Original Paper Cerebrovasc Dis 2014;37:43–50 DOI: 10.1159/000356840
Received: July 19, 2013 Accepted: October 28, 2013 Published online: December 18, 2013
Systemic Thrombolysis for Cerebral Venous and Dural Sinus Thrombosis: A Systematic Review L.D. Viegas a E. Stolz b P. Canhão a J.M. Ferro a
b
Department of Neurosciences (Neurology), Hospital de Santa Maria, University of Lisbon, Lisbon, Portugal; Neurologische Klinik, Caritasklinik St. Theresia, Saarbrücken, Germany
Key Words Cerebral venous thrombosis · Dural sinus thrombosis · Intravenous thrombolysis · Recombinant tissue plasminogen activator · Urokinase
Abstract Background: The use of thrombolytics is frequently considered in patients with cerebral venous and dural sinus thrombosis (CVT) who deteriorate despite anticoagulant therapy. Purpose: To collect all the published information about the use of systemic thrombolysis in CVT in order to assess its efficacy and safety. Methods: We performed a PubMed search, checked all reference lists of studies found and used data from the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Outcome was classified at the last available follow-up by the modified Rankin Scale (mRS). The cases were stratified according to variables that might influence outcome. Results: A total of 16 reports (26 patients, 2 from the ISCVT and 24 from the systematic review of the literature) were included. No randomized clinical trial was found. Seven patients presented with isolated intracranial hypertension syndrome (26.9%), 17 with encephalopathy (65.4%) and 2 were comatose (7.7%). The superior sagittal sinus was the one most often affected (n = 21; 80.8%), and there was thrombosis of the deep cerebral venous system in 5 patients (19.2%). Urokinase was the thrombolytic agent most frequently administered (n = 19; 73.1%), whereas strep-
© 2013 S. Karger AG, Basel 1015–9770/13/0371–0043$38.00/0 E-Mail [email protected] www.karger.com/ced
tokinase and recombinant tissue plasminogen activator were used in 2 cases each (7.7%). Intracranial hemorrhages occurred in 3 cases (11.5%). Extracranial hemorrhages occurred in 5 cases (19.2%), and overall there were 3 cases of serious bleeding (11.5%), including 2 deaths (7.7%). Partial or complete recanalization was verified in most patients (n = 16; 61.5%). The survival rate was 92.3% (24/26 patients). At the last available follow-up, 22/25 patients regained independency (mRS scores 0–2; 88%), 2/25 died (mRS score 6; 8%) and 1/25 was severely dependent (mRS scores 3–5; 4%). Conclusions: In all, 88% of the CVT patients treated with systemic thrombolysis regained their independency, but 2 deaths associated with intracranial hemorrhage occurred. The mortality rate and disability at the last available followup were similar to those found in 2 previous systematic reviews concerning the use of thrombolytics in CVT. Due to the small sample size and lack of controls, the efficacy of systemic thrombolysis in acute CVT cannot be assessed from the published information. Concerning safety, a nonnegligible proportion of bleedings was reported. © 2013 S. Karger AG, Basel
Introduction
The immediate administration of systemic anticoagulants is considered the first-line treatment in cerebral venous and dural sinus thrombosis (CVT) by recent Prof. José M. Ferro Department of Neurosciences (Neurology), Hospital de Santa Maria Avenida Professor Egas Moniz PT–1649-035 Lisbon (Portugal) E-Mail jmferro @ fm.ul.pt
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a
Methods We attempted to identify all published studies that reported on the use of systemic thrombolysis in CVT patients by searching the PubMed electronic database up to December 31, 2011, without language restrictions. The following key words were used: cerebral veins, dural sinus, cranial sinus, venous thrombosis, sinus thrombosis, thrombolysis, thrombolytics, fibrinolytics, fibrinolysis, urokinase, streptokinase, rt-PA (recombinant tissue plasminogen activator) and alteplase. We supplemented our search by manually checking the reference lists of all the articles retrieved for additional studies, continuing this method of cross-checking until no further studies were found. All retrieved titles and abstracts were reviewed independently by 2 investigators (J.M.F. and L.D.V.). Full publications were obtained based on the titles or abstracts selected by at least 1 of the reviewers. Full publications were reviewed to select the cases to be included in the review. Inclusion criteria were reports describing patients: (1) with CVT; (2) diagnosed by angiography, magnetic resonance imaging (MRI), MR angiography and/or MR venography; (3) treated by systemic thrombolytic therapy, with or without additional treatments, except for local chemical and/or mechanical thrombolysis; and (4) with follow-up information on survival and/or disability, at least at hospital discharge. We only included publications that allowed extraction of individual patient data. In doubtful cases, authors were contact-
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Cerebrovasc Dis 2014;37:43–50 DOI: 10.1159/000356840
ed to provide additional information. In the case of 2 articles, written in Japanese [13] and Polish [14], with only the abstract written in English, summary translations of the articles were provided by the author himself and a Polish-speaking neurologist, respectively. Additionally, we used data from the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) cohort, a multinational observational study on 624 consecutive symptomatic patients with CVT [8]. In this study, the choice of treatment was left to the treating physician, but all treatments were systematically recorded. We selected the patients who were treated by systemic thrombolysis. The following data were extracted by means of a standardized data extraction form: • Baseline findings: year of study; age, gender and race of patients; mode of symptom onset (acute if 1 month); clinical syndromes, symptoms and signs; delay from symptom onset to admission and to diagnosis; ancillary procedures used for diagnosis establishment; affected sinuses and number of affected sinuses; hemorrhagic and nonhemorrhagic intracranial lesions on computed tomography (CT) and/or MRI prior to thrombolytic treatment; and risk factors for CVT • Treatment: delay from symptom onset to thrombolytic treatment; thrombolytic agent used, dose (in the cases where dose was expressed per kilogram, we assumed the patient was an average adult of 70 kg in order to calculate the total dose administered) and duration of thrombolytic treatment; and use of anticoagulation and other additional treatments • Outcome measures – efficacy outcomes: partial or complete recanalization of the affected veins and sinuses recognized via MRI/angiography, length of hospital stay and of follow-up, and death and functional outcome at discharge and during follow-up, as assessed by the modified Rankin Scale (mRS); when other scales were used or only descriptive information on outcome was available, transformation into mRS grades was performed independently by 2 observers (J.M.F. and L.D.V.) and a consensus was reached if grading did not coincide; the primary outcome was the score on the mRS at the last follow-up dichotomized between independent survival (mRS scores 0–2) and death or dependency (mRS scores 3–6); secondary outcomes were complete recovery (mRS scores 0–1) and death at the last available follow-up (mRS score 6); in the cases where there was no information about clinical evolution and clinical presentation at the last follow-up, only survival was evaluated • Outcome measures – safety outcomes: intracranial and extracranial hemorrhagic complications and their severity, severe bleeding being defined as any intracranial bleeding or systemic bleeding, either fatal or leading to surgery or transfusion; considering that some variables could influence outcome, we analyzed the main outcomes (death/dependency, death and complete recovery) according to the following stratification: year of study, age, gender, mode of symptom onset, clinical syndrome, sinuses affected, multiple sinus thrombosis and type of thrombolytic agent used To test for the association between predictors and outcomes, we used the median test for the variable ‘age’, Pearson’s χ2 test for the variable ‘mode of symptom onset’, and Fisher’s exact test for the remaining variables.
