Shields Textbook of Glaucoma (Allingham, Shields' Textbook of Glaucoma)

923 Pages·2010·35.36 MB·English

by  Karim F. Damji, Sharon Freedman, Sayoko E. Moroi, Douglas Rhee, M. Bruce Shields

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Authors: Allingham, R. Rand
Title: Shields Textbook of Glaucoma, 6th Edition
Copyright ©2011 Lippincott Williams & Wilkins
> Front of Book > Authors
SENIOR AUTHOR
R. Rand Allingham MD
Richard and Kit Barkhouser Professor of Ophthalmology
Duke University School of Medicine
Chief Glaucoma Service
Duke Eye Center
Durham, North Carolina, USA
ASSOCIATE AUTHORS
Karim F. Dam JI, MD, MBA

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Authors

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Professor of Ophthalmology
University of Alberta—Faculty of Medicine & Dentistry
Director, Ophthalmology Fellowship Programs
Royal Alexandra Hospital
Edmonton, Alberta, Canada
Sharon F. Freedman MD
Professor of Ophthalmology and Pediatrics
Duke University School of Medicine
Chief Pediatric Ophthalmology and Strabismus Service
Duke Eye Center
Durham, North Carolina, USA
Sayoko E. Moroi MD, PHD
Associate Professor of Ophthalmology and Visual Sciences
University of Michigan Medical School
Director, Glaucoma Fellowship Program
The University of Michigan W. K. Kellogg Eye Center
Ann Arbor, Michigan, USA
Douglas J. Rhee MD
Assistant Professor of Ophthalmology
Harvard Medical School
Associate Chief, Practice Development
Massachusetts Eye and Ear Infirmary
Boston, Massachusetts, USA

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Authors: Allingham, R. Rand
Title: Shields Textbook of Glaucoma, 6th Edition
Copyright ©2011 Lippincott Williams & Wilkins
> Front of Book > Foreword
Foreword
Most of us, as we approach the “golden years” of life, can look back with joy and pride on how we watched our
children grow from infancy through adolescence to adulthood, with accomplishments well beyond the ability of
their parents. My feelings are much the same with this book. During its infancy in the early 1980s, it was small
and naïve, and it grew slowly over the next 20 years, due in large measure to kind encouragement from
generous readers. But the day came, as we crossed into the new century, when I could no longer fully provide
for the book—the remarkable advances in glaucoma on so many fronts were exceeding my ability to keep up—
and I was fortunate to have an extended family step in and author the fifth, and now this sixth, edition.
When I first approached each of them with the request to assume authorship of the book, to the person they did
not hesitate to agree (at least they showed no outward hesitation), for which I will always be profoundly grateful.
And it truly has been a family affair. My Duke partner and longtime friend, Dr. R. Rand Allingham, graciously
agreed to serve as managing author, despite his heavy load as Chief of the Duke Glaucoma Service, and
skillfully guided the preparation of the latest two editions. Three of the authors, in whom I take great pride, are
former Duke glaucoma fellows who have gone on to become leaders in our profession at major universities: Drs.
Karim F. Damji, University of Alberta; Sharon F. Freedman, Duke University; and Sayoko E. Moroi, University of
Michigan. The final author of the fifth edition was my Yale partner, Dr. George Shafranov, who has since gone
into private practice and has been replaced in the sixth edition by Dr. Douglas J. Rhee, also a rising star at the
Massachusetts Eye and Ear Infirmary in the fine tradition of Drs. Paul A. Chandler and W. Morton Grant.
Each of these talented friends has added immensely to the editions in their areas of expertise, and I am grateful
to them not only for taking the time from their busy practices to perpetuate this textbook but also for truly raising
it to a new level. Sales of the fifth edition have approached 9000, which is quite remarkable (I felt good if we
broke 2000 with the earlier editions). This success is undoubtedly due to the contributions of the team of
authors. They not only updated all the chapters with the latest advances but also added new chapters on
molecular genetics and clinical epidemiology and expanded information on evolving technologies, including
ultrasound and image analysis. They updated information on the clinical forms of glaucoma, most notably

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exfoliation syndrome, and greatly enhanced the chapters on filtering surgery, glaucoma drainage-device
surgery, and glaucoma surgery for children.
While the fifth edition was a vast improvement over the previous ones, the sixth edition offers even more. Two
special features are the addition of color illustrations throughout the book and the accompanying Internet
version (the latter is an example of how times are changing, since the Internet was not even heard of when the
book began).
A goal of this book from the beginning has been to base the content on a moderately extensive bibliography of
both the classic and recent literature and to provide balanced viewpoints where controversy exists. The authors
have adhered admirably to this goal, and I hope it will continue to be the foundation of any future editions.
Another strength of the book is its limited number of authors. Multiple-author textbooks, which are in the majority
today, have the advantage of providing viewpoints by many individuals in their area of expertise, but a book that
is written, rather than edited, by a small number of authors provides the advantages of more cohesiveness and
consistent style throughout the book. This means more work for each author, several of whom were responsible
for a dozen chapters or more, but I hope that this feature can also be perpetuated in future editions.
And so my hat is off to Rand, Karim, Sharon, Sy, and Doug for this latest accomplishment. I also want to again
thank Mr. Jonathan Pine and all those at Lippincott Williams & Wilkins for their continued support over these
past 30 years. Now I will sit back, like the proud parent, and watch with profound gratitude and admiration as
these good friends continue to advance our understanding of glaucoma for the ultimate goal of preserving the
precious gift of sight in our patients.
M. Bruce Shields

