Advances in the Treatment of Cerebral Venous Thrombosis

Curr Treat Options Neurol (2014) 16:299 DOI 10.1007/s11940-014-0299-0

Cerebrovascular Disorders (HP Adams, Jr., Section Editor)

Advances in the Treatment of Cerebral Venous Thrombosis J. M. Coutinho, MD, PhD1,* S. Middeldorp, MD, PhD2 J. Stam, MD, PhD1 Address *,1Department of Neurology of the Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands Email: [email protected] 2 Department of Vascular Medicine of the Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands

Published online: 16 May 2014 * Springer Science+Business Media New York 2014

This article is part of the Topical Collection on Cerebrovascular Disorders Keywords Cerebral venous thrombosis

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Cerebral sinus thrombosis

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Anticoagulation

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Heparin

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Stroke

Opinion statement Patients with recent cerebral venous sinus thrombosis (CVT) should be fully anticoagulated with heparin as soon as the diagnosis is confirmed, even in the presence of cerebral hemorrhagic venous infarcts. Fixed-dose subcutaneous low-molecular-weight heparins (LMWH) in therapeutic dosage have a better safety profile and are probably more effective than dose-adjusted intravenous unfractionated heparin. After the patient is stabilized , oral anticoagulant treatment is started, aimed at an INR value between 2.0 and 3.0 for at least three months after the acute phase. Since about 40 % of patients with CVT have epileptic seizures at onset or during the first days, many require treatment with anti-epileptics. Prophylactic anti-epileptic treatment is an option, but its efficacy has not been investigated. If no new seizures occur after the acute phase, anti-epileptics can be tapered after three to six months. The efficacy of endovascular treatment, with mechanical and/or pharmacologic thrombolysis, has only been published in small case series, and cannot be regarded as proven effective treatment for CVT. Its theoretical advantage of more rapid clearance of thrombi may be offset by severe bleeding complications, and the limited availability and higher cost of the procedure. Patients who deteriorate because of large space-occupying venous infarcts have a high risk of dying from cerebral herniation. In such cases an emergent decompressive hemicraniectomy is often life-saving. Experience from different centers with this procedure shows a good clinical outcome in the majority of these patients. Patients with CVT may develop – and sometimes present with - chronic intracranial hypertension with headache and papilledema. In such patients the priority is

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Curr Treat Options Neurol (2014) 16:299

prevention of visual function loss; intracranial hypertension should be controlled with acetazolamide, and occasionally with repeated lumbar punctures if vision is threatened. Refractory cases will need a CSF shunting procedure.

Introduction Thrombosis of the cerebral sinuses and veins (CVT) has long been recognized as a potentially incapacitating or even lethal localization of venous thrombosis. Before the advent of modern imaging techniques the diagnosis was often made post-mortem, and mortality was high [1]. Older studies typically reported mortality figures of 20-40 %. Improved diagnosis, first by angiography, now by CT and MRI scanning, has resulted in the detection of less severe cases. This, in combination with better treatment, has led to a significantly improved in survival and better clinical outcomes during the last decades [2]. CVT may be regarded as a rare kind of stroke, since it often presents with acute cerebral symptoms, such as hemiplegia, aphasia, hemianopia, caused by impaired venous drainage from different areas of the brain [3•, 4]. There is, however a number of important differences with arterial stroke:

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CVT is much rarer. Its yearly incidence according to recent studies is about 1.3 per 100.000 [5•, 6]. The incidence of arterial stroke is about 100 times higher. – the median age of CVT is much lower than for arterial stroke, with a peak incidence at 30-40 years. – CVT affects women far more frequently than men, because of the higher risk of venous thrombosis for women in the reproductive age, related to pregnancy and the use of hormonal contraceptives [7•]. – CVT can present with many different clinical manifestations, ranging from an unusual headache in the outpatient clinic, to an emergency presentation with hemiplegia, seizures or coma. Diagnosing CVT can be challenging due to the abovementioned factors. Most neurology departments will admit no more than two or three cases yearly, and, therefore, the experience of neurologists and radiologists is often limited. If the diagnosis is clinically considered, careful scrutiny of even a standard non-contrast enhanced CT scan of the brain may yield useful clues. Thrombosed sinuses may be swollen and hyperdense, and venous hemorrhagic infarcts often have a typical appearance (Fig. 1a). Subtle signs should be looked for, such as bilateral tha-

