Original Paper Received: June 11, 2014 Accepted: July 29, 2014 Published online: November 1, 2014
Eur Neurol 2015;73:37–43 DOI: 10.1159/000366200
Post-Thrombolysis Hemorrhage Risk of Unruptured Intracranial Aneurysms Fujian Chen a Shenqiang Yan b Xinchun Jin b Chen Lin c Jin Cao b
c
Department of Neurology, the People’s Hospital of Anji, Huzhou, and Departments of b Neurology and Surgical Oncology, the 2nd Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, PR China
Key Words Thrombolysis · Aneurysm · Ischemic stroke · Hemorrhage
Abstract Background/Aims: It has been questioned whether patients with unruptured intracranial aneurysms (IAs) are at a greater risk for the development of intracerebral hemorrhage (ICH) following thrombolytic therapy. We thus performed a meta-analysis to better quantify the risk of post-thrombolysis ICH in patients with acute ischemic stroke and incidental IAs. Methods: We searched PubMed, Web of Science and EMBASE for studies assessing ICH risk in patients with acute ischemic stroke treated with thrombolysis, in relation to the presence of pretreatment IAs. A fixed-effects model metaanalysis was performed. Results: We identified four studies totaling 707 participants receiving intravenous thrombolysis. The prevalence of unruptured IAs was 6.8%. Pooled analysis demonstrates relative risk (RR) for the presence of unruptured IAs and the development of any ICH to be 1.204 (95% CI 0.709–2.043; p = 0.492; I2 = 0.0%). The RR for sICH is 1.645 (95% CI 0.453–5.970; p = 0.449; I2 = 28.1%). Conclusion: Intravenous thrombolysis was safe among patients with acute ischemic stroke and incidental unruptured IAs. Future prospective studies with much larger sample sizes are required to clarify the significance of the association between pre-existing unruptured IAs and the development of © 2014 S. Karger AG, Basel post-thrombolysis ICH.
© 2014 S. Karger AG, Basel 0014–3022/14/0732–0037$39.50/0 E-Mail [email protected] www.karger.com/ene
Introduction
Intravenous thrombolysis is currently the only effective licensed treatment for acute ischemic stroke [1]. One of the complications of thrombolytic therapy that is of great concern is bleeding, especially intracranial hemorrhage (ICH). Symptomatic ICH (sICH) occurs in about 2.4–10% of cases within 24–36 h (depending on the different definitions) after thrombolysis [2]. It is important to take into account the risk of post-thrombolysis ICH with or without thrombolysis, as well as the risk of neurological deficit due to cerebral infarction in individuals. The main predictors of clinically significant ICH were age, clinical stroke severity, as assessed by the National Institute of Health Stroke Scale (NIHSS) score [3] on admission, high blood pressure, hyperglycemia, early ischemic CT changes, large baseline diffusion lesion volume and white matter hyperintensities (leukoaraiosis) on MRI, but there is still no reliable way to predict severe ICH [2]. Traditionally, patients with unruptured intracranial aneurysms (IAs) were deemed ineligible due to a theoretical increased risk of ICH from post-thrombolytic rupture of aneurysm. Although anecdotal case reports have indicated IAs might rupture following intravenous or arterial thrombolysis for acute ischemic stroke, a small number of nonrandomized observational researches are yet to produce a statistically significant association [4–7]. Shenqiang Yan, MD Department of Neurology, the 2nd Affiliated Hospital of Zhejiang University School of Medicine, #88 Jiefang Road Hangzhou 310009 (PR China) E-Mail shenqiangyan @ yahoo.com
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a
As all of these studies were confounded by small sample sizes, the safety of thrombolysis in acute ischemic stroke patients with unruptured IAs remains presently unknown. We therefore performed a meta-analysis to assess the evidence whether pre-existing unruptured IAs resulted in an increased risk of ICH and/or sICH in acute ischemic stroke patients receiving thrombolytic therapy.
Data Analysis We used a fixed-effects model (Mantel and Haenszel method) to calculate the pooled relative risk (RR) of any ICH and sICH in patients with versus without unruptured IAs, where weights were calculated using the inverse variance method. Since adjusted data were not available, raw outcome data were used to yield unadjusted RRs. Subgroup analysis was performed to isolate patients with saccular IAs. Statistical heterogeneity was assessed using Isquared and x-squared statistics. Publication bias was evaluated with Egger’s test, Begg’s test and the funnel plot. All statistical analysis was performed with Stata 11.2 (StataCorp LP, Tex., USA).
Material and Methods
Search Strategy We searched appropriate articles by systematic queries of NCBI (PubMed), ISI Web of Science and EMBASE databases on the 10th of April 2014, using the following search terms: ‘aneurysm(s)’ in association with ‘thrombolysis’ or ‘thrombolyses’ or ‘thrombolytic’ or ‘fibrinolysis’ or ‘fibrinolyses’ or ‘fibrinolytic’ or ‘tissue plasminogen activator’ or ‘rt(-)PA’ or ‘t(-)PA’ or ‘alteplase’. Papers not published in English and case reports were excluded. The references of all identified publications were reviewed for any additional studies not indexed. We contacted authors when there were questions regarding their studies. Two authors (F.C. and X.J.) identified potentially relevant studies, resolving any uncertainties with a third author (S.Y.). Eligibility Criteria Randomized controlled trials or controlled observational studies (retrospective or prospective) were eligible for inclusion if they had assessed ICH risk in patients with acute ischemic stroke treated with thrombolysis, and quantified this risk in relation to the presence of unruptured IAs. Articles were included if they met the following criteria: provided information on the methodology of thrombolytic therapy; ascertainment of ICH based on neuroimaging and/or autopsy with clinical evidence of deterioration on neurological examination as part of the definition for sICH; and imaging type for IA identification (CTA or MRA or conventional angiography). Outcome measures of interest were any postthrombolysis ICH and/or sICH. Study Selection and Data Extraction Two authors (F.C. and X.J.) considered all titles and abstracts for eligibility in a systematic manner, and went through all articles selected as relevant and extracted data independently. We extracted information on the study design, the number and demographics of participants (including age and sex), clinical stroke severity (assessed by NIHSS), imaging type for IA identification, follow-up period, number of participants with unruptured IAs, number of participants with the outcome event (any ICH or sICH defined according to standard criteria) and the characteristics of IAs (type, location and size) by using a unified data form. Discrepancies were resolved by consensus. Authors of the included articles were contacted for data needing clarification.
