EDITOR

Leonard B. Nelson, MD, MBA

Director, Strabismus Center
Co-Director, Pediatric Ophthalmology and Ocular Genetics
Wills Eye Hospital
Associate Professor of Ophthalmology and Pediatrics
Jefferson Medical College of Thomas Jefferson University
Philadelphia, Pennsylvania

SECTION EDITORS
Michael J. Bartiss, OD, MD
Caroline DeBenedictis, MD
Kammi B. Gunton, MD
Judith B. Lavrich, MD
Kara C. LaMattina, MD
Alex V. Levin, MD, MHSc, FRCSC
Scott E. Olitsky, MD
Bruce M. Schnall, MD
Aldo Vagge, MD, PhD student
Barry N. Wasserman, MD

SERIES EDITOR
Christopher J. Rapuano, MD
Director and Attending Surgeon, Cornea Service
Co-Director, Refractive Surgery Department
Wills Eye Hospital
Professor of Ophthalmology
Sidney Kimmel Medical College at Thomas Jefferson University
Philadelphia, Pennsylvania
 Wills Eye Hospital
COLOR ATLAS & SYNOPSIS
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Pediatric
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LWW.com
 To my wife, Helene, for her understanding, patience, and support.
To my children, Jen, Kim, and Brad, who have taught me what is important in
life.
To my sons-in-law, Josh and Justin, and daughter-in-law, Julie, who all
embody the meaning of family.
To my grandsons, Jake, Ryan, Brandon, Joey, and Jordan, and
granddaughters, Lily and Chloe, who never cease to amaze me.

And to the memory of several individuals who passed away recently and who
had a profound effect on my personal and professional life:
Dean Henry S. Coleman, whose extraordinary guidance through my college
years at Columbia University fine-tuned my future goals.
A. Stone Freedberg, MD, who was instrumental in my matriculating and
succeeding as a medical student at Harvard Medical School.
Marshall M. Parks, MD, who taught me pediatric ophthalmology and whose
skills in all aspects of the subspecialty I have always tried to emulate.
 Editors
SERIES EDITOR
Christopher J. Rapuano, MD
Director and Attending Surgeon
Cornea Service
Co-Director
Refractive Surgery Department
Wills Eye Hospital
Professor of Ophthalmology
Sidney Kimmel Medical College at Thomas Jefferson University
Philadelphia, Pennsylvania

EDITOR
Leonard B. Nelson, MD, MBA
Director, Strabismus Center
Co-Director, Pediatric Ophthalmology and Ocular Genetics
Wills Eye Hospital
Associate Professor of Ophthalmology and Pediatrics
Jefferson Medical College of Thomas Jefferson University
Philadelphia, Pennsylvania

SECTION EDITORS
Michael J. Bartiss, OD, MD
Private Practice
Family Eye Care of the Carolinas
Aberdeen, North Carolina
Director of NICU Eye Services
FirstHealth of the Carolinas
Pinehurst, North Carolina
Caroline DeBenedictis, MD
Attending
Department of Pediatric Ophthalmology
Wills Eye Hospital
Clinical Instructor
Department of Ophthalmology
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Kammi B. Gunton, MD
Assistant Professor
Department of Pediatric Ophthalmology
Wills Eye Hospital
Associate Professor
Department of Ophthalmology
Sidney Kimmel Medical College at Thomas Jefferson University
Philadelphia, Pennsylvania
Kara C. LaMattina, MD
Assistant Professor
Department of Ophthalmology
Boston University School of Medicine
Boston Medical Centre
Boston, Massachusetts
Judith B. Lavrich, MD
Associate Surgeon
Department of Pediatric Ophthalmology and Ocular Genetics
Wills Eye Hospital
Clinical Instructor
Sidney Kimmel Medical College at Thomas Jefferson University
Philadelphia, Pennsylvania
Alex V. Levin, MD, MHSc, FRCSC
Chief
Pediatric Ophthalmology and Ocular Genetics
Wills Eye Hospital
Professor
Ophthalmology and Pediatrics
Sidney Kimmel Medical College at Thomas Jefferson University
Philadelphia, Pennsylvania
Scott E. Olitsky, MD
Professor
Department of Ophthalmology
University of Missouri—Kansas City School of Medicine
Chief
Section of Ophthalmology
Children’s Mercy Hospitals and Clinics
Kansas City, Missouri
Bruce M. Schnall, MD
Associate Surgeon
Department of Pediatric Ophthalmology
Wills Eye Hospital
Philadelphia, Pennsylvania
Aldo Vagge, MD, PhD Student
Attending Physician
Faculty Member
University Eye Clinic–Pediatric Ophthalmology and Strabismus Service
Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and
Child Health (DiNOGMI)
University of Genoa
IRCCS Policlinic Hospital San Martino
Genoa, Italy
Barry N. Wasserman, MD
Associate Professor
Department of Ophthalmology
Sidney Kimmel Medical College at Thomas Jefferson University
Clinical Instructor
Department of Pediatric Ophthalmology, Strabismus and Ocular Genetics
Wills Eye Hospital
Philadelphia, Pennsylvania
 Contributors
Alok S. Bansal, MD
Fellow
Vitreoretinal Surgery
Retina Service
Wills Eye Hospital
Philadelphia, Pennsylvania
UCSF VA Medical Center
San Francisco, California
Michael J. Bartiss, OD, MD
Private Practice
Family Eye Care of the Carolinas
Aberdeen, North Carolina
Director of NICU Eye Services
FirstHealth of the Carolinas
Pinehurst, North Carolina
Caroline DeBenedictis, MD
Attending
Department of Pediatric Ophthalmology
Wills Eye Hospital
Clinical Instructor
Department of Ophthalmology
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Anuradha Ganesh, MD
Fellow
Pediatric Ophthalmology and Ocular Genetics
Wills Eye Hospital
Philadelphia, Pennsylvania
Department of Ophthalmology
Sultan Qaboos University Hospital
Sultanate of Oman
Debra A. Goldstein, MD
Magerstadt Professor of Ophthalmology
Department of Ophthalmology
Northwestern University Feinberg School of Medicine
Director, Uveitis Service
Department of Ophthalmology
Northwestern Memorial Hospital
Chicago, Illinois
Kammi B. Gunton, MD
Assistant Professor
Department of Pediatric Ophthalmology
Wills Eye Hospital
Associate Professor
Department of Ophthalmology
Sidney Kimmel Medical College at Thomas Jefferson University
Philadelphia, Pennsylvania
Kara C. LaMattina, MD
Assistant Professor
Department of Ophthalmology
Boston University School of Medicine
Boston Medical Centre
Boston, Massachusetts
Judith B. Lavrich, MD
Associate Surgeon
Department of Pediatric Ophthalmology and Ocular Genetics
Wills Eye Hospital
Clinical Instructor
Department of Ophthalmology
Sidney Kimmel Medical College at Thomas Jefferson University
Philadelphia, Pennsylvania
Alex V. Levin, MD, MHSc, FRCSC
Chief
Pediatric Ophthalmology and Ocular Genetics
Wills Eye Hospital
Professor
Ophthalmology and Pediatrics
Sidney Kimmel Medical College at Thomas Jefferson University
Philadelphia, Pennsylvania
Leonard B. Nelson, MD, MBA
Director, Strabismus Center
Co-Director, Pediatric Ophthalmology and Ocular Genetics
Wills Eye Hospital
Associate Professor of Ophthalmology and Pediatrics
Jefferson Medical College of Thomas Jefferson University
Philadelphia, Pennsylvania
Scott E. Olitsky, MD
Professor
Department of Ophthalmology
University of Missouri—Kansas City School of Medicine
Chief
Section of Ophthalmology
Children’s Mercy Hospitals and Clinics
Kansas City, Missouri
Bruce M. Schnall, MD
Associate Surgeon
Department of Pediatric Ophthalmology
Wills Eye Hospital
Philadelphia, Pennsylvania
Emily Schnall, BFA
Independent freelance artist
Carol L. Shields, MD
Professor of Ophthalmology
Thomas Jefferson University Hospital
Co-Director
Oncology Service
Wills Eye Hospital
Philadelphia, Pennsylvania
Anya A. Trumler, MD
Fellow in Pediatric Ophthalmology and Ocular Genetics
Wills Eye Hospital
Philadelphia, Pennsylvania
Aldo Vagge, MD, PhD Student
Attending Physician
Faculty Member
University Eye Clinic–Pediatric Ophthalmology and Strabismus Service
Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and
Child Health (DiNOGMI)
University of Genoa
IRCCS Policlinic Hospital San Martino
Genoa, Italy
Barry N. Wasserman, MD
Associate Professor
Department of Ophthalmology
Sidney Kimmel Medical College at Thomas Jefferson University
Clinical Instructor
Department of Pediatric Ophthalmology, Strabismus and Ocular Genetics
Wills Eye Hospital
Philadelphia, Pennsylvania
 About the Series

T he beauty of the atlas/synopsis concept is the powerful combination of illustrative

photographs and a summary approach to the text. Ophthalmology is a very visual
discipline that lends itself wonderfully to clinical photographs. Whereas the seven
ophthalmic subspecialties in this series—Cornea, Retina, Glaucoma, Oculoplastics,
Neuro-ophthalmology, Uveitis, and Pediatrics—employ varying levels of visual
recognition, a relatively standard format for the text is used for all volumes.
The goal of the series is to provide an up-to-date clinical overview of the major areas
of ophthalmology for students, residents, and practitioners in all the health care
professions. The abundance of large, excellent-quality photographs (both in print and
online) and concise, outline-form text will help achieve that objective.

Christopher J. Rapuano
Series Editor
 Preface

W ills Eye Hospital has been my “academic home” for over 30 years. During that
time, I have witnessed remarkable changes in pediatric ophthalmology as it has
become a more established and rapidly expanding subspecialty. Although many changes
have occurred at Wills over those years, certain things have remained constant,
including the outstanding faculty, fellows, residents, and staff, as well as the
commitment to excellent patient care and academic endeavors. Wills is a rich
storehouse of clinical material and has provided the major background for this book. In
particular, the Pediatric Ophthalmology and Ocular Genetics Department at Wills,
which cares for thousands of children each year, provides a rare opportunity for the
study of an extremely wide variety of pediatric ocular disorders. It has been a pleasure
to oversee the production of this book because each contributor has been part of the
“Wills family.”
The advances that have occurred in the understanding of pediatric ocular disease and
newer modalities of treatment require a constant updating of knowledge about these
conditions. This text was written in an effort to provide practicing ophthalmologists,
pediatric ophthalmologists, and residents in training with a concise update of the
clinical findings and the most recent treatment available for a wide spectrum of
childhood ocular diseases. The disorders are grouped according to the specific ocular
structure involved. The atlas format should provide readers with a clear and succinct
outline of the disease entities and stimulate a more detailed pursuit of the specific
ocular disorders.

Leonard B. Nelson
Editor
 Acknowledgments

I t is with pleasure and gratitude that I acknowledge a number of individuals who

helped make this publication possible. I appreciate the members of the Audio-Visual
Department at Wills Eye Hospital, Roger Barone and Jack Scully, who helped in the
preparation of many of the photographs. I am grateful to Katurrah Hayman for her
exceptional secretarial skills. I am indebted to Louise Biekig, the developmental editor,
for her continuous suggestions and help throughout the preparation of this book. Finally,
I wish to thank all the authors who gave of their time, unselfishly, in the writing of this
book.
 Contents
Editors
Contributors
About the Series
Preface
Acknowledgments

CHAPTER 1 Abnormalities Affecting the Eye as a Whole

Judith B. Lavrich
Anophthalmia
Microphthalmia
Nanophthalmia
Typical

CHAPTER 2 Congenital Corneal Opacity

Bruce M. Schnall and Michael J. Bartiss
Sclerocornea
Birth Trauma: Tears in Descemet Membrane
Ulcer or Infection
Mucopolysaccharidosis
Peters Anomaly
Congenital Hereditary Endothelial Dystrophy
Corneal Dermoid
Anterior Staphyloma
Wilson Disease (Hepatolenticular Degeneration)
Herpes Simplex Infection
Herpes Simplex Virus Epithelial Dendrite or Ulceration
Herpes Simplex Virus Corneal Stromal Disease
Herpes Zoster Ophthalmicus
 Chickenpox
Limbal Vernal Keratoconjunctivitis

CHAPTER 3 Glaucoma
Alex V. Levin and Anya A. Trumler
Primary Congenital Glaucoma
Juvenile Open-Angle Glaucoma
Glaucoma Following Cataract Surgery
Uveitic Glaucoma
Sturge-Weber Syndrome
Congenital Ectropion Uveae
Aniridia
Posterior Embryotoxon

CHAPTER 4 Iris Anomalies

Michael J. Bartiss and Bruce M. Schnall
Central Pupillary Cysts (Pupillary Margin Epithelial Cysts)
Aniridia
Brushfield Spots
Ectopia Lentis Et Pupillae
Heterochromia Iridis
Iris Coloboma
Iris Stromal Cysts
Juvenile Xanthogranuloma
Lisch Nodules
Melanosis Oculi (Ocular Melanocytosis)
Persistent Pupillary Membrane
Posterior Synechiae
Axenfeld-Rieger Anomaly
Iris Flocculi

CHAPTER 5 Lens Anomalies

Caroline DeBenedictis
Congenital and Developmental Cataracts
Ectopia Lentis
 Anterior Lenticonus
Posterior Lenticonus
Spherophakia

CHAPTER 6 Pediatric Uveitis

Kara C. LaMattina and Debra A. Goldstein
Introduction
Juvenile Idiopathic Arthritis
Tubulointerstitial Nephritis and Uveitis
Blau Syndrome/Early-Onset Sarcoidosis
Post Infectious Autoimmune Uveitis
Traumatic Uveitis
Herpesviridae
Pars Planitis
Toxoplasmosis
Toxocariasis
Tuberculosis
Idiopathic Uveitis
Masquerades

CHAPTER 7 Congenital Abnormalities of the Optic Nerve

Aldo Vagge and Leonard B. Nelson
Optic Nerve Hypoplasia
Morning Glory Disc Anomaly
Optic Disc Coloboma
Optic Disc Pits
Tilted Disc Syndrome
Peripapillary Staphyloma
Optic Disc Drusen (Pseudopapilledema)

CHAPTER 8 Retinal Anomalies

Best Disease
Barry N. Wasserman
Choroideremia
Barry N. Wasserman
 Gyrate Atrophy
Barry N. Wasserman
Leber Congenital Amaurosis
Barry N. Wasserman
Astrocytic Hamartoma
Anuradha Ganesh
Incontinentia Pigmenti
Anuradha Ganesh and Alex V. Levin
Coats Disease
Barry N. Wasserman and Carol L. Shields
Retinoblastoma
Carol L. Shields
Congenital Hypertrophy of the Retinal Pigment Epithelium
Anuradha Ganesh and Alex V. Levin
Familial Exudative Vitreoretinopathy
Anuradha Ganesh and Alex V. Levin
Persistent Fetal Vasculature
Alok S. Bansal
Juvenile Retinoschisis
Barry N. Wasserman
Retinopathy of Prematurity
Anuradha Ganesh and Barry N. Wasserman
Retinitis Pigmentosa
Barry N. Wasserman
Myelinated Nerve Fibers
Barry N. Wasserman
Stargardt Disease/Fundus Flavimaculata
Barry N. Wasserman

CHAPTER 9 Eyelid Anomalies

Kammi B. Gunton
 Ankyloblepharon Filiforme Adnatum
Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome (BPES)
Childhood Ectropion
Congenital Entropion
Congenital Ptosis
Eyelid Colobomas
Epiblepharon
Epicanthus
Capillary Hemangiomas

CHAPTER 10 Lacrimal Anomalies

Bruce M. Schnall, Leonard B. Nelson, and Emily Schnall
Congenital Nasolacrimal Duct Obstruction
Dacryocele
Lacrimal Fistula

CHAPTER 11 Strabismus Disorders

Scott E. Olitsky and Leonard B. Nelson
Pseudoesotropia
Congenital (Infantile) Esotropia
Inferior Oblique Overaction
Dissociated Vertical Deviation
Refractive Accommodative Esotropia
Nonrefractive Accommodative Esotropia
Nonaccommodative or Partially Accommodative Esotropia
Congenital Exotropia
Intermittent Exotropia
A and V Pattern Strabismus
Third Nerve Palsy
Fourth Nerve Palsy
Sixth Nerve Palsy
Duane Syndrome
Brown Syndrome
Möbius Syndrome
Monocular Elevation Deficiency
 Congenital Fibrosis of the Extraocular Muscles

Index
 CHAPTER
1

Abnormalities Affecting the

Eye as a Whole
Judith B. Lavrich ■
ANOPHTHALMIA

A nophthalmia, also known as anophthalmos, is a congenital anomaly that is

characterized by the complete absence of ocular tissue within the orbit. Primary
o r true anophthalmia is a very rare condition and can involve one or both eyes.
Extreme microphthalmos is far more common and can be mistaken for this condition.
Anophthalmia has a prevalence of 0.18 per 10,000 births and has no racial or sexual
predilection.

Etiology
During embryogenesis, there is an arrest in the development of the neuroectoderm of the
primary optic vesicle, which stems from the anterior neural plate of the neural tube.
Anophthalmia is most frequently idiopathic and sporadic but can be inherited as a
dominant, recessive, or sex-linked trait. It is associated with maternal infections during
pregnancy (e.g., toxoplasmosis, rubella) as well as syndromes with craniofacial
malformations (e.g., Goldenhar, Hallermann-Streiff, Waardenburg syndromes). It is
linked with genetic defects, including trisomies 13 to 15; chromosomal deletion in band
14q22-23 with associated polydactyly; and mutations involving SOX2, RBP4, and
OTX2.

Signs
The eye is the stimulus for proper growth of the orbital region; therefore, an infant
born with anophthalmia has the following:
Orbital findings
Small orbital rim and entrance
Reduced size of bony orbital cavity
Globe is completely absent.
Extraocular muscles are usually absent.
Lacrimal gland and ducts may be absent.
Small or maldeveloped optic foramen
Eyelid findings
Narrow palpebral fissures
Foreshortening of the eyelids
Shrunken conjunctival fornices
Levator function is decreased or absent with poor eyelid folds.
Contracture of the orbicularis oculi muscle

Symptoms
Unilateral or bilateral blindness because of the absence of the globe(s)

Differential Diagnosis
Microphthalmos, which includes the following:
Secondary anophthalmos: the development of the eye begins but gets arrested,
resulting in only residual eye tissue or extreme microphthalmos.
Degenerative anophthalmos: there is formation of the optic vesicle, but subsequent
degeneration occurs because of lack of blood supply or other causes.
Cryptophthalmos: abnormal fusion of the entire eyelid margin with absence of the
eyelashes
Cystic eye: a cyst of neuroglial tissue lacking normal ocular structures

Diagnostic Evaluation
Anomalous eyelid and orbital features (Fig. 1-1)
Ultrasound imaging: B-scan ultrasonography of the orbit will show a complete
absence of the globe. After 22 weeks’ gestation, transvaginal ultrasonography can detect
eye malformations, but its sensitivity in the detection of anophthalmia is not known.
Magnetic resonance imaging (MRI) of the head and orbits: MRI will show the soft
tissue within the orbital cavity (Fig. 1-2). Associated intracranial abnormalities can
also be evaluated. Individuals with bilateral anophthalmos may have a related
hypoplastic or absent optic chiasm as well as agenesis or dysgenesis of the corpus
callosum.
Computed tomography (CT) scan of the head and orbits: CT scan will image the
bony changes and intracranial and craniofacial abnormalities seen with anophthalmia.

Treatment
Medical care
Orbital conformers can be placed in the orbital cavity to stimulate growth of the
bony orbit (Fig. 1-3). As the orbit grows, the conformers are changed and
progressively increased in size to further expand the orbital cavity. This serial
augmentation takes time and cooperation from both the patient and the parents.
Contraction and reversal of the benefit often occur if the conformer is left out of the
orbit for a significant amount of time. With unilateral anophthalmos, the family should
be aware that, most likely, the final result will not mirror the normal healthy orbit.
An ocular prosthesis can be fitted over the conformer to simulate the eye and
improve appearance.
Surgical care
The small bony cavity is a cosmetic deformity that may not allow proper fitting of
a prosthesis. Therefore, surgery may be indicated for either of these problems.
Inflatable tissue expanders are used if conformers are not well tolerated or cannot
be fit. The inflatable silicone expander is surgically positioned deep in the orbit and
is accessed through a tube placed at the lateral orbital rim. The expander is filled
with saline and gradually reinflated on a weekly or biweekly schedule. Compared
with solid conformers, inflatable expanders may allow more rapid and extensive
expansion of the bony orbit. When the desired volume is achieved, the port and
bladder need to be removed and replaced with a permanent implant.
Hydrogel (methyl methacrylate and N-vinylpyrrolidone) expanders are self-
expanding hydrophilic expanders that are implanted in the orbital tissue in their dry,
contracted state through a small incision. The implant gradually expands in size by
osmotic absorption of surrounding tissue fluid. The benefit of this method is the
controlled self-expansion, reducing the risk of tissue atrophy, and without the need
 for repeat fittings or surgery.
Dermal fat grafting, which involves biocompatible grafts that grow slowly over
time, can be a good option to restore volume to the hypoplastic orbit. The graft is
harvested from a second surgical site, typically the buttocks. However, the graft
compatibility and growth can be variable. In some cases, the fat can atrophy. Rarely,
the fat can hypertrophy, necessitating debulking.
Injectable calcium hydroxylapatite (Radiesse) is a semipermanent dermal filler
that has been reported as a new, simple, cost-effective technique to treat volume
deficiency in the anophthalmic orbit in adults. Augmentation is accomplished with
serial injections of the filler until adequate volumization is achieved. The results
have shown lasting effect in the orbit of 1 year or more.
Orbitocranial advancement surgery is used for orbital expansion if conformers and
expanders are unsuccessful. This method involves multiple osteotomies to divide the
periocular bones and advancing them forward and outward with bone grafts and
plates.
Because the foreshortening of the eyelids may limit the passage of a large
conformer, a lateral canthotomy or cantholysis may be needed to increase the
horizontal length of the palpebral fissure. Other methods to lengthen the eyelids may
include skin, mucosal, or cartilage grafts.

Prognosis
Severe cosmetic deformities can result from anophthalmia, especially if not treated
early. Even with proper treatment, the results are often cosmetically suboptimal, with
incomplete expansion of the orbit, malformations and immobility of the eyelids, and
complete immobility of the ocular prosthesis.
Psychosocial issues caused by absence of an eye and facial disfigurement can result.
Referral for psychological counseling may be indicated for these children.

REFERENCES
Bardakiian T, Weiss A, Schneider AS. Anophthalmia/microphthalmia overview. In: Pagon RA, Bird TC, Dolan CR,
Stephens K, eds. GeneReviews. Seattle, WA: University of Washington; 2007:1993–2004.
Bernardino R. Congenital anophthalmia: a review of dealing with volume. Middle East Afr J Ophthalmol. 2010;17:156–
160.
https://en.wikipedia.org/wiki/Anophthalmia
Verma AS, Fitzpatrick DR. Anophthalmia and microphthalmia. Orphanet J Rare Dis. 2007;2:47.
FIGURE 1-1. Anophthalmia. A. External examination of bilateral anophthalmia. B. Clinical
examination of bilateral anophthalmia showing empty orbits. (Courtesy of Leonard B. Nelson, MD.)
FIGURE 1-2. Anophthalmia. Magnetic resonance image showing unilateral anophthalmia with
absence of the globe. (Courtesy of Carol Shields, MD.)
 FIGURE 1-3. Anophthalmia. Fitting orbital conformers in bilateral “clinical anophthalmia” (severe
microphthalmia). (Courtesy of Bruce Schnall, MD.)

MICROPHTHALMIA

M icrophthalmia is a congenital unilateral or bilateral condition in which the globe

has a reduced axial length that is at least two standard deviations below the
mean for age. The appearance of the globe and the severity of axial length reduction
define the classification of microphthalmia:
Simple or pure microphthalmia: an eye that is anatomically intact except for its short
axial length. Simple microphthalmia is suspected in the presence of high hyperopia (≥8
diopters) or microcornea. Visual loss can occur in a subset of microphthalmos
associated with posterior segment abnormalities.
Severe microphthalmia: an eye that is severely reduced in size, with an axial length
of less than 10 mm at birth or less than 12 mm after age 1 year and a corneal diameter of
less than 4 mm (Fig. 1-4). The globe may be inconspicuous on clinical examination, but
remnants of ocular tissue, an optic nerve, and extraocular muscles will be seen with
imaging.
Complex microphthalmia: a globe with reduced size associated with developmental
ocular malformations of the anterior or posterior segment (or both).
There are two types of microphthalmos: noncolobomatous and colobomatous
(microphthalmos with cyst) (Fig. 1-5). The prevalence of microphthalmia is 1.5 per
10,000 births. There is no racial or sexual predilection.

Etiology
Microphthalmia results from an arrest in the development at any stage during the growth
of the optic vesicle.
Environmental: prenatal exposure of alcohol, thalidomide, retinoic acid, or rubella
Heritable: via autosomal dominant, recessive, or X-linked inheritance
Multiple chromosomal abnormalities
Single-gene disorders causing syndromic microphthalmia (e.g., CHARGE
[coloboma of the eye or central nervous system anomalies, heart defects, atresia of
the choanae, retardation of growth or development, genital or urinary defects, and ear
anomalies or deafness]; Lenz microphthalmia; Goltz, Aicardi, Walker-Warburg, and
Meckel-Gruber syndromes, Norrie disease; incontinentia pigmenti)
Other genes: SIX6, SHH, VSX2, RAX and others.
Unknown causes: Goldenhar syndrome; cases associated with basal encephalocele
and other central nervous system anomalies

Signs
Significant variability exists, depending on the severity of the microphthalmos.
Orbital findings
Small orbital rim and entrance
Reduced size of bony orbital cavity
Globe is extremely small and can be malformed.
 Extraocular muscles are present but are usually hypoplastic.
Lacrimal gland and ducts are present but are usually hypoplastic.
Optic nerve is present but is usually hypoplastic.
Small or maldeveloped optic foramen
Eyelid findings
Narrow palpebral fissures
Foreshortening of the eyelids
Shrunken conjunctival fornices
Levator function is decreased or absent with poor eyelid folds.
Contracture of the orbicularis oculi muscle

Symptoms
The extent of visual loss depends on the severity of the microphthalmos and the
presence of related anomalies.

Differential Diagnosis
Microcornea with a normal-sized globe
High hyperopia

Diagnostic Evaluation
Anomalous eyelid and orbital features
Clinical examination looking for evidence of a cornea or globe
Palpation of the orbit to estimate globe size
Measurement of corneal diameter (normal range, 9.0–10.5 mm in neonates)
B-scan ultrasonography to evaluate the internal structures of the globe (Fig. 1-6A)
CT scan or MRI of the brain and orbits to evaluate the size of the globe and its
internal structures, the presence of optic nerve and extraocular muscles, and brain
anatomy (Fig. 1-6B and C)

Treatment
For severe microphthalmia, the treatment is the same as for anophthalmia.
For simple or complex microphthalmos with vision
 Treatment of amblyopia: patching of the healthy eye to stimulate as much potential
vision as possible
Protection of the healthy eye in children with unilateral involvement
Visual aids and other visual resources for children with reduced vision
Orbital conformers: placed over the microphthalmic eye to stimulate growth of the
bony orbit. These can be painted or with the pupil left clear for vision.
Ocular prosthesis: can be fitted over the globe to improve appearance, if needed

Prognosis
For severe microphthalmia, the prognosis is the same as for anophthalmia.
For simple microphthalmia, the visual prognosis depends on the severity of the
condition and the associated ocular abnormalities.

REFERENCES
Bardakiian T, Weiss A, Schneider AS. Anophthalmia/microphthalmia overview. In: Pagon RA, Bird TC, Dolan CR,
Stephens K, eds. GeneReviews. Seattle, WA: University of Washington; 2007:1993–2004.
Bernardino R. Congenital anophthalmia: a review of dealing with volume. Middle East Afr J Ophthalmol. 2010;17:156–
160.
https://en.wikipedia.org/wiki/Microphthalmia
Verma AS, Fitzpatrick DR. Anophthalmia and microphthalmia. Orphanet J Rare Dis. 2007;2:47.
FIGURE 1-4. Microphthalmia. A. Unilateral microphthalmia. B. Severe microphthalmia.
FIGURE 1-5. Microphthalmia. Microphthalmia with a cyst. (Courtesy of Carol Shields, MD.)

FIGURE 1-6. Microphthalmia. A. Magnetic resonance image showing unilateral microphthalmia.

Note the presence of extraocular muscles and an optic nerve. B. B-scan ultrasonography of
microphthalmia with a cyst showing a posterior staphyloma. C. Computed tomography scan of
microphthalmia with a cyst showing disorganization of ocular tissues and posterior cyst. (Courtesy of
Carol Shields, MD.)
NANOPHTHALMIA

N anophthalmia is a subtype of simple microphthalmia. It is a congenital and

typically bilateral condition (Fig. 1-7), although it can be unilateral. It is
characterized by reduced globe volume, although the eye is otherwise grossly normal.

Etiology
Nanophthalmia results from an arrest in the growth of the eye during the embryonic
stage and may result from a smaller optic vesicle anlage.
Most cases are sporadic, but both autosomal recessive and autosomal dominant
inheritance have been reported.

Signs
Reduced axial length of the globe (<20 mm)
Very high hyperopia (>10 diopters)
Reduced corneal diameter
Lens is normal in size.
Shallow anterior chamber
Thick sclera
Fundus may show crowded optic disc, vascular tortuosity, and macular hypoplasia.
Because of the anatomy, these eyes have a high risk for angle-closure glaucoma.
They tolerate intraocular surgery poorly with a high rate of complications, including
uveal effusion and retinal detachment.

Differential Diagnosis
High hyperopia in a normal eye

Diagnostic Evaluation
Measurement of corneal diameter
A-scan to measure the axial length of the eye
Pentacam and ultrasound biomicroscopy to image the anterior chamber and assess its
depth (Fig. 1-8).

Treatment
 Management of narrow-angle or angle-closure glaucoma is initially medical,
although the response to treatment is typically poor, and miotics may even worsen the
condition by relaxing the lens zonules. Peripheral laser iridotomy may be moderately
successful. Caution must be used with fistulizing glaucoma surgery because
postoperative malignant glaucoma can ensue. Laser trabeculoplasty, if performed, must
be done early before permanent damage to the outflow mechanism occurs.
Removal of the lens must be anticipated and can be complicated by uveal effusion
and nonrhegmatogenous retinal detachments. Although challenging in these high-risk
eyes, small-incision cataract surgery is safe and diminishes the need for prophylactic
sclerotomies.

Prognosis
The prognosis for vision is good if glaucoma is treated early and successfully.

REFERENCES
Bardakiian T, Weiss A, Schneider AS. Anophthalmia/microphthalmia overview. In: Pagon RA, Bird TC, Dolan CR,
Stephens K, eds. GeneReviews. Seattle, WA: University of Washington; 2007:1993–2004.
Bernardino R. Congenital anophthalmia: a review of dealing with volume. Middle East Afr J Ophthalmol. 2010;17:156–
160.
https://eyewiki.aao.org/Nanophthalmos
Sharan S, Grigg JR, Higgins RA. Nanophthalmos: ultrasound biomicroscopy and Pentacam assessment of angle
structures before and after cataract surgery. J Cataract Refract Surg. 2006;32:1052–1055.
Verma AS, Fitzpatrick DR. Anophthalmia and microphthalmia. Orphanet J Rare Dis. 2007;2:47.
FIGURE 1-7. Bilateral nanophthalmia. Note the reduced corneal diameter.

FIGURE 1-8. Nanophthalmia. Ultrasound biomicroscopy of the anterior chamber in nanophthalmos.

 The iris is bowed forward, creating a plateau-like configuration of the narrow angle (arrow), and the
anterior sclera (arrowhead) shows increased thickness. (From Buys YM, Pavlin CJ. Retinitis
pigmentosa, nanophthalmos, and optic disc drusen: a case report. Ophthalmology. 1999;106:619–622.)

TYPICAL COLOBOMA

T he term coloboma is derived from the Greek koloboma, meaning mutilated or

curtailed. It is a congenital malformation and refers to a notch, gap, hole, or fissure
in any of the ocular structures. Typical colobomas are frequently bilateral and are often
associated with microphthalmia.

Etiology
“Typical” colobomata are caused by defective closure of the optic fissure during the
fifth to seventh weeks of fetal life and because of the location of the fetal fissure and are
found in the inferonasal quadrant in the eye. (“Atypical” colobomata are less frequent
malformations located outside the inferotemporal quadrant, for which the etiology is
still unclear.)
Most cases are idiopathic and sporadic, but all types of inheritance (i.e., autosomal
dominant, autosomal recessive, and X-linked) have been reported and may be
associated with various syndromes, such as CHARGE, Meckel-Gruber, Lenz
microphthalmia, Aicardi, Patau, and Edwards syndromes. The prevalence of coloboma
is 0.7 per 10,000 births.

Signs
Ocular colobomata may affect any of the structures or the entire globe traversed by
the fetal fissure from the iris to the optic nerve. It has a variable appearance, depending
on the extent and severity of the coloboma.
Iris: transillumination defect, heterochromia iridis, and “teardrop” pupil (Fig. 1-
9A)
Lens: defect or flattening of lens or absence of lens zonules inferiorly
Chorioretina: thinning of the choriocapillaris; pigment clumping along the line of
optic fissure closure; colobomatous defect usually with sharp edges and
circumscribed by irregular pigmentation; white sclera is seen through defect if all
layers of chorioretina are absent; floor of defect sometimes bulges, forming
staphyloma
Leukocoria: if the uveal defect is large
 Optic nerve: enlarged, excavated, vertically oval; retinal vessels may radiate in a
spoke-like fashion from the nerve (Fig. 1-9B and C)
Globe: microphthalmia in some cases
Vision: ranges from normal to no light perception
May be associated with a variety of other developmental defects

Differential Diagnosis
Atypical coloboma
Retinal toxoplasmosis
Optic nerve pits
Morning glory syndrome
Optic nerve hypoplasia

Diagnostic Evaluation
Clinical examination of the eye

Treatment
Patching for amblyopia: if unilateral with optic nerve involvement to stimulate as
much potential vision as possible
Treat ocular complications: cataract, subretinal neovascularization, and retinal
breaks or detachment

Prognosis
Vision depends on involvement of the optic nerve, macula, and papulomacular
bundle. However, visual acuity cannot be predicted from either coloboma size or optic
nerve involvement because patients with large colobomata with optic nerve
involvement can have almost normal vision.

REFERENCES
Chang L, Blain D, Bertuzzi S, et al. Uveal coloboma: clinical and basic science update. Curr Opin Ophthalmol.
2006;17:447–470.
Onwochei BC, Simon JW, Bateman JB, et al. Ocular colobomata. Surv Ophthalmol. 2000;45:175–194.
FIGURE 1-9. Coloboma. A. Iris coloboma. B. Coloboma involving the retina and optic nerve showing
an enlarged optic nerve and radiating retinal vessels. C. Extensive chorioretinal and optic nerve
coloboma. Note the round, yellow-appearing optic nerve and the significant disorganization of the tissues.
 CHAPTER
2

Congenital Corneal Opacity

Bruce M. Schnall and Michael J. Bartiss ■
T he differential diagnosis for congenital corneal opacity can be remembered using
the mnemonic STUMPED:
Sclerocornea
Tears in Descemet membrane or birth trauma
Ulcer or infection
Mucopolysaccharidosis (MPS)
Peters anomaly
Endothelial dystrophy, congenital hereditary (CHED)
Dermoid

SCLEROCORNEA
Etiology
Developmental anomaly of the cornea
Defective mesodermal migration during embryogenesis, resulting in tissue
resembling sclera rather than clear corneal stroma
Can be autosomal dominant, recessive, or sporadic
Has been associated with the 22q11.2 deletion syndrome

Symptoms
Opacified cornea present since birth
Signs
Usually bilateral but can be unilateral
Opacification of the cornea with the peripheral cornea more opacified than the
central cornea (Fig. 2-1)
May have fine blood vessels

Differential Diagnosis
Tears in Descemet membrane or birth trauma
Ulcer or infection
MPS
Peters anomaly
CHED
Dermoid
Glaucoma

Treatment
Evaluation by a genetic specialist to look for associated congenital anomalies
If the central cornea is clear, it can be associated with cornea plana and a high
refractive error.
Penetrating keratoplasty should be considered if the central visual axis is involved
and the posterior segment is relatively normal.

Prognosis
Visual outcome with or without keratoplasty depends on the presence of other ocular
and systemic abnormalities.
 FIGURE 2-1. Sclerocornea. The corneal opacification is more severe peripherally than centrally.

REFERENCES
Binenbaum G, McDonald-McGinn DM, Zackai EH, et al. Sclerocornea associated with the chromosome 22q11.2
deletion syndrome. Am J Med Genet A. 2008;146(7):904–909.
Doane JF, Sajjadi H, Richardson WP. Bilateral penetrating keratoplasty for sclerocornea in an infant with monosomy
21. Case report and review of the literature. Cornea. 1994;13(5):454–458.
Kim T, Cohen EJ, Schnall BM, et al. Ultrasound biomicroscopy and histopathology of sclerocornea. Cornea.
1998;17(4):443–445.

BIRTH TRAUMA: TEARS IN DESCEMET

MEMBRANE
Etiology
Trauma to the cornea during vaginal delivery resulting in tears in Descemet
membrane
May be associated with the use of forceps
Symptoms
Corneal edema or opacification present at birth, which may resolve within the first
few days of life

Signs
Unilateral corneal edema or opacification present at birth (Fig. 2-2A)
Often observed to have eyelid swelling and evidence of trauma to eyelids at birth
Corneal edema often resolves within the first few days of life, revealing the
Descemet membrane ruptures, which usually appear as vertical linear tears (Fig. 2-2B
and C). Descemet tears associated with congenital glaucoma are usually oriented
horizontally or curvilinearly (Fig. 2-3).
Multiple tears are often present.
Associated with high astigmatism

Differential Diagnosis
Sclerocornea
Ulcer or infection
MPS
Peters anomaly
CHED
Dermoid
Glaucoma

Treatment
Descemet tears are associated with high astigmatism, which is amblyogenic.
Treatment of the amblyopia includes correction of the refractive error with glasses or
contacts and part-time occlusion of the fellow eye.
Penetrating keratoplasty should be considered if the corneal edema does not resolve.

Prognosis
Visual outcome depends on the success of amblyopia treatment.

REFERENCE
Lambert SR, Drack AV, Hutchinson AK. Longitudinal changes in the refractive errors of children with tears in
Descemet’s membrane following forceps injuries. J AAPOS. 2004;8(4):368–370.

FIGURE 2-2. Descemet tears due to birth trauma. A. Corneal opacification in a newborn from
Descemet tears associated with birth trauma. B. The vertically oriented linear Descemet membrane
ruptures can now be seen in the same infant a few days later after the corneal edema has cleared. C.
The vertically oriented Descemet membrane breaks from birth trauma can be seen in this older child at
the slit lamp with retroillumination.

FIGURE 2-3. Descemet tears due to congenital glaucoma. A. Recent Descemet membrane
ruptures associated with glaucoma. Note that the breaks are oriented horizontally. They are recent and
therefore have overlying corneal edema. B. Breaks in Descemet membrane caused by glaucoma. The
horizontally oriented breaks can be seen more clearly after resolution of the corneal edema.
ULCER OR INFECTION
Etiology
Acquired bacterial or herpetic infection

Symptoms
Acquired corneal opacity usually associated with conjunctival injection and eyelid
swelling (Fig. 2-4)

Signs
Usually unilateral
Corneal opacity with overlying epithelial defect
Associated with conjunctival injection and other signs of inflammation
May have associated systemic infection
May have associated eyelid lesions or eyelid abnormalities

Differential Diagnosis
Sclerocornea
Tears in Descemet membrane from birth trauma
MPS
Peters anomaly
CHED
Dermoid
Glaucoma

Treatment
Depends on underlying cause or organism
Prompt systemic treatment may be needed.

Prognosis
May result in a visually significant corneal scar

REFERENCE
Luchs JI, Laibson PR, Stefanyszyn MA, et al. Infantile ulcerative keratitis secondary to congenital entropion. Cornea.
1997;16:1:32–34.

FIGURE 2-4. Corneal ulceration. Corneal ulcer in an infant caused by congenital entropion of the
lower eyelid.

MUCOPOLYSACCHARIDOSIS
Etiology
Inborn error of metabolism
Enzyme deficiency leads to a block in the metabolic pathway, which results in
accumulation of material in the cornea.

Symptoms
Acquired opacification of the cornea:
Hurler syndrome, or MPS 1H, is associated with corneal clouding by 6 months of
age.
Scheie syndrome, or MPS 1S, is associated with corneal clouding by 12 to 24
months of age.
Signs
Acquired corneal cloudiness or haze (Fig. 2-5)
Associated systemic features (coarse facial features, mental retardation, poor
growth, deafness)

Differential Diagnosis
Sclerocornea
Tears in Descemet membrane or birth trauma
Ulcer or infection
Peters anomaly
CHED
Dermoid
Glaucoma

Diagnosis
Evaluation by a genetic specialist
Urine testing for MPS
Enzyme assay
Gene testing for gene defect

Treatment
Enzyme replacement
Bone marrow transplant

Prognosis
Depends on severity of systemic disease and success of systemic treatment

REFERENCE
Kenyon KR, Navon SE, Haritoglou C. Corneal manifestations of metabolic diseases. In: Krachmer JH, Mannis MJ,
Hollane EJ, eds. Cornea. 2nd ed. Vol 1. Philadelphia, PA: Elsevier Mosby; 2005:749–776.
 FIGURE 2-5. Hurler syndrome. Note the generalized corneal haze. (Courtesy of Alex Levin, MD.)

PETERS ANOMALY
Etiology
Congenital
Can be autosomal dominant, recessive, or sporadic
May be associated with mutation of the PAX6 gene
Symptoms
Central corneal opacity present at birth (Fig. 2-6)
Eighty percent are bilateral.

Signs
Central corneal leukoma with adherent iris strands (Fig. 2-7)
Adherent iris strands usually originate from the iris collarette to the posterior surface
of the corneal leukoma.
May have associated cataract and glaucoma

Differential Diagnosis
Sclerocornea
Tears in Descemet membrane or birth trauma
Ulcer or infection
MPS
CHED
Dermoid
Glaucoma

Diagnosis
Examination under anesthesia may be needed to confirm diagnosis and rule out
glaucoma.

Treatment
Evaluation by a genetic specialist to look for associated anomalies and to rule out
Peters plus syndrome
Treat glaucoma if present.
Penetrating keratoplasty should be considered within the first few months of life if
the central visual axis is involved and the posterior segment is relatively normal.
If a visually significant cataract is present, cataract removal may be needed.

Prognosis
Depends on involvement of the anterior segment; prognosis is poorer if a cataract or
glaucoma is present.
 Depends on success of amblyopia treatment
Early keratoplasty may reduce amblyopia.

REFERENCES
Mailette De Buy Wenniger-Prick LJ, Hennekam RC. The Peters’ plus syndrome: A review. Ann Genet.
2002;45(2):97–103.
Yang LL, Lambert SR, Drews-Botsch C, et al. Long-term visual outcome of penetrating keratoplasty in infants and
children with Peters anomaly. J AAPOS. 2009;13(2):175–180.
Yang LL, Lambert SR, Lynn MJ, et al. Long-term results of corneal graft survival in infants and children with Peters
anomaly. Ophthalmology. 1999;106(4):833–848.

FIGURE 2-6. Peters anomaly. Note the central opacity and the clear corneal periphery.
 FIGURE 2-7. Peters anomaly. Slit-lamp photograph of Peters anomaly. Note the iris adherent to the
central corneal leukoma. (Courtesy of Alex Levin, MD.)

CONGENITAL HEREDITARY ENDOTHELIAL

DYSTROPHY
Etiology
Congenital
Can be autosomal dominant, recessive, or sporadic

Symptoms
Corneal haze present since birth (Fig. 2-8)

Signs
Bilateral symmetrical corneal edema
Swollen, thickened cornea with minimal epithelial edema
Rarely associated with glaucoma

Differential Diagnosis
 Sclerocornea
Tears in Descemet membrane from birth trauma
Ulcer or infection
MPS
Peters anomaly
Dermoid
Glaucoma

Diagnosis
CHED can be confused with congenital glaucoma.
Corneal thickness two to three times normal
Examination under anesthesia may be needed to confirm corneal thickening and to
rule out glaucoma.

Treatment
Mild edema can be treated with hypertonic saline solutions.
Penetrating keratoplasty is usually needed if corneal haze is significant. Descemet
stripping endothelial keratoplasty may be an alternative to penetrating keratoplasty.

Prognosis
Depends on graft survival and amblyopia
Early keratoplasty may reduce amblyopia.

REFERENCES
Javadi MA, Baradaran-Rafii AR, Zamani M, et al. Penetrating keratoplasty in young children with congenital
hereditary endothelial dystrophy. Cornea. 2003;22(5):420–423.
Mittal V, Mittal R, Sangwan VS. Successful Descemet stripping endothelial keratoplasty in congenital hereditary
endothelial dystrophy. Cornea. 201;30(3):354–656.
 FIGURE 2-8. Congenital hereditary endothelial dystrophy. (Courtesy of Alex Levin, MD.)

CORNEAL DERMOID
Etiology
Developmental anomaly of the cornea
Limbal dermoids may be associated with Goldenhar syndrome, also known as facio-
auricular vertebral syndrome and oculo-auriculo-vertebral dysplasia.

Symptoms
 Corneal opacity present since birth

Signs
Dome-like mass of the cornea
Most commonly located at the corneal limbus (epibulbar dermoid) but can be located
centrally (Fig. 2-9)
May contain hairs or fatty tissue (lipodermoids)
Normal intraocular pressure (IOP) and corneal diameter

Differential Diagnosis
Sclerocornea
Tears in Descemet membrane from birth trauma
Ulcer or infection
MPS
Peters anomaly
CHED
Glaucoma

Treatment
Often associated with astigmatism, which will result in amblyopia
Patching and correction of refractive error may be needed to treat amblyopia.
Some corneal or limbal dermoids can be treated by shaving flush with corneal
surface or lamellar keratoplasty.
Penetrating keratoplasty can be considered if the central visual axis is involved.

Prognosis
Visual outcome depends on success of amblyopia treatment.

REFERENCES
Arora R, Jain V, Mehta D. Deep lamellar keratoplasty in corneal dermoid. Eye (Lond). 2005;19(8):920–921.
Mansour AM, Barber JC, Reinecke RD, et al. Ocular choristomas. Surv Ophthalmol. 1989;33(5):339–358.
Watts P, Michaeli-Cohen A, Abdolell M, et al. Outcome of lamellar keratoplasty for limbal dermoids in children. J
AAPOS. 2002;6(4):209–215.
 FIGURE 2-9. Corneal dermoid. A. Centrally located corneal dermoid. Note the satellite-like lesions.
B. Dermoid located at the limbus superiorly.

ANTERIOR STAPHYLOMA
Etiology
Developmental anomaly of the anterior segment

Symptoms
Bulging opacified cornea

Signs
Bulging or protuberant congenital corneal opacity that may prevent the eyelids from
closing fully
Can be unilateral or bilateral (Fig. 2-10)
Cornea usually thinned and enlarged

Differential Diagnosis
Sclerocornea
Tears in Descemet membrane from birth trauma
Ulcer or infection
MPS
Peters anomaly
CHED
Dermoid

Treatment
Often treated with evisceration or enucleation (Fig. 2-11)
Corneoscleral transplant can be considered.

Prognosis
Visual prognosis is poor.

REFERENCE
Lunardelli P, Matayoshi S. Congenital anterior staphyloma. J Pediatr Ophthalmol Strabismus. 2009;25:1–2.
FIGURE 2-10. Anterior staphyloma. A. Unilateral anterior staphyloma. B. Bilateral anterior
staphyloma.
 FIGURE 2-11. Enucleation specimen of anterior staphyloma. A. Gross specimen of enucleated
eye with anterior staphyloma; note the bulging cornea. B. Specimen showing view of lens and anterior
staphyloma to the right of the lens.

