**1. Introduction**

128 Venous Thrombosis – Principles and Practice

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In 1825, Ribes described a case of a 45-year old man who died after a 6-month history of epilepsy, seizures and delirium. The autopsy examination revealed thrombosis of the superior sagittal sinus, the left lateral sinus and a cortical vein in the parietal region. This was probably the first detailed description of extensive cerebral venous sinus thrombosis (CVST). Since then, the literature describing this disease has comprised of case reports, series and some newer prospective studies, including recent reviews and guidelines (statement) on the diagnosis and management of CVST (Siddiqui & Kamal, 2006; Stam, 2005; Saposnik et al, 2011; Brown & Thore, 2011).

The cerebral venous sinus thrombosis is a challenging condition and it is most common than previously thought. CVST accounts for 0.5% to 1.0% of all strokes and usually affects young individuals. Important advances have been made in the understanding of the pathophysiology of this vascular disorder. The diagnosis of CVST is still frequently overlooked or delayed as a result of the wide spectrum of clinical symptoms and the often sub-acute or lingering onset. Patients with CVST commonly present with headache, although some develop a focal neurological deficit, decreased level of consciousness, seizures, or intracranial hypertension without focal neurological signs. Uncommonly, an insidious onset may create a diagnostic challenge. The main problem of this disorder is that it is very often unrecognised at initial presentation. In particular, a prothrombotic factor or a direct cause is identified in approximately 66% of the CVST patients (a list of most important causal and risk factors are listed in **Table 1**).

Cerebral venous thrombosis is more common in women than men, with a female to male ratio of 3:1 (cited in Ferro & Canhao, 2011). The imbalance may be due to the increased risk of CVST associated with pregnancy and puerperium and with oral contraceptives. The female predominance in CVST is found in young adults, but not in children or older adults.

Cerebral Venous Sinus Thrombosis - Diagnostic Strategies and Prognostic Models: A Review 131

Fig. 1. MRI venogram of the cerebral venous system and most frequent location of CVST. *Reproduced with the written permission from the paper by Saposnik et al. (2011)* as derived from data on 624 patients in the International Study on Cerebral Venous and Dural Sinuses

The pathogenesis of CVST remains incompletely understood because of the high variability in the anatomy of the venous system, and the paucity of experiments in animal models of CVST. However, there are at least two different mechanisms that may contribute to the clinical features of CVST: a) *thrombosis of cerebral veins or dural sinus leading to cerebral parenchymal lesions or dysfunction*; and b) *occlusion of dural sinus resulting in decreased cerebrospinal fluid (CSF) absorption and elevated intracranial pressure*. (**Figure 2**). Obstruction of the venous structures may result 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 CVST 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 the Na+/K+ ATPase pump, and consequent cytotoxic edema

Thrombosis as reported by Manolidis & Kutz (2005).

(Ferro & Canhao, 2011).

Table 1. Most important causes of and risk factors associated with cerebral venous sinus thromobosis. *Reproduced with the written permission from the paper by Stam (2005).*

In the prospective International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVST) cohort of 624 adults with CVST, women comprised 465 (75%) of the patients. Compared with men, women had significantly lower mean age (42 vs 34 years). Furthermore, a gender specific risk factor — oral contraceptives, pregnancy, puerperium, and hormone replacement therapy — was identified in 65% of the women. CVST is more common in neonates than it is in infants, children or adults. In adults, CVST affects patients who are younger on average than those with arterial types of stroke. In the ISCVST, the mean age of patients with CVST was 39 years, and only 8% of them were older than 65 years (Ferro & Canhao, 2011). Topographically, the most frequent occurrence of CVST has been observed in the superior sagitral sinus (62%) followed by the transverse (lateral) sinus (41- 45%) (**Figure 1**).

Table 1. Most important causes of and risk factors associated with cerebral venous sinus

In the prospective International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVST) cohort of 624 adults with CVST, women comprised 465 (75%) of the patients. Compared with men, women had significantly lower mean age (42 vs 34 years). Furthermore, a gender specific risk factor — oral contraceptives, pregnancy, puerperium, and hormone replacement therapy — was identified in 65% of the women. CVST is more common in neonates than it is in infants, children or adults. In adults, CVST affects patients who are younger on average than those with arterial types of stroke. In the ISCVST, the mean age of patients with CVST was 39 years, and only 8% of them were older than 65 years (Ferro & Canhao, 2011). Topographically, the most frequent occurrence of CVST has been observed in the superior sagitral sinus (62%) followed by the transverse (lateral) sinus (41-

thromobosis. *Reproduced with the written permission from the paper by Stam (2005).*

45%) (**Figure 1**).

