Cerebral Venous Sinus Thrombosis: Update on Diagnosis and Management

Transcription

1 Curr Cardiol Rep (2014) 16:523 DOI /s STROKE (AB SINGHAL, SECTION EDITOR) Cerebral Venous Sinus Thrombosis: Update on Diagnosis and Management José M. Ferro & Patrícia Canhão Published online: 30 July 2014 # Springer Science+Business Media New York 2014 Abstract Cerebral venous thrombosis (CVT) is less frequent than ischemic stroke or intracerebral haemorrhage. Its incidence is comparable to that of acute bacterial meningitis in adults. Because of the increased use of magnetic resonance imaging (MR) for investigating patients with acute and subacute headaches and new onset seizures, CVT are now being diagnosed with increasing frequency. CVT have a more varied clinical presentation than other stroke types as they rarely present as a stroke syndrome. Their most frequent presentations are isolated headache, intracranial hypertension syndrome, seizures, a focal lobar syndrome and encephalopathy. The confirmation of the diagnosis of CVT relies on the demonstration of thrombi in the cerebral veins and/or sinuses by MR/MR venography or veno CT. The more frequent risk factors for CVT are prothrombotic conditions, either genetic or acquired, oral contraceptives, puerperium and pregnancy, infection and malignancy. The prognosis of CVT is in general favourable, as only around 15 % of the patients remain dependent or die. The main intervention in the acute is anticoagulation with either low molecular weight or unfractionated heparin. In patients in severe condition on admission or who deteriorate despite anticoagulation, local thrombolysis or thrombectomy is an option. Decompressive surgery is life-saving in patients with large venous infarcts or haemorrhage. After the acute phase patients remain This article is part of the Topical Collection on Stroke J. M. Ferro (*): P. Canhão Department of Neurosciences, Serviço de Neurologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, University of Lisbon, Av. Prof. Egas Moniz, Lisbon, Portugal jmferro@fm.ul.pt P. Canhão pcanhao@fm.ul.pt anticoagulated for a variable period of time, depending on their inherent thrombotic risk. CVT patients may experience recurrent seizures. Prophylaxis with antiepileptics is recommended after the first seizures, in particular in those with hemispheric lesions. There are several ongoing multicentre registries sand trials which will improve evidence-based management of CVT in the near future. Keywords Dural sinus thrombosis. Cerebral venous thrombosis. MR. Angiography. Prothrombotic conditions. Pregnancy. Contraceptives. Anticoagulants. Heparin. Thrombolysis. Antiepileptic drugs. Decompressive surgery Introduction Cerebral vein and dural sinus thrombosis (CVT) are less frequent than ischemic infarcts and intracerebral hemorrhages. In a nationwide hospital-based series in Portugal, an incidence of 0.22/ /year was reported [1]. In a cross-sectional study in the Netherlands, the incidence of CVT was 1.32/ /year [2 ]. This incidence is superior to that of bacterial meningitides in adults. CVT affect patients younger than those with other types of strokes and the incidence decreases in older subjects. CVT is more frequent in females. CVT have a more varied clinical presentation than other stroke types and hence they are more difficult to recognize. They rarely present as a stroke syndrome, i.e. as the sudden onset of focal symptoms and signs in a patient with classical vascular risk factors. Because of the increased use of magnetic resonance imaging (MR) for investigating patients with acute and subacute headaches and new onset seizures, CVT are now being diagnosed with increasing frequency.

2 523, Page 2 of 10 Curr Cardiol Rep (2014) 16:523 Aetiology (Table 1) The more frequent risk factors for CVT are prothrombotic conditions, either genetic or acquired, oral contraceptives, puerperium and pregnancy, infection and malignancy [3]. Subjects are at increased risk of developing a CVT when exposed to CVT precipitants if they have genetic or acquired thrombophilic disorders. The most frequent genetic thrombophilias are G20210A prothrombin and factor V Leiden mutations, followed by protein C, S and antithrombin III deficiencies [4 8]. Hyperhomocysteinemia is a risk factor for VT, but the role of MTHFR/C677T mutation is controversial [8, 9, 10 ]. Among acquired thrombophilias are systemic conditions such as antiphospholipid syndrome, cancer, inflammatory bowel disease and nephrotic syndrome. Polycythemia and thrombocythemia also predispose to CVT. In endemic areas (and in migrants form endemic areas), Behçet s disease is a common cause of CVT. Infective causes have declined as a cause of CVT, but in developing countries systemic and nervous system infections may remain an important cause of CVT [11]. The most common infections associated with CVT are otitis, mastoiditis and sinusitis. Nowadays, facial cutaneous infections are a cause of the rare cavernous sinus thrombosis. The most frequent risk factors in young women are oral contraceptive use and pregnancy and puerperium [3, 12 ]. CVT has also been reported in association with hormone replacement therapy, the day-after pill and in vitro fertilization [13]. Several diagnostic and treatment procedures that pierce the dura such as lumbar puncture and spinal anesthesia, neurosurgery interventions, jugular and other central venous catheters and several drugs with prothrombotic action, including androgens, tamoxifen, steroids, L-asparaginase, cyclosporine, lithium, and thalidomide are also listed as precipitants of CVT [3, 14]. In about 13 % of adult CVT patients despite extensive search, no underlying risk factor is found [3]. In the aetiological investigation of a case of CVT a systematic search for a prothrombotic condition is mandatory even if a precipitant, such as contraceptives, puerperium or infection is obvious. A prothrombotic condition will increase the risk of recurrence of thrombotic events and