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Acute Ischemic Stroke Treatment in Infective Endocarditis: Systematic Review
ARTICLE IN PRESS
Acute Ischemic Stroke Treatment in Infective Endocarditis: Systematic Review Sofia Bettencourt, MD,* and Jose M Ferro, MD, PhD*,† Background: Ischemic stroke is a frequent neurologic complication of infective endocarditis. This systematic review aims to evaluate the efficacy and safety of thrombectomy in comparison to thrombolysis and to combined treatment in patients with infective endocarditis associated acute ischemic stroke. Methods: A systematic literature review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The review included case reports, cases series, cross-sectional studies, case control studies, randomized controlled trials or nonrandomized controlled trials, which reported the treatment of endocarditis-related acute ischemic stroke with mechanical thrombectomy, intravenous or intra-arterial thrombolysis in adult patients. Data sources: Scielo, b-on, Pubmed and Cochrane, from inception to April 2019. Reference lists were also checked. We compared the efficacy (independence, neurological improvement) and safety (intracranial bleeding, death) of acute ischemic stroke treatment with thrombolysis, thrombectomy and combined therapy. Results: Through systematic review 37 articles describing 52 patients met criteria. The risk of intracranial hemorrhage was 4.14 times higher in patients treated with intravenous thrombolysis (P = .001) and 4.67 times higher in patients treated with combined treatment (P = .01). There was trend for independence (P = .09) and neurological improvement (P = .07) in favor of thrombectomy, when comparing this group to the group treated with intravenous thrombolysis. Conclusions: With the limitation of the low quality of the available evidence, thrombectomy in infective endocarditis associated stroke appears to be safer than thrombolysis, or combined treatment. These results may be useful to guide clinical decisions, in selected patients. Key Words: Ischemic stroke—infective endocarditis—thrombolysis— thrombectomy—cerebral embolism—acute stroke treatment © 2019 Elsevier Inc. All rights reserved.
Introduction Neurological events are one of the most common extra cardiac complications of infective endocarditis, affecting between 25% to 70% of the patients.1,2 Acute ischemic stroke is the most common neurological complication of infective endocarditis, manifesting clinically in almost 40% of these patients and it is frequently associated with high morbidity and
From the *Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; and †Department of Neurosciences and Mental Health, Servi¸c o de Neurologia, Hospital Santa Maria/Centro Hospitalar Lisboa Norte, Lisboa, Portugal. Received September 30, 2019; revision received December 7, 2019; accepted December 9, 2019. Address correspondence to Sofia Bettencourt, Servi¸c o de Neurologia, 6th floor, Hospital de Santa Maria, 1649-028 Lisboa, Portugal. E-mails: sofi[email protected], sofi[email protected]. 1052-3057/$ - see front matter © 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.104598
mortality. 3,2 It typically affects the middle artery in more than 40% of the cases. 3,4 Intravenous recombinant tissue plasminogen activator (rt-PA) is recommended for selected patients who may be treated within 4.5 hours after stroke onset.5,6 Mechanical thrombectomy is recommended in ischemic stroke patients with large-artery occlusions.6,7 The safety and efficacy of intravenous (IV) and/or intra-arterial (IA) thrombolytic therapy in the management of ischemic stroke in the setting of infective endocarditis is not well established.1,2 There are some reports of an increased risk of intracranial hemorrhagic complications which may worsen clinical outcome.8,9 Thrombectomy appears to have a similar efficacy and less risk of serious bleeding than thrombolysis, but there are insufficient clinical observations to support robust recommendations. This systematic review aims to evaluate the efficacy and safety of thrombectomy in comparison to thrombolysis and to combined treatment (thrombolysis plus thrombectomy).
Journal of Stroke and Cerebrovascular Diseases, Vol. &&, No. && (&&), 2019: 104598
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ARTICLE IN PRESS S. BETTENCOURT AND J.M. FERRO
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Methods Protocol and guidance: The study protocol and methods of the systematic review followed PRISMA guidelines.10 Eligibility criteria: We included case reports, cases series, cross-sectional studies, case control studies, randomized controlled trials or nonrandomized controlled trials that reported the treatment of endocarditis-related acute ischemic stroke with mechanical thrombectomy, IV or IA thrombolysis or their combination, in adult patients (18 years old). Outcomes: Intracranial hemorrhage, National Institutes of Health Stroke Scale score (NIHSS) before and after treatment, functional independence according to the modified Rankin scale (mRS), dichotomized less than or equal to 2 and greater than 2, recanalization, and mortality. Information sources and search strategy: Systematic search of the reports published until April 2019, was conducted in Pubmed, Cochrane, Scielo and B-on for relevant articles. For the search strategy we combined the terms (stroke AND endocarditis) with (thrombolysis OR recombinant tissue plasminogen activator OR urokinase OR streptokinase) or (thrombectomy). We also did the same search, but without the word “stroke”. Only reports published in English, Spanish, French, and Portuguese were considered. Study selection: Title and abstracts of all retrieved articles were assessed for inclusion. For those meeting the eligibility criteria, full-text articles were obtained and reviewed by 2 observers. Reference lists of selected articles were also checked for any additional relevant studies not identified through the initial search. Discrepancies were solved by consensus. Data collection process: We extracted the following information from reports: age, gender, baseline National Institutes of Health stroke scale scores, site of arterial occlusion, mycotic aneurisms, whether or not the infective endocarditis was already suspected before the stroke treatment, modality of treatment, delay from stroke onset to treatment, length of follow up and other information to assess methodological quality. The outcomes of interest extracted were: recanalization, intracranial hemorrhage, NIHSS score after treatment, functional independence measured by the mRS and mortality. Whenever mRS was not provided we attributed mRS grades based on the clinical description presented on the article. Neurological improvement was defined as a decrease of at least 1 point on the NIHSS score or, if NIHSS was not available, the description of improvement of neurological symptoms in the article. Risk of bias in individual studies: The quality of the articles was examined according to the Quality Assessment Tool for Case Series Studies of National Heart, Lung, and Blood Institute and to the Case Reporting Guidelines of Care (2013). The length of follow-up was considered adequate whenever it was of at least 3 months. Data synthesis: We used 2 £ 2 tables statistics (Chi square and Fisher’s exact test) to compare the outcomes of
thrombectomy, intravenous (IV) thrombolysis and combined treatment (IV/intra-arterial thrombolysis plus thrombectomy). To compare continuous variables we used the median test. We assessed if there was a statistically significant difference of age and baseline NIHSS between treatment groups.
Results Study Selection The database search yielded 459 relevant records published until April 2019: B-on (n = 200), Cochrane (n = 6), Pubmed (n = 250), Scielo (n = 3); and other sources (n = 5). After duplicates were removed 202 articles were identified. After screening the titles and abstracts 41 were selected and were reviewed in full. Four of these articles were excluded due to: not mentioning stroke treatment (n = 2), not segregating patients treated with IV thrombolysis from those treated with combined treatment (n = 1), presenting aggregated results rather than individualpatient results (n = 1). Thirty seven articles were included (Fig 1).
Study Characteristics All the selected articles were case reports except for 3, single-center, retrospective, case series. All patients described were adults. We included 16 articles which used IV thrombolysis for the stroke treatment (Table 1)11-26 making a total of 18 patients. We only found 1 article in which the treatment modality was IA thrombolysis (Table 2).27 For thrombectomy we included 13 articles (Table 3),28-40 making a total of 22 patients. For combined treatment (Table 4)16,17,35,41-47 we identified 10 articles, making a total of 11 patients. Only 19 patients had a length of follow up that we considered in the methods as appropriate (12 weeks). The median age of the 16 patients with this information reported was 56 years old (interquartile range 20.3). In the group treated with thrombectomy the median age of the 20 patients was 67 years old (interquartile range 32). In what concerns to the group of patients treated with a combined treatment the median age of the 8 patients described was 40.5 years old (interquartile range 29.3). The median baseline NIHSS was 15 points (interquartile range 5) in the group treated with IV thrombolysis (1 score was not reported). In the group treated with thrombectomy (3 not reported) the median was 14 (interquartile range 5.5). In the group that used a combined treatment (all of the 11 scores reported) the median baseline NIHSS was 16 points (interquartile range 3). The most common site of occlusion (available for 73.1% cases, n = 38) was middle cerebral artery (n = 31, 81.6% of the cases with information). The maximal time from symptom onset to intravenous thrombolysis was of 3 hours19 and 5 hours to thrombectomy.29
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Figure 1. Study selection flow diagram.
