Ce r e b r a l venous sinus thrombosis has remained a. A review of therapeutic strategies for the management of cerebral venous sinus thrombosis

Transcription

1 Neurosurg Focus 27 (5):E6, 2009 A review of therapeutic strategies for the management of cerebral venous sinus thrombosis Ri c k y Me d e l, M.D., 1 St e p h e n J. Mo n t e i t h, M.D., 1 R. We b s t e r Cr o w l e y, M.D., 1 a n d Aar o n S. Du m o n t, M.D. 1,2 Departments of 1 Neurological Surgery and 2 Radiology, University of Virginia Health System, Charlottesville, Virginia Object. Although initially described in the 19th century, cerebral venous sinus thrombosis (CVST) remains a diagnostic and therapeutic dilemma. It has an unpredictable course, and the propensity for hemorrhagic infarction produces significant consternation among clinicians when considering anticoagulation. It is the purpose of this review to analyze the evidence available on the management of CVST and to provide appropriate recommendations. Methods. A thorough literature search was conducted through MEDLINE and PubMed, with additional sources identified through cross-referencing. A classification and level of evidence assignment is provided for recommendations based on the American Heart Association methodologies for guideline composition. Results. Of the publications identified, the majority were isolated case reports or small case series. Few prospective trials have been conducted. Existing data support the use of systemic anticoagulation as an initial therapy in all patients even in the presence of intracranial hemorrhage. Chemical and/or mechanical thrombectomy, in conjunction with systemic anticoagulation, is an alternative strategy in patients with progressive deterioration on heparin therapy or in those who are moribund on presentation. Mechanical thrombectomy is probably preferred in patients with preexisting intracranial hemorrhage. Conclusions. Effective treatments exist for the management of CVST, and overall outcomes are more favorable than those for arterial stroke. Further research is necessary to determine the role of individual therapies; however, the rarity of the condition poses a significant limitation. (DOI: / FOCUS09154) Ke y Wo r d s sinus thrombosis thrombectomy thrombolysis tissue plasminogen activator angioplasty Ce r e b r a l venous sinus thrombosis has remained a diagnostic and therapeutic dilemma since its initial description by Ribes in He described a 45-year-old man who had suffered a 6-month course of headache, seizures, and delirium before succumbing to his disease. An autopsy revealed thrombosis of the SSS, straight sinus, and cortical veins. Since then, numerous publications, largely in the form of case reports and small clinical series, have been added to the literature; however, a consensus regarding the appropriate treatment remains elusive. As a rare cause of stroke, CVST is estimated to occur with an incidence of 2 4 per million per year. 57,66 In contrast to arterial infarction, CVST most commonly afflicts those of middle age with a female predominance. 30,61 The Abbreviations used in this paper: CVST = cerebral venous sinus thrombosis; ICH = intracranial hemorrhage; ICP = intracranial pressure; ISCVT = International Study of Cerebral Vein and Dural Sinus Thrombosis; LMWH = low-molecular-weight heparin; NS = not significant; PTT = partial thromboplastin time; SSS = superior sagittal sinus. lack of pathognomonic features obscures its presentation so that the correct diagnosis is initially reached in < 60% of cases. 63 Headache represents the most common symptom (80 90%), with a usual pattern similar to that of benign intracranial hypertension. Other features include seizures, focal neurological deficits, and decreased mental status. 7,21,50,57,63 Identification is further complicated by the subtle nature of its signs on noncontrast CT, and definitive diagnosis requires MR imaging, MR angiography and venography, or digital subtraction angiography. Although described as carrying an extremely grave prognosis, 35 the disease s clinical course varies considerably, with reported rates of dependency and death ranging from 8 to 40%. 28,30,44,45,63,72 Factors commonly found to predict a poor outcome include male sex, older age, coma, hemorrhage, infection of the CNS, and cancer. 23,30,36 While the presence of such factors can provide some indication of the possible outcome, reliable prediction is impossible which in turn complicates therapeutic strategies. When infection and trauma represented the most common causes, therapy involved watchful waiting and antibiotics. And while trauma remains a frequent 1

2 R. Medel et al. cause, aseptic thrombosis occurring as a result of a multitude of factors (puerperium, malignancy, dehydration, oral contraceptives, and thrombophilia) is now more common than infection. 71 This change in etiology has shifted treatment to systemic anticoagulation, endovascular thrombectomy (either chemical or mechanical), and occasionally surgical decompression or open thrombectomy. Despite evidence supporting the efficacy of anticoagulation, clinicians remain apprehensive about its use given the concomitant propensity for ICH, which occurs in ~ 40% of affected patients. 30 It is our purpose in this paper to analyze existing evidence and provide recommendations for the most appropriate course of management, with a focus on the role of endovascular modalities. Classification of the recommendations and levels of evidence are assigned based on the American College of Cardiology (ACC) and the American Heart Association (AHA) Methodology Manual for ACC/AHA Guideline Writing Committees. 