will modify the duration of anticoagulation after the acute phase. If meningitis is suspected, it is safe to perform a lumbar puncture [15 ]. To avoid the risk of a spinal hematoma, lumbar puncture should be performed before starting anticoagulation, or anticoagulants must be temporarily discontinued. In patients aged 40 or more with no apparent cause for CVT, we usually perform a search for an occult neoplasm and repeat complete blood cell count and platelets and blood tests for antiphospholipid syndrome in a follow up visit. Table 1 Risk factors associated with cerebral venous thrombosis Transient risk factors Infections Central nervous system (empyema, meningitis) Ear, sinus, mouth, face and neck (otitis, mastoiditis, tonsillitis, stomatitis, sinusitis, cellulitis) Systemic infections (sepsis, endocarditis, tuberculosis, human immunodeficiency virus, malaria) Pregnancy and puerperium Physical precipitants Head trauma Lumbar puncture, myelography, intrathecal medications, spinal anesthesia Radical neck surgery Neurosurgical procedures Jugular and subclavian catheters Drugs with prothrombotic action Oral contraceptives, hormone replacement therapy, androgens, medroxyprogesterone acetate, L- asparaginase, cyclosporine, tamoxifen, steroids, lithium, thalidomide, ecstasy, sildenafil Other conditions Dehydration Diabetic metoacidosis Permanent risk factors Prothrombotic conditions Genetic (Protein S, C, antithrombin deficiencies, factor V Leiden and prothrombin mutations) Acquired (antiphospholipid syndrome, nephrotic syndrome, cyanotic congenital heart disease) Malignancy Central nervous system (meningioma) Solid tumour outside central nervous system Haematological (leukemias, lymphomas) Haematological condition Anaemias (sickle cell disease and trait, iron deficiency, folic acid deficiency) Paroxysmal nocturnal hemoglobinuria Polycythemia (primary or secondary) Thrombocythemia (primary or secondary) CNS disorders Dural fistulae Inflammatory diseases Behçet s disease Systemic lupus erythematosus Sjögren s syndrome Wegener s granulomatosis Temporal arteritis Thromboangiitis obliterans Inflammatory bowel disease Sarcoidosis Other disorders Thyroid disease (hyper and hypothyroidism)

3 Curr Cardiol Rep (2014) 16:523 Page 3 of 10, 523 Clinical Aspects The clinical presentation of CVT is highly variable and its onset can be acute, subacute and less frequently chronic. Symptoms and signs of CVT can be grouped in three more frequent syndromes: 1) isolated intracranial hypertension syndrome, consisting of headache with or without vomiting, papilloedema and visual troubles [16], including isolated headache 2) focal syndrome, depicting focal deficit such as paresis and aphasia, seizures or both and 3) encephalopathy, when bilateral or multifocal signs, delirium, dysexecutive or consciousness disturbances occur [1, 6]. Less frequent presentation syndromes include cavernous sinus syndrome, syndromes of multiple palsies of the lower cranial nerves and subarachnoid haemorrhage, either generalized or localized to a single or few cortical sulci of the hemispheric convexity [17]. Headache is the most frequent symptom of CVT, usually the initial one and can be the sole manifestation of CVT [18]. The most frequent type of headache is the intracranial hypertension type, a severe, generalized headache of progressive onset, worsening with Valsalva s manoeuvres and when lying down [19]. Transient loss of vision can occur in association with episodes of intense headache. A few cases of CVT present with thunderclap headache [20, 21] or even migraine with aura [22]. The clinical presentation of CVT varies according to the age of the patient, the time to diagnosis and location of the thrombosis. Encephalopathy is more frequent is elderly patients [23]. Isolated intracranial hypertension and papilloedema are more frequent in patients with a chronic presentation [24, 25]. In cavernous sinus thrombosis, there is headache, orbital pain, chemosis, proptosis, ptosis, diplopia and oculomotor palsies. Typically, cortical vein thrombosis produces motor and or sensory deficits and seizures [26 28]. In the occlusion of the sagittal sinus motor deficits can be unilateral or bilateral, and focal or generalized seizures are frequent. Patients with isolated thrombosis of the lateral sinus often present as isolated intracranial hypertension, but aphasia is frequent in left transverse sinus occlusion. If the deep cerebral venous system is occluded the clinical picture is often severe with coma, mental deficits and paresis. and include the cord sign (thrombosed cortical or deep vein), the dense triangle sign (visualization of the clot inside the sinus), and the empty delta sign, visible after contrast injection. Parenchymal lesions may occur in % of cases, and some topographic lesions are suggestive of a specific sinus occlusion: bilateral parasagittal hemispheric lesions, temporooccipital, bilateral thalamic lesions, which are highly suspected of thrombosis of the superior sagittal sinus, lateral sinus and deep venous system, respectively. A small subdural haematoma or subarachnoid haemorrhage may rarely be demonstrated. In serial CTs, new lesions may appear and some may disappear ( vanishing infarcts ) [29]. Helical CT venography with bolus injection of contrast material provides excellent anatomic detail of venous circulation and can demonstrate filling defects in the dural sinus and cortical veins, sinus wall enhancement and increased collateral venous drainage [30 33]. Magnetic resonance imaging (MRI) combined with magnetic resonance venography (MRV) (Fig. 1) is currently the best method to confirm the diagnosis of CVT. The combination of an abnormal signal in a sinus and a corresponding absence of flow on MRV supports the diagnosis of CVT. In the first five days the signal of the thrombus is predominantly isointense on T1-weighted images and hypointense on T2-weighted images. After the first days, the diagnosis Confirmation of the Diagnosis The confirmation of the diagnosis of CVT relies on the demonstration of thrombi in the cerebral veins and/or sinuses by neuroimaging. In the evaluation of patients suspected of CVT or presenting with subacute headache, computed tomography (CT) is useful to rule out tumour, subdural haematoma or abscess. Direct signs of CVT can be found in about one-third of cases Fig. 1 Right transverse sinus thrombosis demonstrated by veno-mr in a 26 years old woman with mastoiditis and oral contraceptive use. Notice increased venous collateral circulation on the side of the thrombosed sinus

