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Should cerebral microbleeds on magnetic resonance imaging contraindicate thrombolysis in patients with ischaemic stroke?
Radiography 17 (2011) 254e259
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Radiography journal homepage: www.elsevier.com/locate/radi
Review Article
Should cerebral microbleeds on magnetic resonance imaging contraindicate thrombolysis in patients with ischaemic stroke? A systematic review of the evidence Kate Smith a, b a b
John Radcliffe Hospital, Oxford, UK University of Salford, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 September 2010 Received in revised form 5 April 2011 Accepted 8 April 2011 Available online 4 May 2011
Rationale: Cerebral microbleeds (CMBs) may be a marker for increased risk of symptomatic intracranial haemorrhage (SICH) following thrombolysis of patients with ischaemic stroke. This study aims to determine whether the risk of SICH in patients with CMBs is sufficient that thrombolysis should be withheld. Methodology: Systematic review, with literature searched using bibliographic databases and crossreferencing from relevant papers to identify papers meeting predefined criteria. Conclusions: Current research indicates that while risk of SICH may be slightly elevated in patients with CMBs who receive thrombolysis, it is outweighed by the potential benefits of thrombolysis. It is not clear whether large numbers, or particular patterns, of CMBs indicate significantly increased risk. Evidence was found of inconsistency in both the diagnosis and prevalence of CMBs in the studies. Further research should assess whether severe CMBs indicate a clinically significant risk, and investigate classification and epidemiology of CMBs. Ó 2011 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.
Keywords: Cerebral microbleeds Stroke Magnetic resonance imaging Thrombolysis
Introduction Stroke affects 110,000 new patients per year in England, many of whom suffer significantly decreased quality of life e 300,000 people live with disability as a result of stroke1 (data from 2005). Prompt treatment with thrombolytic (“clot-busting”) drugs can lead to better outcomes for those patients who meet the tight qualification criteria. The National Audit Office estimated that increasing the rate of thrombolysis in England from less than 1% to 9% of patients with stroke, a rate achieved by some Australian hospitals considered in the analysis, would enable complete recovery in 1500 patients who otherwise would die or be left with long term disability.2 Thrombolysis increases the risk of intracerebral haemorrhage (ICH) in stroke patients, and patients with an elevated risk of haemorrhage are excluded from thrombolytic treatment. Imaging is a key part of patient assessment, and both computed tomography (CT) and magnetic resonance imaging (MRI) may be used. Both modalities give the vital information about whether there is an acute haemorrhage, but each has advantages and disadvantages in terms of clinical information, availability and patient tolerance.
E-mail address: [email protected].
Cerebral microbleeds (CMBs) are artefacts of asymptomatic old cerebral haemorrhages which are seen only on some MRI sequences. It has been suggested that CMBs may indicate an increased risk of ICH following thrombolysis. This study reviews the literature to determine whether on current evidence the presence of CMBs should influence the decision to administer thrombolysis to stroke patients. If CMBs emerge as a predictor of haemorrhage, the arguments for including MRI in the assessment of patients for thrombolysis would be strengthened.
Background Stroke, imaging and thrombolysis Strokes produce symptoms such as one-sided muscle weakness, and vision, speech and swallowing problems. The major distinction in types of stroke is between ischaemic stroke (70e80% of strokes), where a blood clot blocks a cerebral blood vessel, and haemorrhagic stroke, where there is bleeding in the brain tissue.3 Both cause cell death due to hypoxia, either because of obstruction of a blood vessel in ischaemic stroke, or because of lack of blood supply downstream of a bleed in haemorrhagic stroke.
1078-8174/$ e see front matter Ó 2011 The College of Radiographers. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.radi.2011.04.003
K. Smith / Radiography 17 (2011) 254e259
Swift treatment with thrombolytic drugs, which stimulate the breaking down of blood clots, can improve the prognosis for patients with acute ischaemic stroke. The drugs inhibit the formation of blood clots and cause them to deteriorate, thus restoring blood supply to the areas of the brain supplied by the artery.4 Thrombolytic treatment may be given intravenously (IV) or intraarterially (IA), using tissue plasminogen activator (tPA) or urokinase (UK). Before thrombolysis, it must be established that the stroke is ischaemic rather than haemorrhagic, as if acute haemorrhage exists it will be exacerbated by thrombolysis. This is most commonly done using CT, which is widely available, better tolerated by patients than MRI, and sufficient to rule out haemorrhage.5 However, MRI is also sensitive to intracranial haemorrhage6 and can visualise other tissue characteristics of clinical significance, including the ischaemic penumbra of tissue potentially salvageable by thrombolysis,7 making it an appropriate choice for emergency assessment of stroke patients8 where not contraindicated. Thrombolysis increases the risk of ICH,9 and when assessing whether it is safe for a patient to receive thrombolysis, it is vital to identify other factors which may increase the risk of ICH. Recent reviews confirm that ICH following thrombolysis is still a significant and incompletely understood problem.10,11 It is important to understand what patient characteristics make haemorrhagic transformation following thrombolysis more likely so that these patients can be excluded from potentially harmful treatment.
255
They also point out that it is difficult to implement identical pulse sequences on different MRI equipment, complicating multi-centre comparisons. Because the appearance of CMBs is inherently an artefact of the imaging process, it is sensitive to the parameters used. Cordonnier et al.15 identified inconsistency in MRI parameters as a significant weakness in the current body of evidence on CMBs. Lee et al.,16 Cordonnier et al.17 and Gregoire et al.18 have proposed classification schemes for CMBs. Lee et al.16 relate severity to number of visible bleeds, while Cordonnier et al.17 and Gregoire et al.18 incorporated the locations and numbers of CMBs. These classification schemes have not yet been tested in any documented clinical applications. The low usage of these classification schemes may be due to the continuing uncertainty about the clinical significance of CMBs, and also because those of Cordonnier et al.17 and Gregoire et al.18 were recently proposed. It has been found that the presence of CMBs makes spontaneous haemorrhage12,19 more likely, so it is plausible to hypothesise that haemorrhage following thrombolysis is also more likely. It has been proposed that thrombolysis should be withheld from patients with CMBs.20 This review assesses studies into the incidence of ICH following thrombolysis in stroke patients with and without CMBs, to see whether CMBs are likely to be a significant risk factor for post-thrombolysis ICH, and on the basis of these makes recommendations for clinical practice and further research. Methodology
Cerebral microbleeds Formulation of research question Cerebral microbleeds (CMBs) are signal voids seen only on T2*-weighted MRI.12 They appear as rounded, hypointense lesions of less than 0.5 cm in size13 (see Fig. 1). Histological investigation of these appearances found them to be the breakdown products of old bleeds from cerebral vessels which are in themselves asymptomatic, but are indicative of several types of small blood vessel disease which make future ICH more likely.14 CMBs are microscopic (<1 mm in diameter) but their high magnetic susceptibility, due to their iron content, causes much larger signal voids on T2*-weighted sequences, an effect known as “blooming”.12 There is significant variation in the distribution and severity of CMBs which may reflect their clinical significance. In a systematic review of CMB studies, Cordonnier et al.15 found considerable uncertainty about the clinical and therapeutic significance of CMBs. Greenberg et al.12 discuss the sensitivity of the detection of CMBs to MRI parameters: field strength; slice thickness; echo time; and choice of echo-planar imaging or conventional T2*-weighted imaging all have significant effects on the apparent size of the CMB.
