Pediatric Retina 3rd Ed.
Pediatric Retina 3rd Ed.
Pediatric Retina 3rd Ed.
THIRD EDITION
PEDIATRIC RETINA
THIRD EDITION
M. Elizabeth Hartnett, MD, FACS, FARVO
Distinguished Professor in Ophthalmology and Visual Sciences
University of Utah
Calvin S. and JeNeal N. Hatch Presidential Endowed Chair in
Ophthalmology and Visual Sciences
Director of Pediatric Retina
Vitreoretinal Medical and Surgical Service
Adjunct Professor of Pediatrics Adjunct Professor of Neurobiology and
Anatomy Principal Investigator, Retinal Angiogenesis Laboratory
John A. Moran Eye CenterSalt Lake City, Utah
Section Editors
Arlene V. Drack, MD
Ronald Keech Professor of Pediatric Genetic Eye Disease
Research
Institute for Vision Research
Department of Ophthalmology and Visual Sciences
University of Iowa
Iowa City, Iowa
Michael T. Trese, MD
Clinical Professor
Department of Ophthalmology
Oakland University William Beaumont School of Medicine
Rochester, Michigan
Cynthia A. Toth, MD
Joseph AC Wadsworth Professor of Ophthalmology
Department of Ophthalmology
Duke University
Durham, North Carolina
George Caputo, MD
Chairman
Department of Ophthalmology
Rothschild Hospital Foundation
Paris, France
Acquisition Editor: Chris Teja
Development Editor: Eric McDermott
Editorial Coordinator: Cody Adams
Marketing Manager: Phyllis Hitner
Project Production Manager: Kirstin Johnson
Manufacturing Coordinator: Beth Welsh
Design Coordinator: Steve Druding
Production Service: SPi Global
Third Edition
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From MEH: To Bill, my love and source of creativity and fun, and
to my parents and family who always have supported and
encouraged me.
From Michael Trese: To Caron who keeps our whole family
together and inspires my work.
From Antonio Capone Jr: In honor of my parents, and with love to
my family.
From Arlene Drack: To Bill, Anya, and Elise for love and support,
and in honor of my parents, Earle and Mary Pagotto Drack.
From Cynthia Toth: To David for your love and support.
From George Caputo: To my family that I thank for their love and
support.
Generally from all: To our patients, mentors, and students who
inspire us to continue in our pursuits.
In the memory of Yomtov Robert Barishak (deceased 2018) and
Mina Millicent Chung (deceased 2020), whose invaluable
contributions enrich pediatric retinal clinicians and scientists
worldwide.
CONTRIBUTORS
Tomas S. Aleman, MD
Associate Professor
Department of Ophthalmology
University of Pennsylvania Perelman School of Medicine
Philadelphia, Pennsylvania
Tala Al-Khaled, BA
Medical Student Researcher
Department of Ophthalmology and Visual Sciences
Illinois Eye and Ear Infirmary
University of Illinois at Chicago
Chicago, Illinois
David Ancona-Lezama, MD
Professor of Ophthalmology
Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud
Institute of Ophthalmology and Visual Sciences
Hospital Zambrano Hellion
Monterrey, Nuevo Leon, Mexico
Stephen D. Anesi, MD
Physician
Department of Ophthalmology
Massachusetts Eye Research and Surgery Institution
Waltham, Massachusetts
Samuel Asanad, BS
Medical Student
Department of Ophthalmology
David Geffen School of Medicine
University of California Los Angeles
Los Angeles, California
Laura Bagdonaite-Bejarano, MD
Clinical Fellow
Department of Ophthalmology
Boston Children’s Hospital and Harvard Medical School
Boston, Massachusetts
Audina M. Berrocal, MD
Professor of Clinical Ophthalmology
Medical Director of Pediatric Retina and ROP
Vitreoretinal Fellowship Director
Bascom Palmer Eye Institute
Miller School of Medicine
University of Miami
Jackson Memorial Health System
Miami, Florida
Jesse L. Berry, MD
Associate Professor of Ophthalmology
Clinical Scholar
Keck School of Medicine at University of Southern California
Associate Director, Ocular Oncology
The Vision Center at Children’s Hospital Los Angeles
USC Roski Eye Institute
Los Angeles, California
Meghan M. Brown, BS
MD Candidate
Oakland University William Beaumont School of Medicine
Rochester, Michigan
Beaumont Hospital
Royal Oak, Michigan
Charles M. Calvo, MD
Vitreoretinal Specialist
Retina Consultants of Nevada
Las Vegas, Nevada
George Caputo, MD
Chairman
Department of Ophthalmology
Rothschild Hospital Foundation
Paris, France
Michael F. Chiang, MD
Knowles Professor of Ophthalmology & Medical Informatics and Clinical
Epidemiology
Associate Director, Casey Eye Institute
Oregon Health & Science University
Portland, Oregon
Itay Chowers, MD
Professor and Chairman
Department of Ophthalmology
Hadassah–Hebrew University Medical Center
Jerusalem, Israel
Mina Chung, MD
Associate Professor of Ophthalmology
Flaum Eye Institute
University of Rochester
Rochester, New York
Hanna M. De Bruyn, MS
Researcher
Department Ophthalmology
Boston Children’s Hospital
Boston, Massachusetts
Arlene V. Drack, MD
Ronald Keech Professor of Pediatric Genetic Eye Disease Research
Institute for Vision Research
Department of Ophthalmology and Visual Sciences
University of Iowa
Iowa City, Iowa
Alina V. Dumitrescu, MD
Assistant Professor
Department Ophthalmology
University of Iowa
Iowa City, Iowa
Anna L. Ells, MD, FRCS(C)
Clinical Professor
Department of Surgery
Faculty of Medicine
University of Calgary
Adjunct Professor
Department of Electrical and Computer Engineering
Schulich School of Engineering
University of Calgary
Pediatric Retina Specialist
Alberta Children’s Hospital
Retina Specialist
Calgary Retina Consultants
Calgary, Alberta, Canada
Lisa J. Faia, MD
Associate Professor in Ophthalmology
Oakland University William Beaumont School of Medicine
Rochester, Michigan
Director of Ocular Immunology and Uveitis Service
Vitreoretinal Medical and Surgical Service
Associated Retinal Consultants, P.C.
Co-Director of Ocular Immunology and Uveitis Service
Beaumont Eye Institute
William Beaumont Hospital
Vitreoretinal Surgeon
Vitreoretinal Medical and Surgical Service
Associated Retinal Consultants, P.C.
Royal Oak, Michigan
Philip J. Ferrone, MD
Staff Physician
Long Island Vitreoretinal Consultants
Clinical Associate Professor
Department of Ophthalmology
Donald and Barbara Zucker School of Medicine of Northwell Hospital
Great Neck, New York
Clarisse M. Fligor, BS
Graduate Student
Department of Biology
Indiana University Purdue University at Indianapolis
Indianapolis, Indiana
Anne B. Fulton, MD
Professor
Department of Ophthalmology
Boston Children’s Hospital and Harvard Medical School
Boston, Massachusetts
Mrinali P. Gupta, MD
Assistant Professor of Ophthalmology
Director, Medical Retina Fellowship Program
Department of Ophthalmology
Weill Cornell Medical College
New York, New York
Roger P. Harrie, MD
Adjunct Professor of Ophthalmology
Director of Ophthalmic Echography
John A Moran Eye Center
University of Utah
Salt Lake City, Utah
Ronald P. Hobbs, MD
Retinal SpecialistArizona Retina Associates
Mesa, Arizona
Kang-Chieh Huang, MS
Graduate Student
Department of Biology
Indiana University Purdue University at Indianapolis
Indianapolis, Indiana
Laryssa A. Huryn, MD
Director, Ophthalmic Genetics Fellowship Program
Ophthalmic Genetics and Visual Function Branch
National Eye Institute
National Institutes of Health
Bethesda, Maryland
Sana Idrees, MD
Vitreoretinal Fellow
Department of Ophthalmology
University of Rochester
Rochester, New York
J. Michael Jumper, MD
Partner, West Coast Retina Medical Group
Clinical Professor and Vice Chairman
Department of Ophthalmology
California Pacific Medical Center
San Francisco, California
Pavlina S. Kemp, MD
Pediatric Ophthalmology and Strabismus
Clinical Assistant Professor of Ophthalmology and Visual Sciences
Clinical Assistant Professor of Pediatrics
University of Iowa Hospitals and Clinics
Director of Medical Student Education
Department of Ophthalmology and Visual Sciences
University of Iowa Hospitals and Clinics
Iowa City, Iowa
John B. Kerrison, MD
Researcher
Department of Genetic Engineering and Molecular Ophthalmology
Wilmer Eye Institute
Johns Hopkins Medicine
Baltimore, Maryland
Arif O. Khan, MD
Consultant, Pediatric Ophthalmology & Ocular Genetics
Eye Institute
Cleveland Clinic Abu Dhabi
Abu Dhabi, United Arab Emirates
Professor
Department of Ophthalmology
Cleveland Clinic Lerner College of Medicine of Case Western University
Cleveland, Ohio
Matin Khoshnevis, MD
PGY3
Department of Ophthalmology
Temple University
Philadelphia, Pennsylvania
Sylvia R. Kodsi, MD
Professor, Chief of Pediatric Ophthalmology and Strabismus
Department of Ophthalmology
Donald and Barbara Zucker School of Medicine at Hofstra/Northwell
Great Neck, New York
Robert K. Koenekoop, MD, PhD, MSc, FRCS(C), FARVO
Professor of Paediatric Surgery
Human Genetics and Adult Ophthalmology
McGill University Health Centre
Director, McGill Ocular Genetics Laboratory
Chief Paediatric Ophthalmology
Fellowship Director, AAPOS
Principle Investigator for Retinal Therapeutics at Center for Innovative
Medicine
RI-MUHC
Adjunct Professor of Experimental Medicine
McGill University and Optometry Université de Montréal
Montréal, Quebec, Canada
Alaa Koleilat, MS
PhD Candidate
Department of Clinical and Translational Sciences
Mayo Clinic Graduate School for Biomedical Sciences
Rochester, Minnesota
Nikisha Kothari, MD
Fellow
Department of Ophthalmology
University of California, Los Angeles
Los Angeles, California
Eric Kunz, BS
Lab Specialist
John A. Moran Eye Center
The University of Utah
Salt Lake City, Utah
Sailee S. Lavekar, MS
Graduate Student
Department of Biology
Indiana University Purdue University at Indianapolis
Indianapolis, Indiana
Jessica G. Lee, MD
Staff Physician
Long Island Vitreoretinal Consultants
Clinical Assistant Professor
Department of Ophthalmology
Donald and Barbara Zucker School of Medicine of Northwell Hospital
Great Neck, New York
Associate Adjunct Surgeon
Department of Ophthalmology
New York Eye and Ear Infirmary of Mount Sinai
New York, New York
Thomas C. Lee, MD
Retinal Surgeon
Department of Ophthalmology
Children’s Hospital of Los Angeles
Los Angeles, California
Nathalie Lepvrier-Chomette, MD
Pediatric Ophthalmologist
La Maison Medicale
London, United Kingdom
T. Y. Alvin Liu, MD
Assistant Professor
Department of Ophthalmology
Johns Hopkins Medicine Wilmer Eye Institute
Baltimore, Maryland
Gerard A. Lutty, PhD
G. Edward and G. Britton Durell Professor of Ophthalmology
Director of the Ocular Angiogenesisi and Vasculogenesis Lab
Wilmer Ophthalmological Institute
Johns Hopkins Hospital
Baltimore, Maryland
Albert M. Maguire, MD
Professor
Department of Ophthalmology
University of Pennsylvania Perelman School of Medicine
Philadelphia, Pennsylvania
Niranjan Manoharan, MD
Fellow
Department of Ophthalmology
University of California, Los Angeles
Los Angeles, California
D. Scott McLeod
Technician
Department of Ophthalmology
Wilmer Eye Institute
Johns Hopkins Medicine
Baltimore, MarylandAlice R. McPherson, MD, DSc, FACS, FICSProfessor
of OphthalmologyDepartment of OphthalmologyBaylor College of
MedicineHouston, Texas
P. Anthony Meza, MD
Attending Anesthesiologist
Department of Anesthesiology
Beaumont Health System
Bloomfield Hills, Michigan
Mikel Mikhail, MD
Retina Fellow
Associated Retina Consultants
Royal Oak, Michigan
Darius M. Moshfeghi, MD
Professor, Chief of Retina
Byers Eye Institute
Horngren Family Vitreoretinal Center
Stanford University School of Medicine
Palo Alto, California
Stavros N. Moysidis, MD
Retina Fellow
Associated Retinal Consultants, P.C.
Royal Oak, Michigan
Kean T. Oh, MD
Clinical Assistant Professor
Department of Surgery
Michigan State University College of Human Medicine
Partner
Associated Retinal Consultants, P.C.
Traverse City, Michigan
Samir N. Patel, MD
Resident Physician
Department of Ophthalmology
Wills Eye Hospital
Thomas Jefferson University
Philadelphia, Pennsylvania
Bridget J. Peterson, BA
Researcher
Department of Ophthalmology
Boston Children’s Hospital and Harvard Medical School
Boston, Massachusetts
Supalert Prakhunhungsit, MD
Assistant Professor of Ophthalmology
Vitreoretinal Unit
Ophthalmology Department
Faculty of Medicine
Siriraj Hospital
Mahidol University
Bangkok, Thailand
Aniket Ramshekar, MS
Graduate Student
John A. Moran Eye Center
The University of Utah
Salt Lake City, Utah
Sasha Rosen, BS
MS IV
Loyola University Health System
Medical School
Maywood, Illinois
Stephen R. Russell, MD
Dana J. Schrage Professor of Macular Degeneration Research
Clinical Director, Carver Family Center for Macular Degeneration
Institute for Vision Research
Department of Ophthalmology and Visual Sciences
Director, Vitreoretinal Service
Department of Ophthalmology and Visual Sciences
University of Iowa Hospitals and Clinics
Iowa City, Iowa
Sherveen S. Salek, MD
Fellow, Vitreoretinal Surgery
Department of Ophthalmology
Emory University School of Medicine
Atlanta, Georgia
Briana L. Sawyer, MS
Cardiovascular Genetic Counselor
Division of Pediatric Cardiology
Department of Pediatrics
University of Utah
Salt Lake City, Utah
Jonathan E. Sears, MD
Staff
Cole Eye Institute and Cardiovascular and Metabolic Sciences
Cleveland Clinic
Cleveland, Ohio
J. Sebag, MD, FACS, FRCOphth, FARVO
Senior Research Scientist
Doheny Eye Institute
University of California, Los Angeles
Professor of Clinical Ophthalmology
Geffen School of Medicine
University of California, Los Angeles
Los Angeles, California
Founding Director
VMR Institute for Vitreous Macula Retina
Huntington Beach, California
Carol L. Shields, MD
Director of Ocular Oncology Service
Wills Eye Hospital
Thomas Jefferson University
Consultant at Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania
Julia P. Shulman, MD
Assistant Professor of Ophthalmology
New York Medical College—TouroValhalla, New York
Chair, Department of Ophthalmology
Jamaica Hospital Medical Center
Richmond Hill, New York
Abraham Spierer, MD
Clinical Professor
Department of Ophthalmology
Sheba Medical Center at Tel Hashomer
Ramat Gan, Israel
C. Gail Summers, MD
Professor
Department of Ophthalmology and Visual Neurosciences
Pediatric Ophthalmology and Strabismus
University of Minnesota
Minnesota Lions Children’s Eye Clinic
Minneapolis, Minnesota
Cynthia A. Toth, MD
Joseph AC Wadsworth Professor of Ophthalmology
Department of Ophthalmology
Duke University
Durham, North Carolina
Michael T. Trese, MD
Clinical Professor
Department of Ophthalmology
Oakland University William Beaumont School of Medicine
Rochester, Michigan
Lejla Vajzovic, MD
Associate Professor
Department of Ophthalmology
Duke University
Durham, North Carolina
Kirstin B. VanderWall, BA
Graduate Student
Department of Biology
Indiana University Purdue University at Indianapolis
Indianapolis, Indiana
Juliette Varin, MS
PhD Student
Department of Genetics
Sorbonne University
Paris, France
Victor M. Villegas, MD
Associate Professor
Department of Ophthalmology
Universidad de Puerto Rico
San Juan, Puerto Rico
Anand Vinekar, MD, FRCS
Associate Professor and Head of Pediatric Retina
Postgraduate Institute of Ophthalmology
Narayana Nethralaya
Bangalore, India
Albert T. Vitale, MD
Professor
Department of Ophthalmology
University of Utah Hospital
Salt Lake City, Utah
Mark E. Wilkinson, OD
Clinical Professor of Ophthalmology
Director, Vision Rehabilitation Service
Department of Ophthalmology and Visual Sciences
Iowa Institute for Vision Research
Carver College of Medicine
University of Iowa
Iowa City, Iowa
Edward H. Wood, MD
Retina Fellow
Associated Retinal Consultants, P.C.
Royal Oak, Michigan
Lauren M. Wright, MD
Vitreoretinal Surgery Fellow
Department of Ophthalmology
Boston Medical Center
Boston, Massachusetts
Yoshihiro Yonekawa, MD
Assistant Professor of Ophthalmology
Wills Eye Hospital/Mid Atlantic Retina
Thomas Jefferson University
Philadelphia, Pennsylvania
Alice R. McPherson, MD
PREFACE
In honor of the memory of Jonathan Pine, who was open to the idea of the
first edition of Pediatric Retina and encouraging as we developed the table of
contents. He understood the need for education in pediatric retinal conditions
that required bringing together experts in genetics (knowledge that was
emerging then), imaging, science, visual rehabilitation, surgery, and other
fields as well as the importance of an atlas of images that would alert the
reader to chapters describing conditions with similar fundus appearances. He
strongly supported the second edition. The third edition has expanded greatly
as our knowledge of pediatric retina conditions, their pathophysiology,
genetics, and science surrounding them has increased and technology in
imaging has allowed us to visualize retinal changes over time and test
management strategies. Furthermore, advances in publishing now allow us to
provide the e-book along with the print version.
There are many individuals to thank—
To all our section editors: Antonio Capone Jr, George Caputo, Arlene
Drack, Cynthia Toth, and Michael Trese for their exhaustive work to enhance
their sections, assuring current content. To all the authors of the third edition
and previous editions, who are experts providing knowledge, careful review
of the literature, their own research data, and input from their patients.
Thanks for careful proofing of each chapter’s material to meet the book’s
organization and need for accurate and comprehensive material. The
collective knowledge will allow us to develop better future treatments and
provide outstanding care to pediatric retina patients worldwide.
To my administrative coordinator, Maria Isabel Gomez, who was
essential in the entire process and assured on my end that the organization of
chapters and images were in order.
To the many photographers who provided outstanding images of retinal
conditions, angiographic studies, ultrasonography, and optical coherence
tomography. I especially thank Melissa Chandler CRA, OCT-C, James
Gilman, CRA, ROPS, and Glen Jenkins, CRA, OCT-C, COA for cover
design images. The work of the photographer is technical as well as an art.
We recognize the importance of engaging the small child to catch the most
instructive snapshot and that it is a skill. We have acknowledged their images
throughout the book and thank them here collectively.
To the staff at Wolters Kluwer Health who have been dedicated to create
this multi-dimensional edition. They have coordinated the drafts and videos
into a seamless end product and have been organized in their execution. I
thank specifically Chris Teja, the acquisition editor, who supported the third
edition and continued to see it through; Cody Adams, who has been
organized in assuring the drafts and images of the chapters are in order; and
Eric McDermott, who has organized the final aspects of the print edition and
the e-book edition; and thanks to Kirstin Johnson, Arunmozhivarman
Shenbagakutti and SPi Global for guiding the book through production. It has
been a pleasure to work with them all, and without their hard work this book
could not have happened.
We all, as pediatric retina specialists, recognize the importance of our
patients who not only encourage us to do our best and to find better
treatments for their rare conditions but also show us how valuable every
aspect of vision is in life. They keep us moving forward.
CONTENTS
Contributors
Foreword
Preface
Acknowledgments
SECTION I
DEVELOPMENT OF THE EYE AND RETINA
1 Embryology of the Retina and Developmental Disorders
Yomtov Robert Barishak and Abraham Spierer
2 The Hyaloidal Vasculature and Its Role in Development
Charles M. Calvo, Ronald P. Hobbs, and M. Elizabeth Hartnett
3 Vitreous and Developmental Vitreoretinopathies
Samuel Asanad and J. Sebag
4 Vitreous Biochemistry and Pharmacologic Vitreolysis
Sasha Rosen, Matin Khoshnevis, and J. Sebag
5 Retinal Vascular Development
Michelle E. LeBlanc, Jinling Yang, and Patricia A. D’Amore
6 Human Choriocapillaris Development
Gerard A. Lutty and D. Scott McLeod
7 Development of Cone Photoreceptors and the Fovea Centralis
and the Impact of Prematurity
Jan M. Provis and Michele C. Madigan
8 Retinal Development
Thomas A. Reh and Anna La Torre
SECTION II
ASSESSMENT AND REHABILITATION OF
VISUAL FUNCTION IN PEDIATRIC RETINAL
CONDITIONS
SECTION III
IMAGING OF THE INFANT AND CHILD EYE
AND RETINA
15 Retinal Photography and Multi-Wavelength Imaging in
Infants and Children
C. K. Patel and Andrew Blaikie
16 Optical Coherence Tomography in Infants and Children
Lejla Vajzovic, Anand Vinekar, and Cynthia A. Toth
17 Fluorescein Angiography in Pediatric Retinal Diseases
Nikisha Kothari, Niranjan Manoharan, and Irena Tsui
18 Ultrasonographic Imaging in Infants and Children
Roger P. Harrie
19 Imaging Analysis in Infants and Children
Sang Jin Kim, John Peter Campbell, and Michael F. Chiang
20 Image Storage and Retrieval and Telemedicine
Marco H. Ji, Darius M. Moshfeghi, and Antonio Capone Jr
SECTION IV
GENETICS AND DEVELOPMENTAL
DISORDERS IN PEDIATRIC RETINA
SECTION VI
TUMORS
44 Retinoblastoma
Jesse L. Berry and Joan Marie O'Brien
45 Treatment of Retinoblastoma
Lauren A. Dalvin, David Ancona-Lezama, and Carol L. Shields
46 Tumors in Infants and Children
Victor M. Villegas and Timothy G. Murray
SECTION VII
UVEITIS IN INFANTS AND CHILDREN
SECTION VIII
RETINOPATHY OF PREMATURITY
50 Worldwide Causes of Childhood Blindness
Clare E. Gilbert and Nathalie Lepvrier-Chomette
51 Education and Management of Retinopathy of Prematurity
Worldwide
Tala Al-Khaled, Samir N. Patel, and R. V. Paul Chan
52 Clinical Trials and Management of Retinopathy of Prematurity
Julia P. Shulman and M. Elizabeth Hartnett
53 Anti-VEGF Treatment in Retinopathy of Prematurity
Anna L. Ells, Wei-Chi Wu, and Darius M. Moshfeghi
54 Evolution of Stage 4 Retinopathy of Prematurity
Antonio Capone Jr and Michael T. Trese
55 Treatment of Stages 4 and 5 Retinopathy of Prematurity
Antonio Capone Jr, Michael T. Trese, and M. Elizabeth Hartnett
SECTION IX
PRINCIPLES OF SURGERY FOR PEDIATRIC
RETINAL CONDITIONS
SECTION X
MANAGEMENT OF VITREORETINAL
CONDITIONS OF INFANTS AND CHILDREN
63 Pediatric Rhegmatogenous Retinal Detachment
Lejla Vajzovic
64 Coats Disease
J. Michael Jumper
65 Persistent Fetal Vasculature Syndrome
Supalert Prakhunhungsit and Audina M. Berrocal
66 Pediatric Vitreoretinopathies: Familial Exudative
Vitreoretinopathy, Norrie Disease, and Incontinentia Pigmenti
Lauren M. Wright and Yoshihiro Yonekawa
67 Epiretinal Membrane and Combined Hamartoma of the Retina
and Retinal Pigment Epithelium
Cynthia A. Toth
68 Surgery for Gene Therapy
Jonathan F. Russell, Albert M. Maguire, and Stephen R. Russell
69 Childhood Ocular Trauma
Mrinali P. Gupta and Philip J. Ferrone
70 Nonaccidental Head Trauma
George Caputo and Wei-Chi Wu
ATLAS
ATLAS A Hemorrhages
George Caputo
ATLAS B Macula
George Caputo
ATLAS C Pigmentary Changes
George Caputo
ATLAS D Posterior Segment Masses
George Caputo
ATLAS E Flecks and Spots
Michael T. Trese, Antonio Capone Jr, and M. Elizabeth Hartnett
ATLAS F Abnormal Retinal Vasculature
George Caputo
ATLAS G Retinal Detachment and Schisis
George Caputo
ATLAS H Optic Nerve
George Caputo
Index
EBOOK CHAPTERS
The development of the retina (Tables 1-1 to 1-3) starts at the 4th week of
gestation with the invagination of the optic vesicle and formation of the optic
cup (Fig. 1-1) with the two layers of the optic cup that constitute the
rudimentary basis or anlage of the retina: the external layer of the retinal
pigment epithelium (RPE) and the internal layer of the sensory retina. The
invagination involves the ventrocaudal wall of the optic vesicle and causes
the formation of the embryonic fissure, which permits the hyaloid artery to
enter the developing optic cup cavity. Invagination also involves the optic
stalk and progressively occludes the optic vesicle cavity. The apposition of
the inner layer of the optic cup (the anlage of the sensory retina) to the
external layer of the optic cup (the anlage of the RPE) allows the axons of the
first ganglion cells to penetrate into the optic stalk. The narrowing optic
vesicle cavity becomes the potential subretinal space. At the end of the 4th
week, the vessels surrounding the neural tube spread over the optic cup and
the cells of the external layer of the cup, the prospective RPE cells. The RPE
cells acquire pigmentation. At this stage, the optic cup is surrounded by the
secondary mesenchyme as migration of neural crest cells into the primary
mesenchyme has already taken place.
At the 5th week, the RPE cell is made up of two to three layers of columnar,
pseudostratified pigmented cells attached one to another by junctional
complexes, the anlage of the membrane of Verhoeff. The inner layer of the
optic cup is the prospective sensory retina and is made up of an external layer
of nuclei, called the proliferative or germinative zone, and an anuclear,
marginal zone. The outermost cells of the germinative zone have cilia that
project toward the potential subretinal space and are joined to one another by
zonula adherens, the anlage of the external limiting membrane of the retina.
The anuclear, marginal zone is covered internally by a basal lamina, the
anlage of the inner limiting membrane of the retina. Four zones can be
distinguished at the distal portion of the optic cup. The first zone is the one
that constitutes the contact area between the outer retinal pigment epithelial
layer and the inner retinal neuroblastic layer. The second zone constitutes the
anlage of the marginal sinus of the iris. The third is a zone of progenitor cells,
and the fourth will be the anlage of the RPE and the neural retina (1).
The 6th week is characterized by the closure of the embryonic fissure.
The closure starts at the center of the fissure and proceeds anteriorly toward
the anterior rim of the optic cup and posteriorly into the optic stalk.
During the 7th week, the embryonic fissure closes completely and the
anterior notch at the anterior rim of the optic cup and the posterior notch at
the site of the prospective optic disc around the hyaloid artery disappear. The
RPE cells extend posteriorly as the layer of the outer cells of the optic stalk,
the precursor of the peripheral glial mantle of the optic nerve, which later
develops into the barrier between the axons of the optic nerve and the
surrounding mesenchyme (2). The RPE cells also differentiate by developing
apical villi, basal infoldings, smooth and rough endoplasmic reticulum,
ribosomes, premelanosomes, and melanosomes (3). In the sensory retina,
germinative cells proliferate and migrate inward giving rise to the outer
neuroblastic layer, the inner neuroblastic layer, and the layer of Chievitz in
between (Fig. 1-2). The outermost cells of the outer neuroblastic layer are the
anlage of the photoreceptors. At the posterior pole, around the future optic
disc, the innermost cells of the inner neuroblastic layer migrate inward. The
first cells to migrate inward are the ganglion cells.
FIGURE 1-2 A 7-week-old embryo. Cells from the
common neuroblastic layer of the retina arrange
themselves into an outer and an inner neuroblastic layer
causing the appearance of the layer of Chievitz in between.
(From Embryology of the eye [film]. San Francisco:
American Academy of Ophthalmology, 1950. Copyright
© 2020 American Academy of Ophthalmology. Courtesy
of Dr. Michael Hogan.)
At the 8th week, the first ganglion cells extend axons toward the optic stalk
(Fig. 1-3). These axons will develop into the future nerve fiber layer. The
axons extend to and penetrate the optic stalk requiring first the apoptosis
(programmed cell death) of the primitive neuroectodermal cells that fill the
optic stalk (4). As more ganglion cells differentiate and axons penetrate into
the optic stalk, a Bergmeister papilla forms as a conic mass of glial cells
covering the future optic disc area (5). Migrating retinal glioblasts, the future
retinal astroglia, arrange themselves along the axons and on the internal
limiting membrane (6).
FIGURE 1-3 A 7-week-old embryo. Migration inward of
the ganglion cells and appearance of their axons. (From
Embryology of the eye [film]. San Francisco: American
Academy of Ophthalmology, 1950. Copyright © 2020
American Academy of Ophthalmology. Courtesy of Dr.
Michael Hogan.)
At the 3rd month, the differentiation of the retina starts at the posterior pole
and progresses gradually toward the periphery; the peripheral retina
differentiates a short time after birth. Proliferation starts in the outer cells of
the neuroblastic layer and progresses inward, while differentiation starts at
the inner cells of the neuroblastic layer and extends outward. That is why the
ganglion cells are the first to differentiate and the outermost cells, the anlage
of the photoreceptors, are the last to differentiate (7). The differentiation in
the inner neuroblastic layer manifests as the formation of a separate layer of
ganglion cells, the formation of dendrites by the ganglion cells, the migration
inward of the amacrine cells, and the appearance of glycogen granules in the
cytoplasm of primitive Müller cells (8). The outer neuroblastic layer
differentiates by an inward migration of its most internal cells, the future
bipolar cells, and of those external to the bipolar cells, the future horizontal
cells. The migration of the future bipolar and horizontal cells causes the
occlusion of the layer of Chievitz and the formation of the external plexiform
layer (the internal plexiform layer was formed as a result of the migration of
the ganglion cells). The outermost cells of the outer neuroblastic layer are
connected one to the other with adherent junctions, which make up the future
external limiting membrane.
At the 4th month, all the major constituents of the retina are present (Fig.
1-4). The ora serrata appears as a line of demarcation at the peripheral retina.
At the posterior pole, the outer nuclear layer becomes the precursor of the
rod-free zone, the future fovea. The inner plexiform layer acquires ribbon and
conventional synapses. As neurons mature, so do primitive Müller cells,
which acquire more glycogen, intermediate filaments, myelin-associated
protein, and hyaluronic acid. The differentiation of the photoreceptors
manifests by the production of F-actin and alpha-tubulin, components of the
microtubules. At this point, there is not yet a subretinal space present. The
most important event occurring at this stage is the appearance of retinal
vessels. Cells originating inside the optic disc from the walls of the two
venous channels located on either side of the hyaloid artery and from the
adventitia of the hyaloid artery proliferate and migrate into the inner retina.
They differentiate into endothelial cells, which first make cords and then
canalize to form capillaries. These cells possess a vascular precursor marker,
such as CD39, and have been named angioblasts. The initial process of
retinal vascularization is attributed to the formation of de novo vessels from
precursor vascular cells and is thus believed due to vasculogenesis (9).
FIGURE 1-4 A 4-month-old human fetus. All the major
constituents of the retina are present. Cones (C), rods (R),
external plexiform layer, internal nuclear layer (INL),
internal plexiform layer (IPL), ganglion cell layer (GCL),
nerve fiber layer, and internal limiting membrane can be
clearly distinguished (×540). (Reprinted from Hollenberg
MJ, Spira AW. Early development of the human retina.
Can J Ophthalmol 1972;7(4):472–491. Copyright © 1972
Canadian Ophthalmological Society. With permission.)
The pars plana begins to develop and renders the ora serrata more clearly
distinguishable. Retinal vascularization progresses rapidly. Newly formed
capillaries extend peripherally and form arteries and veins; the arteries and
veins present at the optic disc become the central retinal artery and veins. In
capillaries, cells in contact with the blood flow become endothelial cells, and
those surrounding endothelial cells become pericytes. Processes of astrocytes
attach to the collagenous matrix surrounding the capillaries (see also Chapter
5). A study was performed on the proteome profiles of the vitreous in human
embryos aged 14 to 29 weeks of gestation compared to those in young adults.
During the second trimester, the proteome started to undergo substantial
changes, and that was manifested by a marked decrease in most of the
proteins (12).
At the 6th month, cone photoreceptor differentiation occurs. Cone nuclei
are arranged in a row adjacent to the external limiting membrane, whereas
rod nuclei are located more internally. Tubular structures increase in number,
and mitochondria, ribosomes, and endoplasmic reticulum appear in the
prospective inner segment and primitive cone pedicles. Contact synapses are
apparent, but ribbon synapses have not formed (13). For the first time, the
macula appears as a bulging area with a thickened ganglion cell layer (Fig. 1-
6). Most of the photoreceptors are cones. There is a remnant of the layer of
Chievitz. Ganglion cells mature and accumulate cytoplasm: This maturation
starts at the posterior pole and progresses toward the periphery along with
developing retinal vascularization. Ganglion cells posterior to the edge of
advancing vessels are more mature than those anterior to them (14). Müller
cells are developing and are strongly attached to the internal limiting
membrane. Myelin-associated protein is present throughout all the layers of
the retina. Retinal vascularization continues its rapid progression by a process
of angiogenesis. More capillaries appear. Arterial and venous channels
develop while some of their side branches retract and atrophy, giving rise to
the formation of capillary-free perivascular zones. In all mammals with an
intraretinal capillary system, one can see that the capillary-free zone around
arteries is wider than that around veins. The width of the capillary-free zone
depends on the oxygen concentration in the blood flow. Raising the oxygen
concentration in the blood widens the periarterial capillary-free zone, while
reducing it narrows the capillary-free zone (15). The fetal retina is avascular
until the 4th month (16). With the development of the photoreceptors,
increased oxygen consumption is believed to cause hypoxia, which induces
the process of retinal vascularization. Retinal maturation precedes vascular
outgrowth. During the second trimester, the presence of lutein and its
oxidized forms has been detected in the RPE, retina, and vitreous body. The
antioxidant role of the carotenoids has been suggested as a factor in the
normal development of the retina (17).
At the 7th month, the rods differentiate in the same way cones have
previously (Fig. 1-7). In the cones, tubular structures arrange as lamellar sacs,
and mitochondria aggregate at the ellipsoid. Cone and rod terminals develop
synaptic vesicles and ribbons. As a greater number of photoreceptors
develop, the subretinal space enlarges. The ora serrata appears as a circular
line covered by a fold of peripheral retina, the Lange fold (18). The macula
still lacks a foveal depression, and no new cones are generated in this area.
The fovea forms as a result of two kinds of migration. One wave of migration
takes place in the inner retina and causes the formation of the foveal pit and
foveal slope. It consists of the centrifugal displacement of ganglion cells,
their dendrites and synapses to bipolar cells, and the axons of the
photoreceptors. The axons of the outer plexiform layer elongate and form the
fibers of Henle layer. The second wave takes place in the external
photoreceptor layer and consists of a centripetal migration of photoreceptors,
cones, rods, and RPE cells (19). There is no vascularization within the fovea.
The macular area is encircled by capillaries, which do not proliferate over the
center. An interesting theory has been advanced by Springer (20) regarding
the formation of the foveal pit. He claims that two mechanical parameters are
needed to explain the passive movement of the inner retinal cells and that is
deformability and a force that deforms. Because vasculature is mechanically
stiff in relation to the retina at the foveal avascular zone, the inner retina at
the avascular fovea can be considered deformable. The second parameter is
the onset of the intraocular pressure, which acts on the deformable foveal
avascular zone. As a supporting finding to his theory, Springer argues that the
ciliary body and Schlemm’s canal develop before the foveal pit. So the
internal retinal cells do not have to migrate outward; they are instead pushed
outward. The author cannot offer an explanation for the inward migration of
the cones into the foveal pit.
FIGURE 1-7 A 7-month-old human fetus. Development
of the photoreceptor. A:Two outer segments (OS) of
which one is seen attached to an inner segment (IS) by a
connecting cilium (CC) and the other not; they contain
tubular structures. N, nucleus of pigment epithelial cell.
Inset: A primitive outer segment shows an invaginated
plasma membrane (arrows) at the lateral and apical
surfaces. Some tubular structures show a swelling at their
end. B:The OS contain numerous tubular structures
intermingled with each other; they are surrounded by the
apical surface and processes of RPE cells. T, terminal bar
between two pigment epithelial cells. Inset: Tubular
structures at higher magnification. (Reproduced from
Yamada I. Submicroscopic morphogenesis of the human
retina. In Rohen, ed., The Structure of the Eye, symposium
ii. Stuttgart: Schattauer; 1965, with permission. Copyright
© 1965 Schattauer / Thieme Group.
https://trove.nla.gov.au/work/209461253?
q&versionId=229835068.)
PATHOLOGIC CONDITIONS
ASSOCIATED WITH ABERRANT
EMBRYOLOGIC DEVELOPMENT
During the 7th week, the embryonic fissure closes completely. Failure of
closure of the anterior (proximal) end of the embryonic fissure can result in
coloboma of the iris, ciliary body, and choroid at the inferonasal quadrant of
the globe (Fig. 1-8A and B). Failure of closure of the posterior end causes
coloboma of the optic disc (31). These colobomas are defined as typical
colobomas; atypical colobomas can be located anywhere in the globe and,
therefore, probably do not result from an embryonic fissure defect.
Abnormally persistent vascularized strands of the tunica vasculosa lentis
prevent normal iris growth and result in atypical coloboma of the iris in the
location where regression of the tunica vasculosa lentis failed (32). Coloboma
of the iris varies from a small notch at the pupillary margin to a large sector
defect. Cases with isolated iris coloboma usually have normal visual acuity.
FIGURE 1-8 Coloboma of the iris (A) and the retina and
choroid (B) in the same eye.
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2
The Hyaloidal Vasculature and Its
Role in Development
Charles M. Calvo, Ronald P. Hobbs, and M. Elizabeth Hartnett
The structure of the hyaloid artery consists of three layers, the intima, the
media, and the adventitia (3). The intima consists of flattened nonfenestrated
endothelial cells connected by tight junctions that have a basement membrane
and an incomplete layer of pericytes. The media has concentric layers of
smooth muscle with basement membranes around each fiber. The adventitia
contains scattered fibroblasts and collagen. The walls of the vasa hyaloidea
propria and the tunica vasculosa lentis are small capillaries that consist of a
complete layer of nonfenestrated endothelium with intervening tight
junctions between adjacent endothelial cells encircled by a continuous
basement membrane and incomplete layer of pericytes in primates (4). The
formation of the hyaloid vasculature has been proposed to occur by
hemovasculogenesis (5) and becomes most prominent between 8 and 12
weeks. Regression of the hyaloidal circulation begins at 12 weeks (6) with
the vasa hyaloidea propria, followed by the tunica vasculosa lentis, and then
the pupillary membrane. The process of regression finishes at about 35 to 36
weeks of gestation with the complete loss of blood flow in the hyaloidal
artery (2). As the hyaloidal vasculature regresses, there is contemporaneous
development of the retinal vasculature. The primary vitreous retracts and
collagen fibers and hyaluronic acid are produced, making up the secondary
vitreous. The posterior segment is composed largely of the secondary
vitreous by the 6th month of gestation, and the primary vitreous at this point
is reduced to a central extension from the optic disc to the posterior lens
surface known as Cloquet canal (Figure 2-2).
FIGURE 2-2 A:Artist diagram of a 48-mm human
embryo with hyaloidal artery regression and early
formation of primary and secondary vitreous. A, primary
vitreous; B, secondary vitreous being formed by
disappearance of vasa hyaloidea propria. B:Artist diagram
of a 65-mm human embryo demonstrating Cloquet canal
and the contained hyaloid artery in central primary
vitreous. The condensation between primary and
secondary vitreous is seen forming the wall of Cloquet
canal. a, primary; b, secondary vitreous. (Reprinted from
Mann I. Development of the human eye, 3rd ed. Australia:
Grune & Stratton, 1964. Copyright © 1964 Elsevier. With
permission.)
Ida Mann described the regression of the human hyaloid through detailed
observations (2). She noted that as the lens increased in size, the mesh of
intertwined vessels that made up the tunica vasculosa lentis along the
posterior capsule became stretched and developed decreased vessel caliber.
At the same time, the vasa hyaloidea propria branches had reduced caliber at
their proximal ends near the origin at the main hyaloid artery and eventually
lost connection with it, although the distal ends of the vasa hyaloidea propria
remained continuous with vessels on the posterior surface of the lens (Figure
2-3). The atrophy of the vasa hyaloidea propria and of the more central set of
vitreous branches is normally complete by 8½ months. During the 7th month,
atrophy of the anterior tunica vasculosa lentis or pupillary membrane begins.
The atrophy of the pupillary membrane begins centrally over the lens where
the vessels undergo a gradual shrinkage of the vessel walls with decreasing
lumen size and ultimately cessation of blood flow. Once the cessation of
blood flow occurs, the central vessels shrink away (Figure 2-4). By 8½
months, most of the central loops of the pupillary membrane have atrophied.
Endothelial cell processes then fill the lumen, and macrophages form a plug
that occludes the vessel. The cells in the vessel wall then undergo necrosis
and are phagocytized by mononuclear phagocytes (7). Frequently, remains of
the pupillary membrane can be seen as fine strands that extend along the
pupillary margin.
FIGURE 2-3 Artist diagram showing the relation of the
hyaloid vessels on the lens during atrophy of the vasa
hyaloidea propria. 1, remains of the vasa hyaloidea
propria; 2, vessels of tunica vasculosa lentis; 3, pupillary
membrane vessels. Note main trunk of hyaloid posterior to
lens. (Reprinted from Mann I. Development of the human
eye, 3rd ed. Australia: Grune & Stratton, 1964. Copyright
© 1964 Elsevier. With permission.)
Regression of the hyaloid artery and its associated branches usually occurs
completely and without complications. Persistence of the hyaloid vascular
system occurs in 3% of full-term infants and in 95% of premature infants. A
persistent hyaloid artery can be associated with prepapillary or vitreous
hemorrhage (8). Anomalies involving incomplete regression of the
embryonic hyaloid vascular system occur in more than 90% of infants born
younger than 36 weeks of gestation and in over 95% of infants weighing <5
pounds at birth (9).
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3
Vitreous and Developmental
Vitreoretinopathies
Samuel Asanad and J. Sebag
Invisible (Figure 3-1) “by design,” vitreous was long unseen as important in
the physiology and pathology of the eye. Recent studies have determined that
vitreous plays a significant role in ocular health (1) and disease (1,2),
including a number of important vitreoretinal disorders that arise from
abnormal embryogenesis and development. Vitreous embryology is presented
in detail in Chapter 1. Notable is that primary vitreous is filled with blood
vessels during the first trimester (Figure 3-2). During the second trimester,
these vessels begin to disappear as the secondary vitreous is formed,
ultimately resulting in an exquisitely clear gel (Figure 3-1). The following
will review vitreous development and the congenital disorders that arise from
abnormalities in hyaloid vessel formation and regression during the primary
vitreous stage and biochemical abnormalities related to secondary vitreous
dysgenesis.
FIGURE 3-1 Vitreous from a 9-month-old child was
dissected of the sclera, choroid, and retina. In spite of the
specimen being on a surgical towel exposed to room air,
the gel state is maintained. (Specimen is courtesy of the
New England Eye Bank.)
FIGURE 3-2 Human primary vitreous featuring the
hyaloid artery (3) arising from the optic disc and
branching to form the VHP (2), which anastomoses with
the TVL and PM (1).
BIOCHEMISTRY OF THE VITREOUS
BODY (SEE ALSO CHAPTER 4)
At birth, vitreous is composed primarily of collagen, while hyaluronan (HA)
synthesis begins after birth. This results in a dense appearance on dark-field
slit microscopy (Figure 3-3), because collagen scatters light intensely. Due to
considerable hydrophilicity, HA generates a “swelling” pressure within the
burgeoning vitreous that contributes to growth of the eye and also spreads
apart the collagen fibrils to minimize light scattering, inducing transparency
(Figures. 3-1 and 3-4). This is evident when comparing dark-field
microscopy of a human embryo (Figure 3-3) with that in a 4-year-old child
(Figure 3-4).
Primary Vitreous
Vitreous vascularization begins with the hyaloid artery entering the “eye”
through the optic cup. By 10 weeks of gestation (WG), the hyaloid system is
well established, branching to form the vasa hyaloidea propria (VHP) with
anastomoses to a dense capillary network, the tunica vasculosa lentis (TVL),
which is posterior to the lens, and the pupillary membrane (PM) adherent to
the anterior surface of the lens and iris diaphragm (14). Maximal
development of the hyaloid vasculature is reached by 12 to 13 WG (15)
although evidence of regression is apparent as early as 11 WG (16). The
hyaloid system shows clear signs of regression by 13 to 15 WG beginning in
the VHP followed by the TVL and then the PM (16–18).
The precise biochemical process involved in formation of the hyaloid
vasculature and its regression is poorly defined. However, recent studies have
revealed critical roles for various growth factors in vascular development.
Notably, hypoxia and vascular endothelial growth factor (VEGF) may trigger
the growth of the TVL and PM (19–22). Thus, decreased VEGF levels may
induce vessel regression. In addition, recent studies using whole-mount
immunostaining in mice have demonstrated the role of neurons in regulating
vessel regression. In particular, retinal neurons were shown to control the
precise switch from the fetal to the postnatal circulatory systems by timely
sequestering VEGF (23). In addition, immunohistochemical studies of human
umbilical vein endothelial cells (EC) and mouse eyes have demonstrated that
autophagy, in addition to apoptosis, may play a role in hyaloid vessel
regression during development, especially under hypoxic conditions. This
suggests that while hypoxia is a critical trigger for ocular development, it can
similarly induce autophagy and apoptosis in vascular EC for regression (24).
Furthermore, transforming growth factor (TGF) has been implicated in ocular
vessel remodeling since all four forms of TGF-β are found in vitreous
hyalocytes (25). There is also evidence that members of the Wnt signaling
pathway, particularly Wnt7b expressed in macrophages, are involved in
normal hyaloid regression (26) in the mouse, although this mechanism has
not been confirmed in humans.
Along with growth factors, a number of transcription factors have been
shown to regulate hyaloid vessel formation and regression. Using a mouse
model, Chen et al. illustrated the mechanistic role of the transcription factor,
Cited2 (Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-
terminal domain, 2). They demonstrated the role(s) of Cited2 together with
paired box 6 (Pax6) in the normal formation/regression of the hyaloid
vasculature through negative modulation of hypoxia-inducible factor-1 (HIF-
1) signaling (27). Moreover, proteomic investigations of primary vitreous
composition have shown dynamic changes in protein composition as a
function of vessel formation and regression. In particular, studies of vitreous
from 14 to 20 WG human embryos and young adult human eyes have
identified 1,217 proteins, 768 of which were not previously identified. It was
learned that the protein profile of human embryonic vitreous differs from
young adults and that in the embryo, this changes significantly during the
second trimester (14 to 20 WG). Alteration in protein composition was
shown to happen concurrently with regression of embryonic vitreous vessels,
as well as other developmental changes in the eye. These findings suggest
that the associated changes in proteomic profile of human fetal vitreous
during the second trimester may be related to the regression of the embryonic
vitreous vasculature (28).
Multidimensional liquid chromatography and tandem mass spectrometry
studies examined the proteomic profiles of vitreous substructures (the
anterior vitreous cortex, posterior vitreous cortex, central vitreous body, and
vitreous base) finding distinct molecular profiles associated with each
substructure, perhaps related to their unique functions (29). These recent
findings support previous hypotheses that vitreous may function to prevent
infection and regulate oxidative stress. Concerning the latter, there is
increasing evidence that vitreous regulates lens exposure to oxygen and
oxidative stress (30). Deficiencies in these properties due to inherited
vitreoretinal dystrophies, perinatal vitreous malformation, and vitreous
degeneration in aging may contribute to cataracts via oxidative stress.
Protease signaling, including the blood coagulation cascade and matrix
metalloproteases, may also be a major feature of the vitreous physiology in
health. In understanding disease, this knowledge can help link specific
proteins and their respective protein pathways to pathophysiologic processes
including age-related vitreous degeneration, cataract formation with aging
and after vitrectomy, proliferative vitreoretinopathy, diabetic
vitreoretinopathy, and various inflammatory disorders, such as
endophthalmitis and posterior uveitis (29).
In addition to regulatory factors, the developmental modality of the
human hyaloid vascular system remains controversial. In contrast to previous
studies, which suggested embryonic vitreous vessel formation via
vasculogenesis, current concepts are more inclined toward angiogenesis as
the mode of development. More recent studies examining embryonic and
vascular development support the view that similar to the choriocapillaris, the
hyaloid vasculature develops by hemo-vasculogenesis, which is the process
by which vasculogenesis, erythropoiesis, and hematopoiesis occur
simultaneously from common hemangioblast precursors (31).
Atrophy of the vessels begins posteriorly with dropout of the VHP,
followed by the TVL. Recent studies have detected the onset of apoptosis in
the EC of the TVL as early as day 17.5 in the mouse embryo (19). At the
240-mm stage (7th month) in the human, blood flow in the hyaloid artery
ceases. Regression of the vessel itself begins with glycogen and lipid
deposition in the EC and pericytes (PC) of the hyaloid vessels (32). EC
processes then fill the lumen, and macrophages form a plug that occludes the
vessel. The cells in the vessel wall then undergo necrosis and are
phagocytized by mononuclear phagocytes (33) identified as hyalocytes (34).
Recent studies suggest that the VHP and the TVL regress via apoptosis (35).
Mitchell et al. (19) point out that the first event in hyaloid vessel regression is
EC apoptosis and propose that lens development separates the fetal
vasculature from VEGF-producing cells, decreasing the levels of this survival
factor for vascular endothelium, inducing apoptosis. Following EC apoptosis,
there is loss of capillary integrity, leakage of erythrocytes into the vitreous,
and phagocytosis of apoptotic endothelium by hyalocytes. Meeson et al. (36)
proposed that there are actually two forms of apoptosis that are important in
regression of the fetal vitreous vasculature. The first (“initiating apoptosis”)
results from macrophage induction of apoptosis in a single EC of an
otherwise healthy capillary segment with normal blood flow. The isolated
dying EC project into the capillary lumen and interfere with blood flow. This
stimulates synchronous apoptosis of downstream EC (“secondary apoptosis”)
and ultimately obliteration of the vasculature. Removal of the apoptotic
vessels is achieved by hyalocytes.
Proteomic analysis of embryonic (aged 14 to 20 WG) human vitreous
(vitreomics) revealed that during hyaloid vessel regression, there is a
significant decrease in profilin-1 actin-binding protein and significant
increases in cadherin-2 cell adhesion protein, cystatin-C protease inhibitor,
dystroglycan cell adhesion molecule, clusterin, as well as pigment
epithelium–derived factor (PEDF), both known to have antiangiogenic
influences (37). The presence of dystroglycan and profilin-1 was confirmed
in the hyaloid vessels of 10, 14, and 18 WG embryonic human eyes by
immunolabeling (38). Clusterin was not present in the HA or TVL of 10 and
14 WG eyes, but was found in the HA of 18 WG eyes. Cadherin was not
found in the hyaloid vessels of the 10 WG eyes but was observed in the
hyaloid vessels at 14 and 18 WG (38).
Comparison of the protein composition of the adult human and
developing human vitreous from the second trimester (14 to 20 WG) revealed
314 and 1,213 proteins, respectively, including 78 proteins that were unique
to the adult and 1,002 unique to the fetal vitreous (39). A large fraction of the
fetal vitreous proteins are intracellular and may be involved in the remodeling
of the hyaloid vasculature and retina during the second trimester. Proteins
that were found in greater abundance in fetal vitreous compared to adult
vitreous included low molecular weight (MW) kininogen-1, cystatin-B,
insulin-like growth factor–binding protein (IGFBP)-2 and IGFBP-4,
thrombospondin-1 and thrombospondin-4, thioredoxin, mu-crystallin, alpha
2-antiplasmin, nidogen-2 and growth differentiation factor 8, as well as
secreted proteins PEDF, AMBP (α-1-microglobulin), hemoglobin, and Ig
chains. Low MW extracellular matrix proteins detected in fetal vitreous
included COL5A1, 6A3, 11A1, 15A1, 1A1, 2A1, 4A2, and 18A1 (39).
Bioinformatic analysis of the protein profile of fetal (14 to 20 WG)
human vitreous revealed that most proteins were members of either the free
radical scavenging, molecular transport, or small molecule biochemistry or
connective tissue disorder networks. Those proteins involved in free radical
scavenging, molecular transport, and small molecule biochemistry networks
were all intracellular and decreased during the second trimester. In contrast,
the proteins in the connective tissue disorder networks were all extracellular
and increased during the second trimester. This pattern is consistent with
replacement of the cellular primary vitreous with the acellular collagenous
secondary vitreous. This analysis further revealed that EIF2 signaling and
protein ubiquitination were the top canonical pathways (40). While intriguing
and essential (because they are in humans), these studies lack controls, so
mechanisms remain unclear and more research in this area is needed.
Studies of abnormal hyaloid vessel regression found that germ-line
deletion of Bim (proapoptotic factor) results in persistent hyaloid vasculature,
increased retinal vascular density, and prevents retinal vessel regression in
response to hyperoxia (41). Recently, researchers have sought to determine
whether retinal vascular regression is attributable to Bim expression in EC or
PC using transgenic mice. Interestingly, these studies observed attenuation of
hyaloid vessel regression and postnatal vascular pruning specifically in mice
lacking Bim in EC or PC. In addition, apoptosis and proliferation were also
decreased in the retinal vasculature of BimEC and BimPC mice (42).
Secondary Vitreous
Secondary (avascular) vitreous formation arises from a remodeling of the
earlier primary (vascular) vitreous (43). By the 40- to 60-mm stage in
humans, the VHP has reached maximum maturity and regression begins (22).
The posterior VHP is the first component to degenerate. Regression continues
to move centrally affecting the TVL and finally the hyaloid artery itself.
Although flow through the hyaloid artery decreases during this time ceasing
entirely around the 240-mm stage, the artery may continue to elongate as the
eye lengthens (44). As the primary vitreous regresses, its “remnants” provide
a framework for collagen fibrils of the secondary vitreous to form via
interactive remodeling. As this occurs, the primary and secondary vitreous
coexist in the same space during this transitional developmental period
(43,44).
VITREOUS STRUCTURE
In the human embryo, vitreous structure has a dense homogenous appearance
(Figure. 3-3) primarily due to the aforementioned collagen synthesis during
secondary vitreous formation (45–51). HA synthesis after birth separates
collagen fibrils, inducing transparency (Figure 3-4). In the absence of
diabetes and myopia, vitreous remains largely transparent until around the
fourth or fifth decade when fine, parallel fibers appear coursing in an
anteroposterior direction (Figure 3-5B and C) (2,48–50). The fibers arise
from the vitreous base (Figure 3-5H) where they insert anterior and posterior
to the ora serrata. As the peripheral fibers course posteriorly, they are
circumferential with the vitreous cortex, while central fibers “undulate” in a
configuration parallel with Cloquet canal (51). The fibers are continuous and
do not branch. Posteriorly, these fibers insert into the vitreous cortex (Figure
3-5E and F).
FIGURE 3-5 A–H:Dark-field slit microscopy of human
vitreous in eyes dissected of the sclera, choroid, and retina.
The anterior segment is below and the posterior pole is
above in all images. (Specimens courtesy of the New York
Eye Bank for Sight Restoration. Images used with
permission from Sebag J. The Vitreous – Structure,
Function, and Pathobiology. New York, NY: Springer-
Verlag; 1989:41.)
Ultrastructural studies (52) demonstrated that collagen fibrils are the only
microscopic structures that could correspond to these fibers. These studies
also detected the presence of bundles of packed, parallel collagen fibrils.
Eventually, the aggregates of collagen fibrils attain sufficiently large
proportions so as to be visualized in vitro (Figure 3-5) and clinically. The
areas adjacent to these large fibers have a low density of collagen fibrils
separated by HA molecules and therefore do not scatter light as intensely as
the bundles of collagen fibrils.
Vitreous Base
The vitreous base is a three-dimensional zone extending 1.5 to 2 mm anterior
to the ora serrata, 1 to 3 mm posterior to the ora serrata (53), and several
millimeters into the vitreous body itself (54). The posterior extent of the
posterior border of the vitreous base varies with age (55,56). In a variety of
developmental vitreoretinal disorders, the secondary vitreous never forms
temporally, likely due to the lack of proper formation of the peripheral retina
in this location. Thus, there is a different peripheral terminus bounded by
vitreous gel posteriorly and liquid vitreous anteriorly (see below).
Proteomic studies of different parts of the vitreous body found low
complexity protein networks in the vitreous base relative to the highly
complex networks in the anterior and posterior vitreous cortices. In particular,
the largest network unique to the vitreous base was the glycogen synthase
kinase 3 beta subunit (GSK3 beta) protein complex. Other pathways in the
vitreous base include protein kinase R (PKR) in apoptosis, DNA replication,
methionine–cysteine–glutamate metabolism, high-temperature requirement
A1 (HTRA1) signaling, protein kinase A (PKA) signaling, sulfur
metabolism, and interferon immune response (29). The relationship between
these findings and the different functions of different substructures of the
vitreous body remain to be determined.
Vitreous fibers enter the vitreous base by splaying out to insert anterior
and posterior to the ora serrata (Figure 3-5H). The anterior-most fibers form
the “anterior loop” of the vitreous base, a structure that is important in the
pathophysiology of anterior proliferative vitreoretinopathy (2,57–59). Studies
by Gloor and Daicker (60) showed that cords of vitreous collagen insert into
gaps between the neuroglia of the peripheral retina. They likened this
structure to Velcro (a self-adhesive nylon material) and proposed that this
would explain the strong vitreoretinal adhesion at this site. In the anterior
vitreous base, fibrils interdigitate with a reticular complex of fibrillar
basement membrane material between the crevices of the nonpigmented
ciliary epithelium (61). The vitreous base also contains intact cells that are
fibroblast-like anterior to the ora serrata and macrophage-like posteriorly.
Damaged cells in different stages of involution and fragments of basal
laminae, presumed to be remnants of the embryonic hyaloid vascular system,
are also present in the vitreous base (61). Exposure of the adult immune
system to these previously sequestered fetal remnants (antigens) later in life
may play a role in peripheral uveitis, perhaps better termed “peripheral
anterior vitritis.”
Vitreous Cortex
The vitreous cortex is the peripheral shell of the vitreous body that courses
forward and inward from the anterior vitreous base to form the anterior
vitreous cortex and posteriorly from the posterior border of the vitreous base
to form the posterior vitreous cortex. The anterior vitreous cortex, often
referred to as the “anterior hyaloid face,” begins about 1.5 mm anterior to the
ora serrata. The posterior vitreous cortex is 100 to 110 μm thick (62) and
consists of densely packed collagen fibrils (Figure 3-6, bottom). There is no
vitreous cortex over the optic disc (Figure 3-4A), and the cortex is thin over
the macula due to rarefaction of the collagen fibrils (62). The prepapillary
hole in the posterior vitreous cortex can sometimes be visualized clinically
when the posterior vitreous is detached from the retina. If peripapillary glial
tissue is torn away during posterior vitreous detachment (PVD) and remains
attached to the vitreous cortex around the prepapillary hole, it is referred to as
Vogt or Weiss ring. Vitreous can extrude through the prepapillary hole in the
vitreous cortex (Figure 3-4A) but does so to a much lesser extent than
through the premacular vitreous cortex where it can produce traction and
certain forms of maculopathy (63–65).
FIGURE 3-6 Scanning electron microscopy of the
anterior surface of the ILM of the retina (A) and the
posterior aspect of the posterior vitreous cortex in a human
(B).
Hyalocytes
Hyalocytes are mononuclear cells (Figure 3-7) that are embedded in the
vitreous cortex and widely spread apart in a monolayer 20 to 50 μm from the
retina. Quantitative studies of cell density in the bovine (66) and rabbit (67)
vitreous found the highest density of hyalocytes in the vitreous base,
followed by the posterior pole, and the lowest density at the equator.
Hyalocytes are oval or spindle-shaped, are 10 to 15 μm in diameter, and
contain a lobulated nucleus, a well-developed Golgi complex, smooth and
rough endoplasmic reticula, and many large periodic acid–Schiff-positive
lysosomal granules and phagosomes (62,68). Balazs (69) pointed out that
hyalocytes are located in the region of highest HA concentration and
suggested that these cells are responsible for vitreous HA synthesis. There is
evidence to suggest that hyalocytes maintain ongoing synthesis and
metabolism of glycoproteins within the vitreous (70,71). Hyalocytes have
also been shown to synthesize vitreous collagen (72) and enzymes (73).
FIGURE 3-7 Transmission electron micrograph of human
hyalocyte embedded in the posterior vitreous cortex with
its dense matrix of collagen fibrils. (Original magnification
×11,670.)
The phagocytic capacity of hyalocytes has been described in vivo (74) and
demonstrated in vitro (75,76), consistent with the presence of pinocytic
vesicles and phagosomes (68) and surface receptors that bind
immunoglobulin G and complement (76). Hyalocytes become phagocytic
cells in response to inducting stimuli and inflammation. HA may have a
regulatory effect on hyalocyte phagocytic activity (77,78). As an extension of
this phagocytic activity, hyalocytes can be antigen-presenting cells that
modulate intraocular inflammation while also keeping the vitreous clear via
phagocytic activity. Finally, collagen membranes within hyalocytes are
known to contract in the presence of certain stimulants, such as TGF-β2. This
phenomenon may explain the contraction of preretinal cortical vitreous
responsible for a myriad of pathologies with preretinal membranes, especially
macular pucker (79).
With respect to adult macular pathology, recent studies have illustrated
the role of vitreoschisis and anomalous PVD in macular holes and macular
pucker pathogenesis. In these vitreomaculopathies, hyalocytes likely play an
early, if not primary, role in the contractile premacular membrane resulting
from vitreoschisis, since these cells undergo myofibroblastic
transdifferentiation in the posterior vitreous cortex and have contractile
properties in the presence of TGF-β (80). Indeed, histopathologic evaluation
of the vitreoretinal interface in 14 monkey eyes and in vivo optical imaging in
humans suggest that the premacular vitreous cortex containing hyalocytes
may be important in pathologic premacular membrane formation (81). Using
a murine model, Vagaja demonstrated that under varying physiologic and
pathologic conditions, hyalocytes were responsive to aging, hyperglycemia,
locally produced VEGF, and both systemic and ocular-derived toll-like
receptor (TLR) ligands (82). Similar pathophysiologic mechanisms may be at
play in pediatric vitreoretinopathies.
Vitreoretinal Interface
In the child, it is virtually impossible to mechanically detach the posterior
cortical vitreous from the retina, resulting in surgical complications such as
retinal breaks. The interface between the vitreous and retina consists of a
complex formed by the posterior vitreous cortex and the inner limiting
membrane (ILM), which includes the basal lamina of Müller cells (83,84)
(Figure 3-6) (see also Chapter 4). The ILM is composed of type IV collagen
closely associated with glycoproteins (85–87). Immediately adjacent to the
Müller cells is the lamina rara, which is 0.03 to 0.06 μm thick and
demonstrates no species variations nor changes with topography or age. The
lamina densa is thinnest at the fovea (0.01 to 0.02 μm). It is thicker elsewhere
in the posterior pole (0.5 to 3.2 μm) than at the equator or vitreous base. At
the rim of the optic nerve head, the retinal ILM ceases, although the basement
membrane continues as the ILM of Elschnig (88). This membrane is 50 nm
thick and is believed to be the basal lamina of the astroglia in the optic nerve
head. At the central-most portion of the optic disc, the membrane thins to 20
nm, follows the irregularities of the underlying cells of the optic nerve head,
and is composed only of glycosaminoglycans and no collagen (89). This
structure is known as the central meniscus of Kuhnt. Balazs (7) has stated
that the Müller cell’s basal lamina prevents the passage of cells as well as
molecules larger than 15 to 20 nm. Consequently, the thinness and chemical
composition of the central meniscus of Kuhnt and the membrane of Elschnig
may account for, among other effects, the frequency with which abnormal
cell proliferation arises from or near the optic nerve head (57,59).
Zimmerman and Straatsma (90) claimed that there are fine, fibrillar
attachments between the posterior vitreous cortex and the ILM and proposed
that this was the source for the strong adhesion between the vitreous and
retina. The composition of these fibrillar structures is not known, and their
presence has never been confirmed. It is more likely that an extracellular
matrix “glue” exists between the vitreous and retina in a fascial as opposed to
focal apposition (48,85,86), composed of fibronectin, laminin, and other
extracellular matrix components (91). Western blots of separated proteins
derived from dissected vitreoretinal tissues identified two chondroitin
sulfate–containing proteoglycans of approximately 240-kDa MW that are
believed to function as adhesive molecules at the vitreoretinal interface.
These findings formed the rationale for experimental and clinical studies on
pharmacologic vitreolysis (92) using ABC chondroitinase (see Chapter 4).
Studies of human donor eyes and human retinectomy samples have
identified the distribution of the specific collagen subtypes constituting the
vitreoretinal interface. In particular, immunostaining studies have revealed
collagen type VI in the ILM and type VII in several layers of the retina. Both
collagens can anchor matrix components, and type VI may likely be involved
in vitreoretinal attachment. Furthermore, the presence of collagen mRNA in
human retinectomy samples may be an indication of postnatal collagen
production by retinal cells (93). Such knowledge regarding collagen
distribution may serve useful in understanding the pathophysiology of a
spontaneous, mechanical, or pharmacologically induced PVD (see below).
DEVELOPMENTAL ABNORMALITIES
OF VITREOUS
Many developmental vitreoretinal disorders result from abnormalities in the
embryonic vascular system of the vitreous (VHP) and lens (TVL). These
attain maximum prominence during the 9th week of gestation or 40-mm stage
(94). Hyaloid vessel development around the seventh WG appears to be
associated with high expression of VEGF165 (an isoform of VEGF-A).
However, once the hyaloid vascular system reaches completion, the
alternatively spliced antiangiogenic VEGF165b isoform begins to dominate
(95).
Marfan Syndrome
In Marfan syndrome, an autosomal dominant disorder featuring poor
musculature, lax joints, aortic aneurysms, and arachnodactyly, there is lens
subluxation, thin sclera, peripheral fundus pigmentary changes, and vitreous
liquefaction at an early age. Myopia, vitreous syneresis, and abnormal
vitreoretinal adhesions at the equator likely account for the frequency of
rhegmatogenous retinal detachment caused by equatorial or posterior
horseshoe tears (148). Marfan syndrome is associated with mutations in the
FBN1 gene that encodes the connective tissue protein fibrillin 1.
Ehlers-Danlos Syndrome
Systemic manifestations: Ehlers-Danlos syndrome has some similarities to
Marfan syndrome, most notably joint laxity, aortic aneurysms, and an
autosomal dominant pattern of inheritance. However, there are as many as six
types of Ehlers-Danlos patients, and both autosomal dominant and autosomal
recessive forms have been described. A further distinction from Marfan
patients is hyperelastic skin and poor wound healing of all connective tissues,
including the cornea and sclera. Ehlers-Danlos syndrome has been associated
with mutations in numerous collagen genes, including COL1A1, COL1A2,
COL3A1, COL5A1, and COL5A2.
Ocular manifestations: Ocular manifestations include lens subluxation,
angioid streaks, thin sclera, and high myopia due to posterior staphyloma.
Vitreous liquefaction and syneresis occur at a young age. Vitreous traction
causes vitreous hemorrhage, perhaps also due to blood vessel wall fragility,
and retinal tears with rolled edges, often causing bilateral retinal detachments
(148).
Stickler Syndrome
Genetics: In 1965, Stickler et al. described a condition in five generations of a
family that was found to be autosomal dominant with complete penetrance
and variable expressivity (149). Stickler syndrome is the most common type
II/XI collagenopathy, arising from mutations in at least three collagen genes.
Although typically inherited in an autosomal dominant fashion, families with
an autosomal recessive pattern of inheritance have been described (150).
Stickler syndrome is most commonly associated with mutation in COL2A1, a
54-exon–containing gene coding for type II collagen. In one instance
(151,152) of a family with typical Stickler syndrome, posterior chorioretinal
atrophy and vitreoretinal degeneration were found, even though they have
been classically associated with Wagner disease. Vitreous findings from that
study validated reports that mutations in the COL2A1 gene result in an
optically empty vitreous with retrolenticular membrane phenotype.
Systemic manifestations: General features of Stickler syndrome are a
marfanoid skeletal habitus and orofacial and ocular abnormalities.
Subsequent studies identified subgroups with short stature and a Weill-
Marchesani habitus. The skeletal abnormalities now accepted as
characteristic of Stickler syndrome are radiographic evidence of flat
epiphyses, broad metaphyses, and especially spondyloepiphyseal dysplasia
(153). In general, the systemic manifestations can vary greatly, even within a
family all possessing the same genotype. Distinguishing features can include
deafness, cleft palate, joint hypermobility, and premature arthritis (136).
Recently, however, an ocular-only subgroup has been identified, which has
no systemic features but a high risk of rhegmatogenous retinal detachments
(154,155).
Ocular manifestations: Ocular abnormalities are high myopia, >−10
diopters in 72% of cases (156), and vitreoretinal changes characterized by
vitreous liquefaction, fibrillar collagen condensation, quadrantic lamellar
cortical lens opacities (157), and a perivascular lattice-like degeneration in
the peripheral retina believed to be the cause of a high incidence (>50%) of
retinal detachment (153). There is some evidence of phenotype/genotype
correlation, which has led to the classification of Stickler syndrome patients
into five subgroups (157). Additionally, the vitreous can exhibit three distinct
phenotypes, membranous (type 1), beaded (type 2), or normal (158). Patients
with abnormalities in the genes coding for type II procollagen and type XI α1
procollagen are the ones who have severe vitreous abnormalities. Patients
with type XI α2 procollagen defects typically present without ocular
manifestations (159). Another study (160) analyzed the ultrastructural
features of a vitreous membrane with multiple fenestrations in a patient with
a Stickler syndrome. A type 2 vitreous phenotype was found in the left eye,
whereas the fellow eye’s vitreous abnormalities appeared to result from
conversion to a type 1 phenotype. In such a conversion, a fenestrated
membrane may represent the posterior vitreous cortex in a complete PVD.
The fenestrated membrane is made of avascular fibrocellular tissue with cells
arranged cohesively around the fenestration. Proliferating Müller cells and
collagen fibrils were shown to be similar to normal vitreous by ultrastructural
examination. The authors concluded that collagen molecules are not
functionally modified, but they are probably quantitatively insufficient during
vitreous development. Aside from high myopia in childhood, the majority of
patients with Stickler syndrome have no vision loss unless they have a retinal
detachment. In addition to premacular vitreous changes, recent studies
evaluated foveal structure in 25 patients with Stickler syndrome using swept-
source optical coherence tomography, finding mild foveal hypoplasia with
persistence of the inner retinal layer (161).
Stickler syndromes are the most common causes of inherited and
childhood retinal detachment; however, no consensus exists regarding the
effectiveness of prophylactic intervention. Recent studies evaluated the long-
term safety and efficacy of the Cambridge prophylactic cryotherapy protocol,
a standardized retinal prophylactic treatment developed to prevent retinal
detachment arising from giant retinal tears in type 1 Stickler syndrome. In
487 patients with type I Stickler syndrome, the Cambridge prophylactic
cryotherapy protocol was not only safe but also markedly reduced the risk of
retinal detachment (162).
Knobloch Syndrome
Knobloch (163) described an autosomal recessive syndrome similar to
Stickler syndrome with hypotonia, relative muscular hypoplasia, and mild to
moderate spondyloepiphyseal dysplasia causing hyperextensible joints. The
vitreoretinopathy is characterized by vitreous liquefaction, veils of vitreous
collagen condensation, and perivascular lattice-like changes in the peripheral
retina. Retinal detachment in patients with Knobloch syndrome has been
explained by loss-of-function mutations in COL18A1, the gene encoding the
α1-chain of collagen XVIII based on findings from one investigation (164)
demonstrating that collagen XVIII is crucial for anchoring vitreous collagen
fibrils to the ILM. New electrophysiologic studies described previously
unreported clinical features. In particular, a recent study of the detailed
phenotypes and molecular genetic findings in seven affected families
revealed pigment dispersion syndrome and glaucoma in addition to cone–rod
dysfunction on electroretinography. Two patients had normal neuroradiologic
findings, emphasizing that some affected individuals have isolated ocular
disease (165).
Wagner Syndrome
First described in 1938 by Wagner in a Swiss family (166), this syndrome is a
rare, dominantly inherited vitreoretinopathy with near-complete penetrance
(167). Caused by mutation of the versican (VCAN) gene in chromosome 5q
(previously known as CSPG2), the hallmark feature of this syndrome is an
optically empty vitreous body composed of strands, membranes, or veils. It
can be particularly difficult to distinguish Wagner syndrome from Stickler
syndrome, especially the ocular subtype, based solely on ocular phenotype.
However, consideration of the vitreous phenotype can assist with
distinguishing these two vitreoretinopathies (168).
Myopia
It has been proposed (169) that myopia unrelated to the aforementioned
arthro-ophthalmopathies should also be considered a disorder of vitreous
collagen. The anomalous PVD (146,147) that results from extensive
liquefaction of vitreous (myopic vitreopathy) and propensity for retinal
detachment due to peripheral retinal traction and myopic peripheral retinal
degeneration suggest that this postulate deserves closer scrutiny. Indeed,
vitreomacular traction has already been identified as an important component
in the pathogenesis of myopia-related pathologies, including myopic foveal
retinoschisis (170). Recent swept-source OCT studies of PVD in 151 highly
myopic eyes found larger posterior precortical vitreous pockets (actually the
bursa premacularis of Jan Worst) compared with normal eyes. In addition,
highly myopic eyes are likely to develop PVD at younger ages, often
anomalous with the posterior vitreous cortex more frequently remaining
attached to the macula inducing traction (171). Although the exact
mechanism for increased vitreous liquefaction in high myopia is unclear,
several theories have been proposed. Dysfunctional Müller cell activity is an
older hypothesis that derived from studies showing abnormal B wave results
on electroretinograms of highly myopic patients (current thinking is that the
B wave does not arise from Müller cells but perhaps from ON-center bipolar
cells) (172). However, the absence of abnormally thick inner limiting laminae
in myopic patients (173) suggests that Müller cells may not be the culprit.
Another study showed that highly myopic patients with ocular pathology
(macular detachments or macular hole) had increased vitreous and serum
levels of transthyretin (TTR) compared to controls (174). Additionally, the
TTR in the macular detachment cases was abnormally stable suggesting a
misfolded protein. TTR is a homotetrameric protein that functions as a carrier
for both thyroxin and retinol-binding protein and has previously been
implicated in several amyloid-related diseases such as vitreous amyloidosis,
Alzheimer disease, and familial amyloidotic polyneuropathy (174,175).
These results suggest that TTR may be a biomarker of myopic vitreopathy
while also playing a role in the pathophysiology of myopic ocular conditions.
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4
Vitreous Biochemistry and
Pharmacologic Vitreolysis
Sasha Rosen, Matin Khoshnevis and J. Sebag
VITREOUS BIOCHEMISTRY
Vitreous is an extended extracellular matrix composed of 98% water and 2%
structural components, primarily collagens and glycosaminoglycans (GAGs).
Biochemical analyses of 27 patients undergoing vitrectomy found significant
amounts of electrolytes and metals including copper, zinc, selenium, and iron
(7). Although this study offered the distinct advantage of analyzing undiluted
human vitreous samples (as compared to previous studies that utilized animal
models or postmortem human samples), the fact that all subjects were
undergoing vitrectomy for specific vitreoretinal diseases suggests the results
may not be applicable to healthy eyes or other diseases (8). Of note, the study
featured a mix of diabetic and nondiabetic patients. The authors noted that in
the case of the diabetic patients, vitreous glucose more closely correlated with
serum HbA1C than did serum glucose, suggesting that subclinical alterations
in vitreous biochemistry may forewarn a risk for diabetic retinopathy and
cardiovascular events (7). These findings confirm previous studies that found
elevated levels of glucose (9) and advanced glycation end products (10,11) in
human diabetic vitreous, underscoring the importance of considering diabetes
effects upon vitreous independent from effects on the retina (12). Indeed,
studies in diabetic children have identified structural differences from
nondiabetics that likely result from glucose-induced cross-linking of vitreous
collagen (13). Oxidative stress is probably also involved in these structural
changes within the vitreous body as well as changes at the vitreoretinal
interface, where extracellular superoxide dismutase has been shown to be
important (14).
Collagens
Collagen content is highest where vitreous is a gel (15). As shown in Figure
4-1, individual vitreous collagen fibrils are organized as a triple helix of three
alpha chains. The major collagen fibrils are thin, uniform, and heterotypic,
consisting of more than one collagen type. Recent studies of pepsinized
forms of collagen confirm that vitreous contains collagen type II (60% to
75%), type IX (15% to 25%), and a hybrid of types V/XI (10% to 25%)
(4,6,16).
Type IX Collagen
Type IX collagen is a heterotrimer that is disulfide bonded with an (α1 [IX]
α2 [IX] α3 [IX]) configuration. It is oriented regularly along the surfaces of
the major collagen fibrils in a “D periodic” distribution, where it is cross-
linked onto the fibril surface. Type IX is a member of the fibrillar-associated
collagens with interrupted triple helixes group of collagens. It contains
collagenous regions described as COL1, COL2, and COL3 interspersed
between noncollagenous regions called NC1, NC2, NC3, and NC4 (19,20). In
vitreous, as opposed to cartilage, the NC4 domain is small and not highly
charged, thus not likely to exhibit extensive interaction with other
extracellular matrix components (21). In vitreous, type IX collagen always
contains a chondroitin sulfate GAG chain (19,20), which is linked covalently
to the α2 (IX) chain at the NC3 domain, enabling the molecule to assume a
proteoglycan form. Electron microscopy of vitreous stained with cationic
dyes visualizes the chondroitin sulfate chains of type IX collagen,
occasionally found distributed along the surface of vitreous collagen fibrils
(22) and often bridged between neighboring collagen fibrils. Duplexing of
GAG chains from adjacent collagen fibrils may result in a “ladder-like”
configuration (23). It has been recently suggested that type IX collagen
modulates the spatial arrangement of collagen fibrils by both bridging
together and spacing apart individual fibrils (16,24).
Type VI Collagen
Although there are only small amounts of type VI collagen in vitreous, the
ability of this molecule to bind both type II collagen and hyaluronan (HA)
suggests that it could be important in organizing and maintaining the
supramolecular structure of vitreous gel.
Glycosaminoglycans
GAGs do not normally occur as free polymers in vivo but are covalently
linked to a protein core, the ensemble called a proteoglycan. A sulfated group
is attached to oxygen or nitrogen in all GAGs except HA. Studies in the
rabbit (28) found a total vitreous GAG content of 58 ng with 13% chondroitin
sulfate and 0.5% heparan sulfate.
Hyaluronan
Although HA is present throughout the body, it was first isolated from bovine
vitreous (29). HA appears in human vitreous after birth possibly synthesized
by hyalocytes (30), although other plausible candidates are the ciliary body
and retinal Müller cells. HA is synthesized at a constant rate in the adult.
Although there is no extracellular degradation, HA levels are in a steady state
because the molecule escapes via the anterior segment of the eye (31).
HA is a long, unbranched polymer of repeating glucuronic acid β-1,3-
N,N-acetylglucosamine disaccharide moieties linked by β 1 to 4 bonds (32),
with a molecular weight of 3 to 4.5 × 106 in adult human vitreous (31). HA is
a linear, left-handed, threefold helix with a rise per disaccharide on the helix
axis of 0.98 nm (33). This periodicity, however, can vary depending on
whether the helix is in a “compressed” or “extended” configuration (34).
Changes in the degree of “extension” of HA could be important in retinal
disease, since the volume of the unhydrated HA molecule is about 0.66
cm3/g, whereas the hydrated specific volume is 2,000 to 3,000 cm3/g (31).
Thus, the degree of hydration has a significant influence on the size and
configuration of the HA molecular network. HA also interacts with the
surrounding mobile ions and can undergo changes in its conformation that are
induced by changes in the surrounding ionic milieu (35). A decrease in
surrounding ionic strength can cause the anionic charges on the
polysaccharide backbone to repel one another, resulting in an extended
configuration of the macromolecule. An increase in surrounding ionic
strength can cause contraction of the molecule and, in turn, the entire vitreous
body. As a result of HA’s entanglement and immobilization within the
vitreous collagen fibril matrix, this mechanical force can be transmitted to the
retina, optic disc, and other structures, such as neovascular complexes. This
can be important in certain pathologic conditions that feature fluctuations in
ionic balance and hydration, such as diabetes (12), especially type I diabetes
in children who have a solid gel vitreous firmly adherent to the retina.
Recently, covalent HA coating of lipoplexes has been proposed for delivery
of retinal gene nanomedicines via intravitreal injection (36).
Chondroitin Sulfate
Vitreous contains two chondroitin sulfate (CS) proteoglycans. The minor
type is actually type IX collagen, which was described earlier. The majority
of vitreous CS is in the form of versican; concentration = 0.06 mg
protein/mL, about 5% of the total protein content (37). This large
proteoglycan has a globular N-terminus that binds HA via a 45-kDa link
protein (38). In human (but not bovine) vitreous, versican is believed to form
complexes with HA as well as microfibrillar proteins, such as fibulin-1 and
fibulin-2 (6).
Heparan Sulfate
This sulfated proteoglycan is normally found in basement membranes and on
cell surfaces throughout the body. It was first detected in bovine vitreous in
1977 (39) and in chick vitreous (as “agrin”) in 1995 (40). However, it is not
clear whether heparan sulfate is a true component of vitreous or a
contaminant from adjacent basement membranes, such as the inner limiting
membrane of the retina (41). As pointed out by Bishop, this may also be the
case for nodogen-1, the aforementioned fibulins, and fibronectin (6).
Fibrillins
Fibrillin-containing microfibrils are more abundant in vitreous than type VI
collagen microfibrils. They are found in vitreous gel as well as in the zonules
of the lens, explaining why in Marfan syndrome, defects in the gene encoding
fibrillin-1 (FBN1 on chromosome 15q21) result in both ectopia lentis and
vitreous liquefaction (6). The latter probably plays a role in the high
incidence of rhegmatogenous retinal detachment in these patients.
Opticin
The major noncollagenous protein of vitreous is opticin, a leucine-rich repeat
(LRR) protein, which is bound to the surface of the heterotypic collagen
fibrils (42). Formerly called vitrican, opticin is believed to be important in
collagen fibril assembly and in preventing the aggregation of adjacent
collagen fibrils into bundles. Thus, a breakdown in this property or activity
may play a role in age-related vitreous degeneration (43). A recent study
attempted to determine the structure, location, and expression of the mouse
opticin gene (Optc) (44). The gene was found to be localized to mouse
chromosome 1, consisting of seven exons. Additionally, in situ hybridization
revealed that opticin mRNA is localized exclusively to the ciliary body
during development and to the nonpigmented ciliary epithelium of the adult
mouse eye. The researchers concluded that opticin may represent a marker
for the differentiation of ciliary body. Besides regulating vitreous collagen
fibrillogenesis, it may also have other functions as demonstrated by its
continued expression in the adult mouse eye. Indeed, Bishop and colleagues
recently demonstrated that opticin is capable of modulating
neovascularization in the posterior segment. In their study, an opticin
knockout mouse and a wild-type mouse were compared in an oxygen-
induced retinopathy model. Although the knockout mouse initially had
normal vascular development, following exposure to high oxygen conditions,
the knockout model developed significantly more preretinal
neovascularization. Additionally, intravitreal injections of opticin into the
wild-type mouse significantly reduced preretinal neovascularization when
exposed to the oxygen-induced retinopathy conditions (45).
Supramolecular Organization
Bishop has emphasized the importance of understanding what prevents
collagen fibrils from aggregating and by what means the collagen fibrils are
connected to maintain a stable gel structure (6). CS chains of type IX
collagen bridge between adjacent collagen fibrils in a ladder-like
configuration spacing them apart (46). This arrangement might account for
vitreous transparency, in that keeping vitreous collagen fibrils separated
would minimize light scattering and allow unhindered transmission of
photons to the retinal photoreceptors. However, depolymerizing with
chondroitinase does not destroy the gel, suggesting that CS side chains are
not essential for vitreous collagen spacing. Complexed with HA, however,
the CS side chains might space apart the collagen fibrils (23,46), although
Bishop believes that this form of collagen–HA interaction is “very weak.”
Instead, he proposes that the LRR protein opticin is the predominant
structural protein in short-range spacing of collagen fibrils. Concerning long-
range spacing, Scott (23) and Mayne et al. (47) have claimed that HA plays a
pivotal role in stabilizing the vitreous gel via this mechanism. However,
studies (48) using HA lyase to digest vitreous HA demonstrated that the gel
structure was not destroyed, suggesting that HA is not essential for the
maintenance of vitreous gel stability, leading to the proposal that collagen
alone is responsible for the gel state of vitreous (6).
Total collagen content in the vitreous gel remains at about 0.05 mg until
the third decade (2). As collagen concentration does not appreciably increase
during this time but the size of the vitreous increases, the network density of
collagen fibrils effectively decreases, potentially weakening the collagen
network and destabilizing the gel. However, since there is net synthesis of
HA during this time, it likely stabilizes the thinning collagen network (31).
Although previous studies suggested the lack of postnatal synthesis of
vitreous collagen (16,49), Wang et al. (50) demonstrated some postnatal
collagen synthesis, indicating that the formation of vitreous collagen is a
more dynamic than previously thought (16). The loss of type IX collagen
over time in concert with augmented surface exposure of type II collagen
causes disruption in the parallel organization of collagen fibrils as well as
subsequent aggregation (16,51). Bishop highlights the constitutional role of
the heterotypic collagen fibrils in promoting the stability of the vitreous gel
and proposes that future studies should aim to further describe all of the
macromolecules present on the surface of vitreous collagen fibrils and the
nature of their interactions with other macromolecules as well as collagen
fibrils (6).
Note: tPA (tissue plasminogen activator); plasmin, ocriplasmin, nattokinase, vitreosolve are believed to
be both liquefactants and interfactants.
aFormerly known as microplasmin.
bNonenzymatic agents.
Reprinted with permission from Sebag J. Pharmacologic vitreolysis-premise and promise of the first
decade. Retina 2009;29(7):871–874.
Adverse Events
Ocriplasmin’s enzymatic activity is nonspecific and may dissolve vitreous
proteins and possibly interact with proteins within the retina, choroid, and
lens (100). However, intravitreal injection of ocriplasmin has not been shown
to alter the biomechanical properties of the human inner limiting membrane
by atomic force microscopy, and there is no evidence to suggest any
enzymatic effect on basement membranes (113). Adverse effects of
intravitreal ocriplasmin are almost exclusively transient with recovered visual
acuity. Known complications include subfoveal lucency, ellipsoid zone
disruption, and full-thickness macular hole base enlargement (106). Of these,
only the latter two have been linked to visual decline. Other adverse effects
that are possibly related include acute reduction in visual acuity, ERG
changes, dyschromatopsia, retinal tear or detachment, lens subluxation or
phacodonesis, abnormal pupillary reflex, retinal vascular changes, and OCT
ellipsoid zone alterations (114). In one recently reported case of ocriplasmin-
induced PVD, the patient experienced new clinically significant floaters and
acutely reduced contrast sensitivity function, both of which resolved with
limited vitrectomy (115).
Although most of the reported cases of ocriplasmin-induced acute visual
dysfunction are transient, some patients may not achieve complete resolution
(116–118). According to a report cited in an FDA Advisory Committee
briefing document, nine patients experienced a drastic and abrupt visual
acuity impairment as well as dyschromatopsia and electroretinographic
changes; however, most of those patients had fully recovered vision after a
median time of 2 weeks (118). It has been proposed that the mechanism for
these changes may involve transient traction during vitreomacular separation.
Moreover, a retrospective case series by Singh et al. that analyzed anatomic
visual outcomes of patients treated with ocriplasmin found that the mean time
to ellipsoid loss and the time to return of the ellipsoid zone was 5 days and
29.3 days, respectively, and all of the patients’ inner and outer segment
structures fully recovered (119,120).
In a postapproval retrospective review conducted by the American
Society of Retina Specialists Therapeutic Surveillance Committee, aggregate
data through July 16, 2013, were analyzed to characterize adverse events
associated with ocriplasmin for symptomatic vitreomacular adhesion, and
with each of those adverse events, postapproval safety data were compared to
that of preapproval studies. The study included 999 preapproval injections
and 4,387 postapproval injections. The categories of adverse events included
acute reduction in visual acuity attributable to either worsening of macular
pathology or development of subretinal fluid, electroretinogram changes,
dyschromatopsia, retinal tears and detachments, lens subluxation or
phacodonesis, impaired pupillary reflex, and retinal vessel findings. Ellipsoid
zone findings on OCT were only noted in postapproval data. The study found
that adverse events were typically transient with similar incidences in the pre-
and postapproval groups, though the committee warns of potential
underreporting of postapproval adverse effects (121).
OASIS (122,123) is a 2-year, phase IIIb study of 220 patients that
employed ERG and microperimetry to evaluate untoward effects on visual
function and retinal electrophysiology. All participants underwent spectral-
domain OCT (SD-OCT) imaging, allowing for prospective evaluation of
structural effects. The results showed significant resolution of vitreomacular
adhesion at day 28 in the ocriplasmin group compared to the sham group
(41.7% vs. 6.2%, respectively). In the group treated with ocriplasmin,
presence of focal vitreomacular adhesion or full-thickness macular hole,
absence of premacular membrane with pucker, and pseudophakia were
associated with increased likelihood of successful release of vitreomacular
adhesion. This trial found ocriplasmin to be both safe and effective for long-
term resolution of symptomatic vitreomacular adhesion with improved
outcomes, and no new safety signals were identified when compared to
previous phase 3 trials. The effect of ocriplasmin treatment at 6 months was
sustained at 12 and 24 months.
ORBIT and INJECT are prospective, multicenter studies that will provide
safety and efficacy data for ocriplasmin use in routine clinical settings (124).
They will survey the type, frequency, severity, and treatment relationship of
adverse events during the 12-month study period, mean changes in BCVA,
anatomic changes detected by SD-OCT, and the incidence of vitrectomy or
other ocular procedures. In a preliminary report outlining demographic data
collected over the first 6 months of the ORBIT study, preinjection ocular
symptoms were noted in >3% of study participants, including decreased
visual acuity, metamorphopsia, floaters, central visual field defect/central
black spot, difficulty reading at close distance, photopsia, and eye pain/ocular
discomfort (125).
In a multicenter, retrospective study of persistent macular hole after
ocriplasmin injection that underwent vitrectomy, there were no functional or
anatomical differences when compared to eyes with persistent macular hole
without preoperative pharmacologic vitreolysis (126).
OZONE (127) is a retrospective, postapproval review of 200 patients
treated with ocriplasmin for vitreomacular adhesion imaged with SD-OCT.
This study will collect data on clinical characteristics, the treatment course,
and anatomic changes over the initial 6 months posttreatment with the aim of
characterizing anatomic and symptomatic outcomes after ocriplasmin
injection, including ellipsoid zone changes, subretinal fluid, dyschromatopsia,
electroretinographic changes, and vascular changes.
ACKNOWLEDGMENTS
Sam Asanad of UCLA provided excellent assistance with the biochemistry
section.
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5
Retinal Vascular Development
Michelle E. LeBlanc, Jinling Yang, and Patricia A. D’Amore
The Fovea
One of the unique features of primate retina is the fovea, a structural
depression in the retina temporal to the optic disc (10,11). Although the fovea
begins to form at 22 WG, this structure is not complete until 15 to 45 months
postpartum (12). The fovea is composed of high-density cone photoreceptors
and is specialized for high-resolution vision. In addition, the retinal
vasculature is absent from this specialized area so that there are no vascular
structures present to deflect light and no blood cells moving across the fine
grain foveal cone mosaic. During retinal vascular development, radially
growing vessels appear to avoid this area, also termed as FAZ (10,11). The
avascular properties of the FAZ are attributed to high levels of antiangiogenic
factors including pigment epithelium-derived factor (PEDF) and brain
natriuretic peptide precursor B (NPPB) (13,14). The FAZ forms a complete
circle and measures 500 μm at 35 WG; however, this size is reduced to 170
μm at 37 to 41 WG (15) (see also Chapter 7).
Because this entire process can be visualized using flat mounts, the mouse is
frequently employed for the study of the cellular and molecular regulation of
retinal vascularization. The postnatal vascularization of the mouse retina has
also led to the development of a widely used model of oxygen-induced
neovascularization, with aspects that are reminiscent of the retinopathy of
prematurity as well as proliferative diabetic retinopathy.
Mfsd2a
Mfsd2a regulates transcytosis during the BRB formation. Mfsd2a−/− mice
showed an increase in HRP-filled vesicles without a change in vessel
permeability, implicating a role for Mfsd2a in suppressing transcytosis.
Accordingly, Mfsd2a was expressed in proximal vessels with intact tight
junctions but not distal leaky vessels, while at the same time, claudin-5 a tight
junction protein was expressed in the distal vessels. Mfsd2a localization and
phenotype observed in Mfsd2a−/− mice suggest a role for this protein in
regulating the formation of endothelial transcytosis and thus a functional
BRB (20).
PDGF-B
It has been shown that pericyte-EC interactions and PDGF-B/PDGFRB
signaling was not essential for BRB integrity in quiescent adult ECs but was
required for the formation of the BRB in retinal development (22).
Retinoic Acid
Retinoic acid (RA) is a metabolite of vitamin A that binds to the CRALBP-2
and signals through 3 nuclear RA receptors and scaffolding retinoid X
receptors. RA is essential for BRB development and maintenance; inhibition
of RA synthesis and RA binding to its receptor resulted in the breakdown of
the BRB in zebrafish larvae and adults (21). It remains unclear if RA acts
directly on ECs to regulate BRB or acts indirectly through neighboring
neuronal cells (21). RA is synthetized through aldehyde dehydrogenase 1
family member A1 (Aldh1a1). Studies have shown that loss of Aldh1a1
results in decreased choroid vasculature due to lower VEGF levels and
decreased Sox9 expression. The effects of Aldh1a1 could be rescued by
overexpression of RA, confirming that the reduction in vasculature and
decreased VEGF levels were due to lower levels of RA. RA synthesized by
Aldh1a1 in the neuronal retina stimulates the RPE to secrete VEGF. This
links RA levels with VEGF expression and proper vessel development (46).
Pericytes
Following the formation of the early capillary plexus by the endothelium,
mural cells are recruited and mediate the process of vessel maturation. Mural
cells, the collective term for smooth muscle cells and pericytes, surround and
enclose the newly formed vessels. Mural cells associated with arterioles and
venules have a higher expression of α-smooth muscle actin than pericytes and
enable the contractile feature of those cells. Pericytes, the mural cells that are
associated with capillaries, express lower levels of α-smooth muscle actin,
but higher desmin (an intermediate filament protein) than smooth muscle
cells. However, their abluminal location on the vessel wall is consistent with
a role for the pericyte in regulating blood flow (6,47).
In addition to regulating blood flow, mural cells maintain endothelial cell
quiescence by inhibiting their proliferation and migration and facilitating
formation of tight junctions between endothelial cells (11,48–50). At the
front of newly forming capillary beds, mural cell investment is low, leaving
those endothelial cells vulnerable to regression, growth factor stimulation,
and remodeling (6). Moreover, loss of pericytes leads to instability of mature
vessels (51,52). Retinal capillaries have higher pericyte coverage than brain
capillaries, suggesting stricter regulation of the retinal vasculature compared
to brain capillaries (53).
Astrocytes
In the retina, there are two types of neuroglia cells: astrocytes and Müller
cells. The association of neuroglia cells with retinal vascular development has
been extensively studied. In humans, staining of the developing retina for
GFAP reveals a population of cells extending toward peripheral avascular
areas several hundred microns ahead of the vascular front. Those astrocytes
proliferate and migrate from the optic nerve, lie in front of the developing
primary vascular plexus, and act as a template for retinal vessel growth (8). In
the mouse retina, astrocyte precursors migrate from the optic nerve head and
distribute in the retinal whole mount before retinal vascular development, but
in human, they migrate into the retina during retinal vascular development
(8,18). As the retinal vessels begin to develop, they differentiate radially from
optic nerve to the periphery through retinal ganglion cell–derived PDGFα and
guide vessel growth (54). A scaffold of astrocytes with low GFAP expression
lies under the mature retinal vessels and is thought to facilitate the formation
of endothelial tight junction (55–57).
During mouse vascular development, astrocytes guide the growth of
VEGFR2+ endothelial tip and stalk cells through secretion of a tightly
regulated VEGF gradient (58). Interestingly, pharmacological or genetic
depletion of astrocytes does not cause abnormal vessel growth into the
neuroretina, suggesting an alternative mechanism for directing retinal vessel
growth away from the neuroretina (54,59). Recent work has shown that
neuronal expression of VEGFR2 is higher than receptor expression on ECs.
These high levels of VEGFR2 serve to bind and endocytose VEGF ligand,
thus limiting its availability to the vasculature. In this way, neurons titrate
VEGF expression in the retina during development (16).
Similar to the absence of retinal vasculature in the FAZ, there is also no
astrocyte invasion into this area during development, further supporting the
critical role of astrocytes in retinal vascular development (8). Müller cells are
located in the INL and guide the formation and maturation of the deeper
vessel layers (60).
Microglia
Microglia migrate into the retina along with the developing vessels but are
positioned behind the vascular front in human retina at approximately 14 WG
(56). Distinct from the subpopulation of microglial cells that invade the retina
before vascular development around 10 WG, these cells express the
macrophage marker S22, in addition to microglial markers CD45, MHC I,
and II and remain in close contact with vessels during development as well as
after they have matured. In spite of the documentation of their presence, little
is known about the role that microglia might play in vascular development
(61,62). Disruption of SDF-1/CXCR4 signaling during murine retinal
vascularization resulted in a reduced number of microglia along with
impaired tip cell development, leading the authors to speculate regarding a
role for microglia in tip cell activation (63). Induction of systemic
inflammation in P4 mouse pups by lipopolysaccharide (LPS) led to a
significant increase in retinal vascular density that was preceded by elevated
numbers of microglia in the RLC and OPL layers (64). In adulthood, the
retinas of these exhibited decreased vascular density and impaired retinal
function.
Hypoxia-Inducible Factor-2
It is well established that HIF-1α modulates hypoxia through maintenance of
VEGF gradients in the developing vasculature (77). However, less is known
regarding the role of hypoxia-mediated HIF-2α in vascular development.
Recent work has shown that deleting HIF-2α in murine neuroprogenitor cells
leads to a decreased number of arteries and veins as well as reduced density
of the deep vascular plexus in the periphery. These findings coincided with a
reduction in proangiogenic VEGF and erythropoietin expression, and an
increase in antiangiogenic endostatin levels. Given that HIF-2α is localized
exclusively to the neuroprogenitor cells, these findings demonstrate cross-talk
between neuroprogenitors and vascular development, through oxygen-
dependent up-regulation of HIF-2α (65).
VEGF Accessibility
In addition to the regulation of VEGF at the level of its expression, the
distribution of VEGF through its binding to heparan sulfate plays a critical
role in vessel growth and patterning. Alternative splicing of VEGF-A mRNA
gives rise to several variants that have different heparan sulfate–binding
capabilities with the major isoforms being VEGF120, VEGF164, and
VEGF188 in mouse and VEGF121, VEGF165, and VEGF189 in human (79).
VEGF120, lacking two highly charged domains, is the shortest isoform
and most soluble, whereas VEGF188 has the strongest binding ability and
VEGF164 is intermediate. Transgenic mice engineered to express only
VEGF120 isoform exhibit severe defects in vascular outgrowth and
patterning, whereas VEGF188 mice have normal venular outgrowth but
impaired arterial development. However, mice expressing only VEGF164
have normal retinal vascular development (84,85).
Notch Signaling
Endothelial cells at the front of developing vasculature are divided into tip
and stalk cells. Although these two populations of cells are virtually adjacent
to one another, they are very different morphologically and display distinct
responses to VEGF. Tip cells are, as the name suggests, at the front of the
growing vessel, they rarely divide, and are characterized by their long and
dynamic protrusions, named filopodia, that survey directional cues from
surrounding environment. On the other hand, stalk cells have fewer filopodia,
proliferate, and form lumens. A body of recent work has documented the role
of Notch signaling in coordinating VEGF signaling to specify the cell fate of
tip and stalk cells (59).
Notch is an evolutionary-conserved pathway that is involved in
embryonic development, regulating cell fate determination, tissue patterning,
and morphogenesis by mediating communication between neighboring cells.
Members of the Notch family are cell surface receptors on signal-receiving
cells, heterodimers of extracellular domain, and membrane-bound
intracellular domain. Upon binding with its ligands of the Jagged/Delta
family from the neighboring cell, the Notch intracellular domain (NICD) is
released by ADAM and γ-secretase and translocated into the nucleus where it
regulates gene expression. The extracellular domain of Notch that is bound to
the ligand on the surface of neighboring cells is transendocytosed by the
ligand-expressing cells.
At the growing front of developing vessels, Delta-like 4 (Dll4)/Notch1
pathway is involved in tip and stalk cells specification. Cells with higher
levels of Dll4 act as signal-sending cells. Binding to Notch1 receptor on the
neighboring cells results into Notch-dependent regulation of gene expression,
particularly down-regulation of VEGFR2 and Dll4 and up-regulation of
VEGFR1, the decoy receptor for VEGF. Thus, the neighboring cell, with a
reduced response to VEGF, acquires stalk cell fate, while Dll4-expressing
cells preserve its tip cell fate. During vessel formation, cell fate of tip cells
and stalk cells is dynamic and constantly changing as a function of the
Dll4/Notch ratio between a cell and its neighbor (90,91). Recent studies have
identified the transcription factor Krüppel-like factor 4 (KLF4) is upstream of
Notch; endothelial-specific overexpression of KLF4 resulted in increases in
vessel density, branching, and number of tip cells at P6 that, interestingly,
remodels during the subsequent day to a normal morphology in the adult
(92).
Vascular Remodeling
Remodeling is critical to the establishment of a mature, stable vasculature.
Blood vessels are either formed de novo as a tube, such as the aorta, or as a
primitive plexus, as is the case for the majority of retinal vascularization. In
either circumstance, the vessel is subsequently remodeled to form the final
vascular structure by the addition of wall cells (smooth muscle in larger
vessels and pericytes in the microvasculature—collectively referred to as
mural cells), deposition of a basement membrane, and for larger vessels, the
addition of the adventitia (consisting of fibroblasts and their associated
connective tissues). In addition to the growth factors discussed below,
vitamin D has been shown to contribute to vascular stability. Mice with
global deletion of the vitamin D receptor displayed normal vascular
development but exhibited an increase in the density of both pericytes and
endothelial cells in P42 vitamin D receptor–deficient mice (93).
Platelet-Derived Growth Factor (PDGF B) Signaling
Proliferating endothelial cells secrete PDGF B, which has been shown in
tissue culture studies to act as a chemoattractant and mitogen for mural cells
and their precursors (94,95). Consistent with these findings, mice that are
deficient of PDGF B have reduced numbers of smooth muscle cells in their
arteries and a paucity of pericytes in their microvascular bed (96).
Angiopoitein-1/Tie-2 Signaling
In addition to VEGFR2, a receptor tyrosine kinase, as a master regulator of
angiogenesis, Tie-2 belongs to another class of receptor tyrosine kinases and
is critical for vascular development. Tie-2 was cloned and characterized as a
type I transmembrane protein including intracellular tyrosine kinase domain,
transmembrane domain, three fibronectin type III repeats, and two
immunoglobulin-like loop domains flanking three epidermal growth factor
repeats (103). Angiopoitein-1 and 2 (Ang-1 and Ang-2) were identified as the
endogenous agonist and antagonist, respectively, for Tie-2 (104,105). Tie-2 is
abundantly expressed by endothelial cells in developing vasculature but
lower in the adult vascular system (103,106). Ang1 appears to be expressed
mainly by perivascular and mural cells (107,108). Although the binding of
Ang-1 and Tie-2 leads to tyrosine phosphorylation of Tie-2, it does not
promote the growth of cultured endothelial cells (104). Ang-1 is primarily
expressed following or in immediate vicinity with developing vessel, while
Ang-2 is abundantly expressed at the front of invading vessels, suggesting
Ang-1 is mediating vessel maturation, remodeling, and stabilization, while
Ang-2 is cooperating with VEGF signaling for angiogenesis (105). Gene
deletion studies on Ang-1 and Tie-2 also suggest that they are required for
normal interactions between perivascular cells and endothelial cells
(108–110).
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6
Human Choriocapillaris Development
Gerard A. Lutty and D. Scott McLeod
INTRODUCTION
The human choroid forms the posterior portion of the uveal tract (the iris,
ciliary body, and choroid). The choroid is a thin, pigmented, and highly
vascularized tissue that lies beneath the sensory retina. The outer boundary of
the choroid is the lamina fusca and the inner boundary is Bruch membrane
(BrM), a pentalaminar structure upon which the single layer of retinal
pigment epithelium (RPE) sits. The adult choroidal vasculature has three
layers: the outermost Haller layer with large vessels; Sattler layer of
intermediate vessels in the middle; and the innermost layer being
choriocapillaris (CC), which is composed of broad capillaries with flat
lumens (20 to 50 mm diameter). The CC lies immediately adjacent and
posterior to Bruch membrane. The CC has a lobular pattern and is arranged in
a single layer restricted to the inner portion of the choroid. Feeding arterioles
and draining venules enter at right angles from Sattler layer in the posterior
pole. The choroidal vascular plexus in the periphery and equatorial areas of
choroid have arterioles and veins in the same plane as the CC, and the CC is
in a ladder-like arrangement. The choroidal vasculature is positioned between
two pigmented cell types, outer choroidal melanocytes of neural crest origin
and apical RPE of neuroepithelial origin. The basement membrane of the
adult CC constitutes the most posterior layer of BrM, and the endothelial
cells are fenestrated mostly on the retinal side. Fenestrated endothelium
usually is involved in secretion and/or filtration, for example, kidney
glomerulus. The CC is also sided in terms of receptor expression: VEGF
receptors 1, 2, and 3 (VEGF-R1, R2, R3) are most prominent on the retinal
side of the CC lumens (1). Vascular endothelial growth factor (VEGF)
appears to be secreted from the basal side of the RPE, which probably is
necessary for maintenance of the CC fenestrations (1) and for its survival
(2,3). CC is also one of the few capillary systems in which the endothelial
cells constitutively express ICAM-1 (4).
The adult CC transports nutrients and oxygen to the RPE and
photoreceptors (PRs) and removes waste from the RPE. The CC provides all
of the metabolic requirements for the PRs from serum components to 90% of
the O2 consumed by the PR in darkness (5). The PRs consume more oxygen
per gram of tissue weight than does any cell in the body. The tissue oxygen
level at the inner segments is near zero in the dark (5). Therefore, disruption
in choroidal blood flow would be detrimental to PR function and/or survival.
Abnormalities in the choroidal vasculature result in several congenital and
adult diseases, like choroidal coloboma and age-related macular degeneration
(AMD) (6–8).
This review summarizes our studies on the development of the human
CC from 5.5 until 22 weeks’ gestation (WG). The CC is a primitive vascular
system at 5.5 WG and will have almost an adult morphology by 22 WG.
9 to 12 Weeks’ Gestation
Between 9 and 12 WG, development of intermediate and deeper choroidal
vessels was observed in choroidal stroma. This development was more
advanced in the posterior pole than in the equatorial choroid, suggesting it
started in the posterior pole (11). The forming vessels expressed EC markers
including CD31, CD34, and CD39. Proliferation was observed in some ECs
that were budding from the scleral side of the CC using CD34 and Ki67
double labeling, suggesting that intermediate vessels form by angiogenesis
(9). A rather linear pattern was observed in flat CD39-labeled preparations of
choroid (Figure 6-3B) at 9 WG and then a chicken wire–like pattern of
vessels with a few free CD39-positive cells between the vascular segments at
12 WG (9). This suggested that some angioblasts were still present in the
choroid (10) at 12 WG; however, the pattern of CC was approaching an
adult-like lobular pattern but the density of 12 WG CC was much less than
the adult CC (16).
Adult CC is fenestrated mostly on the retinal side of the CC lumens, so
we investigated the presence and position of fenestrations and their
components at different ages. PV-1, also called PLVAP (plasmalemmal
vesicle–associated protein), is an integral membrane glycoprotein in the
diaphragms of fenestrations (23,24). All vessels were negative for PV-1 at
and before 12 WG. Occasional fenestrations were observed with TEM, but
they were associated with filipodial-like structures both in and around the
lumens (11). Because of their unusual position, these fenestrations were
probably not functional.
We and Sellheyer and Spitznas observed that the CC at 9 WG was
composed of aggregates of progenitor cells with only slit-like lumens (13).
We observed some cells adventitial to cells lining the primitive lumens, but
the two cell types were indistinguishable in ultrastructural appearance in
periphery (11). Some plump progenitor cells that bordered on the lumens had
tight junctions. Some Weibel-Palade bodies, organelles found only in
vascular endothelial cells, were present as well. Central choroid (area from
disc to equator) had more definitive pericyte-like cells on the more developed
vessels (11). Pericytes had a nuclear organization that appeared distinct from
the endothelial cells on the lumens of more mature central blood vessels.
Complex membranous infoldings that resembled filopodial processes
extended into the slit-like lumens from the lumenal cells. At the equator,
some lumens were more open and the filopodia appeared to touch
erythrocytes in the lumen; the plasma membranes of the two cells could not
be discerned. Basal lamina was not observed around these developing vessels
(11).
14 to 16 Weeks’ Gestation
At 14 WG, pericyte-like cells, progenitors in the ablumenal position, formed
peg-in-socket-like contacts with endothelial cells lining the lumen, a
characteristic of normal adult microvasculature (11). Maturation of these
ablumenal cells was evaluated by localizing two pericyte markers: NG-2, a
glycosaminoglycan present on the surface of pericytes, and alpha smooth
muscle actin (aSMA), present in mature pericytes and smooth muscle cells
(SMC). NG2 immunoreactivity was very prominent at 14 WG, but there was
limited aSMA immunoreactivity.
PV-1 was present at low levels in some areas of CC at 16 WG,
suggesting the presence of some fenestrations. This was confirmed with
TEM, which showed a few fenestrations in the CC, but these were not
continuous in the thin endothelial cell processes on the retinal side of the
lumens (Figure 6-5). The CC in the posterior pole had the most fenestrations
compared to peripheral regions and was most mature morphologically. In the
broader lumens at 14 WG, the number of filopodia in lumens appeared
greatly reduced compared to 11 WG (Figure 6-5C). EC nuclei had less dense
chromatin and were more oval and uniform in shape and BrM organization
was more advanced. The CC and intermediate choroidal vessels, which were
more abundant at 14 WG, had intense APase and prominent CA IV and
eNOS immunoreactivity.
21 to 22 Weeks’ Gestation
Three layers of blood vessels, as demonstrated with EC markers, were
apparent at 21 WG within the posterior pole (Figure 6-4C). Short
rudimentary inner segments were present at the outer most portion of the
neuroblastic layer, providing the first evidence of PR maturation (11). PV-1
immunoreactivity was present in most of the CC, but it was more intense in
the posterior pole than in the periphery. However, PV-1 was uniformly
intense and more apparent on the retinal side of the CC lumens in the adult
human eye used as a positive control (11). eNOS was prominent in EC
cytoplasm and cell membrane of all choroidal blood vessels. nNOS was
mostly nuclear in both pericytes and SMC labeled with αSMA as well as in
ECs, which were double labeled with von Willebrand factor (vWf) (Figure 6-
6) (20).
CC endothelial cells were thin and fusiform ultrastructurally at 22 WG.
The CC had contiguous areas of fenestrations in the narrow endothelial
processes on the retinal side of the broad lumens (Figure 6-5D). Endothelial
cells had well-formed tight junctions, Weibel-Palade body numbers had
increased, and a continuous basement membrane was present. Collagen and
elastin was clearly deposited in BrM under the RPE basement membrane.
αSMA+ cells were present in the CC, as well as intermediate and large
choroidal blood vessels at 22 WG. Pericytes were apparent by TEM at this
age (Figure 6-5D), NG2 was very prominent, and the pericytes were located
primarily on the scleral side of the CC.
aData from Baba T, Grebe R, Hasegawa T, et al. Maturation of the fetal human choriocapillaris. Invest
Ophthalmol Vis Sci 2009;50(7):3503–3511.
bData from Hasegawa T, McLeod DS, Bhutto IA, et al. The embryonic human choriocapillaris
develops by hemo-vasculogenesis. Dev Dyn 2007;236:2089–2100.
cData from McLeod D, Baba T, Bhutto I, et al. Co-expression of endothelial and neuronal nitric oxide
synthases in the developing vasculatures of the human fetal eye. Graefes Arch Clin Exp Ophthalmol
2012;250(6):839–848.
dData from Baba T, McLeod DM, Edwards MM, et al. VEGF165b in the developing vasculatures of
the fetal human eye. Dev Dyn 2012;241:595–607.
WG, weeks of gestation; Hemo-vas, Hemo-vasculogenesis; TEM, Transmission electron microscopy;
SMA, smooth muscle actin; CAIV, carbonic anhydrase IV; APase, alkaline phosphatase; eNOS,
endothelial nitric oxide synthase; nNOS, neuronal NOS; VEGF, vascular endothelial growth factor.
ACKNOWLEDGMENTS
Grant support: NIH grants EY016151 (GL), EY01765 (Wilmer); RPB
unrestricted funds (Wilmer), the Altsheler-Durell Foundation; and a gift from
the Himmelfarb Family Foundation in the name of Morton F. Goldberg.
Gerard Lutty is an RPB Senior Investigator. The authors acknowledge the
excellent electron microscopy of Rhonda Grebe, and confocal microscopy of
Takuya Hasegawa and Takayuki Baba. Takuya Hasegawa and Takayuki
Baba were Bausch and Lomb Japan Vitreoretinal Research Fellows, and
Takayuki Baba was also a Uehara Memorial Foundation Research Fellow.
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7
Development of Cone Photoreceptors
and the Fovea Centralis and the
Impact of Prematurity
Jan M. Provis and Michele C. Madigan
The first cells to exit the mitotic cycle in the developing human retina are the
foveal cone photoreceptors. Although the genes responsible for specification
of the location of the fovea in the early eyecup have not been identified,
histologic studies show that cone photoreceptors prevail in this “central”
region of the retina from around 10 to 12 weeks of gestation (WG) (1,2).
Very few rods are ever seen at this highly specialized part of the
photoreceptor mosaic (3–5), which we subsequently refer to as the “foveal
cone mosaic.” While the foveal cone mosaic differentiates early, the foveal
depression is not discernable until many weeks later—at approximately 26 to
28 WG (6–9). We also now know that formation of a fovea is critically
dependent upon development of the retinal capillary network in the future
macular region and definition of a foveal avascular zone (FAZ) (10,11). With
the advent of advanced imaging technologies, particularly optical coherence
tomography (OCT), it is possible to track foveal development longitudinally;
this approach is proving its utility in understanding how the fovea is affected
by prematurity and why individuals born prematurely may experience
uncorrectable vision loss (12,13).
DIFFERENTIATION OF CONES—
NORMAL DEVELOPMENT
The maturation of the cone photoreceptor population during intrauterine and
early postnatal development follows a rather surprising trajectory. That is,
even though foveal cone photoreceptors are the first cells to differentiate in
the retina, they are the last to achieve the adult-like characteristics of foveal
cones. This oddity in maturation of foveal cones has been known of for at
least a century (6) but is now achieving clinical significance, since the
delayed maturation of the fovea is now widely recognized as a feature that
distinguishes OCT images from adult and neonatal maculae (30–33). The
differences between foveal cones and those on the foveal rim are illustrated at
mid-gestation (20 WG) and full term (40 WG) in Figure 7-2. At 20 WG,
cones in the foveal cone mosaic (“fovea”) are similar in size and appearance
to their neighbors on the foveal rim, which are interspersed with rods. At 40
WG, cones in the central fovea are only a little more differentiated and
slightly taller than at 20 WG. In contrast, cones on the rim of the fovea at 40
WG are highly differentiated and significantly narrower and taller than those
on the rim at 20 WG as well as those within the fovea at 40 WG.
FIGURE 7-2 Cones from within the fovea, and from the
foveal rim, drawn to scale at mid-gestation (20 WG) and at
full term (40 WG). At 20 WG cones are cuboidal cells
apposed to the RPE layer. They have no axonal process,
and the inner and outer segments are undifferentiated, as
seen by light microscopy. Cones on the foveal rim at 20
WG are beginning to elaborate axonal processes, and
differentiation of the inner and outer segments is slightly
more advanced. At 40 WG, cones on the foveal rim are
adult-like, having distinct axonal processes that are
sandwiched by rod somas as well as distinct inner and
outer segments. However, in the fovea at 40 WG, cones
are relatively unchanged since mid-gestation; inner and
outer segments are becoming evident, and the axonal
processes are beginning to narrow. However, overall, they
are only slightly taller than cones at 20 WG and
significantly shorter than those on the foveal rim, at birth.
(Drawings in Figure 2 are by Renee Argaet.)
Thus the fovea is immature at full-term birth in that first, the outer nuclear
layer (ONL) of the fovea at full term comprises cone photoreceptors of a very
immature morphology, which are not stacked into tiers of cells (as in the
adult fovea); rather, they remain in a monolayer of cuboidal cells and are
little changed in shape or size since mid-gestation. Second (as we will see
below), at full term, the fovea still includes cells in the ganglion cell and
inner nuclear layers.
The cellular mechanisms that mediate morphologic transformation of
cones are not clearly understood. It is known that aggregation and elongation
of photoreceptors in central retina is common among primates, even in those
species that do not have a fovea (34). Narrowing and elongation of cones is
the key mechanism that mediates the accumulation of cones in the fovea and
adjacent macula (35), a process commonly referred to as “cone packing.” By
becoming narrower and more elongated, cones can be packed tightly together
in a space-efficient hexagonal pattern, allowing more cones to be
accommodated per unit area in the foveal cone mosaic, while the cell–cell
relationships that were established early in development are preserved. Thus
changes in cell shape mediate cone packing. Fibroblast growth factor (FGF)
2 signaling via FGF receptors, which are differentially distributed across the
soma, axon, and inner and outer segments of cones during development has a
role in mediating the changes in cell shape which favor cone packing (36,37).
Establishment of a high density of cones in the foveal cone mosaic is the
anatomical basis of high acuity vision, and visual acuity is directly
proportional to the packing density of cones within the foveal cone mosaic.
Developmentally (and evolutionarily), there is a drive toward increased
cone density retina in the foveal cone mosaic. The spatial density of cones in
the foveal cone mosaic increases from around 10 K/mm2 to approximately 30
K/mm2 during intrauterine life (2,35), without newly generated cells being
added to the mosaic. This increase in cone density would be seen to be even
greater if cone density in the parafovea (rather than fovea) was compared
over time, since it is now understood that maturation (narrowing and
elongation) of cones in the fovea, and hence their packing, is delayed until
the postnatal period, while cones adjacent to the fovea achieve adult-like
features prenatally (7,36,38–40).
The spatiotemporal pattern of cone packing over time can be observed in
flat-mounted retinas, using the population of cones sensitive to blue/short-
wavelength light (S-cones) as a population “marker.” S-cones constitute
approximately 6.8% of the cone population within 4 mm of the foveal center
(41). They can be identified in postmortem retinas using an antibody against
the short wavelength–sensitive opsin contained in the outer segments of
mature photoreceptors and also present in the cell bodies of developing S-
cones (4). In Figure 7-3, the spatial density of S-cones along the horizontal
meridian of the retina between the fovea and optic disc is shown at three
different ages—18 WG, 6 weeks postnatal (P 6 weeks), and in the adult (data
from (42)). The graphs show that S-cone density just outside the central fovea
(at ~15% of the fovea-to-optic disc (OD) distance, or ~500 μm eccentricity)
increases between 18 WG (pale blue line) and adulthood (black line), while
S-cone density near the optic disc is significantly reduced over the same
period. The graphs indicate that high cone density near the fovea, and in the
macula in general, is achieved by mass displacement of cones from more
eccentric locations (centripetal displacement, indicated by the arrow), since
there is no detectable cell death during this period, and no photoreceptors are
added to the mosaic (4). Note that the S-cone population cannot be used to
indicate changes in total photoreceptor density closer than approximately 1
mm from the foveal center, because S-cones are absent from the fovea in
adults and throughout development.
FIGURE 7-3 Graphs illustrating the change in distribution
of cones in the fovea-to-optic disc region, between 18 WG
and adulthood. The population of cones sensitive to blue
light (short-wavelength–sensitive or S-cones) has been
used as a marker population, representing approximately
6.8% of the total cone population. Also note that because
S-cones are absent from the fovea, numbers in the 10%
closest to the fovea (left side of the figure) are not
indicative of the total cone population. No photoreceptors
are added to the mosaic in this region after approximately
18 WG, and there is negligible cell death. The graphs
show that early in development, cones are more numerous
near the disc than near the fovea; but during in utero
development, there is mass displacement of cones toward
the fovea (indicated by the arrow). This displacement
continues for some months, postnatal. Thus the
mechanisms that affect displacement of cones toward the
fovea act over quite long distances—at least up to
approximately 3 mm. (Reprinted from Cornish E,
Hendrickson A, Provis J. Distribution of short wavelength
sensitive cones in human fetal and postnatal retina: early
development of spatial order and density profiles. Vision
Res 2004;44(17):2019–2026. Copyright © 2004 Elsevier.
With permission.)
ACKNOWLEDGMENTS
Figure 7-1 is from a retina labeled by Anita Hendrickson, imaged by JP.
Drawings in Figure 7-2 are by Renee Argaet. The OCT image in Figure 7-4
was kindly provided by Adam Dubis and Joe Carroll. Thanks to all those who
have donated fetal tissue for study.
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8
Retinal Development
Thomas A. Reh and Anna La Torre
During the past few decades, the breadth of knowledge in the field of retinal
development has expanded dramatically. In this chapter, we attempt to
provide an overview of some of the main features of retinal development,
both classic and recent, but a comprehensive review of this rapidly growing
field is not possible in a single chapter. The reader is, therefore, referred to a
number of excellent review articles that cover specific areas in more detail. In
addition, in this volume, there are several other reviews that contain relevant
and complementary information about other aspects of eye development.
The progenitor cells of the retina are for the most part able to generate all the
different types of cells and, therefore, have been called multipotent
progenitors (27,28). The multipotential nature of these cells has been
demonstrated by tracking the lineages of individual cells, after infection of
progenitors with a retrovirus containing a reporter gene (27,28) or following
injection of the cells with a permanent dye (29,30). More recently, it has been
possible to track the lineages of progenitors that express specific transcription
factors using inducible Cre-recombinase methods (31,32). These studies have
shown that progenitors can produce multiple different types of retinal
neurons and Müller glia up to their last cell division; however, there do
appear to be at least three distinct types of progenitors in the mouse: (a)
progenitors that express Ascl1 can produce moderate-sized clones with all
types of retinal neurons, except ganglion cells (Figure 8-3); (b) Neurog2-
expressing progenitor cells produce clones with no more than two cells. For
that reason, these progenitors are likely in their last cell division and in
contrast with Ascl1-expressing progenitors; Neurog2 cells can make ganglion
cells; and (c) true multipotent progenitor cells can make large clones
containing all cell types (31).
FIGURE 8-3 Tracking the lineages of retinal cells shows
that there are several types of multipotent progenitor cells
that underlie cellular diversity. The schematic diagram
shows examples of lineages of (1) a retinal progenitor that
expresses Ascl1 (green) that can produce a clone of cells
that include all cell types (HORizontal cells, CONes,
AMAcrine cells, BIPolar cells, ROD photoreceptor cells
and Müller glia), except ganglion cells, which are
produced by (2) an earlier progenitor (black) that is
competent to produce ganglion cells, and then produce an
Ascl1+ progenitor. The diagram also shows the results of
tracking the Neurog2-expressing progenitor lineage in red.
Neurog2 is expressed in both the Ascl1+ and Ascl1−
progenitors but only at the last division of the progenitor
cells. The panel on the right shows an example of a clone
containing rods (r), a bipolar cell (b), and an amacrine cell
(a) derived from the Ascl1 lineage.
The fact that the different types of retinal cells are generated in a sequence
has led to several hypotheses about the nature of the mechanisms that
underlie this phenomenon. One proposal is that each cell type induces the
progenitor cells to produce the cell type that follows in the sequence. In this
model, the first cell type generated by the progenitor cells, the retinal
ganglion cells, produces a signal to the progenitor cells to direct them to
begin producing horizontal cells, the next cell type in the sequence; the
horizontal cells in turn signal to the progenitors to instruct them to make cone
photoreceptors, and so on. In other words, this model proposes that
progenitors can be influenced by their surrounding microenvironment to form
the types of cells they produce. One of such factors is the signaling molecule
SHH, mentioned earlier in the chapter in the context of the eye field. SHH is
expressed by the retinal ganglion cells, regulates the rate of proliferation and
timing of cell cycle exit of the progenitor cells, and consequently determines
the number of ganglion cells in the retina (33). An alternative model to
explain the sequential production of the different retinal cell types proposes
that the progenitors undergo a progressive change in their “internal state,”
like a clock ticking through the different cell fates (34,35). In this model, the
progenitor cells progressively change in their competence to produce
different types of cells in a cell-autonomous manner; their initial state has a
bias for producing retinal ganglion cells, but after a day, some fraction of the
progenitor cells shift their competence to become biased to produce later cell
types, for example, horizontal cells, followed by cone photoreceptors, and so
on. Cell culture experiments provide support for this type of mechanism;
progenitor cells isolated from the early stages of retinal development
predominantly differentiate into early cell types (36), whereas culturing the
progenitor cells with retinal cells from later stages of development biases
them to adopt later cell identities (37–39). The molecular mechanism
underlying such a progressive shift in competence could be a cascade of
transcription factors, and Ikaros genes have been shown to be involved in this
process (40). Recent data have also implicated miRNAs in regulating the
developmental timing. Deletion of the DICER1 gene, which is necessary for
miRNA production as well as the inhibition of 3 miRNAs (Let-7, miR-9, and
miR-125b), leads to a failure in the progenitor cells to progress beyond the
early state, and they continue to generate early cell fates, like ganglion cells,
cones, and horizontal cells for the entire period of retinogenesis (Figure 8-4)
(41–43).
FIGURE 8-4 MicroRNAs are required during retinal
development to allow the progenitors to make late retinal
cell types. When the Dicer gene is knocked out in mouse
retinas, the progenitors overproduce the early-generated
ganglion cells (Brn3+) and do not progress to the state
where they can generate late cell fate types like rods,
bipolar cells, and Müller glia.
PHOTORECEPTOR DEVELOPMENT
The photoreceptors develop somewhat later than the ganglion cells in most
species and somewhat ahead of the bipolar cells and Müller glia. A few key
points of photoreceptor development are reviewed here. Our knowledge of
photoreceptor development comes from studies of a wide variety of
vertebrates from fish to humans, but studies of the rhesus monkey have been
particularly informative of events in human photoreceptor development.
Rhesus monkeys have a fovea similar to the human, whereas the mouse,
another model organism for retinal developmental studies, does not have a
fovea and has relatively fewer cones. Thymidine birthdating studies have
shown that foveal cones are born between gestational days E38 and E50 in
the monkey. Although the cone photoreceptors are produced by the
progenitor cells prior to the rod photoreceptors, rods express rhodopsin
before the cones express their characteristic opsins (93,94); the first foveal
cones are generated on fetal day 38 and do not express S-opsin until fetal day
75. The delay between birthdate and opsin expression occurs in other
vertebrates as well. This phenomenon suggests that the regulation of
specification to cone fate and the factors that regulate opsin expression are
distinct; data in mice support this idea.
As noted previously, retinal cells are arranged in mosaics that cover the
retinal surface like tiles. The mosaics of cone photoreceptors can reach a high
degree of order in some species with almost a crystalline array of the
different subtypes. The factors that control the formation of these mosaics are
still unknown, although some of the same types of CAMs important for inner
retinal neuron organization may also function in the formation of the cone
mosaics. In primates and mice, the first cone photoreceptors to express their
opsins are the S-opsin–expressing cones (93). S-opsin expression begins in
the central retina and sweeps to the periphery. After much of the retinal
surface contains S-opsin–expressing cones, the L-/M-opsin cones in the
central retina begin to express opsin (95) and also sweep from central to
peripheral retina following the S-opsin cones (96).
The molecular mechanisms that control the expression of opsins and
other aspects of photoreceptor differentiation are understood to some extent;
several different transcription factors play critical roles at each stage of
development. OTX2, a transcription factor described earlier in the context of
eye field formation, is expressed in photoreceptors very early in their
specification (48,49). Deletion of Otx2 in retinal progenitors in mice prevents
them from adopting the photoreceptor fate, and instead they develop into
amacrine cells. OTX2 then induces the expression of cone–rod homeobox
gene (CRX) in the early developing photoreceptors, which is required for the
expression of photoreceptor-specific genes, like the opsins (97). The
immature proto-photoreceptors are then specified to become either rods or
cones; if the cells express neural retina leucine (NRL) zipper transcription
factor, they differentiate as rods (51). Photoreceptors that do not express NRL
differentiate as cones; the specification of cone subtype is determined by two
additional transcription factors, thyroid hormone receptor-β2 (TRβ2) and
RXR-gamma (98,99). These transcription factors act as heterodimers (or
possibly homodimers) and promote M-opsin expression but inhibit S-opsin
expression. TRβ2 knockout mice do not have M-opsin–expressing cones but
only contain S-opsin cones (99). RXR-gamma knockout mice contain cones
that all express both M-opsin and S-opsin. In vitro studies have identified
several factors that regulate photoreceptor development. Most of the studies
have focused on rod photoreceptors. Rod photoreceptors do not develop well
in low-density cultures, but the addition of specific signaling molecules
promotes rhodopsin expression in vitro (14). These soluble signaling factors
can be used to promote photoreceptor development in embryonic stem cell–
derived retinal cells (100,101).
After the cones and rods have begun their differentiation, they begin to
form synapses with the horizontal cells and bipolar cells in the OPL. In the
monkey, for example, the first cones have begun to make synaptic
connections with bipolar cells in the OPL by E55, more than 2 weeks after
they had been generated. The molecules that regulate synapse formation
between the photoreceptors and their targets are not known, but there is
evidence that the dendrites in the OPL interact to define their receptive field
extent. The dendritic extent of horizontal cells is a function of the ratio of
rods to cones. Experimentally reducing cone number during retinal
development in mice increases the branching of horizontal cell dendrites.
Ribbon synapses, synaptic specializations involving rod and cone pedicles
with horizontal and bipolar cell dendrites, require normal activity in the cells:
If phototransduction is blocked in cones during the period of ribbon synapse
formation, the cone bipolar cells make synapses with rods instead of cones
(102). Conversely, inhibiting transmitter release from rods during this period
causes the rod bipolar cells and the horizontal cells to produce aberrant
processes that extend into the outer nuclear layer (ONL) and form synapses
with cones (103,104).
FOVEAL DEVELOPMENT
The differentiation of the fovea is among the last major events in retinal
development. The fovea, a small, avascular depression, contains only cone
photoreceptors and Müller glia. Foveal development in primates has been
extensively characterized (105–108). Initially, among the thickest regions of
the retina, the fovea becomes transformed into a pit or depression by cell
migration and deformation. Between the 24th and 26th fetal week in humans,
the ganglion cells begin to migrate away from the center of the fovea, and the
amacrine cells and bipolar cells follow. By the time the fovea forms, the
synapses have already been formed in the plexiform layers; therefore, since
the cone photoreceptors remain in the fovea while the inner retinal neurons
migrate away, the processes of the bipolar cells become extremely elongated.
At birth in humans, the GCL and INL constitute only a single layer of cells.
However, after birth, the inner retinal neurons continue to migrate radially
from the fovea and pile up around it, whereas the photoreceptors become
more concentrated and the ONL increases in thickness. By 4 years of age in
humans, there are six to seven layers of cone nuclei in the foveal ONL. The
molecular mechanisms that drive this very dramatic rearrangement of cells
are still unknown (see also Chapter 7).
CONCLUSIONS
The development of the retina is a remarkably complicated process, and
although quite a lot is known about the cellular and molecular events that
occur during histogenesis and early specification, there are many gaps in our
knowledge. In other aspects of development, like the formation of specific
connections among the retinal cells, very little is known. Nevertheless, there
has been amazing progress in the past 20 years, and the findings have had and
will continue to have an impact on our understanding of developmental
diseases of the eye. Moreover, technologies for producing retinal cells and
organized retinal tissue from human embryonic stem cells and induced
pluripotent stem cells combined with experimental animal studies of retinal
development have the potential to inform both normal retinal development
and developmental pathologies.
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SECTION II
Assessment and Rehabilitation of
Visual Function In Pediatric Retinal
Condition
9
Assessment of Vision and Retinal
Function in Infants and Children
Anne B. Fulton, Ronald M. Hansen, Bridget J. Peterson, Laura
Bagdonaite-Bejarano, and James D. Akula
Cpd, cycles per degree; Dec VA, decimal visual acuity; MAR, minimum angle of resolution; min arc,
minutes of arc.
DEVELOPMENT OF NORMAL
RETINAL FUNCTION
Noninvasive studies of normal retinal function have linked developmental
changes in function to molecular events in the retinal cells. In pediatric
patients, delineation of retinal activity, on the one hand, yields insights into
the action of protein products of genes and, on the other hand, may explain
visual behavior. Coupled with clinical examination, including
ophthalmoscopy, fundus photography, and retinal imaging, studies of
function help to secure diagnoses, delineate severity of disease, track the
course of retinal disease, and monitor the response to interventions.
Retinal function depends on the physical properties of the photoreceptors,
the retinal cells proximal to the photoreceptors, and the neural connections
among the cells. The properties of retinal cells change during postnatal
development. Electroretinographic and psychophysical measures of retinal
function that are constrained by physical immaturity provide a body of
information about the development of human retinal processes. Age-specific
values for parameters of normal retinal function against which a patient’s
data can be compared are available. ERG and psychophysical procedures are
used to obtain these parameters.
Electroretinography
Full-Field ERG
ERG responses to full-field stimuli assess activity in the retina as a whole.
Full-field stimuli are designed to stimulate all retinal cells. The ERG is
initiated when the stimulating flash of light falls on the retina and the visual
pigment in the photoreceptor outer segment absorbs quanta, thus activating
the biochemical phototransduction cascade. In the rods, the visual pigment is
rhodopsin. The first few milliseconds of the a-wave depend on this
biochemical activity.
Application of a mathematical model of the activation of
phototransduction (13,14) to the a-wave allows one to draw inferences about
the sensitivity and saturated amplitude of the photoreceptor response; this
model is applicable to infants as well as adults (15–18). Rod photoreceptor
sensitivity and saturated amplitude, derived from the a-wave, are low in
young infants. For example, at age 10 weeks postterm, both rod
photoresponse parameters, sensitivity and saturated amplitude, are
approximately half the adult values (15). In normal development, the rod and
rod-driven a- and b-wave parameters are scaled by the rhodopsin content of
the retina (15).
Sample ERG records obtained in scotopic conditions from a dark-adapted
10-week-old infant (awake) and an adult, recorded using Burian-Allen
bipolar corneal contact electrodes, are shown in Figure 9-2. The adult
responds to dimmer stimuli, and the maximum amplitude of the a-wave and
the b-wave is larger than in the infant (15).
FIGURE 9-2 Scotopic ERG responses from normal
subjects. Dark-adapted ERG responses to a series of short-
wavelength (blue) flashes are shown for a 10-week-old
infant (upper left) and an adult (upper right). Stimulus
strength in log scotopic troland seconds (scot td s), a unit
of retinal illuminance, is indicated to the left of the traces;
responses to dim (bottom) and then to increasingly bright
(top) stimuli are shown. This unit takes the area of the
subject’s pupil into account. The calibration bar pertains to
both infant and adult waveforms. In the lower panels, b-
wave amplitude is plotted as a function of stimulus
strength for the infant (left) and adult (right). The smooth
curves plot the equation V = VMAX [I/(I + σ)] where
VMAX is the saturated b-wave amplitude, the flash that
produces a half VMAX, and I the stimulus. In each panel,
the VMAX and log σ are indicated by arrows.
where V is the amplitude of the b-wave and I is the strength of the stimulus,
specified in scotopic troland seconds (scot td s). VMAX is the saturated b-
wave amplitude; σ is the stimulus evoking a response with half the amplitude
of VMAX. Thus, 1/σ is an index of sensitivity (22). Logistic growth curves
summarize the developmental changes in log σ and VMAX (Figure 9-3).
FIGURE 9-3 Development of normal scotopic ERG b-
wave. Logistic growth curves summarizing the
developmental changes in parameters log σ (upper panel)
and VMAX (lower panel) are shown (18). Each parameter
is plotted as a function of age. The curves were fit to data
from 136 healthy control subjects; the 50th percentile is
shown as a heavy, solid red line. After infancy, there is
little change in these parameters.
Multifocal ERG
The multifocal ERG (mfERG) is used to evaluate functional topography in
the central approximately 40 degrees of retina, including the macula (Figure
9-5, top panel). Responses from a large number of discrete retinal regions,
centered on the fovea, are evoked by multiple contiguous stimuli, the
luminance of which alternates under control of an m-sequence, a
pseudorandom binary sequence (27,28).
FIGURE 9-5 Multifocal ERG responses to a pattern of
hexagons that subtended 43 degrees around a central
fixation cross (11). Upper panel: The cone drive
functional topography of the central retina is represented
by the response density map for a healthy adult. The peak
response is at the fovea; response density decreases with
eccentricity. Middle panel: Representative waveforms
from an infant (red traces) and adult (black traces). These
responses were constructed by averaging the responses in
concentric rings from the center (Ring 1) to the periphery
(Ring 5). These subjects had response amplitude near the
median for their age groups. Lower panel: P1 amplitude
as a function of eccentricity for 10-week-old infants and
adults. The difference in P1 between infants and adults
was greatest in the center (Ring 1) and decreased with
eccentricity (ring number). Amplitude was measured from
the baseline to the first positive peak of the response.
Error bars represent the standard error of the mean.
Spectral sensitivity confirms that these thresholds are rod mediated (43).
Cross-sectional and longitudinal data show that the DAT matures by
approximately age 6 months (16).
Developmental elongation of the rod outer segments and consequent
increase in quantum catch account for threshold maturation in infancy (16,42).
Longitudinal DAT data from patients with a history of mild ROP show
improving retinal sensitivity albeit with a slower course than normal
development (16,18,37), worsening retinal sensitivity in LCA and stable
sensitivity in CSNB. The LCA and CSNB data are shown later in this
chapter.
Psychophysical tests have been used to delve into retinal processes that
are not accessible by ERG procedures. In a number of retinal diseases,
including ROP, results of studies of spatial and temporal summation and
background adaptation disclose abnormal retinal processing that cannot be
deduced from ERG data (33,43–45).
Spatial Summation
Receptive field size determines the ability to integrate visual information over
area (spatial summation). By measuring peripheral retinal thresholds for
detection of spots of light of varying diameters, it is determined that the
receptive field diameter is approximately 1 to 2 degrees in adults, whereas in
10-week-old infants, it is much larger, approximately 6 degrees (16,46,47), the
larger receptive field is a strategy to increase the probability of catch of
quanta despite short outer segments and low rhodopsin content. Furthermore,
the center–surround organization of the immature retina has a larger
excitatory center than does the mature retina (46,47).
Temporal Summation
In the normal, mature retina, threshold decreases with increasing stimulus
duration for stimuli <100 ms, as temporal summation prevails; for stimuli
longer than 100 ms, there is little decrease in threshold (48). Healthy young
infants do not show temporal summation at any duration, possibly due to
immature photoreceptor processes affecting the visual threshold. Abnormal
temporal summation functions in children with a history of ROP are
associated with photoreceptor dysfunction (44,48).
Background Adaptation
The effect of steady background light on rod-mediated visual threshold
(DAT) has been studied in healthy infants using psychophysical procedures.
Thresholds are measured in the dark-adapted state and then with stimuli
presented on a series of increasingly intense adapting fields resulting in an
increment threshold function. Very dim backgrounds have little effect on
threshold. For brighter backgrounds, log threshold increases linearly over a
several log-unit range of background intensity. The background intensity at
which threshold is elevated 0.3 log units above the dark-adapted level is
called the eigengrau; at that background, the number of thermal and
photoisomerizations is equal. Thus, the eigengrau is an index of intrinsic
retinal noise (31). In healthy retinas, the eigengrau is greater in infants than
adults, and greater in some diseased than healthy retinas (33,45,51,52).
Models of the resulting increment threshold function allow testing of
hypotheses about the photoreceptor or postreceptor site of immaturity or
disease (33,45). The increment threshold function is summarized by the
equation:
log T = log TD + log [(Ao + I)/Ao]
RETINOPATHY OF PREMATURITY
Subnormal vision is quite frequent in patients with a history of preterm birth.
Prematurity puts an infant at risk for disturbance not only of the retina but
also of the brain (53) and central visual pathways; the brain abnormality may
have minor to marked impact on vision (54,55). Given that as much as 50%
or more of the brain is involved in vision, brain injury of prematurity is
associated with vision problems due to abnormal processes in the brain. On
the other hand, in some former preterms, visual impairment is mainly due to
ROP. Among the most numerous of ROP patients—those with a history of
mild ROP that required no treatment—best-corrected acuity may be in the
20/40 to 20/25 range rather than 20/20. Deficits in acuity occur even if active
ROP produced no ophthalmoscopically detectable abnormality of the macula.
Subnormal acuity has been thoroughly described (56) both in mild ROP that
never required treatment and in more severe ROP. Although by
ophthalmoscopy the macula may look normal, ocular coherence tomography
(OCT) studies have shown alterations in foveal architecture in former
preterms both without and with ROP (57–60) that, by clinical criteria, never
affected the macula even if the ROP was so severe that laser ablation of the
peripheral avascular retina was given.
The extramacular retina contains the overwhelming majority of rod
photoreceptors, which mature later than the peripheral cones. In the normal
macula, maturation of photoreceptors, both cones and rods, is delayed
relative to peripheral photoreceptors, with the foveal cones being the last to
reach maturity. The macular rods (37) and cones (60) appear to be vulnerable
to the effects of even mild ROP, whereas the extramacular cones, as assessed
by full-field ERG testing, appear little affected by ROP unless the active
disease was severe (61). The amplitude of the mfERG responses, mediated by
the central cones and thus an index of photopic activity in the macula,
remains attenuated many years after active ROP has resolved completely
(62,63) (Figure 9-7). It is thought that the mfERG result is due to prematurity
and ROP interacting with development of the late maturing cells in the
central retina (60).
FIGURE 9-7 Mean N1 to P1 amplitude (±SEM) for
subjects with a history of preterm birth compared to term-
born subjects is plotted for rings 1 (center) to 5 (most
peripheral). The preterm subjects are divided into those
who never had ROP (No ROP), those who had mild ROP
that resolved without treatment, and those who had severe
ROP that required laser ablation of peripheral retina.
Description of the patients is in Altschwager et al. (63).
The stimulus was an array of 103 hexagonal elements that
subtended approximately 23 degrees around a central
fixation target.
Normal DAT mediated by the rods in the macula is delayed in development
compared with the threshold mediated by more peripheral rods (42). The
state of rod maturity (length of outer segments; number of rods per unit area)
and consequent quantum catch account for the thresholds. Mild ROP causes
further delay in development of the central retina, as demonstrated by our
longitudinal study of rod-mediated thresholds (37); threshold did not reach
maturity until age 12 months or later rather than by 6 months, as is the case in
normal development (42).
Rod-mediated ERG responses to full-field stimuli are altered by ROP
(16) and to some extent by prematurity itself (64). The ERG responses from
dark-adapted former preterms show deficits in rod photoreceptor sensitivity
(derived from the a-wave) that are present in infancy and persist in childhood.
In childhood, postreceptor sensitivity (b-wave) improves significantly in mild
ROP but not in severe ROP. We also find this pattern of rod photoreceptor
and rod-driven postreceptor activity in a large cross-sectional sample of
former preterms (18,65), tested in infancy (median age 10 weeks) and in
childhood (median age 10 years). Postreceptor sensitivity does not improve in
childhood in those who had severe ROP. Significant deficits in rod
photoreceptor sensitivity are present in infancy and childhood in both mild
and severe ROP. Low rod sensitivity is a sign of photoreceptor dysfunction
and injury. This is predicted by the onset of active ROP at the age when
photoreceptor development proceeds rapidly with escalating metabolic
demands (Figure 9-8).
FIGURE 9-8 Human rhodopsin growth curve and
retinopathy of prematurity (ROP) onset. The logistic
growth curve represents the developmental increase in
rhodopsin (66). At the time of preterm birth, rhodopsin
content is very low. As the rod outer segment undergoes
developmental elongation and increase in rhodopsin,
phototransduction activity, the circulating current, and
turnover of outer segment material escalate. These
processes require energy. ROP has its onset at the ages of
rapid developmental increase in rhodopsin content of the
retina. The red arrow marks the onset of prethreshold ROP
(67). The photoreceptors are the most oxygen-greedy cells
in the body (68). The energy demands for the
aforementioned processes increase as the outer segment
matures.
ACHROMATOPSIA
ACHM is a group of congenital, predominantly autosomal recessive retinal
disorders in which there is an absence or paucity of functioning cones.
Clinical features include reduced visual acuity (Figure 9-9), photophobia,
nystagmus, impaired color discrimination, and paradoxical pupil constriction
to dark. Due to the photophobia, acuity may be better when measured in dim
rather than typical room light. Hyperopia is common (Figure 9-9), although a
broad range of refractive errors is reported.
Blue cone monochromatism (BCM) is an X-linked condition with
features similar to achromatopsia but sometimes less severe and typically
showing myopic refractive error. The Berson plates (91) or the Mollon-Reffin
minimal test (92) may facilitate identification of BCM in boys whose clinical
features are suggestive of achromatopsia. Rather than hyperopia, myopia is
typical in BCM. While these conditions have traditionally been reported to be
stationary and to have normal fundus appearance, there have been recent
reports of progressive loss of function (92,93). Structural changes in the
macula (94–97) are reported but are quite stable in both children and adults
(97).
Full-field ERG is indispensable in securing a clinical diagnosis of
achromatopsia and should be considered for any patients showing the clinical
characteristics described above. Sample records for achromatopsia are
included in the appended “Atlas of ERG Responses.” In achromatopsia and
blue cone monochromatism, cone and cone-driven ERG responses are
nondetectable or markedly attenuated. Rod and rod-driven responses have
been reported to be normal or near normal (98,99), but several recent studies
have found abnormal, but recordable, scotopic ERGs (93,94,100–102). One
study found that the ERG abnormalities were accompanied by reduced
expression of rod-specific proteins, including rhodopsin, and disruption of the
functional and structural integrity of rod synaptic terminals (102). Despite
scotopic ERG deficits (100), the dark-adapted thresholds (DATs) are normal
in achromatopsia (Figure 9-9).
Additional evidence for structural abnormalities in patients with
achromatopsia is provided by high-resolution OCT and adaptive optics
scanning laser ophthalmoscopy (SLO) studies. OCT findings include
disruption or loss of cone inner and outer segments, reduced retinal thickness
in the macular region, and foveal hypoplasia (lack of foveal pit formation).
SLO evaluation showed disruption of the foveal photoreceptor mosaic, but
residual cone inner segment structure was present in most patients (94).
Generally, the structural abnormalities advance with age, providing further
evidence that achromatopsia is not completely stationary.
A functional magnetic resonance imaging study showed reorganization of
cortical maps in rod monochromats (103). Cortical regions in V1 that
responded only to signals from cones in normal controls responded to rod-
initiated signals in these individuals, suggesting that early, anomalous retinal
inputs affect the organization of the visual cortex.
The most common molecular causes of achromatopsia are mutations in
CNGA3 and CNGB3. Mutations in GNAT2 and PDE6C are less frequent
causes of achromatopsia. All four genes are expressed in the cone
photoreceptor and are involved in cone phototransduction. CNGA3 and
CNGB3 are cyclic guanosine monophosphate (cGMP)–gated cation channel
genes, GNAT2 is a transducin protein, and PDE6C is a cone
phosphodiesterase. Genetic testing for all four of these genes is available. The
most common molecular causes of BCM are mutations in the opsin gene’s
array of long and medium wavelength-sensitive cone visual pigments, located
adjacently on the X chromosome.
Restoration of visual function in animal models of achromatopsia (mouse
(104) and dog (105)) has been accomplished using adeno-associated virus
(AAV) gene replacement therapy. In the treated animals, recovery of cone
function was demonstrated by an increase in photopic ERG amplitude to
near-normal levels. These results hold promise for future treatment in humans
with achromatopsia. The report of age-dependent changes suggests that,
ideally, treatment should be applied early. ERG recording and imaging
techniques can be useful in identifying patients with relatively well-preserved
cone function and structure, respectively, and in assessing the response to
treatment in clinical trials.
CONGENITAL STATIONARY NIGHT
BLINDNESS (SEE ALSO CHAPTER 34)
CSNB is a group of heritable retinal conditions characterized by night
blindness that is considered nonprogressive (106,107). There is difficulty
adapting to low light levels (night blindness). An infant with CSNB may have
difficulty finding the bottle in dim light; youngsters with CSNB may exhibit
anxiety in dimly lit environments. As shown in Figure 9-9, the DAT, acuity,
and SE vary among the genetic types of CSNB with considerable overlap
(108,109). The DAT measured using psychophysical procedures is typically
quite stable over time (Figure 9-9), although progressive compromise of
night vision has been documented in some (106,110,111).
Moderate deficits in visual acuity, such as 20/50 or 20/75, are common in
CSNB, although a broad range (108,109) of acuity is found (Figure 9-9).
Myopia at an early age is common, although some patients who are destined
to become highly myopic are not myopic in early infancy (Figure 9-9).
The combination of common, nonspecific features—inability to correct
visual acuity with glasses, myopia, nystagmus, paradoxical pupil constriction
to darkness, and reduced vision in the dark, along with the normal fundus—
leads the clinician to include CSNB in the differential diagnosis. Nonetheless,
these common features are not necessarily all present in individuals with
CSNB; patients with TRPM1-associated CSNB, for example, were recently
reported to rarely complain of night blindness in childhood (112). Therefore,
maintaining some level of suspicion of CSNB and being prepared to move
forward with functional phenotyping (below) by ERG and DAT testing
becomes important.
In most cases of CSNB, the fundus appears normal except for changes
associated with high myopia or in small subgroups of CSNB, such as those
with fundus albipunctatus in which white dots are present (RDH5, RLBP1)
and Oguchi disease with adaptation-dependent change in fundus color (SAG,
GRK1) (see Chapter 34). Approximately two-thirds of our patients with
CSNB have nystagmus and strabismus, and paradoxical pupil constriction to
darkness is present in approximately half of individuals with CSNB (34).
Among the patients with CSNB, there is a wide range of SE (Figure 9-9)
from low hyperopia to high myopia; myopia is quite prevalent (34,108).
Functional phenotyping by ERG testing and psychophysical assessment of
dark adaptation and DAT are used to help secure a diagnosis of CSNB. To
differentiate CSNB from degenerative retinal disorders, testing for visual
field defects and abnormal autofluorescent pattern are important adjuncts to
the ERG and psychophysical tests.
Clinical categorization of CSNB into CSNB1 (complete) and CSNB2
(incomplete) is based on ERG and psychophysical data. In CSNB1, the dark-
adaptation curve shows little evidence of rod branch (or break), and the DAT
is elevated (Figure 9-10). CSNB2 shows some evidence of rod recovery and
more modest elevation of the DAT. CSNB1 and CSNB2 are associated with
particular genetic diagnoses (Figure 9-10) and altered bipolar cell activity
(113–115).
Both CSNB1 and CSNB2 show a negative ERG waveform; that is, a
robust negative-going a-wave and a significantly reduced b-wave (Figure 9-
11). In general, the changes are more marked in CSNB1 than in CSNB2.
(Table 9-3) (see also appended “Atlas of ERG Responses”).
FIGURE 9-10 Dark adaptation functions in CSNB and
control subjects. These theoretical curves plot threshold as
a function of time following exposure to a bright adapting
field. The solid black curve represents typical results from
a control subject. The first part of the function represents
cone system adaptation, and the second rod system
adaptation. In CSNB1, there is little or no evidence of rod
function (red curve). In CSNB2, there is some evidence of
rod adaptation (blue curve). Although there is a range of
thresholds and some overlap, threshold at 30 minutes
remains elevated in both CSNB1 and CSNB2. Genes
associated with each type of CSNB are in the boxes to the
right of the graph (39,40).
FIGURE 9-11 Sample negative ERG waveform. The red
trace is from a patient with CSNB1; the b-wave–a-wave
ratio is <1. The black trace is from a control subject; the b-
wave–a-wave ratio is >1. The ERG waveforms are in
response to the ISCEV 3.0 dark-adapted condition (116).
Table 9-3 Summary of ERG and psychophysical
responses in CSNB
ERG, electroretinographic; CSNB, congenital stationary night blindness; ISCEV, International Society
for Clinical Electrophysiology of Vision; DAT, dark-adapted visual threshold.
Raghuram A, Hansen RM, Moskowitz A, et al. Photoreceptor and postreceptor responses in congenital
stationary night blindness. Invest Ophthalmol Vis Sci 2013;54(7):4648–4658; Komaromy AM,
Alexander JJ, Rowlan JS, et al. Gene therapy rescues cone function in congenital achromatopsia. Hum
Mol Genet 2010;19(13):2581–2593; Miyake Y, Yagasaki K, Horiguchi M, et al. Congenital stationary
night blindness with negative electroretinogram. Arch Ophthalmol 1986;104(7):1013–1020; Stunkel
ML, Brodie SE, Cideciyan AV, et al. Expanded retinal disease spectrum associated with autosomal
recessive mutations in GUCY2D. Am J Ophthalmol 2018;190:58–68.
SUMMARY
ERG and psychophysical studies of visual and retinal function can contribute
key diagnostic information. Furthermore, even after genetic diagnosis is
secured, measures of retinal and visual function are used to delineate the
severity of the condition and to track the course of disease.
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10
ERG Waveforms in Inherited
Pediatric Retinal Diseases
Hanna M. De Bruyn, Wanda Pfeifer, Arlene V. Drack, Ronald M.
Hansen, and Anne B. Fulton
REFERENCES
1. Fulton AB, Hansen RM, Moskowitz A, et al. The neurovascular retina in retinopathy of
prematurity. Prog Retin Eye Res 2009;28:452–482.
2. Hansen RM, Moskowitz A, Akula JD, et al. The neural retina in retinopathy of prematurity.
Prog Retin Eye Res 2017;56:32–57.
3. McCulloch DL, Marmor MF, Brigell MG, et al. ISCEV standard for full-field clinical
electroretinography (2015 update). Doc Ophthalmol 2015;130(1):1–12.
4. Fulton AB, Hansen RM, Westall CA. Development of ERG responses: the ISCEV rod, maximal
and cone responses in normal subjects. Doc Ophthalmol 2003;107(3): 235–241.
5. Moskowitz A, Hansen RM, Akula JD, et al. Rod and rod-driven function in achromatopsia and
blue cone monochromatism. Invest Ophthalmol Vis Sci 2009;50: 950–958.
11
Amblyopia in Pediatric Retinal
Conditions
Alina V. Dumitrescu and Pavlina S. Kemp
Even the most elegant and anatomically successful retinal surgery in a child
can fail to improve vision—or even worsen it—due to amblyopia. Amblyopia
is a preventable, treatable form of vision loss due to lack of visual input from
an eye to the visual cortex during the critical period of visual development.
From birth to 4 months of age, amblyogenic factors are emergencies, and
they continue to be a serious concern until about 9 to 10 years of age. When
considering retinal surgery for children in the amblyopic age range, timing
and type of procedure, as well as postoperative amblyopia treatment, must be
carefully considered in order to achieve an optimal visual outcome.
PREVALENCE
Amblyopia has an estimated prevalence worldwide between 2% and 5% (1),
similarly distributed among racial and ethnic groups. It is most commonly
unilateral but can be bilateral. Typically, amblyopia can only occur from birth
to age 10 years while the visual system is developing and is most efficiently
treated during this important window of time (2,3). Although some treatment
success has been reported at older ages (4,5), development of the disease has
not.
Pediatric retinal disorders are part of a heterogeneous group of
conditions, including many diseases affecting vision early in life. They can be
acquired or inherited and can threaten vision throughout childhood. Patients
with retinal diseases with onset in the first decade of life carry the additional
risk of developing unilateral or bilateral amblyopia with long-term visual
consequences. Amblyopia and its risk factors may result from the retinal
disorder itself or the treatment thereof.
The diagnosis and treatment of amblyopia must be part of the
management plan for children with retinal disorders, starting at diagnosis.
Amblyopia risk should be considered in treatment plans and addressed in
consent for procedures. Retina specialists treating pediatric patients should be
familiar with the principles described in this chapter and may find it helpful
to collaborate with their pediatric ophthalmologist colleagues when caring for
young children with retinal disorders.
ENVIRONMENTAL FACTORS
Amblyopia is caused by abnormal visual input to the brain during the critical
period of visual development (6,7). This can result from various causes, such
as strabismus, refractive error, or visual deprivation (8), each of which can
occur independently, due to retinal disorders or as a result of their treatment.
Visual deprivation, due to corneal, lens or vitreous opacity, retinal
malformation, or degeneration, may result in amblyopia in addition to the
primary organic cause of the vision loss. As a result, retinal disorders have a
much higher risk of vision loss in childhood than if they are acquired in
adolescence or adulthood. Complications from treating retinal disorders or
the necessary postoperative course following successful treatment can also
introduce additional amblyopia risk factors. Environmental factors such as
ocular trauma or infection in childhood can lead to unilaterally or bilaterally
decreased visual acuity. Poor visual acuity at a very young age often results
in nystagmus.
General lack of resources to treat refractive error with glasses or contact
lenses, as well as shortage of medical and surgical expertise, may lead to
amblyopia in situations where it could have otherwise been avoided.
GENETICS
Although amblyopia itself is not considered an inherited disorder, amblyopia
risk factors, such as strabismus, refractive error, and anisometropia, are often
familial. The inheritance of these risk factors seems to be multifactorial and is
not well established (9). Prematurity, associated developmental delays, and
other environmental factors contribute to the risk of developing amblyopia
(10).
Retinal disorders with onset in childhood are often inherited with a well-
established genetic profile. The association of childhood-onset retinal
disorders with amblyopia is common.
WORLDWIDE IMPACT
Due to the treatable nature of amblyopia, the impact of diagnosis and
treatment is tremendous. Every single case of amblyopia, if diagnosed and
treated promptly, can lead to a lifelong improvement in vision (11).
As will be repeatedly emphasized in this chapter, amblyopia that
develops in association with a retinal disorder has its own particularities in
diagnosis and treatment. On the one hand, childhood-onset retinal disorders
are either traumatic or associated with complex ocular pathology and,
therefore, difficult to treat and often are associated with less-than-perfect
vision even when optimally treated. On the other hand, the final visual
outcome is difficult to predict and often surprising in children. However, if
overlying amblyopia develops and is not recognized or treated, the final
visual acuity can be permanently and severely impacted (12,13).
PATHOPHYSIOLOGY
According to the American Association for Pediatric Ophthalmology and
Strabismus (AAPOS), amblyopia is defined as “decreased vision in one or
both eyes due to abnormal development of vision in infancy or childhood.”
(14) Amblyopia is the leading cause of vision loss among children and is
often called “lazy eye” in lay terminology. Vision loss occurs due to
insufficient stimulation of neural pathways between the brain and the eye
during the critical developmental period. This results in abnormal processing
of visual images and leads to decreased visual acuity (15). The brain often
favors one eye due to poor vision in the other eye. Most commonly, there is
no structural problem of the eye or visual pathway. Amblyopia can, however,
occur in eyes with a structural abnormality and cause further reduction in
visual acuity. This is sometimes termed “organic amblyopia.” This type of
amblyopia is especially common in pediatric retinal disorders and may be
missed or not considered because 100% of vision loss is attributed to the
underlying pathology. Every child under the age of 10 years with a retinal
disorder should be considered to have amblyopia as a cofactor in his or her
vision loss.
Unilateral amblyopia is thought to result from competition and inhibition
between the inputs received by neurons processing the visual information
from the two eyes. If the images are not clear (due to blur) or not fusible (due
to strabismus or retinal noncorrespondence), domination of cortical vision
centers by the fixating or better-seeing eye will develop. This further
chronically reduces the responsiveness to input from the nonfixating eye (6).
The Basic and Clinical Science Course, Section 6: Pediatric
Ophthalmology and Strabismus defines unilateral amblyopia as a “two-line
difference in verbal recognition visual acuity measured with linear Allen,
HOTV, or Snellen (not LogMAR acuity) (16).”
Unilateral amblyopia is defined as mild, moderate, or severe, and the
level of severity has implications for visual prognosis and treatment. A two-
line difference but less than a four-line difference is defined as mild
amblyopia. Moderate amblyopia is defined as a four-line difference to less
than six-line difference. A six-line difference or more is defined as severe
amblyopia (15). In preliterate children, mild amblyopia is central, steady,
unmaintained (CSUM) fixation, as compared with central, steady, maintained
(CSM) fixation in the nonamblyopic eye; uncentral, steady, unmaintained
(UCSUM) fixation is considered moderate, and uncentral, unsteady,
unmaintained (UCUSUM) fixation is considered dense amblyopia (8).
Generally, bilateral amblyopia is defined as best-corrected visual acuity
in each eye worse than 20/50 for 3-year-olds and worse than 20/40 in 4- to 5-
year-old children (6).
Strabismus
Although any ocular misalignment can be associated with the development of
amblyopia, unilateral vision loss is more likely to result from nonalternating
and constant strabismus. Esodeviations more commonly cause amblyopia
than exodeviations. Acquired childhood strabismus is more often associated
with amblyopia than is congenital strabismus (6). Development of the
compensatory mechanisms of cross-fixation and alternating fixation help
young children maintain equal vision in both eyes and avoid diplopia.
Unilateral vision loss, such as that from retinal disease, can lead to loss of
binocularity and fusion and can result in sensory strabismus followed by
further visual compromise from strabismic amblyopia. Young children are
more likely to develop sensory esotropia than older children and adults, who
tend to develop sensory exotropia. A child with a latent or intermittent
exotropia, who suffers a vitreous hemorrhage, may develop a manifest
exotropia within a few weeks due to the decreased ability to fuse. This then
worsens the amblyopia caused by the vitreous hemorrhage itself.
Visual Deprivation
Deprivation amblyopia is a consequence of decreased input from one or both
eyes due to anterior segment media opacities, such as corneal scars or edema,
inflammation, cataract, ptosis obscuring the visual axis, and/or vitreous and
retinal hemorrhages, retinal detachment, or retinal scars. Patching or covering
the eye or blurring the vision with plastic shields, atropine, or ointment can
potentially cause amblyopia if the child is young enough and the distortion
persists long enough. Deprivation amblyopia can begin at birth or develop
later. It is the least common form of amblyopia but is often the most severe
and difficult to treat. The degree of amblyopia is correlated with the degree of
visual obstruction and the age of onset. Visual deprivation amblyopia is the
most severe form of amblyopia especially if the onset of deprivation is in
infancy (30).
Severely reduced visual input to the brain from an eye due to vitreous
hemorrhage, cataract, or patching causes dense amblyopia. Reports suggest
dense amblyopia from deprivation begins at approximately a week of
complete occlusion per year of age of the patient (31). There are no
confirmatory studies, but visual outcome data on natural history of untreated
congenital cataract (17) as well as reports on occlusion amblyopia (32) are
supportive of this timeline. For example, a 9-year-old child with a vitreous
hemorrhage or a dense traumatic cataract has about 9 weeks before
amblyopia will be a concern, whereas a 1-year-old child has only 1 week.
Therefore, surgical removal of vitreous hemorrhage is elective in adults,
fairly urgent in school age children, and an emergency in infants and children
of 1 to 2 years of age.
Occlusion amblyopia is an acquired, iatrogenic form of deprivation
amblyopia that can occur in the previously better-seeing eye after therapeutic
patching or cycloplegic penalization. It can also occur due to prolonged
postoperative patching, especially in very young children. The incidence and
severity depend on the length of occlusion time, but occlusion amblyopia
generally is believed to be mild and reversible. In at least one prospective
randomized trial, reversal of amblyopia developed in 1% of children patching
for 6 or more hours per day and in as many as 9% of children given one drop
of topical atropine daily after 6 months of treatment (29,33). A retrospective
study of full-time patching for treatment of unilateral amblyopia reported that
as many as 25% of children developed occlusion amblyopia (33). In nearly
every case, the visual acuity in the fellow eye returned to baseline with
discontinuation of the current patching therapy. Other studies that evaluated
lower doses of patching, <6 hours, and shorter duration of atropine found
lower rates of occlusion amblyopia (21,34). Younger children and those with
higher patching doses should be followed at closer intervals and monitored
for amblyopia to decrease the risk of occlusion amblyopia. Postoperative
patching of the operated eye should be done for the shortest time possible,
and a shield with perforations should be used, if available.
General rule of thumb: Amblyopia starts to develop when the inciting condition has been present for
about 1 week per year of age of the patient. For example, in a 2-year-old child, amblyopia will start to
be a factor after 2 weeks of vitreous hemorrhage. This is also approximately the time it will take to start
reversing amblyopia with treatment. For example, a 4-year-old child with amblyopia from a vitreous
hemorrhage will need patching or other penalization therapy for at least 4 weeks before an
improvement in vision will be seen.
Vitreoretinal disorders can occur at any age, but inherited disease frequently
manifests early in life. Visual acuity and long-term visual potential are often
poor due to the underlying disease, as well as nystagmus. Despite visual
limitation due to retinal pathology itself, the presence of refractive error,
anisometropia, strabismus, asymmetric disease, or visual deprivation should
raise the suspicion of concomitant amblyopia.
Retinopathy of prematurity (ROP), its related complications, trauma with
cataract and/or posterior segment involvement, as well as infections and
inflammatory systemic diseases with ocular involvement are also common
early in life. If a disorder or its treatment introduces amblyogenic risk factors,
these should be added to the consent, prognosis, follow-up, and treatment
plan.
MANAGEMENT OF AMBLYOPIA
FREQUENTLY ENCOUNTERED IN
PEDIATRIC RETINAL DISEASES
Refractive Error
Some diseases are associated with bilateral high refractive error. Stickler
syndrome, congenital stationary night blindness, Ehlers-Danlos syndrome,
and others are associated with bilateral high myopia with onset before school
age. Leber congenital amaurosis (LCA), oculocutaneous albinism, juvenile
X-linked retinoschisis, and others are associated with high hyperopia from a
very young age. Although these children will have anatomical reasons for
limitation of vision, for example, from staphylomas or foveal hypoplasia,
they will benefit from optical correction as early as possible to develop their
best vision and avoid bilateral refractive amblyopia.
Separately from the underlying disease process, any child can have
unrelated refractive error. Because of this, children with vitreoretinal disease,
as with all other children, should have an eye examination that includes
cycloplegic refraction and should be prescribed glasses, when appropriate,
despite their underlying diseases. It is generally accepted that myopia of at
least −6 D, hyperopia of at least +5 D without esotropia, and astigmatism
more than 2 D are amblyogenic and need to be corrected (6).
Anisometropia can occur in any child and at any age and is a risk factor
for amblyopia. Additionally, asymmetric or unilateral disease, unilateral
surgery, including scleral buckle, vitrectomy, silicone oil placement, or other
types of unilateral treatment, including laser or cryotherapy, increase the risk
of developing anisometropia and unilateral amblyopia.
Retinopathy of prematurity of all levels of severity is a significant risk
factor for developing refractive error, anisometropia, and strabismus. Long-
term follow-up studies have shown that 26% of premature babies with ROP
severe enough to require peripheral laser treatment underwent additional
retinal surgery; 18% had cataract surgery; 20% developed amblyopia, and
10% developed strabismus requiring surgery (20). Approximately 66% of
eyes with high-risk prethreshold ROP observed during the neonatal period
were myopic in preschool and early school years (35). Pathologic progressive
myopia that presents at a very early age is also more common in children
who have had ROP and affects up to 5% of patients (36). Many children who
were born prematurely have foveal anomalies and hypoplasia on OCT even if
they did not have severe ROP (37,38). For these reasons, it is recommended
that children with a history of prematurity and/or ROP have periodic
evaluations for vision, ocular alignment, and cycloplegic refraction (39)
especially early in life.
Additionally, peripheral laser treatment for ROP can be associated with
retinal or vitreous hemorrhages that can precipitate the development of
deprivational amblyopia if they are large or long-lasting.
Vitreous and retinal hemorrhages in childhood can occur spontaneously
from anemia, leukemia, and thrombocytopenia or juvenile X-linked
retinoschisis or in the context of trauma related to vaginal delivery,
nonaccidental or accidental causes, or surgery. Vitreous hemorrhage in early
childhood is rare and may cause few or no symptoms. In the absence of a
known causative event, it may not be discovered for a long time. Absence of
a red reflex is often the reason for an evaluation. Vitreous and retinal
hemorrhages can clear spontaneously, but the process usually takes months or
even longer in large vitreous hemorrhages due to the formed vitreous of
children. During this time, severe unilateral or bilateral amblyopia may
develop. As described above, the severity of amblyopia depends on the
patient’s age. In very young infants within the first 3 months of life,
deprivation from dense vitreous hemorrhage can lead to irreversible
amblyopia within weeks (31). In older children, deprivation amblyopia can
also occur but will develop more slowly.
Unless the vitreous hemorrhage clears spontaneously, its treatment is
surgical removal. The risks and benefits of such surgery need to be weighed
in the disease context and the age of the infant or child. Very young infants
need clear media as soon as possible to develop vision; however, one of the
common complications of vitrectomy is cataract formation, which occurs
about 20% of the time (40). Cataracts will need to be addressed surgically
early in life and will lead to aphakia or pseudophakia, anisometropia and
refractive error, and the added risk of secondary glaucoma. The same is true
of older children but to a lesser degree.
Young children with trauma, either accidental or nonaccidental, and
retinal and/or vitreous hemorrhages often have associated traumatic cataract,
corneal lacerations, cerebral injuries, and intracranial hemorrhages leading to
additional surgeries, cortical visual impairment, and other disabilities.
Recovery is sometimes slow, and anesthesia risk is high. Therefore, although
the goal to gain as much visual recovery is important, the risks and benefits
of surgery, patient’s age, severity of the ocular disease, and effects from
associated neurologic abnormalities must be weighed. In cases in which the
ocular versus cortical component is unclear, serial visually evoked potential
(VEP) tests and/or electroretinograms (ERG) may be useful to assess
changes.
Regardless of age, etiology, and associated comorbidities, the treatment
of retinal and vitreous hemorrhages is not complete without amblyopia
management.
Lensectomy in children is recommended for congenital or acquired
cataract from trauma or secondary to surgery. Congenital cataracts, especially
when unilateral, are often associated with persistent fetal vasculature and its
associated findings: retinal folds, funnel- or stalk-shaped retinal detachment,
spontaneous vitreous hemorrhage, and a congenitally small eye (see also
Chapter 6). Unilateral congenital cataract in general is highly amblyogenic.
When associated with posterior pole disease, visual prognosis is limited (41).
The decision between aphakia and intraocular lens implant is based on
age, laterality, and access to optical rehabilitation. The postoperative
refractive target is based on the child’s age. Glasses will be needed even if
contact lenses are used, because the loss of accommodation will require near
correction. Near vision is very important for development and schoolwork
and needs to be part of pediatric visual rehabilitation.
Retinal detachment is uncommon in children compared with adults, and
the causes and challenges are also different (see also Chapters 60–63). Only
3% to 7% of all retinal detachments occur in the pediatric population (42).
Risk factors associated with retinal detachment in children are accidental and
nonaccidental trauma (see also Chapters 69 and 70), high myopia, hereditary
vitreoretinopathies such as Stickler syndrome and Marshall syndrome,
familial exudative vitroretinopathy (see also Chapters 3, 35, 37, and 66),
Marfan syndrome (see also chapter 37), ROP (see also Chapters 38–41, 43,
51–55), sickle cell retinopathy, previous intraocular surgery, inflammation
(see also Chapters 47 and 48) and Coats disease (see also Chapter 64). The
most frequent type of pediatric retinal detachment is trauma-associated, and
the most common cause of inherited retinal detachment is from
vitreoretinopathies, which can be spontaneous or related to minor trauma
(described in detail in Chapters 4, 7, 48, 54, 55, and 64). (43). A significant
challenge of unilateral retinal detachment without known major trauma is the
lack of symptoms or complaints from the child, which lead to delayed
diagnosis and treatment.
The treatment of pediatric retinal detachment is complex due to several
factors: the high rate of vision-threatening pathology in the fellow eye in
cases of systemic disorders and the considerable financial, emotional, and
time-based investment of attempted repair. Amblyopia risk is an important
component of this decision. Increased risk of proliferative vitreoretinopathy
and increased frequency of macular involvement due to late presentation are
other important factors (43).
The anatomic success of surgery for retinal detachment due to any
etiology in children tends to be lower than in adults and may require more
than one surgery (44). Postoperative vision is correlated with visual acuity at
presentation and the reason for the detachment, but visual acuity better then
20/200 has been reported in some studies as occurring in <50% of cases (45).
The most common primary repair used in children is a scleral buckle;
however, vitrectomy, laser retinopexy, and combinations of these procedures
may be necessary and are addressed in other chapters (see also Chapters 60–
63). Use of silicone oil may also be needed, because postoperative
positioning is difficult in the pediatric population.
The unilateral use of a scleral buckle or silicone oil induces
anisometropia. Scleral buckle placement can lead to axial myopia. Silicone
oil placement will induce variable changes in refraction based on the status of
the lens in the eye. Generally, silicone oil induces a hyperopic shift in a
phakic eye and a myopic shift in an aphakic eye (46). These refractive errors
should be corrected early postoperatively because they can lead to refractive
amblyopia. Postsurgical strabismus and cataract formation are relatively
common complications of retinal detachment surgery. Postoperative
strabismus tends to be restrictive and can be variable. These are all
amblyogenic factors, which have to be considered and included in the visual
rehabilitation plan.
As mentioned above, the age of the pediatric patient is very important
with younger children having a higher risk of developing denser amblyopia in
a shorter duration of time.
Posterior uveitis is not common in children and represents only 5% to
10% of cases of all uveitis (47). However, uveitis can be challenging to
diagnose and treat due to its bilateral and asymptomatic nature in children
(see also Chapters 47 and 48). Most cases are idiopathic, infectious, or
secondary to systemic inflammatory conditions and, therefore, bilateral.
Cases associated with infection tend to also present unilaterally (47). The
most common infections that cause posterior uveitis are acquired or
congenital toxoplasmic retinochoroiditis, necrotizing herpetic retinitis,
toxocariasis, Bartonella henselae, and nematode-associated neuroretinitis. In
infants, ToRCH-related syndromes (toxoplasmosis, rubella, cytomegalovirus,
herpes virus) and lymphocytic choriomeningitis virus and West Nile virus
congenital infections are the most common causes of congenital posterior
uveitis (48) with Zika virus being a more recent concern (49).
Posterior uveitis can lead to the development of band keratopathy,
chorioretinal scars and epiretinal membrane formation, and choroidal
neovascular membranes, all of which can be amblyogenic especially when
associated with unilaterally decreased vision in young children. Treatment of
uveitis requires long-term steroid use and, in some cases, intra- and
periocular steroid injections in combination with systemic treatment. These
treatments have potential complications, including cataract formation,
increased intraocular pressure or frank glaucoma, and retinal detachment
(50). Consequent surgical procedures, such as lensectomy, vitrectomy, and
filtering procedures, can lead to the development of amblyopia risk factors of
anisometropia from pseudophakia or aphakia or strabismus from setons.
Amblyopia should always be suspected when amblyogenic factors are
present, and a diagnostic trial of patching may be considered especially if
acuity is worse than the retinal anatomy would suggest.
Organic amblyopia can develop in any case in which organic disease is
unilateral or asymmetric.
Chorioretinal colobomas, foveal hypoplasia, inherited retinal dystrophies,
and congenital infections, when unilateral or bilateral but asymmetric, will
lead to the development of amblyopia in the worse-seeing eye. The challenge
in such situations is to determine how much of the visual asymmetry is due to
amblyopia versus how much is organic or structural due to the disease
process. It is also difficult to determine the visual potential of the presumed
amblyopic eye and to decide how much and for how long to treat. Often, a
trial of amblyopia treatment is needed to assess the potential for
improvement. Collaboration with a pediatric ophthalmologist is helpful to
determine visual potential.
Retinal dystrophies are often associated with the development of cystoid
macular edema (CME), which should be suspected if a sudden vision
decrease is noted. Chronic CME leads to epiretinal membrane formation and
additional vision loss. Topical or systemic treatment with carbonic anhydrase
inhibitors may lead to improvement or resolution of edema, which can be
recurrent and sometimes require long-term treatment. When unilateral or
asymmetric, CME can create the circumstances for development of
amblyopia.
LCA and other retinal degenerative disorders of childhood can be
associated with amblyopia. The degree of visual loss associated with LCA is
variable and largely dependent on the gene and mutations involved. This is
also true for other childhood-onset retinal degenerations. Refractive error,
anisometropia, strabismus, as well as nystagmus and abnormal head position
are often associated with these conditions. Diagnosing amblyopia and
treating it are essential.
Gene replacement therapy for LCA is now available for at least one gene
(biallelic RPE65 mutations). Clinical trials and posttrial analysis show that
patients who had low vision through the entire period of critical vision
development and treated with gene replacement therapy responded to the
treatment (51) and patients treated at <10 years of age had similar visual
improvement as older patients treated after age 10. Additionally, a study
using noninvasive multimodal neuroimaging showed normalization along the
visual fibers in the visual pathway of the treated eye to levels comparable to
normally sighted people, and the degree of plasticity and recovery did not
depend on the patient’s age at the time of the treatment (52). The impact of
amblyopia in future gene therapy or stem cell-derived therapy for unilateral
or bilateral retinal dystrophy is yet unknown. There is no study showing a
direct effect of amblyopia on the success of the therapy, but it is inevitable
that we will learn more about the implications of amblyopia as treatments for
more common inherited retinal diseases become available, and children of
various ages are studied.
Oculocutaneous albinism and foveal hypoplasia are often associated with
high hyperopia, nystagmus, and various degrees of esotropia. Treatment of
hyperopia and strabismus are always recommended regardless of degree of
foveal hypoplasia or visual acuity. Often, vision improves with glasses.
Because some diseases have no current treatment options and can lead to
further vision loss due to disease progression, parents and physicians may
question the need to treat amblyopia in such cases. Further knowledge of
amblyopia treatment will help with such decisions.
ETHICAL CONSIDERATIONS
Dense amblyopia with significant underlying disease is very difficult to treat,
and visual outcomes are often poor. Large differences in vision between the
two eyes allow only limited treatment options and make it more difficult for
the family and child to comply with treatment. Long-term patching for
treatment of amblyopia is more difficult in children with very poor vision in
the amblyopic eye as well as in children with associated morbidities and
developmental problems. Patching can carry a significant social stigma for
children and impact the quality of life for both children and their parents.
Goals of treatment and prognosis should be clear and reasonable. A clear end
point for reevaluation of patching should be discussed at the outset; if a
plateau is reached with no improvement, patching should be discontinued or
tapered off.
It should be emphasized to patients and their parents that even in children
with underlying organic diseases, visual acuity can improve with amblyopia
therapy. In one retrospective review, 51% of patients with underlying organic
abnormities achieved a visual acuity of at least 20/80 with FTO for up to 7
months with younger patients responding faster and obtaining better final
visual acuity (59).
Every age group and etiology for amblyopia have their own treatment
challenges. Young children with dense amblyopia will find it very difficult to
patch, but a close and sustained collaboration with families can lead to
successful results. Older children may be more resilient, but need to be
involved in the treatment and motivated to participate.
Studies have shown somewhat contradictory information about long-term
implications of amblyopia in people’s lives. In one study of 370 children and
adults with unilateral amblyopia, acquired vision loss in the non-amblyopic
eye resulted in severe visual impairment in 23% of patients (60), indicating
the importance of rehabilitating amblyopic eyes whenever possible. A
different study following 1,037 patients with unilateral vision loss due to
amblyopia found no functional impact on childhood motor development,
teenage self-esteem or adult socioeconomic status during follow-up when
compared to peers with good vision in both eyes (61).
Although sometimes unachievable, the ultimate goal of treatment is
lasting equal visual acuity between the two eyes.
FUTURE TREATMENTS
Amblyopia does not resolve spontaneously and will lead to permanent vision
loss in the affected eye unless treated with patching, pharmacologic
penalization, glasses when needed, or surgery when necessary (14).
Use of refractive surgery to correct for anisometropia and refractive
errors has been proposed and is used in selected cases at this time (62). If
long-term safety and efficacy are proven, refractive surgery might be used
more commonly in the pediatric population.
The addition of new treatment modalities with pharmacologic agents like
levodopa/carbidopa alone or in combination with patching or atropine (63)
has been proven to have some efficacy but is still not widely used. Similarly,
the use of citicoline has been described with some efficacy in improving
vision in amblyopic eyes of older patients when used alone or in association
with patching or atropine (64).
New trends and nonoperative interventions using modern technology for
treatment of amblyopia are still under scrutiny; these include the use of liquid
crystal glasses (65), perceptual learning (66), transcranial magnetic
stimulation (67), dichoptic training (68), or acupuncture (69). Small studies
have shown the value of each of these approaches in isolation or in
combination with traditional treatment at various ages.
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12
Workup of Infantile/Congenital
Nystagmus
Brittni A. Scruggs and Arlene V. Drack
PREVALENCE
Approximately 14 children per 10,000 live births have INS worldwide (1). In
the United States, the birth prevalence of INS is estimated to be 12 children
per 10,000 live births with a two- to threefold male predominance (2,3). A
study by Nash et al. revealed that 87% of all pediatric patients with
nystagmus can be classified as having INS (2).
ENVIRONMENTAL FACTORS
No known external environmental factors cause INS. Premature birth and
intrauterine infections or toxins that result in central nervous system or ocular
damage increase the risk of INS. Young maternal age (<18 years) and
intrauterine exposure to alcohol or diabetes increase the risk of optic nerve
hypoplasia, which is an important cause of INS.
GENETICS
INS is a descriptive name for an eye movement disorder with many different
etiologies. In one study of 202 INS patients, the vast majority had a genetic
cause (4). Genes causing INS can result in progressive or stable conditions,
and inheritance can be autosomal dominant, autosomal recessive, X-linked,
mitochondrial, or sporadic. Some of the more common genetic causes will be
discussed in this chapter.
WORLDWIDE IMPACT
Because of the heterogeneity of etiologies, exact worldwide prevalence data
for INS are not known. An estimated 1.4 million children are blind
worldwide affecting about 1.5 per 1,000 children in low-income countries
with high pediatric mortality rates and around 0.3 per 1,000 children in high-
income countries with low pediatric mortality rates (5). Most children with
early-onset blindness develop INS as a result of vision loss, and many have
persistent nystagmus as adults; other children and adults have INS as a
primary condition.
PATHOPHYSIOLOGY
A retrospective study of 202 patients with INS revealed that there are three
major categories of INS etiologies: (a) eye movement/oculomotor disorders,
(b) vision-related disorders, and (c) neurologic disorders (4). The most
common INS etiologies are shown in Figure 12-1. The patients in the
oculomotor disorder category have idiopathic INS, also called congenital
motor nystagmus (CMN), and represent about 10% of all INS patients (4).
CMN is a diagnosis of exclusion, so this diagnosis should never be made
without a complete workup. The pathogenesis of idiopathic CMN is still not
completely elucidated, and no single causative lesion in the ocular motor
control system has been identified. However, there are many connections
between the eye and various brain locations, and defects in fixation, saccades,
the motor neural integrator, the optokinetic reflex, or the pursuit eye
movement systems may contribute to the development of nystagmus (6).
In INS, there are varied manifestations, but the eye movements are mostly
conjugate (10). Nystagmus with acceleration during the slow phase with a
typical frequency of 2 to 4 Hz is characteristic of INS (Figure 12-3) (6). Jerk
nystagmus with fast corrective saccades and pendular waveforms with slow
initiating and corrective movements also can occur in infantile cases (3,6).
Any saccadic intrusion, or fast eye movement away from a target, should
raise suspicion that the child does not have INS and, instead, may have
opsoclonus secondary to neuroblastoma (3). CSNB often has associated INS
with unusual waveforms, including vertical and opsoclonus-like (4,11).
FIGURE 12-3 Typical nystagmus waveforms in infantile
nystagmus syndrome. A:Nystagmus with acceleration
during the slow phase and fast corrective saccades is
characteristic of jerk-type infantile nystagmus syndrome.
B:Pendular waveforms with slow initiating and corrective
movements also can occur in infantile cases. Most
infantile nystagmus waveforms have a frequency of 2 to 4
Hz. (Reprinted from Richards M, Wong A. Infantile
nystagmus syndrome: clinical characteristics, current
theories or pathogenesis, diagnosis, and management. Can
J Ophthalmol 2015;50(6):400–408. Copyright © 2015
Canadian Ophthalmological Society. With permission.)
It is common for infants to minimize their nystagmus by keeping their eyes in
a null position or zone; such foveation periods minimize visual symptoms
(e.g., oscillopsia) and improve visual acuity (12). Alexander law states that
nystagmus is more pronounced when the gaze is directed toward the side of
the fast-beating component. Thus, a patient with a left jerk nystagmus would
expect to have a left head turn. These abnormal head positions should be
noted in the initial examination; a small lateral head turn is the most common
position adopted as the null point is usually within 10 degrees of fixation.
Acquired forms of nystagmus can often be localized to a specific
anatomic region based on waveform. For example, downbeat nystagmus
usually localizes to the vestibulocerebellum (e.g., cerebellar degeneration,
Chiari malformation, etc.). The same localization is not possible for early-
onset nystagmus forms like INS. The presence of oscillopsia, which is the
perception of visual motion, further differentiates pathologic acquired
nystagmus from INS as patients with INS rarely complain of this.
INS should also be distinguished from latent nystagmus (fusion
maldevelopment nystagmus), which occurs in approximately 50% of patients
with infantile esotropia and, less frequently, in other types of infantile
strabismus. Latent nystagmus is predominantly a bilateral, horizontal jerk
nystagmus elicited by occluding either eye. The slow phase is toward the side
of the occluded eye with an exponential decrease in the slow-phase velocity.
In INS, there is a reversed optokinetic nystagmus (OKN) response in which
the fast-beating phase of the induced nystagmus is in the same direction as
the OKN stimulus; this is compared to the normal OKN response in which
the fast phase beats in the opposite direction to the stimulus movement (13).
DIAGNOSTIC APPROACH
Clinical History
An initial clinic visit for INS should include detailed family, birth, medical,
and developmental histories of the child. The age of nystagmus onset should
be determined given INS is rarely present at birth and more commonly begins
by 3 months of age (3). Onset after 6 months should raise suspicion of an
acquired nystagmus, which has a different workup and is not covered in this
chapter. Relevant vision impairment, strabismus, abnormal head posture,
kidney diseases, and neurologic disorders in the family or child should be
discussed, and pedigrees should be drawn to determine the pattern of
inheritance when appropriate.
Clinicians should be aware that in certain inherited disease states, there
are wide phenotypic variations within a family. For example,
nephronophthisis (NPHP) gene mutations can lead to progressive cystic
kidney disease with or without profound vision loss due to LCA. The
combination of LCA with NPHP is caused by mutations in NPHP5 or
NPHP6 (also called IQCB1 and CEP290) and is referred to as Senior-Löken
syndrome (14). The first symptom is usually nocturia or bed-wetting due to
an inability to concentrate urine. Cerebellar ataxia, skeletal involvement,
congenital oculomotor apraxia, and hepatic fibrosis can also be present in
these patients (14). Conversely, of all patients with idiopathic INS (i.e., no
evidence of ocular or systemic disease), up to 50% have a family history of
nystagmus without other findings.
Gestational age, developmental milestones (e.g., walking, talking), delays
or regressions, and growth curves (e.g., head circumference, weight, height)
should be reviewed. As children get older, abnormalities that suggest the
presence of an underlying ocular or neurologic disease state should be
identified, including:
Clinical Examination
A complete pediatric eye examination commonly narrows down the diagnosis
in INS and is indicated for all infants with nystagmus, ideally prior to
imaging or further testing.
Examination findings that may increase the probability of specific ocular
disorders associated with INS are listed in Table 12-1. The examination
should begin with careful external inspection of the child. For example,
albinism often presents with hypopigmentation of the child’s eyes, skin, and
hair secondary to reduced quantity of melanin in melanosomes. The
phenotypic variations of OCA are provided in Figure 12-4.
Neurofibromatosis type I, which can cause optic nerve gliomas and resultant
INS, has characteristic signs of neurofibromas (i.e., peripheral nerve tumors),
café au lait spots, axillary freckling, and/or osseous lesions or deformities.
Lisch nodules of the iris can be seen on slit lamp examination in about 80%
of children by 8 years of age. Obesity may signal a syndrome, such as
Bardet-Biedl or Alström.
A relative afferent pupillary defect (RAPD) increases the likelihood that there
is an optic nerve pathology as the INS etiology, whereas bilateral sluggish
pupils may be present in certain retinal dystrophies, such as LCA.
Paradoxical pupils can be seen in a number of congenital optic nerve and
retinal disorders. It should be noted if the child has good vision or poor
vision; best-corrected visual acuity helps guide the workup, as described later
in this chapter. The preverbal child should be evaluated using the CSM
method: central fixation (C), steadiness of fixation (S), and maintenance of
fixation (M). To determine if the child has central fixation, each eye should
be covered and then uncovered while the child fixates on a target of interest
to determine if fixation is central or eccentric. Similarly, testing for steadiness
is done monocularly to determine if the patient can fixate without nystagmus.
Maintenance is a binocular test; for orthotropic patients, a prism of 14
diopters is placed in front of one eye base down as the child views a target of
interest at near and then at distance. If vision is equal, the eye behind the
prism will deviate upward to view the displaced image; as the second image
is noted in the fellow eye, the eyes will then deviate downward. If one eye
sees better than the other, the eyes will remain in the position corresponding
to the image for that eye. If a child has strabismus, alternately covering the
eyes and watching for movement of which eye is fixating can be done
without a prism. The eyes should be observed in all cardinal gazes to
characterize the nystagmus waveform, to detect the presence of a null zone,
and to identify red flags. Gaze-evoked nystagmus with changes in the plane
of oscillation may be associated with posterior fossa lesions (3).
Cycloplegic refraction may detect high refractive errors and guide further
testing, such as LCA molecular testing in INS patients with high hyperopia
and poor vision. Strabismus and amblyopia are detected in up to 35% and
14%, respectively, of all pediatric patients with nystagmus (2); however,
compared to INS, latent nystagmus is more commonly related to comorbid
amblyopia, strabismus, or syndromic disorders (e.g., Trisomy 21) that disrupt
binocularity (3). Slit lamp or penlight assessment help rule out lens, cornea,
or iris abnormalities. Iris transillumination defects, deficient iris tissue, ovoid
pupils, or ectopic pupils should be investigated further for disease processes
such as albinism or PAX6-associated ocular diseases (e.g., aniridia or partial
aniridia).
The dilated fundus examination should be carefully performed, and there
should be a low threshold to perform an examination under anesthesia (EUA)
if the fundus view is inadequate or if the child is uncooperative in the clinic
setting. The optic nerve should be evaluated for colobomatous changes and
disc size; optic nerve hypoplasia commonly leads to INS and can be
associated with pituitary and/or septum pellucidum defects (septo-optic
dysplasia) secondary to congenital malformation. Brain MRI to assess
pituitary and midline brain anatomy as well as endocrine evaluation is
indicated in cases of isolated optic nerve hypoplasia. Optic nerve hypoplasia
may also be a feature of albinism or aniridia, and if it can be proven that it is
part of these syndromes, brain MRI is usually not needed as these types of
optic nerve hypoplasia are not reported to be associated with pituitary
dysfunction. The combination of optic nerve atrophy and INS warrants head
imaging to rule out intracranial pathology. Foveal hypoplasia suggests the
presence of albinism or aniridia but has also been reported to occur in
Stickler syndrome, familial exudative vitreoretinopathy (FEVR), premature
birth, and as an isolated anomaly. Retinal pigmentation abnormalities,
arteriolar attenuation, and/or blunted foveal light reflex should raise suspicion
for LCA, retinitis pigmentosa (RP), achromatopsia, or other inherited eye
diseases that should be investigated, as described later in this chapter.
Many children with INS will initially present to pediatricians or
neurologists, and they will undergo an MRI before a complete eye
examination is performed. A complete history and a complete pediatric eye
examination with dilation as well as ancillary tests of ocular function are
necessary for all children with INS, even those with a negative MRI. A
negative brain MRI should never be the only test performed on a child with
INS.
Brain Imaging
INS alone does not necessarily warrant obtaining brain imaging given the low
diagnostic yield of MRI testing in the absence of other findings. However, a
low threshold remains for ordering a brain MRI with and without contrast on
a child with INS who has asymmetric or unilateral nystagmus, neurologic
signs, developmental delays, small or large head circumference for age,
and/or changing growth curve percentiles over time. If nystagmus onset was
after 6 months of age, brain MRI should be considered. It should be noted
that dominant optic atrophy usually presents with temporal optic nerve pallor
and slow vision loss without the development of nystagmus. Thus, evidence
of optic nerve atrophy or hypoplasia in patients with INS should warrant
brain imaging. The shimmering, asymmetric nystagmus seen in patients with
spasmus nutans should always be further evaluated given that certain CNS
tumors, especially diencephalic syndrome, can mimic spasmus nutans, which
presents with the triad of nystagmus, head nodding, and torticollis (9,15).
Children with significant perinatal history (e.g., prematurity, traumatic brain
injury, hypoxia, infection, etc.) should be evaluated with a brain MRI to
identify structural causes of cortical visual impairment (3). If a child has a
known ocular etiology of his/her nystagmus but has additional unexplained
neurologic findings, it is prudent to investigate further. For example,
progressive optic atrophy in a patient with known CSNB would be
uncharacteristic for the ocular disease state and may represent an
undiagnosed intracranial disease process.
A negative brain MRI is reassuring that the cause of INS is likely not
neurologic, but it should never be the final test in the workup. A negative
MRI means ocular causes should be explored. Even in the case of spasmus
nutans, which has been described as a developmental, self-resolving
condition of the first few years of life, a normal MRI should be followed by
an electroretinogram (16). There are many reports of CSNB and
achromatopsia presenting as spasmus nutans-like nystagmus that resolves as
the child ages. Conversely, some LCA patients present with a spasmus
nutans-like nystagmus that usually does not resolve over time.
Electroretinography
Electroretinography (ERG) is a powerful diagnostic tool for INS and should
be obtained in any case with a nondiagnostic MRI. It can also be helpful to
obtain prior to head imaging when evaluating patients with poor vision,
nystagmus, and no other findings; the diagnostic yield for these cases has
been reported to be 56% (17). A normal ERG does not rule out all ocular
causes of nystagmus and does not replace a complete ophthalmologic
examination. In general, a flat ERG suggests severe cone and rod disease,
likely secondary to LCA or RP. Abnormal cone responses with relatively
preserved rods are seen in achromatopsia and cone dystrophies, whereas an
electronegative ERG should increase suspicion of CSNB, X-linked juvenile
retinoschisis (XLRS), or Batten disease. ERG may be successfully performed
in awake children in clinic from birth to about 6 months of age and then after
about 3 to 4 years of age depending on the child. A patient, expert clinician is
necessary to perform atraumatic pediatric ERGs. Dawson-Trick-Litzkow
(DTL) electrodes, which allow normal blinking and are less difficult to apply
than contact lens electrodes, greatly reduce the trauma of pediatric (and adult)
ERGs and yield comparable amplitudes with only slightly more background
noise. Jet electrodes and skin electrodes can also be used. Each electrode has
its own pluses and minuses, which should be thoroughly understood by
whomever is interpreting the test to avoid under- and overdiagnosis of retinal
disorders. It should also be remembered that the ERG evolves over the first
year of life. A very low-amplitude ERG at 6 months of age may evolve into a
higher amplitude or electronegative ERG at 18 months of age. If ERG in the
clinic is not possible but is necessary, ERG can be performed under
anesthesia. Amplitudes may be decreased by up to 50% due to anesthesia,
particularly the rod ERG, so this must be taken into account when
interpreting these ERGs.
There is increased crossing of temporal ganglion cell axons in the optic
chiasms of patients with albinism, and this can be detected using a
multichannel visual-evoked potential (VEP) (18). VEP is easier to perform in
children than ERG because electrodes are placed on the head rather than the
eyes. However, detection of abnormal decussation in albinism is variable and
may become undetectable at older ages. This VEP finding has also been
described in aniridia and, therefore, is not specific enough for clinical
diagnosis.
MANAGEMENT
Optical Treatments
INS can result from uncorrected high hyperopia, high myopia, or high
astigmatism; optimal refractive correction and treatment of amblyopia are
essential for these children. Thus, a cycloplegic refraction must be performed
on every child presenting with nystagmus. For adult patients with lifelong
nystagmus and binocular vision, base-out prisms can be used to induce
convergence during the viewing of far targets; convergence-induced
accommodation must be accounted for in the final prescription with the
addition of minus lens power in young patients (6). A recent randomized
controlled trial of contact lens therapy in INS failed to show reduction in
nystagmus. However, contact lenses, which reduce the prismatic effects of
spectacles and keep the optical center of the lens in line with the center of the
pupil, remain an option for children with nystagmus and high refractive
errors. Some clinicians add prisms to correct a small anomalous head position
where the apex is pointed in the direction of the patient’s gaze (6).
For INS patients with poor vision, vision rehabilitation services should be
provided to help these children perform everyday tasks. Use of electronic
devices, large print, tablet computers, and magnification devices can
significantly improve their quality of life (27).
Pharmacologic Therapies
Systemic medications are not commonly used in INS given the side effects
that may occur with long-term use. Furthermore, most medical therapies are
generally not effective for afferent visual system problems (i.e., secondary
nystagmus), which constitute the majority of INS. The available treatment
options aim to increase the duration of foveation periods and minimize visual
symptoms that are more common in adult populations (6). Baclofen, which
activates gamma-aminobutyric acid receptors, has been shown to be effective
in improving visual acuity and correcting abnormal head postures in patients
with infantile periodic alternating nystagmus; however, half of these treated
patients developed side effects requiring medication cessation (34). One
double-blind randomized controlled trial in 2007 showed that both
gabapentin and memantine reduce the nystagmus intensity (i.e., amplitude ×
frequency) and slightly improve visual acuity in idiopathic INS patients
without serious side effects (35); however, the mechanism of these effects
remains unknown. Oral and topical carbonic anhydrase inhibitors (e.g.,
brinzolamide, acetazolamide) reportedly suppress INS, but larger studies
showing efficacy are needed (36).
Subretinal Gene Therapy
The blood–retina barrier limits the risk of immune reactions to subretinal
gene therapy; there are several retinal degenerative diseases that cause INS
that may be amenable to such therapy. Clinical trials for these disorders can
be found at www.clinicaltrials.gov.
The causative gene must be known in order to determine if a patient will
qualify for a trial. Only one gene therapy for a retinal degeneration causing
INS is clinically available: Luxturna for RPE65-associated LCA. The Food
and Drug Administration has approved subretinal administration of an adeno-
associated virus gene vector containing a normal copy of the RPE65 gene in
both eyes of patients. This treatment has led to meaningful improvements in
ambulatory vision and nystagmus for children with this blinding condition
(37,38). Not all adults experienced marked improvement; however, some did,
including a 44-year-old patient. The treatment is approved for children as
young as 1 year old (although the youngest patients in the clinical trial were 4
years old) and adults with RPE65-associated LCA or RP.
VISION REHABILITATION
Some patients with INS have normal vision and do not need vision
rehabilitation; however, the majority of INS patients will benefit from special
accommodations at school, use of technology, and special evaluation for
driving licenses, test taking, using a microscope (a microscope with a video
screen is required), and other highly visual tasks. INS patients with best-
corrected visual acuity of <20/40 or any field loss should be referred to a low
vision clinic. Chapter 14 describes the low vision services available in more
detail.
FUTURE TREATMENTS
Patients with intact outer and inner retinal layers may be candidates for gene
therapy; in these trials, intraocular transplantation of a viral vector containing
the gene of interest leads to the transduction of affected photoreceptor cells,
which may be beneficial. In more advanced disease states, stem cell therapy
to replace lost photoreceptor cells is needed. Data show that cultured human-
induced pluripotent stem cells have the ability to form all retinal cell types,
integrate into retinal layers, and contribute synaptically (43–45). These cells
have substantially improved vision in animal models; when injected into
mouse RP models, these cells survive and differentiate into functional
photoreceptor cells (46). Research is ongoing into this type of treatment and
may offer hope to patients with nystagmus due to photoreceptor loss in the
future.
CONCLUSIONS
INS is an oscillatory eye movement disorder that presents before the age of 6
months. Diagnosis and management of INS requires a clinician to obtain a
thorough history, perform a detailed clinical examination, and order selective
ancillary testing to determine the cause. In many INS cases, there is an
underlying retinal disease that can be readily diagnosed with cycloplegic
refraction, a dilated fundus examination, heightened clinical suspicion, and
appropriate studies, including ERG, OCT, and genetic studies. Neurologic
causes of INS in otherwise developmentally normal healthy children are rare
but should not be overlooked; thus, a brain MRI should be ordered when
clinically indicated. Other specialists should be involved in cases of
syndromes associated with INS. Pharmacologic, surgical, and optical
management of underlying ocular disorders and systemic diseases is an
essential part of addressing the needs of pediatric patients with infantile
nystagmus. As gene therapy and other regenerative medicine techniques
become available, the importance of an accurate clinical diagnosis in these
patients becomes even more important.
ACKNOWLEDGMENTS
The Ronald Keech Professorship supported this work.
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13
Early Intervention and Rehabilitation
in Infants and Children With Visual
Impairment
Lea V. M. Hyvärinen
INTRODUCTION
Changes in retinal structure and functioning begin in infants and children at
varying ages and affect vision. Diseases of the visual system often present in
this age range, some of which also involve hearing, cognitive, and motor
functions. More than 50 groups of diseases with variation in severity are
covered in this book and present a broad range of phenotypes within and
among diagnoses. Several retinal diseases are parts of syndromes or occur in
children, some following intrauterine infections. Therefore, the effects of
diseases on the visual system and on general functioning vary greatly and
require numerous observations, vision tests, and follow-up to define a child’s
needs in the early intervention and later in special education and
rehabilitation. For each child and family and the rehabilitation service/school,
the findings of the clinical examinations should depict, clarify, and support
the functions and skills observed by parents, therapists, and teachers so that
the child’s visual functioning and needs for further development can be
understood and planned correctly.
