Cerebral sinus-venous thrombosis (CSVT) is a rare disease

Vascular Medicine Long-Term Evaluation of the Risk of Recurrence After Cerebral Sinus-Venous Thrombosis Ida Martinelli, MD, PhD; Paolo Bucciarelli, MD; Serena M. Passamonti, MD; Tullia Battaglioli, MD; Emanuele Previtali, MD; Pier Mannuccio Mannucci, MD Background The clinical course of cerebral sinus-venous thrombosis (CSVT) is largely unknown because prospective studies with a long follow-up and with the goal to assess thrombosis recurrence rate and predisposing factors for recurrence are lacking. Methods and Results One hundred forty-five patients with a first CSVT were followed up for a median of 6 years after discontinuation of anticoagulant treatment. End points were recurrent CSVT or other clinical manifestations of venous thromboembolism. CSVT recurred in 5 patients (3%) and other manifestations of venous thromboembolism (deep vein thrombosis of the lower limbs or pulmonary embolism) were seen in 10 additional patients (7%), for a recurrence rate of 2.03 per 100 person-years (95% confidence interval, 1.16 to 3.14) for all manifestations of venous thromboembolism and 0.53 per 100 person-years (95% confidence interval, 0.16 to 1.10) for CSVT. Nearly half of the recurrences occurred within the first year after discontinuation of anticoagulant therapy. Risk factors for recurrent venous thrombosis were male sex (adjusted hazard ratio, 9.66; 95% confidence interval, 2.86 to 32.7) and, for thromboses other than CSVT, severe thrombophilia resulting from antithrombin, protein C, protein S deficiency, anti-phospholipid antibodies, or combined abnormalities (adjusted hazard ratio, 4.71; 95% confidence interval, 1.34 to 16.5). Conclusions The risk of recurrent CSVT is low and is higher in the first year after discontinuation of anticoagulant treatment and among men. Mild thrombophilia abnormalities are not associated with recurrent CSVT, but severe thrombophilia entails an increased risk of deep vein thrombosis of the lower limbs or pulmonary embolism. (Circulation. 2010;121:2740-2746.) Key Words: cerebrovascular disorders risk factors thrombophilia venous thromboembolism Cerebral sinus-venous thrombosis (CSVT) is a rare disease with an estimated annual incidence of 3 to 4 cases per 2 million adults and 7 cases per 1 million neonates, even though its incidence is not known accurately because epidemiological studies are scanty. 1,2 Established risk factors for CSVT are tumors in the brain or other sites, 3,4 cerebral infections or traumas, 3,5 oral contraceptive use, 6,7 pregnancy, puerperium, 8,9 and thrombophilia abnormalities, 6,7,10 but in 15% to 20% of patients, the disease is apparently unprovoked, ie, occurring in the absence of predisposing factors. 1 Death in the acute phase is caused mainly by cerebral herniation, with a mortality rate ranging from 4.3% to 13% in the first month. 3 Only 7% to 20% of surviving patients have a poor neurological outcome, whereas the remaining 80% have a favorable prognosis. 3,11 13 In the last decade, there has been increasing evidence that early diagnosis and anticoagulant treatment reduce morbidity of CSVT and improve survival. 14,15 However, the optimal duration of anticoagulant treatment is not established because little information is available on the rate of CSVT recurrence after anticoagulant discontinuation. The largest multinational prospective study published so far included 600 patients with acute CSVT, but they were followed up for a relatively short median period of 16 months from the onset of the event. 3 The recurrence rate was 2.2% for CSVT and 4.3% for venous thromboses in other sites. These estimates were confirmed by a recent meta-analysis of 19 studies that were mainly retrospective, had small sample sizes, and were based on short periods of follow-up. 13 To estimate more accurately the long-term recurrence rate and to identify risk factors for recurrence of CSVT and other manifestations of venous thromboembolism, we followed up a large cohort of patients with a first episode of CSVT for a median of 6 years after discontinuation of anticoagulant treatment. Clinical Perspective on p 2746 Methods Patient Cohort and Follow-Up Patients with a first episode of CSVT consecutively referred between January 1991 and June 2008 for thrombophilia screening to the Received November 28, 2009; accepted April 29, 2010. From the A. Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Internal Medicine and Medical Specialties, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy. Correspondence to Ida Martinelli, MD, PhD, Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda, Ospedale Maggiore Policlinico, University of Milan, Via Pace, 9, 20122 Milan, Italy. E-mail martin@policlinico.mi.it 2010 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.109.927046 2740

