Perfusion Imaging for AIS Is There a Role in Patient Selection? · 2014. 12. 29. · Disclosures...

Perfusion Imaging for AIS –

Is There a Role in Patient

Selection?

Albert J. Yoo, MD Director of Acute Stroke Intervention

Diagnostic and Interventional Neuroradiology

Massachusetts General Hospital

Disclosures

• Penumbra, Inc.

– Research grant (significant) for core imaging lab activities for

THERAPY, START, and PICS trials

• Remedy Pharmaceuticals, Inc.

– Research support (significant) for core imaging lab for GAMES Pilot trial

• Covidien Neurovascular

– SWIFT Prime trial investigator and member of imaging subcommittee

• NIH/NINDS

– MR RESCUE trial investigator and member of publication committee

• Dutch Heart Foundation

– MR CLEAN trial angiographic core imaging lab

2

Overview

• Perfusion imaging for:

– Treatment decision making

– Assessing tissue viability

– Alternative clinical uses

3 3

Overview





4 4

Penumbral imaging

• Treatment-Relevant Acute Imaging Targets (TRAITs)

– Goal of imaging is to improve clinical outcomes

– Achieved through proper patient selection for treatments

– Therefore, imaging selection biomarkers must be treatment-specific

• IV tPA vs. IAT vs. novel fibrinolytics?

• Which time window?

• Benefit/efficacy vs. risk/safety vs. both?

Stroke 2013; 44:2628-2639.

Reperfusion approaches for acute stroke

• IV tPA

– Efficacy supported by multiple RCTs (Class I, LOE A)

– Broad stroke cohort

– Narrow time window: <3 (to 4.5 hours: Class I, LOE B)

– Limited effectiveness for recanalizing proximal occlusions

• Intra-arterial therapy

– Efficacy of local thrombolysis (< 6 hours) supported by one RCT and subsequent meta-analysis (Class I, LOE B: PROACT II)

– Mechanical thrombectomy recently demonstrated to be effective within 6 hrs (Class I, LOE B: MR CLEAN)

– Major stroke patients with proximal occlusions

– Extended time window

– Excellent revascularization of proximal occlusions (70-90%)

Stroke 2013; 44:870-947.

Imaging for IV tPA: Time is brain

• Emphasis on speed of treatment delivery

• Imaging criteria:

– Rule out hemorrhage

– Rule out well-defined hypodensity in >1/3rd

MCA territory

– Exclude early ischemic injury in >1/3rd MCA

territory*

* in 3-4.5 hr window

No role for perfusion imaging!

Imaging selection for IAT

• There is no standard imaging approach for

selecting patients for intra-arterial therapy

• Major imaging questions:

– Hemorrhage?

– Proximal artery occlusion?

– Core infarct size?

Stroke 2013; 44:870-947.

Vessel imaging

• Vessel imaging recommended as a preliminary step for IAT (Class I, LOE A)

– Identify treatment target

– Plan treatment approach (e.g., ICA stenting)

– Provide prognostic information (e.g., terminal ICA vs. M1)

– Predict IV tPA failure

• ICA-T: 4.4% recanalization

• M1: 32.3%

• M2: 30.8%

• Basilar: 4%

Stroke 2013; 44:870-947.

Stroke 2010; 41:2254-2258.

Vessel imaging: CTA vs. MRA

• CTA

– vs. DSA: 98.4% sens, 98.1% spec, 98.2% accuracy for proximal artery occlusion (JCAT 2001; 25:520-8)

– Facilitated by thick section, overlapping MIPs

– High interobserver reliability

• MRA

– 3D TOF vs. DSA: 84-87% sens, 85-98% spec for PAO (AJNR 2005; 26:1012-1021; Can J Neurol Sci 2006; 33:58-62)

– Suboptimal evaluation of M2 branches

– Prone to motion and flow artifact

– Moderate interobserver reliability (κ=0.5)

• CTA and MRA Class I, LOE A

Stroke 2009; 40:3646-3678.

Parenchymal imaging

Stroke 2013; 44:870-947.

