Anatomy and Pathophysiology of Aqueous Production and Outflow by Thomas F. Freddo, OD, PhD Thomas F.

Freddo, OD, PhD Boston University School of Medicine · Boston, MA Reprinted from Freddo TF. Anatomy and pathophysiology of aqueous production and outflow. In: Sassani JW, ed. Ophthalmic Fundamentals: Glaucoma. Thorofare, NJ: Slack; 1999:33. Introduction The mechanisms that underlie aqueous production and drainage are complex. To understand the glaucomas, the basic anatomy and physiology of aqueous humor production and drainage must first be mastered. The tutorial is an overview and introduction to these subjects and is not meant to be comprehensive. Aqueous Humor Aqueous humor is a clear nutritive fluid that supports most of the metabolic demands of the avascular tissues of the eye. Aqueous is derived from a filtrate of plasma and secreted by the bilayered ciliary epithelium into the posterior chamber of the eye at a rate of approximately 2.5 µL to 3.0 µL per minute. Given that the combined volumes of the anterior (250 µL) and posterior (50 µL) chambers of the eye total 300 µL, it is simple to calculate that the entire volume of the aqueous humor is replaced approximately every 100 minutes. Numerous studies have compared the relative concentrations of the various constituents in plasma and aqueous humor (Table 1). Although many similarities exist between the aqueous and plasma, several significant differences are found, as well. As one important example, aqueous humor has a substantially higher concentration of ascorbate, which is assumed to be present as an antioxidant and scavenger of superoxide radicals.1

Table 1 Free amino acid levels vary with respect to their relative concentrations in plasma. Certain amino acids including arginine, isoleucine, leucine, methionine, phenylalanine, serine, threonine, tyrosine, and valine are in higher concentration in the aqueous than in plasma, suggesting that active transport mechanisms are involved.2,3

Slide 1. Mean percent signal enhancement from magnetic resonance images of the ciliary body and anterior and posterior chambers of the normal rabbit eye following intravenous administration of gadolinium-DTP. Enhancement occurs rapidly in the ciliary body and more slowly in the anterior chamber. Note that virtually no enhancement occurs in the posterior chamber during the 90-minute time course. (Reprinted with permission from Kolodny N, Freddo T, Lawrence B, et al. Contrastenhanced magnetic resonance imaging confirmation of an anterior protein pathway in normal rabbit eyes. Invest Ophthalmol Vis Sci. 1996;37[8]:1602-1607. Copyright by Association for Research in Vision and Ophthalmology.) The protein concentration of aqueous humor, as sampled from the anterior chamber, is less than 1% of that found in plasma (ratio of aqueous/plasma = 0.024/7 g/dL). Recent improvements in protein chemistry methods have permitted a more complete analysis of this protein spectrum.4,5 Although the blood-derived proteins present in aqueous generally reflect their relative concentrations in plasma, there are some clear exceptions. Among these are certain proteins found in higher concentration in aqueous than in plasma, including transferrin, an ironscavenging protein.6 Still other proteins are locally produced within the tissues of the eye and serve an array of recently identified regulatory functions. Foremost among these proteins are growth factors, the most intensively studied of which is TGF-beta. TGF-beta has been shown to play important roles in the unique immunoregulatory processes of the anterior chamber.7 A most provocative finding has been preliminary data suggesting that TGF-beta-2 may be elevated in the

