Correlation between Retinal Blood Flow, Retinal Anatomy, and

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Correlation between Retinal Blood Flow, Retinal Anatomy, and Visual Field in Glaucoma

David Huang, MD, PhDWeeks Professor of Ophthalmic Research

Prof. of Ophthalmology & Biomedical Engineering

Casey Eye Institute,

Oregon Health & Science University

Portland, Oregon

Financial Interests:Optovue, Inc.: stock options, patent royalty, grants, speaker honorarium & travel supportCarl Zeiss Meditec, Inc.: patent royalty

ARVO ISIE MeetingFort Lauderdale, 30 April 2011

Coauthors

SriniVas Sadda, MD

John Hwang, MD

Ranjith Konduru, MBBS

Ou Tan, PhD

Xinbo Zhang, PhD

Rohit Varma, MD, MPH

Brian Francis, MD

David Greenfield, MD

Mitra Sehi, PhD

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Conventional glaucoma pathophysiology

Elevated intraocular pressure (IOP)

Loss of retinal ganglion cells &

nerve fibers

Loss of visual field

What is the role of blood flow?

Elevated IOP


nerve fibers


Decreased blood flow

?

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5

The relationship of OBF and retinal and optic nerve structure should be investigated.

Statistically significant thinning of the RNFL in association with reduced retrobulbar blood flow velocities was previously observed in OAG patients.1

An ideal device would assess both structure of the retina and optic nerve and blood flow in a single device

There is a consensus to investigate structure and blood flow in glaucoma

1. Januleviciene I, Sliesoraityte I, Siesky B, Harris A..Acta Ophthalmol. 2008 Aug;86(5):552-7.

A technique for rapid & accurate quantitation of total retinal blood flow is needed

Fluorescein & ICG angiography - qualitative

Doppler ultrasound -inaccurate

Laser doppler flowmeter –time consuming

David Huang, MD, PhD www.AIGStudy.net

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OCT could quantify retinal blood flow by measuring both Doppler shift and incidence angle

α V

Probe beamvv

v


)cos(2/ vV

Dopplershift

Incidenceangle

Methods of measuring blood flow velocity with OCT

Dual BeamDave DP, Milner TE, Opt Lett 2000;25:1523Pedersen CJ, et al. Opt Lett 2007;32:506-8

*Werkmeister RM et al. Opt Lett 2008;33:2967

Dual Plane

3D*Wehbe, H.M., et al. Opt. Express 15, 15193-15206 (2007)

Michaely, R., et al. J. Biomed Optics, 12, 041213-1~7 (2007)Makita, S., Fabritius, T., and Yasuno, Y. Opt. Lett. 33, 836-838 (2008)

David Huang, MD, PhD www.COOLLab.net

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Flow direction relative to OCT beam is measured by 2 parallel cross-sections

Double circular scan Flow profile and directiondetermined on parallel sections

Y. Wang, B. Bower, J. Izatt, O. Tan, D. Huang,”In vivo total retinal blood flow measurement by Fourier-domain Doppler optical coherence tomography,” Journal of Biomedical Optics 2007;12:041215-22.

Yimin Wang, PhD & David Huang, MD, PhD www.COOLLab.net

Double circular scan transects all retinal branch vessels 6 times per second

Inner Circle

Outer Circle


6

dxdz

cos2

∑Total Retinal Blood Flow

Flow in Veins

Algorithm for Total Retinal Blood Flow

0

1

2

3

4

5

0 0.5 1 1.5 2

Time (second)

Flo

w (

mic

rolit

er/

min

ute

)

Y. Wang, et. al., Journal of Biomedical Optics 13, 064003, (2008)

Flow value : 40.8 to 52.9 l/min, CV: 10.5%

Wang Y, et al. Br J Ophthalm, 93:634 (2009)

x

z

vessel velocitycross section

Flow in a single vessel

Average flow over 2 seconds for each vessel

Doppler anglemeasurement

Yimin Wang, PhD & David Huang, MD, PhD www.COOLLab.net

Pilot study showed that glaucoma, PDR and NAION all decreased retinal blood flow

Group(# of eyes)

Blood Flow(μl/min)

Venous Area(mm2)

Venous Velocity(mm/s)

Arterial Area(mm2)

Arterial Velocity(mm/s)

Normal (20)

47.6 ± 5.4 0.046 ± 0.008 17.7 ± 3.1 0.033 ± 0.005 24.6 ± 4.0

Glaucoma (16)

34.1 ± 4.9(p<0.001)

0.046 ± 0.008(p=0.977)

12.7 ± 1.7(p<0.001)

