Cerebral venous thrombosis (CVT) is a rare but potentially devastating cause of neurologic disease. CVT accounts for 1% of all strokes, leads to poor outcome or death in about 15% of patients, and preferentially impacts a younger population [1,2]. Nearly 85% of CVT cases have at least one identifiable risk factor, including pregnancy, oral contraceptive pill (OCP) use, inherited and acquired thrombophilia, dehydration, trauma, malignancy, or infection [1]. Standard therapy consists of anticoagulation, typically with parenteral anticoagulation followed by an oral anticoagulant such as vitamin K antagonists or a direct oral anticoagulant [3-5]. In addition to preventing clot propagation and recurrent venous thrombosis, anticoagulant treatment improves the likelihood of vessel recanalization, which is associated with favorable outcomes and lower mortality after CVT [6].

Several studies have evaluated predictors of recanalization after CVT. However, results have been conflicting, likely due to the small sample size and heterogeneity of the patient population and treatments used [7-11]. Additionally, studies investigating the rate and temporal profile of recanalization in patients with CVT produced variable results [7,10]. Recently, a multicenter study suggested that recanalization can start after a few days of treatment and is associated with decreased likelihood of expansion of associated brain lesions [12]. Another analysis of the RE-SPECT CVT (A Clinical Trial Comparing Efficacy and Safety of Dabigatran Etexilate With Warfarin in Patients With Cerebral Venous and Dural Sinus Thrombosis) trial showed nearly 85% full or partial recanalization rates after 6 months of treatment [5].

Given the link between recanalization and clinical outcomes, we sought to identify clinical and imaging predictors of recanalization and examine improvement in recanalization in patients with CVT receiving oral anticoagulation treatment.

Of 1,025 patients, 551 patients (mean age, 44.4±16.2 years, 66.2% women) met inclusion criteria for our analysis (Figure 1). Patients included in the analysis were younger, more likely to be women, have a family history of VTE, use OCPs, and longer duration of symptom onset to anticoagulation initiation compared to patients that were excluded (Supplementary Table 1). The majority of included patients were non-Hispanic (90.0%) and White (74.9%). Among those that identified as women, 42.5% were on an OCP and 4.6% were in the 12-week postpartum period when they had the CVT. Factor V Leiden and/or prothrombin gene G20210A mutation were detected in 10.7% patients. A minority of patients (11.3%) had both superficial and deep vein involvement.

The median number of follow-up imaging studies was 2 (interquartile range [IQR], 1-2). The median follow-up was 411 days (IQR, 202-759), and median time to first follow-up imaging study was 110 days (IQR, 60-187). During follow-up time, 219 (39.7%) had complete, 267 (48.5%) had partial, and 65 (11.8%) had no recanalization. The majority of patients had the same imaging modality performed during their initial diagnosis and follow-up (73.3%).

In a large, multicenter, international, retrospective, observational study of patients with CVT, we found that older age, male sex, and lack of parenchymal changes were associated with no recanalization after CVT. The majority of improvement in recanalization and complete recanalization occurred within the first 3 months.

Our findings add to the growing literature on predictors and rates of recanalization after CVT [6]. Two studies found that younger age (using <50 and <37 years as cut-off) was associated with a greater rate of recanalization [7,10] while others found no association between age and recanalization [8,9]. Apart from lower rates of recanalization, older age is an independent predictor of higher rates of death and disability after CVT, perhaps due to the differences in clinical presentation and associated risk factors such as hypercoagulability of malignancy [18]. Similarly, the data on sex and recanalization is inconsistent, with some studies finding that women were more likely to have complete recanalization [9,10], while others found no difference [7,8,11]. Our study is line with a systematic review and meta-analysis showing that younger age and female sex were the most consistent predictors of recanalization [6]. Our study builds on these findings by using a larger and heterogenous cohort of patients, thereby increasing the power of detecting a statistically meaningful association.