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guidelines [1, 2]. Another treatment option is the use of systemic or local thrombolysis, with or without mechanical thrombus disruption. This modality of treatment has some theoretical advantages over heparin treatment, the most important being that, if successful, the bulk of the thrombotic material can be removed from the major sinus within hours, leading to recanalization more frequently and rapidly than heparin alone [3–6]. So far, there are no randomized, double-blind, placebo-controlled trials to support thrombolysis as a first-line therapy compared with standard heparin therapy. Some authors and guidelines advocate thrombolysis only for those patients with neurological deterioration despite adequate anticoagulation [1–3, 7], for those with poor prognostic factors [8–11] and for those where the course is felt to be unpredictable with potentially dangerous deterioration [12]. There are also no data to indicate which route of thrombolytic administration is better, as the literature is dominated by cases treated by local thrombolysis. Systemic thrombolysis has been reported in only a few single case reports and small case series. The aim of this investigation was to collect all the published information about the use of systemic thrombolytic therapy in CVT in order to try to assess its efficacy and safety.
Electronic search (n = 307)
Studies excluded after title and abstract screening with inclusion criteria (n = 206)
Studies retrieved for more detailed evaluation (n = 101)
Studies excluded after article screening with inclusion criteria (n = 93)
Studies included (n = 8)
Only anticoagulation and/or other treatment modalities were used (n = 66)
ISCVT (n = 1)
Local and/or mechanical thrombolysis was used (n = 23)
Studies identified by manual review of the references (n = 7)
Diagnosed by CT only (n = 1)
Articles in other languages, translation not obtained (n = 3)
Total of studies included (n = 16)
Fig. 1. Study flow chart. n = Number of
studies.
A total of 307 citations were identified by our systematic search strategy. After screening of the title and abstract using the predefined inclusion and exclusion criteria, 101 studies were retrieved for more detailed information. The following were excluded: 66 because only anticoagulation and/or other treatment modalities, but no thrombolytic treatment, were used to treat the patients; 23 because local and/or mechanical thrombolysis was used, with or without systemic thrombolysis; 1 because CVT was diagnosed by CT only; and 3 because they were written in languages (Japanese, Chinese and Finnish) for which translation could not be obtained. Two cases from the ISCVT [8] and 7 additional studies [14–20], Systemic Thrombolysis for CVT
which were identified by manual review of references, were included. Therefore, 16 studies [8, 13–27], totaling 26 patients, were included in the review (fig. 1). The studies were published from 1971 to 2008. No randomized clinical trial was found, nor any casecontrol studies. All studies were case reports or case series. Two studies [19, 22] reported on 5 patients and 10 studies [13–18, 21, 23, 26, 27] were single-case reports. Hence, the quality of the evidence was poor. Baseline Findings The main demographic, clinical and imaging features are shown in table 1. The mode of symptom onset was acute in 5 patients (19.2%), subacute in 12 (46.2%), chronic in only 1 (3.8%), and in 8 cases there was no informaCerebrovasc Dis 2014;37:43–50 DOI: 10.1159/000356840
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Results
Table 1. Demographic, clinical and imaging features of patients
Table 2. Risk factors for CVT for patients included
included n Demographics Mean age, years Median age, years Female gender Clinical syndrome/symptoms and signs Isolated intracranial hypertension syndrome Headache Vomiting/nausea Visual loss Papilledema Sixth nerve palsies Retinal hemorrhages Meningeal signs Aphasia Dysarthria Hemiparesis Sensory symptoms Dizziness Ataxia Nystagmus Focal seizure Seizure with generalization Encephalopathy Mental status disorder Stupor/coma Parenchymal lesions on CT/MRI Hemorrhagic Nonhemorrhagic Occluded sinus/veins Superior sagittal sinus Right lateral sinus Left lateral sinus Straight sinus Deep cerebral venous system
31 (1–76) 28 17 65.4 7 24 14 2 9 6 1 5 2 1 10 5 1 3 1 2 5 17 15 2
26.9 92.3 53.8 7.7 34.6 23.1 3.8 19.2 7.7 3.8 38.5 19.2 3.8 11.5 3.8 7.7 19.2 65.4 57.7 7.7
2 7
7.7 26.9
21 11 6 6 5
80.8 42.3 23.1 23.1 19.2
Value in parenthesis denotes range. n = Number of patients.
tion. The median delay from symptom onset to admission was 3 days (mean: 11.3 days; range: 0–120 days; missing data in 9 cases), and from symptom onset to diagnosis 4 days (mean: 17.2 days; range: 1–120 days; missing data in 17 cases). The diagnosis of CVT was established by intraarterial angiography in 16 patients (61.5%), by MRI in 2 (7.7%), by MR venography in another 2, by MR angiography in 3 (11.5%) and by multiple imaging methods in the remaining 3 patients. Fourteen patients had only one sinus occluded (53.8%), while the other 12 presented with multiple sinus occlusion (46.2%). The risk factors for CVT are summarized in table 2. 46
Cerebrovasc Dis 2014;37:43–50 DOI: 10.1159/000356840
%
% Prothrombotic conditions Protein S deficiency Antiphospholipid antibodies Lupus anticoagulant Mutation G20210A of factor II Malignancy Carcinoma Hematological Systemic diseases Inflammatory bowel disease Nonspecified vasculitis Other Puerperium1 Infection Central nervous system Parameningeal infections (ear, sinus, mouth, face and neck) Other Mechanical precipitants Central venous catheter Oral contraceptives1 Surgery None identified
1 1 1 1
3.8 3.8 3.8 3.8
1 1
3.8 3.8
1 1 1 3
3.8 3.8 3.8 25.0
1
3.8
4 1
15.4 3.8
2 2 2 7
7.7 16.7 7.7 26.9
Cases may have >1 risk factor. n = Number of patients. 1 Percentages among 12 females between 16 and 50 years of age.