0.034 ± 0.008(p=0.454)

17.1 ± 3.6(p<0.001)

NAION (7)

28.2 ± 8.2(p<0.001)

0.030 ± 0.007(p<0.001)

15.4 ± 3.2(p=0.109)

0.025 ± 0.006(p=0.002)

19.0 ± 3.4(p=0.003)

PDR(5)

15.8 ± 10.1(p<0.001)

0.024 ± 0.007(p<0.001)

10.4 ± 3.6(p=0.001)

0.018 ± 0.011(p<0.001)

16.0 ± 5.0(p=0.001)

Wang Y, Fawzi AA, Varma R, Sadun AA, Zhang X, Tan O, Izatt JA, Huang D. Pilot study of optical coherence tomography measurement of retinal blood flow in retinal and optic nerve diseases. Invest Ophthalmol Vis Sci 2011; 52:840-845

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The dual circular scan OCT Doppler retinal blood flow measurement technology has been licensed by USC to Optovue for commercial development

Optovue RTVue26 kHz, 6 circles/secDavid Huang, MD, PhD www.AIGStudy.net

Semi-automated grading software was developed for Doppler OCT reading center

Probe beam

Doppler angle

En face view of 3D OCT scan

Vessel-normal vector

Vessel cross-sections from double circular scans

Doppler OCT of Retinal Circulation (DOCTORC) software uses both double-circular and 3D volumetric scans

Flow vector

Ou Tan, PhD & David Huang, MD, PhD www.COOLLab.net

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Doppler OCT of Retinal Circulation (DOCTORC) study group was organized

Organizers Center for Ophthalmic Optic & Laser, (OHSU/Huang)

Optovue, Inc.

Participants Advanced Imaging for Glaucoma Study

(OHSU/Huang) Clinical Centers: USC/Varma, U

Pittsburgh/Schuman, U Miami/Greenfield, OHSU/Morrison

Doheny Image Reading Center (Sadda)

Casey Translational

Indiana U (Harris)

UC San Diego (Weinreb, Liu)

U Erlangen (Michelson)

U Toronto (Flanagan, Hudson)

Doheny Retina Service (USC/Fawzi)

Doheny Neuroophthalmology (USC/Sadun)

Chinese Eye Study (USC/Varma) David Huang, MD, PhD www.COOLLab.net

R01 EY013516 www.AIGStudy.net

Site PI: James G.

Fujimoto, PhD

Consortium PI: David Huang

MD, PhD

Site PI: Joel S. Schuman,

MD

Site PI: David Greenfield,

MD

Yimin Wang, PhD

Ou Tan, PhD

Xinbo Zhang, PhD

Carolyn Quinn, MD

Krisha S. Kishor, MD

Mitra Sehi, PhD

Robert Noecker, MD

Gadi Wollstein, MD

Hiroshi Ishikawa, MD

Larry Kagemann, MS

Site PI:Bo Hu, PhD

Sharon Bi, MCIS

Site PI:Rohit Varma, MD,

MPH

Vikas Chopra, MD

Brian Francis, MD

Michelle Montalto

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Stratus OCTOptical coherence tomographyNerve fiber layer (NFL) thickness GDx-ECC SLP

Scanning laser polarimetryNFL thickness

HRT3 SLTScanning laser tomography Disc rim area

Standard quantitative imaging modalities were used to measure loss of retinal nerve fibers

David Huang, MD, PhD www.COOLLab.net

Case control comparison confirms that glaucoma decreases total retinal blood flow

Variable NormalPerimetricGlaucoma p-value

#eyes 27 51# Systemic Hypertension 9 (33%) 16 (31%)# Diabetes Mellitus 1 (4%) 3 (6%)Age (Years) 60.3 ± 9.0 61.6 ± 8.6 0.51Blood Flow (μl/min) 45.5 ± 9.5 34.8 ± 8.2 < 0.001Arterial Area (mm²) 0.033 ± 0.0077 0.028 ± 0.0073 0.004Venous Area (mm²) 0.041 ± 0.012 0.039 ± 0.0084 0.006Arterial Velocity (mm/sec) 24.9 ± 7.2 21.9 ± 7.1 0.23Venous Velocity (mm/sec) 16.3 ± 2.8 14.5 ± 3.5 0.024VF MD (dB) 0.23 ± 1.00 -4.34 ± 4.22 < 0.0001VF PSD (dB) 1.63 ± 0.38 6.45 ± 4.55 < 0.0001OCT NFL Thickness (µm) 97.1 ± 8.9 75.5 ± 11.6 < 0.0001SLT Rim Area (mm²) 1.60 ± 0.48 0.99 ± 0.28 < 0.0001SLP NFL Thickness (µm) 55.3 ± 4.7 44.2 ± 6.2 < 0.0001


matched

VF = visual field; MD = mean deviationPSD = pattern standard deviation

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Glaucoma decreased blood flow, vessel area, velocity