Penumbra (at risk)

Core (irreversibly damaged)

Courtesy of T.M. Leslie-Mazwi

Core principle of treatment selection

Risk

Benefit

• For proximal artery occlusions treated with IAT,

smaller core infarct volumes better outcomes • Xe-enhanced CT:

• Jovin et al, Stroke. 2003; 34: 2426-33

• MRI DWI (reference standard):

• Yoo et al., Stroke. 2009; 40: 2046-54

• Lansberg et al., Lancet Neurol. 2012; 11: 860-7 (DEFUSE 2)

• Olivot et al., Stroke. 2013; In press

• CT Perfusion CBV:

• Gasparotti et al., AJNR. 2009; 30: 722-7

• CTA Source Images:

• Lev et al., Stroke. 2001; 32: 2021-28

• NCCT ASPECTS:

• Hill et al., Stroke. 2003; 34: 1925-31 (PROACT-II)

• Hill et al., AJNR. 2006; 27: 1612-16 (IMS-1)

• Goyal et al., Stroke. 2011; 42:93-7 (Penumbra Pivotal)

Benefit vs. Core infarct size

Risk of sICH vs. Core infarct size

• In multicenter study of 645 pts treated with IV or IA thrombolysis, (Ann Neurol. 2008; 63:52-60.)

– Larger baseline DWI lesion volume (i.e. core infarct volume) independent predictor of sICH

– DWI volume >100 mL 16.1% sICH rate

• DEFUSE post hoc analysis (Stroke. 2007; 38:2275-8)

– Risk of sICH in large infarcts is further increased by reperfusion

• 139 patients with anterior circulation PAO and pre-treatment DWI

• DWI lesion volume was an independent predictor of dependency, death and HT after IAT

Stroke. 2013; 44:2205-11.

How big is too big?

• An acute infarct volume threshold of >70 cm3 has a high

specificity for predicting a poor outcome1,2

• Patients with infarcts >70 cm3 respond poorly to IAT

– Yoo AJ et al. Stroke. 2009; 40:2046-54.

– Lansberg MG et al. Lancet Neurol. 2012; 11:860-7.

(DEFUSE 2)

– Olivot JM et al. Stroke. 2013; 44:2205-11.

1Sanak et al. Neuroradiology. 2006; 48:632-9. 2Yoo et al. Stroke. 2010; 41:1728-35.

• Does perfusion imaging add information to

knowledge of core infarct size?


Stroke. 2003; 34:2426-35. CBF (mL/

100g/min):

0 to 8

8 to 20

>20

• PWI/DWI mismatch is not discriminatory in

the setting of large vessel occlusion

– volume of MCA territory is ~300 cm3


• 116 pts with ICA or proximal MCA occlusions

• MRI DWI/PWI (MTT or TTP with 4 sec delay threshold)

• 90/93 pts with DWI volume ≤100mL had at least 100% mismatch

Courtesy of Dr. R. Gilberto González

Definitions

Variable Criteria

Target Mismatch PWI(Tmax>6s) / DWI ≥1.8 AND DWI <70 ml AND PWI(Tmax>10s) <100 ml

Reperfusion (PWI criteria)* >50% reduction in PWI(Tmax>6s) volume at early follow-up

Reperfusion (DSA criteria)** TICI 2b or 3 at completion of procedure

Favorable Clinical Response ≥8 point improvement in NIHSSS at day 30 or NIHSSS of ≤1 at day 30

*in patients with a baseline PWI(Tmax>6s) lesion that is ≥10 ml

**in patients with a major vessel occlusion (TICI 0 or 1) on baseline imaging

DEFUSE 2

Courtesy of Dr. Greg Albers

Primary Analysis: Comparison of the odds ratios for the

association between reperfusion and FCR:

Target Mismatch vs. No Target Mismatch

Odds Ratios No Target

Mismatch

(n=21)

Target

Mismatch

(n=78)

p for

difference

Unadjusted 0.2 (0.0 – 1.4) 5.0 (1.9 – 13) 0.004

Adjusted for Age and

DWI

0.2 (0.0 – 1.6) 8.8 (2.7 – 29) 0.003

DEFUSE 2


Baseline characteristics

Target Mismatch (n=78)

No Target Mismatch (n=26)

Mean (SD) age (years) 66 (16) 63 (13)

Median (IQR) NIHSSS 14 (11-20) 18 (12-19)

Number (%) pretreated with IV tPA treatment 36 (46%) 19 (73%)

Median (IQR) DWI volume (ml) 13 (5-26) 45 (2-68)

Median (IQR) PWI(Tmax>6s) volume (ml) 80 (50-108) 74 (10-166)

Median (IQR) time from onset to IA treatment (hrs)

6.2 (4.9-8.1) 4.7 (3.7-6.4)

DEFUSE 2

Age & baseline DWI lesion volume were the only

independent predictors of favorable clinical response


• Can the NIHSS score be used to identify a

clinically significant territory at risk?