The problems in early intervention and rehabilitation are in three areas:
EARLY DETECTION
Early detection of diseases and disorders of vision requires systematic
observations of infants’ and children’s visual functioning by the medical and
educational services and referrals to pediatric ophthalmologic services. All
pediatric medical services should have awareness campaigns on sensory
functions, and each newly diagnosed visual disease in ophthalmologists’
offices should lead to consultation at pediatric, neuropediatric, and/or
neuropsychological services so that early intervention, rehabilitation, and
educational services can be wisely chosen for each child and family.
Premature infants with or without retinopathy are a large group with
atypical vision; they may require long treatments in hospital with follow-up
and treatment of retinopathy of prematurity (ROP). They may also have
changes in brain functions leading to visual processing disorders and visual
field losses and changes in other sensory, cognitive, and motor functions.
Contact with parents may be limited due to the infant being in an incubator
connected to monitors, and, therefore, development of bonding and
interaction is in danger in these families.
Early intervention has not developed to cover problems in infants’
development of functioning caused by retinal damage and prematurity. The
medical care has improved with standardized treatment. Similarly, early
intervention for visual dysfunction is likely to improve if assessment of
vision starts early and covers several functional areas. Present problems
include delay in diagnoses other than ROP and issues related to treatment and
variation in the testing and training vision. Therefore, further work is needed
to optimize visual development.
In the follow-up of development of vision, the Teller Preferential
Looking Grating test for research laboratories seems to be used most often,
but the values are reported as visual acuity values, which are not correct.
Preference and response to looking at the grating in preferential looking tests
(Teller and LEA Grating tests [www.lea-test.fi]) do not reveal whether the
infant has good detail discrimination, only whether one grating looks more
interesting than another. Optotype values on the Teller Preferential test were
demanded by the ophthalmologists, although Davida Teller explained that
they were not valid to describe visual acuity. The grating can be seen badly
distorted, and yet it is a strong stimulus, preferred to an evenly gray or white
area. Errors in measurement have been noted from the earliest days of grating
acuity (GrA) testing (Figure 13-1): correct GrA cannot be measured
accurately until the child can understand and respond to questions regarding
the intricacies related to visual function. For example, the question of where
he sees the lines: “at the edge or in the center” and “whether lines are straight
or tangled,” the answer can be “There are no lines in the middle.”
Distortions of fine grating lines occur in many conditions that disturb exact
coding of the line information in the retina or in the primary visual cortex
(V1) in the occipital lobe.
The use of grating tests requires training, so that the tester shows first
broad full contrast lines that are easy to see and the child shows with hand or
on answering cards the direction of the lines. When the direction of lines is
understood, the tests are shown according to the instructions (in www.lea-
test.fi). This may be possible first at the age of 4 to 6 years. We should be
aware of the difference between gratings and optotypes and know that the
preferential looking tests do not result in a real grating acuity value but show
the preferential response. These tests are useful to detect a marked preference
for one eye, possibly signifying amblyopia or organic vision loss, but not the
absolute visual acuity of either eye.
Active use of vision on day 1 or 2 has been registered in thousands of
pictures showing stable eye contact with the mother in some pictures even
copying expressions. In Chitrakoot, India, a pilot study on feasibility of
assessment of stable eye contact as a part of the routine examination of facial
structures, eyes, and red reflex by the pediatrician was found to be easily
performed and took <1 minute during the discussion with the mother. Of the
70 newborn infants, all but 1 had typical stable eye contact when it was
initiated by the mother. This nonresponding infant was premature; her
refractive error was +3.50, so test glasses +6 were placed in front of her eyes.
She immediately had stable eye contact. Accommodation had not yet
developed in this premature baby, but the visual response to eye contact was
present. This test is short and easy but requires either training of pediatricians
or access to a pediatric ophthalmologist or optometrist when the pediatrician
examines infants the day before they leave the hospital. Hyperopia and delay
in development of accommodation are assessed in 2 minutes when
noncycloplegic or “dry retinoscopy,” and a set of test glasses +2, +4, +6, and
+8 are used. If a newborn does not make eye contact with a parent on the day
of discharge, dry retinoscopy is performed, and trial lenses of that correction
plus three diopters for near are placed on the baby. The baby is then observed
with the parent again, and if eye contact is better, glasses with this
prescription are dispensed to be used until accommodation develops. If this
does not improve eye contact, an ophthalmology consult should be obtained.
This technique continues to be studied, but enough is now known to
recommend recording stable eye contact in newborns prior to hospital
discharge and suspecting deficient accommodation if it is not present.
Newborn and young infants use the tectopulvinar pathway that transfers
low-contrast information about motion, that is, the infants can see facial
expressions on adult persons’ faces and can even respond during the first
week when the mirror neuron network moves visual information to motor
activation of the baby’s facial muscles resulting in a smile and feeling of
happiness. The brain functions in the infant are activated, and the parents
support the infant response by increased bonding. At 10 to 12 weeks of age,
infants’ visual behaviors depict development best, although individual
variation is great. Some infants are “talkative” at the age of 8 weeks and use
vision and voice; other infants smile and listen until 12 weeks. The visual
milestones are a good guide during the first months (Table 13-1).
Contrast sensitivity depicts vision at all contrast levels (y-axis) at the visual
acuity (x-axis) range used as in Figure 13-2A, C, D. The slope of the contrast
sensitivity (CS) curve can be quickly defined, because between full and 2.5%
contrast, the slope is close to a straight line that depicts the curve well
(Figure 13-3).
Most students in Figure 13-3 had cerebral palsy (CP). The slopes varied in
their inclination; some slopes are steep and have almost the same value at full
contrast VA on the x-axis and at the level of 2.5% contrast. Another large
group has slightly more difference between these two values; the inclination
of the slope is a little flatter than in the first group; in the third group, the
slope is very flat, that is, the difference between VA values at full and 2.5%
contrast can be 20/12 to 20/200. The low-contrast visual acuity values add
important information in the assessment of functioning and takes <2 minutes
to measure with the 2.5% chart after the full contrast value is measured. In
this group of 50 students, VA was <20/60 in 12 students; in 10 students, it
was 20/20 or higher. Note that the majority of students had VA > 20/60 (0.3).
In most of the United States, in order to obtain an unrestricted driving license,
visual acuity must be at least 20/40 in one eye; restricted driving, such as
daytime only or off highway only, may be possible at lower acuities. Chapter
14 discusses the low-vision evaulation for driving in more detail.
In 2008, visual acuity limit 20/60 (0.3) was used for the first time to
divide students with visual processing disorders into those with VA < 20/60
(“low vision”), who had “cortical visual impairment” (CVI) who were
eligible to have TVI services, and those with VA > 20/60 who were not
eligible for services. This diagnosis was an educational diagnosis, but was
soon used as if it were a medical diagnosis.
Within a few years, 20/60 became the VA value that divided all children
with visual disorders, so only those with VA < 20/60 were examined in many
university hospitals worldwide. Visual acuity was recently recommended not
to be a divider of services in the United States, but follow-up information is
not yet available. In India, this VA limitation ended earlier this year. Eye care
providers in the United States often measure only distance VA in children.
This decreases the possibility to notice weak accommodation as a potential
common problem in school. Often near work magnification need is based on
distance vision. Near vision is the most used visual function in children in
demanding tasks, especially in school age and should be tested at each visit.
Children with amblyopia or certain visual processing disorders may have
reduced ability to read due to the crowding phenomenon. In this condition,
letters in close proximity appear to overlap each other and become
unreadable. If a patient with the crowding phenomenon is tested using
individual widely spaced optotypes, acuity will be normal, yet they are
unable to read words of the same size. The LEA near vision test (www.lea-
tes.fi) used at 40 cm distance (the length of the cord on the test) has the
standard line test with typical spacing between letters. On the reverse side,
the tests have tighter spacing between the letters at 50% and 25% to detect
crowding. If crowding is detected, large texts can be used to improve reading
ability in schools, even if line acuity is normal. This near test can be used as a
distance test at 2 or 3 m distance, so there are five tests on this small card that
was created especially for developing countries where rehabilitation teams
must travel long distances and bring test materials with them. The small LEA
low-contrast VA test, the 10M test, and the Hiding Heidi test (www.lea-
test.fi) for assessment of communication distance complete the VA testing
material until the students start to use local letters and numbers. These
abstract forms are processed differently from the LEA symbols that are
pictures of concrete objects and thus can be used earlier than abstract letters
and numbers. Letters are composed of short straight and curved lines, so
grating acuity should be tested as early as possible.
Motor problems, such as poor head control, or neurologic impairment of
the visual system may also affect ability to track and process words (3). If a
child has atypical “dyslexia,” a small dome magnifier with an arrow inside
can function as a “reading stick” and may stabilize fixation.
Visual fields can have atypical structure: a hemianopic field can contain
motion perception (4). The tectopulvinar pathway may transfer visual motion
information normally (4) while damage in the optic tract causes loss of
hemifield measured with automated perimetry. The size and structure of the
visual field in retinal degenerations should be assessed in young children (5)
by observing strategies that the child uses in moving, such as searching for
edges with feet or hands. The peripheral visual field may require large stimuli
for the measurement. The child depicts vision of large surfaces in the
environment, which is important. The “blind” areas in automated perimetry
should not be marked with black before motion vision is measured within
them, because movement may still be perceived in these fields.
All measurable functions should be assessed and recorded in teenagers
and young adults with retinal diseases and atypical vision when training for
driver’s licenses. Diagnoses should be based on careful assessment of visual
functioning in clinics specialized in visual functioning in demanding
conditions, so the limits for driving will be individually tested (Figure 13-
2D). VA is the limiting function, but the test may not be standardized with
the international standard, the Landolt C test; VA values based on
nonstandard tests should not be used. See Chapter 14, which discusses
driving with low vision in more detail.
Visual pathways are not well known, especially the tectopulvinar
pathway. The tectopulvinar pathway functions at birth and transfers low-
contrast information in motion; therefore, newborn infants can perceive facial
expressions on adults’ faces. Their mirror neuron networks change visual
information to motor functions in the baby’s facial muscles allowing infants
to smile on the 2nd day of life and feel happiness, which activates brain
functions. Newborn infants’ vision is not poor, “less than 20/200”; they
see motion well in low contrast so they perceive facial expressions.
Assessment of visual functioning requires that all visual areas are
considered (Figure 13-4): (a) Visual information leaving the eyes via the
retinocalcarine pathway changes its content in the LGN nucleus based on
information arriving from specific cortical areas (marked with the thick arrow
from V1 to LGN in Figure 13-4C) so that less information leaves from the
LGN compared with what arrived, and this information is then carried on to
specific cortical areas. (b) Early processing in the occipital cortex (Figure 13-
4B) is the “feature level” coding for colors, forms, length and direction of
lines, depth, movement, motion, stereovision, textures, surface qualities,
object background, figure ground, visual closure, filling in, and visual
illusions. In V1, tactile and haptic information, and auditory space are
coded, so that they can be recognized and used with visual information in the
higher processing functions in the large parietal and temporal networks at the
“object level.” In education, children’s difficulties at the feature level
dominate in preschool and early grades and should be detected, because if
started early, a well-planned training often normalizes functioning.
Figure 13-4 A:The retinocalcarine pathway (blue) with its
lateral geniculate nucleus (LGN) transfers information to
the first visual area, V1; the tectopulvinar pathway (green)
with its pulvinar nucleus (PULV) transfers information to
V5/MT. B:Decoding and recoding of information, colors,
forms (lines, edges), and movement occur in different
parts of V1. C:Greatly simplified connections of functions
between the thalamic nuclei (LGN to V1), superior
colliculus (SC), and pulvinar to V5/MT and all visual
areas in the occipital lobe. Notice the two-way movement
of information and the thick arrow from V1 to LGN.
D:From the early processing in the occipital lobe, the
“feature level visual information” moves into the large
temporal and parietal networks for the “object level”
information processing. NOTE: More information moves
to the occipital lobe from higher cortical areas than from
the occipital lobe toward temporal and parietal lobes
(arrows are thicker toward occipital lobe). (From
Hyvärinen L, Jacob N. What and how does this child see?
Assessment of visual functioning for development and
learning, 2nd ed. Helsinki: VISTEST Ltd., 2013.)
Ophthalmologists usually have limited time for testing at the feature level of
early processing, so rehabilitation therapists, TVI, and others generally
administer and use these tests. At the age of 4 to 5 years, students with
complex processing problems benefit from testing by pediatric
neuropsychologists to get an overall picture of the functions that should be
trained.
Visual Processing at the “Feature Level”
Processing functions at the feature level in the occipital lobe are
especially important in preschool and the first grade in school, so that the
abstract space for forms and math develops. Many teachers observe preschool
and first grade children’s basic visual concepts and eye–hand coordination to
choose additional training. Therefore, the information that is found in clinical
assessments is especially important for the development of these young
students.
Together with special schools, easy-to-use tests were developed for
feature level processing when the first Vision Rehabilitation Centre in
Helsinki, Finland, started in 1976 (Figure 13-5).
INITIAL INFORMATION
Early intervention traditionally starts as a part of the first assessment of an
infant’s or child’s vision when there is a suspicion of vision loss or disease.
The parents are often worried about vision, especially if it affects early visual
communication. They are anxious to have a thorough description of their
infant’s condition. Most young parents have no experience with visual
impairment and may only relate to the alarming concept of total blindness. If
the infant is their first child, they have little knowledge on how to care for an
infant and virtually no information about the care of a visually impaired
infant. In such a delicate situation, it is important that the discussion of the
findings, prognosis, and planned management is undertaken by an
experienced pediatric ophthalmologist or pediatric retinal specialist who is
trained to discuss disability-related matters, knows the support systems, and
connects the parents with an early intervention professional who has the time
and the expertise to talk with the parents immediately after diagnosis. Ideally,
the early intervention professional should be present during the initial
discussion of the diagnosis and continue to support the parents. Parents may
remember only a fraction of what has been said. Terminology has been
frightening and confusing, and parents may feel overwhelmed and grieve the
loss of the perfect baby of their dreams.
Some doctors may contact the family the next day to make sure that the
family has connected with the local services and is not abandoned. If parents
are simply given a phone number to call an early intervention worker
directly, they may be unprepared to make that call for months since the
parents do not know that an early intervention worker assigned to them
would be able to assist them in developing communication and interactive
skills and to help them to enjoy and love their child without the reward of
normal visual communication. Without this assistance, the family may not
know how to care for their infant at the critical time of the early months,
which can lead to parental depression.
Early intervention should consider all developmental areas in each case and
find an answer to the basic question: “How much and what kind of vision is
present for different functions and for the development of each particular
function?” “For which functions should the infant/child be taught to learn
strategies of exploration typical to blind children?”
Training of vision-related brain functions can start during the first
assessment, which also serves as an introduction for the local therapist into
work with visually impaired infants. The local therapist has usually met the
infant at home before the first assessment of visual functioning (Figure 13-8)
and introduced himself or herself to start the assessment. If an infant has been
in hospital for a long time and experienced that a “new voice” means “a new
type of pain,” using the local therapist in the beginning of the assessment
makes the situation easier for the infant. If the infant is relaxed and expects a
pleasant play situation, several functions may be assessed at their best level.
The test situation is also a smooth introduction of a child’s vision into the
therapist’s usual neurodevelopmental therapy.
Visual field can be measured using an illuminated ball, that is, a penlight
illuminating a small plastic ball with uneven surface (Figure 13-8) (e.g., a toy
for kittens with a bell in it). If the infant responds only in the midline, the use
of the visual field can be activated by helping the infant to see his or her
hands as shadows against the illuminated ball. Information about the form
and surface of the ball combined with the movements of the hand and arm
may help the infant to watch his or her hand for the first time. The better
functioning hand is used first; then, the hemiplegic arm and hand are
supported to a position where the infant can see the fingers against the light.
Vision loss affects nearly all areas of development. The most important
areas of functioning in which vision plays a central role are
Communication and interaction
Motor functions and balance
Body awareness, visual spatial concepts, and orientation in space
Auditory spatial concepts, typically built within the normal visual space
Object permanence
Language
Incidental learning
Social skills
Many of the functional areas mentioned above are included in the usual
therapies for infants. Development of visual functions and their use in all
areas of functioning can and should become an integral part of therapies and
enrich the therapist’s work. Therapists need vision for communication with
the infant and are highly motivated to learn about the infant’s visual
functioning in detail. They also have the opportunity to observe the
development of the infant two to three times a week and can teach the parents
to use the training activities several times each day.
Communication and interaction are the first activities on the list, because
they are the most important functions for the emotional development of the
infant and parents and the bonding between them. Tactile exploration of
parents’ faces is started early, especially if there is suspicion that hearing
might also be affected.
Tadoma, the technique of speech reading by feeling the mouth, facial
muscles, and the vibration of the vocal cords with an adult’s hand, is
modified for the little hands to feel the movements of the mouth and the
vibration of the vocal cords in turn (Figure 13-9).
Large “little rooms” are constructed for blind school-age children with
developmental delay. These “rooms” have a clear ceiling, whereas visually
impaired infants and children with useful vision should have a nontranslucent
ceiling and narrow slits up on the sides so that the space is a visual and
auditory space. The walls should have visuotactile areas as landmarks for
exploration. Toys and objects hanging from a thick rubber band do not
disappear when the infant lets them go, which supports the development of
object permanence.
A resonance board makes the infant aware of the movements of the feet
even if they are difficult to see (Figure 13-10C). In therapy, the infant’s
hands are helped to meet in the midline and, from there, to the mouth: this
supports development of motor functions. Hands are also guided to feel feet
and legs and together with them create a closed space around a big ball on the
stomach, a closed space created with the infant’s own body. Notice that this
infant with aniridia has dark glasses to prevent photophobia.
Carrying the baby in a sling gives experiences of movement patterns,
creates opportunities for incidental learning, and increases communication
between the adult and the infant. If the infant without motor problems is
helped to become an active explorer and learner, early development may not
notably differ from that of a sighted child. Exploration takes more time and
requires thinking when vision does not give its usual firm framework for
multisensory experiences. Numerous repetitions of movements are needed to
learn and remember the tactilely and kinesthetically studied structure of
objects, that is, movements of a door to learn how it sounds and mouthing of
objects to explore details with the tip of the tongue and lips. Mouthing and
repetitive movements can often be mistaken for autistic behavior in a visually
impaired infant/child. Autistic children have similar repetitive movements
and actions as visually impaired children. It is not known how often autistic
children are visually impaired and have skillfully learned to use techniques
that compensate for loss of visual information. We should carefully look for
the difference between exploration and meaningless repetitive movements.
These at-risk groups should be seen immediately if they have any symptoms
of communication problems at the usual screening ages of 6 to 8 weeks.
Large refractive errors should be corrected early (with undercorrection of
large myopic corrections to encourage focus at near). If an infant has
difficulty in early communication, accommodation should be measured and
near correction given for therapy and to facilitate communication. Infants
with birth trauma and insufficient convergence, especially if they are
hypotonic, nearly always show loss of accommodation; therefore, their needs
of near correction should be addressed and early communication supported.
Since children with CP often develop deformation of their spine, good
ergonomic postures are important. This is also true for visual tasks.
Spectacles should be specially designed to meet the needs related to poor
head posture, which makes the line of gaze pass unusually high up through
the lens when looking at a computer or a TV screen prior to the reading age.
Retinal degeneration in deaf infants may cause night blindness during the
first year but arises more commonly when the child is a few years old. If the
hearing impairment is moderate, assessment of vision may be forgotten until
school age. In populations with Nordic ancestry or of Acadian descent (see
Chapter 23), Usher syndrome type III with progressive hearing and vision
loss in school age is more common (see also Chapter 33). Early intervention
and contact with other families with hearing-impaired children of the same
age are important so that the children learn to live in the two cultures.
Cochlear implants make them semihearing, but there may be situations in
which they cannot use the implant and need to be able to communicate with
sign language. Some hospitals still claim that a child does not have dual
sensory impairment if visual acuity is better than 20/60. These children’s
visual problems are related to photophobia and slow adaptation into low
luminance levels, not to visual acuity. Since retinal sensory cells of animals
with retinitis pigmentosa–like retinal degeneration have shown damage when
exposed to short wavelength light, good filter lenses may delay the
development of retinal changes. Therefore, education as to use of hats and
spectacles that protect against damaging wavelengths is advised.
There is great variation in the progression of retinal changes in genetic
conditions, even within the same family; painting a bleak picture of future
complete blindness is not productive. The family should have opportunities to
meet with other children with retinal degenerations and dystrophies with or
without hearing problems and learn that most children with dual sensory loss,
even deafblindness, are healthy and active. Young children learn from the
older children with the same disease a realistic picture of their future and may
avoid the typical period of depression around the age of 9 years (10).
To care for those with vision impairment particularly in hearing impaired
or with multiple impairments, such as children with rubella or other
syndromes, requires careful observation and training in all vision-related
functions. In this group of children, even major changes in the midline (cleft
lip and palate, etc.) and microphthalmia with colobomas may not prevent the
child from developing into a student with exceptional abilities. Infants and
children with severe communication and developmental delay should have
appropriate glasses, particularly with large progressive near correction if
accommodation is insufficient. The behavior related to changes in color,
contrasts, and movement in the near environment should be observed
carefully so that a well-structured near space is created. Many children are
hypersensitive to touching (tactile defensiveness), which can be often
decreased using the child’s own hands. Covering the hands first with soft
material and progressively increasing the roughness of the material makes it
easier for the child to accept the desensitization.
In all pediatric rehabilitation, not only the infant or child but also the
whole family, including parents, siblings, grandparents, and even neighbors,
should be considered.
PROBLEMATIC BEHAVIORS AND
SITUATIONS
Visually impaired infants may start pressing on their eyes, which is called the
oculodigital reflex. The causes of the oculodigital reflex are not clear, but
self-stimulation seems to be more common when the infant is not occupied
by play or interaction. Eye poking causes pressure atrophy of fat tissue in the
orbit and of the bony rim of the orbit and can also cause keratoconus or
retinal detachment. Since a child usually cannot report a change in vision,
retinal detachment may be picked up so late that surgical results are poor.
Deep-set eyes are a cosmetic problem that affects the child later in life. Often,
the skin around the eye becomes darker. Gently redirecting the preverbal
child’s attention to other activities, or sometimes providing a barrier such as
well-fitting glasses, can decrease this behavior. The child should not be
spanked or scolded. Once children are old enough to understand that the
behavior is harmful, they will usually stop.
Depression is common among children with disabilities. Nearly every
child with a disability due to chronic illness or an impairment goes through a
subtle or obviously expressed depression around the age of 9 years (10). This
happens when children become aware that parents and medical experts are
unable to make them like their peers, and they must accept their impairment
and disability as a feature of their self-image. Since the depression period is
so common, it is wise to talk more about the good functions in vision than
what is lost. Arrangement for age-appropriate devices and training for new
strategies that benefit the child should be put in place. Contact with other
children with similar problems can help the child to accept his or her situation
and to develop compensatory strategies and become an advocate of his or her
own needs. Anxiety is also common in adolescents.
If an infant does not start to recognize family members by their faces at
the age of 7 to 10 months but does recognize them by their voices, the infant
may obtain such a poor quality of visual image that he or she cannot see the
differences in people’s facial features. In infants with neurologic issues, there
may also be a specific loss of the cortical function responsible for face
recognition, called prosopagnosia (www.faceblind.org). An ophthalmologist
and pediatric neurologist should investigate the child’s functioning without
delay. Some infants also have no recognition and interpretation of facial
expressions and, therefore, cannot understand the emotional content of visual
communication. These two deficits in cognitive visual functions are the
socially most important ones and should be observed during therapy and
discussed during each ophthalmologic and neurologic examination of infants
and toddlers. The degree of loss varies; for example, some children are aware
of the presence of eyes and mouth but do not see changes in facial
expressions due to lack of motion perception, whereas others if asked what
they see in the face of their teacher may answer “skin.” They know the facial
structures as tactile information, but visually the face is a featureless surface.
Faces should be explored using tactile information, magnifying mirrors, and
visuotactile pictures, so that the child has a good foundation for imagination.
COMMUNICATION IN EARLY
INTERVENTION FOR TODDLERS AND
PRESCHOOLERS
Vision plays a central role in the communication of a toddler. If we bring
together five or six toddlers for the first time, it takes them less than half an
hour to decide “who is the boss” and “who is the underdog” and what the
ranking order is between these two. There has been no discussion as there is
no speech possible yet, but body language and expressions make the status of
each child quite clear. When a visually impaired toddler is brought to a
daycare center, limitations in visual communication must be described to the
personnel, for example, poor contrast sensitivity and visual acuity, loss of
central visual field, or cognitive problems in recognition of facial features
and/or expressions. A teacher’s aide with good communication skills should
function as the intervener structuring the play situation of the visually
impaired child and explaining to the other children if the visually impaired
child does not respond as expected. Sometimes dark glasses must be
prescribed as a distinguishing feature for the child to help the other children
understand that the child does not see well.
Personnel in daycare centers should have information about the
disadvantages of extraneous noise when the auditory channel is the dominant
sense in that the child may need play time in a quiet corner. The limited
vision of the child is demonstrated to the teachers who present pictures and
objects to a group of children. A good way to do this is with “demonstration
glasses” made of clear kitchen plastic wrap folded over lensless eyeglass
frames as many times as needed to decrease the teacher’s visual acuity to the
level of that of the child when looking through the folded material.
Well-planned pediatric orientation and mobility (O&M) training is key to
integration into the local school and society. If an instructor is unavailable
locally, the child’s therapist should have support from an O&M instructor so
that the child is taught proper strategies in orientation and moving. In such
cases, training during summer camps or weekend gatherings can only
partially compensate for the lack of formal training in O&M, an important
part of special education.
SCHOOL AGE
School age brings a major change in the life of a visually impaired child and
his or her family. Many children go to a local school and are integrated into
the mainstream education programs.
In 1996, the Expanded Core Curriculum for Students with Visual
Impairments was first introduced in the United States (11). While the
common core includes subjects all students learn in schools, for example,
mathematics and science, the Expanded Core includes nine areas that are
considered essential for students with low vision and blindness to function in
schools, homes, and communities. They are compensatory skills (skills that
enable a student to access the general education core curriculum), sensory
efficiency skills (including, but not limited to, the use of low-vision and
multisensory approaches to learning), orientation and mobility skills, social
interaction skills, independent living skills, technology skills, career
education skills, recreation and leisure skills, and self-determination skills.
Ideally, each visually impaired child has an individual educational plan (IEP)
or an individual learning plan (ILP) that covers all requirements of special
learning techniques and identifies who is going to teach these skills. Each
disabled child has the right to study in the least restrictive environment.
Visually impaired children with severe learning disabilities are in special
schools or special classes in local schools in which knowledge of learning
strategies of visually impaired children often may be limited. Recent pilot
studies show that half of the children in such schools may not have glasses or
only have glasses correct for distance vision without correction for much
more important and relevant near vision tasks. If glasses get broken, new
glasses may not be prescribed in a timely manner. There is a need for an
international, well-planned survey on current provision services for visually
impaired children with intellectual disabilities. This survey should include all
children with brain damage–related vision loss, especially children with CP,
because their special educational and rehabilitation needs are not met in
schools in many countries.
Ophthalmologists’ reports together with other physicians’ reports are
important in informing the schools about common multidisabilities of
children with brain damage (12). When the child’s needs are well stated, it
usually is possible to arrange appropriate special education. Among children
with several disabilities, 40% to 80% have vision problems and need
treatment and rehabilitation. It is, therefore, important that these children
have a targeted clinical assessment using tests specifically developed for
each type of disorder.
At the end of the examination, I told the boy that he had performed well;
most of his results (in sensory tests) were good. He answered by pointing at
large letters with his stick that he had used during the examination and wrote
an old Finnish proverb:
“Don’t judge a dog by its fur.”
CONCLUSION
Early intervention and rehabilitation for infants and children with atypical
visual development is based on early detection. High-risk groups of infants
and children, such as with CP and other motor problems or Down syndrome,
often have weak accommodation and also large errors in refraction (as in
Down syndrome), which should be corrected early. Ideally, each infant and
child should be observed whether he or she needs help in early development,
so that they can develop knowing how to manage the weaker areas in their
knowledge and find support for further learning.
All infants with delays in visual milestones during the first year should
have their sensory and motor functions carefully assessed and should have
near correction in comfortable frames when needed. When the infant starts to
sit, bifocals with large flat-top reading adds are useful. Visual information in
the newborn is transferred by tectopulvinar pathway as low-contrast motion
information, so infants see facial expressions as fast-moving low-contrast
shadows and may copy expressions during the first week. There are tests to
assess vision for communication and recognition of movement at the age of 3
months, but observations on communication and interaction reveal the most
important features in the infant’s and child’s early development. Therefore
parents, therapists, and teachers should get detailed information on each area
of development and the visual tasks within it and be made aware of what to
observe during development.
Several inherited and acute diseases and accidents can damage the retina,
visual pathways, and brain, so assessment of visual functions and the
development of visual functioning are an integral part in the care of all
infants and children. Early intervention and supporting special education with
clinical examination and interdisciplinary exchange of information on a
child’s needs are important for rehabilitation and participation in school-age
activities. This helps children and their families learn to live with atypical
vision using many specific skills and devices that improve the child’s
functioning and further learning.
The unfortunate definition of low vision as “impaired vision” in the ICD-
9 misguided people to look at what the children did not have instead of what
they have. Choosing one detail, full contrast visual acuity, as the measuring
stick of quality was inadequate. In audiology, the whole frequency area is
tested; the same should be done also in vision, that is, contrast sensitivity,
motion perception, peripheral vision, and more, because vision is a complex
sense.
REFERENCES
1. International Classification of Diseases, Ninth Revision (ICD-9). IRIS: World Health
Organization, 1976–1978. https://apps.who.int/iris/handle/10665/39473.
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specification of visual acuity. Report of working group 39. Assembly of Behavioral and Social
Sciences. National Research Council, National Academy of Sciences, Washington, D.C. Adv
Ophthalmol 1980;41:103–148.
3. Nyman G, Laurinen P, Hyvärinen L. Topographic instability of spatial vision as a cause of
dyslectic disorder: a case study. Neuropsychologica 1982;20:181–186.
4. Henriksson L, Raninen A, Näsänen R, et al. Training-induced cortical representation of a
hemianopic hemifield. J Neurol Neurosurg Psychiatry 2007;78:74–81.
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https://doi.org/10.1177/0264619616640567.
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Physiol Rev 2009;89: 453–479. doi: 10.1152/physrev.00041.2007.
7. World Health Organization (WHO). ICF-CY, International Classification of Functioning,
Disability and Health: Children & Youth Version. Geneva: World Health Organization, 2007.
8. Sonksen PM, Levitt SL, Kitzinger M. Identification of constraints acting on motor development
in young visually disabled children and principles of remediation. Child Care Health Dev
1984;10:273–286.
9. “Leo learns by doing.” Video produced originally by Finnish Federation of Visually Impaired.
Chicago, IL: Good-Lite, 2011.
10. Lagerheim B. “Why me?”—a depressive crisis at the age of nine in handicapped children. In:
Gyllensvärd Å, Laurén K, eds. Psychosomatic diseases in childhood. Stockholm: Sven Jerring
Foundation, 1983.
11. Sapp W, Hatlen P. The expanded core curriculum: where we have been, where we are going,
and how we can get there. JVIB 2010;104(6):338–348.
12. Hyvärinen L. Assessment of visual processing functions and disorders. In: Ravenscroft J, ed.
The Routledge handbook of visual impairment: social and cultural research. New York:
Routledge, 2019.
13. Sakki H, Dale N, Sargent J, et al. Is there consensus in defining childhood cerebral visual
impairment? A systematic review of terminology and definitions. Br J Ophthalmol
2018;102(4):424–432. doi: 10.1136/bjophthalmol-2017-310694.
14. Wiesel TN, Hubel DH. Comparison of the effects of unilateral and bilateral eye closure on
cortical unit responses in kittens. J Neurophysiol 1965;28(6):1029–1040.
15. Hyvärinen J, Hyvärinen L, Färkkilä M, et al. Modifications of visual functions of the parietal
lobe at early age in the monkey. Med Biol 1978;56:103–109.
16. Hyvärinen J. Modification of area 7 and functional blindness after visual deprivation. In:
Hyvärinen J, ed. The parietal cortex of monkey and man. Berlin: Springer-Verlag, 1982.
17. http://www.lea-test.fi
14
Low Vision Management of Children
and Teens With Retinal Disorders
Mark E. Wilkinson and Khadija S. Shahid
Statistics
United States data estimates that 0.2% of the school-age population is
composed of children with low vision or blindness (7). Of these, only 10% to
15% are considered to be functionally or totally blind (8,9). Despite the low
prevalence of visual impairment in the school-age population, childhood
vision impairment is a significant public health problem as it affects children
across their lifespans.
Eye conditions that result in childhood visual impairment include
congenitally acquired conditions, such as albinism, achromatopsia, aniridia,
congenital glaucoma, congenital cataracts, Leber congenital amaurosis,
nystagmus, optic nerve hypoplasia, and retinopathy of prematurity, as well as
conditions that develop after birth such as cone–rod dystrophy, dominant
optic atrophy, retinitis pigmentosa, and Stargardt disease. Systemic
conditions that result in childhood visual impairment include genetic and
developmental syndromes, such as Usher syndrome and Bardet-Biedl
syndrome, as well as congenital or acquired neurologic conditions that result
in cortical visual impairment or cerebral visual impairment (CVI). The
additional disabilities associated with systemic conditions can impact how the
clinical low vision evaluation is performed and what treatment strategies are
to be employed by the low vision team.
Studies have found that 40% to 66% of children with visual impairments
have additional disabilities that can include cognitive limitations, speech and
language problems, hearing impairment and deafness, and motor and
orthopedic difficulties, such as cerebral palsy, seizures, and autism, among
many other conditions. Despite these multiple impairment challenges, 75% to
80% of this population have some useful level of vision (10,11).
Technology
Technologic advances to assist students with low vision include optical
character recognition and text-to-speech synthesizers, computer speech
synthesis, variable size fonts, and contrast enhancement devices. The
technology team and rehabilitation specialist will review with the educational
team those options that are appropriate for a given child. The expertise of a
technology consultant is invaluable in answering questions regarding access
to technology and use of technology to increase functioning.
When appropriate, the technology consultant reviews assistive
technology to improve current functioning. The technology consultant
considers low-tech to high-tech solutions, facilitates access to technology,
makes referrals for local follow-up, or provides follow-up in the student’s
home, school, and community. Review of technology options should be a
part of the ongoing process to determine what additional learning and literacy
media will best meet the needs of students with visual impairments. To
address questions, the technology consultant considers factors as outlined in
the Student, Environment, Tasks, and Tools (SETT) framework (12).
SETT:
Student information
The eye condition(s)
Low vision evaluation findings
Functional vision information
Consideration of other impairments Environments
Home
School
Vocational
Community tasks
The activities the student may require assistive technology for
Tools
What are required by the student to function as independently,
efficiently, and competitively as possible
LITERACY
The development of literacy skills for children with visual impairments is one
of the most common functional concerns reported in a clinical low vision
evaluation (13–15). The term literacy is often used, but rarely defined in an
objective and meaningful way (16). Literacy, as defined by Webster’s New
World Dictionary, Third College Edition, is the “state or quality of being
literate, specifically the ability to read and write.” Koenig (16) stated that
“literacy is demonstrated by successful and meaningful application of reading
and writing skills to accomplish desired and required literacy tasks in all
environments.”
Throughout an individual’s life, literacy is demonstrated at different
levels that go beyond the basic stage. For the individual with a visual
impairment, strategies to increase independent and efficient literacy skills
must be determined through a combination of assessment of the individual’s
level of visual functioning, determination of literacy needs, and the ability to
use adaptations and/or devices for successful access (17–26).
For children with visual impairments, the development of functional
literacy skills will be critical to their success in adult life (13–15). Reading
and writing are essential elements in the majority of vocational and
educational activities, as well as for avocational and recreational activities
(14). Koenig and Holbrook state: “There are perhaps few decisions made on
behalf of students with visual impairments that are more crucial, yet subject
to more confusion and controversy, than the decision regarding an
appropriate reading medium. Determination of the appropriate reading
medium is not a concern for those who have no visual impairment (i.e., they
will learn to read visually, using standard-sized print). Nor is it a concern for
those who are totally blind (i.e., they will learn to read using tactile braille
and/or audio reading). Difficulties arise, however, in making decisions for
those students who are visually impaired, but not totally blind” (27).
Most students with visual impairments can read visually using one or
more adaptations. This can include a closer viewing distance (relative
distance magnification), the use of an optical or electronic magnification
device, higher-contrast materials, large print, or digital materials. These
strategies facilitate the effective use of residual vision in achieving literacy
(22,23). The challenge, and a long-standing dilemma, lies in selecting which
of the above adaptations is most appropriate for the student who is visually
impaired. For example, multiple authors have found that eye care
practitioners and teachers often recommend large print books without
collecting objective data or using any systematic process to support the need
for such materials (17,27–38). The authors have noted, and the literature has
shown, that judgments are made about the reading mode for individual
children without regard to the child’s particular needs. As noted by Koenig,
Layton, and Ross, “although most professionals and parents would confirm
the need to make individual decisions for individual students, this philosophy
does not appear to hold for the provision of large print books” (39).
It has been recognized for years that many children, with significantly
reduced distance acuity (20/200 or worse), read standard or even very small
print faster and more effectively than they do large print (28,37,38,40).
Unfortunately, confusion still exists regarding the most appropriate mode of
reading for these students, especially when distance visual acuity is all that is
known or reported about the visual function. Little relationship has been
found between distance acuity and the most efficient mode of reading
(40–43). Sykes stated, “distance visual acuity is unreliable as a guide to
reading ability, although higher distance acuities undoubtedly facilitate
reading speed” (38).
Historical Perspective
As far back as the 1920s, it was thought that if an individual with a visual
impairment used their remaining sight, they would further impair what little
vision remained (44). This archaic thinking led to the practice of blindfolding
all children who were visually impaired to instruct them in braille. In the
1940s, similar thoughts led to the recommendation of providing all children
who were visually impaired with large print to avoid “unnecessary stress on
the eyes” (28). It wasn’t until 1964 that Barraga demonstrated the importance
of using vision from a young age to develop the highest level of visual
functioning (29). And in the 1970s, Sloan and Habel further demonstrated
that the students’ reading speed and comprehension scores were equal when
comparing performance with standard print versus large print (37). It is now
known that reading speed is faster when students are given regular-size print,
with or without the use of vision enhancing devices, compared to reading
large print (39).
Yet large print had been advocated for decades and continues to be
recommended for students with visual impairments. The disadvantages of
this practice are numerous. For example, “large print” suggests bigger font
size, with no standard size indicated and often without considering the need
to further magnify special characters such as fractions, exponential numbers,
or diagram labels. This “one size fits all” approach is never appropriate for
individual rehabilitation treatment. Additionally, as mentioned above, reading
speeds are slower when using large print compared to regular print even if a
vision enhancing device is needed to read regular-size print. This is because
the total head sweep needed to read large print is time-consuming and tiring.
An additional problem with large print materials is their size and weight,
which makes them more difficult to transport between classrooms and from
classroom to home. Finally, it is important to note that once a student
graduates from high school, the availability of large print reading material is
significantly reduced in higher education settings, employment opportunities,
and leisure reading tasks.
Despite these disadvantages, the practice of large print continues to be
recommended by eye or other doctors, often without reasonable information
to validate this recommendation, and by general education teachers and
parents, simply because this has been standard practice for years prior. For
some schools, there is a perception of advocating for a student with visual
impairment by using these specialized large-print textbooks and materials.
And for some TVIs, the recommendation is made when they don’t have any
additional data (from the primary eye care provider) to support a more
appropriate choice.
Optical and/or electronic magnification devices provide students with
immediate access to printed material at their desks. Some devices also allow
access to educational information at extended distances, such as on traditional
or interactive white boards. These devices should be used in conjunction with
the best corrective lenses provided for distance viewing. Options such as
telescopes will improve detail vision at distances beyond arm’s length, such
as reading the board in school and street signs in the community. Electronic
magnification devices (aka closed-circuit television or CCTV) provide access
for both near and distance tasks in the classroom. These devices enhance the
student’s accessibility in the classroom and beyond, resulting in increased
visual independence.
Braille
Despite the body of work promoting the use of available vision for learning
and the use of assistive technology to enhance access to educational
materials, promotion of a braille-based approach to education for a majority
of students with low vision continues to persist among some groups. Section
614 (d)(3)(B)(iii) of IDEA states that “The Individualized Educational Plan
(IEP) Team shall, in the case of a child who is blind or visually impaired,
provide for instruction in braille and the use of braille unless the IEP Team
determines, after an evaluation of the child’s reading and writing skills,
needs, and appropriate reading and writing media (including an evaluation of
the child’s future needs for instruction in braille or the use of braille), that
instruction in braille or the use of braille is not appropriate for the child.”
In 2009 the National Federation for the Blind (NFB) published a report
on literacy titled “The Braille Literacy Crisis in America.” The report
declared that children who are visually impaired or blind requiring braille
instruction were unable to obtain timely and appropriate training. The report
stated that braille instruction should be incorporated into the educational plan
for the majority of children with vision loss. To support their agenda, the
NFB developed the National Reading Media Assessment (NRMA). The
NRMA does not allow the student to use any vision enhancing tools other
than corrective lenses and visors. The use of optical and/or electronic
magnification devices is prohibited during this assessment. Additionally, the
NRMA states that all assessment materials will remain flat on the desk or
table and not held at the habitual or preferred reading distance of the student.
The approach promoted by the NRMA is in direct contrast to IDEA and
Individuals with Disability Improvement Act (IDEIA) of 2004, which
requires that an assistive technology assessment be provided to determine
what tools are needed by the student to access the general education
curriculum. Additionally, the NRMA recommendation that testing materials
should not be brought closer to the eyes is inconsistent with how students
with visual impairments function. Additionally, IDEA allows for
accommodations on tests, which the NRMA does not allow. There continues
to be no published data on the NRMA that proves this assessment
methodology is a valid and/or reliable assessment tool.
Many braille proponents state that a student should learn braille
immediately, because they may need it in the future. The problem with this
approach is that it assumes the world is static and does not consider
technology advances, including gene or stem cell therapies that are
anticipated to be available in the near future for some patients. Additionally, a
student learning both braille and print reading will often only learn braille as
well as they can see it. Finally, trying to learn to read in both print and braille
can take time away from learning other educational areas. Experience
demonstrates that those that truly need to learn braille will learn it. A recent
study of 29 sighted adults naïve to tactile braille reading given a 9-month
course in braille found that the majority could read whole words at 6 words
per minute by the end of the course, demonstrating that learning braille as a
child is not a necessity (51). Novel technologies that combine electronics
with tactile braille reading are being developed (52).
Optical Devices
Optical devices were first prescribed for school-aged children in the early
1960s, about the time when educators were starting to believe that vision
should be developed for efficiency, rather than conserved and saved (29).
Sykes (38) and Sloan and Habel (37) found that students who were visually
impaired performed as well using 10-point type with optical devices as they
did with 18-point type without optical devices.
The Division for the Visually Impaired of the Council for Exceptional
Children published a position paper that stated “any child who can benefit
from the use of a device should receive a clinical low vision rehabilitation
evaluation by an ophthalmologist or optometrist who is knowledgeable in the
prescription of such devices” (53). The position paper also noted that the
evaluation and the optical device(s) can often be obtained at an overall lower
cost than large type books. Therefore, when funds are redirected to clinical
evaluations and prescribed optical devices, the result can be a decreased
burden of cost to taxpayers and an increased accessibility to regular print
materials to the student with visual impairment (53,54).
Corn and Ryser (17) found that students who use optical devices gain
certain advantages for functioning in the sighted world. The use of optical
devices, for those who can benefit from them, should be viewed as the least
restrictive approach to gain access to regular print materials for near and
distance tasks. The use of prescribed telescopic devices gives the student
access to chalkboards, signs, and events in the distance. Corn and Ryser
stated (17) “optical devices should be considered individualized educational
tools that are just as important to a child with low vision as is a brace to a
child with a physical disability or a hearing aid to a child with a hearing
impairment.”
Evaluations by qualified low vision rehabilitation practitioners are critical
to the educational process because they yield a starting point for the
prescription of a low vision device or devices. After the initial prescription,
the TVI teaches the student to use the device and works alongside others on
the educational team to evaluate its usefulness in real-life settings. Proper
prescription and instruction must be a joint effort by clinical low vision
rehabilitation practitioners and educators. Both contribute unique information
to the decision-making process that should not be accomplished separately
(39).
For the student whose primary literacy medium is print, the use of a
handheld or full-sized video magnifier, or an optical device as a tool to
supplement the use of regular print, will likely allow access to all printed
medium needs in all types of settings.
Koenig and Holbrook (27) proposed “the need to fill a student’s ‘toolbox’
with all the ‘tools’ necessary to accomplish the demands of specific tasks and
thereby demonstrate functional literacy.” The choice of tools will be specific
to the needs of each student and may include digital audio media; the
assistance of a sighted reader; optical and electronic magnification; radio
reading service; print (standard or large type); braille; and accessible
technology such as word processing and/or computer applications, speech
synthesis devices, large print terminal displays, and optical recognition
scanners. An individual at the functional level of literacy will determine the
requirements of a given task and then select the tools to accomplish the task
most appropriately and efficiently.
Because of the unique characteristics of students with visual impairments,
no generalizations about reading media are possible. For this reason, the
educational team must provide an individually administered and interpreted
learning media assessment to identify personal differences for individual
students.
The selection of the most efficient reading medium for a given student
must reflect the input from each member of the educational team. Decisions
should consider the individual sensory ability and capabilities of each
student, as well as their immediate and future needs. The need to provide
additional instruction in other reading media should be reviewed through
continuous evaluation as the student’s needs change or expand. When no
educationally relevant differences exist between print options, selection of the
option that is least restrictive is key. When the most efficient option is not the
least restrictive one, the team must build additional skills in the least
restrictive option. By objectively determining each student’s most efficient
print reading option, overall reading efficiency can be assured.
The importance of low vision rehabilitation practitioners and educators
working collaboratively to meet the individual needs of a child with a visual
impairment cannot be overemphasized. This is especially true when a change
in the primary literacy medium is warranted. For example, changing to large
print should not be provided without objective data to support that decision.
A clinical low vision assessment, provided by a low vision rehabilitation
practitioner, is essential to assist the educational team in making literacy
medium decisions.
Eye care practitioners should avoid unilateral decisions. They are only
one of the many professionals responsible for the child’s educational
development. Eye care practitioners must remember that the literacy needs of
children are different than the literacy needs of adults. Most adults who seek
low vision care (because of acquired vision loss) already know how to read
and write. For this reason, adults simply need assistance to use the same
reading and writing skills they developed in their youth. Children, on the
other hand, are just learning to read and write, which requires ongoing,
multidisciplinary services. When a collaborative relationship is developed
between eye care practitioners and educational specialists, timely and
appropriate educational decisions can be made for children with low vision.
Reports
When reporting a child’s visual status, it is important to include the following
elements in the report:
Diagnosis
Prognosis that realistically states the expected course of the visual
condition over time
Eye medications
Color vision deficiencies
Visual acuity: distance
Visual acuity: near with working distance for reading
Recommended reading print size if known
Visual field limitations
Photophobia that requires intervention when indoors as well as outdoors
Restrictions in activities including the need to restrict certain sports
activities, such as small ball sports and/or having an adapted physical
education program. If a student may participate in contact sports only if
Trivex or polycarbonate sports safety glasses are worn, this should be
stated. These lenses are impact and breakage resistant; Trivex may have
superior optics and impact resistance than the older polycarbonate
lenses.
Special contrast needs and/or lighting requirements
Is a spectacle correction needed for general use, distance only, or
reading only?
Optical and/or electronic magnification devices
recommended/prescribed
Next evaluation date
BARRIERS TO CARE
There are barriers to accessing low vision rehabilitation services for many
children and young adults with low vision. Those barriers included the cost of
low vision services, lack of availability of low vision practitioners,
geography, as well as the attitudes of parents and teachers about what can be
done to help students with visual impairments. Also, beliefs about what to
expect from students with visual impairments in addition to a lack of
knowledge concerning visual impairments in general can be factors that
impede widespread availability of low vision clinical information.
SUMMARY
Low vision rehabilitation is the only nonsurgical treatment modality for
vision loss. This is why it is essential that children with visual impairments
have access to ongoing clinical low vision rehabilitation care. Ongoing
clinical low vision rehabilitation evaluations, performed by optometrists or
ophthalmologists trained and experienced in low vision rehabilitation, are an
essential component in the educational planning for every child with a visual
impairment. The clinical low vision rehabilitation evaluation provides all
adults involved in the care, education, and habilitation/rehabilitation of
children with visual impairments with critical information about the nature
and severity of a child’s visual impairment and strategies for enhancing the
child’s use of remaining vision. These strategies include corrective lenses,
magnification, and other low vision adaptive devices, as well as services and
accommodations that would increase the child’s access to visual information
at school and during activities of daily living.
Students with visual impairments should have access to prescribed
optical and/or electronic adaptive devices, instruction in the use of prescribed
devices, and recommended habilitation/rehabilitation services throughout
their educational program. Information provided by ongoing clinical low
rehabilitation vision evaluations ensures that Early Intervention Programs for
young children and Individualized Educational Programs for school-age
children are truly individualized for the visual needs of children with visual
impairments and provides these children with the best opportunity for
successful growth and development.
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SECTION III
Imaging of the Infant and Child Eye
and Retina
15
Retinal Photography and Multi-
Wavelength Imaging in Infants and
Children
C. K. Patel and Andrew Blaikie
INTRODUCTION
The chapter considers the basic requirements of visualizing the retina to
record an image with emphasis on historical milestones in photography that
have led us to contemporary methods of retinal imaging. A classification of
devices used in pediatric ophthalmology and retina is presented based on the
wavelength of light used for image acquisition, image quality, ease of use,
and cost. How some of the devices are used will be described in detail. The
utility of these imaging techniques will be illustrated with case histories.
I, internal angle; V, video: Cost in U.S. dollars defined as high (>20 K), mid (2.5 to 20 K), low (0.3 to
2.5 K), and ultralow (<0.3 K).
The basic elements of image quality are resolution and FOV. There is no
consistency on how best to describe the resolution of imaging devices.
Manufacturers may fail to state objective measures of resolution and simply
use adjectives such as high. When objective statements are made, reference to
the specification of the sensor within the device is made implying that this
will reflect the real resolution of the final image. The specification of the
sensor, however, can be meaningless if the optical system projects an image
of low quality onto a high-resolution sensor. As with a HI-FI system, the
quality of sound generated by expensive big speakers is irrelevant if they are
being driven by a low-quality turntable and amplifier. Manufacturers could
consider stating resolution as the size of the smallest resolvable retinal detail
that can be reliably imaged, such as “10 microns.” Another measure could be
sensor pixels per micron of retina or per degree of field. These approaches
would offer more clinically relevant information that will relate to the
genuine quality of the image generated. Although instinctively a device that
generates images of high resolution would feel like a positive asset, not all
pathologies demand extreme granularity of detail for reliable interpretation
and consequently may be unnecessarily over specified. For instance, one may
not require the same level of fine lateral resolution to assess plus disease as
would be needed to discern diabetic microaneurysms.
The nomenclature around FOV in pediatric retinal imaging has been
reviewed to ensure that devices are comparable (15). Figure 15-1 shows that
three different angles referenced to the nodal point (E,I) and center of the eye
(C) describe the same area of retina being imaged. The central angle is largest
and internal angle smallest.
Several devices have been developed to maximize the FOV recorded. This
technology was driven by the clinical wish to image a specific disease where
peripheral imaging is important such as in ROP, familial exudative
vitreoretinopathy (FEVR), and peripheral retinal degenerations that may
predispose to rhegmatogenous retinal detachment. Group 1 devices include
those devices, tabletop and handheld, that produce images with a FOV 80
degrees or greater. Traditional desktop retinal imaging cameras (group 2)
employ noncontact conventional optics generating a FOV in the range of 30
to 50 degrees that displays the macula and surrounding vessels in a single
unedited image. This FOV is similar to the noncontact handheld devices
(group 3), binocular indirect ophthalmoscopes with video (group 4), as well
as devices that exploit cameras on mobile phones when using a high powered
condensing lens (group 5). Optically, group 5 is akin to a monocular form of
binocular indirect ophthalmoscopy (BIO) but replacing the viewers’ two eyes
with the single camera lens of the phone. Retinal imaging devices that exploit
direct ophthalmoscopy techniques (group 6) are innately limited to a small
FOV of around 5 to 15 degrees depending on nature of the piggyback device,
the diameter of the pupil, and how close the camera is to the iris plane. To
overcome the limitation of a still image with a narrow FOV, assessing a
video sweep of the area of interest is another strategy. Alternatively, software
can automatically stitch frames together either from a number of single
images of different regions of the fundus or from video sweep, although
artifacts can be introduced when a stitched montage is created. The apparent
FOV of innately narrow field devices can then be artificially expanded to
generate a wider FOV.
There are benefits and drawbacks to ease of use for the different camera
systems. Some of the U-WFI cameras (group 1) require considerable
cooperation to reliably acquire an image in a short period of time without
unduly upsetting the child. All devices that require contact with the cornea
require anesthesia and restriction of movement. A minimum requirement is
topical anesthesia combined with swaddling to restrict movement of the baby.
In older children, deep sedation or general anesthesia is needed. Other
devices are restricted to imaging patients upright, requiring the placing of the
child’s head in a cage-like rest (group 2) or requiring the child to peer into a
black hole. This is generally impractical for many preschool children but can
be worthwhile in selected cases. Light handheld noncontact devices can allow
the user to quickly maneuver into position to accommodate a wiggly child,
but motion artifact has the potential to compromise image quality. In this
situation, acquisition of high-resolution video rather than intermittent single
frames offers advantages. Review of the video after the examination allows
editing of the best segments or selection of the most informative single
frames for a second opinion or analysis. Several new devices offer this useful
function, thereby increasing the opportunity for acquiring clinically useful
images.
The retinal cameras vary in weight, portability, and cost. Devices
designed for U-WFI are innately large and heavy making them impractical to
transport swiftly and reliably between sites, and the cost may limit purchase
of a system for each site. The ideal retinal camera for a rural primary eye care
setting in a low-income country would be robust yet light, taking up little
volume and allowing it to be quickly packed up and safely moved between
clinics. There are now a number of handheld devices that meet these criteria,
although they are still relatively expensive with most devices falling into the
mid cost range. The most compact devices are also those that cost the least by
exploiting the cameras of mobile phones. They are, however, dependent on
the optics, software, and sensors of the camera within the phone.
Consequently, the quality of image is variable depending on the make and
model of phone with little published information on the FOV and resolution.
A recent device on the market that is an outlier is the epiCam made by
Epipole Limited (Rosyth, Scotland). This device exploits the power supply
and computing hardware of a mobile phone but uses its own software and
optics. It acquires high resolution at 15 frames per second video in gray scale
and falls into the low-cost range (https://www.epipole.com/epicam-m/ ).
The additional hardware needed to acquire retinal images in this way
varies in cost from 10 to 1,000 British pounds (>$1,200 American dollars)
with the additional cost of acquiring a suitable mobile phone camera.
Thus, there is no overall ideal retinal imaging device; the reality is that
there are cameras for specific settings and specific pathologies with a
constant tradeoff between image quality, portability, and cost. What works
well for a child with ROP under a general anesthetic in a tertiary referral
center in a high-income country may not be the device of choice for a child in
a primary care clinic in rural sub-Saharan Africa with cerebral malaria.
Moore law suggests that technology improves significantly each year with a
paradoxical reduction in cost. It can be hoped that retinal imaging will also
benefit from this trend with higher quality, easier to use, and lower cost
devices, further democratizing access to relevant retinal imaging.
CONSIDERATION FOR IMAGING IN
INFANTS AND CHILDREN
As a general rule, the advantages of innovation in imaging of the retina in
adults have been useful in imaging the retina of children 5 years of age or
more as they are likely to cooperate with the need to maintain steady fixation.
In less cooperative children including infants, the options include cameras
that require contact with the cornea or are noncontact systems. Contact
cameras are useful both at the bedside and in the operating room, as
exemplified by the RetCam. One of the authors (CKP) has direct experience
using the portable version of RetCam-II known as RetCam shuttle. RetCam-
III is the latest iteration and retains a 3-chip charge-coupled device (CCD)
camera yielding a 24-bit color image with the main modifications being a
lighter handheld “gun,” improved review software and extended duration of
video capture with options of modules that allow for fluorescein angiography.
Figure 15-3 shows a RetCam-III being used in the operating room following
the insertion of a lid speculum. The D1300 focusing lens is the most popular
for ROP and attaches to the handheld “gun,” which is placed on a baby’s eye
through a coupling gel. Achromatic light from a ring-based illumination is
focused through the entrance pupil. A foot-pedal attachment is used to
modify illumination and focus and then a foot switch is actuated to capture an
image. The gun has to be rotated about the visual axis to capture images of
the peripheral retina (Figure 15-3A). For assessment of ROP, the standard
examinations consist of either three images (central [C], nasal [N], temporal
[T]) or five captured images if superior and inferior images are also added.
There is an option to record a video of the real-time examination from which
still images can be extracted. The images are then graded for ROP by medical
(11,17) or nonmedical personnel (18). There are now several alternatives to
RetCam-III including the Icon, 3nethra-neo, PanoCam from Phoenix
(Pleasanton, California), Forus (Bengaluru, India), and Visunex (Freemont,
California), respectively. The PanoCam has wireless capability for color
images and fluorescein angiography that is a potential advantage for
telemedicine paradigms.
FIGURE 15-3 RetCam-III being used in the operating
room under general anesthesia showing how it is held
centrally (C) over the eye (A-C, B-C) to obtain disc and
macular views with tilting required (A-T, A-N) for
temporal and nasal vies of the left eye in this patient. Note
that rotation of the device about the visual axis affects the
orientation of the fundal image with respect to the primary
position of the eye.
There are several advantages to the contact cameras. They are portable and
can, therefore, be used easily in different hospital settings including
ophthalmic outpatients, neonatal intensive care units, and the operating room.
Contact cameras yield true color images, which accurately convey critical
diagnostic features of retinal pathology and are also able to image anterior
segment structures. A narrow depth of field can yield inferences about three-
dimensional aspects of pathology as shown by the diagnosis of stage 4 ROP
(Figure 15-4).
The contact cameras also have limitations. Ring illumination yields variable
exposure across an image, such that the periphery is less clear and can impact
adversely on telemedicine grading required for ROP (19). Clarity is
compromised in darkly pigmented fundi and in the presence of small pupils
and media opacity. Ocular blood flow is impaired by excess globe pressure,
potentially compromising the diagnosis of plus disease in ROP (20). Retinal
hemorrhages have been ascribed to globe contact (21), and infection control
is of paramount importance when using these devices between patients.
The Optos device, although a tabletop device, also can be used for infant
and child imaging. Initial reports from Oxford (9) and Scotland (22) have
been followed by wider adoption of these devices for use in neonates from
other countries, including India (23) and the United States (24). Figure 15-5
shows the imaging technique in premature infants in the neonatal unit for
ROP screening. The process involves the use of an eyelid speculum, often
taped to the cheek following instillation of local anesthetic eye drops. The
flying baby position is used to securely hold a baby. The neck is extended
slightly as the baby’s face is brought close to the aperture of the Optos
200Tx. The lumbar area of the large more mobile baby requires support to
minimize body movement. Ocular alignment is optimized on the grayscale
monitor with small movement of the head while the photographer clicks a
handheld switch multiple times to capture a series of pseudocolor images.
The cornea is hydrated intermittently. The vestibulo-ocular reflex is used to
encourage ocular alignment if the eye rotates out of the primary position. The
index and ring finger of the hand supporting the chin can also be used to
support an endotracheal tube allowing ventilated babies to undergo imaging
with full medical supervision in the neonatal intensive care unit (15,25).
There is a virtual reality video demonstrating the technique (26).
FIGURE 15-5 Flying baby positioning for Optos ultra-
widefield imaging. The baby is lifted from the cot, held
horizontally while the assistant inserts taped lieberman
style speculums into anesthetized eyes (A). The cornea is
hydrated and the ventral torso of the baby is supported by
the forearm while the thumb and forefinger support the
chin and face (B). Once the baby is rotated, the
contralateral hand supports the occiput with the neck
slightly extended to allow approximation of the eye to the
camera (C, D). It is helpful if the hand supporting the chin
touches the camera to provide proprioceptive feedback
while the grayscale monitor is observed to facilitate ocular
alignment.
By rotating the infant’s eye from the primary position in the flying baby
technique, it is possible to improve the FOV of the superior and inferior
retina with the Optos 200Tx (27) as shown in Figure 15-6. There are
advantages to imaging infants and children with the noncontact ultra-
widefield Optos system. The confocal laser optics yield a more uniform focus
across the FOV. Image capture occurs rapidly over 0.25 seconds. Adequate
ocular alignment can usually be obtained with examination times of 10 to 30
seconds once the flying baby technique is mastered. The FOV is not limited
by pupil size, and the laser illumination less often compromises clarity when
media opacity, such as a corneal scar, is present (28). The narrow 0.3-mm
scanning beam of the Optos and a virtual focal point that is behind the plane
of the anterior lens capsule allow for visualization of the retina in the
presence of an axial cataract. Such a cataract can prevent experts from seeing
the retina using BIO (29). High quality of images with fundus fluorescein
angiography (FFA) is achievable in awake neonates, potentially reducing the
requirement for general anesthesia and reducing morbidity as well as cost
(30). FAF U-WFI uses green laser for excitation, which is less absorbed by
macular pigment and potentially yields better signal from the macula.
Noncontact systems avoid traumatic sequelae and infection risk associated
with contact-based systems.
FIGURE 15-6 The image on the right (B) was taken with
the baby’s left eye rotated approximately 90 degrees and
shows improved visibility of the superior and inferior
retina above and below the arrows, which shows
corresponding vascular landmarks relative to the figure on
left (A).
There are also limitations to the use of the Optos system for infant and child
imaging. There is an instinctive reluctance to consider the use of the flying
baby technique in medically vulnerable groups, such as premature infants.
Although we have demonstrated that it is feasible to image even the most
vulnerable babies, for example, those who are ventilated, there is the potential
for statistically significant morbidity (31) although it is debatable if this is
clinically relevant (32). The Optos 200Tx is not portable, which limits its
potential use across a hospital site in the way that RetCam shuttle could be
used. The Optos California device has a smaller footprint and is mounted on
a table that can be moved but lacks a mobile power source. The FOV varies
with the distance of the baby from the device at the time of image capture
(27). FAF U-WFI does not use image averaging, which can limit quality.
The artifacts produced during pediatric retinal imaging have been
systematically studied and reported (27). They were classified according to
descriptors illustrated in Figure 15-7.
The U-WF imaging module can be used to obtain grayscale infrared, FFA
and ICG-A images, individually or simultaneously. Following proof of
concept that it could also acquire optical coherence tomography (OCT)
images when manually held over an infant’s eye (33), we customized an arm
to support it for use in the operating room to acquire OCT scans and
angiograms (34) (Figure 15-9D and E). Heidelberg engineering
subsequently developed a servo-assisted arm called the Flex to perform a
similar function for supine patients, such as infants in the operating room
(35). The platform is, therefore, able to deliver the full range of retinal
imaging to the pediatric patient, including infrared, multicolor, infrared, and
blue FAF imaging. Optical coherence tomography angiography has also
recently become available.
One clear advantage of the Spectralis platform is the integration of OCT
with retinal imaging that incorporates a tracker. This allows for accurate
localization of pathology and facilitates monitoring of diseases in clinical and
research domains. The images are less distorted compared with images from
Optos devices. Image averaging algorithms facilitate higher quality
autofluorescence imaging. Media opacity and pupil size affect image quality
less than systems that use achromatic light.
Limitations to the system are that the device usually requires general
anesthesia to obtain good quality images in infants. It is not portable. Dark
condensation artifact with FFA has been reported and attributed to the close
working distance of the ultra-widefield lens to the eye during anesthesia (36)
(Figure 15-9C). The artifact can be eliminated by generating air currents near
the eye. The macular autofluorescence with blue light is reduced because of
absorption by luteal pigment.
The Optomap is also valuable for ruling out sight-threatening ROP when
media opacity such as anterior polar cataract precludes adequate binocular
indirect fundoscopy (Figure 15-12).
Use of a contact camera focusing at different levels in the vitreous cavity can
be helpful in the diagnosis of acute tractional retinal detachment (Figure 15-
4), which is less well seen by Optos devices. The true color representation of
lesions afforded by contact-based cameras that use achromatic light is
important in the differential diagnosis of retinal neoplasia and forms of
uveitis and chorioretinitis.
Multimodal images that also incorporate OCT are very useful
diagnostically. For example, in the management of a child with vitreous
hemorrhage, infrared and OCT imaging of the contralateral eye can suggest a
diagnosis of congenital X-linked retinoschisis (Figure 15-13). FAF imaging
is key to the diagnosis of a retinal dystrophy, such as Stargardt disease, and
acquired problems, such as laser-induced maculopathy.
Screening and TreatmentBasic fundus images, WFI, and U-WFI are useful in
the screening and documentation of many retinal conditions in infants and
older children to provide a useful reference as to the location, severity, and
extent of a vitreous or retinal finding, including vitreous or retinal
hemorrhage, choroidal nevus, coloboma, chorioretinal scar, vitelliform
lesion, or retinitis. The RetCam and allied cameras are well established for
the documentation of retinal hemorrhages in the diagnosis of abusive head
trauma in infants (details in Chapter 70). Optomap U-WF images are an
alternative option in the outpatient setting that can be used in conjunction
with a speculum using the flying baby technique when safe to the infant (39).
In heavier larger infants, when visual function is impaired bilaterally from
premacular hemorrhage, it is worth attempting imaging without a speculum
while supporting an infant held vertically to avoid distress. FFA can be
helpful in establishing that a suspected macular obscuring preretinal
hemorrhage is in fact intraretinal schitic hemorrhage with inner retinal vessels
visible on FFA (39). The Spectralis platform is able to show how FFA can
also be valuable in establishing the later complication of peripheral retinal
ischemia (Figure 15-14).
Basic fundus images play a role in the management of retinal vascular disease
through documentation of macular exudation, vascular abnormalities, retinal
and vitreous hemorrhage, and location of laser treatment spots. As in adult
disease, retinal images may be examined to screen for or document status of
diabetic or sickle retinopathy. Screening of children with sickle cell is
suggested to commence at 9 years of age for SC genotype and 13 for SS
genotype. Retinal WFI and U-WFI may be useful in the screening and
documentation; however, the additional use of FFA with U-WFI, SD-OCT,
and OCTA have the potential to detect proliferative disease earlier in the
natural history before sight-threatening neovascular complications ensue
(44). Fluorescein angiography is well established as key for image-guided
treatment paradigms allowing for precise dosing of laser treatment in
ischemic and exudative retinopathies, such as ROP, Coats disease, and FEVR
(15,38). FAF can be helpful in the assessment after laser treatment, because
laser treatment sites appear as hypo-autofluorescent spots. Thus FAF images
can be used to locate sites for augmenting laser treatment such as in the
surgical management of optic disc pit maculopathy (Figure 15-16).
FIGURE 15-16 Disc pit maculopathy recurred following
primary treatment with barrier laser photocoagulation with
the OCT showing submacular and intraretinal fluid (A)
with the corresponding 55-degree Spectralis blue FAF
image (C) showing the old laser burns around the disc,
diffuse (black arrow) and punctate (yellow arrow) hyper-
autofluorescence secondary to bisretinoid accumulation.
Six months following vitrectomy, gas tamponade, and
endolaser, there was subtotal resolution of subretinal fluid
(B) with improved vision. The 30-degree blue FAF image
(D) show a missing area of laser (blue arrow) that was
augmented with outpatient slit lamp delivered laser
photocoagulation as the 15-year-old teenager was
cooperative.
RESEARCH
Morphometry, the quantitative analysis of size and shape, is one of the pillars
of scientific endeavor and essential in research and clinical care of retinal
disease. Retinal imaging involves translating a three-dimensional curved
surface into a two-dimensional representation. This process is constrained by
the optics of devices and results in distortion of images, such as exaggeration
of the size of peripheral versus central features. For quantitative analysis, a
variety of grids have been developed to overlay across images for grading
features, such as nonperfusion in diabetic retinopathy (48). Software
modifications have attempted to reduce distortion to facilitate accurate
morphometry, but distortion especially in the far periphery remains a problem
that requires consideration and potentially adjustment during image analysis
(49). This peripheral distortion is pertinent to grading of ROP with WFI and
U-WFI, since the International Classification of Retinopathy of Prematurity
(ICROP) zones are circles centered around the optic nerve. For example,
because of distortion of retinal images, it is not known if it is accurate to
assume that the distance between disc to fovea is the same as the
corresponding distance nasal to the disc, when overlaying circles on images.
Artificial intelligence is now a well-established modality facilitating
pattern recognition. Large datasets of retinal images can be processed by deep
learning algorithms to assist with diagnosis. In pediatric retina, screening for
ROP is a large public health issue, which is focused on the need to make a
diagnosis of plus disease. The current gold standard of indirect
ophthalmoscopy and image-based screening has not yet delivered a
universally accepted effective system. Deep learning may deliver this in the
near future (50) and is addressed in greater detail in Chapter 19.
Additional research measurements from imaging will play a future role in
pediatric disease. One example is the differential reflectance of
oxyhemoglobin and deoxyhemoglobin with the dual-laser wavelength
imaging platform of the Optomap. This technique allows the measurement of
oxygen tension in the retina and has been demonstrated in healthy neonates
(51). Changes in these measures in the retina can be a proxy for disease in the
central nervous system. Thus there is potential for retinal imaging in children
to identify biomarkers of pediatric degenerative brain disease much in the
same way as is being explored for adult disease (52) or for retinal oximetry to
be applied in ROP (15). With the development of handheld oximeters, retinal
oxygen metabolism in pediatric retinal vascular disease should provide new
insights that could prove useful in better understanding disease
pathophysiology and potentially clinically (53).
SUMMARY
The pediatric retina can be interrogated by conventional white light, filtered
light, or with single wavelengths of light, which yield color, pseudocolor,
grayscale, angiographic, and autofluorescence images. Advances in
information technology and physics have delivered platforms that allow us to
overcome the barrier of ocular fixation that has in the past prevented imaging
the retina of infants and children. These advances facilitate clinical care of
children by assisting with diagnosis, follow-up, screening, treatment, and
research to improve outcomes for a population that is the future of every
society.
ACKNOWLEDGMENTS
1. Photographers at Oxford Eye Hospital: Lewis Smith and Jon Brett
2. Peter Charbel Issa for reviewing manuscript
3. Caroline Justice: ROP nurse specialist
4. All trainees that transit through Pediatric retinal service at Oxford
5. Optos, Heidelberg Engineering, and Epipole for their support in
developing instrumentation for pediatric imaging
6. Our families for their support
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16
Optical Coherence Tomography in
Infants and Children
Lejla Vajzovic, Anand Vinekar, and Cynthia A. Toth
Terminology
1. Central Foveal Thickness: The thickness of the entire retina extends
from the inner aspect of the internal limiting membrane (ILM) to the
inner aspect of the RPE at the foveal center.
2. Inner Retina: The inner retinal layers (IRLs) include all the retinal layers
from the inner aspect of the ILM to the outer border of the INLs.
3. Outer Retina: The outer retinal layer extends from the inner aspect of the
OPL to the inner border of the RPE.
4. Photoreceptor Layer: The photoreceptor layer (PRL) extends from the
outer aspect of the OPL to the inner border of the RPE.
The axial length of the infant eye changes by 9 mm from birth to age 10, and
this affects reference arm length for OCT imaging and the scaling factor for
lateral measurements. While this is also relevant for measurements across
different adult eyes, only in children do we need to consider the change in
axial length in the same patient from month to month (6). Particularly, one
should take into account patient’s age and optics of the eye when setting
imaging parameters for infants and young children and measuring ocular
structures on those images (6).
The portable, noncontact, handheld SDOCT unit (Envisu 2300, Leica,
NC) consists of an imaging hand piece connected via a flexible cable to an
SDOCT engine mounted on a rolling cart. The SDOCT system has a
calibrated knob to adjust the reference arm position settings for the axial
length of the eye based on age (6). The handheld probe has a focus correction
adjustment with a range of +10 to −12 D, which limits imaging in the setting
of aphakia. When imaging infant eyes in the clinic or hospital unit, we have
found that the near infrared light of SDOCT imaging is tolerated better by
infants than the clinical exam with white-light indirect ophthalmoscopy. The
illumination from the Envisu system appears to the patient as a faint red line
against a black background. Swept source OCT, which typically uses light
even further in the infrared, is usually not visible to the patient. We have also
found that the operator could readily hold the eyelids open in the awake or
sleeping infant and that a lid speculum was thus not necessary for this
imaging. Adding artificial tears before imaging, especially when under
anesthesia, provides a more stable tear film and often better signal in the OCT
images.
Retinopathy of Prematurity
The current gold standard for retinopathy of prematurity (ROP) diagnosis is
clinical examination performed by trained specialist using indirect
ophthalmoscopy. Additionally, telemedicine has gained traction, and in
certain centers, screenings are facilitated by capturing and reviewing wide-
field fundus photographs using contact camera systems such as RetCam
(Clarity MSI, CA, USA). These bedside examination tools allow for
ophthalmoscopic en face viewing of the premature retina. The cross-sectional
visualization of the retina and its vasculature from OCT imaging in preterm
infants and young children has added relevant information about the effects
of ROP across the developing retina. The previously unrecognized retinal
findings in ROP will be useful in the assessment of clinical outcomes (31).
As noted above, with SDOCT imaging, the premature eye has a
shallower foveal pit, presence of IRLs at the foveal center, thinner outer
retinal layers including attenuated photoreceptors, and absence of inner and
OS (Figure 16-2) (1,25). Notably, 20% to 50% of premature infants have
intraretinal cystoid changes described as macular edema of prematurity
(Figure 16-6) (32–37). Intraretinal cystoid spaces are only rarely seen in term
infants, and if these do occur, they are most common with a systemic disease
such as liver failure (38). Macular cystoid spaces are a subclinical feature
only identified by OCT, although in severe cases of macular edema, the
blunted fovea may be discerned on the clinical examination; in some cases, it
has been shown to leak on FA (39). Furthermore, macular edema of
prematurity has, in some cases, been associated with poorer visual acuity and
neurodevelopmental outcomes (40).
FIGURE 16-6 Macular edema of prematurity in 36-week-
old premature infants. Note the hyporeflective intraretinal
cystoid spaces of so-called macular edema (ME) of
prematurity. They resemble macular edema seen in adult
diseases. Varying degrees of macular edema are illustrated
starting with mild ME (foveal depression persists with
small cystoid spaces), moderate ME (loss of foveal
depression and retinal thickening with columnar-like
cystoid spaces), and severe ME (marked retinal thickening
with columnar-like cystoid spaces).
Incontinentia Pigmenti
Incontinentia pigmenti (IP) is a rare, inherited retinal vascular disordered
with X-linked dominance (discussed in Chapters 36 and 66). It presents with
ocular findings that include retinal vascular occlusion, neovascularization,
hemorrhages, foveal abnormalities, and retinal detachments, some of which
are readily recognized on FA. However abnormalities such as inner and outer
retinal thinning are identified on SDOCT that are likely related to ischemia
and are not readily picked up on clinical exam or funduscopic imaging and
may explain changes in visual acuity (51,52) (Figure 16-9).
Coats Disease
Coats disease, a retinal vascular disease, is typically unilateral and affects
young boys (more details Chapter 64). Although clinical examination and
fluorescein-guided treatment remains gold standard, SDOCT can be used to
identify and monitor distinct retinal and subretinal features such as
intraretinal or subretinal exudation, intra- or subretinal fluid, outer retinal
layer loss, subretinal fibrosis, and retinal thickening (53,54) (Figure 16-10).
The SDOCT features of subretinal fibrosis and outer retinal atrophy are
associated with poorer visual acuity. Thus, OCT contributes to the prognostic
factors and response to treatment.
Retinoblastoma
In patients with retinoblastoma (Chapters 44 and 45), OCT can detect
recurrent retinal tumors that are not visible clinically, as well as
retinoblastoma-associated epiretinal deformation, retinal edema, subretinal
fluid, and optic nerve and vitreous changes (59). It is also useful in evaluating
diffuse infiltrating retinoblastoma and monitoring the response to treatment
(60).
Trisomy 21
OCT appears useful to study subclinical features of the macula and correlate
them with visual acuity and vision development in trisomy 21 or Down
syndrome (DS). Inner retinal fusion was noted in only 15% of cases
compared to all cases of matched normal children. Other layers that were
abnormal in children with trisomy 21 include the OPL, the ELM, and the IZ.
Thus far, these OCT findings have not been linked to visual acuity. It is
possible that in the future, OCT will help us understand the anatomical basis
of subnormal vision development in this and other syndromes where the
fundus may appear clinically normal (61,62).
Inherited Retinal Diseases
OCT and OCT-A are especially useful for inherited retinal diseases. As
described in the disease-specific (Chapters 22–37), OCT information is often
diagnostic and can provide important information as to the severity of the
phenotype and the interval disease progression. For example, in albinism,
foveal hypoplasia is visible on a macular volume OCT. Similar to the fovea
in preterm infants and infants treated for ROP in which the IRLs persist at the
foveal center, there is absence of a FAZ (63). In juvenile X-linked
retinoschisis, characteristic foveal schisis occurs first in the INL and then in
OPL/ONL on OCT (12,64). The extent and severity of outer retinal atrophy
and loss of photoreceptors or retinal nerve fiber layer (RNFL) atrophy can be
readily noted on OCT in diseases such as Leber congenital amaurosis, Best
disease, Stargardt disease (Figure 16-12), and other inherited retinal diseases
(8). These features can be useful in documenting anatomic disease severity
and progression.
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44. Chen X, et al. Capturing macular vascular development in an infant with retinopathy of
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17
Fluorescein Angiography in Pediatric
Retinal Diseases
Nikisha Kothari, Niranjan Manoharan, and Irena Tsui
FLUORESCEIN DYE
Sodium fluorescein is an orange-red crystalline hydrocarbon with a molecular
weight of 376 daltons. It is available as 10% fluorescein dye (Fluorescite,
Alcon Inc., Fort Worth, TX), and pediatric patients are dosed by weight (5 to
7.5 mg/kg, maximum dosage 500 mg) for intravenous use. In a clinic setting,
intravenous access and image acquisition can be challenging in children.
Prior to injection, a clear imaging plan should be communicated between
multiple team members. Typically, one person is positioning the head, the
second person is injecting dye in a standard 6-second bolus or faster fashion,
and a third person is using the camera. Transparent tubing is attached to a 25-
gauge butterfly needle for injection, and blood should be seen to draw back
before injecting. An intravenous line can be preplaced if early phases of the
angiography are important to acquire, but they are often not crucial in
pediatric patients.
Performance of FA requires a fundus camera with an excitation and
barrier filter to selectively image retinal vasculature and detect pathology.
White light passes through an excitation filter to only allow blue light at 465
to 490 nm to illuminate the retina. Eighty percent of fluorescein is protein
bound, mainly to albumin, and not available for fluorescence. The remaining
20% unbound fluorescein molecules absorb blue light, fluoresce, and emit
yellow-green light at 520 to 530 nm. The barrier filter then only allows
yellow-green light to reach the camera. Ideally, images are acquired
immediately after injection and then at varying intervals until 10 to 15
minutes after injection (2).
In the absence of pathology, fluorescein dye stays within the circulation
of the retina. The endothelial cells of retinal blood vessels branching from the
central retinal artery serve as the inner blood–retina barrier. Fluorescein dye
normally passes through the fenestrated walls of the choriocapillaris. The
zonulae occludens between retinal pigment epithelial cells provides the outer
blood–retina barrier, separating the pool of fluorescein in and around the
choriocapillaris from the retina.
Fluorescein dye and its metabolites are eliminated by the liver and
kidney. Skin can have a yellowish tinge hours after a fluorescein injection,
and urine can remain fluorescent for 24 to 36 hours. Large series in adults
have estimated rates of mild adverse events to be 1% to 14% and most
commonly, transient nausea and vomiting (3). In high-risk elderly and
hypertensive adults, the overall adverse reaction rate has been reported to be
11% (4). Other less common side effects include vasovagal syncope,
urticaria, pyrexia, and rarely a more serious reaction, such as bronchospasm
or even anaphylaxis. In newborns, cell-mediated immunity does not develop
until 2 to 3 months of age, so an adverse reaction to fluorescein dye is less
likely (5).
Angiographic phases consist of choroidal flush, arterial phase,
arteriovenous phase, venous phase, and recirculation. Choroidal filling occurs
slightly early at 10 to 12 seconds (2). In the following 10 seconds, laminar
venous flow can be observed. Thirty seconds after injection, fluorescein
begins to empty from the choroidal and retinal vasculature. Typically, after
10 minutes, minimal fluorescein dye is visible in the retinal vasculature;
however, structures that normally stain such as the optic nerve head, Bruch
membrane, and sclera become visible during this time. The macula is dark
due to blockage of choroidal fluorescence by densely packed retinal pigment
epithelial cells and xanthophyll pigment (2).
Abnormal findings in a FA can be categorized as areas of
hypofluorescence or hyperfluorescence. Common examples causing hypo-
and hyperfluorescence are listed in Table 17-1.
INDOCYANINE GREEN
ANGIOGRAPHY
Indocyanine Green (ICG; Akorn, Lake Forest, IL) is a 775 dalton water-
soluble dye that is used to image the retina and choroid with an excitation
filter of 805 nm and barrier filter of 500 and 810 nm. ICG is contraindicated
in patients who are allergic to shellfish or iodine. The product comes as a
green powder with aqueous solvent and should be used within 6 hours of
mixing. ICG is 98% protein bound after intravenous injection and therefore
stays within the choriocapillaris, making it advantageous for imaging the
choroidal circulation. In children, ICG angiography may be useful for
evaluating posterior uveitis, choroidal hemangiomas, or other suspected
choroidal pathology. The Spectralis (Heidelberg, Germany) uses a scanning
laser ophthalmoscope (SLO) and performs simultaneous FA and ICG
angiography. In addition, the California (Optos, Dunfermline, MA) can now
provide ultra–wide-field ICG angiography.
FIELD OF VIEW
Traditional fundus cameras capture a single frame 30- to 60-degree field of
view and require patient cooperation and time to focus the camera, and these
limitations make traditional FA challenging in children. Moreover, the time-
sensitive nature of FA adds an additional obstacle to capturing simultaneous
peripheral sweeps and producing montage images using traditional cameras.
It was not until the advent of handheld FA (RetCam, Clarity Medical
Systems, Pleasanton, CA) that allowed access to a wide field of retinal view
in supine infants and ultra–wide-field imaging (Optos, Dumfernline, MA) of
upright young patients using scanning laser technology and decreased image
acquisition time when FA in children began to be routinely performed. The
major ocular factor affecting field of view is pupil size, and, therefore,
dilation is helpful in children regardless of the type of camera used. There are
various definitions of what constitutes wide-field imaging with one definition
being images with a >80 degree field of view while reserving ultra–wide-
field terminology for images that capture >130 degree field of view.
Recently, an International Wide-Field Imaging Study Group has proposed the
term wide field be applied to imaging that captured retinal imaging beyond
the macula but posterior to vortex vein ampulla. They recommended using
the term ultra-wide field to refer to images that capture the retina anterior to
the vortex vein ampullae (9).
Fundus images from the RetCam are valuable to document injury and disease
as demonstrated in fundus photographs and FA of ROP (Figures 17-2 and
17-3). The use of FA in ROP posttreatment has increased now that anti–
vascular endothelial growth factor (anti-VEGF) is being used as first-line
therapy (Figure 17-3). In nonaccidental trauma, fundus photographs are
important for medical legal documentation and to record number, extent, and
location of retinal hemorrhages (Figure 17-4), and FA can detect
nonperfusion that may benefit from laser prophylaxis or help counsel
regarding prognosis. In retinoblastoma, tumor infiltration, nonperfusion, and
retinal detachment can be detected with FA (11,12) (Figure 17-5).
Figure 17-2 RetCam fundus photograph images (A, B)
and FA Figure 17-2(Continued ) (C) of a 38-week
postmenstrual-age neonate born at 25 weeks of gestation
with a birth weight of 670 g demonstrate tortuous vessels,
peripheral nonperfusion, and leakage.
Figure 17-3 RetCam fundus images (A, B) and FA Figure
17-3(Continued) (C, D) of a 48-week neonate born at 24
weeks and 5 days of gestation with a birth weight of 540 g
and treated with bevacizumab 0.625 mg in both eyes at 34
weeks demonstrate peripheral nonperfusion and vascular
leakage in both eyes.
Figure 17-4 RetCam fundus images and FA demonstrate
retinal hemorrhages and nonperfusion 5 days after
nonaccidental trauma (A, B) and resolution of
hemorrhages with persistent nonperfusion 5 months after
trauma (C, D). (Photograph courtesy of Audrina Berrocal,
Bascom Palmer Eye Institute, Miami, FL.)
Figure 17-5 RetCam fundus image (A) and FA (B)
demonstrate a sensory retinal detachment (arrowhead),
tumor infiltration (arrow), microvascular changes (arrow
on FA), and nonperfusion (arrowhead on FA) in a patient
with retinoblastoma. (A: Reproduced from Kim JW, Ngai
LK, Sadda S, et al. Retcam fluorescein angiography
findings in eyes with advanced retinoblastoma. Br J
Ophthalmol 2014;98(12):1666–1671. With permission
from BMJ Publishing Group Ltd.; B: Photograph courtesy
of Michael Trese, Associated Retinal Consultants, Royal
Oak, MI.)
Another contact camera for pediatric retina use is the Phoenix ICON
(Pleasanton, CA), which has the ability to perform FA. The Phoenix may
provide optimal color images in deeply pigmented eyes. An example of the
peripheral view can be seen in a Phoenix ICON FA image of FEVR treated
with panretinal photocoagulation (Figure 17-6).
Figure 17-6 Phoenix ICON FA in a patient with FEVR
demonstrates staining of laser scars. (Photograph courtesy
of Michael Trese, Associated Retinal Consultants, Royal
Oak, MI.)
NONCONTACT IMAGING
MODALITIES
Ultra–wide-field fluorescein angiography (UWFFA) with the Optos (Optos,
Dumfernline, MA) has allowed noncontact FA imaging in a clinic setting
since 2005. Optos captures up to 200 degrees of the fundus and does not
require dilation in adults. In children, dilation is recommended to reduce
cooperation requirements by decreasing image acquisition time (5,6). The
technology uses an elliptical mirror and creates a virtual focal point inside the
patient’s eye to image the far periphery. Each picture is 3,900 × 3,072 pixels.
Besides FA, wide-angle color fundus photographs, red-free, infrared,
autofluorescence, and ICG images can be taken with the Optos camera.
Optos FA has been used to evaluate retinal vascular diseases and other
peripheral retinal pathology in adults (13). The device provides several
unique advantages in the pediatric population: wide field of view, complete
fundus imaging at one point in time, rapid acquisition time (0.2
seconds/frame), and use of a confocal SLO platform, which reduces optical
aberrations (14). The lower age limit in cooperative children has generally
been 3 years of age (6,15,16). The advantages of Optos FA over traditional
FA include facile detection of far peripheral pathology such as nonperfusion
(Figure 17-7), neovascularization, and vascular leakage, which are relevant
in pediatric diseases, such as ROP, FEVR, and Coats disease. The camera can
also visualize the retina through moderate media opacities, such as cataract
and vitreous hemorrhage. The Optos viewing software can process images
either manually or automatically to adjust image quality and contrast, and
steering software allows automated montage images.
Figure 17-7 A, B: UWFFA demonstrates peripheral
nonperfusion in both eyes of a 10-year-old child with
history of prematurity.
Retinopathy of Prematurity
Although FA is not a routine part of retinopathy of prematurity (ROP)
screening, it has been used in evaluating ROP infants for 50 years (21). FA
does increase the sensitivity and specificity of staging by helping to identify
neovascularization and the vascular–avascular junction not visible on the
fundus view (Figure 17-2) and to sometimes distinguish treated ROP from
the progressive nature of FEVR in cases of clinical ambiguity (22,23). FA in
FEVR shows irregular spouts of vascularization with progressive ischemia,
whereas eyes with classic ROP have a more homogeneous vascular edge that
resolves after adequate treatment (23). It is important to distinguish ROP
from FEVR and/or recognize when the two entities coexist in the same
patient, coined ROPER, to follow patients at appropriate intervals (Table 17-
2).
ROP, retinopathy of prematurity; FEVR, familial exudative vitreoretinopathy; DR, diabetic retinopathy;
SS, sickle cell.
Coats Disease
Coats disease typically presents in school-age children with strabismus,
leukocoria, or failed eye screening. The disease is idiopathic and affects
young boys. Findings include unilateral vascular telangiectasia, nonperfusion,
and exudation that can even lead to macular fibrosis. Although the exudation
is often visible without FA, noncontact Optos UWFFA provides typical
findings that can aid in differentiating Coats from other diseases and assess
the severity and extent of retinal involvement in very young children in the
clinic setting. In younger or noncooperative children who require an EUA,
and during an EUA at the time of treatment, RetCam FA is a valuable tool for
this same assessment.
The typical appearance of active disease on FA is hyperfluorescence of
telangiectasias, hypofluorescence of exudates, and “light bulb” dilation of the
aneurysmal vessels (Figure 17-8). The vessels often show early and
persistent leakage, which leads to exudation (Table 17-2). In stage 3 disease
with retinal detachment, subretinal exudation, and dilated retinal vasculature,
retinovascular findings on FA can help differentiate between Coats disease
and retinoblastoma.
Figure 17-8 In a 7-year-old boy with Coats disease, UWF
fundus imaging (A) demonstrates exudates in the posterior
pole and foveal center and telangiectatic vessels, and
UWFFA (B) demonstrates early blockage from exudation,
peripheral nonperfusion and leakage, telangiectasias, and
tortuous vessels in the temporal retina.
Incontinentia Pigmenti
Incontinentia pigmenti (IP), also known as Bloch-Sulzberger syndrome, is an
X-linked dominant syndrome affecting the skin, hair, teeth, eye, and central
nervous system.
The pathophysiology of IP is elucidated to be dysregulation of
eosinophils causing endothelial cell dysfunction (42). It is presumed that this
mechanism of increased inflammation leads to vaso-occlusion and ischemia
in the retina, which may vary between the eyes due to genetic mosaicism.
Retinal findings, similar to FEVR, include peripheral retinal
neovascularization and nonperfusion, hemorrhages, and exudative and
tractional retinal detachment (43). Avascular retina should be treated with
laser photocoagulation or cryotherapy. FA is used to detect areas of
peripheral retinal nonperfusion, neovascularization, enlargement in the foveal
avascular zone, and arteriovenous shunts. UWFFA imaging in clinic without
sedation not only reveals the extent of avascular retina and neovascularization
(Figure 17-9A), but is useful to monitor the response to treatment (Figure
17-9B).
Figure 17-9 UWFFA demonstrates periphery
nonperfusion and leakage consistent with
neovascularization before (A) and after (B) targeted retinal
photocoagulation in the left eye in a 14-year-old girl with
incontinentia pigmenti syndrome.
Uveitis
Uveitis can be a challenging disease to evaluate and treat in pediatric patients.
Posterior uveitis constitutes 40% of all pediatric uveitis compared to 20% in
adults (44). Etiologies can be categorized as infectious (i.e., toxocariasis,
toxoplasmosis, herpetic, cytomegalovirus, tuberculosis, Lyme) or
noninfectious (i.e., juvenile rheumatoid arthritis, pars planitis, multiple
sclerosis, Blau syndrome, sarcoidosis, Vogt-Koyanagi-Harada (VKH)
syndrome) (see also Chapters 47 and 48). FA helps in demarcating the areas
of capillary nonperfusion seen in tuberculosis. In VKH syndrome, early
choroidal hypofluorescence is a typical finding wherein initial pinpoint
hyperfluorescent dots are seen along with late pooling of the dye in the
subretinal space (45). FA can detect the characteristic “petaloid” pattern of
parafoveal hyperfluorescence in uveitic cystoid macular edema, retinal
vasculitis, periphlebitis, neovascularization, and staining of the optic nerve
head. Up to 90% of patients with intermediate uveitis have peripheral retinal
vasculitis (46). Often the extent of retinal vascular inflammation is difficult to
gauge on clinical examination alone and can be limited by media opacities. In
addition, vascular sheathing can persist longer than active inflammation. FA
has been used to monitor response to treatment and modify systemic, local, or
surgical therapy accordingly.
Diabetic Retinopathy
Diabetic retinopathy (DR) in children with type 1 diabetes mellitus typically
develops during puberty or in the mid-teen years (47). Recently, type 2
diabetes mellitus has become increasingly common in obese teenagers with
poor dietary habits, sedentary lifestyles, and at-risk family histories (48). The
utility of FA in children with DR is similar to its role in the management of
adults with DR. FA is able to stage and reveal the extent of nonperfusion,
neovascularization, microaneurysms, and macular leakage better than clinical
exam or color fundus photography alone (49,50).
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18
Ultrasonographic Imaging in Infants
and Children
Roger P. Harrie
TECHNOLOGY
The fundamental principle of ultrasonography is based on the ability to
discriminate among captured reflections from a high-frequency sound beam
that is focused at a tissue and reflected from different tissue interfaces.
Ultrasound is generally defined as sound waves generated and reflected at
a frequency beyond the range of human hearing (20 kHz). Impedance is
defined as sound velocity times tissue density (Z = v × d). It is the difference
in impedance between different tissues that is responsible for the strength of
the reflected sound waves.
An extremely thin ceramic crystal membrane in the tip of the probe
undergoes a mechanical vibration when stimulated by an electric current,
which generates a sound beam. This same membrane acts as a receiver of the
reflected sound waves (the piezoelectric effect). These signals are amplified
and displayed onto a screen as either vertical lines in the A-scan or as a
coalescence of bright dots in the B-scan. The A-scan probe generates sound
waves in a linear direction with reflection of the focused beam from a focal
area, whereas the B-scan transducer oscillates about 25 times a second in a
plane and generates a sound beam, which is reflected from a 60-degree sector
of the globe. All B-scan probes have a mark on them to indicate the direction
of the oscillation. The frequencies used most commonly in clinical
ophthalmology are 8 MHz for the diagnostic A-scan and 10 MHz for the B-
scan but can be as high as 60 MHz in clinical ultrasound biomicroscopy. The
resolution of the image is dependent on the frequency of the generated and
reflected sound beam. Generally, higher frequency ultrasound provides
greater resolution of images but less penetration. Therefore, 40 to 50 MHz is
generally used in ophthalmology for anterior segment imaging, whereas 10 to
15 MHz is used for posterior segment imaging. Digital ultrasound images are
commonly uploaded to a server and used as reference for follow-up
examinations. It is important to record the orientation of the probe (see
below) with the image.
EXAMINATION WITH
ULTRASONOGRAPHY
The globe is first examined with the probe at a transverse position in which
the mark on the probe is parallel to the limbus (Fig. 18-1). Six quadrants are
evaluated starting at the 6:00 position with the probe directed superiorly. This
allows for evaluation of the superior 60 degrees (lateral to medial) segment of
the fundus. The probe is pointed directly at the posterior pole and angled as
far superiorly as possible. This process is repeated by placing the probe at the
4:00 position to image the superior temporal fundus; then at the 2:00 position
to image the inferior temporal fundus; then at the 12:00 position to image the
inferior fundus; then at the 10:00 position, which images the inferior nasal
fundus; and finally at the 8:00 position to image the superior nasal fundus.
The probe is then placed with the mark perpendicular to the limbus and is
placed at the same six positions on the globe to obtain a longitudinal view as
the transducer sweeps from the anterior to the posterior fundus. This allows a
more peripheral view that extends almost to the ciliary body. This technique
of probe positioning permits visualization of the entire posterior segment
from the optic disc to the pars plana. While ultrasound is useful to document
findings, it is also important to communicate the orientation of the probe
relative to the globe when documenting findings. In the case of measuring
tumor thickness, it is important to use standardized scans.
FIGURE 18-1 B-scan probe positions. Transverse
position with transducer moving parallel to limbus as
indicated by mark on probe directed vertically (left).
Longitudinal position with transducer moving
perpendicular to limbus as indicated by mark on probe
directed horizontally (right).
BENEFITS OF ULTRASONOGRAPHY IN
INFANTS AND CHILDREN
Echography can be very helpful in a number of pediatric vitreoretinal
conditions especially when there are media opacities such as corneal scars,
cataracts, anterior chamber hyphema, and vitreous opacities. It is very useful
in the detection of retinal detachment; characterization of visible fundus
lesions such as retinoblastoma or other tumors; identification of intraocular
foreign bodies; and biometry in congenital glaucoma, anisometropic
amblyopia, and unilateral persistent fetal vasculature (PFV) in which axial
length differences between eyes can be determined. It is also useful in
differentiating causes of microphthalmia, such as PFV versus congenital
microphthalmos with a coloboma or cyst.
Many of the above conditions present with a white pupil or leukocoria,
which is the most common indication for ophthalmic ultrasonography in the
pediatric population (2). The most serious cause of leukocoria is
retinoblastoma, which is potentially life-threatening if not promptly
diagnosed and treated.
Coats Disease
Coats disease is the second most common condition to cause diagnostic
confusion with retinoblastoma as compared to the other entities associated
with leukocoria. This typically unilateral condition is most common in
children with an average age of about 7 years and occurs in males versus
females at a ratio of 2.5:1. The subretinal space can be filled with lipid
including cholesterol crystals with leakage of serum from telangiectatic
vessels. In advanced cases, there can be slow convection movement of
subretinal exudate on ultrasound. In cases of Coats with marked subretinal
exudation, ultrasonography can produce an image simulating a
retinoblastoma with diffuse punctate high reflectivity from subretinal
cholesterol clefts (Fig. 18-9).
Ocular Toxocariasis
Ocular toxocariasis is the third most common condition incorrectly diagnosed
as retinoblastoma (6). The parasitic roundworms Toxocara canis or Toxocara
cati can migrate into the posterior segment usually in children or young
adults and cause an isolated fundus lesion or diffuse vitreous inflammation
presenting as clinical leukocoria. This process presents with a focal
peripheral retinal granuloma in 50% of cases, a macular lesion in 25%, and
moderate to severe vitreous inflammation in 25% (6). In some cases with a
peripheral lesion, there may be a vitreous membrane extending from the
lesion to the posterior fundus (Fig. 18-10), and there may be a posterior
retinal fold or traction detachment. Echography is useful in demonstrating
these findings in the presence of media opacity from vitreous inflammation or
hemorrhage. These findings may mimic familial exudative vitreoretinopathy
(FEVR) and retinopathy of prematurity (ROP), and, therefore, a history can
be useful.
Retinopathy of Prematurity
ROP is another entity in the differential diagnosis of leukocoria (7).
Ultrasound is useful in detecting a detached retina particularly when
leukocoria is present. The peripheral fibrovascular tissue can contract and
detach the peripheral retina with the resultant echographic appearance of
loops of retina (Fig. 18-11) or in total retinal detachment as a tight funnel
(Fig. 18-12). In the later stages of ROP (4A, 4B, and 5) with partial or
complete tractional retinal detachment, ultrasonography is useful in assessing
the diameter of the detached retinal funnel which may be beneficial in
surgical planning (8).
Retinal Detachment
Retinal detachment may itself cause leukocoria, or it can accompany other
causes of a white pupil. The echographic criteria for the diagnosis of a
detached retina include a highly reflective membrane attaching at the optic
nerve head (Fig. 18-13), a membrane demonstrating high reflectivity in the
periphery, and B-scan mobility characteristics of somewhat stiff and tethered
after movements compared to the loose and wider excursions of a vitreous
membrane. Therefore, dynamic echography is important in the diagnosis.
Retinal detachments are generally more highly reflective on A-scan than
vitreous membranes (Fig. 18-14).
FIGURE 18-13 B-scan of retinal detachment (arrows).
The highly reflective membrane with an attachment at the
optic nerve head is usually diagnostic of a retinal
detachment, but a vitreous membrane can occasionally
have this appearance.
FIGURE 18-14 A-scan of retinal detachment (second
arrow). The reflectivity of the retinal spike is at the same
height as the initial spike (first arrow) and the scleral spike
(third arrow) as opposed to vitreous membranes, which
are not as highly reflective.
The disease processes discussed to this point account for almost 70% of the
conditions reported to simulate retinoblastoma (4,9). Other less common
causes of leukocoria include Norrie disease (see Chapter 35) and FEVR (see
Chapter 66), which may have the echographic findings of radial retinal folds
and/or an exudative retinal detachment (Fig. 18-15).
FIGURE 18-15 B-scan of FEVR showing marked
subretinal exudate with a detached retina (arrows).
Choroidal Effusion
Ultrasonography is also useful in revealing fluid in the suprachoroidal space
and in differentiating posttraumatic choroidal hemorrhage or serous fluid
seen in choroidal effusion (12)
Limitations
Limitations of echography include replication of the scan. Because
ultrasound is captured in two-dimensional scans, this cross-sectional view (as
opposed to a three-dimensional view) may lead to misinterpretation of the
image. It may also be difficult in complex vitreous hemorrhage, to distinguish
blood or organized membranes from retinal detachment. Shadowing from
anterior structures may also limit a deeper view. Because the probe may
transmit pressure to the globe, it has limitations for use in trauma when there
is a possible open globe. The value of the information obtained from
echography is a function of the experience of the examiner. Subtle diagnostic
cues can be missed by the less experienced clinician.
CONCLUSION
Despite the limitations, echography is a useful ancillary test in the pediatric
population. Many types of intraocular pathology can be detected and often be
accurately diagnosed by ultrasound.
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2. Harrie RP. Clinical ocular ultrasonography: a case study approach. New York: Springer, 2008.
3. Brisse HJ, Guesmi M, Aerts I, et al. Relevance of CT and MRI in retinoblastoma for the
diagnosis of postlaminar invasion with normal-size optic nerve: a retrospective study of 150
patients with histological comparison. Pediatr Radiol 2007;7(7):649–956.
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19
Imaging Analysis in Infants and
Children
Sang Jin Kim, John Peter Campbell, and Michael F. Chiang
CHANGING PARADIGMS IN
RETINOPATHY OF PREMATURITY
DIAGNOSIS
Traditionally, diagnosis of ROP is made by ophthalmoscopy in the neonatal
intensive care unit (NICU), although a number of factors contribute to the
rising use of telemedicine for primary ROP screening (7). More than 80% of
infants in an ROP screening program in the United States have less than
severe ROP and could safely have deferred ophthalmoscopic examinations
(8,9). The number of clinicians who are trained and willing to manage
patients with ROP is decreasing in the United States for a number of reasons,
including high medicolegal liability, inadequate training, and poor
reimbursement (10,11). ROP is increasingly becoming a disease of low- and
middle-income countries where the population at risk is higher, and the
human resources are becoming more scarce (12).
Screening guidelines now recognize telemedical interpretation of wide-
field ROP images as reasonable with appropriate safeguards to ensure quality
control and follow-up (7). In both ophthalmoscopic examination and
telemedicine, clinical diagnosis is based on parameters defined by the
international classification of ROP (ICROP): zone, stage, clock hour extent,
and plus disease (13,14). The NIH-sponsored multicenter cryotherapy for
ROP (CRYO-ROP) (9,15) and early treatment for ROP (ETROP) trials
determined that the presence of plus disease, defined as venous dilatation and
arteriolar tortuosity in central retinal vessels greater than or equal to that of a
standard published photograph, is the most important factor in identifying
infants with severe treatment-requiring disease at risk for blindness (14).
Therefore, it is critical to accurately diagnose plus disease to determine the
need for treatment in ROP.
MACHINE LEARNING
Machine learning uses the processing power of a computer to “learn” patterns
from operator-defined features that best solve a particular problem (Fig. 19-
2). The Imaging and Informatics in ROP (I-ROP) consortium published the
results of the “i-ROP ASSIST” program in 2016 (3,33). Manually segmented
images from a trained grader, who manually traced vessels from raw images,
were used as inputs, and a machine learning strategy used support vector
machines and gaussian mixed models as methods to quantify and classify
features. The i-ROP ASSIST program used a vascular metric termed
“acceleration” that was found to have the best diagnostic performance in a 6-
disc-diameter circular crop of wide-angle RetCam images when all retinal
vessels combined were considered. With the real-world application of this
system being limited by the requirement of manual segmentation, the
performance was on par with clinical experts (3,33).
FIGURE 19-2 Schematic representation of machine
learning model. Traditional severity score models, for
example, the Early Treatment for Diabetic Retinopathy
Scale (ETDRS), utilize differentially weighted, operator-
defined features, such as microaneurysms and intraretinal
hemorrhages, to develop a scoring system that has some
prognostic significance. In a machine learning approach,
the features may be defined a priori, and the weights are
learned by the computer. In a deep learning program using
a convolutional neural network, no features are defined a
priori. (Figure courtesy of James Brown, PhD and
Jayashree Kalpathy-Cramer, PhD.)
DEEP LEARNING
Recent advances in deep learning take this one step farther by removing any
defined features. Deep convolutional neural networks (CNN) are a form of
supervised machine learning that use only the input data, usually an image,
and the output, or the ground truth about the problem being solved, such as
the status of plus disease, and then iteratively learn the features that predict
the output without exploiting defined features through the parallel processing
power of the graphics processing unit (GPU) (34). Using raw images from
the i-ROP cohort study as the input, the “i-ROP DL” program was able to
classify plus disease with an AUC of 0.98, outperforming 7/8 experts (6). The
i-ROP DL system works by using two CNNs together; the first one produces
a vascular segmentation automatically (Fig. 19-3), and the second operates
only on the segmented image to classify disease.
FIGURE 19-3 Example of a vascular segmentation of a
retinal fundus photograph. This image was produced in the
first step of the Imaging and Informatics in ROP Deep
Learning (i-ROP DL) program that automatically
diagnosed plus disease based on fundus images. The
image was classified as plus by clinical experts.
CHALLENGES
There are several challenges to the application of CBIA in ROP: Humans
often disagree on ROP diagnosis (16–18,27) making the “gold standard” used
to train the CNN less robust. This generally raises the number of images
required to fully train a network. Operator-defined features or datasets may
be biased, and these biases may be conveyed through to CBIA. CNNs require
large amounts of data to train, potentially limiting the application of CNN-
based CBIA techniques in less common pediatric retinal diseases. The image
quality and field of view necessary for diagnosis are not defined. Therefore,
subtle differences in an input image, which have been shown to affect CNN
performance, need to be defined for clinical use. Similarly, it remains to be
proven that CNN outputs can be independent of the camera used to obtain an
image. Whereas CNNs are often quite powerful for image classification tasks,
the layers of the CNN are a “black box” in the sense that it is not easy to
unpack the layers of the CNN to explain how it is working. This lack of
transparency is an obstacle for some clinicians and regulatory bodies to
approve software programs for clinical use and is an area of active research
(35). One approach to unpacking the black box utilizes “heatmaps,” which
evaluate how much each part of an image contributes to the overall
classification of the image (Fig. 19-4).
FUTURE DIRECTIONS
Though the applications of CBIA in plus disease diagnosis have been the
most well studied, there is the potential to apply similar technology to the
diagnosis of other pediatric retinal diseases such as Coats disease,
incontinentia pigmenti (IP)-associated retinopathy, familial exudative
vitreoretinopathy, inherited retinal degenerations, retinoblastoma, and others.
In addition, though color fundus photographs have primarily been used for
studies of plus disease, CBIA of other images, such as OCT and FA, has also
been investigated (36). CBIA would bring the similar potential advantages,
including quantification of disease severity, automated and objective
diagnosis, standardization of diagnosis between clinicians, and incorporation
in tele-screening programs, to these other applications and modalities as it
does to fundus photographs in ROP. Deep learning may be applied to the
increasing number of approaches to newborn fundus screening, which has not
yet become standard of care in the United States but is being used
increasingly in other parts of the world. Finally, at this time, the numbers of
papers published on CBIA outweighs the numbers of patients who have truly
benefited from the implementation of these technologies into clinical
practice. More work is needed to translate the theoretical advantages of these
technologies into real-world impact for patients.
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20
Image Storage and Retrieval and
Telemedicine
Marco H. Ji, Darius M. Moshfeghi, and Antonio Capone Jr
Safety of RDFI
Clinical examination using BIO is very stressful for preterm infants and can
elicit a considerable amount of discomfort and pain, inducing changes in
blood pressure, apnea, bradycardia or tachycardia, emesis, and epistaxis
(79–84). Also, paralytic ileus, necrotizing enterocolitis, and cardiopulmonary
arrest have been reported but in the sickest infants who required respiratory
support and who had neurologic injuries or infections (85–87). A wide
variety of causes have been proposed including the mechanical effect of the
speculum or the scleral depressor, the oculocardiac reflex, the systemic
effects of anticholinergic and alpha-adrenergic agents used for mydriasis, the
bright light of the camera, and the supine position required for the exam
(79–83). RDFI exposes the preterm infants to the same mydriatic
medications, similar eye manipulation, and bright light and, in addition to
these, the camera in contact with a gel applied to the eye. RDFI causes
comparable discomfort and pain with similar physiologic changes compared
to BIO (83–88), although BIO may produce fewer events (8% BIO vs. 15%
RDFI) (84). This spectrum of physiologic changes and adverse events occurs
principally in the sickest and more fragile infants who are also the ones in
greatest need of ROP screening and timely treatment for ROP (84).
Limitations of RDFI
Despite many advantages, telemedicine can present some caveats. The
accuracy of RDFI is lower for the milder forms of ROP due to the difficulty
to visualize the periphery that can prevent a valid evaluation of zone III
disease, although it is unlikely to be clinically significant in the absence of
Plus disease (89). The lack of perception of depth could reduce the accuracy
of recognition of the fibrovascular proliferation and hence stage 3 disease
(90). Telemedicine performs worse in terms of accuracy, reliability, and
image quality in infants at younger PMAs because of many factors including
more corneal or vitreous opacity and narrow palpebral fissures (57). The BIO
examination allows real-time evaluation of the infants, and in the case of
telemedicine, protocols need to define that the results of the image
assessment should be delivered to the ROP specialist promptly (<24 hours)
(91).
IMPLEMENTATION OF AN RDFI
SCREENING PROGRAM FOR ROP
Personnel
The RDFI team includes the RDFI reader/treater, the nurse photographers,
the bedside nurse, the NICU team (physician, social work, nurse
practitioners), the front desk schedulers, the legal consultants, the hospital
administration, and the family members. Each group has a role to play to
ensure a smooth transition from birth, identification of need for screening,
screening, implementation of reader recommendations, discharge, handoff
and communication to outside screen, and completion of screening
termination criteria. The easiest method for delineating roles is through the
ROP screening contract. In addition to outlining each team member’s
responsibilities, the contract can serve to head off disputes about what to do
when a photographer is unavailable, when an infant needs treatment, when
there is an equipment malfunction, and the like.
Photographic Technique
The photographic screening protocol most widely employed is derived from
the PHOTO-ROP study (Fig. 20-3) using a RetCam (Fig. 20-4). Images are
taken by nonphysician nurses or other trained personnel who have received
training and, ideally, certification in the use of the camera and imaging
technique, such as through Focus ROP or Natus medical online training
program. In the SUNDROP program, the nurse photographers utilized such
training and then have additional annual training with the RDFI reader.
Dilation is key to good photographs. Feedings should be held for at least an
hour around an imaging session to reduce the risk of apnea, bradycardia, and
aspiration. We recommend that the bedside nurse be present throughout the
photographic session. A speculum is an absolute requirement, and the
Alphonso speculum appears well suited for the 130-degree lens of the
RetCam. We do not advocate for routine usage of scleral depressors. With
respect to imaging frequency, RDFI images are most useful when there is a
longitudinal record, and, therefore, a screening frequency of at least weekly is
most likely to ensure continuity of care, instill in the team members the
importance of the enterprise, as well as capture rapidly advancing disease.
RetCam remains the most commonly used camera for neonatal ophthalmic
imaging so far in both clinical and research settings, but several fundus
cameras designed for neonatal use have been developed over the years. The
ICON (Phoenix, Pleasanton, CA) is a wide-field contact camera coupled a
handheld probe with direct annular illumination that provides a 100-degree
field of view and a resolution of 8 MP. The PanoCam LT, PRO, and Solo
(Visunex, Fremont, CA) are wide-field wireless cameras that render a 130-
degree field of view and a resolution, respectively, of 8, 13 and 13/8 MP. The
3nethra neo (Forus Health Pvt. Ltd., Bangalore, India) is a lightweight wide-
field portable contact camera, which provides a 120-degree field of view with
a handheld probe, uses warm LED light as the illumination source, and can
capture images with 4 MP resolution. The Pictor Plus (Volk Optical,
Cleveland, OH) and Nidek NM200-D (Nidek Inc., Gamagori, Japan) are two
portable noncontact digital cameras that provide images with, respectively, 5
and 1.5 MP resolution but with a 45- and 30-degree field of view. The Optos
Optomap (Optos PLC, Dunfermline, UK) is a noncontact ultra–wide-field
imaging system that can capture retinal images up to 200 degrees, but it is
table mounted; the only way to examine a newborn with this machine is
utilizing the “flying baby technique,” and because of that, it is inappropriate
for routine ROP screening. The Heidelberg Spectralis (Heidelberg
Engineering, Heidelberg, Germany) became available recently as modified
version “Flex Module” that allows examination of patients in supine position.
The latter is a noncontact camera that offers wide-field 55-degree fundus and
OCT imaging.
RDFI Report
The report of the images taken at each examination will become a permanent
part of the medical record and require general documentation, documentation
per eye and a summary of the interpretation, a recommendation as to future
examinations or treatment, as well as an educational handout for the family
members explaining to them the disease grading and recommendations (24)
(Table 20-1). If the reader finds that the images are unacceptable for grading,
for example, lack sufficient quality, have incomplete image sets or have
artifacts, and are mislabeled, then a request should be made to repeat the
evaluation within 24 hours. Reports should be created and returned no later
than 24 hours after receipt of images, unless other arrangements have been
made in advance such as communicating the results in person or by phone.
These reports serve many functions in addition to their medical support role,
such as education of the NICU team, education of family members, creation
of RDFI team solidarity, and use in institutional review board (for human
studies)-approved studies.
FUTURE DIRECTIONS
Telemedicine opens the doors to a multitude of future directions. The
Newborn Eye Screen Testing (NEST) and its substudy the Global Universal
Eye Screen Testing (GUEST) are currently investigating the impact of the
universal eye screening in newborns; this could help to detect many
abnormalities that are missed at the neonatologic physical examination and
also collect data about early life physiologic development (114,115). Besides
the recent hardware improvements, the software developments have been
progressing even faster, and it has involved every field of medicine. One of
the most exciting aspects of telemedicine is the computer-based image
analysis software platforms that can objectively analyze and quantify retinal
features. Many systems have been developed to date, such as Retinal Image
multiScale Analysis (RISA), and its successor Computer-Aided Image
Analysis of the Retina (CAIAR) developed at Imperial College London,
ROPtool developed at Duke University, VesselMap (IM-EDOS GmbH,
Weimar, Germany), and i-ROP with promising results. In the near future, as
has already happened in other medical fields, AI image analysis systems will
be able to predict outcomes and prognosis with a further improvement of the
management of this disease (116).
SUMMARY
There is a large and growing body of evidence to support the use of RDFI
screening for the identification of referral and TW-ROP. The exact methods
of screening continue to be refined, but the systematic approach championed
by the PHOTO-ROP trial and the SUNDROP telemedicine outreach
programs that utilize standard image sets and trained nurse photographers,
experts in ROP evaluation, and mentored readers with integrated ROP safety
nets has demonstrated that with such approaches, all TW-ROP can be
identified in a timely fashion to prevent blindness. The major trade-off with
the use of RDFI is that of not identifying every bit of ROP disease in the eye
that BIO may potentially do and instead only identifying ROP that requires
treatment to prevent blindness. RDFI programs have the potential to improve
accessibility, quality, and cost of ROP care in both developed and developing
countries and should be initiated with clear contractual understanding of each
team members’ roles and responsibilities predicated further on each member
receiving adequate training and certification.
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SECTION IV
Genetics and Developmental
Disorders in Pediatric Retina
21
Genetic Counseling for Pediatric
Retinal Diseases
Karmen M. Trzupek and Briana L. Sawyer
INTRODUCTION
The completion of the Human Genome Project laid the foundation for a
seemingly infinite number of research programs with goals as audacious as
they are impactful: cataloguing the breadth of common human genetic
variation, identifying and characterizing every functional component of the
genome, and discovering and understanding rare genetic variants associated
with human disease. The success of the latter programs—associating rare
genetic variants with Mendelian genetic diseases—has led to a tremendous
surge in clinically relevant genetic information. This information has the
potential to significantly impact medical care and decision-making for not
only the patient but also their family.
Genetic information can also have emotional, reproductive, social, legal,
and ethical implications; therefore, health care providers involved in ordering
genetic testing or treating patients with genetic diseases should provide their
patients with resources to help explain the meaning of genetic information.
Ophthalmologists managing these patients should have a basic understanding
of the genetics of that condition, the impact of genetic test results on medical
management, and potential implications for the patient and family. A more
detailed discussion of inheritance, family/social implications, recurrence
risks, and options for genetic testing may necessitate a comprehensive
genetics consultation.
Many physicians bridge this need by partnering with genetic counselors,
who can collect detailed family histories, provide genetic and prognostic
counseling, and review molecular testing options with patients. Genetic
counselors carefully review genetic variants in test reports and research their
potential contribution to disease. We all have many variants from the
standard sequence in our genes, as our diverse traits are directed by different
versions of the same genes. A variant is often called a pathogenic mutation if
it is disease-causing. Whether or not a specific variant is disease causing or
benign requires complex analysis of the change in protein structure and
analysis of the literature. Variants may be classified as benign, likely
pathologic, pathologic or uncertain. The American College of Medical
Genetics (ACMG) concludes that both pathogenic and likely pathogenic
variants should be interpreted as disease causing and actionable. For the
purposes of this chapter, the word mutation will be used to signify pathologic
and likely pathologic variants.Following genetic testing, the genetic
counselor may coordinate additional testing of family members, enroll the
patient in research or patient registries, and discuss clinical trials. Genetic
counselors also provide support for the emotional impacts genetic
information and testing results can have on a patient and their family.
GENETIC COMPLEXITY OF
INHERITED RETINAL DISEASES
In 1984, Shom Shamker Bhattacharya, PhD, and colleagues mapped the RP2
gene associated with X-linked retinitis pigmentosa (RP) (1). The ensuing 30
plus years have seen tremendous advances: today, nearly 300 inherited retinal
disease genes have been mapped, and more than 250 of those genes have
been cloned (2).
Retinal disease genetics have proven to be a model of genetic complexity,
displaying not only allelic heterogeneity, where many different disease-
causing mutations are found within a particular gene, but also:
Most individuals who are diagnosed with Best disease have a parent who is
also affected, although a wide degree of variability in age of onset and
severity of vision loss is not uncommon. Even within the same family, the
age of onset of symptoms can range from childhood or adolescence to middle
adulthood.
Autosomal recessive disorders are those in which an individual must have
mutations on both copies of the disease-related gene in order to be affected
(see Fig. 21-1B). We all carry multiple single copy recessive mutations
without any effect, and for two unrelated parents, the chances of each
carrying a mutation in the same gene is low but varies based on the
prevalence of the disease. Approximately 1 in 70 people carries a mutation in
an albinism causing gene, for example, whereas the carrier frequency is much
lower for LCA. The affected individual may be compound heterozygous
(having a different mutation on each copy of the disease gene) or
homozygous (having two copies of the same mutation: 1 inherited from each
parent). Homozygosity occurs more frequently when the patient’s parents are
related by blood or have ancestors from the same small ethnic community.
Carriers have only one copy of the mutation and are usually
asymptomatic and phenotypically unaffected. Typically, both parents of a
child affected with an autosomal recessive condition are carriers, and each of
their offspring has a 25% chance of inheriting the disorder. Multiple family
members in a single generation (e.g., siblings) may be affected, as shown in
Figure 21-1B. All children born to a parent affected with an autosomal
recessive condition will at least be carriers of the condition. If a child inherits
a second genetic mutation from the other parent, they too will be affected.
For a rare genetic disorder, this occurs very uncommonly. However, the
probability is increased if the parents are related or from an ethnic
background with a relatively high prevalence of the disorder. (See discussion
of pseudodominance below.) Stargardt disease and Usher syndrome are
conditions that are inherited in an autosomal recessive manner.An X-linked
disorder is one in which the causative genetic mutation is located on the X
chromosome. Because males have only one X chromosome, all males who
inherit a mutation are expected to develop the disorder. Females have two X
chromosomes; thus, if they inherit one copy of the mutation, they are carriers
(see Fig. 21-1C). For a classic X-linked recessive disorder, female carriers are
typically not affected, although they may display some symptoms due to
skewed X inactivation. Generally, these symptoms are milder than those seen
in affected males. Because fathers do not pass an X chromosome to their
sons, the lack of male-to-male transmission is a characteristic feature of X-
linked inheritance. All daughters of a man with an X-linked recessive
condition will be carriers. When the mother is a carrier, the risks to her
children depend on their gender: sons of carrier females have a 50% risk of
being affected, whereas daughters of carriers have a 50% chance of being
carriers as shown in Figure 21.1C. Juvenile retinoschisis caused by mutations
in the RS1 gene is a condition that follows a classic X-linked recessive
inheritance pattern. Female carriers of an RS1 mutation rarely express fundus
abnormalities, although clinical findings have been reported in a few cases
(9). On the other hand, female carriers of mutations in the RPGR gene,
associated with X-linked RP, frequently do develop retinal disease, and may
be diagnosed with “typical” RP (10). Women in some X-linked RP families
may be affected to the degree that the inheritance appears dominant.
While rare, some conditions display X-linked dominant inheritance, in
which females with one copy of the mutation are affected. X-linked dominant
conditions are often embryonically lethal in males. An important example of
an X-linked dominant condition is incontinentia pigmenti (IP), which has
both skin and ocular manifestations (discussed in Chapter 36). Girls with this
condition classically develop the triad of ectodermal dysplasia, CNS
abnormalities, and retinal neovascularization, predisposing to retinal
detachment (11). Women with IP may report multiple miscarriages, generally
around the 3rd or 4th month of gestation, presumably of affected male
fetuses. Some cases of males with IP have been reported due to mosaicism or
a karyotype of 47,XXY providing an additional X chromosome, which
allows for viability.
Genetic conditions can also result from mutations in mitochondrial DNA
(12). Mitochondria are almost exclusively inherited from the mother, and
family histories with a pattern demonstrating mitochondrial inheritance will
often reveal an affected mother with affected children of both genders, as
shown in Figure 21-1D. Extremely rare examples of paternal transmission of
mitochondria have been recently reported, however (13). The presence of
equally affected females and males can help distinguish this inheritance
pattern from X-linked inheritance. Complicating mitochondrial inheritance is
the presence of heteroplasmy, which occurs when cells have some normal
and some have mutated copies of their mitochondrial DNA. In general, an
individual will only show symptoms of a mitochondrial condition if the
proportion of mutated mitochondrial DNA reaches a certain threshold.
Therefore, the disease could be clinically absent in a woman but present in
both her mother and her children. A classic example of mitochondrial
inheritance in the pediatric ophthalmology clinic is Leber hereditary optic
neuropathy (LHON), which causes painless, subacute vision loss, most
frequently in males aged 15 to 30. Although men and women are equally
likely to inherit the mitochondrial mutation, males are four to five times more
likely to lose vision. Less commonly, individuals who inherit an “LHON
mutation” will develop a multiple sclerosis-like illness; females are more
likely than males to develop the neurologic phenotype (14). The reasons for
the gender differences in this mitochondrial condition are unknown.
Another important example of mitochondrial inheritance in the retina
clinic is Kearns-Sayre syndrome, which is associated with pigmentary
retinopathy, progressive external ophthalmoplegia, ptosis, neurologic and
neuromuscular dysfunction, and variable cognitive impairment. However,
nearly all patients with Kearns-Sayre syndrome have deletions of the
mitochondrial DNA that arose sporadically and were not inherited from the
mother. The mother of a proband with a mtDNA deletion syndrome is usually
unaffected and does not have mtDNA deletions in her tissues; therefore, the
risk to the sibs of a proband is low, but not zero, due to the possibility of
germ line mosaicism. Empirically, the recurrence risk is estimated to be 1%
to 4% (15).
Family History
The family history is an important tool for determining differential diagnoses,
risk assessment, and the most appropriate genetic testing. Additionally, the
family history allows the genetic counselor to assess patient education needs
and psychosocial influences. A family history is obtained in virtually all
genetic counseling sessions, generally includes at least three generations, and
often assesses a variety of health concerns. For this reason, the family history
is arguably one of the most important tools in both screening and prevention
of common diseases (21,22).
Targeted questions regarding the status of affected as well as unaffected
individuals can help the genetic counselor determine the most likely
diagnosis as well as risk to other family members.
Inheritance patterns and disease-specific risk assessments can be
generated from family history alone in many cases.
The family history and/or pedigree should be an integral part of the
medical record. The term pedigree refers to the way the family history is
visualized. Pedigrees should be drawn in a standard fashion to allow for easy
interpretation by other health care providers. Guidelines for pedigree
documentation have been developed by the National Society of Genetic
Counselors (23).
Figure 21-2 provides an overview of the most commonly used pedigree
symbols. Full names, dates of birth, or any other potentially identifying
information about family members should be excluded from the pedigree in
order to maintain the confidentiality of family members. How to best capture
family history information in the electronic medical record (EMR) is the
subject of a great deal of research. For the past several years, a variety of
institutions and researchers have worked to create a pedigree tool that is
compatible with the EMR; however, clinics and research institutions vary
according to practice.
FIGURE 21-2 Common symbols used in pedigree
construction. (From Bennett RL, French KS, Resta RG, et
al. Standardized human pedigree nomenclature: update
and assessment of the recommendations of the National
Society of Genetic Counselors. J Genet Couns
2008;17:424–433. Copyright © 2008 National Society of
Genetic Counselors, Inc. Adapted by permission of John
Wiley & Sons, Inc.)
Parents should be asked specifically if they are both the biologic parents of
the affected child before undertaking a complex pedigree drawing. Although
this may seem obvious, there are many types of families, and adoptive
parents may not realize that only the medical conditions of biologic relatives
are important to a genetic pedigree. In addition, some families may not have
shared family of origin information with their child; parents should be given
the opportunity to provide additional family information at a later time if they
request that.
Risk Assessment
In most genetic counseling sessions, some discussion of risk will occur. This
may be the risk of an individual developing symptoms, the risk for family
members to carry a genetic mutation, or the risk of progression to more
severe disease. Those present may include the patient and other family
members who wish to understand the risk to themselves and their children (or
future children). To best tailor the counseling session to the needs of the
patient, it is important to identify the patient’s motivation for requesting risk
information. Regardless of the type of risk discussion taking place, the risk
assessment is a crucial part of the genetic counseling session and involves
detailed assessment of the family’s medical history.
Determining the likely inheritance pattern of the condition is the first step
in estimating a specific risk for the patient. This necessitates the
determination of (even mildly) affected family members. In some cases, the
inheritance type can be inferred directly from pedigree analysis or clinical
diagnosis. For example, Best macular dystrophy in a young boy with an
affected father is a dominant disease. Usher syndrome type 1, on the other
hand, is a recessive condition.
Genetic testing may still be valuable for these patients for further risk
stratification within the family but is not critical to determine the risk of
recurrence since autosomal recessive inheritance carries a 25% risk for each
child. However, for many other diseases— particularly RP and LCA—
genetic testing is critical to the determination of the correct inheritance type,
because these diseases may have different inheritance patterns (AR, AD, or in
the case of RP, XL).
For Mendelian diseases, risks are calculated based on the proven
inheritance pattern. In the absence of an identified genetic mutation,
calculations may require more complex statistical methods. For example,
Bayesian analysis can be used to estimate residual risk when an individual is
suspected to have a Mendelian condition such as RP, but genetic test results
are negative.
Genetic Testing
Families and physicians have a variety of motivations for choosing to pursue
genetic testing for inherited eye diseases (24). Historically, these reasons
include confirmation of clinical diagnosis, medical management guidance,
and clarification of inheritance and resulting risk to additional family
members. Today, the most frequent reason patients and families cite for
pursuing genetic testing is potential qualification for gene-specific therapies
and research studies trials. The American Academy of Ophthalmology
supports genetic testing for all patients with a presumed or suspected
inherited, or Mendelian, retinal disease (25).
Clinical Diagnosis
While many inherited retinal conditions have distinct ophthalmologic features
that enable reliable clinical diagnosis, others have overlapping features that
make the diagnosis much more challenging. In these cases, genetic testing
may elucidate the diagnosis and reduce the need for additional
electrophysiology and/or serologic testing frequently used to narrow down
the differential diagnoses. In a young child, this may eliminate the need for
additional sedation or time spent waiting for features to develop.
In the pediatric ophthalmology or retina clinic, determining whether an
ocular condition is isolated or part of an underlying syndromic disease is
critical to providing appropriate care and prognostic counseling. For example,
some children with LCA will develop intellectual disability and/or kidney
disease, whereas most will not. Prior to the availability of comprehensive
genetic testing, many inherited retinal disease specialists recommended
baseline brain MRI testing and periodic renal function studies in all LCA
patients. With genetic testing, only those with mutations in genes that cause
these additional features need this surveillance. Similarly, some children who
present with cone dystrophy or achromatopsia have a syndromic disease
called Alström syndrome, which also predisposes to obesity and liver and
cardiac dysfunction. Children with retinal diseases due to mitochondrial
disorders may require cardiac monitoring; patients with Bardet-Biedl
syndrome may develop diabetes and renal failure. When the molecular cause
of disease can be identified, patients with high risk can be followed
appropriately, but if the mutated gene is known to be associated with
nonsyndromic disease, costly and unnecessary medical screening can be
avoided.
When genetic testing is ordered to rule in or rule out syndromic disease,
thoughtful pretest genetic counseling is critical. Families should be prepared
to face the possibility that their child could have a more extensive disease—
and much more significant health and cognitive consequences—than they
would with retinal disease alone. The choice of genetic test should also be
considered through this lens; genes associated with potentially fatal
conditions such as infantile or late infantile NCL (or Batten disease) are
frequently included on large genetic testing panels but should not be tested
without adequate pretest consent and discussion.
Medical Management
Genetic testing can also assist physicians and patients in pursuing appropriate
medical management. For example, if a patient has a clinical presentation of
cone dysfunction and genetic testing identifies causative mutations in the
ABCA4 gene, then supplementation with vitamin A would be contraindicated
(26). Genetic testing can also identify patients with childhood onset retinal
dystrophy who are at risk for choroidal neovascularization or cystoid macular
edema, as genetic mutations in certain genes, such as CRB1 and BEST1, are
known to be associated with those conditions (27).
With advances in understanding of genotype–phenotype correlations,
genetic testing continues to provide critical information for determining
effective medical management as well as clues to underlying disease
pathology.
Gene-Based Therapies
Recently, demand for genetic testing for inherited retinal diseases has
dramatically increased in response to several significant factors: the
development of gene-based therapies, improvements in genetic testing
capabilities, and reduced cost (with resulting increased access).
In 2017, the FDA approved Voretigene neparvovec–now known as
Luxturna® for the treatment of RPE65-associated retinal dystrophy as the
first US-approved gene therapy for the treatment of a genetic disease.
Therapies for other retinal diseases promise to follow, with gene-based
clinical trials in progress for some types of Usher syndrome, LCA, RP,
Stargardt macular dystrophy, and choroideremia (www.clinicaltrials.gov).
Genetic testing is a vital first step in the identification of patients as
candidates for gene-based therapies and clinical trials. Of course, many
patients will receive positive molecular test results but not qualify for a
current clinical therapy or trial. However, these patients and families can still
contribute to the development of future trials by enrolling in a patient registry
and/or engaging with a clinical research center. As the available database of
patients with known molecular diagnoses grows, clinical trial enrollment
becomes more efficient, and the likelihood of trial success increases.
Improvements in genetic testing methodologies have not only increased
the detection rate of these tests but have done so while decreasing cost. As a
result, patients with pediatric onset retinal diseases now have a very high
likelihood of receiving a positive molecular test result, identifying the cause
of their disease. In fact, in late 2018, the detection rate of genetic testing for
patients with a diagnosis of LCA was approximately 80%, compared with
<50% 5 years earlier (internal communications with clinical genetic testing
labs).
Inheritance and Risk
When genetic testing is successful in identifying the cause of disease, the
clinician can provide accurate risk estimates not only to family members but
also to couples seeking guidance about family planning decisions.
For many families affected with inherited retinal diseases, a genetic
diagnosis does not change their plans for future children. However, other
families choose to pursue genetic testing either before or during pregnancy.
Families who wish to have biologic children without the genetic condition
have two options for genetic testing: in vitro fertilization (IVF) with
preimplantation genetic diagnosis (PGD) or prenatal diagnosis through either
chorionic villus sampling (CVS) or amniocentesis. IVF with PGD allows a
couple to prevent an affected pregnancy by only implanting unaffected
embryos. To date, this option is still expensive and unavailable to many
couples. It also requires a molecular genetic diagnosis before beginning IVF.
If a couple chooses to pursue pregnancy naturally, testing is available in the
first trimester through CVS or after 15 weeks through amniocentesis. While
more affordable than IVF with PGD, both procedures have a small risk of
miscarriage, and the couple may be faced with deciding between terminating
an affected pregnancy or continuing the pregnancy with the knowledge that
the child will be affected. In all cases in which families are weighing
decisions about family planning, a prenatal genetic counselor should be
involved.
After the identification of the underlying genetic mutation(s), at-risk
family members may be interested in being tested. Presymptomatic genetic
diagnosis is appropriate in some cases but should be approached with caution
when testing at-risk family members for conditions where reduced penetrance
or a wide degree of variability in clinical symptoms is known to occur. For
some dominant or X-linked conditions, such as dominant RP or
choroideremia, parents may request genetic testing for an at-risk child. The
American College of Medical Genetics and the American Academy of
Pediatrics explicitly discourage routinely testing at-risk minors for adult-
onset conditions with no available therapy (28). Occasionally though, even
after a thoughtful discussion of this guideline, the family (or child) has strong
reasons for wanting to be tested presymptomatically. In these circumstances,
the consultation of a hospital ethics board may be appropriate. It is important
to note that this guideline for avoiding presymptomatic genetic testing in
minors applies only to conditions that are adult-onset and untreatable. Testing
for Usher syndrome, for example, in a newborn with a sibling who has Usher
syndrome may help guide surveillance and care of the child.
Genetic Privacy
As health care continues to expand and a variety of health care providers
incorporate genetic testing into their practice, some patients worry that this
increased use of genetic information leaves them more vulnerable. Many
patients fear that their genetic information or status will not be maintained
confidentially. To address privacy concerns, legislation has been enacted in
both state and federal arenas over the past 20 years. In 1999, President
Clinton signed an executive order prohibiting any federal agency from using
genetic information in any hiring, firing, or promotion action. Parts of the
Americans with Disabilities Act of 1990, the Health Insurance Portability and
Accountability Act of 1996, and Title VII of the Civil Rights Act of 1964
have also been interpreted to include some protection from genetic
discrimination. Several prominent medical and genetics societies supported
these orders, including the American Medical Association, American College
of Medical Genetics, National Society of Genetic Counselors, and the
Genetic Alliance.
Despite the best intentions of lawmakers, this patchwork of state laws left
many individuals unprotected from perceived, and sometimes real, threats of
discrimination. Clearly, federal legislation was needed to give the public
greater protection and security. Individuals felt that state laws were not
adequate in addressing genetic information specifically, such as genetic test
results or family history information. This was especially true for privately
purchased health insurance plans. In 2008, President Bush signed the Genetic
Information Nondiscrimination Act (GINA) into law (31). GINA provides
additional protection against genetic discrimination: This act more
specifically addresses the definition of genetic information and offers
protection against discrimination by private insurance companies. As such, it
prohibits health insurance plans from determining eligibility or adjusting
premiums based on genetic information. Still, GINA does not extend to life
insurance and long-term disability insurance. With the rise in direct-to-
consumer genetic testing, conversations about genetic privacy and data
ownership have once again emerged on a national stage. Clinicians who order
genetic testing would be wise to follow these discussions in order to address
patient questions.
GENETIC COUNSELORS IN
OPHTHALMOLOGY
With the increasing availability of gene-based treatments and clinical trials, a
larger number of ophthalmologists have become interested in genetic testing.
Even motivated specialists, eager to screen patients as candidates for gene-
based treatment and clinical trials, struggle to meet the demands of
incorporating genetic testing and genetic counseling into routine medical
practice. Comprehensive family history collection, risk assessment, and
discussion of genetic testing options and results require a significant amount
of time, which many clinicians do not have in their regular patient care
setting. Genetic counselors are specifically trained to address both the
educational and social needs of patients and their families and are, therefore,
becoming a more common addition to the clinical team in ophthalmology
either on site or through the use of telemedicine services.
A major component of the genetic counseling process is patient
education, which is crucial for empowering patients to understand their health
care as well as to become their own health advocates. In a 2018 study,
researchers examined the impact of genetic counseling on patients with
inherited heart disease. Using five different measures, they sought to
characterize how genetic counseling affected patients’ empowerment,
knowledge, and anxiety, as well as their relationship with their counselor and
satisfaction with their service. According to the authors, “Genetic counseling
was associated with significantly increased empowerment” (32).
Genetic counselors offer patients in-depth education about the inherited
condition, including an explanation of genes and inheritance patterns. This
often leads to a discussion of additional family members who could be at risk
for the genetic condition. Timing is key with patient education, as patients
may or may not be emotionally ready for complex genetic information at the
time of diagnosis; some would like immediate information, and others may
need weeks to months to process the news of their diagnosis and be ready to
take additional steps. When patients are connected with a genetic counselor,
the counselor can assess patient readiness and pursue patient education when
the timing is most appropriate.
Patients and families nearly always ask questions about long-term
prognosis. These questions are frequently complicated by disappointment
related to how the disease may impact previously held hopes and plans for
the future. Genetic counseling provides patients with both anticipatory
guidance and support in the process of adjusting to changes in expectations
due to a confirmed genetic diagnosis. Genetic counselors are uniquely trained
in short-term counseling related to illness and disability and excel in their
ability to provide patients with psychosocial support.
Many counseling issues can arise in a consultation with the family of a
patient diagnosed with a pediatric retinal condition, including feelings of loss
of independence for both children and parents. Many parents need assistance
in learning to adjust to caring for a child with visual impairment. Parents may
also need assistance in knowing how to discuss vision loss with their affected
child as well as other family members, care providers, and educators. Vision
loss and the psychosocial issues that can accompany this diagnosis are unique
and require a health care provider who is familiar with these issues and has
expertise in counseling patients and families with these conditions.
Genetic counselors also provide patients with contacts for appropriate
local and national support groups and organizations and offer patients support
materials for educating family and community members. Over time, genetic
counselors frequently check in with families to adjust support resources as
patient and family desires and coping abilities change. Additionally, genetic
counselors may utilize services of a social worker or other support person
who can offer longer-term counseling and support resources to the patient
and family.
There are psychosocial risks associated with the diagnosis of a genetic
disease and the disclosure of genetic test results. Patients and families
sometimes describe an emotional burden from learning that their family
members may also develop a genetic disease. Others experience intense
disappointment or anger when genetic testing does not indicate that the
patient will qualify for a clinical trial or therapy. Patients undergoing
presymptomatic genetic testing have reported that receiving abnormal test
results has changed their family structure; they often feel emotionally closer
to family members who have also received abnormal results or the same
diagnosis. Patients who receive normal test results have reported feeling
isolated, especially if they will be the primary caregiver for affected family
members (33). Patients should be supported through these complex emotions
and encouraged to consider and prepare for possible emotional reactions to
the results of testing.
In addition to the familial implications, patients who encounter a
diagnosis of a genetic condition may find themselves facing various ethical
challenges in assimilating the diagnosis into their lives. Perhaps the most
striking example of these challenges is presented in the decision to have, or
not to have, children. Quality of life issues and concerns may present when
examining the risks of having a child, whether it is a patient deciding about
having his or her first child or a couple deciding whether to have future
children. Ethical issues also arise when other family members at risk for the
same condition either do not want to know whether they have a genetic
mutation or simply do not want to share this information with others. In these
situations, the health care provider can be faced with the dilemma of
maintaining patient confidentiality when other family members may wish to
know their own risk. Careful, compassionate, and supportive genetic
counseling can help address the apprehensions of the individual while
ensuring he or she understands the full implications of nondisclosure.
For all of these reasons, patients receiving genetic test results deserve the
time of a trained professional who can explain the significance of the
findings, validate emotional responses, and identify individuals in need of
additional support. Clinical genetic professionals can be identified through
the National Society of Genetic Counselors, the American College of
Medical Genetics, or the American Society of Human Genetics.
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22
Anomalies of the Optic Nerve
Chrysanthi Basdekidou and George Caputo
TILTED DISC
Introduction
Tilted optic discs have been considered to be relatively small optic nerve
heads with an oblique or horizontal orientation and oval disc shape that occur
in eyes without high myopia (1–4).
A tilted appearance of the optic disc is a relatively frequent finding
during the course of an ophthalmic examination and forms one component of
the tilted disc syndrome, which includes the following signs (Figure 22-1):
FIGURE 22-1 A, right eye and B, left eye.Bilateral nasal
tilted disc syndrome, associated with inferonasal
staphyloma in a 20-year-old patient. Vision is 20/20 with a
corrected astigmatism.
1. Subnormal vision
2. Myopic astigmatism with oblique cylinders
3. Transposition or tilting of the optic disc downward and nasally
4. Inferior or inferonasal crescent, also called congenital conus
5. Nasal or inferonasal ectasia associated with thinning of the retinal
pigment epithelium and choroid
6. Bilateral temporal loss of visual field (5–8)
A number of reports (6,9–12) stated that more women than men had tilted
discs. Although many studies reported a high frequency of bilateral
involvement (9–12), there are a number of cases that remain misdiagnosed.
Vongphanit et al. (4) found that the tilted disc appearance was bilateral in
37.5% of cases, whereas Riise (10) reports a 74% rate of bilateral
involvement but he included “slighter cases…which would have been
described as normal in the usual ophthalmoscopy.”
Prevalence
In the majority of cases (80%), the tilted disc syndrome is bilateral. There
have been very few past reports of the prevalence of tilted discs. In a report
from a Norwegian practice series of 300 participants aged 7 years or older,
Riise reported that the tilted disc syndrome was found in five (1.7%) (10). An
identical figure was found for tilted discs in an Italian community of 300
participants, reported by Casteldacchia (13). In a German report from 1922
that included tilted disc illustrations, von Szily reported 3.4% of 32,500 eyes
from a clinic had a nontemporal (“heterotypical”) distribution of peripapillary
atrophy (14) described by some authors as the quintessential feature of the
tilted discs (10,15).
The prevalence in an Australian population was 1.6% and is comparable
to the rate of 1.7% reported by both Giuffre (11) and Riise (10). Given that
the tilted disc appearance varies considerably even between eyes within an
individual (10), the use of dysversion alone may lead to an underestimation
of its prevalence and bilaterality. Dysversion of the optic nerve head has also
been referred to as segmental hypoplasia and is characterized by central
retinal vessels emerging temporal to the vertical midline of the disc and being
directed nasally or the nerve head tilting in a vertical direction resulting in a
downward or oblique tilting of the discs with the blood vessels emerging at
the superior or inferior disc rim.
Tilted optic discs occur in about 4 out of 1,000 nonhighly myopic eyes of
adult Chinese (16). As in Caucasians (1,3), tilted discs were associated with
moderate myopia, astigmatism, inferiorly located beta zone of peripapillary
atrophy, decreased visual acuity, and visual field defects. One may infer that
a visual field defect in an eye with a tilted disc is not proof of an acquired
optic nerve disease, such as glaucoma.
Etiology
It is thought that the spectrum of signs present in any given eye is dependent
on the severity of the embryonic optic fissure malclosure at the 6-week stage
of gestation (8). The 6th week shows the incipient differentiation of the inner
layer of the optic cup into a sensory retina, the formation of the secondary
vitreous, the transformation of the posterior cells of the lens vesicle into
primary lens fibers, the development of the periocular vasculature, and the
appearance of the first eyelid folds and of the anlage of the nasolacrimal duct.
The spectrum ranges from a minimal defect as a tilted disc to more severe
fundus involvement, including inferonasal ectasia and frank coloboma (5).
However, some believe this assumption does not explain adequately the
origin of all ocular anomalies found in the syndrome like refractive errors due
to myopia, hypermetropia or corneal astigmatism, and various types of visual
field defects. Fewer retinal nerve fibers than normal enter the defective side
of the disc (15), whereas the opposite side presents fiber crowding, which
may give an erroneous impression of edema. Therefore, it has been suggested
that atrophy of the ganglion cell fibers of the inferonasal retina might occur
following an anomalous closure of the embryonic cleft. This in turn would
explain the hypoplasia of the inferonasal quadrant, the inferior crescent and
lack of fibers in the inferior optic disc, and the anomalous appearance of the
optic nerve head and of the retinal vessels with shifting of the disc upward
due to the imbalance between the ganglion cell fibers coming from the
superior and inferior retina (11). Furthermore, this shift accounts for the
upper temporal visual field defects mostly found in the syndrome. Kim et al.
(17) studied 107 eyes of 107 patients with tilted discs using coronal views of
swept-source optical coherence tomography (OCT). They were able to
correlate the amount of optic disc torsion with different types of posterior
sclera configuration and postulate that the main pathology was in the
posterior sclera rather than the optic nerve itself.
The heredity of the condition is not yet established perhaps because of the
variability in the phenotype in family members of affected individuals and
may account for the lack of reports of a familial nature of the syndrome.
Single clinical features like inferior crescent or transposition of the optic disc
have been reported as associated with various inheritance patterns (10). On
the other hand, Riise believes that the tilted disc syndrome can be familial
with a polygenic mode of inheritance similar to that of refraction anomalies
(10). Bottoni et al. presented a family with dominant penetrance of a tilted
disc (18). The tilted disc syndrome has also been reported in patients with X-
linked congenital stationary blindness (14). The tilted disc syndrome is
believed to be nonprogressive (5).
Clinical Appearance
The most frequent orientation of tilted discs is inferonasal (60%) (Figure 22-
1), thus tilting to the nasal side of the vertical meridian; however,
inferotemporal tilting has also been reported (28%) (5). The appearance of
tilting arises from the pseudorotation of the superior pole of the optic disc (5),
angulation of the optic cup axis inferonasally, and elevation of the
superotemporal neuroretinal rim (6). The optic disc configuration of tilted
discs can sometimes be confused with optic disc swelling, papilledema (6,8),
or presumed optic disc drusen (9), because the elevated retinal nerve fiber
layer (RNFL) appearance may cause blurring of the disc margin and visual
field changes. Although inferonasal tilting is most frequent, inferior tilting is
the most severe (4).
Best corrected visual acuity (BCVA) is reduced in eyes with tilted discs.
This reduction in BCVA is believed to be due to the Stiles-Crawford effect as
the photoreceptors stand obliquely in relation to the visual axis (10). Several
reports (6,8–10,12,19,20) revealed that a high proportion of people with tilted
discs had myopia and astigmatism with the plus axis parallel to the fundus
ectasia in the inferior quadrant. Corneal topography studies indicate that an
irregular curvature contributes to the associated astigmatism and suggests a
corneal origin of the astigmatism (21). Vongphanit et al. have quantified this
relationship and showed a strong association between the tilted disc
appearance and the level of either astigmatism (93.5%) or spherical refractive
error; myopia was present in 62% of subjects with tilted disc syndrome
compared to individuals with normal optic discs. Oblique astigmatism was
also present in over 50% of the cases (4). In addition, central corneal
thickness and corneal volume were found to be thinner in patients with tilted
disc syndrome than in normals (22).
Reduced visual acuity in association with bitemporal depression of the
visual field that is typically incomplete corresponding to the inferonasal optic
fiber loss (Figure 22-2) can suggest a lesion near the optic chiasm.
Recognition of the fundus abnormalities, possible improvement of the field
defect with proper refractive correction (10), and lack of the vertical
boundary at the midline of the visual field should obviate the need for a
major neurologic workup.
FIGURE 22-2 Nasal tilted disc syndrome, fundus
appearance (A), and OCT scan showing fiber-optic layer
thickening on the nasal inferior and superior portion of the
disc (B).
Many field defects have been described in association with the tilted disc
syndrome. The most frequent sites are superotemporal, temporal, and
superior (6,9,12), but nasal, inferior, and paracentral defects have also been
reported. Some studies have reported that the majority of patients with tilted
discs had a visual field defect, whereas other studies have indicated that field
defects were not consistently found (15,20). In some studies, visual field
defects were associated with myopia >6 diopters (8,23). Repeat perimetry
after addition of a −4 lens often eliminated the visual field abnormality,
confirming the refractive nature of this defect (6).
Visual field defects associated with “scooping out” of the optic disc have
been misdiagnosed as glaucomatous (Figure 22-3) (1,8). Bitemporal
hemianopia associated with tilted discs may also be confused with field
defects resulting from chiasmal compression leading to unnecessary
neuroradiologic investigations (1,10).
FIGURE 22-3 Tilted optic disc with marked central
excavation.
Certain features of the field defect help distinguish defects associated with
the tilted disc syndrome from other pathology. The defects tend to be relative
in nature (9,10) and nonprogressive (6,8) and may resolve with a larger test
stimulus or after optical correction (9,10). Defects are usually surrounded by
normal peripheral visual fields and frequently cross the vertical meridians of
the visual field (6,9).
Although not frequently associated with severe visual impairment, tilted
discs may be associated with choroidal neovascularization (7,11,19,20),
chorioretinal atrophy (19), and neurosensory macular detachment (2). Long-
term follow-up of 48 eyes with tilted disc and serous retinal detachment did
not show a benefit of treatment (24). Posterior staphyloma is commonly
associated (11,13) and may affect vision due to choroidal neovascularization
and chorioretinal atrophy (5). Anomalies at the junction of the staphyloma
may cause serous macular detachments or atrophy over time (Figure 22-4).
FIGURE 22-4 A, right eye and B, left eye.Same patient
as Figure 22-1, 10 years later showing marked pigmented
epithelial changes in the area of the inferior staphyloma
and peripapillary inferonasal atrophy.
Conclusion
In children, detection of tilted discs may prompt refractive measurement and
correction to exclude corneal astigmatism and prevent amblyopia.
When tilted disc syndrome is accompanied by a visual field defect that
respects the vertical meridian, neuroimaging is recommended.
Clinical Evaluation
In affected patients, the configuration of the optic nerve head is variable, and
the drusen may be visible on the disc surface or buried within the disc
(Figure 22-5). Differentiation of ODE from ONHD is crucial and can lead to
diagnostic uncertainty. Examination techniques commonly performed are
optic disc autofluorescence, fluorescein angiography, B-scan
ultrasonography, OCT, and CT scanning (26,37).
FIGURE 22-5 A, right eye and B, left eye. Bilateral
optic disc drusen in a 10-year-old girl. The nasal side of
the optic nerve is irregular.
B-scan ultrasonography may detect drusen in 43% of patients with optic disc
swelling (39) (Figure 22-7). Frisen et al. (40) examined five patients with
high-resolution CT scan and noted calcified drusen had increased attenuation
within the optic nerve head (Figure 22-8). MRI performed in order to
exclude other optic nerve or brain anomaly was found to be a complementary
diagnostic instrument showing a surface disc transparency. However, MRI is
expensive, requires special techniques and considerable patient cooperation,
and is, therefore, unlikely to be the first choice of investigation in patients
with ONHD. B-scan ultrasonography, on the other hand, is rapid,
noninvasive, and inexpensive. Furthermore, B-scan ultrasonography has been
shown to be superior to autofluorescence and CT scanning (41).
Recently, there have been a number of reports using OCT to distinguish optic
nerve edema from ONHD that focused on measurements of the peripapillary
RNFL thickness (27,42–45) and direct visualization of the optic nerve head
as important features (27). RNFL thickness, especially in the nasal quadrant,
has been shown to be decreased in ONHD when compared with optic nerve
edema (27). Lee et al. using SDOCT detected 80.0% sensitivity and 88.9%
specificity for nasal RNFL thickness >78.0 mm (27). Johnson et al. reported
80% specificity and 70% sensitivity for nasal RNFL thickness >86 mm for
the differentiation of ONHD from optic nerve edema (46) (Figure 22-9). In
some patients with ONHD, photoreceptor changes also have been
documented (47). Using OCT, Savini et al. (43) identified the SHYPS,
subretinal hyporeflective space, a hyporeflective space located between the
sensory retina and the retinal pigment epithelium and choriocapillaris in ODE
patients. Johnson et al. (46) found a decrease in the mean SHYPS thickness
in ONHD patients compared with those with optic nerve edema. Thus, they
characterized the OCT appearance of optic nerve edema as an elevated optic
nerve head with a smooth internal contour and a SHYPS thickness under the
optic nerve head with a gradient taper away from the disc: An enlarged
basement membrane opening is observed in optic nerve edema. An irregular
surface of the disc creating a “lumpy bumpy” internal optic nerve contour
and a more abrupt taper of the SHYPS were suggestive of ONHD (47).
ONHD has a signal-poor core, with a hyperreflective margin, and is located
anterior to the lamina cribrosa; it is best seen with EDI-OCT or swept-source
OCT (48).
Complications
ONHD have been reported to cause myriad local vascular complications,
including central retinal artery and vein occlusion and peripapillary choroidal
neovascularization (49).
The presence of bilateral ONHD causing choroidal neovascularization in
children is a rare occurrence with the earliest reported case in a 3-year-old
child (50). Peripapillary choroidal neovascularization can cause central vision
loss by subfoveal progression of the choroidal neovascularization, serous
macular detachment, or submacular hemorrhage (50). Various treatment
strategies have been advocated. Observation may be a viable option, but there
are insufficient data from studies comparing observation with reported
treatment modalities.
Laser photocoagulation was reported successful at 2 years by Delyfer et
al. (51) as a treatment for two patients with bilateral choroidal neovascular
membranes from ONHD and subretinal hemorrhages extending into the
macula. Photodynamic therapy with verteporfin (Visudyne; Novartis
Ophthalmics, Basel, Switzerland) has also been used. Silva et al. (52) were
the first to report successful treatment of bilateral choroidal
neovascularization associated with ONHD in a 10-year-old girl. After two
sessions of photodynamic therapy, no recurrences were noted after 2 years of
follow-up. Surgery is another treatment option. Mateo et al. (53) surgically
removed choroidal neovascular membranes in four eyes with ONHD, all of
which showed significant visual recovery without any recurrence during 12
to 42 months of follow-up. Antivascular endothelial growth factor (VEGF)
agents are now commonly used to treat adults with choroidal
neovascularization from a variety of causes (54). Their use in children has
been reported in Coats disease (55), Best disease (56), and coloboma-related
choroidal neovascularization (57,58). Knape et al. presented a case of
bilateral choroidal neovascular membranes associated with ONHD in a 5-
year-old boy who was successfully treated with a combination of focal laser
photocoagulation and intravitreal bevacizumab (59). Until the safety of anti-
VEGF therapy has been established in the pediatric population, consideration
of these medications should be reserved for select cases of choroidal
neovascularization threatening central visual acuity.
NAION may occur at an unusually young age in patients with optic disc
drusen; it has been described in a 13-year-old child and in several patients in
their later teens and early twenties (36,60–62). The visual outcomes in these
patients vary, although they are slightly better than for other NAION patients.
Some patients do well clinically (60,61). Proposed mechanisms of vision loss
include distortion of blood vessels by drusen (36). Systemic hypotension,
dehydration, and altitude have been suggested as contributory factors for
NAION in the setting of ONHD and may provide an explanation for why
patients often discover symptoms upon awakening (63). No effective
prevention or treatment for NAION is known. The risk of contralateral
involvement is estimated around 15%.
Conclusion
ONHD, despite being a benign condition, have been reported to cause a
number of local vascular complications, including central retinal artery and
vein occlusion, peripapillary choroidal neovascularization, and NAION.
Patients should be aware of these risks and seek ophthalmologic follow-up.
We recommend that parents of children with optic disc drusen be instructed
about the risk of NAION and potential contributory factors, such as
dehydration and altitude, to help prevent vision loss in their children.
A role for vitreous traction has also been postulated from the observation that
maculopathy becomes symptomatic in the fourth decade of life and that it can
resolve after spontaneous posterior vitreous detachment (PVD) (86). Bonnet
previously reported that none of the eyes with macular detachment in their
series had evidence of a PVD and that the two eyes that demonstrated
spontaneous reattachment did so after a PVD developed (86). In addition,
Theodossiadis et al. described vitreous abnormalities, such as vitreomacular
traction and vitreous strands over the optic disc associated with optic disc pit
maculopathy (87). In their study, Hirakata et al. provided equivalent evidence
that vitreoretinal traction is an important factor in the pathogenesis of optic
disc pit maculopathy and that induction of PVD relieving any anteroposterior
traction on the macula is effective in reversing macular elevation without the
need for laser treatment (88). During induction of a PVD, a tight adhesion of
the posterior hyaloid or abnormal membrane, such as anomalous Cloquet
canal, to the margin of the disc pit has been reported (89,90).
When there is posterior hyaloid traction caused by age-related vitreous
liquefaction or trauma, it pulls on the optic disc pit. Because the pit is pulled
up like a tent by vitreous traction, the turbulent flow may have increased
access around the vessels to the intraretinal space. This traction affects the
peripapillary retina, especially around the pit. This further facilitates IRF
accumulation. When a PVD occurs, the anterior traction is released. The pit
decompresses and moves downward, and access to the subretinal space
becomes limited. Any traction on the peripapillary retina also is released.
Treatment
Patients normally seek ophthalmologic evaluation because of diminished
visual acuity or the discovery may be made incidentally during a routine
ophthalmologic assessment. When an optic pit is detected, performing an
OCT can be very useful in order to detect the presence of a PVD, a schisis-
like separation, and/or SRF. In cases with severe maculopathy associated
with vitreomacular traction, vitrectomy allows release of the vitreoretinal
traction and should be routinely performed. The ablation of the fibrotic
prepapillary material, the peeling of the internal limiting membrane, and the
peripapillary photocoagulation can be performed but remain controversial
and haven’t proven anatomical and functional benefit (79). The use of a gas
tamponade agent may not be necessary for success (88) but is generally
associated. In fact, subretinal migration of gas or silicone oil has been
reported (91,92). Theoretical calculations suggest that the pressure
differential required for migration of gas through a small defect in the roof of
a cavitary disc lesion is within the range of expected fluctuations in CSF
pressure. Explanations should be given concerning the nature of this
pathology and the visual acuity outcome.
Conclusion
Optic disc pits are usually unilateral, sporadic, and not associated with
systemic disease. The etiology of the associated serous maculopathy still
remains unclear. It could be suggested that the unusual movement of fluid
between the vitreous cavity and subarachnoid space and the traction around
the posterior hyaloid may contribute to the pathogenesis of this disease.
Vitrectomy with induction of a PVD without a gas tamponade or laser
photocoagulation allows resolution of optic disc pit maculopathy in most
cases.
OPTIC NERVE COLOBOMA
Introduction
Colobomas of the optic nerve result from incomplete or abnormal closure of
the primitive embryonic fissure (93). In certain instances, the defect may
extend to involve the choroid, retina, ciliary body, and iris. The term
“coloboma” derives from Greek and means “defect” (from the adjective
“colobos” that means “mutilated” or “cut short”).
Optic disc coloboma comprises a clearly demarcated bowl-shaped
excavation of the optic disc, which is typically decentered and deeper
inferiorly (94). The coloboma occupies the lower part of the optic nerve head.
The neuroretinal rim is absent inferiorly but is usually identifiable superiorly
(Figure 22-14). In cases in which the adjacent inferior retina and choroid are
deficient, microphthalmia may also be evident (95). Optic disc colobomas
may appear as large excavations of the nerve head up to 25 diopters deep and
involving nearly all of the disc, which may be enlarged (96).
FIGURE 22-14 Optic nerve coloboma in a 16-year-old
patient having lost her left eye by retinal detachment.
Macular pigment is visible on the edge of the coloboma
and vision is 20/100.
Coloboma-Related Complications
The presence of an optic nerve coloboma implies some possible
complications. A small proportion of cases are associated with cysts arising
from the optic nerve sheath, which communicate with the subarachnoid space
(108). Rarely, such cysts can enlarge and lead to compressive optic
neuropathy (109). Peripapillary choroidal neovascularization has been
described in association with optic nerve coloboma (110,111). Studies have
shown good response of this type of neovascular membrane to treatment with
intravitreal bevacizumab (57).
Retinal detachment occurs in approximately 45% of patients with optic
nerve coloboma (66) (Figure 22-17). The source of the SRF is not known but
could derive from fluid entering the retrobulbar space from the surrounding
orbital tissue, from the choriocapillaris, or from the CSF. In contrast to
retinochoroidal colobomas, rhegmatogenous detachment is probably not a
recognized association (112). The retinal detachments associated with optic
nerve colobomas typically are more extensive and more bullous than those
caused by optic nerve pits, which affect only the macular area and are often
accompanied by schisis. The pathophysiology appears to be similar in both of
these conditions with a defect in the abnormal papillary tissue allowing fluid
to communicate to the subretinal space and detach the retina. In patients with
an optic nerve head coloboma, the extent of abnormal tissue is much greater
than it is in optic pits. This papillary defect along with a poorly differentiated
retina and retinal pigment epithelium, an abnormal lamina cribrosa, and an
enlarged scleral canal potentially allows the vitreous cavity, subretinal space,
subarachnoid space, and orbital space to communicate in these patients (113).
If a defect develops and liquefied vitreous has access to the hole, then the
retina detaches. Circumferential intrascleral smooth muscle has been
observed histologically (114) and may account for the rare observation of
spontaneous contractility of the colobomatous optic disc (115). Spontaneous
reattachment however may occur (116).
FIGURE 22-17 Retinal detachment complicating a large
optic nerve coloboma in a 6-month-old boy. The presence
of folds including the macula and the pigment epithelial
changes favor the hypothesis of a congenital retinal
detachment.
Conclusion
Chromosomal analysis should be considered in children with optic disc
colobomas as well as MRI imaging in both unilateral and bilateral cases. A
trial of patching may result in improvement of vision in the child presenting
early in life, and optimal refractive correction may be indicated. OCT
imaging assists with understanding the contributing factors to retinal
detachment in individual cases of colobomatous optic disc anomalies and can
thereby assist with determining the most effective approach to management.
Etiology
The etiology of the anomaly is unknown, and no hereditary tendency is
evident. The association with midline craniofacial anomalies has been
attributed to a developmental defect in embryogenesis during the second
gestational month (129).
The pathogenesis of this condition is unknown. One hypothesis is that the
abnormality results from failed closure of the fetal fissure, similar to what
occurs with optic nerve coloboma. Another theory suggests that there is an
error in mesenchymal differentiation that results in abnormal closure of the
scleral wall and lamina cribrosa (136). Recently, mutations in the PAX6 gene,
which is involved in ocular morphogenesis, have been identified in patients
with MGDA (105).
Clinical Presentation
MG discs are more common in females and rare in black individuals. Most
cases are unilateral. Visual acuity is usually poor in the affected eye and often
with associated amblyopia, although there are rare reports of cases with good
visual acuity (128,133,137). Several bilateral cases have been reported
(124,138).
The clinical diagnosis of the MGDA is established primarily by
ophthalmoscopic examination. The disc is markedly enlarged; it is orange or
pink and appears to be elevated centrally within the confines of a funnel-
shaped peripapillary excavation (138). A wide annulus of peripapillary
excavation surrounds the disc. The blood vessels appear to be increased in
number and often arise from the periphery of the disc. Close inspection
occasionally reveals the presence of small peripapillary arteriovenous
communications (139) (Figure 22-18). The macula may be incorporated into
the excavation (macular capture) (124).
There are some additional tests that can provide further information, such
as visual field examination, visual evoked potentials, and B-scan
ultrasonography (140).
Baer et al. (141) described the first OCT finding in an atypical MGDA
patient with peripapillary excavation lined by retinal pigment epithelium in
2003 but provided no quantitative details. Srinivasan et al. (142) recently
reported quantitative OCT data of a 25-year-old woman with MGDA. They
provided the evidence of increased RNFL thickness and reduced macular
thickness.
Wu et al. reported the OCT analysis of a case of a 4-year-old boy with
MGDA (140). The optic disc OCT revealed exceedingly high cup/disc ratio
in the affected eye. In addition to the greater average thickness of the RNFL,
the temporal RNFL thickness was much greater than the inferior (196 μm vs.
157 μm). This finding is contrary to the “ISNT” rule in normal optic discs, in
which normal disc thickness becomes thinner from inferior to superior to
nasal to temporal (143). Srinivasan et al. (142) also noted this interesting
finding.
Contractile movements occur in morning glory discs (138). Two main
mechanisms have been proposed to explain this phenomenon: pressure
balance (144) and muscular contraction (138,139,145). The muscular
contraction theory was suggested (139,144,145) by several authors and later
supported by the discovery of heterotopic smooth muscle cells in the sclera of
an eye with an optic disc coloboma (146). This explanation is further
supported by the finding of nonvascular contractile smooth muscle cells in
the posterior choroid and sclera of normal eyes (147,148). These cells have
been colocalized with sympathetic nerve terminals in the choroid and
nitroxidergic parasympathetic terminals in the sclera (147) and have proven
to be functionally contractile on immunohistochemical staining for
smoothelin, which is considered to be present only in contractile smooth
muscle cells (148). In light of this, the actions of such contractile cells might
be clear in the excavated and colobomatous eye but might not be evident in
the eye with normal scleral coverage. In addition, the transient monocular
visual loss observed in patients with good visual acuity (139,144,149) further
supports the action of intermittent muscular contraction, which might
contribute to the intermittent compression around the optic nerve.
Lee et al., using computerized analysis, demonstrated contractile
movement mainly around the optic nerve margin in a horizontal direction
(150). Although these findings do not confirm a definitive mechanism, the
authors support smooth muscle contraction for the pathogenesis of the
contractile movement. This observation might be explained by the
distribution patterns of the nonvascular smooth muscle cells, in which a
group of cells were arranged in a semicircular pattern around the optic disc
and another group of cells were located in the foveal region of the temporal
quadrant (148).
Complications
In morning glory syndrome, the peripapillary retina extends into the
anomalous peripapillary scleral defect. The retinal tissue within the defect has
been observed to be thinner, incompletely developed, and atrophic.
Sometimes, the retina is detached in this area.
The pathogenesis of retinal detachment in morning glory disc and the
origin of SRF from vitreous cavity (151–157) or subarachnoid space
(158–160) remain controversial (152,155). Rhegmatogenous retinal
detachment has been reported in 37% of cases and is often confined to the
peripapillary retina (161) (Figure 22-19).
FIGURE 22-19 Inferior and temporal retinal detachment
complicating morning glory anomaly in a 7-year-old girl.
Pigment epithelial mottling is visible at the surface of the
retina confirming the rhegmatogenous mechanism.
Akiyama and colleagues postulated that the origin of the SRF was from the
anomalous disc and most probably from a break on the disc margin (155). Ho
et al. (162) in a series of five eyes used OCT to demonstrate subtle slit-like
breaks at the margin of excavation. Bartz-Schmidt and Heimann (151)
demonstrated a communication between the subretinal space and vitreous
cavity resulting in rhegmatogenous retinal detachment.
In the absence of a retinal break, spontaneous resolution of retinal
detachment with MGDA can occur and should be considered before planning
surgery (153).
Subretinal neovascularization may occasionally develop within the
circumferential zone of pigmentary disturbance adjacent to a morning glory
disc (163).
Conclusion
Since this anomaly is associated with amblyopia, a trial of occlusion therapy
is warranted in small children. Patients with MGDA should undergo
neuroimaging because of the potentially severe consequences of intracranial
vascular anomalies such as Moyamoya disease. OCT can play a role in the
diagnosis of MGDA and its associated ocular complications (162). It
provides more detailed information of the configuration of this congenital
anomaly, thus offering a better way to understand and follow the
pathophysiologic change.
Etiology
A lesion that causes a reduction of the total number of retinal ganglion cells
before the supportive tissues are fully developed in the first to second
trimester may result in a small disc because the supportive structures may still
be able to adapt to the subnormal size of the nerve tissue of the optic
disc/nerve. Correspondingly, a “late” lesion in the third trimester might result
in a normal-sized disc with a large cup, because the supportive elements have
reached their full size, creating a normal-sized disc, whereas the degeneration
of nervous tissue creates a loss of substance identified as a large cup (182).
There is interest in the theory that ONH represents an exaggeration of the
normal process of axonal cell death that occurs in the developing visual
pathways. Further investigation of the development of the normal optic nerve
is necessary before some of the puzzles that surround the pathophysiology of
ONH and optic atrophy can be unraveled.
The cause of ONH is probably multifactorial. Differentiation of the
retinal ganglion cells begins at 6 weeks of embryonic life, and it has been
suggested that a failure of this differentiation is the cause of ONH.
Consequently, the lesion would be induced before the seventh week of
gestation (183). However, a recent report demonstrates an important role of
the homeobox gene in the development of SOD, which indicates that ONH
might develop even earlier than previously thought (184). In addition, the
frequent association between ONH and other CNS anomalies suggests that
another explanatory factor for ONH may be a secondary degeneration of
ganglion cells and their fibers (185). Depending on the anatomic location of
the insult, this degeneration could be transsynaptic retrograde, as suggested in
periventricular leukomalacia (PVL), or simply retrograde, as suggested in, for
example, craniopharyngioma (185). In addition, various teratologic agents,
such as alcohol, may cause anterograde ONH (186).
The vast majority of cases of ONH cannot be attributed to genetic
mutations at the current time. Familial cases have been reported and are
usually autosomal recessive. However, <1% of cases of ONH in a large series
were found to have mutations in HESX1, a gene known to cause optic nerve
anomalies, and none were found to have SOX2 mutations (187). PAX6
mutations have been reported to result in a wide variety of congenital optic
nerve abnormalities, including hypoplasia (105,188).
ONH has been associated with both postmaturity and prematurity
(189,190). A Swedish study found an increased risk with young maternal age,
primiparity (first-time pregnancy), and early prenatal smoking exposure
without drug or alcohol exposure (191).
The role of teratogens in some cases of OHN has been more convincingly
established. Maternal ingestion of quinine (192), Dilantin (193), lysergic acid
diethylamide (LSD) (194,195), and phencyclidine (196) has all been reported
to be associated with ONH in infancy. However, the evidence for teratogenic
effects is strongest for the genesis of ONH in the fetal alcohol syndrome
(186,197,198).
As demonstrated by Hoyt et al., patients with congenital hemianopsia had
obvious segmental atrophy of the optic disc but also a reduced horizontal
diameter, suggesting that the optic nerves were also hypoplastic (199). Margo
et al. reported optic atrophy with normal-sized nerves in two similar patients
(200). On the basis of these data, Hoyt and Good suggested that the same
type of lesion could result in either ONH or optic atrophy, depending on the
timing of the lesion (201). It may also be speculated that a primary prenatal
adverse event causing ONH might result in a higher vulnerability for a
perinatal secondary insult. It seems possible that the timing of the lesion
might be an explanatory factor for the varying appearance of the optic disc
noted in children with a clinical diagnosis of ONH.
Clinical Presentation
Poor visual behavior is usually the first sign of ONH. Nystagmus usually
develops at 1 to 3 months of age followed by strabismus—typically esotropia
—in the first year of life. Children with markedly asymmetric or unilateral
ONH may present primarily with strabismus rather than nystagmus. Myopia
and hyperopia have been equally found (182).
More than 80% of bilateral cases are legally blind (202). Most children
experience some improvement in their vision in the first few years of life.
This may be due to optic nerve myelination that occurs in the first 4 years of
life and leads to improved axonal conduction (183).
Observations of developmental delay in association with ONH range
from isolated focal defects to global delay. Garcia-Filion et al. (176) found
developmental delays in 71% of ONH patients using standardized
neuropsychological instruments in a prospective study. Motor delays were
the most common (75%), and communication delays were the least common
(44%). The prevalence of autism appears even higher in children with ONH
among the visually impaired children.
Taylor proposed the following criteria concerning the clinical
presentation of ONH (167):
1. Isolated ONH.
2. Absent septum pellucidum. This anomaly has not been associated with
significant intellectual, behavioral, or neurologic dysfunction (169,171).
3. Posterior pituitary hypoplasia commonly associated with endocrine
dysfunction.
4. Neuronal migrational anomalies in the cerebral hemispheres. This
includes, for example, thinning of the corpus callosum, which is
predictive of neurodevelopmental problems.
The optimal method for diagnosing ONH in a young child is direct or indirect
ophthalmoscopy, according to the child’s age. Magnification may be needed,
and documentation using optic head photos may facilitate the optic nerve
head analysis. First, and most important, is an assessment of the area of the
disc relative to the size of the central retinal vessels overlying it. ONH
classically manifests as a small optic nerve head with the distance between
the center of the disc and fovea exceeding three disc diameters and is
frequently accompanied by a double-ring sign and anomalous retinal vessel
morphology. Although most patients with disc diameter/disc to macula
(DD/DM) ratios <0.35 have generally been described as having ONH, some
with DD/DM ratios of 0.30 to 0.35 have normal vision. Fundus photography
may help in the diagnosis.
Small optic disc(s) and the double-ring sign are the hallmarks of the
severe condition. The double-ring sign indicates that a small nerve is present
within the confines of a wider scleral canal (Figure 22-21). In patients with
ONH, a ring of hypopigmentation or hyperpigmentation often, but not
always, surrounds the disc defining the area of the putative scleral canal. This
is presumably caused by migration of sensory retina and/or retinal pigment
epithelium from their original margin at the edge of the optic canal to a new
position at the border of the hypoplastic optic disc (203). This “double-ring”
sign does not define ONH, because a similar appearance may be present in
other conditions, such as myopia. In less marked cases, the diagnosis is
reached first by clinical suspicion and the subsequent measurement of the
relative and absolute size of the disc (Figure 22-22). Abnormal visual fields
and nerve fiber layer photographs are helpful for the diagnosis (179).
Reduced optic nerve diameter from the normal range of 4 to 4.5 mm
measured by ultrasound has been described, and the diameter of the optic
canal may be reduced (204).
FIGURE 22-21 Mild optic nerve hypoplasia in the right
eye of a 5-year-old girl; vision is 20/80 OD and 20/20 OS.
A small hypopigmented rim surrounds the smaller optic
nerve (A) not seen in the fellow eye (B).
FIGURE 22-22 Severe optic nerve hypoplasia in a 2-year-
old girl. Double-ring sign with hyperpigmentation around
the optic nerve. Vision is limited to fix and follow. The
fellow eye was lost by severe intraocular bleeding due to
thrombocytopenia.
OCT studies show that the ONH is associated with thinner RNFL and
ganglion cell layer; the outer nuclear layer has a more dome-shaped aspect
and the macula presents some degree of foveal hypoplasia. Horizontal disc,
horizontal rim, and horizontal cup diameters are also reduced in ONH (205).
The refractive state of the eye should always be assessed as high
hypermetropia may give a false impression of ONH. Segmental ONH, which
is mostly appreciated in the superior disc, can be identified using OCT (206).
ERG can be useful in severe bilateral cases in which the diagnosis of Leber
amaurosis and achromatopsia must be considered. ONH should have normal
ERG amplitudes.
The vision of young children with ONH should be monitored at least
annually, and any refractive errors should be treated. Patching of the better
eye can result in improvement of vision in the worse eye. However, if the
ONH is very asymmetric, maintenance of improved vision requires
prolonged patching that can be disruptive to development in a child with
many other handicaps. Thus, amblyopia therapy should be reserved for those
cases in which the potential vision in each eye is felt to be fairly good or in
which there are failed attempts previously in children with unilateral or
markedly asymmetric ONH.
Conclusion
All infants with poor visual behavior, strabismus, or nystagmus by 3 months
of age should have an ophthalmoscopic examination to rule out ONH. The
finding of reduced vision in a patient with a small optic disc thus supports the
diagnosis of ONH. In cases with reduced vision but normal to subnormal disc
size, other morphologic signs, including reduced rim area, pallor of the disc,
double ring, and abnormal vessels, may be used as additional diagnostic aids.
Once ONH is confirmed ophthalmoscopically, an MRI of the brain
should be obtained. The MRI can rule out treatable conditions such as
hydrocephalus but can also be used to anticipate developmental delay
associated with corpus callosum hypoplasia or other major malformations.
Parents, pediatricians, neurologists, and endocrinologists should be informed
of the potential risk for endocrine dysfunction in affected children to ensure
close monitoring for clinical signs of hypopituitarism (206).
Embryology
The choroidal vasculature is normal in ONA suggesting that eye development
is normal through the 2nd month, but absence of retinal vessels and lacunar
retinal defects in ONA suggest defective retinal development and failure of
retinal angiogenesis in the third to fourth month contribute to the
degeneration of retinal ganglion cells (215). Defective retinal angiogenesis
and retinal dysplasia in ONA could be associated with coloboma of the eyes.
One can look at ONA as either a failure of the mesoderm to enter the
fetal fissure and provide vascularization of the retina and optic nerve or as a
result of absent retinal ganglion cell axons, which inhibit retinal ganglion cell
development and provoke subsequent lack of mesodermal induction. Warfel
suggested that there is an initial development of the eye with subsequent
“degeneration” (216). Oster et al. suggest there is a failure of genetic control
of development; the authors propose that since ONH but not ONA results in
the absence of Netrin-1, a protein involved in axonal growth function in
mice, there are other mechanisms involved that act on axons during
development (217).
Different authors have given their approach concerning ONA
development. Weiter et al. suggest that ventral invagination of the optic
vesicle causes nerve fiber misdirection and secondary atrophy (218). Yanoff
et al. (219) postulate a primary failure of ganglion cells to develop and send
out axons. This failure results in a lack of induction of mesodermal ingrowth
including a lack of retinal blood vessel development. Hotchkiss and Green
(220) agree that failure of mesodermal induction secondary to a neuronal
defect in the ganglion cell layer is probably responsible for the development
of aplasia. The fact that eyes with optic aplasia may be nearly normal in size
and have a normal lens suggests the initial development of the eye proceeds
normally with primitive multipotent retinal ganglion cells with vascular
supply from both the hyaloid artery and the annular vessel (221).
PAX6 and OTX2 mutations have been associated with ONA (105).
Because Pax6/PAX6 is expressed in numerous tissues important for optic
nerve development—including the CNS, optic stalk and retinal progenitors at
an early stage, and retinal ganglion cells at a late stage; it is not surprising
that more variable phenotypes are caused by PAX6 mutations. Meier et al.
reported the only study of an autosomal dominant form of nonsyndromic
unilateral and bilateral ONA. They demonstrated that neuroimaging (MRI)
may have an important diagnostic value for uncovering ONA in
microphthalmic patients while implicating the deletion of the CYP26A1 and
CYP26C1 genes as potential susceptibility factors for ONA (221).
Pregnancies are described as normal, but environmental factors might be
a consideration since clinical histories from case reports mention exposure to
a viral-like episode during the first trimester (222), acetone exposure as in
this case, or smoking during pregnancy (223). Aplasia may be produced
experimentally further implicating the potential role of environmental factors
in ONA.
Diagnostic Criteria
According to Taylor, the diagnostic criteria are summarized as follows (167).
The optic disc is absent or rudimentary. There are no, or few, and abnormal
retinal vessels. The vision is extremely poor or absent. There is sometimes a
coloboma of the fundus or iris, and aniridia may occur (218). There may be a
retinal pigment disturbance especially at the site where the optic disc might
have been. There may be other systemic and eye developmental defects such
as coloboma, microphthalmos, cataracts, and sclerocornea (215). Published
reports have described a spectrum of eye abnormalities on the affected side.
Frequently, these eyes are microphthalmic and enophthalmic, and ptosis of
the affected eye is present. Esotropia of the affected eye is common. The
vitreous is usually clear, but a fibrovascular strand may extend from a
choroidal vessel toward the lens, representing hyperplastic primary vitreous
(218). Retinal dysplasia is frequent in histopathologic cases. Choroidal
neovascularization is an occasional finding. Microphthalmos or
anophthalmos may occur in the fellow eye (167).
The ERG wave may be flat. If present, the A- and B-waves are
diminished. An absent or depressed ERG in eyes with aplasia indicates a
more profound retinal dysfunction than merely reduced ganglion cells and
axons. A defect in the development of all retinal cells, both functionally and
anatomically, seems to occur in aplasia of the optic nerve (224). Visual
evoked potential recordings suggest abnormal crossing with greater-than-
normal contralateral fiber projections of the normal nerve (18).
Conclusion
ONA is an extremely rare condition whose origin still remains unclear. It is
mostly a unilateral condition frequently associated with other malformations
in the affected eye. The typical fundus presentation and the pupillary reflex
are sufficient to establish the diagnosis. In microphthalmic patients,
neuroimaging (MRI) may have an important diagnostic value for uncovering
ONA. In bilateral cases, neuroimaging is essential in order to reveal CNS
malformations, whereas other systemic malformations should be questioned.
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23
Albinism
Katherine Ann Lee, Sylvia R. Kodsi, Joseph Carroll, and C. Gail
Summers
INTRODUCTION
Albinism (albus, Latin, meaning white) is a group of disorders involving
melanin pigment biosynthesis with the specific gene in which mutations
occur defining the type. The phenotypic spectrum can be broad among the
different types of albinism and within a specific type. Most are inherited as
autosomal recessive disorders, but ocular albinism (OA1) is inherited as X-
linked recessive. Some types of albinism are syndromic as they have
associated systemic manifestations that can cause more morbidity than the
ocular features.
Most types of albinism are oculocutaneous, meaning that the abnormality
in melanin production affects the skin, hair, and eyes, although the extent
varies. In ocular albinism, the pigment abnormality is primarily limited to the
eyes. Syndromic albinism is associated with oculocutaneous albinism (OCA).
PREVALENCE
Albinism affects approximately 1 per 17,000 persons worldwide, but there is
substantial geographic variability in the prevalence of individual types (1–3).
To date, seven types of nonsyndromic OCA have been identified.
Approximately 1 in 70 persons carries a mutation for a type of albinism (4,5).
ENVIRONMENTAL FACTORS
There are no known environmental factors that cause albinism, but
environmental factors can contribute greatly to morbidity from the condition.
For example, people with albinism lack melanin protection in their skin from
the sun’s damaging rays. For affected individuals who live in sunny parts of
the world, near the equator, or at high altitude, the risk of skin cancer
increases markedly compared to those who live in less sunny areas. Access to
sunscreen products and skin protective clothing also affects risk of skin
cancer in these individuals. In parts of Africa with intense sunlight and little
access to sunscreen, virtually 100% of patients with albinism have been
reported to develop skin cancer by their 30s or 40s. For patients with
syndromic albinism who have a bleeding diathesis, predisposition to lung and
liver fibrosis, and susceptibility to infections, living in a safe, controlled
environment with access to excellent medical care may extend life far beyond
that of patients living without these advantages.
GENETICS
OCA1 is caused by mutations of the tyrosinase gene (TYR) (6). Tyrosinase is
critical to the first step of melanin biosynthesis. Historically, OCA1 has been
divided into two categories clinically, OCA1A and OCA1B. OCA1A patients
have white hair and skin at birth and they do not gain pigment with age.
OCA1A is the most severely affected type of OCA. Persons with OCA1B are
also lightly pigmented at birth but gain pigmentation in skin and hair with
time, sometimes showing pigmented nevi and the ability to tan (7). OCA1 is
the most common type of albinism in America and China (1:40,000) (8). In
the era of genetic testing, we now understand that what was historically
called OCA1A represented a complete lack of enzyme activity needed to
produce melanin. The most common gene associated with this is TYR, but
with genetic testing, severe null mutations of other genes in pigment
pathways, for example, OCA2, OCA4, and some Hermansky-Pudlak
syndrome genes, may clinically appear to be OCA1A. Many different genetic
types of albinism may clinically fall into the OCA1B description. Over time,
the subtypes of albinism are being referred to by the gene affected, rather
than by historical names based on amount of pigment present.
OCA2, the most common type of albinism worldwide (1:39,000), is the
most common type of albinism in Africa, with a prevalence up to 1 in 3,900
in areas of Southern Africa (9). Among African Americans, the prevalence of
OCA2 is approximately 1 in 10,000 (10,11). The OCA2 product is important
in melanosome biosynthesis and transport of melanosome-associated
proteins. OCA3 is caused by mutations in tyrosinase-related protein 1
(TYRP1), an abundant melanosome protein with several functions. It has a
prevalence of 1:8,500 in Southern Africa related to a founder effect, but it is
also seen in Pakistani, German, Indian, and Japanese populations (9). OCA4
is caused by mutations in a gene that encodes a melanosome membrane
transporter protein (MATP or SLC45A2). The overall prevalence of OCA4 is
1:100,000, but it accounts for 24% of Japanese OCA (12). OCA5, OCA6, and
OCA7 are much more rare, and their phenotypic characteristics are not fully
described (see Table 23-1).
WORLDWIDE IMPACT
As discussed in the previous section, due to founder effects, different types of
albinism are more prevalent than others in certain geographic regions of the
world and in the diaspora of those communities. Taken together, however,
albinism is found all around the world in every ethnicity and geographic
region. Although, for example, Hermansky-Pudlak syndrome is relatively
more common in Puerto Rico than in other parts of the world, patients from
any ethnicity can have Hermansky-Pudlak syndrome. Although
understanding the increased prevalence of specific types based on ancestry
can be helpful, it can also prevent some patients from receiving a timely
diagnosis if they do not fit the typical description.
PATHOPHYSIOLOGY
Melanocytes are melanin-producing cells found in skin, hair follicles, eyes,
inner ear, heart, and brains of humans. Melanin is produced and packaged
into lysosome-like intracellular melanosomes. In the epidermis, mature
melanosomes are distributed by phagocytosis to surrounding keratocytes and
hair follicles (17). Hypopigmentation in albinism is related to reduced
production of melanin, defects in melanosome function and distribution to
surrounding cells, and defects in proteins integral to multiple organelles
including melanosomes.
Melanin synthesis begins with the rate-limiting conversion of L-tyrosine
to L-DOPA by membrane-bound tyrosinase. In subsequent steps L-DOPA is
converted to brownish, black eumelanin or reddish, yellow pheomelanin
(Figure 23-1). Eumelanin confers ultraviolet (UV) light protection;
pheomelanin does not. OCA1 is caused by a complete or partial absence of
tyrosinase and has a profound effect on skin and hair pigmentation as well as
visual function. The functions of the gene products of the other
nonsyndromic and syndromic albinism types are less well understood but
generally involve maintenance of the structural integrity of melanosomes and
similar intracellular organelles and to the distribution of melanosomes to
surrounding keratocytes.
FIGURE 23-1 Simplified diagram of melanin
biosynthesis within the melanocyte. Tyrosine, combined
with enzymes such as tyrosinase (TYR) and tyrosine-
related protein 1 and 2 (TRP1 and TRP2) changes into
eumelanin and pheomelanin pigments. (Reprinted with
permission from Cichorek M, Wachulska M, Stasiewicz
A, et al. Skin melanocytes: biology and development. Adv
Dermatol Allergol 2013;30:30–41. doi:
10.5114/pdia.2013.33376.)
Melanin-producing retinal pigmentary epithelial (RPE) cells present early in
embryogenesis and are important in visual system development. Melanin in
neuroectoderm-derived RPE cells is important to the development of the
fovea. Animal models demonstrate that tyrosinase activity is necessary for
controlled decussation of retinostriate projections at the chiasm and altered
RPE cell melanin production alters retinal ganglion cell projections. In
albinism, absence of melanin results in foveal hypoplasia as well as excess
decussation of nerve fibers at the chiasm (Figure 23-2) disrupting the normal
layering of cells at the lateral geniculate nucleus and reducing stereopsis
(18–20).
OCULAR FEATURES
Typical ocular features of albinism include nystagmus, reduced iris and RPE
pigmentation, abnormal retinostriate projections, and foveal hypoplasia (25a).
Nystagmus is usually present in albinism and starts in early infancy. It is
most often horizontal and conjugate and damps in the first few years of life.
The null zone is where the amplitude of the nystagmus is diminished and
vision is improved. Pendular, periodic alternating, and rotary nystagmus have
been described in albinism.
Melanin pigment is reduced in the posterior iris epithelium, derived from
neuroectoderm, whereas anterior iris stromal melanocytes are derived from
the neural crest. This leads to mild to marked pigment defects best
appreciated by transillumination of the irises with slit lamp biomicroscopy
and slit lamp photography (Figure 23-3). A decrease in pigmentation of the
retinal epithelial cells gives a yellow-orange hue to the retina and allows a
variable increased view of the choroidal vessels in the macula and retinal
periphery (Figure 23-4). A characteristic feature of albinism is the excessive
decussation of retinostriate nerve projections at the optic chiasm where both
nasal and some temporal retinal ganglion cells project to the contralateral
lateral geniculate nucleus (Figure 23-2) (25b). This excessive crossing can be
demonstrated by flash or pattern visual evoked potential with occipital
recording. The misrouting frequently disrupts stereoacuity. The small number
of patients who have stereoacuity typically has relatively better vision and
less iris transillumination and may show granular melanin pigment in their
maculas compared to those without stereoacuity (26).
NONSYNDROMIC ALBINISM
The most common types of albinism are OCA1 and OCA2. Therefore, the
phenotypes are more completely described than the less prevalent types of
albinism, OCA3 and OCA4, or the more recently described types of albinism,
OCA5, OCA6, and OCA7.
Ocular Albinism
OA1, also designated Nettleship-Falls ocular albinism (81,82), is the only
type of albinism that is not inherited as an autosomal recessive disorder.
Males affected with this X-linked disorder typically show only the ocular
features of albinism, but their skin and hair appear to have a normal amount
of melanin, although it may be somewhat lighter than what is typical for their
families. Despite the name, skin biopsies of affected males and carrier
females may show macromelanosomes, indicating OA1 is not solely ocular
(83). A family history of males being affected over several generations is
often obtained. Female carriers are rarely symptomatic (84), but up to 90%
will show the variegated pigmentation of the fundi, which represents random
inactivation of the X chromosome, also known as lyonization or pigmentary
mosaicism (Figure 23-7) (82,85). Many carriers also have iris
transillumination, particularly in families with constitutive light
pigmentation.
FIGURE 23-7 The “mud-splattered” fundus of the
obligate carrier of X-linked OA1 is an example of random
inactivation of the X chromosome, referred to as
lyonization or pigmentary mosaicism. The darker areas
represent expression of the normal X chromosome,
whereas the areas without melanin pigment represent the
expression of the X chromosome carrying the mutation in
GPR143 that causes OA1.
Vision is variably reduced in OA1, with mean best corrected visual acuity of
20/63 (range 20/50 to 80) reported by Winsor et al. (52). Others have noted
vision as poor as 20/200 to 20/400 (28,86–90), but occasionally vision is as
good as 20/40 or better (86,88,89).
When the obligate carrier is affected, the pedigree may suggest autosomal
dominant nystagmus or a pigmented type of AD albinism; however, there
will never be male to male transmission. Examination of the mother’s retina
showing the characteristic pigmentary mosaicism establishes the diagnosis. If
the affected male has a new mutation in GPR143, the family history will be
negative, examination of the mother will be negative, and testing with a
genetic panel will be necessary to establish this type of albinism. Counseling
should include that no male offspring will be affected but all female offspring
will be carriers for OA1. Female carriers have a 50% (1 in 2) chance of
passing the mutation to male offspring who will be affected and to female
offspring who will be carriers.
Some have described an autosomal recessive ocular albinism, but most of
these have been shown to have a mildly pigmenting type of OCA (91–93).
The range of pigmentation present in all genetic types of albinism varies
widely based on the residual protein activity of the defective gene product.
Genetic testing rather than assessment of external pigmentation should be
used to diagnose the subtypes of albinism.
SYNDROMIC ALBINISM
Hermansky-Pudlak Syndrome
HPS, first described in 1959 in two unrelated Czechoslovakians (94), refers
to a heterogeneous group of disorders characterized by OCA, a platelet
storage pool deficiency causing a bleeding diathesis, and in some types,
associated with granulomatous colitis, interstitial lung disease, and/or
immunodeficiency. Electron microscopy of platelets shows absence of dense
bodies (Figure 23-8).
FIGURE 23-8 Electron micrograph of normal control
(Ctrl) platelets left, with dense bodies (arrowheads),
compared to platelets without dense bodies from a patient
with HPS (right). (Reprinted from Carmona-Rivera C,
Golas G, Hess RA, et al. Clinical, molecular, and cellular
features of non-Puerto Rican Hermansky-Pudlak
syndrome patients of Hispanic descent. J Invest Dermatol
2011;131:2394–2400. Copyright © 2011 The Society for
Investigative Dermatology, Inc. With permission.)
HPS-1
In the northwest part of the island of Puerto Rico, 1 in 1,800 people have a
homozygous 16-base pair (bp) duplication in exon 15 of the HPS-1 gene due
to a founder effect. Other Hispanic individuals who have HPS-1 but who do
not have ancestors from Puerto Rico do not have this duplication (104). HPS-
1 is associated with an increased risk of pulmonary fibrosis. Brantly et al.
found a mean age of onset of pulmonary symptoms at age 35 years (96).
A study of 21 individuals with the 16-bp deletion showed mean visual
acuity of approximately 20/125 and moderate iris transillumination and
macular translucency (103). Another study of 16 persons with HPS-1 showed
mean visual acuity of 20/160-2 (range 20/40 to 500) and significantly more
iris transillumination when compared to a group with HPS-3 (105).
Yousaf et al. described 11 individuals with HPS-1 in 3 Pakistani families
(106). Affected persons had golden, golden-brown, or brown hair, white skin,
and hazel-green to green irises, lighter than unaffected family members. All
were photosensitive but three siblings, ages 10 to 25 years, had no
nystagmus. Of the three who had visual acuity measured, all siblings had
nystagmus, two had acuity of 6/18 in each eye, and the third, who had a large
amount of hyperopic astigmatism, had count fingers vision. Eight had
gastrointestinal problems and the remaining three were 15 years old or
younger.
One study reported the eye findings in 45 Puerto Rican patients with the
16-bp duplication. Median best corrected visual acuity was 20/400 (range
20/40 to 1,300). Most had complete iris transillumination although some
variability was reported. Most had a somewhat translucent macula, allowing
choroidal vessels to be partially visualized, but again, variability was
reported. In addition, most patients were noted to have periodic alternating
nystagmus (107).
Ten Japanese persons with HPS-1 were noted to have blond to brown hair
and blue to brown irises. All but one had nystagmus. One patient, who was
60 years old, had pulmonary fibrosis (108).
HPS-2
HPS-2 is severe and rare. It was first reported in two brothers in a family of
Dutch origin, ages 20 and 25 years, who had a history of congenital
acetabular dysplasia (109). They had bruising and epistaxis in childhood.
Recurrent otitis media and upper respiratory infections, greater than in their
unaffected siblings, were noted. Examination showed dysmetria and poor
tandem gait; the older brother also had a tremor. Magnetic resonance imaging
of the head was normal. Both had mild pulmonary fibrosis and neutropenia.
The brothers were found to have mutations in the β3A subunit, which caused
either degradation or destabilization of all four of the adaptor complex-3
subunits and interference with the trafficking of lysosomal membrane
proteins (110). They had white hair early in life but it eventually turned
blond. Both had nystagmus and almost complete iris transillumination.
Corrected visual acuity measured 20/200 in the right eye and 20/160 in the
left eye for each brother. Radial lens opacities were noted.
Huizing et al. reported a third patient with HPS-2 who was a 5-year-old
Cajun/native American boy (111). He was born with white hair that darkened
to silvery blond to tan at age 5. He had melena associated with a rotavirus
infection but did not bleed excessively with circumcision. He had multiple
episodes of respiratory distress, and at age 20 months, a biopsy showed
nonspecific interstitial pneumonitis. Severe neutropenia was treated with G-
CSF (Neupogen). The patient had short stature and was very delayed in
acquiring developmental skills. He had tricuspid regurgitation and pulmonary
hypertension. Dysmorphic facial features included epicanthus; low-set,
posteriorly rotated ears; broad nasal root; thin upper lip with long philtrum;
and retrognathia. Other findings included a severe pectus deformity and genu
valgus. He had horizontal pendular nystagmus and blue irises with full iris
transillumination. A visual evoked potential was consistent with the
retinostriate misrouting seen in albinism.
More recently, six children with HPS-2 were reported to highlight their
pulmonary disease and how pulmonary disease in HPS-2 can occur at an
earlier age than in HPS-1. Symptoms began an average of 3.3 years prior to
diagnosis. Diagnosis of pulmonary fibrosis was made at a mean age of 8.8
years (range 2 to 15 years). The pulmonary fibrosis was rapidly progressive
and was complicated by recurrent infections exacerbated by neutropenia,
pneumothoraces, and scoliosis.
A pair of siblings with the same mutations was noted to have dissimilar
clinical courses (112).
HPS-3
HPS-3 has been identified in central Puerto Rico where approximately 1 in
16,000 is affected. It is due to a 3,904-bp deletion due to a founder effect
(113). HPS-3 has also been found in those with Ashkenazi Jewish heritage
and in non–Puerto Ricans without the 3,904-bp deletion (114). A common
splice-site mutation removing exon 5 from the gene found among Ashkenazi
Jewish patients is felt to be due to a founder effect. A 4-year-old boy from the
Arabian Peninsula with easy bruising was also identified with HPS-3 (115).
Hypopigmentation is minimal (hair color tan to light brown) and bleeding is
generally mild in HPS-3, manifested as epistaxis, bruising, and menorrhagia.
Pulmonary fibrosis and gastrointestinal issues do not seem to be associated
with this type of HPS. This type of HPS can be easily overlooked and
diagnosed as a type of OCA or OA1.
In a study of eight non–Puerto Ricans with HPS-3, ages 3 to 52 years,
visual acuity ranged from 20/60 to 20/160 (114). A study of 14 individuals
with HPS-3 found mean visual acuity of 20/125 + 2 (range 20/50 to 320).
Visual acuity was significantly better and iris transillumination was less than
that in those with HPS-1 (105).
A study of 19 patients with HPS-3 found median best corrected visual
acuity to be 20/200 (range 20/25 to 400), significantly better when compared
to 45 patients with HPS-1. This study also found that those with HPS-3 had
significantly less iris transillumination and less macular translucency than
those with HPS-1 (107).
HPS-4
Anderson et al. identified seven persons of varied ethnicities with HPS-4,
ages 3 to 61 years. All gave a history of excessive bleeding and one had
granulomatous colitis. Three had restrictive lung disease, with one dying at
age 61. The true prevalence of pulmonary fibrosis in this group with HPS-4 is
unknown as four were under age 20 and were asymptomatic. Hair and skin
pigmentation varied markedly with unaffected family members. Visual acuity
ranged from 10/30 to 20/200 (116).
Two Pakistani siblings in a family of Sindh origin were also reported to
have HPS-4 (106). They had brown hair, pink white skin, and brown irises.
They reported photosensitivity and had nystagmus. They were 34 and 38
years old and appeared to have a milder phenotype, reporting no bleeding
diathesis.
HPS-5
HPS-5 is relatively rare compared with other types of HPS. Individuals with
HPS-5 are mildly hypopigmented and bleeding problems are mild. They do
not seem to have the other systemic manifestations of HPS. Because of this, a
diagnosis of HPS can be missed without molecular analysis.
Huizing et al. reported on four patients with HPS-5 (117). A 10-year-old
boy with a European heritage had bruising and light brown hair. He had
nystagmus and almost full transillumination. Vision was 20/200. A 51-year-
old Swiss woman had bruising, mild epistaxis, and prolonged menstrual
periods, but no postpartum bleeding. She had nystagmus, moderate iris
transillumination, and vision of 20/100 in one eye and 20/125 in the other.
Her hair was blond at birth but darkened to brown. She did not have
pulmonary disease or granulomatous colitis. Her 43-year-old sister had
bruising in addition to some bloody stools, but her gastrointestinal evaluation
was normal; albinism was diagnosed at age 12, and she had almost full iris
transillumination. Vision measured 20/100 in one eye and 20/125 in the
other. A 21-year-old with bruising, epistaxis, and prolonged menses had light
brown hair and almost complete iris transillumination. Vision was 20/160 in
one eye and 20/200 in the other. She did not have evidence of interstitial lung
disease or colitis.
A Venezuelan Cuban boy with HPS-5 had no bleeding with surgery but
had leg bruising and minor epistaxis; his vision was 20/100 in one eye and
20/125 in the other (104).
A series of 11 patients with HPS-5, most of French or Turkish origin,
reported that hair color was typically light brown, irises were blue to brown,
and skin did not tan. All had nystagmus and foveal hypoplasia. All but two
who were just 1 year old had reduced visual acuity (118).
HPS-6
HPS-6 is associated with mild hypopigmentation and mild bleeding
problems. A 39-year-old Belgian woman with epistaxis and bleeding
following dental extractions was diagnosed with HPS-6. She had no
symptoms to suggest pulmonary or gastrointestinal disease. She had OCA.
Her brother had similar findings and was also found to have HPS-6. There
was no history of consanguinity, but both parental families were from a
similar locale and siblings had a homozygous deletion in the HPS-6 gene.
This is an ortholog of the ruby eye mouse (ru) gene. Mutations in ru lead to a
mouse model of HPS. Electron microscopy showed only a rare dense body in
platelets (119).
Yousaf et al. reported two Pakistani siblings with HPS-6 (106). Both had
red hair, pink white skin, and dark brown irides. Vision measured 6/18 in
each eye of the 14-year-old and was 6/60 in the right eye and 6/36 in the left
eye of the 10-year-old. Both were photosensitive but only the younger one
had nystagmus. The younger sibling had a normal bleeding time and a normal
clotting time. Neither had gastrointestinal problems.
Huizing et al. studied four patients with HPS-6 (120). The first was a 36-
year-old woman of Irish and German origin, who was diagnosed with HPS at
age 26 due to bleeding problems and albinism. She had several surgeries
requiring transfusions and had a history of bruising, menorrhagia, and
frequent infections. Evaluation showed no evidence of interstitial lung
disease. Her hair was light brown. Vision was 20/100 in one eye and 20/125
in the other. She had nystagmus, marked iris transillumination, and foveal
hypoplasia. The second patient was a 22-year-old woman of Scottish,
English, and German origin. She had prolonged bleeding and epistaxis early
in life but a diagnosis of HPS was not made until age 16. Chest CT showed
no evidence of pulmonary fibrosis. Her hair was brown. Vision measured
20/80 in the right eye and 20/63 in the left. She had nystagmus, marked iris
transillumination, and foveal hypoplasia. The next patient was a 13-year-old
girl of German and Dutch heritage. She had nearly white eyelashes, brows,
and hair early in life but developed pigment later. A diagnosis of tyrosinase-
positive albinism was made and a diagnosis of HPS wasn’t made until age
16. She had strabismus surgery without bleeding problems. She had
developmental delay and bruised easily. Visual acuity was 20/200 in each
eye. The last patient was a 52-year-old Italian man with rotary nystagmus and
a history of bruising in childhood. HPS was diagnosed at age 44 due to OCA
and gastrointestinal symptoms, which included gastroesophageal reflux,
esophageal dysmotility, hiatal hernia, and dysphagia. High-resolution chest
CT showed no evidence of interstitial lung disease. He had brown hair.
Vision measured 20/160 in one eye and 20/125 in the other. He had moderate
transillumination of his brown irises, and foveal hypoplasia.
Despite these reports of relatively mild disease, a 58-year-old Caucasian
woman, born to consanguineous parents, reported no history of albinism but
did have a history of severe bleeding that included severe menorrhagia
requiring transfusions and bleeding after vaginal delivery and gastric polyp
removal that required treatment for hemodynamic instability. She was found
to have HPS-6 without colitis or pulmonary fibrosis. An eye examination
disclosed vision of 20/25 in the right eye and 20/40 in the left. She had no
nystagmus and very mild iris transillumination (121).