2 Systemic Anticoagulation Lyons 47 described the first successful use of systemic heparin in 1941, when it along with antibiotics was used to treat 2 cases of infectious cavernous sinus thrombosis. Subsequently, numerous reports were published, including one by Bousser et al. 8 who retrospectively reviewed 38 cases of CVST. Twenty-three patients had been treated with heparin, all of whom experienced improvement, with 19 making a complete recovery. The correlation of treatment with outcome was not attempted given the retrospective nature of the study. However, not a single death occurred in those receiving anticoagulants, and the majority of these patients experienced a dramatic clinical improvement the day after treatment was initiated. Given these findings, the authors concluded that heparin was the treatment of choice in any patient experiencing clinical deterioration, including those with hemorrhagic infarcts. To better elucidate the effect of treatment on outcome, Einhaupl and colleagues 28 conducted a randomized, prospective placebo-controlled trial of heparin therapy. Although enrollment was intended to include 60 patients, the trial was stopped prematurely after a planned interim analysis of the first 20 patients (10 in each arm) revealed a significant difference in outcomes. Outcome was assessed using a newly designed, unvalidated sinus thrombosis severity scale (0 = asymptomatic, 9 = dead). Heparin was administered as a bolus followed by continuous infusion with a target PTT of seconds. After 21 days of treatment, the treatment group had an average score of 0.6 versus 3.9 for the control group (p < 0.005) on the above described scale. At the 3-month follow-up 8 patients in the treatment group had completely recovered and 2 had minor neurological deficits. Conversely, in the control group only 1 patient made a complete recovery, 6 had neurological deficits, and 3 died (p < 0.01). One of these deaths was believed to be due to a pulmonary embolism, a not infrequent complication of sinus thrombosis, occurring in up to 11% of patients; note that systemic heparinization provides the additional benefit of reducing this risk. 18,25 With regard to ICH, 3 patients in the treatment group and 2 in the control group had a hemorrhage on the institution of therapy; however, no new cases of hemorrhage occurred in the heparin group. Three patients in the control group experienced a new (2 patients) or worsened (1 patient) hemorrhage. Included in Einhaupl and colleagues report was a retrospective review of patients treated at the same institution but outside of the clinical trial. Among patients with an ICH at the start of therapy, there was a 15% mortality rate (4 of 27 patients) in those receiving heparin versus 69% (9 of 13 patients) in the group treated without anticoagulation. While these data provided considerable support regarding the safety and efficacy of heparinization, the study was criticized for several reasons: In addition to its small sample size, there was a significant delay from symptom onset to the initiation of therapy (~ 30 days in each group). The authors also used an outcome measure that had not been previously validated. In an attempt to alleviate these deficiencies, de Bruijn and Stam 22 conducted the second randomized, placebocontrolled trial of anticoagulation for CVST. Instead of unfractionated heparin, these authors chose to use LMWH in the form of nadroparin. This usage was justified based on trials demonstrating equitable results for LMWH and intravenous unfractionated heparin in the treatment of extracranial deep venous thrombosis and pulmonary embolism. 16 Based on the treatment effect observed in the earlier study, a sample size of 60 patients was determined to be appropriate. Patients received 180 antifactor Xa U/ kg/24 hrs (the treatment dose of deep venous thrombosis) or placebo for 3 weeks following diagnosis, after which the nadroparin group received oral anticoagulants for an additional 10 weeks. Following 3 weeks of therapy, 20% (6 patients) of the LMWH group, as compared with 23% (7 patients) in the control group, had a poor outcome (Barthel Index score < 15). At 12 weeks after the start of therapy, 13% (4 patients) of the treatment group versus 20% (6 patients) of the control group had a poor outcome that is, death or an Oxford Handicap Scale score 3 (NS). Seven percent (2 patients) of the nadroparin group died versus 13% (4 patients) of the control group (NS); 1 patient in the former group died of a pulmonary embolism. No new episodes of ICH occurred; however, 1 patient in the treatment arm did suffer from a significant gastrointestinal hemorrhage. Although not significant, there was a trend toward improved outcomes in the treatment group, and this trend further reaffirmed the safety of anticoagulation in the setting of ICH. Subsequently, a meta-analysis of these 2 studies was performed by the Cochrane Collaboration, with those in the initial trial being reclassified according to standard outcome measures. 66 Under these conditions there was a 0.33 relative risk of death (95% CI ) and a 0.46 risk of death or dependency (95% CI ) for those treated with anticoagulation. The patients also maintained the additional benefit of deep venous thrombosis and pulmonary embolism prevention. Overall, the authors concluded that anticoagulation was safe and associated with a nonsignificant, yet potentially important, improvement in outcome. More recently, investigators in the International Study of Cerebral Vein and Dural Sinus Thrombosis (ISCVT), an observational study, found that 83% of patients under- 2

