J Thromb Thrombolysis DOI 10.1007/s11239-015-1205-7
Endovascular treatments for cerebral venous sinus thrombosis Zhongming Qiu1,2 • Hongfei Sang3 • Qiliang Dai3 • Gelin Xu1,3
Ó Springer Science+Business Media New York 2015
Abstract Cerebral venous sinus thrombosis (CVST) is an uncommon but potentially fatal condition. CVST usually occurs young adults with a female predominance. The current mainstay for treating CVST is anticoagulation with heparin. However, more aggressive interventions, endovascular treatment as an example, may be indicated in selected patients who are non-responsive to heparin and other anticoagulants. Endovascular approaches include catheter-based local chemical thrombolysis, balloon angioplasty and mechanical thrombectomy, all of which may rapidly recanalize the occluded venous sinus, restore the blood flow, reduce the increased intracranial pressure, and subsequently relieve the corresponding symptoms. However, as an invasive strategy, endovascular procedures per se may cause complications, such as intracranial hemorrhage, vessel dissection and pulmonary embolization, which may substantially decrease the benefit–risk ratio of the treatment. Due to the rareness of the condition and the limited indication of this invasive strategy, safety and efficacy of endovascular procedures in treating CVST are
Zhongming Qiu and Hongfei Sang have contributed equally to this work. & Gelin Xu [email protected]; [email protected] 1
Department of Neurology, Jinling Hospital, Second Military Medical University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, China
2
Department of Neurology, The 117th Hospital of PLA, 14 Lingyin Road, Xihu District, Hangzhou 310013, Zhejiang Province, China
3
Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, China
less feasible to be evaluated in large randomized clinical trails. Therefore, the evidences for justifying this treatment strategy are largely derived from case reports, cohort studies and clinical observations. Keywords Cerebral venous sinus thrombosis Endovascular procedures Thrombectomy Thrombolytic therapy
Introduction Cerebral venous sinus thrombosis (CVST) is the presence of thrombosis (a blood clot) in the dural venous sinuses, which drain blood from the brain. CVST is rare, with an estimated incidence of five per million annually in adults. While it may occur in all age groups, it is most common in the third decade, and 75 % cases are female [1]. CVST accounts for 0.5–1 % of all stroke cases. The overall mortality of CVST has been reported as 4.39 %, but in patients with encephalopathy or impending encephalopathy the mortality may be as high as 53 % [1–4]. The most common risk factor of CVST is inherited or acquired thrombophilia, followed by oral contraceptives. Other risk factors included pregnancy and puerperium, infection and malignancy. According to the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT), 43.6 % of the 624 enrolled CVST patients had more than one risk factor [1]. Superior sagittal sinus is the most frequently (62 %) affected one, followed by lateral sinuses (45 % left, 41 % right), straight sinus (18 %), and cavernous sinus (1.3 %). Deep venous involvement may result in death or dependency in 29 % patients [1]. The clinical severity of CVST usually depends on the extent of the thrombosis, the
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territory of the involved vessels, the compensation of venous collaterals and the duration of the thrombus. Computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance venography (MRV) and digital subtraction angiography (DSA) are useful tools in diagnosing CVST. Currently, the first-line treatment for CVST is anticoagulation with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin (LMWH) [5, 6]. However, about 10 % patients had poor outcomes despite adequate anticoagulation. Large cohort studies reported that CVST was associated with a combined morbidity and mortality rate of 13.4 % after regular treatments [1]. This high morbidity and mortality rate became an impetus for introducing more aggressive strategies, endovascular procedures as an example, as alternatives in treating CVST. Endovascular procedures, including catheter-based local chemical thrombolysis and mechanical thrombectomy, may rapidly recanalize occluded venous sinus, restore blood flow, reduce increased intracranial pressure, and subsequently relieve the related symptoms. However, as an invasive treatment, endovascular procedures per se may cause complications, such as intracranial hemorrhage, vessel dissection and pulmonary embolization. So the benefit–risk ratio should be carefully weighted in individual patients before endovascular procedures being performed. We searched PubMed database for all publications on endovascular treatment of CVST in English. The search returned 142 publications (involved 642 patients), which included 67 case reports, 27 case series, 8 observational studies, 24 reviews, and 16 other type studies. Studies of large series which more than five cases are summarized in Table 1.
Catheter-based pharmacological thrombolysis Most guidelines recommended that CVST patients should be treated with either activated partial thromboplastin time (APTT) adjusted intravenous heparin or body weight adjusted subcutaneous LMWH [5, 6]. These treatments are based on the rationale that these agents may reverse the causal thrombotic process. Three small randomized trials have showed a beneficial, although not statistically significant, effect of heparin [7–9]. A meta-analysis showed that anticoagulant was associated with a 54 % relative risk reduction of death or dependency when compared with placebo [10]. Another treatment option is systemic (intravenous) thrombolysis. This treatment has theoretical advantages over heparin treatment. Generally, thrombolysis combined with heparin can result in earlier and higher rate of recanalization than merely heparin treatment [11]. Vines and
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Davis, for the first time, reported five cases of sagittal sinus thrombosis treated with systemic thrombolysis with intravenous urokinase in 1971 [12]. Thereafter, Di Rocco et al. reported 5 CVST patients recovered complete after intravenous urokinase thrombolysis [13]. One disadvantage of systemic thrombolysis lies in that it may take a long time, e.g. several days, for the occluded venous sinus to be recanalized due to the dilution of the drug after system delivery [14]. Compared with systemic thrombolysis, local administration can enormously increase the on site drug concentration as well as the drug-thrombus contact surface by infusing the drug directly into the thrombus with a microcathater [15, 16]. Local thrombolysis may also decrease the total dosage of thrombolytic agents, which in turn lower the risk of hemorrhage [17]. Thanks to the flexibility of recently developed catheters and the relatively rapid metabolism of thrombolytics such as urokinase and recombinant tissue plasminogen activator (rt-PA), intracranial complications of local thrombolysis appeared comparative to those of systemic anticoagulation [18]. According to the data from two systemic reviews, CVST patients treated with local thrombolysis had worse clinical condition than those treated with systemic thrombolysis prior to treatment, with a higher proportion of patients in coma [difference: -0.24; 95 % confidence interval (CI) -0.34 to -0.06]. Regarding the partial recanalization rates, however, local thrombolysis was more effective than systemic thrombolysis (difference: -0.23; 95 % CI -0.38 to -0.02) [19, 20]. Scott and his colleagues