Clinical OCT Angiography Atlas [2 ed.] 9789354655036

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Clinical OCT Angiography Atlas second edition

Clinical OCT Angiography Atlas second edition Marco Rispoli MD(Italy) Surgery and Emergency Unit, Rome Eye Hospital Centro Italiano Macula, Rome, Italy

Bruno Lumbroso MD(Italy) Centro Italiano Macula, Rome, Italy

David Huang MD PhD(USA) Associate Director & Director of Research, Casey Eye Institute Peterson Professor of Ophthalmology Professor of Biomedical Engineering Oregon Health & Science University Portland, USA

Yali Jia PhD(USA) Jennie P Weeks Professor of Ophthalmology Associate Professor of Biomedical Engineering Casey Eye Institute, Oregon Health & Science University Portland, USA

Maria Cristina Savastano MD PhD(Italy) Clinical Research Coordinator, Ophthalmology Unit Policlinico Universitario A Gemelli (IRCS), Catholic University, Rome Centro Italiano Macula, Rome, Italy Foreword by

James Fujimoto

JAYPEE BROTHERS Medical Publishers The Health Sciences Publisher New Delhi | London

Jaypee Brothers Medical Publishers (P) Ltd Headquarters Jaypee Brothers Medical Publishers (P) Ltd 4838/24, Ansari Road, daryaganj new delhi 110 002, india Phone: +91-11-43574357 Fax: +91-11-43574314 email: [email protected]

Overseas Office J.P. Medical Ltd 83 Victoria street, London sW1H 0HW (UK) Phone: +44 20 3170 8910 Fax: +44 (0)20 3008 6180 email: [email protected] Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2021, Jaypee Brothers Medical Publishers the views and opinions expressed in this book are solely those of the original contributor(s)/author(s) and do not necessarily represent those of editor(s) of the book. All rights reserved. no part of this publication may be reproduced, stored or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission in writing of the publishers. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. the publisher is not associated with any product or vendor mentioned in this book. Medical knowledge and practice change constantly. this book is designed to provide accurate, authoritative information about the subject matter in question. However, readers are advised to check the most current information available on procedures included and check information from the manufacturer of each product to be administered, to verify the recommended dose, formula, method and duration of administration, adverse effects and contraindications. i t is the responsibility of the practitioner to take all appropriate safety precautions. neither the publisher nor the author(s)/editor(s) assume any liability for any injury and/or damage to persons or property arising from or related to use of material in this book. this book is sold on the understanding that the publisher is not engaged in providing professional medical services. if such advice or services are required, the services of a competent medical professional should be sought. every effort h as b een m ade w here n ecessary t o c ontact h olders o f c opyright t o o btain p ermission t o r eproduce copyright material. if any have been inadvertently overlooked, the publisher will be pleased to make the necessary arrangements at the first o pportunity. the CD/DVD-ROM ( if a ny) p rovided i n t he s ealed e nvelope w ith t his b ook i s complimentary and free of cost. Not meant for sale. Inquiries for bulk sales may be solicited at: [email protected] Clinical OCT Angiography Atlas / Marco Rispoli, Bruno Lumbroso, David Huang, Yali Jia, Maria Cristina Savastano First Edition: 2015 Second Edition: 2022 isBn: 978-93-54655-03-6

Foreword The first edition of the Clinical OCT Angiography Atlas was a landmark in the clinical and scientific development of optical coherence tomography angiography (OCTA). It is published in 2015, only one year after the commercial introduction of OCT angiography, the Atlas led international awareness and acceptance of OCTA, providing a reference not only for interpreting this new imaging modality, but also mapping the range of possible clinical applications, and predicting its future potential. Since that time, clinical and fundamental science research groups have performed extensive studies on a broad range of ocular pathologies and all major commercial ophthalmic manufacturers have introduced OCTA instruments. OCTA is performed at points of care ranging from retinal, glaucoma, and neuro-ophthalmology to comprehensive ophthalmology, and optometry. OCT angiography provides critical new information on threedimensional microvascular structure in the retina, choriocapillaris, and optic nerve head. It enables visualization and quantification of pathology such as capillary nonperfusion and neovascularization with a clarity and accuracy that was previously unachievable. The ability to image on every patient visit, where fluorescein or indocyanine green angiography would not be indicated, has

enabled powerful studies of disease progression and treatment response. At the same time, OCTA is inherently more complicated than structural OCT and special care is required to clinically interpret OCTA image data. The scope, complexity, and promise of this new imaging modality have attracted a diverse community researchers in fundamental science, engineering, and image analysis to clinical ophthalmology. The second edition of the Clinical OCT Angiography Atlas is edited by Marco Rispoli, David Huang, Yali Jia, Maria Cristina Savastano, and Bruno Lumbroso provides a comprehensive view of the state of the art in OCTA clinical applications, research, and technology. Extensive new material has been added to reflect key advances. The contributing authors are international leaders in clinical medicine, fundamental science, and technology, providing complementary perspectives on the exciting and impactful developments in this field. James G Fujimoto Elihu Thomson Professor of Electrical Engineering and Computer Science Massachusetts Institute of Technology

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Preface to the second edition The first edition of this OCT Angiography Atlas was published in 2015, when optical coherence tomographic angiography (OCTA) was a fairly new imaging modality. It was one of the first books in the world about the clinical use of this new noninvasive technology. OCT angiography offers precise and separate visualization of blood flow in the four retinal vascular plexuses, showing the complexity of its networks. It has introduced revolutionary new understanding of retinal vascular anatomy. OCT angiography is today widely available to eye practitioners. Since the first edition of this Atlas, it has seen shattering new developments and exponential adoption. OCTA is recognized all over the world as an indispensable device for study, diagnosis, and follow-up of retinal diseases and glaucoma in everyday clinical work and research. OCT angiography has replaced, in most fields, the more invasive dye-based angiography. Fluorescein angiography is no longer the gold standard of retinal vascular imaging. This new edition of the Clinical OCT Angiography Atlas wishes to show the innovative principles of clinical OCTA imaging. As in the first edition, the key word is “clinical”, helping users to interpret OCTA images, guiding clinicians to understand the features of angiographic images. This Atlas edition has been

deeply transformed and developed. All chapters have been completely rewritten; some are entirely new and groundbreaking. We report the great advances OCTA has obtained in the clinical field. OCTA allowed us to identify new pathologies, recognize new syndromes, and organize disorders in new classifications. Known diseases are now better understood and new diseases are described. In this book, the operating principles, clinical applications, and future promises of OCTA are clearly explained by world-renowned original developers of the technology. Optical coherence tomographic angiography holds an immense practical interest for clinical ophthalmology and its importance will continue to grow in the coming years. We trust this handbook will help ophthalmologists, optometrists, residents, and ophthalmic technicians to understand and appreciate the new possibilities offered by the use of OCTA in everyday clinical practice. Marco Rispoli Bruno Lumbroso David Huang Yali Jia Maria Cristina Savastano

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Preface to the first edition OCT angiography is a new high resolution imaging method for visualizing the retinal and choroidal circulation without the injection of any dye. By rapidly detecting intravascular flow when needed and being able to repeat the images, as often as necessary, at no risk to the patient, clinicians will come to appreciate OCT angiography as one of the most important applications of en face OCT imaging because of its ability to offer precise visualization of intravascular flow in the inner and outer retinal layers, as well as the inner choroid. An added advantage of this imaging strategy is that the same images acquired during OCT angiography can also be viewed as typical OCT B-scans. While it is no longer the domain of just a few privileged researchers and retina specialists, OCT angiography is now widely available to eye practitioners. As the quality of OCT angiography imaging improves and its availability becomes even more widespread, we predict that this noninvasive technology will become a new standard for imaging both the retinal and choroidal vasculature and anatomy. The aim of this Clinical OCT Angiography Atlas is to show OCT users the utility of clinical OCT angiography imaging. The keyword is ‘clinical’. We hope to develop interest in the use of OCT angiography in everyday clinical activities and help users

interpret OCT angiographic images. The operating principles and the future of OCT angiography are explained by some of the original developers of the technology, and well-known authors from around the world wrote the clinical chapters. This atlas should guide the general ophthalmologists to select the best OCT angiographic views and to be able to identify the typical and atypical features of the OCT angiographic images. The everyday use of OCT angiographic imaging in the clinics has already generated enormous interest and its importance will grow rapidly in the next few years. Our atlas is designed to appeal a wide audience with interest in a variety disorders. We hope that this atlas fulfills a huge unmet clinical need to learn more about OCT angiography. Bruno Lumbroso David Huang Ching J Chen Yali Jia Marco Rispoli André Romano Nadia K Waheed

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Contents Foreword v Preface to the second edition

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Preface to the first edition

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Contributors xv

part 1: Technology and interpretation Section 1: M  ethods and techniques of oct angiography examination Chapter 1 Principles of OCT angiography Yali Jia, Tristan T Hormel, David Huang

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Chapter 2 Interpretation of OCT angiography Tristan T Hormel, Yali Jia, David Huang

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Chapter 3 OCT angiography: Terminology David Huang, Tristan Hormel, Yali Jia

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Chapter 4 OCT angiography in everyday clinical practice Bruno Lumbroso, Marco Rispoli, Maria Cristina Savastano

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Chapter 5 Retinal normal vascularization Maria Cristina Savastano, Marco Rispoli, Bruno Lumbroso

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Chapter 6 Corneal and anterior segment OCT angiography Yan Li, David Huang, Yali Jia

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part 2: OCT angiography study of diseases and disorders Section 2: Retina OCT angiography examination: Age-related macular degenerations Chapter 7 OCT angiography of macular neovascularization in neovascular amd 35 Alexandra Miere, Eric Souied xi

Chapter 8 OCT angiography of choroidal nonexudative neovascular membrane Riccardo Sacconi, Carlotta Senni, Federico Fantaguzzi, Giuseppe Querques

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Chapter 9 OCT angiography other cnv not from AMD Adil El Maftouhi, Maddalena Quaranta-El Maftouhi

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Chapter 10 OCT angiography follow-up of neovascularization after treatment Bruno Lumbroso, Marco Rispoli, Maria Cristina Savastano

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Chapter 11 Non-neovascular age-related macular degeneration Varsha Pramil, Eric M Moult, Jay S Duker, James G Fujimoto, Nadia K Waheed

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Section 3: Retina oct angiography examination: Other macular diseases Chapter 12 Diabetic retinopathy Talisa E de Carlo, Varsha Pramil, James G Fujimoto, Nadia K Waheed

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Chapter 13 Central serous chorioretinopathy and pachychoroid Maria Cristina Savastano, Marco Rispoli, Bruno Lumbroso Chapter 14 OCT angiography examination of type 2 idiopathic macular telangiectasia Luca Di Antonio, Leonardo Mastropasqua Chapter 15 OCT angiography of vascular occlusions CRVO, BRVO, CRAO, BRAO, and microvascular occlusions Marco Rispoli, Bruno Lumbroso, Maria Cristina Savastano Chapter 16 Microvascular occlusions: DRIL, AMN, and PAMM Dmitrii S Maltsev, Alexei N Kulikov, Maria A Burnasheva, Alexander S Vasiliev Chapter 17 OCT angiography in inflammatory diseases André C Romano, William Warr Binotti, Paula M Marinho, Allexya AA Marcos, Heloisa Nascimento, Rubens Belfort

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Section 4: Myopia and pathologic myopia Chapter 18 OCT angiography examination in high myopia Luca Di Antonio, Leonardo Mastropasqua xii

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Section 5: Tumors Chapter 19 OCT angiography in ocular tumors Gilda Cennamo, Daniela Montorio, Giovanni Cennamo

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Section 6: Glaucoma and optic nerve Chapter 20 OCT angiography examination in glaucoma David Huang, Michel Puech, Yali Jia, Liang Liu, Mourtaza Aimadaly

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Chapter 21 OCT angiography examination in neurodegenerative diseases Emliano Di Carlo, Albert J Augustin

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part 3: Future developments in oct angiography Chapter 22 The future of OCT and OCT angiography Federico Corvi, Giovanni Staurenghi

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Index 165

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Contributors Marco Rispoli MD Surgery and Emergency Unit Rome Eye Hospital Centro Italiano Macula Rome, Italy

Bruno Lumbroso MD Centro Italiano Macula Rome, Italy

David Huang MD PhD Associate Director & Director of Research Casey Eye Institute Peterson Professor of Ophthalmology Professor of Biomedical Engineering Oregon Health & Science University Portland, USA Yali Jia PhD Jennie P Weeks Professor of Ophthalmology Associate Professor of Biomedical Engineering Casey Eye Institute Oregon Health & Science University USA Maria Cristina Savastano MD PhD Clinical Research Coordinator Ophthalmology Unit Policlinico Universitario A Gemelli (IRCS) Catholic University, Rome Centro Italiano Macula Rome, Italy

James G Fujimoto PhD Elihu Thomson Professor of Electrical Engineering and Computer Science Massachusetts Institute of Technology, USA

Mourtaza Almadaly OS MSD Director of Explore Vision Rueil Malmaison (France) Luca Di Antonio MD PhD UOC Ophthalmology and Surgical Department ASL-1 Avezzano-Sulmona-L’Aquila, Italy Ophthalmology Clinic National High-Tech Center in Ophthalmology Center of Excellence in Ophthalmology University “G. d’Annunzio” of Chieti-Pescara Chieti, Italy Albert J Augustin MD Professor of Ophthalmology Senior Consulting Physician for Ophthalmology Director of the Eye Clinic at Staedtisches Klinikum Karlsruhe Germany Visiting Professor at University of Tel Aviv Israel Jenny Atorf Enrico Borrelli MD FEBO Medical Retina & Imaging Unit Department of Ophthalmology University Vita Salute IRCCS Ospedale San Raffaele Milan, Italy Maria A Burnasheva MD Department of Ophthalmology Military Medical Academy Botkinskaya St Petersburg, Russia Emiliano Di Carlo MD Consulting Physician for Ophthalmology at Staedtisches Klinikum Karlsruhe Germany Talisa de Carlo MD Vitreo retinal surgery fellow University of Colorado Vitreo retinal surgery department Aurora, USA Gilda Cennamo MD Federico II University Naples, Italy Giovanni Cennamo MD Federico II University Naples, Italy

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Federico Corvi MD Consultant Clinica Oculistica Universitaria Ospedale Sacco Milano, Italy Federico Fantaguzzi MD Department of Ophthalmology University Vita Salute IRCCS Ospedale San Raffaele Milan, Italy Tristan Hormel PhD Postdoctoral Scholar Center for Ophthalmic Optics and Lasers Casey Eye Institute Oregon Health & Science University USA Alexei N Kulikov MD DSc Department of Ophthalmology Military Medical Academy Botkinskaya St St Petersburg, Russia Liang Liu MD Genentech, Inc., South San Francisco California, United States Yan Li PhD Research Associate Professor Casey Eye Institute Oregon Health & Science University, USA Adil El Maftouhi OD Centre Ophtalmologique Rabelais Lyon Paris, France Maddalena Quaranta-El Maftouhi MD Centre ophtalmologique Rabelais Lyon, France Dmitrii S Maltsev MD PhD Department of Ophthalmology Military Medical Academy Botkinskaya St St Petersburg, Russia Leonardo Mastropasqua MD Ophthalmology Clinic National High-Tech Center in Ophthalmology Center of Excellence in Ophthalmology Italian School of Robotics in Ophthalmology University “G. d’Annunzio” of Chieti-Pescara Chieti, Italy Alexandra Miere MD PhD Ophthalmologist Retina Specialist Department of Ophthalmology Centre Hospitalier Intercommunal de Créteil, France Daniela Montorio MD Federico II University Naples, Italy

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Varsha Pramil MD Tufts University Medical school USA Michel Puech MD MSD Founder and director of Explore Vision centers Paris Founder and director of VuExplorer Institute Board member of Société Française d’Ophtalmologie Milan, Italy Giuseppe Querques MD PhD Head, Medical Retina & Imaging Unit Department of Ophthalmology University Vita Salute IRCCS Ospedale San Raffaele, Milan, Italy André Romano MD Retina Service Director Neovista Eye Institute Americana - SP Brazil Adjunct Professor at University of Miami Miller School of Medicine Miami, Florida Visiting Professor at Henry C Witelson Ocular Pathology Laboratory, McGill University Health Centre Research Institute Montreal, Canada Riccardo Sacconi MD FEBO Department of Ophthalmology University Vita Salute IRCCS Ospedale San Raffaele Milan, Italy Carlotta Senni MD Department of Ophthalmology University Vita Salute IRCCS Ospedale San Raffaele Milan, Italy Eric Souied MD PhD Chef de Service, Ophtalmologie Hôpital Intercommunal, Hôpital Henri Mondor Créteil Université Paris Est Créteil President de la FFM, France Giovanni Staurenghi MD Full Professor of Ophthalmology University of Milan Ospedale Sacco, Italy Alexander S Vasiliev MD Department of Ophthalmology Military Medical Academy Botkinskaya St Petersburg, Russia Nadia K Waheed MD MPH Professor in Ophthalmology Tufts University Medical School USA

PART 1 Technology and interpretation Section 1: Methods and techniques of oct angiography examination chapter 1: Principles of OCT angiography Yali Jia, Tristan T Hormel, David Huang chapter 2: Interpretation of OCT angiography Tristan T Hormel, Yali Jia, David Huang chapter 3: OCT angiography: Terminology David Huang, Tristan Hormel, Yali Jia chapter 4: oct angiography in everyday clinical practice Bruno Lumbroso, Marco Rispoli, Maria Cristina Savastano

chapter 5: Retinal normal vascularization Maria Cristina Savastano, Marco Rispoli, Bruno Lumbroso chapter 6:

Corneal and anterior segment OCT angiography Yan Li, David Huang, Yali Jia

Chapter 1 Principles of OCT angiography Yali Jia, Tristan T Hormel, David Huang

■■ABSTRACT Optical coherence tomography angiography (OCTA) data is generated by measuring motion contrast between sequential optical coherence tomography (OCT) scans. Here we review how the OCT data is collected and how flow signal can be measured using either amplitude, phase, or complex signals.

■■INTRODUCTION Optical coherence tomography (OCT) uses interferometry to measure tissue reflectance.1 Interferometry relies on the interaction between a reference beam and light reflected from the sample arm after interaction with the tissue. The depths of tissue reflections are resolved by coherence gating, which refers to the mutual coherence between reference and sample reflections. Transverse scanning of the beam in the sample arm makes OCT a three-dimensional imaging modalit y. OCT usually employs inv isible infrared light, which is advantageous for patient comfort in ophthalmic applications. The axial resolution of OCT systems ranges from 2 to 10 µm, depending on the spectral bandwidth and wavelength.2 This enables noninvasive visualization of the internal layers of thin structures such as the retina not possible with any other technology. These advantages have made OCT the most commonly performed imaging procedure in ophthalmology,3 where it is used to diagnose disease and assess treatment efficacy.4 In structural OCT, inherent variation in tissue reflectivity enables the identification of different structures. For instance, the inner nuclear layer of the retina has relatively low reflectivity, and can be distinguished from the more reflective inner and outer plexiform layers around it. However, this does not provide good contrast for capillaries, which usually have similar reflectivity to the tissues in which they are embedded. Structural OCT measurements are consequently incapable of achieving adequate detail to construct an angiogram at capillary-scale detail. Early attempts at OCT angiography (OCTA) uses the Doppler shift measured between adjacent axial scans, but this proved unreliable because the OCT beam often strikes retinal blood vessel at near perpendicular incidence, which makes the Doppler shift too small to measure.5,6 Reliable OCTA eventually emerged as more robust methods to detect motion between successive OCT cross-sectional scans (B-scans) were developed.

■■GENERATING OCTA DATA FROM MOTION CONTRAST Optical coherence tomography angiography relies on motion contrast to highlight blood vessels down to the capillary level. Blood flow changes the OCT reflectance signal between sequential B-scans (Figures 1A to D). This change constitutes flow signal.

Because OCTA is based on OCT data, it has many of the character­ istics of structural OCT imaging. OCTA is also a noninvasive, threedimensional modality. OCTA data is automatically coregistered with the structural OCT data used to produce it. This can be useful for assessing the location of vasculature relative to the tissue in which it is embedded and for correlating the structural and vascular features to enhance the diagnosis of retinal pathologies.

■■METHODS FOR MEASURING MOTION CONTRAST There are a number of ways to measure motion contrast. OCT signal is complex valued—including both amplitude and phase components. Consequently, OCTA can be either phase-based, amplitude-based, or complex-signal-based. The first attempts to achieve angiography from OCT devices relied on Doppler phase shifts. Doppler OCT can measure the absolute blood flow velocity based on the phase shift between consecutive axial scans and the beam incidence angle. The Doppler shift is proportional to the off-perpendicular angle between the OCT beam and the direction of blood flow. Unfortunately, for retinal OCT scanning, this angular offset is often close to zero. To overcome this limitation, researchers next turned to phase variance (rather than phase shift) as the flow signal.7-9 However, phase-based OCTA is very susceptible to corruption by phase noise due to bulk tissue motion and OCT system noise (especially swept-source output).10 There are several methods that compensate for phase noise, which largely rely on the statistical properties (e.g., the mean or histogram) of the flow signal distribution within an OCTA volume.9-12 While no method can completely remove phase noise, a recent approach that relies on using the standard deviation of flow values within a line scan can reliably and efficiently compensate for phase shifts.12 To avoid the difficulties with phase noise, most commercial OCTA systems are amplitude-based. While amplitude-based OCTA lose some flow sensitivity compared to phase measurements, it is sensitive enough to measure capillary. Because it is less susceptible to noise from tissue bulk motion and other sources of phase variation, amplitude-based OCT is more reliable and easier to implement. Optovue, Heidelberg, and Topcon instruments all rely on amplitude-based motion contrast. But the exact algorithm differs. Heidelberg OCTA measures the temporal amplitude distribution within a given voxel in order to estimate the probability that it belongs to static tissue or a vessel.13 To achieve enough information to adequately sample, these amplitude distributions require 4–7 consecutive B-frames at each scan location.13 Optovue systems employ the split-spectrum amplitude-decorrelation angiography (SSADA) algorithm that requires only two consecutive B-frames for compute a high-quality angiogram. Topcon instruments use a ratio analysis approach [termed “OCTA ratio analysis (OCTARA)”] in which the ratio between the minimum and maximum voxel value

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Section 1: Methods and techniques of oct angiography examination

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Flow voxels are detected due to the change in OCT reflectance signal between B-scans

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Figures 1A to D Optical coherence tomography angiography (OCTA) signal generation. (A) Two sequential cross-sectional structural OCT scans (scan A and scan B) are generated by collecting data from a sample beam at a detector. (B) When the sample beam (red and blue arrows) encounters a blood vessel, flowing blood imparts a change in the reflectance signal between scan A and scan B. (C) On the other hand, when the sample beam encounters static tissue, the reflectance signal in scan A and scan B will be essentially identical. (D) By measuring the change between scan A and scan B, blood flow can be identified.

at two different time points is compared in order to construct the OCTA signal.14 This algorithm also requires at least four repeated B-scans to achieve adequate results. Complex-signal-based OCTA uses both the phase and amplitude components of the OCT signal. It is highly susceptible to phase noise like phase-based OCTA. The most prominent complex-signalbased OCTA generation algorithm is “optical microangiography” (OMAG). This algorithm uses frequency modulation in the interferogram in order to separate the static signal from the flow signal. The specifics of how this offset is achieved have changed as the technique improved over time.15-18 OMAG requires adequate phase compensation in order to remove noise from bulk motion. Zeiss instruments use the ultrahigh sensitive OMAG algorithm,19 which has recently achieved high-quality angiographic images from just two repeated B-scans on 100-kHz swept-source OCT prototype (Figures 2A to F).20,21

■■SPECTRAL SPLITTING Optical coherence tomography phase, amplitude, and complex signals can all be enhanced using spectral splitting, in which the OCT signal is processed separately in different frequency sub-bands and then averaged to produce the OCTA angiogram. Spectral splitting improves the flow detection signal-to-noise ratio (SNR) (and, consequently, downstream measurements such as vessel density or connectivity). The enhanced signal comes at the cost of reduced axial resolution, since each of the constituent

frequency bands must be narrower than the full spectrum (which achieves optimal resolution). In ophthalmic imaging, this is not problematic since even at reduced axial resolution, spectrally split OCTA measurements can still unambiguously separate the vascular plexuses. Lowering axial resolution by spectral splitting reduces susceptibility to noise due to cardiac pulsation and other axial bulk motion, which further enhances the SNR of flow detection. The first commercial OCTA instruments were developed by Optovue and made use of SSADA.22 SSADA is a purely amplitudebased OCTA processing algorithm, but research studies have made use of spectral splitting for phase- and complex-based processing as well.23 In each case, improvements in image SNR and contrast have been measured. Optovue instruments employing the SSADA algorithm require just two repeated B-scans in order to construct OCTA volumes.24 Due to this efficiency, recently SSADA has been able to achieve 12 × 12-mm field of view in a single scan (Figure 3) using the latest 120-kHz Solix system (Optovue, Inc.).

■■CONCLUSION Optical coherence tomography angiography uses motion contrast to detect flow down to the capillary level. Flow signal is computed from the change in OCT reflectance between consecutive B-scans. Several different approaches can be used to compute the flow signal. The most efficient algorithms can obtain adequate flow SNR and image quality using only two consecutive B-scans at each location.

CHAPTER 1: Principles of oct angiography

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Superficial retinal layer Deep retinal layer Outer retinal layer

Color-coded layers and segmentation

Figures 2A to F  Ultrahigh sensitive optical microangiography (OMAG) images of retinal vasculature at several scales compared to fundus photography. (A) A fundus photography image of a healthy retina. (B) A montaged OMAG en face image of the nerve fiber layer. (C) A superficial retinal slab shows the vascular network in the ganglion cell layer and outer plexiform layer. (D) Retinal slab corresponding to the deep vascular complex. (E) Image showing the vasculature in both (C) and (D), with vessels color-coded according to depth (red: superficial; green: intermediate; blue: deep). (F) Magnified image detailing the blue box in (E), along with a structural cross-section with flow overlaid at the position indicated by the dotted dashed line. Capillary details are clearly visible in the magnified version. Source: Reprinted with permission from Zhang Q, Lee CS, Chao J, et al. Wide-field optical coherence tomography based microangiography for retinal imaging. Sci Rep 2016; 6:22017. Figure 3  12 × 12-mm, 600 × 600-pixel resolution image of a normal retina from a commercial instrument (Solix, Optovue, CA) employing SSADA OCTA processing. This efficient algorithm requires only two sequential scans to capture the detail shown here.

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■■REFERENCES 1. Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science 1991; 254:1178–1181. 2. Drexler W, Fujimoto JG. Optical coherence tomography: technology and applications. Switzerland: Springer International Publishing, 2010. 3. Swanson EA, Huang D. Ophthalmic OCT reaches $1 billion per year. Retin Physician 2011; 45:58–59. 4. Brand CS. Management of retinal vascular diseases: a patient-centric approach. Eye 2012; 26:S1–S16. 5. Chen Z, Milner TE, Srinivas S, et al. Noninvasive imaging of in vivo blood flow velocity using optical Doppler tomography. Opt Lett 1997; 22:1119– 1121. 6. Izatt JA, Kulkarni MD, Yazdanfar S, Barton JK, Welch AJ. In vivo bidirectional color Doppler flow imaging of picoliter blood volumes using optical coherence tomography. Opt Lett 1997; 22:1439–1441. 7. Fingler J, Schwartz D, Yang C, Fraser SE. Mobility and transverse flow visualization using phase variance contrast with spectral domain optical coherence tomography. Opt Express 2007; 15:12636–12653. 8. Fingler J, Readhead C, Schwartz DM, Fraser SE. Phase-contrast OCT imaging of transverse flows in the mouse retina and choroid. Invest Ophthalmol Vis Sci 2008; 49:5055–5059. 9. Makita S, Hong Y, Yamanari M, Yatagai T, Yasuno Y. Optical coherence angiography. Opt Express 2006; 14:7821–7840. 10. Szkulmowski M, Grulkowski I, Szlag D, Szkulmowska A, Kowalczyk A, Wojtkowski M. Flow velocity estimation by complex ambiguity free joint spectral and time domain optical coherence tomography. Opt Express 2009; 17:14281–14297. 11. Wang RK, An L. Doppler optical micro-angiography for volumetric imaging of vascular perfusion in vivo. Opt Express 2009; 17:8926–8940. 12. Wei X, Camino A, Pi S, et al. Fast and robust standard-deviation-based method for bulk motion compensation in phase-based functional OCT. Opt Lett 2018; 43:2204–2207.

13. Rocholz R, Teussink MM, Dolz-Marco R, et al. SPECTRALIS optical coherence tomography angiography (OCTA): principles and clinical applications. Heidelb Eng Acad 2018; 1–10. 14. Reisman CA, Wang Z, Liu JJ, et al. Swept source OCT angiography based on ratio analysis. Invest Ophthalmol Vis Sci 2016; 57:452. 15. Wang RK, Jacques SL, Ma Z, et al. Three dimensional optical angiography. Opt Express 2007; 15:4083–4097. 16. 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. 17. An L, Qin J, Wang RK. Ultrahigh sensitive optical microangiography for in vivo imaging of microcirculations within human skin tissue beds. Opt Express 2010; 18:8220–8228. 18. An L, Shen TT, Wang RK. Using ultrahigh sensitive optical microangiography to achieve comprehensive depth-resolved microvasculature mapping for human retina. J Biomed Opt 2011; 16:106013. 19. Tan AC, Tan GS, Denniston AK, et al. An overview of the clinical applications of optical coherence tomography angiography. Eye (Lond) 2018; 32:262–286. 20. Wang RK, Zhang A, Choi WJ, et al. Wide-field OCT angiography enabled by 2 repeated measurements of B-scans. Opt Lett 2016; 41:2330–2333. 21. Zhang Q, Lee CS, Chao J, et al. Wide-field optical coherence tomography based microangiography for retinal imaging. Sci Rep 2016; 6:22017. 22. Jia Y, Tan O, Tokayer J, et al. Split-spectrum amplitude-decorrelation angiography with optical coherence tomography. Opt Express 2012; 20:4710–4725. 23. Liu G, Jia Y, Pechauer AD, Chandwani R, Huang D. Split-spectrum phasegradient optical coherence tomography angiography. Biomed Opt Express 2016; 7:2943–2954. 24. 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.

Chapter 2 Interpretation of OCT angiography Tristan T Hormel, Yali Jia, David Huang

■■ABSTRACT The interpretation of optical coherence tomography (OCT) angiography data requires the display and quantification of information. Since OCT angiography (OCTA) is a three-dimensional imaging modality, several different data representations are possible. In this chapter, we review advantages and limitations of each, and also discuss how to interpret the flow signal itself.

■■INTRODUCTION Because OCTA is a high-resolution, three-dimensional imaging modality, the amount of information a single procedure procures is large compared to dye-based angiography such as fluorescein angiography. Since the data is three-dimensional, it can be naturally represented as a data volume with dimensions given by the number of voxels along each axis, for example, a 304 × 304 × 600 data “cube” may be acquired. However, we view OCTA data on two-dimensional displays, which means frame selection or projection operations are needed. To interpret OCTA images, it is important to understand this process. We will return to data visualizations, but let us first discuss the nature of flow signal on OCTA images.

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Optical coherence tomography angiography is constructed by measuring motion contrast.1-3 The motion contrast is referred to as flow signal and its magnitude can be represented on a gray scale or various color scales. The flow signal value is related to vessel caliber,4 blood flow velocity,5 as well as reflectance signal strength.6 Flow phantom calibration experiments indicate that flow signal is nonlinearly related to blood flow velocity, with both a detection threshold below which flow is not detected and a saturation value above which all flow velocities approach a ceiling (Figures 1A and B).4 This saturation value is influenced by vessel caliber. For all of these reasons, a simple mapping of flow signal value to velocity or volumetric flow rate is not possible. However, by averaging the flow signal in a standardized area on en face OCTA, it is possible to calculate a flow index that is monotonically related to blood flow in that anatomic region. A change in the flow index in the same area can be interpreted as a change in flow. Bulk motion is an important artifact in OCTA because it adds to flow-related motion. When there is rapid eye motion, such as during a microsaccade, even avascular tissue can appear bright

Decorrelation (D)

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■■INTERPRETATION OF FLOW SIGNAL VALUE

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Figures 1A and B:  (A) Flow signal (decorrelation) as a function of flow velocity and channel width in a flow phantom experiment. In this experiment, human blood cells flowing through channels of controlled width were manually tracked to determine velocity. Velocity and channel width were then compared to the OCT angiography (OCTA) flow value generated from the same sample. Here, the flow signal was determined as a decorrelation value, which over the range of flow velocities examined achieved a channel dependent saturation value. (B) Between flow velocities of 0 and 2.5 mm/s, the flow signal was approximately linear with blood flow velocity. Source:  Reprinted with permission from Su JP, Chandwani R, Gao SS, Pechauer AD, Zhang M, Wang J, et al. Calibration of optical coherence tomography angiography with a microfluidic chip. J Biomed Opt 2016; 21:86015.

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Section 1: Methods and techniques of oct angiography examination

on OCTA images. This can be recognized as artifactual because it appears as bright lines or strips on en face OCTA images. Another important artifact is flow projection, where flow from superficial blood vessels is projected onto deeper highly reflective tissue. Projection artifacts appear as vertical streaks or tails on blood vessels on cross-sectional OCTA, and as projection of superficial vascular patterns onto deeper slabs on en face OCTA. These artifacts can be removed using postprocessing algorithms.7 However, many OCTA systems do not yet employ these cleanup algorithms and the clinician should be aware of them when interpreting OCTA images.

■■OCTA VISUALIZATION There are three useful ways to visualize OCTA data: In cross section (similar to a B-frame), with en face projection, or by volume rendering (Figures 2A to C).8 Cross-sectional OCTA images are useful for showing the depth of vascular pathologies. A cross-sectional image can represent a single B-frame or can be formed by projecting across a slab comprised of several adjacent B-frames 9 to reduce speckle noise and accentuate contiguous vascular features. By convention, cross-sectional OCTA is a composite of structural and perfusion information, with nonvascular pixels represented by reflectance signal scale and vascular pixels (pixels with flow signal above a certain threshold) shown in color (Figures 2A to C). The color can be coded to represent different segmented slabs that correspond to anatomic layers or plexuses. In structural OCT, cross-sectional images are used frequently to detect pathologic features such as edema or retinal detachments.10-13 Some important vascular pathologies can also be analyzed in cross section.14 For example, retinal angiomatous proliferation can be directly imaged in cross section (Figures 3A to C).9 Similarly, the

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depth of certain features such as choroidal neovascular lesions can be used to distinguish different types of pathology (in this case, type I or type II CNV; Figures 3A to C). However, since the retinal plexuses are oriented perpendicular to the OCT scan direction,15 they are best viewed using en face images. Simply by virtue of the fact that they can capture detailed views of plexuses, en face images are the most common means of viewing OCTA data. They are also analogous to the two-dimensional format of convention fundus photography and fluorescein angiography, and so are useful for correlation between imaging modalities. Construction of en face images involves the projection of flow signal across an anatomic slab. This slab could be the entire OCTA data volume, but projection over such a large region can lead to cluttered images that are difficult to interpret. Instead, it is often useful try and isolate only single plexuses or complexes, since plexus-specific analysis offers improved diagnostic value.16 This requires accurate delineation of retinal layer boundaries (Figures 4A to F).17 Many algorithms that seeking to automate this process have been reported;17-25 however, the task is complicated by a wide variety of pathologic developments that can disorganize retinal layers10-12 and lead to image processing issues such as vanishing gradients. Mis-segmented retinal layers can lead to flow signal from one plexus being mapped to another or to an avascular region of the retina, which could lead to a false diagnosis if one is unwary. It is therefore, often a good idea to verify layer segmentation results by examining cross-sectional scans. Once the slab of interest has been identified, the flow signal within the slab must be projected to a two-dimensional surface. Projection can be performed in several ways. Within the retina, maximum-value projection, in which the brightest voxel within a line scan is chosen for display, leads to the best results.26 Figures 2A to C:  Optical coherence tomography angiography (OCTA) data representations. (A) Cross-sectional images can be generated from individual B-frames, or by projecting a slab comprising several adjacent B-frames. Tissue structure (reflectance signal) is shown in gray scale and perfusion (flow signal) in typically color coded (here in red). In the example images here, three anatomic boundaries are shown in red, green, and blue. (B) The flow signal can be projected in slabs defined by the aforementioned boundaries to create en face representations, which are akin to color fundus photography and dye injection angiography images. (C) Since OCTA is a three-dimensional imaging modality, volume renderings can also be used. Source: Reprinted with permission from Hormel TT, Hwang TS, Bailey ST, Wilson DJ, Huang D, Jia Y. Artificial intelligence in OCT angiography. Prog Retin Eye Res 2021; 100965.

CHAPTER 2: Interpretation of oct angiography

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Figures 3A to C:  En face and cross-sectional optical coherence tomography angiography (OCTA) representations highlighting retinal neovascularization (RNV), choroidal neovascularization (CNV), and retinal angiomatous proliferation (RAP). In each image, the flow signal is color coded according to its position (orange: vitreous; violet: inner retina; yellow: outer retina, red: choroid). (A1 and A2) The RNV lesion can be clearly located in the en face and cross-sectional images due to its location in the vitreous. (B1 and B2) Here, the outer retinal vessels are additionally colored according to location relative to the retinal pigment epithelium (green: above; yellow: below). This enables easy identification of type I (yellow) and type II (green) CNV, and can help to identify mixed lesions such as the example here. (C1 and C2) A cross-sectional view clearly shows the RAP vessels e xtending between the choroid and outer retina. In all of the examples shown, both the en face and cross-sectional images can help to identify and characterize the pathology. Projection artifacts have been removed using a projection-resolved OCT algorithm to produce these images.

It is often advantageous to combine both en face and crosssectional images in order to fully characterize a pathology (Figures 3A to C). In this manner, both the depth and lateral location of any pathology can be identified. It may also be useful to false color flow signal based on depth. This can be particularly useful when certain pathologies are typed by their relationship to an anatomic layer, as with choroidal neovascularization (Figures 3A to C). The resulting images can easily distinguish one type of the pathology from another. The three-dimensionality of OCTA data can also be leveraged to produce volume renderings (Figures 5A and B). Unfortunately, due to the complicated vasculature of the retina, volume renderings can be difficult to interpret. For this reason, they are not frequently used in OCTA analysis. Nonetheless, it should be remembered that ultimately OCTA data is three-dimensional, and the process of projecting three-dimensional data onto a two-dimensional plane can distort some image metrics.27

■■QUANTIFICATION OF PERFUSION In addition to visual identification of features, OCTA data can also be quantified to aid in diagnosis and staging of diseases.

Probably the single most frequently measured quantity in OCTA is vessel density. Vessel density can be calculated as an area percent (the number of vascular pixels divided by the total number of pixels in an image) or as a line density (the length of skeletonized vessels divided by the analytic area). Skeletonization avoids measurement bias caused by artifactual broadening of vessels due to the OCT beam spot diameter (typically 15–20 μ), which is larger than capillaries (5–10 μ). However, the skeletonization step in image processing may introduce additional error, especially if the image quality is poor and the vascular pixels are not perfectly contiguous. Different commercial instruments may use either area or line density. Clinicians should be aware of the distinction. Vessel density can also be measured in a volumetric basis, but that can be greatly inflated by projection artifacts, if the artifact is not cleanly removed. So, volumetric flow density is not commonly used yet. Vessel density measurement is a measure of perfusion and can distinguish between healthy eyes and several diseases.28 An alternative perfusion metric is nonperfusion area (NPA). Measurements of NPA quantif y the extent of pathologically vessel-free regions of the retina (Figures 6A to C). 32 Like vessel density measurements, NPA measurements can be used to distinguish healthy from diseased eyes. 33-35 Capillary dropout does

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Section 1: Methods and techniques of oct angiography examination

Decorrelation value

Figures 4A to F: Retinal layer segmentation in the peripapillary retina. (A) Structural optical coherence tomography (OCT) image of the peripapillary retina, with the optic disk highlighted in green. (B) Disarticulated retinal layers at the location of the red line in (A). From top to bottom: nerve fiber layer (NFL, red), ganglion cell layer (GCL, green), inner plexiform layer (IPL, yellow), inner nuclear layer (INL, indigo), B A C outer plexiform layer (OPL, magenta), outer nuclear layer (ONL, cyan), retinal pigment epithelium (RPE, orange), and 0.31 choroid (blue). (C) Equivalent visualization at the location of the blue line in (A), passing through the optic disk. (D) En face superficial vascular plexus OCT angiography (OCTA) angiogram generated based on the segmented boundaries. (E) Cross-sectional structural OCT image with retinal layer 0.00 boundaries overlaid at the D E F location of the red line in (A). From top to bottom: vitreous/ inner limiting membrane (red), NFL/GCL (green), IPL/INL (yellow), INL/OPL (indigo), OPL/ONL (magenta), ONL/ellipsoid zone (cyan), ellipsoid zone/RPE (orange), RPE/Bruch’s membrane (blue). (F) Equivalent visualization at the location of the blue line in (A). These boundaries were generated using a deep learning network. Source: Reprinted with permission from Zang P, Wang J, Hormel TT, Liu L, Huang D, Jia Y. Automated segmentation of peripapillary retinal boundaries in OCT combining a convolutional neural network and a multi-weights graph search. Biomed Opt Express 2019; 10:4340–4352.

Figures 5A and B: Volume renderings of an eye with a macular hole. (A) View looking down from the superficial vascular complex and (B) looking up from the deep capillary plexus. Blue indicates intraretinal cystoid spaces, with light blue indicating a location in the inner nuclear layer and dark blue between the outer plexiform layer and Henle’s fiber layer. Volumetric representations can avoid misleading images in which extended fluid volumes may appear small due to their projected area in crosssectional or en face images. A

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Source: Reprinted with permission from Hormel TT, Hwang TS, Bailey ST, Wilson DJ, Huang D, Jia Y. Artificial intelligence in OCT angiography. Prog Retin Eye Res 2021; 100965.

CHAPTER 2: Interpretation of oct angiography

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Figures 6A to C: Nonperfusion area detection using deep learning.32 (Top row—A1, B1, C1) En face OCTA images of eye with severe nonproliferative diabetic retinopathy show large nonperfusion areas in the deep capillary plexus (DCP) and intermediate capillary plexus (ICP), and especially in the superficial vascular complex (SVC). (Bottom row—A2, B2, C2): A neural network outputs the probability that a pixel is part of a nonperfusion area (teal). Source: Reprinted with permission from Hormel TT, Hwang TS, Bailey ST, Wilson DJ, Huang D, Jia Y. Artificial intelligence in OCT angiography. Prog Retin Eye Res 2021; 100965.

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not need to leave a region of the eye completely bereft of vessels in order for pathology to be detected; in glaucomatous eyes, for example, low perfusion areas (in which vessels still exist, but at a diminished number relative to a healthy baseline) can also detect pathology. 36 Data from OCTA procedures can also be used to quantify specific pathologies. For example, choroidal neovascular lesion area can be used to help assess the efficacy of anti-vascular endothelial growth factor (anti-VEGF) treatments.37 Even features that are usually characterized using structural OCT can benefit from OCTA data, as for example with retinal fluid volumes. Since fluid regions will necessarily be avascular, OCTA data can help to identify their boundaries, which can improve segmentation.27 Independent of the feature being quantified, it is important to respect the effect of artifacts on OCTA measurements. Perfusion measurements made on posterior plexuses without projection

C2

artifact removal will blend vessel characteristics from the target plexus with any superficial plexuses. Similarly, quantification of choroidal neovascularization can be easily disrupted by prominent projection artifacts occurring at the highly reflective retinal pigment epithelium. Shadow artifacts, on the other hand, can cause what appears to be capillary dropout which is actually the result of signal attenuation. Fortunately, many state-of-the-art algorithms can account for artifacts such as these so as to prevent them from significantly adversely effecting quantification. 37-39

■■CONCLUSION The clinician should become familiar with both en face and crosssectional displays of OCTA for its interpretation. Both vessel density and NPA are important methods of quantifying perfusion using OCTA.

■■REFERENCES 1. Jia Y, Tan O, Tokayer J, Potsaid B, Wang Y, Liu JJ, et al. Split-spectrum amplitude-decorrelation angiography with optical coherence tomography. Opt Express 2012; 20:4710–425. 2. Wang RK, Jacques SL, Ma Z, Hurst S, Hanson SR, Gruber A. Three dimensional optical angiography. Opt Express 2007; 15:4083–4097. 3. Makita S, Hong Y, Yamanari M, Yatagai T, Yasuno Y. Optical coherence angiography. Opt Express 2006; 14:7821–7840. 4. Su JP, Chandwani R, Gao SS, Pechauer AD, Zhang M, Wang J, et al. Calibration of optical coherence tomography angiography with a microfluidic chip. J Biomed Opt 2016; 21:86015. 5. Choi W, Moult EM, Waheed NK, Adhi M, Lee B, Lu CD, et al. Ultrahighspeed, swept-source optical coherence tomography angiography in nonexudative age-related macular degeneration with geographic atrophy. Ophthalmology 2015; 122:2532–2544.

