Role of MRI in acute stroke Role of MRI in acute stroke patients for thrombolysispatients for thrombolysis

D Šaňák, D Horák, A Bártková, I Vlachová, S Buřval, M Král, M Heřman, P Kaňovský

Stroke Centre, Dept. Of Neurology and Radiology, Stroke Centre, Dept. Of Neurology and Radiology, University University HHospital Olomoucospital Olomouc

What we alreadyWhat we already know….know….

MRI may help to identify patients, who have the MRI may help to identify patients, who have the most potential to benefit from thrombolytic most potential to benefit from thrombolytic therapytherapy

Rotta et al., Rotta et al., N Eng J Med N Eng J Med 1997; Schellinger et al., 1997; Schellinger et al., Stroke Stroke 20002000; Ann Neur 2001; Ann Neur 2001;; FiebachFiebach et al., 2001; Röther et al., et al., 2001; Röther et al., Stroke Stroke 2002; 2002; Shilh et all., Stroke 2003; Shilh et all., Stroke 2003; Dávalos et al.,Dávalos et al., Neurology Neurology 20042004, Barber et al,J Neuroimaging 2004; Hacke et al., Stroke 2005; Ribo et , Barber et al,J Neuroimaging 2004; Hacke et al., Stroke 2005; Ribo et

al.,al., Stroke 2005.Stroke 2005.

Nevertheless, up to date, few studies have Nevertheless, up to date, few studies have evaluated the impact of evaluated the impact of „„pre-treatmentpre-treatment““ MRI MRI parameterparameterss on the resulting clinical outcome on the resulting clinical outcome after thrombolysisafter thrombolysis……

Röther JRöther J et al. et al. , , Stroke Stroke 20022002; ; Dávalos ADávalos A et al. , Neurology et al. , Neurology 20042004; ; Nighoghossian Nighoghossian N N et al., Stroke et al., Stroke 20032003. . Derex LDerex L et al., J Neur Sci et al., J Neur Sci 20042004, Prosser et al, Stroke , Prosser et al, Stroke 2005, 2005,

Is MRI really useful for Is MRI really useful for thrombolysis? thrombolysis?

MRI improves diagnostics of acute cerebral MRI improves diagnostics of acute cerebral infarctioninfarction

quantification of actual infarct volume quantification of actual infarct volume accurate infarctaccurate infarct localization localization

using diffusion-weighted images using diffusion-weighted images

Warach et al., Warach et al., Neurology Neurology 1992; Ay et al., 1992; Ay et al., Neurology Neurology 1999; 1999; OppeOppenheimnheim et al., et al., Neuroradiology Neuroradiology

2000,2000, Stroke 2000Stroke 2000;; Jansen et al., 2002; Mullins et al., Jansen et al., 2002; Mullins et al., Radiology Radiology 2002,2002, Am J Roentgenol 2000 Am J Roentgenol 2000

Inspiration…..Inspiration…..

Idea….Idea….

Assess the influence of Assess the influence of initial infarct volume on initial infarct volume on resulting clinical outcome in resulting clinical outcome in acute stroke patients with acute stroke patients with MCA occlusion, who MCA occlusion, who underwentunderwent IVT/IAT IVT/IAT

Does „mismatch“ between Does „mismatch“ between stroke severity (NIHSS) and stroke severity (NIHSS) and infarct volume on DWI infarct volume on DWI predict follow-up infarct predict follow-up infarct progressionprogression and response to and response to thrombolysis? thrombolysis?