NIHSS <10 predicts a good outcome

• 88% of pts with NIHSS <10 had good outcome

PROACT II: IA efficacy vs. NIHSS

JAMA. 1999; 282:2003-2011

Target NIHSS: ≥10

• Clinically significant penumbra for IAT:

– Proximal artery occlusion

– Significant neurological deficit (NIHSSS ≥10)

– Small pre-treatment core infarct (≤70 mL)

• With the best available method:

diffusion MRI

• Highly sensitive (91-100%) and specific

(86-100%) within the first 6 hrs of stroke

onset

– Similar accuracy to 11C flumazenil PET

• Allows volumetric quantification

• Excellent inter-reader agreement

• Class I, level of evidence A

recommendation*

How should we measure core?

* Stroke. 2009; 40:3646-3678.

Neurology. 2010; 75:177-185.

Is diffusion lesion reversal a problem?

• Several reports of DWI lesion reversibility (8-44%)

– Tissue reperfusion is a prerequisite

– Other predictors: earlier time to imaging and reperfusion, smaller reduction in ADC

• However unlikely to be clinically significant

– Has not been demonstrated to improve clinical outcomes*

– Delayed regrowth into the initial lesion is seen, even when blood flow is restored

– Mean volumes of tissue reversal are small (5-16 cm3)

– DEFUSE-EPITHET analysis**: when taking into account chronic infarct involution and gliosis, true reversal in 6.7% with median volume of 2.3 cm3

* Stroke. 2004; 35:514-519.

Ann Neurol. 2004; 55:105-112.

** JCBFM. 2012; 32:50-6.

Stroke. 2013; 44:681-5.

• 27 DEFUSE-2 pts with >90% reperfusion:

– Final infarcts were 5 cc (median) larger than DWI lesions

• Time from MRI start to procedure end = median 1.5 hrs

– 2 (7.4%) pts with final infarct volumes >2 cc smaller than baseline DWI lesion

– 1 (3.7%) with significant lesion volume reversal

Available CT-based techniques

• CT perfusion

• CTA source imaging

• NCCT

Technique dependent,

significant noise

unreliable for infarct

detection

Reliable, highly specific

for infarction

NCCT signs of acute ischemia

• Loss of gray-white

matter differentiation:

– “Insular ribbon”

– Basal ganglia

– Cortex

Insular

ribbon

Basal

ganglia Cortex

Optimizing NCCT detection

Standard Optimal

Lev et al. Radiology. 1999:

-Sensitivity 57% 71%

-Specificity 100%

Standardizing NCCT evaluation

• Alberta Stroke

Program Early

CT Score

• Reliable, semi-

quantitative

• Scored from 0

to 10 – lower

score indicates

a larger infarct

C

IC

L

M1

M2

M3

M4

M5

M6

I

NCCT ASPECTS predicts IAT response

• PROACT II (154 pts):

– Patients with small infarcts (ASPECTS 8-10) had 5

times higher rate of good outcome with IAT

– No difference in outcomes between IAT vs. placebo in

ASPECTS 0-7

JAMA. 1999; 282:2003-11.


• PICS-Pivotal (249 pts):

Stroke. 2014: 45:746-51.

8-10

5-7

0-4


• MR CLEAN:

Courtesy of Dr. Diederik Dippel


• Major imaging questions:

– Hemorrhage?

– Proximal artery occlusion?

– Core infarct size?

• Is there a role for perfusion imaging?

– Not for identifying “penumbral” tissue small

core is enough

– How about for determining core infarct??

Stroke 2013; 44:870-947.