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Eur Neurol 2015;73:37–43 DOI: 10.1159/000366200
Results
We identified 2,341 articles of PubMed, 1,061 of Web of Science and 4,846 of EMBASE in our initial search. Articles numbering 8,205 were excluded after reviewing titles and abstracts, then 23 articles were excluded due to duplicated titles, and 14 case reports and 2 reviews were also excluded. Finally, four studies (all published) met our predetermined criteria, and were pooled in a meta-analysis [9–12]. The characteristics of included studies are summarized in table 1. All studies used intravenous thrombolysis. Each study had a follow-up schedule that included both neuroimaging and clinical assessment using the NIHSS. Three studies defined sICH according to the ECASS II criteria [9, 10, 12], that is, ICH associated with at least a four-point worsening on the NIHSS [13, 14], and the remaining one according to the NINDS criteria [11], that is, ICH associated with at least a one-point worsening on the NIHSS within 36 h of thrombolysis [15]. The main source of bias within all the studies was the lack of adjusted data. Only one study indicated that patients with and without IAs were significantly different in age and gender [12]. Sheth et al. also reported some other risk factors for sICH, including atrial fibrillation and MRI-based infarct volume [11]. Study demographics are summarized in table 2. Collectively, the four studies were composed of 707 patients (study sample size range: 105–236), 48 (6.8%) of which had unruptured IAs. The characteristics of IAs are summarized in table 3. Forty patients had saccular aneurysms, seven patients had fusiform aneurysms, and one patient had a multilobulated aneurysm. In addition, four patients had multiple aneurysms. The location of aneurysms was as follows: the internal carotid artery (n = 18), middle cerebral artery (n = 8), anterior cerebral artery (n = 3), anterior communicating artery (n = 7), posterior communicating artery (n = 9), vertebral artery (n = 3), basilar artery (n = 1), superior cerebellar artery (n = 1) and ophChen/Yan/Jin/Lin/Cao
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We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [8].
Table 1. Characteristics of included studies Study; country
Design
Inclusion criteria
Edwards et al. [9], 2012; US
Retrospective, (1) Acute ischemic stroke two centers within 4.5 h (2) CT/MRI along with CTA/MRA before thrombolysis (3) CT/MRI within 24–36 h
Imaging for IA Treatment Follow-up identification schedule
Outcome measures
Definition of sICH
CTA/MRA
(1) Any ICH (2) sICH (3) SAH
ICH with clinical NA decompensation as measured by an increase in the NIHSS of at least 4 points [14]
IV tPA, CT/MRI 0.9 mg/kg within 24–36 h
Other risk factors for sICH
Kim et al. Retrospective, (1) Acute ischemic stroke CTA or MRA IV tPA or conventional [10], 2012; single center within 3 h angiography Korean (2) CTA or MRI/A or conventional angiography within 24–36 h (3) follow-up CT 5–7 days after the onset
(1) HT (any ICH) (1) CTA or MRI/A within (2) sICH (3) SAH 24–36 h (2) CT 5–7 days after the onset
NA ICH associated with an increase in the NIHSS score of 4 points or more according to the ECASS II criteria [14]
Sheth et al. Retrospective, (1) Acute ischemic stroke CTA/MRA [11], 2012; single center (2) CTA/MRA at any point during their admission US
NA
(1) Any ICH (2) sICH (3) In-hospital mortality
sICH was defined according to the NINDS criteria [15]
a 24-hour CT scan
(1) any ICH (2) sICH (3) SAH (4) In-hospital mortality (5) 3-month mRS
NA sICH was classified according to the ECASS II criteria [13]
IV tPA
Mittal Retrospective, (1) Acute ischemic stroke 85 with MRA, IV tPA 19 with CTA, et al. [12], multi center (2) CTA or MRA or 2013; US conventional angiography 1 with catheter arteriography
Atrial fibrillation, MRI-based infarct volume
IA = Intracranial aneurysm; sICH = symptomatic intracranial hemorrhage; IV = intravenous; tPA = tissue plasminogen activator; SAH = subarachnoid hemorrhage; NIHSS = National Institute of Health Stroke Scale; ECASS = Second European-Australasian Acute Stroke Study; NINDS = National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group; NA = information not provided.
Table 2. Study demographics and outcomes
Study
Edwards et al. [9]
Kim et al. [10]
Sheth et al. [11]
Mittal et al. [12]
Total
Population size Mean age (years) Male (%) IA prevalence (%) Baseline NIHSS Any ICH (%) sICH (%) SAH (%)
236 74# 40.9# 22 (9.3) 12 (mean)# 44 (18.6) 10 (4.2) 13 (5.5)
194 69.5 60.8 7 (3.6)& 11.6 (mean)# 66 (34.0) NA 2 (1.0)
172 62.4 47.1 8 (4.7) 12 (median), range 6–17 35 (20.3) 7 (4.1) NA
105 69 56.2 11 (10.5)* 8 (mean) 11 (10.5) 2 (1.9) 0 (0.0)
707 48 (6.8) 156 (22.1) 3.7 2.8
Thrombolysis with Intracranial Aneurysms
Eur Neurol 2015;73:37–43 DOI: 10.1159/000366200
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IA = Intracranial aneurysm; NIHSS = National Institute of Health Stroke Scale; sICH = symptomatic intracranial hemorrhage; SAH = subarachnoid hemorrhage; NA = information not provided. # Data only provided in the patients with IAs. & Eight reported, 1 excluded (pseudoaneurysm rather than an aneurysm). * 1 patient with a fusiform IA was also included.
