Transcript CME Objectives 1. Identify new skills that can be applied to practice

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Ophthalmology Grand Rounds – January 18
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©2014 MFMER | slide-1
Accreditation
Mayo Clinic College of Medicine is accredited by the Accreditation Council for Continuing Medical
Education to provide continuing medical education for physicians.
Mayo Clinic College of Medicine designates this live activity for a maximum of 0.75 AMA PRA
Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their
participation in the activity.
CME Objectives
1) Identify/summarize/describe concepts related to clinical eye care
2) Apply new knowledge to relevant clinical situations.
As a provider accredited by ACCME, Mayo Clinic College of Medicine, (Mayo School of CPD) must ensure balance,
independence, objectivity and scientific rigor in its educational activities. Course Director(s), Planning Committee
Members, Faculty, and all others who are in a position to control the content of this educational activity are required to
disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational
activity. Safeguards against commercial bias have been put in place. Faculty also will disclose any off label and/or
investigational use of pharmaceuticals or instruments discussed in their presentation. Disclosure of this information will
be published in course materials so those participants in the activity may formulate their own judgments regarding the
presentation.
Listed below are individuals with control of the content of this program who have disclosed…
Relevant financial relationship(s) with industry:
Raymond Iezzi, M.D. is a consultant to Alcon, Alimera, Vergent
No relevant financial relationship(s) with industry:
Dept. of Ophthalmology Planning Committee includes members of the Education Committee: Drs. Sophie Bakri, Sanjay Patel,
Keith Baratz, Andrew J. Barkmeier, Elizabeth Bradley, William Brown, John Chen, Amir Khan, Sunil Khanna, Leo Maguire,
Michael Mahr, Brian Mohney, Wendy Smith, Linda Mrozek, Kari Sczepanski.
©2014 MFMER | slide-2
DISCLOSURE
Speaker: Arthur J. Sit, M.D.
Relevant Financial Relationship
None
Off Label Usage
None
©2014 MFMER | slide-3
Presentation Learning Objectives
• Understand the techniques used for measuring
ocular biomechanical properties
• Understand the role of ocular biomechanics in
glaucoma management
©2014 MFMER | slide-4
Measurement of
Ocular Biomechanical Properties
Arthur J. Sit, SM, MD
Associate Professor of Ophthalmology
Mayo Clinic
©2015 MFMER | slide-5
Pre-Test Questions
1. Ocular biomechanical properties can be used
in the routine clinical care of glaucoma:
• True
• False
2. Corneal modulus of elasticity is greater
(stiffer) than scleral modulus of elasticity
• True
• False
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Ocular Biomechanics
• Keratoconus
• Pathologic myopia
• Glaucoma
©2015 MFMER | slide-7
Effect of Ocular Biomechanics on
Optic Nerve Head
• Elevation of IOP results in distension of the lamina cribrosa
• What tissue properties will protect against IOP related damage?
Stiff tissues may result in greater lamina deformation
How can we measure ocular biomechanical properties?
Downs JC. Optic nerve head biomechanics in aging and disease. Exp Eye Res. 2015 Apr;133:19-29.
©2015 MFMER | slide-8
Human Cadaver Models
Elsheikh A, Alhasso D, Rama P. Biomechanical properties of human and porcine corneas. Exp Eye Res. 2008.
©2015 MFMER | slide-9
Ocular Response Analyzer
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Ocular Response Analyzer
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Ocular Biomechanics and Glaucoma
30
• Lower CH results in greater annual VFI decline for a given IOP
-5
-4
25
-3
-2
15
20
-1
0
1
10
Intraocular Pressure (mmHg)
-6
4
5
6
7
8
9
10
11
Corneal Hysteresis (mmHg)
How is CH related to standard biomechanical properties?
