical clinical characteristics or temporal profile. In the 2004 International Classification of Headache Syndromes, headache associated with CVST is classified as follows: (1) any new headache, with or without neurological signs, that fulfills the second and third criteria; (2) headache with neuroimaging evidence of CVST; (3) headache (and neurological signs, if present) that develops in close temporal relation to CVST.26

Despite its polymorphism, the most frequent clinical features of CVST can be grouped into three syndromes, according to their physiopathology: (1) intracranial hypertension syndrome (IHS); (2) stroke-related syndrome; and (3) encephalopathic syndrome.

Intracranial Hypertension Syndrome

Headache is the most common clinical symptom of IHS, reported in 75% to 95% of patients.6 It represents the inaugural symptom in 70% to 75% of cases and is often the unique clinical manifestation of IHS.6–27 The headache may be any grade of severity, diffuse or localized, and persistent or intermittent. The onset is usually subacute (2 to 30 days) but can also be acute (>2 days) or chronic (>30 days).1,2 Attacks may mimic migraine or may be interpreted as a subarachnoid hemorrhage manifesting as a thunderclap-type headache, with instantaneous onset and coming on very quickly.27 Papilledema is observed in about 50% of affected patients.11 Only 20% to 40% of patients have the complete syndrome of isolated IHS with headache, nausea, vomiting, papilledema, transient visual obscurations, and eventually cranial nerve VI palsy. The involvement of other cranial nerves is very rare.6 IHS resulting from CVST should be differentiated by the idiopathic intracranial hypertension or pseudotumor cerebri, with a complete neuroradiological workup. IHS is more frequently caused by the occlusion of the dural sinuses, particularly the SSS.1,2,27

Stroke-Related Syndrome

This syndrome is typically related to the occurrence of a venous infarction that can be both ischemic and hemorrhagic. In the majority of cases, the pattern is represented by multiple small intraparenchymal hemorrhages, surrounded either by normal parenchyma or by ischemic areas. Its clinical features are ill-defined and differ from those of an arterial stroke, which is more sharply outlined and wedge-shaped. The abundance of collateral vessels and anastomosis of the venous circulation, in comparison with the arterial circulation, is responsible for the lack of topographic localization of the lesions. Focal neurological signs (sensory and motor deficits, speech disturbances, hemianopia) are present in 40% to 60% of all cases.6 Headache, vomiting, and ataxia with acute onset are the most frequent symptoms in patients with cerebellar vein thrombosis, which is always associated with a concomitant effect on the lateral sagittal sinus and SSS.6

Encephalopathic Syndrome

This condition is the least frequent manifestation of CVST but also the most severe. It is typically related to the involvement of the deep venous system, with diffuse damage of the white matter, basal ganglia, thalamus, and mesencephalon. Parenchymal damage may be related to necrosis, hemorrhages, and brain swelling.1,2,28 The clinical syndrome is characterized by generalized seizures, psychiatric disturbances, confusion, and variable levels of consciousness, disorders of which range from stupor to coma.1,2,6,10,11,25 Major cognitive impairments are reported in only 15% to 19% of cases.6

Focal or generalized seizures are present in more than 40% of patients with CVST2 and may occur in every related clinical syndrome. During the puerperium, the incidence is even higher (76%).6,12 Among the focal forms, the jacksonian type is the most common and is characteristically associated with Todd’s postconvulsive paresis, which is rare in idiopathic epilepsy.6,12,29 Nonetheless, only a few cases progress to epilepsy.29

Cavernous sinus thrombosis provokes a peculiar neurological syndrome characterized by any combination of unilateral chemosis, proptosis, and eyelid edema (caused by inadequate ocular venous drainage from the ophthalmic vein), with diplopia resulting from the involvement of the oculomotor nerves. Myosis and ptosis may also be present as a result of involvement of the third cranial nerve, as may mydriasis, caused by the involvement of the pericarotic sympathetic plexus. Retro-orbital and/or frontotemporal pain and anesthesia in the territories of the first and second branches of the trigeminus may also be present, constituting the so-called painful ophthalmoplegia. In the case of slow occlusion of the sinus, the only clinical manifestation may be limited to the sixth nerve palsy accompanied with pain. The thrombosis may extend to the contralateral sinuses. The differential diagnosis should take into consideration other causes of painful ophthalmoplegia such as the Tolosa-Hunt syndrome, which is an idiopathic granulomatous inflammation of the dural wall of the cavernous sinuses; giant cells arteritis; sarcoidosis; local or general neoplasm; pseudotumor orbitae; and infectious thrombophlebitis caused by the propagation of a septic process from the face or neck into the cavernous sinuses.30

