MRI ELASTOGRAPHY:PRIMER, QC AND ARTIFACTS

RAMSÉS HERRERAHunter Holmes McGuire VA Medical Center

DISCLOSURES

1. Research collaboration with Philips Medical Systems (Koninklijke Philips NV).

OUTLINE1. RVAMC2. Liver Disease3. Elastography

1. Stiffness2. Shear Waves3. Inversion problem

4. MRE Physics1. Pulse Sequence2. Phase contrast Imaging3. MRE

5. MRE Indication of Liver Disease6. Artefacts & Pitfalls7. Quality Control8. Future & Challenges

Hunter Holmes McGuire VAMC Only VA MC with in-house Heart Transplants Home site of VALOR trial

o Multi-Phase, National clinical trialo SBRT vs. Lung Lobectomy

Primary VA MC for spinal cord injury Part of RSNA Quantitative Imaging Biomarker Alliance (QIBA)

o First to implement new lung nodule screening criteriao First to certify CT Low Dose Lung nodule scans with QIBA phantom (CTLX1)

Second Largest government facility in Virginiao Largest is the Pentagon

Most MRE in the Eastern United Stateso Second in USA to Mayo Clinico 4 – 6 MRE’s per week

Chronic Liver Disease MOST FORMS OF Chronic Liver Disease (CLD) lead to:

Fibrosis

Cirrhosis

CAUSES ARE: Alcoholism

Viral

Non-Alcoholic Fatty Liver Disease (NAFLD)

Autoimmune

Genetic

Metabolic (Diabetes Millietus)

Chronic Liver Disease CDC estimates are:

240 Million World Wide with Hepatitis B ( 1.4 M in USA)

160 Million World Wide with Hepatitis C (3.2 M in USA)

NAFLD affects 27% - 34% of U. S. population

> 30 Million Americans have CLD, majority from NAFLD.

Liver Fibrosis It is vital to be able to accurately stage the degree of Fibrosis

o Liver Fibrosis is an independent risk factor for Hepatocellular Carcinoma (HCC)

o Prognosis and Management depend on Staging

o Outcome of surgical resection of HCC depend on Fibrosis staging.

Available diagnostics:o Blood Test (Platelet, PT, albumin, total bili, aminotransferase, hyaluronic acid, α2-Macroglobulin)

o Pro: Inexpensive & easily available

o Cons: Low Specificity (‘positives not overlooked’) & Limited ability to quantify Fibrosis.

o Panel of these testso Pro: Considered superior to stand-alone test.

o Cons: at < 0.2, NPV = 98%, >0.8,PPV = 62% (Exclude or confirm disease, cannot stage)

Liver Fibrosis (Diagnostics Cont’) Cross-sectional Imaging

CT, MRI, US Can give some idea of disease state

o Anatomic signs/distortion, change in density (attenuation), echotexture

o Ratio > 0.65 of Caudate lobe width to right lobe width = 100% Cirrhosis.

o Insensitive for Early Fibrosis – only useful at full cirrhosis.

Biopsyo Pros: Gold Standard (5 -11 portal tracts sampled)o Cons:

o Invasive (1.7% risk Morbidity, 0.01%-1.0% risk Mortality)

o Excellent stablishing disease, but less reliable for staging

o Large inter/intra observer variability in staging

o 20% Error rate in staging among expert pathologists

o Requires yearly repetition

o SAMPLING ERROR (not enough of the Liver is sampled)

Elastography: Elasticity & Shear waves Elasticity: Tendency to return to normal state after a force is exerted. Strain: Relative amount of deformation

o Young’s Modulus – tendency to deform along the axis of stress

o Shear Modulus – change in shape w/o change in volume

Generally assume that tissue is linearly elastic & isotropic

o Follows Hooke’s Law: 𝑭𝑭 = 𝒌𝒌 × ∆𝒙𝒙o Young’s Modulus (E) is related to Shear Modulus (µ)

o 𝑬𝑬 = 𝟑𝟑𝝁𝝁

The shear modulus of linear, isotropic tissue is:o 𝜇𝜇 = 𝜌𝜌𝜈𝜈𝑠𝑠2 - 𝜌𝜌 𝑖𝑖𝑖𝑖 𝑚𝑚𝑚𝑚𝑖𝑖𝑖𝑖 𝑑𝑑𝑑𝑑𝑑𝑑𝑖𝑖𝑖𝑖𝑑𝑑𝑑𝑑 & 𝜈𝜈𝑠𝑠 𝑖𝑖𝑖𝑖 𝑣𝑣𝑑𝑑𝑣𝑣𝑣𝑣𝑣𝑣𝑖𝑖𝑑𝑑𝑑𝑑 𝑣𝑣𝑜𝑜 𝑝𝑝𝑝𝑝𝑣𝑣𝑝𝑝𝑚𝑚𝑝𝑝𝑚𝑚𝑑𝑑𝑖𝑖𝑣𝑣𝑑𝑑

Shear Waves: Transverse waves in elastic medium due to shearo Shear – Change in shape w/o change in volume.