Quality of Studies The overall quality was low among studies. Assessment of study quality was performed using the Quality Assessment Tool for Case Series Studies of National Heart, Lung, and Blood Institute and the Case Reporting Guidelines of Care checklist.
Synthesis of Results Outcomes concerning recanalization, neurological improvement, functional independence after treatment, identification of intracranial hemorrhage and mortality are summarized in Tables 1 to 3. Neurological worsening was stated as the cause of death in 5 patients, 3 treated with IV thrombolysis,16,23 and17 and 2 treated with combined treatment.17 All the other deaths had non-neurological causes or the cause was not reported. Only 1 case of IA thrombolysis treatment was described, so we did not include it in the statistical analysis (Table 5 and Table 6). We also did not include one of the patients of the combined treatment group16 because there was no indication on the article on the type of endovascular intervention performed. We did not compare the frequency of recanalization between groups once there were only 6 reported cases in the group treated with IV thrombolysis. There were no statistical significant differences of the median age and baseline NIHSS between treatment groups
(age P value = .16; NIHSS P value = .15 in both comparisons).The risk of an intracerebral hemorrhage was 4.14 times higher in the group treated with IV thrombolysis comparing to the group treated with thrombectomy (Table 5). There was also a higher risk of an intracerebral hemorrhage when comparing the group treated with combined treatment to the group treated with thrombectomy (Table 6). There was a trend for functional independence and for neurological improvement when comparing the group treated with thrombectomy to the group treated with IV thrombolysis. We did not perform a meta-analysis once there was only 1 article describing 6 or more patients and there were no randomized trials comparing or describing subjects treated with thrombectomy versus IV thrombolysis or combined treatment.
Discussion Our search did not found any randomized trials to study the efficacy and safety of thrombectomy in infective endocarditis related acute ischemic stroke. Moreover, there are very few reported cases of thrombolysis or mechanical thrombectomy in this setting, and the overall quality of the case series that have been published on this matter is low, with high risk of several types of bias. Based on 34 case reports and 3 single-center, retrospective, descriptive case series, we found that patients with
4
Table 1. Characteristics of patients with stroke and infective endocarditis treated with IV thrombolysis RecanalizMycotic IE suspected Modality of aneurisms treatment and delay ation from stroke onset
Site of occlusion
(11)
27
F
15
NR
(12)
70
M
13
M2/M3 of left MCA NR
(13)
68
M
12
Yes
(14)
56
M
15
M2 of left MCA NR
(15)
49
M
17
M1 of left MCA
NR
(16)
46
M
15
Right MCA
No
65
F
21
Left MCA
No
15
NR
NR
8
NR
NR NR
(17)
NR NR
No
NR
62
M
18
(19)
57
M
14
(20)
72
M
10
Supraclinoid segment of ICA M1 of left MCA NR
(21)
25
F
16
NR
NR
(22)
65
M
18
NR
No
(23)
51
M
22
NR
Yes
(24)
56
M
NR
NR
NR
NR NR
NR Yes NR NR
NIHSS 1 (6 mo later) NIHSS 5 (6 wk later) NIHSS 1 (7 mo later) NIHSS 4 (48 h later) -
Neurological ICH improvement
Mortality
Time of follow up (wk)
2 (6 mo later)
Yes
No
No
24
2 (6 wk later)
Yes
No
No
6
2 (7 mo later)
Yes
Yes
No
28
2 (9 mo later)
Yes
No
No
36
6
No
Yes
Septic shock with myocardial infarction 5 d later Yes
1
NR
-.
6
No
Yes
No
NR
4 (time NR)
Yes
Yes
No
NR
NR
5 (time NR)
No
Yes
No
NR
-
6 (time NR)
No
Yes
Yes
No
NR
3 (6 mo later)
Yes
No
No
24
No
NR
5 (time NR)
No
Yes
No
NR
NR
4 (9 wk later)
No
Yes
No
9
NR
NIHSS 12 (6 h later) -
6
No
Yes
IV rtPA 30 min
NR
NR
2 (at discharge)
Yes
No
IV rtPA 2 h
Yes
-
6
No
Yes
Yes
NA
rtPA (time NR)
NR
NR
0 (at discharge)
Yes
No
No
NR
PostIV rtPA (0,9 mg/ thrombolysis kg) 3 h PostIV rtPA 72 mg 90 thrombolysis min PostIV rtPA 1 h thrombolysis Postthrombolysis Postthrombolysis Postthrombolysis
NR
mRS
DIC 12 d after thrombolysis No
NR
NR
NA
8
S. BETTENCOURT AND J.M. FERRO
(18)
PostIV rtPA (0,9 mg/kg) thrombolysis 2:35 h PostIV rtPA (0,9 mg/kg) thrombolysis 2:30 h PostIV rtPA (0,9mg/kg) thrombolysis 2:15 h PostIV rtPA 2:36 h thrombolysis Post9mg bolus of IV thrombolysis rtPA (2:05 h) followed of an infusion of 81 mg. PostIV rtPA (0,9 thrombolysis mg/kg) 1:50 h PostIV rtPA (0,9 thrombolysis mg/kg) 2 h IV rtPA (time NR) Postthrombolysis PostIV rtPA (time NR) thrombolysis PostIV rtPA 40 min thrombolysis
Follow up NIHSS
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Source Age Gender Baseline NIHSS score
Source Age Gender Baseline NIHSS score
Site of occlusion
Mycotic IE suspected Modality of Recanalizaneurisms treatment and delay ation from stroke onset
(25)
36
M
10
NR
No
(26)
41
M
21
NR
NR
Postthrombolysis Postthrombolysis
IV Alteplase (0,9 mg/kg) 67 min IV rtPA 50 mg
Follow up NIHSS
mRS
Neurological ICH improvement
Mortality
Time of follow up (wk)
Yes
0 (24 h later) 2 (at discharge)
Yes
Yes
No
NR
NR
23 (24 h later)
No
No
No
1 year
NR
Abbreviations: DIC, disseminated intravascular coagulation; F, female; ICA, internal carotid artery; ICH, intracerebral hemorrhage; IE, infective endocarditis; IV, intravenous; MCA, middle cerebral artery; M-male, mRS- modified Rankin scale; NIHSS, National Institutes of Health stroke scale; NR, not reported; rtPA, recombinant tissue plasminogen activator.
Table 2. Characteristics of patients with stroke and infective endocarditis treated with IA thrombolysis Source Age Gender Baseline Site of Mycotic IE suspected NIHSS occlusion aneurisms score (27)
31
F
13
Basilar artery
No
Modality of treatment and delay from stroke onset
Prethrombolysis IA thrombolysis 5h
Recanalization Follow mRS up NIHSS
Yes
5 (3 wk later)
2 (3 wk later)
Neurological ICH Mortality Time of improvement follow up (wk) Yes
No
No
3
Abbreviations: F, female; IA, Intra-arterial; ICH, intracerebral hemorrhage; IE, Infective Endocarditis; mRS, modified Rankin scale; NIHSS, National Institutes of Health stroke scale.
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ISCHEMIC STROKE TREATMENT IN ENDOCARDITIS
Table 1 (Continued)
5
6
Table 3. Characteristics of patients with stroke and infective endocarditis treated with mechanical thrombectomy
(28)
67
F
NR
(29)
40
F
15
(30)
33
M
14
(31)
78
F
16
(32)
23
F
NR
(33)
40
NR
3
(34)
33
M
14
67
M
13
39
F
15
NR
NR
12
NR
NR
18
(36)
72
M
NR
Between segments M1 and M2 of left MCA M1 of the left MCA M1 of the left MCA M2 of the right MCA M1 of the right MCA M1 of the right MCA M1 of the left MCA M1 of the right MCA M2 of the left MCA M1 of the right MCA M2 of the MCA M2 of the left MCA
(37)
70
F
24
(38)
79
M
9
69
F
10
(35)
M2 of the left MCA M1+Carotid subocclusion
Basilar artery
Mycotic aneurisms
IE suspected
NR
Prethrombectomy
NR NR NR NR NR NR NR NR NR NR NR
No NR
NR
Modality of Recanaliza- Follow up NIHSS treatment and tion delay from stroke onset MT (time NR)
PrethromMT; 5 h bectomy PrethromMT; 2:30 h bectomy PrethromMT; 3 h bectomy PrethromMT bectomy (time NR) PrethromMT bectomy (time NR) PrethromMT (time NR) bectomy PostMT thrombectomy (time NR) PrethromMT bectomy (time NR) PrethromMT bectomy 130 min NR MT (time NR) PostMT thrombectomy (time NR) Prethrombectomy Prethrombectomy
MT (time NR) MT 135 min
Prethrombectomy
MT 255 min
mRS
Neurological ICH Mortality improvement
Time of follow up (wk)
Yes
-
6
No
No
Pulmonary embolism 1 wk later.