reported in 1988 the dramatic effects of local thrombolysis in a patient with superior sagittal sinus thrombosis. Presented initially with decerebrate, the patient improved rapidly over a couple of days, and remained with only mild dysphasia 28 days after endovascular thrombolysis [21]. Subsequently, several investigators published case reports and small series emphasizing the advantages of local thrombolysis in treating CVST. In a large case series, Guo et al. reported the outcomes of 37 CVST patients treated with local thrombolysis. At the 6-month follow-up, 34 (91.9 %) patients had good clinical outcomes (modified Rankin Scale, mRS \3). Only 1 (2.7 %) patient remained with severe neurologic deficits, and 2 (5.4 %) patients died [22]. When performing catheter-based local pharmacological thrombolysis, a standard microcatheter along a microguidewire is usually navigated to the target dural sinus through a sheath or guiding catheter located in the jugular bulb. The procedures were usually performed under general anesthesia [15, 17, 23, 24]. Most procedures were performed via femoral vein or via internal jugular vein access, with a few procedures performed via a fontanelle puncture, burr holes, or craniotomy [21, 22, 25–28]. Local thrombolysis was usually initiated with a bolus, followed by a continuous infusion through the catheter in situ
19
15
1999
1997
1995
1995
Barnwell [71]
Tsai [72]
Wasay [33] Frey [30]
Kim [14]
2001 1999
Baker [70]
Philips [57]
2003
2001
Soleau [34]
2007
2006
Tsai [68]
2008
Stam [50]
Anand [69]
20
2008
Zhang [54]
6
18
6
9
6
20 12
5
18
93
6
5
2009
6
2009
2010
Yue [17]
Peng [67]
2010
Kumar [25]
37 6
6
9
9
52
11
13
34
29
26
10
Cases (n)
Pfefferkorn [66]
2012 2012
2013
Li [15]
Guo [22] Waugh [29]
2013
Guo [26]
2012
2013
Dashti [31]
Jankowitz [41]
2014
Siddiqui [28]
2013
2014
Siddiqui [28]
2013
2014
Shui [64]
Poulsen [24]
2014
Garge [32]
Mortimer [23]
Year of publication
First authors and reference number
32 (6 d–58)
NA
33 (24–52)
33 (14–75)
34 (4–61) 32.5 (20–55)
47 (19–67)
NA
43.8
38 (19–57)
32 (12–57)
26 (14–49)
27 (17–41)
30 (18–51)
40.5 (22–57)
32 (17–46)
31 (17–42) 12 (9–17)
NA
21.1 (15–31)
5 (1.5–16)
33 (10–77)
25 (19–35)
45 (17–73)
35 (12–57)
32 (4–61)
28.9 (18–46)
41.4 (26–60)
Age, mean (range) years
50.0
NA
66.7
66.7
60.0 75.0
80.0
NA
38.0
66.7
80.0
83.3
60.0
66.7
66.7
57.9
67.6 0
83.3
89.0
77.8
42.3
100.0
53.8
76.5
69.0
73.1
60.0
Sex, female (%)
LT
LT
LT
LT/MT
LT LT
LT/MT
LT/MT
LT
LT/MT
LT/MT
LT/MT
LT/MT
LT/MT
LT/IVT
LT/MT
LT LT/MT
LT/MT
LT/MT
LT/MT
LT/MT
LT
MT
LT/MT
LT
BD/MT
LT
Endovascular treatment strategies
Table 1 Case series (n C 5) of CSVT treated with endovascular treatments
NA
NA
Heparin/OAC
Heparin/OAC
Heparin/OAC Heparin/OAC
Heparin
Heparin/OAC
Heparin/OAC
Heparin
Heparin
Heparin/OAC
Heparin
Heparin/OAC
Heparin/OAC
Heparin/OAC
Heparin/OAC Heparin
Heparin
NA
NA
Heparin/OAC
Heparin/OAC
Heparin/OAC
Heparin
Heparin
LMWH
OAC
Anticoagulation treatment
5/34 (15.0)
[6
NA
NA
3
12–35
4 (1–15) 10 (1–30)
NA
27 (2–84)
NA
NA
3–6
11 (6–15)
6
NA
3
6.3 (6–8)
6 NA
3
6–48
NA
6
6
0
1/6 (16.7)
2/9 (22.2)
0
2/20 (10.0) 3/12 (25.0)
3/5 (60.0)
5/18 (27.8)
NA
6/15 (40.0)
5/20 (25.0)
0
0
0
0
2/19 (10.5)
1/37 (3.0) 5/6 (83.3)
0
7/9 (77.8)
1/9 (11.1)
0
0
1/13 (7.7)
4/29 (14.0)
[6 7
0
1/10 (10.0)
e
Periprocedural hemorrhage proportion (%)d
42.3 (12–62)
1
FU, mean (range) month(s)
0
2/6 (33.3)
0
0
0 0
0
4/18 (22.2)
22/93 (23.7)
0
6/20(30.0)
2/6 (33.3)
1/5 (20.0)
2/6 (33.3)
1/6 (16.7)
3/19 (15.8)
2/37 (6.0) 0
0
0
1/9 (11.1)
6/52 (11.5)
0
2/13 (15.4)
NA
NA
0
1/10 (10.0)
Periprocedural death proportion (%)
18/18 (100.0)
4/4 (100.0)
NA
5/6 (83.3)
NA 12/12 (100.0)
4/5 (80.0)c
13/14 (92.8)
NA
15/15 (100.0)
12/14 (85.7)c
4/4 (100.0)c
4/4 (100.0)
2/6 (33.3)
5/5 (100.0)
14/19 (73.7)
34/35 (97.1) 4/6 (66.7)
3/6 (50.0)
8/8 (100.0)
8/8 (100.0)
45/46 (97.8)
11/11 (100.0)
7/9 (77.8)
16/22 (73.0)
11/12 (92.0)
26/26 (100.0)b
9/9 (100.0)c
Good clinical outcomes proportion (%)a
Endovascular treatments for cerebral venous sinus thrombosis
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123
Periprocedural hemorrhage defined as new hemorrhage
Numbers were evaluated as new or increased hemorrhage e
d
Numbers were evaluated as GCS = 15
Good clinical outcomes defined as a mRS score of 0 or 1
Numbers were evaluated as mRS B2 c
b
a
BD balloon dilatation, d day, FU follow-up, GCS Glasgow Coma scale, IVT intravenous thrombolysis, LMWH low molecular weight heparin, LT local thrombolysis, mRS modified Rankin scale, MT mechanical thrombectomy, NA not available, OAC oral anticoagulants
6/6 (100.0) 0 1/7 (14.2) 20 (8–37) Heparin/OAC LT/MT 57.1 40 (25–71) 1994 Smith [73]
7
10/10 (100.0) 1/12 (8.0) 5/12 (41.7) NA Heparin/OAC LT 58.3 33.5 (0.1–65) 1994 Horowitz [18]
12
Year of publication First authors and reference number
Table 1 continued
Cases (n)
Age, mean (range) years
Sex, female (%)
Endovascular treatment strategies
Anticoagulation treatment
FU, mean (range) month(s)
Periprocedural hemorrhage proportion (%)d
Periprocedural death proportion (%)
Good clinical outcomes proportion (%)a
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[26–29]. Venography was always performed to assess the patency of venous sinus. Thrombolysis was discontinued when there was radiological patency of the occluded venous sinus or in the presence of neurological deterioration or the maximum dose of thrombolytic agent was reached [15, 22, 25]. Frey et al. reported their experience in treating CVST with a mean rt-PA dose of 46 mg (ranged from 23 to 128 mg). The authors inserted a microcatheter into the thrombus, and then injected a bolus of rt-PA followed by continuous infusion until the recanalization being observed [30]. Other authors reported single bolus injection or merely continuous infusion [23]. During the procedure of thrombectomy, systemic anticoagulation with heparin was usually administrated continuously to maintain an activated clotting time (ACT) of 250–300 s [31]. During the procedure of local thrombolysis, in which increased risk of hemorrhage is a concern after rt-PA administration, some authors used heparin but with a shortened goal ACT of 200–250 s [17], others did not use anticoagulations [32]. Following the endovascular procedure, most patients were on systemic heparinization for several days for facilitating vessel recanalization or for preventing the re-occlusion of the recanalized vessels. Some studies suggested a target partial thromboplastin time (PTT) between 50 and 70 s [22, 33, 34]. Others did not mention this treatment index [15, 23, 28]. As the total cases reported are still limited, extrapolating data from studies of coronary reperfusion with a goal PTT of 50–70 s may be reasonable. Most studies indicated that heparinization after the endovascular procedure should last several days (e.g. 1 week). After that, long term oral anticoagulation (e.g. warfarin) should initiate with a goal international normalized ratio (INR) of 2.0–3.0 [15, 22, 26, 27]. For secondary CVST which was associated with modifiable or short-term conditions such as contraceptive usage or puerperium, oral anticoagulant therapy may be continued for 3 months. For idiopathic CVST or those with thrombophilia, oral anticoagulant therapy may be continued for 6–12 months or even longer [5, 6]. A few studies reported that they used antiplatelets after interventional therapy in CVST patients. The antiplatelets used include aspirin, clopidogrel and ticlopidine. Choosing antiplatelets other than anticogulations in CVST patients after interventional therapy were usually not rationalized in these studies. No study to date compared the efficacy and safety between antiplatelets and anticogulations in CVST patients after interventional therapy. So the role of anti-platelet therapy for long term management of CVST after interventional therapy remains undetermined [35–38]. There is only one case reported applied dual antiplatelet therapy after interventional treatment. The patient was neurologically normal at 6-week follow-up [39]. In our center, we usually introduce a 6F vascular sheath into the right femoral vein under local anesthesia. The
