Go With the Flow: An OCT Angiography Primer Lorne Yudcovitch, OD, MS, FAAO

Go With the Flow: An OCT Angiography Primer Lorne Yudcovitch, OD, MS, FAAO yudcovil@pacificu.edu OCT Angiography (OCTA) History 2000 - First Doppler flowimetry OCT on human retina 2005 Speckle analysis for OCTA adapted 2008 - Optical Microangiography (OMAG) OCT developed 2009 25,000 scan/sec OCTA comparable to FA 2011 125,000 scan/sec widefield OCTA achieved 2012 Split-spectrum amplitude-decorrelation created 2014 First use of modern OCTA (mouse) 2015 First FDA-approved instrument (ZEISS Cirrus 5000 with AngioPlex ) 2016 Second FDA-approved instrument (Optovue AngioView ) What is OCT Angiography? 1. Non-invasive imaging of retinal and choroidal vasculature without use of contrast dyes 2. Isolates blood vessels from static tissue by assessing change in OCT signal from blood cell flow 3. Allows 3-dimensional evaluation of blood vessel pattern and blood flow 4. Horizontal and vertical scans for OCTA to reduce artifacts and improve resolution OCTA Technology 1. Non-invasive technique to image ocular microvasculature 2. Uses laser light reflectance off surface of moving red blood cells to accurately depict vessels 3. Eliminates need for intravascular dyes 4. Tissue repeatedly imaged; differences analyzed between scans, identifying high flow (significant changes between scans) and slow/no flow (similar or the same appearance between scans) 5. SD-OCT with approx. 800nm wavelength or SS-OCT with approx.. 1050nm wavelength 6. OCTA uses one of two methods for motion detection: a. Amplitude decorrelation b. Phase variance decorrelation 7. OCTA uses two averaging methods to reduce noise: a. Split spectrum amplitude decorrelation b. Volume averaging OCTA Advantages 1. Visualize to capillary level 2. Rapid acquisition 3. Non-invasive 4. Fluorescein, indocyanine-green angiography require injectable dye a. takes time to reach retinal vessels, possible systemic adverse effects/anaphylaxis 5. Repeatable on same day if needed 6. Useful in assessing CRAO flow following CRA occlusion treatment 7. Higher resolution of microcirculation and capillaries 8. Quantitative analysis of retinal vessels 9. 3-D imaging information of ocular vascular layers 10. Visualizes peripapillary capillaries that supply retinal nerve fiber layer LBY OCTA PRIMER 1

Commercial OCTA Instruments 1. ZEISS CIRRUS Angioplex a. 68,000 A-scans per second 2. Optovue AngioVue a. 72,000 A-scans per second 3. Heidelberg Engineering Spectralis OCTA Module a. 85,000+ A-scans per second 4. Zeiss Plex Elite 9000 a. 100,000 A-scans per second 5. Topcon Triton b. 100,000+ A-scans per second OCTA Identifiable Zones 1. Five zones: a. Vitreal (avascular) b. Superficial vascular plexus c. Deep vascular plexus d. Outer retina (avascular) e. Choriocapillaris 2. These zones primarily evaluated clinically in en face (frontal) view 3. Unlike traditional OCT, which is mainly evaluated in cross-sections OCTA Clinical Applications 1. Diabetic retinopathy - microaneurysms, neo, quantifying foveal avascular zone, nonperfusion 2. Dry age-related macular degeneration - decrease in choriocapillaris flow, beyond atrophy border 3. Wet age-related macular degeneration CNVM detection, follow-up after intravitreal injections. 4. Central serous chorioretinopathy - may help differentiate PED from CNVM 5. Vascular occlusions - evaluation of nonperfusion and integrity of superficial and deep plexus 6. Macular telangiectasia - telangiectatic vessel identification and possibly choroid communication 7. Choroidal neovascular membranes - good sensitivity and specificity for detection/classification 8. Optic nerve disorders - ie. glaucoma 9. Uveitis posterior involvement Projection artifact what is it? 1. Fluctuating shadows cast by flowing blood resulting in variation of OCT signal in deeper layers 2. Most notable in outer retina angiograms 3. Inner retinal vessel projections on highly reflective RPE produce false positive vascular signal 4. Can interfere with CNV identification 5. Masking larger inner retinal vessels or all inner retinal vessels helps reduce this artifact 6. Non-exudative AMD with large drusen commonly produces false positive bright signal areas OCTA Motion Detection Limitations 1. OCTA motion detection has fast flow and slow flow cut-offs 2. Vascular structures with very fast flow such as large choroidal vessels are poorly imaged 3. Vascular structures with very slow flow such as microaneurysms, fibrotic CNV membranes, or capillaries within areas of ischemia may be poorly imaged or not imaged at all LBY OCTA PRIMER 2