WILSON DISEASE (HEPATOLENTICULAR

DEGENERATION)
Etiology
Autosomal recessive inherited disorder caused by multiple allelic substitutions or
deletions in the DNA coding for B-polypeptide, Cu++ transporting, and ATPase
Defect linked to chromosome 13q14.3-q21.1
Systemic decreased level of ceruloplasmin causing decreased ability to properly
transport copper
Copper deposition in liver and kidneys followed by brain and Descemet membrane

Symptoms
Muscular rigidity, tremor, and involuntary movements (can resemble Parkinson
disease)
Speech difficulties and dementia also occur.

Signs
Golden brown, red, or green ring of pigmentation (known as Kayser-Fleischer ring)
at the level of the posterior lamella of Descemet membrane (Fig. 2-12)
Usually begin at the 12- and 6-o’clock positions in the cornea and spread
circumferentially around the cornea
May be several millimeters thick

Differential Diagnosis
Intrahepatic cholestasis of childhood
Biliary cirrhosis
Chronic active hepatitis

Treatment
Kayser-Fleischer rings gradually disappear with successful treatment.
D-penicillamine (works via chelating Cu++ ions)
British anti-Lewisite
Copper-deficient diet
Liver transplantation

Prognosis
Studies have shown retinal electrophysiologic abnormalities improving with
successful treatment.

REFERENCES
Liu M, Cohen EJ, Brewer GJ, Laibson PR. Kayser-Fleischer ring as the presenting sign of Wilson disease. Am J
Ophthalmol. 2002;133(6):832–834.
Slovis TL, Dubois RS, Rodgerson DO, Silverman A. The varied manifestations of Wilson’s disease. J Pediatr.
1971;78(4):578–584.
 FIGURE 2-12. Wilson disease. Kayser-Fleisher ring in a patient with Wilson disease. Note the
brown-red ring in the periphery of the cornea.

HERPES SIMPLEX INFECTION

Etiology
Infection with herpes simplex virus (HSV) type 1 or 2
Usually acquired during childhood, occasionally acquired during the birth process
Ocular infection with HSV can affect the eyelids, conjunctiva, or cornea.
HSV blepharoconjunctivitis

Symptoms
Vesicular lesions on the eyelid or red inflamed eye
Vesicles cross the dermatomes and progress to crusting (Fig. 2-13).
Usually unilateral
 May be recurrent

Signs
Clear vesicles with an erythematous base
Often associated with an enlarged preauricular lymph node on the affected side
Conjunctival involvement results in conjunctival injection and eyelid swelling.
May be associated with a conjunctival dendrite, which is best seen at the slit lamp
with fluorescein

Differential Diagnosis
Herpes zoster ophthalmicus: Rash is dermatomal and does not cross the midline.

Diagnosis
Based on characteristic clinical findings
In atypical cases, diagnosis can be confirmed by viral cultures, polymerase chain
reaction (PCR) testing, or the appearance of multinucleated giant cells on Giemsa
staining of scrapings.

Treatment
Topical (trifluridine drops or ganciclovir ophthalmic gel) or systemic (acyclovir or
valacyclovir) antiviral agents (or both topical and systemic agents) may be used.
Long-term oral antiviral prophylaxis is recommended for children with multiple
recurrent episodes.
FIGURE 2-13. Herpes simplex blepharitis. A. Vesicular lesions, some of which are now crusted.
 B. The vesicular lesions cross dermatomes.

HERPES SIMPLEX VIRUS EPITHELIAL DENDRITE OR

ULCERATION
Symptoms
Red, painful eye
Tearing, photophobia, decreased vision
History of previous HSV infection
Usually unilateral

Signs
Dendrite that appears as a linear branching epithelial defect with terminal bulbs (Fig.
2-14A)
May appear as a geographic ulceration (Fig. 2-14B)
Epithelial edges of herpetic lesions are swollen and stain intensely

Diagnosis
Based on characteristic clinical findings
In atypical cases, diagnosis can be confirmed by viral cultures, PCR testing, or the
appearance of multinucleated giant cells on Giemsa staining of corneal scrapings.

Treatment
Topical (trifluridine drops or ganciclovir ophthalmic gel) or systemic (acyclovir or
valacyclovir) antiviral agents (or both topical and systemic agents) may be used
Consider cycloplegics for significant photophobia or uveitis if present.
Debridement can remove infected epithelium.
FIGURE 2-14. Herpes simplex virus epithelilal disease. A. Herpes simplex corneal dendrite. The
dendrite stains with fluorescein when viewed with cobalt blue light. (Courtesy of Alex Levin, MD.) B.
Herpes simplex geographic corneal ulcer in an infant. Note the white, raised leading edge of the ulcer.
HERPES SIMPLEX VIRUS CORNEAL STROMAL DISEASE
Symptoms
Unilateral corneal opacity (Fig. 2-15)
Red, painful eye
Tearing, photophobia, decreased vision
History of previous HSV infection

Signs
Disciform keratitis (Fig. 2-16A)
Disc-shaped stromal opacity
Intact epithelium
Mild anterior chamber reaction
Keratoprecipitates are common.
Interstitial keratitis (Fig. 2-16B)
Multiple or diffuse white stromal infiltrates
Neovascularization or ghost vessels

Diagnosis
Based on characteristic clinical findings
Decreased corneal sensation

Treatment
Combination of antiviral agents and steroids

REFERENCES
Chong EM, Wilhelmus KR, Matoba AY, et al. Herpes simplex virus keratitis in children. Am J Ophthalmol.
2004;138(3):474–475.
Hsiao CH, Yeung L, Yeh LK, et al. Pediatric herpes simplex virus keratitis. Cornea. 2009;28(3):249–253.
Schwartz GS, Holland EJ. Oral acyclovir for the management of herpes simplex virus keratitis in children.
Ophthalmology. 2000;107(2):278–282.
FIGURE 2-15. Herpes simplex virus stromal disease. Corneal opacity in an uninflamed eye
months after herpes simplex infection.
 FIGURE 2-16. Herpes simplex virus stromal disease. A. Active herpes simplex interstitial
keratitis. B. Disciform keratitis. Note the disc-like corneal haze seen in the slit-lamp photograph.

HERPES ZOSTER OPHTHALMICUS

Etiology
Reactivation of latent varicella (chickenpox virus) from cranial nerve ganglia
More common in the elderly population but may occur if the child had chickenpox in
utero or within the first 6 months of life
Has occurred in children immunized for chickenpox
Can occur in individuals who are immunocompromised

Symptoms
Unilateral vesicular lesions associated with pain
May be preceded by headache or neuralgia in affected dermatome

Signs
Vesicular rash isolated to the dermatome of the fifth cranial nerve (Fig. 2-17)
Rash usually respects the midline
May develop conjunctivitis, small epithelial dendrites (pseudodendrites), disciform
keratitis, and uveitis
Corneal disease and uveitis may not begin until several days to weeks after the onset
of the skin eruption.

Differential Diagnosis
Herpes simplex: Rash is not dermatomal and crosses the midline.

Diagnosis
Based on characteristic clinical findings and associated skin vesicles

Treatment
Systemic antivirals are recommended within 4 days of onset of skin eruptions.
Analgesics may be needed to treat associated pain.
Conjunctivitis and pseudodendrites can be treated with lubrication.
Disciform keratitis and uveitis are treated with topical steroids.

REFERENCE
De Freitas D, Martins EN, Adan C, et al. Herpes zoster ophthalmicus in otherwise healthy children. Am J Ophthalmol.
2006;142(3):393–399.
 FIGURE 2-17. Herpes zoster ophthalmicus. Note the dermatomal distribution of the vesicles (A and
B) and the significant eyelid edema (B).

CHICKENPOX
Etiology
Primary infection with varicella (chickenpox virus)

Symptoms
Disseminated vesicular lesions that affect the skin and mucous membranes
Red eye, conjunctival lesion (Fig. 2-18)

Signs
Conjunctival vesicle or ulceration
Less commonly may develop superficial punctate keratitis, dendrite without terminal
bulbs, or disciform keratitis
Often associated with a transient mild anterior uveitis but can trigger a persistent
uveitis that requires treatment

Diagnosis
Based on characteristic clinical findings and associated skin vesicles

Treatment
Self-limited conjunctivitis
Topical antibiotics may prevent secondary bacterial infection.

Prognosis
Usually resolves without conjunctival or corneal scarring

REFERENCE
Pavan-Langston D. In: Smolin G, Thoft RA, eds. The Cornea. Boston, MA: Little, Brown and Company; 1983:189.
 FIGURE 2-18. Chicken pox. Chickenpox lesion can be seen just inferior to the cornea in the left eye
and on the face.

LIMBAL VERNAL KERATOCONJUNCTIVITIS

Etiology
Most common cause is seasonal allergies.

Symptoms
Elevated gelatinous mass along the corneal limbus
Red, itchy eyes
Mucous production

Signs
Discrete gray-white nodules at cornea limbus. These nodules have a whitish center
that is filled with eosinophils (Horner-Trantas dots; Fig. 2-19).
 The nodules may become confluent.
Conjunctiva surrounding these nodules is injected.
Usually bilateral, but involvement may be asymmetrical

Diagnosis
Based on characteristic clinical findings
History of seasonal allergies

Treatment
Topical antihistamine and mast cell stabilizers
Topical steroids may be needed; best used in pulsed doses. When using topical
steroids, careful monitoring, including monitoring IOP, is needed to prevent steroid side
effects.
Oral antihistamines and removal of suspected allergens can be helpful.

REFERENCE
Krachmer JH, Mannis MJ, Hollane EJ, eds. Cornea. 2nd ed. Vol 1. Philadelphia, PA: Elsevier Mosby; 2005:552–558.

FIGURE 2-19. Limbal vernal. White, elevated lesions (Horner-Trantas dots) can be seen along the
corneal limbus superiorly.
 CHAPTER
3

Glaucoma
Alex V. Levin and Anya A. Trumler ■
PRIMARY CONGENITAL GLAUCOMA

G laucoma diagnosed within the first 4 years of life and not associated with other
findings of anterior segment dysgenesis is classified as primary congenital
glaucoma and is further subdivided into neonatal onset (onset ≤ 1 month old), infantile
onset (>1–24 months old), and late onset (> 2 years old). Typical findings include
buphthalmos, which is usually characterized by corneal enlargement, Haab striae
(breaks in Descemet’s membrane), corneal edema, and increasing axial length, with
patches of anterior iris insertion on gonioscopy. These patients have no other
predisposing factors such as cataract surgery, trauma, or steroid use. Neonatal
presentation portends a worse prognosis.

Epidemiology and Etiology

The incidence varies in different populations of the world, with a reported incidence
of 1 in 10,000 in the United States. It has a much higher incidence in Saudi Arabia and
the Gypsies of Romania (1 per 2500 and 1 per 1250, respectively), with both
populations having a higher rate of consanguinity and allele frequency.
Mutations in the CYP1B1 gene (2p21), which encodes a cytochrome P450 protein,
are one cause. Two other genes and at least two other loci have been identified. In the
Arabic and Gypsy populations, a homozygous mutation in CYP1B1 has been found in
more than 94% of cases, consistent with autosomal recessive inheritance. In isolated
cases, and in North America, the frequency of CYP1B1 mutation decreases to 10% to
15%.
Congenital glaucoma is a primary goniodysgenesis. The theory of an imperforate
membrane (Barkan membrane) over the trabecular meshwork is controversial. Rather,
there appears to be a failure of complete neural crest differentiation, resulting in
impaired aqueous outflow. Clinically, the angle is characterized on gonioscopy as a flat
or patchy high insertion with absence of the angle recess and iris inserting directly on
the trabecular meshwork (Fig. 3-1).

History
Primary congenital or infantile glaucoma is bilateral in 75% of cases, which can
create a delay in diagnosis because parents may simply believe their child has
“beautiful big eyes.”
The classic symptoms include photophobia and epiphora due to corneal stromal or
epithelial edema (Fig. 3-2). A “cloudy eye” is often the presenting sign.
Elevated intraocular pressure (IOP) causes stretching of the cornea with resultant
breaks in Descemet’s membrane, called Haab striae (Fig. 3-3). Buphthalmos also thins
the sclera giving it a blue appearance because of the underlying hue of the uvea.

Signs
Characteristic findings include optic nerve cupping, corneal enlargement, Haab
striae, increasing axial length, and gonioscopic findings (see “Diagnostic Evaluation”
section). IOP may be artifactually low in the presence of corneal epithelial edema.

Differential Diagnosis
Congenital hereditary endothelial dystrophy
Congenital hereditary stromal dystrophy
Mucopolysaccharidosis
Peters anomaly and other causes of sclerocornea
Keratitis
Forceps birth trauma
Megalocornea (X-linked recessive or autosomal recessive)
Contralateral microphthalmia
Nasolacrimal duct obstruction

Diagnostic Evaluation
A patient with corneal clouding, increased corneal diameter, and optic nerve cupping
should raise the suspicion for primary congenital glaucoma and prompt further
evaluation, if needed, with an examination under anesthesia, including slit-lamp
biomicroscopy, corneal pachymetry, corneal diameter measurement, gonioscopy,
refraction, axial length measurement, and (if possible) optic nerve photography.
When measuring IOP under anesthesia, attention should be paid regarding the type of
anesthetic agent used. Whereas ketamine increases IOP measurements, halothane lowers
IOP, as do other anesthetic agents but to a lesser extent.
Corneal edema falsely lowers the IOP measurements, whereas stromal edema may
stiffen the cornea and cause falsely high measurements. Asymmetry of IOP is also a
suggestive indication of an abnormality.
The normal maximum corneal diameter in an infant younger than 1 year is 11 mm. A
corneal diameter greater than 12 mm, asymmetry between the eyes, and significant
progression over time are all suggestive of congenital glaucoma.
Retinoscopy and axial length measurement using immersion A-scan provide
objective measurements to suggest increased axial length. The mean axial length at birth
is 17 mm and increases to 20 mm by 1 year of age.

Treatment and Prognosis

Medical management with antiglaucoma medications in primary congenital or
infantile glaucoma is used as a temporizing agent, with definitive treatment being
surgical.
Antiglaucoma medications, including carbonic anhydrase inhibitors (both topical and
oral), low-dose beta-blockers, and prostaglandins, may be used to clear the cornea for
surgical intervention. Brimonidine should not be used in infants younger than 1 year
because there is a risk of potentially life-threatening apnea, hypotension, bradycardia,
and hypothermia.
The primary procedure of choice is goniotomy or trabeculotomy depending on the
preference of the surgeon and adequate visualization of the anterior chamber angle that
is needed for goniotomy. Both have reported short-term success rates of 60% to 90%.
Goniotomy has the advantage of leaving the conjunctiva untouched. Endoscopic
goniotomy can be performed if the cornea is too cloudy to allow for a standard
gonioscopic view. Another procedure that has been popularized is 360-degree
trabeculotomy.
In patients who have a history of failed goniotomy or trabeculotomy, secondary
surgical interventions may include goniosurgery on the remaining angle, trabeculectomy,
or glaucoma drainage device implantation. Neonatal onset congenital glaucoma more
often requires surgery beyond or other than goniotomy or trabeculotomy.
 The goal of primary congenital or infantile glaucoma treatment is more than
achieving a normal IOP. More importantly, attaining and maintaining normal visual
function is paramount the biggest obstacle to which is amblyopia. Aggressive treatment
of refractive error, amblyopia, and visually significant optical opacities are important
components to the infant’s care. Lifelong follow-up of these patients is needed to
monitor for glaucoma progression.
Optic nerve cupping in infants is reversible and is a hallmark of successful glaucoma
management.

REFERENCES
Bejjani BA, Lewis RA, Tomey KF, et al. Mutations in CYP1B1, the gene for cytochrome P4501B1, are the
predominant cause of primary congenital glaucoma in Saudi Arabia. Am J Hum Genet. 1998;62:325–333.
Chen TC, Chn PP, Francis BA, et al. Pediatric glaucoma surgery: a report by the American Academy of
Ophthalmology. Ophthalmology. 2014;121:2107–2115.
Taylor RH, Ainsworth JR, Evans AR, et al. The epidemiology of pediatric glaucoma: the Toronto experience. J
AAPOS. 1999;3:308–315.
Yassin SA, Al-Tamimi E. Surgial outcomes in children with primary congenital glaucoma: a 20-year experience. Eur J
Ophthalmol. 2016;26(6):581–587.
Zagora SL, Funnell CL, Martin FJ, et al. Primary congenital glaucoma outcomes: lessons from 23 years of follow-up.
Am J Ophthalmol. 2015;159:788–796.

FIGURE 3-1. Infantile glaucoma. Gonioscopic view of a child with infantile glaucoma angle showing
patches of high iris insertion (arrows).
FIGURE 3-2. Congenital glaucoma. Buphthalmos and corneal clouding of the right eye. Miosis in the
right eye is caused by the use of pilocarpine.

FIGURE 3-3. Haab striae, which are breaks in Descemet’s membrane, are delineated by the
appearance of two scrolled-back edges (arrows denote the bottom Haab stria; there is also one more
superiorly).
JUVENILE OPEN-ANGLE GLAUCOMA

J uvenile open-angle glaucoma (JOAG) is a form of open-angle primary glaucoma

unassociated with ocular malformations or other inciting factors, with an age of
onset from 4 to 40 years. JOAG generally has a more aggressive course than the later-
onset adult primary open-angle glaucoma.

Epidemiology and Etiology

The incidence of JOAG is 1 per 50,000 cases of all glaucoma. It has autosomal
dominant inheritance with variable expression and penetrance. One known mutated gene
is the myocilin gene (MYOC) on chromosome 1q21-q31 (termed GLC1A). Myocilin is
a glycoprotein that is expressed in the trabecular meshwork, with its function largely
unknown. Mutations in the CYP1B1 gene on chromosome 2p21 have been associated
with autosomal recessive inheritance of juvenile onset glaucoma. Patients with a
mutation in CYP1B1 in addition to MYOC have a more severe phenotype than those
with MYOC mutation alone.
The pathophysiology of JOAG is unknown but is thought to be impaired aqueous
outflow through the trabecular meshwork. There are usually no abnormalities on
gonioscopy in affected patients, although there are histologic reports of thickening of the
trabecular meshwork outflow system and clinical reports of increased iris processes
(“pectinate ligaments”) crossing the trabecular meshwork.
Most cases of JOAG that have a strong family history of disease are associated with
mutation in MYOC and demonstrate an autosomal dominant pattern.

History
Patients are usually asymptomatic. Often, the disorder is noted as an incidental
finding during routine examination.
Because it is most commonly an autosomal dominant disorder, at-risk family
members of affected individuals should have a comprehensive examination.

Signs
JOAG is an aggressive, usually bilateral, disease that results in optic nerve cupping,
visual field changes, and nerve fiber layer thinning in the presence of elevated IOP.

Differential Diagnosis
Glaucoma associated with acquired conditions
 Glaucoma associated with nonacquired ocular anomalies
Glaucoma associated with nonacquired systemic disease or syndrome
Optic atrophy
Physiologic cupping

Diagnostic Evaluation
At-risk children based on family history (one affected parent or sibling) should have
IOP measurements at least every 6 months even if sedation or anesthesia is required.
Evaluation should include a comprehensive ophthalmic examination, including vision,
refraction, slit-lamp examination, corneal pachymetry, and ophthalmoscopy.
Gonioscopy is not diagnostic but is useful in evaluating for secondary causes of
glaucoma. The presence of increased numbers of iris processes may or may not
represent an indicator of risk for JOAG.
Patients with the clinical appearance of glaucomatous optic neuropathy with normal
IOP on isolated visits can also undergo diurnal curve testing to assess pressure
variation as well as maximum daily pressure.
Automated visual field testing in young patients can be difficult, with Goldman visual
field testing often being an easier if not more reliable assessment tool.
Optical coherence tomography (OCT) currently has available normative data for
children older than 4 years, but asymmetry between the two eyes and changes over time
are important indicators of abnormality.
Optic nerve photography is useful in documenting and monitoring changes in the
appearance of the optic nerves.
Physiologic cupping, also an autosomal dominant condition, must be considered (Fig.
3-4) but is difficult to distinguish from JOAG other than the absence of elevated IOP,
change over time, or visual field deficits. Physiologic cups tend to have distinct sharp
borders and may be eccentric within the disc. Parents of the proband should be
examined for similar findings and, if present, their IOP should be checked as well. It
may take several visits over months or years to be confident that there is no progression
and thus no JOAG.

Treatment and Prognosis

JOAG tends to be more aggressive, more resistant to medical therapy, and associated
with more severe visual impairment.
The use of topical antiglaucoma medications is the first line of treatment followed by
oral carbonic anhydrase inhibitors.
 JOAG patients require close follow-up until maintenance of an acceptable IOP is
achieved.
Many cases over the long term are progressive and require surgical intervention.
Some evidence indicates that goniotomy or trabeculotomy can be successful. More
traditionally, trabeculectomy or glaucoma drainage device surgery is the first surgical
intervention. Trabeculectomy has similar success rates to those done on patients with
primary open-angle glaucoma.

REFERENCES
Coppens G, Stalmans I, Zeyren T, Casteels I. The safety and efficacy of glaucoma medications in the pediatric
population. J Pediatr Ophthalmol Strabismus. 2009;46:12–18.
Park SC, Kee C. Large diurnal variation of intraocular pressure despite maximal medical treatment in juvenile open
angle glaucoma. J Glaucoma. 2007;16:164–168.
Stoilova D, Child A, Brice G, et al. Novel TIGR/MYOC mutations in families with juvenile onset primary open angle
glaucoma. J Med Genet. 1998;35:989–992.
Vincent AL, Billingsley G, Buys Y, et al. Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier
gene. Am J Hum Genet. 2002;70:448–460.
Yeung HH, Walton DS. Goniotomy for juvenile open-angle glaucoma. J Glaucoma. 2010;19:1–4.
 FIGURE 3-4. Physiologic cup. Note the sharp margin to the cup and scooped-out appearance. The
vessels disappear as they turn posteriorly at the margin of the cup. The father, who did not have
glaucoma, has a similar appearance to his optic nerve heads.

GLAUCOMA FOLLOWING CATARACT SURGERY

A ll children who have cataract surgery, regardless of whether they are left aphakic
or pseudophakic, are at risk for glaucoma. The phrase glaucoma following
cataract surgery applies to any child who has had cataract surgery and then developed
glaucoma, even if they have other preexisting risk factors such as ocular anomalies,
uveitis, or steroid use. This category of glaucoma is divided into closed angle if more
than 50% of the angle is closed, or open angle.

Epidemiology and Etiology

Aphakic glaucoma is the most common complication of congenital cataract surgery,
with an incidence up to 32%. Theories as to the etiology include abnormal development
of the anterior chamber angle, genetic predisposition, barotrauma incurred during
surgery, decreased structural support to the drainage angle, vitreous affecting angle
structures, and release of chemical mediators through an open posterior capsule that
affect aqueous drainage.
Despite advances in cataract surgery, it is clear that the prevention of glaucoma after
cataract surgery has not been well achieved. Even with the use of intraocular lens
implantation in the pediatric population, the incidence of glaucoma appears to be
unchanged.
Factors associated with a higher risk of development of glaucoma are surgery within
the first year of life, corneal diameter less than 10 mm, presence of other ocular
anomalies, retained lens material, nuclear cataract, and eyes that require secondary
surgeries.

History
Similar to primary congenital glaucoma, the symptoms of photophobia, epiphora, and
blepharospasm are often seen in those who develop aphakic glaucoma before age 3
years. Older patients are usually asymptomatic.
The onset of glaucoma may occur early after surgery or later in childhood, with the
average age to onset approximately 4 to 8 years after surgery.
Routine lifelong screening of all children who have had cataract surgery is important
for the early diagnosis of glaucoma.

Signs
Early signs of glaucoma include a decrease in the amount of rapid loss of hyperopia
caused by globe elongation, corneal clouding, increased corneal diameter, and even
Haab stria in patients who develop glaucoma generally before age 3 years.
Most patients are asymptomatic, and elevated IOP and optic nerve cupping are found
on screening examination.
The presence of peripheral or midperipheral anterior synechia or posterior synechia
with iris bombe speaks to an inflammatory component.

Differential Diagnosis
Primary congenital glaucoma
Glaucoma associated with acquired conditions
Glaucoma associated with nonacquired ocular anomalies
 Glaucoma associated with nonacquired systemic disease or syndrome

Diagnostic Evaluation
Pediatric patients who have had cataract surgery should be examined for glaucoma
on a regular basis, certainly no less than annually. When patients are too young for IOP
measurement or optic nerve evaluation, an examination under anesthesia or sedation
may be needed.
Early signs of glaucoma include a decrease in the amount of aphakic refraction,
corneal clouding, increased corneal diameter in young patients, and optic nerve
cupping.
Ultrasound biomicroscopy, corneal pachymetry (which is often elevated in aphakia
and pseudophakia), and gonioscopy may offer information that is useful in diagnosis and
management. Gonioscopy may show an angle configuration similar to that seen in
primary infantile glaucoma (Fig. 3-5), a closed angle, or peripheral anterior synechia.
Axial length measurement, OCT, and optic nerve photography are all important tools
to monitor the disease.

Treatment and Prognosis

The first line of treatment of patients with aphakic glaucoma is one or more
antiglaucoma medications, which in many cases prove effective in lowering the IOP.
When topical and oral medications fail, surgery is often successful, with goniotomy
or trabeculotomy being effective in approximately 55% of patients, usually those that
have an angle configuration similar to that seen in primary congenital glaucoma.
Trabeculectomy or glaucoma drainage device may be used. Endoscopic diode
cyclophotoablation may provide another early option for treatment. Otherwise,
cycloablation plays a role only in cases of refractive glaucoma.
Early detection and treatment of glaucoma are important in improving the likelihood
of preventing optic nerve progression and preserving visual function.
Aggressive treatment of refractive error, amblyopia, and visually significant optical
opacities are also vital components of obtaining the best vision outcomes.

REFERENCES
Bothun ED, Guo Y, Christiansen SP, et al. Outcome of angle surgery in children with aphakic glaucoma. J AAPOS.
2010;14:235–239.
Chen TC, Walton DS, Bhatia LS. Aphakic glaucoma after congenital cataract surgery. Arch Ophthalmol.
2004;122:1819–1825.
Levin AV. Aphakic glaucoma: a never-ending story? Br J Ophthalmol. 2007;91:1574–1575.

FIGURE 3-5. Aphakic glaucoma. Gonioscopy of the angle in aphakic glaucoma appears similar to
infantile glaucoma with patches of high iris insertion. This patient may be a good candidate for goniolytic
surgery.

UVEITIC GLAUCOMA

G
angle.
laucoma due to uveitis is a form of glaucoma associated with acquired conditions
and can be further divided into those with open angle (≥50% open) and closed

Epidemiology and Etiology

The prevalence of pediatric uveitis is 30 cases per 100,000. Over a 5-year follow-
up period, 35% of all children with uveitis have an episode of elevated IOP.
Uveitis is associated with an increased risk of glaucoma not only because of the
underlying process of uveitis but also because of the long-term use of corticosteroid
treatments. However, the risk of glaucoma from untreated uveitis is far greater than the
risk of steroids.
 The pathophysiology of uveitis inducing glaucoma is complex. In uveitis, vascular
permeability is increased in the ciliary body, which results in aqueous hypersecretion
and increased protein content. There is an increase in aqueous prostaglandins, which
increases uveoscleral outflow at low concentrations but decreases uveoscleral outflow
at higher concentrations.
Aqueous outflow through the trabecular meshwork can be decreased by inflammatory
cells and fibrin in the angle. Uveitis may also induce swelling or dysfunction of the
trabecular meshwork and trabecular endothelium, decreasing outflow (trabeculitis).
Peripheral anterior synechiae form in uveitis, with the most severe cases resulting in
angle-closure glaucoma.
Posterior synechia can result in pupillary block with iris bombe (see Fig. 3-6).
Chronic inflammation and ischemia can lead to neovascular glaucoma.
Although glaucoma can occur in every type of uveitis, certain etiologies of uveitis
have a higher incidence, particularly juvenile idiopathic arthritis (JIA). Posterior
uveitis has a lower risk of inducing glaucoma than anterior uveitis.

History
Acute anterior uveitis is characterized by photophobia, pain, redness, decreased
vision, and epiphora except for children with JIA who are usually asymptomatic until
late in the disease when they may present with irregularity of the pupil, band
keratopathy, or decreased vision from cataracts, inflammation, and posterior synechiae.
In posterior uveitis, the only symptoms may be floaters and blurred vision.
Glaucoma is asymptomatic unless an acute significant elevation in IOP occurs as may
be seen with pupillary block due to posterior synechia.
In patients with uveitis, it is important to obtain a thorough history, including past
medical history and review of symptoms along with appropriate laboratory testing to try
to determine the etiology of the inflammation and thus improve management.

Signs
Slit-lamp examination is useful to quantify the amount of inflammation, assess
peripheral and central anterior chamber depth, and diagnose the presence of posterior
synechiae and neovascularization.
Peripheral anterior synechiae can be visualized on gonioscopy. The extent of
peripheral anterior synechiae is not diagnostic for glaucoma but is a risk factor.
As in all forms of glaucoma, optic nerve evaluation is important in diagnosing and
monitoring disease progression.
Diagnostic tests such as OCT and visual fields become more difficult because media
opacities are more likely to be present in patients with uveitis.

Differential Diagnosis
Other causes of glaucoma associated with acquired conditions include:
Steroid-induced glaucoma
Angle-closure glaucoma
Tumor (masquerade syndrome, e.g., leukemia, retinoblastoma)
Ghost cell glaucoma following hemorrhage
Traumatic glaucoma

Diagnostic Evaluation
As in all cases of uveitis, the extent of ocular involvement is determined by a
comprehensive ophthalmic examination.
Despite active or inactive disease, continued monitoring for glaucoma is imperative.
On slit-lamp biomicroscopy, the examination of the anterior segment includes cornea
for keratoprecipitates, band keratopathy and epithelial dendrites, anterior chamber
depth, and evaluation for cells and flare; examination of the iris for stromal atrophy,
nodules, posterior synechiae, and peripheral anterior synechiae; and examination of the
lens for cataract.
IOP should be checked in all patients with uveitis during every visit if possible.
Shallowing of the anterior chamber, increased IOP, and peripheral anterior
synechiae are indications for performing gonioscopy if possible.
Dilation with thorough examination of the posterior segment is necessary to help
determine the extent as well as the cause of the uveitis. The optic nerve appearance
should also be monitored for changes of glaucomatous optic neuropathy.
In patients with acute uveitis and healthy optic nerves, transient elevated IOP might
be monitored because a decrease may occur with aggressive treatment of the
inflammation. Chronic and recurrent uveitis with elevated IOP or at-risk nerves requires
a lower threshold for treatment.
A steroid-related increase in IOP rarely occurs within 2 weeks of initiating
treatment, but the clearance of protein and cells from the anterior chamber may cause an
acute and often transient elevation of IOP.
 The distinction between steroid responsiveness versus uveitic glaucoma may be
achieved by changing treatment to a nonglaucomagenic anti-inflammatory agent (e.g.,
fluorometholone) or steroid-sparing systemic agents (e.g., methotrexate, anti–tumor
necrosis factor [TNF] agents) without starting glaucoma drops.
If the uveitis cannot be managed without continuing steroid therapy, then medical
and, as needed, surgical glaucoma management are required.

Treatment and Prognosis

The prognosis of uveitic glaucoma depends on the underlying disease and success of
the treatment regimen.
Treatment includes treating the underlying disease, ocular inflammation, and
glaucoma.
Systemic immunomodulatory medications may be necessary to provide control of the
underlying disease. In patients with JIA, use of systemic anti-TNF agents is thought to
lower the ocular complications of cataracts, band keratopathy, and glaucoma.
Control of chronic uveitis, especially in JIA, may require chronic frequent topical
steroids with slow weans over months to years.
Mydriatic drops are essential in decreasing the risk of pupillary block by increasing
the pupil size and breaking posterior synechiae.
Elevated IOP is treated by determining the glaucoma mechanism (e.g., steroid-
induced vs. iris bombe).
Patients with glaucoma are treated primarily with topical antiglaucoma drops. A
suggested general rule is that surgery is to be avoided when possible because the eyes
often have an aggressive inflammatory response.
Patients who do require surgery should be treated with preoperative oral prednisone
as well as frequent topical prednisone.
Goniotomy is an effective first-line surgical option for young patients with chronic
uveitis and glaucoma without significant peripheral anterior synechia or iris bombe who
fail medical glaucoma management.
Trabeculectomy, especially in pediatric patients with uveitis, has a lower success
rate because of aggressive scar formation.
Glaucoma drainage devices are used in refractory cases and can provide good long-
term glaucoma control comparable to those without uveitis.
Intraocular lens implantation in children with uveitic cataracts may cause significant
aggravation of the iritis and induce or worsen uveitis, which may cause or aggravate
glaucoma.

REFERENCES
Freedman SF, Rodriguez-Rosa RE, Rojas MC, et al. Goniotomy for glaucoma secondary to chronic childhood uveitis.
Am J Ophthalmol. 2002;133:617–621.
Rachmiel R, Trope GE, Buys YM, et al. Ahmed glaucoma valve implantation in uveitic glaucoma versus open-angle
glaucoma patients. Can J Ophthalmol. 2008;43:462–467.
Sijssens KM, Rothova A, Berendschot TT, et al. Ocular hypertension and secondary glaucoma in children with uveitis.
Ophthalmology. 2006;113:853. e2–859. e2.

FIGURE 3-6. Uveitic glaucoma. Posterior synechia can result in pupillary block with iris bombe.
STURGE-WEBER SYNDROME

E ncephalotrigeminal angiomatosis (Sturge-Weber syndrome) is a syndrome of port-

wine birthmark—with or without ipsilateral risk of glaucoma—and central
nervous system involvement, including possible developmental delay, seizures, and
radiographic evidence of leptomeningeal calcification or cerebral atrophy. It is an
example of glaucoma associated with nonacquired systemic disease or syndrome.

Epidemiology and Etiology

There is no gender, race, or sexual predilection to the disorder.
The classic Sturge-Weber port-wine birthmark respects the midline and follows the
distribution of one or more of the trigeminal ganglion branches (Fig. 3-7).
Up to 50% of patients develop glaucoma on the ipsilateral side, and eyes at higher
risk have the upper eyelid affected.
Whereas an onset of glaucoma early in life is thought to be the result of congenital
goniodysgenesis, later-onset glaucoma, usually between 4 and 14 years, is related to
elevated episcleral venous pressure.
Sturge-Weber syndrome is caused by somatic mutation in the GNAQ gene.
The risk for glaucoma is increased when choroidal hemangioma is present.

History
The facial cutaneous lesion is usually the first component of Sturge-Weber syndrome
to be observed and is visible at birth. It may become darker with age and is more
noticeable in those with fair skin.
Early-onset glaucoma presents with buphthalmos, epiphora, and photophobia as in
primary congenital glaucoma.
Later-onset glaucoma is diagnosed based on screening ophthalmic examination
because there are usually no symptoms.

Signs
The port-wine birthmark is a clinical marker to identify patients and eyes at risk for
ocular complications.
The hypervascularity of this disorder is evident on ocular examination with
increased conjunctival and episcleral vascularity (Fig. 3-8) in up to 70% of patients.
Heterochromia of the iris occurs in 10%, with increased pigment on the affected side
caused by a relative increase in melanocyte activity or abnormal iris vasculature.
Approximately 10% of patients with Sturge-Weber syndrome have bilateral disease.
Diffuse choroidal hemangioma can be detected with indirect ophthalmoscopy
showing indistinguishable choroidal markings (Fig. 3-9). It is usually seen in the
posterior pole and can show thickening and elevation during adolescence and
adulthood. Secondary changes to the overlying retina include vascular tortuosity,
exudate, cystic changes, gliosis, and edema.
On gonioscopy, blood visualized in Schlemm canal is suggestive of elevated
episcleral venous pressure.

Differential Diagnosis
Capillary hemangioma
Klippel-Trenaunay-Weber syndrome (Sturge-Weber syndrome plus hemihypertrophy
of soft and bony tissues)
Transient nevus flammeus of infancy
Primary congenital glaucoma
JOAG
Cutis marmorata telangiectasia congenita
Phakomatosis pigmentovascularis

Diagnostic Evaluation
Patients with a port-wine birthmark of the face involving any portion of the eyelids
require referral for a complete ophthalmic evaluation with screening for glaucoma.
Ocular testing for glaucoma includes a careful assessment of IOP, corneal diameter,
corneal pachymetry (often elevated in those with Sturge-Weber syndrome), gonioscopy,
cycloplegic refraction, axial length, and optic nerve cupping evaluation.
Ocular ultrasonography may be useful, showing high internal reflectivity in a solid
echogenic mass characteristic of choroidal hemangiomas and/or subretinal fluid.
Enhanced depth OCT is also useful.
Computed tomography scan and magnetic resonance imaging can be used to detect
malformations in the brain and meninges.

Treatment and Prognosis

Topical antiglaucoma medications are the initial treatment modality except in infancy
when the treatment paradigm is usually surgical (goniotomy or trabeculotomy) as for
primary congenital glaucoma.
As the underlying pathophysiology becomes elevated episcleral venous pressure,
medical treatment is still the desired first-line option, but trabeculectomy or drainage
tube surgery may be needed.
There is an increased risk of choroidal effusion and hemorrhage secondary to
surgery.
A diffuse choroidal hemangioma is associated with an increased risk of
nonrhegmatogenous retinal detachment as well as vision loss caused by cystoid macular
edema.

REFERENCES
Aggarwal NK, Gandham SB, Weinstein R, et al. Heterochromia iridis and pertinent clinical findings in patients with
glaucoma associated with Sturge-Weber syndrome. J Pediatr Ophthalmol Strabismus. 2010;47:361–365.
Comi A, Levin AV, Kaplan E, et al. Leveraging a Sturge-Weber gene discovery: an agenda for future research.
Pediatric Neurology. 2016;58:12–24.
Khaier A, Nischal KK, Espinosa M, Manoj B. Periocular port wine stain: the Great Ormond Street Hospital
experience. Ophthalmology. 2011;118:2274–2278.
Maslin JS, Dorairaj SK, Ritch R. Sturge-Weber syndrome (encephalotrigeminal angiomatosis): recent advances and
future challenges. Asia Pac J Ophthalmol. 2014;3:361–367.
Shiau T, Armogan N, Yan DB, Thomson HG, Levin AV. The role of episcleral venous pressure in glaucoma
associated with Sturge-Weber syndrome. J AAPOS. 2012;16:61–64.
FIGURE 3-7. Sturge-Weber syndrome. Port-wine mark involving V1 to V3 on the right side and V2
to V3 on the left. The right eye has buphthalmos with corneal clouding.

FIGURE 3-8. Sturge-Weber syndrome. Dilated tortuous conjunctival and episcleral vessels,
ipsilateral to the side with port-wine mark (not shown).
 FIGURE 3-9. Choroidal hemangioma. Note the absence of choroidal markings and diffuse red-
orange hue. Note the increased cup-to-disc ratio caused by glaucoma and the choroidal hemangioma.

CONGENITAL ECTROPION UVEAE

C ongenital ectropion uveae is a rare disorder characterized by persistent cells of

neural crest origin on the anterior surface of the iris and trabecular meshwork
associated with varying degrees of ectropion uveae. Patients have an anterior insertion
of the iris and dysgenesis of the anterior segment angle with an increased risk of
glaucoma. It is an example of glaucoma associated with nonacquired ocular anomalies.

Epidemiology and Etiology

Congenital ectropion uveae is a rare condition with an undefined incidence. It is
almost always a unilateral disorder.
Histopathologic studies have also described a fibrovascular surface membrane
covering the anterior iris surface, suggesting that contraction causes the ectropion uveae
and further growth into the angle inducing glaucoma.
No genetic etiology or heritability has been described.

History
Patients are usually asymptomatic and come to attention with concern about the
iris/pupil appearance being different than the unaffected eye. Sometimes, the disorder is
noted as an incidental finding during routine pediatric or ophthalmic examination.

Signs
Slit-lamp biomicroscopy reveals iris posterior pigmented epithelium on the anterior
surface of the iris (Fig. 3-10). The remainder of the iris appears smooth and cryptless
with an overlying whitish coating.
On gonioscopy, there is anterior insertion of the iris onto the trabecular meshwork
and goniodysgenesis.
IOP elevation and optic nerve cupping are indicative of the development of
glaucoma.
Mild ptosis with good levator function is reported in up to 50% of cases.

Differential Diagnosis
Axenfeld-Rieger spectrum
Anisocoria
Iridocorneal endothelial syndrome
Uveitis
Rubeosis
Trauma

Diagnostic Evaluation
Congenital ectropion uveae can be associated with other anterior segment anomalies;
thus, a thorough ophthalmoscopic and systemic evaluation is indicated.
Reported rare associations include neurofibromatosis, facial hemihypertrophy,
Axenfeld-Rieger spectrum, and Prader-Willi syndrome.

Treatment and Prognosis

Although ectropion uveae is considered nonprogressive, this disorder is an
indication for screening and continued surveillance for the development of glaucoma.
 Glaucoma almost inevitably develops, with the age of onset ranging from early
childhood to adulthood.
Treatment with standard antiglaucoma medications can result in an initial IOP-
lowering effect but is short lived, and definitive treatment with trabeculectomy or
glaucoma tube surgery is often required.

REFERENCES
Dowling JL Jr, Albert DM, Nelson LB, et al. Primary glaucoma associated with iridotrabecular dysgenesis and
ectropion uveae. Ophthalmology. 1985;92:912–921.
Harasymowycz PJ, Papamatheakis DG, Eagle RC Jr, et al. Congenital ectropion uveae and glaucoma. Arch
Ophthalmol. 2006;124:271–273.
Ritch R, Forbes M, Hetherington J Jr, et al. Congenital ectropion uveae with glaucoma. Ophthalmology. 1984;91:326–
331.

FIGURE 3-10. Congenital ectropion uveae. Iris pigment epithelium on the anterior surface of the iris
(asterisk). Much of the remaining iris appears whitened with a loss of iris crypts.

ANIRIDIA
A niridia is a panocular disorder with a cardinal feature of complete or partial iris
absence with associated foveal hypoplasia, resulting in decreased visual acuity
and early-onset nystagmus. Aniridia occurs as a result of a sporadic or autosomal
dominant inherited mutation affecting the PAX6 gene, or deletion of nearby
chromosomal material. It is an example of glaucoma associated with nonacquired ocular
anomalies.

Epidemiology and Etiology

The incidence of aniridia is 1 in 40,000 to 100,000.
The amount of residual iris may differ between the two eyes.
Disease-causing mutations have been reported in the PAX6 gene (11p13) or the
allelic regulatory regions controlling its expression. The PAX6 gene encodes a
transcriptional regulator that controls the expression of other genes involved in
oculogenesis.
Up to 20% of sporadic cases of aniridia have been found to have a deletion in 11p13
on cytogenetic testing. This deletion may involve the Wilms tumor gene (WT1) and
intervening genes as part of WAGR syndrome (Wilms tumor, Aniridia, Genital
anomalies, and Retardation).
Patients with aniridia have up to a 50% lifetime risk of developing glaucoma.
Glaucoma may be due to goniodysgenesis, hypoplasia/aplasia of Schlemm canal, or
a closed angle due to migration anteriorly of the residual iris stub.

History
Aniridia is discovered early in life usually by the presence of nystagmus in infancy.
Visual acuity, when able to be tested, is often in the range of 20/100 to 20/200 but
may be as good as 20/40 in patients with low expression.
Patients may also experience photophobia.
Only 20% of affected patients have a positive family history.

Signs
Aniridia shows variable expression regarding the extent of iris abnormality and other
ocular findings.
Foveal hypoplasia is the primary cause of the decreased vision and is evident on
ophthalmoscopy and can be confirmed with OCT.
Other frequent ocular abnormalities include corneal pannus due to limbal stem cell
deficiency, optic nerve hypoplasia, cataract (most commonly anterior pyramidal), and
glaucoma.
Less commonly, patients may have ectopia lentis, microphthalmia, ptosis, or Peters
anomaly.
Patients with aniridia and new-onset eye irritation require urgent evaluation for
glaucoma as well as keratopathy.

Differential Diagnosis
Axenfeld-Rieger spectrum
Iris coloboma
Gillespie syndrome
Trauma or iatrogenic iris defect
Bilateral congenital mydriasis
Pharmacologic mydriasis

Diagnostic Evaluation
Slit-lamp biomicroscopy is needed to detect corneal pannus, which often begins as
peripheral gray superficial avascular changes.
Examination under anesthesia is useful in obtaining complete ophthalmic testing,
including IOP measurement and gonioscopy in young infants. In young children, the
development and progression of glaucoma can be assessed by an increase in corneal
diameter, increase in the axial length, and loss of hyperopia or increased myopia on
cycloplegic refraction.
Gonioscopic examination reveals a rudimentary iris stub, rather than complete
absence, possibly with areas of upturned iris blocking the trabecular meshwork (Fig. 3-
11).
In infants with significant corneal opacities, an anterior segment ultrasound
biomicroscopy can demonstrate iris hypoplasia and show angle anomalies.
Systemic findings associated with WAGR includes cryptorchidism and other
genitourinary abnormalities, intellectual disability, neurologic abnormalities (e.g.,
hypertonia, hypotonia, epilepsy), skeletal anomalies (craniofacial anomalies, growth
retardation, or scoliosis), hearing loss, and obesity.

Treatment and Prognosis

Individuals without a family history of aniridia should undergo cytogenetic and
molecular genetic testing to detect possible WAGR syndrome. Those with aniridia and
WT1 deletion require renal ultrasound every 3 months until approximately 8 years of
age. In the absence of molecular testing to exclude WAGR, renal screening should be
conducted every 4 to 6 months. Those without WAGR still require continued periodic
ophthalmic examinations for glaucoma, corneal abnormalities, and cataracts.
The treatment of glaucoma in aniridia is based on gonioscopy and age. Goniosurgery
may be useful as a primary procedure, particularly in infants.
The decision to perform cataract surgery requires consideration of other causes of
diminished vision such as foveal hypoplasia, optic nerve hypoplasia, and nystagmus.
Aniridic eyes can have poor zonular stability, affecting how the surgery is done and the
type of lens implant used.

REFERENCES
Fischbach BV, Trout KL, Lewis J, et al. WAGR syndrome: a clinical review of 54 cases. Pediatrics. 2005;116:984–
988.
Netland PA, Scott ML, Boyle JW, Lauderdale JD. Ocular and systemic findings in a survey of aniridia subjects. J
AAPOS. 2011;5:562–566.
Ramaesh K, Ramaesh T, Dutton GN, et al. Evolving concepts on the pathogenic mechanisms of aniridia related
keratopathy. Int J Biochem Cell Biol. 2005;37:547–557.
Schneider S, Osher RH, Burk SE, et al. Thinning of the anterior capsule associated with congenital aniridia. J Cataract
Refract Surg. 2003;29:523–525.
 FIGURE 3-11. Aniridia. Gonioscopic view of aniridic eye with the iris root turned up in multiple places
(arrows), obstructing the trabecular meshwork.

POSTERIOR EMBRYOTOXON

P osterior embryotoxon is the anterior displacement of Schwalbe’s line and

structurally represents an anteriorized junction of the peripheral termination of
Descemet’s membrane. Clinically, it appears as a white circumferential line on the
inner surface of the cornea near the limbus. Histologically, it consists of collagen fibers
covered by a thin layer of Descemet’s membrane and endothelium.

Epidemiology and Etiology

The prevalence of posterior embryotoxon is 6.8% to 32% of the general population.
It may occur as an isolated finding or be associated with other anterior segment or
systemic findings as in Axenfeld-Rieger spectrum and Alagille syndrome. It is
considered a developmental neurocristopathy.
There has not been a specific mutated gene associated with isolated posterior
embryotoxon, but mutations in PITX2, FOXC1, and JAG1 each are associated with the
clinical findings of the syndromic forms.
The risk of glaucoma in isolated posterior embryotoxon is not well defined but likely
elevated. In Axenfeld-Rieger spectrum, the risk may be as high as 50%.

History
Patients are usually asymptomatic. Often the disorder is noted as an incidental
finding during slit-lamp biomicroscopy and gonioscopy.