Endovascular treatments for cerebral venous sinus thrombosis
Fig. 1 Roadmap of endovascular procedure for treating CVST
local thrombolysis or thrombectomy was performed after systematic heparinization. We have 6 CVST patients treated with local thrombolysis, and no complications related to venous puncture were observed. For local thrombolysis, the guiding catheter (Envoy; Cordis, Miami Lakes, Florida, USA) was usually advanced into the internal jugular bulb. A ProwlerÒ 14 microcatheter (Codman; Johnson & Johnson, UK) was advanced over the guidewire into the superior sagittal sinus where the thrombus was usually located, and then about 20 mg rt-PA was infused (Fig. 1). Of the six cases treated with local thrombolysis, no complications related to the procedure were observed. One patient died on the next day after the procedure due to herniation (probably due to large cerebral infarction and delayed treatment). The other five cases reached total recanalization immediately after the procedures and recovered completely at 3-month follow-up. With the advances in endovascular techniques and devices, more and more local thrombolysis are now performed in combination with mechanical thrombectomy. Strategies for removing clot included thrombus disruption with guidewire or balloon catheter, thrombus suction with rheolytic catheter, using Merci clot retrieval device, Penumbra clot aspiration system, or Solitaire FR device [14, 23, 24, 39–42]. The combined treatments may reduce the dosage of thrombolytic drug and accelerate recanalization due to the increased exposure surface of thrombus exposed to drug, and subsequently reduce the risk of thrombolysis related hemorrhage and decrease intracranial pressure. Thrombus of CVST can be classified as red, white, and collagen-rich thrombus, which may reflect the duration and the source of the thrombus. The type and duration of the thrombus have not been associated with the responsiveness to thrombolytic agents. For example, a chronic clot with
different temporal components which have existed for several years may be dissolved by thrombolytic agents [38]. In clinical practice, most thrombolysis treatments for CVST were performed in chronic phase due to the delayed diagnosis. The ISCVT revealed that median duration from onset to hospital admission was 4 days, and that from onset to diagnosis was 7 days [1]. Urokinase, streptokinase, and rt-PA have been used as thrombolytics in treating CVST. Urokinase and rt-PA were reported with similar efficacies when infused directly into the thrombus [43]. In 2001 Wasay et al. reviewed the outcomes of 96 patients with superior sagittal sinus thrombosis treated with local thrombolysis. Urokinase was used in most (75 %) patients [33]. An international survey in 2011, however, showed that rt-PA became the dominant agent in treating CVST with endovascular thrombolysis [44]. The reported dosages and the infusion durations in local chemical thrombolysis vary among studies. In 1997, Kim and Suh treated 9 patients with local infusion of rt-PA. The mean dose of rt-PA was 135 mg (ranged from 50 to 300 mg). All patients achieved total recanalization with improved clinical outcomes. Minor hemorrhages were observed in intrapelvic and puncture site in two separate cases [14]. In 2011, Blackham performed local thrombolysis with 2 mg rt-PA infused 20 min before suction thrombectomy [41]. Canha˜o et al. review on local thrombolysis comprehensively, showed when urokinase was used in local chemical thrombolysis, doses usually ranged from 12,000 to 13,790,000 IU; when rt-PA was used, doses usually ranged from 8 to 300 mg [20]. Coutinho et al. suggested regimens of urokinase as 100,000–600,000 IU for initial bolus, 80,000–120,000 IU/h for the subsequent 24 h continuous infusion. Regarding rt-PA, they suggested 1–5 mg for initial bolus, 1–2 mg/h for continuous infusion lasting 24 h or longer [45]. The optimal duration of local thrombolytic treatment has not been established to date. In a retrospective study, Wasay et al. compared the safety and efficacy of system heparinization and local chemical thrombolysis. In patients with thrombolysis treatment (n = 20), urokinase was delivered into superior sagittal sinus with a microcathater, followed by system heparinization; while the heparinization group (n = 20) received intravenous heparin only. Although patients in the thrombolysis group had worse neurological functions than those in heparinization group before treatment, they had better neurological functions than patients treated with heparinization (P = 0.019) [33]. Siddiqui et al. reviewed 29 CVST cases underwent local thrombolysis at 3 large centers. There were 9 periprocedural complications, of which 1 was catheter-related. At the 6-month follow-up, 11 of the 12 (92 %) followed patients had a mRS score of 0 or 1 [28].
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Cathater-based local thrombolysis was even used in CVST patients with evident cerebral edema or hemorrhage as manifested by CT or MRI [14, 32, 33, 46, 47]. In a small prospective single-center study, 10 CVST cases with proven cerebral hemorrhagic venous infarcts were treated with local thrombolysis successfully [31]. Rapid improvements were observed in 9 patients, and incidental symptomatic hemorrhage occurred in 1 patient. Guo et al. also reported favorable outcomes of local thrombolysis in treating 23 CVST patients with previous hemorrhagic infarction [22]. Hemorrhage related neurological deterioration was identified in only 2 of the 23 treated patients. Currently, there exist major controversies concerning whether patients with previous intracranial hemorrhage should be submitted to thrombolysis. After analyzing the data from publications, Canha˜o et al. concluded that CVST patients with previous intracranial hemorrhage had higher risk of intracranial hemorrhage after local thrombolysis. They suggested that endovascular thrombolysis should not be recommended to those with previous intracranial hemorrhage [20]. Anyway, intracranial hemorrhage after trauma should be considered as a contraindication for chemical thrombolysis with either rt-PA or urokinase [48]. Considering the possible publication bias, the favorable results of local thrombolysis should be interpreted carefully. Studies with positive results are more prone to be published than studies with negative results. After reviewing 15 studies (156 cases in total) of thrombolysis treatment, Dentali et al. emphasized the noticeable high incidence (15/156, 9.8 %) of major hemorrhage after thrombolysis, and 12/156 (7.6 %) were intracranial hemorrhage, of which 7/12 (58.3 %) died [49]. These results are different from those reported previously, but may reflect, to some extent, the real situation in clinical practice. Local pharmacological thrombolysis has several limitations. Organized thrombi may be refractory to thrombolytic agents. Lysing the large thrombi in venous sinus may take too much time to prevent irreversible brain injury in some severe cases [30]. As shown in a study by Stam et al. 20 CVST patients treated with local thrombolysis had similar mortality secondary to herniation as those without this treatment [50].