through the uninterrupted stromal pathway to the root of the iris. Anatomy." may play a role in generating normal outflow resistance as they are carried by aqueous flow into the trabecular meshwork. magnetic resonance imaging with contrast materials (Slide 1). In: Ritch R. Freddo TF. 2nd ed. Using fluorophotometry and. (Reprinted with permission from Morrison JC. plasmaderived proteins entering the aqueous humor. St Louis. eds.) Other recent evidence suggests that the amount of plasma-derived protein present in the aqueous humor of the anterior chamber is supplemented just prior to its entry into the outflow pathway. Predominant pathway taken by nontransported.15 Aqueous Circulation . bypassing the posterior chamber. this additional protein enters the aqueous humor. more recently. Mo: CV Mosby Co.13 There is some evidence to support the theory that certain of the proteins added to aqueous humor.12 Additional protein likely enters the adjacent outflow pathways that lead to Schlemm's canal (Slide 2). and ultrastructure of the ciliary body. Slide 2.9-11 In the absence of an epithelium on the anterior iris surface.aqueous humor of patients with primary open-angle glaucoma (POAG). microcirculation.8 The significance of this finding remains to be fully explored. 1996. but it speaks to the importance of further inquiry into the mechanisms of these important classes of proteins in aqueous humor. Shields MB.14. The question of whether any of these additional proteins are factors in aqueous outflow resistance is only beginning to be examined. The Glaucomas. it has been demonstrated that an anterior diffusional protein pathway exists in the normal eye that moves protein from a depot in the ciliary body stroma. Krupin T. particularly those of low molecular weight and known as "fines. Proteins entering the anterior chamber in this fashion are prevented from returning to the posterior chamber by tight junctions joining the posterior epithelial cells of the iris.

particulates such as pigment tend to sediment out and are phagocytosed by the corneal endothelium. Upon entering the anterior chamber. To enter the anterior chamber. Major (M) and minor (m) ciliary processes are evident in the pars plicata region of the ciliary body (x16). realizing that these two steps are not independent. Rising posteriorly and falling anteriorly. Aqueous humor formation is most easily described as a two-step process. a vertically oriented line of pigment gradually becomes evident decorating the inferior half of the central cornea (Krukenberg's spindle). . Because the aqueous humor is normally free of particulates. Aqueous Formation Slide 3. when particulates are present. Changes in the anatomical relationship between the pupillary margin and anterior capsule of the lens can reduce the flow of aqueous humor into the anterior chamber (relative pupillary block). inflammation-induced adhesions of the pupillary margin to the anterior surface of the lens (posterior synechiae) can obstruct aqueous flow. If sufficient pigment is released. As the aqueous falls along the inward curvature of the inferior cornea. Scanning electron micrograph of the inner surface of the iris and ciliary body with the lens and some zonules removed. aqueous circulates in a convection current driven by the temperature difference between the warmer iris and the cooler cornea. the aqueous humor finally leaves the eye via one of two principal outflow pathways described later. this circulation is difficult to appreciate. Similarly. and the second is formation of aqueous humor from this filtrate by the ciliary epithelium and its secretion into the posterior chamber.Aqueous humor is secreted by the ciliary epithelium into the posterior chamber. one can often observe that the particulates in the posterior portion of the anterior chamber are rising while those just posterior to the cornea are falling. However. The first step is elaboration of a filtrate of plasma from the ciliary body microvasculature into the ciliary body stroma. such as uveal pigment in pigment dispersion syndrome or inflammatory cells in anterior uveitis. aqueous must pass through the pupil.

the intermediate portion of the uvea. Primary Care of the Glaucomas. which extends from the root of the iris posteriorly to the choroid.) Gross Anatomy The ciliary body is grossly subdivided into two regions. The third function is to provide the active. Sketch demonstrating the relationships between the ocular tissues of the anterior segment and denoting the pathway of aqueous flow. The pars plicata is named for the numerous finlike ciliary processes that project into the posterior chamber (Slide 3). Conn: Appleton and Lange. Ocular anatomy and physiology related to aqueous production and outflow. (2) Scleral spur. The most anterior region begins at the iris root and is termed the pars plicata. Two layers of epithelial cells line the inner surface of the ciliary body. (9) Circular bundle of the ciliary muscle. while the layer closest to the ciliary body stroma is the pigmented ciliary epithelium. eds. (3) Canal of Schlemm. (5) Trabecular meshwork. The second function is enhancement of aqueous outflow through the connections of its longitudinal bundle of smooth muscle pulling the scleral spur posteriorly. (7) Longitudinal bundle of the ciliary muscle. (6) Ciliary body stroma of pars plana region. Aqueous humor production by the ciliary epithelium is one of three principal functions ascribed to the ciliary body. (Modified from Freddo T. (1) Supraciliary space. 1993. . (4) Schwalbe's line. energy-requiring component of accommodation through contraction of the circular bundle of the ciliary muscle. (8) Radial bundle of the ciliary muscle. Slide 4. In: Lewis T. The layer closest to the posterior chamber is the non-pigmented ciliary epithelium.The Ciliary Body Aqueous humor is produced exclusively by the ciliary body. Stamford. Fingeret M.

