8202019 cerabral microbleeds

httpslidepdfcomreaderfullcerabral-microbleeds 15

SHORT REPORT

Cerebral microbleeds and the risk of intracerebralhaemorrhage after thrombolysis for acute ischaemicstroke systematic review and meta-analysis

Andreas Charidimou1 Puneet Kakar2 Zoe Fox34 David J Werring1

An additional supplementary 1047297gure and supplementarytables 1 to 3 are publishedonline only To view these 1047297 lesplease visit the journal online(httpdxdoiorg101136jnnp-2012-303379)

1Stroke Research GroupDepartment of Brain Repair andRehabilitation UCL Institute of Neurology and The NationalHospital for Neurology and

Neurosurgery Queen SquareLondon WC1N 3BG UK2Department of StrokeMedicine Imperial CollegeHealthcare NHS TrustLondon UK3Biomedical Research CentreUCL London UK4Education Unit UCL Instituteof Neurology London UK

Correspondence toDr David J WerringStroke Research GroupDepartment of Brain Repair andRehabilitation UCL Institute of

Neurology and National Hospitalfor Neurology and NeurosurgeryBox 6 Queen Square LondonWC1N 3BG UKdwerringuclacuk

Received 3 June 2012Revised 13 August 2012Accepted 28 August 2012Published Online First28 September 2012

ABSTRACT

Background Intracerebral haemorrhage (ICH) remainsthe most devastating yet unpredictable complication of intravenous thrombolysis for acute ischaemic stroke We

performed a systematic review and meta-analysis toassess whether the presence of cerebral microbleeds(CMBs) on prethrombolysis MRI scans is associated with

an increased risk of ICHMethods We searched PubMed for studies assessingICH risk in patients with acute ischaemic stroke treated

with thrombolysis in relation to the presence of pre-treatment CMBsResults We identi 1047297ed 1047297ve studies including 790 patients

and pooled data in a meta-analysis The CMB (+) versusCMB (minus) groups were not signi 1047297cantly different in agegender or stroke severity The overall prevalence of CMBs

was 135790 (171) Amongst patients with CMBs10135 (74) experienced a symptomatic ICH afterthrombolysis compared to 29655 (44) patients

without CMBs The pooled relative risk of ICH was 190(95 CI 092 to 393 p=0082)Conclusions The available evidence does not

demonstrate a statistically signi 1047297cant increased risk of symptomatic ICH after thrombolysis for ischaemic stroke inpatients with CMBs However in view of themethodological limitations of the studies included the

clinical relevance of any potential hazard associated withCMBs remains uncertain Further studies are warranted toevaluate whether the risk of ICH might outweigh the bene 1047297t

of thrombolysis especially in patients with multiple lobar

CMBs suggestive of cerebral amyloid angiopathy

INTRODUCTIONIntravenous thrombolysis is the only effectivelicensed treatment for acute ischaemic strokeHowever the improved outcomes overall come atthe cost of a small increase in risk of intracerebralhaemorrhage (ICH) the most devastating yetunpredictable complication1 Symptomatic ICHoccurs in about 24ndash10 of cases within 24ndash36 hof thrombolysis (depending on the de1047297nitionused) and may be disabling1 2 Identifying patientsat higher risk for ICH following thrombolysis isthus an urgent clinical priority a reliable and safeway to do this could increase the overall safety pro1047297le of this widely used treatment Markers of increased risk include increasing age early ischae-mic CT changes high blood pressure hypergly-caemia clinical stroke severity as assessed by the

National Institute of Health Stroke Scale score onadmission large baseline diffusion lesion volume

and cerebral white matter changes (leukoaraiosis)but there is currently no reliable way to predictsevere ICH1 Cerebral microbleeds (CMBs)mdashsmallperivascular haemorrhages seen as well-demarcated hypointense rounded lesions on MRIsequences sensitive to magnetic susceptibility mdasharea marker of haemorrhage-prone microangiopathies(mainly hypertensive arteriopathy or cerebralamyloid angiopathy (CAA)) Because CMBs are arather speci1047297c marker for previous bleeding from

pathologically fragile cerebral small vessels3

they might help to identify a subpopulation of patientsat high risk of clinically signi1047297cant ICH4 Previousstudies have given con1047298icting results regarding thepossible risk of ICH after thrombolysis in indivi-duals with CMBs5 6 We therefore performed a sys-tematic review and meta-analysis to assess theevidence whether the presence of CMBs on pre-thrombolysis MRI scans is associated with anincreased risk of ICH

