Furlan-Wake-up-Stroke-&-Mismatch

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Rock Around the Clock Wake Up Stroke and Mismatch Anthony J Furlan MD Gilbert Humphrey Professor Chairman Department of Neurology Co-Director Neurological Institute University Hospitals Case Medical Center Case Western Reserve University School of Medicine


IV tPA Stroke Treatment Window Decreasing Efficacy Over time

ECASSIII

tPA = tissue plasminogen activator

ATLANTIS/ECASS/NINDS mRS 0-1 at Day 90

Lancet. 2004


80% of stroke patients arrive > 3 hours from onset

UCLA Stroke Center



Tissue Clock vs. Time Clock: Many Patients > 3 HRS Have Tissue At Risk

=

Early time is surrogate marker for “penumbra” But not recanalization or tissue reperfusion

> 3 Hrs % Patients with “Penumbra”

< 3 Hrs

Imaging required to assess pathophysiology 100 75 50 25 0 0

3

6

9

12

15

18

24

Time From Onset (Hours) Courtesy Chelsea Kidwell MD



•Wintermark M, etal Annals of Neurology •2002: 51: 417-432.


MR Mismatch > 3 Hours is Common Saver JL. Stroke. 2006; 37(1): 263 - 266.

Kidwell CS et al. Stroke. 2003;34:2729-2735

Proximal Arterial Occlusion

N=68

Copen WA et al., Radiology 2008 No Proximal Arterial Occlusion

N=41

% stroke patients with “mismatch� over time


MISMATCH


DEFUSE Mismatch associated with good outcomes following reperfusion

Before tPA NIHSS 16

3 cc

65 cc

? M2 Flow

0 cc

Improved

4.5 hrs After tPA NIHSS 5 6 cc


DEFUSE Favorable Clinical Response* Target Mismatch with Early Reperfusion vs. Target Mismatch without Early Reperfusion

TMM + ER (n=15) 67%

Median NIHSS: 14 Mean Age: 79**

TMM - ER (n=16)

19%

Median NIHSS: 13 Mean Age: 68

0

Odds Ratio 8.7 P = 0.011

20

40

60

80

*NIHSS 0-1 / > 8 pt improvement at 30 days No difference in baseline NIHSS, OTT, Glucose, DWI vol, PWI vol **Age significantly higher in TMM with ER (p=0.04)


DEFUSE The Malignant Mismatch Pattern

Before tPA 105 cc

215 cc

M1 Occlusion

4 hr after tPA

>100 cc

77 cc

M1 open Courtesy Gregory Albers MD


DEFUSE Malignant Pattern Outcomes Modified Rankin Scale at Day 30

0-1

Malignant Pattern n=6

4-6

17 33

All other Patterns n=68

12

33 83

33

0-1

2-3

4-6

12 31

28 57

41 19 p=0.06

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

• All fatal ICHs occurred in malignant pattern patients with early reperfusion; n = 3 75

• No SICH occurred in malignant patient without early reperfusion; 1 patient (45 yrs) 43 43 14 had a favorable outcome (Rankin 1)

100%


Reversible Acute DWI lesion Already Reperfused RADAR

JM Olivot et al. Stroke, 2009 in press


Example of DWI reversal after IV tPA

baseline DW (270” from stroke onset)

baseline PW Tmax (270” from stroke onset)

27 day flair (pink) over baseline DW

Olivot, J.-M. et al. Stroke 2009;40:1692-1697

Copyright ©2009 American Heart Association


Acute Infarction with normal DWMR but Abnormal PWMR: Total Mismatch

Ay, H. et al. Neurology 1999;52:1784


MRI Relative Mismatch and % Good Clinical Response at 90 Days DIAS/DEDAS/DIAS-2 70 60

% good outcome

50 40 30 20 10 0

MM >X %:All

20

40

60

80 100 120 140 160 180 200 220 240 260 280 300 350 400 450 500 550 600 700 800 900 1000 Response P- MRI (%)

Response 90- MRI (%)

Response 125- MRI (%)

Linear (Response 125- MRI (%))

Linear (Response 90- MRI (%))

Linear (Response P- MRI (%))


Absolute Mismatch Volume (with discrep) vs Response: Effect size vs Placebo DIAS-2- MRI (3) 35 30 25 20 15 10 5 0 -5 -10 >X cc: All

10

20

30

40

50

60

70

Effect size 90- MRI (%)

80

90

100

110

120

Effect size 125- MRI (%)

130

140

150

160


Brain perfusion and ADC

16 stroke patients imaged <6.5 hrs after onset

ADC <600 corresponds with CBF <10

Lin et al. Stroke 2003;34:64-70.