HPS-7
A 48-year-old Portuguese woman, born to consanguineous parents, was
identified with HPS-7 (122). She had bruising and a tendency to bleed, but
pulmonary function and CT of her lungs were normal.
A 6-year-old boy from Paraguay with HPS-7 and delay in his motor and
language development was reported by Bryan et al. (123). The boy had easy
bruising and posttraumatic hemorrhage resulting in pulmonary scarring and
right hemiparesis. He had no evidence of interstitial pulmonary fibrosis,
colitis, or immunodeficiency. His hair was light brown and his skin was
hypopigmented, much lighter than his parents. He had nystagmus, almost full
iris transillumination of his brown irises, and best corrected visual acuity was
reduced to 20/200 in each eye.
HPS-8
A homozygous germline frameshift BLOC1S3 mutation was identified as the
cause of HPS-8 in a 21-year-old Pakistani male, born to consanguineous
parents. His hair was silvery at birth and darkened to gold. His irises were
hazel and his skin was pale and did not tan. Visual acuity was 6/60 in each
eye. He had iris transillumination and foveal hypoplasia, and a visual evoked
potential showed excessive retinostriate decussation. His sister was similarly
affected but she had high myopia and her vision was 6/36. Other family
members were similarly affected with vision ranging from 6/36 to 6/120.
Easy bruising, prolonged bleeding from wounds, epistaxis, and menorrhagia
were common. Pulmonary fibrosis and colitis were not (124).
An Iranian boy with HPS-8, born to consanguineous parents, had
nystagmus noted early in life. He began wearing glasses at 3 months of age.
His skin was lighter than his parents. At age 6 years, his vision measured
20/200 in the right eye and 20/125 in the left eye. He had iris
transillumination, foveal hypoplasia, and an exotropia. He had easy bruising
and gingival bleeding but did not have excessive bleeding with circumcision
(125).
HPS-9
A 17-year-old woman from Northern Italy with absent PLDN protein
expression, indicative of HPS-9, was reported by Badolato et al. (126). She
had nystagmus related to OCA and recurring cutaneous infections.
Leukopenia and immunodeficiency were noted. She had a fever associated
with seizures at age 6. Exam showed leukopenia and thrombocytopenia. She
was found to have homozygous nonsense mutation in the pallidin (PLDN)
gene.
A 4-year-old Pakistani boy has also been reported to have PLDN
mutations (106). He had OCA with photophobia and nystagmus. His hair was
golden white, his skin was pink white, and his irises were light brown. Both
his bleeding time and clotting time were prolonged.
Okamura and colleagues reported a 52-year-old Japanese woman with
HPS-9 and consanguineous parentage. Her hair was blond and her irises were
brown. She had nystagmus and mild visual impairment. There was no history
of interstitial pulmonary disease or colitis (127).
HPS-10
Only one person with HPS-10 has been described to date. This Turkish boy,
born to consanguineous parents, had microcephaly and developed myoclonic
and generalized seizures that became intractable. He had severe
neurodevelopmental delay. Imaging showed a large arachnoid cyst in the
posterior fossa, a small telencephalon, enlarged internal and external
cerebrospinal fluid spaces, and reduced myelination. Otoacoustic potentials
and brainstem evoked audiometry were reduced (128).
The boy had chronic neutropenia and an immunodeficiency with frequent
infections. His immunoglobulin levels were normal but he had impaired NK-
and T-cell degranulation. Bone marrow aspirate showed hypersegmented
neutrophils. The patient had chronic interstitial lung disease and at age 3.5
years, developed pneumonia with sepsis and died (128).
Hair was lightly pigmented and he had intermittent nystagmus and no
ocular fixation. Other features included large, low-set ears, hypotelorism, a
flat philtrum, retrognathia with Pierre Robin sequence, flat acetabula, and
hepatosplenomegaly. The boy did not have a bleeding diathesis, but Ammann
et al. (128) indicated that the patient may have had a subclinical platelet
granule defect. The homozygous truncating mutation in the AP3D1 gene was
identified by exome sequencing, with genetic and phenotypic similarities to
the “mocha” mouse (129).
Chédiak-Higashi Syndrome
CHS is another type of syndromic OCA inherited as an autosomal recessive
disorder. Hair is white to blond to brown and develops a silvery gray sheen.
Frequent bacterial infections and a bleeding disorder are common and over
time, peripheral neuropathy develops. Bacterial infections are due to
neutropenia and dysfunctional natural killer (NK) cells. Bleeding is due to a
storage pool deficiency in platelets; electron microscopy shows irregular and
a reduced number of dense bodies (130). Hematopoietic stem cell
transplantation (HSCT) is preferred prior to the accelerated lymphohistiocytic
phase, which is fatal, typically within the first decade of life when left
untreated (131,132). HSCT successfully treats the hematologic and
immunologic manifestations of CHS. The neuropathy, with both central and
peripheral components and involving both motor and sensory nerves, appears
to progress despite successful transplantation. HSCT also does not affect the
pigment dilution.
CHS is caused by mutations in the CHS1/LYST gene, which regulates the
size and movement of lysosomal organelles. Enlarged granules that are
peroxidase-positive are found in cells due to abnormal lysosomal
enlargement (Figure 23-9). Melanosomes are enlarged in melanocytes and
delta bodies are enlarged in platelets. The cells may be inappropriately
distributed, accounting for the hypopigmentation, bacterial susceptibility, and
neuropathy (133,134).
DIAGNOSTIC STUDIES
The clinical diagnosis of albinism is made by ocular examination with the
findings of foveal hypoplasia, iris transillumination defects, nystagmus,
decreased pigmentation of the fundus, and lighter skin color than other
members of the family. In those patients in whom the diagnosis of albinism is
unclear or not obvious, visual evoked potentials can be used to show
excessive retinostriate decussation of the nerve fiber at the chiasm in
albinism; this test is helpful if abnormal decussation is documented, but not
finding abnormal decussation does not rule out albinism (136). If the patient
is male and thought to possibly have OA1, the mother can be examined to
look for characteristic mosaic patterns of hypopigmentation in the iris and
retina (137). It is important in all patients with albinism to identify any
patient who may be classified as having an HPS phenotype because these
patients may have associated systemic disease. Therefore, all newly
diagnosed patients with albinism should have either molecular genetic testing
with an albinism panel containing all known genes, electron microscopy of
platelet morphology to look for absence of dense bodies, or platelet
aggregation studies. If there is a history of easy bruising or epistaxis, frequent
infections or lung disease, or if surgery is planned, this testing is imperative
(138). If the patient has silvery hair along with OCA, then the diagnosis of
CHS should be considered and along with a prolonged bleeding time, there
will be giant peroxidase-positive lysosomal-like organelles seen in the blood
leukocytes (139). Alternatively, genetic panels can be sent to see if the patient
has any mutations in the genes known to cause HPS or CHS (138).
Albinism genetic testing panels can be performed to identify the exact
genetic mutation present in each patient with albinism. If the genetic mutation
can be identified, the family can be offered preimplantation genetic testing
and in vitro fertilization with unaffected embryos, allowing the family to
conceive a disease-free child (140).
DIFFERENTIAL DIAGNOSIS
OCA with marked iris transillumination, foveal hypoplasia, nystagmus, and
extremely pale skin is not confused with many other disease entities.
However, as described previously, not all patients have the aforementioned
clinical appearance. Foveal hypoplasia, which is seen in essentially all
albinism patients either clinically or subclinically by OCT, can be seen in
many other disorders including aniridia, achromatopsia, isolated foveal
hypoplasia, Aland eye disease/incomplete congenital stationary night
blindness, Stickler syndrome (141), prematurity, and even in normal eyes
(142–146). ERG testing would differentiate Aland eye/incomplete congenital
stationary night blindness and achromatopsia from albinism. Aniridia can be
differentiated from albinism by abnormalities of the iris (which may at times
be subtle). Isolated foveal hypoplasia does not have the iris transillumination
defects seen in albinism. Slit lamp examination of the iris prior to pupillary
dilation is extremely important in differentiating albinism from other diseases
with foveal hypoplasia when nystagmus is present. Iris transillumination
defects in children can also be seen in X-linked megalocornea, trauma, iris
atrophy (after herpes infection or uveitis), and Axenfeld-Rieger spectrum. In
adults, pseudoexfoliation and pigment dispersion syndrome are the most
common causes of iris transillumination (138). Patients with Stickler
syndrome usually have high degrees of myopia from preschool age.
Albinism is one of the most common etiologies of congenital sensory
nystagmus in infancy. In a study of 202 consecutive patients presenting to
pediatric ophthalmology with congenital nystagmus, 19% had a diagnosis of
albinism (147). Other causes of congenital sensory nystagmus with minimal
fundus changes include Leber congenital amaurosis, congenital stationary
night blindness, achromatopsia, and optic nerve hypoplasia. Clinical
examination can be useful to identify the above retinal dystrophies because
they often present with paradoxical pupils and abnormalities of color vision,
which are absent in albinism. A large positive angle kappa is also useful in
helping make the clinical diagnosis of albinism (148). Electroretinography
and genetic testing can also be used to identify congenital retinal dystrophies.
Dermatologic Issues
Strict sun protection in albinism should begin in infancy and be continued
lifelong because affected persons are at increased risk for all types of skin
cancer (163). This includes avoiding UV light exposure during peak hours of
sunlight, wearing protective clothing, using sunscreen and frequent
reapplication, and avoiding medications that increase photosensitivity. Recent
studies have found that sunscreen ingredients attain blood levels after topical
application (164). No detrimental effects have been shown for these levels,
and the increased risk of skin cancer must be considered, but frequent
dermatologic examinations should begin by the teenage years. Any
suspicious or concerning lesions should be evaluated by a dermatologist.
Systemic Issues
Children with albinism have normal neurologic development despite visual
impairment (165). However, children and adults have a higher prevalence of
attention deficit/hyperactivity disorder (ADHD). The prevalence of ADHD
appears to be unrelated to best corrected visual acuity or type of albinism
(166).
Because sunlight avoidance is recommended in OCA, patients with
albinism may not produce enough vitamin D. However, studies have shown
that vitamin D levels tend to be adequate due to enough incidental UV light
exposure (167). If there is concern about low vitamin D levels, then serum
vitamin D levels can be drawn.
At this writing (May 2019), there are no gene therapy trials for albinism.
However, research is being done in mouse models that may be applicable for
human studies. An AAV vector to supply human tyrosinase to a mouse model
for OCA1 resulted in melanin production in neuroectodermally derived
(RPE) and neural crest–derived (choroid, iris) cells (168). Another study
successfully used lentiviral-mediated transfer of the HPS-1 gene in vitro into
a patient’s dermal melanocytes (169). One mouse model study has shown
that eye and skin pigmentation can be improved in OCA1B mice, which has
residual tyrosinase activity, by treatment with nitisinone, which is an FDA-
approved inhibitor of tyrosine degradation (170). Nitisinone also increased
melanin in melanocytes in a human with OCA1B. A similar effect was not
observed in OCA3 mice in which albinism is caused by mutations in
tyrosinase-related protein 1 (171). A human study in patients with OCA1B is
under way to determine if visual function can be improved with nitisinone.
Patients with either HPS or CHS should avoid the use of aspirin and
aspirin-containing products and nonsteroidal anti-inflammatory agents. Skin
wounds can be treated with gel foam soaked in thrombin. Prophylaxis with
aminocaproic acid or desmopressin can be helpful, but when surgical wounds
are expected to be more extensive, platelet transfusions may be needed to
control bleeding.
Persons with CHS require treatment with antibiotics for infections
although their response to treatment may be slower than normal. Early
treatment with HSCT prior to the accelerated phase treats the immunologic
and hematologic complications of CHS.
Persons with HPS and pulmonary fibrosis require preventative and
supportive care. Influenza and pneumococcal vaccines should be given.
Oxygen can be given as needed and air pollutants, including smoking, should
be avoided (97). Neither steroids nor pirfenidone, an antifibrotic agent, has
been shown to be effective for treatment of pulmonary fibrosis in HPS (172).
The only effective treatment for the advanced lung disease in HPS is lung
transplantation. Three patients have been reported with successful lung
transplant and no evidence of recurrence up to 6 years after transplant.
Avoidance of alloimmunization is recommended for optimal success (173).
ETHICAL CONSIDERATIONS
Genetic testing and/or platelet testing should be offered for ascertaining
which albinism patients have syndromic, potentially life-threatening forms.
Genetic counseling should be offered for family planning purposes.
FUTURE TREATMENTS
There is hope that medical treatment such as nitisinone, or gene replacement
therapies, may be available in the future for patients with albinism.
RESOURCES
National Organization for Albinism and Hypopigmentation (NOAH)
—www.albinism.org
World Albinism Alliance—worldalbinism.org
Albinism Fellowship UK and Ireland—www.albinism.org.uk
Albinism Trust New Zealand—albinism.org.nz Albinism Fellowship of
Australia—www.albinismaustralia.org HPS Network—HPSnetwork.org
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24
Neuronal Ceroid Lipofuscinoses and
Lysosomal Storage Diseases
Sana Idrees, and Mina Chung
NEURONAL CEROID
LIPOFUSCINOSES
The neuronal ceroid lipofuscinoses (NCLs) are a unique group of inherited
lysosomal storage disorders characterized by retinopathy progressing to
blindness, progressive decline of cognitive and motor capabilities, variable
cerebellar atrophy, myoclonic epilepsy, and premature death. Storage
material is found in various cell types, but the destruction of tissue is largely
confined to the central nervous system. There are 14 genetically distinct
forms of human NCLs. Classically, NCLs were categorized by the age of
onset, but more recently as causative genes have been identified, a genetic
classification has emerged.
Otto Christian Stengel published the first clinical description of NCL in
Norway in 1826. Stengel was a general practitioner who observed four
siblings with unremarkable early development go on to develop blindness,
progressive mental deterioration, loss of speech, and epileptic seizures. Two
of the siblings died by age 20 and 21 years (3). However, Stengel’s
description went unnoticed to the scientific community until the 1950s (4).
In the early 20th century, further studies of familial cases of progressive
vision loss and psychomotor retardation of later onset were described. Late
infantile NCL (LINCL) was described by Jan Janský and Max Bielschowsky,
otherwise known as Janský-Bielschowsky disease (5,6). Frederick Batten,
Wolfgang Spielmeyer, and Heinrich Vogt all described juvenile NCL
(JNCL), which was known as Batten-Spielmeyer-Vogt disease at that time
(7–9). In 1925, Hugo Kufs described adult-onset mental deterioration with
similar intraneuronal storage but without vision loss. This subtype was later
termed adult NCL (ANCL) or Kufs disease (10). Later, Matti Haltia and
Pirkko Santavuori identified a subtype of NCL with early onset that is now
known as infantile NCL (INCL) or Haltia-Santavuori (11–13).
The term Batten disease has been used in the literature to refer to NCLs
as a group but, in particular, JNCL.
Incidence
Collectively, the NCLs are the most common cause of childhood-onset
neurodegeneration (14,15). The incidence of NCLs varies by geographic
area. The estimated incidence in the United States is 1.6 to 2.4/100,000,
whereas in Finland, the incidence is estimated at 4.8/100,000 and in Iceland,
7/100,000 (16,17).
Genetics
At least 14 genes, CLN1 through CLN14, have been implicated in the
development of NCL. Most NCLs are autosomal recessively inherited,
although cases of autosomal dominant NCL have been described (18,19).
Additional genes and mutations are being recognized regularly; below is a
summary of known genes reported in PubMed at this writing.
The underlying defect in CLN1 disease is the lack of activity of the
lysosomal palmitoyl protein thioesterase (PPT1), an enzyme that removes
palmitate residues from proteins (20). The physiologic function of PPT1 is
not well understood but appears to be necessary for the maintenance of
cellular processes, such as apoptosis, endocytosis, vesicular trafficking,
synaptic function, and intracellular signaling (21). To date, 71 mutations have
been described in CLN1 (22).
CLN2 encodes the lysosomal enzyme tripeptidyl peptidase (TPP1) of the
serine carboxyl proteinase family, and mutations in this gene generally cause
LINCL (23). Thus far, 129 mutations in this gene have been found (22).
TPP1 has been associated with the removal of tripeptides from the N-termini
of small polypeptides, such as the subunit c of mitochondrial ATP synthase
(24).
The CLN3 gene associated with the most common subtype, also termed
JNCL or Batten disease, encodes a membrane protein whose function is
unknown. This protein is present predominantly in the endolysosome system,
but it has been reported to localize to membrane lipid rafts in synaptosomes,
Golgi apparatus, cell membrane, and mitochondria (25). Seventy-eight
mutations have been identified in CLN3. In most patients, at least one of their
two mutations is a common ancestral 1-kb deletion founding mutation (26).
The CLN4/DNAJC5 gene encodes cysteine-string protein α (CSPα),
which underlies the autosomal dominant adult form of NCL that is also
known as Parry disease. It has been suggested that CSPα is a substrate of
PPT1, and thus, CLN1 and CLN4 diseases are related, and aberrant protein
palmitoylation may be critical in the pathogenesis of NCL disease (27,28).
CLN5 encodes a soluble protein that is directed toward the lysosome and
reported to interact with the gene products of CLN2 and CLN3, which
suggests that there may be a common molecular pathway or critical
interaction between pathways involved in various NCL subtypes (20). To
date, 37 mutations in this gene have been identified (22).
CLN6 encodes a protein of unknown function with seven transmembrane
domains localized to the endoplasmic reticulum (ER) (29,30). Seventy
mutations have been identified in CLN6 (22).
The CLN7 gene product MFSD8 belongs to the large major facilitator
superfamily (MFS), which transports specific classes of substrates (31).
There are 38 known disease-causing mutations in this gene (22).
CLN8 encodes a polytopic membrane protein that localizes to the ER and
shuttles between the ER and ER–Golgi complex. The exact function of the
protein is unknown. It is known to belong to the TRAM-Lag1p-CLN8 (TLC)
protein family, which has roles in biosynthesis, metabolism, transport, and
detection of lipids (31). Thirty-five mutations in this gene have been
identified (22).
CLN9 has been proposed as a NCL entity, but no specific gene has been
identified (32).
CNL10 encodes for cathepsin D (CTSD), a lysosomal enzyme involved
in neuronal stability. Alterations in the macroautophagy–lysosomal
degradation pathway have been implicated in the mediation of
neurodegeneration in CNL10 disease (33,34). Ten mutations have been
described in this gene (22).
Mutations in the GRN gene have been implicated in the development of
CLN11 disease (35).
CNL12 disease was reported in a single family and resulted from a
mutation in ATP13A2 (36).
CLN13 has been associated with 11 mutations involving cathepsin F
(CTSF) deficiency (22,37).
A single mutation has been associated with CLN14, which encodes for
KCTD7, a potassium channel tetramerization domain-containing protein 7
(38).
Pathophysiology
Molecular genetic studies have identified more than 360 mutations in the 14
genes underlying the various subtypes of human NCL (39). The genes
implicated in NCL are of importance in the normal development and
maintenance of cerebral neurons. Some of the known genes encode for
soluble lysosomal enzymes. Several of the other known genes involved in
NCL encode for transmembrane proteins with largely unknown functions.
The molecular genetic heterogeneity of NCLs is in stark contrast with the
uniform histopathologic features of the group of NCL diseases (40).
All forms of NCL share at least two essential features. First, there is
accumulation in the lysosomes of nerve cells and, to a lesser extent, other
cells of autofluorescent, electron-dense, periodic acid-Schiff and Sudan black
B-positive granules. The storage material in INCL is easily extractable and
autofluorescent. The electron-dense storage cytosomes in LINCL and JNCL
are largely resistant to lipid solvents (41,42). The second essential feature is
that NCL is associated with progressive and selective loss of neurons,
particularly in the cerebral and cerebellar cortex, and less consistently in the
retina. These changes are associated with mental, motor, and visual
deterioration (40,43).
NCLs are considered LSDs as many of the NCL-associated proteins are
present in lysosomes and lipofuscin-like ceroid lipopigments also accumulate
in lysosomes in NCLs. However, unlike classic LSDs, the storage material in
NCLs is not disease specific. The ultrastructural inclusion patterns under
electron microscopy were formerly thought to be unique and characteristic
for each major clinical subtype of NCL but have since been demonstrated to
not correlate absolutely with clinical presentation. A single subtype of NCL
may contain more than one pattern of inclusion (44).
Studies of NCL mouse models have suggested that the pathophysiology
of the disease involves dysregulation of autophagy. Animal models of CLN3,
CLN5, CLN6, and CLN7 disease have shown lysosomal dysfunction in the
brain and defective autophagosome maturation with increased autophagic and
lysosomal compartments and substrates (45–51).
Diagnostic Studies
The approach to diagnosis of NCL should take into account the age of onset
and clinical presentation. With the advent of gene panels for specific clinical
presentations, such as retinal degenerations, and panels of NCL genes,
molecular genetic testing is usually the first diagnostic step. However,
clinical features in combination with electron microscopy demonstrating
characteristic storage material can also be diagnostic of NCL, albeit without
specificity of type. Enzymatic testing can be used to diagnose some subtypes.
For example, epilepsy and microcephaly in a neonate should prompt further
investigation into CLN10 disease as a possible diagnosis, and enzymatic
testing for CTSD can be considered. If enzymatic testing is negative for
CTSD, further or concurrent testing for PPT1 (CLN1) and TPP1 (CLN2)
should be considered. The benefit of performing molecular genetic testing
initially is that if positive, it confirms NCL and gives a granular description
of genetic subtype and mutation. The downside is that because not all genes
or mutations are known, molecular genetic testing is sometimes normal in
patients with NCL. Index of suspicion must remain high, and multimodal
testing including molecular genetics, biopsy, leukocyte assay, and enzyme
levels may be used in concert.
CLN1 and CLN2 diseases are more likely considerations in young
children under the age of 6 with otherwise unexplained epilepsy and
developmental arrest. Even if enzyme testing for PPT1 and TPP1 is negative,
if electron microscopy demonstrates characteristic storage material, genetic
testing for CLN5, CLN6, CLN7, CLN8, and CLN14 should be performed.
School-aged children between ages 4 and 7 presenting with rapid vision
loss should be tested for CLN3 disease. CLN3 is included in many early-
onset retinal degeneration panels, and parents of children being tested with a
broad panel should be counseled ahead of time about the possibility of
neurologic conditions on the panel. Lymphocytes can be assessed for the
presence of vacuoles, and enzymatic testing for PPT1, TPP1, and CTSD can
be performed. A skin biopsy is indicated to determine if characteristic NCL
storage material is present either simultaneously or after other testing is
negative. A mucosal, conjunctival, or skin biopsy will demonstrate the typical
storage material in all the genetic subtypes.
In adults with suspected NCL, the first line of diagnostic investigations
includes enzymatic assays for PPT1, TPP1, CTSD, and CTSF. If the
enzymatic assays are normal, ultrastructural examination for storage material
should be performed. If storage material is present, genetic testing for
autosomal recessive CLN6, CLN11, CLN13, and autosomal dominant CLN4
should be considered. If negative, the remaining genes associated with NCL
should be tested.
In high-risk cases, prenatal testing on fetal cells obtained by chorionic
villus sampling at 10 to 12 weeks of gestation or by amniocentesis between
15 and 18 weeks of gestation can reveal deficient activity of enzymes PPT1,
TPP1, and CTSD or mutations associated with NCL (65). Couples who have
had a child affected with NCL have a 25% risk with each subsequent
pregnancy of another affected child. If genetic testing is performed on the
affected child, parents may choose to use in vitro fertilization with
preimplantation genetic testing for subsequent conceptions to reduce the risk
of having other affected children.
Given that visual decline is among the first symptoms in the most
common subtype, CLN3, detection of retinal degeneration, which occurs
early in the LSD, is critical in diagnosis. Ophthalmoscopic findings may
include cystoid macular edema, bull’s-eye maculopathy, macular–retinal
pigment epithelium (RPE) atrophy, attenuated retinal vessels, peripheral
pigmentary deposition, and widespread atrophy in advanced disease (Figure
24-1A) (66–69).
Management
The treatment of NCLs is largely symptomatic and directed to improve the
quality of life. Antiepileptics of choice are valproic acid and lamotrigine
(77–79). Benzodiazepines and sedatives are commonly used for sleep
disturbance, anxiety, and spasticity (80). Melatonin has also been used, but
evidence regarding its efficacy has been inconclusive (81–83).
Trihexyphenidyl improves dystonia and sialorrhea. Delusions and
hallucinations can be managed with atypical neuroleptics, such as risperidone
or olanzapine. Selective serotonin reuptake inhibitors may be useful if
depression is suspected.
Vision Rehabilitation
There is no treatment for retinal degeneration in NCL. As the visual
deterioration progresses, affected individuals can be referred for low vision
aids to optimize their ability to function.
Roles of Other Physicians and Health Care Providers
Patients with NCLs benefit from a team-based management approach. They
are typically followed by a primary care provider, neurologist, and
ophthalmologist. Additionally, they often benefit from therapy by a physical
therapist, occupational therapist, and speech therapist. Palliative care should
be involved early in the course to support families.
Ethical Considerations
When the disease is advanced in NCL, patients often cannot be fed naturally.
The decision to institute or withhold artificial nutrition should be made by the
parents or their representatives who are emotionally and intellectually
prepared to do so (84).
Future Treatments
NCL genes appear to be significant in the normal development and
maintenance of cerebral neurons. Elucidation of their specific functions and
interactions in health and disease is important for the identification of
therapeutic targets. Progress in the understanding of the natural history and
the biochemical and molecular cascade of events involved in the
pathogenesis of the NCLs will be required to achieve significant therapeutic
advances in the future.
Current and future approaches to treatment of NCL involve enzyme
replacement, gene therapy, neural stem cell replacement, immune therapy,
and other pharmacologic approaches (85).
ERT is being actively investigated as a therapeutic option for LSDs,
including NCLs. Numerous animal models of ERT have been studied and
shown reduction in the storage material accumulation in the brain and
improved disease phenotype and pathology (86–93). Cerliponase alfa
(recombinant TPP1) has been FDA approved for treatment of CLN2 disease.
A study of 17 patients receiving intraventricular infusion every 2 weeks over
a period of 2 years compared to matched historical controls showed a slower
rate of decline in motor and language function compared to controls (94).
Overall ERT appears to be a promising therapeutic approach for NCL.
Feasibility may be limited by the need for intraventricular infusion, but
further investigations including the development of compounds that can cross
the blood–brain barrier are necessary.
Gene therapy studies in animal models using adeno-associated virus and
lentivirus vectors have shown promise in the treatment of NCLs (95–102).
Gene therapy clinical trials in humans are underway, and a preliminary report
from study NCT00151216 (ClinicalTrials.gov) showed promise in reducing
the rate or progression in LINCL (103).
HSCT with umbilical cord blood and bone marrow transplantation has
been attempted in patients with NCL. However, the effect has been small
(104–107). Neuronal stem cell therapies have been investigated for LSDs,
(108,109) and a phase I clinical trial studying human neural stem cell
transplantation in INCL and LINCL showed that the therapy was well
tolerated (110). Further studies are required to explore the efficacy of stem
cell therapy in NCLs.
Antioxidant therapy has also been considered for treatment in NCL. This
is based upon the theory that free oxygen radicals cause a peroxidation defect
of polyunsaturated fatty acids, which leads to damage to fat deposits.
However, there is no clear conclusion on the effectivity of antioxidants in the
treatment of NCLs (111,112).
The use of anti-inflammatory medications has been explored based upon
the suggestion that inflammation throughout the central nervous system is a
key component in the pathogenesis of neurodegeneration in NCL. Mouse
model studies have shown decreased neuroinflammation, decreased
deposition of immunoglobulin G in the brain, and neuroprotective effects of
mycophenolate mofetil (113). Mycophenolate has been shown to be well
tolerated in JNCL, but further studies regarding its efficacy are necessary
(114,115).
In INCL disease, the affected enzyme cleaves fatty acid thioesters in
plasma membranes, and it has been suggested that small-molecule
compounds cysteamine and N-acetylcysteine may provide some benefit.
Studies of these two drugs have shown a delay in the development of
isoelectric EEG, depletion of the characteristic storage deposits seen on
electron microscopy known as granular osmiophilic deposits (GRODs), and
subjective benefits, such as decreased irritability as reported by parents and
physicians. However, they have not shown significant benefit in halting
disease progression (116,117).
An ideal treatment approach for NCL would be a drug-based therapy,
which would be less invasive than a gene or enzyme replacement methods
that require surgical access to the central nervous system. However, treatment
with most drugs or with gene or enzyme replacement would all face the
challenge of crossing the blood–brain barrier (118). Work in animal models
has suggested that there may be benefit in presymptomatic treatment (118).
Clinical trial designs must be optimized, and target outcome measures are
selected for these rare conditions (119,120). As new treatments become
available, a heightened awareness among clinicians can facilitate earlier
diagnosis.
SIALIDOSIS
Genetics
Sialidosis type 1 and type 2 are autosomal recessively inherited (121). Both
types are caused by mutations in the NEU1 gene (122).
Pathophysiology
Deficiency of the lysosomal enzyme neuraminidase 1 encoded by NEU1
leads to a disorder of glycoprotein degradation and the lysosomal
accumulation of sialylated glycopeptides (121).
Diagnostic Studies
The diagnosis of sialidosis is suggested based upon increased urinary bound
sialic acid excretion (121). A definitive diagnosis can be made with genetic
analysis (126).
GALACTOSIALIDOSIS
Genetics
Galactosialidosis is an autosomal recessive condition (127,128) associated
with mutations in the CTSA gene (129).
Pathophysiology
The protective protein/cathepsin A (PPCA) encoded by CTSA forms a
complex with the lysosomal enzymes β-galactosidase and neuraminidase to
digest glycoproteins. Defective PPCA leads to decreased β-galactosidase and
neuraminidase function (127,128).
Diagnostic Studies
Diagnosis is based upon an enzyme assay demonstrating combined
deficiency of β-galactosidase and neuraminidase (127,128).
GAUCHER DISEASE
Prevalence
Gaucher disease is the most common LSD with an estimated prevalence of 1
in 40,000 worldwide and as high as 1:1,000 among Ashkenazi Jews (130).
Genetics
Gaucher disease is an autosomal recessive caused by mutations in the gene
encoding β-glucosidase (GBA) (131).
Pathophysiology
Deficiency in β-glucocerebrosidase results in intracellular accumulation of
glucosylceramide within macrophages, termed “Gaucher cells.” (132).
Diagnostic Studies
The detection of insufficient β-glucosidase enzyme activity in peripheral
leukocytes is diagnostic of Gaucher disease, which can be definitively
confirmed by identification of two pathogenic variants on the GBA gene
(136).
NIEMANN-PICK DISEASE
Genetics
Niemann-Pick disease (NPD) types A and B are caused by mutations in the
sphingomyelin phosphodiesterase-1 gene SPMD1 (137) and type C by
mutations in NPC1 and NPC2 (138). All three types are autosomal
recessively inherited.
Pathophysiology
NPD is characterized by defective lysosomal sphingomyelin metabolism. In
types A and B, defects in acid sphingomyelinase (ASM) encoded by SPMD1
lead to the accumulation of sphingomyelin (139). In type C, defects in NPC
proteins lead to impaired egress of cholesterol from the lysosomes, resulting
in the accumulation of unesterified cholesterol, a major component of
sphingomyelin (138).
Clinical Signs and Symptoms
Type A NPD, a severe infantile form, presents in early infancy with
hepatosplenomegaly, hypotonia, and weakness, with evidence of
developmental delay at 6 months of age. At age 1 to 2 years, fundus exam
may demonstrate a cherry-red spot in the macula, and ERG is abnormal
(140). Some affected children may demonstrate a gray, granular appearance
of the macula, which is referred to as the macular halo syndrome (141).
Survival beyond 2 years of age is rare (137).
Type B NPD tends to be milder in its phenotype. Clinical presentation is
typically later. In some cases, splenomegaly does not become apparent until
adulthood. Patients with type B NPD may develop respiratory complications
at 15 to 20 years of age secondary to alveolar infiltration. The central nervous
system is usually spared. Some patients with type B NPD may have cherry-
red spots in the macula. The age of onset and rate of progression is variable,
and they frequently live into adulthood (137,139).
Type C NPD classically presents in late childhood with survival into the
second decade; however, a spectrum of phenotypes can occur ranging from
neonatal jaundice, vertical gaze palsy, seizures, and neurodegeneration, to
late onset, slowly progressive disease with intellectual impairment beginning
in adolescence or early adulthood (142).
Diagnostic Studies
The diagnosis of type A or B NPD is confirmed by measurement of
decreased ASM levels from peripheral leukocytes, cultured fibroblasts, or
lymphoblasts (137). Bone marrow biopsy may demonstrate lipid-laden
macrophages termed “sea-blue histiocytes.” In type C NPD, cultured
fibroblasts show impaired cholesterol esterification and positive filipin
staining (142).
Management
Type C NPD is treatable with the SRT miglustat, which can be administered
orally, cross the blood–brain barrier, and slow the progression of neurologic
symptoms. Improved swallowing reduces the incidence of aspiration
pneumonia (143–145).
GM1 GANGLIOSIDOSIS
Genetics
GM1 gangliosidosis is an autosomal recessive disorder caused by mutations
in β-galactosidase-1 (GLB1) (146).
Pathophysiology
Deficiency of β-galactosidase leads to lysosomal ganglioside accumulation
and neurodegeneration. The clinical presentation is variable, with infantile,
late infantile/juvenile, and adult forms (146).
Diagnostic Studies
Enzyme assay for β-galactosidase shows markedly reduced or absent enzyme
activity in leukocytes or fibroblasts (147).
GM2 GANGLIOSIDOSIS (TAY-SACHS
DISEASE)
Prevalence
Tay-Sachs disease has a carrier frequency of 1 in 25 among the Ashkenazi
Jewish population. The incidence in unscreened Jewish populations is 1 in
3,900 births. It is rare in most other populations (148).
Genetics
Tay-Sachs disease, an autosomal recessive condition, is caused by mutations
in the α subunit of the hexosaminidase A gene (HEXA). Severe HEXA mutant
alleles have been demonstrated in the Ashkenazi Jewish population, and 96%
of Jewish Tay-Sachs disease carriers have one of three common mutations
(148).
Pathophysiology
Deficiency of β-hexosaminidase α-subunits, which normally participate in the
hydrolysis of ganglioside GM2, results in the accumulation of GM2
ganglioside in the lysosomes of the central nervous system (149).
Diagnostic Studies
The diagnosis is confirmed by assay of β-hexosaminidase α-subunits in
serum, leukocytes, or other tissues. Genetic analysis can confirm the
diagnosis (150).
Management
Although no treatment is currently available, improvements in supportive
care have been shown to increase survival from 1.5 years to 5 to 6 years of
age (151).
Carrier screening for Tay-Sachs disease has been effective in reducing
the incidence of this disease in the at-risk Ashkenazi population (152).
Pathophysiology
The β subunit of both β-hexosaminidase α (Hex A) and β-hexosaminidase β
(Hex B) is defective, leading to the accumulation of GM2 ganglioside and
oligosaccharides carrying terminal N-acetylhexosamine residues, resulting in
neurologic and systemic manifestations (152). Gene expression profiling has
suggested a role of inflammation as a factor in the neurodegenerative process
(154).
FARBER DISEASE
Genetics
Farber disease is an extremely rare autosomal recessive disorder associated
with mutations in the ASAH1 gene, which encodes acid ceramidase (AC),
also called N-acylsphingosine amidohydrolase (ASAH). Approximately 160
cases have been reported to date in the worldwide literature (155).
Pathophysiology
AC is responsible for the degradation of the glycolipid ceramide, which plays
a central role in sphingomyelin metabolism. AC deficiency leads to
lysosomal accumulation of ceramide (155).
Diagnostic Studies
The diagnosis of Farber disease is made based upon clinical presentation and
confirmed with an assay of ceramidase activity in leukocytes, plasma, skin
fibroblasts, and other tissues. Histopathology of granulomatous tissue shows
proliferation of connective tissue with hyalinization, cholesterol crystal-like
changes, lipid-laden macrophages, and inclusions known as “Farber bodies.”
(155).
FABRY DISEASE
Genetics
Fabry disease is an X-linked condition primarily affecting males caused by
mutations in the GLA gene, which encodes α-galactosidase A (GLA) (160).
Heterozygous females also manifest multisystem disease and thus should not
be considered carriers (161).
Pathophysiology
GLA deficiency results in the accumulation of the lysosomal
glycosphingolipid globotriaosylceramide (GL-3) in nerves and other organs
(160).
Diagnostic Studies
The diagnosis is confirmed by enzyme assay demonstrating deficiency of
GLA in leukocytes, plasma, serum, fibroblasts, or other tissues (160).
Management
The clinical management of Fabry disease requires a comprehensive
multidisciplinary approach to address the various organs involved (164). ERT
with intravenous α-galactosidase A has been shown to reduce tissue GL-3
levels (165) and ameliorate cardiomyopathy (166). Oral therapy with
migalastat, a small-molecule chaperone that stabilizes some mutant forms of
the GLA enzyme, can maintain renal function in amenable cases (167).
MUCOPOLYSACCHARIDOSIS TYPE I
(HURLER SYNDROME, HURLER-
SCHEIE SYNDROME, AND SCHEIE
SYNDROME)
Prevalence
Hurler syndrome occurs in 1 in 100,000 births. Male and female children are
equally affected (168).
Genetics
Mucopolysaccharidosis type I is an autosomal recessive disorder caused by
mutations in the gene encoding α-L-iduronidase (IDUA) (168).
Pathophysiology
The α-L-iduronidase enzyme hydrolyzes the glycosaminoglycans heparan
sulfate and dermatan sulfate (168). Deficiency of IDUA leads to the
accumulation of these mucopolysaccharides.
Diagnostic Studies
Diagnosis is suspected based upon clinical exam and measurement of urinary
glycosaminoglycan levels. Diagnosis is confirmed with enzyme activity
assays of fibroblasts, leukocytes, plasma, or serum (168).
Management
Hematopoietic stem cell transplant, performed before 2 years of age, provides
an opportunity to improve the neurocognitive outcome, eliminate
hepatosplenomegaly, and reduce airway obstruction (170). ERT with
recombinant α-L-iduronidase (laronidase) has been shown to improve
pulmonary function but is not effective for the orthopedic manifestations
(171).
MUCOPOLYSACCHARIDOSIS TYPE II
(HUNTER SYNDROME)
Genetics
Hunter syndrome is X-linked and primarily affects males, though some
female patients have been described (172). It is associated with mutations in
the gene encoding iduronate-2-sulfatase (IDS).
Pathophysiology
Deficiency of IDS, an enzyme responsible for the metabolism of heparan
sulfate and dermatan sulfate, leads to the accumulation of these
glycosaminoglycans in multiple organ systems (173).
Diagnostic Studies
Screening is performed by quantitative assessment of urinary
glycosaminoglycan excretion. Diagnosis is confirmed by enzyme activity
assay in leukocytes, fibroblasts, or plasma. Genetic testing is available for
genetic counseling and carrier detection (172).
Management
ERT with idursulfase, a recombinant form for IDS, is effective at improving
somatic signs and symptoms of the disease. However, it does not cross the
blood–brain barrier, and consequently treatment of the neurologic aspect of
the disease remains a challenge (174).
Pathophysiology
Deficiency in one of the four enzymes involved in the catabolism of heparan
sulfate leads to its accumulation, particularly in the central nervous system
(175).
MUCOPOLYSACCHARIDOSIS TYPE IV
(MORQUIO SYNDROME)
Genetics
Mucopolysaccharidosis IV comes in two forms, both autosomal recessive.
Type IVA, also known as Morquio A syndrome, results from mutations in the
gene encoding galactosamine-6-sulfate sulfatase, GALNS (180). Type IVB, or
Morquio B syndrome, results from mutations in the gene encoding β-
galactosidase, GLB1 (181).
Pathophysiology
In mucopolysaccharidosis IVA, deficiency of GALNS leads to the
accumulation of keratin sulfate and chondroitin-6-sulfate, whereas in
mucopolysaccharidosis IVB, deficiency of β-galactosidase causes
accumulation of only keratin sulfate (180,182).
Diagnostic Studies
Urine and blood analysis for keratan sulfate is suggestive of the diagnosis in
Morquio A syndrome, but enzyme activity assay is necessary to confirm the
diagnosis (183).
Urinary excretion of keratan sulfate and oligosaccharides is abnormal in
Morquio B syndrome and suggestive of the diagnosis (182).
Management
Bone marrow transplant has been performed in some patients, and ERT has
shown promising results in Morquio A (183,184).
MUCOPOLYSACCHARIDOSIS TYPE VI
(MAROTEAUX-LAMY SYNDROME)
Genetics
Maroteaux-Lamy syndrome is an autosomal recessive disorder caused by
mutations in the gene encoding N-acetyl-galactosamine 4-sulfatase
(arylsulfatase B), ARSB (185).
Pathophysiology
Deficiency of arylsulfatase B leads to the accumulation of dermatan sulfate
and chondroitin sulfate in multiple tissues (185).
Management
ERT with galsulfase has demonstrated efficacy, particularly when initiated
early (187).
Pathophysiology
The enzyme β-glucuronidase is deficient in Sly syndrome, resulting in the
accumulation of glucuronic acid (189).
Diagnostic Studies
Diagnosis is made by enzyme activity assay demonstrating a deficiency of β-
glucuronidase in serum, leukocytes, or cultured fibroblasts. Molecular genetic
analysis can confirm the diagnosis (192).
CYSTINOSIS
Prevalence
The incidence of cystinosis is variable worldwide and occurs in
approximately 1 in 100,000 to 200,000 live births in North America (193).
Genetics
Cystinosis is an autosomal recessive disorder caused by mutation in the
CTNS gene (194).
Pathophysiology
Cystinosin, the protein encoded by CTNS, is a transmembrane protein
responsible for the transport of cystine from the lysosome into the cytoplasm.
Defective cystinosin function leads to the accumulation of cystine in cells and
tissues (193).
Management
Cystine-depleting therapy with oral cysteamine (β-mercaptoethylamine) has
been shown to improve renal function and other clinical parameters of the
disease, particularly when instituted early. Diligent cysteamine therapy can
prevent hypothyroidism, enhance growth, deplete cystine in the muscle
parenchyma, and prevent multiple other systemic complications. Oral
cysteamine therapy can also reduce or delay retinopathy. Cysteamine eye
drops can dissolve corneal crystals and relieve photophobia. End-stage renal
failure is treated with hemodialysis and renal transplantation (197–200).
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25
Retinal Manifestations of Metabolic
Disease in Children
Arif O. Khan
ENVIRONMENTAL FACTORS
Many pediatric metabolic disorders with retinal manifestations are
monogenic diseases associated with classic clinical features that were defined
from severe cases and before the widespread availably of genetic testing.
However, it is now clear that for virtually all of these diseases, age of onset,
degree of systemic involvement, and clinical severity can be highly variable.
The phenotypic heterogeneity is related to the degree of protein dysfunction
from the particular gene mutation as well as to other genetic and
environmental factors.
Disorder of Ornithine Metabolism (Gyrate Atrophy)
Gyrate atrophy is an autosomal recessive retinal dystrophy caused by
mutations in the gene for ornithine aminotransferase (OAT) (1,2). The rarity
of gyrate atrophy limits prevalence data; many reported cases are from
Finland (3). The lack of OAT, a vitamin B6-dependent mitochondrial
enzyme, disrupts the conversion of ornithine to pyrroline-5-carboxylate and
results in hyperornithinemia, which is the presumed mechanism of disease.
Gyrate atrophy of the retina is exceptional as an inborn error of
metabolism in that the systemic manifestations are primarily in the retina in
childhood. In adults, neuromuscular and hair findings occur (4–6) as well as
central nervous system changes (5). The diagnosis can be confirmed by
metabolic or genetic testing. A low-arginine diet and protein restriction can
slow disease progression (7,8). Dietary supplementation with pyridoxine
(vitamin B6), a cofactor for OAT, may provide additional benefit (9).
Affected children typically present with nyctalopia and loss of peripheral
vision as teenagers. Some present earlier, typically because of progressive
myopia. Early cataracts can occur. Retinal examination reveals characteristic
peripheral circular areas of chorioretinal atrophy and scalloped retinal
pigment epithelium (1,3). The macula is typically preserved in childhood, but
over decades, macular changes, optic atrophy, and arteriolar attenuation occur
as the degeneration is progressive. Some patients develop cystoid macular
degeneration early or later in the course of disease. Dietary modification may
resolve the cystoid macular degeneration that occurs in some patients (10).
Older patients show nonspecific end-stage chorioretinal atrophy, but
sometimes, the outline of former peripheral scalloped edges can be
appreciated (Figure 25-1).
Figure 25-1 (Gyrate atrophy): A male in his late 20s
presented with long-standing poor vision since childhood,
but he could not provide details. He had had cataract
surgery both eyes in his early 20s with no improvement in
vision. Vision was 20/200 either eye. Examination
revealed severe chorioretinal atrophy and cystoid macular
degeneration in the central macula in both eyes. The
outlines of old scalloped lesions can be appreciated in the
midperiphery of both eyes (A, B). The macula looks
abnormally dark in both eyes; however, this is because it is
an island of viable retina and is actually the only relatively
normal retina in each eye. In the left eye (B), the preserved
macular pigment is irregular in shape due to the scalloped
configuration of encroaching degeneration typical of
gyrate atrophy. Electroretinography was nonrecordable.
Blood ornithine levels were elevated and genetic testing
confirmed homozygous OAT mutation. The right (A) and
left (B) eyes were similar as is typical in genetic eye
disease.
DISORDER OF LIPOPROTEIN
METABOLISM
(ABETALIPOPROTEINEMIA)
Abetalipoproteinemia (Bassen-Kornzweig syndrome) is a malabsorption
syndrome caused by lack of plasma apolipoprotein B-containing lipoproteins,
that is, chylomicrons, very low–density lipoprotein, and low-density
lipoprotein (19). These are carriers of fat and fat-soluble vitamins (A, E, K),
and, therefore, affected children develop manifestations of impaired fat and
fat-soluble vitamin absorption. Biallelic mutations in the 97 kDa subunit of
microsomal triglyceride transfer protein (MTP) cause the disease (19).
Abetalipoproteinemia is rare in the general population and estimated to occur
in one in a million.
The earliest signs of deficient fat and fat-soluble vitamin absorption
include diarrhea, steatorrhea, and failure to thrive. Neurologic impairment,
particularly spinocerebellar degeneration and axonal neuropathy, occur
during early or later childhood along with muscle weakness (20). Vitamin K
deficiency leads to a bleeding diathesis. Laboratory testing reveals low levels
of cholesterol, plasma chylomicrons, very low–density lipoproteins, and low-
density lipoproteins; in addition, acanthocytosis is characteristic and may
result in anemia (20). The diagnosis can be confirmed in a patient with
suspected signs by laboratory or genetic testing. Because
abetalipoproteinemia is most amenable to treatment by vitamin
supplementation at an early stage, it is important to diagnosis as early as
possible. A peripheral blood smear for acanthocytosis is a simple readably
accessible test that can be helpful in quickly confirming a suspected
diagnosis. Affected children for whom supplementation is initiated prior to 2
years of age tend not to develop the neurologic complications usually
associated with untreated abetalipoproteinemia (21). Reduced intake of
dietary fats relieves gastrointestinal symptoms.
Retinal degeneration is part of the phenotype and often begins during
early or later childhood. Children present with central visual loss and an
atypical retinopathy although, for some, nyctalopia is the initial visual
complaint. Yellowish dots and mottling are often seen in the posterior pole
and midperiphery. A gliosis can be appreciated over the central macula (20).
With time, the entire retina is eventually affected by pigmentary retinopathy.
Angioid streaks have been reported (22), as has helicoid peripapillary
degeneration (23). Early vitamin supplementation attenuates retinal
degeneration but retinal changes can still progress (21,24). The diagnosis
should be suspected in a child with retinal dystrophy in the setting of
neurologic impairment and muscle weakness (Figure 25-3).
LCHAD Deficiency
Lack of the mitochondrial enzyme long-chain 3-hydroxyacyl-CoA
dehydrogenase (LCHAD) causes LCHAD deficiency, a disorder of fatty acid
breakdown. LCHAD is part of the mitochondrial trifunctional protein, an
enzyme complex consisting of four α and four β subunits. The α subunit
contains LCHAD; biallelic mutations in the gene hydroxyacyl-CoA
dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase α subunit
(HADHA) cause LCHAD deficiency (30). LCHAD deficiency is more
common in Northern Europe (1/100,000 in Sweden), and many European
patients have the same homozygous HADHA mutation (30,31). An affected
child does not produce sufficient ketone bodies during fasting, leading to a
severe, life-threatening hypoketotic hypoglycemia and potential sudden
infantile death syndrome. Other infantile features include hypertrophic
cardiomyopathy, hepatomegaly, polyneuropathy, and intermittent
rhabdomyolysis. The diagnosis can be confirmed by metabolic or genetic
testing. Newborn screening for LCHAD deficiency and other trifunctional
protein deficiency is available via acylcarnitine profiling of dried blood spots.
Early recognition and dietary modification through avoidance of long-chain
triglycerides increases life expectancy.
LCHAD deficiency is unique among disorders of fatty acid metabolism
in that it commonly affects the retina. Macular pigmentary changes can be
seen within the first 2 years of life (32) and may be accompanied by
photophobia. In those patients who survive to older ages, macular
chorioretinal atrophy occurs, pigmentary changes develop in the periphery
and eventually become atrophic as well, and electroretinography readings
progressively decline to eventually become nonrecordable (32).
Developmental supranuclear flake-like lens opacities and progressive myopia
can be seen in older patients (32). Dietary modification and supplementation
can help preserve retinal function and may improve visual acuity in some
children (33). Fasting-induced hypoketotic hypoglycemia in an infant with
central chorioretinopathy strongly suggests the diagnosis of LCHAD
deficiency (Figure 25-4).
Figure 25-4 A 5-year-old girl who originally presented
with liver failure at 9 months old was confirmed to have
LCHAD deficiency and was referred for ophthalmic
evaluation. Dilated fundus examination revealed retinal
pigment epithelium mottling and clumping just outside the
vascular arcades and increased pigment in the central
macula in both eyes (A,B). (Courtesy Scott E. Brodie,
MD, PhD).
LYSOSOMAL STORAGE DISEASE
Lysosomes are membrane-enclosed organelles responsible for the
degradation of a variety of biomolecules. Two major classes of biomolecules
that require regular degradation are complex carbohydrates such as
mucopolysaccharides and complex lipids such as sphingolipids. Gene
mutations that impair enzymes responsible for lysosomal degradation of these
particular biomolecules are a common mechanism for lysosomal storage
disease that often affects the retina. A rarer mechanism for lysosomal storage
disease is defective small molecule transport. This is the mechanism for
cystinosis, which has retinal manifestations. For some forms of lysosomal
storage disease, the genetic basis is known, but the associated protein
function has not been fully elucidated. One such example is CLN3-related
neuronal ceroid lipofuscinosis, which typically first manifests as retinal
degeneration.
Mucopolysaccharidoses
Mucopolysaccharidoses are a group of lysosomal diseases due to deficiency
of enzymes that degrade glycosaminoglycans (i.e., mucopolysaccharides).
Although individually mucopolysaccharidosis (MPS) is rare, as a group, the
estimated prevalence is 1/7,700 in Australia (34). The resultant buildup of
glycosaminoglycans in various tissues causes a spectrum of systemic clinical
features. These can include course facies, short stature, skeletal and joint
deformities, respiratory compromise, neurologic impairment, and cardiac
disease (35). In the eye, virtually all tissues can be affected by the
glycosaminoglycan deposition (36). Retinal degeneration can occur, and
electroretinography findings may be more prominent than ophthalmoscopic
findings (37). Axial shortening with hyperopia is common, and congested
retinal vessels can be seen if axial lengths are significantly shortened from
scleral glycosaminoglycan deposition. Other common ocular manifestations
include corneal haze, optic nerve swelling and atrophy, iris cysts, ocular
hypertension, and glaucoma (34). Depending on the specific enzyme
deficiency and its severity, different forms have characteristic clinical
features and range from being obvious and fatal in infancy to being subtle
and compatible with a normal life span. All are autosomal recessive except
for Hunter syndrome, which is X-linked. Table 25-1 summarizes the major
forms. The diagnosis can be confirmed by laboratory and genetic testing, and
urinalysis is a useful screening tool (38). Treatment modalities, such as bone
marrow transplantation and enzyme replacement therapy, are available for
several subtypes (35). Thus, it is important to make the systemic diagnosis as
early as possible.
Individuals with MPS are often seen by many different specialists before (or
without) the diagnosis being made (39). It may be the astute ophthalmologist
who first suspects the diagnosis, particularly in early-onset cases (Figure 25-
5) or in milder cases. The diagnosis should be suspected when an individual
has retinal findings or corneal haze in the context of clinical features
compatible with systemic glycosaminoglycan deposition (Figure 25-6).
Figure 25-5 (Mucopolysaccharidosis): Course facial
features can be appreciated in this infant child with
undiagnosed mucopolysaccharidosis. He was referred for
potential glaucoma because of cloudy corneas. Review of
systems revealed recurrent upper respiratory injections and
multiple joint laxity. There was no glaucoma; the corneal
haze was from glycosaminoglycan deposition.
Figure 25-6 (Mucopolysaccharidosis): A 30-year-old male
was referred for dry eye. He had short stature. Review of
symptoms revealed recurrent upper respiratory infections,
bilateral carpal tunnel syndrome, and sleep apnea.
Ophthalmic examination was significant for hyperopia,
bilateral iridociliary cysts, and retinal vascular congestion.
The ocular findings in the context of the review of systems
are virtually pathognomonic for systemic
glycosaminoglycan deposition as seen in
mucopolysaccharidosis. Images of the ciliary body cysts
and retinal vascular congestion with dilated, engorged
veins from the right eye are shown in (A) and (B),
respectively.
Sphingolipidoses
Sphingolipids are glycolipids important for cellular membrane function,
particularly in the brain and nervous tissue (40). Sphingolipidoses vary in
severity and age of onset depending upon the degree of the specific enzyme
dysfunction. With a few notable exceptions (e.g., Gaucher disease and Fabry
disease), sphingolipidoses are characterized by childhood neurodegenerative
disease; when this occurs, there is often accompanying retinal degeneration.
Regional loss of retinal transparency occurs where undigested biomolecules
accumulate in the thick ganglion cell layer that surrounds the fovea. Since the
fovea lacks ganglion cells, the resultant contrast in color between the
perifovea and fovea results in a central foveal “cherry-red spot” (Figure 25-
7). Often the cherry-red spot is a sign of significant systemic disease. It is
characteristic for Tay-Sachs and Sandhoff disease and can sometimes be seen
in Niemann-Pick disease, GM1 gangliosidosis, Farber disease, and
metachromatic leukodystrophy (41). Because it can sometimes disappear
over time as the intumescent ganglion cells die and optic atrophy develops,
the absence of a cherry-red spot should not be used to rule out a diagnosis,
particularly for older children (42).
Figure 25-7 (Cherry-red spot): A 14-year-old boy with
sialidosis, a rare lysosomal storage disease, had macular
cherry-red spots (right eye shown). He also had snowflake
cataracts. Genetic testing confirmed biallelic NEU1
mutations.
Mucolipidoses
Mucolipidoses are rare conditions that share combined features of
mucopolysaccharidoses and sphingolipidoses. Sialidosis from biallelic
mutations in NEU1 and galactosialidosis from biallelic mutations in CTSA
can include cherry-red spots (Figure 25-7) (51,52).
Cystinosis
Cystinosis is an autosomal recessive lysosomal storage disease of cystine due
to biallelic mutations in cystinosin (CTNS), which encodes a lysosomal
cystine carrier protein (65). It is rare, with the infantile form estimated to
occur in 1/325,000 births in France (66). Proximal renal tubular defect
(Fanconi-like), hypothyroidism, and crystalline corneal deposits are the main
clinical features. Diagnosis can be confirmed by genetic testing in a patient
with suspicious clinical features. The mainstay of treatment is the cystine-
depleting agent cysteamine, both orally and topically. Early recognition and
treatment optimize outcomes.
Retinal changes are part of the phenotype, although corneal haze and
photophobia can limit detailed examination of the retina. The most common
retinal finding is depigmentation of the peripheral retina with pigment
epithelial mottling, which has been observed as early as 6 months of age (67).
With time, pigment migration into the retina can cause a retinitis pigmentosa
appearance. Electroretinography of older cystinosis patients shows decreased
cone and rod function (67). Intraretinal crystals can sometimes be appreciated
on fundus examination or by optical coherence tomography (68,69). Oral
treatment seems to improve the retinal findings (67). The diagnosis should be
suspected in a child with nephropathy and crystals in the cornea or retina.
PEROXISOMAL DISORDERS
Peroxisomes are cellular organelles that participate in multiple catabolic and
synthetic biochemical pathways, the majority of which involve intermediary
lipid metabolism (70). The well-characterized pathways of very long-chain
fatty acid β-oxidation, α-oxidation of phytanic acid, and plasmalogen
biosynthesis are used routinely for the biochemical diagnosis of peroxisome
biogenesis disorders (71). Disorders that were previously considered separate
conditions—Zellweger syndrome, neonatal adrenoleukodystrophy, Refsum
disease, and Heimler syndrome—are now recognized as a continuum of
peroxisomal disease phenotypes, known as Zellweger spectrum disorders,
and retinal dystrophy is a major recurrent feature (72,73). Biallelic mutations
in 14 different peroxisomal genes (PEX genes) are responsible for the
majority of cases (73). Peroxisomal disorders often cause deafness as well as
retinal degeneration, and patients may be misdiagnosed as having Usher
syndrome. It has been estimated that peroxisomal biogenesis disorders occur
in 1/50,000 births in North American, but the prevalence is likely higher (73).
Rhizomelic chondrodysplasia punctata (PEX7 mutations) is a related
peroxisomal disorder but with an associated ocular phenotype of pediatric
cataract rather than retinal dystrophy, although there is one case report for
which retinitis pigmentosa developed (74). Primary hyperoxaluria is a
peroxisomal disorder that can include a crystalline retinopathy.
Zellweger Spectrum Disorders
Children with the severe congenital phenotype of Zellweger spectrum
disorder (cerebrohepatorenal syndrome; classic Zellweger syndrome) are
hypotonic, feed poorly, and fail to show developmental progression (73,75).
They have seizures, liver cysts with hepatic dysfunction, and often a recurrent
facies (round face, high forehead, large anterior fontanel, hypertelorism,
epicanthic folds, high-arched palate, and micrognathia). Bony stippling
(chondrodysplasia punctata) of the knees and hips can be seen by X-ray.
Those who survive develop sensorineural hearing loss and retinal dystrophy
(73,75). Cataracts and glaucoma can also occur. Less severe phenotypes in
this spectrum show a wide range of presentations and variable involvement of
the potentially affected organ syndromes. With the identification of additional
peroxisomal genes and advances in genetic testing, phenotypes that would
have been previously thought to be too mild for peroxisomal disease have
been found to be due to PEX mutations. For example, Heimler syndrome—
sensorineural hearing loss, amelogenesis imperfecta, nail abnormalities, and
juvenile or adult-onset retinal dystrophy—can be caused by biallelic
mutations in PEX7 (72). For a child with retinal dystrophy in the setting of
multiple organ disease, peroxisomal disorder is part of the differential
diagnosis (Figure 25-11).
Figure 25-11 (Peroxisomal facies): This 2-year-old boy
with hypotonia and developmental delay was seen because
of poor visual behavior. The retinal appearance was
grossly normal but electroretinography was nonrecordable.
Genetic testing revealed homozygous mutations in the
recently recognized peroxisomal gene ACBD5. His facial
features were consistent with peroxisomal disease: round
face, high forehead, apparent hypertelorism, and
prominent epicanthal folds.
Primary Hyperoxaluria
Primary hyperoxaluria type I is a disorder of progressive calcium oxalate
urolithiasis and nephrocalcinosis caused by biallelic mutations in the
peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT) (76). In the
absence of AGT, glyoxylate is converted to oxalate, which forms insoluble
calcium oxalate crystals that accumulate in the kidney and other organs.
Treatment is supportive and includes dietary modification with high fluid
intake (77). Primary hyperoxaluria type I is very rare in the general
population, with an estimated prevalence of one in a million.
Oxalate-induced crystalline retinopathy seems to be correlated with the
severity of the disease. It is characterized by numerous discrete yellow flecks
scattered throughout all layers of the retina and retinal pigment epithelium
starting in the macula but extending throughout the retina. With time, there
are areas of irregular chorioretinal atrophy, retinal pigmentary changes,
confluent patches of retinal pigment epithelium hyperplasia, and patches of
fibrosis (78).
CONGENITAL DISORDERS OF
GLYCOSYLATION
Glycosylation is a process used by eucaryotic cells to enhance specialized
functions for biomolecules and cellular processes (79). Congenital disorders
of glycosylation are an increasingly recognized group of disorders secondary
to genetic defects in the synthesis and attachment of glycoprotein and
glycolipid glycans. Each is individually rare, but as a group, more than 125
such disorders have been recognized (79). The phenotypic and genetic
spectrum is wide and continues to be defined with presentations ranging from
severe neonatal lethal to mild adult onset. Neurologic impairment is the most
common unifying feature. Retinal findings been clearly documented for
several forms of the disease, as summarized in Table 25-4 (Figure 25-12).
The prevalence of congenital disorders of glycosylation in Europe has been
estimated at one in a million (80).
MITOCHONDRIAL DISORDERS
Through oxidative phosphorylation and ATP production, mitochondria are
the major energy source for the cell. The number of mitochondria within a
specific cell is related to the cell’s energy requirements. Mitochondria are
organelles with their own semiautonomous genome that is maternally
inherited and can vary in sequence among different tissues or even in the
same cell, a characteristic known as heteroplasmy (81). Mutations of the
mitochondrial genome can cause mitochondrial disease that is associated with
retinopathy. The severity of the phenotype for a patient carrying a given
mitochondrial mutation is related not only to the mutation itself but also to
the degree of mitochondrial heteroplasmy. Diagnosis in a suspected case can
be confirmed by mitochondrial DNA genome analysis of blood or tissue.
Because most proteins required for mitochondrial function are encoded in
nuclear DNA, mitochondrial disease can follow Mendelian rather than
maternal inheritance (78). One such example is LCHAD deficiency
(discussed under Disorders of Lipid Metabolism). Mitochondrial diseases are
likely more common than currently recognized with an estimated prevalence
of 1/8,500 (82). Mutations of the mitochondrial genome should be suspected
when a patient presents with atrophic macular retinal pigment epitheliopathy
in association with ocular motility disorders, deafness, or generalized
weakness.
Kearns-Sayre Syndrome
Kearns-Sayre syndrome is a form of chronic progressive external
ophthalmoplegia with pigmentary retinopathy that begins in childhood or
young adulthood, by definition before 20 years of age (83). Cardiac block is a
common feature, and ptosis often accompanies the chronic progressive
external ophthalmoplegia. Other systemic features can include short stature,
cerebellar ataxia, muscle weakness, endocrine abnormalities, and progressive
hearing loss. (80). The majority of cases are sporadic, from new
mitochondrial DNA deletions (84,85). The retinopathy shows widespread
retinal pigmentary changes and a “salt and pepper–like” appearance. Age of
onset and progression is variable, but most patients do not progress to severe
visual loss with nonrecordable electroretinography. A patient with retinal
dystrophy in the setting of chronic external ophthalmoplegia should be
investigated for the possibility of cardiac conduction defects (Figure 25-13).
Figure 25-13 A 16-year-old boy presented with a 5-year
history of slowly progressive ptosis and ophthalmoplegia
(A). Fundus examination confirmed pigmentary
retinopathy with mottled peripheral pigment and irregular
pigmentation of the macula. A darkly pigmented precursor
to a typical bone spicule–like lesion can also be seen (B,C:
arrowhead).
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26
Generalized Retinal and Choroidal
Diseases
Meghan M. Brown, and Kean T. Oh
INTRODUCTION
In 1990, evidence that rhodopsin mutations caused retinitis pigmentosa (RP)
heralded a new perception of the pathophysiology and an evolving approach
to retinal dystrophies. Since then, an ever-increasing number of genes have
been identified as causative in retinal and choroidal dystrophies. With the
identification of disease-causing genes, ophthalmologists have elucidated the
pathophysiology of ocular diseases and have suggested therapies for
previously untreatable diseases. For example, mutations in RPE65 cause
Leber congenital amaurosis (LCA) or rod–cone dystrophy in adults. Gene
therapy using viral vectors to introduce working copies of the gene has been
validated by animal models and clinical trials. It is now available for RPE65-
related LCA (1,2) (see also Chapters 27 and 28).
The advent of treatments for genetic diseases will likely be specific for
certain gene products. Therefore, clinical diagnoses will be important to
identify patients with phenotypes who would benefit from specific therapies.
Furthermore, understanding and characterizing the natural history of disease
will be necessary to accurately interpret future clinical trials.
The goal of this chapter is to provide the clinical descriptions, prevalence,
genetics, differential diagnoses, and pathophysiologies of inherited retinal
and choroidal disorders that may present in infancy and early childhood.
Ancillary studies, such as electroretinography (ERG) and perimetry, and
molecular pathophysiology are reviewed for specific diseases. In the course
of writing this chapter, the Web site, Online Mendelian Inheritance in Man,
was used to review these conditions from the molecular genetic etiology
standpoint (http://www.ncbi.nlm.nih.gov/omim). Diagnostic studies, gene
therapy, and visual rehabilitation are covered in greater depth elsewhere in
the text.
Cone–Rod Dystrophy
The definition of the group of cone–rod dystrophies is based primarily on
electrophysiologic characteristics. It now includes a number of phenotypic
expressions once believed to represent entirely separate diseases. Cone–rod
dystrophies are generalized photoreceptor disorders characterized on ERG by
a greater loss of cone function than rod function and consequently have
common symptomatic presentations (3). Like RP, cone–rod dystrophies are
heterogeneous with a wide range of presentations, disease courses, and
severity.
cGMP, cyclic guanosine monophosphate; RPGR, retinitis pigmentosa GTPase regulator; PDE,
phosphodiesterase enzyme; ATP, adenosine triphosphate.
Choroideremia
Choroideremia is an X-linked disorder resulting in choroidal degeneration
with subsequent loss of retinal function. It was first described in 1871 by
Mauthner. The gene (CHM) was identified in 1992. Late-stage choroideremia
has an unmistakable appearance of widespread loss of RPE, choriocapillaris,
and larger choroidal vessels with occasional patches of pigment and sparing
of a small patch of RPE and retina in the macula. When choroideremia
presents in childhood and adolescence, its symptoms and clinical appearance
can be very similar to those of RP.
Molecular Findings
The CHM gene was identified in 1993 by Sankila and further characterized
by Seabra (37–39). The CHM gene codes for a Rab escort protein (REP-1)
for the enzyme geranylgeranyl transferase, which is involved in adding a
geranylgeranyl moiety to the end of Rab proteins, in a process known as
prenylation (38–40). Rab proteins are used for intracellular signaling in
photoreceptors and for breakdown and clearance of outer segment disc
membranes in RPE cells (41). Thus, the major mechanism of retinal cell
death is thought to be a result of the buildup of unprenylated Rab proteins
(42). Nearly all disease-causing changes in the CHM gene were found to
prevent translation or result in significant truncation of the protein product.
There was one reported case of a missense mutation resulting in disease (43),
although in a review of 57 families with choroideremia, missense mutations
did not account for a significant fraction of disease-causing changes.
Transitions and transversions in the CHM gene accounted for more than 40%
of identified changes, small deletions (<5 base pairs [bp]) an additional 28%
of the mutations, partial gene deletions 9%, and complete deletions 4% (44).
At this time, the severity of the mutation does not appear to correlate with
either disease severity or carrier state manifestations.
Thus far, CHM gene replacement therapy has proven effective in CHM
mice using AAV2 and in cells of patients with CHM mutations in vitro (42).
These advances have led to two clinical trials beginning in 2015 to assess the
safety and efficacy of gene vector treatment in CHM patients (42,45). Initial
findings support improvement of rod and cone function after treatment with
retinal gene therapy (46).
Achromatopsia
Achromatopsia is a congenital inability to discriminate color. It is a rare
condition estimated to have a prevalence of 3 in 100,000. However, the
prevalence of achromatopsia on the island of Pingelap in Micronesia is 4% to
10% due to a sharp reduction in the population after a typhoon that struck in
the late 1700s. All affected individuals trace their lineage back to 1 of about
20 survivors, who was a carrier of the gene mutation (47). Huddart first
described in 1,777 a patient with achromatopsia from a family with two
affected brothers and three unaffected siblings. However, Daubeney is
credited with the first overall description of achromatopsia in 1684 (48).
Achromatopsia is divided into two groups: complete achromatopsia (rod
monochromacy) and incomplete achromatopsia (blue cone monochromacy).
Complete achromatopsia is autosomal recessive and results in loss of all cone
function, whereas incomplete achromatopsia is X-linked recessive and results
in loss of red and green opsins only. Several other cone disorders may result
in deficient color vision and overlap in phenotype with achromatopsia and
blue cone monochromacy.
The most common cone dysfunction syndromes include complete and
incomplete achromatopsia, oligocone trichromacy, bradyopsia, and Bornholm
eye disease (49) (Table 26-2).
The differential diagnosis for a child with decreased vision and nystagmus
includes albinism, LCA, achromatopsia, CSNB, chorioretinal coloboma,
peroxisomal disorders, optic nerve hypoplasia, aniridia/PAX6 variants, and
central nervous system causes. ERG characteristics and a patient’s presenting
symptoms are useful in differentiating among conditions. A study by Lambert
et al. (53) documented the misdiagnosis of LCA in 40% of patients. The most
common misdiagnoses were CSNB, Joubert syndrome (retinal dystrophy
with hypoplasia of the cerebellar vermis), RP, and achromatopsia. Other
conditions that have been misdiagnosed as LCA include infantile Refsum
disease, Zellweger syndrome, Senior-Löken syndrome (nephrophthisis and
retinal dystrophy), cone–rod dystrophy, and Alström syndrome (53,54). An
algorithm for the evaluation of patients with congenital nystagmus is
therefore useful; a version developed after evaluating the cause of congenital
nystagmus in 202 consecutive patients has been reported (55) and is
discussed extensively in Chapter 12.
Oligocone Trichromacy
Oligocone trichromacy was first reported by van Lith in 1973 with additional
patients subsequently being reported in the literature. This condition is
extremely rare and related to achromatopsia. The clinical presentation of
oligocone trichromacy differs from achromatopsia with normal or minimally
affected color discrimination. Otherwise, patients can present with subnormal
visual acuity, congenital nystagmus, a normal fundus, and photophobia. The
ancillary studies also mirror achromatopsia with normal visual fields and an
absence of cone function on ERG. Several achromatopsia genes, such as
CNGB3, CNGA3, PDE6C, and GNAT2, have been implicated, and Anderson
et al. (62) suggest that this condition is a mild version of achromatopsia with
preferential loss of peripheral cones and reduced number of foveal cones
(49).
Bradyopsia
Bradyopsia is a condition characterized by stationary cone dysfunction. It
was first described in 1991 in a series of three unrelated Dutch patients (63).
These patients presented with stationary subnormal vision, photophobia, and
prolonged electroretinal response suppression. In 2004, Nishiguchi et al.
identified mutations in the RGS9 or RGS9BP (R9AP) genes. The proteins
encoded by these genes interact with transducin to turn off the light-evoked
response. Patients with bradyopsia present with mildly reduced visual acuity,
photosensitivity, no dyschromatopsia, and normal or near-normal color
discrimination. Visual field testing shows mildly reduced general sensitivity
possibly with more pronounced central loss of function, and full-field ERG
testing demonstrates markedly abnormal cone responses. However, diagnosis
in young children can be difficult due to normal structural ophthalmic
examinations and improvement of visual acuity with pinhole (64–66). This
condition has only been reported in a very limited number of patients and is
considered to be a stationary cone dysfunction condition (67). Literature
notes varied mutations in patients of Dutch, Pakistani, Afghani, Guatemalan,
Chinese, British, Saudi, and Japanese descent—with a founder effect on the
Arabian Peninsula (65).
Bradyopsia shares many clinical characteristics with oligocone
trichromacy, making it difficult to discern the two conditions on clinical
findings alone (68). Differences are found at a cellular (photoreceptor) level
—with bradyopsia demonstrating an intact and normal photoreceptor
mosaicism compared to a sparse mosaic found in oligocone trichromacy (68).
Strauss et al. (68) highlighted the importance of cellular imaging to
distinguish these two conditions as well as to determine potential therapeutic
options.
MISCELLANEOUS MACULAR
DYSTROPHIES
Pattern Dystrophy
Pattern dystrophy encompasses a heterogeneous group of macular
dystrophies with a wide range of phenotypic presentations. It is characterized
by a buildup of lipofuscin causing variable patterns of damage to the retinal
tissue. It is frequently caused by mutations in the peripherin/RDS gene,
renamed PRPH2 (73). A recent study also implicates OTX2 mutations in the
development of pattern dystrophy in two families (74). Pattern dystrophy
should be included in the differential diagnosis of macular dystrophies but is
not dealt with in detail in this chapter because of its later onset of
presentation. Typical patients with pattern dystrophies are identified in
adulthood. Even in pedigrees with known disease, macular changes are
typically noted in the third decade of life.
Best Disease
Best disease was first described by Adams in 1883. However, it was named
for Frederick Best, who described eight members of one family with the
classic macular changes 1905. The mode of inheritance is autosomal
dominant with incomplete penetrance and variable expressivity as some
patients have the abnormal allele and a normal-appearing fundus.
Consequently, the true prevalence of this condition is unknown. Still, it is not
a common disease; it has a reported prevalence of <1 in 10,000 in Iowa (75).
Clinical Findings
The clinical appearance of Best disease is highly variable and includes a
normal-appearing fundus (5% to 32%), macular RPE atrophy, or a gliotic
scar from choroidal neovascularization (76,77). The classic ophthalmoscopic
appearance of Best disease is symmetrical, bilateral, yellow-orange
vitelliform lesions (Figure 26-6) (76). The vitelliform lesion represents
lipofuscin pigment and has been reported to develop as early as shortly after
birth and as late as age 64 years (78). The vitelliform appearance seems to be
the least stable of the range of fundus manifestations seen in Best disease.
Vitelliform lesions evolve into one of several appearances depending on the
resorption of lipofuscin and include (a) a well-circumscribed gliotic scar; (b)
a pseudohypopyon; (c) a “vitelleruptive” scrambled, scattered distribution of
lipofuscin; and (d) simple macular atrophy. Attempts had been made to
classify the various findings into stages (77). Staging, however, implies a
chronologic progression from one appearance to another that is not
necessarily true in Best disease. Eccentric vitelliform lesions (ectopic
vitelliform lesions) and midperipheral fleck-like deposits also can be seen in
these patients (Figure 26-7) (75). Multifocal Best disease may occur as a
variant or represent a completely different condition (76). Gliotic nodules
were previously thought to be preceded by choroidal neovascularization
because classic choroidal neovascularization has been documented in Best
disease (78,79). However, choroidal neovascularization does not necessarily
precede gliotic lesions and is not required to be present when hemorrhage is
noted clinically. Incidental trauma has been documented to cause subretinal
hemorrhage in the absence of choroidal neovascularization in patients with
vitelliform lesions. Many of these patients will spontaneously recover vision,
depending on the amount of hemorrhage and degree of vision loss. However,
demonstration of a definite choroidal neovascular complex or severe vision
loss associated with hemorrhage may be an indication for intervention to
surgically evacuate the hemorrhage and extract the choroidal neovascular
complex (Figure 26-8) (79).
FIGURE 26-6 Best disease. Left macula of a 19-year-old
man with Best disease. Note the vitelliform lesion in the
macula. The other eye demonstrates a smaller vitelliform
lesion than the left eye. Visual acuity is 20/30 OD and
20/40 OS.
FIGURE 26-7 Flecks present in Best disease. Right eye of
a 54-year-old male with Best disease is shown using a
photographic montage. Note midperipheral lipofuscin
deposits. Visual acuity was 20/40 OD. (Reproduced with
permission from Mullins RF, et al. Late development of
vitelliform lesions and flecks in a patient with best disease:
clinicopathologic correlation. Arch Ophthalmol
2005;123(11):1588–1594. Copyright © 2005 American
Medical Association.)
FIGURE 26-8 Best disease with choroidal
neovascularization. A:Right eye demonstrates RPE
elevation and subretinal hemorrhage. B:Fundus
fluorescein angiography in the late phases shows leakage
consistent with choroidal neovascularization. Early phases
clearly demonstrated lacy choroidal neovascularization.
(Reprinted with permission from Chung M, et al. Visual
outcome following subretinal hemorrhage in Best’s
disease. Retina 2001;21:575–580, with permission.)
The visual prognosis for patients with Best disease is good; 75% of patients
maintain 20/40 or better vision in one eye through age 50 years (80). From a
series in Iowa, the average visual acuity was 20/25 for patients younger than
30 years, 20/30 for patients aged 30 to 60 years, and 20/40 for patients older
than 60 years (81). Even in the presence of a large vitelliform lesion, patients
typically retained relatively good visual acuity.
Lipofuscin blocks fluorescence on fluorescein angiography. Thus,
vitelliform lesions will block background fluorescence through most of the
angiogram. With evolution of the lesion, hyperfluorescence can be seen as a
window defect from RPE atrophy or as leakage from a choroidal neovascular
membrane (76). The ERG is normal in patients with Best disease, whereas
the electrooculogram (EOG), which measures the standing electrical potential
across the RPE, is markedly abnormal. The EOG is reported as a ratio
between the highest amplitude measured in a light-adapted state and the
lowest amplitude measured in the dark-adapted state. The EOG normally is
>1.7, but in patients with Best disease, it is below 1.5 and often 1.0 (76).
Differential Diagnosis
The differential diagnosis relates to the variable clinical appearances of Best
disease. Pattern dystrophy can present with a small vitelliform lesion or
atrophy. This phenotypic presentation of pattern dystrophy is often described
as adult vitelliform macular dystrophy. However, pattern dystrophy rarely
presents with visual symptoms or clinical signs in childhood. Stargardt
disease, North Carolina macular dystrophy (NCMD), and Best disease can all
have macular atrophy.
Family history and examination of family members can help to
differentiate these conditions. Multifocal Best disease (multifocal vitelliform
dystrophy) has also been described as a distinct autosomal dominant disease
with classic vitelliform lesions and a normal EOG.
Pathophysiology
Best disease was linked to chromosome 11q13 in 1992 (82), and the gene
was identified by Marquardt et al. in 1998. The gene product was called
bestrophin (83). Marmorstein et al. (84) localized bestrophin to the
basolateral plasma membrane of the RPE. A recent study also noted a
potential disruption of the polarized conductance due to a mutation in BEST1,
leading to a mislocalization of bestrophin-1 from the basolateral membrane to
the apical membrane (85). Sun et al. (86) and Gomez et al. (87) hypothesized
that bestrophin functions as a chloride channel or a putative ion exchanger.
This gene product now is recognized as a calcium-activated chloride channel
involved in regulating voltage-dependent calcium channels. Several
mutations have been implicated in defective calcium-activated chloride
channel export, as well as disruption of interactions between the N and C
terminus, resulting in altered chloride channel function (85). This gene also
plays a role in ocular development causing a distinct disease, autosomal
dominant vitreoretinochoroidopathy related to that function (88). This
condition is characterized by peripheral retinal and choroidal changes,
presenile cataracts, glaucoma, iris dysgenesis, and nanophthalmos (89,90).
Genetics
The presence of a family history of macular disease in a patient suspected of
having Best disease was a strong predictor of identifying a disease-causing
sequence variation in the gene (91).
Meunier et al. systematically screened patients with vitelliform lesions
for disease-causing changes in both the bestrophin gene (BEST1) and the
peripherin gene (PRPH2). They concluded that age of onset (<40 years) was
the major criterion to distinguish between Best disease and pattern dystrophy.
A disease-causing mutation in BEST1 was detected in 83% of patients
suspected of having Best disease, based on a family history and an abnormal
EOG (92). Boon et al. evaluated patients with multifocal vitelliform
dystrophy. They concluded that this group of patients was both clinically and
genetically heterogeneous. In this study, changes were found in the BEST1
gene (9/15 subjects) and the PRPH2 gene (1/15 subjects) (93).
Finally, the BEST1 gene is involved in causation of an autosomal
recessive bestrophinopathy (ARB). This disease is characterized by
lipofuscin deposition that is often multifocal in the retina, central vision loss,
and a markedly abnormal EOG. It is associated with many different biallelic
missense and nonsense mutations in BEST1. The abnormal gene products
from the identified mutations did not impair formation of wild-type channels
in a heterozygous state. The authors proposed that patients with ARB
represent the null phenotype for bestrophin disease in humans (94).
North Carolina Macular Dystrophy
First described in 1971 by Lefler et al. (95) and later in 1984 by Hermsen and
Judisch (96) as central areolar pigment epithelial dystrophy, NCMD was
renamed by Gass in 1987. Each of the families described in these initial
publications was related to the same family in the mountains of North
Carolina. The family was traced back to 1715 and now consists of more than
5,000 individuals throughout the United States. NCMD was the first macular
dystrophy demonstrating a clear inheritance pattern, but the causative gene
was elusive for many years (97). The gene was finally identified to be a
retinal transcription factor, PDRM13, in 2016 by Small et al. (98). Both
mutations and duplications have been reported to result in NCMD (98). This
disease was previously considered rare but has now been identified in
pedigrees in South Korea, Britain, Germany, and France. Additional families
in the United States that could not trace their ancestry to the original family
have also been identified (99–106).
Clinical Findings
NCMD is an autosomal dominant congenital macular disorder believed to be
completely penetrant with variable expressivity. Patients typically have much
better vision than would be predicted by their clinical appearances, with
visual acuities ranging from 20/20 to 20/400 and a median visual acuity of
20/60 (106). The fundus appearance can vary from a few scattered macular
drusen (Figure 26-9) to a large excavated macular staphyloma-like lesion
(Figure 26-10). Small (107) established a grading system for the fundus
characteristics. Grade I described scattered fine hard drusen, while grade II
described patients with confluent drusen in the central macula and grade III
described patients with a macular staphyloma-like lesion. The staphyloma
frequently has associated gliotic tissue involved in or at its rim (99,108–111)
and has been documented in a patient as young as age 3 months. Khurana et
al. assessed 13 members of a family with NCMD using spectral domain
ocular coherence tomography and ultrasonography. The classic lesion,
previously described as a staphyloma or coloboma, was found to not involve
the sclera but rather to represent deep chorioretinal excavations. They
suggested that these pathognomonic lesions for NCMD be termed “macular
caldera” (112). In general, NCMD is considered nonprogressive or, at worst,
minimally progressive. The congenital nature of this condition allows the
development of eccentric fixation and relatively good vision, better than
would be predicted, despite grade III changes (100). Choroidal
neovascularization has been documented and appears to be most common in
patients who present with extensive drusen in the central macular area. The
presence of choroidal neovascularization may result in severe vision loss
(108–111).
Differential Diagnosis
For patients without the large bilateral macular staphylomata, the differential
diagnosis can include other macular dystrophies, such as Stargardt disease or
Best disease. Cone dystrophies may also present with macular changes but
will have characteristic symptoms and a diagnostic ERG. Congenital
toxoplasmosis and potentially other congenital infections can also present
with large excavated lesions and present in infancy and childhood.
Molecular Genetics
NCMD was first linked to chromosome 6 in 1991 with subsequent refinement
of its locus (MCDR1) to 6q16–21 (108–111). Since the first description of
MCDR1, families in France and Belize have been described with very close
linkage to the MCDR1 locus and a clinical appearance consistent with that of
the originally described family. There are 10 genes in the MCDR1 locus, and
in the original NCMD family, it was determined that a variant lies upstream
of the PRDM13 gene (98). This gene encodes a retinal transcription factor
and has been found to be the only gene in the MCDR1 region that is solely
expressed in the neural retina (98). As a member of a family of “helix–loop–
helix” DNA-binding proteins, PRDM13 plays a role in regulating gene
expression during development (98). Other families with a clinical
appearance resembling NCMD have been excluded from the MCDR1 locus
(112–115). Two groups studying families in Britain and Denmark,
respectively, subsequently identified a locus on chromosome 5 (5p13–p15)
associated with an autosomal dominant macular dystrophy—now known as
MCDR3—closely resembling NCMD (98,114,116). It was later determined
that a tandem duplication in the MCDR3 locus, downstream of transcription
factor IRX1, is likely the disease-causing mutation (98,117). Pattern, spatial
dosage, and timing of expression of IRX1 may be important in macular
development—as it was found to be highly expressed in the fetal macula at
19 to 20 weeks of gestation (117). Between the two loci, there is some degree
of genetic heterogeneity for patients who demonstrate the clinical features
and course of NCMD.
Differential Diagnoses
In the early stages, a fundus phenotype of atrophic macular degeneration with
or without yellowish flecks is shared with several other retinal conditions
(120). These conditions include fundus flavimaculatus, progressive dominant
cone dystrophy, pattern dystrophy, peripherin/RDS mutations, toxic
retinopathies, as well as autosomal recessive Stargardt macular dystrophy.
The progressive pathology, loss of central vision, atrophy of the RPE, and
accumulation of lipofuscin are also characteristic of age-related macular
degeneration—the difference being that STGD3 presents with an early onset
(118). The progressive nature of the disease also distinguishes it from
NCMD, whose gene is also located on the long arm of chromosome 6 (125).
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27
Leber Congenital Amaurosis
Razek Georges Coussa, Robert K. Koenekoop, and Elias I.
Traboulsi
PREVALENCE
In 1869 Theodore Leber first described a very early-onset form of severe
vision loss that manifested itself before age 1 year and in which patients had
nystagmus and sluggishly reactive pupils. Franceschetti subsequently
demonstrated that these patients had markedly reduced or nonrecordable
electroretinograms (1). The spectrum of clinical inherited retinal diseases that
is now referred to as Leber congenital amaurosis (LCA) has become broader
and includes patients with vision that ranges from no perception of light
(NLP) to fairly preserved central vision. To complicate this further, we now
recognize many systemic disorders that have a retinal degeneration that
simulates LCA. In 1985, Foxman proposed subdividing patients into four
groups based on the onset of their retinal disease, and any associated systemic
findings. Group 1 is composed of uncomplicated LCA with ophthalmic
findings but no systemic disease. Group 2 includes patients with retinal
disease and systemic findings such as Senior-Löken syndrome (SLSN) or
cerebrohepatorenal syndrome of Zellweger. Groups 3 and 4 consist of
children with initially normal vision but with very early onset of signs and
symptoms consistent with retinitis pigmentosa (RP) (2). Most important in
the definition of LCA is the absence of another specific retinal or multisystem
disorder (3). Today, LCA is recognized as a heterogeneous group of inherited
retinal disorders that together account for approximately 5% of all retinal
dystrophies and approximately 10% to 20% of all cases of congenital
blindness (4,5). The estimated prevalence of this clinical group of diseases
ranges from 1:33,000 (6) to 1:81,000 (7).
ENVIRONMENTAL FACTORS
There are no environmental factors that contribute to LCA at this writing.
GENETICS
Currently, 20 genes associated with LCA account for more than 70% of cases
of nonsyndromic LCA in the Western world (8). These genes, which are all
related to retinal function or structure are GUCY2D (LCA1), RPE65 (LCA2),
SPATA7 (LCA3), AIPL1 (LCA4), LCA5 (LCA5), RPGRIP1 (LCA6), CRX
(LCA7), CRB1 (LCA8), NMNAT1 (LCA9), CEP290/NPHP6 (LCA10),
IMPDH1 (LCA11), RD3 (LCA12), RDH12 (LCA13), LRAT (LCA14),
TULP1 (LCA15), IQCB1/NPHP5, CLUAP1, PRPH2, KCNJ13, and IFT140.
Interestingly, the 20 causal LCA genes can be categorized into seven
distinct molecular pathways, each affecting a particular aspect of retinal
function and/or structure and, thus, potentially causing specific phenotypic
manifestations (Table 27-1).
WORLDWIDE IMPACT
The contribution of each gene to the totality of cases in any one population
varies according to geographic location possibly due to founder effect–related
predominance. For example, the NPHP6 (CEP290) gene accounts for 15% to
20% of LCA in Northwestern Europe and as much as 30% of LCA in North
America (7). However, mutations in this gene are rare causes of LCA in other
geographic regions, such as southern India (9). Mutations in RPE65 account
for <10% of cases in North America but about 85% in Costa Rica (10).
PATHOPHYSIOLOGY
The wide range of clinical phenotypes and severity of vision loss in patients
with LCA can probably be explained on the basis of the underlying genetic
heterogeneity as well as gene–gene interactions and epigenetic factors (7).
Interestingly, some of the LCA genes have been associated with later-onset
retinal degeneration as well as with congenital onset (Table 27-2).
TULP1 has been a cause of early-onset RP rather than LCA (4,11,12).
CRX (95) and GUCY2D (96) have been associated with both autosomal
dominant cone–rod dystrophies, and with congenital night blindness (13).
CRB1 has been reported to cause RP12 with the particular phenotype of
preservation of periarteriolar RPE (14,15). RPE65 has also been associated
with later-onset retinal dystrophies (16). Mutations in another uncommon
gene causing autosomal recessive LCA, RDH12, has resulted in autosomal
dominant RP phenotype (17). Table 27-2 summarizes the different types of
LCA, designated by their underlying genetic etiology, and their sometimes
unique clinical characteristics (2,18,19).
DIAGNOSTIC STUDIES
Due to the extensive phenotypic heterogeneity and the potential overlap with
other conditions associated with nystagmus and decreased vision early in life,
clinical testing with electroretinography, OCT, fundus autofluorescence
(FAF), and Goldmann visual field when possible are all useful and
complementary (Table 27-1).
DIFFERENTIAL DIAGNOSIS
Any child who presents with infantile nystagmus, inability to track visually
early in life, and/or decreased vision should have an exhaustive ophthalmic
exam. The differential diagnosis for infantile nystagmus, which is the most
common sign for infantile and early-onset inherited retinal dystrophies, is
broad and includes primary sensory retinal abnormalities (LCA,
achromatopsia, blue cone monochromacy, and congenital stationary night
blindness [CSNB]), vitreoretinal abnormalities (retinopathy of prematurity,
Norrie disease, Familial exudative vitreoretinopathy), foveal hypoplasia
(albinism, aniridia), optic nerve disorders (hypoplasia, coloboma), congenital
infectious retinochoroidopathies (syphilis, rubella, TB, toxoplasmosis),
congenital glaucoma, bilateral amblyogenic cataracts, as well as severe
corneal opacifications due to congenital malformations or systemic diseases
causing corneal depositions. One negative test should never be definitive as
the end of a workup. Rather a decision tree that directs attention to alternate
tests after a negative finding is helpful in the workup of infantile nystagmus
(113).
In most cases, LCA presents typically as an isolated condition without
syndromic manifestations. Occasionally, similar retinal findings are
associated with systemic diseases (syndromes) that may carry significant
morbidity and potentially mortality for the infant. Hence, it is crucial not to
overlook medical conditions for which additional systemic care by other
medical specialty services may be necessary as the correct diagnosis would
allow genetic counseling and family planning. Systemic abnormalities that
should raise red flags include deafness, dilated infantile cardiomyopathy
(Alström syndrome) nephropathies, neurodevelopmental delay,
microcephaly, and CNS malformations as well as skeletal abnormalities. In
many of these situations, associated systemic findings, such as seizures,
failure to thrive, and other neurologic or systemic signs, will lead the
diagnosis away from isolated LCA, but the potential still exists for the
ophthalmologist to assist in making the definitive syndromic diagnosis for the
patient and his/her family. Imaging studies, metabolic/biochemical studies,
and a pediatric and medical genetic evaluation are indicated in these cases
(114).
In one study, the rate of LCA misdiagnosis was 40% (3). The most
common misdiagnoses were CSNB, RP, achromatopsia, and Joubert
syndrome (early-onset LCA-like retinal dystrophy, hypoplasia of the
cerebellar vermis, hypotonia, developmental delay, cystic nephronophthisis).
Other conditions that have been misdiagnosed as LCA include Refsum
disease (cerebellar ataxia, peripheral neuropathy, elevated cerebrospinal fluid
protein levels, progressive deafness, anosmia, cardiac dysfunction and RP),
Zellweger syndrome (neurologic dysfunction, craniofacial abnormalities,
hepatomegaly, renal cysts, hypotonia, and RP), Alström syndrome (childhood
obesity, sensorineural hearing loss, hyperlipidemia, type 2 diabetes mellitus,
dilated cardiomyopathy, renal and hepatic dysfunction, alopecia, and RP) (3).
In Senior-Löken syndrome, a typical LCA presentation may be followed in
later life by nephronophthisis and renal failure; all of the systemic
manifestations of syndromes may not be present in infancy; therefore, a
review of systems and reassessment as the child ages are important in follow-
up.
Distinguishing between LCA and early-onset RP may be more of a
semantic issue, especially when mutations in some of the genes implicated in
LCA (e.g., RPE65, CRX, TULP1, RDH12) may also be a cause of later-onset
RP. LCA is almost exclusively autosomal recessive (CRX mutations cause an
autosomal dominant form), while RP has varied forms of inheritance (113).
Patients with early-onset RP will frequently lack searching nystagmus and
have a slightly older age of onset as well as better central vision (4,12). For
the overwhelming majority of patients with LCA, the ERG is essentially
nonrecordable for all stimuli, while that in early-onset RP may relatively
spare the photopic component. Fazzi et al. suggested that the visual
impairment in LCA is more stable compared to RP that results in a more
progressive visual decline (113). Koenekoop suggested that the genetic
changes associated with LCA may affect normal retinal development (6,114).
CLASSIFICATION
There are four possible classification schemes for LCA based on (a) VA and
natural progression, (b) the disease molecular pathway (Table 27-2), (c)
foveal OCT findings (Table 27-3) (42), and (d) histopathology of the retina
from enucleated eyes of patients with LCA (Table 27-3) (6).
MANAGEMENT
The first step in managing children suspected of having LCA is early and
accurate clinical and molecular genetic diagnosis. The latter would then allow
the proper course of clinical interventions that impact the child’s visual and
functional development, education, as well as future family planning. It is
imperative to rule out systemic diseases with an LCA retinal phenotype.
Currently most gene panels for LCA will include genes that cause many if
not all such syndromes, including Alström syndrome, Joubert syndrome, as
well as several other ciliopathies. It is important to review all of the genes
included in a panel when ordering to avoid either omission of possible
syndromic genes of interest or inclusion of genes that should be discussed
ahead of time, such as those that cause fatal illnesses like Batten disease. One
of the challenges is the attribution of any developmental delay to the child’s
blindness, when in fact it could be a sign of CNS dysfunction. Many
clinicians routinely obtain renal function tests in patients with LCA; others
order brain MRIs looking for evidence of Joubert syndrome. Appropriate
molecular genetic testing and the identification of the responsible gene is the
single most important diagnostic step in the management of patients with
LCA and other retinal dystrophies, as accurate molecular genetic diagnosis
helps guide additional medical workup and surveillance.
Families are always devastated as they learn about their child’s disease
and need counseling and support. There are numerous family support groups,
many centered on a particular LCA gene. Families can be directed to join
such groups and discuss potential challenges with others, but they should be
cautioned about the variability in the severity of the diseases and their natural
course even within the same underlying gene group.
In December 2017, the Food and Drug Association (FDA) approved, for
the first time, the use of subretinal injections of adeno-associated virus
(AAV) vectors carrying RPE65 cDNA for the purpose of gene replacement
and augmentation in patients with RPE65-associated inherited retinal
dystrophies (19). The treatment resulted in significant improvement in the
ability of patients to navigate under dim lighting conditions; this
improvement was maintained for at least 3 years posttreatment (18,115).
In December 2018, a new form of treatment was successfully tested and
showed promising results. Cideciyan et al. treated 10 LCA patients with
pathologic mutations in CEP290, at least one of which was 2991+1655A>G,
which alters splicing, with intravitreal injections of antisense oligonucleotide.
The authors reported improvements in visual acuity or retinal sensitivity in
four patients, which were retained at the 6-month follow-up.
Most eyes tolerated treatment well; however, some lenticular opacities
were reported (116). More detailed information on LCA treatment is
discussed in Chapters 28 and 68.
VISION REHABILITATION
When an infant is diagnosed with vision loss, an early intervention plan must
be put in place immediately to assure that the child begins to learn by
nonvisual means and that parents know how best to support this. Local public
school systems usually have a developmental team in place to assess and
support visually impaired children even before school age, and families
should be encouraged to contact their local school system. All children and
adults with LCA should be referred to a low-vision clinic upon diagnosis.
Low-vision specialists follow these patients throughout life and can
recommend appropriate accommodations as needs and goals change (see
Chapter 14). School accommodations are especially important. The
Americans with Disabilities Act states that by law, public schools must
provide disabled students with all necessary accommodations, but these must
be delineated and advocated for in each student’s case. Technology has
revolutionized academic and personal access to visual information for the
visually impaired. Children and parents should be connected to resources to
educate them about these devices and applications.
ETHICAL CONSIDERATIONS
With the advent of an FDA-approved gene therapy for one type of LCA,
there is a heightened moral obligation for clinicians to arrive at an accurate
molecular genetic diagnosis in early life for children with infantile nystagmus
and/or poor vision. Because genetic results may also impact family planning,
physicians should consider referring families to a genetic counselor or
medical geneticist for an in-depth discussion of recurrence risk for other
children and procedures such as IVF with preimplantation genetic testing to
reduce the risk of having other affected children.
FUTURE TREATMENTS
Gene therapy is already a reality for one form of LCA. Although other
genetic types may not be as easy to correct as RPE65 with gene
replacement/augmentation, there is hope that gene therapy or cell therapy will
improve vision for many patients with LCA in the future.
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28
Gene Therapy
Tomas S. Aleman, Albert M. Maguire, and Jean Bennett
INTRODUCTION
Status of Gene Therapy for Genetic Disease
The progress in identifying the structure of DNA, deciphering the genetic
code, and generation of tools with which to manipulate DNA in the 1950s-
1960s led many to realize that it might be possible to manipulate and deliver
genes to humans in order to ameliorate disease (1). The first human gene
transfer experiment was done in 1970 by Stanfield Rogers, an American
doctor at the Oak Ridge National Laboratory in Tennessee. Rogers, along
with a German physician, attempted to treat two sisters (18 months and 5
years old) with seizures and mental impairment due to argininemia (2). They
used the Shope papilloma virus to try to reduce the patients’ arginine levels,
thinking (erroneously) that delivery of a gene that regulated arginine
expression would ameliorate the disease. While their efforts may have been
well intentioned, they did not have a well-devised study design and the study
results were never published. The event did attract the attention of other
scientists, however. Concern about the conduct of this gene therapy
experiment led to establishment of a Recombinant DNA Advisory Committee
(RAC; established 1974) whose mission was to regulate recombinant DNA
research.
When another physician, Martin J. Cline, MD, went to Italy in 1980 and
delivered bone marrow cells exposed to recombinant DNA to 2 patients with
β-thalassemia, there was general outrage (3). The actions were in direct
opposition to NIH gene therapy guidelines and university guidelines.
Fortunately, no one was harmed, and as a result of his action, Dr. Cline’s
research career came to an abrupt end. The first approved human gene
transfer study was initiated in September 1990 and that targeted adenosine
deaminase (ADA) deficiency, a form of severe combined immune deficiency.
The intervention involved intravenous delivery of white blood cells infected
ex vivo with an ADA-containing retrovirus (4). The patient, who was treated
during childhood, is now in her 30s and remains healthy. This study and
further developments in technology for cloning genes, for generating
transgene cassettes, and for developing recombinant viral vectors provided
further impetus to the field.
While the gene therapy field had significant setbacks around the turn of
the century, technologic developments and sophisticated study designs are
now beginning to pay off. The first country to approve a commercial gene
therapy product, an oncolytic adenovirus, was China in 2004 (5). Glybera,
which targets lipoprotein lipase deficiency, was the first gene therapy to be
approved in Europe (in 2012). The first gene therapy drug to be approved by
the Food and Drug Administration (FDA) in the United States and recently
the European Medicines Agency (EMA) is Luxturna (voretigene neparvovec-
rzyl), an agent designed to ameliorate a pediatric onset inherited retinal
dystrophy (see below) (https://seekingalpha.com/news/3411817-novartis-
lands-luxturna-approval). A number of combination cell and ex vivo gene
therapy reagents have also been approved in the United States, including
Kymriah and Yescarta, reagents targeting B-cell acute lymphoblastic
leukemia and lymphoma, respectively.
These successes have fueled interest and investment in further
development of gene therapies, including those that target pediatric retinal
disease.
RPE65 Deficiency
The first gene therapy clinical trials targeting LCA due to RPE65 mutations
were initiated more than 11 years ago (2007; Table 28-1). LCA, one of the
most severe forms of RP because it is manifest in infancy or early childhood,
is rare and can be caused by mutations in any of at least 20 different genes.
The severely impaired vision early in life slowly deteriorates due to
progressive degeneration of retinal photoreceptors (Figure 28-3A and B). A
lack of RPE65 protein impairs the visual transduction (retinoid) cycle,
making it nearly impossible for rod photoreceptors to respond to light (83).
The first proof-of-concept that gene augmentation therapy could ameliorate
this condition was gathered in a spontaneous RPE65 mutant dog, the Swedish
Briard. The data demonstrating that blindness in this dog model could be
reversed by gene therapy (40,78,79), supported near-simultaneous initiation
of three different dose escalation clinical trials testing AAV2-mediated gene
augmentation therapy for LCA due to RPE65 mutations. Additional groups
initiated RPE65 clinical trials thereafter, and the current tally of RPE65 gene
therapy clinical trials is 9 (Table 28-1).
FIGURE 28-3 En-face imaging in retinal degenerations.
A:Fundus photography and photoreceptor thickness
topography in RPE65-LCA. Fundus image is rather
normal, but there is severe photoreceptor layer (ONL)
thinning with a central to superior region of better
preservation mapped in shades of green. B:Macular
changes in association with an overt pigmentary
retinopathy with areas of preservation in peripapillary
retina and nasal midperiphery in RDH12-IRD.
C:Unimpressive macular appearance on fundus exam of a
young patient with ABCA4-STGD but obvious fast
progressing maculopathy on near-infrared fundus
autofluorescence (NIR-FAF).
The initial three studies and most of the subsequent studies used an AAV
serotype 2 vector (AAV2) delivering the wild-type human RPE65 cDNA
subretinally to the RPE in one eye. One later trial used AAV4 (84) and
another is using AAV5 (Table 28-1). There are numerous other variables that
differ between the groups, including inclusion criteria, type of promoter,
dose, location of injection, immunomodulation protocols, and outcome
measures. Reports from all of the trials revealed a high degree of safety
(43,77,84–86). Safety seemed to relate predominantly to the surgical
procedure and most of the adverse events were reversible. The second subject
in one of the early trials developed a macular hole after injection, and surgical
procedures were modified thereafter so as to minimize the possibility of that
outcome. (Nevertheless, that individual showed strong gains in the retinal
function and vision from his treated eye.) (54) The outcome measures
reported to be improved in one or more of the early trials included increase in
light sensitivity, improved visual acuity and visual fields, improved pupillary
light reflex (PLR), and improved mobility (47,50,87). More than 150
different eyes have now been injected in various clinical trials with AAV
carrying the wild-type RPE65 cDNA (Table 28-1), and there is an excellent
safety record. There has been no evidence of vertical transmission—an initial
concern of the U.S. FDA. Several of the subjects conceived and delivered
children who are healthy and thriving.
Further, there were generally large improvements in retinal/visual
function (43,76,85,88). Two of the phase 1 studies reported a decline in
retinal and visual function (in 3 of the 16 patients injected) after the 3-year
timepoint. However, in one of these studies, the level of retinal function
continued to be substantially higher beyond the 3-year timepoint than at
baseline (88). There was also a concern that the degenerative process
continued although, again, improvements in visual function persisted. The
second group that reported decline in response had used a cell-specific (RPE)
promoter to drive expression of the hRPE65 cDNA. That team reported a
decrease in sensitivity after 6 to 12 months in 6 of 12 participants (43).
However, the subjects had not responded as dramatically in that study as in
other studies. It is possible that the lower response was due to use of the
weaker promoter or to other variables that differed from the other studies.
One variable that differed considerably from the other studies was the volume
injected under the retina during AAV delivery. In any case, it is impossible to
make a direct comparison of the results between the various phase 1 dose
escalation studies because there were so many variables that differed between
the studies, including vector design and methods of purification, whether or
not surfactant was used to minimize adherence of vector to inert surfaces,
whether systemic steroids were administered, the exact dosing, surgical
delivery procedures, and outcome measures used to evaluate treatment effect.
After consulting with the FDA about plans for developing a phase 3
clinical trial, the team at Children’s Hospital of Philadelphia (CHOP)
designed a follow-on study for the phase 1 dose escalation trial that aimed to
deliver the gene therapy reagent to the contralateral retina. The FDA had
stated that if the reagent was approved, doctors would attempt to deliver it to
both eyes, and so the team should test safety and efficacy of both eyes being
treated. The subjects welcomed this guidance, as they had been requesting
(unbeknownst to the FDA) injection of their second eyes.
The contralateral eye readministration studies were preceded by large
animal studies aiming to be sure that this would be safe. The concern was that
an immune response to the vector delivered in the first eye could impair the
outcome in the second eye. An immune response could also potentially block
binding of the AAV and prevent improvement of the second eye. The large
animal studies did indeed provide reassuring safety and efficacy data (75).
Individuals who had enrolled in the phase 1 dose escalation study were
invited to participate in the contralateral eye “follow-on” study, in some cases
years after the injection in their first eye. The follow-on study data
demonstrated both safety and robust improvements in retinal and visual
function (76,89). The majority of the subjects gained function as assessed by
multiple outcome measures, including light sensitivity, PLR, visual fields,
and ability to navigate an obstacle course under low light conditions. The
results also mark the first successful readministration of a gene therapy for a
genetic disease. A phase III (registration) trial was then implemented (Spark
Therapeutics, Sponsor) in which AAV-hRPE65v2 vector was delivered by
bilateral subretinal delivery (48,76) (Tables 28-1 and 28-2). This was a
randomized, multicenter, controlled trial and the primary endpoint was
devised to measure a “clinically meaningful” difference in visual behavior.
This test was based on the ability to ambulate through a mobility course
illuminated at set light levels—the “multi-luminance mobility test (MLMT).”
Subjects, who were 4 years of age or older, were randomized 2:1 to
intervention versus no treatment. The individuals who did not receive
treatment were followed over the course of a year and then crossed over to
the intervention group. The intervention group received bilateral injections of
the AAV-hRPE65v2 within a 2-week interval. The primary endpoint was
improved navigation on the MLMT. Secondary endpoints included full-field
light sensitivity, visual fields, and visual acuity.
The phase 3 trial met its primary and secondary endpoints (77). An FDA
Advisory Committee voted unanimously to approve AAV2-hRPE65v2
(voretigene neparvovec-rzyl; Luxturna) in October 2017, and Luxturna was
formally approved as a drug by the FDA on December 19, 2017. This is the
first gene therapy reagent targeting a genetic disease to be approved drug
status by the U.S. FDA. It is also the first gene therapy for a retinal disease to
be approved worldwide. A surprise was that the drug was approved for
individuals age 1 year of age and older (even though the clinical trials had not
enrolled individuals that young).
A challenge for Spark Therapeutics was to establish Centers of
Excellence where assurance could be obtained not only about the eligibility
of each patient (i.e., presence of bi-allelic RPE65 disease, presence of
sufficient retinal cells, etc.) but also that the accuracy of the subretinal
injection (Figure 28-4) could be assured. The first three centers reported
near-simultaneous injections on March 20, 2018. Recently, the Committee
for Medicinal Products for Human Use (CHMP) at the EMA, the European
equivalent to the U.S. FDA, recommended approval of Luxturna. The
European Commission authorized EU-wide marketing on November 23,
2018. Decisions about price and reimbursement will take place in each
European country. Availability will be further expanded through Novartis
(90).
Choroideremia
Choroideremia (CHM) is a slowly progressive, XL recessive retinal
degeneration. CHM gene therapy studies were first initiated at University of
Oxford in 2013, and now there are six different CHM trials (enrolling >75
adult male patients) in progress (Tables 28-1 and 28-2). The initial goal in
CHM gene therapy is to preserve central vision (and to halt further
progression of the disease). This is because as the disease progresses, few
viable (resuscitatable) cells remain in the periphery (Figures 28-5 and 28-6).
Because of the slow progression of this disease, it may take several years to
obtain a complete efficacy assessment. The reports to date from the Oxford
group indicate that there is a high degree of safety associated with the
subretinal injection procedure targeting the fovea and that visual acuity can
improve (and the improvement can persist) in a subset of participants (91,92).
An earlier report from another Center in Alberta, Canada, using the same
AAV2.REP1 vector as a center of a NightStarX-sponsored trial, showed no
effect of intervention on the rate of decline of functional RPE in the treated
eye versus the untreated eye after 2 years of follow-up (93). A Spark
Therapeutics–sponsored clinical trial with centers at the University of
Pennsylvania and Harvard University as well as NightStarX-sponsored trials
with centers in Miami, Oxford, and Tubingen have confirmed this
observation (93–96). As of November of 2018, adverse events consisting of
permanent changes in the outer retina after the subfoveal injections have been
reported by both the Nightstar Therapeutics–sponsored trials (Alberta = 1/6
treated eyes, Miami = 2/6, Oxford = 2/12 eyes, Tubingen = 1/6 eyes) and a
center of the Spark Therapeutics trial in Philadelphia (1/9 eyes) (93–96). Six-
month data were reported by Aleman et al. for nine subjects injected
subretinally with a similar vector showing no significant differences in visual
acuity or retinal sensitivity in the treated versus the untreated eye and
individual vulnerability to subfoveal injection (97). Longer-term follow-up of
these studies is pending. Roche is planning a new clinical trial for
choroideremia using intravitreal injection of an AAV7m8, generated by
evolutionary design (Table 28-1). Biogen is planning a new trial using
subretinal injection of AAV8. One question facing the CHM investigators is
whether it may be more effective to treat the peripheral retina of younger
individuals affected with CHM.
FIGURE 28-5 Colocalized structure and function
correlations in choroideremia. Images are 9-mm long, SD-
OCT cross sections along the horizontal meridian through
the fovea in patients with the earliest central abnormalities
(top 2 panels) compared with patients (bottom 2 panels)
with later stage abnormalities. Nuclear layers are labeled.
Bars above the scans show psychophysically determined
rod (blue bar: dark-adapted, 500-nm stimulus) and cone
(gray bar: light-adapted, white stimulus) sensitivities.
Lines above bars define lower limit (mean − 2 standard
deviations) of sensitivity for the dark-adapted (dashed
lines) and light-adapted (dotted lines) conditions in normal
subjects. Calibration bar to the bottom left.
Achromatopsia
This rare condition causes extreme photophobia, poor visual acuity, and poor
color vision. Four different achromatopsia (ACHM) gene therapy studies
have been initiated: two targeting the CNGB3 form of the disease and two
targeting the CNGA3 form (Table 28-1). These studies are using
photoreceptor-specific promoters and AAVs (AAV8, AAV2tYF) that
transduce photoreceptors more efficiently than AAV2. Preliminary data have
been published through the 3-month timepoint for the first three subjects in
the RD-CURE CNGA3 trial (98). These subjects had received 1 × 1010 vg
AAV8.CNGA3 subretinally. None of them showed clinically evident ocular
inflammation; however, one patient had asymptomatic hyperreflective spots
visualized by OCT in the treated retina peaking 2 weeks after surgery. These
resolved with systemic steroid treatment.
XL Retinoschisis
XL retinoschisis results in splits (schisis) between the different layers of the
retina. When these splits occur in the macula, they can impair visual acuity.
The condition is caused by a lack of a secreted protein (retinoschisin). Two
different trials enrolled a total of 51 affected males (Table 28-1). Both studies
used intravitreal injection of AAV delivering the RS1 gene. Intravitreal
delivery may be effective in this disease due to the diffusability of the
secreted protein through the retina. The intravitreal route of delivery also
minimizes the possibility that an injection itself might lead to an additional
split in these vulnerable retinas. Results from one of the trials, the dose
escalation phase ½ trial run at NEI/NIH, were recently reported. There was
dose-related inflammation and immune response, some of which decreased
visual function, but this ultimately returned to baseline. Retinal cavities
closed transiently in one participant in the high-dose (1e11 vg) group
although there was moderate inflammation and no improvement in visual
acuity or ERGs were noted (99).
Retinitis Pigmentosa
Six different forms of RP are targets in clinical trials using different AAVs,
delivery routes, and strategies (Table 28-1). MERTK deficiency, a disease
manifest in RPE cells, was the first to be addressed. The initial results using
subretinal injection show a high degree of safety. However, it was not clear
whether there were long-term improvements (100). A second RP study
delivers optogenetic therapy to retinas of patients with end-stage
degeneration. The goal is to render other cells in the degenerated retinas
(ganglion cells) light sensitive. Another optogenetic therapy trial recently
enrolled its first subject using both delivery of a modified channelopsin as
well as use of a device (https://www.gensight-
biologics.com/2018/10/26/gensight-biologics-enrolls-first-subject-in-first-in-
man-pioneer-phase-i-ii-clinical-trial-of-gs030-combining-gene-therapy-and-
optogenetics-for-the-treatment-of-retinitis-pigmentosa/). A third RP trial
targets the retinal component of Usher syndrome due to MYO7A mutations.
The MYO7A cDNA is too large to fit within the AAV confines and so a
lentiviral (EIAV) vector was used. The fourth form of RP to be targeted is X-
linked and due to mutations in RPGR. Three different groups are conducting
RPGR clinical trials that differ in AAV serotype (AAV2-tyrosine modified,
AAV5, or AAV2), promoter (hRK, GRK1, or CBA), and age of subjects.
Two other rare forms of RP are also under investigation in phase I/I studies: a
form due to PDE6β-deficiency and one due to RLBP1 (also known as
CPK80) deficiency (Table 28-1).
Stargardt Disease
Mutations in the ABCA4 gene, expressed in photoreceptors, result in
autosomal recessive Stargardt disease (Figures 28-3C and 28-7). ABCA4
mutations can result in a spectrum of disease, including cone–rod dystrophy,
fundus flavimaculatus, RP, and possibly AMD. Similar to the MY07A trial,
the Stargardt trial in progress uses a lentiviral vector in order to accommodate
the large size of the ABCA4 cDNA (Table 28-1).
CEP290 (ProQR)
On September 5, 2018, ProQR Therapeutics announced positive interim
results from a phase I/II clinical trial of an antisense RNA, QR-110, in
patients heterozygous or homozygous for the common p.Cys998X mutation
found in patients with CEP290 mutations (also known as LCA10; Table 28-
1) and published 3-month interim results shortly thereafter (101). The plan
was to administer repeated doses (a total of 4 doses over 1 year) of low,
medium, and high titers of this reagent since the expectation was that it
would have a limited half-life.
The total number of individuals treated in the phase 1/2 trial was
ultimately 10, with an interim report presenting data from the first 8 patients,
including one “super responder” who improved from LP to 20/400 vision.
Subjects ranged in age from 8 to 44 years of age at the time of treatment. All
eight subjects were followed through 3 months after receiving low and
medium doses and 4 of the patients had been followed at least 6 months.
The doses were administered through unilateral intravitreal injection of
an RNA antisense oligonucleotide. The investigators reported improvement
in visual function observed starting at 2 months after treatment, which was
maximal by 3 months. Visual function was assessed through best-corrected
visual acuity (BCVA), which showed a mean improvement of −0.67
logMAR, with 62.5% of individuals showing an improvement of more than
−0.3 logMAR compared to baseline (i.e., more than 15 letters or 3 lines on
the eye chart). There were negligible changes in the contralateral eye (0.02
logMAR, one letter).
There were improvements in additional outcome measures, which had
been previously tested in LCA10 (and other) subjects (102). These included
red and blue light sensitivity as judged by full-field stimulus testing. Those
were −0.74 and −0.91 log cd/m2, respectively. Further, the individuals
improved several light levels in performing the mobility test. There was
comparable activity observed in the first two dose levels, with improvements
in visual acuity and ability to navigate a mobility course at the 3-month
timepoint. Adverse events included cataracts and cystoid macular edema.
This is the first human study targeting a disease originating in
photoreceptors to evaluate the safety and efficacy of an RNA-based
therapeutic and we must await publication of the longer term results to fully
assess their impact. However, because of the positive interim results, ProQR
is planning a pivotal phase 2/3 trial.
OUTCOME MEASURES,
THERAPEUTIC WINDOWS, AND NEW
TARGETS
Outcome measure research is at the center of clinical trial design for IRDs.
The heterogeneous nature of the primary abnormalities at the molecular and
histologic level in these diseases, the diversity of the potential cellular targets
for treatments, and the wide spectrum of disease severity present an equally
heterogeneous structural and functional landscape to explore. The ideal
outcome measure would be easy to implement and deliver, sensitive, specific,
reproducible and able to provide a read out in the short term.
Outcome measures of safety and efficacy must be tailored not only to the
specific disease but also to the disease stage and age of the patient. Whereas
early-onset retinal degenerations (EORDs) constitute attractive platforms
where the risk/benefit ratio may be stacked in favor of visual gain,
implementing outcome measures in the pediatric population is far from
simple. For some EORDs, there is evidence that there will be no option but to
treat at a younger age and regulatory bodies will be expected to require
outcome measures that are similar or equivalent to those used in earlier gene
therapy clinical trials in the adult population, adding complexity to clinical
trial design. Whereas evaluating vision in children older than about 8 to 10
years of age may be possible using the same outcome measures used in
adults, the situation is very different for younger children (103). Irrespective
of the age, an effort should always be made to obtain measures of vision in
young pediatric patients. Techniques that rely on preferential looking may be
used to obtain measures of visual acuity, for example, with the use of Teller
acuity cards. Later in infancy and childhood, a transition can be made to age-
appropriate measures of acuity. Full-field stimulus or sensitivity testing
(FST) techniques were developed in preparation for the earliest gene therapy
trials in an effort to overcome the difficulties in determining visual
sensitivities in patients with severe vision loss that exceeds the dynamic
range of conventional perimetry and in whom poor fixation and nystagmus is
expected to complicate the interpretation of the perimetric tests, often
preventing investigators from using visual fields altogether (117,118).
Although FST technology has been successfully used in a number of gene
therapy trials, there is paucity of information on its reproducibility
particularly in pediatric populations (93,102,118–120). Commercially
available instruments and software allow for customization of FST testing
protocols to accommodate testing of children (Figure 28-8). Protocols should
be as brief as feasibly possible with short interstimulus intervals, limited
number of repeats and stimulation conditions, and starting stimulus
luminances that are appropriate to the expected sensitivity losses of the
specific condition and/or patient (104). Binocular testing and participation of
the tester and family with encouragement during testing may be considered.
A reassuring recent report suggests that these general guidelines can yield
results that are as reproducible in children as in adult populations (103).
An added advantage of this form of testing is the possibility of
determining photoreceptor mediation of vision and the depth of the visual
deficit, which are important diagnostic features of these disorders and may be
part of eligibility criteria for treatment trials. Certain molecular forms of
IRDs, for example, are expected to show mostly residual cone-mediated
vision (e.g., CEP290, RPE65), whereas others (e.g., CRB1, RDH12, AIPL1,
GUCY2D) may show substantial rod vision (Figure 28-3)
(102,103,121–125). The information obtained can provide a more specific
clinical diagnosis, guide and confirm molecular results, and serve as
measures of safety and efficacy in clinical trials.
Complementary objective measures of vision in pediatric IRDs are
desirable giving the intrinsic uncertainty of measuring vision
psychophysically in this group of patients. Although there is a role for
electrophysiologic tests of vision in early-onset cone
dystrophies/dysfunctions, gold standard, diagnostic tests for retina-wide rod
and cone retinal degenerations, such as the electroretinogram (ERG), may not
be informative as outcome measures due to the limited signal available for
detection as a result of early-onset abnormalities. The quantitation of the PLR
by pupillometry is a promising alternative already proven effective in
confirming treatment efficacy during early RPE65-LCA trials
(47,49,126,127). There is scarcity, however, of information on the
reproducibility of the measures, particularly in children, which will be needed
to document subtle changes in vision following the interventions. Like FST,
the transient PRL (TPLR) provides objective information about the depth of
the sensitivity losses and photoreceptor mediation of vision (Figure 28-9)
(103,126). Evidence that TPLR thresholds and photoreceptor mediation of
the TPLR responses correspond well with psychophysically determined
measures of vision by FST has been recently provided supporting the role of
this testing modality in the retinal degeneration clinic and research.
The retinal appearance in pediatric IRDs ranges from deceivingly benign
to the presence of an unmistakable pigmentary retinopathy (Figure 28-3).
Certain findings in isolation or in the context of syndromes may serve as
diagnostic hints of certain molecular subtypes. Examples include the
refractive state of the eye (CRB1) (122), the presence of atrophic
maculopathies and macular pseudo-colobomas (IDH3A, RDH12, AIPL1,
MMACHC, NMNAT1, ABCA4, CRX, DHX38, PRDM13, CNNM4, CNGA3,
PDE6C, ATF) (103,128–138) or true
colobomas/microphthalmia/anophthalmia (SOX2, OTX2, PAX6, STRA6,
ALDH1A3, RARB, VSX2, RAX, FOXE3, BMP4, BMP7, GDF3, GDF6,
ABCB6, ATOH7, C12orf57, TENM3,ODZ3, VAX1, SALL2, YAP1, CRB1)
(139,140), optic nerve drusen (RDH12, MFRP, CRB1) (140–142), and of
early and peculiar pigmentary changes (NR2E3, NRL, CRB1) (143–146).
Once established, however, these nonpathognomonic qualitative signs are of
limited use as outcome measures in clinical trials.
En-face retinal imaging with scanning laser ophthalmoscopy and cross-
sectional retinal imaging of the structural detail of the retina with spectral
domain optical coherence tomography (SD-OCT) have offered new
quantitative possibilities to the study of retinal degenerations. Measures of
photoreceptor-specific vision colocalized to the underlying retinal structure
imaged with SD-OCT constitutes a powerful, yet not widely used tool to
explore these conditions (Figure 28-5), and a proven outcome measure of
efficacy of IRDs in RPE65-LCA (49). The premise for gene therapy for outer
retinal degenerations is the demonstration of treatable photoreceptors, which
can be identified with SD-OCT (147). Confirmation of vision loss in excess
of that expected for the photoreceptor loss has been deemed the ideal setting
to treat with gene augmentation (102,147). In such situation, the predominant
dysfunction may be acutely improved after the correction of the underlying
defect such as in RPE65-LCA.
This scenario of structural–functional dissociation, however, is not the
most frequently encountered. The more common picture in IRDs is that of
pure photoreceptor degeneration in which there is proportionality between the
loss of photoreceptors and the associated vision loss (147). In this common
situation, outcomes that measure progression or modification of the natural
history of the disease after treatment are needed. Detection of fast progressing
windows of structural and functional changes that indicate where to intervene
may be desirable (Figures 28-6 and 28-7) (103,129). Careful quantitation of
the structural changes at the level of the outer retina, specifically at the level
of the photoreceptor outer segments (POSs), however, may provide a new
level of structural–functional situation that may be corrected with gene
therapy and that can provide acute evidence of the efficacy of the
interventions (102). That is, vision loss that is purely associated with POS
abnormalities may exist in the presence of a normal photoreceptor layer
(outer nuclear layer, ONL) thickness, providing a new setting of structural–
functional dissociation that may be improved after the physiology of the POS
is restored with treatment (102,104).
FIGURE 28-7 Short-term follow-up of an ABCA4-STGD
patient with SD-OCT demonstrates progression detectable
only by imaging. Shown are 7.6-mm horizontal cross
sections through the fovea at baseline and a year later.
Nuclear layers and outer retinal bands are labeled: GCL,
ganglion cell layer; INL, inner nuclear layer; ONL, outer
nuclear layer; ELM, external limiting membrane; IS/OS,
outer segment/inner segment interface band; IZ,
interdigitation of the photoreceptor outer segment with
apical RPE; RPE/BrM, RPE/Bruch’s membrane.
Horizontal arrow shows sequence of loss of the bands in
the outer retina: IZ →IS/OS → ELM → foveal ONL
thinning. Vertical arrows signal place interruption or loss
of the IS/OS that corresponds with the loss of the POS;
arrows are offset horizontally at baseline compared to a
year later due to the centripetal progression of the
abnormalities.
FUTURE CHALLENGES
SUMMARY
The recent approval of the first retinal gene therapy product, Luxturna, for
RPE65-related retinal dystrophy by U.S. and European regulators has fueled
the development of gene therapy for additional pediatric-onset retinal disease
targets. Gene therapy clinical trials are either in progress or are being planned
for many of these diseases. Additional strategies and novel vectors and
delivery systems are being developed for others. With the continued pace of
progress with ocular gene therapy, gene-based approaches will likely soon
become standard of care for additional, currently untreatable, early-onset
blinding diseases.
ACKNOWLEDGMENTS
We gratefully acknowledge support by the Foundation Fighting Blindness–
sponsored CHOP-PENN Pediatric Center for Retinal Degenerations, the
Brenda and Matthew Shapiro Stewardship and the Robert and Susan
Heidenberg Investigative Research Fund for Ocular Gene Therapy, RDH12
Fund for Sight, Research to Prevent Blindness, the Paul and Evanina Mackall
Foundation Trust, the Center for Advanced Retinal and Ocular Therapeutics,
and the F.M. Kirby Foundation. Most importantly, we acknowledge the
pioneering efforts of patients in participating in clinical research studies.
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29
Congenital Stationary Night Blindness
(CSNB)
Christina Zeitz, Juliette Varin, and Isabelle Audo
PREVALENCE
Congenital stationary night blindness (CSNB) is a clinically and genetically
heterogeneous inherited retinal disorder. To our knowledge, the frequency of
CSNB in the general population has not been documented. Together from our
and published data, we estimate that at least 700 index patients worldwide
have a genetically confirmed diagnosis of CSNB (1). From our worldwide
cohort, approximately 170 French patients have a genetically confirmed
diagnosis of CSNB (1,2). Thus, the prevalence in France with 67.19 million
people would be at least approximately 1:400,000. This is very rare, but we
speculate that many cases are undiagnosed. Only by using specific clinical
examinations and/or molecular genetic testing can CSNB be correctly
diagnosed. In respect to the collection of our large European cohort with
inherited retinal disorders, including approximately 5,000 index cases, 2% of
those present with CSNB.
Modified from Vincent A, Audo I, Tavares E, et al. Biallelic mutations in GNB3 cause a unique form
of autosomal-recessive congenital stationary night blindness. Am J Hum Genet. 2016;98:1011–1019;
Zeitz C, Friedburg C, Preising MN, et al. [Overview of congenital stationary night blindness with
predominantly normal fundus appearance]. Klin Monbl Augenheilkd 2018;235:281–289.
GNB3-CSNB
Recently a novel gene defect underlying CSNB was identified (49,50). The
phenotype cannot further be classified (51). Only a few cases have been
described so far, and the phenotypes seem to be variable even in those. At
low light intensities (DA 0.01), the b-wave is reduced. At a bright flash, only
the b-wave is reduced, while the a-wave is normal (DA 10.0), confirming
normal rod phototransduction. The photopic responses are very variable: the
LA 30 Hz ERG can be reduced and delayed. In the single-flash cone ERG
(LA 3.0), the a-wave is normal but can be delayed, and the b-wave is reduced
and delayed. Long duration stimulation shows abnormalities of the ON but
not of the OFF responses. Patients with mutations in GNB3 may be night
blind, showing myopia and nystagmus. More patients with the same gene
defect to be identified in the future may help to better classify this novel form
of CSNB.
GNB3-Gene Defect
As mentioned above, the GNB3 gene defect cannot be strictly classified in the
different subforms of CSNB. Thus, we did not include the protein
localization of GNB3 in Figure 29-1. GNB3 coding the β subunit of the G
protein heterotrimer (Gαβγ) is known to be expressed in cones and ON-
bipolar cells and modulates ON-bipolar cell signaling and cone transducin
function in mice (99). Due to its expression in cones as well in ON-bipolar
cells, the dual phenotype associated with GNB3 mutations maybe explained
(49).
DIAGNOSTIC STUDIES
Genetic testing of CSNB patients is important for genetic counseling of
patients and their families to distinguish from progressive retinal dystrophies
with similar phenotypic features (1). For example, night blindness is one of
the first presenting signs of progressive rod–cone dystrophy, also called
retinitis pigmentosa. At a young age, patients may initially show normal or
near-normal fundus appearance. Therefore, in addition to accurate
phenotyping, molecular confirmation of CSNB helps to correctly diagnose
and counsel patients. CSNB patients with largely normal fundus, a Riggs-
ERG and autosomal dominant or autosomal recessive inheritance should be
screened for mutations in RHO = GNAT1 > PDE6B and SLC24A1 > GNAT1,
respectively. For patients with autosomal recessive mode of inheritance and
FA, RDH5 should be targeted, while patients with autosomal recessive CSNB
and a phenotype suggestive of OD should be screened for mutations in GRK1
and SAG (1). Patients and especially male patients with the Schubert-
Bornschein type of CSNB should be first screened in CACNA1F and NYX
(1). Both genes are located on the X chromosome and represent the major
causes of this form of CSNB. If a clinical discrimination of icCSNB versus
cCSNB is made, only CACNA1F or NYX needs to be investigated. Our
experience showed that at least 80% of these cases show mutations in one of
those genes. Females and excluded male patients with icCSNB could be
screened in CABP4 and CACNA2D4, especially if they present with high
hyperopia and photophobia. Cases of cCSNB should be screened for defects
in TRPM1 > GRM6 > GPR179 > LRIT3. In cases where no difference
between icCSNB and cCSNB is made, the following mutation detection
strategy should be applied
CACNA1F > NYX > TRPM1 > GRM6 > GPR179 > CABP4 > LRIT3 >
CACNA2D4.
We developed this strategy, based on the prevalence of the specific gene
defects (1). Our recent experience showed that intronic variants and
synonymous variants may be also disease causing and should not be
overlooked (2). In case only preliminary clinical phenotyping data are
available, unbiased microarray analysis and targeted next generation
sequencing (NGS) could be applied (Genetic Testing Registry at
https://www.ncbi.nlm.nih.gov/gtr) (100–102). The prior method is based on
allele-specific primer extension analysis, which allows the detection of
known mutations. The array is regularly updated with new mutations in
known genes and mutations that will be identified in novel gene defects.
However, since there are only a few mutation hotspots and founder mutations
in CSNB and their implicated genes, targeted NGS approaches seem to be
more appropriate. Albeit, initially GC-rich and repetitive regions were less
well covered by the latter methods, more recent techniques seem to overcome
these challenges. After exclusion of mutations by the above-mentioned
method, targeted whole genome sequencing or whole exome or whole
genome sequencing should be applied to identify the disease causing
mutation.
SUMMARY
Inherited retinal disorders are very heterogeneous and can be deciphered
depending on the congenital or progressive course of the disease or by the
type of retinal cell that are involved. Herein we describe the genetic and
phenotypic characterization of CSNB. Depending on the mutated gene,
CSNB patients can present a rod-photoreceptor defect (Riggs type of CSNB)
with or without fundus abnormalities (Oguchi disease, fundus albipunctatus)
or a transmission defect from photoreceptor to bipolar cells (Schubert-
Bornschein type). The incomplete form of Schubert-Bornschein type of
CSNB is due to a defect of proteins localized at the photoreceptor synapse,
while the complete form results from a defect of proteins localized in ON-
bipolar cells. Together with other clinical symptoms, clear genotype–
phenotype correlations can be made as described herein.
FUTURE TREATMENTS
To date, CSNB is still an incurable disease. Gene therapy seems to be the
more suitable approach to treat CSNB as it is largely a stationary disorder and
the gene defect underlying the disease has been diagnosed in about every
patient. This kind of treatment has already showed its efficacy in inherited
retinal disorders as for LCA due to mutations in RPE65 (103,104) using
adeno-associated virus (AAV) vector (105–107). Concerning CSNB, a gene
therapy approach for X-linked cCSNB has been studied (108). Intravitreal
injection of the wild-type copy of Nyx using an AAV vector in mice lacking
this gene led to a partial rescue of the b-wave in scotopic conditions and
gating of the cation channel TRPM1. The partial rescue was obtained in
extremely young mice, while the treatment was inefficient in adult mice.
Nevertheless, the improvement following the treatment was mild, and further
investigations on the restoration of the visual acuity were not documented.
Such treatment has not been tested in nonhuman primates so far. More
investigations concerning this therapeutic strategy for other CSNB need also
to be done.
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30
Stargardt Macular Dystrophy/Fundus
Flavimaculatus: From Disease and
Gene Discovery to Identification of
Disease Pathways to the Development
of Therapies
Robert K. Koenekoop and Thomas M. Aaberg Sr
Professor Deutman, in The Netherlands (9), was the first to use the term
“Stargardt flavimaculatus,” reopening the discussions of STGD1 and FF
being separate or the same disease. Professor Aaberg, in the United States
(10), reported that both STGD1 and FF patients can coexist within the same
families. He stressed that STGD1 patients present with atrophic macular
changes and subtle or obvious subretinal yellow flecks in childhood or young
adulthood (see Figure 30-4).
FIGURE 30-4 Fundus photo and FAF of the right and left
eyes. STGD1 with significant macular atrophy and flecks
with a significant macular hypofluorescence and
surrounding hyperfluorescent flecks.
The debate about whether STGD1 and FF are the same or different entities
has been settled as genetic studies have demonstrated a firm molecular
relationship between the two diseases (11–13) following discovery of ABCA4
mutations in both clinical disorders. The designation STGD1 in this chapter
refers to both entities. STGD1 can be severe and early onset but develops
after normal early visual development, normal foveation, and proper, early
development of the fixation reflex, which may provide opportunities for
meaningful therapeutic interventions.
How STGD1 evolved from disease description and naming in 1909, to
gene and protein discovery more than 100 years later in 1997, and to
potential treatments today represents an exciting scientific story. This history
serves as a model for understanding and advancing research into all inherited
retinal degenerations (IRDs).
GENE DISCOVERY
ABCA4 gene discovery started with linkage analyses of large multiplex
STGD1 families, followed by gene identification through positional cloning,
culminating in protein identification and characterization. Professor Josseline
Kaplan, in Paris, performed linkage analysis on eight French multiplex
STGD1 families and assigned the STGD1 disease locus for the first time to
chromosome 1p21-p13 (14).
Gerber et al. in 1995, then reported mapping of the FF disease locus to
chromosome 1p13-p21 as well, in the genetic interval near locus D1S435 in
four multiplex FF families (15).
At about this time, Professor Rando Allikmets was characterizing the
protein superfamily of mammalian ABC transporters and mapping and
correlating (assigning) its members as possible candidates to various human
disease phenotypes. The ABC superfamily includes genes whose products are
transmembrane proteins involved in energy-dependent transport of a wide
spectrum of substrates across membranes (5). One of the studied ABC
transporters, ABCR (now called ABCA4), mapped to the human chromosome
1p13-p21 region close to microsatellite markers D1S236 and D1S188.
Northern blot analyses showed that ABCA4 expression is uniquely retina
specific and not found in other human tissue. Mutational analysis of the
ABCA4 gene in 48 STGD1 families revealed a total of 19 different mutations,
the majority representing missense mutations in conserved amino acid
positions (5).
Clinical studies, together with more recent molecular genetics studies,
demonstrate that STGD1 and FF are variable expressions of the same
disorder (16); other disorders have joined this list to reveal an expanding
spectrum of disease types and severities including autosomal recessive
ABCA4 mutations in retinitis pigmentosa (RP), Stargardt maculopathy (see
Figure 30-5), and cone–rod dystrophy (see Figure 30-6). Heterozygous
ABCA4 mutations have been postulated by some authors and refuted by
others to play a role in age-related macular degeneration (AMD) (17,18).
PREVALENCE
Although STGD1 is one of the most common causes of early-onset macular
degeneration, it is still a rare disease having an estimated prevalence of
1:10,000 (19).
ENVIRONMENTAL FACTORS
Because the accumulation of abnormal catabolic debris in the RPE is
believed to lead to oxidative damage at the cellular level, and the fact that
oxidative damage from light exposure and smoking can influence other
macular diseases, such as age-related macular degeneration, it is possible that
these environmental stressors may be cofactors in disease progression in
STGD1. It has also been suggested that mutations in ABCA4 may make
patients more susceptible to retinal toxic medications (20). Because by-
products of vitamin A generated after light bleaching are part of the abnormal
accumulations in STGD1, excess vitamin A in the diet may worsen retinal
function and should be avoided. Vitamin supplements containing vitamin A
are contraindicated. Similarly, bright light exposure may hasten vision loss; a
study of patching one eye in a STDG1 patient resulted in better vision in that
eye (21).
Weng and associates reported a substantial deposition of A2E in the
mouse RPE of the knockout mouse model (abca4−/−) for STGD1. The mice
also developed delayed dark adaptation (DA) (22). If these mice were
sheltered from bright light, the retinal degeneration was attenuated (23). Radu
and coworkers demonstrated that vitamin A supplementation significantly
increased lipofuscin pigment in the RPE of the Abca4 knockout mouse model
of Stargardt disease (24). Studies like these support the concept that lifestyle
modifications may delay the progression of disease and perhaps preserve
useful vision.
PATHOPHYSIOLOGY
Some of the questions surrounding STGD1 are about how ABCA4 mutations
cause retinal cell death, which cell populations die first and in what sequence.
Also, how fast does the maculopathy expand and does it correlate to RPE
loss? In addition, is the expansion of atrophy (measured by the ellipsoid zone
(EZ line) on optical coherence tomography (OCT) a good clinical outcome
measure to study the possible efficacy and safety of new experimental
treatments?
To answer these questions, the pathogenic sequence of ABCA4-associated
disease must first be determined. Does the disease commence in RPE (and
then affect PR death) or in photoreceptors first (and then spread to RPE) or
are both cells affected concurrently?
Hypothesis 1: STGD1 Commences in the RPE Cells
Evidence that STGD1 is initiated in the RPE cells came from multiple
mouse and human histopathologic studies and was the first disease sequence
hypothesis to be proposed. Eagle et al. found the accumulation of lipofuscin
in RPE on histopathology studies of cadaver eyes and postulated that STGD1
commences in the RPE. Clinical studies led to a proposed disease model of a
pathogenic sequence of lipofuscin accumulation leading to RPE cell damage
and then to photoreceptor loss (25).
In ABCA4-associated diseases, one of the most noticeable retinal
changes is the presence of autofluorescent foci (yellowish subretinal fundus
flecks) captured by short wave length (SW-AF) signals and imaging. For
many years, it had been assumed that flecks represented lipofuscin-laden
RPE cells. Flecks are dynamic features of the STGD1 fundus; therefore,
Paavo et al. analyzed flecks in a precise sequence of short wave length (SW-
AF), near-infrared autofluorescence (NIR-AF), and infrared reflectance (IR-
R) imaging, followed by SD OCT and by quantitative AF (qAF) (26). They
related these multimodal findings to structural information acquired by SD-
OCT. They then studied images from 12 STGD1 patients (6 females and 6
males; age range from 9 to 61 years old) who had been recruited after
obtaining a clinical diagnosis of STGD1 and positive ABCA4 genetic testing.
They found that isolated flecks in SW-AF images are often situated
within hypo autofluorescent (hypo AF) zones in NIR-AF images. Hypo AF in
NIR indicates RPE atrophy. They also found that the flecks visualized in SW-
AF images corresponded to hyperreflective aberrations extending radially
within photoreceptor-attributable bands (EZ) on the SD-OCT scans. These
observations suggested that fundus flecks are a manifestation of degenerating
photoreceptor cells in STGD1, not lipofuscin-laden RPE cells (26).
Hypothesis 2: STGD1 commences in photoreceptors. Some authors have
documented by histopathology and in vivo imaging that photoreceptor (PR)
loss occurs earlier than RPE loss in the disease pathophysiology. In these
studies, photoreceptors have shorter OSs even when the apposing RPE still
appears to be organized, whereas adaptive optics studies showed increased
photoreceptor spacing with normal RPE spacing (27,28). In a 2-year study of
16 STGD1 patients studying loss of the EZ on SD-OCT imaging, Cai et al.
demonstrated that a gradual expansion in the total area of EZ loss in STGD1
occurs at around 0.31 mm2/year, similar to the expansion of the RPE loss on
FAF at 0.33 mm2/year (29). The expansion is nonuniform and is not seen
equally at all edges of an existing lesion (29) (see Figure 30-7). These
studies, however, do not provide definitive proof that PR loss precedes RPE
loss, as each study has limitations.
FIGURE 30-7 OCT images of EZ zone and measurements
in STGD, year 1 and year 2. Note the unequal, but
measurable expansion of the macular atrophy. (Reprinted
from Cai C, Light J, Handa J. Quantifying the rate of
ellipsoid zone loss in Stargardt disease. Am J Ophthalmol
2018;186:1–9. Copyright © 2017 Elsevier. With
permission.)
To investigate early STGD1, Song et al. (27) used AOSLO to evaluate two
brothers with macular atrophy, a mild phenotype, and their unaffected
parents. One son (more severe phenotype) was found to have FAF indicating
central hypo AF, surrounding hyper AF at 0.7 mm, and uniform AF at 1.7
mm. The other son (less severe phenotype) had a subtle bull’s-eye
maculopathy with no peripheral flecks. OCT showed foveal preservation of
the OS with a thickened external limiting membrane, perifoveal atrophy of
the outer retina and RPE, and normal layers at 1.7 mm. Fundus AF indicated
a bull’s-eye with central hyper AF, and surrounding annular hypo AF, then
hyper AF at 0.7 mm. Autofluorescence was uniform at 1.7 mm. Although
both affected individuals manifested macular atrophy without flecks,
photoreceptor spacing was significantly increased peripheral to the clinically
detectable lesions. FAF was homogeneous at these locations, suggesting that
a decline in photoreceptors precedes lipofuscin accumulation in RPE in the
macular atrophy phenotype. Thus, this second hypothesis suggests that the
disease sequence in ABCA4-related STGD1 commences in rods and cones
and proceeds to the RPE, opposite of the hypothesis of Cideciyan (25). A
third hypothesis is that the disease sequence commences in the RPE and
photoreceptors at the same time.
Cukras et al. examined the temporal–spatial patterns of FAF with
excitation at both 488 nm (standard FAF) and at 795 nm (near-infrared
autofluorescence, NIR) (Figure 30-8) in a longitudinal case series involving
8 eyes of 4 patients (range of follow-up, 11 to 57 months; mean, 39 months)
(30).
FIGURE 30-8 STGD1 patient retinal photo STGD1
patient retinal photo (A), standard FAF (B), and NIR (C)
studies. The photo of the left eye shows the macular
atrophy and yellow subretinal flecks. The standard FAF
shows the central hypo FAF, and the surrounding hyper
FAF, corresponding to the clinical flecks. NIR shows more
extensive hypo FAF in the center, and alternating hypo
and hyper FAF of the clinical flecks. (Reproduced with
permission from Cukras CA, Wong WT, Caruso R, et al.
Centrifugal expansion of fundus autofluorescence patterns
in Stargardt disease over time. Arch Ophthalmol
2012;130(2):171–179. Copyright © 2012 American
Medical Association.)
The goal of this study was to elucidate molecular and cellular mechanisms
underlying STGD1 by studying longitudinal hyper and hypofluorescent
patterns both with NIR and regular FAF imaging. In addition, they evaluated
if these findings may constitute potential outcome measures in clinical trials.
NIR evaluates melanin-containing RPE cells, while standard FAF evaluates
photoreceptor health. With aging in normal eyes, melanin, unlike lipofuscin,
decreases in the RPE; melanin granules in RPE cells decrease in number as
those containing lipofuscins accumulate. These trends have led to the
hypothesis that melanin in RPE cells may regulate lipofuscin accumulation
and/or the photo-oxidation of lipofuscin-related compounds. Research has
demonstrated that lipofuscin-related compounds can act as photosensitizers,
increasing the production of reactive oxygen species. Chemical modification
of proteins and DNA could then induce RPE cell death. The study by Cukras
et al. (30) explores these melanin–lipofuscin interactions and how they
contribute to the accelerated course of lipofuscin accumulation in STGD1
(Figure 30-9).
The ellipsoid zone (EZ) represents the inner segment/outer segment junction
(IS/OS jct) of photoreceptor cells. In the center of the fovea, this represents
the IS/OS jct of the cones. Tanna et al. explored EZ parameters in 41 patients
and found a mean annual rate of transverse EZ loss (± SD) was 279.5 ± 259.9
μm/year. The mean rate of area of EZ loss (± SD) was 1.20 ± 1.29 mm2/year.
This highlights the reliability of SD-OCT in measuring EZ loss, which
appears to be a robust measurement of photoreceptor integrity (31).
To elucidate the cellular origin of AF abnormalities in STGD1, Song et
al. utilized fluorescence adaptive optics (FAO) scanning light
ophthalmoscopy to provide autofluorescence (AF) images in vivo with
microscopic resolution. They found that AO images of cones, rods, and RPE
cells at the “leading edge” of the macular atrophy show AF signals that
appear to colocalize with photoreceptors. Their observation is consistent with
reports of fluorescence arising from photoreceptors in STGD1 (32).
There is extensive variability in both phenotypic and gene expression
associated with ABCA4 mutations. This variability manifests itself in the
wide spectrum of disease “types” (e.g., STGD1, FF, CRD, RP, possibly
AMD, etc.). Variability is also found in the severity spectrum associated with
STGD1 itself (i.e., ranging from severe, early onset to late onset with foveal
sparing). Added to this phenotypic diversity is the variability linked to the
diversity of expression patterns of ABCA4 in both rods and cones and in RPE
cells. Documenting and predicting the spatial and temporal progression of
ABCA4-associated diseases is, therefore, critical for the development of
potential therapies. Therapeutic windows, disease stages, disease
classification, and severity ranges must be established to consider what,
when, where, and how to deliver the agents now being tested (drugs, genes,
and/or cells) for treatments, either to slow, halt, or reverse the disease course.
In an attempt to explain the diversity of phenotypes associated with
ABCA4, ranging from FF and STGD1 to severe autosomal recessive (ar)RP
and autosomal recessive cone–rod dystrophy (arCRD), a genotype–
phenotype model was proposed (33). According to this model, the severity of
the functional consequences of the combination of ABCA4 mutations
correlates with the severity of the clinical phenotype (33,34). Patients with a
severe and a mild variant or two moderately severe variants are expected to
present with STGD1, patients with a severe and a moderately severe mutation
develop CRD, and individuals with two severe mutations develop a severe
form of CRD. The CRD phenotype has been associated with an early age at
onset (<10 years) (35,36) and in a later stage often resembles RP. The amount
of remaining ABCA4 protein function is thus inversely correlated with the
severity of the resulting disease phenotype under this hypothesis, which has
been validated with later studies (37).
According to the above model, two “mild” or “hypomorphic” variants are
expected not to give rise to a disease phenotype (34). This model explains
how there can be an unusually high carrier frequency of mild variants in the
general population, which can be as high as 5.5% (e.g., c.2588G>C; p.
Gly863Ala, Gly863del) in Sweden (38) and 11.3% (c.5882G>A; p.
(Gly1961Glu) in Somalia (Figure 30-11) (39,40) when the disease itself is
rare. Some nonexomic and synonymous variants in ABCA4 have been shown
to be disease causing in combination with more severe alleles (41).
Adult- and late-onset Stargardt disease phenotypes are often associated with
milder missense mutations, which may retain partial ABCA4 protein
function. This is very much unlike the null mutations in ABCA4, which are
associated with early-onset STGD1, arRP, and arCRD. Many late-onset
Stargardt disease cases were found to have only one mutant allele while the
second allele could not be found. A report by Zernant et al. demonstrated that
the second allele in many of these cases harbored a single ABCA4 variant,
p.N1868I (c.5603A>T) (43) (Figure 30-12). Importantly, this variant was
previously considered not to be disease causing, because the frequency of the
p.Asn1868Ile allele, 7%, is unusually high in the general population for a
disease-causing allele. Deep intronic variants and deletions account for other
cases of “single allele” Stargardt (44).
Stargardt macular dystrophy is now believed to be a spectrum of
maculopathies with overlapping and diverging phenotypic characteristics, all
caused by a spectrum of ABCA4 mutations. Early onset (juvenile STGD1),
early adulthood, late onset, foveal sparing, and FF are five broad clinical
groups of diseases. In the past 20 years, attempts have been made to stage
and group STGD1 further by classifying STGD1 clinically using
electrophysiologic, autofluorescence, and acuity measures. Here follows three
commonly used staging classifications for STGD1 disease.
Subtypes of STGD1
An increasing number of ABCA4 mutations are being correlated to various
STGD1 phenotypes. The p. G1961E (p.G1961E) ABCA4 mutation
phenotypic subtype of STGD1 is a common, mild type of STGD1,
characterized by bull’s-eye maculopathy and mild progression (see Figure
30-11). There is lower accumulation of lipofuscin (autofluorescence [AF])
and often long-term preservation of cone and rod function.
Another STGD1 phenotype is ROC, rapid-onset chorioretinopathy (49).
Characteristically, there is a homogenous ring distribution of hyper
autofluorescence (AF) apparent at an early-disease stage with nascent fleck
development in the mid-periphery. A dense, homogeneous distribution of
autofluorescence concentrated across the macula subsequently progresses to
macular atrophy. This spatially corresponds to reduced signal on NIR-AF
indicating a widespread loss of underlying RPE in this region while flecks
develop in the periphery over time. Most ABCA4 mutations causing ROC are
null alleles, with no expected ABCA4 protein (24). The ROC phenotype is
characterized by early onset (<10 years of age) and a rapid progression to
advanced disease. Rapid accumulation of bisretinoid lipofuscin in
photoreceptor cells, secondary deposition in the RPE, followed by
widespread RPE death in the macula, thinning of the choriocapillaris and CS
layer, diffuse, multifocal atrophy, and generalized electrophysiologic
dysfunction lead to significant visual decline at a much younger age than in
other cases of ABCA4 disease (24).
Genetics
STGD1 is an autosomal recessive disease caused by biallelic mutations in the
ABCA4 gene. However, in multiple international cohort studies, complete
sequencing of the ABCA4 locus in STGD1 patients identifies two expected
disease-causing alleles in approximately 75% of patients and only one
mutation in approximately 15% of patients. Thus, approximately 10% of
ABCA4 mutations remain to be determined. One of the hallmarks of ABCA4
and STGD1 is the aforementioned extensive phenotypic variability; in age of
onset, rate of progression, disease types, attained severity and remaining
vision. Phenotypic variability is caused in large part by the extensive ABCA4
disease-associated genetic variation, as more than 1,000 definitely or possibly
disease-causing variants have been determined in the coding sequences and
splice sites of the ABCA4 gene.
It is important to identify the remaining 25% of disease causing ABCA4
mutations. Recently, the understanding of disease-causing genetic variations
in ABCA4 improved as a result of two major advances (44). First, many
noncoding, (outside of the exons) disease-associated ABCA4 alleles have
been identified and proven to be pathogenic, mostly by affecting splicing.
Splicing is the molecular mechanism that removes introns and joins together
exons as the DNA is transcribed into messenger RNA. Second, it was
recently determined that some ABCA4 variants, which had been considered
benign because of high minor allele frequency (MAF) in the normal, general
population, are in fact very mild conditional alleles. These mild mutations
result in STGD1 disease only when in trans (trans means in an association
with a mutation on the other allele) with a deleterious mutation. These mild
mutations are now called “extreme hypomorphs” (41). Deep intronic and
hypomorphic alleles have added to our understanding of ABCA4 and allowed
an increased number of patients to be designated “definitely caused by
ABCA4,” important for entry into studies and therapeutic trials. Even in 2018,
21 years after ABCA4 discovery, new ABCA4 mutations are still identified,
likely because there are important geographical isolates. Nassisi et al. (61)
collected DNA samples of 397 index subjects from France and analyzed the
exons and flanking intronic regions of ABCA4 (NM_000350.2) by microarray
analysis and direct Sanger sequencing. At the end of the screening, at least
two likely pathogenic mutations were found in 302 patients (76.1%) while 95
remained unsolved: 40 (10.1%) with no variants identified, 52 (13.1%) with
one heterozygous mutation, and 3 (0.7%) with at least one variant of
uncertain significance (VUS). Sixty-three novel variants were identified in
the cohort. Three of them were variants of uncertain significance. The other
60 mutations were classified as likely pathogenic or pathogenic and were
identified in 61 patients (15.4%). The majority of those were missense (55%)
followed by frameshift and nonsense variants (30%), intronic (11.7%)
variants, and in-frame deletions (3.3%). Clinical evaluation of each subject
confirms the tendency that truncating mutations lead to a more severe
phenotype than missense mutations with more severe electroretinographic
(ERG) impairment (P = 0.002) and an earlier age of onset (P = 0.037) (61).
Out of 36 STGD1 probands with one or no ABCA4 variants found, in 24
(67%), deep-intronic variants were identified (62). Five novel variants
resulted in pseudo-inclusions of messenger RNA due to strengthening of
cryptic splice sites or by disrupting a splicing silencer motif, analyzed, and
demonstrated by using in vitro splice assays in HEK293T cells and patient-
derived fibroblasts. Remarkably, antisense oligonucleotides targeting the
aberrant splice processes resulted in (partial) correction of all splicing
defects.
GENETIC TESTING FOR PATIENTS
WITH STGD1
Commercially available Stargardt genetic testing now utilizes both
microarray testing and sequence analysis of the entire coding region of the
ABCA4 gene, and more than 1,000 mutations have been identified. Many
gene testing panels include phenocopies of Stargardt such as pattern
dystrophy, cone–rod dystrophy, and genes for other types of early-onset
maculopathy.
ABCA4 is highly polymorphic, making interpretation of genetic results
complex. There are five possible types of genetic variants that may be
discovered:
One of the most characteristic primate reflexes in the visual system is the
fixation reflex at around week 6 after birth. Without the development of this
reflex, nystagmus ensues. Foveal fixation is made possible by several waves
of poorly understood events, including centrifugal migration of the retinal
inner layers (including the NFL, ganglion layer, inner plexiform, inner retinal
layer, and outer plexiform layers) and foveal avascular zone development and
cone packing. STGD1 patients develop this reflex but lose the foveal cones
early in the disease process. The foveal reflex mechanism learned in infancy
forces the STGD1 patient to continue to put the visual image on the atrophic
fovea, a deep central scotoma. Many patients slowly, automatically learn to
diverge from this learned fixation location and develop a PRL outside the
atrophic lesion. Many patients have a superior PRL, for reasons still
unknown. Some STGD1 patients need help in discovering their PRL. Low
vision specialists can assist with learning the PRL. Reinhard et al. show that
the majority (70%) of STGD1 patients, who fixated eccentrically, used a PRL
that was located above the lesion on the retina, which is below the scotoma in
the visual space (64).
Ethical Considerations
Because this is an AR disorder, parents of an affected child have a 25% risk
with each subsequent child that the child may be affected. Formal genetic
counseling detailing the risks should be offered. IVF with preimplantation
genetic testing of the embryos before implantation can be considered if there
is a molecular genetic diagnosis prior to initiation of pregnancy. Affected
patients are obligate carriers and will always pass on one mutant allele to all
of their offspring but cannot pass on the disease itself; this will only happen if
their partner is also a carrier. Because AR STGD1 is caused by only one
gene, carrier testing of partners can be accomplished and can be used to
provide accurate information to patients and their partners. It is the ethical
responsibility of physicians caring for patients with STGD1 to explain their
genetic risks and/or to refer them for in depth genetic counseling. There is
also an obligation to inform patients about the possibility of enrolling in
clinical trials. Providing patients with the address for www.clinicaltrials.gov,
and offering referral to a genetic eye disorder center, gives patients the ability
to learn more about their options www.clinicaltrials.gov does not vet clinical
trials, however, so it is wise to advise patients to discuss trials they are
considering with a knowledgeable physician.
SUMMARY
In summary, STGD1 is a major childhood and adult hereditary retinal
degeneration. The causal ABCA4 gene is involved in retinal health,
maintenance, and physiology and when mutated causes a spectrum of retinal
degenerations. The story of the description of this retinal degeneration, the
subsequent discovery of the causative gene and disease pathway, and the
progress toward treatments are representative of the strides being made for
patients with blinding retinal diseases in the molecular genetic era.
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31
Mitochondrial, Peroxisomal,
Glycosylation Disorders
Samer Khateb, Ann Saada, Patrick Yu-Wai-Man, John B. Kerrison,
and Itay Chowers
MITOCHONDRIA
Mitochondria are intracellular, dynamic organelles present in all nucleated
cells that are essential for maintaining cellular metabolism and homeostasis.
They regulate a number of metabolic processes involving steroid and heme
biosynthesis; pyruvate, urea, nucleotide, and sulfur metabolism; and fatty
acid and amino acid degradation. Mitochondria also play critical roles in
calcium homeostasis, caspase-dependent apoptosis, the cellular stress
response, and protein degradation. However, their central function is the
production of cellular energy in the form of adenosine triphosphate (ATP).
This process of oxidative phosphorylation (OXPHOS) is carried out by the
five multisubunit respiratory chain complexes that are embedded within the
mitochondrial inner membrane (IM). Complexes I to IV transfer electrons
with oxygen as the terminal electron acceptor, and the energy released is used
to establish an electrochemical proton gradient across the IM, which, in turn,
is utilized by complex V (ATP synthase) to phosphorylate ADP to ATP.
A unique feature of mitochondria is that they harbor their own genetic
code in the form or a small, circular DNA molecule (16.5 kb), which is a
legacy from the organelle’s endosymbiotic origin. The number of
mitochondria in a cell is dictated by its energetic demand, and each
mitochondrion contains several mitochondrial DNA (mtDNA) molecules,
resulting in a high copy number. As a result, there can be a combination of
both wild-type and mutant mtDNA, resulting in a situation known as
heteroplasmy. In some cases, the level of the mutant mtDNA species
correlates with the severity of the resulting clinical phenotype. The
mitochondrial genome encodes for 13 OXPHOS proteins, 2 ribosomal RNAs,
and 22 transfer RNAs involved in mitochondrial protein synthesis. The
remaining subunits (~70) are encoded by the nuclear genome, including all
components of complex II. The majority of proteins (~1,500) that constitute
the mitochondrial machinery are nuclear-encoded, and following import into
mitochondria, these mediate a host of function including mtDNA replication,
transcription, and translation. The mitochondrial genome is maternally
inherited, whereas nuclear-encoded mitochondrial genes will be inherited in a
Mendelian pattern, which can complicate molecular diagnosis and genetic
counseling (1–3).
Mitochondrial Disorders
Mitochondrial disorders are genetically and phenotypically highly variable,
with patients presenting with either isolated or multisystem organ
involvement (4). About half of all patients will manifest neuro-
ophthalmologic features, in particular involvement of the optic nerve, outer
retina, and extraocular muscles (5,6). Leber hereditary optic neuropathy
(LHON; OMIM #535000) is a classical mitochondrial optic neuropathy
caused by mtDNA point mutations. The importance of mitochondria for
normal optic nerve function is further highlighted by autosomal dominant
optic atrophy (ADOA; OMIM #165300 and #165500) caused by mutations in
nuclear genes encoding for the OPA1 and OPA3 mitochondrial proteins.
Progressive degeneration of the outer retina is seen in a number of
mitochondrial syndromes, such as (a) the Kearns-Sayre syndrome (KSS;
OMIM #530000) (7–9) in combination with chronic progressive external
ophthalmoplegia (CPEO; OMIM #258450, #609286) (10–13); (b)
mitochondrial myopathies without external ophthalmoplegia (14,15); (c) the
neuropathy, ataxia, and retinitis pigmentosa (NARP; OMIM #551500)
syndrome (16–18); and (d) Leigh syndrome marked by involvement of the
basal ganglia and brainstem (19,20). The retinopathy seen in patients with
mitochondrial disease can be generalized with primary involvement of the
peripheral retina or localized to the macula. On fundus examination, the
pigmentary disturbance can resemble the typical bone spicule appearance
seen in retinitis pigmentosa with choriocapillaris atrophy, or it can be more
variable with areas of retinal hyperpigmentation and/or hypopigmentation
(14,21–23).
LEBER HEREDITARY OPTIC
NEUROPATHY
Prevalence and Worldwide Impact
LHON is the most common primary mtDNA disorder in the general
population with an estimated prevalence of 1 in 25,000 to 1 in 40,000 in
northern Europe (21,24). This phenotype was noted initially by Albrecht von
Graefe (1858) (25) and then characterized further by Theodor Leber (1840–
1917) as a familial neuro-ophthalmologic disease (26).
Pathophysiology
Central to the pathophysiology of LHON is OXPHOS dysfunction with
impaired assembly and functioning of complex I of the mitochondrial
respiratory chain (44). Studies performed on various tissues from patients
with LHON, including lymphocytes, platelets, fibroblasts, and muscle
biopsies, have confirmed reduced complex I–driven mitochondrial respiration
with reduced ATP production, increased levels of reactive oxygen species
(ROS), and glutamate excitotoxicity (5,30,34,45,46). The generation of
retinal ganglion cells (RGCs) from induced pluripotent stem cells and the
development of more faithful animal models, which have proven challenging,
will provide further insight into the complex pathophysiology of LHON (47).
Systemic Manifestations
The majority of patients with LHON will develop isolated optic atrophy due
to the preferential susceptibility of RGCs within the inner retina. However,
extraocular neuromuscular features have been reported in a small subgroup of
patients with LHON, including cerebellar ataxia, movement disorders,
myopathy, and peripheral neuropathy (59,60). Dystonia and myoclonus are
two movement disorders that have been consistently associated with the three
primary mtDNA LHON mutations (61). Another well-characterized
syndromic association is the development of a multiple sclerosis (MS)-like
illness in patients with LHON. This LHON-MS overlap syndrome, or
Harding disease, was first reported in women carrying the m.11778G>A
mtDNA mutation, but it was subsequently described with the m.3460G>A
and m.14484T>C mtDNA mutations as well (62). Patients with the LHON-
MS overlap syndrome have a better visual prognosis compared with classical
LHON, but they usually have recurrent episodes of vision loss that can be
accompanied with ocular pain similar to demyelinating optic neuritis (63). It
should be stressed that establishing a true causal association has not always
been possible in so-called LHON-plus phenotypes, for example, the link
between LHON and an increased risk of cardiac arrhythmias is still uncertain
(57,61,64).
Diagnostic Studies
The differential diagnosis includes demyelinating, ischemic, compressive,
infiltrative, infectious, and neoplastic causes of a bilateral optic neuropathy.
A definitive diagnosis is made upon the identification of a pathogenic
mtDNA mutation known to cause LHON with molecular genetic testing.
Brain MRI, VEPs, flicker fusion, color vision testing, and visual field testing
in addition to visual acuity and intraocular pressure measurement should be
part of the workup of patients with optic atrophy. A careful personal and
family history, as well as nutritional history, is warranted.
Management
No established treatments are available at the present time to prevent vision
loss, arrest the progression of vision loss, or restore vision. However,
significant progress was made in recent years toward the development of
targeted treatments for LHON. Ubiquinone (CoQ10) is an electron essential
carrier within the inner mitochondrial membrane ensuring efficient transfer of
electrons along the mitochondrial respiratory chain from complexes I and II
to complex III. Idebenone is a short-chain ubiquinone analogue that crosses
the blood–brain barrier, and its safety and efficacy were investigated as part
of a randomized controlled trial (RHODOS) that recruited 85 patients
carrying the m.3460G>A, m.11778G>A, and m.14484T>C mtDNA
mutations (65). Although RHODOS failed its primary outcome measure, a
subgroup of treated patients was found to benefit, and this observation was
confirmed in a larger retrospective case series of 103 patients treated with
variable doses of idebenone (66). An expert panel has recommended that
idebenone should be started as soon as possible (at a dose of 300 mg three
times per day) for patients with LHON with visual loss of <1 year (67). This
regimen should be continued for at least 1 year to determine whether there is
a treatment effect, and if a clinically relevant response is observed, the
treatment should be continued for 1 year after the plateau phase has been
reached. The expert panel concluded that there was not enough evidence to
recommend treatment for chronic LHON cases. An open-label clinical trial
on five patients with LHON suggested that EPI-743, an orally absorbed small
molecule, which targets the enzyme NADPH quinone oxidoreductase 1, may
be beneficial in arresting visual loss in LHON (68,69). Another potential
future treatment technique for LHON is gene therapy. A gene-replacement
strategy based on allotopic expression has been described to correct the
defect in complex I function in cells harboring the m.11778G>A mutation
(70). The in vivo feasibility, efficacy, and safety of such a technique are
currently being evaluated in a number of clinical trials (39,71).
Pathophysiology
The OPA1 protein is most highly expressed in the retina but is also expressed
in the brain and muscle. It associates with mitochondrial IM phospholipids
such as cardiolipin and plays a pivotal role in the maintenance of
mitochondrial morphology. Specifically, OPA1 protein is involved in
mitochondrial fusion and the maintenance and modulation of the
mitochondrial cristae allowing adaptation to metabolic demands. OPA1 is
important for preserving the mitochondrial membrane structure and integrity
(79) and is also involved in mtDNA maintenance. Loss of OPA1 will,
therefore, lead to decreased mtDNA stability and decreased ATP production
leading to cell damage and apoptosis.
Studies suggest that patients with ADOA are born with fewer optic nerve
axons and smaller optic discs, supporting the hypothesis that subsequent
vision loss depends on further age-related loss of fibers, which also occurs in
control subjects. It may also suggest OPA1 involvement in eye development
(80). Interestingly, some mutations in DNML1, a protein involved in
mitochondrial fission (i.e., opposite function of OPA1), also result in ADOA
(81).
The pathologic mechanism of OPA3 mutations associated with the
autosomal recessive and dominant (less common) forms of 3-
methylglutaconic aciduria type III (Costeff syndrome) seems to be similar to
that of OPA1 mutations, as mutant OPA3 mice also showed disrupted
mitochondrial morphology in the retina confirming the importance of the
mitochondrial network in retinal function (74,82–84). Notably, other diseases
linked to abnormal mitochondrial morphology involving mitochondrial
membrane and mitochondria-associated ER membranes (MAMs), such as
Charcot-Marie-Tooth type 2A (MFN2), hereditary motor and sensory
neuropathy type VI (DST), hereditary spastic paraplegia (SPG7), and
Wolfram syndromes (WFS1 and CIDS2), also exhibit ocular manifestations
(5,85–88).
Systemic Manifestations
ADOA is characterized by the preferential loss of RGCs. However, OPA1 is
expressed also in the inner ear, and the most frequent extraocular
manifestations of OPA1 mutations are sensorineural deafness present in about
two-thirds of the cases (ADOAD). Additionally, up to 20% of patients with
OPA1 mutations will develop a more severe disease variant (ADOA “plus”)
with additional neuromuscular features including ataxia, myopathy,
peripheral neuropathy, CPEO, or MS-like disorders. Muscle pathology
resembles classical mitochondrial diseases with cytochrome c oxidase–
deficient fibers and ragged red fibers. Patients also harbor mtDNA deletions
in the affected muscle tissue. Notably, individuals with mutations that affect
the OPA1 GTPase domain are more likely to develop multisystem neurologic
disease (24,73,92,94). A recent study showed that classic ADOA patients
were more likely to harbor mutations in exons 8 and 9 and were more
commonly maternally inherited while ADOA-plus patients had mutations in
exons 14, 15, and 17 with being mostly paternally inherited (79).
Diagnostic Studies
The differential diagnosis includes all common causes of optic neuropathy:
LHON and other inherited optic neuropathies such as Leigh syndrome,
Wolfram syndrome, compressive, inflammatory, ischemic, and toxic; these
may be differentiated from ADOA by clinical examination; systemic
manifestations; family history; specialized testing, such as VEP; and, most
importantly, molecular genetic testing.
Management
Current management includes genetic counseling. A small retrospective case
series has explored the use of idebenone in patients with DOA carrying
confirmed pathogenic OPA1 mutations. The evidence presented is limited,
and a larger study is needed to define the therapeutic role of idebenone in this
group of patients (95). Future treatment may include better targeted oral
neuroprotective strategies and gene therapy (96).
Systemic Manifestations
Neurologic manifestations in KSS may include cerebellar ataxia, hearing
loss, dementia, and weakness of facial, pharyngeal, trunk, and extremity
muscles. Heart block is a characteristic finding (7,112,113). POLG mutations
have an overlapping spectrum of symptoms involving the nervous system as
well as liver and muscle. One of the most severe manifestations is fatal
hepatic failure, the Alpers-Huttenlocher syndrome, which is caused by over
50 different POLG mutations. Other mtDNA deletion syndromes may also
present with extraocular manifestations including hearing loss, muscle
weakness, and neuropathy (103) or juvenile-onset sensory-ataxia neuropathy,
dysarthria, and ophthalmoplegia (SANDO), combination of spinocerebellar
ataxia and epilepsy (SCAE) with or without external ophthalmoplegia, and
mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) caused by
TYMP mutations is characterized by prominent gastrointestinal symptoms
(11,102,114). Diabetes mellitus may be present in Pearson syndrome.
Diagnostic Studies
KSS is suspected when the typical ocular, neurologic, and cardiac
manifestations occur. Ancillary tests include blood and spinal fluid lactic acid
levels and spinal tap for increased protein level (>1 g/L; the underlying cause
of which is still unknown). Electrocardiography is useful to detect and
evaluate the severity of the heart block, and genetic testing can establish the
diagnosis in cases of doubt. Muscle biopsy can demonstrate characteristic
ragged red fibers, electron microscopy may show large numbers of abnormal
mitochondria, and enzymatic assays show decreased activities of complexes
I, III, and IV with intact II. In some KSS, patient’s serum creatine kinase,
gamma globulin, and pyruvate may be elevated in the blood. The
identification of a disease-causing mutation confirms the diagnosis and
facilitates genetic counseling. CT scan may identify calcium accumulation in
specific areas of the brain.
Management
As there is no cure, management is symptomatic and supportive. Careful
correction of ptosis or strabismus may be beneficial in selected cases. The
cardiac conduction defect may be life threatening and is treated with a
pacemaker and antiarrhythmic drug therapy. Hormonal replacement therapy
is administered for endocrinopathies, and cochlear implants can be used for
patients with sensorineural hearing loss. CoQ10 (ubiquinone) is used in KSS
patients as a mitochondrial antioxidant.
Tetracycline treatment has been evaluated in CPEO; however, the results
did not formally support its effectiveness (115). At present, only
mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) has been
successfully treated by allogeneic hematopoietic stem cell transplantation
(116). Genetic therapies are being developed for KSS (117). Heteroplasmy
shifts through selective degradation of mutant DNA is a promising emerging
technology using heterodimeric mitochondrially targeted zinc finger
nucleases (mtZFNs) (118).
Chowers et al. (16) described three members from a family harboring the
8993 mtDNA mutation in whom great variability in the clinical
manifestations of the disease was observed. Two of the three patients had
ocular abnormalities that were different from classic RP. The clinical
findings, visual fields, and ERG were typical of cone–rod dystrophy in one of
the patients and progressive cone dystrophy in another patient. Other retinal
findings in NARP include a bull’s-eye maculopathy and rod–cone type of
retinal dystrophy (14).
As discussed, there is great variability in the ocular and systemic
manifestations among patients carrying the mtDNA 8993 mutation. Several
factors could account for the spectrum of abnormalities observed. First, the
burden of mutant mtDNA in a particular tissue may vary thus influencing
phenotype, with a higher proportion of mutant mtDNA in blood lymphocytes
being a marker for more severe clinical manifestations. However, Chowers et
al. (16) observed that patients with a lower percentage of mutant mtDNA in
the blood lymphocytes can have a more severe ocular disease compared with
patients with higher proportion of mutant mtDNA. This can be partially
explained if the proportion of mutant mtDNA in the retinas differs from that
in the blood or other tissues, especially the central nervous system (CNS), but
such differences have not yet been demonstrated (119). Differences among
patients may also depend on age. Ortiz et al. (21) described two patients,
aged 12 and 14 years, who suffered from NARP syndrome and had a rod–
cone type of ERG dysfunction. The retinopathy of these patients was much
less advanced than that of patients reported by Chowers et al. who were of a
similar age but with a predominantly cone dysfunction. Thus, patients with
the NARP syndrome may manifest either rod- or cone-dominant retinal
dystrophy at a similar age. It is likely that other factors, not yet understood,
modulate the phenotypic expression of the 8993 mtDNA mutation. In support
of this, two of the three reported NARP pedigrees undergoing ERG had
predominantly cone dysfunction, while the third pedigree had predominantly
rod dysfunction. This finding could not be explained by the differences in
age, stages of the disease, or percentage of mutant mtDNA among families.
Diagnostic Studies
Diagnosis is based on identification of the typical combination of ocular and
systemic manifestations along with the mitochondrial inheritance pattern.
Ancillary tests may include ERG, color vision, and fluorescein angiography.
Lactate levels are constantly elevated in spinal tap and sometimes also in
blood tests. Brain imaging shows certain topology of the brainstem and basal
ganglia lesions, often in association with leukodystrophy and cerebral
atrophy. Definitive diagnosis is made by genetic workup.
Management
No treatment has been shown to be of benefit in arresting the progression of
retinal dystrophy in patients carrying the mtDNA 8993 mutation. In addition,
patients should be referred to a clinical geneticist for evaluation of medical
and family history because although the 8993 mutation is transmitted from
mother to each of her offspring, the proportion of mutant mtDNA in each
offspring can differ considerably from that of the mother and with it the
clinical manifestations. New therapeutic approaches include sodium pyruvate
to improve the redox state and increase ATP production via glycolysis (130).
A single-arm clinical trial using EPI-743, a derivative of coenzyme Q10,
included 10 consecutive children aged 1 to 13 years, reversed the progression
of the diseases (69,131). Idebenone or gene therapy may be beneficial for
NARP and Leigh syndrome patients (132,133).
MITOCHONDRIAL
ENCEPHALOPATHY, LACTIC
ACIDOSIS, AND STROKE-LIKE
EPISODE (MELAS) SYNDROME
While vision loss in mitochondrial genetic disorders more commonly occurs
from retinal degeneration or optic nerve disease, it can occur also from
damage to the retrochiasmal visual pathways as in MELAS (134,135), a
condition that is mostly caused by a mutation at mtDNA nucleotide position
3243 in the leucine tRNA gene. Other features included diabetes mellitus and
deafness. Of note, the m.3243A>G mutation may also be associated with a
pigmentary retinopathy or optic neuropathy as well as CPEO (136). Other
mitochondrial diseases, caused by mitochondrial and nuclear mutations,
frequently present with lactic acidosis and encephalomyopathy. These
include isolated complex I deficiency and mutations in c12of65 (137), and
the majority of these patients also manifest visual impairment (138). A
retrospective study of patients with molecularly defined mitochondrial
disease detected that nearly half of them had some form of visual impairment
(3).
Diagnostic Studies
The diagnosis is based on clinical findings and molecular analysis, which is
often preceded by enzymatic analysis of muscle biopsy, especially in the
cases of disorders caused by mutations in nuclear genes.
Management
Although no treatment is established, novel therapies such as oral L-arginine
(149), succinate (150), EPI-743 (69), and idebenone (151) or gene therapies
are being investigated in several clinical trials and may be beneficial for
MELAS. Similar to other mitochondrial diseases, MELAS patients should
avoid mitochondrial toxins such as smoking, aminoglycoside antibiotics,
dichloroacetate, linezolid, and alcohol. Valproic acid should be also avoided
in the treatment of seizures.
THE PEROXISOMES
Peroxisomes are single membrane–enclosed cytoplasmic organelles derived
from the endoplasmic reticulum. There are several hundred peroxisomes per
cell, but unlike mitochondria, they do not contain DNA even though they
replicate by division. Numerous catabolic and anabolic processes take place
within the peroxisomes and involve more than 50 enzymes. Major functions
of the peroxisomes are beta-oxidation of very long (>C22) fatty acids
(VLCFA) and alpha-oxidation of 3-methyl–branched fatty acids such as
phytanic acid. Peroxisomes also perform biosynthetic functions and are
involved in the synthesis of plasmalogens and docosahexaenoic acid (DHA),
which are critical for cellular membrane function and bile acids. They are
also involved in detoxification of glyoxylate and in D-amino acid and pipe
colic acid oxidation. Some of abovementioned reactions generate hydrogen
peroxide (hence the name peroxisome), which is used for oxidation of
additional molecules or detoxified by conversion to water and oxygen by the
enzyme catalase.
Proteins required for peroxisome assembly are targeted to the peroxisome
by either carboxy (peroxisome targeting signal 1 or PTS1) or amino (PTS2)
terminus targeting signals. Specific translocation complexes then mediate
their transport into the peroxisome. Sixteen proteins that control peroxisome
assembly, division, and inheritance, which are encoded by PEX genes, are
named peroxins, and they are essential for normal development (152–154).
Peroxisomes are not isolated entities but interact with most organelles mainly
mitochondria and endoplasmic reticulum; and peroxisomal proteins are
sometimes even shared with other cellular compartments.
Peroxisomal Disorders
Peroxisomal disorders are a group of rare diseases presenting with
overlapping clinical manifestations and affecting multiple tissues including
the eye. They are mostly detected by measuring saturated very long-chain
fatty acids (VLCFA), phytanic and pristanic acids in plasma, and decreased
erythrocyte plasmalogens; however, since many genes are involved, the final
diagnosis is molecular.
Peroxisomal diseases are usually classified into two main categories:
peroxisome biogenesis disorders (PBD) and single enzyme/transporter (PED)
defects. Several PBDs commonly affect the retina: Zellweger syndrome (ZS;
OMIM #214100), the most severe form, and the intermediate and milder
forms, previously termed neonatal adrenoleukodystrophy (NALD), and
infantile Refsum disease (IRD) are parts of the Zellweger spectrum disorders
(ZSDs). ZSDs are associated with mutations in a large number of different
PEX genes. At the cellular level, defects causing ZSD lead to decreased
numbers of enlarged but dysfunctional peroxisomes, called “ghosts.” A
distinct PDB is rhizomelic chondrodysplasia punctata type I (RCDP type I;
OMIM #215100), which is mainly associated with cataract and mutated
PEX7 (155).
The second group of peroxisomal disorders comprises those for which the
function of the peroxisome is abnormal, but its assembly is not affected. This
group includes entities such as X-linked adrenoleukodystrophy (OMIM
#300100), primary hyperoxaluria type 1 (PHT1) (OMIM #259900), classical
Refsum disease (OMIM #266500), and RCDP types II and III. X-linked
adrenoleukodystrophy is associated with mutations in the ABCD1 gene,
resulting in a defect in peroxisomal beta-oxidation. This leads to the
accumulation of VLCFA in all tissues of the body, with clinical
manifestations that are primarily related to the adrenal cortex, CNS myelin
(including visual disturbance), and Leydig cell dysfunction (154,156). In
recent years, a number of newly identified peroxisomal disorders have been
described caused by mutations in genes coding for peroxisomal proteins,
exemplified by HAO1, PMP70, ACBD5, and ACOX2 (154).
PEROXISOMAL BIOGENESIS
DISORDERS AFFECTING THE RETINA
Environmental Factors and Genetics
More than 20 genes related to peroxisome biogenesis have been identified.
PBDs have been associated with mutations in 14 of these genes (PEX1,
PEX2, PEX3, PEX5, PEX6, PEX7, PEX10, PEX11b, PEX12, PEX13, PEX14,
PEX16, PEX19, PEX26). Frequently, mutations in the same peroxin gene can
lead to any of the PBD phenotypes, although defects in some peroxins are
only associated with the more severe ZS phenotype (163). In general, disease
severity correlates with the patient age at onset of symptoms and the
predicted consequence on peroxin function, capacity for matrix protein
import, residual enzyme functions, and peroxisome numbers. The most
severe form of ZS presents at birth with a classic malformation syndrome
described by its characteristic features as cerebro-hepato-renal syndrome
including severe hypotonia, seizures, and characteristic craniofacial
dysmorphisms. Eye disease includes cataracts, congenital glaucoma, retinal
dystrophy, and optic atrophy (153).
The generation of mouse models for PBD has provided interesting
insights into the pathogenesis of these diseases. Disruption of PEX2, PEX5,
and PEX11b in mouse models can frequently result in findings similar to
PBD in humans, including neuronal migration defects, hypotonia,
developmental delay, and neonatal lethality. However, in mice with PEX11b
disruption, there is no detectable defect in peroxisomal protein import, and
only mild defects in peroxisomal fatty acid beta-oxidation and peroxisomal
ether lipid biosynthesis are present (164). These findings are intriguing in that
features of the PBD phenotype that are present in these PEX11b-deficient
mice, but they do not have the biochemical and cellular abnormalities usually
associated with PEX mutations, as they have apparently an intact peroxisomal
biogenesis. A more recent mouse recapitulating mild human ZSD (PEX1-
G843D knockin) developed a retinopathy similar to that observed in human
patients, with evidence of cone photoreceptor cell death, and will be useful
for evaluating therapies (165).
Systemic Manifestations
ZS (cerebro-hepato-renal) presents in the neonatal period, but other ZSDs can
manifest any time from infancy and during the first decade of life. All PBDs
are associated with a variety of systemic abnormalities, additionally to the
ocular manifestations. Death in ZS occurs within a few months of birth, while
milder ZSDs survive for longer periods.
ZS patients present with skeletal and dysmorphic features including
talipes equinovarus, limb contractures, high forehead, epicanthal folds,
hypoplastic supraorbital ridge, micrognathia, high-arched palate, and
hypertelorism. Dysmorphism can be intermediate or mild or even absent in
other ZSDs. Less affected patients have adrenal and cortical atrophy but do
not develop adrenal insufficiency as ZS. Neurologic manifestations include
seizures, psychomotor retardation, hypotonia, cerebellar ataxia, and reduced
hearing. Additional abnormalities include hepatomegaly, jaundice, congenital
heart defects, leukodystrophy, osteopenia, and peripheral neuropathy
(163,168). Generally, clinical features vary with age of onset (153).
Diagnostic Studies
The differential diagnosis includes a long list of other inborn errors of
metabolism sharing the systemic manifestations such as Prader-Willi
syndrome, spinal muscular atrophy, congenital myotonic dystrophy type 1,
and other congenital myopathies. ZSDs may be confused with other causes of
sensorineural hearing loss and decreased vision in infancy including Usher
syndromes 1 and 2, Cockayne syndrome, Leber congenital amaurosis, and
neuronal ceroid lipofuscinosis.
The diagnosis is based on identifying the combination of typical systemic
and ocular manifestations mentioned previously together with genetic
workup. Ancillary tests may include an ERG test, which is severely reduced
or extinguished in all three diseases. Plasma VLCFA, pipecolic acid, bile
acid, and phytanic and pristanic acids are typically increased, whereas the
plasmalogen level in red blood cells is reduced. Of note, phytanic and
pristanic acids are diet dependent and could remain normal in young infants.
Genetic testing and identification of the characteristic mutations can establish
the diagnosis.
Management
Management is mainly supportive such as feeding and nutrition, hearing aids,
cataract removal, antiepileptic drugs, and cholic acid–replacement therapy.
Recently, allogeneic hematopoietic cell transplantation (HCT) has been
shown to provide long-term disease stabilization and survival (5-year
survival: 55% for untreated and 78% for treated). The success rate is largely
dependent on the pre-HCT neurologic status and the age it is given (169,170).
Gene therapy was already tested on two NALD patients, who showed
cerebral demyelination arrest (171). Large-scale screening has identified
small molecules, which may rescue peroxisome function in ZSDs. The in
vivo effect of such compounds is still unknown (172). Additional substances
that stimulate peroxisomal biogenesis are being investigated currently
(173,174).
Systemic Manifestations
Refsum disease usually manifests between the first and third decades.
Multiple systems are involved. Neurologic manifestations include peripheral
polyneuropathy and cerebellar signs such as ataxia, anosmia, and decreased
hearing. Additional manifestations are cardiac arrhythmia (that can be life
threatening), skeletal malformations (mostly epiphyseal dysplasia), and
ichthyosis-like skin changes (177,179,180,184,187).
Diagnostic Studies
The diagnosis is based on typical clinical findings. Ancillary tests may
include kinetic perimetry, which is useful in documenting visual field loss
and in following its progression, and ERG, which shows decreased photopic
and scotopic responses. Skeletal radiography and brain MRI may be helpful
in demonstrating structural abnormalities. Blood levels of phytanic acid are
typically elevated (>10 to 50 mg/dL), and low-density lipoprotein (LDL) and
high-density lipoprotein (HDL) cholesterol levels are decreased and increased
protein concentration in cerebrospinal fluid (CSF) (156,161,188). Mutation
detection confirms the final diagnosis.
Management
Refsum disease is a rare case of an RP-like disease that is amenable to
treatment. As phytanic acid cannot be synthesized in humans, its
accumulation in Refsum disease patients depends on exogenous intake.
Accordingly, a diet free of foods containing phytol, phytanic acid, or their
precursors leads to reduced phytanic acid levels in the blood and to clinical
improvement. Plasmapheresis to remove phytanic acid can be an alternative
effective approach to diet in preventing the clinical manifestations of Refsum
disease and in severe or rapidly worsening cases (189–191). It is thus
imperative that Refsum disease diagnosis be made as early as possible (192).
Novel potential treatments include CYP4, which was shown to be effective in
eliminating phytanic acid (193).
Management
Decreasing oxalate load in the body is one approach, although kidney
transplantation is associated with a high recurrence rate. Pyridoxine is useful
in 10% to 30% of cases to decrease the body’s production of oxalate. Liver
transplantation, when successful, is a definitive treatment for this disease
(201,209).
CONGENITAL DISORDERS OF
GLYCOSYLATION (CDG)
Environmental Factors, Genetics, and Pathophysiology
Over half of all intracellular proteins are posttranslationally glycosylated
(glycans) either by N-glycosylation of asparagine or O-glycosylated to serine
or threonine. The synthesis of N-glycans is complex and involves three
compartments, cytosol, endoplasmic reticulum, and Golgi apparatus, while
O-glycosylation mainly occurs in the Golgi. A CDG is a rapidly expanding
group of inherited disorders with abnormal glycan metabolism leading to
impaired glycosylation of proteins and lipids. The nomenclature has varied,
but currently there are four different biochemical groups involving defects in
protein N-linked glycosylation, protein O-linked glycosylation, glycolipid,
and GPI anchor glycosylation and a group with defects in multiple
glycosylation pathways. The first described and most frequent CDG, which
was reported in 1984 by Jaeken et al. (210), is phosphomannose mutase
deficiency PMM2-CDG (previously CDG1a) affecting protein N-
glycosylation. Since then, over 130 human genetic disorders have been
associated with abnormal glycosylation, and the number is still increasing
(211).
Systemic Manifestations
The systemic manifestations of the different CDGs are extremely variable
depending on the specific gene and mutation involved. PMM2-CDG patients
typically present with dysmorphic facial features, strabismus, inverted
nipples, abnormal fat distribution, endocrine abnormalities, and coagulation
defects; and MPI-CDG (formerly CDG1b) patients present with liver disease,
coagulopathy, hyperinsulinemic hypoglycemia, and gastrointestinal
symptoms (protein-losing enteropathy). Other glycosylation diseases are
much more difficult to classify by phenotype. Presentations include a
pleiotropy of symptoms including neurologic deficits, facial dysmorphism,
skeletal dysplasia, muscular dystrophy, joint and skin laxity, congenital
malformations, and developmental delay as recently reviewed by Ferreira et
al. (211,223).
Diagnostic Studies
As the clinical manifestations of CDGs are so varied, they frequently overlap
with other neurologic and mitochondrial disorders (211,223), and with a few
exceptions, biochemical and molecular workup is imperative to reach a
diagnosis. Many CDGs are linked to deficient sialylation of serum
transferrin, and thus, transferrin isoelectric focusing (TIEF) or transferrin
capillary electrophoresis is widely used to screen for N-glycosylation CDGs.
Notably abnormal transferrin pattern can also be secondary to alcoholism,
liver disease, galactosemia, and fructosemia. Advancements in diagnostic
techniques performed in specialized laboratories now include the analysis of
whole serum N-glycans by MALDI-TOF mass spectrometry and transferrin
analysis by high-resolution QTOF mass spectrometry. O-glycans are
analyzed by isoelectric focusing and by mass spectrometry analysis of apoC-
III (224). As many genes are involved in CDG, whole exome and genome
analysis might be performed in parallel or even prior to biochemical
techniques to obtain a final diagnosis.
Management
To date, management of CDGs is largely symptomatic. Only a few specific
CDGs benefit from oral supplementation in the form of mannose (MPI-CDG)
or galactose (PGM1-CDG, TMEM165-CDG), and correct diagnosis is
imperative before starting treatment. Thus, novel treatment strategies are
urgently needed (211).
VISION REHABILITATION
Optic atrophy from any cause may result in central scotomas that decrease
acuity and prevent good vision for reading and other important functions.
Patients should be referred to a low-vision specialist for evaluation and
rehabilitation. See Chapter 14 for a full discussion of vision rehabilitation.
ETHICAL CONSIDERATIONS
Mitochondrial disorders are inherited through the maternal lineage, and some
have more severe expression in males than females. A detailed discussion
about recurrence risks for the patient and other family members is essential.
This may ideally be accomplished through referral to a medical geneticist or
genetic counselor.
FUTURE TREATMENTS
Human gene therapy trials are underway for one mitochondrial disorder
causing blindness, LHON. In the future, there will likely be more. Patients
should be offered a molecular genetic diagnosis in order to be able to take
advantage of advances in treatment. Patients can be referred to
www.clinicaltrials.gov for information on clinical trials. At this writing,
www.clinicaltrials.gov is only lightly curated, so the validity and
appropriateness of a trial for each patient must be discussed with a physician
knowledgeable in the field.
SUMMARY
Mitochondrial, peroxisomal, and glycosylation disorders have been the
subject of intense research in recent years. Multiple genes associated with
these disorders have been identified, and significant insight into the genetics
has been gained, especially due to the significant progress in high-throughput
sequencing techniques, including whole genome and exome sequencing,
leading to new classifications and to development of diagnostic genetic tests
for many of these disorders. On the other hand, the pathogenesis of the
diseases described in this chapter is still unclear in many instances despite the
discovery of the causative gene. The variable disease course in patients with
the same mutations suggests that additional yet unrecognized modifying
factors playing an important role in these disorders. Of note, the significant
advancement in ophthalmology imaging techniques contributes largely to the
precise phenotyping of these similar diseases in terms of the ocular findings
leading to novel subclassifications and better diagnosis, follow-up, and
prognostic prediction.
Furthermore, the complex and unique inheritance mode of mitochondrial
disorders, heteroplasmy in particular, hampers the potential for prenatal
diagnosis in many instances. For example, although all offspring of a mother
carrying the NARP-causing mtDNA 8993 point mutation will also carry the
same defect, the phenotype may vary considerably between offspring; some
may be asymptomatic, and others may be severely affected. In this instance,
determining the fraction of mtDNA with the mutation by prenatal diagnostic
testing will not necessarily reliably reflect the fraction in the target tissue for
this disorder such as the retina and brain. Thus, basing decisions regarding
pregnancy on such diagnostic tests raises complex ethical and moral issues.
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32
Bardet-Biedl Syndrome
Seongjin Seo, and Arlene V. Drack
BARDET-BIEDL SYNDROME
Prevalence
How many genes in the human body, when mutated, can cause the specific
constellation of extra fingers and toes, retinitis pigmentosa (RP), obesity,
renal and gonadal dysfunction, and developmental/behavioral issues?
Surprisingly, the number is 21 and counting for the autosomal recessive
disorder known as Bardet-Biedl syndrome (BBS), a ciliopathy that is
teaching us much about this class of disease and the roles of cilia in health
and disease (1). BBS is diagnosed clinically when a patient has four primary
features or three primary and two secondary features from a list of
characteristics originally described by Beales et al. in 1999 (2) and updated
by Forsythe and Beales in 2013 (3).
Primary and secondary features include the following.
Primary
Cone–rod dystrophy
Polydactyly (typically postaxial)
Truncal obesity
Learning difficulties
Genital anomalies
Renal anomalies
Secondary
Speech delay
Developmental delay
Diabetes mellitus
Dental anomalies
Congenital heart disease
Brachydactyly/syndactyly
Ataxia/poor coordination
Anosmia/hyposmia
Environmental Factors
There are no known environmental factors impacting the development of
BBS, other than consanguinity. Obesity is a feature of BBS and may be
amenable to environmental intervention in the form of reduced calorie diets;
however, management is difficult, especially in young children. Experimental
evidence suggests that the obesity seen in BBS is due to resistance to leptin, a
hormone that signals satiety to the brain (7,8).
Genetics
Between the World Wars, Georges Bardet (in Paris) and Albert Biedl (at the
German University of Prague) each described patients with features that
would become cardinal phenotypes of BBS (9–12) and postulated on the
familial nature of these features. Subsequent reports of small families showed
that BBS is inherited as an autosomal recessive disorder.
The identification of the genes that cause rare autosomal recessive
diseases is difficult in outbred populations, in which mating between
unrelated individuals leads to increased genetic variation. Inbred populations
that are genetically isolated were proposed to be especially useful for
identifying rare disease-causing genes that act through an autosomal
recessive pattern of inheritance, since the frequency of homozygous
mutations is so much higher (about 6.25% of the alleles in the offspring of
first cousins are homozygous). Studying inbred populations has been fruitful
in mapping and discovering the genes responsible for BBS. The Bedouin-
Arab population of the Negev region of Israel shows a high degree of
traditional consanguineous marriages, in addition to generally having
relatively large families (which increases the likelihood of identifying
multiple affected members in a generation when on average only one in four
offspring is affected).
Linkage analysis initially mapped BBS in one Bedouin kindred to
chromosome 16 (13). The unusual set of features and rarity of the disease
might suggest that BBS is likely due to the action of one mutation, or
mutations in one gene. However, subsequent screening to determine if this
region of the genome segregated with BBS in a second Bedouin population
showed that BBS exhibits locus heterogeneity (13). Later studies that
identified loci and genes responsible for BBS revealed that disruption of any
of several genes can lead to essentially the same phenotypes (14).
As of the date of this writing, Online Mendelian Inheritance in Man
reports 21 BBS genes (http://www.omim.org/entry/209900) (Table 32-1).
With some exceptions, these genes did not initially show obvious homology
to genes with known functions. The mechanism(s) by which homozygous or
compound heterozygous mutations in any of these disparate genes results in
the same clinical findings was elusive for several years, but then biochemical
data provided a compelling explanation: the protein products of many of
these genes interact in multiprotein complexes and are intimately related in
function (see next section of this chapter and Figure 32-1).
TABLE 32-1 Genes associated with Bardet-Biedl
syndrome
Like most genetic disorders, BBS has been reported as having variable
expressivity, which is notable in the retinal pathology as well as other
features of the disease. About 90% of patients exhibit retinal degeneration
with lower percentages of patients having the other manifestations (1,3). BBS
has been suggested to show triallelic inheritance, a condition in which two
mutations in one gene are not sufficient to cause disease but require an
additional mutation at a second locus (15). It is undoubtedly the case that
genetic background influences the phenotype(s) associated with BBS, and
variations in other BBS genes are good candidates for these influences
especially given what is now known about the interactions of BBS proteins
(described below). Generalizations about a disorder caused by multiple
genes, including many that probably remain to be discovered, are precarious;
the majority of familial BBS behaves as an autosomal recessive disorder
(16–18). It is estimated that up to 10% of BBS families harbor mutations in
more than one BBS gene, but the role this plays in disease is still uncertain
(4). In mouse models of BBS, mutations in two alleles at one BBS locus are
sufficient to cause BBS phenotypes (19–22); however, heterozygous
mutations of CEP290 have been shown to modify the phenotype (23,24).
Digenic inheritance has not been reported. Webb et al. screened BBS
patients in Newfoundland for known BBS mutations and found three
members of a large BBS1 family who carried one BBS1 mutation in addition
to a BBS3 mutation that would be predicted to cause disease if homozygous
(25). None of these individuals exhibited any features of BBS, which argues
against digenic inheritance, at least for these two genes. These same authors
also noted no increase in incidence of renal disease in heterozygous carriers
of a disease-causing mutation (25). Fan et al. found that a heterozygous
mutation in BBS3 modified the phenotype in homozygous M390R BBS1
(26).
BBS has been conflated with Lawrence-Moon syndrome (LMS) (OMIM
# 245800); however, the latter condition has not been consistently shown to
exhibit polydactyly or obesity, cardinal features of BBS, and the relationship
between these syndromes is not entirely clear. One study found that two
patients who clinically fit the phenotype of LMS both had mutations in
known BBS genes (BBS2 and BBS6) (6). It seems probable that BBS and
LMS are different manifestations of overlapping phenotypes caused by the
interactions of related genes.
At this writing, there are 21 genes reported to cause classic BBS or a
BBS-like syndrome: BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8,
BBS9, BBS10, TRIM32, BBS12, MKS1, CEP290, WDPCP, SDCCAG8,
LZTFL1, BBIP1, IFT27, IFT74, and C8ORF37 (Table 32-1). There are likely
to be more discovered. In turn, this will broaden the clinical diagnosis of BBS
as more patients with partial forms are discovered to harbor mutations in
known BBS genes. The nomenclature of ophthalmology, and all of medicine,
is changing to reflect the new level of knowledge that comes from molecular
diagnoses.
Pathophysiology
Studies during the past two decades have uncovered that BBS gene products
localize to primary cilia, and loss of BBS gene functions causes ciliary
dysfunction in multiple tissues (27,28) (and references therein). Primary cilia
are small sensory organelles that protrude from the cell surface and receive
signals from the surrounding environment (29) (and references therein). As
sensory organelles, primary cilia harbor various signaling molecules
including receptors and maintain a unique protein composition compared to
the rest of the cell body. Certain molecules enter and exit cilia upon
activation or inactivation of signaling pathways. BBS proteins are involved in
protein trafficking in and out of cilia and ciliary protein homeostasis (30,31)
(and references therein).
Insights into the pathophysiology of BBS have been gained through the
use of animal models in which specific BBS genes are disrupted. Inactivation
of BBS genes in mice results in lack of flagella in spermatozoa as well as
abnormalities in cilia in brain ependymal cells, airway epithelial cells, and
olfactory neurons (19–22,32–35). Inactivation of BBS genes also causes
photoreceptor degeneration in the retina (19–22,32,34–39). The
photoreceptor outer segment is a highly specialized form of primary cilia,
filled with proteins necessary for light perception and phototransduction. In
contrast, proteins involved in other cellular activities such as protein
synthesis, energy production, or synaptic transmission are excluded from this
compartment. Recent studies uncovered that loss of BBS gene functions leads
to accumulation of non–outer segment proteins in the outer segment and
outer segment malformation (37–39). Combined with studies in
Chlamydomonas reinhardtii BBS mutants (40,41), these findings suggest that
the primary function of BBS proteins is to export nonciliary proteins out of
cilia (Figure 32-1). Further investigation is needed to understand how these
abnormalities induce photoreceptor cell death. Besides retinal degeneration,
human BBS patients often exhibit polydactyly and obesity. Although precise
mechanisms are not sufficiently understood, polydactyly is thought to be
related to a defect in the sonic hedgehog (SHH) signaling pathway during
limb development (42,43), and obesity may be due to defects in leptin, NPY,
and MCHR1 signaling pathways in the hypothalamus (7,8,44,45).
Specific roles of individual BBS proteins are also emerging (Figure 32-
1). Of the 21 BBS proteins identified thus far, eight (BBS1, BBS2, BBS4,
BBS5, BBS7, BBS8, BBS9, and BBS18 [aka BBIP1]) form a stable complex,
known as the BBSome (46,47). This complex is thought to mediate protein
trafficking in and out of cilia by interacting with intraflagellar transport (IFT)
particles, which transport ciliary proteins along the axonemal microtubules
(40,46,48–52). BBS3 (aka ARL6) is a member of the Ras superfamily of
small GTPases and controls BBSome recruitment to the plasma or ciliary
membranes (50,53). BBS17 (aka LZTFL1) is currently thought to mediate
the interaction between the BBSome and IFT particles and facilitate ciliary
exit of the BBSome (43,50,52). BBS6, BBS10, and BBS12 have sequence
homology to the CCT/TRiC family of group II chaperonins (54–57). These
proteins form another complex, the BBS/CCT chaperonin complex together
with six CCT chaperonins (CCT1, CCT2, CCT3, CCT4, CCT5, and CCT8),
and facilitate BBSome assembly (58). Consistent with their closely related
molecular functions around the BBSome, null mutations in these 13 BBS
genes result in typical BBS phenotypes described earlier, and no obvious
genotype–phenotype correlation has been observed.
The rest of the BBS proteins are more remotely linked to the BBSome.
BBS13 (aka MKS1), BBS14 (aka CEP290), BBS15 (aka WDPCP), and
BBS16 (aka SDCCAG8) localize to the transition zone at the ciliary base (59)
(and references therein). These proteins are part of a protein network that
builds the ciliary gate and controls entry and exit of ciliary proteins. BBS19
(IFT27) and BBS20 (IFT172) are components of the IFT complex. Null
mutations in these genes result in phenotypically overlapping but distinct
ciliopathies such as Meckel-Gruber syndrome (MKS), Joubert syndrome
(JBTS), Senior-Löken syndrome (SLSN), and Jeune syndrome (27,28) (and
references therein). In contrast, mutations in these genes found in patients
with a clinical diagnosis of BBS are usually hypomorphic alleles, indicating
that partial loss of these protein functions results in BBS-like phenotypes.
Although the precise molecular function of BBS21 (C8ORF37) is currently
unknown, inactivation of BBS21 also results in OS morphogenesis defects
(60).
Polydactyly
The diagnosis of BBS may be suspected at birth if polydactyly is present.
This may be manifested as extra fingers, toes, or both. The supernumerary
digits are typically extra-axial near the little finger or toe, although there is a
report of an extra finger between the third and fourth digits (61). Digits may
be rudimentary or fully formed. An unrelated syndrome of isolated autosomal
dominant polydactyly also exists and is relatively common, so extra digits
may be ligated and removed shortly after birth leaving only tiny scars.
Parents may not mention this on history, and patients may be unaware that
extra digits were present at birth. For this reason, specific questions about
extra digits should be asked, and hands and feet examined if BBS is
suspected. Sixty-three to eighty-one percent of BBS patients have
polydactyly, which may involve all four limbs or any combination of upper
or lower (3).
Retinal Degeneration
In the absence of polydactyly, the first symptom of BBS is often decreased
vision in dim light, typically noticed around the age of 5 to 7 years. The
electroretinogram (ERG) may be abnormal before this; in a large cohort of
families with BBS, all patients with genetically proven BBS who were older
than 3 years had some evidence of retinal degeneration (62). Cone–rod
dystrophy has been reported in 93% of BBS patients (3). What begins as
night blindness progresses to visual field loss and RP. Visual acuity is often
good in the early stages of retinopathy, and since young children have limited
independent activities in dim light at this age, specific questions must be
asked to elicit symptoms. Questions such as “Can he/she find a seat in a dark
movie theater without assistance?” and “Can he/she see stars at night?” are
often illustrative. Parents may report noticing that the child has difficulty
ambulating when camping at night or trick-or-treating on Halloween. In
bright light, the child may appear to see perfectly normally. Nystagmus has
been reported in 59% of patients (62) but is not considered a typical finding
in BBS. 43.7% of patients in one study developed cataracts (62). Most
patients in this study were legally blind by late teens or early adulthood, but
no patient lost all light perception. At a young age, the fundus appears
normal. Many patients develop a “bull’s-eye maculopathy” appearance,
which may begin as a blunted fovea (Figure 32-2). The peripheral vision
decreases steadily, but central vision, while imperfect, is retained longer.