Study Study 1: 1: designdesign

25 consecutive acute ischemic stroke patients with MCA 25 consecutive acute ischemic stroke patients with MCA occlusion (M1-2 segment) occlusion (M1-2 segment) - - detected on MR angiographydetected on MR angiography

Underwent IVT or IATUnderwent IVT or IAT according the recent guidelines*according the recent guidelines* between January and September 2005 between January and September 2005

Stroke severity (NIHSS, mRS)Stroke severity (NIHSS, mRS)

MRI stroke protocol (EPI-DWI, T2, FLAIR, MRA) MRI stroke protocol (EPI-DWI, T2, FLAIR, MRA)

Infarct volume quantification on DWI (Infarct volume quantification on DWI (bb-1000) -1000)

** EUSI Recommendations for stroke management update 2003EUSI Recommendations for stroke management update 2003. . Highasida RT, Highasida RT, Furlan AJFurlan AJ. . Trial design and reporting standards for intra-arterial cerebral Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic stroke. Stroke thrombolysis for acute ischemic stroke. Stroke 2004.2004.

MRIMRI

Magnetom Symphony 1.5 T Maestro ClassMagnetom Symphony 1.5 T Maestro Class (Siemens, Erlangen, Germany)(Siemens, Erlangen, Germany), , Quantum gradients Quantum gradients (syngo2004A)(syngo2004A)

MRI protocolMRI protocol:: LocalizerLocalizer T2TSE (Turbo Spin Echo)T2TSE (Turbo Spin Echo) FLAIR FLAIR EPI-EPI-DWI DWI 3D TOF MRA 3D TOF MRA

Total aTotal accquisition timequisition time:: 11:28 min. 11:28 min.

Subject demographicSubject demographic and clinical characteristicsand clinical characteristics

MalesMales 1616

FemalesFemales 99

Mean ageMean age 59.1 ± 13.959.1 ± 13.9

Mean baseline NIHSSMean baseline NIHSS 14.2 ± 5.814.2 ± 5.8 Mean time from stroke onset to MRI Mean time from stroke onset to MRI examination (minutes)examination (minutes)

149 ± 37149 ± 37

Number of patients treated by Number of patients treated by IVTIVT 2121

Number of patients treated by Number of patients treated by IATIAT 44

Relation between initial infarct volume Relation between initial infarct volume (V(VDWI-IDWI-I) ) andand stroke severity (NIHSSstroke severity (NIHSS))

0

5

10

15

20

25

0 50 100 150 200 250 300 350

Initial infarct volume (ml)

NIH

SS

AnalysisAnalysis

RRelation between the initial infarct volume and elation between the initial infarct volume and neurological deficit severity was assessed, neurological deficit severity was assessed, defining a cut-off point for maximum Vdefining a cut-off point for maximum VDWI-IDWI-I associated still with a good clinical outcomeassociated still with a good clinical outcome

Several cut-off points of VSeveral cut-off points of VDWI-IDWI-I were subsequently were subsequently tested with the goal to maximize both sensitivity tested with the goal to maximize both sensitivity and specificity for good clinical outcome (mRS 0-and specificity for good clinical outcome (mRS 0-2)2)

Cut-offCut-off point of maximum V point of maximum VDWI-I DWI-I still associated still associated

with a good clinical outcomewith a good clinical outcome and corresponding toand corresponding to

maximum achieved sensitivity and specificitymaximum achieved sensitivity and specificity (80%) (80%)

0

10

20

30

40

50

60

70

80

90

100

0 50 100 150 200 250 300 350

initial infarct volume (ml)

%

sensitivity

specificity

Resulting cut-off Resulting cut-off point point divided the patients into divided the patients into

2 subgroups (V2 subgroups (VDWI-I DWI-I ≤ 70 ml; >70 ml)≤ 70 ml; >70 ml)

Patient subgroupPatient subgroup VVDWI-IDWI-I ≤ 70 ml ≤ 70 ml VVDWI-IDWI-I > 70 ml > 70 ml

NN 56 ± 1156 ± 11 61 ± 961 ± 9

AgeAge 56 ± 1156 ± 11 61 ± 961 ± 9

Baseline NIHSSBaseline NIHSS 12.6 ± 4.612.6 ± 4.6 19.5 ± 6.219.5 ± 6.2

NIHSS after 24 NIHSS after 24 hourshours

5.2 ± 4.65.2 ± 4.6 26.2 ± 9.626.2 ± 9.6 (p (p == 0.0018) 0.0018)

mRSmRS (90 day) (90 day) 1.2 ± 1.11.2 ± 1.1 4.4 ± 1.14.4 ± 1.1 (p = 0.003)(p = 0.003)