The PICO (Patient, Intervention, Comparison, Outcome) model21 was used: Patient: patients who have suffered ischaemic stroke (diagnosed by either MRI or CT), and who have CMBs visible on pretreatment MRI; Intervention: thrombolysis; Comparison: patients without CMBs; Outcome: SICH; to give the research question: Is the incidence of ICH following thrombolysis greater for patients with CMBs than for those without? The question was addressed by a systematic review of literature. Systematic review is robust because the full range of preceding work can be included, improving generalisability by combining studies conducted on different populations, and enabling the reviewer to choose the best studies available.22
Figure 1. Appearance of cerebral microbleeds on T2* MRI.
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Search strategy Online research databases were searched: OVID, ISI Web of Science and the Cochrane collaboration. Hand searching and citation maps (Scopus) were used to follow up references in key papers and ensure that the most up-to-date research was included.23 The keywords used were: stroke, MRI, microbleeds, haemorrhage, thrombolysis. Limits were applied by setting parameters on the database search:
analysis, and studies were not chosen to be “combinable” in this way.27 This review is a descriptive review aimed at applying evidence to practice rather than integrating studies to generate new evidence of greater precision than the original papers.28 To achieve objective and structured analysis, a critical appraisal tool was used,29 which sets out generic issues relevant to study design such as sampling techniques and outcome measures used. Additional factors relevant to this question were added to highlight key variations in method between the studies:
Literature in English only, as resources were not available for translation; Studies dated from 2002-present day e the initial papers in the field24,25 appeared in 2002.
MRI protocol; Characteristics of clinicians reporting scans; Thrombolysis regime; Method of monitoring during thrombolysis; Definition and classification of CMBs.
Inclusion criteria Primary research papers; Patients with ischaemic stroke, diagnosed clinically with acute haemorrhage excluded by imaging (MRI or CT), who have CMBs visible on MRI; Treatment with thrombolytic drugs: tPA or UK delivered intravenously or intraarterially; Patient monitoring with MRI or CT and clinical measures to assess occurrence of ICH.
Ethics Ethical approval was not sought because it is not required for systematic reviews which do not directly involve people or their data, and does not fall into any category evaluated by Research Ethics Committees.30 Results Search, carried out in August 2008, and repeated in November 2010, found 5 papers meeting all criteria.24,31e35 Key data are summarised in Table 1.
Exclusion criteria Interventions with anti-thrombotic drugs, which increase the risk of bleeding in patients with CMBs19 e it would be difficult to attribute any increase in haemorrhage to thrombolysis; Co-morbidities such as Moya Moya disease and sickle cell anaemia, which are independent causes of stroke.26
Analysis Literature analysis requires evaluation of the quality of studies, summary of evidence presented and interpretation of results.23 In this case, resources were not available to enable a statistical meta-
Discussion Experimental design Kidwell et al.24 detail a case study of a 96-year-old female with two CMBs, who developed ICH at the site of a CMB distant from the ischaemic field. Other cases have been reported where catastrophic ICH has occurred at the location of a CMB following thrombolysis.36e39 Such case studies are interesting spurs to further research, but in themselves constitute only anecdotal evidence which needs to be more systematically investigated.40
Table 1 Summary of studies included in systematic review. Study
Study type
Kidwell et al., 2002
Retrospective, single centre
Derex et al., 2004 Kakuda et al., 2005
Kim et al., 2006 Fiehler et al., 2007
CMB definition
Thrombolysis regime
Outcome criteria
Conclusions
41
Present/not present, <5 mm
ICH with worsening of 4 points on NIHSS or 1 point on level of consciousness
CMBs may be a marker of increased risk of ICH following thrombolysis
Retrospective, single centre
44
70
ICH with worsening of 4 points on NIHSS or 1 point on level of consciousness Minor SICH: ICH with 2e3 point deterioration on NIHSS; Major SICH: ICH with 4 point deterioration on NIHSS ICH with any worsening on NIHSS within 48 h
Patients with CMBs can be thrombolysed safely
Prospective, 3 centres (USA, Canada and Belgium) Retrospective, single centre
Present/not present, <5 mm Present/not present, <5 mm
IV/IA tPA within 3 h; IA UK or tPA within 6 h (ant. circulation ischaemia) or 12 h (post. circulation ischaemia) (numbers of patients not given); mechanical clot disruption during IA thrombolysis IV tPA at two different doses within 7h
Prospective, 13 centres (Europe, North America, Asia)
Sample size
65
570
Graded 1-4 (as in Lee et al., 2002) Present/not present, <5 mm
IV tPA within 6 h
IV tPA within 3 h (12 patients), IA UK within 6 h (53 patients) IV tPA within 6 h
ICH with worsening of 4 points on NIHSS
CMBs do not appear to increase the risk of ICH or SICH following thrombolysis Small and large numbers of CMBs are not independent risk factors for ICH or SICH after thrombolysis Increased risk of SICH following thrombolysis in patients with CMBs is unlikely to exceed the benefits of thrombolysis
K. Smith / Radiography 17 (2011) 254e259
Three of the studies (Kidwell et al.,24 Derex et al.31 and Kim et al.33) are retrospective studies based on patients at a single centre. Retrospective studies, based on analysis of cases that took place prior to the study commencing, are susceptible to variations in clinical practice where no study protocol was defined, compromising the consistency of assessment and treatment.41 Including patients from only one centre increases the likelihood that results are due to characteristics of the local population or of clinical practice at that centre, reducing the generalisability of the study. Prospective, multi-centre studies were carried out by Kakuda et al.32 and Fiehler et al.34 Kakuda et al.32 include patients from study centres in USA, Canada and Belgium, while Fiehler et al.34 ran an international collaboration incorporating several research groups who prospectively studied 570 patients at 13 centres in Europe, North America and Asia. The inclusion of these diverse populations and treatment centres reduces the likelihood of bias due to local demographics or clinical practice and means the results are more likely to be applicable to a variety of settings. Planning studies prospectively means that protocols can be designed to ensure comparability of the participating centres. The study of Kakuda et al.32 is part of a larger project (the Diffusionweighted imaging Evaluation For Understanding Stroke Evolution (DEFUSE) study) so advantage could be taken of an existing network of stroke centres and pre-agreed protocols. Fiehler et al.34 defined consistent standards for thrombolytic treatment and definition of ICH. The only study to perform a power calculation to determine a sufficient sample size is that of Fiehler et al.34 The variables they use for prevalence of CMBs, incidence of haemorrhage in stroke patients receiving thrombolysis, and risk of ICH in patients without CMBs, are appropriately chosen with reference to relevant literature. Their calculation gives a minimum sample size of 568 patients to rule out a statistically significant increased risk of ICH in patients with CMBs. By this standard, Fiehler et al.34 is the only paper reviewed here to have an adequate number of study participants. All of the other authors recognise small sample size as a limitation of their study.