Treatment The median delay from symptom onset to thrombolytic treatment was 3.5 days (mean: 13.5 days; range: 1–120 days; missing information in 12 cases). Loading doses, total doses and mean infusion time varied widely among the studies and are described in table 3. Concerning urokinase, the mean dose was 2,965,625 U, total doses ranging between 360,000 and 4,717,500 U (missing information in 7 cases). The duration of thrombolytic treatment was mentioned in 17 cases. The median duration was 96 h (mean: 107.1 h; range: 2–216 h). Twenty-four patients were also anticoagulated (92.3%). Additional treatments included osmotherapy and antiepileptic drugs [n = 5 (19.2%) each], antiplatelet drugs, steroids and antibiotics/antifungals [n = 4 (15.4%) each], and diuretics (n = 1; 3.9%). Two patients required mechanical ventilation, and another 2 a blood transfusion (7.7% each), one for hemorrhagic complications and the other for concomitant anemia. Viegas/Stolz/Canhão/Ferro
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n
Table 3. Treatment characteristics of patients included
Study
n
Type of thrombolytic
Dosage
Duration of treatment
Total dose
Vines and Davis [19]
5
urokinase
–
–
–
Gettelfinger and Kokmen [20]
1
urokinase
1,800,000 U in 30 min initially, and 900,000 U 8 h later
8.5 h
2,700,000 U
di Rocco et al. [22]
5
urokinase
3,500 U/kg/h by continuous infusion for 6–9 h initially, continued with 3,000 U/kg/6–8 h for 2–6 days
2–6 days
4,717,500 U
Albumiya et al. [13]
1
urokinase
60,000 U/day
7 days
420,000 U
Manthous and Chen [15]
1
urokinase
3,500 U/kg/h for 6 h initially, continued with 3,000 U/kg/6 h for 4 days
4 days
4,620,000 U
Nagatomo et al. [23]
1
urokinase
–
–
–
Ossemann et al. [24]
2
streptokinase
100,000 U/h
11 h
1,100,000 U
streptokinase urokinase
100,000 U/h of streptokinase for 6 days, followed by 2,000 U/kg/h of urokinase for 2 days (thrombolytic agent had to be changed due to an allergic reaction with temperature)
8 days
streptokinase: 14,400,000 U; urokinase: 6,720,000 U
Tsujikawa et al. [16]
1
urokinase
60,000 U/day
6 days
360,000 U
Nagai et al. [26]
1
urokinase
120,000 U on the 1st day, continued with 60,000 U/day
7 days
480,000 U
Funabiki et al. [25]
1
urokinase
60,000 U/day
7 days
420,000 U
Huh et al. [17]
1
urokinase
bolus of 1,500,000 U initially, continued with 1,500,000 U infused continuously over 2 h
2h
3,000,000 U
Strzyzewska-Lubos et al. [14]
1
streptokinase
1,500,000 U
–
1,500,000 U
Tarani et al. [18]
1
rt-PA
0.6 mg/kg/day infused continuously over 6 h
9 days
378 mg
Ferro et al. [8]
2
not specified
–
6 days
–
not specified
–
1 day
–
Misra et al. [21]
1
rt-PA
0.9 mg/kg
–
63 mg
Sakai et al. [27]
1
urokinase
–
–
–
Outcome Measures Efficacy Outcomes. Partial (n = 6; 23.1%) or complete (n = 10; 38.5%) recanalization was verified in most patients (n = 16; 61.5%). On 10 patients there was no information regarding this outcome. Data on length of hospital stay were available in 19 cases. The median duration of hospital stay was 16 days (mean: 25.8 days; range: 3–120 days). The median duration of follow-up was 1 month (mean: 7.7 months; range: 3 days to 25 months). The survival rate was 92.3% (24/26 patients). In 1 case there was no information concerning the clinical evalua-
tion at the last follow-up, although the patient was discharged alive. Among the remaining 25 cases, at the last follow-up (which includes discharge when no more follow-up information was available), most patients regained independency (n = 22; 88%), 2 died (8%) and 1 was severely dependent (4%). Safety Outcomes. De novo intracranial hemorrhages (after thrombolytic treatment) were reported in 3 cases (11.5%), 2 of them associated with clinical deterioration and death (7.7%): one in the left internal capsule, the other in the right parietal lobe and left cerebellar hemisphere.
Systemic Thrombolysis for CVT
Cerebrovasc Dis 2014;37:43–50 DOI: 10.1159/000356840
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n = Number of patients.
Subgroup Analysis Two patients out of the 5 presenting with thrombosis of the cerebral deep venous system died (p = 0.031). These patients also had intracranial bleedings after thrombolysis. No other significant differences were found in main outcomes (death, death/dependency or complete recovery) according to year of study, age, gender, mode of symptom onset, clinical syndrome, multiple sinus thrombosis or type of thrombolytic agent used (data not shown; available on request).