Mechanical thrombectomy Treating CVST with mechanical thrombectomy has been reported for several decades. Combined mechanical thrombectomy and chemical thrombolysis has been demonstrated with higher rates of technique success, and with less iatrogenic complications. Although there were no randomized trials on this point, data from an adult series indicated that favorable outcomes can be achieved in over
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90 % patients [22]. Given the high recanalization rate and low risk of hemorrhage, mechanical thrombectomy has been suggested as the first-line treatment for CVST by some authors [31]. In addition, some investigators proved that mechanical thrombectomy is non-inferior to systemic heparin and local chemical thrombolysis [34]. Mechanical thrombectomy with or without combined chemical thrombolysis has advantages in treating CVST, however, there are potential limitations that should be paid attention to. The outcome of the procedure is highly skilldependent. Systemic training, therefore, is mandatory. Moreover, the cost of endovascular procedures and the availability of the facilities may limit their generalization in clinic practice. Finally, endovascular procedures may cause catheter-related complications, for example, the catheter may damage the endothelium and increase the risk of iatrogenic thrombus [34, 51]. Fragmented or dislodged thrombus during mechanical thrombectomy may lead to pulmonary embolism. Hemorrhage after combined treatment of thrombolysis and thrombectomy may be disastrous [50]. A number of different mechanical endovascular strategies have been reported, either as separate or combined approaches. These include rheolytic thrombectomy, balloon angioplasty with or without stenting, clot maceration, Merci device, Penumbra system, and Solitaire FR device [28, 31, 40, 42, 46–48, 52]. Rheolytic thrombectomy is developed based on Bernoulli principle. The most commonly used rheolytic device is AngioJet system (Possis Medical; now Medrad, Warrendale, Pennsylvania) [53]. Dashti et al. reported 13 patients with CVST treated with AngioJet. Immediate recanalization of the occluded sinuses was observed in all patients and most of them achieved satisfied neurological recovery [31]. Limitations of AngioJet included the large profile and stiffness of the delivery system. These features make navigation difficult and prevent its access in smaller vessels, especially in pediatric patients. Another limitation was its inability in dilating organic stenosis [46, 54]. The main component of Penumbra clot aspiration system (Penumbra Inc, Alameda, California) is a reperfusion catheter, which can aspirate thrombus with the help of a wire-linked separator. The catheter allows for continuous suction of thrombus fragment and the separator is atraumatic to the vascular walls. Smaller profile and flexible delivery system make Penumbra more feasible in navigating through the intracranial venous sinuses. Choulakian and Alexander reported 4 CVST patients treated with 0.041-inch Penumbra system that was the largest one available at the time. Technical success was achieved and blood flow restored in all patients, and no complications were observed during the procedures [55]. However, the larger internal diameter of these catheters provided
Endovascular treatments for cerebral venous sinus thrombosis
stronger aspiration power for thrombectomy, potentially lead to the observed rapid recanalization in all treated patients [56]. The Merci clot retriever (Concentric Medical, Mountain View, California) is a snare-type device that removes thrombus with the help of a corkscrew-shaped wire. The Merci device, compared with AngioJet, is more maneuverable but may be associated with increased risk of endothelium damage, although this risk may be decreased in the case of CVST due to the dural coverage of sinuses [51]. Newman et al. reported a case with extensive CVST recanalized with Merci retrieval device. Blood flow was restored in internal cerebral veins, the vein of Galen and the straight sinus. At the 6-week follow-up, the patient was neurologically intact [39]. In using a Merci device, the microsnare can be guided through intravascular microcatheters and inserted into the thrombus. Repeatedly pulling and pushing the microsnare in the clot may increase the surface area of the thrombus exposed to thrombolytic agents. The loop configuration of Merci snare and the ability to be switched open and close enhanced the effects of recanalization. Whereas the flexibility and maneuverability decrease the risk of vessel injury as compared with using the microcatheter alone. There were two publications reported the combined treatments with a mechanical thrombectomy and a microsnare device. Bagley et al. performed venography postprocedure revealed dramatic improvement in the affected dural sinuses. The patient’s headache and lethargy resolved immediately. MRV confirmed the patency of the dural sinuses at 2-week follow-up. In a case series Philips et al. reported all 6 patients’ clinical symptoms and neurological deficits resolved after procedures and no procedural complications occured [16, 57]. Balloon catheters can be used to smash the thrombus and to pull back thrombus when inflated distally. To minimize vascular injury, smaller balloon and lower dilatepressure have been advocated [58]. Angioplasty with a balloon catheter has the advantage over rheolytic thrombectomy in that the former approach can dilate the stenotic lesions [46]. However, angioplasty balloons may be difficult to navigate across the intracranial vessels such as the straight sinus. Balloon angioplasty may dissect or rupture the dural sinus, and impair nearby cortical veins. Balloon angioplasty has been reported in treating CVST since 1996 and been applied in pediatric patients [58]. Both balloon catheter and rheolytic catheter have been used for smashing thrombus in treating CVST patients [47, 48, 54]. Balloon angioplasty with or without stenting may be favorable in certain cases, and there are few studies to support this method [59, 60]. The Solitaire FR device (Covidien Neurovascular, Irvine, California) is a laser-cut, self-expanding, fully
retrievable stent which was approved by FDA for restoring blood flow in patients with ischemic stroke due to large intracranial vessel occlusion [61]. In a case report, Froehler suggested that the large-size (6 mm) Solitaire device performed much better than the smaller (4 mm) one [42]. Compared with the AngioJet, Solitaire is more feasible to be delivered and deployed in the thrombolized sigmoid and transverse sinus. Its indications for repeated use and ability of fast flow restore have been proved as advantages in improving clinical outcomes. Pukenas et al. reported their experiences in treating a CVST patient successfully with Solitaire FR. A venography immediately after the procedure indicated total recanalization of the target vessel. At discharge, the patient showed a dramatic recovery from the clinical symptoms [62]. Favorable results have been reported in treating CVST patients sequentially using Penumbra system and Solitaire FR device [52, 63]. Several authors concluded that mechanical thrombectomy with or without local chemical thrombolysis had a trend of increased risk of periprocedural complications compared with local chemical thrombolysis alone [28]. However, in an observational study with 52 CVST cases enrolled, Li et al. reported the safety and efficacy of mechanical thrombectomy combined with chemical thrombolysis. After the combined treatment, most cases have favorable outcome. Simultaneously, the recanalization rate is desirable and the perioperative complications are relatively low [15]. In another case series with 26 CVST patients, Shui et al. used balloon dilatation and thrombus extraction approaches. There were no complications during or after the procedure. Recanalization and neurological function improvement have been achieved in all patients. It’s been concluded that endovascular therapy appears to be a safe and effective approach for treating CVST [64].
Candidate patients for endovascular treatment The ISCVT revealed that factors associated with poor outcomes included age [37 years (hazard ratio, HR 2.0), male sex (HR 1.6), coma (HR 2.7), mental status disorder (HR 2.0), thrombosis of the deep cerebral venous system (HR 2.9), intracranial hemorrhage (HR 1.9), malignancy (HR 2.9), and central nervous system infection (HR 3.3). About 30 % of patients with one or more of these risk factors had a poor outcome despite prolonged heparin treatment [1]. These patients may be potential candidates for endovascular treatments. Currently, there are no established criteria for endovascular procedures in treating CVST. However, clinical deterioration despite appropriate anticoagulation seems to be a reasonable indication, at least in some carefully selected patients. Rahman et al. suggested that CVST patients with severe neurological deficits
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(GCS score B8) should be strongly recommended for endovascular treatment [65]. Guo et al. reported their criteria for endovascular treatment as (1) lack of adequate clinical response to heparin, (2) rapid worsening of neurological deficits, (3) an assumed poor prognosis due to altered mental status, (4) deep venous sinus thrombosis such as straight sinus thrombosis, or (5) large space-occupying stroke. Rapid resolution of symptoms was observed in 92 % patients according to their criteria [22]. Guidelines made by American Heart Association/American Stroke Association (AHA/ASA) and European Federation of Neurological Societies (EFNS) recommended that endovascular treatment should be considered as a treatment option in patients who, despite adequate anticoagulation, have worsening symptoms, do not have intracranial hemorrhage or impending herniation from a large hemorrhagic infarction, and have only a mild mass effect [5, 6].
Conclusion Endovascular treatment may be performed in carefully selected CVST patients who are non-responsive to adequate anticoagulation therapy. This policy should be limited to centers with optimal standards of logistics and interventional expertise. Well-designed randomized controlled trials are warranted to establish endovascular treatment as a standard of care in treating CVST.