Signs
Posterior embryotoxon is visible with slit-lamp biomicroscopy as a fine silver-white
circumferential line on the inner aspect of the cornea, anterior to the limbus (Fig. 3-12).
It occurs more commonly nasally and temporally.
The presence of iridocorneal strands to the posterior embryotoxon identifies the
mildest form of Axenfeld-Rieger spectrum. With Axenfeld-Rieger spectrum, systemic
anomalies include redundant periumbilical skin, abnormal facies, sensorineural hearing
loss, skeletal malformations, and dental malformations.
Ophthalmoscopic findings suggestive of Alagille syndrome include retinal pigment
epithelial irregularities and optic nerve anomalies. It is a disorder primarily of biliary
atresia or milder liver dysfunction and a characteristic facies.

Differential Diagnosis
Axenfeld-Rieger spectrum
Alagille syndrome
Peters anomaly
Cornea plana
Anterior segment mesodermal dysgenesis
Peripheral anterior synechiae
Trauma

Diagnostic Evaluation
The characteristic appearance of posterior embryotoxon should enable the clinician
to make the diagnosis and differentiate it from other lesions. Gonioscopy can be used to
identify cases that are not otherwise evident on slit-lamp examination.
Although not needed to make the diagnosis, anterior segment OCT can also show the
abnormality.
Patients should have a complete ophthalmic examination, including IOP and dilated
fundus examination. More aggressive monitoring is needed in patients with findings of
Axenfeld-Rieger spectrum.
Screening of family members may be helpful clinically because presentation is
variable.

Treatment and Prognosis

Medical management is the first line to treat glaucoma in this condition.
Goniotomy and trabeculotomy when glaucoma is present are technically challenging
and have lower success rates.

REFERENCES
Ozeki H, Shirai S, Majima A, et al. Clinical evaluation of posterior embryotoxon in one institution. Jpn J Ophthalmol.
1997;41:422–425.
Rennie CA, Chowdhury S, Khan J, et al. The prevalence and associated features of posterior embryotoxon in the
general ophthalmic clinic. Eye (Lond). 2005;19:396–399.
FIGURE 3-12. Posterior embryotoxon appears as a white or gray circumferential line anterior to the
limbus (arrows).
 CHAPTER
4

Iris Anomalies
Michael J. Bartiss and Bruce M. Schnall ■
CENTRAL PUPILLARY CYSTS (PUPILLARY
MARGIN EPITHELIAL CYSTS)
Etiology
Usually congenital in origin
Can be acquired from cholinesterase-inhibiting eye drops, such as phospholine
iodide, when used in young phakic patients to treat accommodative esotropia
Rarely inherited

Symptoms
Patients are usually asymptomatic.
Pigmented epithelial cysts occurring at the pupillary border (Fig. 4-1)
May be detected by a pediatrician on red reflex testing of neonate

Signs
Pigmented cysts along the margin of the pupil of involved eyes
Have a nontransparent lining (as opposed to iris stromal cysts)
Rarely increase in size and typically remain stationary

Differential Diagnosis
Iris stromal cysts
Ciliary body cysts
 Iris melanoma

Treatment
Congenital pupillary margin epithelial cysts rarely require treatment; they usually
remain stationary in size or slowly involute over time.
If size and location cause visual compromise, surgical intervention may be indicated.
Acquired pupillary margin cysts from cholinesterase-inhibiting eye drops can be
prevented with the use of phenylephrine (2.5%) eye drops daily.

Prognosis
Excellent; rarely require treatment
Complications can include formation of iris flocculi in cases of cyst rupture,
glaucoma, and spontaneous intraocular detachment of the cysts.
If treatment is required, can be treated with simple excision or yttrium aluminum
garnet puncture

REFERENCES
Shields JA, Kline MW, Augsburger JJ. Primary iris cysts: a review of the literature and report of 62 cases. Br J
Ophthalmol. 1984;68(3):152–166.
Shields JA, Shields CL, Lois N, et al. Iris cysts in children: classification, incidence and management: the 1998
Torrence A Makley, Jr., lecture. Br J Ophthalmol. 1999;83(3):334–338.
Sidoti PA, Valencia M, Chen M. Echographic evaluation of primary cysts of the iris pigment epithelium. Am J
Ophthalmol. 1995;120:161–167.
 FIGURE 4-1. Pigmented epithelial cysts. Pigmented cysts along the margin of the pupil. (Courtesy
of Judith Lavrich, MD.)

ANIRIDIA
Etiology
Bilateral disorder characterized by underdevelopment (rather than true absence of
the iris), with rudimentary iris located peripherally
Associated with PAX6 gene (control gene for eye morphogenesis) on chromosome
11p13, involving inability of single gene allele to activate transduction of
developmental genes (haploinsufficiency)
Often associated with foveal hypoplasia, nystagmus, glaucoma, optic nerve
hypoplasia, cataracts, and acquired corneal pannus
Autosomal dominant (complete penetrance with variable expressivity), autosomal
recessive (Gillespie syndrome with mental retardation and cerebellar ataxia), and
sporadic inheritance patterns
Two-thirds of children with aniridia have affected parents.
Sporadic aniridia is associated with an increased incidence of Wilms tumor.
WAGR complex (Wilms tumor, aniridia, genitourinary malformations, and mental
retardation) occurs from contiguous gene deletions.

Symptoms
Clinical absence of the iris
Subnormal visual acuity is common (usually less than 20/100).
Nystagmus
Photophobia

Signs
Apparent bilateral absence or severe hypoplasia of iris (Fig. 4-2)
Congenital nystagmus
Acquired corneal pannus
Strabismus
Cataract
Ectopia lentis
Glaucoma
Posterior synechiae

Differential Diagnosis
Other causes of pupillary dilation (e.g., pharmacologically dilated pupils, Adie
pupil)

Treatment
Evaluation with a geneticist
Screening for Wilms tumor includes abdominal ultrasonography evaluations every 3
months until 7 to 8 years of age.
Screen for glaucoma and treat if present.
Cataract surgery if visually significant cataract is present
Maximize visual potential with appropriate refractive error correction.
Polarized sun wear or use of Transitions spectacles lenses to decrease glare and
photophobia

REFERENCES
Adeoti CO, Afolabi AA, Ashaye AO, et al. Bilateral sporadic aniridia: review of management. Clin Ophthalmol.
2010;4:1085–1089.
Lee H, Meyers K, Lanigan B, et al. Complications and visual prognosis in children with aniridia. J Pediatr Ophthalmol
Strabismus. 2010;47(4):205–210.
Weissbart SB, Ayres BD. Management of aniridia and iris defects: an update on iris prosthesis options. Curr Opin
Ophthalmol. 2016;27(3):244–249.
Yeung HH. Large Pupils in Infancy…Suspected Aniridia. Multisystemic smooth muscle dysfunction syndrome
secondary to an ACTA2 mutation. J Pediatr Ophthalmol Strabismus. 2016;53(1):7, 8.

FIGURE 4-2. Aniridia. Severe hypoplasia of iris with outline of lens visible. (Courtesy of Alex V.
Levin, MD, MHSc, Wills Eye Hospital, Philadelphia.)

BRUSHFIELD SPOTS
Etiology
Occur in up to 90% of patients with Down syndrome (trisomy 21)
Can be present in patients without Down syndrome

Symptoms
 Patients are asymptomatic.

Signs
Whitish elevated spots on the anterior surface of the iris, often occurring in a
concentric ring around the pupil (Fig. 4-3)
Congenital, normal to hypercellular hypopigmented areas of iris tissue with
surrounding relative stromal hypoplasia

Differential Diagnosis
Wolfflin nodules (similar appearing nodules occurring in patients without Down
syndrome, which are accumulations of fibrous tissue in the anterior border layer of the
iris)
Iris nevi
Brushfield spots
Juvenile xanthogranuloma (JXG)
Iris mamillations

Treatment
No treatment indicated

Prognosis
No effect on visual function
Severity of functional cognitive impairment of patients with trisomy 21 is extremely
variable.

REFERENCES
Brooke Williams RD. Brushfield spots and Wolfflin nodules in the iris: an appraisal in handicapped children. Dev Med
Child Neurol. 1981;23(5):646–649.
Ljubic A, Trajkovski V, Tesic M, Tojtovska B, Stankovic B. Ophthalmic manifestations in children and young adults
with Down syndrome and congenital heart defects. Ophthalmic Epidemiol. 2015;22(2):123–129.
Shapiro BL. Down syndrome and associated congenital malformations [review]. J Neural Transm Suppl. 2003;
(67):207–214.
Stirn Kranjc B. Ocular abnormalities and systemic disease in Down syndrome. Strabismus. 2012;20(2):74–77.
 FIGURE 4-3. Brushfield spots. Hypopigmented elevated spots on the anterior iris surface in a
concentric ring around the pupil. (Courtesy of Alex V. Levin, MD, MHSc, Wills Eye Hospital,
Philadelphia.)

ECTOPIA LENTIS ET PUPILLAE

Etiology
Autosomal recessive inherited, nonprogressive disorder in which the pupil and lens
are displaced in opposite directions (pupil usually inferonasally and lens
superotemporally)
Posterior displacement of lens–iris diaphragm
Typically bilateral and asymmetric
Believed to occur during neuroectodermal tissue development (pigmented layers of
iris, iris dilator, and zonules are all involved)

Symptoms
Decreased uncorrected visual acuity secondary to dislocated lens

Signs
Bilateral lens dislocation causing high myopia with astigmatism
 Asymmetrical, eccentrically located pupils (usually inferonasally)
Slit-shaped or oval pupil (Fig. 4-4A)
Persistent pupillary membrane is present in approximately 85% of affected
individuals (Fig. 4-4B)
Microspherophakia, miosis, and poor dilation with mydriatic agents
Myopia, which may be severe
May have an enlarged corneal diameter
Cataract
Abnormal iris transillumination
Retinal detachment
+⁄− Megalocornea

Differential Diagnosis
Other causes for bilateral dislocated lenses, Marfan syndrome, homocystinuria,
Weil-Marchesani syndrome, sulfite oxidase deficiency, hyperlysinemia
Iris coloboma
Trauma to iris sphincter
After anterior segment surgery
Corectopia
Axenfeld-Rieger syndrome

Treatment
Refractive error correction to maximize visual potential
Anisometropic amblyopia often occurs in the more affected eye. Amblyopia should
be treated with correction of refractive error and occlusion of the fellow eye.
May develop a visually significant cataract and therefore may require cataract
surgery
Screen for glaucoma

Prognosis
Nonprogressive; visual prognosis depends on timely treatment of refractive error.
Amblyopia in more affected eye is often severe and may not respond to treatment.
REFERENCES
Byles DB, Nischal KK, Cheng H. Ectopia lentis et pupillae. A hypothesis revisited. Ophthalmology. 1998;105(7):1331–
1336.
Colley A, Lloyd IC, Ridgway A, et al. Ectopia lentis et pupillae: the genetic aspects and differential diagnosis. J Med
Genet. 1991;28(11):791–794.
Goldberg MF. Clinical manifestations of ectopia lentis et pupillae in 16 patients. Ophthalmology. 1988;95(8):1080–1087.
Sadiq MA, Vanderveen D. Genetics of ectopia lentis. Semin Ophthalmol. 2013;28(5–6):313–320.
Sharifi Y, Tjon-Fo-Sang MJ, Cruysberg JR, Maat-Kievit AJ. Ectopia lentis et pupillae in four generations caused by
novel mutations in the ADAMTSL4 gene. Br J Ophthalmol. 2013;97(5):583–587.
FIGURE 4-4. Ectopia lentis et pupillae. A. Inferonasally eccentrically located slit-shaped pupil.
(Courtesy of Alex V. Levin, MD, MHSc, Wills Eye Hospital, Philadelphia.) B. Note the persistent
pupillary membrane, which is being stretched in this pharmacologically dilated pupil. The superior edge of
the dislocated lens is visible.
HETEROCHROMIA IRIDIS
Etiology
A congenital or acquired condition characterized by a relative hyperpigmentation or
hypopigmentation of the involved iris
Acquired cases of hyperpigmented irides in children include trauma, siderosis, iris
ectropion syndrome, chronic iridocyclitis, and extensive rubeosis as well as intraocular
surgery and topical prostaglandin analog medications
Ocular melanocytosis or oculodermal melanocytosis and sector iris hamartoma can
also cause hyperpigmented irides.
Congenital and acquired hypopigmented irides can occur because of Horner
syndrome, Fuchs heterochromia, Waardenburg-Klein syndrome, nonpigmented iris
tumors, and hypomelanosis of Ito.

Symptoms
Patients are typically asymptomatic in the absence of rubeosis, increased intraocular
pressure (IOP), and intraocular inflammation.

Signs
Different-colored irides with or without anatomic iris abnormalities
In cases of melanosis oculi, the more pigmented iris may appear thicker with
mamillations (Fig. 4-5).
Associated with miosis and ptosis (typically 2 mm) on the ipsilateral side in cases of
Horner syndrome (Fig. 4-6)

Differential Diagnosis
Differential diagnosis is extensive.
Acquired cases of hyperpigmented irides in children include trauma, siderosis, iris
ectropion syndrome, chronic iridocyclitis, and extensive rubeosis as well as intraocular
surgery and topical prostaglandin analog medications.
Ocular melanocytosis or oculodermal melanocytosis and sector iris hamartoma can
also cause hyperpigmented irides.
Congenital and acquired hypopigmented irides can occur because of Horner
syndrome, Fuchs heterochromia, Waardenburg-Klein syndrome, nonpigmented iris
tumors, and hypomelanosis of Ito.
 Neuroblastoma (located along the sympathetic chain) must be ruled out in cases of
Horner syndrome, especially in acquired cases in children.

Treatment
Assessment as to which iris has the abnormal color can often be assisted by
assessing skin pigmentation, parental eye color, and earlier photographs of the patient.
Timely and appropriate workup of acquired Horner syndrome
Hearing testing if Waardenburg syndrome is suspected
In cases of acquired hyperpigmentation, imaging may be needed to rule out an
intraocular foreign body (siderosis) and intraocular tumor.

Prognosis
Depends on the underlying cause

REFERENCES
Brazel SM, Sullivan TJ, Thorner PS, et al. Iris sector heterochromia as a marker for neural crest disease. Arch
Ophthalmol. 1992;110(2):233–235.
Liu XZ, Newton VE, Read AP. Waardenburg syndrome type II: phenotypic findings and diagnostic criteria. Am J Med
Genet. 1995;55(1):95–100.
Milunsky JM. Waardenburg syndrome type I. In: Pagon RA, Bird TC, Dolan CR, Stephens K, eds. GeneReviews.
Seattle: University of Washington; 2004.
Radke P, Schimmenti LA, Schoonveld C, Bothun ED, Summers CG. The unique association of iris heterochromia with
Hermansky-Pudlak syndrome. J AAPOS. 2013;17(5):542–544.
FIGURE 4-5. Heterochromia iridis. A. Right iris is more heavily pigmented in this child with
melanosis oculi. B. Sector melanosis oculi.
 FIGURE 4-6. Left congenital Horner syndrome. Note the miotic pupil, mild ptosis, and
hypopigmented iris on the left. The ptosis is best observed by looking at the distance from the corneal
light reflex to the pupillary margin.

IRIS COLOBOMA
Etiology
Typically bilateral inferonasal defect in the iris caused by failure of embryonic
fissure closure during the fifth gestation week
May be part of a spectrum of anatomic developmental abnormalities including
microphthalmia
Autosomal dominant inheritance in approximately 20% of cases
Atypical iris colobomas located other than inferonasally can occur and are probably
caused by developmental abnormalities of the anterior hyaloids and papillary membrane
systems and are not associated with posterior segment colobomas
Numerous chromosomal abnormalities, including trisomy 13, 4p-, 11q-13r, and 18r,
are associated with colobomas.
Numerous syndromes are associated with uveal colobomas, most notably CHARGE
syndrome (coloboma of the eye or central nervous system anomalies, heart defects,
atresia of the choanae, retardation of growth or development, genital or urinary defects,
and ear anomalies or deafness).
Other associated syndromes include Goltz syndrome (focal dermal hypoplasia),
basal cell nevus syndrome, linear sebaceous syndrome, Klinefelter syndrome, and
Goldenhar syndrome.

Symptoms
Keyhole- or bulb-shaped pupil
Patients are often asymptomatic if only the iris is involved.
Patients are sometimes bothered by their cosmetic appearance.
Visual acuity depends on involvement of the posterior segment.

Signs
Inferonasal, lightbulb-shaped iris defect (Fig. 4-7)
Colobomatous defect can also involve ciliary body, retina, choroid, and optic nerve.
Lens zonules may be missing in a sector of the coloboma.
Involvement may be asymmetric.
Nystagmus presents in cases with concomitant bilateral optic nerve or macula
involvement.

Differential Diagnosis
Traumatic iris injury
After an iridectomy
Ectopic pupil
Corectopia

Treatment
Evaluation by a geneticist if other congenital anomalies are found or a syndrome is
suspected
Maximize visual acuity with appropriate refractive error correction.
Colored contact lenses (with iris detail) are often helpful if psychosocial issues are
present, especially in patients with lightly colored irides.
Impact-resistant spectacles, especially in cases with functional vision in only one
eye

Prognosis
Visual prognosis depends on involvement of the optic disc and macula. Visual
potential is very difficult to predict on the basis of clinical examination alone even in
cases with significant posterior segment involvement.
Visual acuity often remains stable after it has been maximized.
Risk of retinal detachment

REFERENCES
Deml B, Reis LM, Lemyre E, Clark RD, Kariminejad A, Semina EV. Novel mutations in PAX6, OTX2 and NDP in
anophthalmia, microphthalmia and coloboma. Eur J Hum Genet. 2016;24(4):535–541.
Mets MB, Erzurum SA. Uveal tract in infants. In: Isenberg SJ, ed. The Eye in Infancy. 2nd ed. St. Louis, MO: Mosby;
1994:308–317.
Onwochei BC, Simon JW, Bateman JB, et al. Ocular colobomata. Surv Ophthalmol. 2000;45:175–194.
Takkar B, Chandra P, Kumar V, Agrawal R. A case of iridofundal coloboma with persistent fetal vasculature and lens
subluxation. J AAPOS. 2016;20(2):180–182.
 FIGURE 4-7. Iris coloboma. A. Unilateral iris coloboma. Lightbulb-shaped inferonasal defect in iris of
the left eye. B. Bilateral iris coloboma.

IRIS STROMAL CYSTS

Etiology
Probably occur because of sequestration of epithelial cells during embryologic
development
Typically contain goblet cells

Symptoms
 Can enlarge over time, obstructing the visual axis and causing decreased visual
acuity
Iritis with increased IOP and photophobia can occur if cysts leak.
Often diagnosed during infancy

Signs
Clear to whitish appearing cyst on the anterior surface of the iris (Fig. 4-8)
Epithelium-lined cysts occurring on the anterior surface of the iris with a visible
vasculature
May enlarge, causing decreased vision by obstructing the visual axis, iritis (from
cyst leakage), corneal decompensation, and glaucoma

Differential Diagnosis
Secondary cyst formation from traumatic or surgical epithelial implantation
Solid iris tumors
Ciliary body tumors

Treatment
Surgical excision with sector iridectomy may be the preferred treatment because it
may lessen risk of cyst leakage causing iritis and increased IOP and will better the
chance of removing the entire tumor, lessening the chance of recurrence.

Prognosis
Guarded

REFERENCES
Casey M, Cohen KL, Wallace DK. Recurrence of iris stromal cyst following aspiration and resection. J AAPOS.
2002;6(4):255–256.
Pochop P, Mahelková G, Cendelín J, Petrušková D. Early detection of recurrent primary iris stromal cyst using
ultrasound biomicroscopy. J AAPOS. 2014;18(2):184–186.
Shields CL, Arepalli S, Lally EB, Lally SE, Shields JA. Iris stromal cyst management with absolute alcohol-induced
sclerosis in 16 patients. JAMA Ophthalmol. 2014;132(6):703–708.
Shields JA, Shields CL, Lois N, Mercado G. Iris cysts in children: classification, incidence and management: the 1998
Torrence A Makley, Jr., lecture. Br J Ophthalmol. 1999;83(3):334–338.
Shields JA. Primary cysts of the iris. Trans Am Ophthalmol Soc. 1981;79:771–809.
Wiwatwongwana A, Ittipunkul N, Wiwatwongwana D. Ab externo laser photocoagulation for the treatment of
spontaneous iris stromal cyst. Graefes Arch Clin Exp Ophthalmol. 2012;250(1):155–156.
 FIGURE 4-8. Iris stromal cyst. Whitish clear-appearing cyst in iris stroma. (Courtesy of Jerry Shields,
MD.)

JUVENILE XANTHOGRANULOMA
Etiology
Disorder of unknown etiology characterized by abnormal proliferation of non-
Langerhans histiocytes with Touton giant cells occurring predominantly in infancy and
early childhood
Most often occurs unilaterally
Common in children with neurofibromatosis type 1 (NF1)
Optic nerve, retina, and choroid can also be infiltrated

Symptoms
May cause spontaneous hyphema with decreased vision and increased IOP, corneal
enlargement, and perilimbal flush and photophobia
Children with skin lesions of JXG are routinely screened for eye involvement.

Signs
Can present as vascular, discrete reddish or yellow lesions or diffusely causing
heterochromia irides (Fig. 4-9)
Spontaneous or recurrent unilateral hyphema
Skin lesions appear as an acquired tan or orange papule or nodule. Skin lesions are
self-limited.

Differential Diagnosis
Leukemic infiltrates
Lisch nodules
Brushfield spots
Iris mamillations

Treatment
Biopsy of skin lesion to confirm diagnosis in patients with concomitant skin lesions
Anterior chamber paracentesis can be performed in patients without skin lesions.
Avoid iris biopsy because of the high risk of hemorrhage.
Topical or subconjunctival steroids can be used as the first line of treatment.
Radiotherapy (with dose not exceeding 500 cGy) can be used if the initial treatment
is unsuccessful and the risk-to-benefit ratio is acceptable.

Prognosis
Good with timely and appropriate diagnosis and treatment

REFERENCES
DeBarge LR, Chan CC, Greenberg SC, et al. Chorioretinal, iris, and ciliary body infiltration by juvenile
xanthogranuloma masquerading as uveitis. Surv Ophthalmol. 1994;39(1):65–71.
Kontos G, Borooah S, Khan A, Fleck BW, Coupland SE. The epidemiology, clinical characteristics, histopathology and
management of juvenile- and adult-onset corneoscleral limbus xanthogranuloma. Graefes Arch Clin Exp
Ophthalmol. 2016;254(3):413–420.
Samara WA, Khoo CT, Say EA, et al. Juvenile xanthogranuloma involving the eye and ocular adnexa: tumor control,
visual outcomes, and globe salvage in 30 patients. Ophthalmology. 2015;122(10):2130–2138.
Shields CL, Shields JA, Buchanon HW. Solitary orbital involvement with juvenile xanthogranuloma. Arch Ophthalmol.
1990;108(11):1587–1589.
Surapaneni KR, Wang AL, Burkat CN. Juvenile xanthogranuloma. Ophthalmology. 2015;122(5):870.
Zamir E, Wang RC, Krishnakumar S, et al. Juvenile xanthogranuloma masquerading as pediatric chronic uveitis: a
clinicopathologic study. Surv Ophthalmol. 2001;46(2):164–171.
 FIGURE 4-9. JXG. Reddish-yellow lesions on iris with signs of past intraocular inflammation.
(Courtesy of Alex V. Levin, MD, MHSc, Wills Eye Hospital, Philadelphia.)

LISCH NODULES
Etiology
Discrete dome-shaped nodules, which are melanocytic hamartomas occurring in
patients with NF1
Occurs in children affected with NF1 at an incidence approximately equal to 10
times the child’s age in years up to age 9
Rare in NF2

Symptoms
Nodules do not affect vision directly.

Signs
Bilaterally occurring, discrete dome-shaped nodules appearing anywhere on the
anterior iris surface (including the angle when gonioscopic observation may be
necessary to see them) (Fig. 4-10)
 Most are round, mildly pigmented (tan), and may be distributed more on the inferior
iris surface than the superior iris surface.
NF1 sometimes associated with pulsatile exophthalmos secondary to absence of the
greater wing of the sphenoid bone and plexiform neuroma of the eyelid, giving an S-
shaped deformity to the upper eyelid in early childhood

Differential Diagnosis
Iris nevi
Brushfield spots
JXG
Iris mamillations

Treatment
Observation of Lisch nodules in a child not carrying the diagnosis of NF should
trigger a workup for the disease and evaluation of family members.

Prognosis
Depends on the presence or absence of concomitant abnormalities associated with
NF, such as optic nerve glioma

REFERENCES
Friedman JM. Neurofibromatosis 1. In: Pagon RA, Bird TC, Dolan CR, Stephens K, eds. GeneReviews. Seattle:
University of Washington; 2009.
Jett K, Friedman JM. Clinical and genetic aspects of neurofibromatosis 1 [review]. Genet Med. 2010;12(1):1–11.
 FIGURE 4-10. Lisch nodules. Discrete, mildly pigmented dome-shaped nodules on the anterior iris
surface of a white patient (A) and an African American patient ( B). C. Slit-lamp photo of Lisch nodules
on the anterior iris surface of an African American patient.

MELANOSIS OCULI (OCULAR MELANOCYTOSIS)

Etiology
Congenital
Increase in the number of melanocytes in the iris, sclera, uvea, and surrounding
tissues. The melanocytes are located deep within the sclera, yielding a slate-gray
pigmentation rather than the normal brownish pigmentation usually associated with
melanin.

Symptoms
Increased pigmentation of the iris; discoloration of the sclera
Usually none unless associated with increased IOP or malignant melanoma
Signs
A congenital, flat, slate-gray discoloration of the sclera, iris, and uveal tract (Fig. 4-
11). The conjunctiva is not involved.
Most often unilateral but can occur bilaterally
Eyelid skin may be involved as well. Some patients, especially those of Asian
ancestry, may have associated increased pigmentation of the eyelid and adjacent skin
(oculodermal melanocytosis, nevus of Ota), which can appear brown, bluish, or black
without another skin abnormality (Fig. 4-12).

Differential Diagnosis
Bilateral patches of slate-gray scleral pigmentation common in Asian and African
American children (which have no clinical significance)
Congenital nevocellular nevus of the eyelids
Conjunctival nevi
Melanosis of the sclera and skin sometimes associated with Sturge-Weber syndrome
and Klippel-Trenaunay-Weber syndrome

Treatment
Increased risk of glaucoma and malignant melanoma occurs with increased
intraocular pigmentation.
Routine screening for glaucoma and dilated fundus examination yearly to rule out
uveal melanoma

Prognosis
Depends on the presence or absence of glaucoma and malignant melanoma

REFERENCES
Chernoff KA, Schaffer JV, Cutaneous and ocular manifestations of neurocutaneous syndromes. Clin Dermatol.
2016;34(2):183–204.
Daitch Z, Shields CL, Say EA, Mashayekhi A, Shields JA. Sub-millimeter choroidal melanoma detection by enhanced
depth imaging optical coherence tomography in a patient with oculodermal melanocytosis. Retin Cases Brief Rep.
2016;10(1):6–10.
Ellis FD. Selected pigmented fundus lesions of children. J AAPOS. 2005;9(4):306–314.
Gray ME, Shaikh AH, Corrêa ZM, Augsburger JJ. Primary uveal melanoma in a 4-year-old black child. J AAPOS.
2013;17(5):551–553.
Honavar SG, Shields CL, Singh AD, et al. Two discrete choroidal melanomas in an eye with ocular melanocytosis
 [review]. Surv Ophthalmol. 2002;47(1):36–41.
Mashayekhi A, Kaliki S, Walker B, et al. Metastasis from uveal melanoma associated with congenital ocular
melanocytosis: amatched study. Ophthalmology. 2013;120(7):1465–1468.
Shields CL, Kaliki S, Livesey M, et al. Association of ocular and oculodermal melanocytosis with the rate of uveal
melanoma metastasis: analysis of 7872 consecutive eyes. JAMA Ophthalmol. 2013;131(8):993–1003.
Shields CL, Nickerson SJ, Al-Dahmash S, Shields JA. Waardenburg syndrome: iris and choroidal hypopigmentation:
findings on anterior and posterior segment imaging. JAMA Ophthalmol. 2013;131(9):1167–1173.

FIGURE 4-11. Ocular melanocytosis. Flat, slate-gray discoloration of sclera.

 FIGURE 4-12. Oculodermal melanocytosis. Note the increased pigmentation of the sclera, eyelids,
and adjacent skin on the left side.

PERSISTENT PUPILLARY MEMBRANE

Etiology
Common developmental abnormality of the iris
Results from incomplete involution of anterior tunic vasculosa lentis (which
normally begins to involute at the beginning of the third trimester)

Symptoms
Visually insignificant in almost all but most severely involved eyes

Signs
Membranes attach to iris collarette, may be free floating, or span the pupil and attach
on the opposite side to the iris or to the anterior lens surface (which may be extensive)
(Fig. 4-13).
Can be associated with cataract (usually centrally located), microcornea,
megalocornea, microphthalmos, and coloboma

Differential Diagnosis
 Fibrinous anterior uveitis
Ectopia lentis et pupillae

Treatment
In the rare cases when vision is affected by persistent papillary membranes, medical
therapy (papillary dilation and amblyopia therapy) is usually adequate.
Surgical interventions (including iridectomy, removal of membrane, and laser
therapy) have been attempted in the past with mixed success.

Prognosis
Usually very good without treatment

REFERENCES
Kothari M, Mody K. Excision of persistent pupillary membrane using a suction cutter. J Pediatr Ophthalmol
Strabismus. 2009;46(3):187.
Kurt E. A patient with bilateral persistent pupillary membrane: a conservative approach. J Pediatr Ophthalmol
Strabismus. 2009;46(5):300–302.
Meyer-Rüsenberg B, Thill M, Vujancevic S, et al. Conservative management of bilateral persistent pupillary
membranes with 18 years of follow-up. Graefes Arch Clin Exp Ophthalmol. 2010;248(7):1053–1054.
 FIGURE 4-13. Persistent pupillary membrane spanning the pupil and attaching to the anterior lens
surface. (Courtesy of Alex V. Levin, MD, MHSc, Wills Eye Hospital, Philadelphia.)

POSTERIOR SYNECHIAE
Etiology
Congenital adhesions from the iris margin to the lens capsule. Congenital adhesions
may occur in association with cataract, intrauterine inflammation, and aniridia. May
also represent isolated remnants of the tunica vasculosa lentis (which are benign).
Acquired adhesions occur more frequently and are most often associated with
iridocyclitis.

Symptoms
Patients are typically asymptomatic unless associated iridocyclitis or active
sarcoidosis is present.

Signs
Misshaped pupil
Adhesions between the iris margin and lens capsule (Fig. 4-14)
Congenital synechia may be associated with small anterior polar cataract at the point
where the iris inserts into the lens capsule.
Pigments on the anterior lens capsule surface often found in a circular pattern after
intraocular inflammatory synechiae are broken.

Differential Diagnosis
Persistent pupillary membrane
Acquired synechia can also be associated with sarcoidosis, with Koeppe or Busacca
nodules.

Treatment
Congenital synechia with anterior polar cataract may be associated with hyperopia
astigmatism and anisometropic amblyopia.
Pharmacologic treatment with eye drops to dilate the pupil can often successfully
break fresh acquired synechia.
 Surgical synechialysis is sometimes required when posterior synechia are present for
a significant amount of the circumference of the papillary aperture or risk of angle
closure is present.

REFERENCES
Kadayifçilar S, Eldem B, Tumer B. Uveitis in childhood. J Pediatr Ophthalmol Strabismus. 2003;40(6):335–340.
Levy-Clarke GA, Nussenblatt RB, Smith JA. Management of chronic pediatric uveitis [review]. Curr Opin
Ophthalmol. 2005;16(5):281–288.

FIGURE 4-14. Posterior synechiae. Adhesion between iris and anterior lens surface. (Courtesy of
Jonathan Salvin, MD.)

AXENFELD-RIEGER ANOMALY
Etiology
Part of a group of anterior segment defects (formerly known as mesodermal
dysgenesis) with both genotypic and phenotypic overlap
Iris and pupil abnormalities associated with anterior displacement of Schwalbe line
with iris bands extending to the cornea (Axenfeld anomaly)
Autosomal dominant inheritance is most common.
Called Rieger syndrome if associated with dental and skeletal abnormalities
Mutations in RIEG1/PITX2 gene (gene that regulates expansion of other genes during
embryological development) on chromosome 4q25 have been identified.
Mutations in FOXC1 (transcription factor gene) also associated with this condition

Symptoms
Abnormally shaped iris or pupil
Photophobia secondary to significant iridodysgenesis

Signs
Prominent iris processes that insert to an anteriorly displaced Schwalbe line (Fig. 4-
15); may have a thinned iris stroma, bilateral iridodysgenesis with iris
transillumination, peripheral anterior synechia, an eccentric and displaced pupil

Differential Diagnosis
Posterior embryotoxon
Peters anomaly
Ectopic pupil

Treatment
Fifty percent risk of glaucoma development; timely and appropriate monitoring for
the development of glaucoma, including gonioscopy
No treatment for underlying abnormalities
Appropriate sunwear for photophobia symptoms
Colored contact lens for glare and cosmesis concerns
Genetic evaluation if systemic involvement is suspected

Prognosis
Depends on involvement of the anterior segment and the presence of glaucoma

REFERENCES
Cella W, de Vasconcellos JP, de Melo MB, et al. Structural assessment of PITX2, FOXC1, CYP1B1, and GJA1
 genes in patients with Axenfeld-Rieger syndrome with developmental glaucoma. Invest Ophthalmol Vis Sci.
2006;47(5):1803–1809.
Micheal S, Siddiqui SN, Zafar SN, et al. Whole exome sequencing identifies a heterozygous missense variant in the
PRDM5 gene in a family with Axenfeld-Rieger syndrome. Neurogenetics. 2016;17(1):17–23.
Singh DV, Sharma YR, Azad RV, et al. Familial ectopia lentis with Axenfeld-Rieger anomaly. J Pediatr Ophthalmol
Strabismus. 2007;44(1):59–61.
Yi K, Walden PG, Chen TC. What’s your diagnosis? Axenfeld-Rieger anomaly without glaucoma. J Pediatr
Ophthalmol Strabismus. 2007;44(6):333, 355.

FIGURE 4-15. Axenfeld-Rieger anomaly. Iris processes inserting to an anteriorly displaced

Schwalbe line. (Courtesy of Alex V. Levin, MD, MHSc, Wills Eye Hospital, Philadelphia.)

IRIS FLOCCULI
Etiology
Arise from iris pigment epithelium (congenital)

Symptoms
Rarely cause visual symptoms

Signs
Spherical or teardrop-shaped lesions overlapping pupil (Fig. 4-16)
Differential Diagnosis
Iris stromal cysts

Treatment
Can be surgically removed

Prognosis
Excellent visual prognosis
Associated with gene mutation in ACTA2 and/or MYH11 gene (smooth muscle gene)
These gene defects are associated with familial thoracic aortic aneurysm and
dissection (TAAD) (Fig. 4-17).
Long-term follow-up for TAAD is required as there is a reported case of TAAD
occurring 55 years after diagnosis of iris flocculi.

REFERENCES
Shields JA, Magrath GN, Shields C, et al. Dissecting aortic aneurysm 55 years after diagnosis of iris floccule. Ocul
Oncol Pathol. 2016;2(4):222–225.
Shields JA, Shields CL, Lois N, Mercado G. Iris cysts in childhood: classification, incidence, and management. Br J
Ophthalmol. 1999;83:334–338.
Willoughby CE, McGimpsey SJ, McConnell V. Iris flocculi are an ocular marker of smooth muscle-actin (ACTA2)
mutation in familial thoracic aortic aneurysms leading to acute aortic dissections (TAAD). Investigative Ophthalmol
Vis Sci. 2008;9(13):3121.
FIGURE 4-16. Iris flocculi overlapping pupil. (Courtesy of Jerry Shields, Wills Eye Hospital.)
FIGURE 4-17. Thoracic acute aneurysm and dissection—TAAD. (Courtesy of Jerry Shields, Wills
Eye Hospital.)
 CHAPTER
5

Lens Anomalies
Caroline DeBenedictis ■
CONGENITAL AND DEVELOPMENTAL
CATARACTS

A cataract is an opacification of the lens inside the eye. Congenital cataracts are
present at or soon after birth, whereas developmental cataracts develop during
childhood. They can be unilateral or bilateral and cause obstruction of the visual axis.
This leads to amblyopia, decreased visual acuity, or blindness (Fig. 5-1).

Etiology
The prevalence is 1 to 4.24 per 10,000 children.
Idiopathic (60% bilateral cases, 80% unilateral cases)
Familial (30% cases)
Most common morphologies: total cataract (31%), nuclear (27%), posterior
subcapsular (27%)
Genetic and metabolic diseases associated with cataract
Galactosemia
Alport syndrome
Fabry disease
Myotonic dystrophy
Diabetes mellitus
Trisomy 21
 Trisomy 18
Trisomy 13
Systemic illnesses associated with cataract include:
Juvenile idiopathic arthritis
Systemic lupus erythematosus
Malignancies
Ocular abnormalities associated with cataract include:
Aniridia
Persistent hyperplastic primary vitreous
Anterior segment dysgenesis
Maternal infection associated with cataract includes:
Rubella
Cytomegalovirus
Varicella
Herpes simplex virus
Toxoplasmosis
Syphilis

Signs and Symptoms

Variable degree of lens opacification (small spots to total opacification)
Variation of color changes (dark spots, white discoloration, total leukocoria)
Decreased visual acuity
Asymmetric, diminished, or absent red reflex
Nystagmus
Photophobia
Strabismus
Failure to meet developmental milestones
Poor visual development in infants
Poor visual function in older children

Diagnostic Evaluation
 Detailed history with specific attention to family history, trauma, systemic or topical
steroid use, radiation exposure, maternal infection, systemic illness in child, and visual
developmental milestones or visual changes
Physical examination includes complete ophthalmologic examination with visual
acuity testing, slit-lamp examination, pupillary dilation, retinoscopy, and indirect
ophthalmoscopy
B-scan ultrasonography
Infants may require general anesthesia for full examination.
Full physical examination with attention paid to growth and developmental
milestones and appropriate referral for genetic, infectious, and metabolic testing

Treatment
Visually significant cataract requires surgery with or without intraocular lens
implant: cataract >3 mm, dense cataract, cataract preventing refraction, poor red reflex
associated with nystagmus or strabismus
Congenital visually significant cataracts require initiation of treatment within 4 to 8
weeks of life depending on laterality.
Developmental cataracts in children younger than 7 years of age require initiation of
treatment within weeks after diagnosis to avoid development or delay in treatment of
amblyopia.
Partial cataracts may require surgery or may be managed medically (glasses,
patching, pupil dilation) depending on the extent of the cataract and surgical risks. If
visual acuity can be accurately measured to be better than 20/50, medical management
should be considered. If the visual acuity cannot be accurately measured or is measured
to be 20/50 or, worse, surgery should be considered.
Postoperative aphakic refractive correction (glasses or contact lenses) initiated as
soon as possible after surgery with appropriate treatment for amblyopia
Appropriate referral of patient for evaluation and treatment of any underlying disease

Prognosis
Depends on the age at diagnosis, morphology, laterality, concomitant ocular or
systemic disease, and surgical complications
In young children, postoperative prognosis depends on adherence to amblyopia
treatment.
REFERENCES
Amaya L, Taylor D, Russell-Eggitt I, et al. The morphology and natural history of childhood cataracts. Surv
Ophthalmol. 2003;48:125–144.
Lim Z, Rubab S, Chan YH, et al. Pediatric cataract: the Toronto experience-etiology. Am J Ophthalmol.
2010;149(6):887–892.
Lin AA, Buckley EG. Update on pediatric cataract surgery and intraocular lens implantation. Curr Opin Ophthalmol.
2010;21(1):55–59.
Wu X, Long E, Lin H, et al. Prevalence and epidemiological characteristics of congenital cataract: a systematic review
and meta-analysis. Sci Rep. 2016;6:28564.
 FIGURE 5-1. Congenital cataract. A. Anterior polar cataract: central anterior lens opacity generally
less than 1 mm in diameter. These are rarely visually significant. B. Congenital nuclear cataract: large
central nuclear opacity. This cataract is visually significant and requires surgical removal. C. Stellate
congenital cataract: stellate, spoke-like cortical lens opacity. Initially, this may not be visually significant,
but it may progress to a total opacity.

ECTOPIA LENTIS

E ctopia lentis is the displacement of the lens of the eye (Fig. 5-2). Subluxation is
defined as partial dislocation with the lens remaining attached to the ciliary body
via the lens zonules. Luxation is the complete detachment of the lens from the ciliary
body.

Etiology
Trauma
Congenital
Ocular conditions
Simple ectopia lentis
Ectopia lentis et pupillae
 Spherophakia/microspherophakia
Aniridia
Iris coloboma
Congenital glaucoma
Retinitis pigmentosa
Axenfeld-Rieger syndrome
Ciliary medulloepithelioma
Ciliary block glaucoma
Systemic diseases associated with ectopia lentis:
Marfan syndrome
Homocystinuria
Weill-Marchesani syndrome
Ehlers-Danlos syndrome
Sulfite oxidase deficiency
Hyperlysinemia
Congenital syphilis
Crouzon syndrome
Apert disease
Myotonic dystrophy

Symptoms
Mild to severely decreased visual acuity due to progressive or acute changes in
refractive error
Pain associated with pupillary block glaucoma

Signs
Partial lens displacement posteriorly or anteriorly
Complete lens displacement into anterior chamber or posterior pole
Pupillary block glaucoma
Induced irregular refractive errors (irregular astigmatism, high myopia, or aphakia)
 Amblyopia
Iridodonesis

Diagnostic Evaluation
Detailed history to determine the etiology with special attention paid to recent head,
orbit, or eye trauma
Full ocular exam including visual acuity, slit-lamp examination, and dilated
fundoscopic examination
Appropriate genetic, metabolic, and/or infectious studies if trauma is ruled out

Treatment
Refractive correction with corrective lenses
Amblyopia management
Lensectomy with postoperative aphakic glasses or contact lenses
Lensectomy with intraocular lens implantation if possible
Treatment of secondary ocular conditions (i.e., pupillary block glaucoma)
Refer to appropriate specialist for evaluation and treatment of underlying medical
condition.

Prognosis
Ninety percent of patients have a visual acuity of 20/40 or better after surgery with
appropriate refractive correction.

REFERENCES
Colley A, Lloyd IC, Ridgway A, et al. Ectopia lentis et pupillae; the genetic aspects and differential diagnosis. J Med
Genet. 1991;28(11):791–794.
Gupta NK, Simon JW, Walton DS, et al. Bilateral ectopia lentis as a presenting feature of medulloepithelioma.
JAAPOS. 2001;5(4):255–257.
Neely DE, Plager DA. Management of ectopia lentis in children. Ophthalmol Clin North Am. 2001;14(3):493–499.
Young TL. Ophthalmic genetics/inherited eye disease. Curr Opin Ophthalmol. 2003;14(5):296–303.
 FIGURE 5-2. Ectopia lentis: lens dislocation in the superonasal direction more typically seen in
Marfan syndrome.

ANTERIOR LENTICONUS

A nterior lenticonus is the anterior protrusion of the anterior lens through a weak or
thin portion of the anterior lenticular capsule, often with associated lens
opacification (Fig. 5-3).

Etiology
May be associated with anterior subcapsular or anterior polar cataracts
Alport syndrome, an inherited disorder (X-linked in 85%) with hemorrhagic
nephritis and sensorineural hearing loss
Trauma

Symptoms
Small (<2–3 mm) may have no symptoms
Blurred vision or induced amblyopia
Signs
Typically bilateral
Central, conical anterior protrusion of the anterior lens capsule seen on slit-lamp
examination (Fig. 5-3)
Central “oil-droplet” appearance on red reflex examination
Induced myopic or astigmatic refractive errors
Color changes such as whitened red reflex

Diagnosis
Detailed history, including family history for Alport syndrome
Complete eye examination, including visual acuity, slit-lamp examination, dilated
fundoscopic examination, retinoscopy, and refraction
Referral for appropriate nephrology and hearing evaluation

Treatment
Refractive correction
Amblyopia management
Pharmacologic pupillary dilation for small opacities
Cataract extraction if visually significant opacity
Clear lensectomy if unable to improve vision with refractive correction or pupillary
dilation
Treatment of underlying systemic nephrology disease
Hearing loss management

Prognosis
Good vision is possible with early diagnosis, close observation, and cataract
extraction when indicated.

REFERENCES
Flinter F. Alport’s syndrome. J Med Genet. 1997;34:326–330.
Savige J, Sheth S, Leys A, et al. Ocular features in Alport syndrome: pathogenesis and clinical significance. Clin J Am
Soc Nephrol. 2015;10(4):703–709.
Trivedi R, Wilson ME. Anterior lenticonus in Alport syndrome. In: Wilson ME, Trivedi R, Pandey S, eds. Pediatric
Cataract Surgery; Techniques, Complications, and Management. Philadelphia, PA: Lippincott Williams & Wilkins;
 2005:194–198.

FIGURE 5-3. Anterior lenticonus.

POSTERIOR LENTICONUS

P osterior lenticonus is a thinning of the posterior capsule with an associated

posterior bowing of the central lens capsule and cortical material (Fig. 5-4).
Posterior lens opacification is progressive and can become full posterior subcapsular
cataracts. Often at the time of cataract surgery, there is an associated hole in the
posterior capsule that may lead to vitreous prolapse during surgery.

Etiology
Congenital
Hereditary (X-linked or autosomal dominant)
Symptoms
Often no early symptoms
Decreased vision with progression

Signs
Oil-droplet sign on red reflex test
Posterior lens changes seen on slit-lamp examination
Amblyopia
Irregular or high lenticular astigmatism
Partial or complete opacification of visual axis
Variable degrees of leukocoria

Diagnosis
Detailed history, including family history
Complete eye examination, including visual acuity, slit-lamp examination, dilated
fundoscopic examination, retinoscopy, and refraction

Treatment
Observation if small (less than 2–3 mm)
Amblyopia management
Refractive correction
Cataract extraction if visually significant, with or without intraocular lens
Clear lensectomy if unable to improve vision with refractive correction or dilation
Special care to manage posterior capsule during surgery as most patients likely have
capsular defect
Given that this can be progressive, continued monitoring is recommended even if
visually insignificant at diagnosis

Prognosis
Congenital posterior lenticonus has a guarded but potentially good prognosis.
Acquired or progressive posterior lenticonus can have a good prognosis.

REFERENCES
Amaya L, Taylor D, Russell-Eggitt I, et al. The morphology and natural history of childhood cataracts. Surv
Ophthalmol. 2003;48:125–144.
Khali M, Saheb N. Posterior lenticonus. Ophthalmology. 1984;91:1429–1430.

FIGURE 5-4. Posterior lenticonus: posterior lens opacification. Initially, this may not be visually
significant, but it may progress to complete posterior subcapsular opacity.

SPHEROPHAKIA

S pherophakia occurs when the lens has a spherical shape instead of the normal
biconvex shape. This causes increased lens thickness, increased curvature, and
forward lens displacement with resultant lenticular myopia. Microspherophakia is when
the lens is spherical and small. This is associated with the increased risk of dislocation
(ectopia lentis) (Fig. 5-5).

Etiology
Idiopathic or congenital
Weill-Marchesani syndrome
Marfan syndrome

Symptoms
 Mild to severely decreased visual acuity caused by progressive or acute changes in
refractive error.
Pain associated with pupillary block glaucoma

Signs
High lenticular myopia
Irregular astigmatism
Amblyopia
Pupillary block glaucoma
Anterior or posterior lens dislocation

Diagnosis
Detailed history to determine the etiology with special attention to systemic and
family history
Full ocular examination, including visual acuity, slit-lamp examination, and dilated
fundoscopic examination
Appropriate genetic or metabolic testing

Treatment
Refractive correction
Amblyopia management
Lensectomy with postoperative aphakic glasses or contact lenses
Lensectomy with intraocular lens if possible
Treatment of secondary ocular conditions (i.e., pupillary block glaucoma)
Refer to appropriate specialist for evaluation and treatment of underlying medical
condition.

