TEXTBOOK OF
`
`GLAUCOMA
`
`‘
`
`FOURTH EDITION
`
`M. Bruce Shields
`
`Petitioner - New World Medical
`Ex.1011, p. 1 of 63
`
`

`

`Williams & Willdns
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`Ex.1011, p. 2 of 63
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`Printed in the United States of America
`
`First Edition, 1982
`Second Edition, 1987
`Third Edition, 1992
`
`Library of Congress Cataloging-in-Publication Data
`Shields, M. Bruce.
`Textbook of glaucoma/M. Bruce Shields, --4th ed.
`p.
`cm.
`Includes bibliographical references and index.
`ISBN 0---683-07693-0
`1. Glaucoma.
`I. Title.
`(DNLM: 1. Glaucoma. WW 290 S555t 1997)
`RE871.S447 1997
`617.7'41-dc21
`DNLM/DLC
`for Library of Congress
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`CIP
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`Chapter 1
`AN OVERVIEW
`OF GLAUCOMA
`
`HISTORICAL BACKGROUND
`Although our modem understanding of glaucoma dates
`
`back only to the mid-19th century, this group of disor-
`ders was apparently recognized by the Greeks as early as 400
`BC. In Hippocratic writings, it appears as "glaucosis," in ref-
`erence to the bluish-green hue of the affected eye (1). This
`term, however, was applied to a larger group of blinding con-
`ditions that included cataracts. Although an association with
`elevated intraocular pressure 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 blind-
`ness in 5.1 million persons, or 13.5% of global blindness
`(behind cataracts and trachoma at 15.8 million and 5.9 mil-
`lion persons, or4 l.8% and 15.5% of global blindness, respec-
`tively) (2). In the United States, it is the second leading cause
`of blindness and the most frequent cause 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 those 40 years of age
`or older to be approximately 1.5 million (1.7%) among
`Caucasians and others (including Hispanics, Asians and Na-
`tive Americans) and 0.5 million (5.6%) among African-
`Americans. Glaucoma is also the second most common
`reason for ambulatory visits to ophthalmologists in the U.S.
`by Medicare beneficiaries and the leading cause 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 Medicare beneficiaries among African-
`Americans and 154 for Caucasians (compared to 136 and
`194 office visits for cataracts, respectively) (3). Although
`glaucoma more commonly afflicts the elderly, it occurs in all
`segments of our society with significant health and economic
`consequences ( 4 ), 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 dis-
`orders that are 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 insert cautions against it in
`patients with glaucoma, and he was not informed that this
`only relates to certain types of glaucoma.
`
`Terminology
`The teym glaucoma should only be used 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 denom-
`inators. When referring to the diagnosis of a patient, one of
`the more precise terms, such as chronic open-angle glau-
`coma, should be used, which relates to the specific type of
`glaucoma that that individual is believed to have.
`
`Common Denominator
`The common denominator of all the glaucomas is a character-
`istic optic neuropathy, which derives from various risk factors
`including increased intraocular pressure (IOP) (5). Although
`elevated IOP is clearly the most frequent causative risk factor
`for glaucomatous optic atrophy, it is not the only factor, and
`attempts to define glaucoma on the basis of ocular tension are
`no longer advised. Nevertheless, IOP and aqueous humor dy-
`namics, which regulate the pressure, are critical to our under-
`standing of glaucoma, not only because they are the most
`1
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`2
`
`Textbook of Glaucoma
`
`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 neuropa-
`thy. Additionally, current classifications of glaucoma are
`based either on the multitude of initiating events that ulti-
`mately lead to elevated IOP, or on the alterations in aqueous
`humor dynamics that are directly responsible for the pressure
`rise. As continued research expands our knowledge of the var-
`ious factors leading to glaucomatous optic neuropathy, both
`our classifications of glaucoma and approaches to manage-
`ment will undoubtedly change. For now, however, the most
`important point to recognize is that glaucomatous optic neu-
`ropathy is associated with a progressive loss of the visual
`field, which can lead to total, irreversible blindness if the con-
`dition is not diagnosed and treated properly. In Section One,
`therefore, we consider these three crucial parameters as they
`relate to our current understanding of glaucoma: intraocular
`pressure, the optic nerve, and the visual field.
`
`PREVENTION OF BLINDNESS
`FROM GLAUCOMA
`Once the blindness of glaucoma has occurred, there is no
`known treatment that will restore the lost vision. However,
`
`in nearly all cases, blindness from glaucoma is preventable.
`This prevention requires early detection and proper treat-
`ment. Detection depends on the ability to recognize the early
`clinical manifestations of the various glaucomas. In Section
`Two, we consider the many forms of glaucoma and the clin-
`ical and histopathologic features by which they are charac-
`terized. 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 con-
`trol the IOP. In Section Three, we consider these 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 77:369, 1991.
`2. Thylefors, B, Negrel, A-D, Pararajasegaram, R, Dadzie, KY: Global
`data on blindness. Bull World Health Org 73: 115, 1995.
`Javitt, JC: Ambulatory visits for eye care by Medicare beneficiaries.
`Arch Ophthal 112:1025, 1994.
`4. Leske, MC: The epidemiology of open-angle glaucoma. A review. Am
`J Epidemiol 118:166, 1983.
`5. Van Buskirk, EM, Cioffi, GA: Glaucomatous optic neuropathy. Am J
`Ophthal 113:447, 1992.
`
`3.
`
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`