6. Yu JJ, Camino A, Liu L, Zhang X, Wang J, Gao SS, et al. Signal strength reduction effects in OCT angiography Ophthalmol Retina 2019; 3:835– 842. 7. Hormel TT, Huang D, Jia Y. Artifacts and artifact removal in optical coherence tomographic angiography 2021; 11:1120–1133. 8. Hormel TT, Hwang TS, Bailey ST, Wilson DJ, Huang D, Jia Y. Artificial intelligence in OCT angiography. Prog Retin Eye Res 2021; 100965. 9. Bhavsar KV, Jia Y, Wang J, Patel RC, Lauer AK, Huang D, et al. Projectionresolved optical coherence tomography angiography exhibiting early flow prior to clinically observed retinal angiomatous proliferation. Am J Ophthalmol Case Rep 2017; 8:53–57. 10. Das R, Spence G, Hogg RE, Stevenson M, Chakravarthy U. Disorganization of inner retina and outer retinal morphology in diabetic macular edema. JAMA Ophthalmol 2018; 136:202–208.

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Section 1: Methods and techniques of oct angiography examination 11. Sun JK, Radwan SH, Soliman AZ, Lammer J, Lin MM, Prager SG, et al. Neural retinal disorganization as a robust marker of visual acuity in current and resolved diabetic macular edema. Diabetes 2015; 64:2560–2570. 12. Sun JK, Lin MM, Lammer J, Prager S, Sarangi R, Silva PS, et al. Disorganization of the retinal inner layers as a predictor of visual acuity in eyes with center-involved diabetic macular edema. JAMA Ophthalmol 2014; 132:1309–316. 13. Browning DJ, Glassman AR, Aiello LP, Bressler NM, Bressler SB, Danis RP, et al. Optical coherence tomography measurements and analysis methods in optical coherence tomography studies of diabetic macular edema. Ophthalmology 2008; 115:1366–1372. 14. Patel RC, Wang J, Hwang TS, Zhang M, Gao SS, Pennesi ME, et al. Plexusspecific detection of retinal vascular pathologic conditions with projectionresolved OCT angiography. Ophthalmol Retina 2018; 2:816–826. 15. Campbell JP, Zhang M, Hwang TS, Bailey ST, Wilson DJ, Jia Y, et al. Detailed vascular anatomy of the human retina by projection-resolved optical coherence tomography angiography. Sci Rep 2017; 7:42201. 16. Hormel TT, Jia Y, Jian Y, Hwang TS, Bailey ST, Pennesi ME, et al. Plexusspecific retinal vascular anatomy and pathologies as seen by projectionresolved optical coherence tomographic angiography. Prog Retin Eye Res 2021; 80:100878. 17. Zang P, Wang J, Hormel TT, Liu L, Huang D, Jia Y. Automated segmentation of peripapillary retinal boundaries in OCT combining a convolutional neural network and a multi-weights graph search. Biomed Opt Express 2019; 10:4340–4352. 18. Shi F, Chen X, Zhao H, Zhu W, Xiang D, Gao E, et al. Automated 3-D retinal layer segmentation of macular optical coherence tomography images with serous pigment epithelial detachments. IEEE Trans Med Imaging 2015; 34:441–452. 19. Bai F, Marques MJ, Gibson SJ. (2017). Cystoid macular edema segmentation of optical coherence tomography images using fully convolutional neural networks and fully connected CRFs. [online] Available from http://arxiv. org/abs/1709.05324 [Last accessed June, 2021]. 20. Chiu SJ, Allingham MJ, Mettu PS, Cousins SW, Izatt JA, Farsiu S. Kernel regression based segmentation of optical coherence tomography images with diabetic macular edema. Biomed Opt Express 2015; 6:1172–1194. 21. Antony BJ, Abràmoff MD, Lee K, Sonkova P, Gupta P, Kwon Y, et al. Automated 3D segmentation of intraretinal layers from optic nerve head optical coherence tomography images. Biomed Appl Mol Struct Funct Imaging 2010; 7626:76260U. 22. Fang L, Cunefare D, Wang C, Guymer RH, Li S, Farsiu S. Automatic segmentation of nine retinal layer boundaries in OCT images of nonexudative AMD patients using deep learning and graph search. Biomed Opt Express 2017; 8:2732–2744. 23. Kugelman J, Alonso-Caneiro D, Read SA, Vincent SJ, Collins MJ. Automatic segmentation of OCT retinal boundaries using recurrent neural networks and graph search. Biomed Opt Express 2018; 9:5759–5777. 24. Guo Y, Camino A, Zhang M, Wang J, Huang D, Hwang T, et al. Automated segmentation of retinal layer boundaries and capillary plexuses in widefield optical coherence tomographic angiography. Biomed Opt Express 2018; 9:4429–4442. 25. Devalla SK, Renukanand PK, Sreedhar BK, Subramanian G, Zhang L, Perera S, et al. DRUNET: a dilated-residual U-Net deep learning network

to segment optic nerve head tissues in optical coherence tomography images. Biomed Opt Express 2018; 9:3244–3265. 26. Hormel TT, Wang J, Bailey ST, Hwang TS, Huang D, Jia Y. Maximum value projection produces better en face OCT angiograms than mean value projection. Biomed Opt Express 2018; 9:6412–6424. 27. Guo Y, Hormel TT, Xiong H, Wang J, Hwang TS, Jia Y. Automated segmentation of retinal fluid volumes from structural and angiographic optical coherence tomography using deep learning. Transl Vis Sci Technol 2020; 9:54. 28. Chen CL, Zhang A, Bojikian KD, Wen JC, Zhang Q, Xin C, et al. Peripapillary retinal nerve fiber layer vascular microcirculation in glaucoma using optical coherence tomography-based microangiography. Investig Ophthalmol Vis Sci 2016; 57:475–485. 29. Coscas F, Cabral D, Pereira T, Geraldes C, Narotamo H, Miere A, et al. Quantitative optical coherence tomography angiography biomarkers for neovascular age-related macular degeneration in remission. PLoS One 2018; 13:e0205513. 30. Zhang Q, Rezaei KA, Saraf SS, Chu Z, Wang F, Wang RK. Ultra-wide optical coherence tomography angiography in diabetic retinopathy. Quant Imaging Med Surg 2018; 8:743–753. 31. Samara WA, Shahlaee A, Adam MK, Khan MA, Chiang A, Maguire JI, et al. Quantification of diabetic macular ischemia using optical coherence tomography angiography and its relationship with visual acuity. Ophthalmology 2017; 124:235–244. 32. Wang J, Hormel TT, You Q, Guo Y, Wang X, Chen L, et al. Robust nonperfusion area detection in three retinal plexuses using convolutional neural network in OCT angiography. Biomed Opt Express 2020;11: 330–345. 33. Jia Y, Simonett JM, Wang J, Xiaohui Hua, Liang Liu, Thomas S. Hwang, et al. Wide-field OCT angiography investigation of the relationship between radial peripapillary capillary plexus density and nerve fiber layer thickness. Invest Ophthalmol Vis Sci 2017; 58:5188–5194. 34. Hwang TS, Jia Y, Gao SS, Bailey ST, Lauer AK, Flaxel CJ, et al. Optical coherence tomography angiography features of diabetic retinopathy. Retina 2015; 35:2371–2376. 35. Nesper PL, Roberts PK, Onishi AC, Chai H, Liu L, Jampol LM, et al. Quantifying microvascular abnormalities with increasing severity of diabetic retinopathy using optical coherence tomography angiography. Invest Ophthalmol Vis Sci 2017; 58:BIO307–BIO315. 36. Liu L, Edmunds B, Takusagawa HL, Tehrani S, Lombardi LH, Morrison JC, et al. Projection-resolved optical coherence tomography angiography of the peripapillary retina in glaucoma. Am J Ophthalmol 2019; 207: 99–109. 37. Wang J, Hormel TT, Gao L, Zang P, Guo Y, Wang X, et al. Automated diagnosis and segmentation of choroidal neovascularization in OCT angiography using deep learning. Biomed Opt Express 2020; 11:927–944. 38. Guo Y, Hormel TT, Xiong H, Wang B, Camino A, Wang J, et al. Development and validation of a deep learning algorithm for distinguishing the nonperfusion area from signal reduction artifacts on OCT angiography. Biomed Opt Express 2019; 10:3257–3268. 39. Camino A, Jia Y, Yu J, Wang J, Liu L, Huang D. Automated detection of shadow artifacts in optical coherence tomography angiography. Biomed Opt Express 2019; 10:1514–1531.

Chapter 3 OCT angiography: Terminology David Huang, Tristan Hormel, Yali Jia

■■INTRODUCTION Clinical use of optical coherence tomography angiography (OCTA) expanded rapidly since its introduction in 2014. The vocabulary describing OCTA features and measurements has similarly expanded. This chapter defines and updates the most important terms likely to be encountered in OCTA applications.

■■AVASCULAR AREA Avascular areas within the eye do not include vessels. Healthy retina normally contains an avascular area known as the foveal avascular zone. Pathological capillar y dropout leads to the formation of additional avascular areas.

consecutive cross-sectional scans (B-scans) due to the motion of blood cells. Since the OCT signal is complex, flow can be measured by variation in either its amplitude, phase, or both. The flow signal can be computed as variance, difference, ratio, or decorrelation between the repeated OCT B-scans. The flow signal is nonlinearly related to f low velocity; it has both a sensitivity (the lowest detectable flow signal) and a saturation limit. The flow signal also depend on the reflectance signal strength and the caliber of the blood vessels.13

■■NONPERFUSION AND LOWPERFUSION AREAS

Motion artifacts are produced by motion contrast not attributable to blood f low. Common sources of these artifacts are micro­ saccades (which cause bright stripes in OCTA images), ocular pulsation, and drift. Postprocessing algorithms can remove motion artifacts by sampling noise statistics from the OCTA data volume and applying a suitable correction.1-7 Motion artifacts can also be reduced by tracking systems that follow the eye’s movement and trigger a rescan of affected B-frames. 8-10

Nonperfusion areas are regions of the eye that normally contain vessels but are avascular due to pathologic capillary dropout. Nonperfusion area can detected as abnormally large gaps between blood vessels.14 The nonperfusion area is a sensitive metric for detecting diseases in which distinct areas of capillary dropout is interspersed with areas with normal vessel density. In other diseases, vessel density can be reduced without forming large gaps. These diseases are better detected by identifying lowperfusion areas—areas where the vessel density is significantly lower than that in the corresponding location in the perfusion map averaged from a reference population of healthy eyes.15

■■EN FACE AND CROSS-SECTIONAL IMAGES

■■OPTICAL COHERENCE TOMOGRAPHIC ANGIOGRAPHY

Since OCTA data is three-dimensional, it must be projected onto two dimensions in order to be easily viewed on a computer screen. En face projections create direct-facing images of retinal vasculature analogous to the familiar fundus photography image. En face OCTA images are used for clinical inspection and the basis for additional processing and quantification. Creating an en face OCTA image requires first identifying an anatomic slab and then projecting the flow signal either by averaging (“mean projection”) or taking the maximum value (“maximum value projection”).11 Cross-sectional images are useful for identifying the depth of vascular pathology within the retina. They can be displayed as individual B-frames, but often visualization of features can be enhanced by averaging multiple frames.12

Optical coherence tomography angiography is a functional extension of OCT that detects blood vessels by motion contrast. This enables the visualization of capillaries and other small vessels not visible on structural OCT. OCTA scans contain both reflectance and flow signal and can be used to provide both structural and angiographic images in three dimensions.

■■MOTION ARTIFACTS

■■FLOW SIGNAL Optical coherence tomography angiography detects f low by measuring the variation in the OCT reflectance signal between

■■PROJECTION ARTIFACTS Moving blood cells scatter the OCT beam and cause variation in OCT signal in distal tissue. This variation produces artifactual flow signal that appears as duplication of superficial vasculature in deeper slabs in en face images, and as “tails” descending from vessels in cross-sectional images.16 Projection artifacts falsely increase vessel density measured in deeper slabs and can cause erroneous detection neovascularization in the normally avascular outer retina.

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Section 1: Methods and techniques of oct angiography examination

■■PROJECTION-RESOLVED OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY

vignetting (iris), vitreous floaters, and hyperreflective material within the retina.

An OCTA postprocessing technique that analyzes both f low and reflectance signals to distinguish between in situ vascular flow and projected flow. Projected flow signal is removed while keeping vascular flow signal intact.17,18 Projection-resolved OCTA (PR-OCTA) operates volumetrically, and so can remove projection artifacts both from en face images and cross-sectional scans.

Signal strength is an important quality metric of an OCT image. Low signal strength can be caused by defocusing, poor tear film, vignetting, cataract, and vitreous opacities. Signal strength can affect the measurement of vessel density on OCT images and requires compensation.

■■REFLECTIVITY Ref lectiv it y is a material propert y that measures a tissue’s propensity to reflect incident light. The reflectivity of a material generally varies with the wavelength, incidence angle, and polarization of the illuminating light source. Retinal layers vary in reflectivity, which causes some layers to appear relatively dark and others to appear relatively bright. Fluid spaces in the retina have very low reflectivity. The nuclear layers have relatively low reflectivity. The retinal pigment epithelium has high reflectivity due to high content of melanosomes. The nerve fiber layer and Henle’s fiber layer have directional reflectivity that is brightest with perpendicular light incidence relative to the fibers.

■■REFLECTANCE SIGNAL The ref lectance signal is measured in structural OCT, where coherence gating is used to resolve the depth from which light is backscattered. The reflectance amplitudes are represented in color scale or gray scale in structural OCT images. Reflectance depends on intrinsic tissue reflectance as well as extrinsic factors such as shadowing and polarization shift from more superficial tissue structures, and beam defocus and incidence angle.

■■SCAN There are several types of scans in OCT. A line scan, or A-scan (also called A-line), is a measurement of reflectance versus depth at a single lateral position. A cross-sectional scan, or B-scan (also called B-frame) is composed of A-lines formed by lateral scanning of the OCT beam. A volumetric scan is a collection of B-scans, the sample of a contiguous tissue volume. The full volume scan is usually what is meant by an “OCT scan” or an “OCTA scan.” A C-scan is an image formed by resampling the volumetric scan in an en face plane perpendicular to the A-scan direction.

■■SHADOW ARTIFACTS Shadow artifacts are produced by reflectance signal attenuation due to scattering, absorption, or polarization shift by tissue in the OCT beam path.16 This in turn leads to loss of flow signal. In OCTA images, shadowing can appear similar to capillary drop out. So measurements of vessel density must take both flow and reflectance signal into account to more accurately detect blood vessels and exclude regions where vessels cannot be reliably detected due to severe shadowing.19 Common causes of shadow artifacts are

■■SIGNAL STRENGTH

■■SLAB SEGMENTATION The segmentation of tissue slabs is a necessary image processing step for creating en face OCTA images of retinal plexuses or complexes. The boundaries between retinal anatomic layers are identified by reflectivity transitions in structural OCT. This then form the basis for identifying the boundaries of the retinal plexuses and complexes (Table 1).20-23

■■SPLIT-SPECTRUM AMPLITUDEDECORRELATION ANGIOGRAPHY Split-spectrum amplitude-decorrelation angiography (SSADA) is an OCTA algorithm that enhances the signal-to-noise ratio (SNR) for flow detection through spectral-splitting, in which the reflectance signal is measured separately in different spectral subbands and then averaged to produce the flow signal. 24 This averag ing procedure reduces a x ia l resolut ion, but SSA DA measurements retain sufficient axial resolution to measure retinal vascular plexuses in isolation. Spectral splitting increases the flow detection SNR by (1) enhancing speckle contrast within the spectrally split subbands, since narrower spectrum increases the depth range of speckle grain, (2) summing of speckle contrast from spectral subbands, since each carries unique speckle pattern, and (3) damping axial bulk motion noise due to decreased axial resolution. SSADA can increase the SNR of flow detection by a factor of four and enables the construction of high-quality OCT images based on only two B-scans at each tissue location, the minimum possible.

Table 1  Relationship between retinal vascular plexuses and complexes to anatomic layers. Anatomic layer

Plexus

Complex

Nerve fiber layer (NFL)

Nerve fiber layer plexus (NFLP)

Combined ganglion cell and inner plexiform layer (GCIPL) Inner nuclear layer (INL)

Ganglion cell layer plexus (GCLP) Anterior three quarters of GCIPL Intermediate capillary plexus (ICP) Posterior quarter GCIPL and anterior half of INL Deep capillary plexus (DCP) Posterior half of INL and entire OPL

Superficial vascular complex (SVC)

Outer nuclear layer (OPL)

Deep vascular complex (DVC)

CHAPTER 3: OCT angiography: Terminology

■■STRUCTURAL OPTICAL COHERENCE TOMOGRAPHY In structural OCT, a beam of light is used to scan tissue and the backscattered light detected interferometrically to obtain depth information. Lateral scanning of the beam is used to provide threedimensional volumetric imaging of tissue microstructure.25 OCT is most widely used in ophthalmology to resolve the layered structure of the retina and cornea with micrometer resolution, but it is also used to image many other tissues, such as skin,26 or nonbiological materials, for example paintings.27

■■VASCULAR PLEXUSES AND COMPLEXES The ret ina contains four vascular plex uses t hat form t wo complexes. 28 From most anterior to most posterior these are the nerve fiber layer plexus, the ganglion cell layer plexus, the intermediate capillary plexus, and the deep capillary plexus. The nerve fiber layer plexus and ganglion cell layer plexus are both

named for the anatomic layers in which they are found. The nerve fiber layer plexus also called the radial peripapillary capillary plexus near the optic disk. Together the nerve fiber layer and ganglion cell layer plexuses form the superficial vascular complex, while the intermediate and deep capillary plexuses form the deep vascular complex. Table 1 shows the relationship between retinal plexuses and anatomic layers.

■■VESSEL METRICS Optical coherence tomography angiography is used to measure vessel metrics. The most common are vessel densities, which can be measured as area density (the number of flow pixels divided by the total number of pixels in an en face image of a vascular plexus or complex), line density (similar measurement made after vessels have been skeletonized, leading to a length/area ratio), or volume density (vascular voxels as a fraction of total number of voxels within a tissue volume).29 Vessel density measurements is used to quantify tissue perfusion and detect pathological loss of vessels. 30-32 Other vessel metrics use to detect pathology include measurement of the vessel area of neovascularization,33 area of dilated capillaries,34 fractal dimension,35,36 and tortuosity.37

■■REFERENCES 1. 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. 2. Camino A, Jia Y, Liu G, Wang J, Huang D. Regression-Based Algorithm for Bulk Motion Subtraction in Optical Coherence Tomography Angiography. Biomed Opt Express 2017; 8:3053–3066. 3. Camino A, Zhang M, Gao SS, et al. Evaluation of artifact reduction in optical coherence tomography angiography with real-time tracking and motion correction technology. Biomed Opt Express 2016; 7:3905–3915. 4. Kraus MF, Potsaid B, Mayer MA, et al. Motion correction in optical coherence tomography volumes on a per A-scan basis using orthogonal scan patterns. Biomed Opt Express 2012; 3:1182–1199. 5. Makita S, Hong Y, Yamanari M, Yatagai T, Yasuno Y. Optical coherence angiography. Opt Express 2006; 14:7821–7840. 6. Wei X, Camino A, Pi S, et al. Fast and robust standard-deviation-based method for bulk motion compensation in phase-based functional OCT. Opt Lett 2018; 43:2204–2207. 7. Vienola KV, Braaf B, Sheehy CK, et al. Real-time eye motion compensation for OCT imaging with tracking SLO. Biomed Opt Express 2012; 3:2950– 2963. 8. Braaf B, Vienola KV, Sheehy CK, et al. Real-time eye motion correction in phase-resolved OCT angiography with tracking SLO. Biomed Opt Express 2013; 4:51–65. 9. Wei X, Hormel TT, Guo Y, Hwang TS, Jia Y. High-resolution wide-field OCT angiography with a self-navigation method to correct microsaccades and blinks. Biomed Opt Express 2020; 11:3234–3245. 10. Zhang Q, Huang Y, Zhang T, et al. Wide-field imaging of retinal vasculature using optical coherence tomography-based microangiography provided by motion tracking. J Biomed Opt 2015; 20:066008. 11. Hormel TT, Wang J, Bailey ST, Hwang TS, Huang D, Jia Y. Maximum value projection produces better en face OCT angiograms than mean value projection. Biomed Opt Express 2018; 9:6412–6424. 12. Patel RC, Wang J, Hwang TS, et al. Plexus-Specific Detection of Retinal Vascular Pathologic Conditions with Projection-Resolved OCT Angiography. Ophthalmol Retina 2018; 2:816–826. 13. Su JP, Chandwani R, Gao SS, et al. Calibration of optical coherence tomography angiography with a microfluidic chip. J Biomed Opt 2016; 21:86015. 14. Jia Y, Bailey ST, Hwang TS, et al. Quantitative optical coherence tomography angiography of vascular abnormalities in the living human eye. Proc Natl Acad Sci USA 2015; 112:E2395–E2402.

15. Liu L, Edmunds B, Takusagawa HL, et al. Projection-Resolved Optical Coherence Tomography Angiography of the Peripapillary Retina in Glaucoma. Am J Ophthalmol 2019; 207:99–109. 16. Hormel TT, Huang D, Jia Y. Artifacts and artifact removal in optical coherence tomographic angiography 2021; 11:1120–1133. 17. Wang J, Zhang M, Hwang TS, et al. Reflectance-based projection-resolved optical coherence tomography angiography [Invited]. Biomed Opt Express 2017; 8:1536–1548. 18. Zhang M, Hwang TS, Campbell JP, et al. Projection-resolved optical coherence tomographic angiography. Biomed Opt Express 2016; 7:816–828. 19. Guo Y, Hormel TT, Xiong H, et al. Development and validation of a deep learning algorithm for distinguishing the nonperfusion area from signal reduction artifacts on OCT angiography. Biomed Opt Express 2019; 10:3257–3268. 20. Guo Y, Camino A, Zhang M, et al. Automated segmentation of retinal layer boundaries and capillary plexuses in wide-field optical coherence tomographic angiography. Biomed Opt Express 2018; 9:4429–4442. 21. Srinivasan PP, Heflin SJ, Izatt JA, Arshavsky VY, Farsiu S. Automatic segmentation of up to ten layer boundaries in SD-OCT images of the mouse retina with and without missing layers due to pathology. Biomed Opt Express 2014; 5:348–365. 22. Yin X, Chao JR, Wang RK. User-guided segmentation for volumetric retinal optical coherence tomography images. J Biomed Opt 2014; 19:086020. 23. Zang P, Wang J, Hormel TT, Liu L, Huang D, Jia Y. Automated segmentation of peripapillary retinal boundaries in OCT combining a convolutional neural network and a multi-weights graph search. Biomed Opt Express 2019; 10:4340–4352. 24. Jia Y, Tan O, Tokayer J, et al. Split-spectrum amplitude-decorrelation angiography with optical coherence tomography. Opt Express 2012; 20:4710–4725. 25. Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science 1991; 254:1178–1181. 26. Chen Z, Rank E, Meiburger KM, et al. Non-invasive multimodal optical coherence and photoacoustic tomography for human skin imaging. Sci Rep 2017; 7:17975. 27. Liang H, Peric B, Hughes M, Podoleanu A, Spring M, Saunders D. Optical coherence tomography for art conservation and archaeology. O3A Opt Arts Archit Archaeol 2007; 6618:661805. 28. Campbell JP, Zhang M, Hwang TS, et al. Detailed Vascular Anatomy of the Human Retina by Projection-Resolved Optical Coherence Tomography Angiography. Sci Rep 2017; 7:42201.

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Section 1: Methods and techniques of oct angiography examination 29. Wang B, Camino A, Pi S, et al. Three-dimensional structural and angiographic evaluation of foveal ischemia in diabetic retinopathy: method and validation. Biomed Opt Express 2019; 10:3522–3532. 30. Durbin MK, An L, Shemonski ND, et al. Quantification of retinal microvascular density in optical coherence tomographic angiography images in diabetic retinopathy. JAMA Ophthalmol 2017; 135:370–376. 31. Toto L, Borrelli E, Di Antonio L, Carpineto P, Mastropasqua R. Retinal vascular plexuses’ changes in dry age-related macular degeneration, evaluated by means of optical coherence tomography angiography. Retina 2016; 36:1566–1572. 32. Triolo G, Rabiolo A, Shemonski ND, et al. Optical coherence tomography angiography macular and peripapillary vessel perfusion density in healthy subjects, glaucoma suspects, and glaucoma patients. Invest Ophthalmol Vis Sci 2017; 58:5713–5722.

33. Jia Y, Bailey ST, Wilson DJ, et al. Quantitative optical coherence tomography angiography of choroidal neovascularization in agerelated macular degeneration. Ophthalmology 2014; 121:1435–1444. 34. Hwang TS, Gao SS, Liu L, et al. Automated quantification of capillary nonperfusion using optical coherence tomography angiography in diabetic retinopathy. JAMA Ophthalmol 2016; 134:367–373. 35. Bhardwaj S, Tsui E, Zahid S, et al. Value of Fractal Analysis of Optical Coherence Tomography Angiography in Various Stages of Diabetic Retinopathy. Retina 2017; 38:1816–1823. 36. Zahid S, Dolz-Marco R, Freund KB, et al. Fractal Dimensional Analysis of Optical Coherence Tomography Angiography in Eyes With Diabetic Retinopathy. Invest Opthalmol Vis Sci 2016; 57:4940–4947. 37. Yasuda S, Kachi S, Kondo M, Ueno S, Kaneko H, Terasaki H. Significant correlation between retinal venous tortuosity and aqueous vascular endothelial growth factor concentration in eyes with central retinal vein occlusion. PLoS One 2015; 10:e0134267.

Chapter 4 OCT angiography in everyday clinical practice Bruno Lumbroso, Marco Rispoli, Maria Cristina Savastano

■■INTRODUCTION Optical coherence tomography (OCT) angiography clinical applications in everyday clinical practice have improved and made easier diagnosis and follow-up of retinal disorders. They help the ophthalmologist in his everyday problems of diagnosis in the frequent, less frequent, and difficult cases. The first OCT angiography (OCTA) devices appeared in clinics 6 years ago and their diffusion was immediate and massive. The impact of OCTA has been huge and very fast in all countries. Optical coherence tomography angiography applications have entered everyday normal clinical practice, leading to a progressive decrease in the use of fluorescein angiography (FA) as OCTA is easier, faster, and noninvasive. OCTA has become a very helpful diagnostic device even if there are some practical challenges to applying this technology in everyday practice. Interpretation is not easy at the outset and the learning curve is abrupt. Difficulties in OCTA reading comprise interpretation, segmentation, and projection artifacts.

■■COMPARISON TO FLUORESCEIN ANGIOGRAPHY Fluorescein angiography is a widely used imaging modality and was, until few years ago, the gold standard for multiple retinal conditions including retinal and choroidal neovascularization (CNV). FA is still valid in many disorders, including inflammatory conditions, as it documents leakage and gives a wide field of view. OCTA is for the moment unable to detect leakage.

■■ADVANTAGES OF OCT ANGIOGRAPHY Major advantages of OCTA over FA include its quick imaging time, noninvasiveness, and lower cost. The most obvious advantage of OCTA over FA is that it is noninvasive, although the risks of fluorescein injection are relatively low. Image acquisition speed is much shorter than 5–15 minutes we wait for late-phase FA images, and it eliminates the time needed for preparing f luorescein injection. It significantly improves clinic flow. The image detail and resolution are remarkable, and there are no focusing issues as can be seen with traditional angiography. OCTA images are much more detailed and are not obscured by leakage from damaged vessel walls. OCTA has the capability to segment layers of the retina and deep vasculature. For example, one can image the deep retinal capillary plexus separate from the overlying superficial vessels. Using this segmentation feature, one can better identify early changes to the foveal avascular zone in patients with diabetic retinopathy and understand and visualize conditions affecting the middle retina [e.g. paracentral acute middle maculopathy (PAMM)].

Visualization of the choroid and choriocapillaris provides unique insights into patients with recently recognized conditions such as pachychoroid pigment epitheliopathy and choroidal sclerosis, or atrophy. It is superior to indocyanine green (ICG) when evaluating the details of these hard-to-image layers. OCTA enables us to perform quantitative measurements on blood flow in the eye, which allows perfusion mapping of the macula.

■■DISADVANTAGES OF OCT ANGIOGRAPHY The principal difficulty to OCTA use is the device cost and a lack of increased reimbursement for use of a new imaging modality. Physicians are not paid any more for OCTA than for traditional OCT, despite the additional time required and the cost of the technology. Note that when the device is acquired, the costs of everyday use are much inferior to those of FA. From a clinical perspective, there are few disadvantages to adopting OCTA. The most obvious is the fact that OCTA is a “static” imaging technique, whereas FA is dynamic. Currently, many spectral-domain OCT systems have a maximum field of view of around 8 × 8 mm. However, numerous devices will get wide angle field in a short time.

■■OCT ANGIOGRAPHY CONTRIBUTION TO RETINAL DISORDERS STUDY, MONITORING, AND TREATMENT IN EVERYDAY CLINICAL PRACTICE Optical coherence tomography angiography contribution to retinal disorders in everyday practice can be divided into two main groups: 1. Inner retinal disorders as epiretinal membranes, maculopathies, retinopathies, vascular acquired or congenital disorders, and malformations 2. Outer retinal and choroidal disorders, mainly neovascularization (NV).1

■■Vascular modifications due to aging Vascular aging modifications are normal. In superficial plexus in young man 20 years old, the capillary net is dense, meshes are regular. Avascular zone is regular with continuous arcade. In man, 80 years old, the capillary net is less dense, less regular, meshes are wider, avascular zone is wider with slightly interrupted arcade. In deep plexus, we observe similar differences due to aging (Figures 1A to D).

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Figures 1A to D  (A) Superficial plexus in young man 20 years old. Capillary net is dense, meshes are regular. Avascular zone is regular with continuous arcade. (B) Superficial plexus in man 80 years old. Capillary net is less dense, less regular, meshes are wider. Avascular zone is wider with slightly interrupted arcade. (C) Deep plexus in young man 20 years old. Capillary net is dense, regular. Avascular zone is regular with continuous arcade. (D) Deep plexus in man 80 years old. Capillary net is less dense, less regular. some capillaries are wider. Avascular zone is wider with irregular arcade.

■■Inner retinal disorders

Superficial retinal anomalies, epiretinal membranes and macular pucker, holes and pseudoholes Epiretinal membranes, pucker, retinal folds, and retraction cause course anomalies at level of the superficial plexus. The vessels lose

most of their normal network features and mostly follow the folds course (Figures 2A and B).

Vascular disorders Vascular diseases of the eye were the first disorders whose study and treatment were influenced and improved by the use of OCTA. In all vascular disorders, OCTA greatly helps diagnosis and

CHAPTER 4: Oct angiography in everyday clinical practice Figures 2A and B  (A) Macular pucker: Retinal folds and retraction cause course anomalies at level of the superficial plexus that loses normal spider-net features and follows the folds course; (B) Macular pucker: Deep plexus is difficult to explore due to superficial retinal opacities. The radial retinal folds are better seen in en face OCT.

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follow-up by highlighting to the ophthalmologist the vascular conditions in each case.

Retinal anomalies and Coats’ disease Leber–Coats’ disease presents telangiectasia and aneurysmal vasodilation. 2 In the later stages of the disorder, exudates and exudations appear. In OCTA, at the level of the superficial plexus, the vessels lose some or most of their collateral branches. They show harmonious shaped waves. The capillaries are rarefied and vasodilatation and aneurysms are evident. At deep plexus level, capillary dropout is even more evident, as flow alterations and morphological anomalies. The capillar y fans are ver y irregular. Inside the deep vascular net, we can see flow anomalies (vasodilation) more evident in the deeper levels (Figures 3A and B).

Macular telangiectasia In macular telangiectasia (MacTel) type 2, the vascular alterations are mainly detectable in the deep vascular plexus (DVP) and much better detectable with OCTA rather than with fluorangiography.3 Progressive capillary rarefaction, dilation of the vessels, and abnormal anastomosis appear. Subsequently, the OCTA shows anastomoses between the superficial and deep vascular networks. In 15% of cases, intraretinal neovascular membranes appear after a long evolution, diagnosed without difficulty with OCTA (Figures 4A and B).

Macroaneurysms Optical coherence tomography angiography shows the macro­ aneurysm as a rounded cavity located in the deep retinal vascular plexus level. It is surrounded by edema. After laser treatment, the vascular anomaly and edema disappear (Figures 5A and B).

Diabetic retinopathy Optical coherence tomography angiography allows to analyze the structure, level, and topography of microvascular anomalies associated with diabetic retinopathy, especially by scanning microaneurysms and other intraretinal microvascular anomalies.4 It also allows to follow the evolution of diabetic macular edema and eventually the NV. An important point is the possibility of quantitatively measuring macular perfusion and analyzing the various vascular plexuses at different levels. The absence of fluorescein avoids dye leakage and therefore the masking of many points of interest. Recent studies have revealed the relationships between macular perfusion and retinal peripheral perfusion. Other studies have shown a relationship between macular perfusion and the developmental stage of diabetic retinopathy. The OCTA highlighted the importance of the size of the avascular foveal area and the vascular density useful for assessing macular perfusion.

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Section 1: Methods and techniques of oct angiography examination Figures 3A and B  (A) Coats’ disease: At superficial plexus level, the vessels are twisted irregular and display many areas of capillary loss and some loops. The capillaries are rarefied and show anomalies in size, some microaneurysms are apparent; Crosssection scan displays a typical cystoid edema. (B) Coats’ disease: At deep plexus level, capillary irregularities and dropout areas, size alterations, flow alterations, and morphological anomalies are obvious. Capillary fans and avascular zone are very uneven. Cross-section scan shows cystoid edema.

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Figures 4A and B  (A) Macular telangiectasia. Superficial retinal vessels lose most of their collateral branches and present loops and twirls. Capillaries are rare with enlarged sections and macroaneurysms; Crosssection scan shows retinal irregular, angular cavities, and pigment deposits. (B) Macular telangiectasia. At deep plexus level, we observe evident flow alterations. The capillary fans are irregular. Avascular zone is wider and irregular. Cross-section scan shows retinal irregular cavities and pigment deposits.

Optical coherence tomography angiography can also be used to assess the visual prognosis. Vision may be associated with the degree of loss of capillaries in the deep vascular network. Fluorescein diffusion leakage is useful in some diagnostic features. Cunha-Vaz and his team developed OCTA software capable of measuring leakage and therefore replacing, at least in part, the fluorangiography dye.

Diabetic patients without retinopathy—the avascular zone In diabetic patients, even in the absence of retinopathy, OCTA shows that the avascular foveal area is larger than in healthy individuals. Even before the onset of diabetic retinopathy, as there are changes in the macular capillary network. The size of some capillaries increases, some are thicker while others are

CHAPTER 4: Oct angiography in everyday clinical practice

A Figures 5A and B  (A) Macroaneurysm: Top row—OCTA. Dropout areas are evident and the macroaneurysm is seen as a rounded flow; Second row: En face OCT shows the hard exudates; Bottom row: OCTA—crosssection scan. Macroaneurysm: A rounded cavity is surrounded by cystoid edema cells. There are hard exudates around the vascular lesion. (B) Macroaneurysm: The macroaneurysm is seen as an irregular flow, surrounded by a dark halo.

B

closed and thus, we see a looser network with larger and sparser meshes. There is an increase in the size of the foveal avascular area that normally is about 500 μ large. This early sign appears before microaneurysms and at this stage the condition is still reversible. As retinopathy evolves more marked alterations will appear such as mild congestion of capillaries and some dilation. The presence of small nonperfused areas at the posterior pole will lead to the occlusion of small branches; the network becomes at first more irregular, and later, the small areas of ischemia will grow and then merge with the central enlarged avascular area (Figures 6 and 7).

Background diabetic retinopathy In patients with background retinopathy, capillary nonperfusion areas, evident. OCTA shows a larger number of capillary loops and arteriovenous anastomoses. At the level of the deep capillary vascular plexus, the capillary dropout is more evident. Changes in size, in flow, and in the morphology of the plexus are obvious. Often the scarce capillaries have the shape of a fan. The connections between superficial and deep vascular network are evident; these are not seen on the fluorangiography. OCTA offers a much better view of shunts, deep connections, and vascular loops. The deep new vessels are more clearly seen than with angiography. Rare retinal

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Section 1: Methods and techniques of oct angiography examination Figure 6  Diabetic nonproliferative retinopathy. Superficial vascular plexus: Retina shows microaneurysms and irregular capillary dropout areas. The size of the foveal avascular area is increased. This is an early sign that goes before the onset of the diabetic retinopathy and microaneurysms. The level of ischemic retinal damage is in the superficial capillary plexus is defined “disorganization of the internal layers of the retina” (DRIL). DRIL may be seen in some vascular disorders; however, it is mainly observed in diabetic retinopathy. The structural OCT in the DRIL shows a loss at the level of the internal retinal layers, from the ganglion complex to the internal nuclear layer while the NFL and outer retina remain intact.

Figure 7 Diabetic nonproliferative retinopathy. Deep vascular plexus: microaneurysms, enlargement avascular zone. Increase in the size of the foveal avascular area and microaneurysms. Vascular fans are irregular. Dropout areas are augmented.

hemorrhages are visible as masked areas. OCTA does not show up all the microaneurysms—those evident are the ones where there is blood flow.

Advanced diabetic retinopathy and retinal ischemia Retinal ischemia, with OCTA is much sharper than as with fluorangiography because there is no masking effect by dye leakage. In OCTA, the ischemic areas can be easily identified on the basis of texture and of flow alterations (Figure 8). Initial NV is seen as thickened and irregular vessels that may emerge from the surface of the retina or from the optic disk (Figure 8).

Proliferative diabetic retinopathy The natural evolution of ischemic area in diabetic retinopathy is characterized by the progressive formation of new vessels. OCTA

of preretinal and prepapillary neovascular membranes allows the operator to make a very precise evaluation of the extent and morphology of the vascular network without the problems linked to dye leakage (Figure 9).

Vascular occlusions

Central vein and branch vein occlusion OCTA studies have shown marked alterations at the level of the deep vascular network but also marked alterations at the boundary between perfused and nonperfused territory. The OCTA allows to monitor the evolution with great precision and to quantitatively evaluate the transformation of venous occlusions, especially those parcel or branch. In eyes affected by branch vein occlusion, OCTA highlights the vascular network with evident areas of capillary loss that correspond

CHAPTER 4: Oct angiography in everyday clinical practice

Figure 9  Diabetic proliferative retinopathy. OCTA of prepapillary neovascular membranes allows to make a very precise evaluation of the extent and morphology of the proliferative network without any masking by dye leakage. The flow and morphology of the neovascular network are perfectly visible.

Figure 8  Diabetic nonproliferative retinopathy Ischemic areas show sparse capillaries against a dark background. Capillaries inside the wide nonperfusion areas are truncated, showing shunts. Connections with the deep network are well seen.

to areas of nonperfusion in fluorangiography. These areas, however, look sharper because there is no masking effect due to dye leakage. Some capillaries increase in size while many more are closed. We see thus a looser network with larger and sparser meshes and a fine, grayish texture. In venous occlusions, we see changes in the structure of the superficial plexus especially in macular ischemia. The vascular signal (flow) is not linear but has focal deviations, the wall thickness is not regular but shows focal segmentation and lumen narrowing; the vessels course shows abrupt interruptions with some dilation around the avascular foveal area that appears widened. Vessel flow can be segmented. The vascular network is seen more sharply, and the arteriovenous anastomoses and vascular loops are easier to see. The DVP shows more alteration than the superficial plexus. Capillaries distribution is irregular with various deviations in vessel course in nonperfused zone (Figure 10).

Central artery and branch artery occlusion In case of branch artery occlusion, the superficial vascular network loses collateral branches. Capillaries of the deep plexus are more affected by the vascular event. Important capillary dropout is evident, some capillaries increase in size while many more are closed. Deep network is loser with larger and sparser meshes (Figures 11A and B).

Paracentral acute middle maculopathy In acute paracentral maculopathy, OCTA has allowed us to observe the pathophysiology of the vascular disease, highlighting the abrupt, acute or chronic, decrease in the flow of the deep vascular network and other plexuses.

Figure 10  Branch vein occlusion. In the occluded area, capillary dropout is seen, some capillaries increase in size while many more are closed. We see a looser network with larger and sparser meshes. Increase in the size of the foveal avascular area.

■■Outer retinal disorders neovascular membranes in age-related macular degeneration

The OCTA of neovascular membranes allows a ver y precise evaluation of the extent and morphology of the network without the problems linked to dye leakage or staining. Flow and morphology of the neovascular network are always visible.5 OCTA in the follow-up of intravitreal treatments allows to observe the regression of the new vessels. Optical coherence tomography angiography shows the all neovascular branches where blood is flowing and allows a precise diagnosis detecting directly both nonexudative and exudative NV and giving a better understanding of other retinal abnormalities physiopathology. Structural OCT can identify exudation from these vessels. Nonexudative NVs are not seen on FA. FA and ICG

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Section 1: Methods and techniques of oct angiography examination

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B Figures 11A and B  (A) Branch artery occlusion, superficial network. With OCTA, it is possible to highlight the main superficial retinal vessels in the arterial occluded area. Some, but not all the collateral branches are indiscernible after the ischemic event. This feature concerns and the superficial vascular plexus deep before vascular. (B) Branch artery occlusion, deep network. The capillaries of the deep plexus are intensely interested by arterial occlusion. In the occluded area capillary dropout is observed. Some capillaries increase in size while many more are closed. Vessels are fragmented, uneven and irregular. Vascular network, when seen, shows a wider network with larger meshes. Cross-section scan in the first weeks after the event displays a thick edema of the inner layers, while deep outer layers look quite normal. En face OCT allows a sharp, precise assessment of the occluded area.

angiography (ICGA) are still useful in some cases, but OCTA is fast replacing them. When clinical and OCT symptoms consistent with NV are observed, our first step is to perform OCTA. Most of the time, if OCTA demonstrates NV, FA may not be necessary, and treatment can begin immediately. Type 1 CNVs are located below retinal pigment epithelium (RPE) and above Bruch’s membrane above the choroid. The new vessels are thin and irregular, inside fibrovascular tissue. Their shape is difficult to define and describe. A feeder trunk can almost or a bunch of feeder vessels are difficult to identify. Anastomoses are irregular (Figure 12). Ty pe 2 CN Vs are located above t he pigment epit helium (Figure 13). OCTA may show the neovascular membranes as cartwheels or bicycle wheels with anastomoses of the peripheral branches that have the peculiarity of being.

Figure 12 Type 1 CNV. The new vessels are thin, irregular with a continuous arcade. A feeder trunk is present but difficult to identify. Anastomoses are irregular. In the cross-section scan, we localize the NV below retinal pigment epithelium (RPE) and above Bruch’s membrane above the choroid. There is a small fluid elevation of the retina.

Type 3 CNVs are the less, located inside the nonvascular outer retina. They appear as irregular rounded flow formations observed at the level the outer retina layers (Figure 14).

Post-treatment monitoring of NV flows On the day following the injection of anti-vascular endothelial growth factor (anti-VEGF), many neovascular branches disappear, showing only thinned and sparse residual branches. The vascular network, however, is again visible after 7–10 days. The new vessels regression almost always precedes the reabsorption of the subretinal or subepithelial fluid and of the edema. After repeated treatment, OCTA shows thin and irregular networks inside the connective tissue. A partial regression of the new vessels can be observed. There are different long-term responses to therapy, due to both the efficacy of the therapeutic substance and the chronic nature of the disorder.

Neovascularization flows in scars In the more advanced NV forms, the OCTA shows an irregular vascular network inside a capsular formation. The capillaries

CHAPTER 4: Oct angiography in everyday clinical practice

Figures 13 Type 2 CNV is located above retinal pigment epithelium (RPE). The neovascular membrane has a medusa-like aspect, with fine ramifications that seem to infiltrate the subretinal (outer retina) and choriocapillaris. New vessels are thin and irregular. A feeder trunk is present. Anastomoses are regular.

Figure 14 Type 3 CNV is located inside nonvascular outer retina. We observe an irregular rounded flow formation. A feeder trunk is present. However, it is difficult to identify. Anastomoses are irregular. The cross-section scan shows the neovascular membrane, cystoid edema, subretinal fluid, hard exudates, and pigment epithelium detachment.

Figure 15  Neovascular membrane in myopic eye. Neovascular membrane is seen as an irregular close-knit flow formation at the level the deeper retina layers, in contact with retinal pigment epithelium (RPE). It is a type 2 CNV. In this case, we do not see the vascular arcade nor the typical myopic glomerular features. Cross-section scan shows a dense flow formation at the level the deeper retina layers, in contact with RPE. We also see a small fluid elevation of the retina.

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Section 1: Methods and techniques of oct angiography examination

are thin and irregular inside nonvascular tissue. The OCT scan will need thickness necessary to detect residual flows inside the fibrotic tissue.

Neovascular membranes in myopic eyes Optical coherence tomography angiography highlights neovascular membranes in myopic eyes as irregular flow formations observed at the level the deeper retina layers, in contact with RPE. Subretinal myopic new vessels are thin and irregular, at times with a glomerular feature, frequently corresponding to scleral tunnels (Figure 15).

