Intern Emerg Med (2012) 7 (Suppl 3):S221–S225 DOI 10.1007/s11739-012-0806-9
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Cerebral sinus-venous thrombosis Ida Martinelli • Serena Maria Passamonti Elena Rossi • Valerio De Stefano
•
Ó SIMI 2012
Abstract Cerebral sinus-venous thrombosis (CSVT) is a rare life-threatening disease with an estimated annual incidence of 3–4 cases per million in adults and 7 cases per million in neonates. Brain tumors, cerebral infections and traumas are local risk factors for CSVT, but the commonest encountered risk factors are oral contraceptive use, pregnancy and puerperium that make the disease predominant in female sex. In 15–20 % of patients, the disease remains unprovoked, i.e., occurring in the absence of predisposing factors. Thrombophilic abnormalities either inherited [deficiency of the natural anticoagulant proteins antithrombin, protein C or protein S, mutations in the factor V gene (factor V Leiden) or prothrombin gene (prothrombin G20210A)] or acquired (antiphospholipid antibodies) are worthy to be investigated in patients with CSVT, as well as hyperhomocysteinemia. In a small proportion of patients, CSVT is the first manifestation of a myeloproliferative neoplasm. The proportion of patients with recurrent CSVT is low, but venous thromboembolism (deep vein thrombosis in the lower limbs or pulmonary embolism) can develop particularly in patients with a first idiopathic CSVT. In the past decade, there has been increasing evidence that early diagnosis and anticoagulant treatment reduce morbidity of CSVT and improve survival. However, the optimal duration of anticoagulant treatment is not well established, because
limited information is available on the rate of CSVT recurrence after anticoagulant discontinuation. Keywords Cerebral sinus Venous thrombosis Thrombophilia Risk factors Anticoagulant therapy
Introduction Venous thrombosis affects mainly the lower extremities but may rarely involve other venous districts, such as cerebral veins and sinuses, and splanchnic and upper extremity veins. In a nationwide epidemiological study, rare venous thromboses (defined as migrating thrombophlebitis, abdominal and cerebral venous thrombosis, and renal vein thrombosis) accounted for 4 % of hospitalized cases with venous thrombosis, with an overall incidence lower than one per 100,000 person-years [1]. Among the rare sites of venous thrombosis, the cerebral circulation is one of the most life threatening. Because in the vast majority of patients thrombosis develops concomitantly in sinuses and veins, the disease is commonly named cerebral sinus-venous thrombosis (CSVT).
Epidemiology and clinical manifestations I. Martinelli (&) S. M. Passamonti Department of Internal Medicine and Medical Specialities, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Via Pace, 9, 20122 Milan, Italy e-mail:
[email protected] E. Rossi V. De Stefano Institute of Hematology, Catholic University, Rome, Italy
The incidence of CSVT is uncertain, because of the absence of epidemiological studies. At variance with arterial stroke, CSVT affects mainly young adults and children, with an estimated annual incidence of 3–4 cases per 1 million adults and 7 cases per 1 million neonates and children [2, 3]. The most frequent locations of thrombosis are the superior sagittal (62 % of patients) and the transverse sinus (40–45 %), but in two-thirds of cases more than
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one sinus are involved. Symptoms are varied and related to the involved venous structure. When thrombosis involves the cortical veins, localized edema and parenchymal infarction generally develop [2]. The presence of large intracranial infarcts or hemorrhages leads to stupor or coma in 15 % of patients with CSVT [2, 4–6]. Overall, intracranial hemorrhage complicates 14–39 % of CSVT [4–6]. The most common symptoms and signs are headache and papilledema due to intracranial hypertension, seizures, focal neurological deficits and altered consciousness. Headache occurs in 90 % or more of patients, and papilledema (30 % of patients) may cause visual loss and, if the sixth cranial nerve is compressed, diplopia. Focal or generalized seizures develop in up to 40 % of patients, as well as motor deficits, whereas symptoms such as dysarthria and aphasia are uncommon [4, 6, 7]. In a large series of 220 consecutive patients with CSVT, one-third had hemorrhagic infarct or intracerebral hemorrhage. In patients with hemorrhagic lesions, headache (99 %), behavioral disturbances (55 %), consciousness disturbances (35 %), seizures (41 %), and language deficits (42 %) were significantly higher than in those without. Dependency or death was higher in patients with hemorrhagic lesions (32 %) than in those without (12 %) [8]. The onset of symptoms is subacute, developing from 2 days to 1 month in 50–80 % of patients, and can be even longer in 10–20 % of patients with isolated intracranial hypertension [4–6]. Rarely, symptoms simulate those of arterial stroke, but a slower development, a tendency to fluctuate and the symptoms of intracranial hypertension and seizures are important clinical differences. Prognosis of CSVT is favorable in more than 80 % of cases [9], because poor neurological outcome is seen in 7–20 % [4–7] and recurrence in 2.2–3 % of patients [4, 6, 10]. Death is mainly caused by cerebral herniation in the acute phase and to underlying illnesses, e.g. cancer, during follow-up. Mortality rates, as high as 50 % in older studies [11], have been recently estimated to range from 4.3 to 13 % during the first month and from 7.7 to 17.7 % after 6 months [9].