lamic hypodensity, caused by thrombosis of the deep cerebral venous system (straight sinus, Galen’s vein, and internal cerebral veins, Fig. 1b). One or more small hemorrhages just below the cortex – called juxtacortical hemorrhages – are very specific for CVT and occur in approximately 25 % of patients with CVT and an intracerebral hemorrhage (Fig. 1c) [8]. If the diagnosis CVT is considered, either clinically or based upon the plain CT scan, confirmation is usually easy with contrast CT venography or with various MRI techniques, including gradient echo and MR venography. Diagnostic pitfalls are still numerous but are outside the scope of this paper [9••]. Conventional angiography is now rarely needed to diagnose CVT. A lumbar puncture is usually not helpful and should be avoided in patients with CVT, who need full dose anticoagulation with a form of heparin immediately. The only exception is in rare patients with imminent visual loss by severe papiloedema and intracranial hypertension, who should have an emergent lumbar puncture to measure and reduce the pressure. Although now widely accepted as standard treatment for CVT and recommended in international guidelines [10••, 11••, 12], the use of heparin for CVT has long been controversial. The fact that about 40 % of all patients with CVT have some degree of cerebral hemorrhage at baseline explains why in the past neurologists were reluctant to use anticoagulation in these patients. Others argued that the cause of these hemorrhages, actually mostly hemorrhagic infarcts, is thrombosis and that consequently anticoagulant treatment is the better choice. Trials are notoriously difficult to conduct in this rare and variable disease. Yet, some small randomized trials have been performed, that we reviewed in a recently updated meta-analysis in the Cochrane Library [13••]. In summary, we identified only two small trials which complied with predefined methodological standards. The first one, published in 1991, compared intravenous, dose-adjusted unfractionated heparin (UFH) with placebo. It was stopped after ten patients were included in each treatment arm because three patients had died in the control group, versus none in the UFH group [14]. Although methodological problems impeded generaliza-


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Fig. 1. Characteristic CT findings in patients with CVT. Axial non-contrast enhanced CT images of three patients with CVT. (a) Venous hemorrhagic infarct in the right hemisphere with both hypodense (edema) and hyperdense (hemorrhagic) areas. (b) Symmetrical hypodense aspect of the basal ganglia and thalami, indicating edema, which can be present in patients with thrombosis of the deep venous system. (c) Single juxtacortical hemorrhage in the right parietal lobe. The hemorrhage is located just below the cortex and has no surrounding edema.

tion of this result, many clinicians considered it as confirmation of what they believed to see in practice, namely that heparin was safe and probably effective. A second trial compared fixed-dose subcutaneous low molecular weight heparin (LMWH) with placebo in 59 patients, and found a small, non-significant advantage of LMWH [15]. The two trials combined showed a non-significant absolute risk reduction of poor outcomes (death or dependency) of 13 % (95 %CI -30 to 3 %) [13••]. Although not statistically significant, the fact that both trials included patients with CVT and cerebral hemorrhages, and that there were no new or increased cerebral hemorrhages in the patients treated with heparin, convinced most physicians that heparin is safe in these patients and increases the chance of a good outcome.

Endovascular thrombectomy or thrombolysis (ET) has the theoretical advantage of more rapid recanalization than can be expected after anticoagulation. However, the procedure can be technically difficult and is not without risk [16]. Because of the rarity of the disease, few centers can accumulate sufficient experience with endovascular treatment of CVT. Since most patients with CVT have a good prognosis with heparin treatment, we do not advocate routine ET for patients with CVT [17••]. In a subgroup with a poor prognosis, ET may be more effective than heparin, but this has not been investigated in a randomized controlled manner. A clinical trial of ET compared to standard treatment is now recruiting patients [16].