Overview





40

Penumbra (at risk)

Core (irreversibly damaged)

Courtesy of Dr. T.M. Leslie-Mazwi

Penumbra: Definitions

• Pathophysiologic definitions

– Ischemic core: ischemic brain tissue that is irreversibly injured and will proceed to infarction despite immediate reperfusion

– Ischemic penumbra: functionally impaired tissue that is at high risk for subsequent infarction without early reperfusion

• Operational (imaging) definitions

– Specific to imaging modality (CT vs. MRI), technique and parameters, and thresholds

– Probabilistic and prone to measurement error

Stroke 2013; 44:2628-2639.

Assessing core vs. penumbra:

challenges of perfusion imaging

• Theoretical challenges:

– Collateral flow is only one factor that determines tissue

viability

• Other factors: duration of ischemia, tissue susceptibility to

ischemia

– Imaging is a snapshot in time collaterals fluctuate

or

CBV CBF MTT Tmax

Alternate pathway,

CPP preserved

Compensated low CPP

Underperfused

Overperfused

(post-ischemic

hyperperfusion)

Core

or not

Where is

the core?

Core

or not

Core

or not

Core

or not

WA Copen

Guideline recommendations:

Perfusion assessment of core infarction

Stroke 2013; 44:870-947.

CT CBV, 9:45 PM DWI, 10:09 PM

William A. Copen, MD

Can CT CBV substitute for DWI?

CBV ≠ DWI

CBV ≠ Core

DWI

CBV

WA Copen

Guideline recommendations:

Perfusion assessment of core infarction

WRONG!

Stroke 2013; 44:870-947.

Assessing core vs. penumbra:

challenges of perfusion imaging

• Theoretical challenges:

– Collateral flow is only one factor that determines tissue

viability

• Other factors: duration of ischemia, tissue susceptibility to

ischemia

– Imaging is a snapshot in time collaterals fluctuate

• Practical challenges:

– No well-validated parameter or threshold to distinguish core/penumbra or penumbra/benign oligemia (poor standardization)

– Reliability of CBF quantification using CT or MR

perfusion is poor

What CTP parameter best defines core?

• CBV

– Wintermark M, et al. Stroke; 37: 979-985

– Schaefer PW, et al. Stroke; 39: 2986-2992

• CBF

– Bivard A, et al. Cerebrovasc Dis 2011; 31: 238-245

– Kamalian S, et al. Stroke 2011; 42:1923-1928

Stroke. 2011; 42:1923-1928.

• Results:

• CBF is the most accurate parameter for DWI core

• Between three different post-processing algorithms,

significant variation exists in optimal parameter

thresholds (optimal CBF: 4.7 vs 5.4 vs 10 ml/100g/min)

• Conclusion: Quantitative thresholds have limited

generalizability between platforms

Sources of variability in perfusion imaging

• Patient

– Delay and dispersion (variable collaterals and stenoses between AIF and tissue)

• Acquisition

– Duration of cine imaging (truncation of tissue contrast-time curve)

– Shuttle mode (increased image noise)

• Post-processing

– ROI selection of AIF and VOF

– Delay-sensitive vs. delay correction

– Blackbox algorithms (vendor-specific and not well validated)

• Analysis

– Choice of perfusion parameter

• “Until reproducibility is

improved…, MR is not

suitable for reliable

quantitative perfusion

measurements….”

JCBFM 2002; 22: 1149-56.

MR- and CT-based perfusion imaging cannot produce

accurate absolute perfusion measurements.

Hagen T et al., JCAT 1999;

23(2):257-64.

Lin W et al., JMRI 1999;

14(6):659-67.

MRI WA Copen

Nabavi DG et al., JCAT 1999;

23(4): 506-15.

CT WA Copen



CT

Wintermark M et al., AJNR 2001;

22(5):905-14.

WA Copen



• “…on the basis of postprocessing variability alone, if the true CBF value is 20 mL/100g/min, measurements of CBF…can vary by approximately ±7-10 mL/100g/min….”

Intraobserver variability Interobserver variability

AJNR. 2004; 25:97-107.

• The problem with CTP

is image noise

– each additional step in

image processing

introduces uncertainty

noise

– CNR >4 associated with

reliable lesion conspicuity

• CTP maps often have

CNR <<4

– poor CNR indistinct

lesion boundaries and

major uncertainty in

lesion volume

JNIS. 2012; 4:242-5.

