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13th Annual Yale Glaucoma Symposium, New York Academy of Medicine New York, NY, November 6, 2009

Structural & Functional Optical Coherence Tomography in Glaucoma Diagnosis

David Huang, MD, PhD

Charles C Manger III MD Chair of C. III, Corneal Laser Surgery Assoc. Prof. of Ophthalmology & Biomedical Engineering Doheny Eye Institute, University of Southern California

Financial Interests: Optovue, Inc.: stock options, patent royalty, travel, grant Carl Zeiss Meditec, Inc.: patent royalty


Prof. James Fujimoto MIT


A Generational Leap



Fourier domain


Simultaneous 1024 pixels at a time


Sequential 1 pixel at a time

Motion artifact

Speed (A-scans /sec)

400 100

Time domain

Zeiss OCT1/2 1996 Zeiss Stratus 2002

Small blood vessels IS/OS






RTVue has 65x speed & 2x resolution of Stratus

David Huang, MD, PhD

512 A-scans in 1.28 sec 1024 A-scans in 0.04 sec Higher speed, higher definition and higher signal.

David Huang, MD, PhD

Fourier Domain Technology Lead to An Explosion of New OCT Products

FD-OCT Retinal Scanners: Basic Parameters

Manufacturer Bioptigen Carl Zeiss Meditec Heidelberg Engineering Device 3D SD-OCT Cirrus Spectralis HRA+OCT Spectral OCT/SLO RTVue-100 Copernicus HR 3D-OCT-1000 Axial Resolution 3*-5 µm 5 µm 7 µm 5-6 µm 5 µm 3 µm 6 µm Scanning Speed 17,000 A-scan/sec 27,000 40,000 27,000 26,000 50,000 27,000 Accessory Imaging IR Fundus, handheld, mouse, pediatric LSLO CSLO, FA + ICG Autofluorescence SLO Microperimetry IR Fundus IR/Red Fundus Color Fundus

Zeiss Cirrus

Optovue RTVue Heidelberg Spectralis Tomey SS-1000

OPKO (OTI) Optovue Optopol Topcon


Topcon 3D-OCT Optopol Copernicus


David Huang, MD, PhD

* High resolution option

David Huang, MD, PhD



How to use speed and resolution to advantage?

Microstructure identification 3D anatomic measurements (mapping) ( i )

Ou Tan, PhD

Posterior Segment Application

Structural Imaging in Glaucoma

3D Function (blood flow)

David Huang, MD, PhD

Glaucoma affects 3 areas in the posterior segment of the eye

Glaucoma preferentially thins the Ganglion Cell Complex (GCC) which includes the axons, cell bodies, and dendrites of retinal ganglion cells





Cupping Nerve fiber thinning Glaucoma with thinner GCC GCC

Ganglion cell loss

David Huang, MD, PhD

Ishikawa H , et al., IOVS 2005 Tan O, et al., Ophthalmology, 2008;115:949-56.

David Huang, MD, PhD

Glaucoma: Macular Ganglion Cell Mapping

RTVue FD-OCT, FD26,000 A-scan perper-second 5 micron axial resolution Ganglion Cell Complex (GCC) 7 mm scan area 14,944 a-scans, 0.58 sec

GCC Deviation Map

% loss = actual scan value ­ normal value normal value

David Huang, MD, PhD

color coded map





Percent loss value at each pixel location relative to normal based on age-adjusted normative database of over 300 healthy eyes

Blue = thinning 20-30% relative to normal Black = 50% loss or greater

David Huang, MD, PhD

GCC = Ganglion Cell Complex

mGCC thickness map




GCC Significance Map

FD-OCT provided improved diagnostic accuracy for assessment of macular ganglion cells loss in glaucoma

OCT system

Thickness Parameter

AROC 0.90 0.92 0.92 0 92 0.92 0.85




color coded map shows regions where the change from normal reaches statistical significance

Green = values within normal range (p-value 5% to 95%) Yellow = borderline results (p-value < 5%) Red = outside normal limits (p-value <1%)

David Huang, MD, PhD

Global mGCC-GLV Loss Volume Focal mGCC-FLV mGCC FLV Loss cpNFL-Avg Volume


Tan O, Chopra V, Lu ATH, Schuman JS, Ishikawa H, Varma R, Huang D, Detection of macular ganglion cell loss in glaucoma by Fourier-domain optical coherence tomography. Ophthalmology 2009; in press

FD-OCT improved the repeatability of macular ganglion cell complex compared to TD-OCT circumpapillary nerve fiber layer measurements, thus improving the potential to track glaucoma over time

OCT system Group Thickness Parameter CV (%) N PPG PG

GCC Progression Analysis


mGCC-avg 1.09 1.23 1.25

Stratus TD-OCT cpNFL-avg 1.72 1.75

2x 2.86

David Huang, MD, PhD

David Huang, MD, PhD

Combining measurements from all 3 anatomic regions with machine learning classifiers further boosted diagnostic accuracy

Diagnostic Parameter Service Vector Machine (SVM) Best NFL Best GCC Best Disc AROC 0.963 P < 0 02 0.02 0.924 0.920 0.886 Sensitivity

(at 5 percentile cutoff)

High-speed FD-OCT allows correlation of glaucoma disease patterns ­ Pre-Perimetric Glaucoma

86% P < 0 01 0.01 67% 68% 56%

Optic Nerve RNFL scan

Macular GCC Significance Map



85 normal eyes, 72 perimetric glaucoma eyes

David Huang, MD, PhD

Optic Nerve Photo

Vikas Chopra, MD

Pattern Deviation

Visual field



High-speed FD-OCT allows correlation of glaucoma disease patterns ­ Perimetric Glaucoma