`

`F
`
`Section I
`
`P.
`
`• VI
`
`liv101
`
`THE BASIC ASPECTS OF
`
`GLAUCOMA
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`Chapter 2
`AQUEOUS HUMOR
`DYNAMICS
`I. Anatomy and Physiology
`
`I. How aqueous humor dynamics influence intraocu-
`lar pressure
`II. An overview of the anatomy
`III. Production of aqueous humor
`A. Histology of the ciliary body
`B. Ultrastructure of the ciliary processes
`C. Theories of aqueous humor production
`D. Rate of aqueous humor production
`IV. Function and composition of aqueous humor
`V. Aqueous humor outflow
`A. Histology of the conventional aqueous out-
`flow system
`
`T he study of glaucoma deals primarily with the conse-
`
`quences of elevated intraocular pressure (IOP). A logi-
`cal place to begin this study, therefore, is with the physio-
`logic factors that control the IOP, which are the dynamics of
`aqueous humor flow.
`
`HOW AQUEOUS HUMOR
`DYNAMICS INFLUENCE
`INTRAOCULAR PRESSURE
`To reduce a 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 re-
`mains constant.
`Inflow is related to the rate of aqueous humor produc-
`tion, while outflow depends on the resistance to the flow of
`aqueous from the eye and the pressure in the episcleral
`veins. The control of IOP, therefore, is a function of (a) pro-
`duction of aqueous humor; (b) resistance to aqueous humor
`outflow; and (c) episcleral venous pressure.
`The remainder of this chapter deals with these three
`parameters and their complex interrelationship with the
`IOP.
`
`B. Ultrastructure of the trabecular meshwork
`and Schlemm's canal
`C . Unconventional aqueous outflow pathways
`D . Normal resistance to aqueous outflow
`1. Resistance in the trabecular meshwork
`2. Resistance in Schlemm's canal
`3. Resistance in the intrascleral outflow
`channels
`4. Resistance to unconventional outflow
`E. Episcleral venous pressure
`
`AN OVERVIEW OF THE ANATOMY
`Aqueous humor is involved"with virtually all portions of the
`eye, although the two main structures related to aqueous hu-
`mor dynamics are the ciliary body, the site of aqueous pro-
`duction, and the limbus, the principal site of aqueous out-
`flow. The stepwise construction of a schematic model, as
`shown in Fig. 2.1 (A-D), illustrates the close relationship
`between these two structures and the surrounding anatomy:
`1. The limbus is the transition zone between the cornea and
`the sclera. On the inner surface of the limbus is an in-
`dentation, the scleral sulcus, which has a sharp posterior
`margin, the scleral spur, and a sloping anterior wall that
`extends to the peripheral cornea.
`2. A sieve-like structure, the trabecular meshwork, bridges
`the scleral sulcus and converts it into a tube, called
`Schlemm 's canal. Where the meshwork inserts into
`the peripheral cornea a ridge is created, known as
`Schwalbe 's line. Schlemm's canal is connected by in-
`trascleral channels to the episcleral veins. The trabecular
`meshwork, Schlemm's canal, and the intrascleral chan-
`nels comprise the main route of aqueous humor outflow.
`3. 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
`5
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`