DIAGNOSTIC METHODS

Venous angiography was the first instrumental technique used to diagnose CVST. Today, its clinical use is limited to dubious cases because of its excellent sensitivity. Angiography shows venous thrombosis as an interruption of flow that may be differentiated by sinus aplasia by the presence of a tortuous collateral circulation, consisting of “corkscrew vessels.”1,2 These vessels cannot be visualized by any other technique, and thus angiography remains the most important diagnostic tool in these cases.31

CT scan is usually the first investigation performed in the emergency department6; thus, it plays an important role in differential diagnosis, allowing the clinician to rule out disorders that may mimic CVST, such as tumors, encephalitis, brain abscesses, and subarachnoid hemorrhage.32 However, CT scans may be normal in 25% to 30% of patients.6

On CT scan, CVST may show direct and indirect signs. Direct signs are as follows:

1. The empty delta sign is the most frequent direct sign of CVST, being detected in 25% to 30% of patients with CSVT.6 Visible only after injection of contrast material, it appears as a hypodense area, because of the presence of a clot in the torcular Herophili, surrounded by a hyperdense triangular (delta-shaped) image, because of the enhancement of collateral vessels developed in the context of the dural wall.1,2,6,10,11,33 False-positive findings may result from early division, septa, or duplications of SSS.6,10
2. The cord sign is a focus of increased density, resulting from the presence of fresh thrombus, on the vessel parallel to the scanning plane. Its specificity is low.
3. The triangle sign is a fresh thrombus localized in the posterior part of SSS and may be visualized as a hyperdense triangle in the coronal slices without contrast. A hyperdensity may also be visible in other sinuses when they are involved in the thrombotic process.

Indirect signs, more frequent than the direct ones, are not specific but may be suggestive of a CVST:

1. Local or generalized brain swelling, as indicated by the presence of small ventricle and sulci and diffuse relative low density of the white matter.
2. Intense contrast enhancement of the falx cerebri or the tentorium cerebelli, as a result of dural venous collaterals or stasis.
3. Hypodense parenchymal lesions corresponding to venous infarction or hyperdense lesions related to hemorrhagic areas. Hemorrhagic infarcts range from a large hematoma (very rare) to petechial areas within a hypodensity.1,2,6,11 Unlike the arterial hemorrhage, a venous one is frequently caused by diapedesis and not the breaking of a vessel. A bilateral altered density of thalami is highly suggestive of cerebral deep venous system thrombosis, and it is associated with a poor prognosis.
4. Subarachnoid hemorrhage is a rare event, but it is possible in CVST, particularly when it achieves a gyral extension. In a subarachnoid hemorrhage secondary to CVST, vascular alterations are absent.34 Subdural hemorrhage related to CVST is possible, but it is a rare event.

Since 2000, new CT techniques have improved the diagnostic sensitivity in detecting CVST. In particular, helical CT venography has improved the sensitivity of computed tomography to 95%,35 demonstrating an even higher sensitivity than digital subtraction angiography of the venous phase used to visualize thrombosis in cavernous sinuses and ISS. Multislice CT angiography is frequently available in the emergency department, and it is useful to differentiate arterial from venous infarction.36

