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COLOR ATLAS & SYNOPSIS OF Clinical Ophthalmology Retina FOURTH EDITION Wills Eye Hospital

EDITORS Michael N. Cohen, MD Attending Surgeon, Retina Service

Wills Eye Hospital Mid Atlantic Retina

Assistant Professor of Ophthalmology Thomas Jefferson University Hospital Philadelphia, Pennsylvania Mitchell S. Fineman, MD Attending Surgeon, Retina Service

Wills Eye Hospital Mid Atlantic Retina

Associate Professor of Ophthalmology Thomas Jefferson University Hospital Philadelphia, Pennsylvania

Allen C. Ho, MD Co-Director, Wills Eye Retina Service, Director of Retina Research Attending Surgeon, Retina Service

Wills Eye Hospital Mid Atlantic Retina Professor of Ophthalmology Thomas Jefferson University Hospital Philadelphia, Pennsylvania

SERIES EDITOR Christopher J. Rapuano, MD

Director and Attending Surgeon, Cornea Service Co-Director, Refractive Surgery Department Wills Eye Hospital Professor of Ophthalmology Sidney Kimmel Medical College at Thomas Jefferson University Philadelphia, Pennsylvania

COLOR ATLAS & SYNOPSIS OF Clinical Ophthalmology Retina FOURTH EDITION Wills Eye Hospital

Acquisitions Editor: Chris Teja Development Editor: Eric McDermott Editorial Coordinator: Venugopal Loganathan Marketing Manager: Kirsten Watrud Production Project Manager: Justin Wright Manager, Graphic Arts & Design: Stephen Druding Manufacturing Coordinator: Lisa Bowling Prepress Vendor: S4Carlisle Publishing Services Fourth Edition Copyright © 2025 Wolters Kluwer.

Copyright © 2019 Wolters Kluwer. Copyright © 2012 by Lippincott Williams & Wilkins, A Wolters Kluwer business. All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the above-mentioned copyright. To request permission, please contact Wolters Kluwer at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at permissions@lww.com, or via our website at shop.lww.com (products and services). 9 8 7 6 5 4 3 2 1 Printed in the United States of America

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This work is provided “as is,” and the publisher disclaims any and all warranties, express or implied, including any warranties as to accuracy, comprehensiveness, or currency of the content of this work. This work is no substitute for individual patient assessment based upon healthcare professionals’ examination of each patient and consideration of, among other things, age, weight, gender, current or prior medical conditions, medication history, laboratory data and other factors unique to the patient. The publisher does not provide med ical advice or guidance and this work is merely a reference tool. Healthcare professionals, and not the publisher, are solely responsible for the use of this work including all medical judgments and for any resulting diagnosis and treatments. Given continuous, rapid advances in medical science and health information, independent professional verifica tion of medical diagnoses, indications, appropriate pharmaceutical selections and dosages, and treatment options should be made and healthcare professionals should consult a variety of sources. When prescribing medication, healthcare professionals are advised to consult the product information sheet (the manufacturer’s package insert) accompanying each drug to verify, among other things, conditions of use, warnings and side effects and identify any changes in dosage schedule or contraindications, particularly if the medication to be administered is new, infrequently used or has a narrow therapeutic range. To the maximum extent permitted under applicable law, no responsibility is assumed by the publisher for any injury and/or damage to persons or property, as a matter of products liability, negligence law or otherwise, or from any reference to or use by any person of this work. shop.lww.com

This edition is dedicated in memory of our colleagues and mentors Joseph I. Maguire (1957–2018), J. Arch McNamara (1955–2010), and William Tasman (1929–2017), whose clinical skills, compassion, wisdom, and teachings inspire us in the care of others.

Editors

Michael N. Cohen, MD Attending Surgeon, Retina Service

Allen C. Ho, MD Co-Director, Wills Eye Retina Service, Director of Retina Research Attending Surgeon, Retina Service Wills Eye Hospital Mid Atlantic Retina Professor of Ophthalmology Thomas Jefferson University Hospital Philadelphia, Pennsylvania SERIES EDITOR Christopher J. Rapuano, MD

Wills Eye Hospital Mid Atlantic Retina

Assistant Professor of Ophthalmology Thomas Jefferson University Hospital Philadelphia, Pennsylvania Mitchell S. Fineman, MD Attending Surgeon, Retina Service

Wills Eye Hospital Mid Atlantic Retina

Associate Professor of Ophthalmology Thomas Jefferson University Hospital Philadelphia, Pennsylvania

Contributors

Christopher M. Aderman, MD Retina Specialist Retina Division EyeHealth Northwest Portland, Oregon Gary C. Brown Chief Medical Officer Center for Value-Based Medicine Hilton Head, SC Director Emeritus, Retina Service Wills Eye Hospital Philadelphia, PA Professor of Ophthalmology Thomas Jefferson University Hospital Philadelphia, PA Mitchell S. Fineman, MD Attending Surgeon, Retina Service Associate Professor of Ophthalmology Thomas Jefferson University Hospital Philadelphia, Pennsylvania Allen C. Ho, MD Co-Director, Wills Eye Retina Service, Director of Retina Research Attending Surgeon, Retina Service Wills Eye Hospital Mid Atlantic Retina Professor of Ophthalmology Thomas Jefferson University Hospital Philadelphia, Pennsylvania Wills Eye Hospital Mid Atlantic Retina

Richard S. Kaiser, MD Co-Director Wills Eye Retina Fellowship Program Attending Surgeon, Retina Service Wills Eye Hospital Mid Atlantic Retina Professor of Ophthalmology Thomas Jefferson University Hospital Philadelphia, Pennsylvania

M. Ali Khan, MD, FACS Vitreoretinal Surgeon Roseville, California

Michael A. Klufas, MD Attending Surgeon, Retina Service

Wills Eye Hospital Mid Atlantic Retina

Assistant Professor of Ophthalmology Thomas Jefferson University Hospital Philadelphia, Pennsylvania