2
Yes
3 (48 h later) 0 (4 d later) 12 (24 h later) NR
Yes
No
No
12
Yes
No
No
NR
Yes
No
No
NR
No
No
No
6
Yes
No
No
2
Yes
No
No
12
Yes
No
No
NR
Yes
No
No
12
Yes
No
No
NR
Yes
No
No Pulmonary embolism 9 d after No
NA
Yes (cardiorespiratory arrest during MT) No
12
Yes
0 (13 d later) 1 (at discharge) 0 (mo later) 4 (at discharge) 1
Yes
5
2 (3 mo later) 1 (4 d later) 4 (24 h later) 3 (6 wk later) 0 (13 d later) 1 (3 mo later) 1 (mo later) 2 (3 mo later) 2 (at discharge) 2
-
6
No
No
NR
1
Yes
No
No
35 (24 h later)
6 (3 mo later)
No
No
Yes
2 (24 h later)
0 (3 mo later)
Yes
No
Yes Yes NR Yes Yes Yes Yes
Yes, but reoclusion 24 h later Yes
4d
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Site of occlusion
S. BETTENCOURT AND J.M. FERRO
Source Age Gender Baseline NIHSS score
Source Age Gender Baseline NIHSS score
(40)
Mycotic aneurisms
56
F
19
M1
NR
72
M
35
Basilar artery
NR
79
M
5
M1
NR
85
M
8
M1
NR
57
M
13
Right ICA
NR
66
M
15
Left ICA
70
F
10
Right ICA and right MCA
IE suspected
Prethrombectomy Postthrombectomy
Prethrombectomy Postthrombectomy
Modality of Recanaliza- Follow up NIHSS treatment and tion delay from stroke onset MT 140 min MT 190 min
Yes Yes
MT 100 min
Yes
MT 158 min
Yes
NR
MT 180 min
Yes
NR
NR
MT 110 min
Yes
NR
Prethrombectomy
MT (time NR)
Yes
mRS
Neurological ICH Mortality improvement
2 (24 h later) 35 (24 h later)
0 (3 mo later) 6 (3 mo later)
yes
No
No
No
2 (24h later) 0 (24 h later)
2 (3 mo later) 6 (3 mo later)
Yes
No
Yes
1 (3 mo later) 2 (3 mo later) 1 (3 mo later)
Yes
No Yes (died due to cardiac arrest 6 wk after stroke) No No
Yes
No
No
Yes
No
No
2 (postprocedural 8(postprocedural) 1(postprocedural)
Time of follow up (wk)
No Yes(after palliative care for multiple comorbid conditions) No
12
12
Abbreviations: F, female; ICA, internal carotid artery; ICH, intracerebral hemorrhage; IE, infective endocarditis; M, male, MCA, middle cerebral artery; MT, mechanical thrombectomy; mRS, modified Rankin scale; NIHSS, National Institutes of Health stroke scale; NR, not reported.
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(39)
Site of occlusion
ISCHEMIC STROKE TREATMENT IN ENDOCARDITIS
Table 3 (Continued)
7
8
Table 4. Characteristics of patients with stroke and infective endocarditis treated with combined treatment Site of occlusion
(41)
73
M
20
(42)
24
F
18
Right ICA, right M1 and A1 Left ICA and M1 of the MCA
(43)
39
F
16
(44)
42
M
(45)
36
(46)
Mycotic IE suspected aneurisms
Pretreatment
NR
Pretreatment
M1 of the MCA
NR
Post-treatment
3
M2 of the MCA
NR
Pretreatment
M
16
Right M1
NR
Post-treatment
31
M
18
Yes
Post-treatment
(47)
75
M
16
Right ICA bifurcation Right MCA
NR
Post-treatment
(16)
61
M
17
NR
No
Post-treatment
14
NR
14
NR
19
M1 of MCA
(17)
(35)
NR NR
NR
NR
NR
Post-treatment
Post-treatment
NR
NR
Recanalization
Thrombectomy + IA rtPA (10 mg) IA rtPA (4 mg) + mechanical thrombectomy + aspiration thrombectomy + ballon angioplasty IA Thromblolysis + Mechanical thrombectomy Mechanical thrombectomy +IA rtPA IV rtPA+Mechanical thrombectomy IV rtPA 96 min + MT 125 min IV rtPA + clot aspiration thrombectomy IV rtPA (0,9 mg/kg) 1:30 h + IA intervention IA rtPA + mechanical thrombectomy IV rtPA + mechanical thrombectomy IA rtPA + mechanical thrombectomy
Yes
0 (8 mo later) 0 (8 mo later)
Yes
No
No
32
Yes
2 (2 mo later) 2 (2 mo later)
Yes
No
No
8
Yes
3 (1 mo later) 2 (1 mo later)
Yes
No
No
4
Yes
0 (4 wk later) 0 (4 wk later)
Yes
No
No
8
Yes
2 (24 h later)
Yes
No
No
NR
Yes
Yes
No
12
Yes
Follow up NIHSS
mRS
1 (5 d later) 0 (48 h later) 0 (3 mo later)
Neurological ICH Mortality Time of improvement Follow up (wk)
Yes
NA
6 (few d later)
NA
Yes
NR
NR
4 (time NR)
Yes
Yes
Yes (septic shock) No
NR
-
6
No
Yes
Yes
NR
-
6
No
Yes
Yes
Yes
17
5 (time NR)
Yes
No
No
NA
NR
NA
NR
Abbreviations: F, female; IA, intra-arterial, ICA, internal carotid artery; ICH, intracerebral hemorrhage; IE, infective endocarditis; M, male; mRS, modified Rankin scale; NIHSS, National Institutes of Health stroke scale; NR, not reported; rtPA, recombinant tissue plasminogen activator.
S. BETTENCOURT AND J.M. FERRO
No
Modality of treatment and delay from stroke onset
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Source Age Gender Baseline NIHSS score
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Table 5. Comparison between patients treated with IV thrombolysis and patients treated with thrombectomy Parameter (Median) ICH Neurological improvement mRS Mortality
Yes No Yes No 2 >2 Yes No
IV thrombolysis
Thrombectomy
11 7 9 9 7 10 5 13
0 22 17 5 15 7 5 17
P value
Risk ratio
Risk difference
.00
4.14
75.86%
.07
.54
29.67%
.09
.54
27.01%
.49
-
-
Abbreviations: ICH, intracerebral hemorrhage; mRS, modified Rankin scale; NIHSS, National Institutes of Health stroke scale.