Slide 5a. They actually represent two simple epithelia arranged with their apical surfaces in apposition. Drainage from the ciliary muscle to choroidal veins has been removed at the asterisk (x110). which extends to the anterior choroid. the zonular fibers are channeled into the valleys between adjacent ciliary processes before making their insertions onto the anterior and posterior edges of the equatorial lens capsule. Double arrow denotes the choroidal vein. This flat portion. Despite their appearance. Upon reaching the pars plicata. The major arterial circle (MAC) gives rise to an anterior (arrow) and posterior (arrowhead) arteriole. and ultrastructure of the ciliary body. 2nd ed. In: Ritch R. This layer is continuous anteriorly with the posterior pigmented epithelium of the iris and posteriorly with the sensory retina at the ora serrata. The basal surface of these cells face the ciliary body stroma. Shields MB. 1996. under normal circumstances only the ridges of the pars plicata region remain exposed in the posterior chamber. Anatomy. is termed the pars plana. The layer closest to the posterior chamber contains no melanin pigment granules and is termed the nonpigmented ciliary epithelium (Slide 4). Thus. . The epithelial layer closest to the ciliary body stroma contains melanin pigment granules and is termed the pigmented ciliary epithelium. microcirculation. This layer is continuous with the anterior myoepithelium of the iris anteriorly and with the retinal pigmented epithelium at the ora serrata. A cast of the microvasculature within a single ciliary process. Mo: CV Mosby Co. The zonular fibers that support the crystalline lens originate within the epithelial layers covering the inner surface of the posterior pars plana. these two cell layers do not constitute a compound or stratified epithelium. St Louis.Continuing from the posterior margin of the ciliary processes. The Glaucomas. Krupin T. This unique arrangement is the result of invagination of the neuroectoderm of the optic cup during embryologic development. Van Buskirk EM. Freddo TF. running forward along its inner surface as a continuous mat. (Reprinted with permission from Morrison JC. eds. the ciliary body has a flat inner surface.) Histology The inner surface of the ciliary body is covered by two layers of epithelial cells.

The direction of blood flow in both sets of arterioles is from anterior to posterior. Van Buskirk EM. Freddo TF. carrying with it its vascular supply. this thin strip of stroma continues anteriorly to become continuous with the iris stroma at the iris root. The microvascular pattern of the ciliary body has only recently been documented with the advent of vascular casting methods.) The ciliary body stroma is a loose. The posterior arteriole. each process receives an anterior and posterior arteriole.16 Emanating from the discontinuous major circle of the iris. which lie against the sclera. and ultrastructure of the ciliary body. The . Diagrammatic representation of the vascular cast shown in Slide 5A.Slide 5b. Elegant scanning electron micrographs by Morrison and colleagues now document that each of the ciliary processes actually has a dual vascular supply (Slide 5A). microcirculation. Shields MB. Elaboration of a Plasma Filtrate from the Microvasculature of the Ciliary Body The physiological process whereby fluid is forced across a membrane by pressure is termed filtration. and gives rise to nonfenestrated capillaries that do not normally leak plasma proteins. which give rise to a more robust vascular system of large fenestrated capillaries. areolar connective tissue continuous with the iris stroma anteriorly and with the choroid at the ora serrata (see Slide 4). By contrast. 2nd ed. In: Ritch R. The ciliary body stroma in the pars plana region is a thin layer between the pigmented ciliary epithelium and the smooth muscle fibers of the ciliary muscle. toward a network of choroidal veins (Slide 5B). eds. (Reprinted with permission from Morrison JC. St Louis. 1996. the tip of each ciliary process is served by one of a series of larger anterior arterioles. The amount of filtrate crossing a particular membrane depends upon the pressure difference across the membrane and the surface area over which filtration can occur. Anatomy. Krupin T. The stroma also extends into the core of each of the ciliary processes. In the pars plicata region. which is smaller in diameter. provides the vascular supply for the ciliary muscle. The Glaucomas. Mo: CV Mosby Co.