Discussion
In this systematic review of the available literature and of the ISCVT database, we succeeded in obtaining information on 26 acute CVT patients treated by systemic thrombolysis. Only 8% of the patients included were comatose or had intracranial hemorrhagic lesions prior to thrombolysis, whereas 27% presented with isolated intracranial hypertension. In general, the outcome was good, with most patients regaining independency. However, 2 deaths associated with intracranial bleeding were reported. Both patients who died presented with thrombosis of the cerebral deep venous system and 1 had an intracerebral hemorrhagic lesion prior to thrombolysis. This observation is in accordance with current knowledge which indicates that thrombosis of the deep venous system and intracerebral hemorrhage are important prognostic factors for death/dependency in CVT. It also raises the question whether direct local thrombolysis could have saved these 2 patients. 48
Cerebrovasc Dis 2014;37:43–50 DOI: 10.1159/000356840
Our study has some results similar to those reported in 2 previous systematic reviews concerning the use of thrombolysis in CVT patients, especially regarding the mortality rate and disability at the last available followup. The first one, written by Canhão et al. [28], is a review of the literature up to July 2001, reporting 72 publications involving 169 patients. At discharge, 10 cases (7%; 95% CI: 3–12%) were dependent and 9 cases (5%; 95% CI: 2–9%) died. In comparison with our study, the patients who were treated by local thrombolysis in the first study were in a worse clinical condition than those treated by systemic thrombolysis in ours, with a higher proportion of patients in coma (difference: –0.24; 95% CI: –0.34 to –0.06). Local thrombolysis appeared to be more effective in the first study than systemic thrombolysis in ours, with a higher partial recanalization rate (difference: –0.23; 95% CI: –0.38 to –0.02). No other significant differences between proportions were found. A comparison of the results between the 2 studies is shown in table 4. Recently, Dentali et al. [29] reviewed the literature up to June 2010, reporting 15 studies including a total of 156 CVT patients treated with all types of thrombolysis (systemic, local and/or mechanical). Twelve patients died after the treatment (weighted mean: 9.2%; 95% CI: 4.3, 15.7%) and 15 had a major bleeding complication (weighted mean: 9.8%; 95% CI: 5.3, 15.6%). Twelve hemorrhages were intracranial (weighted mean: 7.6%; 95% CI: 3.5, 13.1%) and 7 of these patients died (weighted mean: 58.3%; 95% CI: 32.0, 80.7%). The mortality rate and the number of patients with major bleeding complications in this study were slightly higher compared with the results of our study, whereas the number of patients with intracranial hemorrhages was somewhat lower. Our systematic review has several limitations. The first one is the small number of patients included, which makes it difficult to reach robust results applicable to a wider population. A second limitation is related to publication bias. Selective submission and acceptance of case reports with good results over case reports with poor results may have underestimated outcome and complications. To decrease this kind of bias, we have made a thorough search and included publications other that in the English language. Another limitation concerns the quality of the studies, all being case reports or case series. Treatment was given nonblindly, leading to a possible bias in evaluating outcomes. Individual data on the characteristics of the patients, treatment and measures of outcome were not systematically reported. To overcome some of these problems, we collected all the Viegas/Stolz/Canhão/Ferro
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The location in the third case was not specified. The intracranial hemorrhage in 1 patient whose CT had shown it prior to thrombolytic treatment did not enlarge after thrombolysis, and cleared in follow-up neuroimaging. In the other patient, treatment was complicated by fatal systemic and intracranial bleeding. Extracranial sites of hemorrhages were reported on 5 occasions (19.2%), and they included cutaneous puncture sites (n = 3; 11.5%), epistaxis and diffuse ecchymotic lesions [n = 1 (3.8%) each]. Blood transfusion was required in 1 case (3.8%). One of the 2 patients who presented with intracranial hemorrhage associated with clinical deterioration and death was also the one who presented with extracranial bleeding (cutaneous puncture sites), which required a blood transfusion. Therefore, overall, there were 8 hemorrhagic complications in 7 patients (26.9%), 2 of them intracranial and fatal (7.7%). There were no other complications reported.
Table 4. Comparison of results between systematic reviews for thrombolysis in acute CVT (n/N)
Case characteristics
Clinical syndrome Isolated intracranial hypertension syndrome Encephalopathy Coma Deep cerebral venous system thrombosis Sinus occlusion One Multiple Hemorrhagic lesions on CT/MRI prior to thrombolytic treatment Hemorrhagic complications of thrombolytic treatment Intracranial hemorrhage Severe intracranial hemorrahge Extracranial hemorrhage Severe extracranial hemorrhage Recanalization Partial Complete mRS score at last available follow-up 0–1 2 3–5 6
Canhão et al. [28]
Our study
local thrombolysis
systemic thrombolysis
systemic thrombolysis
18/134 (13) 64/134 (48) 43/134 (32) 41/134 (31)
4/16 (25) 9/16 (56) 2/16 (13) 3/16 (23)
7/26 (26.9) 17/26 (65.4) 2/26 (7.7) 5/26 (19.2)
48/131 (37) 83/131 (63) 39/120 (33)
8/16 (50) 8/16 (51) 2/5 (40)
14/26 (53.8) 12/26 (46.2) 2/26 (7.7)
16/97 (16) 5/97 (5) 10/97 (20) 2/97 (2)
1/9 (11) – 4/9 (44) –
3/26 (11.5) 2/26 (7.7) 5/26 (19.2) 1/26 (3.8)
61/132 (46) 64/132 (48)
4/15 (26) 6/15 (40)
6/26 (23.1) 10/26 (38.5)
64/89 (71.9) 14/89 (15.7) 3/89 (3.4) 8/89 (9)
9/11 (81.8) 1/11 (9.1) 0/11 (0) 1/11 (9.1)
20/25 (80) 2/25 (8) 1/25 (4) 2/25 (8)
available evidence and extracted as many individual data as possible. Another problem is related to variation in the intervention under study, as criteria for using systemic thrombolysis, as well as the type, duration and dose of thrombolytic agent were not the same in all patients. An additional limitation is the large range of publication years, which may explain the long delays in diagnosis and onset of treatment in cases reported on before MRI became widely available and the diagnosis of dural sinus thrombosis was routinely considered in suspected cases. Finally, a possible confounding factor in measuring the effect of thrombolytics is that several cases were also exposed to other treatments that may affect outcome, such as anticoagulant therapy, osmotherapy, antiepileptic drugs and antibiotics. It is possible that those interventions may increase the real magnitude of effects of thrombolysis, making treatment effects appear stronger than they actually are.
Currently, the ongoing TO-ACT (Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis) Trial [30], a multicenter, prospective, randomized, open-label, blinded endpoint trial, aims to determine whether endovascular thrombolysis improves the functional outcome of patients with a severe form of CVT, in comparison with standard therapy with therapeutic doses of heparin. Considering that there is a greater experience concerning the local route of administration, it is not surprising that this was the one selected for being tested in a randomized clinical trial. Nevertheless, there are potential advantages of noninvasive systemic treatment over direct endovascular thrombolysis, especially in mild cases, where the latter might be too invasive. Systemic thrombolysis is a more feasible and available route. According to our study, it seems to be reasonably safe, although its efficacy cannot be assessed from the published information, mainly because of the lack of a control group.
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Values in parentheses denote percentages. n = Number of cases with each characteristic; N = total number of cases on which information was available.