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Authors: Allingham, R. Rand
Title: Shields Textbook of Glaucoma, 6th Edition
Copyright ©2011 Lippincott Williams & Wilkins
> Front of Book > Preface
Preface
Nearly 30 years have passed since A Study Guide for Glaucoma was published by M. Bruce Shields in 1982.
The first edition of the series that we now know as Shields Textbook of Glaucoma, has been embraced by
generations of practitioners at all levels of training. No small measure of this book's popularity is the fact that it
has become the leading subspecialty textbook on the subject of glaucoma. This should come as no surprise
since the core qualities of simple organization and ease to read were adroitly established by Bruce Shields
himself.
Over the past few decades, we have witnessed a logarithmic expansion of information in all areas of science
and medicine. This certainly has been the case for the subspecialty of glaucoma, where our complete
armamentarium consisted of three drugs after which surgery was the next step. Ironically, the mainstay of our
treatment 30 years ago—pilocarpine, epinephrine, and systemic carbonic anhydrase inhibitors—is seldom, if
ever, used today. Now, joining timolol, prostaglandin analogs, a2-agonists, and topical carbonic anhydrase
inhibitors is a multitude of laser surgical treatments, with many more therapeutic interventions in development.
Similarly, technology for diagnosing and following glaucoma has undergone major changes. Optical coherence
tomography is an increasingly used technology that will likely replace fundus photography as a mainstay to
diagnose and monitor glaucoma. Keeping up with the broad advance in technology and treatment strategy is
challenging but is essential if we are to utilize this knowledge effectively for patient care.
It has been a great joy seeing how Shields Textbook of Glaucoma is also evolving. It is immediately apparent
that the sixth edition, like the field of glaucoma itself, continues to evolve. With the incorporation of full color,
there is a sharper sense of what one sees clinically. Additionally, Shields has taken its place on the Internet,
making it accessible almost anywhere or anytime. With increasing types of data, the ability to analyze and utilize
multiple types of information will only increase. The need to have rapid and accurate information immediately at
hand is becoming essential to the practice of medicine as the demands for higher efficiency and efficacy
continue.
As you open the sixth edition of Shields Textbook of Glaucoma, we hope you, the reader, will appreciate the
efforts of a dedicated team that values the tradition that was started so long ago.
R. Rand Allingham

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Authors: Allingham, R. Rand
Title: Shields Textbook of Glaucoma, 6th Edition
Copyright ©2011 Lippincott Williams & Wilkins
> Front of Book > ACKNOWLEDGMENTS
ACKNOWLEDGMENTS
It has been a great pleasure and an honor to serve as the senior author of the sixth edition of Shields Textbook
of Glaucoma. What would seem a daunting task has been an exciting and enjoyable journey. This landmark
work, initiated almost 3 decades ago by Bruce Shields, has become the leading textbook on glaucoma
worldwide. What Bruce did himself now takes a dedicated and talented team. I have had the honor of sharing
this journey with four seasoned and gifted authors, Karim, Doug, Sy, and Sharon. Remarkably, this group has
managed to keep the passion and spirit of this great work. This is no small undertaking when one considers the
tidal wave of new information and technology that has occurred over the intervening years.
To assist us in this process has been the addition of a talented new member on our team, Cris Coren, our
manager, copyeditor, and amazing “fix it” person! Cris was selected and elected to this position by unanimous
decree of the authors and editor. She has seamlessly edited text, managed references and figures, improved
flow, and organized the authorship and editing process. Being a stickler for detail, Cris refined the language and
structure of Shields, not unlike a conductor for a symphony. In brief, Cris has made this edition of Shields better
while making the journey a true pleasure.
Of course, none of this would be possible without the many dedicated and talented persons at Lippincott
Williams & Wilkins who have shepherded this process from the beginning. Not only is this the first complete
four-color edition, it is also the first to have an online version. This enhances the value to our readership and
allows us to pursue new content in an increasingly wireless society. In particular, I would like to thank Eric
Johnson at Red Act Group for his steady encouragement and wise counsel; Emilie Moyer, who has worked her
magic on the appearance and “feel” of this edition; Jonathan Pine, a seasoned veteran at LWW whose oversight
and guiding hand have been crucial to our success over the years; and Purnima Narayanan and the talented
compositor and copyeditor teams at MPS Limited, a Macmillan Company, for their exceptional attention to detail
and professionalism. Thanks as well to Julie Cancio Harper, our “permissions guru,” for help with copyright
clearance; and Beth Jenkinson and Ryan McCammon, for valuable editorial assistance.
Of course, all success derives from family and friends. Bruce Shields remains the person I come to for advice,
counsel, and a heart-to-heart. Thank you, dear friend, for these many years together and those to come! My
undying gratitude goes to Robin Goodwin, who has, most would say miraculously, kept order in my professional
life at Duke for over 17 years. Erin, my daughter and soon-to-be English professor, who has been my “in-house”
resource for all things literate! Michael, my son and evolving ophthalmologist and scientist, I can only imagine
how the world of Ophthalmology will change in your lifetime. Of course, Anna, my wife, whose patience,
understanding, and support have been central to this and so many other undertakings.
Finally, I wish to thank all of you who read and benefit from the knowledge contained in these pages. Your kind
and constructive comments are critically important to us as we strive to provide lucid and useful information that
will help those who suffer from glaucoma.
Rand Allingham
I am grateful to Bruce and Rand for having provided the opportunity to participate in this undertaking, which I
regard as a privilege and an honor. I consider them exemplars par excellence. I have also enjoyed collaborating
with my coauthors and have learned many new things from them. Over the years, residents and fellows,
particularly from the Universities of Ottawa and Alberta, have offered many helpful suggestions. I am thankful for
their feedback and hope that users of this book continue to provide input. My wife, Salima, daughters, Safeera,
Nabeeha, and my parents, Fateh and Gulshan Damji, have provided incredible inspiration. I am particularly
indebted to Salima, whose extraordinary strength, encouragement, and understanding have made it a joy to
dedicate time and effort to this endeavor.
Karim Damji
I express my gratitude to my husband, Neil, and to our wonderful children, Rebecca and Benjamin, for
unwavering encouragement and support. I am grateful to Rand and Bruce for the privilege of participating in this
wonderful creation; to my coauthors for continuing to teach me so much about glaucoma; to Cris Coren for
making the process seamless and simple; and to Bruce Shields, my mentor, inspiration, and friend.
Sharon Freedman