REFERENCES
Jensen AD, Cross HE, Paton D. Ocular complications in the Weill-Marchesani syndrome. Am J Ophthalmol.
1974;77:261–269.
Pikkel J, Irena E. Isolated spherophakia and glaucoma. Case Rep Med. 2013;2013:516490.
Ritch R, Chang BM, Liebmann JM. Angle closure in younger patients. Ophthalmology. 2003;110:1880–1889.
ACKNOWLEDGMENT
Jonathan H. Salvin and Hillary Gordon are acknowledged for their work and
contributions in the writing of this chapter.

FIGURE 5-5. Microspherophakia. Patient with microspherophakia. The small and spherical lens edge
is visible nasally. (Courtesy of Alex Levin, MD.)
 CHAPTER
6

Pediatric Uveitis
Kara C. LaMattina and Debra A. Goldstein ■
INTRODUCTION

P ediatric uveitis is a rare entity, accounting for anywhere from 5% to 10% of uveitis
cases in tertiary referral centers. Although it is uncommon, it is an important
condition as it presents diagnostic and therapeutic challenges and carries significant risk
of morbidity. Children are often asymptomatic in diseases like juvenile idiopathic
arthritis (JIA)–associated uveitis and may be preverbal and unable to express
symptoms, both of which can lead to a delay in diagnosis. Diagnosis may also be
delayed because children can be more difficult to examine than adults. In addition to the
morbidities seen in adults (cataract, band keratopathy, glaucoma, cystoid macular
edema [CME]), children also carry the risk of amblyopia, which may limit topical
treatment options. They may also have unique side effects of systemic steroids,
including growth retardation, which can further limit therapeutic options.

JUVENILE IDIOPATHIC ARTHRITIS

T he most common systemic disease associated with pediatric uveitis, JIA is

arthritis of unknown etiology with onset before age 16 with persistence for more
than 6 weeks. The classification criteria as proposed by the International League of
Associations for Rheumatology (ILAR) are outlined below.

Epidemiology and Etiology

Oligoarthritis
 Accounts for 50% to 60% of cases of JIA
Involves four or fewer joints within the first 6 months of disease onset (usually
knees, ankles, and fingers)
Peak age of onset is 2 to 4 years
Uveitis affects 30% to 50% of patients
More common in females
Subtypes include persistent (involves four or fewer joints throughout the disease
course) and extended (may involve more than four joints after the first 6 months)

Polyarticular Rheumatoid Factor–Positive

More than four joints involved in the first 6 months
Accounts for ~2% of cases of JIA
Mean age of onset between 9 and 12 years
Rarely develop uveitis

Polyarticular Rheumatoid Factor–Negative

More than four joints involved in the first 6 months
Accounts for 20% to 30% of cases of JIA
Bimodal age of onset: 1 to 3 years and 9 to 14 years
Uveitis affects 5% to 10% of patients

Psoriatic Arthritis
Arthritis with psoriasis, or arthritis with two or more of the following: dactylitis,
nail pitting or onycholysis, psoriasis in a first-degree relative
Accounts for ~5% of cases of JIA
Bimodal age of onset: 1 to 2 years and 8 to 12 years
Uveitis affects 10% to 20% of patients

Enthesitis-Related Arthritis
Arthritis and enthesitis, or arthritis or enthesitis with two or more of the following:
sacroiliac joint tenderness or inflammatory lumbosacral pain, HLA-B27 positivity,
arthritis in a male after 6 years of age, ankylosing spondylitis, enthesitis-related
arthritis, sacroiliitis with inflammatory bowel disease (IBD), reactive arthritis, or acute
anterior uveitis in a first-degree relative
 Mean age of onset >10 years
Affects boys more frequently than girls
Uveitis affects 10% to 15% of patients

Systemic Arthritis
Accounts for 10% of cases of JIA
Mean age of onset <5 years
No gender predilection
Associated with fever, rash, lymphadenopathy, hepatosplenomegaly, pericarditis,
peritonitis
Can affect hip, cervical spine, temporomandibular joints
Uveitis affects <1% of patients

Undifferentiated Arthritis
Includes arthritis that does not fulfill inclusion criteria for a category, or fulfills
criteria for more than one category
Accounts for 5% to 10% of cases of JIA

Symptoms
Uveitis associated with oligoarthritis is typically asymptomatic (screening is
required).
Polyarticular rheumatoid factor–negative JIA also tends to be asymptomatic
(screening is required).
Uveitis associated with enthesitis-related arthritis typically presents with pain,
redness, and photophobia and usually affects one eye at a time, as in adult HLA-B27–
positive patients (screening is not required).

Signs
Oligoarthritis
Typically bilateral, nongranulomatous anterior uveitis
Anterior chamber cell/flare ± anterior vitreous cell
May develop band keratopathy, posterior synechiae, anterior synechiae, pupillary
membranes (Fig. 6-1)
Can be complicated by cataract, glaucoma, macular edema, hypotony
Enthesitis-Related Arthritis
Severe acute anterior uveitis (often with fibrin and hypopyon, Fig. 6-2)
Children with IBD may present with acute or chronic anterior uveitis, scleritis,
CME, or retinal vasculitis

Differential Diagnosis
Early-onset sarcoidosis/Blau syndrome
Tubulointerestitial nephritis and uveitis (TINU)
Post infectious uveitis

Diagnostic Evaluation
Antinuclear antibody (ANA) in children with asymptomatic anterior uveitis
HLA-B27 in patients with acute symptomatic anterior uveitis
Workup for TINU, especially with bilateral acute anterior uveitis (urine β2
microglobulin as screening test, see below)
Workup for sarcoidosis (chest x-ray)
Regular screening for uveitis of patients with JIA (see Tables 6-1 and 6-2)

Treatment
Limit topical and systemic corticosteroids.
Early initiation of systemic immunomodulatory therapy is associated with better
visual outcomes (methotrexate is the most frequent first-line agent).

Prognosis
Depends on the extent of disease on presentation.
Generally good if diagnosed early and appropriate aggressive therapy is instituted.
Outcomes are better with early initiation of steroid-sparing immunomodulatory
therapy.

TABLE 6.1. American Academy of Pediatrics Guidelines for the Ophthalmological

Screening of Children with JIA

Age of Onset

JIA Subtype <7 y >7 y

Pauciarticular
ANA(+) Every 3–4 mo Every 6 mo
ANA(−) Every 6 mo Every 6 mo

Polyarticular
ANA(+) Every 3–4 mo Every 6 mo
ANA(−) Every 6 mo Every 6 mo
Systemic Every 12 mo Every 12 mo
ANA, antinuclear antibody; JIA, juvenile idiopathic arthritis. Reprinted with permission from American Academy of
Pediatrics Section on Rheumatology and Section on Ophthalmology. Guidelines for ophthalmologic examinations in
children with juvenile rheumatoid arthritis. Pediatrics. 1993;92(2):295–296.

REFERENCES
Ernst BB, Lowder CY, Meisler DM, et al. Posterior segment manifestations of inflammatory bowel disease.
Ophthalmology. 1991;98:1272–1280.
Gregory AC II, Kempen JH, Daniel E, et al; Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study
Research Group. Risk factors for loss of visual acuity among patients with uveitis associated with juvenile idiopathic
arthritis: the Systemic Immunosuppressive Therapy for Eye Diseases Study. Ophthalmology. 2013;120(1):186–192.
Hafner R, Michels H. Psoriatic arthritis in children. Curr Opin Rheumatol. 1996;8:467–472.
Heiligenhaus A, Niewerth M, Ganser G, et al; German Uveitis in Childhood Study Group. Prevalence and
complications of uveitis in juvenile idiopathic arthritis in a population-based nation-wide study in Germany: suggested
modification of the current screening guidelines. Rheumatology.2007;46:1015–1019.
Kesen MR, Setlur V, Goldstein DA. Juvenile idiopathic arthritis-related uveitis. Int Ophthalmol Clin. 2008;48:21–38.
Kotaniemi K, Kaipiainen-Seppänen O, Savolainen A, et al. A population-based study on uveitis in juvenile rheumatoid
arthritis. Clin Exp Rheumatol. 1999;17:119–122.
Levy-Clarke GA, Nussenblatt RB, Smith JA. Management of chronic pediatric uveitis. Curr Opin Ophthalmol.
2005;16:281–288.
Petty RE, Smith JR, Rosenbaum JT. Arthritis and uveitis in children: a pediatric rheumatology perspective. Am J
Ophthalmol. 2003;135:879–884.
Petty RE, Southwood TR, Manners P, et al; International League of Associations for Rheumatology. International
League of Associations for Rheumatology classification of juvenile idiopathic arthritis, second revision, Edmonton,
2001. J Rheumatol. 2004;31:390–392.
Stoll ML, Zurakowski D, Nigrovic LE, et al. Patients with juvenile psoriatic arthritis comprise two distinct populations.
Arthritis Rheum. 2006;54(11):3564–3572.
Wu EY, Van Mater HA, Rabinovich CE. Juvenile idiopathic arthritis. In: Kliegman R, Stanton B, Schor N, St. Geme J,
Behrman R, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: Elsevier Health Sciences; 2011:829–
838.
Zierhut M, Michels H, Stübiger N, et al. Uveitis in children. Int Ophthalmol Clin. 2005;45(2):135–156.

TABLE 6.2. Recommendations for Screening Based on the ILAR Classification of JIA

JIA Subtype ANA Age at Onset of JIA (y) Duration of JIA (y) Screening (mo)
Oligoarthritis + ≤6 ≤4 3

RF-negative polyarthritis + ≤6 >4 6

Psoriatic arthritis + ≤6 ≥7 12
Undifferentiated arthritis + >6 ≤2 6

+ >6 >2 12
− ≤6 ≤4 6
− ≤6 >4 12
− >6 NA 12
Enthesitis-related arthritis NA NA 12

RF-positive polyarthritis NA NA 12
Systemic arthritis NA NA 12
ANA, antinuclear antibody; ILAR, International League of Associations for Rheumatology; JIA, juvenile idiopathic
arthritis; RF, Rheumatoid Factor.
Reprinted with permission from Heiligenhaus A, Niewerth M, Ganser G, Heinz C, Minden K; German Uveitis in
Childhood Study Group. Prevalence and complications of uveitis in juvenile idiopathic arthritis in a population-based
nation-wide study in Germany: suggested modification of the current screening guidelines. Rheumatology.
2007;46:1015–1019.

FIGURE 6-1. Juvenile idiopathic arthritis. Band keratopathy and posterior synechiae in a 7-year-old
girl with juvenile idiopathic arthritis.
 FIGURE 6-2. Enthesitis-associated uveitis. Fibrin membrane in a patient with enthesitis-associated
acute anterior uveitis.

TUBULOINTERSTITIAL NEPHRITIS AND UVEITIS

A ccounting for 15% to 20% of acute kidney injury, acute tubulointerstitial nephritis
is frequently drug induced (about 70% of cases). This disease entity was first
linked to uveitis in 1975 and accounts for 1% to 2% of all uveitis in tertiary referral
centers. Uveitis may develop between 2 months before to 14 months after the onset of
systemic symptoms (median 3 months after).

Epidemiology and Etiology

Mean age of onset 15 years
Conflicting reports on gender predilection
Accounts for 1.1% to 2% of all pediatric uveitis in published literature, but true
prevalence may be higher.

Symptoms
Systemic: fever, weight loss, fatigue, malaise, anorexia, weakness, arthralgias,
myalgias
May have abdominal or flank pain
 Ocular: pain, redness, blurred vision, photophobia

Signs
Predominantly bilateral, anterior, nongranulomatous inflammation
Posterior findings (including vitritis, pars plana exudates, retinal vascular sheathing,
intraretinal hemorrhages and exudates, focal chorioretinitis, and multifocal choroiditis)
are seen in at least 20% of patients (Figs. 6-3 and 6-4).

Differential Diagnosis
Early-onset sarcoidosis/Blau syndrome
Post infectious uveitis
JIA-associated uveitis

Diagnostic Evaluation
Urine β2 microglobulin
Renal function (blood urea nitrogen, creatinine)
HLA-DRB1
May require kidney biopsy for definitive diagnosis

Treatment
Topical and systemic corticosteroids
May require immunomodulatory therapy if unable to wean off steroids

Prognosis
Generally favorable with appropriate therapy
Kidney disease usually self-limited, eye disease typically more chronic

REFERENCES
Dobrin RS, Vernier RL, Fish FJ. Acute eosinophilic interstitial nephritis and renal failure with bone marrow-lymph node
granulomas and anterior uveitis. Am J Med. 1975;596:325–333.
Howarth L, Gilvert RD, Bass P, et al. Tubulointerstitial nephritis and uveitis in monozygotic twin boys. Pediatr Nephrol.
2004;19:917–919.
Kump LI, Cervantes-Castaneda RA, Androudi SN, et al. Analysis of pediatric uveitis cases at a tertiary referral
center. Ophthalmology. 2005;112:1287–1292.
Levinson RD, Park MS, Rikkers SM, et al. Strong associations between specific HLA-DQ and HLA-DR alleles and
 the tubulointerstitial nephritis and uveitis syndrome. Invest Ophthalmol Vis Sci. 2003;44:653–657.
Mackensen F, Billing H. Tubulointerstitial nephritis and uveitis syndrome. Curr Opin Ophthalmol. 2009;20(6):525–531.
Mandeville JT, Levinson RD, Holland GN. The tubulointerstitial nephritis and uveitis syndrome. Surv Ophthalmol.
2001;46:195–208.
Raghavan R, Eknoyan G. Acute interstitial nephritis—a reappraisal and update. Clin Nephrol. 2014;82(3):149–162.
Rosenbaum JT. Bilateral anterior uveitis and interstitial nephritis. Am J Ophthalmol. 1988;105:534–537.
Smith JA, Mackensen F, Sen HN, et al. Epidemiology and course of disease in childhood uveitis. Ophthalmology.
2009;116(8):1544–1551.
Vohra S, Eddy A, Levin AV, et al. Tubulointerstitial nephritis and uveitis in children and adolescents. Four new cases
and a review of the literature. Pediatr Nephrol. 1999;13:426–432.

FIGURE 6-3. Tubulointerstitial nephritis and uveitis. Neovascularization of the disc in a 10-year-
old boy with tubulointerstitial nephritis and uveitis.
 FIGURE 6-4. Tubulointerstitial nephritis and uveitis. Peripheral granulomas and vitreous
hemorrhage in a 10-year-old boy with tubulointerstitial nephritis and uveitis.

BLAU SYNDROME/EARLY-ONSET SARCOIDOSIS

B lau syndrome (also known as Blau-Jabs syndrome) is the autosomal-dominant

familial form of early-onset sarcoidosis, with both entities characterized by
granulomatous dermatitis, polyarthritis, and uveitis, with absence of the lung disease
typically seen in sarcoidosis. Both diseases are correlated with NOD2 mutations,
although early-onset sarcoidosis is associated with a sporadic mutation. Both typically
first present in children younger than age 4. There are two other subsets of pediatric
sarcoidosis—infantile-onset panniculitis with uveitis and systemic granulomatosis and
pediatric-onset “adult-type” sarcoidosis—which are not associated with this mutation.
The pediatric-onset adult-type sarcoidosis tends to occur in early adolescence, with
lung involvement in 90% to 100%.

Epidemiology and Etiology

 Systemic onset between the ages of 2 and 4 years
Uveitis affects 60% to 80% of patients
Uveitis occurs at a mean age of 4 years
Accounts for 1.1% to 4.7% of cases of pediatric uveitis

Symptoms
Skin (typically first manifestation): fine, scaly, erythematous, maculopapular rash on
trunk/extremities
Polyarthritis of metacarpal-phalangeal, metatarsal-phalangeal, and proximal-
interphalangeal joints of hands and feet
May also have wrist, knee, ankle, and elbow involvement
Pain, redness, blurred vision, photophobia

Signs
Bilateral, chronic, or recurrent granulomatous anterior or posterior uveitis
Mutton-fat keratic precipitates (KP)
May have anterior uveitis, intermediate uveitis, chorioretinitis, periphlebitis,
macular edema, vein occlusion, optic neuropathy (Figs. 6-5 and 6-6)

Differential Diagnosis
JIA-associated uveitis
Pediatric-onset adult-type sarcoidosis
Tuberculosis

Diagnostic Evaluation
Skin biopsy shows noncaseating epithelioid and giant-cell granulomas
Testing for CARD15/NOD2 mutations

Treatment
Limited topical and systemic steroids
Systemic immunomodulatory therapy with antimetabolites and/or biologic agents
(often needed)

Prognosis
 Generally good, although posterior complications can lead to moderate to severe
vision loss

REFERENCES
Blau EB. Familial granulomatous arthritis, iritis, and rash. J Pediatr. 1985;107:689–693.
Hoffmann AL, Milman N, Byg KE. Childhood sarcoidosis in Denmark 1979–1994: incidence, clinical features and
laboratory results at presentation in 48 children. Acta Paediatr. 2004;93:30–36.
Jabs DA, Houk JL, Bias QB, et al. Familial granulomatous synovitis, uveitis, and cranial neuropathies. Am J Med.
1985;78(5):801–804.
Kanazaaw N, Matsushima S, Kambe N, et al. Presence of a sporadic case of systemic granulomatosis syndrome with
a CARD15 mutation. J Invest Dermatol. 2004;122(3):851–852.
Khairallah M, Attia S, Zaouali S, et al. Pattern of childhood-onset uveitis in a referral center in Tunisia, North Africa.
Ocul Immunol Inflamm. 2006;14(4):225–231.
Kump LI, Cervantes-Castaneda RA, Androudi SN, et al. Analysis of pediatric uveitis cases at a tertiary referral
center. Ophthalmology. 2005;112:1287–1292.
Miceli-Richard C, Lesage S, Rybojad M, et al. Card15 mutations in Blau syndrome. Nat Genet. 2001;29(1):19–20.
Petty RE, Laxer RM, Lindsley CB, et al. Textbook of Pediatric Rheumatology. Philadelphia, PA: Elsevier Saunders;
2016:517–525.
Rahimi M, Oustad M, Ashrafi A. Demographic and clinical features of pediatric uveitis at a tertiary referral center in
Iran. Middle East Afr J Ophthalmol. 2016;23(3):237–240.
Raiji VR, Miller MM, Jung LK. Uveitis in Blau syndrome from a de novo mutation of the NOD2/CARD15 gene. J
AAPOS. 2011;15:205–207.
Rose CD, Doyle TM, McIlvain-Simpson G, et al. Blau syndrome mutation of CARD15/NOD2 in sporadic early onset
granulomatous arthritis. J Rheumatol. 2005;32(2):373–375.
Rosé CD, Pans S, Casteels I, et al. Blau syndrome: cross-sectional data from a multicenter study of clinical,
radiological and functional outcomes. Rheumatology (Oxford). 2015;54(6):1008–1016.
Smith JA, Mackensen F, Sen HN, et al. Epidemiology and course of disease in childhood uveitis. Ophthalmology.
2009;116(8):1544–1551.
Vaphiades MS, Eggenberger E. Childhood sarcoidosis. J Neuroophthalmol. 1998;18(2):99–101.
Wouters CH, Maes A, Foley KP, et al. Blau syndrome, the prototypic auto-inflammatory granulomatous disease.
Pediatr Rheum Online J. 2014;12:33.
FIGURE 6-5. Blau syndrome. Periphlebitis in a 17-year-old girl with Blau syndrome.

FIGURE 6-6. Blau syndrome. Granulomatous keratic precipitates in a child with Blau syndrome.
POST INFECTIOUS AUTOIMMUNE UVEITIS

M ost commonly seen after group A streptococcal infection, post infectious

autoimmune uveitis typically occurs 1 to 6 weeks after systemic illness with
bilateral anterior uveitis.

Epidemiology and Etiology

Mean age 10.9 years
Accounts for ~7% of cases of pediatric uveitis

Symptoms
Flu-like illness and sore throat
Blurred vision, pain, photophobia

Signs
Acute bilateral anterior uveitis
+⁄– CME, papillitis

Differential Diagnosis
JIA-associated uveitis
Tubulointerstitial nephritis and uveitis
Early-onset sarcoidosis/Blau syndrome

Diagnostic Evaluation
Serum antistreptolysin O titers (if continuing to rise may require further antibiotic
therapy)

Treatment
Appropriate antibiotic therapy
Topical steroid therapy is usually adequate.

Prognosis
Excellent, usually self-limited
REFERENCES
Benjamin A, Tufail A, Holland GN. Uveitis as the only clinical manifestation of post streptococcal syndrome. Am J
Ophthalmol. 1997;123(2)258–260.
Birnbaum AD, Jiang Y, Vasaiwala R, et al. Bilateral simultaneous-onset nongranulomatous acute anterior uveitis:
clinical presentation and etiology. Arch Ophthalmol. 2012;130(11):1389–1394.
Gallagher MJ, Muqit MM, Jones D, et al. Post-streptococcal uveitis. Acta Ophthalmol Scand. 2006;84(3):424–428.
Holland GN. Recurrent anterior uveitis associated with streptococcal pharyngitis in a patient with a history of post-
streptococcal syndrome. Am J Ophthalmol. 1999;27:345–347.
Paroli MP, Spinucci G, Liverani M, et al. Uveitis in childhood: an Italian clinical and epidemiological study. Ocul
Immunol Inflamm. 2009;17(4):238–242.
Ur Rehman S, Anand S, Reddy A, et al. Poststreptococcal syndrome uveitis: a descriptive case series and literature
review. Ophthalmology. 2006;113(4)701–706.

TRAUMATIC UVEITIS

M ild unilateral ocular inflammation is often seen after blunt trauma.

Epidemiology and Etiology

Males are more commonly affected (70%–79%).
Mean age 31 ± 16.5 years
Typically unilateral disease

Symptoms
Pain, redness, photophobia

Signs
Miosis
Ciliary flush
Decreased intraocular pressure
+⁄– Hyphema

Differential Diagnosis
JIA-associated uveitis: enthesitis subtype (HLA-B27-associated anterior uveitis)
Sarcoidosis

Diagnostic Evaluation
 Gonioscopy
Ultrasound if suspicion of foreign body
If inflammation is severe or persistent, consider etiologies other than trauma.

Treatment
Topical corticosteroids
Topical cycloplegics

Prognosis
Excellent if no concomitant traumatic nerve/retinal damage, usually self-limited

REFERENCES
Engelhard SB, Patrie J, Prenshaw J, et al. Traumatic uveitis in the mid-Atlantic United States. Clin Ophthalmol.
2015;9:1869–1874.
Rosenbaum JT, Tammaro J, Robertson JE Jr. Uveitis precipitated by nonpenetrating ocular trauma. Am J Ophthalmol.
1991;112(4)392–395.

HERPESVIRIDAE

A ccounting for up to 30% of infectious uveitis, herpes viruses (including varicella

zoster, herpes simplex, and cytomegalovirus) can cause uveitis affecting both the
anterior and posterior segments.

Epidemiology and Etiology

No gender predilection
Accounts for 1.5% to 6.2% of cases of pediatric uveitis
May have history of perinatal exposure or chickenpox

Symptoms
Redness, pain, photophobia, blurred vision

Signs
Dendritiform corneal lesion
Interstitial keratitis (Fig. 6-7)
 Mild-moderate anterior chamber reaction
White or pigmented, granulomatous or stellate KP (often diffuse and not confined to
Arlt triangle)
Sectoral or patchy iris atrophy
Elevated intraocular pressure
Retinal necrosis and vasculitis, in cases with posterior involvement

Differential Diagnosis
Fuchs heterochromic iridocyclitis
JIA-associated uveitis: enthesitis subtype
Toxoplasmosis

Diagnostic Evaluation
All patients need a dilated fundus examination to rule out retinitis.
Consider anterior chamber tap with polymerase chain reaction (PCR) in cases where
diagnosis is unclear.

Treatment
Systemic antivirals
Topical corticosteroids

Prognosis
Generally very good for anterior uveitis, depends on severity of retinitis in cases
with posterior involvement

REFERENCES
Barron BA, Gee L, Hauck WW, et al. Herpetic Eye Disease Study. A controlled trial of oral acyclovir for herpes
simplex stromal keratitis. Ophthalmology. 1994;101(12):1871–1872.
Hettinga YM, de Groot-Mijnes JD, Rothova A, et al. Infectious involvement in a tertiary center pediatric uveitis cohort.
Br J Ophthalmol. 2015;99(1):103–107.
Khairallah M, Attia S, Zaouali S, et al. Pattern of childhood-onset uveitis in a referral center in Tunisia, North Africa.
Ocul Immunol Inflamm. 2006;14(4):225–231.
Kump LI, Cervantes-Castaneda RA, Androudi SN, Foster CS. Analysis of pediatric uveitis cases at a tertiary referral
center. Ophthalmology. 2005;112:1287–1292.
Rahimi M, Oustad M, Ashrafi A. Demographic and clinical features of pediatric uveitis at a tertiary referral center in
Iran. Middle East Afr J Ophthalmol. 2016;23(3):237–240.
Siverio Júnior CD, Imai Y, Cunningham ET Jr. Diagnosis and management of herpetic anterior uveitis. Int Ophthalmol
Clin. 2002;42(1):43–48.
Van der Lelij A, Ooijman FM, Kijlstra A, Rothova A. Anterior uveitis with sectoral iris atrophy in the absence of
keratitis: a distinct clinical entity among herpetic eye diseases. Ophthalmology. 2000;107(6):1164–1170.
Wilhelmus KR, Gee L, Hauck WW, et al. Herpetic Eye Disease Study. A controlled trial of topical corticosteroids for
herpes simplex stromal keratitis. Ophthalmology. 1994;101(12):1883–1895.

FIGURE 6-7. Herpes keratitis. Herpetic interstitial keratitis in a young girl.

PARS PLANITIS

P ars planitis is a form of intermediate uveitis with no known infectious or

inflammatory etiology. There is a risk of developing multiple sclerosis (MS).

Epidemiology and Etiology

Mean age of onset 8 to 10 years
Male predominance (57%–84%)
Accounts for 17% to 20.8% of cases of pediatric uveitis

Symptoms
Floaters, blurred vision
 Photophobia in cases with concurrent anterior uveitis

Signs
Usually bilateral (asymmetric) involvement
May present with strabismus or amblyopia
Mild-moderate anterior chamber reaction
Vitreous cell
Snowbanks and snowballs (Figs. 6.8 and 6.9)
Periphlebitis

Differential Diagnosis
MS-associated intermediate uveitis
Sarcoidosis
Syphilis
Tuberculosis

Diagnostic Evaluation
Neurologic review of systems with magnetic resonance imaging as indicated to rule
out MS
Consider ultrasound if fundus exam is limited by vitritis

Treatment
Topical, periocular, and systemic steroids
May require systemic immunomodulatory therapy
Tumor necrosis factor inhibitors: consider risk of MS
Pars plana vitrectomy with laser (or cryo) peripheral retinal ablation

Prognosis
Dependent on development of complications (cataract, glaucoma, CME, vitreous
hemorrhage, retinoschisis, retinal detachment)
Good if caught early in the disease course and appropriately treated

REFERENCES
Giuliari GP, Chang PY, Thakuria P, Hinkle DM, Foster CS. Pars plana vitrectomy in the management of paediatric
uveitis: the Massachusetts Eye Research and Surgery Institution experience. Eye (Lond). 2010;24(1):7–13.
Jain R, Ferrante P, Reddy GT, et al. Clinical features and visual outcome of intermediate uveitis in children. Clin Exp
Ophthalmol. 2005;33:22–25.
Kump LI, Cervantes-Castañeda RA, Androudi SN, Foster CS. Analysis of pediatric uveitis cases at a tertiary referral
center. Ophthalmology. 2005;112:1287–1292.
Malalis JF, Bhat P, Shapiro M, et al. Retinoschisis in pars planitis. Ocul Immunol Inflamm. 2017;25:344–348.
Maris K, Van Castler J, Wouters C, et al. Clinical symptoms and complications of pars planitis in childhood. Bull Soc
Belge Ophthalmol. 2005;295:29–33.
Nikkhah H, Ramezani A, Ahmadieh H, et al. Childhood pars planitis: clinical features and outcomes. J Ophthalmic Vis
Res. 2011;6(4):249–254.
Paroli MP, Spinucci G, Liverani M, Monte R, Pezzi PP. Uveitis in childhood: an Italian clinical and epidemiological
study. Ocul Immunol Inflamm. 2009;17(4):238–242.
Romero R, Peralta J, Sendagorta E, Abelairas J. Pars planitis in children: epidemiologic, clinical, and therapeutic
characteristics. J Pediatr Ophthalmol Strabismus. 2007;44:288–293.
Smith JA, Mackensen F, Sen HN, et al. Epidemiology and course of disease in childhood uveitis. Ophthalmology.
2009;116(8):1544–1551.

FIGURE 6-8. Pars planitis. Snowballs in an 8-year-old boy with pars planitis.
 FIGURE 6-9. Pars planitis. Very active pars planitis in a 10-year-old girl.

TOXOPLASMOSIS

T oxoplasma gondii is an intracellular parasite that can be transmitted congenitally

or acquired postnatally. Postnatal infection is generally caused by consumption of
contaminated water, undercooked meat, or exposure to cat feces, as cats serve as the
definitive host of the parasite.

Epidemiology and Etiology

Most common cause of posterior uveitis in children
Accounts for 3.3% to 25.6% of all pediatric uveitis
Affects up to 1 in 770 live-born infants in endemic regions
Mean age 9.5 ± 4.4 years
No gender predilection
Bilateral in 30% to 63.5% of cases, although disease tends to be active in one eye at
a time

Symptoms
Blurred/poor vision, redness, floaters

Signs
Microcephaly, hydrocephalus, microphthalmia (congenital infection)
Strabismus
Acute anterior and intermediate uveitis (not typical in neonates)
Retinitis with or without adjacent chorioretinal scars (Figs. 6-10 to 6-12)
Papillitis
Retinal vasculitis
Intraocular pressure (IOP) often elevated at presentation

Differential Diagnosis
Behçet disease
Acute retinal necrosis
Pars planitis
Endophthalmitis

Diagnostic Evaluation
Diagnosis is typically made clinically.
PCR of vitreous or aqueous fluid in atypical cases

Treatment
Antiparasitics (e.g., trimethoprim/sulfamethoxazole, azithromycin, pyrimethamine)
with or without topical and/or systemic corticosteroids
Congenital infection is treated in collaboration with pediatrician for the first year of
life with sulfadiazine, pyrimethamine, and folinic acid.

Prognosis
Dependent on location
REFERENCES
Garza-Leon M, Garcia LA. Ocular toxoplasmosis: clinical characteristics in pediatric patients. Ocul Immunol Inflamm.
2012;20(2):130–138.
Hettinga YM, de Groot-Mijnes JD, Rothova A, de Boer JH. Infectious involvement in a tertiary center pediatric uveitis
cohort. Br J Ophthalmol. 2015;99(1):103–107.
Kump LI, Cervantes-Castaneda RA, Androudi SN, Foster CS. Analysis of pediatric uveitis cases at a tertiary referral
center. Ophthalmology. 2005;112:1287–1292.
Pivetti-Pezzi P. Uveitis in children. Eur J Ophthalmol. 1996;6:293–298.
Rahimi M, Oustad M, Ashrafi A. Demographic and clinical features of pediatric uveitis at a tertiary referral center in
Iran. Middle East Afr J Ophthalmol. 2016;23(3):237–240.
Smith JA, Mackensen F, Sen HN, et al. Epidemiology and course of disease in childhood uveitis. Ophthalmology.
2009;116(8):1544–1551.
Standford MR, Tan HK, Gilbert RE. Toxoplasmic retinochoroiditis presenting in childhood: clinical findings in a UK
survey. Br J Opthhalmol. 2006;90:1464–1467.
Vasconcelos-Santos DV, Machado Azevedo DO, Campos WR, et al. Congenital toxoplasmosis in Southeastern Brazil:
results of early ophthalmologic examination of a large cohort of neonates. Ophthalmology. 2009;116(11):2199–2205.
Wallon M, Kodjikian L, Binquet C, et al. Long-term ocular prognosis in 327 children with congenital toxoplasmosis.
Pediatrics. 2004;113(6):1567–1572.

FIGURE 6-10. Congenital toxoplasmosis. Macular scar in a 12-year-old girl with congenital
toxoplasmosis.
FIGURE 6-11. Active acquired toxoplasmosis. Note the white patch of retinitis, vitreous haze, and
vasculitis.
 FIGURE 6-12. Recurrent toxoplasmosis. Recurrent toxoplasmosis with active white retinitis
adjacent to old scar.

TOXOCARIASIS

T oxocariasis is most commonly caused by Toxocara canis, a roundworm carried by

dogs and shed in the feces, and Toxocara cati, a roundworm carried by cats. It is
typically acquired by ingestion of contaminated food or water.

Epidemiology and Etiology

Mean age of onset 6 years
Accounts for 0.3% to 7.4% of cases of pediatric uveitis

Symptoms
Blurred vision, pain, photophobia
Flashes, floaters
 Asymptomatic

Signs
Leukocoria
Retinal granuloma in peripheral retina or posterior pole (Fig. 6-13)
Endophthalmitis
Vitritis, vitreous strands
Tractional retinal detachment
Typically unilateral

Differential Diagnosis
Tuberculosis
Sarcoidosis
Toxoplasmosis
Retinoblastoma
Pars planitis

Diagnostic Evaluation
Serum titers

Treatment
Topical and systemic corticosteroids
Can treat systemic disease with antiparasitics, but generally not indicated for
isolated ocular involvement (parasite assumed to be dead when patient presents with
eye disease)

Prognosis
Depends on localization, but generally unilateral, so does not result in bilateral
visual impairment

REFERENCES
Hettinga YM, de Groot-Mijnes JD, Rothova A, de Boer JH. Infectious involvement in a tertiary center pediatric uveitis
cohort. Br J Ophthalmol. 2015;99(1):103–107.
Khairallah M, Attia S, Zaouali S, et al. Pattern of childhood-onset uveitis in a referral center in Tunisia, North Africa.
 Ocul Immunol Inflamm. 2006;14(4):225–231.
Kump LI, Cervantes-Castaneda RA, Androudi SN, Foster CS. Analysis of pediatric uveitis cases at a tertiary referral
center. Ophthalmology. 2005;112:1287–1292.
Liu Y, Zhang Q, Li J, Ji X, Xu Y, Zhao P. Clinical characteristics of pediatric patients with ocular toxocariasis in
China. Ophthalmologica. 2016;235(2):97–105.
Paroli MP, Spinucci G, Liverani M, Monte R, Pezzi PP. Uveitis in childhood: an Italian clinical and epidemiological
study. Ocul Immunol Inflamm. 2009;17(4):238–242.
Rahimi M, Oustad M, Ashrafi A. Demographic and clinical features of pediatric uveitis at a tertiary referral center in
Iran. Middle East Afr J Ophthalmol. 2016;23(3):237–240.

FIGURE 6-13. Toxocariasis. Peripheral retinal toxocara lesion in a 10-year-old boy with falciform
retinal fold.

TUBERCULOSIS

C aused by the airborne pathogen Mycobacterium tuberculosis, tuberculosis can

affect multiple organ systems.

Epidemiology and Etiology

Accounts for 0.3% to 0.5% of cases of pediatric uveitis
Symptoms
Pain, redness, photophobia
Blurred vision
Flashes, floaters

Signs
Granulomatous anterior inflammation: mutton-fat KP, iris nodules
Broad-based posterior synechiae
Vitritis
Single or multiple choroidal tubercles
Serpiginous-like choroiditis
Periphlebitis

Differential Diagnosis
Sarcoidosis
Syphilis
Vogt-Koyanagi-Harada disease

Diagnostic Evaluation
Tuberculin skin test, such as purified protein derivative
Interferon gamma release assay such as QuantiFERON gold
Chest x-ray (limit computed tomography scan use to reduce radiation exposure in
pediatric population)

Treatment
Four-drug therapy (rifampin, isoniazid, ethambutol, and pyrazinamide) for 2 months
followed by 4 to 9 months of therapy with rifampin and isoniazid, typically managed by
infectious disease specialist
Topical and systemic corticosteroids
May require addition of systemic immunomodulatory therapy

Prognosis
Depends on localization (posterior segment disease may be aggressive and poorly
responsive to therapy)

REFERENCES
Cutrufello NJ, Karakousis PC, Fishler J, Albini TA. Intraocular tuberculosis. Ocul Immunol Inflamm. 2010;18(4):281–
291.
Gupta A, Bansal R, Gupta V, Sharma A, Bambery P. Ocular signs predictive of ocular tuberculosis. Am J Ophthalmol.
2010;149(4):562–570.
Hettinga YM, de Groot-Mijnes JD, Rothova A, de Boer JH. Infectious involvement in a tertiary center pediatric uveitis
cohort. Br J Ophthalmol. 2015;99(1):103–107.
Paroli MP, Spinucci G, Liverani M, Monte R, Pezzi PP. Uveitis in childhood: an Italian clinical and epidemiological
study. Ocul Immunol Inflamm. 2009;17(4):238–242.
Patel SS, Saraiya NV, Tessler HH, Goldstein DA. Mycobacterial ocular inflammation: delay in diagnosis and other
factors impacting morbidity. JAMA Ophthalmol. 2013 Jun;131(6):752–758.

IDIOPATHIC UVEITIS

I diopathic uveitis is a diagnosis of exclusion and can present as anterior,

intermediate, posterior, or panuveitis. It accounts for anywhere from 21.5% to 50%
of pediatric uveitis. Differential diagnosis depends on localization and clinical
presentation, and treatment is based on location and severity of uveitis.

REFERENCES
Friling R, Kramer M, Snir M, Axer-Siegel R, Weinberger D, Mukamel M. Clinical course and outcome of uveitis in
children. J AAPOS. 2005;9(4):379–382.
Khairallah M, Attia S, Zaouali S, et al. Pattern of childhood-onset uveitis in a referral center in Tunisia, North Africa.
Ocul Immunol Inflamm. 2006;14(4):225–231.
Smith JA, Mackensen F, Sen HN, et al. Epidemiology and course of disease in childhood uveitis. Ophthalmology.
2009;116(8):1544–1551.
Tugal-Tutkun I, Havrlikova K, Power WJ, Foster CS. Changing patterns in uveitis of childhood. Ophthalmology.
1996;103(3):375–383.

MASQUERADES
It is important to note that neoplasms such as leukemia and retinoblastoma can present
with pseudohypopyon, spontaneous hyphema, or iris masses that may be misdiagnosed
as uveitis. The pseudohypopyon is typically creamy (leukemia) or chalky
(retinoblastoma) white in color. The iris masses are larger and may be less well
defined than inflammatory iris nodules and may be vascularized. Another disorder that
could be mistaken for uveitis is juvenile xanthogranuloma (JXG), which typically
presents with unilateral, flesh-colored iris nodules. Diagnosis in all cases requires high
clinical suspicion; leukemia can be diagnosed with anterior-chamber paracentesis and
cytologic examination. Diagnosis of JXG may require tissue biopsy.

REFERENCES
Croxatto JO, Fernandez MR, Malbran ES. Retinoblastoma masquerading as ocular inflammation. Ophthalmologica.
1983;186(1):48–53.
Fontanilla FA, Edward DP, Wong M, Tessler HH, Eagle RC, Goldstein DA. Juvenile xanthogranuloma masquerading
as melanoma. J AAPOS. 2009;13(5):515–518.
Rowan PJ, Sloan JB. Iris and anterior chamber involvement in leukemia. Ann Ophthalmol. 1976;8(9):1081–1085.
Schwartz LW, Rodrigues MM, Hallett JW. Juvenile xanthogranuloma diagnosed by paracentesis. Am J Ophthalmol.
1974;77(2):243–246.
Tahan SR, Pastel-Levy C, Bhan AK, Mihm MC Jr. Juvenile xanthogranuloma. Clinical and pathologic
characterization. Arch Pathol Lab Med. 1989;113(9):1057–1061.
Wolintz AH, Goldstein JH, Seligman BR, Rosner F, Wesely AC, Lee SL. Secondary glaucoma in leukemia. Ann
Ophthalmol. 1969;82(6):771–773.
Zakka KA, Yee RD, Shorr N, Smith GS, Pettit TH, Foos RY. Leukemic iris infiltration. Am J Ophthalmol.
1980;89(2):204–209.
 CHAPTER
7

Congenital Abnormalities of
the Optic Nerve
Aldo Vagge and Leonard B. Nelson ■
OPTIC NERVE HYPOPLASIA
Optic nerve hypoplasia (ONH) is a congenital, nonprogressive developmental
abnormality in which the optic nerve is smaller than usual because of reduced numbers
of retinal ganglion cells. It is frequently associated with other central nervous system
(CNS) abnormalities.
ONH may be unilateral or bilateral (80%) and may be asymmetric.
Most common congenital optic disc anomaly
Optic nerve aplasia is rare. No pupillary light reflex and absence of the optic disc,
nerve fiber layer, and retinal blood vessels on examination.

Etiology
Not completely understood
Parental drug and alcohol abuse contributes to an increasing prevalence of ONH.
Drug associations include exposure to carbemazepine, isotretinoin, phenytoin, quinine,
and valproic acid. Young maternal age and maternal insulin-dependent diabetes have
also been implicated in some cases (associated with subtype—superior segmental optic
hypoplasia).

Genetics
Most cases are sporadic.
 Bilateral ONH is inherited in an autosomal-dominant pattern based on the few
families reported. Mutation in the PAX6 (11q13) gene is responsible.
Mutation in the HESX1 gene has been identified in sporadic septo-opto dysplasia
and pituitary disease.
Mutation in the TUBA8 gene is associated with polymicrogyria and ONH.

Symptoms
Decreased vision in one or both eyes
Strabismus may be associated with unilateral ONH.

Signs
Range of visual acuity is 20/20 to no light perception since vision is determined
primarily by the integrity of the papillomacular nerve fibers more than the overall size
of the disc.
Amblyopia as a result of accompanying strabismus and anisometropia
Nystagmus: often develops at 1 to 3 months of age in bilateral cases
Strabismus may be associated with unilateral ONH.
Afferent pupil defect in asymmetric or unilateral cases
Visual fields (VFs) often have localized defects as well as general constriction.
Abnormally small optic nerve head, often gray or pale in color with “double-ring
sign” (scleral canal surrounds a small optic nerve) (Fig. 7-1)
Superior segmental hypoplasia of the optic nerve is a segmental form of ONH
occurring in some children of insulin-dependent diabetic mother.
Retinal vascular tortuosity is common.

Associated Conditions
Septa-optic dysplasia: combination of small anterior visual pathways, absence of the
septum pellucid, and thinning or agenesis of the corpus callosum
Endocrine dysfunction: pituitary gland abnormalities in approximately 15% of
patients with ONH. Patients are at risk for hypothalamic and pituitary dysfunction such
as growth hormone deficiency (most common), hypothyroidism, hyperprolactinemia,
panhypopituitarism, and diabetes insipidus.
Cerebral anomalies such as error in hemispheric migration (schizencephaly, cortical
heterotopias) or hemispheric injury (periventricular leukomalacia [PVL],
encephalomalacia). PVL can be associated with another form of ONH characterized by
large optic cups and a thin neuroretinal rim contained within normal-sized optic discs.
This occurs secondary to trans-synaptic degeneration of optic axons caused by bilateral
lesions in the optic radiations.
Developmental delay more common in patients with bilateral ONH, highly
correlated with corpus callosum hypoplasia and hypothyroidism

Diagnostic Evaluation
Magnetic resonance imaging (MRI) to rule out CNS malformations
Refer to a pediatric endocrinologist if patients show clinical signs of endocrine
dysfunction or pituitary abnormalities on MRI. Pediatrician should follow growth chart
for endocrine changes. Undiagnosed endocrine deficiencies are at risk for impaired
growth, hypoglycemia, seizures, and death.
Automated VF testing may be useful but children are often too young to cooperate.

Differential Diagnosis
Optic atrophy
Optic nerve coloboma
Ocular albinism

Treatment
No treatment available to improve the vision in ONH
Correction of refractive errors
Treatment for superimposed amblyopia
Surgery for concurrent strabismus or nystagmus may be considered.
Consider polycarbonate eye glasses for protection of the better-seeing eye.

Prognosis
Visual acuity is generally nonprogressive. Complications are in general related to
endocrinopathies and CNS malformations.
 FIGURE 7-1. Optic nerve hypoplasia. Note the double-ring sign.

MORNING GLORY DISC ANOMALY

Morning glory disc anomaly (MGDA) is a rare, congenital, usually unilateral funnel-
like excavation of the posterior fundus that incorporates the optic disc.
The name derives from the similarity to the morning glory flower.
More common in female and rare in African Americans.

Etiology
The embryologic basic of MGDA is unclear. A defect in fetal fissure closure or a
primary mesenchymal abnormality has been hypothesized as embryonic origins of
morning glory anomaly.

Symptoms
Decreased vision most common in the involved eye
Color vision defect

Signs
 Visual acuity can range from normal vision to no light perception but in general is
approximately 20/100 to 20/200.
Strabismus
Leucokoria
Amblyopia
Myopia
Afferent pupil defect
VF defects, commonly enlarged blind spots
The optic disc is markedly enlarged, orange or pink in color, with a surrounding
annular ring of pigmented uveal tissues. Retinal vessels increased in number emanate
radially from the disc, a central white tuft of glial tissue. Macula may be incorporated
into the excavation (macular capture) (Fig. 7-2).
Serous retinal detachment (RD) in one-third of patients

Associated Conditions
Trans-sphenoidal basal encephalocele associated with midfacial anomalies
(hypertelorism, flat nasal bridge, midline notch in the upper lip, and sometimes a
midline cleft in the soft palate).
Midline or other brain abnormalities (e.g., agenesis of the corpus callosum, pituitary
abnormalities)
Ipsilateral abnormalities of the carotid circulation such as stenosis or aplasia of the
carotid arteries with or without Moyamoya syndrome (progressive stenosis of the
terminal portion of the internal carotid artery and its main branches)
Associated with ipsilateral orofacial hemangioma—this association may fall within
the spectrum of the PHACE syndrome (posterior fossa malformation, large facial
hemangioma, arterial anomalies, cardiac anomalies and aortic coarctation, and eye
anomalies)
Associated with neurofibromatosis type 2
MGDA has been described as part of the spectrum of renal coloboma syndrome.

Diagnostic Evaluation
MRI and magnetic resonance angiography should be obtained to rule out brain and
vascular abnormalities.
Rule out endocrine dysfunction (thyroid-stimulating hormone and growth hormone
levels) and kidney involvement (basic metabolic panel and urinalysis)

Differential Diagnosis
Optic nerve coloboma
Peripapillary staphyloma

Treatment
No treatment available to improve the vision in MGDA
Correction of refractive errors
Treatment for amblyopia if associated
RD is usually addressed with pars plana vitrectomy and long-standing gas
tamponade.

Prognosis
Vision is usually stable unless RD occurs. Optic neuritis and progressive optic
atrophy have been documented.
 FIGURE 7-2. Morning glory disc. Morning glory disc anomaly showing an enlarged excavation,
abnormal retinal vascular pattern, annular pigmentation surrounding the nerve head, and central glial tuft
and peripapillary changes. (Courtesy of Alex Levin, MD.)

OPTIC DISC COLOBOMA

Clearly demarcated bowl-shaped excavation of the optic disc, which is typically
decentered and deeper inferiorly.
Unilateral and bilateral optic disc coloboma occur with similar frequencies.
Occasionally involvement of the entire disc occurs.
Other types of uveal coloboma can coexist.
They may be isolated or part of a systemic syndrome.

Etiology
 Thought to result from incomplete or abnormal fusion of the two sides of the
proximal end of the embryonic fissure
Most cases are sporadic but may be autosomal dominant, autosomal recessive, or X-
linked recessive.
A wide variety of mutations have been documented in patients with coloboma
—CHD7 mutation is associated with 60% of cases of CHARGE syndrome.

Symptoms
Visual acuity may be mildly or severely decreased in one or both eyes—the degree
of foveal involvement by the coloboma is the only feature that relates to visual outcome.

Signs
White, bowl-shaped excavation that occurs in an enlarged optic disc. The excavation
is decentered inferiorly and the superior neuroretinal rim is relatively spared. In case of
complete excavation of the entire disc, the excavation is deeper inferiorly.
Chorioretinal coloboma can be associated—if so, microphthalmia is frequently
present
Iris and ciliary body colobomas often coexist.
Rhegmatogenous or serous RD may develop in some patients—rhegmatogenous are
often associated when chorioretinal coloboma, whereas serous detachment is more
common in case of isolated optic nerve coloboma.