`

`6
`
`I: The Basic Aspects of Glaucoma
`
`A.
`
`Cornea
`
`I
`
`B.
`
`LIM
`
`\
`
`C.
`
`Soleral Sulcus
`Scleral Spur
`
`=...,..._Schwalbe's
`Line
`Schlemm's Canal
`
`Trabecular Meshwork
`
`D.
`
`Anterior
`Chamber
`Angle
`
`Figure 2.1. Stepwise constuction of a schematic model, depicting the relationship of structures involved in
`aqueous humor dynamics: A . Limbus. B. Main route of aqueous outflow. C . Ciliary body (site of aqueous
`production). D . Iris and lens.
`
`actual site of aqueous production) occupy the innermost
`and anteriormost portion of this structure in the region
`called the pars plicata (or corona ciliaris). The ciliary
`processes consist of approximately 70 radial ridges (ma-
`jor ciliary processes) between which are interdigitated
`an equal number of smaller ridges (minor or intermedi-
`ate ciliary processes) (1) (Fig. 2.2). 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 4.6-5.2 mm nasally to 5.6-6.3
`mm temporally, according to various reports, with the
`pars plana accounting for approximately 75% of this to-
`tal length. At birth, these measurements are 2.6-3.5 mm
`nasally and 2.8-4.3 mm temporally, and reach three-
`fourths of the adult dimensions by 24 months, with a
`constant ratio between pars plicata and pars plana (2).
`4. The iri'S inserts into the anterior side of the ciliary body,
`leaving a variable width of the latter structure visible be-
`tween the root of the iris and scleral spur, referred to as
`
`the ciliary body band. The lens is suspended from the
`ciliary body by zonules and separates the vitreous, pos-
`teriorly, from the aqueous, anteriorly. The iris separates
`the aqueous compartment into a posterior and an ante-
`rior chamber, and the angle formed by the iris and the
`cornea is called the anterior chamber angle. Further de-
`tails regarding the gonioscopic appearance of the ante-
`rior chamber angle are considered in Chapter 3.
`
`PRODUCTION OF
`AQUEOUS HUMORa
`Histology of the Ciliary Body
`The ciliary body is one of three portions of the uveal tract,
`or vascular layer of the eye, the other two structures in
`
`"Refer to Shields, MB: Color Atlas of Glaucoma. Baltimore, Williams &
`Wilkins, I 998, Plate 12.
`
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`2: Aqueous Humor Dynamics: I. Anatomy and Physiology
`
`7
`
`this system being the iris and choroid. The ciliary body
`measures 6 mm from the scleral spur to the ora serrata and
`is composed of (a) muscle, (b) vessels, and (c) epithelia
`(Fig. 2.3).
`
`Ciliary Muscle
`The ciliary muscle consists of two main portions: the longi-
`tudinal and the circular fibers. It is the longitudinal fibers
`which 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 circu-
`lar fibers occupy the anterior and inner portion of the ciliary
`body and run parallel to the limbus. A third portion of the
`ciliary muscle has been described as radial fibers, which
`connect the longitudinal and circular fibers.
`
`Figure 2.2. Gross anatomical view of the ciliary body showing
`the radial ridges of the ciliary processes (arrows).
`
`Ciliary Vessels
`Traditional teaching holds that the vasculature of the ciliary
`body is supplied by the anterior ciliary arteries and the long
`posterior ciliary arteries, which anastomose near the root of
`the iris to form the major arterial circle, from whence
`branches supply the iris, ciliary body, and anterior choroid.
`More recent studies with vascular casting techniques and se-
`quential microdissection in primates have shown this to be a
`complex vascular arrangement with collateral circulation on
`at least three levels (3): (a) The anterior ciliary arteries on
`the surface of the sclera send out lateral branches which sup-
`ply 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 lim-
`bal 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. A similar anastomosing circle has been described in
`the human eye (4). Divisions of the anterior ciliary arteries
`also provide capillaries to the ciliary muscle and iris, and
`send recurrent ciliary arteries to the anterior choriocapil-
`laris. (c) The "major arterial circle," which lies near the iris
`root anterior to the intramuscular circle, is actually the least
`consistent of the three collateral systems. Although the pri-
`mate studies reveal a contribution from perforating anterior
`ciliary arteries, microvascular casting studies of human eyes
`(4, 5), as well as several nonprimate animals (6, 7), 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.
`There is evidence from human studies that blood in the
`anterior ciliary arteries, contrary to traditional teaching,
`flows from the inside of the eye to the outside. This is based
`on studies with rapid sequence fluorescein angiography (8)
`and the observations that an increase in IOP is associated
`
`Figure 2.3. Three major components of
`the ciliary body. (1) The ciliary muscle,
`composed of longitudinal (LCM) and
`circular (CCM) fibers. (2) The vascular
`system, formed by branches of the an-
`teior ciliary arteries (ACA) and long
`posterior ciliary arteries (LPCA),
`which form the major arterial circle
`(MAC). (3) The ciliary epithelium
`(CE), composed of an outer pigmented
`and an inner nonpigmented layer.
`
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`