METHODS

Search strategy and selection criteria

We searched PubMed between 1 January 1995 and1 February 2012 using the following search termslsquomicrobleed(s)rsquo or lsquomicro(-)h(a)emorrhage(s)rsquo orlsquogradient-echorsquo in association with lsquothrombolyrsquo orlsquotPA rsquo or lsquotissue plasminogen activator rsquo Referencelists from all included articles and the authorsrsquoown 1047297les were also searched for relevant publica-tions Papers not published in English and casereports were excluded Two authors (AC and PK)identi1047297ed potentially relevant studies resolvingany uncertainties with a third author (DJW)

Eligibility criteriaStudies were eligible for inclusion if they had

assessed ICH risk in patients with acute ischaemicstroke treated with thrombolysis and quanti1047297edthis risk in relation to the presence of CMBs onpretreatment MRI scans

Data extractionTwo authors (AC and PK) went through all articlesselected as potentially relevant and extracted dataindependently We extracted information on type of study number and nature of participants (includingmean age and sex) MRI parameters duration of follow-up number of participants with at least oneCMB and number of participants with the outcome

event (symptomatic ICH de1047297ned according to stand-ard criteria) Consensus was reached by discussion

J Neurol Neurosurg Psychiatry 201384277ndash280 doi101136jnnp-2012-303379 277

Cerebrovascular disease

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httpslidepdfcomreaderfullcerabral-microbleeds 25

Studies were critically appraised against a checklist of key quality indicators with reference to the STROBE (STrengthening theReporting of OBservational studies in Epidemiology) statementand the ideal characteristics for a study of CMBs7 (see online sup-plementary table S1) (Clearly de1047297ned CMB criteria clear de1047297n-ition of the study population standardised MRI parametersclearly de1047297ned ICH criteria awareness of gt2 CMB mimics stan-dardised rating scale or trained observer with reported inter-rater

intra-rater agreement data on CMB distribution and adjustmentfor other ICH risk factors)

Meta-analysis We used a 1047297xed effects model to calculate the pooled relativerisk (RR) of symptomatic ICH in patients with versus withoutCMBs where weights were calculated using the inverse vari-ance method We assessed heterogeneity using I-squared andx-squared statistics and through visual inspection of the forestplot We explored publication bias with the funnel plotMeta-analyses were performed using Stata 112 (StataCorp LPTexas USA) We prepared this report with reference to MOOSE(meta-analyses of observational studies) guidelines8

RESULTS We identi1047297ed 62 articles in our initial search of PubMed 1047297vestudies including a total of 790 patients (135 with CMBs) metour inclusion criteria and were pooled in a meta-analysis5 6 9ndash11

One study was excluded12 because of overlap with a previously published cohort6 A summary of the characteristics of includedstudies is provided in table 1 and online supplementary tables S2and S3 There was no evidence of publication bias in the funnelplot (see online supplementary 1047297gure S1) The CMB (+) versusCMB (minus) groups were not signi1047297cantly different in age genderor stroke severity except that in one study higher age wasassociated with CMBs6 The overall prevalence of CMBs on pre-treatment MRI scans was 171 Amongst patients with CMBs

10135 (74) experienced a symptomatic ICH after thromboly-sis compared to 29655 (44) patients without CMBs thepooled RR of ICH was 190 (95 CI 092 to 393 p=0082)(1047297gure 1) The results were consistent from study to study (p=0800)

DISCUSSIONOur systematic review and meta-analysis in nearly 800 patientswith acute ischaemic stroke shows that the presence of CMBson a pretreatment MRI scan is not associated with a statistic-ally signi1047297cant increased risk of symptomatic ICH followingthrombolysis However there was a trend for a higher ICH riskin those patients with CMBs (pooled RR 190 95 CI 092 to393 p=0082)

