HHS Public Access Author manuscript Author Manuscript
Stroke. Author manuscript; available in PMC 2017 September 01. Published in final edited form as: Stroke. 2016 September ; 47(9): 2364–2372. doi:10.1161/STROKEAHA.116.014096.
Leukoaraiosis, cerebral hemorrhage and outcome after IV thrombolysis for acute ischemic stroke: A meta-analysis (v1) Andreas Charidimou, MD, MSc(Clinical Neurology), PhD1,2,†, Marco Pasi, MD1,2,6,†, Marco Fiorelli, MD, PhD3, Sara Shams, MD4, Rüdiger von Kummer, Prof Dr med5, Leonardo Pantoni, MD, PhD6, and Natalia Rost, MD, MPH1,2 1J.
Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA, USA
Author Manuscript
2Harvard
Medical School, Boston, MA, USA
3Department
of Neurology and Psychiatry, Sapienza University of Rome, Viale dell’Università 30, 00185 Rome, Italy
4Karolinska
Institutet, Karolinska University Hospital, Stockholm, Sweden
5Institute
of Diagnostic and Interventional Neuroradiology, Dresden University Stroke Centre, Dresden, Germany 6NEUROFARBA
Department, Neuroscience section, University of Florence, Florence, Italy
Abstract Author Manuscript
Background-and-Purpose—We performed a meta-analysis to assess whether leukoaraiosis on brain CT scans of acute ischemic stroke patients treated with intravenous (IV) thrombolysis is associated with an increased risk of symptomatic intracerebral hemorrhage (sICH) and/or poor functional outcome at 3–6 months post-stroke. Methods—We searched PubMed and pooled relevant data in meta-analyses using random effects models. Using odds ratios (OR), we quantified the strength of association between the presence and severity of leukoaraiosis and post-thrombolysis sICH or 3–6 month modified Rankin Score (mRS) >2.
Author Manuscript
Results—Eleven eligible studies (n=7194) were pooled in meta-analysis. The risk of sICH was higher in patients with leukoaraiosis (OR: 1.55; 95%CI: 1.17–2.06, p=0.002) and severe leukoaraiosis (OR: 2.53; 95%CI: 1.92–3.34, p2 (or >4 if each hemisphere was rated separately). There was no evidence of publication bias in the funnel plot (data not shown).
Author Manuscript Author Manuscript
The crude prevalence of leukoaraiosis on pre-treatment CT scans was 40% (95%CI: 33%– 48%), while severe leukoaraiosis was found in 15% (95%CI: 10%–20%) of the patients (based on 7/9 studies that provided data on leukoaraiosis severity). Post-treatment sICH occurred in 4% (95%CI: 2%–6%) of patients without any leukoaraiosis vs. 6% (95%CI: 4%–8%) in patients with evidence of leukoaraiosis and 9% (95%CI: 6%–12%) in those with severe leukoaraiosis (p1 as in RCTs of thrombolysis. Several methodological aspects of the included studies and limitations of our analyses deserve careful consideration. First, the visual rating schemes for leukoaraiosis assessment slightly varied between studies, although this is unlikely to have affected the prevalence of any or severe leukoaraiosis. A previous study indicated that despite differences, the validated visual rating scales for leukoaraiosis correlate well, especially the van Swieten and Fazekas
Stroke. Author manuscript; available in PMC 2017 September 01.
Charidimou et al.
Page 7
Author Manuscript Author Manuscript Author Manuscript
scales.30 Second, the incidence of sICH following IV thrombolysis might vary according to the clinical, radiological and time criteria used to define it. However, most definitions used across centres included sICH associated with clinical deterioration, hence are likely to be clinically relevant. An important source of heterogeneity is the inclusion of both observational (retrospective and prospective) studies and RCTs. Estimates in separate sensitivity analyses indicated that the effect size is greater in observational studies than in RCTs (but still in the same direction), raising a concern about bias and inflation of the overall results by the non-RCTs. For example, the study by Curtze et al.,5, 6 the largest prospective observational study on the topic, provided similarly conservative effect estimates to RCTs,4, 15, 18 in contrast to retrospective small studies. Finally, the main limitation of our analysis is that it is not fully adjusted for other important variables that can potentially affect the risk for thrombolysis-related sICH and outcome, such as time from stroke onset to IV thrombolysis, baseline serum glucose, infarct volume, early ischemic CT signs, pre-stroke functional status etc. It is possible that certain variables, such as age and hypertension, might be strongly associated with sICH and both leukoaraiosis and stroke outcome. Age and hypertension might, thus, account for some portion of these relationships, despite no evidence of interaction in our meta-regression analyses. In addition, poor outcomes in patients with leukoaraiosis could be partly accounted for by the higher risk of sICH post thrombolysis, but the data to explore this hypothesis were not available. Reassuringly, our sensitivity pooled analyses of adjusted effect estimates were consistent with our main findings, suggesting an independent relation between leukoaraiosis, sICH risk, and poor post-stroke functional outcome. These adjusted pooled estimates, nevertheless, should be treated with caution since they are derived only from a proportion of the published studies, using different multivariable models and effect sizes (leading to high statistical heterogeneity). Thus, the adjusted estimates are still at risk of confounding. In light of these limitations, the current findings should be considered hypothesis-generating.