4 523, Page 4 of 10 Curr Cardiol Rep (2014) 16:523 becomes easier due to an increased signal on both T1 and T2- weighted images; after the first month there is a variable pattern of signal, which may more frequently become isointense or hyperintense on T2-weighted images and hypointense or isointense on T1 [34 36]. Echo-planar T 2 * susceptibility-weighted imaging (T 2 *SW) sequences improve the diagnosis of CVT enabling the identification of intraluminal thrombus as a hypointense area. T 2 *SW sequences are particularly useful in the acute stage of dural sinus thrombosis and in the diagnosis of isolated cortical venous thrombosis [37 39]. MRI is also useful in showing parenchymal lesions secondary to venous occlusion, demonstrating hypo- or isointense lesions on T1-weighted images and hyperintense on T2-weighted images, or hemorrhagic lesions, appearing as hyperintense lesions in both MRI sequences. In contrast to arterial infarct, in venous infarcts, ADC and DWI images do not always match [40] and infarct appears larger in the FLAIR than in DWI. Venous MR TOF demonstrates the absence of flow in the thrombosed vessel. Limitations of MR venography are the diagnosis of cortical vein thrombosis, diagnosis of partial occlusion and distinction between hypoplasia and thrombosis [41]. At present, intra-arterial angiography is rarely required for diagnosis. It may be performed mainly when the diagnosis of CVT is doubtful, or when it is mandatory to exclude a dural arteriovenous fistulae or distal aneurysm, such as the presence of subarachnoid haemorrhage. Typical signs of CVT on angiography are partial or complete lack of filling of veins or sinuses, delayed emptying, dilated collaterals, and the sudden stop of cortical veins surrounded by dilated and tortuous collateral corkscrew veins. Anatomical variations may complicate the interpretation of angiography, such as hypoplasia of the anterior part of the superior sagittal sinus, duplication of the superior sagittal sinus, and hypo- or aplasia of the transverse sinuses. D-Dimers Most acute CVT patients had increased D-dimer levels, but patients presenting later after onset of symptoms or with isolated headache exhibited normal D-Dimers levels [42, 43 ]. D-Dimer assay has a high negative predictive value ( %) but a low sensitivity (83-95 %). Although normal levels make CVT diagnosis unlikely, they cannot rule out the diagnosis, and consequently they are not a good screening test in patients with suspected CVT. Prognosis The aggregate death or dependency rate in recent CVT cohorts at the end of follow up in these studies was 15 %. In the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) cohort, 79 % recovered completely [3]. In a meta-analysis that also included retrospective studies [44], the overall rate of acute death was 5.6 %, of death at the end of follow up was 9.4 % and of complete recovery was 88 %. The prognostic factor for poor outcome are age more than 37 years, male gender, Glasgow Coma Scale score <9 on admission, mental status disorder, thrombosis of the deep venous system, intracranial haemorrhage on admission CT/MRI, malignancy and infection of the Central Nervous System [3]. This predictive model was validated in two independent validation cohorts [45]. From the model a risk score was derived. A score of 3 points indicates a higher risk of unfavourable outcome [45]. Four percent of acute CVT patients die in the acute phase. For the majority of patients who die in the acute phase the cause of death is transtentorial herniation secondary to a large hemorrhagic lesion [46]. Other patients die due to herniation secondary to diffuse brain oedema, status epilepticus and medical complications including pulmonary embolism [47]. Complications after the acute phase include venous thrombotic events, seizures and headaches. The underlying disease, in particular malignancies, may lead to death in the months or years following CVT. Headaches severe enough to require bed rest or hospital admission afflict 14 percent of patients with CVT [3]. Recurrent CVT is rare and sometimes difficult to document. It is useful to have a MR/MR angiography at 3 to 6 months after the venous thrombosis to document the extent of recanalisation. If new symptoms occur, suggesting recurrence of CVT, MR and MR venography should be repeated and the images compared with previous ones. Other thrombotic events, specifically deep venous thrombosis of the limbs or pelvis and pulmonary embolism occur in about 5 % of the patients. Male gender, polycythemia/thrombocythemia and severe thrombophilia are associated with a higher risk of recurrent venous thrombotic events [48, 49]. Seizures may occur in up to 11 % of the patients. Risk factors for these remote seizures are seizures during the acute phase, a hemorrhagic supratentorial parenchymal lesion or a motor deficit [50]. Severe visual loss due to intracranial hypertension is very rare nowadays [3]. A few CVT survivors may have subnormal visual acuity or visual fields and esodeviation [51]. In spite of the apparent general good recovery, several studies pointed out that psychological and cognitive complaints are not uncommon among CVT survivors. About half of the survivors of CVT feel depressed or anxious and demonstrate minor cognitive or language deficits, which may preclude that they resume their previous level of professional activity [52, 53, 54 ].