3 Sinus thrombosis went anticoagulation with either unfractionated or intravenous heparin at therapeutic dosages. 30 Although a trend toward improved outcomes in the anticoagulation group was found (12.7% dead or dependent in the anticoagulation group vs 18.3% in the control group), the difference was not significant. Despite the lack of definitive evidence, multiple reviews 7,9,64,65 and the recently published European Federation of Neurological Societies (EFNS) guidelines 27 continue to support anticoagulation s safety and probable efficacy in CVST (Class IIa, Level B). Given the rarity of this condition, it is estimated that a trial enrolling 300 patients would be necessary to statistically confirm the treatment effect as determined by the Cochrane review. 65 Interventional Therapies Although systemic anticoagulation appears to provide considerable improvement over the more conservative method of watchful waiting, there are some patients in whom it is insufficient. Consequently, several additional modalities have been used to facilitate recanalization and symptomatic improvement in this patient population. Bolstered by the initial successes of these treatments, clinicians have, in some instances, used them as primary modalities in patients not presenting in extremis; 58 however, this approach is not widely supported, especially when considering thrombolytics. Fibrinolytic Agents In 1971 Vines and Davis 71 described 10 patients with sinus thrombosis, 5 of whom received systemic urokinase. All 5 of these patients went on to demonstrate some improvement, with dramatic improvement occurring in 1 patient. Several other studies followed, but the results were inconsistent. 24,33 Therefore, Scott et al. 59 sought to improve the safety profile through local infusion. A 33-year-old man presented with progressive headache, but his condition quickly deteriorated to a comatose state. Computed tomography scanning and subsequent digital subtraction angiography revealed thrombosis of the superior, straight, and both transverse sinuses. The insertion of an ICP monitor revealed pressures ranging from 60 to 90 mm Hg. Given these findings, a frontal craniectomy was performed, and an infusion catheter was guided into the SSS through a small incision. After obtaining a sinogram, the local infusion of urokinase was instituted and continued for 8 hours, at which time a temporal hemorrhage was discovered on CT. Nonetheless, the patient experienced clinical improvement from decerebrate posturing to only mild dysphasia and short-term memory impairment. Despite persistent skepticism regarding the risk of hemorrhagic transformation, this early report provided the foundation for a novel avenue in the management of CVST. Multiple case reports and small case series have subsequently appeared 4,37,39,52,62 as therapy has moved from direct puncture to a transfemoral approach. Horowitz et al. 39 treated a series of 13 patients via this method, 5 of whom had a pretreatment ICH. Clinical improvement occurred in all but 1 patient, and 8 had an excellent outcome. The patient without improvement had protein C deficiency with a more than 2-month history of sinus thrombosis, and it was believed that the clot was sufficiently organized, thereby decreasing the efficacy of fibrinolytics. Importantly, in no instance was there worsening of a preexisting ICH or any new cases of hemorrhage. Data in this study, while not conclusive, provided considerable support for the safety of local fibrinolytic infusions in sinus thrombosis. To better elucidate the role of this methodology, several trials and case studies have been conducted (Table 1), 3 of which are particularly notable. 32,67,72 Frey et al. 32 treated 12 consecutive patients with combined tissue plasminogen activator and heparin. All 12 patients had significant symptoms without evidence of convalescence, and there was MR imaging evidence of hemorrhage in 7. Therapy consisted of systemic heparin to achieve a PTT twice that of controls and local injection of tissue plasminogen activator throughout the clot (1-mg boluses at 1- to 2-cm intervals via transfemoral catheterization) followed by local infusion (1 2 mg/hour). Complete flow restoration occurred in 6 patients, partial recanalization in 3, and no improvement in 3. Clinically, 5 patients experienced a complete recovery and 6 had a symptomatic benefit. Two patients had worsening of a preexisting ICH, requiring surgical evacuation in 1. This latter patient made a full recovery; however, the patient who did not undergo surgical evacuation experienced a worsening language deficit requiring rehabilitation. Later, Wasay and colleagues 72 performed a multiinstitutional retrospective analysis comparing the local infusion of urokinase with systemic heparinization. Twenty patients were included in each treatment group, and segregation by centers was present because of policies regarding management. Seven hemorrhagic infarctions were present before treatment (4 heparin and 3 urokinase). The heparin group received a systemic dose titrated to a PTT between 50 and 60 seconds, while the urokinase group received an intranidal bolus of 250,000 U followed by a continuous infusion of 80,000 U/hour. Pretreatment characteristics were similar for the 2 groups. Neurological status at discharge was better in the urokinase group, with 16 versus 9 patients in the heparin group making a complete recovery (p = 0.019). Remarkably, no patient in the urokinase group experienced a worsening or new ICH, although 1 instance of subdural hematoma and 1 of retroperitoneal hemorrhage did occur. While these studies were encouraging, a subsequent prospective trial by Stam et al. 67 demonstrated less positive results. These authors chose 20 patients whose disease was presumed to have a poor prognosis; 14 had hemorrhagic infarcts at the time of enrollment, and the average initial Glasgow Coma Scale score for the entire group was 7.6. All patients except 1 were treated with heparin at the time of diagnosis, with thrombolysis administered as a bolus of urokinase (120, ,000 U) followed by a continuous infusion (100,000 U/hour). Fifteen of these patients also underwent mechanical thrombectomy with either a rheolytic or Fogarty catheter, and 1 patient did not receive treatment because of the treating physician s inability to enter the sinuses. Nine patients had a complete recovery, 3 had a minor deficit, 2 had a severe 3