With the introduction of T2-weighted gradient-recalledecho (T2-GRE) and susceptibility-weighted imaging CMBsare increasingly detected in patients with acute ischaemicstroke4 Evidence suggests that CMBs are a prognostic markerfor future ICH risk after stroke13 14 However only 1047297ve studieshave reported on the risk of ICH following thrombolysis foracute ischaemic stroke in patients screened for CMBs5 6 9ndash11

Recent studies indicate that the rate of symptomaticthrombolysis-related ICH is increased in the presence of moderate-to-severe leukoaraiosis implying that cerebral smallvessel is a risk factor for ICH15 16 However leukoaraiosis lackspathological speci1047297city by contrast with CMBs which appearto speci1047297cally re1047298ect small areas of haemorrhage from vessels

affected by bleeding-prone arteriopathies (mainly hypertensivearteriopathy or CAA)3

Several methodological aspects of the included studiesdeserve consideration Importantly most had a small samplesize only the multicentre BRASIL (bleeding risk analysis instroke imaging before thromboLysis) study (n=570) had morethan 100 patients and hence dominated our meta-analysis6

Furthermore all studies are subject to selection bias since notall acute stroke patients undergo T2-GRE and such patientswere excluded

Imaging parameters varied between studies which couldaffect the prevalence of CMBs4 17 In some centres in theBRASIL study 6 a small proportion of stroke patients hadCMBs and only six patients had 1047297ve or more CMBs suggest-ing that some MRI protocols were not optimal to detectCMBs which are typically found in about 20ndash30 of ischae-mic stroke patients7 Moreover the studies did not use standar-dised rating scales for CMBs and did not report on ICH risk inrelation to CMB number and anatomical location

Although the outcome de1047297nitions for ICH were not standar-dised among the studies included all included ICH associatedwith clinical deterioration and thus likely to be clinically relevant

A range of different thrombolysis protocols were used (table 1and online supplementary table S3) for example Kim et al

9

included both intravenous and intra-arterial thrombolysis butfound no statistically signi1047297cant difference between the groupsin haemorrhagic complications9 The study by Derex et al

11

included two drug doses but found no signi1047297cant in1047298uence of dose on the risk of ICH

Some studies did not provide full details of some baselinecharacteristics likely to be important for thrombolysis-relatedICH for example hyperglycaemia hypertension prior use of antiplatelet and anticoagulant medications or recurrent stroke

CMBs might increase the risk of thrombolysis-related ICHeither as the direct source of the ICH or as a general marker of small vessel fragility About 20 of patients with acute ischae-mic stroke develop new CMBs in the 1047297rst few days18 suggest-

ing an active diffuse microangiopathy which with theadministration of thrombolysis could cause symptomatic ICHSince most new CMBs in this study 18 developed in patientswith baseline CMBs prethrombolysis CMBs may be a markerfor patients at most risk of symptomatic ICH However thefree circulating plasma half-life of alteplase is very short(between 4ndash6 min) and that the exact mechanisms of ICHpost-thrombolysis remain uncertain

Deep CMBs in the basal ganglia and brainstem are mostlikely related to hypertensive arteriopathy while multiplestrictly lobar CMBs are likely to re1047298ect CAA4 CAA may be aparticular risk factor for post-thrombolysis ICHs which areoften lobar multiple and occur remote from the infarct inaround 20 of patients19 Pathological studies also support arole of pre-existing CAA one study reported that 70 of patients with thrombolysis-related ICH had autopsy-provenCAA compared to 22 of unselected ICH patients of similarage20 Finally an increased risk of ICH was associated withintravenous thrombolysis in CAA transgenic mice21 Strictly lobar CMBs form an important part of recent diagnostic cri-teria for CAA22 so may be of particular prognostic value forICH but this has not been addressed by previous studies

CONCLUSIONSOur analysis suggests a trend of increased risk of symptomaticICH after thrombolysis for ischaemic stroke if CMBs are presenton pretreatment MRI Although the risk was not statistically

signi1047297cant at the 005 level the data do not rule out a possibleclinically important increased hazard for thrombolysis in