■■OCT ANGIOGRAPHY IN RURAL TERRITORIES, LOW MEDICALIZED AREAS, OR UNDERDEVELOPED COUNTRIES Optical coherence tomography angiography has rapidly shown to be helpful not only for the eye specialist in normal conditions, but also for the lonely specialist located far from medical centers, in difficult conditions. It has a bearable cost and allows fast examination with low resources and reduced personnel, simplicity, and speed of execution of the assessment. It is noninvasive, complement to the structural OCT examination (same equipment), repeatable as many times as necessary. It gives information to elect therapy in the shortest possible time, immediately verify the clinical diagnostic suppositions, follow the evolution of a disease, and confirm the efficacy of a therapy. Optical coherence tomography angiography has revealed itself to be a great help for ophthalmologist on his own, isolated in a large rural territory, a medical desert or underdeveloped countries. The ophthalmologist gets the diagnostic faster, and may decide the treatment immediately for many ocular diseases of anterior segment

and posterior segment. It has a very large field of use: Age-related macular degeneration (AMD), diabetes, before cataract surgery, high astigmatism, refractive surgery follow-up, glaucoma, neurological diseases—Parkinson, Alzheimer, and cognitive problems. Optical coherence tomography angiography has earned a prominent and central role in the clinical work organization of a rural ophthalmology office in a little medicalized area, far from big hospitals with imaging centers where fluorescein or ICGA can be realized. Here is an example of time schedule in a rural area where there is no OCTA: Refraction—2 minutes, decide investigations—OCT, mydriasis—10 minutes, OCT—5 minutes, interpretation OCT—5 minutes. The Imaging center in hospital (FA) is at 70 km, telephone for appointment; arrangements FA about 10 days, treatment decision— intravenous thrombolysis (IVT), time for diagnosis and treatment decision—10 days and 40 minutes. If the specialist has OCTA technology: refraction—2 minutes, decide investigations—OCTA, mydriasis—10 minutes, doing OCTA, retina and optic nerve examination, 15 minutes, treatment decision—IVT, total time for diagnosis and treatment decision—17 minutes. Fluorescein angiography use is now decidedly decreased, and it is no more used systematically. Optical coherence tomography angiography is very convenient when the ophthalmologist is alone in a large territory. It brings to patients a necessary safety, and gives to the lonely specialist comfort for an exact diagnosis, and a suitable treatment. Internet consents professional improvement of the remote and lonely specialist, with possibility of telematic consultation with an “expert” colleague, in a distant town or a different country. Optical coherence tomography angiography obviously is the technology of present and future, for ophthalmologists in highly medicalized area and, even more in unwell medicalized, rural area or underdeveloped countries. OCTA has become the best standard diagnostic method for the lone ophthalmologist, isolated in a medical desert. It is also the future for all ophthalmologists.

■■REFERENCES 1. Gariano RF. Special features of human retinal angiogenesis. Eye (Lond) 2010; 24:401–407. 2. Jones JH, Kroll AJ, Lou PL, Ryan EA. Coats’ disease. Int Ophthalmol Clin 2001;41:189–198. 3. Yannuzzi LA, Bardal AM, Freund KB, et al. Idiopathic macular telangiectasia. 2006. Retina 2012; 32:450–460.

4. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet 2010; 376:124–136. 5. Jia Y, Bailey ST, Wilson DJ, et al. Quantitative optical coherence tomography angiography of choroidal neovascularization in age-related macular degeneration. Ophthalmology 2014; 121:1435–1444.

Chapter 5 Retinal normal vascularization Maria Cristina Savastano, Marco Rispoli, Bruno Lumbroso

■■INTRODUCTION Our understanding of the retinal vascular networks derived from pioneering studies on primate histology.1 In the past, the anatomy could only be seen in histological sections and vessel casts. With the study of the anatomy of the retina using optical coherence tomography (OCT) angiography, we see the histological vascular structure of the retina in vivo without the using any dye.2 Understanding OCT angiography imaging demands in-depth knowledge of histology. The classical anatomic studies carried out in the first half of the 20th century showed that the distribution of retinal vessels is organized into three distinct layers: (1) superficial plexus, observable with the ophthalmoscope with the large and average sized vessels distributed in the retinal nerve fiber layer (NFL); (2) inner plexus, a body of small-sized capillaries located close to the inner surface of the internal nuclear layer; and (3) outer plexus, morphologically similar to the internal plexus but located on the outer surface of the external plexiform layer.3 The OCT angiography has confirmed these studies in vivo and allows us to study separately the two vascular plexuses, the superficial vascular plexus (SVP) and the complex internal/ external plexus that we have considered as a single deep plexus. The two plexuses clearly have different features that cannot be distinguished by classical fluorescein angiography (FA) (Figure 1).4

FA

With dye

In FA, SVP and deep vascular plexus (DVP) are overlapped and therefore cannot be assessed separately. The visualization of both plexuses does not make it possible to analyze the superficial and deep vascular features that could be involved separately in some pathological disorders. In healthy eyes, the superficial plexus consists of larger vessels with respect to the deep complex: both plexuses are distributed according to a centripetal pattern around the avascular foveolar zone. The deep plexus consists of small fan-shaped vessels that interconnect to form a complex pattern. The SVP is supplied by the central retinal artery and composed of larger arteries, arterioles, capillaries, venules, and veins vessels primarily in the ganglion cell layer (GCL). There are two deeper capillary networks above and below the inner nuclear layer (INL) referred to as the “intermediate” and “deep” capillary plexuses, or intermediate vascular plexus (IVP) and DVP, respectively, which are supplied by vertical anastomoses from the SVP (Figure 2 and 3). 5 The fourth plexus is the radial peripapillary vascular plexus (RPVP) that runs in parallel with the NFL axons. Campbell et al. recently introduced a new nomenclature of vascular complexes and plexuses.6 The transition from FA to OCT angiography implies a qualitative change in the way images are looked at. At the beginning, OCT angiography allows only the study of the posterior pole inside the

OCTA superficial plexus

OCTA deep plexus

Without dye

Figure 1  Fluorescein angiography (FA) shows the details of retinal vascular layers after the vein dye injection. By FA implies the overlapped analysis of superficial capillary plexus (SCP) and deep capillary plexus (DCP). OCT angiography (OCTA) allows the study of singular vascular layer without dye.

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Section 1: Methods and techniques of oct angiography examination

Superficial plexus

angioFLOW

Intermediate plexus

angioFLOW

Deep plexus

angioFLOW

Figure 2  The superficial vascular plexus (SVP) is composed of arterioles, capillaries, venules, and veins primarily in the ganglion cell layer (GCL). There are two deeper capillary networks above and below the inner nuclear layer (INL) referred to as the “intermediate” and “deep” capillary plexuses, or intermediate vascular plexus (IVP) and deep vascular plexus (DVP), respectively, which are supplied by vertical anastomoses from the SVP.

Nerve fiber layer Superficial capillary plexus

Ganglion cell layer

Intermediate capillary plexus

Inner plexiform layer

Deep capillary plexus

Inner nuclear layer

Outer plexiform layer

Outer nuclear layer

A

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Figures 3A and B  The two vascular plexuses are connected by small slanted interconnection anastomoses between the superficial and deeper vessels. From the lower extremity of the vertical or diagonal connecting anastomoses, horizontal vessels fan out that interconnect to form a complex pattern.10

vascular arcades and the optic disk. Currently new devices are able to study a large retinal vascular area in using wide field (Figures 4A and B).

■■ARTERIES AND RETINAL VEINS The optic disk has a diameter of 1,500 μm while the retinal veins at the edge of the disk have a maximum diameter of around 120 μm. In the midperiphery, the veins have an average diameter of 60 μm. The retinal arteries have a smaller diameter: 80 μm at the edge of the disk, and 50 μm in midperiphery. In contact with the retinal vessels, in the periarterial avascular area, the capillaries are very

rare, virtually absent. Sizes of the arterial and venous capillaries of the retina range between 5 and 10 μm.

■■RETINAL VASCULAR PLEXUS The sensory retina is supplied with two clearly distinct systems: (1) superficial and (2) deep. Some authors divide the deep plexus in two (inner and outer) nets. The two parts of the deep plexus cannot be clearly differentiated, since the smaller of 30 μm structures do not have sufficient resolution to give clinically useful imaging. These two parts of the deep plexus are generally considered as a single vascular entity.

CHAPTER 5: Retinal normal vascularization

A

B

Figures 4A and B  (A) Superficial vascular plexus (SVP) study by OCT angiography composite of 4 patterns of 9 × 9 mm for a full field of 18 × 18 mm. The image was acquired by Solix FullRange OCT (Optovue Inc., Freemont CA, USA). (B) Deep vascular plexus (DVP) study by OCT angiography composite of 4 patterns of 9 × 9 mm for a full field of 18 × 18 mm. The image was acquired by Solix FullRange OCT (Optovue Inc., Freemont CA, USA).

■■Superficial vascular plexus It is located in the GCL and in the NFL. The feature of SVP is similar to the spider web.5

■■Deep vascular plexus It is located in the INLs and external plexiform. From the anatomical standpoint, this plexus consists of two additional nets located respectively on the inside of the inner nuclear and on the outside of the outer plexiform layer. They cannot be individually seen by the OCT angiography devices and therefore in this chapter we consider them to be a single plexus. The feature of DVP are small complex fans with multiple interconnections with irregular features around the foveal avascular zone.5 In order to study, the two vascular plexuses all devices used default parameters in the intraretinal level [inner limiting membrane (ILM), inner plexiform layer (IPL), retinal pigment epithelium (RPE), the thickness of the scan being examined and the offset. The SVP is represented by the large retinal vessels located in the innermost layers who measure on average 120 µm. The DVP extends between the innermost portion and outer portion of the outer plexiform layer that measures on average around 60 µm in heathy eyes. The SVP and DVP are strictly interconnected by multiple horizontal and vertical interconnections (Figure 5). Intermediate and deep plexuses cannot be easily individually seen by the OCT angiography and therefore we consider them as a single plexus. Superficial plexus: The features of the superficial plexus show multiple linear vessels converging toward the fovea and originating from the large upper and lower vascular arcades. Secondary vessels leave the main vessels, forming a web. The thickness of the vessels is homogeneous throughout the length of the scan. The web is

grossly regular without vascular meanders or loops. Around the avascular area, the capillaries form continuous perifoveal arcades with regular meshes. Intermediate vascular plexus: The IVP has been visualized, thanks to new device evolution algorithms.7,8 The morphological features are recognized very similar to the deep plexus, so some researchers considered only one layer including the deep plexus for the clinical application. However, the recognition of IVP become important especially in case of vascular diseases involving the deep layer.9 Deep plexus: It consists of vessels whose orderly pattern distribution around the avascular foveal zone presents interwoven thin horizontal and radial interconnections. The pattern is concentric around the avascular foveal zone. Thickness of the vessels is constant throughout the scan as is their flow. Connections between superficial and deep nets: The two vascular net works are connected by small slanted interconnection anastomoses between the superficial and deeper vessels. From the lower extremity of the vertical or diagonal connecting anastomoses, horizontal vessels fan out that interconnect to form a complex pattern.10 This complex pattern is divided into two layers by some authors (Figures 3A and B). Avascular foveal zone: Around the avascular area, the capillaries form continuous perifoveal arcades with regular meshes (Figure 5). One of the important OCT angiography limitations is the inability to detect the real exudation features; however, the details observable with new devices may help to observe vascular changes associated to the exudation. Furthermore, the learning curve associated to the association with postprocessing new algorithms allows to measure even the smallest variations both at the retinal and choroidal layers.

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Section 1: Methods and techniques of oct angiography examination Figure 5  New algorithms allow the assessment of foveal avascular zone (FAZ) features as the area (mm2), perimeter (mm), and flow density (FD) around the avascular area (flow in yellow double circle).

■■REFERENCES

1. Provis JM. Development of the primate retinal vasculature. Prog Retin Eye Res 2001; 20:799–821. 2. Jia Y, Tan O, Tokayer J, et al. Split-spectrum amplitude-decorrelation angiography with optical coherence tomography. Opt Express 2012; 20:4710–4725. 3. Hogan MJ, Alvarado JA, Weddell JE. Histology of the human eye: an atlas and textbook. Philadelphia: WB Saunders, 1971. 4. Spaide RF, Klancnik JM Jr, Cooney MJ. Retinal vascular layers imaged by fluorescein angiography and optical coherence tomography angiography. JAMA Ophthalmol 2015; 133:45–50. 5. Savastano MC, Lumbroso B, Rispoli M. In vivo characterization of retinal vascularization morphology using optical coherence tomography angiography. Retina 2015; 35:2196–2203.

6. Campbell JP, Zhang M, Hwang TS, et al. Detailed vascular anatomy of the human retina by projection-resolved optical coherence tomography angiography. Sci Rep 2017; 7:42201. 7. Garrity ST, Iafe NA, Phasukkijwatana N, Chen X, Sarraf D. Quantitative analysis of three distinct retinal capillary plexuses in healthy eyes using optical coherence tomography angiography. Invest Ophthalmol Vis Sci 2017; 58:5548–5555. 8. Hormel TT, Jia Y, Jian Y, et al. Plexus-specific retinal vascular anatomy and pathologies as seen by projection-resolved optical coherence tomographic angiography. Prog Retin Eye Res 2021; 80:100878. 9. Scharf J, Freund KB, Sadda S, Sarraf D. Paracentral acute middle maculopathy and the organization of the retinal capillary plexuses. Prog Retin Eye Res 2021; 81:100884. 10. Duke-Elder S. The anatomy of the visual system. London: Henry Kimpton Publishers, 1961:372–376.

Chapter 6 Corneal and anterior segment OCT angiography Yan Li, David Huang, Yali Jia

■■ABSTRACT Corneal and anterior segment optical coherence tomography (OCT) angiography was demonstrated using an 840-nm spectraldomain OCT scanner with a corneal adapter module (CAM). Projection-resolved OCT angiography delineates rich conjunctival and scleral vasculatures separately. Iris vessels are clear visible in lightly pigmented eyes, but are obscured to various degrees in darkly pigmented eyes.

■■INTRODUCTION Optical coherence tomography (OCT) provides higher speed and resolution than other noncontact corneal and anterior segment imaging tests. Commercial available OCT systems, either dedicated to anterior eye imaging (such as Casia 2 or Anterion) or hybrid retina/cornea platforms (such as Avanti or Cirrus), have been widely used in managing corneal diseases, monitoring the anterior angle structure, and planning for anterior eye surgeries.

■■ANTERIOR SEGMENT OCT ANGIOGRAPHY Conventional OCT only illustrates the structure information of the biotissue. As OCT technology advances, the new development of OCT angiography offers a precise visualization of intravasal flow without the injection of contrast agents (such as fluorescein or indocyanine green).1,2 OCT angiography was initially applied to evaluate posterior segment eye conditions such as retinopathies or choroidal neovascularization.3,4 In brief, OCT angiography detects motion caused by moving blood cells or flow. Repeated crosssectional images (B-scans) at the same scan location were acquired in order to generate motion contrast. If the tissue is stationary, all the pixels will be the same in repeated B-scans. If there is motion between the repeated B-scans due to blood cells or flow, there will be fluctuations in the OCT signal at pixels where the blood vessels are located. These OCT signal fluctuations can be characterized by decorrelation values calculated at each pixel. Performing a series of repeated B-scans covering an area of interest can create volumetric three-dimensional OCT angiography data. Notably, the inventing of the split-spectrum amplitude-decorrelation angiography (SSADA) and optical microangiography (OMAG) techniques greatly improved the in vivo blood flow detection. 5-7 OCT angiography has been used to delineate vessels in anterior eye. Several studies examined corneal neovascularization with OCT angiography and demonstrated good agreement with indocyanine green angiography (ICGA) for vessel delineation. 8,9 More recent studies used OCT angiography to investigate the vasculature of conjunctiva, sclera, and iris in both normal and pathologic conditions.10-14

In this chapter, we demonstrated OCT angiography in anterior segment of the eye using an ultra-high speed commercial Fourierdomain OCT (Avanti, Optovue Inc., Fremont, CA) with a CAM. The Avanti OCT operates at an 840 nm working wavelength range and generates 70,000 axial-scans per second. An AngioRetina scan pattern (two repeated B-scans at 304 raster positions, each B-scan consisting of 304 axial-scans, one horizontal priority plus one vertical priority raster scan volumes) was used to image the ocular conjunctiva, sclera, and iris of healthy volunteers. Using the CAM lens, the nominal scan sizes of 3 × 3 mm and 6 × 6 mm of the AngioRetina scan pattern correspond to 4.5 × 4.5 mm and 9 × 9 mm actual scan areas on corneal and anterior segment of the eye, respectively. SSADA technique was used to detect flow and construct angiograms.6 Software motion correction was applied to reduced eye motion and combine the horizontal and vertical raster scan volumes (ReVue software version 2018.1.0.56). The merged SSADA data was downloaded from the Avanti OCT.

■■Conjunctival and scleral oct angiography Conjunct iva l and sclera l vasculat ures are responsible for supply i ng ox ygen a nd nut r it ion to t he l i mba l a rea. OCT angiography is helpful documenting the vascular patterns in conjunctival and scleral disease. In order to image a wider area on the ocular surface with Avanti OCT (scan depth is approximately 2 mm in tissue), the subject was instructed to look toward the opposite side of the scan. For example, the subject should rotate his/her eye toward the nasal side if the temporal side of the conjunctiva is scanned. A custom software algorithm was used to identify conjunctival and scleral boundaries and generate depth resolved en face conjunctival and episcleral angiograms by maximum flow projection. The OCT angiograms revealed rich vascular systems in conjunctiva and episclera (Figures 1A to C).

■■Iris OCT angiography Iris angiography is an important method for examination of disorders of the iris and anterior chamber. Light-colored and dark-colored irises of normal volunteers were imaged with OCT angiography. The subjects were instructed to look straight ahead while OCT images were acquired. The iris angiogram exhibited radial iris vessel patterns in normal light-colored eyes (Figures 2A and B). However, OCT operating at 840 nm wavelength penetrates poorly into highly scattering tissues. In dark iris, the anterior pigment layer produced shadowing and flow artifacts that obscure deeper vasculature (Figures 3A and B). OCT angiography working at a longer wavelength can provide better penetration and is needed to reveal vasculature in dark-colored irises.

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Section 1: Methods and techniques of oct angiography examination

Bulbar conjunctival angiogram

Episcleral angiogram

Cross-sectional OCT image overlaid with angiogram Temporal

C

B

1 mm A

Figures 1A to C  En face bulbar conjunctival (A) and episcleral (B) optical coherence tomography (OCT) angiograms of a human eye. The cross-sectional line scan (C) location was denoted by white lines in A and B. Depth resolved conjunctival (pink) and episcleral (yellow) angiography was overlaid on the cross-sectional OCT structure image.

Cross-sectional OCT image overlaid with angiogram

Iris angiogram

1 mm

Figures 2A and B  Iris optical coherence tomography (OCT) angiogram of a light-colored eye. The cross-sectional line scan location was denoted by white lines in A. The iris angiography (pink) was overlaid on the cross-sectional OCT image (B).

B

A

Decorrelation projection

1 mm A

Cross-sectional OCT image overlaid with decorrelation signal

Figures 3A and B  Iris optical coherence tomography (OCT) angiographic en face projection of a dark-colored eye (A). The cross-sectional line scan (B) location was denoted by white lines in A.

B

■■SUMMARY Depth-resolved anterior segment OCT angiography can visualize vascular patterns in conjunctiva, sclera and iris. This technology

is potentially useful for the assessment of anterior eye vasculature and local microcirculation.

CHAPTER 6: Corneal and anterior segment oct angiography

■■REFERENCES 1. Makita S, Hong Y, Yamanari M, Yatagai T, Yasuno Y. Optical coherence angiography. Opt Express. 2006; 14:7821–7840. 2. Wang RK, Jacques SL, Ma Z, Hurst S, Hanson SR, Gruber A. Three dimensional optical angiography. Opt Express 2007;15:4083–4097. 3. Martinet V, Guigui B, Glacet-Bernard A, et al. Macular edema in central retinal vein occlusion: correlation between optical coherence tomography, angiography and visual acuity. Int Ophthalmol 2012; 32: 369–377. 4. Jia Y, Bailey ST, Wilson DJ, et al. Quantitative optical coherence tomography angiography of choroidal neovascularization in age-related macular degeneration. Ophthalmology 2014; 121:1435–1444. 5. Li P, An L, Reif R, Shen TT, Johnstone M, Wang RK. In vivo microstructural and microvascular imaging of the human corneo-scleral limbus using optical coherence tomography. Biomed Opt Express 2011; 2:3109–3118. 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. Choi W, Mohler KJ, Potsaid B, et al. Choriocapillaris and choroidal microvasculature imaging with ultrahigh speed OCT angiography. PLoS One 2013; 8:e81499.

8. Ang M, Cai Y, MacPhee B, et al. Optical coherence tomography angiography and indocyanine green angiography for corneal vascularisation. Br J Ophthalmol 2016; 100:1557–1563. 9. Stanzel TP, Devarajan K, Lwin NC, et al. Comparison of Optical Coherence Tomography Angiography to Indocyanine Green Angiography and Slit Lamp Photography for Corneal Vascularization in an Animal Model. Sci Rep 2018; 8:11493. 10. Akagi T, Uji A, Huang AS, et al. Conjunctival and Intrascleral Vasculatures Assessed Using Anterior Segment Optical Coherence Tomography Angiography in Normal Eyes. Am J Ophthalmol 2018; 196:1-9. 11. Skalet AH, Li Y, Lu CD, et al. Optical Coherence Tomography Angiography Characteristics of Iris Melanocytic Tumors. Ophthalmology 2017; 124:197–204. 12. Zhao F, Cai S, Huang Z, Ding P, Du C. Optical Coherence Tomography Angiography in Pinguecula and Pterygium. Cornea 2020; 39:99–103. 13. Liu Z, Karp CL, Galor A, Al Bayyat GJ, Jiang H, Wang J. Role of optical coherence tomography angiography in the characterization of vascular network patterns of ocular surface squamous neoplasia. Ocul Surf 2020; 18:926–935. 14. Brouwer NJ, Marinkovic M, Bleeker JC, Luyten GPM, Jager MJ. Anterior Segment OCTA of Melanocytic Lesions of the Conjunctiva and Iris. Am J Ophthalmol 2021; 222:137–147.

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PART 2 OCT angiography study of diseases and disorders Section 2: Retina OCT angiography examination: Age-related macular degenerations chapter 7: OCT angiography of macular neovascularization in neovascular amd Alexandra Miere, Eric Souied chapter 8: OCT angiography of choroidal nonexudative neovascular membrane Riccardo Sacconi, Carlotta Senni, Federico Fantaguzzi, Giuseppe Querques chapter 9: OCT angiography other cnv not from AMD Adil El Maftouhi, Maddalena Quaranta-El Maftouhi

chapter 10: OCT angiography follow-up of neovascularization after treatment Bruno Lumbroso, Marco Rispoli, Maria Cristina Savastano chapter 11: Non-neovascular age-related macular degeneration Varsha Pramil, Eric M Moult, Jay S Duker, James G Fujimoto, Nadia K Waheed

Section 3: Retina oct angiography examination: Other macular diseases chapter 12: Diabetic retinopathy Talisa E de Carlo, Varsha Pramil, James G Fujimoto, Nadia K Waheed chapter 13: Central serous chorioretinopathy and pachychoroid Maria Cristina Savastano, Marco Rispoli, Bruno Lumbroso chapter 14: OCT angiography examination of type 2 idiopathic macular telangiectasia Luca Di Antonio, Leonardo Mastropasqua

chapter 15: OCT angiography of vascular occlusions CRVO, BRVO, CRAO, BRAO, and microvascular occlusions Marco Rispoli, Bruno Lumbroso, Maria Cristina Savastano chapter 16: Microvascular occlusions: DRIL, AMN, and PAMM Dmitrii S Maltsev, Alexei N Kulikov, Maria A Burnasheva, Alexander S Vasiliev chapter 17: OCT angiography in inflammatory diseases André C Romano, William Warr Binotti, Paula M Marinho, Allexya AA Marcos, Heloisa Nascimento, Rubens Belfort

Section 4: Myopia and pathologic myopia chapter 18: OCT angiography examination in high myopia Luca Di Antonio, Leonardo Mastropasqua

Section 5: Tumors chapter 19: OCT angiography in ocular tumors Gilda Cennamo, Daniela Montorio, Giovanni Cennamo

Section 6: Glaucoma and optic nerve chapter 20: OCT angiography examination in glaucoma David Huang, Michel Puech, Yali Jia, Liang Liu, Mourtaza Aimadaly

chapter 21: OCT angiography examination in neurodegenerative diseases Emliano Di Carlo, Albert J Augustin

Chapter 7 OCT angiography of macular neovascularization in neovascular AMD Alexandra Miere, Eric Souied

■■INTRODUCTION Macular neovascularization (MN V) plays a central part in the pathogenic sequence of neovascular age-related macular degeneration (nAMD).1 Although factors such as age, oxidative stress, metabolic dysfunction, sun damage, circulatory disturbances, and inflammatory immune response2 are involved in AMD pathogenesis; recent literature has highlighted the key role of the inflammatory immune in both the formation and progression of MNV. 3 With the advent of antivascular endothelial growth factor (anti-VEGF) treatment for nAMD, an improvement of the visual prognosis in these patients has been possible.4,5 Nevertheless, due to the interaction between cytokines, i.e. VEGF, inflammatory cells, and

A

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extracellular matrix in the development of MNV, the response to anti-VEGF therapy is somewhat limited6 and the natural history of neovascular AMD ultimately leads to either subretinal fibrosis or macular atrophy and a subsequent poor functional prognosis. The advent of OCT angiography and its ever-increasing technical advances has allowed, in recent years, both a shift in the diagnosis and follow-up of MNVs, as well as a refined understanding of pathogenesis. OCT angiography allows a noninvasive visualization of MNVs, as a high-flow lesion, with variable sensitivity when compared with conventional multimodal imaging. Moreover, although MNV harbors various morphological features, these high-f low networks share, however, a similar microvascular organization.6-10 Furthermore, several studies have focused on

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ORCC

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Choriocapillaris

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Custom

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Figures 1A to H  Multimodal imaging of an 81-year-old man presenting with loss of visual acuity in his left eye (LE). Early fluorescein angiography (A) reveals the presence of a hyperfluorescent, ill-defined lesion, with pinpoints and leakage in the late frames of the examination (B). Early indocyanine green angiography (C) reveals the presence of a feeder vessel (green arrowhead), while late indocyanine green angiography reveals a hyperreflective plaque, suggestive of type 1 macular neovascularization (MNV) (D) (arrow). On spectral-domain optical coherence tomography (E), a hyperreflective, multilayered pigment epithelium detachment (PED), evoking type 1 MNV. Swept-source optical coherence tomography angiography (SS-OCTA) en face flow image and corresponding B-scan confirm the presence of a high-flow neovascular network in the “outer retina to choriocapillaris” (ORCC) segmentation (F). The high-flow neovascular membrane is also visualized in the “choriocapillaris” segmentation (G), as well as in the RPE-RPE fit custom segmentation (H).

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Section 2: Retina OCT angiography examination: Age-related macular degenerations

changes induced in treatment-naïve MNVs by anti-VEGF therapy, demonstrating that, under treatment, these MNVs will progress from immature MNVs (i.e., with present thin ramifications) to mature MNVs11 and hypermature MNVs12 (i.e. with the persistence of mainly large vascular trunks). Finally, using image analysis software, three-dimensional (3D) rendering of MNVs has been possible, offering additional volumetric information.13,14 Besides providing a novel approach for quantification of MNV complexity, these studies have suggested that a more complex 3D vascular structure is indeed associated with more frequent anti-VEGF intrav itreal injections. 13,14 Vascular remodeling, both t wodimensional, as seen on the en face flow images, and 3D, derived from volume-rendering studies, has allowed characterizing not only less responsive eyes (i.e. constant pattern),11 but also to understand which current therapies impact the evolution of MNVs (i.e. the progressive area increase in type 1 and 2 MNVs, independent of the presence/absence of exudative signs).11,12 But to derive this important information from OCT angiography images, clear comprehension of both the technique and its pitfalls is necessary, with regards to image artifacts, manual versus automatic segmentation, quantification tools, or signal strength limitations (to state just a few). For instance, Mrejen et al. have recently shown that the detection of a high-flow network on OCT angiography for type 1 MNVs was highly dependent on the use of manual segmentation slabs [improving detection from 40.3 to 56.1% for pigment epithelial

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ORCC

F

detachments (PEDs) >250 μm, and from 89.1 to 100% in those < 250 μm].15 Therefore, automatic slabs should be interpreted with caution for the detection of vascularized PEDs. Figures 1A to H show the differences in visualization using different segmentations (slabs) in the case of type 1 MNV, while Figures 2A to I highlight this variable visualization in type 2 MNV. Figure 3 highlights the visualization of type 3 MNV on spectral-domain OCT angiography. Moreover, the presence of a subretinal hemorrhage, illustrated in Figures 4A to D, may induce masking, making the neovascular membrane, although present, nondetectable. Another issue is quantification. Lately, the quantification of the total surface area of the lesion, as well as of the vascular surface area of the neovascularization, has been added to the functionalities of some OCT angiography instruments. These allow objective monitoring, by quantitative variables, of the evolution over time. The comparison/multiscan view function also allows a qualitative comparison of the lesion between several visits. Figures 5A to H illustrate a case of type 1 MNV followed up using spectral-domain OCT angiography, disclosing the loss of small ramifications following anti-VEGF treatment and subsequent vessel arterialization. Figure 6 illustrates the follow-up of type 2 MNV, with a massive decrease in the (visualized) neovascular area following treatment. Figures 7A to F show that, in type 3 MNV, at onset OCT angiography will reveal detectable flow dragging from the deep vascular complex (DVC) to the retinal pigment epithelium

E

Avascular

G

Choriocapillaris

H

Custom

I

Figures 2A to I  Multimodal imaging of an 82-year-old woman presenting with a sudden loss of visual acuity on her right eye (RE). Early fluorescein angiography (A) reveals the presence of a hyperfluorescent, well-defined retrofoveal lesion, with massive leakage in the late frames of the examination (B). Early indocyanine green angiography (C) reveals a slight hyperfluorescent lesion, while late indocyanine green angiography reveals a washout of the lesion (D) (arrow). On spectraldomain optical coherence tomography (E), a hyperreflective lesion is present, located above the retinal pigment epithelium (RPE), suggestive for type 2 macular neovascularization (MNV). Swept-source optical coherence tomography angiography (SS-OCTA) en face flow image and corresponding B-scan confirm the presence of a high-flow neovascular network in the “outer retina to choriocapillaris” (ORCC) segmentation (F). Nevertheless, the high-flow neovascular membrane is visualized in neither the “avascular” segmentation (G) nor in the “choriocapillaris” segmentation (H). Note that a custom segmentation incorporating the neovascularization can disclose the high-flow network (I).

CHAPTER 7: Oct angiography of choroidal nonexudative neovascular membrane

(RPE)/sub-RPE space,8,16,17 but after treatment, at the nonexudative stage, the flow inside the tuft-shaped lesions reduced/disappeared and the connection to the RPE/sub-RPE space regressed.16,17 Nevertheless, it is important to note that, while several devices allow the quantification of the (neo)vascular surface, the same instrument should be used in the follow-up of the same lesion, as there are differences in MNV visualization between spectraldomain and swept-source OCT angiography. In a recent article, Mastropasqua and colleagues demonstrated, by comparing the area of the new vessels in AngioVue (Optovue Inc, Fremont CA, USA), Spectralis OCT2 (Heidelberg Engineering, Heidelberg, Germany) (both in spectral-domain), and PLEX Elite (Carl Zeiss Mediatec, Dublin, Ireland) (swept-source), that indeed, the outer retinachoriocapillaris segmentation (outer retina to choriocapillaris, ORCC) showed the highest detection rate for the detection of types 1, 2, and mixed MNVs, regardless of the device used. Additionally, ORCC segmentation on the swept-source instrument had shown the highest detection rate.18 In the particular case of type 3 neovascularization, the lesion is seen, as shown before, in the

“outer retinal”/“avascular layer”/“avascular” segmentations, but microvascular abnormalities are also visualized in the DVC and/or choriocapillaris. Its origin in the DVC has been controversial,19 but both recent clinicopathological correlations and imaging studies confirm that type 3 arises from the DVC.20 Figures 8A to I illustrate a 3D rendering of a type 3 neovascularization, clearly demonstrating the dragging of vessels from the DVC onto the outer retina to form the type 3 lesion. This in vivo visualization of vascular connectivity offers new insights into type 3 MNVs. In summary, OCT angiography reveals in a majority of cases of high-flow vascular networks, corresponding to MNV. By allowing a noninvasive assessment of MNV, OCT angiography images provide not only an easier way to diagnose and follow these eyes but also a better understanding of the abnormal angiogenesis occurring in eyes with advanced AMD. Aside from the qualitative assessment of MNVs, a quantitative assessment of the lesion’s area and vascular density are also available, demonstrating the potential of OCT angiography-derived criteria to become standard imaging biomarkers.

FA

Tuft-shaped lesion SVC

DVC

Avascular layer

Choriocapillaris

Figure 3  Type 3 macular neovascularization. Upper panels: Fluorescein angiography (FA, upper left) and spectral-domain optical coherence tomography (SDOCT) and SD-OCT angiography (SD-OCTA) with flow overlay (middle right and right). FA discloses a small, hyperfluorescent lesion situated in the inferior part of the foveal avascular zone. SD-OCT (middle left) shows a hyperreflective intraretinal complex accompanied by intraretinal fluid, suggestive for early type 3 neovascularization. SD-OCTA reveals the presence of intraretinal overlaid flow (white arrowhead). On the lower panels, the four automated segmentations, from left to right: Superficial vascular complex (SVC), deep vascular complex (DVC), avascular layer, where the tuft-shaped high-flow lesion is easily visualized (white arrowhead), and choriocapillaris, where no corresponding lesion is found.

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Section 2: Retina OCT angiography examination: Age-related macular degenerations

Baseline

Year 2

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Figures 4A to D  Spectral-domain optical coherence tomography (SD-OCT) and SD-OCT angiography of type 1 macular neovascularization complicated by subretinal hemorrhage. The left column corresponds to baseline examination. (A) SD-OCT scan passing through the lesion, revealing the presence of a fibrovascular pigment epithelial detachment (PED) associated with an area of hyperreflective hemorrhage above the retinal pigment epithelium (RPE), as well as subretinal fluid. (B) En face flow image of the “avascular layer” segmentation, showing central masking generated by the hemorrhage (dashed line). Note that on the corresponding B-scan with flow overlay no flow is detected within the PED. (C) SD-OCT at two years follow-up, after 15 antivascular endothelial growth factor (anti-VEGF) intravitreal injections. (D) En face flow image of the “avascular layer” segmentation clearly discloses the presence of a mature high-flow neovascular network, consisting mainly of dilated vascular trunks and several vascular loops. The corresponding B-scan with flow overlay shows the presence of flow within the PED.

CHAPTER 7: Oct angiography of choroidal nonexudative neovascular membrane Figures 5A to H Spectraldomain optical coherence tomography angiography (SD-OCTA) of type 1 macular neovascularization. Baseline (A) En face flow image of the “choriocapillaris” segmentation, showing a high-flow neovascular network, and, on the corresponding B-scan, the presence of overlaid flow within the pigment epithelial detachment (PED) and intraretinal fluid. (B) Segmentation of the G A C E neovascular network. (C) One month follow-up shows the high-flow neovascular network, and, on the corresponding B-scan, the disappearance of intraretinal fluid. (D) Segmentation of the neovascular network. (E) Two-month follow-up and (F) Segmentation of the neovascular network. (G) Three-month follow-up and (H) Segmentation of the neovascular network. Note that during antivascular H endothelial growth factor B D F (anti-VEGF) treatment, the small ramifications within the neovascular membrane in panel B. have progressively disappeared, revealing, in panel H., the persistence of mainly large vascular trunks, suggestive of vessel arterialization. Baseline

Month 1

Month 2

Month 3

Figure 6 Spectral-domain optical coherence tomography angiography (SD-OCTA) of a 79-year-old woman with loss in visual acuity in the right eye. The right column corresponds to baseline SD-OCTA “avascular complex” segmentation, revealing the presence of flow on the B-scan with flow overlay (upper left) accompanied by massive subretinal fluid and, on the en face flow image, a highflow neovascular network, with the visualization of the feeder vessel (blue arrowhead). The middle column corresponds to the 1 month follow-up with SD-OCTA “avascular complex” segmentation, after the first intravitreal antivascular endothelial growth factor (anti-VEGF) injection. B-scan with flow overlay reveals the complete resolution of subretinal fluid and persisting flow corresponding to the neovascular lesion (upper middle). On the en face flow image, note that the small ramifications of the high-flow neovascular network have disappeared, with a considerable reduction in the (visualized) neovascular area. The left column corresponds to follow up on SD-OCTA “avascular layer” segmentation after the second anti-VEGF intravitreal injection, revealing the absence of exudation and a persistent flow within the neovascular lesion on the B-scan with flow overlay (upper right). On the en face flow image (lower right), a high-flow neovascular network is visible, consisting mainly of large vascular trunks. Note that for the follow-up of these eyes we used the same segmentation (“avascular layer”). Basline

Month 1

Month 2

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Section 2: Retina OCT angiography examination: Age-related macular degenerations

Outer retina

Choriocapillaris

Basline

DVC

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A

Outer retina

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DVC

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Figures 7A to F Long-term follow-up of type 3 macular neovascularization (MNV). Upper panels (A to C) show baseline spectral-domain optical coherence tomography angiography (SD-OCTA). (A) On the deep vascular complex (DVC) en face flow image and corresponding B-scan with flow overlay, two small high-flow vessels (green asterisk) drag posteriorly to the “outer retina” (B), forming a characteristic tuft-shaped high-flow lesion (dotted circle). In the choriocapillaris segmentation (C), no corresponding high-flow lesion is found. Note, on the corresponding B-scan with flow overlay that flow is intraretinal (white arrowhead). At 3 years follow-up (lower panels), note the disappearance of the high-flow vessels in the DVC segmentation (D), as well as the lack of visualization of the tuft-shaped lesion in the “outer retina” segmentation (E). On the choriocapillaris segmentation (F), note the presence of atrophy, confirmed, in the exact spot of the type 3 MNV, by posterior hypertransmission (green arrow) on the B-scan with flow overlay.

F

■■REFERENCES 1. Fine SL, Berger JW, Maguire MG. Age-related macular degeneration. N Engl J Med 2000; 342:483–492. 2. Holz FG, Pauleikhoff D, Klein R, Bird AC. Pathogenesis of lesions in late agerelated macular disease. Am J Ophthalmol 2004; 137:504–510. 3. Ding X, Patel M, Chan CC. Molecular pathology of age-related macular degeneration. Prog Retin Eye Res 2009; 28:1–18. 4. Hwang JC, Del Priore LV, Freund KB, Chang S, Iranmanesh R. Development of subretinal fibrosis after anti-VEGF treatment in neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2011; 42:6–11. 5. Rosenfeld PJ, Shapiro H, Tuomi L, Webster M, Elledge J, Blodi B. Characteristics of patients losing vision after 2 years of monthly dosing in the phase III ranibizumab clinical trials. Ophthalmology 2011; 118:523–530. 6. Kuehlewein L, Bansal M, Lenis TL, et al. Optical coherence tomography angiography of type 1 neovascularization in age-related macular degeneration. Am J Ophthalmol 2015; 160:739–748. 7. El Ameen A, Cohen SY, Semoun O, et al. Type 2 Neovascularization secondary to age-related macular degeneration imaged by optical coherence tomography angiography. Retina 2015; 35:2212–2218.

8. Miere A, Querques G, Semoun O, El Ameen A, Capuano V, Souied EH. Optical coherence tomography angiography in early type 3 neovascularization. Retina 2015; 35:2236-2241. 9. Miere A, Semoun O, Cohen SY, et al. Optical coherence tomography angiography features of subretinal fibrosis in age-related macular degeneration. Retina 2015; 35:2275–2284. 10. Costanzo E, Miere A, Querques G, Capuano V, Jung C, Souied EH. Type 1 Choroidal Neovascularization Lesion Size: Indocyanine Green Angiography Versus Optical Coherence Tomography Angiography. Invest Ophthalmol Vis Sci 2016; 57:OCT307–OCT313. 11. Miere A, Butori P, Cohen SY, et al. Vascular remodeling of choroidal neovascularization after anti-vascular endothelial growth factor therapy visualized on optical coherence tomography angiography. Retina 2019; 39:548–557. 12. Xu D, Dávila JP, Rahimi M, et al. Long-term Progression of Type 1 Neovascularization in Age-related Macular Degeneration Using Optical Coherence Tomography Angiography. Am J Ophthalmol 2018; 187:10–20. 13. Borrelli E, Mastropasqua L, Souied E, et al. Longitudinal assessment of type 3 macular neovascularization using three-dimensional volume-rendering OCTA. Can J Ophthalmol 2021; S0008-4182(21)00164-2.

CHAPTER 7: OCT angiography of macular neovascularization in neovascular AMD

A E

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Figures 8A to I  Multimodal imaging and three-dimensional (3D) rendering of type 3 macular neovascularization. (A) Early fluorescein angiography (FA) and (B) late FA disclose a small hyperfluorescent lesion inferior to the foveal avascular zone (white arrows). (C) Early indocyanine green angiography (ICGA) shows a punctiform hyperfluorescent lesion (green arrow), evolving into a characteristic hyperfluorescent “hot spot” (green arrow, panel D), in the late frame of the examination (D). Spectral-domain optical coherence tomography angiography “outer retina” segmentation, without (E) and with (F) 3D projection artifact removal, shows a tuftshaped high-flow lesion (dotted yellow circle). Note that on the corresponding B-scan with flow overlay, the flow is intraretinal. (G) 3D rendering of the “outer retinal segmentation”, showing the tuft-shaped lesions. (H) Two vessels of the deep vascular complex dragging down toward the “outer retina” segmentation to form the type 3 macular neovascularization. (I) 3D rendering of four automated segmentations, revealing, as observed on the zoomed image.

14. Nesper PL, Soetikno BT, Treister AD, Fawzi AA. Volume-Rendered Projection-Resolved OCT Angiography: 3D Lesion Complexity Is Associated With Therapy Response in Wet Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci 2018; 59:1944–1952. 15. Mrejen S, Giocanti-Auregan A, Tabary S, Cohen SY. Sensitivity of 840nm spectral domain optical coherence tomography angiography in detecting type 1 neovascularization according to the height of the associated pigment epithelial detachment. Retina 2019; 39:1973– 1984. 16. Sacconi R, Battista M, Borrelli E, et al. OCT-A characterisation of recurrent type 3 macular neovascularisation. Br J Ophthalmol 2021; 105:222–226.

17. Miere A, Querques G, Semoun O, et al. Optical coherence tomography angiography changes in early type 3 neovascularization after anti-vascular endothelial growth factor treatment. Retina 2017; 37:1873–1879. 18. Mastropasqua R, Evangelista F, Amodei F, et al. Optical Coherence Tomography Angiography in Macular Neovascularization: A Comparison Between Different OCTA Devices. Transl Vis Sci Technol 2020; 9:6. 19. Freund KB, Zweifel SA, Engelbert M. Do we need a new classification for choroidal neovascularization in age-related macular degeneration? Retina 2010; 30:1333–1349. 20. Li M, Dolz-Marco R, Messinger JD, et al. Clinicopathologic Correlation of Anti-Vascular Endothelial Growth Factor-Treated Type 3 Neovascularization in Age-Related Macular Degeneration. Ophthalmology 2018; 125:276–287.

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Chapter 8 OCT angiography of choroidal nonexudative neovascular membrane Riccardo Sacconi, Carlotta Senni, Federico Fantaguzzi, Giuseppe Querques

■■INTRODUCTION The pathological ingrowth of newly formed vessels [i.e. macular neovascularization (MN V) or choroidal neovascularization (CNV)] either in the subretinal pigment epithelium (RPE) space or in the subretinal one or within retinal layers characterizes the neovascular form of age-related macular degeneration (AMD). Usually, neovascular AMD shows abnormal fluid accumulation (i.e. exudation) that alters the retinal physiological structure and morphology, being responsible for the typical visual disturbances. However, in several cases of neovascular AMD, MNV could not show exudative signs, developing a quiescent or nonexudative MNV. In the last years, thanks to the advances in retinal imaging evaluation, there was a growing interest in the evaluation of treatment-naïve neovascularizations. Herein, the term “quiescent choroidal neovascularization” was coined to describe the presence of a well-detectable neovascular tissue on fluorescein angiography (FA) and indocyanine green angiography (ICGA) in absence of intraretinal/subretinal exudation on multiple optical coherence tomography (OCT) scans, for a minimum of 6-month period of

A

time (Figures 1 and 2).1 In accordance with the classification of Gass, this type of CNV remains beneath the retinal pigment epithelium, but unlike typical type-1 CNV in neovascular AMD, it is not associated with clinical signs of activity (i.e. exudation). The first evidence of nonexudative NVs dates back to the 1970s and comes from postmortem studies of patients affected by AMD. 2,3 Thereafter, these lesions were observed in vivo in patients with unilateral exudative AMD. Indeed, the occurrence of a neovascular exudative lesion in one eye and of a nonexudative form in the fellow eye is not uncommon. Schneider et al.4 investigated angiographic features in a series of 124 contralateral eyes of patients with exudative complications in the other eye. Authors detected the presence of a MNV in 11 of 124 fellow eyes by means of ICGA; whereas, FA did not detect any lesions and fundus examination only showed the presence of drusen. On ICGA, lesions appeared as late hyperfluorescence plaques, consistent with a type-1 MNV, located below the RPE. Since these patients did not present with exudationrelated symptomatology, the authors defined these findings as “early, quiet intra-Bruch’s membrane/subpigment epithelial MNVs”.4 Although the risk of activation of such lesions could not

B

Figures 1A and B  Early (A) and late (B) phases of fluorescein angiography of a patient affected by quiescent nonexudative choroidal neovascularization in the left eye.