5 Curr Cardiol Rep (2014) 16:523 Page 5 of 10, 523 Recanalisation of thrombosed cerebral vein and sinus occurs in 40 to 90 percent of patients after CVT, mostly within the first four months [55]. Recanalization of the occluded sinus is not related with outcome after CVT [56], except in children. The presence of hyperintensities in the veins/sinus in DWI MR predicts low recanalization rate [57]. Treatment (Table 2) The treatment of CVT includes 1) antithrombotic treatment, 2) symptomatic treatment of intracranial hypertension, seizures, headache and visual failure, 3) aetiological treatment to manage the associated conditions and risk factor [58, 59 ]. Antithrombotic Treatment The aims of antithrombotic treatment in CVT are: 1) to recanalize the occluded sinus/vein, 2) to combat the propagation of the thrombus, 3) to prevent pulmonary embolism, 4) to treat the underlying prothrombotic state. Two randomized controlled trials (RCTs) of anticoagulation in acute CVT were performed [60, 61]. The meta-analysis of these trials [62 ] showed a relative risk of 0.46 (95 % CI 0.16 to 1.31) (60 % relative risk reduction) of death or dependency after anticoagulant therapy as compared to placebo. The possibility that heparin may be harmful was recently raised in a systematic review of observational studies and randomized trials [63]. This review has serious methodological flaws, including missing data and selection bias [64, 65]. In our experience and in the ISCVT cohort the risk of new or increased intracerebral haemorrhage is low. Furthermore such haemorrhages do not influence outcome. Anticoagulants are also safe to use in patients with intracranial haemorrhages, either intracerebral or subarachnoid [66, 67 ]. Nowadays there is a large consensus on the use of heparin or LMWH in acute CVT. Guidelines on the treatment of CVT recommended that patients with CVT without contraindications for anticoagulation should be treated either with APTT adjusted IV heparin or body-weight-adjusted low-molecular-weight heparin [58, 59 ]. Regarding the option between IV unfractionated heparin and low molecular weight heparin, a case control study and a randomized clinical trial support the preference for the later [68, 69 ]. This is in general our option, except in patients who are expected to undergo an invasive procedure (lumbar puncture, surgery). Thrombolysis Direct thrombolysis through endovascular venous access has been used in some centres as an alternative for systemic anticoagulation, particularly in CVT patients with severe clinical condition or not improving or worsening despite anticoagulation. Despite widespread use and the publication of multiple successful case reports and case series, the efficacy and safety of local thrombolysis in CVT patients remains to be proved by a randomized clinical trial. A systematic review of 169 patients [70] treated with local thrombolysis reported that only 5 % of patients died during the acute phase of CVT and 8 % were dependent at discharge, suggesting a possible benefit for severe CVT cases. Intracranial haemorrhages were reported in 17 % of cases, and 5 % were then associated with clinical deterioration. In 19 % of patients extracranial haemorrhages were reported, and they were severe in 2 %. A more recent systematic review [71] emphasized the nonnegligible incidence of major bleeding (9.8 %) complications, including 7.6 % intracranial hemorrhages, 58.3 % of which were fatal. Furthermore, there is certainly a publication bias in the literature, with under-reporting of cases with poor outcome and complications. In a recent single center series of 20 patients treated with IV local thrombolysis, this type of treatment was not useful to prevent death secondary to herniation of large infarcts [72]. These results are worse than those in the previously published literature, but may reflect the prevailing results in clinical practice. Endovascular thrombolysis may be performed in selected centres with expertise in interventional radiology, as a therapeutic option, in patients with a poor prognosis, such as those with thrombosis of the cerebral deep venous system who worsen despite the best medical treatment and anticoagulation, provided that other causes of worsening are excluded and treated. A randomized trial to compare endovascular treatment (TO-ACT) is currently ongoing [73 ]. Prevention of Thrombotic Events after the Acute Phase Recurrence of cerebral venous thrombosis is rare, but nonetheless occurs in 2 to 7 % of patients. Extracerebral venous thrombosis can occur in about 5 % of patients. To prevent these recurrent thrombotic events, anticoagulation with warfarin is recommended, usually for 3 to 12 months after acute CVT. The EFNS and the AHA/ASA Guidelines suggest that when CVT is related to a transient risk factor (e.g. pregnancy, infection), anticoagulants may be used for a short period (3 or 3-6 months). In patients with idiopathic CVT or CVT associated with mild thrombophilia, the period of anticoagulation must be longer (6 to 12 months). In patients with combined or severe thrombophilia (e.g. two or more prothrombotic abnormalities; antithrombin III, protein C or S deficiencies, antiphospholipid syndrome, cancer) or recurrent venous thrombosis, anticoagulants should be given for life. A clustered randomized trial (EXCOA-CVT) ( was recently launched and aims to compare the efficacy and safety of a short (3-6 months) and long (12 months) term

6 523, Page 6 of 10 Curr Cardiol Rep (2014) 16:523 Table 2 CVT treatment: adapted from EFNS guidelines Acute phase 1. Treatment of the permanent or transient risk factors, if applicable 2. Antithrombotic treatment i. Sc. Low molecular weight heparin or IV heparin in therapeutical dosages ii. Local IV thrombolysis and/or mechanical thrombectomy is an option if neurological worsening occurs despite best medical treatment, is not explained by an herniating lesion, occurs despite best medical treatment and other causes of neurological deterioration (e.g. non convulsive epileptic seizures, meningitis) are excluded 3. Symptomatic treatment a. Antiepileptics i. In patients with acute seizures and supratentorial lesions ii. Consider as an option also for patients with acute seizures without supratentorial lesions b. Intracranial hypertension i. Headache. 1. Analgesics 2. Lumbar puncture, if there are no parenchymal lesions; perform before starting anticoagulation 3. Acetazolamide. ii. Impairment of consciousness or herniation 1. Osmotic therapy 2. Sedation and hyperventilation 3. Decompressive surgery (hemicraniectomy and hematoma evacuation) iii. Threatened vision 1. Lumbar puncture, if there are no parenchymal lesions; perform before starting anticoagulation. 2. Acetazolamide 3. Lumboperitoneal shunt 4. Optic nerve fenestration Post-acute phase 1. Treatment of the permanent or transient risk factor, if applicable 2. Antithrombotic treatment a. Oral anticoagulants i. For 3-6 months, if CVT is associated with a transient risk factor ii. For 6-12 months, if CVT is idiopathic or associated with a mild hereditary thrombophilia iii. Permanent, if CVT is recurrent or associated with a combined or severe hereditary thrombophilia 3. Symptomatic treatment a. Antiepileptics i. In patients with acute seizures or seizures in the post-acute phase and supratentorial lesions ii. Consider as an option also for patients with acute seizures or seizures in the post-acute phase without supratentorial lesions b. Headache i. Paracetamol ii. Acetazolamide iii. Lumbar puncture (s) iv. Lumboperitoneal shunt c. Threatened vision i. Acetazolamide ii. Lumbar puncture (s) iii. Optic nerve fenestration iv. Lumboperitoneal shunt anticoagulation policies to prevent venous thromboembolic events after acute CVT. There is limited clinical experience with the new anticoagulants in CVT [74].