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ACKNOWLEDGMENTS

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To my husband, Mike Fetters, and my four sons, Kori, Tomo, Kazu, and Taka, for understanding and supporting
my contributions to this book. I am grateful to Gale Oren and her staff for medical information and literature,
Richard Hackel and the photography staff for their support of this project, my coauthor colleagues and Cris
Coren for their patience and support of this project, and my mentor and friend Bruce Shields.
Sayoko (“SY”) Moroi
I would like to thank my lovely wife, Tina, for your continual support, patience, and encouragement. To our
daughters, Ashley and Alyssa, whose smiles and laughter bless our lives. To my father and mother, Dennis and
Serena Rhee, for your support and guidance. To Susan Rhee, for your understanding, and to all my families—
Rhee, Chang, Kim, and Chomakos. Finally, to my friends and coauthors, for the honor of working with you, and
to Bruce Shields, our inspiration.
Douglas Rhee

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Authors: Allingham, R. Rand
Title: Shields Textbook of Glaucoma, 6th Edition
Copyright ©2011 Lippincott Williams & Wilkins
> Front of Book > Introduction: An Overview of Glaucoma
Introduction: An Overview of Glaucoma
HISTORICAL BACKGROUND
Although our modern understanding of glaucoma dates back only to the mid-19th century, this group of
disorders was apparently recognized by the Greeks as early as 400 BC. In Hippocratic writings, it appears as
“glaucosis,” in reference to the bluish-green hue of the affected eye (1). This term, however, was also applied to
a larger group of blinding conditions that included cataracts. Although an association with elevated intraocular
pressure (IOP) is found in 10th-century Arabian writings, it was not until the 19th century that glaucoma was
clearly recognized as a distinct group of ocular disorders.
SIGNIFICANCE OF GLAUCOMA
Glaucoma is a leading cause of irreversible blindness throughout the world. World Health Organization
statistics, published in 1995, indicate that glaucoma accounts for blindness in 5.1 million persons, or 13.5% of
global blindness (behind only cataracts and trachoma at 15.8 million persons, or 41.8% of global blindness, and
5.9 million, or 15.5%, respectively) (2). Worldwide, it has become the second most common cause of bilateral
blindness. Open-angle glaucoma and angle-closure glaucoma were estimated to affect approximately 66.8
million persons by the year 2000, with 6.7 million experiencing bilateral blindness (3).
In the United States, glaucoma is the second leading cause of blindness and the most frequent cause of
blindness among African Americans. The U.S. Department of Commerce's Bureau of the Census 1990
population data (provided by the National Society to Prevent Blindness in 1993) estimated the total number of
glaucoma cases among persons 40 years of age or older to be 0.5 million (5.6%) among African Americans and
1.5 million (1.7%) among whites and others (including Hispanics, Asians, and Native Americans). Glaucoma is
also the second most common reason for ambulatory visits to ophthalmologists in the United States by
Medicare beneficiaries and is the leading cause of such visits among African Americans. An analysis of a
random 5% subsample of 1991 Medicare beneficiaries (National Claims History File—Part B) revealed
approximately 223 office visits for glaucoma per 1000 patients among African Americans and 154 such visits for
whites (compared with 136 and 194 office visits, respectively, for cataracts) (4). Although glaucoma more
commonly affects older adults, it occurs in all segments of society, with significant health and economic
consequences (5), making it a major public health problem.
A DEFINITION OF GLAUCOMA
A Group of Diseases
The most fundamental fact concerning glaucoma is that it is not a single disease process. Rather, it is a large
group of disorders characterized by widely diverse clinical and histopathologic manifestations. This point is not
commonly appreciated by the general public, or even by a portion of the medical community, which frequently
leads to confusion. For example, a patient may have difficulty understanding why she has no symptoms with her
glaucoma, when a friend experienced sudden pain and redness with a disease of the same name. Another
individual may avoid the use of cold medications because the package inserts cautions against its use in
patients with glaucoma, but this caution is only warranted for certain types of glaucoma.
Terminology