Table 3. Characteristics of the intracranial aneurysms
Study
Edwards et al. [9]
Kim et al. [10]
Sheth et al. [11]
Mittal et al. [12]
Type
18 saccular, 4 fusiform
5 saccular, 1 fusiform, 1 multilobulated#
7 saccular, 1 fusiform
10 saccular, 1 fusiform
Multiple aneurysms
2 (1 saccular and 1 fusiform)
none
none
2
Location (including each in patient with multiple aneurysms)
11 in ICA, 4 in MCA, 1 in ACA, 2 in A-com, 4 in P-com, 2 in VA, 1 in BA, 1 in ophthalmic artery
2 in ICA, 1 in MCA, 1 in A-com, 2 in P-com, 1 in SCA
3 in ICA, 2 in ACA, 1 in VA, 2 in ophthalmic artery
2 in ICA, 3 in MCA, 4 in A-com, 3 in P-com
Size (mm) Mean Range
3.6 1.0–8.0
4.5 2.3–8.0
6.3 1.5–26.0
3.2 2.0–7.0
Any ICH (%)
3 (13.6)
3 (42.8)
3 (37.5)
2 (18.2)
sICH (%)
0 (0.0)
1 (14.3)
1 (12.5)
1 (9.1)
SAH (%)
1 (4.5)
0 (0.0)
NA
0 (0.0)
ICA = Internal carotid artery; MCA = middle cerebral artery; ACA = anterior cerebral artery; A-com = anterior communicating artery; P-com = posterior communicating artery; VA = vertebral artery; BA = basilar artery; SCA = superior cerebellar artery; sICH = symptomatic intracranial hemorrhage; SAH = subarachnoid hemorrhage; NA = information not provided. # Eight reported, 1 excluded (pseudoaneurysm rather than an aneurysm).
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Eur Neurol 2015;73:37–43 DOI: 10.1159/000366200
IAs (RR = 1.343, 95% CI 0.774–2.332; p = 0.294; I2 = 0.0%). sICH occurred in 5.7% of patients with saccular IAs in comparison to 3.6% of patients without IAs (RR = 1.944, 95% CI 0.535–7.066; p = 0.312; I2 = 23.1%).
Discussion
Our systematic review and meta-analysis in 707 patients with acute ischemic stroke shows that the presence of unruptured IAs is not associated with a statistically significant increased risk of any ICH (p = 0.492) or sICH (0.449) following intravenous thrombolysis. Aneurysmal SAH is a rare complication after intravenous thrombolysis in the acute ischemic stroke patients with pre-existing unruptured IAs. Only a few patients had fusiform IAs; thus, we also performed a subgroup analysis excluding patients with fusiform IAs and found similar results. As few of the studies within the analysis were designed to determine long-term clinical outcome measures [12], whether preexisting unruptured IA is a marker of poor functional outcome remains uncertain. In the general population, the prevalence of IAs is anywhere from 3–6% [16], and may be more common among patients with ischemic stroke because aneurysms are of a Chen/Yan/Jin/Lin/Cao
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thalmic artery (n = 3). One patient with a pseudoaneurysm was excluded from this meta-analysis [10]. Among patients with IAs, 11/48 (22.9%) experienced any ICH after intravenous thrombolysis, compared to 145/659 (22.0%) patients without IAs. Pooled analysis demonstrates RR for the presence of unruptured IAs and the development of any post-thrombolysis ICH to be 1.204 (95% CI 0.709–2.043; p = 0.492) with no evidence of statistical heterogeneity (I2 = 0.0%) (fig. 1). There was no evidence of a publication bias either from the result of Egger’s test (p = 0.952) or Begg’s test (p = 1.000), and the shape of the funnel plot seemed symmetrical (fig. 2). Three studies were used to calculate the pooled RR of sICH [9, 11, 12], as Kim et al. did not report the sICH rate in the patients without IAs [10]. sICH developed in 3.7% of the included subjects and occurred in 4.9% of patients with IAs in comparison with 3.6% of patients without IAs. The RR for the presence of unruptured IAs and the development of sICH is 1.645 (95% CI 0.453–5.970; p = 0.449) with a low level of statistical heterogeneity (I2 = 28.1%) (fig. 3). Only one patient with IA was reported to develop subarachnoid hemorrhage (SAH) [9]. In subgroup analysis that only included saccular aneurysms, any ICH occurred in 25.0% of patients with saccular IAs in comparison with 22.0% of patients without
Study
Fig. 1. Meta-analysis of the association be-
tween intracerebral hemorrhage risk in patients with acute ischemic stroke treated with intravenous thrombolysis, in relation to the presence of preexisting unruptured intracranial aneurysms.
%
ID
RR (95% CI)
Weight
Edwards (2012)
0.71 (0.24, 2.11)
44.83
Kim (2012)
1.27 (0.53, 3.06)
26.66
Sheth (2012)
1.92 (0.75, 4.95)
17.46
Mittal (2013)
1.90 (0.47, 7.69)
11.06
Overall (I2 = 0.0%, p = 0.521)
1.20 (0.71, 2.04)
100.00
Heterogeneity chi2 = 2.26 (d.f. = 3) p = 0.521 0.13
1
7.69
2
logrr
1
0
–1
Fig. 2. Publication bias from studies about
0
the association between intracerebral hemorrhage risk and the presence of preexisting unruptured intracranial aneurysms.
0.2
0.4
0.6
0.8
s.e. of: logrr
Study
tween symptomatic intracerebral hemorrhage risk in patients with acute ischemic stroke treated with intravenous thrombolysis, in relation to the presence of preexisting unruptured intracranial aneurysms.