Conclusions
Author Manuscript
Although our analysis demonstrates that pre-existing leukoaraiosis might increase the risk of early sICH after thrombolysis and poor outcome post-stroke, it is important to note that despite these potential risks, patients with leukoaraiosis still appear to benefit clinically from IV tPA, as indicated in our sub-analysis of RCTs.4, 31 Accordingly, our results do not justify withholding IV thrombolysis from otherwise eligible candidates solely on the basis of leukoaraiosis present on brain CT. The data presented here, however, reinforce the need for further investigation of the clinical relevance of small vessel disease markers in large multicenter studies of acute stroke and form the basis for an individual-patient data metaanalysis on the topic.
Supplementary Material Refer to Web version on PubMed Central for supplementary material.
Acknowledgments None
Stroke. Author manuscript; available in PMC 2017 September 01.
Charidimou et al.
Page 8 Sources of Funding
Author Manuscript
R. von Kummer reports personal fees from Boehringer Ingelheim during the conduct of ECASS-1-2, H. Lundbeck A/S, Covidien, Brainsgate, and Penumbra, Inc, outside the submitted work. N. Rost is in part supported by NIHNINDS R01 NS082285 & R01 NS086905.
References
Author Manuscript Author Manuscript Author Manuscript
1. Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: A meta-analysis of individual patient data from randomised trials. Lancet. 2014; 384:1929–1935. [PubMed: 25106063] 2. Debette S, Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: Systematic review and meta-analysis. BMJ. 2010; 341:c3666. [PubMed: 20660506] 3. Busl KM, Nogueira RG, Yoo AJ, Hirsch JA, Schwamm LH, Rost NS. Prestroke dementia is associated with poor outcomes after reperfusion therapy among elderly stroke patients. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2013; 22:718–724. [PubMed: 22182760] 4. group ISTc. Association between brain imaging signs, early and late outcomes, and response to intravenous alteplase after acute ischaemic stroke in the third international stroke trial (ist-3): Secondary analysis of a randomised controlled trial. Lancet Neurol. 2015; 14:485–496. [PubMed: 25819484] 5. Curtze S, Melkas S, Sibolt G, Haapaniemi E, Mustanoja S, Putaala J, et al. Cerebral computed tomography-graded white matter lesions are associated with worse outcome after thrombolysis in patients with stroke. Stroke. 2015; 46:1554–1560. [PubMed: 25899244] 6. Curtze S, Haapaniemi E, Melkas S, Mustanoja S, Putaala J, Sairanen T, et al. White matter lesions double the risk of post-thrombolytic intracerebral hemorrhage. Stroke. 2015; 46:2149–2155. [PubMed: 26111888] 7. van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988; 19:604–607. [PubMed: 3363593] 8. van Swieten JC, Hijdra A, Koudstaal PJ, van Gijn J. Grading white matter lesions on ct and mri: A simple scale. J Neurol Neurosurg Psychiatry. 1990; 53:1080–1083. [PubMed: 2292703] 9. Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. Mr signal abnormalities at 1.5 t in alzheimer’s dementia and normal aging. AJR Am J Roentgenol. 1987; 149:351–356. [PubMed: 3496763] 10. Wahlund LO, Barkhof F, Fazekas F, Bronge L, Augustin M, Sjogren M, et al. A new rating scale for age-related white matter changes applicable to mri and ct. Stroke. 2001; 32:1318–1322. [PubMed: 11387493] 11. DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled clinical trials. 1986; 7:177– 188. [PubMed: 3802833] 12. Willer L, Havsteen I, Ovesen C, Christensen AF, Christensen H. Computed tomography--verified leukoaraiosis is a risk factor for post-thrombolytic hemorrhage. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2015; 24:1126–1130. [PubMed: 25920756] 13. Costello CA, Campbell BC, Perez de la Ossa N, Zheng TH, Sherwin JC, Weir L, et al. Age over 80 years is not associated with increased hemorrhagic transformation after stroke thrombolysis. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2012; 19:360–363. [PubMed: 22245278] 14. Aries MJ, Uyttenboogaart M, Vroomen PC, De Keyser J, Luijckx GJ. Tpa treatment for acute ischaemic stroke in patients with leukoaraiosis. European journal of neurology : the official journal of the European Federation of Neurological Societies. 2010; 17:866–870. 15. Demchuk AM, Khan F, Hill MD, Barber PA, Silver B, Patel S, et al. Importance of leukoaraiosis on ct for tissue plasminogen activator decision making: Evaluation of the ninds rt-pa stroke study. Cerebrovasc Dis. 2008; 26:120–125. [PubMed: 18560214]