278 J Neurol Neurosurg Psychiatry 201384277ndash280 doi101136jnnp-2012-303379

Cerebrovascular disease

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Table 1 Characteristics of included studies

Study Study design

Patient

number

( men)

Mean age

(years)

Initial stroke

severity

(NIHSS)

T2-GRE MRI parameters

CMBs

prevalence

(95 CI)

Differences

CMBs(+) versus

CMBs (minus) groups

Thrombolysis

(see online

supplementary

table S3)

Field

strength

(Tesla)

Echo time

(ms)

Section

thickness

(mm)

Fiehler

2007

Prospective

multicentre (13)

570 (ndash) 69 (59ndash77) 13 (IQR8ndash17) ndash 14ndash49 5ndash7 151 (91

to 197)

No differences in sex

and NIHSS score

Median age (IQR) 72

(65ndash79) versus 69 (58ndash

77) (p=0001)

IV tPA within 6 h

Kim

2006

Retrospective

single centre

65 (57) 67 ndash ndash 30 5 157 (81

to 264)

Hypertension and age

associated with CMBs

(plt005)

IV tPA within 3 h

(n=12) IA UK

within 6 h

(n=53)

Kakuda2005

Prospectivemulticentre (3)

70(443)

705 11plusmn9213plusmn98CMB (+)(minus)

(meanSD)

15 14ndash

47 5 385 (267to 514)

No differences in agetime to treatment blood

pressure NIHSS

hypertension Diabetes

dyslipidaemia smoking

IV tPA within 6 h

Derex

2004

Retrospective

single centre

44 (ndash) 632+ minus141 14plusmn58 (mean

SD)

15 26 5 182 (82

to 327)

ndash IV tPA at two

different doses

within 7 h

Kidwell

2002

Retrospective

single centre

41 (ndash) ndash ndash 15 15 7 122 (41

to 262)

No differences in age

hypertension diabetes

hypercholesterolaemia

smoking and severity of

pretreatmentneurological deficit

IVIA tPA within

3 h IA UK or

tPA mechanical

clot disruption

during IAthrombolysis

CMB cerebral microbleeds FU follow-up GRE gradient-recalled echo IA intra-arterial ICH intracerebral haemorrhage IQR interquartile range IV intravenous NIHSS National Institute of Health Strplasminogen activatorMedian age (interquartile range)

8202019 cerabral microbleeds

httpslidepdfcomreaderfullcerabral-microbleeds 45

individuals with CMBs particularly in view of the signi1047297cantmethodological limitations of included reports Our data thusreinforce the need for further large multicentre studies ( for sug-gested ideal study characteristics see online supplementary table S1) to evaluate whether the risk of ICH outweighs thebene1047297t of thrombolysis in patients with CMBs particularly those with multiple lobar CMBs suggestive of CAA23

Contributors AC PK DJW study concept and design AC PK acquisition of dataAC ZF DJW analysis and interpretation of data AC PK DJW drafting of themanuscript AC PK ZF DJW critical revision of the manuscript for importantintellectual content ZF AC statistical analysis DJW study supervision

Funding AC receives research support from the Greek State Scholarship Foundationthe British Heart Foundation and the Stroke Association DJW receives researchsupport from the Department of HealthHigher Education Funding Council for England(Clinical Senior Lectureship Award) the British Heart Foundation and the StrokeAssociation Part of this work was undertaken at UCLHUCL that received aproportion of funding from the Department of Healthrsquos National Institute for HealthResearch Biomedical Research Centrersquos funding scheme

Competing interests None

Provenance and peer review Not commissioned externally peer reviewed

Open Access This is an Open Access article distributed in accordance with theCreative Commons Attribution Non Commercial (CC BY-NC 30) license whichpermits others to distribute remix adapt build upon this work non-commercially andlicense their derivative works on different terms provided the original work isproperly cited and the use is non-commercial See httpcreativecommonsorg licensesby-nc30