water. Evidence suggests that blood flow in the ciliary body is regionalized and that these various regions respond differently to agents such as epinephrine. (Reprinted with permission from Morrison JC.. 1996. St Louis.19 This reduction in blood flow likely reduces filtrate production. In: Ritch R. moderate elevations of IOP can actually suppress aqueous inflow indirectly leading to a decrease in IOP. Anatomy. but also to plasma proteins. Freddo TF. leaks through fenestrations (arrows) from a capillary in the ciliary body stroma into the surrounding stroma (x40. In a rabbit. and the effect is insufficient to serve as a protective mechanism against the elevated pressure that characterizes POAG.g.18. These capillaries also lack continuous tight junctions and are freely permeable not only to solute and ions.20 This hydrostatic pressure is dependent upon neuroregulatory and/or humoral influences that serve to control the amount of filtrate available in the ciliary body stroma.17 Adrenergic nerve endings are associated with the ciliary body microvasculature. eds.20 Thus. ions.. which prompt a reduction in blood flow following sympathetic stimulation.800). The Glaucomas. The hydrostatic pressure within the microvasculature is opposed by the interstitial fluid pressure of the ciliary body stroma. Certain methods for measuring outflow facility. The ions. there is an important clinical consequence of the relationship between IOP and inflow. and ultrastructure of the ciliary body.) Unlike the capillaries of the ciliary muscle. A filtrate of plasma is produced across the walls of the microvasculature within the ciliary processes. Nonetheless. contributing a significant oncotic pressure.composition of the filtrate (e. Van Buskirk EM. fluid. microcirculation. The interstitial fluid pressure increases with intraocular pressure (IOP). The dynamics of this relationship are actually more complex. Transmission electron micrograph demonstrates that granular horseradish reaction product. but this effect manifests itself as an effect on the measurement of aqueous outflow. 2nd ed. the capillaries derived from the anterior arterioles are fenestrated (Slide 6). such as tonography and constant pressure . Shields MB and Krupin T. which are nonfenestrated. Mo: CV Mosby Co. by the permeability of the blood vessel wall). and small molecules of the plasma filtrate also leave the fenestrated microvasculature driven by the hydrostatic pressure within the capillaries of the ciliary processes. Slide 6.e. proteins) is determined largely by the size of the pores in the membrane (i. mimicking the distribution of plasma proteins. the concentration of plasma protein in the ciliary body stroma reaches nearly 75% of that in the bloodstream.

Although early estimates suggested that pseudofacility might account for as much as 20% of total outflow in humans. emphasizing the importance of recording time of day when taking tonometric measurements of IOP.perfusion techniques.23 methodological refinements have reduced this estimate to only about 5% to 10% of the total human outflow. schematic overview of major ion movement in the non-pigmented ciliary epithelium in aqueous humor production. A diurnal fluctuation in the rate of aqueous production is known to occur.25 The magnitude of this effect is significant (approximately a 50% decrease). (Modified from Freddo T. The percent of total outflow represented by pseudofacility appears to vary markedly among species.21. Primary Care of the Glaucomas.22 Because reduction in aqueous production contributes a fraction of this fall in IOP.) . Conn: Appleton and Lange. Stamford. 1993. Ocular anatomy and physiology related to aqueous production and outflow. Slide 7.24 Formation and Secretion of Aqueous Humor from the Plasma Filtrate by the Ciliary Epithelium The formation of aqueous humor by the ciliary epithelium depends primarily upon two forces: hydrostatic pressure and the magnitude of the oncotic pressure gradient across the ciliary epithelium. rely upon artificially elevating the IOP and then calculating the outflow facility from the rate of decrease in the elevated pressure over time. The proportion of total outflow facility resulting from the pressureinduced reduction in aqueous production is termed pseudofacility. eds. Fingeret M. Simplified. Flow rates are highest just after awakening and reach their lowest during sleep. the resulting outflow facility is proportionally increased. In: Lewis T.