`

`8
`
`I: The Basic Aspects of Glaucoma
`
`with a decrease in anterior cilia r y arterial pressure (9, 10)
`and an increase in the diameter of these vessels (10).
`The cilia r y processes in primates are supplied by two
`types of branches from the major arterial circle: the anterior
`and posterior ciliary process arterioles (11). Anterior ciliary
`process arterioles supply the anterior and marginal (inner-
`most) aspects of the major ciliary processes. These arterioles
`have luminal constrictions before producing irregularly di-
`lated capillaries within the processes, suggesting precapilla r y
`arteriolar sphincters. This may represent the anatomic site of
`adrenergic neural influence on aqueous humor production by
`regulation of blood flow through the cilia r y processes in re-
`sponse to physiologic and pharmacologic mediators (6, 7).
`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 ar-
`terioles have interprocess anastomoses. 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 (Figs. 2.4 and 2.5).
`Vascular casting studies of capilla r y networks in the cil-
`ia r y processes of human eyes suggest three different vascu-
`lar territories with discrete arterioles and venules (4). The
`first is located in the anterior end of the major ciliary
`
`processes and is drained posteriorly by venules without sig-
`nificant connections to other venules in the cilia r y processes.
`The second is in the center of the major processes, while the
`third capilla r y network occupies the minor processes and
`posterior third of the major processes. Both of the latter ter-
`ritories are drained by marginal venules, which are situated
`at the inner edge of the major processes. It is felt that these
`three vascular territories may reflect a functional differenti-
`ation in the process of aqueous humor production (4).
`
`Ciliary Epithelia
`Two layers of epithelium line the inner surface of the cil-
`iary processes and the pars plana: (a) pigmented epithelium
`comprises the outer layer, adjacent to the stroma, and is
`composed of low cuboidal cells, while (b) nonpigmented
`epithelium makes up the inner layer, adjacent to the aque-
`ous in the posterior chamber, and consists of columnar
`cells (see further details under "Ultrastructure of the Cil-
`iary Processes").
`
`Ultrastructure of the Ciliary Processes
`Each ciliary process is composed of (a) capillaries, (b)
`stroma, and (c) epithelia (Fig. 2.6).
`
`arteriole
`
`veins
`
`Figure 2.4. Vascular interconnections of two contiguous major ciliary processes. Lateral anterior arteriolar
`branches join to form interprocess capillary networks (arrowhead) which provide communication between major
`processes. Laterally directed posterior arterioles form posterior interprocess networks through which the minor
`ciliary processes receive blood. In addition, both anterior and posterior interprocess networks drain directly into
`the choroidal veins (arrows). M A C , major arterial circle. (Reprinted by permission from Morrison, J C , Van
`Buskirk, E M : Ciliary process microvasculature of the primate eye. A m J Ophthalmol 97:372, 1984.)
`
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`

