What Is New in Optical Coherence Tomography. Ultrahigh-speed OCT makes 3D better

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1 OOAA 66 th Meeting & CEI 20 th Birthday Casey Eye Institute, Portland, OR, 17 June 2011 What Is New in Optical Coherence Tomography David Huang, MD, PhD Weeks 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 support Carl Zeiss Meditec, Inc.: patent royalty Ultrahigh-speed OCT makes 3D better 12x12 mm area 1100x1100 A-scans 10 registered volumes 200 khz swept-source 1050 nm wavelength Martin Krause, Joachim Hornegger, U. Erlangen + James G. Fujimoto, MIT 1

2 Ultrahigh-speed 1050 nm OCT at Casey Eye Institute Glaucoma Total retinal blood flow Disc & lamina cribosa Nerve fiber layer & ganglion cell complex Macular Diseases Retinal angiography Choroidal angiography 3D structures 1050 nm OCT penetrates deeper into lamina cribosa and choroid 0 micron 708 micron 2

3 Time adds another dimension Tear film dynamics 2 to 7 seconds after blink Ultrahigh resolution OCT at Casey Eye Institute 3µm resolution Tear film dynamics Tear meniscus dynamics Corneal imaging 3

4 Other Anterior Segment OCT Studies at Casey Eye Institute LASIK planning Keratoconus Detection Guiding PTK David Huang, MD, PhD Contact Lens IOL Power Calculation Beyond Structure: OCT for Blood Flow Imaging & Measurement Abnormal retinal blood flow are involved in the leading causes of blindness: glaucoma, AMD, and diabetic retinopathy 4

5 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 Loss of retinal ganglion cells & nerve fibers? Decreased blood flow Loss of visual field 5

6 There is a consensus to investigate structure and blood flow in glaucoma 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. An ideal device would assess both structure of the retina and optic nerve and blood flow in a single device. 11 A technique for rapid & accurate quantitation of total retinal blood flow is needed Laser doppler flowmeter time consuming Fluorescein & ICG angiography - qualitative Doppler ultrasound - inaccurate 6

7 OCT could quantify retinal blood flow by measuring both Doppler shift and incidence angle v v v Probe beam V v / 2cos( ) α V Doppler shift Incidence angle Double circular scan transects all retinal branch vessels 6 times per second Inner Circle Outer Circle 7

8 Flow (microliter/minute) Algorithm for Total Retinal Blood Flow Doppler angle measurement Flow in a single vessel 5 z x 2cos dxdz vessel velocity cross section Y. Wang, et. al., Journal of Biomedical Optics 13, , (2008) Time (second) Average flow over 2 seconds for each vessel Total Retinal Blood Flow Flow in Veins Flow value : 40.8 to 52.9 l/min, CV: 10.5% Wang Y, et al. Br J Ophthalm, 93:634 (2009) Yimin Wang, PhD & David Huang, MD, PhD Pilot study showed that glaucoma, PDR and NAION all decreased retinal blood flow Group (# of eyes) Blood Flow (μl/min) Venous Area (mm 2 ) Venous Velocity (mm/s) Arterial Area (mm 2 ) Arterial Velocity (mm/s) Normal (20) Glaucoma (16) (p<0.001) (p=0.977) (p<0.001) (p=0.454) (p<0.001) NAION (7) (p<0.001) (p<0.001) (p=0.109) (p=0.002) (p=0.003) PDR (5) (p<0.001) (p<0.001) (p=0.001) (p<0.001) (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:

9 The dual circular scan OCT Doppler retinal blood flow measurement technology has been licensed by USC to Optovue for commercial development Optovue RTVue 26 khz, 6 circles/sec Semi-automated grading software was developed for Doppler OCT reading center Vessel-normal vector Doppler angle Probe beam Vessel cross-sections from double circular scans Flow vector En face view of 3D OCT scan Doppler OCT of Retinal Circulation (DOCTORC) software uses both double-circular and 3D volumetric scans OuTan, PhD & David Huang, MD, PhD 9