When central vision does decrease, it may be attributable to cystoid macular
edema (CME) and/or epiretinal membranes. Over time, atrophy of the macula
occurs (Figure 32-3). On slit lamp examination of the anterior vitreous in
childhood, a significant cellular reaction can be seen (63) (Figure 32-4). This
may precede a decline in vision (Drack, unpublished observations). The cells
seen in the vitreous may be an inflammatory or autoimmune overlay related
to the retinal degeneration but may also be debris related to cell death.
Posterior subcapsular cataracts may develop over time. Legal blindness often
develops by the time patients are in their 20s or 30s due to severely decreased
visual field, maculopathy causing poor acuity, or both. A typical RP picture
with waxy pale disc, thinned arteriole, and bone spicule–like pigmentation
eventually occurs (Figure 32-5). In mouse models of BBS, a striking loss of
outer retinal layers is seen on histology (Figure 32-6).
FIGURE 32-2 Left fundus of a 10-year-old with BBS1.
Visual acuity was 20/70 right and 20/40 left. The child had
been followed since age 3 years for nystagmus, esotropia,
and amblyopia as well as obesity. Referral was made when
nyctalopia was noted.
FIGURE 32-3 Red free and OCT of the right fundus
shows subtle bull’s-eye appearance and thinning of outer
retinal layers. Note the relatively preserved outer nuclear
layer just beneath the foveal depression. Outer segment
lengthening has been lost.
Obesity
Obesity may precede vision loss but is infrequently suspected to be due to
BBS unless an astute clinician searches for other features. The obesity is
truncal. While infants with BBS are usually of normal weight, many children
are noticeably obese by 1 to 5 years of age. The obesity that accompanies
BBS is especially difficult to manage. Studies in mice and humans have
demonstrated that it is due to leptin resistance (7,64). Leptin is a hormone
that triggers a feeling of satiety, so resistance renders those afflicted with
BBS not feeling full after eating a sufficient quantity of food. In addition,
animal studies have shown that even when eating the same amount of food as
unaffected littermates, BBS mice gain more weight (7), suggesting that
energy expenditure also plays a role. Obesity has been reported in 72% to
92% of patients (3). Adolescents and adults with BBS often are able to better
control food intake than young children who cannot yet understand that they
must stop eating before satiety.
Renal and Genital Anomalies
Kidney disorders occur in 53% of patients (3) and may be progressive. One
study suggests that BBS10 patients may have the most severe renal disease
(62). Renal ultrasound evaluation should be recommended early in the course
and followed by a kidney specialist if abnormal. Urine concentrating ability
may be diminished leading to copious urine production and difficulty with
bed wetting. Genital anomalies have been reported in up to 98% of patients
(3). Although BBS mice models do not have significant renal impairment,
spermatogenesis is impaired and males are infertile (19–22).
Developmental Disability
Developmental delay and psychiatric disorders are overrepresented in BBS
patients but are not universal. In one study, patients with BBS due to
mutations in BBS1 or in BBS12 appeared to have milder cognitive disorders;
many BBS patients have university degrees (62). About 61% of BBS patients
have been reported to have learning difficulties and 50% to 91% have been
reported to have developmental delays (3), but poor vision may play a role in
testing. In a behavioral study of 21 BBS patients, repetitive behaviors,
obsessions, and autistic features were noted, but none had diagnosable
autism. Anxiety, depression, and difficulty with social interactions and with
attention were also noted (65). BBS mice exhibit a defect in social dominance
phenotype (21).
Other Features
Later-occurring complications include diabetes mellitus and hypertension, but
these can present in childhood especially in the setting of obesity. Some
patients have heart defects. Anosmia has been reported in 60% of patients
(3), although patients may not be aware of it since it is present from early life;
BBS2 mice have anosmia (21,66). Hearing loss and “glue ear” (serous otitis
media) have been reported in some BBS patients. Surveillance for these
disorders should commence in childhood, and the importance of close follow-
up should be discussed.
Diagnostic Studies
When BBS is suspected based on ocular history or physical findings, workup
begins with a history and full eye examination. Careful inspection of the
hands and feet for surgical scars or remnants of extra digits should be
performed. The retina may appear normal early in the course even though the
ERG is not; therefore, a prudent first step is an ERG. This is a challenging
test for many children to perform, especially if they have developmental or
behavioral issues as is often the case with BBS. Using DTL electrodes rather
than contact lens electrodes may make an otherwise unobtainable
examination possible. If an ERG is not possible while the child is awake,
ERG with sedation or anesthesia should be considered keeping in mind that
ERG amplitudes may be variably reduced by up to 50% by anesthetic agents.
Sedation and anesthesia have a small but significant risk of complications.
Therefore, if the clinical picture is typical and ERG cannot be performed
easily, doing genetic testing before ERG is advisable. The ERG in BBS early
in the course is usually a rod-cone dystrophy, but cone-rod pattern has also
been reported (67). Later the ERG eventually becomes nonrecordable.
Optical coherence tomography (OCT) may be easier for children to cooperate
with and shows thinning of the outer retina, but this may not be detectable
very early in the disease. Kidney ultrasonography should be recommended
once the diagnosis is made.
Genetic Testing
Approximately 80% of patients will have a molecular diagnosis on genetic
testing (4). Certainty of diagnosis is important to rule out other causes of
retinal degeneration in children and to put into place the proper surveillance
for systemic disorders. In addition, since this is an autosomal recessive
disorder, genetic counseling for recurrence risk is important for families.
Clinical laboratories testing for BBS can be found at www.genetests.org.
Many patients have novel mutations, so complete sequencing of all of the
known BBS genes is often necessary. A certified genetic counselor or
medical geneticist may be consulted to help patients and families understand
the implications of genetic testing results and to counsel about recurrence
risk. It is important to remember that at this time, a negative genetic test
never rules out a disorder due to genes yet to be found and limitations of
testing. Identification of rare variants predicted to change the protein product
of a gene is often, but not always, diagnostic. Every person has a large
number of variations from the norm in their genome, and most are not
pathologic. When a mutation is found in a BBS gene on genetic testing, it
must be evaluated for pathogenicity by determining whether there are
mutations on both of the patient’s alleles (often achieved by testing parental
samples), whether the change has been reported in other patients, whether
and how often it is found in normal controls, and whether or not a conserved
amino acid would be changed in the final protein. Some genetic changes
cannot be classified definitively as disease causing versus benign at this time.
Most genetic testing laboratories provide this data in the test report; it is
outside of the expertise of most clinicians to assess which molecular changes
are likely to be pathologic, and even for experts the knowledge used to make
these determinations is being continuously acquired.
All patients who can cooperate should have a slit lamp biomicroscopic
examination to look for cells in the anterior vitreous and subsequent posterior
subcapsular cataract. If central acuity is diminished, OCT is helpful to
diagnose CME.
Differential Diagnosis
Several disorders overlap clinically with BBS despite being caused by genes
that do not cause typical BBS. In other cases, mutated genes, which cause the
clinical phenotype of disorders such as Leber congenital amaurosis (LCA)
can also cause the clinical phenotype known as BBS. Our nomenclature is in
flux as our knowledge expands. In addition, there may be phenocopies of
BBS such as autosomal dominant polydactyly plus retinitis pigmentosa or
obesity plus retinitis pigmentosa. Molecular genetic diagnosis is especially
important to differentiate these overlap syndromes.
When a child presents in the 5- to 7-year-old age range with either
nyctalopia or decreased vision, with or without nystagmus, BBS should be in
the differential diagnosis. If visual acuity is poor and nystagmus is present,
LCA should also be considered. Two types of LCA, caused by mutations in
CEP290 and NPHP5, may overlap BBS with early-onset retinal degeneration
and renal and/or neurologic disease. Patients with CEP290-associated LCA
may also have anosmia. If a bull’s-eye maculopathy is present, Batten disease
should be considered. This is a progressive neurodegenerative disorder that
begins with rapid retinal degeneration (see Chapter 24). Stargardt disease (see
Chapter 30) presents with a similar macular appearance and age of onset but
is an isolated retinopathy. If Stargardt disease is suspected, genetic testing for
ABCA4 and ELOVL4 should be considered. If obesity is present, BBS and
Alström rise to the top of the list. Alström syndrome shares obesity, retinal
degeneration, hearing loss, “glue ear,” and some other features of BBS but is
caused by mutations in the ALMS1 gene (68). Alström syndrome is also a
ciliopathy, but presents with photophobia in most cases. Orofacial–digital
syndrome (OFDS or Mohr syndrome) may be in the differential diagnosis
due to digit anomalies but can be differentiated clinically by a bifid thumb
and tachypnea/hypoventilation episodes. Like BBS, OFDS encompasses
multiple genes and ciliopathy syndromes; however, unlike BBS, only one
type includes a progressive retinal dystrophy (69). Other disorders in the
differential diagnosis include McKusick-Kaufman syndrome, JBTS,
Biemond syndrome, and obesity plus congenital stationary night blindness.
Management
The only prevention for BBS itself is carrier testing and subsequent family
planning for identified carriers. If carrier state is known and genotyped,
preimplantation genetic testing combined with in vitro fertilization can be
considered to reduce the risk of an affected child. Unfortunately, at this
writing there is no way to prevent the retinal degeneration from occurring in
patients with biallelic BBS mutations, even though the retina is normal or
very mildly affected for the first several years of life. This long span of time
before retinal degeneration occurs should afford time for a preventive
treatment, and significant research is ongoing in this endeavor.
If CME is present, a systemic or topical carbonic anhydrase inhibitor
(CAI) such as dorzolamide may be prescribed. This has been shown to
improve both anatomy and acuity in some patients with different types of RP
(70). Topical brinzolamide may be better tolerated by children because it
does not sting upon installation (Drack, unpublished data).
It is unknown whether treating the vitreous cellular reaction in RP, and
specifically in BBS, is beneficial. While the disease is not primarily
inflammatory, just as the inflammatory response to a disease or infection may
cause secondary damage in other parts of the body, the same may be true in
the eye. If the vitritis is inflammatory, steroids, nonsteroidal anti-
inflammatories or biologics may have a role in treatment. Side effects of
steroids can be significant, particularly elevated blood glucose in susceptible
individuals such as those with BBS. More research is necessary into this
aspect of genetic retinal disorders (63).
Experimental approaches to intervene in the retinal degeneration that
occurs in BBS are similar to those of other retinal dystrophies. For the
purpose of brevity, we will discuss three areas of intervention: light
modulation, antiapoptotic agents, and gene transfer.
Modulation of light exposure may be of benefit in a variety of retinal
degenerative diseases, as there is evidence from animal models that increased
light exposure is harmful and avoidance of light exposure may be beneficial
(71). Blue light (wavelength 400 to 480 nm) appears to be especially
damaging through a variety of mechanisms (72,73). The efficacy of light
reduction in RP has not been proven. There are anecdotal reports of slowed
progression when wearing tinted contact lenses; however, there is also a
published report of a patient with RP and unilateral cataract who did not have
any apparent preservation of retina in the eye with limited light exposure
(71). In a mouse model of BBS1 homozygous for the p.M390R mutation,
little preservation of retinal function was seen with darkrearing, and operating
microscope light exposure did not increase the rate of retinal degeneration
(74).
Tauroursodeoxycholic acid (TUDCA) is a bile acid found in bear bile,
which is used in traditional Chinese medicine. In using this substance to treat
liver disorders, it was noted that in addition to the bile acid effect, TUDCA
also appeared to decrease apoptosis, the programmed cell death that leads to
organ failure. Studies in animal models of neuro and retinal degeneration
showed promising results (75,76). In the Bbs1M390R/M390R mouse model, we
found that administration of TUDCA significantly slowed the retinal
degeneration as evidenced by both ERG and histologic examination (77). In
addition, Bbs1 mice that received TUDCA had significantly lower body
weight than untreated mice (77). In humans, TUDCA has been found to
improve insulin utilization (78). These findings make TUDCA a prime
candidate for human clinical trials of treatment for BBS, and possibly
Alström syndrome. Since TUDCA is not FDA approved, patients should not
attempt to procure it and treat themselves. The optimal dose for treatment in
humans is not known. UDCA is a related compound, which is FDA
approved, but the taurine moiety it lacks may be important to the desired
effect.
Subretinal gene therapy in animals and humans can improve retinal
function in at least one type of genetic retinal degeneration, RPE65-
associated LCA (79,80). Subretinal gene therapy for this indication is now
FDA approved for children as young as 1 year of age.
Since the genetic defect resides in the RPE, the layer under the
photoreceptors, it is an ideal candidate for this type of therapy. The
ciliopathies may present challenges to gene replacement since the gene
products of several genes must act in concert and establishing the appropriate
ratio of BBSome components may be important.
Some success in improving retinal health over small areas of retina has
been reported with subretinal gene replacement therapy in the mouse model
of BBS4 (81). Our group has shown small improvements in ERG in Bbs1 and
Bbs2 mice as well as biochemical rescue of the BBSome (82); however,
overexpression toxicity has also been noted (83). Subretinal gene therapy in
the Bbs10-null mouse has shown early promising results (84).
Attempts to prevent obesity may be successful if eating habits are
carefully taught and monitored. Likewise, diabetes, hypertension, and renal
failure may be ameliorated by early dietary intervention and close monitoring
with medication as indicated.
Vision Rehabilitation
A low-vision specialist should advise the school about methods to improve
education. Enlarging print materials through the use of a CCTV and the use
of auditory and other technology can be life changing for patients with low
vision. Patients should be advised to carry a flashlight at all times in case they
find themselves inadvertently in dimly lit surroundings. Some patients may
have vision adequate for driving in the teenage years, but since the retinal
degeneration is progressive, this should be monitored closely. See also
Chapter 14.
Ethical Considerations
As in all genetic eye disorders, physicians have an ethical obligation to
inform patients/parents that the condition may be genetic and that accurate
genetic testing is available. Consultation with medical geneticists, genetic
counselors, and/or reproductive care geneticists should be offered as in vitro
fertilization with preimplantation genetic testing may be desired by some
families to reduce the risk of having future affected offspring. Genetic
information should be offered in a nonjudgmental manner, referring
patients/parents to other specialists as needed. There is also an obligation to
inform patients/parents that there is a plethora of ongoing research that may
be applicable to them now or in the future and to offer websites such as
www.clinicaltrials.gov, referral to other specialists, and other resources to
help manage their condition.
Future Treatments
Ongoing research into gene therapy for retinal degenerative conditions in
which many cells are still viable offers hope of gene replacement therapy in
the future for BBS. The success of in vivo correction of genetic mutations
using oligonucleotides or CRISPR is also encouraging (85,86). For patients
in whom too many retinal cells have been lost, stem cell replacement of the
photoreceptors is under active investigation (87).
CONCLUSION
BBS has been considered an extremely rare disorder that few
ophthalmologists will see in practice. We now know it is far more
pleiomorphic, and likely more common, than was thought. The interesting
finding of multiple genes leading to the same striking phenotype has led to
knowledge about how cilia affect every organ system in the body and to the
understanding of the interaction of multiple genetic protein products in a new
way. Finally, BBS is a prime example of how not only our understanding but
also our naming of clinical entities is evolving in the genetic era. Whereas
BBS was initially confidently diagnosed as a combination of obesity, RP, and
polydactyly with LMS separate due to lack of polydactyly and presence of
spastic gait, we now know that there are myriad overlapping disorders due to
mutations in genes that contribute to the same protein complexes and cilia
functioning that can cause parts or all or additions to what was initially called
BBS. The nomenclature is now a combination of the name of the gene
affected (e.g., BBS1, BBS2, etc.), and the clinical features, for example,
patients with mutations in CEP290, may be called either BBS or LCA
depending on the patient’s clinical manifestations. While this can be
confusing, the primary goal remains the same: to give patients and families
an accurate diagnosis in order to help them manage their disorder and give
them hope that continuing research will find treatments and eventually cures.
ACKNOWLEDGMENTS
The authors wish to acknowledge Dr. Val Sheffield for generation of mouse
models and his pioneering work on Bardet-Biedl Syndrome. Supported in
part by the Ronald Keech Professorship (Drack).
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33
Usher Syndrome
Alaa Koleilat, Raymond Iezzi Jr, and Lisa A. Schimmenti
PREVALENCE/WORLDWIDE IMPACT
Usher syndrome (USH) is the most common genetic cause of deafness and
blindness worldwide. In the general population, USH impacts 4 to 17 people
per 100,000 but can be diagnosed in 3% to 6% of all deaf and hard-of-hearing
children (1–3). USH is considered a rare disease in the general population. In
the United States, a rare disease is defined as a condition that affects fewer
than 200,000 Americans. However, among the deaf/hard-of-hearing
population, it is a common condition, supporting the need for greater
awareness of this condition.
As hearing loss precedes vision loss in USH, the diagnosis may not be
made until the second decade as the loss of night and peripheral vision
impacts activities such as driving. The only way to make a definitive
diagnosis of USH prior to the loss of vision is through genetic testing;
however, electroretinogram (ERG) may be suggestive since the ERG often
becomes abnormal before major symptoms are noticed. USH is a public
health concern and, for deaf/blind adults who are visual communicators, can
result in social isolation, loneliness, and depression (4); therefore, early
identification and diagnosis can impact decision-making for communication
and, in time, may identify individuals who could benefit from emerging
therapies.
ENVIRONMENTAL FACTORS
Usher syndrome is a genetic condition, and there is no current literature that
indicates any environmental factors contributing to the disease.
GENETICS
Usher syndrome is a genetic disorder that has an autosomal recessive
inheritance pattern. This means that an affected individual would need to
inherit mutations in the same Usher gene that can be different from one
another: one of which comes from the biologic mother and one from the
biologic father.
There is no X-linked nor sex limitation to USH; females and males are
equally likely to inherit the disease. Ten genes have been identified to cause
Usher syndrome as well as one modifier gene (Table 33-1). If each parent
carries one copy of the same gene with a pathogenic variant, then each child
has a 25% chance of inheriting both abnormal copies and will be born with
Usher syndrome. A parent that is a carrier for a gene that causes Usher
syndrome will not present with the disease, and may or may not have a
family history.
PATHOPHYSIOLOGY
Usher Proteins in the Hair Cell
The overall process of hearing is the translation of a mechanical signal to a
chemical signal in the cochlea. It has been estimated that the cochlea has over
20,000 hair cells. Each hair cell has a collection of small actin-filled
projections at the apical end of the cell called stereocilia (25); they are
typically ordered from shortest to tallest. When a hair cell is deflected toward
the tallest stereocilia due to sound, tip links composed of PCDH15 and
CDH23 cause the mechanotransduction (MET) channels—located at the top
of the stereocilia or lower tip link density—to open, allowing positively
charged ions (K+ and Ca2+) to flow into the cell (25–30). The increase in
cations in the hair cell changes the membrane potential necessary for
depolarization. L-type voltage-gated calcium channels (Cav1.3) open in
response to depolarization and increase intracellular calcium (31). Calcium is
critical in the hair cell as it mediates the release of glutamatergic vesicles
tethered to the ribbon synapse, a structure not only important for transporting
neurotransmitters but also necessary for clustering of Cav1.3 channels at the
presynapse and for stabilizing contact with afferent neurons. Once vesicles
from the ribbon synapse fuse with the plasma membrane, their contents are
released into the synaptic cleft and bind onto AMPA receptors for synaptic
transmission (32,33) (Figure 33-1). Variants in many genes involved in this
process can cause hearing loss; however, variants in genes involved
specifically in the mechanotransduction process can cause Usher syndrome
and prevent the mechanical signal (sound deflection) from being converted to
a chemical signal (neurotransmitter release).
FIGURE 33-1 This illustration of a typical human hair
cell depicts localization of Usher proteins myosin7A, sans,
harmonin, cadherin 23, and protocadherin 15 (inset) and
their role in the process of stereocilia deflection and tip
link structure.
DIAGNOSTIC STUDIES
Newborn hearing screening occurs in nearly all developed nations, and it has
been a topic of discussion since the late 1960s. Newborn hearing screening is
now part of the standard of care for newborns that identifies children who are
at risk of having hearing loss and require additional testing. It also has been
instrumental in identifying children who have medical conditions that can
cause late-onset hearing loss. In 2016, over 94.8% of babies born in the
United States were screened for hearing loss before 1 month of age (CDC,
2016), and over 6,100 infants were identified and diagnosed with hearing
loss. If an infant fails the newborn hearing screening, they will be referred to
an audiologist for further testing. A failed hearing assessment does not
automatically suggest hearing loss; a baby may have other reasons for not
passing the newborn hearing screen such as fluid in the ear canal. However, if
an audiologist confirms hearing loss, one of the first actions is to determine
the type of hearing loss. More than 50% of hearing loss in newborns has a
genetic basis (43,45); therefore, genetic testing is typically the next step in
determining a diagnosis. Arun Sharma and colleagues reported that about
20% of children with sensorineural hearing loss also have vision problems;
therefore it is important to detect genetic hearing loss as early as possible,
because patients may be identified presymptomatically for vision loss (46).
This is particularly important for patients with Usher syndrome, because
onset of vision loss is different depending on the type of Usher syndrome and
will, therefore, affect the timeline for treatment and management of the vision
loss. In addition, since all patients with hearing loss depend to some degree
on watching lip movements to help understand speech, easily correctable
problems such as refractive error that might interfere with lip reading can be
diagnosed and treated.
The clinical evaluation of a patient with retinitis pigmentosa includes a
full medical history, nutritional history, and history of vision symptoms,
focused on nyctalopia, decreased visual acuity, and glare. Further, a family
history is critical. Ideally, a comprehensive eye examination should include
funduscopy, optical coherence tomography (OCT), visual field testing, and
full-field electroretinography, documenting A-wave and B-wave amplitudes
as well as implicit time. Examinations must be tailored to the age of the
patient, and, if necessary, some aspects must be performed under anesthesia.
With the advent of genetic testing, diagnosis can often be made with
molecular genetics rather than by subjecting a child to general anesthesia for
testing. Examination findings of retinitis pigmentosa may include peripheral
bone spicules, optic nerve pallor, attenuation of the retinal vasculature,
cataract, and in some cases cystoid macular edema (CME), low-grade ocular
inflammation, and epiretinal membrane.
Edwards et al. (47) made the observation that visual field area and visual
acuity are more impaired in USH1 patients than USH2; however, a more
recent publication reports that visual field area, visual acuity, and the
incidence of macular lesions did not differ between USH1 and USH2 patients
(48). Seelinger et al. used electroretinography testing to show that although
patients with USH 1 and USH2 have similar loss of amplitude, there are
significant differences in implicit times or peak times (49). Patients with
USH2 had marked delay in implicit times, whereas USH1 patients had
normal to moderate delays. In 2002, Tsilou et al. (48) also reported that
electroretinographic amplitude did not differ between USH1 and USH2
patients. Testa et al. assessed the distribution of macular abnormalities in
USH patients using OCT (50). They observed that USH1 and USH2 patients
have a high prevalence of CME and epiretinal membrane. Consequently,
OCT screening in USH patients plays an important role in their management
and treatment. Lastly, videonystagmography is used to detect involuntary eye
movements that might indicate balance abnormalities.
MANAGEMENT
One of the most important aspects of managing USH is early identification.
At this time, nearly all USH1 and USH2 patients will be diagnosed to be deaf
or hard of hearing, but genetic testing can determine presymptomatically if
that child will go on to have vision loss later in childhood or teenage years.
Christine Yoshinaga-Itano and her colleagues reported that there is
significantly better language development when children are identified to be
deaf or hard of hearing before 6 months of age (51), thus providing evidence
for the importance of newborn hearing screening. Additionally, early
identification of children who are deaf and may go on to have vision
impairment allows families and intervention specialists time to develop the
support and acquire the resources necessary to address both developmental
and educational needs. Some patients with USH2 may pass the newborn
hearing screen; if there is a family history of USH2, early genetic testing may
be appropriate. Proper management and treatment for patients with USH
requires an interdisciplinary team approach once they are identified.
The treatment plan for affected individuals depends on the type of USH
they are diagnosed with; for example, patients with USH1 are profoundly
deaf and typically may not experience benefit from hearing aids. Cochlear
implantation would be of benefit for children diagnosed with USH1, and
more specifically early implantation at or before 1 year of age will provide
the most benefit for developing oral language in anticipation of the fact that
vision loss may become severe enough to make American Sign Language
difficult. Although tactile sign language is a possibility, the rarity of
interpreters with expertise in tactile sign language limits its utility to allow
ready access to communication.
Patients with USH1 typically suffer from vestibular abnormalities. Thus,
early identification through newborn hearing screening and genetic testing
can be of benefit for planning physical therapy needs. For children and adults
with Usher syndrome type 1, balance problems related to vestibular
anomalies pose significant issues. In childhood, walking is delayed past 18
months of age. In older children, difficulty with activities that require balance
such as bicycling or skating may limit the ability of the child to participate
fully. Adults may have difficulty with balance and may experience falls.
Physical therapy to help with balance and fall risk can be of benefit. Many
patients make remarkable adaptations and learn to participate in many
activities requiring balance over time.
At the present time, no FDA-approved treatments for USH related to
retinitis pigmentosa are available. In 1993, a large randomized clinical trial
was conducted over a 6-year time span in which adults with retinitis
pigmentosa—including USH2 patients—ingested 15,000 IU vitamin A
palmitate supplements daily. This study showed that, on average, patients
taking vitamin A palmitate experienced a 20% slower annual decline of ERG
amplitude loss. This study did not demonstrate preservation of visual field,
however. Therefore, it is unclear whether supplementation with vitamin A
palmitate is of therapeutic benefit to patients with USH associated retinitis
pigmentosa (52). High doses of vitamin A can be toxic and medical
monitoring is required for long-term use. Additionally, patients with USH2
may experience CME. This is often associated with mild to moderate
decreases in visual acuity.
Treatment with topical carbonic anhydrase inhibitors may be effective in
up to 30% of patients (53). If the CME does not respond to topical treatment,
oral carbonic anhydrase inhibitors may be effective. Systemic treatment
requires monitoring of liver enzymes, electrolytes, white blood count, and
maintenance of hydration. Side effects may include dose-related tingling in
the hands and feet that may improve over time or with dosage adjustment.
Additional side effects include fatigue, alteration of taste, gastrointestinal
upset, and nephrolithiasis. Patients should be informed of these issues prior to
starting treatment and monitored over the course of treatment. For those
patients who cannot tolerate systemic carbonic anhydrase inhibitors,
sustained-release intraocular dexamethasone implants may induce temporary
resolution of CME. Long-term repeat injections may be required to treat the
CME; however, this may cause steroid-induced ocular hypertension (54).
The care of individuals with Usher syndrome is best provided through a
team approach. This team includes experts in Audiology, Ophthalmolgy,
Otorhinolaryngology, Genetics, Pediatrics, Speech and Language Pathology,
and Rehabilitation Medicine. As patients will present with hearing loss first,
particularly if hearing loss is picked up by newborn hearing screening or by
language delay in the first 2 years of life, the early years of management will
be primarily through Audiology, Otorhinolaryngology, and Speech and
Language services. Although many deaf/hard-of-hearing children will be
referred for vision examinations, a normal eye examination in early
childhood does not rule out Usher syndrome. Genetic evaluations and testing
are part of the care for all deaf/hard-of-hearing children; genetic testing
panels that include all known genes for Usher syndrome as well as other
genes associated with early-onset hearing loss are recommended. Positive
genetic testing for Usher syndrome will provide guidance for early
management in anticipation of onset of vision loss in later years.
VISUAL REHABILITATION
Low vision services that include support for reading, daily activities, and use
of a cane for mobility would be similar to patients affected with retinitis
pigmentosa of other causes; however, tactile interventions may be necessary
for older patients with USH who have not had cochlear implants (see also
Chapter 14, low vision).
ETHICAL CONSIDERATIONS
With the increased access and ease of genetic testing, ethical dilemmas arise
related to the implications genetic variants have on families. Although
genetic testing is extremely beneficial to diagnosing disease and determining
prognoses for patients, the interpretation of results can be complex and
should be provided in the context of genetic counseling. Additionally, as
Usher syndrome is an autosomal recessive condition, genetic testing results
will have implications for future offspring; thus, genetic counseling is
warranted.
Many USH patients may define themselves as being culturally Deaf,
meaning that they communicate with American Sign Language and are part
of the Deaf (capital “D”) Community, Deaf individuals do not view deafness
as a disability or medical condition, but rather another aspect of their life that
can be managed and does not inhibit their ability to function in their daily
lives. This should be taken into consideration especially if one or both parents
are deaf or consider themselves to be culturally Deaf; they may not choose to
support medically treating the deafness or supporting oral language for their
child. Thus, information about language choices should be presented in a
nonjudgmental manner allowing parents to make choices for their children
while providing full information about future vision loss, which may limit
visual language ability.
FUTURE TREATMENTS
Since the completion of the Human Genome Project, there have been
significant improvements in genetic sequencing technology that increase
speed and lower costs. Currently in 2019, patients can have their entire
genome sequenced for a few thousand dollars. With over 110 chromosomal
loci and more than 65 genes identified to cause hearing loss, genetic
sequencing is critical to identify a diagnosis as well as proactively plan for
the vision loss in USH patients (56). Genetic sequencing technology has
contributed greatly to the increasing literature on specific pathogenic variants
prevalent in different populations that cause USH (1,57–60). Identification of
these pathogenic variants is critical in understanding the molecular
mechanisms and functions of proteins encoded by these genes. This has led to
a more complete and deeper understanding of the visual and auditory
systems.
Although there is no cure for the hearing loss or vision loss due to USH,
there are many treatments currently being pursued, specifically for the
retinopathy associated with USH. Zinc finger nucleases are DNA binding
proteins that target and edit a region of the DNA by inducing a double-
stranded break. This technology was shown to induce gene repair
mechanisms in USH1C, at p.R31X, resulting in recovery of protein
expression (61). About 10% of pathogenic variants that cause USH lead to an
early stop codon. One approach to treat USH is to use pharmacologic
compounds to force the cell to translate beyond the stop codon, thereby
resulting in a full-length protein. This method was investigated by Goldmann
et al. in which a drug, PTC124, was used in cell culture and on mice to treat
the retinal USH phenotype. They found that PTC124 was able to read-
through the stop codon and restore protein function (62).
With over 2,500 clinical trials currently in process worldwide, gene
therapy has been a groundbreaking advancement in medicine and has shown
promise to treat human disease (63). Gene therapy has been used to treat the
retinopathy in animal models with USH1 or USH2 with some success. Mice
with USH do not develop vision loss, even though they lack the normal
protein associated with the defective gene in the retina. Thus, biochemical
rather than functional vision assays are needed. Hashimoto et al. used a
CMV-MYO7A chimeric promoter and found that in vivo abnormal
accumulation of opsin was rectified in the connecting cilium of the
photoreceptors, and melanosomes were localized to their normal location—
indicating a functional myosin7a protein through the use of lentiviral gene
replacement therapy (64). In 2011, another study used the most common gene
delivery system—the adeno-associated virus (AAV)–to transport mouse
whirlin cDNA driven by the human rhodopsin kinase promoter. This vector
was injected under the retina of whirlin deficient mice, and they concluded
that whirlin was successfully restored, and the protein complex whirlin forms
with usherin and GPR98 was produced for up to 6 months after the injection
(65).
There are a two clinical trials taking place, at the time of writing, which
use gene therapy in patients with retinitis pigmentosa due to USH1B: they
included the UshStat trial (NCT01505062) and the STELLAR trial
(NCT03780257). The UshStat trial is currently recruiting for a phase I/IIa
safety study of subretinal injection of UshStat—a recombinant EIAV-based
lentiviral vector expressing MYO7A that showed efficacy in the mouse
model of USH1b (66). The STELLAR trial is conducted by ProQR, a biotech
company based in the Netherlands, which seeks to develop therapies for rare
diseases. This Phase I/II trial will investigate the intravitreal injection of a
drug called QR-421a to treat retinitis pigmentosa in patients with USH2A
specifically due to variants in exon 13. This drug is designed to skip exon 13
during the synthesis of the protein resulting in a truncated yet functional
usherin protein. ProQR is also developing an additional therapy to target a
specific USH2A pathogenic variant, c.7595-2144A>G.
Few studies have been conducted using gene therapy for the treatment of
the hearing loss associated with USH. One study assessed the efficacy of an
AA-Clrn1-UTR vector in Clrn-1 deficient mice. They identified that one
injection of this vector preserved the hair bundle structure and hearing of
mice through their adult life (67). This same group also identified a small
molecule that reduces hearing loss in the mouse model of USH3 (68) and
published the first study to explore the use of pharmacologic agents to treat
hearing loss in a mouse model of USH.
CONCLUDING REMARKS
There has been considerable progress in the last decade in understanding the
clinical findings in Usher syndrome as well as discovery of the genetic bases
of Usher syndrome and their consequences at the molecular and cellular
levels in both vision and hearing. Cost-effective and accurate diagnostic tests
are available and currently implemented in clinical practice including specific
sequencing panels for suspected genetic hearing loss. Lastly, there are
multiple studies both in humans and animals underway using gene therapy as
a treatment for the retinal degeneration for all three types of USH that show
promise. We are enthusiastic about potentially new treatments for USH
patients and to further understanding the mechanisms behind this life-altering
disease.
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34
X-Linked Retinoschisis
Catherine A. Cukras, Laryssa A. Huryn, Michael T. Trese and Paul
A. Sieving
PREVALENCE
X-linked retinoschisis (XLRS) is a congenital vitreoretinal dystrophy seen in
males with an estimated prevalence of 1:5,000 to 1:25,000 (1). Affected
patients typically present at an early stage with vision loss due to macular
changes with characteristic cystic maculopathy (Figure 34-1).
FIGURE 34-1 Fundus photographs showing the typical
presentation of XLRS. A: Affected male with spoke–
wheel pattern of foveal cysts. B: Affected male with
visible inner leaf schisis margin with adjacent white
dendriform retinal vessels in the inferotemporal quadrant.
ENVIRONMENTAL FACTORS
Environmental and genetic factors, including modifier genes, are predicted to
account for some of the phenotypic variation in an XLRS mouse model (4)
and, hence, are possible contributors to the wide phenotypic heterogeneity
found across the ages of members of XLRS families (5,6).
However, modifier genes have not been described for human XLRS.
Affected males lack a fully functional retinoschisin protein that normally
participates in holding retinal layers together and that contributes to the
integrity of the retinal architecture through its adhesive properties (7–9).
Hence, XLRS disease is believed to leave the retina vulnerable to mechanical
shock and injury. Contusive or acceleration–deceleration trauma can
exacerbate vision loss in XLRS patients. Prudent medical advice to XLRS
males includes avoiding excessive body contact sports and wearing sports
goggles for all contact sports if they do choose to participate. Environmental
factors are not currently suspected of contributing to the etiology or
progression of the condition.
GENETICS
The RS1 gene for XLRS was identified on the X chromosome by positional
cloning in 1997 (10). The RS1 gene contains 6 exons that encode a 224-
amino acid protein called retinoschisin. More than 150 mutations in RS1 have
been reported (11), and a comprehensive list of allelic variants (sequence
polymorphisms) is maintained through the Retinoschisis Consortium
database (www.dmd.nl/rs/). Most variants are missense mutations that are
clustered in the discoidin domain (exons 4 to 6) and lead to misfolded
protein. Founder effects are recognized, as 95% of XLRS patients with
Finnish ancestry have one of three mutations in the RS1 gene: p.E72K
(c.214G>A), p.G74V (c.221G>T), and p.G109R (c.325G>C) (12). Exons 1,
2, and 3 of the RS1 gene are susceptible to major deletions, splice site
mutations, and introduction of a stop codon, all of which would cause a
truncated or absolute loss of protein. We observed that less severe mutations
tend to occur in exons 4 to 6, and the more severe mutations involve exons 1
to 3 (5,13–15), the exception being alterations involving the addition or
subtraction of a cysteine residue, which is believed to confer a severe
mutation, as it would potentially disrupt a disulfide bond important for
tertiary folding that is predominantly found to occur in exons 1 to 3 (15).
XLRS is inherited in classical X-linked recessive manner and is not a
syndromic condition. Women carriers have a 50% chance of transmitting the
disease-causing mutation in each pregnancy. Males who harbor the mutation
are affected, and they transmit the mutation to all their daughters and none of
their sons. Females who inherit the mutation will be carriers and nearly
always are asymptomatic but can transmit the trait to their sons.
Sporadic cases of bilateral symmetrical maculopathy without known
family history of other affected males can be particularly challenging to the
clinician who is trying to establish a diagnosis and prognosis for the patient
and family. Electrophysiologic testing and supplemental molecular genetic
analysis are key diagnostic aids. Mutation analysis can identify mutations in
the RS1 gene in at least 90% of affected males (16). The value of
supplemental molecular genetic analysis is exemplified by the report of a
patient with the referring diagnosis of bull’s-eye maculopathy and selective
reduction in the b-wave of the ERG (17). Clinical findings suggested the
possibility of XLRS, and the patient was subsequently shown to have a novel
mutation (p.A100P) in the RS1 gene (17).
The methods to grade clinical severity of XLRS disease are not
standardized and vary considerably (2,18–23), which makes it difficult to
harmonize definitive genotype–phenotype correlations across different
reports. As the disease affects both central and peripheral function, the
utilization of combinations of visual acuity as a central functional measure
and full-field ERGs as a measure of whole-retina and synaptic function have
been utilized to grade severity. Despite these caveats, in general, disease
severity and clinical characteristics associated with missense mutations are
thought to present with relatively similar and with modest clinical severity
(19,23). Our recent reports (14,15,24) indicate that RS1 mutations that disrupt
the formation of retinoschisin protein and give a null-protein phenotype,
along with mutations that cause loss of a cysteine residue with consequent
anomalous protein folding, cause more severe disease with major reduction
of b-wave amplitudes and b/a ratios and with delayed a-wave implicit time.
By contrast, RS1 mutations that cause conservative amino acid substitutions
tend to be less severe. Many examples have been published of severe
phenotypes in families with RS1 deletions or splice site mutations that
produce premature truncated or no retinoschisin protein; severe disease
included retinal detachment and extensive macular lesions with low visual
acuity and subnormal or undetectable b-wave and reduced a-wave amplitudes
(1,15,22). By contrast, patients with conservative RS1 missense mutations
likely to alter protein structure minimally frequently had normal or
measurable ERG b-waves (18).
Even with these general patterns, gene-to-clinical correlation remains
difficult, as even family members with the same mutation or mutation type
can exhibit considerable variation (5,6,18,25,26).
Severe XLRS disease, including low vision, vitreous hemorrhage, and
varying extent of peripheral schisis, was reported within a Chinese family
with a conservative missense mutation (6), and three adult XLRS male
patients with a cysteine residue mutation (typically causing severe effects on
protein structure) had mild clinical disease and well-preserved ERGs (25).
Cysteine residue mutations disrupt disulphide bonds that are important in
stabilizing the protein configuration, generally with catastrophic
consequence. Phenotypic variability was found even between identical twin
boys presenting with nystagmus in early infancy and similar fundus
involvement limited to foveal schisis. Neither twin subsequently experienced
severe anatomical complications of the disease. The refraction of one twin at
age 2.3 years was +5.00 +2.50 ×105 (OD) and +6.00 +2.25 ×90 (OS).
Although his vision remained stable throughout his early childhood, he had
only 20/200 acuity when last tested at 22 years of age. His identical twin
brother was less hyperopic, measured at +3.75 OU, and always had less
severe nystagmus and has maintained approximately 20/40 acuity in both
eyes.
PATHOPHYSIOLOGY
Photoreceptors are an abundant primary site of retinoschisin synthesis (27).
Retinoschisin was also found in the inner retina, which suggests that the
protein is secreted by or transported to sites beyond the photoreceptors where
it is produced. Retinoschisin can be secreted by differentiated retinoblastoma
(Weri-Rb1) cells, implying that the protein is produced by photoreceptors and
then secreted (27). Antibody to retinoschisin binds to photoreceptors and
bipolar cells but not to Müller cells (28); this challenges the long-held
hypothesis that retinoschisin was a Müller cell defect. We observed that
retinoschisin is expressed by nearly all retinal neurons during development
and in the adult retina of mice (29).
The retinoschisin protein has a single discoidin domain that is thought to
help maintain cell adhesion to extracellular matrix proteins and mediate cell–
cell interactions (7,30). This may be particularly important in maintaining the
photoreceptor synapse with the bipolar cell (8).
Retinoschisin may also help regulate the fluid balance between
photoreceptor compartments (31). This hypothesis is based on the co-
localization of retinoschisin with the NaK-ATPase, a retinal cationic channel
(7,32).
Three mouse models of XLRS have been described that result in a
deficiency of endogenous murine retinoschisin (8,33,34). The scotopic ERG
of the male Rs1-KO mice mimics that of XLRS patients and has selective b-
wave reduction. One mouse model also shows an additional severe effect in
the cone ERG (8). The retina of the Rs1-KO mouse has a disorganized
architecture with areas of schisis in the inner nuclear layer, photoreceptor
loss, and shorter outer segments (8,33,35). These findings of the murine
XLRS retina support a functional role of retinoschisin in maintaining cell–
cell adhesion.
More recently (36), study of the synapse in the Rs1-KO mouse has
revealed abnormally low concentrations of intracellular Ca2+ in photoreceptor
terminals, indicating that the presynaptic function is disrupted by the absence
of Rs1 protein expression. The postsynaptic terminal also demonstrated
abnormalities in the Rs1-KO mouse with greatly diminished TRPM1 staining
at the dendritic tips with relatively normal localization of mGluR6 receptors.
Interestingly, months after AAV8-RS1 application, intracellular Ca2+
concentrations in photoreceptor presynaptic terminals were restored to near
wild type and TRPM1 receptors on postsynaptic dendritic tips also increased.
These studies revealed a role for RS1 in addition to its structural role of
maintaining cell -cell adhesion in the synapse of photoreceptor–bipolar cell
signaling. This synaptic role would be in line with the changes to the ERG b-
wave that is observed in both the human disease as well as the Rs1-KO mice.
DIAGNOSTIC STUDIES
Visual acuity is nearly always subnormal and can reach 20/200 or less in
some patients. Lesch et al. (2) described no substantial differences of mean
best-corrected visual acuity of “cystic” (<25 years old) versus “atrophic”
(>25 years old) XLRS groups, in agreement with previous reports (21,22).
However, a trend of decreased visual acuity with increasing age has been
reported (40). Peripheral visual field is affected by peripheral schisis, which
can produce absolute scotomas.
Color vision is generally unaffected, and patients do not complain of
night blindness.
OCT has revealed schisis lesions that frequently lie deeper in the retina
than previously thought, often in the midretinal layers (61) (Figure 34-3).
Areas appearing clinically intact can show shallow schisis across the macula,
termed flat or lamellar schisis (20) found in the macular area between the
arcades and associated with an abnormal ERG. Gerth et al. (62) showed using
OCT images, evidence of extrafoveal schisis occurring within the outer and
inner nuclear and ganglion cell layers, and evidence of photoreceptor outer
and inner segment layer disruption. Also Gregori et al. (63) identified cystoid
spaces accounting for retinal splitting in the inner nuclear layer and outer
plexiform layer. Small cysts, separate from those involved in foveal splitting,
can be found in the outer nuclear layer and in the ganglion cell layer and/or
nerve fiber layer using OCT.
We find that OCT changes may be associated with surgical outcomes. In
one case of a patient who had bilateral surgical intervention, one eye
recovered good of visual function in the eye which macular schisis resolved
on OCT. However, in the fellow eye that failed to recover visual function, the
macular schisis remained. Gupta et al. report a case of foveal schisis
resolution after vitrectomy for retinal detachment involving the macula (64).
The OCT combined with clinical appearance of the retina on funduscopy
has been used as one classification system for XLRS (Table 34-1). In a report
by Prenner et al. (20), patients were classified into four types based on the
presence of foveal cysts only (type 1), foveal cysts by clinical examination
plus lamellar macular schisis detected by OCT (type 2), findings of type 2
XLRS plus peripheral schisis (type 3), or foveal cysts and peripheral schisis
(type 4) (20). Lesch et al. used OCT in their large cohort of XLRS subjects to
understand the progression of disease across the lifespan and the effect of age
on the phenotype and genotype in XLRS (2). The authors found correlations
between younger age and thicker foveas and between younger age and larger
b-wave amplitudes. Based on these findings, the authors proposed the
definition of a (a) cystic form of XLRS found before 26 years of age or (b) an
atrophic form of XLRS found 26 years of age or older. In the younger group,
there were OCT findings of (a) increased foveomacular thickness due to
intraretinal cysts, and in the older group of patients, there was (b) central
thinning from macular atrophy. Our data have also corroborated this finding
of older individuals having age-related thinning with foveal atrophy being the
predominant finding in patients over 45 years of age (40). Interestingly, we
did not find a statistically significant correlation between OCT thinning and
visual acuity. We have proposed that functional worsening of ERG responses
with age by cross-sectional study of families with XLRS suggests the
progressive nature of XLRS disease (5). However, longitudinal study of
patients over a mean time of 6.8 years demonstrated no statistically
significant change in the ERG b/a ratio within eyes over this length of time,
indicating that potential progressive changes are slow moving (40).
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of the electronegative ERG includes congenital
stationary night blindness, Batten disease, BRAT1 mutations, cancer-
associated retinopathy, and vascular occlusions among others. Careful
history, age of onset, and especially molecular genetic testing are useful to
differentiate from other causes of reduced b-wave on the ERG.
Isolated cases of XLRS offer no opportunity to examine other family
members and not infrequently are mislabeled as some disorder that may
mimic retinoschisis (Table 34-2). Amblyopia, retinal dialysis, congenital
infection, and retinitis pigmentosa (RP) as the initial referring diagnoses were
later diagnosed as XLRS in a cohort of 56 males in 16 British families (42).
An isolated case of a male XLRS does not imply a new mutation, because the
female carrier mother essentially never exhibits clinical signs of the trait and
has normal vision. De novo mutations have been reported for XLRS (74), but
such instances are exceedingly uncommon.
MEDICAL MANAGEMENT
No proven treatment is currently available for XLRS; however, there are
reports of the utilization of carbonic anhydrase inhibitors (CAIs) to decrease
macular cysts. The proposed therapeutic mechanism of CAI use in XLRS is
thought to involve an increase in RPE cells’ ability to transport fluid from the
apical side through the basement membrane with subsequent transport into
the choroid. Apushkin et al. were the first to report on the effect of topical
CAIs (Dorzolamide 2%) on cystic macular cavities in XLRS. They described
a reduction in macular thickness as measured with OCT as well as
improvement in visual acuity, defined as 7 or more letter increase in BCVA
on ETDRS in 5 of 8 patients within 2 months of medication administration
(78). Since then, multiple case reports have been published utilizing both
topical and oral CAIs with variable degrees of structural change—ranging
from decrease in cysts to worsening of cysts—and variable, but most often
little, effect on visual acuity (79–85). Abalem et al. noted significant variation
of central foveal thickness throughout a day of measurements, proposing this
as an explanation for inconsistent responses to CAIs (86). In serial
observations of seven XLRS patients, we observed fluctuations of macular
schisis cavities and OCT thickness over weeks to months without any
intervention. Pennesi et al. reported on a prospective evaluation of 51 XLRS
patients treated with topical and/or oral CAIs (87). They noted variable
changes in retinal cyst cavity volume over time but no significant change in
visual acuity. The topical treatment is well tolerated for the most part and has
a favorable safety profile; however, larger studies with longer duration are
needed to evaluate efficacy. Long-term safety of systemic CAIs is unknown.
None of these CAI approaches are FDA approved for XLRS treatment.
At least two human XLRS gene therapy trials have been mounted. One
recently published 18-month results evaluated the safety and tolerability of an
RS1 adeno-associated virus (AAV8) in a dose escalation study
(ClinicalTrials.Gov NCT02317887) (93). Nine participants were assigned to
three dosage groups (1e9 vector genomes (vg)/eye, 1e10 vg/eye and 1e11
vg/eye) administered by intravitreal injection. Intravitreal delivery of a viral
vector offers advantages for the potential to reach a larger area of the retina,
and this route of administration would be particularly suited to XLRS disease
in which there is structural change to the retina. The RS1-AAV8 vector was
well tolerated in all but one individual who developed significant intraocular
inflammation leading to subsequent tractional sequelae. Systemic antibodies
to AAV8 were observed in a dose-related manner, but no systemic antibodies
were observed to the RS1 protein. One subject showed collapse of the
macular cystic cavities after receiving the higher dose of 3e11 vg/eye, which
provided a signal of possible efficacy, and this study is continuing as of this
time.
In the future, gene delivery may afford an opportunity to use protein
replacement as a treatment strategy to stabilize the retina of affected males
with XLRS. However, the lack of evidence of functional improvement for
any participant in this first reported clinical trial means that further studies are
needed. Both the window of opportunity (94) as well as the appropriate dose
and immunosuppressive regimen will have to be considered in future trials.
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35
Norrie Disease
Kimberly A. Drenser
PREVALENCE
The incidence and prevalence of Norrie disease are not known. Norrie disease
is a rare X-linked recessive disorder with clinical manifestations extensively
characterized by Warburg (1–6). The first reports were in Denmark, and since
then, it has been reported across various ethnicities. Norrie disease represents
the most severe phenotype in the spectrum of Wnt-associated
vitreoretinopathies, in which the ligand (norrin) is a functional knock-out.
More minor mutations affecting norrin lead to suboptimal binding to the
receptor complex and result in X-linked familial exudative vitreoretinopathy
(FEVR) (7). There is a complex relationship among FEVR, Norrie,
retinopathy of prematurity, and Coats disease that is still not fully understood.
Although there are several different genetic and environmental factors that
influence this range of phenotypes, this chapter will primarily consider Norrie
disease.
ENVIRONMENTAL FACTORS
None known.
GENETICS
Ocular manifestations are severe and often the presenting finding at the time
of diagnosis. Additionally, approximately one-third of patients develop
hearing loss and two-thirds mental retardation. Boys with Norrie disease are
typically blind, lacking light perception (LP) from birth or shortly thereafter,
most often by 3 months of age secondary to severely dysplastic retinae.
Findings in infancy include leukocoria, iris atrophy, retrolental fibroplasia,
vitreous hemorrhage, dysplastic retinae with gray or grayish-yellow
pseudoglioma appearances, retinal folds, and retinal detachments that are
often hemorrhagic. These eyes subsequently develop cataracts and opaque
corneas and become phthisical within the first decade of life. Historically, no
treatment has been offered other than management of a blind, painful eye.
Norrie disease is associated with mutations in the NDP gene, which is
located on the short arm of chromosome X at position 11.4. The gene
product, norrin, is a small secreted protein with a cysteine-knot motif (7–10).
Norrin is a member of the mucin-like subgroup of 10-membered cysteine-
knot proteins. The cysteine-knot motif is highly conserved in many growth
factors, including transforming growth factor-β, human chorionic
gonadotropin, nerve growth factor, and platelet-derived growth factor. Norrin
has two primary domains, a signal peptide that directs localization of the
molecule and a cysteine-knot, which provides the structural conformation
required for receptor binding and activation of signal transduction. Norrin
acts as a nontraditional ligand in a Wnt receptor: β-catenin signal
transduction pathway, which plays a regulatory role in retinal development
and regression of hyaloid vessels in the eye (8,10,11). Frizzled receptors are
coupled to the β-catenin canonical and noncanonical signaling pathway,
which results in activation of Wnt target genes. A Fzd4 knockout mouse
demonstrates and highlights the importance of this pathway in vasculogenesis
and normal retinal development. Lack of Fzd4 results in abnormal vessel
growth with anomalous capillary maturation and increased areas of avascular
retina. A mouse model lacking norrin expression results in impaired retinal
capillary beds, specifically the intermediate and deep plexi (8,11). Computer
modeling of norrin supports the importance of the cysteine residues and their
disulfide bonds in the structural conformation of norrin and, presumably, in
norrin function (13). Correlations between genotype and phenotype have
confirmed that interfering with the cysteine knot-motif significantly
compromises norrin’s ability to bind its receptor and activate the signal
transduction pathway (7). Mutations not affecting cysteine residues may alter
protein folding and compromise pathway activation to varying degrees, but
their effect on norrin structure and function is not as clear and appears to
result in partial pathway activation, resulting in a less pathologic heritable
phenotype as seen in FEVR. Untranslated regions within NDP have
regulatory functions that control the expression and stability of norrin.
Mutations in these regions have also been associated with Norrie disease
(13–15).
The Norrie disease protein (NDP), originally named EVR2, was
described over a decade ago, giving way to the classification of a number of
congenital retinopathies as “NDP-related.” These include persistent fetal
vasculature syndrome (PFVS), retinopathy of prematurity (ROP), Coats
disease, and X-linked FEVR (13,16,17). These vitreoretinopathies, however,
may involve mutations in genes other than NDP, such as FZD4, LRP5,
TSPAN12, ZNF408, and ATOH7 (18). Severe presentations of these diseases,
as well as stage 5 ROP, can be indistinguishable from Norrie disease by
examination alone (Figure 35.1) making a differential diagnosis with careful
attention to excluding other causes important.
PATHOPHYSIOLOGY
The norrin protein is a ligand specific for development and maintenance of
the retina, inner ear, and parts of the CNS. Wnt 7 may also act in the ear and
CNS to activate the Fzd4 and Lrp5 receptors, but it does not exist in the
retina, which may explain why mutations that eliminate norrin function have
an absolute impact on the eye and more variable impact on hearing and
cognition (19).
DIAGNOSTIC STUDIES
Norrie disease remains a clinical diagnosis based initially on eye findings. An
examination under anesthesia is often required to evaluate the retina for
bilateral stalks with detached and poorly developed retina in the setting of an
infant with poor vision and abnormal red reflex. A differential diagnosis
should include ROP, FEVR, and PFV. Genetic testing using a panel, which
includes the NDP gene is key. Hearing tests, monitored over the lifespan of
the child, and neurodevelopmental evaluation are recommended. Family
history may be helpful, as affected male family members generally have
severe vision loss documented at or near birth. Abnormal hearing and/or
cognitive issues are seen in both Norrie disease and extreme prematurity.
Birth history and clinical course will help distinguish between these two
entities. Retinoblastoma must also be ruled out. Often this can be done easily
by clinical examination alone, but occasionally computed tomographic
scanning, brain and orbit magnetic resonance imaging, and/or ultrasound are
necessary when leukocoria is the presenting sign.
MANAGEMENT
Historically only supportive measures have been available for patients.
Warburg’s extensive study of Norrie disease only revealed rare cases with
vision beyond infancy. Out of 24 patients in her series, all had no LP except
for one boy who could count fingers until age 12 when LP was lost and
another boy who could perceive light (4). In Warburg’s review of the
literature (1966), she identified an additional 106 patients with Norrie
disease. Of these, only six patients were noted to have LP or pupillary
reactivity after 3 months of age. Jacklin et al. (20) reported on a patient who
underwent lensectomy and vitrectomy in one eye and found that the operated
eye avoided phthisis bulbi at 2 years of age unlike the unoperated eye. With
early surgical intervention, we found that 70% of patients maintained at least
LP vision in one eye after vitrectomy. Additionally, only 8% of eyes became
phthisical (21). Therefore, we believe that surgical intervention at the earliest
time point may be beneficial for these patients.
We have found in all of our Norrie disease patients that there is residual
stalk tissue (hyaloidal vessel remnant) connecting the posterior lens to the
dysplastic retina. Transection of this stalk tissue releases significant traction
on the retina. It is our belief that this release of the anteroposterior traction on
the retina is likely to, at least in part, explain the benefit of vitrectomy for
Norrie disease. Release of this traction not only allows the retina to settle
posteriorly but also eliminates an anteroposterior tether that likely restricts
normal ocular development and progressive damage to the lens and ciliary
body in addition to worsening the tractional retinal detachment. In cases in
which there is a dense retrolental plaque with total retinal detachment,
meticulous peeling away of this tissue from the retinal surface and ciliary
processes not only affords the opportunity for the retina to gradually reattach
but also decreases the likelihood of hypotony secondary to ciliary body
traction. Given the natural history of the disease (loss of LP by 3 months of
age in the vast majority of cases), we perform vitrectomy as early as possible.
If there is significant lens opacity obscuring our view of the fundus or
significant retrolental fibroplasia intimately apposed to the lens, then we
often remove the lens in addition to performing a vitrectomy (21).
Interestingly, despite the presence of large areas of avascular retina
(which we have not treated with laser photocoagulation, cryotherapy, or anti-
VEGF agents), we have not noted any neovascularization in our patients.
Perhaps the avascular retina is so dysgenic that it does not mount a significant
up-regulation in vascular endothelial growth factor or other angiogenic
factors.
When patients develop phthisis, enucleation is reasonable if the eye
becomes painful.
VISION REHABILITATION
Patients with Norrie disease may have some ambulatory vision, although
most retain LP only after surgery. Working with a low vision specialist is
recommended. Chapter 14 discusses low vision services.
Roles of other physicians and health care providersNorrie disease is a
neurodevelopmental syndrome, and as such requires multiple specialists to be
involved in the care of the child. A pediatric neurologist will be the most
important caregiver. Patients will also need counseling from a geneticist and
will require repeated hearing tests.
REFERENCES
1. Warburg M. Norrie disease: a new hereditary bilateral pseudotumor of the retina. Acta
Ophthalmol (Copenh) 1961;39:757–772.
2. Warburg M. Norrie’s disease (atrofia bulborum hereditaria). Acta Ophthalmol (Copenh)
1963;41:134–146.
3. Warburg M. Norrie disease. Trans Ophthalmol Soc U K 1965;85:391–408.
Warburg M. Norrie disease: a congenital progressive oculo-acoustico cerebral degeneration.
4. Acta Ophthalmol (Copenh) 1966;(Suppl 89):1–47.
5. Warburg M. Norrie disease. Birth Defects Orig Artic Ser 1971;7(3):117–124.
6. Warburg M. Norrie disease: differential diagnosis and treatment. Acta Ophthalmol (Copenh)
1975;53(2):217–236.
7. Wu WC, Drenser K, Trese M, Capone A Jr, Dailey W. Retinal phenotype-genotype correlation
of pediatric patients expressing mutations in the Norrie disease gene. Arch 8. Ophthalmol
2007;125(2):225–230.
8. Xu Q, Wang Y, Dabdoub A, et al. Vascular development in the retina and inner ear: control by
Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell 2004;116:883–895.
9. Black G, Redmond RM. The molecular biology of Norrie disease. Eye 1994;8:491–496.
10. Berger W. Molecular dissection of Norrie disease. Acta Anat 1998;16:95–100.
11. Robitaille J, MacDonald ML, Kaykas A, et al. Mutant frizzled-4 disrupts retinal angiogenesis in
familial exudative vitreoretinopathy. Nat Genet 2002;32:326–330.
12. Ohlmann AV, Adamek E, Ohlmann A, Lutjen-Drecoll E. Norrie gene product is necessary for
regression of hyaloid vessels. Invest Ophthalmol Vis Sci 2004;45:2384–2390.
13. NDP Related Retinopathies [database online]. Bethesda, MD: National Institute of Health;
2005.
14. Kenyon JR, Craig IW. Analysis of the 5' regulatory region of the human Norrie disease gene:
evidence that a non-translated CT dinucleotide repeat in exon one has a role in controlling
expression. Gene 1999;227:181–188.
15. Davuluri RV, Suzuki Y, Sugano S, Zhang MQ. CART classification of human 5' UTR
sequences. Genome Res 2000;10: 1807–1816.
16. Drenser KA, Fecko A, Dailey W, Trese MT. Characteristic phenotypic retinal appearance in
Norrie disease. Retina 2007;27(2):243–246.
21. Schulman J, Jampol LM, Schwartz H. Peripheral proliferative vitreoretinopathy in a full-term
infant. Am J Ophthalmol 1980;90:509–514.
17. Kondo H. Complex genetics of familial exudative vitreoretinopathy and related pediatric retinal
detachments. Taiwan J Ophthalmol 2015;5(2):56–62.
18. Wang Y, Cho C, Williams J, et al. Interplay of the Norrin and Wnt7a/Wnt7b signaling systems
in blood-brain barrier and blood-retina barrier development and maintenance. Proc Natl Acad
Sci U S A 2018;115(50):E11827–E11836.
19. Jacklin HN. Falciform fold, retinal detachment and Norrie disease. Am J Ophthalmol
1980;90(1):76–80.
20. Walsh MK, Drenser KA, Capone A Jr, Trese MT. Early vitrectomy effective for Norrie disease.
Arch Ophthalmol 2010;128(4):456–460.
36
Incontinentia Pigmenti
T. Y. Alvin Liu, and Morton F. Goldberg
INTRODUCTION
Incontinentia pigmenti (IP), also known as Bloch-Sulzberger syndrome, is a
rare inherited disease in which a generalized abnormality of ectodermal
structures manifests as characteristic skin lesions (Figure 36-1) and variable
degrees of retinal and central nervous system (CNS) disease due to a
progressive vasculopathy.
FIGURE 36-1 A newborn infant with IP and stage 1
dermatologic manifestations. The vesicles and erythema
are distributed linearly along the trunk and arms, sparing
the face.
WORLDWIDE IMPACT
IP has been reported in patients around the world. Although the total number
of patients affected is small, untreated severe cases can cause blindness,
increasing the burden of vision impairment.
GENETICS
Pedigrees of IP reflect classic mendelian inheritance in an X-linked dominant
pattern. Because homozygosity is lethal in utero, only women inherit the
disease. Although highly penetrant, the expressivity of the disease is quite
variable presumably due to female X chromosome inactivation (lyonization).
De novo mutations appear to be common, as an affected pedigree is identified
in only half of new cases (2). Affected women in such pedigrees often had
male miscarriages. Extended pedigree analysis has demonstrated a 2:1 ratio
of daughters to sons among affected mothers. Most reports of males with IP
have no family history of the disease, suggesting somatic mosaicism (6). Rare
reports of males with inherited IP can be explained by a Klinefelter karyotype
(47,XXY), thus being exceptions that prove the rule (7). All males with the
disease should have their karyotypes evaluated for this reason. Appropriate
genetic counseling should be offered to all affected families.
DISEASE PATHOGENESIS
In 2000, the International Incontinentia Pigmenti Consortium identified
mutations in the gene encoding for nuclear factor kappa B (NF-kB) essential
modulator protein (NEMO) at locus Xq28 (8) as the cause of the disease (9).
This small protein acts as a regulatory subunit for activation of NF-kB, a
transcription factor that plays a critical role in the expression of genes crucial
to cell survival and proliferation. NF-kB regulates genes involved in critical
developmental processes, innate and adaptive immune responses, cell
adhesion, and apoptosis. It also mediates inflammatory cascades (10). A
genomic deletion accounts for 80% to 90% of the disease and suggests that
the disease is caused by loss of function.
Indeed, targeted deletion of the gene encoding NEMO in mice
recapitulates the human disease. NEMO-deficient male mice die in utero. The
female mice develop patchy skin lesions characterized by granulocyte
infiltration and hyperproliferation of keratocytes, similar to the histology of
patients with IP (11).
Histopathologic studies of the eyes of NEMO-deficient mice have helped
elucidate the pathogenesis of the retinal disease. Their retinal vasculature is
characterized by increased arteriolar tortuosity. The arteriolar lumens are
narrowed due to endothelial hypertrophy and basement membrane thickening
(12). Complete retinal vasoocclusion is commonly observed in human
histopathology of IP but was not seen in these mice (13). It seems plausible
that the luminal narrowing represents an earlier stage of the disease evolution.
Interestingly, the inflammatory changes and perivascular eosinophilic
infiltration seen in dermatologic histology were not observed in the retinas of
these mice.
The peripheral retinal perfusion of many patients with IP is abnormally
reduced and appears to be responsible for many of the blinding complications
of the disease. Fluorescein angiography (FA) of the disease reveals many
similarities between the retinopathy of IP and retinopathy of prematurity
(ROP). In both cases, vascular tortuosity is prominent. A rather abrupt
transition occurs between mature vascular central retina and an avascular
periphery (Figure 36-2). In severe cases, later fibrovascular proliferation,
exudation, and retinal detachment occur in a manner quite similar to ROP.
The advent of ultra–wide-field (UWF) retinal imaging, defined by the
Diabetic Retinopathy Clinical Research Network (DRCR.net) as a field of
view of 100 degrees or more (14), has permitted better characterization of
vascular abnormalities in the far peripheral retina in various retinal vascular
diseases, including IP (15). UWF FA findings in IP include abnormal
vascular anastomoses, pathologically straightened retinal vessels, varying
degrees of nonperfusion, and microaneurysms (Figure 36-3) (16).
SYSTEMIC MANIFESTATIONS OF
DISEASE
IP was originally recognized as a dermatologic disease. The widely adopted
clinical criteria for diagnosing IP emphasize the dermatologic manifestations
and do not account for the common CNS manifestations of the disease (Table
36-1) (30). These criteria were developed before identification of the genetic
defect but still prove useful for establishing a clinical diagnosis (1,28).
However, genetically confirmed cases of IP without clinical dermatologic
manifestations have been reported (30).
Stage 1: Diffuse blisters and erythema with relative sparing of the face.
Stage 2: Hyperkeratotic papules develop on the distal limbs and scalp.
Stage 3: Linear hyperpigmented streaks and whorls along the lines of
Blaschko.
Stage 4: Pale, hairless patches often seen on the posterior calves.
DIAGNOSTIC STUDIES
Genetic sequence analysis is available to detect both the genomic deletion
that accounts for 80% of the disease and smaller mutations (usually in exon
10) that account for another 8.6% of the disease. For rare cases in which
genetic testing does not establish a diagnosis, peripheral eosinophilia and skin
biopsy findings of eosinophilic infiltration and extracellular melanin can
support the diagnosis (46).
FA is an invaluable tool for evaluating the retinal vasculature. For
patients with IP, it can reveal the extent of peripheral nonperfusion and
subclinical neovascularization and guide peripheral ablation by
photocoagulation (47,48). A large series of infants examined by FA
demonstrated irregular and distorted foveal avascular zones in all eyes (19).
Careful sequential examination of the macula with FA revealed abnormal
macular perfusion and dynamic remodeling of the fovea as well as a macular
infarct.
Recent advancements in retina imaging, including UWF FA, OCT, and
OCTA, have permitted detection of structural and vascular abnormalities that
may not be apparent on standard ophthalmoscopy in IP patients (15,22).
UWF FA can capture pathologies that are peripheral to standard views of 30-
degree FA even with peripheral sweeps (16). Simultaneous multimodal
imaging shows that IP patients can have severe peripheral vascular
pathologies with near-normal macular structure and vasculature, suggesting a
potential difference in susceptibility of the central and peripheral retina to
vascular insult. Areas of flow loss on OCTA are associated with inner retinal
thinning on structural OCT in the same locations, although the exact temporal
relationship between pathologies seen on these two imaging modalities needs
further investigation (16).
When vitreous hemorrhage, cataract, and retrolental fibroplasia prevent
an adequate retinal exam, ocular ultrasonography can characterize the extent
of disease and narrow the differential diagnosis by excluding calcification
and/or mass lesions. The electroretinographic recordings of a 13-month-old
girl with IP have been reported (49). Both photopic and scotopic responses
were markedly diminished. The decreased flicker response to 30 Hz and
abnormal oscillatory potentials indicate cone function compromise consistent
with the foveal abnormality observed in this patient.
DIFFERENTIAL DIAGNOSIS
IP has a highly characteristic dermatologic appearance. When the skin lesions
are present, peripheral retinal nonperfusion and the associated vitreoretinal
sequelae are best explained by this diagnosis. Occasionally, the skin lesions
are subtle or subclinical, and alternative ophthalmologic diagnosis must be
entertained. ROP, familial exudative vitreoretinopathy, Norrie disease, Eales
disease, and sickle cell retinopathy are all characterized by peripheral retinal
nonperfusion and secondary neovascularization. Extensive peripheral
nonperfusion on FA has been shown in children who sustained nonaccidental
trauma (50,51). Epiretinal neovascularization has been observed in this
setting (52). If no view of the posterior pole is possible, the differential
diagnosis must be expanded to include other causes of leukokoria.
Screening
Of all the various manifestations of IP, the peripheral retinal vascular disease
is most amenable to treatment. Like many diseases of the peripheral retinal
vasculature, prompt, thorough ablative therapy with laser photocoagulation,
preferably, or cryotherapy may prevent and/or halt the vision-threatening
sequelae of retinal neovascularization, exudation, hemorrhage, and retinal
detachment. Because the incidence of vasoocclusive events peaks in the early
postpartum period, early diagnosis of the disease and recognition of the need
for ophthalmic monitoring are critical. Children with IP should be evaluated
soon after diagnosis by an ophthalmologist skilled in examination of the
pediatric peripheral retina and strong consideration should be given to
performing a UWF FA to detect areas of nonperfused retina that might be
missed on funduscopic examination (15). When no retinal pathology is
evident, the interval of follow-up depends on the age of the child and the
extent to which the periphery can be evaluated. When the diagnosis is
suspected at birth, due to either characteristic skin lesions or family history,
retinal examination within 1 or 2 weeks of birth is optimal. Even very subtle
vascular abnormalities warrant close follow-up, as the retinal vascular disease
can progress rapidly over the first few weeks of life (44). Generally, we
believe that if ablative treatment is delivered for nonperfused retina and/or no
significant pathology develops by 6 months of age, then the interval of
follow-up can be extended. Examination under anesthesia is often required.
More studies are required to better understand the long-term risk in these
patients.
MANAGEMENT
Peripheral Ablation
Some children with IP and peripheral retinal avascularity develop profound
visual loss due to retinal detachment. Initial reports of peripheral ablation
with cryotherapy and laser photocoagulation described prompt control of the
neovascular response and prevention of retinal detachment (53–55).
Subsequent reports of treatment for milder degrees of neovascularization and
for extensive nonperfusion without neovascularization support peripheral
ablation as an effective therapy for stabilizing the disease (56–60). However,
the criteria for treatment of these milder cases are not clear, as the
proliferative retinopathy of IP often stabilizes without intervention and
peripheral ablation can be associated with an increased risk of cicatricial
pathology such as epiretinal membranes and proliferative vitreoretinopathy.
One report describes a girl, with peripheral nonperfusion, neovascularization,
and macular ectopia, who maintained vision over 13 years of follow-up
without treatment (61). In our practice, five children with mild
neovascularization have been monitored without treatments and remained
stable with follow-up ranging from 1 to 6 years. Nonetheless, some adults
present with tractional detachments related to IP and nonperfused retina that
had not been previously treated, suggesting a reason for early treatment of
nonperfused retina.
Vitreoretinal Surgery
Repair of retinal detachment due to IP is possible, although anatomic success
rates appear low in total retinal detachment and may be similar to eyes with
stage 5 ROP (27). Often, a combination of vitrectomy and scleral buckling is
employed (see also Chapters 60 and 61). Preservation of vision may depend
on the extent of the retinal detachment and of ischemic retina that might
affect the macula (22). In early studies, prior to UWF FA and indirect laser
management, at least one child retained fixation behavior and limited
ambulatory vision (27). Similar to ROP, central involvement is associated
with poor anatomic outcomes (62). In cases of localized neurosensory
detachment, observation without surgery occasionally may be reasonable, as
there is a report of a patient with retinal pigment epithelium
hypopigmentation and retinoschisis in a pattern suggestive of a spontaneously
resolved localized retinal detachment (63).
Strabismus
Strabismus in children with IP often presents in infancy, is usually attributed
to sensory deprivation due to retinal pathology, and can be addressed for
cosmesis in later childhood (29). Pediatric eyes with significant macular
pathology can occasionally have surprisingly good visual acuity. However,
and if the child has good vision in both eyes, ocular alignment surgery should
be considered in the first years of life to maximize the chance for stereopsis.
Amblyopia therapy may be appropriate for many children with ocular
manifestations of IP. In the setting of a normal-appearing retina,
neuroimaging may be considered.
Enucleation
In contrast to ROP, the vitreoretinal disease of IP is often markedly
asymmetric. Good visual function is often present in the fellow eye. Thus,
aggressive attempts at surgical repair of very advanced cases are sometimes
not performed because of the possibility of phthisis and intractable pain.
Enucleation in the setting of advanced IP has been reported, although painful
amaurosis fortunately appears rare (29).
Visual Rehabilitation
Some patients with IP develop low vision or legal blindness despite the best
ophthalmologic care. These patients should be referred at the earliest possible
time to a low vision service for guidance and assistance in procuring
accommodations for home, work, and school.
ETHICAL CONSIDERATIONS
All affected women, regardless of the severity of their phenotype, should
understand the importance of timely neonatal eye exams for their daughters
and the likelihood of lethality in males. Genetic counseling should be
provided. If a woman has a molecular genetic diagnosis, in vitro fertilization
with preimplantation genetic testing may be possible to reduce the chance of
an affected offspring. Families should be counseled that spontaneous
mutations do occur, so not having a family history does not mean the
condition is not genetic. In addition, due to extremely variable expressivity, it
is important for families to understand that future affected generations may
be more or less severely affected than the current generation.
FUTURE TREATMENTS
Therapies to replace the defective NEMO protein may be a possibility for
patients in the future. Continued evolution of surgical techniques for
alleviating retinal traction and detachment may improve the outcome for
patients who have severe disease.
ACKNOWLEDGMENT
We would like to acknowledge and thank Dr. David Baranano for his
invaluable contribution to the previous edition’s chapter on incontinentia
pigmenti.
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37
High Myopia and Vitreoretinopathies
Sherveen S. Salek, and G. Baker Hubbard III
PATHOPHYSIOLOGY AND
ENVIRONMENTAL FACTORS
High myopia is characterized by elongation of axial length followed by
stretching of the posterior eye wall, leading to complications such as
choroidal thinning, staphyloma, macular schisis, macular hole, and changes
in optic nerve morphology (4).
Both environmental and genetic factors are thought to play a role in axial
length elongation, although the exact etiology and mechanisms remain
unknown. Time spent outdoors in childhood is thought to play a role in
preventing onset of myopia, although the correlation of time spent outdoors
with progression of myopia remains less clearly established (5). A correlation
between increased levels of schooling or professional education and myopia
has also been found (6). Recent studies have found an increase in prevalence
of myopia, up to 80%, in Asian schoolchildren. The rate of high myopia in
these children has increased to 20% (7). In East and Southeast Asian
children, high myopia significantly increases in prevalence around the age of
11, with affected children appearing to become myopic initially around the
age of 6. Time spent outdoors appears to affect the progression of these
children to high myopia, and several interventions have been proposed to
increase time outdoors for schoolchildren with the aim of addressing this
public health challenge. There are increasing numbers of prospective studies
evaluating the role of time spent outdoors in development and progression of
myopia, which have tried various methods of standardization to ensure that
time spent outdoors is accurately measured (8).
GENETICS
The continuing epidemic of nonsyndromic myopia in recent decades has
raised the question of whether genetic or environmental factors are more
relevant. Numerous genes have been associated with nonsyndromic myopia.
One review of recent literature listed 21 candidate myopia genes, some of
them identified in earlier genome-wide association studies, which are
involved in cellular and biochemical processes as diverse as mannosylation,
glycosylation, lens development, gliogenesis, and Schwann cell
differentiation (9). Many of these processes are involved in connective tissue
formation. The goal of future studies is to identify the pathogenesis of these
mutations and study potential interventions for nonsyndromic myopia based
on this knowledge.
Stickler syndrome is a hereditary connective tissue disorder with multiple
ocular and extraocular phenotypes caused by a broad array of genetic
mutations. Abnormalities of the vitreous gel, commonly termed as the
pathognomonic “membranous vitreous,” constitute type I Stickler syndrome
and constitute the majority of patients (10,11). This phenotype correlates with
mutations in the COL2A1 gene. Type II Stickler syndrome consists of the
beaded and irregular strands of vitreous scattered sparsely throughout the
vitreous cavity and has been shown to correlate with COL11A1 mutations
(12). More recent investigations, however, have found patients with COL2A1
mutations with a hypoplastic vitreous phenotype with sparse irregular
lamellae.
The early onset of high myopia with vitreous abnormalities is thought to
be a marker for Stickler syndrome and should warrant further investigation,
including a detailed family history, retinal examination of both eyes, skeletal
survey, and consideration of genetic testing (13). Genetic testing is especially
useful in patients with early-onset high myopia (defined as greater than minus
6 D of refractive error prior to age 7) and whose evaluations do not reveal
additional systemic abnormalities or family history. Examination of children
with early-onset high myopia with mutations in COL2A1 and COL11A1 may
reveal the presence of posterior vitreous detachment, foveal hypoplasia,
hypermobility of the elbow joint, and vitreous abnormalities (14).
Wagner syndrome is caused by mutations in the VCAN gene (also known
as Versican or CSPG2), resulting in haploinsufficiency and an autosomal
dominant phenotype. Like Stickler syndrome, Wagner syndrome can also
have extraocular manifestations. A case report by Ankala and colleagues
found that an 11.7 kilobase (kb) deletion encompassing exon 8 of VCAN was
correlated with distinctive facial features and gastrointestinal symptoms (15).
Mosaicism in VCAN mutations is also correlated with a milder Wagner
phenotype, demonstrating asymmetry between each eye (16).
Marfan syndrome is caused by mutations in FBN1, which encodes the
fibrillin-1 protein. Fibrillin microfibrils are found in association with elastic
fibers and are essential components in many extracellular matrix tissues (17).
Histologic examination of aborted human fetal eyes from 5 to 11 weeks of
gestational age reveals increased expression of fibrillin-1 protein in vascular
structures, bridging the ciliary body and the developing lens, hyaloid, and
retina, which suggests a scaffolding role for this vasculature in the embryonic
development of these structures (18).
Initial genetic mapping in 1996 localized the causative mutation in
Knobloch syndrome to the 21q22.3 locus and consequently identified
COL18A1 as the causative gene (19). The encoded protein has a role in
determination of retinal architecture and is also thought to affect
embryogenesis and neural tube closure. A recent review of 12 patients from 7
families found presence of anterior segment abnormalities in Knobloch
syndrome, including cataract, lens subluxation, absent iris crypts, and
transillumination defects (TIDs) in the iris (20). The presence of TIDs was
associated with glaucoma in two patients in this series. Fundus characteristics
in this autosomal recessive condition include a collapsed vitreous appearance,
macular atrophy, and mottling of the fundus. Interestingly, COL18A1
mutations have been linked with iridocorneal angle closure in adults without
any other ocular or systemic features of Knobloch syndrome (21). This
finding lends further support to the role of the collagen-encoding gene in the
formation of angle structure, in addition to the retinal architecture.
CLINICAL FEATURES
Myopia can be diagnosed on the basis of the spherical equivalent of the
negative refractive error. Retinal findings in myopia include chorioretinal
atrophy, lattice degeneration, pigmentary degeneration, lacquer cracks,
posterior staphyloma, Fuchs spot, macular degeneration, as well as retinal
breaks and RD (22). Nonsyndromic myopia refers to the absence of any other
extraocular manifestations.
Stickler syndrome, also called hereditary arthro-ophthalmopathy or
hereditary arthro-ophthalmo-dystrophy, is an inherited disorder of collagen
formation. Besides its ocular manifestations, patients also have
musculoskeletal, orofacial, and auditory abnormalities. The condition remains
rare with an incidence of approximately 1 in 7,500 to 9,000 live births (23).
Stickler syndrome is characterized by the variable presence of a small
mandible, flat nasal bridge, upturned nasal tip, bifid uvula, cleft palate,
vitreous abnormalities, cataract, and increased rate of RD (24) (Figure 37-1).
Stickler syndrome is divided into the type I, type II, and nonocular type III
phenotypes. As discussed previously, type I patients have mutations in
COL2A1 and have the distinct optically empty or, by some descriptions,
membranous vitreous appearance, whereas type II Stickler patients have
strands of beaded vitreous present with mutations in the COL11A2 gene (25).
Cortical cataracts, often wedge-shaped, can be present in Stickler syndrome,
and increased incidence of infantile-onset glaucoma is also observed (26).
The fundus examination can reveal both radial perivascular and
circumferential lattice degeneration. RDs can occur in 50% of patients with
Stickler syndrome and result from giant retinal tears, usually located
anteriorly, as well as posterior breaks in the retina. Careful examination of the
retinal periphery is warranted in all patients with Stickler syndrome or with a
suspected family history.
Extraocular manifestations of Stickler syndrome that can aid in the
diagnosis include the above-mentioned craniofacial anomalies, in particular
the flat nasal bridge. Additional findings include thoracolumbar spinal
anomalies. One series reported 34% of patients with scoliosis, 74% endplate
abnormalities, 64% Schmorl nodes, 43% platyspondylia, and 43%
Scheuermann-like kyphosis (27). Of note, only 1 patient in this series of 53
patients had absence of any spinal abnormalities. Although the findings were
usually associated with symptoms of back pain, they were generally self-
limited and did not require spinal surgery. Stickler syndrome is also
associated with sensorineural hearing loss. Type I patients have
predominantly higher-frequency hearing loss on audiometric testing, and type
II patients have more moderate hearing loss across low and high frequencies
(28). Conductive hearing loss has also been reported in patients with Stickler
syndrome who have cleft palate defects. Patients with mutations in COL11A1
and COL11A2 (Type II phenotype) appear to have a higher association with
clinical hearing impairment than those with COL2A1 mutations (Type I) (29).
Wagner syndrome is an autosomal dominant inherited vitreoretinopathy
caused by a mutation in the VCAN gene. The prevalence is unknown, and
only 300 cases have been described worldwide with approximately half in the
Netherlands (30). Patients with Wagner syndrome present with ocular
findings consisting of empty vitreous, lattice degeneration, chorioretinal
atrophy, and mild myopia. Peripheral tractional RDs are observed in patients
with Wagner syndrome and usually do not have extraocular manifestations
(31) unlike patients with Stickler syndrome. Dark adaptation responses are
usually preserved. However, unlike Stickler syndrome, Wagner syndrome
can be associated with diminished B-wave amplitudes on both light-adapted
and dark-adapted electroretinography (ERG). Furthermore, multifocal ERG
and visual fields can also be severely restricted in these patients (32).
Marfan syndrome is an autosomal dominant connective tissue disorder
present in approximately 1 in 5,000 people (33). Marfan syndrome is caused
by mutations in the fibrillin gene, FBN1, which encodes an extracellular
protein, fibrillin-1, and is associated with numerous ocular (including
vitreoretinal), musculoskeletal, and cardiac abnormalities associated with
significant morbidity and mortality (34). Previous investigators have noted an
incidence of RD of 3.5% to 11% in patients with Marfan syndrome (35).
Patients with ectopia lentis or prior lens extraction have a higher incidence of
RD with one study reporting RD in 38% (36).
Knobloch syndrome is a rare autosomal recessive condition characterized
by high myopia and, in some cases, occipital encephalocele. The prevalence
is unknown (37). Patients also have increased risk of RD, vitreoretinal
degeneration, lens subluxation, cataract, smooth irides, and persistent fetal
vasculature (20).
Ehlers-Danlos syndrome is a heterogeneous group of connective tissue
disorders most commonly characterized by joint hypermobility and laxity and
is associated with an increased risk of RD (38). Categorized into various
subtypes, the condition is present in approximately 1 in 5,000 individuals
(39). However, the prevalence of retinal pathology in these patients is
unknown.
DIAGNOSTIC STUDIES
The diagnosis of high myopia is based on meeting the threshold refractive
error of a spherical equivalent of at least minus 6 D. Several investigators
have sought to determine if there are factors that can predict nonsyndromic
pediatric high myopia. A large observational cohort study found that the
presence of low hyperopia or moderate myopia on spherical equivalent
refraction was associated with later development of juvenile myopia and
subsequent progression (40). Lens power, axial length, and accommodative
convergence to accommodation (AC/A) ratio also had a statistically
significant association, but these measurements are difficult to ascertain in a
clinical setting. Closer reading distance, in addition to a more myopic
baseline refraction, has been associated with faster progression of myopia
over a 1-year period in a study of second grade schoolchildren in Taiwan
(41).
Slit lamp and dilated fundus examination form the cornerstone of the
diagnosis of both juvenile myopia and the inherited vitreoretinopathies. A
careful family history can alert one as to whether additional workup of family
members or more advanced diagnostics are necessary. In patients suspected
of having Stickler syndrome, genetic testing may be warranted and can help
with counseling of other family members. Radiographic studies, audiometry,
and electrocardiography can also alert the clinician to the presence of
extraocular manifestations that require monitoring and potential treatment.
Similarly, patients with Marfan syndrome may benefit from genetic testing
and further consultation with pediatrics and cardiology for monitoring of
potentially life-threatening aortic vascular pathology (42).
MANAGEMENT
Myopia and vitreoretinopathies may result in RDs that can warrant surgical
interventions (see also Chapters 60 and 61). This section discusses several
key areas of management of juvenile myopia and inherited
vitreoretinopathies that do not involve intraocular surgery or scleral buckling.
Equipment
Cryopexy system or indirect laser.
Outcome Expectations
Of note, about 9.0% of patients failed prophylactic therapy. Failure of
prophylactic therapy was attributed to both untreated posterior breaks as well
as anterior breaks that extended through the cryotherapy barrier (43,44).
Although the published Cambridge protocol from 2014 is the most robust
data available to support prophylactic cryotherapy in patients with Stickler
syndrome to reduce the risk of RD, there are no randomized clinical trials yet
available. Furthermore, many ophthalmologists find it more facile to treat
with laser retinopexy as opposed to cryotherapy and extrapolate the results of
the Cambridge protocol to the former treatment (Figure 37-2). Case series of
successful prophylactic laser for Stickler syndrome have been reported in the
literature, although the reports are on a smaller scale (45). The optimal laser,
location, and extent of treatment remain unknown (46). Even with successful
treatment, retinal detachment can occur from breaks i the posterior retina
(Figure 37-3).
Complications
The authors note that only a single patient had an RD that was attributed to a
new break that was formed as a result of contraction at the posterior border of
the cryotherapy treatment. No serious side effects (choroidal hemorrhage,
macular pucker, or unexplained visual loss) were reported in the study, and
the most common side effect was eyelid or conjunctival inflammation.
Accommodative insufficiency and anisocoria/mydriasis were reported in
9.6% and 2.0% of patients, respectively. Most accommodative insufficiency
resolves after about a month in children (43,44).
Outdoor Time and Myopia
Outdoor time has been hypothesized to prevent onset and progression of
myopia. One of the challenges of large studies to evaluate outdoor time and
light exposure has been ensuring standardization and appropriate
measurement of light exposure and activity both during and after school
hours. Most studies on this subject depend on questionnaires of children,
parents, and teachers. However, these assessments can be subject to recall
bias, especially given that they depend mostly on parents’ completion (47). A
combination of accelerometers and global positioning system (GPS) devices
has been used to track indoor versus outdoor times for children, but even
these methods can sometimes fail to distinguish between these two settings.
The devices may also not accurately measure activity, although they are
continuing to improve in terms of accuracy and cost and are being used more
often in myopia studies. Sensors can be incorporated into custom-designed
wearable vests in order to ensure adherence and proper measurement (48).
Portable light meters have also been used to measure light exposure, which is
the direct variable that has been hypothesized to affect myopia onset and
progression through the light-dopamine pathway (49).
A randomized controlled trial in Taiwan examined the effectiveness of
increased outdoor time in schoolchildren aged 6 and 7 and controlled for light
intensity in outdoor activities (50). Participants in the intervention group were
encouraged to have 11 or more hours of outdoor activity each week and wore
light meters during school hours in order to record light exposure accurately.
Outside of school, participants kept logs to record outdoor exposure. At the
end of 1 year, patients in the intervention arm with increased outdoor
exposure had reduced rates of onset of myopia, progression of refractive
myopia, as well as reduced axial elongation (0.28 mm vs. 0.33 mm).
Although these results were statistically significant, their clinical significance
is still being studied.
An additional study of 382 first graders from Beijing found less time
spent outdoors, more time spent indoors, and parental myopia to be
associated with axial elongation during a 4-year follow-up. This study was
based on a questionnaire of recall for outdoor exposure. Paternal education,
family income, gender, and region of residence were also associated with
axial length elongation and progression of myopic refractive error but only in
univariate analysis (51).
Atropine
Topical atropine has gained increasing utilization for prevention of myopia
and progression with multiple randomized controlled trials, demonstrating its
safety and efficacy (52). In Taiwan, 49.5% of children diagnosed with
myopia were prescribed topical atropine in 2007 (53). Global surveys have
shown that this trend has gone worldwide with an increasing number of
pediatric ophthalmologists initiating treatment with topical atropine for
children with progression of myopia (54). Additional studies in China have
demonstrated reduced axial length elongation in children 7 to 12 years of age
who receive atropine (55). Increasingly lower concentrations of atropine are
being used due to studies concluding equal effectiveness with reduce adverse
effects. Atropine arrives in a standard 1% concentration, but diluted 0.01%
atropine has been reported to slow myopic progression over 1 year of follow-
up. Children with low baseline refractive error (less than minus 1 D) have
been reported to respond especially well to diluted atropine in comparison
with controls (56).
A large meta-analysis of atropine for treatment of myopia examined
3,137 children from 19 unique studies (both randomized controlled trials and
cohort studies). Weighted mean differences in myopic progression between
treatment and control groups were 0.50 D per year for low-dose atropine,
0.57 D per year for moderate-dose atropine, and 0.62 D per year for high-
dose atropine (57). The authors concluded that all doses were equally
beneficial with respect to myopia progression. High-dose atropine was,
however, associated with more photophobia (43.1%) than low-dose atropine
(6.3%) in the meta-analysis. Interestingly, there were differences in axial
length elongation between the various concentrations of atropine, although
the reduction of spherical equivalent refractive error was similar (58). In
addition to photophobia, other common adverse effects of atropine include
poor near visual acuity and allergy (57). Due to the potential for systemic
absorption and its antimuscarinic effects (including irritability, fever, and
delirium), atropine topical drops are not recommended under the age of 3
months and are limited to one drop per eye per day in children under 3 years
of age. In addition, there are no data on efficacy of atropine in syndromic
myopia and, therefore, it is not recommended.
Refractive Surgery
Although excimer laser refractive surgery is FDA-approved and widely used
for adults age 18 and older, there is less data for its use in children. Use in
children should be restricted to cases of anisometropic amblyopia or bilateral
high refractive error with poor compliance with refractive correction (59).
There are several challenges to its use in a pediatric population that include
the need for sedation or general anesthesia in younger children; the need to
transport heavy and expensive excimer laser equipment from the clinic to a
hospital or surgery center where pediatric anesthesiology is available; and the
difficulty in preventing children from eye rubbing in the postprocedure
period (60). Changing spherical equivalent refraction and axial length during
growth and development are additional challenges to pediatric refractive
surgery. However, laser in situ keratomileusis (LASIK), photorefractive
keratectomy (PRK), and phakic intraocular lens (pIOL) implantation have all
gained increasing use in the pediatric population for a broad range of
refractive errors. PRK has been used in children as young as 1 year old,
whereas LASIK has been reported for children as young as 5 years of age
(61). Parents should be counseled that, in addition to potential procedural
complications, additional correction with glasses or contact lenses might still
be necessary after LASIK or PRK in children. More frequent postoperative
checks may be necessary, and ophthalmologists should emphasize the need to
avoid eye rubbing to parents and children who have undergone refractive
surgery. Potential LASIK complications include flap dislocation and potential
destabilization of the corneal stroma. PRK complications can include corneal
haze and substantial postoperative pain. Potential complications of pIOL
include pupillary block, pigment dispersion, ocular hypertension, endothelial
cell loss, RD, and endophthalmitis (60).
Orthokeratology
Orthokeratology refers to the reshaping of the corneal surface through contact
lens wear and is effective for treating myopic spherical error up to minus 5.0
D and up to 1.5 D of astigmatism (62). The normal cornea has a prolate
curvature, meaning that it is steep centrally and flat in the periphery. Reverse
geometry gas permeable lenses have a flat secondary curvature and are worn
in order to produce a flattening of the central cornea, allowing for treatment
of myopia (63). The lens “pushes” against the central cornea and “pulls” on
the periphery, creating a flatter, more plateau-shaped architecture. Several
randomized controlled trials have shown a benefit to gas permeable
orthokeratology lenses at slowing myopic progression and reducing axial
length elongation. However, the effects on axial length elongation do fade
after 5 years (64). Lens hygiene should be emphasized, as there is a risk of
microbial keratitis associated with orthokeratology lenses. Several factors
have resulted in an improved safety profile for orthokeratology lenses in
clinical practice over the last few years. These include advances in lens
material and design with good oxygen permeability, coupled with rigorous
education of parents, children, and providers, which includes specific
certification required in order to fit these lenses. Despite these improvements,
the risk of microbial keratitis remains. Patients should be encouraged to
discontinue lenses and to have an evaluation promptly for any discomfort.
Common organisms from culture results include Acanthamoeba and
Pseudomonas aeruginosa (65).
Vision Rehabilitation
Refractive error and amblyopia are common indications for low vision
evaluation and services in various global settings, especially in children age 6
and above (66,67). Visual disability secondary to refractive error in children
is common, is often uncorrected, and poses a significant public health
challenge for providers in almost any educational setting (68). Correction of
refractive error secondary to myopia and hereditary vitreoretinopathies
should remain the priority for the clinician in order to maximize vision
potential and prevent amblyopia in the growing child. There remains a dearth
of data from clinical trials evaluating the efficacy of low vision aids
specifically for myopia in children, and such future investigations would
yield insight as to which interventions would be most helpful for this
population (69). In particular, further study of assistive technologies for low
vision is necessary (70). This may assist patients with macular pathology
whose vision does not improve with refraction.
ETHICAL CONSIDERATIONS
Genetic testing for syndromic hereditary vitreoretinopathies causing myopia
continues to unlock additional information about the pathophysiology and
potential treatments of these conditions. Family members can be alerted of
important screening for sight-threatening conditions, and both the patient and
family can receive counseling on the need to evaluate for other systemic
associations with the condition based on the specific gene testing result (see
also Chapter 21). As discussed previously, the effects of each gene can vary
greatly even within the same condition. Proper training of physicians and
ancillary care personnel is becoming essential, along with referral to genetic
counseling to help interpret testing results specifically for the patient and
family and gauge their understanding of the results to guide further
communication (82).
Direct-to-consumer commercial genetic testing has become increasingly
available and accessible to the lay public over the last 5 years and in some
cases promises patients information about their susceptibility to an increasing
array of ocular conditions. The American Academy of Ophthalmology
continues to recommend against the inclusion of such genes in these kits, as
the ramifications of specific results may require expertise in interpretation for
each individual patient (83). With the rapid advances in this field, the impetus
is on ophthalmologists to be prepared to guide patients to appropriate avenues
for genetic testing and counseling, including those with the above conditions
(see also Chapter 21).
OTHER TREATMENTS
Atropine has been discussed above as a treatment for myopia, specifically to
reduce myopic progression. Given its widespread use in East Asian countries,
an interesting question is whether treatment with dilute atropine in premyopic
children can prevent the onset of myopia. A retrospective cohort study from
Taiwan examined the use of 0.025% atropine versus placebo in children 6 to
12 years of age and found a clinically and statistically significant reduction in
onset of myopia at 1 year of follow-up (21% vs 54%, p = 0.0002) (84). A
current phase 3 randomized controlled trial is enrolling patients to study the
effect of atropine 0.01% for prevention of myopia (85). The results should
provide important data as to a potential way to help slow the onslaught of this
public health epidemic.
Scleral collagen cross-linking is another promising treatment for myopic
progression. Animal studies in rabbit sclera have elucidated important
findings about the biomechanics of this condition and treatment (86).
Additional studies have shown reduced expression of a cross-linking enzyme,
lysyl oxidase (LOX), in guinea pig sclera with form deprivation myopia,
presenting a possible pharmacologic target for future cross-linking
interventions (87).
Figure 37-1 Orofacial findings in Stickler syndrome.
Prominent features include flat nasal bridge, large myopic
eyes (blocked for anonymity), upturned nasal tip, and
small mandible (micrognathia). (Photos courtesy G. Baker
Hubbard III, MD; Emory Eye Center, Atlanta, GA.)
Figure 37-2 Right eye of patient with Stickler syndrome
treated with prophylactic laser. (Photo courtesy G. Baker
Hubbard III, MD; Emory Eye Center, Atlanta, GA.)
Figure 37-3 Posterior retinal break causing
rhegmatogenous RD in a patient with Stickler syndrome.
Prophylactic laser barricade in the periphery would not
have prevented this detachment due to the posterior
location of the retinal break. (Photo courtesy G. Baker
Hubbard III, MD; Emory Eye Center, Atlanta, GA.)
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SECTION V
Pathophysiology In Retinal Diseases
38
Mechanisms of VEGF Signaling in
Developmental and Pathologic
Angiogenesis Related to Retinopathy
of Prematurity
M. Elizabeth Hartnett, Haibo Wang, Aaron B. Simmons, Colin A.
Bretz, Eric Kunz, and Aniket Ramshekar
Variability in Training
As a result of different resources worldwide, ROP is seen in larger and more
developmentally mature infants in countries with limited resources compared
to countries with adequate resources and trained ophthalmologists to
accurately screen, diagnose, and classify ROP by indirect ophthalmoscopy or
using a contact camera (see Chapters 20, 50, and 51). Indirect delivery of
laser also requires skill and may not be delivered at a sufficient spot density
or location in the retina. Follow-up of infants to determine additional
treatment or surgical intervention requires skill.
Genotypic Variability
Some infants carry mutations of genes, such as in genes that regulate the
Norrie disease (NDP)/frizzled-4 (FZD4) pathway (29–32). Those infants
manifest severe ROP despite being of older gestational age or larger birth
weight than otherwise would be considered at risk (30). Other infants may
survive extreme prematurity by not having these genotypes but lack
protective mechanisms to reduce risk of ROP (33), and the predispositions
might be picked up only on genetic testing that may not be present
universally. For example, in a candidate gene study from 1,000 extremely
low–birthweight infants, intronic variants in the gene encoding brain-derived
neurotrophic factor (BDNF) were associated with severe (treatment-
warranted) ROP, and previous studies showed low BDNF in the bloodstream
in association with more severe ROP (33,34). Therefore, the genotype–
phenotype relationship complicates the picture.
Diagnostic Variability
The decision to treat ROP is based on clinical trials that used different
classifications of severe or treatment-warranted ROP. Two clinical trials
defined “treatment-warranted” ROP differently from one another (35)
(ClinicalTrials.gov), and both definitions differed from type 1 ROP tested in
another clinical study (36) or threshold ROP that was the definition used at
the time of the CRYO-ROP study (see Chapter 52). These concerns reduce
the ability to relate studies that use different treatment modalities or are from
different regions of the world to one another. Of course, clinical trials are
needed, but because of differences in infant genotype and phenotype, ability
to diagnose treatment-warranted ROP, and effect of treatment, the diagnosis
of what constitutes treatment-warranted ROP makes comparing clinical trials
from different regions of the world challenging.
VEGF/Oxygen in ROP
VEGF was first described as vasopermeability factor (42). Numerous
investigators have studied VEGF related to adult diseases. When VEGF was
recognized as an important factor in adult pathologic retinopathies, like
diabetic retinopathy and retinal vein occlusion, and in neovascular age-related
macular degeneration, preclinical studies used animal models of oxygen-
induced retinopathy to test the effect of anti-VEGF agents (43–50). These
models share some features of human ROP. Therefore, it was logical that
VEGF would also be involved in pathologic IVNV in ROP. However, VEGF
is important in physiologic angiogenesis in retinal vascular development (38).
Therefore, there was a concern that inhibiting VEGF in the premature infant
eye, in which retinal blood vessel development was ongoing, might not only
reduce pathologic IVNV but also interfere with normal retinal vascular
development. This set of events could set up a scenario in which persistent
avascular retina would lead to recurrent IVNV and also reduce visual field.
Therefore, our lab was interested in extending PRVD in an effort to reduce
the stimulus for recurrent IVNV in treatment-warranted ROP. We focused on
the question why blood vessels grew into the vitreous instead of into the
retina proposed to be hypoxic in the premature infant eye once the infant was
removed from high supplemental oxygen.
When ROP was first described in the 1940s and 1950s, premature infants
were about 2 months premature and exposed to constant high oxygen but
may have had more peripheral retinal vascular development than extremely
premature infants, who are often 4 or more months premature when they
develop ROP today. Therefore, the original two-phase hypothesis, posed by
Ashton in the 1950s, has changed. Ashton posited that high oxygen damaged
newly formed retinal capillaries (termed, “vaso-obliteration” in phase I),
thereby creating broad areas of avascular retina. When the infant was
removed from high supplemental oxygen and placed into ambient air, the
avascular retina became hypoxic, which stimulated angiogenesis that led to
blood vessels growing into the vitreous rather than into the retina (termed,
“vasoproliferation” in phase II). Today, phase I not only includes the oxygen
damage to newly formed vasculature, or “compromised physiologic
vascularity,” but also includes a delay in PRVD, proposed to occur as a result
of fluctuations in oxygenation that affect VEGF expression (see also
Chapters 40 and 43) and potentially through oxidative damage or signaling
(51) (see also Chapter 41). Phase II involves vasoproliferation into the
vitreous as IVNV and plus disease, which is characterized by increased
tortuosity and dilation of retina arterioles and veins (see Chapter 52) (Figure
38-1). VEGF is an important angiogenic factor in ROP, but other factors may
also play a role, including the angiopoietins and erythropoietins. In addition,
other risk factors besides high oxygen at birth have been identified, including
poor nutrition and growth (see Chapter 39) and activation of oxidative
signaling mechanisms (see Chapter 41).
Figure 38-1 The rat OIR model represents features of
human ROP. A:Superior view of early ROP demonstrating
avascular retina and ridge (yellow arrow). B:Temporal
view of vascular ROP demonstrating neovascular tufts
showing stage 3 ROP (white arrow) and thickened
demarcation line (yellow arrow). C:Postnatal day 14 rat
retinal flatmount with delayed PRVD (white arrow) and
compromised physiologic vascularity with capillary
crossings (yellow box). D:Postnatal day 20 rat retinal
flatmount with intravitreal neovascularization (white
arrow) and peripheral avascular retina. OIR, oxygen-
induced retinopathy; P14, postnatal day 14; P20, postnatal
day 20; PRVD, physiologic retinal vascular development;
ROP, retinopathy of prematurity.
Safety of Anti-VEGF
The anti-VEGF agent, bevacizumab, has been used at doses of 1 to 10 mg/kg
as an intravenous drug for cancers. Known adverse events include impaired
wound healing, thromboembolism, proteinuria, and gastrointestinal
perforation (58). The concentration of bevacizumab in the eye is much lower
(52), but the drug accesses the systemic circulation and is potentially less
diluted in the small preterm infant blood volume compared to that of the adult
(59). Lower doses are being evaluated with reported efficacy for treating
severe ROP (36). Measured levels of VEGF in the bloodstream are reduced
in premature infants for at least 2 months after a single intravitreal injection
of bevacizumab or aflibercept (60), but VEGF levels in the blood are less
affected with ranibizumab (61). The effect of intravitreal anti-VEGF is also
noted in adult eyes (54) with certain diseases without systemic effects noted.
Nonetheless, the duration and effect of anti-VEGF in the developing infant
raise concerns and are being studied (see also Chapter 53).
VEGF has been reported as essential for the development of the kidney,
lung, brain, and other organs (28), and inhibition of VEGF has been
associated with damage to organs. Experimental studies reported pulmonary
hypertension in a rat model following an injection of an anti-VEGF agent
(62). Also, renal VEGF was shown to be regulated by changes between high
and low oxygen in the rat (63). Hypoxia can increase the expression of VEGF
and be pathologic to retinal vessels, but potentially protective in various
oxygen stresses. Some clinical studies report impairment of neurocognitive
development, but there is controversy, and many studies have had limitations
(64,65). However, a recent report from the Neonatal Research Network in the
United States again raises concerns (66). Therefore, the effect on premature
infants treated with anti-VEGF agents raises concerns about the development
of systemic organs (see Chapter 53).
In order to study the molecular mechanisms involved in the
pathophysiology of ROP and potential treatments on development
systemically, experiments are performed using models of oxygen-induced
retinopathy (OIR) most representative of human ROP.
Anti-VEGF and VEGFR2 inhibitors were delivered by intravitreal injection at P12. Lentiviral vectors
(MC-VEGFAshRNA, MC-VEGF164shRNA, EC-VEGFR2shRNA, and EC-STAT3shRNA) were
delivered by subretinal injection at P8. All comparisons are relative to control.
aAnti-VEGF agents caused recurrent IVNV and reduced PRVD at P25.
—, no change; ↓, reduced; ↑, increased; EC, endothelial cell; ERG, electroretinograms; IVNV,
intravitreal neovascularization; MC, Müller cell; N.D., not determined; PRVD, physiologic retinal
vascular development; shRNA, short hairpin RNA; VEGF, vascular endothelial growth factor;
VEGFR2, VEGF receptor 2.
SUMMARY
ROP has evolved from the time RLF was first described by Terry in the
United States in 1942 (2). However, throughout the world, ROP varies based
on the developmental age and size of the infants potentially because of
differences in oxygen regulation and monitoring, prenatal and perinatal
resources to deliver care, ability to diagnose ROP, agreement of what
constitutes “treatment-warranted ROP,” and potentially genetic or epigenetic
factors. Now, infants are less developmentally mature and of smaller size in
the United States and developed nations than in emerging nations. This may
have impact on treatments recommended to reduce the bioactivity of VEGF,
which is important to the developing infant and retina. Anti-VEGF agents
may affect neural development in the retina and CNS and when delivered into
the eye of an extremely premature infant be less diluted in the small blood
volume and have greater deleterious impact in the less developmentally
mature than in a larger and more developmentally mature infant. Anti-VEGF
agents delivered into the vitreous affect not only the VEGFR2 signaling
pathway in endothelial cells of the retina but also VEGFR2 and other VEGF
receptors in cells of the neural retina and glia. Experimentally, anti-VEGF at
too high a dose may lead to thinner retinas in oxygen-stressed eyes. Taken
together, these studies support the continued work toward better treatments
for ROP for neuroprotection and vascular health.
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39
Weight Gain and Retinopathy of
Prematurity
Ann Hellström, Lois E. H. Smith, and Anna-Lena Hård
INTRODUCTION
For developing children, a normal increase in weight is an indicator of health.
Extrauterine growth restriction is common among very preterm infants, and
subnormal weight gain, both before and after birth, has been identified as an
important risk factor for severe retinopathy of prematurity (ROP) (1). This
knowledge can be used to predict severe ROP and potentially to prevent ROP
through improvements in neonatal care that improve growth.
Low gestational age (GA) is the most important risk factor for ROP. Low
weight at birth has also been described as an important risk factor, but low
birth weight (BW) may simply reflect low GA if the BW is appropriate for
gestational age (AGA).
In this chapter, we will address
Thus, it appears that prenatal growth restriction is a risk factor for ROP at
least in some older GA groups. Differences in impact of SGA at birth on
ROP depends on different degrees of immaturity (GA) at birth may be due to
the use of different definitions of SGA and growth curves used in studies as
well as higher mortality in the most infants born at the lowest GA.
In 1953, Lubchenco et al. reported that retrolental fibroplasia, the end
stage of ROP, occurred in infants with low BW but also in infants with
greater weight loss during the neonatal period followed by a relatively fast
weight gain. This observation sheds light on the importance of postnatal
growth (21).
Oxygen Supplementation
The influence of oxygen treatment on general growth in preterm infants is
largely unknown. In rat pups, exposure to alternating hyperoxia and hypoxia,
which is common in preterm babies, leads to severe OIR in association with
low body weight and low systemic IGF-I levels (90). Very preterm (low GA)
infants are especially vulnerable to oxidative stress secondary to both
hypoxia and hyperoxia and also secondary to inflammation, parenteral
nutrition, and high levels of free iron in combination with inadequate
antioxidant protection (91–93).
Optimal oxygenation of very preterm (low GA) infants is still unknown.
Combined data from five studies with similar designs comparing higher (91%
to 95%) and lower (85% to 89%) oxygen saturation targets were analyzed in
the NeOProM study (Neonatal Oxygen Prospective Meta-analysis)
Collaboration. A lower oxygen saturation target was associated with
decreased frequency of ROP needing treatment. However, there was no
difference in weight at discharge between the two oxygen target groups (94).
Oxygen supplementation is a very strong risk factor for ROP, and the value
of postnatal weight gain in the prediction of severe ROP is influenced by
oxygen supplementation strategies (60).
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40
Oxygen as a Pathogenic Factor in
Retinopathy of Prematurity (ROP)
Dolly A. Padovani-Claudio, Megan E. Capozzi, Colin A. Bretz, and
John S. Penn
INTRODUCTION TO RETINOPATHY
OF PREMATURITY
Although therapeutic oxygen in preterm infants is vital for tissue, organ, and
cognitive development, it can have detrimental consequences even when
strictly managed. One such consequence is retinopathy of prematurity (ROP).
ROP results from dysregulated tissue oxygenation in the retinas of preterm
infants and is a major cause of irreversible vision loss in children worldwide.
Development of the retinal vasculature begins at approximately 15 to 16
weeks of gestation in humans and proceeds radially in a circular wave from
the optic nerve head to the retinal periphery leading to the formation of the
primary superficial retinal vascular plexus. Angiogenesis and vascular
remodeling contribute to the radial expansion of the superficial plexus and to
the growth of the secondary deep retinal vascular plexus (1). These events are
driven largely by tissue growth and the subsequent increased oxygen demand
within the relatively hypoxic uterine environment (arterial blood partial
pressures of oxygen [PaO2] in the range of 20 to 30 mm Hg) (2). Tissue
hypoxia promotes the production of angiogenic growth factors such as
vascular endothelial growth factor (VEGF), an endothelial cell mitogen
tightly regulated by tissue oxygen tension (3–7). Peripheral retinal
vascularization increases with gestational age, and, under normal
developmental conditions, vascularization of the retina is completed by 38 to
40 weeks (8). In full-term infants, the blood-borne oxygen delivered by the
newly grown vasculature in combination with the relatively hyperoxic
postnatal environment (PaO2 between 55 and 85 mm Hg or higher) into
which an infant is born prevents persistent vascular proliferation by inhibiting
the production of VEGF and other growth factors (2,9,10).
In premature infants, the retinal vasculature is incompletely developed,
and the peripheral retina is avascular at the time of birth. Exposure to the
hyperoxic postnatal environment leads to suppression of VEGF production
and delayed physiologic retinal vascularization, which poses increased risk of
insufficient peripheral retina vascularization. Under these circumstances,
retinal oxygen levels are temporarily maintained primarily by the neighboring
choroidal circulation, which is unique in that its autoregulatory response to
altered oxygen tension results in limited vasoconstriction (11,12). Oxygen
diffuses from the choroidal circulation into the retinal tissue, bathing the
retina and worsening the inhibitory effect of hyperoxia on the growth and
maintenance of sensitive retinal capillaries (13,14). In combination, these
events define the first phase of ROP: stunted physiologic retinal vascular
development. Clinically, the radial location of the junction of the vascularized
and the peripherally avascular retina determines the zone of ROP (Table 40-
1).
Eventually, the oxygen demands imposed by the growing retina and the rapid
development of retinal neurons are unfulfilled, leading to hypoxia in the
avascular peripheral retina. Retinal hypoxia induces the second phase of
ROP: vasoproliferation. During the vasoproliferative phase of ROP, the
hypoxic retina dramatically up-regulates VEGF production, leading to
increased vascular growth. In some infants, this vascular growth is abnormal,
with vascular beds that are poorly perfused, and fragile, worsening tissue
hypoxia. Moreover, dysfunctional autoregulatory mechanisms that may
further restrict retinal blood flow can potentiate this retinal hypoxia (15). The
consequence of these alterations is the persistent growth of abnormal vessels.
Fragile vessels can leak or rupture and bleed, therefore posing a threat to
retinal and visual development. In addition, vascular growth, intended to be
oriented toward the retinal periphery, can be misdirected to the vitreous
cavity. Ultimately, if this intravitreal neovascularization is left untreated, it
may cause fibrovascular contraction of the vitreous leading to tractional
retinal detachment and blindness (16,17). As this pathologic retinal vascular
growth is highly hypoxia-driven, weaning premature infants from oxygen
therapy during the vasoproliferative phase, although not required for ROP
development, is thought to predispose to ROP or contribute to ROP
worsening (18). Clinically, the severity of retinal abnormalities resulting from
the vasoproliferative response determines the stage of ROP (Table 40-1) (see
Chapter 52).
Adapted from Gilbert C. Retinopathy of prematurity: a global perspective of the epidemics, population
of babies at risk and implications for control. Early Hum Dev 2008;84:77–82. Ref. (33).
CONCLUSIONS
In 1945, the esteemed surgeon and scientist, Julius H. Comroe, Jr., stated “the
clinician must bear in mind that oxygen is a drug and must be used in
accordance with well recognized pharmacologic principles; i.e., since it has
certain toxic effects and is not completely harmless (as widely believed in
clinical circles) it should be given only in the lowest dosage or concentration
required by the particular patient.” This admonition is particularly pertinent
to the care of premature infants at risk for ROP. From the time of the initial
identification and characterization of ROP, investigators have strived to
define the precise role of oxygen in its pathogenesis. Much of this work was
conducted using animal models of OIR and tightly controlled experimental
conditions. Subsequently, large-scale clinical trials have sought to further
refine our understanding of the role of oxygen in disease progression. Great
effort has been expended to understand the pathogenic role of oxygen and
oxidative stress at the molecular, cellular, and tissue levels and to define
optimal oxygen supplementation protocols to establish appropriate standards
of care for preterm infants. Despite this, we have yet to arrive at an optimally
efficacious course of action. Additional studies directed at better
understanding the role of oxygen in retinal vascular development and disease
progression remain crucial for better management and treatment of ROP.
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41
Oxidative Mechanisms and Signaling
Pathways Related to Pathogenesis of
Retinopathy of Prematurity
Haibo Wang, and M. Elizabeth Hartnett
INTRODUCTION
Retinopathy of prematurity (ROP) is complex and is affected by heritable and
environmental factors (1). Some preterm infants may be predisposed or
vulnerable to environmental risks based on genotype or genetic expression. In
addition, maternal or environmental factors may modulate the regulation of
gene expression through processes, such as gene–gene interactions or
epigenetic modifications.
The goals of this chapter are to address the current understanding of ROP
with focus on the role of factors, for example, oxygen concentration and
oxidative stress, and how these trigger or regulate signaling pathways to
cause pathologic features of severe ROP, involving first damaged or
incompletely vascularized retina and second aberrant intravitreal
neovascularization. We also will discuss briefly the temporal effects of retinal
neural development and the evidence regarding the interrelationship of this
with retinal vascular development in ROP.
BACKGROUND
The Infant
The in Utero and Perinatal Setting of the Infant with
ROP
In the human fetus, early retinal vessels first appear around the optic nerve at
about 14 weeks’ gestational age (2) and, by term birth, have extended to the
ora serrata in at least two major vascular plexuses, the inner plexus at the
nerve fiber layer and the deeper vascular plexus at the inner nuclear layer (see
Chapter 5). The preterm infant, therefore, has incompletely vascularized
retina at birth. However, after birth, some preterm infants have a further delay
in physiologic retinal vascular development. There are several hypotheses for
this occurrence. One is based on lack of maternally supplied growth factors
and nutrients during normal birth in the third trimester, which the preterm
infant is unable to make and that are essential for retinal vascular
development and also overall growth (2,3). Also, the nascent vessels of the
preterm infant are vulnerable to oxidative compounds and high oxygen.
Preterm birth increases generation of oxidative compounds (3), and the
preterm infant is unable to adequately quench oxidative compounds because
of insufficient antioxidant enzyme systems. In addition, in utero, the oxygen
concentration to the fetus is believed to be <40 mm Hg. At birth, the relative
change in oxygen concentration, particularly if high oxygen is used, can
potentially injure newly formed retinal capillaries, leading to areas of
avascular retina, which stimulate later development of intravitreal
neovascularization (Figure 41-1). There is also a developing hypothesis in
which some infants can call upon potential mechanisms that protect against
ROP despite extreme prematurity and oxygen/oxidative insults. These
include possible ischemic preconditioning that may occur because of repeated
fluctuations in oxygenation (4). Further studies are indicated to test this
hypothesis.
FIGURE 41-1 Factors contribute to the development of
ROP. Low serum insulin-like growth factor-1 (IGF-1) and
its binding protein 3 IGFBP3 derived from preterm birth
lead to impaired retinal vascular development. At birth,
particularly in the units that have not implemented oxygen
monitoring, relatively high oxygen concentration increases
ROS generation, which can damage newly formed
endothelial cells and leads to capillary constriction.
Postnatal oxygen stresses including fluctuations in oxygen
delay ongoing physiologic retinal vascular development,
leading to the phase of reduced peripheral retinal vascular
development. Reduced retinal vascularization and
increased oxygen demand by photoreceptor differentiation
cause retinal hypoxia, which leads to uncontrolled
disordered angiogenesis and results in intravitreal
neovascularization, the phase of vasoproliferation.
Postnatal Oxygen
When ROP was first described in the 1940s prior to the implementation of
oxygen regulation, very high oxygen likely caused damage to newly formed
capillaries and led to ROP (8,9). To study the causes of ROP described in the
1940s, several models of oxygen-induced retinopathy (OIR models) were
developed in which animals that vascularize their retinas postnatally were
exposed to oxygen at different concentrations (10–13). The results of this
early research led to improvements in oxygen monitoring and the avoidance
of excessive, unregulated oxygen at birth (14). However, as infants of
younger gestational ages and smaller birth weights survived, ROP reemerged.
It is recognized now that, besides high oxygen at birth, postnatal fluctuations
in oxygen levels are also associated with severe ROP. It is not clear if it is
fluctuations in inspired oxygen alone that are associated with ROP risk or
those caused secondarily from bradycardia, apnea of prematurity, ventilation–
perfusion deficits related to lung disease, and other conditions of prematurity.
However, healthy newborn animals exposed to repeated fluctuations in
inspired oxygen consistently develop features of acute severe ROP
supporting the role of oxygen fluctuations in causing severe ROP features
(13). There are also conflicting reports about the role of supplemental oxygen
in the development of severe ROP. The Supplemental Therapeutic Oxygen
for Prethreshold Retinopathy of Prematurity study found no adverse effect
from supplemental oxygen and perhaps a beneficial effect in a subgroup (15).
Others have advocated later supplemental oxygen to reduce the risk of severe
ROP (16,17). However, several studies have also found correlations between
high oxygen saturations and ROP (18,19). Two multicenter clinical trials
(SUPPORT, BOOSTII) (20) found that low oxygen saturation targets were
associated with less severe ROP, but there was increased mortality, although
another multicenter study did not find a relationship (21). Currently, neonatal
units tend to develop guidelines regarding oxygen saturation targets based on
their units and outcomes.
The initial phase of avascular retina from compromised physiologic
retinal vascularity and delayed physiologic retinal vascular development is
postulated to become hypoxic once the infant is removed from supplemental
oxygen. Currently, there is no available technique to accurately measure
retinal tissue oxygenation in the human infant in vivo, but experimental
evidence provides support that retinal hypoxia precedes the development of
disordered angiogenesis (22,23) that grows outside the retinal plane and into
the vitreous as intravitreal neovascularization, rather than into the retina as
postnatal retinal vascularization. Most studies strive to understand the
mechanisms leading to this intravitreal neovascularization in ROP, but also
important is finding ways to promote retinal vascularization of the avascular
areas, protect vascularized retina from damage, and promote neuroprotective
mechanisms for normal retinal development.
Animal models of OIR are used to study how oxygen levels activate
signaling pathways that cause features of severe acute ROP; however they
only mimic the vascularly active phases of ROP, that is, plus disease and
intravitreal neovascularization (stage 3 ROP), and do not generally develop
fibrovascular features, that is, stages 4 and 5 ROP.
Retinas can be removed from eyes, flattened, and stained to visualize the
vasculature in retinal flat mounts. Areas of normal retinal vascularization,
intravitreal neovascularization, and avascular retina can be measured as
compared to total retinal area. There are two broad categories of models:
those in which high oxygen damages newly formed capillaries and variable
oxygen models in which oxygen fluctuations delay ongoing vascular
development and also compromise newly formed capillaries. Each is useful
to address different experimental questions (Figure 41-2).
Variable Oxygen
Variable oxygen is common in neonatal units that regulate oxygen. There are
a number of models of variable oxygen stresses (35–37) (Table 41-1). The
most characterized is the rat OIR model developed by John Penn, in which
newborn rat pups are exposed to fluctuations in inspired oxygen, first 50%
oxygen for 24 hours, followed by 10% oxygen for 24 hours (13). The 24-hour
cycles are repeated until day 14, at which time animals are returned to room
air. At postnatal day 14, there is peripheral avascular retina and by day 18,
aberrant intravitreal neovascularization at the junction of vascular and
avascular retina. The rat OIR model may simulate the pattern of oxygen
exposure experienced by preterm infants in the United States today. The
oxygen extremes cause arterial oxygen levels similar to transcutaneous
oxygen levels measured in human preterm infants (5). The appearance of the
retina is similar to zone II, stage 3 ROP characterized by a central
vascularized retina with some compromised physiologic vascularity and a
peripheral avascular area. Hypoxic retina is present in the avascular
peripheral retina as well as in avascular regions around retinal vessels (22).
Uteroplacental insufficiency (UPI) has been considered a risk factor of ROP.
To determine the potential effects of maternal UPI on ROP, a modification of
the rat OIR model was made in which dams underwent bilateral uterine artery
ligation and pups were born and placed into oxygen fluctuations (38). In the
modified rat OIR model, oxygen concentrations were maintained at 50% O2
for the first 48 hours instead of for the first 24 hours as in the standard rat
OIR model, and subsequently cycled between 10% and 50% O2 until day 15
(4).
Erythropoietin
Erythropoietin (EPO) is believed to be an oxygen-regulated hormone,
produced by the kidney in response to ischemia and hypoxia. EPO promotes
erythrocyte formation in the bone marrow. Recombinant EPO is used to treat
anemia in patients with chronic kidney failure secondary to diabetes mellitus
or preterm infants with anemia of prematurity. In these groups of patients,
some studies have found an associated increased risk of severe ROP with
EPO use (89). In the mouse OIR model, retinal EPO expression was
suppressed during hyperoxia-induced vaso-obliteration and elevated during
intravitreal neovascularization (76). Exogenous EPO administered during
hyperoxia prevented both hyperoxia-induced vessel loss and later hypoxia-
induced intravitreal neovascularization and retinal neuron apoptosis;
however, exogenous erythropoietin treatment during hypoxia-induced
proliferation did not protect against retinal vessel loss and worsened
pathologic intravitreal neovascularization (90).
In the rat OIR model, down-regulation of retinal EPO contributed to
avascular retina prior to the development of intravitreal neovascularization.
The mechanism for the reduced expression appeared to be activation of the
JAK/STAT pathway (91). STAT3 was activated in Müller cells by increased
retinal VEGF following repeated oxygen fluctuations. Activated STAT3
delayed retinal vascularization by down-regulating EPO mRNA expression in
Müller cells. Exogenous EPO given early at days of life 2, 4, and 6 increased
peripheral retinal vascularization without causing increased intravitreal
neovascularization (91). Others reported that EPO recruited proangiogenic
bone marrow–derived progenitor cells and activated NF-κB signaling by the
activated EPO receptor on retinal vessels and neurons (76). In a combined rat
model of maternal UPI and OIR, increased circulating EPO was associated
with extension of physiologic retinal vascular development and reduced
pathologic intravitreal neovascularization in rat pups (4). However, EPO has
been associated with worse OIR features experimentally depending on timing
of administration.
Anti-VEGF
The current approved treatment for severe ROP is laser (preferred to
cryotherapy) delivered in a nearly confluent pattern to the peripheral
avascular retina (see Chapter 52). Even though these treatments reduce the
risk of untoward structural outcomes and poor vision, peripheral vision lost is
still inevitable in some cases. Several clinical studies tested the effect of a
complete VEGFA-specific neutralizing antibody on severe ROP. Initial
results appeared promising with reduction in intravitreal neovascularization
(stage 3 ROP), plus disease, and avascular retina (64). However, recurrent
intravitreal neovascularization (92), persistent avascular retina and adverse
outcomes including reduced serum free VEGF and IGF-1 (93) are being
reported. There is also concern about fluorescein angiographic evidence of
areas of nonperfused retina within the already vascularized central retina in
infants treated with bevacizumab (94). Greater study of the inhibitory effects
of different VEGF doses or agents on pathologic and normal vascularization
is needed. Several clinical trials have tested de-escalating doses of
bevacizumab and have compared ranibizumab to laser and are covered in
greater detail (95) (see Chapters 38 and 53).
ACKNOWLEDGMENT
We thank James Gilman, CRA, FOPS, for his help in creating the figures and
table.
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42
Signaling Pathways in Wnt and
Effects on Disease
Eric Nudleman, Geoffrey Weiner, and Kimberly A. Drenser
Genetics
The Wnt pathway in the retina consists of Norrin, FZD4, LRP5, and
TSPAN12. Mutations in all of those genes have been described to cause one
of the ND/FEVR spectrum disorders. ND is associated with mutations in the
NDP gene, which is located on the short arm of chromosome X at position
11.3 and thus is inherited in an X-linked recessive pattern (58–60). Note that
mutations in NDP also cause EVR2 or X-linked EVR, reflecting
nomenclature that predates the cloning of NDP. FEVR can be associated with
mutations in FZD4, LRP5, or TSPAN12, and the specific mutation determines
the inheritance pattern (58,61,62). Mutations in FZD4, located at 11q14.2,
cause EVR1 and are autosomal dominant (63). Mutations in LRP5, located at
11q13.2, cause EVR4 and can be autosomal dominant or recessive (64).
Mutations in TSPAN12, located at 7q31.31, cause EVR5 and are also
autosomal dominant (62,65). Overall, the most common inheritance pattern
for FEVR is autosomal dominant. (Also see Chapter 66.)
There are 107 single-nucleotide polymorphisms (SNPs) reported in the
NDP gene, 28 of which are nonsense and 64 are missense mutations and
almost always cause ND (59). In vitro studies have confirmed that the most
common pathogenic mutations in NDP result in dysfunctional Norrin protein
and impaired Wnt signaling (38,39,66). Although the cysteine-knot motif
appears to be important in conferring biologic activity to Norrin both
biologically and computationally, untranslated regions within NDP are also
sometimes mutated and have regulatory functions that control the expression
and stability of Norrin (38,67,68). To date, 37 different SNPs in FZD4 have
been described, 12 of which are nonsense and 24 are missense mutations. A
small number of mutations have been tested in vitro, with all mutants
showing at least 30% reduction in activity compared to wild type (39,66,69).
There are 90 known mutations in LRP5, 27 of which are nonsense and 58 are
missense. Many mutations do not result in FEVR but do result in dysfunction
in other body systems, reflecting the widespread expression of LRP5 in
various tissues and developmental stages. When studied in vitro, LRP5
mutants show the most variability in the degree of Wnt pathway inhibition,
likely due to the fact that LRP5 is the target of endogenous Wnt inhibitors
and thus the effect of any given mutation is highly base pair specific
(66,70–72). TSPAN12 is the most recently described FEVR-associated gene,
and only eight mutations are reported, with four of them being nonsense
mutations and two of them missense mutations (65,73).
Although it might be expected that the clinical phenotype of mutations in
the numerous genes of the Wnt pathway would correlate with the known
effects of those mutations, this is not generally observed. This lack of strong
genotype–phenotype correlation could be due to genetic interactions with
other loci in the genome. Or it may suggest that the Wnt pathway subserves
additional functions in the retina that have yet to be understood. Some of
those other functions are just beginning to be investigated. For example,
recent evidence in animal models suggests that Norrin serves a
neuroprotective function (41,42,74).
Clinical Diagnosis
Diagnosis is based on birth history, family history, and clinical examination
and is supported by genetic mutations in the NDP, FZD4, TSPAN12, or LRP5
genes. Classic ND typically presents with leukocoria and poor vision in both
eyes (49,54). Extraocular manifestations (hearing loss and cognitive
impairments) are often identified subsequently (38,54–56). The eyes are of
average size (corneal diameter 9 to 10 mm) initially but typically become
smaller with time as the traction tethering the posterior lens capsule and
posterior retina limits eye growth (Figure 42-1). Incomplete maturity of the
iris vessels is common with elongation of the ciliary processes due to traction
(Figsures 42-1 and 42-2). A fold of retina (resembling a stalk in persistent
fetal vasculature syndrome [PFVS]) may be present and attach anteriorly to
the peripheral retina, ciliary processes, or posterior aspect of the lens with
variable size footplates. The base of the fold generally involves the optic
nerve, often with exudation (Figure 42-2). Unbranched retinal vessels can be
seen coursing through the fold tissue (Figure 42-2). The periphery is
avascular and can have underlying areas of pigment changes.
FIGURE 42-2 Retinal fold in FEVR in a patient with a
mutation in FZD4. A: External view demonstrating
leukocoria in the left eye with a slightly smaller cornea. In
the right eye, a small opacity is visible inferotemporally.
B: Fundus photo of the right eye, demonstrating a tight
(falciform) retinal fold with retinal dragging
inferotemporally. C–E: Fluorescein angiogram of the right
eye. The retinal vessels are seen pulled into the fold (C)
forming a sheet of retina-to-retina apposition. The
remaining retina is attached with some evidence of
vasculature but extensive peripheral retina. D: Insertion of
the fold into the inferotemporal periphery and ciliary
processes. E: Peripheral retinal avascularity. F,G: Wide-
field fluorescein angiography of the patient’s
asymptomatic mother helps to confirm the diagnosis,
demonstrating typical avascular periphery in the left eye
(G).
The FEVR classification system has five stages (Table 42-1) (75). Classic
FEVR features avascular peripheral retina and findings of vascular buds at
the junction of the avascular and vascularized retina. The vessels are often
dragged in the posterior pole, and retinal folds are common (Figure 42-2).
Consistent with animal models, OCT-A has recently demonstrated a
reduction in the vascular density, particularly in the deep vascular plexi, and
blunted vessels in the superficial plexus in humans with FEVR (76–78).
These vessels often exhibit dysfunction of the blood-retinal barrier, and large
amounts of subretinal exudate may be present. In eyes with retinal
detachment, both traction from fibrosis and subretinal exudate can be seen.
Histologically, inflammatory elements are found that reflect the chronic
process (79). A positive family history is very helpful in making a diagnosis
but not essential. The lack of a diagnosis of FEVR in family members does
not rule out a diagnosis of FEVR, either because of de novo mutations or
because of undiagnosed asymptomatic FEVR (80). Identical mutations
causing FEVR can have variable expression and incomplete penetrance.
Therefore, if the diagnosis of FEVR is suspected, a thorough peripheral
retinal examination including wide-field fluorescein angiography is
recommended for all family members (Figure 42-2).
Presentations of FEVR are both variable and asymmetric. It is not unusual for
one eye to present with advanced disease while the fellow eye has an
asymptomatic avascular periphery. Therefore, examination of the fellow eye
is essential to confirming the diagnosis. In a patient referred with presumed
PFVS based on microphthalmia and white pupil in one eye, it is prudent to
perform an EUA with a wide angle FA to assure the fellow eye is normal
(81). If FEVR is suspected in patients presenting with retinal dysgenesis
and/or disorganized retinal detachments, genetic testing should also be
offered, which is now done most cost-effectively by whole genome
sequencing (WGS). A mutation in one of the known genes is helpful to
confirm the diagnosis. However, WGS fails to identify a mutation in one of
the known genes in approximately one-half to one-third of cases (73,82) and
does not definitively rule out FEVR. Rather, the results may be helpful in
identifying novel new variants. Patients with ND/FEVR may benefit from
genetic counseling to better understand the implications for themselves and
other family members.
Clinical Course
Warburg’s seminal study of ND described only rare cases with vision beyond
infancy (83). Out of 24 patients in her series, all had no light perception
except for one boy who could count fingers until age 12 when light
perception was lost and another boy who could perceive light. In Warburg’s
review of the literature, she identified an additional 106 patients with ND. Of
these, only six patients were noted to have light perception or pupillary
reactivity after 3 months of age. Untreated, this process will continue to
contract resulting in a retrolental plaque with pseudogliosis and eventual
phthisis.
However, the FEVR patient population is characterized by a spectrum of
disease presentation (75). FEVR eyes that present in the first year of life have
a worse prognosis, but many children present later in life due to asymmetric
disease identified during school vision screening or strabismus. With
appropriate management (discussed in detail in Chapter 66), improved vision
can be achieved. FEVR likely is underdiagnosed, with earlier milder stages of
FEVR often asymptomatic, and advanced disease commonly confused for
other retinal disorders (Table 42-2). Therefore, a thorough family history,
wide-field angiography, and genetic testing have become invaluable tools in
distinguishing between disease entities.
Treatment
Surgical approaches to ND/FEVR will be addressed in Chapter 66. Here we
consider the evidence for ablative therapy, anti-VEGF agents, and emerging
therapies. FEVR often has a progressive long-term course, with periods of
waxing and waning, and requires lifelong screening, particularly with new
symptoms such as reduced vision or floaters. In animal models of FEVR,
elevated expression of vascular endothelial growth factor (VEGF) have been
measured (84,85). It is likely that avascular retina and capillary dropout
contribute to this finding. Because the stimulus for neovascularization in the
avascular retina is believed to be similar to that in ROP, treating the avascular
peripheral retina with laser ablation is recommended if hemorrhage, or
leakage on fluorescein angiography, is present. In children younger than 3
years with FEVR of stage 2 or greater (Table 42-2), treating any avascular
retina is recommended. Laser ablation is performed using a pattern similar to
the retinal ablation for ROP, adding near-confluent spots, one-half spot size
from one another (see also Chapter 58). It is not recommended to monitor
these eyes until they develop exudates. Rather, treatment is recommended to
prevent exudation before it occurs, because ablative therapy becomes less
effective once subretinal fluid and exudation develop. Drainage of subretinal
fluid followed by laser or cryotherapy often is disappointing, because the
fluid is thick and drainage incomplete. Aggressive treatment of avascular
retina with laser ablation results in improved long-term control. Small studies
of anti-VEGF therapies have reported improved outcomes, but larger trials
are needed (86–89). In the future, new pharmacologic therapy may be the
best way to approach ND/FEVR to offset the effects of growth factors and
abnormal Wnt signaling. As the genetics of ND/FEVR are further explored,
the disease may become a candidate for modulation with specific molecules,
such as adding Norrin to conditions that have mutatons in NDP.
Coats Disease
Coats disease is a congenital retinopathy that presents with unilateral
telangiectasia, microaneurysm, and lipid exudates (see also Chapter 64). It
typically presents in males in the first to second decade of life. Most cases are
sporadic, and although the genetic driver is not definitively established,
somatic mutations in NDP have been reported in retinal tissue from a Coats
patient (99), and in one case, a FZD4 polymorphism was present (100).
However, the majority of patients with Coats disease do not have identifiable
Wnt pathway mutations or polymorphisms known to be pathologic. It is
possible that somatic mutations in Wnt-associated genes are drivers for the
disease, but at this point, the link between Coats disease and Wnt is not
definitively established.
Coloboma
Coloboma is the result of variably incomplete closure of the optic fissure or
choroidal fissure during development. It is associated with a number of
systemic congenital malformations. In animal models of Wnt pathway
dysfunction, coloboma is also sometimes present (101,102). In at least one
case, a mutation in FZD5 has been found to cause autosomal dominant
coloboma (103). Given the locus heterogeneity of mutations associated with
this condition, it is likely that mutations in the many pathways that contribute
to patterning during development are capable of causing coloboma, including
Wnt and others (see also Chapter 22).
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43
Hypoxia-Inducible Factors and
Prevention of ROP
Jonathan E. Sears, and George Hoppe
INTRODUCTION
Survival after premature birth requires oxygen supplementation that is
simultaneously toxic to some premature developing tissues (see also Chapter
40). The fetal circulation is designed to provide oxygenation to the brain
while decreasing negative outcomes of oxygen toxicity. This is achieved by
creating a large oxygen gradient across the placenta. Maternal oxygen
concentration preplacenta is 90 to 100 mm Hg, whereas the fetal umbilical
vein has an oxygen concentration of 32 to 35 mm Hg (for reviews see (1,2)).
The normal oxygen saturation of a fetus in utero at the inferior vena cava
streaming to the foramen ovale to enter the left atrium is 80% to 85%. This
creates a carotid and coronary artery concentration of 25 to 28 mm Hg (58%
to 65% SaO2), which contrasts sharply with accepted target saturations in
premature infants after birth of 91% to 95% that yield a mean PaO2 close to
80 mm Hg (nl adult arterial saturations = 75 to 100 mm Hg). Furthermore,
oxygen saturations >93% can yield PaO2 higher than 100 mm Hg (3). An
additional factor contributing to the effect of oxygen is fetal hemoglobin,
which shifts the oxygen disassociation curve to the left, resulting in greater
binding of oxygen to fetal hemoglobin than it would to adult hemoglobin
under high oxygen tension. The destructive effects of oxygen create
retinopathy of prematurity (ROP), a vasoproliferative disease that blinds
170,000 infants annually worldwide (see Chapter 52). Recent randomized
clinical trials have tested “static” or continuous low oxygen targets to high
oxygen targets, and determined lower oxygen targets are associated with
reduced ROP but increased mortality (4). Although infant targets are often
outside of these ranges, it may be the high continuous set-point that affects
gene expression, not the range or the low set-point, as discussed below.
Balancing the needs of oxygen for survival with oxygen-induced defects
in multiple organ systems such as the brain, eye, lung, and kidney led to the
thinking that hypoxic preconditioning might be effective in preventing ROP
because it induced stabilization of the oxygen-sensitive transcription factors
and hypoxia-inducible factors (HIFs), which are heterodimeric transcription
factors that regulate the expression of cytoprotective, erythropoietic, and
angiogenic genes (5). Normally, HIFs are degraded in hyperoxia but
stabilized in hypoxia. Experiments that demonstrated the central role vascular
endothelial growth factor (VEGF) played in the development of oxygen-
induced retinopathy (OIR) provided a platform for prevention of ROP. VEGF
supplementation during the hyperoxic phase 1 of ROP prevented vascular
obliteration and retinovascular growth attenuation and thereby removed the
stimulus for ROP by permitting physiologic vascular growth even in
hyperoxia (6,7). VEGF expression was later found to be regulated by HIF (8).
These discoveries led to the hypothesis that stimulating angiogenesis during
hyperoxia by activating HIF (hypoxiamimesis) would reduce avascular retina
that becomes the stimulus for aberrant angiogenesis during hypoxia in OIR
(9).
HYPOXIA-INDUCIBLE FACTOR
HIFs are heterodimeric transcription factors comprised of HIFα and HIFβ.
HIFβ is an aryl hydrocarbon nuclear translocator that regulates the expression
of hundreds of genes relevant to cytoprotection, erythropoiesis, angiogenesis,
and metabolism (23). HIFs were originally discovered in 1992 by Semenza as
a factor that bound the 3″ hypoxia-inducible enhancer to the erythropoietin
(EPO) gene (5). The hypoxia response element (HRE) is a 5 nucleotide
sequence (5′-G/ACTCG-3′) found in all DNA binding sites for HIFs (24).
HIFs include two abundant isoforms, HIF-1 and HIF-2, composed of α
subunits that have 48% homology that dimerize with the identical β subunit
(aryl nuclear translocator receptor, ARNT). A third isoform HIF-3 is less well
described and thought to function as a soluble receptor. HIFβ is constitutively
expressed. It is an 87 kD member of the basic helix-loop-helix family of
proteins that contains a per-ARNT-sim (PAS) binding site. Although RNA
levels of HIF are fairly stable, the gene product is regulated
posttranslationally. The stability of HIF can be regulated by multiple
pathways including hydroxylation and ubiquination, phosphorylation,
sumoylation, and inhibition by intermediary metabolites such as succinate
and 3-OH-pyruvate (25,26). Nevertheless, HIF is predominantly regulated
through posttranslational hydroxylation within the oxygen-dependent
degradation domain (ODDD) at Pro 405 and Pro 564 of HIF (Figure 43-1A)
(27). This hydroxylation occurs in normoxia and hyperoxia and serves to
make HIFα a substrate for E3-ubiquitin ligases by permitting ubiquitination
at lysine residues on HIFα at Lys 532, 538, and 547 (Figure 43-1B) (28,29).
Hydroxylation of these proline residues within the ODDD is at the N-
terminal domain compared to hydroxylation of the asparaginyl residues at the
C-terminal domain. When the C-terminal domain is hydroxylated, HIFα is
allowed to bind factor inhibiting HIF (FIH) and interfere with chaperone
p300 from binding the HIF heterodimer, thereby preventing transcriptional
activity (30). In terms of different functions of HIF-1 versus HIF-2, we and
others have found evidence experimentally that Müller cell HIF-2 controls
pathologic angiogenesis, whereas stimulation of HIF-1 controls the normal
physiologic development of retinal blood vessels (31).
FIGURE 43-1 A: Structure of the HIFα gene
demonstrates key proline residues within the oxygen-
dependent degradation domain are trans-4-hydroxylated to
make HIα a substrate of the VHL protein, an E3 ubiquitin
ligase. The N-terminal activation domain (NTAD) has an
asparaginyl residue that is also hydroxylated, but this
makes HIFα a binding partner to HIF, which blocks
binding of HIF to the hypoxia response element. B:
Overall schema of the oxygen sensor within all cells.
Prolyl hydroxylase enzymes, part of the dioxygenase
family, are Fe metalloenzymes sensitive to local oxygen
concentrations. In hypoxia, HIF PHD is inhibited, whereas
hyperoxia induces rapid hydroxylation and subsequent
catabolism of HIFα. C: Replacing α-ketoglutarate with a
competitive inhibitor such as a carbonyl glycine,
benzolamides, or hydrazones. The latter competes for Fe,
whereas the two former small molecules are bound by the
catalytic site of HIF PHD. (C, Cleveland Clinic.)
HIF PROLYLHYDROXYLASES
The oxygen sensor within all cells is HIF prolylhydroxylase, a member of the
dioxygenase enzyme family that requires the cofactors Fe, oxygen, and 2-
oxoglutarate. The fact that these enzymes regulate HIFs by using oxygen and
2-oxoglutarate cofactors makes them central to metabolic plasticity. Oxygen
naturally is the final electron acceptor in respiration, and 2-oxoglutarate is a
tricarboxylic acid (TCA) cycle intermediate that stands at the crossroads of
oxidative phosphorylation and glutamate metabolism. The
prolylhydroxylases are nonheme iron–containing enzymes that possess an
octahedral ferrous iron active site that oxidizes Fe II to Fe IV with carbon–
oxygen bond formation with the α keto group of 2-oxoglutarate. Following
this reaction, the carbon 1-2 bond is cleaved to trans-4-proline that
hydroxylates HIFα in the ODDD with the reaction products being succinate
and carbon dioxide (CO2) (32). The oxygens necessary for hydroxylation of
the ODDD and the formation of succinate are derived from molecular
dioxygen (Figure 43-2A). The affinity of prolyl hydroxylases for oxygen is
relatively low (Km 250 μM) (33–35), which allows prolylhydroxylases to be
sensitive to local oxygen concentrations. It is key that prolylhydroxylase uses
oxygen and α-keg, a central substrate of the TCA cycle and an acceptor of
ammonia to make glutamate, a key player of neuronal transmission,
demonstrating the interplay between oxygen tension and metabolism.
FIGURE 43-2 A:Overall reaction accomplished by HIF
prolyl hydroxylases. Molecular dioxygen is split in the
oxidation of Fe II to Fe IV adding one oxygen to
oxoglutarate and second to proline on the target protein
while decarboxylating α-ketoglutarate to succinate. B: HIF
prolyl hydroxylase inhibition works in the mouse OIR
model and (C) the rat 50/10 model. (B reprinted from
Sears JE, Hoppe G, Ebrahem Q, et al. Prolyl hydroxylase
inhibition during hyperoxia prevents oxygen-induced
retinopathy. Proc Natl Acad Sci U S A
2008;105(50):198980903. Copyright © 2008 National
Academy of Sciences, U.S.A. C republished with
permission of Association for Research in Vision &
Ophthmology, from Trichonas G, Lee TJ, Hoppe G, et al.
Prolyl hydroxylase inhibition during hyperoxia prevents
oxygen-induced retinopathy in the rat 50/10 model. Invest
Opthalmol Vis Sci 2013;54(7):4919–4926; permission
conveyed through Copyright Clearance Center, Inc.)
There are three isoforms of HIF PHD, PHD 1, 2, and 3. These enzymes are
also known as ELGN-2, ELGN-1, and ELGN-3 from their original cloning
from Caenorhabditis elegans. PHD 1 is constitutively found in the nucleus
and hydroxylates both proline residues within the ODDD. The most abundant
and potent isoform is PHD 2, which occurs in the cytoplasm and
hydroxylates both proline residues. PHD 3 hydroxylates only Pro562 and is
found in both the cytoplasm and nucleus. Conditional knockout of all three
enzymes, PHD 1, 2, and 3, is embryonically lethal, whereas inducible
knockout of PHD2 leads to a hypervascular state (36). Each PHD enzyme is
only about 50% homologous in the C-terminal half of the protein. Although
there has been preliminary evidence that suggests a preference of PHD2 for
HIF-1α in vitro, this finding has been difficult to recapitulate in vivo. It is
known that all the PHDs are selective for the C- and not the N-terminal
activation domain. This is important because the biologic effects of PHDs or
of FIH can alter the extent of inhibition of hypoxia-induced transcription of
factors (37).
From Hong SS, Lee H, Kim KW. HIF-1alpha: a valid therapeutic target for tumor therapy. Cancer Res
Treat 2004;36:343. Copyright © 2004 Korean Cancer Association.
HIF STABILIZATION IN
EXPERIMENTAL ROP BY SMALL
MOLECULES
HIF stabilization is proangiogenic, whereas HIF inhibition is antiangiogenic.
Early in studies of HIF stabilization, we postulated that ROP is a reflection of
systemic oxygen toxicity, which also leads to bronchopulmonary dysplasia
and nephron loss (38). Therefore, we sought to develop a therapy that could
be applied systemically in order to address the global toxicity of oxygen. Our
early studies involved the use of dimethyl oxaloylglycine, a carbonyl amide
that mimics the 2-oxoglutarate cofactor to HIF PHD but inhibits the enzyme
by occupying the binding site of this cofactor to HIF PHD, which in turn
inhibits the trans-4-prolyl hydroxylation of the ODDD and the subsequent
activation or stabilization of HIFα (Figure 43-1C). Administering 200 μg/g
pup weight of DMOG completely abrogated oxygen-induced vaso-
obliteration and attenuation of retinovascular growth in both the mouse and
rat experimental OIR models (9,39). These findings were striking because
stabilization of HIF was effective in two species (Figure 43-2B and C) and
satisfied the different oxygen stresses that are believed to be involved in the
pathophysiology of ROP. The success of this strategy in two different models
also supported the thinking that the overall high set-point of oxygen
saturations is important in ROP pathophysiology, as described by previous
investigators.
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SECTION VI
Tumors
44
Retinoblastoma
Jesse L. Berry, and Joan Marie O'Brien
INTRODUCTION
Retinoblastoma (RB) is a disease that has advanced our understanding of the
management of pediatric solid tumors and our fundamental understanding of
the etiology of cancer. With steady advances in knowledge of the natural
history, epidemiology, pathogenesis, cellular biology, and therapeutics for
RB, in Western societies more than 90% of children are treated at an early
stage while the tumor is still confined to the globe with excellent prospects
for life (1). Morbidity today has also been dramatically reduced, and a large
majority of children affected by RB can look forward to good vision in at
least one eye and excellent cosmesis (2,3). The study of RB has also led to
concomitant advances in our understanding of the genetic basis for malignant
transformation as the RB1 gene was the first described tumor-suppressor
gene. Although our understanding of the genetics and molecular biology of
RB has undoubtedly had an impact on screening for the disease, surprisingly
to date, this knowledge has had little direct influence on directed therapy or
clinical prognosis, which has advanced empirically.
HISTORICAL CONTEXT
The foundations for modern understanding of RB can be traced back to the
early 19th century, when the Scottish surgeon James Wardrop first
recognized RB as a distinct pathologic entity and published detailed
descriptions of this condition (4). Through his meticulous work, Wardrop
identified the retinal origin of the tumor, characterized the clinical course of
advanced disease, and described optic nerve invasion. He also proposed that
enucleation could be curative. His observations and clinical predications have
proved to be remarkably accurate, and they remain of clinical relevance
today. It was not until the development of the ophthalmoscope by Helmholtz
in 1851 that Wardrop’s ideas regarding treatment could be tested. The
ophthalmoscope allowed diagnosis of intraocular disease, and enucleation
was accomplished before the tumor had spread outside the globe (5). The
work of von Graefe and others improved surgical techniques for enucleation
(6–8). By isolating the rectus muscles, von Graefe achieved proptosis of the
globe and obtained a longer section of optic nerve, thereby reducing the risk
of unresected tumor remaining at the surgical margin of the optic nerve. This
technique improved survival from 5% in 1869 to 57% by the turn of the
century (9,10).
Subsequent decades witnessed advances in understanding the pathology
of RB. In 1864, Virchow (11) proposed the term retinal glioma for this
tumor, reflecting his now rejected hypothesis that the tumor arose from cells
of glial origin. Later, Flexner (12) and Wintersteiner (13) proposed a
neuroepithelial origin for RB and interpreted the rosettes that bear their
names as attempts at photoreceptor differentiation. Verhoeff and others
stressed the embryonic nature of RB and suggested that the tumor was
derived from undifferentiated embryonic retinal cells or retinoblasts. He
proposed the term retinoblastoma to reflect this cell of origin (14). In recent
decades, more differentiated tumors displaying benign characteristics have
been recognized and called retinocytoma or, more recently, retinoma (15,16).
While studies point toward a cone precursor cell of origin (17,18), the
histogenesis of RB continues to be a subject of considerable research interest
and debate.
Hilgartner (19), followed by Schoenberg (20), first advocated the use of
radiotherapy to treat RB. Radiotherapy provided a successful alternative to
enucleation and had particular application in bilaterally affected patients.
While effective for tumor control, the resultant bony midface hypoplasia
(21–23) and, worse, an increase in secondary neoplasms (24) limited its
success. Beginning in the 1990s, systemic chemotherapy used in conjunction
with local consolidative therapy (laser, cryotherapy) improved globe salvage
rates minimizing the need for enucleation and for external beam radiotherapy
(25,26).
In parallel with progress in clinical understanding, significant progress
has been made in understanding the genetics of RB. From RB pedigree
studies in 1971, Knudson concluded that RB could be caused by a germinal
or a somatic mutation and proposed his “two-hit hypothesis.” In this
hypothesis, Knudson proposed that two “hits” or mutations were required to
produce RB. Knudson also collated information regarding clinical
characteristics of patients, including patterns of disease, laterality of disease,
age of onset, and family history, which would pave the way for precise
localization and eventual cloning of the RB tumor susceptibility gene
(27–30).
The identification and cloning of the RB tumor suppressor gene (RB1) in
1987 produced a quantum leap in our understanding of the etiology of cancer
(28–30). Prior to the identification of RB1, it was widely believed that cancer
was caused by activation of oncogenes. Even in the 1980s, studies involving
the fusion of normal cells with cancer cells in culture suggested the existence
of elements within normal cells that could suppress the malignant phenotype.
These elements remained enigmatic until the work of Dryja, Murphree,
Gallie, Friend, and Cavanee that led to the cloning of RB1 in 1987, which
provided the first unequivocal proof of the existence of tumor suppressor
genes for carcinogenesis (28–32). Since the identification of RB1, many other
tumor suppressor genes have been identified. The protein products of these
genes are important in regulating cellular growth and differentiation. When
the function of the retinoblastoma protein (pRB) is reduced through mutation
or deletion in the germ line or as a somatic mutation in the retina, RB may
develop. Abnormalities in RB1 have also been detected in many other
malignancies aside from RB, such as breast, lung, and prostate cancer (33).
These observations suggested that RB1 dysfunction or pathway deregulation
plays a central role in the development of many cancers aside from just RB.
Why germ-line loss of one copy of the RB1 gene so uniquely predisposes to
tumor formation in the retina in young children is not fully understood;
however, cone precursor cells in the developing retina display a particular
tropism for RB1 and a heightened sensitivity to loss of a functional protein
product (17,18).
Basic science understanding of the RB1 gene and its protein product pRB
has so far preceded our ability to apply this knowledge to the human disease
in the form of precision therapies. It is likely that advances in our
understanding of this disease at the molecular level will yield dramatic
improvements in the lives of RB patients and their families.
EPIDEMIOLOGY AND PREVALENCE
RB is the most common primary eye cancer of childhood. The disease affects
approximately 1 in 20,000 live births leading to approximately 9,000 new
cases of RB diagnosed annually worldwide (34–36). An increasing incidence
of RB and other pediatric cancers has been reported in the developed world;
the basis for this increase is not currently understood (37). Patients in
developing regions present with RB at a much later stage in the course of
their disease and have a considerably worsened outcome, suggesting a need
for strategies to improve diagnosis and treatment of this disease in the
developing world (37).
The vast majority of RBs arise from mutations in both copies of the RB1
gene. The first mutation may either involve the germ line or be confined to
the tumor itself. This distinction produces two fundamentally different forms
of the disease: heritable RB and nonheritable RB. Heritable and nonheritable
RBs have quite distinct epidemiologic and clinical features. In brief,
approximately 40% of patients have heritable or germ-line RB; only 10% of
these patients have a positive family history and the others are from a new
sporadic germ-line mutation. These patients are at nearly 45% risk for the
development of RB because the trait is transmitted in an autosomal dominant
fashion with 90% penetrance. Patients with heritable RB have an 80% to 90%
risk of developing multiple tumors and bilateral eye disease in infancy, and
these patients have a lifetime predisposition to develop other secondary
nonocular cancers (38,39). Approximately 5% of germ-line RB patients will
develop a second primary intracranial malignancy in childhood, termed
trilateral RB (36). These tumors represent primitive neuroectodermal
malignancies for which treatment is less effective than for primary intraocular
RB, although there have been recent improvements in treatment modalities
and survival (40–44). Thirty percent of heritable RB patients will develop a
nonocular neoplasm by age 40 years (45).
The remaining 60% of RB patients have the nonheritable or somatic form
of the disease. In these patients, both RB1 mutations occurred within a single
retinal cell, resulting in unilateral, unifocal eye disease. The ocular disease
remains unilateral in these patients, and the cancer syndrome is not
transmissible to future offspring of the patient. There is no predisposition to
develop later nonocular malignancies in these somatic RB patients. A third
group of patients who have mosaic mutations in some portions of their
cellular makeup has also been recognized.
The mean age at diagnosis for RB patients is 13 months for bilateral RB
and 24 months for unilateral cases (46). Patients diagnosed as a result of
family screening are considerably younger, and many cases are detected near
birth. More than two-thirds of RB cases develop in children younger than 2
years, and 95% occur in children younger than 5 years (46). The onset of new
tumors after age 7 years is unusual, although rare cases presenting in
adolescence or adulthood have been reported that may represent malignant
conversion of a benign retinoma (47–53). Patients diagnosed with RB must
be very closely monitored for the development of new retinal tumors, which
are likely to occur in early childhood in those patients with heritable disease.
In those with somatic disease, close monitoring is also required as tumors
may recur and require further treatment.
ENVIRONMENTAL FACTORS
New germ-line mutations in the human RB gene are known to arise
preferentially on paternally derived chromosomes. Some studies have
suggested an increased parental age in sporadic hereditary RB (54,55).
Approximately 80% of heritable RB cases have a paternally derived mutant
allele, although no differences in paternal age between paternally and
maternally derived mutations have been observed (56). We do not yet
understand what environmental factors, if any, influence the development of
initial mutations in the RB1 gene. Some have postulated that human
papillomavirus (HPV) may play a role in sporadic RB. Environmental
factors, however, likely have a role in the predisposition to second cancers
observed in adults with the heritable form of RB, because the distribution of
second cancers in these patients is influenced by previous exposure to
radiotherapy.
WORLDWIDE IMPACT
The exact number of cases of RB worldwide is unknown. It has been
estimated at approximately 9,000 cases annually (34). Countries with the
highest number of annual births, China and India, are thought to harbor the
largest number of new cases. Limited access to cancer registries in
developing countries makes accurate assessments difficult.
PATHOPHYSIOLOGY
Thorough understanding of pathologic features, including growth patterns
and mode of tumor extension, is critical for diagnosis, staging, and
management decisions in RB patients. RB represents a malignant tumor of
neuroectodermal origin arising from the nucleated layers of the retina.
Malignant cells usually are poorly differentiated, rounded cells of variable
size and shape with a high nuclear-to-cytoplasmic ratio and numerous
mitoses. RB may display variable cellular differentiation, although most
cases encountered are relatively undifferentiated (57,58). RB is composed of
a solid well-vascularized tumor mass with regions of viable tumor cells
surrounding vessels and interspersed zones of necrosis and calcification, a
hallmark of RB. Additionally, apoptotic cells, cells of the mononuclear
phagocyte series, lymphocytes, and reactive glial cells have been observed in
these tumors (59,60).
Photoreceptor differentiation is suggested by tumor cell rosette and
fleurette formation; the morphologic features of these structures have been
meticulously demonstrated by a number of histopathologic and ultrastructural
studies (Figure 44-1) (12,13,61,62). The Flexner-Wintersteiner rosette is not
specific for RB, but it does represent a characteristic pathologic feature.
These rosettes have also been observed in pineoblastoma and
medulloepithelioma (63). The Homer-Wright rosette is less frequently
observed in RB and is less specific; this rosette is found in a variety of other
neuroblastic tumors (64). Glial differentiation may be observed in RB (65).
Although true glial differentiation is difficult to distinguish from reactive
gliosis, studies in tissue culture have demonstrated the potential of RB cells
to differentiate along a neuronal or glial cell lineage (59,60,65).
FIGURE 44-1 A: Hematoxylin and eosin–stained section
from an RB specimen. A region of viable tumor cells
demonstrating rosette formation. A prominent Flexner-
Wintersteiner rosette is indicated (arrow). A tumor
vascular complex is present at the top right-hand corner
(×25). B: Toluidine blue–stained section from an RB
specimen showing fleurette formation, an expression of
photoreceptor differentiation (×100).
RB cells are poorly cohesive; they readily disseminate throughout the globe,
a clinical phenomenon called seeding. One mechanism underlying loss of
cellular cohesion in RB may include deranged expression of intercellular
adhesion molecules such as N-cadherin (80,81). RB cells are shed into the
vitreous as small clumps of tumor cells called vitreous seeds (from
endophytic growth) or into the subretinal space (from exophytic lesions),
called subretinal seeds. (See clinical presentation below.) RB tumor cells
frequently disseminate away from the main tumor mass, involving ocular
structures such as distant retina, lens capsule, or anterior chamber. This
dissemination can result in secondary ocular complications such as glaucoma
or pseudouveitis (57). Retinal seeding can occasionally mimic multicentric
RB, leading to the inaccurate diagnosis of germinal mutation. In large tumors
with extensive vitreous and subretinal seeding, the distinction between
unifocal and multifocal disease may be impossible to determine clinically.
RISK OF METASTASIS
RB may spread extraocularly and extend outside the eye by a number of
routes. The most frequently observed route of extension is through invasion
of the central nervous system (CNS) through the optic nerve, followed by
direct extraocular spread and involvement of the orbit. Tumor cells may
invade the optic nerve directly or may invade the leptomeninges, gaining
access to the orbital apex, optic chiasm, base of the brain, and subarachnoid
space (57). Extension of RB cells into the optic nerve is considered a major
histopathologic risk factor for the development of metastases, particularly
when the tumor extends beyond the lamina cribrosa. If the optic nerve is
involved posterior to the line of surgical transection at the time of
enucleation, patients demonstrate a dramatically worsened clinical course
(82–85). RB tumor cells may also invade the retinal pigment epithelium,
Bruch membrane, and choroid (86,87). Exposure to the rich choroidal
vasculature provides tumor cells access to emissary vascular channels and
ultimately to the systemic circulation. The sclera may also be directly invaded
by tumor cells. It has been suggested that the exophytic growth pattern is
associated with increased risk for choroidal or orbital involvement and
metastases, although this hypothesis remains clinically unproven (86). It has
also been suggested that massive invasion of the choroid is an independent
risk factor for disease dissemination (88–95). Tumor cells that spread
hematogenously produce widespread metastases to the lungs, brain, bone,
and other viscera. Lymphatic dissemination of RB may occasionally occur in
cases that extend anteriorly and allow tumor cells access to the bulbar
conjunctiva and to the eyelid lymphatics (57).
The complex molecular interactions among tumor cells, parenchymal
tissues, and extracellular matrices are currently not fully understood. Recent
research suggests that a growth and invasion advantage may be conferred on
subgroups of tumor cells that become independent of normal mechanisms for
cell death or apoptosis and avoid tissue constraints, allowing spread to distant
sites. These clones of more aggressive cells arise through ongoing mutagenic
and epigenetic phenomena within the tumor. Some molecular mechanisms
identified in RB and other tumors that could facilitate these changes include
up-regulation of telomerase activity, N-myc oncogene amplification, p53
inactivation, changes in cell adhesion molecules (e.g., cadherins), altered
expression of integrin subunits by tumor cells, and increased expression of
angiogenic factors (81,96–98). Greater understanding of these critical
molecular processes is likely to yield better and more specific therapies for
this disease in the future.
OVERVIEW OF RETINOBLASTOMA
GENETICS
Retinoblastoma Gene and Protein Product
RB is one of very few cancers in which a single genetic mutation predicts
disease development at very high penetrance. The presence of an underlying
genetic mutation in RB was predicted by Knudson in 1971, and this
prediction led to identification of the RB susceptibility gene locus, with
subsequent cloning of this tumor suppressor gene in 1987. Identification of
the RB1 gene provided definitive evidence that loss of tumor suppressor gene
function is important in the etiology of all human cancers. Although it
appears that other genes may be involved in the subsequent tumorigenesis of
RB (99), in order for RB to arise, a mutation on both alleles of the RB1 gene
is required in the great majority of cases (16). Rarely, RB is initiated by
primary MYCN amplification in the absence of a RB1 mutation. This occurs
in approximately 2% of unilateral cases (100).
The RB1 gene encompasses 180,000 base pairs on chromosome 13q14
and contains 27 exons. The gene encodes a 4.7-kDa message that results in a
105-kDa nuclear phosphoprotein. The RB protein, known as pRB, is a
transcriptional modulator expressed throughout development in all cells of
adult humans (101–104). The protein has two conserved regions where
important functional domains reside and which also represent sites for viral
oncogene binding (e.g., SV40 T-antigen, adenovirus E1A, and HPV E7).
Oncogenic viruses are capable of inactivating pRB through binding, thereby
inducing malignant transformation. Many of the clinically relevant mutations
that have been observed in RB1 affect these conserved regions of the protein
(38,105–107). Mutations have also been observed in the promoter region of
the gene; these mutations affect recognition sequences for transcription
factors (e.g., ATF and SP-1) (108).
Mutations affecting the RB1 locus appear to be very heterogeneous. Few
preferential sites for mutation, or “hotspots,” have been identified (38,109).
Only 3% to 5% of constitutional mutations in RB1 are cytogenetically
recognizable; these include interstitial deletions or translocations involving
13q. The remainder of mutations are submicroscopic, including point
mutations, microdeletions, and duplications. In more than 90% of RB1
mutations, deoxyribonucleic acid (DNA) alterations result in a truncated
mRNA product (38,101). The second mutation that occurs in the retinal cell
of origin of the tumor is a result of chromosomal abnormalities, such as
nondisjunction, loss of heterozygosity due to mitotic recombination, or large
deletion (101). This second event may be more influenced by environmental
factors, including ionizing radiation. Therapeutic radiation exposure
influences the distribution of nonocular tumors.
The RB protein has a critical and complex role in the regulation of
cellular growth and differentiation. pRB binds to more than 30 separate
cellular proteins, including transcription factors, nuclear matrix proteins,
growth regulators, protein phosphatases, and protein kinases (110). One of
the best understood functions of pRB involves regulation of the cell cycle
through inhibition of the transcription factor E2F (111–113). In this role, the
active hypophosphorylated form of pRB acts at a restriction point in late G1
of the cell cycle to inhibit the E2F family of transcription factors. These
factors in turn regulate expression of a large set of genes, including, among
others, c-myc, b-myb, cdc2, E2F-1, and the dihydrofolate reductase gene
associated with cell division in S phase (112,113). The phosphorylation and
dephosphorylation of pRB itself are controlled by a complex series of cell
cycle–dependent and cell cycle–independent enzymes, including cyclin–
cyclin-dependent kinase (cyclin–CDK) complexes and cyclin-dependent
kinase inhibitors (CDKIs) (114,115) (Figure 44-3).
In addition to its role in cell cycle regulation, pRB has important effects on
cellular differentiation. These effects include cell cycle arrest, suppression of
apoptosis, and transcriptional activation of tissue-specific genes (103). These
effects may be particularly important in tissues such as muscle, bone, fat, and
nerve (116–120). Despite the ubiquitous expression of pRB in all dividing
cells, germ-line mutations leading to loss of functional RB protein in humans
seem to uniquely cause RB and, later, tumors of mesenchymal origin.
These mesenchymal tumors include osteosarcoma, leiomyosarcoma, and
malignant fibrous histiocytoma (121). In contrast, somatic alterations in pRB,
which occur mainly through functional inactivation of upstream regulators,
are involved in the progression of many common cancers. These include
carcinoma of the breast, bladder, and prostate; small cell lung cancer;
leukemia; and glioblastoma (33). For example, mutation of p16Ink4a (a CDKI)
and amplification of cyclin D, both upstream regulators of pRB, are
frequently observed in these malignancies (122,123). The vulnerability of
RB1-deficient cells in the retina and certain connective tissues to tumor
development in the presence of RB1 germ-line mutation has never been
adequately explained. It is possible that this vulnerability arises from a
critical requirement for pRB in terminal differentiation of these tissues.
Although mutation in both RB1 alleles initiates RB, other secondary
chromosomal abnormalities and mutations have also been consistently
observed. These other consistent genetic and genomic abnormalities include
trisomy 1p, loss of heterozygosity for chromosome 17, and isochromosome
formation at 6p (124–127). These abnormalities could represent secondary
changes due to genetic instability and could play a role in mediating
malignant progression, allowing clones of malignant cells to acquire selective
growth advantage. Interestingly, reconstitution of RB cells, RB-null
carcinoma cells, or sarcoma cells with functional pRB only partially
modulates the malignant phenotype (128). This suggests that other consistent
genomic alterations such as the highly recurrent chromosomal aberrations
include gain of 1q, 2p, and 6p and loss of 13q and 16q. A better
understanding of the target genes contained in these regions may inform
understanding of RB tumorigenesis and phenotype (99,129).
Clinical Genetics
Heritable Retinoblastoma
Although only 10% of RB patients have a family history of this disease, new
germ-line mutations account for an additional 30%, meaning that 40% of RB
patients have a heritable form of RB. Patients with heritable disease have a
mutation (or first “hit,” according to Knudson’s hypothesis) involving RB1 in
every cell of their bodies. This is termed a germ-line mutation because the
mutation either was inherited from a parent or, more commonly, developed at
the one-cell stage of embryonic development in the affected individual (or as
a mosaic in which the mutation developed during embryogenesis but after the
one-cell stage; the % of mosaicism in a patient is determined by the timing of
this mutation). Individuals with germ-line mutations in RB1 are capable of
passing on the mutation to their offspring. Mutation in the other copy of RB1
(the second “hit” described by Knudson) occurs in an undifferentiated
embryonic retinal cell that gives rise to the malignant tumor. In this heritable
form of RB, patients usually demonstrate bilateral, multifocal retinal tumors,
which are pathognomonic for heritable disease. Although the RB gene at the
cellular level is recessive (i.e., both RB alleles must be abnormal in order for
the tumor phenotype to be expressed) at the level of the individual, the
mutation behaves in an autosomal dominant manner, with 80% to 90%
penetrance (130) (Table 44-1).
Nonheritable Retinoblastoma
The remaining 60% of RB cases represent nonheritable or somatic disease. In
this nonheritable form, mutations in both RB1 alleles (i.e., both the first and
the second “hits”) occur within a single retinal cell of origin for the tumor.
Such events are rare; therefore, these patients demonstrate a single unilateral,
unifocal tumor. Unilateral disease presents, on average, at a later age than
does bilateral disease given the additional time needed to acquire the first and
then second mutation in these cases. This observation was the basis for much
of Knudson’s hypothesis. These children with unilateral involvement also
present at a later age because they retain vision in the unaffected eye.
It should be recognized that approximately 15% of patients who present
with unilateral RB have the heritable form of this disease, but by chance they
have developed a tumor in only one eye (131). For this reason, all children
with RB should undergo genetic testing for evaluation of somatic mutations,
and this can be critically impactful in unilateral cases as it dictates risk of
subsequent ocular and nonocular tumors and risk to future offspring. The
relationship between the clinical and the genetic forms of RB is summarized
in Table 44-1.
Genetic Mosaicism
It has been recognized that at least 10% of RB families demonstrate germ-
line or somatic mosaicism (134). Mosaicism refers to the presence of two or
more cell lineages differing in genotype in an individual. If a mutation
develops at the RB1 locus during later stages of embryonic development, the
lineage of cells derived from this original mutation-bearing cell will carry an
identical RB1 mutation. In contrast, cells derived from unaffected lineages
will carry normal copies of RB1. If the mutant RB1 is carried in the gametes
but not in the eye, the affected individual could pass the mutation to offspring
without personally demonstrating clinical evidence of RB. The practical
significance of mosaicism in one of a proband’s parents is that siblings of this
proband would be at higher risk for developing the disease than previously
believed (134). Therefore, siblings should receive early and regular screening
for development of this disease or genetic testing to better define the risk
(135). Parents who are mosaic for mutant RB1 may also be at personal risk to
develop malignancies in cell lineages that carry the mutant gene. These
individuals should receive prompt referral to an oncologist if systemic
complaints suggestive of malignancy develop. It should also be noted that
while the initial familial mutation may present in a mosaic fashion, future
generations will only develop RB if the mosaic RB mutation involves the
gametes of the affected individual.
Low-Penetrance Retinoblastoma
Forms of RB have been described in families where a proportion of RB1
mutation carriers do not develop eye tumors. This clinical circumstance is
termed low-penetrance RB. In other families, RB1 mutation carriers either
develop unilateral disease or demonstrate a benign variant of RB called
retinoma. This clinical circumstance is described as low-expressivity RB.
Low-penetrance and low-expressivity forms of RB have been associated with
RB1 mutations that either partially inactivate the protein or reduce protein
expression (136). Recognition of these clinical situations is important
because they allow more accurate genetic counseling for affected families
(130,137).
DIFFERENTIAL DIAGNOSIS
The clinical diagnosis of RB always requires that this malignant tumor be
distinguished from other simulating disease processes by an ocular
oncologist. In a study of 500 patients referred to the Wills Eye Hospital for
suspected RB, only 58% of referred patients were found to have RB on
clinical evaluation. The remaining 212 patients received diagnoses of 23
different forms of pseudoretinoblastoma (157). The most common simulating
lesions were persistent hyperplastic primary vitreous (PHPV) (28%), Coats
disease (16%), and presumed ocular toxocariasis (16%), followed by
retinopathy of prematurity and retinal hamartoma. Other simulating lesions
included hereditary conditions, such as familial exudative vitreoretinopathy,
congenital retinoschisis, Norrie disease, and incontinentia pigmenti. Similar
findings and referral accuracy were found in a study from Sloan Kettering
Cancer Center (164). Developmental conditions that are mistaken for RB
included retinal or optic nerve coloboma, retinal dysplasia, congenital retinal
folds, and myelinated nerve fibers. Inflammatory or infectious conditions,
including congenital toxoplasmosis or toxocariasis or cytomegalovirus or
herpesvirus retinitis, can also simulate RB. Tumors such as
medulloepithelioma, choroidal hemangioma, glioneuroma, capillary
hemangioma, and ocular infiltrates from leukemia occasionally can present
initially as RB. It should always be recalled in the setting of media opacities,
such as hyphema, cataract, or vitreous hemorrhage, that the diagnosis of RB
is not excluded until the retina has been thoroughly examined or imaged to
exclude a concomitant tumor. RB coexisting with other conditions, such as
PHPV or cataract, has been reported (165). In practice, most clinical cases of
RB can be diagnosed through careful clinical evaluation by an experienced
examiner and the judicious application of supplemental investigations. Table
44-2 summarizes the salient diagnostic features of the more common lesions
that simulate RB.
aRB can produce a Coats-like reaction with a large amount of retinal exudation. In these eyes, US can
usually detect the retinal tumor beneath the exudate.
bCorrespond to the refractile cholesterol particles seen clinically. These particles are much less
reflective than the calcium particles seen with RB. (From Shields JA, Shields CL, Parsons HM.
Differential diagnosis of retinoblastoma. Retina 1991;11:232–243.)
cCalcification is not specific to RB, although it is very characteristic. The calcification in astrocytomas
appears clinically as refractile yellow areas versus the chalky white appearance in RB.
RB, retinoblastoma; PHPV (PFV), persistent hyperplastic primary vitreous (persistent fetal
vasculature); CT, computed tomography; Dx, diagnosis; FA, fluorescein angiography; HA, hyaloid
artery; HI, high intensity; Hx, history; ILM, internal limiting membrane; LBW, low birth weight; MI,
medium intensity; MRI, magnetic resonance imaging; RD, retinal detachment; RPE, retinal pigment
epithelium; US, ultrasound; AD, autosomal dominant.
STAGING EXAMINATION
Whenever RB is suspected, a detailed medical history should be taken at
initial examination, including a prenatal and birth history. Historical features
suggesting a pseudoretinoblastoma should be specifically investigated (Table
44-2). A family history should be obtained, and a detailed family tree should
be diagrammed in the medical record. A history of RB or other forms of
cancer, as well as a history of ocular malformations, blindness, or enucleation
in other family members, should be explored. Enucleation or blindness
occurring within a family is often better remembered than the precise
diagnosis of RB. The family tree should document the ages and health status
of all siblings and near relatives.
In every child with suspected RB, a complete physical examination is
required. Specific features associated with simulating lesions and/or RB
syndromes or systemic metastases should be evaluated. For example, the
child should be examined for evidence of tuberous sclerosis (e.g., ash leaf
spots) or dysmorphic features suggesting a 13q deletion syndrome. Evidence
for underlying systemic disease or metastases, such as cachexia, wasting, or
developmental delay, should be investigated. Clinical features of PNETs
associated with trilateral RB include abnormal eye movements, vomiting,
seizure, headache, and changes in cognition. We routinely refer all patients
with suspected RB to a knowledgeable pediatric oncologist for a complete
history and physical examination.
The ophthalmologic evaluation of a child with suspected RB should be
detailed, complete, and performed under general anesthesia. While there is a
priority placed on visual acuity and visual function, the primary goal is
always cancer control. The visual potential of each eye is an important
determinant for future therapy, and patients with unilateral disease and eyes
that have been functionally destroyed by the tumor should be considered for
enucleation as a curative procedure. External examination of the patient
should evaluate for dysmorphic features, lymphadenopathy, or proptosis.
Pupils and eye movements should be evaluated for evidence of a concomitant
intracranial disease process. Careful anterior segment examination is
necessary to evaluate the size of the corneas and the clinical appearance of
anterior segment structures. For example, a unilateral small corneal diameter
may suggest PHPV particularly in the setting of anteriorly rotated ciliary
body processes, rather than RB. An enlarged diameter may be seen in the
setting of buphthalmos from an eye with advanced disease and high
intraocular pressure. Signs of intraocular inflammation should be sought on
slit lamp evaluation (handheld is often used during examination under
anesthesia [EUA]). Although RB may rarely produce a pseudouveitis or
tumor hypopyon, signs of intraocular inflammation are more often associated
with granulomatous uveitis, such as toxocariasis, or with other pediatric
uveitis syndromes. Intraocular pressures for each eye should be recorded, and
the cause of any pressure elevation including angle closure or
neovascularization of the iris should be investigated.
Bilateral dilated fundus examination with scleral depression is performed
under general anesthesia. Scleral indentation must be performed for 360
degrees of the globe in order to inspect the entire surface of the retina to
detect anteriorly located tumors. In one series, RB in the periphery of the
fundus was detected using scleral indentation in 65% of cases (166). Color
fundus photos with a wide-angle contact camera and retinal drawings should
be performed to document the size and location of all retinal tumors. This
documentation is essential to plan treatment and to monitor subsequent
treatment response (167).
DIAGNOSTIC STUDIES
Supplementary investigations are frequently used to aid in the diagnosis and
staging of patients referred with RB. Ultrasonography is a useful tool,
particularly for confirming the initial diagnosis and for evaluating features of
intraocular disease. In larger tumors, A-scan echography typically
demonstrates high-intensity echoes within the tumor that correspond to areas
of tumor calcification. The tumor surface nearest the sclera may be anechoic.
B-scan often demonstrates an intraocular mass with scattered highly
reflective echoes within the tumor and with attenuation of normal soft tissue
signals posterior to the tumor. In patients with advanced disease, exudative
retinal detachment, vitreous seeding, and subretinal seeding also may be
demonstrated by ultrasound (Figure 44-7) (168). Fluorescein angiography
(FA) can also be performed. This is useful for staging in two ways; the first is
that if there is a concern for Coats disease, it can help to characterize the
lesion vasculature. More often in the setting of RB, FA can be used to
determine subclinical neovascularization of the iris, which in the setting of
increased intraocular pressure affects staging (150,169).
FIGURE 44-7 A: Ultrasound scan of RB showing a
retinal mass located at the posterior pole. Both (A) and (B)
scans demonstrate that the mass has areas of high internal
reflectivity due to intrinsic calcification. Intrinsic tumor
calcium may produce a shadowing of the soft tissues
behind the tumor. B: CT scanning performed with contrast
demonstrates bilateral RB tumors involving the posterior
poles with dense calcium deposits. C: T1-weighted MRI
scan with gadolinium enhancement demonstrating an
enhancing PNET in a patient with heritable RB.
MRI is used to evaluate for extraocular extension of disease via the optic
nerve, orbit, subarachnoid space, and meninges, as well as to exclude all
PNETs. Gadolinium-enhanced MRI is particularly valuable for evaluating
optic nerve extension or CNS disease. RB is hyperintense on T1-weighted
images and hypointense on T2-weighted images (Figure 44-7) (170–172).
Most experts prefer MRI over CT to avoid any radiation exposure in this
high-risk population.
Bone marrow aspiration and lumbar puncture may be obtained to
evaluate for systemic spread, although it is not routinely performed in most
centers. Other investigations, such as bone scans, are performed based on the
overall clinical assessment of the patient. In most cases, complete metastatic
evaluation is reserved for patients who present with features of highly
advanced disease.
GROUP CLASSIFICATION
At the time of initial clinical evaluation, the patient should be staged, and the
extent of intraocular disease should be classified as a means of assisting the
ocular oncologists in assessing the likelihood of salvaging the eye. The first
such system was proposed by Reese and Ellsworth in the 1960s (173). This
presurgical grouping system proved highly useful for decades throughout the
primary radiotherapy era. However, once this treatment modality was
supplanted by systemic intravenous chemotherapy, a new system was needed
to fill this clinical void. In 2005, Murphree proposed the International
Intraocular Retinoblastoma Classification (IIRC) system for retinoblastoma
(169), which groups eyes from A to E by the extent of disease with Group A
eyes having small tumors far from critical structures and Group E eyes being
anatomically and functionally destroyed by the cancer. The IIRC was
developed with international cooperation among oncologists and
ophthalmologists; however, it has not been strictly followed, and other
classifications with small differences are used across centers (174). The
controversy over differences in classification system has limited the ability of
the RB community to truly compare outcomes across centers (particularly for
advanced Group D and E eyes) and has led to calls for uniformity in
classification. Multicenter clinical trials to assess the management of RB,
such as those performed through the Children’s Oncology Group, also require
a uniform staging system and used the IIRC clinical classification with a
minor variation, which is the size of subretinal fluid allowable in Group B
eyes (3 vs. 5 mm).
In 2017, the eighth edition of the AJCC (175) was published, which
introduced a comprehensive reclassification of the RB grouping system
including the addition of the H “heritable trait” for genetic status of the
patient. This was based on retrospective evaluation between 2001 and 2011
of 1,728 eyes diagnosed from multiple RB centers. Kaplan-Meier survival
analyses of the proportion of eyes salvaged (without the need for external
beam radiation) were evaluated based on clinical features. The salvage of
eyes based on the TNM grouping was the most predictive of all clinical
classification systems and is growing in acceptance among ocular oncologists
and RB centers worldwide.
Families with a new diagnosis of RB require considerable psychological
and emotional support during this period of initial diagnosis. The attending
ophthalmologist, pediatrician, pediatric oncologist, and other health
professionals play an important role in this and in responding to the needs of
the patient, the parents, and other family members with regard to emotional
support and information. The attending ophthalmologist needs to be available
to spend considerable time with the family of a child with newly diagnosed
RB. Showing the parents images of the tumor will frequently assist in the
process of enabling them to accept the recommended treatment plan. Support,
information, and visual documentation of the disease are particularly helpful
when enucleation is being considered. Parents need to be given time to deal
with a new diagnosis of RB. Often, parents are surprised by the initial
diagnosis, and little information from the first consultation is assimilated.
Discussion of the child’s case at a multidisciplinary pediatric tumor board
with consensus on appropriate treatment is frequently reassuring to families.
Many families obtain benefit by referral to a multidisciplinary RB follow-up
clinic, where it is apparent that older children with this diagnosis are leading
full and healthy lives after successful treatment. An inordinate delay in
proceeding to treatment should be discouraged, however, because a delay of
weeks can make a difference in staging and subsequently in salvage. There
should be very minimal delay in definitive therapy for an eye that is unsafe
for the patient due to high pressure from advanced intraocular disease or
signs of optic nerve involvement on MRI imaging (132,176).
MANAGEMENT
A treatment plan should be individualized for each patient and will be
determined by many factors, including the age of the patient and laterality of
disease; the size and location of the ocular tumor(s); the presence of optic
nerve, orbital, or metastatic disease; and, finally, the visual potential of the
affected eye (see also Chapter 45).
In recent years, significant changes have occurred in initial approaches to
the therapy of RB. As the therapy for this disease is complex and involves
expertise across a variety of specialties, management usually is performed
through a multidisciplinary approach at centers of expertise in pediatric and
ocular cancer. Treatment modalities, including surgery, local therapies (laser
ablation, diode hyperthermia, or cryotherapy), intravenous and intra-arterial
chemotherapy (IAC), and brachytherapy or external beam radiotherapy, may
be used. Also important are psychological and social support for the child and
family, visual rehabilitation, achievement of best cosmesis involving experts
in prosthetics, and finally the scheduling of ongoing examinations for the
patient, genetic counseling for the family, and screening for other at-risk
pediatric family members. Given this complexity and the diverse clinical
presentations, the therapeutic approach is tailored to the extent of disease,
needs of the family, and expectation of ability to save the eye and to save any
functional vision.
The majority of children with unilateral RB present with leukocoria. This
presentation usually represents advanced local disease with >60%
involvement of the globe. Enucleation should certainly be considered in these
children because it spares them the toxicity of systemic chemotherapy or
radiation and provides an acceptable cosmetic outcome. It is also a curative
procedure for the vast majority of these patients (177–181). Other clinical
indications for enucleation include advanced neovascular glaucoma
producing pain or RB in an eye that is devoid of visual potential. It should be
noted that while enucleation may not be chosen as primary therapy (e.g., the
therapy initiated at diagnosis), it is often required for persistent or recurrent
tumors not responsive to salvage therapy; this is termed secondary
enucleation.
Whether primary or secondary, the surgical approach to enucleation in
children with RB should facilitate obtaining a long section of optic nerve and
should avoid inadvertent globe penetration. Any tumor at the surgical margin
is an undesirable outcome that is associated with a significantly increased risk
for the development of metastatic disease, and this situation mandates
significant further therapy (86,178,179). If RB is confined to the globe, an
orbital prosthesis is routinely placed at the time of enucleation; therefore, it is
important to preserve the conjunctiva, Tenon capsule, and extraocular
muscles for integration of the implant. It also is important to completely
cover the prosthesis with Tenon capsule and conjunctiva; we use a
meticulous three-level closure to minimize exposure and extrusion and to
provide the best long-term cosmesis. Both porous and nonporous implants
have been used successfully in the management of the anophthalmic socket in
children with RB, and each has a separate side effect profile (177,180,182).
Unilateral cases, particularly if detected at an early stage with reasonable
visual potential, are usually successfully managed by modalities that preserve
the globe. These approaches include systemic or IAC with use of local
therapies including brachytherapy. For small tumors detected early, serial
application of laser ablation, diode hyperthermia, and cryotherapy may
occasionally be sufficient. However, the presence of vitreous seeding
indicates more advanced disease and consolidative therapy alone is rarely
indicated. It is worth noting that for larger localized tumors located more than
2 mm away from the macula and optic nerve or in patients with focal relapse
after local therapy, good responses to brachytherapy may be obtained,
including successful control of mild-to-moderate vitreous seeding close to the
main retinal lesion. Tumors considered for brachytherapy should ideally be
smaller than 15 mm in basal diameter and <8 mm in thickness (183).
Complications associated with plaque placement include radiation
retinopathy and papillopathy and early cataract formation (183). Patients who
have had previous chemotherapy have an increased risk for development of
neovascular complications following brachytherapy, and dose reduction may
be considered (184–187).
Although external beam radiation therapy (EBRT) very effectively treats
RB, it is associated with significant complications, including secondary
tumors inside and outside the radiation field and midfacial bony hypoplasia,
especially if radiation is administered at age <1 year (24). Less serious
complications include growth hormone deficiency; radiation retinopathy,
vasculopathy, and optic neuropathy; neovascular glaucoma; and dry eye
(188–190). A common problem in management following radiation is the
high incidence of cataract (~10%), especially when an anterior port for
therapy is used. Although cataracts can be successfully removed surgically,
an eye with RB cannot undergo intraocular surgery when any concern exists
regarding disease activity, because tumor cells could be disseminated.
Delaying cataract extraction results in visual deprivation during a critical
period and has produced amblyopia in these RB patients. The presence of
cataract can also make small intraocular tumor recurrences that would be
amenable to local therapy difficult to detect (191,192).
Radiation therapy in RB patients has been associated with increased
frequency of second primary malignancies within the radiation field
(24,39,45,132,193–195). The original studies describing this problem
reviewed patient outcomes following treatment with older radiotherapy
techniques, such as orthovoltage sources and single-port delivery systems.
Newer radiation techniques, including lens-sparing techniques, have
considerably reduced the dose received by surrounding tissues during the
treatment of RB (132). RB patients who receive EBRT after age 1 year may
show a lower rate of second tumor development, suggesting that EBRT may
still have a role if therapy is delayed (24).
Intravenous chemoreduction using three-drug systemic chemotherapy
combined with local therapy (photoablation, cryotherapy, or thermotherapy)
has been a mainstay of therapy for bilateral disease since the 1990s; it has
replaced enucleation and EBRT in many patients with heritable RB. The goal
of chemoreduction is to reduce the volume of retinal tumors in order to allow
ablation of residual disease with local therapy. This approach frequently
preserves the eye often with visual potential; however, the likelihood of this
depends on the stage of the eye (25,196–201). With more advanced Group D
disease successfully avoiding EBRT for salvage only in half of the cases
(197), although with newer modalities this is somewhat improved (202),
concomitant local therapy is needed to definitively treat the tumor. Thus, a
treatment plan consists of a number of cycles of chemotherapy during which
patients also receive local therapy. A number of studies suggest that local
therapy acts synergistically with chemotherapy, possibly by increasing the
uptake of the chemotherapeutic agents into the eye. The agents currently used
for systemic chemotherapy include carboplatin, vincristine, etoposide (VP-
16), and sometimes cyclosporin A. The dosage range varies across centers,
although standard regimens have been developed by protocols sponsored by
the Children’s Oncology Group of the National Institutes of Health. In
general, higher-dose regimens are used for patients with larger tumors
associated with vitreous and subretinal seeding. Children with smaller tumors
may respond well to lower-dose or fewer cycle protocols (201).
All chemotherapeutic agents are associated with potential toxicity.
Carboplatin may produce otologic toxicity and high-frequency hearing loss
that is unacceptable in children who already may have reduced vision.
Pretreatment audiologic testing and ongoing surveillance for the development
of hearing loss are imperative (203). Long-term mutagenesis and reduced
fertility have also been reported. Vincristine (VP-16) may have major
neurologic toxicities, including numbness and tingling in the extremities and
loss of deep tendon reflexes, which may be reversible with dose reduction or
cessation of therapy (204). Severe constipation may also be observed with
this agent; to prevent paralytic ileus, it is not prescribed for children <3
months of age per the Children’s Hospital Los Angeles protocol (196). The
dose-limiting toxicity for VP-16 is leukopenia that occurs during treatment.
Leukopenia may be treated by bone marrow–stimulating medications. The
risk also exists for development of nonlymphocytic leukemia associated with
a translocation at chromosome 11q23. This disease appears a short time
interval (usually between 1 and 3 years) after cessation of VP-16
chemotherapy. Although rare, it appears that the standard doses used for
chemoreduction in RB may be associated with a low risk for the development
of this devastating complication (205). Additionally, nausea, vomiting,
diarrhea, and stomatitis are observed in 15% of patients receiving VP-16
intravenously (204).
Systemic chemotherapy may be associated with other problems. Multiple
anesthetics are needed, both for application of local treatment and for
increased surveillance required to detect new tumors following completion of
this treatment. Chemotherapy remains less effective against very large tumors
and vitreous and subretinal seeding. In advanced cases, enucleation may be
required for the worse eye in bilateral disease. Finally, for the heritable form
of RB, we have not defined the potential mutagenicity of these
chemotherapeutic agents will have upon the incidence of second cancers in
later life.
Patients with persistent or relapsed intraocular disease that cannot be
controlled by standard consolidative therapy have a number of treatment
options still available to them. Such patients may be candidates for increased
dose chemotherapy with the addition of subconjunctival carboplatin, although
given the associated periocular fibrosis, this therapeutic approach is less
frequently utilized (206). Some centers employ cyclosporin A that may be
added to the chemotherapeutic regimen; this agent has been shown to be
effective in managing advanced intraocular disease, including vitreous and
subretinal seeding (207). Cyclosporin A competitively inhibits the P-
glycoprotein (P-gp) pump. Up-regulation of this pump reduces the
concentration of some chemotherapeutic agents in cancer cells by pumping
agents out of the cell into the extracellular space. The expression of P-gp
appears to be up-regulated on tumor cells by prior exposure to
chemotherapeutic agents and may be a source of resistance to chemotherapy.
Unfortunately, cyclosporin A is associated with increased toxicity, including
renal dysfunction, tremor, hypertension, hyperlipidemia, hirsutism, and gum
hyperplasia (204). EBRT remains an effective option in the treatment of RB,
and ERBT may have a role in salvaging an only eye that has not responded to
other therapies when the only alternative is enucleation. The majority of eyes
that are initially treated with intravenous chemotherapy and consolidation,
without appropriate disease response, are currently treated with IAC.
Starting in the 2000s, with the goal of increasing rates of salvage for
advanced disease, and decreasing systemic toxicity, there has been a move
toward a more localized approach to chemotherapy by administering the
drug(s) directly into the ophthalmic vasculature and bypassing the systemic
circulation (208–223). IAC was initially developed by Kaneko in Japan
decades ago (224). He devised a technique in which a balloon catheter was
introduced into the femoral artery and guided just past the ostia of the
ophthalmic artery via the carotid under fluoroscopy. After inflation of the
balloon, melphalan was injected into the intraocular vasculature. Abramson et
al. modified the technique by inserting the catheter directly into the lumen of
the ophthalmic artery. Initially, it was described in the setting of advanced
unilateral disease but has since been subsequently modified for bilateral RB.
It can be administered as a primary and salvage technique with various agents
such as carboplatin, topotecan, and methotrexate injected in a similar fashion,
although melphalan is the most commonly used agent. Intraoperative ERG
has been used to monitor the ocular toxicity of these agents on the retina
(225). In many cases, three injections of single-agent IAC with adjuvant local
therapy can cure an eye of advanced RB with higher success rates per group
than the standard six cycles of intravenous chemotherapy and with reasonable
visual outcomes. As with any therapy, there are associated complications
including vascular events, intraocular hemorrhage, and stroke (226–228).
While IAC is more effective at ocular salvage than intravenous
chemotherapy, it does not provide appropriate systemic coverage for high-
risk pathologic tumor invasion. It is hypothesized that due to this, the risk of
metastatic disease is slightly (1% to 3%) higher with IAC over intravenous
chemotherapy, but the exact incidence is hard to define (cite). Recently,
deaths from pathologic spread of RB have been reported in the scientific
literature (208) and popular press.
INTRAVITREAL CHEMOTHERAPY
Intravitreal chemotherapy (IVC) was introduced initially in the 1962 to treat
vitreous seeding, a common cause of tumor relapse, but was abandoned due
to concerns of extraocular spread (229). In 2012, Munier introduced a safety-
enhanced procedure for intravitreal injection of chemotherapy (230). As an
initial safety mechanism, a limbal paracentesis with removal of aqueous
humor is performed to lower the intraocular pressure and prevent reflux of
active seeds to the scleral injection site. The chemotherapy injection can then
be performed via the pars plana in a quadrant of the eye confirmed free of
tumor by ultrasound biomicroscopy. A 32-gauge needle is placed into the
midvitreous cavity and visualized behind the lens during injection.
Cryotherapy is then applied at the injection site as the needle is
withdrawn. The eye is shaken to distribute the chemotherapy, and the surface
is bathed in sterile water, which is cytotoxic. The described toxicities of this
treatment modality are retinal pigment epithelium mottling, hypotony,
anterior segment inflammation, and cataract formation (153).
Rarely, severe complications such as maculopathy, optic neuropathy,
phthisis, and acute hemorrhagic retinopathy (231) can occur (Figure 44-8).
The efficacy for treating vitreous seeds with intravitreal injections has been
reported to be 100% at many centers and has enabled many children to be
successfully treated without EBRT (152,202,232–234).
Retinoblastoma Screening
When the RB mutation is detected in a family, precise individualized genetic
counseling is provided. However, in some cases, the RB gene mutation is not
identified, usually because of lack of access to genetic testing due to
insurance restrictions (241). In this situation, even if the proband has
unilateral RB, offspring and siblings born into a family with RB are
examined first at birth and then again within the first weeks of life in order to
detect intraretinal tumors while they are small and amenable to local
therapies. OCT can be critical during this time period (158,242). Periodic
dilated ophthalmoscopy with a depressed examination to the ora 360 degrees
is continued throughout infancy and childhood as siblings with initially
normal examinations occasionally can develop tumors months after the initial
normal examination (135). We now recognize that germ-line mosaicism for
RB1 mutations occurs in at least 10% of RB families (134). This finding,
along with recognition of low-penetrance kindreds, suggests that a significant
minority of patients exists who have inherited a mutant RB1 gene from an
asymptomatic carrier. Without definitive genetic testing available for some
families, at the present time, we regard these RB patients as potentially
heritable cases. If genetic testing is not available to inform the true risk of
disease, serial screening examinations under anesthesia are justified in order
to detect this significant minority of patients with heritable disease before
symptoms arise.
PROGNOSIS
With steady advances in the diagnosis and treatment of RB, children with this
disease now have an excellent prognosis for life with decreased ocular and
visual morbidity. In developed countries, the mortality rate associated with
RB has fallen to <5%. Although the risk for metastatic disease in children
with bilateral RB appears to be higher than for individuals with unilateral RB,
the survival from metastatic disease is similar for both groups (243).
Survivors with heritable RB have a worse long-term prognosis than patients
with nonheritable RB because germ-line RB1 mutation confers a
predisposition for the development of second nonocular cancers (45). A 50%
overall mortality has been observed 25 years after the diagnosis of bilateral
RB (244). This statistic emphasizes the need to counsel patients with
heritable RB that careful follow-up for second tumor development is required
and that annual second tumor screening should be a family priority.
The outlook for vision in RB has improved with the development of
treatments that preserve vision and avoid enucleation. In one recent series of
74 children, the enucleation rate was 62%, and 58% of patients had a visual
acuity in the better eye between 20/20 and 20/40. Only 9% of patients
demonstrated visual acuity of 20/400 or worse. The final visual acuity in this
series was influenced by multiple factors, most notably tumor location. The
final visual outcome could not be predicted by the disease stage at initial
presentation (2) although macular tumor location and extensive retinal
detachment remain risk factors for poorer visual outcomes (3).
Management of metastatic RB continues to be a difficult clinical
problem. One factor that improves the prognosis for survival in patients with
metastatic disease is early detection. A number of studies have examined risk
factors for the development of metastatic disease. Early recognition of these
risk factors and prompt treatment may help to reduce mortality associated
with disease dissemination (86). Major clinical risk factors for the
development of metastatic RB include advanced intraocular disease at
diagnosis, delays in diagnosis, or history of prior intraocular surgery
(86,244–246). Accepted histopathologic risk factors include tumor cells
extending to the surgical margin of the optic nerve and microscopic
extraocular involvement by tumor cells (84,240). While multimodal therapies
have improved the overall survival for extraocular disease (235,238), the
importance of primary enucleation for highly advanced eyes (247) with
adjuvant therapy for high-risk pathologic features (248) cannot be
understated.
VISION REHABILITATION
The three priorities in the management of patients with RB in descending
order are salvage of life, salvage of eye(s), and salvage of vision. In all
unilateral cases with a normal contralateral globe, patients should be screened
for refractive errors, placed in shatterproof lenses, and follow monocular
precautions.
It may be difficult to predict final visual acuity in cases of advanced
bilateral disease. Patients with significant focal scarring in the macula and
fovea of their remaining eye have been known to retain better than expected
vision. As described elsewhere, cataract extraction may need to be deferred
until all intraocular tumors are stable and completely regressed. A pediatric
ophthalmologist can serve a critical role on the RB team by aiding in
decisions regarding patching, maximizing refraction, and visual rehabilitation
for these children.
ETHICAL CONSIDERATION
Access to specialized care remains a significant obstacle to the care of
children with RB in the developing world. As newer modalities such as IAC
become available worldwide, it is critical that experts acknowledge the
lifesaving role that early detection and primary enucleation still play in areas
where more expensive modalities may not be available. World outreach
programs are underway to reduce mortality from RB in the developing world
(249).
ACKNOWLEDGMENT
This work was supported by the National Eye Institute, Bethesda, Maryland
(grant #1RO1EY023557-01) and the Department of Ophthalmology at the
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Funds also come from the Vision Research Core Grant (P30 EY001583),
F.M. Kirby Foundation, Research to Prevent Blindness, The UPenn Hospital
Board of Women Visitors, The Paul and Evanina Bell Mackall Foundation
Trust, and, the NEI intramural program under eyeGENE® - protocol 06-EI-
0236 funded in part under Contract No. HHS-N-263-2017-00001-C. The
sponsor or funding organization had no role in the design or conduct of this
research. Dr. Berry has grant support from National Cancer Institute of the
National Institute of Health Award Number K08CA232344, TheWright
Foundation, the Knights Templar Eye Foundation, American Cancer Society
#IRG-16- 181-57, Hyundai Hope on Wheels, Childhood Eye Cancer Trust.
Dr. Berry has indirect support from The Larry and Celia Moh Foundation,
The Institute for Families, Inc., Children’s Hospital Los Angeles, an
unrestricted departmental grant from Research to Prevent Blindness.
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45
Treatment of Retinoblastoma
Lauren A. Dalvin, David Ancona-Lezama, and
Carol L. Shields
INTRODUCTION
Retinoblastoma management has evolved over the past several decades, but
the ultimate goals of care remain unchanged with preservation of life and the
globe, if possible, and maximization of visual acuity (1). The primary goal of
retinoblastoma therapy is cure of the malignancy with prevention of
metastatic disease. Secondary goals are to preserve the eye, prevent related
pineoblastoma, and minimize secondary systemic cancers (1). There is a
tertiary goal in management that focuses on protection of useful visual acuity.
With earlier detection and remarkable treatment advances, globe salvage with
preservation of visual acuity is possible in more cases than ever before.
Treatment of retinoblastoma can be complex and depends on several
factors such as patient age, germline genetic status, anticipated visual acuity,
globe classification, and ultimate risks for metastasis. Treatment is
individually tailored to each patient (Figure 45-1). The various treatment
modalities include systemic intravenous chemotherapy (IVC), intra-arterial
chemotherapy (IAC), intravitreal chemotherapy (IvitC), intracameral
chemotherapy (ICC), focal therapies (cryotherapy, laser photocoagulation,
transpupillary thermotherapy [TTT]), external beam radiotherapy (EBRT),
plaque radiotherapy, and enucleation. In this chapter, we discuss current
retinoblastoma treatment modalities, including applications, outcomes, and
side effects.
FIGURE 45-1 Management of retinoblastoma: decision
tree by patient presentation. Decision tree is a rough
guideline only. Real life management can be much more
complex. If tumor control cannot be achieved, optic nerve
becomes involved or cannot be visualized for 3
consecutive months, or the eye becomes blind and painful,
consider enucleation with or without adjuvant systemic
chemotherapy. IAC, intra-arterial chemotherapy; IvitC,
intravitreal chemotherapy; EBRT, external beam radiation
therapy.
RETINOBLASTOMA CLASSIFICATION
Retinoblastoma is classified prior to any treatment administration, according
to the features found in each globe independently (2). The classification is
listed in Table 45-1.
INTRAVENOUS CHEMOTHERAPY
Systemic IVC for retinoblastoma was introduced in the early 1990s and
remains an essential component of treatment in many cases. For many
patients, IVC is a preferred first treatment choice, particularly in patients with
bilateral disease, family history of retinoblastoma, known germline mutation,
presenting patient weight <6 kg, or cases suspicious for optic nerve or
choroidal invasion (Figure 45-2) (3). IVC can treat local disease in the eye as
well as prevent distant metastasis and second cancers. In patients with
germline retinoblastoma, IVC is especially important because it can protect
against the development of pineoblastoma and secondary cancers (4–6).
INTRA-ARTERIAL CHEMOTHERAPY
The use of IAC for retinoblastoma was introduced in 2004 in Japan and later
in the United States as a targeted therapy for retinoblastoma. This modality
has earned a particularly important role in retinoblastoma management,
especially for unilateral tumors (17–20). IAC is employed as primary therapy
for nongermline, unilateral, group B, C, D, or E retinoblastoma or as
secondary therapy for unilateral or bilateral advanced disease with recurrence
or failure to regress following IVC or plaque radiotherapy (Figures 45-3 and
45-4) (1,3,21,22). Some centers use IAC as primary therapy for bilateral
disease as tandem therapy. IAC is effective for treatment of subretinal seeds,
even those that are extensive and involving two or more quadrants. IAC can
also be effective for treatment of vitreous seeds, especially when seeding is
limited and in close proximity to the retina (3). If IAC is used as primary
therapy in patients with known or suspected germline mutation, careful
consideration must be given to the need for subsequent systemic IVC for
prevention of metastasis, pineoblastoma, and second cancers (4–6). Likewise,
caution is advised, especially for group D or E eyes, especially if there is
suspicion for high-risk features, including tumor invasion of the optic nerve,
uvea, or anterior chamber. (See section on high-risk retinoblastoma below.)
High-risk retinoblastoma warrants enucleation and additional systemic
chemotherapy to prevent metastatic disease (23). Due to anatomic challenges
with arterial catheterization in small-caliber vessels, use of IAC is typically
limited to patients older than 3 or 4 months (3). In younger patients, IVC can
be used as bridge therapy until weight reaches 6 kg, allowing for safe
delivery of IAC (24).