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Section 2: Retina OCT angiography examination: Age-related macular degenerations

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Figures 2A to D  Early (A), middle (B), and late (C) phases of indocyanine green angiography disclosed the presence of a quiescent nonexudative choroidal neovascularization (CNV) in the left eye (i.e. hyperfluorescent lesion in the late phases of examination). Structural optical coherence tomography (D) showed the presence of a flat irregular pigment epithelium detachment matching to nonexudative CNV.

D

be objectively quantified, it was hypothesized that in patients with exudative AMD, the presence of a late hyperfluorescence plaque on ICGA in the contralateral eye was associated with an increased risk of developing exudative complications.4 Later on, the presence of abnormal ICGA findings in 11% of eyes with drusen and no suspicious signs at FA was reported by Hanutsaha and co-workers, thus confirming the observations of Schneider’s group.5 This last study relied on a larger sample of 432 consecutive patients diagnosed with unilateral exudative AMD. The overall occurrence of exudative changes during the mean follow-up time of 21.7 months was 16%. They also reported that abnormal signs at ICGA were detected in 11% of patients with drusen, and these eyes had a much higher risk of exudative changes (24%). Particularly, the risk increased to 27% in patients who had lesions > 1 optic disk (2.6 times more frequent than that noted in drusen eyes with normal ICGA). This study suggested that ICGA could detect a subset of patients with MNV in an inactive state, who are at major risk of having exudative changes. However, the use of dye-based angiographies, besides being invasive and potentially accompanied by systemic effects such as allergic and anaphylactic reactions, does not allow objective quantification of intraretinal and subretinal f luid. Thanks to the wide diffusion of optical coherence tomography (OCT) and subsequently optical coherence tomography angiography (OCTA); minimal exudative changes may be now detected in an easy, fast, and noninvasive way.

■■MULTIMODAL IMAGING OF NONEXUDATIVE CHOROIDAL NEOVASCULARIZATION In the era of anti-vascular endothelial growth factor (VEGF) agents for the treatment of neovascular exudative AMD, the development of optical coherence tomography (OCT) technology was of paramount relevance in the diagnosis and follow-up of the patients. Indeed, the evaluation of intra-/subretinal fluid thanks

to OCT is essential to decide the time for injections. Patients undergoing anti-VEGF therapy for CNVs on an as-needed basis and showing absence of retinal exudation on follow-up evaluations may skip retreatment until fluid recurrence. Similarly, asymptomatic treatment-naïve nonexudative CNV may be left untreated until activation in the form of exudation is documented. The ongoing development of different imaging modalities allows us to perform a combined morphological and functional evaluation, thus improving preclinical assessment, diagnosis, and therapeutic monitoring. Herein, a brief description of principle imaging findings in quiescent nonexudative CNVs is reported.

■■Dye angiography As aforementioned, Hanutsaha and co-workers were the first to describe the presence of abnormal indocyanine green angiography findings (ICGA) in 432 consecutive nonexudative eyes with exudative AMD in the fellow eye (Figure 2). By enhancing imaging of the choroid thanks to its special properties of high proteinbinding capacity and near-infrared fluorescence, ICGA allows an easier visualization of occult sub-RPE neovascular membranes. These last ones correspond to areas of abnormal hyperfluorescence in early to late phases, which may present either as focal spots (focal areas of hyperfluorescence 1 disk area in size). By providing a clear delineation of neovascular complex, ICGA may act as a complementary technique to f luorescein angiography, where quiescent CNVs appear as late speckled hyperfluorescent lesion lacking well-demarcated borders without late-phase dye leakage and pooling, due to dye accumulation within fibrovascular pigment epithelium detachment (PED).4,5

■■Structural OCT On structural OCT examination, quiescent CNVs correspond to areas of irregular slightly elevated RPE with moderate reflectivity, showing a major axis in the horizontal plane (Figure 2). Usually,

CHAPTER 8: Oct angiography of choroidal nonexudative neovascular membrane

Bruch’s membrane hyper-ref lective band is clearly visualized beneath the neovascular tissue. Structural characterization of retinal layers by means of OCT reveals the absence of CNV signs of activity such as the presence of intraretinal hyperreflective flecks, mid-reflective exudative material, or poorly defined lesion boundaries.1

■■OCT angiography A further imaging tool for both detecting and defining treatmentnaïve quiescent neovascularizations is represented by OCT angiography (OCTA), which is a noninvasive, dyeless, fast, and three-dimensional method used to visualize ocular blood flow in retinal and choroidal vasculature. Thanks to the development of OCTA, it is now possible to image the actual neovascularization rather than just the structural changes resulting from fluid leakage within the macular layers.1 Also, the quiescent neovascular network may be detected prior to the appearance of anatomic alterations or visual disturbances (Figures 3 and 4). In fact, the appearance of CNVs does not depend on their activity rate and vascular leakage, so both nonexudative and exudative NVs are detectable by OCTA. Carnevali et al.6 investigated the detection rate of quiescent MNVs in 22 eyes with AMD. They reported a sensitivity and specificity in qMNV detection of 81.8% and 100%, respectively. In the same study, Carnevali and colleagues investigated the most commonly found lesion patterns in terms of size, morpholog y, vascular caliber, and location. These assessments were performed on the enface image. Lesions may be circular or irregularly shaped, may or may not have a visible core, may or may not have defined margins, and may present a small or large vascular caliber.1,6,7

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Figure 4  En-face optical coherence tomography angiography and B-scan with flow showing the presence of a large quiescent nonexudative choroidal neovascularization.

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Figures 3A to C  En-face optical coherence tomography (OCT) angiography and structural OCT showing the presence of a quiescent nonexudative choroidal neovascularization at the baseline (A) that developed increasing subretinal fluid (i.e. exudation) during the 6-month and 10-month follow-up (B and C, respectively).

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Section 2: Retina OCT angiography examination: Age-related macular degenerations

Furthermore, the presence of nonexudative quiescent MNV was reported in geographic atrophy (GA) patients by Capuano and colleagues.8 In their series, OCTA revealed a flow signal beneath the small irregular elevation of the RPE at the site of the quiescent MNV visualized by structural OCT. Furthermore, the authors reported that, at last follow-up, 92% of the quiescent MNV seemed to cover the area spared from atrophy, suggesting a potential role of quiescent MNV in preventing GA enlargement in that area.8

■■NATURAL HISTORY OF QUIESCENT NONEXUDATIVE CNVs Understanding the natural course of quiescent CNVs by performing multimodal imaging may help in the better management of the disease. For example, in establishing an appropriate time interval between follow-up visits, every lesion is characterized by a different risk of progression depending on a combination of several possible intervening factors. With this regard, De Oliveira Dias et al. used SS OCTA to determine the prevalence, incidence, and natural history of subclinical MNV in eyes with neovascular nonexudative AMD.7 Of 160 patients enrolled in the study (110 with iAMD and 50 with GA), subclinical MNV was detected in a total of 23 eyes at the time of first imaging, for a prevalence of 14.4%. Six eyes demonstrated subclinical MNV during the follow-up. Of 134 eyes with follow-up visits, a total of 13 eyes demonstrated exudation, and, out of these 13 eyes, 10 were found to have pre-existing subclinical MNV. By 12 months, the Kaplan–Meier cumulative incidence of exudation for all 134 eyes was 6.8%. For eyes with subclinical MNV at the time of first swept source (SS) OCTA imaging, the incidence of exudation was 21.1% during the follow-up, whereas the incidence of exudation was 3.6% in the group of eyes without subclinical MNV. However, there was no difference in the cumulative incidence of exudation from pre-existing MNV in eyes with iAMD or GA.7 Overall, the detection of subclinical MNV increased the risk of exudation by a factor of 15.2. The same study was then extended up to 2 years, reporting a cumulative incidence of exudation of 34.5%.9 Conversely, when strictly following the criteria for diagnosis of quiescent CNVs, which include the absence of intraretinal or subretinal exudation on repeated structural SD-OCT examinations over at least 6 months, different results emerge. Indeed, Carnevali and co-workers required a 6-month follow-up w ithout the development of exudation to enroll patients in their longitudinal study.10 During strict monitoring of treatment-naïve quiescent CNVs evolution by means of OCTA, no changes were reported in terms of CNV core, margin, and location. However, the biological

activity of the quiescent tissue was demonstrated by showing lesion growth over 12 months. Nevertheless, biological activity was not accompanied in most cases with clinical activity as documented by the absence of exudation development over time. In particular, when compared with previous studies, which did not require a minimum follow-up period for the definition of quiescent CNV, a lower rate of activation was found.10 Clinical relevance of quiescent nonexudative CNVs: Should OCTA features be used as biomarkers to predict future exudation? The recent development of OCTA devices and post-acquisition image-processing algorithms allowed us to better understand the pathophysiology of several chorioretinal diseases and to better investigate the features of different MNVs. For this reason, Querques et al.11 investigated different OCTA features at the baseline that could predict the activation (i.e. exudation) of treatment-naïve nonexudative quiescent MNV. Analyzing 31 nonexudative MNVs, the authors identified two different patterns for subclinical MNVs— subclinical MNVs characterized by short-term activation (i.e. before 6 months starting from the diagnosis) which could represent simply a pre-exudative stage in the development of an ordinary type 1 MNV and quiescent MNVs characterized by the low rate of growth and possible long-term activation (after 6-month follow-up). Analyzing the monthly MNV growth rate by means of OCTA, the short-term activated MNV group showed a significantly higher growth rate in comparison to the persistently quiescent MNV group and the long-term activated quiescent MNV group. Furthermore, at the baseline, perfusion density of the short-term activated MNV group was significantly greater in comparison to the persistently quiescent MNV group, and long-term activated MNV group. For these reasons, the authors concluded that OCTA features could predict short-term activation for subclinical MNV, but no features could predict the long-term activation.

■■CONCLUSION Overall, it is unclear whether quiescent CNVs may be considered a pre-exudative stage of exudative type-1 MNV or if it should be considered a separate entity. Probably, there are different entities in the spectrum of nonexudative MNV. It is noteworthy that OCTA analysis has become an essential tool in the evaluation of such lesions. By precisely characterizing anatomical metrics of the neovascular complex, such as vessel density, lesion size, and lesion margins, OCTA may help in the early detection of patients at major risk of exudative changes, thus contributing to the amelioration of the disease management and in a deeper understanding of quiescent CNV nature.

■■REFERENCES 1. Querques G, Srour M, Massamba N, et al. Functional characterization and multimodal imaging of treatment-naive “quiescent” choroidal neovascularization. Invest Ophthalmol Vis Sci 2013; 54:6886–92. 2. Sarks SH. New vessel formation beneath the retinal pigment epithelium in senile eyes. Br J Ophthalmol 1973; 57:951–65. 3. Green WR, Key SN 3rd. Senile macular degeneration: a histopathologic study. Trans Am Ophthalmol Soc 1977; 75:180–254. 4. Schneider U, Gelisken F, Inhoffen W, Kreissig I. Indocyanine green angiographic findings in fellow eyes of patients with unilateral occult neovascular age-related macular degeneration. Int Ophthalmol 1997; 21:79–85.

5. Hanutsaha P, Guyer DR, Yannuzzi LA, et al. Indocyanine-green video angiography of drusen as a possible predictive indicator of exudative maculopathy. Ophthalmology 1998; 105:1632–6. 6. Carnevali A, Cicinelli MV, Capuano V, et al. Optical Coherence Tomography Angiography: A Useful Tool for Diagnosis of TreatmentNaive Quiescent Choroidal Neovascularization. Am J Ophthalmol 2016; 169:189–98. 7. de Oliveira Dias JR, Zhang Q, Garcia JMB, et al. Natural History of Subclinical Neovascularization in Nonexudative Age-Related Macular Degeneration Using Swept-Source OCT Angiography. Ophthalmology 2018; 125:255–66.

CHAPTER 8: Oct angiography of choroidal nonexudative neovascular membrane 8. Capuano V, Miere A, Querques L, et al. Treatment-Naïve Quiescent Choroidal Neovascularization in Geographic Atrophy Secondary to Nonexudative Age-Related Macular Degeneration. Am J Ophthalmol 2017; 182:45–55. 9. Yang J, Zhang Q, Motulsky EH, et al. Two-Year Risk of Exudation in Eyes with Nonexudative Age-Related Macular Degeneration and Subclinical Neovascularization Detected with Swept Source Optical Coherence Tomography Angiography. Am J Ophthalmol 2019; 208:1–11.

10. Carnevali A, Sacconi R, Querques L, et al. Natural History of TreatmentNaive Quiescent Choroidal Neovascularization in Age-Related Macular Degeneration Using OCT Angiography. Ophthalmol Retina 2018; 2:922–30. 11. Querques G, et al. Treatment-naïve quiescent macular neovascularization secondary to AMD: The 2019 Young Investigator Lecture of Macula Society. Eur J Ophthalmol. 2021. doi: 10.1177/1120672120986370. Online ahead of print

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Chapter 9 OCT angiography other CNV not from AMD Adil El Maftouhi, Maddalena Quaranta-El Maftouhi

■■INTRODUCTION A new insight in the comprehension and imaging interpretation of several neovascular diseases is now possible thanks to optical coherence tomography (OCT) angiography. The aim of this chapter is to give an overview of the use of OCT angiography in some of the more frequent neovascular pathologies of the posterior pole.

■■TYPE-1 CNV IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY First of all, we studied the OCT angiographic appearance of chronic cent ral serous chorioret inopat hy (CSC), in which type-1 neovascularization (CNV) has been recently described.

Despite the use of a multimodal imaging procedure, it is hard to affirm the presence of CNV and to differentiate which case presents CNV and which is secondarily complicated with a typical polypoidal choroidal vasculopathy (PCV) (Figure 1). Using standard OCT examination, we found that chronic CSC can present with two different patterns according to the appearance of the retinal pigment epithelium (RPE) complex. Patients could present either with a flat profile of the RPE, or with a slightly elevated and undulating RPE complex. On OCT angiography, all patients with this second RPE complex pattern appeared to be vascularized (Figure 2) even when indocyanine green (ICG) angiography failed to detect any clear sign of choroidal neovascularization. New vessels were located between the elevated RPE and the Bruch’s membrane (type-1 CNV). The neovascular network was wheel rays in shape, and presented some dilatations along with the major trunks, but not typical signs of polypoidal dilatations (Figure 3).

Figure 1  Left eye of a 48-year-old patient diagnosed with central serous chorioretinopathy (CSC) 5 years earlier. Appearance of a thin flat irregular pigment epithelium detachment (FIPED), without exudation in B-scan that OCT-A depicted as neovascularized with very obvious decorrelation signal within the pigment epithelium detachment (PED).

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Section 2: Retina OCT angiography examination: Age-related macular degenerations

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Cube 3 × 3, AngioVue, Optovue, Fremont USA

Cube Prototype HD 2 × 2 mm

Figures 2A to E  (A) Same eye than Figure 1A. Using a cube of 3 × 3 mm2, optical coherence tomography angiography (OCTA) (AngioVue, Optovue, Fremonte) shows the flow of choroidal new vessels. (B) Corresponding OCTA overlay in B-scan demonstrates the location of decorrelation signal within this slight PED. (C) “En face” OCT shows some reticular-shaped abnormalities of the fundus reflectance. (D) The neovascular elevation of retinal pigment epithelium (RPE) in B-scan appears as a mildly hyperreflective zone. (E) Same neovascular network with more definition as visualized on a prototype HD cube of 2 × 2 mm2 (400 × 400) (AngioVue, Optovue, Fremonte).

FS: 0.088 mm2

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Figure 3  Optical coherence tomography angiography (OCTA) follow-up with flow surface quantification of neovascular network as in Figure 1. Type-1 choroidal neovascularization (CNV) gradually increased in size along a period of 23 but persisted quiescent without any exudative signs.

Optical coherence tomography angiography contributes to clearly give the diagnosis of type-1 CNV secondary to chronic CSC, and allowed to find out that there is a correlation between the slightly elevated and undulated RPE profile on OCT scans and choroidal neovascularization.

■■POLYPOIDAL CHOROIDAL VASCULOPATHY In PCV, ICG angiography is pathognomonic. One or multiple early hyperfluorescent spots peripheral or above an interconnecting

neovascular network represent the essential clues for diagnosis (Figures 4A to C). On OCT scans, the polypoidal dilations are dome-shaped elevations of the RPE over an abnormally visible Bruch’s membrane. Round and optically empty dots are frequently visible inside the RPE detachment and correspond to the polyp itself. The interconnecting neovascular network appears as an undulated and slightly elevated RPE profile (Figure 4D). On OCT angiography (Figures 5 and 6), both polyps and inter­ connecting neovascular networks are visible under the RPE. The shape of the whole polypoidal complex is shoestring in shape and this aspect is typical of polypoidal lesions. Along with the

CHAPTER 9: Oct angiography other cnv not from amd

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Figures 4A to E  (A and B) Early and late phase indocyanine green (ICG) angiography frames showing the polypoidal vascular dilation (white arrow) at the superior border of an interconnecting neovascular network (red arrow). (C) Color picture showing a whitish zone (white arrow) corresponding to the polypoidal lesion. (D) B-scan optical coherence tomography (OCT) highlights an elevation of the retinal pigment epithelium (RPE). Note as the PED abruptly rises from bruchs memebrane plane and contains an optically empty circle corresponding to the polypoidal dilation (white arrow). Close to the polyp, the neovascular interconnecting network appears as a mildly reflective elevation of the RPE above a straight thickened and abnormally visible Bruch’s membrane. (E) The polypoidal dilation seems to grow over a network of dilated choroidal vessels very well defined on “en face” OCT picture (yellow arrow).

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Figures 5A to C  (A) Same polypoidal lesion than Figure 4 visualized by optical coherence tomography angiography (OCTA). The interconnecting neovascular network (red arrow) is well visualized. The polyp itself presents a very weak decorrelation signal. This is probably due to a low flow in the polypoidal dilation (B), or to the fact that only the laminar flow is detected while the turbulent flow in the dilation does not created a decorrelation signal strong enough to become visible. (B) Zoom in OCTA overlay in B-scan confirms the presence of slight decorrelation signal synonymous to flow inside the polyp but the segmentation must be more thin to highlight it. (C) Manual segmentation is required in case of low flow as in this case. Customize slab with very thin slab focused in the polyps area can show decorrelation signal in OCTA with the C-scan view.

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Section 2: Retina OCT angiography examination: Age-related macular degenerations

+ PDT

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21-12-2017 14:04 [HDto 6.0 mm] 25-01-2018 10:33 [HD 6.0 mm] SQ 4/10 10:06 [HD 6.0 mm] SQ 7/10 01-03-2018 10:42 [HDfollow-up 6.0 mm] SQ 6/10 during the 31-05-2018 09:57 [HDgrowth 6.0 mm] SQ 8/10 Figures 6A E  SQ (A8/10 to C) Optical coherence tomography angiography (OCTA) loading phase with anti-vascular 26-07-2018 endothelial factor (VEGF) preceded by photodynamic therapy (PDT). Note the vasoconstriction of the branching network after the first treatment. (D and E) A recurrence occurred 6 months later with reperfusion and increase of the decorrelation signal. A second combination treatment was performed.

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interconnecting neovascular vessels, some dilatations (polyps) can be seen. However, polyps and neovascular network are not on the same plane and so, their visualization needs the analysis of two or more sequential slabs, the thickness of which has to be adapted to the size of polyps (Figure 5C).

■■CNV IN PATHOLOGIC MYOPIA Choroidal neovascularization of pathologic myopia is usually small in size and presents a mild late leakage on fluorescein angiography. Despite the fact that myopic CNV are classic and located beneath the RPE, their precise structure is difficult to see on conventional FA. The high sensitivity and specificity of OCT angiography allow visualizing very small CNVs in detail (Figure 7). Major vessels contrast on a hypoperfused zone. It is not yet established, if the dark zone encircling and underlying new vessels is due to exudative material or to hypoperfusion. The peripheral fringe of CNV, made of more thin, immature, and leaking vessels, seems to present a hazy blood flow, which is probably due to an optic attenuation of blood flow signal due to exudation overlying CNV (Figures 8 and 9).

Figures 7A to D  (A) Color retinal fundus picture of a large choroidal new vessel in a Fuch’s lesion of severe myopia. (B) Above the retinal pigment epithelium (RPE), B-scan optical coherence tomography (OCT) shows a reflective and fusiform-shaped choroidal neovascularization (CNV) within the Fuch’s spot associated with retinal serous detachment and diffuse edema. (C) Very well-defined network of choroidal new vessels in optical coherence tomography angiography (OCTA) with a maturation of the main structure of the new vessels and anastomosis of the edge of the lesion. (D) Optical coherence tomography angiography (OCTA) overlay on B-scan shows clearly the decorrelation signal above retinal pigment epithelium (RPE) in choroidal neovascularization (CNV) type 2.

■■ANGIOID STREAKS AND CHOROIDAL NEOVASCULARIZATION Angioid streaks (AS) are breaks of the Bruch’s membrane due to a pathologic calcification of elastic tissues. On ICG angiography, we described their late hyperfluorescence scattered with tiny pinpoints. Type-2 CNV can complicate AS and diagnosis is normally based on FA or, only in some more difficult cases, on ICG angiography (Figure 10). On OCT angiography, we could individualize not only type-2 CNV (hyperreflective network localized above the RPE complex), but also type-1 CNV (perfused CNV localized between RPE and Bruch’s membrane). Type-1 CNV could be just beside the classic component, but also at distance along the bed of the AS (Figure 11). For the first time, OCT angiography allowed to clarify the neovascular nature of some ICG hyperfluorescences and to diagnose perfused type-1 CNV in AS (Figures 12 and 13).

CHAPTER 9: Oct angiography other cnv not from amd Figures 8A to C  (A) Type-2 choroidal neovascularization (CNV) 2 of the severe myopia as visualized on optical coherence tomography angiography (OCTA) angiogram: a welldefined neovascular network with peripheral anastomosis. (B) Decorrelation signal spots are visualized at mainly above the retinal pigment epithelium (RPE) plane according to choroidal neovascularization (CNV) type 2. (C) The hyperreflective subretinal material visualized as grayish aspect on the B-scan optical coherence tomography (OCT) seems to be nonvascularized and directly correlated to the exudation. Note as the hyperreflective sub-retinal material disorganizes the outer retinal layers up to the nuclear outer zone.

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Figures 9A to D  Follow-up of the same eye than Figure 8— (A and B) After an intravitreal injection of ranibizumab, the decorrelation signal due to choroidal new vessels vanished and it is no more detected. (C) 3 months later, the recurrence appears nasally to the previous neovascular spot. (D) 2 months after the 2nd intravitreal injection, the decorrelation signal seems to disappear again. Note as the photoreceptors layer disorganized by the exudative hyperreflective material never recovers its normal structure.

The good response of anti-vascular endothelial growth factor (VEGF) therapy is very evident in OCT angiography by the lack of decorrelation (Figure 12).

■■BEST MACULAR DYSTROPHY Best macular dystrophy is an autosomal-dominant macular dystrophy w ith bilateral v itelliform lesions resulting from pathogenic variation of BEST1 gene (Figure 15A).

Choroidal neovascularization can complicate best dystrophy and early diagnosis is important to obtain better visual outcome (Figures 14 and 15). Serous detachment is often associated with vitelliform deposit in B-scan with several variation during follow-up and that is why OCTA gives additional and valuable information about CNV growth to propose anti-VEGF therapy when necessar y (Figure 16).

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Section 2: Retina OCT angiography examination: Age-related macular degenerations Figures 10A to D  (A and B) Fluorescein angiography of classic, late leaking choroidal neovascularization (CNV) (white arrow) along the bed of the streak. (C and D) Indocyanine green (ICG) angiography barely shows CNV in the early phase frame (white arrow), while the fluffy fluorescence on the late frame allows to differentiate CNV from the hyperfluorescent AS. A second zone of late hyperfluorescence (red arrow) is visualized.

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Figures 11A and B  (A) Optical coherence tomography (OCT) B-scan depicts a mild hyperreflective sub-retinal material corresponding to recent classic choroidal neovascularization (CNV) associated to a small retinal pigment epithelium (RPE) detachment (red arrow). (B) Optical coherence tomography (OCT) B-scan passing on the indocyanine green (ICG) hyperfluorescent zone visualized on late ICG picture. The RPE is elevated by a mildly reflective material.

CHAPTER 9: Oct angiography other cnv not from amd Figures 12A and B  (A and B) Optical coherence tomography (OCT) angiography, thanks to an adequate segmentation, visualizes the whole choroidal neovascularization (CNV) and allows to disclose the presence of an occult component at the level of the small RPE detachment (red arrow).

A Angioflow

B Angioflow

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Figure 13  After an anti vascular endothelial growth factor (VEGF) treatment the decorrelation signal has disappeared in both neovascular foci, but on B-scan OCT, a slight elevation of retinal pigment epithelium (RPE) persists.

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X5 4 years later

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Figures 14  Optical coherence tomography angiography (OCTA) of the same eye than Figures 10 to 12, 4 years later. Choroidal neovascularization (CNV) visualized in A recurred and needed 5 additional intravitreal injections of anti-vascular endothelial growth factor (VEGF). 4 years after the beginning of treatment, the surface of decorrelation signal has increased but persisted beyond the RPE plane.

E

Figures 15A to E  (A) Color retinal fundus of Best disease with characteristic appearance of egg-yolk in the macula area in a 27-yearold woman. (B) The presence of a serous retinal detachment is typical of the late evolution stages of the Best material as in this B-scan, stays stable during follow-up, and is not associated to vascular recurrences. (C) Optical coherence tomography angiography (OCTA) highlights the presence of a quiescent neovascular lesion secondary to a Best disease. Note as on OCTA overlay in B-scan (D) the decorrelation signals are leaked in the scar tissue. This last feature must be known to avoid useless treatments for an otherwise quiescent neovascularization. (E) 3D volume rendering acquisition with Solix (Optovue, Fremonte) of this quiescent neovascular lesion showing a dome-shaped appearance of this choroidal neovascularization (CNV) in 3D according to the protruding shape of the lesion in B-scan.

CHAPTER 9: Oct angiography other cnv not from amd

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Figure 16  During the follow-up, optical coherence tomography angiography (OCTA) allows to confirm the stability of this neovascular network. The comparison between the two visits shows a stable decorrelation signal at the level of choroidal neovascularization (CNV).

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Figures 17A and B  (A) Fluorescein angiography of classic choroidal neovascularization (CNV) secondary to MC. Early hyperfluorescent CNV is encircled by a ring of elevated hypofluorescence. Late leakage masks the details of CNV. Multiple early hyperfluorescent spots due to window defect are the angiographic sign of the past choroiditis. On indocyanine green (ICG) angiography, the small size of CNV does not allow the visualization of the neovascular details. Choroiditis scars persist hypofluorescent (B) Optical coherence tomography (OCT) scan depicts a mildly reflective sub-retinal material typical of classic choroidal neovascularization (CNV) associated with a serous retinal detachment. On OCT angiography (cube 3 × 3 mm2), the sea fan shape neovascularization is perfectly visible as a lace of vessels.

B Angioflow

■■CNV IN MULTIFOCAL CHOROIDITIS (FIGUREs 17A AND B) In multifocal choroiditis (MC), classic CNV penetrates under the neurosensory retina through a post-inflammatory discontinuation of Bruch’s membrane and RPE (Figure 17A). On OCT angiography, CNVs are not different from classic CNV of AMD showing a typical sea fan or wheel-rays shape, but type-1 CNVs are always absent (Figure 17B).

Anti-VEGF treatment usually obtains a regression of the subretinal neovascular component, but the CNV at the penetration site persists perfused. This persistence can be the reason for further recurrences (Figures 18A and B). Optical coherence tomography angiography may provide some information about peculiar details of CNV complicating retinal diseases, which cannot be imaged with other techniques. In our experience, OCT angiography is the new fundamental tool for early and proper diagnosis and management of choroidal neovascularization.

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Figures 18A and B  (A) Choroidal neovascularization (CNV) before and (B) after anti-vascular endothelial growth factor (VEGF) treatment. The regression of the sub-retinal CNV is complete. Only the vessels at the penetration site through the retinal pigment epithelium (RPE) (postinflammatory disruption of Bruch’s membrane and RPE) persist perfused.

■■REFERENCES 1. Jia Y, Bailey ST, Wilson DJ, et al. Quantitative optical coherence tomography angiography of choroidal neovascularization in age-related macular degeneration. Ophthalmology 2014; 121:1435–44. 2. Jia Y, Tan O, Tokayer J, et al. Split-spectrum amplitude-decorrelation angiography with optical coherence tomography. Opt Express 2012; 20:4710–25. 3. Jia Y, Wei E, Wang X, et al. Optical coherence tomography angiography of optic disc perfusion in glaucoma. Ophthalmology 2014; 121:1322–32.

4. Lumbroso B, Huang D, Jian Y, Fujimoto JG, Rispoli M. Clinical guide to Angio-OCT. New Delhi: Jaypee Brothers Medical Publisher (P) Ltd.; 2014. 5. Spaide RF, Klancnik JM Jr, Cooney MJ. Retinal vascular layers imaged by fluorescein angiography and optical coherence tomography angiography. JAMA Ophthalmol 2015; 133:45–50. 6. Wei E, Jia Y, Tan O, Potsaid B, et al. Parafoveal Retinal Vascular Response to Pattern Visual Stimulation Assessed with OCT Angiography PLoSOne 2013; 8:e81343.

Chapter 10 OCT angiography follow-up of neovascularization after treatment Bruno Lumbroso, Marco Rispoli, Maria Cristina Savastano

■■INTRODUCTION Optical coherence tomography (OCT) angiography allows to perform easily, and without problems for the patient, more than a few examinations in order to follow closely the evolution after treatment. We report OCT angiographic choroidal neovascularization (CNV) response to treatment in type 1, type 2, and type 3 CNVs. The software shows the blood flow inside the CNV (average pixel density) and the CNV area, correlated with the intravitreal injections and visual acuity. Our experience confirms Lumbroso and Huang publication and shows that reopening of CNV vessels occurs generally 2 weeks prior to fluid re-accumulation. It appears that CNV flow and area are leading indicators that precede fluid accumulation and visual decline. OCT angiography might be useful in guiding the interval between injections so that fluid reaccumulation does not occur. It is also interesting whether more frequent injections that do not allow the reopening of CNV channels might affect earlier and more permanent CNV regression.

■■IMMEDIATE FOLLOW-UP Vascular changes appear immediately: 24 hours after the injection, the vascular network is brusquely reduced and fragmented. The secondary branches and most of the loops disappear immediately after the intravitreal injection. Flow is disrupted. This characteristic could be due to a slower flow or to a pulsated flow, which makes circulation invisible, or to a true temporary closure of the capillaries involved. The feeder vessel or a bundle of central branches always remains visible. The dark halo is unaffected. 7–15 days after the injection: The secondary branches and most of the loops continue to decrease slowly until the 15th day. The dark halo dimensions decrease markedly. After 20–25 days, few branches reappear. Fluid reaccumulation: Reopening of NV vessels occurs generally 2 weeks prior to fluid reaccumulation.

membrane surface is smaller with less branches, less loops and fewer, thicker, and straighter vessels. Subsequent treatments lead to further increases in flow, in trunk diameter and to greater arterialization (Figures 1 to 4).

■■1-YEAR FOLLOW-UP ■■Recurrences arterialization– maturation When monitoring NV evolution for 1 year, one kind of recurrence is observed: Normal, cyclic recurrence after each treatment. Acute nonperiodic recurrences will appear after more than 1 year. During these 6–12 months period, vessel maturing initiates and then becomes permanent. After 6 months, vessel maturation begins. Scaffold vessels are more clearly delineated and still evolutive. They decrease and sometimes disappear after each new injection. Small capillaries continue to disappear and reappear following 60 days cycles after each injection. Peripheral anastomoses are the first small vessels to disappear. After each treatment, the same main vessels reappear with increased flow and decreased branch density. Some main branches are less affected by treatment. Before treatment, vessel pattern is complex, after treatment pattern is less complex with tangled features (Boxes 1 to 3). After 1 year, maturation features are permanent. Scaffold vessels are persistent, without variation even after new injections. Capillaries density decreases permanently. At onset, the vascular NV net shows complex pattern. After 6 months, pattern is simplified. After 1 year, arterialization or maturation pattern seems permanent.

■■NV FLOW FOLLOW-UP OVER SEVERAL YEARS AND NUMEROUS INJECTIONS

4 weeks later: The main vessels reappear and seem and thicker than before treatment. They look original vessels but thicker and less winding, with a faster flow. The increase in flow modifies the walls and will lead later to a histological change and to vessel arterialization. They are arterialized, and their surface is smaller.

After 1 or 2 years of evolution and injections of anti-VEGF, the new vessels are larger, thicker, and straighter, than in naïve NV, with an irregular flow; thin capillaries or fine loops disappear.

New thicker branches: New branches appear and pre-existing thin branches reappear enlarged. In the first recurrence, the neovascular

When monitoring NV evolution for a long time (2 or more years), two different kinds of recurrences are observed:

■■RECURRENCES

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Figure 1  AngioFlow evolution sequence of neovascularization (NV) treated with Aflibercept injections. NV network is clearly seen. Red Cross indicates the Aflibercept injection. 24 hours after the injection, small capillaries disappear, as the blood flow inside decreases and are not seen, due to their occlusion, or, more probably because flow is too low or pulsating to be apparent. Main vessels form a scaffold that persists during the follow-up. 15–20 days later, capillaries reopen. The new injection causes again the small capillaries to disappear. Below we see the B-scan structural sequence correlated to the AngioFlow images. Cross-section scans allow to study with precision intra- and sub-retinal fluid evolution and the progressive fluid resorption.

The first treatment in naïve patient gives most evident results w ith N V area showing a sharp decrease, immediately after the injection. 24 hours after IVT, new vessel density decreases immediately giving a tangled pattern, the area where vessels regressed appear darker and reaching maximum regression 10–15 days later. 7 days after IVT (maximum effect), some branches disappear leaving a very low-density dark area. There is a fluctuation, increase, and decrease of the obscure halo area, in dimensions and in darkness. The sharp NV area regression is followed by a slow increase of NV area till 50–60 days. 30–40 days after injection, a part of lesser vessels reopens. High flow highlights the only large vessels. The full recurrence is observed 50–60 days after anti-VEGF injection, after every injection.

Figure 2  Neovascularization (NV) area hand drawing. The operator draws manually the NV limits, and flow areas are highlighted in yellow.

1. Normal, cyclic recurrences after treatment 2. Acute nonperiodic recurrences, occurring independently from treatment 1. Normal, cyclic recurrences after treatment: After the loading phase in type 1 and type 2 NV, we observe normal cyclic periodic recurrences after each treatment, with a periodicity of 50–60 days after intravitreal injection. Before the first injection and between recurrences, we observe a dark halo area of about 50 µ around the CNV.

The cycle seems to be quite regular: Variation between cycles does not change more than 10–20 days. There are exceptions in this evolution after treatment—tachyphylaxis, nonresponder, but the normal NV area curve is quite repetitive—sharp downward slope, followed by slow upward slope. A few days before recurrences, the CNV density and vessel thickness increase locally. Relapses, in our observation, sprout most of the time from some focal hyperdense spots located in focal NV loops. Parallel to hyperdense spots the dark halo increases in dimension and darkness. Fluid reaccumulation: It occurs generally 2 weeks after N V reopening. The recurrence morphology after repeated injections shows a variety of features, but the basic pattern is always the same. After each treatment, the same main scaffold vessels seem to reappear with increased flow and decreased branch density. A dark halo area of about 50 µ surrounds the NV. It seems some main branches are less affected by treatment. Dark halo dimensions decrease when the vessel density decreases. Before treatment, we observe an intricate vascular pattern; after treatment, we see a less intricate tangled pattern.

CHAPTER 10: OCT angiography follow-up of neovascularization after treatment

Figure 3  Neovascularization (NV) treated with ranibizumab, AngioFlow sequence. We can clearly see the NV network. Red stars indicate ranibizumab injection. 24 hours after the injection, small capillaries disappear, as flow is too low to be apparent. Main vessels form a scaffold that remains constant during the follow-up. 15–20 days later, capillaries reopen. The new injection causes again the small capillaries to vanish. Below we see the B-scan structural sequence correlated to the AngioFlow images. Cross-section scans allow to study with precision intra- and sub-retinal fluid evolution and the progressive fluid resorption. Cystoid edema cells disappear.

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CNV area 6000 5000 4000 3000 2000 1000 0 21-lug 21-ago 21-set 21-ott 21-nov 21-dic 21-gen

2. Acute nonperiodic recurrences are not related to treatment: Acute nonperiodic recurrences, occurring autonomously from treatment, show features that can be shoot, bud, sprout, and outgrowth. Acute, noncyclic recurrences sprout from some focal hyperdense spots located in focal CNV loops. The normal cyclic recurrence generally is extensive and global. It could be more rarely localized. Acute, nonperiodic recurrences, occurring independently from treatment, may have a specific location—terminal, axillary, lateral, adventitious, and localized in different layers (superior or inferior layer). These acute, nonperiodic recurrences occur independently from treatment once or twice a year (Box 4).

■■LONG-TERM FOLLOW-UP OUTCOMES AFTER 4- OR 5-YEARS TREATMENT: STABILIZATION, CHRONICITY, FIBROSIS, AND ATROPHY Long-term follow-up: After 5 years or more monitoring, the end results possibilities of NV evolution are four—stabilization, chronicity, fibrosis, and atrophy. Our group analyzed 451 eyes of type-1 NV in exudative AMD, treated with anti-VEGF during 4 years follow-up, using structural OCT and optical coherence tomography angiography (OCTA).

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Box 1  Choroidal neovascularization (CNV) evolution after treatment.

Box 2  Choroidal neovascularization (CNV) network and dark halo long-term evolution over years.

Early changes:

After 50 or more injections:

24 hours after injection: Immediate regression:

•• •• •• •• ••

•• Vascular network fragmentation •• Secondary branches and most of the loops disappear •• Feeder trunk or a bundle of central branches remain visible •• Dark halo unchanged 7–15 days maximal regression: •• Halo dimensions decrease markedly 20–25 days—some larger vessels reappear: •• Less tortuous •• Straighter •• Thicker 30–40 days—more large new vessels reappear: •• Same course of the original vessels •• Thicker, less winding, and faster flow •• Arterialized 40–50 days—CNV is visible again: •• Increases in flow •• In trunk diameter •• Greater arterialization

Box 4  Recurrences.

Fibrous scar Large vessels, thick and straight, and frequently segmented Irregular flow No thin capillaries or fine loops Dark round shadow behind and around CNV

Box 3  Arterialization–maturation. After 6 months—main vessels arterialization: •• A vascular scaffold appears •• Vessels less sinuous, thicker, and straighter than naïve CNV vessels After 1 year, maturation features are permanent: •• Scaffold vessels constant, without variation even after new injections •• Small capillaries density decreases permanently •• After each treatment, the same main vessels seem to reappear with increased flow and decreased branch density. It seems some main branches are less affected by treatment at onset complex pattern •• After 6 months, less complex pattern •• After one year, arterialization Table 1  Type-1 NV long-term evolution.

Two different kinds of recurrences:

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•• Periodicity of 50–60 days after intravitreal injection •• Cycle be quite regular •• Dark halo area of about 50 micron •• Full recurrence occurs 50–60 days after injection •• Cycle variation between 10 and 20 days •• Features extensive and global •• Recurrence morphology basic pattern is always the same •• Same main vessels with increased flow and decreased branch density •• After treatment, less complex tangled pattern 2. Acute nonperiodic recurrences: •• •• •• ••

Occur independently from treatment Features: Shoot, bud, sprout, and outgrowth Sprout from some focal hyperdense spots located in focal loops May have a specific location: Terminal, axillary, lateral, adventitious, and localized in different layer (superior or inferior layer) •• Independent from treatment, once or twice a year

Half of the participants attained BCVA stabilization although there were some eyes in which the BCVA decreased brutally. Two possible NV developments were observed: 1. Vision increased or stabilized (positive evolution) 2. Vision decreased (negative evolution) (Table 1)

■■Improvement—Stabilization We considered NV stabilized when we observed a long-term remission and absence of fluid or hemorrhages for >6 months. NV evolution seems at a standstill and no activity signals are seen. Clinical appearance is silent with no exudation. Type-1 NV “positive evolution” as stabilization or improvement corresponds to 20% while chronicity to 35% of cases (Figure 5).

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(NV: neovascularization; RPE: retinal pigment epithelium)

■■Chronicity We diagnosed N V chronicit y when neovascularizat ion re­­ appearances needed repeated reinjection. Acute disease changed to chronic disease. NV appeared quiescent most of the time with constant frequent repeated recurrences (Figure 6).

■■Fibrous scars After a long evolution with 50 or more injections of anti-VEGF, the new vessels are encased in a fibrovascular scar. Inside the scar, vessels are large, thick, and straight, with an irregular flow; thin capillaries or fine loops have disappeared. The fibrous scar almost always contains a residual vascular network. The OCT images highlight a perfused neovascular net work in the subretinal fibrosis. Inside the fibrous scar, neovascular patterns, dead tree pattern, or tangled network can be seen. Flow is irregular and no capillary structure is evident. A dark round shadow behind and around the neovascular network is present and should be assessed (Figure 7) (Box 5).

■■Atrophy Neovascularization is associated to atrophy. Structural OCT shows no exudation above hyperreflective material below retinal pigment

CHAPTER 10: OCT angiography follow-up of neovascularization after treatment Figure 5  Stabilized neovascularization (NV) after treatment. Structural optical coherence tomography (OCT) shows lack of intraretinal exudation and irregular retinal pigment epithelium (RPE) contour in foveal region. OCT angiography reveals flow signal with well-defined outline and dark halo absence. Vessels are thick and straight, few small capillaries are seen, few anastomoses and broken arcade. This eye received three intravitreal injections and became stable for more 12 months. Good vision—20/80. OCT angiography top figure left, Structural cross-section OCT angiography bottom left, en face figure top right, structural crosssection OCT bottom right.

Figure 6  Chronic neovascularization (NV). Optical coherence tomography (OCT) angiography top figure left, structural cross-section OCT angiography bottom left, en face figure top right, and structural cross-section OCT bottom right. Structural OCT shows presence of exudation with intraretinal cystic spaces. Small fluid retinal elevation. Stratified hyperreflective material below RPE can be observable in foveal region. Optical coherence tomography angiography (OCTA) exposes the presence of flow signal with few thin capillaries and dark halo around the NV. These eyes need multiple treatments to remain stable. This eye was treated for 2 years with cyclic recurrences after injections. Good vision—20/80.

epithelium (RPE). Foveal backscattering is well observable for RPE atrophy as choroidal vessels behind. OCTA revealed the presence of rounded flow signal without capillary fringe. This eye did not need to be injected; further, the presence of atrophy will compromise visual recovery (Figures 8 and 9).

Hemorrhages or RPE tears Hemorrhages or RPE tears are rare and grave sudden complications during negative evolution. Hemorrhages or RPE tears develop in a few months to fibrosis or atrophy.

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Section 2: Retina OCT angiography examination: Age-related macular degenerations Figure 7  Fibrotic neovascularization (NV). Optical coherence tomography (OCT) angiography top figure left, structural cross-section OCT angiography bottom left, en face figure top right, structural cross-section OCT bottom right. Structural OCT shows no exudation above hyperreflective material below retinal pigment epithelium (RPE). Bruch’s membrane is well evident as well choroidal vessels and fibrovascular tissue. OCTA reveals large-flow signal with evident main feeder trunk and “dead tree” feature. At the en face figure, close to fibrosis, an area of atrophy can be seen. This eye had poor visual acuity and did not improve after treatment.