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Table 2 Imaging protocols for detection of CMBs. Study
Protocol for identifying CMBs
Kidwell et al., 200224 GRE sequence, 1.5 T, 7 mm slice thickness, TE 15 ms (7 patients) or EPIeSWI 1.5T, 5e7 mm slick thickness, TE 60 ms (all 41 patients) GRE sequence, 1.5T, 5 mm slice thickness, TE 26 ms Derex et al., 200431 Kakuda et al., 200532 GRE sequence, 1.5T, 5 mm slice thickness, TE 14e47 ms Kim et al., 200633 GRE sequence, field strength unspecified, 5 mm slice thickness, TE 30 ms 34 GRE sequence, field strength unspecified, Fiehler et al., 2007 5e7 mm slice thickness, TE 14e49 ms
could be due to confounding factors related to the recruitment of patients. Fiehler et al.34 find significant variability in the prevalence of CMBs at the 13 centres. They conclude that single centre data cannot be easily generalised to other centres. No data is supplied about the locations or characteristics of the centres with unusually high or low prevalence of CMBs. Correspondence from Vernooij et al.44 following the publication of Fiehler et al.34 debated the significance of the variation in prevalence, suggesting that CMBs were underreported due to variations in MRI sequences. Fiehler et al.34 cite the result of Lee et al.45 that interobserver agreement on CMBs is high, but this study only considers two operators at the same institution which is inadequate to extrapolate to an international study using diverse MRI scanners and protocols. Vernooij et al.44 argue that the use of consistent MRI protocols could reveal a significant risk of ICH following thrombolysis for patients with CMBs. All studies except that of Kim et al.,33 who stratify according to number of CMBs, have only two groups of patients: one with CMBs and one without CMBs. There is no further analysis of the number or location of CMBs. However, a greater number of CMBs may indicate more severe microangiopathy and a greater risk of haemorrhage. The location and severity of CMBs should be analysed in case a relationship can be observed between a certain distribution of CMBs and the prevalence of ICH.
Thrombolytic interventions The studies reviewed vary in their thrombolysis regimes (see Table 1). This variation in treatment is a possible confounding factor when comparing study results as UK has been associated with higher rates of haemorrhage than tPA,42 as has IA thrombolysis using either UK or a combination of UK and tPA.43 Identification and classification of CMBs The definition of CMBs is similar in all studies (see Table 1). Table 2 shows a selection of the imaging parameters used for identifying CMBs, based on the parameters identified as important by Greenberg et al.12 There is variability in the parameters used, which is inevitable when different imaging equipment is being compared. These parameters have been identified as having a significant effect on appearance of CMBs: further study is warranted to evaluate the comparability of protocols across centres. Table 3 shows the prevalence of CMBs found in each study, which are similar apart from that of Kim et al.33 which is significantly higher. Kim et al.33 do not discuss the high prevalence of CMBs in their population compared with that of previous studies. This difference suggests that either the population is not comparable or the identification of CMBs on MRI is different, because of rater variability or differences in imaging parameters. In their systematic review, Cordonnier et al.15 identified a higher prevalence of CMBs among Asians with ischaemic stroke, but suggest this
Outcome measures When considering the effects of thrombolysis, symptomatic ICH (SICH) should be used as the outcome measure, to avoid overestimating negative outcomes.46 All of the studies use a combination of imaging (CT or MRI) and clinical assessment using the NIHSS assessment, which incorporates indicators of consciousness and visual, motor and speech function to give an overall stroke severity score.47 The time points at which patients are examined vary: all do some kind of imaging within 1e3 days, but subsequent imaging varies considerably (Table 4). None explicitly justify their choice of monitoring point with any reference to usual times of onset of SICH following thrombolysis. The National Institute of Neurological Disorders and Stroke study48 found the onset of SICH that can be
Table 3 Prevalence of CMBs in studies. Study
Sample
Sample with CMBs
Prevalence of CMBs (%)
Kidwell et al., 200224 Derex et al., 200431 Kakuda et al., 200532 Kim et al., 200633 Fiehler et al., 200734
41 44 70 65 570
5 8 11 25 86
12.20 18.18 15.71 38.46 15.09
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Table 4 Imaging protocols for monitoring ICH. Study
Protocol for monitoring SICH
Kidwell et al., 200224 Derex et al., 200431
CT and NIHSS immediately and at 24 h. CT and NIHSS at 24 6 h, day 7 and on neurological deterioration. MRI and NIHSS at 3e6 h and day 30 and MRI or CT on neurological deterioration. MRI at 1e3 days, NIHSS 24 h and day 7. MRI and NIHSS at 1e10 days after stroke onset either because of clinical deterioration or after a predefined interval of 5e10 days.