Martinelli et al Risk of Recurrent Cerebral Vein Thrombosis 2741 outpatient clinic of the thrombosis center formed the cohort of this observational study. Demographic data, location of thrombosis, type of symptoms, medical history focusing on potential risk factors for thrombosis (cancer, infections, trauma, oral contraceptive use, pregnancy, puerperium), and treatment were recorded on the day of blood sampling for thrombophilia testing. In the absence of the aforementioned predisposing factors, CSVT was considered unprovoked. Only patients who had CSVT diagnosed with objective methods (cerebral digital angiography, computed tomography angiography, magnetic resonance, or magnetic resonance angiography) and were available to be followed up for a prolonged period of time were included in the study. Follow-up started at the time of discontinuation of anticoagulant therapy and was carried out on annual basis by means of a visit at the center, telephone contact, or a mailed questionnaire on the signs and symptoms of thrombosis, followed by phone contact. All patients were asked to undergo a control imaging of CSVT at the time of anticoagulant discontinuation. Patients were invited to return to the center immediately in case of symptoms suggestive of recurrent CSVT and were questioned about symptoms of deep vein thrombosis in other sites (lower and upper extremities, abdomen) or pulmonary embolism. Patients who could not reach the center to undergo objective testing were instructed to refer to the nearest hospital and to provide us with the corresponding diagnostic documentation, which was validated by us regardless of local diagnosis. For all patients and their physicians, a 24-hour active telephone number answered by one of us was available. Follow-up ended at the time of objectively documented recurrence of CSVT or other manifestations of venous thromboembolism or on January 15, 2009 (administrative censoring). Patients with a follow-up 1 month were not included in the study. We calculated inclusion in the cohort of 150 patients on the basis of an expected 3% annual incidence of recurrent venous thromboembolism, 3 a 10% increase in the annual incidence of recurrent venous thromboembolism, 16 a median follow-up period of at least 5 years, a 40% prevalence of persistent risk factors (presence of thrombophilia) for recurrent venous thromboembolism, 3,10 a 2.5 relative risk of recurrent venous thromboembolism in carriers of thrombophilia versus noncarriers, and a maximum of 5% of patients lost to follow-up, with 1-sided error of 0.05 and 80% power. The Institutional Review Board of the hospital approved the study, which was carried out and is reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for observational studies. 17 Patients gave written informed consent to participate in the study. Laboratory Tests Blood samples were taken at the time of the first visit for thrombophilia testing and anticoagulated with sodium citrate (3.8% wt/vol). Thrombophilia screening included DNA analysis for the 1691 guanine-to-adenine substitution in coagulation factor V gene (factor V Leiden) and for the 20210 guanine-to-adenine substitution in the 3 -untranslated region of the prothrombin gene, which are both gain-of-function mutations associated with hypercoagulability 18,19 ; functional and/or antigenic assays for plasma fibrinogen, antithrombin, protein C, and protein S 20 ; and anti-phospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies). 21 Patients who were taking vitamin K antagonists at the time of the first visit were asked to provide a second blood sample after discontinuation because this therapy affects measurements of protein C and protein S. We defined severe thrombophilia as the presence of antithrombin, protein C or protein S deficiency, anti-phospholipid antibodies, and 1 abnormality; we defined mild thrombophilia as the presence of heterozygous factor V Leiden, prothrombin G20210A, and dysfibrinogenemia. 22,23 Statistical Analysis Continuous variables were expressed as medians with minimum and maximum values; categorical data are given as counts and percentages. The annual incidence of recurrent thrombosis was calculated for the whole group of venous thromboses and separately for CSVT and other venous thromboses by dividing the number of events by 194 initial cohort 145 entered the follow-up 24 long term anticoagulant therapy 10 follow-up < 1 month 6 brain tumors or systemic cancer 5 inadequate objective diagnosis 4 declined informed consent 8 lost to follow-up 3 died (not for thrombosis) 2 restart anticoagulant therapy 132 reached the end of follow-up Figure 1. Study flow diagram. the total number of patient-years. The 95% confidence intervals (CIs) were based on the exact approximation of the Poisson distribution. Because of the low recurrence rate of venous