Medeiros FA, Meira-Freitas D, Lisboa R, Kuang TM, Zangwill LM, Weinreb RN. Corneal hysteresis as a risk factor
for glaucoma progression: a prospective longitudinal study. Ophthalmology. 2013 Aug;120(8):1533-40.
©2015 MFMER | slide-12
Ultrasound Elastography
Based on measurement of strain due to a constant external stress
Detorakis ET, Drakonaki EE, Tsilimbaris MK, et al. Real-time ultrasound elastographic imaging of ocular and
periocular tissues: a feasibility study. Ophthalmic Surg Lasers Imaging. 2010 Jan-Feb;41(1):135-41.
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Measurement of Ocular Biomechanical
Properties
• Other techniques have not been suitable for in vivo
measurements
• Goals:
•
•
•
•
Noninvasive
Quantitative assessment of standard material properties
Reproducible
High spatial resolution
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Non-Invasive Measurement of Ocular
Biomechanical Properties
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Measuring Biomechanics Using Waves
1. P-wave (longitudinal)
Basis for ultrasound imaging, cannot
be used for tissue elasticity
2. Shear wave (transverse)
Basis for most elastography
techniques
3. Surface wave (at interface)
Particularly useful for substrates with
material interfaces
Wave speed is dependent on the tissue material properties
©2015 MFMER | slide-17
Two types of surface waves
Longitudinal and
transverse
Transverse
Rayleigh waves are easier to measure
18
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Ultrasound Surface Wave Elastography
6MHz Linear Array Ultrasound
(Verasonics, Inc, Kirkland, WA)
Mechanical Shaker
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Dependence of Velocity on Frequency in
Viscoelastic Materials
• Perfectly elastic material
• Velocity depends only on material properties (elasticity, density)
• Viscoelastic material
• Velocity changes depending on the frequency of vibration
• Dispersive properties reflect the viscous characteristics of the
medium
• Viscoelastic properties can be obtained by measuring wave
phase velocity as a function of frequency
©2015 MFMER | slide-20
Wave Speed - Phase Gradient Method
Wave speed (cs ) measurement 𝑐𝑠 𝑓 = 𝑓∆𝑟/∆𝜙
where
𝑓 is the frequency
∆𝜙 is the wave phase change
∆𝑟 is the radial distance between 2 locations
𝑐𝑠
1
∆𝜙
2
∆𝑟
Multiple position regression
∆𝜙 = −𝛼Δ𝑟 + 𝛽
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Calculation of Young’s Modulus of Elasticity
For cornea modelled as a thin plate:1
𝜌𝑐 4
𝐸=9
(2𝜋𝑓ℎ)2
𝜌 is density, c is wave speed, f is frequency, h is thickness
1. Tanter M, Touboul D, Gennisson JL, Bercoff J, Fink M. High-resolution quantitative imaging of cornea elasticity using
supersonic shear imaging. IEEE Trans Med Imaging. 2009 Dec;28(12):1881-93.