7 Curr Cardiol Rep (2014) 16:523 Page 7 of 10, 523 Symptomatic Treatment Treatment of Intracranial Hypertension In acute CVT patients with severe headache with or without papilloedema, intracranial hypertension can be reduced and headache relieved through a therapeutical lumbar puncture when not contraindicated by parenchymal lesions. In more severe acute cases one or multiple large haemorrhagic lesions or infarcts or massive brain oedema may lead to fatal brain herniation. Some of these patients may improve or be transiently stabilized by osmotic diuretics such as mannitol, or by ICU care including sedation and hyperventilation. Corticosteroids may decrease vasogenic oedema, but they may also promote thrombosis. A case control-study failed to demonstrate any benefit of steroids even in patients with parenchymal lesions [75]. In patients with impending herniation due to large unilateral hemispherical lesion, decompressive surgery, either hemicraniectomy or hematoma evacuation, is life-saving and often results in good functional outcome, even in patients with severe clinical conditions [76, 77, 78, 79 ]. In a multicentre registry and systematic review of published cases up to 2011, 38 % recovered completely and only 16 % died and 6 % were alive and dependent [77 ]. Shunting alone is not effective in preventing death from brain herniation in acute CVT [80 ]. Acute obstructive hydrocephalus is rare in acute CVT. Despite shunting half of these patients have a bad outcome [80 ]. In patients with chronically increased intracranial pressure, treatment of intracranial hypertension is necessary to improve headache and prevent visual failure. A diagnostic/therapeutic lumbar puncture decreases CSF pressure and offers headache relief. Diuretics such as acetazolamide or furosemide, can also be used. If severe headaches persist or if visual acuity is decreasing, repeated lumbar punctures, a lumbo-peritoneal shunt, stenting of a sinus stenosis [81] or fenestration of the optic nerve sheet can be considered [82]. Treatment and Prevention of Seizures Patients with seizures in the acute phase, should be treated in the acute phase with antiepileptic medications, especially if they have supratentorial lesions [83]. Prophylactic antiepileptics are not recommended for patients without seizures [58, 59 ]. The long term risk of remote seizures is approximately 11 % [3]. To prevent recurrent seizures and status epilepticus, antiepileptics are recommended for patients with seizures in the acute phase and for those who experience a seizure after the acute phase, in particular if the patients also have other risk factors for remote seizures, such as supratentorial hemorrhagic lesions or motor deficits [50]. The optimal duration of antiepileptic treatment is unknown. General recommendations for the selection and withdrawal of anti-epileptic drugs can be used as options. Contraception and Future Pregnancies Women who had a CVT must not become pregnant while on oral anticoagulants, because of their teratogenic effects. They should use contraceptive methods other than oral or parental contraceptives. Emergency contraception is also contraindicated [84]. Hormonal replacement therapy should be stopped. CVT and pregnancy or puerperium-related CVT are not a contraindication for future pregnancy. The risk of venous thrombotic events during subsequent pregnancies among women who have a history of CVT is low although a high number of miscarriages were observed [85 ]. Conclusions and Future Directions During the last decade there was a surge in interest and increased awareness of CVT, in part due to the possibility of confirming the clinical diagnosis of CVT by MR. Results of large multicentre studies outlined the frequency of major transient and permanent risk factors, described the acute and long term prognosis and the prognostic factors for the outcome of CVT. In the years to come ongoing registries, multicentre observational studies and randomized controlled clinical trials evaluating genetic factors, diagnostic serum biomarkers, decompressive surgery, thrombolysis and the duration of post-acute anticoagulation, will undoubtedly increase the evidence-basis body supporting guidelines and clinical practice in this condition. Compliance with Ethics Guidelines Conflict of Interest José M. Ferro has board membership with Lundbeck. He has been a consultant for Boehringer Ingelheim, and has received payment for development of educational presentations including service on speakers bureaus. Patrícia Canhão declares that she has no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. References Papers of particular interest, published recently, have been highlighted as: Of importance 1. Ferro JM, Correia M, Pontes C, for the Cerebral Venous Thrombosis Portuguese Collaboration Study Group (VENOPORT), et al. Cerebral venous thrombosis in Portugal Cerebrovasc Dis. 2001;11:

8 523, Page 8 of 10 Curr Cardiol Rep (2014) 16: Coutinho JM, Zuurbier SM, Aramideh M, Stam J. The incidence of cerebral venous thrombosis: a cross-sectional study. Stroke. 2012;43: A well designed cross-sectional epidemiological study performed in the Netherlands showing a incidence of CVT of 1.32/ /year. 3. Ferro JM, Canhão P, Stam J, ISCVT Investigators, et al. Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke. 2004;35: Biousse V, Conard J, Brouzes C. Frequency of GA mutation in the 3 - untranslated region of the prothrombin gene in 35 cases of cerebral venous thrombosis. Stroke. 1998;29: Martinelli I, Sacchi E, Landi G, et al. High risk of cerebral-vein thrombosis in carriers of prothrombin-gene mutation and in users of oral contraceptives. N Engl J Med. 1998;338: Deschiens MA, Conard J, Horellou MH, et al. Coagulation studies, factor V Leiden, and anticardiolipin antibodies in 40 cases of cerebral venous thrombosis. Stroke. 1996;27: Zuber M, Toulon P, Marnet L, et al. Factor V Leiden mutation in cerebral venous thrombosis. Stroke. 1996;27: Lauw MN, Barco S, Coutinho JM, Middeldorp S. Cerebral venous thrombosis and thrombophilia: a systematic review and metaanalysis. Semin Thromb Hemost. 2013;39: Gouveia LO, Canhão P. Allele 677T MTHFR: Prothrombotic risk factor for cerebral venous thrombosis? A meta-analysis. Cerebrovasc Dis. 2008;25: Marjot T, Yadav S, Hasan N, et al. Genes associated with adult cerebral venous thrombosis. Stroke. 2011;42: A systematic review of studies investigating the association of CVT with different genetic mutations, showing that genes in the clotting cascade are more important in venous than in arterial stroke. 11. Khealani BA, Wasay M, Saadah M, et al. Cerebral venous thrombosis. A descriptive multicenter study of patients in Pakistan and Middle East. Stroke. 2008;39: Khan M, Wasay M, Menon B, et al. Pregnancy and puerperiumrelated strokes in Asian women. J Stroke Cerebrovasc Dis. 2013;22: A multicentre retrospective study in Asia showing that CVT is an important contributor to pregnancy-related strokes. 13. Edris F, Kerner CM, Feyles V, et al. Successful management of an extensive intracranial sinus thrombosis in a patient undergoing IVF: case report and review of the literature. Fertil Steril. 2007;88: 705.e Saadatnia M, Fatehi F, Basiri K, et al. Cerebral venous sinus thrombosis risk factors. Int J Stroke. 2009;4: Canhão P, Abreu LF, Ferro JM, ISCVT Investigators, et al. Safety of lumbar puncture in patients with cerebral venous thrombosis. Eur J Neurol. 2013;20: This nested case control study shows that it is safe to perform a lumbar puncture in patients with CVT. 16. Biousse V, Ameri A, Bousser MG. Isolated intracranial hypertension as the only sign of cerebral venous thrombosis. Neurology. 1999;53: Geraldes R, Sousa PR, Fonseca AC, et al. Nontraumatic convexity subarachnoid hemorrhage: different etiologies and outcomes. J Stroke Cerebrovasc Dis. 2014;23:e Cumurciuc R, Crassard I, Sarov M, et al. Headache as the only neurological sign of cerebral venous thrombosis: a series of 17 cases. J Neurol Neurosurg Psychiatry. 2005;76: Lopes MG, Ferro J, Pontes C, for the Venoport Investigators, et al. Headache and cerebral venous thrombosis. Cephalalgia. 2000;20: De Bruijn SF, Stam J, Kappelle LJ, CVST Study Group. Thunderclap headache as first symptom of cerebral venous sinus thrombosis. Lancet. 1996;348: Sharma B, Satija V, Dubey P, Panagariya A. Subarchnoid haemorrhage with transient ischemic attack: another masquerade in cerebral venous thrombosis. Indian J Med Sci. 2010;64: Martins IP, Sá J, Pereira RC, et al. Cerebral venous thrombosis May mimic migraine with aura. Headache Q. 2001;12: Ferro JM, Canhão P, Bousser MG, et al. ISCVT Investigators. Cerebral vein and dural sinus thrombosis in elderly patients. Stroke. 2005;36: Ferro JM, Lopes MG, Rosas MJ, VENOPORT Investigators, et al. Delay in hospital admission of patients with cerebral vein and dural sinus thrombosis. Cerebrovasc Dis. 2005;19: Ferro JM, Canhão P, Bousser MG, ISCVT Investigators, et al. Delay in the diagnosis of cerebral vein and dural sinus thrombosis (CVT). Influence on outcome. Cerebrovasc Dis. 2008;25 suppl 2: Jacobs K, Moulin T, Bogousslavsky J, et al. The stroke syndrome of cortical vein thrombosis. Neurology. 1996;47: Cakmak S, Hermier M, Montavon A, et al. T2*-weighted MRI in cortical venous thrombosis. Neurology. 2004;63: Duncan IC, Fourie PA. Imaging of cerebral isolated cortical vein thrombosis. AJR Am J Roentgenol. 2005;184: Buonanno F, Moody DM, Ball MR, et al. Computed cranial tomographic findings in cerebral sino-venous occlusion. J Comput Assist Tomogr. 1978;2: Casey SO, Alberico RA, Patel M, et al. Cerebral CT venography. Radiology. 1996;198: Ozsvath RR, Casey SO, Lustrin ES, et al. Cerebral venography: comparison of CT and MR projection venography. AJNR Am J Neuroradiol. 1997;169: Rodallec MH, Krainik A, Feydy A, et al. Cerebral venous thrombosis and multidetector CT angiography: tips and tricks. RadioGraphics. 2006;26:S5 S Wetzel SG, Kirsch E, Stock KW. Cerebral veins: comparative study of CT venography with intra-arterial digital subtraction angiography. Am J Neuroradiol. 1999;20: Dormont D, Anxionnat R, Evrard S, et al. MRI in cerebral venous thrombosis. J Neuroradiol. 1994;21: Isensee C, Reul J, Thron A. Magnetic resonance imaging of thrombosed dural sinuses. Stroke. 