thromboembolism, when the analysis was limited to specific subgroups, only crude estimates of the incidence were given. Recurrence-free survival was calculated by the Kaplan Meier method. The Cox proportional-hazard model was used to calculate the risk of thrombosis recurrence in patients with thrombophilia of different severities compared with those with no thrombophilia. We first gave unadjusted hazard ratios estimates and then adjusted the estimates for such possible confounders as age, sex, body mass index, and duration of anticoagulant treatment. Because the relatively low number of recurrences could make the full adjusted model unstable, we also fitted separate models, adjusting for each of the single potential confounding variables. P 0.05 was chosen as the cutoff for statistical significance. All statistical analyses were performed with the R release 2.9.2 statistical software (R Project for Statistical Computing, Vienna, Austria). Results One-hundred ninety-four patients with a first CSVT were referred for thrombophilia screening during the study period. Forty-nine were excluded for the reasons shown in Figure 1. Hence, 145 patients entered the follow-up. Their baseline demographic and clinical characteristics are listed in Table 1. The most frequently involved cerebral sinuses were the superior sagittal and the lateral (each in 47% of patients). In 31 patients (21%), CSVT was unprovoked; 65 (45%) had a single risk factor and 49 (34%) had multiple risk factors for thrombosis. Two thirds of the patients were women, and they had developed CSVT during oral contraceptive use, pregnancy, or puerperium in 92% of cases. The most frequent thrombophilia abnormality was heterozygous prothrombin G20210A mutation (19% of patients). The combination of oral contraceptive use or pregnancy and thrombophilia abnormalities was present in 35 women (37%) of reproductive age. At the time of thrombophilia screening, 85 patients were still on anticoagulant therapy; the remaining 60 were referred for screening within 12 months after anticoagulant withdrawal. Median duration of anticoagulant treatment was 12

2742 Circulation June 29, 2010 Table 1. Characteristics of the Study Cohort Male/female 39/106 Age at first CSVT, median (minimum-maximum), y 33 (11 79) Age at referral, median (minimum-maximum), y 34 (12 80) Body mass index, median (minimum-maximum), y 23.6 (14.5 41.5) Site of thrombosis, n (%) Superior sagittal sinus 28 (19) Lateral sinus 23 (16) Straight sinus 5 (3) Cavernous sinus 4 (3) Cortical veins 3 (2) Jugular vein 2 (1) Inferior sagittal sinus 1 (1) Combined 79 (55) Risk factors at first CSVT, Infections 11 (8) Trauma 4 (3) Oral contraceptive use 73 (90) Pregnancy/puerperium 14 (64) Thrombophilia 52 (36) Factor V Leiden 12 (8) Prothrombin G20210A mutation 27 (19) Antithrombin, protein C or protein S deficiency, 13 (9) anti-phospholipid antibodies, combined abnormalities Symptoms and signs, n (%) Intracranial hypertension 119 (82) Headache 113 (78) Nausea/vomiting 50 (35) Papilledema 9 (6) Diplopia 6 (4) Photophobia 4 (3) VI cranial nerve defect 3 (2) Focal neurological defects 84 (58) Sensory symptoms 24 (17) Visual loss 23 (16) Aphasia/dysarthria 23 (16) Any paresis 35 (24) Vertigo 14 (10) Seizures 39 (27) Impaired consciousness 45 (31) Mental status disorders 29 (20) Coma 16 (11) Anticoagulant therapy, n (%) Heparin (UFH or LMWH) vitamin K antagonists 111 (76) Heparin alone 17 (12) None 17 (12) UFH indicates unfractionated heparin; LMWH, low molecular-weight heparin. *Some patients had 1 risk factor. Percentage calculated on 95 women of reproductive age; oral contraceptive use and pregnancy are mutually exclusive. months (1 to 62 months). Follow-up took place with regular visits at the center for 62 patients (43%) or by phone contact and questionnaire for the remaining 83 (57%). Median duration of follow-up was 72 months (1 to 202 months) for a Table 2. Recurrence Rate of Venous Thromboembolism After a First Episode of CSVT Recurrence Rate, % Patient-y Type of recurrent venous thromboembolism CSVT 0.53 (0.16 1.10) Deep vein thrombosis and/or pulmonary 1.05 (0.49 1.82) embolism Time from discontinuation of anticoagulant therapy, y 1 5.04 (1.95 9.57) 3 2.63 (1.23 4.55) 10 1.74 (0.96 2.76) Sex Male 4.95 (2.31 8.57) Female 0.67 (0.20 1.40)* Thrombophilia None 1.35 (0.56 2.47) Mild 1.01 (0.18 2.51) Factor V Leiden 2.47 (0.21 7.19) Prothrombin G20210A 0.46 (0.00 1.85) Severe 6.50 (1.62 14.6) Crude incidence estimates are given. *0.87 (0.0 3.49) excluding women with the first CSVT during oral contraceptive use or pregnancy/puerperium. total of 952 patient-years. Eight patients (6%) were lost to follow-up, 2 died, and 2 restarted vitamin K antagonists for reasons other than venous thrombosis. Recurrent Venous Thrombosis Fifteen patients (10%) developed an objectively diagnosed