Treatment Pharmacological treatment: anticoagulation & & &

The aim of anticoagulant treatment in acute CVT is to arrest the thrombotic process and prevent extension of the thrombus. Heparins act by strongly catalyzing the natural anticoagulant protein antithrombin, and, thus, inactivates both factors Xa and IIa (thrombin). Heparin is not a thrombolytic drug. Dissolution and recanalization of the thrombus occurs by natural fibrinolysis, which is expected to begin after the acute thrombosis and extension has been halted by heparin.

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&

For rapid anticoagulation, two kinds of heparin are available: lowmolecular-weight heparins (LMWH) and unfractionated heparin (UFH). LMWH is given as fixed dose subcutaneous injections based on body weight, once or twice daily. Routine monitoring in not required, but when indicated the anticoagulant effect can only be assessed by LMWH-specific anti-Xa tests. UFH is the classic intravenous heparin, that needs to be dose-adjusted based on activated partial thromboplastin time (APTT) measurements. Clinical trials and meta-analyses have shown that LMWH is safer and more effective than UFH in extracerebral thrombosis [18]. A small randomized trial and a non-randomized study suggest that LMWH is also superior to UFH for the treatment of patients with CVT [19•, 20•].

Low molecular weight heparins Standard therapeutic dosage

Depends on the preparation used. Preparations should be used once or twice daily. Since – in rare situations – it may be necessary to acutely reverse LMWH treatment, and since protamin sulphate is only partially effective, we prefer a twice daily dosage schedule with a lower dosage per injection resulting in lower peak anti-Xa levels. Some frequently used preparations: Dalteparin 100 anti X-a U/kg twice daily Nadroparin 86 anti X-a U/kg twice daily Enoxaparin 1 mg/kg twice daily Tinzaparin 175 anti Xa U/kg once daily For maximum daily doses we refer to the manufacturer’s labeling information.

Contraindications to therapeutic dose LMWH (not exhaustive, see manufacturer’s labeling)

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Active major bleeding (exception: venous hemorrhagic infarcts caused by CVT are not a contraindication)

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When conditions with increased risk of bleeding are present, risk benefit should be balanced

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Recent or planned (interval shorter than 24 hours) major surgical procedure or lumbar puncture

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Known type I allergy to LMWH or heparin

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Recent history (shorter than three months) of confirmed heparin induced thrombocytopenia with antibodies still present.

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Severe renal insufficiency (eGFRG30 ml/min)

Main drug interactions

Drugs that interact with normal coagulation: oral anti-coagulants, platelet inhibitors. Corticosteroids may cause gastric ulcers which may render patients more prone to bleeding in the presence of heparin.

Curr Treat Options Neurol (2014) 16:299 Main side effects

Page 5 of 9, 299 Bleeding, skin reactions (type IV allergy), transient increase in liver transaminases . Rare: type I allergy (anaphylaxis), heparin-induced thrombocytopenia (HIT).

Special points

The anticoagulant effect of LMWH cannot be fully reversed by protamine sulphate. This disadvantage is most likely compensated by the more reliable, predictable, convenient and safe anticoagulant effect of LMWH.

Cost effectiveness

No formal cost-effectiveness analyses are available but given their effectiveness regarding neurological outcomes, LMWH are likely to be cost effective.

Unfractionated heparin Standard dosage

Unfractionated heparin (UFH) is given intravenously. Because of the short half-life, an initial bolus dose of 5000 IU i.v. is followed by a continuous infusion of 20.000–40.000 IE per 24 hr. The dose is adjusted by measuring APTT, and several algorithms aimed at achieving stable anticoagulation exist. However, in practice many patients on UFH have unpredictable responses and may by seriously overdosed or underdosed at least part of the time [21, 22].