10 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 Chinese Eye Study (USC/Varma) Doheny Image Reading Center (USC/Sadda) Doheny Retina Service (USC/Fawzi) Doheny Neuroophthalmology (USC/Sadun) Indiana U (Harris) Joslin Diabetes Center (Harvard/Aiello) UC San Diego (Weinreb, Liu) U Erlangen (Michelson) U Toronto (Flanagan, Hudson) David Huang, MD, PhD R01 EY Consortium PI: David Huang MD, PhD Ou Tan, PhD Yimin Wang, PhD Xinbo Zhang, PhD Michelle Montalto Site PI: Brian Francis, Rohit Varma, MD, MD MPH Vikas Chopra, MD Site PI: David Greenfield, MD Mitra Sehi, PhD Carolyn Quinn, MD Krisha S. Kishor, MD Site PI: Bo Hu, PhD Sharon Bi, MCIS Site PI: Joel S. Schuman, MD Robert Noecker, MD Gadi Wollstein, MD Hiroshi Ishikawa, MD Larry Kagemann, MS Site PI: James G. Fujimoto, PhD 10

11 Standard quantitative imaging modalities were used to measure loss of retinal nerve fibers Stratus OCT Optical coherence tomography Nerve fiber layer (NFL) thickness GDx-ECC SLP Scanning laser polarimetry NFL thickness David Huang, MD, PhD HRT3 SLT Scanning laser tomography Disc rim area Case control comparison confirms that glaucoma decreases total retinal blood flow Variable Normal Perimetric Glaucoma p-value #eyes # Systemic Hypertension 9 (33%) 16 (31%) matched # Diabetes Mellitus 1 (4%) 3 (6%) Age (Years) 60.3 ± ± Blood Flow (μl/min) 45.5 ± ± 8.2 < Arterial Area (mm²) ± ± Venous Area (mm²) ± ± Arterial Velocity (mm/sec) 24.9 ± ± Venous Velocity (mm/sec) 16.3 ± ± VF MD (db) 0.23 ± ± 4.22 < VF PSD (db) 1.63 ± ± 4.55 < OCT NFL Thickness (µm) 97.1 ± ± 11.6 < SLT Rim Area (mm²) 1.60 ± ± 0.28 < SLP NFL Thickness (µm) 55.3 ± ± 6.2 < VF = visual field; MD = mean deviation PSD = pattern standard deviation 11

12 Case control comparison confirms that glaucoma decreases total retinal blood flow Glaucoma decreased blood flow, vessel area, velocity Variable Normal Perimetric Glaucoma p-value #eyes # Systemic Hypertension 9 (33%) 16 (31%) # Diabetes Mellitus 1 (4%) 3 (6%) Age (Years) 60.3 ± ± Blood Flow (μl/min) 45.5 ± ± 8.2 < Arterial Area (mm²) ± ± Venous Area (mm²) ± ± Arterial Velocity (mm/sec) 24.9 ± ± Venous Velocity (mm/sec) 16.3 ± ± VF MD (db) 0.23 ± ± 4.22 < VF PSD (db) 1.63 ± ± 4.55 < OCT NFL Thickness (µm) 97.1 ± ± 11.6 < SLT Rim Area (mm²) 1.60 ± ± 0.28 < SLP NFL Thickness (µm) 55.3 ± ± 6.2 < VF = visual field; MD = mean deviation PSD = pattern standard deviation Case control comparison confirms that glaucoma decreases total retinal blood flow Variable Normal Perimetric Glaucoma p-value #eyes # Systemic Hypertension 9 (33%) 16 (31%) # Diabetes Mellitus 1 (4%) 3 (6%) Age (Years) 60.3 ± ± Blood Flow (μl/min) 45.5 ± ± 8.2 < Arterial Area (mm²) ± ± Venous Area (mm²) ± ± Arterial Velocity (mm/sec) 24.9 ± ± Venous Velocity (mm/sec) 16.3 ± ± VF MD (db) 0.23 ± ± 4.22 < VF PSD (db) 1.63 ± ± 4.55 < OCT NFL Thickness (µm) 97.1 ± ± 11.6 < SLT Rim Area (mm²) 1.60 ± ± 0.28 < SLP NFL Thickness (µm) 55.3 ± ± 6.2 < VF = visual field; MD = mean deviation PSD = pattern standard deviation Glaucoma caused visual field loss 12