Relationship between the initial infarct volume Relationship between the initial infarct volume

and 24-hour clinical outcomeand 24-hour clinical outcome

0

5

10

15

20

25

30

35

0 50 100 150 200 250 300 350

Initial infarct volume (ml)

NIH

SS

aft

er 2

4 h

ou

rs

Resulting cut-off Resulting cut-off point point divided the patients divided the patients

into 2 subgroups (Vinto 2 subgroups (VDWI-I DWI-I ≤ 70 ml; >70 ml)≤ 70 ml; >70 ml)

Patient subgroupPatient subgroup VVDWI-IDWI-I ≤ 70 ml ≤ 70 ml VVDWI-IDWI-I > 70 ml > 70 ml

NN 56 ± 1156 ± 11 61 ± 961 ± 9

AgeAge 56 ± 1156 ± 11 61 ± 961 ± 9

Baseline NIHSSBaseline NIHSS 12.6 ± 4.612.6 ± 4.6 19.5 ± 6.219.5 ± 6.2

NIHSS after 24 NIHSS after 24 hourshours

5.2 ± 4.65.2 ± 4.6 26.2 ± 9.626.2 ± 9.6 (p (p == 0.0018) 0.0018)

mRSmRS 1.2 ± 1.11.2 ± 1.1 4.4 ± 1.14.4 ± 1.1 (p = 0.003)(p = 0.003)

Relationship between the initial infarct volume Relationship between the initial infarct volume

and 90-day clinical outcomeand 90-day clinical outcome

0

1

2

3

4

5

0 50 100 150 200 250 300 350

Initial infarct volume (ml)

mR

S

90-day mortality90-day mortality

71.5 % in Subgroup V71.5 % in Subgroup VDWI-IDWI-I >70 ml versus 0 % in >70 ml versus 0 % in SubgroupSubgroup VVDWI-IDWI-I ≤ 70 ml ≤ 70 ml

All these patients died within first 7 days after All these patients died within first 7 days after thrombolysisthrombolysis

brain edema was the cause of death in all cases brain edema was the cause of death in all cases aadditionally, intracranial hemorrhage occurred in 3 dditionally, intracranial hemorrhage occurred in 3

out of these patients. out of these patients.

DiscussionDiscussion

We did not find any direct relation between the initial We did not find any direct relation between the initial infarct volume measured on DWI and the neurological infarct volume measured on DWI and the neurological deficit on admissiondeficit on admission

Two patients with the same severity of deficit and the same Two patients with the same severity of deficit and the same type of arterial occlusion (MCA, M1-2 segment) can have type of arterial occlusion (MCA, M1-2 segment) can have VVDWI-IDWI-I differing by as much as tens of ml differing by as much as tens of ml

This difference is mainly caused by the individual actual This difference is mainly caused by the individual actual state of cerebral collateral flowstate of cerebral collateral flow

Comparison of different initial infarct volumes Comparison of different initial infarct volumes in two patients with MCA occlusion on in two patients with MCA occlusion on

admissionadmission

Quantification of initial infarct volume could predict Quantification of initial infarct volume could predict clinical outcome in acute stroke patients with MCA clinical outcome in acute stroke patients with MCA occlusion treated by intravenous/intra-arterial occlusion treated by intravenous/intra-arterial thrombolysisthrombolysis..

Patients with VPatients with VDWI-I DWI-I ≤ 70 ml had significantly better ≤ 70 ml had significantly better resulting outcomeresulting outcome..

Sanak et al., Neuroradiology 2006; 48: 632-639. Sanak et al., Neuroradiology 2006; 48: 632-639.