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1 Einhäupl K, Stam J, Bousser MG, de Bruijn SF, Ferro JM, Martinelli I, Masuhr F, European Federation of Neurological Societies: EFNS guideline on the treatment of cerebral venous and sinus thrombosis in adult patients. Eur J Neurol 2010;17:1229–1235. 2 Saposnik G, Barinagarrementeria F, Brown RD Jr, Bushnell CD, Cucchiara B, Cushman M, deVeber G, Ferro JM, Tsai FY, American Heart Association Stroke Council and Council on Epidemiology and Prevention: Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42:1158–1192. 3 Bousser MG: Cerebral venous thrombosis: nothing, heparin, or local thrombolysis? Stroke 1999;30:481–483. 4 Ciccone A, Canhão P, Falcão F, Ferro JM, Sterzi R: Thrombolysis for cerebral vein and dural sinus thrombosis. Cochrane Database Syst Rev 2004;1:CD003693. 5 Wasay M, Bakshi R, Bobustuc G, Kojan S, Sheikh Z, Dai A, Cheema Z: Cerebral venous thrombosis: analysis of a multicenter cohort from the United States. J Stroke Cerebrovasc Dis 2008;17:49–54. 6 Canhão P, Ferro JM, Stam J: Cerebral venous thrombosis; in Fisher M (ed): Handbook of Clinical Neurology. Amsterdam, Elsevier, 2009, vol 93, pp 809–822. 7 Benamer HT, Bone I: Cerebral venous thrombosis: anticoagulants or thrombolytic therapy? J Neurol Neurosurg Psychiatry 2000; 69: 427–430. 8 Ferro JM, Canhão P, Stam J, Bousser MG, Barinagarrementeria F, ISCVT Investigators: Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke 2004;35:664–670. 9 Gala N, Agarwal N, Barrese J, Gandhi CD, Prestigiacomo CJ: Current endovascular treatment options of dural venous sinus thrombosis: a review of the literature. J Neurointerv Surg 2013;5:28–34.
Received: July 19, 2013 Accepted: October 28, 2013 Published online: December 18, 2013
Systemic Thrombolysis for Cerebral Venous and Dural Sinus Thrombosis: A Systematic Review L.D. Viegas a E. Stolz b P. Canhão a J.M. Ferro a
b
Department of Neurosciences (Neurology), Hospital de Santa Maria, University of Lisbon, Lisbon, Portugal; Neurologische Klinik, Caritasklinik St. Theresia, Saarbrücken, Germany
Key Words Cerebral venous thrombosis · Dural sinus thrombosis · Intravenous thrombolysis · Recombinant tissue plasminogen activator · Urokinase
Abstract Background: The use of thrombolytics is frequently considered in patients with cerebral venous and dural sinus thrombosis (CVT) who deteriorate despite anticoagulant therapy. Purpose: To collect all the published information about the use of systemic thrombolysis in CVT in order to assess its efficacy and safety. Methods: We performed a PubMed search, checked all reference lists of studies found and used data from the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Outcome was classified at the last available follow-up by the modified Rankin Scale (mRS). The cases were stratified according to variables that might influence outcome. Results: A total of 16 reports (26 patients, 2 from the ISCVT and 24 from the systematic review of the literature) were included. No randomized clinical trial was found. Seven patients presented with isolated intracranial hypertension syndrome (26.9%), 17 with encephalopathy (65.4%) and 2 were comatose (7.7%). The superior sagittal sinus was the one most often affected (n = 21; 80.8%), and there was thrombosis of the deep cerebral venous system in 5 patients (19.2%). Urokinase was the thrombolytic agent most frequently administered (n = 19; 73.1%), whereas strep-
© 2013 S. Karger AG, Basel 1015–9770/13/0371–0043$38.00/0 E-Mail [email protected] www.karger.com/ced
tokinase and recombinant tissue plasminogen activator were used in 2 cases each (7.7%). Intracranial hemorrhages occurred in 3 cases (11.5%). Extracranial hemorrhages occurred in 5 cases (19.2%), and overall there were 3 cases of serious bleeding (11.5%), including 2 deaths (7.7%). Partial or complete recanalization was verified in most patients (n = 16; 61.5%). The survival rate was 92.3% (24/26 patients). At the last available follow-up, 22/25 patients regained independency (mRS scores 0–2; 88%), 2/25 died (mRS score 6; 8%) and 1/25 was severely dependent (mRS scores 3–5; 4%). Conclusions: In all, 88% of the CVT patients treated with systemic thrombolysis regained their independency, but 2 deaths associated with intracranial hemorrhage occurred. The mortality rate and disability at the last available followup were similar to those found in 2 previous systematic reviews concerning the use of thrombolytics in CVT. Due to the small sample size and lack of controls, the efficacy of systemic thrombolysis in acute CVT cannot be assessed from the published information. Concerning safety, a nonnegligible proportion of bleedings was reported. © 2013 S. Karger AG, Basel
Introduction
The immediate administration of systemic anticoagulants is considered the first-line treatment in cerebral venous and dural sinus thrombosis (CVT) by recent Prof. José M. Ferro Department of Neurosciences (Neurology), Hospital de Santa Maria Avenida Professor Egas Moniz PT–1649-035 Lisbon (Portugal) E-Mail jmferro @ fm.ul.pt
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a
Methods We attempted to identify all published studies that reported on the use of systemic thrombolysis in CVT patients by searching the PubMed electronic database up to December 31, 2011, without language restrictions. The following key words were used: cerebral veins, dural sinus, cranial sinus, venous thrombosis, sinus thrombosis, thrombolysis, thrombolytics, fibrinolytics, fibrinolysis, urokinase, streptokinase, rt-PA (recombinant tissue plasminogen activator) and alteplase. We supplemented our search by manually checking the reference lists of all the articles retrieved for additional studies, continuing this method of cross-checking until no further studies were found. All retrieved titles and abstracts were reviewed independently by 2 investigators (J.M.F. and L.D.V.). Full publications were obtained based on the titles or abstracts selected by at least 1 of the reviewers. Full publications were reviewed to select the cases to be included in the review. Inclusion criteria were reports describing patients: (1) with CVT; (2) diagnosed by angiography, magnetic resonance imaging (MRI), MR angiography and/or MR venography; (3) treated by systemic thrombolytic therapy, with or without additional treatments, except for local chemical and/or mechanical thrombolysis; and (4) with follow-up information on survival and/or disability, at least at hospital discharge. We only included publications that allowed extraction of individual patient data. In doubtful cases, authors were contact-
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ed to provide additional information. In the case of 2 articles, written in Japanese [13] and Polish [14], with only the abstract written in English, summary translations of the articles were provided by the author himself and a Polish-speaking neurologist, respectively. Additionally, we used data from the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) cohort, a multinational observational study on 624 consecutive symptomatic patients with CVT [8]. In this study, the choice of treatment was left to the treating physician, but all treatments were systematically recorded. We selected the patients who were treated by systemic thrombolysis. The following data were extracted by means of a standardized data extraction form: • Baseline findings: year of study; age, gender and race of patients; mode of symptom onset (acute if 1 month); clinical syndromes, symptoms and signs; delay from symptom onset to admission and to diagnosis; ancillary procedures used for diagnosis establishment; affected sinuses and number of affected sinuses; hemorrhagic and nonhemorrhagic intracranial lesions on computed tomography (CT) and/or MRI prior to thrombolytic treatment; and risk factors for CVT • Treatment: delay from symptom onset to thrombolytic treatment; thrombolytic agent used, dose (in the cases where dose was expressed per kilogram, we assumed the patient was an average adult of 70 kg in order to calculate the total dose administered) and duration of thrombolytic treatment; and use of anticoagulation and other additional treatments • Outcome measures – efficacy outcomes: partial or complete recanalization of the affected veins and sinuses recognized via MRI/angiography, length of hospital stay and of follow-up, and death and functional outcome at discharge and during follow-up, as assessed by the modified Rankin Scale (mRS); when other scales were used or only descriptive information on outcome was available, transformation into mRS grades was performed independently by 2 observers (J.M.F. and L.D.V.) and a consensus was reached if grading did not coincide; the primary outcome was the score on the mRS at the last follow-up dichotomized between independent survival (mRS scores 0–2) and death or dependency (mRS scores 3–6); secondary outcomes were complete recovery (mRS scores 0–1) and death at the last available follow-up (mRS score 6); in the cases where there was no information about clinical evolution and clinical presentation at the last follow-up, only survival was evaluated • Outcome measures – safety outcomes: intracranial and extracranial hemorrhagic complications and their severity, severe bleeding being defined as any intracranial bleeding or systemic bleeding, either fatal or leading to surgery or transfusion; considering that some variables could influence outcome, we analyzed the main outcomes (death/dependency, death and complete recovery) according to the following stratification: year of study, age, gender, mode of symptom onset, clinical syndrome, sinuses affected, multiple sinus thrombosis and type of thrombolytic agent used To test for the association between predictors and outcomes, we used the median test for the variable ‘age’, Pearson’s χ2 test for the variable ‘mode of symptom onset’, and Fisher’s exact test for the remaining variables.