Kakuda et al., 200532 Kim et al., 200633 Fiehler et al., 200734
related to thrombolysis to be between 24 and 36 h, so the monitoring time period of all studies except Kidwell et al.24 should be appropriate to detect cases of SICH. No study found a statistically significant increase in the risk of SICH among ischaemic stroke patients with CMBs undergoing thrombolysis, although most studies had too small a sample size to form a statistically significant conclusion. The largest scale study34 found that a risk cannot be ruled out, but emphasised the clinical decision to be made in recommending a patient for thrombolysis: risks of undergoing the treatment should be weighed against potential benefits. They find that any additional risk of SICH following thrombolysis in patients with CMBs is small, and outweighed by the benefits of thrombolysis. Limitations of studies The most rigorous form of study is the randomised controlled trial (RCT).49 No study reviewed here reaches this standard. An RCT would require patients to be randomly assigned to groups, one receiving thrombolysis and one receiving a placebo. However, the current understanding of the benefits of thrombolysis is such that it would be unethical to deny this treatment. No analysis is made of the relationship of CMB location and severity to the incidence of ICH in any study except for that of Kim et al.,33 which was limited by small sample size. In all studies, there are small numbers of patients with many CMBs. Fiehler et al.34 recognise this limitation and recommend a large-scale study on patients with multiple CMBs. The only thrombolysis regime used consistently is IV tPA in isolation. It is not possible on the evidence available to come to any conclusion about the effect of other methods of thrombolysis on incidence of ICH in patients with CMBs. The generalisability of the patient groups studied is questionable: there is higher prevalence of CMBs in the study of Kim et al.33 which could be real, or chance. This, with the variation in prevalence of CMBs in Fiehler et al.,34 is an area of inconsistency that should be further researched. Potential areas of exploration include consistency of MRI protocols; consistency of identification of CMBs by radiologists; variations in prevalence of CMBs according to factors such as age, sex, race, co-morbidities, or lifestyle factors. Conclusion These studies range from initial small studies raising alarm about the possibility of inducing ICH by administering thrombolysis to stroke patients with CMBs,24 to larger studies finding no significant risk.34 However, questions remain about patients with a large extent of CMBs and the relationship of more detailed CMB characteristics to bleeding-prone microangiopathy, and there is uncertainty about consistency of identification of CMBs across multiple centres.
This review suggests that there is currently no justification for excluding patients with CMBs from thrombolysis, indeed that to do so would be unethical. However, there is insufficient evidence about patients with severe CMBs, who may have a significantly increased risk of ICH. Inconsistencies in the parameters for imaging CMBs and in their classification could also mask an important link. CMBs and their relation to ICH following thrombolysis remain incompletely understood. On the existing evidence there is no need to make MRI an essential part of pre-thrombolysis assessment in order to identify CMBs (although there may be other compelling arguments for this, given MRI’s superior early lesion detection, out of the scope of this study), to redesign MRI protocols, or to focus more on CMBs when reporting scans of stroke patients. Conflict of interest statement There are no conflicts of interest. Acknowledgements This study was conducted as a student of the University of Salford. Thanks to Leslie Robinson of the University of Salford for her support and encouragement. References 1. Department of Health. National stroke strategy; 2007. 2. National Audit Office. Reducing brain damage: faster access to better stroke care, http://www.nao.org.uk/publications/nao_reports/05%E2%80%9306/0506452. pdf; 2005 (03/05/2009). 3. Book D. Alterations in brain function. In: Porth C, editor. Essentials of pathophysiology. Lippincott Williams & Wilkins; 2004. 4. Gunderman RB. Essential radiology. Thieme; 2006. 5. Kohrmann M, Juttler E, Fiebach JB, et al. MRI versus CT-based thrombolysis treatment within and beyond the 3 h time window after stroke onset: a cohort study. Lancet Neurol 2006;5:661e7. England. 6. Fiebach JB, Schellinger PD, Gass A, et al. Stroke magnetic resonance imaging is accurate in hyperacute intracerebral hemorrhage: a multicenter study on the validity of stroke imaging. Stroke Feb 2004;35(2):502e6. 7. Fink JN, Caplan LR. The importance of specific diagnosis in stroke patient management. In: Davis S, Fisher M, Warach S, editors. Magnetic resonance imaging in stroke. Cambridge University Press; 2003. 8. Chalela JA, Kidwell CS, Nentwich LM, et al. Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison. Lancet Jan 27 2007;369(9558):293e8. 9. Larrue V, von Kummer RR, Muller A, Bluhmki E. Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the EuropeaneAustralasian Acute Stroke Study (ECASS II). Stroke Feb 2001; 32(2):438e41. 10. Derex L, Nighoghossian N. Intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: an update. J Neurol Neurosurg Psychiatr Oct 2008; 79(10):1093e9. 11. Kidwell CS, Wintermark M. Imaging of intracranial haemorrhage. Lancet Neurol Mar 2008;7(3):256e67. 12. Greenberg SM, Vernooij MW, Cordonnier C, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol Feb 2009;8(2):165e74. 13. Werring D. Cerebral microbleeds in stroke. Adv Clinical Neuroscience Rehabilitation 2007;7(1):6e8. 14. Fazekas F, Kleinert R, Roob G, et al. Histopathologic analysis of foci of signal loss on gradient-echo T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds. AJNR Am J Neuroradiol Apr 1999;20(4):637e42. 15. Cordonnier C, Al-Shahi Salman R, Wardlaw J. Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. Brain 2007;130:1988e2003. England. 16. Lee SH, Bae HJ, Yoon BW, Kim H, Kim DE, Roh JK. Low concentration of serum total cholesterol is associated with multifocal signal loss lesions on gradientecho magnetic resonance imaging: analysis of risk factors for multifocal signal loss lesions. Stroke Dec 2002;33(12):2845e9. 17. Cordonnier C, Potter GM, Jackson CA, et al. improving interrater agreement about brain microbleeds: development of the Brain Observer MicroBleed Scale (BOMBS). Stroke Jan 2009;40(1):94e9. 18. Gregoire SM, Chaudhary UJ, Brown MM, et al. The Microbleed Anatomical Rating Scale (MARS): reliability of a tool to map brain microbleeds. Neurology Nov 24 2009;73(21):1759e66.