INTRAVITREAL CHEMOTHERAPY
The initial use of IvitC in the United States was by our team in 2006, based
on early observations from Japanese investigators (39). This therapy was later
widely adopted in the United States and Europe in 2012 (40–42). Despite
significant improvements in survival, tumor control, and globe salvage in the
IVC and IAC eras, group D and E eyes often necessitated enucleation or
external beam radiation for vitreous seed recurrence (3,43,44). In 2003,
Kaneko and Suzuki introduced IvitC to the modern armamentarium of
available treatments for retinoblastoma (1,39,45). IvitC is now commonly
used in combination with IAC to achieve tumor control in eyes that otherwise
would have been enucleated, especially in advanced group D and E tumors
(Figures 45-6 and 45-7). IvitC is currently indicated for the presence of
persistent (refractory) or recurrent vitreous seeds from retinoblastoma
following other treatments. Most ocular oncologists use IvitC as secondary
therapy given limited efficacy on the primary tumor. Relative
contraindications for IvitC include presence of tumor or vitreous seeds at the
planned site of needle entry, tumor invasion of the pars plana, and anterior
chamber seeding. Careful clinical examination with or without ultrasound
biomicroscopy can be employed to rule out pars plana involvement prior to
IvitC.
Intracameral Chemotherapy
The use of ICC was recently introduced by Munier et al. to provide sufficient
drug bioavailability for treatment of anterior chamber tumor retinoblastoma
seeding (60). Previously, aqueous seeding remained an indication for
enucleation or anterior chamber plaque radiotherapy due to pharmacokinetic
properties that impeded tumoricidal doses of chemotherapy from reaching the
anterior chamber via conventional routes of administration. In Munier’s
technique, patients were given oral acetazolamide 5 mg/kg preoperatively to
suppress aqueous humor secretion in order to avoid drug dilution (60).
Aqueous humor was then aspirated from the anterior and posterior chambers
through a transcorneal approach with a 34-gauge long needle, facilitated by
contralateral limbus indentation. Without removing the needle, a syringe
exchange was performed to replace a comparable volume of aqueous with
melphalan at a concentration of 15 to 20 μg/0.05 mL (Table 45-2), minus any
volume planned to be injected into the vitreous. The dose was
compartmentalized, distributing 1/3 of the dose to the anterior chamber, and
the remaining 2/3 to the posterior chamber via a transiridal approach.
Following injection, cryotherapy was applied to the entry site at the time of
needle removal. In a case report, the authors reported tumor regression
following seven injections of ICC with melphalan into the anterior chamber
(total dose 15.8 μg) with recurrence 3.5 months later, ultimately controlled by
an additional six injections of ICC with melphalan targeting the posterior
chamber (total dose 35 μg) (60). Intracameral topotecan (7.5 μg/0.015 mL)
injected into the anterior chamber for retinoblastoma seeds has also been
explored after failure of intravitreal melphalan (20 μg/0.05 mL) and yielded
tumor regression after a single injection without toxic effects at 9-month
follow-up (61). ICC has also been investigated in combination with plaque
brachytherapy with complete tumor control in one case after 3-year follow-up
(62).
Complications at 5-year follow-up of intracameral delivery of
chemotherapy include iris heterochromia and progressive cataract formation
in the treated eye with stable corneal endothelial cell density (60). Others
retrospectively analyzed the outcomes of patients treated with ICC combined
with other therapies and achieved globe preservation in 71% of patients with
intact anterior hyaloid membrane and 25% in patients with disrupted anterior
hyaloid membrane secondary to previous vitrectomy with silicone oil or
intracapsular lensectomy (62). The authors attributed outcomes to two
possible mechanisms: drug dilution and/or tumoral cross-contamination
between anterior and posterior segments (62). Salvaged eyes remained event-
free after 17-month follow-up.
FOCAL THERAPIES
Focal therapies are often used for tumor consolidation in conjunction with
IVC or IAC (63). IVC alone achieves suboptimal tumor control in many
cases, with up to 28% of cases requiring additional adjuvant therapy to
achieve tumor control (64). Therefore, targeted local treatments, including
cryotherapy, laser photocoagulation, and TTT, remain important in disease
management. The choice of adjuvant treatment is individualized to the tumor
size and location. Less commonly, focal therapies can be used alone as
primary therapy when patients present with isolated, small, unilateral tumors.
In our center, we have had success with tumor consolidation after IVC with
the single exception of foveal tumors in which we do not treat the tumor
directly. For eyes treated with IAC, we do not need to provide consolidation.
Cryotherapy
Cryotherapy is a reliable treatment that is still regularly used in management
of intraocular retinoblastoma. Indications include treatment of small tumors
and foci of subretinal seeds <3 mm in diameter (63). Cryotherapy to the
peripheral ora serrata is often performed on the same day as systemic
chemotherapy, immediately preceding chemotherapy delivery, to facilitate
improved drug penetration to the tumor(s).
Treatment is performed under indirect ophthalmoscopic visualization,
placing the cryotherapy probe on the conjunctiva for peripheral lesions or
directly on the sclera through a conjunctival cut down incision for more
posteriorly located lesions. A triple freeze–thaw technique is employed,
visualizing the tumor becoming entirely encased in an ice ball and then
waiting for a complete thaw prior to applying the second and third freeze–
thaw cycles. Typically, three sessions are required, administered on a
monthly basis, with the end point being a completely flat tumor scar. In a
study of 67 retinoblastomas treated with cryotherapy, tumor control was
achieved in 53 (79%) tumors, with complete control of all tumors ≤2.5 mm in
largest basal diameter and ≤1.0 mm in thickness confined to the neurosensory
retina without adjacent vitreous seeding (65). Presently, cryotherapy is rarely
used alone and is more frequently used in combination with chemotherapy.
Laser Photocoagulation
Laser photocoagulation is not often used for treatment of retinoblastoma
anymore, as it has been replaced by chemotherapy. For those eyes receiving
IVC, laser is certainly not used, as laser coagulates the vascular supply of the
tumor, preventing adequate chemotherapy delivery. In the past, laser was
performed with xenon arc, argon, or yttrium aluminum garnet lasers.
Indications included small tumors <3 mm in diameter and 2 mm in thickness
with no vitreous seeding and that were located posterior to the equator where
cryotherapy application would be technically difficult (66,67).
Laser was applied with approximately 200 μm spot size and sufficient
power to achieve a white burn. A double row of laser spots encircling the
tumor was applied to occlude tumor vasculature, with median of two laser
sessions required to achieve the desired flat chorioretinal scar. Direct tumor
treatment with laser must be avoided, as rupture of the overlying internal
limiting membrane could potentially cause iatrogenic vitreous seeding
(49,68). In one study of 30 tumors in 20 eyes, complete tumor regression was
seen in 21 eyes (70%) following treatment with laser photocoagulation (66).
Transpupillary Thermotherapy
TTT using diode laser has now largely supplanted laser photocoagulation for
treatment of retinoblastoma. As with cryotherapy, TTT can be used in
combination with chemotherapy or as primary treatment for small tumors <3
mm in diameter (63).
TTT is administered under indirect ophthalmoscopic visualization using
an 810-nm diode laser on continuous mode. Spot size when using indirect
ophthalmoscopy and a 20 diopter lens is 1.2 mm, with multiple spots often
required to cover the entire tumor. Laser power can be increased from 300 to
800 mW and is titrated to induce a gray-white discoloration of the treated
tumor after several seconds, with higher power required for thicker, more
calcified lesions. The entire tumor surface is treated, and time of application
depends on visualized response to the laser, with larger tumors requiring
longer application times to achieve a satisfactory gray-white color change.
Other signs, including microhemorrhages and retinal edema surrounding the
lesion, can signal when treatment is complete (63). Eyes with darker retinal
pigment epithelium pigmentation and darker choroid tend to respond to lower
power and shorter duration treatments. Multiple sessions of TTT, ranging
from 2 to 6, are usually required at 4- to 6-week intervals to achieve the end
point of a flat scar or completely calcified tumor (69). Persistence of
noncalcified fish flesh is a risk factor for tumor recurrence (70,71).
TTT can be effective as a primary therapy when used appropriately. In a
series of 91 small tumors in 22 eyes, 84 tumors (92%) were cured with TTT
alone (72).
Indocyanine green (ICG) can be used to enhance the effects of TTT in
cases of suboptimal response, tumor recurrence, or in a lightly pigmented
fundus. ICG is infused at a dose of 0.3 to 0.5 mg/kg approximately 1 minute
prior to TTT application. The technique for TTT application is otherwise as
above. Prior studies have demonstrated tumor control with this technique in
30 of 30 treated eyes (73), and ICG-enhanced TTT can be combined with
both systemic chemotherapy and IAC (Figure 45-9) (74).
PLAQUE RADIOTHERAPY
Plaque radiotherapy for retinoblastoma was first described in 1929 and was
initially used as globe salvage therapy for recurrent tumor following EBRT
(91–93). Other indications for plaque radiotherapy prior to the introduction of
IAC and IvitC included primary therapy for small- to medium-sized
retinoblastoma and secondary therapy for localized tumor recurrence
following failure of cryotherapy, laser photocoagulation, or TTT (94–97). In
the present era, plaque radiotherapy is typically used as secondary treatment
for small- to medium-sized (≤16 mm in largest basal diameter and >3 to ≤9
mm in thickness), chemoresistant tumors with or without localized vitreous
or subretinal seeding following recurrence after systemic chemotherapy or
IAC (98). Plaque radiotherapy can also be used to manage diffuse anterior
segment retinoblastoma with or without systemic chemotherapy in the
absence of choroidal or retinal tumors (Figure 45-10) (99).
ENUCLEATION
Enucleation was previously the standard of care for advanced unilateral or
bilateral retinoblastoma. However, the introduction of systemic
chemotherapy and IAC have allowed for globe salvage in many cases that
would have been previously treated with primary enucleation. Nevertheless,
enucleation remains an important treatment modality for advanced unilateral
group E disease (Figure 45-12), anterior chamber involvement, neovascular
glaucoma, pars plana tumor seeding, long-standing retinal detachment, poor
tumor visualization (e.g., due to vitreous hemorrhage), optic nerve invasion,
orbital invasion, after failure of other treatment modalities, and if there is no
expectation of useful vision (107–111).
FIGURE 45-12 Group E retinoblastoma managed with
enucleation. A:Retinoblastoma with total retinal
detachment. B:Left prosthesis with good cosmesis 1 year
after enucleation.
At the time of surgery, the correct eye should be confirmed by marking the
site in front of the parent(s) or guardian(s). Under general anesthesia in the
operative suite, the correct eye should again be confirmed using indirect
ophthalmoscopy, review of consent forms, and agreement during surgical
time out by the entire surgical team. In cases of a small palpebral fissure,
particularly in the Asian population, a lateral canthotomy can be performed to
facilitate globe removal. Following conjunctival peritomy, each of the four
rectus muscles is isolated and secured with double-armed 5-0 Vicryl sutures
before disinsertion from the globe, and the medial rectus stump is left long
for globe manipulation. The two oblique muscles are then disinserted. Using
long, straight enucleation scissors placed in the orbit nasally and pointing to
the orbital apex, the optic nerve is cut, attempting to obtain a long segment.
The globe is removed and an implant is placed. The conjunctival tissue is
closed. Fresh tissue is harvested from the globe for genetic assessment on a
separate surgical field, and the surgeon re-gloves prior to returning to the
patient to avoid contamination of the orbit with malignant cells.
Complications following enucleation include chemosis, conjunctival cyst,
pyogenic granuloma, blepharoptosis, lagophthalmos, superior sulcus defect,
enophthalmos, symblepharon, implant exposure, and infection (112). Implant
exposure requires return to the operating room for wound repair (112).
Infection can be managed with topical and/or systemic antibiotics but can
require implant removal in severe cases. Giant papillary conjunctivitis can
occur secondary to prosthesis wear and can be managed with a combination
of antibiotic–steroid ointment and refitting of the prosthesis in severe or
recurrent cases. Following enucleation, the globe should be evaluated
histopathologically to confirm the diagnosis of retinoblastoma and to assess
for invasive (high-risk) features.
High-Risk Retinoblastoma
On histopathologic evaluation, the enucleated globe should be evaluated for
high-risk features, including postlaminar optic nerve invasion, massive
choroidal invasion (>3 mm diameter), and any degree of optic nerve and
choroidal invasion (113,114). In an analysis of 519 enucleated eyes with
retinoblastoma, high-risk features were found in 17% of group D and 24% of
group E eyes (115). There were no enucleated eyes in that study classified as
groups A, B, or C.
Patients with high-risk features require adjuvant systemic chemotherapy
to prevent systemic metastasis. A VEC regimen, with doses comparable to
those used in IVC, can be used in these cases. Kaliki et al., in a study of 55
patients with high-risk retinoblastoma treated with six cycles of adjuvant
VEC, found no case of metastatic disease over mean follow-up of 66 months
(116).
ORBITAL DISEASE
Orbital involvement of retinoblastoma can be due to delayed detection of
intraocular retinoblastoma or secondarily due to recurrence following
enucleation (117). Orbital disease must be managed with combination
therapy, including surgical excision, systemic chemotherapy, and
radiotherapy to effectively eradicate orbital disease and prevent recurrence or
metastasis (117). The initial therapy consists of high-dose systemic
chemotherapy with a VEC regimen for three to six cycles with serial imaging
to monitor for complete resolution of the orbital component. Following
complete resolution of the orbital component or after completion of three to
six cycles of VEC, enucleation surgery is performed and followed by
radiotherapy in fractionated doses, totaling 50 Gy. The systemic
chemotherapy is continued to complete a total of 12 cycles.
Orbital retinoblastoma imparts poor prognosis, with a 10 to 27 times
higher risk of systemic metastasis and mortality rates ranging from 25% to
100% (118–122). However, combination therapy has improved treatment
success. In a series of 16 patients presenting with orbital retinoblastoma and
no intracranial extension or systemic metastasis, combination therapy
achieved complete tumor resolution without recurrence or metastatic disease
after 36-month follow-up in 14 patients (87.5%) (123,124). Efforts toward
earlier detection, especially in less developed countries, are critical to
improving vision and life prognosis for retinoblastoma patients.
METASTATIC DISEASE
Metastatic disease is rare in developed countries, affecting <5% of patients
(125). However, metastases remain a significant cause of mortality in
retinoblastoma patients in the developing world likely due to delayed disease
detection (126,127). Limited evidence is available for the treatment of
metastatic retinoblastoma. Given that most tumors are sensitive to
chemotherapy, successful treatment involves intensive high-dose
chemotherapy with autologous stem cell rescue. Radiotherapy can be added
for residual bulky disease.
Reports have been limited to small numbers of patients, but eradication of
cancer can be achieved in 60% to 70% with better prognosis in patients
without central nervous system involvement (128–133). Unfortunately, such
intensive treatment regimens are not often available in developing countries
where metastatic disease is most prevalent. Education of patients and
physicians with more timely disease detection remain important goals in the
developing world.
GENETIC TESTING
We recommend genetic testing in all cases of retinoblastoma both for the
patient and subsequently for the parents and siblings if germline disease is
confirmed. Patients with germline mutation should be managed with IVC,
often in combination with other treatment modalities, to prevent
pineoblastoma, and such patients require careful monitoring with MRI of the
brain and orbits twice per year until the child is 5 years old (4–6). Patients
and parents should be counseled about the risk for retinoblastoma in future
offspring, and in vitro fertilization with preimplantation diagnosis can be
discussed as part of family planning. In the case of pregnancy with a possible
germline retinoblastoma mutation, amniocentesis can be used to aid in
diagnosis with in utero ultrasonographic monitoring throughout the
pregnancy (134).
CONCLUSION
Management of retinoblastoma is complex. Each case is unique, and
treatment regimens must be carefully customized for varying disease
presentations and family goals of care. Close cooperation between the
treating ocular oncologist and pediatric oncologist is critical to patient
success, with both parties prioritizing patient safety and preservation of life.
ACKNOWLEDGMENTS
Support provided in part by an unrestricted grant from Research to Prevent
Blindness, Inc., New York, New York (LAD); the Heed Ophthalmic
Foundation, San Francisco, CA (LAD); and the Eye Tumor Research
Foundation, Philadelphia, PA (CLS). The funders had no role in the design
and conduct of the study; in the collection, analysis and interpretation of the
data; and in the preparation, review, or approval of the manuscript. Carol L.
Shields, MD has had full access to all the data in the study and takes
responsibility for the integrity of the data and the accuracy of the data
analysis.
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46
Tumors in Infants and Children
Victor M. Villegas, and Timothy G. Murray
CIRCUMSCRIBED CHOROIDAL
HEMANGIOMA
Prevalence
Circumscribed choroidal hemangioma is the most common benign vascular
tumor of the choroid. These tumors may be classified into two types, diffuse
and circumscribed, based on the degree of choroidal involvement (1–4). The
diffuse process occurs in Sturge-Weber syndrome (SWS) (discussed later in
this chapter), whereas the circumscribed form is usually not associated with
cutaneous lesions or other systemic findings (2). In 1976, Witschel and Font
(5) reported the clinicopathologic characteristics of 71 choroidal
hemangiomas. In their study, 37% represented the diffuse type and 63% were
circumscribed.
The exact incidence of circumscribed choroidal hemangioma is unknown.
However, choroidal hemangioma is diagnosed in approximately 1 case per 40
cases of posterior uveal melanoma (3). Because these lesions are often
asymptomatic and may remain undiagnosed, their prevalence may be much
higher than expected.
Worldwide Impact
Because these tumors are mostly unilateral and may not affect visual acuity,
they are likely to have a limited role on worldwide childhood blindness.
Diagnostic Studies
The diagnosis of choroidal hemangioma is usually made based on
ophthalmoscopic findings; however, several ancillary studies can be used to
confirm the diagnosis. Ultrasonography classically shows high internal
reflectivity on standardized A-scan and a homogenous hyperechoic mass with
vascularity on B-scan images. Fluorescein angiography (FA) demonstrates
early filling within large vascular channels constituting the tumor. Late
frames show diffuse hyperfluorescence due to leakage of dye from the tumor
surface (12). Indocyanine green angiography (ICG) shows accumulation of
dye early with subsequent washout later in the study (13). ICG pattern may
be particularly helpful in challenging cases, such as choroidal hemangiomas
with significant retinal pigment epithelium (RPE) changes or preretinal
fibrosis. Optical coherence tomography (OCT) shows a smooth, gently
sloping choroidal mass without compression of the choriocapillaris (14).
Subretinal fluid, intraretinal fluid, or retinoschisis may be present on OCT.
Diffuse vascular anomalies can be seen in optical coherence tomography
angiography (OCTA) (15).
Differential Diagnosis
Despite the characteristic clinical features of choroidal hemangioma, this
tumor can be challenging to distinguish from other choroidal tumors
including amelanotic melanoma, choroidal osteoma, choroidal metastasis, or
retinoblastoma. In addition, these lesions can mimic posterior scleritis and
other inflammatory conditions.
Management
Treatment of circumscribed choroidal hemangiomas is generally limited to
those that are vision threatening, and treatment planning depends upon tumor
size and location (13). Hemangiomas that do not affect vision and are not
associated with subretinal fluid are generally observed. Most lesions are
characteristically nonprogressive in nature.
Laser photocoagulation can be an important treatment and is indicated
when the tumor causes loss of vision secondary to serous retinal detachment
(9,16). Historically, focal lesions were treated with laser to cause resorption
of subretinal fluid and readhesion of the neurosensory retina and RPE.
Subretinal fluid has been reported to resolve in 62% to 100% of cases
following laser therapy (7).
Radiation therapy has also been used frequently in the treatment of
choroidal hemangioma, including external beam radiation, plaque
radiotherapy, or proton beam irradiation. Numerous reports have indicated
that these treatments offer excellent anatomical outcomes (17–19). Previous
studies (7) have recommended early low-dose plaque radiotherapy or external
beam radiation in cases with recurrent subretinal fluid after laser therapy and
subfoveal lesions. Metamorphopsia may improve significantly following
brachytherapy.
Photodynamic therapy (PDT) has become a commonly used therapy for
subfoveal circumscribed choroidal hemangiomas. Multiple studies have
reported on the efficacy of PDT for subretinal fluid in subfoveal lesions
(16,20–22). Most patients show positive anatomical and visual outcomes
after only one cycle of PDT (16,21). However, choroidal ischemia may limit
visual acuity following PDT therapy.
Vision Rehabilitation
Despite the benign nature of these tumors, approximately 50% of diagnosed
patients have long-term visual acuity of 20/200 or worse (7). Final visual
acuity is dependent upon numerous factors including initial visual acuity,
failure of previous laser treatment, multiple quadrants of subretinal fluid,
chronic submacular fluid, chronic cystoid macular edema, or chronic retinal
pigment epithelial changes (7).
Children with circumscribed choroidal hemangiomas may also develop
amblyopia in the affected eye. Amblyopia may be secondary to hyperopic
shift, astigmatism, or subretinal fluid. Because early intervention can be
effective in achieving resolution of subretinal fluid and restoration of visual
function, prompt referral to an ophthalmologist with experience treating
circumscribed choroidal hemangioma is especially important in children
suspected of having this lesion.
Ethical Considerations
Not applicable.
Future Treatments
Intravitreal bevacizumab has been used in the primary treatment of
circumscribed choroidal hemangioma with positive outcomes (23). Most
recently, Arevalo and associates have reported faster resolution of subretinal
fluid when PDT with verteporfin is used in combination with intravitreal
bevacizumab (24). Other authors have had similar results with combination
PDT and intravitreal bevacizumab. Further studies are needed to evaluate the
role of intravitreal bevacizumab in the treatment of circumscribed choroidal
hemangioma.
MEDULLOEPITHELIOMA
Prevalence
Medulloepithelioma is a rare embryonal tumor that arises from the medullary
epithelium on the inner layer of the developing optic cup (25). The exact
prevalence is still unclear. Verhoeff (26) first described this tumor
histopathologically as a teratoneuroma in 1904. Medulloepithelioma is
classified into teratoid and nonteratoid forms. The nonteratoid form,
otherwise known as a dictyoma, represents only medullary epithelial cells. In
contrast, teratoid forms of this tumor contain heterotopic tissues including
cartilage, skeletal muscle, and brain-like tissue (27). Either form can be
benign or malignant (25,28,29).
Intraocular medulloepithelioma often has a malignant histologic
appearance. Extraocular extension with distant metastasis to the lungs,
mediastinum, and lymph nodes has been documented (28,30). Broughton and
Zimmerman (28) reported 56 cases in which 66% were malignant and 30%
were teratoid. Other authors have reported up to 90% malignancy (31).
Despite a malignant histologic appearance, distant metastases are rarely seen
in the absence of local extraocular extension (28,29,31).
Worldwide Impact
The worldwide epidemiology of this malignancy is unclear due to the rarity
of this malignancy. As with other intraocular tumors, delay in diagnosis,
particularly in less developed countries, can result in metastasis and death.
Pathophysiology
Differentiation of the medullary epithelium that lines the optic cup normally
produces the retinal photoreceptors, glial and neuronal tissues, nonpigmented
ciliary epithelium, pigmented epithelium of the iris, muscles of the iris, and
components of the vitreous.
Histopathologic studies demonstrate that medulloepithelioma contains
elements that resemble the medullary epithelium, optic cup and/or vessel,
pigmented and nonpigmented ciliary epithelium, vitreous, or neuroglia (28).
Medulloepitheliomas often contain heterotopic tissues such as cartilage,
rhabdomyoblasts, skeletal muscle, and brain-like tissues (27). This feature
results from the capacity of the primitive medullary epithelium to
differentiate into a variety of neural and mesenchymal tissue types.
Clinical Symptoms and Signs
Medulloepithelioma characteristically presents before 10 years of age as a
white fimbriated ciliary body mass; however, it may also arise in adults (29).
The most common location at presentation is the ciliary body. However,
primary optic nerve, retinal, and orbital involvement has been reported
(32–35).
Medulloepithelioma frequently presents with decreased vision and pain.
Other common signs include leukocoria and a nonpigmented iris or ciliary
body (Figure 46-2) tumoral mass (28). One of the earliest signs may be a
lenticular notch in the quadrant of the tumor (36). This coloboma occurs
because the embryonal tumor prevents normal zonular development in the
associated lens quadrant.
Diagnostic Studies
The diagnosis of medulloepithelioma is primarily a clinical one, and the role
of additional studies to confirm the diagnosis is not well established. A-scan
ultrasonography has been reported to show irregular high internal reflectivity
with areas of moderate reflectivity, and B-scan can demonstrate characteristic
cysts within the tumor (38). Dense hyperechoic areas in medulloepithelioma
may be similar in appearance to calcifications in retinoblastoma (39).
Intrinsic tumor vascularity has been demonstrated with FA with associated
leakage (37,39).
Magnetic resonance imaging (MRI) of medulloepithelioma is
hyperintense on T1-weighted images and hypointense on T2-weighted
images similarly to malignant melanoma (40). Ultrasound biomicroscopy has
recently emerged as a helpful diagnostic tool for evaluating tumors involving
the anterior uveal tract; this approach may be particularly useful in
demonstrating the multicystic appearance of medulloepithelioma (39).
Anterior segment OCT may also help evaluate growth over time.
Differential Diagnosis
Given the wide variety of presentations and possible locations for
medulloepithelioma, the differential diagnosis is broad. Diagnoses that
should be considered include congenital and inflammatory conditions, such
as persistent hyperplastic primary vitreous (persistent fetal vasculature
syndrome), pars planitis, or vascular malformations, and numerous tumors,
including retinoblastoma, melanoma, melanocytoma, iridociliary cyst,
rhabdomyosarcoma, neuroblastoma, or teratoma.
Management
Definitive treatment of medulloepithelioma continues to be enucleation.
Medulloepithelioma frequently recurs following local resection (29,37).
Some cases may be observed until definitive change is documented. Cataract
surgery should be avoided if medulloepithelioma is suspected. Patients with
extrascleral extension may require exenteration.
The roles of cryotherapy, radiation, and chemotherapy are not well
established for the treatment of medulloepithelioma. In cases involving risk
for recurrence of the tumor, these methods may be used as adjunctive
therapy.
Vision Rehabilitation
The visual outcome in pediatric patients diagnosed with medulloepithelioma
is poor mostly due to amblyopia, cataract, and glaucoma. Despite the
malignant nature of medulloepithelioma, patients with complete tumor
resection have excellent survival rates. In the largest series of 56 patients with
medulloepithelioma, four known tumor-associated deaths were reported. The
most important prognostic feature was extraocular extension (29).
As with other intraocular tumors, early diagnosis is important in
determining the final clinical outcome. Unfortunately, diagnosis is often
delayed in patients with medulloepithelioma; most of these patients
experience a delay in surgical treatment for more than 1 year after the initial
onset of symptoms (29).
Future Treatments
Recently, vincristine (1.5 mg/m2), carboplatin (560 mg/m2), and etoposide
(150 mg/m2) have been used with tumor burden control in an adult patient
(41). Cyclophosphamide has also been used (42) in combination with
vincristine, carboplatin, and etoposide with positive outcomes.
Radiation has also been used in primary treatment of ocular
medulloepithelioma (29,42,43). Most reports have prescribed a dose between
40 and 50 Gy with encouraging outcomes. Brachytherapy is preferred over
external beam radiation to minimize the morbidity associated with therapy.
CHOROIDAL OSTEOMA
Prevalence
Choroidal osteoma is a benign ossifying choroidal tumor that was first
described by Gass et al. (44) in 1978. Choroidal osteoma may present at any
age, is more common in females, and typically is located adjacent to the optic
nerve or involving the macula.
The prevalence of choroidal osteoma is unknown, and it has been
suggested that it may be more common than initially suspected (45).
However, since many lesions are asymptomatic, most choroidal osteomas
may be undiagnosed.
Worldwide Impact
Worldwide impact is unknown as many of these cases are believed to be
asymptomatic. Cases with asymmetric visual acuity may not come to medical
attention in many developing parts of the world.
Pathophysiology
Choroidal osteoma is composed of bony trabeculae with osteoblasts,
osteocytes, and osteoclasts (44,46). Large, endothelial-lined, cavernous
spaces are covered with small capillary blood vessels. The choriocapillaris
can be partially or completely dysplastic in the involved areas. Overlying
RPE can undergo degeneration.
The pathogenesis of choroidal osteoma is not known. Previous reports
have suggested that focal choroidal inflammation may lead to calcification of
the choroid (47–49). It may also represent an osseous choristoma: normal
bone tissue in an ectopic location (48).
Intraocular calcification can be associated with trauma, long-standing
retinal detachment, inflammation, abnormalities in calcium and phosphorus
levels, and phthisis bulbi. Serum calcium, phosphorus, and alkaline
phosphatase levels are, however, found to be within the normal range in
patients with choroidal osteoma.
Females are more frequently affected than males, but endocrine
abnormalities have not been documented in these patients. A hereditary
component in the pathogenesis has been suggested by some familial cases
(50). Noble (50) hypothesized that a congenital, possibly inherited, defect in
the choroid may remain undetectable until osseous calcification is initiated
through the influence of additional factors.
Diagnostic Studies
Choroidal osteoma can be highly suspected clinically. However, confirmation
of calcium with other imaging modalities is paramount for diagnosis.
Ultrasonography is particularly useful in differentiating choroidal
osteoma from other lesions. A-scan ultrasonography demonstrates a high-
intensity echo spike from the inner surface of the tumor, with decreased
amplitudes of orbital soft tissue echoes posterior to the tumor. B-scan shows
a homogenous hyperechoic choroidal mass with acoustic shadowing posterior
to the tumor (46,52).
A retrospective case series that evaluated fundus autofluorescence in
patients with choroidal osteoma found hyperautofluorescence in areas of
decalcification and granular hypoautofluorescence in areas of RPE mottling
(56). FA demonstrates early diffuse, irregular hyperfluorescent vascular tufts
with associated late staining. In the late FA frames, the spider-like vascular
tufts may stand out in negative relief as hypofluorescent lines against a bright
background (46,52). Choroidal neovascular membranes exhibit an early lacy
pattern of hyperfluorescence with early leakage. Recently, OCT and OCTA
have been used to detect CNV in a patient with choroidal osteoma (57).
On computed tomography (CT) scan, choroidal osteoma demonstrates the
same density as bone. On MRI, these tumors are hyperintense compared to
the vitreous on T1-weighted imaging and hypointense on T2-weighted
imaging (58).
Differential Diagnosis
The differential diagnosis of choroidal osteoma includes other intraocular
tumors, such as sclerochoroidal calcification, amelanotic choroidal nevi,
choroidal melanoma, choroidal metastasis, and circumscribed choroidal
hemangioma. Choroidal osteoma may also appear similar to osseous
metaplasia that can occur in other choroidal tumors. Choroidal osteoma
should be carefully distinguished from posterior scleritis or subretinal
hemorrhage. Idiopathic sclerochoroidal calcifications should be included in
the differential diagnosis for choroidal osteoma; however, the former are
typically multiple, often bilateral, and classically found along the
superotemporal vascular arcades (51).
Linear nevus sebaceous syndrome (59) presents with osseous choroidal
choristoma, which should be carefully distinguished from choroidal
hemangioma. This syndrome, however, also presents with characteristic
systemic findings: midline facial linear nevus of Jadassohn, seizures,
cognitive developmental deficits, and multiple eye findings including
lipodermoids; colobomas of the lids, iris, and choroid; and choroidal
calcification (59).
Management
Most cases of choroidal osteoma are asymptomatic and may be observed.
Periodic dilated fundus examinations and self-monitoring with the use of an
Amsler grid can facilitate timely diagnosis in patients who develop choroidal
neovascular membranes or subretinal fluid.
Argon laser photoablation has been associated with regression of
choroidal osteoma (60) and been efficacious for treatment of a subfoveal
neovascularization threatening the fovea (45,61). Laser treatment may cause
retinal anastomosis with both arteriolar and venular vessels within the tumor
in select cases (45). Successful treatment of focal RPE leakage with laser has
been reported (45). The use of PDT for subretinal neovascular membranes in
choroidal osteoma has also been described (62).
Because the etiology of choroidal osteoma is unknown at this time, no
preventive measures have been suggested.
Vision Rehabilitation
Visual loss to 20/200 or worse has been reported to occur in approximately
60% of patients with choroidal osteoma after 20 years of follow-up (52). The
most common cause of severe vision loss is CNV. The long-term CNV
incidence is over 50%. Previous studies have reported a low success rate
(25%) after laser ablation of neovascular membranes (52). Hemorrhage
associated with choroidal osteoma typically resolves but may cause a
subretinal, vision-limiting, disciform scar. Prognosis is poor once subfoveal
hemorrhage is present.
Severe visual loss can occur in bilateral cases. Low-vision rehabilitation
with appropriate aids such as magnifiers and specialty lenses may be
indicated.
Ethical Considerations
Not applicable.
Future Treatments
Intravitreal bevacizumab monotherapy has been used in the treatment of
secondary subretinal neovascular membranes associated with choroidal
osteoma with success (57). Other vascular endothelial growth factor (VEGF)
antagonists have also been used successfully (63,64). PDT combined with
intravitreal bevacizumab has also been reported (65). Intravitreal
bevacizumab has been used with positive results in patients with exudative
retinal detachment without neovascular membranes in patients with choroidal
osteoma (66). Additional studies that evaluate the role of VEGF antagonists
for the treatment of secondary neovascular membranes and/or exudative
detachments are needed to better understand the optimal treatment regimen.
CONGENITAL HYPERTROPHY OF THE
RETINAL PIGMENT EPITHELIUM
Prevalence
Congenital hypertrophy of the retinal pigment epithelium (CHRPE) was first
described by Buettner (67) in 1975. CHRPE are hyperpigmented, isolated
lesions that are flat, circumscribed, and well demarcated and represent
congenital hypertrophy of the pigment epithelium with no primary
involvement of the overlying retina (Figure 46-4). Hypopigmented lacunae
are typically present. Because most CHRPE lesions are asymptomatic and
likely undiagnosed, the exact prevalence of this disease is unknown.
Worldwide Impact
None, as these lesions rarely affect vision and malignant transformation is
rare.
Pathophysiology
Idiopathic solitary CHRPE histopathologically exhibits a monolayer of
hypertrophied RPE cells with large pigment granules and photoreceptor
degeneration overlying the RPE (67).
In contrast, the histopathology described in Gardner syndrome
demonstrates a more pervasive melanogenesis of the RPE (68). Several
different configurations are described: a monolayer of hypertrophied cells, a
mound of pigmented RPE cells between the RPE basement membrane and
Bruch membrane, or a multilayered mound of hyperplastic RPE in a nodular
or mushroom-shaped configuration (82,84). All of these conformations show
cellular hyperplasia of the RPE. Although the fundus lesions in Gardner
syndrome are referred to as CHRPE, this distinctive feature of cellular
hyperplasia corresponds to a hamartomatous malformation of the RPE, not
hypertrophy alone.
Electron microscopy has shown absence of autofluorescent lipofuscin
granules in CHRPE lesions, suggesting that RPE cells in CHRPE lack the
catabolic functions of normal RPE cells (85).
Diagnostic Studies
CHRPE epithelium lesions are very distinctive and are generally diagnosed
clinically. Studies, however, can support the diagnosis. FA demonstrates
blockage of choroidal fluorescence in the hyperpigmented areas of the lesions
in all phases of the study (69). Hypopigmented areas can exhibit
hyperfluorescence, both early and late (window defect). CHRPE lesions do
not leak on FA, as the overlying retinal vasculature and choriocapillaris are
normal (69).
OCT of CHRPE is characterized by retinal thinning, photoreceptor loss,
disorganized retinal anatomy, increased RPE thickness, and decreased
reflectivity of the choroid (69,92,93). Choroidal cavitation has been reported
on OCT (94). Fundus autofluorescence is characterized by
hypoautofluorescence, although the lacunae may show mild
hyperautofluorescence. Fluorescein angiography typically demonstrates
blocking, although the lacunae may show window defects. A corresponding
visual field defect is typically associated (69). Intraretinal extension of the
RPE is a feature not seen in CHPRE lesions that may be unique to some of
the pigmented lesions of FAP and has been detected on OCT (70).
Visual field testing may show scotomas that correspond to the location of
these lesions, presumably representing progressive degeneration of the
overlying photoreceptors (67). Because CHRPE lesions are flat, ultrasound
studies may be unremarkable.
Differential Diagnosis
The differential diagnosis of solitary CHRPE lesion should include choroidal
nevus, choroidal melanoma, RPE adenoma, RPE adenocarcinoma, and
combined hamartoma of the RPE. Multiple bilateral CHRPE lesions indicate
greater suspicion of an underlying polyposis syndrome. Chorioretinal scars
from toxoplasmosis, secondary hyperplasia of the RPE, sickle cell disease
(sunburst lesions), sector retinitis pigmentosa, and pigmented retinopathies
should also be considered in the differential diagnosis of CHRPE lesions.
Management
Treatment is not indicated for either solitary or multifocal CHRPE lesions.
These lesions should be observed routinely, and if the patient’s medical
history is suggestive, FAP or Gardner syndrome should be investigated. As
rare malignant transformation has been described, an annual dilated
examination is recommended.
Ethical Considerations
Not applicable.
Future Treatments
Most cases of CHRPE do not require therapy. However, atypical cases may
develop exudation and may respond to VEGF antagonist therapy (95,96).
Because of the rarity of the exudative complications associated with CHRPE,
prospective studies may be limited, and treatment should be performed on an
individualized basis after a complete explanation of risks and potential
benefits.
Worldwide Impact
Unknown, but likely very small as most cases are unilateral.
Pathophysiology
A hamartoma is a benign proliferation of cells that normally are found in the
affected area. Combined hamartoma of the retina and RPE appears
histopathologically as dysplastic retina and overlying retinal vascular
tortuosity (14). Hyperplastic RPE cells migrate into the retina (97). Gliosis
and epiretinal membrane formation commonly are present at the retinal
surface leading to retinal distortion and folding (98). The vitreoretinal
interface is also altered, and tractional changes may be present (99).
These ocular hamartomatous lesions are characterized by benign growth
of glial, vascular, or pigmented tissue from the RPE (100). Some lesions
contain prominent vascular tissue, while others are composed predominantly
of glial tissue, which can lead to formation of preretinal or epiretinal
membranes (97–102).
The pathogenesis of combined hamartoma of the RPE and retina is
uncertain. Although the majority of patients with combined hamartoma do
not present with other systemic diseases, these lesions have been reported in
association with neurofibromatosis (NF), tuberous sclerosis (TS),
incontinentia pigmenti, bilateral colobomas of the optic disc, optic nerve head
drusen, juvenile retinoschisis, juvenile nasopharyngeal angiofibroma, Gorlin
syndrome, and sickle cell anemia (103–116). These associations may indicate
a developmental etiology, as suggested by Gass (97).
Diagnostic Studies
Historically, FA has been a useful tool in evaluating combined hamartoma of
the retina and the RPE. Early FA phases demonstrate large tortuous vessels
within the tumor, abnormal retinal capillaries, and late leakage from
anomalous tumor vessels.
Ultrasound studies may show a hyperechoic mass with or without
calcification (120). Ultrasound may also aid in detecting tractional
components.
OCT shows an elevated hyperreflective retinal thickening, retinal
disorganization, hyporeflective shadowing of the underlying tissues, retinal
striae, retinal edema, epiretinal membrane formation, and tractional
components (121,122). OCTA may also aid the diagnosis by highlighting the
anomalous vascular complexes (123).
Differential Diagnosis
Combined hamartoma can be a challenging diagnosis due to variable
pigmentation and mass effect (124). Epiretinal membrane formation typically
leads to dysplastic vascular alterations that can be seen in OCT and OCTA
(122,123). Pigmentation and elevation may be similar to choroidal
melanoma; however, dysplastic retinal changes are typically not associated
with melanoma. Early retinoblastoma may also show retinal thickening with
anomalous vasculature; however, pigmentation is not a prominent feature in
early retinoblastoma. Calcification may be present in some combined
hamartomas of the retina and RPE (120).
Peripapillary combined hamartoma has a presentation similar to morning
glory disc anomaly, although the latter condition does not exhibit the
characteristic elevation of combined hamartoma. Advanced cases may show
prominent vascular anomalies that may be similar to those in cicatricial
retinopathy of prematurity.
Management
No well-established treatment plan has been developed for combined
hamartoma of the retina and RPE. Therapy for this lesion has included
treatment for amblyopia, which has demonstrated utility in selected patients
(98). Vitreous surgery with epiretinal membrane removal is another treatment
with reported success (125–129). Other patients with combined hamartoma
have been treated with pars plana vitrectomy and membrane peeling without
any subsequent improvement in their visual acuity (128). Visual prognosis is
guarded.
Vision Rehabilitation
Patients with combined hamartoma of the retina and RPE demonstrate a wide
spectrum of visual acuity. In one study, approximately one-quarter of the
patients lost at least two lines of visual acuity; approximately one-third of
patients exhibited vision of 20/200 or worse (102). A patient affected with the
characteristically unilateral form of this disease typically experiences normal
vision in the unaffected eye. No report has been made of malignant
transformation of combined hamartoma of the retina and RPE lesions. The
prognosis for life in these patients is normal.
In cases with extreme unilateral visual loss, amblyopia management may
be considered.
Ethical Considerations
Not applicable.
Future Treatments
Currently, children in the amblyopic age range may benefit from early
treatment prior to amblyopia therapy especially with newer small-gauge
vitreoretinal platforms. Vitreomacular and vitreopapillary traction should be
addressed surgically in order to maximize the potential visual outcomes
(126,129). Postsurgical treatment of macular edema with intravitreal
triamcinolone acetonide has also been performed (130). Recently, macular
edema has been treated successfully with VEGF antagonists in atypical cases
(96,131). Recalcitrant vascular activity may also be treated with laser
photocoagulation or PDT (132).
Prospective studies on combined hamartoma of the retina and RPE are
limited due to the rarity of the disease and treatment is typically
individualized depending on the extent of the disease and potential visual
acuity prognosis.
PHAKOMATOSES
The phakomatoses are a group of syndromes characterized by multiple
associated lesions in multiple organ systems. Characteristically, patients with
phakomatoses demonstrate hamartomatous malformations, which are
abnormal proliferations of tissues that are normally found in the affected
organ system. All these syndromes demonstrate ocular manifestations upon
fundus examination. Phakomatoses discussed individually in this chapter
include von Hippel-Lindau (VHL) syndrome, TS, NF, Wyburn-Mason
syndrome (WMS), and SWS.
Prevalence
VHL syndrome is an autosomal dominant condition characterized by
hemangioblastomas of the retina, cerebellum, brain stem, and spine,
accompanied by adenomas, angiomas, and cysts of the kidney, liver, and
pancreas. Renal cell carcinoma occurs in approximately 25% of VHL
patients, and pheochromocytoma occurs in approximately 10% (133).
Incidence of VHL is estimated at 1 in 36,000 births (133).
Pathophysiology
Histopathologically, the retinal lesions of VHL are hemangioblastomas
identical to the lesions also found in the central nervous system (CNS) (134).
These vascular masses are composed of retinal capillaries exhibiting normal
endothelium, basement membrane, and pericytes. Capillaries within the
lesion may demonstrate abnormal fenestrations (134,135). Plump vacuolated
interstitial cells with foamy cytoplasm, which are likely of glial origin,
separate the capillary channels (134–136). Growth of these retinal lesions can
extend inward toward the vitreous (endophytic type) or outward toward the
choroid (exophytic type) (137–140).
Clinical Features
Retinal hemangioblastoma is observed in approximately two-thirds of
patients with VHL disease (153,154). Of reported VHL patients with retinal
tumors, 25% will demonstrate associated cerebellar hemangioblastoma.
Many other organs are affected by cysts, including the pancreas, kidneys,
liver, adrenal glands, and epididymis. VHL is also characterized by renal cell
carcinoma (22%), and pheochromocytoma is a less common but serious
association (154). Although patients with VHL demonstrate brain and CNS
tumor involvement, they exhibit normal cognitive capacity.
A patient with VHL disease may present with decreased visual acuity or
may be asymptomatic with retinal tumors discovered as an incidental finding
upon routine ophthalmologic examination. Alternatively, a patient may
become symptomatic when retinal lesions cause a visual field defect
associated with subretinal fluid or retinal detachment; these lesions may also
cause metamorphopsia, macular edema, traction, full-thickness macular hole,
or epiretinal membrane formation (155). Retinal lesions in VHL may become
visible upon ophthalmologic examination during childhood. Because patients
are frequently asymptomatic, they may be diagnosed at any time throughout
adulthood.
In VHL disease, retinal capillary hemangioblastoma appears as globular
red-orange masses in the fundus. A characteristic feature of these retinal
tumors is a pair of dilated, tortuous feeding and draining vessels traveling
between the lesion and the optic nerve (Figure 46-7). Hemangioblastomas
may form anywhere in the fundus: rarely at the posterior pole (1%), more
commonly at the optic disc (8%), and most frequently in the temporal
peripheral retina (156).
FIGURE 46-7 Retinal capillary hemangioblastoma in
VHL syndrome has a striking appearance. This example
demonstrates a pair of tortuous feeder vessels.
Patients with VHL disease demonstrate retinal masses that are solitary or
multiple, with the mean number of these lesions in genetic carriers of the
disease reported as 1.85 (range of 0 to 15) (153). Lesions may present either
unilaterally or bilaterally. Solitary unilateral lesions are less likely to be
associated with VHL disease, whereas multiple bilateral lesions are
invariably indicative of VHL syndrome. The size of these lesions varies,
ranging from small vascular tufts to large masses. Retinal tumors in VHL
demonstrate limited ability to proliferate; however, leakage of thin vessels
with subsequent fluid buildup may result in the appearance of tumor growth.
Lipid exudate in the macula is a common cause of decreased visual acuity in
these patients.
Complications of retinal hemangioblastoma in VHL include exudation of
fluid into the subretinal space and subsequent retinal detachment. Preretinal
membranes may form causing traction on the retina. Patients who develop
retinal detachments are at significant risk for secondary glaucoma, cataract,
or vitreous hemorrhage. Disc and retinal neovascularization may also occur
(156).
Differential Diagnosis
The differential diagnosis of retinal capillary hemangioblastoma associated
with VHL disease varies with the location of the lesions. Peripheral lesions
with dilated feeding and draining vessels are highly characteristic and are
frequently diagnosed based on ophthalmoscopic appearance. In the presence
of massive subretinal exudation with retinal detachment, however, the lesion
may resemble other entities. In children, the differential diagnosis should
primarily include Coats disease, familial exudative vitreoretinopathy, and
retinoblastoma. Additional lesions considered in the differential may include
racemose hemangioma, retinal cavernous hemangioma, sickle cell
retinopathy, retinal astrocytoma, and nematode endophthalmitis (153).
The differential diagnosis for juxtapapillary capillary hemangioblastoma,
particularly the exophytic form, involves entities distinct from those
considered in the diagnosis of peripheral lesions. Exophytic juxtapapillary
hemangioblastoma may obscure the disc margin, making this lesion
challenging to distinguish from other causes of disc edema. The swollen disc
appearance in juxtapapillary capillary hemangioblastoma is more frequently
unilateral, although bilateral cases have been reported. Papilledema
subsequent to increased intracranial pressure may be a diagnostic
consideration in patients presenting with intracranial VHL lesions. CNV and
choroidal hemangioblastoma may also enter the differential diagnosis in VHL
(156,157).
Diagnostic Studies
The diagnosis of peripheral capillary hemangioblastoma is frequently made
prior to performing any ancillary studies because of the characteristic
appearance of the lesion on ophthalmoscopy. Standard fundus photography is
helpful to document lesion growth, stability, or response to treatment. FA
shows rapid filling of the tumor by the feeding artery in early phases.
Midphase photographs show intense staining of the tumor, and late frames
show leakage of dye from the tumor into the vitreous (156). FA may be
particularly useful in distinguishing juxtapapillary capillary
hemangioblastoma from other causes of disc edema.
OCT and OCTA may also aid in the diagnosis by allowing visualization
of the retinal tumoral mass, highlighting the feeder and draining vessels, and
showing retinal edema in the juxtatumoral retina (158,159). OCT helps to
identify exophytic and endophytic growth. However, to localize small
tumors, FA may be preferable since some may be undetected by
ophthalmoscopy.
A detailed family history should be taken in all patients diagnosed with
retinal hemangioblastoma, with suspicion of VHL disease. In addition,
patients presenting with retinal hemangioblastoma should be screened for
other manifestations of VHL, with an MRI of the head and spine, as well as a
CT scan of the abdomen.
Management
Management of retinal capillary hemangioblastoma is oriented toward
reducing the destructive exudation associated with these lesions. Various
methods for ablating retinal capillary hemangioblastoma have been
previously reported; mainstays of treatment, however, have included laser
photocoagulation and cryotherapy (160–168). Small asymptomatic lesions
may remain stable for many years, and observation on regular follow-up is an
option in these patients (162). For symptomatic patients, laser
photocoagulation is effective in treating smaller and more posterior lesions
not associated with significant retinal detachment. Cryotherapy is efficacious
in larger and more anterior lesions. In a large series, laser photocoagulation
effectively controlled 18 of 18 (100%) extrapapillary hemangioblastomas
measuring 1.5 mm or smaller in diameter and 8 of 17 (47%) larger lesions
(162). Seven of eight juxtapapillary lesions were controlled with laser.
Extrapapillary lesions larger than 1.5 mm were successfully controlled with
cryotherapy in 28 of 39 (72%) cases (162). More than one session of
cryotherapy or laser treatment may be required for control of the exudative
process. For lesions larger than 3.5 to 4 mm, treatment with plaque
radiotherapy (Figure 46-8) has been demonstrated to be more effective than
cryotherapy (162,169). In cases involving large exudative detachments,
rhegmatogenous detachments, or tractional detachments of the macula,
operative intervention with scleral buckling or vitrectomy may be beneficial
(170–175).
Visual Rehabilitation
Untreated, retinal hemangioblastoma typically has a poor prognosis. Severe
vision loss has been associated with presentation of retinal lesions at an early
age (153). In one study, the prognosis for vision in patients presenting with
retinal hemangioblastoma was reported as better in those individuals whose
diagnosis did not include VHL disease than in those who were diagnosed
with the VHL syndrome (183). Another study found equal visual outcome in
both these groups (184).
Ethical Considerations
Not applicable.
Future Treatments
Discovery of the VHL protein targeting hypoxia-inducible factors and the
protein’s role in angiogenesis may facilitate the development of new
treatments. Development of drugs specifically active on hypoxia-inducible
factors and VEGF may play a role in the future in treating VHL disease
(185). Recent clinical studies evaluating the potential benefits of ranibizumab
only showed efficacy with intravitreal VEGF antagonists when tumors were
small (186). Recent studies have shown that intravitreal VEGF antagonists
may prove beneficial either alone or in combination with other modalities
(187,188). Intravitreal corticosteroids have also been used with success for
secondary macular edema (189). In pediatric patients, laser photocoagulation
and PDT may be preferable in select cases to decrease the burden of
intravitreal injections (190). Advanced cases may be managed with low-dose
external beam radiotherapy and plaque brachytherapy (191). Selective intra-
arterial bevacizumab has also been used with positive outcomes (192). Future
prospective studies are needed to better understand how intravitreal VEGF
antagonists and corticosteroids may be used with optimal outcomes.
Tuberous Sclerosis
Prevalence
TS is a rare, hereditary phakomatosis first described by Bourneville (193) in
1880. The disorder has been classically characterized by a triad of presenting
symptoms: seizures, cognitive developmental deficits, and adenoma
sebaceum of the skin (194). Clinical expression of TS, however, is highly
variable. The National Tuberous Sclerosis Association has established a more
complex set of diagnostic criteria based on the presence of one or more of the
following features: adenoma sebaceum, ungual fibroma, cortical tubers,
subependymal nodules, retinal astrocytic hamartoma, cardiac rhabdomyoma,
hypopigmented (ash-leaf) skin patches, and infantile spasms, among other
features (195). The incidence of TS has been estimated at 1 in 15,000 live
births. Retinal astrocytic hamartoma develops in approximately 50% of
patients with TS (196,197).
Pathophysiology
Histologically, retinal astrocytic hamartoma in TS is composed of spindle-
shaped fibrous astrocytes containing small oval nuclei arising from the nerve
fiber layer of the retina (200,201). Larger lesions may have areas of calcific
degeneration and may contain cystoid spaces filled with serous exudate or
blood. A rare histopathologic variant, giant cell astrocytoma, has also been
reported (202).
Differential Diagnosis
Retinoblastoma is an important consideration in the differential diagnosis of
retinal astrocytic hamartoma in TS, due to the frequent characteristic
presence of focal areas of calcification in both types of lesions. Other entities
within the differential diagnosis include presumed solitary circumscribed
retinal astrocytic proliferation, amelanotic choroidal melanoma, Coats
disease, myelinated nerve fiber layer, and choroiditis. In patients with TS,
systemic findings of the disease, such as the various skin lesions and
intracranial findings, provide specific clues to aid in diagnosis. Retinal nerve
fiber layer involvement in OCT without outer retinal involvement is highly
characteristics of astrocytic hamartomas.
Management
Except in rare cases, retinal astrocytic hamartoma of TS requires no
treatment. Current treatments for this syndrome are supportive rather than
curative. One complication of TS requiring long-term care is seizure,
necessitating neurologic consultation and management. Antiepileptic drugs,
dermatology treatments, and occupational therapy for developmental deficits
are commonly employed in treating TS patients.
Visual Rehabilitation
In patients with ocular lesions associated with TS, the prognosis for vision is
good, because visual acuity is frequently unaffected unless retinal tumors
involve the fovea. The most common causes of morbidity in patients with TS
are neurologic complications of intractable seizures and hydrocephalus.
Renal hamartoma in TS patients may also be associated with significant
complications. Cardiac or pulmonary complications may arise in the presence
of lesions in the heart or lungs.
Ethical Considerations
Not applicable.
Future Treatments
Intravitreal VEGF antagonists and corticosteroids have been used
successfully in cases of exudative retinopathy and macular edema in patients
with TS (217). Vitreoretinal surgery combined with VEGF antagonists has
also been reported to be beneficial in a patient with exudative retinal
detachment (218). Recent studies have shown systemic everolimus and
sirolimus may be efficacious at inducing regression of astrocytic hamartomas
in select cases (219,220).
Neurofibromatosis
Prevalence
NF is a heritable phakomatosis characterized by lesions composed of
melanocytes or neuroglial cells (221). Initial signs of the disease may be
present at birth or develop throughout childhood and adolescence as the
disease progresses. NF-1 and NF-2 are two distinct forms of NF, each
demonstrating different clinical and genetic features. The primary retinal
lesions in NF-1 are astrocytic hamartomas, which can be identical to those
found in TS. NF-1, the much more common form, affects approximately 1 in
4,000, while NF-2 affects approximately 1 in 50,000.
Pathophysiology
NF is a disorder of the neuroectodermal cell line. NF tumors originate from
neural crest cells, such as sensory neurons, Schwann cells, and melanocytes.
Clinical Features
NF-1 is a progressive disease with numerous and variable manifestations
affecting multiple organ systems including the eye, skin, and CNS. Retinal
tumors associated with NF-1 include retinal astrocytic hamartoma (most
common), retinal capillary hemangioblastoma, vasoproliferative tumors, and
combined hamartoma of the RPE and retina. These lesions may all cause
vision loss in these patients.
Similar to the retinal astrocytic lesions in TS, retinal astrocytic
hamartomas in NF-1 are benign and are often located near the optic disc. One
series reported 42 cases of astrocytic retinal tumors. Of these patients, 14%
had NF, and their tumors were more frequently located adjacent to or on the
disc (222). These lesions demonstrate the white, mulberry-cluster appearance
of astrocytic hamartoma also observed in TS.
Combined hamartoma of the retina and RPE in NF has been reported
(101,223). Retinal capillary hemangioblastoma has also been described in
association with NF (224). Optic nerve glioma is another characteristic tumor
in NF-1, which can cause significant vision loss or proptosis (225). These
lesions may be unilateral or bilateral and may also affect the optic chiasm.
Optic nerve glioma typically presents symptomatically in young children.
Nonocular complications of this tumor include pituitary dysfunction and
hydrocephalus. Optic nerve sheath meningioma may also be associated with
NF-1, although this lesion is less common in childhood.
NF-1 is characterized by uveal masses of the iris and choroid. On dark
irides, the iris lesions, termed “Lisch nodules,” may appear hypopigmented,
whereas on light irides, the masses demonstrate darker pigmentation. The iris
lesions increase in number with age and are observed nearly universally in
adults with NF-1 (226). Choroidal lesions in NF-1 are less common than
those in the iris but are still demonstrated in approximately one-third of these
patients as flat masses, ranging in coloration from white to yellow to darkly
pigmented. Patients with NF-1 are also believed to have an increased risk for
development of uveal melanoma.
Numerous nonocular findings are demonstrated in NF-1. Flat,
hyperpigmented macules (café au lait spots) are the most common cutaneous
presentation in this disease (221). The number and size of these cutaneous
macules vary, and they become larger and more numerous with increasing
age. Other distinctive findings in NF-1 include nodular cutaneous and
subcutaneous neurofibroma, plexiform neurofibroma, and bony lesions (221).
Plexiform neurofibroma in NF-1 may involve the eyelid, giving it an S-
shaped appearance. These eyelid lesions may cause ptosis and may be
challenging to resect.
Pheochromocytoma, other soft tissue tumors, and benign and malignant
CNS tumors have also been reported in association with NF-1. Patients with
CNS abnormalities may demonstrate hydrocephalus, seizures, cognitive
deficits, and developmental delay. Other findings of NF-1 include visceral
tumors such as gastrointestinal neurofibromas, enlarged corneal nerves,
choroidal ovoid bodies, and orbital neurofibromas.
NF-2 is less prevalent than NF-1 and is characterized by acoustic
neuroma, neurofibroma, meningioma, glioma, and/or schwannoma. The most
common eye finding in NF-2 is either cortical or posterior subcapsular
cataract (227). NF-2 patients often have secondary keratopathy due to facial
palsies. As in NF-1, retinal hamartoma and Lisch nodules may be present,
although these lesions are much less common in NF-2 (226). Complications
of both NF-1 and NF-2 arise primarily due to progression of the
hamartomatous tumors in the eye, skin, and CNS.
Diagnostic Studies
Patients demonstrating any findings suggestive of NF-1 should have a
complete ophthalmologic examination to evaluate optic nerve function, iris,
disc appearance, choroid, and intraocular pressure. On FA, retinal
astrocytoma, the most common retinal lesion in NF-1, is hypofluorescent on
early phases with late staining. B-scan ultrasonography may reveal focal
calcifications in these lesions. CT scanning and MRI are helpful in evaluating
extension of optic nerve or optic chiasm glioma, although routine screening
with MRI in the absence of nerve abnormalities on ophthalmologic
examination may not be indicated in all cases (229).
OCT has been used to differentiate lesions and monitor progression in
patients with intraocular and orbital tumors associated with NF-1 and NF-2
(230–233). Decrease in retinal nerve fiber layer may characteristically be
seen in patients with optic nerve gliomas.
Differential Diagnosis
When NF-1 or NF-2 is suspected, the differential diagnosis of a retinal mass
resembling an astrocytic hamartoma in a child or teenager should also include
retinoblastoma, Coats disease, toxoplasmosis, toxocariasis, and choroidal
melanoma. Presentation with other associated manifestations of NF,
including cutaneous lesions, is also diagnostically helpful.
Management
Retinal astrocytomas associated with NF are typically observed. However, in
one series of patients with NF-1, these retinal lesions progressed requiring
surgical intervention including retinal detachment repair, photocoagulation,
or cryopexy (110).
Optic nerve glioma continues to be a therapeutic challenge due to
variable progression. Optic nerve tumors in NF-1 frequently do not progress
in the years immediately following diagnosis (234). Unless these lesions
exhibit aggressive growth, they are often observed. Surgical excision of optic
nerve glioma can be globe preserving, although resection frequently does not
preserve vision in the affected eye. Radiation and chemotherapy have been
employed as treatments in optic nerve glioma with varying degrees of success
(101,235,236). Optic nerve glioma has also been reported to exhibit
spontaneous regression (237).
A medical regimen is typically the initial treatment for NF-1–associated
glaucoma, although this condition may prove intractable to medical therapy.
Surgical intervention is frequently required including goniotomy,
trabeculotomy, trabeculectomy, and installation of an aqueous shunt.
Treatment of cutaneous manifestations of NF includes possible resection
of the neurofibroma tumors. However, these lesions often recur and are only
excised in cases in which the patient is experiencing pain or significant
impairment. Pigmentation defects in NF are not treated. CNS manifestations
of this disease may require treatment with anticonvulsants, and in the setting
of hydrocephalus, neurosurgical treatment may be necessary. Visceral tumors
may also require surgical resection.
Visual Rehabilitation
Visual acuity in NF-1 patients with optic nerve abnormalities is often
reduced, particularly in patients demonstrating concurrent amblyopia in the
affected eye. Patients may have increased morbidity and mortality when they
exhibit more severe presentations of NF, such as CNS tumors, severe
seizures, or other aggressive malignancies.
Ethical Considerations
Not applicable.
Future Treatments
Knowledge of the role in tumorigenesis of the Ras protein and VEGF has led
to treatment of some patients with VEGF antagonists (238,239). Most
recently, intravitreal bevacizumab has been used to treat retinal
vasoproliferative tumors in NF-1 (240). Intravitreal VEGF antagonists and
corticosteroids have also used successfully in cases of exudative retinopathy
and macular edema in patients with astrocytic hamartomas (217).
Vitreoretinal surgery combined with VEGF antagonists has also been
beneficial in select cases (218). Recent studies have shown systemic
everolimus and sirolimus may be efficacious at inducing regression of some
astrocytic hamartomas (219,220). Patients with optic nerve gliomas and NF-1
may also benefit from systemic VEGF antagonists (241).
Wyburn-Mason Syndrome
Prevalence
Initially described and named after its discoverer in 1943, WMS is a rare,
nonheritable disorder characterized by AV malformations of the eye and CNS
(242). Congenital AV malformations in WMS primarily involve the retina,
optic disc, and midbrain; the retinal lesion is known as racemose
hemangioma. AV malformations may also occur elsewhere in the body in
WMS, including the skin, nasopharynx, orbit, lung, and spine. Although the
exact incidence is unreported, WMS is considered a rare condition
worldwide.
Pathophysiology
Although it has been determined that WMS is a congenital, nonheritable
disorder, the pathogenesis has not otherwise been delineated (243,244).
Vessel walls demonstrate fibromuscular medial coats of variable thickness
and acellular fibrohyaline adventitial coverings. Dilated vascular channels
may occupy the entire thickness of the retina. Cystoid changes may be
observed, as well as loss of ganglion cell bodies and axons (245,246). Further
details of the histopathology of racemose hemangioma in WMS remain to be
discovered.
Clinical Features
Most patients with racemose hemangioma in WMS experience reduced visual
acuity. The extent of the vascular malformation varies widely, and the lesions
have been divided into three groups with clinicopathologic characteristics
ranging from least to most severe (244). Group I is comprised of patients
demonstrating interposition of an abnormal capillary plexus between a major
communicating artery and vein. These patients are typically asymptomatic,
and retinal lesions in this group are rarely associated with cerebrovascular
malformations. Group II patients demonstrate direct AV communications
without the interposition of capillary elements. Microvasculature adjacent to
AV lesions may be altered, and beading and multiple fusiform dilations of the
large vessel walls may be observed. Group III patients demonstrate many
anastomosing channels of large caliber. These channels are so intertwined
and convoluted that separation into their arterial and venous components may
be difficult. Perivascular sheathing, exudation, and pigmentary degeneration
may also be observed. Fundus changes in group III patients are similar to
those originally described by Wyburn-Mason (242,243), and visual acuity in
this group is frequently poor. Group III patients also demonstrate a high
incidence of CNS lesions (244). One study suggests that group I and II retinal
vascular lesions are typically isolated. If patients in these first two groups are
asymptomatic, systemic workup is not indicated (247). More severe cases
may be associated with retinal vascular occlusion, retinal ischemia, and focal
exudation, which can lead to progressive vision loss (248–250). Racemose
hemangioma manifests unilaterally and is typically nonprogressive although
the pattern of vascular tortuosity may alter over time.
CNS AV malformations in WMS are more frequently observed ipsilateral
to the retinal lesions. In one series of 80 cases of retinal AV malformations,
30% of these patients also demonstrated CNS malformations (251). Retinal
lesions in WMS may extend from an intracranial AV malformation, traveling
along the optic nerve to the retinal vasculature.
Visual acuity in WMS patients with retinal AV malformations depends
upon the size and extent of the defective vasculature and ranges from normal
to severely reduced. Patients with diffuse, large, markedly dilated, and
tortuous vessels are frequently severely impaired and are consequently often
diagnosed earlier than asymptomatic patients with milder forms of WMS.
Reported visual field defects in patients with this syndrome indicate scotoma
associated with retinal AV malformations (252). Complications of the retinal
AV malformations reported in WMS include intraocular hemorrhage,
secondary neovascular glaucoma, macular hole, central retinal vein
obstruction, macroaneurysm, retinal hemorrhage, and vitreous hemorrhage
(248–253). Extensive peripheral retinal ischemia, neovascularization, and
choroidal infarction have also been reported (254). Retinal detachment and
exudation are not typical in racemose hemangioma.
Neurologic symptoms in WMS depend on the location and size of the
CNS lesions. Patients demonstrating these lesions may develop headaches,
cranial nerve palsies, visual field abnormalities, seizures, weakness, mental
status changes, and papilledema. CNS lesions in WMS are commonly
hemorrhagic.
Diagnostic Studies
In most cases, the diagnosis of racemose hemangioma in WMS may be
determined upon examination by indirect ophthalmoscopy. FA demonstrates
rapid filling of the vascular malformation and provides dramatic
documentation of the lesion. In advanced cases, differentiation between
artery and vein may not be possible. MRI of the brain is indicated to delineate
CNS manifestations in patients with more severe forms of WMS. OCT may
show diffuse or focal retinal thickening, vascular ectasia, and vitreoretinal
interface anomalies (255,256). B-scan shows hyperechoic fundus thickening
with vascularity.
Differential Diagnosis
Other retinal vascular abnormalities, such as retinal arterial and venous
collaterals, retinal telangiectasis, retinal capillary hemangioblastoma, retinal
cavernous hemangioma, and retinal vasoproliferative tumors, should be
included in the differential diagnosis of racemose hemangioma in WMS.
Management
No treatment is indicated for the primary lesions in WMS. The utility of laser
photocoagulation or cryotherapy for these lesions has yet to be clearly
defined.
Visual Rehabilitation
Visual prognosis for patients with ocular AV malformations in WMS varies
widely depending upon the extent of retinal or optic nerve involvement. In
patients demonstrating less severe forms of this disease, the prognosis for
vision and quality of life is typically good. For patients with more severe
manifestations of WMS, associated CNS vascular malformations can lead to
cerebral hemorrhage with potentially devastating consequences.
Role of Other Physicians and Health Care Providers
WS is best treated in a multidisciplinary setting with neurologists providing
primary care.
Ethical Considerations
Not applicable.
Future Treatments
Intravitreal VEGF antagonists have been used with visual and anatomic
improvements in a patient with WMS and central retinal vein occlusion
(257). These may play a role in patients with WMS that develop serous
retinal detachment and cystoid macular edema (258). The medical literature
continues to be scarce regarding potential targets for ocular therapy in
patients with WMS.
Sturge-Weber Syndrome
Prevalence
SWS, also referred to as encephalotrigeminal angiomatosis, is a
nonhereditary phakomatosis manifesting a range of symptoms from partial to
complete expression of the disease (259). In its complete form, SWS is
characterized by ipsilateral angiomatous malformations involving the face,
brain, and eye (260). Patients frequently demonstrate seizures and intracranial
calcifications (196,206). Characteristic ocular findings of SWS include
diffuse choroidal hemangioma and glaucoma (5,260). The exact incidence
and prevalence of SWS are not known.
Pathophysiology
In contrast to circumscribed choroidal hemangioma, the diffuse type
observed in SWS demonstrates a gradual transition at the margin of the lesion
with progressively less engorgement of the vessels as observed on light
microscopy (5). In one large histopathologic series, diffuse choroidal
hemangiomas were classified as mixed cavernous and capillary-type tumors
exhibiting both large and small blood vessels (5).
The pathogenesis of SWS is poorly understood. SWS is believed to be
associated with a defect in neural crest cell migration and differentiation
(261). These precursor cells give rise to ocular tissues, meninges, and the
dermis. Overproduction of angiogenic factors may play a role in the
pathogenesis of this disease.
Dilated and tortuous retinal vessels are commonly observed in eyes with
diffuse choroidal hemangioma. Patients with SWS may also demonstrate
exudative retinal detachment with cystoid degeneration of the macula. These
exudative detachments are associated with subretinal fluid that shifts with
movement of the patient’s head. Total retinal detachment with secondary
cataract and leukocoria may be observed (263). Development of CNV
associated with choroidal hemangioma has also been described (11).
Glaucoma is the most common and most serious ocular manifestation in
SWS, presenting in approximately 70% of SWS patients (260). Intraocular
pressure may be elevated at birth as a form of congenital glaucoma, or
glaucoma may become symptomatic later during childhood. Intraocular
pressure in patients with SWS may be elevated secondary to increased
episcleral venous pressure or a developmental defect in the angle. Additional
ocular manifestations in patients with SWS include vascular malformations
of the eyelids, episclera, conjunctiva, retina, and choroid. Patients with SWS
may demonstrate retinal vascular tortuosity, iris heterochromia, and
strabismus (260). SWS with bilateral optic neuropathy has been reported
(264).
Cutaneous and CNS lesions of SWS are also congenital. Cutaneous
lesions, or nevus flammeus, present ipsilaterally to brain vascular
malformations. Characteristically, SWS patients demonstrate a sharply
demarcated port-wine–colored lesion that may involve the scalp, forehead,
eyelids, and lower face. These cutaneous lesions may undergo thickening
over time, with hypertrophy of underlying bone and soft tissues. CNS
angiomatosis in SWS may lead to calcium deposition in the brain. Decreased
cerebral volume with venous abnormalities and enlargement of the choroid
plexus may also be observed. Clinically, these lesions may present in SWS
patients as seizures, cognitive developmental deficits, hemiplegia, and other
focal neurologic deficits.
Diagnostic Studies
SWS is frequently diagnosed clinically based upon the presence of a port-
wine stain and choroidal thickening due to diffuse choroidal hemangioma, as
well as upon other characteristic ocular and CNS symptoms. FA shows
diffuse early choroidal enhancement (263). In cases where chronic exudative
detachments are present, patchy blocking of the choroidal pattern may be
seen in areas of corresponding hyperpigmentation. B-scan ultrasonography
demonstrates marked thickening of the choroid, often with overlying retinal
detachment, while A-scan ultrasound demonstrates high internal reflectivity.
On FA, widespread early filling of the tumor with late leakage is observed
(263). OCT invariably shows increased choroidal thickness (265). Subretinal
fluid, deep retinal alterations, and intraretinal fluid may also be detected on
OCT (265). Although not commonly utilized in SWS, CT and MRI scans can
be helpful because CT scan can demonstrate abnormal thickening of the
choroid with enhancement of the globe while MRI exhibits a distinctive high
signal on T1-weighted images (266).
Differential Diagnosis
The differential diagnosis of choroidal hemangioma in SWS includes
circumscribed choroidal hemangioma unassociated with SWS, amelanotic
choroidal nevus or melanoma, choroidal osteoma, retinal pigment epithelial
detachment, scleritis, and retinal capillary hemangioblastoma.
Ethical Considerations
Not applicable.
Future Treatments
Intravitreal VEGF antagonists have been used with visual and anatomic
improvements in a patient with SWS and exudative retinal detachment (270).
PDT has also been employed successfully to treat focal subretinal exudation
in patients with diffuse choroidal disease (271). Some authors have reported
successful therapy with oral propranolol 60 mg twice a day (272). Some
diffuse choroidal hemangiomas may not respond to oral beta-blocker therapy
(273). Most recently, low-dose brachytherapy has been employed with visual
and anatomic improvements (274).
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SECTION VII
Uveitis in Infants and Children
47
Uveitis and Endophthalmitis Affecting
Infants and Children
Christopher D. Conrady, Stephen D. Anesi, C. Stephen Foster, and
Albert T. Vitale
INTRODUCTION
Pediatric uveitis encompasses a wide array of infectious and noninfectious
entities that may be isolated to the eye or the manifestation of an underlying
systemic condition. This subject requires special attention due to important
diagnostic and therapeutic challenges specific to this patient population. To
start, a comprehensive history and review of systems may not be possible in a
preverbal child and a complete ocular examination, including measurement of
intraocular pressure and indirect ophthalmoscopy, may require general
anesthesia in an uncooperative youngster. The differential diagnosis can vary
considerably with age, an important consideration given the
overrepresentation of infectious etiologies among younger children and the
presence of pediatric-specific neoplastic masquerade syndromes such as
retinoblastoma (RB) and acute leukemia. Certain endogenous noninfectious
entities such as juvenile idiopathic arthritis (JIA), Kawasaki disease,
tubulointerstitial nephritis and uveitis (TINU) syndrome, chronic infantile
neurologic cutaneous and articular/neonatal-onset multisystem inflammatory
disease (CINCA/NOMID) syndrome, and familial juvenile systemic
granulomatosis (Blau syndrome) are diseases found only in children and
young adults. The clinical presentation of other entities such as early-onset
sarcoidosis (EOS) differs from that seen in the adult while the choice and
interpretation of laboratory data must be modified to reflect differences in the
normative values of certain tests in children such as a physiologically
elevated angiotensin-converting enzyme (ACE).
Ocular inflammatory disease in children is typically chronic, recurrent,
and difficult to manage with the frequent development of ocular structural
complications. Presentation with established ocular pathology is itself not
only a risk factor for the development of further complications but also
graphic testimony to diagnostic delay and screening failure in this population.
To further complicate matters, ocular structural complications, such as the
development of a cataract in the pediatric population, require more prompt
attention than do those found in adults due to the risk of amblyopia in
children <10 years of age. These factors influence judgments with respect to
the aggressiveness of medical therapy and the timing of surgical intervention.
Therapeutic dilemmas in the medical management of noninfectious
pediatric uveitis include concerns regarding the promotion of cataract,
glaucoma, and growth retardation with the chronic use of corticosteroids
versus therapeutic timidity surrounding the early introduction of steroid-
sparing immunomodulatory therapy (IMT) for fears of potential toxicity
associated with these agents. Corticosteroid monotherapy and the late or
subtherapeutic introduction of IMT conspire to place children at greater risk
for visual loss from ocular structural complication both iatrogenically and
from uncontrolled inflammation. Children represent greater surgical risks due
to their well-known exuberant inflammatory response to surgical trauma as
well as the inherent complications associated with specific disease entities
such as JIA.
While the incidence and prevalence of childhood uveitis is significantly
less than that in adults, the proportion of children at risk for blindness and
severe visual loss and the impact of this visual debility over the life span of
the patient may be greater in children. Tolerance of low-grade intraocular
inflammation, prolonged use of corticosteroids, and reluctance to employ
steroid-sparing IMT when clinically indicated results in ongoing and
irreversible damage to ocular structures critical for visual function with
devastating effects for these young patients and their parents. Retina
specialists should be keenly aware of these issues in their approach to the
management of pediatric uveitides as accurate diagnosis, the timely and
appropriate use of antimicrobial agents in cases of infectious uveitis, and
early implementation of steroid-sparing IMT for chronic noninfectious
entities are critical for the maintenance and preservation of vision in this most
vulnerable population.
EPIDEMIOLOGY
Children account for anywhere from 2.2% to 21.65% of patients in various
uveitis clinics (1–5). A review of recent U.S. insurance claims found rates of
29 uveitis cases per 100,000 children (6). This is in contrast to much higher
prevalence rates in adults of 58 to 115.3 cases of uveitis per 100,000 adults in
the United States (7–9). Despite a lower prevalence and fewer children in
uveitis clinics compared to adults, the rate of vision loss and ocular
complications is higher in the pediatric population (10,11).
Large retrospective studies have identified a slight female predominance
and bilateral involvement in pediatric uveitis. Chronic or recurrent disease
represents up to 87% of cases, and there is a delay between diagnosis and
referral to a uveitis specialist that can range from <6 months to 14 years (5).
Anterior uveitis is the most frequent anatomical location, constituting nearly
half of all cases of pediatric uveitis (1,3–5,12–16). Intermediate uveitis
accounts for approximately another quarter of all disease, while panuveitis
and posterior uveitis are much less common, representing a quarter of disease
combined (3–5,13–17). JIA-associated uveitis is the most common type of
pediatric uveitis, and is easily the most frequent cause of anterior uveitis with
rates as high as 47% of all anterior uveitides (3–5,12–17). Pars planitis is the
most common form of intermediate uveitis, while toxoplasmic
retinochoroiditis is the most frequent etiology of posterior uveitis (17).
Systemic disease can be identified in 42% of cases with JIA being the most
common underlying etiology (5). Despite recent advances in molecular and
immunologic diagnostic tools, upward of 60% of pediatric patients’ disease is
considered idiopathic or undifferentiated (4,5,17).
There is significant geographic variation with respect to the anatomic
distribution, the prevalence of infectious etiologies, and so, the diagnosis of
uveitis among children. For example, toxoplasmosis is seen in only 2% to
10% of all cases of pediatric uveitis cases in Western industrialized countries,
but accounts for much higher rates in the Middle East and India with rates
approaching 35% to 40% of posterior uveitides in some reports from India
(13,17–20). Likewise, Behçet disease, while uncommon in the United States,
is more frequently encountered among patients along the ancient “Silk Road”
with Korean, Japanese, Chinese, Turkish, and Middle Eastern ancestry
(17,21–24). Finally, there has been a notable increase in panuveitis with
concurrent decrease in posterior uveitis over the last several decades. This is
likely due to the decrease in toxoplasmosis and toxocariasis in children
within developed countries (5). Table 47-1 illustrates the anatomic
distribution, association with systemic disease, infectious etiologies, and
geographic differences of pediatric uveitis (50).
The number of patients included in each study is shown by in the sample size column, while the
affected intraocular locations and specific diagnoses are expressed in percentages
(1–5,10,12–17,25–49).
DIFFERENTIAL DIAGNOSIS
The differential diagnosis for pediatric uveitis can be divided into three broad
categories: infectious, noninfectious (autoimmune, autoinflammatory, or
idiopathic in origin), and masquerade syndromes. The most common
infectious causes of anterior uveitis are herpes viruses (HSV and VZV), and
toxoplasmosis is the most common cause of posterior infectious uveitis (51).
In one of the only large retrospective cohorts of its kind to evaluate cases of
infectious uveitides in children, an infectious etiology was identified in 17%
with T. gondii representing 60% of cases and viral infections another 30%
(51). The most common noninfectious cause of anterior uveitis in children is
JIA, which represents at least a third of all pediatric uveitis cases at tertiary
referral centers (25,52). There are also specific forms of uveitis much more
prevalent in the pediatric population such as toxocariasis, TINU syndrome,
Kawasaki disease, postviral, and diffuse unilateral subacute neuroretinitis
(DUSN). Intermediate uveitis may also represent a slightly larger portion of
cases in children than adults. This is supported by estimates of burden of
disease as high as one-fifth of all cases of pediatric uveitis being diagnosed
with intermediate uveitis and approximately 85% of all cases of pars planitis
occurring in children <14 years of age in one study (53). Masquerade
syndromes in children are also not uncommon and include primary
intraocular neoplasms such as RB and ocular involvement of systemic
leukemia (Figure 47-1, Table 47-2).
DIAGNOSTIC APPROACH
A comprehensive medical history and review of systems, together with a
complete ocular examination, employing general anesthesia, as necessary,
form the cornerstones to the diagnostic approach in pediatric uveitis.
Laboratory tests and ancillary investigations are guided by the above and by
the putative differential diagnosis (Table 47-5). Laboratory tests are used in
most cases to confirm the clinical impression or to exclude diagnostic
possibilities, especially infectious entities rather than a “shotgun approach”
where false-negative and false-positive results can obfuscate the underlying
diagnosis. As such, disease-specific testing should be performed when there
is an elevated pretest probability for the disease based off of the history and
ocular examination or the risk of missing the diagnosis could lead to
permanent loss of vision or the eye altogether.
ACE, angiotensin converting enzyme; ANA, antinuclear antibody titers; CBC, complete blood count;
FTA-Abs, fluorescent treponemal antibody absorption test; LD, lyme disease antibody titers and
Western blot; PPD, purified protein derivative skin testing; RPR, rapid plasma reagin; UA, urinalysis.
COMPLICATIONS OF PEDIATRIC
UVEITIS
The risk for the development of ocular complications among the pediatric
population is greater than in adults with uveitis due to the chronicity of
inflammation, the frequent lack of symptoms and longer delays between
diagnosis and initiation of appropriate treatment. Ocular structural
complications include band keratopathy, secondary glaucoma, posterior
synechiae, cataract formation, vitreous hemorrhage, rubeosis, papillitis,
papilledema, CME, epiretinal/neovascular/cyclitic membranes, retinal
detachment (RD), hypotony, and phthisis. To complicate matters, ocular
complications associated with pediatric uveitis such as visually significant
media opacities, especially in very young children, can lead to the
development of amblyopia. This necessitates aggressive medical and surgical
treatment to prevent profound and permanent vision loss. The presence of
ocular complications on baseline examination is an important risk factor for
the development of subsequent complications (56,57).
The most common complications of pediatric uveitis are posterior
synechiae, cataract formation, CME, secondary glaucoma, band keratopathy,
and hypotony (4,5,15,16,58,59). Moreover, ocular hypertension affects a
significant minority of children with noninfectious uveitis and requires
vigilant monitoring particularly when strong risk factors, including local
corticosteroid use (in a dose- and route of administration–dependent
relationship) and contralateral IOP elevation, are present due to the risk of
developing a glaucomatous optic neuropathy (60). Complication rates have
been shown in studies from tertiary referral centers on pediatric uveitis to be
as high as 64% of children will develop cataracts, 58% posterior synechiae,
46% band keratopathy, and/or 25% glaucoma. (4,5,15,16). Furthermore, most
children will develop at least one complication from uveitis (4,5,15,16,25).
Children with JIA-associated iridocyclitis are particularly vulnerable as
compared to other forms of uveitis with the risk of developing any ocular
complication of 0.33 per eye-year and at least one ocular complication noted
in 67% of patients at time of diagnosis (4,5,56,59,61,62). Maculopathy
(including CME) and epiretinal and neovascular membranes are most
commonly found in association with intermediate uveitis, while papillitis and
optic nerve edema occur most frequently in posterior uveitis and panuveitis
(4,5).
Flare is also an important marker of anterior segment inflammation and
blood–aqueous breakdown. Its presence is thought to represent a dynamic
sign of disease activity. There are emerging imaging modalities currently
available that are being tested for their ability to objectively and accurately
quantitate the presence of flare. The most commonly employed method is
laser flare photometry (LFP). Measurements with this device have correlated
well with complications noted at baseline and over time and overall outcomes
in children with chronic anterior uveitis (63). High baseline and first flare
values also correlate well with risk of vision loss to <20/50 and vision-
threatening ocular complications independent of the presence of anterior
chamber cells (64). Anterior segment ocular coherence tomography (OCT)
has recently been shown to correlate well with LFP and clinical examination
in measuring anterior chamber flare (65). Consequently, the measurement of
aqueous flare is likely to become an important prognostic tool in uveitis. In
contrast, the presence of anterior chamber cell is indicative of active disease
and is more responsive to treatment, making it less helpful in defining long-
term prognosis.
VISUAL OUTCOMES
Not surprisingly, vision loss has been reported to be more common in
pediatric uveitis than in adults given the high rates of complications and
chronicity of disease observed in many childhood entities (66). In the 1960s,
30% of children with chronic uveitis became blind (26). More recent analyses
have estimated that between a quarter and a third of children with uveitis will
have severe vision loss (66). The most frequent causes of vision loss to
20/200 or worse include band keratopathy, cataract, vitreous opacities,
glaucoma, CME, and choroidal neovascular membranes and/or scars
(4,12,14). Interestingly, patients with posterior uveitis and panuveitis were
referred sooner to tertiary centers (11 and 7 months, respectively) than those
with intermediate (19 months) or anterior uveitis (33 months), likely due to
more vision-threatening disease (5). A more recent study suggests that cases
of posterior infectious uveitis have the worst visual prognosis, requiring
timely and accurate diagnosis, including the use of aqueous humor analysis
and prompt, directed therapy (11).
In cases of JIA-associated uveitis, the most extensively studied entity, a
worse prognosis has been historically associated with increasing severity of
disease. Ocular complications at initial evaluation, longer duration of uveitis,
younger age of presentation, male sex (56,67), and delayed referrals to a
uveitis specialist are all known risk factors of more severe disease (5,68).
Blindness from disease complications ranges from 0% to 17.5% and is much
more common in African Americans than non-Hispanic Caucasians (68–70).
However, visual outcomes have improved with early treatment with IMT
with 92% of patients having 20/40 or better vision 5 years after presentation
(17,52).
In our view, the currently guarded visual prognosis for pediatric uveitis is
potentially modifiable with early diagnosis and referral to a uveitis specialist
with appropriately aggressive anti-inflammatory and/or antimicrobial
therapy. Our experience and that of others suggests that the judicious
implementation of steroid-sparing IMT is essential in the treatment of chronic
noninfectious uveitis in children as this approach is effective both in
achieving inflammatory control and in reducing structural and steroid-
associated complications and so, improving visual outcomes (71,72).
Inflammatory quiescence for a minimum of 3 months prior to intraocular
surgery is recommended to improve outcomes and reduce the risk of
perioperative complications (61,73). Finally, the novel application of imaging
modalities such as OCT and laser-flare photometry to more quantitatively
assess inflammation and a reassessment of the current screening guidelines
may serve to more accurately identify those children at greatest risk of vision
loss and the development of ocular complications, thereby reducing the long-
term burden, socioeconomic, and psychosocial impact of these ocular
diseases (74).
We support this opinion as far too many children with JIA-associated uveitis
lose vision to the point of being permanently visually handicapped, as a
consequence of delayed diagnosis, inadequate treatment including reliance on
or reluctance to taper off corticosteroid therapy, and prolonged duration of
disease. We reported on 77 adult JIA uveitis patients (135 eyes, mean age
29.72 years) at their last visit exhibiting the presence of at least one
complication in 72% of eyes and ongoing inflammation in 52% of patients,
with patients presenting for tertiary care older than age 16 having more
complications and worse vision (125). De Boer et al. showed a positive linear
correlation between macular thickening and duration of JIA uveitis follow-
up, with 13 of 61 patients developing macular edema after mean follow-up of
11.6 years, and eventual macular thinning after longer follow-up (126).
Additional risks of developing complications may exist as older children are
lost to follow-up during transition to adult care, with a preadult dropout rate
reported as high as 22% versus 3% for younger children and 10% for adults
(127). A study from the Bascom Palmer Eye Institute reported on 34 JIA
anterior uveitis patients among a series of 112 noninfectious pediatric uveitis
patients followed for up to 10 years, finding JIA patients with the highest risk
ratio for band keratopathy, cataract, and posterior synechiae, with the
cumulative proportion of patients with complications continuing to rise
through time, with substantial numbers of eyes and patients with visual acuity
of 20/200 or less in the better eye (4). As previously mentioned, the disparity
in the literature with respect to visual outcome in patients with JIA-associated
iridocyclitis, with more favorable outcomes reported among population-based
studies and surveys of JIA-associated iridocyclitis referred to pediatric
hospitals as opposed to poorer outcomes in our experience and those reported
from other tertiary care ophthalmic centers, may be more the reflection of
sampling bias and lack of long-term follow-up, obfuscating the harsh reality
of significant visual debility often associated with this disease
(4,27,62,75,124,125,128).
Our therapeutic approach to JIA uveitis is not unlike our approach to
other forms of noninfectious uveitis and includes the elimination of all active
inflammation with limited tolerance for steroids and the early introduction of
steroid-sparing IMT (129). The use of IMT in recalcitrant disease has been
associated with decreased risk of uveitis onset and frequency, vision loss,
ocular complications, and improved outcomes after surgery (72,97,130,131).
We recently reported a series of 30 JIA uveitis patients from 1990 to 2011
who achieved successful corticosteroid-free (no use of topical or systemic
corticosteroid) remission using IMT for 2 years followed by medication
withdrawal and maintenance of remission for at least 1 year in which 56.7%
remained in long-term remission thereafter, with a total population median
time of 7 years, with longer times significantly associated with patients
receiving IMT at an earlier age and earlier in the course of their disease
(132). Conversely, Acharya et al. reported a relapse rate of 68% in 19
patients (including 82% of 11 on tumor necrosis factor [TNF] inhibitors)
from 1988 to 2011 after achieving corticosteroid-sparing control of
inflammation (allowed use being prednisone ≤10 mg, prednisolone acetate
dose <3 drops/day) followed by withdrawal of IMT with a shorter median
time to relapse of 288 days, however; 69% of these patients were on topical
corticosteroids, with 17% on oral prednisone, and discontinuation of IMT in
some was due to reasons other than achieving steroid-sparing control of
inflammation (i.e., adverse reaction, poor efficacy, cost, pregnancy) (133).
Differences in outcomes between these reports likely reflect the notable
differences in length of use of IMT as well as allowed or acceptable amounts
of corticosteroid during steroid-sparing therapy.
Initial treatment of JIA-associated uveitis is commenced with topical
corticosteroids with regional corticosteroid injections (generally requiring
anesthesia) being added to the program should the uveitis not respond. We
use a so-called stepladder algorithmic paradigm in our care of patients with
JIA-associated uveitis, with brief (not >3 months) administration of systemic
corticosteroids representing the first step. Chronic oral nonsteroidal anti-
inflammatory drug (NSAID) therapy, commonly with naproxen or tolmetin,
represents step 2, and may be employed in instances in which uveitis of mild
to moderate severity recurs with every attempt at tapering topical steroids.
Some children with JIA may already be on NSAIDs for their arthritis. The
usual caveats pertain, of course, with respect to NSAID use, and therapy
should be coordinated with the patient’s pediatrician and/or pediatric
rheumatologist. Some patients with JIA-associated uveitis have recurrences
of the uveitis despite the chronic use of NSAIDs, or more severe disease that
would not be expected to respond to lower level anti-inflammatory therapy
(134). These patients must be advanced to the third step on the stepladder:
IMT.
A variety of immunomodulatory medications have been used in this
context (Table 47-8); however, the antimetabolite methotrexate has, by far,
the longest safety and efficacy record and is the agent of first choice in the
treatment of pediatric uveitis in general, and in JIA-associated iridocyclitis
specifically among treating physicians across multiple specialties (135–139).
We typically commence therapy at 0.15-mg/kg body weight once weekly by
mouth with 1 mg folic acid daily; weekly dosing reduces the risk of
hepatotoxicity (140) We advance the dose of methotrexate every 6 to 8
weeks, as needed and tolerated, to achieve the goal of complete freedom of
all recurrences of all inflammation at all times off all corticosteroids. Uveitis
associated with JIA often requires much higher doses of methotrexate to
induce durable remission than does arthritis. Fortuitously, children tolerate
such doses quite well, with no significant differences in side effects or ocular
complications seen between patients started on lower versus higher doses
(141). The bioavailability of the medication is variable after oral
administration; therefore, we switch patients to subcutaneous administration
at doses above 17.5 mg. Potential side effects include hepatotoxicity, bone
marrow suppression, interstitial pneumonitis, mucositis, nausea, fatigue, and
alopecia. For this reason, it is mandatory that patients be regularly monitored
by an expert in the prescribing and monitoring of IMT. We monitor patients
every 6 weeks, both by personal observation and query and by hematologic
assay of liver enzymes, renal function, and complete blood count (CBC) with
differential. Suppression of the bone marrow, in our experience, is
extraordinarily rare. Rising liver enzymes is an indication of hepatotoxicity,
and we typically back off on the dose if the patient has elevated enzymes on
two occasions separated by 2 weeks. Interstitial pneumonitis and chemical
hepatitis are reversible with cessation of drug if detected early in the course
of development.
Seronegative Spondyloarthropathies
The juvenile seronegative spondyloarthropathies (JSpA) are a series of
related rheumatic diseases in children under age 16 characterized by
enthesitis (inflammation of tendons, particularly at their points of insertion
into bone) and involvement of peripheral large joints and with a
predisposition to sacroiliitis, uveitis, and the HLA-B27 gene. By definition
(“seronegative”), the patients are RF negative. Classification has varied over
the last few decades with the development of various criteria, with
considerable overlap found between these disorders and some forms of JIA,
given their similarities, and includes ankylosing spondylitis (AS), reactive
arthritis, psoriatic arthritis, and inflammatory bowel disease. These are very
similar to the adult variants; however, differences exist with respect to
symptoms at disease onset and severity through course of disease. Juvenile
psoriatic arthritis, by ILAR criteria, is classified as a subtype of JIA; however
it is, perhaps more so related to a form of JSpA. MRI has increasingly been
thought to be more sensitive than radiography in detecting early
inflammation, including prior to axial involvement, and may show early
characteristic findings that may differ by disease subtype (213). For the
ophthalmologist, the symptomatic presentation of acute anterior uveitis
(AAU) seems to be more often found in patients with the juvenile
spondyloarthropathies than JIA and may help to distinguish these patients in
order to better predict disease course.
Ankylosing spondylitis
Pediatric AS is a well-characterized syndrome. As in adults, HLA-B27–
positive males predominate in the pediatric population. Conversely, unlike
the adult form, in which initial onset is typically arthralgia with morning,
lower back stiffness and axial involvement, enthesitis with exquisite
tenderness in the areas of tendon inflammation, and peripheral arthritis are
more prominent early in the children with AS and usually involve knees,
shoulders, hips, or even ankles. As with JIA, the temporomandibular joint
(TMJ) may be involved and may be the single peripheral joint involved. AS
in children typically begins after age 10. Anterior uveitis associated with AS
as with all of the seronegative spondyloarthropathies is generally acute,
unilateral, and recurrent but may become bilateral and alternating. As many
as 15% of children with juvenile AS may develop chronic iridocyclitis (214).
HLA-B27 positivity is not required for the diagnosis; 5% to 10% of patients
with AS are HLA-B27 negative. Unlike JIA uveitis, the uveitis associated
with JSpA is often symptomatic and presents with a red eye, ocular
discomfort, and photophobia and may become severe quite rapidly or in a
delayed manner 1 to 2 weeks after initial symptoms despite initiation of
topical therapy. Therapy should include aggressive topical corticosteroids
often administered every 30 to 60 minutes while awake along with
cycloplegia; however; in the presence of severe inflammation, indicated by
the presence of fibrin in the anterior chamber on slit lamp evaluation or when
topical therapy does not result in a significant reduction in the intensity of
anterior chamber reaction, a short burst of systemic corticosteroid (1.0
mg/kg/d) with a rapid taper, such as a dosage reduction every 5 to 7 days, and
aggressive cycloplegia is appropriate. More recalcitrant cases may require
regional corticosteroid injections, and this generally requires brief general
anesthesia in children.
HLA-B27–associated uveitis tends to be recurrent, and our experience
suggests that oral NSAIDs, especially celecoxib and diflunisal, are
particularly useful in long-term management of patients with
nongranulomatous, acute idiopathic, or HLA-B27–associated recurrent
anterior uveitis, as well as with concurrent active systemic manifestations,
allowing a reduction in the amount of corticosteroid required to achieve
inflammatory quiescence and often enabling patients to maintain quiescence
once steroids have been discontinued (215). One should be guided by the
child’s rheumatologist as to the choice and dosing of the NSAID.
Antimetabolites may be used if the NSAID is not able to control disease.
TNF-α has been shown to be involved in the pathophysiology of both adult
and juvenile AS; thus, TNF-inhibitors have been widely studied in the
treatment of systemic disease and have been effective in one double-blind
study versus placebo; however, patients are not often able to discontinue
therapy without relapse (216–218).
Reactive arthritis
Reactive arthritis (previously “Reiter syndrome”) was originally defined as
the triad of arthritis, conjunctivitis, and noninfectious urethritis, but uveitis
may substitute for or be present along with conjunctivitis. It may rarely occur
in children, and may present after infections, such as Shigella, Salmonella,
Yersinia, Clostridium difficile, or streptococcal pharyngitis, the last of which
is differentiated in part from acute rheumatic fever by duration of arthritis and
response to therapy (219). Whereas 75% of adults who develop reactive
arthritis are HLA-B27 positive, 90% of children with it are HLA-B27
positive, and 2% of pediatric patients with reactive arthritis develop uveitis.
The intraocular inflammation is identical to that seen with AS or HLA-B27–
associated uveitis without spondyloarthropathy and is generally anterior,
nongranulomatous, and recurrent with the initial attack being typically
unilateral and acute. Hypopyon uveitis may also occur. Therapy is similar to
that described above for AS-associated intraocular inflammation.
Psoriasis
Children may develop uveitis in association with psoriasis, with or without
the development of arthritis. Stoll et al. first reported that disease onset is
bimodal, which was later corroborated by the CARRA cohort that showed an
average early onset near age 3 and late onset at approximately age 11.
However, these groups differed on whether uveitis onset was more common
in the early group or similar between the two (220,221). Girls are slightly
more likely than boys to develop psoriasis (3:2) with a mean age of onset of
approximately 9 years. The uveitis associated with psoriasis without arthritis
is slightly different from that of uveitis associated with psoriatic arthritis or
HLA-B27–associated uveitis (222). The mean age of onset is older, and it
tends to be bilateral and of longer duration and requires oral treatment with
NSAIDs. Retinal vasculitis, macular edema, and papillitis are more
frequently seen.
The skin lesions of psoriasis typically precede the development of either
joint or ocular inflammation; however, we have made the diagnosis of
psoriasis in numerous instances while examining the skin of patients during
their initial evaluation of uveitis, which was confirmed by subsequent
dermatologic referral. Small hidden patches of itchy, scaly dermatitis may
come and go, in the axilla, on the umbilicus, on the genitalia, on the back, or
on the scalp. Dactylitis and nail pitting may also be present. The prevalence
of uveitis in patients with psoriasis is unknown and may occur in up to 20%
in pediatric psoriatic arthritis (223,224). As with AS and reactive arthritis,
psoriasis-associated uveitis presents with acute, anterior, recurrent,
nongranulomatous, unilateral inflammation, but with time can develop into
bilateral involvement. The uveitis is more severe and more recalcitrant in
patients who are HLA-B27 positive. Patients who develop uveitis associated
with psoriatic arthritis are also more commonly ANA positive (80%) with
oligoarticular arthritis presenting as long as 10 years before the onset of the
dermatologic manifestations of psoriasis; hence, the diagnosis of seronegative
oligoarticular JIA has often been (erroneously) made earlier in these children.
Therapy is with aggressive topical corticosteroids and cycloplegics.
Chronic oral NSAID therapy may also be helpful in reducing the likelihood
of recurrent inflammation. Treatment-resistant cases may respond to low-
dose once-weekly methotrexate or daily cyclosporine. A recent small case
series of 6 patients suggested that younger patients (age 6 or less) may suffer
more severe and chronic disease requiring TNF-α inhibition to control
disease (225).
Sarcoidosis
Sarcoidosis is a chronic multisystem noncaseating granulomatous disease of
unknown cause that occurs rarely in children. There are two presentations in
children: EOS, <4 years of age, and late onset, between 8 and 15 years of age
(248,249). EOS patients are primarily Caucasian, who present most
commonly with the triad of arthritis, skin lesions, and uveitis. Pulmonary
involvement is less common (35%), making it more difficult to establish the
diagnosis, especially since articular involvement may mimic JIA (250,251).
In contrast, older children and adolescents usually present with multisystem
disease similar to that seen in adults with sarcoidosis. There is generally no
familial history of sarcoidosis, and bilateral hilar lymphadenopathy or
pulmonary involvement may be present on chest radiographs in 90% of
cases. Eye and skin lesions occur in 30% of late-onset juvenile sarcoidosis.
Since other diseases, including mycobacterial or fungal infection and
berylliosis, as well as foreign body reaction, can also produce noncaseating
granulomas, the histologic diagnosis of sarcoidosis is made by exclusion.
Vasculitis is a relatively unique complication associated with juvenile
sarcoidosis.
Blau syndrome, also known as familial juvenile systemic granulomatosis
and/or Jabs syndrome, is an autosomal dominant granulomatous disease of
childhood with clinical features almost identical to EOS. Patients with Blau
syndrome have mutations in the NOD2 gene (CARD15) on chromosome 16.
Renal and hepatic granulomas have been described in this disease (252–255).
Granulomas of the skin and synovial biopsy from Blau syndrome are
identical to those seen in sarcoidosis (255).
Sarcoidosis is rare in children, but a patient as young as 3 months old has
been reported (256). The annual incidence has been estimated at two to three
cases per million with a higher prevalence in females; however, the majority
of reported pediatric cases are similar between genders (257,258). In the
southeastern United States, sarcoidosis has a higher incidence among African
Americans (259,260). In children age 4 years and younger with sarcoidosis,
7% to 28% were African Americans, whereas among children aged 8 to 15
years, the percentage of African Americans increases to 72% to 81%
(248,261,262). Within the United States, approximately 80% of childhood
cases have been reported in the southeastern and south central states,
suggesting they are an endemic area for childhood sarcoidosis
(259,261,263–265). The disorder is common in Scandinavian countries but
rare in India, Southeast Asia, New Zealand, and China (264).
As mentioned above, EOS is characterized by the triad of skin eruptions,
arthritis, and uveitis without bilateral hilar lymphadenopathy, which may
mimic JIA. Intermittent fever and synovial swelling may further contribute to
this masquerade. Early differentiation of sarcoidosis from JIA is important in
planning treatment strategies and in counseling patients and families with
skin changes serving to help differentiate these diseases at their onset. The
rash seen in JIA is transient and composed of pink macules, whereas that
observed in sarcoidosis presents with variable erythema, papules, plaques,
and ichthyosiform lesions (266). The cutaneous manifestations may be the
earliest sign and occurs before joint or eye involvement with papules,
plaques, nodules, erythema nodosum, and hypo- or hyperpigmented areas.
Lupus pernio is frequent in adults but rare in children (267,268). A skin
biopsy should be performed if lesions are present given their accessibility in
an effort to confirm the diagnosis. Sarcoid arthritis in children is
characterized by painless, boggy synovial and tendon sheath effusions with
mild limitation of motion, whereas in JIA, there is pain, limitation of
movement, and destructive changes found on radiographs. Parotid gland
enlargement is a frequent finding in children with sarcoidosis, especially
EOS, and represents an additional easily accessible biopsy site.
Late-onset juvenile sarcoidosis presents similarly to that seen in adults—
a multisystem disease with lymphadenopathy, hepatosplenomegaly, parotid
fullness, and pulmonary involvement as well as generalized constitutional
signs and symptoms (fever, anorexia, and malaise) (267,268).
A wide spectrum of systemic vasculitis in pediatric sarcoidosis has been
reported, including leukocytoclastic vasculitis, vasculitis of small- to
medium-sized vessels, and large-vessel vasculitis. EOS patients should be
carefully followed for development of vasculitis.
Neurologic dysfunction secondary to sarcoidosis is rare in children.
Granulomas are most common in the basal area of the meninges and brain,
causing seventh nerve palsy and hydrocephalus (269). Growth deficiency has
been reported in association with brain MRI abnormalities, and hypothalamic
infiltration can manifest as diabetes insipidus (270,271).
Hypercalcemia may be present due to increased 1-α hydroxylase activity
and interferon (IFN)-γ production, both leading to elevated levels of active
1,25-vitamin D and increased gut absorption of calcium (272,273). Renal
involvement may be related to the presence of granuloma in the renal
parenchyma or to hypercalciuria with nephrocalcinosis (270,274–279).
Granulomatous tubulointerstitial nephritis may present with uveitis and
appear as TINU, with biopsy being required to differentiate it from
sarcoidosis (245). Sarcoid liver granuloma may be present in up to 90% of
patients, and liver enzymes are often mildly elevated in such instances. A
needle biopsy may identify the lesions (280).
The ocular manifestations of sarcoidosis in children are similar to those
seen in adults and were the second most common initial presenting findings
in a study in Louisiana (263). Anterior uveitis is the most common ocular
manifestation in both the younger (81%) and older pediatric groups (21% to
48%) (263). The inflammation may be chronic and granulomatous with
minimal pain and photophobia. Multiple areas of interstitial keratitis (IK),
corneal limbal nodules, mutton fat keratic precipitates, and iris nodules may
be observed (Figure 47-2) (274,275). An acute, nongranulomatous type of
uveitis can also occur, typically characterized by pain, redness, and
photophobia. Posterior segment involvement is the most vision threatening,
manifesting with vitritis, pars planitis, papillitis, chorioretinal granulomas,
macular edema, branch retinal vein occlusion, retinal periphlebitis, subretinal
neovascular membranes, and optic nerve granulomas. Lacrimal gland
involvement, commonly found in adult patients with sarcoidosis, rarely
occurs in children (281).
FIGURE 47-2 Iris nodules in pediatric sarcoidosis.
ACE, produced by macrophages and epithelioid cells, reflects the total body
granuloma load. ACE levels are commonly higher in children than in adults,
and ACE is not specific for sarcoidosis, because it is elevated in several other
systemic diseases that affect the lungs or the liver. When ACE levels are
compared to age-matched controls, 80% of children with pediatric
sarcoidosis have elevated ACE (282). Gundlach et al. reported that elevated
levels of soluble interleukin-2 receptor (sIL2R), also nonspecific and known
to be released activated T lymphocytes, may be a useful screening tool in
newly diagnosed adult uveitis. sIL2R has higher sensitivity (98%) compared
to ACE (22%) or chest radiography (50%) in known sarcoidosis; there is
comparable high specificity among all three tests; however, no pediatric
patients were included (283). Hilar adenopathy may be seen with or without
parenchymal involvement. Gallium scanning and thin-cut spiral CT scanning
are more sensitive imaging methods to detect early lung involvement.
Contrast-enhanced MRI with fast imaging sequencing has been found to be
comparable to CT in evaluating pulmonary and cardiac lesions without the
same risk of radiation to children as CT and has been useful in establishing
the diagnosis of sarcoidosis in children who present with fever of unknown
origin by revealing multifocal nodular lesions in the bone marrow of the
lower extremities (284,285). Fine needle aspiration biopsy cytology has been
suggested as an adjunct in the diagnosis of children with suspected
sarcoidosis with the demonstration of epithelioid histiocytes and
multinucleated foreign-body–type giant cells without accompanying necrosis
or acute inflammation (280). Ideally, biopsy of easily accessible sites, such as
skin, lymph nodes, and conjunctiva, especially when conjunctival nodules are
present, is highly recommended in this diagnostic effort (286). As in adults,
sarcoidosis in children may act as a “great imitator,” appearing similar to
other entities such as JIA uveitis or even early-onset birdshot
retinochoroidopathy, but where hilar node biopsy may confirm the diagnosis
(287). Likewise, sarcoid may be suspected in cases where another etiology is
the masquerade, as in a case of a 6-year-old girl with nodular anterior uveitis
with corneal nodules responding to “anti-inflammation treatment,” which,
after aqueous analysis, turned out to be diffuse infiltrating anterior RB (288).
The course of sarcoidosis is unpredictable with the prognosis of
childhood sarcoidosis not significantly different from that in adults. The
disease is characterized by either progressive chronicity or periods of activity
interspersed with remission, sometimes permanent and spontaneous, or
initiated by steroid therapy. Overall, most affected patients recover with
minimal or no residual manifestations, whereas a small portion have
permanent loss of some pulmonary function or permanent visual impairment.
Some patients die of cardiac or central nervous system (CNS) damage.
The therapy of choice for sarcoidosis in children with multisystem
involvement is oral corticosteroids, which produce rapid symptomatic
improvement but may not affect the long-term prognosis. Corticosteroid
treatment should be instituted in the presence of respiratory symptoms or in
the presence of severe impairment of pulmonary function tests and are the
primary treatment for ocular manifestations of this disease. Methotrexate is a
safe and effective steroid-sparing strategy in children with severe chronic
uveitis who are dependent on but not well controlled by or develop
unacceptable side effects from systemic corticosteroid monotherapy
(289,290).
Other immunomodulatory medications used successfully in the care of
both adults and children with sarcoidosis include azathioprine, cyclosporine,
cyclophosphamide, and the TNF inhibitors infliximab and adalimumab
(145,166,291–295). Some debate exists as to the efficacy of anti-interleukin-
1β therapy with anakinra for Blau syndrome, and studies for EOS or late-
onset pediatric sarcoid uveitis have not been reported to date (296,297).
Intermediate Uveitis
Intermediate uveitis including the idiopathic variant, pars planitis, is
estimated to represent about one-fifth of all cases of pediatric uveitis, with no
definite predilection for race or gender. The prevalence peaks between
childhood and the fourth decade (327). Seventy to ninety percent of cases are
bilateral. About a third of patients with unilateral involvement at the time of
presentation develop bilateral involvement. No inheritance pattern has been
defined, but isolated reports of familial cases support the idea that this disease
may have genetic predispositions (328–337).
Patients with intermediate uveitis generally present with floaters and
blurred vision and typically have a “quiet” and white eye. In some children,
including the preverbal age group, intermediate uveitis is found accidentally
on routine screening or may be found because of leukocoria, amblyopia, or
strabismus. Pain, redness, tearing, and photophobia are signs and symptoms
of anterior segment inflammation, which are seen more commonly in
children with intermediate uveitis than in adults. Moderate to severe cells and
flare, keratic precipitates, posterior subcapsular cataract, band keratopathy,
and even posterior synechiae may be found. Children presenting with
intermediate uveitis have a worse visual acuity both at initial diagnosis and at
follow-up than do adults (338).
Vitreous cells are the most important finding in intermediate uveitis and
are the sine qua non for making the diagnosis. Cellular exudates in the
vitreous and on the pars plana are seen on depressed peripheral examination
of retina in patients with active pars planitis, whereas old cellular debris,
crenated residua of prior vitreal exudates, and a collagen band are generally
present in the patient whose pars planitis is inactive. The terms “snowballs”
and “snowbank” are frequently used in describing examination findings in
this disease; however, we prefer to avoid these terms in practice as they can
be misleading, oftentimes being mistakenly used interchangeably to describe
either active or old inactive inflammatory changes in vitreous and along pars
plana, respectively. Extent of inflammation may vary from a few clock hours,
mostly inferiorly, to 360 degrees of the retinal periphery. Collagen banding
may be acellular or contain fibrous astrocytes, and reflects inflammation
involving the peripheral retina and the vitreous base (339). Although vitreous
and pars plana exudates are not required to make the diagnosis of
intermediate uveitis, they are prominent clinical features of pars planitis and
are found in 74.1% and 66.7%, respectively, in one case series and serve to
delineate pars planitis as a subset of intermediate uveitis (340). The presence
of pars plana exudate is associated with worse visual outcome (341,342).
Other signs of disease include diffuse or peripheral retinal vasculitis with
sheathing of both venules and arterioles (Figure 47-3). Vasculitis may lead to
occlusion, peripheral retinal nonperfusion, and neovascularization of
peripheral retina and optic nerve (343–345).
FIGURE 47-3 Pars planitis. Mid-phase wide field
fluorescein angiogram of the right eye of a 16-year-old
female with active, severe pars planitis demonstrating
periphlebitis in a fern-like pattern with leakage of the
macular and peripheral capillaries, optic nerve head
leakage, and peripheral, inferotemporal nonperfusion.
Adamantiades-Behçet Disease
Adamantiades-Behçet disease (ABD) is a chronic, recurrent–remitting, and
progressive, idiopathic multisystem inflammatory vascular disorder, which is
characterized by the presence of recurrent oral aphthous and genital ulcers,
skin lesions, and intraocular inflammatory disease together with other
systemic findings. The diagnosis is a clinical one based on specific criteria,
which vary depending on the classification system employed (377–379).
Onset is usually after puberty, predominantly in young adults between ages
20 and 40, but there are observations of putative patients with onset before
puberty (380,381). Since Mundy and Miller reported the first pediatric case in
1978, additional reports from different parts of the world have followed, most
of which include small numbers of patients. Even fewer studies compare the
expression of childhood- to adult-onset ABD (380,382–387). Most of these
reports defined pediatric ABD based on age of presentation before 16 years
(387).
There are no definitive diagnostic laboratory findings for the disease. The
diagnosis of ABD relies on the identification of specified clinical criteria as
described by several classification systems; the most commonly employed
are those enumerated by the International Study Group for Behcet’s Disease.
Juvenile-onset disease is characterized by an increase in familial cases, a
lower incidence of severe complications, and a delay of the clinical course; it
is less severe than adult-onset disease, especially because the frequency of
systemic involvement is higher in adults (387–389). A clinical study of ABD
in childhood compared to adult-onset disease showed that all patients had
recurrent oral ulcers, similar ocular and skin lesions, positive pathergy test,
and similar amounts of arthritis, vascular involvement, and recurrent
headaches (390). Genital ulcers were significantly more common in adults, as
were nonspecific GI symptoms and CNS involvement other than headaches.
ABD is classically felt to be a polygenic autoinflammatory disease with
strong association with the HLA-B51 allele along with other newly
discovered risk loci (391). More recently, a separate entity has been
described, which closely mimics ABD, and is caused by an autosomal
dominant mutation in the TNFAIP3 gene encoding the TNFα-induced protein
3 (TNF/AIP3), also called A20. A20 is a down-regulator of the NF-κB
pathway. Mutations lead to haploinsufficiency of A20 (HA20), which in turn
leads to increased production of inflammatory cytokines such as IL-1β, IL-6,
and TNF and facilitation of differentiation and activation of various
proinflammatory lymphocytes including Th17 cells (392,393).
Children with this disorder often meet major criteria for ABD; however,
significant differences exist between this condition and more classical ABD,
including infrequent HLA-B51 association, early age onset (median age 5.5
years), ubiquitous geographic distribution, preponderance of females,
recurrent fever, more significant abdominal findings, and poor response to
colchicine (394). It is unclear as to the extent to which this entity has been
included in previous studies of ABD and requires further investigation to
distinguish the two seemingly separate disorders. At least a similar pathway
may exist between them that may be important in the development of ocular
inflammation, since decreased A20 has been shown in peripheral blood
monocytes and dendritic cells in ABD patients with active versus inactive
uveitis (393).
Age distribution of disease onset in children has been reviewed in several
studies (384–390,395–398). Most patients were Caucasian of Turkish,
Iranian, or European descent with mean age at onset of 8.4 years (0 to 16
years), and mean age at diagnosis of 13 years. A transient neonatal form of
(ABD) disease has been described in infants born to mothers with the
syndrome with three criteria for the diagnosis of (ABD) disease: stomatitis,
genital ulcers, and bullous skin lesions. There is no consensus regarding the
age at which juvenile disease should be differentiated from that in adults, nor
whether juvenile ABD should be defined by fulfillment of the classical versus
updated or new classification criteria (377,378). More recent studies confirm
the following clinical features for children believed to have ABD as
described below (384,398,399).
Buccal aphthosis (painful ulcers found on lip, cheek, tongue, palate,
tonsil, gingiva, and pharynx mucosa) is present in almost all (96% to 100%)
children and may be the presenting symptom in 60% with mean age of onset
of 4 years. Lesions are discrete, round or oval white ulcerations 3 to 15 mm
in diameter with red a rim. Attacks vary from 3 per year to being present
almost constantly. Genital ulcers occur in 70% of cases and are similar in
appearance, usually appearing later in children who are older at disease onset
and affecting the vulva, scrotum, and penis as well as the perianal region
(384,395).
Skin lesions are present in 90% of pediatric ABD patients and include
papules, pustules, acneiform lesions, pyoderma gangrenosum–type lesions,
palpable purpura, hypopigmented areas, and purulent bullae; pustular
eruptions are the commonest skin lesion (400). A pathergy test is positive in
80% of the patients. Arthritis is usually pauciarticular, involving knee, ankle,
hip, metatarsophalangeal joints, the shoulder, and the sternoclavicular joint.
Gastrointestinal (GI) involvement varies widely, depending on region or the
report, and includes abdominal pain, vomiting, flatulence, diarrhea, and
constipation. Radiologic examinations demonstrate thickened mucosal folds,
pseudopolyps, deformity of bowel loops, ulcerations, and fistulae.
Ulcerations are localized or diffuse, with the majority (76%) occurring in the
ileocecal region, and rarely in esophagus (401–404). The vasculitic process
affects both arterial and venous systems. Venous thrombosis has been
observed in 15% of children with ABD, most often in the lower extremities
but can occur in the cerebral circulation, inferior vena cava, and central retina
artery or vein, whereas arterial complications, including aneurysms and
thrombosis, may be fatal. Pulmonary artery involvement can lead to life-
threatening hemoptysis from pulmonary hemorrhage. Pulmonary signs
include generalized lymphadenopathy, parenchymal infarction related to
venous thrombosis, chest pain, and hemoptysis (397). Renal involvement
results in proteinuria and hematuria. Urethritis and orchitis, or epididymitis,
may occur. Myocarditis and arrhythmia may also occur in children with
ABD.
Neurologic signs are present in 15% of pediatric ABD patients and are
the most serious manifestations of disease. They include headache,
meningitis, benign intracranial hypertension, brainstem involvement,
neuropsychiatric symptoms, and meningoencephalitis, hemiparesis or
paraparesis with spastic quadriparesis, and seizures. MRI and CT findings
include ventricular dilatation and hyperintensity signals in the pons,
brainstem, putamen, and upper medulla (390). A cerebral venous and dural
sinus thrombosis may occur (405,406). Cerebral spinal fluid analysis may
show elevated protein and hypercellularity, with lymphocytosis and negative
culture. Organic psychiatric disturbances were reported with severe
neurologic symptoms. Depression, loss of memory, and personality changes
may occur.
Eye lesions are present in 60% of ABD children and include
conjunctivitis, scleritis, uveitis, optic disk edema, retinal vasculitis, and optic
atrophy (407,408). An international collaborative study of 86 cases showed
that uveitis was strictly anterior in 8% of the cases, strictly posterior in 9%,
and panuveitic in 28%, usually bilateral. Eighty-nine percent of patients had
severe uveitis, retinal vasculitis, or both, and uveitis was significantly more
frequent in boys than girls (407). Panuveitis was the most common type of
uveitis in cases with childhood-onset Behçet disease in a study on children
from Turkey. Cataract was the most common anterior segment complication,
and optic atrophy was the most common posterior segment complication
(395). Cataract, maculopathy, and optic nerve atrophy were found to be the
most common complications and seen in over 40% of all eyes each (408).
The choice of medical therapy is based on the severity of the disease. In
general, treatment should be more aggressive when the following are present:
complete ABD, vascular involvement, retinal and bilateral involvement, CNS
involvement, male sex, and a geographic origin in the Mediterranean basin or
Far East. A wide variety of agents have been employed in the treatment of
severe uveitis associated with ocular ABD including corticosteroids,
azathioprine, chlorambucil, cyclophosphamide, cyclosporine, methotrexate,
MMF, α-interferon, and TNF inhibitors such as infliximab, the latter being
the first-line drug of choice by many uveitis experts for this indication (148).
Other treatment modalities have included colchicine, plasmapheresis,
penicillin, thalidomide, and other various biologic medications including
anakinra and rituximab (409–411).
Kawasaki Disease
Kawasaki disease (KD), also known as mucocutaneous lymph node
syndrome, is a primary vasculitis often seen in childhood. It is mediated by
immunoglobulin A (IgA), affects mostly small- and medium-sized vessels,
and can lead to a fibrinoid necrosis in vessel walls (412). The disease
damages the intima layer to perivascular area of vessels, leading to aneurysm
formation in several different stages in a childhood polyarteritis. This is a
systemic vasculitis, but preferentially manifests in coronary arteries (413).
KD is the leading cause of acquired heart disease in children. Although
approximately 80% of patients are <5 years of age, older children and
teenagers may exhibit this disease. KD is more common in boys than girls,
and the majority of cases are diagnosed in the winter and early spring.
Although it is more prevalent among children of Asian and Pacific Island
descent, KD affects people of all racial and ethnic groups.
The cause of KD is unknown. Modified criteria for the diagnosis of KD
include the major criterion of fever persisting for at least 5 days, plus four of
the following five features: changes in peripheral extremities or perineal area,
polymorphous exanthema, bilateral conjunctival injection, changes of lips
and oral cavity or injection of oral and pharyngeal mucosa, and cervical
lymphadenopathy. In the presence of coronary artery involvement detected
on echocardiography and fever, fewer than four of the remaining five criteria
are sufficient (414). Common symptoms leading parents to bring their
children to medical attention include high fever that lasts for 5 or more days;
rash, often worse in the groin area; red bloodshot eyes without drainage or
crusting; bright red, swollen, cracked lips; “strawberry” tongue, which
appears with shiny bright red spots after the top coating sloughs off; swollen
hands and feet and redness of the palms and soles of the feet; and enlarged
lymph nodes in the neck (Figure 47-4).
FIGURE 47-4 Kawasaki disease. A 5-year-old child with
fever for 5 days and diagnosed with Kawasaki disease
with characteristic findings of (A) desquamative rash of
the fingers and feet, (B) rash often worse in the groin area,
and (C) swollen, cracked lips.
Vogt-Koyanagi-Harada Disease
VKH disease is a multisystem disorder involving the ocular, auditory,
nervous, and integumentary systems. Ocular manifestations include most
commonly bilateral granulomatous panuveitis with exudative RDs. VKH
disease is an uncommon cause of uveitis in children. Children with VKH
represented 16% of all children with uveitis in a tertiary referral center in
Saudi Arabia and 8.2% in India (28,450). In the Western Hemisphere, the
disease is rare. Treatment is usually commenced with systemic
corticosteroids with the majority of pediatric patients requiring
immunomodulatory agents. Methotrexate, azathioprine, cyclosporine,
cyclophosphamide, chlorambucil, MMF, and biologic agents such as
infliximab and rituximab may be successfully used to treat pediatric VKH
disease (451,452).
Juvenile Dermatomyositis
Juvenile dermatomyositis (JDM) is a rare autoimmune disease mainly
affecting striated muscle and skin and is also associated with systemic
vasculitis and calcinosis involving the heart, lungs, and gastrointestinal tract.
Symptoms generally include bilateral symmetric proximal muscle weakness
along with dermatologic manifestations such as Gottron papules seen on
hands and knuckles as well as the classic violaceous periorbital heliotropic
rash. Other systemic features may include fever, arthralgia, asthenia,
anorexia, and general malaise. Serum creatine kinase may be significantly
elevated. Overlap features with other diseases may be present, such as
systemic sclerosis, SLE, and mixed connective tissue disease. The incidence
is 3.2 per 1 million children yearly in the United States and is more common
in females. The typical presenting age is between 5 and 10 years. A genetic
susceptibility has been suspected given association with various HLA class I
and class II alleles, such as HLA-DQA1*0501. Unlike the adult form, JDM is
not associated with malignancy (470,471).
Ocular manifestations of JDM include the above mentioned periorbital
heliotropic rash in 45% to 100% (pathognomonic for JDM), steroid-induced
cataracts in 17%, and retinal findings, possibly incidental, in a small number
of patients (472–474). Eleven cases of retinal pathology have been described
in the literature, with findings including diffuse retinal exudates centered over
the macula and optic nerve, intraretinal hemorrhage, macular edema, and a
Purtscher-like retinopathy. We described the first JDM-associated case of
paracentral acute middle maculopathy (PAMM) in a 13-year-old girl,
presenting with inner retinal whitening, macular edema, and Purtscher
flecken. Fluorescein angiography demonstrated bilateral diffuse retinal
perivenous leakage and punctate choroidopathy. OCT showed diffuse
intraretinal and subretinal fluid initially, and later in the course of disease, a
hyperreflective band along the inner nuclear layer and outer plexiform layer
junction became evident. These acute findings resolved completely while the
patient received aggressive IMT from her rheumatologist and left behind
atrophic retinal changes consistent with PAMM (473). Hence, patients with
JDM and vision changes should have a thorough dilated evaluation for
possible retinal involvement.
Polyarteritis Nodosa
Polyarteritis nodosa (PAN) is a necrotizing medium-sized–vessel vasculitis
associated with aneurysmal nodules along the walls of medium-sized
muscular arteries. In adults in Europe and the United States, PAN has an
estimated annual incidence of 2.0 to 9.0/million (475). While rare in
childhood, it is the most common form of systemic vasculitis after Henoch-
Schönlein purpura and KD (476,477). Peak age of onset in childhood is 7 to
11 years, often with a male preponderance. Ocular manifestations include
scleritis, peripheral ulcerative keratitis, and retinal vasculitis, albeit extremely
rare in children. A recent review by Iudici et al. of systemic characteristics in
childhood versus adult PAN showed no ocular findings in their 21 pediatric
patients (478). In addition, patients with deficiency in the protein adenosine
deaminase 2 (DADA2) have been shown to have symptoms, which closely
mimic those of PAN (479).
Sympathetic Ophthalmia
Sympathetic ophthalmia (SO) is a bilateral autoimmune granulomatous
panuveitis, which presents after penetrating insult to the globe, be it
accidental or surgical, as well as nonpenetrating procedures such as proton
beam irradiation. Inflammation ensues, typically 2 weeks to 3 months after
the insult but may occur decades after and is from exposure of uveal proteins
to the systemic immune system that leads to excitation and up-regulation of a
pro-inflammatory T-lymphocyte population. These T lymphocytes can occur
in both the excitatory and sympathizing, that is, nontraumatized, fellow eye.
The incidence was seen to be as low as 0.24% (6/2511) in a southern Indian
cohort of children presenting with open globes over 10 years (489). HLA
associations have been made, including HLA-DRβ1*04, an allele also found
in increased frequency in VKH, to which this disease is often compared
because of similar phenotypic and immunopathologic features.
Clinical examination may show anterior segment findings such as
anterior uveitis and corneal endothelial attenuation with bullous keratopathy.
Posterior segment choroidal thickening, best visualized on enhanced depth
OCT imaging, with multiple white-yellow lesions, known as Dalen-Fuchs
nodules, is seen in about half of patients with disease. Papillitis with optic
nerve hyperemia is also characteristically observed. Complications include
glaucoma, cataract, optic atrophy, and RD. Fluorescein angiography presents
similar to VKH with early multifocal hyperfluorescent patchy leakage and
expand and coalesce late consistent with an exudative RD. Aggressive
topical, regional, or systemic corticosteroid therapy is the mainstay of
treatment for acute disease with early introduction of steroid-sparing IMT in
an effort to prevent and reduce the severity of recurrent inflammatory disease.
Various agents ranging from antimetabolites to biologic therapy have been
successfully employed, including adalimumab and infliximab in treatment-
resistant cases (490,491). Also, the 0.7-mg intravitreal dexamethasone
implant has been shown to have efficacy (209).
Masquerade Syndromes
There are other ocular conditions, both malignant and nonmalignant, that are
not primarily inflammatory in nature but may “masquerade” as uveitis (see
Chapters 44, 45 and 49). Malignancy is an infrequent, but important,
masquerader of pediatric uveitis. Childhood neoplasias that may have
intraocular manifestations include acute leukemias, posttransplant
lymphoproliferative disorders, RB, uveal melanoma, intraocular–CNS
lymphomas, and metastatic cancer. As these malignant entities are
exceedingly rare in the pediatric population, clinicians may fail to even
consider them in cases of steroid-resistant uveitis, and diagnosis and
treatment of the conditions may be delayed. The acute leukemias (acute
myelogenous leukemia and acute lymphoblastic leukemias) may masquerade
as a pediatric uveitis, and intraocular involvement can be the initial
manifestation of systemic disease (492). Intraocular involvement may include
cancerous cells resembling normal lymphocytes within the anterior chamber
and/or the vitreous masquerading as inflammation and even a
pseudohypopyon (Figure 47-5). This mass of leukemic cells is creamy white
in color and may shift depending on the patient’s position. In contrast, a
nonshift or delayed shift is characteristic of a true inflammatory hypopyon
due to fibrin deposition within the white cell mass (493). Cytology obtained
from an anterior chamber paracentesis is consistent with the malignant blood
dyscrasia. A secondary glaucoma from leukemic infiltration of the trabecular
meshwork is rare but can also occur. Diffuse invasion of the iris can produce
heterochromia, and more focal lesions can create the appearance of iris
nodules. Perivascular sheathing and/or avascular leukemic exudates
mimicking retinal vasculitis are frequent findings of posterior segment
involvement (494,495). The choroid is the most common anatomical site
affected with a subretinal mass, serous RD, or diffuse choroidal thickening
most apparent on ultrasound and these findings are highly suggestive in a
patient with a history of leukemia (494,496). These clinical signs are in
contrast to those of leukemic retinopathy in which Roth spots, cotton-wool
spots, and extensive preretinal and retinal hemorrhages are the heralding
features of ongoing thrombocytopenia and anemia (496,497). Orbital
infiltration can also occur in both acute and chronic forms of leukemia and
can range from an insignificant mass to a large, space-occupying lesion. The
presentation of orbital involvement is variable but may include proptosis,
ecchymosis, chemosis, diplopia, visual disturbances, and/or extraocular
motility deficits. Orbital involvement is much more common in acute
leukemias in children than adults.
FIGURE 47-5 Pseudohypopyon in a patient with acute
lymphocytic leukemia.
INFECTIOUS UVEITIDES
Toxoplasmosis
Toxoplasmosis is caused by the obligate intracellular protozoan, Toxoplasma
gondii that may be transmitted by the injection of undercooked meats,
contaminated water, fruit, unpasteurized milk, and/or vegetables, or
inadvertent contact with cat feces or litter or soil containing oocysts. The
organism can also be transmitted transplacentally if primary maternal
infection occurs during pregnancy or through inadvertent direct inoculation
from skin puncture, blood transfusion, or organ transplant. In most cases,
infection with the organism is asymptomatic; however, the parasite is
responsible for as much as 70% of pediatric posterior and panuveitis cases
and is the leading cause of posterior uveitis in all age groups (514).
Congenital toxoplasmosis occurs in approximately 0.23 to 0.50 cases per
10,000 live births in the United States; however, the true incidence may
actually be higher due to lower sensitivity rates of newborn screenings and
fetal losses not included in these data (515). The risk of acquisition is greatest
the later in pregnancy the mother develops acute disease with rates
approaching 60% during the third trimester if left untreated (516). Early
treatment of the mother during pregnancy reduces this risk substantially
(517). On the other hand, the severity of disease is inversely proportional to
the gestational age at time of acquisition. Earlier infections can result in
spontaneous abortions or severe congenital disease. Congenital infections
may cause a wide range of findings including peripheral retinal scars, low
birth weight, jaundice, and the classic triad of convulsions, cerebral
calcifications, and chorioretinitis (518). The virulence of the toxoplasma
strain can vary tremendously based on geographic location resulting in a
spectrum of disease severity worldwide (519). Of the three major clonal
lineages initially described, type II is the most common in North America and
Europe but also the least virulent (520). Atypical genotypes such as those
circulating in Southern Brazil have been shown to cause high rates of ocular
involvement (520). In most cases, congenital infection results in a subclinical
infection with ocular and CNS sequelae appearing much later. In long-term
studies of infants with congenital toxoplasmosis, 85% will develop one or
more episodes of chorioretinitis within 4 years resulting in significant visual
impairment and even blindness (521,522). Historically, it was believed that
the vast majority of toxoplasmic inflammatory foci were the reactivation of
congenitally acquired infection (523,524). More recent observations have
challenged this view such that it is currently held that the majority of ocular
toxoplasmosis is acquired postnatally and that ocular disease can present
following this infection without concurrent systemic signs or symptoms
(525,526). These observations not only underscore a paradigm shift in the
pathogenesis of ocular toxoplasmosis but also suggest a change in the focus
of primary preventative strategies that target children and adults, as well as
pregnant women who may be at risk for developing ocular disease as a result
of postnatal infection.
The diagnosis of toxoplasmic chorioretinitis or congenital toxoplasmosis
in most cases is made clinically by the identification of characteristic lesions
on dilated fundus examination, and in the case of congenital disease, other
systemic findings (Figure 47-7). Serologic evidence is used to support the
diagnosis especially when the ocular findings are atypical. Caution should be
exercised when interpreting IgG antibody levels in any neonate as IgG may
cross the placenta, but IgM cannot. This can result in positive passive titers
for over a year and false-positive tests. Elevated IgM and IgA levels within
the first year of life are indicative of prenatal infection and usually decline to
undetectable levels by the child’s first birthday. The presence of IgG in older
children could be the result of either congenital or postnatal acquisition but is
at least indicative of prior exposure. PCR analysis of aqueous or vitreous
specimens can also help confirm the diagnosis, and in congenital disease, be
used to identify the pathogen within the CSF (527–529). The measurement of
intraocular and serologic antibody titers can be used to establish the
Goldmann-Witmer coefficient with a ratio greater than three being
considered diagnostic of intraocular toxoplasmosis (530). Lastly, tissue
culture techniques have also been used successfully to detect tachyzoites in
vitro (531).
FIGURE 47-7 Congenital toxoplasmosis. A large,
pigmented chorioretinal scar within the macula in a patient
with congenital toxoplasmosis with a satellite lesion
superiorly.
Toxocariasis
Toxocariasis is a worldwide zoonotic disease caused by the roundworm
larvae of Toxocara canis or Toxocara cati. The parasitic worms complete
their life cycles within the small intestines of dogs or cats. Transmission to
humans occurs through contact with infected fomites, fecal–oral routes, or
ingestion of contaminated foods, mainly undercooked meats (540). A history
of pica and/or contact with dogs, specifically puppies, can usually be elicited
in children with toxocariasis. Once the eggs have been ingested, the
roundworm larvae hatch and travel through the bloodstream to the brain,
eyes, heart, liver, lungs, and/or muscles. Most people remain asymptomatic
during this time; however, two forms of toxocariasis can occur: visceral larva
migrans (VLM) or ocular larva migrans (OLM). In VML, a self-limited
condition of fever, pulmonary symptoms (cough, bronchospasms, and
asthma), hepatosplenomegaly, and pronounced eosinophilia occurs in young
children (usually 15 to 30 months old) (541). Pronounced eosinophilia is so
common in this disease that some authors have suggested that patients of any
age with a chronic eosinophilia of unknown origin should be evaluated for
toxocariasis (542–544). In those children that develop VLM, OLM is
unlikely to appear as evident by a large, retrospective study that identified
that only 5% of children with VML developed OLM at any point in time
(540). Furthermore, OLM usually presents in older children (7.5 to 8.6 years
of age), and eosinophilia is not a typical feature (545). However, the disease
has been reported in young adults and those up to the age of 77 (546).
Ocular toxocariasis is most commonly a disease of children presenting
with painless, unilateral vision loss, strabismus, and/or leukocoria. Bilateral
ocular involvement is extremely rare but has been reported (547). The
anterior chamber is usually quiet, and the posterior segment findings can vary
depending on the primary anatomical site of involvement. The four forms of
the disease are as follows: peripheral granuloma, posterior pole granuloma
(Figure 47-8), chronic endophthalmitis, and atypical presentations. The
posterior pole granuloma is the most common presentation and found in 44%
of cases, whereas the localized forms (peripheral and posterior pole
granulomas) are believed to arise from cicatricial changes following
resolution of the acute inflammatory phase of the disease (545). A unilateral
pars planitis with extensive inflammatory exudates is an uncommon variant
of the peripheral granuloma (548). Atypical presentations include
neuroretinitis, mobile subretinal nematodes, scleritis, cataracts, anterior
segment involvement, and a diffuse chorioretinitis (546,549).
FIGURE 47-8 Macular granuloma in the left eye of a
child with toxocara chorioretinitis.
Infants with natal or postnatal herpes infections can be classified into one of
three groups: those involving the skin, eye, and/or mouth; those involving the
CNS; or disseminated disease. Forty-five percent of cases are isolated to
mucocutaneous sites, 30% to the CNS, and the remaining 25% to
disseminated variants (585). CNS involvement may include any of the
following: lethargy, body temperature instability, irritability, seizures, and a
bulging fontanelle with untreated mortality rates as high a 50% (591).
Disseminated disease usually presents with a clinical presentation similar to
that of sepsis with ongoing respiratory and hepatic failure, lethargy, and
disseminated intravascular coagulation and can affect almost any organ
system. Untreated disseminated disease has a mortality rate as high as 85%
with only 50% of those who survive having normal neurologic development
(591). The use of high-dose intravenous acyclovir (60 mg/kg/d) has reduced
mortality rates to 29% in disseminated disease and 4% with CNS infections.
High-dose intravenous acyclovir also substantially improved neurologic
outcomes (592). Ocular manifestations of neonatally acquired HSV include
corneal ulcers and even perforation, anterior uveitis, cataracts, vitritis,
chorioretinitis, optic atrophy, and rarely, persistent fetal vasculature and acute
retinal necrosis (ARN) (589,593,594).
The diagnosis of intrauterine and perinatal herpetic infection is made in
the appropriate clinical context and by isolation of the virus from vesicular
fluid, nasal or conjunctival secretions, whole blood, or cerebral spinal fluid. It
is important to differentiate quiescent or active ocular HSV from other
nonherpetic infectious diseases such as Toxoplasma, rubella, and CMV
infections as the infection and its associated findings may or may not be
present at the time of birth. Diagnosing reactivated ARN in a child may be
especially difficult in cases where there is nonspecific peripherally
chorioretinal scarring with concurrent inflammation. For these reasons, a past
medical history of a neonatal ocular or systemic herpes infection is a key
component to make the correct diagnosis (595). In unclear cases, a diagnostic
paracentesis of the anterior chamber or vitreous biopsy should be performed.
The drug of choice for disseminated (including HSV retinitis) or CNS-
involving HSV infections in neonates is intravenous acyclovir at a dose of 30
to 60 mg/kg/d for 10 days to 4 weeks depending on the age of the child.
Nephrotoxicity is the most frequently encountered side effect of systemic
acyclovir and is more common with doses above 15 mg/kg/d (596). There is
emerging evidence of HSV strains resistant to acyclovir, so an incomplete or
poor response to the drug should warrant further questions including
reevaluating the diagnosis and the possibility of resistance (597). In cases of
ARN, oral valacyclovir at 20 mg/kg may obviate the need for multiple rounds
of intravenous medications (598,599). Vidarabine, which is an equally
effective alternative to acyclovir, may also be administered as a single
intravenous infusion, 15 to 30 mg/kg/d over a 12-hour period, with potential
side effects including hepatic toxicity and bone marrow suppression (600). In
cases in which ARN worsens despite intravenous acyclovir, intravenous or
intravitreal foscarnet or cidofovir are effective alternatives (601).
Varicella–Zoster Virus
VZV is another herpes virus family member that causes two distinct diseases:
a primary cutaneous infection that is usually relatively benign but extremely
contagious during childhood (chickenpox) or a reactivation of the virus
within a sensory dermatome resulting in an eruption of painful, cutaneous
vesicles in older adults (herpes zoster, shingles). Vaccines are currently
available to induce immunity and boost waning vaccine-induced immunity to
the virus (602,603). Ocular-related complications with primary infections or
reactivation of the virus in children include orbital myositis, ARN, keratitis,
orbital apex syndrome, and dacryoadenitis (604).
Congenital varicella is rare, and if acquired within the first 20 weeks of
gestation, can cause congenital varicella syndrome (CVS) in approximately
2% of infants (605,606). The syndrome is defined by one or more of the
following; low birth weight, hypertrophic cicatrix of the skin, hypoplastic
limbs and digits, cortical atrophy, ventriculomegaly, microcephaly, and/or
psychomotor retardation. These children are at risk for developing
intracerebral VZV reactivation later in life (607). If maternal disease should
develop 5 days prior to delivery, mortality may be as high as 50% due to
fulminant systemic disease in an infant with a rudimentary immune system
and the absence of maternally supplied antibodies (608). Ocular findings in
CVS include congenital cataracts, unilateral or bilateral microphthalmia,
pendular nystagmus, chorioretinal scarring, atrophy and hypoplasia of the
optic nerve, Horner syndrome, and bulbar palsies (609,610). Chorioretinal
scarring consists of a central area of pigment clumping surrounded by a halo
of hypopigmentation with normal-appearing retina between scars and is
usually found in the macula or peripheral retina of one eye. The scars may
resemble those seen with congenital rubella, syphilis, and inactive
toxoplasmosis, especially in cases with more posterior involvement. Active
chorioretinitis has never been reported in cases of CVS as the chorioretinitis
has likely resolved by time of delivery.
Congenital disease, primary infections, and reactivation of VZV in
children can result in necrotizing retinitis in which disease severity varies
depending on both host and viral factors (611). ARN syndrome was first
described in 1971 as part of a spectrum of necrotizing herpetic retinopathies
(612,613) (Figure 47-10B). In immunocompetent children, the development
of peripheral retinitis, vasculitis, iridocyclitis, and vitritis defines ARN. A
variant of ARN, progressive outer retinal necrosis (PORN), is seen in the
immunocompromised and is unique in that it may affect the macula initially
with a paucity of intraocular inflammation (614). Although the spectrum of
necrotizing herpetic retinopathies is more common in adults despite
acquisition of the virus during childhood, there are a few case reports in
children with the youngest patient at time of diagnosis being 4 years old
(615–618).
The diagnosis of CVS is essentially clinical with the recognition of the
characteristic defects in the neonate and a history of maternal varicella. In
cases of inactive chorioretinal scars and with an unclear history, other
TORCH (toxoplasmosis, others, rubella, CMV, and HSV [“others” include
syphilis, VZV, EBV, HIV, and lymphocytic choriomeningitis virus
(LCMV)]) infections should be considered. Serologic testing of the infant and
mother may then be pursued based on the clinical history and examination to
identify the offending pathogen. In cases of VZV, the diagnosis is also
clinical with the appearance of the typical vesicular lesions that respect the
midline in the setting of prior exposure. The treatment for CVS is directed
toward reducing the risk of acquisition and by the administration of exposure
prophylaxis in nonimmune mothers and neonates with varicella–zoster
immune globulin (619,620). In infants that acquire the virus after birth,
acyclovir dosed at 30 to 100 m/kg/d should be administered for 5 to 8 days
(621).
Cytomegalovirus
CMV is another extremely common herpes virus that establishes latency
within monocytes with characteristic large intracellular inclusion bodies
(622). It is the most common congenital viral infection affecting one out of
every 200 live births in the United States as reported by the Centers for
Disease Control and Prevention (CDC). Transmission may occur prenatally
during maternal viremia secondary to primary infection or reinfection or due
to reactivation of a latent infection while exposure to genital secretions
during delivery or ingestion of breast milk may produce viral infection during
the natal and postnatal periods (623). A majority of congenital CMV
infections are asymptomatic or subclinical, but intrauterine growth
retardation, thrombocytopenic purpura, jaundice, hepatosplenomegaly,
pneumonia, microcephaly, seizures, and sensorineural hearing loss can occur
(624). The most common intraocular manifestation of congenital CMV is
chorioretinitis with subsequent scarring similar to that seen in toxoplasmosis
(625). As in the adult, CMV retinitis may present as one of three common
variants in children: classical or fulminant retinitis, a peripheral granular
retinitis, and a perivasculitis. In the classic form, there are large areas of
retinal hemorrhage against a background of whitened, edematous, and
necrotic retina, typically appearing in the posterior pole, from the disk to the
vascular arcades in the distribution of the nerve fiber layer (Figure 47-10C).
The granular variant is more often peripheral and characterized by less retinal
edema and hemorrhage with active retinitis appearing at the borders of the
lesion having a “brush fire” appearance. In the perivascular form often
described as a variant of frosted branch angiitis, a retinal perivasculitis
initially described in immunocompetent children, there is predominance of
retinal periphlebitis seen in association with peripheral retinitis (Figure 47-
10D). It is important to recognize these variations in presentation of CMV
retinitis, as the diagnosis is essentially clinical and made in the context of
immunosuppression. Strabismus, cortical visual impairment, nystagmus, and
optic nerve atrophy/coloboma/hypoplasia are other ocular complications of
the disease (626). In this study, symptomatic patients experienced more
ophthalmologic sequelae and significantly worse visual outcomes than did
asymptomatic CMV and control patients. Risk factors of severe visual
impairment were symptomatic status, optic nerve atrophy, chorioretinitis,
cortical visual impairment, and sensorineural hearing loss (626). Ocular
findings are also much more commonly associated with cases of systemic
disease but have also been described in isolation (627,628).
The diagnosis of congenital disease is suggested by clinical appearance of
chorioretinal scarring in combination with inclusion bodies or positive real-
time (RT)-PCR results of urine, saliva, blood, and/or subretinal fluid (629).
RT-PCR and other emerging PCR methods have supplanted more traditional
virus isolation techniques from tissue samples that are both more expensive
and labor intensive (630). Complement-fixation tests for CMV-specific IgM
may be helpful after loss of maternal antibodies that occurs approximately 6
to 12 months after birth. Treatment of clinically significant CMV requires
intravenous ganciclovir and/or foscarnet; however, once therapy is
discontinued, viral shedding in urine and saliva reconvenes (631). In cases
where systemic therapy is contraindicated, intravitreal ganciclovir can be
used for local control (632).
Epstein-Barr Virus
EBV is a ubiquitous double-stranded DNA herpesvirus that is transmitted
through bodily fluids, mainly the saliva, and commonly causes a flu-like
illness in childhood (633). If acquired during adolescence or adulthood, EBV
is most commonly associated with infectious mononucleosis (IM), which
causes a systemic illness with fever, lymphadenopathy, splenomegaly, and
extreme fatigue (633). The virus establishes latency in B lymphocytes where
it may cause cellular transformation and has been implicated in the
pathogenesis in various types of cancer (i.e., Burkitt and Hodgkin
lymphomas, and nasopharyngeal and gastric carcinomas) (634). Ocular
manifestations of EBV may arise from congenital infections, or more
commonly, during primary infection in the context of IM (635). Congenital
cataract has been reported in association with congenital EBV infection
(636). The most common ocular manifestation of IM is a self-limited
follicular conjunctivitis during the early stages of the disease (637).
Episcleritis or stromal or epithelial keratitis may also occur. Less commonly,
a severe, bilateral granulomatous iridocyclitis may appear (638,639). Less
frequent complications of IM include dacryoadenitis, Parinaud
oculoglandular syndrome, conjunctival masses, and cranial nerve palsies
(637,640).
Various posterior segment abnormalities may arise secondary to EBV
including optic disk edema or optic neuritis, vitritis, retinal hemorrhages,
retinitis, choroiditis, and macular edema (Figure 47-10E) (638,641–649).
Case reports of children with primary EBV infections have also described
“punctate outer retinitis” and progressive subretinal fibrosis and uveitis with
secondary choroidal neovascularization (642,643). Most, if not all, of these
cases were associated with clinical IM; however, there are isolated reports,
mainly in adults, of anterior or posterior uveitis without clinical IM. Wong et
al. described three patients ranging from 15 to 30 years of age with serologic
evidence of chronic EBV infection that developed bilateral uveitis, ranging
from steroid-responsive granulomatous anterior uveitis to severe panuveitis,
cataract, optic disk swelling, macular edema, and chorioretinal scarring (644).
Usui and Sakai reported three otherwise healthy young adults with elevated
EBV viral capsid antibody titers in the aqueous humor who presented with a
viral prodrome with the subsequent development of acute, bilateral, fibrinous,
anterior uveitis followed by a chronic, granulomatous inflammatory reaction
marked by disk hyperemia, minimal vitritis, and the development of an early
“sunset glow” fundus. The ocular changes were responsive to systemic
steroids resulting in good visual outcomes in all three cases (639). Finally,
EBV has been implicated but not substantiated in the pathogenesis of certain
uveitic syndromes, including multifocal choroiditis and panuveitis (MCP)
(645,646).
The diagnosis is made clinically and based on serologic analysis of
antibodies against a variety of EBV-specific capsid antigens. During IM, the
VCA IgM antibody, followed by the VCA IgG antibody, rises during viral
incubation 4 to 5 weeks following exposure to the virus to a maximum IgG
titer approximately 120 days after symptom onset. The early antigen (EA)
rises with the onset of clinical disease usually within 5 to 10 weeks of
exposure and rises to a maximum approximately 2 months after exposure.
The antibody titers fall to undetectable levels 6 to 12 months after resolution
of the infection. The EBV nuclear antigen antibody appears slowly within 2
months and persists for life, whereas the VCA IgM titer falls to undetectable
levels after resolution of the infection. The diagnosis of chronic EBV
infection is best supported by abnormally elevated anti-VCA IgM and anti-
EA antibody levels (647,648). Most ocular disease is self-limited and does
not require treatment. However, the presence of iridocyclitis may necessitate
the use of topical corticosteroids and cycloplegia, and systemic steroids may
be required to treat posterior segment inflammation. Little is known
regarding the efficacy of antiviral therapy for ocular involvement, and their
use is controversial even in severe systemic infections among
immunocompetent patients (650).
Rubella
The rubella virus is an enveloped, single-stranded RNA virus of the
Togaviridae family that is highly contagious and spread through aerosolized
droplets to cause rubella (German measles). In most cases, the virus causes a
mild illness of a low-grade fever, sore throat, conjunctivitis, and
maculopapular rash that starts on the face and spreads to involve the patient’s
entire body. The disease is exceedingly rare in the United States due to
widespread vaccination programs (651). In adults, the demonstration of
rubella virus in the aqueous humor of patients with Fuchs uveitis syndrome
and the concurrent decline in its incidence concurrent with widespread
vaccination against the virus in the United States has implicated it in the
pathogenesis of this syndrome (652–654). In contradistinction, congenitally
acquired rubella is associated with more significant morbidity including the
classic triad of sensorineural deafness, eye abnormalities, and congenital
heart defects. The risk of congenital birth defects is greatest if the virus is
acquired during the first trimester. Ocular findings include unilateral or
bilateral pigmentary retinopathy (“salt-and-pepper”) in 25% to 50%, cataracts
in 15%, and glaucoma in 10% (655,656). The salt-and-pepper fundus can
range from finely stippled, black, bone spicule-like irregularities to gross
pigment changes with coarse mottling. These posterior segment findings may
be stationary or progressive. Even with extreme pigmentary abnormalities
and loss of the foveal light reflex, vision and ERG usually remain unaffected.
Congenital cataracts, the development of glaucoma, and microphthalmia are
the most common causes of vision loss (657).
Rubella is part of the TORCH group of pathogens, and thus, an important
cause of congenital disease. A detailed clinical history including pregnancy
history, serologic evidence from both the mother and child, and retinal
examination findings are important in differentiating the various TORCH
pathogens and in the diagnosis of the congenital rubella syndrome. A
fourfold increase in antirubella IgG titers between paired sera 1 to 2 weeks
apart or the emergence of IgM titers is diagnostic for an ongoing or recent
rubella infection (655). Cord blood may be used to confirm the diagnosis, as
the fetus is capable of mounting an immune response to the virus. Treatment
of rubella is guided by the specific ocular findings and symptoms including
both surgical and medical treatment of glaucoma and cataract surgery.
Measles Virus
The measles virus is a highly contagious, enveloped, single-stranded RNA
virus that is transmitted either directly or via aerosolization of
nasopharyngeal secretions to mucus membranes of the conjunctiva or
respiratory tract of susceptible individuals. Humans and monkeys are the only
natural hosts. Acquired infection results in a self-limited prodromal phase
exemplified by high fever, fatigue, cough, coryza, and conjunctivitis, which
is followed by a maculopapular rash that develops first on the face and
quickly spreads centrifugally to the rest of the body (676). The early signs
and symptoms of cough, conjunctivitis, and coryza, define the classic triad of
measles. Clustered, blue-white lesions surrounded by red areolae develop on
the buccal mucosa (Koplik spots) or on the conjunctiva (Hirschberg spots)
within a few days and just prior to the onset of the rash. Patients are
contagious 4 days prior to the rash and remain contagious 4 days after the
rash appears. Measles can also be transmitted transplacentally from the
infected mother. However, the disease is usually one of childhood and a
vaccine against the disease had nearly eradicated the disease from the United
States until recently, when some parents have refused to vaccinate their
children (677,678). This has led to the reemergence of the disease and a
localized loss of herd immunity (677).
The most common ocular manifestations of measles are mild, papillary,
nonpurulent conjunctivitis and epithelial keratitis. In the United States, both
the keratitis and conjunctivitis resolve without sequelae; however, in other
parts of the world, “postmeasles blindness” can occur with corneal
complications leading to severe visual impairment. Measles retinopathy may
also occur and is more common in acquired cases of the disease. Retinopathy
manifests 6 to 12 days after the appearance of the exanthema in the presence
or absence of encephalitis. Ophthalmic findings include attenuated arterioles,
scattered retinal hemorrhages, diffuse retinal edema, a macular star, blurred
disk margins, and clear media (679). Following resolution of systemic and
ocular symptoms, optic disk pallor, persistence of arteriole attenuation with
or without perivascular sheathing, and a pigmentary retinopathy with either a
“bone spicule” or “salt-and-pepper” appearance develop in the posterior pole.
A retinopathy of pigmented paravenous retinochoroidal atrophy with visual
field and ERG abnormalities developing years later has also been described
as long-term sequela (680).
In patients with acute retinopathy from measles, fluorescein angiography
is likely to show diffuse leakage from retinal edema. In the resolving phases
of the disease, generalized choroidal hyperfluorescence is found due to retinal
pigment epithelial disruption (680). Widespread retinal dysfunction results in
an extinguished ERG during the acute phase. Similarly, visual field changes
may include severe, generalized constriction, ring scotomas, or small
peripheral, residual islands of vision. Useful vision and ERG activity may
return following resolution of acquired measles retinopathy; however, the
visual prognosis is guarded (679,680). In one study, 43.7% of students in
blind school institutions were severely visually impaired as a consequence of
measles infection (681).
The diagnosis of measles and attendant ocular sequelae is made clinically
by observation of the sequence of symptoms. The virus may be recovered
from the nasopharynx, conjunctiva, lymphoid tissues, respiratory mucus
membranes, urine, and blood for a few days prior to the appearance of the
rash and for several days thereafter (682).
Leukopenia is common during the prodromal phase of the disease. A
variety of tests are available for serologic confirmation of measles infection,
including complement fixation, ELISA, immunofluorescent and
hemagglutination inhibition assays. The differential diagnosis of measles
retinopathy includes VKH syndrome, toxoplasmic retinochoroiditis, central
serous chorioretinopathy, retinitis pigmentosa, Leber stellate idiopathic
neuroretinitis, and other viral retinopathies. These diseases can be readily
distinguished with a detailed patient history, differences in clinical findings,
and serologic testing.
The treatment of measles is supportive as the disease is generally self-
limited. In certain high-risk populations such as the immunocompromised,
children under 1, and pregnant women, gamma globulin administered within
5 days of exposure may prevent the disease, and its use was supported by a
recent Cochrane review (683,684). Likewise, the ocular manifestations of
measles are treated symptomatically with topical antiviral or antibiotics to
prevent secondary infections in patients with keratitis or conjunctivitis.
Consideration should be given to the use of systemic corticosteroids for cases
of acute measles retinopathy. Finally some have suggested that in children
with severe cases of measles, intramuscular vitamin A should be provided to
prevent vision loss; however, there are insufficient data to support this
recommendation (685).
Syphilis
Syphilis is an uncommon cause of uveitis in the pediatric age group with
ocular involvement occurring in both the acquired and congenital forms of
the disease as a result of infection with the spirochete, Treponema pallidum.
Acquired infection is most commonly due to sexual contact with infected
individuals. The progression of untreated, acquired syphilis has been well
described, the signs and symptoms of both ocular and systemic disease
varying with the stage of the disease. Classically, the primary infection is
characterized by a single chancre teeming with spirochetes that erupts
approximately 3 weeks after exposure and spontaneously resolves within 12
weeks. Six to eight weeks following the appearance of the chancre, the
disseminated portion of the disease, secondary syphilis, appears as a diffuse
maculopapular rash involving both the palms of the hands and soles of the
feet and generalized lymphadenopathy. Multiple organ systems including the
eye can be involved during this stage with uveitis occurring in approximately
10% (735). Latent syphilis then develops and is defined by positive serologic
markers of infection in asymptomatic patients; however, congenital
transmission is still possible during this time (736). One-third of untreated
patients with latent syphilis will progress to tertiary syphilis with
manifestations of gummas, noncancerous growths, obliterative endarteritis,
and cardiac and neurologic abnormalities years to decades later. Intraocular
inflammation may occur in any stage of the disease and should regarded as
neurosyphilis.
Congenital syphilis may arise either due to transplacental infection after
the 10th week of pregnancy or, less commonly, through direct contact with a
genital chancre during birth. Acquired disease in a child should raise
questions of sexual abuse or precocity. Furthermore, any child found to have
acquired HIV due to sexual abuse should be evaluated for syphilis due to
high rates of coinfection (736). Pregnant women with untreated or
inadequately treated syphilis may transmit the spirochete to their fetus during
any stage of disease and time throughout pregnancy. In fact, untreated
women have about a 70% chance of transmitting the infection to their fetus
during the first 4 years of disease (737). In general, the longer the interval
between maternal infection and pregnancy, the more benign the outcome in
the infant (Kassowitz law) (738). If the infection is transmitted late in
pregnancy, the infant may appear completely normal at birth, and if left
untreated, develop manifestations of the disease over time (739). For this
reason, the CDC recommends that all pregnant women be tested for syphilis
(non–treponemal-based testing) during their first prenatal visit, and if at risk
of contracting the disease, again during the third trimester (740). If
nontreponemal testing is positive, confirmatory treponemal serology should
be performed with complete medical evaluation. Although this strategy will
fail to detect primary maternal syphilis acquired late in pregnancy, a careful
prenatal examination of the mother for signs of infection and prompt
treatment may mitigate this risk. Another important consideration is the
development of the “prozone” effect when nontreponemal antibody titers are
so high that the test is erroneously interpreted as negative if not properly
diluted (741). Maternal surveillance is paramount to reducing the risk of
congenital syphilis in the neonate.
The prevalence of syphilis drastically declined with widespread
availability of penicillin following World War II. In 2000 and 2001, the CDC
reported the lowest rates of syphilis since reporting began in 1941. Despite
continued efforts to reduce disease burden further, syphilis rates have instead
risen since 2001, and in 2015–2016 alone, the rate among women rose
35.7%. This mirrors the rise in congenital syphilis cases that have increased
86.9% from 2012 to 2016. In total, of 628 cases of congenital syphilis and 41
stillbirths were reported in 2016, due in large part to an absence of testing
among pregnant until late in pregnancy, if at all (742,743). Syphilis should be
always be in the differential of any patient with unexplained intraocular
inflammation, including young children, as a delay in diagnosis and treatment
can lead to significant ocular and systemic morbidity, especially considering
that the infection is curable with appropriate antibiotic therapy and the
disease is on the rise in the United States.
The clinical manifestations of congenital syphilis have been arbitrarily
divided into early and late onset (after age 2) (738). The most commonly
reported systemic findings in early congenital syphilis include desquamative
skin rash, low birth weight, failure to thrive, severe anemia, generalized
lymphadenopathy, distended abdomen, hepatosplenomegaly, radiographic
evidence of characteristic and symmetric long bone changes of the lower
extremities, and pneumonia (738). Other less common manifestations include
rhinitis, bloodstained coryza or snuffles, and CNS involvement such as
meningitis, hydrocephalus, cognitive delay, and seizures. Late manifestations
of congenital syphilis develop as the result of scarring from early systemic
disease and include fissures and mucous patches (rhagades), Hutchinson
incisors, mulberry molars, perforation of the hard palate, abnormal facies,
bossing of the frontal and parietal bones, saber shins, progressive
sensorineural deafness, and neurosyphilis (737). Cardiovascular
complications are an uncommon complication of congenital syphilis.
Ocular manifestations of congenital syphilis are uncommon but
increasing in frequency according to retrospective data analysis and in line
with the rising caseload of the disease (744,745). Ocular inflammation related
to congenital syphilis may be present at birth or not present for years.
Spirochetes have been isolated from aqueous humor, choroid, retina, and
inflamed corneal stroma of neonates with congenital syphilis (746,747).
Ocular findings of congenital syphilis include uveitis, interstitial keratitis,
iridoschisis, congenital cataracts, optic neuritis, and glaucoma (748).
Nonulcerative interstitial keratitis (IK) is the most common inflammatory
finding of untreated, late congenital syphilis (20% to 50% of cases) and is
usually accompanied by anterior uveitis (749). IK is more common in girls
and is typically bilateral in congenital cases while unilateral in acquired
disease. The most common uveitis is a multifocal chorioretinitis, and less
commonly, retinal vasculitis that results in the development of a salt-and-
pepper fundus (750). The salt-and-pepper appearance is due to alternating
RPE hyperplasia and atrophy usually most prominent in the peripheral fundus
but may include the entire retina.
In acquired syphilis, intraocular inflammation may occur as an isolated
finding in any anatomic region of the eye (anterior, intermediate, posterior or
panuveitis), but most commonly presents with posterior segment findings,
including vitritis, papillitis, neuroretinitis, chorioretinitis, necrotizing retinitis,
and retinal vasculitis. Two distinctive posterior segment presentations
deserve special mention: acute syphilitic posterior placoid chorioretinitis
(ASPPC) and panuveitis with superficial retinal precipitates as their
biomicroscopic and imaging findings are highly suggestive of the diagnosis
of ocular syphilis (751–753) (Figure 47-15). In ASPPC, uniform inner/outer
choroidal inflammation manifests as discrete, nonelevated, pale yellow,
oval/circular lesions in the posterior pole that, on fluorescein angiography
(FA), become progressively hyperfluorescent, while indocyanine green
angiography (ICGA) shows confluent hypofluorescence. OCT of these
lesions demonstrates focal thickening and nodularity of the RPE with
disruption of the overlying IS-OS junction, which resolves with treatment
(Figure 47-15) (752,754,755). These findings warrant a lumbar puncture and
treatment with intravenous penicillin G.
Lyme Disease
LD is a multisystem disorder caused by the spirochete Borrelia burgdorferi
sensu lato (773). The disease was first recognized in 1975 and is now
considered the most common vector-borne disease of Europe and the United
States (774,775). According to the CDC, in 2016 there were 26,203 proven
cases of LD and another 10,226 that were considered probable cases. Boys
aged 5 to 9 years are the most commonly affected (776). The clinical course
of systemic LD has been divided three stages analogous to that of syphilis.
Early disease is characterized by the development of constitutional
symptoms, an expanding targetoid-appearing macular rash known as
erythema chronicum migrans within 2 weeks at the site of the tick bite in
60% to 80% of individuals (stage 1). If left untreated, the spirochete
disseminates (stage 2) to cause arthralgias (monoarticular or oligoarthritis
with preference for the knee); facial nerve palsies, meningitis, and
atrioventricular heart block may ensue (777). The disease can then progress
to cause persistent arthritis, polyneuropathies, encephalopathy, and frank
psychosis in late LD (stage 3) (777,778).
Ocular findings associated with LD vary with the stage of the disease
(779). The most common ocular finding in stage 1 of the disease is a
follicular conjunctivitis, and keratitis predominates the persistent stages
(780). Intermediate uveitis is the most common intraocular manifestation
during stages 2 and 3 of the disease in adults (781). A granulomatous anterior
chamber reaction, severe vitritis, papillitis, neuroretinitis, choroiditis, and/or
panuveitis may also occur (782–784). In children, case reports have described
an isolated anterior uveitis; however, anterior chamber reactions are much
more common in association with cases of keratitis or intermediate uveitis
(782–789). Intermediate uveitis is rare in pediatric LD (790). LD can also
rarely cause ocular motor abnormalities, paralytic strabismus, optic
neuropathies, posterior uveitis with fibrosing scars of the macula, and an
acute transverse myelitis in children (791–794). In a cohort of 84 children
with LD-associated arthritis from Europe, only 4% of patients developed
ocular involvement (1 each of keratitis, anterior uveitis, and intermediate
uveitis) (785). The authors concluded that regular screening examinations
were unnecessary due to the very low rate of affected children (785). This is
in contradistinction to the most important differential diagnosis in LD-
associated uveitis, JIA-associated uveitis, in which screening guidelines for
the detection of intraocular inflammation have been recommended for all new
diagnoses of JIA.
The diagnosis is clinical with identification of residence in or travel to
endemic areas, exposure to blacklegged ticks, and objective physical
examination findings (erythema chronicum migrans). Laboratory data are
used to support the presumed diagnosis as the tests available lack
standardization of positive values and cross-reactivity among the various
spirochetes causes high rates of false-negative and false-positive results. Due
to this, the CDC currently recommends a two-step test to diagnose LD. The
first step is an enzyme-linked immunosorbent assay or indirect
immunofluorescence assay. If the first step is positive, a Western immunoblot
should be performed as the second step. The results are considered positive
only if both steps are positive. PCR-based assays have been successfully used
to amplify both genomic and plasmid B. burgdorferi DNA from a variety of
tissues, including ocular fluids, and the highest yields are obtained from skin
(782,795). LD-associated intraocular inflammation should be considered a
manifestation of CNS infection and careful neurologic evaluation including a
lumbar puncture is required in these cases. Antibiotic dosing should be dosed
for CNS involvement and guided by an infectious disease expert.
If the tick is removed within 36 hours of implanting, the transmission of
LD is significantly reduced (796). If LD should develop, prompt
administration of antibiotics, preferably doxycycline, is usually curative
(797). In children under age 8 in whom doxycycline is contraindicated,
amoxicillin, cefuroxime, and azithromycin are other options. In more severe
infections, intravenous ceftriaxone should be considered. In cases where there
is intraocular involvement, topical corticosteroids and mydriatics should be
used to quiet an anterior chamber reaction while under appropriate antibiotic
coverage. Systemic corticosteroids have been used in the management of LD;
unfortunately, their use is controversial due to higher rates of treatment
failures. As with syphilis, a Jarisch-Herxheimer reaction, a hypersensitivity to
spirochete antigens released during the first 24 hours of treatment that cause
constitutional symptoms and increased intraocular inflammation, may
complicate antibiotic treatment. In these cases, local and/or systemic
corticosteroids may be required, but resolution without long-term visual
sequelae occurs in the majority of cases with observation alone.
Tuberculosis
TB kills over a million people per year worldwide (798). According to the
CDC, in 2017 there were 9,093 cases reported in the United States, a decline
from 2016 and the lowest count on record (799). Foreign-born children and
adults are much more likely to have TB than U.S. born peers (799). In the
United States in 2016, children (<15 years old) represented approximately
4% of all TB cases with those aged 10 to 14 years having rates of
extrapulmonary involvement approaching 35% according to the CDC (799).
Fortunately, TB-related ocular and systemic diseases are relatively
uncommon in the United States. Although TB is considered one of the “great
mimickers” of various other uveitis entities and may cause intraocular
inflammation in any anatomical subtype of uveitis, ocular involvement is
uncommon even in parts of the world where TB is endemic (Figure 47-16)
(800). Nevertheless, TB should always be considered in the differential of
new onset of uveitis and excluded in children being considered for treatment
with IMT, particularly with TNF inhibitors. Ocular TB has been identified in
children as young as 1 year of age and in children with disseminated disease
(801,802). In areas of the world where TB is much more common, clinical
observations have noted worse intraocular inflammation from TB in children
compared to adults and thus children require more aggressive anti-
inflammatory treatment (803).
FIGURE 47-16 TB-associated macular star and choroidal
granuloma. A large macular star associated with active
tuberculosis. Inset shows a choroidal granuloma within the
macula in this same patient.
Catscratch Disease
CSD is a feline-associated zoonotic disease caused by a genus of gram-
negative bacilli known as Bartonella. There are currently 21 recognized
species with eight known to cause disease in humans. The most well known
is Bartonella henselae, a pathogen distributed worldwide and responsible for
CSD and the principal cause of neuroretinitis (805). CSD, as its name
implies, is transmitted most frequently from immature cats to humans
through a bite or scratch; however, there are confirmed cases where no
animal encounter can be elicited (806). The syndrome is defined by regional
lymphadenopathy, low-grade fever, and an erythematous papule or pustule
that develops within 3 to 10 days of exposure at the inoculation site. The
systemic signs and symptoms such as lymphadenopathy and fever develop 1
to 2 weeks after the local pustule has appeared (807). CSD occurs in the
immunocompetent of all age groups, but the highest age-specific incidence is
found among children (808). In fact, B. henselae is one of the most common
causes of chronic lymphadenopathy in children (808).
Ocular manifestations of CSD occur in approximately 5% to 7% of
patients, and the most common is Parinaud oculoglandular syndrome in
which there is fever, a unilateral granulomatous conjunctivitis, and ipsilateral
preauricular lymphadenopathy (809,810). Facial nerve palsies and Horner
syndrome have also been recorded (811,812). Intraocular manifestations
include unilateral or bilateral neuroretinitis, optic neuritis, optic neuropathies,
inflammatory and vascular lesions of the optic nerve, vascular occlusions,
uveitis (anterior, posterior, or panuveitis), multifocal chorioretinitis, and
serous detachments of the macula (Figure 47-17) (813–823).
FIGURE 47-17 Neuroretinitis in a patient with catscratch
disease. Optic disk swelling, moderate vascular
engorgement, and partial macular star right eye.
Conclusions
Uveitis in children is relatively common in ophthalmology clinics and has a
devastating impact on their lives, those of their families, and society as a
whole. Despite significant advances the diagnosis, management, and the
availability of new therapeutic agents, legal blindness still occurs in around
8% to 10% of cases (15,840). With the concerted efforts of uveitis specialists,
pediatric ophthalmologists and pediatric and adult retina specialists, pediatric
rheumatologists, and pediatricians, this risk of lifelong blindness is
potentially modifiable through earlier diagnoses, referrals to subspecialists,
and aggressive measures to suppress intraocular inflammation and place it in
remission. The broader armamentarium of anti-inflammatory drugs with the
introduction of biologic agents has expanded our therapeutic options;
however, postsurveillance marketing and randomized controlled trials are
necessary to minimize risk of harm and define efficacy of these newer
immunomodulatory agents in this vulnerable population. The novel
applications of imaging modalities such as OCT and laser-flare photometry to
more quantitatively assess inflammation and a reassessment of the current
screening guidelines may serve to more accurately identify those children at
greatest risk of vision loss and the development of ocular complications.
Moving forward, the use of real time, quantitative, PCR-based assays will
help to classify more infectious causes of uveitis especially for cases of
unsuspected or unusual pathogens (707). Moreover, the advent of unbiased
metagenomic deep sequencing may identify infectious organisms (fungi,
parasites, DNA and RNA viruses) in eyes with otherwise idiopathic or
undifferentiated uveitis requiring very small volumes of intraocular
specimens, possibly changing our paradigms of the etiopathogenesis for
many uveitic entities (841).
Lastly, we propose the following changes or areas of emphasis to help
identify children at risk of developing uveitis and the complications related to
ocular inflammation that would benefit from early referral to specialists in the
field:
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48
Surgical Approaches to Uveitis
Stavros N. Moysidis, Edward H. Wood, Baruch D. Kuppermann,
and Lisa J. Faia
INTRODUCTION
Pediatric uveitis is a subspecialty of vitreoretinal diseases within the field of
ophthalmology, which may be due to infectious and noninfectious etiologies.
The goal of treatment is to achieve control of ocular inflammation, whether
by local therapies, systemic corticosteroids, or other immunomodulatory
drugs. The workup and treatment vary based on the patient and etiology of
the uveitis and are based on the best clinical judgment of the physician.
Occasionally, surgical intervention is necessary in a child with uveitis.
Diagnostic surgery may be needed in the pursuit of the underlying diagnosis.
Therapeutic surgery may be needed to treat the sequelae of chronic
inflammation, including vitreous hemorrhage, iridocyclitic membranes,
epiretinal membranes, retinal detachments, and hypotony. The
implementation of small-gauge instrumentation has allowed for an expansion
of the indications for surgical intervention in pediatric uveitis. Prior to the
advent of 23-gauge vitrectomy, there was a higher incidence of postoperative
complications in these patients, including uncontrolled inflammation,
hypotony, and phthisis. Advances in small-gauge instrumentation have
contributed to safer surgical intervention in uveitic eyes. In addition to
surgical advances, more aggressive control of chronic and recurrent
inflammation by ophthalmologists using systemic immunosuppressants has
led to improved outcomes (1,2).
Corticosteroids and systemic immunosuppression play critical roles in the
treatment of pediatric uveitis. Tight control of intraocular inflammation can
prevent irreversible complications of uveitis. Aggressive treatment with high-
frequency topical corticosteroid dosing is crucial at the onset of
inflammation. Periocular, intravitreal, or systemic corticosteroids may also be
needed to achieve control of the inflammation. Steroids should be tapered
when possible, and patients should be monitored for adverse effects related to
chronic steroid use. Patients who are on steroids long-term may require
immunosuppressant medications to allow for tapering of the steroid, as long-
term steroid use is not recommended in the pediatric population. The treating
ophthalmologist may need to coordinate care with a rheumatologist or
primary care physician for immunosuppressant therapy and the monitoring of
toxicity with physical examination and laboratory testing (see also Chapter
47).
The decision to pursue therapeutic surgery in a child with uveitis should
be carefully considered (Table 48-1). Surgery in a pediatric eye with chronic
or recurring inflammation is a daunting task and is accompanied by unknown
intraoperative risks and an uncertain postoperative course (3,4). In order to
try to eliminate as many postoperative complications as possible, these eyes,
if possible, should have at least 3 months of quiescence of their disease
before surgical intervention. Surgery alone can be daunting without also
having to deal with the postoperative complications, which can result in the
loss of the eye. Surgery in these eyes can be technically challenging due to
corneal opacification, posterior synechiae, delicate iris vasculature,
hemorrhage diathesis, iridocyclitic membranes, and miotic pupils (5). The
combination of the pediatric heightened immune response and a uveitic eye
may result in a recalcitrant postoperative inflammatory response and may
lead to hypotony or phthisis. The decision to operate must be carefully
weighed.
DIAGNOSTIC SURGERY
Diagnostic surgery may be necessary to establish the etiology of uveitis.
Diagnosis begins with a careful history, ocular examination, and focused
laboratory testing with an understanding of the natural history of the patient’s
disease and potential complications. A diagnostic surgical procedure may be
reasonable if (a) the history-taking, examination, and noninvasive workup
have failed to reveal the underlying diagnosis; (b) the patient is not
responding to medical therapy and the diagnosis is being reconsidered; (c) the
patient develops significant complications during treatment and additional
diagnostic information is needed to guide therapy; or (d) malignancy is
suspected.
Indications
Anterior chamber paracentesis is safe and easily performed; it provides a
small volume of aqueous humor for laboratory analysis. Inflammation leads
to breakdown of the blood–ocular barrier and can lead to higher than normal
antibody titers and immunoglobulin concentrations in the aqueous humor. To
compare antibody concentrations in aqueous and serum, both samples must
be obtained on the same day. The Goldmann-Witmer (GW) coefficient can be
used to determine whether there is a localized ocular antibody production; it
is measured by enzyme-linked immunosorbent assay (ELISA) and defined as
GW = A/S, where A is the specific antibody concentration in the aqueous
divided by the total IgG in the aqueous and S is the specific antibody
concentration in the serum divided by the total IgG in the serum (Figure 48-
1) (7).
Procedure
In a child, anterior chamber paracentesis may need to be performed under
anesthesia, but it varies based on the age and the individual patient’s ability
to remain still for the procedure. The anterior chamber is entered at the
limbus with a 30-gauge needle on a 1-cc syringe, and about 0.2 mL of
aqueous humor is removed. The aqueous can be sent for cell studies,
antibody measurement, bacterial or fungal culture, or viral antigen detection
with polymerase chain reaction. A vitreous sample may be higher yield in an
infectious workup.
Vitrectomy
Indications
Diagnostic vitrectomy may be considered when less invasive methods have
failed to establish a diagnosis. This is especially important for patients who
are not responding to medical treatment for the presumed diagnoses, patients
who are developing complications from current therapies, or in the case of a
suspected malignancy or other masquerader. The goal of the diagnostic
vitrectomy is to determine the etiology of inflammation in order to guide
treatment. A vitreous specimen may be obtained by direct aspiration,
typically performed using a 25- or 27-gauge needle through the pars plana or
by surgical vitrectomy. A diagnostic vitrectomy may be preferable to direct
aspiration, as it is more controlled; allows for a larger sample; and carries a
lower theoretical risk of retinal tear or detachment than direct aspiration and
traction on the more adherent vitreous base.
Procedure
A diagnostic vitreous sample is obtained via a three-port vitrectomy. A
longer infusion (4 to 6 mm) may be required in eyes with uveitis, as patients
may have scleral thickening, choroidal edema, or retinal separation that may
result in inadvertent suprachoroidal infusion placement (7). Direct
visualization of the infusion cannula within the vitreous cavity is critical prior
to turning on the infusion.
The initial specimen in a diagnostic vitrectomy should be obtained before
turning on the infusion, so that the sample is undiluted. A sample of vitreous,
typically 0.5 to 1 mL, depending on the child’s age, can be obtained with the
vitrector on low suction and with the infusion turned off. The specimen can
be aspirated directly into a syringe from the vitrector. Next, the infusion line
is opened and 1 mL of vitreous and fluid is aspirated into a separate syringe
from the vitrector. A therapeutic vitrectomy, again, depending on the child’s
age, may then be performed, if necessary. Although it may be beneficial for
the adult patient to have a posterior vitreous detachment induced at the time
of surgery, this is not the case in a child, because the strong adherence of the
vitreous to the retina may cause a retinal tear or detachment.
Both the undiluted vitreous sample and the diluted vitreous aspirate
should be immediately sent for microbiologic and cytologic analysis.
Millipore filtration can be performed on the dilute sample to concentrate any
microorganisms and cellular elements (2). Immunohistochemistry can be
performed and cellular specimens can be sorted for monoclonality and cell
subtyping. Polymerase chain reaction and cDNA probes may be used to
detect DNA from many infectious agents, such as the herpetic viruses and
Toxoplasma gondii. If flow cytometry is indicated, Roswell Park Memorial
Institute (RPMI) solution (Thermo Fisher Scientific, Grand Island, NE)
should be obtained from the flow cytometry lab on the day of surgery, and
the concentrated sample of vitreous cells should be immediately stored in the
RPMI solution and sent to the flow lab. Otherwise, samples should be sent
fresh and not in any fixatives.
Indications
In some conditions, the infectious or inflammatory process is localized
primarily to the retina or choroid, and aqueous or vitreous testing may be
negative. Chorioretinal biopsy may be considered in patients with sight-
threatening disease or inflammation refractory to medical treatment.
Procedure
The retinal or chorioretinal biopsy site should be selected to maximize the
diagnostic value and minimize potential complications. Biopsy sites located
in the superior retina allow for better and longer gas tamponade, although gas
is not necessarily needed during these cases. An optimal chorioretinal biopsy
is performed at the border of normal retinal and active retinal disease to
afford the pathologist more clinical information.
A vitrectomy is performed, and the retinal or chorioretinal biopsy site is
identified. In rare cases where there is simultaneously a retinal detachment,
retinal scissors or the vitrector can be used to perform the biopsy. In most
cases, the retina is attached; in those cases, a retinotomy can be made, and
saline can be injected subretinally to create a bleb. If the retinotomy is large
enough, retinal forceps can be used to grasp the tissue and remove it. If
visualization is not sufficient, a partial retinectomy can be performed to gain
access to the biopsy site (7). The intraocular pressure (IOP) may be elevated
to minimize bleeding. Endodiathermy may also be used for a deeper
chorioretinal biopsy to ensure hemostasis. If a bimanual technique is
required, a chandelier can be used for lighting, but it is not required in most
cases (8). The specimen should be removed with care, so that the specimen is
not lost in the trocar or the sclerotomy. The physician should keep in mind
the gauge of the instrumentation; a larger specimen may be more difficult to
remove through a 25-gauge trocar (0.55 mm) than a 23-gauge trocar (0.72
mm). Alternatively, the trocar can be removed and pulled out over the forceps
as the forceps is being removed from the eye, so as to allow the specimen to
exit through a larger space, directly through the sclerotomy. In rare cases, a
larger scleral incision can be made in order to remove the specimen with as
little damage as possible and closed with nylon sutures. A fluid–air exchange
is then performed, and all retinal breaks are treated with endolaser. Some
physicians prefer to perform endolaser prior to creating the retinotomy. Many
physicians will then exchange air with gas for tamponade, but for smaller
retinotomies, leaving the eye filled with air may also be appropriate.
In cases where a full-thickness choroidal biopsy is desired, this can also
be performed externally, with or without vitrectomy, in cases where a
specimen is located peripherally, preferably anterior to the equator. If the
physician elects for vitrectomy prior to the biopsy, the vitrectomy can be
performed first, and the biopsy site is identified. Scleral depression can be
performed with direct visualization under wide-field viewing system, or with
indirect ophthalmoscopy, and the biopsy site can be marked with indentation
with the scleral depressor and a marking pen. A scleral flap is performed with
a crescent blade or another knife of the surgeon’s preference, and a 6 mm × 6
mm flap is typically sufficient to achieve the biopsy. The hinge for the scleral
flap is often left at the posterior-most location, and the scleral cut-down
should be as thick as possible without penetrating the globe. After a flap of
sufficient thickness, the inner wall will appear gray or brown in color,
indicating to the surgeon that the choroid is less than a few hundred microns
away. Diathermy is performed on the inner bed of the sclera to minimize
bleeding. A smaller rectangle of sclera and choroid is then incised with a
needle or blade and removed with retinal scissors; typically, a 4 mm × 3 mm
or 3 mm × 3 mm biopsy is taken. The specimen is then grasped with forceps
and removed, and the scleral flap is sutured closed. If a vitrectomy was
performed, the eye may be filled with gas.
The retinal or chorioretinal biopsy specimen should be carefully
subdivided into three sections. The first section is sent for light and electron
microscopy, the second section is sent for viral or fungal culture or
polymerase chain reaction analysis, and the third section is sent for
immunohistochemical studies to determine the type of predominant immune
response (2).
THERAPEUTIC SURGERY
Despite appropriate medical therapy to control ocular inflammation,
therapeutic surgery may be needed to treat the sequelae of chronic
inflammation. The physician should be prepared to encounter surgical
challenges unique to a chronically or recurrently inflamed eye. Even a
minimally traumatic and efficient surgery may elicit severe postoperative
inflammation in a child with uveitis. Careful control of inflammation
preoperatively, intraoperatively, and postoperatively allows the greatest
chance of a successful surgery.
Band Keratopathy
Indications
Calcific band keratopathy is a degeneration of the superficial cornea with the
accumulation of calcium hydroxyapatite primarily in Bowman membrane but
also in the epithelial basement membrane and the basal epithelium. There can
be multiple etiologies of band keratopathy; however, in this chapter we focus
on the causes secondary to chronic uveitis in children, which include juvenile
idiopathic arthritis (JIA), sarcoidosis, or chronic intermediate uveitis (9). The
calcific deposits can lead to a rough corneal surface that elevates the
epithelium and leads to pain, foreign body sensation, recurrent corneal
erosions, and decreased vision. Indications for surgery include rehabilitation
of vision, improvement of ocular surface and pain, or improving the view to
allow for adequate clinical examination.
Band keratopathy can be removed by disodium
ethylenediaminetetraacetic acid (EDTA) chelation and superficial, lamellar
keratectomy. A second method for removing band keratopathy is by excimer
laser phototherapeutic keratectomy (PTK); however, this typically results in a
highly irregular base due to the nonuniformity of the calcium density in the
band across the cornea (10). PTK effectively treats ocular surface symptoms,
but improvement in visual acuity can be variable. Stewart and Morrell (11)
reported that 55% of patients who underwent PTK for visual rehabilitation of
band keratopathy had improvement or no change in visual acuity, and 45% of
patients had a decrease in visual acuity; meanwhile, 83% of patients who
underwent PTK for ocular surface improvement noted an improvement in
symptoms. Chelation with EDTA is the preferred treatment option for band
keratopathy, and multiple treatments are likely to be needed in chronically
inflamed eyes, due to recurrences.
Procedure
Although chelation can be performed with local anesthesia, general
anesthesia is preferred for most children. Foster has previously described his
technique for EDTA chelation and superficial keratectomy (1). The corneal
epithelium is scraped off with a no. 15 Bard-Parker blade, taking care not to
penetrate through Bowman’s. A well can then be made by cutting off the
back end of a 3-mL plastic syringe, which can be positioned over the affected
area with the cut side up. A few milliliters solution of 0.35% EDTA is placed
in the watertight well and held in position for approximately 5 minutes. This
allows for chelation of calcium in the affected area while simultaneously
protecting the limbal stem cells. The well is then removed, and the cornea is
irrigated with multiple washes of balanced salt solution. The no. 15 blade is
then used to scrape off the loosened flakes of calcium. The procedure is
repeated as many times as necessary to remove the calcium from the central
cornea. Care must be taken to avoid scarring of the Bowman’s within the
visual axis. Cycloplegic and antibiotic drops are given, a continuous-wear
bandage soft contact lens is placed, and the eye is patched. Topical antibiotic
and steroid are used postoperatively. Bandage contact lens, cycloplegia, and
oral analgesics help with pain control. The epithelium generally has covered
the corneal surface within 1 week following surgery, and the bandage soft
contact lens can be removed.
Glaucoma
Angle-Closure Glaucoma
Indications
Children with uveitis may develop posterior synechiae, which can lead to
pupillary block, iris bombé, and secondary angle closure. The initial
treatment of choice for acute angle closure is laser peripheral iridotomy;
however, there is a high incidence of posttreatment iridotomy scarring and
closure in children with active inflammation. Thus, laser iridotomy may serve
as an appropriate initial choice but likely will not offer a definitive, long-term
treatment. Furthermore, many children will not tolerate a laser iridotomy in
clinic. A larger, controlled, surgical iridectomy under general anesthesia is
the preferred procedure in a child with uveitis and secondary angle closure.
Procedure
Surgical iridectomy consists of five steps: (a) incision, (b) exteriorization of
the iris, (c) excision of the iris, (d) repositioning of the iris, and (e) closure of
the incision. The incision may be made in the sclera under a conjunctival flap
or through clear cornea. It is technically more challenging to perform the
procedure through a clear corneal incision (CCI), but this minimizes
conjunctival scarring in anticipation of possible future glaucoma surgery.
A partial-thickness incision is made perpendicularly into clear cornea.
Sutures are then preplaced on either side of the incision. The corneal incision
is then extended perpendicularly until the anterior chamber is entered. Gentle
pressure can be applied to the posterior lip of the wound to prolapse and
exteriorize the iris. If the iris does not prolapse, then nontoothed forceps can
be used to grasp and externalize it. The iris is then excised. Often, the iris will
internalize into the anterior chamber after the iridectomy, but if it remains
prolapsed, viscoelastic or an iris spatula can be used to reposition it. The
cornea is then closed with 10-0 nylon suture. Corticosteroids may be given
subconjunctivally intraoperatively or topically postoperatively.
Uveitic Glaucoma
Children with chronic or recurrent uveitis who also have uveitic glaucoma are
challenging to treat (12). When medical therapy or glaucoma laser procedures
are inadequate to attain the IOP goal, surgical intervention may be necessary.
Failure rates for trabeculectomy are higher in eyes with uveitis than in
noninflamed eyes, although some studies report successful 1- and 2-year
results of trabeculectomy with or without antimetabolites in patients with
uveitis (13–16). Glaucoma drainage implants appear in some studies to trend
toward better long-term success rates than trabeculectomy in patients with
uveitis; however, a large clinical trial in children would be required to better
answer this question. Either technique can be used successfully according to
the physician’s preference (14,17–20). Choroidal effusions, hypotony, and
cystoid macular edema comprise the most common postoperative
complications for either surgery.
After incisional surgery, an extensive inflammatory response should be
anticipated in the pediatric eye with uveitis. The recurrent or chronic nature
of inflammation can result in fibrous tissue growth and subsequent closure of
the filtering bleb in a patient who underwent trabeculectomy. Adjunctive
antimetabolites have been shown to be effective in preventing this from
occurring in the short-term, but late or persistent inflammation may later
close the filtering bleb. One- and two-year success rates after trabeculectomy
without antimetabolite therapy range from 67% to 92% (13–16). However, 5-
year success rates decrease dramatically, with Towler et al. (16) reporting a
drop from 80% success at 2 years to 30% at 5 years.
The 1- and 2-year success rates after glaucoma drainage devices range
from 92% to 94% (14,17–20). A 91.7% success rate at both 1 and 2 years
with IOPs of 5 to 21 mm Hg was reported in 24 eyes treated with Baerveldt
glaucoma drainage implant (17). A 94% success rate at 1 year with IOP ≤ 21
mm Hg was reported in 21 eyes treated with Ahmed valve implantation (18),
whereas a 79% success rate was obtained at both 1 and 2 years with IOP of 6
to 21 mm Hg with Molteno device implantation (14). A 95% success at 27
months and a 90% success at 52 months with IOP ≤ 22 mm Hg with Molteno
device implantation were reported in 27 eyes with secondary glaucoma
caused by JIA (19). In a prospective case series of 40 eyes, the probability of
the Molteno implant to control IOP ≤ 21 mm Hg was calculated to be 87% at
5 years and 77% at 10 years after surgery (20).
In the child with uveitis, surgery is best undertaken after the
inflammation is maximally controlled with corticosteroid or
immunosuppressant medications for as long as possible preoperatively,
especially in patients undergoing nonurgent glaucoma surgery. In general, it
is preferable for the eye to be quiet for at least 3 months prior to incisional
surgery, although this is not always possible in more urgent cases. A
glaucoma drainage device may be implanted in the standard fashion between
Tenon fascia and sclera and secured in place. The silicone tube is tied off if
the Baerveldt implant is used. The tube is placed through either the limbus or
the pars plana in vitrectomized eyes. The tube and its insertion site are
covered with a patch of preserved donor sclera or cornea. Topical
corticosteroids are used postoperatively. Maximum control of inflammation
preoperatively, intraoperatively, and postoperatively allows the greatest
chance of a successful surgery.
In the pediatric aphakic uveitic patient, postoperative amblyopia therapy
is vital with proper spectacles or an aphakic contact lens. If a glaucoma
drainage implant is placed in a vitrectomized, aphakic, pediatric patient, a
pars plana tube placement will better allow contact lens fitting following
surgery (1).
Cataract
Cataract is one of the most common complications of uveitis, with a
prevalence of up to 50%, and can be attributed to chronic inflammation and
corticosteroid use (21,22). Cataract surgery in pediatric uveitic eyes is
challenging, with unknown risks faced intraoperatively and an uncertain
postoperative course (3,4). Posterior synechiae, delicate iris vessels, pupillary
membranes, miotic pupils, and corneal opacification can increase the
complexity of the case (5).
Indications
Indications for cataract surgery in a child with a uveitic cataract include
visual rehabilitation, prevention or treatment of amblyopia, and improving
the ophthalmologist’s view of the posterior segment.
Cataract extraction with intraocular lens (IOL) implantation has become
increasingly successful over the past 20 years as a result of improved
microsurgical techniques and viscoelastics, as well as more rigorous control
of recurrent inflammation and chronic low-grade inflammation (1,2).
Currently, cataract extraction with endocapsular posterior chamber IOL is an
accepted practice in the management of many adults with uveitic cataract,
provided the inflammation has been quiescent for a sustained period before
surgery (23). However, the decision whether to implant an IOL in a pediatric
patient with uveitis remains controversial.
In the setting of aphakia with inadequate capsular support, there are
several options to correct the resultant large hyperopic refractive error
including (a) aphakic spectacles (best if bilaterally aphakic), (b) contact lens
use, or (c) IOL implantation in the form of (i) anterior chamber IOL (ACIOL)
or (ii) fixation of IOL either with sutures to the iris/sclera or sutureless within
the sclera. Although the sutureless scleral fixated lens technique has been
successfully used in the pediatric population (24), it has only been used a
handful of times in the pediatric uveitic eye, and longer-term studies are
needed. This technique has been successfully used in the adult population
with uveitis (25) with good long-term outcomes. In pediatric eyes with 70
years or more of life ahead, this technique minimizes the associated risks of
corneal decompensation or anterior uveitis reactivation from ACIOLs or
suture erosion from sutured IOLs and maximizes visual pathway
development and visual potential (24).
Procedure
The surgical technique for cataract extraction in a child with uveitis should
include removal of the cataract, including the posterior capsule, all
retrolenticular and cyclitic membranes, and most of the vitreous. It is usually
not possible to fully separate the posterior hyaloid from the retina in a child.
Pars plana lensectomy with pars plana vitrectomy is the preferred approach
(26). For the pars plana approach, the lens and posterior and anterior capsules
are cut and aspirated. This is followed by a near-total vitrectomy. Removal of
the lens capsule and anterior hyaloid must be performed to prevent posterior
capsular opacification (PCO) and to remove the scaffold on which secondary
membranes can form and grow (21). This reduces the likelihood of
subsequent posterior synechiae and cyclitic membrane formation and
decreases the need for postoperative neodymium-doped yttrium aluminum
garnet (Nd:YAG) laser capsulotomy, which may not be feasible in many
children (26–29). A surgical peripheral iridectomy should be considered as
prophylaxis against secondary angle closure if recurrent or chronic
inflammation is anticipated.
Cataract extraction may also be accomplished by a combined limbal
approach with phacoemulsification and pars plana vitrectomy. During the
limbal approach, synechiolysis and pupilloplasty may be performed, or iris
hooks may be used to ensure adequate exposure. Then a capsulorrhexis,
hydrodissection, and phacoemulsification are performed in standard fashion,
and the incision is closed with a suture. This is followed by a pars plana
approach for complete posterior capsule excision, followed by a meticulous
vitrectomy. It is usually not possible, nor desirable, to surgically induce a
posterior vitreous detachment in a child.
The decision for IOL implantation in a pediatric patient with uveitis
remains controversial. The decision must carefully consider the individual
patient and the risk of recurrent inflammation. If chronic or recurrent
inflammation is anticipated, there is a high risk of developing perilenticular
membranes and iris capture. The IOL itself may provide a stimulus for
intraocular inflammation or a scaffold for inflammatory membranes, which
can lead to ciliary body dysfunction, ocular hypotony, and chronic macular
edema. Treatment of these membranes with Nd:YAG capsulotomy may incite
further inflammation and reformation of membranes. This also can be
difficult to perform in the pediatric population. Surgical posterior
capsulectomy, retrolental membranectomy, and near-total vitrectomy
represent more definitive treatments, but even with this approach, significant
perilenticular membranes may persist or recur. In addition, chronic
inflammation refractory to therapy or cyclitic membranes can result in
hypotony, which may necessitate the removal of the IOL (23). Younger age
and recurrent inflammation are risk factors for subsequent IOL explantation
(23). IOL implantation is contraindicated in children with JIA-associated
uveitic cataracts (1,2,21,30). Some will use a staged approach in which the
cataract is removed and the surgeon waits until full quiescence is reached
again. An IOL is then placed several months later.
The choice of IOL may affect postoperative inflammation and formation
of perilenticular membranes. Acrylic lenses are thought to be the least
inflammatory (31,32). In a randomized, double-masked trial of 36 adult
uveitic eyes that underwent cataract extraction with IOL placement with four
types of IOLs (silicone, polymethylmethacrylate [PMMA], heparin-coated
PMMA, or acrylic lenses), acrylic IOLs had the lowest rates of postoperative
inflammation, PCO, and cystoid macular edema and the best postoperative
final visual acuity (31). Another study also showed a lower PCO rate in
acrylic IOLs, when comparing silicone, PMMA, heparin-coated PMMA, and
acrylic IOLs in adults with uveitis (32). Secondary IOL implantation after
cataract removal in children with JIA-associated uveitis resulted in lower
incidence of secondary glaucoma, compared to primary IOL implantation in a
study of 40 eyes of 40 patients (33). A study assessing primary IOL
implantation in 34 eyes of 24 children with chronic JIA-associated uveitis
showed 65% of patients achieved final visual acuity of 20/40 or better,
secondary glaucoma in 24% of eyes, PCO and secondary membrane
formation in 44%, macular edema in 15%, and phthisis in 6%; the median
age at diagnosis was 5.3 years and median age of cataract extraction with IOL
placement was 9.7 years of age (34). In another study of 80 eyes in children
with uveitis, females were more likely to experience recurrent uveitis
postoperatively, and a heparin-surface-modified IOL appeared to reduce the
incidence of postoperative inflammation (35). The use of heparin in the
infusion solution for pediatric uveitic cataract surgery is controversial
(36,37).
If structural issues do not allow for lens placement in the usual position, a
three-piece lens can be fixated with scleral tunnels (Video 48-1 ). Walsh
et al. (24) describe the procedure in the pediatric population. The technique
begins by making a conjunctival peritomy superiorly and inferiorly at the
limbus. Diathermy is typically not used to avoid the risk of scleromalacia. A
standard three-port vitrectomy setup is initiated, with the trocars placed 2 to 3
mm posterior to the limbus depending on the patient’s age. Measuring 1.5 to
2.5 mm from the limbus at 12:00 and 6:00, a 2- to 3-mm long intrascleral
tunnel is made with 25-g trocars (achieved by maintaining a 30- to 40-degree
bevel) both superiorly and inferiorly. A toric marker is used to ensure a
consistent 180-degree separation of the tunnels, and mild conjunctival
displacement prior to tunnel creation helps bury the haptic following
externalization. Biasing the distal end of the tunnel slightly closer (0.25 to 0.5
mm) to the limbus may decrease lens tilt and decentration. For the left eye,
these tunnels end up extending nasally from the 12:00 sclerotomy and
temporally from the 6:00 sclerotomy and vice versa for the right eye. In the
pediatric setting, if not already done so, a vitrectomy is completed. When
implanting a three-piece IOL, a superotemporal paracentesis is created with a
no. 75 supersharp blade, and viscoelastic is injected into the anterior
chamber. One then makes a standard CCI with a 2.8-mm keratome. It is best
to choose the IOL power in conjunction with the pediatric ophthalmologist
who will be managing the patient’s refractive error for years to come. A
three-piece lens is then inserted using a monarch injector, either leaving the
trailing, superior haptic outside the eye through the CCI or suspended on iris.
Intraocular forceps are inserted through the inferior 6:00 cannula comprising
the intrascleral tunnel, and under direct visualization, one engages the tip of
the leading haptic in the mid-vitreous cavity with forceps. It is important to
attempt to grasp the tip of the haptic to prevent haptic kinking and/or
breakage. The haptic tip is then brought to the internal opening of the
cannula, and one then slowly slides the cannula up the shaft of the forceps.
Finally, the haptic is externalized through the sclerotomy. Once externalized,
the haptic is left to rest on the surface. For the trailing haptic, the same
forceps are used through the superior 6:00 cannula into the anterior vitreous
with the technique of externalization performed, as above. If there is
difficulty in grabbing the trailing haptic, one may enter the anterior chamber
via the paracentesis with another intraocular forceps and “hand” the haptic to
the forceps engaged in the cannula. Once both haptics are externalized, the
tips may be flanged with gentle low-temp cautery and/or gently reengaged
into the tunnel proper. The conjunctiva is reapproximated to overly the
haptics, and one may choose to further fixate the haptics to the sclera with 9-
0 nylon suture if the child is very young with potential for significant eye
rubbing. A repeat limited vitrectomy is performed to remove any debris
and/or viscoelastic, the main wound is sutured with 10-0 nylon, and the
trocars are removed. We typically suture all sclerotomies in a pediatric case
with 7-0 absorbable polyglactin (Vicryl) sutures and close the conjunctiva
with 6-0 plain gut suture. The use of atropine is avoided, but acetylcholine
chloride intraocular solution (Miochol-E, Novartis, East Hanover, NJ) may
be used at the end of the case.
Management of Inflammation
Vigilant control of inflammation preoperatively, perioperatively, and
postoperatively is critical for children with uveitis undergoing cataract
extraction. Some surgeons will prophylactically increase a patient’s
immunosuppression and/or add oral steroids before surgery in order to
maintain better control after cataract surgery. Cataract surgery has an
increased chance for a successful outcome if it is performed after the
inflammation has been quiescent for as long as possible, ideally more than 3
months. Surgery in the presence of active inflammation carries a much higher
potential for complications. The optimal time to operate is after the active
inflammatory phase of the uveitis has burned out (38). In some patients with
chronic inflammation, it is not possible to achieve complete quiescence.
Although attempts should be made to maximally quiet the eye, surgery
should not be delayed if the delay would lead to irreversible loss of vision or
damage to the eye.
Systemic immunosuppressive therapy may be needed for adequate
preoperative control of inflammation in children with JIA-associated uveitis.
In 2003, a favorable outcome was reported in six eyes of five children
younger than 13 years with JIA-associated uveitis, all of whom underwent
standard phacoemulsification cataract extraction without a posterior
capsulectomy and with posterior chamber IOL implantation (7).
Postoperative visual acuity was 20/40 or better in all six eyes. Median follow-
up was 44 months. Preoperatively, four children (five eyes) were on low-dose
methotrexate immunosuppressive therapy for a median length of 1.25 years
before surgery. Preoperatively, two children (three eyes) were on additional
immunosuppressants or systemic corticosteroids. All eyes received frequent
topical corticosteroid therapy for a median of 2 weeks preoperatively and 8.5
weeks postoperatively. Five eyes required Nd:YAG capsulotomy. One eye
needed a subsequent surgical posterior capsulectomy and pars plana
vitrectomy. The authors concluded that children with JIA-associated uveitis
might have favorable surgical outcomes after cataract surgery with posterior
chamber IOL implantation provided they had adequate long-term
preoperative and postoperative control of intraocular inflammation with
systemic immunosuppressive therapy and intensive perioperative topical
corticosteroid therapy (39). As previously mentioned, a second study
assessing primary IOL implantation in 34 eyes of 24 children with chronic
JIA-associated uveitis showed 65% of patients achieved final visual acuity of
20/40 or better, secondary glaucoma in 24% of eyes, PCO and secondary
membrane formation in 44%, macular edema in 15%, and phthisis in 6% of
eyes (34).
Perioperative control of inflammation is vital, as the pediatric uveitic eye
often has an intense postoperative inflammatory reaction. The goal of
perioperative medications is to control and reduce the anticipated severe
postoperative inflammation. Although specific medications and dosing
schedules vary, the concepts are similar. In general, surgeons will
prophylactically add oral steroids or increase immunosuppression 1 to 3 days
preoperatively, even if there is no evidence of active inflammatory disease. If
the child is not on systemic immunosuppression and the uveitis has been
quiescent for an extended period of time, aggressive topical therapy may be
enough, although most surgeons will give a short course of oral steroids
before and after surgery. Intraoperatively, patients may receive a periocular
steroid injection, if possible, or an intravenous bolus of steroids or both, if
previous steroids have not been started. Periocular injections may be
delivered to the sub-Tenon’s space. In small children, 20 mg of triamcinolone
acetonide is effective (40). A study published by Cleary et al. (41) has shown
that 4 mg (4 mg/0.1 mL) of intracameral preservative-free triamcinolone
(Triesence, Alcon, Inc., Fort Worth, TX) used at the conclusion of the
cataract surgery can effectively control postoperative inflammation in a safe
manner in the pediatric population. Postoperatively, patients should receive
aggressive anti-inflammatory treatment in the form of aggressive topical
steroid regimens, increased immunosuppression, or oral steroids. The
increase in immunosuppression should remain for at least 3 to 6 months,
though longer if smoldering inflammation appears to persist.