Our study found a possible association between recanalization and parenchymal changes and superficial and deep vein involvement. Parenchymal changes such as venous infarct, cerebral edema, or intracranial hemorrhage typically cause neurological deficits and seizures, both of which may result in earlier presentation to the emergency room and a lower likelihood of misdiagnosing a CVT [19]. Parenchymal changes may also be a marker for an acutely developing rather than a chronic clot, which may be more responsive to anticoagulation therapy. Although we were unable to confirm this association in our secondary analysis, we suspect this may have been due to a lack of power rather than a lack of association. The presence of both superficial and deep vein involvement showed a trend towards an association with recanalization in our primary analysis, and an association was present in the secondary analysis restricted to recanalization status 6 months after diagnosis. Possible explanations include an underlying thrombophilia causing a more generalized clot that is responsive to anticoagulation, or a more severe disease from an extensive clot leading to earlier presentation and treatment.

Several studies have examined recanalization rates after CVT [6]. In a meta-analysis of 8 studies with 382 patients, approximately 80% of cases demonstrated recanalization (complete or partial) 9 months after diagnosis [6]. In addition, the RE-SPECT CVT trial showed that 85% of patients achieved recanalization at 6 months [5]. However, many of these studies were retrospective, or with small sample size, or with imaging not obtained at routine time intervals, thereby limiting the ability to estimate rates of recanalization. Furthermore, a recent important yet small study showed that very early partial recanalization occurred in 68% of CVT cases and was associated with increased odds of regression and reduced odds of progression of non-hemorrhagic brain lesions [12]. Our study builds on prior findings by showing the greatest improvement in recanalization and complete recanalization occurs within the first 3 months and thus continuation of anticoagulation beyond this time frame may not be beneficial in achieving further recanalization.

The strengths of our study lie in its use of a large cohort of patients from academic and non-academic hospitals from various countries, increasing the generalizability of our results. Our findings must be considered in light of several limitations. First, the retrospective and observational design of the study limits our ability to assess for recanalization at scheduled intervals (for example, every 3 months), given that the time between imaging was left at the discretion of the treating physician. Additionally, around 45% of patients in the original ACTION-CVT cohort did not have recanalization data and were not included in our analysis. Therefore, our findings are only relevant to patients who survived and had at least one repeat imaging study performed. Similarly, given that our study was a secondary analysis, we were reliant on provoking factors that were documented in the initial ACTION-CVT cohort. We therefore lacked information on additional provoking factors for CVT, such as presence of inflammatory disorders. Second, patients with history of known antiphospholipid syndrome, pregnancy, and active malignancy were excluded from the original cohort. This may introduce a selection bias and limit our ability to determine whether these CVT risk factors may be associated with recanalization. Third, the retrospective nature of our study does not allow us to control for differences in imaging modality and their diverse accuracies during initial admission and follow-up. However, the majority of patients had the same imaging modality performed throughout their disease course. Fourth, we lacked central adjudication of our images. To reduce bias in the absence of centralized scoring of images, the primary outcome was determined by official radiology reads rather than site investigators. However, no scale was used to quantify recanalization, and accuracy and interobserver agreement of the recanalization status is unknown. Fifth, in patients with multiple vein involvement, we also do not have data on recanalization of each vein, which limits our knowledge on whether there is a difference in recanalization rates between superficial and deep veins. We also lack information on reversible parenchymal lesions, which has previously been found to be associated with early recanalization [12]. Sixth, our second objective, the timing of recanalization, is limited by the expectation that patients who are not recanalized by a certain time point are the ones that are going to continue getting rescanned. This bias may affect the percentage of patients with improvement and complete recanalization, especially as time elapses from the index event. Similarly, repeat imaging was not systematically performed, which can introduce a selection and indication bias. Seventh, we lack information on the direct oral anticoagulant doses and percentage of time that international normalized ratio was within therapeutic range, both of which could influence recanalization.

In a large, multicenter cohort of patients with CVT, we found that older age, male sex, and lack of parenchymal changes were associated with no recanalization. The majority of improvement in recanalization in CVT occurs within the first 3 months, suggesting that anticoagulation therapy beyond the first 3 months may have limited value in achieving further recanalization. Our study also suggests a low utility in assessing for further recanalization after the first 6 months; however, given our limitations, further studies are needed to validate our findings. Future studies should aim to determine whether certain antithrombotic regimens may be more effective in patients with predictors of no recanalization. Prospective studies with imaging performed at several defined time intervals (potentially 2 weeks, 3 months, 6 months, and 1 year) are needed to overcome the limitations of our study and prior studies and address the issue of timing of recanalization in CVT patients.