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Endovascular treatments for cerebral venous sinus thrombosis Zhongming Qiu1,2 • Hongfei Sang3 • Qiliang Dai3 • Gelin Xu1,3
Ó Springer Science+Business Media New York 2015
Abstract Cerebral venous sinus thrombosis (CVST) is an uncommon but potentially fatal condition. CVST usually occurs young adults with a female predominance. The current mainstay for treating CVST is anticoagulation with heparin. However, more aggressive interventions, endovascular treatment as an example, may be indicated in selected patients who are non-responsive to heparin and other anticoagulants. Endovascular approaches include catheter-based local chemical thrombolysis, balloon angioplasty and mechanical thrombectomy, all of which may rapidly recanalize the occluded venous sinus, restore the blood flow, reduce the increased intracranial pressure, and subsequently relieve the corresponding symptoms. However, as an invasive strategy, endovascular procedures per se may cause complications, such as intracranial hemorrhage, vessel dissection and pulmonary embolization, which may substantially decrease the benefit–risk ratio of the treatment. Due to the rareness of the condition and the limited indication of this invasive strategy, safety and efficacy of endovascular procedures in treating CVST are
Zhongming Qiu and Hongfei Sang have contributed equally to this work. & Gelin Xu [email protected]; [email protected] 1
Department of Neurology, Jinling Hospital, Second Military Medical University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, China
2
Department of Neurology, The 117th Hospital of PLA, 14 Lingyin Road, Xihu District, Hangzhou 310013, Zhejiang Province, China
3
Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, China
less feasible to be evaluated in large randomized clinical trails. Therefore, the evidences for justifying this treatment strategy are largely derived from case reports, cohort studies and clinical observations. Keywords Cerebral venous sinus thrombosis Endovascular procedures Thrombectomy Thrombolytic therapy
Introduction Cerebral venous sinus thrombosis (CVST) is the presence of thrombosis (a blood clot) in the dural venous sinuses, which drain blood from the brain. CVST is rare, with an estimated incidence of five per million annually in adults. While it may occur in all age groups, it is most common in the third decade, and 75 % cases are female [1]. CVST accounts for 0.5–1 % of all stroke cases. The overall mortality of CVST has been reported as 4.39 %, but in patients with encephalopathy or impending encephalopathy the mortality may be as high as 53 % [1–4]. The most common risk factor of CVST is inherited or acquired thrombophilia, followed by oral contraceptives. Other risk factors included pregnancy and puerperium, infection and malignancy. According to the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT), 43.6 % of the 624 enrolled CVST patients had more than one risk factor [1]. Superior sagittal sinus is the most frequently (62 %) affected one, followed by lateral sinuses (45 % left, 41 % right), straight sinus (18 %), and cavernous sinus (1.3 %). Deep venous involvement may result in death or dependency in 29 % patients [1]. The clinical severity of CVST usually depends on the extent of the thrombosis, the
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territory of the involved vessels, the compensation of venous collaterals and the duration of the thrombus. Computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance venography (MRV) and digital subtraction angiography (DSA) are useful tools in diagnosing CVST. Currently, the first-line treatment for CVST is anticoagulation with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin (LMWH) [5, 6]. However, about 10 % patients had poor outcomes despite adequate anticoagulation. Large cohort studies reported that CVST was associated with a combined morbidity and mortality rate of 13.4 % after regular treatments [1]. This high morbidity and mortality rate became an impetus for introducing more aggressive strategies, endovascular procedures as an example, as alternatives in treating CVST. Endovascular procedures, including catheter-based local chemical thrombolysis and mechanical thrombectomy, may rapidly recanalize occluded venous sinus, restore blood flow, reduce increased intracranial pressure, and subsequently relieve the related symptoms. However, as an invasive treatment, endovascular procedures per se may cause complications, such as intracranial hemorrhage, vessel dissection and pulmonary embolization. So the benefit–risk ratio should be carefully weighted in individual patients before endovascular procedures being performed. We searched PubMed database for all publications on endovascular treatment of CVST in English. The search returned 142 publications (involved 642 patients), which included 67 case reports, 27 case series, 8 observational studies, 24 reviews, and 16 other type studies. Studies of large series which more than five cases are summarized in Table 1.
Catheter-based pharmacological thrombolysis Most guidelines recommended that CVST patients should be treated with either activated partial thromboplastin time (APTT) adjusted intravenous heparin or body weight adjusted subcutaneous LMWH [5, 6]. These treatments are based on the rationale that these agents may reverse the causal thrombotic process. Three small randomized trials have showed a beneficial, although not statistically significant, effect of heparin [7–9]. A meta-analysis showed that anticoagulant was associated with a 54 % relative risk reduction of death or dependency when compared with placebo [10]. Another treatment option is systemic (intravenous) thrombolysis. This treatment has theoretical advantages over heparin treatment. Generally, thrombolysis combined with heparin can result in earlier and higher rate of recanalization than merely heparin treatment [11]. Vines and