Table 6. Comparison between patients treated with thrombectomy and patients treated with combined treatment Parameter (median) ICH Neurological improvement mRS Mortality
Yes No Yes No 2 >2 Yes No
Thrombectomy
Combined treatment
0 22 17 5 15 7 5 17
4 6 7 2 6 4 3 7
P value
Risk ratio
Risk difference
.01
4.67
78.57%
.68
-
-
.47
-
-
.49
-
-
Abbreviations: ICH, intracerebral hemorrhage; mRS, modified Rankin scale; NIHSS, National Institutes of Health stroke scale.
endocarditis related acute ischemic stroke were more likely to suffer an intracerebral hemorrhage when treated with IV thrombolysis or combined treatment comparing to patients that were treated with thrombectomy alone. In fact, there were no intracranial hemorrhages reported in any patient treated with thrombectomy, while 61% of patients treated with IV thrombolysis and 45% of patients treated with combined treatment suffered an intracranial hemorrhage after stroke treatment. The odds of having an intracranial hemorrhage was 4 times higher in patients treated with IV thrombolysis or combined treatment comparing to patients treated with thrombectomy. Besides that there was also a trend towards more frequent independence and neurological improvement in patients who were treated with thrombectomy comparing to patients treated with IV thrombolysis. In our review, 68.2% of patients treated with thrombectomy became functionally independent. Mechanical thrombectomy has showed a significant benefit comparing to IV thrombolysis in patients with acute ischemic stroke of the large intracerebral vessels.48 In this review, the most common site of occlusion in infective endocarditis associated ischemic stroke was middle cerebral artery (81.6%). Although mycotic aneurisms are thought to be one of the causes that makes patients with infective endocarditis related stroke more prone to intracranial hemorrhage after IV thrombolysis, they are infrequent, being found in less than 3% of the cases.3,16 In this systematic review there
were only 3 cases of intracranial hemorrhage in whom mycotic aneurisms were detected. IV thrombolysis was used in 2 patients and combined treatment in the third. They all suffered intracranial bleedings, indicating that thrombolysis is unsafe in patients with mycotic aneurysms. As thrombectomy is decided only after computed tomography (CT) angiography, this technique can also be helpful to rule out mycotic aneurisms. Moreover, the pathologic confirmation of the retrieved clots may also confirm the diagnosis of suspected endocarditis.30,29,39 In our study from the 28 patients who were treated with thrombectomy (with or without associated thrombolysis) 14 had a pathologic or microbiologic analysis of the specimen, with the majority reporting the presence of fibrinoid or necrotic material with inflammatory cells and gram positive cocci. DNA sequences of Tropheryma Whipplei were identified in 1 article40 and Candida Parapsilosis in an immunosuppressed patient.46 Besides the confirmation of infective endocarditis the results from microbiologic analysis of the specimens may be helpful to guide directed antibiotic therapy at an early stage. Limitations of our study are related to the low quality of the studies and the small number of cases which could be retrieved. There were no randomized controlled trials, the sample size was low in the majority of the studies, follow up was too short or not reported and outcome results were not always presented in objective scales. There is also a potential publication bias in favor of cases with favorable outcomes. The fact that all the patients treated with IV
ARTICLE IN PRESS S. BETTENCOURT AND J.M. FERRO
10
thrombolysis were diagnosed with infective endocarditis after stroke treatment while the majority of those treated with trombectomy were diagnosed previously to the treatment is an additional limitation to our study. For instance, patients diagnosed with infective endocarditis before stroke treatment could already be under antibiotic treatment, making the 2 groups very different. This limitation imposes that our results should be interpreted with caution.
Implications for Clinical Practice The results of this systematic review favor the use of thrombectomy rather than IV thrombolysis or combined treatment, as a safer option for patients with infective endocarditis associated stroke.
Implications for Research A randomized controlled trial comparing thrombectomy versus IV thrombolysis and with combined treatment is unlikely to be feasible. A prospective multicenter registry of acute treatments for infective endocarditis associated stroke with blinded and objective assessment of neurological outcomes and longer follow up could add considerable information regarding the safety and efficacy of the different modalities of acute stroke treatment.
Conclusion Our systematic review suggests that thrombectomy is a safer treatment option than IV thrombolysis or combined treatment for patients with infective endocarditis related stroke.
Conflict of Interest There is no conflicts of interest.
References 1. Morris NA, Matiello M, Lyons JL, et al. Neurologic complications in infective endocarditis: identification, management, and impact on cardiac surgery. Neurohospitalist 2014;4:213-222. 2. Sotero F, Rosario M, Fonseca A, et al. Neurological complications of infective endocarditis. Curr Neurol Neurosci Rep 2019;19:23. 3. Sonneville R, Mourvillier B, Bouadma L, et al. Management of neurological complications of infective endocarditis in ICU patients. Ann Intensive Care 2011;1:10. 4. Ferro J, Fonseca A. Infective endocarditis. In: Biller Jose, Ferro Jose M, eds. Handbook of Clinical Neurology, Elsevier; 2014;119:75-91. 5. Ringleb P, Bousser M, Ford J, et al. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008;25:457-507. 6. Powers W, Rabinstein A, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2018;49:e46-e110.
7. Turc G, Bhogal P, Fischer U, et al. European Stroke Organisation (ESO) European Society for Minimally Invasive Neurological Therapy (ESMINT) Guidelines on Mechanical Thrombectomy in Acute Ischaemic Stroke. Eur Stroke J 2019;4:6-12. 8. Novya E, Sonnevillae R, Mazighib M, et al. Neurological complications of infective endocarditis: new breakthroughs in diagnosis and management. Medecine et maladies infectieuses 2013;43:443-450. 9. Asaithambi G, Adil M, Qureshi A. Thrombolysis for ischemic stroke associated with infective endocarditis results from the nationwide inpatient sample. Stroke 2013;44:2917-2919. 10. Liberati A, Altman D, Tetzlaff J. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009;339:b2700. https://doi. org/10.1136/bmj.b2700. 11. Brownlee W, Anderson N, Barber P. Intravenous Thrombolysis is unsafe in stroke due to infective endocarditis. Intern Med J 2013;44:195-197. 195-7. 12. Sontineni S, Mooss A, Andukuri V, et al. Effectiveness of thrombolytic therapy in acute embolic stroke due to infective endocarditis. Stroke Res Treat 2010;2010:841797. https://doi.org/10.4061/2010/841797. 13. Ong E, Mechtouff L, Bernard E, et al. Thrombolysis for stroke caused by infective endocarditis: an illustrative case and review of the literature. J Neurol 2013;260:1339-1342. 14. Junna M, Lin C, Espinosa R, et al. Successful intravenous thrombolysis in ischemic stroke caused by infective endocarditis. Neurocrit Care 2007;6:117-120. 15. Fuentes Fern andez I, Morales Ortíz A, Sanmartín Monz o J, et al. Fatal outcome following thrombolysis for stroke secondary to infectious endocarditis. Neurología 2016;31:421-423. 16. Bhuva P, Kuo S, Hemphill J, et al. Intracranial Hemorrhage Following Thrombolytic Use for Stroke Caused by Infective Endocarditis. Neurocrit Care 2010;12:79-82. 17. Walker K, Sampson J, Skalabrin E, et al. Clinical characteristics and thrombolytic outcomes of infective endocarditis-associated stroke. Neurohospitalist 2012;2:87-91. 18. Jung J, Park M, Kwon D, et al. Safety of intravenous thrombolysis in embolic stroke by infective endocarditis. Neurology Asia 2013;18:209-211. 19. Tversky S, Libman R, Schloss E, et al. Catastrophic intracranial hemorrhages after IV tPA in a patient with insidious onset of fever and back pain. J Stroke Cerebrovasc Dis 2016;25:e69-e70. 20. Vales M, García-Pastor A, V azquez-Alen P, et al. Intravenous thrombolysis in ischemic stroke caused by infective endocarditis: a dangerous combination. Revista de Neurología 2016;62:426-428. 21. Silva F, Diaz G, Rodríguez V, et al. Neurological complications of infective endocarditis: controversies. Revista Colombiana de Cardiología 2011;18:212-219. 22. Ashkanani A, Bitar Z, Maadrani O. Acute stroke thrombolysis in infective endocarditis. SAGE Open Med Case Rep 2018;6:2050313X18807629. https://doi.org/10.1177/ 2050313X18807629. 23. Glenn J, Strecker-McGraw M, McGraw I, et al. Rupture of an occult intracranial mycotic aneurysm after intravenous thrombolysis with recombinant tissue plasminogen activator for acute ischemic stroke. J Emerg Med 2017;53(5):717-721. 24. Ren B, Lasam G. A rare case of native mitral valve bacillus cereus endocarditis culminating into a cerebrovascular infarction. Cardiol Res 2018;9(3):173-175.