Diagnosis Because of the wide spectrum of clinical presentations and the varying speed of onset of symptoms, diagnosis of CSVT is frequently overlooked or delayed, while early diagnosis and treatment are essential to minimize morbidity and improve survival. Indirect imaging signs include parenchymal abnormalities, such as venous infarcts, brain edema, hydrocephalus and compression of the fourth ventricle; development of collateral venous network; changes in the
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mastoid region and erosion of middle air structures [12]. Direct signs are those of interrupted venous flow or occlusion, and visualization of the actual thrombus [12]. The first recommended exam is a plain computerized axial tomography, which main utility is to rule out brain tumors [6]. Contrast medium administration is essential, but other techniques such as magnetic resonance imaging, magnetic resonance venography or dynamic spiral computed tomography venography are required when contrast computed tomography is diagnostically insufficient [13]. Ultrasound examination (transcranial Doppler or color-coded duplex sonography through the temporal acoustic bone window) of the cerebral venous system has the great advantages of noninvasiveness, cost-effectiveness and wide availability of the technique. However, its accuracy is limited and at present ultrasound examination can only be recommended as complementary to other imaging techniques [12].
Risk factors In children and neonates, the main risk factors for CSVT are gestational or perinatal complications (24 % of cases), dehydration (25 %), head infections (18 %) and thrombophilia (32 %) [3]. While until the mid 1970s, CSVT affected equally adult men and women, in the last few decades it shifted to a disease affecting predominantly women of childbearing age [2]. Indeed, two-thirds of adult patients are women. Responsible of the sex disparity is the increasing use of oral contraceptives, as reported by several case–control studies, eight of which were recently reviewed in a meta-analysis that showed an almost sixfold increased risk of CSVT in oral contraceptive users [14]. It is uncertain, in the absence of specific studies, whether or not oral contraceptives containing desogestrel or gestodene as progestogen are associated with a higher risk of CSVT than those containing levonorgestrel, as demonstrated for deep vein thrombosis of the lower limbs. No data are available on the risk of CSVT and hormone replacement therapy. Inherited thrombophilia is another established risk factor for CSVT (Table 1), the relative risk being approximately fourfold and tenfold increased in the presence of factor V Leiden or prothrombin G20210A mutation [14–16]. There is a synergistic interaction between oral contraceptives and inherited thrombophilia due to the forementioned gain-of-function mutations, and also to the metabolic abnormality hyperhomocysteinemia [15]. The relationship between the risk of CSVT and the lack-offunction deficiencies of the naturally occurring anticoagulants antithrombin, protein C and protein S, as well as that associated with the acquired thrombophilia due to the presence of antiphospholipid antibodies, are less established because of the relatively small number of patients
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Table 1 Risk factors for cerebral sinus and vein thrombosis in adults Cerebral sinus and vein thrombosis Local risk factors (%) Acquired Brain tumors
patients with CSVT, 4 % had an overt MPN and 2 % developed the disease within a follow-up period of 8 years [22]. Hence, investigation of patients with CSVT for the somatic mutation V617F in the Janus kinase (JAK2) gene, i.e., a specific marker of myeloproliferative neoplasms, is recommended [22].