To be To be continued…continued…

„„Mismatch problem…..“Mismatch problem…..“

Patients with PWI/DWI mismatch may have Patients with PWI/DWI mismatch may have higher benefit from thrombolytic therapy higher benefit from thrombolytic therapy even beyond 3 hours than patients without even beyond 3 hours than patients without mismatchmismatch

Alberts et al., Stroke 1999; Parsons et al., Ann Neurol 2002, Hacke et al., Alberts et al., Stroke 1999; Parsons et al., Ann Neurol 2002, Hacke et al., Neurology 1999; Shih et al., Stroke 2003Neurology 1999; Shih et al., Stroke 2003

PWI/DWI mismatch conceptPWI/DWI mismatch concept

DWI and PWI DWI and PWI

Lesions are Lesions are

equivalentequivalent

DWI DWI

infarctioninfarction

PWI ischemiaPWI ischemia

Non-Non-mismatchmismatch

Mismatch:Mismatch: PWI PWI >> DWIDWI

PWI/DWI mismatchPWI/DWI mismatch

DWI

TTP

CBV

CBF

„„Mismatch problem…..Mismatch problem…..““

Although the PWI/DWI mismatch is largely used in Although the PWI/DWI mismatch is largely used in stroke studies and clinical routine, the concept is still stroke studies and clinical routine, the concept is still controversialcontroversial::

Several different definitions of PWI/DWI mismatch are Several different definitions of PWI/DWI mismatch are establishedestablished

limitation of accuracy of PWI technique is still under limitation of accuracy of PWI technique is still under discussiondiscussion

PPWI cannot also reliably distinguish the benign oligemia WI cannot also reliably distinguish the benign oligemia and real penumbraand real penumbra

Barber et al., Neurology 1999; J Neuroimaging 2004; Chalela et al., Ann NeurolBarber et al., Neurology 1999; J Neuroimaging 2004; Chalela et al., Ann Neurol2004; Hacke et al, Stroke 2005;Ribo et al, Stroke 2005; Simonsen et al, Magn 2004; Hacke et al, Stroke 2005;Ribo et al, Stroke 2005; Simonsen et al, Magn Res Imaging 2000; Smith et al, Magn Res Imaging 2000; Zacharchuk et al, J Cereb Res Imaging 2000; Smith et al, Magn Res Imaging 2000; Zacharchuk et al, J Cereb

Flow Met Flow Met 2000; Grandin et al., Radiology 2000.2000; Grandin et al., Radiology 2000.

New approach: Clinical-DWI New approach: Clinical-DWI mismatchmismatch

Mismatch between stroke severity (assessed with Mismatch between stroke severity (assessed with NIHSS) and infarct volume on DWI predict follow-up NIHSS) and infarct volume on DWI predict follow-up infarct expansion and response to thrombolysis infarct expansion and response to thrombolysis

An NIHSS An NIHSS 8 and DWI infarct volume 8 and DWI infarct volume 25 ml was 25 ml was defined as a clinical-diffusion mismatch (CDM)defined as a clinical-diffusion mismatch (CDM)

CDM could beCDM could be surrogate for PWI/DWI mismatch. surrogate for PWI/DWI mismatch.

Dávalos ADávalos A et al. et al. Neurology 2004; 62: 2187-2192. Neurology 2004; 62: 2187-2192. Prosser JProsser J et al. et al. Stroke 2005; 36: 1700-1704. Stroke 2005; 36: 1700-1704.

Does the CDM predict good clinical Does the CDM predict good clinical outcome in acute stroke patients treated outcome in acute stroke patients treated

with IVT?with IVT?

to compare acute ischemic stroke patients to compare acute ischemic stroke patients with and without CDM treated by intravenous with and without CDM treated by intravenous thrombolysis (IVT) within 3 hours inthrombolysis (IVT) within 3 hours in::

infarct growthinfarct growth clinical outcome clinical outcome incidence of intracerebral hemorrhage incidence of intracerebral hemorrhage

Study 2: designStudy 2: design

Seventy-nineSeventy-nine patients treated with IVT between patients treated with IVT between IX/IX/2004 and 2004 and XII/XII/2006 at our stroke unit2006 at our stroke unit

CDMCDM was defined as was defined as NIHSS NIHSS 8 8 and and DWI volume ≤ 25 DWI volume ≤ 25 mlml

non-non-CDMCDM as as NIHSS NIHSS 8 8 and and DWI > 25 ml.DWI > 25 ml.