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Davis, for the first time, reported five cases of sagittal sinus thrombosis treated with systemic thrombolysis with intravenous urokinase in 1971 [12]. Thereafter, Di Rocco et al. reported 5 CVST patients recovered complete after intravenous urokinase thrombolysis [13]. One disadvantage of systemic thrombolysis lies in that it may take a long time, e.g. several days, for the occluded venous sinus to be recanalized due to the dilution of the drug after system delivery [14]. Compared with systemic thrombolysis, local administration can enormously increase the on site drug concentration as well as the drug-thrombus contact surface by infusing the drug directly into the thrombus with a microcathater [15, 16]. Local thrombolysis may also decrease the total dosage of thrombolytic agents, which in turn lower the risk of hemorrhage [17]. Thanks to the flexibility of recently developed catheters and the relatively rapid metabolism of thrombolytics such as urokinase and recombinant tissue plasminogen activator (rt-PA), intracranial complications of local thrombolysis appeared comparative to those of systemic anticoagulation [18]. According to the data from two systemic reviews, CVST patients treated with local thrombolysis had worse clinical condition than those treated with systemic thrombolysis prior to treatment, with a higher proportion of patients in coma [difference: -0.24; 95 % confidence interval (CI) -0.34 to -0.06]. Regarding the partial recanalization rates, however, local thrombolysis was more effective than systemic thrombolysis (difference: -0.23; 95 % CI -0.38 to -0.02) [19, 20]. Scott and his colleagues reported in 1988 the dramatic effects of local thrombolysis in a patient with superior sagittal sinus thrombosis. Presented initially with decerebrate, the patient improved rapidly over a couple of days, and remained with only mild dysphasia 28 days after endovascular thrombolysis [21]. Subsequently, several investigators published case reports and small series emphasizing the advantages of local thrombolysis in treating CVST. In a large case series, Guo et al. reported the outcomes of 37 CVST patients treated with local thrombolysis. At the 6-month follow-up, 34 (91.9 %) patients had good clinical outcomes (modified Rankin Scale, mRS \3). Only 1 (2.7 %) patient remained with severe neurologic deficits, and 2 (5.4 %) patients died [22]. When performing catheter-based local pharmacological thrombolysis, a standard microcatheter along a microguidewire is usually navigated to the target dural sinus through a sheath or guiding catheter located in the jugular bulb. The procedures were usually performed under general anesthesia [15, 17, 23, 24]. Most procedures were performed via femoral vein or via internal jugular vein access, with a few procedures performed via a fontanelle puncture, burr holes, or craniotomy [21, 22, 25–28]. Local thrombolysis was usually initiated with a bolus, followed by a continuous infusion through the catheter in situ
19
15
1999
1997
1995
1995
Barnwell [71]
Tsai [72]
Wasay [33] Frey [30]
Kim [14]
2001 1999
Baker [70]
Philips [57]
2003
2001
Soleau [34]
2007
2006
Tsai [68]
2008
Stam [50]
Anand [69]
20
2008
Zhang [54]
6
18
6
9
6
20 12
5
18
93
6
5
2009
6
2009
2010
Yue [17]
Peng [67]
2010
Kumar [25]
37 6
6
9
9
52
11
13
34
29
26
10
Cases (n)
Pfefferkorn [66]
2012 2012
2013
Li [15]
Guo [22] Waugh [29]
2013
Guo [26]
2012
2013
Dashti [31]
Jankowitz [41]
2014
Siddiqui [28]
2013
2014
Siddiqui [28]
2013
2014
Shui [64]
Poulsen [24]
2014
Garge [32]
Mortimer [23]
Year of publication
First authors and reference number
32 (6 d–58)
NA
33 (24–52)
33 (14–75)
34 (4–61) 32.5 (20–55)
47 (19–67)
NA
43.8
38 (19–57)
32 (12–57)
26 (14–49)
27 (17–41)
30 (18–51)
40.5 (22–57)
32 (17–46)
31 (17–42) 12 (9–17)
NA
21.1 (15–31)
5 (1.5–16)
33 (10–77)
25 (19–35)
45 (17–73)
35 (12–57)
32 (4–61)
28.9 (18–46)
41.4 (26–60)
Age, mean (range) years
50.0
NA
66.7
66.7
60.0 75.0
80.0
NA
38.0
66.7
80.0
83.3
60.0
66.7
66.7
57.9
67.6 0
83.3
89.0
77.8
42.3
100.0
53.8
76.5
69.0
73.1
60.0
Sex, female (%)
LT
LT
LT
LT/MT
LT LT
LT/MT
LT/MT
LT
LT/MT
LT/MT
LT/MT
LT/MT
LT/MT
LT/IVT
LT/MT
LT LT/MT
LT/MT
LT/MT
LT/MT
LT/MT
LT
MT
LT/MT
LT
BD/MT
LT
Endovascular treatment strategies
Table 1 Case series (n C 5) of CSVT treated with endovascular treatments
NA
NA
Heparin/OAC
Heparin/OAC
Heparin/OAC Heparin/OAC
Heparin
Heparin/OAC
Heparin/OAC
Heparin
Heparin
Heparin/OAC
Heparin
Heparin/OAC
Heparin/OAC
Heparin/OAC
Heparin/OAC Heparin
Heparin
NA
NA
Heparin/OAC
Heparin/OAC
Heparin/OAC
Heparin
Heparin
LMWH
OAC
Anticoagulation treatment
5/34 (15.0)
[6
NA
NA
3
12–35
4 (1–15) 10 (1–30)
NA
27 (2–84)
NA
NA
3–6
11 (6–15)
6
NA
3
6.3 (6–8)
6 NA
3
6–48
NA
6
6
0
1/6 (16.7)
2/9 (22.2)
0
2/20 (10.0) 3/12 (25.0)
3/5 (60.0)
5/18 (27.8)
NA
6/15 (40.0)
5/20 (25.0)
0
0
0
0
2/19 (10.5)
1/37 (3.0) 5/6 (83.3)
0
7/9 (77.8)
1/9 (11.1)
0
0
1/13 (7.7)
4/29 (14.0)
[6 7
0
1/10 (10.0)
e
Periprocedural hemorrhage proportion (%)d
42.3 (12–62)
1
FU, mean (range) month(s)
0
2/6 (33.3)
0
0
0 0
0
4/18 (22.2)
22/93 (23.7)
0
6/20(30.0)
2/6 (33.3)
1/5 (20.0)
2/6 (33.3)
1/6 (16.7)
3/19 (15.8)
2/37 (6.0) 0
0
0
1/9 (11.1)
6/52 (11.5)
0
2/13 (15.4)
NA
NA
0
1/10 (10.0)
Periprocedural death proportion (%)
18/18 (100.0)
4/4 (100.0)
NA
5/6 (83.3)
NA 12/12 (100.0)
4/5 (80.0)c
13/14 (92.8)
NA
15/15 (100.0)
12/14 (85.7)c
4/4 (100.0)c
4/4 (100.0)
2/6 (33.3)
5/5 (100.0)
14/19 (73.7)
34/35 (97.1) 4/6 (66.7)
3/6 (50.0)
8/8 (100.0)
8/8 (100.0)
45/46 (97.8)
11/11 (100.0)
7/9 (77.8)
16/22 (73.0)
11/12 (92.0)
26/26 (100.0)b
9/9 (100.0)c
Good clinical outcomes proportion (%)a
Endovascular treatments for cerebral venous sinus thrombosis
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Periprocedural hemorrhage defined as new hemorrhage
Numbers were evaluated as new or increased hemorrhage e
d
Numbers were evaluated as GCS = 15
Good clinical outcomes defined as a mRS score of 0 or 1
Numbers were evaluated as mRS B2 c
b
a
BD balloon dilatation, d day, FU follow-up, GCS Glasgow Coma scale, IVT intravenous thrombolysis, LMWH low molecular weight heparin, LT local thrombolysis, mRS modified Rankin scale, MT mechanical thrombectomy, NA not available, OAC oral anticoagulants
6/6 (100.0) 0 1/7 (14.2) 20 (8–37) Heparin/OAC LT/MT 57.1 40 (25–71) 1994 Smith [73]
7
10/10 (100.0) 1/12 (8.0) 5/12 (41.7) NA Heparin/OAC LT 58.3 33.5 (0.1–65) 1994 Horowitz [18]
12
Year of publication First authors and reference number
Table 1 continued
Cases (n)
Age, mean (range) years
Sex, female (%)
Endovascular treatment strategies
Anticoagulation treatment
FU, mean (range) month(s)
Periprocedural hemorrhage proportion (%)d
Periprocedural death proportion (%)