Elastography Palpation, to feel difference in mechanical properties of tissues

Abnormal tissue

Normal tissue

Manual palpation depends on:o Organ proximity to surface

o Subjective to touch/ sensitivity of practitioner

Conventional imaging modalities are not capable of assessing properties of palpationo ELASTIC MODULUS

Mechanical properties of tissue vary at different physiological and pathological states. i.e., Breast cancer palpation

Elastography: Types Static Stimulus:

o Manual Palpation

o Strain elastography (internal motion… cardiac/breath, mild compression)

o Superficial tissues

Dynamic Stimulus:o Induce vibrations in 50 – 500 Hz

o Image the propagation of waves from excitation

o US & MR

Elastography: Types Static Stimulus:

o Manual Palpation

o Strain elastography (internal motion… cardiac/breath, mild compression)

o Superficial tissues

Dynamic Stimulus:o Induce vibrations in 50 – 500 Hz

o Image the propagation of waves from excitation

o US & MR

Elastography: Static

Static Stimulus:o Mainly used in Ultrasound

o Qualitative interpretation

o Gauge for pressure applied

o Cannot accurately stage Fibrosis

Elastography: Shear Wave

Dynamic Stimulus: Ultrasound

o Uses shear waves

o Semi Quantitative

o Disease specific staging criteria

o Sampling error like biopsy

MRI Elastography (MRE) Uses external, pneumatic driver to create shear waves

o ‘shake’ the livero GE uses 60 Hzo Relative Amplitude – 70o Breath-hold (expiration)o 12 hour Nils per Os

Usually 3 to 4 slices of liver acquired

Motion Encoding gradients usedo Same type as in phase contrast angiography (MRA)o Motion encoding in direction of propagationo Wave displacement maps created with four (4) phase-offso Acquisition – 14 seconds per slice (56 sec)

MRI Phase Contrast A quickie!! Wave have two three fundamental properties:

o Amplitude (A)

o Frequency (F)

o Phase (𝜙𝜙)

When spatial gradients are applied (𝐺𝐺𝑧𝑧) phase is ‘remembered’ after gradient off

Changes in phase accumulation can be converted to displacement.

o HOW: 𝐺𝐺𝑧𝑧 changes proton frequency as function of distance in a very precise way.

o Tissue that does not move has no ‘net-phase accumulation’o Can be cancelled out from an initial reference image

𝑧𝑧 = 𝐴𝐴 cos 𝐾𝐾𝑑𝑑 − 𝑤𝑤𝑑𝑑 + 𝜙𝜙

MRI Phase Contrast Movement-related

dephasing:o Moving tissue

o Static tissue

o Uni-polar gradient - Gz

Phase of static tissues also grows

We want static phase to be zero.

G0

0 T𝐺𝐺𝑧𝑧 = 1 , 0 < 𝑑𝑑 < 𝑇𝑇

𝐺𝐺𝑧𝑧 Φ2 - phaseΦ2-position

Φ1 - phase

Φ1-position

Gz gradient

𝑤𝑤 = 𝛾𝛾 𝐵𝐵𝑜𝑜 + �⃗�𝐺𝑧𝑧 � ∆𝑧𝑧 𝜙𝜙 = �0

𝑇𝑇𝑤𝑤 𝑑𝑑𝑑𝑑𝑡

Φ2-moving tissue

Φ1 – static tissue

MRI Phase Contrast Movement-related

dephasing:o Moving tissue

o Static tissue

o Bi-polar gradient - Gz

Phase of static tissues also grows

We want static phase to be zero.