Thrombolysis with Intracranial Aneurysms
RR (95% CI)
% Weight
Edwards (2012)
0.45 (0.03, 7.35)
72.55
Sheth (2012)
3.42 (0.46, 25.11)
19.95
Mittal (2013)
8.55 (0.57, 127.22) 7.49
Overall (I2 = 28.1%, p = 0.249)
1.64 (0.45, 5.97)
100.00
Heterogeneity chi2 = 2.78 (d.f. = 2) p = 0.249 0.00786
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Fig. 3. Meta-analysis of the association be-
ID
higher occurrence in older patients and also because smoking and hypertension are risk factors for both conditions. About 3.6–10.5% stroke patients receiving intravenous thrombolysis were noted to have IAs within the analysis population. Usually, IAs could be preexisting without treatment, or treated by clipping or embolization, or diagnosed by multimodal imaging during the onset of stroke. Strict universal exclusion of all these patients with IAs might prohibit some patients from reaping the benefit of thrombolytic therapy. The presence of an incidental unruptured aneurysm is listed as an exclusion from thrombolysis in guidelines [17]. Recently, only four retrospective studies have reported on the risk of ICH following thrombolysis for acute ischemic stroke in patients screened for IAs [9–12]. Unruptured IAs are significantly more likely to rupture in women, old age, posterior circulation, and large size [18, 19]. There has been one report of anterior communicating artery aneurysm rupture after intravenous tPA for acute ischemic stroke [5]. However, this case might have had a sentinel bleed from an IA before the onset of stroke symptoms. Another aneurysm rupture after thrombolysis was diagnosed with acute myocardial infarction and received 100 mg of tPA and heparin perfusion [6]. Recently, Haji et al. firstly reported a patient with multiple unruptured IAs suffered massive (and ultimately fatal) SAH following intravenous tPA [4]. Furthermore, one case also showed that intra-arterial thrombolysis may have additional risk of hemorrhages especially when aneurysm was hidden by the occluding clot [7]. Some unruptured IAs were located within the symptomatic territory of ischemic lesion. The proposed mechanisms for stroke secondary to unruptured non-giant IAs included dislodgement of aneurysm thrombi to distal vessels, extension of aneurysm clot into the parent vessel and parent vessel occlusion due to extrinsic compression by the thrombosed aneurysm [20].
Our study had several limitations. First, our analysis had inherent biases associated with the use of observational studies. All studies are subject to selection bias since not all acute stroke patients undergo angiography, and such patients were excluded. However, there was no randomized controlled trial evaluating the risks and benefits of thrombolytic therapy in the patients with IAs so far. Second, the use of unadjusted data rendered our analysis vulnerable to confounding variables. Some studies did not provide full information of some baseline characteristics likely to be important for thrombolysisrelated ICH. Third, the outcome definitions for sICH were not standardized among the studies included, which might relate to the difference of sICH rates [21]. Fortunately, all included sICH were found to be associated with clinical deterioration and thus likely to be clinically relevant. With the exception of one patient with a giant aneurysm (26 mm, developed sICH without IA rupture) [11], all aneurysms were ≤8 mm in diameter. Thus, a conclusion that intravenous thrombolysis was safe among patients with acute ischemic stroke and incidental unruptured IAs ≤8 mm in diameter seemed more cautious. Future prospective studies with much larger sample sizes are required to clarify the significance of the association between pre-existing unruptured IAs and the development of post-thrombolysis ICH. Additionally, the association between pre-existing unruptured IAs and the development of post-thrombolysis ICH in acute ischemic stroke patients receiving intra-arterial thrombolysis needs further investigation. Acknowledgments We thank Dr. Alejandro A. Rabinstein (Department of Neurology, Mayo Clinic, Rochester, Minn., USA) for providing detailed information about their research.
1 Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995; 333: 1581– 1587. 2 Derex L, Nighoghossian N: Intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: an update. J Neurol Neurosurg Psychiatry 2008;79:1093–1099. 3 Brott T, Adams HP Jr, Olinger CP, et al: Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989;20:864–870.
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4 Haji F, van Adel B, Avery M, Megyesi J, Young GB: Intracranial aneurysm rupture following intravenous thrombolysis for stroke. Can J Neurol Sci 2014;41:95–98. 5 Rammos SK, Neils DM, Fraser K, Klopfenstein JD: Anterior communicating artery aneurysm rupture after intravenous thrombolysis for acute middle cerebral artery thromboembolism: case report. Neurosurgery 2012; 70:E1603–E1607; discussion E1607. 6 Lagares A, Gomez PA, Lobato RD, Alen JF, Campollo J, Benito-Leon J: Cerebral aneu-
rysm rupture after r-TPA thrombolysis for acute myocardial infarction. Surg Neurol 1999;52:623–626. 7 Ritter MA, Kloska S, Konrad C, Droste DW, Heindel W, Ringelstein EB: Rupture of a thrombosed intracranial aneurysm during arterial thrombolysis. J Neurol 2003;250: 1255– 1256. 8 Moher D, Liberati A, Tetzlaff J, Altman DG: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535.
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References
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13 Hacke W, Kaste M, Fieschi C, et al: Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995; 274: 1017–1025. 14 Hacke W, Kaste M, Fieschi C, et al: Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet 1998; 352: 1245– 1251. 15 Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. The NINDS t-PA Stroke Study Group. Stroke 1997; 28: 2109–2118. 16 Vlak MH, Algra A, Brandenburg R, Rinkel GJ: Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol 2011; 10:626–636.
Eur Neurol 2015;73:37–43 DOI: 10.1159/000366200
17 De Keyser J, Gdovinova Z, Uyttenboogaart M, Vroomen PC, Luijckx GJ: Intravenous alteplase for stroke: beyond the guidelines and in particular clinical situations. Stroke 2007; 38:2612–2618. 18 Wiebers DO, Whisnant JP, Sundt TM Jr, O’Fallon WM: The significance of unruptured intracranial saccular aneurysms. J Neurosurg 1987;66:23–29. 19 Wiebers DO, Whisnant JP, Huston J 3rd, et al: Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 2003; 362:103–110. 20 Cohen JE, Gomori JM, Leker RR: Thrombosis of non-giant unruptured aneurysms causing ischemic stroke. Neurol Res 2010;32:971–974. 21 Seet RC, Rabinstein AA: Symptomatic intracranial hemorrhage following intravenous thrombolysis for acute ischemic stroke: a critical review of case definitions. Cerebrovasc Dis 2012;34:106–114.
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9 Edwards NJ, Kamel H, Josephson SA: The safety of intravenous thrombolysis for ischemic stroke in patients with pre-existing cerebral aneurysms: a case series and review of the literature. Stroke 2012; 43: 412– 416. 10 Kim JT, Park MS, Yoon W, Cho KH: Detection and significance of incidental unruptured cerebral aneurysms in patients undergoing intravenous thrombolysis for acute ischemic stroke. J Neuroimaging 2012; 22: 197–200. 11 Sheth KN, Shah N, Morovati T, Hermann LD, Cronin CA: Intravenous rt-PA is not associated with increased risk of hemorrhage in patients with intracranial aneurysms. Neurocrit Care 2012;17:199–203. 12 Mittal MK, Seet RC, Zhang Y, Brown RD Jr, Rabinstein AA: Safety of intravenous thrombolysis in acute ischemic stroke patients with saccular intracranial aneurysms. J Stroke Cerebrovasc Dis 2013;22:639–643.