Associated Conditions
CHARGE association: coloboma, choanal atresia, congenital heart disease, and
multiple other abnormalities
Walker-Warburg syndrome
Goltz focal dermal hypoplasia
Aicardi syndrome
Goldenhar sequence
Linear sebaceous nevus syndrome
Dandy-Walker malformation
Renal coloboma syndrome—with a mutation of PAX2 transcription
Microphthalmia—in case of chorioretinal involvement
Diagnostic Evaluation
Optical coherence tomography (OCT) has been useful in observing the intercalary
membrane that covers the chorioretinal defect and is continuous with the neural retina.
A complete systemic evaluation is important to rule out other associated anomalies.

Differential Diagnosis
MGDA
Peripapillary staphyloma

Treatment
No specific treatment is available for optic disc coloboma
Treatment for amblyopia, if associated
Optimal refractive correction may be indicated.
RD surgery as indicated

Prognosis
Vision is usually stable unless RD occurs

OPTIC DISC PITS

Optic disc pit (ODP) is an oval or round excavation of variable color, depth, and
location in the optic disc.
The temporal optic disc side is the most commonly involved.
Often unilateral, although bilateral cases have been reported in 15% of the cases.
They are rare, with an estimated incidence of 1 in 11,000 people.

Etiology
It is not entirely clear—they are thought to result from an imperfect closure of the
superior edge of the embryonic fissure.
Histologically, an ODP is a herniation of dysplastic retina into a collagen-rich
excavation that extends into the subarachnoid space through a defect in the lamina
cribrosa.
The pathogenesis of the macular changes is still controversial—the fluid may be
vitreous fluid, cerebrospinal fluid, leakage from blood vessels at the base of the pit, or
leakage from the choroid. Also, serous macular detachment is caused by direct
communication between the optic pit and the subretinal space or from the optic pit and
retina. In the latter case, fluid may move into the retina, causing a schisis-like separation
of the inner and outer layers, with the neurosensory serous RD occurring secondary to
this schisis. In addition, vitreous traction appears to be an important factor in the
pathogenesis of optic pit–related macular detachment.
ODPs are generally sporadic, although familial occurrence has been reported as a
dominant trait.

Symptoms
Optic pits are asymptomatic unless there is subretinal fluid—approximately 45% of
the eyes develop serous macular detachment usually in the second or third decades of
life. When subretinal fluid is present, visual acuity decreases to 20/40–20/60.

Signs
ODPs are usually seen as single, oval-shaped depressions at the optic disc. They are
most commonly found at the inferotemporal aspect of the optic disc, but may also be
found elsewhere, including centrally. Usually they are gray, white, or yellowish in color
(Fig. 7-3).
The signs associated with ODP maculopathy include intraretinal and subretinal fluid
accumulation, and retinal pigment changes.
Amblyopia in children especially in eye with serous macular detachment

Associated Conditions
Rarely associated with basal encephalocele

Diagnostic Evaluation
OCT to evaluate the subretinal fluid—typically OCT may show a schisis-like
separation between the inner and outer retina.
VF—arcuate scotoma is most common
Intravenous fluorescein angiography (IVFA) is helpful in the differential diagnosis of
serous detachment.
Amsler grid can be used to monitor the macular involvement.

Differential Diagnosis
 Optic disc anomalies such as choroidal and scleral crescent
Tilted disc syndrome (TDS)
Circumpapillary staphyloma
Hypoplastic disc
Glaucomatous optic neuropathy
Central serous retinopathy and subretinal neovascular membranes for serous macular
detachment

Treatment
No treatment is required for an isolated optic pit.
Laser photocoagulation (between the area of the serous RD and the optic disc),
macular buckling, and a combination of posterior vitrectomy, photocoagulation, and gas
tamponade are the commonly used procedures for the treatment of ODP maculopathy.
Less-invasive treatments like laser photocoagulation should be tried initially.

Prognosis
Isolated ODP has usually an excellent prognosis.
Associated retinal complications such as serous macular detachment can be
progressive and decrease significantly visual acuity—advice patients about the
importance of regular comprehensive eye exams and the use of Amsler grid testing.
Posterior macular reattachment can occur in rare instances.
 FIGURE 7-3. Optic disc pit. Congenital pit of the optic nerve head.

TILTED DISC SYNDROME

TDS is a congenital, nonhereditary bilateral condition where the optic nerve appears
to enter the eye in an oblique angle.
Elevated superior pole of the optic disc with posterior displacement of the inferior
nasal disc resulting in an oval appearance of the optic nerve head
Often accompanied by:
Scleral crescent located inferiorly and inferonasally (Fig. 7-4)
Situs inversus of retinal vessel
Posterior ectasia of the inferonasal retina and choroid
Typically associated with myopic astigmatism because of the fundus abnormalities
(posterior ectasia)

Etiology
Unknown, but may have some pathogenic relationship with colobomatous defect.

Symptoms
 Best corrected visual acuity (BCVA) may be reduced.

Signs
Myopic astigmatism
Tilted disc with associated features as previously described
VF defects are often associated with complete bitemporal hemianopia that does not
respect the midline. Repeat perimetry after addition of a −4.00 lens often eliminates the
VF abnormalities (refractive nature of the defects). In some cases, VF defects persist
despite refractive correction due to an abnormal inferonasal ectasia. However, TDS has
been reported with true bilateral hemianopsia and congenital suprasellar brain tumor.
Amblyopia

Associated Conditions
Suprasellar brain tumors
Tilted disc without retinal ectasia occurs in patients with trans-sphenoidal
encephalocele.
Craniofacial anomalies such as hypertelorism, Crouzon syndrome, and Alport
syndrome have been observed in association with tilted disc.
Other conditions reported with tilted disc are:
Ehler-Danlos type III
Hemifacial atrophy
Congenital horizontal gaze palsy
Familial dextrocardia
Exotropia

Diagnostic Evaluation
Refraction and dilated fundus exam—diagnosis can be made based on the
fundoscopic appearance of the optic disc.
VF often shows complete bitemporal hemianopia that does not respect the midline
(unlike chasmal lesions).
MRI brain in any patient with TDS and VF defects to rule out suprasellar tumors

Differential Diagnosis
ONH
 Optic nerve coloboma
Peripapillary staphyloma
Papilledema

Treatment
No medical treatment for the primary disorder
Appropriate refractive error correction
Amblyopia therapy as indicated may improve nonorganic visual loss.

Prognosis
Broad range of BCVA

FIGURE 7-4. Tilted disc. Note the temporal scleral crescent.

PERIPAPILLARY STAPHYLOMA
 Peripapillary staphyloma is a generally sporadic, rare, usually unilateral optic disc
anomaly characterized by a deep excavation of the area of the fundus surrounding the
optic disc.
Optic disc head sits at the base of the posterior pole excavation.
Not associated with glial or vascular abnormalities of the disc, uveal coloboma, and
progression
Affected eyes typically are emmetropic or slightly myopic, although high myopia has
been reported.

Etiology
The etiology is unknown. It appears to arise as incomplete differentiation of sclera.
Staphyloma may be the consequence of the development of normal intraocular pressure
causing scleral herniation.

Symptoms
Visual acuity is usually mildly or severely reduced.

Signs
Peripapillary staphyloma is usually associated with a relatively normal appearance
of the optic disc.
Centrocecal scotomas commonly occur in eyes with decreased vision.

Associated Conditions
Usually absence of associated systemic abnormalities or intracranial diseases
Peripapillary staphyloma has been reported to be associated with basal
encephalocele in patients with midfacial abnormalities.
PHACE syndrome, linear nevus sebaceous syndrome, and 18q-syndrome have been
observed in association with peripapillary staphyloma.
Nystagmus, strabismus, and head turn
Increased risk of RD

Diagnostic Evaluation
Ocular ultrasound and electroretinogram (ERG) can help the diagnosis especially in
pediatric patients.
OCT can be used to evaluate a peripapillary staphyloma.
 VF can show a centrocecal scotoma especially in eyes with decreased vision.
MRI of the brain is indicated for children with midfacial abnormalities.

Differential Diagnosis
MGDA
Optic disc coloboma
TDS

Treatment
No medical treatment for the primary disorder
Amblyopia therapy and strabismus surgery as needed
RD surgery as indicated
Consider polycarbonate eye glasses.

Prognosis
Risk of RD

OPTIC DISC DRUSEN (PSEUDOPAPILLEDEMA)

Optic disc drusen are acellular calcific deposits located within the optic nerve head.
Optic drusen are typically buried in the optic disc early in life and become more
superficial later.
Often bilaterally
Most common form of pseudopapilledema—anomalous elevation of the optic disc
unrelated to increased intracranial pressure

Etiology
The etiology is unknown—they are thought to result by a disturbance in axonal
metabolism with slowed axoplasmic flow, congenitally dysplastic discs with a
propensity for drusen formation, or a small scleral canal that physically compresses the
optic nerve, causing ganglion cell death, with extrusion and calcification of
mitochondria.
Optic drusen may be transmitted as an irregular dominant trait—they are frequently
familial.
Symptoms
Usually asymptomatic with no visual complaints
Rarely (especially in children) transient visual obscuration—probably secondary to
transient disc ischemia

Signs
Disc is often elevated and its margins are blurred and obscured.
Disc vessel is clearly visible, without hyperemia, dilated capillaries, or venous
congestion.
Absence of exudates and cotton wool spots
Retinal vasculature of eyes is frequently anomalous—higher frequency of cilioretinal
arteries
Afferent pupillary defect and acquired dyschromatopsia may be present and they are
signs of an optic neuropathy.
VF can show peripheral defects that tend to increase in frequency with increasing
age. The progression is generally slow. The most common VF defects are nasal defect,
concentric constriction, and enlarged blind spot.
Peripapillary or disc hemorrhage, choroidal neovascular membrane (CNVM),
nonarteritic anterior ischemic optic neuropathy (NAION), and retinal artery or vein
occlusion can be complications of optic disc drusen.

Associated Conditions
Optic disc drusen have been reported in association with many ocular and systemic
disorders.
Space-occupying lesions have been harbored with optic disc drusen and progressive
visual loss.
The most commonly associated conditions are:
Retinitis pigmentosa
Pseudoxanthoma elasticum and angioid streaks
Alagille syndrome

Diagnostic Evaluation
B scan ultrasonography: drusen appear with high reflectivity and posterior
shadowing
Fundus autofluorescence: drusen display autofluorescence (poor reliability in buried
drusen)
Fluorescein angiography: drusen stain in late stage. Helpful to distinguish between
optic disc drusen and true optic disc edema
OCT: focal hyper reflective mass posterior to the outer plexiform and outer nuclear
layers, with loss of the inner and outer segment photoreceptor junction (poor reliability
at distinguishing buried drusen vs. true optic disc edema)
VF testing should be performed as soon as children can do so reliably.
Orbital CT—calcification in optic disc
MRI brain in any patient with associated progressive visual loss

Differential Diagnosis
Optic neuritis
Posterior scleritis
Toxoplasmosis
Idiopathic intracranial hypertension
Ischemic optic neuropathy
Compressive optic neuropathy
Optic nerve infiltrates
Papilledema
Sarcoidosis
Optic nerve tumors
Leber hereditary optic neuropathy

Treatment
Drusen alone need no medical therapy.
CNVMs may require laser photocoagulation or intravitreal anti-VEGF.
Ischemic complications (NAION and retinal vascular occlusions) managed in the
absence of drusen

Prognosis
Usually very good but complications can occur
 VF defects are identified in up to 51% of children and become more common with
increasing age.
Hemorrhagic complications—peripapillary or disc hemorrhage
CNVM
NAION
Retinal artery or vein occlusion

REFERENCES
Dutton GN. Congenital disorders of the optic nerve: excavations and hypoplasia [review]. Eye (Lond).
2004;18(11):1038–1048.
Hoyt C, Taylor D. Pediatric Ophthalmology and Strabismus. 4th ed. St. Louis, MO: Elsevier Saunders; 2013:543–560.
Maguire JI, Murchison AP, Jaeger EA. Wills Eye Hospital 5-Minute Ophthalmology Consult. Philadelphia, PA:
Lippincott Williams & Wilkins; 2012.
 CHAPTER
8

Retinal Anomalies
BEST DISEASE

Barry N. Wasserman ■
Etiology
An autosomal dominant disorder also called vitelliform macular dystrophy, Best
disease leads to retinal pigment epithelium (RPE) degeneration and secondary loss of
photoreceptors in the macula. Mutations lead to abnormal bestrophin, a Ca2+ sensitive
Cl− channel protein. Lipofuscin accumulates in the RPE cells yielding a characteristic
“egg yolk” appearance (hence the name vitelliform) in the fovea and macula. Multifocal
lesions may also occur. Several genes have been identified, including the BEST1 and
PRPH2, which is associated with an adult form. In families negative for these genes,
IMPG1 and IMPG2 genes have been identified as causal.

Symptoms
Early in the disease process, patients may be asymptomatic, but later metamorphopsia
and decreased visual acuity occur. Symptoms are variable and may be asymmetric, with
significant vision loss in adulthood.

Signs
Stages are described on the basis of phenotypic appearance in the macula, which may
be asymmetric between the eyes. Early stage may only reveal subtle RPE mottling or
may be normal. Later, yellow-orange material collects in the macula as a 0.5-to-5.0-
mm-diameter lesion, yielding the classic “egg yolk” appearance. Clear fluid slowly
builds around the lesion in the subretinal space, with resultant cystic appearance with
fluid level (Fig. 8-1A). As this fluid dissipates, the lesion again changes to a more
“scrambled egg” (vitelliruptive) stage, associated with pigment clumping (Fig. 8-1B).
Later stages include atrophic changes with fibrosis, macular degeneration, and
significant vision loss, followed sometimes with choroidal neovascularization.

Differential Diagnosis
Stargardt disease
Sorsby macular dystrophy
Pattern dystrophy
North Carolina macular dystrophy
Solar retinopathy
Coalescence of basal laminar drusen
Central serous retinopathy with fibrinous exudate
Pigment epithelial detachment of age-related macular degeneration
Adult foveomacular dystrophy
Age-related macular degeneration

Diagnostic Evaluation
Diagnosis is based on clinical findings, along with electrophysiologic studies revealing
normal electroretinogram and abnormal electrooculogram. In addition, there is high
autofluorescence. Optical coherence tomography (OCT) detects subretinal deposits and
fluid. Genetic studies may reveal mutation in the bestrophin gene.

Treatment
No treatment for early disease, but late choroidal neovascularization has been treated
with intravitreal injection of bevacizumab. Genetic counseling and examination of
family members are recommended, as are low vision and occupational consultations.

Prognosis
Some patients maintain good vision (20/40) throughout life. In others, good vision
(20/20 to 20/50) usually persists through the early stages but decreases to 20/200 in the
fifth and sixth decades as the atrophic and cicatricial stages progress.

REFERENCES
Goodwin P. Hereditary retinal disease. Curr Opin Ophthalmol. 2008;19:255–262.
Leu J, Schrage NF, Degenring RF. Choroidal neovascularisation secondary to Best’s disease in a 13-year-old boy
treated by intravitreal bevacizumab. Graefes Arch Clin Exp Ophthalmol. 2007;245(11):1723–1725.
Meunier I, Manes G, Bocquet B, et al. Frequency and clinical pattern of vitelliform macular dystrophy caused by
mutations of interphotoreceptor matrix IMPG1 and IMPG2 genes. Ophthalmology. 2014;121:2406–2414.
Spaide RF, Noble K, Morgan A, et al. Vitelliform macular dystrophy. Ophthalmology. 2006;113:1392–1400.

FIGURE 8-1. Best disease. A. Best disease with early macular “egg yolk” appearance. B. Best
disease with later scrambled-egg appearance.

CHOROIDEREMIA

Barry N. Wasserman ■
Etiology
An X-linked recessive disease, choroideremia is a progressive retinal degeneration.
Males carriers show loss of choriocapillaris and RPE. Female carriers can show mild
signs of the disease, with patchy retinal abnormalities and corresponding visual field
(VF) defects due to Lyonization, but are generally asymptomatic. Mutation in the CHM
gene affects production of the Rab escort protein 1 (REP-1). Degeneration begins in the
midperiphery and progresses centrally both toward the macula and toward the
periphery.

Symptoms
Patients present in the first two decades of life with early loss of night vision and
peripheral vision. Central vision may be maintained until around the fifth decade but is
eventually lost.
Signs
Retinal examination reveals loss of the RPE and choriocapillaris, with exposure of the
larger choroidal vessels (Fig. 8-2). Remaining RPE may have a salt-and-pepper
appearance. Later in the disease, large areas of exposed sclera may be seen on
fundoscopy. Posterior subcapsular cataracts may be associated.

Differential Diagnosis
Advanced retinitis pigmentosa
Gyrate atrophy
Pathologic myopia
Chorioretinitis (e.g., acute retinal necrosis, following cytomegalovirus [CMV]
retinitis)

Diagnostic Evaluation
X-linked inheritance with typical fundus appearance is seen in male patients. VF testing
demonstrates constriction. Fluorescein angiography reveals large choroidal vessels due
to loss of overlying RPE and choriocapillaris. Electroretinogram may be consistent with
a rod–cone dystrophy early in the disease but eventually becomes extinguished. Genetic
analysis to assess mutation in the CHM gene may be performed, and analysis of
peripheral blood is available to demonstrate absence of the Rab escort protein 1.
Female carriers may demonstrate patches of irregular pigmentation in the RPE. SD-
OCT may demonstrate reduced subfoveal choroidal thickness and increased foveal
thickness as the disease progresses, despite unchanged visual acuity.

Treatment
Genetic counseling for family members should be suggested. Low vision evaluation and
treatment may be helpful. Gene therapy has shown some success in animal models.

Prognosis
Patients progressively lose night and peripheral vision. Central vision is often
maintained into adulthood but is ultimately lost.

REFERENCES
Kamron KN, Islam F, Moore AT, et al. Clinical and genetic features of choroideremia in childhood. Ophthalmology.
2016;123(10):2158–2165.
Lee TK, McTaggart KE, Sieving PA, et al. Clinical diagnoses that overlap with choroideremia. Can J Ophthalmol.
 2003;38(5):364–372.
MacDonald IM, Russell L, Chan CC. Choroideremia: new findings from ocular pathology and review of recent
literature. Surv Ophthalmol. 2009;54(3):401–407.
MacDonald IM, Smaoui N, Seabra MC. Choroideremia. In: Pagon RA, Bird TC, Dolan CR, Stephens K, eds.
GeneReviews [Online]. Seattle: University of Washington; 2010.

FIGURE 8-2. Choroideremia. Choroideremia at advanced stage, with complete loss of retinal pigment
epithelium and choriocapillaris.

GYRATE ATROPHY

Barry N. Wasserman ■
Etiology
Gyrate atrophy is an autosomal recessive disease caused by the deficiency of the
mitochondrial enzyme, ornithine aminotransferase. Elevated ornithine levels are toxic to
the RPE, causing gradual loss of peripheral vision and night vision. Mutations of the
ornithine aminotransferase gene (10q26) have been identified.

Symptoms
Nyctalopia and loss of visual field may begin in the first two decades but may not be
manifest until the fifth decade. The disease affects both eyes symmetrically. Central
vision is spared usually until the fourth or fifth decade but then declines. Symptoms and
signs may vary widely in patients in all age groups.

Signs
Fundus examination early in the disease shows scalloped areas of geographic atrophic
RPE and choriocapillaris (Fig. 8-3). The macula is relatively spared until late in the
disease, though epiretinal membranes and cystoid macular edema can occur. Patients
may have cataracts and myopia.

Differential Diagnosis
Choroideremia
Retinitis pigmentosa
Choroidal atrophy
Chorioretinitis (e.g., acute retinal necrosis, following CMV retinitis)

Diagnostic Evaluation
Ocular examination may reveal mildly decreased visual acuity, and refractive error is
commonly myopic. Cataracts may be seen on slit-lamp evaluation. Fundoscopy shows
midperipheral and peripheral scalloped geographic areas of RPE and choriocapillaris.
Areas of intact RPE may have increased pigmentation. The macula is usually spared
early in the disease, but cystoid macular edema may be demonstrated with OCT. Optic
atrophy and attenuated retinal vessels are seen later in the disease. VFs are markedly
constricted, and electroretinogram reveals absent photopic and scotopic responses. SD-
OCT may demonstrate intraretinal cystic spaces and hyperreflective deposits in the
ganglion cell layer. Outer retinal tubulations are round tubular, rosette-like structures
found in the outer nuclear layer of some patients with advanced disease. Plasma
ornithine levels are markedly elevated.

Treatment
Genetic counseling is suggested. A diet restricting arginine will lower the plasma
ornithine and may slow the loss of visual function. Low vision services should be
recommended.

Prognosis
Although dietary arginine restriction delays the loss of function, the macula is eventually
affected in most patients.

REFERENCES
Kaiser-Kupfer MI, Caruso RC, Valle D, et al. Use of an arginine-restricted diet to slow progression of visual loss in
patients with gyrate atrophy. Arch Ophthalmol. 2004;122:982–984.
Peltola KE, Nanto-Salonen K, Heinonen OJ, et al. Ophthalmologic heterogeneity in subjects with gyrate atrophy of
choroid and retina harboring the L402P mutation of ornithine aminotransferase. Ophthalmology. 2001;108:721–729.
Sergouniotis PI, Davidson AE, Lenassi E, et al. Retinal structure, function, and molecular pathologic features in gyrate
atrophy. Ophthalmology. 2012;119(3):596–605.
Tamara TL, Andrade RE, Muccioli C, et al. Cystoid macular edema in gyrate atrophy of the choroid and retina: a
fluorescein angiography and optical coherence tomography evaluation. Am J Ophthalmol. 2005;140:147–149.
 FIGURE 8-3. Gyrate atrophy. Gyrate atrophy with scalloped geographic atrophy of the retinal pigment
epithelium and choriocapillaris. The macula is spared early in the disease.

LEBER CONGENITAL AMAUROSIS

Barry N. Wasserman ■
Etiology
Leber congenital amaurosis is a severe congenital retinal dystrophy affecting both cones
and rods. Vision is often less than 20/200. Mutations in over 14 genes have been
identified. The disease is mainly autosomal recessive and rarely autosomal dominant.

Symptoms and Signs

Patients present with nystagmus at 2 to 3 months of age. Children show poor visual
behavior and some show self-stimulatory eye poking (oculodigital reflex). Pupils may
be sluggish or paradoxical. Ophthalmoscopic findings are highly variable and may
include a normal fundus appearance. Highly abnormal findings may also include
chorioretinal atrophy, macular “coloboma” (Fig. 8-4A), retinal pigment epithelial
irregularities, leopard spotting, nummular pigmentary abnormalities (Fig. 8-4B), and
subretinal flecks. Retinal vessel attenuation and optic disc pallor are frequently present.
Cataract, keratoconus, and strabismus may be associated findings.

Differential Diagnosis
Achromatopsia
Cone dystrophy
Goldmann-Favre disease
Refsum phytanic acid storage disease
Bassen-Kornzweig (abetalipoproteinemia) syndrome
Juvenile retinal dystrophy
Toxoplasmosis (when macular “coloboma” is present)

Diagnostic Evaluation
Family history may reveal consanguinity or distantly related affected individuals.
Examination including retinal evaluation, combined with extinguished electroretinogram
findings, is diagnostic. Molecular genetic mutation screens are now available. Systemic
and blood testing are important to rule out treatable causes, like Refsum phytanic acid
storage disease. As there may be associated abnormalities of kidneys, liver, or hearing,
appropriate testing is recommended.

Treatment
Low vision evaluation and treatment can aid in function in some patients. Gene transfer
via subretinal administration of adeno-associated viral (AAV) vectors encoding has
demonstrated safety and in some cases efficacy for patients with mutations in the gene
RPE65. RPE65 mutations account for 6% to 16% of Leber congenital amaurosis, and
treatment with recombinant AAV vector expressing RPE65 has not been associated with
serious adverse events, and follow-up studies reveal durable improvement in some
patients. The magnitude of improvement did decline with time in some patients in early
studies.

Prognosis
Vision for most patients is poor. Future advances in gene therapy are promising.

REFERENCES
Goodwin P. Hereditary retinal disease. Curr Opin Ophthalmol. 2008;19:255–262.
Simonelli F, Maguire AM, Testa F, et al. Gene therapy for Leber’s congenital amaurosis is safe and effective through
1.5 years after vector administration. Mol Ther. 2010;18(3):643–650.
Traboulsi EI. The Marshall M. Parks memorial lecture: making sense of early-onset childhood retinal dystrophies—the
clinical phenotype of Leber congenital amaurosis. Br J Ophthalmol. 2010;94(10):1281–1287.
Weleber RG, Pennesi ME, Wilson DJ, et al. Results at 2 years after gene therapy for RPE65-deficient Leber
congenital amaurosis and severe early childhood onset retinal dystrophy. Ophthalmology. 2016;123(7):1606–1620.
 FIGURE 8-4. Leber congenital amaurosis. Leber congenital amaurosis with macular “coloboma”
(A) and nummular pigmentary abnormalities (B).

ASTROCYTIC HAMARTOMA

Anuradha Ganesh ■
Retinal astrocytic hamartoma is a glial tumor arising from the retinal nerve fiber layer.
It is most frequently associated with tuberous sclerosis (Bourneville disease) but may
very rarely be seen in neurofibromatosis or as an isolated ocular finding in otherwise
normal individuals.
Astrocytic hamartomas are believed to be congenital in most cases but may not be
recognized until later in childhood. Patients with these lesions are usually
asymptomatic.

Epidemiology and Etiology

Most astrocytic hamartomas occur congenitally in association with tuberous sclerosis, a
phakomatosis characterized by the triad of seizures, mental retardation, and skin lesions.
Tuberous sclerosis has an estimated incidence of 1 in 15,000 to 100,000 and exhibits
autosomal dominant inheritance. About 60% of cases are spontaneous mutations.
Mutations in either the TSC1 or TSC2 gene, on chromosomes 9q34 and 16p13,
respectively, result in tuberous sclerosis (Table 8-1).

Signs
About 50% of patients with tuberous sclerosis develop astrocytic hamartomas,
approximately 50% of whom have bilateral involvement. Retinal astrocytic hamartomas
are usually small, ranging from 0.5 to 5.0 mm in diameter, and are principally of two
types. Small, flat, smooth tumors appear as subtle, ill-defined, semitranslucent
thickening of the nerve fiber layer (Fig. 8-5A). Over time, they may become more
opaque and contain calcification and may be associated with subretinal fluid and
cystoid retinal edema. Larger, opaque, calcified, sessile, whitish-yellow nodular
masses (“mulberry lesion”) are found at the optic nerve (Fig. 8-5B). VF testing may
reveal a scotoma in the area corresponding to the tumor. SD-OCT shows these lesions
as “moth eaten” optically empty spaces arising from the nerve fiber layer.
TABLE 8-1. Typical Manifestations of Tuberous Sclerosis

Skin lesions (<95% incidence)

Hypomelanotic macules
Facial angiofibromas (adenoma sebaceum)
Brain
Seizures (<90% incidence)
Developmental delay (<60% incidence)
Additional manifestations
Periungual fibromas
Pleural cysts and spontaneous pneumothorax
Renal angiomyolipoma
Cardiac rhabdomyoma
Hamartomas of the liver, thyroid, pancreas, or testis

Occasionally, lesions may produce vitreous hemorrhage, vitreous seeding, subretinal

hemorrhage, or retinal detachment. Presence of yellow, lipoproteinaceous exudation in
the sensory retina and subretinal space is an uncommon feature.
Less frequent ocular manifestations include patches of iris or RPE hypopigmentation
and hamartomas of the iris and ciliary body.
Patients with an astrocytic hamartoma of the retina or optic nerve should be evaluated
for tuberous sclerosis, which is characterized by the triad of skin lesions, seizures, and
mental retardation. Additional manifestations include hamartomas in various organ
systems. Diagnostic criteria for tuberous sclerosis facilitate identifying definite,
probable, and possible cases.

Differential Diagnosis
Retinoblastoma
Retinocytoma
Myelinated nerve fibers
Retinal or optic nerve granuloma
Drusen of the optic nerve
Papillitis/papilledema
Optic nerve infiltration (e.g., tuberculosis, sarcoid, leukemia)
Diagnostic Evaluation
OCT: The astrocytic hamartoma replaces normal retinal architecture and appears as
an optically hyperreflective mass with retinal disorganization, moth-eaten spaces, and
posterior shadowing.
Fluorescein angiography: The tumor appears relatively hypofluorescent in the
arterial phase. Superficial find blood vessels are seen during the venous phase. The
tumor stains intensely and homogeneously in the late phases. This test is rarely
indicated.
B-scan ultrasonography: A larger, calcified lesion often appears as a discrete, oval,
solid mass with a sharp anterior border.
Biopsy: In rare cases, differentiation from retinoblastoma (young patient) or
choroidal melanoma (older patient) requires fine-needle aspiration biopsy.
Imaging/ultrasonography: To detect astrocytomas in the brain and other parts of the
body including chest and abdomen.

Treatment and Prognosis

Most cases of retinal astrocytoma are asymptomatic and do not require treatment.
Rarely some tumors can exhibit aggressive behavior and cause hemorrhage, retinal
detachment, and, even more uncommonly, neovascular glaucoma. Serial follow-up is
indicated. Retinal detachment can be treated with demarcating laser photocoagulation.
Progressive lesions may require measures such as endoresection, brachytherapy, and at
times enucleation. Family members should be examined for manifestations of tuberous
sclerosis. Genetic testing may be useful in confirming the diagnosis and identifying
affected relatives, allowing for early detection of problems associated with tuberous
sclerosis, thus leading to earlier treatment and better outcomes.

REFERENCES
Northrup H, Sing Au K. Tuberous sclerosis complex Bourneville disease. In: Pagon RA, Bird TC, Dolan CR, et al,
eds. GeneReviews. Seattle: University of Washington; 2009.
Roach ES, Sparagana SP. Diagnosis of tuberous sclerosis complex. J Child Neurol. 2004;19:643–649.
Shields CL, Benevides R, Materin MA, et al. Optical coherence tomography of retinal astrocytic hamartoma in 15
cases. Ophthalmology. 2006;113:1553–1557.
Shields CL, Say EA, Fuller T, et al. Retinal astrocytic hamartoma arises in nerve fiber layer and shows “moth-eaten”
optically empty spaces on optical coherence tomography. Ophthalmology. 2016;123:1809–1816.
Shields JA, Eagle Jr RC, Shields CL, et al. Aggressive retinal astrocytomas in 4 patients with tuberous sclerosis
complex. Arch Ophthalmol. 2005;123:856–863.
Shields JA, Shields CL. Atlas of Intraocular Tumors. Philadelphia, PA: Lippincott Williams and Wilkins; 1999:269–286.
 FIGURE 8-5. Astrocytic hamartoma. A. Small, ill-defined thickening of the nerve fiber layer. The
arrows indicate the edge of the lesion. B. Large, opaque, calcified, sessile, whitish-yellow nodular mass
(“mulberry lesion”) at the optic nerve.

INCONTINENTIA PIGMENTI

Anuradha Ganesh and Alex V. Levin ■

Incontinentia pigmenti (IP), or Bloch-Sulzberger syndrome, is a rare X-linked dominant
disorder of skin pigmentation that is accompanied by ocular, dental, and central nervous
system (CNS) manifestations.

Epidemiology and Etiology

The incidence of incontinentia pigmenti is 1/40,000 live births. In most cases,
incontinentia pigmenti is caused by mutations in the NEMO (NF-kappa-B essential
modulator) gene at chromosome Xq28. As an X-linked dominant condition, it is usually
lethal in males and thus is only seen in female infants. An affected male with Klinefelter
syndrome (XXY) or genetic mosaicism may rarely survive. Incontinentia pigmenti
refers to the histologic feature of “incontinence” of melanocytes in the basal layer of the
epidermis of their pigment, which is then found in the superficial dermis.

History
Characteristic skin lesions are usually present at birth. Ophthalmic findings are noted in
infancy or sometimes later in life. A pedigree may reveal a history of male fetus
miscarriages.

Signs
The hallmark of ophthalmic involvement, present in over 40% of patients, is peripheral
retinal capillary nonperfusion (Fig. 8-6). This avascular retina may be demarcated by an
intervening peripheral ring of neovascularization or otherwise abnormal retinal vessels,
reminiscent of the clinical findings in retinopathy of prematurity. Retinal ischemia leads
to the arteriovenous anastomoses and neovascularization. The disease may resolve
spontaneously, but 10% of infants develop retinal folds, traction, and rhegmatogenous
retinal detachment with consequent visual impairment. The ocular abnormalities are
often asymmetric. Other eye findings are largely secondary and include strabismus in
one-third of infants, cataracts, and retinal pigmentary changes with mottled, diffuse
hypopigmentation, and foveal hypoplasia.
Skin findings include vesicular eruptions at birth that later evolve into desquamating
erythematous lesions (Fig. 8-7A) followed by swirling hyperpigmentation (marble-cake
appearance; Fig. 8-7B) and then scarring. Dental abnormalities occur in over 90% of
affected individuals and include hypodontia, delayed eruption, and malformed, cone-
shaped crowns. Associated CNS abnormalities include seizures, spastic paralysis, and
mental retardation.

Differential Diagnosis
Retinopathy of prematurity
Familial exudative vitreoretinopathy
Sickle cell disease (in older children)
Other causes of infantile retinal nonattachment or detachment should also be
considered.

Diagnostic Evaluation
The diagnosis of incontinentia pigmenti is based on clinical criteria (Table 8-2). Tests
that may help in confirming the diagnosis include skin biopsy (although there is a wide
differential diagnosis for the findings described earlier), neuroimaging (cerebral
atrophy, agenesis of corpus callosum), fluorescein angiography (avascular peripheral
retina, anomalous vessels in vascular-avascular junction), and genetic testing (for
mutations in the NEMO gene). Careful skin, dental, and ocular examination of the
patient’s mother may be useful as variable expression.

Treatment and Prognosis

Patients with incontinentia pigmenti require careful retinal examination early in infancy
to detect peripheral retinal nonperfusion. If present, frequent follow-up is indicated to
enable early detection of change that might suggest development of retinal
neovascularization, vascular leakage, and traction. No treatment is indicated unless such
changes develop, in which case laser photocoagulation is performed in an effort to
prevent progression to retinal traction and detachment. One long-term follow-up study
indicated a bimodal distribution of retinal detachments, with early childhood traction
retinal detachments in some patients and later adult rhegmatogenous retinal detachments.
Lifetime follow-up is needed. Genetic counseling is also highly recommended.

TABLE 8-2. Diagnostic Criteria for Incontinentia Pigmenti

Major Criteria
Four stages of skin lesions from infancy to adulthood:
A. Linear vesicles and bullae of stage 1
B. Dark brown colored verrucous papules and plaques of stage 2
C. Light brown colored swirling hyperpigmentation of stage 3
D. White atrophic patches of stage 4
Minor Criteria
A. Teeth: hypodontia, anodontia, or microdontia
B. Hair: alopecia, wiry hair
C. Nails: mild ridging or pitting
D. Retina: peripheral neovascularization

The clinical diagnosis of incontinentia pigmenti can be made if at least one of the major criteria is present. The
presence of minor criteria supports the clinical diagnosis; the complete absence of minor criteria should raise doubt
regarding the diagnosis.
Adapted from Landy SJ, Donnai D. Incontinentia pigmenti (Bloch-Sulzberger syndrome). J Med Genet. 1993;30:53–
59.

REFERENCES
Chen CJ, Han IC, Tian J, et al. Extended follow-up of treated and untreated retinopathy in incontinentia pigmenti:
analysis of peripheral vascular changes and incidence of retinal detachment. JAMA Ophthalmol. 2015;133:542–548.
Holmstrom G, Thoren K. Ocular manifestations of incontinentia pigmenti. Acta Ophthalmol Scand. 2000;78:348–353.
Landy SJ, Donnai D. Incontinentia pigmenti (Bloch-Sulzberger syndrome). J Med Genet. 1993;30:53–59.
Scheuerle A, Ursini MV. Incontinentia pigmenti (Bloch-Sulzberger syndrome). In: Pagon RA, Bird TC, Dolan CR,
Stephens K, eds. GeneReviews. Seattle, WA: University of Washington; 2010.
Smahi A, Courtois G, Vabres P, et al. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause
of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature. 2000;405:466–472.
FIGURE 8-6. Incontinentia Pigmenti (IP). Fundus of a patient with IP showing peripheral retinal
capillary nonperfusion (asterisk), arteriovenous anastomoses (arrows), and exudates (arrowhead).
FIGURE 8-7. Skin findings in Incontinentia Pigmenti (IP). Vesicular and desquamating
erythematous lesions in an infant with IP (A) and swirling hyperpigmentation (“marble-cake”
appearance) (B).
COATS DISEASE

Barry N. Wasserman and Carol L. Shields ■

Coats disease is a nonhereditary condition characterized by unilateral retinal
telangiectasia, exudation, and exudative retinal detachment that occurs most often in
young patients.

Etiology
Coats disease is more common in males and generally occurs as a unilateral trait. The
average age at onset is 2 to 8 years. Telangiectatic arterioles or venules lead to
subretinal and intraretinal exudation of fluid and lipid, which eventually leads to
exudative retinal detachment and vision loss. There is some evidence that Coats disease
is related to a somatic mutation in the Norrie disease protein (NDP) gene or the frizzled
4 gene (FZD4).

Symptoms
The symptoms include painless vision loss, particularly when the disease occurs at an
older age. Younger patients often present with strabismus or xanthocoria. Rarely,
patients manifest neovascular glaucoma and a red, painful eye. In an analysis of 150
cases of Coats disease, the symptoms included decreased visual acuity (43%),
strabismus (23%), xanthocoria (20%), pain (3%), heterochromia (1%), nystagmus
(1%), and no symptoms (8%).

Signs
The findings in Coats disease include telangiectasia (100%), retinal exudation (99%),
exudative retinal detachment (81%), retinal hemorrhage (13%), retinal macrocyst
(11%), vasoproliferative tumor (6%), and neovascularization of disc (2%), retina (1%),
and iris (8%). Anterior chamber cholesterolosis occurs in 3% of cases.

Differential Diagnosis
Retinoblastoma
Retinopathy of prematurity
Retinal hemangioblastoma
Retinal vasoproliferative tumor
 Sickle cell retinopathy
Familial exudative vitreoretinopathy
Toxocariasis
Leukemia
Persistent fetal vasculature (persistent hyperplastic primary vitreous)
Radiation retinopathy
Retinopathy of hypertensive crisis
Cataract
Coloboma

Diagnostic Evaluation
The diagnosis is established by recognition of the clinical features on ophthalmoscopy.
Retinal telangiectatic vessels with fusiform and nodular vascular dilation and adjacent
nonperfusion are found, classically in the temporal quadrant. Related intraretinal and
subretinal exudation is noted and often retinal detachment is found (Figs. 8-8 and 8-9).
Fluorescein angiography confirms these findings and additionally reveals vascular
leakage and macular edema. The classification of Coats disease, proposed by Shields et
al, is:
Stage 1: Retinal telangiectasia (T)
Stage 2: T + exudation (E)
Stage 3: T + E + subretinal fluid (F)
Stage 4: T + E + F + neovascular glaucoma (G)
Stage 5: T + E + F + G + phthisis bulbi

Treatment
Laser photocoagulation and cryotherapy are used to obliterate leaking vessels. The role
of intravitreal antivascular endothelial growth factors is being explored. Pars plana
vitrectomy with drainage of subretinal fluid and exudation is used for advanced cases.

Prognosis
Visual prognosis is often poor. In one analysis of 150 cases, poor visual acuity of
20/200 or worse was found in no patient with stage 1 disease, whereas 50% of stage 2,
70% of stage 3, and 100% of stages 4 and 5 show poor vision. The goal of treatment is
stabilization of the eye with resolution of retinal detachment and exudation and
prevention of neovascular glaucoma and loss of the eye. There are no systemic
implications. However, patients with bilateral “Coats” disease should be evaluated for
systemic syndromes.

REFERENCES
Morris B, Foot B, Mulvihill A. A population-based study of Coats disease in the United Kingdom I: epidemiology and
clinical features at diagnosis. Eye (Lond). 2010;24(12):1797–1801.
Mulvihill A, Morris B. A population-based study of Coats disease in the United Kingdom II: investigation, treatment,
and outcomes. Eye (Lond). 2010;4(12):1802–1807.
Shields JA, Shields CL Honavar S, Demirci H. Coats disease. Clinical variations and complications of Coats’ disease
in 150 cases. The 2000 Sanford Gifford Memorial Lecture. Am J Ophthalmol. 2001;131:561–571.
Shields JA, Shields CL, Honavar SG, et al. Classification and management of Coats disease. The 2000 Proctor lecture.
Am J Ophthalmol. 2001;131:572–583.
FIGURE 8-8. Coats disease. Coats disease (stage 2) with mild temporal macular exudation (A) from
telangiectatic vessels (B) that showed resolution following therapy (C) with cryotherapy and laser
photocoagulation, allowing for good visual acuity.
 FIGURE 8-9. Coats disease. Coats disease (stage 3) with xanthocoria (A) from massive subretinal
exudation (B) and leaking retinal telangiectasia (C).

RETINOBLASTOMA

Carol L. Shields ■
R etinoblastoma is the most common intraocular malignancy of children. It accounts
for 4% of all childhood cancers. It is grouped into unilateral or bilateral
involvement and subgrouped into sporadic or familial predisposition. This tumor
manifests in young children, often those within the first year of life. Worldwide, it is
estimated that there are approximately 7202 children per year with retinoblastoma
distributed in Asia excluding Japan (4027), Africa (1792), Latin America/Caribbean
(622), Europe (414), North America (258), Japan (59), and Oceania (21).

Etiology
Retinoblastoma occurs in approximately 1 in 15,000 live births. Children with bilateral
retinoblastoma are typically diagnosed around 12 months and those with unilateral
retinoblastoma around 18 months. There is no race or gender predilection.
Approximately 2/3 of all cases are unilateral and 1/3 are bilateral.
Retinoblastoma results from mutation of the Rb gene located on chromosome 13q14. In
1971, Knudson’s “two-hit” hypothesis for the development of retinoblastoma was
proposed. In 1980, research confirmed that both alleles of retinoblastoma gene (RB1) at
chromosome 13q14 locus were mutated in retinoblastoma. Currently, there are
arguments that genomic instability and aneuploidy are likely responsible for the genesis
of Rb.
Bilateral and familial retinoblastomas arise from germ line mutation in the
retinoblastoma gene whereas unilateral disease is more often a result of somatic
mutation but can result from germ line mutation in 15% of cases. Germ line mutation
retinoblastoma tends to be multifocal and can be associated with systemic cancers such
as pinealoblastoma and remote cancers. A small subset of retinoblastoma patients
display the 13q syndrome which occurs from the mutation on chromosome 13 and
involves features of microcephaly, broad nasal bridge, hypertelorism, microphthalmos,
epicanthus, ptosis, micrognathia, short neck, low-set ears, facial asymmetry, anogenital
malformations, hypoplastic thumbs and toes, and mental and psychomotor retardation.
Symptoms
Retinoblastoma most often presents quietly with the painless development of leukocoria
or strabismus (Fig. 8-10). It is most often discovered by the parents or grandparents
more so than pediatricians. Occasionally, the child might have pain from secondary
glaucoma that manifests in about 17% of patients. Rarely does the child complain of
vision loss.

Signs
The anterior segment classically displays leukocoria, and this feature is more prominent
relative to tumor size. Neovascularization of the iris is occasionally found.
Fundoscopically, retinoblastoma appears as a solid, yellow-white tumor within the
retina. It can appear with different growth patterns such as intraretinal, subretinal
(exophytic), vitreal (endophytic), and flat (diffuse). Small tumors appear intraretinal
with a slightly dilated artery and vein. As the tumor enlarges, the vessels dilate and
become slightly tortuous. Calcification can develop within the mass. Subretinal fluid,
subretinal seeds, and vitreous seeds then develop. Occasionally, seeds can extend into
the anterior chamber producing a neoplastic pseudohypopyon. Advanced tumors lead to
neovascularization of the iris with glaucoma, retinal neovascularization with vitreous
hemorrhage, and invasion into the optic nerve and choroid.

Differential Diagnosis
Retinal detachment from retinoblastoma can simulate:
Coats disease
Persistent hyperplastic primary vitreous (persistent fetal vasculature)
Toxocariasis
Retinal astrocytic hamartoma
Retinal astrocytoma
Combined hamartoma of the retina and RPE
Retinal detachment
Familial exudative vitreoretinopathy
Retinopathy of prematurity
Incontinentia pigmenti
Vitreous seeding from retinoblastoma can simulate:
 Intraocular inflammation
Endophthalmitis
Vitreous hemorrhage
Leukemic infiltration
Leukocoria from retinoblastoma can simulate:
Cataract
Glaucoma

Diagnostic Evaluation
The diagnosis of retinoblastoma is established in the office setting using indirect
ophthalmoscopy in the hands of an experienced examiner. Examination under anesthesia
is reserved for detailed analysis of each eye, confirmation with diagnostic tests, and
therapy. The tumor is confirmed on ultrasonography, showing it as a calcified dome-
shaped mass. Fluorescein angiography will show intrinsic luxurious vascularity. OCT
will show subretinal fluid in cooperative children. Computed tomography (CT) will
confirm the calcification within the mass, but most clinicians prefer magnetic resonance
imaging (MRI) to CT because there is no radiation exposure with the former. MRI will
show the enhancing intraocular mass and can be used to image the orbit and the brain,
evaluating for optic nerve invasion and pinealoblastoma. Fine-needle aspiration biopsy
should be avoided.
Each affected eye is classified according to the International Classification of
Retinoblastoma (ICRB) (Fig. 8-11):
Group A: retinoblastoma ≤3 mm
Group B: retinoblastoma >3 mm or in the macula or with clear subretinal the fluid
Group C: retinoblastoma with subretinal or vitreous seeds ≤3 mm from th e tumor
Group D: retinoblastoma with subretinal or vitreous seeds >3 mm from tumor
Group E: extensive retinoblastoma fill >50% globe or with hemorrhage or iris
neovascularization

Treatment
Retinoblastoma management is complex and depends on many issues including tumor
laterality, macular involvement, tumor size, vitreous or subretinal seeding, relationship
of the tumor to surrounding tissues including the optic disc, choroid, iris, sclera, and
orbit, general patient age and health, and the family wishes. Laser photocoagulation,
cryotherapy, thermotherapy, and plaque radiotherapy remain vitally important in the
management of selective retinoblastoma. Enucleation, intravenous chemoreduction,
intra-arterial chemotherapy, and external beam radiotherapy are used for more
advanced retinoblastoma. External beam radiotherapy is usually reserved for last
alternative treatment because of its numerous side effects and risks for late-onset
cancers in germ line mutation children.
Enucleation is used for advanced eyes, particularly unilateral tumors. Following
enucleation, the eye should be evaluated pathologically for high-risk features.
Systemic intravenous chemoreduction is used for bilateral cases in which there are
multiple tumors and often seeding (Fig. 8-12). Groups A, B, and C show >90% success
with chemoreduction and group D shows about 50% success. Group E eyes are often
enucleated.
Intra-arterial chemotherapy is showing promise as a primary treatment for
retinoblastoma and after failure of other methods. In our preliminary experience, we
have had 100% tumor control for groups C and D retinoblastoma and 33% control for
group E (Fig. 8-13). Groups A and B retinoblastoma are not offered intra-arterial
chemotherapy yet as there are potentially profound risks such as cerebrovascular
accident and ophthalmic artery obstruction.
In rare instances, retinoblastoma can undergo spontaneous regression and show clinical
features of complete tumor resolution without therapeutic intervention. Occasionally,
this can lead to phthisis bulbi.

Prognosis
Retinoblastoma is a highly malignant tumor with nearly 100% mortality if left untreated.
In developed nations, most children present before high-risk features are found; thus,
good prognosis with life-saving measures is achieved. In an analysis of retinoblastoma
worldwide, mortality paralleled the development of the nation.
There are histopathologic factors that predict metastatic disease, including optic nerve
invasion beyond the lamina cribrosa, massive choroidal invasion > 3 mm, scleral
invasion, orbital invasion, and anterior chamber invasion. Some globes enucleated with
retinoblastoma have high-risk features such as retrolaminar optic nerve invasion or
massive uveal invasion of more than 3 mm. Patients with these features should receive
additional chemotherapy.
Children with germinal retinoblastoma have an increased risk of developing other
primary malignancies over the course of their lifetimes. These tumors include
principally intracranial retinoblastoma, osteogenic sarcoma of the long bones, and
sarcoma of soft tissues. The risk is estimated to be 30% by age 30, and the use of
external beam radiotherapy can increase the risk in the field of irradiation.