Nowadays, MRI is the “gold standard” for diagnosing CVST. The signal characteristics of venous thrombi evolve in several stages. In the first days, the thrombus is isointense on T1-weighted sequences and hypointense on T2-weighted sequences. If the posterior part of the SSS is involved, a dural wall hyperintensity, similar to the CT delta sign, is visible after gadolinium injection. Afterward, the clot becomes hyperintense, first in T1-weighted sequences and later also in T2-weighted sequences, with a characteristic progression of the hyperintensity from the periphery to the center. This phenomenon results from the transformation of hemoglobin into methemoglobin.6,11,24 After the first month, the hyperintensity disappears, first in T1- and then in T2-weighted sequences; therefore, the persistent occlusion can be visible, as an isointense signal, only in flow-sensitive gadolinium-enhanced sequences.1,2,6,11,24 Venous infarction on MRI appears as multiple areas of hyperintensity mixed with isointense or hypointense areas.6,24 Magnetic resonance venous angiography is an excellent tool for diagnosing the sharp interruption of a dural sinus; however, its capability to diagnose thrombosis of specific cortical veins is still weak, because of the individual variability and complexity of the cerebral venous system. Resolution and sensitivity are increased with the phase-contrast technique in regard to the time-of-flight technique.6

Magnetic resonance venous angiography is also useful for studying the hypoplasia of intracranial sinuses, an important source of pitfalls in the diagnosis of CVST.37

A promising technique is the gadolinium-enhanced auto-triggered elliptical centric-ordered magnetic resonance venography, which produces three-dimensional and digitally amplified images and is more sensitive than the classic gadolinium-enhanced magnetic resonance venography.38

Diffusion-weighted imaging (DWI) has demonstrated high sensitivity in detecting ischemic strokes in their initial phase. In CVST, DWI may be used to diagnose a venous infarction in the earlier hours, when it is more likely to be ameliorated with adequate medical intervention.6,24 It demonstrates the coexistence in the venous infarction of cytotoxic and vasogenic edema24,39,40 (Fig. 46-3). Another possible application of DWI may be to detect early recanalization, as demonstrated by Bousser and coworkers. Twenty-eight patients with recent CVST were studied with DWI in the acute phase, in order to identify hyperintense signals in the sinuses that corresponded to the thrombus. DWI hyperintense signals in the sinuses were detected in 12 of the 28 patients (43%) corresponding to 20 occluded veins or sinus. Two or three months after the beginning of anticoagulant administration, this phenomenon significantly decreased (35% versus 88%; P = 0.05) probably because of the different molecular structure of the clot.41

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Figure 46-3 Fluid-attenuated inversion recovery (A), T2-weighted (B), and diffusion-weighted (C) magnetic resonance imaging sequences of a thalamocapsular venous infarction in a patient with transverse sinus thrombosis.

Since 2000, some advances have been made in testing possible applications of transcranial Doppler (TCD) imaging in CVST. In patients with CVST, higher values of peak systolic, end-diastolic, and mean blood flow velocities have been reported in the deep venous system than in controls.42,43 However, although blood flow alterations in patients with CVST are more frequent than in controls, the sensitivity of TCD imaging is lower than that of MRI.43,44 Interestingly, patients with CVST showed a decrease in velocity values after starting heparin therapy, with a rebound of velocity values immediately after heparin suspension. Higher velocities in the acute phase were significantly associated with disturbances of consciousness. No relation was found between increased flow velocities and disease onset, severity of motor deficits, and presence of bleeding. In addition, the initial blood flow velocity was not predictive of stroke outcome.44

In another study, 26 patients with CVST, all treated with intravenous heparin and then with warfarin for 12 months, were monitored for a mean of 316 days, in order to evaluate whether hemodynamic factors, related to alternative flow patterns, could predict stroke outcome. All patients underwent TCD sonography at admission. The majority of patients (69%) showed pathological blood flow velocities at admission. Four alternative drainage patterns were found:

1. In the cavernous sinus drainage type, there was increased flow into this sinus and its major contributors (sphenoparietal sinus and the superior petrosal sinus). Headache was the only symptom affected patients complained of, and the outcome was good. It was related to sigmoid sinus thrombosis.
2. In the deep cerebral venous drainage type, there was increased flow in the galenic system. It was related to SSS occlusion, and affected patients had a good prognosis.
3. In the reverse flow in the basal vein of Rosenthal drainage type, inversion of flow in this vein resulted from the occlusion of the straight sinus. Headache was the only symptom, and the outcome was good.
4. In the transverse sinus drainage type, inversion of flow in the proximal part of the sinus occurred when the distal was occluded; an increased flow in the contralateral transverse sinus was found in proximal occlusions. This TCD pattern was related to the encephalopathic syndrome, and affected patients had the worst outcome.45