Good clinical outcomes proportion (%)a
Z. Qiu et al.
[26–29]. Venography was always performed to assess the patency of venous sinus. Thrombolysis was discontinued when there was radiological patency of the occluded venous sinus or in the presence of neurological deterioration or the maximum dose of thrombolytic agent was reached [15, 22, 25]. Frey et al. reported their experience in treating CVST with a mean rt-PA dose of 46 mg (ranged from 23 to 128 mg). The authors inserted a microcatheter into the thrombus, and then injected a bolus of rt-PA followed by continuous infusion until the recanalization being observed [30]. Other authors reported single bolus injection or merely continuous infusion [23]. During the procedure of thrombectomy, systemic anticoagulation with heparin was usually administrated continuously to maintain an activated clotting time (ACT) of 250–300 s [31]. During the procedure of local thrombolysis, in which increased risk of hemorrhage is a concern after rt-PA administration, some authors used heparin but with a shortened goal ACT of 200–250 s [17], others did not use anticoagulations [32]. Following the endovascular procedure, most patients were on systemic heparinization for several days for facilitating vessel recanalization or for preventing the re-occlusion of the recanalized vessels. Some studies suggested a target partial thromboplastin time (PTT) between 50 and 70 s [22, 33, 34]. Others did not mention this treatment index [15, 23, 28]. As the total cases reported are still limited, extrapolating data from studies of coronary reperfusion with a goal PTT of 50–70 s may be reasonable. Most studies indicated that heparinization after the endovascular procedure should last several days (e.g. 1 week). After that, long term oral anticoagulation (e.g. warfarin) should initiate with a goal international normalized ratio (INR) of 2.0–3.0 [15, 22, 26, 27]. For secondary CVST which was associated with modifiable or short-term conditions such as contraceptive usage or puerperium, oral anticoagulant therapy may be continued for 3 months. For idiopathic CVST or those with thrombophilia, oral anticoagulant therapy may be continued for 6–12 months or even longer [5, 6]. A few studies reported that they used antiplatelets after interventional therapy in CVST patients. The antiplatelets used include aspirin, clopidogrel and ticlopidine. Choosing antiplatelets other than anticogulations in CVST patients after interventional therapy were usually not rationalized in these studies. No study to date compared the efficacy and safety between antiplatelets and anticogulations in CVST patients after interventional therapy. So the role of anti-platelet therapy for long term management of CVST after interventional therapy remains undetermined [35–38]. There is only one case reported applied dual antiplatelet therapy after interventional treatment. The patient was neurologically normal at 6-week follow-up [39]. In our center, we usually introduce a 6F vascular sheath into the right femoral vein under local anesthesia. The
Endovascular treatments for cerebral venous sinus thrombosis
Fig. 1 Roadmap of endovascular procedure for treating CVST
local thrombolysis or thrombectomy was performed after systematic heparinization. We have 6 CVST patients treated with local thrombolysis, and no complications related to venous puncture were observed. For local thrombolysis, the guiding catheter (Envoy; Cordis, Miami Lakes, Florida, USA) was usually advanced into the internal jugular bulb. A ProwlerÒ 14 microcatheter (Codman; Johnson & Johnson, UK) was advanced over the guidewire into the superior sagittal sinus where the thrombus was usually located, and then about 20 mg rt-PA was infused (Fig. 1). Of the six cases treated with local thrombolysis, no complications related to the procedure were observed. One patient died on the next day after the procedure due to herniation (probably due to large cerebral infarction and delayed treatment). The other five cases reached total recanalization immediately after the procedures and recovered completely at 3-month follow-up. With the advances in endovascular techniques and devices, more and more local thrombolysis are now performed in combination with mechanical thrombectomy. Strategies for removing clot included thrombus disruption with guidewire or balloon catheter, thrombus suction with rheolytic catheter, using Merci clot retrieval device, Penumbra clot aspiration system, or Solitaire FR device [14, 23, 24, 39–42]. The combined treatments may reduce the dosage of thrombolytic drug and accelerate recanalization due to the increased exposure surface of thrombus exposed to drug, and subsequently reduce the risk of thrombolysis related hemorrhage and decrease intracranial pressure. Thrombus of CVST can be classified as red, white, and collagen-rich thrombus, which may reflect the duration and the source of the thrombus. The type and duration of the thrombus have not been associated with the responsiveness to thrombolytic agents. For example, a chronic clot with
different temporal components which have existed for several years may be dissolved by thrombolytic agents [38]. In clinical practice, most thrombolysis treatments for CVST were performed in chronic phase due to the delayed diagnosis. The ISCVT revealed that median duration from onset to hospital admission was 4 days, and that from onset to diagnosis was 7 days [1]. Urokinase, streptokinase, and rt-PA have been used as thrombolytics in treating CVST. Urokinase and rt-PA were reported with similar efficacies when infused directly into the thrombus [43]. In 2001 Wasay et al. reviewed the outcomes of 96 patients with superior sagittal sinus thrombosis treated with local thrombolysis. Urokinase was used in most (75 %) patients [33]. An international survey in 2011, however, showed that rt-PA became the dominant agent in treating CVST with endovascular thrombolysis [44]. The reported dosages and the infusion durations in local chemical thrombolysis vary among studies. In 1997, Kim and Suh treated 9 patients with local infusion of rt-PA. The mean dose of rt-PA was 135 mg (ranged from 50 to 300 mg). All patients achieved total recanalization with improved clinical outcomes. Minor hemorrhages were observed in intrapelvic and puncture site in two separate cases [14]. In 2011, Blackham performed local thrombolysis with 2 mg rt-PA infused 20 min before suction thrombectomy [41]. Canha˜o et al. review on local thrombolysis comprehensively, showed when urokinase was used in local chemical thrombolysis, doses usually ranged from 12,000 to 13,790,000 IU; when rt-PA was used, doses usually ranged from 8 to 300 mg [20]. Coutinho et al. suggested regimens of urokinase as 100,000–600,000 IU for initial bolus, 80,000–120,000 IU/h for the subsequent 24 h continuous infusion. Regarding rt-PA, they suggested 1–5 mg for initial bolus, 1–2 mg/h for continuous infusion lasting 24 h or longer [45]. The optimal duration of local thrombolytic treatment has not been established to date. In a retrospective study, Wasay et al. compared the safety and efficacy of system heparinization and local chemical thrombolysis. In patients with thrombolysis treatment (n = 20), urokinase was delivered into superior sagittal sinus with a microcathater, followed by system heparinization; while the heparinization group (n = 20) received intravenous heparin only. Although patients in the thrombolysis group had worse neurological functions than those in heparinization group before treatment, they had better neurological functions than patients treated with heparinization (P = 0.019) [33]. Siddiqui et al. reviewed 29 CVST cases underwent local thrombolysis at 3 large centers. There were 9 periprocedural complications, of which 1 was catheter-related. At the 6-month follow-up, 11 of the 12 (92 %) followed patients had a mRS score of 0 or 1 [28].
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Cathater-based local thrombolysis was even used in CVST patients with evident cerebral edema or hemorrhage as manifested by CT or MRI [14, 32, 33, 46, 47]. In a small prospective single-center study, 10 CVST cases with proven cerebral hemorrhagic venous infarcts were treated with local thrombolysis successfully [31]. Rapid improvements were observed in 9 patients, and incidental symptomatic hemorrhage occurred in 1 patient. Guo et al. also reported favorable outcomes of local thrombolysis in treating 23 CVST patients with previous hemorrhagic infarction [22]. Hemorrhage related neurological deterioration was identified in only 2 of the 23 treated patients. Currently, there exist major controversies concerning whether patients with previous intracranial hemorrhage should be submitted to thrombolysis. After analyzing the data from publications, Canha˜o et al. concluded that CVST patients with previous intracranial hemorrhage had higher risk of intracranial hemorrhage after local thrombolysis. They suggested that endovascular thrombolysis should not be recommended to those with previous intracranial hemorrhage [20]. Anyway, intracranial hemorrhage after trauma should be considered as a contraindication for chemical thrombolysis with either rt-PA or urokinase [48]. Considering the possible publication bias, the favorable results of local thrombolysis should be interpreted carefully. Studies with positive results are more prone to be published than studies with negative results. After reviewing 15 studies (156 cases in total) of thrombolysis treatment, Dentali et al. emphasized the noticeable high incidence (15/156, 9.8 %) of major hemorrhage after thrombolysis, and 12/156 (7.6 %) were intracranial hemorrhage, of which 7/12 (58.3 %) died [49]. These results are different from those reported previously, but may reflect, to some extent, the real situation in clinical practice. Local pharmacological thrombolysis has several limitations. Organized thrombi may be refractory to thrombolytic agents. Lysing the large thrombi in venous sinus may take too much time to prevent irreversible brain injury in some severe cases [30]. As shown in a study by Stam et al. 20 CVST patients treated with local thrombolysis had similar mortality secondary to herniation as those without this treatment [50].