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16. Palumbo V, Boulanger JM, Hill MD, Inzitari D, Buchan AM. Leukoaraiosis and intracerebral hemorrhage after thrombolysis in acute stroke. Neurology. 2007; 68:1020–1024. [PubMed: 17389306] 17. Neumann-Haefelin T, Hoelig S, Berkefeld J, Fiehler J, Gass A, Humpich M, et al. Leukoaraiosis is a risk factor for symptomatic intracerebral hemorrhage after thrombolysis for acute stroke. Stroke; a journal of cerebral circulation. 2006; 37:2463–2466. 18. Fiorelli M, Di Piero V, Vicenzini E, vonKummer R. Leukoaraiosis was not associated with an increase of parenchymal hemorrhage in the combined ecass 1-ecass 2 cohort (abstract). Stroke. 2002; 33:382. 19. Huang YH, Zhuo ST, Chen YF, Li MM, Lin YY, Yang ML, et al. Factors influencing clinical outcomes of acute ischemic stroke treated with intravenous recombinant tissue plasminogen activator. Chinese medical journal. 2013; 126:4685–4690. [PubMed: 24342312] 20. Poggesi A, Pasi M, Pescini F, Pantoni L, Inzitari D. Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: A review. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2016; 36:72–94. 21. Mazya M, Egido JA, Ford GA, Lees KR, Mikulik R, Toni D, et al. Predicting the risk of symptomatic intracerebral hemorrhage in ischemic stroke treated with intravenous alteplase: Safe implementation of treatments in stroke (sits) symptomatic intracerebral hemorrhage risk score. Stroke. 2012; 43:1524–1531. [PubMed: 22442178] 22. Derex L, Nighoghossian N. Intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: An update. J Neurol Neurosurg Psychiatry. 2008; 79:1093–1099. [PubMed: 18223014] 23. Charidimou A, Shoamanesh A, Wilson D, Gang Q, Fox Z, Jager HR, et al. Cerebral microbleeds and postthrombolysis intracerebral hemorrhage risk updated meta-analysis. Neurology. 2015; 85:927–924. [PubMed: 26296519] 24. Cai J, Fu J, Yan S, Hu H, Lin C. Clinical outcome in acute ischemic stroke patients with microbleeds after thrombolytic therapy: A meta-analysis. Medicine. 2015; 94:e2379. [PubMed: 26717385] 25. Saba L, Raz E, Bassareo PP, di Martino M, de Cecco CN, Mercuro G, et al. Is there an association between cerebral microbleeds and leukoaraiosis? Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2015; 24:284–289. [PubMed: 25440349] 26. Yamada S, Saiki M, Satow T, Fukuda A, Ito M, Minami S, et al. Periventricular and deep white matter leukoaraiosis have a closer association with cerebral microbleeds than age. European journal of neurology : the official journal of the European Federation of Neurological Societies. 2012; 19:98–104. 27. Inzitari D, Pracucci G, Poggesi A, Carlucci G, Barkhof F, Chabriat H, et al. Changes in white matter as determinant of global functional decline in older independent outpatients: Three year follow-up of ladis (leukoaraiosis and disability) study cohort. BMJ. 2009; 339:b2477. [PubMed: 19581317] 28. Ay H, Arsava EM, Rosand J, Furie KL, Singhal AB, Schaefer PW, et al. Severity of leukoaraiosis and susceptibility to infarct growth in acute stroke. Stroke; a journal of cerebral circulation. 2008; 39:1409–1413. 29. Arsava EM, Rahman R, Rosand J, Lu J, Smith EE, Rost NS, et al. Severity of leukoaraiosis correlates with clinical outcome after ischemic stroke. Neurology. 2009; 72:1403–1410. [PubMed: 19380699] 30. Pantoni L, Simoni M, Pracucci G, Schmidt R, Barkhof F, Inzitari D. Visual rating scales for agerelated white matter changes (leukoaraiosis): Can the heterogeneity be reduced? Stroke. 2002; 33:2827–2833. [PubMed: 12468777] 31. Larrue V. Brain ct signs and the effect of alteplase after stroke. Lancet Neurol. 2015; 14:458–460. [PubMed: 25819483]
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Author Manuscript Author Manuscript Figure 1.