ARTICLE IN PRESS ISCHEMIC STROKE TREATMENT IN ENDOCARDITIS 25. Miran M, Roering L, Maud A, et al. Thrombolytic use in acute ischemic stroke patients with concurrent infective endocarditis: emphasis on history, physical exam, outcomes, and review of literature. J Neurol Transl Neurosci 2017;5:1077. 26. Li W, Chen Y, Wann S. Lactococcus garvieae endocarditis with initial presentation of acute cerebral infarction in a healthy immunocompetent man. Intern Med 2008;47: 1143-1146. 27. Siccoli M, Benninger D, Schuknechtb B, et al. Successful intra-arterial thrombolysis in basilar thrombosis secondary to infectious endocarditis. Cerebrovasc Dis 2003; 16:295-297. 28. Dababneh H, Hedna S, Ford J, et al. Endovascular intervention for acute stroke due to infective endocarditis. Neurosurg Focus 2012;32(2):1-4. https://doi.org/10.3171/2011.11. FOCUS11263. E1. 29. Kim J, Jeon J, Kim Y, et al. Forced arterial suction thrombectomy of septic embolic middle cerebral artery occlusion due to infective endocarditis: an illustrative case and review of the literature. Neurointervention 2014;9:101-105. 30. Sukumaran S, Jayadevan ER, Mandilya A, et al. Successful mechanical thrombectomy of acute middle cerebral artery occlusion due to vegetation from infective endocarditis. Neurol India 2012;60:23. 31. Kan P, Webb S, Siddiqui A, et al. First reported use of retrievable stent technology for removal of a large septic embolus in the middle cerebral artery. World Neurosurg 2012;77:591. 32. Akkoyunlu Y, Iraz M, Kocaman G, et al. Abiotrophia defectiva endocarditis presenting with hemiplegia. Jundishapur J Microbiol 2013;6:e8907. 33. Ladner T, Davis B, He L, et al. Complex decision-making in stroke: preoperative mechanical thrombectomy of septic embolus for emergency cardiac valve surgery. J NeuroIntervent Surg 2015;7:e41. 34. Sveinsson O, Herrman L, Holmin S. Intra-arterial mechanical thrombectomy: an effective treatment for ischemic stroke caused by endocarditis. Case Reports in Neurology 2016;8:229-233. 35. Scharf EL, Chakraborty T, Rabinstein A, et al. Endovascular management of cerebral septic embolism: three recent cases and review of the literature. J NeuroIntervent Surg 2017;9:463-465. 36. Nishino W, Tajima Y, Inoue T, et al. Severe vasospasm of the middle cerebral artery after mechanical thrombectomy due to infective endocarditis: an autopsy case. J Stroke Cerebrovasc Dis 2017:30281
11 37. Liang J, Bishu K, Anavekar N. Infective endocarditis complicated by acute ischemic stroke from septic embolus: successful solitaire FR Thrombectomy. Cardiol Res 2012; 3:277-280. 38. Ambrosioni J, Urra X, Hern andez-Meneses M, et al. Mechanical thrombectomy for acute ischemic stroke secondary to infective endocarditis. Clin Infect Dis 2018;66 (8):1286-1289. 39. Hern andez-Fern andez F, Rojas-Bartolome L, García-García J, et al. Histopathological and bacteriological analysis of thrombus material extracted during mechanical thrombectomy in acute stroke patients. Cardiovasc Intervent Radiol 2017;40(12):1851-1860. 40. Elodie O, Labeyrie PE, Aubry M, et al. Whipple’s endocarditis diagnosed by thrombus analysis retrieved by successful mechanical thrombectomy. J Neurol Sci 2019; 400:42-43. 41. Toeg H, Al-Atassi T, Kalidindi N, et al. Endovascular treatment for cerebral septic embolic stroke. J Stroke Cerebrovasc Dis 2014;23:e375-e377. 42. Bain M, Hussain M, Gonugunta V, et al. Successful recanalization of a septic embolus with a balloon mounted stent after failed mechanical thrombectomy. J Neuroimaging 2011;21:170-172. 43. Kang G, Yang T, Choi J, et al. Effectiveness of mechanical embolectomy for septic embolus in the cerebral artery complicated with infective endocarditis. J Korean Med Sci 2013;28:1244-1247. 44. Bolognese M, Hessling A, Muller M. Successful thrombectomy in endocarditis-related stroke: case report and review of the literature. Interv Neuroradiol 2018;24 (5):529-532. 45. Bhaskar S, Cordato D, Cappelen-Smith C, et al. Clarion call for histopathological clot analysis in “cryptogenic” ischemic stroke: implications for diagnosis and treatment. Ann Clin Transl Neurology 2017;4(12):926-930. 46. Sgrecciaa A, Carit ab G, Coskunc O, et al. Acute ischemic stroke treated with mechanical thrombectomy and fungal endocarditis: A case report and systematic reviewof the literature. J Neuroradiol 2019. 47. Distefano M, Calandrelli R, Arena V, et al. A Puzzling Case of Cryptogenic Stroke. J Stroke Cerebrovasc Dis 2019;28(4):e33-e35. 48. Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. Lancet 2016;387(10029):1723-1731.
Acute Ischemic Stroke Treatment in Infective Endocarditis: Systematic Review Sofia Bettencourt, MD,* and Jose M Ferro, MD, PhD*,† Background: Ischemic stroke is a frequent neurologic complication of infective endocarditis. This systematic review aims to evaluate the efficacy and safety of thrombectomy in comparison to thrombolysis and to combined treatment in patients with infective endocarditis associated acute ischemic stroke. Methods: A systematic literature review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The review included case reports, cases series, cross-sectional studies, case control studies, randomized controlled trials or nonrandomized controlled trials, which reported the treatment of endocarditis-related acute ischemic stroke with mechanical thrombectomy, intravenous or intra-arterial thrombolysis in adult patients. Data sources: Scielo, b-on, Pubmed and Cochrane, from inception to April 2019. Reference lists were also checked. We compared the efficacy (independence, neurological improvement) and safety (intracranial bleeding, death) of acute ischemic stroke treatment with thrombolysis, thrombectomy and combined therapy. Results: Through systematic review 37 articles describing 52 patients met criteria. The risk of intracranial hemorrhage was 4.14 times higher in patients treated with intravenous thrombolysis (P = .001) and 4.67 times higher in patients treated with combined treatment (P = .01). There was trend for independence (P = .09) and neurological improvement (P = .07) in favor of thrombectomy, when comparing this group to the group treated with intravenous thrombolysis. Conclusions: With the limitation of the low quality of the available evidence, thrombectomy in infective endocarditis associated stroke appears to be safer than thrombolysis, or combined treatment. These results may be useful to guide clinical decisions, in selected patients. Key Words: Ischemic stroke—infective endocarditis—thrombolysis— thrombectomy—cerebral embolism—acute stroke treatment © 2019 Elsevier Inc. All rights reserved.
Introduction Neurological events are one of the most common extra cardiac complications of infective endocarditis, affecting between 25% to 70% of the patients.1,2 Acute ischemic stroke is the most common neurological complication of infective endocarditis, manifesting clinically in almost 40% of these patients and it is frequently associated with high morbidity and
From the *Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; and †Department of Neurosciences and Mental Health, Servi¸c o de Neurologia, Hospital Santa Maria/Centro Hospitalar Lisboa Norte, Lisboa, Portugal. Received September 30, 2019; revision received December 7, 2019; accepted December 9, 2019. Address correspondence to Sofia Bettencourt, Servi¸c o de Neurologia, 6th floor, Hospital de Santa Maria, 1649-028 Lisboa, Portugal. E-mails: sofi[email protected], sofi[email protected]. 1052-3057/$ - see front matter © 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.104598
mortality. 3,2 It typically affects the middle artery in more than 40% of the cases. 3,4 Intravenous recombinant tissue plasminogen activator (rt-PA) is recommended for selected patients who may be treated within 4.5 hours after stroke onset.5,6 Mechanical thrombectomy is recommended in ischemic stroke patients with large-artery occlusions.6,7 The safety and efficacy of intravenous (IV) and/or intra-arterial (IA) thrombolytic therapy in the management of ischemic stroke in the setting of infective endocarditis is not well established.1,2 There are some reports of an increased risk of intracranial hemorrhagic complications which may worsen clinical outcome.8,9 Thrombectomy appears to have a similar efficacy and less risk of serious bleeding than thrombolysis, but there are insufficient clinical observations to support robust recommendations. This systematic review aims to evaluate the efficacy and safety of thrombectomy in comparison to thrombolysis and to combined treatment (thrombolysis plus thrombectomy).