exchanger (symport). This decrease does not always lead to a reduction in IOP because significant elevation of aqueous humor serum protein concentration can obstruct aqueous outflow. potassium. in a cyclical fashion.28.42 The conformation presented to the cytoplasmic surface exhibits a high affinity for sodium but a low affinity for potassium. these ions move to the nonpigmented ciliary epithelial cells via gap junctions that unite both cell layers into a functional syncytium through both electrotonic and metabolic coupling. Evidence that such a system is central to the process of aqueous secretion comes from studies that have localized sodium potassium ATPase activity to the nonpigmented ciliary epithelium43 and others documenting that inhibition of this enzyme with ouabain reduces aqueous secretion. thus leading to a variable reduction in aqueous production. This added protein scatters light and is clinically referred to as flare. thus constituting the anatomical equivalents of the blood-aqueous barrier. Recent evidence suggests that sodium. Cl-. directing it toward the posterior chamber. The tight junctions of the ciliary epithelium31 and those of the iris vascular endothelium32 serve to limit diffusion of macromolecules into the aqueous humor. Sodium potassium ATPase is the enzyme that drives the Na+/K+ exchange pump. Evidence Supporting the Model Evidence for the dependency of aqueous secretion upon oxidative metabolism comes from numerous studies demonstrating that metabolic inhibitors.30 From the nonpigmented epithelial cells.ions are pumped into the intercellular clefts between adjacent nonpigmented ciliary epithelial cells. The exchange is thus not electrically neutral and results in a net outward movement of positive charge. reduction of oxygen tension.37 thus compensating for the reduction in inflow. A more detailed discussion of the numerous ion channels and ports that have recently been documented in various ciliary body preparations is available elsewhere. The tight junctions joining the apicolateral surfaces of the nonpigmented cells restrict aqueous flow at the apical end of the cleft.One of the most commonly cited models for the process of aqueous secretion is the modified Diamond-Bossert model for standing gradient osmotic flow. three sodium ions are extruded and two potassium ions are imported per ATP molecule.41. Na+.39 . and HCO3. By successively switching from one conformation to the other. The presence of these solutes creates a standing osmotic gradient that draws water into the cleft. The affinities of the alternate conformation. Compromise of these junctions also reduces the oncotic pressure gradient from the ciliary body stroma into the posterior chamber.20.27 To produce aqueous. Compromises in the integrity of this barrier caused by such provocations as anterior uveitis33-35 or paracentesis36 permit macromolecules to stream into the aqueous.29 Once inside the pigmented ciliary epithelial cells.38-40 Na+/K+ ATPase. and hypothermia all reduce the rate of aqueous production. and chloride ions are actively transported from the plasma filtrate in the ciliary body stroma into the pigmented ciliary epithelial cells by a resident Na+/K+/2Cl. are opposite. A currently accepted model of this pump (Post-Albers) proposes that the enzyme switches successively between two conformations within the cell membrane.26 An extremely simplified version is presented in (Slide 7). the ions that leave the microvasculature in the ciliary processes must enter the ciliary epithelial cells. presented to the extracellular surface under normal conditions.