Ajay E. Kuriyan, MD, MS Attending Surgeon, Retina Service

Wills Eye Hospital Mid Atlantic Retina

Associate Professor of Ophthalmology Thomas Jefferson University Hospital Philadelphia, Pennsylvania Nikolas J. S. London, MD, FACS Physician Retina Consultants San Diego Poway, California

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viii Contributors

Sonia Mehta, MD Attending Surgeon, Retina Service

Linnet Rodriguez, MD Vitreoretinal Diseases and Surgery Fellow Wills Eye Hospital, Retina Service Wills Eye Hospital Philadelphia, PA

Wills Eye Hospital Mid Atlantic Retina

Assistant Professor of Ophthalmology Thomas Jefferson University Hospital Philadelphia, Pennsylvania

Mithlesh C. Sharma, MD Retina Specialist Ophthalmology University of New Mexico Albuquerque, New Mexico

John D. Pitcher III, MD Ophthalmologist Retina Service Eye Associates of New Mexico Albuquerque, New Mexico Ehsan Rahimy, MD Physician Ophthalmology Palo Alto Medical Foundation Palo Alto, California Franco M. Recchia, MD Physician and Partner Vitreoretinal Surgery Tennessee Retina, PO Nashville, TN

Jayanth Sridhar, MD Associate Professor of Ophthalmology Bascom Palmer Eye Institute Miami, Florida James F. Vander, MD Attending Surgeon, Retina Service Wills Eye Hospital Mid Atlantic Retina Professor of Ophthalmology Thomas Jefferson University Hospital Philadelphia, Pennsylvania

David Xu, MD Physician

Carl D. Regillo, MD Director, Retina Service

Wills Eye Hospital Mid Atlantic Retina Philadelphia, Pennsylvania

Wills Eye Hospital Mid Atlantic Retina Professor of Ophthalmology Thomas Jefferson University Hospital Philadelphia, Pennsylvania

Yoshihiro Yonekawa, MD Attending Surgeon, Retina Service

David A. Reichstein, MD Vitreoretinal Surgeon

Wills Eye Hospital Mid Atlantic Retina

Associate Professor of Ophthalmology Thomas Jefferson University Hospital Philadelphia, Pennsylvania

Ocular Oncologist Tennessee Retina Nashville, Tennessee

About the Series

T he beauty of the atlas/synopsis concept is the powerful combination of illustrative photographs and a summary approach to the text. Ophthalmology is a very visual discipline that lends itself wonderfully to clinical photographs. Whereas the seven ophthalmic subspecialties in this series—Cornea, Retina, Glaucoma, Oc uloplastics, Neuro-ophthalmology, Uveitis, and Pediatrics—employ varying levels of visual rec ognition, a relatively standard format for the text is used for all volumes.

The goal of the series is to provide an up-to date clinical overview of the major areas of ophthalmology for students, residents, and practitioners in all the health care professions. The abundance of large, excellent-quality pho tographs (both in print and online) and con cise, outline-form text will help achieve that objective.

Christopher J. Rapuano, MD Series Editor

Preface

Vitreoretinal disease is a privileged visual discipline. There are significant barriers to its study beyond the constricted pupil. Ophthal mology trainees first acquire the observational skills and facility with diagnostic instrumen tation such as the slit lamp biomicroscope and the indirect ophthalmoscope to begin to explore diseases that affect the posterior seg ment of the eye. It takes clinical experience to discern normal variation from significant pathology. Unfortunately, most nonophthal mic physicians are limited, as the use of direct ophthalmoscope only affords a keyhole view of the back of the eye. We are privileged to be lifelong students, practitioners, clinical re searchers, and teachers of this aspect of the eye at Wills Eye Hospital. When we were asked to create a concise color atlas and synopsis of vitreoretinal disease we knew our challenges would be to be concise and to be selective since there is great rich ness of clinical detail, both visually and with words. Our aim was to balance the breadth of the subject material with enough focused de tail to provide the framework of our thinking

regarding important clinical signs, associated clinical features, poignant differential diag nosis, diagnostic evaluation, and prognosis and management of hundreds of vitreoretinal conditions. We want this to be a “go-to” field manual but realize that it cannot be an ency clopedic reference. This color atlas and synopsis includes over 300 color images and over 100 black-and-white images. Our goals were to present the images in their highest quality native colors and con trasts, to limit photographic artifact and to highlight certain clinical features of the images with annotations or image insets. Ultimately, our intent is to present this color atlas and synopsis as an aid to the diagnosis and management of vitreoretinal diseases in the care of patients and as a resource for stu dents studying these conditions.

Michael N. Cohen, MD Mitchell S. Fineman, MD Allen C. Ho, MD

Acknowledgments

G rateful acknowledgment is given to these consultants for their efforts and expertise in imaging and for their contributions to this publication:

Crystal Harmer Veronica Herman Allison Hurd MaryAnn Jay Zafiirah Khodabukus Jay Klancnik, MD Leah Kritzwiser Lisa Lavetsky Henry C. Lee, MD Netanya Lerner Jennifer Makarczyk Courtney Machin Erin O’Donnell Anthony Obeid, MD Lila Ortiz

Suely Bascope Christie Bisschop Vicki Carr Brittany Castro Melissa Dinnell Xin Gao, MD Hillary Giordano Elaine Gonzales Adele Grandizio Samantha Groch

Contents

Editors vi Contributors vii About the Series ix Preface x Acknowledgments xi

Chapter 1 Age-Related Macular Degeneration 2 Jayanth Sridhar and Allen C. Ho Introduction 2

Nonexudative Age-Related Macular Degeneration 2 Neovascular Age-Related Macular Degeneration 18