Journal of Stroke and Cerebrovascular Diseases, Vol. &&, No. && (&&), 2019: 104598
1
ARTICLE IN PRESS S. BETTENCOURT AND J.M. FERRO
2
Methods Protocol and guidance: The study protocol and methods of the systematic review followed PRISMA guidelines.10 Eligibility criteria: We included case reports, cases series, cross-sectional studies, case control studies, randomized controlled trials or nonrandomized controlled trials that reported the treatment of endocarditis-related acute ischemic stroke with mechanical thrombectomy, IV or IA thrombolysis or their combination, in adult patients (18 years old). Outcomes: Intracranial hemorrhage, National Institutes of Health Stroke Scale score (NIHSS) before and after treatment, functional independence according to the modified Rankin scale (mRS), dichotomized less than or equal to 2 and greater than 2, recanalization, and mortality. Information sources and search strategy: Systematic search of the reports published until April 2019, was conducted in Pubmed, Cochrane, Scielo and B-on for relevant articles. For the search strategy we combined the terms (stroke AND endocarditis) with (thrombolysis OR recombinant tissue plasminogen activator OR urokinase OR streptokinase) or (thrombectomy). We also did the same search, but without the word “stroke”. Only reports published in English, Spanish, French, and Portuguese were considered. Study selection: Title and abstracts of all retrieved articles were assessed for inclusion. For those meeting the eligibility criteria, full-text articles were obtained and reviewed by 2 observers. Reference lists of selected articles were also checked for any additional relevant studies not identified through the initial search. Discrepancies were solved by consensus. Data collection process: We extracted the following information from reports: age, gender, baseline National Institutes of Health stroke scale scores, site of arterial occlusion, mycotic aneurisms, whether or not the infective endocarditis was already suspected before the stroke treatment, modality of treatment, delay from stroke onset to treatment, length of follow up and other information to assess methodological quality. The outcomes of interest extracted were: recanalization, intracranial hemorrhage, NIHSS score after treatment, functional independence measured by the mRS and mortality. Whenever mRS was not provided we attributed mRS grades based on the clinical description presented on the article. Neurological improvement was defined as a decrease of at least 1 point on the NIHSS score or, if NIHSS was not available, the description of improvement of neurological symptoms in the article. Risk of bias in individual studies: The quality of the articles was examined according to the Quality Assessment Tool for Case Series Studies of National Heart, Lung, and Blood Institute and to the Case Reporting Guidelines of Care (2013). The length of follow-up was considered adequate whenever it was of at least 3 months. Data synthesis: We used 2 £ 2 tables statistics (Chi square and Fisher’s exact test) to compare the outcomes of
thrombectomy, intravenous (IV) thrombolysis and combined treatment (IV/intra-arterial thrombolysis plus thrombectomy). To compare continuous variables we used the median test. We assessed if there was a statistically significant difference of age and baseline NIHSS between treatment groups.
Results Study Selection The database search yielded 459 relevant records published until April 2019: B-on (n = 200), Cochrane (n = 6), Pubmed (n = 250), Scielo (n = 3); and other sources (n = 5). After duplicates were removed 202 articles were identified. After screening the titles and abstracts 41 were selected and were reviewed in full. Four of these articles were excluded due to: not mentioning stroke treatment (n = 2), not segregating patients treated with IV thrombolysis from those treated with combined treatment (n = 1), presenting aggregated results rather than individualpatient results (n = 1). Thirty seven articles were included (Fig 1).
Study Characteristics All the selected articles were case reports except for 3, single-center, retrospective, case series. All patients described were adults. We included 16 articles which used IV thrombolysis for the stroke treatment (Table 1)11-26 making a total of 18 patients. We only found 1 article in which the treatment modality was IA thrombolysis (Table 2).27 For thrombectomy we included 13 articles (Table 3),28-40 making a total of 22 patients. For combined treatment (Table 4)16,17,35,41-47 we identified 10 articles, making a total of 11 patients. Only 19 patients had a length of follow up that we considered in the methods as appropriate (12 weeks). The median age of the 16 patients with this information reported was 56 years old (interquartile range 20.3). In the group treated with thrombectomy the median age of the 20 patients was 67 years old (interquartile range 32). In what concerns to the group of patients treated with a combined treatment the median age of the 8 patients described was 40.5 years old (interquartile range 29.3). The median baseline NIHSS was 15 points (interquartile range 5) in the group treated with IV thrombolysis (1 score was not reported). In the group treated with thrombectomy (3 not reported) the median was 14 (interquartile range 5.5). In the group that used a combined treatment (all of the 11 scores reported) the median baseline NIHSS was 16 points (interquartile range 3). The most common site of occlusion (available for 73.1% cases, n = 38) was middle cerebral artery (n = 31, 81.6% of the cases with information). The maximal time from symptom onset to intravenous thrombolysis was of 3 hours19 and 5 hours to thrombectomy.29
ARTICLE IN PRESS ISCHEMIC STROKE TREATMENT IN ENDOCARDITIS
3
Figure 1. Study selection flow diagram.
Quality of Studies The overall quality was low among studies. Assessment of study quality was performed using the Quality Assessment Tool for Case Series Studies of National Heart, Lung, and Blood Institute and the Case Reporting Guidelines of Care checklist.
Synthesis of Results Outcomes concerning recanalization, neurological improvement, functional independence after treatment, identification of intracranial hemorrhage and mortality are summarized in Tables 1 to 3. Neurological worsening was stated as the cause of death in 5 patients, 3 treated with IV thrombolysis,16,23 and17 and 2 treated with combined treatment.17 All the other deaths had non-neurological causes or the cause was not reported. Only 1 case of IA thrombolysis treatment was described, so we did not include it in the statistical analysis (Table 5 and Table 6). We also did not include one of the patients of the combined treatment group16 because there was no indication on the article on the type of endovascular intervention performed. We did not compare the frequency of recanalization between groups once there were only 6 reported cases in the group treated with IV thrombolysis. There were no statistical significant differences of the median age and baseline NIHSS between treatment groups
(age P value = .16; NIHSS P value = .15 in both comparisons).The risk of an intracerebral hemorrhage was 4.14 times higher in the group treated with IV thrombolysis comparing to the group treated with thrombectomy (Table 5). There was also a higher risk of an intracerebral hemorrhage when comparing the group treated with combined treatment to the group treated with thrombectomy (Table 6). There was a trend for functional independence and for neurological improvement when comparing the group treated with thrombectomy to the group treated with IV thrombolysis. We did not perform a meta-analysis once there was only 1 article describing 6 or more patients and there were no randomized trials comparing or describing subjects treated with thrombectomy versus IV thrombolysis or combined treatment.
Discussion Our search did not found any randomized trials to study the efficacy and safety of thrombectomy in infective endocarditis related acute ischemic stroke. Moreover, there are very few reported cases of thrombolysis or mechanical thrombectomy in this setting, and the overall quality of the case series that have been published on this matter is low, with high risk of several types of bias. Based on 34 case reports and 3 single-center, retrospective, descriptive case series, we found that patients with
4
Table 1. Characteristics of patients with stroke and infective endocarditis treated with IV thrombolysis RecanalizMycotic IE suspected Modality of aneurisms treatment and delay ation from stroke onset
Site of occlusion
(11)
27
F
15
NR
(12)
70
M
13
M2/M3 of left MCA NR
(13)
68
M
12
Yes
(14)
56
M
15
M2 of left MCA NR
(15)
49
M
17
M1 of left MCA
NR
(16)
46
M
15
Right MCA
No
65
F
21
Left MCA
No
15
NR
NR
8
NR
NR NR
(17)
NR NR
No
NR
62
M
18
(19)
57
M
14
(20)
72
M
10
Supraclinoid segment of ICA M1 of left MCA NR
(21)
25
F
16
NR
NR
(22)
65
M
18
NR
No
(23)
51
M
22
NR
Yes
(24)
56
M
NR
NR
NR
NR NR
NR Yes NR NR
NIHSS 1 (6 mo later) NIHSS 5 (6 wk later) NIHSS 1 (7 mo later) NIHSS 4 (48 h later) -
Neurological ICH improvement
Mortality
Time of follow up (wk)
2 (6 mo later)
Yes
No
No
24
2 (6 wk later)
Yes
No
No
6
2 (7 mo later)
Yes
Yes
No
28
2 (9 mo later)
Yes
No
No
36
6
No
Yes
Septic shock with myocardial infarction 5 d later Yes
1
NR
-.