second episode of nonfatal venous thrombosis, ie, CSVT in 5 (3%) and other manifestations of venous thromboembolism in the remaining 10 (7%; 8 cases of proximal lower-extremity deep vein thrombosis and 2 cases of isolated pulmonary embolism). Recurrent CSVT was diagnosed with the same objective methods as the first event, lower-extremity deep vein thrombosis with compressive B-mode ultrasound and pulmonary embolism with ventilation/perfusion lung scan or helical computed tomography. The overall incidence of recurrent venous thromboembolism (adjusted for duration of anticoagulant therapy) was 2.03 per 100 person-years (95% CI, 1.16 to 3.14). Table 2 reports the recurrence rate of venous thromboembolism after a first episode of CSVT according to type of recurrent venous thromboembolism, time from discontinuation of anticoagulant therapy, sex, and thrombophilia status. The incidence of recurrent venous thromboembolism was higher in the first year of follow-up after discontinuation of anticoagulant treatment than in subsequent periods, in men than in women, and in patients with severe thrombophilia than in those without or with mild thrombophilia. Table 3 shows the main clinical and laboratory features of patients who had recurrences of venous thromboembolism. Median duration of anticoagulant treatment was 13 months (3 to 44 months) in patients with recurrence and 12 months (1 to

Martinelli et al Risk of Recurrent Cerebral Vein Thrombosis 2743 Table 3. Type of Thrombosis and Risk Factors in the 15 Patients With Recurrent Venous Thromboembolism After a First CSVT Type CSVT Lower-extremity deep vein thrombosis and/or pulmonary embolism 62 months) in those without. Ten of the 15 patients with recurrence were male, for a hazard ratio (adjusted for age, body mass index, presence of thrombophilia, and duration of anticoagulant treatment) of 9.66 (95% CI, 2.86 to 32.7) compared with female patients, which became slightly lower when adjustment was made separately for each of the single potential confounding variables (Table 4). All men with recurrences had had a first unprovoked CSVT, and 50% had thrombophilia (severe in 3, mild in 2). One-hundred twenty-five patients (86%) had at least 1 objective imaging method repeated at the end of anticoagulant therapy and before entering the follow-up; recanalization of CSVT was complete in 58 (46%), partial in 56 (45%), and absent in 11 (9%). Recurrent CSVT involved a new sinus in all cases and was unprovoked in the 4 male patients; the only female patient with recurrent CSVT was diagnosed with Sex Age at First Thrombosis, y Anticoagulant Treatment, mo Follow-Up, mo Thrombophilia Other Risk Factors at First CSVT Other Risk Factors at Recurrence M 37 3 41 None None None M 43 7 5 None None None M 58 44 22 None None None M 32 12 8 None None None F 38 7 41 None Oral contraceptives Myeloproliferative neoplasm* M 11 24 3 Protein C deficiency and None Trauma dysfibrinogenemia M 25 0 53 Protein C deficiency None None F 26 22 26 Protein C deficiency and factor V Leiden Oral contraceptives Pregnancy (3rd mo) F 33 0 7 None Postpartum None M 25 19 104 Factor V Leiden None Venous catheter M 28 13 6 Prothrombin G20210A None None mutation F 47 0 1 Factor V Leiden None None F 26 37 94 None Oral None contraceptives M 58 3 10 None None None M 21 7 30 Protein S deficiency None Trauma *Essential thrombocytemia diagnosed during follow-up. essential thrombocytemia during follow-up and had had the first event during oral contraceptive use. Signs and symptoms of recurrent CSVT were generally mild (headache with or without nausea, vomiting, photophobia), but 2 patients had impaired consciousness accompanied by seizures in 1 patient and transient hemisyndrome in the other. During follow-up, none of the 95 women of reproductive age used oral contraceptives, and 31 became pregnant for a total of 44 pregnancies. Anticoagulant prophylaxis with low-molecularweight heparin was implemented in 37 pregnancies (27 ended successfully, 4 had obstetric complications, 6 terminated), whereas 7 pregnancies received no anticoagulant prophylaxis (2 ended successfully, 4 ended in miscarriage, 1 ended in termination). A woman who did not receive low-molecular-weight heparin during her first pregnancy had a recurrent deep vein thrombosis on the 11th gestational week. Table 4. Risk of Recurrent Venous Thromboembolism Associated With Sex Age Thrombophilia BMI Adjusted for Duration of Anticoagulation Sex Without With Crude Hazard Ratio Female 101 (70) 5 (3) 1 (Reference) 1 (Reference) 1 (Reference) 1 (Reference) 1 (Reference) Male 29 (20) 10 (7) 6.51 (2.22 19.1) 6.59 (2.24 19.4) 7.01 (2.34 21.0) 7.96 (2.56 24.8) 7.35 (2.41 22.4) BMI indicates body mass index. *Percentage calculated on the total number of patients. Continuous variable. Three categories (no, mild, and severe thrombophilia).