Eur Neurol 2015;73:37–43 DOI: 10.1159/000366200
Post-Thrombolysis Hemorrhage Risk of Unruptured Intracranial Aneurysms Fujian Chen a Shenqiang Yan b Xinchun Jin b Chen Lin c Jin Cao b
c
Department of Neurology, the People’s Hospital of Anji, Huzhou, and Departments of b Neurology and Surgical Oncology, the 2nd Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, PR China
Key Words Thrombolysis · Aneurysm · Ischemic stroke · Hemorrhage
Abstract Background/Aims: It has been questioned whether patients with unruptured intracranial aneurysms (IAs) are at a greater risk for the development of intracerebral hemorrhage (ICH) following thrombolytic therapy. We thus performed a meta-analysis to better quantify the risk of post-thrombolysis ICH in patients with acute ischemic stroke and incidental IAs. Methods: We searched PubMed, Web of Science and EMBASE for studies assessing ICH risk in patients with acute ischemic stroke treated with thrombolysis, in relation to the presence of pretreatment IAs. A fixed-effects model metaanalysis was performed. Results: We identified four studies totaling 707 participants receiving intravenous thrombolysis. The prevalence of unruptured IAs was 6.8%. Pooled analysis demonstrates relative risk (RR) for the presence of unruptured IAs and the development of any ICH to be 1.204 (95% CI 0.709–2.043; p = 0.492; I2 = 0.0%). The RR for sICH is 1.645 (95% CI 0.453–5.970; p = 0.449; I2 = 28.1%). Conclusion: Intravenous thrombolysis was safe among patients with acute ischemic stroke and incidental unruptured IAs. Future prospective studies with much larger sample sizes are required to clarify the significance of the association between pre-existing unruptured IAs and the development of © 2014 S. Karger AG, Basel post-thrombolysis ICH.
© 2014 S. Karger AG, Basel 0014–3022/14/0732–0037$39.50/0 E-Mail [email protected] www.karger.com/ene
Introduction
Intravenous thrombolysis is currently the only effective licensed treatment for acute ischemic stroke [1]. One of the complications of thrombolytic therapy that is of great concern is bleeding, especially intracranial hemorrhage (ICH). Symptomatic ICH (sICH) occurs in about 2.4–10% of cases within 24–36 h (depending on the different definitions) after thrombolysis [2]. It is important to take into account the risk of post-thrombolysis ICH with or without thrombolysis, as well as the risk of neurological deficit due to cerebral infarction in individuals. The main predictors of clinically significant ICH were age, clinical stroke severity, as assessed by the National Institute of Health Stroke Scale (NIHSS) score [3] on admission, high blood pressure, hyperglycemia, early ischemic CT changes, large baseline diffusion lesion volume and white matter hyperintensities (leukoaraiosis) on MRI, but there is still no reliable way to predict severe ICH [2]. Traditionally, patients with unruptured intracranial aneurysms (IAs) were deemed ineligible due to a theoretical increased risk of ICH from post-thrombolytic rupture of aneurysm. Although anecdotal case reports have indicated IAs might rupture following intravenous or arterial thrombolysis for acute ischemic stroke, a small number of nonrandomized observational researches are yet to produce a statistically significant association [4–7]. Shenqiang Yan, MD Department of Neurology, the 2nd Affiliated Hospital of Zhejiang University School of Medicine, #88 Jiefang Road Hangzhou 310009 (PR China) E-Mail shenqiangyan @ yahoo.com
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a
As all of these studies were confounded by small sample sizes, the safety of thrombolysis in acute ischemic stroke patients with unruptured IAs remains presently unknown. We therefore performed a meta-analysis to assess the evidence whether pre-existing unruptured IAs resulted in an increased risk of ICH and/or sICH in acute ischemic stroke patients receiving thrombolytic therapy.
Data Analysis We used a fixed-effects model (Mantel and Haenszel method) to calculate the pooled relative risk (RR) of any ICH and sICH in patients with versus without unruptured IAs, where weights were calculated using the inverse variance method. Since adjusted data were not available, raw outcome data were used to yield unadjusted RRs. Subgroup analysis was performed to isolate patients with saccular IAs. Statistical heterogeneity was assessed using Isquared and x-squared statistics. Publication bias was evaluated with Egger’s test, Begg’s test and the funnel plot. All statistical analysis was performed with Stata 11.2 (StataCorp LP, Tex., USA).
Material and Methods
Search Strategy We searched appropriate articles by systematic queries of NCBI (PubMed), ISI Web of Science and EMBASE databases on the 10th of April 2014, using the following search terms: ‘aneurysm(s)’ in association with ‘thrombolysis’ or ‘thrombolyses’ or ‘thrombolytic’ or ‘fibrinolysis’ or ‘fibrinolyses’ or ‘fibrinolytic’ or ‘tissue plasminogen activator’ or ‘rt(-)PA’ or ‘t(-)PA’ or ‘alteplase’. Papers not published in English and case reports were excluded. The references of all identified publications were reviewed for any additional studies not indexed. We contacted authors when there were questions regarding their studies. Two authors (F.C. and X.J.) identified potentially relevant studies, resolving any uncertainties with a third author (S.Y.). Eligibility Criteria Randomized controlled trials or controlled observational studies (retrospective or prospective) were eligible for inclusion if they had assessed ICH risk in patients with acute ischemic stroke treated with thrombolysis, and quantified this risk in relation to the presence of unruptured IAs. Articles were included if they met the following criteria: provided information on the methodology of thrombolytic therapy; ascertainment of ICH based on neuroimaging and/or autopsy with clinical evidence of deterioration on neurological examination as part of the definition for sICH; and imaging type for IA identification (CTA or MRA or conventional angiography). Outcome measures of interest were any postthrombolysis ICH and/or sICH. Study Selection and Data Extraction Two authors (F.C. and X.J.) considered all titles and abstracts for eligibility in a systematic manner, and went through all articles selected as relevant and extracted data independently. We extracted information on the study design, the number and demographics of participants (including age and sex), clinical stroke severity (assessed by NIHSS), imaging type for IA identification, follow-up period, number of participants with unruptured IAs, number of participants with the outcome event (any ICH or sICH defined according to standard criteria) and the characteristics of IAs (type, location and size) by using a unified data form. Discrepancies were resolved by consensus. Authors of the included articles were contacted for data needing clarification.