REFERENCES1 Derex L Nighoghossian N Intracerebral haemorrhage after thrombolysis for acute

ischaemic stroke an update J Neurol Neurosurg Psychiatry 2008791093ndash9

2 Group Nr-PS Tissue plasminogen activator for acute ischemic stroke The National

Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group N Engl J

Med 19953331581ndash7

3 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 199920637ndash42

4 Charidimou A Werring DJ Cerebral microbleeds detection mechanisms and

clinical challenges Future Neurology 20116587ndash611

5 Kidwell CS Saver JL Villablanca JP et al Magnetic resonance imaging detection

of microbleeds before thrombolysis an emerging application Stroke 20023395ndash8

6 Fiehler J Albers GW Boulanger JM et al Bleeding risk analysis in stroke imaging

before thromboLysis (BRASIL) pooled analysis of T2-weighted magnetic resonanceimaging data from 570 patients Stroke 2007382738ndash44

7 Cordonnier C Al-Shahi Salman R Wardlaw J Spontaneous brain microbleeds

systematic review subgroup analyses and standards for study design and reporting

Brain 20071301988ndash2003

8 Stroup DF Berlin JA Morton SC et al Meta-analysis of observational studies in

epidemiology a proposal for reporting Meta-analysis Of Observational Studies in

Epidemiology (MOOSE) group Jama 20002832008ndash12

9 Kim HS Lee DH Ryu CW et al Multiple cerebral microbleeds in hyperacute

ischemic stroke impact on prevalence and severity of early hemorrhagic

transformation after thrombolytic treatment AJR Am J Roentgenol

20061861443ndash9

10 Kakuda W Thijs VN Lansberg MG et al Clinical importance of microbleeds in

patients receiving IV thrombolysis Neurology 2005651175ndash8

11 Derex L Nighoghossian N Hermier M et al Thrombolysis for ischemic stroke in

patients with old microbleeds on pretreatment MRI Cerebrovasc Dis

200417238ndash41

12 Fiehler J Siemonsen S Thomalla G et al Combination of T2W and FLAIR

abnormalities for the prediction of parenchymal hematoma following thrombolytic

therapy in 100 stroke patients J Neuroimaging 200919311ndash16

13 Soo YO Yang SR Lam WW et al Risk vs bene 1047297t of anti-thrombotic therapy

in ischaemic stroke patients with cerebral microbleeds J Neurol 2008255

1679ndash86

14 Lovelock CE Cordonnier C Naka H et al Antithrombotic drug use cerebral

microbleeds and intracerebral hemorrhage a systematic review of published and

unpublished studies Stroke 2010411222ndash8

15 Palumbo V Boulanger JM Hill MD et al Leukoaraiosis and intracerebral

hemorrhage after thrombolysis in acute stroke Neurology 200768

1020ndash4

16 Neumann-Haefelin T Hoelig S Berkefeld J et al Leukoaraiosis is a risk factor for

symptomatic intracerebral hemorrhage after thrombolysis for acute stroke Stroke

2006372463ndash6

17 Gregoire SM Werring DJ Chaudhary UJ et al Choice of echo time on GRET2-weighted MRI in 1047298uences the classi 1047297cation of brain microbleeds Clin Radiol

201065391ndash4

18 Jeon SB Kwon SU Cho AH et al Rapid appearance of new cerebral microbleeds

after acute ischemic stroke Neurology 2009731638ndash44

19 Ahmed N Wahlgren N Grond M et al Implementation and outcome of

thrombolysis with alteplase 3ndash45 h after an acute stroke an updated analysis from

SITS-ISTR Lancet Neurol 20109866ndash74

20 McCarron MO Nicoll JA Cerebral amyloid angiopathy and thrombolysis-related

intracerebral haemorrhage Lancet Neurol 20043484ndash92

21 Winkler DT Biedermann L Tolnay M et al Thrombolysis induces cerebral

hemorrhage in a mouse model of cerebral amyloid angiopathy Ann Neurol

200251790ndash3

22 Knudsen KA Rosand J Karluk D et al Clinical diagnosis of cerebral amyloid

angiopathy validation of the Boston criteria Neurology 200156537ndash9

23 Charidimou A Gang Q Werring DJ Sporadic cerebral amyloid angiopathy revisited

recent insights into pathophysiology and clinical spectrum J Neurol Neurosurg

Psychiatry 201283124ndash37

Figure 1 Meta-analysis of the association between intracerebral haemorrhage (ICH) risk in patients with acute ischaemic stroke treated with