The Doppler technique is also useful in patients with CVST in detecting microembolic signals in the internal jugular vein, which are higher than in controls.46 Echocontrast techniques have been applied in order to increase TCD resolution.47

RISK FACTORS

Several conditions have been found to be associated with CVST, but only few of them produce an effective increase of the relative risk. The most common risk factors for CVST are listed in Table 46-1. Idiopathic cases account for 25% to 30% of cases of CVST.1,2,10,11,25

TABLE 46-1 Risk Factors for Cerebral Vein and Sinus Thrombosis

Septic thrombosis Bacterial (including syphilis), fungal (Mucor, Aspergillus, Rhizopus), viral (HIV, herpes zoster) and parasitic (Trichinella) infections
Head injuries Penetrating and nonpenetrating head injuries, surgery, intravascular foreign bodies, iopamidol myelography
Hematological disorders Polycythemia vera, altitude-induced polycythemia, sickle cell anemia, cryofibrinogenemia, paroxysmal nocturnal hemoglobinuria, thrombocytosis, multiple myeloma, severe anemia
Thrombophilic disorders Antithrombin III deficiency, protein C and/or protein S deficiency, activated protein C resistance, G20210A prothrombin mutation, antiphospholipid antibody syndrome, disseminated intravascular coagulation, MTHFR mutation, hyperhomocysteinemia, factor V Leiden, transfusion reaction, nephrotic syndrome
Metabolic disorders Homocystinuria, carbon monoxide, diabetes, thyroid disorders, hypertriglyceridemia
Neoplasia Metastatic (usually hematogenous malignancies), nonmetastatic complications, meningioma
Inflammatory states Behçet’s syndrome, inflammatory bowel disease (ulcerative colitis, Crohn’s disease), Wegener’s granulomatosis, Cogan’s syndrome, Köhlmeier-Degos disease, polyarteritis nodosa, systemic lupus erythematosus, sarcoidosis, thromboangiitis obliterans, rheumatoid arthritis
Phakomatoses Sturge-Weber syndrome
Hormonal Pregnancy and puerperium, thyrotoxicosis
Vascular disorders Arteriovenous malformations, arterial occlusions, jugular catheter occlusion, dural fistula
Medications Androgens, oral contraceptives, progestogens, L-asparaginase, pentosan, hormone replacement therapy, cocaine
Others Dehydration, fever, cardiac decompensation, skull abnormalities (achondroplasia, craniometaphyseal dysplasia), lumbar puncture, epidural anesthesia, CSF hypotension

CSF, cerebrospinal fluid; HIV, human immunodeficiency virus; MTHFR, methylene-tetrahydrofolate reductase.

Etiological factors may be divided into two main categories: septic CVST, which accounts for 5% to 15% of the cases, and aseptic CVST, which is predominant in industrialized countries. There are local and general causes for CVST. Local causes are related to head and neck infections (10.3%), tumors (2.2%), head injuries (1.1%), and neurosurgery (0.6%)13,48 (Fig. 46-4). Lumbar puncture, particularly with an intrarachidian injection of drugs (1.9%), may also produce CVST.49,50 In women, the most frequent general causes are pregnancy, puerperium, use of oral anticoagulants, and hormone replacement therapy. All these conditions are associated with high estrogen levels13,51–53 (Fig. 46-5). In the absence of thrombophilias, recurrence of CVST during another pregnancy is very rare.54 On the other hand, recurrences are very frequent in cases of puerperal CVST, which carry the greatest day-by-day risk of development of a vein thrombosis.6 Thus, anticoagulation is recommended in all patients with previous puerperal thrombosis.55 Thrombophilias, both hereditary and acquired, are reported in 20% to 50% of patients with CVST.13 In a series of 121 patients with CVST, prothrombin G20210A was present in 21.5% of patients, factor V Leyden in 12.4%, protein C deficiency in 5.2%, protein S deficiency in 3.1%, and antithrombin III deficiency in 2.5%.56 The presence of prothrombin G20210A and factor V Leyden increased the odds of developing CVST even in the heterozygous form by acting as cofactors with other conditions.56 Less common genetic thrombophilias such as hyperfibrinogenemia, alteration in the plasmin cascade,57 and hyperhomocysteinemia are associated with an increased risk of developing CVST.56,58 Hyperhomocysteinemia may provoke CVST, inducing endothelial toxicity, which is higher for the cerebral vascular system,59,60 and interferes with the clotting cascade.60,61 In the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT), the rate of with hyperhomocysteinemia in the whole population was 4.5%, reaching 27% in the series specifically dedicated to estimate the incidence and the risk of CVST associated with thrombophilic disorders.13 Acquired thrombophilic disorders accounted for 6.5% of patients: 5.9% were referable to antiphospholipid antibody syndrome and 0.6% to nephrotic syndrome.13