Chapter 2 Macular Diseases 48

Christopher M. Aderman, Nikolas J. S. London, and Mitchell S. Fineman Macular Epiretinal Membrane 48 Idiopathic Macular Hole 54 Disorders of the Vitreomacular Interface 64

Vitreomacular Adhesion 64 Vitreomacular Traction 64

Cystoid Macular Edema 66 Polypoidal Choroidal Vasculopathy 70 Degenerative Myopia 74 Angioid Streaks 80 Central Serous Retinopathy 86 Choroidal Folds 98 Hypotony Maculopathy 102 Chapter 3 Diabetic Retinopathy 104

Ajay E. Kuriyan, James F. Vander, and Mitchell S. Fineman Diabetic Retinopathy 104 Nonproliferative Diabetic Retinopathy 105 Proliferative Diabetic Retinopathy 122 Diabetic Papillopathy 142

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Contents xiii

Chapter 4 Retinal Vascular Disease 144 M. Ali Khan and Gary C. Brown Cotton-Wool Spots 144 Hypertensive Retinopathy 148

Cilioretinal Artery Obstruction (Occlusion) 154 Branch Retinal Artery Obstruction (Occlusion) 156 Central Retinal Artery Obstruction (Occlusion) 160 Acute Ophthalmic Artery Obstruction (Occlusion) 164 Combined Central Retinal Artery and Vein Obstruction (Occlusion) 168 Ocular Ischemic Syndrome 170

Branch Retinal Vein Obstruction (Occlusion) 174 Central Retinal Vein Obstruction (Occlusion) 178 Retinal Arterial Macroaneurysm 184 Idiopathic Juxtafoveal (Parafoveal) Telangiectasis 188

Sickle Cell Retinopathy 192 Radiation Retinopathy 196 Lipemia Retinalis 202 Chapter 5 Retinal Degenerations and Dystrophies 204 David Xu, John D. Pitcher III, Mithlesh C. Sharma, and Allen C. Ho Best Disease 204 Choroideremia 226 Gyrate Atrophy 230 Congenital Stationary Night Blindness 234 Fundus Albipunctatus 234 Oguchi Disease 234 Albinism 238 Retinitis Pigmentosa 242 Systemic Diseases Associated With Retinitis Pigmentosa 246 Carcinoma-Associated Retinopathy Syndrome 248 Cone Dystrophy 210 Pattern Dystrophy 214 Stargardt Disease 220

Chapter 6 Retinal and Choroidal Tumors 252 David A. Reichstein and Franco M. Recchia Astrocytic Hamartoma 252 Retinoblastoma 254 Retinal Capillary Hemangioblastoma 258 Retinal Cavernous Hemangioma 262

Congenital Hypertrophy of the Retinal Pigment Epithelium 264 Combined Hamartoma of the Retina and Retinal Pigment Epithelium 268 Choroidal Nevus 270

xiv Contents

Choroidal Melanoma 274 Optic Disc Melanocytoma 280 Choroidal Melanocytoma 284 Choroidal Metastasis 286 Choroidal Hemangioma 292 Primary Vitreoretinal Lymphoma 296

Choroidal Lymphoma 298 Choroidal Osteoma 300 Choroidal Granuloma 304 Vasoproliferative Retinal Tumor 306 Chapter 7 Congenital and Pediatric Retinal Diseases 310

Michael A. Klufas, Yoshihiro Yonekawa, Nikolas J. S. London, and Richard S. Kaiser Retinopathy of Prematurity 310 Incontinentia Pigmenti 324 Familial Exudative Vitreoretinopathy 328 Coats Disease 336

Chorioretinal Coloboma 338 Persistent Fetal Vasculature 348 X-Linked Retinoschisis 350 Leber Congenital Amaurosis 354 Chapter 8 Traumatic and Toxic Retinopathies 356

Sonia Mehta, J. Luigi Borrillo, Linnet Rodriguez, and Carl D. Regillo Commotio Retinae 356 Choroidal Rupture 358 Avulsed Vitreous Base 360

Solar Maculopathy 362 Valsalva Retinopathy 366 Shaken Baby Syndrome 368 Terson Syndrome 370 Purtscher Retinopathy 372 Traumatic Macular Hole 374 Chorioretinitis Sclopetaria 376 Intraocular Foreign Body 378

Dislocated Lens 380 Talc Retinopathy 382 Chloroquine or Hydroxy-Chloroquine Retinopathy 384 Thioridazine Retinopathy 390 Pentosan Polysulfate Sodium Maculopathy 394 Mitogen-Activated Protein Kinase Inhibitor–Associated Retinopathy 396 Ocular Decompression Retinopathy 398

Contents xv

Chapter 9 Peripheral Retinal Disease 400 Ehsan Rahimy and James F. Vander Retinal Break or Tear 400 Rhegmatogenous Retinal Detachment 412 Proliferative Vitreoretinopathy 422 Lattice Degeneration 426 Vitreoretinal Tuft and Meridional Fold 428 Cobblestone Degeneration 430 Peripheral Grouped Pigmentation 432 Degenerative Retinoschisis 434 Exudative Retinal Detachment 438 Choroidal Detachment 442

Index 443

COLOR ATLAS & SYNOPSIS OF Clinical Ophthalmology Retina FOURTH EDITION Wills Eye Hospital

CHAPTER

Retinal and Choroidal Tumors 6 ■ David A. Reichstein and Franco M. Recchia

ASTROCYTIC HAMARTOMA A strocytic hamartoma is a congenital, min- imally progressive, benign tumor arising from the glial cells of the retina and usually lo cated around the optic disc. It is often associated with the systemic condition tuberous sclerosis (TS; Bourneville disease), occasionally with neu rofibromatosis or retinitis pigmentosa but also oc curs sporadically in otherwise normal individuals. Epidemiology and Etiology ● Most astrocytic hamartomas occur con genitally in association with TS, a familial phakomatosis characterized by the triad of seizures, mental retardation, and skin lesions. TS has an estimated incidence of 1 in 15,000 to 1 in 100,000 and exhibits autosomal dominant inheritance. Roughly half of the patients with TS have astrocytic hamartomas. Causative genes ( TSC1 and TSC2 ) have been identified on chromosomes 9q34 and 16p13. History ● Patients with astrocytic hamartomas are usually asymptomatic. Visual field testing, if clinically feasible, may reveal a scotoma in the area corresponding to the tumor.