4 R. Medel et al. TABLE 1: Literature summary of studies on the interventional management of CVST* Authors & Year No. of Patients Treatment Modality Complications Outcome Scott et al., direct urokinase infusion temporal hemorrhage m ild dysphasia, short-term memory impairment Higashida et al., direct urokinase infusion none neurologically intact Persson & Lilja, di rect streptokinase infusion, open thrombectomy small cerebellar hemorrhage q uadriparesis w/ speech difficulties but independent Barnwell et al., urokinase infusion se psis, bleeding from jugular all clinically improved puncture site Smith et al., urokinase infusion & angioplasty (1) infected femoral site, hematuria al l clinically improved, 1 required angioplasty, 1 required surgical repair of DAVF Horowitz et al., urokinase infusion P E, hematuria, groin hematoma, retroperitoneal hematoma, bacteremia Kim & Suh, alteplase infusion s mall intrapelvic hemorrhage, bleeding at femoral site 11 of 12 patients experienced good clinical outcome, 1 died of PE all clinically improved Renowden et al., tpa infusion none re covery w/ minimal neurological deficit D Alise et al., urokinase infusion none symptomatic resolution Frey et al., tpa infusion w orsening ICH (2), groin hematoma c omplete recovery (5), symptomatic improvement (6), treatment-associated worsened language deficit w/ functional recovery (1) Kuether et al., urokinase infusion none intact except for a CN VI palsy Philips et al., ur okinase infusion & mechanical thrombectomy (2) hematuria, UTI, pneumonia g ood to excellent outcome in all patients Malek et al., m echanical thrombectomy, balloon none neurologically intact angioplasty, stenting Opatowsky et al., ur okinase infusion, rheolytic thrombectomy femoral pseudoaneurysm sl ight lt upper extremity weakness, otherwise intact Dowd et al., ur okinase infusion, rheolytic thrombectomy none minimal cognitive deficit Chaloupka et al., ur okinase infusion, balloon angioplasty none near-complete resolution of deficits Scarrow et al., rh eolytic thrombectomy none complete symptomatic resolution Gomez et al., rh eolytic thrombectomy, urokinase none near-complete resolution of deficits infusion Chow et al., ur okinase infusion, rheolytic thrombectomy in creased parenchymal hemorrhage near-complete resolution of deficits & IVH Wasay et al., urokinase infusion su bdural hematoma, retroperitoneal hemorrhage c omplete resolution (16), mild deficit (3), moderate deficit (1) Baker et al., rh eolytic thrombectomy, urokinase infusion fe moral pseudoaneurysm (2), posterior fossa hematoma requiring evacuation pneumonia, anemia 4 of 5 recovered w/o significant disability, 1 had persistent disability Curtin et al., rh eolytic thrombectomy, balloon angioplasty, tpa infusion neurologically intact Chahlavi et al., direct mechanical thrombectomy none re covered to baseline w/ mild residual deficits Yamashita et al., ba lloon angioplasty, urokinase none neurologically intact infusion Agner et al., rh eolytic thrombectomy, tpa infusion none neurologically intact (continued) 4

5 Sinus thrombosis TABLE 1: Literature summary of studies on the interventional management of CVST* (continued) Authors & Year No. of Patients Treatment Modality Complications Outcome Prasad et al., tpa infusion, balloon angioplasty none near-complete resolution Kirsch et al., rheolytic thrombectomy none 4 of 5 w/o deficit, 1 died Tsai et al., ** tp A or urokinase infusion, mechanical none reported c omplete recovery (8), mild residual deficit (6), DAVF (1) thrombectomy Stam et al., m echanical thrombectomy, urokinase infusion increased ICH (5) no to minimal symptoms (9), minor handicap (3), moderate to severe handicap (2), deceased (6) Sidani et al., tpa infusion none improved aphasia Zhang et al., tpa infusion, rheolytic thrombectomy none excellent (2), good (2), deceased (2) Sujith et al., urokinase infusion none complete recovery (2), persistent visual deficit (1) Hocker et al., tpa infusion none neurologically intact Bishop et al., balloon angioplasty none ambulatory, verbal, following commands * Numbers in parentheses refer to the number of patients. Abbreviations: CN = cranial nerve; DAVF = dural arteriovenous fistula; IVH = intraventricular hemorrhage; PE = pulmonary embolism; tpa = tissue plasminogen activator; UTI = urinary tract infection. Describes the modality used to achieve acute recanalization. In almost all cases, this was combined with systemic heparin and subsequent oral anticoagulation. One of the 2 patients with worsening ICH required surgical evacuation. The study was conducted as a nonrandomized comparison of local thrombolysis versus heparinization with 20 patients in each group. One patient had subarachnoid hemorrhage at baseline and therefore a rheolytic thrombectomy catheter was used in isolation. This patient suffered from reocclusion requiring multiple procedures as well as posterior fossa hemorrhage requiring evacuation. ** The study was conducted as a retrospective analysis of patients treated for CVST. Ten patients received heparin therapy only, whereas 15 underwent thrombolysis or thrombectomy with or without systemic anticoagulation. The patient had previously undergone hemicraniectomy and suboccipital decompression. deficit, and 6 died. Factors significantly associated with death included malignancy (p = 0.02), large hemorrhage (p = 0.04), greater midline shift (5.2 vs 1.7 mm, p = 0.02), and a longer delay until the initiation of treatment (8.2 vs 2.7 days, p = 0.01). Five patients, 4 of whom died, had evidence of increased ICH following thrombolysis. These results contradict the findings in the 2 previous trials as well as in numerous case reports (Table 1), and thus appropriately invite uncertainty with regard to this modality. Some