`

`2: Aqueous Humor Dynamics: I. Anatomy and Physiology
`
`9
`
`Figure 2.5. Microvascular casting of a single ciliary process. Constricted anterior arterioles (arrows) enter the anterior
`portion of the process to provide large irregular vein-like capillaries that occupy the margins of the process. Posteriorly,
`larger caliber arterioles (arrowheads) originate and enter the middle of the process to divide into smaller capillaries that in
`general are confined to the base of the process. All capillaries travel posteriorly to drain into the choroidal veins (CV).
`M A C , major arterial circle. (X 150) (Reprinted by permission from Morrison, J C , Van Buskirk, E M : Ciliary process mi-
`crovasculature of the primate eye. A m J Ophthalmol 97:372, 1984.)
`
`Figure 2.6. Light microscopic view of
`ciliary processes, sectioned perpendicular
`to radial ridges, showing major ciliary
`processes (large arrows) and minor
`ciliary processes (small arrows). Note
`vascular stroma (s) surrounded by outer
`pigmented and inner nonpigmented ep-
`ithelium (E). (Hematoxylin & eosin
`stain; bar = 100 µ,m)
`
`Ciliary Process Capillaries
`The capillary networks occupy the center of each process.
`The endothelium is very thin with fenestrae, or false
`"pores," which represent areas of absent cytoplasm with fu-
`sion of the plasma membranes, and which may be the site of
`increased permeability. A basement membrane surrounds
`the endothelium, and mural cells, or pericytes, are located
`within the basement membrane (12).
`
`Ciliary Process Stroma
`A very thin stroma surrounds the capillary networks and
`separates them from the epithelial layers. The stroma is
`composed of ground substance, consisting of mucopolysac-
`charides, proteins and solute of plasma ( except those of
`large molecular size), a very few collagen connective tissue
`fibrils, especially collagen type III (13), and wandering cells
`of connective tissue and blood origin (12). Tubular mi-
`
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`

`IO
`
`I: The Basic Aspects of Glaucoma
`
`crofibrils with and without elastin have been demonstrated
`in bovine ciliary body, especially in the stroma of the pars
`plana, in relationship to lens zonules (14).
`
`Ciliary Process Epithelia
`Two layers of epithelium surround the stroma, with the api-
`cal surfaces of the two cell layers in apposition to each other
`(Fig. 2.7).
`
`PIGMENTED EPITHELIUM. Pigmented epithelium is charac-
`terized by numerous melanin granules in the cytoplasm and
`an atypical basement membrane on the stromal side. The cy-
`toskeletal element, cytokeratin 18, has been observed in the
`crests of the pars plicata and the posterior pars plana (15).
`
`NONPIGMENTED EPITHELIUM. The basement membrane is
`composed of fibrils in a glycoprotein with labeling for
`laminin and collagens I, III, and IV (16). This membrane,
`which faces the aqueous, is also called the internal limiting
`membrane and fuses with the lens zonules. Numerous mito-
`chondria are seen in the cytoplasm, along with poorly de-
`veloped, rough and smooth endoplasmic reticulum, and a
`scant amount of ribosomes. The nonpigmented epithelium
`stains less intensely than the pigmented layer for cytokeratin
`18, but more so for vimentin, with the predominant distri-
`bution again in the crests of the pars plicata and the poste-
`rior pars plana (15). It also stains with antibodies against
`S-100 proteins (13). The nucleus has a nucleolus that appears
`to contain ribosomes. The cell membrane is 200 A thick and
`is characterized by infoldings or interdigitations, especially
`surface infoldings on the free surface and lateral interdigita-
`tions, which are actually different cuts of the same structure.
`
`A variety of intercellular junctions have been described
`which connect adjacent cells within each epithelial layer, as
`well as the apical surfaces of the two layers (17-19). Electro-
`physiologic studies of rabbit ciliary epithelium suggest that
`all of the cells in the epithelium function as a syncytium (20).
`Tight junctions create a permeability barrier between the non-
`pigmented epithelial cells, which forms part of the blood-
`aqueous barrier. These tight junctions are said to be the
`"leaky" type, in contrast to the "nonleaky" type in the blood-
`retinal barrier, and may be the main diffusional pathways for
`water and ion flow (21, 22). Microvilli separate the two layers
`of epithelial cells. In addition, "ciliary channels" have been
`described as spaces between the two epithelial layers (23).
`They are felt to be related to the formation of aqueous humor
`since they develop between the fourth and sixth months of
`gestation, corresponding to the start of aqueous production.
`
`Theories of Aqueous Humor Production
`Aqueous humor appears to be derived from plasma within
`the capillary network of the ciliary processes. To reach the
`posterior chamber, therefore, the various constituents of
`aqueous humor must traverse the three tissue layers of the
`ciliary processes, i.e., the capillary wall, stroma, and epithe-
`lia. The principal barrier to transport across these tissues is
`the cell membrane and related junctional complexes, and
`substances appear to pass through this structure by one of
`three mechanisms (24): (a) diffusion (lipid-soluble sub-
`stances are transported through the lipid portions of the
`membrane proportional to a concentration gradient across
`the membrane); (b) ultrafiltration (water and water-soluble
`substances, limited by size and charge, flow through theo-
`
`Posterior Chamber
`
`NON-PIGMENTED
`EPITHELIAL
`CELL
`
`PIGMENTED
`EPITHELIAL
`CELL
`
`Figure 2.7. The two layers of the ciliary epithelium. Apical
`surfaces are in apposition to each other. Basement membrane
`(BM) lines the double-layer and constitutes the internal limit-
`ing membrane (ILM) on the inner surface. The nonpigmented
`epithelium is characterized by mitochondria (M), zonula oc-
`cludens (ZO), and lateral and surface interdigitations (I). The
`pigmented epithelium contains numerous melanin granules
`(MG). Additional intercellular junctions include desmosomes
`(D) and gap junctions (GJ).
`
`Ciliary Strama
`
`Petitioner - New World Medical
`Ex.1011, p. 12 of 63
`
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`

