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
â&#x20AC;˘Wintermark M, etal Annals of Neurology â&#x20AC;˘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 â&#x20AC;&#x153;mismatchâ&#x20AC;? 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%
â&#x20AC;˘ All fatal ICHs occurred in malignant pattern patients with early reperfusion; n = 3 75
â&#x20AC;˘ 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 â&#x20AC;&#x201C; peer review only