Flow chart of literature search and study selection. LA = Leukoaraiosis; sICH = symptomatic intracerebral hemorrhage
Author Manuscript Author Manuscript Stroke. Author manuscript; available in PMC 2017 September 01.
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Author Manuscript Author Manuscript Author Manuscript Figure 2.
Author Manuscript
Forest plots of leukoaraiosis and risk of post-thrombolysis symptomatic intracerebral haemorrhage. Meta-analysis of the association between symptomatic intracerebral haemorrhage (sICH) risk in patients with acute ischaemic stroke treated with thrombolysis, in relation to the presence of leukoaraiosis (A) and severe leukoaraiosis (B) on CT scans (**severe LA was defined with a lower cut-off; effect sizes are consistent with these two studies excluded16, 17). (C) Pooled adjusted odds ratios analysis of cohorts providing relevant data. (LA=Leukoaraiosis, sLA=Severe Leukoaraiosis, OR=Odds Ratio).
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Figure 3.
Forest plots of leukoaraiosis and risk of poor functional outcome. (A) Pooled analysis of poor functional outcome 3–6 months post-stroke according to leukoaraiosis presence, in the subset of cohorts providing relevant data. (B) Pooled adjusted odds ratios analysis for poor outcome in cohorts providing relevant data. Poor outcome was defined as mRS>2 at 3 months in three studies,6, 14, 18 mRS≥2 at 3months in two studies (**effect sizes are consistent with these two studies excluded)15, 19 and Oxford Handicap scale >2 at 6 months in the IST-3 trial.4 (LA=Leukoaraiosis, mRS=modified Rankin scale, OR=Odds Ratio).
Author Manuscript Stroke. Author manuscript; available in PMC 2017 September 01.
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Author Manuscript Author Manuscript Figure 4.
Author Manuscript
Forest plot of exploratory subanalyses of RCTs showing the effect of treatment (tPA vs. control) in patients with LA on symptomatic ICH (sICH) (A) and poor outcome (B) risk.
Author Manuscript Stroke. Author manuscript; available in PMC 2017 September 01.
Author Manuscript
Stroke. Author manuscript; available in PMC 2017 September 01.
Retrospective single centre
Retrospective single centre
Retrospective single centre
Retrospective single centre
Prospective multicentre
Prospective multicentre
Retrospective multicentre
RCT (rtPA arm)
RCT (rtPA arm)
Huang, 201319
Curtze, 20145
Costello, 201213
Aries, 201014
Demchuk, 200815
Palumbo, 200716
Neumann-Haefelin, 200617
IST-3, 20154
ECASS-1–218
1507
706 (60%)
Europe, Australia, NZ (1992–94 1996–98)
363
Europe-USA -
2000–2011
820 (57%)
299
400 (53%)
206 (44%)
2481 (62%)
101 (49%)
Canada (1999–2001)
USA (1991/1994)
Holland (2002–2008)
Australia (2004–2009)
Finland (2001–2014)
China (2009–2012)
2451 (51%)
Denmark -
Finland (2001–2014)
311
Country (period)
65±11
-
65±14
78.3
-
68±14
81 (8)
73 (64–79)
66
78 (72–83)
75.8
11 in 52%
13.4±5.8
188±64 min
No upper limit
34%
50%
-
-
33%
24%
3h) 2)
Van Swieten (per hemisph. >2)
Van Swieten (>2)
24–72 hours (CT)
7 days (CT)
36 hours (MRI)
24 hours (CT)
24 hours (CT)
-
sICH within 24 hours from thrombolytic treatment with any neurologic deterioration
ECASS-2
SITS-MOST
mRS>2 at 3 months
Oxford Handicap scale >2 at 6 months
-
mRS≥2 at 3 months
Any neurological deterioration within 24 h associated with SICH
PH
mRS>2 at 3 months
-
mRS≥2 at 3 months
mRS>2 at 3 months
-
Functional outcome poststroke (used in our analysis)
Type 2 PH with worsening of ≥4 points on NIHSS
SITS–MOST: HT with worsening of ≥4 points on NIHSS
48 hours (CT or MRI) 24–36h (CT)
ECASS-2
ECASS-2
-
ECASS-2: ICH with worsening of ≥4 points on NIHSS
Symptomatic ICH definition
24 hours (CT)
-
Only LA presence assessed Van Swieten (>2)
-
36 hours (CT)
FU time (modality)
Van Swieten
ARWMC
LA visual scale used (severe LA definition if provided)
ARWMC = Age-Related White Matter Changes; FU: follow-up; IA: intra-arterial; PH: parenchymal haemorrhage; sICH: symptomatic intracerebral haemorrhage; IV: intravenous; LA = Leukoaraiosis; N/A=Not Assessed; NIHSS= National Institute of Health Stroke Scale; tPA: tissue plasminogen activator.
