Local thrombolysis combined with balloon dilation for patients with severe cerebral venous sinus thrombosis

Cerebral venous sinus thrombosis (CVST) is a rare disease involving thrombosis of the cerebral veins and sinuses. Severe consequences may occur if CVST is not treated promptly and appropriately, including intracranial hypertension and cerebral venous infarcts due to venous block that can cause epilepsy, severe neurological morbidity, or even death.^[1]

The standard treatment for CVST includes anticoagulation with unfractionated heparin or low-molecular-weight heparin (LMWH). Despite a great reduction in mortality because of the widespread use of anticoagulant therapy, 5% to 30% of affected patients die of CVST each year.^[1] For those not responding to adequate systemic anticoagulation, endovascular treatment should be considered.^[2]

The endovascular treatment of CVST primarily includes two specific techniques, i.e. local thrombolysis with infusion of the thrombolytic drug and mechanical thrombectomy with special devices. Sometimes the two methods are used together.^[3] The merit of local thrombolysis lies in its precise localization of the drug infusion. Theoretically, the thrombus dissolves faster after it is broken by balloon dilation. However, the safety and effectiveness of the combined treatment of balloon dilation and local thrombolysis remains undetermined.

In this study, we recruited 40 patients with CVST that were refractory to heparin treatment and evaluated the value of combined treatment. These patients were admitted to the Second Affiliated Hospital of Zhejiang University School of Medicine between October 2015 and November 2019. The diagnosis of CVST was confirmed by contrast-enhanced magnetic resonance venography (CEMRV). Anticoagulation with subcutaneous LMWH was the first treatment for all patients. When a patient did not respond to adequate anticoagulation therapy, endovascular treatment was provided. The indications for endovascular treatment include a lack of improvement or progressive deterioration of neurological impairment and an abnormal state of consciousness.^[4] This study was approved by the Ethics Committee of the Second Affiliated Hospital of Zhejiang University, School of Medicine. Informed consent for the procedure was provided by the patients’ relatives. Pretreatment computed tomography or magnetic resonance imaging was performed to assess the hemorrhage, lesion size, and mass effect.

Endovascular treatment was performed using a combination of balloon dilatation and local thrombolysis. First, a 6F 90-cm shuttle sheath (Cook Medical, Bloomington, IN, USA) was inserted percutaneously from the femoral vein to the jugular bulb under local or general anesthesia. Second, with the help of a 300-cm, 0.014-inch guide wire (Stryker Neurovascular, West Valley City, CA, USA), a Rebar microcatheter (Micro Therapeutics, Irvine, CA, USA) was advanced into a frontal position in the superior sagittal or straight sinus. Next, a 4 mm × 20 mm rapid exchange dilatation catheter (Abbott, Santa Clara, CA, USA) was inserted into the thrombotic venous sinus. It was inflated repeatedly to crush the thrombus from the distal to proximal venous sinus. Finally, the Rebar microcatheter was inserted in the superior sagittal or straight sinus using the exchange technique again. Normal saline (48 mL) was added to 500,000 U of urokinase and injected continuously through the microcatheter with a micropump at 4 mL/h. Urokinase (1,000,000 U/day) was injected until the microcatheter was removed. During thrombolysis therapy, direct venous sinus angiograms were performed with the microcatheter every 2 or 3 days. The infusion was stopped in any of the following conditions: (1) patency of the dural venous sinus on the repeated direct venous sinus angiogram; (2) presence of active extra- and intracranial bleeding, (3) if the clinical symptoms improved despite no obvious venous sinus patency more than 7 days after the catheterization; and (4) the patient's condition continued to deteriorate and vital signs could not be sustained. Dilute heparin was continuously used through the shuttle sheath during the thrombolytic therapy. The dosage of heparin was adjusted to maintain an activated partial thromboplastin time of 60 to 90 s. CEMRV was performed to assess the short-term result before discharge. Sequentially, all patients were offered long-term oral anticoagulation (warfarin therapy). The dosage of warfarin was adjusted according to an international normalized ratio of 2–3.

Patients were followed up via outpatient visits or telephone calls for 3 to 6 months. Sinus recanalization was evaluated by CEMRV again after 3 months. The clinical outcomes were measured by modified Rankin scale (mRS) scores. Treatment response was assessed as follows: satisfactory improvement (mRS scores of 0, 1, 2), partial improvement (mRS scores of 3 and 4), or poor outcome (mRS scores of 5 and 6).

All calculations were made using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). Continutous variables are presented as mean ± standard deviation (SD) or median (range). Discrete data are shown as counts and percentages.

The patients’ baseline characteristics are presented in Supplementary Table 1. The mean patient age was 37.9 ± 14.6 years (range, 16–67 years). The median time from symptom onset to diagnosis was 7 days (range, 3–360 days). The median time from diagnosis to anticoagulation was 0 day (range, 0–6 days). The median time from anticoagulation to thrombolysis was 4 days (range 0–170 days). In addition, before endovascular treatment, 16 patients had disturbed consciousness (stupor or coma), 17 had tonic-clonic seizures, and 21 had intracranial hemorrhage.