Contraindications

– Active major bleeding (exception: venous hemorrhagic infarcts caused by CVT are not a contraindication)

– When conditions with increased risk of bleeding are present, risk benefit should be balanced

– Recent or planned (interval shorter than 24 hours) major surgical procedure or lumbar puncture

– Known type I allergy to LMWH or heparin – Recent history (shorter than three months) of confirmed heparin induced thrombocytopenia with antibodies still present. Note: severe renal insufficiency is not a contraindication. Main drug interactions

Drugs that interact with normal coagulation: oral anti-coagulants, platelet inhibitors. Corticosteroids may cause gastric ulcers which may render patients be more prone to bleeding in the presence of heparin.

Main side effects

Bleeding, transient increase in liver transaminases. Rare: type I allergy (anaphylaxis), heparin-induced thrombocytopenia (HIT).

Special points

The anticoagulant effect of UFH can be reversed with protamine sulphate. This is an advantage over LMWH, which only can be reversed partially. However, this advantage is offset by the less predictable response of UFH and the higher rate of bleeding.

Special points

The anticoagulant effect of UFH can be reversed with protamine sulphate. This is an advantage over LMWH, which only can be reversed partially. However, this advantage is offset by the less predictable response of UFH and the higher rate of bleeding.

Cost effectiveness

No formal cost-effectiveness analyses are available but given their effectiveness regarding neurological outcomes, UFH are probably cost effective.

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Interventional procedures & &

Treatment aim and theoretical advantage: faster recanalization to improve neurological outcome. At present endovascular thrombolysis or thrombectomy for CVT cannot be regarded as a proven effective and safe procedure. The only available evidence is weak, and consists of a handful of small case series (typically 10-20 patients) and many case reports, with often unsatisfactory reporting of clinical outcomes and a considerable risk of suffering from publication bias [16].

Endovascular thrombectomy and/or pharmacologic thrombolysis Standard procedure

A catheter is advanced into the thrombosed sinus. Approach can be through the jugular or femoral vein. The catheter has to pass the sigmoid sinus and the transverse sinus, which may also be thrombosed. Maneuvering along the different curves carries a small risk of rupture of a sinus wall or a cortical vein. When a catheter is correctly placed - as distally as is safely possible mechanical thrombectomy can be attempted with hydrolyser or fogerty catheters. Alternatively, pharmacologic thrombolysis can be attempted by locally injecting urokinase or alteplase into the thrombosed sinus. The reported dosages and the duration of the infusion vary considerably. Typical dosage schedules are: & Urokinase: Bolus 100.000 to 600.000 IU Infusion: 80.000 to 120.000 IU/hour during 24 hours or longer if needed & Alteplase (rt-PA): Bolus 1-5 mgr. Infusion: 1-2 mgr./hour during 24 hours or longer if needed. ET is performed with concurrent heparin treatment.

Contraindications

Known contrast allergy. Severe active or recent bleeding is a contraindication for thrombolytic drugs. Mechanical thrombectomy can still be attempted. We do not regard intracerebral bleeding due to CVT an absolute contraindication against endovascular treatment.

Complications

Rupture of sinus wall or cortical vein. Intracerebral hemorrhage. Hemorrhage at puncture site. Major systemic bleeding.

Special points

Occasionally it proves impossible to enter the sinus due to the presence of probably organized thrombus. Since CVT is a rare disease, most interventionists have a low exposure, and it is difficult to obtain and maintain experience with the procedure. If performed at all, endovascular treatment of CVT should be concentrated in high volume hospitals, and preferably as part of a clinical trial [16].

Cost effectiveness

Endovascular procedures are expensive in terms of personnel (anesthesia, neuroradiologist, nurses), resources (angiography facilities, intensive care) and instrumentation. Since the effectiveness compared to standard treatment has not yet been proven, we cannot assess whether this procedure is cost-effective.

Surgery &

Hemicraniectomy: prevention of (further) cerebral herniation in rare cases of space-occupying hemorrhagic infarcts.


& &

Page 7 of 9, 299 Ventricular shunting procedure: reduction of intracranial pressure in rare cases of medication resistant chronic intracranial hypertension. Direct thrombectomy (now obsolete): removal of thrombus from the superior sagittal sinus through a small craniotomy or burr holes.