Viegas/Stolz/Canhão/Ferro
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guidelines [1, 2]. Another treatment option is the use of systemic or local thrombolysis, with or without mechanical thrombus disruption. This modality of treatment has some theoretical advantages over heparin treatment, the most important being that, if successful, the bulk of the thrombotic material can be removed from the major sinus within hours, leading to recanalization more frequently and rapidly than heparin alone [3–6]. So far, there are no randomized, double-blind, placebo-controlled trials to support thrombolysis as a first-line therapy compared with standard heparin therapy. Some authors and guidelines advocate thrombolysis only for those patients with neurological deterioration despite adequate anticoagulation [1–3, 7], for those with poor prognostic factors [8–11] and for those where the course is felt to be unpredictable with potentially dangerous deterioration [12]. There are also no data to indicate which route of thrombolytic administration is better, as the literature is dominated by cases treated by local thrombolysis. Systemic thrombolysis has been reported in only a few single case reports and small case series. The aim of this investigation was to collect all the published information about the use of systemic thrombolytic therapy in CVT in order to try to assess its efficacy and safety.
Electronic search (n = 307)
Studies excluded after title and abstract screening with inclusion criteria (n = 206)
Studies retrieved for more detailed evaluation (n = 101)
Studies excluded after article screening with inclusion criteria (n = 93)
Studies included (n = 8)
Only anticoagulation and/or other treatment modalities were used (n = 66)
ISCVT (n = 1)
Local and/or mechanical thrombolysis was used (n = 23)
Studies identified by manual review of the references (n = 7)
Diagnosed by CT only (n = 1)
Articles in other languages, translation not obtained (n = 3)
Total of studies included (n = 16)
Fig. 1. Study flow chart. n = Number of
studies.
A total of 307 citations were identified by our systematic search strategy. After screening of the title and abstract using the predefined inclusion and exclusion criteria, 101 studies were retrieved for more detailed information. The following were excluded: 66 because only anticoagulation and/or other treatment modalities, but no thrombolytic treatment, were used to treat the patients; 23 because local and/or mechanical thrombolysis was used, with or without systemic thrombolysis; 1 because CVT was diagnosed by CT only; and 3 because they were written in languages (Japanese, Chinese and Finnish) for which translation could not be obtained. Two cases from the ISCVT [8] and 7 additional studies [14–20], Systemic Thrombolysis for CVT
which were identified by manual review of references, were included. Therefore, 16 studies [8, 13–27], totaling 26 patients, were included in the review (fig. 1). The studies were published from 1971 to 2008. No randomized clinical trial was found, nor any casecontrol studies. All studies were case reports or case series. Two studies [19, 22] reported on 5 patients and 10 studies [13–18, 21, 23, 26, 27] were single-case reports. Hence, the quality of the evidence was poor. Baseline Findings The main demographic, clinical and imaging features are shown in table 1. The mode of symptom onset was acute in 5 patients (19.2%), subacute in 12 (46.2%), chronic in only 1 (3.8%), and in 8 cases there was no informaCerebrovasc Dis 2014;37:43–50 DOI: 10.1159/000356840
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Results
Table 1. Demographic, clinical and imaging features of patients
Table 2. Risk factors for CVT for patients included
included n Demographics Mean age, years Median age, years Female gender Clinical syndrome/symptoms and signs Isolated intracranial hypertension syndrome Headache Vomiting/nausea Visual loss Papilledema Sixth nerve palsies Retinal hemorrhages Meningeal signs Aphasia Dysarthria Hemiparesis Sensory symptoms Dizziness Ataxia Nystagmus Focal seizure Seizure with generalization Encephalopathy Mental status disorder Stupor/coma Parenchymal lesions on CT/MRI Hemorrhagic Nonhemorrhagic Occluded sinus/veins Superior sagittal sinus Right lateral sinus Left lateral sinus Straight sinus Deep cerebral venous system
31 (1–76) 28 17 65.4 7 24 14 2 9 6 1 5 2 1 10 5 1 3 1 2 5 17 15 2
26.9 92.3 53.8 7.7 34.6 23.1 3.8 19.2 7.7 3.8 38.5 19.2 3.8 11.5 3.8 7.7 19.2 65.4 57.7 7.7
2 7
7.7 26.9
21 11 6 6 5
80.8 42.3 23.1 23.1 19.2
Value in parenthesis denotes range. n = Number of patients.