however.Carbonic Anhydrase.47 . remains unclear. but also the entry of sodium ions.44 The valleys between the major ciliary processes. Within the ciliary epithelium. primarily to offset the net outward movement of cations by the Na+/K+ ATPase pump.movement may serve to alter pH in order to optimize Na+/K+ ATPase activity. is alkaline relative to plasma. accelerating the hydration of carbon dioxide to carbonic acid. normally covered by bundles of zonular fibers. which is low in bicarbonate. which is high in bicarbonate.+ H+ The roles of the ionic products of this reaction in the overall process of aqueous humor secretion remain uncertain. One theory regarding the role played by bicarbonate ions in aqueous humor production maintains that HCO3. this enzyme has been histochemically localized solely to the nonpigmented layer at the tips of the ciliary processes. The enzyme carbonic anhydrase also plays a central but as yet incompletely understood role in the process of aqueous secretion by generating bicarbonate ions. whereas human aqueous humor. is acidic relative to plasma (see Table 1). One function of bicarbonate ion in aqueous is to alter pH. Rabbit aqueous humor.45 Whether a direct linkage between sodium and bicarbonate transport exists. Inhibition of carbonic anhydrase decreases not only the entry of bicarbonate ions into the posterior chamber. The role of bicarbonate ion in aqueous production may vary by species. The basic reaction catalyzed by the enzyme is straightforward. do not exhibit staining for carbonic anhydrase. which dissociates into hydrogen and bicarbonate ions according to the following equation: H2O + CO2 <²> H2CO3 <²> HCO3. Still other theories include facilitation of chloride transport46 and/or alteration of the transepithelial voltage difference. Another states that transported in parallel with Na+.

a host of additional neuropeptides (e. and alpha-2 receptors. in the treatment of glaucoma.51. Ocular anatomy and physiology related to aqueous production and outflow.. Fingeret M. possibly mediated via nitric oxide.49 Receptor Systems Related to Aqueous Production An array of receptors have been identified in the ciliary body of various species. the importance of this enzyme to aqueous secretion is amply illustrated by the clinical utility of carbonic anhydrase inhibitors (CAIs). Stamford.52 Beta-Adrenergic Receptors. which appears to have its effects primarily through the adenylyl-cyclase enzyme-receptor complex. 1993. (Reprinted with permission from Freddo T.) Regardless of the mechanisms. substance P) has been identified within the tissues of the ocular anterior segment. such as acetazolamide45 and the more recently available topical derivative. beta-2. Also of interest is a proposed role for various nitrovasodilators in control of IOP. The most thoroughly examined receptor system relating to aqueous production is that of the betaadrenergic receptor.53 Stimulation of these receptors initiates a signal transduction cascade beginning with . vasoactive intestinal peptide. Primary Care of the Glaucomas.Slide 8.g. Conn: Appleton and Lange. Schematic outline of major steps in signal transduction pathways following binding of beta-1. eds. Uncovering possible roles for these agents in aqueous dynamics is at an early stage.50 Moreover. including those for natriuretic peptides and others. In: Lewis T. Beta-adrenergic receptors have been localized to the ciliary epithelium.48. opioids. neuropeptide Y.

The scleral spur (f) projects into the meshwork forming a point of attachment for the fibers of the longitudinal bundle of the ciliary muscle (g). is the belief that neither beta-agonists nor beta-antagonists .activation of a regulatory intramembranous G-protein. the episcleral vessels (c). it does seem clear that betaantagonists such as timolol maleate lead to reductions in both aqueous inflow and IOP.58 Regardless of the molecular mechanisms at work. in turn.) What is currently unclear is the mechanism through which these events lead to the ultimate effect on aqueous humor inflow. broadening from its apex to become continuous with the iris and ciliary body (j). 1971. The limbal conjunctiva (A) is formed by an epithelium (1) and an areolar connective tissue stroma (2). if not well explained. An iris process is evident (k). The trabecular meshwork (i) originates from Schwalbe's line (double arrows).59 Equally well established. In the case of beta-adrenergic stimulation. Histology of the Human Eye. the G-protein activates the second messenger adenylyl cyclase. single arrow. Drawing of the limbal region. (Reprinted with permission from Hogan M.56 The literature in this area is remarkably contradictory. (b) corneal arcades. Weddell J.57. which has also been localized to the ciliary body. terminus of Bowman's layer. Philadelphia. Aqueous flows into Schlemm's canal (h) and from there into a deep scleral plexus (e).54. The limbal corneosclera occupies area D. leads to elevation of cyclic-AMP levels resulting in phosphorylation of protein kinase-A (Slide 8). even disregarding the added complexities that arise in trying to compare data obtained from different species. Slide 9. Pa: WB Saunders. and finally. Tenon's capsule (B) forms an ill-defined layer of connective tissue over the episclera (C). (a) Conjunctival vessels. Alvarado J.55 This. intrascleral plexus (d).