`2: Aqueous Humor Dynamics: I. Anatomy and Physiology
`
`11
`
`retical "micropores" in the protein of the cell membrane in
`response to an osmotic gradient or hydrostatic pressure); or
`(c) secretion (water-soluble substances of larger size or
`greater charge are actively transported across the cell mem-
`brane). The latter mechanism is believed to be mediated by
`globular proteins in the membrane and requires the expendi-
`ture of energy. All three transport mechanisms are probably
`involved in aqueous production, possibly in accordance with
`the following simplified three-part scheme:
`
`Accumulation of Plasma Reservoir
`Tracer studies suggest that most plasma substances pass eas-
`ily from the capillaries of the ciliary processes, across the
`stroma, and between the pigmented epithelial cells before
`accumulating behind the tight junctions of the nonpig-
`mented epithelium (25, 26). Studies with normal rats sug-
`gest that pericapillary permeability of the ciliary processes
`is influenced by the presence of fixed anionic groups which
`favor the penetration and accumulation of cationic tracers
`(27). This movement takes place primarily by ultrafiltration,
`and drugs that alter ciliary perfusion may exert their influ-
`ence on IOP at this level (5-7, 11, 28).
`
`Transport Across Blood-Aqueous Barrier
`The tight junctions between the non pigmented epithelial cells
`create part of the blood-aqueous barrier, and certain sub-
`stances appear to be actively transported across this barrier
`into the posterior chamber, thereby establishing an osmotic
`gradient. Studies with isolated rabbit ciliary processes suggest
`that aqueous humor could be secreted by the generation of a
`modest osmotic gradient across the nonpigmented cell basal
`membrane (29). There is a specific secretory pump for sodium
`ions (30, 31 ), and approximately 70% of this electrolyte is
`actively transported into the posterior chamber (32), while
`the remainder enters by passive ultrafiltration (24) or diffu-
`sion (32). The active transport of Na+ is Na+K+ -activated
`ATPase-dependent (33), but does not appear to be related to
`the concentration of Na+ in the plasma (34).
`A much smaller percentage of the chloride ion is actively
`transported, and this appears to be dependent on the presence
`of sodium, as well as the pH (35, 36). Potassium ions are
`transported by secretion and diffusion (37). One proposed
`model for the exit of Na+ and c1- into the aqueous humor is
`that Na+K+ -ATPase pumps Na+ in exchange for K+ in the
`aqueous. K+ recycles through K+ channels, and c1- pas-
`sively diffuses through c1- channels into the aqueous (38).
`Electrolyte movement across the ciliary epithelium is mea-
`sured primarily by electrochemical gradients, but studies
`with rabbit ciliary epithelium have demonstrated electrically
`silent Na+ and c1- fluxes, suggesting an additional pathway
`for electrolyte movement (39).
`Ascorbic acid is secreted against a large concentration
`gradient (32), with a probable small contribution from pas-
`sive diffusion ( 40). Amino acids are secreted by at least three
`
`carriers (41). The rapid interconversion between bicarbon-
`ate and CO2, which is catalyzed by carbonic anhydrase,
`makes it difficult to determine the relative proportions of
`these two substances. However, bicarbonate formation has
`been shown to influence fluid transport through its effect on
`Na+ (42), possibly by regulating the pH for optimum active
`transport of Na+ (24 ).
`
`Osmotic Flow
`The osmotic gradient across the ciliary epithelium, which
`results from the active transport of the above substances,
`leads to the movement of other plasma const