Box 5  Causes of vascularized retinal scars. •• •• •• •• •• ••

Advanced macular degeneration Diabetic fibrovascular membrane Myopic fibrous scars Chorioretinitis scars Trauma Laser scars

■■TREATMENT RESULTS Optical coherence tomography angiography provides images of blood flow in the retina and choroid with high levels of detail and affords more information than dye angiography (fluorescein angiography/FA and indocyanine green angiography/ICG).1-3 OCTA allows to understand, quantify, and follow the evolution after new vessels treatment. NV treatment should be early, before widespread structural damage and patient should be monitored through treatment and retreatment. Structural B-scan section highlights retinal alterations in morphology and structure of retinal layers. The vascular layers of blood vessels, superficial and deep capillary networks, are well apparent with OCTA.4 It allows better investigation in many disorders and new treatments.3 Anti-vascular endothelial growth factor (anti-VEGF) treatment is universally recognized to give positive results in reducing NV activity and maintaining good vision for years.5-7 Numerous trials have verified visual improvement of about 10 letters at 2 years in eyes with neovascular AMD receiving monthly anti-VEGF therapy.8-10 5-year results from the CATT trial have shown long-term visual decline with chronic anti-VEGF therapy.11 More than a few factors play a role in producing vision damage in eyes with long-term anti-VEGF therapy. One possible cause has been postulated by Dansingani and Freund that observed a

mature tangled vascular pattern in type-1 lesions as resistance factor to macular atrophy.12 Christenbury et al. described high level of macular atrophy development predominantly eccentric to the PED with long-term anti-VEGF therapy for eyes with type-1 NV secondary to AMD.13 Many studies stated chorioretinal atrophy and BCVA decreased results; however, several other trials described the advantages in vision preserved or improved. OCTA allows to understand, quantify, and follow the evolution after new vessels treatment. NV treatment should be early, before the occurrence of widespread structural damage. And, patient is monitored for treatment and retreatment.14,15

■■Positive evolution We considered NV stabilized when we observed a long-term remission and absence of fluid or hemorrhages for more than 6 months. NV evolution seems at a standstill and no activity signals are seen. Clinical appearance is silent with no exudation. Evolution was positive in 55% of cases with 20% stabilization and NV 35% chronicity. Even with no exudation, NV area is larger at the end of the observation period.

■■Negative evolution Negative evolution has been observed in 45% of cases with fibrosis (18%), atrophy (25%), and hemorrhages or RPE tears (2%). We d iag nosed N V chronicit y when neovascu la r izat ion reappearances needed repeated reinjection. Acute disease changed to chronic disease. NV appeared quiescent most of the time with constant frequent repeated recurrences. NV area was regularly larger at the end of the observation period. The NVs monitored in long-term evolution showed that the new vessels become larger, thicker, and straighter. Flow is faster. No

CHAPTER 10: OCT angiography follow-up of neovascularization after treatment Figure 8  Neovascularization (NV) associated to macular geographical atrophy. Optical coherence tomography (OCT) angiography top figure left, structural cross-section OCT angiography bottom left, en face figure top right, structural cross-section OCT bottom right. Structural OCT shows no exudation above hyperreflective material below retinal pigment epithelium (RPE). Retina is thin. Foveal backscattering is well observable for RPE atrophy as choroidal vessels behind. Optical coherence tomography angiography (OCTA) reveals the presence two irregularly rounded flow signals without capillary fringe (nonactive NV). At the en face figure, a large area of atrophy can be seen. This eye did not need to be injected. Vision—20/200.

Figure 9  Optical coherence tomography (OCT) angiography of type-1 neovascularization (NV) treated by anti-vascular endothelial growth factor (VEGF) in long (5 years) follow-up. OCT angiography outer retina top figure left, OCT angiography choriocapillaris top figure left. Structural cross-section OCT angiography bottom. Optical coherence tomography angiography (OCTA) shows arterialization of the new vessels that become larger, thicker, and straighter over time. They are hypermature. The NV area finally is larger than before treatment and the visual acuity worse (20/400).

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Section 2: Retina OCT angiography examination: Age-related macular degenerations

thin capillaries or fine loops are visible. Whatever the evolution, the vessel area will be finally larger than before treatment. After each treatment,the same main vessels seem to reappear with increased flow and decreased branch density. It seems some main branches are less affected by treatment. As previously described by Spaide, at onset complex pattern after treatment, the less complex feature of NV becomes detectable—arterialization.16

■■MONITORING NV EVOLUTION A few hours after the injection, the vascular network is brusquely fragmented. The secondary branches and most of the loops fade immediately after the intravitreal injection. This could be due to a slower flow or to a pulsated flow, which makes circulation invisible, or to a true temporary closure of the capillaries involved. The feeder vessel or a bundle of central branches always remains visible. The dark halo is unaffected. Reopening of NV vessels occurs generally 2 weeks prior to fluid reaccumulation. Four weeks later, the main vessels reappear, thicker than before treatment, with a faster flow. The increase in flow modifies the walls and will lead later to vessel arterialization. During long-term follow-up, we observe two kinds of evolution— positive and negative evolution.17 Neovascularization “positive evolution” as stabilization or improvement corresponds to 20% while chronicity to 35% of cases. Most eyes with chronic evolution had cyclic periodic reactivation after treatment, with a periodicit y of 50–60 days after each intravitreal injection. Before the first injection and between recurrences, we observed a dark halo area of about 50 µ around the NV. The meaning of dark halo is debated;18-21 however, it is probably due to blood sequestering by NV reactivation; increased dark halo means NV growth.22 An acute nonperiodic reactivation may occur independently from treatment. “Negative evolution” as fibrosis was observed in 18% of eyes, chorioretinal atrophy in 25%, and hemorrhages or RPE tears in 2%. Optical coherence tomography angiography is crucial to evaluate and quantify NV, highlight NV activity, and permit assessment,

treatment, and monitoring of neovascularization. NV morphological aspect evaluated by OCTA is able to differentiate silent NV lesions from exudative NV.17

■■When should we stop treatment? The treatment suspension conditions are definitely linked to the visual function and the structural feature. The OCT structural aspect in these patients is very important, as it allows us to estimate a potential recovery based on the tissue integrity of the retina. As long as the vision remains good, we should treat. If the contralateral eye is better, an eye with vision 40 years old (mostly females) with bilateral fashion.1 MacTel2 is linked to several systemic vascular diseases such as hypertension and diabetes. Gass and Blodi firstly described and classified the disease using ophthalmoscopic and fluorescein angiography (FA) examinations.2,3 Later, Yannuzzi and coworkers showed the clinical features by means of multimodal retinal imaging.4 Diagnosis of MacTel2 is often random during a routinely eye examination, because in the early stages, it does not cause any visual impairment. The clinical findings include loss of retinal transparency, crystalline deposits, right-angle venules, presence of intraretinal cystoid spaces, and migration of retinal pigment resulting in black hyperplastic plaques formation (Figure 1). In the late stage of the disease, MacTel2 could be complicated by subretinal macular neovascularization (SRMNV) as well as the anastomosis between the retinal and choroidal circulations. Because the clinical features of MacTel2 are rather subtle by ophthalmoscopic examination in the earlier stages, a multimodal

Figure 1  Color fundus picture of a 69-year-old woman with MacTel2 showing typical clinical findings such as mild grayish discoloration with loss of retinal transparency in the temporal macular sector, multiple and golden intraretinal crystalline deposits, right-angle venule, and retinal pigmented black hyperplastic plaques.

retinal imaging approach is mandator y for diagnosing, for monitoring the progression of the disease, and for its management.5 The FA examination showed the presence of telangiectatic capillaries, mainly in the deep retinal layer of the temporal macula, and hyperf luorescence in the early and/or late phases of the angiogram (Figure 2). Optical coherence tomography (OCT) showed the presence of hyporeflective cavities (cystic spaces) in the inner and outer retina, hyperreflective material in the middle retina, loss of the photoreceptors (disruption of ellipsoid zone), subretinal highreflective materials, and then retinal atrophy. It is not surprising that FA leakage is not related to retinal cysts (Figure 3). It has been postulated that they match with Müller cell depletion, as well as a loss of macular pigments.6 Furthermore, it has always been intriguing that deep capillary plexus is not clearly imaged by using FA examination in both healthy and diseased subjects. Since its introduction, the OCT angiography (OCTA) has been widely used for imaging and for quantifying, layer-by-layer, retinal microcirculation in healthy and eye diseased,7 and by overcoming the use of standard FA.8 Several authors described morphological features and vascular changes of MacTel2 by means of OCTA.9-11 A lt hough its pat hogenesis remains unclear, it has been speculated that the degeneration of the Müller cells is the “primum movens” that lead to irreversible retinal tissue injury.12 Subsequently, the subsidence of the glial cell scaffold leads earlier to the invasion of deep plexus vessels in the outer retina. The displacement of inner retinal vessels would bring the deep capillaries closer to the “hypoxic” environment of the inner segments of the photoreceptors.13 This latter “hypoxic” phenomena could explain dilation and proliferation of retinal vessels, as well as the development of SRMNV, mainly due to the imbalance of retinal vascular growth factors.13 An OCTA-based model of a hypothetical MacTel2 pathogenesis has been previously described (Figure 4). OCTA examination demonstrated that the vascular changes begin earlier in the deep capillary plexus, mainly in the temporal perifoveal area, and later spread circumferentially with the progression of the disease.13 Furthermore, it has been highlighted that the decrease of vessel density may occur only in the superficial capillary plexus, particularly in the temporal sector.11 Recently, it has showed an excellent reliability and validity of the OCTA examination for detecting and grading the different stages of the disease by comparing with well-established retinal imaging techniques.11 In detail, four grades of the disease have been reported according to the lateral extension of vascular abnormalities (Figure 5). Regardless to the grade of the disease, OCTA examination detected the main features of MacTel2 as rarefaction of the superficial capillary plexus with increasing intervascular spaces, dilated vessels of the deep capillary plexus, and the presence of right-angle

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Figures 2A to F Multimodal retinal imaging assessment of a 57-year-old woman with MacTel2. Color fundus picture (A) showing loss of parafoveal retinal transparency, inner retinal crystalline deposits, telangiectasis, and rightangled venule, and barely visible cavities. Fluorescein angiography (FA) showing early hyperfluorescence due to dilated vessels (B) and late leakage (C). Optical coherence tomography angiography (OCTA) showing rarefaction of the superficial capillary plexus with increasing intervascular spaces, and right-angle venule (D), and microvascular abnormalities due to dilated vessels in the deep capillary plexus (E). OCTA slab of the outer retina highlighting the intraretinal proliferation (F) missed with FA. (Reproduced by authorization from S Karger AG, Basel, copyright holder).

Figures 3A and B  Simultaneously fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT) examinations in patient with MacTel2. Late phase of FA (Panel-A, top left) showing oval-shaped parafoveal hyperfluorescence (green arrow). Note as the leakage matched with middle retinal features (green line) seen with SD-OCT (Panel-A, top right). Conversely, SD-OCT (Panel-B, bottom right) showed retinal thinning, the presence of cystic spaces in the inner and outer retina (green line), and loss of the photoreceptors (disruption of myoid, ellipsoid, and interdigitation zones) that are not related with FA (Panel-B, bottom left) features (green arrow). A

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C Figures 4A to C  Drawings (A), spectral domain optical coherence tomography (SD-OCT) (B), and optical coherence tomography angiography (OCTA) (C) images illustrating the pathogenesis of MacTel2 (see explanation in the text). Loss of Müller cells leads to the early retinal tissue injury (Panel-A, top). SD-OCT with flow overlay showing early changes as cystoid spaces (Panel-B, top). OCTA highlighting early microvascular abnormalities of deep vascular plexus, mainly temporal to the macula (Panel-C, top). Invasion of the deep vessels in the outer retina following the subsidence of Müller cells scaffold (Panel-A, middle). SD-OCT with flow overlay showing cavitation and hyperreflective material between middle and outer retina (Panel-B, middle). OCTA showing proliferation in the outer retina (Panel-C, middle). Extension of the proliferation and development of subretinal macular neovascularization (SRMNV) (Panel-A, bottom). SD-OCT showing cavitation, and flow signal (shown in red) within the subretinal hyperreflective material (Panel-B, bottom). OCTA detecting SRMNV as roundish flow signal in the outer retina (Panel-C, bottom). Source: Spaide RF, Klancnik JM Jr, Cooney MJ, et al. Volume-rendering optical coherence tomography angiography of macular telangiectasia type 2. Ophthalmology 2015; 122:2261–2269. Figure 5 Optical coherence tomography angiography (OCTA) grading of MacTel2: Grade 1—vascular anomalies in the deep and/or superficial plexus temporal to the fovea; Grade 2—vascular anomalies in the deep and/or superficial plexus temporal and nasal to the fovea; Grade 3—markedly diffuse circumferential vascular anomalies in the deep and superficial plexus; and Grade 4— neovascularization in the outer retina with any OCTA signs of Grade 1 to 3. (T: temporal; N: nasal; S: superior; I: inferior; NV: neovascularization). (Reproduced by authorization from ARVO, copyright holder).

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Figures 6A to C Retinal imaging assessment of a 57-year-old woman with MacTel2. Fundus color picture (A) showing temporal loss of retinal transparency, tiny intraretinal deposits, right-angle venule, and focal hyperplastic plaque. Optical coherence tomography angiography (OCTA) examination revealing rarefaction and increased intervascular spaces in superficial plexus (B) and abnormally dilated deep vessels (C).

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Figures 7A and B  Angio retina trend analysis comparison (2-years follow-up) between healthy subject (Panel-A) and patient affected by MacTel2 (Panel-B). Note the significant increasing, due to progressive temporal dragging of macular vessels, of the acircularity index in MacTel2 compared to healthy age-matched control.

venule (Figure 6). Subsequently, progressive vascular displacement with temporal dragging of macular vessels14 may significantly increase the acircularity index compared to healthy age-matched controls (Figure 7). This latter aspect could reflect the severity of the disease.15 Outer retina invasion by deep retinal capillaries leads to sprouting of intraretinal proliferation and/or SRMNV, as a well as a development of retinal-choroidal anastomosis (RCA) in the later stages of the disease. Intraretinal proliferation usually involves outer retina by connecting with both deep and superficial capillaries, and draining into the right-angle venule (Figure 8A). It would seem to match with the “dark area” of ellipsoid zone loss observed on structural en-face OCT image (Figure 8B).16 Furthermore, intraretinal proliferation might appear as a well-defined flow area by using a project–artifacts–removal (PAR) algorithm that automatically cleans flow signal projections from avascular retinal layer while preserving the morphology of the deep capillary plexus (Figure 9).17 OCTA has the potential to image SRMNV compared to FA. It is more able to see what we do not see with standard FA,

because it does not suffer by masking of leakage of dye (Figure 10). Moreover, being noninvasive examination, it is useful for close follow-up in patients treated with antivascular endothelial growth factor (anti-VEGF) drugs (Figure 11). Indeed, intravitreal injection of anti-VEGF has been found to be safe and effective in treatmentnaïve SRMNV secondary to MacTel2.18 More recently, OCTA has also established the presence of RCA as a vascular connection from the retina to the choroid (Figure 12). It has been speculated that RCA may occur before SRMN V, rather than after subretinal pigmented epithelium neovascularization development.19 This latter aspect may suggest that RCA could happen during the remodeling and/or healing of the retinal degenerative injury. In conclusion, OCTA examination is relatively new, fast, and safe tool that may give more insight depth into the retina. It could be considered as a first-choice ret i na l i m ag i ng met hod for detec t i ng a nd ma nag i ng of MacTel2. 20

CHAPTER 14: OCT angiography examination of type 2 idiopathic macular telangiectasia Figure 8  Optical coherence tomography angiography (OCTA) findings in a 62-year-old woman with proliferative MacTel2. Colorcoded OCTA and coregistered structural B-scan (A) showing rarefaction of the superficial capillary plexus (in white color) with increasing intervascular spaces, right-angle venule, and vascular displacement with temporal dragging of macular vessels; the deep capillary plexus (in magenta color) showing dilated vessels. Note the intraretinal proliferation (in cyan color) involving outer retina space as flow-signals in the structural B-scan (cyan arrowheads), and connecting to the capillaries of both deep and superficial capillaries, and draining into right-angled venule (white arrowhead). The structural en-face OCT image (B) at level of ellipsoid zone with the superimposition of the intraretinal proliferation (in cyan color) showing a dark area (between arrowheads) corresponding to the ellipsoid zone loss clearly seen on the structural B-scan (between arrowheads). (Reproduced by authorization from S Karger AG, Basel, copyright holder). A

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Figures 9A and B Optical coherence tomography angiography (OCTA) findings in a 57-year-old man with proliferative MacTel2 by comparison of different retinal layers before (A) and after suppression of projection artifacts (B). The projection artifacts are clearly visible in the coregistered structural B-scan as vertical red streaks trailing below the retinal capillaries and projected on the outer retina (A, arrowheads). Projection artifacts removal (PAR) software automatically cleaned the flow projections from avascular retina, as seen in B-scan (B, arrowheads), while preserving the morphology of the deep capillary plexus, outer retina, and choriocapillaris. (Reproduced by the permission of S Karger AG Basel, the copyright holder).

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CHAPTER 14: OCT angiography examination of type 2 idiopathic macular telangiectasia Figures 12A to D Sequence of en-face optical coherence tomography angiography (OCTA) angiograms and coregistered structural B-scan slabs by scrolling down depth into the retina, and showing RCA’s feature in a 57-year-old man with MacTel2 complicated with SRMNV. Superficial and deep capillary plexus (A and B), outer retina (C), and choriocapillaris (D) OCTA slabs and co-registered B-scan with C A B D flow overlay (shown in red) highlighting the course of retinal choroidal anastomosis (RCA) as a vertical bridge connecting both retinal and choroidal circulation (yellow arrow) and within an outer “conical” retinal hyperreflective lesion (white arrowhead).

■■REFERENCES 1. Klein R, Blodi BA, Meuer SM, et al. The prevalence of macular telangiectasia type 2 in the Beaver Dam eye study. Am J Ophthalmol 2010; 150:55–62.e2. 2. Gass JD, Oyakawa RT. Idiopathic juxtafoveolar retinal telangiectasis. Arch Ophthalmol 1982; 100:769–780. 3. Gass JD, Blodi BA. Idiopathic juxtafoveolar retinal telangiectasis. Update of classification and follow-up study. Ophthalmology 1993; 100:1536–1546. 4. Yannuzzi LA, Bardal AMC, Freund KB, et al. Idiopathic macular telangiectasia. Arch Ophthalmol. 2006; 12:450–460. 5. Sallo FB, Leung I, Clemons TE, et al. Multimodal imaging in type 2 idiopathic macular telangiectasia. Retina 2015; 35:742–749. 6. Powner MB, Gillies MC, Zhu M, et al. Loss of Müller’s cells and photoreceptors in macular telangiectasia type 2. Ophthalmology 2013; 120:2344–2352. 7. Mastropasqua R, Di Antonio L, Di Staso S, et al. Optical coherence tomography angiography in retinal vascular diseases and choroidal neovascularization. J Ophthalmol 2015; 2015:343515. 8. Savastano MC, Rispoli M, Lumbroso B, et al. Fluorescein angiography versus optical coherence tomography angiography: FA vs OCTA Italian Study. Eur J Ophthalmol 2020; 31:514–520. 9. Thorell MR, Zhang Q, Huang Y, et al. Swept-source OCT angiography of macular telangiectasia type 2. Ophthalmic Surg Lasers Imaging Retina 2014; 45:369–380. 10. Spaide RF, Klancnik JM Jr, Cooney MJ. Retinal vascular layers in macular telangiectasia type 2 imaged by optical coherence tomographic angiography. JAMA Ophthalmol 2015; 133:66–73. 11. Toto L, Di Antonio L, Mastropasqua R, et al. Multimodal imaging of macular telangiectasia type 2: focus on vascular changes using optical coherence tomography angiography. Invest Ophthalmol Vis Sci 2016; 57:268–276.

12. Zhao M, Andrieu-Soler C, Kowalczuc L, et al. A new CRB1 rat mutation links to Müller glial cells to retinal telangiectasia. J Neurosci 2015; 35:6093–6106. 13. Spaide RF, Klancnik JM, Cooney MJ, et al. Volume-rendering optical coherence tomography angiography of macular telangiectasia type 2. Ophthalmology 2015; 122:2261–2269. 14. Spaide RF, Marco RD, Yannuzzi LA. Vascular distortion and dragging related to apparent tissue contraction in macular telangiectasis type 2. Retina 2017; 0:1–10. 15. Ersoz MG, Hocaoglu M, Sayman Muslubas I, Arf S, Karacorlu M. Macular telangiectasia type 2: Acircularity Index and Quantitative Assessment of Foveal Avascular Zone Using Optical Coherence Tomography Angiography. Retina 2020; 40:1132–1139. 16. Gaudric A, Krivosic V, Tadayoni R. Outer retina capillary invasion and ellipsoid zone loss in macular telangiectasia type 2 imaged by optical coherence tomography angiography. Retina 2015; 35:2300–2306. 17. Zhang M, Hwang TS, Campbell JP, et al. Projection-resolved optical tomographic angiography. Biomed Opt Express 2016; 7:816–828. 18. Narayanan R, Chhablani J, Sinha M, et al. Efficacy of anti-vascular endothelial growth factor therapy in subretinal neovascularization secondary to macular telangiectasia type 2. Retina 2012; 32:2001–2005. 19. Breazzano MP, Yannuzzy LA, Spaide RF. Genesis of retinal-choroidal anastomosis in macular telangiectasia type 2: a longitudinal study. Retina 2021; 41:464–470. 20. Mastropasqua R, Toto L, Di Antonio L. Optical coherence tomography angiography in idiopathic macular telangiectasia. ESASO course series, Basel, Karger 2020; 11:68–80.

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Chapter 15 OCT angiography of vascular occlusions CRVO, BRVO, CRAO, BRAO, and microvascular occlusions Marco Rispoli, Bruno Lumbroso, Maria Cristina Savastano

■■RETINAL VEIN OCCLUSIONS Vein occlusions may affect the central retinal vein or only some branches. Vein occlusions present two basic alterations—anomalies in vessel permeability and retinal ischemia.1 Vein occlusions can, therefore, be subdivided into: ⦁⦁ Edematous occlusions: The abnormal permeability of the vessels causes retinal edema, hemorrhages, and exudates with intraretinal fluid leakage (Figure 1) ⦁⦁ Ischemic occlusions: The ischemia leads to the appearance of cotton–wool exudates and highlights hypofluorescent sectors for hypo- or non-perfusion of the capillaries (Figure 2) ⦁⦁ Mixed edematous ischemic occlusions: As a consequence of a vein occlusion, mixed forms may occur with both edematous and ischemic components, with at times one form prevailing over the other (Figure 3)

⦁⦁ Vein inflammatory occlusions in young patients: They usually regress spontaneously (Figure 4) Various factors control the progress of vein occlusions:2 ⦁⦁ Age-related factors and cause of the obstruction ⦁⦁ Extent of the obstruction: This depends on the morphology of the lamina cribrosa and on the possibility of anastomoses of the optic-ciliary vessels. Fluorescein angiography (FA) is no more necessary for the diagnosis and study of the evolution of vein occlusions and for determining the type of treatment. FA also makes it possible to assess the presence, if any, of retinal and iris neovascularization that precedes neovascular glaucoma. In edematous capillar y disorders where blood stasis and vasodilation prevail, there is a quick formation of cystoid macular edema with severe visual impairment. In the forms with ischemic capillary diseases instead, non­ perfusion prevails with involvement of the arterioles. New vessels

Figure 1  Fluorescein angiography. Edematous branch vein occlusion: This fluorescein angiography shows intense staining of the occluded area that prevents visualization of the underlying vascular network. The fluorescein leaks inside the retina and diffuses in the edema zones.

Figure 2  Fluorescein angiography. Ischemic branch vein occlusion: Hypofluorescence is evident for lack of perfusion in the occluded area. Ischemic dropout areas are very dark. In this, we can clearly see shunts and truncated vessels, dilated vessels, microaneurysms, particularly at the border between normal and occluded retina. Courtesy: Luca Di Antonio

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Figure 3  Fluorescein angiography. Edematous branch vein occlusion: Areas with reduced perfusion coexist alongside areas with late fluorescein staining. We observe truncated vessels, dilated and twisting vessels, microaneurysms, principally at the border between normal and occluded retina.

Figure 4  Fluorescein angiography. Inflammatory vein occlusion in young patient: The vessels course is altered, winding; there is marked congestion, flame or rounded hemorrhages, and hemorrhagic masking associated with little leakage of the optic disk; the prognosis of this syndrome is usually good.

may appear with dangerous hemorrhages. In some cases, the nonperfusion develops neovascular glaucoma. The prognosis of untreated vein occlusions is always negative except for the juvenile forms that usually regress spontaneously. New treatments have improved venous occlusion prognosis.

lines were manually tuned to be located at desired position. Blood flow between these segmentation lines was registered. An artifact removal function was used to eliminate the retinal vessel shadowing.

■■Clinical features

In vein occlusions, we see changes in the structure of the superficial plexus particularly in macular ischemia. The vascular signal (flow) is not linear but has focal deviations; the wall thickness is not regular but shows focal segmentation and lumen narrowing; the vessels course shows abrupt interruptions with some dilation around the avascular foveal area that appears to be widened with respect to healthy individuals. Vessel flow can be segmented. The vascular network is seen more sharply, and the arteriovenous anastomoses and vascular loops are easier to see. We can observe features, which are not possible to observe in fluorangiography because dye leakage hides them in the intermediate and later stages of the examination. Retinal hemorrhages are visible as masked areas, but they are much less evident than in fluorangiography. Retinal edema areas cannot be seen because there is no dye staining or leakage. However, in case of edema, we observe a widening and distortion of the capillary network meshes and a decrease in the sharpness of the widened capillaries.

Central retinal vein occlusion (CRVO) presents intense edema of the retina and optic disk. Hard exudates are evident. Veins are enlarged, irregular, swollen, and distorted, with flame and dot hemorrhages. Cotton–wool exudates appear. Visual acuity for ischemic and edematous CRVO is generally about 20/100 (2/10).

■■Fluorescein angiography aspects Central occlusions may be ischemic, edematous, or mixed. 3 The site of the central occlusion is located at the optic disk. The venous wall is intensely stained by the dye. There is fluorescein leakage; the capillaries are dilated and tortuous with leakage, exudates, and hemorrhages. Visual loss occurs right from the earlier stages of the disorder. In the ischemic or mixed forms of central vein occlusion, new vessels may appear in the occluded area. In these cases, treatment may prevent hemorrhaging and neovascular glaucoma.

■■OCT angiography features in vein occlusions All the optical coherence tomography (OCT) angiography figures in this chapter were obtained with a commercial spectral domain OCT device (SD-OCT, XR Avanti “AngioVue”, Optovue, Fremont, CA) imaging at 840-nm wavelength. Two automated segmentation

■■Superficial vascular plexus

■■Deep vascular plexus The deep vascular plexus shows more lesions than the superficial plexus. It varies significantly with considerable differences mainly in the ischemic areas. Capillaries distribution is irregular with various changes in vessel course in nonperfused zone. The wall vessels are thicker in the pathologic area; the vessels course shows multiple shunts along various retinal planes.

CHAPTER 15: OCT angiography of vascular occlusions CRVO, BRVO, CRAO, BRAO, and microvascular occlusions

■■BRANCH VEIN OCCLUSION ■■Clinical features

the entire thickness of the retina. The outer limiting membrane and ellipsoid are fragmented. A limited serous central retinal elevation is frequent.

Occlusions of branch vein present localized edema in the area of the affected branch. Some hard exudates are visible. Veins are enlarged, irregular, swollen, and distorted with flame and dot hemorrhages. Cotton–wool exudates appear around the dropout areas. Most BRVOs occur in the supratemporal quadrant due to the specific anatomy of this zone and to frequency of arteriovenous crossings in this area. Nasal BRVOs go frequently ignored by patients. Decrease in visual acuity for ischemic BRVO and edematous BRVO is generally about 20/60 (4/10).

■■Oct angiography aspects

■■Fluorescein angiography aspects Branch vein occlusions may be ischemic, edematous, or mixed.3 It is important to locate the site of the occlusion by means of FA. The occlusion usually occurs at an arteriovenous crossing and the venous wall is intensely stained by the fluorescein. There may also be fluorescein leakage. In the occluded area, the capillaries are visibly dilated, convoluted, and there is fluorescein leakage. Often, the occluded area is covered with exudates and hemorrhages. If the macular and perimacular circulations are involved, visual loss occurs right from the earlier stages of the disorder. In the edematous form, at the periphery of the affected area, collateral vessels may be observed with arteriovenous anastomoses and capillary dilatation. Any interruption of the perifoveal arch will have a negative prognosis. In the ischemic or mixed forms of branch vein occlusion, new vessels may appear at the edges of the occluded area. In these cases, treatment may prevent hemorrhaging and neovascular glaucoma.

■■Structural OCT features Optical coherence tomography shows retinal thickening and edema in the occluded area. Hard exudates are seen as hyperreflective intraretinal deposits in the outer retina at limit between normal and edematous tissue. There are diffuse retinal edema and/or cystoid cavities in the outer retina with cystoid edema cells. Cystoid edema small cells occupy the inner nuclear layer, while the outer plexiform layer is involved with larger and more irregular cystic cavities. Large edematous cystoid cavities may appear later in evolution and invade

In eyes affected by vein occlusion, OCT angiography shows the vascular network with evident areas of nonperfusion that correspond to the areas of nonperfusion visible on the FA. These areas are easily seen because there is no “masking” caused by fluorescein leakage in the intermediate and late stages.

■■Superficial plexus An increase in the size of some capillaries may be observed while others have a narrower lumen. The ensuing configuration is a coarse network of vessels with meshes of irregular shapes and a grayish background (Figure 5). Vascular details are sharper than can be seen with FA as, for instance, the arteriovenous anastomoses and the vascular loops. Often the capillaries within the nonperfused areas are truncated, with abrupt interruptions, or there are arteriovenous anastomoses, and connections to the capillary layers of the deep vascular network at the level of the inner nuclear layer. The areas of retinal edema can be easily identified because there is no staining, but a widening and distortion of the meshes of the capillary network can be noticed as well as a decrease in the sharpness of the dilated capillaries. When the FA shows vessel walls stained with fluorescein, OCT angiography instead shows a very weak flow (corresponding to the lumen itself) surrounded by a dark shadow that corresponds to the thickened vessel wall. In this case, therefore, there is a clear-cut visual difference between FA and OCT angiography. Retinal hemorrhages are visible as masking areas but they are much less evident than can be seen with FA. In the presence of ischemic occlusions, changes are observed in the structure of the superficial plexus. In these cases, there are focal deviations, and wall thickness is irregular with focal segmentation and lumen narrowing; the course of the vessels is abruptly interrupted with terminal dilatations around the avascular foveal area that appears to be larger than in healthy eyes. The blood flow is segmented. The foveal avascular zone is wider with interruption of the arcade and vascular abnormalities (Figures 6 and 7). Figure 5 Optical coherence tomography (OCT) angiography and cross-section OCT of ischemic area in a vein occlusion. The ischemic area is clearly perceived as dropout areas, truncated vessels, dilated and twisting vessels, microaneurysms, mainly at the limit between normal and occluded retina. Note anastomoses and collateral circulation at edges of the ischemic area. Cross-section OCT shows cystoid edema in the occluded area.

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Figures 7A to C  Optical coherence tomography (OCT) angiography in branch vein occlusion with vertical anastomosis: (A) superficial vascular plexus, (B) deep plexus, (C) fluorescein angiography. Confronting OCT angiography: (A) superficial vascular plexus, (B) the deeper plexus, and (C) traditional fluorescein angiography. In fluorescein angiography, staining and leakage prevent the observer from seeing a vertical shunt in the temporal macular area that is associated with marked congestion of the deep vascular plexus.

■■Deep plexus The deep plexus shows variation, mainly in the ischemic areas (Figure 8). Distribution is irregular, with the vessels frequently changing direction in the pathologic area. Vessel walls are thicker in the affected area and the vessels show many shunts between retinal layers. The texture is different in the area where the vascularization is impaired and there is often an increase in pathologic connections between the superficial and deep plexus with marked impairment of vessel size and course (Figure 9). Vessel walls are thicker in the affected area and the vessels show many shunts between retinal layers. The texture is different in the area where the vascularization is impaired and there is often an increase in pathologic connections between the superficial and deep plexus with marked impairment of vessel size and course. The affected capillaries show a slower flow. Vessels appear thin and often with truncated endings at the ischemic areas’ limits. Congestion and dropout areas are mainly localized at the border between occluded zone and normal retina. Vascular congestion at the border between the healthy and unperfused retina is mainly found in the deep network (Figures 8 to 10).

■■CENTRAL AND BRANCH RETINAL ARTERY OCCLUSION Central retinal artery occlusion is an acute stroke of the eye that results in severe visual loss. Current standard therapies that aim to restore perfusion to the retina and optic nerve head have not shown results. It is frequently an early indicator of atherosclerotic disease, foretelling a cerebrovascular or a cardiovascular occurrence. Main causes of arterial occlusions are hypertension, atheroma, carotid disorders, and emboli. Giant cell arteritis causes 2% of central retinal artery occlusions. The patient should be addressed to a cardiologist who will prescribe preventive therapy. In structural OCT, the edematous inner retinal layers appear to be quite reflective. Atrophy of the inner retinal layers initiates after a few weeks. En-face imaging features show it better than OCT angiography. At deep network level, capillaries of the deep plexus are intensely involved by arterial occlusion. Important capillary dropout is evident. Some capillaries increase in size, while many more are

CHAPTER 15: OCT angiography of vascular occlusions CRVO, BRVO, CRAO, BRAO, and microvascular occlusions Figures 8A and B  (A) Superficial plexus and (B) deep plexus in retinal vein occlusion (RVO). (A) Superficial plexus between and (B) deep plexus in the case of a branch retinal vein occlusion: The ischemic area is evident; no flows, truncated vessels, winding vessels, and microaneurysms, mainly at the limit between normal and occluded retina. Note anastomoses and collateral circulation at edges of the ischemic area.

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Figure 9A  Fluorescein angiography branch retinal vein occlusion (BRVO) case. In this visualization, we can appreciate all overlapping networks. Ischemic areas are clearly seen. Dropout areas, truncated vessels, winding vessels, microaneurysms, and leakage, mainly at the limit between normal and occluded retina.

Figure 9B  Optical coherence tomography (OCT) angiography, same case. AngioFlow of the superficial vascular plexus—ischemic tissue shows very large zones of complete flow loss. The ischemic area is obvious; no flows, truncated vessels, twisting vessels, dilated shunts, microaneurysms, anastomoses, and collateral circulation at limits of the dropout area.

closed. Deep network shows larger and sparser meshes (Figures 11A and B). When occlusion is recent, OCT angiography shows a dense edema that interests the inner retina. There is opacity of the inner layers, large dropout areas at deep network level. Capillary density is decreased in occluded areas. In central and arterial branch occlusions, the superficial vascular network shows a capillary dropout with loss of collateral vessels. The superficial network loses some, but not all the collateral branches after the ischemic event. The deep vascular network is totally disrupted with capillary loss and total closure in a considerable number of others. The deep capillary network presents larger than normal meshes.

After a few months, the inner retinal layers develop an atrophy, clearly seen on structural OCT, en-face OCT and retinal maps, where the affected area is much thinner than surrounding retina (Figures 12A and B).

■■PATHOLOGY OF THE RETINAL MICROCIRCULATION Radial peripapillary capillary infarcts, disorganization of the retinal inner layers (DRIL), paracentral acute middle maculopathy (PAMM), and acute macular neuroretinopathy (AMN):

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Figures 10A and B  (A) Morphological differences in normal eye superficial plexus and (B) normal deep plexus.

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Figure 11A  Branch artery occlusion, optical coherence tomography (OCT) angiography and OCT cross-section angiography: superficial network. With angio-OCT, it is possible to highlight the main superficial retinal vessels in the arterial occluded area that lose some, but not all the collateral branches after the ischemic event. This aspect concerns superficial vascular plexus. The crosssection shows inner retina dense edema.

Figure 11B  Branch artery occlusion, optical coherence tomography (OCT) angiography, and OCT cross-section angiography: deep network. The capillaries of the deep plexus are intensely interested by arterial occlusion. In the occluded area, capillary dropout is important. Some capillaries increase in size while many more are interrupted or completely closed. We see looser network with larger meshes. The cross-section shows inner retina dense edema.

CHAPTER 15: OCT angiography of vascular occlusions CRVO, BRVO, CRAO, BRAO, and microvascular occlusions Figure 12A  Branch artery occlusion, cross-section optical coherence tomography (OCT), event recent (7 days): inner retina edema, with some retinal folds.

Figure 12B  Branch artery occlusion, cross-section optical coherence tomography (OCT), after 1-year old event: inner retina atrophy.

The complexity of the retinal microcirculation justifies the diversity of the retinal vascular micropathology. In the central retina, the microcirculation includes four capillary plexuses. This new and important topic will be treated in depth by Dmitrii Maltsev in Chapter 16 of this Atlas (Box 1). ⦁⦁ The involvement of the radial peripapillary capillary plexus, which irrigates the nerve fiber layer (NFL mainly in the parapapillary area), causes infarcts of the nerve fiber layer, presence of peripapillary cotton wool exudates, and arcuate loss of nerve fibers seen at visual field. ⦁⦁ The following level of ischemic retinal damage is the superficial capillary plexus. At this level, the DRIL appears. DRIL is mainly observed in diabetic retinopathy. The structural OCT in the DRIL shows a loss at the level of the internal retinal layers, from the ganglion complex to the internal nuclear layer while the NFL and outer retina remain intact. ⦁⦁ Next level is alterations of the deep plexus. However, the superficial plexus is frequently involved in PAMM. Large symptomatic PAMM may also be a component of retinal vascular disease and small resolved asymptomatic lesion. Asymptomatic PAMM lesions can be observed in healthy individuals as well as in patients with cardiovascular risk factors. Changes in the Avascular Zone are found. Capillary leakage becomes evident in the deep vascular plexus (Figures 13 and 14). ⦁⦁ The next deeper level for retinal ischemia occurs in the deep vascular plexus with AMN (acute neuromaculopathy). In the acute phase, AMN manifests itself with hyper-reflectivity of the outer nuclear layer with its subsequent thinning. Indeed, the analysis of some cases of resolved AMN demonstrates the

Box 1  Levels of retinal capillary ischemia. •• NFL infarction—nerve fiber layer infarction •• DRIL—disorganization of the retinal inner layers •• PAMM—paracentral acute middle maculopathy •• AMN—acute macular neuroretinopathy

maximum of flow gaps in the deep vascular plexus. In most cases, there is alteration of the photoreceptors and involvement of the choriocapillaris with flow gaps. It can be concluded that the inhibition of perfusion in distinct capillary plexuses is not clearly isolated except for NFL infarction, which is associated with isolated alteration of RPCP. In fact, in DRIL, the loss of perfusion occupies not only the superficial plexus but also the intermediate and deep plexuses. In PAMM, the superficial plexus is minimally affected and the maximum of flow disturbances can be found in the intermediate and deep plexuses. Finally, in AMN, the superficial plexus remains unchanged and the deep plexus is primarily affected, but the intermediate plexus and choriocapillary also demonstrate hypoperfusion. In conclusion, four distinct patterns of isolated retinal capillary ischemia can be defined, which can be considered as nerve fiber infarction, DRIL, PAMM, and AMN syndromes. Each of these syndromes affects a definite level of retinal microcirculation. Each syndrome can manifest itself as an isolated condition or be associated with severe retinal vascular disorders. The ischemia in these syndromes is never complete or isolated and it extends to nearby retinal microcirculatory levels.

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Section 3: Retina OCT angiography examination: Other macular diseases Figure 13  Structural optical coherence tomography (OCT) in paracentral acute middle maculopathy (PAMM), recent. In PAMM cross-section OCT shows ischemia or infarction of the inner nuclear layer (INL) caused by hypoperfusion of the deep vascular complex (DVC). OCT shows a hyperreflective band predominantly at the level of INL (arrows).

Figure 14  Paracentral acute middle maculopathy (PAMM), old PAMM, optical coherence tomography (OCT) angiography, and cross-section OCT. Structural cross-section OCT shows a hyperreflective band predominantly at the level of inner nuclear layer (INL) (arrows). The OCT angiography shows dropout area at the level of the INL caused by hypoperfusion of the deep vascular complex (arrows).

■■REFERENCES 1 2

Hayreh SS. Ocular vascular occlusive disorders: natural history of visual outcome. Prog Retin Eye Res 2014; 41:1–25. London NJ, Brown G. Update and review of central retinal vein occlusion. Curr Opin Ophthalmol 2011; 22:159–165.

3

Jaulim A, Ahmed B, Khanam T, Chatziralli IP. Branch retinal vein occlusion: epidemiology, pathogenesis, risk factors, clinical features, diagnosis, and complications. An update of the literature. Retina 2013; 33:901–910.

Chapter 16 Microvascular occlusions: DRIL, AMN, and PAMM Dmitrii S Maltsev, Alexei N Kulikov, Maria A Burnasheva, Alexander S Vasiliev

■■ACUTE MACULAR NEURORETINOPATHY The first known description of damage to isolated retinal layers was identified as acute macular neuroretinopathy (AMN) by Bos and Deutman in 1975. The AMN patients were mostly young females with a recent history of viral infection, or who were taking hormonal contraception, or who had an unremarkable medical history. They demonstrated paracentral scotoma, wedge-shaped spots in the macula, and moderate vessel dilatation in the parafovea with fluorescein angiography (FA).1 With AMN, structural optical coherence tomography (OCT) shows normal appearance of the retinal pigment epithelium (RPE) and choriocapillaris as well as a hyperreflective band in the outer nuclear layer. Further thinning of the outer nuclear layer is associated with alteration of the outer limiting membrane, ellipsoid, myoid, and photoreceptor outer segment layer. OCT suggests

that these alterations may result from changes in the choroidal perfusion with ischemic damage to the outer nuclear layer followed by alteration of the outer limiting membrane and photoreceptors. The role of inner choroidal or choriocapillaris ischemia in damage to the outer retinal layers is supported by multimodal imaging, including OCT, FA, and indocyanine green angiography (IGC). In resolved AMN, however, OCT angiography (OCTA) shows significant hypoperfusion of the deep capillary plexus, which, it is assumed, also supplies the outer retinal layers. At the same time, the choriocapillaris beneath resolved AMN lesion may appear to be unchanged (Figures 1A to G). Apart from sporadic AMN, the following AMN cases have been described—after intravenous contrast injection,2 after intravenous injection of sympathomimetics, 3 aftershock,4 in acute coronary syndrome,5 in sickle-cell disease,6 and during COVID-19.7 Although AMN is described as a distinct condition, acute choroidal and choriocapillaris hypoperfusions in choroiditis are also accompanied by hyper-reflectivity of the outer nuclear layer followed by thinning.8

Figures 1A to G  Acute macular neuroretinopathy at resolved stage in a 23-year-old male 1 month after onset. (A) Cross-sectional optical coherence tomography (OCT) showing thinning of the outer nuclear layer and some attenuation of the photoreceptor outer segment layer (arrowheads). (B) Optical coherence tomography angiography (OCTA) projection of the superficial capillary plexus slab showing normal perfusion. (C) OCTA projection of the middle capillary plexus slab showing reduced perfusion (arrowheads). (D) OCTA projection of the deep capillary plexus slab showing reduced perfusion (arrowheads). (E) No abnormalities seen on the OCTA projection of the choriocapillaris slab. (F) Color fundus photography showing no changes. (G) Retinal thickness map showing local retinal thinning corresponding to the acute macular neuroretinopathy (AMN) lesion.

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■■PARACENTRAL ACUTE MIDDLE MACULOPATHY Paracentral acute middle maculopathy (PAMM) as a distinct condition was identified among AMN cases based on structural OCT imaging and demographic data, which showed that, whereas AMN frequently affects young females, PAMM is more prevalent among adult or elderly persons.9 With indirect ophthalmoscopy, a PAMM lesion appears as a barely visible grayish area within the macula corresponding to a relative scotoma. On a pseudocolor image, PAMM is defined as a greenish area and more clearly visible with infrared reflectance. With fundus autof luorescence (FAF), PAMM lesions are often undetectable or, due to the blockage of the autofluorescence signal, these can appear as a mildly hypofluorescent region. FA may show delay in arterial or venous filling, depending on the associated condition (retinal vein or arterial occlusion, for example), or mild regional hypofluorescence. However, a combination of multimodal imaging findings depends on the severity of the PAMM injury and may be nondetectable. The key feature of acute PAMM is hyper-reflectivity at the level of the inner nuclear layer caused by isolated hypoperfusion in the deep vascular complex, which supplies the middle retinal layers. These hyper-reflective lesions resolve spontaneously after several months. In acute and resolved PAMM, OCTA shows normal or slightly decreased vessel density in the superficial capillary plexus, and substantially decreased vessel density in the deep vascular complex (including both middle and deep capillary plexus). Resolution of acute ischemic damage is followed by thinning of the

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inner nuclear layer and elevation of the outer plexiform and outer nuclear layers. Paracentral acute middle maculopathy is associated with insufficiency of deep retinal microcirculation, mainly in the deep vascular complex, normally characterized by reduced oxygen saturation due to proximity to the venous pole.10,11 Therefore, regional or global reduction of the retinal blood flow velocity causes a decline of oxygen saturation, initially at the level of the inner nuclear layer, followed by ischemic injury. However, some PAMM cases may have distinctions in the distribution of ischemia when ischemic injury is closer to the arterial pole and when ischemic injury is closer to the venous pole of the retinal microcirculation. Although, the term PAMM is widely adopted, the term “oxygenationinduced hypoperfusion maculopathy” may be more universal and better describes the damage to the inner nuclear layer.12 Many studies reveal a wide spectrum of systemic and ocular conditions related to PAMM, primarily among patients with a cardiovascular pathology. PAMM has been shown in patients with hypertension, sickle-cell disease,13 after mitral valve implantation,14 closed-globe trauma, migraine, after flu-like illness,15,16 Purtcher retinopathy,17 after filler injections,18 reticular asphyxia,19 occlusive retinovasculitis, and other conditions which compromise the blood clotting system, including antiphospholipid syndrome, juvenile dermatomyositis,20 Behçet’s disease,21 birdshot choroidopathy,22 and coronavirus disease 2019 (COVID-19).23 On the other hand, several cases describe PAMM lesions in individuals with an unremarkable medical history.24,25 PAMM has been also described as a complication of intraocular surgery, including cataract surgery,26 vitrectomy in proliferative diabetic retinopathy eyes,27 and inner limiting membrane piling.28 Figures 2A to F  Multimodal imaging in arteriolar paracentral acute middle maculopathy in a 20-year-old man 2 weeks after onset. (A) Color fundus photography showing no apparent changes. (B) Optical coherence tomography angiography (OCTA) projection of the deep vascular complex slab showing hypoperfusion corresponding to the hyper-reflective area in C. (C) Structural en-face projection in the inner nuclear layer showing a single hyper-reflective area alongside the cilioretinal artery. (D) Infrared reflectance image demonstrating a hyporeflective area (white arrowheads) in the center of the macula. The white line indicates the position of B-scan in F. (E) Fluorescein angiography showing early hypofluorescence (arrowheads) within the region supplied by a cilioretinal artery. (F) Crosssectional optical coherence tomography scan showing a hyper-reflective band within the outer nuclear layer (arrowheads).