13 Case control comparison confirms that glaucoma decreases total retinal blood flow Glaucoma caused loss of disc rim and retinal nerve fibers Variable Normal Perimetric Glaucoma p-value #eyes # Systemic Hypertension 9 (33%) 16 (31%) # Diabetes Mellitus 1 (4%) 3 (6%) Age (Years) 60.3 ± ± Blood Flow (μl/min) 45.5 ± ± 8.2 < Arterial Area (mm²) ± ± Venous Area (mm²) ± ± Arterial Velocity (mm/sec) 24.9 ± ± Venous Velocity (mm/sec) 16.3 ± ± VF MD (db) 0.23 ± ± 4.22 < VF PSD (db) 1.63 ± ± 4.55 < OCT NFL Thickness (µm) 97.1 ± ± 11.6 < SLT Rim Area (mm²) 1.60 ± ± 0.28 < SLP NFL Thickness (µm) 55.3 ± ± 6.2 < VF = visual field; MD = mean deviation PSD = pattern standard deviation Blood flow is strongly correlated with VF but not with neural tissue loss Blood flow was most strongly correlated with VF mean deviation VF MD VF PSD (<0.01) VF PSD Blood Flow* 0.51 (<0.01) -0.26(0.07) Blood Flow OCT NFL Thickness SLT Rim Area OCT NFL Thickness* 0.31 (0.04) (0.17) (0.54) SLT Rim Area* 0.32 (0.02) (0.03) 0 (.99) 0.37 (0.01) SLP NFL Thickness* 0.25 (0.08) (0.04) 0.52 (<0.01) (0.01) Correlation coefficient R (p-value) in the perimetric glaucoma group *converted to db scale by 10 * log 10 (value / normal_average) 0.66 (<0.01) 13

14 Blood flow is strongly correlated with VF but not with neural tissue loss Blood flow had no or paradoxical correlation with structural loss Visual Field MD Visual Field PSD (<0.01) Visual Field PSD Blood Flow* 0.51 (<0.01) -0.26(0.07) Blood Flow OCT NFL Thickness SLT Rim Area OCT NFL Thickness* 0.31 (0.04) (0.17) (0.54) SLT Rim Area* 0.32 (0.02) (0.03) 0 (.99) 0.37 (0.01) SLP NFL Thickness* 0.25 (0.08) (0.04) (0.01) 0.52 (<0.01) Correlation coefficient R (p-value) in the perimetric glaucoma group *converted to db scale by: 10 * log 10 (value / normal_average) 0.66 (<0.01) Visual field was independently correlated with both blood flow and neural tissue loss Models for visual field mean deviation (MD) Model Intercept Blood Flow OCT NFL SLT Rim Area R 2 MD ~ BF (0.02) 1.90 (<0.001) 0.26 MD ~OCT NFL (0.08) 1.90 (0.04) MD ~ SLT Rim Area (0.15) 1.15 (0.02) 0.1 MD ~ BF + OCT NFL 0 (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 Each db decrease in blood flow was associated with 1.9 db loss in VF MD BF = blood flow All values in db scale Independent of NFL or disc rim loss 14

15 Conclusion: Blood flow has a direct effect on visual function independent of neural structural loss Elevated IOP Loss of retinal ganglion cells & nerve fibers Decreased blood flow Loss of visual field The role of blood flow in glaucoma monitoring and treatment deserve further investigation Elevated IOP?? Loss of retinal ganglion cells & nerve fibers Capillary dropout Defective autoregulation Depressed neural activity Systemic factors? Decreased blood flow Loss of visual field 15

16 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 Ou Tan, PhD Yimin Wang, PhD Maolong Tang, PhD Yan Li, PhD Xinbo Zhang, PhD Bing Qin, MD Jenner Banbury Michelle Montalto Janice Van Norman, COT Jason Tokayer, MS 16