Retrospective single centre
Retrospective single centre
Willer, 201512
Curtze, 20156
Study design
Study reference
Mean/m edian age (years)
Author Manuscript
Patient number (% men)
Author Manuscript
Characteristics and methodological aspects of included studies.
Author Manuscript
Table 1 Charidimou et al. Page 14
Charidimou et al.
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Table 2
Author Manuscript
Univariable random effects meta-regression analyses of the association between key characteristics of included cohorts and post-thrombolysis symptomatic intracerebral hemorrhage. Results presented are for the metaanalysis shown in Figure 2A. Potential confounder
OR
95% CI
P-value
Mean age (per year increase)
1.03
0.92–1.16
0.465
NIHSS at presentation
1.00
0.74–1.34
0.963
Glucose at admission (mmol/L)
0.44
0.14–1.39
0.108
Mean systolic blood pressure (mmHg)
1.11
0.66–1.85
0.485
Mean diastolic blood pressure (mmHg)
0.74
0.07–7.95
0.350
Prevalence of hypertension
0.13
7.90e−14 to 2.21e+11
0.529
Author Manuscript Author Manuscript Author Manuscript Stroke. Author manuscript; available in PMC 2017 September 01.
Stroke. Author manuscript; available in PMC 2017 September 01. Published in final edited form as: Stroke. 2016 September ; 47(9): 2364–2372. doi:10.1161/STROKEAHA.116.014096.
Leukoaraiosis, cerebral hemorrhage and outcome after IV thrombolysis for acute ischemic stroke: A meta-analysis (v1) Andreas Charidimou, MD, MSc(Clinical Neurology), PhD1,2,†, Marco Pasi, MD1,2,6,†, Marco Fiorelli, MD, PhD3, Sara Shams, MD4, Rüdiger von Kummer, Prof Dr med5, Leonardo Pantoni, MD, PhD6, and Natalia Rost, MD, MPH1,2 1J.
Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA, USA
Author Manuscript
2Harvard
Medical School, Boston, MA, USA
3Department
of Neurology and Psychiatry, Sapienza University of Rome, Viale dell’Università 30, 00185 Rome, Italy
4Karolinska
Institutet, Karolinska University Hospital, Stockholm, Sweden
5Institute
of Diagnostic and Interventional Neuroradiology, Dresden University Stroke Centre, Dresden, Germany 6NEUROFARBA
Department, Neuroscience section, University of Florence, Florence, Italy
Abstract Author Manuscript
Background-and-Purpose—We performed a meta-analysis to assess whether leukoaraiosis on brain CT scans of acute ischemic stroke patients treated with intravenous (IV) thrombolysis is associated with an increased risk of symptomatic intracerebral hemorrhage (sICH) and/or poor functional outcome at 3–6 months post-stroke. Methods—We searched PubMed and pooled relevant data in meta-analyses using random effects models. Using odds ratios (OR), we quantified the strength of association between the presence and severity of leukoaraiosis and post-thrombolysis sICH or 3–6 month modified Rankin Score (mRS) >2.
Author Manuscript
Results—Eleven eligible studies (n=7194) were pooled in meta-analysis. The risk of sICH was higher in patients with leukoaraiosis (OR: 1.55; 95%CI: 1.17–2.06, p=0.002) and severe leukoaraiosis (OR: 2.53; 95%CI: 1.92–3.34, p2 (or >4 if each hemisphere was rated separately). There was no evidence of publication bias in the funnel plot (data not shown).