2744 Circulation June 29, 2010 Figure 2. Kaplan Meier curves showing the thrombosis-free survival after a first episode of CSVT in patients with no thrombophilia (dotted line), mild thrombophilia (broken line), and severe thrombophilia (solid line). Numbers at the bottom of the figure represent the subjects at risk at follow-up. Seven of the 15 patients (47%) with recurrent thrombosis had thrombophilia, which was found in none of those with recurrent CSVT and in 7 (70%) of those with other manifestations of venous thromboembolism (Table 3). The cumulative thrombosis-free survival curves (Figure 2) show that only patients with severe thrombophilia had a significantly higher risk of developing any manifestation of venous thromboembolism compared with those without thrombophilia or with mild thrombophilia. After 3 years of follow-up, the cumulative probability of survival free from recurrent thrombosis was 0.94 (95% CI, 0.89 to 0.99) for patients without thrombophilia, 0.95 (95% CI, 0.88 to 1.00) for those with mild thrombophilia, and 0.74 (95% CI, 0.48 to 0.98) for those with severe thrombophilia. The hazard ratio (adjusted for age, sex, body mass index, and duration of anticoagulant treatment) of recurrent thrombosis associated with severe thrombophilia was 4.71 (95% CI, 1.34 to 16.5), which did not change substantially when adjustment was made separately for each potential confounding variable (Table 5). Discussion This single-center, prospective observational study of patients who survived a first episode of CSVT had as its main goal assessing the recurrence rate of CSVT and other manifestations of venous thromboembolism and investigating the risk factors for recurrence. Owing to the rarity of the disease, studies on CSVT are mainly retrospective with a small sample size and short follow-up. The largest retrospective study (77 patients) showed an 11.7% rate of CSVT recurrence over a median follow-up period of 63 months. 24 Among the few prospective studies, only the International Study on Cerebral Vein and Dural Sinus Thrombosis investigated the natural history of the disease in a large number of patients (624) admitted for a symptomatic event at 89 hospitals worldwide. 3 The study provided detailed information on the pattern of clinical presentation and risk factors for CSVT, but follow-up was relatively short (median, 16 months), and the major risk factor of thrombophilia was not systematically evaluated. Our patient population is different and more selected because ours is a tertiary care center for patients referred for thrombophilia workup and counseling on the secondary prevention of venous thromboembolism (eg, need and duration of anticoagulant therapy and prophylaxis in high-risk situations). Another important difference is the start of follow-up, which was the time of anticoagulant discontinuation in this study and the time of CSVT diagnosis in the International Study. 3 Owing to the different times chosen to start follow-up, most patients in the International Study were still on anticoagulant therapy, so the results of that study do not help us understand the influence of stopping this therapy on the rate of recurrence. Nevertheless, at the 16-month follow-up, the prevalence of recurrences was very similar (1.3% in this study, 2.2% in the International Study; 3.4% and 3.0%, respectively, for other manifestations of venous thromboembolism) despite the fact that the International Study included patients with local or systemic cancer, which is an independent and strong risk factor for thrombosis that was excluded from our study. We found that male sex compared with female sex has a 7- to 8-fold increased risk of recurrence, which did not change when only the risk factors shared by the 2 sexes were considered (ie, excluding women with the first CSVT during oral contraceptive use or pregnancy/puerperium). Nearly three fourths of men with a first unprovoked CSVT and thrombophilia had recurrences compared with one third of those with a first unprovoked event without thrombophilia. A lower recurrence rate in women has also been reported for deep vein thrombosis of the lower extremities that is inde- Table 5. Risk of Recurrent Venous Thromboembolism Associated With Thrombophilia Age Adjusted for Duration of Anticoagulation Thrombophilia Without With Crude Hazard Ratio Sex BMI None 85 (59) 8 (5) 1 (Reference) 1 (Reference) 1 (Reference) 1 (Reference) 1 (Reference) Mild 36 (25) 3 (2) 0.86 (0.23 3.23) 0.85 (0.22 3.20) 1.25 (0.32 4.79) 0.87 (0.23 3.28) 0.89 (0.24 3.35) Severe 9 (6) 4 (3) 4.13 (1.24 13.7) 4.19 (1.25 14.0) 5.02 (1.49 17.0) 4.19 (1.25 14.0) 4.03 (1.20 13.5) *Percentage calculated on the total number of patients. Continuous variable. Heterozygous factor V Leiden or prothrombin G20210A mutations. Antithrombin, protein C or protein S deficiency, anti-phospholipid antibodies, combined abnormalities.