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The term glaucoma should be used only in reference to the entire group of disorders, just as the term cancer is
used to refer to another discipline of medicine that encompasses many diverse clinical entities with certain
common denominators. When referring to a diagnosis, one of the more precise terms, such as chronic open-
angle glaucoma, should be used to indicate the specific type of glaucoma that the individual is believed to have.
Common Denominator
The common denominator of the glaucomas is a characteristic optic neuropathy, which derives from various risk
factors that include but are not limited to increased IOP (6). Although elevated IOP is clearly the most frequent
causative risk factor for glaucomatous optic atrophy, it is not the only factor; therefore, to define glaucoma on
the basis of ocular tension is unwise and in many instances misleading. Nevertheless, aqueous humor
dynamics, which are integrally related to ocular pressure, are critical to our understanding of glaucoma, not only
because they are the most common and best understood of the causative risk factors for glaucoma but also
because they are presently the only factors that can be controlled to prevent progressive optic neuropathy.
At present, current classifications of glaucoma are based on the multitude of initiating events that ultimately
leads to elevated IOP or the alterations in aqueous humor dynamics that are directly responsible for the
pressure increase. As continuous research expands modern knowledge of the various factors leading to
glaucomatous optic neuropathy, both classifications
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of glaucoma and approaches to management will no doubt change. The unraveling of the genetic underpinnings
of glaucoma continues at an accelerating rate. Most forms of this group of diseases are extremely complex. In
the end, however, this knowledge will greatly alter how we classify and treat the various forms of glaucoma. For
now, the most important point to recognize is that glaucomatous optic neuropathy causes progressive loss of
the visual field, which can lead to total, irreversible blindness if the condition is not diagnosed and treated
properly. In Section I, three crucial parameters—IOP, the optic nerve, and the visual field—are considered as
they relate to our current understanding of glaucoma.
Prevention of Blindness from Glaucoma
Once the blindness of glaucoma has occurred, there is no known treatment that will restore the lost vision. In
nearly all cases, however, blindness due to glaucoma is preventable. This prevention requires early detection
and proper treatment. Detection depends on the ability to recognize the early clinical manifestations of the
various glaucomas. Section II discusses the many forms of glaucoma and the clinical and histopathologic
features by which they are characterized. Appropriate treatment requires an understanding of the pathogenic
mechanisms involved, as well as a detailed knowledge of the drugs and operations that are used to control the
IOP. Section III considers the medical and surgical modalities that are used in the treatment of glaucoma.
REFERENCES
1. Fronimopoulos J, Lascaratos J. The terms glaucoma and cataract in the ancient Greek and Byzantine writers.
Doc Ophthal. 1991;77(4):369-375.
2. Thylefors B, Négrel AD, Pararajasegaram R, et al. Global data on blindness [review]. Bull World Health Org.
1995;73(1):115-121.
3. Quigley HA. Number of people with glaucoma worldwide [review]. Br J Ophthal. 1996;80(5):389-393.
4. Javitt JC. Ambulatory visits for eye care by Medicare beneficiaries. Arch Ophthal. 1994;112(8):1025.
5. Leske MC. The epidemiology of open-angle glaucoma: a review. Am J Epidemiol. 1983;118(2):166-191.
6. Van Buskirk EM, Cioffi GA. Glaucomatous optic neuropathy [review]. Am J Ophthal. 1992;113(4):447-452.

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Authors: Allingham, R. Rand
Title: Shields Textbook of Glaucoma, 6th Edition
Copyright ©2011 Lippincott Williams & Wilkins
> Table of Contents > SECTION I - The Basic Aspects of Glaucoma > 1 - Cellular and Molecular
Biology of Aqueous Humor Dynamics
1
Cellular and Molecular Biology of Aqueous Humor Dynamics
The study of glaucoma deals with factors involved in the pathophysiology of progressive optic
neuropathy characterized by “cupping” of the optic disc. These factors include the following disciplines:
(a) clinical epidemiology, (b) clinical research and outcome studies, (c) pharmacology of glaucoma
therapeutics, (d) genetics, (e) embryology and development of ocular structures, and (f) basic science
investigations of the anterior and posterior segments of the ocular structures relevant to glaucoma.
Because the role of lowering intraocular pressure (IOP) as a treatment of glaucoma has been
substantiated by several prospective, randomized clinical trials (see Chapter 27), a logical place to begin
this study is with an overview of the basic anatomy of the structural determinants responsible for
aqueous humor dynamics. The basic anatomy of the optic nerve, retina, and choroid is presented in
Chapter 4.