DWI infarct volume was measured on DWI infarct volume was measured on DWIDWI. . Neurological deficit was evaluated using NIHSS and Neurological deficit was evaluated using NIHSS and

mRS. mRS. Independent Samples, Chi-Square and Fisher's exact Independent Samples, Chi-Square and Fisher's exact

test were used for statistical evaluation test were used for statistical evaluation

Patient demographic and baseline Patient demographic and baseline

characteristicscharacteristics CDMCDM Non-CDMNon-CDM

NN 3737 1515

MalesMales 2222 1111

FemalesFemales 1515 44

Age (Mean Age (Mean SD) SD) 66.3 66.3 14.7 14.7 69.4 69.4 9.5 9.5

Baseline NIHSSBaseline NIHSS

MedianMedian 11.011.0 17.017.0

Mean Mean SD SD 11.3 11.3 2.6 2.6 16.9 16.9 4.8 4.8 Baseline DWI infarct Baseline DWI infarct volume (ml)volume (ml)

Mean Mean SD SD 6.9 6.9 5.8 5.8 60.3 60.3 29.1 29.1

ResultsResults

CDMCDM Non-CDMNon-CDM

24-hour24-hour NIHSS: Median NIHSS: Median 4.04.0

pp-0.191-0.19115.015.0

MRS (day 90)MRS (day 90): Median : Median 2.12.1

pp-0.002-0.0025.05.0

24-hour i24-hour infarct volume nfarct volume progression (ml)progression (ml): : Mean Mean SDSD

- 5.8 - 5.8 14.4 14.4

pp-0.039-0.03953.1 53.1 88 88

ICHICH 8.1 %8.1 %

pp-0.036-0.03633.3 %33.3 %

Symptomatic ICHSymptomatic ICH 0 % 0 %

pp-0.079-0.07913.3 %13.3 %

Mortality within first 7 Mortality within first 7 daysdays

0 %0 % 13.3 %13.3 %

CDM - discussion CDM - discussion

CDM indicateCDM indicatess the existence of a large volume of the existence of a large volume of tissue at risk of infarction* tissue at risk of infarction*

Patients with the CDM had significantly better Patients with the CDM had significantly better 90day clinical outcome and less ICH*90day clinical outcome and less ICH*

Patients without CDM had higher infarct volume Patients without CDM had higher infarct volume progression after 24 hours*progression after 24 hours*

CDM should be prospectively tested as a CDM should be prospectively tested as a predictor of response of thrombolysis between 3 predictor of response of thrombolysis between 3 and 6 hours from stroke onsetand 6 hours from stroke onset

**Sanak et al., Eur J Neurol 2007; 14 (Suppl 1): 69Sanak et al., Eur J Neurol 2007; 14 (Suppl 1): 69

ConclusionsConclusions

Quantification of initial infarct volume could Quantification of initial infarct volume could predict clinical outcome in acute stroke predict clinical outcome in acute stroke patients with MCA occlusion treated by patients with MCA occlusion treated by IVT/IAT.IVT/IAT.

Patients with VPatients with VDWI-I DWI-I ≤ 70 ml had significantly ≤ 70 ml had significantly betterbetter resulting outcome resulting outcome

CDM may help identify patients with higher CDM may help identify patients with higher benefit from thrombolysis. benefit from thrombolysis.

Patients with CDM had significantly better 90day Patients with CDM had significantly better 90day clinical outcome and significantly less ICH.clinical outcome and significantly less ICH.

Is MRI really useful for thrombolysis? Is MRI really useful for thrombolysis?

Yes!Yes! Particularly beyond 3 hours*…… Particularly beyond 3 hours*……

**EUSI EUSI Recommendations for Stroke Management.Recommendations for Stroke Management.…..…..

Thank you for your Thank you for your attention!attention!