6
No
Yes
No
NR
4 (time NR)
Yes
Yes
No
NR
NR
5 (time NR)
No
Yes
No
NR
-
6 (time NR)
No
Yes
Yes
No
NR
3 (6 mo later)
Yes
No
No
24
No
NR
5 (time NR)
No
Yes
No
NR
NR
4 (9 wk later)
No
Yes
No
9
NR
NIHSS 12 (6 h later) -
6
No
Yes
IV rtPA 30 min
NR
NR
2 (at discharge)
Yes
No
IV rtPA 2 h
Yes
-
6
No
Yes
Yes
NA
rtPA (time NR)
NR
NR
0 (at discharge)
Yes
No
No
NR
PostIV rtPA (0,9 mg/ thrombolysis kg) 3 h PostIV rtPA 72 mg 90 thrombolysis min PostIV rtPA 1 h thrombolysis Postthrombolysis Postthrombolysis Postthrombolysis
NR
mRS
DIC 12 d after thrombolysis No
NR
NR
NA
8
S. BETTENCOURT AND J.M. FERRO
(18)
PostIV rtPA (0,9 mg/kg) thrombolysis 2:35 h PostIV rtPA (0,9 mg/kg) thrombolysis 2:30 h PostIV rtPA (0,9mg/kg) thrombolysis 2:15 h PostIV rtPA 2:36 h thrombolysis Post9mg bolus of IV thrombolysis rtPA (2:05 h) followed of an infusion of 81 mg. PostIV rtPA (0,9 thrombolysis mg/kg) 1:50 h PostIV rtPA (0,9 thrombolysis mg/kg) 2 h IV rtPA (time NR) Postthrombolysis PostIV rtPA (time NR) thrombolysis PostIV rtPA 40 min thrombolysis
Follow up NIHSS
ARTICLE IN PRESS
Source Age Gender Baseline NIHSS score
Source Age Gender Baseline NIHSS score
Site of occlusion
Mycotic IE suspected Modality of Recanalizaneurisms treatment and delay ation from stroke onset
(25)
36
M
10
NR
No
(26)
41
M
21
NR
NR
Postthrombolysis Postthrombolysis
IV Alteplase (0,9 mg/kg) 67 min IV rtPA 50 mg
Follow up NIHSS
mRS
Neurological ICH improvement
Mortality
Time of follow up (wk)
Yes
0 (24 h later) 2 (at discharge)
Yes
Yes
No
NR
NR
23 (24 h later)
No
No
No
1 year
NR
Abbreviations: DIC, disseminated intravascular coagulation; F, female; ICA, internal carotid artery; ICH, intracerebral hemorrhage; IE, infective endocarditis; IV, intravenous; MCA, middle cerebral artery; M-male, mRS- modified Rankin scale; NIHSS, National Institutes of Health stroke scale; NR, not reported; rtPA, recombinant tissue plasminogen activator.
Table 2. Characteristics of patients with stroke and infective endocarditis treated with IA thrombolysis Source Age Gender Baseline Site of Mycotic IE suspected NIHSS occlusion aneurisms score (27)
31
F
13
Basilar artery
No
Modality of treatment and delay from stroke onset
Prethrombolysis IA thrombolysis 5h
Recanalization Follow mRS up NIHSS
Yes
5 (3 wk later)
2 (3 wk later)
Neurological ICH Mortality Time of improvement follow up (wk) Yes
No
No
3
Abbreviations: F, female; IA, Intra-arterial; ICH, intracerebral hemorrhage; IE, Infective Endocarditis; mRS, modified Rankin scale; NIHSS, National Institutes of Health stroke scale.
ARTICLE IN PRESS
ISCHEMIC STROKE TREATMENT IN ENDOCARDITIS
Table 1 (Continued)
5
6
Table 3. Characteristics of patients with stroke and infective endocarditis treated with mechanical thrombectomy
(28)
67
F
NR
(29)
40
F
15
(30)
33
M
14
(31)
78
F
16
(32)
23
F
NR
(33)
40
NR
3
(34)
33
M
14
67
M
13
39
F
15
NR
NR
12
NR
NR
18
(36)
72
M
NR
Between segments M1 and M2 of left MCA M1 of the left MCA M1 of the left MCA M2 of the right MCA M1 of the right MCA M1 of the right MCA M1 of the left MCA M1 of the right MCA M2 of the left MCA M1 of the right MCA M2 of the MCA M2 of the left MCA
(37)
70
F
24
(38)
79
M
9
69
F
10
(35)
M2 of the left MCA M1+Carotid subocclusion
Basilar artery
Mycotic aneurisms
IE suspected
NR
Prethrombectomy
NR NR NR NR NR NR NR NR NR NR NR
No NR
NR
Modality of Recanaliza- Follow up NIHSS treatment and tion delay from stroke onset MT (time NR)
PrethromMT; 5 h bectomy PrethromMT; 2:30 h bectomy PrethromMT; 3 h bectomy PrethromMT bectomy (time NR) PrethromMT bectomy (time NR) PrethromMT (time NR) bectomy PostMT thrombectomy (time NR) PrethromMT bectomy (time NR) PrethromMT bectomy 130 min NR MT (time NR) PostMT thrombectomy (time NR) Prethrombectomy Prethrombectomy
MT (time NR) MT 135 min
Prethrombectomy
MT 255 min
mRS
Neurological ICH Mortality improvement
Time of follow up (wk)
Yes
-
6
No
No
Pulmonary embolism 1 wk later.
2
Yes
3 (48 h later) 0 (4 d later) 12 (24 h later) NR
Yes
No
No
12
Yes
No
No
NR
Yes
No
No
NR
No
No
No
6
Yes
No
No
2
Yes
No
No
12
Yes
No
No
NR
Yes
No
No
12
Yes
No
No
NR
Yes
No
No Pulmonary embolism 9 d after No
NA
Yes (cardiorespiratory arrest during MT) No
12
Yes
0 (13 d later) 1 (at discharge) 0 (mo later) 4 (at discharge) 1
Yes
5
2 (3 mo later) 1 (4 d later) 4 (24 h later) 3 (6 wk later) 0 (13 d later) 1 (3 mo later) 1 (mo later) 2 (3 mo later) 2 (at discharge) 2
-
6
No
No
NR
1
Yes
No
No
35 (24 h later)
6 (3 mo later)
No
No
Yes
2 (24 h later)
0 (3 mo later)
Yes
No
Yes Yes NR Yes Yes Yes Yes
Yes, but reoclusion 24 h later Yes
4d
ARTICLE IN PRESS
Site of occlusion
S. BETTENCOURT AND J.M. FERRO
Source Age Gender Baseline NIHSS score
Source Age Gender Baseline NIHSS score
(40)
Mycotic aneurisms
56
F
19
M1
NR
72
M
35
Basilar artery
NR
79
M
5
M1
NR
85
M
8
M1
NR
57
M
13
Right ICA
NR
66
M
15
Left ICA
70
F
10
Right ICA and right MCA
IE suspected
Prethrombectomy Postthrombectomy
Prethrombectomy Postthrombectomy
Modality of Recanaliza- Follow up NIHSS treatment and tion delay from stroke onset MT 140 min MT 190 min
Yes Yes
MT 100 min
Yes
MT 158 min
Yes
NR
MT 180 min
Yes
NR
NR
MT 110 min
Yes
NR
Prethrombectomy
MT (time NR)
Yes
mRS
Neurological ICH Mortality improvement
2 (24 h later) 35 (24 h later)
0 (3 mo later) 6 (3 mo later)
yes
No
No
No
2 (24h later) 0 (24 h later)
2 (3 mo later) 6 (3 mo later)
Yes
No
Yes
1 (3 mo later) 2 (3 mo later) 1 (3 mo later)
Yes
No Yes (died due to cardiac arrest 6 wk after stroke) No No
Yes
No
No
Yes
No
No
2 (postprocedural 8(postprocedural) 1(postprocedural)
Time of follow up (wk)
No Yes(after palliative care for multiple comorbid conditions) No
12
12
Abbreviations: F, female; ICA, internal carotid artery; ICH, intracerebral hemorrhage; IE, infective endocarditis; M, male, MCA, middle cerebral artery; MT, mechanical thrombectomy; mRS, modified Rankin scale; NIHSS, National Institutes of Health stroke scale; NR, not reported.