Shields > SECTION I - The Basic Aspects of Glaucoma >
1 - Cellular and Molecular Biology of Aqueous Humor Dynamics

Figure 1.1 Stepwise construction of a schematic model, depicting the relationship of structures involved

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OVERVIEW OF THE ANATOMY
Aqueous humor has multiple physiologic functions throughout the various ocular structures. The two
main structures related to aqueous humor dynamics are the ciliary body, the site of aqueous humor
production, and the limbal region, which includes the trabecular meshwork, the principal site of aqueous
humor outflow. Figure 1.1 shows the close relationship between these two structures and the
surrounding anatomy.
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The limbus is the transition zone between the cornea and the sclera. On the inner surface of the limbus is
an indentation; the scleral sulcus, which has a sharp posterior margin; the scleral spur; and a sloping
anterior wall that extends to the peripheral cornea.
A sieve-like structure, the trabecular meshwork, bridges the scleral sulcus and converts it into a tube,
called the Schlemm canal. Where the meshwork inserts into the peripheral cornea, a ridge is created,
known as the Schwalbe line. The Schlemm canal is connected by intrascleral channels to the episcleral
veins. The trabecular meshwork, Schlemm canal, and the intrascleral channels make up the main route
of aqueous humor outflow
The ciliary body attaches to the scleral spur and creates a potential space, the supraciliary space,
between itself and the sclera. On cross section, the ciliary body has the shape of a right triangle, and the
ciliary processes (the actual site of aqueous humor production) occupy the innermost and anterior-most
portion of this structure in the region called the pars plicata (or corona ciliaris). The pars plicata region is
also composed of smooth muscle, which serves the important functions of accommodation and
uveoscleral outflow. The ciliary processes consist of 70 to 80 radial ridges (major ciliary processes),
between which are interdigitated an equal number of smaller ridges (minor or intermediate ciliary
processes) (1) Figure 1.2. The posterior portion of the ciliary body, called the pars plana (or orbicularis
ciliaris), has a flatter inner surface and joins the choroid at the ora serrata.
The anterior-posterior length of the ciliary body in the adult eye ranges from 4.6 to 5.2 mm nasally to
5.6 to 6.3 mm temporally, according to various reports, with the pars plana accounting for
approximately 75% of the total length. The most rapid phase of growth of the proportions of the pars
plana occurs between 26 and 35 weeks' gestation (2). At birth, these measurements are 2.6 to 3.5 mm
nasally and 2.8 to 4.3 mm temporally, and they reach three fourths of the adult dimen-sions by 24
months, with a constant ratio between pars plicata and pars plana (3).

in aqueous humor dynamics. A: Limbus. B: Main route of aqueous humor outflow (“conventional” or
trabecular outflow). C: Ciliary body (site of aqueous humor production and other outflow route of
“unconventional” or uveoscleral outflow). D: Iris and lens.

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The iris inserts into the anterior side of the ciliary body, leaving a variable width of the latter structure
visible between the root of the iris and the scleral spur, referred to as the ciliary body band. The lens is
suspended from the ciliary body by zonules and separates the vitreous posteriorly from the aqueous
humor anteriorly. The iris separates the aqueous humor compartment into a posterior and an anterior
chamber, and the angle formed by the iris and the cornea is called the anterior chamber angle. Further
details regarding the gonioscopic appearance of the anterior chamber angle are considered in Chapter 3.
With this basic outline of the anatomic structures that regulate aqueous humor dynamics, it is important
to review the development of these structures and other structures of the eye. Current clinical training
teaches clinicians to subclassify various ocular disease phenotypes among patients who have “outside”
ocular abnormalities (or ocular phenotypes) that often have a strong genetic component, which is
discussed in Chapter 8. (Another useful resource for information on human diseases with a genetic
component is “Online Mendelian Inheritance in Man,” or OMIM. It can be accessed at
www.ncbi.nlm.nih.gov.) As more disease genes are identified, the clinical phenotypic presentations,
which are an “outside in” approach to understand disease, will merge with an “inside out” approach,
whereby identified gene mutations and risk alleles are related to the ocular and systemic phenotypes.
Our knowledge of the human genome, which has approximately 30,000 genes (4), and proteinomics (5),
which is the study of proteins, will provide a blueprint for understanding individual variations in eye
anatomy and ocular disease presentations (6).
EMBRYOLOGY OF THE EYE
The eye shows incredible diversity among the various phyla from simple eye spots, through compound
eyes, to complex structures with a single lens and photoreceptor arrays (7). The developmental biology
of the vertebrate eye from surface ectoderm, neural crest, and mesodermal mesenchyme has been
extensively investigated (8). An overall schematic of eye development is summarized in Figure 1.3. The
tissue origin of the various ocular structures is summarized in Table 1.1.