Martinelli et al Risk of Recurrent Cerebral Vein Thrombosis 2745 pendent of oral contraceptive use. 25 The association between oral contraceptive use or pregnancy is stronger for CSVT than for lower-limb deep vein thrombosis, 7 9 so it is likely that after a first CSVT, the avoidance of oral contraceptives and the use of antithrombotic prophylaxis during pregnancy dramatically reduced the probability of thrombosis recurrence in women. Hence, although the first event occurs preferentially among women of reproductive age, recurrences are more frequent in men because sex-related risk factors are removed in women who developed CSVT. Thrombophilia was not associated with an increased risk of recurrent CSVT but was associated with deep vein thrombosis of the lower limbs or pulmonary embolism. However, this was true only for carriers of high-risk abnormalities (antithrombin, protein C and protein S deficiency, anti-phospholipid antibodies, combined abnormalities) and not for the commonest abnormalities of factor V Leiden and prothrombin G20210A gain-of-function mutations in the heterozygous state, the latter being particularly frequent in patients with a first CSVT (19% in our series). 6,7 Perhaps mild thrombophilia alone is not sufficient to trigger recurrent CSVT when it is not associated with other synergistic risk factors such as oral contraceptives, which were avoided in women who had an episode of CSVT. 6,7,10,26 Because of their high risk of recurrent venous thromboembolism, patients with severe thrombophilia are currently recommended to continue vitamin K antagonists indefinitely after they develop a first unprovoked episode of lower-limb deep vein thrombosis or pulmonary embolism. 27 This study makes this recommendation also for patients with CSVT, mainly to prevent recurrence of other manifestations of venous thromboembolism. In addition, men with a first unprovoked CSVT have a particularly high risk of recurrence and may require anticoagulant therapy of indefinite duration. One may wonder why 13 patients with severe thrombophilia had chosen to discontinue anticoagulant treatment; their decision was based on several factors such as a first single sinus cerebral thrombosis (9 patients), prompt recanalization (11 patients), or the removal of transient risk factors (8 patients). The main limitation of this study is that our selected population may decrease the generalizability of the results and may have led to an overestimation of the risk of recurrence, which still was low. In addition, the observed event rate is lower than hypothesized; therefore, the study has lower power than originally designed for. The rarity of CSVT and the selection criteria made the duration of this study rather long, so among the established causes of mild thrombophilia, high plasma levels of factor VIII were not considered owing to the recent inclusion of this test in our thrombophilia screening. A further limitation is that we could not evaluate whether the degree of recanalization of CSVT influences the probability of recurrence as it does in lowerextremity deep vein thrombosis, 28 not only because of the low recurrence rate but also because all recurrent episodes occurred in new sinuses. On the other hand, study strengths are the long duration of follow-up after anticoagulant withdrawal and the size of the cohort diagnosed and followed up homogeneously with objective methods in a single clinical unit. Conclusions In this prospective study, the recurrence rate of CSVT and other manifestations of venous thromboembolism was low, with nearly half of recurrent thrombosis occurring within the first year after discontinuation of anticoagulant therapy. Patients with severe thrombophilia had a 4- to 5-fold increased risk of developing recurrent deep vein thrombosis of the lower extremities or pulmonary embolism and therefore have an indication for anticoagulant therapy of indefinite duration. The latter may also be indicated for men who had had a first unprovoked CSVT. Acknowledgments We thank Dr Gianluca Landi, consultant neurologist, for his valuable help in discussing the medical histories of a number of patients. We are grateful to the patients who agreed to be visited and interviewed annually for the purpose of this study. Source of Funding The study was supported by funding from Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico of Milan, Italy. None. Disclosures References 1. 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