Glaucoma caused visual field loss



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Glaucoma caused loss of disc rim and retinal nerve fibers



Blood flow is strongly correlated with VF but not with neural tissue loss

VF MD VF PSDBlood Flow

OCT NFL Thickness

SLT Rim Area

VF PSD -0.88 (<0.01)

Blood Flow* 0.51 (<0.01) -0.26(0.07)

OCT NFL Thickness* 0.31 (0.04) -0.20 (0.17)0.093 (0.54)

SLT Rim Area* 0.32 (0.02) -0.30 (0.03) 0 (.99) 0.37 (0.01)

SLP NFL Thickness* 0.25 (0.08) -0.29 (0.04)-0.35 (0.01)

0.52 (<0.01)0.66

(<0.01)

Correlation coefficient R (p-value) in the perimetric glaucoma group*converted to dB scale by 10 * log10(value / normal_average)

Blood flow was most strongly correlated with VF mean deviation


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Blood flow is strongly correlated with VF but not with neural tissue loss

Visual Field MD

Visual Field PSD

Blood Flow

OCT NFL Thickness

SLT Rim Area

Visual Field PSD -0.88 (<0.01)

Blood Flow* 0.51 (<0.01) -0.26(0.07)

OCT NFL Thickness* 0.31 (0.04) -0.20 (0.17)0.093 (0.54)

SLT Rim Area* 0.32 (0.02) -0.30 (0.03) 0 (.99) 0.37 (0.01)

SLP NFL Thickness* 0.25 (0.08) -0.29 (0.04)-0.35 (0.01)

0.52 (<0.01)0.66

(<0.01)

Blood flow had no or paradoxical correlation with structural loss

Correlation coefficient R (p-value) in the perimetric glaucoma group*converted to dB scale by: 10 * log10(value / normal_average)


Visual field was independently correlated with both blood flow and neural tissue loss

Model Intercept Blood Flow OCT NFLSLT Rim

AreaR2

MD ~ BF -1.88 (0.02) 1.90 (<0.001) 0.26MD ~OCT NFL -2.10 (0.08) 1.90 (0.04) 0.095

MD ~ SLT Rim Area -1.78 (0.15) 1.15 (0.02) 0.1MD ~ BF + OCT

NFL0 (0.99) 1.87 (<0.001) 1.60 (0.04) 0.37

MD ~ BF + SLT Rim Area

0.68 (0.57) 1.90 (<0.001) 1.15 (0.009) 0.36

Regression coefficients (p-value) in the perimetric glaucoma group

BF = blood flowAll values in dB scale

Models for visual field mean deviation (MD)

Each dB decrease in blood flow was associated with 1.9 dB loss in VF MD


Independent of NFL or disc rim loss

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Conclusion: Blood flow has a direct effect on visual function independent of neural structural loss

Elevated IOP


nerve fibers




The role of blood flow in glaucoma monitoring and treatment deserve further investigation

Elevated IOP


nerve fibers



Depressed neural activityLocal vasculopathy

Systemic factors

??


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Questions for future glaucoma studies

Could retinal blood flow be improved by lowering intraocular pressure?

Could retinal blood flow be improved by eye drops or systemic medications?

Could improved retinal blood flow improve visual field function?

Could improved retinal blood flow slow visual field loss in glaucoma?


David Huang, MD, PhD

Maolong Tang, PhD

Yan Li, PhD

Ou Tan, PhD Yimin Wang, PhD

Xinbo Zhang, PhD

www.COOLLab.net

Jason Tokayer, MS

Bing Qin, MD

Janice Van Norman, COT

Jenner Banbury

Hrebesh Subhash, PhD

Michelle Montalto

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RETINAL BLOOD FLOW IN GLAUCOMATOUS EYES WITH SINGLE-

HEMIFIELD DAMAGE

M Sehi, PhD1; MC Reyes, MD1; R Konduru, MBBS2; O Tan, PhD3; D Huang, MD3; and DS Greenfield, MD1

1. Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Palm Beach Gardens, FL;

2. Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California.

3. Casey Eye Institute, Department of Ophthalmology, Oregon Health and Science University, Portland, OR

Please come to poster board # 45

Correlation between Retinal Blood Flow, Retinal Anatomy, and

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