Author Manuscript Author Manuscript
The crude prevalence of leukoaraiosis on pre-treatment CT scans was 40% (95%CI: 33%– 48%), while severe leukoaraiosis was found in 15% (95%CI: 10%–20%) of the patients (based on 7/9 studies that provided data on leukoaraiosis severity). Post-treatment sICH occurred in 4% (95%CI: 2%–6%) of patients without any leukoaraiosis vs. 6% (95%CI: 4%–8%) in patients with evidence of leukoaraiosis and 9% (95%CI: 6%–12%) in those with severe leukoaraiosis (p1 as in RCTs of thrombolysis. Several methodological aspects of the included studies and limitations of our analyses deserve careful consideration. First, the visual rating schemes for leukoaraiosis assessment slightly varied between studies, although this is unlikely to have affected the prevalence of any or severe leukoaraiosis. A previous study indicated that despite differences, the validated visual rating scales for leukoaraiosis correlate well, especially the van Swieten and Fazekas
Stroke. Author manuscript; available in PMC 2017 September 01.
Charidimou et al.
Page 7
Author Manuscript Author Manuscript Author Manuscript
scales.30 Second, the incidence of sICH following IV thrombolysis might vary according to the clinical, radiological and time criteria used to define it. However, most definitions used across centres included sICH associated with clinical deterioration, hence are likely to be clinically relevant. An important source of heterogeneity is the inclusion of both observational (retrospective and prospective) studies and RCTs. Estimates in separate sensitivity analyses indicated that the effect size is greater in observational studies than in RCTs (but still in the same direction), raising a concern about bias and inflation of the overall results by the non-RCTs. For example, the study by Curtze et al.,5, 6 the largest prospective observational study on the topic, provided similarly conservative effect estimates to RCTs,4, 15, 18 in contrast to retrospective small studies. Finally, the main limitation of our analysis is that it is not fully adjusted for other important variables that can potentially affect the risk for thrombolysis-related sICH and outcome, such as time from stroke onset to IV thrombolysis, baseline serum glucose, infarct volume, early ischemic CT signs, pre-stroke functional status etc. It is possible that certain variables, such as age and hypertension, might be strongly associated with sICH and both leukoaraiosis and stroke outcome. Age and hypertension might, thus, account for some portion of these relationships, despite no evidence of interaction in our meta-regression analyses. In addition, poor outcomes in patients with leukoaraiosis could be partly accounted for by the higher risk of sICH post thrombolysis, but the data to explore this hypothesis were not available. Reassuringly, our sensitivity pooled analyses of adjusted effect estimates were consistent with our main findings, suggesting an independent relation between leukoaraiosis, sICH risk, and poor post-stroke functional outcome. These adjusted pooled estimates, nevertheless, should be treated with caution since they are derived only from a proportion of the published studies, using different multivariable models and effect sizes (leading to high statistical heterogeneity). Thus, the adjusted estimates are still at risk of confounding. In light of these limitations, the current findings should be considered hypothesis-generating.
Conclusions
Author Manuscript
Although our analysis demonstrates that pre-existing leukoaraiosis might increase the risk of early sICH after thrombolysis and poor outcome post-stroke, it is important to note that despite these potential risks, patients with leukoaraiosis still appear to benefit clinically from IV tPA, as indicated in our sub-analysis of RCTs.4, 31 Accordingly, our results do not justify withholding IV thrombolysis from otherwise eligible candidates solely on the basis of leukoaraiosis present on brain CT. The data presented here, however, reinforce the need for further investigation of the clinical relevance of small vessel disease markers in large multicenter studies of acute stroke and form the basis for an individual-patient data metaanalysis on the topic.
Supplementary Material Refer to Web version on PubMed Central for supplementary material.
Acknowledgments None
Stroke. Author manuscript; available in PMC 2017 September 01.
Charidimou et al.
Page 8 Sources of Funding
Author Manuscript
R. von Kummer reports personal fees from Boehringer Ingelheim during the conduct of ECASS-1-2, H. Lundbeck A/S, Covidien, Brainsgate, and Penumbra, Inc, outside the submitted work. N. Rost is in part supported by NIHNINDS R01 NS082285 & R01 NS086905.