CHAPTER 16: Microvascular occlusions: DRIL, AMN, and PAMM

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Figures 3A to E  Multimodal imaging in fern-like perivenular paracentral acute middle maculopathy (PAMM) in a 64-year-old male 3 days after onset. (A) Color fundus photography demonstrating barely visible retinal whitening and intraretinal hemorrhages. (B) Cross-sectional optical coherence tomography (OCT) scan showing patchy hyperreflectivity of the inner nuclear layer. (C) Structural en-face OCT projection of the deep vascular complex slab showing multiple perivenular areas of PAMM. (D) Fluorescein angiography showing preserved retinal profusion and some intraretinal hemorrhages. (E) Infrared reflectance showing multiple hyporeflective lesions corresponding to the areas of deep retinal ischemia.

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Based on the OCTA data, three PAMM patterns were described in relation to three regions of capillary ischemia—arteriolar (periarterial capillary ischemia) (Figures 2A to F), fern-like (perivenular capillary ischemia) (Figures 3 and 4), and globular (distal periarterial and perivenular capillary ischemia) (Figures 5A to F).29 These patterns may occur in combination, for example periarterial and fern-like PAMM (Figures 4A to D), or in sequence where the globular pattern follows the fern-like PAMM. Optical coherence tomography plays an important role in the diagnosis of PAMM, since it may be the only modality that shows retinal abnormalities.30 With FAF, ICG, and FA, on the other hand, in some PAMM cases, the eye fundus may appear normal. OCT, therefore, may be the sole instrument, which allows diagnosis and follow-up in PAMM. Although OCTA is a powerful tool in the diagnosis of isolated forms of retinal ischemia, the interpretation of OCTA data requires care and attention. For example, hyper-reflectivity of the inner nuclear layer may alter segmentation. This may result in inclusion in the inner nuclear layer slab outer or inner plexiform layer, which may distort vessel density. Moreover, directional changes in cross sectional OCT scans may simulate hyper-reflectivity of the inner nuclear layer close to the fovea. The clinical significance of the PAMM is defined by the contribution of the PAMM to the functional deficiency in patients with ischemic maculopathies. On the other hand, association of the PAMM and cardiovascular morbidity, shown in numerous studies, may be used for clinical decisions.

■■DISORGANIZATION OF RETINAL INNER LAYERS Disorganization of retinal inner layers (DRIL) is an OCT phenomenon, reflecting multilevel alteration of retinal perfusion. 31 Initially, the term DRIL was used by Sun J and coauthors in 2015 during the identification of retinal biomarkers for the prediction of visual outcomes in patients with diabetic retinopathy (DRP). 32 DRIL is defined as loss of visual borders between some retinal layers— ganglionar cell complex/inner plexiform layer and inner nuclear layer/outer plexiform layer (Figures 6A to D). Fluorescein angiography showed the association between DRIL lesions and capillary nonperfusion. 33 This was born out by the link, which was established between ischemic changes on FA and the prevalence of the DRIL lesions in central retinal vein occlusion (CRVO) eyes after resolution of retinal edema. 34 With the introduction of OCTA, the multilevel loss/reduction of the retinal perfusion was shown in DRIL. The ischemia was found in all retinal capillary plexuses with a maximum in the deep capillary plexus. In accordance with this finding, the DRIL apparently results from relatively acute ischemia in superficial and middle capillary plexus, which is laid over pre-existing ischemia in the deep retinal plexus (which is considered to alter in the earliest stages of DRP). 31 An alternative theory suggests the leading role of mechanical effects of diabetic macular edema (DME) on the inner nuclear layer and consequent death of the

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Section 3: Retina OCT angiography examination: Other macular diseases Figures 4A to D  Multimodal imaging in a combination of arterial and fern-like perivenular paracentral acute middle maculopathy (PAMM) in a 58-year-old female 1 week after onset. (A) Color fundus photography demonstrating barely visible retinal whitening. (B) Structural en-face OCT projection of the deep vascular complex slab showing a large area of arterial PAMM and multiple perivenular areas of PAMM. (C) Crosssectional optical coherence tomography (OCT) scans showing patchy and confluent hyper-reflectivity in the inner nuclear layer. (D) Optical coherence tomography angiography (OCTA) projection of the deep vascular complex slab showing reduced perfusion within arteriolar PAMM lesion. B

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Figures 5A to F  Multimodal imaging in globular paracentral acute middle maculopathy (PAMM) in a 56-year-old male 10 days after onset. (A) Infrared reflectance image showing a globular hyporeflective lesion corresponding to the area of inner nuclear layer damage in B. (B) Structural en-face optical coherence tomography (OCT) projection of the deep vascular complex slab showing a confluent area of hyper-reflectivity in the inner nuclear layer occupying the center of the macula. (C) Cross-sectional optical coherence tomography scan showing hyper-reflectivity in the inner nuclear layer. (D) Optical coherence tomography angiography (OCTA) projection of the superficial capillary plexus slab showing normal perfusion. (E) OCTA projection of the middle capillary plexus slab showing reduced perfusion. (F) OCTA projection of the deep capillary plexus slab showing reduced perfusion.

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Figures 6A to D  Disorganization of retinal inner layers in a 68-year-old patient with severe nonproliferative diabetic retinopathy. (A) Optical coherence tomography angiography (OCTA) projection of the superficial capillary plexus showing nonperfused areas of the retina. The dotted line shows the position of the scan in B. (B) Cross-sectional OCT scan showing disorganization of retinal inner layers (arrowheads). (C) Scanning laser ophthalmoscopy with green light showing no acute ischemic lesions. (D) Fluorescein angiography showing a nonperfused area exactly corresponding to the disorganization of retinal inner layers.

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Figures 7A to F  Evolution of disorganization of retinal inner layers. (A) Scanning laser ophthalmoscopy with green light showing ischemic lesion (arrowhead) resolved over a year of follow-up in B. (C) Full retina optical coherence tomography angiography (OCTA) projection showing nonperfusion area corresponding to the ischemic lesion, which remains stable over followup in D. (E) Cross-sectional structural OCT scan showing ischemic lesion (arrowhead) in the inner retinal layers. (F) Cross-sectional structural OCT scan showing disorganization of retinal inner layers after resolution of ischemic lesion.

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bipolar neurons. 32 In contrast to AMN and PAMM, DRIL was not reported as an acute event and, possibly, this is one of the reasons for the absence of a clear pathophysiological explanation for the DRIL. Among many questions, it is not known, if the DRIL is a consequence of a regional microcirculatory alteration and if the DRIL is a subtype of arterial ischemia. At least some cases show that, before DRIL appears on OCT, a persisting inner retinal whitening with/without cotton-wool spots appears within that area (Figures 7A to F). Although the outer retina beneath the DRIL lesion generally remains unchanged, attenuation of the ellipsoid more frequently coexists with these areas and partially explains the association between the DRIL and visual acuity. 31 The quantitative evaluation of the DRIL has a practical value since the longer the DRIL areas within the fovea, the poorer the visual prognosis. 32 The length of the DRIL correlates with the severity of the metamorphopsia in eyes with DME, 35 as well as with the restoration of visual acuity in DME eyes after vitrectomy or intravitreal dexamethasone implant injection. DRIL is a reliable prognostic factor for visual acuity in CRVO, fibrosis of the inner limiting membrane, 36 uveal macular edema, and sickle-cell disease. 37 DRIL was found in various retinal pathologies, including diabetic retinopathy, 31,32 retinal vein occlusions, 34 central retinal artery occlusion, 38 uveitis, 39 fibrosis of the inner limiting membrane, 36 and macular telangiectasia type 1.40 Apart from a direct association with functional status, it seems that DRIL may reflect the severity of the vascular retinal disorders where ischemic events cumulate naturally over time or occur at the onset of the disease. For example, eyes with DRP and DRIL more often belong to the patients with longer diabetes duration, higher

body mass index, and demonstrate lower visual acuity, contrast sensitivity, as well as outer and inner retinal thinning.41 It was shown that not only horizontal measurements of DRIL, but also the vertical as well as foveal DRIL with other OCT characteristics are of prognostic value for visual acuity.

■■CONCLUSION Today, enough data has been collected on the pathophysiology and clinical signs of AMN, PAMM, and DRIL to indicate multiple causes of these conditions, a key feature being the relatively isolated ischemic damage to the retina, both in terms of regional microcirculation and involvement of particular capillary plexus. This leads us to the conclusion that AMN, PAMM, and DRIL are not distinct diseases of the retina but, rather, ischemic phenomena or syndromes associated with local or systemic vascular disorders. Different combinations of AMN, PAMM, and DRIL in common vascular retinal disorders, such as diabetic retinopathy or retinal vein occlusions, clearly indicate this. All these phenomena involve the deep vascular complex—the most vulnerable part of retinal microcirculation. The pathophysiology of retinal ischemia at the level of deep vascular complex is not completely understood; however, we suggest that it could occur both as arterial and as venous microcirculatory insufficiency, something which also agrees with the universal character of these phenomena. All these phenomena are important retinal biomarkers, not only for ocular, but also for systemic pathology in a large cohort of patients. However, understanding of the actual clinical significance of recent findings is far from complete, and further studies in this field are warranted.

■■REFERENCES 1. Bos PJM, Deutman AF. Acute macular neuroretinopathy. Am J Ophthalmol 1975; 80:573–584. 2. Sieving PA, Fishman GA, Salzano T, Rabb MF. Acute macular neuroretinopathy: early receptor potential change suggests photoreceptor pathology. Br J Ophthalmol 1984; 68:229–234. 3. O’Brien DM, Farmer SG, Kalina RE, Leon JA. Acute macular neuroretinopathy following intravenous sympathomimetics. Retina 1989; 9:281–286. 4. Leys M, Van Slycken S, Koller J, Van de Sompel W. Acute macular neuroretinopathy after shock. Bull Soc Belge Ophtalmol 1991; 241:95– 104. 5. Agarwal P, Kumar V, Singh P, Banerjee M. Acute macular neuroretinopathy in a patient with acute coronary syndrome. BMJ Case Rep 2020; 13:e238625. 6. Ong SS, Ahmed I, Scott AW. Association of acute macular neuroretinopathy or paracentral acute middle maculopathy with sickle cell disease. Ophthalmol Retina 2021; S2468–6530(21)00013-0. 7. Zamani G, Ataei Azimi S, Aminizadeh A, et al. Acute macular neuroretinopathy in a patient with acute myeloid leukemia and deceased by COVID-19: a case report. J Ophthalmic Inflamm Infect 2021; 10:39. 8. Desai R, Nesper P, Goldstein DA, et al. OCT Angiography Imaging in Serpiginous Choroidopathy. Ophthalmol Retina 2018; 2:351–359. 9. Sarraf D, Rahimy E, Fawzi AA, et al. Paracentral acute middle maculopathy: a new variant of acute macular neuroretinopathy associated with retinal capillary ischemia. JAMA Ophthalmol 2013; 131:1275–1287. 10. Rahimy E, Sarraf D, Dollin ML, Pitcher JD, Ho AC. Paracentral acute middle maculopathy in nonischemic central retinal vein occlusion. Am J Ophthalmol 2014; 158:372–380.e1. 11. Browning DJ. Patchy ischemic retinal whitening in acute central retinal vein occlusion. Ophthalmology 2002; 109:2154–2159. 12. McLeod D. En Face Optical Coherence Tomography Analysis to Assess the Spectrum of Perivenular Ischemia and Paracentral Acute Middle Maculopathy in Retinal Vein Occlusion. Am J Ophthalmol 2017; 182:203–204.

13. Hussnain SA, Coady PA, Stoessel KM. Paracentral acute middle maculopathy: precursor to macular thinning in sickle cell retinopathy. BMJ Case Rep 2017; 2017:bcr2016216124. 14. Shah D, Saurabh K, Roy R. Multimodal imaging in paracentral acute middle maculopathy. Indian J Ophthalmol 2018; 66:1186–1188. 15. Chen X, Rahimy E, Sergott RC, et al. Spectrum of Retinal Vascular Diseases Associated With Paracentral Acute Middle Maculopathy. Am J Ophthalmol 2015; 160:26–34.e1. 16. Rahimy E, Kuehlewein L, Sadda SR, Sarraf D. Paracentral Acute Middle Maculopathy: What We Knew Then and What We Know Now. Retina 2015; 35:1921–1930. 17. Tokimitsu M, Murata M, Toriyama Y, et al. Delineation of capillary dropout in the deep retinal capillary plexus using optical coherence tomography angiography in a patient with Purtscher’s retinopathy exhibiting normal fluorescein angiography findings: a case report. BMC Ophthalmol 2016; 16:113. 18. Sridhar J, Shahlaee A, Shieh WS, Rahimy E. Paracentral acute middle maculopathy associated with retinal artery occlusion after cosmetic filler injection. Retin Cases Brief Rep 2017; 11:S216–S218. 19. Baciu P, Nofar CM, Spaulding J, Gao H. Branch retinal artery occlusion associated with paracentral acute middle maculopathy in a patient with livedo reticularis. Retin Cases Brief Rep 2017; 11:356–360. 20. Trese MG, Thanos A, Yonekawa Y, Randhawa S. Optical Coherence Tomography Angiography of Paracentral Acute Middle Maculopathy Associated With Primary Antiphospholipid Syndrome. Ophthalmic Surg Lasers Imaging Retina 2017; 48:175–178. 21. Kido A, Uji A, Morooka S, et al. Outer Plexiform Layer Elevations as a Marker for Prior Ocular Attacks in Patients With Behcet’s Disease. Invest Ophthalmol Vis Sci 2018; 59:2828–2832. 22. Carey A, Cohen S. Paracentral acute middle maculopathy in birdshot chorioretinopathy: a novel association. Retin Cases Brief Rep 2016; 10:151–153.

CHAPTER 16: Microvascular occlusions: DRIL, AMN, and PAMM 23. Virgo J, Mohamed M. Paracentral acute middle maculopathy and acute macular neuroretinopathy following SARS-CoV-2 infection. Eye (Lond) 2020; 34:2352–2353. 24. Haskes C, Santapaola S, Zinn J. An Atypical Case of Paracentral Acute Middle Maculopathy. Optom Vis Sci 2017; 94:845–850. 25. Chen Y, Hu Y. The optical imaging of idiopathic paracentral acute middle maculopathy in a Chinese young man and review of the literature. Photodiagnosis Photodyn Ther 2017; 19:383–387. 26. Creese K, Ong D, Sandhu SS, et al. Paracentral acute middle maculopathy as a finding in patients with severe vision loss following phacoemulsification cataract surgery. Clin Exp Ophthalmol 2017; 45:598–605. 27. Nakashima H, Iwama Y, Tanioka K, Emi K. Paracentral Acute Middle Maculopathy following Vitrectomy for Proliferative Diabetic Retinopathy: Incidence, Risk Factors, and Clinical Characteristics. Ophthalmology 2018; 125:1929–1936. 28. Ang MJ, Chen JJ, McDonald HR. Paracentral acute middle maculopathy after epiretinal membrane removal. Retin Cases Brief Rep 2019; Online ahead of print. 29. Ghasemi Falavarjani K, Phasukkijwatana N, Freund KB, et al. En-Face Optical Coherence Tomography Analysis to Assess the Spectrum of Perivenular Ischemia and Paracentral Acute Middle Maculopathy in Retinal Vein Occlusion. Am J Ophthalmol 2017; 177:131–138. 30. Grewal DS, Polascik BA, Kelly MP, Fekrat S. Widefield en face optical coherence tomography to quantify the extent of paracentral acute middle maculopathy. Can J Ophthalmol 2017; 52:e85–e88. 31. Onishi AC, Ashraf M, Soetikno BT, Fawzi AA. Multilevel ischemia in disorganization of the retinal inner layers on projection-resolved optical coherence tomography angiography. Retina 2019; 39:1588–1594.

32. Sun JK, Radwan SH, Soliman AZ, et al. Neural Retinal Disorganization as a Robust Marker of Visual Acuity in Current and Resolved Diabetic Macular Edema. Diabetes 2015; 64:2560–2570. 33. Nicholson L, Ramu J, Triantafyllopoulou I, et al. Diagnostic accuracy of disorganization of the retinal inner layers in detecting macular capillary nonperfusion in diabetic retinopathy. Clin Exp Ophthalmol 2015; 43:735–741. 34. Berry D, Thomas AS, Fekrat S, Grewal DS. Association of Disorganization of Retinal Inner Layers with Ischemic Index and Visual Acuity in Central Retinal Vein Occlusion. Ophthalmol Retina 2018; 2:1125–1132. 35. Nakano E, Ota T, Jingami Y, et al. Correlation between metamorphopsia and disorganization of the retinal inner layers in eyes with diabetic macular edema. Graefes Arch Clin Exp Ophthalmol 2019; 257:1873–1878. 36. Dell’Arti L, Barteselli G, Riva L, et al. Sickle cell maculopathy: identification of systemic risk factors, and microstructural analysis of individual retinal layers of the macula. PLoS One 2018; 13:e0193582. 37. Garnavou-Xirou C, Xirou T, Gkizis I, et al. The Role of Disorganization of Retinal Inner Layers as Predictive Factor of Postoperative Outcome in Patients with Epiretinal Membrane. Ophthalmic Res 2020; 63:13–17. 38. Yilmaz H, Durukan AH. Disorganization of the retinal inner layers as a prognostic factor in eyes with central retinal artery occlusion. Int J Ophthalmol 2019; 12:990–995. 39. Grewal DS, O’Sullivan ML, Kron M, Jaffe GJ. Association of Disorganization of Retinal Inner Layers with Visual Acuity In Eyes With Uveitic Cystoid Macular Edema. Am J Ophthalmol 2017; 177:116–125. 40. Guo J, Tang W, Ye X, et al. Predictive multi-imaging biomarkers relevant for visual acuity in idiopathic macular telangiectasis Type 1. BMC Ophthalmol 2018; 18:69. 41. Joltikov KA, Sesi CA, de Castro VM, et al. Disorganization of Retinal Inner Layers (DRIL) and Neuroretinal Dysfunction in Early Diabetic Retinopathy. Invest Ophthalmol Vis Sci 2018; 59:5481–5486.

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Chapter 17 OCT angiography in inflammatory diseases André C Romano, William Warr Binotti, Paula M Marinho, Allexya AA Marcos, Heloisa Nascimento, Rubens Belfort

■■INTRODUCTION Uveitis is a major cause of visual morbidity in the working age group with an average annual incidence of 14–17 per 100,000. It is the 5th most common cause of visual loss in the developed world, accounting for about 10–15% of the cases of total blindness (World Health Authority definition) and up to 20% of legal blindness.1 Cystoid macular edema (CME) and macular edema are considered the main cause of visual loss in uveitis, approximately 30% of all complications.1 The most common presentation form is the anterior uveitis; however, the posterior pole involvement varies from 14 to 40% or as a panuveitis in approximately 18% of cases.2,3 The main causes of infectious retinitis/chorioretinitis are cytomegalovirus, toxoplasmosis, varicella-zoster, and herpes simplex virus.3 However, since the introduction of highly active antiretroviral therapy (HAART) intraocular cytomegalovirus has decreased greatly due to immune recovery of the human immunodeficiency virus-infected patients.4 Moreover, recent reports indicate an increase of syphilitic uveitis due to an epidemic of the disease.5 Many noninfectious uveitis can cause a retinitis/chorioretinitis, such as Vogt–Koyanagi–Harada (VKH) disease, sympathetic ophthalmia, birdshot chorioretinopathy, the white dot syndromes, acute zonal occult outer retinopathy (AZOOR), and sarcoidosis. Therefore, a precise determination of vitreal, retinal, or choroidal involvement is essential not only to diagnose these different pathologies, but also for a better clinical understanding of uveitic diseases. Multimodal imaging is a technique that has proven useful in investigating many retinal diseases. 6 In posterior uveitis, this approach provides important information for diagnosis, monitoring, and better understanding of the natural history of the disease.7,8 It has been reported in several inflammatory entities such as macular serpiginous choroiditis,9 acute posterior multifocal placoid pigment epitheliopathy (APMPPE),10 VKH,11 birdshot chorioretinopathy,12 persistent placoid maculopathy,13 and syphilitic multifocal retinitis14 showing how it can reliably provide supportive evidence for the diagnosis and management, with a better differentiation of disease activity from inactivity.

■■OPTICAL COHERENCE TOMOGRAPHY ■■Optical coherence tomography techniques Optical coherence tomography (OCT) is a noninvasive imaging technique that provides a three-dimensional cross-sectional

view of the retina with micrometer scale-depth resolution. It uses a near infrared light to measure the reflection and backscattered light from the tissue using a low-coherence interferometr y. Spectral-domain OCT (SD-OCT) allows for high axial resolution imaging of the retina and vitreous, whereas swept-source OCT (SS-OCT), which has a longer wavelength thus increasing the tissue penetration, allows for better visualization of deeper tissues such as choroid.15 New generation SS-OCT with greater scans per second and scan density provide high image resolution of the vitreous, retina, and choroid simultaneously.15,16 Hence, higher scan density per image acquisition on SS-OCT can compensate for its inherent trade-off in the OCT beam sensitivity and axial resolution, compared to SD-OCT.16 Moreover, a system combining confocal ophthalmoscopy and OCT was developed to generate en face OCT images.17,18 This technique allows for a transversal or frontal view of the structures, similar to fundoscopy, with the main advantage of visualizing the retina at multiple layers and depths. These features are particularly useful in inflammatory diseases since different layers of the retina may be affected and delineation of the potential retinal pathology is important (Figures 1A to F). The role of the choroid on OCT remains challenging due to image degradation caused by dense pigmentation and light scatter from choroidal vascular network; however, advances in SD-OCT significantly improved the image of the choroid. In example, enhanced depth imaging (EDI) OCT is a method that shifts the peak sensitivity closer to the sclera, so deeper structures such as the choroid can be appreciated in greater detail, i.e. choroidal thickness.19,20 However, there is trade-off sensitivity of the vitreous, which is better visualized by the conventional method (SD-OCT), and simultaneous visualization of vitreous, retina, and choroid is limited on EDI OCT. Another technique called full-depth imaging OCT combines conventional SD-OCT, to enhance the vitreoretinal interface, with EDI OCT for the choroid by averaging multiple OCT scans in real time (Figures 2A to D).21 When compared with SS-OCT, full-depth OCT was superior in providing a real-time full-depth image of the vitreoretino-choroidal structures. Nevertheless, the SS-OCT showed sharper visualization of fine choroidal details.22 Thus, the selection of the appropriate OCT technology and software should be according to its application in clinical settings.

■■Optical coherence tomography in uveitis In the assessment of chorioretinal inflammatory conditions, the importance of OCT has been extensively recognized.23,24 In posterior uveitis, OCT is valuable for many reasons including measurement

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Figures 1A to F Fundus photograph of the right eye of a 23-year-old male patient with macular serpiginous chorioretinitis (A). Nonactive lesions showing hypoautofluorescence in fundus autofluorescence (B) with hypofluorescence in the central portion of the lesion surrounded hyperfluorescence at the margins in the early stages and staining at the borders in the late phase of fluorescein angiography (C and D). (E) Microperimetry showing decrease of visual sensitivity at the fovea corresponding to the macular lesion. (F) Spectraldomain optical coherence tomography showing the hyperreflective lesion above the retinal pigment epithelium of the fovea. Source: Adapted from https://www.dropbox. com/s/pg3nzb0dr7gx9oy/ FIGURE%201.jpg?dl=0

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of central choroidal thickness, quantifying CME through central macular thickness and in supporting early diagnosis of secondary choroidal neovascularization (CNV) and subretinal fibrosis. 20 Moreover, abnormalities of the vitreoretinal interface, such as vitreomacular traction and epiretinal membrane, can occur in approximately half of the eyes with uveitis and contribute to macular edema and secondary visual impairment. OCT is extremely valuable in identifying such abnormalities, providing important information about the fluid distribution and the morphology of the vitreoretinal interface (Figures 3A and B).25,26 Visual acuity and visual prognosis in uveitic CME are strictly correlated to the integrity of the retinal layers, more specifically the ellipsoid zone (formerly known as inner-outer segment junction).27 Studies have shown a good relation between fundus fluorescein angiography (FFA) and OCT in detecting uveitic macular edema.25 They also showed that OCT had high sensitivity in detecting serous macular detachment and a negative correlation between central macular thickness and visual acuity.25,28,29

With the introduction of OCT, the diagnosis and management of various diseases of the vitreous, retina and choroid were redefined. OCT helps determine the extent, depth, and thickness of the inflammatory lesions that helps locate the retinochoroidal layer involved.30 Further, van Velthoven et al. showed through en face OCT that in active serpiginous choroiditis lesions the involvement was limited to the deeper retina and choroid, whereas in active multifocal choroiditis it extended to the inner retina with local thickening of the retina.18 Therefore, OCT and en face OCT can differentiate these choroiditis manifestations at the same stage. Before the advent of OCT, AZOOR was defined as a rapid visual loss and retinal dysfunction without corresponding visible retinal lesions. However, OCT revealed loss of the ellipsoid zone of the photoreceptors layer and thinning of inner nuclear layer that corresponded to visual field defects. 31 In addition, OCT allows characterization of atypical cases, such as punctate outer retinal toxoplasmosis (PORT), showing lesions that develop at the level of the outer retinal layers and the retinal pigment epithelium (RPE)

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Figures 2A to D  (A) Ultra wide-field (UW) fundus image of a 17-year-old male patient with multiple evanescent white dot syndrome (MEWDS) surrounding the optic nerve and also the macula of the right eye. (B) UW autofluorescence shows confluent peripapillary hyperautofluorescence affecting the macula also. (C) Microperimetry shows extensive and intense decrease of visual sensitivity of the macula. (D) Full-depth imaging optical coherence tomography shows inflammatory cells in the vitreous and areas of attenuation of the retinal pigment epithelium and ellipsoid zone (blue arrows). Source: Adapted from https://www.dropbox. com/s/ohi8jwkminfgwco/ FIGURE%204.jpg?dl=0

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Figures 3A and B  A 33-yearold female patient with bilateral ocular toxoplasmosis. (A) Spectral domain optical coherence tomography (OCT) of the right eye shows a dense hyperreflective mass above the retinal pigment epithelium (RPE) with disorganization of the subsequent retinal layers (white arrow) and formation of an epiretinal membrane (black arrowheads). (B) Full-depth imaging OCT of the left eye shows a serous retinal detachment (white asterisks), a cluster of retinal tissue and fibrosis (white arrow), intraretinal cysts (black asterisk), and posterior hyaloid detachment (white arrowheads). Source: Adapted from https:// www.dropbox.com/s/ sxvzsl9nk6pb0oj/FIGURE%206. jpg?dl=0

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with thickening and elevation of the RPE and focal hyperreflectivity limited beneath the RPE.32 In summar y, OCT can provide not only quantitative and qualitative data, especially in macular edema, but the involvement of the ellipsoid zone of the photoreceptor layer may be an indicator for visual prognosis and treatment response in posterior segment inflammation. 23 Also, the importance of choroidal thickness in uveitis makes EDI or full-depth OCT a unique and noninvasive parameter for posterior segment inflammation detection, especially and also for treatment response.16,33 Interestingly, EDI OCT may be useful to differentiate serpiginous from serpiginous-like chorioretinitis by characterizing the choroidal involvement. 34

■■OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY Opt ica l coherence tomog raphy a ng iog raphy (OCTA) is a noninvasive imaging technique that visualizes microvasculature through motion contrast of the blood f low, without the need for dye injection. Sequential OCT B-scans are acquired at the same cross-sectional region and then compared to generate a blood flow angiogram. 35,36 The principle is that the movement, or flow, of blood cells in the vessels produce changes in signal (decorrelation) in contrast with the low decorrelation signal from the surrounding static tissue. OCTA provides both the structural (en face OCT) and blood f low information of the retinal and choroidal microvasculature in a matter of seconds. Optical coherence tomography angiography has been widely used in age-related macular degeneration patients to detect CNV with precision and great specificity. 37 Because there is no diffuse hyperf luorescence from dye leakage, OCTA has the potential to generate images with higher contrast and resolution of the microvasculature than conventional FFA. 38 Recently, similar CNV findings on OCTA have been reported in patients with tuberculous

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serpiginous-like chorioretinitis,39 multifocal choroiditis,40 punctate inner choroidopathy (PIC),41 and AZOOR.42 In the setting of PIC, OCT and OCTA are capable of detecting subclinical CNV formation beneath a fibrotic macular scar (Figures 4A to G). In another example of serpiginous choroiditis with secondary CNV, OCTA can clearly delineate the neovascularization borders and can track the vascular regression, specifically vessel diameter and total vascular area, allowing a better follow-up after intravitreal injections (Figures 5A to D). However, the recurrence and outcomes of inflammatory CNV vary within different etiologies and are still unknown. OCTA can potentially shed more light on their natural course and help predict risk factors for progression or poor prognosis. As in other retinal diseases, OCTA can provide useful noninvasive retinal capillary parameters to assess disease severity and monitor progression.43,44 In birdshot choroidopathy, ischemia of both the superficial and deep capillary plexi have been reported.45,46 Interestingly, recent findings of a more significant flow impairment of the deep capillaris on OCTA may indicate that, in addition to the underlying inflammation, ischemia might also contribute to the complications in birdshot, i.e. CNV.46 Whether the retinal ischemia is a triggering factor for CNV or a consequence of the well-known retinal thinning that occurs in birdshot is still unknown and warrants investigation. Further, ischemia of the superficial capillary plexus has also been shown in inflammatory retinal vasculitis, not deep plexus.47 Whereas, in uveitic macular edema, the latter is greatly decreased with no significant differences in superficial plexus.47 It is postulated that ischemia at the deep capillary plexus is an important mechanism in the development of CME, similar to diabetic retinopathy.48 The ability to image the choroidal circulation in vivo with very high resolution and noninvasively has made OCTA an emerging tool in retinitis with primary or secondary involvement of the choroid. Recent reports show areas of decreased blood flow in the choriocapillaris corresponding to the lesions of APMPPE and other related placoid disorders, with progressive reperfusion after clinical

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Figures 4A to G  (A) Fundus photography of the right eye of a 36-year-old female with a fibrotic punctate inner choroidopathy macular lesion. (B) Autofluorescence shows hypoautofluorescence in the center of lesion with hyperautofluorescence at the border nasally. (C) En face optical coherence tomography (OCT) with an irregular hyper- and hyporeflectance mesh at the outer retina level. (D) OCT angiography shows a choroidal neovascularization below the lesion. (E and F) Full-depth imaging and B-scan OCT, respectively, show a hyperreflective mass above the retinal pigment epithelium with disorganization of the above retinal layers and intraretinal cysts. (G) Microperimetry shows an eccentric fixation temporal to the lesion with shifting of the fixation points (blue dots). Source: Adapted from https://www.dropbox.com/s/5xq3wg44fcb4atf/FIGURE%208.jpg?dl=0

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Figures 5A to D  (A) Redfree fundus photography of the left eye of a 23-yearold male patient choroidal neovascularization (CNV) secondary to macular serpiginous chorioretinitis. The macular central thickness map shows a maximum retinal elevation of 363 µm (B) where the CNV can be appreciated in details with optical coherence tomography (OCT) angiography (C). (D) Full-depth imaging OCT shows a retinal pigment epithelium disruption with a hyperreflective mass above it. Source: Adapted from https://www.dropbox. com/s/2seypwflrm8b3zo/ FIGURE%2010.jpg?dl=0

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resolution.49 Overall, uveitic patients with choroidal involvement showed greater choroidal f low voids on OCTA, compared to those without choroidal involvement.50 Furthermore, in birdshot chorioretinopathy, OCTA may reveal microvascular abnormalities, such as vessel telangiectasia, capillary loops and dilations, and choriocapillaris hypoperfusion below the disrupted RPE.45 Moreover, PIC is characterized by bilateral and multiple small chorioretinal lesions and can also evolve with peripapillary atrophy and secondary CNV.51 It may present recurrent inflammation when associated with CNV (Figures 6A to F). Therefore, OCT and OCTA can assess longitudinal progression of retinal lesions or CNV and help guide management, even when not clinically evident on fundoscopy.23,44 Typically, small vessels of the choriocapillaris present a slow flow; therefore, decorrelation signal is lower in the OCT angiogram. In multiple evanescent white dot syndrome (MEWDS), the disruption of the ellipsoid zone on SS-OCT with the preservation of retinal and choriocapillaris flow on OCTA suggests the outer retina as the primary site of inflammation (Figures 7A to E). 52 Therefore, the combination of OCT and OCTA can precisely localize and detect disease activity, making this technology useful in the management of these diseases.23,44 Furthermore, a recent study by Khairallah et al. showed that OCTA allowed better characterizing of the perifoveal microvasculature than fluorescein angiography in Behçet uveitis, highlighting the severe changes that occur in the deep capillary plexus.53 The limitations of this technique are its limited field of visualization, requires patient fixation requirement, interference of media opacities, the inability to detect leakage, the inability to detect

blood flow below its threshold limit and the increased potential of image artifacts. Since OCTA detects flow by motion contrast from repeated scans, retrobulbar pulsation, breathing, tremor, and microsaccades of the eye can produce changes on B-scans and can be misinterpreted as flow. Also, the more intense flow from the superficial capillaries of the retina can cause projection artifacts when imaging deeper layers of the retina as well as the choriocapillaris. Under s t a nd i n g O C TA i m a ge a r t i f ac t s a r e i mp or t a nt for accurate clinical assessment. 38 Nevert heless, constant improvements in technolog y help minimize these artifacts. OCTA software implementations can reduce projection artifacts by subtracting them from images below or reduce sensitivity to axial eye motion. 38 In addition, eye-tracking technology combined with scanning laser ophthalmoscope creates a real-time eye motion correction tracking system that dramatically minimizes motion artifacts. 54,55 In summary, OCTA may be a useful tool to enhance diagnosis and to monitor the progression of retinal and choriocapillaris ischemia of inflammatory diseases. OCT provides a noninvasive tool to detect the presence of inflammation through detection of vitreal inflammatory cells, macular edema, choroidal thickening, and even CNV (subretinal hyperreflective material). In contrast, OCTA is capable of detecting subclinical CN V w ithout the cumbersome dye leakage on fluorescent angiography studies and can additionally highlight areas of ischemia in the superficial and deep retinal plexi and choriocapillaris layers. Further, OCTA can depict intralesional neovascularization in infectious and inflammatory granulomatous diseases.

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Figures 6A to F  (A) Fundus photography of the left eye of a 36-year-old female patient with punctate inner choroidopathy lesions at the macula, nonactive due to the hypoautofluorescence (B). (C) Microperimetry shows a mild sensitivity decrease without scotomas. (D) Scanning laser ophthalmoscope image shows the optical coherence tomography (OCT) cuts through the macula. (E) Crossline spectral domain OCT shows subtle focal elevations of the retinal pigment epithelium (RPE) (yellow arrows). (F) Cross-line full-depth imaging OCT show the focal RPE elevations (yellow arrows) and subtle inflammatory cells in the vitreous. Blue box: OCT angiography shows focal capillary dropout areas of the choriocapillaris (CC) corresponding to the lesions, the other layers are apparently unaltered. Green box: En face OCT also shows focal hyporeflectant areas of the CC. Superficial capillary plexus (SCP), deep capillary plexus (DCP), and outer retina (OR).

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Source: Adapted from https:// www.dropbox.com/s/ au6y44kyoeylod5/FIGURE%207. jpg?dl=0

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Figures 7A to E  (A) Color fundus of the right eye of a 14-year-old male patient with multiple evanescent white dot syndrome (MEWDS) and optic disk swelling. (B) Autofluorescence shows discrete perifoveal hypoautofluorescent dots. (C) En face optical coherence tomography (OCT) of the outer retina— retinal pigment epithelium (RPE) level shows similar hyporeflectant dots and a mild confluent hyporeflectance of the perimacula. (D) Fulldepth imaging OCT shows hyperreflective inflammatory cells in the vitreous and attenuation of the peripapillary RPE and ellipsoid zone (blue arrows). (E) OCT angiography of the choriocapillaris shows increased flow signal peripapillary (white arrowheads) with an apparent decreased flow signal toward the macula. Source: Adapted from https://www.dropbox. com/s/4hqbo47hbhp8fmu/ FIGURE%205.jpg?dl=0

11. Attia S, Khochtali S, Kahloun R, et al. Clinical and multimodal imaging characteristics of acute Vogt-Koyanagi-Harada disease unassociated with clinically evident exudative retinal detachment. Int Ophthalmol 2016; 36:37–44. 12. Teussink MM, Huis In Het Veld PI, de Vries LA, Hoyng CB, Klevering BJ, Theelen T. Multimodal imaging of the disease progression of birdshot chorioretinopathy. Acta Ophthalmol 2016; 94:815–823. 13. Nika M, Kalyani PS, Jayasundera KT, Comer gm. Pathogenesis of persistent placoid maculopathy: A Multimodal Imaging Analysis. Retina 2015; 35:1531–1539. 14. Curi AL, Sarraf D, Cunningham ET Jr. Multimodal Imaging of Syphilitic Multifocal Retinitis. Retin Cases Brief Rep 2015; 9:277–280. 15. Potsaid B, Baumann B, Huang D, et al. Ultrahigh speed 1050nm swept source/Fourier domain OCT retinal and anterior segment imaging at 100,000 to 400,000 axial scans per second. Opt Express 2010; 18:20029– 20048. 16. Mrejen S, Spaide RF. Optical coherence tomography: imaging of the choroid and beyond. Surv Ophthalmol 2013; 58:387–429. 17. Helb HM, Charbel Issa P, Fleckenstein M, et al. Clinical evaluation of simultaneous confocal scanning laser ophthalmoscopy imaging combined with high-resolution, spectral-domain optical coherence tomography. Acta Ophthalmol 2010; 88:842–849. 18. van Velthoven ME, Ongkosuwito JV, Verbraak FD, Schlingemann RO, de Smet MD. Combined en-face optical coherence tomography and confocal ophthalmoscopy findings in active multifocal and serpiginous chorioretinitis. Am J Ophthalmol 2006; 141:972–975. 19. Tian J, Marziliano P, Baskaran M, Tun TA, Aung T. Automatic segmentation of the choroid in enhanced depth imaging optical coherence tomography images. Biomed Opt Express 2013; 4:397–411. 20. Hoseini-Yazdi H, Vincent SJ, Collins MJ, Read SA, Alonso-Caneiro D. Repeatability of wide-field choroidal thickness measurements using enhanced-depth imaging optical coherence tomography. Clin Exp Optom 2019; 102:327–334. 21. Barteselli G, Bartsch DU, Freeman WR. Combined depth imaging using optical coherence tomography as a novel imaging technique to visualize vitreoretinal choroidal structures. Retina 2013; 33:247–248.

22. Barteselli G, Bartsch DU, Weinreb RN, et al. Real-time full-depth visualization of posterior ocular structures: Comparison Between FullDepth Imaging Spectral Domain Optical Coherence Tomography and Swept-Source Optical Coherence Tomography. Retina 2016; 36:1153– 1161. 23. Onal S, Tugal-Tutkun I, Neri P, C PH. Optical coherence tomography imaging in uveitis. Int Ophthalmol 2014; 34:401–435. 24. Pakzad-Vaezi K, Or C, Yeh S, Forooghian F. Optical coherence tomography in the diagnosis and management of uveitis. Can J Ophthalmol 2014; 49:18–29. 25. Iannetti L, Accorinti M, Liverani M, Caggiano C, Abdulaziz R, Pivetti-Pezzi P. Optical coherence tomography for classification and clinical evaluation of macular edema in patients with uveitis. Ocul Immunol Inflamm 2008; 16:155–160. 26. Markomichelakis NN, Halkiadakis I, Pantelia E, et al. Patterns of macular edema in patients with uveitis: qualitative and quantitative assessment using optical coherence tomography. Ophthalmology 2004; 111:946–953. 27. Roesel M, Henschel A, Heinz C, Spital G, Heiligenhaus A. Time-domain and spectral-domain optical coherence tomography in uveitic macular edema. Am J Ophthalmol. 2008; 146:626–627; author reply 627–628. 28. Estafanous MF, Lowder CY, Kaiser PK. Patterns of macular edema in uveitis patients. Ophthalmology. 2005; 112:360; author reply 360–361. 29. Tran TH, de Smet MD, Bodaghi B, Fardeau C, Cassoux N, Lehoang P. Uveitic macular oedema: correlation between optical coherence tomography patterns with visual acuity and fluorescein angiography. Br J Ophthalmol 2008; 92:922–927. 30. Parchand S, Gupta V, Gupta A. En Face Optical Coherence Tomography Scan in Inflammatory Disorders. In: Lumbroso B, Huang D, Romano A, Rispoli M, Coscas G, (Eds). Clinical En Face OCT Atlas. New Delhi: Jaypee Brothers Medical Publishers; 2013:302–317. 31. Spaide RF, Koizumi H, Freund KB. Photoreceptor outer segment abnormalities as a cause of blind spot enlargement in acute zonal occult outer retinopathycomplex diseases. Am J Ophthalmol 2008; 146:111–120. 32. de Souza EC, Casella AM. Clinical and tomographic features of macular punctate outer retinal toxoplasmosis. Arch Ophthalmol 2009; 127:1390– 1394.

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Section 3: Retina OCT angiography examination: Other macular diseases 33. Gupta V, Gupta P, Singh R, Dogra MR, Gupta A. Spectral-domain Cirrus high-definition optical coherence tomography is better than timedomain Stratus optical coherence tomography for evaluation of macular pathologic features in uveitis. Am J Ophthalmol 2008; 145:1018–1022. 34. Rifkin LM, Munk MR, Baddar D, Goldstein DA. A new OCT finding in tuberculous serpiginous-like choroidopathy. Ocul Immunol Inflamm 2015; 23:53–58. 35. Mahmud MS, Cadotte DW, Vuong B, et al. Review of speckle and phase variance optical coherence tomography to visualize microvascular networks. J Biomed Opt 2013; 18:50901. 36. Schwartz DM, Fingler J, Kim DY, et al. Phase-variance optical coherence tomography: a technique for noninvasive angiography. Ophthalmology 2014; 121:180–187. 37. de Carlo TE, Bonini Filho MA, Chin AT, et al. Spectral-domain optical coherence tomography angiography of choroidal neovascularization. Ophthalmology 2015; 122:1228–1238. 38. Spaide RF, Fujimoto JG, Waheed NK. Image Artifacts in Optical Coherence Tomography Angiography. Retina 2015; 35:2163–2180. 39. Yee HY, Keane PA, Ho SL, Agrawal R. Optical Coherence Tomography Angiography of Choroidal Neovascularization Associated with Tuberculous Serpiginous-like Choroiditis. Ocul Immunol Inflamm 2016; 24:699–701. 40. Baumal CR, de Carlo TE, Waheed NK, Salz DA, Witkin AJ, Duker JS. Sequential Optical Coherence Tomographic Angiography for Diagnosis and Treatment of Choroidal Neovascularization in Multifocal Choroiditis. JAMA Ophthalmol 2015; 133:1087–1090. 41. Klufas MA, O’Hearn T, Sarraf D. Optical Coherence Tomography Angiography and Widefield Fundus Autofluorescence in Punctate Inner Choroidopathy. Retin Cases Brief Rep 2015; 9:323–326. 42. Levison AL, Baynes K, Lowder CY, Srivastava SK. OCT Angiography Identification of Choroidal Neovascularization Secondary to Acute Zonal Occult Outer Retinopathy. Ophthalmic Surg Lasers Imaging Retina 2016; 47:73–75. 43. de Carlo TE, Romano A, Waheed NK, Duker JS. A review of optical coherence tomography angiography (OCTA). Int J Retina Vitreous 2015;1:5.