REFERENCES
Eagle RC Jr. High-risk features and tumor differentiation in retinoblastoma: a retrospective histopathologic study. Arch
Pathol Lab Med. 2009;133:1203–1209.
Kivela T. The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death.
Br J Ophthalmol. 2009;93:1129–1131.
Shields CL, Shields JA. Basic understanding of current classification and management of retinoblastoma. Curr Opin
Ophthalmol. 2006;17:228–234.
Shields CL, Shields JA. Retinoblastoma management: advances in enucleation, intravenous chemoreduction, and intra-
arterial chemotherapy. Curr Opin Ophthalmol. 2010;21:203–212.
Shields JA, Shields CL. Retinoblastoma. In: Shields JA, Shields CL. Atlas of Intraocular Tumors. Philadelphia, PA:
Lippincott Williams Wilkins; 2008:293–365.
Wong FL, Boice JD Jr, Abramson DH, et al. Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk.
JAMA. 1997;278:1262–1267.

FIGURE 8-10. Retinoblastoma. Leukocoria (left eye) from retinoblastoma.

FIGURE 8-11. Retinoblastoma. Examples of the international classification of retinoblastoma into
groups A, B, C, D, and E.
FIGURE 8-12. Retinoblastoma. Response of retinoblastoma to intravenous chemoreduction in two
cases before therapy (A and C) and after therapy (B and D).
 FIGURE 8-13. Retinoblastoma. Response of retinoblastoma to intra-arterial chemotherapy showing
before therapy (A) and after therapy (B).

CONGENITAL HYPERTROPHY OF THE RETINAL

PIGMENT EPITHELIUM

Anuradha Ganesh and Alex V. Levin ■

Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is a benign,
asymptomatic condition, consisting of one or more well-demarcated, pigmented, flat,
nonmitotic lesions at the level of the RPE.

Epidemiology and Etiology

Solitary CHRPE occurs in approximately 1/60 in the general population. No racial
predilection has been reported. Histopathologically, the lesion consists of a focal area
in which the RPE cells are taller and more densely packed with melanosomes. The
individual melanosomes are larger and more spherical as compared with those of the
normal RPE. The associated depigmented lacunae, halos, or “tails” correspond to areas
where the melanosomes are sparse.

History
Patients are usually asymptomatic. Often the disorder is noted as an incidental finding
during ophthalmoscopy.

Signs
CHRPE may take one of two forms:
Solitary: This is the most common form. It is characteristically a unilateral, deeply
pigmented, flat, circular lesion, with a well-circumscribed margin. These may be
pinpoint or two or three disc diameters in size. The lesion may be solid black with a
marginal halo of hypopigmentation. Depigmented lacunae may be seen within the lesion.
Multiple: Multifocal CHRPE lesions are seen in over 80% of patients with familial
adenomatous polyposis (FAP) or Gardner syndrome, a familial condition of colonic
polyps and extraintestinal osteomas and fibromas with uniform progression to colonic
cancer if not treated. The lesions are bilateral, multiple, scattered, and more often have
a “cometoid” configuration with a hypopigmented tail on the side of the lesion closer to
the macula (Fig. 8-14).

Differential Diagnosis
Choroidal melanoma
Choroidal nevus
Combined hamartoma of the retina and RPE
Reactive hyperplasia of the RPE (e.g., posttraumatic)
Bear tracks
Chorioretinal scars (e.g., toxoplasmosis, congenital varicella)

Diagnostic Evaluation
The characteristic appearance of CHRPE should enable the clinician to make the
diagnosis and differentiate it from other lesions. Fluorescein angiography reveals
hypofluorescence throughout all phases of the angiogram, except in the region of the
haloes and lacunae, which show transmission hyperfluorescence. The lesions are not
associated with subretinal fluid or orange pigment. Enhanced depth imaging OCT
reveals flat lesions with irregular RPE and absent RPE in the lacunae. There may be
loss of outer nuclear layer and retinal photoreceptors, and subretinal clefts.
Treatment and Prognosis
Although overlying photoreceptor loss and alterations of the RPE may lead to VF
defects, CHRPEs are usually benign and asymptomatic and do not affect visual acuity or
visual field. Over time, subtle enlargement of the lesions and development of an
elevated nodule representing adenoma or adenocarcinoma has rarely been reported.
Hence, they should be observed periodically for growth. Patients with bilateral or
multiple unilateral lesions suggestive of those seen in FAP or Gardner syndrome should
be referred for periodic colonoscopy usually beginning at 7 or 8 years of age.

REFERENCES
Fung AT, Pellegrini M, Shields CL. Congenital hypertrophy of the retinal pigment epithelium: enhanced-depth imaging
optical coherence tomography in 18 cases. Ophthalmology. 2014;121:251–256.
Shields JA, Eagle RC Jr, Shields CL, et al. Malignant transformation of congenital hypertrophy of the retinal pigment
epithelium. Ophthalmology. 2009;116:2213–2216.
Shields JA, Shields CL. Tumors and related lesions of the pigment epithelium. In: Shields JA, Shields CL, eds.
Intraocular Tumors. A Text and Atlas. Philadelphia, PA: WB Saunders; 1992:437–460.
Traboulsi EI, Maumenee IH, Krush AJ, et al. Congenital hypertrophy of the retinal pigment epithelium predicts
colorectal polyposis in Gardner’s syndrome. Arch Ophthalmol. 1990;108:525–526.
Traboulsi EI. Ocular manifestations of familial adenomatous polyposis (Gardner syndrome). Ophthalmol Clin North
Am. 2005;18:163–166.

FIGURE 8-14. Congenital hypertrophy of the retinal pigment epithelium. Fundus photograph
both retinas shows bilateral hyperpigmented retinal lesions in a patient with Gardner syndrome. The
lesion in the right eye has a “cometoid” appearance with a hypopigmented tail on the side of the lesion
closer to the macula. The lesions in both eyes show a marginal halo of depigmentation.

FAMILIAL EXUDATIVE VITREORETINOPATHY

 Anuradha Ganesh and Alex V. Levin ■
Familial exudative vitreoretinopathy (FEVR) is a hereditary vitreoretinal disorder
characterized by failure of peripheral retinal vascularization and resulting in secondary
complications such as neovascularization, retinal folds, traction, and detachment.

Epidemiology and Etiology

FEVR is a rare disorder. The prevalence has not been calculated. Ninety percent of
affected individuals may be asymptomatic. FEVR is genetically heterogeneous and is
associated with mutations in the Frizzled-4 (FZD4; autosomal dominant FEVR), LRP5
(autosomal dominant and recessive FEVR), NDP (X-linked recessive FEVR), and
TSPAN12 (autosomal dominant FEVR) genes. Autosomal dominant inheritance is the
most common mode of inheritance.

History
The clinical appearance of FEVR varies considerably, even within families, with
severely affected patients often registered as blind during infancy and mildly affected
patients having few or no visual problems. Infants may present with strabismus or
leukocoria due to retinal detachment. There is no association with prematurity or oxygen
exposure.

Signs
Infants born with FEVR are otherwise healthy. Ophthalmic findings are frequently
asymmetric and highly variable. The classic finding in FEVR is peripheral retinal
capillary nonperfusion (Fig. 8-15). Usually, the avascular zone is confined to the
temporal periphery, but it may extend for 360 degrees. The disease may not progress
further or may lead to peripheral neovascularization at the border of posterior
vascularized and anterior avascular retina (Fig. 8-16). Retinal fold, peripheral
fibrovascular mass, vitreous hemorrhage, and progression to even more severe changes
such as tractional, exudative, and even rhegmatogenous retinal detachment may occur.
Intraretinal and subretinal exudation may be associated. In severe cases with retinal
detachment, there may be cataract, band keratopathy, neovascular glaucoma, and/or
phthisis. Asymptomatic individuals may manifest regions of peripheral avascularity
with abnormal vascular anastomoses visible clinically or only on intravenous
fluorescein angiography.

Differential Diagnosis
 Retinopathy of prematurity
Incontinentia pigmenti
Coats disease
Persistent fetal vasculature
Sickle cell retinopathy
Other causes of infantile retinal nonattachment or detachment

Diagnostic Evaluation
The diagnosis of FEVR is based on a family history compatible with autosomal
dominant, autosomal recessive, or X-linked recessive inheritance and bilateral
peripheral retinal avascularity. If FEVR is suspected, examination of the peripheral
retina of asymptomatic family members may also reveal findings consistent with the
diagnosis. Tests that may help in confirming the diagnosis include fluorescein
angiography (abrupt cessation of peripheral retinal capillary network and possible
abnormal vasculature) and genetic testing. SD-OCT may reveal a broad spectrum of
microstructural findings including dysgenic posterior hyaloid, cystoid macular edema,
and both inner and outer retinal abnormalities.

Treatment and Prognosis

Laser photocoagulation to the peripheral avascular retina and neovascularization may
prevent progression of fibrovascular complications. The value of prophylactic treatment
is controversial and most authors suggest treatment only if neovascularization is present.
Prevention of retinal detachment is far more effective than treatment once detachment
occurs. FEVR is a lifelong disease, and events like neovascularization, retinal
detachments, and vitreous hemorrhage may occur at any age. Perinatal screening,
continued for several years, is advisable in at-risk individuals.

REFERENCES
Robitaille JM, Zheng B, Wallace K, et al. The role of Frizzled-4 mutations in familial exudative vitreoretinopathy and
Coats disease. Br J Ophthalmol. 2011;95(4):574–579.
Shukla D, Singh J, Sudheer G, et al. Familial exudative vitreoretinopathy (FEVR). Clinical profile and management.
Indian J Ophthalmol. 2003;51:323–328.
Toomes C, Downey L. Familial exudative vitreoretinopathy, autosomal dominant. In: Pagon RA, Bird TC, Dolan CR,
Stephens K, ed. GeneReviews. Seattle: University of Washington; 2008.
Yonekawa Y, Thomas BJ, Drenser KA, et al. Familial exudative vitreoretinopathy: spectral-domain optical coherence
tomography of the vitreoretinal interface, retina, and choroid. Ophthalmology. 2015;122:2270–2277.
 FIGURE 8-15. Familial exudative vitreoretinopathy. Fundus fluorescein angiogram clearly
demonstrates bilateral peripheral retinal capillary nonperfusion and leakage (arrows).

FIGURE 8-16. Familial exudative vitreoretinopathy. Retinal tractional fold (arrow) causing
straightening of vessels at the disc.

PERSISTENT FETAL VASCULATURE

Alok S. Bansal ■
Persistent fetal vasculature (PFV), formerly referred to as persistent hyperplastic
primary vitreous (PHPV), is a developmental malformation of the eye that results from
failure of regression of the primary vitreal hyaloidal vessels and other associated
vessels in the tunica vasculosa lentis and/or iris.
PFV is most often unilateral and nonheritable. When bilateral (10%), there is more often
systemic associations and the potential for a genetic basis (Table 8-3).

Signs
There are many forms of PFV, ranging in a spectrum from anterior findings to posterior
findings. Isolated anterior PFV (Fig. 8-17A) is characterized by a retrolental
vascularized membrane, variable degree of cataract, drawn-in ciliary processes (Fig. 8-
17B), traction on the peripheral retina due to a membranous transformation of the
anterior vitreous face, shallow anterior chamber, poor pupil dilation, and
microphthalmos. Congenital fibrovascular pupillary membranes may be an isolated
variant of anterior PFV. The more severe posterior PFV is characterized by a stalk of
tissue extending from the optic nerve to the retrolental area, a retinal fold with or
without tractional retinal detachment (Fig. 8-17C), macular pigmentary disruption, and
variable degrees of optic nerve dysplasia. The lens can be clear in isolated posterior
PFV.

Differential Diagnosis
Norrie disease
Coats disease
Toxocariasis
Retinopathy of prematurity
FEVR
Incontinentia pigmenti
Retinal dysplasia
Retinal detachment (overt or covert trauma)

Diagnostic Evaluation
The diagnosis of PFV can be made with careful ophthalmoscopic exam. Depending on
the age of the child, an exam under anesthesia may be considered. If significant media
opacity precludes a view of the fundus, B-scan ultrasonography may demonstrate a stalk
or retinal detachment. Careful examination of the iris may reveal anterior signs of
persistent vasculature.

TABLE 8-3. Systemic and Genetic Basis of Ocular Disorders

Syndrome Inheritance Chromosome Gene Function

Wagner AD 5q14.3 CSPG2 Binds to hyaluronan in vitreous
Knobloch AR 21q22.3 COL18A1 Cleaves to endostatin
PFV AR 10q11-21 Not known

PFV XLR Xp11.4 NDP Signaling pathways for morphogenesis

ASMD AD 10q22.3-25 PITX3 Regulates ocular morphogenesis
AD, autosomal dominant; AR, autosomal recessive; ASMD, anterior segment mesenchymal dysgenesis; COL18A1,
collagen type 18 alpha 1; CSPG, chondroitin sulfate proteoglycan; NDP, Norrie disease pseudoglioma; PFV,
persistent fetal vasculature; PITX3, paired like homeodomain 3; XLR, X-linked recessive.

Treatment
The goals of management include clearing the media opacity in order to allow visual
development and prevent complications of untreated PFV such as glaucoma and retinal
detachment. Either anterior limbal or pars plana approaches to lensectomy,
membranectomy, and vitrectomy may be employed. Aggressive amblyopia treatment
with aphakic contact lenses are required to achieve optimum vision. The prognosis for
pure anterior PFV is better than posterior PFV.

REFERENCES
Goldberg MF. Persistent fetal vasculature (PFV): an integrated interpretation of signs and symptoms associated with
persistent hyperplastic primary vitreous (PHPV). LIV Edward Jackson Memorial Lecture. Am J Ophthalmol.
1997;124(5):587–626.
Lambert SR, Buckley EG, Lenhart PD, et al. Congenital fibrovascular pupillary membranes: clinical and histopathologic
findings. Ophthalmology. 2012;199:634–641.
Pollard, ZF. Persistent hyperplastic primary vitreous: diagnosis, treatment, and results. Trans Am Ophthalmol Soc.
1997;95:487–549.
 FIGURE 8-17. Persistent fetal vasculature (PFV). A. The retrolental stalk is due to failure of
regression of the primary vitreal hyaloidal vessels. B. PFV demonstrating a vascularized retrolental
membrane, cataract, and drawn-in ciliary processes. C. PFV demonstrating a retinal fold with an
associated tractional retinal detachment.

JUVENILE RETINOSCHISIS

Barry N. Wasserman ■
Etiology
An X-linked inherited disease, juvenile retinoschisis is the most common cause of
macular degeneration in young males. Mutation of the XLRS1 gene results in retinal
dysfunction due to splitting of the retinal layers and the characteristic inner retinal layer
schisis and stellate maculopathy.

Symptoms
Patients may present with mildly reduced vision that may deteriorate to less than
20/400, though one study suggested no significant disease progression in children over
an average of 12 years of follow-up. Visual loss is caused by foveal schisis or retinal
detachment.

Signs
Fundus examination reveals foveal schisis in a stellate pattern. In approximately 50% of
patients, peripheral retinoschisis of the nerve fiber layer occurs with inner layer holes
and possible progression to full-thickness retinal detachment. Whitish dots or patches in
the retinal midperiphery and periphery (snowflakes) may be seen and are thought to
represent abnormal Müller cell footplates. Pigmented demarcation lines indicate prior
full-thickness detachment. Spontaneous vitreous hemorrhage results from vessels
bridging the inner retinal layer holes.

Differential Diagnosis
Nicotinic acid maculopathy
Rhegmatogenous retinal detachment
Goldmann–Favre disease
Wagner vitreoretinal dystrophy and other vitreoretinopathies
Cystoid macular edema
Norrie disease

Diagnostic Evaluation
Characteristic family history of affected males with intervening unaffected female
carriers. Fundus examination reveals stellate appearance in fovea, which resembles
cystoid macular edema (Fig. 8-18). Fluorescein angiography does not show leakage.
Retinal pigment epithelial pigmentary changes and vitreous veils are seen. Optical
coherence tomography may demonstrate schisis extending into the retinal periphery (Fig.
8-19). One study using SD-OCT demonstrated increased inner foveal thickness and
decreased perifoveal inner retinal thickness correlating with worse visual acuity.
Electroretinogram reveals diminished B-wave amplitudes, but electrooculogram is
normal.

Treatment
Genetic counseling is recommended for families with X-linked juvenile retinoschisis.
Some patients with cystoid macular changes have shown improvement in visual acuity
and OCT finding when treated with topical or oral carbonic anhydrase inhibitors.
Prophylactic laser photocoagulation is not recommended and can lead to retinal
detachment. Surgery utilizing scleral buckling and pars plana vitrectomy can be
performed for vitreous hemorrhage and retinal detachment.

Prognosis
Some patients maintain good vision into adulthood, but visual acuity commonly
deteriorates particularly when peripheral retinal schisis is present.

REFERENCES
Andreoli MT, Lim JI. Optical coherence tomography retinal thickness and volume measurements in X-linked
retinoschisis. Am J Ophthalmol. 2014;158:567–573.
Apushkin MA, Fishman GA. Use of dorzolamide for patients with X-linked retinoschisis. Retina. 2006;26:741–745.
Goodwin P. Hereditary retinal disease. Curr Opin Ophthalmol. 2008;19:255–262.
Kjellström S, Vijayasarathy C, Ponjavic V, et al. Long-term 12 year follow-up of X-linked congenital retinoschisis.
Ophthalmic Genet. 2010;31(3):114–125.

FIGURE 8-18. Juvenile X-linked retinoschisis. Juvenile X-linked retinoschisis with cystic
 appearance in the macula.

FIGURE 8-19. Juvenile X-linked retinoschisis. Optical coherence tomography of macula

demonstrating schisis cavities.

RETINOPATHY OF PREMATURITY

Anuradha Ganesh and Barry N. Wasserman ■

R etinopathy of prematurity (ROP) is a proliferative retinopathy of premature, low-
birth-weight infants.

Epidemiology and Etiology

Each year, ROP is believed to affect an estimated 14,000 to 16,000 premature, low-
birth-weight infants in the United States. The majority of infants who develop ROP
undergo spontaneous regression (85%). The rest will develop severe ROP requiring
treatment, and 6% to 7% of infants will become legally blind despite treatment. Infants
born before 32 weeks of gestation or those with a birth weight of less than 1500 g who
have received oxygen therapy are at risk.
In preterm infants, retinal vascular development is incomplete. Instead of continued
progression from the optic nerve head anteriorly along the plane of retina, vascular
migration ceases, leading to an area of avascular retina. The extent of avascular retina
depends mainly on the degree of prematurity at birth. The resultant hypoxia stimulates
production of substances such as vascular endothelial growth factor (VEGF) which
trigger neovascularization, known as extraretinal fibrovascular proliferation (ERFP),
off the surface of the retina. ERFP may lead to hemorrhage and contraction with
resultant retinal detachment. In many cases, the retinopathy abnormalities spontaneously
regress without treatment.
History
Infants are considered high risk and are screened for ROP if birth weight is less than
1500 g or gestational age is 32 weeks or less. Selected infants with an unstable clinical
course, including those requiring cardiorespiratory support, with a birth weight between
1500 and 2000 g, or gestational age of more than 32 weeks, may also be screened at the
discretion of the neonatologist.

Signs
The International Classification of ROP (ICROP) categorizes ROP by location, called
the Zone, or by severity, called the Stage. In addition, the presence or absence of plus
disease is evaluated (Table 8-4, Fig. 8-20). An eye has plus disease when there are at
least two quadrants of dilatation of veins and tortuosity of arterioles in the posterior
pole (Fig. 8-20C). Iris engorgement, pupillary rigidity, vitreous haze, or retinal
hemorrhages are often seen in plus disease. Plus disease denotes increased severity.
Pre-plus disease refers to more mild posterior pole vascular dilation and tortuosity, that
is insufficient for diagnosis of plus disease.

TABLE 8-4. International Classification of Retinopathy of Prematurity

Location
Zone I Posterior circle of retina centered on the optic nerve with a radius of twice the disc-fovea distance
Zone II Circular area of retina from the edge of Zone I to the nasal ora serrata
Zone III Remaining temporal crescent of retina

Extent
Number of clock hours or 30-degree sectors involved

Severity
Stage 1 Demarcation line at the junction of posterior vascularized and anterior avascular retina
Stage 2 Ridge (demarcation line with volume)
Stage 3 Ridge with extraretinal fibrovascular proliferation
Stage 4 Subtotal retinal detachment
Stage 4A Extrafoveal
Stage 4B Fovea is detached
Stage 5 Total retinal detachment with funnel
Reprinted with permission from International Committee for the Classification of Retinopathy of Prematurity. The
International Classification of Retinopathy of Prematurity revisited [review]. Arch Ophthalmol. 2005;123(7):991–999.
“Popcorn” lesions are named so because of their similarity to kernels of white fluffy
popcorn floating above the developed retina. They represent buds of vascular
proliferation behind the ridge or demarcation line. Popcorn is only significant when part
of active ERFP. Vitreous hemorrhage and preretinal hemorrhage can occasionally be
seen in eyes with severe ERFP.
In acute posterior ROP (AP-ROP), vascularization is only present in Zone I and there is
plus disease. This subtype of ROP previously termed “rush” disease is associated with
an aggressive course and a risk for rapid progression into stage 4 or 5.
After treatment of ROP, most will regress by a process of involution or cicatrization,
often yielding good visual acuity. This may be accompanied by a broad range of
sequelae such as failure of peripheral retinal vascularization, abnormal branching of
retinal vessels, retinal pigmentary changes, vitreoretinal interface changes, retinal folds,
and distortion and ectopia of the macula.
The characteristic findings of ROP are present in the setting of infants born prematurely,
of low birth weight with a history of oxygen exposure and other disorders associated
with prematurity such as sepsis, intraventricular hemorrhage, anemia, and feeding
difficulties.

Differential Diagnosis
Differential diagnosis depends on the stage of the disease.
In less severe ROP, conditions that cause peripheral retinal vascular changes and
retinal dragging should be considered:
Incontinentia pigmenti
FEVR
PFV
Other causes of infantile retinal nonattachment or detachment
In advanced cicatricial ROP, the differential diagnosis is consistent with retinal
detachment or leukocoria:
Retinoblastoma
Cataract
Coats disease
Toxocariasis

Diagnostic Evaluation
Careful examination of neonates with indirect ophthalmoscopy in the intensive care
nursery or at discharge is recommended between 4 and 6 weeks of chronologic
(postnatal) age or, alternatively, within the 31st to 33rd week of postconceptional or
postmenstrual age (gestational age at birth plus chronologic age), whichever is later.
Digital imaging is an useful adjunct during fundus examinations.

Treatment and Prognosis

The purpose of screening for ROP is to identify infants with advanced ROP who would
progress to retinal detachment unless treated. Older treatment criteria utilized the term
‘threshold’, but this has now been replaced by ‘Type 1 and Type 2.’ “Prethreshold”
disease is defined as any Zone I-stage of ROP or Zone II-stage 2 + ROP/stage 3
ROP/stage 3 + ROP but less extensive than threshold disease. The early treatment for
ROP (ET-ROP) study divided prethreshold eyes into two groups ( Table 8-5) and
recommended that peripheral retinal ablation be applied to any eye with type 1
prethreshold ROP.
Peripheral retinal ablation of the anterior avascular zone may be performed with
cryotherapy or laser photocoagulation. The latter, delivered with an indirect
ophthalmoscope, has replaced cryotherapy for threshold ROP (Fig. 8-21). Better visual
outcomes have been achieved with laser treatment. More advanced stages of ROP
(stages 4 and 5) require scleral buckling or vitrectomy, or both. The prognosis for
visual recovery after retinal detachment remains poor.

TABLE 8-5. Early Treatment of ROP Prethreshold Types

Type I
Zone I: any stage ROP with plus disease
Zone I: stage 3 ROP without plus disease
Zone II: stage 2 or 3 ROP with plus disease
Type II
Zone I: stage 1 or 2 ROP without plus disease
Zone II: stage 3 ROP without plus disease
ROP, retinopathy of prematurity.
Reprinted with permission from Vander JF, McNamara JA, Tasman W, et al. Revised indications for early treatment
of retinopathy of prematurity. Arch Ophthalmol. 2005;123:406–407.

Despite appropriate screening and timing of intervention, ROP in some babies continues
to progress. This has led to research into newer and more effective modalities of
therapy. Ongoing studies evaluating the efficacy and safety of intravitreal injections of
anti-VEGF drugs for ROP suggest this therapeutic modality may produce similar or
better outcomes than laser photocoagulation. However, use of anti-VEGF drugs has
been associated with late recurrence of the ROP, and vigilant follow-up every 1 to 2
weeks for up to 55 weeks may be indicated. These medications escape the eye and may
lead to temporary impairment of systemic vasculature development. One study
recommended caution after an increased incidence of developmental delay was noted in
children treated with anti-VEGF for ROP.

REFERENCES
Davitt BV, Wallace DK. Plus disease. Surv Ophthalmol. 2009;54:663–670.
Kemper AR, Wallace DK, Quinn GE. Systematic review of digital imaging screening strategies for retinopathy of
prematurity. Pediatrics. 2008;122:825–830.
Mintz-Hittner HA, Geloneck MM, Chuang AZ. Clinical management of recurrent retinopathy of prematurity after
intravitreal bevacizumab monotherapy. Ophthalmology. 2016;123:1845–1855.
Mintz-Hittner HA, Kuffel RR Jr. Intravitreal injection of bevacizumab (avastin) for treatment of stage 3 retinopathy of
prematurity in zone I or posterior zone II. Retina. 2008;28:831–838.
Morin J, Luu TM, Superstein R, et al; Canadian Neonatal Network and the Canadian Neonatal Follow-Up Network
Investigators. Neurodevelopmental outcomes following bevacizumab injections for retinopathy of prematurity.
Pediatrics. 2016;137:e20153218.
Patel JR, Ranjan SS, Wasserman BN. Antivascular endothelial growth factor in the treatment of retinopathy of
prematurity. Curr Opin Ophthalmol. 2016;27:387–392.
Reynolds JD. Retinopathy of prematurity. Int Ophthalmol Clin. 2010;50:1–13.
Section on Ophthalmology American Academy of Pediatrics; American Academy of Ophthalmology; American
Association for Pediatric Ophthalmology and Strabismus. Screening examination of premature infants for
retinopathy of prematurity. Pediatrics. 2006;117(2):572–576.
Vander JF, McNamara JA, Tasman W, et al. Revised indications for early treatment of retinopathy of prematurity.
Arch Ophthalmol. 2005;123:406–407.
FIGURE 8-20. Retinopathy of prematurity. A. Zone II, stage 2 disease with mild to moderate plus
disease. At the superior aspect of the retina, the vessel development has ceased, and a white ridge
(arrows) is seen. Avascular, undeveloped retina is seen beyond the ridge. (Courtesy of Sharon Lehman,
MD.) B. Zone II, stage 3 disease with plus disease. Neovascularization is seen rising into the vitreous
above the ridge (asterisks). (Courtesy of William Tasman, MD.) C. Plus disease with severe vascular
dilation and tortuosity. (Courtesy of William Tasman, MD.)
 FIGURE 8-21. Retinopathy of prematurity after successful treatment with laser photocoagulation and
peripheral chorioretinal scars. (Courtesy of William Tasman, MD.)

RETINITIS PIGMENTOSA

Barry N. Wasserman ■
Etiology
Retinitis pigmentosa is a group of diseases characterized by night blindness
(nyctalopia), slow painless, progressive peripheral visual field loss, and progressive
deterioration of the electroretinogram. Virtually every inheritance pattern has been
reported and over 70 genes have been shown to be causative when mutated. Phenotypic
and genetic heterogeneity are common. The common pathway is retinal receptor cell
death via apoptosis. Retinitis pigmentosa may be found in isolation or in association
with systemic or neurodegenerative disease.

Symptoms
Retinitis pigmentosa begins in childhood, adolescence, or early adulthood with
nyctalopia and issues of light to dark adaptation. Patients may also complain of loss of
peripheral vision. Other symptoms may include photophobia, variable visual acuity, and
unusual colors in visual perception.

Signs
Visual acuity may range from 20/20 to no light perception but is usually preserved early
in the disease. VF constriction is progressive. Posterior subcapsular cataracts are
common in adult patients. Retinal findings may be minimal in children, but eventually
classic “bone spicule” pattern of midperipheral hyperpigmentation occurs, with
associated arteriolar thinning and waxy pallor of the optic nerve (Fig. 8-22). Other
macular changes including loss of foveal reflex, irregularities of the internal limiting
membrane, and cystoid maculopathy can occur. Electroretinogram findings progress to
nondetectable.

Differential Diagnosis
Retinitis pigmentosa can be divided into nonsyndromic and syndromic types.
Nonsyndromic types include the autosomal dominant and recessive forms, as well as X-
linked forms. Rare mitochondrial DNA mutation types also occur.
Syndromic types of retinitis pigmentosa are extremely varied and include
Syndromes associated with deafness, most commonly Usher syndrome
Syndromes associated with metabolic diseases including Abetalipoproteinemia
(Bassen-Kornzweig disease), Zellweger syndrome (cerebrohepatorenal syndrome),
Refsum disease, mucopolysaccharidoses types I, II, III, and neuronal ceroid
lipofuscinosis (Batten disease)
Kearns–Sayre syndrome
Syndromes with renal associations including Fanconi, cystinosis, Senior Loken
syndrome
Dysmorphic syndromes including Cohen syndrome, Jeune syndrome, Cockayne
syndrome
Pigmentary retinopathies: pseudo retinitis pigmentosa
Cancer-associated retinopathy
Congenital infections including syphilis, rubella, and CMV
Drug-associated retinopathy including phenothiazines and chloroquine
Retinal vascular occlusion

Diagnostic Evaluation
Ocular examination may show classic findings but may be normal early in the disease.
VF testing reveals constriction, and electroretinogram shows rod and cone signals are
depressed or extinguished. Contrast sensitivity is sometimes decreased. Genetic testing
may be helpful for determining subtypes and prognosis.

Treatment
Genetic counseling is advised. The use of vitamin A is controversial. Oral or topical
carbonic anhydrase inhibitors can be helpful for patients who have associated macular
edema. Cataract extraction should be performed when indicated but may have a higher
risk of postoperative cystoid macular edema. Gene therapy is under investigation.
Retinal pigment epithelial transplant and electronic retinal implants are also under
investigation. Low vision services are recommended as the disease progresses.

Prognosis
Visual acuity may remain better than 20/40 in over half of patients in their 40s.
However, 25% may have less than 20/200 and are considered legally blind. Only 1 in
every 1000 patients come to have no light perception. X-linked types may have the
worst visual acuity prognosis, whereas sector-type autosomal dominant retinitis
pigmentosa patients generally retain good vision.

REFERENCES
Goodwin P. Hereditary retinal disease. Curr Opin Ophthalmol. 2008;19:255–262.
Grover S, Fishman GA, Anderson RJ, et al. Visual acuity impairment in patients with retinitis pigmentosa at age 45
years or older. Ophthalmology. 1999;106(9):1780–1785.
Hamel C. Retinitis pigmentosa. Orphanet J Rare Dis. 2006;1:40.
Jackson H, Garway-Heath D, Rosen P, et al. Outcome of cataract surgery in patients with retinitis pigmentosa. Br J
Ophthalmol. 2001;85(8):936–938.
Jacobson SG, Cideciyan AV. Treatment possibilities for retinitis pigmentosa. N Engl J Med. 2010;363:1669–1671.

FIGURE 8-22. Retinitis pigmentosa. A. Retinitis pigmentosa fundus photos demonstrating optic
nerve waxy pallor, vascular attenuation, and midperipheral “bone spicule” pigmentary retinopathy. B.
Higher magnification photos of midperipheral “bone spicule” retinopathy.

MYELINATED NERVE FIBERS

Barry N. Wasserman ■
Etiology
Whitish sheets or patches of myelin distributed along portions of the nerve fiber layer of
the retina. Usually unilateral, myelin is produced by oligodendrocytes and is normal
along the optic nerve but does not normally progress beyond the lamina cribrosa.
Ectopic oligodendrocytes are associated with myelin in the retinal nerve fiber layer
generally near the optic nerve. Myelinated nerve fibers may be found in 1% of eyes, and
may be an isolated finding, or may be associated with other abnormalities including
neurofibromatosis and Gorlin syndrome.

Symptoms
May be asymptomatic but sometimes associated with high axial myopia and amblyopia
in affected eye

Signs
Poor vision on examination associated with feathery gray-white patches along the
retinal nerve fiber layer. They are often found at the optic nerve and along the vascular
arcades, more commonly superiorly (Fig. 8-23A). There may also be a patch
unconnected to the optic nerve (Fig. 8-23B). High myopic astigmatism with
anisometropic amblyopia is reported. If extensive, they can cause leukocoria (Fig. 8-
24).

Differential Diagnosis
Branch retinal artery occlusion
Cotton wool patches
When extensive, myelinated nerve fibers can yield leukocoria, in which case it must
rule out:
Retinoblastoma
Coats disease
Coloboma
Cataract
ROP
PFV
FEVR

Diagnostic Evaluation
Myelinated nerve fibers are diagnosed by clinical fundus examination. Feathery gray-
white patches are noted superficially in the nerve fiber layer along the vascular arcades,
often in close proximity to the optic disc. VF field testing may reveal absolute or
relative scotomas corresponding to the myelinated fibers. SD-OCT has shown
thickening of the retinal nerve fiber layer but normal morphology of the fovea,
suggesting amblyopia may be more related to anisometropia than anatomic abnormality.

Treatment
No treatment is needed for asymptomatic myelinated nerve fibers. When associated with
anisometropic amblyopia, appropriate aggressive amblyopia treatment should be
instituted.

Prognosis
When dense amblyopia is associated with myelinated nerve fibers, the prognosis is
variable and guarded. Outcomes are worse when associated with high myopia and
history of associated strabismus.

REFERENCES
Gharai S, Prakash G, Kumar DA, et al. Spectral domain optical coherence tomographic characteristics of unilateral
peripapillary myelinated retinal nerve fibers involving the macula. J AAPOS. 2010;14:432–434.
Lee MS, Gonzalez C. Unilateral peripapillary myelinated retinal nerve fibers associated with strabismus, amblyopia,
and myopia. Am J Ophthalmol. 1998;125:554–556.
Shelton JB, Digre KB, Gilman J, et al. Characteristics of myelinated retinal nerve fiber layer in ophthalmic imaging:
findings on autofluorescence, fluorescein angiographic, infrared, optical coherence tomographic, and red-free
images. JAMA Ophthalmol. 2013;131:107–109.
Tarabishy AB, Alexandrou TJ, Traboulsi EI. Syndrome of myelinated retinal nerve fibers, myopia, and amblyopia: a
review. Surv Ophthalmol. 2007;52:588–596.

FIGURE 8-23. Myelinated nerve fibers. A. Fundus photo with extensive feathery white myelination
extending in all directions from the optic nerve. B. Myelinated nerve fibers superior to the optic nerve
without direct connection to the optic nerve. (Courtesy of William Tasman, MD.)
 FIGURE 8-24. Myelinated nerve fibers. Leukocoria in a patient with extensive myelinated nerve
fibers. (Courtesy of William Tasman, MD.)

STARGARDT DISEASE/FUNDUS FLAVIMACULATA

Barry N. Wasserman ■
Etiology
A largely autosomal recessively inherited atrophic macular dystrophy, Stargardt disease
is associated with mutations of the ABCA4 gene on chromosome 1p. It encodes a retina-
specific adenosine triphosphate-binding cassette transporter, and defects result in death
of retinal pigment epithelial cells, as well as overlying photoreceptor cells. Specific
mutations have not been correlated with electroretinographic characteristics or fundus
appearance. This gene may also act as a modifier gene in other retinal dystrophies with
other known gene mutations. Lipofuscin accumulation in the RPE is associated with
vision loss. Other types of Stargardt include autosomal dominant phenotypes associated
with mutations in the genes ELOVL4 or PROM1 and mitochondrial phenocopies.

Symptoms
Decreased central visual acuity is usually acute and precipitous in the first or second
decade of life. Vision loss is sometimes seen in absence of ophthalmoscopic findings.
Painless, progressive, slow visual deterioration to the 20/200 range may occur through
the third decade.

Signs
Visual acuity is decreased to varying degrees at presentation. Fundus exam may be
normal or only a loss of foveal reflex early in the disease, but later yellow subretinal
“flecks” are seen (Fig. 8-25). Classically, the flecks are found centrally in Stargardt
disease, with more profound and progressive vision loss, and in the midperiphery in
fundus flavimaculata, with better vision prognosis. Flecks have been described as “fish-
scale shaped” and hence the name “pisciform.” Eventually, the macula takes on a beaten
bronze appearance and sometimes a bull’s eye maculopathy. Fluorescein angiography
may reveal a silent choroid in most patients, as the lipofuscin in the RPE blocks the
appearance of dye in the choroidal vessels (Fig. 8-26). Later in the disease, there may
be fluorescein hyperfluorescence in the atrophic central macula. Early
electroretinogram findings may be normal, but a subset of patients do have changes with
prolonged dark adaptation. Multifocal electroretinogram usually has mild abnormalities.

Differential Diagnosis
Fundus albipunctata
Retinitis punctata albescens
Cone dystrophy
Batten disease
Hydroxychloroquine toxicity
Autosomal dominant drusen
Multifocal best
Doyne honeycomb
Sorsby dystrophy
Malattia leventinese
Bestrophinopathy
Diagnostic Evaluation
Decreased vision in a child, with classic dark choroid on angiography, and sometimes
yellow pisciform subretinal lesions are diagnostic. VF testing most commonly reveals a
central scotoma, but paracentral and other variants may be seen. Electroretinogram
findings may be helpful to rule out other causes of pediatric vision loss but are often
normal in early Stargardt disease. SD-OCT demonstrates hyperreflective foci not only
in the retina, but also in the choroidal layers including membrane/RPE complex and
choriocapillaris. Genetic testing of the patient and other family members is often
helpful.

Treatment
Genetic counseling and low vision services are recommended. No other specific
treatments have proven effective to date. Avoid vitamin A supplementation.

Prognosis
Some variants of fundus flavimaculata are associated with better visual prognosis, but
Stargardt disease is generally associated with moderate to poor central visual acuity.

REFERENCES
Goodwin P. Hereditary retinal disease. Curr Opin Ophthalmol. 2008;19:255–262.
Oh KT, Weleber RG, Stone EM, et al. Electroretinographic findings in patients with Stargardt disease and fundus
flavimaculatus. Retina. 2004;24(6):920–928.
Piri N, Nesmith BLW, Schaal S. Choroidal hyperreflective foci in Stargardt disease shown by spectral-domain optical
coherence tomography imaging: correlation with disease severity. JAMA Ophthalmol. 2015;133:398–405.
Testa F, Melillo P, Di Iorio V, et al. Macular function and morphologic features in juvenile Stargardt disease.
Ophthalmology. 2014;121:2399–2405.
Westerfeld C, Mukai S. Stargardt’s disease and the ABCR gene. Semin Ophthalmol. 2008;23(1):59–65.
FIGURE 8-25. Stargardt disease/fundus flavimaculata. Fundus photos with macular yellow
subretinal flecks.
FIGURE 8-26. Stargardt disease/fundus flavimaculata. Fluorescein angiogram revealing dark or
silent choroid, as lipofuscin in the retinal pigment epithelium block choroidal vessel.
 CHAPTER
9

Eyelid Anomalies
Kammi B. Gunton ■
ANKYLOBLEPHARON FILIFORME ADNATUM
Etiology
Ectodermal dysplasia, temporary epithelial arrest, and rapid mesenchymal
proliferation allow fusion of eyelid margin. Normal eyelids are only fused until the fifth
gestational month.
May be sporadic or associated with three ectodermal syndromes: ankyloblepharon-
ectodermal dysplasia-clefting (AEC) (TP63 gene deficits), popliteal pterygium
syndrome with webbing in lower limbs (IRF6 gene deficits), or curly hair-
ankyloblepharon-nail dysplasia
Has also been associated with meningocele, hydrocephalus, patent ductus arteriosis
or ventral septal defects, iridogoniodysgenesis with glaucoma, imperforate anus,
bilateral syndactyly

Symptoms
Inability to open eye
May occur unilaterally or bilaterally

Signs
Partial or complete fusion of eyelid margins along portion of their length by webs of
skin (Fig. 9-1) arise from gray line anterior to the meibomian glands and posterior to the
cilia
Shortened vertical palpebral fissure
Differential Diagnosis
Cryptophthalmos, failure of differentiation of eyelid structures; the cornea is attached
to eyelid skin
Congenital coloboma, defect within the eyelid, small notch or entire eyelid absent
Epiblepharon, with extra fold of orbicularis, in the lower eyelid, turning eyelashes
inward; no attachment between eyelids

Diagnostic Evaluation
External examination of the eyelids reveals strands or a web of skin attaching the
eyelid margin.
Underlying cornea and eye structures are intact and unaffected.
Consultation for associated ectodermal and other conditions
Molecular genetic testing for TP63 or IRF6 mutations if indicated

Treatment
Spontaneous resolution may occur, but surgical incision may be needed to prevent
amblyopia.
Hemostat to connective tissue followed by excision of skin strands or webs. Edges
of conjunctiva and eyelid margin are apposed with sutures to prevent readhesion of
skin.

Prognosis
Excellent prognosis with treatment

REFERENCES
Alami B, Maadane A, Sekhsoukh R. Ankyloblepharon filiforme adnatum: a case report. Pan Afr Med J. 2013;15:15.
Jain S, Atkinson A, Hopkisson B. Ankyloblepharon filiforme adnatum. Br J Ophthalmol. 1997;81(8):705.
Lopardo T, Loiacono N, Marinari B, et al. Claudin-1 is a p63 target gene with a crucial role in epithelial development.
PLoS One. 2008;3(7):e2715.
Scott MH, Richard JM, Farris BK. Ankyloblepharon filiforme adnatum associated with infantile glaucoma and
iridogoniodysgenesis. J Pediatr Ophthalmol Strabismus. 1994;31(2):93–95.
 FIGURE 9-1. Ankyloblepharon with coloboma, right eyelid. (Courtesy of Robert Penne, MD,
Department of Oculoplastics, Wills Eye Hospital, Philadelphia.)

BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS

INVERSUS SYNDROME (BPES)
Etiology
Autosomal dominant inheritance
Associated with FOXL2 mutations, commonly autosomal dominant

Symptoms
Present congenitally
Severe ptosis may cause ametropic amblyopia with blurred vision
Chin-up head posture

Signs
Shortened horizontal palpebral fissure with three associated major signs: telecanthus
(widened intercanthal distance with normal interpupillary distance), epicanthus inversus
(skin fold from lower eyelid running upward), and severe ptosis (Fig. 9-2)
 Additional signs include lower eyelid entropion, a poorly developed nasal bridge,
hypoplasia of superior orbital rim, low-set ears, a short philtrum, refractive errors,
strabismus, amblyopia, hypertelorism, laterally displaced inferior punctum in lower
eyelid, abnormal intelligence with larger genetic rearrangements in FOXL2 gene.
Type I BPES (blepharophimosis, ptosis, epicanthus inversus syndrome) is associated
with ovarian dysfunction, leading to premature ovarian failure.
Type II BPES—classic features with no other associations

Differential Diagnosis
Congenital ptosis: would occur with absence of other features
Epicanthus, isolated finding

Diagnostic Evaluation
Based on the presence of four classic signs: blepharophimosis, ptosis, epicanthus
inversus, and telecanthus
Ophthalmic evaluation for associated conditions
Genetic testing for FOXL2 to assess risk of ovarian dysfunction
Referral to endocrinologist for ovarian dysfunction if indicated, pelvic ultrasound,
bone density assessment

Treatment
Staged surgical treatment of signs, medial canthoplasty including double Z or Y-V-
plasty and intranasal wiring of medial canthus tendons to correct telecanthus at age 3 to
5 followed later by bilateral frontalis sling or levator resection as indicated for ptosis.
With bilateral ametropic amblyopia, ptosis repair may need to be expedited.
Simultaneous medial canthoplasty and blepharoptosis correction in select patients
and correction of lower eyelid transposition may be helpful.

Prognosis
With surgical correction, improved cosmesis is achieved.
Visual prognosis is guarded because of amblyopia development. Timing of surgical
correction is critical to prevent amblyopia.
Ovarian dysfunction is treated with hormone replacement therapy, and reproductive
issues may be addressed with reproductive technologies, including embryo or egg
donation.
REFERENCES
Decock CE, Claerhout I, Leroy BP, Kesteleyn P, Shah AD, De Baere E. Correction of the lower eyelid malpositioning
in the blepharophimosis-ptosis-epicanthus inversus syndrome. Ophthal Plast Reconstr Surg. 2011;27:368–370.
Sebastiá R, Herzog Neto G, Fallico E, Lessa S, Solari HP, Ventura MP. A one-stage correction of the
blepharophimosis syndrome using a standard combination of surgical techniques. Aesthetic Plast Surg. 2011;35:820–
827.
Verdin H, DeBaere E. Blepharophimosis, ptosis and epicanthus inversus. In: Pagon RA, Adam MP, Ardinger HH, et
al, eds. GeneReviews. Seattle: University of Washington; 2015.

FIGURE 9-2. Child with blepharophimosis syndrome. Note blepharophimosis with telecanthus
(widened intercanthal distance), epicanthus inversus, and severe ptosis. (Courtesy of Robert Penne, MD,
Department of Oculoplastics, Wills Eye Hospital, Philadelphia.)

CHILDHOOD ECTROPION
Etiology
Congenital or acquired
Congenital resulting from absence or atrophy of tarsal plate and anterior lamella
 Acquired resulting from paralytic, cicatricial, or mechanical causes in childhood
with vertical shortening of anterior lamella such as congenital malformations with skin
retraction, floppy eyelid syndrome, trauma, burns, ichthyosis (cicatricial), inflammatory
conditions from medications, bilateral eyelid eversion during delivery, allergies with
orbicularis spasm, or tumors (mechanical)
May occur in association with BPES, euryblepharon, microphthalmos, orbital cysts,
and Down syndrome

Symptoms
Chronic epiphora, conjunctival injection/chemosis, foreign body sensation,
photophobia, reduced vision

Signs
Eversion of eyelid margin; lower eyelid is more commonly involved because of a
vertical deficiency of skin (Fig. 9-3)
Exposure keratitis and conjunctivitis

Differential Diagnosis
Congenital tarsal kink: upper eyelid bent back with 180-degree fold of the upper
tarsal plate
Congenital entropion: distal portion of lower tarsal plate bent inward
Euryblepharon: downward displacement of temporal portion of lower eyelid caused
by enlargement of the lateral aperture

Diagnostic Evaluation
Based on external examination with eversion of the eyelid

Treatment
Mild cases require lubrication with artificial tears or ointments.
With corneal exposure, surgical repair is required with lateral tarsorrhaphy or
lateral canthoplasty to eliminate horizontal eyelid laxity to reposition the eyelid to the
globe.
In severe cases, a full-thickness skin graft is required.
In tarsus agenesis, a uricular cartilage may be used in the graft.
Prognosis
With surgical correction, and skin graft in cases of vertical deficiency of skin, there
is good prognosis.
Must prevent permanent corneal scarring from exposure keratitis, with resulting
amblyopia

REFERENCES
Bedran EG, Pereira MV, Bernandes TF. Ectropion. Semin Ophthalmol. 2010;25:59–65.
Cavuoto KM, Hui JI. Congenital eyelid eversion. J Pediatr Ophthalmol Strabismus. 2010;47:Online:e1-3
doi:10.3928/01913913-20100507-02.
Fea A, Turco D, Actis AG, et al. Ectropion, entropion, trichasis. Minerva Chir. 2013;68:27–35.
Piskiniene R. Eyelid malposition: lower lid entropion and ectropion. Medicina (Kaunas). 2006;42:881–884.
Vallabhanath P, Carter S. Ectropion and entropion. Curr Opinion Ophthalmol. 2000;11:345–351.