©2015 MFMER | slide-22
Wave Propagation in the Eye
Depth (mm)
5
Cornea
10
15
Lens
Optic Nerve
20
25
30
Sclera
35
0
5
10
15
20
25
30
35
Distance(mm)
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Depth (mm)
Measurement of Corneal Wave Speed
∆𝜙 = −𝛼Δ𝑟 + 𝛽
𝑐𝑠 𝑓 = 𝑓∆𝑟/∆𝜙 = 1.81 ± 0.18m/s
Distance(mm)
𝑓 is the frequency
∆𝜙 is the wave phase change
∆𝑟 is the distance between 2 locations
©2015 MFMER | slide-24
Depth (mm)
Measurement of Scleral Wave Speed
∆𝜙 = −𝛼Δ𝑟 + 𝛽
𝑐𝑠 𝑓 = 𝑓∆𝑟/∆𝜙 = 2.55 ± 0.31m/s
Distance(mm)
𝑓 is the frequency
∆𝜙 is the wave phase change
∆𝑟 is the distance between 2 locations
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In Vivo Human Pilot Study Protocol
• Healthy Subjects
• IOP by GAT
• CCT by ultrasound pachymetry, Scheimpflug imaging
• Axial length by Zeiss IOL Master
©2015 MFMER | slide-26
In Vivo Human Pilot Study Protocol
• Ultrasound surface wave elastography:
•
•
•
•
Subject in supine position
Eyes closed
Ultrasound probe used to image the eye
Small local vibration is delivered to the eye with shaker
• 100 Hz for 0.1 second
• Statistics:
• Pearson correlations with significance from GEE models
©2015 MFMER | slide-27
Results
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Subject Characteristics
• 20 eyes of 10 healthy subjects
• Age 43-64 years; mean 51 years
• IOP: 12.6 ± 2.7 mmHg
• Central corneal thickness: 540 ± 39 μm
• Refractive error: -0.45 ± 1.47 diopters (spherical equiv)
• Axial length: 23.7 ± 0.8 mm
©2015 MFMER | slide-29
Wave Speed vs IOP
Sclera
3.5
3.5
3
3
Wave Speed (m/s)
Wave Speed (m/s)
Cornea
2.5
2
1.5
y = 0.0267x + 1.4852
R² = 0.5558
1
0.5
2.5
2
1.5
y = 0.0431x + 2.0965
R² = 0.5816
1
P<0.001
0.5
P<0.001
0
0
0
5
10
15
20
IOP (mmHg)
0
5
10
15
20
IOP (mmHg)
P<0.001
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𝜌𝑐 4
𝐸=9
(2𝜋𝑓ℎ)2
Young’s Modulus vs IOP
Sclera
1800
1800
1600
1600
1400
1400
1200
1000
800
600
y = 39x + 246
R² = 0.4993
P<0.001
400
200
Young's Modulus (kPa)
Young's Modulus (kPa)
Cornea
1200
1000
800
600
400
y = 73.338x + 202.6
R² = 0.5749
200
P<0.001
0
0
5
10
15
20
5
10
15
20
IOP (mmHg)
IOP (mmHg)
E = 735 ± 147 kPa
E = 1123 ± 258 kPa
P<0.001
©2015 MFMER | slide-31
Young’s Modulus vs Axial Length
Sclera
1800
1800
1600
1600
1400
1200
1000
800
600
y = -1.2857x + 765.86
R² = 5E-05
P>0.9
400
200
0
22
23
24
Axial Length (mm)
25
26
Young’s Modulus (kPa)
Young’s Modulus (kPa)
Cornea
1400
1200
1000
800
600
y = -3.4978x + 1205.7
R² = 0.0001
P>0.9
400
200
0
22
23
24
25
26
Axial Length (mm)
©2015 MFMER | slide-32
Young’s Modulus vs Age
Cornea
Sclera
1800
1600
1600
y = 9.203x + 262.41
R² = 0.193
P=0.06
1400
1200
Young's Modulus (kPa)
Young's Modulus (kPa)
1800
1000
800
600
400
1400
1200
1000
800
600
200
200
0
0
0
20
40
Age (years)
60
80
y = 1.661x + 1037.6
R² = 0.002
P=0.85
400
0
20
40
60
80
Age (years)
©2015 MFMER | slide-33
Young’s Modulus vs CCT
Sclera
1800
1800
1600
1600
Young's Modulus (kPa)
Young's Modulus (kPa)
Cornea
1400
1200
1000
y = 0.2683x + 590.26
R² = 0.0045
P=0.79
800
600
400
200
1400
y = 2.7436x - 361.84
R² = 0.1544
1200
1000
P=0.09
800
600
400
200
0
0
0
200
400
600
Central Corneal Thickness (µm)
800
0
200
400
600
800
Central Corneal Thickness (µm)
©2015 MFMER | slide-34
Corneal vs Scleral Young’s Modulus
1800
Scleral Young's Modulus (kPa)
1600
1400
1200
1000
800
y = 0.9628x + 414.89
R² = 0.3018
600
400
P<0.05
200
0
0
200
400
600
800
1000
1200
Corneal Young's Modulus (kPa)
©2015 MFMER | slide-35
Discussion
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Ex Vivo Corneal Elasticity
•
No comparable in vivo data
available
•
Comparison with ex vivo data:
• Young’s modulus smaller
→ effect of post-mortem edema?