G0

0

T𝐺𝐺𝑧𝑧 = 1 , 0 < 𝑑𝑑 < 𝑇𝑇

𝐺𝐺𝑧𝑧

Φ1-position

Gz gradient

�𝑇𝑇 2

𝑤𝑤 = 𝛾𝛾 𝐵𝐵𝑜𝑜 + �⃗�𝐺𝑧𝑧 � ∆𝑧𝑧

𝜙𝜙 = �0

�𝑇𝑇 2𝑤𝑤 𝑑𝑑𝑑𝑑′ − �

�𝑇𝑇 2

𝑇𝑇𝑤𝑤 𝑑𝑑𝑑𝑑𝑡

Φ2-moving tissue

Φ1 – static tissue

PurposeMeasure shear modulus (stiffness) of liver

Capable of detecting fibrosis (staging possible)

MethodUse mechanical waves to “shake” liver tissue at 60Hz (GE) and set up traveling shear waves

Use concurrent oscillating gradients to map periodic displacement into a periodic MR phase map

MRI Elastography (MRE)

HowKeep track of the accumulated phase…

𝜙𝜙 𝑝𝑝,𝜃𝜃 = 2𝛾𝛾𝛾𝛾𝑇𝑇 𝐺𝐺𝑜𝑜� 𝜉𝜉0𝜋𝜋

cos 𝑘𝑘 � 𝑝𝑝 + 𝜃𝜃

z0 = 0

Physics Fundamentals: Pulse Sequence

1

2

AA

z0 = 0

1

2

Physics Fundamentals: Pulse Sequence

𝜙𝜙

z0 = 0

1

2

Physics Fundamentals: Pulse Sequence

𝜙𝜙

PHYSICS FUNDAMENTALS: Traveling Waves

Stay on crest of wave (travel with the wave):

𝑧𝑧 = 𝐴𝐴 cos 𝐾𝐾𝑑𝑑 −𝑊𝑊𝑑𝑑 ≡ 𝐴𝐴 cos 𝐾𝐾 𝑑𝑑 −𝑊𝑊𝐾𝐾𝑑𝑑

A = AmplitudeK = Wave numberW = Angular frequencyF = FrequencyT = period𝑊𝑊 = 2𝜋𝜋𝜋𝜋 ≡

2𝜋𝜋𝑇𝑇

K = 2𝜋𝜋𝜆𝜆

𝑑𝑑 −𝑊𝑊𝐾𝐾 𝑑𝑑 = 0 𝑚𝑚𝑑𝑑 𝑣𝑣𝑝𝑝𝑑𝑑𝑖𝑖𝑑𝑑 ⟶

𝑑𝑑𝑑𝑑 = 𝑣𝑣 = 𝜋𝜋𝐹𝐹 ≡

𝑊𝑊𝐾𝐾

This is the wave velocity

MRI Elastography (MRE) Phase Accumulation:

𝜙𝜙 = �0

𝑇𝑇𝑤𝑤 𝑑𝑑𝑑𝑑

𝐿𝐿𝑚𝑚𝑚𝑚𝑣𝑣𝐿𝐿𝑝𝑝 𝜋𝜋𝑝𝑝𝑑𝑑𝐹𝐹𝐿𝐿𝑑𝑑𝑑𝑑𝑣𝑣𝑑𝑑: 𝑤𝑤 = 𝛾𝛾 𝐵𝐵𝑜𝑜

𝐺𝐺𝑝𝑝𝑚𝑚𝑑𝑑𝑖𝑖𝑑𝑑𝑑𝑑𝑑𝑑 𝑚𝑚𝑝𝑝𝑝𝑝𝑣𝑣𝑖𝑖𝑑𝑑𝑑𝑑 𝑖𝑖𝑑𝑑 �̂�𝑧:𝑤𝑤 = 𝛾𝛾 𝐵𝐵𝑜𝑜 + 𝐺𝐺𝑧𝑧 � ∆𝑧𝑧 …In rotating frame of reference

𝑧𝑧 = 𝐴𝐴 cos 𝐾𝐾𝑑𝑑 −𝑊𝑊𝑑𝑑 + 𝜃𝜃

&0 T

G0

Bi-polar Gradient𝐺𝐺𝑧𝑧 =1, 0 < 𝑑𝑑 <

𝑇𝑇2

−1,𝑇𝑇2 < 𝑑𝑑 < 𝑇𝑇

&

MRI Elastography (MRE) Phase accumulation:

𝜙𝜙 = 𝛾𝛾𝐺𝐺𝑜𝑜 �𝑜𝑜

�𝑇𝑇 2

𝑧𝑧0 + 𝐴𝐴 cos 𝐾𝐾𝑑𝑑 − 𝑤𝑤𝑑𝑑 + 𝜃𝜃 𝑑𝑑𝑑𝑑 − ��𝑇𝑇 2

𝑇𝑇𝑧𝑧0 + 𝐴𝐴 cos 𝐾𝐾𝑑𝑑 − 𝑤𝑤𝑑𝑑 + 𝜃𝜃 𝑑𝑑𝑑𝑑

𝜙𝜙 = γ𝐺𝐺𝑜𝑜 𝑧𝑧𝑜𝑜𝑇𝑇2− 0 − 𝐴𝐴

𝑤𝑤sin 𝐾𝐾𝑑𝑑 − 𝑤𝑤 𝑇𝑇

2+ 𝜃𝜃 − sin 𝐾𝐾𝑑𝑑 + 𝜃𝜃 − 𝑧𝑧0 𝑇𝑇 − 𝑇𝑇

2− 𝐴𝐴

𝑤𝑤sin 𝐾𝐾𝑑𝑑 − 𝑤𝑤𝑇𝑇 + 𝜃𝜃 − sin 𝐾𝐾𝑑𝑑 − 𝑤𝑤 𝑇𝑇

2+ 𝜃𝜃

G0

0

T𝐺𝐺𝑧𝑧 = 1 , 0 < 𝑑𝑑 < 𝑇𝑇

𝐺𝐺𝑧𝑧

Φ1-positionGz gradient

�𝑇𝑇 2

Φ2-moving tissue

Φ1 – static tissue

MRI Elastography (MRE)

𝜙𝜙 = −𝛾𝛾𝐺𝐺0𝐴𝐴𝑤𝑤 sin 𝐾𝐾𝑑𝑑 − 𝜋𝜋 + 𝜃𝜃 − sin 𝐾𝐾𝑑𝑑 + 𝜃𝜃 − sin 𝐾𝐾𝑑𝑑 − 2𝜋𝜋 + 𝜃𝜃 + sin 𝐾𝐾𝑑𝑑 − 𝜋𝜋 + 𝜃𝜃 𝜙𝜙 = −

4𝛾𝛾𝐺𝐺0𝐴𝐴𝑤𝑤 sin 𝐾𝐾𝑑𝑑 + 𝜃𝜃 |𝑤𝑤= �2𝜋𝜋

𝑇𝑇

𝜙𝜙 = −2𝛾𝛾𝐺𝐺0𝐴𝐴𝑇𝑇

𝜋𝜋 sin 𝐾𝐾𝑑𝑑 + 𝜃𝜃 𝜙𝜙 𝑝𝑝,𝜃𝜃 = 2𝛾𝛾𝛾𝛾𝑇𝑇 𝐺𝐺𝑜𝑜� 𝜉𝜉0𝜋𝜋

cos 𝑘𝑘 � 𝑝𝑝 + 𝜃𝜃𝜙𝜙𝑛𝑛 = −2𝛾𝛾𝑑𝑑𝐺𝐺0𝐴𝐴𝑇𝑇

𝜋𝜋 sin 𝐾𝐾𝑑𝑑 + 𝜃𝜃

𝐺𝐺𝑧𝑧

Φ1-positionGz gradient

Φ2-moving tissue

Φ1 – static tissue

MRI Elastography (MRE) We’ve tracked the phase evolution

o Phase velocity

But we want stiffness…

𝜙𝜙 𝑥𝑥,𝑑𝑑 → 𝐹𝐹 𝑥𝑥,𝑑𝑑 → 𝜇𝜇 𝑥𝑥,𝑑𝑑

𝜈𝜈 = �𝜇𝜇 𝜌𝜌 𝜈𝜈 = 𝜋𝜋𝐹𝐹

𝜇𝜇 𝑥𝑥,𝑑𝑑 = 𝜌𝜌 � 𝜐𝜐 𝑥𝑥,𝑑𝑑 2 → 𝜌𝜌𝜋𝜋2 𝐹𝐹 𝑥𝑥,𝑑𝑑 2

…Et voilà!

𝐹𝐹 = 𝑤𝑤𝑚𝑚𝑣𝑣𝑑𝑑𝑣𝑣𝑑𝑑𝑑𝑑𝑝𝑝𝑑𝑑𝑤𝜇𝜇 = 𝑆𝑆𝑤𝑑𝑑𝑚𝑚𝑝𝑝 𝑚𝑚𝑣𝑣𝑑𝑑𝐿𝐿𝑣𝑣𝐿𝐿𝑖𝑖 (𝑘𝑘𝑘𝑘𝑚𝑚)𝜋𝜋 = 𝑜𝑜𝑝𝑝𝑑𝑑𝐹𝐹𝐿𝐿𝑑𝑑𝑑𝑑𝑣𝑣𝑑𝑑𝜌𝜌 = 𝑚𝑚𝑚𝑚𝑖𝑖𝑖𝑖 𝑑𝑑𝑑𝑑𝑑𝑑𝑖𝑖𝑖𝑖𝑑𝑑𝑑𝑑

MRI Elastography (MRE)

MRE: Indications of Liver Disease So what do we end up with?