Yimin Wang, PhD

Optic Nerve RNFL scan

Macular GCC Significance Map

New Frontier

Functional OCT: Doppler Measurement of Retinal Blood Flow

Visual field

Optic Nerve Photo

Vikas Chopra, MD

Current techniques do not allow practical measurement of total retinal blood flow

The leading causes of blindness are all associated with abnormal ocular circulation: Glaucoma Diabetic Retinopathy Macular Degeneration

David Huang, MD, PhD

Fluorescein Angiography

Laser doppler flowmeter


David Huang, MD, PhD

David Huang, MD, PhD

Measurement of both Doppler shift and incidence angle are needed to compute flow in a vessel

Measuring Total Flow Velocity

Dual Beam

Dave DP, Milner TE, Opt Lett 2000;25:1523 Pedersen CJ, et al. Opt Lett 2007;32:506-8 *Werkmeister RM et al. Opt Lett 2008;33:2967

v + v


Dual Plane

Probe beam

v = 2V cos( ) / (



David Huang, MD, PhD David Huang, MD, PhD *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

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

David Huang, MD, PhD

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

Inner Circle

Double circular scan

Flow profile and direction determined 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.

Outer Circle

Algorithm for Total Retinal Blood Flow

Doppler angle measurement Flow in a single vessel


Glaucoma reduces retinal blood flow

Group Number of Subjects Total retinal blood flow (l/min) Average g Range g 40.73-52.91 23.6-40.88

F Flow (microliter/minute)

4 3 2 1 0 0 0.5 1 1.5 2

x z vessel velocity l l it cross section

2 cos dxdz

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

Time (second)

Average flow over 2 seconds

Normal Perimetric Glaucoma

8 10

45.64 33.54

Total Retinal Blood Flow

Flow in Veins

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

Y. Wang, British Journal of Ophthalmology, 93, 634-637, (2009)

p < 0.0003

Wang, Y., Tan, O., Huang, D. SPIE Proceeding, 7168, (2009)

David Huang, MD, PhD

Visual field pattern standard deviation was highly correlated with retinal blood flow

R2=0.77 p=0.0009

Superior Branch Vein Occlusion & Proliferative Diabetic Retinopathy










Amani Fawzi, MD


15 20 25 30 35 40 45 50

Venous Flow Case Normal mean±SD (Range)

Superior (l/min) 8.2 23.5 ± 3.0 (19.2-27.5)

Inferior (l/min) 12.1 22.2 ± 2.6 (19.6-27.4)

Total Blood Flow (l/min)

Wang, Y., Tan, O., Huang, D. SPIE Proceeding, 7168, (2009)

David Huang, MD, PhD



Non-arteritic anterior ischemic optic neuropathy

Glaucoma, PDR and NAION Show Different Patterns of Retinal Blood Flow Change

Group (N) Total Retinal Blood Total Venous CrossFlow Sectional Area (microliter/min) (mm^2) 34.1±4.9 (p<.001) 0.047±0.0080 (p =0.638) Average Venous Velocity (mm/sec) 12.3±1.6 (p=<.001)

Venous Flow

Superior ( (l/min) ) 12.99

Inferior ( (l/min) ) 19.47

Glaucoma (16)

Case Normal mean±SD (Range)

Alfredo Sadun, MD, PhD


28.2±8.2 (p<.001)

0.031±0.0068 (p=0.002)

15.0±3.5 (p=0.078)

23.5 ± 3.0 22.2 ± 2.6 (19.2-27.5) (19.6-27.4)

PDR ( 5)

16.8±9.5 (p<.001)

0.025±0.0068 (p<.001)

10.9±3.3 (p<.001)

Normal (13)




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

Doppler OCT of Retinal Circulation (DOCTORC) Group *Advanced Imaging for Glaucoma Study Group (USC, Pittsburgh, Miami) (USC U Pitt b h U Mi i) *Indiana U (Harris) *UC San Diego (Weinreb, Liu) *U Erlangen (Michelson) *U Toronto (Flanagan, Hudson) *USC (Fawzi, Sadun)

David Huang, MD, PhD

David Huang, MD, PhD

Optovue RTVue 26 kHz, 6 circles/sec

FD-OCT provides more information than other advanced imaging technologies

FD-OCT ppNFL thickness Macular GCC Disc & Cup Total retinal blood flow Angle Cornea + + + * + +

David Huang, MD, PhD

FD-OCT may have a growing role in glaucoma diagnosis


SLP (GDx) +


*Under development, not yet released commercially

David Huang, MD, PhD



R01 EY013516

Consortium PI: David Huang MD, PhD

Brian Francis, Site PI: Rohit Varma, MD, MPH MD

Vikas Chopra, MD

Ou Tan, PhD

Yimin Wang, PhD

Xinbo Zhang, PhD

David Huang, MD, PhD

Ou Tan, PhD

Yimin Wang, PhD

Site PI: David Greenfield, MD

Mitra Sehi, PhD

Carolyn Quinn, MD

Krisha S. Kishor, MD

Robert DiLaura

Sharon Bi, MCIS

Doheny Eye Institute

Maolong Tang, PhD Yan Li, PhD Xinbo Zhang, PhD

Site PI: Joel S. Schuman, MD

Robert Noecker, MD

Gadi Wollstein, MD

Hiroshi Ishikawa, Larry Kagemann, MD MS

Site PI: James G. Fujimoto, PhD

Sylvia Ramos, COA

Nihal Samy, MD

Bing Qin, MD

Timothy Hsia, MS

Wei Wu, MS

Jason Tokayer, MS



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