• Correlated with IOP
• Not correlated with age
→ due to small study?
244 kPa
E = 735 ± 147 kPa
Elsheikh A, Alhasso D, Rama P. Biomechanical properties of human and porcine corneas.
Exp Eye Res. 2008 May;86(5):783-90.
©2015 MFMER | slide-37
Ex Vivo Scleral Elasticity
E = 1.12 ± 0.26 MPa
Geraghty B, Jones SW, Rama P, Akhtar R, Elsheikh A. Age-related variations in the biomechanical
properties of human sclera. J Mech Behav Biomed Mater 2012 Dec;16:181-91.
©2015 MFMER | slide-38
Ex Vivo Scleral Elasticity
• Much higher than our in vivo
measurements
• Measured at stress of:
• 0.05 MPa
• At 15 mmHg IOP, would
expect stress of 0.01 MPa
• Modulus of elasticity is highly
dependent on stress
Geraghty B, Jones SW, Rama P, Akhtar R, Elsheikh A. Age-related variations in the biomechanical
properties of human sclera. J Mech Behav Biomed Mater 2012 Dec;16:181-91.
©2015 MFMER | slide-39
Relationships with CCT, Age, Axial Length
• Young’s modulus not correlated with CCT
• Inherent tissue properties
• Global measures (e.g., CH) affected by CCT1,2
• Young’s modulus not related to Age, Axial Length
• Study Limitations
• Small sample – pilot study
• Relatively narrow age range
• All normal subjects
1. Medeiros FA, Meira-Freitas D, Lisboa R, Kuang TM, Zangwill LM, Weinreb RN. Corneal hysteresis as a risk factor for glaucoma
progression: a prospective longitudinal study. Ophthalmology. 2013 Aug;120(8):1533-40.
2. Deol M, Taylor DA, Radcliffe NM. Corneal hysteresis and its relevance to glaucoma. Curr Opin Ophthalmol. 2015 Mar;26(2):96-102..
©2015 MFMER | slide-40
Conclusions and Future Directions
• Scleral elasticity is significantly greater than Corneal
elasticity
• Current clinical devices focus on corneal properties
• Scleral and Corneal elasticity are correlated, but only
moderately
• To understand diseases of posterior segment, it will be
necessary to measure scleral elasticity
©2015 MFMER | slide-41
Conclusions and Future Directions
• USWE is a safe and non-invasive technique for
measurement of ocular biomechanical properties
• Young’s modulus of elasticity from pilot study are
consistent with ex vivo data
• Next steps:
•
•
•
•
•
Optimize for the eye
Measurement of viscosity
Normal database
Glaucoma patients
Other ocular conditions
©2015 MFMER | slide-42
Acknowledgments
• Department of Physiology and Biomedical Engineering, Mayo Clinic
• Xiaoming Zhang, PhD
• Department of Ophthalmology, Mayo Clinic
•
•
•
•
Jay W. McLaren, PhD
Arash Kazemi, MD
Sophie Lin, MD
Christopher Pruet, MD
• Funding:
• Hoeft Benefactor-Funded Career Development Award
• NIH 1R21 EY026095-01
©2015 MFMER | slide-43
Pre-Test Questions
1. Ocular biomechanical properties are used in
routine clinical care:
• True
• False
2. Corneal modulus of elasticity is greater
(stiffer) than scleral modulus of elasticity
• True
• False
©2015 MFMER | slide-44