Mechanical thrombectomy Treating CVST with mechanical thrombectomy has been reported for several decades. Combined mechanical thrombectomy and chemical thrombolysis has been demonstrated with higher rates of technique success, and with less iatrogenic complications. Although there were no randomized trials on this point, data from an adult series indicated that favorable outcomes can be achieved in over
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90 % patients [22]. Given the high recanalization rate and low risk of hemorrhage, mechanical thrombectomy has been suggested as the first-line treatment for CVST by some authors [31]. In addition, some investigators proved that mechanical thrombectomy is non-inferior to systemic heparin and local chemical thrombolysis [34]. Mechanical thrombectomy with or without combined chemical thrombolysis has advantages in treating CVST, however, there are potential limitations that should be paid attention to. The outcome of the procedure is highly skilldependent. Systemic training, therefore, is mandatory. Moreover, the cost of endovascular procedures and the availability of the facilities may limit their generalization in clinic practice. Finally, endovascular procedures may cause catheter-related complications, for example, the catheter may damage the endothelium and increase the risk of iatrogenic thrombus [34, 51]. Fragmented or dislodged thrombus during mechanical thrombectomy may lead to pulmonary embolism. Hemorrhage after combined treatment of thrombolysis and thrombectomy may be disastrous [50]. A number of different mechanical endovascular strategies have been reported, either as separate or combined approaches. These include rheolytic thrombectomy, balloon angioplasty with or without stenting, clot maceration, Merci device, Penumbra system, and Solitaire FR device [28, 31, 40, 42, 46–48, 52]. Rheolytic thrombectomy is developed based on Bernoulli principle. The most commonly used rheolytic device is AngioJet system (Possis Medical; now Medrad, Warrendale, Pennsylvania) [53]. Dashti et al. reported 13 patients with CVST treated with AngioJet. Immediate recanalization of the occluded sinuses was observed in all patients and most of them achieved satisfied neurological recovery [31]. Limitations of AngioJet included the large profile and stiffness of the delivery system. These features make navigation difficult and prevent its access in smaller vessels, especially in pediatric patients. Another limitation was its inability in dilating organic stenosis [46, 54]. The main component of Penumbra clot aspiration system (Penumbra Inc, Alameda, California) is a reperfusion catheter, which can aspirate thrombus with the help of a wire-linked separator. The catheter allows for continuous suction of thrombus fragment and the separator is atraumatic to the vascular walls. Smaller profile and flexible delivery system make Penumbra more feasible in navigating through the intracranial venous sinuses. Choulakian and Alexander reported 4 CVST patients treated with 0.041-inch Penumbra system that was the largest one available at the time. Technical success was achieved and blood flow restored in all patients, and no complications were observed during the procedures [55]. However, the larger internal diameter of these catheters provided
Endovascular treatments for cerebral venous sinus thrombosis
stronger aspiration power for thrombectomy, potentially lead to the observed rapid recanalization in all treated patients [56]. The Merci clot retriever (Concentric Medical, Mountain View, California) is a snare-type device that removes thrombus with the help of a corkscrew-shaped wire. The Merci device, compared with AngioJet, is more maneuverable but may be associated with increased risk of endothelium damage, although this risk may be decreased in the case of CVST due to the dural coverage of sinuses [51]. Newman et al. reported a case with extensive CVST recanalized with Merci retrieval device. Blood flow was restored in internal cerebral veins, the vein of Galen and the straight sinus. At the 6-week follow-up, the patient was neurologically intact [39]. In using a Merci device, the microsnare can be guided through intravascular microcatheters and inserted into the thrombus. Repeatedly pulling and pushing the microsnare in the clot may increase the surface area of the thrombus exposed to thrombolytic agents. The loop configuration of Merci snare and the ability to be switched open and close enhanced the effects of recanalization. Whereas the flexibility and maneuverability decrease the risk of vessel injury as compared with using the microcatheter alone. There were two publications reported the combined treatments with a mechanical thrombectomy and a microsnare device. Bagley et al. performed venography postprocedure revealed dramatic improvement in the affected dural sinuses. The patient’s headache and lethargy resolved immediately. MRV confirmed the patency of the dural sinuses at 2-week follow-up. In a case series Philips et al. reported all 6 patients’ clinical symptoms and neurological deficits resolved after procedures and no procedural complications occured [16, 57]. Balloon catheters can be used to smash the thrombus and to pull back thrombus when inflated distally. To minimize vascular injury, smaller balloon and lower dilatepressure have been advocated [58]. Angioplasty with a balloon catheter has the advantage over rheolytic thrombectomy in that the former approach can dilate the stenotic lesions [46]. However, angioplasty balloons may be difficult to navigate across the intracranial vessels such as the straight sinus. Balloon angioplasty may dissect or rupture the dural sinus, and impair nearby cortical veins. Balloon angioplasty has been reported in treating CVST since 1996 and been applied in pediatric patients [58]. Both balloon catheter and rheolytic catheter have been used for smashing thrombus in treating CVST patients [47, 48, 54]. Balloon angioplasty with or without stenting may be favorable in certain cases, and there are few studies to support this method [59, 60]. The Solitaire FR device (Covidien Neurovascular, Irvine, California) is a laser-cut, self-expanding, fully
retrievable stent which was approved by FDA for restoring blood flow in patients with ischemic stroke due to large intracranial vessel occlusion [61]. In a case report, Froehler suggested that the large-size (6 mm) Solitaire device performed much better than the smaller (4 mm) one [42]. Compared with the AngioJet, Solitaire is more feasible to be delivered and deployed in the thrombolized sigmoid and transverse sinus. Its indications for repeated use and ability of fast flow restore have been proved as advantages in improving clinical outcomes. Pukenas et al. reported their experiences in treating a CVST patient successfully with Solitaire FR. A venography immediately after the procedure indicated total recanalization of the target vessel. At discharge, the patient showed a dramatic recovery from the clinical symptoms [62]. Favorable results have been reported in treating CVST patients sequentially using Penumbra system and Solitaire FR device [52, 63]. Several authors concluded that mechanical thrombectomy with or without local chemical thrombolysis had a trend of increased risk of periprocedural complications compared with local chemical thrombolysis alone [28]. However, in an observational study with 52 CVST cases enrolled, Li et al. reported the safety and efficacy of mechanical thrombectomy combined with chemical thrombolysis. After the combined treatment, most cases have favorable outcome. Simultaneously, the recanalization rate is desirable and the perioperative complications are relatively low [15]. In another case series with 26 CVST patients, Shui et al. used balloon dilatation and thrombus extraction approaches. There were no complications during or after the procedure. Recanalization and neurological function improvement have been achieved in all patients. It’s been concluded that endovascular therapy appears to be a safe and effective approach for treating CVST [64].
Candidate patients for endovascular treatment The ISCVT revealed that factors associated with poor outcomes included age [37 years (hazard ratio, HR 2.0), male sex (HR 1.6), coma (HR 2.7), mental status disorder (HR 2.0), thrombosis of the deep cerebral venous system (HR 2.9), intracranial hemorrhage (HR 1.9), malignancy (HR 2.9), and central nervous system infection (HR 3.3). About 30 % of patients with one or more of these risk factors had a poor outcome despite prolonged heparin treatment [1]. These patients may be potential candidates for endovascular treatments. Currently, there are no established criteria for endovascular procedures in treating CVST. However, clinical deterioration despite appropriate anticoagulation seems to be a reasonable indication, at least in some carefully selected patients. Rahman et al. suggested that CVST patients with severe neurological deficits
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(GCS score B8) should be strongly recommended for endovascular treatment [65]. Guo et al. reported their criteria for endovascular treatment as (1) lack of adequate clinical response to heparin, (2) rapid worsening of neurological deficits, (3) an assumed poor prognosis due to altered mental status, (4) deep venous sinus thrombosis such as straight sinus thrombosis, or (5) large space-occupying stroke. Rapid resolution of symptoms was observed in 92 % patients according to their criteria [22]. Guidelines made by American Heart Association/American Stroke Association (AHA/ASA) and European Federation of Neurological Societies (EFNS) recommended that endovascular treatment should be considered as a treatment option in patients who, despite adequate anticoagulation, have worsening symptoms, do not have intracranial hemorrhage or impending herniation from a large hemorrhagic infarction, and have only a mild mass effect [5, 6].
Conclusion Endovascular treatment may be performed in carefully selected CVST patients who are non-responsive to adequate anticoagulation therapy. This policy should be limited to centers with optimal standards of logistics and interventional expertise. Well-designed randomized controlled trials are warranted to establish endovascular treatment as a standard of care in treating CVST.
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