Figure 1.2 Gross anatomic view of the inside view of the anterior segment showing the radial ridges of
the ciliary processes at the pars plicata portion of the ciliary body.

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Ocular development from these three tissue sources involves complex, specific cell growth, and
differentiation processes, which are not fully understood. These complex processes involve carefully
timed expression of various growth factors and their receptors, other signaling molecules and their
pathways, transcription factors, and structural components (9). In general, the genes that regulate
development can be categorized into different functional classes as follows: (a) structural genes, such as
cytoskeletal components, which may be considered as “housekeeping” genes that carry out ubiquitous
biochemical and structural functions; (b) regulatory genes, such as transcription factors (i.e., molecular
switches that control mRNA production by other genes) and cell signaling molecules, which mainly
determine specialized expression of
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genes; and (c) cell-specific genes encoding for specialized proteins of a particular cell type within an
organ, such as the unique proteins expressed in the photoreceptors. Abnormalities in expression of the
individual genes or interaction among multiple genes caused by gene mutations or altered expression
can lead to congenital defects and human disease (Table 1.2).

Figure 1.3 Schematic of early eye development from the optic vesicle stage (A), lens placode stage (B),
and optic cup stage (C). During the optic cup stage (C), the neurogenesis of the retina proceeds in a
highly regulated process with ganglion cells differentiating first, followed by the amacrine cells, bipolar
cells, horizontal cell photoreceptors, and Müller (glial) cells. (Modified from Traboulsi El, ed. Genetic
Diseases of the Eye; 1998:12, 15. By permission of Oxford University Press.)

Table 1.1 Derivatives of Embryonic Tissues

Neuroectoderm
Cranial Neural Crest
Cells

Surface Ectoderm
Mesoderm

Neurosensory
retina

Corneal stroma and
endothelium

Epithelium, glands,
cilia of skin of lids,

Fibers of extraocular; muscles
endothelial lining of all orbital

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The following regulatory genes have been grouped into large families of transcription factors:
homeobox genes, zinc finger genes, and helix-loop-helix genes. Homeobox genes encode for a 60-amino
acid DNA-binding element and specifically determine the target gene for a transcription factor. These
genes are frequently involved in determining the regional identity of the embryo or individual fate and
differentiation of cells (10). Examples of homeobox genes include the PAX family and POU domain
family. The zinc finger family of genes is thought to be the most abundant of the transcription factors.
These genes
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share a common motif of a zinc atom binding to a group of histidine and cysteine amino acids and
holding together a small loop of amino acids. Examples of this gene family include the retinoic acid
receptors (RAR) and retinoid × receptor (RAX), which direct the binding of retinoic acid. Mutations in
these receptors have been associated with abnormal eye development (11). The helix-loop-helix family
of genes is characterized by two helical DNA-binding domains held together by a special domain or
region called as “leucine zipper” (12).

Retinal pigment
epithelium

Pigmented ciliary
epithelium

Nonpigmented
ciliary epithelium

Pigmented iris
epithelium

Sphincter and
dilator muscles of
iris

Optic nerve, axons,
and glia

Vitreous

Sclera (see also
mesoderm)

Trabecular meshwork

Sheaths and tendons of
extraocular muscles

Connective tissues of iris

Ciliary muscles

Choroidal stroma

Melanocytes (uveal and
epithelial)

Meningeal sheaths of
the optic nerve

Schwann cells of ciliary
nerves

Ciliary ganglion

Most orbital bones,
cartilage, and
connective tissue of the
orbit

Muscular layer and
connective tissue sheaths
of all ocular and orbital
vessels

and caruncle

Conjunctival
epithelium

Lens

Lacrimal gland and
drainage system

Vitreous

and ocular blood vessels;
temporal portion of sclera;
vitreous

Table 1.2 Selected Genes Involved in Vertebrate Eye Development

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Gene (Gene Family)Function
Tissue Expression
Animal Model
Human Disease

BMP4 (TGF-ß)
Regulatory
Optic primordium
Mouse anterior
segment dysgenesis,
IOP, abnormal teeth

Not reported

BMP7 (TGF-ß)
Regulatory
Optic primordium.
cornea, kidney,
skeleton

Mouse knockout—
microphthalmia
Mouse Polydactyly

Not reported

Brn3B (POU
Domain)

Regulatory
Retinal ganglion cells Mouse knockout—

optic nerve Mouse
hypoplasia

Not reported

Chx10 (Homeobox) Transcription

factor

Retina, brain
Mouse ocular
retardation

Microphthalmia,
cataracts, abnormal iris
sclerocornea

CRB1
Structural
Retina
Drosophila
photoreceptor
abnormalities

Leber congenital
amaurosis, retinitis
pigmentosa

CYP1B1
Regulatory
Mouse anterior
segment dysgenesis

Congenital glaucoma

?-crystallin (ß?-
crystallins)

Structural
Lens
Mouse eye lens
obsolescence (Elo),
cataract

Coppock cataract,
congenital lamellar,
punctate, and nuclear

FoxCl
(FKHL7/FREAC3)
(Bicoid homeobox)