Important Clinical Signs ● The appearance of a retinal astrocytic ham artoma is principally of two types: Smaller, noncalcified, flat, smooth tumor that appears as mild thickening of the nerve fiber layer Larger, calcified, whitish-yellow nodular mass (mulberry lesion) ● Aspects of both may be seen in the same lesion, as it is likely that calcification pro gresses slowly over many years ( Fig. 6-1 ). ● Punched-out depigmented retinal pigment epithelial lesions can be an ocular manifesta tion of TS complex. ● Every patient with an astrocytic hamartoma of the retina or optic nerve must be evaluated for TS. Typical manifestations of TS are as follows: Skin lesions (~95% incidence) Hypomelanotic macules: oval (ash-leaf), polygonal, or punctate (confetti) in shape. Usually present at birth and often the first presenting sign Reddish-brown papular rash over the face (termed adenoma sebaceum , but actually angiofibromas), often mistaken for acne. Rarely present before a few years of age.

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ASTROCYTIC HAMARTOMA 253

Seizures (~90% incidence): myoclonic spasms lasting 10 to 50 seconds; tend to become grand mal type later in life. Mental retardation (~60% incidence) Associated Clinical Signs ● Ocular: occasionally, may produce vitreous hemorrhage, vitreous seeding, subretinal hemorrhage, or retinal detachment ● Systemic (additional manifestations of TS): Ungual fibromas, pleural cysts (leading to spon taneous pneumothorax), renal angiomyolipoma, cardiac rhabdomyoma, and hamartomas of the liver, thyroid, pancreas, or testis may occur. Differential Diagnosis

the venous phase. The tumor stains intensely and homogeneously in the late phases. ● B-scan ultrasonography: A larger, calcified lesion often appears as a discrete, oval, solid mass with a sharp anterior border. ● Neuroimaging: Subependymal hamarto mas, characteristic of TS, may be seen with computed tomography (CT) or magnetic resonance imaging (MRI). Prognosis and Management ● Most retinal astrocytic hamartomas are asymptomatic and do not require treatment. ● Patients diagnosed with TS may require systemic mTOR inhibitor treatment for giant cell astrocytomas. These inhibitors have been shown to shrink retinal astrocytic hamartomas. ● Associated exudative retinal detachments can often be treated with demarcating laser photocoagulation and vitrectomy. ● Anti–vascular endothelial growth factor (anti-VEGF) therapy may be required in rare cases of choroidal neovascularization (CNV). Subretinal fluid tends to be resolved after a short course of injections. ● Patients and family members should be examined regularly for manifestations of TS.

● Retinoblastoma (Rb) ● Myelinated nerve fibers ● Retinal granuloma ● Drusen of the optic disc ● Retinocytoma/retinoma ● Papillitis Diagnostic Evaluation

● Fluorescein angiography: The tumor appears relatively hypofluorescent in the arterial phase. Superficial fine blood vessels are seen during

FIGURE 6-1. Astrocytic hamartomas in a teenage patient with tuberous sclerosis (TS). A peripheral astrocytic hamartoma can be observed with scattered depigmented chorioretinal lesions (indicated by arrows ). (Dr. David Reichstein, Oncology Service, Tennessee Retina PC, Nashville, TN.)

254 6 Retinal and Choroidal Tumors

RETINOBLASTOMA R b is the most common primary intraocu- lar malignancy of children. Rb can occur either sporadically (as an isolated unilateral tumor in a family without prior disease) or secondary to a germline mutation (autosomal dominant familial disease often seen bilater ally in multiple family members). The tumor arises from cells in the developing retina of one or both eyes as a result of mutations in the RB1 tumor suppressor gene. Rb presents most often as a white intraocular retinal mass that has the potential to invade the underly ing choroid, sclera, and adjacent optic nerve. If there is considerable optic nerve invasion, direct intracranial extension is possible. Epidemiology and Etiology ● Rb occurs in approximately 1 in 15,000 live births. Most children are diagnosed at a mean of 18 months. ● Rb is rarely fatal in developed countries, but fatality may be seen in developing countries due to lack of timely intervention. ● No predilection for race or gender has been shown. ● Roughly two-thirds of the cases are unilat eral and one-third of the cases are bilateral. Unilateral cases are more likely to be diag nosed at an older age (mean of 24 months) and are most often nonfamilial (sporadic). Bilateral cases are diagnosed at a mean of 12 months, are usually familial, and are nearly always multifocal. ● Rb results from mutations or loss of both alleles of the RB1 gene, located on chromo some 13q14. The RB1 gene product appears to function as a regulator of cellular prolif eration through inhibitory effects on gene transcription at specific stages of the cell cycle. The timing of allelic inactivation deter mines whether the mutation is germinal (i.e., heritable by offspring of the affected child)

or somatic (nonheritable). In germinal cases, a mutant allele is present before fertilization, most commonly as a result of inheritance from either parent. In somatic cases, both alleles are present and active at fertilization, and spontaneous mutations in each allele arise subsequently. History ● A white pupillary reflex (leukocoria) and strabismus are the two most common find ings reported by parents. In fewer than 10% of cases is a family history known at the time of diagnosis. Important Clinical Signs ● Most patients present with leukocoria and strabismus. Small Rbs appear as flat or minimally elevated, translucent, white retinal lesions ( Fig. 6-2 ). With growth, the tumor appears more solid, elevated, and chalky white, with overlying dilated tortuous blood vessels. ● Three growth patterns have been described. Endophytic: The tumor grows from the retina inward to seed the vitreous cavity or anterior chamber ( Fig. 6-3 ). Exophytic: The tumor grows from the retina outward to occupy the subretinal space, often causing an exudative retinal detachment. Diffuse infiltrating: The least common form, this is characterized by a shallow spread of tumor along the entire retina and into the vitreous and anterior chamber. ● The other important findings are iris neovascularization, which occurs in nearly one-fifth of all cases, and “pseudohypopyon” (settling of tumor and inflammatory cells in the anterior chamber). Associated Clinical Signs ● Absence of cataract unless mass fills the posterior segment lens