thrombolysis in relation to the presence of cerebral microbleeds (CMBs) on pretreatment MRI scans This 1047297

gure is only reproduced in colour in theonline version

280 J Neurol Neurosurg Psychiatry 201384277ndash280 doi101136jnnp-2012-303379

Cerebrovascular disease

groupbmjcomon November 11 2014 - Published by httpjnnpbmjcom Downloaded from

8202019 cerabral microbleeds

httpslidepdfcomreaderfullcerabral-microbleeds 45

individuals with CMBs particularly in view of the signi1047297cantmethodological limitations of included reports Our data thusreinforce the need for further large multicentre studies ( for sug-gested ideal study characteristics see online supplementary table S1) to evaluate whether the risk of ICH outweighs thebene1047297t of thrombolysis in patients with CMBs particularly those with multiple lobar CMBs suggestive of CAA23

Contributors AC PK DJW study concept and design AC PK acquisition of dataAC ZF DJW analysis and interpretation of data AC PK DJW drafting of themanuscript AC PK ZF DJW critical revision of the manuscript for importantintellectual content ZF AC statistical analysis DJW study supervision

Funding AC receives research support from the Greek State Scholarship Foundationthe British Heart Foundation and the Stroke Association DJW receives researchsupport from the Department of HealthHigher Education Funding Council for England(Clinical Senior Lectureship Award) the British Heart Foundation and the StrokeAssociation Part of this work was undertaken at UCLHUCL that received aproportion of funding from the Department of Healthrsquos National Institute for HealthResearch Biomedical Research Centrersquos funding scheme

Competing interests None

Provenance and peer review Not commissioned externally peer reviewed

Open Access This is an Open Access article distributed in accordance with theCreative Commons Attribution Non Commercial (CC BY-NC 30) license whichpermits others to distribute remix adapt build upon this work non-commercially andlicense their derivative works on different terms provided the original work isproperly cited and the use is non-commercial See httpcreativecommonsorg licensesby-nc30

REFERENCES1 Derex L Nighoghossian N Intracerebral haemorrhage after thrombolysis for acute

ischaemic stroke an update J Neurol Neurosurg Psychiatry 2008791093ndash9

2 Group Nr-PS Tissue plasminogen activator for acute ischemic stroke The National

Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group N Engl J

Med 19953331581ndash7

3 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 199920637ndash42

4 Charidimou A Werring DJ Cerebral microbleeds detection mechanisms and

clinical challenges Future Neurology 20116587ndash611

5 Kidwell CS Saver JL Villablanca JP et al Magnetic resonance imaging detection

of microbleeds before thrombolysis an emerging application Stroke 20023395ndash8

6 Fiehler J Albers GW Boulanger JM et al Bleeding risk analysis in stroke imaging

before thromboLysis (BRASIL) pooled analysis of T2-weighted magnetic resonanceimaging data from 570 patients Stroke 2007382738ndash44