Fig. 1. MRI venogram of the cerebral venous system and most frequent location of CVST. *Reproduced with the written permission from the paper by Saposnik et al. (2011)* as derived from data on 624 patients in the International Study on Cerebral Venous and Dural Sinuses Thrombosis as reported by Manolidis & Kutz (2005).

The pathogenesis of CVST remains incompletely understood because of the high variability in the anatomy of the venous system, and the paucity of experiments in animal models of CVST. However, there are at least two different mechanisms that may contribute to the clinical features of CVST: a) *thrombosis of cerebral veins or dural sinus leading to cerebral parenchymal lesions or dysfunction*; and b) *occlusion of dural sinus resulting in decreased cerebrospinal fluid (CSF) absorption and elevated intracranial pressure*. (**Figure 2**). Obstruction of the venous structures may result 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 CVST 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 the Na+/K+ ATPase pump, and consequent cytotoxic edema (Ferro & Canhao, 2011).

Cerebral Venous Sinus Thrombosis - Diagnostic Strategies and Prognostic Models: A Review 133

was found in 22% of all patients. Although infectious causes of CVST were frequently reported in the past, they are responsible for only 6 to 12 percent of cases in modern-era studies of adults with CVST. As with venous thrombosis in other parts of the body, multiple risk factors may be found in about half of adult patients with CVST. No underlying etiology or risk factor for CVST is found in approximately 13% of adult patients. However, it is important to continue searching for a cause even after the acute phase of CVST, as some patients may have a condition such as the antiphospholipid syndrome (APS), polycythemia, thrombocythemia, or malignancy that is discovered weeks or months after the acute phase. It should be noted that the risk for CVST is influenced by the individual's genetic background. In the presence of some prothrombotic conditions, patients are at an increased risk of developing CVST 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: antithrombin deficiency, protein C deficiency or protein S

deficiency, Factor V Leiden mutation or G20210 A prothrombin gene mutation.

Table 2. Classification of systemic and local conditions increasing the risk of cerebral venous thrombosis. *Reproduced with the written permission from the paper by Ferro & Canhao (2011).*

Fig. 2. Possible mechanisms of the development of CVST. *Reproduced with the written permission from the paper by Ferro & Canhao (2011).*

Advances in our understanding of the venous occlusion pathophysiology have been achieved by the use of newer magnetic resonance imaging (MRI) methods, mainly diffusionweighted MRI (DWI) and perfusion-weighted MRI (PWI). These techniques have demonstrated the coexistence of both cytotoxic and vasogenic edema in patients with CVST. The other effect of venous thrombosis is impairment of CSF absorption. Normally, CSF absorption occurs in the arachnoid granulations (Leach et al, 2008), 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.

As shown in Table 1, many causes or predisposing conditions are associated with CVST. The major risk factors for CVST in adults can be grouped in two classes: *transient* or *permanent* (**Table 2**) . In more than 85% of the adult patients, at least one risk factor for CVST can be identified, most often a prothrombotic condition as mentioned above. In the ISCVST cohort, a prothrombotic condition was found in 34%, and a genetic prothrombotic condition

Fig. 2. Possible mechanisms of the development of CVST. *Reproduced with the written* 

Advances in our understanding of the venous occlusion pathophysiology have been achieved by the use of newer magnetic resonance imaging (MRI) methods, mainly diffusionweighted MRI (DWI) and perfusion-weighted MRI (PWI). These techniques have demonstrated the coexistence of both cytotoxic and vasogenic edema in patients with CVST. The other effect of venous thrombosis is impairment of CSF absorption. Normally, CSF absorption occurs in the arachnoid granulations (Leach et al, 2008), 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

As shown in Table 1, many causes or predisposing conditions are associated with CVST. The major risk factors for CVST in adults can be grouped in two classes: *transient* or *permanent* (**Table 2**) . In more than 85% of the adult patients, at least one risk factor for CVST can be identified, most often a prothrombotic condition as mentioned above. In the ISCVST cohort, a prothrombotic condition was found in 34%, and a genetic prothrombotic condition

*permission from the paper by Ferro & Canhao (2011).*

in the superior sagittal sinus.

was found in 22% of all patients. Although infectious causes of CVST were frequently reported in the past, they are responsible for only 6 to 12 percent of cases in modern-era studies of adults with CVST. As with venous thrombosis in other parts of the body, multiple risk factors may be found in about half of adult patients with CVST. No underlying etiology or risk factor for CVST is found in approximately 13% of adult patients. However, it is important to continue searching for a cause even after the acute phase of CVST, as some patients may have a condition such as the antiphospholipid syndrome (APS), polycythemia, thrombocythemia, or malignancy that is discovered weeks or months after the acute phase. It should be noted that the risk for CVST is influenced by the individual's genetic background. In the presence of some prothrombotic conditions, patients are at an increased risk of developing CVST 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: antithrombin deficiency, protein C deficiency or protein S deficiency, Factor V Leiden mutation or G20210 A prothrombin gene mutation.