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Figure 46-4 A, Magnetic resonance image of a brain abscess of the right temporal lobe, caused by a septic otomastoiditis in a young adult without human immunodeficiency virus. B, Magnetic resonance venous angiogram in the same patient, showing septic thrombosis in the right superior sagittal sinus, straight sinus, and petrosal sinus.

image

Figure 46-5 A, Magnetic resonance image of frontal hematoma related to complete thrombosis of the left transverse sinus and superior sagittal sinus and partial thrombosis of the right transverse sinus occurred during the puerperal period. B, Magnetic resonance venogram of the same patient.

Another important category of risk factors for CVST is represented by systemic inflammatory disorders, especially if associated with vasculitis. In the ISCVT, systemic lupus erythematosus was found in 1% of patients, Behçet’s disease in 1%, rheumatoid arthritis in 0.2%, thromboangiitis obliterans in 0.2%, inflammatory bowel disease (ulcerative colitis and Crohn’s disease) in 1.6%, and sarcoidosis in 0.2%13 (Fig. 46-6).

image

Figure 46-6 Complete left transverse sinus and partial right transverse sinus thrombosis in a female patient affected by Sjögren’s syndrome.

Systemic infections are reported in 4.3% of patients; cultures and sensitivities are necessary to determine treatment. More diffuse in the past and related to very poor hygienic conditions and the absence of antibiotics, they remain an important cause of CVST and deep vein thrombosis in less industrialized countries. Systemic infections may be an important cause of thrombosis in neonates and young children. These patients are also very frequently at risk for anemia with CVST.62,63 Aseptic cerebral venous thrombosis is also reported in association with tuberculosis.64

TREATMENT

Treatment of CVST should address the thrombotic process (causal treatment), the consequences of CVST (symptomatic treatment), and the underlying causes.

Treatment of the Thrombotic Process

Among the causal treatments, anticoagulants are the more widely used. They are expected not to eliminate an already formed thrombus but to prevent extension of thrombosis to other venous channels. Nonetheless, the use of anticoagulants in patients with CVST is still debated.65–69 The main argument against anticoagulation is the risk of a major hemorrhage in the venous infarct, which is often already a hemorrhagic infarct. Several retrospective trials have shown a potential benefit of anticoagulation in patients with CVST.65,68 To date, however, findings from only two randomized placebo-controlled trials of anticoagulation in CVST are available. The first case-control study involved dose-adjusted intravenous heparin and was prematurely discontinued because of a statistically significant difference in favor of treated patients over controls.67 This was the first study demonstrating that the benefits of intravenous heparin also apply to patients with intracranial hypertension. Furthermore, no additional intracranial hypertension was detected during heparin treatment. In the European double-blind, controlled multicenter trial, weight-adjusted subcutaneous nadroparin for 3 weeks, followed by oral anticoagulation for 3 months, was compared with placebo in 60 patients with CVST. After 3 weeks, a poor outcome (defined as a Barthel Index <15) was observed in 20% of patients receiving nadroparin, in comparison with 24% of the controls. At 12 weeks, a poor outcome was observed in 10% of patients receiving nadroparin, in contrast to 21% of the controls. A complete recovery was observed in 12% of patients receiving nadroparin and 28% of the controls. None of these differences was statistically significant.70 A meta-analysis of the two reported trials showed an absolute risk reduction of 14% in mortality and 15% in mortality and dependency combined in patients undergoing anticoagulation.69 These results, although not statistically significant, are encouraging and strongly endorse, in our opinion, the use of anticoagulants in CVST irrespective of the presence of intracranial hypertension.69,71,72 Anticoagulant treatment should be continued orally for a period of at least 3 to 6 months. In case of puerperium, it should be prolonged for 12 months.73 If prothrombotic risk factors are present, longterm treatment is mandatory.6,73 Of importance is that during pregnancy, particularly in the first 3 months, vitamin K antagonists such as warfarin should be avoided, because they are linked with an increased rate of malformations.73 The first therapeutic choice in this case is therefore low-molecular-weight heparin.6