FIGURE 9-3. Ectropion. Note eversion of lower eyelids. (Courtesy of Jacqueline Carrasco, MD,
Department of Oculoplastics, Wills Eye Hospital, Philadelphia.)

CONGENITAL ENTROPION
Etiology
 Congenital or acquired
Congenital from retractor dysgenesis and shortened posterior lamella, absence or
kinking in tarsal plate
Acquired from acute spastic, involutional and cicatricial from trachoma, Stevens-
Johnson syndrome, herpes zoster, chemical injury, toxic reaction to topical medications
Involutional entropion is more common in Asians
Often associated with epiblepharon, epicanthus, microphthalmos, and enophthalmos

Symptoms
Epiphora, eyelid rubbing, photophobia
Foreign body sensation, eye pain, conjunctival injection, reduced vision

Signs
Inward turning of eyelid
Lower eyelid more commonly affected
No skin fold in eyelid (Fig. 9-4)
Corneal abrasion or keratitis from eyelash abrasions

Differential Diagnosis
Trichiasis
Epicanthus
Epiblepharon

Diagnostic Evaluation
External examination reveals inward turning of the eyelid margin.
Evaluation for presence of the tarsal plate or etiology of entropion

Treatment
Lubrication to prevent keratitis until surgical correction
Excision of horizontal strip of orbicularis 3 mm from the eyelid border with suturing
of lower eyelid retractors to tarsus stops the preseptal orbicularis from riding over the
pretarsal portion.
Upper eyelid entropion treated with excision of skin and orbicularis to tarsus and
rotation of lid margin (Weis procedure)
 Other surgical procedures include everting (Quickert) sutures and orbicularis
transfer technique.

Prognosis
Prevention of corneal scarring yields a good prognosis.
Risk for amblyopia and refractive error

REFERENCES
Katowitz WR, Katowitz JA. Congenital and developmental eyelid abnormalities. Plast Reconstr Surg. 2009;
124(suppl):93e–105e.
Pereira MG, Rodrigues MA, Rodrigues SA. Eyelid entropion. Semin Ophthalmol. 2010;25:52–58.
Takahashi Y, Ikeda H, Ichinose A, Kakizaki H. Congenital entropion: outcome of posterior layer advancement of
lower eyelid retractors and histological study of orbicularis oculi muscle hypertrophy. Orbit. 2014;33:444–448.
Vahdani K, Konstandinidis A, Thaller VT. A simple new technique for treatment of tarsal kink syndrome. Ophthal
Plast Reconstr Surg. 2017;33(3S suppl 1):S77–S79.
Vallabhanath P, Carter S. Ectropion and entropion. Curr Opinion Ophthalmol. 2000;11:345–351.

FIGURE 9-4. Congenital entropion. Inversion of the lower eyelid. (From Levin AV, Wilson TW,
Pashby R, et al. Lids and adnexa. In: Levin AV, Wilson T, eds. The Hospital for Sick Children’s Atlas of
Pediatric Ophthalmology. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:31–39.)
CONGENITAL PTOSIS
Etiology
Unilateral and most commonly isolated finding, 35% associated with genetic,
chromosomal, or neurologic conditions
Most histologic studies support dysgenesis of levator palpebrae superioris muscle or
innervational abnormalities.
Equal frequency among different races and between sexes

Symptoms
Asymmetry of eyelid position
Amblyopia 1% to 12% prevalence in ptosis

Signs
Vertical shortening of the palpebral fissure caused by upper eyelid droop (Fig. 9-5)
Normal upper eyelid position is 1 to 2 mm below the superior limbus.
Chin-up posture for distance viewing

Differential Diagnosis
Marcus-Gunn jaw wink, anomalous eyelid synkineses
Chronic progressive external ophthalmoplegia
Third nerve palsy
Horner syndrome
Congenital fibrosis of extraocular muscles, congenital cranial dysinnervation
disorder
Myasthenia gravis

Diagnostic Evaluation
Evaluation of eyelid position, margin–corneal reflex distance, levator excursion,
presence of eyelid crease, notation of any abnormal head posture
Refractive error, amblyopia assessment
Evaluate for extraocular muscle functions, especially superior rectus and synergistic
eye movements as well as pupillary response and symmetry
Treatment
Multiple surgical treatments available depending on the degree of levator function
and amount of droop, including frontalis sling; levator resection; Whitnall sling; and in
limited cases with mild ptosis, Müllerectomy

Prognosis
Evaluation for anisometropic amblyopia
Refractive error does not significantly change following ptosis surgery.
Concern for corneal exposure into adulthood, especially in the absence of Bell
phenomenon
Recurrence of ptosis with facial growth, laxity in sutures for frontal sling

REFERENCES
Byard SD, Sood V, Jones CA. Long-term refractive changes in children following ptosis surgery: a case series and a
review of the literature. Int Ophthalmol. 2014;34:1303–1307.
Finsterer J. Ptosis: causes, presentation, and management. Aesthetic Plast Surg. 2003;27:193–204.
Ho YF, Wu SY, Tsai YJ. Factors associated with surgical outcomes in congenital ptosis: a 10-year study of 319 cases.
Am J Ophthalmol. 2017;175:173–182.
Stein A, Kelly JP, Weiss AH. Congenital eyelid ptosis: onset and prevalence of amblyopia, associations with systemic
disorders and treatment outcomes. J Pediatr. 2014;165:820–824.

FIGURE 9-5. Congenital ptosis. Congenital ptosis of the left eye.

EYELID COLOBOMAS
Etiology
Localized failure of fusion of embryonic eyelid folds, failure of adhesion of eyelid
folds, or dehiscence of fused eyelid due to inadequate migration of mesenchyme into
ectodermal fold, trauma from amniotic bands
More common for upper eyelid to be affected and occurs unilaterally, one-third
isolated, remainder associated with ocular or craniofacial abnormality
Associated syndromes include CHARGE, Fraser syndrome, Goldenhar syndrome
(oculo-auriculo-vertebral spectrum), craniofacial dysostosis, clefting disorders,
amniotic band sequence, neurocutaneous syndromes, iris and fundus coloboma
No inheritance pattern for isolated upper eyelid coloboma; loose dominant
hereditary pattern for lower eyelid coloboma; syndromes with genetic associations

Symptoms
Epiphora with corneal, conjunctival exposure especially in upper eyelid coloboma

Signs
Defect in eyelid margin; varies from small defect to absence of length of eyelid (Fig.
9-6)
Isolated upper eyelid defect may be quadrangular or triangular and at junction of
medial and central parts of the eyelid
Edges of defect rounded and covered with conjunctiva
Corneal epithelial erosion and ulceration with large coloboma

Differential Diagnosis
Euryblepharon
Congenital ectropion
Tarsal kink

Diagnostic Evaluation
External examination with complete absence of portion of eyelid margin, including
eyelashes
Assessment for associated ocular abnormalities, symblepharon, choristomas, iris or
fundus coloboma, microphthalmia
Consultation for associated syndrome and genetic workup if applicable

Treatment
Up to one-third eyelid margin repaired with direct closure; lateral cantholysis can
provide horizontal relaxation required for closure
Eyelid sharing procedures such as Cutler-Beard and Hughes in children occlude
visual axis, albeit temporarily, and may result in amblyopia.

Prognosis
Cosmesis guarded depending on size of defect
Prevent corneal scarring to prevent amblyopia

REFERENCES
Smith HB, Verity DH, O’Collin JR. The incidence, embryology, and oculofacial abnormalities associated with eyelid
colobomas. Eye. 2015;29:492–498.
Tawfik HA, Abdulhafez MH, Fouad YA. Congenital upper eyelid coloboma: embryologic, nomenclatorial, nosologic,
etiologic, pathogenetic, epidemiologic, clinical and management perspectives. Ophthal Plast Reconstr Surg.
2015;31:1–12.
 FIGURE 9-6. Upper eyelid coloboma. (Courtesy of Robert Penne, MD, Department of
Oculoplastics, Wills Eye Hospital, Philadelphia.)

EPIBLEPHARON
Etiology
Overriding pretarsal orbicularis with horizontal skin layer pushing the cilia
vertically
Possible etiologies for redundant skin include a weak attachment of the pretarsal
orbicularis to the tarsus, hypertrophy of the orbicularis oculi, or failure of septae in the
subcutaneous plane of the pretarsal orbicularis and overlying skin, resulting in poor
adhesion between the lower eyelid retractors and skin or orbicularis.
More common in Asians, involving lower eyelid, and bilateral

Symptoms
Possibly none or vertical orientation of eyelashes
Severe cases: foreign body sensation, epiphora, conjunctival injection, photophobia,
eyelid rubbing

Signs
Presence of excess horizontal skin along the upper or lower eyelid margin that forces
cilia into a vertical position, often against ocular surface with blink (Fig. 9-7)
Tarsus in a normal position relative to the globe
Corneal epithelial defects in severe cases

Differential Diagnosis
Entropion: eyelid turned inward relative to the globe

Diagnostic Evaluation
External examination with eyelid margin in normal position relative to the globe;
excess horizontal skin fold pushing cilia toward the globe into a vertical position
Evaluation of the cornea for staining

Treatment
 In the absence of corneal pathology, no treatment is indicated. Subsequently, facial
growth frequently eliminates condition.
Appropriate lubrication with ointments to protect corneal surface before surgical
correction when corneal keratitis is detected.
If required, horizontal skin from the eyelid margin is excised with the underlying
orbicularis; reapproximation of the skin edges, pulling the cilia away from the ocular
surface, is made.
Alternatively, the above procedure is combined with thermal cautery to the orbital
septum or a rotating suture allowing adhesion of the septum to the preseptal orbicularis
and preventing overriding of muscle and sutures in the inferior tarsus and upper skin
flap to further rotate cilia from ocular surface

Prognosis
Spontaneous resolution in the majority of cases with facial growth (90%)
Primary excision of pretarsal orbicularis is highly effective; patients with Down
syndrome may have a slightly higher recurrence rate.

REFERENCES
Kakizaki H, Leibovitch I, Takahashi Y, et al. Eyelash inversion in epiblepharon: is it caused by redundant skin? Clin
Ophthalmol. 2009;3:247–250.
Kim JS, Jin SW, Hur MC, et al. The clinical characteristics and surgical outcomes of epiblepharon in Korean children:
a 9-year experience. J Ophthalmol. 2014;2014:156501.
Lee KM, Choung HK, Kim NJ, et al. Prognosis of upper eyelid epiblepharon repair in Down syndrome. Am J
Ophthalmol. 2010;150:476–480.e1.
Woo KI, Kim YD. Management of epiblepharon: state of the art. Curr Opin Ophthalmol. 2016;27:433–438.
 FIGURE 9-7. Epiblepharon. Note the excess horizontal skin in the lower eyelid margin pushing cilia
into a vertical position. (Courtesy of Alex Levin, MD, Department of Pediatric Ophthalmology, Wills Eye
Hospital, Philadelphia.)

EPICANTHUS
Etiology
Usually bilateral; can be isolated or associated with ptosis or BPES, especially
epicanthus inversus
More common in Asians
Histologic studies show possible congenital dysplasia of the medial canthal tendon
with disorganized collagen in BPES contributing to epicanthus.

Symptoms
None

Signs
Semilunar fold of skin extending from upper eyelid medially to the margin of the
lower eyelid
Four types:
 Tarsalis: fold of skin most prominent in upper eyelid; most common (Fig. 9-8)
Inversus: skin fold arises from below the canthus; prominent in lower eyelid
Palpebralis: fold equally distributed between the upper and lower eyelids
Supraciliaris: skin fold originates above the canthus from the eyebrow region

Differential Diagnosis
BPES
Hypertelorism; enlarged bony distance between orbits

Diagnostic Evaluation
External examination of eyelids with notation of skin fold origination site and
prominent eyelid involvement

Treatment
Most often none required; facial growth diminishes appearance, unless epicanthus
inversus
If desired, after facial maturity, reconstruction of eyelid is recommended; in
epicanthus palpebralis and inversus a Y-V procedure, in epicanthus tarsalis, a small V-
Y procedure at inner canthus; in severe epicanthus inversus a double Z may be
indicated.

Prognosis
Good cosmesis with surgical correction if required

REFERENCES
Johnson CC. Developmental abnormalities of the eyelids. Ophthalmic Plast Reconstr Surg. 1986;2:219–232.
Katowitz WR, Katowitz JA. Congenital and developmental eyelid abnormalities. Plast Reconstr Surg.
2009;124(suppl):93e–105e.
 FIGURE 9-8. Epicanthus tarsalis. (Courtesy of Alex Levin, MD, Department of Pediatric
Ophthalmology, Wills Eye Hospital, Philadelphia.)

CAPILLARY HEMANGIOMAS
Etiology
Most common vascular orbital benign tumor of childhood
Unencapsulated lesion with lobules of endothelial cells lining blood-filled spaces
with intervening fibrous septa
More common in females
Present at birth to several months of life; rapid growth for 3 to 6 months in the
proliferative phase followed by quiescence for few years, and then involutional phase
with fibrofatty deposition around endothelial cells with fibrosis and involution of the
lesion
During the proliferative phase, basic fibroblast growth factor (bFGF) and vascular
endothelial growth factor (VEGF) play a role.

Symptoms
Blurred vision, ptosis, skin lesion

Signs
Classic superficial strawberry nevus mass lesion in the skin (Fig. 9-9)
Subcutaneous, blue- to purple-colored mass lesion in the orbit
Proptosis without skin discoloration from deep orbital hemangiomas
 Reduced vision; anisometropic astigmatism

Differential Diagnosis
Lymphangioma: no overlying strawberry nevus, episodic hemorrhages around orbit
Rhabdomyosarcoma: rapid growth with proptosis
Orbital dermoid: classic superotemporal location, slow growth

Diagnostic Evaluation
External examination and imaging study as needed to determine the extent of the
hemangioma
Systemic evaluation for Kasabach-Merritt syndrome with thrombocytopenia and
Posterior fossa brain malformations, Hemangioma, Arterial lesions (head or neck),
Cardia abnormalities, and Eye abnormalities (glaucoma, microphthalmia, optic nerve
hypoplasia, among others) (PHACE) syndrome

Treatment
In the presence of amblyopia, options for treatment include oral steroids,
intralesional steroids, argon laser, injection of sclerosing agents, surgical excision, and
oral and perhaps topical propranolol
Propranolol 2 mg/kg/day divided three times a day; response in size at 24 hours.
Extend oral treatment for 12 months. Propranolol causes rapid vasoconstriction and may
reduce expression of VEGF and bFGF or promote apoptosis of capillary endothelial
cells to reduce the hemangioma. Possible side effects of propranolol include
bradycardia, hypotension, and hypoglycemia, so monitoring is required. Residual
scarring may occur with treatment.
Topical 0.25% timolol gel twice daily showed good response in 60% of cases; not
effective in deep orbital lesions

Prognosis
The involutional phase occurs over 5 to 7 years. Complete resolution occurs in 75%
to 90% of children by age 7.
Amblyopia is difficult to treat and more common in upper eyelid lesions, nasal
eyelid location, lesions larger than 1 cm, and diffuse orbital lesions.

REFERENCES
Chambers CB, Katowitz WR, Katowitz JA, Binenbaum G. A controlled study of topical 0.25% timolol maleate gel for
the treatment of cutaneous infantile capillary hemangiomas. Ophthalmic Plast Reconstru Surg. 2012;28:103–106.
Hernandez JA, Chia A, Quah BL, Seah LL. Periocular capillary hemangioma: management practices in recent years.
Clin Ophthalmol. 2013;7:1227–1232.
Leaute-Labreze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe hemangiomas of infancy. N Engl J
Med. 2008;358:2649–2651.
Schwartz SR, Blei F, Ceisler E, et al. Risk factors for amblyopia in children with capillary hemangiomas of the eyelids
and orbit. J AAPOS. 2006;10:262–268.

FIGURE 9-9. Capillary hemangioma. Right upper eyelid capillary hemangioma. (Courtesy of Judith
Lavrich, MD, Department of Pediatric Ophthalmology, Wills Eye Hospital, Philadelphia.)
 CHAPTER
10

Lacrimal Anomalies
Bruce M. Schnall, Leonard B. Nelson, and Emily Schnall ■
CONGENITAL NASOLACRIMAL DUCT
OBSTRUCTION
Congenital nasolacrimal duct obstruction (NLDO) is the most common abnormality
of infants’ lacrimal apparatus, occurring in 6% of infants.

Etiology
Sporadic
An imperforate membrane at the distal level of the nasolacrimal duct is the usual
cause of occlusion.

Symptoms
Usually presents within the first weeks of life with epiphora and crusting on lashes
Discharge in an eye without conjunctival injection

Signs
Typically, the tears spill over the lower eyelid, and there is a “wet look” in the
involved eye(s) (Fig. 10-1).
Eyelashes may be matted together from mucus discharge.
Conjunctiva usually appears white and uninflamed.

Diagnostic Evaluation
Clinical history, symptoms, and signs are usually enough to establish diagnosis.
 Can perform fluorescein dye disappearance test (Fig. 10-2)
May be mimicked by other disorders that cause excessive tearing such as infantile
glaucoma

Treatment
Although controversy continues to exist, most studies have shown spontaneous
remittance in 80% to 90% of affected infants by 12 months of age.
Massage, eyelid hygiene, and occasional antibiotic treatment
If symptoms are still present by 13 months of age, probing is recommended (Fig. 10-
3).
If repeated probing is necessary and does not eliminate symptoms, the patient may
require intubation with silicone tubing or balloon catheter.

Prognosis
Most congenital NLDOs resolve spontaneously before age 1 and do not need
probing.
Most NLDOs that require probing are cured with that procedure and do not require
an intubation or balloon catheter.

REFERENCES
El-Mansoury J, Calhoun JH, Nelson LB, et al. Results of late probing for congenital nasolacrimal duct obstruction.
Ophthalmology. 1986;93:1052–1054.
Nelson LB, Calhoun JH, Menduke H. Medical management of congenital nasolacrimal duct obstruction. J Pediatric
Ophthalmol Strabismus. 1985;76:172–175.
Pediatric Eye Disease Investigator Group. Primary treatment of nasolacrimal duct obstruction with nasolacrimal duct
intubation in children less than four years old. J AAPOS. 2008;12:445–450.
Pediatric Eye Disease Investigator Group. Balloon catheter dilation and nasolacrimal duct intubation for treatment of
nasolacrimal duct obstruction after failed probing. Arch Ophthalmol. 2009;127(5):633–639.
FIGURE 10-1. Nasolacrimal duct obstruction. A. Nasolacrimal duct obstruction (NLDO) showing
the “wet look,” with matting of the lashes. B. Bilateral NLDO, tearing, and matting of the lashes. Notice
that the conjunctiva is clear. C. Right NLDO, no obstruction on left. Notice lashes are matted on right
eye only.

FIGURE 10-2. Nasolacrimal duct obstruction. Dye disappearance test with photograph taken 10
minutes after placing fluorescein dye in both eyes. Fluorescein remains in right eye indicating right
nasolacrimal duct is obstructed. Fluorescein has drained from left eye into the nose and can be seen
draining from the left nares indicating the left nasolacrimal duct is patent.
 FIGURE 10-3. Nasolacrimal system probing. A. Probe in the lacrimal system. B. Probe buried
under nasal mucosa of the inferior turbinate at time of probing viewed by nasal endoscopy. Frequently, a
“pop” can be felt as the probe breaks through the nasal mucosa. C. Probe has now broken through the
nasal mucosa and can be see exiting under the inferior turbinate.

DACRYOCELE
An obstruction proximally and distally in the lacrimal system of a newborn causing
the lacrimal sac to swell, appearing as a mass in the lower lid nasally. The valve of
Hasner distends into the nose, producing an intranasal cyst. It is also referred to as
amniotocele and congenital mucocele.

Etiology
Sporadic
Membrane at the valve of Hasner (where the lacrimal system enters the nose) and
ball valve effect at the valve of Rosenmüller (entrance of canaliculi into the lacrimal
sac) allow fluid to accumulate in the lacrimal system causing the lacrimal sac to
enlarge. This accumulating fluid distends the membrane at the valve of Hasner into the
nose, producing an intranasal cyst.
 Usually present at birth—however, may begin in the first few weeks of life.

Symptoms
Tearing
Difficulty breathing from associated intranasal cyst
Difficulty with breastfeeding on the mother’s breast ipsilateral to the mucocele

Signs
Blue-gray swelling inferior to the medial canthal tendon at birth (Fig. 10-4)
Distended lacrimal sac will displace the medial canthal tendon superiorly, causing
the lid fissure to slant upward nasally.
Secondary infection (erythema of the tissues overlying the lacrimal sac) may occur
(Fig. 10-5).
Will extend intranasally as a submucocele mass beneath the inferior turbinate (Fig.
10-6)

Differential Diagnosis
Hemangioma
Dermoid
Encephalocele
Nasal glioma
Phakomatous choristoma

Treatment
Oftentimes will resolve within a few days with massage, warm compresses, and
topical antibiotics
Dacryocystitis can develop rapidly and requires IV antibiotics and hospitalization.
If the dacryocele cannot be decompressed with massage, within several days, prompt
probing with excision of the associated intranasal cyst with nasal endoscopy is
recommended. Rarely, serious complications of central nervous system infections have
been reported; therefore, some have recommended early probing.
Infected dacryoceles should be treated with 24 hours of IV antibiotics before probing
and excision of intranasal cyst.
Prognosis
The resolution rate with conservative management is approximately 76%.
Probing with intranasal cyst excision has been reported to have a 95% success rate.

REFERENCES
Harris GJ, DiClementi D. Congenital dacryocystocele. Arch Ophthalmol. 1982;100:1763–1765.
Paysee EA, Coats DK, Bernstein JM, et al. Management and complications of congenital dacryocele with concurrent
intranasal mucocele. J AAPOS. 2000;4:46–53.
Schnall BM, Christian CJ. Conservative treatment of congenial dacryocele. J Pediatr Ophthalmol Strabismus.
1996;33:219–222.
Shekunov J, Griepentrog GJ, Diehl NN, Mohney BG. Prevalence and clinical characteristics of congenital
dacryocystocele. J AAPOS. 2010;14:417–420.
FIGURE 10-4. Dacryocele. A. Dacryocele of the nasolacrimal system showing swelling and mild
erythema. The lid fissure slants upward nasally. B. Dacryocele showing more significant swelling and
erythema. C. Bilateral dacryoceles.
FIGURE 10-5. Dacryocele. A. Congenital dacryocele before probing. B. Same patient at time of
office probing with a large amount of material draining from the lacrimal sac.
 FIGURE 10-6. Dacryocele. Intranasal cyst (arrow) associated with a congenital dacryocele viewed by
nasal endoscopy at the time of probing. This intranasal cyst is excised at the time of probing.

LACRIMAL FISTULA
An epithelial-lined tract from the lacrimal system to the overlying skin

Etiology
Congenital
Likely occurs during embryogenesis with the canalization of a cord of epithelial cells
from the lacrimal sac or common canaliculus to the skin

Symptoms
Usually asymptomatic but may be associated with tearing or discharge

Signs
Appears as an umbilication in the skin inferonasal to the medial canthus (Fig. 10-7)
Diagnostic Evaluation
Clinical appearance is usually enough to establish diagnosis. Probing the fistula can
demonstrate its connection to the lacrimal system.

Treatment
If asymptomatic, no treatment is needed.
If associated with discharge or tearing, the fistula tract can be closed with cautery or
excised and the lacrimal system probed.

Prognosis
Most congenital lacrimal fistula do not require treatment.

REFERENCE
Birchansky LD, Nerad JA, Kersten RC, et al. Management of congenital lacrimal sac fistula. Arch Ophthalmol.
1990;108:388–390.
FIGURE 10-7. Lacrimal fistula. A. Congenital lacrimal fistula (arrow) appearing as an umbilication
inferonasal to medial canthus. B. Same patient with congenital lacrimal fistula (arrow) in the left eye.
 CHAPTER
11

Strabismus Disorders
Scott E. Olitsky and Leonard B. Nelson ■
PSEUDOESOTROPIA
Epidemiology and Etiology
Pseudoesotropia is one of the most common reasons an ophthalmologist is asked to
evaluate an infant. In some series, up to half of children with suspected strabismus were
found to have pseudoesotropia.
Pseudoesotropia is characterized by the false appearance of strabismus when the
visual axes are actually aligned (Fig. 11-1).

History
Pseudoesotropia is usually caused by a flat, broad nasal bridge; prominent epicanthal
folds; or a narrow interpupillary distance. An observer may perceive less white sclera
nasally than would be expected, and the impression is that the eye is turned in toward
the nose, especially when the child looks to either side.

Differential Diagnosis
Small-angle strabismus
Intermittent strabismus

Diagnostic Evaluation
Pseudoesotropia can be differentiated from true strabismus when the corneal light
reflex is seen to be centered in both eyes or when the cover–uncover test shows no
refixation movement.
 Tightening the epicanthal folds by pinching the bridge of the nose can also be
effective in demonstrating that the “crossing” is not real.
A complete evaluation should be performed, including cycloplegic refraction, to rule
out excessive hyperopia that could be causing intermittent esotropia.

Treatment
No treatment is needed. Parents can be reassured that most children will outgrow the
appearance of crossing.

Prognosis
As the child grows, the bridge of the nose becomes more prominent and displaces the
epicanthal folds, and the medial sclera becomes proportional to the amount visible on
the lateral aspect of the eye. Parents should be cautioned that children with
pseudoesotropia, like any child, can develop true strabismus later in life. Therefore, if a
change in appearance occurs, a repeat evaluation may be warranted.

CONGENITAL (INFANTILE) ESOTROPIA

Epidemiology and Etiology
The cause of congenital esotropia is unknown. Theories include both a primary
defect in sensory development of the brain that leads to abnormal alignment and a
primary “motor” theory in which the ocular misalignment is the primary abnormality,
which then leads to a secondary disruption of binocular vision. It is likely that both
causes exist and may also be equally responsible for the development of the disorder in
many children.
The incidence of congenital esotropia is approximately 1 in 1000 children.

Signs and Symptoms

Few children who are eventually diagnosed with this disorder are actually born with
an esotropia. Although parents often give a history of their child’s eyes crossing since
birth, the crossing is rarely seen in the newborn nursery and is generally not observed
during the first few weeks of life.
The diagnosis is generally made when an infant presents before 6 months of age with
a large (≥30 prism diopter), constant esotropia, full abduction, a normal level of
hyperopia, and no underlying ophthalmic disorder that could lead to vision loss and a
secondary strabismus (Fig. 11-2). Children with congenital esotropia often appear to
exhibit an apparent abduction deficit. This pseudoparesis is usually secondary to the
presence of cross fixation. If the child has equal vision, he or she will have no need to
abduct either eye. The child will use the adducted, or crossed, eye to look to the
opposite field of gaze. In this case, he or she will show a bilateral pseudoparesis of
abduction. If amblyopia is present, only the better-seeing eye will cross fixate, making
the amblyopic eye appear to have an abduction weakness. To differentiate between a
true abducens paralysis and a pseudoparalysis, a doll’s head maneuver can be used or
abduction can be examined after the infant has worn a patch over one eye for a period of
time.

Differential Diagnosis
Pseudoesotropia
Duane retraction syndrome
Möbius syndrome
Congenital sixth nerve palsy
Early-onset accommodative esotropia
Sensory esotropia
Esotropia in the neurologically impaired

Diagnostic Evaluation
All children with suspected congenital esotropia should undergo a complete
examination, including a dilated funduscopic evaluation and cycloplegic refraction to
rule out possible early-onset accommodative esotropia or a secondary strabismus (Fig.
11-3).
Amblyopia can be diagnosed by looking for a fixation preference.
If an accommodative component to the crossing is considered to be a possibility, the
child should be given the full cycloplegic refraction and reevaluated to look for any
effect on the crossing.

Treatment
The treatment for congenital esotropia consists of strabismus surgery. Surgery is
performed after any associated amblyopia, if present, is treated. It is important to treat
amblyopia before surgery. It is much easier to follow the progress of amblyopia in a
preverbal child while his or her eyes are crossed. In addition, parental compliance with
amblyopia treatment tends to be much lower after the eyes are straightened and appear
“normal.”
The primary goal of treatment in congenital esotropia is to eliminate or reduce the
deviation as much as possible. Ideally, this results in normal visual acuity in each eye,
straight-looking eyes, and the development of binocular vision.

Prognosis
Children with congenital esotropia do not develop normal (bifoveal) binocular
vision. Successful treatment provides the opportunity to develop some degree of
binocular vision (monofixation syndrome), which allows the development of motor
fusion and helps to keep their eyes aligned.
Even with successful initial treatment, many children with a history of congenital
esotropia may redevelop strabismus or amblyopia and therefore need to be monitored
closely during the visually immature period of life.
Recurrent horizontal strabismus is common as are vertical deviations. These may
develop months or years after the initial surgery has been performed. The two most
common forms of vertical deviations to develop are inferior oblique muscle overaction
(IOOA) and dissociated vertical deviation (DVD).

REFERENCES
Archer SM, Sondhi N, Helveston EM. Strabismus in infancy. Ophthalmology. 1989;96:133.
Arthur BW, Smith JT, Scott WE. Long-term stability of alignment in the monofixation syndrome. J Pediatr Ophthalmol
Strabismus. 1989;26:224.
Birch E, Stager D, Wright K, et al. The natural history of infantile esotropia during the first six months of life. J
AAPOS. 1998;2:325–328.
Birch EE, Stager DR, Everett ME. Random dot stereoacuity following surgical correction of infantile esotropia. J
Pediatr Ophthalmol Strabismus. 1995;32:231.
Ing M, Costenbader FD, Parks MM, et al. Early surgery for congenital esotropia. Am J Ophthalmol. 1966;62:1419.
Parks MM. The monofixation syndrome. Trans Am Ophthalmol Soc. 1969;67:609.
FIGURE 11-1. Pseudoesotropia. Pseudoesotropia caused by a wide nasal bridge and epicanthal folds.
Note that the child is looking slightly to the left which also accentuates the false appearance that there is
less sclera in the right eye.

FIGURE 11-2. Congenital (infantile) esotropia. (From Nelson LB, Olitsky SE. A Color Handbook
of Pediatric Clinical Ophthalmology. London, England: Manson Publishing; 2011.)

FIGURE 11-3. Sensory esotropia. Sensory esotropia secondary to a congenital cataract in the right
eye.
INFERIOR OBLIQUE OVERACTION
Epidemiology and Etiology
Inferior oblique overaction occurs in a primary and secondary form. Most patients
with primary IOOA have a history of congenital esotropia, but it may occur in
association with other forms of strabismus as well. Up to 80% of patients with a history
of congenital esotropia may develop IOOA. Secondary IOOA occurs in patients with
superior oblique palsy.

Signs and Symptoms

IOOA results in elevation of the involved eye as it moves nasally (Fig. 11-4).

Differential Diagnosis
DVD
Duane syndrome with upshoot

Diagnostic Evaluation
The amount of overaction is evaluated in the field of action of the inferior oblique
muscle in question. IOOA can be classified as grades I to IV. Grade I represents 1 mm
of higher elevation of the adducting eye in gaze up and to the side. Grade IV indicates 4
mm of higher elevation. These differences in elevation between the two eyes are
measured from the 6-o’clock position on each limbus. A measurement of the degree of
adduction that is required to elicit the overaction is also helpful when considering
treatment.

Treatment
IOOA can be treated surgically. The thresholds for surgery for IOOA are different,
depending on whether weakening the inferior oblique is the only surgery being
contemplated or whether weakening the inferior oblique in conjunction with horizontal
strabismus surgery is being considered. If the inferior obliques alone are weakened,
there should be a significant overaction present to justify surgery. If horizontal surgery
is being performed, smaller grades of inferior oblique overaction may be corrected at
the same time. Inferior oblique recession, myotomy, myectomy, or denervation and
extirpation can be performed to weaken the action of the inferior oblique.
Anterior transposition of the inferior oblique can also be performed to limit the
elevation of the eye and may be the treatment of choice when both IOOA and DVD
occur together.

Prognosis
Surgery is generally successful in improving the overacting inferior oblique muscle.
Care must be taken to not miss any fibers of the muscle at the time of surgery.

REFERENCES
Parks MM. A study of the weakening surgical procedure for eliminating overaction of the inferior oblique. Am J
Ophthalmol. 1972;73:107.
Stager DR. Costenbader lecture. Anatomy and surgery of the inferior oblique muscle: recent findings. J AAPOS.
2001;5:203–208.

FIGURE 11-4. Inferior oblique overaction. Inferior oblique overaction in both eyes. Note the
elevation of each eye in adduction.

DISSOCIATED VERTICAL DEVIATION

Epidemiology and Etiology
Most patients with DVD have a history of congenital esotropia, but it may occur in
association with other forms of strabismus as well.
Up to 90% of patients with a history of congenital esotropia may develop DVD.
DVD appears to be a time-related phenomenon and is not related to successful initial
surgery or the development of binocular vision.

Signs and Symptoms

DVD consists of a slow upward deviation of one or alternate eyes (Fig. 11-5).
Excyclotorsion can often be demonstrated on upward drifting of the eye and
incyclotorsion on downward motion.
DVD may be latent, detected only when the involved eye is covered, or manifest,
occurring intermittently or constantly. It can be differentiated from a true vertical
deviation because no corresponding hypotropia occurs in the other eye on cover testing.
Differential Diagnosis
Inferior oblique overaction
Hypertropia

Diagnostic Evaluation
DVD can be estimated by using the Hirschberg and Krimsky methods or the prism
cover test. A base-down prism is placed over the involved eye. The strength of the
prism is adjusted until no movement occurs as the cover is shifted from the involved to
the fixating eye. Because prism cover measurement is difficult and may be inaccurate,
DVD can also be estimated using a semiquantitative grading scale (1 to 4+).

Treatment
If amblyopia exists, improvement in vision may improve fusional control and
decrease how frequently the deviation is manifest.
If DVD is entirely latent, detected on cover testing only, surgery is not indicated. If it
is intermittent, surgery is determined by the size and frequency of the deviation as well
as the patient’s concern regarding its appearance. Surgical treatment for DVD includes
recession of the superior rectus and recession of the superior rectus combined with a
posterior fixation suture and anterior transposition of the inferior oblique (preferred if
IOOA coexists).

Prognosis
It is often not possible to completely eliminate DVD. The goal of treatment is to
reduce the magnitude of the deviation enough that it is not noticeable when it is manifest.

REFERENCES
Bacal DA, Nelson LB. Anterior transposition of the inferior oblique muscle for both dissociated vertical deviation
and/or inferior oblique overaction: results of 94 procedures in 55 patients. Binocular Vision Eye Muscle Surg.
1992;7:219.
Christoff A, Raab EL, Guyton DL, et al. DVD—a conceptual, clinical, and surgical overview. J AAPOS.
2014;18:378–384.
 FIGURE 11-5. Dissociated vertical deviation. A. Right eye occluded. B. Dissociated vertical
deviation manifest after occlusion. (Courtesy of Alex Levin, MD.)

REFRACTIVE ACCOMMODATIVE ESOTROPIA

Epidemiology and Etiology
The mechanism of refractive accommodative esotropia involves three factors:
uncorrected hyperopia, accommodative convergence, and insufficient fusional
divergence. When an individual exerts a given amount of accommodation, a specific
amount of convergence (accommodative convergence) is associated with it. An
uncorrected hyperopia must exert excessive accommodation to clear a blurred retinal
image. This in turn stimulates excessive convergence. If the amplitude of fusional
divergence is sufficient to correct the excess convergence, no esotropia will result.
However, if the fusional divergence amplitudes are inadequate or motor fusion is
altered by some sensory obstacle, an esotropia will result.

Signs and Symptoms

Refractive accommodative esotropia usually occurs in a child between 2 and 3 years
of age with a history of acquired intermittent or constant esotropia. Occasionally,
children who are 1 year of age or younger present with accommodative esotropia.
The refraction of patients with refractive accommodative esotropia averages +4.75
diopters. The angle of esodeviation is the same when measured at distance and near
fixation and is usually moderate in magnitude, ranging between 20 and 40 prism
diopters. Amblyopia is common, especially when the esodeviation has become
increasingly constant.

Differential Diagnosis
Congenital esotropia
 Nonaccommodative esotropia
Nonrefractive accommodative esotropia

Diagnostic Evaluation
A complete examination should be performed, including a cycloplegic refraction.

Treatment
The full hyperopic correction, determined by cycloplegic refraction, should be
prescribed.

Prognosis
Most children will maintain straight eyes while wearing their glasses (Fig. 11-6).
Some children may show an increase in their hyperopia, which can lead to a recurrent
crossing. A nonaccommodative esotropia may develop in a small percentage of
children. Patients with relatively smaller levels of hyperopia may eventually outgrow
their need for glasses as their hyperopic refractive error lessens with age.

REFERENCES
Coats DK, Avilla CW, Paysse EA, et al. Early-onset refractive accommodative esotropia. J AAPOS. 1998;2:275–278.
Raab EL. Etiologic factors in accommodative esodeviation. Trans Am Ophthalmol Soc. 1982;80:657.

FIGURE 11-6. Refractive accommodative esotropia. A. With the appropriate hyperopic glasses, the
eyes are straight. B. Without glasses, there is an esotropia of 25 prism diopters.

NONREFRACTIVE ACCOMMODATIVE ESOTROPIA

Epidemiology and Etiology
Children with nonrefractive accommodative esotropia usually present between 2 and
3 years of age with an esodeviation that is greater at near than at distance fixation. The
refractive error in this condition may be hyperopic or myopic, although the average
refraction is +2.25 diopters.
In nonrefractive accommodative esotropia, there is a high accommodative
convergence–to–accommodation (AC:A) ratio: The effort to accommodate elicits an
abnormally high accommodative convergence response.

Signs and Symptoms

Some parents notice the crossing that only takes place at near fixation.
There are a number of ways of measuring the AC:A ratio. Most clinicians prefer to
assess the ratio using the distance–near comparison. The AC:A relationship is derived
by simply comparing the distance and near deviation. If the near measurement in a
patient with esotropia is greater than 10 prism diopters, the AC:A ratio is considered to
be abnormally high.

Differential Diagnosis
Refractive accommodative esotropia

Diagnostic Evaluation
A complete examination, including a measurement of the esotropia at both distance
and near fixation as well as a cycloplegic refraction, should be performed.

Treatment
Treatment often involves the use of bifocal lenses to eliminate the accommodative
effort required for near work. The bifocal is usually prescribed as an executive-type
lens that bisects the pupil.
Another treatment option is strabismus surgery. Some patients may be followed
because those with good alignment at distance usually develop normal vision.

Prognosis
Many patients show a normalization of their AC:A ratio over time.
Some patients decompensate and develop a nonaccommodative component that may
require surgery. The risk of decompensation appears to be related to the magnitude of
the distance–near disparity of the crossing.

REFERENCES
Kushner BJ. Fifteen-year outcome of surgery for the near angle in patients with accommodative esotropia and a high
accommodative convergence to accommodation ratio. Arch Ophthalmol. 2001;119:1150–1153.
Ludwig IH, Parks MM, Getson PR. Long-term results of bifocal therapy for accommodative esotropia. J Pediatr
Ophthalmol Strabismus. 1989;26:264.
Pratt-Johnson JA, Tillson G. The management of esotropia with high AC/A ratio (convergence excess). J Pediatr
Ophthalmol Strabismus. 1985;22:238.
Whitman MC, MacNeill K, Hunter DG. Bifocals fail to improve stereopsis outcomes in high AC/A accommodative
esotropia. Ophthalmology. 2016;123:690–696.

NONACCOMMODATIVE OR PARTIALLY
ACCOMMODATIVE ESOTROPIA
Epidemiology and Etiology
Refractive or nonrefractive accommodative esotropias do not always occur in their
“pure” forms. Some patients may show no response to correction of their hyperopia.
Other patients may have a significant reduction in esodeviation when given glasses, but
a residual esodeviation persists despite full hyperopic correction. Still others may show
an initial good response only to develop a crossing that can no longer be completely
corrected with glasses. The crossing not corrected with the glasses is the
nonaccommodative portion. This condition commonly occurs when there is a delay of
months between the onset of accommodative esotropia and antiaccommodative
treatment.

Signs and Symptoms

Patients with nonaccommodative esotropia have little or no hyperopia. They may
also have a level of hyperopia that does not appear compatible with the degree of
crossing.
Patients with a partial accommodative esotropia appear to have a level of hyperopia
that will correct their crossing. However, they do not demonstrate a resolution of their
crossing when wearing their glasses.

Differential Diagnosis
Congenital esotropia
Accommodative esotropia

Diagnostic Evaluation
A complete examination with cycloplegic refraction should be performed. If a
significant level of hyperopia exists, the patient should be prescribed the full hyperopic
correction and return after wearing glasses for a period of time.

Treatment
If the nonaccommodative component of the crossing is large enough to prevent the
development of binocular vision, strabismus surgery should be considered. Some
surgeons will not opt for surgery if the crossing is small and not easily noticed.

Prognosis
Patients with small levels of hyperopia may be able to discontinue wearing their
glasses. Recurrent strabismus is possible in these patients, who often have abnormal
binocular vision even after successful treatment.

CONGENITAL EXOTROPIA
Epidemiology and Etiology
Congenital exotropia behaves in a very similar fashion to congenital esotropia. It
typically occurs early in life and presents with a large, constant out-turning. Congenital
exotropia may be associated with neurologic disease or abnormalities of the bony orbit,
as in Crouzon syndrome.

Signs and Symptoms

Patients with congenital exotropia often appear to have decreased adduction on side
gaze; with gaze right or left, the abducting eye fixates, whereas the opposite eye
approaches midline and stops. This is similar to the cross fixation found in children
with congenital esotropia. Occlusion or the doll’s head maneuver will demonstrate that
good adduction is possible.
Amblyopia is not common because these children typically alternate fixation. The
refractive error is similar to that of the general population.

Differential Diagnosis
Early-onset intermittent exotropia
Third cranial nerve palsy
Bilateral intranuclear ophthalmoplegia

Diagnostic Evaluation
 A complete examination should be performed.
Other signs of a cranial nerve palsy (ptosis, decreased motility) should be
eliminated.

Treatment
Patients with congenital constant exotropia are operated on early in life in the same
manner as patients with congenital esotropia.

Prognosis
Similar to patients with congenital esotropia, early surgery in these patients can lead
to gross binocular vision but not bifoveal fixation.
These patients also tend to develop DVD and IOOA and should be followed closely
for the development of these associated motility disturbances.

REFERENCES
Hunter DG, Kelly JB, Buffenn AN, et al. Long-term outcome of uncomplicated infantile exotropia. J AAPOS.
2001;5:352–356.

INTERMITTENT EXOTROPIA
Epidemiology and Etiology
Intermittent exotropia is the most common exodeviation in childhood.
The etiology of intermittent exotropia is unknown but probably results from a
combination of mechanical and innervational factors.

Signs and Symptoms

The age of onset of intermittent exotropia varies but is often between 6 months and 4
years.
It is characterized by outward drifting of one eye, which usually occurs when a child
is fixating at a distance (Fig. 11-7). The deviation is generally more frequent with
fatigue or illness. Exposure to bright light may cause reflex closure of the exotropic eye.
Because the deviation generally begins with distance fixation and is only seen when
the child is tired, it is often not seen when the child is examined by a primary medical
doctor at close distance or during a well-child visit.
Differential Diagnosis
Congenital exotropia

Diagnostic Evaluation
A complete evaluation should be performed. Motility measurements at both distance
and near fixation should be completed. A qualitative measurement of the control of the
strabismus should be noted.

Treatment
Any coexistent amblyopia should be treated. Significant refractive errors should be
corrected. Some ophthalmologists use medical treatments to avoid surgery in some
patients. These nonsurgical treatments include part-time occlusion, orthoptic therapy,
and over-minus lens therapy. Most patients eventually require strabismus surgery when
the deviation becomes manifest frequently.

Prognosis
Surgery is successful in aligning most patients’ eyes. Some patients will redevelop
strabismus and may require more surgery.

REFERENCES
Kushner BJ. Exotropic deviations: a functional classification and approach to treatment. Am Orthoptic J. 1988;38:81–
93.
Pediatric Eye Disease Investigator Group. A randomized trial comparing part-time patching with observation for
intermittent exotropia in children 12 to 35 months of age. Ophthalmology. 2015:1718–1725.

FIGURE 11-7. Intermittent exotropia. Intermittent exotropia demonstrating manifest exotropia at

distance fixation.
A AND V PATTERN STRABISMUS
Epidemiology and Etiology
A and V patterns are manifested by a horizontal change of alignment as the eyes
move from the primary position to midline upgaze or downgaze.
A number of different theories have evolved to explain the etiology of A and V
patterns. There is no universal agreement of their cause at this time.
Oblique muscle dysfunction is often seen in the setting of A and V pattern strabismus
(Figs. 11-8 and 11-9). The oblique muscles have secondary abducting action.
Therefore, when the superior obliques are overacting, they may cause an A pattern;
when the inferior obliques are overacting or the superior obliques are underacting, a V
pattern often results. However, A and V patterns frequently exist in the absence of
demonstrable oblique dysfunction.

Signs and Symptoms

Esotropia with V pattern increases in downgaze and decreases in upgaze. The
deviation in V exotropia increases in upgaze and decreases in downgaze.
In A esotropia, the deviation increases in upgaze and decreases in downgaze.
In A exotropia, the deviation increases in downgaze and decreases in upgaze.
Anomalous head posture is common in patients with A and V patterns.
Patients with A esotropia and V exotropia and fusion in downgaze may develop a
chin-up position. Conversely, V esotropia and A exotropia may cause chin depression.

Differential Diagnosis
A and V pattern strabismus should be looked for in patients with compensatory chin-
up or chin-down strabismus.
Restrictive or paralytic strabismus may also present with abnormal head postures.
Brown syndrome may manifest a V pattern.

Diagnostic Evaluation
The A and V patterns are demonstrated by measuring a deviation in primary position
and in approximately 25 degrees of upgaze and downgaze while the patient fixates on a
distant object.
An A pattern is said to exist if divergence increases in downgaze by 10 or more
prism diopters.
A V pattern signifies an increase in divergence of 15 or more prism diopters in
upgaze. The smaller amount of change required to make a diagnosis of an A pattern is
caused by the greater effect of the downgaze deviation on reading and other near tasks.

Treatment
Patients with torticollis may benefit from treatment. Patients with large patterns often
have significant oblique dysfunction. Treatment of the oblique dysfunction is usually
needed to treat these large patterns. However, superior oblique weakening should be
done with extreme caution in patients with A pattern strabismus and good binocular
function because an asymmetric result can lead to permanent torsional diplopia. In
patients without oblique dysfunction, vertically moving or offsetting the horizontal
rectus muscle weakens the action of that muscle when the eye is moved in the direction
of the offsetting. For example, if the medial rectus muscles are moved up one-half
tendon width, their horizontal action further decreases in upgaze. Therefore, moving the
medial rectus toward the apex of an A and V pattern or moving the lateral rectus muscle
toward the open end of the A or V is appropriate for correcting the incomitant deviation.
This is true regardless of whether recession or resection is performed. The tendon is
generally moved up or down half of its insertion width.

Prognosis
Surgery is generally effective in collapsing the pattern and decreasing or eliminating
the associated head posture when present.

REFERENCES
Knapp P. Vertically incomitant horizontal strabismus: the so called A and V syndrome. Trans Am Ophthalmol Soc .
1959;57:666–698.
Scott WE, Drummond GT, Keech RV. Vertical offsets of horizontal recti muscles in the management of A and V
pattern strabismus. Aust N Z J Ophthalmol. 1989;17:281.
FIGURE 11-8. V pattern esotropia. The esotropia increases in straight downgaze and decreases in
straight upgaze.
 FIGURE 11-9. A pattern esotropia. The esotropia increases in straight upgaze and decreases in
straight downgaze.

THIRD NERVE PALSY

Epidemiology and Etiology
In children, third nerve palsies are usually congenital. The congenital form is often
associated with a developmental anomaly or birth trauma. Acquired third nerve palsies
can be an ominous sign and may indicate a neurologic abnormality, such as an
intracranial neoplasm or an aneurysm. Other less serious causes include an
inflammatory or infectious lesion, head trauma, postviral syndromes, and migraines.