Hemicraniectomy Standard procedure

Contraindications

Temporary removal of a large bone flap to enable outward swelling of the brain. Published case-series suggest that this procedure may result in good recovery (independence, modified Rankin score 0-2) in about 60 % of patients, who would otherwise probably die or remain severely handicapped [23, 24••]. Virtually none (lifesaving procedure). Anticoagulant therapy should be reversed (if possible).

Complications

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Infections (empyema)

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Subdural hematoma

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General procedural (surgery and anesthesia) complications

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Rarely: progressive and untreatable brain herniation through the hemicraniectomy opening by total obstruction of venous drainage.

Special points

The bone flap should be large enough to accommodate the (outward) swelling of a large part of the affected hemisphere. Bone flaps that are too small may cause additional damage due to compression of brain tissue across the edges of the remaining skull. In patients with hemorrhagic infarcts in the temporal lobe (which is not infrequent), special care should be taken to extent the decompression to the temporal bone.

Cost effectiveness

Since the procedure is potentially lifesaving and may prevent severe neurologic handicap, it is probably highly cost effective.

Physical/speech therapy and exercise &

Physical therapy, speech therapy and exercise are indicated, depending on the nature and degree of neurologic impairment. The same protocols can be used as after arterial stroke.

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Patients in coma, epileptic status, or impaired airway protection should be admitted to an intensive care unit. Patients with epileptic seizures should receive routine anti-epileptic treatment. Prophylactic treatment with anti-epileptic drugs can be considered in patients with parenchymal lesions, although no data on its efficacy are available. Theoretically, patients with extensive vasogenic edema may benefit from treatment with steroids but data on its efficacy for patients with CVT are scarce. A non-randomized study actually found that treatment with steroids was associated with a worse clinical outcome. Until more and

Other treatments

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&

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Curr Treat Options Neurol (2014) 16:299 better data are available, routine use of steroids cannot be recommended [25].

Compliance with Ethics Guidelines Conflict of Interest Dr. Coutinho declares that he has received research grants from The Netherlands Organisation for Scientific Research, Thrombosis Foundation Holland, the Dutch Heart Foundation, and the Netherlands Brain Foundation. He also declares that he has received speaker fees Boehringer Ingelheim, but that all of these fees have been donated to the “Stichting Klinische Neurologie”, a foundation that supports research in the field of neurological disorders. Dr. Middeldorp declares that she has passed consultancy fees to her institution from Boehringer Ingelheim, Bayer, BMS/Pfizer Alliance, and Daiichi Sankyo. She also declares research grant funding from GSK and BMS/Pfizer Alliance, as well as honoraria payments from Boehringer Ingelheim, Bayer, BMS/Pfizer Alliance, and Daiichi Sankyo. Finally, she declares that she has received reimbursement of travel expenses from BMS/ Pfizer Alliance and Daiichi Sankyo. Dr. Stam declares research grant funding from Thrombosis Foundation Holland, the Dutch Heart Foundation, and the Netherlands Brain Foundation. 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 and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

Kalbach RM, Woolf AL. Cerebral venous thrombosis. London: Oxford University Press; 1967. 2. Coutinho JM, Zuurbier SM, Stam J. Declining mortality in cerebral venous thrombosis: a systematic review; Stroke 2014; in press. 3.• Stam J. Thrombosis of the cerebral veins and sinuses. N Engl J Med. 2005;352:1791–8. This review article provides a general overview of cerebral venous thrombosis. 4. Bousser MG, Ferro JM. Cerebral venous thrombosis: an update. Lancet Neurol. 2007;6:162–70. 5.• Coutinho JM, Zuurbier SM, Aramideh M, et al. The incidence of cerebral venous thrombosis: a crosssectional study. Stroke. 2012;43:3375–7. This study found that the incidence of CVT among adults is approximately 4 times higher than previously believed. 6. Janghorbani M, Zare M, Saadatnia M, et al. Cerebral vein and dural sinus thrombosis in adults in Isfahan,