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Radiography journal homepage: www.elsevier.com/locate/radi
Review Article
Should cerebral microbleeds on magnetic resonance imaging contraindicate thrombolysis in patients with ischaemic stroke? A systematic review of the evidence Kate Smith a, b a b
John Radcliffe Hospital, Oxford, UK University of Salford, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 September 2010 Received in revised form 5 April 2011 Accepted 8 April 2011 Available online 4 May 2011
Rationale: Cerebral microbleeds (CMBs) may be a marker for increased risk of symptomatic intracranial haemorrhage (SICH) following thrombolysis of patients with ischaemic stroke. This study aims to determine whether the risk of SICH in patients with CMBs is sufficient that thrombolysis should be withheld. Methodology: Systematic review, with literature searched using bibliographic databases and crossreferencing from relevant papers to identify papers meeting predefined criteria. Conclusions: Current research indicates that while risk of SICH may be slightly elevated in patients with CMBs who receive thrombolysis, it is outweighed by the potential benefits of thrombolysis. It is not clear whether large numbers, or particular patterns, of CMBs indicate significantly increased risk. Evidence was found of inconsistency in both the diagnosis and prevalence of CMBs in the studies. Further research should assess whether severe CMBs indicate a clinically significant risk, and investigate classification and epidemiology of CMBs. Ó 2011 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.
Keywords: Cerebral microbleeds Stroke Magnetic resonance imaging Thrombolysis
Introduction Stroke affects 110,000 new patients per year in England, many of whom suffer significantly decreased quality of life e 300,000 people live with disability as a result of stroke1 (data from 2005). Prompt treatment with thrombolytic (“clot-busting”) drugs can lead to better outcomes for those patients who meet the tight qualification criteria. The National Audit Office estimated that increasing the rate of thrombolysis in England from less than 1% to 9% of patients with stroke, a rate achieved by some Australian hospitals considered in the analysis, would enable complete recovery in 1500 patients who otherwise would die or be left with long term disability.2 Thrombolysis increases the risk of intracerebral haemorrhage (ICH) in stroke patients, and patients with an elevated risk of haemorrhage are excluded from thrombolytic treatment. Imaging is a key part of patient assessment, and both computed tomography (CT) and magnetic resonance imaging (MRI) may be used. Both modalities give the vital information about whether there is an acute haemorrhage, but each has advantages and disadvantages in terms of clinical information, availability and patient tolerance.
E-mail address: [email protected].
Cerebral microbleeds (CMBs) are artefacts of asymptomatic old cerebral haemorrhages which are seen only on some MRI sequences. It has been suggested that CMBs may indicate an increased risk of ICH following thrombolysis. This study reviews the literature to determine whether on current evidence the presence of CMBs should influence the decision to administer thrombolysis to stroke patients. If CMBs emerge as a predictor of haemorrhage, the arguments for including MRI in the assessment of patients for thrombolysis would be strengthened.
Background Stroke, imaging and thrombolysis Strokes produce symptoms such as one-sided muscle weakness, and vision, speech and swallowing problems. The major distinction in types of stroke is between ischaemic stroke (70e80% of strokes), where a blood clot blocks a cerebral blood vessel, and haemorrhagic stroke, where there is bleeding in the brain tissue.3 Both cause cell death due to hypoxia, either because of obstruction of a blood vessel in ischaemic stroke, or because of lack of blood supply downstream of a bleed in haemorrhagic stroke.
1078-8174/$ e see front matter Ó 2011 The College of Radiographers. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.radi.2011.04.003
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Swift treatment with thrombolytic drugs, which stimulate the breaking down of blood clots, can improve the prognosis for patients with acute ischaemic stroke. The drugs inhibit the formation of blood clots and cause them to deteriorate, thus restoring blood supply to the areas of the brain supplied by the artery.4 Thrombolytic treatment may be given intravenously (IV) or intraarterially (IA), using tissue plasminogen activator (tPA) or urokinase (UK). Before thrombolysis, it must be established that the stroke is ischaemic rather than haemorrhagic, as if acute haemorrhage exists it will be exacerbated by thrombolysis. This is most commonly done using CT, which is widely available, better tolerated by patients than MRI, and sufficient to rule out haemorrhage.5 However, MRI is also sensitive to intracranial haemorrhage6 and can visualise other tissue characteristics of clinical significance, including the ischaemic penumbra of tissue potentially salvageable by thrombolysis,7 making it an appropriate choice for emergency assessment of stroke patients8 where not contraindicated. Thrombolysis increases the risk of ICH,9 and when assessing whether it is safe for a patient to receive thrombolysis, it is vital to identify other factors which may increase the risk of ICH. Recent reviews confirm that ICH following thrombolysis is still a significant and incompletely understood problem.10,11 It is important to understand what patient characteristics make haemorrhagic transformation following thrombolysis more likely so that these patients can be excluded from potentially harmful treatment.
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They also point out that it is difficult to implement identical pulse sequences on different MRI equipment, complicating multi-centre comparisons. Because the appearance of CMBs is inherently an artefact of the imaging process, it is sensitive to the parameters used. Cordonnier et al.15 identified inconsistency in MRI parameters as a significant weakness in the current body of evidence on CMBs. Lee et al.,16 Cordonnier et al.17 and Gregoire et al.18 have proposed classification schemes for CMBs. Lee et al.16 relate severity to number of visible bleeds, while Cordonnier et al.17 and Gregoire et al.18 incorporated the locations and numbers of CMBs. These classification schemes have not yet been tested in any documented clinical applications. The low usage of these classification schemes may be due to the continuing uncertainty about the clinical significance of CMBs, and also because those of Cordonnier et al.17 and Gregoire et al.18 were recently proposed. It has been found that the presence of CMBs makes spontaneous haemorrhage12,19 more likely, so it is plausible to hypothesise that haemorrhage following thrombolysis is also more likely. It has been proposed that thrombolysis should be withheld from patients with CMBs.20 This review assesses studies into the incidence of ICH following thrombolysis in stroke patients with and without CMBs, to see whether CMBs are likely to be a significant risk factor for post-thrombolysis ICH, and on the basis of these makes recommendations for clinical practice and further research. Methodology
Cerebral microbleeds Formulation of research question Cerebral microbleeds (CMBs) are signal voids seen only on T2*-weighted MRI.12 They appear as rounded, hypointense lesions of less than 0.5 cm in size13 (see Fig. 1). Histological investigation of these appearances found them to be the breakdown products of old bleeds from cerebral vessels which are in themselves asymptomatic, but are indicative of several types of small blood vessel disease which make future ICH more likely.14 CMBs are microscopic (<1 mm in diameter) but their high magnetic susceptibility, due to their iron content, causes much larger signal voids on T2*-weighted sequences, an effect known as “blooming”.12 There is significant variation in the distribution and severity of CMBs which may reflect their clinical significance. In a systematic review of CMB studies, Cordonnier et al.15 found considerable uncertainty about the clinical and therapeutic significance of CMBs. Greenberg et al.12 discuss the sensitivity of the detection of CMBs to MRI parameters: field strength; slice thickness; echo time; and choice of echo-planar imaging or conventional T2*-weighted imaging all have significant effects on the apparent size of the CMB.