tion. The median delay from symptom onset to admission was 3 days (mean: 11.3 days; range: 0–120 days; missing data in 9 cases), and from symptom onset to diagnosis 4 days (mean: 17.2 days; range: 1–120 days; missing data in 17 cases). The diagnosis of CVT was established by intraarterial angiography in 16 patients (61.5%), by MRI in 2 (7.7%), by MR venography in another 2, by MR angiography in 3 (11.5%) and by multiple imaging methods in the remaining 3 patients. Fourteen patients had only one sinus occluded (53.8%), while the other 12 presented with multiple sinus occlusion (46.2%). The risk factors for CVT are summarized in table 2. 46
Cerebrovasc Dis 2014;37:43–50 DOI: 10.1159/000356840
%
% Prothrombotic conditions Protein S deficiency Antiphospholipid antibodies Lupus anticoagulant Mutation G20210A of factor II Malignancy Carcinoma Hematological Systemic diseases Inflammatory bowel disease Nonspecified vasculitis Other Puerperium1 Infection Central nervous system Parameningeal infections (ear, sinus, mouth, face and neck) Other Mechanical precipitants Central venous catheter Oral contraceptives1 Surgery None identified
1 1 1 1
3.8 3.8 3.8 3.8
1 1
3.8 3.8
1 1 1 3
3.8 3.8 3.8 25.0
1
3.8
4 1
15.4 3.8
2 2 2 7
7.7 16.7 7.7 26.9
Cases may have >1 risk factor. n = Number of patients. 1 Percentages among 12 females between 16 and 50 years of age.
Treatment The median delay from symptom onset to thrombolytic treatment was 3.5 days (mean: 13.5 days; range: 1–120 days; missing information in 12 cases). Loading doses, total doses and mean infusion time varied widely among the studies and are described in table 3. Concerning urokinase, the mean dose was 2,965,625 U, total doses ranging between 360,000 and 4,717,500 U (missing information in 7 cases). The duration of thrombolytic treatment was mentioned in 17 cases. The median duration was 96 h (mean: 107.1 h; range: 2–216 h). Twenty-four patients were also anticoagulated (92.3%). Additional treatments included osmotherapy and antiepileptic drugs [n = 5 (19.2%) each], antiplatelet drugs, steroids and antibiotics/antifungals [n = 4 (15.4%) each], and diuretics (n = 1; 3.9%). Two patients required mechanical ventilation, and another 2 a blood transfusion (7.7% each), one for hemorrhagic complications and the other for concomitant anemia. Viegas/Stolz/Canhão/Ferro
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n
Table 3. Treatment characteristics of patients included
Study
n
Type of thrombolytic
Dosage
Duration of treatment
Total dose
Vines and Davis [19]
5
urokinase
–
–
–
Gettelfinger and Kokmen [20]
1
urokinase
1,800,000 U in 30 min initially, and 900,000 U 8 h later
8.5 h
2,700,000 U
di Rocco et al. [22]
5
urokinase
3,500 U/kg/h by continuous infusion for 6–9 h initially, continued with 3,000 U/kg/6–8 h for 2–6 days
2–6 days
4,717,500 U
Albumiya et al. [13]
1
urokinase
60,000 U/day
7 days
420,000 U
Manthous and Chen [15]
1
urokinase
3,500 U/kg/h for 6 h initially, continued with 3,000 U/kg/6 h for 4 days
4 days
4,620,000 U
Nagatomo et al. [23]
1
urokinase
–
–
–
Ossemann et al. [24]
2
streptokinase
100,000 U/h
11 h
1,100,000 U
streptokinase urokinase
100,000 U/h of streptokinase for 6 days, followed by 2,000 U/kg/h of urokinase for 2 days (thrombolytic agent had to be changed due to an allergic reaction with temperature)
8 days
streptokinase: 14,400,000 U; urokinase: 6,720,000 U
Tsujikawa et al. [16]
1
urokinase
60,000 U/day
6 days
360,000 U
Nagai et al. [26]
1
urokinase
120,000 U on the 1st day, continued with 60,000 U/day
7 days
480,000 U
Funabiki et al. [25]
1
urokinase
60,000 U/day
7 days
420,000 U
Huh et al. [17]
1
urokinase
bolus of 1,500,000 U initially, continued with 1,500,000 U infused continuously over 2 h
2h
3,000,000 U
Strzyzewska-Lubos et al. [14]
1
streptokinase
1,500,000 U
–
1,500,000 U
Tarani et al. [18]
1
rt-PA
0.6 mg/kg/day infused continuously over 6 h
9 days
378 mg
Ferro et al. [8]
2
not specified
–
6 days
–
not specified
–
1 day
–
Misra et al. [21]
1
rt-PA
0.9 mg/kg
–
63 mg
Sakai et al. [27]
1
urokinase
–
–
–
Outcome Measures Efficacy Outcomes. Partial (n = 6; 23.1%) or complete (n = 10; 38.5%) recanalization was verified in most patients (n = 16; 61.5%). On 10 patients there was no information regarding this outcome. Data on length of hospital stay were available in 19 cases. The median duration of hospital stay was 16 days (mean: 25.8 days; range: 3–120 days). The median duration of follow-up was 1 month (mean: 7.7 months; range: 3 days to 25 months). The survival rate was 92.3% (24/26 patients). In 1 case there was no information concerning the clinical evalua-
tion at the last follow-up, although the patient was discharged alive. Among the remaining 25 cases, at the last follow-up (which includes discharge when no more follow-up information was available), most patients regained independency (n = 22; 88%), 2 died (8%) and 1 was severely dependent (4%). Safety Outcomes. De novo intracranial hemorrhages (after thrombolytic treatment) were reported in 3 cases (11.5%), 2 of them associated with clinical deterioration and death (7.7%): one in the left internal capsule, the other in the right parietal lobe and left cerebellar hemisphere.
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n = Number of patients.
Subgroup Analysis Two patients out of the 5 presenting with thrombosis of the cerebral deep venous system died (p = 0.031). These patients also had intracranial bleedings after thrombolysis. No other significant differences were found in main outcomes (death, death/dependency or complete recovery) according to year of study, age, gender, mode of symptom onset, clinical syndrome, multiple sinus thrombosis or type of thrombolytic agent used (data not shown; available on request).