Regulatory
Anterior segment of
the eye

Mouse
hydrocephalus,
skeletal and eye
abnormalities

Axenfeld-Rieger
syndrome, anterior
segment dysgenesis

LMX1B
(Homeodomain)

Regulatory
Anterior segment of
the eye

Mouse
microphthalmia

Nail-patella syndrome
with COAG

Math3 (Basic HLH) Regulatory
Mi (Basic HLH)
Regulatory
Retinal pigment
epithelium, pigment
cells

Mouse
microphthalmia

Waardenburg syndrome,
type II Tietz Albinism-
deafness syndrome

Myoc
Structural
Trabecular meshwork.
cilizary body, iris
musclea

Fluid discharge in
the Drosophilas

Juvenile glaucoma

NR2E3
Regulatory
Regulatory
Mouse retinal
degeneration

Enhanced S cone
syndrome, Goldmann-
Favre syndrome

ocrl-1 (Insitol
phosphatase)

Regulatory
Lens, brain, kidney
function

Mouse knockout
without Lowe
Syndrome
phenotype

Lowe syndrome

Optx2 (Bicoid)
Retina
Mouse pituitary,
retinal. and optic
nerve hypoplasia

Anophthalmia

Otx1/2 (Homeobox) Regulatory
Iris and ciliary
epithelium. ocular
surface

Mouse knockout—
brain seizures;
mouse lacrimal
gland missing

Not reported

Otx2 (Homeobox)
Regulatory
Retinal pigment
epithelium, optic

Mouse knockout—
lethal

Not reported

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The role for these various structural, regulatory, and cellspecific genes in ocular development has been
most extensively examined thus far in the retina, which is highly complex and only partially understood
(12). Although not as extensively studied as retinal development, the anterior ocular segment, including
the ciliary body and lens (13), also has important and complex roles in the development of the normal
eye. The tissue origins of the ciliary epithelium, ciliary smooth muscle, and lens are listed in Table 1.1.
The lens induces differentiation of ciliary epithelium at the edge of the optic cup (Fig. 1.3), and the iris
develops later from the edge of the optic cup. The ciliary muscle and stroma differentiate after the ciliary
epithelium is formed. It is not clear when during gestation the ciliary epithelium becomes active to
secrete aqueous humor, but it is assumed to start very early after formation (14). As the IOP increases,
the eye grows. It is also believed that the increase in IOP provides the force to generate ciliary folds in
the ciliary body and to change the shape of the cornea (15).
Abnormalities in the development of the anterior chamber angle, or anterior segment dysgenesis, are
exemplified in Axenfeld-Rieger syndrome (see Chapter 14). Thus far, genes that have been shown most
frequently to cause anterior segment dysgenesis encode transcription factors that are important in early
development. These transcription factors include PITX2, PITX3, PAX6, FOXC1, FOXC2, and FOXC3
(16). In transgenic mice, the cell signaling molecule, bone morphogenetic proteins, and related signaling
molecules play an important role in normal development of the anterior segment (17).
An approach to study embryology of ocular structures is using data obtained through bioinformatics—a
discipline that integrates the study of genes, pathways, and function. Gene expression data, also known
as transcript or mRNA expression, may be gleaned in discrete ocular tissues and at various time points
in development (18). Such a “global” overview of gene expression in these discrete ocular tissues
enables us to hypothesize and to design studies to answer some fundamental cell biology questions
about these ocular structures. By comparing and contrasting the gene expression profiles of these
discrete ocular tissues at various stages of development and the impact of environmental exposures, we
will understand the function of these eye structures at the cellular and molecular level (see further
discussion in Chapter 8).
BIOLOGY OF AQUEOUS HUMOR INFLOW
The regulation of IOP is a complex physiologic trait that depends on (a) production of aqueous humor,

nerve

Pax2 (Homeobox)
Regulatory
Early optic nerve.
kidney defects

Mouse knockout—
eye, kidney

Renal-coloboma
syndrome

Pax6 (Homeobox)
Regulatory
Lens, retina, nose,
brain

Mouse small eye,
Drosophila
“eyeless”

Aniridia, anophthalmia,
Peters anomaly, brain,
nose defects, optic nerve
hypoplasia, coloboma,
microphthalmia

PITX2 (Bicoid
homeobox)

Regulatory
Brain, pituitary, ocular
mesenchyme, cardiac
mesenchyme, neural
crest

Chicken, frog,
mouse situs
inversus

Axenfeld-Rieger
syndrome

POU (Brn3, RPF-1) Regulatory
Retinal ganglion cells Mouse knockout—

ganglion cell
hypoplasia

Not reported

Thyroid receptor
(TR)

Regulatory
Oligodendrocytes
Mouse ganglion cell
degeneration

Not reported

Xath5 (Basic HLH)
Regulatory

a Skeletal muscle, heart, stomach, thyroid, trachea, bone marrow, thymus, prostate, small intestine,
colon, lung, pancreas, testis, ovary, spinal cord, lymph node, and adrenal gland.
TGF-ß, transforming growth factor beta; IOP, intraocular pressure; COAG, chronic open-angle
glaucoma; HLH, helix-loop-helix.