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Results
We identified 2,341 articles of PubMed, 1,061 of Web of Science and 4,846 of EMBASE in our initial search. Articles numbering 8,205 were excluded after reviewing titles and abstracts, then 23 articles were excluded due to duplicated titles, and 14 case reports and 2 reviews were also excluded. Finally, four studies (all published) met our predetermined criteria, and were pooled in a meta-analysis [9–12]. The characteristics of included studies are summarized in table 1. All studies used intravenous thrombolysis. Each study had a follow-up schedule that included both neuroimaging and clinical assessment using the NIHSS. Three studies defined sICH according to the ECASS II criteria [9, 10, 12], that is, ICH associated with at least a four-point worsening on the NIHSS [13, 14], and the remaining one according to the NINDS criteria [11], that is, ICH associated with at least a one-point worsening on the NIHSS within 36 h of thrombolysis [15]. The main source of bias within all the studies was the lack of adjusted data. Only one study indicated that patients with and without IAs were significantly different in age and gender [12]. Sheth et al. also reported some other risk factors for sICH, including atrial fibrillation and MRI-based infarct volume [11]. Study demographics are summarized in table 2. Collectively, the four studies were composed of 707 patients (study sample size range: 105–236), 48 (6.8%) of which had unruptured IAs. The characteristics of IAs are summarized in table 3. Forty patients had saccular aneurysms, seven patients had fusiform aneurysms, and one patient had a multilobulated aneurysm. In addition, four patients had multiple aneurysms. The location of aneurysms was as follows: the internal carotid artery (n = 18), middle cerebral artery (n = 8), anterior cerebral artery (n = 3), anterior communicating artery (n = 7), posterior communicating artery (n = 9), vertebral artery (n = 3), basilar artery (n = 1), superior cerebellar artery (n = 1) and ophChen/Yan/Jin/Lin/Cao
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We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [8].
Table 1. Characteristics of included studies Study; country
Design
Inclusion criteria
Edwards et al. [9], 2012; US
Retrospective, (1) Acute ischemic stroke two centers within 4.5 h (2) CT/MRI along with CTA/MRA before thrombolysis (3) CT/MRI within 24–36 h
Imaging for IA Treatment Follow-up identification schedule
Outcome measures
Definition of sICH
CTA/MRA
(1) Any ICH (2) sICH (3) SAH
ICH with clinical NA decompensation as measured by an increase in the NIHSS of at least 4 points [14]
IV tPA, CT/MRI 0.9 mg/kg within 24–36 h
Other risk factors for sICH
Kim et al. Retrospective, (1) Acute ischemic stroke CTA or MRA IV tPA or conventional [10], 2012; single center within 3 h angiography Korean (2) CTA or MRI/A or conventional angiography within 24–36 h (3) follow-up CT 5–7 days after the onset
(1) HT (any ICH) (1) CTA or MRI/A within (2) sICH (3) SAH 24–36 h (2) CT 5–7 days after the onset
NA ICH associated with an increase in the NIHSS score of 4 points or more according to the ECASS II criteria [14]
Sheth et al. Retrospective, (1) Acute ischemic stroke CTA/MRA [11], 2012; single center (2) CTA/MRA at any point during their admission US
NA
(1) Any ICH (2) sICH (3) In-hospital mortality
sICH was defined according to the NINDS criteria [15]
a 24-hour CT scan
(1) any ICH (2) sICH (3) SAH (4) In-hospital mortality (5) 3-month mRS
NA sICH was classified according to the ECASS II criteria [13]
IV tPA
Mittal Retrospective, (1) Acute ischemic stroke 85 with MRA, IV tPA 19 with CTA, et al. [12], multi center (2) CTA or MRA or 2013; US conventional angiography 1 with catheter arteriography
Atrial fibrillation, MRI-based infarct volume
IA = Intracranial aneurysm; sICH = symptomatic intracranial hemorrhage; IV = intravenous; tPA = tissue plasminogen activator; SAH = subarachnoid hemorrhage; NIHSS = National Institute of Health Stroke Scale; ECASS = Second European-Australasian Acute Stroke Study; NINDS = National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group; NA = information not provided.
Table 2. Study demographics and outcomes
Study
Edwards et al. [9]
Kim et al. [10]
Sheth et al. [11]
Mittal et al. [12]
Total
Population size Mean age (years) Male (%) IA prevalence (%) Baseline NIHSS Any ICH (%) sICH (%) SAH (%)
236 74# 40.9# 22 (9.3) 12 (mean)# 44 (18.6) 10 (4.2) 13 (5.5)
194 69.5 60.8 7 (3.6)& 11.6 (mean)# 66 (34.0) NA 2 (1.0)
172 62.4 47.1 8 (4.7) 12 (median), range 6–17 35 (20.3) 7 (4.1) NA
105 69 56.2 11 (10.5)* 8 (mean) 11 (10.5) 2 (1.9) 0 (0.0)
707 48 (6.8) 156 (22.1) 3.7 2.8
Thrombolysis with Intracranial Aneurysms
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IA = Intracranial aneurysm; NIHSS = National Institute of Health Stroke Scale; sICH = symptomatic intracranial hemorrhage; SAH = subarachnoid hemorrhage; NA = information not provided. # Data only provided in the patients with IAs. & Eight reported, 1 excluded (pseudoaneurysm rather than an aneurysm). * 1 patient with a fusiform IA was also included.