The PICO (Patient, Intervention, Comparison, Outcome) model21 was used: Patient: patients who have suffered ischaemic stroke (diagnosed by either MRI or CT), and who have CMBs visible on pretreatment MRI; Intervention: thrombolysis; Comparison: patients without CMBs; Outcome: SICH; to give the research question: Is the incidence of ICH following thrombolysis greater for patients with CMBs than for those without? The question was addressed by a systematic review of literature. Systematic review is robust because the full range of preceding work can be included, improving generalisability by combining studies conducted on different populations, and enabling the reviewer to choose the best studies available.22
Figure 1. Appearance of cerebral microbleeds on T2* MRI.
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Search strategy Online research databases were searched: OVID, ISI Web of Science and the Cochrane collaboration. Hand searching and citation maps (Scopus) were used to follow up references in key papers and ensure that the most up-to-date research was included.23 The keywords used were: stroke, MRI, microbleeds, haemorrhage, thrombolysis. Limits were applied by setting parameters on the database search:
analysis, and studies were not chosen to be “combinable” in this way.27 This review is a descriptive review aimed at applying evidence to practice rather than integrating studies to generate new evidence of greater precision than the original papers.28 To achieve objective and structured analysis, a critical appraisal tool was used,29 which sets out generic issues relevant to study design such as sampling techniques and outcome measures used. Additional factors relevant to this question were added to highlight key variations in method between the studies:
Literature in English only, as resources were not available for translation; Studies dated from 2002-present day e the initial papers in the field24,25 appeared in 2002.
MRI protocol; Characteristics of clinicians reporting scans; Thrombolysis regime; Method of monitoring during thrombolysis; Definition and classification of CMBs.
Inclusion criteria Primary research papers; Patients with ischaemic stroke, diagnosed clinically with acute haemorrhage excluded by imaging (MRI or CT), who have CMBs visible on MRI; Treatment with thrombolytic drugs: tPA or UK delivered intravenously or intraarterially; Patient monitoring with MRI or CT and clinical measures to assess occurrence of ICH.
Ethics Ethical approval was not sought because it is not required for systematic reviews which do not directly involve people or their data, and does not fall into any category evaluated by Research Ethics Committees.30 Results Search, carried out in August 2008, and repeated in November 2010, found 5 papers meeting all criteria.24,31e35 Key data are summarised in Table 1.
Exclusion criteria Interventions with anti-thrombotic drugs, which increase the risk of bleeding in patients with CMBs19 e it would be difficult to attribute any increase in haemorrhage to thrombolysis; Co-morbidities such as Moya Moya disease and sickle cell anaemia, which are independent causes of stroke.26
Analysis Literature analysis requires evaluation of the quality of studies, summary of evidence presented and interpretation of results.23 In this case, resources were not available to enable a statistical meta-
Discussion Experimental design Kidwell et al.24 detail a case study of a 96-year-old female with two CMBs, who developed ICH at the site of a CMB distant from the ischaemic field. Other cases have been reported where catastrophic ICH has occurred at the location of a CMB following thrombolysis.36e39 Such case studies are interesting spurs to further research, but in themselves constitute only anecdotal evidence which needs to be more systematically investigated.40
Table 1 Summary of studies included in systematic review. Study
Study type
Kidwell et al., 2002
Retrospective, single centre
Derex et al., 2004 Kakuda et al., 2005
Kim et al., 2006 Fiehler et al., 2007
CMB definition
Thrombolysis regime
Outcome criteria
Conclusions
41
Present/not present, <5 mm
ICH with worsening of 4 points on NIHSS or 1 point on level of consciousness
CMBs may be a marker of increased risk of ICH following thrombolysis
Retrospective, single centre
44
70
ICH with worsening of 4 points on NIHSS or 1 point on level of consciousness Minor SICH: ICH with 2e3 point deterioration on NIHSS; Major SICH: ICH with 4 point deterioration on NIHSS ICH with any worsening on NIHSS within 48 h
Patients with CMBs can be thrombolysed safely
Prospective, 3 centres (USA, Canada and Belgium) Retrospective, single centre
Present/not present, <5 mm Present/not present, <5 mm
IV/IA tPA within 3 h; IA UK or tPA within 6 h (ant. circulation ischaemia) or 12 h (post. circulation ischaemia) (numbers of patients not given); mechanical clot disruption during IA thrombolysis IV tPA at two different doses within 7h
Prospective, 13 centres (Europe, North America, Asia)
Sample size
65
570
Graded 1-4 (as in Lee et al., 2002) Present/not present, <5 mm
IV tPA within 6 h
IV tPA within 3 h (12 patients), IA UK within 6 h (53 patients) IV tPA within 6 h
ICH with worsening of 4 points on NIHSS
CMBs do not appear to increase the risk of ICH or SICH following thrombolysis Small and large numbers of CMBs are not independent risk factors for ICH or SICH after thrombolysis Increased risk of SICH following thrombolysis in patients with CMBs is unlikely to exceed the benefits of thrombolysis
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Three of the studies (Kidwell et al.,24 Derex et al.31 and Kim et al.33) are retrospective studies based on patients at a single centre. Retrospective studies, based on analysis of cases that took place prior to the study commencing, are susceptible to variations in clinical practice where no study protocol was defined, compromising the consistency of assessment and treatment.41 Including patients from only one centre increases the likelihood that results are due to characteristics of the local population or of clinical practice at that centre, reducing the generalisability of the study. Prospective, multi-centre studies were carried out by Kakuda et al.32 and Fiehler et al.34 Kakuda et al.32 include patients from study centres in USA, Canada and Belgium, while Fiehler et al.34 ran an international collaboration incorporating several research groups who prospectively studied 570 patients at 13 centres in Europe, North America and Asia. The inclusion of these diverse populations and treatment centres reduces the likelihood of bias due to local demographics or clinical practice and means the results are more likely to be applicable to a variety of settings. Planning studies prospectively means that protocols can be designed to ensure comparability of the participating centres. The study of Kakuda et al.32 is part of a larger project (the Diffusionweighted imaging Evaluation For Understanding Stroke Evolution (DEFUSE) study) so advantage could be taken of an existing network of stroke centres and pre-agreed protocols. Fiehler et al.34 defined consistent standards for thrombolytic treatment and definition of ICH. The only study to perform a power calculation to determine a sufficient sample size is that of Fiehler et al.34 The variables they use for prevalence of CMBs, incidence of haemorrhage in stroke patients receiving thrombolysis, and risk of ICH in patients without CMBs, are appropriately chosen with reference to relevant literature. Their calculation gives a minimum sample size of 568 patients to rule out a statistically significant increased risk of ICH in patients with CMBs. By this standard, Fiehler et al.34 is the only paper reviewed here to have an adequate number of study participants. All of the other authors recognise small sample size as a limitation of their study.