clinicians have considered these and other such data 63 to indicate that the presence of hemorrhage is a contraindication to thrombolytics. Although this stance is likely an oversimplification, prudence dictates that in the presence of alternative therapies, thrombolytics should only be used with significant discretion. Canhao et al. 11 reviewed the role of thrombolytics in CVST. Seventy-two studies, comprising 169 patients with a range of available data, were identified. Analysis for each category was performed according to the number of patients for whom data were available. The majority (146 patients) were treated with local infusions using urokinase (127 patients). One hundred forty-three (97%) underwent anticoagulation, and 15 underwent thrombectomy or mechanical clot disruption. At discharge, 114 patients were independent (mrs Score 0 2), 10 were dependent (mrs Score 3 5), and 9 died. No significant difference was observed based on the route of administration. Intracranial hemorrhage occurred in 18 patients, but was associated with clinical deterioration in only 5. There were 23 instances of extracranial hemorrhagic complications. The Cochrane Collaboration also conducted a review of chemical thrombolysis in CVST; however, the dearth of trials meeting their inclusion criteria prohibited any conclusion. 15 Overall, there is reasonable evidence to suggest that in some patients the local infusion of fibrinolytic agents can afford significant recovery, although other therapeutic options with a superior safety profile may exist (Class IIb, Level B). Mechanical Thrombectomy Mechanical thrombectomy has been advocated as both a solution to the limitations imposed by chemical thrombolysis and a means of augmentation as described above. First performed for the treatment of CVST in the 1990s, 26,62 this method provides a means of clot removal while affording a decreased risk of hemorrhagic complications when used independently of fibrinolytics. There are several methods by which to perform mechanical thrombectomy: balloon angioplasty, stenting, clot maceration, and rheolytic thrombectomy (Table 1). Several small case series have been published; however, few have been focused on the evaluation of the mechanical methods in isolation. 42,63 Soleau and colleagues 63 documented a retrospective series of 31 patients who had been treated using a variety of methods between 1992 and Eight patients underwent thrombectomy using an endovascular Fogarty balloon catheter in conjunction with systemic anticoagulation. Seven patients (88%) demonstrated clinical improvement, and 1 patient died as a result of excessive anticoagulation. Two hemorrhagic complications were 5

6 R. Medel et al. Fig. 1. Images obtained in a 22-year-old postpartum woman who presented with right-sided hemiplegia. Left: Axial CT scan demonstrating a right frontal hemorrhagic infarction. Right: An MR venogram revealing thrombosis involving the anterior SSS, the left frontal cortical veins, and the right transverse sinus. The patient was placed on systemic anticoagulation; however, her condition subsequently deteriorated, and a CT revealed increased mass effect. At that time a left hemicraniectomy was performed. The patient underwent recanalization of her sinuses following repeat MR venography. She was discharged on oral anticoagulation and made a complete neurological recovery, which she maintained on follow-up 2 years later. encountered, 1 occurring in the patient who died and the other in a patient in whom therapy was unsuccessful. In comparison, 10 patients were treated with chemical thrombolysis, with 6 (60%) having improvement and 4 (40%) experiencing significant deterioration or dying. In 3 of these 4 patients hemorrhagic complications were believed to be responsible for the deterioration. Subsequently, Kirch et al. 42 described a series of 4 patients who had been treated with a rheolytic thrombectomy catheter as well as systemic heparin. Three of these 4 patients experienced a complete clinical recovery, and there were no periprocedural complications. In the fourth patient, there was extensive thrombosis of all the dural venous sinuses and involvement of the deep cerebral venous system. It was not technically feasible to evacuate this clot, and the patient subsequently died. These reports as well as numerous others in which mechanical and chemical thrombolysis were combined demonstrate a reasonable safety profile for this treatment modality and support it as an alternative to chemical thrombolysis in the setting of hemorrhagic infarction (Class IIb, Level B). Surgical Thrombectomy and Decompression Surgical therapies have a limited role in the management of CVST. Although occasionally used to provide access to the cerebral sinuses or performed for open thrombectomy or hematoma evacuation, their role is largely limited to decompression for elevated ICP (Fig. 1). 6,17,37,43,45,52,59 Coutinho and colleagues, 17 driven by the limited success of other modalities in the setting of impending hernation, 67 adopted a strategy of hemicraniectomy in this population. They describe 3 cases in which hemicraniectomy was implemented, 2 of which had excellent clinical outcomes. In the third case there was a period of prolonged coma prior to surgery, and the patient died despite decompression. Again, this procedure represents a therapeutic option in an isolated patient population with refractory elevations in ICP (Class IIb, Level C). Symptomatic Therapies Multiple other therapeutic measures, including steroids, antiepileptics, acetazolamide, diuretics, hyperventilation, and shunting procedures, have been used in the management of CVST. 30 These therapies are directed at managing the symptoms of increased ICP and seizures consequent to the underlying disease, without an effect on the thrombosis itself. The use of steroids was evaluated in a case-control study utilizing the ISCVT data. 10 There was no benefit in their use, and in patients without parenchymal lesions they were in fact detrimental (Class III, Level B). Concerning the other modalities for reducing ICP, no controlled data exist. One must remember that diuresis has the potential to increase blood viscosity and potentiate thrombosis. The use of osmotic therapy can also be injurious, as elimination can be compromised in the setting of venous obstruction. 