Signs and Symptoms

A third nerve palsy, whether congenital or acquired, usually results in an exotropia
and a hypotropia of the affected eye, as well as complete or partial ptosis of the upper
eyelid (Fig. 11-10A). This characteristic strabismus results from the action of the
normal, unopposed muscles, the lateral rectus muscle and the superior oblique muscle.
If the internal branch of the third nerve is involved, pupillary dilation may be noted as
well. Adduction, elevation, and depression are usually limited (Fig. 11-10B).
In congenital and traumatic cases of third nerve palsy, a misdirection of regenerating
nerve fibers may develop, referred to as aberrant regeneration. This results in
anomalous and paradoxical eyelid, eye, and pupil movement, such as elevation of the
eyelid, constriction of the pupil, or depression of the globe on attempted adduction.

Differential Diagnosis
Congenital exotropia
Congenital fibrosis of the extraocular muscles (CFEOM)

Diagnostic Evaluation
Diagnosis is based on the characteristic exotropia and hypotropia with associated
limitation in adduction and vertical movements of the eye.
Pupillary involvement is an especially important sign because it may indicate an
expanding intracranial aneurysm and need for emergent neurologic evaluation and
treatment.
Patients with acquired third nerve palsy should have a neurologic evaluation,
including neuroimaging when indicated.

Treatment
Initial treatment for patients with acquired third nerve palsy involves relief of
diplopia. If there is complete third nerve palsy, the associated complete ptosis will
cover the pupil and prevent diplopia. However, in partial third nerve palsy, the eyelid
may not cover the pupillary space, so diplopia may remain a problem. Occlusion
therapy is then the best solution for the diplopia. In children young enough to develop
amblyopia, the patch should be alternated, so the affected eye will continue to develop
normal vision.
Surgery to correct acquired third nerve palsy should be postponed for several months
after the onset of the condition when possible. If the ptosis is complete and the eyelid
cannot open, early ptosis surgery may be needed in younger children to prevent the
development of amblyopia. In a complete third nerve palsy, the motility of the globe is
severely limited because only the lateral rectus and superior oblique muscles are
functional. Surgical options include lateral rectus recession, superior oblique
weakening or transposition, splitting of the lateral rectus with transposition adjacent to
the medial rectus, and fixation of the globe to the orbital wall with a nonabsorbable
suture or fascia lata.

Prognosis
The goal of surgical intervention is to use the two remaining functional muscles in
such a way as to achieve a straight-ahead eye with only limited movement of the globe.
This goal should be carefully explained to the patient and the parents to avoid
unrealistic postoperative expectations.

REFERENCES
Gokyigit B, Akar S, Satana B, Demirok A, Yilmaz OF. Medial transposition of a split lateral rectus muscle for
complete oculomotor nerve palsy. J AAPOS. 2013;17:402–410.
Keane JR. Third nerve palsy: analysis of 1400 personally-examined inpatients. Can J Neurol Sci. 2010;37:662–670.
 FIGURE 11-10. Third nerve palsy. A and B. Third nerve palsy. (From Nelson LB, Olitsky SE. A
Color Handbook of Pediatric Clinical Ophthalmology. London, England: Manson Publishing; 2011.)

FOURTH NERVE PALSY

Epidemiology and Etiology
Fourth nerve palsy is the most common cause of an isolated cyclovertical muscle
palsy. Paresis of the fourth nerve can be congenital or acquired. Closed-head trauma is
the most common cause of acquired fourth nerve palsy, and other causes include
cerebrovascular accident, diabetes, brain tumor, ethmoiditis, or mastoiditis.
Signs and Symptoms
Patients with unilateral fourth nerve palsy often present with torticollis to reduce
diplopia. This usually consists of a head tilt to the side of the nonparetic eye, a face turn
to the contralateral side, and a small chin-down head posture. Patients with a bilateral
palsy usually place their heads in a chin-down position.
The absence of a head tilt in a preverbal child should raise the suspicion of
amblyopia.
Facial asymmetry has been associated with congenital superior oblique palsy and is
typically manifested by midfacial hemihypoplasia on the dependent side opposite the
affected superior oblique. The nose deviates toward the hypoplastic side, and the mouth
slants so that it approximates a horizontal orientation despite the torticollis.

Differential Diagnosis
Any vertical strabismus that leads to a hypertropia

Diagnostic Evaluation
To evaluate a suspected fourth nerve palsy, a three-step test should be performed. A
patient with a fourth nerve palsy will demonstrate a hypertropia that is worse when
looking to the contralateral side and when the head is tilted to the ipsilateral side of the
affected eye (Fig. 11-11). The three-step test is most useful when the strabismus is acute
and may miss some cases of radiologically confirmed superior oblique palsies.
When a patient presents with a new onset of diplopia secondary to a fourth nerve
palsy, it is important to determine if the palsy has only recently developed or if it
represents a congenital disorder that has decompensated. Several features may help to
determine the acuteness of the deviation. A patient with a congenital superior oblique
palsy will often have large vertical fusional amplitudes and a long-standing head tilt that
can be documented in old photographs. Facial asymmetry may be present.
In patients with a fourth nerve palsy, bilateral involvement should be excluded. Signs
of bilateral fourth nerve palsy include hypertropia that alternates in right and left gaze
and in right and left head tilt, a V pattern esotropia, and a large degree of excyclotorsion
on either double Maddox rod testing or funduscopic evaluation.

Treatment
Except for an occasional patient with a fairly comitant vertical deviation of 10 prism
diopters or less (when prism may be tolerated), most cases of superior oblique palsy
require surgery. In general, surgery for superior oblique palsies should be directed to
those muscles whose greatest action is in the field when the vertical deviation is the
largest. Surgical options include superior oblique tuck, inferior oblique weakening,
ipsilateral superior rectus recession or contralateral inferior rectus recession, or
various combinations of these procedures.

Prognosis
Surgical treatment is helpful in reducing or eliminating the abnormal head posture,
normalizing ocular rotations, and enlarging the area of single binocular vision in most
patients.

REFERENCES
Manchandia AM, Demer JL. Sensitivity of the three-step test in diagnosis of superior oblique palsy. J AAPOS.
2014;18:567–571.
Parks MM. Isolated cyclovertical muscle palsy. Arch Ophthalmol. 1958;60:1027.
Wilson ME, Hoxie J. Facial asymmetry in superior oblique muscle palsy. J Pediatr Ophthalmol Strabismus.
1993;30:315.
 FIGURE 11-11. Fourth nerve palsy. A and B. Fourth nerve palsy.

SIXTH NERVE PALSY

Epidemiology and Etiology
Sixth nerve palsies can be congenital or acquired (Fig. 11-12). Congenital sixth
nerve palsies are rare. Acquired sixth nerve palsy is more common.
The sixth nerve has a long intracranial course, and there are three anatomic areas
where the sixth nerve is most susceptible to injury: (1) as it exits from the
pontomedullary junction, (2) at its penetration of the dura (Dorello canal), and (3)
within the cavernous sinus.
Trauma is probably the most common cause of acquired sixth nerve palsy. Other
causes include neoplastic, inflammatory, vascular, and postviral. Acquired bilateral
sixth nerve palsy is usually a manifestation of a serious intracranial abnormality or an
increase in intracranial pressure (ICP).

Signs and Symptoms

Patients with acute sixth nerve palsy usually present with diplopia. If the palsy is
unilateral, double vision may be avoided by adopting a compensatory head posture with
the eyes in the lateral gaze position away from the palsied eye; this results in a
compensatory horizontal face turn toward the palsied eye.

Differential Diagnosis
Congenital esotropia
Duane syndrome
Möbius syndrome

Diagnostic Evaluation
A complete examination should be performed, and signs of increased ICP
(papilledema) should be sought. Neurologic consultation and neuroimaging should be
considered for most patients. A lumbar puncture may be needed to document increased
ICP.
Most patients with suspected congenital sixth nerve palsy have congenital esotropia
with cross fixation of one or both eyes. It is important to identify these patients to avoid
unnecessary diagnostic procedures.

Treatment
Initial treatment may consist of occlusion to eliminate diplopia. Children with
significant hyperopia should be given glasses to avoid the development of an
accommodative esotropia. If the deviation does not improve over time, surgery may be
necessary.
If there is lateral rectus function, a unilateral medial rectus recession combined with
a lateral rectus resection can be performed.
If little or no function of the lateral rectus exists, a transposition procedure may be
needed.

Prognosis
Many patients can be given single vision with or without a small face turn. Patients
should understand that the range of single binocular vision may be limited; this is
especially true in bilateral cases.

REFERENCES
Brooks SE, Olitsky SE, deB Ribeiro G. Augmented Hummelsheim procedure for paralytic strabismus. J Pediatr
Ophthalmol Strabismus. 2000;37:189–195.
Holmes JM, Beck RW, Kip KE, et al. Botulinum toxin treatment versus conservative management in acute traumatic
sixth nerve palsy or paresis. J AAPOS. 2000;4:145–149.

FIGURE 11-12. Sixth nerve palsy.

DUANE SYNDROME
Epidemiology and Etiology
Duane syndrome is found in approximately 1% of individuals with strabismus. It
occurs more frequently in the left eye than in the right and in females more than in males.
Bilateral involvement is less frequent than unilateral occurrence (Fig. 11-13).
Although Duane syndrome has been well described clinically, the etiology remains
unclear. Various theories include structural and innervational anomalies of the
extraocular muscles as well as absence or hypoplasia of the sixth nerve nucleus.
Up- and downshoots that may be seen in Duane syndrome may occur because of
coinnervation of the horizontal and vertical rectus muscles or slippage of the lateral
rectus muscle above or below the eye, commonly referred to as a “leash phenomenon.”

Signs and Symptoms

The most characteristic clinical findings in Duane syndrome include an absence of
abduction of an eye with slight limitation of adduction, retraction of the globe in
attempted adduction, and up- and downshooting or both in adduction. Classically,
Duane syndrome has been grouped into three types:
Type I: marked limitation or complete absence of abduction; normal or only
 slightly restricted adduction
Type II: limitation or absence of adduction with exotropia of the affected eye;
normal or slightly limited abduction
Type III: severe limitation of both abduction and adduction
Other ocular or systemic anomalies are commonly seen in patients with Duane
syndrome. Ocular anomalies may include dysplasia of the iris stroma, pupillary
anomalies, cataracts, heterochromia, Marcus Gunn jaw winking, coloboma, crocodile
tears, and microphthalmos. The systemic anomalies include Goldenhar syndrome;
dystrophic defects such as Klippel-Feil syndrome; cervical spina bifida; cleft palate;
facial anomalies; perceptive deafness; malformations of the external ear; and anomalies
of the limbs, feet, and hands.

Differential Diagnosis
Sixth nerve palsy
Congenital esotropia
Exotropia

Diagnostic Evaluation
The disorder most commonly confused with Duane syndrome is sixth nerve palsy.
Patients with a sixth nerve palsy generally have a much larger deviation in primary
position than patients with Duane syndrome given the magnitude of the abduction deficit.
In addition, an exotropia can usually be found in gaze to the opposite side in patients
with Duane syndrome and does not occur in sixth nerve palsies.

Treatment
Before surgery is contemplated, coexisting significant refractive errors,
anisometropia, and amblyopia should be treated. Indications for surgery include a
significant deviation in primary position, an anomalous head position, a large up- or
downshoot, or retraction of the globe that is cosmetically intolerable.
Surgery usually involves recession of the medial or lateral rectus for patients with
esotropia of exotropia. Some surgeons prefer transposition surgery. The medial rectus
of the involved eye is usually tight, and forced duction testing results are often positive
because of the contracture of the muscle.
Resection of the ipsilateral lateral rectus should almost never be performed because
it will increase retraction of the globe in adduction. If an up- or downshoot of the eye
occurs, surgical options include recessing a stiff, fibrotic lateral rectus muscle,
performing a Y splitting of the muscle, or placement of a posterior fixation suture to
reduce the leash effect when present.
Patients who have a cosmetically noticeable retraction of the globe in attempted
adduction may benefit from recession of both horizontal recti to reduce the co-
contraction. This can be done in the absence of a deviation in primary gaze or adjusted
to eliminate a deviation if present.

Prognosis
Surgery can help to reduce or eliminate an associated torticollis. Few patients show
improvement in abduction after surgery, and some patients undergoing medial rectus
recession may have a decrease in adduction.
In patients with significant co-contraction, large overcorrections can occur after
medial rectus recession.

REFERENCE
Kekunnaya R, Kraft S, Rao VB, Velez FG, Sachdeva V, Hunter DG. Surgical management of strabismus in Duane
retraction syndrome. J AAPOS. 2015;19:63–69.

FIGURE 11-13. Bilateral Duane syndrome.

BROWN SYNDROME
Epidemiology and Etiology
Brown syndrome may occur as a congenital or acquired defect and can be permanent,
transient, or intermittent. Congenital Brown syndrome occurs because of an anomaly of
the anterior sheath of the superior oblique tendon. The acquired form has been attributed
to a variety of causes, including superior oblique surgery, scleral buckling bands,
trauma, and after sinus surgery and inflammation in the trochlear region.
Brown syndrome can be acquired in patients with juvenile or adult rheumatoid
arthritis and represents a stenosing tenosynovitis of the trochlea that shares similar
characteristics to inflammatory disorders that affect the tendons of the fingers.

Signs and Symptoms

Brown syndrome is characterized by a deficiency of elevation in the adducting
position. Improved elevation is usually apparent in the midline, with normal or near-
normal elevation in abduction (Fig. 11-14). With lateral gaze in the opposite direction,
the involved eye may depress in adduction. Exodeviation (V pattern) often occurs as the
eyes are moved upward in the midline. Many patients are orthophoric in primary
position.
If a hypotropia is present, the patient may develop a compensatory face turn toward
the opposite eye.
In some cases, there is discomfort on attempted elevation in adduction, the patient
may feel or even hear a click under the same circumstances, and there may be a
palpable mass or tenderness in the trochlear region. A positive forced duction test result
is the hallmark of Brown syndrome.

Differential Diagnosis
Inferior oblique palsy
Superior oblique overaction
Monocular elevation deficiency (MED)

Diagnostic Evaluation
Patients will often display a V pattern, which helps distinguish Brown syndrome
from superior oblique overaction (A pattern).
Forced duction testing should be performed; results are positive in individuals with
Brown syndrome.

Treatment
Treatment is generally reserved for patients with a compensatory head posture, a
hypotropia in primary position, or a large downshoot in adduction.
Surgical treatment consists of a weakening procedure of the superior oblique tendon,
which may include partial or full tenotomy, superior oblique recession, or superior
oblique spacer.
Patients with Brown syndrome secondary to an inflammatory process may respond to
corticosteroids or nonsteroidal anti-inflammatory agents given systemically as well as
injection of corticosteroids into the trochlear region.
Prognosis
Up to one-third of patients that undergo superior oblique tenotomy develop an
iatrogenic superior oblique palsy that may require further surgery.
Even with successful surgery, elevation in adduction may continue to be abnormal in
some patients.

REFERENCES
Helveston EM, Merriam WW, Ellis FD, et al. The trochlea. A study of the anatomy and physiology. Ophthalmology.
1982;89(2):124–133.
Parks MM, Eustis HS. Simultaneous superior oblique tenotomy and inferior oblique recession in Brown’s syndrome.
Ophthalmology. 1987;94:1043.
Wright KW. Superior oblique silicone expander for Brown’s syndrome and superior oblique overaction. J Pediatr
Ophthalmol Strabismus. 1991;28:101.

FIGURE 11-14. Acquired Brown syndrome.

MÖBIUS SYNDROME
Epidemiology and Etiology
Möbius syndrome is a rare congenital disturbance consisting of varying involvement
of facial and lateral gaze paresis.
The etiology of Möbius syndrome is presently unknown. Theories to explain this
condition include a mesodermal dysplasia involving musculature derived from the first
and second branchial arches or a vascular theory with disruption of blood flow during
embryogenesis.

Signs and Symptoms

Möbius syndrome is characterized by a unilateral or bilateral inability to abduct the
eyes. Although horizontal movements are usually lacking, vertical movements and
convergence are intact.
Esotropia is common in children with Möbius syndrome (Fig. 11-15).
Unilateral or bilateral complete or incomplete facial palsy is usually observed
during the first few weeks of life because of difficulty with sucking and feeding and
incomplete closure of the eyelids during sleep. These patients typically have masklike
faces with an inability to grin and wrinkle the forehead.

Differential Diagnosis
Congenital esotropia
Bilateral cranial nerve sixth palsy

Diagnostic Evaluation
Similar to that in congenital esotropia. Patients show an abduction deficit and may be
forced duction positive on testing in the operating room.
Most patients carry a diagnosis before seeing an ophthalmologist. However, the
presence of bilateral abduction deficit, typical facial appearance, and difficulty feeding
should prompt a further evaluation with a geneticist if a diagnosis has not been made.

Treatment
Strabismus surgery is usually required to align the eyes. Transposition surgery is
preferred by some ophthalmologists.

Prognosis
Alignment in primary position is possible in most patients.
 FIGURE 11-15. Möbius syndrome. (From Nelson LB, Olitsky SE. A Color Handbook of Pediatric
Clinical Ophthalmology. London, England: Manson Publishing; 2011.)

MONOCULAR ELEVATION DEFICIENCY

Epidemiology and Etiology
MED, formerly called double elevator palsy, suggests that both elevator muscles (the
superior rectus and inferior oblique muscles) of one eye are weak, with a resultant
inability or reduced ability to elevate the eye and a hypotropia in the primary position
(Fig. 11-16). The term is generally used to describe diminished ocular elevation present
in all fields of gaze.
MED may be caused by innervational problems, restrictive conditions, or a
combination of factors.

Signs and Symptoms

Patients may present with a hypotropia or apparent ptosis. Some patients may
develop a compensatory head posture with their chin in an upward position to maintain
binocular vision.
There is an inability to elevate the eye in all fields of gaze.
In patients with restriction of upgaze, there may be an accentuated lower eyelid fold
associated with inferior rectus restriction. This fold becomes more prominent with
attempted upgaze.

Differential Diagnosis
Brown syndrome
 Thyroid-related strabismus with inferior rectus muscle restriction
Orbital floor fracture with entrapment of the inferior rectus muscle

Diagnostic Evaluation
The presence of a true ptosis should be ruled out by forcing the patient to fixate with
the involved eye. In cases of pseudoptosis caused by the ipsilateral hypotropia, the
ptosis will disappear when the eye is brought to midline.
Forced duction testing is needed to eliminate a restricted inferior rectus muscle as
the cause of the MED.

Treatment
In cases of inferior rectus muscle restriction, the involved muscle should be
recessed. When no restriction is present, a transposition procedure (Knapp procedure)
is usually required.

Prognosis
Alignment in primary position and reduction of the abnormal head posture are the
goals of treatment.
Elevation is not usually improved in cases involving a weakness of the elevator
muscles.

REFERENCES
Metz HS. Double elevator palsy. Arch Ophthalmol. 1979;97:901.
Scott WE, Jackson OB. Double elevator palsy: the significance of inferior rectus restriction. Am Orthop J. 1977;27:5.
FIGURE 11-16. Monocular elevation deficiency. Monocular elevation deficiency of the right eye.
Note the pseudoptosis of the right upper eyelid. (From Nelson LB, Olitsky SE. A Color Handbook of
Pediatric Clinical Ophthalmology. London, England: Manson Publishing; 2011.)
CONGENITAL FIBROSIS OF THE EXTRAOCULAR
MUSCLES
Epidemiology and Etiology
CFEOM is a rare disease that occurs in approximately 1 in 230,000 people. Patients
with CFEOM are usually born with ophthalmoplegia and ptosis (Fig. 11-17).
Although the name of the syndrome suggests that it results from a primary
abnormality of muscle, there is evidence that suggests that it may result from a primary
abnormality of the cranial nerve’s innervation of these muscles.
There are four subtypes of CFEOM, and the genes have been localized for three of
them. Both autosomal dominant and autosomal recessive inheritance patterns have been
observed.

Signs and Symptoms

When evaluating an individual with suspected CFEOM, a thorough family history
should be obtained.
CFEOM is present at birth, is nonprogressive, and is frequently associated with
ptosis. Depending on the subtype, it may be unilateral or bilateral.
The specific position of the eyes and pattern of movement define each clinical
subtype of CFEOM.

Differential Diagnosis
Double elevator palsy
Third nerve palsy
Chronic progressive ophthalmoplegia
Thyroid-related strabismus

Diagnostic Evaluation
A family history may reveal other relatives with a similar disorder. Genetic testing
can confirm the diagnosis in some patients.
Forced duction testing results are positive.
During surgery, fibrotic bands can be found under the rectus muscles that must be
located and severed to allow the eye to move during surgery.
Treatment
The goal of surgical management in the general fibrosis syndrome is to center the
eyes and improve the compensatory head posture. In patients with significant
hypotropia, large recession or disinsertion of the inferior rectus muscles is indicated.
However, elevation of the hypotropic eye accentuates the ptosis. Bilateral frontalis
suspension is required soon after the strabismus surgery.
Because these patients often do not have a Bell phenomenon, corneal drying may
occur after ptosis surgery. Therefore, the eyelid should be elevated only to the upper
pupillary border.

Prognosis
These are very challenging patients and may require multiple surgeries to help
reduce their compensatory head posture to provide comfortable vision.

FIGURE 11-17. Congenital fibrosis of the extraocular muscles.

 Index
Note: Page numbers followed by ‘f ’ and ‘t’ refer figures and tables respectively.

A
A and V pattern, 244–245, 246–247f
AAV. See Adeno-associated viral (AAV)
Aberrant regeneration, 248
Abetalipoproteinemia, 192
Abnormalities affecting eye as whole
anophthalmia, 2–4, 5–7f
microphthalmia, 8–11
nanophthalmia, 12–13
Achromatopsia, 160
Acquired corneal cloudiness, 24
Acquired corneal pannus, 74
Acquired pupillary margin cysts, 72
Acute retinal necrosis, 130
Acyclovir, 38
Adeno-associated viral (AAV), 160
Adult foveomacular dystrophy, 155
Advanced retinitis pigmentosa, 156
Afferent pupil defect, 142
Aicardi syndrome, 8, 144
Alagille syndrome, 70, 151
Alport syndrome, 100
Amblyopia, 104, 110, 142, 145, 216, 231, 236
Amniotocele. See Dacryocele
Angioid streaks, 151
Angle-closure glaucoma, 59
Aniridia, 68–69, 69f, 74, 75f, 100, 104
Anisocoria, 66
Anisometropic amblyopia, 78
Ankyloblepharon filiforme adnatum, 200–201, 201f
Anophthalmia, 2–4, 5–7f
Anophthalmos, 2
Anterior lenticonus, 106, 107f
Anterior or posterior lens dislocation, 110
Anterior polar cataract, 102f
Anterior segment dysgenesis, 100
Anterior staphyloma, 32, 33f
Antiglaucoma medications, 49
Antihistamine, 46
Apert disease, 104
Aphakic glaucoma, 56, 57f
Astigmatism, 20
irregular, 110
Astrocytic hamartoma, 162–163, 163f
Autosomal dominant drusen, 196
Axenfeld-Rieger anomaly, 96, 97f
Axenfeld-Rieger spectrum, 66, 68, 70
syndrome, 78, 104

B
BAL. See British anti-Lewisite (BAL)
Bassen-Kornzweig syndrome, 160
Batten disease, 196
Behçet disease, 130
Best disease, 154–155, 155f
Bestrophinopathy, 196
Bilateral congenital mydriasis, 68
Bilateral cranial nerve sixth palsy, 258
Bilateral Duane syndrome, 255f
Bilateral intranuclear ophthalmoplegia, 241
Biliary cirrhosis, 34
Birth trauma, 20
Descemet membrane ruptures, 20, 21f
forceps, 49
Blau-Jabs syndrome. See Blau syndrome
Blau syndrome, 120, 122–123f
Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES), 202–203, 203f,
214
child with, 203f
Blurred vision, 216
Bone marrow transplant, 24
Bourneville disease, 162
BPES. See Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES)
Branch retinal artery occlusion, 194
British anti-Lewisite (BAL), 34
Brown syndrome, 244, 256–257, 257f
Brushfield spots, 76, 77f, 86, 88
Bulging opacified cornea, 32
Buphthalmos, 50, 51f

C
Capillary hemangiomas, 62, 216, 217f
Cataract, 74, 189
extraction, 193
surgery, glaucoma following, 56–57, 57f
Central corneal leukoma, 26
Central corneal opacity, 26
Central pupillary cysts, 72, 73f
Cerebral anomalies, 139
CFEOM. See Congenital fibrosis of extraocular muscles (CFEOM)
CHARGE syndrome, 8, 14, 82, 144
CHED. See Congenital hereditary endothelial dystrophy (CHED)
Chickenpox, 44, 45f
Childhood ectropion, 204, 205f
Chloroquine, 192
Choriocapillaris, 158
Chorioretina, 14
scars, 180
Chorioretinal coloboma, 144
Chorioretinitis, 156, 158
Choroidal atrophy, 158
Choroidal hemangioma, 62, 65f
Choroidal melanoma, 180
Choroideremia, 156, 157f, 158
Chronic active hepatitis, 34
Chronic iridocyclitis, 80
CHRPE. See Congenital hypertrophy of retinal pigment epithelium (CHRPE)
CHSD. See Congenital hereditary stromal dystrophy (CHSD)
Ciliary body
cysts, 72
tumors, 84
Circumpapillary staphyloma, 145
Closed-head trauma, 250
Coats disease, 168–169, 170–171f, 184, 189
with mild temporal macular exudation, 170f
with xanthocoria, 171f
Coloboma
abnormalities affecting eye as whole, 14–15, 15–16f
ankyloblepharon filiforme adnatum, 201f
congenital, 200
eyelid, 210, 211f
iris, 82, 83f
unilateral and bilateral iris, 83f
upper eyelid, 211f
Compressive optic neuropathy, 152
Cone dystrophy, 160, 196
Congenital abnormalities, of optic nerve
morning glory disc anomaly, 142–143, 143f
optic disc coloboma, 144
optic disc drusen, 151–152
optic disc pits, 145–146, 147f
optic nerve hypoplasia, 138–139, 140f
peripapillary staphyloma, 150
tilted disc syndrome, 148, 149f
Congenital and acquired hypopigmented irides, 80
Congenital and developmental cataracts, 100–101, 102–103f
Congenital corneal opacity
anterior staphyloma, 32, 33f
birth trauma, 20, 21f
chickenpox, 44, 45f
corneal dermoid, 30, 31f
hereditary endothelial dystrophy, 28, 29f
herpes simplex infection, 36, 37f
herpes simplex virus epithelial dendrite, 38, 39f
herpes zoster ophthalmicus, 42, 43f
HSV corneal stromal disease, 40, 40–41f
limbal vernal keratoconjunctivitis, 46, 47f
mucopolysaccharidosis, 24, 25f
Peters anomaly, 26, 27f
sclerocornea, 18, 19f
ulcer, 22, 23f
Wilson disease, 34, 35f
Congenital ectropion, 210
uveae, 66, 67f
Congenital entropion, 204, 206, 207f
Congenital esotropia, 231–232, 233f, 234, 258
Congenital exotropia, 241–242
Congenital fibrosis of extraocular muscles (CFEOM), 262, 263f
Congenital glaucoma, 104
Congenital hereditary endothelial dystrophy (CHED), 18, 20, 28, 29f, 49
Congenital hereditary stromal dystrophy (CHSD), 49
Congenital hypertrophy of retinal pigment epithelium (CHRPE), 180–181, 181f
Congenital mucocele. See Dacryocele
Congenital nasolacrimal duct obstruction (NLDO), 218–219, 220–223f
Congenital nuclear cataract, 102f
Congenital nystagmus, 74
Congenital ptosis, 202, 208, 209f
Congenital pupillary margin epithelial cysts, 72
Congenital sixth nerve palsy, 231
Congenital synechia, 94
Congenital syphilis, 104
Congenital tarsal kink, 204
Conjunctival nevi, 90
Contralateral microphthalmia, 49
Copper-deficient diet, 34
Corectopia, 78, 82
Cornea plana, 70
Corneal clouding, 49, 51f
Corneal dermoid, 30, 31f
Corneal edema, bilateral symmetrical, 28
Corneal haze, 28
Corneal opacification, 21f
Corneal opacity, 40f
Corneal pachymetry, 57
Corneoscleral transplant, 32
Cosmetic deformities, 4
Cotton wool patches, 194
Craniofacial anomalies, 148
Crouzon syndrome, 104
Cryptophthalmos, 3, 200
Cutis marmorata telangiectasia congenita, 62
CYP1B1 gene (2p21), 48
Cystic eye, 3
Cystinosis, 192
Cystoid macular edema, 186
Cytomegalovirus, 100

D
D-penicillamine, 34
Dacryocele, 224, 225–227f
Dandy-Walker malformation, 144
Dendritiform corneal lesion, 125
Dermis fat grafting, 4
Dermoid, 18, 20, 224
Descemet tears, 20, 21f
Diabetes mellitus, 100
Diffuse choroidal hemangioma, 62
Dilated tortuous conjunctival and episcleral vessels, 64f
Disciform keratitis, 40, 41f, 42
Dissociated vertical deviation (DVD), 232, 236, 237f
Double elevator palsy. See Monocular elevation deficiency (MED)
Doyne honeycomb, 196
Duane retraction syndrome, 231
Duane syndrome, 234, 254–255, 255f
DVD. See Dissociated vertical deviation (DVD)
Dysmorphic syndromes, 192
Dystrophy
adult foveomacular, 155
cone, 160, 196
hereditary endothelial, 28, 29f
juvenile retinal, 160
myotonic, 100
pattern, 154
E
Early-onset intermittent exotropia, 241
Early-onset sarcoidosis, 120, 122–123f
Ectopia
lentis, 74, 104–105, 105f
lentis et pupillae, 78, 79f, 92
pupil, 82, 96
Ectopic oligodendrocytes, 194
Ectropion, 205f
syndrome, 80
Ehlers-Danlos syndrome, 104
Encephalocele, 224
Encephalotrigeminal angiomatosis. See Sturge-Weber syndrome
Endocrine dysfunction, 139, 142
Endophthalmitis, 130
Enthesitis-related arthritis, 113
Entropion, 212
Enzyme replacement, 24
Epiblepharon, 200, 206, 212, 213f
Epicanthus, 202, 206, 214, 215f
tarsalis, 215f
ERFP. See Extraretinal fibrovascular proliferation (ERFP)
Esotropia
congenital, 231–232, 233f, 258
nonaccommodative or partially accommodative, 240–241
nonrefractive accommodative, 240
refractive accommodative, 238, 239f
sensory, 231–232, 233f
with V pattern, 244, 246–247f
Euryblepharon, 204, 210
Exotropia
congenital, 241–242
intermittent, 242, 243f
Extraretinal fibrovascular proliferation (ERFP), 188
Eyelid anomalies
ankyloblepharon filiforme adnatum, 200–201, 201f
blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES), 202–203,
203f
capillary hemangiomas, 216, 217f
childhood ectropion, 204, 205f
colobomas, 210, 211f
congenital entropion, 206, 207f
congenital ptosis, 208, 209f
epiblepharon, 212, 213f
epicanthus, 214, 215f

F
Fabry disease, 100
Facial hemihypertrophy, 66
Faciao-auricular vertebral syndrome, 30
Familial adenomatous polyposis (FAP), 180
Familial exudative vitreoretinopathy (FEVR), 164, 182–183, 183f
Fanconi syndrome, 192
FAP. See Familial adenomatous polyposis (FAP)
FEVR. See Familial exudative vitreoretinopathy (FEVR)
Fibrinous anterior uveitis, 92
Flocculi, iris, 98, 99f
Fourth nerve palsy, 250–251, 251f
Foveal hypoplasia, 68
Frizzled 4 gene (FZD4), 168
Fundus albipunctata, 196
Fundus flavimaculata, 196–197, 198–199f

G
Galactosemia, 100
Ganciclovir ophthalmic gel, 38
Genetic counseling, 193, 197
Ghost cell glaucoma, 59
Gillespie syndrome, 68
Glaucoma, 18, 20, 74
aniridia, 68–69, 69f
aphakic glaucoma, 56, 57f
following cataract surgery, 56–57, 57f
congenital ectropion uveae, 66, 67f
drainage devices, 60
juvenile open-angle, 52–53, 54f
posterior embryotoxon, 70–71, 71f
primary congenital, 48–50, 50–51f
Sturge-Weber syndrome, 62–63, 64–65f
traumatic, 59
uveitic, 58–60
glaucoma, 61f
Glaucomatous optic neuropathy, 145
Goldenhar sequence, 144
Goldenhar syndrome, 2, 8, 254
Goldman-Favre disease, 160, 186
Goltz, 8
Goltz focal dermal hypoplasia, 144
Gyrate atrophy, 156, 158, 159f

H
Haab striae, 49, 51f
Hallerman-Streiff syndrome, 2
Hemangioma, 224
Hemispheric migration, 139
Hepatolenticular degeneration. See Wilson disease
Herpes simplex blepharitis, 37f
Herpes simplex corneal dendrite, 39f
Herpes simplex infection, 36, 37f
 Herpes simplex virus, 100
epithelial dendrite, 38, 39f
Herpes zoster ophthalmicus, 36, 42, 43f
Herpesviridae, 125, 126f
HESX1 gene, 138
Heterochromia iridis, 14, 62, 80, 81f
Homocystinuria, 104
Horner syndrome, 208
HSV corneal stromal disease, 40, 40–41f
Hurler syndrome, 24, 25f
Hydroxychloroquine toxicity, 196
Hyperlysinemia, 104
Hyperopia, 9, 12
Hyperpigmented irides, 80
Hypertropia, 236
Hypopigmented elevated spots, 77f
Hypoplastic disc, 145
Hypotropia, 256

I
Iatrogenic iris defect, 68
ICROP. See International Classification of ROP (ICROP)
Idiopathic intracranial hypertension, 152
Idiopathic uveitis, 136
Incontinentia pigmenti, 164–165, 165t, 166–167f, 182, 184, 189
Infantile glaucoma, child with, 50, 50f
Infantile retinal nonattachment, 164
Inferior oblique muscle overaction (IOOA), 232
Inferior oblique overaction, 234, 235f
Inferior oblique palsy, 256
Injectable calcium hydroxylapatite, 4
Intermittent exotropia, 242, 243f
Intermittent strabismus, 230
 International Classification of ROP (ICROP), 188
Interstitial keratitis, 40, 41f, 125, 126f
Intrahepatic cholestasis of childhood, 34
Intraocular pressure (IOP), 30
IOOA. See Inferior oblique muscle overaction (IOOA)
IOP. See Intraocular pressure (IOP)
Ipsilateral orofacial hemangioma, 142
Iridocorneal endothelial syndrome, 66
Iridodonesis, 104
Iris
aniridia, 74, 75f
Axenfeld-Rieger anomaly, 96, 97f
brushfield spots, 76, 77f
central pupillary cysts, 72, 73f
coloboma, 15–16f, 68, 78, 82, 83f, 104
ectopia lentis et pupillae, 78, 79f
flocculi, 98, 99f
heterochromia iridis, 80, 81f
juvenile xanthogranuloma, 86, 87f
lisch nodules, 88, 89f
mamillations, 76, 86, 88
melanoma, 72
melanosis oculi, 90, 91f
nevi, 76, 88
persistent pupillary membrane, 92, 93f
pigment epithelium, 67f
posterior synechiae, 94, 95f
stromal cysts, 72, 84, 85f
traumatic injury, 82
Ischemic optic neuropathy, 152

J
Jeune syndrome, 192
JIA. See Juvenile idiopathic arthritis (JIA)
JOAG. See Juvenile open-angle glaucoma (JOAG)
Juvenile idiopathic arthritis (JIA), 58, 61f, 100, 112–115, 116–117f
Juvenile open-angle glaucoma (JOAG), 52–53, 54f
Juvenile retinal dystrophy, 160
Juvenile retinoschisis, 186, 187f
Juvenile X-linked retinoschisis, 187f
Juvenile xanthogranuloma (JXG), 76, 86, 87f, 88, 137
JXG. See Juvenile xanthogranuloma (JXG)

K
Kayser-Fleischer ring, 34, 35f
Keratitis, 49
Keratoprecipitates, 40
Klippel-Feil syndrome, 254
Klippel-Trenaunay-Weber syndrome, 62

L
Lacrimal anomalies
congenital nasolacrimal duct obstruction, 218–219, 220–223f
dacryocele, 224, 225–227f
lacrimal fistula, 228, 229f
Lacrimal fistula, 228, 229f
Leber congenital amaurosis, 160, 161f
Leber hereditary optic neuropathy, 152
Lens anomalies
anterior lenticonus, 106, 107f
congenital and developmental cataracts, 100–101, 102–103f
ectopia lentis, 104–105, 105f
posterior lenticonus, 108, 109f
spherophakia, 110, 111f
Lenticular myopia, 110
Leucokoria, 142
Leukemic infiltrates, 86
Leukocoria, 14, 175f, 194
from retinoblastoma, 173
Limbal vernal keratoconjunctivitis, 46, 47f
Linear sebaceous nevus syndrome, 144
Lisch nodules, 86, 88, 89f
Liver transplantation, 34
Lymphangioma, 216

M
Malattia leventinese, 196
Malignancies, 100
Marcus-Gunn jaw wink, 208
Marfan syndrome, 104
Masquerades, 137
Mast cell stabilizers, 46
Meckel-Gruber syndrome, 8
MED. See Monocular elevation deficiency (MED)
Megalocornea, 49
Melanosis oculi, 81f, 90, 91f. See also Ocular melanocytosis
Mesodermal dysgenesis, 70. See also Axenfeld-Rieger anomaly
MGDA. See Morning glory disc anomaly (MGDA)
Microcornea, 9
Microphthalmia, 8–9, 10–11f, 144
CHARGE, 8, 14
complex, 8
with cyst, 11f
pure, 8
severe, 8
single-gene disorders, 8
unilateral, 10f
Microphthalmos, 3
Microspherophakia, 104, 111f
Möbius syndrome, 231, 258, 259f
Monocular elevation deficiency (MED), 256, 260, 261f
Morning glory disc anomaly (MGDA), 142–143, 143f
Morning glory syndrome, 14
MPS. See Mucopolysaccharidosis (MPS)
Mucopolysaccharidosis (MPS), 18, 20, 24, 25f, 49, 192
Multifocal best, 196
Myasthenia gravis, 208
Mydriatic drops, 59
Myelinated nerve fibers, 162, 194, 195f
Myopia, 142
Myopic astigmatism, 148
Myotonic dystrophy, 100, 104

N
Nanophthalmia, 12, 13f
Nasal glioma, 224
Nasolacrimal duct obstruction (NLDO), 49
congenital, 218–219, 220–223f
NDP. See Norrie disease protein (NDP) gene
Neuroblastoma, 80
Neurofibromatosis, 66
Neuronal ceroid lipofuscinosis, 192
Nicotinic acid maculopathy, 186
NLDO. See Congenital nasolacrimal duct obstruction (NLDO)
NLDO. See Nasolacrimal duct obstruction (NLDO)
Nonaccommodative or partially accommodative esotropia, 240–241
Nonrefractive accommodative esotropia, 240
Norrie disease, 8, 184, 186
Norrie disease protein (NDP) gene, 168
Nyctalopia, 158
Nystagmus, 74, 82, 101
O
Ocular disorders, systemic and genetic basis of, 184t
Ocular melanocytosis, 80
Ocular prosthesis, 3, 9
Oculodermal melanocytosis, 80
ODP. See Optic disc pits (ODP)
Oligoarthritis, 112–113
ONH. See Optic nerve hypoplasia (ONH)
Optic disc coloboma, 144
Optic disc drusen, 151–152
Optic disc pits (ODP), 145–146, 147f
Optic nerve
coloboma, 143
granuloma, 162
hypoplasia, 14
nerve infiltrates, 152
pits, 14
tumors, 152
Optic nerve hypoplasia (ONH), 138–139, 140f
Optic neuritis, 152
Oral antihistamines, 46
Oral antiviral prophylaxis, 36
Orbital conformers, 9
Orbital dermoid, 216
Orbital floor fracture, 260
Orbito-cranial advancement surgery, 4
Ornithine aminotransferase gene (10q26), 158
Ovarian dysfunction, 202

P
Papilledema, 152
Pars planitis, 128, 129f, 130, 134
Pathologic myopia, 156
Pattern dystrophy, 154
PAX6 gene, 74
Pediatric uveitis
Blau syndrome/early-onset sarcoidosis, 120, 122–123f
herpesviridae, 125, 126f
idiopathic, 136
juvenile idiopathic arthritis, 112–115, 116–117f
masquerades, 137
pars planitis, 128, 129f
post infectious autoimmune, 124
toxocariasis, 134, 135f
toxoplasmosis, 130, 131–133f
traumatic, 124–125
tuberculosis, 136
and tubulointerstitial nephritis, 118, 119f
Peripapillary staphyloma, 143, 150
Peripheral anterior synechiae, 58, 70
Periventricular leukomalacia [PVL], 139
Persistent fetal vasculature (PFV), 168, 184–185, 185f
Persistent hyperplastic primary vitreous (PHPV), 100
Persistent pupillary membrane, 92, 93f
Peters anomaly, 18, 20, 26, 27f, 49, 70, 96
PFV. See Persistent fetal vasculature (PFV)
PHACE syndrome, 142, 150
Phakomatosis pigmentovascularis, 62
Phakomatous choristoma, 224
Pharmacologic mydriasis, 68
Phenothiazines, 192
Photophobia, 74, 101
PHPV. See Persistent hyperplastic primary vitreous (PHPV)
Physiologic cupping, 52, 54f
Pigment epithelial detachment, 155
Pigmented cysts, 72, 73f
Plasma ornithine levels, 158
Polyarticular rheumatoid factor, 113
Port wine mark, 63f
Post infectious autoimmune uveitis, 124
Posterior embryotoxon, 70–71, 71f, 96
Posterior lenticonus, 108, 109f
Posterior scleritis, 152
Posterior synechiae, 74, 94, 95f
Prader-Willi syndrome, 66
Primary congenital glaucoma, 48–50, 50–51f
Primary infantile glaucoma, 57
Pseudoesotropia, 230, 231, 233f
Pseudopapilledema. See Optic disc drusen
Pseudoxanthoma elasticum, 151
Psoriatic arthritis, 113
Pupillary block glaucoma, 104, 110
Pupillary margin epithelial cysts. See Central pupillary cysts

R
Rab escort protein 1 (REP-1), 156
RD. See Serous retinal detachment (RD)
Reactive hyperplasia, 180
Recurrent horizontal strabismus, 232
Refractive accommodative esotropia, 238, 239f
Refsum disease, 192
Refsum phytanic acid storage disease, 160
Renal coloboma syndrome, 144
Retinal anomalies
astrocytic hamartoma, 162–163, 163f
Best disease, 154–155, 155f
choroideremia, 156, 157f
CHRPE, 180–181, 181f
 Coats disease, 168–169, 170–171f
detachment from retinoblastoma, 172–173
dysplasia, 184
familial exudative vitreoretinopathy, 182–183, 183f
fundus flavimaculata, 196–197, 198–199f
gyrate atrophy, 158, 159f
incontinentia pigmenti, 164–165, 165t, 166–167f
juvenile retinoschisis, 186, 187f
leber congenital amaurosis, 160, 161f
myelinated nerve fibers, 194, 195f
persistent fetal vasculature, 184–185, 185f
retinitis pigmentosa, 192–193, 193f
retinoblastoma, 172–174, 175–179f
retinopathy of prematurity, 188–190, 191f
Retinal pigment epithelial (RPE), 154
transplant, 193
Retinal toxoplasmosis, 14
Retinal vascular occlusion, 192
Retinitis pigmentosa, 104, 151, 158, 192–193, 193f
Retinitis punctata albescens, 196
Retinoblastoma, 134, 172–174, 175–179f, 189
enucleation, 173
intra-arterial chemotherapy, 173
intravenous chemoreduction, 173
Retinocytoma, 162
Retinopathy of prematurity (ROP), 188–190, 191f
International Classification of, 189t
Retinopathy, solar, 154
Rhabdomyosarcoma, 216
Rhegmatogenous retinal detachment, 186
ROP. See Retinopathy of prematurity (ROP)
RPE. See Retinal pigment epithelial (RPE)
Rubella, 100, 192
 Rubeosis, 66

S
Sarcoidosis, 134, 136, 152
Scheie syndrome, 24
Sclera, discoloration, 90
Sclerocornea, 18, 19f, 20
Senior Loken syndrome, 192
Sensory esotropia, 231–232, 233f
Septa-optic dysplasia, 139
Serous retinal detachment (RD), 142
Severe hypoplasia of iris, 74, 75f
Sickle cell retinopathy, 182
Simple ectopia lentis, 104
Sixth nerve palsy, 252, 253f
Slit-lamp biomicroscopy, 68
Small-angle strabismus, 230
Snowbanks and snowballs, 129f
Sorsby dystrophy, 196
Sorsby macular dystrophy, 154
Spherophakia, 104, 110, 111f
Sporadic aniridia, 74
Staphyloma
enucleation specimen of, 33f
unilateral and bilateral anterior, 33f
Stargardt disease, 154, 196–197, 198–199f
Stellate congenital cataract, 103f
Steroid-induced glaucoma, 59
Strabismus disorders, 74, 101, 142
A and V pattern, 244–245, 246–247f
Brown syndrome, 256–257, 257f
congenital esotropia, 231–232, 233f
congenital exotropia, 241–242
 congenital fibrosis of extraocular muscles, 262, 263f
dissociated vertical deviation, 236, 237f
Duane syndrome, 254–255, 255f
fourth nerve palsy, 250–251, 251f
inferior oblique overaction, 236, 237f
intermittent exotropia, 242, 243f
Möbius syndrome, 258, 259f
monocular elevation deficiency, 260, 261f
nonaccommodative or partially accommodative esotropia, 240–241
nonrefractive accommodative esotropia, 240
pseudoesotropia, 230, 233f
refractive accommodative esotropia, 238, 239f
sixth nerve palsy, 252, 253f
third nerve palsy, 248–249, 249f
Stromal cysts, 84, 85f
Sturge-Weber syndrome, 62–63, 64–65f
Sulfite oxidase deficiency, 104
Superior oblique overaction, 256
Syphilis, 100, 136
Systemic arthritis, 113
Systemic lupus erythematosus, 100

T
TAAD. See Thoracic aortic aneurysm and dissection (TAAD)
Tarsal kink, 210
TDS. See Tilted disc syndrome (TDS)
“Teardrop” pupil, 14
Tears in Descemet membrane, 18
Third cranial nerve palsy, 241
Third nerve palsy, 208, 248–249, 249f
Thoracic aortic aneurysm and dissection (TAAD), 98, 99f
Tilted disc syndrome (TDS), 148, 149f
TINU. See Tubulointerstitial nephritis uveitis (TINU)
Topical antiglaucoma medications, 63
Toxocara canis, 134
Toxocara cati, 134
Toxocariasis, 134, 135f, 184, 189
Toxoplasma gondii, 130
Toxoplasmosis, 100, 130, 131–133f, 134, 152, 160
retinal, 14
Trans-sphenoidal basal encephalocele, 142
Transient nevus flammeus of infancy, 62
Trauma, 66
to iris sphincter, 78
Traumatic uveitis, 124–125
Trichiasis, 206
Trifluridine drops, 36, 38
Trisomy 13, 100
Trisomy 18, 100
Trisomy 21, 100
TUBA8 gene, 138
Tuberculosis, 134, 136
Tuberous sclerosis, 162
Tubulointerstitial nephritis uveitis (TINU), 118, 119f

U
Ulcer, 18, 20, 22
corneal, 23f
Ulceration, 38, 39f
Undifferentiated arthritis, 113
Unilateral and bilateral iris coloboma, 83f
Unilateral vesicular lesions, 42
Uveitic glaucoma, 58–60, 59, 61f
Uveitis, 42, 66

V
Valacyclovir, 38
Varicella, 100
Vesicular lesions on eyelid, 36
Vesicular rash, 42
Visual acuity, 142
Vitelliform macular dystrophy, 154
Vogt-Koyanagi-Harada disease, 136

W
Waardenburg syndromes, 2
Wagner vitreoretinal dystrophy, 186
WAGR complex, 74
Walker-Warburg syndrome, 8, 144
Weill-Marchesani syndrome, 104
Wilson disease, 34, 35f
Wolfflin nodules, 76

Y
YAG. See Yttrium aluminum garnet (YAG) puncture
Yttrium aluminum garnet (YAG) puncture, 72

Z
Zellweger syndrome, 192