Anatomical Image Wave Propagation Image Elastogram Image

MRE: Indications of Liver Disease

Stiffness (kPa) Fibrosis Staging<2.5 None (F 0)

2.5 – 3.0 Normal + Inflammation3.0 – 3.5 F(1) – F(2)3.5 – 4.0 F(2) – F(3)4.0 – 5.0 F(3) – F(4)

>5 F(4)

MRE: Accuracy Systemic review & Meta analysis (Sing et als.,)

o 12 studies

o 697 patients

o < 1 year between MRE & biopsy

ROC analysis – area under curve at 95% C.I.o 0.84 (0.76 – 0.92) for F(1)

o 0.88 (0.84 – 0.91) for F(2)

o 0.93 (0.90 – 0.95) for F(3)

o 0.92 (0.90 – 0.94) for F(4)

Failure rate < 4.3%

MRE: Accuracy Systemic review & Meta analysis (Su et als.,)

o 13 studies

o 989 patients

Pooled Sensitivities and Specificitieso 87% (95%ci: 84%-89%) and 92% (95%ci: 87%-96%) for f ≥ 1,

o 87% (95%ci: 84%-90%) and 92% (95%ci: 89%-95%) for f ≥ 2

o 88% (95%ci: 85%-91%) and 91% (95%ci: 88%-93%) for f ≥ 3

o 91% (95%ci: 87%-94%) and 92% (95%ci: 89%-94%) for f4

The pooled area under the roc curve was 0.95 for f ≥ 1, 0.97 for f ≥ 2, 0.97 for f ≥ 3, and 0.98 for f4.

Case 1: 33 yo, NAFLD (3.4kPa – F(1-2) )

Case 1: 65 yo, (M) NASH (11.5kPa – F(4)

F(1-2) F(4)

Artifacts & Pitfalls

Excessive Noise:• driver pneumatic tube• disconnected

No wave signal

Susceptibility Artifact• Seen on Magnitude Image• Lack of wave propagation• Interposed colon (anatomy)

Artifacts & Pitfalls

Hot Spot:• Artefactual “hot spot” under

driver• Avoid

Partial Volume:• ROI exclude 1 cm inside liver• ROI exclude ½ wavelength• Exclude Fossa, Fissures

Artifacts & Pitfalls1. Vessels > 3 mm do not reflect parenchymal

stiffness2. Waves can interfere

a. Standing wave – Highest stiffnessb. Pseudo standing wave – High stiffnessc. Destructive interference – low stiffness

• Major vessels in liver cause major interference

• Complex boundary conditions for wave propagation

Quality Control Currently not aware of:

o QC recommendation by AAPM, ACR or similar

o No phantoms available

o Must rely on manufacturer calibration

In talks to develop MRE specific phantomo Targets with different stiffness values

o Semi-anthropomorphic

o Simulate major blood vessels

Major cause of artefactso Magnet homogeneity

o Gradient linearity

o Eddy current correction

o Ghosting

Best with dual echo GRE (phase subtraction). Detailed in ACR doc. Alternative: Engineer Can accurately check with ACR phantom

Degrades speed/efficiency of gradient switching – Check the .LSVM files + engineer

Richmond VAMCCurrently testing a prototype phantom

In talks to develop comprehensive MRE phantomo Several stiffness targets

o Semi-anthropomorphic

o Simulate blood vessels

Quality Control

Richmond VAMCCurrently testing a prototype phantom

In talks to develop comprehensive MRE phantomo Several stiffness targets

o Semi-anthropomorphic

o Simulate blood vessels

Quality Control

Future & Challenges MRE - Kidneys MRE – Breast (MQSA 2.0 ???)

Future & Challenges MRE – Lower Extremities MRE – Brain MRE – Cardiac

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23(5):497-511; 2010.3. Venkatesh, S. K., et als., “Magnetic Resonance Elastography of Liver: Technique, Analysis

and Clinical Applications”, J. Magn. Reson. Imaging. 37(3): 544-555; 2013.4. Bernstein, M. A., et als., “Handbook of MRI Pulse Sequesnces”, Elsevier Academic Press,

London, UK; 2004. 5. M. R. Khan, MD, “MR Elastography”, Department Presentation, Hunter Holmes McGuire

VA Medical Center, Richmond, VA 2017.6. Muthupillai R, et. als., “Magnetic Resonance Elastography by Direct Visualization of

Propagating Acoustic Strain Waves.”, Science. 269:1854-1857; 1955, 7. Muthupillai R, et. als., “Magnetic Resonance Imaging of Transverse Acoustic Strain

Waves”, Magnetic Resonance in Medicine. 36:226-274; 1996.

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