and uveoscleral outflow. Aqueous Outflow Slide 10a. In: Lewis T. (Reprinted with permission from Freddo T. Primary Care of the Glaucomas. despite the presence of beta-receptors on cells within the trabecular outflow pathways. they are coupled through G-proteins to adenylyl cyclase. Thin strands of pigmented tissue often rise from the peripheral iris to meet the trabecular meshwork. but in a negative fashion that serves to block the elevations of cyclic-AMP levels induced by beta-agonists (Slide 8). it remains paradoxical that both alpha-adrenergic agonists and alpha-adrenergic antagonists have been reported to lower IOP.60 Like beta-receptors. Expanding as it moves posteriorly from its point of origin.demonstrates an outflow-mediated effect on IOP.61 They appear to act through suppression of aqueous inflow without an apparent effect on outflow facility.) The outflow of aqueous humor occurs predominately through two pathways: trabecular outflow.64. eds. 1993.56 Alpha-Adrenergic Receptors. the trabecular meshwork attaches to the respective stromas of the ciliary body and the peripheral iris. Stamford. These are called iris processes (Slide 9 and Slide 10A). at least on the inflow side of the equation. which is pressure independent. . The apex of this wedge is attached to Schwalbe's line.65 apraclonidine and the more recent and promising brimonidine now are available for management of glaucoma and add useful alternatives to our armamentarium. The Trabecular Meshwork The trabecular meshwork is a wedge-shaped band of tissue encircling and bridging the anterior chamber angle (Slide 9).63 Initially approved only for use prophylactically to prevent acute elevations of IOP that often follow argon laser trabeculoplasty. Ocular anatomy and physiology related to aqueous production and outflow. Macroscopic photograph of angle structures viewed from the same perspective as in gonioscopy.62 although effects mediated via reductions in episcleral venous pressure and ciliary body vascular flow also have been reported. Conn: Appleton and Lange. which is pressure dependent. the peripheral edge of Descemet's membrane of the cornea. Alpha-2 adrenergic receptors also are present in the ciliary body. Schlemm's canal is filled with blood in this specimen showing its relationship to the other structures.56 If this is the actual mechanism. Fingeret M.

Attached to the posterior surface of the scleral spur are the smooth muscle fibers of the longitudinal bundle of the ciliary muscle. they pull the spur posteriorly. TM=trabecular meshwork. Ocular anatomy and physiology related to aqueous production and outflow. When these fibers contract. (Reprinted with permission from Freddo T. In doing so. the layers of the corneoscleral meshwork attached to the anterior surface of the spur are spread apart.66 It is generally assumed that opening the meshwork in this fashion facilitates aqueous drainage and represents the most likely basis for the use of miotics in increasing aqueous outflow to reduce IOP in glaucoma. Conn: Appleton and Lange. IP=iris process. and which is most readily viewed gonioscopically. Fingeret M. is termed the uveal meshwork. SL=Schwalbe's line.Slide 10b. In: Lewis T. The limits of this sulcus are defined by an imaginary line drawn on a sagittal section of the meshwork from Schwalbe's line to the anterior tip of the scleral spur (Slide 9). The portion of the meshwork that is not confined within the sulcus. Stamford. Primary Care of the Glaucomas. 1993. CBB=ciliary body band. . eds. A portion of the meshwork lies wholly within a recess in the sclera termed the internal scleral sulcus. Corresponding sketch of angle structures viewed from the same perspective as in gonioscopy. Within the confines of the sulcus are the corneoscleral and juxtacanalicular (cribriform) regions of the meshwork and the canal of Schlemm.) Projecting into the base of this wedge is a shelf-like projection of sclera termed the scleral spur. Tendons of ciliary muscle fibers also likely change the configuration of the juxtacanalicular region of the meshwork by acting through the cribriform plexus or through contractile cells that have been identified within the scleral spur of the human eye. SS=scleral spur.