Iran: frequency and seasonal variation. Acta Neurol Scand. 2008;117:117–21. 7.• Coutinho JM, Ferro JM, Canhão P, et al. Cerebral venous and sinus thrombosis in women. Stroke. 2009;40:2356–61. This study highlights the differences in clinical manifestations, risk factor profile and outcome between men and women with CVT. 8. Coutinho JM, van den Berg R, Zuurbier SM, et al. Small juxtacortical hemorrhages in cerebral venous thrombosis. Ann Neurol. 2014. doi:10.1002/ana.24180. 9.•• Leach JL, Fortuna RB, Jones BV, Gaskill-Shipley MF. Imaging of cerebral venous thrombosis: current techniques, spectrum of findings, and diagnostic pitfalls. Radiographics. 2006;26 Suppl 1:S19–41. This review article provides a comprehensive overview of the available radiological modalities to diagnose CVT. 10.•• Saposnik G, Barinagarrementeria F, Brown Jr RD, et al. Diagnosis and management of cerebral venous

Curr Treat Options Neurol (2014) 16:299 thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42:1158–92. Most recent version of the AHA guidelines for the treatment of cerebral venous thrombosis. 11.•• 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;17:1229–35. Most recent version of the EFNS guidelines for the treatment of cerebral venous thrombosis. 12. Lebas A, Chabrier S, Fluss J, et al. EPNS/SFNP guideline on the anticoagulant treatment of cerebral sinovenous thrombosis in children and neonates. Eur J Paediatr Neurol. 2012;16:219–28. 13.•• Coutinho J, de Bruijn SF, Deveber G, et al. Anticoagulation for cerebral venous sinus thrombosis. Cochrane Database Syst Rev. 2011;CD002005. Cochrane meta-analysis on the efficacy and safety of anticoagulation for cerebral venous thrombosis 14. Einhäupl KM, Villringer A, Meister W, et al. Heparin treatment in sinus venous thrombosis. Lancet. 1991;338:597–600. 15. de Bruijn SF, Stam J. Randomized, placebo-controlled trial of anticoagulant treatment with lowmolecular-weight heparin for cerebral sinus thrombosis. Stroke. 1999;30:484–8. 16. 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;8:135–40. 17.•• Ferro JM, Canhão P, Stam J, et al. ISCVT Investigators. Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke. 2004;35:664–70. This paper reports the main results of the ISCVT study, the largest international prospective cohort study on CVT.

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Erkens PM, Prins MH. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev. 2010;(9):CD001100. 19.• Coutinho JM, Ferro JM, Canhão P, et al. ISCVT Investigators. Unfractionated or low-molecular weight heparin for the treatment of cerebral venous thrombosis. Stroke. 2010;41:2575–80. The results of this non-randomized study indicate that lowmolecular weight heparins are superior to unfractionated heparin for the treatment of CVT. 20.• 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;19:1030–6. Data from this small randomized study indicate that lowmolecular weight heparins are superior to unfractionated heparin for the treatment of CVT. 21. Fennerty AG, Thomas P, Backhouse G, et al. Audit of control of heparin treatment. BMJ. 1985;290:27–8. 22. Aarab R, van Es J, de Pont AC, et al. Monitoring of unfractionated heparin in critically ill patients. Neth J Med. 2013;71:466–71. 23. Zuurbier SM, Coutinho JM, Majoie CB, et al. Decompressive hemicraniectomy in severe cerebral venous thrombosis: a prospective case series. J Neurol. 2012;259:1099–105. 24.•• Ferro JM, Crassard I, Coutinho JM, et al. Second International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT 2) Investigators. Decompressive surgery in cerebrovenous thrombosis: a multicenter registry and a systematic review of individual patient data. Stroke. 2011;42:2825–31. Retrospective multi-center study on decompressive craniotomy for cerebral venous thrombosis. 25. Canhão P, Cortesão A, Cabral M, et al. Are steroids useful to treat cerebral venous thrombosis? Stroke. 2008;39:105–10.