Table 3. Characteristics of the intracranial aneurysms
Study
Edwards et al. [9]
Kim et al. [10]
Sheth et al. [11]
Mittal et al. [12]
Type
18 saccular, 4 fusiform
5 saccular, 1 fusiform, 1 multilobulated#
7 saccular, 1 fusiform
10 saccular, 1 fusiform
Multiple aneurysms
2 (1 saccular and 1 fusiform)
none
none
2
Location (including each in patient with multiple aneurysms)
11 in ICA, 4 in MCA, 1 in ACA, 2 in A-com, 4 in P-com, 2 in VA, 1 in BA, 1 in ophthalmic artery
2 in ICA, 1 in MCA, 1 in A-com, 2 in P-com, 1 in SCA
3 in ICA, 2 in ACA, 1 in VA, 2 in ophthalmic artery
2 in ICA, 3 in MCA, 4 in A-com, 3 in P-com
Size (mm) Mean Range
3.6 1.0–8.0
4.5 2.3–8.0
6.3 1.5–26.0
3.2 2.0–7.0
Any ICH (%)
3 (13.6)
3 (42.8)
3 (37.5)
2 (18.2)
sICH (%)
0 (0.0)
1 (14.3)
1 (12.5)
1 (9.1)
SAH (%)
1 (4.5)
0 (0.0)
NA
0 (0.0)
ICA = Internal carotid artery; MCA = middle cerebral artery; ACA = anterior cerebral artery; A-com = anterior communicating artery; P-com = posterior communicating artery; VA = vertebral artery; BA = basilar artery; SCA = superior cerebellar artery; sICH = symptomatic intracranial hemorrhage; SAH = subarachnoid hemorrhage; NA = information not provided. # Eight reported, 1 excluded (pseudoaneurysm rather than an aneurysm).
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IAs (RR = 1.343, 95% CI 0.774–2.332; p = 0.294; I2 = 0.0%). sICH occurred in 5.7% of patients with saccular IAs in comparison to 3.6% of patients without IAs (RR = 1.944, 95% CI 0.535–7.066; p = 0.312; I2 = 23.1%).
Discussion
Our systematic review and meta-analysis in 707 patients with acute ischemic stroke shows that the presence of unruptured IAs is not associated with a statistically significant increased risk of any ICH (p = 0.492) or sICH (0.449) following intravenous thrombolysis. Aneurysmal SAH is a rare complication after intravenous thrombolysis in the acute ischemic stroke patients with pre-existing unruptured IAs. Only a few patients had fusiform IAs; thus, we also performed a subgroup analysis excluding patients with fusiform IAs and found similar results. As few of the studies within the analysis were designed to determine long-term clinical outcome measures [12], whether preexisting unruptured IA is a marker of poor functional outcome remains uncertain. In the general population, the prevalence of IAs is anywhere from 3–6% [16], and may be more common among patients with ischemic stroke because aneurysms are of a Chen/Yan/Jin/Lin/Cao
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thalmic artery (n = 3). One patient with a pseudoaneurysm was excluded from this meta-analysis [10]. Among patients with IAs, 11/48 (22.9%) experienced any ICH after intravenous thrombolysis, compared to 145/659 (22.0%) patients without IAs. Pooled analysis demonstrates RR for the presence of unruptured IAs and the development of any post-thrombolysis ICH to be 1.204 (95% CI 0.709–2.043; p = 0.492) with no evidence of statistical heterogeneity (I2 = 0.0%) (fig. 1). There was no evidence of a publication bias either from the result of Egger’s test (p = 0.952) or Begg’s test (p = 1.000), and the shape of the funnel plot seemed symmetrical (fig. 2). Three studies were used to calculate the pooled RR of sICH [9, 11, 12], as Kim et al. did not report the sICH rate in the patients without IAs [10]. sICH developed in 3.7% of the included subjects and occurred in 4.9% of patients with IAs in comparison with 3.6% of patients without IAs. The RR for the presence of unruptured IAs and the development of sICH is 1.645 (95% CI 0.453–5.970; p = 0.449) with a low level of statistical heterogeneity (I2 = 28.1%) (fig. 3). Only one patient with IA was reported to develop subarachnoid hemorrhage (SAH) [9]. In subgroup analysis that only included saccular aneurysms, any ICH occurred in 25.0% of patients with saccular IAs in comparison with 22.0% of patients without
Study
Fig. 1. Meta-analysis of the association be-
tween intracerebral hemorrhage risk in patients with acute ischemic stroke treated with intravenous thrombolysis, in relation to the presence of preexisting unruptured intracranial aneurysms.
%
ID
RR (95% CI)
Weight
Edwards (2012)
0.71 (0.24, 2.11)
44.83
Kim (2012)
1.27 (0.53, 3.06)
26.66
Sheth (2012)
1.92 (0.75, 4.95)
17.46
Mittal (2013)
1.90 (0.47, 7.69)
11.06
Overall (I2 = 0.0%, p = 0.521)
1.20 (0.71, 2.04)
100.00
Heterogeneity chi2 = 2.26 (d.f. = 3) p = 0.521 0.13
1
7.69
2
logrr
1
0
–1
Fig. 2. Publication bias from studies about
0
the association between intracerebral hemorrhage risk and the presence of preexisting unruptured intracranial aneurysms.
0.2
0.4
0.6
0.8
s.e. of: logrr
Study
tween symptomatic intracerebral hemorrhage risk in patients with acute ischemic stroke treated with intravenous thrombolysis, in relation to the presence of preexisting unruptured intracranial aneurysms.
Thrombolysis with Intracranial Aneurysms
RR (95% CI)
% Weight
Edwards (2012)
0.45 (0.03, 7.35)
72.55
Sheth (2012)
3.42 (0.46, 25.11)
19.95
Mittal (2013)
8.55 (0.57, 127.22) 7.49
Overall (I2 = 28.1%, p = 0.249)
1.64 (0.45, 5.97)
100.00
Heterogeneity chi2 = 2.78 (d.f. = 2) p = 0.249 0.00786
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Fig. 3. Meta-analysis of the association be-
ID
higher occurrence in older patients and also because smoking and hypertension are risk factors for both conditions. About 3.6–10.5% stroke patients receiving intravenous thrombolysis were noted to have IAs within the analysis population. Usually, IAs could be preexisting without treatment, or treated by clipping or embolization, or diagnosed by multimodal imaging during the onset of stroke. Strict universal exclusion of all these patients with IAs might prohibit some patients from reaping the benefit of thrombolytic therapy. The presence of an incidental unruptured aneurysm is listed as an exclusion from thrombolysis in guidelines [17]. Recently, only four retrospective studies have reported on the risk of ICH following thrombolysis for acute ischemic stroke in patients screened for IAs [9–12]. Unruptured IAs are significantly more likely to rupture in women, old age, posterior circulation, and large size [18, 19]. There has been one report of anterior communicating artery aneurysm rupture after intravenous tPA for acute ischemic stroke [5]. However, this case might have had a sentinel bleed from an IA before the onset of stroke symptoms. Another aneurysm rupture after thrombolysis was diagnosed with acute myocardial infarction and received 100 mg of tPA and heparin perfusion [6]. Recently, Haji et al. firstly reported a patient with multiple unruptured IAs suffered massive (and ultimately fatal) SAH following intravenous tPA [4]. Furthermore, one case also showed that intra-arterial thrombolysis may have additional risk of hemorrhages especially when aneurysm was hidden by the occluding clot [7]. Some unruptured IAs were located within the symptomatic territory of ischemic lesion. The proposed mechanisms for stroke secondary to unruptured non-giant IAs included dislodgement of aneurysm thrombi to distal vessels, extension of aneurysm clot into the parent vessel and parent vessel occlusion due to extrinsic compression by the thrombosed aneurysm [20].