27 Although the use of prophylactic antiepileptic therapy is also controversial, it is probably indicated in a certain subset of patients. 9,27 Masuhr et al. 49 prospectively evaluated the risk and influence of early seizures on 194 patients with sinus thrombosis. Forty-four percent had early symptomatic seizures, and the mortality rate was 3 times higher in this group. Significant independent predictors of seizure included motor deficit, ICH, and cortical vein thrombosis. Ferro and colleagues 29 also conducted a prospective observational study to further characterize the risks and benefits of antiepileptics in the acute setting. 6

7 Sinus thrombosis Fig. 2. Algorithm indicating the management of CVST. *Systemic anticoagulation is the foundation of treatment in all cases of CVST and is used in conjunction with interventional methods of thrombolysis. They reviewed 624 patients, 39.3% who presented with seizures. In their analysis, the presence of a parenchymal lesion in the supratentorial compartment on CT or MR imaging (OR 3.09, 95% CI ), seizure on presentation (OR 1.74, 95% CI ), and motor deficits (OR 3.63, 95% CI ) were associated with additional seizures. Furthermore, the use of prophylactic therapy significantly lowered the risk of early seizures (OR 0.006, 95% CI ). Given these findings, it is reasonable to place patients presenting with a supratentorial ICH, motor deficit, evidence of cortical venous thrombosis, or seizure on prophylactic anticonvulsant therapy (Class IIb, Level B). Oral Anticoagulation The use of long-term oral anticoagulation following acute therapy is yet another area lacking evidentiary support. Many clinicians follow treatment paradigms established for extracranial thrombosis; 40 however, significant pathophysiological differences make this practice questionable. The cerebral venous circulation, as opposed to the extremities, is not dependent on valves and muscle contraction; therefore, flow is continuous in nature. 5 Furthermore, studies focused on the long-term outcome of patients with CVST have not consistently demonstrated a significant increase in the risk of recurrence. 5,30,31,68 Strupp et al. 68 evaluated the outcomes of 40 patients with sinus thrombosis over a mean follow-up period of 12.1 years (range years). Acutely, all patients received systemic heparinization for at least 10 days, with 35 subsequently receiving oral anticoagulation for at least 2 months (median 6.1 months). Sinus patency was analyzed using MR venography. No patient experienced a recurrence during the follow-up period, even those without complete recanalization. Baumgartner and colleagues 5 prospectively enrolled 33 consecutive patients in an observation study. All patients were treated with unfractionated heparin followed by oral anticoagulation for at least 4 months (median duration 12 months, range 4 12 months). There was no evidence of recurrent sinus thrombosis on MR venography, and no other systemic thromboembolic complications occurred. Later, in the Cerebral Venous Thrombosis Portuguese Collaborative Study Group (VENOPORT) trial, Ferro et al. 31 reviewed the outcomes in 142 patients 51 retrospectively and 91 prospectively, with a mean follow-up period of 3.5 and 1 year, respectively. During this time, only 2 patients in the retrospective group and none in the prospective group had a recurrent episode of CVST. However, 6 patients in the former and 4 in the latter group suffered from systemic thromboembolic events. Combined, 83% of the study population received some form of anticoagulation, but the details of treatment were not provided. Finally, in the ISCVT, over a median follow-up of 16 months, 2.2% of patients (16 patients) experienced recurrent sinus thrombosis, with 4.3% (27 patients) having other thromboembolic events. The median time for such therapy was 7.7 months in the ISCVT. 30 Given the paucity of data there is considerable difficulty in composing recommendations. The European Federation of Neurological Societies guidelines mirror those established for extracranial thromboses, suggesting a 3-month period of anticoagulation for a first-time event in the setting of a temporary risk factor, 6 months in patients with mild thrombophilia (heterozygous factor V Leiden mutations, protein C and S deficiency, or prothrombin G20210A mutations), and indefinitely in those with recurrent events of severe thrombophilia (homozygous factor V Leiden mutations or antithrombin deficiency; Class IIb, Level C). 27 Conclusions Cerebral venous thrombosis remains a therapeutic challenge despite its initial description more than 150 years ago. Based on available evidence, systemic anticoagulation is reasonable as an initial step in the treatment of most patients even in the setting of preexisting ICH (Class IIa, Level B). For those who are moribund on presentation or who experience clinical deterioration, both mechanical and chemical thrombolysis in addition to systemic anticoagulation are viable options (Fig. 2). In patients with ICH the safety of fibrinolysis is uncertain, and mechanical thrombectomy in conjunction with systemic anticoagulation is probably preferred (Class IIb, Level B). Surgical decompression is an option in patients with refractory elevations in ICP as a temporizing measure until sinus patency can be restored (Class IIb, Level C). Although quality prospective trials are needed to accurately evaluate the efficacy of the described interventions, the rarity of CVST is relatively prohibitive. Disclaimer The authors report no conflict of interest concerning the mate- 7