References
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16. Palumbo V, Boulanger JM, Hill MD, Inzitari D, Buchan AM. Leukoaraiosis and intracerebral hemorrhage after thrombolysis in acute stroke. Neurology. 2007; 68:1020–1024. [PubMed: 17389306] 17. Neumann-Haefelin T, Hoelig S, Berkefeld J, Fiehler J, Gass A, Humpich M, et al. Leukoaraiosis is a risk factor for symptomatic intracerebral hemorrhage after thrombolysis for acute stroke. Stroke; a journal of cerebral circulation. 2006; 37:2463–2466. 18. Fiorelli M, Di Piero V, Vicenzini E, vonKummer R. Leukoaraiosis was not associated with an increase of parenchymal hemorrhage in the combined ecass 1-ecass 2 cohort (abstract). Stroke. 2002; 33:382. 19. Huang YH, Zhuo ST, Chen YF, Li MM, Lin YY, Yang ML, et al. Factors influencing clinical outcomes of acute ischemic stroke treated with intravenous recombinant tissue plasminogen activator. Chinese medical journal. 2013; 126:4685–4690. [PubMed: 24342312] 20. Poggesi A, Pasi M, Pescini F, Pantoni L, Inzitari D. Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: A review. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2016; 36:72–94. 21. Mazya M, Egido JA, Ford GA, Lees KR, Mikulik R, Toni D, et al. Predicting the risk of symptomatic intracerebral hemorrhage in ischemic stroke treated with intravenous alteplase: Safe implementation of treatments in stroke (sits) symptomatic intracerebral hemorrhage risk score. Stroke. 2012; 43:1524–1531. [PubMed: 22442178] 22. Derex L, Nighoghossian N. Intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: An update. J Neurol Neurosurg Psychiatry. 2008; 79:1093–1099. [PubMed: 18223014] 23. Charidimou A, Shoamanesh A, Wilson D, Gang Q, Fox Z, Jager HR, et al. Cerebral microbleeds and postthrombolysis intracerebral hemorrhage risk updated meta-analysis. Neurology. 2015; 85:927–924. [PubMed: 26296519] 24. Cai J, Fu J, Yan S, Hu H, Lin C. Clinical outcome in acute ischemic stroke patients with microbleeds after thrombolytic therapy: A meta-analysis. Medicine. 2015; 94:e2379. [PubMed: 26717385] 25. Saba L, Raz E, Bassareo PP, di Martino M, de Cecco CN, Mercuro G, et al. Is there an association between cerebral microbleeds and leukoaraiosis? Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2015; 24:284–289. [PubMed: 25440349] 26. Yamada S, Saiki M, Satow T, Fukuda A, Ito M, Minami S, et al. Periventricular and deep white matter leukoaraiosis have a closer association with cerebral microbleeds than age. European journal of neurology : the official journal of the European Federation of Neurological Societies. 2012; 19:98–104. 27. Inzitari D, Pracucci G, Poggesi A, Carlucci G, Barkhof F, Chabriat H, et al. Changes in white matter as determinant of global functional decline in older independent outpatients: Three year follow-up of ladis (leukoaraiosis and disability) study cohort. BMJ. 2009; 339:b2477. [PubMed: 19581317] 28. Ay H, Arsava EM, Rosand J, Furie KL, Singhal AB, Schaefer PW, et al. Severity of leukoaraiosis and susceptibility to infarct growth in acute stroke. Stroke; a journal of cerebral circulation. 2008; 39:1409–1413. 29. Arsava EM, Rahman R, Rosand J, Lu J, Smith EE, Rost NS, et al. Severity of leukoaraiosis correlates with clinical outcome after ischemic stroke. Neurology. 2009; 72:1403–1410. [PubMed: 19380699] 30. Pantoni L, Simoni M, Pracucci G, Schmidt R, Barkhof F, Inzitari D. Visual rating scales for agerelated white matter changes (leukoaraiosis): Can the heterogeneity be reduced? Stroke. 2002; 33:2827–2833. [PubMed: 12468777] 31. Larrue V. Brain ct signs and the effect of alteplase after stroke. Lancet Neurol. 2015; 14:458–460. [PubMed: 25819483]
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Author Manuscript Author Manuscript Figure 1.
Flow chart of literature search and study selection. LA = Leukoaraiosis; sICH = symptomatic intracerebral hemorrhage
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Author Manuscript Author Manuscript Author Manuscript Figure 2.
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Forest plots of leukoaraiosis and risk of post-thrombolysis symptomatic intracerebral haemorrhage. Meta-analysis of the association between symptomatic intracerebral haemorrhage (sICH) risk in patients with acute ischaemic stroke treated with thrombolysis, in relation to the presence of leukoaraiosis (A) and severe leukoaraiosis (B) on CT scans (**severe LA was defined with a lower cut-off; effect sizes are consistent with these two studies excluded16, 17). (C) Pooled adjusted odds ratios analysis of cohorts providing relevant data. (LA=Leukoaraiosis, sLA=Severe Leukoaraiosis, OR=Odds Ratio).
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Figure 3.