Postoperatively, the eye may appear quiet at first but then may respond
with an intense inflammatory reaction, which typically peaks about 48 hours
after surgery and lasts for 5 to 6 days even in the presence of high doses of
systemic corticosteroids. Postoperatively, children with uveitis should be
examined very closely, every day or every other day, for the first week for
close monitoring (2). Occasionally, a severe dense fibrin that is refractory to
steroids and NSAIDs may occur in the anterior chamber within 6 days after
surgery. Recombinant tissue plasminogen activator (rt-PA) may be used to
treat dense fibrin. A report on 11 pediatric eyes, 3 with uveitis, who
developed dense fibrin clots after cataract surgery that was refractory to
intensive prednisolone acetate and cycloplegic agents showed a benefit of rt-
PA (42). Injection of rt-PA, 100 μL of 10 μg/100 μL, into the anterior
chamber thought a limbal paracentesis, resulted in complete resolution of
fibrin formation in all eyes, except for two eyes in a JIA patient, within 24
hours. The physician may decide to continue corticosteroids at the same time
if there is no improvement in inflammation over the first 5 days
postoperatively, because there can be a delay in treatment response; however,
worsening of inflammation in spite of standard care therapy should prompt
the physician to intensify the treatment or add an additional medication to the
regimen. Aggressive anti-inflammatory treatments, even in the absence of
inflammation, are key to prevent such occurrences, as intracameral t-PA does
require sedation for the child.
Visual Rehabilitation
The surgery is only one part of the visual rehabilitation in a child.
Postoperative amblyopia therapy under the care of a pediatric
ophthalmologist is equally important for achieving the best possible vision.
The child will require proper postoperative spectacles or contact lenses,
orthoptic evaluation, and likely occlusion therapy. Parents must be educated
and reminded about the critical role of amblyopia therapy. Despite an
excellent anatomic and surgical outcome, visual rehabilitation for an aphakic
eye may be suboptimal because many patients of this age are unable to or
refuse to wear an aphakic contact lens or aphakic spectacles (43). Among
children, contact lens intolerance is reported to range from 17% to 38%
(30,44). The frequent concomitant presence of band keratopathy makes
contact lens fitting difficult. Multiple lost contact lenses carry a substantial
expense for the family. Children often are intolerant of aphakic spectacles
because of the aniseikonia and weight. The age of the child at the time of
surgery, the presence or absence of amblyopia, and the presence of
irreversible retinal or optic nerve pathology are the primary factors
influencing the outcome of cataract surgery in the pediatric uveitic patient.
Vitreoretinal Surgery
Scleral buckle procedures, whether encircling or segmental, may be indicated
to treated tractional retinal detachments, combined RRD/TRD, or to relieve
traction caused by snowbanking. In children under the age of 4, the scleral
buckle, if encircling, may need to be segmented to allow growth of the eye,
usually done 3 months after placement as long as traction is settling and other
methods for inflammatory control have been incorporated (Figure 48-2).
FIGURE 48-2 A, B: Color fundus photographs of a 14-
year-old with par planitis with snowbanking causing a
tractional retinal detachment and progression of fluid to
the macula (blue arrows). C, D: Color fundus photographs
after placement of a scleral buckle and cryotherapy with
the red arrow demonstrating the previous area of traction
and fluid that has now resolved and yellow arrow
displaying the scleral buckle. No obvious breaks were
seen.
Indications
There are four objectives in pars plana vitrectomy in patients with chronic
uveitis. The first is to remove opacities in the visual axis. The second is to
remove vitreomacular membranes producing retinal traction or epiretinal
membranes causing macular pucker. The third is to remove cyclitic
membranes or thickened anterior cortical hyaloid causing hypotony. The
fourth is to alter the course of vitreous inflammation refractory to medical
therapy or persistent cystoid macular edema.
Procedure
Vitreoretinal surgery is performed using a standard three-port vitrectomy
procedure. A longer infusion tip (4 to 6 mm) may be required in uveitis
patients to accommodate scleral thickening, choroidal edema, or retinal
separation (1). Direct visualization to confirm that the infusion cannula is
within the vitreous cavity is critical before turning on the infusion.
The infusion is turned on and the endoillumination probe and vitrectomy
cutter are introduced. A complete vitrectomy is performed, although the
posterior hyaloid cannot typically be fully lifted in children. Preretinal and
epiretinal membranes are dissected or stripped from the retinal surface using
a combination of scissors, membrane picks, and forceps. If there is vitreous
base exudation or neovascularization, it may be treated with laser scatter
photocoagulation or cryopexy. Scleral depression is used at the completion of
the case to inspect 360 degrees for any untreated breaks or tears. The hyaloid
is often very adherent in these cases, and attempting to lift it from the retina,
especially in thinner, peripheral retina, can lead to retinal breaks. Any breaks
are treated with retinal laser or cryopexy, and all attempts need to be made to
remove traction from these tears, including a scleral buckle element of sorts,
if needed. Long-acting gas, or more likely, silicone oil, for tamponade of at
least 3-month duration may be needed. Aggressive preoperative
inflammatory control is needed. This is mostly achieved with systemic
medications versus local steroids as systemic immunosuppression is likely to
be effective and less likely to cause other possible postoperative
complications, such as glaucoma.
Lasers
In the nonuveitic eye, lasers often are used to perform peripheral iridotomy
and posterior capsulotomy and to treat retinal or subretinal
neovascularization. In a patient with uveitis, however, a laser procedure may
incite extensive inflammation, leading to additional drop out and increased
retinal neovascularization, entering the child into a vicious cycle.
Periprocedural control of inflammation is important, with frequent topical
corticosteroid dosing and consideration of periocular or systemic
corticosteroids.
Peripheral neovascularization
Patients with intermediate uveitis may develop peripheral retinal
neovascularization. These patients have thick ropy neovascularization in the
far periphery extending over the ora serrata, which often is obscured from
visualization by pars plan exudation and vitritis. In patients with unremitting
chronic pars planitis that is recalcitrant to steroid or nonsteroidal anti-
inflammatory drug (NSAID) therapy, cryotherapy and scatter laser
photocoagulation of the peripheral retina have been reported to be effective in
causing regression of peripheral neovascularization and reduction of
inflammatory activity. This treatment can reduce the frequency of vitreous
hemorrhage and may reduce the severity of the intermediate uveitis and
cystoid macular edema. Cryotherapy is thought to reduce inflammation by
eliminating the inflammation stimulus in the peripheral retinal tissue (50,51).
Reduction in neovascularization may be caused by direct vessel ablation or
by destruction of ischemic retinal tissue (51,52). In more recent times, if
steroid or NSAID therapies are not enough, children are put on systemic
immunosuppression before cryotherapy is done to reduce some of the
inflammation this procedure may cause. Regression of snowbanking and
neovascularization may occur with aggressive systemic immunosuppression
(48,49). If regression is not seen and the pediatric patient is on aggressive
therapies, cryotherapy to the deep retinal neovascularization may be
performed.
In children, cryotherapy is performed under general anesthesia.
Retrobulbar or subconjunctival anesthesia may be given for intraoperative
and postoperative pain control. Cryotherapy is applied directly to the areas of
exudation at the pars plana using a double freeze–thaw technique (29,50).
The ice ball should be seen to cover the exudative area and
neovascularization. Uninvolved pars plana and retina are treated with one
Cryo-tip width beyond the involved area. In areas where the visualization of
the ice ball is precluded, freezing should be continued for a time interval
similar to that required in adjacent areas with adequate visualization.
Periocular steroids may be administered following the procedure. The
procedure may be repeated in 3 to 4 months if there is residual disease.
Cryotherapy was first advocated in 1973 (50) and was later reported to
eliminate inflammation in 78% of 27 eyes (53). Visual acuity improved or
remained unchanged in 89% of eyes and eliminated the need for
corticosteroids therapy in 90% of eyes (53). In the presence of better, more
tolerable, and safer immunosuppression, cryotherapy has become more of a
secondary procedure.
Panretinal scatter photocoagulation has been shown to be effective in the
treatment of peripheral neovascularization associated with intermediate
uveitis. Regression of neovascularization, improvement of cystoid macular
edema, and stabilization of inflammation were reported in 10 eyes with
scatter diode or argon photocoagulation treatment, either alone or in
combination with pars plana vitrectomy (54).
Several rows of photocoagulation are delivered to the inferior retinal
periphery, just posterior to the area of exudation or neovascularization.
Treatment may be carried out with either argon endophotocoagulation or an
indirect ophthalmoscopic delivery system using argon or diode
photocoagulation. Laser photocoagulation appears to be a safe and effective
alternative to cryotherapy and is a useful adjunct during a therapeutic pars
plana vitrectomy.
SLOW-RELEASE STEROID
TREATMENT FOR UVEITIS
Two sustained-release, steroid-based implants or drug delivery devices are
currently are on the market. One device, the Retisert implant, is a reservoir-
based, surgically implanted device containing 0.59 mg of fluocinolone
acetonide (FA); it is designed to release the drug over a 3-year period. The
device initially was developed by Control Delivery Systems (Watertown,
MA) and now is licensed by Bausch & Lomb (Rochester, NY) (Figure 48-3).
The device has been shown to be extremely effective for the treatment of
uveitis, even in patients who have had poor control of their disease with
aggressive systemic therapy (Figures 48-4 and 48-5) (55). A pilot study by
Patel et al. (56) has shown that the Retisert can effectively control posterior
inflammation in the pediatric patients. A total of six eyes of four children
were enrolled in this study. Retisert implants were able to control the
inflammation of all six eyes. The safety profile was very similar to what has
been described in adult patients. One of the six eyes of the pediatric patients
developed visually significant cataract that was surgically removed. Two
patients also developed high IOP, which were treated with glaucoma shunting
procedures. Unfortunately, not much more data is available for the pediatric
population; hence, safety and effectiveness in pediatric patients below the age
of 12 years have not been well established (57).
FIGURE 48-3 FA reservoir device (Retisert, Bausch +
Lomb, Rochester, NY) alongside rulers.
FIGURE 48-4 A: Color fundus photograph 1 year before
FA implant. Optic nerve swelling and peripapillary
necrotizing retinitis with intraretinal hemorrhage are seen.
Image taken with a 30-degree fundus camera. B: Six
months after FA implant. Healed retinitis. Image taken
with a 50-degree fundus camera.
FIGURE 48-5 Fluorescein angiogram taken just before
(A) and 4 months after (B) FA device implantation.
Midarteriovenous phase (A) and late phase (B) are shown.
(Courtesy of Glenn Jaffee, MD.)
Though the use of the local steroid implants may appear attractive, caution
must be taken when using these implants in the pediatric population, as
cataracts and glaucoma are real concerns and can complicate an already
complicated eye. Cataract extraction and filtering procedures are already
more complex in the pediatric population, let alone those also with uveitis.
As with most of the studies, surgical results were usually better achieved if
these complex eyes were being treated with systemic immunosuppression.
Ocular Toxocariasis
Ocular toxocariasis is a monocular disease that affects children.
Pathogenesis
Toxocariasis is an infectious disease caused by the invasion of tissue by the
larvae of Toxocara canis. T. canis is a roundworm of dogs. It is a ubiquitous
worldwide parasite. The incidence of infected puppies has been estimated to
vary from 33% to 100% worldwide (61). Human infection occurs when a
child ingests soil-containing ova. The ova hatch in the small intestine, and the
larvae pass through intestinal wall. The larvae migrate to various tissues,
including the eye, where they may wander about aimlessly for weeks or
months, or the larvae may become encysted by a focal granulomatous
reaction, where they can remain alive for months or years (62). The adult
worms do not develop in humans; thus, Toxocara eggs will not be found in
the stool of an infected person.
Ocular toxocariasis typically affects children at an average age of 7.5
years (range 2 to 31 years); 80% of the cases occur in children younger than
age 16 years (63). Intermediate uveitis from Toxocara is almost always
unilateral, whereas idiopathic intermediate uveitis is bilateral in 70% to 90%
of cases (64); thus, ocular toxocariasis must be suspected in all cases of
unilateral intermediate uveitis, particularly in children.
Clinical Signs
Ocular toxocariasis presents in a variety of clinical patterns. This is on the
differential for leukocoria. A variable amount of vitreous inflammation is
present. The main ocular findings include peripheral retinochoroiditis;
posterior retinochoroiditis, also called a posterior pole granuloma; and
vitritis. Fibrous tractional bands may result in epiretinal membrane formation,
traction retinal detachment, and combined traction–rhegmatogenous retinal
detachment. Vitreoretinal surgery has been shown to be effective in clearing
inflammatory debris from the vitreous cavity and reattaching the macula in
some eyes with retinal detachment (65).
The posterior pole granuloma is a white, elevated, intraretinal or
subretinal mass from 0.5 to 4 disc diameters in size, with tractional bands
from mass to the macula or to the optic disc (Figure 48-8). The granuloma is
the larva of Toxocara surrounded by an eosinophilic abscess with a
granulomatous inflammatory reaction (66). In the periphery, hazy white
inflammatory masses may be seen at the pars plana (Figure 48-9) and often
are associated with retinal folds extending posteriorly toward the optic disc.
Tractional bands from these inflammatory masses to the optic disc may result
in a retinal fold through the macula, macular traction, or macular dragging.
Toxocara endophthalmitis usually presents with a white eye and little pain
but with marked vitreous inflammation, granulomatous keratic precipitates,
and anterior chamber inflammation. A white retrolental mass, which
represents an organization of the inflammatory process into a cyclitic
membrane between a detached retina and lens, may occur and must be
differentiated from retinoblastoma. Amblyopia also may occur as a
complication of toxocariasis.
FIGURE 48-8 Posterior pole of an 8-year-old boy with
inflammatory granuloma caused by T. canis. Note traction
on the surrounding retina. Vitritis has been controlled with
systemic prednisone.
FIGURE 48-9 Fluorescein angiogram of pars plana
inflammatory exudation in an 8-year-old boy with ocular
toxocariasis.
Diagnosis
The diagnosis of ocular toxocariasis usually is presumptive based on the
clinical findings and correlation with serum antibodies to T. canis measured
by serologic ELISA. A 1:8 dilution is considered positive in the presence of
the appropriate clinical findings (62). In cases where the diagnosis is
uncertain, ELISA on aqueous or vitreous biopsy specimens may facilitate the
diagnosis. The presence of eosinophils in aqueous or vitreous biopsy
specimens also suggests the diagnosis of toxocariasis.
Medical Management
Ocular toxocariasis is treated medically. Therapy is directed at the
inflammatory response to prevent inflammation-induced tissue injury and
secondary membrane formation. The inflammation is treated with
corticosteroids, either topically, periocularly, or systemically. If the
inflammation is refractory to steroid treatment, therapy with anthelmintics
directed at the larvae itself may be attempted. Thiabendazole 50 mg/kg/d for
7 days has been proposed if steroid therapy failed (67). There have been
reports of clinical improvement of ocular toxocariasis treated with
thiabendazole (25 mg/kg twice a day for 5 days), albendazole (800 mg twice
a day for 6 days), and mebendazole (100 to 200 mg twice a day for 5 days)
(68).
Surgical Management
For a tractional macular detachment, pars plana vitrectomy and membrane
peeling may be performed in a manner similar to that for other types of
epiretinal membrane (69). The fibrous membranes located between the
peripheral granuloma and the optic disc usually have extensions into the
underlying retina and need to be carefully lifted off from the retinal surface
before they can be severed. These membranes usually remain tightly adherent
to the optic disc and peripheral granuloma; therefore, they often need to be
circumcised rather than delaminated or peeled. Because the granulomas
appear to be an intimal part of the retina, attempts to extirpate the retinal
granuloma usually are unsuccessful and may cause undesirable
complications. Therefore, the granulomas usually are left in place. In most
cases, macular traction can be released without removal of the granuloma,
Outcomes
The use of pars plana vitrectomy for a tractional retinal detachment in cases
related to toxocariasis in the pediatric population has been reported.
Anatomic success for reattachment ranges from 66% to 83% (69–71).
However, the rate of redetachment is fairly high, ranging from 24% to 48%.
Vitreous surgery to treat macular traction due to T. canis was reported in
1977 (72). Later, 12 (71%) of 17 eyes attained retinal reattachment after
vitreoretinal surgery for retinal detachment associated with complications of
toxocariasis (70). Fifteen eyes (88%) had stabilization or improvement in
visual acuity. Redetachment occurred in 4 (24%) of 17 eyes. In a series in
which 10 (83%) of 12 eyes attained retinal reattachment after vitrectomy for
tractional macular disorders associated with toxocariasis, 9 eyes (75%) had
stabilization or improvement in visual acuity (69). Redetachment occurred in
5 (42%) of 12 eyes and was associated with epiretinal membrane
proliferation. The presence of a preoperative tractional fold through the
macula was associated with a poor final visual outcome. In 12 eyes with
toxocariasis-associated complications, only 9 had traction-related macular
problems (71). The other eyes had vitreous opacification alone. Of those with
tractional detachment, 6 (66%) of 9 eyes were reattached, and these cases
improved or were stabilized visually. Redetachment occurred in three eyes
(33%). Recovery of the intraocular larvae usually is usually not possible
because of the small size of the organism (~18 to 21 μm) or because of
destruction of the organism by inflammatory cells. The unintentional
extraction of toxocariasis larvae during vitreoretinal surgery has been
reported (73). Visual prognosis may be guarded in this population, as only
18% of pediatric patients in a series of 45 eyes attained best corrected visual
acuity of 20/50 or better (74).
Postoperative Care
It is essential to remember that a successful operation is only part of the
visual rehabilitation in a child. Postoperative amblyopia therapy in
conjunction with a pediatric ophthalmologist is necessary. The primary
factors influencing the outcome of surgery for the complications of ocular
toxocariasis are factors such as the age of the patient, disease duration before
diagnosis, preexisting amblyopia, and compromise of the macula. The
prognosis for improved visual acuity and normal binocular vision is better
when the onset of the disease occurs in older patients, and the disease is
detected early in its course.
Sarcoidosis
Sarcoidosis is an idiopathic, noncaseating granulomatous inflammatory
disease that may affect any part of the body, most commonly the lungs, but
may include the eye and orbit, lymphatics, heart, kidneys, musculoskeletal
system, and skin (75). The incidence of sarcoidosis is 6 to 10 in 100,000
(76,77). It is 10 times more frequent among African Americans than among
Caucasians (76). Although 75% of affected patients are between 20 and 50
years old, sarcoidosis may occur in children (78).
Children aged 5 years or younger may develop a childhood sarcoid
arthritis (71). The classic triad of symptoms consists of the skin, eye, and
joint lesions; initial pulmonary involvement is rare. It can be easily
misdiagnosed as JIA, which also presents with joint and eye findings (79,80).
However, children with JIA-associated uveitis usually suffer from
pauciarticular arthritis, are antinuclear antibody (ANA) positive, and rarely
develop skin lesions, whereas children with sarcoidosis usually develop
polyarthritis, are ANA negative, often exhibit skin lesions in the form of
erythema nodosum, and have elevated serum angiotensin-converting enzyme
(ACE) (81). One must also consider Jabs-Blau syndrome in patient with
granulomatous involvement of the skin, eyes, and joints in the absence of
lung involvement as this disease has a genetic component, with a known
knockout mutation in the CARD15/NOD2 gene.
Diagnosis
Initial systemic workup consists of a chest radiograph, serum ACE (though
this is may be elevated in children without sarcoidosis), lysozyme, serum and
urine calcium, and liver enzymes (81). If the results of these studies are
negative, high-resolution chest computed tomography and pulmonary
function test should be performed. Gallium scanning may show uptake in the
lacrimal and parotid glands, also known as the panda sign. Sarcoidosis may
first present with uveitis only, with a negative workup, and with extraocular
manifestations evolving slowly over several years (82). Thus, laboratory and
radiologic tests should be repeated periodically in “sarcoid suspects” (81).
The definitive diagnosis of sarcoidosis is a histopathologic one and has
been made by biopsy of the parotid gland, lung, conjunctiva, skin, or lacrimal
gland (81). Conjunctival biopsy is a simple procedure to perform on easily
accessible tissue with a low complication rate. Random conjunctival biopsies
have been reported to be positive in 55% to 71% of patients with biopsy-
proven extraocular sarcoidosis (83,84) and in 28% of patients with suspected
sarcoidosis (83). True sarcoid granulomas may be too small to be seen with
slit-lamp examination, and prominent nodules often turn out to be large
follicles, an ectopic lacrimal gland, or foreign body fibrosis rather than
noncaseating granulomas (85). Because true sarcoid granulomas are often too
small to be seen with slit-lamp examination, random conjunctival biopsy may
be reasonable.
Conjunctival biopsy
The lower fornix is the preferred site for conjunctival biopsy. The lower lid is
retracted and a strip of stretched conjunctiva is excised with Westcott
scissors. The optimal size of biopsy specimen is approximately 1 cm long × 3
mm wide. A topical antibiotic is instilled and pressure is applied for 5 to 10
minutes to prevent hemorrhage and soft tissue edema. No suturing is needed.
There have been no reports of infection or symblepharon formation after
conjunctival biopsy. Multiple sectioning is recommended because the
noncaseating granulomas may be sporadic throughout the conjunctival tissue
(84).
Clinical Signs
The ocular manifestations of sarcoidosis in children are similar to those seen
in adults and include granulomatous anterior uveitis, posterior uveitis, pars
planitis, periphlebitis, macular edema, epiretinal membrane, branch retinal
vein occlusion, retinal neovascularization, tractional retinal detachment,
conjunctival and iris granulomas, and keratoconjunctivitis sicca. Severe
visual loss worse than 20/200 has been reported in 6% to 24% of patients
with ocular sarcoidosis and is more common in patients with chronic
posterior uveitis (82,85).
Medical Management
Sarcoidosis is primarily treated medically. Treatment should be directed
toward absolute control of the inflammation to minimize any potential ocular
complications and structural damage. Mild anterior uveitis is treated with
topical corticosteroids and cycloplegics. Systemic steroids are indicated in
refractory anterior uveitis and in patients with posterior uveitis, retinal
neovascularization, or optic nerve compromise. If inflammation persists with
systemic steroids, the addition of systemic immunosuppression may be
indicated. Immunosuppressive medications such as azathioprine,
cyclosporine, methotrexate, or cyclophosphamide may be required for
refractory disease or as part of a steroid-sparing strategy, as steroid therapy is
not a long-term treatment option for the pediatric population (85–88).
Surgical Indications
Vitreoretinal surgery occasionally may be needed to remove nonclearing
vitreous hemorrhages, peel epiretinal membranes, repair tractional or
rhegmatogenous retinal detachments, or remove inflammatory debris from
the vitreous cavity. Additionally, the complications of chronic uveitis, such as
band keratopathy, glaucoma, and cataract, may need to be treated surgically.
The major cause of poor visual outcome in these patients is macular
pathology, such as cystoid macular edema and epiretinal membrane. Vitreous
hemorrhage secondary to retinal neovascularization may cause decreased
visual acuity as well. Secondary glaucoma may occur as a consequence of
severe anterior segment inflammation. Band keratopathy or cataract may
develop as a consequence of chronic uveitis.
Surgical Management
Iris nodules
Surgical excision of iris nodules may help in the diagnosis and control of
sarcoid uveitis refractory to medical management. The surgical excision of
iris nodules for histopathologic confirmation of the diagnosis of sarcoidosis
in two 10-year-old boys in whom anterior uveitis was refractory to medical
management was reported (89) and resulted in control of inflammation. The
authors hypothesize that the iris granuloma may become a focus of continued
cytokine production and ocular inflammation, and they suggested that total
surgical excision of the iris masses may help in the diagnosis and control of
sarcoid uveitis refractory to medical management.
Cataracts
Cataracts may form as a result of recurrent inflammation from ocular
sarcoidosis. Cataract extraction may be achieved through the limbal approach
with phacoemulsification or through a pars plana approach with lensectomy
in combination with a pars plana vitrectomy. Placement of an IOL in young
patients who will experience future flare-ups of inflammation or have an
anticipated chronic course of inflammation places them at high risk for
developing thick retrolental membranes, severe postoperative inflammation,
iris capture, chronic cystoid macular edema, or hypotony. In a retrospective
analysis of 102 patients with sarcoidosis-associated uveitis (87), the
successful implantation of a posterior chamber lens during cataract surgery
was reported in 19 (90.5%) of 21 adult eyes; however, the success rate is
likely to be much lower in the pediatric eye with sarcoidosis-associated
uveitis. After cataract extraction and IOL implantation, young patients with
sarcoidosis were reported to have a marked postoperative flare-up of
inflammation accompanied by significant fibrin and protein within the eye
that peaked 48 hours after surgery and persisted for 5 to 6 days
postoperatively (2). The consideration of placing an IOL is similar to the
earlier discussion for other uveitic conditions. The removal of the vitreous
scaffold intraoperatively (21), careful control of inflammation with high-dose
steroids during the first postoperative week, and follow-up within 5 to 7 days
after surgery are important (2). Tissue plasminogen activator can be used to
clear severe dense fibrin in the anterior chamber.
Glaucoma
Secondary glaucoma with sarcoid uveitis appears to be a particularly poor
prognostic sign and is associated with severe vision loss (90). Glaucoma
associated with uveitis usually is notoriously difficult to treat. Conventional
filtering surgery has a lower chance of success in these patients with ongoing
uveitis because recurrent inflammation promotes fibrous tissue growth and
subsequent closure of the filtering bleb. Some studies report reasonable
success rates using glaucoma drainage devices, that is, success rates of 77%
to 94% with follow-up from 1 to 10 years, with choroidal effusions,
hypotony, and cystoid macular edema being the most common postoperative
complications (14,17–20).
Vitreoretinal Complications
Retinal manifestations of ocular sarcoidosis include retinal vasculitis,
peripheral retinal and disc neovascularization, choroidal nodules or
granulomas with overlying sensory retinal detachment, subretinal
neovascularization, epiretinal membrane proliferation, and tractional retinal
detachment. Patients with sarcoidosis may develop large areas of retinal
capillary nonperfusion and secondary retinal or disc neovascularization. Both
retinal and disc neovascularization may regress in patients with sarcoidosis in
up to 50% of patients treated by systemic medical therapy alone (48,49).
When persistent or progressive peripheral retinal neovascularization causes
recurrent vitreous hemorrhage, laser grid photocoagulation or cryopexy may
be applied to areas of ischemia as defined by fluorescein angiography. Laser
photocoagulation usually is followed by a significant increase in cystoid
macular edema (48). Steroid therapy should be used in combination with
laser treatment to blunt the anticipated inflammatory response. When disc
neovascularization causes recurrent vitreous hemorrhage, panretinal
photocoagulation may be required to cause regression of the disc vessels.
Vitrectomy has a role in removing nonclearing vitreous hemorrhages that
have result from peripheral retinal or disc neovascularization. Active
neovascularization at the time of surgery may be treated with
endophotocoagulation or peripheral cryopexy. Vitrectomy may be needed for
epiretinal membrane peeling or for repair of tractional or rhegmatogenous
retinal detachments.
Pars plana vitrectomy clears the visual axis by removing media opacities
and vitreous debris in patients with vitreous inflammation refractory to
medical therapy. Vitrectomy may alter the course of inflammation and result
in stabilization of the disease by removing immunocompetent cells and
inflammatory mediators from the vitreous cavity (27,28,45). Vitrectomy may
potentially reduce cystoid macular edema either by eliminating the contact
between an inflamed vitreous body and the macula or by allowing better
penetration or distribution of corticosteroids (26,28,54).
In the pediatric sarcoid-associated uveitis patient, surgery is best
undertaken after the eye has been quiescent for as long as possible but at least
for 3 months. Perioperative inflammation must be rigorously controlled with
aggressive topical, periocular, and possibly systemic corticosteroid use.
Maximum control of inflammation preoperatively, intraoperatively, and
postoperatively allows for the greatest chance of a successful surgery.
Intermediate Uveitis
Intermediate uveitis is a relatively common bilateral disease that affects
otherwise healthy children and young adults. The course is variable, ranging
from a mild self-limiting disease to a chronic disease with exacerbations and
remissions. The main ocular finding is a marked exudative response in the
peripheral retina and inflammation in the anterior vitreous. Vision loss is
most commonly due to vitreous debris, cystoid macular edema, epiretinal
membrane, and cataract. Vitreoretinal surgery may be needed for clearing of
vitreous debris as well as attenuation of inflammation and the exudative
response. Cryotherapy or panretinal scatter photocoagulation may be used for
peripheral neovascularization. Uveitic cataracts may be treated with surgical
intervention.
Intermediate uveitis is an idiopathic intraocular inflammatory syndrome
of the peripheral retina and pars plana, which is known by many names, most
commonly pars planitis and peripheral uveitis. Intermediate uveitis has been
reported in 16% to 33% of all uveitis cases presenting among children (91).
The age of onset ranges from 5 to 65 years, with the mean occurrence in the
third decade of life (29). Severe cases tend to present at an earlier age,
whereas older patients have a milder form of the disease. From 70% to 90%
of cases are bilateral, although the majority of cases are asymmetric (92).
Diagnosis
The differential diagnosis of intermediate uveitis includes many causes of
vitreous inflammation. It is imperative to exclude infectious causes because
antimicrobial therapy may be curative. Infectious entities in the differential
diagnosis include Lyme disease, toxocariasis, Whipple disease, tuberculosis,
syphilis, human T-cell leukemia virus type 1, Epstein-Barr virus, and cat-
scratch disease. Equally important is the exclusion of intermediate uveitis
associated with underlying systemic disease such as sarcoidosis, Behçet
disease, multiple sclerosis, retinoblastoma, or intraocular
leukemia/lymphoma. Initial laboratory studies include a complete blood
count with differential (myeloproliferative and infectious disease), ACE
(sarcoidosis), chest x-ray film (sarcoidosis and tuberculosis), tuberculin skin
test (purified protein derivative) with anergy panel or QuantiFERON Gold
testing or equivalent, microhemagglutinin Treponema pallidum or fluorescent
treponemal antibody absorption test (syphilis), and ANA (systemic lupus
erythematosus and other connective tissue diseases), with consideration of
Lyme or Toxocara antibody testing (29).
Management
Having excluded treatable infections and noninfectious etiologies, treatment
of intermediate uveitis may begin. Intermediate uveitis is treated medically
and is directed toward the complications and sequelae of intraocular
inflammation such as cystoid macular edema, cataract, vitreous opacity,
peripheral neovascularization, or retinal detachment. A five-step regimen has
been proposed (64) that is a modified approach based on a four-step regimen
initially described in 1984 (44): (a) topical corticosteroid for anterior segment
inflammation with periocular corticosteroid injections; (b) oral NSAIDs
should inflammation recur following the third injection, with topical NSAIDs
in the presence of cystoid macular edema; (c) systemic corticosteroids should
inflammation persist or recur despite the previous interventions; (d)
peripheral retinal cryopexy or indirect laser photocoagulation should pars
planitis recur following the sixth regional steroid injection; and (e) pars plana
vitrectomy versus immunosuppressive chemotherapy should inflammation be
recalcitrant to the preceding modalities. Many antimetabolites and
immunosuppressive drugs have been tried, including cyclosporine,
methotrexate, azathioprine, 6-mercaptopurine, cyclophosphamide, and
chlorambucil (63). With the advent of newer immunosuppressive therapies
that are better tolerated, the use of immunosuppression for treatment is now
stared sooner than later in an attempt to reduce both the topical and systemic
steroid load in order to avoid as many steroid side effects/complications in
these young patients.
Vitrectomy
In patients with vitreous opacities impairing vision, causing amblyopia, or
obscuring the ophthalmologist’s view of the periphery, pars plana vitrectomy
is an effective treatment for visual rehabilitation as well as attenuation of
inflammation. Pars plana vitrectomy with or without pars plana lensectomy is
used to treat certain complications of intermediate uveitis, such as vitreous
opacification, tractional retinal detachment, vitreous hemorrhage, and
epiretinal membrane. In cases of vitreous inflammation refractory to medical
therapy, pars plana vitrectomy clears the visual axis by the removal of media
opacities and vitreous debris. Vitrectomy also may alter the course of
inflammation and result in stabilization of the disease by removing
immunocompetent cells and inflammatory mediators from the vitreous cavity
(27,28,45). Vitrectomy may potentially reduce cystoid macular edema either
by eliminating the contact between an inflamed vitreous body and the macula
or by allowing better penetration or distribution of corticosteroids (26,28,54).
General guidelines for vitrectomy for medically refractory intermediate
uveitis include the (a) removal of the posterior hyaloid; (b) removal of as
much anterior vitreous as possible; (c) careful inspection of the periphery,
looking for neovascularization and occult retinal breaks that can be treated
with endolaser photocoagulation; and (d) maximal perioperative control of
inflammation with intravitreal, periocular, and systemic corticosteroid use.
Cataract surgery
Cataract formation is another complication of intermediate uveitis. Cataract
extraction may be achieved through a limbal approach with
phacoemulsification or through a pars plana approach with lensectomy in
combination with a pars plana vitrectomy. If a concurrent vitreous opacity
exists, combined pars plana lensectomy and core vitrectomy is classically the
procedure of choice. A combined limbal cataract extraction and pars plana
vitrectomy approach also can be used.
Implantation of a posterior chamber IOL is dependent on the risk of
future or chronic inflammation. A peripheral iridectomy should be made if
recurrent or chronic inflammation is anticipated. Since the postoperative
course is usually not as problematic, the risk of IOL implantation with
children with intermediate uveitis is not as severe as with children with JIA,
though aggressive care to control inflammation must be taken (96).
In the child with intermediate uveitis, surgery is best undertaken after the
eye has been quiet for at least 3 months. Perioperative inflammation must be
rigorously controlled with aggressive topical, periocular, and possibly
systemic corticosteroid use or steroid-sparing immunosuppression. Maximum
control of inflammation preoperatively, intraoperatively, and postoperatively
allows the greatest chance for a successful surgery.
Medical Management
JIA-associated uveitis is primarily treated medically. Treatment should be
directed toward absolute control of the inflammation with medications.
Although topical and periocular corticosteroid injections remain the first-line
therapy for anterior uveitis, up to 61% of patients with JIA-associated uveitis
either do not respond to corticosteroid treatment or require prolonged
therapy, with its attendant side effects (102). If inflammation persists with
frequent topical steroid dosing or continues to recur every time
corticosteroids are tapered and withdrawn, the addition of chronic oral
NSAIDs may be useful (103). Refractory inflammation should be treated
with steroid-sparing immunosuppression. In one large study, virtually no
toxicity was found in 127 patients in whom low-dose methotrexate was given
for the management of JIA-associated joint disease (30,104). Other
immunomodulatory agents such as cyclosporine, azathioprine, or
chlorambucil may be considered if continued inflammation with loss of
vision occurs despite these measures (5). Newer modalities include biologic
therapies, such as tocilizumab and adalimumab (105,106).
Surgical Indications
Children with JIA-associated uveitis may require surgical treatment for
refractory glaucoma, cataract, or band keratopathy. These patients are at
increased risk for intraoperative and postoperative complications due to
chronic inflammation. Even if the eye appears clinically quiet preoperatively,
it often responds to surgery with excessive bleeding, postoperative
inflammation, and unexpected postoperative IOP responses such as ocular
hypertension or hypotony. General anesthesia with endotracheal intubation
may be complicated by the presence of cervical arthritis or spondylitis,
temporomandibular joint inflammation with restriction of movement, or
micrognathia. The decision to proceed with surgery for the complications of
JIA-associated uveitis in a child is difficult and must be considered carefully.
Cataract surgery
Cataracts occur in 18% to 71% of patients with JIA-associated uveitis and
can be attributed to chronic inflammation and corticosteroid use (21,22).
Cataract surgery in JIA-associated uveitic eyes is daunting to even the most
accomplished cataract surgeon because of the unknown risks that can occur
intraoperatively and the uncertainty of the postoperative course (3,4). Surgery
is frequently technically challenging because of posterior synechiae, iris
vasculature delicacy, pupillary membranes, miotic pupils, and corneal
opacification (5). The combination of the heightened pediatric immune
response and a uveitic eye can result in violent postoperative inflammation if
proper preoperative care is not taken. Loss of vitreous or retention of cortical
material may exacerbate intraocular inflammation. Indications for cataract
surgery include visual rehabilitation, prevention or treatment of amblyopia,
and enhancement of the ophthalmologist’s view of the posterior segment for
ongoing assessment of the optic nerve and retina. Given the risk of surgery
and the sometimes unpredictable postoperative course, prevention of cataract
in patients with JIA is preferable (1).
The surgical technique for cataract extraction in the child with JIA should
include removal of the cataract, including the posterior capsule, all
retrolenticular and cyclitic membranes, and most of the vitreous. Historically,
pars plana lensectomy with pars plana vitrectomy was the procedure of
choice (26). For the pars plana approach, the lens and posterior and anterior
capsules are cut and aspirated with an ocutome probe. This is followed by a
near-total vitrectomy and removal of the lens capsule, anterior hyaloid, and
vitreous scaffold to reduce secondary membrane formation (21). A surgical
peripheral iridectomy should be performed if recurrent or chronic
inflammation is anticipated.
An alternative approach to cataract extraction may be accomplished by a
combined limbal approach with phacoemulsification and pars plana
vitrectomy. During the limbal approach, synechiolysis, pupillary stretching,
and iris hooks are used as needed for adequate exposure. Capsulorrhexis,
hydrodissection, and phacoemulsification are performed in standard fashion,
and the incision is closed. This is followed by a pars plana approach for
complete posterior capsule excision, followed by an anterior vitrectomy.
Classically, IOL implantation had not been recommended in patients with
JIA-associated uveitis (1,2,21,30). The IOL may provide a stimulus for
intraocular inflammation and structural support for inflammatory membranes,
which may induce irreversible ocular pathology. Thus, patients with JIA
usually have been left aphakic after cataract surgery, necessitating the use of
aphakic spectacles or contact lenses. Despite excellent anatomic outcomes,
visual rehabilitation for aphakic eyes may be suboptimal because many
patients of this age are unable to or refuse to wear aphakic contact lens or
aphakic spectacles (9). Among children, contact lens intolerance is reported
to be 17% to 38% (30,44). The frequent concomitant occurrence of band
keratopathy makes contact lens fitting difficult. Multiple lost contact lenses
carry a substantial expense. Children often are intolerant of aphakic
spectacles because of the weight and aniseikonia.
Management of Inflammation
It is critical that cataract surgery with or without IOL implantation be
attempted after absolute and sustained control of uveitis for a minimum of 3
months in patients with JIA. Long-term preoperative systemic
immunosuppressive therapy and aggressive perioperative topical
corticosteroids may vastly improve the outcome of cataract extraction in
children with JIA and may allow for IOL implantation for improved visual
rehabilitation. For aphakic children, vigilant postoperative amblyopia therapy
is critical, and patients should be followed in conjunction with a pediatric
ophthalmologist with proper aphakic contact lens or spectacles, orthoptic
evaluation, and occlusion therapy.
Glaucoma surgery
Elevated IOP frequently accompanies uveitis in patients with JIA. The
incidence of glaucoma in patients with JIA varies between 11% and 38%
(22). The prognosis for patients who develop glaucoma with JIA is poor. One
group (107) reported a 35% incidence of NLP vision in children with uveitis
and glaucoma. Medical therapy often proves inadequate for controlling IOP,
necessitating surgical intervention.
Band keratopathy
Band keratopathy is observed in 6% to 66% of patients with advanced JIA-
associated uveitis (21) and can be removed by EDTA chelation and
superficial keratectomy. For discussion, see “Therapeutic Surgery: Band
Keratopathy” section of this chapter.
Management of inflammation
In the child with JIA-associated uveitis, surgery is best undertaken after the
eye has been quiescent for as long as possible. Good control with systemic
immunosuppressive therapy can help prevent the complications of both
chronic inflammation and chronic corticosteroid use. It also allows an
improved chance of successful surgery with adequate control of
inflammation. Perioperative inflammation must be rigorously controlled with
aggressive topical, periocular, and possibly systemic corticosteroid use.
Maximum control of inflammation preoperatively, intraoperatively, and
postoperatively allows the greatest chance of a successful surgery.
OVERALL
In review, pediatric patients with uveitis require special attention, not only for
treatment but also for surgical intervention. Quiescence is the key, and if
possible, the surgeon should wait for the eye to be inactive for at least 3
months before proceeding with surgery. Proactive and aggressive control of
inflammation, which may require systemic immunosuppression,
preoperatively and perioperatively are essential for good postoperative
outcomes.
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49
Uveitis Masquerade Syndromes
Mikel Mikhail, and Lisa J. Faia
INTRODUCTION
The term masquerade syndrome is typically used in ophthalmology to
describe conditions that include, as part of their presentation, the presence of
intraocular cells but are not related to immune-mediated uveitic entities. The
term was first coined in 1967 to describe a conjunctival carcinoma presenting
as a chronic conjunctivitis (1).
Determining the cause of a masquerade uveitis is a diagnostic challenge,
since a wide variety of conditions present with intraocular cells. These
include immune-mediated processes (whether endogenously or exogenously
triggered), neoplastic conditions, as well as a variety of nonneoplastic
entities. Typically, masquerade syndromes refer to neoplastic entities that
may mimic intraocular inflammation. For the purposes of this chapter, we
have included the most common neoplastic, as well as nonneoplastic
diseases, that may present in the form of anterior or posterior segment
inflammation. Knowledge of these conditions when approaching a child with
a recurrent, chronic, or otherwise atypical uveitis is critical to avoid a delay in
diagnosis and management. Often, such a delay may have a significant
impact on the child’s visual morbidity and potentially, mortality.
PREVALENCE
Although exact numbers regarding the actual prevalence of masquerade
syndromes are difficult to come by in the pediatric literature, these conditions
are thought to constitute <3% of the patient population in subspecialty uveitis
clinics (2–4).
GENETICS AND ENVIRONMENTAL
FACTORS
Most neoplastic masquerade uveitis syndromes in the pediatric population
have an associated genetic component. Understanding of the role of genetics
in these entities is important for establishing a diagnosis, and for predicting
prognosis for visual recovery and/or patient survival.
For example, retinoblastoma is one of the few cancers for which a single
genetic mutation predicts disease development at very high penetrance. In
order for RB to arise, a mutation on both alleles of the RB1 gene is required
(5). A review of the genetics of retinoblastoma is highlighted in (Section III,
Chapter 44). Conversely, ciliary body medulloepithelioma, another neoplastic
entity that can present as a masquerade uveitis, has no identifiable
cytogenetic abnormality and usually presents sporadically (except in the
exceedingly rare case of pleuropulmonary blastoma family tumor and
dysplasia syndrome) (6,7).
Another neoplastic entity that can masquerade as a uveitis in the pediatric
population is leukemia. Acute lymphoblastic leukemia (ALL) is a childhood
disease that occurs as a result of recurrent genetic insults that block precursor
B- and T-cell differentiation and drive the proliferation and survival of
aberrant cells. Approximately 80% of ALL cases involve these chromosomal
abnormalities, which are incorporated into the World Health Organization
classification of acute leukemia (8). These translocations are important for
disease management, because they are also prognostically significant and
guide treatment. For example, the most common genetic lesion occurring in
childhood ALL is a 12;21 translocation (12; 21 (p13.2; q22.1), which is seen
in up to 25 percent of children with the B-lineage disease of ALL (19,22,23).
This translocation predicts a more favorable prognosis. Translocations
involving 11q23.3, although less common, predict a poorer prognosis in both
adults and children (8–11).
While the often cited Philadelphia chromosomal abnormality is common
in adults with ALL, it is only observed in 5% of children (12,13). The T-
lineage ALL are a separate disease entity. T-cell ALL is most commonly seen
in young adult males. 60% of these patients have an abnormal karyotype,
characterized by a pattern of recurrent karyotypic abnormalities involving
both T-cell (TCR) and non-TCR gene loci (14).
Histiocytic disease entities, commonly associated with masquerade
uveitic syndromes, also have a genetic component. For example, somatic
mutations that activate the MAPK signaling pathway are commonly found in
patients with Langerhans cell histiocytosis (LCH) and can help stratify
disease severity (15–18). While juvenile xanthogranuloma (JXG) limited to
the skin does not typically exhibit genetic changes, systemic JXG has been
associated with mutations in several MAPK pathway genes (19,20).
Nonneoplastic diseases that can present as uveitis can also present with
complex gene abnormalities and variable inheritance patterns. For example,
while they rarely masquerade as uveitis, inherited retinal degenerations have
variable genotypic and phenotypic patterns. The examining ophthalmologist
should pay attention to the patient’s family history, as well as associated
systemic features, to be able to identify these masquerade uveitic cases that
may present as retinitis pigmentosa (RP). This is important to confirm the
diagnosis, counsel the patient and his or her family members, and determine
eligibility for clinical trials or approved treatment.
Most masquerade uveitic masquerade syndromes have no identifiable
environmental factors. An exception to this is in cases of vitreous
hemorrhage and intraocular foreign bodies, which are commonly associated
with trauma. An evaluation for nonaccidental trauma in these cases is
important and is thoroughly explored in (Section IX, Chapter 70).
VISION REHABILITATION
Visual rehabilitation of children presenting with masquerade uveitic
syndromes encompasses the same principles of early intervention and
rehabilitation associated with any cause of vision loss. This is further
explored in Section X. Patients with these disease entities are often diagnosed
late in the disease course, due to the “masquerade” nature of these
pathologies. The treating ophthalmologist should order a thorough diagnostic
workup for these patients, a delay in diagnosis should not impede early
intervention and amblyopia management to avoid permanent functional
impairment.
ROLE OF OTHER PHYSICIANS AND
OTHER HEALTH CARE PROVIDERS
A multidisciplinary approach to the care of patients presenting with
masquerade uveitic syndromes is important to avoid visual and systemic
morbidity. The role of other physicians and other health care providers is
critical in the management of these complex patients. Many of these
masquerade syndromes involve neoplastic entities that are systemic in nature.
If there is clinical suspicion of malignancy, the early involvement of a
specialized oncology team is critical to avoid systemic morbidity or
mortality. In benign conditions, these masquerade uveitic syndromes
commonly present with systemic disease, and the involvement of a
pediatrician and/or subspecialists is important for optimal systemic
management of these patients. These patients can present with vision loss as
their primary complaint, and it is incumbent upon the treating
ophthalmologist to refer to specialty services as appropriate. Genetic
counseling, nursing care, social work, as well as occupational and physical
therapy, ensure adequate support to these patients and their families.
Retinoblastoma
Retinoblastoma is the most common intraocular malignancy in children, with
a reported incidence of 1 in 15,000 (21). While leukocoria and strabismus are
the most frequent presenting signs of retinoblastoma, a sizeable percentage of
cases can present with a masquerade uveitis. In fact, up to 40% of patients
with a final pathologic diagnosis of retinoblastoma were initially
misdiagnosed as having uveitis (22). This “pseudouveitis” is most commonly
due to tumor cells seeding in the anterior chamber (23–26). In some reports,
this has been reported to occur in 0.5% of patients with retinoblastoma, and a
pseudohypopyon has been shown to occur in up to 0.25% of patients (24).
Retinoblastoma can also be confused for vitreous hemorrhage, toxocariasis,
toxoplasmosis, or endophthalmitis (27). Despite the atypical nature of these
presentations, it is critical that the ophthalmologist maintain a high degree of
suspicion for retinoblastoma in a child due to the potential associated
morbidity and mortality.
Retinoblastoma can present in its exophytic, endophytic, or diffuse
infiltrating forms (28). The exophytic pattern occurs when the intraretinal
tumor grows in the direction of the subretinal space. Retinal vessels are
typically seen overlying a subretinal mass. The endophytic pattern occurs
when the tumor grows into the vitreous cavity and invades the inner retinal
layers. These tumor cells can seed the vitreous cavity. Vitreous tumor cells
can masquerade as a vitritis. These cells are typically tumor cells, although
they may rarely be inflammatory in nature, particularly if the tumor is large
and undergoes necrosis. The diffuse infiltrating type is characterized by
diffuse involvement of the retina, resulting in a placoid thickness rather than
a well-circumscribed mass, and it is typically seen in older children (29). The
latter pathology is the most likely type to present as a masquerade uveitis
(Figure 49-1). These have been typically described in unilateral, nonfamilial
cases (30). These lesions also do not typically present with intraocular
calcifications, a hallmark of the disease. Imaging to aid in diagnosis in those
cases may not be particularly helpful, given the fact that intraocular
calcifications are often absent.
FIGURE 49-1 This figure demonstrates a case of an 11-
year-old female who presented with a history of unilateral
leukocoria in the right eye (A). She had an anterior and
posterior uveitis with an ill-circumscribed mass inferiorly
(B). Enucleation revealed a poorly differentiated
retinoblastoma with retrolaminar and choroidal invasion
(C). The patient was treated with systemic chemotherapy
and recovered well.
Leukemia
The second most common neoplastic entity to present as a masquerade
uveitis is leukemia. Acute leukemia is the most common systemic
malignancy in children, affecting 1 in 30,000 below the age of 14 years. ALL
is the most common type, accounting for 90% of cases. Abnormal
proliferation of bone marrow blast cells displaces the native bone marrow and
results in pancytopenia (anemia, neutropenia, thrombocytopenia).
Chronic leukemia is less common in children compared to adults.
Leukemic cells commonly infiltrate the choroid and the retina, and
children classically present with a leukemic retinopathy or choroidopathy.
These are relatively straightforward to recognize. Oftentimes, however, iris
and anterior segment involvement can be confused with a uveitis.
Leukemic “uveitis” typically presents as a creamy-white
pseudohypopyon. Leukemia can also show a so-called pink hypopyon due to
intermixing of leukemic cells and the presence of an accompanying hyphema.
This layering of leukemic cells typically shifts with a change in head
position. The trabecular meshwork may also be involved, resulting in a
secondary glaucoma. The iris can be thickened and heterochromic due to
diffuse infiltration by leukemic cells, or it can be nodular in appearance due
to cellular clumping.
Eye involvement in children is reported to occur in about 9% of cases
(46). Leukemia can rarely present with anterior chamber inflammation,
composed of malignant leukemic cells. Although rare, refractory uveitis and a
hypopyon have been reported as the first manifestation of ALL (46). More
commonly, however, anterior chamber inflammation is the sole or
accompanying sign of relapse in a child with a history of acute leukemia
(47–50). Relapse of disease is common in leukemia, and anterior segment
relapse accounts for 0.2% to 2% of all cases of leukemic relapse (46,51). A
review of 196 children treated with acute leukemia showed 2 patients with a
bilateral anterior uveitis that was the first sign of relapse (52). The eye is
considered a sanctuary site for leukemic cells, and these cells are routinely
shielded from systemic treatment. Once chemotherapy is stopped, these cells
can often proliferate even in the absence of clinically apparent systemic
disease (52). Anterior chamber relapse has been reported to occur in the first
few months after finishing maintenance chemotherapy in these children. It is
also important to note that even in the absence of hematologic evidence of
relapse, anterior segment involvement should suffice to warrant further
investigation. Out of 11 cases of ocular relapse reported by Bunin et al., only
one child had concomitant hematologic relapse (53,54).
As with lymphoma, it is imperative to diagnose these lesions since
ocular, including anterior segment, involvement entails central nervous
system involvement. Anterior chamber paracentesis is diagnostic, and blast
cells are usually seen. Early diagnosis and therapy gives the child the best
chance at an ultimate cure. Local radiotherapy and/or intraocular injection
therapy is commonly required to treat ocular involvement with leukemia.
There should also be a diligent search for extraocular spread of leukemic cells
in the event a diagnostic tap demonstrates leukemic involvement of the eye.
Collaboration between the ophthalmologist and oncologist is critical in those
cases.
Juvenile Xanthogranuloma
JXG is a benign, non–Langerhans cell systemic histiocytosis that typically
affects children in the first 2 years of life (55). The disease characteristically
involves the skin, resulting in raised, reddish-yellow papules that are most
commonly found on the face. The most common extracutaneous site of
involvement is the eye, although other organs, such as the testes, spleen, lung,
and bone, can also be involved. Ocular complications due to JXG are rare,
occurring in around 0.5% of patients. They mostly occur in the 1st year of
life (56). The most common presenting ocular symptom is eye redness (57).
In the eye, the most common site of involvement is the iris. JXG can present
as an iris mass or a nodule (Figure 49-2). These iris nodules tend to bleed,
resulting in a spontaneous hyphema (57). This can result in glaucoma and
heterochromia (58–60). Choroidal infiltration can also occur and result in a
retinal detachment and a hemorrhagic infarction of the retina (61). JXG can
also rarely involve the eyelid (62).
FIGURE 49-2 This figure demonstrates a case of a 16-
year-old female who presented with an iris mass of the
right eye (A). This was initially thought to be a uveitis,
later believed to be a melanoma, and finally diagnosed as
juvenile xanthogranuloma. There was no hyphema. She
was treated with intensive topical prednisolone drops
every hour for 3 weeks, with subsequent resolution of
uveitis. The left eye was normal (B). An anterior segment
optical coherence tomography image (AS-OCT) of the
right eye clearly demonstrates the deposition of debris on
the anterior iris surface (C). (Courtesy of Carol Shields,
MD.)
Nonneoplastic Entities
While the term masquerade syndrome typically refers to neoplastic entities
that masquerade as benign processes, a number of nonneoplastic conditions
can present as a uveitis in a child.
These include vitreous hemorrhage, retinal detachment, and intraocular
foreign bodies. Retinal degenerations, such as RP, iris stromal cysts, and
idiopathic nonspecific orbital inflammatory syndrome (NSOI) can also
present with intraocular inflammation.
Vitreous Hemorrhage
An acute vitreous hemorrhage can be readily identified by the clinician. One
to three weeks after the onset of a vitreous hemorrhage, however, red blood
cells become smaller and tan colored.
These so-called ghost cells may resemble white blood cells. As a result,
an old vitreous hemorrhage can masquerade as a uveitis. These cells can layer
down in the anterior chamber, resulting in a pseudohypopyon. They can also
block the trabecular meshwork, and result in increased intraocular pressure,
an entity commonly described as “ghost cell glaucoma.”
A high degree of suspicion should be exercised by the clinician when
examining a child with vitreous hemorrhage. Ruling out nonaccidental
trauma in the context of unexplained vitreous hemorrhage is critical. In
addition, surgical intervention may be necessary due to the amblyogenic
nature of a vitreous hemorrhage, although a clear time frame as to when to
operate has not been established and is beyond the scope of this chapter (see
Chapter 11 on Amblyopia). Most importantly, ruling out a retinal detachment
or tear is paramount. If the vitreous hemorrhage does not permit a clear view
to the posterior segment and an ultrasound cannot be performed or is
equivocal, early clearing of the vitreous hemorrhage should be encouraged
(Video 49-1 ).
Retinal Detachment
Retinal detachment can present as a masquerade uveitis, particularly in the
pediatric population. Children, particularly preverbal children, are unable to
vocalize loss of vision, or they may not recognize a change in vision.
Vitreous hemorrhage, pigmented cells (referred to as tobacco dusting), and
inflammation can occur in eyes with a rhegmatogenous retinal detachment.
Liberated outer segments and inflammatory photoreceptor cells can
migrate anteriorly and block the trabecular meshwork, resulting in elevated
intraocular pressure, commonly referred to as the Schwartz-Matsuo
phenomenon (106–108). These photoreceptor cells can mimic white blood
cells and can be confused for an anterior uveitis.
Retinal Degenerations
Retinal degenerations are typically characterized by a progressive loss of
photoreceptors, nyctalopia, visual field loss, and abnormal electrophysiology.
Most cases are diagnosed in childhood or adolescence. They are a
heterogenous group of disorders and include entities such as RP, Bardet-
Biedl syndrome, Leber congenital amaurosis, Usher syndrome, Batten
disease, and congenital stationary night blindness (CSNB) (see Chapters 24,
26, 27, 29, 32 and 33).
The presence of vitritis in RP in adults is well documented (115,116). As
many as 37% of adult patients with RP have vitreous cells, with a more
significant inflammatory reaction observed in younger (<30 years old)
compared to older RP patients (115). Similarly, Stunkel et al. reported a 38%
incidence of vitritis in pediatric RP patients, with some disease entities such
as Baret-Biedl syndrome, CLN3 Batten Disease, and Leber congenital
amaurosis, reporting a greater number of cells and a higher incidence of
vitritis compared to others such as Stargardt disease or CNSB, in which
vitreous cells are rare (117). Interestingly, it appears that vitritis may be a
predictor of progression and a marker of disease severity. The presence of
vitreous cells may be more apparent in diseases that are typically rapidly
progressive such as Bardet-Biedl, compared to others that are traditionally
stationary, such as CSNB (118). These cells may be truly inflammatory in
nature. Sampling of the aqueous and vitreous fluid in RP eyes has shown an
increased level of proinflammatory cytokines (116). Alternatively, they may
simply represent shed photoreceptor cells, with greater cellular density
implying more progressive retinopathy and loss of neural elements.
Typically, these retinal degenerations present with signs other than
uveitis. These include a posterior subcapsular cataract, optic disk pallor
macular edema, vasculitis, epiretinal membrane, geographic RPE atrophy,
and peripheral pigmentary changes. While these disease entities commonly
overlap, they often have distinct phenotypes that are beyond the scope of this
chapter. A genotypic assessment in those patients is necessary to establish a
diagnosis, guide treatment, and evaluate the patient’s visual prognosis.
SUMMARY
A number of masquerade entities can present as uveitis in a child. These
conditions include both neoplastic and nonneoplastic diseases, as well as
benign and malignant entities. It is important for the clinician to maintain a
high index of suspicion when examining a child with any presentation of
suspected intraocular inflammation. The ophthalmologist should perform a
complete ocular and systemic history and examination to elicit any symptoms
or signs that may highlight an underlying masquerade syndrome. Masquerade
syndromes should always be considered as part of the differential diagnosis
in any case of pediatric uveitis. This is particularly important in cases of
recurrent, chronic, or atypical uveitis.
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SECTION VIII
Retinopathy of Prematurity
50
Worldwide Causes of Childhood
Blindness
Clare E. Gilbert, and Nathalie Lepvrier-Chomette
OUTLINE
This chapter describes what is currently known about the magnitude,
distribution, and causes of blindness in children worldwide and briefly
describes some of the major blinding diseases, concentrating on those that are
avoidable (i.e., preventable or treatable) and emphasizing control at the
population level rather than management of the individual child. More
detailed descriptions of retinal conditions, such as retinopathy of prematurity
(ROP) (see Chapter 52) and toxoplasmosis (see Chapter 47), are available.
INTRODUCTION
Definitions
The following definition of blindness in children are used throughout this
chapter: an individual aged 0 to 15 years (UNICEF definition of childhood)
who has a visual acuity of <6/60 in the better eye or a central visual field of
<10 degrees (the World Health Organization [WHO] categories of severe
visual impairment and blindness) (1). Although this definition can be readily
applied to adults, it is more difficult to measure visual acuity and assess
visual fields in young children, particularly in those with additional
disabilities. This poses particular challenges not only for clinicians but also
for ophthalmic epidemiologists, who may be concerned with identifying
blind children in the community to determine prevalence or who want to
undertake clinical trials or undertake longitudinal studies. This definition also
fails to capture the impact of visual loss on a child’s functional abilities,
quality of life, or sense of well-being.
EPIDEMIOLOGY OF BLINDNESS IN
CHILDREN
Prevalence and Magnitude of Blindness in Children
Population-based, cross-sectional surveys are the gold standard method of
estimating the prevalence of a condition in the population. However,
blindness prevalence surveys of children are difficult to conduct for a variety
of reasons. First, blindness in children is relatively rare, and very large
sample sizes, that is, approximately 30,000 children, are required to give
precise estimates of the prevalence. As there are many different causes, even
larger samples are required to give representative data, as some causes cluster
within families (e.g., congenital cataract and retinal dystrophies). Children of
school age are unlikely to be present at the time the survey team visits the
community, and this leads to an unrepresentative, biased sample, which can
overestimate the prevalence, because visually impaired children are less
likely to be at school. Indeed, in most developing countries, it is estimated
that only 10% of blind children are receiving any form of education. Higher
levels of clinical and diagnostic skills are also needed by team members to
perform surveys on children.
There are also challenges with other sources of data. For example, some
industrialized countries keep registers of the blind and if children are
included would provide population-based data. But to provide reliable
information, the database needs to be obligatory and constantly updated to
remove children who have had sight-restoring treatment or who have died or
who are no longer children. Other forms of registers, such as birth defects
registers, cannot provide blindness data as they do not use a functional
definition. Lastly, information collected from health care facilities, social
welfare organizations, or special education programs are also likely to be
biased as not all the blind children in the relevant population are included.
For example, in some countries, special schools cannot manage children with
other impairments; therefore, blind children with other impairments may not
be represented.
In developing countries, even these potential sources of data are not
available. Other approaches that have been successfully adopted include
training individuals who know their communities well and who then act as
key informants to identify the blind children in their communities. The
children thought to be blind are then examined by a team to confirm the
impairment and determine the cause of blindness. This approach, which was
developed in Bangladesh (2), has been used in a number of low-income
countries (3–7). Advantages of the “key informant method” are that a large
population can be covered relatively quickly, and awareness is created.
Questionnaires to parents and caregivers have also been assessed, and while
this tool has good sensitivity and specificity for identifying children with
physical and cognitive impairments, questionnaires do not reliably identify
children with sensory impairments (8). What is currently recommended is
that a variety of different methods and sources of data be used in the same
population, as has been undertaken in Mongolia (9), Bangladesh (10), Fiji
(11), Vietnam (12), Tanzania (13), and Indonesia (14).
Between the years 2000 and 2018, a literature review identified 22
studies that provided data on the prevalence of blindness in children in 17
countries (5–7,9,11,13–29). The data, together with earlier studies, suggest
that the prevalence of blindness in children is associated with under-five
mortality rates (U5MRs) expressed as deaths per 1,000 live births ranging
from a prevalence of approximately 0.3/1,000 children in countries with low
U5MRs (<10/1,000 live births) to 1.2/1,000 in the poorest countries of the
world in which U5MRs exceed 200/1,000 live births (30,31). Rates are
higher in poor countries because (a) there are potentially blinding conditions
in poor communities, such as vitamin A deficiency, malaria, and the use of
harmful traditional eye medicines, which do not occur in affluent
populations; (b) there is inadequate control of preventable causes of
blindness, including measles infection, ophthalmia neonatorum, and
congenital rubella; and (c) there is inadequate management of conditions
requiring optical or surgical treatment because children are not identified or
referred, parents cannot afford the travel and care, or there are inadequately
trained and equipped eye facilities to evaluate high refractive errors, cataract,
glaucoma, and ROP. Outcomes can also be compromised because children
present very late.
In 1992, there were estimated to be 1.5 million blind children, three-
fourths of whom lived in low-income countries (32). In 2010, the data were
revised to 1.26 million (33) using estimates of the prevalence of blindness in
each country based on their U5MR. For example, country x with a U5MR of
8/1,000 live births was assigned a prevalence of 0.3/1,000, whereas country z
with a U5MR of 112/1,000 was assigned a prevalence of 0.8/1,000. Over the
last few decades, U5MRs have continued to fall in most middle- and low-
income countries apart from the poorest countries in Africa where the decline
is generally slower (34). In 2018, the calculation was repeated, giving a
revised figure of 1.025 million blind children (Table 50-1). This represents a
32% decline from 1992. The group of countries classified as high income by
the World Bank (35) has the lowest number (62,380, 6% of the total), and the
lower middle-income region has the highest (547,640, 53% of the total).
Lower- and middle-income countries have a relatively higher proportion than
the other two regions, and this reflects the higher prevalence in each country
and the larger child population. The following countries have the highest
estimated number of blind children in descending order: India, Nigeria,
China, the Democratic Republic of the Congo, Pakistan, Ethiopia, Indonesia,
and Bangladesh.
The main factors leading to the decline in the estimate are improving
socioeconomic development, greater coverage of public health programs for
control of conditions leading to corneal scarring, and, in many countries,
greater access to tertiary-level eye care services, including for ROP.
Given the variation in prevalence as well as differences in population
structure, the number of blind children/million total population ranges from
approximately 60 in high-income settings to 600 in the poorest countries
(36).
In Figure 50-1, data on the magnitude and causes have been combined.
In addition to the 1.025 million children who are blind from eye diseases,
there are estimated to be a further 12.8 million children who are visually
impaired from uncorrected refractive error (89), principally myopia.
Approximately 2 of the 12.8 million children are blind. The largest number of
myopic children and adolescents live in Southeast Asia.
Regional Variation in Causes and Change Over Time
The pattern of causes has changed over time as global initiatives for the
control of vitamin A deficiency and measles have led to a reduction in
corneal scarring, which in 1992 were believed to be the commonest causes in
low-income countries (32). In many low-income countries, cataract is now
the commonest avoidable cause, whereas ROP has increased in importance in
many middle-income countries and is increasing in importance in lower
middle-income countries (90).
Preterm birth, which affects an estimated 15 million infants globally (91),
contributes substantially to blindness in children from lesions of the higher
visual pathways in high-income countries and ROP in middle-income
countries (92).
Cataract and glaucoma are important causes of blindness in children in all
regions but particularly in low-income countries. While the management of
these conditions should be essentially the same throughout the world, in
practice children in low-income settings often present very late which
compromises the visual outcomes of surgery (93,94). Although increasing in
number, specialist eye care centers for children are still not adequate in terms
of numbers or resources to meet the needs of the population (95), and surgery
is often undertaken by general ophthalmologists who are not always aware of
visual development or the specific problems or long-term implications of
operating on children. There are also considerable barriers from the parents’
perspectives, in terms of cost, fear or poor outcomes, the difficulties of travel,
and beliefs concerning the cause of their child’s problem. In Asia, there is
some evidence that girls with bilateral cataract are less likely to access
services than boys, and this probably reflects cultural preferences for boys
(96).
Secondary Prevention
Treatment of the disease to prevent impairment leading to a reduction in
the incidence of the impairment (e.g., antibiotic treatment of infections,
screening and treatment of type 1 ROP)
Tertiary Prevention
Treatment of the impairment to restore function (e.g., surgery on a
cataract in a blind child), which reduces the prevalence of impairment,
and rehabilitation, which compensates the impairment to reduce
disability (e.g., low-vision or assistive devices).
The available evidence suggests that globally 30% to 40% of children are
blind from conditions amenable to primary and secondary prevention, or
interventions, which restore function from avoidable causes. In high-income
countries, only a few children become or remain blind from avoidable causes,
whereas in low-income settings, at least 50% of blind children have
avoidable causes.
Conjunctival xerosis and Bitot spots are signs of long-standing VADD, found
principally in children aged 3 to 8 years. Children most at risk of
keratomalacia are aged 6 months to 4 years with protein energy malnutrition
who may not exhibit other features of xerophthalmia before the onset of
corneal ulceration. Because not all children who are vitamin A deficient
develop eye signs, it is important to be able to identify communities at risk,
because children with xerophthalmia represent only the “tip of the iceberg” of
those who are deficient in vitamin A in the community. Table 50-3 shows the
WHO minimum prevalence criteria for the different ocular signs of VADD,
which indicate that the condition is frequent enough to be a public health
problem. Under-five mortality rates can also be used to assess the likely risk
that VADD is a public health problem (97).
Secondary Prevention
Vitamin A treatment for all children with signs of xerophthalmia, that is,
three doses given over 2 weeks
Tertiary Prevention
Keratoplasty and optical iridectomy
Measles
The measles virus is highly contagious, and measles infection can be
associated with high case fatality rates (103). The Expanded Program on
Immunization, which includes measles immunization, has had a dramatic
impact on child deaths: in 1999, there were estimated to be 850,000 measles-
related deaths globally, comprising 10% of all childhood deaths, which had
declined to 89,780 by 2016. Indeed, measles and rubella immunization are
thought to have contributed 23% of the overall decline in under-five mortality
rates between 1990 and 2008 (104). More than 95% of the deaths occurred in
low-income countries where measles immunization rates remain below the
target of 80% coverage (Figure 50-5).
FIGURE 50-5 Measles immunization coverage with first
dose of measles containing vaccines in infants, 2016
(Source: WHO/UNICEF coverage estimates 2016
revision. July 2017. Map production: Immunization
Vaccines and Biologicals, (IVB). Word Health
Organization. 194 WHO Member States. Date of slide: 19
July 2017.)
However, the number of measles cases has recently increased in some high-
income countries as a result, in part, of unfounded fears about the risk of
autism following mumps, measles, and rubella (MMR) immunization
(Figure 50-6) (105).
FIGURE 50-6 Provisional measles cases data (February
2018 to January 2019) based on monthly data reported to
WHO (Geneva) as of March 2019. (From World Health
Organization. Global Measles and Rubella Monthly
Update. March 2019. Available from:
https://www.who.int/immunization/monitoring_surveillance/burden/vpd/s
Secondary Prevention
Diagnosis and appropriate treatment of corneal ulceration, that is,
repeated high-dose vitamin A, antibiotics, and antiviral agents
Tertiary Prevention
Optical iridectomy
Harmful Traditional Eye Remedies
In animist societies, disease is thought to have several origins, that is, they
may be supernatural, such as being caused by spirits or by angering ancestors
or breaking taboos; they may arise as a result of conflict, tension, jealousy, or
immoral behavior; they may be the result of the “evil eye” or witchcraft; or
they may be passed down within the family through the mother. Other
conditions are due to weakness, eating unclean food, or lack of respect
toward parents or elders. Remedies are based on these understandings. The
WHO has defined traditional healing in the following terms: “the sum total of
all the knowledge and practices, used in diagnosis, prevention and
elimination of physical, mental or social imbalance and relying exclusively
on practical experience and observation handed down from generation to
generation, whether verbally or in writing” (110).
The use of harmful traditional remedies, initiated or used as part of
cultural practices within the family or community, or administered on the
advice of traditional healers, has been an important cause of corneal blindness
in children in low-income settings. This was particularly the case in Africa,
although use of harmful remedies is probably declining as a result of better
levels of education and the decline in measles, which parents feared would
lead to blindness. However, it is important to recognize that traditional
practices are widespread, and although some may be harmful, many are
benign, such as ritual bathing or dances, or may even be of benefit as in the
case of direct application of breast milk into the eye, steam baths, or
inhalations.
There are several mechanisms whereby traditional remedies can lead to
ocular damage and blindness. Firstly, injury to the adnexa from chemical or
thermal burns can lead to exposure keratitis and secondary infection (Figure
50-7). Exposure keratitis can also occur from parents keeping the eyes of the
children held open, a practice believed to prevent blindness in children with
measles in parts of West Africa. Secondly, objects and material inserted into
the eye can cause mechanical damage. Examples include insertion of twigs
and leaves, ground-up cowrie shells, and liquids or sap from plants, which are
either acidic or alkaline. Thirdly, mechanical damage predisposes toward
infection, particularly from fungi if plant material is inserted. Fourthly,
infected fluids can lead to severe infection (e.g., urine from someone infected
with gonorrhea or breast milk that has been expressed into a contaminated
container) (Figure 50-8). Lastly, harmless traditional remedies can lead to
corneal blindness indirectly, as a consequence of delay in seeking more
appropriate treatment.
Secondary Prevention
Early diagnosis and appropriate treatment of corneal ulcers
Tertiary Prevention
Optical iridectomy
Ophthalmia Neonatorum
Ophthalmia neonatorum, defined as conjunctivitis within 28 days of birth,
was an important cause of blindness in children at the turn of the century in
Europe. The introduction and widespread use of Credé’s prophylaxis
(cleaning of the lids immediately after birth, followed by instillation of
topical silver nitrate solution) resulted in a dramatic decline in blindness even
before antibiotics were available (111). Current data are not available on the
incidence of vision loss in children from ophthalmia neonatorum.
Ophthalmia neonatorum can be due to a range of organisms, but the most
important pathogens are Chlamydia trachomatis and Neisseria gonorrhoeae.
Transmission of these organisms from infected mother to infant is reported to
be 18% to 50% and 28%, respectively. Despite recent public health measures,
rates of chlamydial infection, particularly among teenage girls, are increasing
in many countries in Europe and North America, whereas rates of sexually
transmitted diseases (STDs) in Africa, particularly due to gonorrhea, remain
high. For example, a recent review of 171 studies in Africa involving over
300,000 pregnant women reported that 4% had gonorrhea and 7% had
chlamydial infection of the genital tract (112).
Approaches to the control of ophthalmia neonatorum still rely on Credé’s
prophylaxis, and several clinical trials have been undertaken in different
settings, which show that 1% silver nitrate solution, 1% tetracycline
ointment, and 0.5% erythromycin are all equally effective against gonococcus
(111). These agents have been recommended by the Canadian Task Force
(113). Studies in Africa have shown that 2.5% povidone–iodine aqueous
solution is also effective (114) and has the advantage of being easy and cheap
to manufacture locally. However, although some argue that tetracycline eye
ointment is preferable (115), a recent systematic review concludes that no one
agent is superior to another and that prophylaxis should only be considered
when rates of STDs are high (116).
Treatment of babies with ophthalmia neonatorum due to gonococcal or
chlamydial infection requires systemic as well as intensive topical treatment,
taking into account the susceptibility of the organism as well as availability
and cost of medication.
The control of gonococcal ophthalmia neonatorum is a challenge in low-
income countries as rates of STDs and infection due to penicillinase-
producing N. gonorrhoeae are high and a high but declining proportion of
births take place outside health care facilities, attended either by trained or
untrained traditional birth attendants or by family members.
Secondary Prevention
Prompt diagnosis and tropical and/or systemic treatment with antibiotics
appropriate to the microbiology and local susceptibility
Tertiary Prevention
None
Secondary Prevention
Early detection, referral, and management of children with cataract and
other eye anomalies
Tertiary Prevention
Rehabilitation and low-vision care
Malaria
Neurologic sequelae following severe malaria are another cause of blindness
in children encountered in low-income settings, particularly in Africa.
Malaria due to Plasmodium falciparum is the most severe form, leading to
severe anemia, hemoglobinuria from massive intravascular hemolysis
(blackwater fever), cerebral malaria and its sequelae, and death. Most
cerebral malaria occurs in children in sub-Saharan Africa, where 575,000
children aged <5 years are estimated to be affected annually. Studies
undertaken in Malawi and West Africa have shown that children with
cerebral malaria can develop characteristic disc and retinal findings, that is,
papilledema, retinal hemorrhages, Roth spots, cotton wool spots, and
extensive areas of retinal pallor and edema (127) (Figure 50-9) (128). Retinal
arterioles and veins can also appear orange in color on account of limited
circulation of red blood corpuscles, which are sequestered in the circulation.
Retinal hemorrhages indicate a poor prognosis. Recent studies of fluorescein
angiography and histopathology confirm that the retinal whitening is due to
cytotoxic edema secondary to acute ischemia (129).
Secondary Prevention
Diagnosis and treatment of malaria in children with antimalarial drugs to
which the organism is sensitive
Management of children with cerebral malaria, although evidence is
lacking on the most effective treatments
Tertiary Prevention
Rehabilitation
Secondary Prevention
Early diagnosis and management of neonatal sepsis
Tertiary Prevention
Rehabilitation
Fetal Alcohol Syndrome
Alcohol consumption during pregnancy can lead to a range of phenotypes,
called fetal alcohol spectrum disorders (FASD), which reflects the range of
structural and functional abnormalities that can result from alcohol exposure
in utero. The full syndrome (FAS) is now one of the most common and most,
preventable causes of cognitive impairment in children. For example, in the
United States, FASD has a birth prevalence of 1.9/1,000 live births
(compared with 1.6/1,000 live births for Down syndrome). South Africa is
reported to have the highest rates of FASD anywhere in the world where it
occurs in 3 to 30/1,000 live births (141).
For diagnostic purposes, the child should have each of the following
abnormalities, although they may be present in varying degrees: prenatal
and/or postnatal growth retardation, structural and/or functional CNS
abnormalities, and a characteristic facial appearance (i.e., microcephaly, short
palpebral fissure, poorly developed philtrum, and a flat maxilla). Up to 90%
of children with FASD have ocular signs and symptoms, including optic
nerve abnormalities, such as optic atrophy or optic nerve hypoplasia (48%),
tortuous retinal blood vessels (50%), short palpebral fissure, broad telecanthic
folds, ptosis (50%), and strabismus (40% to 50%) (142). Less frequent
changes include high refractive errors, microphthalmos, nystagmus, cataract,
and corneal opacity, including Peters anomaly. Affected children can also
develop a range of psychosocial disabilities and behavioral problems (141).
The full syndrome occurs in 30% to 50% of the children born to alcoholic
women. Whether there is a safe limit for alcohol consumption during
pregnancy has not yet been clarified, but the current recommendations are to
abstain.
Primary Prevention
Health education before conception and during antenatal care about the
harmful effects of alcohol during pregnancy
Myopia in Children
Myopia, which is the most common type of refractive error, is increasing
globally, particularly among children in the economically advanced countries
of East and Southeast Asia (143–145). In these countries, myopia can start
early, around the age of 6 or 7 years, and can affect 80% of adolescents. In
these countries, the prevalence is higher in children in urban areas where
myopia can have an earlier age of onset and progress to high myopia
throughout adolescence. High myopia is of particular concern as it increases
the risk of vision impairment from myopic macular degeneration, retinal
detachment, cataract, and glaucoma later in life (146). Indeed in 2015, it was
estimated that 10 million people were visually impaired from myopic macular
degeneration, which is projected to increase to 55.7 million by 2050 (147).
Factors implicated in the increasing incidence and severity of myopia
associated with urbanization include greater educational pressure with
prolonged periods of close work and lack of time spent outdoors, the latter
probably being mediated by lack of exposure to daylight (145,148,149).
Having parents with myopia is known to increase the risk, and interactions
between behavioral and environmental factors and genetic variants are an
active area of research, because on their own, genetic variants only explain
0.6% to 2.3% of the variance in refractive error (150).
Several approaches are being explored to reduce the risk of myopia or to
slow its progression and include optical, pharmacologic,
behavioral/environmental, or surgical approaches (151). Interventions include
topical medication with antimuscarinic eye drops, alternative ways of
correcting myopia with bifocal contact lenses or spectacles, for example,
increasing the amount of time children spend in daylight by being outdoors or
by altering the design of classrooms, or surgery to reinforce the sclera.
There is evidence from clinical trials that antimuscarinic eye drops slow
the progression of myopia, but side effects, such as increased sensitivity to
light, blurred near vision and allergies, lack of availability of the medication,
and the need for prolonged treatment, limit their usefulness (152). There is
increasing evidence that the amount of time children are exposed to daylight
reduces the incidence of myopia, with a greater impact among younger
children and by spending longer times outdoors (153–155). However,
paradoxically, this does not seem to reduce the progression of established
myopia. Myopia control is an active area of research given the impact of
uncompensated myopia on academic achievement (156) and the long-term
complications of high myopia.
Primary Prevention
Increasing time spent outdoors (limited evidence)
Secondary Prevention
Topical muscarinic drugs
Tertiary Prevention
Optical correction
Retinopathy of Prematurity
Globally, there are approximately 15 million preterm births, defined as birth
<37 weeks of gestational age (GA), each year, and approximately 2.3 million
are born <32 weeks of GA (157). Ten countries account for 60% of preterm
births: China, India, Nigeria, Pakistan, Indonesia, the United States,
Bangladesh, the Philippines, and the Democratic Republic of the Congo.
Several epidemics of blindness due to ROP have been described (Figure
50-10). The most recent, the third epidemic, started in Latin America and
Eastern Europe in the 1990s, then spread to the Middle East and East and
South Asia, and is beginning to emerge in sub-Saharan Africa (92).
FIGURE 50-10 Epidemics of blindness due to ROP.
(Reprinted from Gilbert C, Malik ANJ, Nahar N, et al.
Epidemiology of ROP update—Africa is the new frontier.
Semin Perinatol 2019;43:317–322. Copyright © 2019
Elsevier. With permission.)
The main driver of the third epidemic is the rapid expansion of intensive
neonatal care as the Ministries of Health strive to reduce neonatal mortality.
However, the level of care can be suboptimal with inadequate equipment to
safely deliver supplemental oxygen from immediately after birth, lack of
qualified staff with high nurse-baby ratios, and overcrowded units, all of
which compromise care. In addition, many countries have an absolute lack of
ophthalmologists to screen and treat ROP, or the number of skilled
ophthalmologists with the requisite time and motivation is low. In addition, in
settings were neonatal care is suboptimal, more mature babies can develop
sight-threatening ROP, which means a high proportion of infants need to be
screened (158).
In 2013, it was estimated that 32,300 infants were becoming blind or
visually impaired from ROP every year (90). All regions are now affected
(Figure 50-11) (159) with studies being reported from sub-Saharan Africa
(160).
Many countries, such as those in Latin America and South Africa, now have
ROP programs with some achieving high coverage of screening and
treatment. Programs are scaling up in India (161) and China, and initiatives
are starting in some sub-Saharan countries, such as Nigeria, Kenya (162),
Ghana, and Tanzania, and in Pakistan and Bangladesh. A study in Latin
America highlighted the importance of national guidelines, health
management information systems, and legislation that mandates ROP
screening as being important factors leading to high coverage (163).
However, many countries do not yet have guidelines (164), which need to
vary depending on the population at risk (165). The active engagement of
Ministries of Health is also vital (166).
Reports of the proportion of infants who develop any ROP or “severe” or
“treatment-warranted” ROP varies considerably depending on the case mix,
the definitions used, the criteria for screening, and the expertise of the
examining ophthalmologists. In the United States, in a multicenter cohort of
7,483 infants, 459 (6%) developed type 1 ROP (167); in Switzerland, 1.9% of
6,719 infants developed stage 3 to 5 ROP (168); and in the United Kingdom,
4% of 8,112 infants were treated (169). In these studies, the majority of
infants treated were extremely preterm. In India, the proportion treated is
often similar despite the use of much wider screening criteria. A higher
proportion develops aggressive posterior ROP (APROP), and the birth weight
and GA of affected infants are far higher. For example, in one study, 4.4% of
4,161 infants were treated for ROP, 17% of whom had APROP (170).
The main risk factors for ROP are increasing prematurity, low birth
weight, and intrauterine growth restriction. Postnatal risk factors include poor
weight gain, sepsis, early hypothermia (171), hyperglycemia, and poorly
regulated oxygen leading to hyperoxia or fluctuating hypoxia/hyperoxia
(172). Other potentially modifiable risk factors include transfusion of blood
products and thrombocytopenia (173). There is also evidence that a course of
antenatal steroids for women threatening preterm delivery improves a range
of outcomes, including ROP (174). (See also Chapter 52.)
Neonatologists have to tread a difficult path in relation to the
administration of supplemental oxygen. A recent meta-analysis of the five
multicenter clinical trials compared the outcomes of different oxygen
saturation targets (NeOProM) (175). The lower target oxygen saturation
target range (85% to 89%) had a higher risk of mortality, but a lower risk of
ROP treatment than the higher target range (91% to 95%). There remains
controversy as to the saturation targets recommended, but some reports have
recommended 90% to 94% (alarm limits 89% to 95%) in high-income
countries (176) and 88% to 95% (alarm limits 89% to 96%) in low- and
middle-income countries (177).
Primary Prevention
Prevention of preterm birth
Secondary Prevention
Screening for ROP of preterm babies at risk, starting 3 to 4 weeks after
birth
Urgent treatment (within 48 hours) of infants developing the sight-
threatening stages of ROP, with close follow-up
Vitreoretinal surgery for stage 4a ROP
Tertiary Prevention
Vitreoretinal surgery for the stage 4b and 5 ROP
Frequent follow-up throughout childhood of babies treated for ROP to
detect and manage complications such as refractive errors and squint
Rehabilitation
Ministries of Health are currently identifying their priorities for UHC in their
respective countries, and this provides a unique opportunity for prioritizing
eye care (184). In particular, it is imperative that eye care for children is
integrated into the broader agenda for child health, including for primary eye
care (185,186), the integration of correction of refractive errors into school
health, ROP screening as an integral component of neonatal care, and eye
care as an essential element of tertiary-level health care.
ACKNOWLEDGMENTS
CG Support from The Queen Elizabeth Diamond Jubilee Trust, United
Kingdom, for work on ROP in India and other Commonwealth countries is
acknowledged.
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51
Education and Management of
Retinopathy of Prematurity
Worldwide
Tala Al-Khaled, Samir N. Patel, and R. V. Paul Chan
INTRODUCTION
First and Second Epidemic of Retinopathy of
Prematurity
Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the
developing retina, described by Terry in 1942 (1). At that time, ROP was
described as “retrolental fibroplasia.” There were few treatment options, and
a significant number of infants developed total retinal detachments (2).
During the 1940s and 1950s, the “first epidemic” of ROP occurred mainly in
developed countries due to unmonitored use of oxygen in premature babies
(3). A better understanding and restriction of oxygen supplementation
subsequently led to reduced blindness. However, as advances in prenatal and
neonatal care led to the increased survival of smaller and less mature babies
in the 1970s and 1980s, another wave of ROP began, leading to the “second
epidemic” of ROP (4).
Fortunately, a better understanding of the natural course of ROP and
advances in treatment have led to improved structural and functional
outcomes, first with the multicenter prospective trial, Cryotherapy for
Retinopathy of Prematurity (CRYO-ROP) (5), then the Early Treatment for
Retinopathy of Prematurity (ET-ROP) trial (6), and, more recently, the
Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of
Prematurity (BEAT-ROP) study, which has reported the utility of intravitreal
antivascular endothelial growth factor (VEGF) agents in some cases (7) (see
also Chapters 52 and 53).
TREATMENT
Advancements in ROP management were facilitated in the 1960s and 1970s,
when both laser photocoagulation and cryotherapy were shown effective as a
treatment (5,14,15). The CRYO-ROP multicenter trial examined cryotherapy
versus observation in eyes of premature babies with threshold ROP. A
significant reduction in unfavorable structural outcomes (retinal detachment,
macular fold, or retrolental tissue) and visual acuity of <20/200 was found in
eyes undergoing cryotherapy compared with untreated eyes (5) (details in
Chapter 52). These early results would continue to hold true as the 15-year
follow-up demonstrated unfavorable structural outcomes in about 30% of
treated eyes compared to over 50% of control eyes. Additionally, unfavorable
visual acuity outcomes (20/200 or worse) were significantly reduced in
treated eyes (16).
Based on the results of the CRYO-ROP trial and the development of a
risk analysis model, investigators subsequently investigated the role of earlier
treatment. The ET-ROP study was initiated in the early 2000s and was a
multicenter clinical trial that compared treatment for eyes with type 1 “high-
risk prethreshold” disease and type 2 “low-risk prethreshold” disease versus
eyes treated at conventional “threshold” ROP. Results showed significantly
decreased unfavorable visual acuity and structural outcomes (6).
There has been an increase in the use of intravitreal bevacizumab
(Genentech Inc., San Francisco, CA) for the management of ROP. Initial case
reports in 2007 showed use in the management of aggressive posterior ROP
and other cases of aggressive disease (17,18). The BEAT-ROP study, a
clinical trial comparing laser and anti-VEGF (bevacizumab 0.625 mg), found
a very short-term benefit of reduced need for further treatment in advanced
ROP even beyond type 1 ROP or the older classification from CRYO-ROP of
threshold ROP and laser in infants (7). In addition, the use of anti-VEGF
appears to have lengthened the time for recurrence or full vascularization,
which was determined as a safe time to stop weekly eye examinations in
treated ROP (see Chapter 52). In the past, these infants had poor outcomes;
the use of bevacizumab offers hope, but until safety and dosing studies are
performed, anti-VEGF is still of concern for both the developing infant and
eye. Currently, at least two multicenter trials are underway for forms of
severe ROP, one by the Pediatric Eye Disease Investigator Group through the
National Eye Institute to assess the lowest effective dose of bevacizumab
given through intravitreal injections and another through Novartis
(RAINBOW Study: RAnibizumab Compared With Laser Therapy for the
Treatment of INfants BOrn Prematurely With ROP), which compare laser to
two doses of ranibizumab in 0.05 mL (19,20).
Potential Solutions
Standardization of ophthalmology fellowship curricula may also help
improve training in ROP management. Currently, the Association of
University Professors of Ophthalmology (AUPO) Fellowship Compliance
Committee is attempting to establish uniform training standards. For
example, there are suggestions to retina fellowship programs regarding
minimum operative numbers for vitrectomies and scleral buckles. However,
fellowship programs are not required to follow these AUPO guidelines, and
in fact, many reputable fellowships are not in compliance. Moreover, even
among fellowship programs adhering to AUPO standards, there are no
recommendations for pediatric ophthalmology and retina fellows regarding
ROP examinations, ROP laser procedures, or assessment of competency in
ROP management (29,30). Perhaps there is a need to establish a minimum
number of ROP examinations and laser procedures as well as incorporate
other tools such as ophthalmic clinical exercises, 360-degree assessments
(evaluations based on multiple sources, such as supervising faculty, peers,
residents, nurses, technicians, students, and patients), and global faculty
performance ratings for ROP fellow training (31–34). These devices have
proven useful in ophthalmology residency training and may be helpful in
fellowship training as well.
Lastly, an area of needed research and commentary is the current
American Board of Ophthalmology certification process for
ophthalmologists. Board certification, and recredentialing every 10 years
under the American Board of Ophthalmology, is widely sought after among
practicing ophthalmologists; however, no credentialing is offered for
subspecialty care, such as advanced surgeries in cornea, glaucoma, or retinal
disease. The clinical significance of this lack of recredentialing regarding
ROP involves results from Kemper et al. (35), which found that many
ophthalmologists without subspecialty training were performing ROP
screening and treatment. It is unclear if formal training in pediatric
ophthalmology or retina makes a difference in competency of ROP
management, but a credentialing process to ensure certain standards of
training would likely help with public accountability (36). Though an
unproven correlate, studies in intensive care medicine, made up of a wide
range of specialists, including critical care medicine, pulmonology, surgery,
anesthesiology, and neurology, have shown that care led by intensivists with
certification in critical care medicine is strongly associated with improved
patient survival (37).
Potential Solutions
Preventative Measures
In the context of the “third epidemic” of ROP, there are discussions regarding
fundamental changes in health care practices and policies with the aim of
improving the care of neonates at risk for ROP. The Every Preemie-Scale
initiative funded by the United States Agency for International Development
(USAID) released a Do No Harm Technical Brief with recommendations
summarized as follows: (a) tailor screening criteria by geography, which
refers to modifying gestational age and birth weight cutoffs in light of care
received in the NICU and oxygen usage; (b) educate health care providers on
the appropriate use of oxygen delivery equipment and the importance of
oxygen level monitoring; (c) ensure adequate workforce is available to
provide neonatal care; (d) secure equipment necessary to perform retinal
exams and assess for ROP; and (e) create national policies that mandate
screening for ROP, as appropriate (45). In regard to implementing policy
change, the Economic Model of Retinopathy of Prematurity (EcROP) was
applied to regions in the United States and Mexico and found that a
comprehensive ROP screening program is cost-effective and cost-saving,
indicating the benefits of establishing national protocols for ROP (46).
Currently, there are many groups working together to prevent, screen for, and
treat ROP (45). These include a number of USAID-funded programs in
collaboration with Helen Keller International, Orbis International, the
Retinopathy of Prematurity Network (ROPNET), the Aravind Eye Health
System, and the Global Education Network for Retinopathy of Prematurity
(GEN-ROP), as well as other global and regional programs (45). Notably,
telemedicine has emerged to play a vital role in promoting ROP screenings
(45).
INTRAVITREAL ANTI-VEGF
THERAPY: GLOBAL IMPLICATIONS
In addition to emerging telemedicine programs, the encouraging results with
anti-VEGF agents for ROP suggest a role for the therapy on the global scale.
As mentioned previously, developing nations are now dealing with increasing
numbers of children with ROP, and clinicians in these countries may lack the
experience, support staff, equipment, or facilities to adequately treat with
laser photocoagulation. Intravitreal anti-VEGF therapy may have advantages
over laser, including ability to administer through opaque media or
significant pupillary neovascularization, ease of use with less time needed for
treatment, and potentially cheaper cost.
Despite its exciting potential, intravitreal anti-VEGF therapy is still not
ready to completely replace laser photocoagulation, which has historically
been the gold standard of treatment. The biggest concerns and unanswered
questions regard the potential systemic and local adverse events of the
antiangiogenic agent. Despite local administration of bevacizumab, it has
been reported to enter the systemic circulation after intravitreal injection in
animal models and has been shown to exhibit a bilateral response after
unilateral administration in adults (80–82). Sato et al. (83) reported levels of
serum bevacizumab, with resultant reduced serum VEGF, in preterm infants
treated with intravitreal bevacizumab. Similarly, Wu and colleagues
identified the persistence of bevacizumab in the circulation of neonates for 8
weeks. The consequential reduction in VEGF levels could carry various
implications, including disruption of normal physiologic development (84).
Although VEGF mediates and drives the ROP disease process, it is crucial
for the survival and growth of many organs, such as the brain, lungs, and
kidneys (85–87). Morin and colleagues identified that neonates treated for
ROP with bevacizumab were at three times greater risk for developing
significant neurologic dysfunction, such as cerebral palsy and loss of hearing
and vision, compared to their counterparts who underwent laser
photocoagulation (88). In the BEAT-ROP study, there was a statistically
nonsignificant increase in mortality in babies treated with bevacizumab
(6.6%) versus those treated conventionally (2.6%) (7). Lepore et al. reported
4-year follow-up data of 21 infants with type 1 ROP who had one eye treated
with 0.5 mg bevacizumab and reported that fluorescein angiography revealed
that all the eyes treated with anti-VEGF therapy had evidence of vascular
irregularities at the peripheral retina and posterior pole (89). Currently, the
functional value to these structural findings is unclear. Additionally, some
circumstantial evidence exists implicating anti-VEGF agents in
thromboembolic events (90). Therefore, there is legitimate concern about the
potential systemic effects and long-term sequelae of an antiangiogenic agent
used in developing neonates. Moreover, despite the “ease” of intravitreal
injections and the potential to train nonophthalmologists in this technique,
local complications occur. Endophthalmitis, retinal hemorrhage, cataract, and
retinal detachment are possible even in trained hands, and specific knowledge
of eye anatomy in a premature baby is critical (91).
Other questions remain regarding the dosing, timing, and frequency of
administration of anti-VEGF agents; management of treatment failure; and
which anti-VEGF agent is most ideal for use in ROP. Initial reports used 1.25
mg bevacizumab, but subsequent studies demonstrated effectiveness with
0.625 mg or even lower dosing (7,17). Recently, a phase 1 dose de-escalation
study found that 0.031 mg bevacizumab, or 5% of the dose used in the
BEAT-ROP trial, was effective for treatment (20). This issue is important
since current reports do not seem to vary dosing based on infant weight,
gestational age, postmenstrual age (PMA), level of supplemental oxygen use,
or nutritional status. Future studies will help answer these important
questions and establish the lowest effective dose that can be used to
neutralize the excess VEGF in the eye without risk to the developing eye or
to systemic organs. The timing of injection seems to be important as well.
Treatment too early may promote significant delay of normal vascularization,
whereas treatment too late may promote retinal detachment in eyes with
preexisting traction from neovascularization (92). Additionally, even though
the response to anti-VEGF agents can be dramatic, with regression of severe
ROP occurring 24 to 48 hours after a single injection, more studies will need
to determine the utility and safety of multiple injections.
Lastly, concerns about disease progression and frequency of follow-up
exist. Vanderveen et al. identified the following trends: (a) recurrence of ROP
is greater following treatment with anti-VEGF compared to laser, which
beckons the need for patients to undergo further interventions; and (b)
revascularization of the retina is hindered with anti-VEGF injections, which
demands more extensive surveillance of patients following treatment (93).
Especially problematic is that disease recurrence following anti-VEGF
treatment seems to occur later in the course of disease than with laser therapy
(even 1 year), which can lead to retinal detachment in eyes that would
normally not have received follow-up after laser treatment based on
conventional standards. For example, Hu et al. reported a review of 17 eyes
with recurrence of ROP after initial bevacizumab treatment as initial
monotherapy. Mean age at treatment-requiring recurrence was slightly <50
weeks PMA, with a maximum at 69 weeks PMA. Of the eyes studied, almost
30% progressed to retinal detachment (94). Given these emerging data,
babies treated with intravitreal anti-VEGF therapy will need longer and likely
more frequent follow-up, which may be problematic in developing countries
with limited resources. See also Chapter 53.
CONCLUSION
Tremendous advances have occurred in ROP management over the past
decades. However, ROP remains a significant clinical challenge in highly
developed countries and a leading cause of preventable pediatric blindness
worldwide. More studies regarding the future ROP workforce in the Unites
States and abroad are needed to ensure an adequate number of high-quality
ophthalmologists capable of managing the rising burden of ROP in middle-
and high-income countries. Additionally, further efforts on spreading
awareness and education of ROP via emerging technologies such as tele-
education need to continue to help address the current “third epidemic” of
ROP globally. The use of pharmacotherapy has profound potential in this
respect as well, but much research is still needed on its potential systemic and
long-term effects before it becomes gold standard.
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52
Clinical Trials and Management of
Retinopathy of Prematurity
Julia P. Shulman, and M. Elizabeth Hartnett
PREVALENCE
Blindness from retinopathy of prematurity (ROP) varies from country to
country and depends in large part on the level of socioeconomic development
and, therefore, likelihood that premature infants survive long enough to
develop ROP. Based on 1993 World Health Organization estimates, over
50,000 children are blind from ROP worldwide with many more who have
unilateral loss of vision or visual impairment (1). In the United States, the
incidence of ROP was estimated in the Early Treatment for Retinopathy of
Prematurity (ETROP) study to be 68% among infants of <1,251 g, similar to
the results in the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP)
study conducted 15 years earlier (2,3). This has been attributed to advances in
neonatal care that allow for improved survival of the extremely low birth
weight infants. In more recent studies, the incidence of ROP has been
reported to range from approximately 0.12% to 0.2% corresponding to 1 in
every 820 live births to as frequent as 1 in every 511 births (4,5). The
incidence of ROP increases with decreasing birth weight and has been
reported to be 33.2% for infants with birth weight <1,000 g, which is much
lower than in the ETROP and CRYO-ROP studies (3–5). This difference may
represent a true decrease in the incidence of disease or simply reflect
differences in the methodology used in the studies and whether they were
prospective or retrospective.
Although advances in neonatal care and ROP management have led to
better visual outcomes than those reported in earlier studies, ROP remains a
leading cause of childhood blindness necessitating further research to achieve
effective prevention and treatment. As larger numbers of extremely low birth
weight infants survive, effective management of ROP will play a greater role
in the quality of life of these patients (3).
This chapter will discuss major clinical trials that frame the
understanding, classification, and management of ROP.
ENVIRONMENTAL FACTORS
Oxygen
High Oxygen
Retrolental fibroplasia (RLF) (Figure 52-1) was first recognized in the 1940s
(6) and likely represented the cicatricial form of the most severe stage of
ROP, stage 5 ROP. The white pupil found in the eyes of a premature infant,
approximately 32 weeks’ gestational age (6), represented a retrolental
fibrovascular membrane behind which existed a total retinal detachment.
Probably the first comparative administered study was performed by Arnall
Patz testing high oxygen administered to all premature infants versus only
those with respiratory distress (7). Scientists were yet to publish their
thoughts on high oxygen in RLF (8). Following strong evidence from this
study for his hypothesis that high oxygen caused RLF, Dr. Patz and Dr.
Kinsey performed a multicenter study to gain greater evidence (9). Once high
and uncontrolled oxygen delivery was recognized as a cause of RLF, efforts
to regulate oxygen were developed and initiated, and, as a result, RLF was
nearly completely eradicated.
FIGURE 52-1 Eye of infant with retrolental fibrovascular
membrane from stage 5 ROP. Total retinal detachment,
determined by ultrasonogram, exists posterior to the white
retrolental membrane.
RD, retinal detachment; ROP, retinopathy of prematurity; CRYO-ROP, Cryotherapy for Retinopathy of
Prematurity; Light-ROP, Light Reduction on Retinopathy of Prematurity; ETROP, Early Treatment for
Retinopathy of Prematurity; OU, both eyes; PMA, postmenstrual age (gestational age plus chronologic
age in weeks).
Oxygen Fluctuations
Oxygen fluctuations, as measured by partial pressure of dissolved arterial
oxygen (PaO2), have been associated in animal studies and clinical trials with
the development of ROP (49–51). Studies by Saito, Cunningham, and Penn
demonstrated increased incidence of ROP and severe ROP in infants exposed
to oxygen fluctuation at the same gestational age and birth weight (49–51).
Oxygen fluctuations were measured either transcutaneously (49) or by
measuring the PaO2 in an arterial blood gas (50,51). Of note, transcutaneous
PO2 measurements estimate PaO2; however, due to the S shape of the
oxygen–hemoglobin dissociation curve, increases in PaO2—even at very high
levels—have little impact on saturation when oxygen saturations >90% in
healthy infants (52). So, dangerously high PaO2 may not be reflected in the
oxygen saturation level. In sick neonates, who are prone to episodes of hypo-
and hyperoxemia, transcutaneous PaO2 becomes a less accurate estimate of
arterial PaO2 (53,54).
Animal studies have demonstrated that PAO2 fluctuations in rat pups
played a key role in the development of abnormal retinal vascularization. In
addition, fluctuations in oxygen were more damaging than constant exposure
even if the total oxygen administered was less (50).
Light
Animal Studies
Light was proposed as a causative factor in ROP because light leads to a
release of free radicals that can cause oxidative damage, death of endothelial
cells, and release of angiogenic compounds. Expression of tumor necrosis
factor-α and vascular endothelial growth factor (VEGF) during retinal
neovascularization can be initiated by lipid hydroperoxides (60). However,
the retina is most metabolically active in the dark; thus, the release of
oxidative compounds conceivably might be greater than that released when
the retina is illuminated.
Animal studies have demonstrated that embryonic hyaloid vasculature
regresses by a light-mediated pathway. Pregnant mice dams placed in the
dark at late gestation with pups raised in the dark until 8 days postpartum
showed persistent hyaloid vessels (61). Investigators demonstrated that light
transmitted through a dam’s abdomen has an effect on retinal vascular
development in the pup early in gestation, corresponding to the first trimester
in humans. They identified a fetal light response pathway in mice that
requires melanopsin to regulate retinal angiogenesis (see also Chapter 2).
Dark rearing of mice from late gestation resulted in retinal hypoxia with an
increase in VEGF expression (61,62). These data suggest that insufficient
exposure to light in early gestation may result in the development of severe
ROP (62).
Brain-derived neurotrophic factor (BDNF) plays a role in ganglion cell
maturation and is reduced in mice reared in the dark (63).
Clinical Trials
The Light Reduction in Retinopathy of Prematurity (Light-ROP) study (Table
52-1) was designed to test the effect of reduced light to the preterm infant’s
retinas on the development of ROP. Infants were randomized to either a
group in which infants wore goggles that reduced ultraviolet light exposure
within 24 hours of birth or a group in which infants did not. There was no
evidence that reduced light exposure had an effect on the incidence of ROP
or the severity of ROP when it developed (32).
Based on the animal studies of Lang, Yang et al. evaluated the average
day length for 90 days from estimated date of conception in 684 eyes of 343
premature infants. Each additional hour of average day length was found to
decrease the likelihood of ROP by 28% (62).
Genetics
Studies have reported that ROP occurs in Caucasians more than in African
Americans (64) or Asians (65). A small study reported that native Alaskans
were more susceptible to ROP compared to nonnative Alaskans (66). A study
of monozygotic and dizygotic twins supported the concept genetic
predisposition in ROP (67). Although race cannot be addressed using animal
models, different strains of rats were shown to develop different degrees of
severity of retinopathy under the same conditions (68).
Genetic variants in the wnt signaling pathway genes including NDP,
FZD4, and TSPAN12, which are known to cause familial exudative
vitreoretinopathy (FEVR), have been reported in association with severe
ROP (69). In addition, variants in VEGF, endothelial PAS domain–
containing protein 1 (EPAS 1) and superoxide dismutase (SOD), have been
reported in association with any ROP. Variants in BDNF have also been
associated with severe ROP in extremely low birth weight infants (70), and
clinical studies reported reduced BDNF in extremely low birth weight infants
who developed ROP (71).
The association of ROP with multiple gestation and use of assisted
reproductive technology suggests a genetic link (72). However, ROP is
known to be affected by external factors such as oxidative stress, nutrition,
and others suggesting that epigenetic modifications by perinatal factors play a
role in the ultimate expressed phenotype of ROP. Epigenetic factors may also
help explain the variability in ROP severity among premature infants (73). In
addition, many reports have limited number of infants enrolled and
differences in gestational ages or birth weights of premature infants.
Extremely premature infants may have lacked the genetic variants that
predisposed less premature infants to develop ROP.
Worldwide Impact
ROP is a growing cause of blindness, especially in middle-income
developing countries where neonatal care is now emerging (see also Chapter
50).
Pathophysiology
Postnatal Growth
Oxidative Stress
Vitamin E
Oxidative stress has been linked to ROP through a number of mechanisms
related to oxygen delivery to retinal tissue in the premature infant. The retina
is believed to be susceptible to oxidative damage because of (a) its abundance
of polyunsaturated fatty acids, the double bonds of which are vulnerable to
peroxidation reactions (83); (b) its high metabolic rate and rapid rate of
oxygen consumption (84); and (c) through its vulnerability to light toxicity.
In addition, the premature infant has an inability to induce oxidative
scavenging mechanisms during times of oxygen stress (85).
A number of early studies tested the use of antioxidants, such as vitamin
E, to reduce ROP in infants. A meta-analysis of six of these studies (36)
found a 52% overall reduction in the incidence of intravitreous
neovascularization in ROP when infants were given vitamin E; however, the
study was limited by the inclusion of only six trials in the meta-analysis
(Table 52-1). Vitamin E administration was accompanied by lower incidence
of ROP in a retrospective study of 402 infants (86). Sepsis or late-onset
necrotizing enterocolitis reported in earlier vitamin E studies did not occur in
a later study performed by the same group and was attributed to improved
immunologic function with ongoing development of the preterm infant (87).
Vitamin E therapy has also been reported in association with a greater
incidence of intraventricular hemorrhage in the premature infant (17). A
Cochrane review in 2003 demonstrated that vitamin E supplementation
reduced the risk of intracranial hemorrhage and increased the risk of sepsis
but reduced the risk of severe ROP and blindness (88). The review did not
support the routine use of vitamin E supplementation.
Lutein
Lutein may reduce oxidative stress and prove a source of macular pigment.
However, randomized trials have shown conflicting results in terms of
incidence and severity of ROP (89,90).
Neurovascular Effects
Sapieha et al. have demonstrated that retinal ganglion cells sense ischemic
stress and regulate production of various antiangiogenic factors (75).
However, it remains early for translation of the findings into clinical
management.
Clinical Symptoms and Signs
There are no symptoms of acute ROP, nor can a specific visual behavior in
the preterm newborn herald a concern for ROP. Therefore, effective
screening is essential for diagnosis.
Age of Onset
Most ROP manifests at about 32 weeks of postmenstrual age (PMA). PMA
equals gestational age plus age after birth in weeks (27,91). The definition of
“treatment-warranted ROP” has evolved over the years and differs between
the United States and Europe (92,93). CRYO-ROP defined treatment-
warranted ROP as threshold disease, in which there was a 50% risk of a poor
outcome (Table 52-5). Threshold ROP peaked at approximately 37 weeks of
PMA (19,33). The ETROP defined treatment-warranted ROP as a less severe
form, type 1 ROP, mainly because of poor outcomes in zone I threshold
ROP. Type 1 ROP was defined as a ≥15% risk of a poor outcome and peaked
in infants at approximately 35 weeks PMA (37). Eyes that rapidly progress to
prethreshold ROP have a greater risk of developing threshold ROP (19,29)
and will develop threshold disease at an earlier PMA. When infants achieve
45 weeks’ PMA without developing prethreshold ROP, they have a low risk
of developing treatment-warranted ROP or of having a poor outcome (27).
Infants treated with anti-VEGF agents can have an altered natural history
with recurrences of severe ROP reported beyond 1 year of age (91,94–96).
The extent of ROP refers to the number of clock hours of the highest stage.
Plus disease refers to dilation and tortuosity of the retinal arterioles and veins
in the posterior pole (Figure 52-3) and was based on a standard photograph
in multicenter trials (10,100). Pre-plus disease was defined as abnormal
dilation and tortuosity of the posterior pole vessels that was insufficiently
severe for the diagnosis of plus disease but was not normal and was defined
after the CRYO-ROP study (100). Aggressive posterior ROP (AP-ROP) is an
aggressive form of posterior retinopathy observed commonly in zone I or
posterior zone II with dilation and tortuosity of the arterioles and veins in all
four quadrants out of proportion to the peripheral retinopathy. AP-ROP does
not usually progress through the classic stages, extends circumferentially, and
can be accompanied by a circumferential vessel. Flat neovascularization at
the junction of the vascularized and nonvascularized retina is different in
appearance from zone II and stage 3 ROP, and this aggressive form of ROP
progresses to stage 5 if not promptly treated (100).
e-ROP
The use of telemedicine in the screening of ROP has been validated in a
multicenter trial from the NEI (e-ROP), which compared screening results
from wide-field retinal images obtained by non–physician certified ROP
imagers using a standard protocol with conventional retinal examinations by
trained ophthalmologists (99). For neonatal care centers utilizing remote ROP
screening, it is recommended that indirect ophthalmoscopy be performed at
least once by a qualified ophthalmologist prior to treatment of ROP or
discontinuation of acute phase screening (91).
Differential Diagnosis
The differential diagnosis of ROP includes FEVR, Norrie disease,
incontinentia pigmenti, congenital retinal fold, Toxocara canis infection, and
other causes of leukocoria (Table 52-7). A white pupil, referred to as
leukocoria, can occur from media opacities at any level from the cornea to
the retina. A history of prematurity and low birth weight are the most helpful
historical data in the differential diagnosis of ROP.
TREATMENT
According to ETROP, once type 1 ROP develops, treatment should be
considered within 48 to 72 hours (91,107). Based on current guidelines,
treatment is laser to the avascular retina or anti-VEGF treatment for selected
cases (91).
Following laser, treated eyes are monitored 1 week later and then weekly
for regression of vascular activity and assurance that no fibrovascular
traction, repeat plus disease, recurrent neovascularization, or vitreous haze
occurs. These features are concerning for need for additional laser
(neovascularization or plus disease) or monitored for possible lens-sparing
vitrectomy (vitreous condensation, ridge thickening, and retinal elevation).
Following anti-VEGF, treated eyes are monitored often 1 day after
injection and then weekly. During follow-up, eyes are evaluated for
regression of vascular activity as defined by plus disease, or stage 3 ROP, and
progressive stage 4 ROP, or full vascularization. Progressive stage 4 ROP
manifests differently in eyes treated with laser compared to those treated with
anti-VEGF. In eyes treated with laser, most of the time progressive stage 4
ROP manifests as thickening of the ridge, vitreous condensation, or
organization at the ridge or optic nerve, plus disease, or vitreous hemorrhage,
particularly over the ridge. Following anti-VEGF treatment, these features
exist, but there can also be vitreous organization and condensation over the
area of the previous ridge especially in eyes with AP-ROP or condensation at
the optic nerve (Figure 52-12). Full vascularization of the retina to the ora
serrata should be confirmed in eyes treated with anti-VEGF since recurrences
even after 2 years of anti-VEGF have been recorded (95). Current guidelines
recommend continued examination until retinal vascularization extends to the
ora serrata or until PMA of at least 65 weeks if anti-VEGF medications were
used (91). Since ROP has been shown to recur past 65 weeks PMA (94–96),
clinicians may monitor for longer durations in anti-VEGF–treated infants.
Some clinicians advocate laser to the peripheral avascular retina in anti-
VEGF–treated eyes that have not had full vascularization. Harper et al.
demonstrated that only 50% of infant achieved vascularization into zone III at
150 weeks PMA and most eyes had vascular abnormalities of fluorescein
angiography after treatment for Type 1 ROP with anti-VEGF agents (108).
Laser
Laser to the avascular retina is the mainstay of treatment for ROP. Current
treatment recommendations are based on the ETROP study, which defined
Type 1 ROP (see Table 52-1) as necessitating ablative therapy to improve
structural and visual outcomes (37). Although techniques for laser
administration vary widely, successful laser ablative therapy is administered
after adequate anesthesia and analgesia have been accomplished and extends
from the vascular–avascular junction to the ora serrata 360 degrees. Near-
confluent burns or painting of the peripheral retina is utilized. As the
intravitreal neovascularization improves after initial treatment, laser can be
added posteriorly to parts of the retina that were not previously accessible or
visible, as occurs following regression of flat neovascularization in AP-ROP.
If there is inadequate regression of disease, laser can be repeated, especially
in any skip areas. Anti-VEGF agents can be considered and have been used
in cases of incomplete response to laser; however, this remains controversial
without knowledge of optimal dosing and full understanding of side effect
profiles (see below).
Anti-VEGF Studies
The Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of
Prematurity (BEAT-ROP) study demonstrated a reduction in the rate of
recurrence of neovascularization in infants with stage 3, zone I ROP treated
with intravitreal bevacizumab (0.625 mg in 0.025 mL) and followed until 54
weeks’ PMA compared to eyes treated with laser. The interval for disease
recurrence was 19.2 ± 8.8 weeks with bevacizumab compared to 6.4 ± 6.7
weeks with laser for zone I disease, introducing the need for longer-term
follow-up to assure no disease recurrence. No difference between the
treatments was found statistically for zone II ROP (39). A follow-up study of
infants in the original BEAT-ROP cohort reported recurrences in 8.3% with
the average peak occurring at 16 weeks (±4 days) after injection (109). See
also Chapter 53.
Late recurrences of ROP after treatment with intravitreal bevacizumab
have been reported (94,95), including a report of a patient with recurrence at
3 years of age (96).
Reduced serum VEGF levels in infants treated with a single intravitreal
bevacizumab injection have been reported, but long-term systemic effects
remain unknown (110). More recent studies investigated the efficacy of
ranibizumab, which has a shorter half-life and reduces serum VEGF for a
shorter duration than bevacizumab (111). When used at the dose of 0.25
mg/0.025 mL (half the standard adult dose), ranibizumab resulted in higher
rates of recurrence than bevacizumab with an overall reactivation rate of 33%
at an average of 8.3 ± 2.7 weeks (111).
The Ranibizumab Compared With Laser Therapy for the Treatment of
Infants Born Prematurely with ROP (RAINBOW) study prospectively
compared treatment with intravitreal ranibizumab at two doses (0.2 and 0.1
mg of 10 mg/mL ranibizumab) compared to laser. Up to two retreatments
were allowed per eye in the ranibizumab groups after 28 days and up to 24
weeks, and re-treatment with laser was allowed. A total of 224 infants was
enrolled in the study, and the primary outcomes were absence of active ROP
and unfavorable structural outcomes in both eyes at week 24. The primary
outcome measure was met in 80% of the ranibizumab 0.2 mg group, 75% of
the ranibizumab 0.1 mg group, and 66.2% in the laser group (111). The
success rate of the laser group was much lower than what was seen in the
ETROP study; however, enrolled infants had more severe treatment-
warranted ROP than type 1 ROP.
To address the optimal dosing of anti-VEGF agents, the Pediatric Eye
Disease Investigator Group (PEDIG) studied de-escalating doses of
bevacizumab in the treatment of ROP. One eye was treated with 0.25 mg in
10 μL intravitreous bevacizumab for type 1 ROP. If an improvement was
seen in plus disease of zone I stage 3 ROP by 5 days or sooner without
recurrence for 4 weeks, the next group of infants received a lower dose of
0.125 mg, then 0.063 mg, and finally 0.031 mg, all in 10 μL volumes (112).
Even the lowest dose of 0.031 mg, which represents 5% of the dose used in
the original BEAT-ROP study, was effective in 9/9 eyes at 4 weeks. Serum
VEGF was reduced and bevacizumab was detected in the serum even at the
lowest doses (112). At 6 months follow-up, 41% of the 61 study eyes
received additional treatment for either early recurrence within 4 weeks of the
initial treatment (5%), late recurrence after 4 weeks (18%), and for persistent
avascular retina (18%). One patient developed a stage 5 retinal detachment, 4
infants died, and 56 of 61 had regression of ROP with normal posterior poles.
These data suggest good structural outcomes with low-dose bevacizumab;
however, additional treatment may be needed (113).
The Comparing Alternative Ranibizumab Dosages for Safety and
Efficacy in ROP (CARE-ROP) study compared 0.12 mg of intravitreous
ranibizumab (20 μL) with 0.2 mg (20 μL) in type 1 ROP in 19 infants and
found the two groups equivalent in terms of not requiring rescue therapy at
24 weeks follow-up (92). This study allowed for reinjection of ranibizumab
after at least 28 days and did not demonstrate plasma VEGF level alteration.
A summary of the key anti-VEGF therapy trials for ROP is presented in
Table 52-8.
Prevention
Prevention of ROP would be accomplished by preventing or reducing
premature births and through good prenatal care (115), reduction in teenage
pregnancies (116), and avoidance of illegal drug use (117).
To reduce the incidence of ROP, in the 1960s, NICUs began to monitor
oxygen delivery to the preterm newborn, particularly in the perinatal period
so as to avoid high oxygen levels, such as those used when RLF was first
recognized (6). NICUs now have the technology to maintain oxygen within
predetermined “safe” limits, defined by the Fetus and Newborn Committee of
the American Academy of Pediatrics and American College of Obstetricians
and Gynecologists (118). However, several studies provide evidence that not
only the concentration but also the variability of oxygen plays a role in the
development and severity of ROP (49,119) (see Chapter 40).
To prevent blindness from ROP in the preterm infant, screening is
important. Beginning with the CRYO-ROP study (11), it has been shown that
laser treatment or cryotherapy (Table 52-9) delivered to the avascular zones
of eyes with threshold ROP within 72 hours reduced unfavorable outcomes
and vision loss (11,14,33). The ETROP trial refined the definition of eyes at
risk of threshold ROP and an unwanted outcome: all zone I eyes with any
ROP and plus disease, zone I eyes with stage 3 ROP without plus disease,
and zone II eyes with stages 2 or 3 ROP and plus disease (Table 52-1, see
also Definitions of Treatment-warranted ROP) (2,37,121). If treatment is
adequate but ROP progresses to stage 4 ROP with certain retinal features (13)
or in eyes with stage 5 ROP, vitreoretinal surgery is considered. Finally,
visual rehabilitation is necessary to treat amblyopia and myopia that occur
more commonly in prematurely born children and even more often in those
who had ROP compared to infants born full term (Tables 52-2 and 52-3)
(22,122). Segmentation of encircling elements used to treat stage 4 ROP or
rhegmatogenous retinal detachment reduces optical irregularities, permits
growth of the globe, reduces myopia, and may improve visual outcomes
(123,124). Further discussion on amblyopia is provided in Chapter 11.
Vision Rehabilitation
Vision rehabilitation is important in all premature infants with or without
ROP. Premature infants are more likely to require strabismus surgery, to be
treated for amblyopia, and to be myopic than full-term infants (Tables 52-2
and 52-3). These conditions are greater in premature infants with more severe
levels of ROP than those with milder ROP (22,47,121,121). Infants with
macular heterotopia may have potential for visual acuity (125), so correction
of refractive errors and treatment of amblyopia are indicated. The ETROP
found patients without obvious macular heterotopia had moderate visual loss
(126). For the aphakic infant who had retinal detachment repair, visual
rehabilitation with special adjustments for low vision is recommended. Even
when grating acuity cannot be measured, low vision can be stratified into
levels characterized by the presence of light perception in different fields of
gaze (126) and may be important to infant and child development. In the
child with macular acuity in one eye and aphakic amblyopia in the fellow
eye, spectacle wear also provides protection against ocular trauma. We
recommend that infants be managed by a pediatric ophthalmologist for visual
rehabilitation starting at an earlier age than that recommended for full-term
infants and that children be enrolled in an early intervention program that
enhances the use of all of the senses.
FUTURE STUDIES
Erythropoietin Derivatives (PENUT)
Early studies of erythropoietin (epo) found an association with severe ROP;
however, later studies suggested that timing of epo administration made a
difference in outcome (73). Erythropoietin has anti-inflammatory and
antiapoptotic effects and promotes neurogenesis and angiogenesis, which will
be studied in the PENUT (Preterm Epo Neuroprotection Trial) in extremely
low gestational age neonates (72). The study will enroll 940 patients and
follow infants to 22 to 26 months corrected age. Safety of epo will be
assessed as well as effects on inflammatory cytokines, brain injury, as well as
clinical outcomes.
RISK FACTORS
Severe (Treatment-Warranted) Retinopathy of
Prematurity
The greatest single risk factor for developing ROP is being born prematurely
(64,132–144). However, we now know much more about the risks of
progression of the disease. The CRYO-ROP study provided data from the
natural history cohort (Table 52-1) on ocular and systemic characteristics
associated with increased risk of ROP, progression to threshold ROP, and
development of an unfavorable macular outcome (Table 52-5) (19). An
important ocular risk factor was zone I. If, at 32 weeks PMA, incomplete
vascularization in zone I was present, 32.8% of eyes developed threshold
ROP, compared to 9.3% with incomplete vascularization in zone II. Eyes
with zone I ROP also were at high risk of developing threshold ROP. Other
ocular risk factors for developing threshold ROP included plus disease, stage
3 ROP (19), ≥6 clock-hour stage 3 (18), and iris vessel dilation (31).
Nonocular risk factors associated with the development of threshold ROP
included young gestational age, multiple births, out-of-nursery birth, low
birth weight (19), and Caucasian race (Table 52-1) (19,28). Once
prethreshold ROP developed, the risk of developing threshold ROP was
about the same given these factors. For each 100-g increase in birth weight,
there was a 27% decrease in the percentage of infants who developed
threshold ROP. Black race was associated with a 6/5% lower chance of
developing threshold ROP compared to Caucasian race if any ROP was
present and a 51% decreased chance of developing threshold if prethreshold
ROP developed. Once threshold ROP developed, the risk of an unfavorable
anatomic outcome (Table 52-5) was about the same in blacks as for
Caucasians (19). Factors associated with increased risk of prethreshold
progressing to threshold ROP included lower PMA at the diagnosis of any
ROP, ROP in zone I at the first screening examination, rapid progression of
ROP to prethreshold characteristics, plus disease at the first prethreshold
examination, and white race (19,29).
UNFAVORABLE MACULAR OUTCOME
In the initial natural history report, ocular characteristics associated with an
unfavorable macular outcome included zone I ROP, plus disease, and stage 3
ROP (Table 52-1). Eyes with zone I ROP had an odds risk of 8.24 toward
developing an unfavorable outcome compared to zone II ROP (19). For each
clock hour of stage 3 ROP >5 clock hours, there was a 26% increased risk of
an unfavorable macular outcome (19). Stage 3 ROP with plus disease in zone
II was associated with a 62% risk of an unfavorable result compared to stage
3 ROP without plus disease in zone II in which the risk was 3%. In the 5.5-
year report from the natural history cohort of CRYO-ROP (18), an
unfavorable anatomic outcome occurred in 62.5% of zone I eyes compared to
44.2% of zone II eyes. All unfavorable anatomic outcomes in this cohort
from CRYO-ROP occurred in eyes with 6 or more clock hours of stage 3
ROP with plus disease in zone I or II (18).
In the ETROP study, at 6-year follow-up, the difference in unfavorable
outcomes for all high-risk prethreshold eyes was 8.9% for early-treated eyes
versus 15.2% for conventionally managed eyes (P < 0.001). The greatest
benefit of early treatment was seen with zone I, stage 3 disease, with or
without plus (unfavorable outcomes were doubled for these eyes in the
conventionally treated group), and zone II, stage 3 disease with plus (40).
EFFECTS OF ENVIRONMENTAL
FACTORS AND NONOCULAR
TREATMENTS ON RETINOPATHY OF
PREMATURITY
Oxygen
The relationship of oxygen to the development of ROP is complex and
incompletely understood. Metabolic and oxygen needs increase during the
development of the retinal vasculature and the maturation of the neural retina
and photoreceptors (145). Early retinal vessels are also sensitive to
fluctuations in outside oxygen delivery. A number of factors also affect
oxygen delivery to the retinal vasculature and neural retina in the premature
infant, including poor blood oxygenation secondary to immature lungs and
respiratory disease, anemia of prematurity, and changes in the ratio of fetal to
adult hemoglobin affecting oxygen affinity to hemoglobin.
Steroids
The role of steroid administration and its effect on ROP remain incompletely
understood. A meta-analysis published in 2018 demonstrated that antenatal
steroids reduced the risk of ROP development and progression to severe ROP
(146).
Prenatal steroids administered to women in preterm labor have resulted in
reduced infant mortality and morbidity, primarily through improved lung
function. There is evidence from several studies that prenatal steroids are
protective for the development of ROP (143,147–149). Later administration
of steroids, for example, when treating lung disease, has been reported to
have an adverse effect (150,151) or no effect (152–154) on the incidence of
ROP. Adverse effects appear to be more likely when steroids are given more
than 3 weeks postnatally (151) and less likely when used within 2 weeks of
birth (152,153).
In a rat model of OIR, an angiostatic steroid, anecortave acetate, believed
to prevent endothelial cell migration, greatly reduced intravitreous
neovascularization (155) with little to no effect on normal retinal vascular
development. Dexamethasone inhibited both normal retinal growth and
pathologic intravitreous neovascularization in rabbits (156). Intravitreous
triamcinolone was found to have dose-dependent reductions in intravitreous
neovascularization (157). Further investigation into possible effects of
steroids on ROP is warranted.
Surfactant
Surfactant therapy that has increased survival in very low birth weight
premature infants initially appeared to be beneficial in reducing the incidence
of ROP (158). However, follow-up studies have failed to confirm this
(18,144,159,159). Studies found a reduced incidence of severe ROP in
preterm infant treated with surfactant therapy (160); however, studies used
historic controls (161). In a recent meta-analysis, inositol, an essential
nutrient and important in maturation of surfactant, was shown to significantly
reduce the incidence of ROP (38,162).
Carbon Dioxide
Clinical studies that analyzed intermittent blood gas samples found that both
hypocarbia (132) and hypercarbia (38,133,163) were associated with the
development of ROP. The only study that analyzed continuous
transcutaneously monitored CO2 showed no association between absolute
blood CO2 level or variability and the subsequent development of ROP (164).
The evidence from animal models, however, is unequivocal. Hypercarbia
alone (165) and metabolic acidosis (166) have induced retinopathy in rats.
When hypercarbia is combined with variable oxygen (165), the severity of
disease is increased.
CO2 affects the retinal vasculature by causing dilation of vessels in part
through relaxation of retinal pericytes (167). With vessel dilation,
oxygenation (166) and blood flow (168) are increased to the retina. The
damaging effect of CO2 in animal models has been speculated to be through
increased delivery of oxygen to the retina, followed by a reduced stimulus for
the release of hypoxia-induced angiogenic factors, such as VEGF, and, in
turn, delay retinal vascular development. Retinal VEGF mRNA down-
regulation, followed by up-regulation prior to the appearance of maximal
neovascularization in hypercarbic OIR, has been demonstrated (169).
A small trial in ventilated preterm infants that allowed the level of carbon
dioxide to passively rise to between 45 and 55 mm Hg PaCO2 showed no
difference in the incidence of ROP (170) compared to infants who were
ventilated to maintain PaCO2 levels of 35 to 45 mm Hg. Infants exposed to
PCO2 in the highest quartile for GA on at least 2 of the first 3 days of life
were found to have an increased risk of severe ROP (59).
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53
Anti-VEGF Treatment in Retinopathy
of Prematurity
Anna L. Ells, Wei-Chi Wu, and Darius M. Moshfeghi
INTRODUCTION
Retinopathy of prematurity (ROP) affects up to 16,000 premature infants in
the United States per year (1,2) and an estimated 184,700 globally (3), and is
a leading cause of childhood blindness (4–10). Incomplete retinal vascular
development predisposes the premature infant to a vasoproliferative
retinopathy characterized first by slowed or even arrested blood vessel
growth followed by abnormal vascular development into the vitreous. When
retinal vascular development restarts, it may proceed as ordered intraretinal
angiogenesis or transition into pathologic pathways with abnormal
angiogenesis followed by gliosis, vitreoretinal traction, and retinal
detachment (11).
To accurately and reproducibly describe the vascular pathology
associated with ROP, the International Classification of Retinopathy of
Prematurity (ICROP) has defined ROP characteristics such as location
(zone), extent of neovascularization (clock hours), severity (stage), and
modifiers (presence of plus, pre-plus, and aggressive posterior disease)
(12,13). (Information on diagnosis, screening parameters, and clinical trials is
found in Chapter 52.)
However, it should be remembered that countries around the world have
different appearances of ROP with larger and older infants than in the United
States and Canada at risk for severe ROP; therefore, many countries have
developed their own recommended screening guidelines (see Chapter 50).
PATHOGENESIS OF ROP
The pathogenesis of ROP is related to interruption of the normal pattern of
retinal vascular development with ensuing pathologic processes. Most studies
performed on normal retinal vascular development have been done in
animals, but there are differences between humans and other species (see
Chapter 5). In normal human retinal development, the initial vasculature is
believed to occur by vasculogenesis beginning in the 16th week of gestation
and continuing through at least 22 weeks of gestation (14). From that time,
how vessels develop in the human infant is believed to occur by a process of
angiogenesis based on animal models.
During vasculogenesis, it is believed that growth factors increase as a
result of relative intrauterine hypoxia and increased metabolic activity
associated with neuronal retinal differentiation and include stromal-derived
factor (14) and its receptors CXCR-4 and vascular endothelial growth factor
(VEGF), produced from retinal ganglion cells (RGCs) and astrocytes (15).
The third trimester is believed to be associated with a transition from
vasculogenesis to angiogenesis for retinal vasculature development.
Angiogenesis is characterized by endothelial sprouting from an existing
vessel and proliferation and is often stimulated by VEGF, as well as
recruitment of mural cells from other factors during blood vessel creation
(16). In humans, angioblasts migrate radially from the optic nerve to the ora
serrata, expressing VEGF in relationship with local tissue hypoxia gradients,
whereas astrocytes have been found important in this process in experimental
animal models (17). Endothelial tip cells direct vessel development (18),
utilizing tractable filopodia, which in turn are patterned by the response of the
numerous guidance receptors they express, including VEGF receptors,
Unc5b, and neuropilin 1 (NRP1) (19–21). Trailing endothelial stalk cells then
establish a fledgling vascular network. VEGFC and VEGFR3 have important
roles in the process of endothelial tip to stalk cell conversion through
regulation of notch signaling (22). Retinal vascular maturation is modulated
by a complex interaction of mural cells, which mature into pericytes and
smooth muscle cells, and apoptosis. Ultimately, it is believed that the dual,
simultaneous process of vascular maturation and involution results in the
development of the retinal vessels (23,24).
The disruption of normal retinal vascular development by ROP has been
characterized by two phases (25): (a) phase I, delayed physiologic retinal
vascular development and vasoattenuation due to oxygen stresses (see also
Chapter 38), and (b) phase II, vasoproliferative intravitreal
neovascularization. It is believed that when a preterm infant is born, there is
insufficient insulin-like growth factor 1 (IGF-1) and other factors that are
usually supplied through the placenta (15). Low IGF-1 is associated with
slow retinal vascular development (see Chapter 39). In addition, a number of
events related to birth and to postnatal insults, including oxygen fluctuations,
inflammatory stimuli, and oxidative stress occur, delaying physiologic retinal
vascular development further and causing aberrant growth of blood vessels
into the vitreous. Birth also may expose the infant to relative extrauterine
hyperoxia (26,27) (see Chapter 40). The oxygen concentration in the tissue is
complicated, because fetal hemoglobin has a greater affinity for oxygen than
does adult hemoglobin, and there can be variable effects based on shunting
and dilution of blood. Early experimental models suggested that high oxygen
injured newly formed retinal capillaries (28–32) in phase I and did not
promote physiologic retinal vascular development. More relevant and recent
experimental models suggest that oxygen stresses of preterm infants today
cause other events that lead to increasing levels of VEGF with delayed
expression of VEGFR2, which lead to first delay in physiologic retinal
vascular development and then, once VEGFR2 is present and activated in
endothelial cells, disordered divisions of endothelial cells that have access to
outside the retinal plane where they proliferate as intravitreal angiogenesis in
phase II. The disordered proliferation of retinal endothelial cells into the
vitreous does not allow them to extend as intraretinal neovascularization in
physiologic retinal vascular development (33,34). The ischemia from the
peripheral avascular retina, then combined with the increasing metabolic
demand of the developing retina, results in tissue hypoxia that induces cells,
including glia, astrocytes, and neurons (35,36) to overexpress angiogenic
factors and trigger angiogenic pathways involving, for example, VEGF and
erythropoietin (15,37,38). Stage 3 ROP occurs at about 32 to 34 weeks of
gestational age and is characterized by pathologic intravitreal
neovascularization (28–35). Extrapolating, it has been postulated that zone I
disease may stem from aberrant vasculogenesis, whereas zone II disease is
likely angiogenesis dependent (39,40). Compared to control eyes undergoing
surgery for congenital cataract, vitreous samples from eyes with stage 4 ROP
requiring surgery demonstrate a nearly 50-fold increase in VEGF
concentrations with the highest levels in eyes with plus disease (41). It is
clear that retinal vascular maturation and the pathogenesis resulting in ROP
have numerous steps involved in interruption of normal development
followed by ROP. Therefore, there may be more than one treatment required.
TREATMENT
The goals of treatment in ROP are to preserve vision potential, preserve
retinal architecture, and limit local and systemic complications related to
therapy. The past decade has included numerous case series and a few
clinical trials that support pharmacotherapy using anti-VEGF drugs.
However, due to limited strong evidence, laser photocoagulation of the
avascular retina remains the gold standard treatment of ROP requiring
therapy (42) based on the results of two large National Eye Institute (NIH)
studies: The Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) trial
and the Early Treatment for Retinopathy of Prematurity (ETROP) trial
(10,43). The conclusions of these studies are ablative therapy for type 1
ETROP, zone I, stage 3 disease; zone I, plus disease; and zone II, stage 2 or 3
with plus disease (43,44), replacing the earlier threshold criteria from the
CRYO-ROP trial (see Chapter 52).
The use of anti-VEGF has made accessible the treatment of ROP, particularly
posterior ROP, in that success routinely exceeds 75% at preventing adverse
anatomic outcomes and visual acuity loss regardless of training of the
physician, anti-VEGF medication choice, dosage, or geographic location
(Table 53-2) (68,73–81). Hence, we enter the fourth era of ROP treatment.
aBEAT-ROP primary outcome was rate of recurrence at 54 weeks of postmenstrual age. The results
reported herein are for the combined pool of zone I and zone II posterior ROP. For zone I-only eyes,
the results were substantially worse—58.0% success (n = 19 of 33 eyes).
bAngiographic and anatomical outcomes, mortality.
cPrimary outcome of bevacizumab versus laser is defined as persistence or recurrence at 54 weeks of
postmenstrual age.
dRAINBOW, despite using two doses, defined primary outcome as superiority of the 0.2-mg
ranibizumab dose relative to laser at 24 weeks with respect to absence of active ROP or absence of
unfavorable structural outcomes.
TABLE 53-5
In the many published case series and clinical trials using IVB and IVR, there
is no standardized terminology used for “recurrence” of ROP that results in
another treatment. In reviewing the published studies referenced above, there
are three clinical scenarios that result in retreatment; early failure of ROP to
regress within the first 4 weeks after initial anti-VEGF injection; recurrence
of ROP (stage 2 or 3) following initial good regression after initial anti-
VEGF injection; and persistent avascular retina in zones II and III following
good regression of ROP after initial anti-VEGF injection. In the case of early
failure, type I ROP does not regress, and a second anti-VEGF injection or
laser is performed depending on the PMA of the infant, location of disease,
and the whether or not there is fibrovascular or cicatricial ROP present. Anti-
VEGF drugs are typically not used in the presence of fibrovascular ROP to
avoid the phenomena known as “crunch” in which the drugs may accelerate
the contraction of the fibrotic extraretinal neovascularization resulting in a
tractional retinal detachment (140). In the more common scenario of
recurrence or reactivation of ROP after good initial regression of severe
disease, ROP may slowly recur weeks, months or even over 2 years after the
anti-VEGF treatment (141). Hu et al. reported a series of infants requiring
retreatment at a range of 36 to 60 weeks of PMA (142), and Karkhaneh et al.
reported a recurrence with retreatment up to 90 weeks of PMA (72). Ells et
al. reported a retreatment range of 46 to 120 weeks of PMA (102), and
Yonekawa’s group reported recurrence as late as 5 years after anti-VEGF
injection for type I ROP. These studies reinforce the importance of
meticulous long-term follow-up of infants treated with anti-VEGF to prevent
undetected cicatricial ROP and associated vision loss or blindness.
Given the high reported rate of recurrence of ROP following anti-VEGF
treatment for ROP, it may be beneficial to perform laser photocoagulation to
persistent avascular retina in zones II or III, at a PMA greater than 55 weeks
for most infants. There are, currently, no standardized protocols for follow-
up, the need for fluorescein angiography, and retreatment or treatment of
persistent avascular retina for these infants; however, we expect to see
published standardized terminology of recurrence and retreatment protocols
in the near future.
CONCLUSION
In summary, we live in an anti-VEGF era in which the treatment has great
promise for primary treatment for type I ROP. These drugs minimize the
permanent destruction of the retina, promote relatively normal angiogenesis,
and act extremely rapidly to induce regression of VEGF-mediated ROP.
Anti-VEGF treatment can be performed safely by an experienced
ophthalmologist at the bedside of an infant in the NICU. However, we still
have many unanswered questions regarding long-term neurodevelopmental
effects of these drugs due to systemic drug exposure and potentially
prolonged suppression of serum VEGF levels in these premature infants. We
need further investigation and understanding for type of anti-VEGF drug for
the premature infant, and we also await further dose-related studies to
determine the fine balance of promoting normal angiogenesis after regression
of ROP while preventing local retinal neural–vascular toxic effects. Given the
high rate of recurrence of ROP following an anti-VEGF injection, potentially
for months to years, standardized terminology of recurrence is needed, and
standardized protocols for follow-up examinations and possible retreatment
with both laser or anti-VEGF drugs are required.
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54
Evolution of Stage 4 Retinopathy of
Prematurity
Antonio Capone Jr, and Michael T. Trese
In the fetus, wound healing responses and scar formation differ depending on
the developmental time in utero. For example, fetal regenerative wounds heal
without scar formation in the second and early third trimesters (13).
Transforming growth factor-β1 (TGF-β1) has been widely studied regarding
its effects on wound healing and in the eye. TGF-β1 leads to excessive scar
formation in fetal wounds and contributes to hyaluronic acid synthesis (14). It
differentially affects adult and fetal fibroblast migration and hyaluronan
synthesis (15). In addition, it down-regulates VEGF in cell culture (12).
Although direct evidence is lacking, TGF-β is present in fetal development
and conceivably could affect collagen structure, vascularity, and wound
healing in the eye. These processes could participate in the development of
retinal detachment seen in stages 4 and 5 ROP.
MECHANISM OF PREDOMINANTLY
EFFUSIVE RETINAL DETACHMENT
Predominantly effusive 4B retinal detachment is believed to occur as a
consequence of vascular leakage into the subretinal space. Sang et al. (20)
observed vessels in the subretinal space of humans in a histologic study;
however, the pathogenesis of the subretinal neovascularization is enigmatic.
Okamoto et al. (21) developed a transgenic mouse model in which VEGF
expression was linked to the rhodopsin promoter and observed intraretinal
and subretinal neovascularization as a result of increased expression of
VEGF in the outer retina. Although direct clinical evidence is lacking, this
model supports the notion that VEGF expressed in the retina can lead to
subretinal neovascularization, leakage of fluid into the subretinal space, and
thus retinal detachment, characteristics clinically noted in the predominantly
effusive form of stage 4B retinal detachment (Figure 54-4).
MECHANISM OF PREDOMINANTLY
TRACTIONAL RETINAL
DETACHMENT
The predominantly tractional retinal detachment of ROP involves one of the
most interesting features of retinal detachment evolution in the premature
child’s eye. The involuting hyaloid system and tunica vasculosa lentis play an
important role. Eyes with predominantly tractional retinal detachments
generally develop sharply peaked retinal folds. These folds are attached to
spokes connecting to the central stalk, best appreciated with endoillumination
during vitreous surgery. The stalk always extends to the disc and can have
other direct isolated strands connecting to the retina at or posterior to the
ROP ridge. The anterior aspect of the stalk often connects to the posterior
lens surface. In eyes with profoundly immature vascular architecture, as seen
in some eyes with aggressive posterior ROP, the retina may detach flatly as a
consequence of diffuse hyaloidal contraction (22).
The traction generally has a dominant direction first toward the center of
eye and then posteriorly toward the optic nerve or anteriorly toward the lens
(Figure 54-7). With progression in the weeks prior to the infant’s original
due date and thereafter, the vitreous organizes and the circumferential folds
are often drawn centrally. Clear to turbid subretinal fluid can be present.
It has been our clinical observation that eyes that show more prominent
clinical evidence of the regressed hyaloid structure following laser often
develop retinal detachment. In a study of late ROP, vitreous haze and the
appearance of the vitreous organization in front of the lens in eyes treated for
threshold ROP predicted progression of stage 4A ROP (23,24). We speculate
that this is the clinical correlate of reduced apoptosis and activated TGF-β1
supporting hypocellular gel contraction. In addition, prominent or persistent
iris vessels at 34 to 35 weeks’ postmenstrual age were associated with
increased risk of threshold ROP and a higher risk of retinal detachment (25).
We speculate that this increase in iris vessel activity reflects a resurgence of
the VEGF activity.
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15. Ellis IR, Schor SL. Differential effects of TGF-β1 on hyaluronan synthesis by fetal and adult
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17. Trese MT. Surgical results of stage V retrolental fibroplasia and timing of surgery.
Ophthalmology 1984;91: 461–466.
18. Arevalo JF, Maia M, Flynn HW, et al. Tractional retinal detachment following intravitreal
bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy. Br J
Ophthalmol 2008;92:213–216.
19. Yonekawa Y, Wu WC, Nitulescu CE, et al. Progressive retinal detachment in infants with
retinopathy of prematurity treated with intravitreal bevacizumab or ranibizumab. Retina
2018;38(6):1079–1083.
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retinopathy of prematurity. In: Shapiro MJ, Biglan AW, Miller MM, eds. Retinopathy of
prematurity. Chicago, IL, 1993:219–222.
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expression of vascular endothelial growth factor in the retina. A new model of intraretinal and
subretinal neovascularization. Am J Pathol 1997;151:281–291.
22. VinekarA, Trese MT, Capone A Jr; Photographic Screening for Retinopathy of Prematurity
(PHOTO-ROP) Cooperative Group. Evolution of retinal detachment in posterior retinopathy of
prematurity: impact on treatment approach. Am J Ophthalmol 2008;145(3):548–554.
23. Hartnett ME, McColm JR. Retinal features predictive of progression to stage 4 ROP. Retina
2004;24:237–241.
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and expected utility of preemptive surgical reintervention. Trans Am Ophthalmol Soc
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Chapter 55
Treatment of Stages 4 and 5
Retinopathy of Prematurity
Antonio Capone Jr, Michael T. Trese, aand M. Elizabeth Hartnett
BASIC CONSIDERATIONS
Surgical Anatomy of ROP-Related Retinal Detachment
Fibrous proliferation and contraction of neovascularization along the ridge
and onto the overlying vitreous precede traction retinal detachment.
Condensation of vitreous into sheets and strands acts as a scaffold for further
extension of the fibrovascular tissue. Traction along the retinal surface and
contraction of the posterior hyaloid face contribute to distortion of the
posterior pole architecture. The configuration of the retinal detachment in
ROP depends primarily on the location of the ridge and the orientation of
vectors of vitreoretinal traction. Tractional forces are exerted in the following
ways:
1. Intrinsic to retina (Figure 55-1). These forces consist of proliferation
intrinsic to the ridge itself causing a tractional vector that cannot be
removed surgically. Contraction of this circumferential vector results in
a radial fold. It can be addressed by scleral buckle alone when it is the
sole tractional vector located near or anterior to the equator.
2. Ridge to lens (Figure 55-2). The most common and easily
conceptualized traction vector, and the most important to interrupt
surgically, often extends circumferentially from the ridge toward the
midperipheral lens.
3. Ridge to ridge (Figure 55-3). This vector extends as a sheet across the
“mouth” of the developing funnel-shaped retinal detachment.
4. Ridge to ciliary body (Figure 55-4). This vector extends from the ridge
anteriorly toward the ciliary body.
5. Ridge to retina. This traction extends from the elevated ridge back
toward the portion of the retina just anterior to the original location of
the ridge.
6. Disc stalk. There are three variants of the proliferative tissue extending
from the optic disc: (a) a typically very adherent epiretinal sheet
extending along the retinal surface to the ridge often seen in eyes in
which the ridge is located posterior to the equator, (b) a transvitreal stalk
extending to the ridge usually seen in eyes with an equatorial ridge, and
(c) a transvitreal sheet extending from ridge-to-ridge sheet usually seen
in eyes with a ridge located anterior to the equator (Figure 55-5).
FIGURE 55-1 Contraction of proliferation intrinsic to the
circumferential ridge (arrow), resulting in a radial fold.
Timing of Surgery
ROP-related detachments may appear stable in the first few weeks or months
after peripheral retinal ablation. Yet neither the stability of the partial
detachment nor visual acuity is predictable from the retinal appearance in
infants with ROP. This is particularly true for untreated eyes or those with
incomplete peripheral retinal ablation. ROP-related retinal detachments can
progress—often very gradually—for years. As the eye grows, the cicatricial
proliferation does not, and retina tethered to the eye wall is vulnerable to
stretching to the point of tractional detachment or development of a retinal
break.
Visual outcome of eyes with even partial ROP-related retinal detachment
is generally poor by age 4.5 years. In the cohort of 61 eyes from the
Multicenter Trial of Cryotherapy for Retinopathy of Prematurity study with
partial retinal detachment 3 months after threshold, only six eyes had vision
of 20/200 or better at age 4.5 years (1,14). The difficulty exists in
determining whether an eye with residual or recurrent features of threshold
ROP will develop progressive stage 4 ROP or show regression after laser
treatment. One retrospective study of retinal features in eyes treated with
laser for threshold ROP determined that ≥6 clock hours of ridge elevation, ≥2
quadrants of plus disease, and vitreous haze were predictive of progressive
stage 4 ROP and that these features should indicate to the ophthalmologist
that this patient likely will require surgery to prevent stage 4B ROP (15).
Although valuable, the study had the limitation of analyzing both eyes of
some infants who underwent bilateral surgery without accounting for
correlation between eyes. Others have found the importance of even a clock
hour of bleeding or fibrovascular proliferation associated with the ridge as
causative harbinger of progressive retinal detachment and vision loss.
In general, earlier surgical intervention is better, as the prognosis for
vision is best when the detachment is least extensive. In eyes with stage 4
detachments and thorough peripheral retinal ablation, surgery typically is
done between 38 and 42 weeks’ postmenstrual age. An exception to this rule
is the eye with stage 4 ROP in a vascularly active eye with marked plus
disease that lacked prior peripheral retinal laser ablation. In such eyes, the
risk of uncontrollable bleeding is much greater, and it is better to treat the
avascular peripheral retina first and delay surgery. Similarly, if the eye has a
stage 5 retinal detachment with significant vascular activity, one may need to
wait until 48 to 52 weeks’ postmenstrual age for the vascular activity to quiet
(16).
Equipment
Standard vitrectomy equipment of any gauge can be employed for surgery on
eyes with advanced ROP. Instrument availability and flex characteristics of
the vitrector and light pipe are the primary reasons that 23-gauge is our “go-
to” platform. Infusion port aside, we do not often use a cannula for the other
two instrument ports, or a short 2-mm cannula is used. For complex stage 4B
and most all stage 5 detachments, dissection will often be carried out with a
23-gauge or 20-gauge Trese spatula (Figures 55-6 and 55-7).
FIGURE 55-6 20-gauge Trese spatula.
PROCEDURAL TECHNIQUES
Scleral buckle and vitrectomy, alone and in combination, have been used to
manage ROP-related retinal detachments. The specific interventions vary
depending on the location and type of traction causing retinal detachment.
Successful surgery in ROP is rooted in visualization, but the anatomic
nuances are sometimes not clearly apparent with the standard diffuse en face
lighting of the operating microscope. Oblique illumination with a standard
endoilluminator positioned transcorneally or intracamerally is often effective
for highlighting subtle tissue planes. The endoillumination probe is
positioned obliquely with respect to the surgeon’s viewing axis through the
operating microscope, directed at the surgical plane of interest. The probe is
held by an assistant when bimanual dissection is required and the tissue of
interest visualized using an unlit operating microscope (17). Endoscope-
assisted surgery has been described to improve visualization of vitreous
planes (18).
Scleral Buckle
We rarely perform scleral buckle for ROP-related retinal detachments, as
scleral buckle procedures do not address transvitreal traction as effectively as
vitrectomy and have several disadvantages described below. Encircling
scleral buckle may be useful when the ridge is located near or anterior to the
equator and for rhegmatogenous detachments. Radial scleral buckle elements
can be placed to relax radial folds running from the disc to the ridge as well
as for focal support of retinal breaks.
The element of choice for encircling scleral buckle in infants is a 40, 41,
or 240 silicone band. If possible, the band is placed to support the ridge on
the anterior portion of the element, placed along the greater curvature of the
eye in order to minimize migration of the band. Sutures are imbricated to
provide height. The anterior chamber is tapped with a 30-gauge needle to
normalize intraocular pressure (IOP). In eyes with substantial subretinal fluid,
drainage through an external sclerotomy, using a scleral cut down, diathermy,
and release of subretinal fluid, can be carried out to permit tightening of the
band, IOP reduction, and reattachment of the retina.
Disadvantages of scleral buckle for stage 4A ROP are the dramatic
anisometropic myopia (19) and the second intervention required for scleral
buckle transection or removal so that the eye can continue to grow. More
importantly, however, not all tractional forces can be alleviated with scleral
buckling alone. In a retrospective comparison of stage 4 ROP treated with
scleral buckle or lens-sparing vitrectomy, progressive stage 4 ROP was
prevented after one procedure in 7 of 11 eyes treated with lens-sparing
vitrectomy compared to only 5 of 16 eyes treated with scleral buckle (P =
0.03, exact chi-square) (20). Sears and Sonnie (21) found that the addition of
scleral buckling to vitrectomy did not improve outcomes.
Lens-Sparing Vitrectomy
Lens-sparing vitrectomy is our preferred approach for most stage 4A
detachments, many stage 4B detachments, and some open-funnel stage 5
detachments. Lens-sparing vitreoretinal surgery is uniquely suited to the
management of stage 4 ROP. Maguire and Trese (22) reported the technique
initially for eyes with subtotal posterior retinal detachment involving the
macula.
A light pipe or pic, vitreous cutter, and membrane peeler cutter scissors
are used in the procedure. The eye is entered through the pars plicata/anterior
pars plana at a clock hour advantageous to approaching the existing traction.
A core vitrectomy is performed addressing the organized vitreous in four
planes: transvitreal ridge to ridge, ridge to periphery, ridge to lens, and
tentacles from the central stalk of organized vitreous extending from the optic
nerve head to the ridge. It is helpful to plan the approach so as to relieve as
much traction as can safely be performed. Releasing traction from the ridge
to lens and then ridge to peripheral retina before releasing the circumferential
ridge to ridge transvitreal traction reduces the potential problem of the ridge
being pulled anteriorly toward the ciliary body once the transvitreal traction
is released. The ridge to peripheral vitreous traction then can be difficult to
address safely. When this dissection is complete, a fluid–air exchange is
performed. During the fluid–air exchange, the retina is not forced to reattach
as subretinal fluid will be reabsorbed over time once the transvitreal traction
has been removed or reduced. The sclerotomies are closed and the infant
positioned such that the air bubble displaces subretinal blood from the
posterior pole. Subretinal fluid may continue to be reabsorbed over weeks in
the postoperative period.
Infants with ROP often have multiple life-threatening comorbidities and
are the retina surgeon’s highest anesthesia risk population as described in
Chapter 57. Furthermore, ROP is a rapidly progressive bilateral
vitreoretinopathy, where both eyes commonly require prompt surgical
intervention. This had traditionally required separate visits to the operating
room for each eye.
One way to minimize the anesthesia risks for the infant, as well interval
progression of the ROP-related tractional retinal detachment, is to operate on
both eyes consecutively during the same anesthesia session. This has been
termed immediate sequential bilateral pediatric vitreoretinal surgery (ISBVS)
(23). Each eye is treated as a completely separate procedure with reprepping,
redraping, rescrubbing, new instruments, medications, and intraocular fluids.
Given the reported incidence of postvitrectomy endophthalmitis of 0.03% to
0.08%, the risk of bilateral endophthalmitis as separate unrelated events
would be assumed to be 1 in 500,000 to 10,000,000 simultaneous vitrectomy
procedures (24,25). In comparison, the risk of anesthesia-related death in
children is as high as 1 in 10,000, and all-cause perioperative mortality is 1 in
100 to 1,000 in children, even higher in neonates, and even higher in
premature infants (26,27). We do not advocate ISBVS for all infants. The
majority of infants can be treated with staged bilateral surgery. However,
ISBVS can be a powerful option for appropriately selected cases.
ENZYMATIC VITREOLYSIS
Separation of the vitreoretinal interface during vitrectomy is challenging in
complex pediatric diseases such as ROP. Sebag has demonstrated
histopathologically that the adhesion between vitreous cortex and internal
limiting membrane of the retina is stronger in humans aged 9 months to 20
years, as compared to those 21 years or older (see also Chapter 4). The
stronger vitreoretinal adhesion in children precludes induction of posterior
vitreous detachment (PVD) during vitrectomy in most infants and young
children. Although a Weiss ring (epipapillary hyaloidal condensation) may be
apparent after attempted mechanical hyaloidal separation in children, the
separation is likely to be lamellar with residual outer cortical vitreous
remaining on the retinal surface.
In proliferative vitreoretinopathies such as ROP and familial exudative
vitreoretinopathy, adequate removal of epiretinal membranes enmeshed
within layers of formed vitreous is crucial to achieve retinal reattachment.
Autologous plasmin enzyme–assisted vitrectomy is well described (28) in a
range of pediatric and adult vitreoretinal diseases with supporting level II and
III published evidence in a variety of pediatric conditions, namely, traumatic
macular hole (29,30), stage 5 ROP (31,32), congenital X-linked retinoschisis
(33), and combined hamartoma of the retina and retinal pigment epithelium
with associated macular-involving epiretinal membrane (34).
Both human-derived plasmin enzyme (both autologous and heterologous)
and ocriplasmin (Jetrea; Thrombogenics, Leuven, Belgium) have been used
as pharmacologic vitreolysis agents to facilitate the induction of PVD during
vitrectomy in ROP (35). Ocriplasmin is a serine protease and truncated form
of plasmin that is active against substrates, such as fibronectin and laminin,
and cleaves the vitreoretinal interface to treat vitreomacular traction in adults
(36–39).
The use of plasmin enzyme to assist surgery has been reported in the
ROP population (32).
The data regarding plasmin was retrospective in nature and lacked control
arms, but it did demonstrate an acceptable safety profile and appeared to
augment vitreous separation. Further studies are warranted here. Ocriplasmin
demonstrated slightly less encouraging results in a prospective study of
pediatric vitreoretinopathies, excluding ROP (40). Although the data
presented in that study do not show a clear-cut benefit to using ocriplasmin as
an adjunct in pediatric retinal surgery, the complexity of the surgeries and the
small sample size limited the analysis, necessitating the need for future
studies and pharmacologic agents. The investigators did note that vitrectomy
appeared to be easier in the treatment arms after the unmasking. In general,
the overall ability to dissociate the hyaloid from the retina with less
mechanical force and improved visualization of surgical planes are
advantageous (see also Chapters 3 and 4).
POSTOPERATIVE CARE
Attention to the emotional needs of a child and their family is essential to a
successful outcome. This includes thorough explanation to family members
and encouragement to patients. Controllable postoperative complications
must be avoided. Ports should be closed with sutures in all but the most
straightforward core vitrectomies in children. Peripheral iridectomies should
be made routinely in aphakic and pseudophakic eyes, generally inferiorly for
safety against iris bombe and angle closure. The trust that a child has in their
retinal specialist depends upon the avoidance of inflicting pain; alienating a
child for the benefit of a better office examination is not a victory.
Postoperative day 1 evaluation consists largely of assessing for infection and
IOP. More detailed examination is obtained in the ensuing visit at 1 week
when it will be better tolerated by the child. If a child is adamant about
refusing dilated fundus examination, usually an office B-scan can suffice for
the short term until a repeat EUA.
COMPLICATIONS
The most important complications of vitreous surgery are endophthalmitis,
rhegmatogenous retinal detachment, and development of cataract. Although
endophthalmitis is potentially devastating, it is rare after vitreous surgery.
The incidence of rhegmatogenous retinal detachment in eyes of infants
undergoing lens-sparing vitrectomy for 4A ROP is low in the setting of
extensive peripheral retinopexy. Cataract, a common complication of vitreous
surgery in adults, is seen in only approximately 16% of children at 2.4 years
(41). Glaucoma is a lifelong risk as well (42). Some of the complications
encountered during follow-up, such as corneal opacity, glaucoma, and
phthisis, are more common in eyes that have had a complicated surgical
course.
OUTCOME EXPECTATIONS
The surgical goal in eyes with macula-sparing ROP–related traction retina
detachments (stage 4A ROP) is an undistorted or minimally distorted
posterior pole, total retinal reattachment, and preservation of the lens and
central fixation vision (Figures 55-8 and 55-9). Surgery for tractional retinal
detachments involving the macula (stage 4B ROP) is performed to minimize
retinal distortion and prevent total retinal detachment (Figures 55-10 and 55-
11). The practical surgical goal is to reattach as much of the retina as is
possible without causing a retinal break. Partial residual retinal detachment
and retinal drag/distortion are common in such eyes. The functional goal for
stage 4B eyes is ambulatory vision.
FIGURE 55-8 Nasal stage 4A ROP–related tractional
retinal detachment located in zone I in a 38-week-old
infant 1 month following laser.
FIGURE 55-9 Resolved nasal stage 4A ROP–related
tractional retinal detachment seen in Figure 55-8
following lens-sparing vitreous surgery. Straightening of
the vessels inferonasal to the optic disc is the only
residuum of the tractional detachment following
vitrectomy.
FIGURE 55-10 Stage 4B ROP–related tractional retinal
detachment prior to surgery. The red reflex visible
superiorly is an area of attached retina.
FIGURE 55-11 Attached posterior retina with residual
subretinal lipid in the eye seen in Figure 55-8 following
lensectomy and vitrectomy.
CONCLUSION
Surgical intervention offers the potential for preservation of vision for eyes
with ROP-related retinal detachment, particularly if performed prior to
macular distortion or detachment (i.e., stage 4A). Surgery for traction retinal
detachments involving the macula (stage 4B ROP) is performed to minimize
retinal distortion and prevent total detachment (stage 5) with the goal of
providing ambulatory vision. Maximal recovery of vision following the insult
of macula-off retinal detachment and interruption of visual development in
infants may take years.
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44. Lakhanpal RR, Sun RL, Albini TA, et al. Visual outcomes after 3-port lens-sparing vitrectomy
in stage 4 retinopathy of prematurity. Arch Ophthalmol 2006;124(5):675–679.
45. El Rayes EN, Vinekar A, Capone A Jr. Three-year anatomic and visual outcomes after
vitrectomy for stage 4B retinopathy of prematurity. Retina 2008;28(4):568–572.
46. Trese MT, Droste PJ. Long-term postoperative results of a consecutive series of stages 4 and 5
retinopathy of prematurity. Ophthalmology 1998;105:992–997.
SECTION IX
Principles of Surgery for Pediatric
Retinal Conditions
56
General Surgical Considerations and
Preoperative Management in Infants
and Children
Michael T. Trese, and Antonio Capone Jr
INFORMED CONSENT
Informed consent in the United States constitutes permission from the parent
or legal guardian for the physician to perform both examination and surgical
therapy. This consent should be obtained prior to any intervention. In the
circumstance in which parental consent is impossible, a court order can be
obtained to perform the needed interventions. In the age of antivascular
endothelial growth factor (VEGF) therapy for pediatric retinal diseases,
consent for off-label use must be recorded and institutional review board
(IRB) and investigational new drug (IND) approvals obtained.
There are many psychological issues that enter into both the consent and
the need for surgical intervention in infants and children. Parents often feel
both a responsibility to protect the child and a concern that they somehow
may be responsible for whatever problem has affected the child. Most parents
of children with known or established medical problems have learned to deal
with these issues by the time they reach the vitreoretinal surgeon, but
occasionally parents lack sensitivity to these issues. It is rare that parents
require psychological counseling, but this should be considered if the family
is having difficulty coping with the issues of a child with severe ocular
problems.
SURGICAL TEAM
In dealing with extremely small infants, who often have young parents and
come from poor socioeconomic settings, it is very important to adopt a team
approach to their care. This frequently requires not only skilled retinal
personnel but also an anesthesiologist who is comfortable with the care of
pediatric patients, particularly with very low-birth-weight premature infants.
It also involves interaction with the pediatrician, neonatologist, social
services, the pediatric ophthalmologist, vision therapist, vision teachers, and
the school system. These patients are a challenge preoperatively,
intraoperatively, and postoperatively, and all of the care must be coordinated
in order to realize maximal development of the visual system. It is important
to remember that these patients are “learning to see” at the time they are
receiving surgical intervention. Care is taken to avoid adding to the
amblyogenic issues, particularly with unilaterally affected infants. In
addition, it is necessary to document that the patient’s family has been told
that they must interact with other members of the team caring for the child.
This requires the surgeon interacting with the other members of the support
staff by providing good communication of the child’s structural findings and
encouraging aggressive refractive and amblyopic care.
Frequently, the surgeon is asked to predict the visual potential of the
child. This is an extremely difficult question to answer and is difficult to
predict based on anatomic results alone. We have seen several children with
extraordinarily distorted retinas, who had visual acuities between 20/20 and
20/60 (4). Conversely, we have seen children with excellent anatomic
outcomes following surgery, who have had no light perception vision. This
supports the philosophy of aggressive refractive and amblyopic care until the
child’s visual potential can be determined, at approximately age 4 or 5 years.
In some older children with anisometropia, vision can improve at older ages.
It is helpful to work with pediatric ophthalmologists who strive to seek the
best visual potential. Working hard for low levels of vision is extremely
important to the child and family as the child develops. The child with low
levels of vision (20/1,900 or less) usually is able to visually ambulate and
function at a much higher level than the adult with the same level of vision
(see also Chapter 13).
REFERENCES
1. Hairston RJ, Maguire AM, Vitale S, et al. Morphometric analysis of pars plan development in
humans. Retina 1997;17:135–138.
2. Verstraeten TC, Chapman C, Hartzer M, et al. Pharmacologic induction of posterior vitreous
detachment in the rabbit. Arch Ophthalmol 1993;111:849–854.
3. Margherio AR, Margherio RR, Hartzer M, et al. Plasmin enzyme-assisted vitrectomy in
traumatic pediatric macular holes. Ophthalmology 1998;105:1617–1620.
4. Ferrone PJ, Trese MT, Williams GA, et al. Good visual acuity in an adult population with
marker posterior segment changes secondary to retinopathy of prematurity. Retina
1998;18:335–338.
5. Chang S, Lincoff H, Coleman DJ, et al. Perfluorocarbon gases in vitreous surgery.
Ophthalmology 1985;92:651–656.
57
Anesthesia for Infants and Children
P. Anthony Meza
INTRODUCTION
Most of this chapter will focus on anesthesia for the premature infant. This
chapter is no replacement for a textbook of pediatric anesthesiology, but it
does provide a description of our anesthetic techniques and the reasons we
use these techniques when caring for children and infants with retinopathy of
prematurity (ROP) and other eye diseases.
For older infants and children, standard pediatric anesthesia techniques
work well for eye surgery. Even though many of these children with a history
of extreme prematurity and very-low-birth weight (VLBW) have some
diminished pulmonary function on to adulthood, they almost always tolerate
general anesthesia very well. Most of these general anesthetics can be done
with a laryngeal mask airway (LMA).
CONCLUSION
Anesthetic care of the VLBW infant for ROP surgery requires a trained
pediatric anesthetist. These patients require extra time and consideration
because of the fragility of their physical condition caused by the multiple
medical problems of extreme prematurity.
Tables 57-1 through 57-8 list the guidelines for medications, endotracheal
tubes, and LMAs we use at William Beaumont Hospital, Royal Oak,
Michigan.
Depth of insertion for the neonate = wt in kg + 6.0 cm. This gives length from distal tip to corner of
mouth. External diameter of the endotracheal tube approximates the size of the patient’s little finger.
Cuffed endotracheal tubes are recommended after age 6 years. Tube tip should be halfway between
thorax inlet and carina. All tubes are checked for placement by auscultation and if necessary by x-ray
film. When ventilating for life support at usual pressures, the uncuffed endotracheal tube should leak at
20-cm H2O inspiratory pressure. The general tube size rules used after age 1 year:
aFor isoproterenol, norepinephrine, and epinephrine, 1.0 mL/h provides 0.1 μg/kg/min.
bEach I mL/h infused will provide the same number of μg/kg/min of dopamine or dobutamine (or 1.0
mL/h provides 1.0 μg/kg/min).
REFERENCES
1. Istaphanous G, Loepke A. General anesthetics and the developing brain. Curr Opin Anesthesiol
2009;22: 368–373.
Randall P, et al. Cognitive and behavioral outcomes after early exposure to anesthesia and
2.
surgery. Pediatrics 2011;128:e1053–e1061.
3. Shih J, et al. Delayed environmental enrichment reverses sevoflurane-induced memory
impairment in rats. Anesthesiology 2012;116:586–602.
4. Davidson AJ, Sun LS. Clinical evidence for any effect of anesthesia on the developing brain.
Anesthesiology 2018;128:840–853.
5. Gregory GA, ed. Pediatric anesthesia, 3rd ed. New York: Churchill Livingstone, 1994.
6. Cook DR, Marcy JH, eds. Neonatal anesthesia. Pasadena: Appleton Davies, Inc., 1988.
7. Seefelder C. Challenges in neonatal anesthesia. Presented at Practical Aspects of Pediatric
Anesthesia, Harvard Medical School, The Children’s Hospital, Massachusetts General Hospital,
May 22–24, 2002.
8. Cote CJ, Lerman J, Anderson BJ, eds. A practice of anesthesia for infants and children, 6th ed.
Philadelphia, PA: Elsevier, 2019:64–65.
9. Haigh P, Chiswick M, O’Donoghue E. Retinopathy of prematurity: systemic complications
associated with different anaesthetic techniques at treatment. Br J Ophthalmol
1997;81:283–287.
10. Ferrari L, Goudsouzian N. The use of the laryngeal mask airway in children with pulmonary
dysplasia. Anesth Analg 1995;81:310–313.
58
External and Minor Surgical
Procedures
Emmanuel Y. Chang, Antonio Capone Jr, and Michael T. Trese
INTRODUCTION
A broad range of noninvasive and minimally invasive surgical procedures is
necessary in the course of managing children with pediatric vitreoretinal
pathology. This chapter details the pertinent aspects of these interventions.
Improved imaging modalities and novel therapeutic targets have expanded
our understanding of the timing and roles of specific therapeutic interventions
in pediatric retinal diseases.
Many of these procedures such as laser retinopexy, cryoretinopexy, and
intravitreal therapy are performed routinely on adults in the clinical setting
with topical, subconjunctival, or retrobulbar anesthesia. However, infants and
children will usually require general anesthesia or monitored sedation for
analogous procedures. Children may also require repeated examination under
anesthesia to determine follow-up care.
FOCAL RETINOPEXY
Focal retinopexy is applied with laser or a cryoprobe depending on the lesion.
Both techniques can be used to treat peripheral retinal breaks, telangiectatic
vascular pathology in Coats disease, retinal vascular hemangiomas, and
peripheral vascular nonperfusion in intermediate uveitis, as well as small (3
mm in basal diameter and 2 mm in thickness) equatorial and peripheral
retinoblastoma lesions (see also Chapters 44 and 45). When treating larger
vascular lesions as in von Hippel-Lindau syndrome or Coats disease, a low-
power long-duration laser treatment is necessary to slowly blanch the
vascular lesion to a white appearance. Retreatment may need to be carefully
applied since larger lesions often times obtain a red appearance again despite
initial treatment in the same treatment session. If the laser power is too
intense, there is the risk of creating an iatrogenic vitreous hemorrhage or
retinal break from overlying hyaloidal contracture. Feeder vessels may also
be treated to accelerate the closure of large vascular retinal lesions. It is
important to explain to family members that a staged multiprocedural
approach in the treatment of large retinal lesions may be necessary.
In general, the techniques of application are similar to those described for
peripheral retinal ablation just above. There are two notable exceptions to this
statement: a triple freeze–thaw technique is employed in treating pars plana
fibroglial inflammatory aggregates (16) (“snowbanks”) and retinoblastoma
(17) when employing cryopexy. Also, laser-induced hyperthermia
(transpupillary thermotherapy) has generally replaced traditional
photocoagulation for the treatment of retinoblastoma (18).
INTRAVITREAL INJECTION OF
PHARMACOLOGIC AGENTS
Intravitreal pharmacotherapy is becoming a rapidly used modality, especially
in the use of anti-VEGF drugs for ROP (21). Although anti-VEGF therapy
reduces vascular activity in severe ROP (see Chapters 52 and 53), many
systemic risk factors and unique considerations of anti-VEGF therapy use
need to be carefully considered.
Injecting a pharmacologic agent directly into the vitreous cavity is not a
trivial procedure, even though it is a quicker procedure than laser or
cryotherapy. Serious complications related to the injection procedure have
occurred in <0.1% of intravitreal injections, including endophthalmitis,
rhegmatogenous retinal detachments, and iatrogenic traumatic cataracts.
Many of the latter issues arise due to a lack of understanding of pediatric
anatomy because neonatal/infant eyes have much larger lenses relative to the
globe size than in adult eyes and the location of the pars plana/ora serrata
varies based on age of the patient. Furthermore, in the very young neonatal
eye or microphthalmic eye, the pars plana may have yet to develop, and
injections are performed through the pars plicata. It is important to use age-
appropriate locations when determining the location to perform an intravitreal
injection (Table 58-1) (22).
aDetermination of ora-limbus distance is based on regression analyses of control and disease subjects,
as measured from the limbus, permitting ≥1 mm from the ora serrata; we recommend nasal
sclerotomies be placed 0.25–0.5 mm shorter than the recommended location.
bWe recommend transillumination-guided identification of the ora serrata, given the variability in ora-
limbus distance and possible anterior–posterior contraction among infants.
FEVR, familial exudative vitreoretinopathy; PFV, persistent fetal vasculature; ROP, retinopathy of
prematurity.
Reprinted from Wright LM, Harper CA, Chang EY. Management of infantile and childhood
retinopathies: optimized pediatric pars plana vitrectomy sclerotomy nomogram. Ophthalmol Retina
2018;2(12):1227–1234. Copyright © 2018 by the American Academy of Ophthalmology. With
permission.
SUMMARY
As is true of adults, children with retinal pathology will often require
noninvasive or minimally invasive interventions. For premature infants,
examination alone is a minor procedure. While anesthesia requirements
generally differ from those for analogous treatments in adults, the procedures
described above are highly effective approaches to disease management and
are standard tools in the armamentarium of the pediatric retinal specialist.
REFERENCES
1. Sammons JS, et al. Outbreak of adenovirus in a neonatal intensive care unit: critical importance
of equipment cleaning during inpatient ophthalmologic examinations. Ophthalmology
2019;126(1):137–143. doi: 10.1016/j.ophtha.2018.07.008.
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Classification of Retinopathy of Prematurity. Arch Ophthalmol 1984;102(8):1130–1134.
3. An international classification of retinopathy of prematurity. II. The classification of retinal
detachment. The International Committee for the Classification of the Late Stages of
Retinopathy of Prematurity. Arch Ophthalmol 1987;105(7):906–912.
4. International Committee for the Classification of Retinopathy of Prematurity. The International
Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol 2005; 123(7):991–999.
Mehta M, Adams GG, Bunce C, et al. Pilot study of the systemic effects of three different
5. screening methods used for retinopathy of prematurity. Early Hum Dev 2005;81: 355–360.
6. Mukherjee AN, Watts P, Al-Madfai H, et al. Impact of retinopathy of prematurity screening
examination on cardiorespiratory indices: a comparison of indirect ophthalmoscopy and
RetCam imaging. Ophthalmology 2006;113: 1547–1552.
7. American Academy of Pediatrics Section on Ophthalmology, American Academy of
Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus, American
Association of Certified Orthoptists. Screening examination of premature infants for retinopathy
of prematurity. Pediatrics 2013;131:189.
8. Balasubramaniam M, Capone A Jr, Hartnett ME, et al. The photographic screening for
retinopathy of prematurity study (Photo-ROP): study design and baseline characteristics of
enrolled patients. Retina 2006;26:S4–S10.
9. Todoroch B, et al. Summary of the Association of Pediatric Retinal Surgeons (APRS) responses
regarding the preferred disinfection technique for contact wide-field fundus camera and
incidence of infection and corneal abrasions correspondence. Retina 2017; 37(5):e52–e54.
10. Wallace DK, Freedman SF, Zhao Z, et al. Accuracy of ROPtool vs individual examiners in
assessing retinal vascular tortuosity. Arch Ophthalmol 2007;125(11): 1523–1530.
11. Brown JM, Campbell JP, Beers A, et al.; Imaging and Informatics in Retinopathy of
Prematurity (i-ROP) Research Consortium. Automated diagnosis of plus disease in retinopathy
of prematurity using deep convolutional neural networks. JAMA Ophthalmol 2018;136(7):
803–810.
12. Levinson JD, Hubbard GB III. 577-nm yellow laser photocoagulation for Coats disease. Retina
2016;36(7):1388–1394.
13. Pandya HK, Faia LJ, Robinson J, et al. Macular development in aggressive posterior
retinopathy of prematurity. Biomed Res Int 2015;2015:808639.
14. Multicenter trial of cryotherapy for retinopathy of prematurity. Preliminary results. Cryotherapy
for Retinopathy of Prematurity Cooperative Group. Arch Ophthalmol 1988; 106(4):471–479.
15. Good WV. Final results of the early treatment for retinopathy of prematurity (ETROP)
randomized trial. Trans Am Ophthalmol Soc 2004;102:233–248; discussion 248–250.
16. Okinami S, Sunakawa M, Arai I, et al. Treatment of pars planitis with cryotherapy.
Ophthalmologica 1991;202(4): 180–186.
17. Shields JA, Parsons H, Shields CL, et al. The role of cryotherapy in the management of
retinoblastoma. Am J Ophthalmol 1989;108:260–264.
18. Shields CL, Santos MC, Diniz W, et al. Thermotherapy for retinoblastoma. Arch Ophthalmol
1999;117:885–893.
19. Carroll C, Papaioannou D, Rees A, et al. The clinical effectiveness and safety of prophylactic
retinal interventions to reduce the risk of retinal detachment and subsequent vision loss in adults
and children with Stickler syndrome: a systematic review. Health Technol Assess
2011;15(16):1–62.
20. Leiba H, Oliver M, Pollack A. Prophylactic laser photocoagulation in Stickler syndrome. Eye
(Lond) 1996;10(Pt 6): 701–708.
21. Mintz-Hittner HA, Kennedy KA, et al.; BEAT-ROP Cooperative Group. Efficacy of intravitreal
bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med 2011;364(7): 603–615.
22. Wright LM, Harper CA, Chang EY. Management of infantile and childhood retinopathies:
optimized pediatric pars plana vitrectomy sclerotomy nomogram. Ophthalmol Retina 2018;
2(12):1227–1234.
23. Cernichiaro-Espinosa LA, Harper CA, Read SP, et al. Reprot of safety of the use of a short 32G
needle for intravitreal anti-vascular endothelial growth factor injections for retinopathy of
prematurity: a multicenter study. Retina 2018;38(6):1251–1255.
59
Anterior Segment Surgery
Combinations With Posterior Segment
Diseases
Mark K. Walsh
KERATOPROSTHESES
The Boston type 1 KPro has been used in select high-risk children with
severe corneal disease given the high rate of PKP rejection/failure in pediatric
patients and the potential for rapid visual recovery and low concern for graft
rejection. The KPro is an artificial cornea consisting of a PMMA optic and
back plate with an intervening corneal graft ring. The first cases in children
were reported in 2006 (6). Placement of the KPro is often accompanied by
lensectomy due to the short distance between the lens and cornea in children,
tube shunt placement because of a high risk of glaucoma in anterior segment
dysgenesis disorders, at least an anterior vitrectomy, and sometimes PPV, if
there is additional posterior pathology. Unfortunately, severe postoperative
complications are much more frequent in children with KPros than adults
with a recent large series reporting no light perception (NLP) vision in 45%
of children at last follow-up (7) due to high rates of endophthalmitis, retinal
detachment, and KPro extrusion. Thus, it has been suggested that without
significant advances to improve KPro outcomes in children, the risks of
placing KPros in children currently outweigh the potential benefits (7,8),
although this viewpoint is controversial with some still advocating for KPro
placement in select pediatric eyes.
COMBINED SUTURELESS
INTRASCLERAL INTRAOCULAR LENS
FIXATION AND PARS PLANA
VITRECTOMY
Eyes that lack sufficient capsule to support an in-the-capsular bag or sulcus-
placed IOL or with significant zonular dehiscence present unique surgical
challenges. Historically, in these instances in adults, IOLs have either been
sutured to the iris or sclera or an anterior chamber IOL (ACIOL) is placed.
For multiple reasons, these techniques are not ideal for pediatric eyes. Sutures
have limited life spans and can eventually break or erode, leading to late IOL
dislocation (11–13), which is especially troubling in children who need
decades of IOL stability. ACIOLs can lead to corneal decompensation and
uveitis–glaucoma–hyphema syndrome, complications, which are likely more
common in smaller pediatric eyes with shallow anterior chambers; therefore,
ACIOLs have largely been avoided in children. Recently in adults, sutureless
intrascleral (SIS) fixation of three-piece IOLs has gained popularity given
their potentially lower risk of side effects and decreased complexity and
surgical time relative to scleral sutured IOL techniques. Additionally, SIS
IOL fixation techniques are more versatile than ACIOLs or iris-fixated IOLs
in that they can be performed in eyes with severely damaged or even absent
irides. There are several surgical variations of SIS IOL fixation (14–16), but
they all involve fixating the haptics of a three-piece IOL into the sclera
without the requirement of sutures to hold the haptics in place. For a variety
of reasons, aphakic children may not always be tolerant of aphakic contact
lenses, and aphakic spectacles create image distortion and prismatic effects
(17). Thus, since 2011, the author has been performing SIS IOL fixation in
children who are aphakic and contact lens intolerant without good capsular or
zonular support or in children who have subluxed crystalline lenses with
zonular dehiscence, such as in Marfan syndrome (18). Fortunately, these
IOLs have been remarkably well tolerated without any significant
postoperative complications such as IOL dislocation, endophthalmitis, haptic
erosion, or retinal detachment with up to 8 years of follow-up (Walsh MK,
unpublished data, 2020). Recently, the author has moved to a novel SIS IOL
fixation technique that is transconjunctival in which the scleral tunnels for the
haptics are made with 27-gauge valved trocar cannulas with subsequent
melting of the tips of the haptics to form bulbs or flanges to theoretically
further decrease the risk of haptic slippage (19,20). As an added benefit,
because this surgery is transconjunctival, the surgery itself is quicker, and
postoperatively patients are more comfortable and tend to heal faster.
After the vitrectomy and scleral tunnels have been completed, attention is
then turned to the IOL. In the case of a dislocated three-piece IOL, it is
elevated into the anterior vitreous cavity with a soft tip cannula using the
extrusion function. The soft tip cannula can be rotated to expose the tip of
one of the haptics into or just posterior to the pupillary plane. A broad-based
platform forceps (e.g., 27-gauge Grieshaber Maxgrip, Alcon) is then inserted
into one of the 27-gauge scleral tunnel cannulas, and just the tip of the haptic
is grasped. A 0.3-mm forceps is then used to slide the 27-gauge cannula up
the shaft of the Maxgrip forceps before gently externalizing the haptic. The
second haptic can sometimes be easily visualized posterior to the iris and can
be externalized in similar fashion, but more frequently, it is easier to use the
posterior visualization lens (e.g., BIOM) with a light pipe in one hand and the
broad-based platform 27-gauge forceps in the other hand to grasp and then
externalize the second haptic. Depending on the angle between the haptic and
forceps shaft, on occasion, the haptic will slip out of the tunnel when trying
to externalize it. Typically, it is simple just to place the forceps right back
into the scleral tunnel to attempt externalization again without having to
reinsert the 27-gauge cannula.
At this point, a 10-0 polyglactin (Vicryl) suture is placed in the CCW and the
knot rotated and/or buried posteriorly, and viscoelastic is removed from the
anterior chamber through the temporal paracentesis using the vitrector. The
author prefers absorbable 10-0 polyglactin, which is monofilament and thus
less irritating to the eye versus larger polyglactin sutures, over 10-0 nylon so
that the corneal suture does not need to be removed postoperatively. The
posterior visualization lens (e.g., BIOM) is then used to facilitate gentle 360-
degree scleral depression to ensure the absence of any iatrogenic peripheral
retinal breaks. Often times, the irides are poorly dilating in these cases, but if
still widely dilated, then acetylcholine chloride intraocular solution (Miochol-
E, Novartis) is injected into the anterior chamber to cause miosis. The
vitrector is then placed through the temporal paracentesis, and a small
peripheral iridectomy is created usually at 12:00. This has eliminated the risk
of postoperative reverse pupillary block. The three 25-gauge cannulas are
then removed, and unlike in adults, in children, these are sutured
transconjunctivally either with 6-0 plain gut, or small conjunctival openings
are made over the sclerotomies and are sutured with 7-0 polyglactin followed
by conjunctival closure with 6-0 plain gut. If the IOP does not seem to be
maintained, a sterile filtered air bubble can be injected into the anterior
chamber followed by an air bubble injected posteriorly on a 30-gauge needle
through the pars plana. The air bubbles help to seal any occult leakage sites.
If an air bubble has been injected, the patient is asked to remain supine until
the first postoperative day. Postoperatively, dilation is avoided indefinitely as
long as the postoperative pupil is at least 3 mm in diameter and the peripheral
retina can be well visualized. This decreases the risk of postoperative iris–
IOL capture, which can happen if the pupil is widely dilated and the
peripheral iris is not adequately supported by residual lens capsule.
Fortunately, the author has not seen this complication in his pediatric series.
Although any three-piece IOL should work for SIS fixation, the author
has the most experience with the Alcon MA50BM, which has a 6.5-mm
optic, which is larger than most optics, and PMMA haptics. The Zeiss CT
Lucia IOL has polyvinylidene fluoride (PVDF) haptics, which appear to be
stronger and upon melting form larger and more uniform flanges,
characteristics that may offset the slightly smaller 6.0-mm optic. The author
has also used the Abbott AR40e three-piece IOL as it has a rounded anterior
optic edge which may theoretically decrease the risk of postoperative cystoid
macular edema. In terms of picking the specific IOL power, the author
always enlists the help of the referring pediatric ophthalmologist as it is a
balancing act between leaving the child too hyperopic initially versus future
eye growth leading to myopia later in life.
CONCLUSIONS
As pediatric retinal surgeons, our patients often have multiple ocular
problems that need to be addressed surgically, including corneal and
lenticular disease, as well as glaucoma. Combined anterior and posterior
segment surgery can theoretically limit the risk of repeated general anesthesia
needed for separate surgeries to address anterior and posterior disease
sequentially. Additionally, eyes that need surgery for secondary IOL
placements in the absence of capsular/zonular support or have subluxed
crystalline lenses due to zonular dehiscence are becoming more commonly
seen in vitreoretinal practices. Newer flanged SIS IOL fixation techniques
combined with PPV offer new hope for aphakic children, who are contact
lens intolerant and at risk for amblyopia.
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expanding the boundaries of diagnosis and treatment. Retina 2017;37:2208–2225.
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2014;25:340–346.
3. Gonnermann J, Klamann MKJ, Maier AKB, et al. Descemet membrane endothelial keratoplasty
in a child with corneal endothelial dysfunction in Kearns-Sayre syndrome. Cornea
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2006;141:308–312.
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Ophthalmology 2010;117:1479–1485.
14. Sharioth GB, Prasad S, Georgalas I, et al. Intermediate results of sutureless intrascleral posterior
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2008;34:1433–1438.
16. Prenner JL, Feiner L, Wheatley HM, et al. A novel approach for posterior chamber intraocular
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18. Walsh MK, Joshi M. Sutureless scleral tunnel intraocular lens fixation in the pediatric
population. Retina 2014;34:807–811.
19. Walsh MK. Sutureless trocar-cannula-based transconjunctival flanged intrascleral intraocular
lens fixation. Retina 2017;37:2191–2194.
20. Stem MS, Wa CA, Todorich B, et al. 27-gauge sutureless intrascleral fixation of intraocular
lenses with haptic flanging; short-term clinical outcomes and a disinsertion force study. Retina
2019;39(11):2149–2154.
21. Yamane S, Sato S, Maruyama-Inoue M, et al. Flanged intrascleral intraocular lens fixation with
double needle technique. Ophthalmology 2017;124:1136–1142.
60
Surgical Approaches to Infant and
Childhood Retinal Diseases: Scleral
Buckles
Jessica G. Lee, and Philip J. Ferrone
INDICATIONS
In the pediatric age range from birth to 18 years of age, there are vitreoretinal
diagnoses requiring retinal surgery that are unique and more common to the
pediatric patient population, especially during the newborn and infant phase
of life. Newborns and infants may present with retinal detachments due to
retinopathy of prematurity (ROP), persistent fetal vasculature (PFV), familial
exudative vitreoretinopathy (FEVR), and other congenital anomalies. With
increasing age, children can present with retinal detachments often related to
trauma with giant retinal tears and/or dialyses, myopia, uveitis, previous
intraocular surgery, or retinal detachments related to Stickler syndrome
(9,10). The surgical management of these retinal detachments can often
involve the placement of a scleral buckle alone or in conjunction with
vitreoretinal surgery.
Patients with Stickler syndrome are at a high risk of vision loss from RRD
caused by a giant retinal tear (see also Chapter 37). Due to the inherited
nature of Stickler syndrome and high rate of bilateral spontaneous retinal
detachments, even “unaffected” family members without a history of a retinal
detachment should be examined. There is some controversy regarding the
best way to prophylactically manage these patients. Some experts advocate
for prophylactic circumferential cryotherapy or laser at the ora serrata, laser
therapy around areas of paravascular pigmented lattice degeneration (23,24),
or the placement of a prophylactic scleral buckle. Retinal detachments caused
by giant retinal tears can be managed with primary vitrectomy with gas or
silicone oil tamponade or combined scleral buckle-vitrectomy. The use of
perfluorocarbon liquid optimizes the management of giant retinal tears by
helping to avoid issues with retinal slippage. In cases where there is a giant
retinal tear with PVR, often a scleral buckle combined with pars plana
vitrectomy using direct perfluorocarbon–silicone oil exchange may be
helpful. Placement of a scleral buckle can be useful to support the vitreous
base (Figure 60-3) (25).
FIGURE 60-3 Top:Wide-field fundus photo of retinal
detachment due to giant retinal tear in a 12-year-old boy.
Bottom:Wide-field fundus photo after repair with pars
plana vitrectomy, scleral buckle (42/72) with silicone oil.
Retinal detachments due to ROP, FEVR, and PFV tend to be more tractional
and often require surgical management with vitrectomy either with or without
a scleral buckle (see also Chapter 66). In the treatment of retinal detachments
due to ROP, the goals of scleral buckling are to reattach the retina and to
reduce the progression from stage 4A or 4B to stage 5 ROP (12,26). A
circumferential scleral buckling procedure is a reasonable approach if the
detachment already has the fibrovascular ridge dragged to the pars plicata
with significant retinal dragging (14). After retinal reattachment, the
encircling scleral buckle should be divided at about 3 months after the scleral
buckling surgery to prevent anisometropia, which can range from 5 to 9 or
more diopters. Division of the scleral buckle reduces the risk of
anisometropia and allows for eye growth (14). If the tractional retinal
detachment involves the macula (stage 4B), a lens-sparing vitrectomy (LSV)
is a more favored approach (27–29). The surgical approach for stage 5 ROP
typically involves lensectomy, pars plicata vitrectomy, and rarely scleral
buckling (14,30).
FEVR is a hereditary disorder characterized by abnormal retinal
angiogenesis that leads to abnormal or incomplete vascularization of the
peripheral retina (see also Chapters 61 and 66). The fundus changes are
similar to those seen in ROP but affects children who were born full-term
with normal birth weight. In severe manifestations of FEVR, the areas of
peripheral avascularized retina can lead to retinal detachments caused by
vitreoretinal traction. Similar to retinal detachments caused by ROP,
depending on the configuration and macular involvement of the retinal
detachment, vitrectomy with or without scleral buckling can be considered. If
the detachment is primarily exudative, scleral buckle alone or with external
drainage can be used to successfully reattach the retina. If the detachment is
primarily tractional, a vitrectomy is often necessary to relieve the
vitreoretinal traction. If there is a rhegmatogenous component to the
tractional detachment, the placement of a scleral buckle can help support the
vitreous base and peripheral ischemic retina and breaks (31).
PFV is a congenital disorder in which the fetal hyaloid vasculature fails
to regress as it should (see also Chapter 65). It usually presents unilaterally
without associated systemic findings in a normal full-term infant. PFV has a
wide spectrum of associated clinical manifestations including cataract,
microphthalmia, optic nerve hypoplasia, glaucoma, dysplastic retina, retinal
fold, and tractional retinal detachment. The severity of the microphthalmia
and the degree of dysplastic retina largely determines the visual prognosis. In
cases of posterior PFV with a vitreous stalk, a vitrectomy with transection of
the stalk can resolve the retinal traction. In such cases, the role of a scleral
buckle is minimal and is not recommended. In cases of tractional retinal folds
or tractional retinal detachment, membrane peeling is often necessary, and a
vitrectomy approach is preferred (32).
EQUIPMENT
In children, over the age of 10 years, the eye is nearly fully grown and is
essentially the same size as an adult eye (11). Commonly used buckle
elements are the 3.5-mm solid silicone band (Type 41), 4-mm band (Type
42), or a 6-mm band (Type 220) with a 2.5-mm encircling band (Type 240).
These different silicone band elements can be used alone or in combination
with pars plana vitrectomy. For younger patients with a smaller eye, smaller
elements such as the 2.5-mm encircling band (Type 240) or 3.5-mm
encircling band (Type 41) may be preferred. The choice of band is often
determined by the size of the eye and the localization of the retinal pathology
on the sclera. There may be a preference for a larger buckle in children
especially if the pathology is inferior, because the development of PVR can
be more aggressive following rhegmatogenous detachment in children (15).
Regarding additional instrumentation besides the buckle elements, varying
sutures and needles can be used depending on surgeon preference. For infants
and young children with thin sclera, spatulated needles are often preferred to
reduce the risk of entering the globe. The authors include a list of preferred
instrumentation for scleral buckling (Table 60-1).
POSTOPERATIVE CARE
At the end of the surgery, a peribulbar block (0.75% Marcaine + 2%
lidocaine; 1:1) is given to reduce postoperative pain after the patient awakens
from general anesthesia. In the immediate postoperative period after scleral
buckling, children can present with more periorbital edema and conjunctival
edema than adult patients. If there are no medical contraindications, in older
children, a Medrol dose pack can be given along with the standard
postoperative steroid eye drops, which can help minimize postoperative
swelling. The advantage of scleral buckling is that it can avoid the need to
require strict head positioning in young patients. However, if head
positioning is required, parents can be asked to encourage children to
participate in activities that require a head down position such as coloring,
working on puzzles, or using their tablet.
It is imperative that pediatric patients are closely comanaged with
pediatric ophthalmologists for amblyopia prevention and follow-up of any
refractive concerns. With the thinner profile scleral buckles that are typically
used today, the myopic shift is usually only a few diopters after scleral
buckling. However, in children that require placement of a larger element or
sponge, large refractive shifts can occur and should be managed closely by
the pediatric ophthalmologist. Infants may also require close follow-up with
pediatric ophthalmologists or optometrists for contact lens fitting if they are
aphakic.
In the long term, children should be examined at least annually if not
more frequently, depending on their ocular status and risk of retinal
detachment. If a child is monocular, follow-up every 6 months may be more
appropriate and monocular precautions need to be emphasized with
protective eyewear recommended. Retinal detachment precautions should be
reviewed with both patient and parents.
COMPLICATIONS
Complications following scleral buckles can include changes in refractive
error, diplopia, strabismus, infection and extrusion of the scleral buckle,
anterior segment ischemia, and choroidal detachments (14). Scleral buckling
can change the shape of the globe and lead to refractive changes with or
without astigmatic changes. In most studies, astigmatic changes are
infrequent but may often be more associated with radial buckles, anteriorly
located buckles, and high buckles (35,36). The most common refractive
change with scleral buckling is increased myopia due to increase in the axial
length of the eye. In the adult population, Smiddy et al. reported on the
refractive outcome of 75 eyes of 69 patients and showed that encircling
elements induced an average of 2.75 diopters of myopia (37). Sato et al.
looked at the refractive change after scleral buckling in 35 eyes of 35
pediatric patients and found that the treated eyes became less myopic than the
fellow eyes and concluded that scleral buckling may be impeding ocular
growth (38). The mean refractive change 1 to 4 years after the scleral
buckling was 0.6 diopters of myopia in the eye with the scleral buckle
compared to the mean change of 1.3 diopters of myopia in the fellow eye.
Diplopia after scleral buckling is usually transient and resolves
completely in about a week; however, rarely it can be permanent and has
been found to occur about 4% of the time postoperatively (39). Long-term
diplopia after retinal detachment surgery has been attributed to the scleral
buckle itself, scarring in the orbital space, or myoscleral adhesions (40,41).
To minimize scarring around the muscles, the rectus muscle sheaths should
be preserved as much as possible. Smaller and thinner silicone elements have
less tendency to cause heterotropia compared to larger sponge elements (39).
Infections after scleral buckling are rare, and the reported incidence
varies from 0.2% to 5.6% (42–44). Many of the previous studies looked at
silicone sponge exoplants. In a 2013 study by Chhablani et al. (44), the
infection rate of solid silicone exoplants was 0.2% compared to 0.5% to 5.6%
in silicone sponges (42,43). The most common causative organism was
coagulase negative staphylococci (44).
Extrusion of the silicone band is also another rare complication. Silicone
band extrusion through the conjunctiva may be seen incidentally on follow-
up examination or may present with eye redness, pain, and irritation.
Depending on the degree of extrusion, the buckle may need to be removed or
resutured with proper closure of Tenon fascia and conjunctiva over the
buckle.
Anterior segment ischemia has been described as a rare complication,
especially in patients with sickle cell hemoglobinopathy. Placement of a high
scleral buckle possibly with the use of excessive cryotherapy may increase
the risk of anterior segment ischemia by causing limited perfusion due to
compromise of the anterior and posterior ciliary arteries (36,45). Anterior
segment ischemia from an encircling band may be prevented by ensuring that
the band is not overly tight around the eye or excessively high.
Serous choroidal detachments can develop shortly after scleral buckling
and usually spontaneously resolve within a few weeks after surgery. They
occur at a rate of 23% to 44% after scleral buckling (36,46,47). Risk factors
that can lead to serious choroidal detachments are excessive photocoagulation
or cryotherapy along with postoperative hypotony and high myopia (48).
OUTCOME EXPECTATIONS
Prior to surgery, it is crucial to have a discussion with the patient’s parents so
that they have a good understanding of their child’s ocular condition, need for
surgery, and have realistic expectations regarding their child’s postoperative
visual potential. In children with ROP, FEVR, PFV, Stickler syndrome, or
other congenital anomalies, parents will need to have a good understanding
of the extent of their child’s ocular disease and the limited visual potential
that their child may have. Wide-field fundus photos, B-scans, OCT, and any
other imaging modalities that can be shown to the parents can be helpful to
explain the complex ocular condition their child may have. If the ocular
condition only affects one eye, comparing the photos of the normal eye to the
affected eye can help parents appreciate the extent of ocular disease their
child may have and the need for surgical repair.
There is a high likelihood that multiple surgeries may be needed for
successful retinal detachment repair in the pediatric population. Children
have a higher risk of PVR, which can require additional retinal repair surgery.
The single-procedure anatomical success rate for pediatric retinal detachment
is reported to range from approximately 50% to 90% (15,49,50). Even if the
retinal detachment is repaired with a single surgery, the child may have
concomitant ocular conditions that need to be addressed surgically. In
traumatic retinal detachments, if the patient sustained a central corneal
laceration, a traumatic cataract, or developed glaucoma in addition to having
a retinal detachment, the patient will require surgeries from other
subspecialties. Combined surgeries with different subspecialties can help ease
the burden of having to undergo general anesthesia multiple times for the
patient. Most importantly, it should be emphasized to the parents that the
recovery process will be a long journey that requires close follow-up and
possibly multiple surgeries. The need for follow-up, patching, contact lenses,
and/or glasses should be continually emphasized. Parents will need to be
reminded to follow-up with the pediatric ophthalmologists or optometrists to
ensure any refractive issues or amblyopia concerns are being properly
addressed. If the visual potential is extremely poor, discussing a low vision
consultation and advising of social work assistance to help navigate different
social and school aid networks to help with vision and activities may be
helpful.
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61
Surgical Approaches to Infant and
Childhood Retinal Diseases:
Intravitreal Surgery
Jon athan E. Sears
INTRODUCTION
Surgical management of pediatric retinal disorders using vitrectomy can be
among the most challenging interventions in patients with vitreoretinal
disease for many reasons. First, diagnosis may require an examination under
anesthesia (EUA). Second, pediatric vitreoretinal disease often accompanies
genetic disorders, and, therefore, surgical intervention is designed to repair or
stabilize the anatomy of tissues that have a molecular basis to their
dysfunction that is not addressed surgically. Finally, the ocular anatomy of
children is different from adults. The vitreous is more adherent to the retina,
and the vitreoretinal interface is different in children than adults. Children
often develop retinal detachment from not only rhegmatogenous origins but
also simultaneous tractional and exudative causes. The following chapter will
outline systematic techniques in the practice of vitrectomy in children.
PREOPERATIVE ASSESSMENT
One of the most critical components of successful surgical outcomes is a
clear surgical plan. Patients that are too young to comply with adequate
preoperative evaluation require an EUA. Although the safety of anesthetic
gases in infants and toddlers has not been established, at no point should an
EUA be avoided if an office visit yields inconclusive data (1). EUAs can be
extended to surgical intervention provided detailed informed consent and
open dialogue with parents and legal guardians is obtained. All EUAs should
involve careful anterior and posterior ophthalmic examination including
cycloplegic retinoscopy, intraocular pressure measurement, measurement of
corneal diameter, and imaging studies as necessary including widefield
photographs, fluorescein angiography, ocular coherence tomography, and
ultrasound as necessary. Perioperative assessment with fluorescein
angiography yields informative data especially relevant to the multiple causes
of peripheral avascularity common to shaken baby syndrome, Coats disease,
familial exudative vitreoretinopathy (FEVR), combined retinal pigment
epithelium (RPE) hamartoma, and retinopathy of prematurity (ROP) (2).
In order to be certain that the safety and efficacy of surgical intervention
is maximized, all children require a detailed preoperative physical
examination from a pediatrician and the knowledge that 23-hour observation
is necessary for any child born prematurely and <1 year old.
PORT PLACEMENT
Although transconjunctival surgery is safe and effective, all beveled pediatric
self-sealing incisions should be closed with a 7-0 Vicryl (4). Therefore, at the
outset, one should consider conjunctival peritomy to facilitate closure of the
sclerotomies but transconjunctival sutures if placed correctly are believed to
be safe. Any delay in sclerotomy closure once the cannula is removed can
cause hypotony and devastating intraocular hemorrhage; the surgeon should
decide on the quickest technique of port closure. Often a preplaced suture at
the infusion site is advantageous.
The first decision in considering vitrectomy is whether entry sites should
be placed at the limbus or pars plana, and whether cannulas for
microincisional vitrectomy should be used at all. There is little doubt that
current 25G instrumentation is superior to larger gauge instrumentation at the
time of this writing. However, the location of port placement depends on the
age and diagnosis of the child. For example, over half of cases involving
persistent fetal vasculature (PFV) involve media opacity that precludes a
view of pars plana. In patients with this disorder, pars plana might be absent,
that is, the retina inserts directly into pars plicata, therefore, risking a
devastating retinal break from an entry site tear (5). This scenario is also true
for stage 5 ROP in which a lensectomy is necessary. In these cases, limbal
ports with iris hooks facilitate lens extraction and necessary posterior
vitrectomy that is safe from creating retinal tears. Limbal incisions are
difficult to make with the standard trochar/cannula set, especially if a contact
lens is required because it will ride on the cannulas. Therefore, one could
consider not using cannulas, such as in the 25G short pack designed to rely
on a shorter, stiffer vitrectomy probe and a sutured infusion cannula with
naked incisions through pars plana or the limbus (Figure 61-2A). On the
other hand, if there is a view of pars plana, placing ports through pars plana
naturally makes posterior manipulation easier. Valved cannulas are a
significant advantage to surgery because the eye remains pressurized as
instruments are exchanged, and in cases that are vascularly active, delay in
closure and hypotony can be disastrous.
Figure 61-2 A:25G short pack relies on a shorter
vitrectomy probe and sutured infusion cannula in the
absence of superior cannulas. This is helpful is smaller
eyes. B:45-degree light pick is helpful for a 3-port
vitrectomy to assist in elevating the posterior hyaloid.
C:Chandelier light source facilitates bimanual surgery.
In all cases other than PFV and stage 5 ROP, sclerotomies can be placed
through pars plicata or pars plana. In all cases, scleral depressed examination
is necessary to ensure that these areas are free from retina. For stage 4A ROP
surgeries, ports can be placed in a phakic eye 1.5 mm from the surgical
limbus (6–8). In most cases and cases that require contact lens viewing, the
superior sclerotomies are recommended without cannulas. In some cases,
end-irrigating light sources can reduce incisions from three sites to two sites.
With the advent of 25G instrumentation, a challenge to these infusion sources
is whether or not adequate volume/eye pressure can be maintained during
vitrectomy. In older children (>2 years), without anomalous anatomy such as
microphthalmia, ports can be placed at 3 mm from the limbus.
INTRAOPERATIVE CONSIDERATIONS
Posterior Hyaloid Separation and Vitrectomy
Elevation of the posterior hyaloid is the first step in all vitrectomy cases.
Although separation of the cortical vitreous is essential to complete
vitrectomy, it is often very challenging to accomplish because of the firm
attachment of the posterior hyaloid. In order to facilitate induction of a
posterior vitreous detachment (PVD), a 45-degree light with active suction
from the vitrectomy probe under high magnification can be useful (Figure
61-2B). Staining of the vitreous with intraoperative triamcinolone acetonide
can be valuable, as can the use of plasmin, cautery, or a flex loop in select
cases (9, 10). There are cases where complete hyaloid removal is difficult,
such as in stage 4A ROP or Stickler’s associated detachment and yet
successful outcomes can still be achieved. Vitreous removal is better safe
than complete. In general, separation of the hyaloid to ante-equatorial
position is sufficient, but naturally elevation of the posterior hyaloid to the
vitreous base is the gold standard and easiest opportunity to provide a
complete vitrectomy.
Membrane Stripping
Membrane stripping often leads to retinal breaks, which are disastrous to the
pediatric patient due to risk of proliferative vitreoretinopathy (PVR).
Therefore, it is favorable to approach membrane stripping with a bimanual
approach that uses a chandelier light source to facilitate the simultaneous use
of forceps and horizontal scissors (Figure 61-2C). Alternatively, a 45-degree
light pick can be useful but does pose a risk for retinal penetration when
applying counter traction.