RETINOBLASTOMA 255

● Heterochromia iridis ● Spontaneous hyphema ● Extrascleral extension ● Pinealoblastoma (trilateral Rb) Differential Diagnosis ● Leukocoria ● Coats disease

● MRI is crucial for assessment of extraocular extension or optic nerve involvement and identifying the presence of pinealoblastoma (trilateral disease). ● Fluorescein angiography reveals early arterial filling of the vessel feeding the tumor, leakage of dye from intrinsic tumor vessels, and late hyperfluorescence of the tumor. Prognosis and Management ● Spontaneous regression is rare and leads to phthisis bulbi. Typically, if untreated, chil dren die within 2 years of diagnosis. Early detection, coupled with improvements and promptness of treatment, has reduced the mortality rate to less than 10%. The main determinant for mortality is optic nerve inva sion. For this reason, it is imperative to obtain as long a section of optic nerve as possible during enucleation. ● Prognostic factors for failure to preserve vision or to preserve the eye are larger tumor size, vitreous seeding, and macular involvement. ● Children with germinal Rb have an increased risk of developing other primary malignancies over the course of their life times. These tumors include principally intracranial Rb, osteogenic sarcoma of the long bones, and sarcoma of soft tissues. The risk is estimated to be approximately 20% within 25 years of treatment. ● Children diagnosed with Rb should undergo evaluation for systemic involvement, including complete blood count, lumbar puncture, neuroimaging, and bone marrow biopsy. Genetic testing of the child and family members should be performed. ● Individual treatment varies according to number, size, and location of tumors, as well as systemic status. Therapeutic options include cryotherapy, laser photocoagula tion, plaque radiotherapy, thermotherapy, intravitreal chemotherapy, intra-arterial

● Persistent fetal vasculature syndrome (for merly termed persistent hyperplastic primary vitreous, or PHPV) ● Toxocariasis ● Retinopathy of prematurity ● Familial exudative vitreoretinopathy ● Retinal astrocytoma ● Cataract ● Retinocytoma/retinoma ● Choroidal granuloma

● Retinochoroidal anastomosis ● Retinochoroidal granuloma ● Norrie disease ● Incontinentia pigmenti ● Vitreous seeding ● Intraocular inflammation ● Endophthalmitis

● Vitreous hemorrhage ● Leukemic infiltration

Diagnostic Evaluation ● Detailed systemic evaluation and examina tion is required, as well as family history and ocular examination of parents, and complete examination of both eyes (often requiring anesthesia for complete visualization of the fundi with scleral depression). ● Ultrasonography: An elevated, rounded, intraocular mass is seen, with high internal reflectivity (calcification) and shadowing of sclera and soft tissue posterior to the lesion.

256 6 Retinal and Choroidal Tumors

chemotherapy, systemic chemotherapy, exter nal beam irradiation, and enucleation. ● Chemoreduction before definitive ocular treatment may be helpful in reducing the need for enucleation and reducing the rate of occurrence of pinealoblastoma ( Fig. 6-4 ). ● Intra-arterial chemotherapy has been shown to be a very successful way to deliver high doses of chemotherapy selectively to the retinal tumor via fluoroscopically guided cannulation of the ophthalmic artery. This treatment, either alone or in combination with other modes of chemotherapy, has led to increased chances of survival and globe salvage and reduced systemic adverse

events, when compared to systemic chemo therapy alone. ● Intravitreal chemotherapy has most recently proven to be an effective treatment for vitreous seeding. Injecting the medication directly into the eye minimizes systemic side effects while providing excellent intraocular tumor control. The injection should be given concurrently with cryotherapy to the needle entry point, to kill tumor cells that may be exuded at the injection site. ● In familial cases, genetic counseling provides parents with important information regarding the probability of further occurrences. Patients with germinal Rb must be warned of the possi bility of transmission to their offspring.

FIGURE 6-2. Small, isolated, minimally elevated retinoblastoma (Rb) in a patient with bilateral disease. (Dr. Amy Schefler, Oncology Service, Retina Consultants of Texas PC, Houston, TX.)

RETINOBLASTOMA 257

FIGURE 6-3. Endophytic macular retinoblastoma (Rb). (Dr. Amy Schefler, Oncology Service, Retina Consul tants of Texas PC, Houston, TX.)

FIGURE 6-4. Multiple retinoblastomas (Rbs) that have demonstrated moderate regression following chemore duction. (Dr. Amy Schefler, Oncology Service, Retina Consultants of Texas PC, Houston, TX.)