Table 2. Classification of systemic and local conditions increasing the risk of cerebral venous thrombosis. *Reproduced with the written permission from the paper by Ferro & Canhao (2011).*

Cerebral Venous Sinus Thrombosis - Diagnostic Strategies and Prognostic Models: A Review 135

important diagnostic consideration in patients with headache and papilledema or diplopia (caused by sixth nerve palsy) even without other neurological focal signs. When a focal brain injury occurs, most common are hemiparesis and aphasia, but other cortical signs and sensory symptoms may be also observed, together with psychosis in such cases. The clinical manifestations of CVST may also depend on the location of the thrombosis as mentioned above (Figure 1). The superior sagittal sinus is most commonly involved. For the lateral sinus thromboses, as a second prevalent location, the symptoms related to an underlying condition (middle ear infection) may be noted, including constitutional symptoms, fever, and ear discharge. Pain in the ear or mastoid region and headache are typical. On examination, an increased intracranial pressure and distention of the scalp veins may be noted (hemianopia, contralateral weakness, and aphasia may sometimes be seen owing to cortical involvement). Approximately 16% of the patients with CVST have thrombosis of the deep cerebral venous system (internal cerebral vein, vein of Galen, and straight sinus), which can lead to thalamic or basal ganglial infarction (van der Bergh et al, 2005). Most patients present with rapid neurological deterioration (Saposnik et al, 2011). Importantly, several principal clinical features distinguish CVST from other cerebrovascular diseases (CVD). Notably, the focal or generalized seizures are frequent, occurring in about 40% of patients; and, secondly, as a clinical correlate to the anatomy of cerebral venous drainage, the bilateral brain involvement is not infrequent. The latter is particularly notable in cases that involve the deep venous drainage system, when bilateral thalamic involvement may occur, causing alterations in level of consciousness without focal neurological findings. Bilateral motor signs, including paraparesis, may also be present due to sagittal sinus thrombosis and bihemispheric injury. Finally, patients with CVST often present with slowly progressive symptoms. It has to be underlined that very frequently the delays in diagnosis of CVST are common and significant. In the ISCVST, symptom onset was acute (<48 hours) in 37% of patients, subacute (>48 hours to 30 days) in 56% of patients, and chronic (>30 days) in 7% of the patients. The median delay from the onset of symptoms to the hospital

admission was 4 days, and from symptom onset to the diagnosis - 7 days.

**Specific diagnostic cues.** About 40% of the patients with CVST present with *intracranial hemorrhage* (ICH). The features suggestive of CVST as a cause of ICH include prodromal headache (which is highly unusual with other causes of ICH), bilateral parenchymal abnormalities, and clinical evidence of a hypercoagulable state. These features may not be present, however, and a high index of clinical suspicion is necessary. An isolated subarachnoid hemorrhage may also occur due to CVST, although this is rare (0.8% of patients in ISCVST). A second specific occurrence is *isolated headache/idiopathic intracranial hypertension* – for example, 25% of the CVST patients may present with isolated headache, and another 25% - with headache in conjunction with papilledema or sixth nerve palsies suggestive of idiopathic intracranial hypertension. In a series of 131 patients who presented with papilledema and clinically suspected idiopathic intracranial hypertension, 10% had CVST at MRI/magnetic resonance venography (MRV). Imaging of the cerebral venous system has been recommended for all patients with the clinical picture of idiopathic intracranial hypertension. Regarding headache - it is an extremely common symptom, and most patients with isolated headache will not have CVST. The cost-effectiveness and yield of routine imaging are highly uncertain. Factors that may suggest the diagnosis, and thus prompt imaging evaluation, include a new, atypical headache; headache that progresses steadily over days to weeks despite conservative treatment; and thunderclap headache, especially if a hypercoagulable state is also present. A third difficult occurrence in CVST is when the patients present with *somnolence or a confusional* 

In particular, 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. Furthermore, the risk for CVST in women using oral contraceptives is increased if they have a prothrombotic defect. In elderly CVST patients, the proportion of cases without identified risk factors is higher (37%) than it is in adults <65 years of age. The most common risk factors in those ≥65 years old are genetic or acquired thrombophilia, malignancy, and hematologic disorders such as polycythemia (Ferro & Canhao, 2011; Plata et al, 2002).