Choice of Tamponade
There is no “set rule” for the choice of tamponade. Certainly, the silicone oil
study has instructed us that in terms of long-term tamponade (C3F8 vs.
silicone oil), both gas and oil are equally effective (11). But in children,
silicone oil creates less acute cataracts than gas and naturally bears less
attention to meticulous face down positioning. Silicone oil also enables vision
through the tamponade and hence is less amblyogenic and easier to examine
in the acute postoperative period. On the other hand, for superior breaks in
rhegmatogenous detachments or pediatric macular holes, SF6 is a good
choice. Therefore, oil is favorable for long-term tamponade and SF6 or gas
for short-term tamponades. There is no evidence of advantages of heavier
centistoke silicone oil versus lighter oil (5,000 vs. 1,000).
POSTOPERATIVE EVALUATION
Attention to the emotional needs of a child and their family is essential to a
successful outcome. This includes thorough explanation to family members
and encouragement to patients that make them feel proud, hopeful, and
trusting. Therefore, all controllable postoperative complications must be
avoided. Ports should be closed with sutures. Peripheral iridectomies should
be made routinely in phakic and pseudophakic eyes, generally inferiorly, to
reduce the risk of iris bombe and angle closure. Intraocular pressure should
be adjusted carefully in the operating room and measured to prevent
tamponade overfill before leaving the OR. Either retrobulbar or peribulbar
anesthesia is essential, and especially if marcaine is used, appropriate dosing
to prevent cardiac arrhythmia should be discussed with pediatric anesthesia
personnel. Finally, the trust that a child has in their retinal specialist depends
upon the avoidance of inflicting pain; alienating a child for the benefit of a
better office examination is not a victory. Small children that can be held
safely can be readily examined with a sterile disposable speculum and scleral
depressor. Postoperative day 1 generally involves making sure there is no
infection, normal intraocular pressure, and a good red reflex. A more detailed
examination could be obtained in the ensuing visit at 1 week. If a child is
adamant about refusing dilated fundus examination, usually an office B-scan
can suffice for the short term until a repeat EUA is considered the only
option.
CONCLUSION
Vitrectomy for children can restore both the normal anatomy and function of
the retina in cases where blindness is a certain outcome. Specific surgical
pearls associated with particular diagnoses are listed in Table 61-1 as a help
to the reader about to intervene in behalf of a child with vitreoretinal disease.
Careful preoperative evaluation by an examination under anesthesia can
direct a successful surgical plan. Port placement is essential to effective
intervention and is dependent on the preoperative diagnosis. Separation of the
posterior hyaloid is necessary but not at the expense of creating devastating
posterior breaks. Internal PFO-assisted external drainage is useful in
completely reattaching retinas intraoperatively without risking conversion of
a tractional/exudative detachment into a combined rhegmatogenous one and
facilitates thermal treatment. Choice of tamponade must consider amblyopia,
visual function during rehabilitation, and particular challenges of the patient.
A kind and caring approach for these vulnerable patients and their families
enriches the lives of caregivers, families, and children.
INTRODUCTION
Achieving consistent surgical outcomes in complex pediatric
vitreoretinopathies such as familial exudative vitreoretinopathy (FEVR) and
retinopathy of prematurity (ROP) remains one of the most difficult
conundrums for experienced pediatric retinal surgeons. In acute ROP with
stage 5 disease or total tractional retinal detachment (TRD), one of the most
surgically challenging vitreoretinal conditions, success following vitrectomy
as defined by partial or complete anatomical reattachment varies widely from
28% (1) to 69% (2) in large retrospective studies. In children who develop
traumatic retinal detachment (RD) following open globe injury, retinal
reattachment rates following vitrectomy similarly vary from 36% (3) to 53%
(4,5), albeit in a more heterogenous disease. In persistent fetal vasculature
(PFV), previously termed persistent hyperplastic primary vitreous, the risk of
iatrogenic rhegmatogenous RD following vitrectomy varies from 9% (6) to
21% (7) in recent studies.
While part of the variability in surgical success rates may be explained by
case selection bias and the very nature of the pathology in these
vitreoretinopathies, in the authors’ experience, the difference between
surgical success and failure is often determined by how well surgical planes
are delineated and appropriately manipulated and dissected. The challenge of
optimal visualization of surgical planes stems from the anteroposterior
orientation of TRD in many of these cases coupled with the suboptimal top-
down perspective through the cornea of microscope-based (conventional)
contact or noncontact viewing systems. Endoscopy offers the surgeon a
unique intraocular perspective, conferring several advantages over current
contact and noncontact viewing systems in certain scenarios, specifically in
complex pediatric vitreoretinopathies. This chapter explores the role and
relevance of endoscopic vitrectomy in children.
Instrument Development
The term endoscope is derived from two Greek words—endon, meaning
within or inside, and skopin, meaning to examine or view. The first
ophthalmic endoscope was developed by Thorpe (8) in 1934. This had an
integrated forceps for removing nonferromagnetic foreign bodies. A separate
illumination was required. Later that same year, Thorpe (9) developed an
endoscope incorporating illumination measuring 6.5 mm in width. Monocular
visualization was achieved through an eyepiece attached to the proximal end
of the endoscope. It was over 40 years later before Norris and Cleasby (10)
developed a markedly smaller 1.7-mm-diameter endoscope for intraocular
and orbital surgery. In 1990, Volkov et al. (11) described the use of a 20-
gauge endoscope through the pars plana with image projection on an
electronic monitor in 23 patients with anterior segment opacities.
Present-day endoscopes are available in 19, 20, or 23 gauge and
incorporate up to three functions in a single instrument, namely, a fiberoptic
video camera, a xenon light source, and an endolaser (12,13). A 23-gauge
endoscope has the advantage of being able to fit through standard 23-gauge
microcannula systems. Although there is a trade-off with a slightly narrower
field of view (FOV) of 90 degrees and the number of fibers that can be
incorporated into a smaller diameter instrument, the image quality with the
10,000 pixel resolution is certainly adequate for surgery for rhegmatogenous
RD, proliferative vitreoretinopathy (PVR), endophthalmitis, and nonclearing
vitreous hemorrhage. With 20-gauge endoscopes, resolution is at 10,000
pixels but with a wider FOV of approximately 110 degrees. With a 19-gauge
endoscope, a 160-degree FOV is attainable at a resolution of 17,000 pixels. In
practical terms, this translates to being able to resolve detail down to 20 μm
or less at an optimum working distance of 3 to 4 mm. Taking into account
that the diameter of a first-order retinal arteriole is approximately 125 μm, the
endoscope allows intraoperative visualization of fine retinal capillaries,
useful for delineating retinal tissue from fibrovascular membranes in these
complex cases. The image resolution with the endoscope is, however, lower
than the natural surgeon’s human retina when seen directly with a microscope
and is akin to the difference between a video filmed at standard definition
versus high definition, respectively. This resolution trade-off between the
endoscope and microscope view is compensated by the ability to access areas
that cannot normally be visualized intraoperatively (see below). Conversely,
with the wide FOV, a panoramic and less magnified view of the retina is
possible by illuminating from the mid-vitreous cavity. Endoscopes are
available in straight or curved configurations. A curved probe can be very
useful for reaching diametrically across the posterior pole of the lens while
avoiding iatrogenic lenticular touch, enabling visualization of very anterior
structures such as the vitreous base, ciliary body, or posterior iris. However,
in the authors’ experience, curved probes can be more difficult to work with
due to the additional axis of rotation compared with a straight instrument.
Optical property
In pediatric vitreoretinopathies such as advanced ROP (stage 4A, 4B, or 5)
and FEVR, anterior retinal pathology is one of the hallmarks of disease.
Being able to visualize and dissect the anterior hyaloid face and vitreous
cortex, whether it is enmeshed within an opaque retrolental fibrovascular
plaque or remains relatively transparent, is particularly important. Pars plana
vitrectomy is most commonly performed using microscope-based contact or
noncontact viewing systems, where light from an endoilluminator is first
reflected off vitreoretinal tissue, subsequently transmitted through the
patient’s pupil plane and cornea, before being seen by the surgeon at the end
of the eyepieces of an operating microscope. Using this technique, it is
difficult to make out a distinct anterior hyaloid face as light is transmitted
through it. In contrast, with the endoscope, the source of endoillumination
and surgeon’s view are coaxial, as the visualization of anatomical structures
is based on the capture of reflected rather than transmitted light. To
demonstrate this, we used lightly frosted cellophane tape to represent the
anterior hyaloid face (Figure 62-1) and placed this over printed paper to
signify the retina. Evidently, visualization of an almost transparent anterior
hyaloid face is better with reflected than transmitted light.
FIGURE 62-1 Simulated view of the vitreous during pars
plana vitrectomy. The anterior vitreous is represented by
lightly frosted cellophane tape. The retinal surface is
represented by alphabets printed on a sheet of reddish-pink
paper. A:With standard microscope (conventional) wide-
angle viewing systems (e.g., BIOM), illumination is
separated from the surgeon’s view through the operating
microscope. In the image below, the cellophane tape is
barely visible overlying the alphabets. B:With endoscopy,
illumination and the surgeon’s view are coaxial. In the
image below, the same frosted tape is now almost opaque
and highly visible, completely obscuring the underlying
alphabets.
Perspective
The anatomical perspective of the endoscope is unique. Microscope-based
(conventional) contact and noncontact viewing systems enable visualization
of posterior segment structures through a bird’s-eye or top-down view
through the pupil, with the most anteriorly visible structure being the vitreous
base and occasionally the pars plana. Even with deep scleral indentation,
anatomical structures anterior to that, that is, the pars plicata, ciliary body,
lens equator, and posterior iris surface, are almost impossible to directly
visualize and manipulate surgically. As ophthalmologists, the bird’s-eye view
is the anatomical perspective with which we are most familiar and
comfortable based upon our experience using direct and indirect
ophthalmoscopes. In contrast, the endoscope provides an unfamiliar side-on
perspective relative to the patient’s visual axis, which is an angle of
visualization approximately perpendicular to the microscope-based bird’s-eye
surgeon’s viewing axis. Through a pars plana sclerotomy, the vitreous base,
pars plana, pars plicata, ciliary body, posterior lens surface, and retroiridial
surface can be directly visualized without distortion from spherical aberration
at the edge of a lens or deep scleral indentation (Figure 62-2). This is
advantageous in pediatric vitreoretinopathies in which adequate dissection of
fibrovascular membranes involving the aforementioned structures can be the
difference between surgical success and failure.
FIGURE 62-2 Intraoperative view through a 20-gauge
higher resolution endoscope. A:This is a child with
aphakic glaucoma and rhegmatogenous RD. Normal
anterior anatomical structures are clearly visualized. C,
ciliary processes; P, pars plana; H, hyaloid (anterior
hyaloid face). Note that the anterior hyaloid face is seen
very clearly, due to the use of reflected rather than
transmitted light. B:This is a neonate with stage 4B ROP.
Anterior traction RD is present. Endoscopy enables direct
visualization and guidance of a 20G MVR blade through
the pars plicata for safer sclerotomy formation. There is
much less space than normal for safe sclerotomy formation
as the anterior TRD is in close proximity to the pars
plicata. Endoscopic guidance reduces the risk of iatrogenic
lens or retinal injury. L, lens; M, MVR blade (20 gauge);
C, ciliary processes; R, retina.
The unique anatomical perspective of the endoscope comes into its own,
when an unhindered direct view behind the iris or under an immobile opaque
tissue plane is required. For instance, in anterior TRD in stage 4 ROP or
FEVR, the RD can be drawn close to the lens or pars plicata, precluding safe
trocar insertion during sclerotomy formation, due to the risk of retinal injury
from an unseen trocar tip entering the eye. The endoscope enables
unhindered direct visualization of the pars plicata and its surrounding areas
normally obscured by iris, thus facilitating safer trocar insertion under direct
internal visualization. For opaque retrolental plaques, the surgeon can
alternate the position of the endoscope between visualizing above and below
opaque fibrovascular membranes. Instead of relying on indirect clues, direct
visualization of otherwise inaccessible safe preretinal dissection planes is
possible, reducing the risk of iatrogenic retinal break formation. Minimizing
the risk of complications is critical for surgical success in these zero error
tolerance eyes. In ROP, unlike rhegmatogenous RD or diabetic TRD in
adults, an iatrogenic retinal break often portends a poor prognosis (14).
Learning Curve
There are several key aspects to the learning curve of endoscopic vitrectomy
(15). Firstly, the surgeon’s view is derived from a video feed projected onto a
monitor, rather than through the eyepieces of the microscope. This is a two-
dimensional image, necessitating the greater use of nonstereoscopic clues
such as shadows and inferring object distance by recognizing the size of
anatomical landmarks relative to the known instrument gauge. It is
noteworthy that intraocular shadows formed with an endoscope provides a
different perspective from conventional viewing systems due to the differing
angle of reflected light captured, that is, coaxial versus noncoaxial
illumination, respectively. Secondly, the intraoperative view is derived from a
live video feed to a monitor, dissociated from the surgeon’s manipulation of
surgical instruments. This requires some relearning of hand-to-eye
coordination and feedback. Thirdly, the advantage of being able to resolve
detail down to at least 20 μm equates to a highly magnified surgical
perspective. It is essential that greater care is taken to maintain awareness of
relative instrument positions within the narrow FOV to avoid inadvertent
retina or lens touch. Fourthly, the endoscope adds rotation to the x-, y-, and z-
axes of movement of conventional viewing systems. Fifthly, there is a need
for regular adjustment of illumination levels. The optimum luminosity
required to illuminate anatomical structures can vary significantly depending
on the distance from the endoscope. The closer the endoscope is to the object
of interest, the less light is required to avoid whiteout. This is the result of the
narrower dynamic range of a digital image capture system such as the
endoscope, relative to the human eye, predisposing to loss of some detail in
the high or low extremes of illumination. Taking these factors into account,
the initial experience with the endoscope is unfamiliar and can be
disorientating. In the author’s experience, the use of a wet lab can be very
useful for accelerating the familiarization process. Having a microscope
simultaneously set up enables the surgeon to switch readily between both
viewing systems, and this is useful for maintaining endoscopic orientation.
The additional surgical time that is initially required is time well invested, as
the ability to directly visualize surgical planes in complex surgical scenarios
pays dividends in terms of reduced complications and improved clinical
outcomes.
Clinical Application
In 1981, the first endoscopy-assisted vitreous surgery was described (16). In
adults, there is good evidence for its use in rhegmatogenous (17) and TRD
(18), PVR (19), endophthalmitis (20,21), penetrating eye injury (22),
intraocular foreign body (22), retained lens fragments (23), and sutured
posterior chamber intraocular lens placement (24). There is growing evidence
of its use in children (24,25). At the time of writing, the authors have
submitted their surgical outcomes of endoscopic vitrectomy in children for
publication. This would likely represent the largest endoscopic surgical series
in children to date. The first unpublished study from Children’s Hospital Los
Angeles (Lee & Wong) present preliminary surgical outcomes data on 210
endoscopic vitrectomies in 154 eyes, with the most common indications
being ROP (20%), trauma (20%), and pars planitis (6%). Across all RD eyes
(tractional and/or rhegmatogenous), 63% retinal reattachment was achieved.
In a second unpublished study by one of our authors from Great Ormond
Street Hospital in London (Wong), 57 consecutive eyes with stage 4A or 4B
had endoscopic vitrectomy. None of the eyes (0%) required primary
lensectomy (or developed treatment-requiring cataract) within 12 months
postoperatively, with a 83% overall primary retinal reattachment rate, highest
in stage 4A (92%). These data support the authors’ clinical experience of
endoscopic vitrectomy in complex pediatric vitreoretinopathies, particularly
ROP traction RD, where a high level of lens preservation can be achieved
with good anatomic reattachment rates.
The optical properties and anatomical perspective of the endoscope and
microscope-based wide-angle viewing systems are complementary. As such,
the authors utilize endoscopy as an adjunct to microscope-based contact and
noncontact wide-angle viewing systems in almost all pediatric vitrectomies.
In experienced hands, pediatric vitrectomies can be performed exclusively
with endoscopy where necessary. Examples of the authors’ indications for
endoscopy are described hereinafter.
The most obvious advantage of endoscopy is its ability to circumvent any
anterior segment opacity precluding visualization of the posterior segment
with conventional (transcorneal) viewing systems. The clinical utility is
relevant to both children and adults with vitreoretinal disease. Although a
temporary keratoprosthesis (26) is an alternative by enabling visualization of
the posterior segment with conventional viewing systems, the patient is
committed to having a penetrating keratoplasty with active ocular disease,
possibly increasing the risk of graft failure. Another option is a permanent
keratoprosthesis, which has significant risks. A retrospective review of 35
cases revealed a 23% vitreoretinal complication rate, which included
intraoperative choroidal hemorrhage, rhegmatogenous RD, vitreous
hemorrhage, and endophthalmitis (27).
Sclerotomy placement in adults is generally straightforward with a few
exceptions such as penetrating trauma, hypotony, and choroidal detachment.
In contrast, in complex pediatric vitreoretinopathies such as advanced ROP,
FEVR, and PFV, atypical anatomical landmarks are commonplace. The retina
may be drawn anteriorly to the posterior lens capsule and, rarely, the
posterior iris surface, precluding safe pars plana sclerotomy placement. The
anatomy of the pars plana itself may be abnormal. The endoscope can be
helpful for internally directing transscleral incisions, minimizing concerns
over safe entry.
One of the major limiting factors of anatomical success in children with
TRDs in diseases such as ROP, FEVR, and PFV is the adequacy of
membrane dissection in the difficult to access area encompassing the anterior
retina, ciliary body, posterior lens capsule, and anterior hyaloid face.
Visualization of these structures is suboptimal and at times impossible with
conventional wide-angle viewing systems. It is not widely appreciated that
the quality of the surgical view with the endoscope is equally good whether at
the macula or pars plicata, because image degradation or distortion at the
edge of the lens of conventional viewing systems does not apply. In complex
pediatric vitreoretinopathies dominated by anterior pathology, the ability to
maintain good visualization in difficult-to-access surgical spaces is highly
advantageous.
In PFV, a stalk typically extends anteroposteriorly toward the posterior
lens surface. Microscope-based viewing systems provide a bird’s-eye view,
through the cornea and lens, of the top of the stalk. This enables an accurate
assessment of the size of the retrolental (anterior hyaloid) plaque, its position
relative to the visual axis, and thus the amblyogenic impact and potential
benefit of surgery. In PFV cases with significant posterior involvement, the
retina may be drawn up along the length of the stalk. The presence and extent
of this is potentially difficult to assess with microscope-based viewing
systems, where the surgeon’s line of sight is roughly parallel to the length of
the stalk. The anteroposterior position at which the stalk is transected is
critical to avoid an iatrogenic retinal break and rhegmatogenous RD. The
endoscope provides a view of the side rather than top of the stalk, thus
enabling the surgeon to track retinal vessels up along the length of the stalk
until it terminates below a safe surgical transection zone.
In children, the primary retinal reattachment rate following pars plana
vitrectomy for rhegmatogenous RDs with or without associated trauma is
lower than adults (15,28). This is partly due to the more aggressive PVR. The
optical properties and unique perspective of the endoscope can aid better
delineation and more complete removal of hyaloidal tissue and pre- and
subretinal membranes, potentially reducing the risk of PVR formation and
reproliferation. The ability to visualize below a tissue plane with the
endoscope can similarly be applied to the retina for removal of subretinal
membranes and bands.
There is a risk of vitreous incarceration in sclerotomy ports during
vitrectomy in pediatric retinal diseases such as ROP and FEVR, due to the
anterior nature of these diseases. Resultant unrecognized postoperative
vitreous traction and retinal break formation can lead to a poor outcome.
Endoscopy enables direct visualization of the internal aspect of the
sclerotomy facilitating adequate vitreous clearance (29).
CONCLUSIONS
The endoscope has unique optical properties that are complementary to
microscope-based contact and noncontact viewing systems. The ability to
visualize and surgically manipulate difficult to access vitreoretinal surgical
planes from a different perspective can be the difference between success and
failure in selected pediatric vitreoretinopathies. The endoscope has become
an indispensable part of the authors’ surgical armamentarium. Its utility value
will be even greater in the future when high-definition stereoscopic
visualization becomes a reality.
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(Phila) 2018;7(3): 200–207.
SECTION X
Management of Vitreoretinal
Conditions of Infants and Children
63
Pediatric Rhegmatogenous Retinal
Detachment
Lejla Vajzovic
INTRODUCTION
Pediatric rhegmatogenous retinal detachments (PRRDs) are complex, rare
occurrences and are often related to trauma, congenital abnormalities, genetic
syndromes, high myopia, and prior ocular surgery. This is in contrast to the
most common causes of rhegmatogenous retinal detachment (RRD) in adults,
which is related to retinal breaks that develop during a posterior vitreous
detachment (PVD).
EPIDEMIOLOGY
In the general population, RRD has an annual incidence of approximately 10
cases per 100,000 population (1). PRRD is much less common with an
annual incidence of only 0.38 to 0.69 per 100,000 in the population under age
20 years (2) but makes up 3% to 13% of all retinal detachments (1,3–8). The
average age at presentation of PRRD is between 7 and 13 years of age
(1,2,9,10). Trauma is the most common cause of PRRD and accounts for
about 40% of all RRD in children compared to 11% of RRD in the adult
population. There is a significant male preponderance of PRRD, especially in
trauma-related cases (up to eighty percent), but even in nontraumatic PRRD
(1,2,9,10).
Congenital abnormalities are also common causes of PRRD and account
for 35% to 56% of all cases in Western populations and 12% to 17% in case
series from East Asia. The incidence is even higher among younger patients
<10 years of age. Geographic differences in rates of PRRD secondary to
congenital abnormalities can be explained by regional differences in other
conditions that predispose to RRD, such as the high incidence of high myopia
in Asia (11–13) and/or of atopic dermatitis in Japan (14). Intraocular surgery,
most often cataract surgery in eyes without trauma, presents with high
incidence of PRRD (15–17).
INDICATIONS
Children often do not recognize or report symptoms of retinal detachment.
Thus at presentation, the pediatric pathology is typically advanced often with
macular involvement, proliferative vitreoretinopathy, chronic duration, and
poor visual acuity. Often there is a high incidence of bilateral pathology.
These features pose significant management challenges. Children with PRRD
may require multiple surgeries and may have ocular malformations, including
associated hereditary and congenital nonhereditary pathologies. For all of
these reasons, visual potential after repair of PRRD may be limited even after
successful surgical repair because of chronicity and the effects of deprivation
amblyopia (2,18–20).
Although PRRD is generally repaired successfully with newer
vitreoretinal surgical techniques, it may require multiple surgical procedures
due to late and advanced presentation. Therefore, there needs to be a clear
understanding that the decision for surgery may incur significant external and
emotional pressures on the family and the patient. Despite these challenges,
in many instances repaired eyes have good vision, and at times better vision
than the fellow eyes; therefore, surgical management is often recommended.
The possibility of bilateral ocular disease also supports surgical intervention
in the presenting eye as well as consideration of therapy for the fellow eye.
However, at times surgical management may not be the best option if PRRD
is too advanced with no light perception vision and secondary sequela such as
neovascular glaucoma, hypotonus, and phthisical eye. Comfort care and a
referral to ocularist might be recommended in these instances. It is always
important to perform a careful examination and potential prophylactic
treatment of the fellow eye.
CLINICAL PRESENTATION
Poor visual acuity on routine screening, strabismus, or leukocoria are
common presenting symptoms. Because PRRD may be chronic due to limited
detection, the timing of retinal detachment can range from several weeks to
many months. In studies that include all age groups, the mean time to RRD
presentation is usually <30 days (1) but is longer in children and can be
difficult to determine. The visual acuity difference is often picked up when
the fellow eye becomes involved. Hence, pediatric patients typically present
with poor visual acuity, greater delay in diagnosis, and with a higher
incidence of macular involvement in 75% to 85% as opposed to 50% in
adults (2,10,18,21–23). Also, pediatric patients also have much higher rates
of PVR, between 30% and 60%, on presentation and with 10% to 20% with
at least PVR grade C (2,9,10). Lastly, they more frequently present with
bilateral retinal detachment than adults (24). Up to 25% of affected pediatric
patients have a diagnosis of bilateral retinal detachment on presentation or
during follow-up period (Figure 63-1) (9). This percentage is higher in
patients with congenital or hereditary abnormalities. When traumatic
etiologies are excluded, pediatric patients with unilateral PRRD have retinal
tears and lattice degeneration.
FIGURE 63-1 Stickler syndrome type 1 and bilateral
retinal detachments. A 10-year-old female presented with
sudden loss of vision (20/200) in both eyes. On clinical
examination, dense vitreous veils, macula involving retinal
detachment in both eyes was noted with superotemporal
giant retinal tear in the right eye and posterior
superotemporal retinal tear in the left eye. Widefield
fundus photo and optical coherence tomography
demonstrate these findings in the right eye (A) and left eye
(B). She underwent sequential retinal detachment repair a
week apart with scleral buckle, vitrectomy,
perfluorocarbon, laser photocoagulation, and long-acting
gas tamponade in both eyes. Visual acuity improved to
20/80 in the right eye (C) and 20/50 in the left eye (D).
ETIOLOGIES
Many of the conditions associated with PRRD are covered in depth elsewhere
(see Chapters 37, 60 and 61). The vasoproliferative retinopathies, particularly
retinopathy of prematurity, persistent fetal vasculature syndrome, and familial
exudative vitreoretinopathy, are generally associated with traction-exudative
retinal detachment and may present with a combined mechanism (see
Chapters 55, 65 and 66).
TRAUMA
Trauma, nonsurgical or surgical, is a leading cause of PRRD and often occurs
late due to the support of a well-formed vitreous. Because spontaneous RRDs
in a child with normal ocular anatomy and without hereditary or congenital
association are very rare, trauma should be considered regardless of history
(9,10,26,27). Nonsurgical traumatic PRRD may present with vitreous
hemorrhage limiting posterior pole visualization and if dense typically
requires earlier pars plana vitrectomy (PPV) to improve vision and reduce
amblyopia and to address retinal traction and repair PRRD. This is often in
combination with a scleral buckle. Traumatic injury to other tissues, such as
cornea, iris root, lens, zonules, and optic nerve, should be considered in
surgical assessment and planning. PRRD has been reported in up to 15% of
cases of traumatic pediatric cataract and should be looked for in the
preoperative evaluation (27). Surgical management of posterior segment
trauma is detailed in Chapter 69.
INHERITED
Several inherited disorders primarily connective tissue disorders are
associated with RRD.
Stickler syndrome is an autosomal dominant genetic condition that
presents in 1:7,500 live births and is the most frequent inherited connective
tissue disorders. It is the most common cause of inherited, childhood retinal
detachments, but it continues to be widely underdiagnosed. At least 6
subgroups have been characterized according to genetic abnormalities of type
II, IX, or XI collagen. These structural proteins are principally and
collectively expressed in the eye and in articular and hyaline cartilage. Thus,
affected patients may present with premature arthropathy and classic
orofacial, auditory, and ocular features (25,31) (see Chapter 37).
If Stickler-related PRRD is suspected, the presence of a GRT is likely.
PPV and/or scleral buckle should be placed especially if there is an inferior
GRT component. If a PPV is planned, the vitreous traction is removed as
carefully as possible and the devitalized retina anterior to the GRT is
removed to decrease a scaffold for future anterior PVR or ischemic signal. In
young children, the vitreous can be very adherent to the highly mobile retina
and may be difficult to completely remove. Nonetheless, it is important to
remove the vitreous traction as much as possible. Perfluorocarbons are used
to help unfold and flatten the retina. Endolaser is performed with 2 to 3 rows
along the posterior, side horns and anterior edges of the GRT. If the anterior
horns cannot be treated adequately, cryotherapy may be placed at the anterior
horns adjacent to the ora serrate. Long-acting gas or silicone oil is used as a
tamponade agent depending on the location of the GRT, positioning
requirements and maturity of patient in maintaining position. Attention to
fellow eye and prophylactic treatment with laser, cryotherapy, or scleral
buckling is recommended (32), but evidence as to the best approaches
remains scarce.
Marfan syndrome is an autosomal dominant genetic disorder that results
in weakening of connective tissue in the musculoskeletal, cardiovascular, and
ocular organ systems. It is the second most common inherited connective
tissue disorder with an incidence of between 1/5,000 and 1/20,000. The
abnormality in over 80% of Marfan patients involves defects in the protein
fibrillin 1 (FBN1) on chromosome 15, a structural component of microfibrils
found in connective tissue throughout the body. More than 500 different
mutations in the FBN1 gene have been identified. The major ocular
abnormality in Marfan syndrome is ectopia lentis or lens subluxation or
dislocation. Clinically, ectopia lentis is bilateral in 60% to 87% of Marfan
patients. The most common direction of dislocation on exam is
superotemporal. Retinal tears and detachments are also quite common in
patients with Marfan syndrome due to high myopia, excess lattice
degeneration, vitreous liquefaction, choroidal and scleral thinning, and
vitreous traction from ectopia lentis. Each of these changes is thought to be
related to fibrillin alterations. Retinal detachment occurs in 5% to 26.5% of
patients with Marfan syndrome and is bilateral in 30% to 42% of these cases
(33,34).
Therefore, when addressing PRRD in patients with Marfan syndrome,
lens status and its stability need to be taken into careful consideration
preoperatively. The subluxed lens is typically addressed at the time of PRRD
and removed through a pars plana approach. The patient is left aphakic with a
surgical peripheral iridotomy to avoid pupillary block secondary to
tamponade agent. Scleral thinning secondary to Marfan syndrome should also
be noted preoperatively and sclerotomy size and sites carefully chosen and
sutured at the end of procedure. Use of small gauge instrumentation is often
important. In rare extreme scleral thinning cases, scleral patch grafts may be
required to cover thin sclera and sclerotomy sites. Use of scleral buckles in
the setting of diffuse scleral thinning should be avoided as there is a risk of
buckle intrusion into the globe.
Ehlers-Danlos syndrome (EDS) is also an inherited connective tissue
disorder caused by defective collagen synthesis, the main features being
hyperelasticity and vulnerability of the skin, recurrent bleeding from fragile
blood vessels, and secondary deformities of the joints. Ocular involvement is
a rare occurrence and may include corneal and scleral rupture from minor
blunt injury, lens displacement, and RRD (35,36).
The surgical approach in EDS patients is similar to Marfan syndrome
described above where subluxation and scleral thinning may add to
complexity of PRRD repair. These features should be carefully considered
preoperatively, discussed with the patient and family and addressed at the
time of PRRD repair.
It is often important to impose more frequent examinations to assess for
retinal pathology and prevent retinal detachment and vision loss in patients
with the above diseases. It is also important to teach and reinforce the
symptoms associated with retinal detachment to family members and the
patients. It is important to perform retinal examinations on both eyes
especially while the patient is under anesthesia. It is also important to
examine family members.
NONTRAUMATIC INFEROTEMPORAL
RETINAL DIALYSIS (“JUVENILE
DIALYSIS”)
A retinal dialysis is a circumferential break occurring at the ora serrata as
opposed to the more typical posterior margin of the vitreous base in giant
tears. Dialyses, in general and following trauma, are more common in the
inferotemporal quadrant (Figure 63-3). However, most dialyses detected
nasally or superiorly are associated with a history of preceding blunt trauma.
Idiopathic retinal dialyses accounted for approximately 2% of retinal
detachments in one series and typically occurred in the inferotemporal
quadrant of young adult eyes. Retinal detachment associated with retinal
dialysis often is subclinical without vision loss or visual symptoms.
Associated findings include demarcation lines, retinal cysts, peripheral
microcystoid degeneration, and yellow-white vitreous opacities (Figure 63-
3A). PVR is rarely seen, likely due to the overlying vitreous base serving as
tamponade limiting access of cells to the central vitreous cavity (37).
Idiopathic retinal dialyses typically present in emmetropic males in the
second decade of life. They may be bilateral and may involve multiple family
members (38–41). Therefore, in patients with bilateral nontraumatic retinal
dialyses, examination of family members is indicated. Depending on the
extent of retinal detachment, these detachments typically are addressed with
scleral buckling and/or laser or cryoretinopexy.
ATOPIC DERMATITIS
Atopic dermatitis, a chronic pruritic skin condition, is an allergic form of
eczema primarily affecting infants, children, and young adults. The onset
usually is in infancy, often with a positive family history of atopic disease.
The prevalence is on the order of 10% in the United States and up to 20% in
Japan. The incidence of atopic dermatitis is thought to be rising with retinal
detachments representing approximately 3% of RRDs seen in Japan. RRD
typically occurs in early adulthood but may be seen in late adolescence
(14,42).
Eyelid dermatitis, blepharitis, conjunctivitis, cataract, and keratoconus
are recognized anterior segment associations. Retinal detachment has been
reported in 6% to 10% of Japanese patients. The peripheral fundus is
characterized by a “fluffy” appearance with signs of vitreous base
contraction, including wrinkling of the pars plana epithelium and oral
dialyses. Retinal breaks often are multiple and located at the ora serrata or in
the nonpigmented ciliary body epithelium. Retinal detachments are generally
low lying and asymptomatic, although GRTs occur as well. Intense pruritus
prompts frequent eye rubbing and face slapping, which are believed to play a
role in causing retinal or ciliary body breaks. Scleral buckle with thorough
peripheral retinopexy is advocated. The presence of dense anterior chamber
angle pigmentation in patients with atopic dermatitis can be a sign of breaks
of the peripheral retina or ciliary body epithelium and should be an indicator
to perform a meticulous peripheral retinal examination (14,42–47). In cases
where retinal detachments involve GRTs, the surgical approach is similar to
above described approach for GRT associated with Stickler syndrome.
SURGICAL TECHNIQUES
Scleral Buckling
A scleral buckle is often used as a primary cerclage or at times as an
encircling band in combination with vitrectomy. It is important to precisely
localize break(s) on a buckle or encircling band in PRRD. The buckling
effect should be broad and low, and there should be adequate treatment with
laser or cryotherapy to create a permanent chorioretinal adhesion. It is
important not to cause significant distortion of the globe, which may further
open the retinal break, creating a “fishmouth” effect allowing vitreous fluid to
enter the subretinal space. When performing scleral buckling in infants or
children <2 years of age, thinner and narrower elements are used but the
same principles apply. The band often ends up being placed just anterior to
the equator. It is important to cut the encircling band in infants or small
children after 3 to 6 months to allow for eye growth. Refractive errors are
also treated aggressively and continuously reassessed in the postoperative
period to maximize visual outcomes. Further specifics about scleral buckling
are discussed in Chapter 60.
Vitrectomy
Today, vitrectomies are mostly performed in small gauges using noncontact
and contact wide-angle viewing systems to visualize the peripheral retina;
some of these lenses are smaller in lateral dimension to allow access to the
infant eye, but adult lenses can also be helpful depending on the size of the
eye. Pediatric patients have lower systolic blood pressure compared to adults
and perfusion of the central retinal artery should be monitored during surgery
to assure that infusion pressure or scleral indentation is safe. In the anterior
trans-limbal vitrectomy approach, the infusion is provided with an anterior
chamber maintainer. Creation of a PVD is an important step, if it can be
safely performed, in the successful management of a retinal detachment
during vitrectomy. This may be essential in managing RRD in older children.
Diluted, sterile triamcinolone can highlight vitreous to help distinguish it
from retina and reduce the creation of a vitreous schisis so that vitreous
removal is achieved. In eyes with proliferative vitreoretinopathy, it is
preferable to perform segmentation instead of delamination when removing
preretinal membranes due to the firm vitreoretinal attachments in children. A
bimanual approach with use of a chandelier illumination system is helpful.
Use of heavy liquid, perfluorocarbon, is preferred in pediatric retinal
detachments to flatten the retina and avoid posterior drainage retinotomies.
Retinotomies or additional breaks are best avoided, because extensive fibrous
proliferation can occur postoperatively and lead to recurrent retinal
detachment. If a retinotomy is unavoidable, it is usually recommended to
create one superiorly and as close to the ora serrata as possible. In the case of
retinal detachment associated with coloboma, there is also an increased risk
of subretinal movement of perfluorocarbon liquid through the colobomatous
defect. Therefore, use of perfluorocarbon liquid should be avoided in these
cases (Figure 63-4B). For vitreous tamponade, the use of long-acting
intraocular gas, such as C3F8, is ideal but may not be feasible if the patient is
unable to be compliant about positioning or there is difficulty removing all of
the cortical vitreous. Therefore, silicone oil is often used except in
colobomatous defects to reduce the risk of silicone oil in the subretinal space
or intracranial cavity. In children, silicone oil emulsifies much more quickly
and an “inverse hypopyon” may be seen (Figure 63-4). Further specifics
about vitrectomy are discussed in Chapter 61.
FIGURE 63-4 Pediatric patients after retinal detachment
repair demonstrate: a pseudohypopyon secondary to
emulsified silicone oil (A, slit-lamp anterior segment
photograph) and central and inferior corneal endothelial
droplets secondary to retained perfluorocarbon liquid (B,
Retcam anterior segment image during exam under
anesthesia).
Vitrectomy
PPV for PRRD is often performed as a primary procedure in PRRD with
vitreous hemorrhage and GRT and is combined with scleral buckle in PRRD
with substantial vitreous tractional components. Any intraocular procedure,
particularly PPV with use of tamponade agents, has increased risk of cataract
formation and elevated intraocular pressure requiring additional treatments
with medication or surgery. Glaucoma is also increased with the use of
postoperative topical steroids in children. Silicone oil tamponade presents
with the risk of silicone oil emulsification and oil movement into the
periocular or retrobulbar tissues.
CONCLUSIONS
The incidence of PRRDs is low and is often associated with inherited
conditions or trauma. Bilateral vision threatening pathology is common, and
thorough examination and prophylactic treatment of the fellow eye are
important. Counseling of patient and parents is critical. Repair of PRRDs
with current advanced vitreoretinal surgical techniques is successful, but
multiple surgical interventions are often indicated.
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64
Coats Disease
J. Michael Jumper
INTRODUCTION
Coats disease is a form of idiopathic retinal telangiectasia most often
occurring unilaterally in male children and young adults. In 1908, George
Coats described three subtypes of retinal disease characterized by massive
retinal exudation and varying degrees of vascular abnormalities (1). He
subsequently revised his classification after concluding that two of the three
subtypes were manifestations of a single clinical condition (the third was
recognized as a separate entity previously described by von Hippel) (2). In
1956, Reece further refined the description and definition to what we now
consider to be Coats disease (3). Recent literature has sought to clarify the
definition, specifying that the term “Coats disease” should refer only to
idiopathic congenital retinal telangiectasia with intraretinal or subretinal
exudation and without appreciable vitreoretinal traction (4). This strict
definition has been applied to distinguish true Coats disease from the myriad
of conditions that result in either retinal telangiectasia or retinal exudation.
Since the original description more than a century ago, much has been
learned regarding the natural history and reasons for vision loss in Coats
disease. We are now better able to preserve vision and prevent the globe-
threatening complications of this disease. Despite this, the cause of Coats
disease remains elusive.
EPIDEMIOLOGY (PREVALENCE,
ENVIRONMENTAL FACTORS,
WORLDWIDE IMPACT)
Coats disease is rare, and prevalence data are lacking. A population-based
study in the United Kingdom estimated an incidence of 0.09 per 100,000 (5).
Coats disease can present at any age and has been diagnosed at 1 month and
79 years of age (6–8). In a tertiary care case series, the median age of
presentation is 5 years with the majority of patients presenting before age 10
(6). The age of presentation in the population-based study was slightly older
at 8 years (5). In all series, the earlier age of presentation is associated with
increased disease severity and accelerated progression (5,6,8). In a series of
advanced Coats disease reported by Haik, 40% presented before 2 years of
age (8). There is no known racial or ethnic predilection and the demographics
and outcomes are similar in all populations studied (9).
The majority (~95%) of Coats cases is clinically unilateral, and the
presence of bilateral disease should raise suspicion of another cause of
exudation. In the cases of bilateral Coats disease, the findings are often
asymmetrical and asynchronous (6,8,10–13). For unknown reasons, 67% to
90% of patients Coats disease are male (6,9). No environmental factors have
been shown to cause or influence the course of Coats disease. Because Coats
disease is rare and clinically unilateral, the worldwide health impact is
minimal.
GENETIC ASSOCIATION
The molecular mechanism underlying the vascular changes in Coats disease
is currently unknown. A genetic cause has been proposed by several
investigators (14,15). Cytogenetic studies of individual cases of Coats disease
have revealed a partial deletion of chromosome 13 in 1 patient and pericentric
inversion of chromosome 3 in another (16,17). Due to the sporadic nature of
Coats disease, linkage analyses have not been possible. A somatic mutation
in the genes encoding proteins involved in vasculogenesis was proposed by
Black and coworkers who reported a mother with Coats disease whose male
offspring had Norrie disease. Both had a missense mutation in the Norrie
Disease (NDP) gene (18). An NDP mutation was then found in one of nine
tissue samples of eyes enucleated with Coats disease (18).
Other studies were unable to find a link between Coats disease and
mutations in the FZD4 gene that is associated with familial exudative
vitreoretinopathy (19). Genes associated with retinitis pigmentosa and a
Coats-like phenotype have been studied including the crumbs homologue 1
(CRB1) gene but no causative association has been made (20–25).
PATHOLOGY/PATHOPHYSIOLOGY
Coats disease is the second most common disease mistaken for
retinoblastoma and is found in 7% of enucleation specimens where the
clinical diagnosis was retinoblastoma. It is important to understand the
distinguishing pathologic findings of Coats disease in order to differentiate it
from retinoblastoma (26). Coats’ description of enucleated eyes demonstrated
the characteristic features of the disease: vessel thickening and hyalinization
alongside endothelial cell thinning and loss; subretinal exudate with
prominent cholesterol crystals and a mononuclear infiltrate (1,27,28).
Electron microscopy confirms thickening of the retinal capillary adventitia
with loss of pericytes and endothelial cells (29,30).
It is believed that the endothelial changes lead to breakdown of the
blood–retinal barrier, fluid movement into the vessel walls that leads to
dilation, telangiectasia, and leakage into and under the retina. It is at this
point when the characteristic deposits of lipid, hemorrhage, fibrin, and
inflammatory cells are seen. The inner retinal layers often contain lipid-laden
“ghost cells” that likely represent transformed retinal pigment epithelial cells
(31,32).
Detailed biochemical analysis of the subretinal fluid in Coats disease
suggests that the elevated cholesterol levels are due to oversaturated and not
dysfunctional retinal pigment epithelial cells (33). Little is known about the
fibrotic nodule that forms in the macula and is a common cause of vision loss
in Coats disease. Jonas and Holbach reported a clinicopathologic correlation
in a patient who underwent surgical removal of “subretinal tissue
proliferation,” at the time of traction retinal detachment repair 8 years after
the macular fibrosis was first identified (34). The cellular mass contained
lipid/hemosiderin-laden macrophages as well as retinal pigment epithelial
cells with fibrous metaplasia. No vascular elements were described. This does
not exclude the possibility that neovascularization was once present.
Pathologic analysis of disciform scar in age-related macular degeneration
failed to identify vascular elements in 25% of cases, presumably because the
vessels were obliterated during the scarring process (35). Ong et al.
demonstrated histopathology of capillaries and retinal vessel ingrowth into
select cases of Coats fibrotic nodules (36). In a histopathologic analysis of 62
eyes with Coats disease, Chang et al. described the accumulation of lipid
exudate in all layers of the retina as well as in the subretinal space. Pigment-
laden macrophages were also present in the subretinal exudate. Subretinal
pigment neovascularization was observed in four eyes in this study (28).
Calcification is uncommon and can be used to distinguish Coats disease
from retinoblastoma except rarely in late, advanced cases of Coats where
osseous metaplasia can occur (37).
Other macular changes that have been described in Coats disease including
vitreomacular traction, epiretinal membrane, and macular hole are all likely
due to exudative abnormalities in the vitreoretinal interface (44–47) (Figure
64-3).
FIGURE 64-3 Vitreomacular traction causing macular
detachment as a complication of Coats disease. A: Color
fundus image and B: corresponding OCT image of
vitreomacular traction causing macular detachment as a
complication of Coats disease.
EQUIPMENT
Laser system with visible (532 nm or 577 nm) or near-infrared (810 nm)
beam delivered via the indirect ophthalmoscope.
Retinal cryopexy system with external contact probe.
PROCEDURAL TECHNIQUES
Ablative Therapies
Postoperative Care
Multiple treatment sessions may be needed to completely ablate the leaking
vessels and repeat treatments should generally be spaced at least 3 months
apart. This also allows adequate time for the resorption of subretinal fluid and
provides a more accurate assessment of treatment efficacy (58). Macrocysts
persist in 10% to 15% of eyes with Coats disease.
Recurrence of disease after initially complete treatment has been
described in up to 7% of Coats patients. Mean time to recurrence in one study
was 10 years highlighting the need for long-term follow-up of Coats patients
(58).
Complications
Overly aggressive cryotherapy may worsen the retinal detachment (58).
Cryotherapy along with intraocular pharmacotherapies may also worsen
detachment as described under pharmacotherapies below. Subfoveal fluid and
macular exudation have been seen to worsen after laser or cryotherapy in
some patients, and it has been suggested that this may be reduced or
prevented by placing several rows of barrier laser posterior to the area of
telangiectatic vessels in a region of attached retina. This barrier is intended to
prevent posterior migration of fluid after subsequent treatment of the
telangiectasias themselves (38).
Intraocular Pharmacotherapies
Equipment
Pharmacotherapeutic: triamcinolone, pegaptanib, bevacizumab, ranibizumab,
or conbercept; syringe with small gauge needle; prep solution such as
betadine; sterile lid speculum; calipers.
Complications
Bergstrom and Hubbard performed cryotherapy 1 to 4 months after a 1-mg
IVT injection in 5 patients with total bullous retinal detachment due to Coats
disease. Cryotherapy was performed over 2 to 3 sessions. Several
complications occurred including elevated intraocular pressure in 4 of 5
patients, severe cataract in 3 of 5 patients, and inoperable rhegmatogenous
retinal detachment with proliferative vitreoretinopathy in 3 of 5 patients.
Time from IVT injection to developing retinal detachment ranged from 4 to
24 months. The authors advised avoiding the combination of IVT and
cryotherapy in pediatric patients with Coats disease (91).
As with IVT, cases of subretinal bands, vitreoretinal fibrosis, and traction
retinal detachment have been encountered when anti-VEGF injection therapy
was combined with ablative therapy, especially cryotherapy (84,92).
Intraocular Surgery
Equipment
For drainage of Coats detachment fluid, the equipment includes intraocular
infusion fluid and delivery needle/cannula, scleral cut down blade and/or
external drainage needle, and laser and/or cryopexy device. For more
complex vitreoretinal procedures for recalcitrant detachment, this may also
include vitrectomy system, endolaser, buckle, long-acting gas, or silicone oil.
Complications
Although no large study has specifically addressed complications of
intraocular surgery for Coats disease, the complications described are similar
to those for other forms of pediatric vitreoretinal surgery. With both drainage-
only and vitrectomy procedures, intraocular hemorrhage, lens damage, and
retinal breaks can occur. Care must be taken when placing intraocular
infusion and surgical instruments into the eye to avoid contact with the lens.
The surgeon should be familiar with the anatomical difference with age in the
pediatric population and plan instrument placement accordingly (see also
Chapter 61). Because phthisis and neovascular glaucoma are common
outcomes of advanced Coats disease, it is difficult to know if this is a surgical
complication when it occurs postoperatively. As with any intraocular surgery,
infection is possible.
OUTCOME EXPECTATIONS
The primary factors determining final visual outcome in patients with Coats
disease are the presenting visual acuity, extent of retinal detachment, and the
extent of macular exudation. As previously mentioned, cases with florid
macular exudation may develop subfoveal fibrosis, which is almost
invariably associated with a poor visual prognosis (4). Stage 1 disease rarely
results in severe visual loss, but stage 2 disease will progress to a final acuity
of 20/200 or worse in half of patients, even with aggressive treatment.
Treatment in stage 3 and 4 disease is primarily aimed at anatomic correction
of the retinal detachment, lowering of intraocular pressure, and prevention of
phthisis. Stabilization or improvement of visual acuity is generally seen in
patients with fewer than 4 clock hours of involved retina (38). It has been
noted that visual outcomes are particularly poor in Coats patients referred
with an initial diagnosis of retinoblastoma, presumably due to the extent of
retinal detachment (10). Long-term follow-up of patients with Coats disease
has shown that the condition can recur after long periods of quiescence, and it
should be emphasized that periodic examination is important even in patients
who have been stable for decades (102).
SUMMARY
More than a century after it was originally described, Coats disease remains a
cause of severe vision loss in the young. Slit-lamp examination and indirect
ophthalmoscopy alone can often differentiate this disease from other causes
of retinal detachment. When necessary, ultrasonography, fluorescein
angiography, and CT can assist in making the diagnosis and ruling out other
disorders such as retinoblastoma.
We now enjoy greater diagnostic accuracy and are able to salvage more
eyes with Coats disease, but the rates of central vision loss remain high due to
complications such as retinal detachment, macular fibrosis, and amblyopia.
Future research in this disease should focus on earlier detection and methods
to maintain macular function.
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65
Persistent Fetal Vasculature Syndrome
Supalert Prakhunhungsit, and Audina M. Berrocal
INTRODUCTION
Persistent fetal vasculature syndrome (PFVS), previously known as persistent
hyperplastic primary vitreous (PHPV), is a spectrum of conditions that are
characterized by failure of involution of the primary hyaloidal vasculature
system, incomplete ocular neurovascular development, or both (1,2). The
term PHPV does not optimally describe the pathologic findings in this
condition, because it fails to acknowledge complete intraocular vasculature
involvement found in this disorder. Therefore, PFVS is more widely used and
accepted as the term to describe this spectrum of diseases.
GENETICS
PFVS is most commonly sporadic. However, there are reports of inheritable
transmission in some families. An autosomal dominant pattern in an Egyptian
family was reported (3). Many other studies demonstrated cases with
autosomal recessive pattern and, normally, they are associated with other
ocular abnormalities (4–8). Furthermore, the ATOH7 gene mutation has been
detected in PFVS cases with autosomal recessive inheritance mapped on
10q21.3 location (9–12). Apart from those two genes, a novel mutation found
in the COX15 gene, a cytochrome c oxidase assembly protein on
chromosome 10, has also been reported in a case with bilateral PFVS (13).
Patients with bilateral PFVS may benefit from a referral to a geneticist for
evaluation of possible syndromic associations and their potential implications
on future offspring (14).
PATHOPHYSIOLOGY
From an embryologic perspective, the intraocular vasculature starts to form
as early as the 3rd week after fertilization. The hyaloid artery enters and
transverses anteriorly through the vitreous compartment branching into
multiple channels making up the vasa hyaloidal propria (1,2,14). The
posterior tunica vasculosa lentis is then formed at the posterior surface of the
developing lens anastomosing with iridohyaloid or capsulopupillary vessels.
As the secondary vitreous forms at the beginning of second trimester, the
involution of vessels starts posteriorly, first in the hyaloid artery, then in the
vasa hyaloidal propria and iridohyaloid vessels, and finally in the tunica
vasculosa lentis. The regression of the physical barrier caused by the
iridohyaloid vessels allows the zonular ligament and lens to develop normally
(1). The failure of normal developmental regression causes the varied degrees
of PFVS phenotypes.
Typically, the characteristic findings of PFVS only occur in the patient’s eyes
as described earlier. When the systemic abnormalities are discovered, the
associated syndromes should be aware of. Trisomy 13 (Patau syndrome)
should be suspected in children with congenital brain, heart, or spinal cord
abnormalities (23). Muscle weakness and wasting starting very early in their
childhood are seen in PFVS patients with Walker-Warburg syndrome
(24–27). Pediatric patients with intellectual or learning disabilities are found
in Dandy-Walker syndrome with cerebellar maldevelopment resulting in
hydrocephalus and in Angelman syndrome with laughter, hand-flapping
movements, and microcephaly (28). Some congenital infections, such as
congenital CMV (27) and congenital rubella (14), are also found associated
with PFVS in the eyes. Glucose 6-phosphate dehydrogenase (G6PD)
deficiency can be found in PFVS patients with a history of hemolytic anemia.
Other reported medical conditions associated with PFVS include pulmonary
stenosis, cerebral palsy, and facial clefting syndrome (14). Maternal cocaine
use during pregnancy has also been reported to be associated with bilateral
PFVS (27,29).
DIAGNOSTIC STUDIES
Fundus Photography
Preoperative or intraoperative fundus photography is recommended for
documentation of these cases. These photographs can also be used to
demonstrate the ocular abnormalities to parents and to discuss treatment
options and further plans for the patients. The anterior chamber angles can be
imaged with a digital camera. Often, the angle of the major vessels of the
retinal arcades can be evaluated preoperatively and compared to subsequent
images. This can document change and may indicate that posterior traction is
pushing the detachment anteriorly and starting to occlude the angle. This may
preempt the development and management of angle-closure glaucoma.
Ultrasonography
Ultrasonography is a useful investigative tool to evaluate the posterior
compartment of the eye, especially when a cataract or media opacity obscures
the posterior segment. The efficacy of ultrasonography for evaluating cataract
cases with either anterior or posterior PFVS was studied. The result was a
high true positive rate, up to 92%, which supports the important role of
ultrasonography for preoperative evaluation in PFVS cases (32). A unilateral
cataract in a newborn infant should trigger potential PFVS, and
ultrasonography should be performed. However, ultrasonography can be very
challenging in pediatric eyes. In some cases, the thin stalk that connects the
optic nerve head to the posterior surface of the lens capsule can easily be
overlooked and be later discovered intraoperatively (33). In such cases, the
cataract surgery alone may not be sufficient for clearing the visual axis, and a
vitrectomy might be needed (33). In cases of complex cataracts, a pediatric
retina specialist is often the person to perform surgery and the pediatric
ophthalmologist the one to manage the patient’s visual rehabilitation.
Ultrasonography reveals details concerning axial length and retinal
involvement that relate to the postoperative visual prognosis in the long term.
When eyes are smaller than 15 mm or when there is a disparity between the
two eyes that is larger than 3.5 mm, best vision outcome is rarely better than
light perception in the shorter eye even with surgical intervention (14).
In addition to ultrasonography to diagnose PFVS, it is also valuable to
distinguish PFVS from other mimicking diseases. Most importantly, the
detection of calcification within intraocular masses or tumors in young
children should heighten suspicion of the diagnosis of retinoblastoma (34,35).
Therefore, a more detailed investigation is needed before considering
surgery.
Differential Diagnosis
When patients with PFVS present with leukocoria, it is important to rule out
other causes of leukocoria, including retinoblastoma, retinopathy of
prematurity, FEVR, Norrie disease, incontinentia pigmenti (2,34), Toxocara
endophthalmitis, scar tissue surrounding an occult intraocular foreign body,
X-linked retinoschisis, and retinal detachments from other causes (2). In
patients younger than 3 years of age, retinoblastoma must be considered until
proven otherwise. Unlike PFVS, microphthalmos is rarely seen in
retinoblastoma unless the affected eye(s) is/are in late stage and phthisis bulbi
occurs. PFVS is generally unilateral, whereas FEVR, Norrie disease, and
incontinentia pigmenti are normally bilateral disorders. However, FEVR can
be asymmetric and an eye with retinal detachment can be smaller than the
fellow eye. However, a clue is that conditions are not PFVS is that they do
not show a connecting trunk and rarely affect the inferonasal aspect of the
posterior lens capsule as PFVS does, even though retinal dragging and
folding can occur.
In cases of bilateral PFVS, Norrie disease or FEVR must be ruled out
(47,48) (see also Chapters 35 and 66). Bilateral cases of PFVS might be
difficult to differentiate from Norrie disease since there are no
pathognomonic features to differentiate one from the other. Patients with
bilateral FEVR rarely present with bilateral retinal detachments. The family
history of inheritance pattern, systemic associations, and especially genetic
testing can be helpful in these cases (48).
Complete history taking, ocular examination, and systemic review as well
as investigations, such as ultrasonography, MRI, and FA, are helpful in
distinguishing other diagnoses from PFVS.
MANAGEMENT
PFVS management is based on the pathologic extent of the anterior or
posterior segment, and this should be assessed (49). Management of PFVS
includes the following objectives: (a) to save vision by eliminating the
amblyogenic media opacities or, in posterior or combined PFVS, by releasing
the retinal tractional forces from multiple directions that cause retinal
abnormalities; (b) to preserve globes and to prevent complications, such as
secondary glaucoma and eventual phthisis bulbi (50,51); and (c) to improve
patient cosmetic appearance in advanced cases (14,18,52). The heterogeneity
of clinical presentations of PFVS makes it especially challenging to manage
surgically. Prior to surgery, the postoperative lifelong risks of retinal
detachment, glaucoma, and other associated complications should be
disclosed and made clear to the parents.
SURGICAL INDICATION
The management of PFVS varies by PFVS phenotype. Indications for
surgical management in PFVS have changed in recent years due to
improvements in knowledge about the disease, surgical techniques, and
surgical instrumentation. In unilateral PFVS cases in which the fellow eye is
normal, the value of surgery continues to be debated since the visual results
are often poor (27). Generally, surgical indications include media opacity,
vitreoretinal traction, retinal detachment (14), progressive shallowing of the
anterior chamber from swollen cataractous lenses, traction on ciliary
processes, recurrent severe vitreous hemorrhage, and uncontrolled intraocular
pressure from secondary glaucoma (2,50).
Surgery is usually not indicated in cases with a clear visual axis,
nonprogressive anatomical pathologies, and an unaffected anterior chamber
(2,53). Similarly, severe microphthalmia (54,55), severe retinal or optic nerve
hypoplasia, and severe associated ocular anomalies or phthisis resulting in
dense afferent pupillary defects or no light perception may be considered as
contraindications for surgery by some surgeons in patients with unilateral
PFVS (14,27). These factors in patients with bilateral PFVS are also
considered to be relative contraindications for surgery since the visual
potential is often poor (14).
TIMING OF SURGERY
If surgical management is considered, the ideal timing should be as early as
possible before the development of deprivational amblyopia or secondary
complications (14,27,56). The delay in surgery in indicated cases could lead
to biologic consequences that develop within weeks to months, such as
retinal detachment and secondary glaucoma. The critical period of visual
development plays an important role in the optimal timing of surgery, and it
facilitates early postoperative visual rehabilitation. Many studies reported the
benefit of early surgery relative to postoperative visual improvement
(27,52,56). Even in bilateral cases, early surgical intervention was found to
increase the potential of achieving functional vision (48,56). In addition to
the visual aspect, Federman et al. reported that early surgical intervention
facilitated better cosmesis and long-term eye growth compared to
nonoperated eyes (57). Conversely, a deferral in surgical intervention could
lead to poor final visual outcome despite adequate anatomical success (49).
From a histologic study of the retrolental fibrovascular stalk—irreversible
retinal folds, macular dragging, and tractional retinal detachment caused by
anteroposterior traction could occur if the glial and vascular components are
left to mature in the eye (56,58). A significant retinal reattachment with
reversal of retinal folds and macular dragging was reported in a patient that
underwent surgery prior to the age of 13 months (56).
EQUIPMENT
Trocars and cannulas with vitrectomy system for limbal approach
Pediatric (short) small gauge trocars and cannulas with vitrectomy system for
3-port posterior surgery
End-irrigating light pipe and vitrectomy system for 2-port posterior surgery
Endodiathermy
Transillumination (optional)
Vitreoretinal scissors, forceps (as needed)
Endoscope (as needed)
SURGICAL INCISIONS
Preference of surgical incision location varies among surgeons, with some
preferring the limbal approach and others opting for the pars plicata or iris
root approach. Since PFVS has dramatically variable ocular presentations and
severity among patients (1), an incision through displaced ocular structures,
such as anteriorly pulled retina or centrally dragged ciliary process, or
abnormal vasculature can cause unfavorable consequences and a worse
prognosis (14,57). Transillumination to locate the ora serrata can be
performed before performing a sclerotomy, but it is often unsuccessful (57).
LIMBAL APPROACH
Limbal incision has been advocated by some retina specialists (1,57,60,61)
since it is associated with the following advantages (Figure 65-6):
THE VITRECTOMY
Anterior PFVS
When the lens opacity or Mittendorf dot is eccentric to the visual axis, it
should be typically left untouched. Rarely, they will progress to
complications such as secondary angle closure from anterior rotation or
swelling of the lens. Cases with purely anterior PFVS with significant
cataract, lensectomy with anterior vitrectomy is usually performed (16,27).
The surgery aims to get rid of the amblyogenic factor from the media opacity.
During the lensectomy, it is crucial to remain inside the capsular bag at all
times to avoid additional vitreous traction, which can cause a retinal tear.
Afterward, the remnant of the lens material and capsular bag should be
adequately eliminated. A peripheral iridotomy is recommended to prevent
shallowing of the anterior chamber and postoperative glaucoma.
Furthermore, sub-Tenon’s steroids will reduce the potential for significant
postoperative inflammation. However, intraocular pressure must be
monitored since infants are prone to respond to steroids with high intraocular
pressure.
ADVANCEMENT IN PEDIATRIC
RETINAL SURGERY FOR PFVS
Intraoperative Optical Coherence Tomography
(Intraoperative OCT)
Intraoperative OCT enables surgeons to visualize the posterior portion of the
lens (Figure 65-9). With intraoperative OCT, it is possible to determine how
the retina and fibrovascular tissue attached to the posterior lens surface and
whether it is necessary to sacrifice the lens. There are PFVS cases in which
the lens is almost normal with only slight opacity. Intraoperative OCT can
determine whether the opacity extends only to the anterior face of the hyaloid
or if it involves the lens resulting in the need for lensectomy procedure. This
is a very important difference to the development of the postoperative vision
in these eyes. Moreover, this information could lead to appropriate surgical
procedures to treat the lens and/or retrolental fibrovascular tissue. In posterior
PFVS, intraoperative OCT can be used to evaluate the extent of the epiretinal
membrane-like structure, vitreomacular traction, and other vitreoretinopathies
that require membrane peeling. Moreover, the intraoperative OCT can be
used to evaluate the macular anatomy in terms of visual prognosis assessment
(Figure 65-10). All of this information can be derived from the real-time use
of intraoperative OCT.
Small-Gauge Surgery
Small-gauge surgery for pediatric cases has many advantages. Pediatric eyes
have a shallower anterior chamber, a relatively larger lens thickness, a shorter
axial length, and less vitreous volume compared to adult eyes (79).
Moreover, affected eyes with PFVS are often smaller than those from age-
matched children. Thus, the instruments used for adult cases are not
appropriate for use in pediatric surgery. Accordingly, pediatric surgical
instruments were designed and introduced to improve surgical outcomes.
Short 25-G vitrectomy designed specifically for pediatric eyes is now
commercially available, with vitrector and light pipe lengths that are
approximately two-thirds the length of their adult-sized counterparts (80).
The reduced length of the short 25G makes instrument manipulation easier in
limited spaces.
The recent development and introduction of 27-G vitrectomy may also
have a potential role in pediatric vitrectomy. Smaller sclerotomies facilitate
better self-sealing wounds, which reduces the risk of postoperative hypotony,
bleeding, and endophthalmitis (81). However, the use of more flexible
instruments and reduced flow rate may be of concern when used in pediatric
cases, especially when membranes are tough or thick (81,82).
NONSURGICAL TREATMENTS
When a patient is not considered a good surgical candidate, conservative
treatment is an alternative. Also, the nonsurgical option is beneficial in mild
PFVS cases with the preservation of normal visual axis, so the surgical
intervention is not fully indicated (Figure 65-11). Some studies reported that
eyes not treated by surgery could survive to adulthood (89–91). Therefore,
conservative treatment may be a reasonable treatment option in selected cases
of PFVS. For example, cases with spontaneous lens resorption that allowed
the anterior chamber to remain deep enough even when contracture of the
retrolental membrane caused the lens to move forward (2). If conservative
treatment is the strategy of choice, the follow-up visit should be scheduled for
the near term to facilitate early detection of possible complications, including
progression of cataract in mild disease and any forms of glaucoma like lens-
inducing glaucoma (92).
FIGURE 65-11 The nonvisually significant stalk
disconnected itself and was floating independently in front
of the optic nerve in a 5-year-old boy. The other end of the
stalk attached to the posterior lens capsule eccentrically. In
this case, the conservative treatment was recommended.
POSTOPERATIVE CARE
The treatment of amblyopia, either from anisometropic or refractive
component, could be augmented by the combined efforts of pediatric
ophthalmologists and optometrists. Concerning amblyopia treatment—
refractive correction, occlusion therapy, or pharmacologic atropinization in
the better eye, and aphakic contact lens fitting in the surgical eye is advised to
achieve the best visual outcome (14). Lastly, protective polycarbonate glasses
should be prescribed to prevent accidental trauma to the remaining eye.
Patients and parents are always informed to observe for abnormal ocular
signs, and they are advised to return to the clinic as soon as possible if any of
those signs appear. In patients with severe microphthalmia that have no light
perception, a referral to an ocularist for a prosthesis to encourage normal
orbital development is recommended.
OUTCOME EXPECTATIONS
The visual outcomes after surgical management are varied due to many
factors. Eyes with chiefly anterior disease produce better visual outcome
compared to eyes with posterior or combined type (14,16,27,60,67,103). Age
at presentation was also reported to be one of the proven prognostic factors in
many studies (52,60,103). The earlier the age of presentation, the better the
visual prognosis. Karr and Scott found a visual outcome better than 20/200 in
children who presented earlier than 2.4 months versus 20/300 or worse in
patients who presented at 4.3 months (60). The visual result is mostly poor in
cases with bilaterality, glaucoma (14,103), concomitant congenital anomalies
that affect the optic nerve or macula (2), severe microphthalmia in which the
axial length is <15 mm or more than 3.5 mm disparity between eyes (14),
massive subretinal blood (48), and severe retinal dysplasia or detachment
(2,64).
Concerning the surgical intervention, the objective of early surgery is to
preserve the globes or to prevent subsequent complications, especially in
patients with posterior disease. Functional vision was only barely obtained
(50,103). However, improvements in instrumentation and surgical technique
in the current vitrectomy procedure, early diagnosis, and intervention
followed by aggressive postoperative measures, such as amblyopia treatment,
significantly improve the visual outcome (27,33,52,56,57,60,97). Sisk et al.
reported that approximately two-thirds of patients who underwent surgery
developed form vision, counting fingers, and fix and follow or better for at
least 6 months postoperatively (14). It is known that bilateral disease is more
associated with the combined type, and the visual prognosis in these cases
might be worse when the patient has two affected eyes. However, Walsh et
al. found that nearly 70% of bilateral cases that had vitrectomy in at least one
eye had at least light perception, and there were only 11% of cases that were
phthisical at the last follow-up. Therefore, surgery in bilateral cases could
restore or maintain vision and avoid a phthisical event (48).
SUMMARY
PFVS is a congenital condition that needs to be detected early in life for the
diagnosis and intervention. The successful management of PFVS starts from
the correct diagnosis and the careful assessment of the anatomical
involvement. The detailed history taking, comprehensive ocular examination,
and investigations play crucial roles for making the correct diagnosis and
differentiating PFVS from mimicking but critical diseases. The treatment
options of PFVS are varied depending on the extent of the pathologic
phenotypes. Fortunately, the advancement of the surgical techniques and
instrumentations improves the surgical and visual outcomes in the recent
years. However, the patients and family members also need to be counseled
preoperatively for the possible treatment options as well as the potential
complications that need to be monitored lifelong. The importance of the
postoperative follow-up and managements such as amblyopia treatment
should be emphasized for the successful PFVS management.
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66
Pediatric Vitreoretinopathies: Familial
Exudative Vitreoretinopathy, Norrie
Disease, and Incontinentia Pigmenti
Lauren M. Wright, and Yoshihiro Yonekawa
INTRODUCTION
Many pediatric vitreoretinopathies have retinal vascular origins of disease,
and the most well known are retinopathy of prematurity (ROP) and familial
exudative vitreoretinopathy (FEVR). Earlier stages of the vitreoretinopathies
are usually characterized by vascular anomalies and peripheral avascular
retina, which lead to neovascular proliferation and subsequent traction retinal
detachment. The goal of management is to first make the correct diagnosis
since there may be systemic implications. Then, we must identify the eyes at
high risk for, or in the earliest stages of, neovascular states, and attempt to
stop the progression. If eyes have progressed to retinal detachment, the goal
is to identify if, when, and how to intervene, in order to maximize the visual
potential of the child. This chapter will provide an overview of the surgical
management of FEVR, Norrie disease, and incontinentia pigmenti (IP). Other
vitreoretinopathies with surgical indications also include ROP, persistent fetal
vasculature, and X-linked retinoschisis, and these are covered in other
chapters. Coats disease is considered more of a retinopathy rather than a
vitreoretinopathy. Therefore, the surgical approaches are distinct and also
covered elsewhere (see Chapter 64).
FAMILIAL EXUDATIVE
VITREORETINOPATHY
Genetics
FEVR is a heritable retinal vascular condition marked by anomalous
vasculature and failure of the retinal vessels to develop into the periphery.
The biologic basis of the disease involves defects in the Wnt signaling
pathways. Many gene mutations have been implicated, and these are
discussed in Chapter 42.
Diagnostic Studies
For many years, fluorescein angiography has remained an important ancillary
test in diagnosing and staging FEVR (7,8). Wide-field angiographic
capabilities has further enhanced our appreciation of the peripheral vascular
anomalies that exist in FEVR (1,2,9) and facilitates precise image-guided
laser treatment and identification of peripheral vascular activity. Ultra
widefield photography alone has been shown to be effective also (10), but
widefield fluorescein angiography is the most sensitive imaging study.
Optical coherence tomography (OCT) has revealed details of the pathologic
microanatomy of the disease, including posterior hyaloid
contraction/organization, vitreomacular traction (VMT), macular edema
(ME), intraretinal exudation, and subretinal lipid aggregation, and outer
retinal changes (11). When possible, OCT obtained in the clinic may help
identify active disease, guide surgical management, and inform postoperative
outcomes. Intraoperative OCT may offer similar utility in operative guidance.
Careful multimodal preoperative assessment can help guide treatment course
and provide prognostic information to families of affected children. In eyes
with hazy cornea or lens/media opacities, B-scan ultrasonography can help
identify the presence of retinal detachment and direction of tractional vectors,
which are useful for planning surgical approach and sclerotomy placement.
For female patients or carriers of inherited vitreoretinopathies like FEVR,
prenatal ocular ultrasound can also serve as a sensitive, valuable tool for
antenatal assessment of ocular pathology (12).
Treatment Indications
Equipment
To choose the most appropriate plan of care for the patient, thorough
preoperative assessment is necessary. An examination under anesthesia
(EUA) is often required to assess the extent and character of pathology in
children with FEVR. If scleral buckling or vitrectomy is being considered,
equipment necessary for these surgeries is ideally available at the time of
EUA when possible to minimize anesthesia exposure. For scleral buckling
and vitrectomy, elements and instrumentation vary depending on surgical
goals. Surgical equipment and instrumentation for pediatric retina surgery is
discussed in detail in Chapters 60 and 61.
Given the predominance of peripheral and anterior pathology in FEVR,
wide-field viewing is essential. The overall view and the visualization of
tractional vectors are usually superior during indirect ophthalmoscopy and
will likely be more of a challenge intraoperatively. Therefore, planning the
surgical maneuvers during the EUA first is useful. Large-scale studies have
not evaluated the safety and efficacy of endoscope-assisted vitrectomy for
eyes with stage 3, 4, and 5 FEVR, but the coaxial illumination and
visualization afforded by the endoscope is particularly useful to visualize
sheets of vitreous that require segmentation and may be an adjunctive option
as well. Choice of instrument gauge depends on surgeon preference and
anatomic goals. 25-gauge and 23-gauge systems are most commonly used.
Many cases can be performed with the vitreous cutter alone, such as to
address posterior tractional vectors and vitreous hemorrhage, but denser
membranes will require bimanual dissection, whether with picks and forceps
for blunt dissection, or with MVR blades, scissors, or needles for sharp
dissection.
Procedural Techniques
We generally follow the adage of “less is more” for these surgeries. Because
children can develop relentless proliferative vitreoretinopathy, retinectomy is
generally not recommended as well. Unlike surgery in adults, the goal is not
to have the retina flat at the end of the case. The goal of surgery should be to
cut tractional vectors to release the traction and watch the retina gradually
reattach over time by the pumping mechanism of the retinal pigment
epithelium (27). This is a similar concept in ROP surgery as well (28).
The above tenants are particularly relevant in surgery for stage 5 FEVR
(total retinal detachment) (25,29). Anterior entry into the eye is often
required, such as through the corneal limbus or via iris root sclerotomies.
Unlike stage 5 ROP where there is often a peripheral trough, especially if the
eye was previously lasered, eyes with stage 5 FEVR tend to have very
anterior adhesions to the eye wall. Lensectomy may serve to release
retrolental traction and/or provide access to peripheral anterior membranes
(2,25,30–32). With removal of the crystalline lens, the capsule must be
removed in its entirety, as residual capsule can behave as a scaffold for
cellular proliferation and result in persistent or worsening retinal detachment.
The lensectomy/capsulectomy alone will shift the retinal detachment complex
more posteriorly. If there was corneal compromise from a shallow anterior
chamber, this step also helps to allow the cornea to clear over time. A staged
surgery can be performed in such cases, where the surgeon can return to the
operating room several weeks later to proceed with the membrane dissection
now with a more clear view.
Careful membrane dissection is performed in a variety of ways depending
on how dense the preretinal membranes and plaques are. Bimanual
techniques are usually required where one hand secures the tissue and the
other hand moves in the other direction to initiate the surgical plane and
undermine the membranes. Sharp or blunt dissection can be performed
depending on the density of the membranes. The retina may become more
mobile as the dissection progresses, which is an encouraging sign, but also
increases the risk for iatrogenic break formation. There is little to no harm in
returning several weeks later to complete the dissection, compared to an
iatrogenic break, which may signify the end of treatment. If the subretinal
fluid resorbs and some of the retina can reattach, that will make for easier
subsequent dissection. Persistent subretinal fluid can also be drained
externally, which may help expedite the process, especially if there is
subretinal hemorrhage.
Tamponade is not required unless there is a rhegmatogenous component
to the retinal detachment. If iatrogenic breaks are created, the
recommendation is to relieve the traction over the break as much as possible
and use silicone oil tamponade. A scleral buckle to support the area may be
beneficial also. Repairing a rhegmatogenous component is exceedingly
difficult in stage 5 retinal detachments, but possible in stage 3 or 4, and
placement of oil may also reduce the stimulus for vascular leakage (33,34).
Primary RRD can occur in FEVR also. Interestingly, FEVR-related
primary RRD appears to be more common in Asia (25,31,35–43). Peripheral
vascular abnormality and atrophic changes may predispose to retinal holes
and breaks, as seems to be the case in ROP (44,45). Myopia may contribute
added risk (42). One series showed the most common etiology of FEVR-
RRD to be retinal holes within lattice, but horseshoe tears and giant retinal
tears also occur (43). In fellow eyes of FEVR-RRD cases, lattice
degeneration may be found as well as peripheral retinal fibrovascular
membranes, vitreous traction, and retinal breaks. These changes may
predispose to later onset detachment compared to TRD, as FEVR-RRD
frequently presents in the second to third decade (43).
Rhegmatogenous detachments in eyes with milder stages of FEVR can be
treated relatively similar to conventional RRD. However, the hyaloid is more
adherent and broadly inserted, so primary scleral buckling can often be
considered over vitrectomy (39). For combined rhegmatogenous–tractional
retinal detachment in eyes with more advanced stages, more aggressive
surgery may be required with vitrectomy with or without scleral buckling. As
described above, since there is already a retinal break, all traction needs to be
released from the break, treated with retinopexy and tamponade.
Postoperative Care
Wide-field angiography remains important during follow-up examinations
with or without laser treatment or surgery. Oral fluorescein may be useful as
an alternative to intravenous fluorescein for angiography performed in the
office setting for children who are old enough for imaging, but too young to
tolerate intravenous needles (27,46,47). There may be long periods of
inactivity in FEVR with late reactivation particularly in the nonvitrectomized
eye; therefore, lifelong screening is recommended. For individuals who have
undergone vitrectomy with long-term silicone oil placement, monitoring for
oil migration or emulsification, glaucoma, and cataract is important. Visual
outcomes in these eyes may be poor, and surgical aphakia is common. FEVR
tends to be asymmetric, so monocular precautions for the better seeing eye
are paramount.
Complications
NORRIE DISEASE
Genetics
Norrie disease is a rare X-linked recessive disorder with invariably severe
clinical manifestations marked by hearing loss, cognitive delay, and blindness
in affected patients. It is caused by severe mutations/deletions in NDP (MIM
310600) (50,51), a gene also implicated in FEVR (52–54); therefore, Norrie
disease may be considered as an extreme phenotype of FEVR. See also
Chapters 35 and 42 on Norrie and Wnt signaling and related diseases.
Clinical Signs and Symptoms
Retinal manifestations are often evident at birth. The hallmark of Norrie
disease is severely dysplastic retina in both eyes, accompanied by
aggressively progressive retinal detachment and in many cases with vitreous
and subretinal hemorrhage (29,55,56). Eyes with Norrie disease classically
present with a posterior “pumpkin” lesion (57), which represents a
disorganized mass of retina-derived glial tissue (58,59). There is extensive
retinal nonperfusion, and TRD usually progresses quickly from contraction of
the primitive vitreous and tissue proliferation.
Indications
Most individuals with Norrie disease will unfortunately develop phthisis
bulbi, but early surgical intervention can be beneficial (57). Given the visual
potential with early intervention, it is ideal for patients with Norrie disease to
have a pediatric retinal examination as soon as the diagnosis is considered,
ideally soon after birth, so that the vitreoretinopathy can be detected and
treated. Prenatal diagnosis of Norrie-based maternal ultrasound has been
described (60,61) and such early recognition may help in timely perioperative
planning. Those with family history of Norrie disease will also be aware of
the possible diagnosis. However, a thorough informed consent process with
the patient’s guardians is recommended to ensure that all parties are aware of
the generally poor visual prognosis in Norrie disease. There are currently no
guidelines dictating at which age or chronicity of the retinal detachment that
surgery becomes futile. The decision to intervene will vary from patient to
patient.
Equipment
Equipment is as described above for FEVR, though scleral buckle is
uncommon due to severe posterior involvement.
Procedural Techniques
Early retinal detachment in Norrie disease is characterized by a traction
retinal detachment surrounding the posterior glial mass. The goal of
vitrectomy is to transect the tractional hyaloid 360 degrees (Figure 66-4). At
this early stage, membrane peeling is usually not necessary. The retina will be
able to settle and reattach. For eyes that have progressed to funnel retinal
detachment, open funnel configurations will yield superior outcomes
compared to closed funnel retinal detachments, so intervention should not be
significantly delayed. Complete retrolental retinal detachment can be
operated on, especially if the funnel closure has been recent, but the surgeries
are challenging and high risk with guarded prognosis. The approach is similar
to stage 5 FEVR surgery as outlined above. The main difference is that the
retina is even more dysplastic than typical eyes with severe FEVR or ROP,
and it can be difficult to distinguish retinal tissue from organized hyaloid and
proliferative tissues.
FIGURE 66-4 Early vitrectomy for traction retinal
detachment in Norrie disease. A 2-week-old boy with a
family history of Norrie disease was screened soon after
birth and noted to have bilateral traction retinal
detachment with vitreous and retinal hemorrhage (A).
Fluorescein angiography shows extensive nonperfusion of
the retina (B). A 23-gauge system is used. The infusion
cannula is placed in the anterior chamber because there is
an anterior retinal detachment in the vicinity. The
superotemporal cannula is placed in the pars plicata as the
retina is confirmed to be attached in that quadrant. The
retinal detachment is very anterior and attached to the lens
capsule nasally, so a limbal incision is made superonasally
(C). Lensectomy is performed because of the insertion of
the retina to the posterior lens capsule. The nasal cannula
is subsequently removed due to the lack of surgical space.
The capsule is removed carefully in its entirety (D).Figure
66-4(Continued) Vitrectomy is performed with the goal of
transecting the hyaloidal face and other hyaloidal
insertions that connects the retina to itself and the eye wall
(arrows, E). This process is continued 360 degrees to
release the retina from progressive hyaloidal traction
(arrows, F). Air fluid exchange is performed to prevent
vitreous incarceration (G). On post-op month 1, the retina
is starting to reattach as seen on ultrasonography (H). The
view is limited from vitreous hemorrhage. On post-op
month 8, the retina is now completely reattached (I) and
confirmed on ultrasonography (J), and the patient retains
brisk light perception. The fellow eye had similar
presentation and management, but developed progressive
vitreous and subretinal hemorrhage, after undergoing
conservative management.
Outcome Expectations
Given the rarity of the disease, and tendency toward no light perception
vision early in life, there are limited reports on surgical interventions for
Norrie disease. However, the literature and our experiences suggest a benefit
to early surgical treatment. In the largest surgical series wherein 14 boys with
definite Norrie disease had vitrectomy with or without lensectomy in at least
1 eye prior to 12 months of age, half of the boys maintained at least light
perception visual acuity (57). The best outcomes are achieved when
intervention is possible prior to advanced retinal detachment.
INCONTINENTIA PIGMENTI
Genetics
Incontinentia pigmenti (IP), or Bloch-Sulzberger syndrome, is a rare X-linked
dominant ectodermal condition caused by mutations in the IKBKG gene. It is
mainly seen in females as it is usually fatal in males. See also Chapter 36.
Diagnostic Testing
Wide-field fluorescein angiography is an important diagnostic tool and can
reveal nonperfused retina, an avascular retinal periphery, arborization,
vascular loops, and leakage of fluorescein from incompetent vasculature and
neovascularization (63–65). Consistent with vascular occlusive disease, OCT
shows abnormal inner retinal structures that can involve the fovea in
symptomatic or asymptomatic eyes (66,67). Ultrasound is helpful in
evaluating the configuration of retinal detachment through vitreous opacities.
Indications
The retinal vascular disease in IP is the most active and progressive the first
several weeks and months of life. Examination as soon the diagnosis is
suspected is recommended, since early treatment can halt progression to
blinding sequelae.
Wide-field fluorescein angiography-guided laser photocoagulation of the
avascular retina is recommended in eyes with retinal neovascularization to
prevent progression to retinal detachment. There are no established guidelines
for treatment of avascular retina without neovascularization; some
recommend laser of all avascular retina, whereas others recommend
observation (68–70). High-risk angiographic signs, such as vascular leakage
and severe nonperfusion, may warrant early treatment. There may be lower
thresholds for treatment in monocular patients and those who may not be able
to regularly maintain follow-up. The tempo of progression in young children
can be very rapid, so diligent follow-up is recommended, regardless of
treatment strategy.
Vitreous hemorrhage is a common finding in severe IP-related
retinopathy. Media opacities will require B-scan ultrasonography to identify
an underlying retinal detachment. The threshold to surgically clear the
vitreous hemorrhage even in the absence of a retinal detachment should be
low in infants with IP, because of the high likelihood of active neovascular
disease that can rapidly progress, and which may be halted with vitrectomy
and laser, in addition to the risks of deprivation amblyopia.
Similar to late presentation of advanced closed funnel retinal detachment
in the other vitreoretinopathies, and perhaps more so in IP, aggressive surgery
should be weighed against the possibilities for quick deterioration with
surgical sequelae. IP can be asymmetric and, if the fellow eye sees well,
conservative management of delayed presentation of complete cicatricial
retinal detachment is a reasonable option. Monocular precautions are of
course emphasized (Figure 66-5).
FIGURE 66-5 Management of incontinentia pigmenti. An
11-year-old monocular boy with genetically confirmed
incontinentia pigmenti (note that incontinentia pigmenti is
rare in boys, as it is usually lethal in males) presented with
floaters in the right eye. He has mild retinal and vitreous
hemorrhage (A) and retinal neovascularization (B). His
fellow eye had undergone surgical interventions as a
newborn for vitreous hemorrhage and subsequent retinal
detachment but was deemed inoperable and now has dense
band keratopathy and corneal blood staining.
Ultrasonography shows a funnel retinal detachment (C).
The right eye was treated with laser photocoagulation for
mild, yet progressive, retinopathy in a monocular patient.
Most progression normally occurs in the neonatal period.
Equipment
Equipment is as described above for FEVR.
Procedural Techniques
In IP, the overall surgical goal is similar to traction retinal detachment
surgery in young children with ROP, FEVR, and Norrie disease, which is to
clear the media and transect the tractional vectors without creating iatrogenic
breaks.
Postoperative Care
Similar to most conditions with avascular peripheral retina, IP is a lifelong
condition. “Reactivation” of neovascular disease is possible but less likely
with age. Rather, the avascular retina predisposes these eyes to
rhegmatogenous complications. As shown in patients with ROP and FEVR,
untreated avascular retina is prone to retinal breaks in teenage years and
young adulthood, as well as when posterior vitreous detachments occur later
in life (69,71). Lasered peripheral retina may be protective in this regard.
SUMMARY
FEVR, Norrie disease, and IP are among pediatric vitreoretinopathies with
significant vasculogenic pathology and potentially devastating visual
outcomes. Identification of ischemic and preproliferative stages of disease
and prompt treatment when indicated is paramount to achieving hopeful
outcomes. When necessary, surgical management must be approached with
care, and avoidance of surgery may at times be in the child’s best interest
depending on disease extent and visual potential, and largely dependent on
the status of the fellow eye and systemic considerations. There are windows
of best opportunity for surgical intervention, so appropriate surgical timing is
an important consideration. Goals of surgery and technical approach will
differ based on diagnosis and stage of disease as described above. We hope
this chapter offers an organized approach to surgical care in these conditions.
Please note that there are many ways to approach these surgeries, and
different surgeons will have different techniques, but we tend to share general
philosophies of treatment. General principles of pediatric retinal surgery are
discussed in Chapters 56-62. We hope that further innovations in surgical
instrumentation, techniques, imaging and visualization, together with
advances in our understanding of the pathophysiology, will continue to
enhance our ability to optimize outcomes for these children.
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67
Epiretinal Membrane and Combined
Hamartoma of the Retina and Retinal
Pigment Epithelium
Cynthia A. Toth
INTRODUCTION
An epiretinal membrane (ERM) with nonvascularized cellular proliferation
along the surface of the retina is rare in infants and children, and when it
occurs, is usually unilateral (1). Whereas contracted preretinal tissue is found
in combined hamartomas of the retina and RPE (CHRRPE) (2–4), pediatric
ERM is more commonly idiopathic or secondary to other conditions
including after trauma (such as after penetrating trauma or intraocular foreign
body, or after nonaccidental trauma with premacular hemorrhage (5) or
without pre- or submacular hemorrhage (6)); in chronic retinal detachment
with proliferative vitreoretinopathy; or secondary to inflammation, retinal
vascular disease (Coats), neovascular disease (retinopathy of prematurity,
familial exudative vitreoretinopathy), or toxocariasis (7,8). Pediatric ERM
that is not a result of another ocular condition, or CHRRPE, may be
associated with neurofibromatosis type 2 and is sometimes the earliest
indicator of the more severe phenotype of the disease (9–13). This chapter
will focus on idiopathic ERM and CHRRPE, although the perioperative
considerations and techniques presented here apply in general to the
management of epiretinal proliferations in children.
Epiretinal Membrane
Idiopathic pediatric ERMs have been found centered on retinal vasculature,
extending from the region of the optic nerve head, within the macula, or in
more peripheral locations (1,14,15) (Figure 67-1). The most notable
distinction between epiretinal proliferation in the child versus in the adult is
the persistent adhesion/attachment of the posterior vitreous even in the
presence of condensed posterior hyaloid and cellular proliferation (Figure
67-2). The structure of the vitreous and the vitreoretinal interface in children
is distinct from adults; vitreous liquefaction is atypical under the age of 20
even after trauma or with retinal detachment and progresses with increasing
age (19). The adhesion between the vitreous and retina across the posterior
pole persists into the third decade of life (20). Despite this, in children, glial
proliferation across the retinal surface may result in axial and lateral traction
to the retinal surface resulting in partial-thickness deformation, full-thickness
folds, schisis, and even retinal detachment and choroidal neovascularization
(21).
DIAGNOSTIC STUDIES
Multiple modes of imaging may be useful in the diagnosis of ERM and
CHRRPE. Fluorescein angiography is important in the evaluation to
differentiate idiopathic ERMs from those associated with retinal vascular
diseases, CHRRPE, other tumors, or inflammation. The characteristic
fluorescein angiographic findings in CHRRPE may vary but include blocked
choroidal fluorescence due to pigmentation, straightening of surrounding
retinal vessels from traction, and tortuous retinal vessels with retinal capillary
dilation telangiectasia shunts and late leakage within the lesion (2,4) (Figures
67-4 and 67-5). Autofluorescence imaging also reveals the pigment blockage
and faint hyperautofluorescence in areas of CHRRPE (25,38).
Especially in peripapillary CHRRPE, the fluorescein angiogram can
reveal associated choroidal neovascularization (Figure 67-5). Optical
coherence tomography (OCT) is well tolerated by children and used to
identify characteristics of the vitreoretinal interface and retinal and subretinal
structures. OCT provides information on the extent of localized vitreous
bands or vitreous separation and of the extent of preretinal tissue and retinal
contact, retinal deformation and folds, schisis, or retinal detachment
associated with the ERM or associated retinal condition (7,8) (Figures 67-3
and 67-5). In contrast to adults, in children, retinal dragging and full-
thickness deep “taco folds” of the retina (Figure 67-6) are more common as
are broad swaths of adhesion between preretinal tissue and the retina (7)
(Figure 67-2). Analyses may also be confounded on OCT imaging by deeply
folded retina in which the layers may appear disorganized due to the atypical
plane of OCT sectioning across steeply folded retina. Similar to adults,
evidence of photoreceptor integrity on OCT appears to be predictive of better
visual outcomes, although dense preretinal tissue and thick retinal folds may
shadow and prevent such a preoperative assessment (7,15).
FIGURE 67-6 A macular epiretinal membrane in a child
with a prominent deep “taco fold” of the retina on OCT
imaging (A, B).
Structural OCT and OCT angiography imaging have further refined our
understanding of CHRRPE. An ERM and retinal adhesion or separation
along with vitreous attachment and retinal deformation and folds is delineated
on the OCT (18,38,39). Inner retinal changes involve thickening, cystoid
spaces, and disorganization of the inner retinal layers and may include
hyperreflective foci, schisis, and striae and either stop at the outer plexiform
layer or involve the deeper layers including the RPE (3,25,39–41).
Hyperreflective, fine sawtooth changes or larger omega-shaped changes in
the outer plexiform layer may occur in lesions in which the outer retinal
changes are less severe (3,39). There is great variability in abnormalities from
mild to severe, including subretinal fluid and RPE alterations, in the outer
retina and RPE (42). Peripapillary CHRRPE demonstrate more severe full-
thickness involvement on OCT compared to macular lesions (25), and
choroidal neovascularization and subretinal fluid may be evident on OCT in
CHRRPE or an ERM (Figure 67-7). In such cases, OCT is a valuable tool for
monitoring response to therapy. Because other ocular or systemic factors
such as brain injury may contribute to vision loss in a child with an ERM (6),
the impact of other disease processes within the eye and of other systemic
health factors should be considered in the evaluation of pediatric ERM,
particularly when considering surgery for visual improvement. On OCTA of
macular CHRRPE, the vessel density in superficial and deep retinal layers
and choriocapillaris has been found to be decreased compared to images of
healthy eyes of the same age (39), or vessels deformation is evident from
traction or schisis (40).
CLASSIFICATION
In light of the range of presentations of retinal involvement with CHRRPE,
Dedania et al. suggested a classification by location (zones 1 to 3 for
posterior, mid periphery, and far periphery), traction (stages 1 to 3 for no
retinal traction, retinal traction/schisis, and retinal detachment), and retinal
components involved based on OCT (A epiretinal component only, B partial
retinal involvement, C complete retinal and RPE involvement) (43). This
classification does not address vascular involvement and leakage and does
not include whether central macula is or is not involved with lesion/ERM
(23), which would be useful to include for studies of interventions or of
functional outcomes.
EQUIPMENT
Small-gauge vitrectomy system.
Fine pick or barbed needle.
Vitreoretinal forceps.
Vitreoretinal scissors may be used for sharp dissection.
Triamcinolone may be used to mark vitreous or membrane.
Indocyanine green or other dye may be used to stain internal limiting
membrane.
Intraoperative OCT imaging, handheld or in the microscope may aid in
viewing tissues.
PROCEDURAL TECHNIQUES
Choroidal neovascularization in peripapillary CHRRPE may involve the
macula and cause vision loss. Treatment with anti–vascular endothelial
growth factor can arrest the vascular leakage and improve visual acuity
(Figure 67-5). Response to such therapy can be monitored with fluorescein
angiography and OCT imaging.
Techniques for ERM surgery include vitrectomy (general principles
addressed in Chapter 61) with posterior hyaloid and membrane removal. The
clear vitreous is readily visualized when marked with triamcinolone. This is
quite useful before separating the posterior hyaloid in the posterior pole by
engaging the vitreous and hyaloid using suction from the vitreous cutter,
grasping with forceps, or snagging with the rough flexible loop (Finesse loop,
Alcon). Recognizing the involvement of condensed posterior hyaloid and
often dense adherence of the vitreous to a pediatric ERM, the epiretinal tissue
may peel from the retina during elevation of the hyaloid, or the hyaloid may
be separated along with removal of a broad sheet of ERM. This step should
be managed to control the direction of the traction relative to the retinal
surface to avoid retinal damage. Thus, membrane and hyaloid removal is
generally from posterior to outside of arcades and with traction at an oblique
angle rather than perpendicular to the retinal surface.
Membrane peeling may be initiated with a barbed needle (e.g., a 27-
gauge needle pressed gently at an oblique angle against a flat metal surface to
create a fine barb), which is often effective to engage and separate smooth
adherent macular membranes in children. The pinch-and-peel technique with
forceps or scratching (with the rough flexible Finesse loop) techniques is also
useful at sites of irregular ERM attachment to initiate the peel. As with adult
surgery, attention is given to limit pressure against the retina and to determine
the extent of the peel to avoid compressing the retina or engaging tissue of
the retinal nerve fiber layer, which may appear whitened in the area of
membrane removal. Focal firm adhesions are more common between an
ERM and retinal surface in children, often over retinal vessels (15,16). Thus,
it is not uncommon in pediatric ERM surgery to both peel epiretinal tissue
and to cut the membrane at a very adherent site, rather than risk tearing the
retina (22).
OCT imaging has been useful to visualize such tissue relationships before
and during surgery (5,7). Recurrence of an ERM in children has been noted
in multiple cases; however, as shown with preoperative OCT imaging, this
may also occur due to removal of a single layer of gliotic tissue in an
unrecognized multilayered membrane (5). Intraoperative OCT is useful to
determine the location and extent of residual ERM and scrolled ILM after
peeling (Figure 67-2). Some surgeons have advocated internal limiting
membrane (ILM) staining to guide ILM peeling in pediatric cases with a goal
of diminishing recurrences (Figure 67-1). The peripheral retina is carefully
inspected; however, peripheral vitreous removal is not pursued unless this is
required to release traction from associated pathology. The surgeon thus
avoids working in close proximity to the crystalline lens.
Surgical considerations and preoperative evaluation of CHRRPE may be
more complex than in idiopathic pediatric ERM, and the severity of the
retinal-RPE involvement may limit visual recovery. CHRRPE has the added
complexity of the unknown extent and depth of involvement, including outer
retinal, vascular, and retinal pigment epithelial components. CHRRPE lesions
are more likely to have firm ERM–retinal attachments and may require sharp
dissection to cut the attachment (15,22). Despite this uncertainty,
histopathology of surgically removed ERM in CHRRPE has not shown
retinal components within the membrane (44).
POSTOPERATIVE CARE
Postoperative considerations include managing intraocular pressure and
monitoring for response of macular morphology and for retinal detachment or
bleeding. In children, ocular ultrasound, Optos wide-field imaging, and OCT
imaging are often tolerated better in the clinic than extensive indirect
ophthalmoscopy and thus provide valuable postoperative information. Other
pediatric eye care team members are important in the postoperative period to
manage refractive status, assist in the need for eye protection, and evaluate
and treat amblyopia in younger children.
COMPLICATIONS
Complications have included retinal breaks, vitreous hemorrhage, retinal
detachment, macular edema, transient and permanent elevated intraocular
pressure, and cataract; and ERM recurrence rates have varied widely
(4,8,14–16,22,38). Improved technology, such as OCT imaging for younger
children, has improved our ability to identify, evaluate and monitor the
progression of ERMs in these patients. Intraoperative OCT enables the
surgeon to assess the retinal surface once membrane removal is thought to be
complete and may reveal sites of subclinical persistent membrane or retinal
injury (5,45).
OUTCOME EXPECTATIONS
To date, surgical guidance for pediatric ERMs is limited as reports are from
small series of cases with multiple etiologies including CHRRPE and from
children of widely varying ages (from 4 months to adulthood)
(4,7,8,14,15,46–48). Surgical interventions in appropriate cases with
decreased visual acuity have resulted in improved visual acuity in the
majority of patients, although many of these studies include not only
idiopathic ERM but also a range of underlying etiologies (1,7,8,15,16).
Visual potential may be limited due to chronicity of a lesion in early
childhood; nevertheless, numerous reports of pediatric ERM cases and series
have demonstrated improvement in visual acuity, which may take over 6
months after surgical ERM removal (4,7,8,14,15,46–48). There are also many
reports of visual acuity improvement after the vitrectomy and ERM removal
in CHRRPE (4,8,15,22,44,46,47). Although the recurrence of ERM may be
more common with CHRRPE than in other ERMs, visual acuity may still
improve (8,46).
SUMMARY
Pediatric ERMs or CHRRPE lesions are often unilateral and may be observed
when they do not involve the macula or cause vision loss. Neurofibromatosis
type 2 may be associated with either lesion. When the macula is involved,
surgical assessment and perioperative planning should consider the age and
visual development of the child. Surgeons should be prepared for
vitreoretinal attachments that may require sharp dissection. OCT and
fluorescein angiographic imaging are useful in the diagnosis, therapeutic
planning, and monitoring of these conditions.
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68
Surgery for Gene Therapy
Jonathan F. Russell, Albert M. Maguire, and Stephen R. Russell
INTRODUCTION
Gene therapy has been broadly defined as “a pharmacological approach
whereby exogenous genes or nucleic acids are introduced into host cells to
effect local production of a therapeutic protein or halt expression of a disease-
associated protein” (1). A more strict definition is “a treatment method [that]
involves replacing, inactivating, or editing diseased genes” (2). For
autosomal recessive, loss-of-function, disease-causing mutations, adding to
the cells one or more functional copies of the mutated gene, a strategy known
as gene augmentation, holds great promise. For example, in Leber congenital
amaurosis (LCA) associated with biallelic RPE65 mutations, gene
augmentation of the mutated RPE65 retinal trans-isomerase that normally
resides within the retinal pigment epithelium (RPE) has been shown to
functionally restore recycling of retinal vitamin A (3). The first human gene
therapy clinical trials began in 1981; since then, nearly 2,000 test cases have
been performed. In December 2017, a successful phase 3 clinical trial of
voretigene neparvovec-rzyl (VN, Luxturna, Spark Therapeutics, Inc.) for
LCA due to biallelic RPE65 mutations culminated in the first U.S. Federal
Drug Administration (FDA) approval of a gene therapy for an inherited
genetic disease (4,5).
TRANSVITREAL SUBRETINAL
DELIVERY
Transvitreal approaches to the subretinal space were first developed in the
1990s for removal of subfoveal choroidal neovascularization (14,15) and for
subretinal injection of tissue plasminogen activator to treat massive macular
subretinal hemorrhage (16). Transvitreal subretinal delivery for gene therapy
was developed in animals, pioneered in adults, and then adapted to children.
In pediatric patients, a number of special considerations apply. Pediatric
patients differ from adults in the dosage of immunomodulation, perioperative
management, and surgical maneuvers.
Small children have high scleral pliability such that any interruption of
infusion increases the risk of globe collapse, catastrophic retinal damage, and
retinal tears. An intraoperative retinal tear in an adult may be managed by the
addition of laser demarcation but in a young child represents potentially a
vision- or even organ-threatening complication. When performing transvitreal
subretinal gene therapy, it is best to avoid any unnecessary or prolonged
vitreous manipulations such as vitreous base shaving. The goal of vitrectomy
is only to create a vitreous-free pathway for safe and reliable delivery of the
vector to the subretinal space. To ensure this is accomplished, an iatrogenic
PVD is completed beyond the site of the anticipated macular injection sites.
In contrast to normal pediatric vitreoretinal adhesion, in RPE65-associated
LCA, the vitreoretinal adhesion is remarkably weak. An iatrogenic PVD can
typically be induced with a silicone-tipped cannula or vitrectomy cutter. The
operating surgeon should then assemble the injection apparatus following the
Luxturna package insert which currently includes a pharmacy-supplied 1 mL
Becton Dickinson syringe containing 0.8 mL of diluted VN, a VN-verified
compatible 6-inch extension tubing with small 0.6- to 0.8-mm lumen, a 39- or
41-gauge injection cannula, and a list of compatibility-tested injection system
components in the VN package insert (19). VN-verified compatibility has
been performed by the manufacturer to assure minimal luminal VN
adsorption and biocompatibility. If alternative components are substituted,
compatibility cannot be assumed. In other trials, injection systems such as the
MedOne injection system (MedOne Microdose Injection Kit, MedOne
Surgical Inc.) have been used, but no safety or comparative studies are
available.
The initial site of subretinal injection is chosen based on the disease and
the preferred location for vector delivery. Dog and primate studies have
demonstrated that RPE transfection with AAV-based vectors only occurs
within the region of exposed apical RPE over the region of a subretinal bleb
(20). Because RPE65-associated LCA is a rod-mediated disease and evidence
suggests that cones may possess a supplemental mechanism for all-trans
retinal trans-isomerization (21), it is unclear whether visual benefit is
conferred with detachment of the fovea. Thus, in RPE65-associated LCA, the
initial site of subretinal delivery is typically chosen along or just outside the
superior arcade (Figures 68-1 and 68-2) in order to treat the central and
inferior macular field needed for ambulation and most near visual tasks. In
addition, this region is thicker than more peripheral retina or the central fovea
and is a good compromise. The closer the injection site is to the fovea, the
greater the risk of inducing a full-thickness macular hole. The further the
injection site is from the fovea, the less control one has over the direction of
subretinal dissection, because the lowest resistance pathway of separation
will determine the direction that the injected subretinal fluid spreads, and this
may not be toward the macula. Generally, the injection site should be no
closer than two disk diameters from the fovea. Occasionally the injected
subretinal fluid will dissect around the disk rather than extend to the macula.
Just prior to introducing the injection cannula or prior to injection, the
intraocular pressure should be reduced to 10 mm Hg to increase the pressure
differential between the injection pressure and the subretinal potential space.
FIGURE 68-2 Transvitreal subretinal injection procedure
for voretigene neparvovec-rzyl: choice of injection site.
Note that this is the surgeon’s view. (Image reproduced
with permission from Spark Therapeutics, Inc.)
The preferred method used to inject into the subretinal space and raise a
retinal bleb is to advance the 39- or 41-gauge injection cannula until the
retina is gently indented (Figure 68-3). Then, the injection elevates the retina
around the statically held cannula (Figures 68-4 and 68-5). It is crucial that
the resulting retinotomy size be minimized to prevent loss of vector into the
vitreous cavity, which will also reduce bleb pressure and/or reduce bleb
enlargement. Since ocular inflammation appears to be related to exposure of
vector capsid to the anterior vitreous cavity structures such as the ciliary body
and iris (22), vitreous exposure should be minimized. Following slow
subretinal injection of 300 μL of VN solution, the injection pressure should
be maintained for at least 5 seconds to allow the bleb pressure to equilibrate
with that in the syringe prior to removing the cannula from the retinotomy. If
the surgeon is unable to complete subretinal injection of 300 μL, the assistant
reports high resistance to injection. If the subretinal elevation extends in an
undesirable direction, alternative additional bleb sites can be chosen and
injected up to the dosage limit total of 300 μL. As with all injection site
choices, the surgeon should be cognizant of the retinal thickness and the
proximity to the fovea at the chosen site to minimize surgical complications.
Injection by an assistant is useful to provide interactive verbal
communication to the operating surgeon that will allow enhanced
troubleshooting of injection difficulties. Maintaining stability of the small
cannula within the subretinal space without stretching the retinotomy is a
remarkably difficult challenge even for experienced surgeons. Thus,
delegating the monitoring of injection resistance and injection volume is
recommended. In the phase 3 VN study, no effort was made to create a “pre”-
bleb by injecting subretinal saline to create a subretinal pocket into which VN
could be injected. However, in other ocular gene therapy trials for
choroideremia, achromatopsia, and others, “pre”-blebs have been utilized
(7,23).
FIGURE 68-3 Transvitreal subretinal injection procedure
for voretigene neparvovec-rzyl: position of subretinal
injection cannula. Note the placement of fine silicone
cannula against inner retina. (Image reproduced with
permission from Spark Therapeutics, Inc.)
Within the phase 1 (3), phase 1 follow on (24), and phase 3 VN studies (5),
no dyes or vitreous marking agents such as indocyanine green or
triamcinolone acetonide (Kenalog) were used or recommended. To date, no
stains or marking agents have been tested for biocompatibility with VN, and
hence the potential effects on efficacy are not known. Therefore, they are
generally avoided unless required for a compelling reason. For postmarketing
VN treatments, vitreous marking agents have been reported to be compatible
by some surgeons (25,26).
During the VN phase 3 trial, intraoperative OCT was unavailable.
However, since this study was completed, a number of investigators have
reported that intraoperative OCT may be especially useful when inherited
retinal diseases, such as choroideremia, have led to pronounced retinal and/or
choroidal thinning. In these situations, it may be difficult or impossible for
the surgeon to intraoperatively distinguish subretinal from sub-RPE or
suprachoroidal injection (23). In studies of transvitreal subretinal bleb
formation in model eyes, OCT has been shown to provide a more accurate
assessment of subretinal volume delivery compared to the surgeon (27).
Because central retinal thickness is generally preserved for RPE65-associated
LCA, intraoperative OCT is not necessary for VN delivery. Several surgeons
have noted that intraoperative OCT may facilitate identification of foveal
bulging that precedes development of an intraoperative full-thickness macular
hole or macular dehiscence, thereby warning the surgeon to slow the rate of
injection or change to an alternative retinal injection site.
After subretinal injection, a thorough peripheral retinal examination using
a wide-field inverting lens or indirect ophthalmoscopy with scleral
indentation is then performed to search for any evidence of retinal tear or
dialysis. If retinal defects are found, they are treated promptly using standard
cryotherapy or retinopexy techniques. An air–fluid exchange is then
performed, both to remove the majority of vitreous remnants of viral
genomes to lower the risk of inflammation and sensitization and in an effort
to “spread” the bleb to cover more surface area. All efforts should be made to
assure retention of the maximum dose of subretinal VN, so aspiration during
the air–fluid exchange should not be near the retinal injection site(s). All
sclerotomies should be sutured closed and the overlying conjunctiva sutured
to cover the sclerotomies.
Postoperative Care
Postoperatively patients should remain supine for at least 4 hours to minimize
exposure of viral capsid to anterior vitreous structures and to encourage bleb
“spread.”
Complications
As noted above, the safety profile of VN is favorable, and appears to be
largely or entirely related to the standard risks of pars plana vitrectomy,
iatrogenic PVD, and subretinal injection (Table 68-1). Ocular inflammation
appears to be minimal with systemic immunosuppression, and full-thickness
macular holes are uncommon when the surgical technique described above is
utilized. Other potential complications from transvitreal subretinal gene
delivery include chemosis, corneal abrasion, vitreous hemorrhage,
rhegmatogenous retinal detachment, inadvertent subretinal injection of air
bubble, sensitization to the vector, or endophthalmitis. For gene therapies, in
general, there is potential risk of off-target mutagenesis which may vary by
vector.
Outcome Expectations
One of the most challenging aspects of gene therapy trials has been
demonstrating clinical benefit. In the VN phase 3 trial, two types of
assessments were performed (5). The first type was conventional in-office
testing, otherwise known as visual function testing, including visual acuity;
OCT; Goldmann visual field; red, blue, and white full-field light sensitivity
(FST); and pupillometry. The second type of assessment was functional
visual testing, which attempts to simulate and measure performance of a
function of daily living that requires an integration of visual abilities. The
latter was the favored assessment by the FDA and was the primary endpoint
of the trial. The functional visual test that was used was the multiluminance
mobility test (MLMT), which is an obstacle course performed under
controlled lighting and timed conditions. The trial demonstrated marked
improvement in the MLMT in those patients treated with VN (5). As of 2018,
the resulting improvements have persisted at least 4 years after treatment (4).
In the nontrial clinical environment, functional visual testing remains too
time consuming for routine clinical use. Simpler, widely available visual
function tests include visual acuity, visual fields, and FST. Because of
concerns on the part of payers regarding the degree of effectiveness and
durability of treatment with VN, the manufacturer of VN (Spark
Therapeutics, Inc., Philadelphia, PA) has negotiated contracts with some
providers to reimburse payers for the cost of VN in the event that a treated
patient were to not reach a prespecified performance threshold. For most
contracts, two thresholds have been agreed to, an early postoperative measure
to prove effectiveness and a later measure to assure durability. The threshold
is an improvement of FST by 0.3 log units from baseline measured at 60 to
90 days following treatment that remains improved at 3 years (Figure 68-6).
If such a payer provision is in place for an individual patient, the surgeon
should perform baseline testing or, for uncooperative younger patients,
document the inability to perform FST and perform any additional supportive
baseline testing available.
INTRAVITREAL DELIVERY
Basic Considerations for Intravitreal Delivery
Intravitreal delivery is an appealing route for delivery of gene- or cell-based
therapies, and a number of early and late phase clinical trials of gene therapy
utilize intravitreal injection rather than transvitreal subretinal injection
(28–30). Intravitreal delivery reduces the risk of procedure-related
complications and may be preferred when administering a small diffusible
molecular agent, including a gene or RNA-interfering oligonucleotide, when
multiple administrations are needed or when inner retinal delivery is
sufficient to address the disease mechanism. Compared to subretinal injection
using either transvitreal or transchoroidal approaches, intravitreal injections
are quick, inexpensive, easily repeatable, lower risk, and commonly
performed and are usually done with topical or subconjunctival anesthesia
(except in children, see below). As opposed to localized distribution within or
near a subretinal bleb, intravitreal injection may achieve distribution of the
therapeutic agent across the entire retinal surface. Also, the vitreous gel likely
serves as a reservoir for sustained release of therapeutic agents, since
intravitreally injected medications have shorter half-lives and more rapid
clearance in vitrectomized eyes (31).
However, there are some potential drawbacks to intravitreal delivery.
Distribution across the entire retinal surface may not be necessary if the
disease pathology is relatively localized. For example, retinal disorders
primarily affecting cones may be best served by restricting therapeutic
delivery to the macula where cones are most dense (32). Similarly, diffuse
distribution may be irrelevant depending on the stage of disease and its
temporal–spatial progression. Advanced retinitis pigmentosa with only
central macular sparing would likely benefit little from pan-retinal
therapeutic distribution, and efforts would be better spent preserving the
remaining viable macula. Even the potential of utilizing the vitreous gel for
sustained release may actually be disadvantageous for gene therapy, because
it is possible that sustained release could exacerbate neutralizing immune
responses and hence limit transduction of target cells.
Agents dispersed into the vitreous chamber may quickly come into
contact with the ciliary body, lens capsule, zonules, iris, and in fact the entire
anterior segment (22). In contrast, subretinal delivery is thought to restrict the
agent to contacting only retina or RPE; there is the theoretical concern that
agents could reflux out of the retinotomy site (33), but in our experience, with
proper transvitreal surgical technique (see above), reflux does not occur or is
minimal. The widespread ocular distribution resulting from intravitreal
injection can result in persistent transgene expression in anterior segment
tissues (22). Expression in nontarget tissues carries the theoretical risk of off-
target mutagenesis or other unknown deleterious effects, and it is likely
related to the strong immune responses that are induced by intravitreal
injections but less so by subretinal injection (22,34,35). Increased immune
responses to intravitreal injections may limit the efficacy of intravitreal gene
therapy, particularly when a patient has preexisting neutralizing antibodies to
adenovirus-associated vector (AAV) (36). In contrast, even preexisting
neutralizing antibodies to AAV present in intraocular fluids do not limit the
expression of AAV if the vectors are injected subretinally (37).
Perhaps the greatest disadvantages of intravitreal delivery vis-à-vis
subretinal delivery are lower transduction efficiency and a diminished ability
to transduce cells of the outer retina and RPE (38,39). Lower transduction
efficiency necessitates higher doses, which are in turn prone to inducing
stronger neutralizing immune responses. Transduction of the outer retina and
RPE after intravitreal injection is thought to be anatomically constrained by
the internal limiting membrane (ILM) (39,40). Similarly, the ILM may serve
as a barrier against the spread of agents from the subretinal space into the
vitreous and ocular fluids. A number of approaches have been tested in
preclinical studies to facilitate intravitreal transduction of outer retinal cells,
including viral vector modification/mutation (41–45), laser photocoagulation
of the ILM (46), surgical ILM peeling (47), and enzymatic lysis (40). One
group found that vitreous aspiration followed by intravitreal injection resulted
in pan-retinal, full-thickness transduction of AAV2/8 in mice (48). If vitreous
aspiration improves transduction, perhaps pars plana vitrectomy with or
without ILM peel could achieve diffuse retinal transduction, but this is
conjecture. In some inherited retinal diseases, such as juvenile X-linked
retinoschisis, the ILM is thought to be pathologically porous, which may
enable viral vector penetration without any adjunctive measures (29). It is
unclear if this is true for other diseases.
Intravitreal delivery was first performed in 1911 with the injection of air
into the vitreous chamber for pneumatic retinopexy to treat rhegmatogenous
retinal detachments (49). Intravitreal delivery of medications began with
penicillin for endophthalmitis (50). With the advent of anti–vascular
endothelial growth factor (VEGF) agents for a variety of indications
including neovascular age-related macular degeneration (51) and diabetic
macular edema (52), intravitreal injections have become the most commonly
performed procedure in ophthalmology (53). The technique is also being
tested and used in preterm infants for the treatment of retinopathy of
prematurity with anti-VEGF therapy (54). Performing intravitreal injections
for gene therapy in children, especially in those with congenital nystagmus
such as in trials for CEP290-associated LCA (28), impose an increased level
of complexity, as all but the most mature children will require general
anesthesia, albeit brief, because of the need for compliance and suppression
of nystagmus.
Complications
Intravitreal injection is a familiar and low-risk procedure. Potential adverse
effects include injection site discomfort, subconjunctival hemorrhage,
chemosis, corneal abrasion from speculum insertion/disinsertion, cataract,
zonular instability, transient or sustained increase in intraocular pressure,
vitreous hemorrhage, rhegmatogenous retinal detachment, and
endophthalmitis. The same set of adverse effects can result from pars plana
vitrectomy with subretinal injection, although cataract is more common after
pars plana vitrectomy (59) and endophthalmitis is probably more common
after intravitreal injection (60). In children especially, intravitreal delivery is
likely safer and easier than transvitreal subretinal delivery, because surgical
induction of a PVD to access the subretinal space can be challenging in
children. PVD induction is relatively straightforward in children with RPE65-
associated LCA treated with VN (see above), presumably because of an
abnormal vitreoretinal interface, but this may not be the case for other
inherited retinal diseases. Also, many inherited retinal diseases feature
atrophic, fragile retinas, making surgical manipulation of the subretinal space
more prone to complications such as iatrogenic retinal breaks than would be
expected with intravitreal delivery.
TRANSCHOROIDAL SUBRETINAL
DELIVERY
Given the disadvantages of intravitreal delivery and surgical challenges of
transvitreal subretinal delivery, multiple investigators have pursued
transchoroidal subretinal delivery for gene and cell-based therapies. This
approach holds special appeal for therapeutic delivery in children because of
the technical challenges and complications inherent to pars plana vitrectomy
and PVD induction in infants (see above). Also, as for transvitreal subretinal
delivery, with transchoroidal delivery, the therapeutic agent can be placed in
direct apposition with the retina and RPE, which are typically the sites of
dysfunction. Presumably the immune responses to transchoroidal subretinal
delivery would be similarly mild like those induced by transvitreal subretinal
delivery, but this is unknown.
FUTURE DIRECTIONS
Other potential approaches to therapeutic delivery for inherited retinal
diseases that also affect the central nervous system (e.g., neuronal ceroid
lipofuscinoses) are intracerebroventricular or intrathecal routes. Whiting et al.
(69) carried out intracerebroventricular gene replacement in a canine model
of CLN2, which delayed neurologic deterioration but seemed to have
minimal effect on retinal degeneration. Thus, effective treatment of the retinal
component of these disorders will likely require therapeutic delivery to the
intravitreal or subretinal space.
Much is unknown. Will the gains of VN and other gene therapies last a
lifetime? Could eyes be re-treated? Could eyes be treated in many more
retinal sites, or with diffuse subretinal delivery? Moving forward, for those
providing pediatric eye care and advice to families it will be imperative to
distinguish between FDA-sponsored trials and therapies, and rogue clinics
that are pursuing dubious therapies with sometimes devastating results (70).
Ultimately, it will probably be necessary to individualize delivery methods
for gene therapy in various disorders and even in individual patients based on
the primary site of retinal dysfunction, that is, inner versus outer retina,
central versus peripheral retina, integrity of the ILM, retinal fragility, and
other factors. Ideally, children with inherited retinal diseases will be
identified in infancy, receive a rapid genetic diagnosis, and undergo prompt
individualized gene therapy to arrest or reverse their retinal degeneration.
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69
Childhood Ocular Trauma
Mrinali P. Gupta, and Philip J. Ferrone
INTRODUCTION
Ocular trauma is a significant cause of retinal pathology among pediatric
patients. Moreover, pediatric patients in particular are at increased risk of
ocular trauma with approximately 34% of blinding eye injuries in the United
States Eye Injury Registry occurring in patients aged 0 to 19 years of age (1).
A thorough understanding of the retinal manifestations of ocular trauma and
of key differences in epidemiology, diagnosis, management, and prognosis in
children, as compared to adults, is essential to mitigate the risk of vision loss
in this population.
As with any case of eye trauma, there are individual aspects that make it
impossible to provide a definitive flowchart relevant to that patient. This is no
different for pediatric patients; however, there are considerations to be made
in the pediatric age group (ages 0 to 18 years) that include vulnerability of
children and infants and need to gently assess them; challenges obtaining
history in children; need to assure optimal visual outcomes by addressing
amblyopia; need to work in teams including pediatrics, pediatric
anesthesiology, and pediatric ophthalmology; and recognition and addressing
the fact that the eye continues to grow and that trauma and certain
procedures, such as scleral buckling, may impair that growth. This chapter
provides an overview of the epidemiology, evaluation, and management of
the pediatric ocular trauma patient.
Open globe injury involves a full-thickness wound in the eye wall. If the
open globe injury is due to a blunt force, the open globe injury is referred to
as a “rupture.” The mechanism for a rupture is transmission of kinetic energy
from the offending object to the eye, resulting in a transient elevation of the
intraocular pressure, which exceeds the resistance or elasticity of the eye wall
and results in a full-thickness rupture. Open globe injuries generally occur in
the regions where the scleral is weakest—for example, concentric to the
limbus, behind the insertion of extraocular muscles, at the equator, and/or in
areas of prior injury or surgery (e.g., prior extracapsular cataract surgery
wounds). If the open globe injury is due to a sharp object, the injury is
referred to as a “laceration.” A laceration, in turn, may be “penetrating,” in
which there is an entry wound, “intraocular foreign body” (IOFB) in which
there is an entry wound and a retained IOFB, or “perforating,” in which there
is both an entry and an exit wound (Figure 69-1). A combination of injury
types may be present. For example, an explosion may result in several sharp
projectile bodies that cause penetrating injuries into the eye, but only some
may be retained in the globe as an IOFB. Moreover, some of the projectiles
may strike the eye without causing a full-thickness wound but inflict
contusive injuries to the eye (2).
The Ocular Trauma Classification Group has definitions for ocular
trauma that mirror those of the BETTS, except for the addition of a subgroup
that exists within the closed globe injury, called “superficial foreign body,” in
which there is neither a lamellar laceration nor blunt force contusion but
rather a foreign body that does not penetrate the eye wall. An example of this
is a corneal foreign body. In addition, the Ocular Trauma Classification
Group defined three distinct zones of open globe injury. Zone 1 injury
involves the cornea; zone 2 injury involves the region from the corneoscleral
junction (limbus) to 5 mm posterior to the limbus; and zone 3 injury involves
a wound posterior to zone 2. For closed globe injuries, zone 1 involves
external injuries limited to the bulbar conjunctiva, sclera, or cornea, including
conjunctival laceration or corneal abrasion; zone 2 involves injuries to
anterior segment structures up to the posterior lens capsule and includes the
pars plicata, including hyphema or traumatic cataract; and zone 3 injuries
involve the remaining posterior segment structures, including injuries to the
retina or choroid (3).
PREVALENCE OF CHILDHOOD
OCULAR TRAUMA
Much of the data regarding the incidence of serious ocular trauma among
pediatric patients is based upon evaluation of the records of hospitalized
patients. These studies suggest an incidence of 6.8 to 15.2 cases per 100,000
individuals per year (4–7). In the United States, the risk of hospital admission
from eye injury was 6.8 per 100,000 individuals per year for patients aged 18
years and younger (7). The true incidence, however, is likely significantly
higher, since the majority of ocular trauma does not require hospitalization.
Overall, ocular trauma afflicts male patients more than females, and the
disparity increases during the pediatric years and approaches a 4- to 6-fold
higher risk in males by young adulthood (1,4–8). The rate of injuries is higher
later in the pediatric years with a notable increase after age 10 (1,6,7).
Common causes of eye injury among pediatric patients include projectiles,
such as compressed air powered guns such as BB guns and paintball air guns,
fireworks, or thrown projectiles; sports-related injuries; airbag and seatbelt
injuries; bungee cord injuries; and inflicted injury, such as nonaccidental
trauma (see also Chapter 70) (9).
Pediatric open globe injuries are most prevalent between ages 7.7 and
11.6 years of age and exhibit a strong male predilection. In the United States,
pediatric open globe injuries most commonly occur at home and from sharp
objects, such as knives, whereas in developing countries, outdoor injuries are
more common. According to the United States Eye Injury Registry,
approximately 34% of blinding ocular injuries in the database occurred in
patients aged 0 to 19 years, which broke out as 12% in patients aged 0 to 9
years and 22% in patients aged 10 to 19 years. Visual outcomes in the
registry were better among pediatric patients with only 23.5% and 20.5% of
eye injuries in patients ages 0 to 9 years and 10 to 19 years with legal
blindness (<20/200) compared to 31% in patients over 20 years of age.
Among all patients surveyed, the rates of blindness from ocular injuries were
23.1% from contusion, 60% from ruptured globe, 23% from penetrating
trauma, 25% from IOFB, and 64% from perforating trauma (1).
External Evaluation
The periocular tissues should be evaluated for evidence of facial or orbital
trauma including evidence of foreign bodies, lacerations, fractures, or
periorbital or orbital swelling. The position of the globe should be assessed to
evaluate for exophthalmos, enophthalmos, hypoglobus, etc. Evidence of
orbital stepoffs, crepitus, or point tenderness to palpation may suggest an
orbital fracture. Ocular motility should be assessed to evaluate for limitations
in motility consistent with orbital pathology or entrapment of muscles in an
orbital fracture site. Evidence of orbital fracture with entrapment should
prompt an immediate oculoplastics evaluation for early intervention. The lids
should be evaluated for evidence of lacerations, and when appropriate, the
lacrimal system must be evaluated to assess for associated injury to the
lacrimal system, which generally would require repair at the time of the lid
laceration repair. In the setting of full-thickness lacerations, an underlying
associated injury to the globe should be considered. When appropriate, the
lids should be everted to evaluate for foreign bodies. In the setting of an open
globe injury, repair of adnexal injuries should occur after repair of an open
globe injury to avoid undue pressure on eye (10,11).
Conjunctiva
The conjunctiva should be evaluated for lacerations and hemorrhages. The
length and location of conjunctival lacerations should be noted. Small
conjunctival lacerations generally self-resolve and need not require surgery,
whereas surgical closure with absorbable suture should be considered in
larger conjunctival lacerations (10,11).
Sclera
In the presence of a conjunctival laceration, the underlying sclera should be
carefully evaluated for scleral wounds suggestive of an open globe injury.
Bullous or widespread subconjunctival hemorrhage may suggest an
underlying scleral injury. The decision to surgically explore these cases
depends on the ability to obtain a sufficient examination, including dilated
fundus examination, the mechanism of injury, and other findings noted on
clinical examination or imaging. For example, an exploration may not be
necessary for a low-risk mechanism of injury with normal intraocular
pressure, an unrevealing dilated fundus examination, and a formed globe on
imaging tests. On the other hand, an exploration would be indicated in the
setting of a high-risk mechanism of injury, such as an injury from a sharp
object concerning for a penetrating injury with bullous subconjunctival
hemorrhage and an associated vitreous hemorrhage (10,11). In such cases, the
sclera should be carefully inspected to evaluate for scleral wounds suggestive
of open globe injury. The presence of such a wound should prompt surgical
repair under anesthesia as described below.
Cornea
The cornea should be evaluated for abrasions, lacerations, and foreign bodies.
Fluorescein staining may reveal corneal abrasions, which may be managed
conservatively with antibiotic drops and cycloplegics with or without a
bandage contact lens. Superficial corneal foreign bodies may be removed at
the bedside, although doing so may require sedation or anesthesia in younger
patients. Deeper foreign bodies may be more difficult to remove and deeply
embedded inert and clean foreign bodies may be left intact, especially if
outside the visual axis. Antibiotic drops and cycloplegia may be prescribed
for the associated epithelial defect (10,11).
Corneal lacerations should be evaluated to determine whether the defect
is lamellar or full thickness. Seidel testing with or without gentle pressure on
the globe may be performed to assess for a full-thickness defect. Partial-
thickness lacerations may be treated with antibiotic drops and cycloplegia,
whereas full-thickness lacerations require treatment. Treatment options for
such lacerations include conservative management with a rigid eye shield,
bandage contact lens, antibiotics, and aqueous suppressants for small and/or
self-sealing wounds. Most full-thickness lacerations, however, require repair
either with glue or surgically. Please see below for a detailed discussion of
surgical technique for repair of zone 1 open globe injuries, that is, corneal
lacerations.
Anterior Chamber
Anterior chamber depth should be assessed. A shallow anterior chamber may
suggest an open globe injury or posterior pressure due to anteriorly dislocated
lens or choroidal hemorrhage or effusion. An excessively deep anterior
chamber may suggest a posterior ruptured globe or posteriorly dislocated lens
(10,11).
The anterior chamber should also be evaluated for presence of cells
suggestive of traumatic iritis or microhyphema. Presence or absence of a
layering hyphema and its vertical height should be noted. The annual
incidence of hyphema is approximately 17 per 100,000 individuals (12).
Two-thirds occur in the setting of blunt trauma, while one-third occur in the
setting of penetrating or perforating injuries (13,14). The most common cause
of pediatric traumatic hyphema is sports-related injury (13,14). In the setting
of hyphema, a medical history or family history of sickle cell should be
elicited, and a sickle cell prep or hemoglobin electrophoresis obtained in
patients is at risk. The risk of rebleeding is highest in the first 4 to 7 days
after injury, and studies have associated rebleeding with worse prognosis
(15). Some clinicians, therefore, recommend restriction of activities,
binocular patching, and/or placement of a shield over the eye to reduce ocular
motility and to reduce the risk of activity- or repeat trauma-induced rebleed.
However, there remains no evidence to support these interventions (15).
Management of hyphema involves elevation of the head of the bed,
cycloplegia, and topical steroids with close monitoring and management of
the intraocular pressure. Indications for anterior chamber washout for
hyphema include uncontrolled intraocular pressure despite maximal medical
therapy (>50 mm Hg for 5 days or >35 mm Hg for 7 days; in patients with
sickle cell disease, >25 mm Hg for over 24 hours), total hyphema for more
than 5 days, corneal blood staining, and/or large clots that persist for more
than 10 days (16). General principles for anterior chamber washout include
irrigation of the anterior chamber through a single paracentesis or placement
of an anterior chamber infusion with irrigation or removal of hemorrhage
using a vitrector through a two paracentesis approach. The latter is
particularly effective in cases of clotted hemorrhage. Patients with traumatic
hyphema are at risk for angle recession and glaucoma. Thus, gonioscopy
should be performed after clearance of the hyphema (12,17,18). Hyphema
and the associated inflammation can also result in posterior or peripheral
anterior synechia, especially in hyphemas of longer duration.
The presence of a foreign body and/or lens material concerning for
anterior capsular injury should be noted. The repair of such injuries as
outlined in further detail below.
Iris
The shape and position of the pupil should be noted. Presence of iridodialysis
or cyclodialysis should be noted. A peaked pupil may suggest a penetrating
or perforating injury. Retroillumination should be performed to assess for iris
transillumination defects, especially in cases where an IOFB is suspected
based on the mechanism of injury. For example, small foreign bodies may
result in self-sealing corneal wounds that are difficult to identify on
examination. The only evidence of a foreign body on clinical examination
may be indirect signs, such as the presence of hyphema, an iris
transillumination defect, and/or focal cataract or anterior capsular injury. As
noted above, iris prolapse noted during repair of an open globe injury is best
managed by repositing the tissue using a blunt instrument such as a
cyclodialysis spatula and viscoelastic, as needed. This may be accomplished
with less trauma by sweeping the iris out of the wound internally through a
separate paracentesis wound rather than externally from the wound itself. If
the IOP is too high, the iris may not reposit until the pressure is reduced. Iris
injury is generally not addressed during primary repair but may be
subsequently performed for repair of visually significant iris defects in eyes
with reasonable visual potential (10,11).
Lens
The position, clarity, and stability of the lens should be evaluated. The
presence of anterior or posterior capsular defects, focal or diffuse cataract,
and/or intralenticular foreign body should be evaluated. An anteriorly
subluxed lens generally requires surgical removal to avoid corneal
decompensation or IOP elevation. A posterior subluxed lens with intact
capsule may be left intact or may be removed in a nonurgent fashion. A
traumatic cataract without capsular violation may be scheduled for surgical
removal by a pediatric ophthalmologist or by a vitreoretinal surgeon if there
is concern for zonular weakness necessitating a posterior approach. The
timing of such intervention is dependent upon amblyopia considerations
based on the age of the patient and severity of the cataract. Cases with
capsular violation require more urgent management since the exposed lens
particles incite a robust inflammatory phacoanaphylactic or phacoantigenic
response. When present, such inflammation should be controlled with
aggressive topical steroids and cycloplegia until the lens is removed. In the
setting of an open globe injury that necessitates repair, the open globe injury
may be addressed prior to removal of the traumatic cataract. Anterior
capsular defects with cataract may be addressed through an anterior limbal
approach with anterior vitrectomy and posterior capsulotomy. A lens injury
with posterior capsular defects is best addressed through a posterior approach
using vitreoretinal surgery. The decision regarding whether or when to place
an intraocular lens depends on the age of the patient and the extent of other
ocular injuries. As with all pediatric ocular diseases, refractive and amblyopia
management are central to maximizing visual potential in eyes with lens
injuries (10,11).
Diagnostic Studies
Ancillary imaging studies may be useful to evaluate the pediatric patient with
an ocular injury. B-scan ultrasonography should be avoided in cases of a
known open globe injury, as pressure on the globe may promote further
extrusion of intraocular tissues. Ultrasound may be useful in closed globe
injuries or in cases of small eye wall wounds with low risk of tissue
extrusion. B-scan ultrasonography may reveal the presence of lens
dislocation, IOFB, vitreous hemorrhage, or retinal tear or detachment in eyes
in which media opacity limits the ability to use indirect ophthalmoscopy. B-
scan alone should not be relied upon to rule out IOFB. CT scan should be
considered in known or suspected open globe injuries, potential intraocular or
intraorbital foreign bodies, or in cases where orbital pathology is suspected.
Metal and glass are hyperdense on CT scan, while wooden and organic
matter are hypodense (10,11). The sensitivity of CT scan for identification of
IOFB is high, approximately 94.9% in one study (19). MRI may also be
considered but should be avoided in the setting of potential metallic or
ferromagnetic foreign bodies. MRI can be useful for confirming the presence
of a hypodense IOFB such as wood, which can be mistaken for air on CT
scan (20). Additional retinal imaging studies, such as optical coherence
tomography (OCT), fluorescein angiography, indocyanine green
angiography, and fundus autofluorescence, are generally not used in acute
settings of trauma and are detailed under the relevant posterior segment
manifestations below.
POSTERIOR SEGMENT
MANIFESTATIONS AND TREATMENT
OF PEDIATRIC OCULAR TRAUMA
Except in the case of a known ruptured globe, a dilated fundus examination
with indirect ophthalmoscopy should be performed to evaluate for vitreous
hemorrhage, IOFB, retinal hemorrhage, retinal dialysis, breaks, or
detachment, commotio retinae, traumatic macular hole, choroidal rupture,
and/or traumatic chorioretinal rupture. Except in the case of a suspected open
globe injury or hyphema, a scleral depressed examination should be
considered to evaluate for anterior retinal pathology, such as retinal dialysis,
breaks, or detachments. An EUA should be considered in cases in which a
sufficient evaluation cannot be performed at the bedside. If an open globe
injury is suspected, early management includes placement of a protective
rigid eye shield and limitation of activity. The tetanus vaccination status
should be determined, and a tetanus shot or booster should be administered
based on the vaccination status and mechanism of injury. Diagnostic studies
and systemic and anterior segment considerations are addressed above.
Please see below for a detailed discussion regarding the diagnosis and
management of specific posterior segment manifestations of trauma.
Equipment
Extraocular tray
Relevant sutures (e.g., 10-0 nylon for zone 1 injuries, 9-0 nylon for zone
2 injuries, and 8-0 nylon for zone 3 injuries; 2-0 silk for hooking
extraocular muscles; 6-0 Vicryl sutures for removal and replacement of
extraocular muscles; 7-0 Vicryl or 6-0 plain gut sutures for conjunctival
closure)
Viscoelastic material as needed for globe reformation
Vitrectomy system (in the setting of IOFB)
Foreign body forceps, rare earth magnet, Finesse flex loop (Alcon, Ft.
Worth, TX), or other instruments as needed for removal of an IOFB
Intraocular gas or oil tamponade as needed for IOFB cases
Scleral buckle and tray, if indicated
Subconjunctival or intravitreal (e.g., vancomycin 1 mg in 0.1 cc and
ceftazidime 2.25 mg in 0.1 cc) antibiotics
Postoperative Care
After surgery, the eye should be dressed with antibiotics and a sterile patch
and shield. During the postoperative period, the patient is monitored to
evaluate for leaks from wounds and for secondary complications, such as
retinal detachment and/or infection. A protective shield should be kept on the
eye for at least the 1st week to reduce the risk of pressure on the globe that
might result in a wound dehiscence and fluid or ocular contents leaking from
the open globe injury site. A standard regimen of topical steroids,
cycloplegics, and antibiotics should be administered. There is no consensus
on systemic antibiotic therapy after open globe repair. The fellow eye should
be monitored in the long term for development of sympathetic ophthalmia.
Amblyopia should be managed in collaboration with a pediatric
ophthalmologist. Monocular precautions and protective eyewear should be
recommended to protect the fellow eye. Subsequent EUAs may be required
to adequately evaluate the eye postoperatively and/or to remove sutures.
Complications
Complications of open globe injury include anterior segment complications,
such as corneal scar or cataract, endophthalmitis, sympathetic ophthalmia,
nonclearing vitreous hemorrhage, choroidal hemorrhage, retinal tear, retinal
detachment, and PVR.
The incidence of endophthalmitis following open globe injury in patients
of all ages ranges from 0% to 16.5%, with increased risk associated with
penetrating injury, IOFB, delay in wound closure over 24 hours from the time
of injury, injury in a rural setting due to the microbes inoculated, and
ruptured lens capsule (26). Commonly associated microbial agents include
Staphylococcus, Bacillus, Streptococcus, Clostridium, Pseudomonas,
Candida, Aspergillus, Paecilomyces, Fusarium, and dematiaceous fungi
species and polymicrobial infections may occur (26).
Studies of pediatric patients with open globe injuries have described an
incidence of retinal detachment of 25% to 31% (27,28). Risk factors for
retinal detachment after an open globe injury in the pediatric patient are
similar to those in adults and include higher zone, that is, more posterior
injury, longer wound length, vitreous hemorrhage, rupture versus laceration,
and retained IOFB (27). In addition to vitreous prolapse and retinal
incarceration, other important mechanistic factors for retinal detachment after
open globe injury include vitreous hemorrhage, secondary inflammation, and
vitreous scaffolding and traction (29).
Outcome Expectations
Studies suggest that 54% to 56% of pediatric open globe injuries achieve a
final vision of 20/40 or better (30–32). Studies have previously reported
scoring systems to predict visual outcome after ocular injury. The ocular
trauma score (OTS), based on data from the United States Eye Injury
Registry, identified poor initial visual acuity, ruptured globe, perforation,
endophthalmitis, retinal detachment, and presence of afferent pupillary defect
as poor prognostic indicators (33). More recently, a pediatric OTS (POTS)
score was reported, in which the impact of visual acuity on score was de-
emphasized in patients in whom visual acuity could not be obtained. Other
factors included in the POTS score include age (younger age portending a
worse prognosis), zone of injury (higher zone associated with worse
prognosis), presence or absence of unclean injury, delay in surgery >48
hours, and presence or absence of associated ocular findings including iris
prolapse, hyphema, traumatic cataract, vitreous hemorrhage, retinal
detachment, and/or endophthalmitis (34). A toddler/infant OTS (TOTS),
which does not include visual acuity given the difficulty of assessing this
metric in infants and toddlers, included only wound size >6 mm and presence
or absence of hyphema, cataract or lens damage, retinal detachment, and
choroidal detachment in scoring and produced a sensitivity of 81% in
predicting visual outcome (35).
Indications
Vitreous hemorrhage and/or retinal detachment after an open globe injury
usually warrants vitrectomy surgery with or without scleral buckle. Vitreous
hemorrhage has been noted in 3.3% to 34% of pediatric open globe injuries
(36). As with adult patients, vitreous hemorrhage associated with open globe
injury, especially that involving zone 2 or zone 3, has a higher risk of
posterior segment pathology, which can result in subsequent retinal
detachment. Thus, these cases often require urgent surgical vitrectomy.
Retinal detachment after blunt injury can occur from a dialysis, retinal
tear, and development of PVR. Depending on the reason, retinal detachments
are treated with a scleral buckle or vitreoretinal surgery. Traumatic macular
hole may also warrant vitreoretinal surgery.
Equipment
Vitrectomy system
Triamcinolone acetonide injectable suspension, if needed to confirm
facilitate PVD induction (e.g., Triesence, Alcon, Ft. Worth, TX)
Additional instrumentation as needed for to induce and carry out the
PVD (pick, bent microvitreoretinal [MVR] blade, a Finesse flex loop
[Alcon, Ft. Worth, TX], and/or forceps)
Endolaser probe
Internal diathermy
PFO heavy liquid, if needed
Tamponade: intraocular gas (SF6, C3F8) or silicone oil
Scleral buckle and tray, if indicated
Procedural Techniques
In cases of vitreous hemorrhage after open globe repair, small-gauge pars
plana vitrectomy may be performed to evacuate the hemorrhage and address
underlying retinal pathology. A PVD may be induced if readily able or if
necessary to address concurrent underlying retinal pathology, such as
tractional/rhegmatogenous retinal detachment. A scleral depressed
examination should be performed to evaluate for peripheral breaks, and if
found, they should be treated with endolaser and tamponade, as necessary. A
prophylactic scleral buckle surgery may be considered particularly in
conditions with some aspect of blunt force. In perforating injuries in eyes of
infants or young children, in which an IOFB is in the orbit and is rendered
too traumatic to remove, release of tractional vitreous forces between the
anterior and posterior wounds can be helpful to reduce later complicated
tractional retinal detachments. Management of amblyopia is important.
In cases of retinal detachment following open globe injury, the central
principles are (a) to identify and treat retinal breaks and (b) to relieve vitreous
traction on the breaks. Disruption of the vitreous or hemorrhage in an open
globe injury predisposes to later inflammation with vitreous organization and
contracture, retinal breaks, detachments, and PVR. A scleral buckle should be
considered prior to vitrectomy. By supporting the vitreous base, a scleral
buckle can relieve tractional forces at the anterior vitreous. Small-gauge
vitrectomy should be performed to remove vitreous hemorrhage and
organized vitreous associated with retinal detachments after open globe
injury. A posterior cortical vitreous separation may be induced as a PVD, if
possible, and vitreous traction must be relieved from the retinal breaks.
Maneuvers that can facilitate PVD induction in the pediatric population
include vitrectomy with triamcinolone acetonide injectable suspension to
stain the vitreous and make it easier to identify the vitreous face to create a
PVD without vitreous schisis. Additional instruments such as a pick, bent
MVR blade, a Finesse flex loop, and/or forceps may be used to create an
initial opening in the hyaloid to facilitate its separation from the retinal
surface. Scleral depression can be used to identify and relieve traction on all
retinal breaks and areas of concern. If significant anterior membranes are
present, lensectomy should be considered to enable adequate relief of anterior
vitreous traction. Subretinal fluid should be drained from existing internal
breaks and the breaks treated with laser. Intraocular gas, generally C3F8, or
silicone oil tamponade should be placed depending on the location of the
breaks, presence or absence of PVR, and the patient’s age and ability to
position. Silicone oil tamponade is often required in younger patients in
whom positioning may be difficult. An inferior surgical iridotomy should be
performed in eyes receiving silicone oil that were rendered aphakic from the
open globe injury or surgically. Retention sutures (9 or 10-0 Prolene) may be
considered in aniridic eyes undergoing placement of silicone oil. There are no
studies comparing outcomes with and without retention sutures in aniridic
eyes with silicone oil tamponade.
Postoperative Care
Postoperative care focuses on monitoring for retinal detachment, PVR,
infection, and complications of silicone oil. A postoperative regimen of
topical steroids, cycloplegia, and antibiotics should be administered. Based
upon the patient’s age and ability to position, positioning should be
recommended after retinal detachment repair to provide optimal tamponade
at the retinal breaks and to reduce complications of intraocular tamponade.
Amblyopia should be managed in collaboration with a pediatric
ophthalmologist. Monocular precautions and protective eyewear should be
recommended to protect the fellow eye. Subsequent EUAs may be required
periodically to properly examine the young patients.
Outcome Expectations
Parents should be counseled regarding the guarded anatomic and functional
prognosis for retinal detachment repair after open globe injury in the pediatric
population. Studies indicate a significantly lower success rate compared to
retinal detachment after closed globe injury, with anatomic success rates in
open globe associated retinal detachments of 21% to 46.7% (27,41–43).
Anatomic failure in these studies was generally due to new breaks or PVR
(41,43). The risk of PVR is significant with some studies reporting up to 64%
of eyes exhibiting grade C or worse PVR at initial presentation. PVR remains
a major risk factor for anatomic failure (43,44). As with all pediatric ocular
pathology, amblyopia may significantly impact final visual outcome in open
globe injury.
Vitreous Hemorrhage
Pediatric patients may also present with vitreous hemorrhage without an open
globe injury. In a large series of pediatric vitreous hemorrhages at a single
center, 73% were attributable to trauma, including 29.5% from
nonpenetrating trauma, 24.7% from penetrating trauma, 8.6% from
nonaccidental trauma, 5.4% noted postoperatively, and 4.8% associated with
birth trauma (45). Vitreous hemorrhage may occur in isolation or may
commonly be associated with other findings such as hyphema, traumatic
cataract or lens dislocation, and/or open globe injury with or without IOFB.
Vitreous hemorrhage or hemorrhage into a schisis cavity may also occur in
the setting of mild trauma in eyes with retinoschisis. Evaluation of these
patients includes appropriate history and evaluation of the eye and ocular
adnexa for associated injuries. Dilated fundus examination with scleral
depression should be performed to assess for associated retinal pathology
such as retinal tears, retinal dialysis, or retinal detachment, and an EUA
should be considered in patients in whom a sufficient bedside examination
with scleral depression is not possible. When vitreous hemorrhage obscures
the retinal evaluation, B-scan ultrasonography should be employed to
evaluate for evidence of retinal tears and detachments.
Vitreous hemorrhage in the absence of open globe injury or associated
retinal pathology may be observed for several months for clearance in older
pediatric patients before pursuing surgery. Due to the formed nature of the
pediatric vitreous, the hemorrhage may be less likely to disperse and is
slower to resorb than in adults. However, it should be noted that vitreous
hemorrhage may result in development of an epiretinal membrane, and
organization of the vitreous hemorrhage over time may produce secondary
vitreous traction and retinal detachment. Earlier intervention should be
considered in cases with high suspicion of associated retinal pathology
warranting treatment based on clinical exam and mechanism of injury. Due to
amblyopia considerations, earlier intervention should also be performed in
pediatric patients age 6 to 8 years and younger, especially those with dense
vitreous hemorrhage or hemorrhage involving the visual axis. Specifically,
extrapolating from the congenital cataract data, irreversible damage from
occlusive amblyopia may occur as early as 6 to 8 weeks in young infants
(46,47). Moreover, occlusion by vitreous hemorrhage may also induce a high
degree of anisometropic amblyopia in infants, which can persist even after
the vitreous hemorrhage clears or removed (48,49). Given the inability to
determine precise onset of media opacity in older patients, there are limited
data on the precise timeline for irreversible occlusive amblyopia in older
patients. Surgical techniques are similar to those described above under
vitrectomy for vitreous hemorrhage from open globe injury.
Retinal dialysis
Retinal dialysis is the most common type of retinal break in pediatric patients
and has been implicated in 14% to 33% of all pediatric retinal detachments
(50,54). While most are associated with trauma, in some cases a definitive
trauma history cannot be elicited. A dialysis is a circumferential disinsertion
of the retina at the ora serrata. A dialysis may be differentiated from a giant
retinal tear by the location relative to the vitreous base: a dialysis is a defect
anterior to the posterior insertion of the vitreous base, whereas a giant retinal
tear is a defect posterior to the posterior insertion of the vitreous base. Most
retinal dialyses are located inferotemporally. Additional breaks may be
present. In the pediatric patient with formed vitreous and absence of a PVD,
progression of the dialysis can be slow with delayed onset of development of
the dialysis-associated retinal detachment (57,58). In one study, 41% of
retinal detachments were diagnosed more than 1 year after the trauma (59).
Associated findings include demarcation lines and/or retinal cysts. PVR is
rarely encountered. Scleral indentation examination of the trauma patient is
essential for detecting a retinal dialysis. Management of retinal dialysis
generally involves surgical repair with scleral buckle, generally with
cryopexy along the dialysis edge (57,58,60) (Figure 69-2A). Segmental
elements can treat the dialysis effectively, while averting some of the
concerns associated with encircling scleral bands, such as myopic shift with
anisometric amblyopia and/or need to divide the buckle in a subsequent
surgery to enable growth of the globe in infants and very young children.
Subretinal fluid drainage may not be necessary but is considered for larger
detachments and those with chronic, viscous fluid. PVR is rare, and single-
surgery success rates are high (59,61–63).
Equipment
25G vitrectomy set (consider 25G small instrumentation)
Triamcinolone acetonide injectable suspension if needed to confirm or
facilitate PVD induction (e.g., Triesence, Alcon, Ft. Worth, TX)
Indocyanine green or brilliant blue stain
Internal limiting membrane (ILM) forceps
Additional instrumentation as needed for PVD induction or ILM peel
initiation (pick, bent MVR blade, Finesse flex loop [Alcon, Ft. Worth,
TX], and/or forceps)
Tamponade: intraocular gas (SF6, C3F8) or silicone oil
Procedural techniques
Surgical management of idiopathic macular holes has been highly successful
and centers upon addressing the pathophysiologic anteroposterior and
tangential tractional forces on the retina through pars plana vitrectomy with
removal of the posterior hyaloid and in most cases, the ILM (76). In contrast
to idiopathic macular holes, the role of vitreous traction in traumatic macular
hole is unclear and likely variable. Nonetheless, a similar surgical approach
to idiopathic macular hole surgery involving pars plana vitrectomy with
removal of the posterior vitreous, gas tamponade, and prone positioning has
been employed for traumatic macular hole with success rates ranging from
45% to 100% (median 92.5%) in small case series. Although most of these
series did not include pediatric cases exclusively, the mean ages in these
series was low, ranging from 10 to 32 years (77).
Surgical principles for traumatic macular hole are similar to those for
idiopathic macular hole. Pars plana vitrectomy with complete removal of the
posterior hyaloid is critical. Pediatric patients pose a particular challenge for
PVD induction due to the well-formed vitreous humor and the strong
adhesion of the posterior hyaloid. Complete removal of the vitreous can be
challenging, in some cases with an apparent Weiss ring noted but only a
lamellar separation of the vitreous with a residual outer layer of cortical
vitreous remaining on the retinal surface. Moreover, complications during
PVD induction can result in iatrogenic retinal breaks, retinal trauma, and/or
hemorrhage. In contrast to adult patients, retinal breaks in pediatric patients
may incite intense PVR with potentially catastrophic ocular outcomes.
Maneuvers that may facilitate PVD induction in the pediatric population
include vitrectomy using triamcinolone acetonide injectable suspension to
stain the vitreous and make it easier to identify the vitreous face to create a
PVD without vitreous schisis. In addition to the vitreous cutter, additional
instruments such as a pick, bent MVR blade, Finesse flex loop, and/or
forceps may facilitate creation of an opening in the hyaloid from which to
carry out the PVD induction.
In light of the difficulties achieving PVD induction in the pediatric
population, surgeons have also used adjunctive agents including autologous
plasmin and ocriplasmin (Jetrea, ThromboGenics, Iselin, NJ) for enzymatic
vitreolysis. Plasmin is a protease that can facilitate PVD by lysing fibronectin
and laminin, two components of the vitreoretinal attachment (78). Margherio
et al. reported four cases of pediatric traumatic macular hole closure after 0.4
international units of autologous plasmin-assisted pars plana vitrectomy with
C3F8 gas and face-down positioning for 2 weeks (79). In this study and
others, surgeons have reported improved ease of PVD induction and high
rates of closure of pediatric traumatic macular hole in plasmin-assisted pars
plana vitrectomy (79–81). One disadvantage of plasmin is the technical and
logistical limitations of generating autologous plasmin from the patient’s
blood. Ocriplasmin is a recombinant truncated form of plasmin with
proteolytic activity against fibronectin and laminin that was FDA approved
for the treatment of adult patients with vitreoretinal traction and/or macular
hole. In a single-center, randomized, place-controlled, double-masked phase
2 study, ocriplasmin (175 μg) versus placebo was administered to pediatric
patients prior to vitrectomy. Of the 22 patients included, one patient
randomized to the ocriplasmin group underwent surgery for traumatic
macular hole. There was no significant difference noted in rates of total
macular PVD, vitreous liquefaction grade, adverse effects in ocriplasmin
versus placebo-treated eyes, or a difference in the duration of vitrectomy. The
study was limited by the heterogeneous nature of the study population and
small sample size. Of note, one patient in the ocriplasmin group developed
zonular dehiscence with lens subluxation (82). While the patient had anterior
segment dysgenesis at baseline, other reports have demonstrated zonular
instability after ocriplasmin. Other ocular adverse effects noted in the adult
ocriplasmin population include retinal tear, retinal detachment, retinal
vascular findings, electroretinogram abnormalities, and abnormalities in the
ellipsoid zone (83). Overall, the use of ocriplasmin for enzymatic vitreolysis
for pediatric vitreoretinal surgery is limited by preliminary data
demonstrating efficacy and safety.
Consistent with the management of macular holes at the time, early
reports of surgery for pediatric traumatic macular hole did not involve ILM
peeling per se. However, the surgical technique frequently involved removal
of “epiretinal membranes” using tools such as the diamond-dusted membrane
peeler (80,84). Such maneuvers may have removed not only residual cortical
vitreous but also some of the ILM. ILM peeling has been shown to
significantly improve the closure rate and visual outcomes in idiopathic
macular holes (85–87). ILM peeling may reduce tangential traction on the
macular hole and may further confirm complete removal of cortical vitreous
and/or epiretinal membranes from the retinal surface. Moreover, ILM peeling
may increase retinal compliance and/or stimulate glial cell proliferation.
Indeed, ILM peeling has become a routine technique for macular hole
surgery as has the use of adjuvants for staining the ILM, such as indocyanine
green, triamcinolone acetonide, and brilliant blue (88–90). ILM peeling is
also routinely employed for surgical repair of traumatic macular holes, and
successful closure of traumatic macular holes, including pediatric macular
holes, has been described with ILM peeling (91,92) and inverted ILM flap
technique for large traumatic macular holes (93).
Intraocular gas tamponade using air, SF6, or C3F8 with prone positioning
has also become standard in surgical repair of idiopathic and traumatic
macular holes. The surface tension of the gas is hypothesized to provide a
seal that prevents reaccumulation of intraretinal fluid as the hole closes as
well as to provide a scaffold for hole closure. There remains debate regarding
optimal tamponade (none, air, SF6, C3F8) and the required duration of
positioning (86,94–101) although the general practice is to use gas
tamponade with a few days or more of prone positioning. Silicone oil
tamponade may also be used, especially in young children in whom
positioning can be difficult. Although studies in idiopathic and traumatic
macular holes suggest worse outcomes with silicone oil tamponade than with
gas tamponade, these studies are limited by their retrospective nature and
potentially worse patient and ocular factors at baseline (102,103). Based on
these considerations, potential side effects from oil, and the need for a second
surgery for removal of the oil, the use of silicone oil is generally reserved for
cases such as large holes, recurrent holes, holes that previously failed closure
after surgery, or in patients such as young children who cannot position
effectively.
Early series describing surgery for traumatic macular holes employed
adjunctive agents including transforming growth factor β (TGF-β) and
platelet concentrates, such as autologous platelet rich plasma (92,104,105).
Autologous platelet rich plasma is obtained by centrifuging the patient’s own
blood and collecting the platelet-rich plasma supernatant, which is applied
into the macular hole using a soft-tip cannula. These adjunctive agents are
thought to facilitate hole closure by stimulating fibroglial proliferation at the
edge of the macular defect. These agents may also provide intrinsic adhesion
support similar to that achieved by the tamponade with facedown positioning.
Subsequent studies demonstrated successful closure of traumatic macular
holes using standard techniques, such as pars plana vitrectomy with or
without ILM peeling and prolonged gas tamponade with face down
positioning (80,84). Although some surgeons report successful closure of
macular holes, including pediatric traumatic macular holes, using autologous
platelets or autologous platelet rich plasma (106,107), there are no studies
comparing surgical outcomes with versus without use of these adjunctive
agents. Nonetheless, these agents may be considered for chronic, large, or
recurrent holes or in pediatric patients who are unable to position.
Postoperative care
A postoperative regimen of prone positioning and topical steroids,
cycloplegia, and antibiotics should be administered. There remains debate
regarding optimal duration of positioning (86,94–101) although the general
practice is to employ a few days or more of prone positioning. In children,
the use of cell phone and iPad video games may help them maintain their
eyes in a facedown position. The patient should be monitored for closure of
the macular hole as well as potential complications such as retinal
detachment, infection, and when applicable, complications of silicone oil
tamponade.
Outcome expectations
Traumatic macular holes may close spontaneously in 10% to 44% in all ages
(68,72–74) and up to 50% in pediatric patients (73). There are limited data on
outcomes in pediatric traumatic macular holes specifically. However, the
literature of surgical outcomes after traumatic macular hole surgery, in which
a majority of subjects were children, suggests anatomic closure rates ranging
from 45% to 100% (70,73,77,79,80,84,91,104,105). Since traumatic macular
holes are frequently encountered with other posterior segment manifestations
of trauma, the contribution of other pathologies that may impact visual
prognosis must be considered. Depending on the duration of the macular hole
prior to closure, amblyopic considerations may also affect prognosis.
Commotio Retinae
Commotio retinae, also known as Berlin edema, was first described by Berlin
in 1873 as transient opacification of the outer retina following blunt ocular
trauma. Patients may be asymptomatic or report visual impairment at
presentation (108,109). Histopathologic and ultrastructural analysis of
commotion retinae have demonstrated that areas of opacification most
commonly found contrecoup or opposite from the site of impact correspond
to fragmented photoreceptor outer segments and damaged photoreceptor cell
bodies (110–112). Initially, commotio retinae presents clinically with a gray-
white opacification of the retina, sometimes with associated RPE mottling
(110–112). Involvement of the foveal region may manifest with a cherry red
spot. The OCT at initial diagnosis can reveal intraretinal edema and
hyperreflectivity of the inner segments, outer segments, and/or RPE. In some
cases, the intraretinal edema and hyperreflectivity also extends into the inner
retinal layers. Subsequently, outer receptor damage promotes RPE migration
and phagocytosis of damaged photoreceptors, leading to the clinical
appearance of RPE atrophy and areas of hyperpigmentation after resolution
of the retinal whitening (Figures 69-2A,B and 69-3A,B). OCT can
demonstrate areas of increased hyperreflectivity or disruption of the
photoreceptor inner and outer segments and RPE, and in some cases, retinal
thinning. There is no known treatment. The degree of long-term impact to the
visual acuity and visual field depends on the region of retina involved and the
degree of photoreceptor damage that ensues (108,109).
Choroidal Rupture
Choroidal rupture is a break in the choroid, Bruch membrane, and the RPE
due to trauma. Choroidal ruptures typically occur from blunt globe trauma
but have also been reported in the setting of open globes. In the largest
reported series of choroidal ruptures, including 111 cases at a single
institution, 72% occurred from closed globe injuries (113). Patients with
angioid streaks may be at increased risk for traumatic choroidal rupture
owing to the calcified and weakened Bruch membrane (114).
The predominating theory regarding pathophysiology of choroidal
rupture involves an indirect injury in which traumatic anteroposterior
deformation of the globe results in expansion of the eye equatorially. This
creates a shear force that is centered at, and radiates concentrically from the
optic disc. This results in rupture of the choroid, Bruch membrane, and RPE
that is most commonly crescent shaped, posterior, and concentric to the optic
disc. Rarely, a rupture may occur due to direct injury at the site of contact
with the globe. These ruptures are anterior and parallel to the ora serrata. The
retina is spared due to its elasticity, whereas the sclera is spared due to its
rigidity (108,115). Rupture of the retina in addition to the choroid, Bruch
membrane, and RPE is a distinct entity known as chorioretinitis sclopetaria
(see below). While most patients present with a single choroidal rupture,
multiple choroidal ruptures have been noted in 18% to 39% of cases
(113,116,117).
Choroidal rupture may be obscured at the time of the trauma due to
overlying subretinal hemorrhage. As the hemorrhage resorbs, the choroidal
rupture may be noted as a curvilinear, crescent-shaped yellow line, often with
tapered edges (Figure 69-2A). As noted above, the ruptures may be
concentric to the optic disc or may be found peripherally, parallel to the ora
serrata. In rare cases, a rupture may occur radially in the horizontal meridian.
With time, the ruptures may evolve into white streaks with RPE hyperplasia
at the margins. Fluorescein angiography reveals early hypofluorescence in
the area of rupture due to disruption in the choroidal signal. The normal
choriocapillaris at the edge of the margin may leak into the scar resulting in
late hyperfluorescence and staining (109,118). Indocyanine green
angiography may demonstrate rupture sites obscured by hemorrhage and
reveals hypocyanescence in all phases (118). Fundus autofluorescence will
reveal hypoautofluorescence in the region of the rupture due to the absence of
RPE in this area (Figure 69-2B). The margin of the rupture may reveal
hyperautofluorescence due to RPE hyperplasia at the edges (Figure 69-2B)
(119,120). OCT through the choroidal rupture may reveal the defect (Figure
69-2C). Two OCT patterns have been described, including a disruption in the
RPE or the RPE–choriocapillaris associated with (a) a forward protrusion of
the RPE–choriocapillaris layer resulting in a pyramid or dome shape or (b) a
posteriorly concave defect with loss of the overlying ellipsoid zone and
external limiting membrane (121). The extent of visual impairment after
resolution of hemorrhage correlates strongly with the location of the defect
and whether if it is foveal or extrafoveal (109,113,116).
Management of traumatic choroidal rupture centers upon monitoring for
and prompt treatment of secondary choroidal neovascularization (CNV).
CNV has been reported in 10% to 20% of choroidal ruptures, and the risk has
been reported to be higher among those with longer choroidal ruptures
(113,116). CNV may be evident by clinical evidence of a greenish-gray CNV
membrane (CNVM) under the retina or by associated intraretinal or
subretinal fluid or hemorrhage. Evidence of a membrane or intraretinal or
subretinal fluid on OCT or leakage consistent with CNV on fluorescein and
or indocyanine green angiogram supports the finding of CNV. Historically,
laser photocoagulation or photodynamic therapy was employed for CNV
from choroidal rupture (122). More recently, case reports in adults and in
children suggest efficacy of intravitreal anti–vascular endothelial growth
factor (VEGF) therapy for CNV in choroidal rupture, often with only a single
or few injections (123–126). Anti-VEGF therapy for CNV secondary to
traumatic choroidal rupture is off label and has certain challenges including
the need for anesthesia in some cases and lack of long-term safety. It is also
important to be aware of the risks associated with pregnancy in young girls.
Moreover, as discussed in Chapter 53, while anti-VEGF injections have been
employed for retinal vascular disorders in children (e.g., retinopathy of
prematurity), their use in the pediatric population exhibits certain challenges,
including the necessity in some cases for anesthesia and the lack of
established data on the long-term systemic safety of these agents. The
discussion with the parents should include these considerations.
CONCLUSION
Ocular trauma disproportionately affects the pediatric population with over
one-third of blinding eye injuries in the United States Eye Injury Registry
occurring in the first two decades of life. Children pose unique challenges to
medical history taking and ophthalmic examination. Moreover, the pediatric
ocular anatomy is distinct from that of an adult and has significant
implications for the clinical manifestations, management, surgical approach,
and prognosis of these patients. Finally, amblyopia is a significant
consideration requiring timely intervention of the acute injury to prevent
irreversible occlusive amblyopia and upon appropriate long-term
management of refractive error and amblyopia to optimize visual outcomes.
ACKNOWLEDGEMENTS
MPG is supported by an unrestricted departmental grant from Research to
Prevent Blindness.
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70
Nonaccidental Head Trauma
George Caputo, and Wei-Chi Wu
DEFINITION
In 1971, Guthkelch reported the cases of two infants with subdural hematoma
suggesting for the first time that babies could be injured by shaking (1). Prior
to this report, in 1968, Ommaya was the first to identify cerebral lesions
induced by a whiplash mechanism on nonhuman primates (2).
Nonaccidental head trauma (NAHT) is also called nonaccidental head
injury (NAHI), or shaken baby syndrome (SBS), but this last term does not
account for all the mechanisms implied in the observed lesions and does not
clearly identify the fact that these injuries result from child abuse. The
specificity of the syndrome is a triad involving the brain, subdural space, and
retina; acceleration and deceleration with or without impact are the main
factors explaining the variety and severity of neurologic damage.
NAHI is the leading cause of head injury in the United States accounting
for 80% of head injury in children under 2 years. It is characterized by the
severity of the outcome; 30% of victims die and two-thirds of survivors
suffer from permanent neurologic damage, including blindness and cognitive
and motor impairment (3–7). The ophthalmologist plays a key role in the
diagnosis that can lead to social and forensic consequences.
PREVALENCE
NAHI has become the leading cause of death by brain injury in children in
the United States with an incidence of 24 to 30/100,000 children leading to
about 1,200 to 1,400 cases per year.
The median age encountered in NAHI is 3.9 to 4.6 months, and most of
the children are <1 year in age with exceptional cases in children up to 5
years of age (4,8). The age range corresponds to the peak age when infants
cry the most (Table 70-1).
PATHOPHYSIOLOGY OF BRAIN
LESIONS
Brain lesions consist of marked ischemia-inducing cerebral edema and
subdural hemorrhage (SDH); the latter finding is present in 90% of the cases
and is highly specific (10) (Figure 70-1). Diffuse axonal damage in the upper
spinal cord in the cervical region is probably responsible for apnea in these
infants (11,12). Hypoxia–ischemia and secondary brain swelling are then
induced and constitute the main abnormalities found on postmortem
histopathologic examination of the most severe cases. Acceleration and
deceleration by a whiplash mechanism is, on the other hand, the main cause
of subdural bleeding postulated to be caused by rupture of the bridging veins
between the dura and the brain (10).
FIGURE 70-1 Baby girl, 1 month old. Nonaccidental
head trauma. A:CT scan. B:MR sagittal slice, T1-weighted
sequence. C:MR axial slice, diffusion-weighted sequence.
Diffuse subdural and subarachnoidal hematomas (arrows)
located into the tentorium, in the interhemispheric space,
and over the left hemisphere (A, B). Parenchymal anoxic
ischemic injuries in the left frontal and occipital lobes (C).
(Courtesy of Pr C. Adamsbaum.)
OCULAR LESIONS
Diagnostic Studies
If available, a fundus wide-field photograph is taken with a portable retinal
camera, such as RetCam, or a detailed drawing is performed after the
examination is completed. Ultrasound can be helpful in distinguishing retinal
configuration, whether from a retinal detachment, traction, or premacular
hemorrhage beneath a vitreous hemorrhage. Fluorescein angiography is
useful to evaluate for retinal nonperfusion (Figure 70-7B) (16).
Retinal Hemorrhages
Retinal hemorrhages are the most specific and common findings of NAHI.
They are present in 70% to 93% of the cases (3–7,9,11,18). Unilateral retinal
hemorrhages are reported in 12% to 40% of the cases (6,20) Multiple studies
support the finding of hemorrhages specifically in NAHI. Pierre-Kahn et al.
compared the presence of intraocular hemorrhage in a series of 241
consecutive infants hospitalized for an SDH across three groups based on the
degree of certainty that they had been shaken (7). Intraocular hemorrhage was
seen in 77.5% of infants presumed to have been shaken, in 20% of infants
with signs of head trauma without a relevant history of accidental trauma, and
in none of the infants with proven severe accidental trauma. The authors
concluded that intraocular hemorrhages are suggestive of SBS. A review by
Vinchon et al similarly reported retinal hemorrhages in 53% to 80% of
children with NAHI, but in only 0% to 10% of children following accidental
trauma (21). From a prospective analysis of 150 cases of head trauma, the
authors calculated a sensitivity of 75%, specificity of 93.2%, positive
predictive value of 89.4%, and negative predictive value of 82.9% for retinal
hemorrhage and child abuse (21).
Schisis
Retinoschisis due to NAHI has been described in severe cases and has been
shown in OCT studies of affected babies (24,26). The features reported are
multilayered retinoschisis affecting areas where the vitreous remains
attached. Vitreous traction could explain the mechanism of these lesions.
Macular Changes
Besides epiretinal or subhyaloid hemorrhages, macular holes and macular
pseudoholes have been reported in rare cases and are distinguished by OCT
(24,27). Epiretinal membranes are a common finding in survivors of NAHI
(28) and often present as a two-layered structure, corresponding to a
proliferating structure and the internal limiting membrane. Also, bilateral
traumatic macular holes were found as a complication of NAHI (Figure 70-
5).
FIGURE 70-5 A 7-month-old infant with NAHI presented
with bilateral large macular holes formation. Both right
eye (A) and left eye (B) showed diffuse retinal
hemorrhages with large traumatic macular hole.
Retinal Folds
Retinal folds have been described concentric to the posterior pole (Figure 70-
8) with vitreous being adherent to the top of the fold and to the vitreous base
(32). These findings initially reported in histopathologic studies have been
confirmed by in vivo OCT imaging (26).
FIGURE 70-8 Fundus photograph of a 4-month-old infant
with NAHI, showing diffuse retinal hemorrhages with
representative circular hypopigmented retinal fold.
Retinal Detachment
Retinal detachment has been reported and occurs in the most severe cases. In
a histopathologic study of 16 infants that died of NAHI, Green found 10
cases of retinal detachment (18).
Retinal detachment as reported above can be related to a tractional
mechanism; a rhegmatogenous cause is involved in cases of direct ocular
blunt trauma with a high proportion being from retinal dialyses or giant
retinal tears (33).
PATHOPHYSIOLOGY AND
SPECIFICITY OF OCULAR LESIONS IN
NAHI
The role of the vitreous has been emphasized, and the lesions observed have
been attributed to the whiplash mechanism of acceleration–deceleration
present following shaking. The strong adherence of the vitreous body to the
retina in babies and the repeated violent movements of the vitreous are held
responsible for shearing of the superficial retinal vessels predominantly
resulting in diffuse hemorrhages. The hypothesis of an associated retinal
ischemic mechanism in NAHI is supported by the fact that chest compression
alone does not explain diffuse retinal hemorrhages as seen in NAHI. In a
prospective trial evaluating retinal hemorrhages after resuscitation maneuvers
inducing chest compression in 43 patients, Odom et al reported bilateral
multiple small punctate retinal hemorrhages that appeared different from
those in NAHI (35).
Based on histopathologic study of brains of infants who died of NAHI,
Geddes in 2001 proposed that the primary feature of brain lesions in NAHI
was anoxia secondary to brainstem lesions in the cervical region. The latter
results in ischemic cerebral edema and intracerebral infarction and bleeding
as well as subdural hematomas. At the retinal level, prolonged tissue
ischemia could be implicated in enhancing vascular extravasation. A sudden
increase in retinal venous pressure and arterial blood pressure due to cerebral
ischemia and brain edema could lead to vascular leak such as what occurs in
a Vasalva-type mechanism. This pathology would be enhanced by hypoxic
lesions in the infants’ immature vessels. Infants suffer from shaking early in
the first year of age at a time when presumably the retinal vasculature is
particularly fragile and immature. More recently, a comparative
histopathologic study of 18 cases of SBS showed diffuse orbital shearing
lesions from acceleration followed by deceleration and confirmed the effect
from whiplash (10).
VISION REHABILITATION
The ophthalmologist plays a key role in the diagnosis and management of
NAHI by detecting ocular involvement and, above all, retinal hemorrhages.
Nonophthalmologists have an 87% detection rate of retinal hemorrhages
making the recourse to the specialist mandatory (36,37).
Retinal hemorrhages resolve in 2 to 4 weeks (Figure 70-9), and visual
gain or maintaining fix and follow vision is seen in 75% of the surviving
patients (7,38). This outcome points to planning for vision rehabilitation in
follow-up, especially in cases with asymmetric vitreous hemorrhage. Kivlin
reported good visual outcome in 68% of survivors, although 19% didn’t
fulfill follow-up. Visual impairment can be severe with the presence of
extensive retinal hemorrhages, retinal folds, retinal scarring, retinal schisis,
and retinal detachment, and is seen in 10% of the patients. Visual cortex
involvement or optic atrophy also explains severe visual loss in the remaining
neurologically impaired infants (5). In infants with subhyaloid hemorrhages
involving the macula, awake time can be spent upright such as in a jumper to
allow settling of the blood out of the visual axis.
FIGURE 70-9 Fundus wide-field image of a child who
sustained retinal hemorrhages from NAHI, demonstrating
the appearance of the fundus several weeks later with
resolution of the hemorrhages.
Indications
In case of intravitreal hemorrhage or subhyaloid lasting more than a few
weeks, a lens-sparing vitrectomy can be performed. The surgical procedure
will be anticipated in case of bilateral involvement.
Secondary epiretinal membrane formation requires surgical removal after
carefully assessing retinal and subretinal changes by repeated OCT
examinations. It appears more judicious to delay the surgical removal to
allow safer dissection with less risk of retinal injury during the procedure
because of a better plane separation after several weeks’ evolution. Wide-
field retinal angiography allows identification of peripheral retinal ischemia
that should be addressed by photoablation of the ischemic retina by indirect,
external, or endocular laser during surgery if performed, to avoid extensive
neovascular proliferation and secondary retinal detachment. Prolonged
follow-up is necessary to address these secondary complications.
Equipment
For evaluation during examination: wide angle fundus camera, fluorescein
angiography system, ultrasound
Small-gauge vitrectomy system
Vitreoretinal forceps for membrane peeling in the case of ERM
Indirect, external microscope adaptor or endolaser
Outcome Expectations
Results after vitrectomy are unpredictable because of the varying underlying
retinal and CNS neurologic lesions (39). Epiretinal membrane peeling is also
achievable, when necessary, but may have limited functional outcomes.
NAHI is a devastating disease, and primary prevention is a main goal in
the future to avoid induced impairment. Primary prevention strategies have
proven effective. Dias set a milestone in a very well-designed prospective
study in 2005, in which there was a 47% reduction in the incidence of SBS
after parents of newborns were provided information on SBS following birth
of their infant and prior to discharge from hospital. The parents were given a
brochure, watched a videotape, and signed a commitment statement with only
minimal demands on hospital staff resources (40).
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ATLAS A
Hemorrhages
George Caputo
Hemorrhages within the posterior segment of the eye can involve the
vitreous, subhyaloid space, inner retina, subretinal space, and choroid. The
determination in children is not always easy or as helpful as it is in adults.
History and specific patterns of hemorrhage become essential in determining
the diagnosis. Long-standing hemorrhage can become khaki colored as
hemoglobin is lost.
Table A-1 shows diagnoses responsible for hemorrhages, while the
following figures are examples of conditions with various hemorrhages in
infants and children. The reader is referred to specific chapters for greater
detail.
aThis table reflects the most common presentations and associations for the listed conditions. There are
always exceptions, and as we learn more about the genetic and phenotypic associations, these tables
may change.
NAHI, nonaccidental head injury; XLRS, X-linked juvenile retinoschisis; ROP, retinopathy of
prematurity; FEVR, familial exudative vitreoretinopathy; RD, retinal detachment.
FIGURE A-1 A 5-month-old male baby with
nonaccidental head trauma presenting with a subhyaloidal
subfoveal hemorrhage expanding into the vitreous (see
also Chapter 70).
FIGURE A-2 Retinal hemorrhages with central whitening
in nonaccidental trauma (see also Chapter 70).
FIGURE A-3 Severe nonaccidental trauma in a 3-month-
old baby, with diffuse hemorrhages in all retinal fields and
circular retinal fold (see also Chapter 70). (Courtesy of Pr
Speeg, Strasbourg.)
FIGURE A-4 Resolution of retinal hemorrhages in a 4-
month-old nonaccidental head injury, showing preretinal
hemosiderin deposits (see also Chapter 70).
FIGURE A-5 Panoramic view of a collected
retrohyaloidal hemorrhage in a 16-year-old boy due to a
Valsalva maneuver.
FIGURE A-6 Noncollected preretinal hemorrhage in an
8-year-old child due to Valsalva mechanism.
FIGURE A-7 Preretinal hemorrhage in a 10-week-old
baby with aggressive posterior retinopathy of prematurity.
Note vessel tortuosity and dilation in all quadrants around
the optic nerve (see also Chapters 52–54).
FIGURE A-8 A:Reabsorbing retrohyaloidal hemorrhage
in a 17-year-old boy secondary to dorsal trauma. B:Optical
coherence tomography of the same patient showing
preretinal condensation and constitution of a preretinal
membrane (see also Chapter 69).
FIGURE A-9 A:A 6-year-old child presenting an
intravitreal hemorrhage secondary to XLRS. B:Diagnosis
was confirmed by the presence of typical lesions in the
fellow eye associating inferior and macular schisis (see
also Chapter 34).
FIGURE A-10 A–C:A 4-year-old boy with acute
leukemia presenting long-lasting intravitreal hemorrhage
treated by 25-G vitrectomy after six cycles of
chemotherapy and biologic remission. Hemorrhage is
dense, and macular scarring is visible. Visual recovery was
20/40. (See also chapters 47 and 49).
ATLAS B
Macula
George Caputo
Macular lesions can result from a very wide variety of diseases ranging from
retinal degeneration to vascular lesions and folds. Table B-1 summarizes the
main differential diagnoses and classification of the different pathologies
observed, while illustrated by clinical cases that appear below. The reader is
referred to specific chapters for greater detail.
aThis table reflects the most common presentations and associations for the listed conditions. There are
always exceptions, and as we learn more about the genetic and phenotypic associations, these tables
may change.
FEVR, familial exudative vitreoretinopathy; ERM, epiretinal membrane; RPE, retinal pigment
epithelium; PR, photoreceptor; ROP, retinopathy of prematurity.
CONGENITAL MACULAR
DYSTROPHIES
FIGURE B-1 Albinism. A, B (OD, OS):A 15-year-old
boy with ocular albinism. Fundus appearance is
hypopigmented throughout allowing abnormal visibility of
the choroidal vascular meshwork. Visual acuity is 20/80.
C (OD), D (OS):Autofluorescence picture and late-phase
indocyanine green (ICG) angiogram OS show small fleck
pattern hyperfluorescence in the foveal area. E (OD), F
(OS):Macular hypoplasia is confirmed by optical
coherence tomography (OCT): partial loss of central
foveal depression and heterogeneity of the outer nuclear
layer in the foveal region (see also Chapter 23).
FIGURE B-2 Best dystrophy. A 15-year-old boy with
Best dystrophy. VA 20/20 in both eyes. A:OD presents
with typical egg yolk, yellowish material starting to
precipitate. B:OS presented 2 years before with choroidal
neovascularization treated by surgical excision: fibrotic
nonactive, nonevolving remnant in upper nasal aspect of
the fovea in OS. C:OCT scan OD showing sub-RPE
material and normal retinal layers. D:OCT scan OS with
stable sub-RPE deposition and possible subretinal fluid
(see also Chapter 26).
FIGURE B-3 Cone dystrophy. A 17-year-old patient with
cone dystrophy. A, B (OD,OS):Autofluorescence images
show perifoveal hyperfluorescence and foveal mottling.
OCT shows atrophy of the external retinal layers in the
foveal region (see also Chapter 26). Green line through
macular image at left represents location of axial OCT
scan demonstrated at right.
FIGURE B-4 Hypermetropia. A 12-year-old boy with
nanophthalmos and 14 diopters of hypermetropia; vision is
20/100 in both eyes. A, B:Right eye and left eye showing
macular fold. C, D:OCT scans confirm the fold and
anatomical preservation of outer layers like the IS/OS line.
Microcavities are visible in the outer nuclear layer. Green
line through macular image at left represents location of
axial OCT scan demonstrated at right.
EXUDATIVE MACULOPATHIES
FIGURE B-5 Coats. A–D:A 6-year-old boy presenting
with extensive subretinal exudates at the posterior pole,
secondary to Coats disease; vascular dilations are present
in midperiphery. The subretinal deposits extend under the
fovea; well-applied laser treatment resulted in resorption
of exudates 3 months later. E, F:Fundus photograph of a
9-year-old boy with fibrotic macular scarring. Fluorescein
angiography shows peripheral leakage at the posterior
margin of laser scars (see also Chapter 64).
FIGURE B-6 IRVAN. An 8-year-old girl with IRVAN
syndrome: idiopathic retinitis vasculitis, aneurysm, and
neuroretinitis. A:Posterior pole on initial presentation:
extensive posterior exudation is evidenced. B:Subretinal
neovascularization developed 6 months after treatment.
C:Wide-angle angiography shows peripheral retinal
ischemia treated with laser.
FIGURE B-7 Neuroretinitis. A:An 8-year-old girl
presenting unilateral neuroretinitis: papilledema and vessel
congestion are present. B:Three weeks later, small
circinate exudates appeared after resorption of the edema.
Patient was treated for cat scratch disease due to
Bartonella (see also Chapter 47).
PRERETINAL MACULOPATHIES
FIGURE B-8 Epiretinal membrane. A, B:Wide-field view
of an epiretinal membrane in a 10-month-old baby with a
history of intravitreal hemorrhage. B:Late-phase
angiography shows no leakage in the macular area.
C:Idiopathic epiretinal membrane in a 7-year-old boy;
converging folds of the inner limiting membrane (see also
chapter 67). D:Outer retinal layers are preserved as seen in
OCT. E:Thick central ERM in a 5-year-old boy. F:OCT
confirms the retracted fibrotic aspect of the membrane,
which appeared fibrovascular during surgery (see also
Chapter 67). Green line through macular image at left
represents location of axial OCT scan demonstrated at
right.
FIGURE B-9 Hamartoma. A:Red-free photograph of a
combined hamartoma of the RPE and choroid around the
optic nerve in a 9-year-old boy. B:Vision is 20/200, and a
thick epiretinal membrane is seen on the OCT scan (see
chapters 46 and 67). C, D:After vitrectomy and membrane
peeling, the hamartoma around the optic disc is more
clearly visible and macula is less ectopic: vision improved
to 20/60 (see also Chapter 46). Green line through macular
image at left represents location of axial OCT scan
demonstrated at right.
FIGURE B-10 Macular hole. Color SLO wide-field
picture of a macular hole in an 18-year-old boy after ball
closed trauma. The hole is wide, oval shaped, with
underlying pigment epithelial and atrophic changes, and
the small operculum appears green because of its
intravitreal position (see also Chapter 69).
FIGURE B-11 Folds. A, B (OD,OS):A 4-month-old girl
presenting retinal dysplasia in both eyes. Pigment
epithelial changes and vessels are visible in retinal fields
outside the fold. C, D:Fold due to persistent fetal
vasculature; vitrectomy was performed to release traction
from the fibrous stalk. Lens was aspirated and implant
placed. (Diagnosis based on unilateral condition.)
E:Retinal fold believed to be due to ROP based on
medical history. F, G:Retinal fold due to familial
exudative retinopathy (FEVR) in a 4-year-old boy with no
history of prematurity. Fellow eye has no major vascular
changes, but wide-field angiography shows anterior
nonperfused retinal areas (see also Chapter 65).
INFLAMMATORY MACULOPATHIES
DEGENERATIVE MACULOPATHIES
FIGURE B-15 Retinitis pigmentosa. A 13-year-old boy
presenting with retinitis pigmentosa. Vision is 20/40 OU,
and no major pigmentary changes are visible. Foveal
reflex is absent (A,B), and autofluorescence of both eyes
shows mild hyperreflective ring around the fovea (C,D).
OCT scan shows mild atrophy and changes in external
nuclear layers and outer segments (see also Chapters 26).
Green line through macular image at left represents
location of axial OCT scan (E,F) demonstrated at right.
FIGURE B-16 X-linked retinoschisis. An 8-year-old boy
with bilateral 20/200 vision. A, B:Color photograph of the
posterior pole showing reflect alterations and central
foveal cyst. C, D:OCT scans show cystoid spaces in outer
and inner nuclear layers and large central space (see also
Chapter 34). Green line through macular image at left
represents location of axial OCT scan demonstrated at
right.
MACULAR HOLES
FIGURE B-17 Traumatic macular hole in a 10-year-old
boy following recent blunt trauma. A:Infrared image of
right eye shows disruption of pigment (left) and OCT
(right) shows full-thickness macular hole. Visual acuity is
20/150. B:Two weeks following ocriplasmin injection in
right eye 30 minutes before pars plana vitrectomy with
posterior hyaloidal removal and 80% fill of 10% C3F8 gas
followed by postoperative face down positioning. Visual
acuity improved to 20/100 and inner retina appears to be
bridging hole. C:Eight months after surgery, visual acuity
is 20/50 showing small defect in foveola and less
disruption of ellipsoid zone (see also Chapter 69).
(Courtesy Mike Trese.)
ATLAS C
Pigmentary Changes
George Caputo
Table D-1 presents differential diagnoses for posterior segment masses, while
illustrated case studies follow below. The reader is referred to specific
chapters for greater detail.
aThis table reflects the most common presentations and associations for the listed conditions. There are
always exceptions, and as we learn more about the genetic and phenotypic associations, these tables
may change.
FEVR, familial exudative vitreoretinopathy.
FIGURE D-1 Coats. A:Fundus image of a 4-year-old boy
presenting with a retinal detachment due to Coats disease
with massive subretinal exudation (stage 4 Coats disease).
B:The same patient following two sessions of laser
photocoagulation to dilated vessels followed by external
subretinal drainage. Subretinal fibrosis secondary to
condensation of the exudation is molded by the retina (see
also Chapter 64).
FIGURE D-2 Retinal dysplasia. A:A 6-month-old infant
with bilateral retinal dysplasia. Fibrous stalk, partial retinal
detachment, and intravitreal hemorrhage are present in this
eye. B:The same patient after vitrectomy and surgical
ablation of the fibrovascular remnants: retina has flattened
back, leaving the pigmented demarcation line of the
previous detachment and an avascular dysplastic retina.
Fixation is present (see also Chapters 35 and 65).
FIGURE D-3 Combined hamartoma of pigment
epithelium and retina. A:Fundus photograph of a 7-year-
old boy presenting a combined hamartoma of pigment
epithelium and retina complicated by an epiretinal
membrane. Note the peripheral traction and the macular
fold and traction at the limit of the lesion. B:Three months
after vitrectomy and membrane peeling, the macular area
is flatter and peripheral traction less. Vision improved
from 20/400 to 20/200 (see also Chapters 46 and 67).
FIGURE D-4 Angioma. Fundus photograph of a
peripheral fibrotic angioma in a 12-year-old boy.
Exudation is surrounded by mild atrophy and pigment
epithelium changes (see also Chapter 46).
FIGURE D-5 Choroidal hemangioma. A:Color
photograph of a hemangioma in a 20-year-old man: a light
orange mass is clearly visible on the upper area of the
posterior pole. B:Blue filter picture showing mild
epiretinal changes. C:Red photograph showing the light
mass. D:The red-free photograph is out of focus in the
area of the lesion. E:Optical coherence tomography scan
of the lesion shows the thickness of the mass and
subretinal exudation causing reduction in visual acuity
(20/40) (see also Chapter 46). Green line through macular
image at left represents location of axial OCT scan
demonstrated at right.
FIGURE D-6 Retinoblastoma. A:Anterior segment
photograph of a 6-month-old boy presenting leukocoria for
1 month. A posterior vascularized ill-defined mass is
clearly visible in the posterior segment. B:Fundus
photograph showing total retinal detachment due to a large
retinoblastoma (see also Chapters 44 and 45).
FIGURE D-7 von Hippel disease. A:Color fundus
photograph of a 12-year-old girl presenting a large
superior peripheral retinal hemangioblastoma responsible
for posterior exudation and retinal detachment. Dilated
afferent and efferent vessels irrigating the mass are clearly
visible. General assessment includes cerebrospinal
magnetic resonance imaging and ultrasound abdomen
examination to rule out other localization and
pheochromocytoma. B:Fellow eye is normal with no
objective lesions (see also Chapter 46).
ATLAS E
Flecks and Spots
Michael T. Trese, Antonio Capone Jr, and M. Elizabeth Hartnett
The following are examples of flecks or multiple white spots. The reader is
referred to specific chapters for greater detail.
aThis table reflects the most common presentations and associations for the listed conditions. There are
always exceptions, and as we learn more about the genetic and phenotypic associations, these tables
may change.
ROP, retinopathy of prematurity; APROP, aggressive posterior ROP; WGA, week gestational age;
FEVR, familial exudative vitreoretinopathy.
FIGURE F-1 Coats disease. A:Retinal angiography of an
8-year-old boy presenting mild Coats disease: dilation of
the capillary meshwork. B:Fundus image; after laser
treatment of vessel dilations (B1, B2). Laser was also
applied in a grid pattern in anterior region of avascular,
and presumed hypoxic, retina fundus appearance (B3) and
angiographic aspect (C1, C2) after laser scarring. (see also
Chapter 64).
FIGURE F-2 Familial exudative vitreoretinopathy
(FEVR). A:Fundus image of a 9-year-old boy presenting a
total retinal detachment OD secondary to FEVR (stage
5B). The detachment is both tractional with severe
preretinal proliferation and vessel dragging, and
rhegmatogenous. Surgery was unsuccessful. B:Fundus
image of the fellow eye showing mild temporal peripheral
changes and suspicious-looking poorly vascularized retina
confirmed by fluorescein angiography. (C, D) (stage 2B).
Avascular retina was treated with laser photocoagulation.
Neovascular buds are present temporally. E:Right eye of a
4-year-old boy treated with vitrectomy and scleral buckle
for stage 5B FEVR. A persistent retinal fold remains with
regression of subretinal exudation. F:The fellow eye has
stage 3B FEVR with peripheral tractional retinal
detachment due to active neovascularization. This eye was
treated with peripheral laser ablation and scleral buckle
(see also Chapters 42 and 66). G, H:Wide-field fundus
image of right and left eyes of a 13-year-old girl following
treatment for FEVR following some resolution of
exudation. Macula is ectopic, and retinal vessels are
dragged. Peripheral pigment epithelial changes are due to
laser photocoagulation and resolution of exudation (see
also Chapters 42 and 66).
FIGURE F-3 Incontinentia pigmenti. A, B:Fundus image
of an 8-month-old infant with retinal detachment OS due
to incontinentia pigmenti. Severe preretinal fibrovascular
proliferation and exudation are apparent in the temporal
retina in association with surrounding avascular retina.
Vitrectomy has a poor prognosis in these advanced cases.
C:Retinal vascularization of the fellow eye is normal (see
also Chapter 36).
FIGURE F-4 Aggressive posterior retinopathy of
prematurity with plus disease. A, B:Aggressive posterior
retinopathy of prematurity in zone 1 in an infant of 33
weeks’ postgestational age (GA) (infant born at 25 weeks’
GA and 520 g birth weight). The ridge is very wide and
the neovascular meshwork mildly elevated. C:Detail at
higher magnification showing vascular dilatation and
tortuosity of vessels at the optic disc in all quadrants.
D:Detail of the “ridge” (junction of vascularized and
avascularized retina) at higher magnification shows
vascular activity (see also Section VIII, Chapters 33–49).
FIGURE F-5 Sickle cell disease. A:Fluorescein
angiogram of a 13-year-old girl with SC sickle cell
anemia. Posterior filling is normal against a very dark
background. B:Interruption of peripheral retinal
vascularization and neovascularization with a “sea fan.”
C:Peripheral avascular retina is surrounded by vascular
buds and thin anastomoses between peripheral vessels.
FIGURE F-6 Vessel tortuosity. Wide-field color fundus
image of a 12-year-old girl with congenital vessel
tortuosity. Visual acuity is normal.
FIGURE F-7 Retinal cavernous hemangioma. Fundus
image of a 12-year-old girl presenting retinal cavernous
hemangioma picked up on routine screening. Vision is
20/20 (see also Chapter 46).
ATLAS G
Retinal Detachment and Schisis
George Caputo
aThis table reflects the most common presentations and associations for the listed conditions. There are
always exceptions, and as we learn more about the genetic and phenotypic associations, these tables
may change.
FEVR, familial exudative vitreoretinopathy; XLRS, X-linked juvenile retinoschisis.
FIGURE G-1 Coats disease. Fundus image of a 4-year-
old boy presenting with leukocoria and a total retinal
detachment. Vessel and capillary dilatations are clearly
seen on the surface of the retina. Exudation gives it a
yellowish appearance, whereas with retinoblastoma, the
appearance can be whiter (see also Chapter 64).
FIGURE G-2 Coloboma. Wide-field fundus image of a
10-year-old boy presenting with a chorioretinal coloboma
complicated by a retinal detachment. The macular pigment
is visible at the edge of the coloboma in this amblyopic
eye (see also Chapter 22).
FIGURE G-3 Giant tear. A:Fundus image of a 12-year-
old highly myopic boy presenting with a total retinal
detachment secondary to a 180-degree giant temporal
retinal tear. B:Shallow retinal detachment in a 12-year-old
boy with a 100-degree temporal retinal tear without
inversion (see also Chapter 63).
FIGURE G-4 Retinoblastoma. A:Anterior segment image
of a 6-month-old infant with total retinal detachment and
leukocoria. The retinal surface has no vascular changes.
B:Fundus image of the same patient showing the
posteriorly located mass of an endophytic retinoblastoma
stage D (see also Chapters 44 and 45).
FIGURE G-5 Rhegmatogenous retinal detachment. A,
B:Total retinal detachment in a 9-month-old infant. The
presence of proliferative vitreoretinopathy and preretinal
pigmented proliferation confirms the rhegmatogenous
component. The infant sustained blunt ocular trauma (see
also Chapters 63 and 69).
FIGURE G-6 Retinopathy of prematurity. A:Stage 4 B
retinal detachment with tractional component, plus
disease, and temporal neovascularization. B:Total
tractional retinal detachment due to stage 5 retinopathy of
prematurity (see also Chapter 55).
FIGURE G-7 Stickler syndrome. A:Color fundus
photograph of a 12-year-old girl with Stickler syndrome.
The vitreous bands prevent focusing on the underlying
retina. B:Wide-field fundus image of the same highly
myopic patient showing numerous vitreous veils and
bands (green appearance). The patient had a retinal
detachment treated with an encircling scleral buckle (see
also Chapters 37 and 63).
FIGURE G-8 Sturge-Weber syndrome. A:Total serous
retinal detachment in a 4-year-old girl with Sturge-Weber
syndrome. No proliferative vitreoretinopathy or retinal
vascular anomalies are visible on the retinal surface.
Ultrasonography showed diffuse thickening of the choroid
due to hemangioma. B:Fellow eye fundus image showing
a reddish fundus reflex suspicious of diffuse quiescent
choroidal hemangioma (see also Chapter 46).
FIGURE G-9 X-linked retinoschisis. A 5-year-old boy
with diffuse temporal retinoschisis. A large hole in the
inner retinal wall is visible inferotemporally. No
pigmentation or subretinal proliferation is visible (see also
Chapter 34).
ATLAS H
Optic Nerve
George Caputo
aThis table reflects the most common presentations and associations for the listed conditions. There are
always exceptions, and as we learn more about the genetic and phenotypic associations, these tables
may change.
FIGURE H-1 Optic atrophy. A, B:Fundus image of a 12-
year-old boy presenting with bilateral optic atrophy
secondary to a surgically resected craniopharyngioma (see
also Chapter 22).
FIGURE H-2 Coloboma. A, B:Central and peripheral
fundus images of a 20-year-old patient with a chorioretinal
coloboma. C, D:Left eye of the same patient. In both eyes,
there is no macular involvement, and visual acuity is
20/25. E:Wide-field fundus image of a 6-month-old male
infant with very large chorioretinal coloboma involving
the macula. F:Left eye of the same patient presenting with
a shallow retinal detachment involving the macula: visual
prognosis is poor. G:Large central optic nerve coloboma
involving the macula with persistent hyaloid artery
attached to the lens in a 2-year-old boy. Vision is limited
to light perception. The appearance is similar to morning
glory syndrome. H:Deep optic nerve staphyloma with a
tilted optic disc in a 2-year-old girl, corresponding to a
form of coloboma (see also Chapter 22).
FIGURE H-3 Dragged optic disc. A, B:Fundus
photograph of a 12-year-old boy with familial exudative
vitreoretinopathy. Mild dragging of the temporal retinal
vessels due to neovascular peripheral proliferation is
visible (see also Chapter 66).
FIGURE H-4 Optic disc edema. A, B:Mild optic nerve
head edema OU from idiopathic normal pressure
hydrocephalus in a 13-year-old girl (see also Chapter 22).
FIGURE H-5 Leber neuroretinitis. A:Unilateral optic
nerve head edema and serous macular involvement in a
10-year-old girl who suffered vision loss from 20/20 to
20/50. B:The same patient, 3 weeks later with small
stellate exudates from resorption of macular fluid
following regression of the disc edema. Serology was
positive to Bartonella henselae, and specific antibiotic
treatment was administered (see also Chapter 47).
FIGURE H-6 Morning glory anomaly. A:Colobomatous
morning glory anomaly in a 3-year-old girl. The central
optic nerve excavation is deep with steep borders, and the
retinal vessels have a radial configuration. B:Morning
glory anomaly with central glial tissue in a 1-year-old
infant showing radial folds involving the macula (see also
Chapter 22). C:Chronic retinal detachment with subretinal
proliferation in an 18-year-old patient with a
colobomatous morning glory anomaly. D:Fundus
photograph of a 12-year-old girl following surgery for
retinal detachment from a deep colobomatous morning
glory anomaly. Silicone oil tamponade was used and was
complicated by subretinal migration and emulsification
due to the presence of a hole on the steep border of the
central excavation (see also Chapter 22).
FIGURE H-7 Persistent fetal vasculature. A:Wide-field
fundus image of a 5-year-old boy following surgery for
posterior persistent fetal vasculature. He initially presented
a peripapillary retinal fold that resolved after cutting the
fibrous stalk surgically. The fibrosis out of the retinal
plane has a green appearance with this scanning laser
imaging technique. B:Bergmeister papilla with central
fibrous vascular remnants causing contraction of the
peripapillary retina and macula (see also Chapter 65).
FIGURE H-8 Optic disc pit. A:Fundus image of an 8-
year-old boy presenting with a chronic serous retinal
detachment due to an optic disc pit. Visual acuity has been
20/40 for 2 years. B:Red-free image of the same patient.
C:Optical coherence tomography (OCT) vertical scan
shows schisis-like appearance in the outer plexiform layer
and chronic macular serous detachment. D:Horizontal
OCT scan shows communication between outer plexiform
layer and defect in optic nerve. Vitreoretinal adhesion is
visible (see also Chapter 22). Green line through macular
image at left represents location of axial OCT scan
demonstrated at right.
FIGURE H-9 Optic nerve hypoplasia. A, B:Wide-field
fundus images of a 6-month-old infant with severe
bilateral optic disc hypoplasia. A very small optic nerve is
visible in the center surrounded by peripapillary pigment
epithelial changes. The patient does not have the ability to
fix and follow (see also Chapter 22).