The use of thrombolytic agents in CVST has been evaluated.65,74–88 Thrombolytic therapy aims at rapid recanalization of the occluded vessel, including, in our case, the cortical veins.71,72 The efficacy and safety of this treatment are debated.74–88

Two different thrombolytic agents have been used in CVST. Urokinase was compared with intravenous heparin in SSS thrombosis. It was fairly well tolerated and more effective than heparin.74–77,83,85,88 The intrathrombus combination of recombinant tissue-type plasminogen activator (rtPA) and intravenous heparin was compared with intravenous heparin alone in patients with sinuses thrombosis. Both treatments were effective and safe, although the outcome was worse in patients with major hemorrhages treated with rtPA.79,82

A retrospective meta-analysis (72 studies, 169 patients enrolled) demonstrated that thrombolytic treatment is associated with a better outcome and is sufficiently safe.83 Nevertheless, to date there is no proof that thrombolytic therapy is better than anticoagulation in patients with CVST. Therefore, it should be used as second choice of therapy in patients whose condition worsens in spite of correct anticoagulation.76,84,89

The use of antiaggregates in patients with acute CVST has been poorly investigated. Experimental studies revealed a better neurological outcome and a higher rate of recanalization with rtPA in combination with the glycoprotein IIb/IIIa direct inhibitor abciximab, in comparison with the association of rtPA with enoxaparine.90 So far, clinical studies investigating the use of glycoprotein IIb/IIIa direct inhibitors in CVST have never been performed.

There is little information concerning the use of mechanical treatments, such as rheolytic catheter thrombectomy or angioplasty in CVST, and further evidence of their efficacy is needed.91–99 A great limitation of these techniques is represented by the inaccessibility to some intracranial vessels, particularly cortical, bridging, and deep veins, because of their size in comparison with the caliber of the catheter.91–93

Open surgical thrombectomy, combined with local infusion of rtPA, showed a good outcome when used in patients with severe dural sinus thrombosis and deterioration despite anticoagulation. All patients returned to normal activities after surgical treatment.100,101

Symptomatic Treatment

The prophylactic use of anticonvulsants in patients with CVST is still controversial because of their negative effects on brain metabolism and on the level of consciousness. The general attitude, and our advice, is to use these drugs only in patients with seizures.1,2,6,25,29 Focal neurological deficits, cerebral edema, and infarction (especially hemorrhagic) observed on neuroimaging seem to be significant predictors of seizure in patients with CVST.29 A prophylactic treatment with anticonvulsants might be justified in these patients.

Treatment of increased intracranial pressure caused by brain swelling is based on the use of mannitol, seldom in association with other diuretics such as acetazolamide or furosemide. Steroids are not indicated, because of their antifibrinolytic activity (although there are no clinical trials demonstrating a worse outcome in CVST patients treated with steroids).1,2,6,11,25 Tris(hydroxymethyl)aminomethane, which decreases intracranial pressure by alkalotic vasoconstriction, could be used in ventilated patients.6

Treatment of septic CVST must be based on the antibiogram, but while the clinician waits for these findings, an empirical treatment may be started with a third-generation cephalosporin (such as ceftriaxone or cefotaxime) or with a penicillinase-resistant penicillin. Metronidazole is the first choice when an anaerobic infection is suspected; in the nosocomial infections, meropenem, ceftazidime, and vancomycin may be used.