258 6 Retinal and Choroidal Tumors

RETINAL CAPILLARY HEMANGIOBLASTOMA O riginally termed angiomatosis retinae , retinal capillary hemangioblastoma is a benign vascular tumor of variable size located in the retina or adjacent to the optic disc. Usu ally diagnosed by the fourth decade, it may be the first manifestation of von Hippel–Lindau (VHL) disease, a familial cancer syndrome with which it is commonly associated. Epidemiology and Etiology ● This tumor may occur in a sporadic or hereditary manner. Retinal capillary heman gioblastoma occurs in up to 80% of patients with VHL syndrome and is often the first man ifestation, diagnosed at a mean age of 25 years. ● The VHL syndrome has an estimated prev alence of 1 in 40,000 and is possibly more common in Whites. It exhibits dominant in heritance and has variable phenotypes within families. ● Mean survival of patients with VHL is 41 years of age. ● VHL syndrome is caused by mutations in the VHL gene, a tumor suppressor gene located on chromosome 3p25. The VHL gene product regulates the expression and function of hypoxia- responsive angiogenic factors (e.g., VEGF). History ● Capillary hemangioblastomas may be di agnosed incidentally or in patients suspected of having VHL syndrome. The tumors may be asymptomatic or may produce painless visual impairment from vitreous hemorrhage, macular pucker, or retinal detachment. Severe vision loss may occur when the tumor occurs on the optic nerve head. Important Clinical Signs ● Retinal capillary hemangioblastoma: usually located peripherally and well

circumscribed. It initially appears as a yellow-red dot with a minimally dilated “feed ing” arteriole or draining venule ( Fig. 6-5 ). With growth, it appears orange-red with more prominently dilated afferent and efferent ves sels. It may have associated exudation, subret inal fluid, or preretinal fibrosis. ● Juxtapapillary capillary hemangioblastoma: orange-red in color, but less well circum scribed. It often lacks feeder vessels. ● VHL syndrome: hemangioblastomas of the cerebellum and spinal cord, renal cell carci noma, or pheochromocytoma Associated Clinical Signs ● Retinal detachment and, rarely, neovas cular glaucoma may complicate capillary hemangioblastoma. ● Hemangioblastomas of the adrenal glands, lungs, and liver, and multiple cysts of the pancreas and kidneys have been observed in some patients with VHL syndrome. Differential Diagnosis ● Retinal capillary hemangioblastoma ■ Other tumors: retinal cavernous heman gioma, racemose hemangioma, choroidal melanoma, and astrocytic hamartoma ■ Vascular diseases: Coats disease, retinal arterial macroaneurysm, familial exudative vitreoretinopathy, and exudative macular degeneration ■ N.B. : A distinction has been made between the retinal angioma of VHL syn drome and an acquired, nonhereditary en tity occurring in older patients and termed vasoproliferative retinal tumor . This latter condition is usually located in the infero temporal peripheral fundus, lacks markedly dilated feeder vessels, and is often associ ated with intraocular inflammation. ● Optic disc hemangioma ■ Papillitis

RETINAL CAPILLARY HEMANGIoblastOMA 259

■ Optic disc granuloma ■ Optic disc glioma Diagnostic Evaluation

location, size, and associated complications, especially those that involve the macula. ● In patients with VHL syndrome, the risk of developing associated tumors increases with age. Morbidity and mortality are related to these associated tumors. Median survival is less than 50 years, with renal carcinoma as the leading cause of death. ● Treatment is recommended for tumors with documented growth or effects on visual function. The goal of treatment is to induce resolution of exudation or subretinal fluid. Laser photocoagulation and anti-VEGF ther apy is reserved for smaller tumors ( < 2 mm in diameter). Larger tumors are best treated with cryotherapy or plaque radiotherapy. Photodynamic therapy and proton beam irradiation may be used in certain cases. Vitreoretinal surgery and, rarely, enucleation may be necessary for patients with advanced or uncontrollable pathology, such as retinal detachment. ● Patients with VHL syndrome and their relatives should be examined regularly for life. This includes regular ultrasonography of the kidneys and MRI of the brain and the spinal cord.

● Ocular: Fluorescein angiography is the most helpful ancillary study ( Fig. 6-6 ). In the arterial phase, a prominent, dilated feeder arteriole may be seen. The tumor appears hyperfluorescent early and remains so through the late phases, sometimes leaking dye into the vitreous. Ultrasonography may be helpful in diagnosing lesions of greater than 1 mm and demonstrates acoustic solidity throughout the lesion. ● Systemic: All patients with retinal capillary hemangioma, as well as relatives, should be evaluated for VHL syndrome. Genetic testing for mutations in the VHL gene is available. If genetic testing is not available or practical, MRI of the brain and spinal cord and CT of the chest and abdomen may be helpful to rule out associated tumors. Prognosis and Management ● The natural history is variable, with both progressive enlargement and spontaneous regression having been reported. Visual prog nosis is highly variable and depends on tumor

260 6 Retinal and Choroidal Tumors

FIGURE 6-5. Retinal capillary hemangioblastoma. Note the orange-red lesion with exudation and the dilated feeder arteriole and draining venule, prominent signs of von Hippel–Lindau (VHL)-related hemangioblastomas. (Dr. David Reichstein, Oncology Service, Tennessee Retina PC, Nashville, TN.)

RETINAL CAPILLARY HEMANGIoblastOMA 261

FIGURE 6-6. Retinal capillary hemangioblastoma. Corresponding fluorescein angiography (recirculation phase) shows a hyperfluorescent vascular lesion with prominent dilated feeder arterioles. (Dr. David Reichstein, Oncology Service, Tennessee Retina PC, Nashville, TN.)

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RETINAL CAVERNOUS HEMANGIOMA R etinal cavernous hemangioma is a benign, rarely progressive, vascular tumor of the retina or optic disc characterized by a collec tion of venous aneurysms. It may be associated with similar vascular anomalies of the skin and the central nervous system (CNS). Epidemiology and Etiology ● Tumor occurrence is mostly sporadic with a slight preponderance for young women. ● Small pedigrees of patients with cavernous hemangioma as part of dominantly inherited neuro-oculocutaneous syndromes (Phakoma toses) syndrome have been reported. History ● Patients are usually asymptomatic, but the tumor may produce painless visual loss sec ondary to associated vitreous hemorrhage. ● A hereditary component may be noted. Important Clinical Signs ● A cluster of dark red, intraretinal aneurysms is located along a retinal venule, appearing as a “cluster of grapes” arising from the inner retinal surface ( Fig. 6-7 ). Often, there is overlying gray fibroglial tissue. Usually, the tumor does not have an associated exudation or a feeding arteriole. Associated Clinical Signs ● Vitreous hemorrhage occurs in up to 10% of patients.