44. Invernizzi A, Cozzi M, Staurenghi G. Optical coherence tomography and optical coherence tomography angiography in uveitis: A review. Clin Exp Ophthalmol 2019; 47:357–371. 45. de Carlo TE, Bonini Filho MA, Adhi M, Duker JS. Retinal and Choroidal Vasculature in Birdshot Chorioretinopathy Analyzed Using Spectral Domain Optical Coherence Tomography Angiography. Retina 2015; 35:2392–2399. 46. Phasukkijwatana N, Iafe N, Sarraf D. Optical Coherence Tomography Angiography of A29 Birdshot Chorioretinopathy Complicated by Retinal Neovascularization. Retin Cases Brief Rep 2017; 11:S68–S72. 47. Kim AY, Rodger DC, Shahidzadeh A, et al. Quantifying Retinal Microvascular Changes in Uveitis Using Spectral-Domain Optical Coherence Tomography Angiography. Am J Ophthalmol 2016; 171:101–112. 48. Spaide RF, Klancnik JM, Jr, Cooney MJ. Retinal vascular layers imaged by fluorescein angiography and optical coherence tomography angiography. JAMA Ophthalmol 2015; 133:45–50. 49. Klufas MA, Phasukkijwatana N, Iafe NA, et al. Optical Coherence Tomography Angiography Reveals Choriocapillaris Flow Reduction in Placoid Chorioretinitis. Ophthalmol Retina 2017; 1:77–91. 50. Chu Z, Weinstein JE, Wang RK, Pepple KL. Quantitative Analysis of the Choriocapillaris in Uveitis Using En Face Swept-Source Optical Coherence Tomography Angiography. Am J Ophthalmol 2020; 218:17–27. 51. Atan D, Fraser-Bell S, Plskova J, et al. Punctate inner choroidopathy and multifocal choroiditis with panuveitis share haplotypic associations with IL10 and TNF loci. Invest Ophthalmol Vis Sci 2011; 52:3573–3581. 52. Pereira F, Lima LH, de Azevedo AGB, Zett C, Farah ME, Belfort R Jr. Sweptsource OCT in patients with multiple evanescent white dot syndrome. J Ophthalmic Inflamm Infect 2018; 8:16. 53. Khairallah M, Abroug N, Khochtali S, et al. Optical Coherence Tomography Angiography in Patients with Behcet Uveitis. Retina 2017; 37:1678–1691. 54. Braaf B, Vienola KV, Sheehy CK, et al. Real-time eye motion correction in phase-resolved OCT angiography with tracking SLO. Biomed Opt Express 2013; 4:51–65. 55. Zhang Q, Huang Y, Zhang T, et al. Wide-field imaging of retinal vasculature using optical coherence tomography-based microangiography provided by motion tracking. J Biomed Opt 2015; 20:066008.

Chapter 18 OCT angiography examination in high myopia Luca Di Antonio, Leonardo Mastropasqua

■■Introduction Myopia is a complex disease affected by both environmental and genetic factors. The prevalence is lower in European, African, and Pacific island individuals and higher in Asian population (about 80%) where it would to be attributed to reduction of the time that children spend outdoors.1 By definition, high myopia (HM) is also known as degenerative or pathological myopia (PM). It refers to a condition in which individuals have an axial length >26 mm corresponding to a refractive error of at least –8.0 diopter.2 HM is a leading cause of irreversible visual loss in worldwide country. Although the vision impairments associated with HM can be easily managed by therapeutic interventions, there is no intervention that can prevent the development and the progression of myopia. The anatomical basis of PM has been substantially enhanced by the application of different retinal imaging techniques, such as fluorescein angiography (FA), indocyanine green angiography (ICGA), optical coherence tomography (OCT), and more recently, by the introduction of OCT angiography (OCTA) into the clinical practice. 3 The reason for the development of myopic maculopathy is still not clear. It might be explained by an excessive axial elongation that leading to both retinal and choroidal thinning, and weakening of the sclera.4 Recently, by using high-resolution three-dimensional magnetic resonance imaging, it has been reported that high myopic eyes are not only elongated, but also deformed, and resulting with loss of the spherical shape. 5 This latter aspect may play a crucial role for the development of visionthreatening condition in eyes affected by HM, mainly due to myopic maculopathy. Based on fundus photography, myopic maculopathy has been classified into five categories of macular atrophy, with different grading of severity, and with possible three additional findings as a “plus” lesion including lacquer cracks, myopic choroidal neovascularization (mCNV), and Fuchs’ spot.6 Recently, a more simple and comprehensive classification has been proposed for describing the expanded-spectrum of myopic maculopathy (Table 1) with high reliability.7 This staging system integrated three key components of myopic maculopathy—atrophy, traction, neovascularization (ATN). Currently, the diagnosis of myopic maculopathy is based on multimodal retinal imaging approach, including OCTA. OCTA examination is a relatively new, safe, and dyeless imaging method that enables visualization of both retinal and choroidal circulation. 3 It has been widely demonstrated its utility for imaging the different features of myopic maculopathy. In the macular and optic nerve head atrophy (patchy atrophy), OCTA enhances the visualization of medium and large choroidal vessels, and of peripapillary circle of Zinn–Haller, due to thinning of retinal pigment epithelium (RPE) and a loss of choriocapillaris (Figure 1).8,9 Lacquer cracks are mechanical breaks in the Bruch membrane-RPE-choriocapillaris complex and represent a risk factor for the development of mCNV.10 OCTA imaging usually does not reveal the presence of the lacquer cracks in highly myopic

eyes (Figures 2 and 3). It has been postulated that choriocapillaris rupture might be less advanced than the breaks of both RPE and Bruch’s membrane.11 OCTA examination was considered as a “game changer” for detecting the presence of choroidal neovessels, and especially in case of macular hemorrhage mimicking lacquer cracks (Figure 4). mCNV is the leading cause of vision loss in patients younger than 50 years and develops in 10% of highly myopic individuals.10 Multimodal retinal imaging has become the standard diagnostic approach for assessing the diagnosis and the genesis of mCNV (Figure 5). The association between the position of perforating scleral vessels (short posterior ciliary arteries) and the presence of both lacquer cracks (Figure 2) and mCNV (Figure 5), respectively, has been described. Furthermore, it has been speculated that the “locus minoris resistentiae” into the sclera due to perforating vessel in highly myopic eyes may play a potential role in the genesis of mCNV, either with or without the presence of lacquer cracks.12,13 Although FA examination still remains the gold standard method for assessing the activity of mCNV, based on the late leakage observed after dye injection, other retinal imaging techniques [i.e. spectral-domain (SD)-OCT and OCTA] have been compared to FA, and showing a high sensitivity, specificity, and reliability.14,15 Particularly, different OCTA systems, using both SD or swept-source technologies, have been introduced for imaging mCNV features into clinical practice (Figure 6). Moreover, OCTA was able to differentiate both active and inactive patterns of mCNV.16 Briefly, mCNV presenting with interlacing aspect, circular shape, and with margin well defined may be considered as an active lesion (Figure 7, Panel A). Conversely, a lesion that appears as a tangled pattern, with irregular shape, and margin poorly defined, may be considered as an inactive lesion (Figure 7, Panel B). Actually, OCTA is considered as a predictive model for the treatment decision based on the presence of different imaging Table 1  Atrophy, traction, and neovascularization (ATN) classification system of myopic maculopathy. Atrophic component (A)

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A0: No myopic retinal lesions

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T1: Inner or outer foveoschisis

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A2: Diffuse chorioretinal T2: Inner + outer foveoschisis atrophy A3: Patchy chorioretinal atrophy

T3: Foveal detachment

A4: Complete macular atrophy

T5: MH + retinal detachment

N2a: Active mCNV N2b: Scar/Fuchs’ spot

T4: Full-thickness MH

(MH: macular hole; CNV: choroidal neovascularization) Source: Adapted from Ruiz-Medrano J, Montero JA, Flores-Moreno I, et al. Myopic maculopathy: Current status and proposal for a new classification and grading system (ATN). Prog Retin Eye Res 2019; 69:80–115.

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Figures 1A to F  Color fundus photography (A) and en-face optical coherence tomography angiography (OCTA) image (B) of peripapillary atrophy. To notice the detailed visualization of Zinn–Haller ring as an annular anastomosis of arterial vessels around the optic nerve head by means of OCTA scan (C, squared magnification). Color fundus photography (D) and en-face OCTA image (E) of patchy atrophy. Chorioretinal patchy atrophy appears as a loss of choriocapillaris flow signal on the en-face OCTA scan (F, squared magnification).

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Figures 2A to F  Multimodal retinal imaging of a 30-year-old woman with high myopia. Color fundus photography (A) showing lacquer crack as a yellowish arcuate lesion (white arrow) close to the fovea (A, squared magnification). Wide-field spectral-domain optical coherence tomography (SD-OCT) (B) scan highlighting scleral perforating vessel (short posterior ciliary artery, white arrow) as a hyporeflective linear structure joining with thinned choroid (B, squared magnification). En-face OCTA images (C to F) showing no vascular alterations, particularly in the choriocapillaris slab.

CHAPTER 18: OCT angiography examination in high myopia

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Figures 3A to I  Multimodal retinal imaging of a highly myopic eye of a 30-year-old woman affecting by lacquer cracks. Color fundus photography showing a cockade-like shaped macular hemorrhage (A). Spectral-domain optical coherence tomography (SD-OCT) scan revealing ovoidal hyper-reflectivity lesion in the outer retina (B). Optical coherence tomography angiography (OCTA) images at different vascular plexuses (C to E) showing partial involvement of the deep capillary plexus (D). After 1 month, we showed a spontaneous resolution of macular hemorrhage, as detected by color fundus photography (F) with the restoration retinal vascular plexuses (G to I), particularly in deep vascular plexus, as showed by OCTA (I).

Figures 4A to D  Color fundus photography showing a tessellated fundus of a myopic eye, and presenting a macular hemorrhage (A, dotted yellow square); the optical coherence tomography angiography (OCTA) slab at level of the outer retina did not show any alteration (B). Color fundus photography showing diffuse atrophy and the presence of macular hemorrhage (C). OCTA examination detected the presence of hyper-flow signal due to choroidal neovessels (D, yellow arrow).

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Figures 5A to F Multimodal retinal imaging assessment of a 50-year-old man with high myopia complicated by myopic choroidal neovascularization (mCNV). Color fundus photography showing grayish–green roundish lesion surrounded by macular hemorrhage (A). Fluorescein angiography (FA) showing late leakage of mCNV (B). Spectral-domain optical coherence tomography (SDOCT) demonstrating scleral perforating vessel (white arrow) as a hyporeflective linear structure terminating just beneath the mCNV (C). Early phases of indocyanine green angiography (ICG-A) examination (D) showing the presence of the scleral perforating vessel (white arrow) terminating in the neovascular network (E). En-face optical coherence tomography angiography (OCTA) image clearly highlighting the scleral perforating vessel (white arrow) terminating just beneath the well-defined mCNVs network (F).

Figures 6A to C Myopic choroidal neovascularization (mCNV) assessment by means of different optical coherence tomography angiography (OCTA) devices in a 42-yearold man affected by double choroidal neovascularization. Spectral-domain optical coherence tomography (SD-OCTA) technology using split spectrum amplitude decorrelation angiography algorithm (A); SD-OCTA A B C technology using full-spectrum amplitude decorrelation angiography algorithm (B); Swept-source OCT (SS-OCT) technology using complex optical microangiography algorithm (C) showing two mCNVs as hyper-flow interlacing pattern surrounded by a “dark halo” in the outer retinal slab.

biomarkers.17 This latter aspect may be a valuable strategy for evaluating neovascular exudation/activity of mCNV (Figure 8). Anti-vascular endothelial growth factor (anti-VEGF) drugs have become the first-line treatment of mCNV, leading to both anatomical and functional improvements.18 Optical coherence tomography angiography, if compared to standard FA, may be considered as a valuable tool for close monitoring patients treated with intravitreal injection of antiV EGF, and show ing improvement of both quantitative and qualitative OCT/OCTA biomarkers (Figures 9 and 10), respectively.15 Choroidal neovascularization can be also detected in highly myopic eyes affected by inflammatory choroiditis. In the latter,

OCTA helps us to identif y neovascular net work w ith more accuracy than in FA, because it does not suffer of leakage of dye (Figure 11).19 OCTA technology having a wide spread in daily clinical practice, and being a new breakthrough for imaging myopic maculopathy, it has some limitations—patients with poor fixation or small lesions could limit both the quality of the images and mCNV detection rate, respectively. This latter aspect might limit the usefulness of OCTA. Recently, it has been developed a diagnostic algorithm in patients with PM who presenting mCNV. It speculated that the combination of both OCTA and SD-OCT or SD-OCT and FA had similar higher sensitivities than each modality alone, for detecting the biomarkers of mCNV activity. 20

CHAPTER 18: OCT angiography examination in high myopia Figures 7A and B  Fluorescein angiography (FA) and optical coherence tomography angiography (OCTA) of two different highly myopic patients presenting myopic choroidal neovascularization (mCNV). Late phase of FA showing leakage of dye (Panel A, left). En-face OCTA image detecting mCNV as a hyper-flow interlacing pattern (Panel A, right). Late phase of FA showing staining of mCNV without leakage (Panel B, left). En-face OCTA image detecting mCNV as a subtle-flow tangled pattern (Panel B, right).

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Figures 8A to D  Optical coherence tomography angiography (OCTA) imaging biomarkers of neovascular activity in myopic choroidal neovascularization (mCNV). Interlacing pattern (A). Anastomotic peripheral arcades and loops (B). Tiny branching (C). Dark halo (D, yellow outlined).

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Section 4: Myopia and pathologic myopia Figures 9A and B Multimodal retinal imaging changes of a 49-year-old woman with recurrence of myopic choroidal neovascularization (mCNV) at baseline (Panel A) and after retreatment with anti-vascular endothelial growth factor (VEGF) intravitreal injection (Panel B). Late fluorescein angiography (FA) frame (Panel A, top-left) showing new leaking vessels (dotted green A 2.416 mm2 arrow) arising from pre-existing lesion, spectral-domain optical coherence tomography (SD-OCT) scan (Panel A, top-middle) showing hyperreflective lesion with fuzzy borders (white arrowheads), optical coherence tomography angiography (OCTA) image (Panel A, top-right) showing peripheral anastomotic arcades and loops (white arrowheads) consistent with active mCNV and flow area (in squared mm). Late FA frame (Panel B, bottom2 B 1.286 mm left) showing no leakage (dotted green arrow); SDOCT (Panel B, bottom-middle) showing slight thickening of retinal pigment epithelium (RPE) (white arrowheads); OCTA scan (Panel B, bottom-right) highlighting disappearance of both arcades and loops (white arrowheads) and the reduction of flow area consistent with inactive mCNV. Figures 10A and B  Comparison between fluorescein angiography (FA) and optical coherence tomography angiography (OCTA) area measurements of myopic choroidal neovascularization (mCNV) at baseline (Panel A) and after intravitreal injection of anti-vascular endothelial growth factor (VEGF) (Panel B)—to notice the reduction of mCNV area after the treatment, and the excellent agreement between FA and OCTA measurements.

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Figures 11A to E Multimodal retinal imaging assessment of a 57-year-old woman with punctate inner choroidopathy complicated by choroidal neovascularization. Multicolor fundus picture (A) showing neovascularization (yellow arrow) surrounded by multiple atrophies (white asterisks). Late frame of fluorescein angiography (FA) (B) showing leakage of dye (yellow arrow) and multiple window-defects (white asterisks). Late frame of indocyanine green angiography (ICG-A) (C) showing a barely visible hyperfluorescence (yellow arrow) and multiple roundish hypofluorescence (white asterisks). Outer retina optical coherence tomography angiography (OCTA) slab (D) showing a well-defined neovascular complex (yellow arrow). Choriocapillaris OCTA slab (E) showing neovascular network (yellow arrow) and multiple choriocapillaris flowdeficits due to chorioretinal atrophies (white asterisks).

■■REFERENCES 1. Rose KA, Morgan IG, IP J, et al. Outdoor activity reduces the prevalence of myopia in children. Ophthalmology 2008; 115:1279–85. 2. Curtin B, Karlin D. Axial length measurements and fundus changes of the myopic eye. Am J Ophthalmol 1971; 71:42–53. 3. Mastropasqua R, Di Antonio L, Di Staso S, et al. Optical coherence tomography angiography in retinal vascular diseases and choroidal neovascularization. J Ophthalmol 2015; 2015:343515. 4. Morgan IG, Matsui KO, Saw SM. Myopia. Lancet 2012; 379:1739–48. 5. Moryama M, Ohno-Matsui K, Hayashi K, et al. Topographical analyses of shape of eyes with pathological myopia by high-resolution threedimensional magnetic resonance imaging. Ophthalmology 2011; 118:1626–1627. 6. Ohno-Matsui K, Kawasaki R, Jonas JB, et al. Meta-analysis for pathologic myopia (META-PM) Study group. International photographic classification and grading system for myopic maculopathy. Am J Ophthalmol 2015; 159:877–83.e7. 7. Ruiz-Medrano J, Montero JA, Ohno-Matsui K, et al. Validation of the recently developed ANT classification and grading system for myopic maculopathy. Retina 2020; 40:2113–2118. 8. Ohno-Matsui K, Lai TY, Lai CC, et al. Updates of pathologic myopia. Prog Retin Eye Res 2016; 52:156–87. 9. Ishida T, Jonas JB, Ishi M, et al. Peripapillary arterial ring of Zinn-Haller in highly myopic eyes as detected by optical coherence tomography angiography. Retina 2017; 37:299–304. 10. Ohno-Matsui K, Yoshida T, Futagami S, et al. Patchy atrophy and lacquer cracks predispose to the development of choroidal neovascularisation in pathological myopia. Br J Ophthalmol 2003; 87:570–573. 11. Sayanagi K, Ikuno Y, Uematsu S, et al. Features of the choriocapillaris in myopic maculopathy identified by optical coherence tomography angiography. Br J Ophthalmol 2017; 101:1524–1529.

12. Querques G, Corvi F, Balaratnasingam C, et al. Lacquer cracks and perforating scleral vessels in pathological myopia: a possible causal relationship. Am J Ophthalmol 2015; 160:759–766. 13. Giuffrè C, Querques L, Carnevali A, et al. Choroidal neovascularization and coincident perforating scleral vessels in pathological myopia. Eur J Ophthalmol 2017; 27:e39–e45. 14. Battaglia Parodi M, Iacono P, Bandello F. Correspondence of leakage on fluorescein angiography and optical coherence tomography parameters in diagnosis and monitoring of myopic choroidal neovascularization treated with bevacizumab. Retina 2016; 36:104–109. 15. Di Antonio L, Toto L, Mastropasqua A, et al. Retinal vascular changes and aqueous humor cytokines changes after aflibercept intravitreal injection in treatment-naïve myopic choroidal neovascularization. Sci Rep 2018; 8:15631. 16. Bruyère E, Miere A, Cohen SY, et al. Neovascularization secondary to high myopia imaged by optical coherence tomography angiography. Retina 2017; 37:2095–2101. 17. Li S, Sun L, Zhao X, et al. Assessing the activity of myopic choroidal neovascularization: comparison between optical coherence tomography angiography and dye angiography. Retina 2020; 40:1757–1764. 18. Toto L, Di Antonio L, Costantino O, Mastropasqua R. Anti-VEGF Therapy in Myopic CNV. Curr Drug Targets. 2021; Epub ahead of print. 19. Gan Y, Zhang X, Su Y, et al. OCTA versus dye angiography for the diagnosis and evaluation of neovascularisation in punctate inner choroidopathy. Br J Ophthalmol. 2020; Epub ahead of print. 20. Bagchi A, Schwartz R, Hykin P, et al. Diagnostic algorithm utilising multimodal imaging including optical coherence tomography angiography for the detection of myopic choroidal neovascularization. Eye (Lond) 2019; 33:1111–1118.

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Chapter 19 OCT angiography in ocular tumors Gilda Cennamo, Daniela Montorio, Giovanni Cennamo

■■introduction Multimodal imaging contributed in prov iding appropriate diagnosis and management of the ocular tumors.1 The introduction of optical coherence tomography angiography (OCTA) turned to be useful into the clinical practice allowing the detection and visualization of blood flow and morphology of retinal and choroidal vessels.2 The role of this technique has become crucial to identify the vascular features of choroidal tumors and to shed light on their etiopathogenesis.3

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Moreover, it could provide, in a noninvasive way, useful information in the differential diagnosis of the various types of choroidal lesions.4-6 The potential utility of OCTA is not limited to diagnosis but also in investigating the clinical course of these lesions and to predict their vascular changes after conservative treatment.7,8 At OCTA images, choroidal nevus does not present anomalous vascular network inside the lesion (Figure 1), whereas choroidal melanoma a fine and irregular vascular network inside the lesion (Figure 2).

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Figures 1A to E  Choroidal nevus. (A) Standardized A-scan ultrasound shows high reflectivity of the lesion. (B) Standardized B-scan ultrasound shows a solid flat lesion below the optic disc. (C and D) At fluorescein angiography, this area shows a light hyperfluorescence while (D) indocyanine green angiography presents a hypocyanescent area. (E) Optical coherence tomography angiography (OCTA) shows absence of pathological blood flow at the choriocapillaris scan. (F) En-face OCT reveals a hyporeflective area.

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Figures 2A to D  Choroidal melanoma. (A) Standardized A-scan ultrasound shows a medium-low reflectivity of the lesion. (B) Standardized B-scan ultrasound shows a dome-shaped hyper-reflective mass. (C) Fluorescein angiography and (C1) indocyanine green angiography presents a hypofluorescent and hypocianescent area with an anomalous vascular network inside the lesion. Optical coherence tomography angiography (OCTA) image reveals the presence of pathological blood flow at the choriocapillaris scan. (A1) Multicolor image of choroidal melanoma before treatment shows orange pigmented and elevated lesion. OCTA of choroidal melanoma before ruthenium-106 plaque brachytherapy (B1) after the treatment (C1) reveals a reduction of vascular network inside the lesion.

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Choroidal hemangioma reveals a dense and dilated choroidal vascular network like to a multilobular pattern (Figure 3). Optical coherence tomography angiography reveals a fine vascular network within the choroidal osteoma (Figure 4) while no blood flow inside the lesion is detected in choroidal metastasis (Figure 5).

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In conclusion, OCTA, together with ecography and structural OCT, turns to be a valid and noninvasive imaging technique that could represent a useful diagnostic support to detect the vascular and anatomical features of choroidal lesions and to follow their changes over time.

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Figures 3A to E  Choroidal hemangioma. (A) Multicolor image shows an orange choroidal mass nasally to the fovea. (B) Fluorescein angiography and (C) indocyanine green angiography present hyperfluorescent and hypercianescent areas in correspondence of the lesions. (D) Structural spectral-domain optical coherence tomography (SD-OCT) shows elevation of retinal pigment epithelium-choroid complex with intra-subretinal fluid. (E) OCT angiography image reveals a network of variably sized vessels, which appeas larger than the surrounding normal choroidal vessels.

A

C

E

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D

Figures 4A to E  Choroidal osteoma. (A) Multicolor image shows the choroidal osteoma below the optic disc, (B) infrared image reveals an hyper reflective lesion. Structural spectral-domain optical coherence tomography (SD-OCT) detects a sponge-like structure of the choroid inferior to the optic disc (C) and in macular region (D). (E) OCT angiography presents a fine vascular texture within the lesion.

CHAPTER 19: OCT angiography in ocular tumors

A

B

E

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D

F

Figures 5A to F  Choroidal metastasis. (A) Multicolor image shows a yellow lesion in superotemporal sectors, mid-periphery. At fluorescein angiography (B) and indocyanine green angiography (C), the lesion appears hypofluorescent and hypocyanescent. (D) Optical coherence tomography (OCT) angiography of choroidal metastasis does not show any vascular network inside the lesion. (E) OCT shows the typical ‘lumpy bumpy’ anterior tumur surface with subretinal fluid at the level of lesion (E) and at posterior pole (F).

■■REFERENCES 1. Shields CL, Dalvin LA, Yu MD, et al. Choroidal nevus transformation into melanoma per millimeter increment in thickness using multimodal imaging in 2355 cases: The 2019 Wendell L. Hughes Lecture. Retina 2019; 39:1852–1860. 2. Pellegrini M, Corvi F, Say EAT, Shields CL, Staurenghi G. Optical coherence tomography angiography features of choroidal neovascularization associated with choroidal nevus. Retina 2018; 38:1338–1346. 3. Cennamo G, Romano MR, Breve MA, et al. Evaluation of choroidal tumors with optical coherence tomography: enhanced depth imaging and OCTangiography features. Eye (Lond.) 2017; 31:906–915. 4. Cennamo G, Comune C, Cennamo G, de Crecchio G. Multimodal Imaging of Optic Nerve Head Capillary Hemangioma. Retina 2018; 38:e50–e52.

5. Cennamo G, Montorio D, Carosielli M, Romano MR, Cennamo G. Multimodal imaging in choroidal metastasis. Ophthalmic Res 2020; 64:411–416. 6. Cennamo G, Romano MR, Iovino C, et al. OCT angiography in choroidal neovascularization secondary to choroidal osteoma. Acta Ophthalmo 2017; 95:e152–e154. 7. Cennamo G, Breve MA, Velotti N, et al. Evaluation of Vascular Changes with Optical Coherence Tomography Angiography after Plaque Radiotherapy of Choroidal Melanoma. Ophthalmic Res 2018; 60:238–242. 8. Cennamo G, Rossi C, Breve MA, et al. Evaluation of vascular changes with optical coherence tomography angiography after ruthenium-106 brachytherapy of circumscribed choroidal hemangioma. Eye (Lond.) 2018; 32:1401–1405.

143

Chapter 20 OCT angiography examination in glaucoma David Huang, Michel Puech, Yali Jia, Liang Liu, Mourtaza Aimadaly

■■INTRODUCTION Glaucoma is associated with reduced blood f low in the optic nerve head (ONH) and retina. The commercially available optical coherence tomography (OCT) devices can map a large area of peripapillary retinal blood flow, which is highly correlated with glaucoma status and the severity of visual field (VF) damage.1,2 Thus, OCT angiography of the ONH and peripapillary retina may add valuable new information for glaucoma assessment that complement conventional structural OCT measurements of the peripapillary retinal nerve fiber layer (NFL) thickness and macular ganglion cell complex (GCC) or ganglion cell layer thickness. Glaucoma also reduces the vessel density in the superficial vascular complex in the macula, which is also useful for glaucoma diagnosis and monitoring.

■■QUANTIFICATION OF PERIPAPILLARY RETINAL FLOW INDEX AND VESSEL DENSITY (FIGURES 1A TO H) A few examples in this chapter were obtained with the Avanti spectral-domain OCT system (Optovue) (Figures 1A to H). In the en face OCT angiogram of the normal eye (Figure 1B), the peripapillary retina shows a dense microvascular network. In comparison, the glaucomatous eye shows reduced density of the peripapillary microvascular network (Figure 1F) with patches of nonperfusion that correlated well with the locations of NFL and VF defects.3

Pattern deviation

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Glaucoma E

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Figures 1A to H  Examples of a normal (top row) and glaucomatous (bottom row) right eye. Disk photographs (A and E), en face optical coherence tomography (OCT) angiograms of optic disk and peripapillary retina (3 × 3 mm) (B and F), retinal nerve fiber layer (NFL) thickness maps with octant classifications (C and G), and visual field (VF) pattern deviation maps (D and H) in a representative normal eye (top row) and perimetric glaucoma eye (bottom row). Nonperfusion area in the peripapillary retina was highlighted in blue on the OCT angiograms. An inferotemporal arcuate nonperfusion area (purple arrow, F) in the glaucomatous angiogram correlated well with the NFL defect (G) and superior arcuate VF defect (H).

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Section 6: Glaucoma and optic nerve

To quantify the peripapillary retinal blood flow, the anatomic boundaries are first established. The disk boundary was drawn along the neural canal opening using structural OCT images. The peripapillary region was defined to be a 0.7  mm wide elliptical annulus ex tending out ward from t he optic disk boundar y (Figures 1B and F, between green circles). The peripapillary retinal flow index was defined as the average decorrelation value on the en face retinal angiogram in the peripapillary region. The vessel density was defined as the percentage area occupied by blood vessels in the peripapillary region in the en face retinal OCT angiogram. The peripapillary flow index and vessel density in the normal eye were 0.086 and 88.5%, respectively. The peripapillary flow index and vessel density in the glaucoma eye were lower at 0.070 and 78.9%, respectively (Figures 1C, D, G, H).

■■CORRELATION BETWEEN PERIPAPILLARY RETINAL OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAM, NERVE FIBER MAP, AND VISUAL FIELD Peripapillary retinal nonperfusion is associated with areas of NFL thinning, ganglion complex thinning, and VF defects (Figures 2). These diagnostic modalities are synergistic.4-8 Using Angiovue optical coherence tomography angiography (OCTA) (Optovue), a correlation study has been done on a series of 363 eyes (182 patients). The Pearson correlation test shown a

GCC significance map

NFL thickness map

A1

A2

A3 Pattern deviation

NFT thickness map

B1

B2

B3 Pattern deviation

NFL thickness map

C1

C2

C3

Figures 2  Three eyes of two glaucoma patients separated into rows. En face optical coherence tomography angiograms (OCTAs) of the optic disk and peripapillary retina (left column), retinal nerve fiber layer (NFL) thickness maps with octant classifications (middle column), ganglion cell complex (GCC) significance map (right column A3), and visual field (VF) pattern deviation maps (left column B2, C3). (A) An inferotemporal arcuate nonperfusion area (yellow arrow, A1) on the en face angiogram correlated well with the inferotemporal NFL loss (red octant, A2) and inferior arcuate GCC defect (A3). (B) Right and (C) left eyes of a patient with broad areas of temporal nonperfusion on the OCT angiogram (between yellow arrows, B1, C1) that correlated well with temporal NFL loss (B2, C2) and central, superior, and nasal scotomas (B3, C3).

CHAPTER 20: OCT angiography examination in glaucoma

relationship between retinal nerve fiber layer (RNFL) thickness and reduction of flow density with a Pearson test: 0.61 (p value < 0.01) and a positive linear correlation. The same test on the quadrants around the ONH shows a positive relationship on each quadrant (Figures 3A to F). A new evolution of the Optovue software can provide analysis around the disk with subtraction of the big vessels to only analyze the small superficial vessels involved in glaucoma, increasing quantification of peripapillary retinal flow index and vessel density. The report of AngioAnalyticsTM software produces an analysis of radial peripapillary capillary (RPC) vessel density only based on small vessels. Results are shown on eight quadrants around the disk, one diagram with comparison superior hemi and inferior hemi, and one diagram with four quadrants (temporal, superior, nasal, inferior) (Figure 4).

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Figures 3A to F  The Pearson correlation test shows a positive relationship on each quadrant between retinal nerve fiber layer (RNFL) thickness and reduction of flow density on the same quadrant: Nasal superior (A), nasal (B), nasal inferior (C), temporal superior (D), temporal (E), and temporal inferior (F).

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For glaucoma patient ganglion cell layer thinning in macular region has been shown associated to RNFL thinning. OCTA can provide macular vessel density on the macula. Many of commercial OCTA devices can provide this analysis. A few studies have shown a correlation between GCC thinning and reduction or vessel density in the same quadrant (Figure 6). Those additional criteria seem to

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■■QUANTIFICATION OF MACULAR VESSEL DENSITY

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Another table of this software gives trend analysis based on small vessels superior and inferior and based on all vessels on the whole image. This tool allows long-term patient follow-up with comparison to RNFL and GCC trend analysis map (Figure 5).

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Section 6: Glaucoma and optic nerve

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Peripapillary

44.4

48.6

- Superior-hemi

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Figure 4 AngioAnalyticsTM report (Solix, Optovue) with quantification of radial peripapillary vessel density superimposed on the optical coherence tomography angiography (OCTA) map (4.5 mm × 4.5 mm) of a glaucoma patient OS. On this map, note the dark blue sector in temporal inferior and the vessel density of 29 in this quadrant. On the table, the left column gives the small vessel density, and the right column gives the vessel density including all the vessels. This report shows also the inferior/superior analysis and the four quadrant analysis (temporal, superior, nasal, inferior).

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Figure 5 AngioAnalyticsTM report (Solix, Optovue) with trend analysis based on small vessels superior and inferior and based on all vessels on the whole image.

CHAPTER 20: OCT angiography examination in glaucoma

100

48

90 80

52

p: > 5%

44

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51

21

70

52

52

52

60 50 40 30

44

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GCC thickness (ILM - IPL)

Vessel density (superficial)

Figure 6 AngioAnaliticsTM macular report with Solix (Optovue): On the left ganglion cell complex (GCC) thickness map shows a thinning in the macular inferotemporal and inferior quadrants. On the right: Macular vessel density map shows reduction of superficial flow in inferotemporal and inferior quadrants (44), with the same localization on GCC map.

be useful and can be used specially in case of artifact on ONH and RNFL analysis. 9-13

■■CONCLUSION For glaucoma patients, OCT angiography gives a new approach for diagnosis and follow-up. Early work showed glaucoma reduce ONH vessel density and flow index. More recent work shows peripapillary

retina and macula to be better diagnostic targets. The relationship between RNFL thinning, VF defects, and reduction of vessel density around the disk has been confirmed by many studies. Reduced vessel density in the macular SVC is correlated with thinning of GCC layer and VF defects. Thus OCT angiography-based perfusion analyses may be useful for the early diagnosis of glaucoma and trend analysis to assess progression.

■■REFERENCES 1. El Beltagi TA, Bowd C, Boden C, Amini P, Sample PA, Zangwill LM, et al. Retinal nerve fiber layer thickness measured with optical coherence tomography is related to visual function in glaucomatous eyes. Ophthalmology 2003; 110:2185–2191. 2. Yarmohammadi A, Zangwill LM, Diniz-Filho A, Suh MH, Yousefi S, Saunders LJ, et al. Relationship between optical coherence tomography angiography vessel density and severity of visual field loss in glaucoma. Ophthalmology 2016; 123:2498–2508. 3. Liu L, Jia Y, Takusagawa HL, Pechauer AD, Edmunds B, Lombardi L, et al. Optical Coherence Tomography Angiography of the Peripapillary Retina in Glaucoma. JAMA Ophthalmol 2015; 133:1045–1052. 4. Jia Y, Simonett JM, Wang J, Hua X, Liu L, Hwang TS, et al. and all. WideField OCT Angiography Investigation of the Relationship Between Radial Peripapillary Capillary Plexus Density and Nerve Fiber Layer Thickness. Invest Ophthalmol Vis Sci 2017; 58:5188–5194. 5. Yu PK, Cringle SJ, Yu DY. Correlation between the radial peripapillary capillaries and the retinal nerve fibre layer in the normal human retina. Exp Eye Res 2014; 129:83–92. 6. Chen CL, Bojikian KD, Gupta D, Wen JC, Zhang Q, Xin C, et al. Optic nerve head perfusion in normal eyes and eyes with glaucoma using optical coherence tomography-based microangiography. Quant Imaging Med Surg 2016; 6:125–133.

7. Chen A, Liu L, Wang J, Zang P, Edmunds B, Lombardi L, et al. Measuring Glaucomatous Focal Perfusion Loss in the Peripapillary Retina Using OCT Angiography. Ophthalmology 2020; 127:484–491. 8. Holló G. Comparison of Peripapillary OCT Angiography Vessel Density and Retinal Nerve Fiber Layer Thickness Measurements for Their Ability to Detect Progression in Glaucoma. J Glaucoma 2018; 27:302–305. 9. Kurysheva NI. Does OCT angiography of macula play a role in glaucoma diagnostics? Ophthalmol Open J 2016; 2:1–11. 10. Wu J, Sebastian RT, Chu CJ, McGregor F, Dick AD, Liu L. Reduced Macular Vessel Density and Capillary Perfusion in Glaucoma Detected Using OCT Angiography. Curr Eye Res 2019; 44:533–540. 11. Lu P, Xiao H, Chen H, Ye D, Huang J. Asymmetry of Macular Vessel Density in Bilateral Early Open-angle Glaucoma With Unilateral Central 10-2 Visual Field Loss. J Glaucoma 2020; 29:926–931. 12. Lee JY, Shin JW, Song MK, Hong JW, Kook MS. Glaucoma diagnostic capabilities of macular vessel density on optical coherence tomography angiography: superficial versus deep layers. Br J Ophthalmol 2021. 13. Tao A, Liang Y, Chen J, Hu H, Huang Q, Zheng J, et al. Structure-function correlation of localized visual field defects and macular microvascular damage in primary open-angle glaucoma. Microvasc Res 2020; 130:104005.

149

Chapter 21 OCT angiography examination in neurodegenerative diseases Emliano Di Carlo, Albert J Augustin

■■INTRODUCTION Brain and retina share different common features, such as neurons, cells, vasculature, and the presence of a blood barrier (Figure 1).1 This peculiar connection between two tissues originating from the central nervous system (CNS) allows the brain to be observed through the retina. In addition, the retinal vascular network shows evident affinities with the blood circulation of the brain.2 It has been described prev iously that optical coherence tomography (OCT) is able to detect various pathologic processes in the retina of patients affected by neurodegenerative diseases such as ganglion cell degeneration, thinning of the retinal nerve fiber layer (RNFL), and loss of axonal projections in the optic nerve. 3 Moreover, it has been proved that neurodegenerative changes are associated with vascular remodeling and cerebral microvasculature impairment.4 Nevertheless, it is known that the cerebral circulation results difficult to access even with the current modern diagnostic tools. For this reason, the similar properties of the vascular network of the eye might permit to overcome these problems. As a consequence, it may be possible to utilize the eye as a mirror for the changes of the brain vasculature in neurodegenerative diseases. Optical coherence tomography angiography (OCTA) measures vascular density and blood perfusion and may represent the optimal tool to quantitatively analyze the brain vasculature in patients suffering from neurodegenerative disease. Among these, the most important are multiple sclerosis (MS), Alzheimer’s disease (AD), and Parkinson’s disease (PD) (Table 1). The aim of this chapter is to summarize the most salient information regarding the usefulness of OCTA in the field of neurodegenerative diseases.

■■OCTA AND MULTIPLE SCLEROSIS Multiple sclerosis is a chronic inflammatory autoimmune disease of CNS in which axons neurodegeneration represents the main cause of clinical disability. An episode of optic neuritis (ON) occurs at least one time in up to 50% of patients during the natural course of the disease.5 Studies conducted w it h t he aim of magnetic resonance angiography (MRA) have showed that brain–blood density in MS patients is significantly impaired.6 Therefore, the use of OCTA may be of considerable importance to detect clinical biomarkers in order to establish an earlier diagnosis. In t his regard, t he most recent researches have clearly demonstrated a significant vessel density reduction in both

peripapillary and macular area (Figures 2 and 3) in patients affected by MS compared with healthy subjects.7-9 In particular, Lanzillo et al.8 highlighted a significant correlation between vessel density, assessed by OCTA, and clinical course of the disease, measured with the Expanded Disability Status Scale (EDSS), suggesting that OCTA might be a good biomarker to also evaluate the clinical course. In addition, a large cohort study included 111 patients affected by relapsing–remitting multiple sclerosis (RRMS) was focused on the quantitative analysis of macular vasculature. The researchers assessed a statistically significant reduction in vessel density at the level of the superficial vascular plexus (SVP), while no differences were found between patients and controls for the deep vascular plexus (DVP).10 The impairment of blood flow, specifically at the SVP level, can play a fundamental role during the daily clinical practice. In this case, the ophthalmologist should consider the possibility to use OCTA for MS patients, especially with regard to vascular flow analysis at SVP. In addition, although one study11 has previously evidenced no significant alterations of the foveal avascular zone (FAZ) in MS patients, a recent report by Kleerekooper et al.7 has shown a significant enlargement of FAZ with the aim of OCTA (Figure 4). Episodes of acute ON can precede the onset of MS or occurs later. The role of OCTA to detect vascular alterations in connection with ON has been evaluated. Murphy et al.10 evidenced that eyes affected by ON showed a lower SVP vessel density compared to eyes which were not affected by ON attacks. Although OCTA data in the acute phase of ON are not numerous, it has been demonstrated that eyes previously affected by an ON attack and completely recovered show reduced macular and optic nerve head (ONH) vessel densities up to 8 months after the episode.12 Unfortunately, a “real-time” assessment of vascular f low and perfusion at the ONH during an ON attack results difficult to obtain, because the disk swelling may limit OCTA signal strength. Nonetheless, OCTA remains a useful tool to evaluate the vasculature of patients formerly affected by an episode of ON, mostly due to the capability of blood flow measurements to correlate with clinical disability.

■■OCTA AND ALZHEIMER’S DISEASE Alzheimer’s disease (AD) is the most common cause of dementia in the aging human population and the characteristic cognitive impairment is due to a neurodegenerative process. Cerebral microvascular changes are currently inaccessible to existing in vivo imaging technologies. Instead, the retinal microvascular network

152

Section 6: Glaucoma and optic nerve

Retinal ganglion cell

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Light

Lens

Vitreous humor Optic nerve

E Immunoregulatory molecules

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D

Astrocyte endfeet Endothelial cell Moller cell process

Tight junctions

Pericyte

Figure 1  The eye and the brain: common features. (A) Retinal ganglion cells (RGCs) are similar to neurons of central nervous system (CNS); (B) RGCs have axons that are myelinated and form the optic nerve, which extends to the brain at the level of superior colliculus; (C) common characteristics are also present in case of optic nerve injury; (D and E) the eye has a unique relationship with the immune system that involves specialized barriers such as the inner blood–retinal barrier, the retinal counterpart of the CNS blood–brain barrier (D), and the constitutive presence of immunoregulatory molecules (E). Source: Modified from London A, Benhar I, Schwartz M. The retina as a window to the brain-from eye research to CNS disorders. Nat Rev Neurol 2013; 9:44–53.

Table 1  Neurodegenerative diseases: Summary of main symptoms and cell types affected. Type of disease

Main symptoms

Cells affected

Multiple sclerosis

Impairment of movement; alteration of vision

Oligodendrocytes and neurons

Alzheimer’s disease

Loss of memory

Neurons in the hippocampus and cortex

Parkinson’s disease

Disorders of movement

Neurons in the substantia nigra

Huntington’s disease

Incapacity to think, talk, and walk

Striatal and cortical neurons

can be directly imaged with OCTA and may provide a unique “window” to study the cerebral vascular pathology.4 Recent studies have showed a significant reduction of vascular density both at SVP and DVP in patients affected by AD compared to normal subjects.13,14 Particularly, macular OCTA measurements regarding the SVP at the parafoveal region evidenced a significant decrease both in vessel and perfusion density for the whole area in AD patients (Figure 5).13,15 Another study has also found a decrease in vascular density, but localized at the superior part of the macular region.16 The OCTA evaluation of the FAZ exhibited results worthy of attention, suggesting new insights concerning the pathophysiological mechanisms of AD. In fact, the FAZ of AD patients appears to be damaged because of a mechanical compression acting on the retinal

CHAPTER 21: OCT angiography examination in neurodegenerative diseases

Healthy Control

MS with optic neuritis

Figure 2  Optical coherence tomography angiography (OCTA) of the optic nerve in patients affected by multiple sclerosis (MS) after an episode of optic neuritis. The comparison between an OCTA of a normal subject and the disk of a patient affected by optic neuritis evidences a reduced flow density of optic nerve head blood vessels. The dark areas in the right image are larger and more evident, thus indicating a reduced blood flow density. Source: Modified from Wang X, Jia Y, Spain R, et al. Optical coherence tomography angiography of optic nerve head and parafovea in multiple sclerosis. Br J Ophthalmol 2014; 98:1368–1373.

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vessels caused by the diffuse aggregation of B-amyloid plaques.17 Various reports have documented a significant increase in FAZ area in patients affected by AD, as compared to healthy controls (Figure 6).13,17,18 This data might be very useful for clinical practice: The simultaneous detection of macular vessel density reduction at SVP level and FAZ area increase can direct the ophthalmologist toward an early AD diagnosis, or at least toward a suspect, only with the use of OCTA. Contrasting results were found analyzing the vascular flow for the deeper retinal layers and choroid and also for the optic nerve vascularization.15,17 For this reason, it would be advisable to be cautious when evaluating these OCTA data. In conclusion, OCTA is able to demonstrate the presence of an impaired blood flow in AD patients. The blood flow reduction and the consequent ischemia seem to lead to a thickness reduction of retinal ganglion cells. The thinning of ganglion cells has also demonstrated

Figure 3  Correlation between vessel density analyzed with optical coherence tomography angiography (OCTA) and spectral-domain OCT (SD-OCT) parameters, such as retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC). (A to D) OCTA vessel density, GCC, and RNFL in a normal eye; the middle images show a patient affected by multiple sclerosis (MS) without optic neuritis who exhibits a reduction of capillary vessel density at OCTA (E) that is correlated with a decrease both of GCC (F and G) and RNFL (H); at the bottom, an MS patient with a history of optic neuritis: OCTA reveals a more evident reduction of vessel density (I) with also an evident reduction of GCC (J and K) and RNFL (L). Source: Modified from Lanzillo R, Cennamo G, Criscuolo C, et al. Optical coherence tomography angiography retinal vascular network assessment in multiplesclerosis. Mult Scler 2018; 24:1706–1714.

a good correlation with the clinical severity of AD.18 Thus, the value of OCTA could be higher, even in the definition of a possible correlation between blood flow assessment and clinical data.