Our study had several limitations. First, our analysis had inherent biases associated with the use of observational studies. All studies are subject to selection bias since not all acute stroke patients undergo angiography, and such patients were excluded. However, there was no randomized controlled trial evaluating the risks and benefits of thrombolytic therapy in the patients with IAs so far. Second, the use of unadjusted data rendered our analysis vulnerable to confounding variables. Some studies did not provide full information of some baseline characteristics likely to be important for thrombolysisrelated ICH. Third, the outcome definitions for sICH were not standardized among the studies included, which might relate to the difference of sICH rates [21]. Fortunately, all included sICH were found to be associated with clinical deterioration and thus likely to be clinically relevant. With the exception of one patient with a giant aneurysm (26 mm, developed sICH without IA rupture) [11], all aneurysms were ≤8 mm in diameter. Thus, a conclusion that intravenous thrombolysis was safe among patients with acute ischemic stroke and incidental unruptured IAs ≤8 mm in diameter seemed more cautious. Future prospective studies with much larger sample sizes are required to clarify the significance of the association between pre-existing unruptured IAs and the development of post-thrombolysis ICH. Additionally, the association between pre-existing unruptured IAs and the development of post-thrombolysis ICH in acute ischemic stroke patients receiving intra-arterial thrombolysis needs further investigation. Acknowledgments We thank Dr. Alejandro A. Rabinstein (Department of Neurology, Mayo Clinic, Rochester, Minn., USA) for providing detailed information about their research.
1 Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995; 333: 1581– 1587. 2 Derex L, Nighoghossian N: Intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: an update. J Neurol Neurosurg Psychiatry 2008;79:1093–1099. 3 Brott T, Adams HP Jr, Olinger CP, et al: Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989;20:864–870.
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4 Haji F, van Adel B, Avery M, Megyesi J, Young GB: Intracranial aneurysm rupture following intravenous thrombolysis for stroke. Can J Neurol Sci 2014;41:95–98. 5 Rammos SK, Neils DM, Fraser K, Klopfenstein JD: Anterior communicating artery aneurysm rupture after intravenous thrombolysis for acute middle cerebral artery thromboembolism: case report. Neurosurgery 2012; 70:E1603–E1607; discussion E1607. 6 Lagares A, Gomez PA, Lobato RD, Alen JF, Campollo J, Benito-Leon J: Cerebral aneu-
rysm rupture after r-TPA thrombolysis for acute myocardial infarction. Surg Neurol 1999;52:623–626. 7 Ritter MA, Kloska S, Konrad C, Droste DW, Heindel W, Ringelstein EB: Rupture of a thrombosed intracranial aneurysm during arterial thrombolysis. J Neurol 2003;250: 1255– 1256. 8 Moher D, Liberati A, Tetzlaff J, Altman DG: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535.
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References
Thrombolysis with Intracranial Aneurysms
13 Hacke W, Kaste M, Fieschi C, et al: Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995; 274: 1017–1025. 14 Hacke W, Kaste M, Fieschi C, et al: Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet 1998; 352: 1245– 1251. 15 Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. The NINDS t-PA Stroke Study Group. Stroke 1997; 28: 2109–2118. 16 Vlak MH, Algra A, Brandenburg R, Rinkel GJ: Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol 2011; 10:626–636.
Eur Neurol 2015;73:37–43 DOI: 10.1159/000366200
17 De Keyser J, Gdovinova Z, Uyttenboogaart M, Vroomen PC, Luijckx GJ: Intravenous alteplase for stroke: beyond the guidelines and in particular clinical situations. Stroke 2007; 38:2612–2618. 18 Wiebers DO, Whisnant JP, Sundt TM Jr, O’Fallon WM: The significance of unruptured intracranial saccular aneurysms. J Neurosurg 1987;66:23–29. 19 Wiebers DO, Whisnant JP, Huston J 3rd, et al: Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 2003; 362:103–110. 20 Cohen JE, Gomori JM, Leker RR: Thrombosis of non-giant unruptured aneurysms causing ischemic stroke. Neurol Res 2010;32:971–974. 21 Seet RC, Rabinstein AA: Symptomatic intracranial hemorrhage following intravenous thrombolysis for acute ischemic stroke: a critical review of case definitions. Cerebrovasc Dis 2012;34:106–114.
43
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9 Edwards NJ, Kamel H, Josephson SA: The safety of intravenous thrombolysis for ischemic stroke in patients with pre-existing cerebral aneurysms: a case series and review of the literature. Stroke 2012; 43: 412– 416. 10 Kim JT, Park MS, Yoon W, Cho KH: Detection and significance of incidental unruptured cerebral aneurysms in patients undergoing intravenous thrombolysis for acute ischemic stroke. J Neuroimaging 2012; 22: 197–200. 11 Sheth KN, Shah N, Morovati T, Hermann LD, Cronin CA: Intravenous rt-PA is not associated with increased risk of hemorrhage in patients with intracranial aneurysms. Neurocrit Care 2012;17:199–203. 12 Mittal MK, Seet RC, Zhang Y, Brown RD Jr, Rabinstein AA: Safety of intravenous thrombolysis in acute ischemic stroke patients with saccular intracranial aneurysms. J Stroke Cerebrovasc Dis 2013;22:639–643.