8 R. Medel et al. rials or methods used in this study or the findings specified in this paper. References 1. Agner C, Deshaies EM, Bernardini GL, Popp AJ, Boulos AS: Coronary angiojet catheterization for the management of dural venous sinus thrombosis. Technical note. J Neurosurg 103: , American Heart Association: Methodology Manual for ACCF/AHA Guideline Writing Committees. americanheart.org/presenter.jhtml?identifier= [Accessed 11 September 2009] 3. Baker MD, Opatowsky MJ, Wilson JA, Glazier SS, Morris PP: Rheolytic catheter and thrombolysis of dural venous sinus thrombosis: a case series. Neurosurgery 48: , Barnwell SL, Higashida RT, Halbach VV, Dowd CF, Hieshima GB: Direct endovascular thrombolytic therapy for dural sinus thrombosis. Neurosurgery 28: , Baumgartner RW, Studer A, Arnold M, Georgiadis D: Recanalisation of cerebral venous thrombosis. J Neurol Neurosurg Psychiatry 74: , Bishop FS, Finn MA, Samuelson M, Schmidt RH: Endovascular balloon angioplasty for treatment of posttraumatic venous sinus thrombosis. J Neurosurg 111:17 21, Bousser MG: Cerebral venous thrombosis: diagnosis and management. J Neurol 247: , Bousser MG, Chiras J, Bories J, Castaigne P: Cerebral venous thrombosis a review of 38 cases. Stroke 16: , Bousser MG, Ferro JM: Cerebral venous thrombosis: an update. Lancet Neurol 6: , Canhao P, Cortesao A, Cabral M, Ferro JM, Stam J, Bousser MG, et al: Are steroids useful to treat cerebral venous thrombosis? Stroke 39: , Canhao P, Falcao F, Ferro JM: Thrombolytics for cerebral sinus thrombosis: a systematic review. Cerebrovasc Dis 15: , Chahlavi A, Steinmetz MP, Masaryk TJ, Rasmussen PA: A transcranial approach for direct mechanical thrombectomy of dural sinus thrombosis. Report of two cases. J Neurosurg 101: , Chaloupka JC, Mangla S, Huddle DC: Use of mechanical thrombolysis via microballoon percutaneous transluminal angioplasty for the treatment of acute dural sinus thrombosis: case presentation and technical report. Neurosurgery 45: , Chow K, Gobin YP, Saver J, Kidwell C, Dong P, Vinuela F: Endovascular treatment of dural sinus thrombosis with rheolytic thrombectomy and intra-arterial thrombolysis. Stroke 31: , Ciccone A, Canhão P, Falcão F, Ferro JM, Sterzi R: Thrombolysis for cerebral vein and dural sinus thrombosis. Stroke 35:2428, The Columbus Investigators: Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 337: , Coutinho JM, Majoie CBLM, Coert BA, Stam J: Decompressive hemicraniectomy in cerebral sinus thrombosis: consecutive case series and review of the literature. Stroke 40: , Crimmins TJ, Rockswold GL, Yock DH Jr: Progressive posttraumatic superior sagittal sinus thrombosis complicated by pulmonary embolism. Case report. J Neurosurg 60: , Curtin KR, Shaibani A, Resnick SA, Russell EJ, Simuni T: Rheolytic catheter thrombectomy, balloon angioplasty, and direct recombinant tissue plasminogen activator thrombolysis of dural sinus thrombosis with preexisting hemorrhagic infarctions. AJNR Am J Neuroradiol 25: , D Alise MD, Fichtel F, Horowitz M: Sagittal sinus thrombosis following minor head injury treated with continuous urokinase infusion. Surg Neurol 49: , Damak M, Crassard I, Wolff V, Bousser MG: Isolated lateral sinus thrombosis: a series of 62 patients. Stroke 40: , de Bruijn SF, Stam J: Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis. Stroke 30: , de Bruijn SFTM, de Haan RJ, Stam J: Clinical features and prognostic factors of cerebral venous sinus thrombosis in a prospective series of 59 patients. J Neurol Neurosurg Psychiatry 70: , Di Rocco C, Iannelli A, Leone G, Moschini M, Valori VM: Heparin-urokinase treatment in aseptic dural sinus thrombosis. Arch Neurol 38: , Diaz JM, Schiffman JS, Urban ES, Maccario M: Superior sagittal sinus thrombosis and pulmonary embolism: a syndrome rediscovered. Acta Neurol Scand 86: , Dowd CF, Malek AM, Phatouros CC, Hemphill JC III: Application of a rheolytic thrombectomy device in the treatment of dural sinus thrombosis: a new technique. AJNR Am J Neuroradiol 20: , Einhaupl K, Bousser MG, de Bruijn SFTM, Ferro JM, Martinelli I, Masuhr F, et al: EFNS guideline on the treatment of cerebral venous and sinus thrombosis. Eur J Neurol 13: , Einhaupl KM, Villringer A, Meister W, Mehraein S, Garner C, Pellkofer M, et al: Heparin treatment in sinus venous thrombosis. Lancet 338: , Ferro JM, Canhão P, Bousser MG, Stam J, Barinagarrementeria F, ISCVT Investigators: Early seizures in cerebral vein and dural sinus thrombosis: risk factors and role of antiepileptics. Stroke 39: , Ferro JM, Canhão P, Stam J, Bousser MG, Barinagarrementeria F, ISCVT Investigators: Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke 35: , Ferro JM, Lopes MG, Rosas MJ, Ferro MA, Fontes J: Cerebral Venous Thrombosis Portuguese Collaborative Study Group: Long-term prognosis of cerebral vein and dural sinus thrombosis. Results of the VENOPORT study. Cerebrovasc Dis 13: , Frey JL, Muro GJ, McDougall CG, Dean BL, Jahnke HK: Cerebral venous thrombosis: combined intrathrombus rtpa and intravenous heparin. Stroke 30: , Gettelfinger DM, Kokmen E: Superior sagittal sinus thrombosis. Arch Neurol 34:2 6, Gomez CR, Misra VK, Terry JB, Tulyapronchote R, Campbell MS: Emergency endovascular treatment of cerebral sinus thrombosis with a rheolytic catheter device. J Neuroimaging 10: , Gowers W: A Manual of Diseases of the Nervous System, ed 1. London: Churchill, 1886, Vol Hameed B, Syed NA: Prognostic indicators in cerebral venous sinus thrombosis. J Pak Med Assoc 56: , Higashida RT, Helmer E, Halbach VV, Hieshima GB: Direct thrombolytic therapy for superior sagittal sinus thrombosis. AJNR Am J Neuroradiol 10:S4 S6, Hocker SE, Dafer RM, Hacein-Bey L: Successful delayed thrombolysis for cerebral venous and dural sinus thrombosis: a case report and review of the literature. J Stroke Cerebrovasc Dis 17: , Horowitz M, Purdy P, Unwin H, Carstens G III, Greenlee R, Hise J, et al: Treatment of dural sinus thrombosis using selective catheterization and urokinase. Ann Neurol 38:58 67, Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, 8