7 Cordonnier C Al-Shahi Salman R Wardlaw J Spontaneous brain microbleeds

systematic review subgroup analyses and standards for study design and reporting

Brain 20071301988ndash2003

8 Stroup DF Berlin JA Morton SC et al Meta-analysis of observational studies in

epidemiology a proposal for reporting Meta-analysis Of Observational Studies in

Epidemiology (MOOSE) group Jama 20002832008ndash12

9 Kim HS Lee DH Ryu CW et al Multiple cerebral microbleeds in hyperacute

ischemic stroke impact on prevalence and severity of early hemorrhagic

transformation after thrombolytic treatment AJR Am J Roentgenol

20061861443ndash9

10 Kakuda W Thijs VN Lansberg MG et al Clinical importance of microbleeds in

patients receiving IV thrombolysis Neurology 2005651175ndash8

11 Derex L Nighoghossian N Hermier M et al Thrombolysis for ischemic stroke in

patients with old microbleeds on pretreatment MRI Cerebrovasc Dis

200417238ndash41

12 Fiehler J Siemonsen S Thomalla G et al Combination of T2W and FLAIR

abnormalities for the prediction of parenchymal hematoma following thrombolytic

therapy in 100 stroke patients J Neuroimaging 200919311ndash16

13 Soo YO Yang SR Lam WW et al Risk vs bene 1047297t of anti-thrombotic therapy

in ischaemic stroke patients with cerebral microbleeds J Neurol 2008255

1679ndash86

14 Lovelock CE Cordonnier C Naka H et al Antithrombotic drug use cerebral

microbleeds and intracerebral hemorrhage a systematic review of published and

unpublished studies Stroke 2010411222ndash8

15 Palumbo V Boulanger JM Hill MD et al Leukoaraiosis and intracerebral

hemorrhage after thrombolysis in acute stroke Neurology 200768

1020ndash4

16 Neumann-Haefelin T Hoelig S Berkefeld J et al Leukoaraiosis is a risk factor for

symptomatic intracerebral hemorrhage after thrombolysis for acute stroke Stroke

2006372463ndash6

17 Gregoire SM Werring DJ Chaudhary UJ et al Choice of echo time on GRET2-weighted MRI in 1047298uences the classi 1047297cation of brain microbleeds Clin Radiol

201065391ndash4

18 Jeon SB Kwon SU Cho AH et al Rapid appearance of new cerebral microbleeds

after acute ischemic stroke Neurology 2009731638ndash44

19 Ahmed N Wahlgren N Grond M et al Implementation and outcome of

thrombolysis with alteplase 3ndash45 h after an acute stroke an updated analysis from

SITS-ISTR Lancet Neurol 20109866ndash74

20 McCarron MO Nicoll JA Cerebral amyloid angiopathy and thrombolysis-related

intracerebral haemorrhage Lancet Neurol 20043484ndash92

21 Winkler DT Biedermann L Tolnay M et al Thrombolysis induces cerebral

hemorrhage in a mouse model of cerebral amyloid angiopathy Ann Neurol

200251790ndash3

22 Knudsen KA Rosand J Karluk D et al Clinical diagnosis of cerebral amyloid

angiopathy validation of the Boston criteria Neurology 200156537ndash9

23 Charidimou A Gang Q Werring DJ Sporadic cerebral amyloid angiopathy revisited

recent insights into pathophysiology and clinical spectrum J Neurol Neurosurg

Psychiatry 201283124ndash37

Figure 1 Meta-analysis of the association between intracerebral haemorrhage (ICH) risk in patients with acute ischaemic stroke treated with

thrombolysis in relation to the presence of cerebral microbleeds (CMBs) on pretreatment MRI scans This 1047297

gure is only reproduced in colour in theonline version

280 J Neurol Neurosurg Psychiatry 201384277ndash280 doi101136jnnp-2012-303379

Cerebrovascular disease

groupbmjcomon November 11 2014 - Published by httpjnnpbmjcom Downloaded from

8202019 cerabral microbleeds

httpslidepdfcomreaderfullcerabral-microbleeds 55

and meta-analysisreviewfor acute ischaemic stroke systematic

thrombolysisintracerebral haemorrhage afterCerebral microbleeds and the risk of

Andreas Charidimou Puneet Kakar Zoe Fox and David J Werring

doi 101136jnnp-2012-303379online September 28 2012

2013 84 277-280 originally publishedJ Neurol Neurosurg Psychiatry

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MaterialSupplementary

htmlhttpjnnpbmjcomcontentsuppl20120927jnnp-2012-303379DC1Supplementary material can be found at

These include

References BIBLhttpjnnpbmjcomcontent843277

This article cites 23 articles 12 of which you can access for free at

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httpcreativecommonsorglicensesby-nc30 non-commercial Seeprovided the original work is properly cited and the use isnon-commercially and license their derivative works on different termspermits others to distribute remix adapt build upon this workCommons Attribution Non Commercial (CC BY-NC 30) license whichThis is an Open Access article distributed in accordance with the Creative

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Notes

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