Distribution of DEFUSE ADC values by reversibility of DWI lesion

core 30%

20%

Optimal cutoff to distinguish between reversible and permanent DWI lesions: ADC value of 615

10%

0%

0 0 0 0 0 0 0 0 0 0 0 0 0 0 8 0 00 10 00 11 00 04 4 00 0-6 6 00 0 3 5 5 7 90 1 11 12 Lin et al. Stroke 2003;34:64-70 ADC values

Apparent Diffusion Coefficient Distinguishes Ischemic Core from Reversible Diffusion Lesions Purushotham, et al. Abstract presented yesterday


Which threshold for PWI? Comparison between PWI and PET in acute stroke patients

• Tmax threshold of 5.5 predicts acute ischaemic penumbra defined by PET scan

Sensitivity

Specificity

Accuracy

66

93

91

PET CBF ratio >0.496

88

PET CBF <20 mL/100 g/min, CMRO2 >63 µmol/100 g/min and OEF >0.55.

Tmax >5.5 48

92

Takasawa, Stroke 2008


Tissue Infarction Risk Maps Ona Wu, MGH-HST Athinoula A Martinos Center for Biomedical Imaging


The Problem with Mismatch • Original “mismatch” was “eyeball technique” – – – –

minimum mismatch easily “eyeballed” is 20% 20% mismatch may not translate into clinical outcome probably need > 50% eyeball mismatch need quantified data for tissue maps

• Mismatch is heterogeneous – imprecise unless quantified – time (RADAR) and location (grey vs white ) dependent


Core is Crucial!

MHL/MGH


Stroke 2003; 34:2426-35

MHL/MGH


CBV

CBF

CT

MAP

CT CBV/CBF Core and Penumbra Maps A 61-year-old male patient with right hemiparesis imaged at 2.3 hours and 3 days. Abnormal areas are outlined on CBV (A), CBF (B), and follow-up CT (C) images. After coregistration, we defined 3 regions on CBF maps (D): region 1 (red), "infarct core"—abnormal on CBV, CBF, and follow-up CT images; region 2 (blue), "penumbra that infarcts"—normal on CBV but abnormal on CBF and follow-up CT images; and region 3 (green) "penumbra that recovers"—abnormal on CBF but normal on CBV and follow-up CT images. P.W. Schaefer, L. Roccatagliata, C. Ledezma, B. Hoh, L.H. Schwamm, W. Koroshetz, R.G. Gonzalez and M.H. Lev American Journal of Neuroradiology 27:20-25, January 2006


“Core” and “Penumbra”: What Modality? n

MR Ø Ø

n

Ø

-

DWI best TTP, MTT, CBF

CT Ø

-

Core: Penumbra: Core: Penumbra:

CBF better than CBV MTT, Tmax, TTP

Wintermark M et al. Ann Neurol 2002 - Koroshetz WJ, Lev MH. Ann Neurol 2002 Schaefer PW, Lev MH et al. AJNR Jan 2006 Schramm, Schellinger, et al. Stroke 2002; 33

MHL/MGH


CBF and CBV ratios and absolute values for core infarct and penumbra

Region 1 Mean Ratio ± SD

Region 2 Mean Ratio ± SD

Region 3 Mean Ratio ± SD

P Value (Region 1 vs 2)

P Value (Region 2 vs 3)

CBV ratio

0.48 ± 0.09

0.84 ± 0.17

0.96 ± 0.19

<0.0001

0.03

CBF ratio

0.19 ± 0.06

0.34 ± 0.06

0.46 ± 0.09

<0.0001

<0.0001

CBV value (ml/100 g)

1.47 ± 0.4

2.83 ± 0.67

2.94 ± 0.45

<0.0001

0.05

CBF value (ml/100 g/min)

8.88 ± 2.3

16.08 ± 5.71

17.92 ± 4.0

<0.0001

0.1

Parameter

Note:— CBF indicates cerebral blood flow; CBV, cerebral blood volume. 1= core; low CBV and low CBF 2 = penumbra that infarcts; normal CBV, low CBF; abnormal CT 3 = penumbra that does not infarct; normal CBV, low CBF; normal CT

P.W. Schaefer, L. Roccatagliata, C. Ledezma, B. Hoh, L.H. Schwamm, W. Koroshetz, R.G. Gonzalez and M.H. Lev American Journal of Neuroradiology 27:20-25, January 2006


Selection for IAT n n n

Proximal artery occlusion Significant deficit (e.g., NIHSS = 10) Small pre-treatment core (e.g., = 70-100 ml)

MHL/MGH


DWI and CTP Assessment in the Triage of WakeUp and Late Presenting Strokes Undergoing Neurointervention: The DAWN Trial

Raul G Nogueira and Tudor Jovin on Behalf of the DAWN Investigators

DAWN Trial

Confidential – peer review only


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