The venous sinuses of all patients could be accessed via catheterization, with a technical success rate of 100% (40/40). Thirty-eight patients underwent balloon dilation to break the thrombus partially or completely. No operation-related complications occurred in any patients.

Thirty-two patients received endovascular treatment within 30 days of onset. The microcatheter could be inserted into the superior sagittal or straight sinus of these 32 patients for thrombolysis [Supplementary Figure 1]. Additionally, eight patients received endovascular treatment beyond 30 days after onset; of them, three could be navigated to a predetermined site for thrombolysis [Supplementary Figure 2], while the other five patients did not undergo local thrombolysis because of failure to navigate to the target position. Therefore, a total of 35 patients underwent local thrombolysis in the superior sagittal or straight sinus; the median time of thrombolysis was 5 days (range 1–7 days).

Eventually, thrombolytic therapy was terminated on day 2 because of rapid deterioration in two patients, who died soon thereafter. Thrombolytic therapy was terminated in one patient on the second day because of bleeding on the floor of the mouth; the other patients were able to tolerate the endovascular treatment. Postoperative CEMRV was performed in 38 patients before discharge. Complete recanalization of the sinus was noted in 36.8% (14/38) of patients, partial recanalization was seen in 57.9% (22/38), and no change was exhibited in 5.3% (2/38). In 33 patients treated with combined technique, complete recanalization of the sinus was noted in 42.4% (14/33) of the patients, and partial recanalization was seen in 57.6% (19/33).

All patients required oral anticoagulants for at least 6 months after discharge. Of the 38 patients, 35 made a full recovery or had no residual symptoms (mRS scores of 0 or 1). Three patients had a moderate disability (mRS score, 3). In addition, during the 3–6 months of follow-up, CEMRV performed in 38 patients revealed complete recanalization of the sinus in 86.8% (33/38) of the patients, partial recanalization in 7.9% (3/38), and no change in 5.3% (2/38) of patients. Complete recanalization of the sinus was noted in all of 33 patients treated with combined technique.

To the best of our knowledge, evidence of the efficacy and safety of endovascular treatment in patients with CVST is lacking, especially that from finished randomized controlled trials. Several case reports and small case series mentioned the therapeutic effect of local thrombolysis in CVST,^[3–5] although with mixed results. In our study, the mortality rate was 5.0% (2/40), and 87.5% (35/40) of the patients had a satisfactory recovery (mRS score of 0 or 1). Our study shows the safety and efficacy of the combined treatment.

We found that intraoperative complete recanalization of the obstructed sinus was not necessary for a good clinical result as mentioned by Lozano-Ros et al.^[6] In our study, despite the relatively low immediate recanalization rate, the clinical outcomes and proportion of complete recanalizations were satisfactory after three months. More importantly, there were no operation-related complications. The favorable result may be attributed to the safer and more convenient procedure of balloon dilation than other thrombectomy devices. After balloon dilatation breaks the thrombus, it not only increases the gap of venous reflux, it also makes the thrombus easier to dissolve. Postoperative thrombolysis and anticoagulation therapy further ensured circulation of the venous sinus.

Poor consciousness often predicts poor prognosis in patients with CVST.^[1,7] Mehraein et al^[7] reported that the mortality rate was 53.3% (8/15) among patients with stupor or coma despite the use of conventional anticoagulation therapy. In our study, 16 patients were comatose before endovascular treatment, and two died after rapid worsening. The mortality rate of comatose patients in our study was lower than that of patients treated with conventional anticoagulation alone. Thus, this study revealed that comatose state remains an important factor for poor prognosis. Active endovascular treatment can decrease the mortality rates and should be administered immediately.

Comatose and confusion are clinical predictors of a poor prognosis. Thrombosis of the deep cerebral vein and cerebral hemorrhage are common imaging markers.^[1] Besides these signs, we found a less highlighted manifestation in previous studies. Ferro et al^[1] reported that the incidence of internal jugular venous thrombosis was 11.9% (74/624) among patients with CVST, while the incidence in our patients reached 82.5% (33/40). We believe that this is another important imaging marker of refractory CVST. If the jugular venous thrombosis was extended from the intracranial venous sinus, endovascular treatment should be provided as soon as possible.

Accordingly, the current study demonstrates that local thrombolysis combined with balloon dilation is a safe and effective treatment for severe CVST. Comatose status was still an important prognostic factor of death. A jugular venous thrombosis extending from an intracranial sinus thrombosis is most likely an imaging biological marker for refractory CVST. More cases are needed to confirm this hypothesis. The major limitations of our study include its observational nature and limited number of cases.

Funding

The study was supported by a grant from the Science and Technology Department of Zhejiang Province (No. 2017C33050).

Conflicts of interest

None.