PROGNOSIS

CVST was long thought to be a rare disease with a poor prognosis.1,2,9–11 Since the mid-1970s, neuroimaging has produced a better understanding of this disease, and the use of anticoagulant therapy has increased the number of good outcomes. In the ISCVT study, after a 16-month median follow-up period, 13.4% of the patients had a modified Rankin scale score of more than 2, and 8.3% had died. Multivariate predictors of death or dependence were central nervous system infections (HR = 3.3%), cancer (HR = 2.9), deep venous system involvement (HR = 2.9), coma (HR = 2.7), age older than 37 years (HR = 2), mental status disorders (HR = 2), hemorrhage visible on CT scan (HR = 1.9), and male gender (HR = 1.6). Only 2.2% of the patients had a recurrent sinus thrombosis, and 4.3% had other thrombotic events.13

The rate of recurrences in patients with CVST ranges from 0% to 11.7%,102 and it is most common in the first year after the previous thrombosis.6,102 The mortality rate ranges between 6% and 33%, and it is higher in septic CVST.11 In one study, researchers investigated the variables influencing the delay between the onset of symptoms and hospital admission for patients with CVST. Twenty-two percent of patients were admitted within 24 hours and 75% within 13 days. In multiple logistic regression analysis, admission within 24 hours was associated positively with mental status disorders (delirium/abulia) and negatively with headache. Intracranial hypertension was associated with an admission delay of more than 4 days, and papilledema, with a delay of more than 13 days. Mean delay between onset and hospital admission was 4 days. Not surprisingly, anticoagulation was started earlier in patients with a more precocious diagnosis, but the proportion of patients treated was not influenced by the delay of admission. Headache was the most common presenting symptom; therefore, CVST should be considered in patients with a new-onset headache or an important change in the clinical features of a preexisting one.11,27

A number of researchers investigated the relationship between delay of anticoagulant treatments and CVST prognosis.103–105 So far, there is no evidence that delay in admission (and diagnosis) might influence CVST prognosis. Female gender, pregnancy, and puerperium, all related to high estrogens levels, seem to be predictive of a good outcome.6,106 Early recanalization, which is a common phenomenon on neuroimaging, has no influence on outcome.107

CONCLUSION

The thrombotic process in CVST leads to a wide spectrum of clinical symptoms varying from isolated headache to focal neurological signs or even coma. Neuroimaging techniques allow a quick diagnosis, limiting the number of cases that remain uncertain to few. Anticoagulation is the first-line therapy for CVST, but some patients may require no therapy at all, whereas others may benefit from more aggressive treatment, such as thrombolysis.

KEY POINTS

• CVST accounts for fewer than 1% of all strokes and for about 0.1% to 9% (mean, about 1%) of all deaths from cerebrovascular diseases. There is great geography- and ethnicity-associated variability.
• The causal factors leading to CVST have been classically grouped into (1) prothrombotic state, (2) venous stasis, (3) direct involvement of the venous wall, and (4) abnormal blood viscosity.
• The clinical features of CVST can be grouped into three syndromes: (1) intracranial hypertension syndrome; (2) stroke-related syndrome; and (3) encephalopathic syndrome.
• Early diagnosis of CVST is crucial, because anticoagulation reduces the risk of fatal outcome and severe disability.

Suggested Reading

Canhao P, Batista P, Falcao F. Lumbar puncture and dural sinus thrombosis: a causal or casual association? Cerebrovasc Dis. 2005;19:53-56.

Camargo EC, Massaro AR, Bacheschi LA, et al. Ethnic differences in cerebral venous thrombosis. Cerebrovasc Dis. 2005;19:147-151.

Ferro JM, Lopes MG, Rosas MJ, et al. Delay in hospital admission of patients with cerebral vein and dural sinus thrombosis. Cerebrovasc Dis. 2005;19:152-156.

Rottger C, Madlener K, Heil M, et al. Is heparin treatment the optimal management for cerebral venous thrombosis? Effect of abciximab, recombinant tissue plasminogen activator, and enoxaparin in experimentally induced superior sagittal sinus thrombosis. Stroke. 2005;36:841-846.

Stolz E, Rahimi A, Gerriets T, et al. Cerebral venous thrombosis: an all or nothing disease? Prognostic factors and longterm outcome. Clin Neurol Neurosurg. 2005;107:99-107.

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