Forest plots of leukoaraiosis and risk of poor functional outcome. (A) Pooled analysis of poor functional outcome 3–6 months post-stroke according to leukoaraiosis presence, in the subset of cohorts providing relevant data. (B) Pooled adjusted odds ratios analysis for poor outcome in cohorts providing relevant data. Poor outcome was defined as mRS>2 at 3 months in three studies,6, 14, 18 mRS≥2 at 3months in two studies (**effect sizes are consistent with these two studies excluded)15, 19 and Oxford Handicap scale >2 at 6 months in the IST-3 trial.4 (LA=Leukoaraiosis, mRS=modified Rankin scale, OR=Odds Ratio).
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Author Manuscript Author Manuscript Figure 4.
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Forest plot of exploratory subanalyses of RCTs showing the effect of treatment (tPA vs. control) in patients with LA on symptomatic ICH (sICH) (A) and poor outcome (B) risk.
Author Manuscript Stroke. Author manuscript; available in PMC 2017 September 01.
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Stroke. Author manuscript; available in PMC 2017 September 01.
Retrospective single centre
Retrospective single centre
Retrospective single centre
Retrospective single centre
Prospective multicentre
Prospective multicentre
Retrospective multicentre
RCT (rtPA arm)
RCT (rtPA arm)
Huang, 201319
Curtze, 20145
Costello, 201213
Aries, 201014
Demchuk, 200815
Palumbo, 200716
Neumann-Haefelin, 200617
IST-3, 20154
ECASS-1–218
1507
706 (60%)
Europe, Australia, NZ (1992–94 1996–98)
363
Europe-USA -
2000–2011
820 (57%)
299
400 (53%)
206 (44%)
2481 (62%)
101 (49%)
Canada (1999–2001)
USA (1991/1994)
Holland (2002–2008)
Australia (2004–2009)
Finland (2001–2014)
China (2009–2012)
2451 (51%)
Denmark -
Finland (2001–2014)
311
Country (period)
65±11
-
65±14
78.3
-
68±14
81 (8)
73 (64–79)
66
78 (72–83)
75.8
11 in 52%
13.4±5.8
188±64 min
No upper limit
34%
50%
-
-
33%
24%
3h) 2)
Van Swieten (per hemisph. >2)
Van Swieten (>2)
24–72 hours (CT)
7 days (CT)
36 hours (MRI)
24 hours (CT)
24 hours (CT)
-
sICH within 24 hours from thrombolytic treatment with any neurologic deterioration
ECASS-2
SITS-MOST
mRS>2 at 3 months
Oxford Handicap scale >2 at 6 months
-
mRS≥2 at 3 months
Any neurological deterioration within 24 h associated with SICH
PH
mRS>2 at 3 months
-
mRS≥2 at 3 months
mRS>2 at 3 months
-
Functional outcome poststroke (used in our analysis)
Type 2 PH with worsening of ≥4 points on NIHSS
SITS–MOST: HT with worsening of ≥4 points on NIHSS
48 hours (CT or MRI) 24–36h (CT)
ECASS-2
ECASS-2
-
ECASS-2: ICH with worsening of ≥4 points on NIHSS
Symptomatic ICH definition
24 hours (CT)
-
Only LA presence assessed Van Swieten (>2)
-
36 hours (CT)
FU time (modality)
Van Swieten
ARWMC
LA visual scale used (severe LA definition if provided)
ARWMC = Age-Related White Matter Changes; FU: follow-up; IA: intra-arterial; PH: parenchymal haemorrhage; sICH: symptomatic intracerebral haemorrhage; IV: intravenous; LA = Leukoaraiosis; N/A=Not Assessed; NIHSS= National Institute of Health Stroke Scale; tPA: tissue plasminogen activator.
Retrospective single centre
Retrospective single centre
Willer, 201512
Curtze, 20156
Study design
Study reference
Mean/m edian age (years)
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Patient number (% men)
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Characteristics and methodological aspects of included studies.
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Table 1 Charidimou et al. Page 14
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Table 2
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Univariable random effects meta-regression analyses of the association between key characteristics of included cohorts and post-thrombolysis symptomatic intracerebral hemorrhage. Results presented are for the metaanalysis shown in Figure 2A. Potential confounder
OR
95% CI
P-value
Mean age (per year increase)
1.03
0.92–1.16
0.465
NIHSS at presentation
1.00
0.74–1.34
0.963
Glucose at admission (mmol/L)
0.44
0.14–1.39
0.108
Mean systolic blood pressure (mmHg)
1.11
0.66–1.85
0.485
Mean diastolic blood pressure (mmHg)
0.74
0.07–7.95
0.350
Prevalence of hypertension
0.13
7.90e−14 to 2.21e+11
0.529
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