● There may also be cutaneous vascular malformations. ● Cavernous hemangiomas of the midbrain or cerebellum may produce seizures or sub arachnoid hemorrhage.

Differential Diagnosis ● Capillary hemangioblastoma ● Acquired vasoproliferative tumor (VPT) ● Racemose hemangioma ● Coats disease Diagnostic Evaluation

● Fluorescein angiography produces a typ ical pattern: The lesion is hypofluorescent in the early arterial phase and exhibits slow hyperfluorescence during the late venous phase as the dye enters the venous channels. A fluorescein–blood interface may be seen within the aneurysms in the late phases of the angiogram. Prognosis and Management ● Most cavernous hemangiomas do not enlarge and can be managed with periodic observation. ● The main complication is vitreous hemor rhage, although this rarely causes permanent visual loss. ● Tumors causing recurrent vitreous hemorrhage may be treated with cryo therapy, laser photocoagulation, or plaque radiotherapy.

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FIGURE 6-7. Retinal cavernous hemangioma. A. Note the “cluster of grapes” appearance of these intraretinal aneurysms. B. There is a lack of exudation, and surface gray retinal fibrous tissue is noted. (Dr. David Reichstein, Oncology Service, Tennessee Retina PC, Nashville, TN.)

264 6 Retinal and Choroidal Tumors

CONGENITAL HYPERTROPHY OF THE RETINAL PIGMENT EPITHELIUM C ongenital hypertrophy of the retinal pig ment epithelium (CHRPE) is a benign, asymptomatic condition, consisting of one or more well-demarcated, pigmented, flat, non progressive lesions, usually found in the equa torial or peripheral fundus. In rare instances, multifocal lesions may be associated with famil ial colonic polyposis (Gardner syndrome). Epidemiology and Etiology ● The condition is likely congenital. ● It occurs with equal frequency among vary ing genders and ethnicities. History ● Patients are usually asymptomatic. Often, the disorder is noted as an incidental finding during ophthalmoscopy. Important Clinical Signs ● Two forms have been described: Solitary: unilateral, deeply pigmented, flat, circular lesion measuring 1 to 6 mm in diameter. Usually sharply demarcated, the lesion may be solid black ( Fig. 6-8A ) or ringed with a small border of hypopigmen tation. Lacunar areas of depigmentation within the lesion may be seen ( Fig. 6-8B ). Multifocal: also termed congenital grouped pigmentation or “bear tracks.” Groups of 3 to 30 small (0.1 to 2 mm) lesions typically appear in one sector of the midperipheral retina. Usually, they lack the internal lacu nae and hypopigmented halo of the solitary form ( Fig. 6-9 ). ● Multifocal fundus lesions resembling CHRPE have been reported in close associ ation with familial adenomatous polyposis

(Gardner syndrome and Lynch syndrome; Fig. 6-10 ), heritable conditions of colonic polyps, and extraintestinal osteomas and fibromas with invariable progression to colonic cancer. The lesions associated with Gardner syndrome, however, are typically bilateral, have irregular borders, and are often scattered in the fundus. ● Testing for the causative genes ( APC and MUTYH ) is available. Differential Diagnosis ● Malignant choroidal melanoma ● Choroidal nevus ● Combined hamartoma of the retina and the retinal pigment epithelium (RPE) Diagnostic Evaluation ● Diagnosis is based on typical ophthalmo scopic features. By fluorescein angiography, the tumor exhibits persistent hypofluores cence. Lacunar areas are seen as hyperfluo rescent, consistent with depigmentation of the RPE. Prognosis and Management ● Most CHRPE lesions are typically non progressive and require only periodic examination. ● In rare instances, adenocarcinomas may emerge from within the CHRPE ( Fig. 6-8C ). Untreated nodular lesions have been shown to progress into pedunculated tumors and may lead to serous retinal detachment in rare cases. Adenocarcinomas of the RPE rarely demonstrate extraocular extension and are rarely associated with metastases. ● Patients with bilateral lesions suggestive of those seen in Gardner syndrome should be referred for colonoscopy and potential genetic testing. Because the gene is inherited in an autosomal dominant manner, genetic testing of family members should be considered.

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FIGURE 6-8. Solitary lesions. A. Note the sharp, discrete borders of the black lesion, lacking lacunar areas of depigmentation. B. Note the small border of hypopigmentation surrounding the lesion, along with lacunar areas of depigmentation within the lesion. C. Adenoma arising from the pigmented lesion containing lacunar areas of depigmentation. (Dr. David Reichstein, Oncology Service, Tennessee Retina PC, Nashville, TN.)

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FIGURE 6-9. Multifocal variant. Grouped hyperpigmented lesions termed bear tracks . (Dr. David Reichstein, Oncology Service, Tennessee Retina PC, Nashville, TN.)

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FIGURE 6-10. Pigmented fundus lesion, Gardner syndrome. A. Pigmented lesion in a patient with known Gardner syndrome. B. A depigmented “tail” can be noted adjacent to the pigmented fundus lesion. (Dr. David Reichstein, Oncology Service, Tennessee Retina PC, Nashville, TN.)