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Table 2 Imaging protocols for detection of CMBs. Study
Protocol for identifying CMBs
Kidwell et al., 200224 GRE sequence, 1.5 T, 7 mm slice thickness, TE 15 ms (7 patients) or EPIeSWI 1.5T, 5e7 mm slick thickness, TE 60 ms (all 41 patients) GRE sequence, 1.5T, 5 mm slice thickness, TE 26 ms Derex et al., 200431 Kakuda et al., 200532 GRE sequence, 1.5T, 5 mm slice thickness, TE 14e47 ms Kim et al., 200633 GRE sequence, field strength unspecified, 5 mm slice thickness, TE 30 ms 34 GRE sequence, field strength unspecified, Fiehler et al., 2007 5e7 mm slice thickness, TE 14e49 ms
could be due to confounding factors related to the recruitment of patients. Fiehler et al.34 find significant variability in the prevalence of CMBs at the 13 centres. They conclude that single centre data cannot be easily generalised to other centres. No data is supplied about the locations or characteristics of the centres with unusually high or low prevalence of CMBs. Correspondence from Vernooij et al.44 following the publication of Fiehler et al.34 debated the significance of the variation in prevalence, suggesting that CMBs were underreported due to variations in MRI sequences. Fiehler et al.34 cite the result of Lee et al.45 that interobserver agreement on CMBs is high, but this study only considers two operators at the same institution which is inadequate to extrapolate to an international study using diverse MRI scanners and protocols. Vernooij et al.44 argue that the use of consistent MRI protocols could reveal a significant risk of ICH following thrombolysis for patients with CMBs. All studies except that of Kim et al.,33 who stratify according to number of CMBs, have only two groups of patients: one with CMBs and one without CMBs. There is no further analysis of the number or location of CMBs. However, a greater number of CMBs may indicate more severe microangiopathy and a greater risk of haemorrhage. The location and severity of CMBs should be analysed in case a relationship can be observed between a certain distribution of CMBs and the prevalence of ICH.
Thrombolytic interventions The studies reviewed vary in their thrombolysis regimes (see Table 1). This variation in treatment is a possible confounding factor when comparing study results as UK has been associated with higher rates of haemorrhage than tPA,42 as has IA thrombolysis using either UK or a combination of UK and tPA.43 Identification and classification of CMBs The definition of CMBs is similar in all studies (see Table 1). Table 2 shows a selection of the imaging parameters used for identifying CMBs, based on the parameters identified as important by Greenberg et al.12 There is variability in the parameters used, which is inevitable when different imaging equipment is being compared. These parameters have been identified as having a significant effect on appearance of CMBs: further study is warranted to evaluate the comparability of protocols across centres. Table 3 shows the prevalence of CMBs found in each study, which are similar apart from that of Kim et al.33 which is significantly higher. Kim et al.33 do not discuss the high prevalence of CMBs in their population compared with that of previous studies. This difference suggests that either the population is not comparable or the identification of CMBs on MRI is different, because of rater variability or differences in imaging parameters. In their systematic review, Cordonnier et al.15 identified a higher prevalence of CMBs among Asians with ischaemic stroke, but suggest this
Outcome measures When considering the effects of thrombolysis, symptomatic ICH (SICH) should be used as the outcome measure, to avoid overestimating negative outcomes.46 All of the studies use a combination of imaging (CT or MRI) and clinical assessment using the NIHSS assessment, which incorporates indicators of consciousness and visual, motor and speech function to give an overall stroke severity score.47 The time points at which patients are examined vary: all do some kind of imaging within 1e3 days, but subsequent imaging varies considerably (Table 4). None explicitly justify their choice of monitoring point with any reference to usual times of onset of SICH following thrombolysis. The National Institute of Neurological Disorders and Stroke study48 found the onset of SICH that can be
Table 3 Prevalence of CMBs in studies. Study
Sample
Sample with CMBs
Prevalence of CMBs (%)
Kidwell et al., 200224 Derex et al., 200431 Kakuda et al., 200532 Kim et al., 200633 Fiehler et al., 200734
41 44 70 65 570
5 8 11 25 86
12.20 18.18 15.71 38.46 15.09
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Table 4 Imaging protocols for monitoring ICH. Study
Protocol for monitoring SICH
Kidwell et al., 200224 Derex et al., 200431
CT and NIHSS immediately and at 24 h. CT and NIHSS at 24 6 h, day 7 and on neurological deterioration. MRI and NIHSS at 3e6 h and day 30 and MRI or CT on neurological deterioration. MRI at 1e3 days, NIHSS 24 h and day 7. MRI and NIHSS at 1e10 days after stroke onset either because of clinical deterioration or after a predefined interval of 5e10 days.