2
Central nervous system infections
2–5
Ear, mouth, face, and neck infections
8–14
Therapy
1–2
To date, prognosis of CSVT is favorable owing to the early identification of the disease that allows treatment in the acute stage. Early anticoagulant treatment with fixed doses of subcutaneous low molecular weight heparin (according to the patient’s body weight) or adjusted doses of intravenous or subcutaneous unfractionated heparin (maintaining the activated partial thromboplastin time ratio between 2.0 and 3.0) is also crucial to limit thrombus extension. Although three small controlled trials [23–25] and one meta-analysis [26] failed to show a significant advantage of heparins over placebo, heparin treatment in the acute stage followed by oral anticoagulants is recommended [27–29]. Heparin is not contraindicated in patients with concomitant intracranial hemorrhage, but it should be used cautiously in patients with large hemorrhagic infarcts at diagnosis [28]. There is no adequate evidence supporting the use of such other treatments as local or systemic thrombolysis that are associated with a high risk of intracranial bleeding and should be considered in patients who deteriorate despite adequate anticoagulation [27]. A trial comparing endovascular thrombolysis (local infusion of recombinant-tissue plasminogen activator or urokinase, mechanical thrombectomy, or both) with therapeutic doses of heparin is ongoing [30]. Antiedema treatment with intravenous osmotic diuretics or acetazolamide is required in 20 % of patients [27]. In case of severe intracranial hypertension, lumbar puncture to lower the cerebrospinal fluid pressure and reduce headache and papilledema, or decompressive surgery to avoid or reverse cerebral herniation can be considered [27]. Data from a multicenter registry were in favor of decompressive surgery in 69 patients with CSVT complicated by large parenchymal lesions, as at 1-year follow-up only 17 % of them had an unfavorable outcome [31]. Oral anticoagulant therapy with vitamin-K antagonists (VKA) follows the initial heparin treatment, but its optimal duration is not established. VKA may be given for 3 months if CSVT was secondary to a transient risk factor, for 6–12 months in patients with idiopathic CSVT and in those with ‘‘mild’’ thrombophilia, such as heterozygous factor V Leiden or prothrombin G20210A mutation and high plasma levels of factor VIII. Indefinite anticoagulation should be considered in patients with recurrent episodes of CSVT, ‘severe’ thrombophilia (such as antithrombin,
Circumstantial Head trauma, neurosurgery, lumbar puncture, jugular catheter Systemic risk factors (%) Inherited Antithrombin deficiency
1–7
Protein C deficiency
3–6
Protein S deficiency
3–8
Factor V Leiden
3–12
Prothrombin G20210A
11–21
Acquired Cancer
3–10
Myeloproliferative neoplasms
1–3
Antiphospholipid antibodies Behc¸et disease
4–17 1
Autoimmune diseases
8
Paroxysmal nocturnal hemoglobinuria
1
Hyperhomocysteinemia
4–29
Inflammatory bowel diseases
2–3
L-asparaginase
1–2
and other drugs
Circumstantiala
a
Oral contraceptives
10–77
Hormone replacement therapy
4–7
Pregnancy or puerperium
2–31
Percentage calculated on the number of women
investigated so far and the low prevalence of these coagulation abnormalities in patients and controls [14–16]. Another risk factor for CSVT exclusive of women is, more than pregnancy, puerperium [17]. In low-income countries, it is the most frequent risk factor for CSVT, accounting for 31 % of cases [7]. Especially the first 3 weeks after delivery are associated with an increased risk of CSVT, because of the persistence of the hypercoagulable state induced by pregnancy [17–19]. Other risk factors for CSVT are listed in Table 1. CSVT can occur in patients with myeloproliferative neoplasm (MPN) and can be the first clinical manifestation of the disease. The association between MPN and thrombosis is valid particularly for splanchnic vein thrombosis, but also for CSVT. In cohorts of patients with MPN, CSVT has been reported in about 1 % of cases [20, 21]; conversely, in a cohort of 152
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protein C or protein S deficiency, homozygous factor V Leiden or prothrombin G20210A mutation, antiphospholipid antibodies and combined abnormalities) or other permanent risk factors such as MPNs, and in those with idiopathic event (may be particularly in lack of recanalization) [27, 28]. Conclusions CSVT is a rare but clinically relevant diseases that to date are diagnosed more frequently than in the past owing to the progress in diagnostic imaging. Thrombophilia abnormalities are well-recognized risk factors for CSVT, especially in cases not related to such strong risk factors as tumors in the brain or other sites, cerebral infections or traumas. The great advances made in molecular medicine allowed to recognize the important role of the common gain-of-function mutations in coagulation factor V and prothrombin that alone or in combination with other systemic or local risk factors contributes to the occurrence of CSVT. A common example of interaction between a genetic and environmental risk factor for CSVT is between thrombophilia and oral contraceptive use or pregnancy/puerperium. This explains at least in part the higher prevalence of a first CSVT in women than men. Thrombophilia seems to be also a risk factor for recurrent CSVT, but only in its severe form (antithrombin, protein C, protein S deficiencies, antiphospholipid antibodies or combined abnormalities). A complete thrombophilia screening should be considered for all patients in whom CSVT is not related to cancer, brain infections or traumas. CSVT can complicate an already overt MPN, but can also be the first manifestation of a latent disease. Hence, the search for the somatic mutation V617F in the Janus kinase (JAK2) gene, i.e., a specific marker of MPNs, is recommended in patients with CSVT. As regarding therapy, other than symptomatic and etiologic treatments, anticoagulant drugs (heparin and oral anticoagulants) are safe and effective in the vast majority of patients. Owing to the rarity of CSVT, there are no randomized trials of adequate sample size addressing the optimal duration of anticoagulant therapy. The frequent decision to continue anticoagulant therapy lifelong in order to prevent recurrences of CSVT does not appear sensible, because the risks of recurrence and long-term complications are relatively low and do not outweigh the risk of bleeding induced by longterm anticoagulant therapy. Long-term therapy should be considered in patients with idiopathic CSVT, severe hypercoagulable states, MPNs, and in those with recurrent thrombosis. Conflict of interest
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None.
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