OCTA and Early Diabetic Retinopathy Changes 1. OCTA may detect in eyes without any notable retinopathy a. FAZ enlargement/remodeling b. Capillary nonperfusion c. Microaneurysms/venous beading 2. FAZ remodeling and nonperfusion significantly more common in diabetic eyes than normals 3. FAZ enlargement in diabetic eyes suggests macular ischemia may be present before clinical DR a. Likely indicates need for better glycemic control 4. OCTA and Capillary Non-Perfusion a. Nonperfusion better detected and delineated via OCTA than FA b. Nonperfusion increases VEGF release and is linked with DR severity c. Quantifying nonperfusion may help predict progression to proliferative DR d. Individuals with non-proliferative diabetic retinopathy (NPDR) and nonperfusion areas with OCTA should be monitored more closely for future PDR and glucose control status e. Anti-VEGF therapy may reverse DR and be useful to prevent PDR in high risk patients OCTA and Proliferative DR 1. PDR Hallmark: neo between ILM and posterior hyaloid of vitreous: vitreoretinal interface (VRI) 2. OCTA definitively distinguishes IRMA from NVE and aids in detection of early neo of the disc 3. NVE will be present in the VRI en face OCT angiogram 4. IRMA is confined to the retina and is absent in the VRI 5. Due to higher resolution and lack of leakage, neo can be precisely identified and measured 6. Allows future automated quantification of neo to track/manage treatment responses OCTA and AMD 1. Helps differentiate nonexudative vs. exudative forms 2. OCTA allows membrane itself to be visualized 3. Direct visualization allows for classification of CNV membranes a. Occult/subRPE b. Classic/subretinal c. Retinal angiomatous proliferation (RAP) 4. OCTA also allows precise localization and size determination 5. Earlier detection means earlier referral for definitive treatment 6. Future studies may identify CNV precursors and high-risk features so exudative AMD may be postponed or avoided OCTA and Glaucoma 1. OCTA provides detailed ONH microcirculation structural and flow imagery a. Normal subjects - Dense microvascular network b. Glaucoma subjects - Visible attenuation of ONH vasculature globally and focally i. Seen prior to visual field loss with 100% sensitivity and specificity 2. Peripapillary vessel density: percentage of area occupied by the large vessels and microvasculature in the peripapillary region 3. OCTA vessel density measurements may have similar diagnostic accuracy to retinal nerve fiber layer (RNFL) thickness measurements for differentiating between healthy and glaucoma eyes 4. Flow index significantly correlated with: a. glaucoma severity b. visual field mean deviation and pattern standard deviation LBY OCTA PRIMER 3

c. Retinal nerve fiber layer (RNFL) d. ganglion cell complex (GCC) 5. Quantitative OCTA may be potentially useful in diagnosis, staging and management of glaucoma OCTA Limitations 1. Media opacities causing signal attenuation and shadowing artifacts 2. Motion error/software correction error: vessel duplication, motion lines, vessel discontinuity 3. Deeper retinal/choroidal vessels obscured by superficial vasculature 4. Projection artifacts (may be filtered out in future software updates) 5. Extremely motion-sensitive and requires good patient cooperation 6. Automated segmentation errors, especially with pathology 7. Limited area of scan (3mm 2 to 12mm 2 ) currently 8. Resolution drops as scan area increases, to reduce scanning time 9. Very slow/no blood flow or fast blood flow may go undetected 10. Cannot detect dye leakage or staining 11. Shadowgraphic flow projection artifacts from flowing blood causing deeper OCT signal variation Future Clinical Uses 1. Correlation with systemic vascular diseases 2. Anterior segment OCT angiography 3. Dermatological applications 4. Quantifiable measures OCTA Summary References 1. Kashani AH, et al. Optical coherence tomography angiography: A comprehensive review of current methods and clinical applications. Prog Retin Eye Res 2017 Sep;60:66-100. doi: 10.1016/ j.preteyeres. 2017.07.002. Epub 2017 Jul 29. 2. Spaide RF et a. Optical coherence tomography angiography. Prog Retin Eye Res. 2017 Dec 8. pii: S1350 9462(17)30056-3. doi: 10.1016/ j.preteyeres.2017.11.003. 3. An L,, Wang RK. In vivo volumetric imaging of vascular perfusion within human retina and choroids with optical micro-angiography. Opt Express. 2008; 16: 11438 11452. 4. Fingler J,, Zawadzki RJ,, Werner JS,, Schwartz D,, Fraser SE. Volumetric microvascular imaging of human retina using optical coherence tomography with a novel motion contrast technique. Opt Express. 2009; 17: 22190 22200. 5. Kim DY,, Fingler J,, Werner JS,, Schwartz DM,, Fraser SE,, Zawadzki RJ. In vivo volumetric imaging of human retinal circulation with phase-variance optical coherence tomography. Biomed Opt Express. 2011; 2: 1504 1513. 6. Jia Y,, Tan O,, Tokayer J,, et al. Split-spectrum amplitude-decorrelation angiography with optical coherence tomography. Opt Express. 2012; 20: 4710 4725. 7. Gao SS,, Liu G,, Huang D,, Jia Y. Optimization of the split-spectrum amplitude-decorrelation angiography algorithm on a spectral optical coherence tomography system. Opt Lett. 2015; 40: 2305 2308. 8. Fujimoto J, Swanson E. The Development, Commercialization, and Impact of Optical Coherence Tomography Investigative Ophthalmology & Visual Science July 2016, Vol.57, OCT1-OCT13. doi:10.1167/iovs.16-19963 LBY OCTA PRIMER 4

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