■■OCTA AND PARKINSON’S DISEASE Parkinson’s disease is the second most common neuro­degener­ ative condition worldwide. Neurological disability with cognitive deterioration occurs as consequence of dopaminergic neurons loss in the CNS. Neural degeneration has been already studied with the aim of OCT, but also the vascular component in PD has been identified to be involved in the pathogenetic pathway.19 On this basis, it is crucial to exhaustively analyze the role of OCTA to assess the retinal microcirculations in patients affected by PD. The first studies that evaluated the ability and usefulness of OCTA to detect vascular f low abnormalities in PD were

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Control

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Figure 4  Foveal avascular zone (FAZ) alteration in multiple sclerosis (MS) patients. The images of MS patients without optic neuritis show a greater FAZ compared to healthy subjects both in superficial (SVP) and deep vascular plexus (DVP).

DVP

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Source: Modified from Kleerekooper I, Houston S, Dubis AM, Trip SA, Petzold A. Optical Coherence Tomography Angiography (OCTA) in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder. Front Neurol 2020; 11:604049.

100 90 80 70

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Figure 5  Optical coherence tomography angiography (OCTA) of macular region in Alzheimer’s disease (AD). The superficial retinal OCT angiograms of the macula (A) and color-coded vessel density maps (B) shows a reduction of vascular density in patients affected by AD compared to normal subjects, as mostly evidenced by the color map where the prevalence of blue corresponds to a reduced flow density. Source: Modified from Lahme L, Esser EL, Mihailovic N, et al. Evaluation of Ocular Perfusion in Alzheimer’s Disease Using Optical Coherence Tomography Angiography. J Alzheimers Dis 2018; 66:1745–1752.

CHAPTER 21: OCT angiography examination in neurodegenerative diseases

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Figure 6  Foveal avascular zone (FAZ) in Alzheimer’s disease (AD). Optical coherence tomography angiography (OCTA) analysis of FAZ in a patient affected by AD in superficial vascular plexus (SVP) (left image) and deep capillary plexus (DCP) (right). The measurement of FAZ indicates a significant increase in FAZ area in patients affected by AD.

41

RNFL

11

85

GCIP

41

26

45

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Source: Modified from Salobrar-Garcia E, MéndezHernández C, Hoz R, et al. Ocular Vascular Changes in Mild Alzheimer’s Disease Patients: Foveal Avascular Zone, Choroidal Thickness, and ONH Hemoglobin Analysis. Pers Med 2020; 10:231.

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Figure 7  Optical coherence tomography angiography (OCTA) microvascular density and retinal thickness analysis in Parkinson’s disease (PD). The whole image shows a comparison of the microvascular density assessed by OCTA and retinal thickness in patients affected by PD and healthy subjects. The first two rows represent the retinal thickness maps and microvascular density of healthy controls and PD patients, respectively. The retinal thickness and microvascular density are indicated by the colors shown in the color bar for each row. The third row shows the corresponding parameters between the healthy controls and the PD patients; blue represents significant thinning (p < 0.05), red represents significant thickening (p < 0.05). OCTA data reveal a statistically significant reduction of microvascular density in PD patients compared to controls. In addition, it may be evidenced a significant correlation between vascular impairment of superficial capillary plexus and thinning of ganglion cell layer. Source: Modified from Kwapong WR, Ye H, Peng C, et al. Retinal Microvascular Impairment in the Early Stages of Parkinson’s Disease. Invest Ophthalmol Vis Sci 2018; 59:4115–4122.

conducted by Kwapong et al.20 They demonstrated that the retinal microvascular density is reduced in PD patients compared to healthy subjects. Moreover, the researchers found a correlation between microvascular impairment in the superficial retinal capillary layer and ganglion cell layer thinning, suggesting a key contribute of vascular flow alteration to the neurodegeneration process (Figure 7). Another study from Robbins et al. 21 has evaluated with the aim of OCTA both retinal vessel and perfusion density and choroidal morphology in individuals with PD. They have interestingly found a significant vessel and perfusion density reduction at the level of SVP in the macular area in comparison to normal subjects. On the contrary, the choroidal area was surprisingly greater in PD patients. The potential diagnostic abilit y to detect PD of OCTA in combination with OCT has been assessed by Zou et al. 22 They

confirmed the above-mentioned results, evidencing a reduced vessel density in the macular region of patients with PD and, moreover, a reduction of FAZ index circularity. The combination of OCTA measurements and OCT parameters, such as RNFL and ganglion cell–inner retinal layer complex (GCL-IPL) thickness, permits to obtain a better efficacy to diagnose PD compared with each test considered alone. Despite the lack of numerous clinical studies, these results confirm that the macular vascular flow seems to be impaired, specifically reduced, in patients affected by PD. As a consequence, it is emphasized the hypothesis that retinal ischemia may contribute to the neurodegenerative damage. It would be important to conduct further studies to define retinal biomarkers, which can be useful to make a prompt diagnosis.

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Figures 8A to F  Optical coherence tomography angiography (OCTA) blood flow analysis and spectral-domain OCT (SD-OCT) retinal thickness in Huntington’s Disease (HD). OCTA exhibits no alteration in superficial capillary plexus (SCP) (A), deep capillary plexus (DCP) (B), choriocapillaris (CC) (C), and an increase (439 μm) in central choroidal thickness (CCT) (D) at enhanced depth imaging spectral-domain OCT (EDI SD-OCT), and a normal thickness in Ganglion Cell Complex (GCC) (E) and retinal nerve fiber layer (RNFL) (F) at structural OCT. Source: Modified from Di Maio LG, Montorio D, Peluso S, et al. Optical coherence tomography angiography findings in Huntington’s disease. Neurol Sci 2021; 42:995–1001.

■■OCTA AND HUNTINGTON’S DISEASE Hunt ing ton’s disease (HD) is a rare autosoma l-dominant neurodegenerative disorder clinically characterized by personality change, dementia, and chorea. Previous OCT studies reported both peripapillary RNFL thinning and macular thickness reduction in patients with diagnosis of HD.23,24 Only one report is present in the literature regarding the use of OCTA in patients affected by HD. Di Maio et al.25 evaluated the retinal and choriocapillaris vascular networks in macular region, but they did not find significant blood flow alterations in both areas (Figure 8).

■■CONCLUSION

both in peripapillary and macular regions of patients affected by neurodegenerative disorders. For this reason, it can be stated that OCTA may play a fundamental pivotal role in the diagnosis and follow-up of these neurological diseases. Moreover, the combination of retinal thickness parameters, such as RNFL and ganglion cell complex (GCC), analyzed with the aim of OCT and vascular measurements, including flow density and perfusion, obtained with OCTA might be used as clinical biomarkers to improve the armamentarium of neuro-ophthalmologists. The possibility to monitor disease progression could be also exploited to develop potential future therapies for disorders that are nowadays challenging to treat or even incurable. Although larger data are needed to establish clear pathological measurements, OCTA can be considered as a viable alternative in the assessment of neurodegenerative diseases.

Opt ic a l coherence tomog raphy a ng iog raphy ha s clea rly demonstrated to be able to detect clinically relevant changes

■■REFERENCES 1. Crair MC, Mason CA. Reconnecting eye to brain. J Neurosci 2016; 36:10707– 10722. 2. London A, Benhar I, Schwartz M. The retina as a window to the brain-from eye research to CNS disorders. Nat Rev Neurol 2013; 9:44–53. 3. Doustar J, Torbati T, Black KL, Koronyo Y, Koronyo-Hamaoui M. Optical Coherence Tomography in Alzheimer’s Disease and Other Neurodegenerative Diseases. Front Neurol 2017; 8:701. 4. Yoon SP, Grewal DS, Thompson AC, et al. Retinal Microvascular and Neurodegenerative Changes in Alzheimer’s Disease and Mild Cognitive Impairment Compared with Control Participants. Ophthalmol Retina 2019; 3:489–499. 5. Wang L, Murphy O, Caldito NG, Calabresi PA, Saidha S. Emerging applications of Optical Coherence Tomography Angiography (OCTA) in neurological research. Eye Vis 2018; 5:11.

6. Ley M, Saindane AM, Ge Y, et al. Microvascular abnormality in relapsingremitting multiple sclerosis: perfusion MR imaging findings in normalappearing white matter. Radiology 2004; 231:645–652. 7. Kleerekooper I, Houston S, Dubis AM, Trip SA, Petzold A. Optical Coherence Tomography Angiography (OCTA) in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder. Front Neurol 2020; 11:604049. 8. Lanzillo R, Cennamo G, Criscuolo C, et al. Optical coherence tomography angiography retinal vascular network assessment in multiplesclerosis. Mult Scler 2018; 24:1706–1714. 9. Wang X, Jia Y, Spain R, et al. Optical coherence tomography angiography of optic nerve head and parafovea in multiple sclerosis. Br J Ophthalmol 2014; 98:1368–1373. 10. Murphy OC, Kwakyi O, Iftikhar M, et al. Alterations in the retinal vasculature occur in multiple sclerosis and exhibit novel correlations with disability and visual function measures. Mult Scler J 2019; 26:815–28.

CHAPTER 21: OCT angiography examination in neurodegenerative diseases 11. Yilmaz H, Ersoy A, Icel E. Assessments of vessel density and foveal avascular zone metrics in multiple sclerosis: an optical coherence tomography angiography study. Eye 2020 34:771–778. 12. Higashiyama T, Nishida Y, Ohji M. Optical coherence tomography angiography in eyes with good visual acuity recovery after treatment for optic neuritis. PloS One 2017; 12:e0172168. 13. Bulut M, Kurtuluş F, Gözkaya O, et al. Evaluation of optical coherence tomography angiographic findings in Alzheimer’s type dementia. Br J Ophthalmol 2018; 102:233–237. 14. Jiang H, Wei Y, Shi Y, et al. Altered Macular Microvasculature in Mild Cognitive Impairment and Alzheimer Disease. J Neuroophthalmol 2018; 38:292–298. 15. Lahme L, Esser EL, Mihailovic N, et al. Evaluation of Ocular Perfusion in Alzheimer’s Disease Using Optical Coherence Tomography Angiography. J Alzheimers Dis 2018; 66:1745–1752. 16. Wu J, Zhang X, Azhati G, et al. Retinal microvascular attenuation in mental cognitive impairment and Alzheimer’s disease by optical coherence tomography angiography. Acta Ophthalmol 2020; 98:e781–e787. 17. Zabel P, Kaluzny JJ, Zabel K, et al. Quantitative assessment of retinal thickness and vessel density using optical coherence tomography angiography in patients with Alzheimer’s disease and glaucoma. PLoS One 2021; 16:e0248284. 18. Salobrar-Garcia E, Méndez-Hernández C, Hoz R, et al. Ocular Vascular Changes in Mild Alzheimer’s Disease Patients: Foveal Avascular Zone,

19. 20. 21. 22. 23. 24. 25.

Choroidal Thickness, and ONH Hemoglobin Analysis. Pers Med 2020; 10:231. Schwartz RS, Halliday GM, Cordato DJ, Kril JJ. Small-vessel disease in patients with Parkinson’s disease: a clinicopathological study. Mov Disord 2012; 27:1506–1512. Kwapong WR, Ye H, Peng C, et al. Retinal Microvascular Impairment in the Early Stages of Parkinson’s Disease. Invest Ophthalmol Vis Sci 2018; 59:4115–4122. Robbins CB, Thompson AC, Bhullar PK, et al. Characterization of Retinal Microvascular and Choroidal Structural Changes in Parkinson Disease. JAMA Ophthalmol 2021; 139:182–188. Zou J, Liu K, Li F, et al. Combination of optical coherence tomography (OCT) and OCT angiography increases diagnostic efficacy of Parkinson’s disease. Quant Imaging Med Surg 2020; 10:1930–1939. Kersten HM, Danesh-Meyer HV, Kilfoyle DH, Roxburgh RH. Optical coherence tomography findings in Huntington’s disease: a potential biomarker of disease progression. J Neurol 2015; 262:2457–2465. Andrade C, Beato J, Monteiro A, et al. Spectral-domain optical coherence tomography as a potential biomarker in Huntington’s disease. Mov Disord 2016; 31:377–383. Di Maio LG, Montorio D, Peluso S, et al. Optical coherence tomography angiography findings in Huntington’s disease. Neurol Sci 2021; 42:995– 1001.

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PART 3 Future developments in oct angiography chapter 22: The future of OCT and OCT angiography Federico Corvi, Giovanni Staurenghi

Chapter 22 The future of OCT and OCT angiography Federico Corvi, Giovanni Staurenghi

■■INTRODUCTION Optical coherence tomography (OCT) and OCT angiography (OCTA) have revolutionized the imaging of the retina becoming a fundamental examination in clinical practice.1 The high axial resolution of current OCT devices allow lesions to be evaluated in three dimensions and the involvement and tissue loss of specific retinal layers can be assessed quantitatively. For example, in eyes with dry age-related macular degeneration (AMD), visualization of the outer retinal layers may allow subtle alterations to be detected before they can be identified by color fundus photography or fundus autofluorescence. 2-4 The layer-by-layer evaluation is fundamental to assess the progressive changes and the severity of cellular loss in this disease. In fact, the use of OCT has been introduced for the identification of robust precursor end points that would facilitate and allow earlier and more precise estimation of tissue loss. In this context, the terms incomplete and complete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA and cRORA), were defined and have already been incorporated into ongoing research studies of atrophy. 3,5-11 The main limitation of the OCT is the standard field of view about 30° that is useful to examine diseases primarily affecting the macula. However, the visualization of the periphery has become essential to the screening, diagnosis, monitoring, and treatment of many vision-threatening eye and this standard field of view may be inadequate.12-14 There are several potential limitations to image the retinal periphery as the limited depth range, optical distortions, low images quality, and increased scan time. In this context, recent advances in imaging techniques have opened new perspectives, leading to the introduction of wide-field (WF) OCT systems allowing for in vivo study of the retinal and choroidal layers in several diseases like never before possible.15-21 In any event, there is much progress still to be made in image acquisition as faster scan speeds and advancements in software analysis in order to improve image quality and consistency. Moreover, OCT is currently used to monitoring for neurondamaging eye and brain diseases like glaucoma. 22 Ganglion cells are one of the primary neurons in the eye that process and send visual information to the brain. 23 In many neurodegenerative diseases like glaucoma, ganglion cells degenerate and disappear, leading to irreversible blindness. The current OCT devices are able to evaluate only the thickness of ganglion cell layer in the retina. In this context, a recent technology called adaptive optics OCT enables imaging sensitive enough to view individual ganglion cells. Adaptive optics is a technology that minimizes the effect of optical aberrations that occur when examining the eye, which are a major limiting factor in achieving high-resolution in OCT imaging. 24 The application of this technology to evaluate in highresolution ganglion cells will generate a new amount of data with the opportunity to diagnose neurodegenerative diseases.

Another new possible scenario could be the improvement of handheld OCT. The introduction of handheld OCT will enable a new generation of devices. Handheld OCT is expected to contribute significantly to a widespread adoption of this imaging modality in point-of-care diagnostics and for diagnostic-driven therapy of major sight-threatening diseases with the aim to improve patient outcome and reduce healthcare costs. Considering the new imaging analysis, the introduction of artificial intelligence may be extremely useful to investigate OCT data in several diseases. Artificial intelligence based on deep learning has generated great global interest in recent years. 25 Deep learning methods have been successfully applied to OCT images for classification, segmentation and prediction of treatment outcome and disease progression. 26-28 It has been found that the performance of an automated method for detection and classification of multiple early AMD biomarkers such as reticular pseudodrusen, intraretinal hyperreflective foci, and hypoflective drusen cores demonstrated an accuracy of 87%. 28 Considering the increasing burden of OCT data, the introduction of automated tools to facilitate diagnosis and staging of disease may prove to be of significant benefit. A more rec ent i mag i ng tech nolog y i s OC TA t hat ha s revolutionized retinal imaging by allowing the retinal and inner choroidal microvasculature to be visualized in high resolution in an efficient and noninvasive manner. 29-31 OCTA offers the opportunity to perform qualitative and quantitative vascular assessments which can be used to provide new markers in the disease progression. 32,33 In particular, this technology is based on the recognition of the intrinsic movement of the particles in the biological tissue to provide a reconstruction of the retinal and choroidal vessels. OCTA technology is based on the repetition of multiple OCT scans at the same location, followed by detection of differences between these scans over time. Of note, the depiction of retinal and choroidal vessels is the result of blood flow detection and for this reason, the vessel representation should be considered as the lumen rather than the entire vessel. The introduction of several OCTA devices on the market has led to variability in measurements of retinal and choroidal metrics and subsequent miscalculation in the interpretation of several studies. 34-36 OCTA devices can be broadly divided into spectral domain (SD) and swept source (SS). This distinction is based on the light source of the device, 840 nm for the SD and 1,050 nm for the SS, resulting in a different penetration of the signal through the RPE, pigment deposits, drusen, and other blocking structures, thereby producing a different visualization of the choroidal layers. 35-37 Furthermore, SD devices are characterized by a broader bandwidth light source which is coupled with a spectrometer, while SS devices is equipped with photodetectors and a tunable laser light source that operates through a range of frequencies. Although the speed of SD-OCTA devices has

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progressively increased (with some devices operating at 100 kHz), SS-OCTA devices are generally faster. As stated before, the main advantage of OCTA is the opportunity to perform qualitative and quantitative analysis. Qualitative analysis is based on the recognition of specific features such as areas of nonperfusion, macular neovascularization (MNV) or microaneurysms which may be of relevance to clinical practice.38-40 The quantitative analyses may not be as relevant to current practice, but are invaluable in research studies, particularly in longitudinal assessments, and may give new insights into the pathogenesis of disease. The incorporation of these parameters into clinical trials and clinical practice requires their repeatability and reproducibility to be established.41 Of course, like many new techniques, the emergence of OCTA imaging and its use to quantify has been accompanied by new challenges due to limited understanding of current technolog y and the inappropriate use of various algorithms.42-45 Researchers have used different OCTA instruments and various analytical methods to characterize retinal and choroidal vessels in ocular diseases such as AMD, diabetic retinopathy, retinal vein occlusion, glaucoma, central serous chorioretinopathy, and ocular oncology.46-50 Using OCTA, one of the hottest topics in ophthalmological research in recent years is the imaging and analysis of the choriocapillaris (CC). It has been found that early outer retinal abnormalities in dry AMD are associated with impairment of the CC. In fact, drusen, the hallmark feature of early AMD, is associated with progressive disruption of the RPE, Bruch’s membrane, and CC. 51 At the same time, eyes with reticular pseudodrusen show unique CC alterations with lower choroidal thickness and volume, higher choroidal vascular index, higher choroidal intensity, and reduced retinal sensitivity. 52-55 These early CC changes may have functional impacts as well. In fact, CC flow impairment was found to correlate with reduced scotopic macular sensitivity in eyes with early or intermediate AMD. 56 For this reason, the assessment of CC on OCTA is a meaningful indicator of the severity of disease in AMD.

Moreover, the status of CC on OCTA may also have predictive power in determining the advancement of disease. In patients with drusen, CC flow deficit predicts both enlargement of the existing drusen and development of new drusen. 57 Greater inner choroidal flow deficit predict progression to incomplete RPE and outer retinal atrophy (iRORA). 58 Similarly, CC flow deficit is greater in intermediate AMD eyes that progress to complete RPE and outer retinal atrophy (cRORA).8 Guided by these findings, OCTA of the CC may provide useful risk stratification or prediction in the future. Considering neovascular AMD, an important application of OCTA is the assessment of MNV. The use of OCTA has transformed the diagnostic power of the clinician to detect MNV and has provided insights into the pathophysiology of neovascular AMD. MNV is often encircled by a “dark-halo” on OCTA, an area devoid of flow which may represent a vascular steal phenomenon; the result of flow diverted through the neovascular membrane or due to inner choroidal ischemia. 59-61 Interestingly, the CC is impaired in the peripheral macula in patients with geographic atrophy compared to both normal eyes and eyes with type 1 or 2 MNV.62 At the same time, CC FD is significantly greater in the peripheral macular regions of eyes with type 3 MNV compared to eyes with type 1 or 2 MNV and normal control eyes. These findings suggest a possible different pathogenic choroidal mechanism in eyes with different MNV subtypes. Whereas focal CC impairment may drive the development of type 1 or 2 MNV, diffuse CC disruption may be more important in eyes with type 3 MNV. In this context, several authors reported a strong association between type 3 MNV and macular atrophy. For all of these reasons, CC flow deficit may be useful for enhancing risk stratification and prognostication of patients with AMD. As a relatively novel imaging modality, there is much progress still to be made in both image acquisition and analysis. Faster scan speeds and advancements in software for motion artifact correction, projection removal, tracking, and segmentation have the potential to improve image quality and consistency. In any event, with continued OCT and OCTA hardware and software innovation, we are all expecting new progression in clinical applications and pathophysiologic discoveries.

■■REFERENCES 1. Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science 1991; 254:1178–1181. 2. Wu Z, Luu CD, Ayton LN, et al. Optical coherence tomography-defined changes preceding the development of drusen-associated atrophy in age-related macular degeneration. Ophthalmology 2014; 121:2415– 2422. 3. Sadda SR, Guymer R, Holz FG, et al. Consensus Definition for Atrophy Associated with Age-Related Macular Degeneration on OCT: Classification of Atrophy Report 3. Ophthalmology 2018; 125:537–548. 4. Wu Z, Pfau M, Blodi BA, et al. OCT Signs of Early Atrophy in AgeRelated Macular Degeneration: Interreader Agreement: Classification of Atrophy Meetings Report 6. Ophthalmol Retina 2021. doi:10.1016/j. oret.2021.03.008. 5. Guymer RH, Rosenfeld PJ, Curcio CA, et al. Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy in Age-Related Macular Degeneration: Classification of Atrophy Meeting Report 4. Ophthalmology 2020; 127: 394–409. 6. Sadda SR, Abdelfattah NS, Lei J, et al. Spectral-Domain OCT Analysis of Risk Factors for Macular Atrophy Development in the HARBOR Study for Neovascular Age-Related Macular Degeneration. Ophthalmology 2020; 127:1360–1370.

7. Eng VA, Rayess N, Nguyen H V, Leng T. Complete RPE and outer retinal atrophy in patients receiving anti-VEGF treatment for neovascular agerelated macular degeneration. PLoS One 2020; 15:e0232353. 8. Corvi F, Tiosano L, Corradetti G, et al. Choriocapillaris flow deficits as a risk factor for progression of age-related macular degeneration. Retina 2021; 41:686–693. 9. Corradetti G, Corvi F, Nittala MG, et al. Natural history of incomplete retinal pigment epithelial and outer retinal atrophy in age-related macular degeneration. Can J Ophthalmol 2021; S0008-4182(2)00015–6. 10. Corvi F, Corradetti G, Nittala MG, et al. Comparison of Spectralis and Cirrus optical coherence tomography for the detection of incomplete and complete retinal pigment epithelium and outer retinal atrophy. Retina 2021; 41:1851–1857. 11. Corvi F, Corradetti G, Tiosano L, McLaughlin JA, Lee TK, Sadda SR. Topography of choriocapillaris flow deficit predicts development of neovascularization or atrophy in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2021. doi:10.1007/s00417-021-05167-3. 12. Kaneko Y, Moriyama M, Hirahara S, Ogura Y, Ohno-Matsui K. Areas of nonperfusion in peripheral retina of eyes with pathologic myopia detected by ultra-widefield fluorescein angiography. Invest Ophthalmol Vis Sci 2014; 55:1432–1439.

CHAPTER 22: The future of OCT and OCT angiography 13. Cereda MG, Corvi F, Cozzi M, Pellegrini M, Staurenghi G. Optical coherence tomography 2: Diagnostic tool to study peripheral vitreoretinal pathologies. Retina 2019; 39:415-421. 14. Ho VY, Wehmeier JM, Shah GK. Wide-field infrared imaging: A Descriptive Review of Characteristics of Retinoschisis, Retinal Detachment, and Schisis Detachments. Retina 2016; 36:1439–1445. 15. Reznicek L, Klein T, Wieser W, et al. Megahertz ultra-wide-field sweptsource retina optical coherence tomography compared to current existing imaging devices. Graefes Arch Clin Exp Ophthalmol 2014; 252:1009–1016. 16. Mori K, Kanno J, Gehlbach PL, Yoneya S. Montage images of spectraldomain optical coherence tomography in eyes with idiopathic macular holes. Ophthalmology 2012; 119:2600–2608. 17. Corvi F, Corradetti G, Wong A, et al. Multimodal imaging of a choroidal nevus with caverns in the setting of pachychoroid disease. Retin Cases Brief Rep 2021. doi:10.1097/ICB.0000000000001138. 18. Corvi F, Zicarelli F, Airaldi M, et al. Comparison between Widefield Optical Coherence Tomography Devices in Eyes with High Myopia. Diagnostics (Basel, Switzerland) 2021; 11:658. 19. Corvi F, Corradetti G, Wong A, Eng JG, Sadda S. Peripheral Optical Coherence Tomography Findings in a Choroideremia Carrier. Retin Cases Brief Rep 2020; Publish Ahead of Print. doi:10.1097/ICB.0000000000001109. 20. Corvi F, Juhn A, Corradetti G, et al. Multimodal Imaging of CRB1 Retinitis Pigmentosa with a Peripheral Retinal Tumor. Retin Cases Brief Rep 2020. doi:10.1097/ICB.0000000000001058. 21. Corvi F, Nguyen TV, Juhn A, et al. Optic disc pit associated with an unusual outer retinal hole and nasal peripheral retinoschisis. Retin Cases Brief Rep 2020; Publish Ahead of Print. doi:10.1097/ICB.0000000000001110. 22. Huang J, Liu X, Wu Z, et al. Macular and retinal nerve fiber layer thickness measurements in normal eyes with the Stratus OCT, the Cirrus HD-OCT, and the Topcon 3D OCT-1000. J Glaucoma 2011; 20:118–125. 23. Almasieh M, Wilson AM, Morquette B, Cueva Vargas JL, Di Polo A. The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res 2012; 31:152–181. 24. Akyol E, Hagag AM, Sivaprasad S, Lotery AJ. Adaptive optics: principles and applications in ophthalmology. Eye (Lond) 2021; 35:244–264. 25. LeCun Y, Bengio Y, Hinton G. Deep learning. Nature. 2015; 521:436–444. 26. Mishra Z, Ganegoda A, Selicha J, Wang Z, Sadda SR, Hu Z. Automated Retinal Layer Segmentation Using Graph-based Algorithm Incorporating Deep-learning-derived Information. Sci Rep 2020; 10:9541. 27. Schmidt-Erfurth U, Sadeghipour A, Gerendas BS, Waldstein SM, Bogunović H. Artificial intelligence in retina. Prog Retin Eye Res 2018; 67:1–29. 28. Saha S, Nassisi M, Wang M, et al. Automated detection and classification of early AMD biomarkers using deep learning. Sci Rep 2019; 9:10990. 29. Spaide RF, Klancnik JM Jr, Cooney MJ. Retinal vascular layers imaged by fluorescein angiography and optical coherence tomography angiography. JAMA Ophthalmol 2015; 133:45–50. 30. Matsunaga D, Yi J, Puliafito CA, Kashani AH. OCT angiography in healthy human subjects. Ophthalmic Surg Lasers Imaging Retina 2014; 45:510– 515. 31. Rocholz R, Corvi F, Weichsel J, Schmidt S, Staurenghi G. OCT Angiography (OCTA) in Retinal Diagnostics. In: Bille JF, (Ed). High Resolution Imaging in Microscopy and Ophthalmology. Cham (CH): Springer; 2019. pp. 135–160. 32. Spaide RF, Fujimoto JG, Waheed NK, Sadda SR, Staurenghi G. Optical coherence tomography angiography. Prog Retin Eye Res. 2018; 64:1–55. 33. Corvi F, Su L, Sadda SR. Evaluation of the inner choroid using OCT angiography. Eye (Lond) 2021; 35:110–120. 34. Corvi F, Pellegrini M, Erba S, Cozzi M, Staurenghi G, Giani A. Reproducibility of Vessel Density, Fractal Dimension, and Foveal Avascular Zone Using 7 Different Optical Coherence Tomography Angiography Devices. Am J Ophthalmol 2018; 186:25–31. 35. Corvi F, Cozzi M, Barbolini E, et al. Comparison between several optical coherence tomography angiography devices and indocyanine green angiography of choroidal neovascularization. Retina 2020; 40:873–880. 36. Miller AR, Roisman L, Zhang Q, et al. Comparison Between Spectral-Domain and Swept-Source Optical Coherence Tomography Angiographic Imaging of Choroidal Neovascularization. Invest Ophthalmol Vis Sci 2017; 58:1499–1505. 37. Parrulli S, Corvi F, Cozzi M, Monteduro D, Zicarelli F, Staurenghi G. Microaneurysms visualisation using five different optical coherence tomography angiography devices compared to fluorescein angiography. Br J Ophthalmol 2021; 105:526–530.

38. Pellegrini M, Cozzi M, Staurenghi G, Corvi F. Comparison of wide field optical coherence tomography angiography with extended field imaging and fluorescein angiography in retinal vascular disorders. PLoS One 2019; 14:e0214892. 39. Corvi F, Cozzi M, Invernizzi A, Pace L, Sadda SR, Staurenghi G. Optical coherence tomography angiography for detection of macular neovascularization associated with atrophy in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2021; 259:291–299. 40. Pellegrini M, Corvi F, Say EAT, Shields CL, Staurenghi G. Optical coherence tomography angiography features of choroidal neovascularization associated with choroidal nevus. Retina 2018; 38:1338–1346. 41. Corvi F, Corradetti G, Parrulli S, Pace L, Staurenghi G, Sadda SR. Comparison and Repeatability of High Resolution and High Speed Scans from Spectralis Optical Coherence Tomography Angiography. Transl Vis Sci Technol 2020; 9:29. 42. Chu Z, Zhang Q, Gregori G, Rosenfeld PJ, Wang RK. Guidelines for imaging the choriocapillaris using OCT angiography. Am J Ophthalmol 2021; 222:92–101. 43. Spaide RF, Fujimoto JG, Waheed NK. Image artifacts in optical coherence tomography angiography. Retina 2015; 35:2163–2180. 44. Corvi F, Sadda SR, Staurenghi G, Pellegrini M. Thresholding strategies to measure vessel density by optical coherence tomography angiography. Can J Ophthalmol 2020; 55:317–322. 45. Mehta N, Liu K, Alibhai AY, et al. Impact of Binarization Thresholding and Brightness/Contrast Adjustment Methodology on Optical Coherence Tomography Angiography Image Quantification. Am J Ophthalmol 2019; 205:54–65. 46. Pellegrini M, Corvi F, Invernizzi A, Ravera V, Cereda MG, Staurenghi G. Swept-source optical coherence tomography angiography in choroidal melanoma: An Analysis of 22 Consecutive Cases. Retina 2019; 39:1510– 1519. 47. Hou KK, Au A, Kashani AH, Freund KB, Sadda SR, Sarraf D. Pseudoflow with OCT Angiography in Eyes with Hard Exudates and Macular Drusen. Transl Vis Sci Technol 2019; 8:50. 48. Hirano T, Kakihara S, Toriyama Y, Nittala MG, Murata T, Sadda S. Wide-field en face swept-source optical coherence tomography angiography using extended field imaging in diabetic retinopathy. Br J Ophthalmol 2018; 102:1199–1203. 49. Akil H, Chopra V, Al-Sheikh M, et al. Swept-source OCT angiography imaging of the macular capillary network in glaucoma. Br J Ophthalmol bjophthalmol-2016-309816. doi:10.1136/bjophthalmol-2016-309816. 50. Hu J, Qu J, Li M, et al. Optical coherence tomography angiography-guided photodynamic therapy for acute central serous chorioretinopathy. Retina 2021; 41:189–198. 51. Abdelsalam A, Del Priore L, Zarbin MA. Drusen in age-related macular degeneration: pathogenesis, natural course, and laser photocoagulationinduced regression. Surv Ophthalmol 1999; 44:1–29. 52. Velaga SB, Nittala MG, Vupparaboina KK, et al. Choroidal vascularity index and choroidal thickness in eyes with reticular pseudodrusen. Retina 2020; 40:612–617. 53. Corvi F, Souied EH, Capuano V, et al. Choroidal structure in eyes with drusen and reticular pseudodrusen determined by binarisation of optical coherence tomographic images. Br J Ophthalmol 2017; 101:348–352. 54. Corvi F, Pellegrini M, Belotti M, Bianchi C, Staurenghi G. Scotopic and fast mesopic microperimetry in eyes with drusen and reticular pseudodrusen. Retina 2019; 39:2378–2383. 55. Corvi F, Souied EH, Falfoul Y, et al. Pilot evaluation of short-term changes in macular pigment and retinal sensitivity in different phenotypes of early age-related macular degeneration after carotenoid supplementation. Br J Ophthalmol 2017; 101:770–773. 56. Nassisi M, Tepelus T, Corradetti G, Sadda SR. Relationship Between Choriocapillaris Flow and Scotopic Microperimetry in Early and Intermediate Age-related Macular Degeneration. Am J Ophthalmol 2020; 222:302–309. 57. Nassisi M, Tepelus T, Nittala MG, Sadda SR. Choriocapillaris flow impairment predicts the development and enlargement of drusen. Graefes Arch Clin Exp Ophthalmol 2019; 257:2079–2085. 58. Corradetti G, Tiosano L, Nassisi M, et al. Scotopic microperimetric sensitivity and inner choroid flow deficits as predictors of progression to nascent geographic atrophy. Br J Ophthalmol 2020; bjophthalmol-2020-316893. doi:10.1136/bjophthalmol-2020-316893.

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Section 6: Glaucoma and optic nerve 59. Forster JC, Harriss-Phillips WM, Douglass MJ, Bezak E. A review of the development of tumor vasculature and its effects on the tumor microenvironment. Hypoxia (Auckl) 2017; 5:21–32. 60. Treister AD, Nesper PL, Fayed AE, Gill MK, Mirza RG, Fawzi AA. Prevalence of Subclinical CNV and Choriocapillaris Nonperfusion in Fellow Eyes of Unilateral Exudative AMD on OCT Angiography. Transl Vis Sci Technol 2018; 7:19.

61. Scharf JM, Corradetti G, Alagorie AR, et al. Choriocapillaris Flow Deficits and Treatment-Naïve Macular Neovascularization Secondary to Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci 2020; 61:11. 62. Alagorie AR, Verma A, Nassisi M, Sadda SR. Quantitative Assessment of Choriocapillaris Flow Deficits in Eyes with Advanced Age-Related Macular Degeneration Versus Healthy Eyes. Am J Ophthalmol 2019; 205:132–139.

Index Note: Page numbers in bold or italic refer to tables, box or figures respectively.

A

Alzheimer’s disease 151, 152, 154 Angioid streaks 54 Anterior segment optical coherence tomography angiography 31 Arteries 28 Atrophy 63, 64, 112, 133 Autosomal-dominant neurodegenerative disorder 156

B

Behçet’s disease 97, 118, 129 Best disease, color retinal fundus of 58 Best macular dystrophy 55 Birdshot chorioretinopathy 95, 97, 118, 125 Blood flow velocity 7 visualization of 141 Brain 151, 152 Branch retinal artery occlusion 112, 114, 115 Branch retinal vein occlusion 42, 113 Bruch’s membrane 51, 54, 71, 133 B-scan 31 optical coherence tomography 54

C

Central nervous system 151, 152 Central retinal artery occlusion 112 Central retinal vein occlusion 119 Central serous chorioretinopathy 51, 51, 93, 95, 96, 97 Central serous retinopathy 97 Chorioretinitis 125 macular serpiginous 129 scars 66 Chorioretinopathy, chronic central serous 51 Choroid, visualization of 17 Choroidal disorders 17 Choroidal hemangioma 142, 142 Choroidal melanoma 97, 141 Choroidal metastasis 143 Choroidal neovascularization 9, 17, 45, 46, 52, 55, 56-58, 60, 61, 63, 64, 97, 126, 129, 133, 136, 139 Choroidal nevus 97, 141 Choroidal nonexudative neovascular membrane, optical coherence tomography angiography of 45 Choroidal osteoma 142 Choroiditis 95, 97, 117 multifocal 59, 95, 97 Circle of Zinn–Haller 133 Classic choroidal neovascularization, fluorescein angiography of 59 Coats’ disease 19, 20 Conjunctiva 32 Conjunctival vasculatures 31 Corneal adapter module 31

Coronavirus disease 2019 118 COVID-19 117, 118 Cross-section optical coherence tomography 93, 115 angiography 9 Cushing’s syndrome 93 Cystic spaces 101 Cystoid edema 111, 125

D

Deep vascular complex 14, 15, 38, 42, 116 Deep vascular plexus 22, 27, 29, 110, 154 Dermatomyositis, juvenile 118 Diabetic fibrovascular membrane 66 Diabetic macular edema 81, 119 Diabetic maculopathy, ischemic 85 Diabetic retinopathy 19, 21, 81, 83, 84, 119 advanced 22 nonproliferative 11, 22, 23, 82, 84, 84-86, 121 proliferative 22, 23, 85, 88, 89-91, 118 Diffuse retinal pigment epitheliopathy 93, 96 Disk, neovascularization of 81 Dye angiography 46

E

Edematous branch vein occlusion 109, 110 En-face optical coherence tomography 93, 94, 99 angiography 47, 134, 145, 146 sequence of 107 Epiretinal membranes 17, 18 Epitheliopathy, chronic 93, 95-97 Epstein–Barr infection 99 Expanded disability status scale 151

F

Fibrosis 63 Fibrotic neovascularization 66 Fibrotic punctate inner choroidopathy macular lesion 128 Fibrous scars 64 Fibrovascular pigment epithelium detachment 46 Fluid reaccumulation 61, 62 Fluorescein angiography 17, 27, 27, 39, 45, 56, 59, 81, 83, 93, 102, 109, 109, 110, 110, 111, 112, 113, 119, 133, 137, 141, 142 examinations 101 Fluorescein diffusion leakage 20 Focal choroidal excavation 95, 97, 98, 99 Foveal avascular zone 30, 81, 154 Fuchs’ lesion 54 Fuchs’ spot 133 Fundus autofluorescence 118 fluorescein angiography 126

G

Ganglion cell 155 combined 14 complex 145, 152, 156 layer 27, 28, 81 plexus 14, 15 Geographic atrophy 48, 73 Giant cell arteritis 112 Glaucoma 145

H

Haller’s layer 93, 95 Haller’s vessel dilatation 97 Hemorrhage 65 intraretinal 119 macular 135, 136 subretinal 40 High myopia 133 Highly active antiretroviral therapy 125 Huntington’s disease 152, 156, 156 Hypertension 118 Hyporeflective cavities 101 Hypotony 97

I

Idiopathic macular telangiectasia 101 Indocyanine green 17, 51 angiography 31, 45, 46, 53, 56, 66, 93, 117, 133, 142, 143 phases of 46 Inflammatory disorders 97, 125 Inflammatory vein occlusion 110 Inner nuclear layer 14, 28, 81 Inner plexiform layer 14, 29, 81 Inner retinal disorders 17, 18 Inner retinal layer atrophy of 112 complex 155 Intermediate capillary plexus 14, 15, 27, 29 Iris 32 optical coherence tomography 32 angiography 31 Ischemia, retinal 22 Ischemic branch vein occlusion 109 Isolated retinal capillary ischemia 115

L

Lacquer cracks 133 Laser scars 66 Leber–Coats’ disease 19 Locus minoris resistentiae 133 Lymphoma 97

M

Macroaneurysm 19, 21 Macular degeneration advanced 66 age-related 23, 45, 71, 74, 94, 97, 161

165

166

index

Macular geographical atrophy 84 Macular hole 133 Macular hole classification of Gass 45 Macular neovascularization 37, 41, 42, 45, 162 Macular neuroretinopathy, acute 113, 115, 117, 117 Macular vessel density, quantification of 147 Magnetic resonance angiography 151 Microphthalmia 97 Microvascular occlusions 117 Mixed edematous ischemic occlusions 109 Müller cell depletion 101 Multiple evanescent white dot syndrome 95, 97, 127, 129, 131 Multiple sclerosis 151, 152, 154 Myopia 133 degenerative 133 Myopic choroidal neovascularization 133, 136-138 recurrence of 138 Myopic eye 25, 26 Myopic fibrous scars 66 Myopic maculopathy 133 atrophy, traction, and neovascularization classification system of 133

N

Neovascular age-related macular degeneration, pathogenic sequence of 37 Neovascular membranes 26 Neovascularization 64, 81 angioflow evolution sequence of 62 chronic 65 nonexudative 93, 94 vessel area of 15 Nerve fiber layer 14, 115 infarction 115 plexus 14, 15 Neurodegenerative diseases 151, 152 Nonexudative choroidal neovascularization, multimodal imaging of 46 Nonneovascular age-related macular degeneration 71

O

Obstruction, extent of 109 Ocular toxoplasmosis, bilateral 127 Ocular tumors 141 diagnosis of 141 management of 141 Ophthalmia, sympathetic 97, 125 Optic disk 28 Optic nerve head 145, 151 optical coherence tomography angiography of 109 Optic neuritis 109, 151 Optical coherence tomography 3, 4, 10, 31, 45, 56, 65, 95, 101, 111, 111, 112, 114, 115, 117, 117, 125, 133, 145, 151, 161 angiography 3, 7, 8, 13, 17, 19, 23, 27, 32, 37, 46, 51, 52-55, 57-59, 66, 67, 72, 73, 73-78, 81, 82, 83-86, 88, 88-91, 94, 96-98, 103, 105, 106, 109-111, 112-114, 116, 117, 118, 121, 128, 135-138, 141, 148, 151, 153156, 161 advantages of 17 applications 17 clinical use of 13 disadvantages of 17 examination 101, 133, 145, 151 features 94, 110

future developments in 159 interpretation of 7 principles of 3 ratio analysis 3 signal generation 4 study 35 terminology 13 visualization 8 scans 3 system 82, 86, 87 techniques 46, 125 Optical microangiography 4, 31 Outer retinal atrophy 162 Outer retinal disorders 23

P

Pachychoroid disorders 93 neovasculopathy 95, 98 pigment epitheliopathy 95, 98 spectrum 93, 95, 97 Paracentral acute middle maculopathy 17, 23, 113, 115, 116, 118, 143 Parkinson’s disease 151-153, 155 Pathologic myopia 54, 133 choroidal neovascularization of 54 Pearson test 147, 147 Peripapillary pachychoroid syndrome 95, 97 Peripapillary retinal flow index and vessel density, quantification of 145 Peripapillary retinal nerve fiber layer 145 Pigment epithelial detachment 38, 51, 93 Polypoidal choroidal vasculopathy 51, 52, 95, 97, 98 Projection-resolved optical coherence tomography angiography 14 Punctate outer retinal toxoplasmosis 126

Q

Retinal vein 28 occlusion 42, 109 Retinitis, infectious 125 Retinopathy 17 acute central serous 94

S

Sarcoidosis 97, 125 Scaffold vessels 61 Sclera 32 Scleral optical coherence tomography angiography 31 Scleritis, posterior 97 Serpiginous 129 Sickle cell disease 117, 118 Signal-to-noise ratio 14 Spectral-domain optical coherence tomography 39, 40, 102, 103, 127, 142 angiography 41, 42, 152, 156 scan 135 Split-spectrum amplitude-decorrelation angiography 3, 14, 31 Subretinal macular neovascularization 85, 101 Subretinal pigment epithelium 45, 98 Superficial capillary plexus 27, 105 Superficial plexus 18, 29, 111 Superficial retinal optical coherence tomography angiography 154 Superficial vascular complex 10, 14, 15 Superficial vascular plexus 22, 27, 28, 29, 29, 110, 112, 112 angioflow of 113

T

Telangiectasia 19 macular serpiginous 19, 20, 101 Trauma 66 Tumors 97

Quiescent choroidal neovascularization 45

R

Radial peripapillary capillary plexus 15 Ranibizumab, intravitreal injection of 55 Relapsing-remitting multiple sclerosis 151 Retina 145, 151 neovascularization of 81 Retinal angiomatous proliferation 9 Retinal anomalies 19 Retinal capillary ischemia, levels of 115 Retinal choroidal anastomosis, development of 104 Retinal detachment 94 serous 97 Retinal diseases 128 Retinal disorders study 17 Retinal edema 110 areas of 111 Retinal folds 18 Retinal ganglion cells 152 Retinal hemorrhages 110, 111 Retinal inner layers, disorganization of 113, 115, 119 Retinal microcirculation, pathology of 113 Retinal nerve fiber layer 27, 81, 146, 147, 147, 151, 152 Retinal pigment epithelium 24, 25, 29, 38, 51, 54, 56, 57, 64, 65, 71, 93, 95, 96, 117, 126, 127, 133, 161 Retinal vascular plexus 14, 28

U

Ultrahigh sensitive optical microangiography 5 Uveal effusion syndrome 97 Uveitis 95, 97, 125

V

Vascular endothelial growth factor 11, 37, 46, 54, 57, 60, 66, 67, 104, 106, 136, 138 Vascular plexuses 15 Vein occlusions 109 Vessel arterialization 61 densities 15 metrics 15 Visual acuity 126 loss of 37, 38 Visual field damage 145 Vitrectomy 118 Vogt–Koyanagi–Harada disease 95, 97, 100, 125

W

White dot syndromes 125

Z

Zinn–Haller ring 134