• CBF map thresholded for core infarction

A picture says a thousand words....

A picture says a thousand words....

• CBF map thresholded for core infarction

Overview





61

What’s the diagnosis?

WA Copen

WA Copen

What’s the diagnosis?

78 year old woman s/p episode of garbled speech last night.

Restrepo L, Jacobs MA, Barker PB, Wityk RJ. Assessment of transient ischemic attack with diffusion- and perfusion-weighted imaging. AJNR: American Journal of Neuroradiology. 2004;25:1645-1652

Krol AL, Coutts SB, Simon JE, Hill MD, Sohn CH, Demchuk AM, Group VS. Perfusion MRI abnormalities in speech or motor transient ischemic attack patients. Stroke. 2005;36:2487-2489

Mlynash M, Olivot JM, Tong DC, Lansberg MG, Eyngorn I, Kemp S, Moseley ME, Albers GW. Yield of combined perfusion and diffusion MR imaging in hemispheric TIA. Neurology. 2009;72:1127-1133

TIA symptoms with negative DWI:

PWI shows an abnormality in 3%-25% of patients

Perfusion imaging tells you that it was a TIA, not a martini.

WA Copen

What’s the etiology? 67 year-old man, awoke with R F/A/L weakness, now resolved, but has

decreased sensation to LT on arm and leg.

DWI Tmax

(different slice locations)

Perfusion imaging tells you that it was an embolus, not a

lacune.

Has the infarct reperfused?

DWI CBF

YE

S

DWI CBF

Has the infarct reperfused?

Spontaneous reperfusion:

16% within eight hours.1

33% within 48 hours.2

42%-60% within one

week.3-4

77% within two weeks.3

1. Rubin G, Firlik AD, Levy EI, Pindzola RR, Yonas H. Xenon-enhanced computed tomography cerebral blood flow measurements in acute cerebral ischemia: Review of 56 cases. Journal of Stroke

and Cerebrovascular Diseases. 1999;8:404-411

2. Hakim AM, Pokrupa RP, Villanueva J, Diksic M, Evans AC, Thompson CJ, Meyer E, Yamamoto YL, Feindel WH. The effect of spontaneous reperfusion on metabolic function in early human

cerebral infarcts. Ann Neurol. 1987;21:279-289

3. Jorgensen HS, Sperling B, Nakayama H, Raaschou HO, Olsen TS. Spontaneous reperfusion of cerebral infarcts in patients with acute stroke. Incidence, time course, and clinical outcome in the

Copenhagen stroke study. Arch Neurol. 1994;51:865-873

4. Bowler JV, Wade JP, Jones BE, Nijran KS, Steiner TJ. Natural history of the spontaneous reperfusion of human cerebral infarcts as assessed by 99mTc HMPAO SPECT. J Neurol Neurosurg

Psychiatry. 1998;64:90-97

78 yo F, s/p recent L carotid stenting,

now with acute onset of aphasia and R hemiparesis. BP

196/85.

CBV CBF MTT

Blood Pressure Management

Conclusions

• For standard IV tPA treatment:

• Emphasis on speed of imaging

• Rule out hemorrhage

• Rule out well-defined hypodensity in >1/3rd MCA territory

• Exclude EIC in >1/3rd MCA territory (3-4.5 hr)

• No role for perfusion imaging

Conclusions

• For intra-arterial treatment:

• No standard imaging approach

• Rule out hemorrhage

• Vessel imaging (CTA or MRA) important to identify proximal occlusion (and evaluate cervical vessels)

• Core infarct size predicts clinical response to IAT (i.e., benefit vs. risk)

‒ Diffusion MRI is the best available method

‒ NCCT is the best validated CT-based approach

‒ Perfusion imaging is unreliable for core infarct delineation

Conclusions

• Potential clinical uses for perfusion imaging:

• Qualitative approaches

• What is the diagnosis?

-Rule out stroke mimic

• What is the etiology?

-Lacune vs. embolus

-Cardioembolic source

• Has the infarct reperfused?

-BP management

Perfusion Imaging for AIS Is There a Role in Patient Selection? · 2014. 12. 29. · Disclosures...

Documents

Transcript of Perfusion Imaging for AIS Is There a Role in Patient Selection? · 2014. 12. 29. · Disclosures...