Index
A
AAV. See Adeno-associated virus (AAV) vector
AAV serotype 2 vector (AAV2)
AAV (adeno-associated virus) vector
ABCA4 gene, cone-rod dystrophy
ABD. See Adamantiades-Behçet disease
Abetalipoproteinemia
Ablation, peripheral retinal, for retinopathy of prematurity complications of
Ablative therapy, Coats disease
complications
postoperative care
supporting evidence and procedural technique
Absent septum pellucidum
Achromatopsia
ACHM gene therapy
using recombinant viruses, for gene therapy
CNGB3 mutations
complete
ERG
gene associated with
incomplete
Acid ceramidase (AC)
Acidosis, lactic, with mitochondrial encephalomyopathy and stroke-like
episode
Acidosis-induced retinopathy (AIR)
Acute lymphoblastic leukemia (ALL)
Acute posterior multifocal placoid pigment epitheliopathy
N-Acylsphingosine amidohydrolase (ASAH)
Adamantiades-Behçet disease
Adeno-associated virus (AAV) vector
Adenosine deaminase (ADA) deficiency
ADOA. See Autosomal dominant optic atrophy (ADOA)
Adult NCL (ANCL)
AGA (appropriate for gestational age)
Age-related macular degeneration (AMD)
AIR (acidosis-induced retinopathy)
Airway, laryngeal mask, for premature infant
Albendazole, for ocular toxocariasis
Albinism
clinical symptoms and signs
diagnostic studies
differential diagnosis
environmental factors
ethical considerations
foveal hypoplasia
future treatments
genetics
management and visual rehabilitation
dermatologic issues
ophthalmic issues
systemic issues
nonsyndromic albinism
ocular albinism
oculocutaneous albinism, type 1
oculocutaneous albinism, type 2
oculocutaneous albinism, type 3
oculocutaneous albinism, type 4
oculocutaneous albinism, type 5
oculocutaneous albinism, type 6
oculocutaneous albinism, type 7
oculocutaneous
pathophysiology
prevalence
syndromic albinism
Chediak-Higashi syndrome
hermansky-pudlak syndrome
worldwide impact
Alström syndrome
Amaurosis Leber congenital
CRX gene
misdiagnosis of
Amblyopia
clinical symptoms and signs
diagnostic studies
anisometropia
in pediatric retina practice
refractive error
strabismus
visual deprivation
differential diagnosis of, retinoschisis
environmental factors
ethical considerations
future treatments
genetics
management of
pathophysiology
physician and health care providers
prevalence
refractive error
anisometropia
lensectomy
organic amblyopia
posterior uveitis
retinal detachment
retinopathy of prematurity
vitreous and retinal hemorrhages
treatment and vision rehabilitation
worldwide impact
AMD (age-related macular degeneration)
Amino acid disorders
Anesthesia
examination under
general, in premature infants
nitrous oxide
for surgery, inhalation, intraocular gas and
Angiogenesis
Angiography
fluorescein (see Fluorescein angiography (FA))
indocyanine green, in choroidal hemangioma diagnosis
Angioma
Anisometropia
Anomalous posterior vitreous detachment
Anterior chamber, in acute pediatric eye trauma, ocular examination
Anterior chamber paracentesis, for uveitis
Antioxidant therapy
Antioxidants, on retinopathy of prematurity
Antivascular endothelial growth factor
Anti-VEGF treatment. See also Retinopathy of prematurity
retinopathy of prematurity
aflibercept
bevacizumab
cryotherapy
intravitreal injections for
laser photocoagulation
long-term safety and neurodevelopmental outcomes
pegaptanib
pharmacodynamics and pharmacokinetics
ranibizumab
rationale for drug
recurrence and retreatment of
success rates
trials
safety
VEGF binding receptors
Apoptosis, in retinoblastoma
Appropriate for gestational age (AGA)
Arthritis
inflammatory bowel disease
rheumatoid, juvenile, uveitis in, surgical approaches to
Artificial intelligence (AI) algorithm
Astigmatism
Astrocytes, retinal, development of
Astrocytic hamartoma
Atrophy, autosomal dominant optic
Autosomal dominant disorders
Autosomal dominant optic atrophy (ADOA)
clinical signs and symptoms
diagnostic studies
genetics
management of
pathophysiology
prevalence of
systemic manifestations
worldwide impact
Autosomal dominant retinitis pigmentosa (PRPF8 mutation)
Autosomal dominant Stargardt-like macular dystrophy
clinical characteristics and disease course
differential diagnoses
molecular genetics of
Autosomal dominant vitreoretinochoroidopathy
Autosomal recessive bestrophinopathy (ARB)
Autosomal recessive disorders
Azathioprine
intermediate uveitis
JIA-associated uveitis
for sarcoidosis
B
Band keratopathy, for uveitis
indications
in juvenile rheumatoid arthritis-associated uveitis, surgery
procedure
Bardet-Biedl syndrome (BBS)
BBS1 mutations
clinical symptoms and signs
anosmia
developmental disability
diabetes mellitus
hearing loss and glue ear
obesity
polydactyly
renal and genital anomalies
retinal degeneration
diagnostic studies in
differential diagnosis
environmental factors
gene therapy
genetics
health care providers
management of
pathophysiology
physicians role
prevalence of
vision rehabilitation
worldwide impact of
Bassen-Kornzweig syndrome. See Abetalipoproteinemia
Batten disease
BBS. See Bardet-Biedl syndrome (BBS)
Benzodiazepines
Bergmeister’s papilla
Berlin edema. See Commotio retinae
Best corrected visual acuity (BCVA)
Best disease
choroidal neovascularization
clinical findings
differential diagnosis
genetics
pathophysiology
Best dystrophy
Best vitelliform macular dystrophy (BVMD)
BETTS (Birmingham Eye Trauma Terminology System)
Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of
Prematurity (BEAT-ROP) study
β-galactosidase deficiency
β-glucocerebrosidase deficiency
β-hexosaminidase α-subunits, deficiency in
Bilateral microphthalmia
Bilateral nasal tilted disc syndrome
Bilateral optic disc drusen
Binocular indirect ophthalmoscopy (BIO)
Biopsy
chorioretinal, in uveitis diagnosis
conjunctival, in sarcoidosis diagnosis
retinal, in uveitis diagnosis
Birmingham Eye Trauma Terminology (BETT) System
Birth weight standard deviation score (BWSDS)
Bitemporal hemianopia
Blindness
childhood (see Childhood blindness)
measles-related
cases data
corneal scarring
immunization
keratomalacia
malabsorption
malnutrition and overcrowding
primary prevention
protein-losing enteropathy
secondary prevention
Bloch-Sulzberger syndrome. See also Incontinentia pigmenti (IP)
Blood–retinal barrier (BBB)
development and maintenance
molecular mediators
Hedgehog signaling pathway
Mfsd2a
PDGF-B
retinoic acid
Wnt/wingless pathway
Blue cone monochromatism (OPN1LW mutation)
Body awareness
Bradyopsia
clinical characteristics
genes associated with
Bronchopulmonary dysplasia (BPD ), in VLBW infant, general anesthesia
and
Bronchospasm
complicating general anesthesia in premature infants
intraoperative, acute, pharmacologic therapy for
BWSDS (birth weight standard deviation score)
C
Candida chorioretinitis, flecks and spots
CAPS. See Cryopyrin-associated periodic syndromes (CAPS)
Capsulotomy laser for uveitis
Carbon dioxide, retinopathy of prematurity and
Cardiovascular drips
Carriers, inheritance patterns
Cataract(s)
in uveitis
indications
inflammation management
for intermediate uveitits
in juvenile rheumatoid arthritis-associated uveitis, surgery
in sarcoidosis, extraction of
surgical technique
visual rehabilitation
Catscratch disease
cCSNB. See Complete form of CSNB (cCSNB)
Central nervous system (CNS)
incontinentia pigmenti
lesions of, childhood blindness from
CEP290 mutations (ProQR)
Cerebral visual impairment
Cerebrohepatorenal syndrome
Cerliponase alfa (recombinant TPP1)
Chédiak-Higashi syndrome (CHS)
Chemoreduction, for retinoblastoma
Chemotherapy
immunosuppressive, for intermediate uveitis
systemic, for retinoblastoma
Cherry-red spot myoclonus syndrome
Chikungunya
Childhood blindness
causes of
avoidable
change in, over time
classification
congenital rubella syndrome
data on
fetal alcohol syndrome
harmful traditional eye remedies
lesions of central nervous system
malaria as
measles as
myopia
ophthalmia neonatorum
regional variation in
retinopathy of prematurity
vitamin A deficiency disorders
definition
epidemiology of
incidence of
magnitude of
mortality
prevalence of
universal health coverage
World Bank economic region
worldwide causes of
Childhood retinal diseases
intravitreal surgery
child phakic or pseudophakic or aphakic
intraoperative considerations
port placement
postoperative evaluation
preoperative assessment
wide-angle viewing system
scleral buckle (see Scleral buckle)
Children
blindness (see Childhood blindness)
endoscopic vitrectomy
external and minor surgical procedures (see Noninvasive/minimally
invasive interventions)
ultrasonography (see Ultrasonography)
Children’s Hospital in Philadelphia Retinopathy Prematurity model (CHOP-
ROP)
Chondroitin sulfate, in vitreous
Choriocapillaris (CC)
embryonic and fetal human development
14 to 16 weeks of gestation
hemovasculogenesis
alkaline phosphatase (APase)
carbonic anhydrase IV (CA IV)
CD31 immunolabeling
CD39-immunolabeled
embryonic hemoglobin (Hb-e) colocalization
endothelial nitric oxide synthase (eNOS)
6.5 WG fetal choroid
9 to 12 weeks of gestation
time line of
21 to 22 weeks of gestation
vascular development
Chorionic villus sampling (CVS), genetic testing
Chorioretinal biopsy, in uveitis diagnosis
Chorioretinitis, differential diagnosis of, retinoschisis
Chorioretinitis sclopetaria. See Traumatic chorioretinal rupture
Choroid, coloboma of
Choroidal effusion
Choroidal hemangioma
circumscribed
Choroidal neovascularization
Choroidal osteoma
clinical symptoms and signs
diagnostic studies
differential diagnosis
environmental factors
ethical considerations
future treatments
genetics
health care providers
management
pathophysiology
physicians role
prevalence
vision rehabilitation
worldwide impact
Choroidal rupture
Choroideremia
clinical presentation and disease course
differential diagnosis
molecular findings
natural history studies, gene therapy
using recombinant viruses, for gene therapy
Chronic progressive external ophthalmoplegia (CPEO)
Ciliary body medulloepithelioma, masquerade uveitis syndromes
Circumscribed choroidal hemangioma
clinical symptoms and signs
diagnostic studies
differential diagnosis
environmental factors
ethical considerations
genetics
health care providers
intravitreal bevacizumab
management
pathology and pathophysiology
physicians role
prevalence
vision rehabilitation
worldwide impact
Classification of eye movement abnormalities and strabismus (CEMAS)
Clinical heterogeneity
CLN3 disease
CLN3 gene, neuronal ceroid lipofuscinosis
CLN4 disease
CLN5 disease
CLN6 disease
CLN7 disease
CLN8 disease
CLN9 disease
CLN12 disease
CLN13 disease
Closed globe injury
definition
ocular sequelae management
choroidal rupture
commotio retinae
giant retinal tear
retinal break
retinal detachment
retinal dialysis
traumatic chorioretinal rupture
traumatic macular hole (see Traumatic macular hole)
vitreous hemorrhage
open globe injury zone
ultrasound imaging
CNS (central nervous system)
incontinentia pigmenti
lesions of, childhood blindness from
Coats disease
antivascular endothelial growth factor therapy
classification of
clinical features of
cryopexy
definition
diagnosis
differential diagnosis of
epidemiology of
fluorescein angiography
genetic associations of
laser ablation
optical coherence tomography
outcomes
pathology/pathophysiology
prognosis
surgery
ablative therapies
equipment
indications
intraocular pharmacotherapies
intraocular surgery
symptoms and signs
systemic associations
Wnt signaling pathway and
worldwide impact of
Cobalamin (vitamin B12), disorder of
Cognitive development
Collagens, in vitreous
disorders of
Coloboma(s)
chorioretinal
choroidal
lens, management of
optic nerve
bilateral
complications
macular pigment
PAX2 transcription
retinal detachment
size of
treatment of
Wnt signaling pathway and
Combined anterior and posterior segment surgery
corneal and retinal surgery
glaucoma drainage device implantation and vitrectomy
keratoprostheses
lenticular and retinal surgery
sutureless intrascleral intraocular lens fixation and pars plana vitrectomy
anterior chamber IOL placement
exchange/secondary IOL placement
flanged sutureless intrascleral IOL fixation
forming haptic bulbs/flanges
in Marfan syndrome
in one-piece PMMA IOL
side effects
surgical variations
Combined hamartoma of pigment epithelium and retina. See Combined
hamartoma of the retina and retinal pigment epithelium
Combined hamartoma of the retina and retinal pigment epithelium (RPE)
clinical symptoms and signs
diagnostic studies
differential diagnosis
environmental factors
ethical considerations
future treatments
genetics
health care providers
management
pathophysiology
physicians role
prevalence
vision rehabilitation
worldwide impact
Combined hamartoma of the retina and RPE surgical considerations
cases
classification
complications
definition
diagnostic studies
differential diagnosis
equipment
location
postoperative care
procedural techniques
vs. retinoblastoma
unilateral
Commotio retinae
Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in
ROP (CARE-ROP) study
Complete form of CSNB (cCSNB)
clinical symptoms and signs
genetics and pathophysiology
Computed tomography (CT)
choroidal osteoma
Coats disease
nonaccidental head injury (NAHI)
in ocular trauma evaluation
Computer-Aided Image Analysis of the Retina (CAIAR)
Computer-based imaging analysis (CBIA)
Cone-rod dystrophy
autosomal dominant
autosomal recessive
clinical presentation and disease course
electrophysiologic characteristics
fundus albipunctatus
genes associated with
macular changes
molecular genetics
Stargardt disease
symptoms
systemic diseases
Cone–rod dystrophy (Bornholm eye disease, OPN1LW mutation)
Cone–rod dystrophy and hearing loss (CRDHL)
Cones
differentiation of
20 WG
40 WG
cone density
cone packing
increased oxygen supply
inner nuclear layers
outer nuclear layer
perifoveal anastomosis
photoreceptor elongation wave
postnatal development
S-cones
dystrophy
Congenital disorder of glycosylation (CDG)
Congenital hypertrophy of the retinal pigment epithelium (CHRPE)
associated with Gardner syndrome and familial adenomatous polyposis
clinical symptoms and signs
diagnostic studies
differential diagnosis
environmental factors
ethical considerations
future treatments
genetics
health care providers
management
pathophysiology
physicians role
prevalence
vision rehabilitation
worldwide impact
Congenital motor nystagmus (CMN)
Congenital pigment epithelial hypertrophy
Congenital rubella retinopathy
Congenital rubella syndrome, childhood blindness
Congenital stationary night blindness (CSNB)
clinical symptoms and signs
complete form of CSNB
fundus albipunctatus
GNB3-CSNB
incomplete form of CSNB
Oguchi disease
Riggs type of
Schubert-Bornschein type
diagnostic studies
ERG phenotype
future treatments
general clinical characteristics
genetics and pathophysiology
complete form of CSNB
fundus albipunctatus
gene defects in
GNB3 gene defect
incomplete form of CSNB
Oguchi disease
Riggs type
mode of inheritance of
prevalence
referral to low vision specialists
Conjunctiva
in acute pediatric eye trauma, ocular examination
biopsy of, in sarcoidosis diagnosis
Consent, informed, for surgery
Contact camera retinopathy of prematurity
e-ROP
International Classification of ROP
Cornea, in acute pediatric eye trauma, ocular examination
Cortex, vitreous
Corticosteroids
for inflammation control in cataract surgery in uveitic eye
for intermediate uveitis
for juvenile rheumatoid arthritis-associated uveitis
for ocular toxocariasis
for sarcoidosis
for uveitis
CPEO (chronic progressive external ophthalmoplegia)
CPK80 deficiency
CRDHL (cone-rod dystrophy and hearing loss)
CRISPR-Cas systems
Cryopexy
for lattice degeneration
for peripheral retinal ablation
retinal, for intermediate uveitis
Cryopyrin-associated periodic syndromes (CAPS)
familial mediterranean fever
periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis
(PFAPA) syndrome
tumor necrosis factor receptor–associated periodic syndrome
CRYO-ROP trial. See Cryotherapy for Retinopathy of Prematurity (CRYO-
ROP) study
Cryosurgery, for retinopathy of prematurity, anesthesia for
Cryotherapy
for Coats disease
for intermediate uveitis
for peripheral neovascularization in uveitis
for retinoblastoma treatment
for retinopathy of prematurity
Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) study
CSNB. See Congenital stationary night blindness (CSNB)
Cyclophosphamide
for intermediate uveitis
for sarcoidosis
Cycloplegics, for sarcoidosis
Cyclosporin
for intermediate uveitis
JIA-associated uveitis
for sarcoidosis
Cystine-depleting therapy
Cystinosis
D
Data Safety Monitoring Board (DSMB)
de Morsier syndrome
Deep learning (DL)
Deep neural networks (DNNs)
Degenerative retinoschisis, differential diagnosis of, retinoschisis
4-Degree grating test
Dengue fever (DF)
Depression
Dexamethasone implantation procedure
Diabetic retinopathy, fluorescein angiography
Digital fundus imaging, neonatal intensive care units
automated algorithms
binocular indirect ophthalmoscopy
digital photography
Icon camera
3nethra Neo
Panocam
repeated examination
RetCam
Retcam3 camera
risk for ROP
software algorithms
standard images
topical anesthesia
Digital wide-field imaging systems. See RetCam
Diligent cysteamine therapy
DNA testing, in retinoblastoma
Dominant exudative vitreoretinopathy
Dragged optic disc
Drugs
pediatric anesthesia
MAC concentrations of
pediatric resuscitation
Drusen, optic head
Dysostosis multiplex
E
Early childhood–onset retinal dystrophies (ECORD)
Early intervention and rehabilitation
cerebral visual impairment
challenging test situations
clinical examination and assessment
communication
4-degree grating test
high-risk groups of infants and children with vision loss
at home and school
initial information
passive “vision stimulation,” 149–150
problematic behaviors and situations
school age
tectopulvinar pathway
during treatment
visual milestones
Early Treatment for Retinopathy of Prematurity (ET-ROP) study
Early-onset inherited retinal degeneration (IRD), animal models of
Early-onset retinal degenerations (EORDs)
Ebola viruses
EBRT (external beam radiation therapy), for retinoblastoma
ECORD (Early childhood-onset retinal dystrophies)
EFTFs (eye-field transcription factors)
Ehlers-Danlos syndrome (EDS)
Electronegative waveform, in X-linked retinoschisis
Electroretinogram (ERG)
Usher syndrome
X-linked retinoschisis (XLRS)
Electroretinographic (ERG) waveforms
achromatopsia (CNGB3 mutations)
Alström syndrome (ALMS1 mutations)
Autosomal dominant retinitis pigmentosa (PRPF8 mutation)
Bardet-Biedl syndrome (BBS1 mutations)
Batten disease (CLN3 mutations)
Blue cone monochromatism (OPN1LW mutation)
b-wave development
cone–rod dystrophy (Bornholm eye disease, OPN1LW mutation).
Enhanced S-cone syndrome (NR2E3 mutations)
in healthy adult and 10-week-old infant’s
ISCEV standard protocol
Joubert (INPP5E mutations)
Leber congenital amaurosis, LCA (CEP290, RPE65, CRB1 mutations)
Night blindness
posterior microphthalmos with retinal folds (MFRP mutations)
Stargardt disease (ABCA4 mutations)
Stickler syndrome (COL11A1 mutation)
Usher syndrome (MYO7A, USH2A mutations
X-linked congenital stationary night blindness, CSNB1 (NYX mutation)
and CSNB2 (CACNAF1 mutation)
X-linked juvenile retinoschisis (RS1 mutation)
X-linked retinitis pigmentosa (RPGR mutation)
Embryology, of retina
Embryonic hyaloid vasculature, vitreous in
Encephalomyopathy, mitochondrial, with lactic acidosis and stroke-like
episodes
Endoscopic vitrectomy
advantage of
clinical application
20-gauge endoscope
hand-to-eye coordination
instrument development
learning curve of
persistent fetal vasculature syndrome
sclerotomy placement
surgically relevant properties
anatomical perspective
optical property
pars plana vitrectomy
Endothelial growth factor, vascular, intravitreous neovascularization
Endotracheal tube size and length by weight and age
End-stage disease and developmental disorders, gene therapy
Enhanced S-cone (Goldmann-Favre) syndrome
Enhanced S-cone syndrome (ESCS)
Environmental factors
Bardet-Biedl syndrome
choroidal osteoma
circumscribed choroidal hemangioma
congenital hypertrophy of the retinal pigment epithelium
Kearns-Sayre syndrome
in Leber’s hereditary optic neuropathy
medulloepithelioma
neuropathy, ataxia, and retinitis pigmentosa
in retinoblastoma
Stargardt macular dystrophy/fundus flavimaculatus
X-linked retinoschisis (XLRS)
Enzymatic vitreolysis, in retinopathy of prematurity
Enzyme replacement therapy (ERT)
Epilepsy
Epiretinal membrane (ERM)
cellophane type
classification
clinical appearance
Coats disease
complications
diagnostic studies
differential diagnosis
equipment
indications
macular
postoperative care
procedural techniques
recurrence
vasocentric
Epstein-Barr virus
ERG. See Electroretinogram (ERG)
e-ROP (multicenter studies)
ERT (enzyme replacement therapy)
Erythropoietin
in ROP and cognitive development
Erythropoietin derivatives (EPO)
associated with severe ROP
ESCS (enhanced S-cone syndrome)
Essential polyunsaturated fatty acids, lack of
Ethical considerations
albinism
amblyopia
choroidal osteoma
circumscribed choroidal hemangioma
combined hamartoma of the retina and retinal pigment epithelium
congenital hypertrophy of the retinal pigment epithelium
future treatments
incontinentia pigmenti
infantile nystagmus syndrome
Leber congenital amaurosis
medulloepithelioma
myopia
neurofibromatosis
neuronal ceroid lipofuscinoses
on retinopathy of prematurity
Stargardt macular dystrophy/fundus flavimaculatus
Sturge-Weber syndrome
tuberous sclerosis
Usher syndrome
Von Hippel-Lindau syndrome
Wyburn-Mason syndrome
X-linked retinoschisis
ET-ROP trial. See Early Treatment for Retinopathy of Prematurity (ET-ROP)
study
Evaluating Acute-Phase ROP (e-ROP) study
Examination under anesthesia (EUA)
infants and children retinal evaluation
ocular examination in acute pediatric eye trauma
scleral buckles
Exogenous erythropoietin
External beam radiation therapy (EBRT), for retinoblastoma
Eye(s)
embryology of
examinations, digital fundus imaging
equipment
potential systemic complications
pupils dilation
schedule
terminated
hyaloidal vasculature (see Hyaloidal vasculature)
remedies for, traditional, harmful blindness from
trauma to
wall of, definition of
Eye-field transcription factors (EFTFs)
F
FA. See Fluorescein angiography (FA); Fundus albipunctatus (FA)
Fabry disease
diagnostic studies
genetics
management
pathophysiology
Familial exudative vitreoretinopathy (FEVR)
basic considerations for technique
classification of
clinical symptoms and signs
complications after
laser treatment
vitreoretinal surgery
diagnostic studies
endoscopic vitrectomy (see Endoscopic vitrectomy)
equipment
fluorescein angiography
genetics of
optical coherence tomography
outcomes
postoperative care
procedural techniques
retinopexy and therapeutic injections
vitrectomy and/or scleral buckle
serial laser treatments
surgical management
treatment indication
for laser and anti-VEGF
for surgery
vitrectomy (see Vitrectomy)
Wnt signaling pathway and
classification system
clinical course
diagnosis
differential diagnosis
genetics
history
presentations
treatment
Familial mediterranean fever
Farber bodies
Farber disease
clinical signs and symptoms
diagnostic studies
genetics
pathophysiology
FAZ. See Foveal avascular zone (FAZ)
Fetal alcohol syndrome, childhood blindness from
FEVR. See Familial exudative vitreoretinopathy (FEVR)
ffERG (full-field electroretinogram)
Fibrillins, in vitreous
Fluocinolone implantation procedure, for uveitis
Fluorescein angiography (FA)
CHRRPE
circumscribed choroidal hemangioma
in Coats disease
contact imaging modalities
epiretinal membrane
field of view
fluorescein dye
incontinentia pigmenti
indocyanine green angiography
noncontact imaging modalities
Coats disease
diabetic retinopathy
familial exudative vitreoretinopathy
incontinentia pigmenti
retinopathy of prematurity
sickle cell retinopathy
uveitis
Norrie disease
oral fluorescein dye
persistent fetal vasculature syndrome
retinal nonperfusion
Focal retinopexy
Focal therapies, for retinoblastoma
adjuvant treatment
complications
cryotherapy
external beam radiotherapy
laser photocoagulation
transpupillary thermotherapy
Folds
Foreign body, intraocular
B-scan ultrasonography studies
computed tomography imaging
definition of
indirect ophthalmoscopy
open globe injury complication
removal of
Fovea
cones differentiation
formation of
postnatal development of
prematurity impacts, development of retinal vessels
retinal, development of
Foveal avascular zone (FAZ)
avascular
EphA
in ganglion cell layer
optical coherence tomography
Foveal hypoplasia, albinism
Foveal schisis, X-linked retinoschisis
FST (full-field stimulus or sensitivity testing) techniques
Full-field electroretinogram (ffERG)
Full-field stimulus or sensitivity testing (FST) techniques
Fundus albipunctatus (FA)
autofluorescence of
clinical symptoms and signs
flecks and spots in
fundus color photographs
genetics and pathophysiology
optical coherence tomography (OCT)
RDH5 gene mutation
Fundus autofluorescence (FAF) imaging
Fundus flavimaculatus. See Stargardt macular dystrophy/fundus
flavimaculatus
G
Galactosialidosis
clinical signs and symptoms
diagnostic studies
genetics
pathophysiology
α-Galactosidase A (GLA) deficiency
Galsulfase, ERT with
Gaucher cells
Gaucher disease
clinical signs and symptoms
diagnostic studies
genetics
pathophysiology
phenotypes
prevalence
Gene(s), retinoblastoma
Gene augmentation therapy
retinal genes targeted in
Gene therapy
animal models of
early-onset inherited retinal degeneration
application of, to pediatric retinal disease
in clinical trials, current path for
current challenges
definition
end-stage disease and developmental disorders
future prospective
gene transfer agents
inherited pediatric-onset retinal diseases
inherited retinal diseases
intraocular gene delivery approaches
intravitreal delivery
agents dispersed into vitreous chamber
clinical trials
complications
disadvantages
equipment for
for gene- or cell-based therapies
medications
postoperative care
procedural technique for
for rhegmatogenous retinal detachment
vitreous gel
for leber congenital amaurosis (LCA)
natural history studies
new disease targets
nucleic acids, clinical trials for retinal diseases
outcome measures and therapeutic windows
posterior segment
principles of
recombinant viruses, clinical trials for retinal diseases
for retinoblastoma
RPE65 mutant animals
status, for genetic disease
transchoroidal subretinal delivery
equipment for
procedural technique for
transvitreal subretinal delivery
basic considerations
benefits, risks, and potential complications
biallelic heterozygous mutations in RPE65
complications
equipment for
outcomes
postoperative care
procedural technique for
in utero
viral vectors in
Gene transfer agents in gene therapy
Gene-based therapies, genetic counseling for pediatric retinal diseases
Genetic counseling
clinical diagnosis
counselor role, in ophthalmology
goal of
patient education
providing support resources
timing
family history in
gene-based therapies
genetic complexity of, inherited
genetic testing
appropriate medical management
changing diagnosis
chorionic villus sampling (CVS)
multi-gene testing
and privacy
results
selection of
in vitro fertilization (IVF)
inheritance and risk
inheritance patterns
autosomal dominant disorder
autosomal recessive disorders
Mendelian inheritance, genetic conditions with
mitochondrial DNA mutations
multifactorial inheritance
pedigree construction, symbols used in
penetrance
X-linked disorder
on retinoblastoma
risk assessment
X-linked retinoschisis (XLRS)
Genetic heterogeneity
Genetic Information Nondiscrimination Act (GINA)
Genetic testing
retinoblastoma
Stargardt macular dystrophy
Genetics
in autosomal dominant optic atrophy
Bardet-Biedl syndrome
choroidal osteoma
in chronic progressive external ophthalmoplegia
circumscribed choroidal hemangioma
of Coats disease
congenital hypertrophy of the retinal pigment epithelium
of familial exudative vitreoretinopathy (FEVR)
glycosylation disorders
incontinentia pigmenti
in Kearns-Sayre syndrome
in Leber hereditary optic neuropathy
in Leigh syndromes
masquerade uveitis syndromes
medulloepithelioma
myopia
of neuropathy, ataxia, and retinitis pigmentosa
Norrie disease
of papillorenal syndrome
persistent fetal vasculature syndrome
of Refsum disease
of retinoblastoma
clinical
retinoblastoma gene and protein product
retinopathy of prematurity
Stargardt macular dystrophy
Usher syndrome
X-linked retinoschisis (XLRS)
Germline mutation, in heritable retinoblastoma
Giant retinal tears (GRTs)
Glaucoma
in juvenile rheumatoid arthritis-associated uveitis, surgery for
in sarcoidosis, surgery for
in uveitis
angle-closure
mechanisms of
Glioma, retinal
Global Education Network for Retinopathy of Prematurity (GEN-ROP)
Global Universal Eye Screen Testing (GUEST)
GLP (Good Laboratory Practices)
Glybera
Glycosaminoglycans, in vitreous
Glycosylation, congenital disorders of
GM1 gangliosidosis
clinical signs and symptoms
diagnostic studies
genetics
pathophysiology
GM2 gangliosidosis (Sandhoff disease)
clinical signs and symptoms
diagnostic studies
genetics
pathophysiology
GM2 gangliosidosis (Tay-Sachs disease)
cherry-red spot
clinical signs and symptoms
diagnostic studies
genetics
management
pathophysiology
prevalence
GNB3 gene, congenital stationary night blindness
Goldmann-Favre syndrome
Goldmann-Witmer (GW) coefficient, in uveitis evaluation
Gonococcal keratoconjunctivitis
Good Laboratory Practices (GLP)
Granular osmiophilic deposits (GRODs)
Granuloma, posterior pole, in ocular toxocariasis
Gyrate atrophy
H
HA. See Hyaluronan
Haltia-Santavuori
Hamartoma
astrocytic
combined
Health Insurance Portability and Accountability Act of 1996
Hemangioma, circumscribed choroidal
Hematopoietic stem cell transplant
Hemianopic field
Hemorrhage(s)
intravitreal
preretinal
retinal
retrohyaloidal
subhyaloidal subfoveal
Heparan sulfate, in vitreous
Heritable retinoblastoma
Hermansky-Pudlak syndrome (HPS)
Herpes simplex viruses
Hexosaminidase A deficiency
cherry-red spot
clinical signs and symptoms
diagnostic studies
genetics
management
pathophysiology
prevalence
High-risk retinoblastoma
Human patient-derived induced pluripotent cell (iPSC) models
Hunter syndrome
clinical signs and symptoms
diagnostic studies
genetics
management
pathophysiology
Hurler-Scheie syndrome
Hyalocytes, in vitreous
Hyaloidal vasculature
hyaloid artery
in 40-mm human embryo
in 48-mm human embryo
during atrophy
prepapillary/vitreous hemorrhage
structure of
hyaloidal vascular regression
angiopoietin receptor
macrophages
postnatal development
vascular endothelial growth factor
Wnt7b deficiency
pupillary membrane
tunica vasculosa
Hyaluronan (HA), in vitreous
Hydrocephalus
Hypermetropia
Hyperoxaluria type 1, primary
Hyperoxia
Hyperoxia-induced vaso-obliteration
Hypoxia
hypoxia-inducible factor-1
hypoxia-inducible factor-2
physiologic
VEGF accessibility
VEGF mRNA stability
Hypoxia-induced VEGF expression
Hypoxia-inducible factor (HIF)
heterodimeric transcription factors
prolylhydroxylases
regulated genes and general pathway analysis
safety and efficacy
stabilization
structure
synergy between liver and retina
Hypoxic retina
I
icCSNB. See Incomplete form of CSNB (icCSNB)
ICROP (International Classification of Retinopathy of Prematurity)
Idiopathic nonspecific orbital inflammatory syndrome
Iduronate-2-sulfatase (IDS), deficiency of
α-L-Iduronidase (IDUA), 311
Idursulfase, ERT with
IGF-1 (insulin-like growth factor)
IGF-1R (insulin-like growth factor receptor)
IGF-I (insulin-like growth factor I)
Image storage and retrieval and telemedicine
definition
remote digital fundus imaging
experimental analysis of
implementation of
KIDROP
limitations
ophthalmic technology assessment
real-world application
safety
SUNDROP
screening guidelines
Imaging and Informatics in Retinopathy of Prematurity (I-ROP)
Immunosuppressive therapy
for inflammation control in cataract surgery in uveitic eye
for intermediate uveitis
JIA-associated uveitis
for sarcoidosis
Impaired vision
In silico approaches
In utero ocular gene therapy
In vitro fertilization (IVF), genetic testing
Incomplete form of CSNB (icCSNB)
clinical symptoms and signs
genetics and pathophysiology
Incomplete penetrance
Incontinentia pigmenti (IP)
adult vitreoretinal sequelae
central nervous system involvement
clinical signs and symptoms
complications
diagnostic studies
diagnostic testing
differential diagnosis of
disease pathogenesis of
enucleation
equipment
ethical considerations
fluorescein angiography
future treatments
genetics
indications
intravitreal antivascular endothelial growth factor therapy
macular pathology
media opacity
optic nerve atrophy
management
optical coherence tomography
outcomes
peripheral ablation
postoperative care
prevalence and environmental factors
procedural techniques
retinal pigment epithelium abnormality
roles of other providers
scleral buckle
screening for
strabismus
systemic manifestations
visual rehabilitation
vitreoretinal surgery
worldwide impact
Indirect ophthalmoscopy, retinopathy of prematurity
Individual educational plan (IEP)
Individual learning plan (ILP)
Indocyanine green angiography, in choroidal hemangioma diagnosis
Infant(s)
endoscopic vitrectomy
premature, general anesthesia in
bronchospasm complicating
drugs for
extubation after
retinopathy of prematurity (ROP)
oxidative stress in preterm infant
postnatal oxygen
postnatal stresses
in utero and perinatal setting
surgical approaches (see Intravitreal surgery; Scleral buckle)
ultrasonography (See Ultrasonography)
Infantile CLN1 disease
Infantile NCL (INCL) disease
Infantile nystagmus syndrome (INS)
clinical signs and symptoms
diagnostic approach
brain imaging
clinical examination
clinical history
electroretinography
eye movement testing
molecular genetic testing
optical coherence tomography
testing
environmental factors
ethical considerations
future treatments
genetics
management
extraocular muscle surgery
optical treatments
pharmacologic therapies
subretinal gene therapy
pathophysiology
physicians and health care providers
prevalence
vision rehabilitation
worldwide impact
Infantile Refsum disease
Inflammatory bowel disease (IBD) arthritis
Informed consent, surgical intervention for infants and children
Inherited pediatric-onset retinal diseases, gene therapy
nonviral vectors, studies using
CEP290 mutations (ProQR)
viral vectors, studies using
achromatopsia (ACHM) gene therapy
choroideremia
leber hereditary optic neuropathy
retinitis pigmentosa
RPE65 deficiency
Stargardt disease
XL retinoschisis
Inherited retinal disease (IRD)
gene therapy in (see Gene therapy)
optical coherence tomography
Insulin-like growth factor (IGF-1)
Insulin-like growth factor 1 (IGF-1)
Insulin-like growth factor I (IGF-I)
Insulin-like growth factor receptor (IGF-1R)
Interfactants, in pharmacologic vitreolysis
Intermediate uveitis
age of onset
bilateral disease
diagnosis
management
antimetabolites
cataract surgery
corticosteroids
immunosuppressive drugs
oral NSAIDs
peripheral laser/cryotherapy
peripheral retinal cryopexy
vitrectomy
symptoms and signs
vitreoretinal surgery
International classification of retinoblastoma (ICRB)
International Classification of Retinopathy of Prematurity (ICROP)
International Pediatric Ophthalmology and Strabismus Council (IPOSC)
International Society for Clinical Electrophysiology of Vision (ISCEV)
Intra-arterial chemotherapy (IAC), retinoblastoma
Intracameral chemotherapy (ICC), retinoblastoma
Intraocular foreign body (IOFB)
B-scan ultrasonography studies
computed tomography imaging
definition of
indirect ophthalmoscopy
masquerade uveitis syndromes
open globe injury complication
removal of
Intraocular gene delivery approaches
Intraocular hemorrhage
Intraocular pharmacotherapy, in Coats disease
complications
equipment
supporting evidence and procedural technique
Intraocular pressure, in acute pediatric eye trauma, ocular examination
Intravenous (IV) access, in premature infant
Intravenous chemotherapy (IVC), retinoblastoma
Intravitreal chemotherapy, retinoblastoma
Intravitreal injection, of pharmacologic agents
Intravitreal lipid hydroperoxides (LHP)
Intravitreal neovascularization
Intravitreal surgery
child phakic or pseudophakic or aphakic
intraoperative considerations
adjuvant scleral buckle
choice of tamponade
drainage of subretinal fluid
membrane stripping
posterior hyaloid separation and vitrectomy
port placement
postoperative evaluation
preoperative assessment
vitrectomy
wide-angle viewing system
Intravitreal triamcinolone (IVT), in Coats disease
IOFB. See Intraocular foreign body (IOFB)
IP. See Incontinentia pigmenti (IP)
iPSC (human patient-derived induced pluripotent cell) models
IRD (inherited retinal disorders)
Iridectomy, laser, for uveitis
Iridocyclitis. See Juvenile idiopathic arthritis–associated (JIA) uveitis
Iris
in acute pediatric eye trauma, ocular examination
nodules, in sarcoidosis, surgical excision of
stromal cysts
IRVAN syndrome
ISCEV (International Society for Clinical Electrophysiology of Vision)
ISCEV standard protocol
Isoflurane, for anesthesia in premature infants
J
Janus kinase/signal transducer and activator of transcription (JAK/STAT)
signaling
Joubert (INPP5E mutations)
Joubert syndrome
Juvenile CLN3 disease
Juvenile idiopathic arthritis–associated (JIA) uveitis
band keratopathy
cataract surgery
combined phacoemulsification and pars plana vitrectomy
daunting
indications
inflammation management
IOL implantation
outcomes
pars plana lensectomy
peripheral iridectomy
risk of
glaucoma surgery
incidence
medical therapy
outcomes
inflammation management
medical management
prevalence
surgical indications
symptoms and signs
Juvenile NCL (JNCL)
Juvenile seronegative spondyloarthropathies (JSpA)
ankylosing spondylitis
inflammatory bowel disease (IBD) arthritis
psoriasis
reactive arthritis
Juvenile xanthogranuloma (JXG)
masquerade uveitis syndromes
K
Karnataka Internet Assisted Diagnosis of Retinopathy of Prematurity
(KIDROP) program
Kawasaki disease (KD)
Kearns-Sayre syndrome
clinical signs and symptoms
diagnostic studies
environmental factors
genetics
management
pathophysiology
prevalence of
systemic manifestations
worldwide impact
Keratomalacia, vitamin A deficiency disorders
corneal ulceration and necrosis
mortality rate
Keratopathy, band, for uveitis
indications
in juvenile rheumatoid arthritis-associated uveitis, surgery
procedure
Keratoprostheses
Knobloch syndrome
clinical features
genetics
Kufs disease
Kufs type B
L
Laceration, definition of
Lacrimal system, associated injury, evaluation for
Lactic acidosis, with mitochondrial encephalomyopathy and stroke-like
episodes
Lamellar schisis
Langerhans cell histiocytosis (LCH)
Laryngeal mask airway (LMA)
patient selection guidelines
for premature infant
Laser
for retinopathy of prematurity
ablative therapy
anti-VEGF studies
ETROP study
surgical iridectomy
panretinal/segmental photocoagulation
peripheral neovascularization
posterior capsulotomy vs. surgical posterior capsulotomy
Laser capsulotomy, for uveitis
Laser iridectomy, for uveitis
Laser peripheral retinal ablation
Laser photocoagulation
choroidal hemangioma
choroidal osteoma
in Coats disease
for intermediate uveitis
for retinoblastoma treatment
retinopathy of prematurity
for uveitis
Laser retinopexy
for abnormal vitreoretinal interface
for lattice degeneration
Laser-induced hyperthermia
Late infantile CLN2 disease
Late infantile NCL (LINCL)
Lattice degeneration
cryopexy for
laser retinopexy for
LCA. See Leber congenital amaurosis (LCA)
LCHAD deficiency
LCPUFAs (long chain polyunsaturated fatty acids)
Least restrictive educational environment
Leber congenital amaurosis (LCA)
CEP290, mutation in
CEP290, RPE65, CRB1 mutations
classification
clinical symptoms and signs
CRB1, mutation in
CRX, mutation in
CRX gene
diagnostic studies
differential diagnosis
environmental factors
ethical considerations
future treatments
genetic heterogeneity of
genetics
GUCY2D, mutation in
Luxturna, subretinal injection of
management
misdiagnosis of
molecular pathways causing
pathophysiology
physicians and health care providers
prevalence
RDH12, mutation in
RPE65, mutation in
TULP1, mutation in
types of
using nucleic acids, for gene therapy
using recombinant viruses, for gene therapy
vision rehabilitation
worldwide impact
Leber congenital amaurosis, retinal dystrophy
Leber hereditary optic neuropathy (LHON)
clinical signs and symptoms
diagnostic studies
environmental factors
genetics
management
pathophysiology
prevalence of
systemic manifestations
using recombinant viruses, for gene therapy
worldwide impact
Leber neuroretinitis
Leigh syndromes
Lens
in acute pediatric eye trauma, ocular examination
coloboma of, management of
Lensectomy
familial exudative vitreoretinopathy
Norrie disease
for retinopathy of prematurity-related retinal detachment
Lens-sparing vitrectomy, vision rehabilitation
Lentiviral vectors, in gene therapy
Leukemia, masquerade uveitis syndromes
Leukocoria
LHP (intravitreal lipid hydroperoxides)
Lids, evaluation for lacerations evidence
Light, retinopathy of prematurity and
animal studies
clinical trials
Light Reduction in Retinopathy of Prematurity (Light-ROP) study
Lipid metabolism
LCHAD deficiency
Sjögren-Larsson syndrome
Lipid-laden macrophages
Lipoprotein metabolism, disorder of
Liquefaction, in pharmacologic vitreolysis
Literacy, low vision
braille
definition
historical perspective
least restrictive educational environment
optical and electronic magnification devices
LMA (laryngeal mask airway)
patient selection guidelines for
for premature infant
LN11 disease
Long chain polyunsaturated fatty acids (LCPUFAs)
Low vision
barriers to care
clinical low vision rehabilitation evaluation
definition
driving with a visual impairment
functional and educational outcomes
literacy
braille
definition
historical perspective
least restrictive educational environment
optical and electronic magnification devices
optical devices
pediatric visual acuity testing
rehabilitation team
statistics
technology
vision enhancement options
Luxturna
Lysosomal storage disease (LSD)
clinical features of
cystinosis
diagnosis of
Fabry disease
diagnostic studies
genetics
management
pathophysiology
Farber disease
clinical signs and symptoms
diagnostic studies
genetics
pathophysiology
galactosialidosis
clinical signs and symptoms
diagnostic studies
genetics
pathophysiology
Gaucher disease
clinical signs and symptoms
diagnostic studies
genetics
pathophysiology
phenotypes
prevalence
GM1 gangliosidosis
clinical signs and symptoms
diagnostic studies
genetics
pathophysiology
Hurler-Scheie syndrome
management
mucolipidoses
mucopolysaccharidosis
type I
type II
type III
type IV
type VI
type VII
neuronal ceroid lipofuscinoses
clinical signs and symptoms
diagnostic studies
ethical considerations
future treatments
genetics
incidence
management
pathophysiology
physicians and health care providers, role of
vision rehabilitation
Niemann-Pick disease (NPD)
clinical signs and symptoms
diagnostic studies
genetics
management
pathophysiology
Sandhoff disease
clinical signs and symptoms
diagnostic studies
genetics
pathophysiology
Scheie syndrome
sialidosis
clinical signs and symptoms
diagnostic studies
genetics
pathophysiology
sphingolipidoses
Tay-Sachs disease
cherry-red spot
clinical signs and symptoms
diagnostic studies
genetics
management
pathophysiology
prevalence
M
Machine learning
Macula
detachments
differential diagnosis
dystrophies
autosomal dominant Stargardt-like macular dystrophy
clinical characteristics and disease course
differential diagnoses
molecular genetics of
Best disease
choroidal neovascularization
clinical findings
differential diagnosis
genetics
pathophysiology
North Carolina macular dystrophy
clinical findings
differential diagnosis
molecular genetics
pattern dystrophy
Sorsby fundus dystrophy
Macular halo syndrome
Macular hole
Coats disease
Macular pseudocolobomas
Maculopathy
optic disc pit
cerebrospinal fluid (CSF) pressure
intraocular pressure
neuroectodermal/astroglial tissue
posterior vitreous detachment (PVD)
prepapillary glial material
treatment of
Magnetic resonance imaging (MRI)
medulloepithelioma
nonaccidental head injury (NAHI)
in ocular trauma evaluation
persistent fetal vasculature syndrome
retinoblastoma
Malaria, childhood blindness from
Marfan syndrome
clinical features
genetics
pediatric rhegmatogenous retinal detachment
vitreous in
Maroteaux-Lamy syndrome
child with
clinical signs and symptoms
diagnostic studies
genetics
management
pathophysiology
Masquerade uveitis syndromes
cause of
definition
environmental factors
genetics
health care providers role
lymphoma
primary CNS
systemic non-Hodgkin
uveal
metastatic tumors
neoplastic disease entities
ciliary body medulloepithelioma
juvenile xanthogranuloma
langerhans cell histiocytosis
leukemia
retinoblastoma
nonneoplastic entities
idiopathic nonspecific orbital inflammatory syndrome
intraocular foreign body
iris stromal cyst
retinal degenerations
retinal detachment
vitreous hemorrhage
physicians role
posttransplant lymphoproliferative disorder
prevalence
uveal melanoma
vision rehabilitation
Measles virus
Measles-related blindness
cases data
corneal scarring
immunization
keratomalacia
malabsorption
malnutrition and overcrowding
primary prevention
protein-losing enteropathy
secondary prevention
Mebendazole, for ocular toxocariasis
Mechanical ventilation, for VLBW infants, general anesthesia
Medulloepithelioma
clinical symptoms and signs
diagnostic studies
differential diagnosis
environmental factors
ethical considerations
genetics
health care providers
management
pathophysiology
physicians role
prevalence
vision rehabilitation
worldwide impact
MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like
episode syndrome)
Melatonin
Mendelian genetic diseases
Metabolic disorder
abetalipoproteinemia
cobalamin-C–type methylmalonic aciduria with homocystinuria
congenital disorder of glycosylation
environmental factors
Gyrate atrophy
lipid metabolism
LCHAD deficiency
Sjögren-Larsson syndrome
lysosomal storage disease
cystinosis
mucolipidoses
mucopolysaccharidoses
neuronal ceroid lipofuscinosis
sphingolipidoses
mitochondrial disorders
Kearns-Sayre syndrome
mitochondrial variants A3243G and T8993G
peroxisomal disorders
primary hyperoxaluria
Zellweger spectrum disorders
prevalence
Metastasis, of retinoblastoma, risk of
Metastatic tumors, masquerade uveitis syndromes
Methotrexate
for inflammation control in cataract surgery in uveitic eye
for juvenile rheumatoid arthritis-associated uveitis
for sarcoidosis
Microcornea, persistent fetal vasculature syndrome
Microglia, retinal, development of
Migalastat, Fabry disease
Mild optic nerve hypoplasia
Mitochondria
disorders of
autosomal dominant optic atrophy
chronic progressive external ophthalmoplegia
ethical considerations
future treatments
health care providers
Kearns-Sayre syndrome
Kearns-Sayre syndrome as
Leber hereditary optic neuropathy
Leigh syndromes
mitochondrial encephalomyopathy, lactic acidosis, and stroke-like
episode syndrome
mitochondrial variants A3243G and T8993G
neuropathy, ataxia, and retinitis pigmentosa
physician role
vision rehabilitation
feature of
function
Mittendorf dot
Mizuo phenomenon, X-linked retinoschisis
Mizuo-Nakamura phenomenon
Morning glory disc anomaly
clinical presentation
complications
etiology of
Morquio syndrome
Morquio A syndrome
clinical signs and symptoms
diagnostic studies
genetics
management
pathophysiology
Morquio B syndrome
clinical signs and symptoms
diagnostic studies
genetics
management
pathophysiology
Mortality, in blind children
Mosaicism, genetic in retinoblastoma
Motor development
Mucolipidoses
Mucopolysaccharidosis
type I
type II
type III
type IV
type VI
type VII
Multifactorial inheritance
Multi-gene testing, genetic counseling for pediatric retinal diseases
Multi-luminance mobility test (MLMT)
Mutation
germline mutation, in heritable retinoblastoma
X-linked juvenile retinoschisis (see X-linked juvenile retinoschisis)
Mycophenolate
Myopia
childhood blindness from
clinical features
diagnostic studies
ethical considerations
genetics
management
atropine
orthokeratology
outdoor time and myopia
physician and health care providers
prophylactic retinopexy in stickler syndrome
refractive surgery
vision rehabilitation
pathophysiology and environmental factors
prevalence
scleral collagen cross-linking
tilted disc syndrome
vitreous in
worldwide impact
N
NAHT. See Nonaccidental head trauma (NAHT)
NARP. See Neuropathy, ataxia, and retinitis pigmentosa (NARP)
Nasal tilted disc syndrome, fundus appearance
National Reading Media Assessment (NRMA)
NCL. See Neuronal ceroid lipofuscinosis (NCL)
NCMD. See North Carolina macular dystrophy
Neonatal intensive care units (NICUs)
digital fundus imaging
automated algorithms
binocular indirect ophthalmoscopy
digital photography
Icon camera
3nethra Neo
Panocam
repeated examination
RetCam
Retcam3 camera
risk for ROP
software algorithms
standard images
topical anesthesia
eye examinations
equipment
potential systemic complications
pupils dilation
schedule
terminated
Neural and vascular interaction
Neurofibromatosis
clinical features
diagnostic studies
differential diagnosis
environmental factors
ethical considerations
future treatments
genetics
health care providers
management
neurofibromatosis 1 associated with glaucoma
pathophysiology
physicians role
prevalence
vision rehabilitation
Neuronal ceroid lipofuscinosis (NCL)
clinical signs and symptoms
CLN3 gene
diagnostic studies
ethical considerations
future treatments
genetics
incidence
management
pathophysiology
physicians and health care providers, role of
vision rehabilitation
Neuronal migrational anomalies
Neuropathy, ataxia, and retinitis pigmentosa (NARP)
clinical signs and symptoms
diagnostic studies
environmental factors
genetics
management of
pathophysiology
prevalence of
systemic manifestations
worldwide impact
Neuropathy, optic, Leber hereditary
Neuroretinitis
Newborn Eye Screen Testing (NEST)
Next generation sequencing (NGS)
NICUs. See Neonatal intensive care units (NICUs)
Niemann-Pick disease (NPD)
clinical signs and symptoms
diagnostic studies
genetics
management
pathophysiology
Night blindness
Nitric oxide (NO)
Nonaccidental head trauma (NAHT)
brain lesions
case studies in
cause
definition
incidence
with localized macular retrohyaloidal hematoma
ocular lesions
clinical symptoms and signs
diagnostic studies
macular changes
neovascularization and retinal ischemia
neural damage
pathophysiology and specificity
retinal detachment
retinal folds
retinal hemorrhages (see Retinal hemorrhages)
schisis
prevalence
vision rehabilitation (see Vision rehabilitation)
Nonarteritic anterior ischemic optic neuropathy (NAION)
Noninfectious uveitides
Adamantiades-Behçet disease
cryopyrin-associated periodic syndromes (CAPS)
familial juvenile systemic granulomatosis
granulomatosis with polyangiitis
intermediate uveitis
juvenile dermatomyositis
juvenile idiopathic arthritis–associated uveitis
juvenile seronegative spondyloarthropathies (JSpA)
ankylosing spondylitis
inflammatory bowel disease (IBD) arthritis
psoriasis
reactive arthritis
Kawasaki disease (KD)
masquerade syndromes
polyarteritis nodosa
sarcoidosis
sympathetic ophthalmia (SO)
systemic lupus erythematosus
tubulointerstitial nephritis and uveitis
Vogt-Koyanagi-Harada disease
Noninvasive/minimally invasive interventions
cryopexy
for lattice degeneration
for peripheral retinal ablation
focal retinopexy
intravitreal injection, of pharmacologic agents
laser retinopexy
for abnormal vitreoretinal interface
for lattice degeneration
neonatal intensive care units (see Neonatal intensive care units (NICUs))
peripheral retinal ablation
cryopexy for
for vascular/VEGF mediated retinopathies
Nonsteroidal antiinflammatory drugs (NSAIDs)
for inflammation control in cataract surgery in uveitic eye
for intermediate uveitis
for juvenile rheumatoid arthritis-associated uveitis
Nonsyndromic albinism
ocular albinism
oculocutaneous albinism
type 1
type 2
type 3
type 4
type 5
type 6
type 7
Norrie disease
basic considerations
clinical diagnosis of
clinical symptoms and signs
complications
environmental factors
equipment
genetics
indications
management
missense mutation
outcomes
pathophysiology
postoperative care
prevalence
procedural techniques
vision rehabilitation
Wnt signaling pathway and
classification system
clinical course
diagnosis
differential diagnosis
genetics
history
presentations
treatment
worldwide impact
North Carolina macular dystrophy
clinical findings
differential diagnosis
molecular genetics
Northern epilepsy (NE)
NPD. See Niemann-Pick disease (NPD)
Nutrition, prenatal weight gain
Nystagmus
O
Obesity, Bardet-Biedl syndrome
Object permanence
OCT. See Optical coherence tomography
Ocular albinism
Ocular inflammatory disease
Ocular lesions, in nonaccidental head injury
clinical symptoms and signs
diagnostic studies
macular changes
neovascularization and retinal ischemia
neural damage
pathophysiology and specificity
retinal detachment
retinal folds
retinal hemorrhages (see Retinal hemorrhages)
schisis
Ocular toxocariasis
clinical signs of
diagnosis of
diagnostic features of
management
medical
surgical
outcomes
pathogenesis of
postoperative care in
surgical indications
Ocular trauma
acute open globe injury management
complications
equipment
intraocular foreign body removal
outcomes
postoperative care
procedural techniques
prophylactic scleral buckle surgery
systemic antibiotic therapy
tetanus shot/booster administration
vitreoretinal surgery complications (see also Vitreoretinal surgery)
Birmingham Eye Trauma Terminology for
definitions
closed globe injury (see also Closed globe injury)
eye wall
intraocular foreign body
laceration
open globe injury (see also Open globe injury)
penetrating injury
perforating
superficial foreign body
diagnostic studies
ocular examination in acute pediatric eye trauma
anterior chamber depth assessment
conjunctiva
cornea
examination under anesthesia
external evaluation
iris
lens
physical examination
pupillary reflex and intraocular pressure
sclera
visual acuity measurement
patient history
posterior segment manifestations
prevalence
Oculocutaneous albinism (OCA). See also Albinism
type 1 (OCA1)
type 2 (OCA2)
type 3 (OCA3)
type 4 (OCA4)
type 5 (OCA5)
type 6 (OCA6)
type 7 (OCA7)
OD. See Oguchi disease (OD)
OFF-bipolar cell
Oguchi disease (OD)
clinical symptoms and signs
genetics and pathophysiology
OIR. See Oxygen-induced retinopathy; Oxygen-induced retinopathy (OIR)
Oligocone trichromacy
ONA (optic nerve aplasia)
ON-bipolar cells
ONH (optic nerve hypoplasia)
ONHD (optic nerve head drusen)
Open globe injury
management
complications
equipment
intraocular foreign body removal
outcomes
postoperative care
procedural techniques
prophylactic scleral buckle surgery
systemic antibiotic therapy
tetanus shot/booster administration
vitreoretinal surgery complications (see also Vitreoretinal surgery)
occurrence
as rupture
zones of
Ophthalmia neonatorum, childhood blindness from
Optic atrophy. See also Autosomal dominant optic atrophy
Optic disc edema (ODE)
Optic disc pit
maculopathy
cerebrospinal fluid (CSF) pressure
intraocular pressure
neuroectodermal/astroglial tissue
posterior vitreous detachment (PVD)
prepapillary glial material
treatment of
Optic nerve
abnormalities of
coloboma
optic disc pit
optic nerve aplasia
optic nerve head drusen (ONHD)
optic nerve hypoplasia
superior segmental optic hypoplasia
tilted disc syndrome
coloboma
development of
Optic nerve aplasia (ONA)
diagnostic criteria
embryology
Optic nerve coloboma
bilateral
complications
macular pigment
PAX2 transcription
retinal detachment
size of
treatment of
Optic nerve head drusen (ONHD)
clinical evaluation of
calcified drusen
color fundus and autofluorescence
hyperreflective
subretinal hyporeflective space (SHYPS)
complications
choroidal neovascularization
NAION
Optic nerve hypoplasia (ONH)
bilateral
clinical presentation
double ring sign
nystagmus
ophthalmoscopy
poor visual behavior
endocrine anomaly
etiology of
mild
prenatal and perinatal risk factors
prevalence of
severe
Optic neuropathy, Leber hereditary
Optical coherence tomography (OCT)
choroidal hemangioma
choroidal osteoma
choroidal rupture
CHRRPE
epiretinal membrane
fundus albipunctatus
inherited retinal diseases
intraretinal edema
maculae
medulloepithelioma
normal full-term retina
in ocular trauma evaluation
pediatric imaging
Coats disease
familial exudative vitreoretinopathy
foveal avascular zone morphology
incontinentia pigmenti
infant foveal development considerations
inherited retinal diseases
methods and limitations
pediatric choroidal neovascular membranes
pediatric epiretinal membranes
retinoblastoma
retinopathy of prematurity
trisomy 21
pediatric rhegmatogenous retinal detachment
persistent fetal vasculature syndrome
retinal layers
Stargardt disease
traumatic macular hole
X-linked retinoschisis (XLRS)
Optical coherence tomography angiography (OCT-A)
abnormalities
application
Opticin, in vitreous
Optogenetic gene therapy
Oral cysteamine therapy
Orbital pseudotumor. See Idiopathic nonspecific orbital inflammatory
syndrome
Orbital trauma
Organic amblyopia
Ornithine metabolism, disorder of
Osteoporosis pseudoglioma syndrome (OPPG)
Oxidative signaling pathways
Oxidative stress, retinopathy of prematurity and
lutein
vitamin E
Oxidative stress in preterm infant
Oxidative stress–related therapy
Oxygen, retinopathy of prematurity and
clinical trials
STOP-ROP study
SUPPORT study
high oxygen
monitoring and management
Benefit of Oxygen Saturation Targeting (BOOST) study
effect of O2 saturation
HOPE-ROP infants
length of time
STOP-ROP trial
TcPO2 levels
oxygen fluctuations
oxygen supplementation
saturation of fetus in utero, 563
Oxygen-induced retinopathy (OIR)
animal models of
clinical studies
anti-VEGF
erythropoietin in ROP and cognitive development
insulin-like growth factor (IGF-1)
hyperoxia-induced vaso-obliteration
with isolectin staining
neural and vascular interaction
oxidative stress–related therapy
oxygen fluctuations and OIR severity
physiologic retinal vascular development and pathogenic
vasoproliferation
potential antioxidant therapies
signaling pathways, postnatal stresses
antioxidants
erythropoietin
oxidative signaling pathways
VEGF signaling
VEGFA
treatment strategies
variable oxygen
P
Pain, in postanesthesia care unit, treatment of
Panda sign, in sarcoidosis
Papilla, Bergmeister
Papillorenal syndrome
Paracentesis, anterior chamber, for uveitis
Parenchymal anoxic ischemic injuries
Pars plana vitrectomy (PPV)
cataract
for intermediate uveitis
juvenile idiopathic arthritis
ocular toxocariasis
sarcoidosis
sutureless intrascleral intraocular lens fixation and
anterior chamber IOL placement
exchange/secondary IOL placement
flanged sutureless intrascleral IOL fixation
forming haptic bulbs/flanges
in Marfan syndrome
in one-piece PMMA IOL
side effects
surgical variations
for uveitis
vitreoretinal complications
Pattern dystrophy
Pax6 mutations
Pediatric choroidal neovascular membranes, optical coherence tomography
Pediatric epiretinal membranes, optical coherence tomography
Pediatric Eye Disease Investigator Group (PEDIG) study
Pediatric retinal diseases, genetic counseling for
clinical diagnosis
counselor role, in ophthalmology
goal of
patient education
providing support resources
timing
family history
gene-based therapies
genetic complexity of, inherited
genetic testing
appropriate medical management
changing diagnosis
chorionic villus sampling (CVS)
multi-gene testing
and privacy
results
selection of
in vitro fertilization (IVF)
inheritance and risk
inheritance patterns
autosomal dominant disorder
autosomal recessive disorders
Mendelian inheritance, genetic conditions with
mitochondrial DNA mutations
multifactorial inheritance
pedigree construction, symbols used in
penetrance
X-linked disorder
risk assessment
Pediatric rhegmatogenous retinal detachment (PRRD)
after ocular surgery
associated inherited disorders
Ehlers-Danlos syndrome (EDS)
Marfan syndrome
Stickler syndrome
atopic dermatitis
causes of
clinical examination
clinical presentation
diagnostic studies
epidemiology
etiology of
incidence
indications
nontraumatic inferotemporal retinal dialysis
occurrences
outcomes
postoperative care
surgerical approach
general considerations
inherited disorders
scleral buckling
traumatic/nontraumatic retinal dialysis
vitrectomy
trauma
Pediatric uveitis
diagnostic approach
differential diagnosis
age of presentation
anatomic regions
categories
juvenile idiopathic arthritis
epidemiology
history
incidence and prevalence
infectious uveitides
catscratch disease
chikungunya virus
cytomegalovirus
dengue virus
diffuse unilateral subacute neuroretinitis
Ebola viruses
Epstein-Barr virus
herpes simplex viruses
Lyme disease
lymphocytic choriomeningitis virus
measles virus
postinfectious and vaccination-associated uveitis
rubella
subacute sclerosing panencephalitis (SSPE)
syphilis
toxocariasis
toxoplasmosis
tuberculosis
varicella–zoster virus
West Nile virus
Zika virus
medical management
noninfectious uveitides (see Noninfectious uveitides)
types of
visual outcomes
Pericytes, retinal, development of
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis
(PFAPA) syndrome
Peripapillary choroidal neovascularization
Peripheral retinal ablation
cryopexy for
for vascular/VEGF mediated retinopathies
Peroxisomal disorders
primary hyperoxaluria
Zellweger spectrum disorders
Peroxisomes
biosynthetic functions
catabolic and anabolic processes
disorders of
biogenetic, affecting retina
classification
clinical manifestations
measuring saturated very longchain fatty acids
prevalence
Refsum disease as
worldwide impact
primary hyperoxaluria type 1
proteins required for
Persistent fetal vasculature syndrome (PFVS)
anterior
bilateral
characteristic findings of
clinical symptoms and signs
combined
complication
diagnostic studies
color Doppler imaging
fluorescein angiography
fundus photography
magnetic resonance imaging
optical coherence tomography
ultrasonography
visual evoked potential
differential diagnosis
genetics
glucose 6-phosphate dehydrogenase (G6PD) deficiency
long-term management
management
nomenclature and types
nonsurgical treatments
outcomes
pathophysiology
posterior
postoperative care
surgery
basic considerations
endoscopic vitrectomy
incisions
indications
intraoperative optical coherence tomography
limbal approach
pars plicata approach
small-gauge surgery
timing of
vitrectomy (see Vitrectomy)
visual rehabilitation
Wnt signaling pathway and
Persistent hyperplastic primary vitreous (PHPV)
Persistent maculopathy
PFVS. See Persistent fetal vasculature syndrome (PFVS)
Pharmacologic vitreolysis
adverse events
indications and contraindications
interfactants
liquefactants
pediatric development
Phenotypic heterogeneity
Photocoagulation, laser. See Laser photocoagulation
Photodynamic therapy (PDT)
choroidal hemangioma
with verteporfin
Photophobia
Photopic ERGs
Photoreceptors
development
differentiation of
retinoschisin synthesis
PHPV (persistent hyperplastic primary vitreous)
Pigmentary changes
Platelet-derived growth factor (PGDF) signaling
angiopoietin-1/tie-2 signaling
transforming growth factor beta1
Plus disease, diagnosis of
Polyarteritis nodosa (PAN)
Polydactyly, Bardet-Biedl syndrome
Postanesthesia care unit, pain in, treatment of
posterior microphthalmos with retinal folds (MFRP mutations)
Posterior pituitary hypoplasia
Posterior segment
hemorrhages in
masses
Posterior uveitis
Postnatal growth, timing of
Postnatal Growth and Retinopathy of Prematurity study (G-ROP)
Postnatal oxygen
Postnatal stresses, increase risk of ROP
Preimplantation genetic diagnosis (PGD). See In vitro fertilization
Premature infants, general anesthesia in
bronchospasm complicating
drugs for
endotracheal tube size and length for
extubation after
intravenous access
Premature Infants in Need of Transfusion ROP (PINT-ROP) study
Prematurity
fovea
at 24 WG
at 28 WG
by 32 WG
anatomy
Eph receptor signaling pathways
FAZ diameter
hypoxia
increased retinal thickness
oxygen-enriched environment exposure
retinopathy of (see Retinopathy of prematurity (ROP))
Prenatal weight gain
in animal studies
in clinical studies
alarm, time after birth
hydrocephalus
hyperoxia of
insulin-like growth factor I (IGF-I)
mild versus severe ROP
ROP Score, 521
at 6 weeks
WINROP
factors contributing to
inappropriate nutrition
increased metabolic rate
lack of essential polyunsaturated fatty acids
lack of growth factors and nutrients
oxygen supplementation
future interventions
nutrition
timing of postnatal growth
as risk factor for ROP
small for gestational age (SGA)
versus AGA
definition of
in mature infants
retrolental fibroplasia
standard deviation scores
Preserved para-arteriolar RPE (PPRPE)
Primary hyperoxaluria
Primary hyperoxaluria type 1
Print Media Assessment Process (PMAP)
Progressive macular atrophy
Progressive rod–cone dystrophy
Protein(s)
retinoblastoma
structural, noncollagenous, in vitreous
Pupillary reflex, in acute pediatric eye trauma, ocular examination
R
Radiation therapy
choroidal hemangioma
for retinoblastoma
Ranibizumab Compared With Laser Therapy for the Treatment of Infants
Born Prematurely with ROP (RAINBOW) study
RDFI. see Remote digital fundus imaging
RDH5 gene, congenital stationary night blindness
RDH12-LCA, full-field sensitivity (FST) testing in
Reactive oxygen species (ROS)
Recombinant adeno-associated virus vectors (rAAV)
Recombinant adenoviral vectors, in gene therapy
Recombinant α-L-iduronidase (laronidase)
Recombinant DNA engineering techniques
Refractive error
anisometropia
lensectomy
organic amblyopia
posterior uveitis
retinal detachment
retinopathy of prematurity
vitreous and retinal hemorrhages
Refsum disease
Rehabilitation
early intervention and
cerebral visual impairment
challenging test situations
clinical examination and assessment
communication
4-degree grating test
high-risk groups of infants and children with vision loss
at home and school
initial information
passive “vision stimulation,” 149–150
problematic behaviors and situations
school age
tectopulvinar pathway
during treatment
visual milestones
retinoblastoma
visual (see also Vision rehabilitation)
after cataract surgery in uveitic eye
Bardet-Biedl syndrome (BBS)
choroidal hemangioma
choroidal osteoma
circumscribed choroidal hemangioma
X-linked retinoschisis (XLRS)
Relative afferent pupillary defect (RAPD)
Remote digital fundus imaging (RDFI)
experimental analysis of
implementation of
binocular indirect ophthalmoscopy (BIO) evaluation
discharge
graders
image transfer and storage
personnel
PHOTO-ROP study
RDFI team
reports
KIDROP
limitations
ophthalmic technology assessment
real-world application
safety
SUNDROP
Respiratory compromise, in VLBW infant, general anesthesia and
Resuscitation medications
RetCam
Retina
4B
predominantly effusive, mechanism of
predominantly tractional, mechanism of
abnormal vasculature
biopsy of, in uveitis diagnosis
complications of sarcoidosis involving
degeneration of
Bardet-Biedl syndrome
degenerations of
animal models of
en-face imaging in
detachments of in retinopathy of prematurity, clinical features of
development of
embryology of
ERG waveforms, inherited pediatric diseases
eye field
foveal development
ganglion cell death
histogenesis, cell types
astrocytes
Dicer gene
FoxN4, 81
H-thymidine “birthdating” technique
lineages tracking
microglia
miRNA production
Müller glial cells
Pax6
progenitor cells
inner
amacrine cells
bipolar cells
cell adhesion molecules
contact inhibition
dendrites
ganglion cells
ganglion cells migration
inner plexiform layer
tiling
laser peripheral retinal ablation
optic cup
peroxisomal biogenesis disorders affecting
clinical symptoms and signs
diagnostic studies
environmental factors
genetics
management of
systemic manifestation
photoreceptor development
retinopathy of prematurity-related, surgical anatomy of
rhegmatogenous (see Rhegmatogenous retinal detachment)
vascular development
Retinal and choroidal dystrophies
achromatopsia
complete
ERG
gene associated with
incomplete
choroideremia
cone-rod dystrophy (see Cone-rod dystrophy)
enhanced S-cone syndrome
Leber congenital amaurosis
CRX gene
misdiagnosis of
retinitis pigmentosa
Retinal cavernous hemangioma
Retinal degenerations
Retinal detachment
masquerade uveitis syndromes
Retinal dialysis, pediatric rhegmatogenous retinal detachment
Retinal dysplasia
Retinal glioma
Retinal hemorrhages
causes of
circular hypopigmented retinal fold
differential diagnosis
hemorrhages resolution
histopathologic studies
incidence
vs. intraocular hemorrhage
with localized macular retrohyaloidal hematoma
Roth spots with fibrin
with traumatic macular hole
Retinal hypoxia
Retinal image analysis
challenges
deep learning
future directions
initial computer based imaging analysis approaches
machine learning
plus disease, diagnosis of
retinopathy of prematurity
Retinal Image multiScale Analysis (RISA)
Retinal imaging
benefits and drawbacks
central, external and internal angles
classification
clinical utility
evolution
imaging consideration
advantages
choroidal circulation
contact cameras
flying baby position
limitations
noncontact U-WF imaging module
Optos device
RetCam-III
stage 4 ROP
vertical red/black line artifacts
limitations
Phantom eye
universal retinal screening of newborn
Retinal pigment epithelium (RPE)
atrophy
development of
Retinitis pigmentosa. See also Progressive rod–cone dystrophy
Retinitis pigmentosa (RP)
Bardet-Biedl syndrome
clinical symptoms and signs
diagnostic studies in
differential diagnosis
environmental factors
gene therapy
genetics
health care providers
management of
pathophysiology
physicians role
prevalence of
vision rehabilitation
worldwide impact of
natural history studies, gene therapy
neuropathy, ataxia
using recombinant viruses, for gene therapy
X-linked, using recombinant viruses, for gene therapy
Retinitis punctata albescens
Retinoblastoma (RB)
classification
clinical presentation of
diagnostic studies
differential diagnosis
diffuse
environmental factors
epidemiology and prevalence
ethical consideration in
follow-up of
future treatments
gene therapy for, animal models of
genetic counseling and DNA testing
genetic mosaicism
genetic testing
genetics of
clinical
retinoblastoma gene and protein product
group classification
health care providers
heritable
historical context of
intravitreal chemotherapy
low-expressivity
low-penetrance
management
decision tree by patient presentation
enucleation
factors for
focal therapies (see Focal therapies)
high-risk retinoblastoma
intra-arterial chemotherapy
intracameral chemotherapy
intravenous chemotherapy
intravitreal chemotherapy
plaque radiotherapy
precision intravitreal chemotherapy
masquerade uveitis syndromes
metastasis, risk of
metastatic disease
monitoring children with
nonheritable
optical coherence tomography
orbital disease
pathophysiology of
physicians role
prognosis of
screening for
second tumor predisposition
staging examination
trilateral
vision rehabilitation
worldwide impact of
Retinocalcarine pathway
Retinocytoma
Retinoma
Retinopathy of prematurity (ROP)
advanced stages of
age of onset
aggressive posterior
anti-VEGF
safety
VEGF binding receptors
anti-VEGF treatment
aflibercept
bevacizumab
cryotherapy
intravitreal injections for
laser photocoagulation
long-term safety and neurodevelopmental outcomes
pegaptanib
pharmacodynamics and pharmacokinetics
ranibizumab
rationale for drug
recurrence and retreatment of
success rates
trials
BEAT-ROP study
blindness (see Blindness)
childhood blindness
epidemics due to
in high-income countries
primary prevention
risk factors for
screening and treatment
secondary prevention
supplemental oxygen
tertiary prevention
visual impairment and blindness
clinical symptoms and signs
clinical trials in
complications
course of
cryotherapy for
development of
diagnosis of
contact camera
indirect ophthalmoscopy
diagnostic features of
differential diagnosis of
education and management
in low-income countries
in middle-income countries
preventative measures
telemedicine and tele-education
in United States (see United States)
worldwide
effect of oxygen, historical perspectives on
endoscopic vitrectomy (see Endoscopic vitrectomy)
environmental factors in
genetics
light
neurovascular effects
oxidative stress
oxygen
pathophysiology
vascular endothelial growth factor
worldwide impact
enzymatic vitreolysis
erythropoietin derivatives
ethical considerations on
ET-ROP trial
evolution and differences worldwide
first and second epidemic of
fluorescein angiography
general anesthesia for
global workforce shortage
health care providers role
historical context
and hypoxia-inducible factors (see Hypoxia-inducible factor (HIF))
Imaging and Informatics in Retinopathy of Prematurity
incidence
infant(s)
oxidative stress in preterm infant
postnatal oxygen
postnatal stresses
in utero and perinatal setting
International Classification of
intravitreal anti-VEGF therapy
late stages of pathogenesis
low weight at birth
management of
neonatal care and
Postnatal Growth and ROP (G-ROP) study
screening
WIN-ROP algorithm
nonocular treatments on
carbon dioxide
oxygen
steroids administration
surfactant therapy
optical coherence tomography
outcomes
oxygen, primary determinant of
oxygen and angiogenesis
oxygen-induced retinopathy (see also Oxygen-induced retinopathy
(OIR))
animal models of
anti-VEGF
erythropoietin in ROP and cognitive development
hyperoxia-induced vaso-obliteration
insulin-like growth factor (IGF-1)
with isolectin staining
neural and vascular interaction
signaling pathways, postnatal stresses
variable oxygen
pathogenesis of
pathophysiology
broad anti-VEGF effects
optimal anti-VEGF dose inhibits IVNV
targeted VEGFR2 inhibition
persistent retinal avascularity, premature birth
phenotype and treatment
physicians role
postnatal weight gain
in animal studies
prematurity in clinical studies
severe ROP prediction
postoperative care
prenatal weight gain as risk factor for (see also Prenatal weight gain)
prethreshold
prevalence
prevention of
procedural techniques
lensectomy and vitrectomy
lens-sparing vitrectomy
scleral buckle
rat OIR model
refractive error
retinal detachment in
clinical features of
equipment
4B, mechanisms of
surgical anatomy of
timing of surgery
retinal hypoxia
retinal image analysis
risk factors for
severe
studies on
tele-education
telemedicine (see Telemedicine)
third epidemic of
threshold
treatment
anti-VEGF treatment
bilirubin
D-penicillamine
laser
predicting progressive stage 4
propranolol
unfavorable macular outcome
unfavorable retinal outcomes
vasopermeability factor
vision rehabilitation for
Wnt signaling pathway and
Retinoschisin synthesis, photoreceptors
Retrolental fibroplasia
Retroviral vectors, in gene therapy
Rhegmatogenous retinal detachment (RRD)
occurrence
scleral buckling
Rheumatoid arthritis, juvenile, uveitis in, surgical approaches to
Riggs type of congenital stationary night blindness
clinical symptoms and signs
genetics and pathophysiology
RLBP1 deficiency
Rod–cone dystrophy. See also Leber congenital amaurosis (LCA)
differential diagnosis of, retinoschisis
Rod-derived cone viability factor (RdCVF)
Rod-photoreceptor dysfunction. See Fundus albipunctatus (FA)
Rods
ROP. See Retinopathy of prematurity (ROP)
ROP Score, 521
ROS (reactive oxygen species)
RPE (retinal pigment epithelium)
RPE65 deficiency
RPE65 mutant, in gene therapy
RPE65-associated retinal dystrophy
Rubella
Rubella syndrome, congenital, childhood blindness from
S
Sandhoff disease
clinical signs and symptoms
diagnostic studies
genetics
pathophysiology
Sanfilippo syndrome
clinical signs and symptoms
diagnostic studies
genetics
pathophysiology
Sarcoid choroiditis, flecks and spots in
Sarcoidosis
clinical signs
conjunctival biopsy
diagnosis of
medical management
phorocoagulation for
surgerical indications
surgical management
cataracts
glaucoma
iris nodules
vitreoretinal complications
Scheie syndrome
Schisis
Schubert-Bornschein type of congenital stationary night blindness
Schwartz-Matsuo phenomenon
Sclera, in acute pediatric eye trauma, ocular examination
Scleral buckle
childhood retinal diseases
combined with pars plana vitrectomy
complications
equipment
general considerations
axial length
examination under anesthesia
familial exudative vitreoretinopathy (see also familial exudative
vitreoretinopathy (FEVR))
imaging technology
partial-thickness scleral sutures
persistent fetal vasculature (PFV) (see also Persistent fetal
vasculature syndrome (PFVS))
placement
PVR
retinal breaks
retinal dialysis
scleral thickness
Stickler syndrome
trauma
indications
outcomes
pediatric rhegmatogenous retinal detachment (see also Pediatric
rhegmatogenous retinal detachment)
complications
fishmouth effect
laser/cryotherapy
postoperative care
procedural techniques
chandelier-assisted scleral buckling
clean tenon capsule
encircling band
external drainage
general principles
retinal break localization
360-degree conjunctival peritomy
vitreoretinal traction
for retinopathy of prematurity-related retinal detachment
vitrectomy and
Sclopetaria. See Traumatic chorioretinal rupture
Scotopic ERGs
SDS (standard deviation scores)
Sea-blue histiocytes
SECORD (severe early childhood-onset retinal dystrophy)
Senior-Löken syndrome (SLSN)
Septo-optic dysplasia (SOD)
Severe combined immune deficiency (SCID)
Severe early childhood–onset retinal dystrophy (SECORD)
Sevoflurane, for anesthesia in premature infants
SGA. See Small for gestational age (SGA)
Shaken baby syndrome (SBS). See Nonaccidental head trauma (NAHT)
Sialidosis
clinical signs and symptoms
diagnostic studies
genetics
pathophysiology
Sickle cell disease
Sickle cell retinopathy, fluorescein angiography
Signaling pathways, postnatal stresses
antioxidants
erythropoietin
oxidative signaling pathways
VEGF signaling
VEGFA
Sjögren-Larsson syndrome
Slow-release steroid treatment, for uveitis
dexamethasone implantation procedure
FA reservoir device
fluocinolone implantation procedure
fluorescein angiogram
optic nerve swelling
peripapillary necrotizing retinitis
SLSN (Senior-Löken syndrome)
Sly syndrome
diagnostic studies
genetics
pathophysiology
Small for gestational age (SGA)
vs. AGA
definition of
in mature infants
retrolental fibroplasia
SMDCRD (spondylometaphyseal dysplasia with cone-rod dystrophy)
Solar retinopathy
Sonic hedgehog (Shh) gene
Sorsby fundus dystrophy
Sorsby pseudoinflammatory macular dystrophy. See Sorsby fundus dystrophy
Spatial concepts
Sphingolipidoses
Spondylometaphyseal dysplasia with cone–rod dystrophy (SMDCRD)
Standard deviation scores (SDS)
Stanford University Network for Diagnosis of Retinopathy of Prematurity
(SUNDROP)
Stargardt disease. See also Stargardt macular dystrophy/fundus
flavimaculatus
ABCA4 mutations
pisciform flecks in
using recombinant viruses, for gene therapy
Stargardt macular dystrophy/fundus flavimaculatus
animal therapeutic studies
bivariate contour ellipse area
clinical classification
autofluorescence classification
ERG classification
ophthalmoscopic/electrophysiologic/psychophysical classification
clinical symptoms and signs
eccentric fixation and preferred retinal locus in
environmental factors
ethical considerations
future treatments
gene discovery
genetic testing for
genetics
historical perspectives
management of
pathologic studies
pathophysiology
prevalence
retinol-binding protein antagonists
BPN-14136
fenretinide
RPE65 (emixustat), inhibition of
school-age issues
subtypes of
visual rehabilitation
worldwide impact
Steroids
retinopathy of prematurity and
for uveitis
glaucoma
slow-release (see Slow-release steroid treatment, for uveitis)
Stickler syndrome
autosomal dominant disorder
bilateral spontaneous retinal detachments
clinical features
COL11A1 mutation
genetics
inherited and childhood retinal detachment
ocular features of
orofacial findings
pediatric rhegmatogenous retinal detachment
buckle/vitrectomy
giant retinal tears associated with
inherited connective tissue disorders
surgical treatment
posterior retinal break
prophylactic retinopexy
complications
equipment
outcome expectations
supporting evidence and cryopexy and laser techniques
right eye, with prophylactic laser
risk of vision loss
type 1, pediatric rhegmatogenous retinal detachment
clinical presentation
Col2A1 mutation
cryoprophylaxis
Stiles-Crawford effect
STOP-ROP (Supplemental Therapeutic Oxygen for Pre-threshold
Retinopathy of Prematurity)
Store-and-forward programs
Strabismus surgery
incontinentia pigmenti
open globe injury repair
Stroke-like episodes, mitochondrial encephalomyopathy, and lactic acidosis
with
Student, Environment, Tasks, and Tools (SETT) framework
Sturge-Weber syndrome
clinical symptoms and signs
diagnostic studies
differential diagnosis
environmental factors
ethical considerations
future treatments
genetics
health care providers
management
pathophysiology
physicians role
prevalence
vision rehabilitation
Subacute sclerosing panencephalitis (SSPE)
Subdural hemorrhage (SDH)
Superior segmental optic hypoplasia
Supplemental oxygen saturation (STOP-ROP)
SUPPORT study (Surfactant, Positive Pressure, and Pulse Oximetry
Randomized Trial)
Surfactant therapy, retinopathy of prematurity and
Surgery
anatomy for
anesthesia for, inhalation, intraocular gas and
cataract (see Cataract(s))
Coats disease, intraocular
complications
equipment
supporting evidence and procedural technique
examination under anesthesia
for gene therapy (see Gene therapy)
informed consent for
intravitreal (see Intravitreal surgery)
patient position for
postoperative care
scleral buckle (see Scleral buckle)
team for
for uveitis (see Uveitis)
vitreoretinal interface in
warning bracelet
Sympathetic ophthalmia (SO)
Syndromic albinism
Chediak-Higashi syndrome
hermansky-pudlak syndrome
Systemic lupus erythematosus
T
Tadoma
Tay-Sachs disease
cherry-red spot
clinical signs and symptoms
diagnostic studies
genetics
management
pathophysiology
prevalence
Teachers of the visually impaired (TVI)
Tectopulvinar pathway
Tele-education
Telemedicine
Teller Preferential test
Therapeutic surgery, for uveitis
angle-closure glaucoma
band keratopathy
indications
procedure
cataract
indications
inflammation management
surgical technique
visual rehabilitation
glaucoma
lasers (see Laser)
uveitic glaucoma
vitreoretinal surgery (see Vitreoretinal surgery)
Thiabendazole, for ocular toxocariasis
Tilted disc syndrome
bilateral nasal
clinical appearance
astigmatism
bitemporal hemianopia
inferonasal optic nerve fiber loss
macular detachments
marked central excavation
myopia
pigmentary accumulation
etiology
prevalence of
Title VII of the Civil Rights Act of 1964
Total tractional retinal detachment (TRD)
Toxocariasis
ocular (see Ocular toxocariasis)
Toxoplasmosis
Traditional eye remedies, harmful blindness from
Transient PRL (TPLR)
Transpupillary thermotherapy (TTT), for retinoblastoma
Transvitreal vitrectomy, vision rehabilitation
Traumatic chorioretinal rupture
clinical features
globe deformation
long-term follow-up
occurrence
retinal and choroidal defect
ultrasound imaging
Traumatic macular hole
equipment
indications and basic considerations
management
OCT
origin
outcomes
pathophysiology
postoperative care
procedural techniques
ILM peeling
intraocular gas tamponade
ocriplasmin
pars plana vitrectomy
plasmin-assisted pars plana vitrectomy with C3F8 gas
platelet rich plasma
silicone oil tamponade
wound closure
subsequent vitreoretinal surgery
visual outcomes
vitreous traction
Trihexyphenidyl
Triple freeze–thaw technique
Trisomy 21, optical coherence tomography
Trophic feeds
Tuberous sclerosis
clinical symptoms and signs
diagnostic studies
differential diagnosis
environmental factors
ethical considerations
future treatments
genetics
health care providers
management
pathophysiology
physicians role
prevalence
vision rehabilitation
Tumor(s)
choroidal osteoma
circumscribed choroidal hemangioma
combined hamartoma of retina and retinal pigment epithelium
congenital hypertrophy of the retinal pigment epithelium
medulloepithelioma
phakomatoses
neurofibromatosis
Sturge-Weber syndrome
tuberous sclerosis
Von Hippel-Lindau syndrome
Wyburn-Mason syndrome
retinoblastoma as
Tumor angiogenesis, in retinoblastoma
Tumor necrosis factor receptor–associated periodic syndrome
Type 1 sialidosis
Type 2 sialidosis
U
Ultrasonography
choroidal osteoma
circumscribed choroidal hemangioma
Coats disease
Norrie disease
pediatric rhegmatogenous retinal detachment
persistent fetal vasculature syndrome
retinoblastoma
in trauma evaluation
Ultrasound
A-scan probe
benefits of
B-scan probe
choroidal effusion
Coats disease
definition
examination
incontinentia pigmenti
in infants and children
intraocular foreign body
in leukocoria
limitations
ocular toxocariasis
persistent fetal vasculature
piezoelectric effect
retinal detachment
retinopathy of prematurity
scleral rupture with vitreous incarceration
Ultra–wide-field fluorescein angiography (UWFFA)
Unilateral amblyopia
United States, education and management of ROP
digital retinal image
international ophthalmology trainees
laser photocoagulation procedures
mean distribution
misdiagnosis
ophthalmology training in
overdiagnosis
potential solutions
residents and residency program
type 2 prethreshold ROP
web-based surveys of training programs
United States Eye Injury Registry
Universal health coverage (UHC)
UPI (uteroplacental insufficiency)
Usher syndrome (MYO7A, USH2A mutations
Usher syndrome (USH)
among deaf/hard-of-hearing population
cause of
classification
clinical symptoms and signs
clinical trials
diagnostic studies
electroretinogram
examination of retinitis pigmentosa
genetic testing
lip reading
newborn hearing screening
environmental factors
ethical considerations
future treatments
genetics
health care providers role
management
pathophysiology
physician role
type 2
Usher proteins
in human hair cell
in photoreceptor
visual rehabilitation
Uteroplacental insufficiency (UPI)
Uveal melanoma, masquerade uveitis syndromes
Uveitis
fluorescein angiography
masquerade syndromes (see Masquerade uveitis syndromes)
pediatric (see Pediatric uveitis)
steroids for
slow-release
surgical approaches to
anterior chamber paracentesis
by disease (see also Intermediate uveitis; Juvenile idiopathic
arthritis–associated (JIA) uveitis; Ocular toxocariasis;
Sarcoidosis)
considerations for
diagnostic
retinal or chorioretinal biopsy
therapeutic (see Therapeutic surgery, for uveitis)
vitrectomy
V
VADD. See Vitamin A deficiency disorders, (VADD), childhood blindness
Variable oxygen
Variant LINCL
Variants of uncertain significance (VUS)
Varicella–zoster virus
Vascular endothelial growth factor (VEGF)
accessibility
anti-VEGF treatment ( see Anti-VEGF treatment)
experimental studies on pathophysiology of ROP
expression of
gradient
hypoxia-inducible factor-1
mRNA stabilization
in normal vascular development
notch signaling
role
Vascular remodeling, retinal, development of
Vascular system
choroid
choriocapillaris (CC) (see Choriocapillaris (CC))
14 to 16 weeks of gestation
Haller layer
9 to 12 weeks of gestation
regulation of
Sattler layer
21 to 22 weeks of gestation
embryonic, vitreous disorders from
notch signaling
retinal, development of
astrocytes
blood-retinal barrier development and maintenance
fovea
in human
hypoxia-inducible factor-1
hypoxia-inducible factor-2
microglia
in mouse
mRNA stability
notch signaling
physiologic hypoxia
platelet-derived growth factor signaling
vascular endothelial growth factor (see Vascular endothelial growth
factor)
vascular remodeling
vasculogenesis and angiogenesis
Vasculature
hyaloid artery
in 40-mm human embryo
in 48-mm human embryo
during atrophy
prepapillary/vitreous hemorrhage
structure of
hyaloidal vascular regression
angiopoietin receptor
macrophages
postnatal development
vascular endothelial growth factor
Wnt7b deficiency
pupillary membrane
tunica vasculosa
Vasculogenesis
VEGF. See Vascular endothelial growth factor (VEGF)
VEGF signaling
retinopathy of prematurity
anti-VEGF
evolution and differences worldwide
oxygen and angiogenesis
pathophysiology
phenotype and treatment
rat OIR model
vasopermeability factor
VEGFA
VEGFRs
Ventilation, mechanical, for VLBW infants, general anesthesia
Very low birth weight (VLBW) infant, general anesthesia in
Vessel tortuosity. See also Plus disease
Viral vectors, gene therapy for inherited pediatric-onset retinal diseases
achromatopsia (ACHM) gene therapy
choroideremia
leber hereditary optic neuropathy
retinitis pigmentosa
RPE65 deficiency
Stargardt disease
XL retinoschisis
Viral vectors, in gene therapy
Vision rehabilitation
amblyopia
asymmetric vitreous hemorrhage
Bardet-Biedl syndrome (BBS)
choroidal osteoma
circumscribed choroidal hemangioma
combined hamartoma of the retina and retinal pigment epithelium
congenital hypertrophy of the retinal pigment epithelium
equipment
incontinentia pigmenti
indications
infantile nystagmus syndrome
Leber congenital amaurosis
masquerade uveitis syndromes
medulloepithelioma
mitochondria disorders
myopia
neurofibromatosis
neuronal ceroid lipofuscinosis
Norrie disease
outcomes
retinoblastoma
Sturge-Weber syndrome
surgical technique
tuberous sclerosis
Von Hippel-Lindau syndrome
Wyburn-Mason syndrome
X-linked retinoschisis (XLRS)
Visual acuity, in acute pediatric eye trauma, ocular examination
Visual and retinal function
achromatopsia
congenital stationary night blindness
electroretinography
full-field
multifocal
leber congenital amaurosis
normal development
normal scotopic retinal sensitivity
background adaptation
dark adaptation after exposure to bright light
dark-adapted visual threshold
rod-mediated visual thresholds
spatial summation
temporal summation
normal visual acuity
retinopathy of prematurity
Visual function testing
Vitamin A deficiency disorders, (VADD), childhood blindness
in animal food sources
Bitot spot in
causes of
communities risk
conjunctival xerosis
definition of
keratomalacia
low dietary intake
malabsorption
in preschool-aged children
primary prevention for
secondary prevention
supplementation coverage
tertiary prevention
xerophthalmia
Vitamin E, retinopathy of prematurity and
Vitrectomy
familial exudative vitreoretinopathy
enzymatic vitreolysis
membrane dissection
primary RRD
rhegmatogenous detachments
silicone oil tamponade
with traction retinal detachment
with/without lensectomy
glaucoma drainage device implantation and
intravitreal surgery (see Intravitreal surgery)
lensectomy and, for retinopathy of prematurity-related retinal
detachment
lens-sparing, for retinopathy of prematurity-related retinal detachment
Norrie disease
pars plana
for traction macular detachment in ocular toxocariasis
for uveitis
pediatric rhegmatogenous retinal detachment
bimanual approach
complications
intraocular gas C3F8
perfluorocarbon liquid
PVD induction
retinal detachments
persistent fetal vasculature syndrome
anterior
posterior and combined
for uveitis
indications
intermediate uveitits
procedure
vision rehabilitation
X-linked retinoschisis (XLRS)
Vitreolysis
enzymatic, in retinopathy of prematurity
pharmacologic
adverse events
indications and contraindications
interfactants
liquefactants
pediatric development
Vitreopathy, myopic
Vitreoretinal interface
surgery and
Vitreoretinal procedures
Vitreoretinal surgery
complications for open globe injuries repair
equipment
indications
outcomes
postoperative care
procedural techniques
techniques
Vitreoretinal surgery for uveitis
indications
course of inflammation
cyclitic membranes, removal of
opacities removal
vitreomacular membranes removal
pars plana vitrectomy
procedure
scleral buckle procedures
Vitreoretinopathies. See also Familial exudative vitreoretinopathy (FEVR)
atropine
familial exudative (see also Familial exudative vitreoretinopathy
(FEVR))
orthokeratology
outdoor time and myopia
physician and health care providers
prophylactic retinopexy in stickler syndrome
refractive surgery
vision rehabilitation
Vitreous
abnormal development of
biochemistry of
collagen disorders
cyst(s)
development and aging
persistent hyperplastic primary (See also Persistent fetal vasculature
syndrome)
persistent hyperplastic primary vitreous
primary
secondary
structure of
supramolecular organization
Vitreous and retinal hemorrhages
Vitreous base, structure of
Vitreous body, biochemistry of
Vitreous cortex
Vitreous hemorrhage, masquerade uveitis syndromes
Vitreous seeds, in retinoblastoma
Vitreous surgery, for retinopathy of prematurity goals of
Vogt-Koyanagi-Harada disease
Von Hippel-Lindau syndrome
clinical features
diagnostic studies
differential diagnosis
environmental factors
ethical considerations
future treatments
genetics
health care providers
management
pathophysiology
physicians role
prevalence
vision rehabilitation
Vulnerable subjects
W
Wagner syndrome
clinical features
genetics
Wagner vitreoretinal dystrophy
Weight IGF-I Neonatal ROP (WINROP)
West Nile virus (WNV)
Wide-field fluorescein angiography, incontinentia pigmenti
WINROP (Weight IGF-I Neonatal ROP)
Wnt signaling pathway
and Coats disease
and coloboma
discovery
microcornea and
molecular pathways in
Norrie disease and FEVR
classification system
clinical course
diagnosis
differential diagnosis
genetics
history
presentations
treatment
and osteoporosis pseudoglioma syndrome
and persistent fetal vasculature syndrome
posterior megalolenticonus and
retinal vasculature development
and retinopathy of prematurity
Wyburn-Mason Syndrome
clinical features
diagnostic studies
differential diagnosis
environmental factors
ethical considerations
future treatments
genetics
health care providers
management
pathophysiology
physicians role
prevalence
vision rehabilitation
X
XL retinoschisis
using recombinant viruses, for gene therapy
X-linked cone-rod dystrophy
X-linked congenital stationary night blindness, CSNB1 (NYX mutation) and
CSNB2 (CACNAF1 mutation)
X-linked disorders
X-linked dominant inheritance
X-linked juvenile retinoschisis (RS1 mutation)
X-linked retinitis pigmentosa (RPGR mutation)
X-linked retinoschisis (XLRS)
classification system for
clinical symptoms and signs
diagnostic studies of
differential diagnosis of
environmental factors
ethical considerations and genetic counseling
future treatments
genetics
health care providers
human XLRS gene therapy
low-vision aids
medical management
pathophysiology
physicians role
prevalence of
surgical treatment of
vision rehabilitation
Z
Zellweger spectrum disorders
Zellweger syndrome
Zika virus
APPENDIX OF PROCEDURAL
VIDEOS
Georges Caputo
A. COATS DISEASE
B. FAMILIAL EXUDATIVE
VITREORETINOPATHY (FEVR)
C. MACULA
D. RETINAL DETACHMENT
Video 10 Management of Retinal Detachment in
Stickler Syndrome
This one eye boy presented a recent retinal detachment due to a giant superior
retinal tear although a few months before, a thorough retinal examination did
not find any predisposing lesions. After placing a 3-mm scleral buckle, a 25-
G vitrectomy is performed. A dye, such as sodium fluorescein, allows better
visualization of the posterior vitreous, and the retinal tear appears to be at the
ora serrata. Perfluorocarbon liquid (PFCL) is used to reposition and stabilize
the retina to apply peripheral laser. A PFCL/silicone oil exchange was then
performed. Long-term results are presented.
PLEASE NOTE: DYE MUST BE APPROVED FOR INTERNAL
USE IN THE VITREOUS AND MAY NOT BE AVAILABLE
EVERYWHERE.
F. POSTERIOR PFV
G. ROP
BACKGROUND
AAO Guidelines for Ordering Genetic Testing for
Inherited Eye Diseases (1)
Genetic t1esting should be performed by a clinician or genetic counselor
familiar with such testing.
Avoid direct-to-consumer testing.
When possible, use a Clinical Laboratory Improvements Amendments
(CLIA)-certified laboratory to ensure quality testing that meets federal
standards for dealing with human clinical specimens and providing a
formal report. (For example, a patient with genetic testing completed in
a non–CLIA-certified lab may be ineligible for a clinical trial until
confirmed by a CLIA-certified lab.)
Use the patient's personal and family history when ordering tests to
identify the most specific test for the patient.
Consider genotype–phenotype correlations when available.
Avoid genetic testing for conditions that do not have a well-defined
molecular association, such as multifactorial conditions, like
nonsyndromic myopia.
The Essential Role of Genetic Counseling
Genetic counseling is recommended for individuals undergoing genetic
testing. This process includes the following goals:
Interpretation of family and medical history to assess the chance of
disease recurrence in future offspring.
Education about inheritance, testing, management, prevention,
resources, and research.
Counseling to promote informed choices and adaptation to the risk
or condition.
Medical geneticists are MDs who specialize in diagnosing, treating, and
counseling for genetic disorders.
Genetic counselors are allied health care professionals who have
specialized education in medical genetics and counseling to interpret
genetic test results and to guide patients through the genetic testing
process.
For more information on genetic counseling, please refer National
Society of Genetic Counselors webpage: https://www.nsgc.org
Ophthalmic geneticists are ophthalmologists who had done special
training and/or have a special interest in genetic eye disorders.
Ophthalmic geneticists diagnose, guide treatment and rehabilitation, and
counsel patients and families about genetic eye disorders. Ophthalmic
geneticists have the expertise to discuss prognosis as well as current
treatment and clinical trial options tailored to each disorder and to each
individual.
Medical geneticists, genetic counselors, and ophthalmic geneticists
working together provide the most comprehensive care to patients with
genetic eye disorders (2).
Definitions
1. Exome—refers to all DNA sequences encoding proteins
2. Genome—refers to all coding and noncoding regions of the DNA
Key Point: A typical patient's exome has 40,000 variants that will differ from
the reference sequence. A typical patient's genome has 3,000,000 variants
that differ from the reference sequence.
TABLE 1-2
Array-Based Techniquesa (Table 1-3)
TABLE 1-3
TABLE 1-4
FIGURE 1-2 Algorithm for testing strategy of a patient
with a suspected genetic disorder. Pre- and posttest genetic
counseling is strongly recommended.
TABLE 2-1
aBoth usually have retinal manifestations (foveal hypoplasia), but the etiology of photodysphoria arises
largely from iris transillumination and hypoplasia, respectively.
bPatients with these diagnoses are not uniformly photodysphoric, initial symptoms depend largely on
whether cone dysfunction predominates in early phases of disease.
AD, autosomal dominant; ANCA, antineutrophil cytoplastic antibody; APS, antiphospholipid
syndrome; AR, autosomal recessive; BCM, blue cone monochromacy; BBS, Bardet Biedl syndrome;
BED, Bornholm eye disease (BED); BEM, bull's eye maculopathy; CHRPE, congenital hypertrophy of
the retinal pigment epithelium; cCSNB, complete congenital stationary night blindness; CNS, central
nervous syndrome; CPEO, chronic progressive external ophthalmoplegia; CRAO, central retinal artery
occlusion; CRD, cone–rod dystrophy; D-15, Farnsworth D-15 dichotomous color blindness test;
ffERG, full-field ERG; ED-OCT, enhanced-depth OCT; EEG, electroencephalogram; GVF, Goldmann
VF; HIV, human immunodeficiency virus; iCSNB, incomplete congenital stationary night blindness;
IOP, intraocular pressure; IP, incontinentia pigmenti; IVFA, intravenous fluorescein angiography;
LCA, Leber congenital amaurosis; LP, lumbar puncture; mfERG, multifocal ERG; MRI, magnetic
resonance imaging; MRV, magnetic resonance venography; NARP, neuropathy, ataxia and retinitis
pigmentosa; POFLs, pigmented ocular fundus lesions; PFV, persistent fetal vasculature (also known as
PHPV, persistent hyperplastic primary vitreous); PVL, periventricular leukomalacia; SD-OCT, spectral
domain optical coherence tomography; SECORD, severe early childhood onset retinal dystrophy;
SNHL, sensorineural hearing loss; SLE, systemic lupus erythematosus; RP, retinitis pigmentosa; RPE,
retinal pigment epithelium; TB, tuberculosis; TORCH, Toxoplasmosis, Other (Syphilis, Zika,
Parvovirus B19), Rubella, Cytomegalovirus, Herpes (simplex, zoster); VF, visual field; VKH, Vogt-
Koyanagi-Harada disease or Harada disease (just ocular involvement); XL, X-linked.
3
Online Resources for Pediatric
Genetic Retinal Disorders
Arlene Drack
INTRODUCTION
Online resources can be and are updated on a regular basis for sites related to
pediatric genetic eye disorders. Because of the rapid expansion of knowledge
in genetics, online resources listing genes that have been identified, which
mutations are pathologic versus normal variants, and which clinical trials are
recruiting are preferable to print, which will be out of date almost as soon as
they are published.
Genetic variation is responsible for the breadth and richness of human
characteristics. Because our knowledge of the human genome is young, our
understanding of the “normal” genetic sequences of genes is incomplete.
Normal human DNA sequences have been culled from a relatively small
number of people who were described as normal, but who may have harbored
genetic abnormalities of which they were unaware. In addition, they did not
represent the full panoply of normal human genetics across the globe.
Subsequently, the range of normal has been expanded and will continue to
be. Novel mutations in known disease-causing genes, new mutations, and
types of mutations in genes previously not connected to a specific phenotype
are also constantly being found. In addition, some variations initially thought
to be benign may actually contribute to polygenic or very common disorders.
In order for a variant in DNA to be classified as disease causing, it must be
proven that it changes the protein product of the gene in a way likely to
disrupt function, and it must not be more common in the general, healthy
population than the disorder is. Because certain variants, either benign or
deleterious, are more common in populations from certain ancestral groups
than others, unless the normative database includes a diverse population,
there will be errors in designation of variants (1). In addition, because some
disorders are not fully penetrant, that is, not everyone who has the
mutation(s) gets the disease, and some genetic conditions are phenotypically
heterogeneous with some affected people having all the features of a
syndrome and others only one or a few, our estimates of disease frequency
may be in error. In this case, mutations found in the reference population may
be deemed too common to cause the disease because the frequency of the
disorder is underestimated (2).
The sites below are a few examples of sites found to be especially useful
to clinicians caring for children with genetic retinal disorders. This list is not
exhaustive; many other sites exist and many more than are available at this
writing are likely to be developed in the years to come. The examples below
provide a starting point to using resources online to aid in the understanding
and treatment of our patients with genetic retinal disorders.
GENEREVIEWS
1. https://www.ncbi.nlm.nih.gov>books>NBK1116
a. GeneReviews is published by the University of Washington,
Seattle.
b. This resource is geared toward clinicians and provides
information on diagnosis, genetics, management, and genetic
counseling.
c. Each chapter focuses on a single phenotype/disease or a single
gene or summarizes the genetics of a common condition.
d. There are currently 759 chapters.
e. Each chapter is written by experts in the field, is peer reviewed,
and is updated at least every 2 to 4 years.
f. GeneReviews chapters are accessible through PubMed.
i. Use this resource
1. To quickly learn about the genes causing a specific condition
2. To quickly learn about the clinical manifestations of a specific condition
3. To review what clinical findings might be present in a patient with
mutation or deletion of a specific gene
ii. Case example
1. A 10-year-old boy is being referred for night blindness. Visual acuity is
20/30, and there is no bone spicule like pigmentation. You suspect X-
linked congenital stationary night blindness. What is the appropriate
workup?
a. Access GeneReviews. Search X-linked congenital stationary
night blindness in the search box.
i. Under Diagnosis/testing, an ERG and genetic testing of the genes
CACNA1F and NYX are suggested. Description of the
characteristic ERG waveform is provided. Different approaches to
genetic testing are outlined. Under Suggestive Findings, myopia is
listed, which can be ascertained on clinical exam.
PUBMED
1. https://www.ncbi.nlm.nih.gov>pubmed
a. This is a free search engine of references and abstracts primarily
in the life sciences and biomedical research. It is maintained by
the United States National Library of Medicine at the National
Institutes of Health.
i. Use this database
1. To find the latest research publications on a specific disease or gene
2. To find high-quality scientific summary and survey articles on a topic
ii. Case example
1. An infant presents with nystagmus and very poor vision. You suspect
LCA. Parents would like to know whether research is being done on
LCA and if so what have the results been.
a. Access PubMed. Enter Leber congenital amaurosis in the search
space.
i. 996 articles are listed ranging from treatment with topical
brinzolamide for associated cystoid macular edema to numerous
gene-specific subtypes such as RDH12 and GUCY2D, to animal
model studies in zebrafish and mice. This gives an overview of
the many facets of research into this condition; you can tell the
parents that this is a very active field of research and there are
many different genetic subtypes—genetic testing or referral to
medical genetics for testing is indicated.
ii. Now, narrow your search to Leber congenital amaurosis and
clinical trial. Results from clinical trials for RPE65 and CEP290
LCA as well as overview articles on retinal gene therapy come up.
These can be summarized or printed for parents.
CLINICALTRIALS.GOV
1. www.clinicaltrials.gov
a. A database of clinical trials provided by the U.S. National
Library of Medicine.
b. As of 9/28/19, there were listings for 317,735 research studies
being conducted in 50 states and 209 countries, including both
privately and publicly funded studies.
c. The U.S. government does NOT evaluate vet or endorse studies
listed on this site, it simply maintains the list.
i. Use this database
1. To learn about which clinical trials are being conducted for specific
diseases and molecular genetic diagnoses
2. To learn which clinical trials are recruiting and what the inclusion and
exclusion criteria are
3. To find contact information for researchers conducting clinical trials
ii. Case example
1. An 18-year-old male patient presents with decreased vision and a strong
family history of choroideremia. He is interested in learning about any
clinical trial that he may be able to enroll in.
a. Go to clinicaltrials.gov. In the search box, type choroideremia.
Twenty studies come up; 6 have been completed; 1 of these has
results available, which can be reviewed and shared with the
patient. Five are recruiting, but only 2 of these are
interventional studies, the others are observational. One of the
interventional studies is a phase 2 safety trial open to males 18
years of age or older with molecular genetically confirmed
choroideremia. The other is a phase 3 efficacy study with the
same inclusion criteria. Some patients will be randomized to a
nontreatment control group for a year in the phase 3 study.
Contact information is given for both studies. Thus, there are
several options with different pros and cons for this patient, and
the first step is molecular genetic testing. A clinical diagnosis,
even with family history, is not adequate to be considered for
the studies.
EXOME AGGREGATION
CONSORTIUM (EXAC)
1. exac.broadinstitute.org
a. This is a collaborative database produced by a coalition of
investigators.
b. As of 9/28/19, it included data on 60,706 individuals who had
their DNA sequenced as part of disease-specific and population
genetic studies.
c. It gives information on how frequent individual variants and
disease-causing mutations are in a wide array of genes.
i. Use this database
1. To study a gene of interest
2. To look into whether a variant found in a patient is likely to be disease
causing
ii. Case example
1. A 10-year-old patient presents with a year long history of decreased
central vision. Fundus appears normal. OCT shows disruption of the
outer nuclear layer in the fovea. Genetic testing for juvenile
maculopathy reveals 2 variants in the ABCA4 gene, one a known
disease-causing mutation, the other a variant thought to be benign.
ExAC can be consulted to further understand the unknown variant.
a. In ExAC, ABCA4 is noted to have 2,342 different variants
reported.
b. The patient's second variant, c.6764 G>T (p.Ser2255Ile),
1:94461717 C/A, has been found as homozygous variants in
1,273 unaffected people, making it very unlikely to be disease
causing.
c. The frequency of this allele across populations is 0.08, and in
people of African descent, it is 0.49; these frequencies are too
high for a disease as rare as autosomal recessive Stargardt
disease.
d. Conclusion: The second variant found is not likely to be disease
causing. Either the patient has a second, occult Stargardt
disease causing mutation, or the patient has a phenocopy of
Stargardt and another etiology of their maculopathy must be
suspected. One caveat: Some variants that are benign in the
homozygous state can be disease causing if they occur with a
much more damaging allele.
REFERENCES
1. Whiffin N, Ware James S, O'Donnell-Luria A. Improving the understanding of genetic variants
in rare disease with large-scale reference populations. JAMA 2019;322(13): 1305–1306.
2. Lek M, Karczewski KJ, Minikel EV, et al. Analysis of protein-coding genetic variation in
60,706 humans. Nature 2016;5369(7616):285–291.
4
Genetic Mutations and Related
Proteins Associated with Inherited
Retinal Diseases
Robert S. Molday
GENERAL CONSIDERATIONS
Inherited retinal diseases are a heterogeneous group of disorders that
represent a significant cause of blindness in the world. They are typically
characterized by the loss in vision resulting from mutations in genes that
encode proteins essential for photoreceptor cell function and/or survival.
Over 271 genes are now known to cause various retinopathies, and the
chromosomal loci of another 36 disease-causing genes have been mapped
using a variety of genetic strategies including candidate gene approaches,
linkage analyses, and next-generation sequencing (NGS)
(http://www.sph.uth.tmc.edu/RetNet/). This accounts for over 85% of the
inherited retinal diseases and includes the most prevalent retinopathies (1,2).
With continued genetic screening of affected patients, the remaining genes
associated with loss in vision will be identified in the near future. These
studies will also provide additional information on the number and types of
disease-causing mutations thereby expanding our understanding of genetic
and molecular mechanisms responsible for retinal diseases, advancing our
knowledge on phenotype–genotype correlations, and importantly serving as a
basis for developing novel rationale treatments that will slow or prevent
vision loss in affected patients.
A significant fraction of genes linked to inherited retinal diseases are
solely or predominantly expressed in developing or adult photoreceptor cells
or retinal pigment epithelial (RPE) cells. These genes encode proteins that
play crucial roles in any of a wide variety of biochemical pathways essential
for the development, structure, function, or survival of these cells. They
include the visual cycle, phototransduction, photoreceptor outer segment
structure and renewal, cilium structure and transport, protein trafficking,
RNA splicing, lipid and nucleotide metabolism, translation and transcription,
posttranslational protein modifications, extracellular matrix, cell–cell and
cell–matrix adhesion, and synaptic structure and function among others
(Figure 4-1). Some genes associated with inherited retinal diseases are
expressed in other tissues as well as the retina. Mutations in these genes may
trigger phenotypes associated with these tissues. Such diseases are referred to
as syndromic diseases. In other cases, however, defective genes are expressed
in a wide variety of tissues as well as the retina, but the phenotype associated
with the genetic defect is only apparent in the retina. Such genes may have
evolved to encode proteins that play essential roles in retinal cell biology but
only redundant functions in other tissues.
GENES
Genetic studies have highlighted the extreme heterogeneity of retinal diseases
(2,10). Clinically defined disease phenotypes often arise from mutations in
any of a large number of different genes. To date, over 80 genes are currently
known to cause retinitis pigmentosa (RP); 27 genes are associated with cone
dystrophy (CD) and cone–rod dystrophies (CRDs); 14 genes have been
linked to Leber congenital amaurosis (LCA1–14); 15 genes are associated
with Usher syndrome; 18 genes are responsible for Bardet-Biedl syndrome
(BBS); and 13 genes are responsible for congenital stationary night blindness
(CSNB) (for an updated listing, see the RetNet Web site:
http://www.sph.uth.tmc.edu/RetNet/) (see also Section on Genetics in
Pediatric Retina and Resources in e-book). Additional genetic screening and
NGS methods including whole-exome and whole-genome NGS will add new
genes to the list of inherited retinal diseases (11, 12, 13).
The inheritance patterns can vary for many retinal diseases. This is best
exemplified for RP, a retinal degenerative disorder typically involving the
degeneration of rod photoreceptor cells and progressive loss in cone cells
(14). The pattern of inheritance can be autosomal dominant, autosomal
recessive, X linked, or in rare cases maternal mitochondrial and digenic. In
the case of autosomal dominant RP (ADRP), a disease-causing mutation in
only one allele is sufficient to cause the progressive loss in vision associated
with the degeneration of photoreceptor cells; for autosomal recessive RP
(ARRP), a disease-causing mutation in each allele has to be present; and for
X-linked RP (XLRP), the defective gene is mapped to the X chromosome.
Currently, 22 genes are known to cause ADRP accounting for about 30% to
40% of RP cases, 41 genes have been implicated in ARRP representing 50%
to 60% of RP cases, and 2 known genes are identified for XLRP accounting
for 5% to 15% of the RP cases of known inheritance pattern. The mode of
inheritance of a large number of RP cases is unknown. These are commonly
referred to as simplex cases. Mutations in the RHO gene encoding rhodopsin
account for approximately 30% of the ADRP cases, mutations in the USH2A
gene encoding usherin, a large membrane protein containing numerous
extracellular domains, account for up to 17% of ARRP cases, and mutations
in RPGR encoding the X-linked RP GTPase regulator, RPGR, that functions
in cilium structure and function account for about 80% of the genetically
identified forms of XLRP (14). In rare cases, RP can arise through digenic
inheritance involving mutations in two different genes. Individuals with
either a L185P mutation in peripherin-2 (PRPH2) or a null mutation in
ROM1 are unaffected, whereas individuals who inherit both mutations
display a RP phenotype (15).
In a number of cases, a given disease phenotype arises from mutations in
a single gene. For example, autosomal recessive Stargardt macular
degeneration (STGD1) is caused by mutations in the ABCA4 gene encoding
the photoreceptor ATP binding cassette transporter ABCA4 (16);
choroideremia is associated with mutations in the CHM gene encoding the
rab escort protein 1, REP1 (17); X-linked juvenile retinoschisis (XLRS1) is
caused by mutations in the RS1 gene encoding the extracellular protein
retinoschisin (also known as RS1) implicated in cell–cell adhesion (18);
Sorsby fundus dystrophy is linked to mutations in TIMP3 gene encoding the
metalloproteinase inhibitor 3 protein, TIMP3 (19); and Best vitelliform
macular dystrophy (BEST1) is caused by mutations in the VMD2 gene
encoding the chloride channel bestrophin-1 in RPE cells (20).
In most cases, any one of a large number of different mutations within the
gene can cause a given clinically defined disease. Over 170 mutations in
RHO are known to cause ADRP, 150 mutations in RPGR cause XLRP, 130
mutations in RS1 cause X-linked retinoschisis, and over 1,000 mutations in
ABCA4 cause autosomal recessive Stargardt macular degeneration and related
retinopathies. The specific mutation within a gene can have a major influence
on the phenotypic features of the disease. Some mutations can result in a
significant reduction in protein expression and accordingly cause a severe,
early-onset disease, whereas others may only partially affect protein
expression leading to a milder, later-onset disease. In some cases, clinical
diagnosis of individuals with early- and late-onset diseases results in distinct
clinical disease classifications. For example, early diagnosis of disease-
causing mutations in ABCA4 reveals characteristics of Stargardt disease,
whereas later stages of the disease may be more characteristic of CRD (21,
22, 23, 24).
In many cases, however, a clinical phenotype can arise from any of a
number of different genes encoding proteins that function in distinct cellular
processes. Genes associated with RP encode proteins that function in
phototransduction, the visual cycle, outer segment disk structure and
morphogenesis, cilium structure and protein trafficking, pre-RNA splicing,
and transcription among others. Defects in genes associated with LCA, a
severe early-onset retinopathy in which children are born with little or no
vision, typically encode key proteins required for photoreceptor or RPE cell
survival and in some cases development. These genes are often
predominantly expressed in both rod and cone photoreceptor cells or RPE
cells required for photoreceptor survival.
Heterogeneity of retinal degenerative diseases is further evident in the
finding that different mutations in a given gene can cause clinically distinct
diseases. Some missense mutations in the PRPH2 gene encoding the
photoreceptor structural protein peripherin-2 (also known as peripherin/rds or
PRPH2) are associated with ADRP, while other mutations in PRPH2 cause
autosomal dominant pattern macular dystrophy (25,26). Genetic defects in
the GUCY2D gene encoding guanylate cyclase 1 (GC1 or RetGC1) can cause
autosomal recessive LCA type 1 (LCA1) or autosomal dominant CRD
(27,28). Mutations in RPE65 localized in RPE cells have been reported to
cause autosomal recessive LCA2, ARRP, or ADRP depending on the
mutation and diagnosis (29, 30, 31). Furthermore, different family members
with the same genetic defect may exhibit different clinical phenotypes as in
the case of different retinopathies associated with a given mutation in the
PRPH2 gene (32). This highlights the difficulty in assigning a disease
phenotype to a genetic mutation. Although the genotype plays a central role
in determining the disease phenotype, other factors including modifier genes,
age of diagnosis of the affected individual, and socio-environmental factors
can alter the clinical description of the disease.
The candidate gene approach was first used to identify genes associated
with retinal degenerative diseases. In this approach, patients with RP or other
diseases were screened for mutations in genes encoding well-characterized
photoreceptor-specific proteins. A mutation in the RHO gene was first
identified by this approach 30 years ago and shown to cause ADRP (33).
Subsequently, individuals with RP were screened for mutations in the PRPH2
and PDE6B, genes which had previously been reported to cause retinal
degeneration in the rds and rd1 mice, respectively (34,35). Genetic screens
have confirmed that mutations in most genes encoding key proteins involved
in phototransduction, the visual cycle, and photoreceptor structure are
responsible for various types of retinopathies (Figure 4-2).
GENETIC MUTATIONS
A wide variety of genetic mutations are known to cause retinal degenerative
diseases. These include nonsense mutations, indels (insertions or deletions),
splice site, and missense mutations. Nonsense mutations produce premature
stop codons typically resulting in a shortened, nonfunctional protein.
Insertions and deletions that are not divisible by 3 typically cause a
downstream frameshift that results in an altered, often truncated protein.
Together with nonsense mutations, indels are often considered as null alleles
since the altered protein lacks function and is typically unstable and rapidly
degraded by the cell. Splice site mutations often result in defective translation
leading to a null allele, although in some cases defective splicing may be
incomplete resulting in reduced levels of the transcripts and encoded protein
(38).
Disease-causing missense mutations result in the substitution of a key
amino acid for another amino acid. Such substitutions can produce a highly
misfolded, nonfunctional protein that is retained in the endoplasmic reticulum
(ER) by the quality control system of the cell and rapidly degraded by the
proteasome (39). Alternatively, a missense mutation may result in a stable
protein, but its function and/or its cellular localization is drastically impaired
(40, 41, 42, 43, 44). Such mutations can result in either a gain or loss in
function. Most missense mutations in the RHO gene that cause ADRP result
in altered expression, localization, and functional properties of rhodopsin
leading to progressive rod photoreceptor cell death (45,46). Autosomal
dominant diseases can also be caused by haploinsufficiency. In this instance,
the protein encoded by the nonmutated (wild-type) allele is produced in
quantities below that required for normal cellular function and/or survival.
This is evident for some mutations in PRPH2 encoding the outer segment
structural protein peripherin-2 and linked to autosomal dominant
retinopathies (47). Most missense mutations linked to recessive retinal
diseases cause protein misfolding and/or a loss in function due to the removal
of a key amino acid (40,43,48,49).
Although most disease-associated mutations are found within the coding
regions of the genes, in some instances, disease causing mutations have been
found in noncoding regions. NGS has been particularly useful in identifying
and locating disease-causing mutations within introns of genes as in the case
of mutations in ABCA4 associated with STGD1 (50,51).
Many studies have been directed toward correlating genotypes with
phenotypes for specific retinal degenerative diseases (32,40,52, 53, 54). For
the most part, this has been a daunting task as the phenotype for many
diseases not only results from the specific mutation but also from other socio-
environmental and genetic factors. In a number of cases, the disease severity
has been shown to be dependent on the residual expression and functional
activity of the mutated protein (40). Nonsense, frameshift mutations, and
splice site mutations that effectively result in null alleles often cause an
earlier onset and more severe phenotype, whereas missense mutations that
produce proteins that retain residual functional activity may result in less
severe, late onset, phenotype (10). In some cases, however, the expression of
a highly misfolded protein can result in a more severe phenotype due to
cellular stress related to the expression and removal of the misfolded protein.
Visual Cycle
The visual or retinoid cycle is another key pathway in the visual response
(94,95). This process incorporates a number of retinoid binding proteins and
enzymes, which function in the conversion of all-trans retinal generated from
photoactivation of rhodopsin and cone opsin to 11-cis retinal for the
regeneration of photopigment (Figure 4-3). In the conventional visual cycle,
a significant fraction of the all-trans retinal derived from the photoactivation
of rhodopsin or cone opsin is first reduced to all-trans retinol by retinal
dehydrogenase 8 (RDH8) present on the cytoplasmic side of photoreceptor
disk membranes. All-trans retinol is transported to RPE cells by the
interphotoreceptor retinoid binding protein (IRBP), and with the aid of
cellular retinol binding protein 1 (RBP1 also known as CRBP1), it is
delivered to lecithin retinol acyltransferase (LRAT) for esterification and
hydrolysis prior to isomerization to 11-cis retinol by retinoid
isomerohydrolase RPE65. Retinal dehydrogenase (RDH5) subsequently
oxidizes 11-cis retinol to 11-cis retinal. With the aid of retinaldehyde binding
protein (RLBP1 also known as CRALBP) and IRBP, 11-cis retinal is
returned to the photoreceptor outer segment disk membranes where it
combines with opsin to regenerate rhodopsin.
Some of the all-trans retinal (~30%) released from rhodopsin or cone opsin
after photoexcitation reversibly react with the phospholipid,
phosphatidylethanolamine (PE) to form the Schiff base adduct, N-
retinylidene-phosphatidylethanolamine (N-Ret-PE) (55,96,97). A significant
fraction (~20% to 30% of N-Ret-PE) is trapped on the lumen side of the disk
membrane. The function of the ATP-binding cassette transporter ABCA4 is
to flip N-Ret-PE from the luminal to the cytoplasmic side of the disk
membrane. There, N-Ret-PE dissociates into all-trans retinal and PE enabling
all-trans retinal to be reduced to all-trans retinol by RDH8 for re-entry into
the visual cycle. This transport function of ABCA4 insures that all of the all-
trans retinal generated from photoactivated rhodopsin and cone opsin is
effectively cleared from disk membranes preventing the buildup of toxic bis-
retinoid compounds. ABCA4 also insures that any excess 11-cis retinal that is
not required for the regeneration of rhodopsin or cone opsin is also removed
via the visual cycle (97).
Recent studies indicate that cone opsin can be regenerated using another
series of reactions that involve cone photoreceptors and Müller cells (98). In
this retinoid cycle, all-trans retinol obtained from the reduction of all-trans
retinal by RDH8 in disk membranes is delivered to Müller cells where it is
isomerized to 11-cis retinol and returned to cone photoreceptors. There it is
oxidized to 11-cis retinal by a dehydrogenase for regeneration of cone opsins.
Several other proteins have also been implicated in the retinoid cycle and
in the detoxification of retinal. Retinal G-protein–coupled receptor (RGR)
encoded by the RGR gene binds and photoisomerizes all-trans retinal to 11-
cis retinal in RPE and Müller cells and may contribute to the regeneration of
photopigments (99). Retinol dehydrogenase 12 (RDH12) encoded by the
RDH12 gene and localized to the inner segments of photoreceptors catalyzes
the reduction of both all-trans and 11-cis retinal to their corresponding retinol
derivative (100). RDH12 is generally thought to play a crucial role in
protecting photoreceptor inner segments from the toxic effect of retinal that
may escape from outer segments. RDH12 may also protect photoreceptors
against toxic aldehyde products resulting from lipid peroxidation.
Mutations in genes encoding proteins that function in the visual cycle and
retinoid processing are known to cause a variety of retinal diseases.
Autosomal recessive Stargardt macular degeneration (STGD1), CRD, and a
subset of ARRP are caused by mutations in ABCA4. LCA14 is caused by
genetic defects in LRAT. Mutations in RPE65 have been reported to cause
LCA2, ADRP, and ARRP, whereas mutations in RDH5 cause fundus
albipunctatus, a form of CSNB display whitish-yellow flecks upon fundus
examination, and mutations in IRBP, RGR, and RLBP1 have been reported to
cause ARRP. Finally, mutations in RDH12 have been linked to LCA13 and
ARRP. Interestingly, to date, disease linked to mutations in RDH8 have not
been reported despite its prominent role in the visual cycle.
Connecting Cilium
The connecting cilium plays a crucial role in transporting proteins and
metabolites between the inner segment and outer segment of photoreceptors.
This structure, equivalent to the transition zone in a nonphotoreceptor cilium,
contains a microtubule-based axoneme that extends from the basal body in
the inner segment far into the outer segment (Figure 4-4). The axoneme in
the photoreceptor is organized with nine microtubules in a circle with no
microtubules in the center known as a 9 + 0 arrangement. Within the
proximal inner segment and connecting cilium, the microtubules exist as nine
doublets. Further into the outer segment, however, the nine microtubules
appear as nine singlets. An intraflagellar transport complex IFT and a protein
complex known as the BBSome together with the motor protein kinesin (128)
transport proteins into and out of the outer segment (39,129, 130, 131).
Biochemical studies indicate that a wide range of membrane and soluble
proteins coordinate the trafficking of proteins through the connecting cilium
(128). Many of these proteins are also found in the cilium of
nonphotoreceptor cells, whereas others appear to be selectively expressed in
photoreceptors.
Mutations in genes encoding a large variety of proteins that play a role in
basal body and ciliary structure and transport have been linked to
nonsyndromic and syndromic diseases. These diseases are collectively known
as ciliopathies and in some classifications include retinal diseases caused by
mutations in outer segment proteins (2). Nonsyndromic diseases associated
with proteins involved in connecting cilium structure and function including
RP, CRDs, and LCA. For example, RP1, a protein associated with
microtubules and important in maintaining the stability of rod outer segment
disks, has been linked to autosomal recessive RP (132), whereas mutations in
CEP290, a large protein that links the ciliary membrane to microtubules of
the axoneme, are known to cause LCA10. Syndromic diseases include Usher
syndrome (see also Chapter 33) involving photoreceptor degeneration and a
loss in hearing; BBS (see also Chapter 32) associated with a loss in vision
due to photoreceptor degeneration and postaxial polydactyly, central obesity,
mental retardation, hypogonadism, and renal dysfunction; Senior-Løken
syndrome (SLS) resulting in early-onset photoreceptor degeneration and
juvenile nephronophthisis; and Joubert syndrome (JBS), a neurologic
disorder characterized by hypotonia, ataxia, abnormal breathing,
developmental delay, and abnormal ocular movements together with
photoreceptor degeneration, among others (see also e-Chapter 2). A partial
list of proteins implicated in basal body and connecting cilium structure and
transport function and associated with nonsyndromic and syndromic diseases
include CEP290, lebercilin, RPGRIP1, RPGR, RP1, USH2A, USH2C,
USH2D, ITF27, ITF38, ITF81, ITF140, ITF144, ITF172, and BBS1-7.
Although considerable progress has been made in identifying proteins
encoded by genes associated with connecting cilium diseases, the
biochemical properties of these proteins have not been thoroughly
investigated and their role in cilium structure and transport is not well
understood.
ACKNOWLEDGMENTS
This work was supported in part by grants from the National Institutes of
Health (EY002422) and the Canadian Institutes of Health Research (PJT
148649).
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5
Extracellular Matrix Regulation of
Vascular Development in the Retina
Saptarshi Biswas, William J. Brunken and Dale D. Hunter
INTRODUCTION
The retina, as the rest of the central nervous system (CNS), vascularizes
primarily by angiogenesis (reviewed in (1,2)). Mechanisms that regulate
angiogenesis remain active throughout life. Disruptions in mechanisms
regulating retinal angiogenesis are the leading causes of adult blindness in the
developed world (reviewed in (1)). For example, diabetic retinopathy is the
main cause of blindness within the working-age population in industrialized
nations (reviewed in (3)). Also, vessel tortuosity and abnormal arterial
collateral formation have been reported in retinal vessel occlusion (4).
Moreover, abnormal arterial and venous patterning, characterized primarily
by direct arteriovenous shunt formation, has been reported in several diseases
with ocular manifestation (4, 5, 6). In premature infants, retinopathy of
prematurity (ROP) is a major cause for blindness (reviewed in (7)).
Therefore, a detailed understanding of the mechanisms that govern retinal
angiogenesis is important for the development of potential treatments.
CNS blood vessels, including those in the retina, acquire a unique
structure called the neurovascular unit (reviewed in (8,9)). The neurovascular
unit, a shared structural component among all mammals, is comprised of
different cell types including endothelial cells, mural cells (pericytes and
vascular smooth muscle cells), astrocytes, neurons and microglia, as well as
the vascular basement membrane (BM). Retinal vasculature sprouts from an
existing artery in the optic nerve head in response to the metabolic demand of
newly active retinal neurons (10, 11, 12), which active glial cells that act to
promote vascular growth and development. Initial events in vascular
development are initiated by retinal ganglion cells, which induce astrocyte
migration over the retinal surface forming a template for the expansion of the
retinal vascular tree (13, 14, 15). Glial cells, astrocytes, and Müller cells
express and secrete vascular endothelial growth factor (VEGF), which drives
endothelial proliferation (15).
Microglia, the resident macrophages of the CNS, regulate branching of
the newly formed vascular network by facilitating anastomosis of emerging
vascular sprouts and mediating turning of vascular sprouts in the deeper
layers of the retina (16,17). Moreover, depending on their activation state,
microglia regulate endothelial cell proliferation. While resting microglia
produce antiangiogenic factors that inhibit endothelial cell proliferation,
activated microglia secrete proangiogenic factors that induce endothelial cell
proliferation (18). It was also known that microglia interact with the
astrocyte-derived components of the vascular BM (19). However, whether
BM components regulate microglial recruitment and activation around the
growing vasculature, the physiologic consequence of that regulation has not
been extensively studied.
Our work focused on the mouse model has shown that γ3-containing
laminins are negative regulators of vascular branching in the mouse. Vascular
branch point-associated microglial density is specifically increased at the
nascent plexus of the Lamc3−/− retina. Consequently, vascular branching
density is also increased in the Lamc3−/− retina, suggesting an increased
occurrence of microglia-mediated vascular anastomotic events. We further
showed that microglia interact with astrocyte-derived laminins via integrin
β1-mediated signaling. Laminins containing γ3-chain also negatively regulate
microglial activation. Microglia become hyperactivated in the Lamc3−/−
retina or when tested in vitro with Lamc3−/− astrocyte-derived matrix. In
addition, mural cells, such as vascular smooth muscle cells and pericytes,
help stabilizing maturing blood vessels (reviewed in (20)).
Several studies demonstrated that BM molecules, especially laminins,
influence several aspects of retinal angiogenesis either by direct endothelial
cell–BM interactions (21) or by mediating cross-talk between different cell
types (22, 23, 24). Moreover, all these cell types as well as the vascular BM
play critical roles in maintaining the barrier property of CNS vessels
(reviewed in (25)). BM disorganization and remodeling occur in several
pathologic conditions with an ocular manifestation such as diabetes (26,27)
and ischemia (reviewed in (25)). Indeed, the inhibition of matrix
metalloproteinase-mediated degradation of the extracellular matrix (ECM)
has been reported to reduce infarct size in the CNS following ischemia (28).
Here, we summarize the role of the BM during retinal angiogenesis, that is,
retinal vascular development, in the context of cell–cell interactions, as well
as direct signaling between the BM and endothelial cells. We focus mainly on
laminins, a major component of the BM (reviewed in (29)).
The growing retinal superficial vascular tree may be subdivided into three
developmental zones: (1) the vascular front, where tip cell/stalk cell
specification takes place; (2) the nascent plexus, where newly formed vessels
branch and proliferate; and (3) the remodeling zone, where morphologically
distinct arterial and veins arise from the undifferentiated nascent plexus
(Figure 5-3; (37)). As the temporal sequence of angiogenesis is spatially laid
out over the retinal surface, the retinal superficial vascular tree proves to be
an ideal model to study all three aspects of developmental angiogenesis in the
CNS.
FIGURE 5-3 Distinct developmental regions in a growing
retinal superficial vascular tree. The lectin, IB4, binds to
sugar moieties that are expressed on endothelial cells. In
the mouse at P5, three different developmental regions
(vascular front, nascent plexus, and remodeling zone) are
present. Vascular sprouts align themselves toward the
angiogenic cue at the vascular front, where tip cell/stalk
cell specification takes place. Behind the vascular front,
newly formed vessels form an immature nascent plexus,
where most endothelial cell proliferation occurs. Further
behind, this nascent plexus undergoes extensive
remodeling to form morphologically distinct arteries,
veins, and the capillary network.
DEVELOPMENTAL REGULATION OF
LAMININ EXPRESSION PATTERNS IN
THE RETINAL VASCULAR BM
Very little is known about the expression patterns of different laminin chains
in the retinal vascular BM and how their expressions are regulated
developmentally. Previous studies suggested that laminin expressions in
retinal vessels are spatially regulated (Figure 5-4B). For example, laminin
◻◻-chain is present throughout the retinal vasculature with higher
expression at the growing vascular front. In contrast, laminin ◻◻-chain is
most prominently present in the nascent plexus immediately behind the
vascular front (21). It has also been reported that there is a patchy distribution
of the laminin ◻◻-chain in the venules in the brain ((45); reviewed in (46)).
In our preliminary results, we have found a more prominent expression of the
laminin ◻◻-chain in arteries than veins in the P10 retina (unpublished
results). The developmental expression pattern of laminin ◻1-chain in the
retinal vasculature has not been extensively studied. In contrast, laminin ◻2-
chain has been shown to be present throughout the retinal vascular tree with
higher expression in the arterial BM than the venous counterpart (24). The
laminin ◻◻-chain is expressed in the basement membrane throughout the
vasculature in the adult retina (40), whereas the laminin ◻3-chain expression
is restricted to the venous and capillary BMs of the mature retinal vasculature
(24,40).
Along with spatial expression differences, there seems to be also a
temporal regulation of laminin expression in the CNS vascular BM. For
example, whereas the laminin ◻◻-chain is expressed in the CNS vascular
BM in all stages of development, the laminin ◻◻-chain expression is
postnatal (reviewed in (46)). However, whether there is a specific temporal
regulation of laminin ◻4 and ◻5 expression patterns in the retina has not
been studied. In a growing retinal vascular tree, laminin ◻3-chain expression
is excluded from tip cells at the vascular front but present around stalk cells.
At the nascent plexus, ◻3-containing laminins are present at vascular branch
points (24). In the mature retinal vascular tree, laminin ◻3-chain expression
is virtually absent in the arterial BM but present in venous and capillary BMs
of a mature retinal vascular tree (24,40). These complex spatial and temporal
expression patterns of various laminins in the vascular BM suggest that
specific laminin isoforms play critical role in different aspects of vascular
development and stabilization in specific regions of the vascular tree.
SUMMARY
Angiogenesis in the retina is a complex developmental process, the
mechanisms that regulate sprouting, proliferation, remodeling, and mural
stabilization remain active throughout life to respond to metabolic needs.
These processes can lead to neovascular diseases as the result of
dysregulation at any step in the process. Our laboratory, together with several
others, has shown that particular isoforms of laminins play critical roles in all
the processes of retinal angiogenesis (Figure 5-6). Laminins in the inner
limiting membrane guide astrocyte migration over the retinal surface
providing a template for endothelial migration and tube formation. Laminins
play key roles in the interactions between endothelial cells and microglial
cells regulating branching, endothelial proliferation, and turning into the
deeper layers of the retina. Laminins also play key roles in the remodeling
events as the nascent plexus is specified into arterial and venous sides.
Laminins also play roles in recruiting and stabilizing pericytes to the vascular
wall. Finally, laminins play critical roles in the blood–retinal and blood–brain
barrier.
ACKNOWLEDGMENTS
The work presented here was funded in part by the NEI R01EY12676 (WJB);
Research to Prevent Blindness, Inc. Unrestricted Grant to the Department of
Ophthalmology and Visual Sciences; Research Development funds from
Upstate Medical University (WJB). The authors also acknowledge the input
and support of fellow members of the Vision Sciences community at Upstate
Medical University, including Francesca Pignoni, Andrea Viczian, and
Huaiyu Hu among others.
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s
6
Visual Anomalies Associated With
Reduced Retinal Pigmentation
Donnell J. Creel
BACKGROUND
From primitive nervous systems, such as the fruit fly Drosophila, through
vertebrates to primates, each side of the nervous system often receives both
ipsilateral and contralateral visual fibers. During stages of development, most
vertebrates have some ipsilaterally projecting optic ganglion fibers. In birds
and fish, these are often transient pathways. Some species of birds have
ipsilateral optic fibers during embryonic periods that do not survive into
adulthood. Most adult birds have few to no ipsilateral projections. The
organization of ipsilateral retinal ganglion cell (RGC) projections in most
vertebrates other than mammals can be described as haphazard at best. In
some vertebrates, ipsilateral fibers re-cross back to the contralateral fiber
tract.
Even closely related vertebrate species often differ dramatically in their
ipsilateral optic projections. Example, most fish have some ipsilateral optic
fibers, whereas the popular genetic model zebrafish have none. In birds, fish,
amphibians, and reptiles, the ipsilateral ganglion fibers originate from
throughout the retina compared to the temporal retinal origin in mammals (1).
Amphibians vary considerably between species with most having some
ipsilateral projections to pretectal, hypothalamic, and primitive lateral
geniculate nucleus (LGN).
Many fish display ipsilateral connections mostly to hypothalamic, ventral
and lateral LGN, and pretectal areas. In nonmammals, some birds and some
fish, the nerves simply overlap at the chiasm with little contact (2). Optic
nerves in fish generally overlap each other rather than interdigitate. Optic
nerves of birds usually interdigitate. Only in the chiasm of primates and
marsupials does one see spatial organization with the ipsilateral fibers of
temporal origin coursing through the chiasm as an organized lateral cluster
(3). In most vertebrates, including cats, the passage of ipsilateral ganglion
cells through the optic chiasm is haphazard.
A feature of the mammalian visual system is the progressive increase of
the temporal retina as the eyes progress frontally from lateral locations in
guinea pig, rabbit, mouse, rat to the frontal position in primates,
commensurate with increase of noncrossing temporal retina ganglion cells at
the optic chiasm. Ipsilateral input progresses from little in rodents to succinct
point to point mapping of the visual world from LGN to cortical binocular
cells in cats, primates, and some marsupials (4). Complete separation of
ipsilateral and contralateral RGCs at the optic chiasm is limited to primates
and some marsupials (5). Figure 6-1 is a schematic of the distribution of
temporal and nasal RGCs at the chiasm in normally pigmented humans.
Primate vision is the most complicated of mammals. The principal hypothesis
of why there is nearly equal representation in each hemisphere of nasal and
temporal retina in primates is that equal representation developed in concert
with frontal vision and stereopsis to aid visually guided hands (6).
FIGURE 6-1 Drawing of approximate distribution of
crossed and uncrossed retina ganglion cells at the optic
chiasm of human beings.
Rodents possess a simple LGN with the 90%+ of crossed RGC terminations
filling the nucleus except for a pocket that contains <10% of the total
terminations located on the ipsilateral side. The LGN of albino rodents lacks
a defined area or pocket of ipsilateral RGC terminations. The few ipsilateral
fibers terminating in the LGN are fragmented with poor organization (Figure
6-3).
FIGURE 6-3 The distribution of optic fiber terminations
in dorsal lateral geniculate nucleus (dLGN) of BLACK
and ALBINO rats shown in serial sections at three levels
of dLGN.
Figure 6-7 depicts the geniculate nuclei of a type 1A albino cat compared to
a normally pigmented cat. The dorsal lateral geniculate nuclei (dLGN) of
albino cats, which includes only one small pocket of ipsilateral RGC
terminations, is as primitive as a rodent dLGN. (The dLGN is the relay
station in the thalamus where RGCs terminate. The next cells send the retinal
information to the cortex.) Four patterns of geniculocortical organization are
described in albino mammals (26, 27, 28, 29). All forms likely exist in
patients with albinism.
FIGURE 6-7 Dark-field autoradiograph of coronal
sections through the ipsilateral (A) and contralateral (B)
dLGN of a pigmented cat, and ipsilateral (C) and
contralateral (D) dLGN of a type 1A albino cat. The one
small pocket of ipsilateral RGC terminations in albino cat
is indicated by arrow in panel D.
The brain of an albino patient (30,31) and an albino monkey brain were
studied and both had anomalous LGNs (32). Defects identified in albino
mammals encompass a decreased number of photoreceptors, foveal/area
centralis hypoplasia, misrouting of the temporal RGC axons across the
chiasm, variation of central RGC terminations, vascular intrusion into area
centralis, anomalous cortical organization, fewer cones and RGCs in the
macular area, and panretinal reduction in the number of rods (33, 34, 35, 36,
37, 38).
The first evidence of optic misrouting at the chiasm in humans was
published in 1974. Scalp-recorded visually evoked potentials (VEPs)
recorded from 20 patients including four genetic forms of oculocutaneous
albinism exhibited electrophysiologic evidence of reduced uncrossed optic
fibers (39). Similar results were published for patients with ocular albinism
(40) and replicated in early studies by Taylor (41) and Coleman et al. (42).
Reviews of research are found in the references (3,35,43,44).
In the normally pigmented primate, there is a distinct dividing line, the
vertical meridian, at the fovea. Retinal ganglion fibers temporal to the fovea
remain ipsilateral in an organized bundle at the chiasm, whereas retinal
ganglion fibers nasal to the fovea cross into the contralateral hemisphere at
the optic chiasm. Figure 6-8 shows the approximate difference in distribution
of retinal ganglion fibers at the chiasm comparing pigmented individuals to
patients with albinism. Ganglion fibers from up to 15 degrees of temporal
retina also cross at the chiasm in patients with albinism. The proportion of
misrouted ganglion fibers and associated anomalies is quite variable,
including in patients with albinism (44), probably due to a combination of
variation in degree of pigment and individual genetic factors. The level of
retinal pigmentation correlates negatively with the severity of expression of
visual anomalies (45,46). It is likely that the more pigment present in the
retina, the more normally routed RGC fibers will be present. Drack (47)
reported that more albinism-related mutations in an individual are associated
with greater expression of albinism.
FIGURE 6-8 Diagram of approximate distribution of the
optic nerve ganglion cells at the optic chiasm in a
pigmented individual and a patient with albinism.
All type 1A albino cats and most patients with albinism have eye movement
disorders. Most patients with albinism have searching nystagmus due to poor
foveal development. Additionally, many Siamese cats, most type 1A albino
cats, and many patients with albinism have strabismus and reversed
optokinetic nystagmus (OKN) due to miswiring of optic projections in the
brainstem (48).
Located in the brainstem are the nuclei integrating visual sensory input
including the superior colliculus (SC) and other nuclei involved in eye
alignment and fixation. Reduced ipsilateral RGCs in albino mammals include
reduced ipsilateral RGCs to mid-brain nuclei that affect strabismus,
nystagmus, and atypical OKN in albino mammals further complicating the
elaborate connections between these nuclei. In albino guinea pigs, rabbits,
and ferrets, there are no ipsilateral optic projections to the ventral lateral
geniculate nucleus (LGNv), SC, pretectum, nucleus of the optic tract (NOT),
or accessory optic system (AOS) (44,49, 50, 51).
In the normally pigmented cat, about 50% of RGCs project via the LGN
to the ipsilateral cortex. Twenty-four percentage of RGCs originating in
temporal retina project to the ipsilateral SC (52), and about 15% of RGCs
project to the ipsilateral pretectum (53). The type 1A albino cat has very few
ipsilateral projections to the pretectum and almost no ipsilateral projections to
SC (21). All type 1A albino cats have nystagmus and many have strabismus.
Aberrant OKN is described in patients with albinism (54, 55, 56). The
nuclei responsible for the OKN are the terminal nuclei of the AOS: the dorsal
terminal nucleus (DTN), lateral terminal nucleus (LTN), medial terminal
nucleus (MTN), and the NOT. For detailed account of brainstem nuclei
controlling eye movement and dissociated vertical deviation (DVD), see
Creel (57).
Readily observable symptoms of albinism, many of which are not limited
to patients with albinism, include iris transillumination, poor foveal
development, and intrusion of capillaries into the foveal avascular zone that is
apparent during ocular fundus examination and fluorescein angiography.
Also, poor foveal development can be apparent in ocular coherence
tomography (OCT), and reduced visual acuity can be seen. The consequences
of having few binocular cells in cats and patients with albinism are poor
binocular stereovision.
Figure 6-9 compares a normal fovea to that of a patient with reduced
retinal pigment. The OCT is in color to emphasize that the nerve fiber layer
in patients with albinism usually continues over the fovea similar to a mouse
that lacks a fovea. Expression of degree of foveal development varies
considerably as does visual acuity.
FIGURE 6-9 Comparison of optical coherence
tomography (OCT) through the foveal area of an ocularly
pigmented human being (A) and a patient with albinism
(B) foveal areas. In (A) note, the foveal depression and
that the nerve fiber layer, that is, red layer on top, is not
present across the foveal area. In most patients with
albinism, the nerve fiber layer (B) continues over the
potential foveal area.
Most patients with albinism have poor visual acuity, but some have good
acuity in spite of no foveal pit. Figure 6-10 shows OCT of a patient with
albinism with 20/30 visual acuity. Although seemingly surprising, there are
normally pigmented individuals with good acuity despite no foveal pit (58).
FIGURE 6-10 Optical coherence tomography (OCT)
through the foveal area of a patient with albinism with
20/30 visual acuity.
There are at least 21 types of human albinism. Many are rare limited to small
groups or associated with syndromes. More will be found. More exist in
animal models. Patients with oculocutaneous and ocular albinism with known
loci include those below (Table 6-1; see also (60)):
THEORY
What is considered abnormal visual system organization in mammals with
reduced retinal pigmentation is normal visual system organization in retinally
pigmented vertebrates phylogenetically preceding these species. Cat visual
system disorganization can approach that of normally pigmented rodents. The
organization of the visual system in rodents resembles premammalian
vertebrates. This theory suggests that an early event in genetic coding for
melanin pigment in the nascent retina is the positive inductive signal that
launches normal retinal development and RGC targeting (57). Genetic
instruction for mammals with insufficient retinal pigmentation defaults to a
simpler, more entrenched genetic platform skewed toward complete crossing
of RGCs at the chiasm. In mammals' retinal pigmentation, retinal
embryogenesis defaults to the conserved genetic package that existed when
the species first evolved and has a cascade of consequences.
Ipsilateral fibers are not consistently present even among closely related
nonmammalian vertebrate species suggesting a vulnerability of ipsilateral
fibers being expressed. Within all vertebrate groups, the contralateral visual
projections are more stable across species than are ipsilateral projections.
Contralateral projection of RGCs at the optic chiasm is the conventional
ancestral state in nonmammalian vertebrates, and reduced nondecussated
optic fibers are the norm in ancestral mammals.
The essence of this theory is that retinal melanin pigment is so
fundamental to retinal, vascular, and early RGC targeting that coding for
insufficient retinal melanin triggers a switch, which thwarts the completion of
genetic instructions. Instead an atavistic expression of the conserved, more
stable, genetic platform skewed toward complete crossing of RGCs at the
chiasm develops consistent with genetics of each species' evolutionary origin.
Phylogenetically, late genetic addenda to conserved instructions are
vulnerable to not being expressed if cues, such as sufficient retinal melanin
pigmentation, are not present to support variation from highly conserved
coding.
ACKNOWLEDGMENTS
Supported in part by an Unrestricted Grant from Research to Prevent
Blindness, Inc., New York, NY, to the Department of Ophthalmology &
Visual Sciences, University of Utah. Images provided courtesy of Moran
Ophthalmic Imaging.
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7
Applications for Human Pluripotent
Stem Cell–Derived Retinal Cells in
Development, Disease, and Cellular
Replacement
Kirstin B. VanderWall, Clarisse M. Fligor, Sailee S. Lavekar,
Kang-Chieh Huang and Jason S. Meyer
INTRODUCTION
Human pluripotent stem cells (hPSCs), including both human embryonic
stem (hES) cells and human-induced pluripotent stem (hiPS) cells, provide an
advantageous model for studying cellular development and disease in vitro,
as they can be cultured indefinitely and have the ability to differentiate into
all cell types of the body. Embryonic stem (ES) cells are cultured from the
inner cell mass of the blastocyst in their pluripotent state and were among the
first types of stem cell to be used for studies of human development in vitro
(1,2). Unlike ES cells, iPS cells can be generated from patient sources
through the genetic reprogramming of cells back into a pluripotent state using
the Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc) (3,4). This technology
has transformed the field of cellular biology with the ability to collect
samples from patients harboring specific genetic determinants for various
diseases and using these cells to study mechanisms and phenotypes in some
of the earliest stages of disease pathogenesis (5,6). More so, the development
of iPS cells has allowed for the new opportunity to screen therapeutic
compounds in vitro, as well as develop novel cellular replacement therapies
(7).
Research in the retina has taken full advantage of hPSCs for studies of
development and disease. Over the past decade, researchers have
demonstrated the differentiation of hPSCs into all major retinal cell types
including retinal pigment epithelium (RPE), photoreceptors, and retinal
ganglion cells (RGCs) (Figure 7-1) (8, 9, 10). Numerous differentiation
protocols have been established that utilize either direct differentiation of
retinal cells using small molecules or stepwise protocols through default
neural specification (Table 7-1). More recent research has largely focused on
the development of retinal organoids from hPSCs, which are three-
dimensional tissue-like structures that mimic the spatiotemporal specification
of retinal neurons during development (18,33). Retinal organoids are of great
interest as they recapitulate the cellular interactions of retinal neurons in vivo
and can be a resourceful tool for reproducibly differentiating large
populations of retinal neurons for isolation and cell replacement strategies.
The ability to derive all major cell types of the retina from hPSCs allows for
in-depth studies of retinal fate specification with the ability to observe some
of some the earliest events of human retinogenesis. Patient-specific iPS cells
provide an advantageous tool for studying retinal diseases and the
mechanisms that result in degeneration of specific cell types. The recent
advent of gene editing approaches, like CRISPR/Cas9, allow for the
development of new disease models through the insertion of a mutation into
isogenic control parent lines as well as the correction of specific mutations in
existing patient iPSCs. Isogenic controls are highly important in the stem cell
field due to the variability known to exist between different cell lines. More
so, these cells can also be utilized for large-scale pharmaceutical screenings
for targeted therapeutics in retinal degeneration. Lastly, hPSCs may serve as
a valuable resource for cell replacement strategies with the ability to derive
unlimited quantities of cells in a reproducible and efficient manner. Current
efforts in the field have demonstrated some degree of success for the
replacement of stem cell–derived RPE and photoreceptors and limited studies
to date demonstrating the ability to replace inner retinal neurons such as
RGCs that degenerate in glaucoma. Ongoing studies of hPSC-derived retinal
cells will assuredly continue to focus on the efficacy of outer cell replacement
strategies and the future development of therapies for inner retinal diseases
causing death and degeneration of RGCs.
RETINAL PIGMENTED EPITHELIUM
Functions and Diseases of the RPE in the Retina
The retina is a highly organized structure located within the back of the eye
that consists of numerous interconnecting cell types working together to
allow for proper vision (Figure 7-2) (34). Each of the cell types that make up
the retina performs specific functions in the visual transduction pathway, and
these functions are perturbed in diseases that cause degeneration of the retina.
The outermost cell type of the retina is the retinal pigmented epithelium
(RPE), which forms a monolayer of pigmented cells between the neuroretina
and the retinal vasculature of the choroid. The apical face of the RPE
interacts closely with photoreceptor outer segments, whereas the basal edge
of the RPE faces the Bruch membrane, which is the innermost layer of the
choroid (35). The close association of the RPE to these two structures heavily
relates to their physiologic functions within the retina.
The RPE serves a variety of important functions within the retina, including
the phagocytosis of photoreceptor outer segments, absorption of light,
transport of nutrients and ions, release of growth factors, and recycling of
important visual cycle compounds (35). Additionally, the RPE contribute to
the outer blood–retinal barrier, which regulates the contents that enter and
exit the retina and allows for its prolonged stability and integrity. As a result
of the continuous visual cycle, photoreceptors are subject to damage caused
by the accumulation of light-induced toxic substances, such as photooxidated
lipids and lipoproteins. Therefore, photoreceptor outer segments are rapidly
shed and replaced with the ingestion of old outer segments by RPE through
phagocytosis. Once inside the RPE, these segments are broken down into
essential molecules and transported back to the photoreceptors. The cycle of
outer segment renewal and phagocytosis is critical for proper
phototransduction, and disruptions to this cycle constitute a main phenotype
in blinding disorders.
When considering the anatomy of the retina, RPE plays the middleman in
the transport of ions and water out of the retina into the choroid through the
Bruch membrane as well as the transport of nutrients and glucose from the
blood into the photoreceptors through transepithelial transport (36). RPE
utilize a number of transporters and channels to serve in this capacity,
including glucose transporters, Na+/K+ ATPase, and Cl−/K+ transporters.
The high metabolic rate of retinal neurons creates a need for the constant
movement of glucose into the retinal layers for energy and the subsequent
removal of water from the inner retina into the choriocapillaris and subretinal
layers through aquaporin-1 channels in the RPE (35). The RPE also delivers
other nutrients into the photoreceptors from the blood such as retinol,
ascorbic acid, and fatty acids, and each of these components plays an
important role in the visual cycle.
With these many functions in mind, the overall health and maintenance of
RPE is crucial to proper visual transduction and longevity of the retina. As
such, many retinal diseases evolve because of dysfunction of the RPE,
including age-related macular degeneration (AMD), Bestrophinopathies (e.g.,
Best disease), Stargardt disease (see Chapter 30), Leber congenital amaurosis
(LCA) (see Chapter 27), and retinitis pigmentosa (RP) (please see e-Chapter
4), and each of these diseases is associated with RPE dysfunction leading to
visual decline. The pathogenesis of each of these diseases can be related to
important RPE pathways that result in a lack of support to the photoreceptors
and lead to loss of vision. Many of these diseases are known to be caused by
hereditary mutations in visual proteins.
RPE dysfunction and vision loss stem from hereditary genetic mutations
in proteins known to play a major role in the visual pathway. Best disease is
an autosomal dominant disease caused by mutations in the BEST1 protein,
which functions as calcium-activated chloride channel; Best disease
manifests in early childhood by the appearance of a “yolk-like lesion” in the
macula (37). A variety of pathophysiologic mechanisms have been associated
with the onset of Best disease, including abnormal fluid flux associated with
the inability to properly move chloride ions out of the retina, accumulation of
proteins and debris, impaired outer segment degradation, and oxidative stress
(38). Dysfunction of these pathways in Best disease leads to progressive
vision loss with increasingly reduced ability to perform tasks, such as reading
and driving.
Stargardt disease also affects the central retina and is the most common
form of hereditary dystrophy. This disease is autosomal recessive and caused
by mutations in the ABCA4 gene or (less commonly the ELOVL4 gene as an
autosomal dominant mutation; see also Chapter 30) and appears in childhood
and early adulthood (39). Lack of ABCA4 results in the impaired transport of
visual cycle by-products and accumulation of bisretinoid A2PE in outer
segment discs. A2PE can be hydrolyzed to form A2E, a highly toxic
metabolite, and accumulates with lipofuscin in the RPE leading to RPE
dysfunction and death with secondary photoreceptor loss. Clinically, patients
demonstrate macular atrophy and display the appearance of yellow-white
flecks in RPE ultimately resulting in central vision loss. Additionally, another
hereditary disease, which affects proteins in the visual cycle is LCA. In a
subset of cases, LCA can be caused by mutations in RPE65 (40). RPE65 is a
protein produced and expressed by the RPE and functions as an isomerase
that converts all-trans-retinyl ester to 11-cis-retinol during the visual cycle.
Mutations in RPE65 result in reduced amounts of 11-cis retinol and esters
accumulation within the RPE leading to abnormal RPE function and early-
onset blindness.
Lastly, forms of hereditary retinitis pigmentosa result in primary RPE
pathology and dysfunction (41). Similar to other proteins mentioned above,
CRALBP is expressed within the RPE and is implicated in the visual cycle. It
has been shown that CRALBP functions during the isomerization step and is
a major acceptor of 11-cis-retinol, which stimulates its conversion from all-
trans retinol during the rod cycle. Clinical manifestations of the disease
include early childhood night blindness and the presence of white dot-like
deposits that remain visible into adulthood. Accumulation of 11-cis retinol in
the RPE alters the normal function of RPE and the visual cycle. Taken
together, numerous hereditary and idiopathic diseases result in the
dysfunction of the RPE and lead to vision loss. These diseases can manifest
from time points of early childhood through elderly adulthood. Major efforts
in recent years have focused on a greater understanding of the underlying
disease mechanisms of these disorders with applications to develop
treatments and therapeutics targeted at improving and restoring vision,
including the use of hPSCs for each of these purposes.
PHOTORECEPTORS
Functions and Diseases of Photoreceptors in the Retina
Photoreceptors are the main light-sensing neurons of the retina and are
responsible for the conversion of light signals into an electrical impulse.
These cells are found in the back of the retina adjacent to the RPE and
constitute the outer nuclear layer (Figure 7-2). The anatomy of
photoreceptors is broken down into five main parts: the outer segments (OS),
the connecting cilium (CC), the inner segment (IS), the nuclear region, and
the synaptic region (Figure 7-4). The OS are found apically and interact
closely with neighboring RPE. Membranous discs are found throughout the
outer segment and contain photopigments like opsins. When light is detected
by the photoreceptors, 11-cis retinal is isomerized to all-trans retinal and
activates opsins. A cascade of events leads to the closing of ion-gated cyclic
nucleotide channels that results in hyperpolarization of the cell. The
hyperpolarization travels through the CC and IS and then finally through the
nuclear region to a specialized ribbon synapse to release glutamate in a
graded fashion to connecting horizontal and bipolar cells that eventually
reach the RGCs, which send visual information to the brain (83).
CONCLUSIONS
hPSC technology has revolutionized the field of developmental retinal
biology with access to some the earliest embryonic time points and the ability
to differentiate these cells into RPE, photoreceptors, and RGCs. More so,
when derived from patient-specific sources, hPSCs can be used to model
retinal diseases and understand disease mechanisms causing the degeneration
of retinal cell types and to screen drugs and therapeutic compounds targeted
at affected pathways. Lastly, hPSCs provide an attractive source for cell
replacement strategies with the transplant of hPSC-derived RPE already in
human clinical trials and hPSC-derived photoreceptors and RGCs in more
preliminary stages of transplantation. Progress in these areas is continually
being made with the overarching goal of developing a treatment for blindness
caused by retinal degeneration.
ACKNOWLEDGMENTS
Grant support was provided by the National Eye Institute (R01 EY024984
and R21 EY031120 to JSM), the Indiana Department of Health Spinal Cord
and Brain Injury Research Fund (JSM), an IUPUI University fellowship
(KCH), and startup funds from the Indiana University School of Medicine.
This publication was also supported by a fellowship from the Indiana Clinical
and Translational Sciences Institute (KBV) made possible with partial
support from UL1TR002529 (A. Shekhar, PI) from the National Institutes of
Health, National Center for Advancing Translational Sciences, Clinical and
Translational Sciences Award.
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8
Applications for Human Pluripotent
Stem Cell–Derived Retinal Cells in
Development, Disease and Cellular
Replacement
Kirstin B. VanderWall, Clarisse M. Fligor, Sailee S. Lavekar,
Kang-Chieh Huang and Jason S. Meyer
INTRODUCTION
The discovery of human pluripotent stem cells (hPSCs), including both
human embryonic stem cells (hESCs) in 1998 (1) and human-induced
pluripotent stem cells (hiPSCs) in 2007 (2,3), offered the possibility to
overcome the limited amount of donor retinal tissue and provided exciting
new opportunities to study the earliest stages of human retinogenesis. The
ability to obtain cells from patient sources allows for in vitro disease
modeling applications and makes it possible to study how genetic makeup
influences biologic responses. Indeed, even within the realm of human tissue,
a particular individual's genetic background can influence disease progression
or drug response, making hPSCs ideal candidates for modeling inherited
degenerative disorders of known genetic origin.
The emergence of hPSC-based protocols for retinal differentiation that
recapitulate major molecular and cellular events of human retinogenesis in
vitro has opened up immense research possibilities, including developmental
studies and disease modeling as well as generation of clinically relevant cells.
To date, a number of studies have focused upon the ability to direct the
differentiation of hPSCs to retinal cell types (4, 5, 6, 7, 8, 9), although these
efforts have mostly utilized stochastic methods of hPSC differentiation with
retinal cells heterogeneously arranged. These retinal cells lack the
organization and maturation typically observed in the retina, which limits
their ability to model retinal development as well as retinal disease pathology.
To address this lack of organization, recent efforts have focused on the
differentiation of these cells as three-dimensional (3D) retinal organoids
where differentiation progresses in a stepwise manner analogous to early
stages of retinal development (10, 11, 12, 13, 14, 15). A remarkable
advantage of retinal organoids is the ability to study early human retinal cell
fate decisions including how these cells interact to generate an organized
retinal-like tissue (6,16,17). Also relevant is the possibility to use hPSC-
derived organoids as a tool to model retinal disease progression in vitro with
studies to date focusing upon how cells of the outer retina are affected in
disease states (16,18, 19, 20, 21, 22).
2D VERSUS 3D CULTURE
Differentiation of hPSCs provides a renewable and reliable source of cells to
generate any cell type of the body from hESCs (1) and hiPSCs (2). Over the
years, various groups have developed multiple retinal differentiation
protocols with some utilizing a step-wise protocol (5,6,10,11,13,14,23) that
mimic the major stages of human retinogenesis; other groups have directly
reprogrammed pluripotent stem cells to their final fate (9,24). Some of these
standard protocols utilized two-dimensional (2D) cell culture approaches to
produce retinal neurons and have contributed to multiple significant
translational milestones (25,26). hPSC-derived neurons observed in 2D
cultures display increased activity compared to those in 3D cultures (27) in
part due to increased density, axonal outgrowth, and lack of regulating
signals present in 3D cultures. Furthermore, 2D culture methods are often
less expensive, less complicated to use, and allow for easier downstream
processing. However, 2D models are less biologically relevant as they do not
recapitulate the complex 3D microenvironment of living tissue (17).
Moreover, 2D-based methods of retinal differentiation are unable to produce
all of the structural components of retinal cells, such as vital cell–cell and/or
cell–matrix interactions, making it challenging to recapitulate development
and disease in a dish. Organoid technology is a fast-growing platform used to
study various aspects of human biology. With the discovery of organoid
technology, publications using retinal organoids have significantly increased
in just the past few years (Figure 8-1), indicating the rapid adoption of these
differentiation approaches as well as how the scientific community sees these
organoids as valuable tools for research.
DEVELOPMENTAL MODELING
The eye is a complex organ that consists of many different cell types that are
organized in a spatially specific manner that allows for proper cell–cell
interaction and signal transduction (28,55,56). Recent studies have
demonstrated the differentiation of hPSCs into retinal organoids, which
permit the generation of all retinal cell types in a 3D organized structure
(42,54). Retinal organoids have proven useful as platforms to study different
aspects of development, especially the earlier stages of development that are
otherwise inaccessible to investigation due to limited availability of tissue or
difficulties to perform genetic manipulations. hPSC-derived retinal organoids
reproduce many aspects of embryonic retinal development, including the
formation of a bilayered optic cup (10) and light-detecting photoreceptors
(11,53,57). Retinal organoid neurons can migrate into their appropriate
relative positions, produce neurites, and colocalized synaptic proteins with
appropriate cellular targets (34,36,53).
PHOTORECEPTORS
Photoreceptors are light sensitive cells that play a crucial role in retinal
functionality (5). The ability to detect and process light information requires
specialized and unique structures such as photoreceptor inner and outer
segments as well as synaptic end feet containing the ribbon synapse (12).
During human fetal development, the process of generating photoreceptors is
relatively slow with morphologically recognizable photoreceptors beginning
to appear around fetal week 10 at the foveal region (10,117). Over the next
15 weeks, differentiation gradually proceeds in the nonfoveal region, which
accounts for the majority of the retina (10). hPSC organoid-derived
photoreceptors can develop these fundamental processes that participate in
receiving and transmitting visual information (11,12,17,35,42,45,57). The
development and function of these structures occurs in a timely manner that
recapitulates what is known about human photoreceptor development.
TRANSLATIONAL APPLICATIONS
The retina is an attractive model to study the central nervous system and has
been studied at the cellular level in excruciating detail for over a century (83).
Due to its location, it is easily accessible with minimal surgery and can be
imaged in vivo. However, there are multiple diseases and injuries that affect
the retina, resulting in loss of vision and/or blindness (19,30,32,33,120,125).
Current therapeutic strategies can slow disease progression, but new
strategies which aim to preserve and restore vision are needed to cure these
disorders. However, many drug discovery platforms rely on simplified 2D
culture systems that do not accurately model in vivo cellular architecture and
physiology (27). With the introduction of hPSC-derived retinal organoids, a
vital tool for generating retinal tissue in vitro has been established and is now
widely used in numerous laboratories worldwide (32,33).
Future Directions
The significant unmet challenges for retinal organoids include generating
sufficient numbers of specific cell types, achieving functional integration of
transplanted cells, and surgical delivery of retinal cells or tissue without
triggering immune responses, inflammation, and/or remodeling. Currently,
retinal organoid technology seems unable to produce correct proportions of
all retinal cell types, particularly those localized in the INL (32). Distinct
plexiform layers are not routinely formed, causing the retinal organoids to not
be fully morphologically or functionally mature (31). Several processes could
be potential sources of organoid variation, such as progenitor proliferation,
cell differentiation, and ontogenetic cell death. High heterogeneity between
cell lines and experimental outcomes, extended culture times, and manual and
laborious procedures currently limits the use of human retinal organoids for
clinical applications. Furthermore, the increasing number of differentiation
protocols vary in their efficiency that can be further compounded with cell
line variability (42). Studies attempting to standardize the field have found
that cell line–specific variables are responsible for differentiation efficiency
during early stages, while organoid generation and culture methods determine
the efficiency of maturation at later stages (42). A greater understanding of
mechanisms of organoid formation will be essential to improving and
standardizing protocols for the production of physiologically relevant tissue
across multiple cell lines.
The heterogeneity in production, composition, and maturation of
organoids represent essential challenges that are problematic for the entire
stem cell field. Beyond varying efficiencies in the differentiation and
maturation between cell lines and protocols, variation can occur between
organoids differentiated at the same time and even within different regions of
the same organoid. This heterogeneity has sparked recent efforts to better
evaluate current capabilities and limitations of retinal organoid structure. A
recent study used a single differentiation protocol, which incorporated
advances in differentiation protocols from multiple laboratories to generate
retinal organoids from 16 hPSC lines (54). Results of the study verified
organoid technology as a powerful and reliable tool that can be standardized
and optimized for use in multiple cell lines. Nevertheless, in order to
overcome heterogeneity and ensure standards for the manufacturing of cell
therapy products, the automation of differentiation and maintenance is
definitely needed (30,139). There is also room for improvement upon
cryopreservation protocols that allow easy distribution of cell products (10).
Despite reports of successful cryopreservation of retinal organoids in cGMP
approaches, conditions that allow for reliable preservation of final cell
products will be essential to establish (35). However, by tackling these
challenges, 3D retina culture systems will be of utmost importance for
regenerative approaches to treat currently incurable retinal degenerative
diseases.
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9
Regenerative Medicine: Hypothesis in
Support of In Situ Retinal
Regeneration
Michael Trese, Edward Wood, Antonio Capone Jr and Kimberly
Drenser
INTRODUCTION
Regenerative medicine is a term used to encompass many approaches to try
to repair and regenerate dead or diseased tissue/organs. There have been
many attempts to achieve this end, many of which have been misleading and,
in some cases, damaging to patients. In 2017, the FDA Director made the
statement that the FDA would clamp down on the charlatans but that
regenerative medicine was no longer science fiction but within reach of
modern medicine. There are centers around the world, which focus on
regenerative medicine in several forms: gene therapy, introduction of stem
cells from outside the body replanted in the space of damaged cells, or the
use of dormant in situ progenitor cells that reactivates the healing repair and
regeneration of tissues. This is a process that already exists in the human
body; for example, the gut lining is regenerated every 5 days by the activity
of progenitor cells. This is often referred to as in situ tissue regeneration and
is being tested in hearing loss, cartilage regeneration, hair growth, and wound
healing. We will confine our comments to in situ retinal regeneration. The
approach we use is to provide the microenvironment that can stimulate the
dormant progenitor cells to grow a healthy retina, recapitulating how it
occurred originally. This type of tissue regeneration has been possible in
lizards and other animals but only in limited fashion in humans, occurring in
the gut, hair, and nail growth. In lower animals, the regrowth of organs is
Wnt (Wingless, Int-1) signaling mediated. Wnt signaling is highly conserved
from Drosophila to humans suggesting its importance.
NORRIN-DRIVEN RETINAL
VASCULAR REGENERATION
The fundamental theme in norrin-driven retinal vascular regeneration is that
the exogenous application of norrin repairs and regenerates vascular
endothelial cells by modifying the gene expression of a myriad of proteins
that improve endothelial cell tight junctions, strengthen the BRB, inhibit the
formation of significant tissue edema, and increase angiogenesis. When blood
vessels in the retina are injured in the setting of retinal vascular disease,
including diabetic retinopathy (DR), retinal vein occlusion (RVO), FEVR,
ROP, Coats, Norrie disease, and others, numerous growth factors, including
vascular endothelial growth factor (VEGF), are up-regulated in an attempt to
promote the growth of blood vessels and increase cellular oxygen delivery
(15). However, VEGF also directs the growth of disorganized and pathologic
immature vessels along the retinal surface and into the vitreous cavity (retinal
neovascularization) and increases the permeability of the BRB, which leads
to leakage of plasma and red blood cells through endothelial cells into the
retina, clinically manifesting as retinal edema. Vascular leakage in the retina
is clinically observed as macular edema or late-angiographic posterior and
peripheral endothelial leakage (LAPPEL) (16). A primary mechanism of
vascular leakage and retinal edema is VEGF-induced expression of
plasmalemma vesicle–associated protein (PLVAP). PLVAP is a cell-specific
protein that plays a pivotal role in transendothelial transport and
pathologically increases within retinal vascular endothelial cells in the setting
of VEGF-driven disease (17).
Contemporary medical therapies for treatment requiring retinal vascular
disease involve tissue destruction with ablative retinal laser therapy and/or
intravitreal injection of anti-VEGF agents (bevacizumab, ranibizumab,
aflibercept) (18). Intravitreal injection of anti-VEGF agents is the most
commonly performed procedure in ophthalmology and possibly all of
medicine (19). Through targeting VEGF, these therapies block an upstream
effector of retinal edema and retinal neovascularization. However, VEGF is
up-regulated for an intended purpose in response to vascular injury, and
numerous reports have shown that the presence of VEGF plays a pivotal role
in wound healing, neuroprotection, and vascular protection (20). Therefore,
long-term anti-VEGF therapy and VEGF suppression may impart unintended
consequences on cells (21). Targeting a more specific effector of retinal
vascular leakage, such as PLVAP, may serve as a more precise approach.
This may be accomplished with the activation of norrin, as the norrin protein
has been shown to directly down-regulate endothelial PLVAP (22), thereby
decreasing retinal edema. Our group has shown that the exogenous
application of norrin significantly decreases PLVAP levels alone and in the
presence of VEGF (Figure 9-1). The exogenous application of norrin also
mobilizes claudin-5, translocating it to the cell membrane, where it can help
restore the BRB and facilitate modulated angiogenesis (10).
FIGURE 9-1 Normalized plasmalemma vesicle-
associated protein (PLVAP) levels within cultured human
retinal endothelial cells in the presence of media alone,
norrin protein (Noregen; 200 ng/mL), VEGF165b (V165b)
25 ng/mL), and VEGF165b (25 ng/mL) and norrin. This
experiment shows that the exogenous application of norrin
significantly decreases PLVAP levels alone and in the
presence of VEGF.
Alternatively, norrin may also act directly and indirectly through trophic
factors on retinal neural cells to improve their health. The Wnt receptor
family of leucine-rich repeat-containing, G-protein–coupled receptors
(LGRs), specifically LGR4, is present within RGCs (25). Norrin binding to
LGR4 activates Wnt signaling and may have a positive effect on RGC health.
Norrin has also been shown to mediate neuroprotection to RGCs by
activating Wnt signaling within Müller cells and promoting them to secrete
neuroprotective trophic factors (26). Additionally, in an animal model where
RPE cells were made to continuously produce the norrin protein, retinal
photoreceptors were protected against light-induced cell damage through
protective effects of brain-derived neurotrophic factor (27). These studies
remind us of the complex relationships between retinal cell types and show
that the norrin protein can promote retinal neural and support cells to act
together for cellular health and repair.
In the presence of norrin, retinal neuronal support cells (e.g., Müller glial
cells) may actually turn into functioning retinal neural cells. This is an
evolutionarily conserved pathway still active in fish and birds where Müller
cells promote continuous and ongoing retinal regeneration (28). In mammals,
it is well known that trauma can induce glial to neural differentiation in the
central nervous system to a small degree that is mediated by inflammation
and related pathways, but there is more evidence pointing toward canonical
Wnt signaling being able to promote this even in the absence of injury (29).
Retinal Müller cells are the last cell type to form from retinal progenitor cells,
indicating that they retain some embryologic memory of turning into other
cell types (30). Essentially, activation of the canonical Wnt signaling pathway
may revert Müller cells back to a progenitor retinal cell type, which
subsequently undergoes differentiation to mature retinal cell types
functioning photoreceptors (31). This process seems to be more prominent in
youth and decreases with age (32), indicating that it may play a role in the
striking ability of children to heal as discussed above. In essence, Müller glial
cells are a source of retinal stem cells, and norrin-driven Wnt signaling may
promote them to participate in the process of retinal regeneration.
CONCLUSION
The concept of in situ retinal regeneration is complex and involves a
multitude of proteins and other signaling systems recreating the complex
milieu, which allowed healthy retinal growth. Certainly the pattern of Norrin
being present as a fetus and infant suggest that Norrin-driven Wnt signaling
is involved in organ generation. Future regenerative medicine clinical studies
and trials will hopefully pave the way for the future of vision restoration.
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7. Birbrair A. Stem cell microenvironments and beyond. Adv Exp Med Biol 2017;1041:1–3.
8. Zhang C, Lai MB, Khandan L, et al. Norrin-induced Frizzled4 endocytosis and enlysosomal
trafficking control retinal angiogenesis and barrier function. Nat Commun 2017;8:16050.
9. Drenser KA. Wnt signaling pathway in retinal vascularization. Eye Brain 2016;8:141–146.
10. Wang Z, Liu C-H, Huang S, et al. Wnt signaling in vascular eye diseases. Prog Retin Eye Res
2019;70:110–133.
11. Mohammed MK, Shao C, Wang J, et al. Wnt/β-catenin signaling plays an ever-expanding role
in stem cell self-renewal, tumorigenesis and cancer chemoresistance. Genes Dis
2016;3(1):11–40.
12. Wang Y, Cho C, Williams J, et al. Interplay of the Norrin and Wnt7a/Wnt7b signaling systems
in blood–brain barrier and blood–retina barrier development and maintenance. Proc Natl Acad
Sci U S A 2018;115(50):E11827–E11836.
13. Clevers H. Eyeing up new Wnt pathway players. Cell 2009;139(2):227–229.
14. Drenser KA, Fecko A, Dailey W, et al. A characteristic phenotypic retinal appearance in Norrie
disease. Retina 2007;27(2):243–246.
15. Dailey WA, Drenser KA, Wong SC, et al. Norrin treatment improves ganglion cell survival in
an oxygen-induced retinopathy model of retinal ischemia. Exp Eye Res 2017;164:129–138.
16. Thanos A, Todorich B, Trese MT. A novel approach to understanding pathogenesis and
treatment of capillary dropout in retinal vascular diseases. Ophthalmic Surg Lasers Imaging
Retina 2016;47(3):288–292.
17. Bosma EK, van Noorden CJF, Schlingemann RO, et al. The role of plasmalemma vesicle-
associated protein in pathological breakdown of blood-brain and blood-retinal barriers: potential
novel therapeutic target for cerebral edema and diabetic macular edema. Fluids Barriers CNS
2018;15(1):24.
18. Diabetic Retinopathy Clinical Research Network; Wells JA, Glassman AR, et al. Aflibercept,
bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med
2015;372(13):1193–1203.
19. Lau PE, Jenkins KS, Layton CJ. Current evidence for the prevention of endophthalmitis in anti-
VEGF intravitreal injections. J Ophthalmol 2018;2018:8567912.
20. Saint-Geniez M, Maharaj ASR, Walshe TE, et al. Endogenous VEGF is required for visual
function: evidence for a survival role on müller cells and photoreceptors. PLoS One
2008;3(11):e3554.
21. Tokunaga CC, Mitton KP, Dailey W, et al. Effects of anti-VEGF treatment on the recovery of
the developing retina following oxygen-induced retinopathy. Invest Ophthalmol Vis Sci
2014;55(3):1884–1892.
22. Liebner S, Corada M, Bangsow T, et al. Wnt/beta-catenin signaling controls development of the
blood-brain barrier. J Cell Biol 2008;183(3):409–417.
23. Tokunaga CC, Chen Y-H, Dailey W, et al. Retinal vascular rescue of oxygen-induced
retinopathy in mice by norrin. Invest Ophthalmol Vis Sci 2013;54(1):222.
24. Ohlmann A, Scholz M, Goldwich A, et al. Ectopic norrin induces growth of ocular capillaries
and restores normal retinal angiogenesis in Norrie disease mutant mice. J Neurosci
2005;25(7):1701–1710.
25. Van Schoore G, Mendive F, Pochet R, et al. Expression pattern of the orphan receptor
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26. Seitz R, Hackl S, Seibuchner T, et al. Norrin mediates neuroprotective effects on retinal
ganglion cells via activation of the Wnt/β-catenin signaling pathway and the induction of
neuroprotective growth factors in Müller cells. J Neurosci 2010;30(17):5998–6010.
27. Braunger BM, Ohlmann A, Koch M, et al. Constitutive overexpression of Norrin activates Wnt/
β-catenin and endothelin-2 signaling to protect photoreceptors from light damage. Neurobiol
Dis 2013;50:1–12.
28. Wan J, Goldman D. Opposing actions of Fgf8a on notch signaling distinguish two Muller glial
cell populations that contribute to retina growth and regeneration. Cell Rep
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29. Yao K, Qiu S, Tian L, et al. Wnt regulates proliferation and neurogenic potential of Müller glial
cells via a Lin28/let-7 miRNA-dependent pathway in adult mammalian retinas. Cell Rep
2016;17(1):165–178.
30. Rapaport DH, Wong LL, Wood ED, et al. Timing and topography of cell genesis in the rat
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31. Del Debbio CB, Balasubramanian S, Parameswaran S, et al. Notch and Wnt signaling mediated
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32. Löffler K, Schäfer P, Völkner M, et al. Age-dependent Müller glia neurogenic competence in
the mouse retina. Glia 2015;63(10):1809–1824.
10
International ROP: Retinopathy of
Prematurity in Chile
B. Andrés Kychenthal and S. Paola Dorta
INTRODUCTION
Shortly after the publication of the multicenter trial of cryotherapy for
retinopathy of prematurity (Cryo-ROP study) (1), the first ROP screening and
treatment program began in Chile. This chapter describes the personal
experience of the authors in the management of ROP cases in Chile from the
1990s to the present. We will describe how we diagnose and treat ROP in our
country, which has served as a model for several ROP programs in other
Latin American countries.
SCREENING STRATEGY
The development of a screening strategy is a key element in any ROP
program. There are certain elements that need to be considered, because they
may be different in each country. Examples include geography and the ability
of patients to travel to access care, phenotype of ROP appearance, which
provides characteristics of infants requiring screening, and level of neonatal
care.
In any ROP screening program, it is necessary to define which preterm
infants are to be examined, at what age, and how screening is to be
performed.
TABLE 10-1
Percentage of preterms born at Hospital Salvador in Santiago, Chile that developed threshold disease in
the period 1995–1997 and 1995–2002.
Accounting for all these data, it was determined that screening begin at a
chronologic age of 4 weeks. The frequency of subsequent examinations was
determined according to the classification of ROP at each examination.
In 2008, the first RetCam arrived in Chile, and we initiated modern screening
techniques and telemedicine. Since then, more of these cameras are in use in
NICUs throughout the country. The geography of the country and the high
concentration of retina specialists in the capital, Santiago, makes the use of
telemedicine a great contribution to ROP management. RetCam images were
taken initially by physicians only, but today they are taken by nurses and
informed by ophthalmologist with ROP training.
ZONE I ROP
Zone I ROP has represented the greatest clinical and therapeutic challenge in
the management of ROP patients.
During the 1990s, there was misunderstanding regarding posterior ROP,
making the diagnosis more difficult and resulting in delays in treatment and
worse outcomes than those of patients with zone II disease. A publication by
Shapiro et al. from 1993 reported findings similar to our experience at that
time (10).
Later, the Early Treatment for Retinopathy of Prematurity Randomized
Trial in 2003 (9) and the International Classification of ROP revisited in 2005
(8) helped to address this problem.
In 2000, we published results on zone I patients treated with threshold
disease as defined by the Cryo-ROP study. Eight out of 20 eyes with zone I
had unfavorable results (40%). Mean BW and GA were similar in zone I and
zone II ROP patients that developed threshold disease, but the mean PMA at
treatment was significantly different, 35.2 weeks for zone I ROP versus 37.2
weeks for zone II ROP, P = 0.006. In this same paper, it was also noted that
special attention should be given to atypical morphology present in zone I
cases: Some zone I cases showed clinical characteristics that were difficult to
analyze according to the 1984 International Classification of Retinopathy of
Prematurity. At times, instead of a demarcatory line between vascular and
avascular retina characteristic of stage 1 ROP, a demarcatory vessel was
observed. This vessel coursed exactly the line of demarcation between
vascular and avascular retina and had a general direction perpendicular to the
retinal vessels. Classic stage 3 disease was not always observed in zone I
despite the presence of plus disease. In many instances, the neovascular
proliferation associated with plus disease took the form of a flat network of
vessels either at the level of the demarcation or slightly more posterior. The
demarcation between vascular and avascular retina was always noticeable;
even if it did not have height as a ridge, there was an abrupt change in color
(11) (Figure 10-3).
In 2006, another paper by our group regarding the clinical characteristics
and treatment outcomes of zone I patients reported the atypical clinical
features observed in patients with zone I ROP including flat preretinal
neovascularization and a demarcation vessel between the vascular and
avascular retina. In this publication, within zone I, 2 anatomic subgroups
were defined (10). Posterior zone I was defined as a circular area limited by
the radius from the disc to the center of the macula. Anterior zone I was
defined as the annular area bounded by posterior zone I and zone II. The
results of laser photocoagulation were that significantly better outcomes were
obtained in the eyes with anterior zone I ROP, with 31 out 48 (65%) eyes
achieving favorable outcomes compared to eyes with posterior zone I ROP
with no eyes achieving a favorable outcome (P < 0.001) (12) (Figure 10-4).
Changes in neonatal care improved survival rates of very low birth weight
preterm infants and produced an increase in zone I ROP. In 2005, the mean
BW and GA were 945 g and 27.5 weeks, respectively, and in 2008, they were
859 g and 25.5 weeks, respectively. At this time, the percentage of zone I
ROP represented 34% of the treated patients.
The poor outcomes for zone I compared to zone II ROP significantly
changed with a better understanding of the clinical characteristics of posterior
ROP, through the use of digital imaging for screening that led to earlier
treatment. Also, the addition of antiangiogenic agent, anti-VEGF, as
therapeutic option, improved these cases.
ROP TREATMENT
Laser Photocoagulation in ROP
When we started treating ROP in 1994, indirect photocoagulation with a
diode laser was utilized. At that time, cryo-coagulation was commonly used
in other countries; however, there were advantages of using diode laser:
fewer local adverse effects and better outcomes.
The laser procedure was indicated for threshold ROP, as defined initially
by the Cryo-ROP study (1) but then changed to the criteria (type 1 ROP)
established by the Early Treatment for Retinopathy of Prematurity
Randomized Trial (9).
The unfavorable outcomes decreased noticeably over the years. From
1995 to 2004, the percentage of unfavorable outcomes in a group that
included 166 eyes was 18.1%, whereas from 2005 to 2008, the percentage of
unfavorable cases decreased to 2% in an group that included 133 eyes with
similar clinical characteristics.
The change to more favorable outcomes was influenced by several
factors: first, the greater technical experience of the medical team, and
second, the implementation of Chilean health reform in 2005 that included
mandatory clinical guidelines for all neonatal units in the country. The
clinical guidelines include a maximum time until treatment of 72 hours for
type 1 ROP requiring photocoagulation. As we mentioned previously, prior
to the implementation of this reform, referrals for treatment could be delayed
excessively thereby leading to worse outcomes (7).
However, as screening and treatment were improved in Chile, so did
neonatal care leading to increased survival of very low birth weight preterm
infants. The increase in extremely preterm infants led to a rise in posterior
ROP, the condition responsible for most of the unfavorable outcomes after
laser treatment.
TABLE 10-2
AP-ROP, aggressive posterior ROP; RE, right eye; LE, left eye; M, male; F, female.
FIGURE 10-6 Case 1 posterior zone I ROP (AP-ROP).
Avastin injection with type 1 ROP at 32 weeks
postmenstrual age, at 4 weeks of birth. Retinal
vascularization does not even reach the macular area (A).
At 35 and 56 weeks postmenstrual age, retinal vessels
reaches the foveal area (B). At 46 weeks postmenstrual
age (14 weeks after the Avastin injection), retinal
vascularization within zone III (C). (From Retina
2010;30:S24–S31 (Figure 1).)
Since that study, anti-VEGF drugs have been used in Chile for the treatment
of ROP, decreasing the number of unfavorable results and blindness due to
this disease. We believe that photocoagulation for type 1 ROP might not be
the appropriate first-line therapy for every case. We currently treat posterior
ROP with anti-VEGF drugs as the first-line therapy. The availability of anti-
VEGF drugs allows establishing the best choice for each patient. We
recognize that more study is needed regarding safety, but for visual outcomes
(see chapters by Ells (53) and Hartnett (38)), anti-VEGF agents have
improved outcomes in Chile.
The reactivation of ROP after the use of anti-VEGF drugs is an important
clinical problem. There are published series with high percentages of
reactivation even a prolonged time after anti-VEGF drug injection. Our
experience has been different with a very low number of cases of
postinjection reactivation.
We believe that there are important differences between preterm infants
from other series and ours, that is, ours may be more representative of
developing countries. Among these are genetic and racial differences and
others such as a higher BW and older GA, on average, for patients from
developing countries. In addition, infants born at larger BW and older GA are
likely more developmentally mature when Avastin is administered than the
extremely preterm infants in developed countries (see Chapter 38).
Considering the possibility of reactivation of ROP, we believe that
photocoagulation of the peripheral retina in patients treated with anti-VEGF
should be contemplated, especially in those cases where prolonged follow-up
is not possible.
We would perform retinal examinations after regression following anti-
VEGF treatment until 60 weeks of PMA, every 2 weeks until week 52 and
then monthly.
REFERENCES
1. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of
cryotherapy for retinopathy of prematurity: preliminary results. Arch Ophtalmol
1988;106:471–479.
2. Gilbert C, Fielder A, Gordillo L, et al.; on behalf of the International NO-ROP Group.
Characteristics of infants with severe retinopathy of prematurity in countries with low,
moderate, and high level of development: implications for screening programs. Pediatrics
2005;115;518–525. doi: 10.1542/peds.2004-1180.
3. Gilbert C, Canovas R, Kocksh R, Foster A. Ceguera Infantil en Chile. Arch Chil Oftalmol
1993;50:49–53.
4. Terry TL. Extreme prematurity and fibroblastic overgrowth of persistent vascular sheath behind
each crystalline lens: I. Preliminary report. Am J Ophthalmol 1942;25:203–204.
5. Evidence-based screening criteria for retinopathy of prematurity. Natural history data from the
Cryo-ROP and Light-ROP studies. For the Cryo-ROP and Ligh-ROP Cooperative Groups. Arch
Ophthalmol 2002;120:1470–1476.
6. Andrés Kychenthal B, Ximena Katz V, Paola Dorta S. Outcome After Laser and Surgical
Treatment for Retinopathy of Prematurity. ARVO Meeting, Fort Lauderdale, 2000.
7. Laser Treatment of Threshold ROP. Pan American Ophthalmology Society Meeting, Santiago,
2005.
8. International Committee for the Classification of Retinopathy of Prematurity. The International
Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol 2005;123(7):991–999.
Review. PubMed PMID: 16009843.
9. Revised indications for the treatment of retinopathy of prematurity. Results of the early
treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol
2003;121:1684–1696.
10. Shapiro MJ, Gieser JP, Warren KA, et al. Zone I Retinopathy of Prematurity. Proceedings of the
International Conference on Retinopathy of Prematurity, Chicago, IL, USA. November 18–19,
1993:149–155.
11. Katz X, Kychenthal A, Dorta P. Zone I retinopathy of prematurity. J AAPOS 2000;4:373–376.
12. Kychenthal A, Dorta P, Katz X. Zone I retinopathy of prematurity; clinical characteristics and
treatment outcomes. Retina 2006;26:S11–S15.
13. Kychenthal A, Dorta P. Vitrectomy after intravitreal bevacizumab (Avastin) for retinal
detachment in retinopathy of prematurity. Retina 2010;30(4 Suppl):S32–S36. doi:
10.1097/IAE.0b013e3181ca146b.
14. Dorta P, Kychenthal A. Treatment of type 1 retinopathy of prematurity with intravitreal
bevacizumab (Avastin). Retina 2010;30(4 Suppl):S24–S31. doi:
10.1097/IAE.0b013e3181ca1457.
15. Kychenthal A, Dorta P. 25-Gauge lens-sparing vitrectomy for stage 4A retinopathy of
prematurity. Retina 2008;28(3 Suppl):S65–S68. doi: 10.1097/IAE.0b013e318159ec49. Erratum
in: Retina 2009;29(1):127.
16. Andres Kychenthal B, Paola Dorta S, eds. Retinopathy of prematurity, current diagnosis and
management. Springer International Publishing AG, ISBN: 978-3-319-52188-6.
17. Dorta P, Kychenthal A. Spectral-domain optical coherence tomography of the macula in
preterm infants treated with bevacizumab for retinopathy of prematurity. Ophthalmic Surg
Lasers Imaging Retina 2015;46(3):321–326. doi: 10.3928/23258160-20150323-04.
11
International ROP: Tele-ROP in India
—A Real World Experience
Anand Vinekar
KIDROP
The first program and currently the largest tele-ROP service is the Karnataka
Internet Assisted Diagnosis for Retinopathy of Prematurity (KIDROP),
initiated in Bangalore, India, in 2007. KIDROP has completed to date over
150,000 screening sessions and identified over 2,500 infants with Type 1
ROP (1, 2, 3, 4, 5). The program currently screens in over 126 neonatal units
in the south Indian state of Karnataka, which has a population of
approximately 65 million. KIDROP addressed these problems of unscreened
rural and semi-urban premature infants for ROP using a novel platform of
telemedicine and employing for the first time nonphysician graders who
travel to remote neonatal intensive care units (NICUs) (1, 2, 3). On average,
the teams undertake 7,000 km of travel to reach these centers wherein 2,000
to 2,500 imaging sessions are performed every month.
KIDROP's services are provided zonally. Each zone covers
approximately 5 to 6 “districts” of the state, which are defined by
geographical contiguity. Each zone has its own equipment, including a wide-
field ROP camera, a vehicle, information technology infrastructure, as well as
a trained team. Each team has a fixed schedule of 6 working days a week
during which over 20 to 50 neonatal units are visited.
A single camera is used per zone, and the screening occurs in the
neonatal unit where preidentified infants are dilated and kept ready by the
nursing staff for imaging. Imaging is performed inside the incubator, on the
warmer, or in an adjoining room under medical supervision. Images are
captured in the video mode and the required still images are saved. The
imagers use the ROP camera to capture retinal images of in-house and
follow-up infants in these outreach centers. They then grade and interpret the
images and make management decisions within the NICU itself after
reviewing the images at the end of the session. Images are also shown to the
treating neonatologist and parents, when possible, and documented on the
“ROP card” given to the mother, in the hospital records, in the online
database, and in the image database (2,4,5), All images are backed up onto a
secure online database and are available for the remote expert to evaluate.
Reporting by nonphysicians is facilitated through a “decision-aiding
algorithm,” (1,2) which was developed with a three-way triaging code of
(Figure 11-1):
FIGURE 11-1 The decision algorithm followed by trained
technicians in the KIDROP program. (Source: Vinekar A,
et al. The KIDROP model of combining strategies for
providing retinopathy of prematurity screening in
underserved areas in India using wide-field imaging, tele-
medicine, non-physician graders and smart phone
reporting. Indian J Ophthalmol 2014;62(1):41–49.)
The imagers are trained to image the retina to include the ora serrata (6). This
reduces the chances of missing ROP that may be present in the retinal
periphery and also allows the “discharge” of the baby without the need of an
ophthalmologist performing indirect ophthalmoscopy to confirm retinal
maturity. All infants are imaged at least once between the postmenstrual ages
of 40 to 44 weeks to coincide with the physiological age of retinal maturity.
This applies to infants who do not develop any stage ROP and vascularize
normally. Those infants who develop any disease or require treatment with
laser are followed up for longer periods. Those infants who have received
anti-VEGF treatment currently need the longest follow-up. This acts as a
“safety net” in a program where there is no manual examination by a ROP
specialist. The remote specialist views and reports these images on his or her
smart phone (1,2). Owing to improved Internet and mobile data packages,
relatively rapid upload and review of images in a single session are possible
in a short period of time. The reporting time on an average after upload is 4
minutes. The time taken to report all “severe cases” of any session that need
urgent attention is <30 minutes (3). These images are uploaded manually
(RetCam) or automatically (Neo) for the ROP specialist to review and report.
Training and accreditation of the “imagers” is a critical contributor to the
success of the KIDROP program since the first “triage of diagnosis and
decision” is made by this cadre of nonphysicians (1,2). The KIDROP STAT
(Score for Training and Accreditation of Technicians) was developed to train
and certify imagers. This comprises three levels (I, II, and III) and has a 20-
point score, which tests the knowledge, skill, and practice patterns of the
imager in his or her native setting (Figure 11-2). On an average, training a
new imager can take between 30 and 90 working days.
FIGURE 11-2 The STAT score developed to train
imagers in the KIDROP program. (Source: Vinekar A, et
al. The KIDROP model of combining strategies for
providing retinopathy of prematurity screening in
underserved areas in India using wide-field imaging, tele-
medicine, non-physician graders and smart phone
reporting. Indian J Ophthalmol 2014;62(1):41–49.)
INNOVATIONS
More recently, a low-cost, portable camera was developed in India, 3Nethra
Neo (“Neo”) (Forus Health, India) with the clinical collaboration of
KIDROP. This affordable, smaller, and more portable device has made
transport, imaging and scaling-up of the program easier (7,8).
The Neo was designed specifically for ROP and infant retinal imaging. It
is a contact camera with a single, monolithic, handheld probe and provides a
120-degree field of view (Figure 11-3). It has a patented liquid lens, which is
integrated into the hand-piece that does not need to be removed after each
session (unlike the RetCam ROP lens). The Neo's illumination source is a
patented warm LED light. The image resolution is 2040 × 2040, compared to
1800 × 1600 of the RetCam (Figure 11-4A and B) and results in a square
image, which provides an extra arc of the superior and inferior retina that
would be cropped out in the rectangular image of other cintact cameras
(Figure 11-5). The systemic and ocular safety of the Neo was established (7).
FIGURE 11-3 The “3Nethra Neo” (“Neo”) ROP Camera
(Forus Health, India) is a monolithic, portable, wide-field,
contact infant retinal camera.
FIGURE 11-4 Comparison of RetCam vs. Neo Images.
A:RetCamShuttle (Natus USA) image of Stage 3 ROP in
the right eye. The image is rectangular due to the 1800 ×
1600 sensor of the camera. B:Neo (Forus Health, India)
camera of the same eye showing a 2040 × 2040 square
image with an additional superior and inferior retinal arc.
(Source: Vinekar A, Bhende P. Innovations in technology
and service delivery to improve retinopathy of prematurity
care. Community Eye Health 2018;31(101):S20–S22.)
FIGURE 11-5 RetCam vs. Neo image. The superimposed
images demonstrate the “extra arcs” of retina (dotted
yellow oval) in the superior and inferior retina,
respectively, that are imaged by the Neo and not on the
RetCam.
SUMMARY
Tele-ROP services in the real world pose unique challenges (20). KIDROP
was built on the tenants of wide-field imaging, wide coverage, and a robust
telemedicine platform. The unique aspects of the program are as follows: (1)
nonphysicians are allowed to report and analyze the images as the first point
of contact, thereby providing the diagnosis and decision to the (rural) mother
before she leaves the center; (2) indirect ophthalmoscopy is not mandated
before an infant can be discharged from screening; and (3) the program aims
at detecting any stage of ROP, not just treatment-warranted ROP. KIDROP,
therefore, differs from other programs that used referral-warranted criteria as
their end-points.
REFERENCES
1. Vinekar A, Gilbert C, Dogra M, et al. The KIDROP model of combining strategies for
providing retinopathy of prematurity screening in underserved areas in India using wide-field
imaging, telemedicine, non-physician graders and smart phone reporting. Indian J Ophthalmol
2014;62:41–49.
2. Vinekar A, Jayadev C, Mangalesh S, et al. Role of telemedicine in retinopathy of prematurity
screening in rural outreach centers in India—a report of 20,214 imaging sessions in the
KIDROP program. Semin Fetal Neonatal Med 2015;20:335–345.
3. Vinekar A, Jayadev C, Bauer N. Need for telemedicine in retinopathy of prematurity in middle-
income countries: EROP vs. KIDROP. JAMA Ophthalmol 2015;133:360–361.
4. Vinekar A, Mangalesh S, Jayadev C, et al. Impact of expansion of telemedicine screening for
retinopathy of prematurity in India. Indian J Ophthalmol 2017;65(5):390–395.
5. Vinekar A, Avadhani K, Dogra M, et al. A novel, low-cost method of enrolling infants at risk
for Retinopathy of Prematurity in centers with no screening program: the REDROP study.
Ophthal Epidemiol 2012;19(5):317–321.
6. Vinekar A, Dogra M, Shetty B. Imaging the ora serrata with the 3Nethra Neo camera—
importance in screening and treatment in retinopathy of prematurity. Indian J Ophthalmol
2020;68(1):270–271.
7. Vinekar A, Rao SV, Murthy A, et al. A novel, low-cost, wide-field, infant retinal camera,
“Neo”: technical and safety report for the use on premature infants. Transl Vis Sci Technol
2019;8(2):2. doi: 10.1167/tvst.8.2.2.
8. Vinekar A, Dogra MR, Jayadev C et al. Evaluation of a new, low-cost, portable, wide-field
digital retinal camera, “Neo” for screening infants or retinopathy of prematurity—a prospective,
multi-center, validation report in Asian Indian infants. Invest Ophthalmol Vis Sci 2016;57(12).
Available at http://iovs.arvojournals.
9. Vinekar A, Bhende P. Innovations in technology and service delivery to improve retinopathy of
prematurity care. Community Eye Health 2018;31(101):S20–S22.
10. Jayadev C, Vinekar A, Mohanachandra P, et al. Enhancing image characteristics of retinal
images of aggressive posterior retinopathy of prematurity using a novel software, (RetiView).
Biomed Res Int 2015;2015:898197
11. Rajashekar D, Srinivasa G, Vinekar A. Comprehensive retinal image analysis for aggressive
posterior retinopathy of prematurity. PLoS One 2016;11(10):e0163923.
12. Vijayalakshmi C, Sakthivel P, Vinekar A. Automated detection and classification of telemedical
retinopathy of prematurity images. Telemed J E Health 2019. doi: 10.1089/tmj.2019.0004.
13. Jayadev C, Vinekar A, Bauer N, et al. Look what else we found—clinically significant
abnormalities detected during routine ROP screening. Indian J Ophthalmol
2015;63(5):373–377.
14. Vinekar A, Govindaraj I, Jayadev C, et al. Universal ocular screening of 1021 term infants
using wide-field digital imaging in a single public hospital in India—a pilot study. Acta
Ophthalmol 2015;93:e372–e376.
15. Gilbert C, Wormald R, Fielder A, et al. Potential for a paradigm change in the detection of
retinopathy of prematurity requiring treatment. Arch Dis Child Fetal Neonatal Ed
2016;101(1):F6–F9.
16. UNDP Social Sector Service Delivery: Good Practices Resource Book 2015 | UNDP in India.
Available at:
http://www.in.undp.org/content/india/en/home/library/democratic_governance/SSS-delivery-
good-practices-2015.html. Accessed January 6, 2017.
17. CDC. Developing an effective evaluation report, 2013. Available at:
https://www.cdc.gov/eval/materials DevelopingAnEffectiveEvaluationReport_TAG508.pdf.
Accessed March 9, 2017.
18. Project Operational Guidelines. Prevention of Blindness from Retinopathy of Prematurity in
Neonatal Care Units. Available at: https://phfi.org/wp-content/uploads/2019/05/2018.ROP-
operational-guidelines.pdf. Accessed May 21, 2019.
19. Vinekar A, Azad R, Dogra MR, et al. The Indian retinopathy of prematurity society: a baby step
towards tackling the retinopathy of prematurity epidemic in India. Ann Eye Sci 2017;2:27.
20. Vinekar A, Dogra M, Azad RV, et al. The changing scenario of retinopathy of prematurity in
middle and low income countries: unique solutions for unique problems. Indian J Ophthalmol
2019;67:717–719.
12
International ROP: Retinopathy of
Prematurity in México
María Ana Martínez-Castellanos, Ana González H. León and
Estephania Feria Anzaldo
INTRODUCTION
Current Mexican Guidelines for ROP Screening
The 2013 reformation on article 61 of the Mexican General Health Law (1)
ruled that ophthalmic assessment of all infants at the 4th week of birth be
mandatory in order to detect early vision and functional threats to vision. It
also emphasized the importance of an extensive ophthalmoscopic
examination in all preterm infants. Moreover, in 2015, the Mexican Secretary
of Health (2) updated the retinopathy of prematurity (ROP) screening and
clinical practice recommendations widening the range for screening to
include a requirement that all infants born at gestational age (GA) ≤ 34 weeks
and/or with a birth weight (BW) of ≤1,750 g be screened. This ruling has
prevented missing many preterm infants at risk of ROP. Because it is not
uncommon to diagnose ROP in infants weighing more than 1,500 g at birth
and/or with a GA of 30 weeks or older in Mexico (2,3); as noted in other
articles, the screening criteria used in more developed nations may not apply
to middle-income countries (4, 5, 6). Mexican guidelines aim to prevent
functional decline and/or organ loss; give an early and appropriate treatment
by establishing standardized detection, diagnosis, and follow-up criteria;
educate healthcare professionals to identify at-risk populations; and refer in a
timely fashion to third-level center patients who require specialized care (2).
SCREENING STRATEGY
Screening for ROP plays an important role in preventing childhood blindness
in preterm infants. Because of the vast diversity in neonatal care, the facilities
available, and the number of trained ophthalmologists who can provide an
adequate screening program around the world, adaptation of guidelines to
each population must be considered (2,4).
In Mexico, Grupo ROP Mexico published the most relevant information
on ROP and the impact in our nation (7). The actual preferred practice
guidelines of ROP management in Mexico (2) acknowledge their
recommendations and suggest ROP screening be performed in the following
infants:
To the treating physician criteria, the preterm infants with associated risk
factors (cardiovascular pathology, associated sepsis, unstable clinical course,
among others).
Since there is an indirect relationship between GA and the time when
ROP manifests, it is recommended to use postmenstrual age (PMA) and is
used to determine the time of the first ophthalmologic exam (2). We base the
beginning of revisions on the Pediatric American Association Guidelines (8)
by commencing screening at a chronologic age of 4 or 32 weeks PMA,
whichever occurs first (2). The frequency and the time of the next check-up
will be determined by the stage of the disease at each examination (9).
Ophthalmoscopic exams should continue until the retinal vasculature is
completely developed or when the disease is regressed after giving treatment
(2).
In Mexico, the majority of screenings are performed with the help of
indirect ophthalmoscopy by an experienced retinal specialist,
ophthalmologist, and, in some cases, the pediatrician or neonatologist (3,10).
Currently, the evaluation by an expert using indirect ophthalmoscopy is the
gold standard for diagnosis and follow-up of patients with ROP; however,
telemedicine is becoming an important tool to detect disease with a similar
sensitivity for zone I disease and type 2 ROP (11); this is especially important
because Mexico lacks sufficient specialized doctors to perform indirect
ophthalmoscopy needed to diagnose infants (12).
ROP TREATMENT
Laser Photocoagulation in ROP
The criteria for laser therapy have been revised from threshold ROP to
include the earlier stage of high-risk prethreshold ROP (13).
Adequate and appropriate laser photocoagulation for ROP is different
from the application of lasers in adult retinal vascular diseases, and many
ophthalmologists need additional training to successfully treat ROP (13,14).
The standard of care in ROP was the diode red (810 nm wavelength)
laser indirect ophthalmoscope. Laser has many advantages over cryotherapy.
There is less posttreatment pain, adnexal edema, exudative retinal
detachment, vitreoretinal traction, and vitreous hemorrhage believed due to
reduced breakdown of the blood–retinal barrier (15).
Visual outcomes reported after laser are better than those after
cryotherapy. It is important to keep close observation after treatment to
ensure there is no need of more (as seen on Figure 12-1) (13,14).
FIGURE 12-1 Fundus photos showing (left side)
confluent grayish white laser burns up to the ridge.
Inadequate regression (top right) requiring more laser and
adequate regression (top bottom) needing only close
follow-up 7 days after laser. (From Good WV, Hardy RJ,
et al. Final visual acuity results in the early treatment for
retinopathy of prematurity study. Arch Ophthalmol.
2010;128:663–671.)
The initial settings on the laser console are chosen based on the fundus
pigmentation and area to be treated. Usually, laser power is 250 mW at 150
ms duration on the repeat mode setting at 300-ms interval. The treatment
must not be faster as this can result in inadequate burns. The intensity is a
grayish white rather than white spot, and placement of spots must be nearly
confluent. The laser power must be varied; less energy is used for the anterior
and superior retina compared to the posterior and inferior retina or to the
retina close to the ridge. A pediatric depressor is used to rotate and stabilize
the globe and to indent the anterior retina for laser (14,15).
It is essential to treat the entire avascular retina from the ridge to the ora
for 360 degrees and not leave untreated “skip” areas near the posterior ridge
of the avascular retina (14).
In a single session, one may place 3,000 to 4,000 spots in each eye to
cover the avascular retina in zone I disease and APROP. A smaller number of
spots, that is, 1,000 to 2,000, are needed to manage type 1 ROP outside zone
I (15).
Group 1 or Nonproliferative
Extensive areas of capillary nonperfusion with widespread arteriovenous
shunting between adjacent primary vessels, tortuosity of primary vessels
(“plus-like” disease), abnormal budding of tertiary vessels and capillaries,
abnormal capillary tuffs, and absence of foveal avascular zone were found.
Vascular changes were readily identified in FA images (17).
Group 2 or Proliferative
Some or all the characteristics of group 1 were seen plus leakage of dye at the
boundary between perfused and nonperfused retina and/or optic disc.
A finding was the absence of avascular foveal zone, which has been
reported by Henaine et al. in 50% of patients born at 36 weeks of GA or more
(17,18).
Optomap Imaging
At the present time, ROP screening is generally performed by binocular
indirect ophthalmoscopy and/or wide-field digital imaging systems. In
Mexico, there are two kinds of wide-field viewing systems in use for the
pediatric age group: contact (3nethra Neo, ICON, PanoCam, RetCam) and
noncontact systems (19).
The Optos uses a noncontact ultra-widefield dual wavelength laser
camera that is able to capture high-quality images from infants with ROP.
The Optomap is a panoramic digital image generated by Optos scanning laser
technology, which shows approximately 82% of the retina (19,20). Figure
12-4 displays an example of a ultra-widefield imaging of a retina in a preterm
male.
FIGURE 12-4 Ultra-widefield imaging. Left eye of a
premature male. Plus disease is seen in all four quadrants.
Avascular retina is seen in all the superior areas.
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