1994;25: Leach JL, Wolujewics M, Strub WM. Partially recanalized chronic dural sinus thrombosis: findings on MR imaging, time-of-flight MR Venography, and contrast-enhancement venography. AJNR Am J Neuroradiol. 2007;28: Selim M, Fink J, Linfante I, et al. Diagnosis of cerebral venous thrombosis with echo-planar T2*-weighted magnetic resonance imaging. Arch Neurol. 2002;59: Fellner FA, Fellner C, Aichner FT, et al. Importance of T2*- weighted gradient-echo MRI for diagnosis of cortical vein thrombosis. Eur J Neurol. 2005;56: Idbaih A, Boukobza M, Crassard I, et al. MRI of clot in cerebral venous thrombosis: high diagnostic value of susceptibilityweighted images. Stroke. 2006;37: Ducreux D, Oppenheim C, Vandamme X, et al. Diffusionweighted imaging patterns of brain damage associated with cerebral venous thrombosis. AJNR Am J Neuroradiol. 2001;22: Ayanzen RH, Bird CR, Keller PJ, et al. Cerebral MR venography: normal anatomy and potential diagnostic pitfalls. AJNR Am J Neuroradiol. 2000;21: Crassard I, Soria C, Tzourio C, et al. A negative D-dimer assay does not rule out cerebral venous thrombosis: a series of seventy-three patients. Stroke. 2005;36: Dentali F, Squizzato A, Marchesi C, et al. D-dimer testing in the diagnosis of cerebral vein thrombosis: a systematic review and a meta-analysis of the literature. J Thromb Haemost. 2012;10: A detailed systematic review depicting the value and limitations of D-Dimer testing to screen for CVT. 44. Dentali F, Gianni M, Crowther MA, et al. Natural history of cerebral vein thrombosis: a systematic review. Blood. 2006;108:

9 Curr Cardiol Rep (2014) 16:523 Page 9 of 10, Ferro JM, Bacelar-Nicolau H, Rodrigues T, ISCVT and VENOPORT investigators, et al. Risk score to predict the outcome of patients with cerebral vein and dural sinus thrombosis. Cerebrovasc Dis. 2009;28: Canhão P, Ferro JM, Lindgren AG, ISCVT Investigators, et al. Causes and predictors of death in cerebral venous thrombosis. Stroke. 2005;36: Diaz JM, Schiffman JS, Urban ES, et al. Superior sagittal sinus thrombosis and pulmonary embolism: a syndrome rediscovered. Acta Neurol Scand. 1992;86: Miranda B, Ferro JM, Canhão P, ISCVT Investigators, et al. Venous thromboembolic events after cerebral vein thrombosis. Stroke. 2010;41: Martinelli I, Bucciarelli P, Passamonti SM, et al. Long-term evaluation of the risk of recurrence after cerebral sinus-venous thrombosis. Circulation. 2010;121: Ferro JM, Correia M, Rosas MJ, et al. Cerebral Venous Thrombosis Portuguese Collaborative Study Group [Venoport]. Seizures in cerebral vein and dural sinus thrombosis. Cerebrovasc Dis. 2003;15: Purvin VA, Trobe JD, Kosmorsky G. Neuro-ophthalmic features of cerebral venous obstruction. Arch Neurol. 1995;52: Buccino G, Scoditti U, Patteri I, et al. Neurological and cognitive long-term outcome in patients with cerebral venous sinus thrombosis. Acta Neurol Scand. 2003;107: de Bruijn SF, Budde M, Teunisse S, et al. Long-term outcome of cognition and functional health after cerebral venous sinus thrombosis. Neurology. 2000;54: Bugnicourt JM, Guegan-Massardier E, Roussel M, et al. Cognitive impairment after cerebral venous thrombosis: a two-center study. J Neurol. 2013;260: A detailed neuropsychological study in two French centers showing that cognitive impairment persists in up to 1/3 of cases of CVT and is associated with failure to return to full-time employment. 55. Baumgartner RW, Studer A, Arnold M, et al. Recanalisation of cerebral venous thrombosis. J Neurol Neurosurg Psychiatry. 2003;74: Strupp M, Covi M, Seelos K, et al. Cerebral venous thrombosis: correlation between recanalization and clinical outcome a longterm follow-up of 40 patients. J Neurol. 2002;249: Favrole P, Guichard JP, Crassard I, et al. Diffusion-weighted imaging of intravascular clots in cerebral venous thrombosis. Stroke. 2004;35: Einhäupl K, Stam J, Bousser MG, et al. European Federation of Neurological Societies. EFNS guideline on the treatment of cerebral venous and sinus thrombosis in adult patients. Eur J Neurol. 2010;17: Saposnik G, Barinagarrementeria F, Brown Jr RD, et al. American heart association stroke council and the council on epidemiology and prevention. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42: A detailed and comprehensive guideline for the diagnosis and management of CVT. 60. Einhäupl KM, Villringer A, Meister W, et al. Heparin treatment in sinus venous thrombosis. Lancet. 1991;338: De Bruijn SF, Stam J. CVST study group. Randomized, placebocontrolled trial of anticoagulant treatment with low-molecularweight heparin for cerebral sinus thrombosis. Stroke. 1999;30: Stam J, de Bruijn SF, deveber G. Anticoagulation for cerebral sinus thrombosis. Cochrane Database Syst Rev. 2011;8:CD Anticoagulant treatment for CVT appears to be safe and is associated with an important reduction in the risk of death or dependency. 63. Cundiff DK. Anticoagulants for cerebral venous thrombosis: harmful to patients? Stroke. 2014;45: Coutinho JM, Bousser MG, Stam J. Response to evidence-basis for anticoagulants for cerebral sinus venous thrombosis? Stroke. 