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COMBINED HAMARTOMA OF THE RETINA AND RETINAL PIGMENT EPITHELIUM C ombined hamartoma of the retina and the RPE is a benign, slightly elevated, partially pigmented tumor located around the optic nerve or in the peripheral fundus. It is composed histologically of proliferated glial cells, fibrovascular tissue, and pigment epithe lial cells. Absence of dysplastic cells raises the possibility of an error of development rather than a neoplastic lesion. Epidemiology and Etiology ● The tumor is often diagnosed in the first or second decade. The preponderance of cases in infants and young children suggests that the lesion may be congenital. No familial associa tions are known. ● An association of combined hamartomas, usually macular and sometimes bilateral, has been seen with neurofibromatosis (most commonly type 2). History ● In cases of juxtafoveal lesions, there is painless visual loss from associated epiretinal membrane traction or subretinal exudation. Important Clinical Signs ● Juxtapapillary variant: ill-defined, elevated, charcoal-gray mass adjacent to, or overlying, the optic disc. A gray-white membrane over lying the tumor causes stretching of retinal blood vessels and retinal striae, often involv ing the macula ( Fig. 6-11 ). ● Peripheral variant: slightly elevated, pig mented ridge concentric to the optic disc. There is dragging of dilated retinal vessels toward the lesion by the overlying membrane.

Associated Clinical Signs ● CNV ● Vitreous hemorrhage

● Manifestations of neurofibromatosis type 2 (bilateral acoustic neuromas, brain menin giomas, spinal cord schwannomas, posterior subcapsular cataracts, etc.) Differential Diagnosis ● Choroidal melanoma ● Choroidal nevus ● Reactive hyperplasia of the RPE ● Melanocytoma ● When lightly pigmented and occurring in children, may be mistaken for Rb or toxocariasis ● Epiretinal membrane secondary to infec tious or noninfectious uveitis ● Bergmeister papilla Diagnostic Evaluation ● Diagnosis is based on ophthalmoscopic features. Optical coherence tomography (OCT) demonstrates contour disruption of the macular retinal tissue from the epiretinal membrane. Fluorescein angiography reveals multiple, dilated, fine blood vessels within the tumor, which may become hyperfluorescent as the angiogram progresses ( Fig. 6-12 ). Prognosis and Management ● Because lesions are usually not progressive, regular observation is appropriate. However, contraction of the overlying fibroglial tissue leads to macular distortion, secondary reti noschisis, and retinal holes. ● In cases of visual loss, vitrectomy and mem brane stripping may rarely be performed. Unless there is clear delineation between epiretinal membrane and macular retinal tissue, outcomes from vitrectomy are often unsatisfying.

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FIGURE 6-11. Combined hamartoma of the retina and retinal pigment epithelium. An elevated, ill-defined mass overlying the optic disc, with an overlying epiretinal membrane puckering the surrounding retinal tissue, including the macula. (Dr. David Reichstein, Oncology Service, Tennessee Retina PC, Nashville, TN.)

Copyright © 2024 Wolters Kluwer, Inc. Unauthorized reproduction of the content is prohibited. FIGURE 6-12. Combined hamartoma of the retina and retinal pigment epithelium. The juxtapapillary mass reveals fluorescent dilated vessels and hyperfluorescence from a blockage within the lesion. (Dr. David Reichstein, Oncology Service, Tennessee Retina PC, Nashville, TN.)

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CHOROIDAL NEVUS C horoidal nevus is a common, benign tu mor of the posterior fundus. The lesion is typically pigmented but amelanotic variations are common as well. Although benign lesions make up the vast majority of these neoplasms, uveal melanomas occur secondary to genetic mutations within rare nevi. Epidemiology and Etiology ● Prevalence in the general population is estimated to be about 5%. The lesion occurs much more commonly in Whites. History ● Patients are usually asymptomatic and the tumor is generally discovered incidentally during routine ophthalmoscopy. ● Vision may be reduced from an extension of the associated subretinal fluid into the mac ula, an associated serous retinal detachment, or CNV arising at the edge of the nevus. These signs may be indications of malignant ● The tumor is most often slate gray or brown in color, but it may be heterogeneously pig mented or even amelanotic (pale yellow). ● Choroidal nevi are usually 1 to 10 mm in diameter, flat or minimally elevated ( < 2 mm in anteroposterior dimension). Lesions greater than 12 mm in diameter may confer malignant transformation. ● Drusen overlying the tumor are common and signify chronicity of the lesion. ● Alterations of the overlying RPE include pigment clumping and fibrous metaplasia (yellow-white plaques). ● “Orange pigment” at the level of the RPE represents aggregates of macrophages contain ing lipofuscin granules and may suggest growth or malignant transformation of the nevus. transformation into melanoma. Important Clinical Signs

● A circumferential ring of hypopigmentation (halo) is thought to represent a low-grade immune response to the tumor and thus sug gests a lower chance of malignant transforma tion ( Fig. 6-13 ). Associated Clinical Signs ● Serous detachment of the neurosensory retina or the RPE ● CNV Differential Diagnosis ● Pigmented lesion ● Choroidal melanoma ● Congenital hypertrophy of the RPE ● Combined hamartoma of the retina and the RPE ● Subretinal hemorrhage ● Amelanotic lesion ● Circumscribed choroidal hemangioma ● Diagnosis is based on characteristic ophthalmoscopic features. Fluorescein angiography or indocyanine green (ICG) angiography, although not specific for cho roidal nevus, may rule out diagnoses such as hemangioma. ● Ultrasonography typically demonstrates a choroidal lesion with low-to-medium internal reflectivity. ● Autofluorescence can identify areas of RPE loss (hypoautofluorescence) or lipofuscin activity (hyperautofluorescence). Lipofuscin is clinically seen as orange pigment and is a risk factor for tumor growth and transformation. ● OCT is valuable for imaging of retinal architecture and for detection of intraretinal and subretinal fluid that is not visible on ● Choroidal osteoma ● Choroidal metastasis ● Choroidal granuloma Diagnostic Evaluation

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