Discussion
In this systematic review of the available literature and of the ISCVT database, we succeeded in obtaining information on 26 acute CVT patients treated by systemic thrombolysis. Only 8% of the patients included were comatose or had intracranial hemorrhagic lesions prior to thrombolysis, whereas 27% presented with isolated intracranial hypertension. In general, the outcome was good, with most patients regaining independency. However, 2 deaths associated with intracranial bleeding were reported. Both patients who died presented with thrombosis of the cerebral deep venous system and 1 had an intracerebral hemorrhagic lesion prior to thrombolysis. This observation is in accordance with current knowledge which indicates that thrombosis of the deep venous system and intracerebral hemorrhage are important prognostic factors for death/dependency in CVT. It also raises the question whether direct local thrombolysis could have saved these 2 patients. 48
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Our study has some results similar to those reported in 2 previous systematic reviews concerning the use of thrombolysis in CVT patients, especially regarding the mortality rate and disability at the last available followup. The first one, written by Canhão et al. [28], is a review of the literature up to July 2001, reporting 72 publications involving 169 patients. At discharge, 10 cases (7%; 95% CI: 3–12%) were dependent and 9 cases (5%; 95% CI: 2–9%) died. In comparison with our study, the patients who were treated by local thrombolysis in the first study were in a worse clinical condition than those treated by systemic thrombolysis in ours, with a higher proportion of patients in coma (difference: –0.24; 95% CI: –0.34 to –0.06). Local thrombolysis appeared to be more effective in the first study than systemic thrombolysis in ours, with a higher partial recanalization rate (difference: –0.23; 95% CI: –0.38 to –0.02). No other significant differences between proportions were found. A comparison of the results between the 2 studies is shown in table 4. Recently, Dentali et al. [29] reviewed the literature up to June 2010, reporting 15 studies including a total of 156 CVT patients treated with all types of thrombolysis (systemic, local and/or mechanical). Twelve patients died after the treatment (weighted mean: 9.2%; 95% CI: 4.3, 15.7%) and 15 had a major bleeding complication (weighted mean: 9.8%; 95% CI: 5.3, 15.6%). Twelve hemorrhages were intracranial (weighted mean: 7.6%; 95% CI: 3.5, 13.1%) and 7 of these patients died (weighted mean: 58.3%; 95% CI: 32.0, 80.7%). The mortality rate and the number of patients with major bleeding complications in this study were slightly higher compared with the results of our study, whereas the number of patients with intracranial hemorrhages was somewhat lower. Our systematic review has several limitations. The first one is the small number of patients included, which makes it difficult to reach robust results applicable to a wider population. A second limitation is related to publication bias. Selective submission and acceptance of case reports with good results over case reports with poor results may have underestimated outcome and complications. To decrease this kind of bias, we have made a thorough search and included publications other that in the English language. Another limitation concerns the quality of the studies, all being case reports or case series. Treatment was given nonblindly, leading to a possible bias in evaluating outcomes. Individual data on the characteristics of the patients, treatment and measures of outcome were not systematically reported. To overcome some of these problems, we collected all the Viegas/Stolz/Canhão/Ferro
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The location in the third case was not specified. The intracranial hemorrhage in 1 patient whose CT had shown it prior to thrombolytic treatment did not enlarge after thrombolysis, and cleared in follow-up neuroimaging. In the other patient, treatment was complicated by fatal systemic and intracranial bleeding. Extracranial sites of hemorrhages were reported on 5 occasions (19.2%), and they included cutaneous puncture sites (n = 3; 11.5%), epistaxis and diffuse ecchymotic lesions [n = 1 (3.8%) each]. Blood transfusion was required in 1 case (3.8%). One of the 2 patients who presented with intracranial hemorrhage associated with clinical deterioration and death was also the one who presented with extracranial bleeding (cutaneous puncture sites), which required a blood transfusion. Therefore, overall, there were 8 hemorrhagic complications in 7 patients (26.9%), 2 of them intracranial and fatal (7.7%). There were no other complications reported.
Table 4. Comparison of results between systematic reviews for thrombolysis in acute CVT (n/N)
Case characteristics
Clinical syndrome Isolated intracranial hypertension syndrome Encephalopathy Coma Deep cerebral venous system thrombosis Sinus occlusion One Multiple Hemorrhagic lesions on CT/MRI prior to thrombolytic treatment Hemorrhagic complications of thrombolytic treatment Intracranial hemorrhage Severe intracranial hemorrahge Extracranial hemorrhage Severe extracranial hemorrhage Recanalization Partial Complete mRS score at last available follow-up 0–1 2 3–5 6
Canhão et al. [28]
Our study
local thrombolysis
systemic thrombolysis
systemic thrombolysis
18/134 (13) 64/134 (48) 43/134 (32) 41/134 (31)
4/16 (25) 9/16 (56) 2/16 (13) 3/16 (23)
7/26 (26.9) 17/26 (65.4) 2/26 (7.7) 5/26 (19.2)
48/131 (37) 83/131 (63) 39/120 (33)
8/16 (50) 8/16 (51) 2/5 (40)
14/26 (53.8) 12/26 (46.2) 2/26 (7.7)
16/97 (16) 5/97 (5) 10/97 (20) 2/97 (2)
1/9 (11) – 4/9 (44) –
3/26 (11.5) 2/26 (7.7) 5/26 (19.2) 1/26 (3.8)
61/132 (46) 64/132 (48)
4/15 (26) 6/15 (40)
6/26 (23.1) 10/26 (38.5)
64/89 (71.9) 14/89 (15.7) 3/89 (3.4) 8/89 (9)
9/11 (81.8) 1/11 (9.1) 0/11 (0) 1/11 (9.1)
20/25 (80) 2/25 (8) 1/25 (4) 2/25 (8)
available evidence and extracted as many individual data as possible. Another problem is related to variation in the intervention under study, as criteria for using systemic thrombolysis, as well as the type, duration and dose of thrombolytic agent were not the same in all patients. An additional limitation is the large range of publication years, which may explain the long delays in diagnosis and onset of treatment in cases reported on before MRI became widely available and the diagnosis of dural sinus thrombosis was routinely considered in suspected cases. Finally, a possible confounding factor in measuring the effect of thrombolytics is that several cases were also exposed to other treatments that may affect outcome, such as anticoagulant therapy, osmotherapy, antiepileptic drugs and antibiotics. It is possible that those interventions may increase the real magnitude of effects of thrombolysis, making treatment effects appear stronger than they actually are.
Currently, the ongoing TO-ACT (Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis) Trial [30], a multicenter, prospective, randomized, open-label, blinded endpoint trial, aims to determine whether endovascular thrombolysis improves the functional outcome of patients with a severe form of CVT, in comparison with standard therapy with therapeutic doses of heparin. Considering that there is a greater experience concerning the local route of administration, it is not surprising that this was the one selected for being tested in a randomized clinical trial. Nevertheless, there are potential advantages of noninvasive systemic treatment over direct endovascular thrombolysis, especially in mild cases, where the latter might be too invasive. Systemic thrombolysis is a more feasible and available route. According to our study, it seems to be reasonably safe, although its efficacy cannot be assessed from the published information, mainly because of the lack of a control group.
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Values in parentheses denote percentages. n = Number of cases with each characteristic; N = total number of cases on which information was available.
References
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