2013;44:e Wingerchuk DM, Wijdicks EF, Fulgham JR. Cerebral venous thrombosis complicated by hemorrhagic infarction: factors affecting the initiation and safety of anticoagulation. Cerebrovasc Dis. 1998;8: Selim M. Cerebral venous thrombosis. Another heparin controversy. Stroke. 2014;45: Ghandehari K, Riasi HR, Noureddine A, et al. Safety assessment of anticoagulation therapy in patients with hemorrhagic cerebral venous thrombosis. Iran J Neurol. 2013;12: An Iranian prospective single center series of 102 CVT patients with hemorrhagic brain lesions of whom 52 were anticoagulated. Clinical course was similar in anticoagulated and non anticoagulated patients, a finding which supports the safety of anticoagulation in CVT patients with hemorrhagic brain lesions. 68. Coutinho JM, Ferro JM, Canhão P, ISCVT Investigators, et al. Unfractionated or low-molecular weight heparin for the treatment of cerebral venous thrombosis. Stroke. 2010;41: Misra UK, Kalita J, Chandra S, et al. Low molecular weight heparin versus unfractionated heparin in cerebral venous sinus thrombosis: a randomized controlled trial. Eur J Neurol. 2012;19: A RCT performed in India comparing the outcome of 32 acute CVT patients randomized to low molecular weight heparin or unfractionated heparin. Low molecular weight heparin resulted in significantly lower hospital mortality. 70. Canhão P, Falcão F, Ferro JM. Thrombolytics for cerebral sinus thrombosis: a systematic review. Cerebrovasc Dis. 2003;15: Dentali F, Squizzato A, Gianni M, et al. Safety of thrombolysis in cerebral venous thrombosis. A systematic review of the literature. Thromb Haemost. 2010;104: Stam J, Majoie BLM, van Delden OM, et al. Endovascular thrombectomy and thrombolysis for severe cerebral sinus thrombosis: a prospective study. Stroke. 2008;39: Coutinho JM, Ferro JM, Zuurbier SM, et al. Thrombolysis or anticoagulation for cerebral venous thrombosis: rationale and design of the TO-ACT trial. Int J Stroke. 2013;8: Description of the protocol of the TO-ACT trial comparing anticoagulation with thrombolysis in patients with severe acute CVT. 74. Hon SF, Li HL, Cheng PW. Use of direct thrombin inhibitor for treatment of cerebral venous thrombosis. J Stroke Cerebrovasc Dis. 2012;21:915.e Canhão P, Cortesão A, Cabral M, for the ISCVT investigators, et al. Are steroids useful to treat cerebral venous thrombosis. Stroke. 2008;39: Théaudin M, Crassard I, Bresson D, et al. Should decompressive surgery be performed in malignant cerebral venous thrombosis? a series of 12 patients. Stroke. 2010;41: Ferro JM, Crassard I, Coutinho JM, Second International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT 2) Investigators, et al. Decompressive surgery in cerebrovenous thrombosis: a multicenter registry and a systematic review of individual patient data. Stroke. 2011;42: A retrospective multicentre registry of 38 patients and a meta-analysis of individual patient data from 31 published cases showing that decompressive surgery (craniectomy or hematoma evacuation) is life saving in acute CVT patients with large brain lesions and impending herniation, and often results in favourable outcome, even in patients with severe clinical condition. 78. Rajan Vivakaran TT, Srinivas D, Kulkarni GB, Somanna S. The role of decompressive craniectomy in cerebral venous sinus thrombosis. J Neurosurg. 2012;117: In this Indian single center experience, 26/34 acute CVT patients treated with decompressive surgery had a good outcome.

10 523, Page 10 of 10 Curr Cardiol Rep (2014) 16: Aaron S, Alexander M, Moorthy RK, et al. Decompressive craniectomy in cerebral venous thrombosis: a single centre experience. J Neurol Neurosurg Psychiatry. 2013;84: An impressive series of 44 CVT patients treated with decompressive surgery in a single center in India, with very good outcomes. 80. Lobo S, Ferro JM, Barinagarrementeria F, et al. Shunting in acute cerebral venous thrombosis: a systematic review. Cerebrovasc Dis. 2014;37: This case series and systematic review shows that shunting alone does not appear to be effective in preventing death due to herniation in acute CVT patients. 81. Higgins JN, Owler BK, Cousins C, et al. Venous sinus stenting for refractory bening intracranial hypertension. Lancet. 2002;359: Murdock J, Tzu JH, Schatz NJ, Lee WW. Optic nerve sheath fenestration for the treatment of papilledema secondary to cerebral venous thrombosis. J Neuroophthalmol. 2014;34: Ferro JM, Canhão P, Bousser MG, ISCVT Investigators, et al. Early seizures in cerebral vein and dural sinus thrombosis: risk factors and role of antiepileptics. Stroke. 2008;39: Horga A, Santamaria E, Quinlez A, et al. Cerebral venous thrombosis associated with repeated use of emergency contraception. Eur J Neurol. 2007;14:e Ciron JK, Godenèche G, Vandamme X, et al. Obstetrical outcome of young women with a past history of cerebral venous thrombosis. Cerebrovasc Dis. 2013;36: A multicentre French study of 45 pregnancies in 24 women with a past history of CVT. The study confirms that CVT is not a contraindication for future pregnancies.

11 本文献由 学霸图书馆 - 文献云下载 收集自网络, 仅供学习交流使用 学霸图书馆 ( 是一个 整合众多图书馆数据库资源, 提供一站式文献检索和下载服务 的 24 小时在线不限 IP 图书馆 图书馆致力于便利 促进学习与科研, 提供最强文献下载服务 图书馆导航 : 图书馆首页文献云下载图书馆入口外文数据库大全疑难文献辅助工具