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(b) resistance to aqueous humor outflow, and (c) episcleral venous pressure.
P.8

To reduce this highly complex and only partially understood situation to its simplest form, IOP is a
function of the rate at which aqueous humor enters the eye (inflow) and the rate at which it leaves the
eye (outflow). When inflow equals outflow, a steady state exists, and the pressure remains constant. The
remainder of this chapter deals with these inflow and outflow parameters and their complex
interrelationships with the IOP.
Cellular Organization of the Ciliary Body and the Ciliary Processes
The ciliary body is one of three portions of the uveal tract, or vascular layer of the eye; the other two
structures in this system are the iris and choroid. The ciliary body is composed of (a) muscle, (b) vessels,
(c) epithelia lining the ciliary processes, and (d) nerve terminals from the autonomic nervous system
(Fig. 1.4).
Ciliary Body Muscle
The ciliary muscle consists of two main portions: the longitudinal and the circular fibers (Fig. 1.4). The
longitudinal fibers attach the ciliary body to the limbus at the scleral spur. This portion of muscle then
runs posteriorly to insert into the suprachoroidal lamina (fibers connecting choroid and sclera) as far
back as the equator or beyond. The circular fibers occupy the anterior and inner portions of the ciliary
body and run parallel to the limbus. One-third portion of the ciliary muscle has been described as radial
fibers, which connect the longitudinal and circular fibers. The physiologic function and pharmacologic
action of parasympathomimetic agents as they relate to the ciliary muscle are discussed in Chapter 32.
Ciliary Body Vessels
On the basis of studies in primate and human eyes, the vessels of the ciliary body appear to have a
complex arrangement with collateral circulation on at least three levels (19, 20): (a) The anterior ciliary
arteries on the surface of the sclera send out lateral branches that supply the episcleral plexus and
anastomose with branches from adjacent anterior ciliary arteries to form an episcleral circle, (b) The
anterior ciliary arteries then perforate the limbal sclera. In the ciliary muscle, branches of these arteries
anastomose with each other as well as with branches from the long posterior ciliary arteries to form the
intramuscular circle. Divisions of the anterior ciliary arteries also provide capillaries to the ciliary
muscle and iris and send recurrent ciliary arteries to the anterior choriocapillaris. (c) The major arterial
circle lies near the iris root anterior to the intramuscular circle and is actually the least consistent of the
three collateral systems. Although the primate studies reveal a contribution from perforating anterior
ciliary arteries, microvascular casting studies of human eyes, as well as several nonprimate animals,
indicate that this “circle” is formed primarily, if not exclusively, by paralimbal branches of the long
posterior ciliary arteries, which begin dividing in the anterior choroid. In any case, the major arterial
circle is the immediate vascular supply of the iris and ciliary processes.

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Each ciliary process in primates is supplied by two branches from the major arterial circle: the anterior
and posterior ciliary process arterioles (20) (Fig. 1.5). Anterior ciliary process arterioles supply the
anterior and marginal (innermost) aspects of the major ciliary processes. These arterioles have luminal
constrictions before producing irregularly dilated capillaries within the processes, suggesting
precapillary arteriolar sphincters. This may represent the anatomic site of adrenergic neural influence on
aqueous humor production by regulation of blood flow through the ciliary processes. The posterior
ciliary process arterioles supply the central, basal, and posterior aspects of the major ciliary processes, as
well as all portions of the minor processes. These arterioles are of larger caliber than the anterior
arterioles and lack the constrictions seen in the latter vessels. Both populations of arterioles have
interprocess anastomoses.
Vascular casting studies of capillary networks in the ciliary processes of human eyes suggest three
different vascular territories with discrete arterioles and venules (19). The first is located at the anterior
end of the major ciliary processes and is drained posteriorly by venules without significant connections
to other venules in the ciliary processes. The second is in the center of the major processes, whereas the
third capillary network occupies the minor processes and posterior third of the major processes. Both of
the latter territories are drained by marginal venules, which are situated at the inner edge of the major
processes. It is thought that these three vascular territories may reflect a functional differentiation in the
process of aqueous humor production. Venous drainage is into choroidal veins, either from the posterior
aspects of the major and minor processes or by direct communication from the interprocess connections
(Fig. 1.6).
Ciliary Processes
The functional unit responsible for aqueous humor secretion is the ciliary process, which is composed of
(a) capillaries, (b) stroma, and (c) epithelia (Figs. 1.4 and 1.6). The ciliary process capillaries occupy the
center of each process. The thin endothelium has false “porous” areas of fused plasma

Figure 1.4 Schematic of the three major components of the ciliary body: (1) the ciliary muscle,
composed of longitudina [LCM), radial, and circular (CCM) fibers; (2) the vascular system, formed by
branches of the anterior ciliary arteries (ACA) and long posterior ciliary arteries (LPCA), which form
the major arteria circle (MAC); and (3) the ciliary epithelium (CE), composed of an outer pigmented and
an inner nonpigmented layer.

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