Kakuda et al., 200532 Kim et al., 200633 Fiehler et al., 200734
related to thrombolysis to be between 24 and 36 h, so the monitoring time period of all studies except Kidwell et al.24 should be appropriate to detect cases of SICH. No study found a statistically significant increase in the risk of SICH among ischaemic stroke patients with CMBs undergoing thrombolysis, although most studies had too small a sample size to form a statistically significant conclusion. The largest scale study34 found that a risk cannot be ruled out, but emphasised the clinical decision to be made in recommending a patient for thrombolysis: risks of undergoing the treatment should be weighed against potential benefits. They find that any additional risk of SICH following thrombolysis in patients with CMBs is small, and outweighed by the benefits of thrombolysis. Limitations of studies The most rigorous form of study is the randomised controlled trial (RCT).49 No study reviewed here reaches this standard. An RCT would require patients to be randomly assigned to groups, one receiving thrombolysis and one receiving a placebo. However, the current understanding of the benefits of thrombolysis is such that it would be unethical to deny this treatment. No analysis is made of the relationship of CMB location and severity to the incidence of ICH in any study except for that of Kim et al.,33 which was limited by small sample size. In all studies, there are small numbers of patients with many CMBs. Fiehler et al.34 recognise this limitation and recommend a large-scale study on patients with multiple CMBs. The only thrombolysis regime used consistently is IV tPA in isolation. It is not possible on the evidence available to come to any conclusion about the effect of other methods of thrombolysis on incidence of ICH in patients with CMBs. The generalisability of the patient groups studied is questionable: there is higher prevalence of CMBs in the study of Kim et al.33 which could be real, or chance. This, with the variation in prevalence of CMBs in Fiehler et al.,34 is an area of inconsistency that should be further researched. Potential areas of exploration include consistency of MRI protocols; consistency of identification of CMBs by radiologists; variations in prevalence of CMBs according to factors such as age, sex, race, co-morbidities, or lifestyle factors. Conclusion These studies range from initial small studies raising alarm about the possibility of inducing ICH by administering thrombolysis to stroke patients with CMBs,24 to larger studies finding no significant risk.34 However, questions remain about patients with a large extent of CMBs and the relationship of more detailed CMB characteristics to bleeding-prone microangiopathy, and there is uncertainty about consistency of identification of CMBs across multiple centres.
This review suggests that there is currently no justification for excluding patients with CMBs from thrombolysis, indeed that to do so would be unethical. However, there is insufficient evidence about patients with severe CMBs, who may have a significantly increased risk of ICH. Inconsistencies in the parameters for imaging CMBs and in their classification could also mask an important link. CMBs and their relation to ICH following thrombolysis remain incompletely understood. On the existing evidence there is no need to make MRI an essential part of pre-thrombolysis assessment in order to identify CMBs (although there may be other compelling arguments for this, given MRI’s superior early lesion detection, out of the scope of this study), to redesign MRI protocols, or to focus more on CMBs when reporting scans of stroke patients. Conflict of interest statement There are no conflicts of interest. Acknowledgements This study was conducted as a student of the University of Salford. Thanks to Leslie Robinson of the University of Salford for her support and encouragement. References 1. Department of Health. National stroke strategy; 2007. 2. National Audit Office. Reducing brain damage: faster access to better stroke care, http://www.nao.org.uk/publications/nao_reports/05%E2%80%9306/0506452. pdf; 2005 (03/05/2009). 3. Book D. Alterations in brain function. In: Porth C, editor. Essentials of pathophysiology. Lippincott Williams & Wilkins; 2004. 4. Gunderman RB. Essential radiology. Thieme; 2006. 5. Kohrmann M, Juttler E, Fiebach JB, et al. MRI versus CT-based thrombolysis treatment within and beyond the 3 h time window after stroke onset: a cohort study. Lancet Neurol 2006;5:661e7. England. 6. Fiebach JB, Schellinger PD, Gass A, et al. Stroke magnetic resonance imaging is accurate in hyperacute intracerebral hemorrhage: a multicenter study on the validity of stroke imaging. Stroke Feb 2004;35(2):502e6. 7. Fink JN, Caplan LR. The importance of specific diagnosis in stroke patient management. In: Davis S, Fisher M, Warach S, editors. Magnetic resonance imaging in stroke. Cambridge University Press; 2003. 8. Chalela JA, Kidwell CS, Nentwich LM, et al. Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison. Lancet Jan 27 2007;369(9558):293e8. 9. Larrue V, von Kummer RR, Muller A, Bluhmki E. Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the EuropeaneAustralasian Acute Stroke Study (ECASS II). Stroke Feb 2001; 32(2):438e41. 10. Derex L, Nighoghossian N. Intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: an update. J Neurol Neurosurg Psychiatr Oct 2008; 79(10):1093e9. 11. Kidwell CS, Wintermark M. Imaging of intracranial haemorrhage. Lancet Neurol Mar 2008;7(3):256e67. 12. Greenberg SM, Vernooij MW, Cordonnier C, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol Feb 2009;8(2):165e74. 13. Werring D. Cerebral microbleeds in stroke. Adv Clinical Neuroscience Rehabilitation 2007;7(1):6e8. 14. Fazekas F, Kleinert R, Roob G, et al. Histopathologic analysis of foci of signal loss on gradient-echo T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds. AJNR Am J Neuroradiol Apr 1999;20(4):637e42. 15. Cordonnier C, Al-Shahi Salman R, Wardlaw J. Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. Brain 2007;130:1988e2003. England. 16. Lee SH, Bae HJ, Yoon BW, Kim H, Kim DE, Roh JK. Low concentration of serum total cholesterol is associated with multifocal signal loss lesions on gradientecho magnetic resonance imaging: analysis of risk factors for multifocal signal loss lesions. Stroke Dec 2002;33(12):2845e9. 17. Cordonnier C, Potter GM, Jackson CA, et al. improving interrater agreement about brain microbleeds: development of the Brain Observer MicroBleed Scale (BOMBS). Stroke Jan 2009;40(1):94e9. 18. Gregoire SM, Chaudhary UJ, Brown MM, et al. The Microbleed Anatomical Rating Scale (MARS): reliability of a tool to map brain microbleeds. Neurology Nov 24 2009;73(21):1759e66.
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