9 Sinus thrombosis Comerota AJ, et al: Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133:454S 545S, Kim SY, Suh JH: Direct endovascular thrombolytic therapy for dural sinus thrombosis: infusion of alteplase. AJNR Am J Neuroradiol 18: , Kirsch J, Rasmussen PA, Masaryk TJ, Perl J II, Fiorella D: Adjunctive rheolytic thrombectomy for central venous sinus thrombosis: technical case report. Neurosurgery 60:E577 E578, Kobayashi S, Hongo K, Koyama T, Kobayashi S: Re-occlusion of the superior sagittal sinus after surgical recanalisation. J Clin Neurosci 11: , Krayenbühl HA: Cerebral venous and sinus thrombosis. Clin Neurosurg 14:1 24, Krayenbühl HA: Cerebral venous and sinus thrombosis. Neurol Med Chir (Tokyo) 10:1 24, Kuether TA, O Neill O, Nesbit GM, Barnwell SL: Endovascular treatment of traumatic dural sinus thrombosis: case report. Neurosurgery 42: , Lyons C: The treatment of staphylococcal cavernous sinus thrombophlebitis with heparin and chemotherapy. Ann Surg 113: , Malek AM, Higashida RT, Balousek PA, Phatouros CC, Smith WS, Dowd CF, et al: Endovascular recanalization with balloon angioplasty and stenting of an occluded occipital sinus for treatment of intracranial venous hypertension: technical case report. Neurosurgery 44: , Masuhr F, Busch M, Amberger N, Ortwein H, Weih M, Neumann K, et al: Risk and predictors of early epileptic seizures in acute cerebral venous and sinus thrombosis. Eur J Neurol 13: , Mehndiratta MM, Garg S, Gurnani M: Cerebral venous thrombosis clinical presentations. J Pak Med Assoc 56: , Opatowsky MJ, Morris PP, Regan JD, Mewborne JD, Wilson JA: Rapid thrombectomy of superior sagittal sinus and transverse sinus thrombosis with a rheolytic catheter device. AJNR Am J Neuroradiol 20: , Persson L, Lilja A: Extensive dural sinus thrombosis treated by surgical removal and local streptokinase infusion. Neurosurgery 26: , Philips MF, Bagley LJ, Sinson GP, Raps EC, Galetta SL, Zager EL, et al: Endovascular thrombolysis for symptomatic cerebral venous thrombosis. J Neurosurg 90:65 71, Prasad RS, Michaels LA, Roychowdhury S, Craig V, Sorrell A, Schonfeld S: Combined venous sinus angioplasty and low-dose thrombolytic therapy for treatment of hemorrhagic transverse sinus thrombosis in a pediatric patient. J Pediatr Hematol Oncol 28: , Renowden SA, Oxbury J, Molyneux AJ: Case report: venous sinus thrombosis: the use of thrombolysis. Clin Radiol 52: , Ribes M: Des recherches faites sur la phlébite. Revue Médicale Française et Etrangére et Journal de Clinique de L Hôtel-Dieu et de la Charité de Paris 3:5 41, Saw VPJ, Kollar C, Johnston IH: Dural sinus thrombosis: a mechanism-based classification and review of 42 cases. J Clin Neurosci 6: , Scarrow AM, Williams RL, Jungreis CA, Yonas H, Scarrow MR: Removal of a thrombus from the sigmoid and transverse sinuses with a rheolytic thrombectomy catheter. AJNR Am J Neuroradiol 20: , Scott JA, Pascuzzi RM, Hall PV, Becker GJ: Treatment of dural sinus thrombosis with local urokinase infusion. Case report. J Neurosurg 68: , Sidani CA, Ballourah W, El Dassouki M, Muwakkit S, Dabbous I, Dahoui H, et al: Venous sinus thrombosis leading to stroke in a patient with sickle cell disease on hydroxyurea and high hemoglobin levels: treatment with thrombolysis. Am J Hematol 83: , Siddiqui FM, Kamal AK: Incidence and epidemiology of cerebral venous thrombosis. J Pak Med Assoc 56: , Smith TP, Higashida RT, Barnwell SL, Halbach VV, Dowd CF, Fraser KW, et al: Treatment of dural sinus thrombosis by urokinase infusion. AJNR Am J Neuroradiol 15: , Soleau SW, Schmidt R, Stevens S, Osborn A, MacDonald JD: Extensive experience with dural sinus thrombosis. Neurosurgery 52: , Stam J: Sinus thrombosis should be treated with anticoagulation. Arch Neurol 65: , Stam J: Thrombosis of the cerebral veins and sinuses. N Engl J Med 352: , Stam J, De Bruijn SF, DeVeber G: Anticoagulation for cerebral sinus thrombosis. Cochrane Database Syst Rev: CD002005, Stam J, Majoie CBLM, van Delden OM, van Lienden KP, Reekers JA: Endovascular thrombectomy and thrombolysis for severe cerebral sinus thrombosis: a prospective study. Stroke 39: , Strupp M, Covi M, Seelos K, Dichgans M, Brandt T: Cerebral venous thrombosis: correlation between recanalization and clinical outcome a long-term follow-up of 40 patients. J Neurol 249: , Sujith OK, Krishnan R, Asraf V, Rahman A, Girija AS: Local thrombolysis in patients with dural venous thrombosis unresponsive to heparin. J Stroke Cerebrovasc Dis 17:95 100, Tsai FY, Kostanian V, Rivera M, Lee KW, Chen C, Nguyen T: Cerebral venous congestion as indication for thrombolytic treatment. Cardiovasc Intervent Radiol 30: , Vines FS, Davis DO: Clinical-radiological correlation in cerebral venous occlusive disease. Radiology 98:9 22, Wasay M, Bakshi R, Kojan S, Bobustuc G, Dubey N, Unwin DH: Nonrandomized comparison of local urokinase thrombolysis versus systemic heparin anticoagulation for superior sagittal sinus thrombosis. Stroke 32: , Yamashita S, Matsumoto Y, Tamiya T, Kawanishi M, Shindo A, Nakamura T, et al: Mechanical thrombolysis for treatment of acute sinus thrombosis case report. Neurol Med Chir (Tokyo) 45: , Zhang A, Collinson R, Hurst R, Weigele J: Rheolytic thrombectomy for cerebral sinus thrombosis. Neurocrit Care 9:17 26, 2008 Manuscript submitted July 20, Accepted August 27, Address correspondence to: Aaron S. Dumont, M.D., Department of Neurological Surgery, University of Virginia Health System, Box , Charlottesville, Virginia asd2f@virginia. edu. 9