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(39)
Site of occlusion
ISCHEMIC STROKE TREATMENT IN ENDOCARDITIS
Table 3 (Continued)
7
8
Table 4. Characteristics of patients with stroke and infective endocarditis treated with combined treatment Site of occlusion
(41)
73
M
20
(42)
24
F
18
Right ICA, right M1 and A1 Left ICA and M1 of the MCA
(43)
39
F
16
(44)
42
M
(45)
36
(46)
Mycotic IE suspected aneurisms
Pretreatment
NR
Pretreatment
M1 of the MCA
NR
Post-treatment
3
M2 of the MCA
NR
Pretreatment
M
16
Right M1
NR
Post-treatment
31
M
18
Yes
Post-treatment
(47)
75
M
16
Right ICA bifurcation Right MCA
NR
Post-treatment
(16)
61
M
17
NR
No
Post-treatment
14
NR
14
NR
19
M1 of MCA
(17)
(35)
NR NR
NR
NR
NR
Post-treatment
Post-treatment
NR
NR
Recanalization
Thrombectomy + IA rtPA (10 mg) IA rtPA (4 mg) + mechanical thrombectomy + aspiration thrombectomy + ballon angioplasty IA Thromblolysis + Mechanical thrombectomy Mechanical thrombectomy +IA rtPA IV rtPA+Mechanical thrombectomy IV rtPA 96 min + MT 125 min IV rtPA + clot aspiration thrombectomy IV rtPA (0,9 mg/kg) 1:30 h + IA intervention IA rtPA + mechanical thrombectomy IV rtPA + mechanical thrombectomy IA rtPA + mechanical thrombectomy
Yes
0 (8 mo later) 0 (8 mo later)
Yes
No
No
32
Yes
2 (2 mo later) 2 (2 mo later)
Yes
No
No
8
Yes
3 (1 mo later) 2 (1 mo later)
Yes
No
No
4
Yes
0 (4 wk later) 0 (4 wk later)
Yes
No
No
8
Yes
2 (24 h later)
Yes
No
No
NR
Yes
Yes
No
12
Yes
Follow up NIHSS
mRS
1 (5 d later) 0 (48 h later) 0 (3 mo later)
Neurological ICH Mortality Time of improvement Follow up (wk)
Yes
NA
6 (few d later)
NA
Yes
NR
NR
4 (time NR)
Yes
Yes
Yes (septic shock) No
NR
-
6
No
Yes
Yes
NR
-
6
No
Yes
Yes
Yes
17
5 (time NR)
Yes
No
No
NA
NR
NA
NR
Abbreviations: F, female; IA, intra-arterial, ICA, internal carotid artery; ICH, intracerebral hemorrhage; IE, infective endocarditis; M, male; mRS, modified Rankin scale; NIHSS, National Institutes of Health stroke scale; NR, not reported; rtPA, recombinant tissue plasminogen activator.
S. BETTENCOURT AND J.M. FERRO
No
Modality of treatment and delay from stroke onset
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Source Age Gender Baseline NIHSS score
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9
Table 5. Comparison between patients treated with IV thrombolysis and patients treated with thrombectomy Parameter (Median) ICH Neurological improvement mRS Mortality
Yes No Yes No 2 >2 Yes No
IV thrombolysis
Thrombectomy
11 7 9 9 7 10 5 13
0 22 17 5 15 7 5 17
P value
Risk ratio
Risk difference
.00
4.14
75.86%
.07
.54
29.67%
.09
.54
27.01%
.49
-
-
Abbreviations: ICH, intracerebral hemorrhage; mRS, modified Rankin scale; NIHSS, National Institutes of Health stroke scale.
Table 6. Comparison between patients treated with thrombectomy and patients treated with combined treatment Parameter (median) ICH Neurological improvement mRS Mortality
Yes No Yes No 2 >2 Yes No
Thrombectomy
Combined treatment
0 22 17 5 15 7 5 17
4 6 7 2 6 4 3 7
P value
Risk ratio
Risk difference
.01
4.67
78.57%
.68
-
-
.47
-
-
.49
-
-
Abbreviations: ICH, intracerebral hemorrhage; mRS, modified Rankin scale; NIHSS, National Institutes of Health stroke scale.
endocarditis related acute ischemic stroke were more likely to suffer an intracerebral hemorrhage when treated with IV thrombolysis or combined treatment comparing to patients that were treated with thrombectomy alone. In fact, there were no intracranial hemorrhages reported in any patient treated with thrombectomy, while 61% of patients treated with IV thrombolysis and 45% of patients treated with combined treatment suffered an intracranial hemorrhage after stroke treatment. The odds of having an intracranial hemorrhage was 4 times higher in patients treated with IV thrombolysis or combined treatment comparing to patients treated with thrombectomy. Besides that there was also a trend towards more frequent independence and neurological improvement in patients who were treated with thrombectomy comparing to patients treated with IV thrombolysis. In our review, 68.2% of patients treated with thrombectomy became functionally independent. Mechanical thrombectomy has showed a significant benefit comparing to IV thrombolysis in patients with acute ischemic stroke of the large intracerebral vessels.48 In this review, the most common site of occlusion in infective endocarditis associated ischemic stroke was middle cerebral artery (81.6%). Although mycotic aneurisms are thought to be one of the causes that makes patients with infective endocarditis related stroke more prone to intracranial hemorrhage after IV thrombolysis, they are infrequent, being found in less than 3% of the cases.3,16 In this systematic review there
were only 3 cases of intracranial hemorrhage in whom mycotic aneurisms were detected. IV thrombolysis was used in 2 patients and combined treatment in the third. They all suffered intracranial bleedings, indicating that thrombolysis is unsafe in patients with mycotic aneurysms. As thrombectomy is decided only after computed tomography (CT) angiography, this technique can also be helpful to rule out mycotic aneurisms. Moreover, the pathologic confirmation of the retrieved clots may also confirm the diagnosis of suspected endocarditis.30,29,39 In our study from the 28 patients who were treated with thrombectomy (with or without associated thrombolysis) 14 had a pathologic or microbiologic analysis of the specimen, with the majority reporting the presence of fibrinoid or necrotic material with inflammatory cells and gram positive cocci. DNA sequences of Tropheryma Whipplei were identified in 1 article40 and Candida Parapsilosis in an immunosuppressed patient.46 Besides the confirmation of infective endocarditis the results from microbiologic analysis of the specimens may be helpful to guide directed antibiotic therapy at an early stage. Limitations of our study are related to the low quality of the studies and the small number of cases which could be retrieved. There were no randomized controlled trials, the sample size was low in the majority of the studies, follow up was too short or not reported and outcome results were not always presented in objective scales. There is also a potential publication bias in favor of cases with favorable outcomes. The fact that all the patients treated with IV
ARTICLE IN PRESS S. BETTENCOURT AND J.M. FERRO
10
thrombolysis were diagnosed with infective endocarditis after stroke treatment while the majority of those treated with trombectomy were diagnosed previously to the treatment is an additional limitation to our study. For instance, patients diagnosed with infective endocarditis before stroke treatment could already be under antibiotic treatment, making the 2 groups very different. This limitation imposes that our results should be interpreted with caution.
Implications for Clinical Practice The results of this systematic review favor the use of thrombectomy rather than IV thrombolysis or combined treatment, as a safer option for patients with infective endocarditis associated stroke.
Implications for Research A randomized controlled trial comparing thrombectomy versus IV thrombolysis and with combined treatment is unlikely to be feasible. A prospective multicenter registry of acute treatments for infective endocarditis associated stroke with blinded and objective assessment of neurological outcomes and longer follow up could add considerable information regarding the safety and efficacy of the different modalities of acute stroke treatment.
Conclusion Our systematic review suggests that thrombectomy is a safer treatment option than IV thrombolysis or combined treatment for patients with infective endocarditis related stroke.
Conflict of Interest There is no conflicts of interest.
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