Because the canal of Schlemm is filled with blood. Goniophotograph of a normal. open angle representing a view analogous to that shown in Slide 10A and Slide 10B. OD.) For any clinician managing glaucoma. Note that trabecular meshwork can be divided into an upper lighter band (anterior) and a lower darker band (posterior) seen just above the scleral spur. understanding the relationship between the views of the meshwork obtained from sagittal sections and those obtained gonioscopically is essential..Slide 11a. Compare the diagrammatic representation of the angle structures seen in a sagittal section (Slide 9) with the appearance of these same structures viewed en face (Slide 10A and Slide 10B). The principal landmarks evident in such a view of an open anterior chamber angle include. from superior to inferior: y y y y Schwalbe's line (i. the peripheral terminus of Descemet's membrane) The trabecular meshwork The scleral spur The ciliary body band . open angle seen Slide 11A and Slide 11B. (Courtesy of Rodney Gutner. the relationship between the canal and the other angle structures also is evident. These views should each be compared with the goniophotograph of a normal.e. New England College of Optometry.

) The portion labeled trabecular meshwork can be further subdivided into a minimally pigmented anterior meshwork and a more heavily pigmented posterior meshwork. CBB=ciliary body band. Influence of Mercurial sulfhydryl agents on aqueous outflow pathways in enucleated eyes. In sagittal sections. SL=Schwalbe's line. et al.25[3]:278-285. Primary Care of the Glaucomas. As a result. In: Lewis T. eds. (Reprinted with permission from Freddo T. SS=scleral spur. Ocular anatomy and physiology related to aqueous production and outflow. Stamford. Slide 12. (Reprinted with permission from Freddo TF. Conn: Appleton and Lange.Slide 11b. lowflow portion of the meshwork is ideally targeted in argon laser trabeculoplasty. Scanning electron micrograph of the face of the uveal meshwork showing intersecting trabecular beams (x504). Invest Ophthalmol Vis Sci. the anterior portion of the meshwork corresponds to the portion of the meshwork that has no Schlemm's canal external to it. Copyright by Association for Research in Vision and Ophthalmology. Scott D. 1984. Fingeret M. This anterior. 1993. this portion of the meshwork sees little aqueous flow and thus its trabecular endothelial cells phagocytose relatively little pigment.) . Patterson M.

Transmission electron micrograph of a trabecular beam surrounded by a single layer of endothelial cells (E) and containing an avascular core of collagen and elastin (el). however. In section. do not support this view. Slide 13. these beams are seen to be composed of a nonvascularized core of collagens and elastin. And contrary to what had been widely presumed some years ago. contributing to the resistance of aqueous outflow that generates normal IOP. surrounded by a basement membrane and a single layer of thin endothelial cells (Slide 13).67.The Uveal and Corneoscleral Meshwork The tissue of the trabecular meshwork delimits a series of progressively smaller spaces for aqueous flow. For many years. Results of more recent histochemical studies. The uveal meshwork is composed of intersecting beams (Slide 12). hyaluronate was found mainly in the juxtacanalicular region.68 . surrounding Schlemm's canal and in collector channels (Slide 14A). Using a biotinylated hyaluronan-binding protein. It also was assumed that a progressive increase in such a gel might likely be the cause of the increased resistance that characterizes POAG. it had been widely assumed that a gel of hyaluronic acid fills the flow spaces of the trabecular meshwork. The corneoscleral meshwork has essentially the same composition but the openings available for aqueous flow are reduced such that the appearance is more aptly described as a perforated sheet. hyaluronate levels in the meshwork decrease with age and decrease even further in glaucomatous eyes when compared to age-matched controls (Slide 14B and Slide 14C).

74 Thus. The endothelial cells of the trabecular meshwork are known to be phagocytic. as with the corneal endothelium.70 They are capable of ingesting both endogenous materials such as pigment71. however.Slide 14a.70 Trabecular endothelial cells.75.69. Red stain denotes location of hyaluronate.73 presumably for the purpose of keeping the trabecular outflow channels free of potentially obstructive debris.76 Whether this cell loss is a major factor leading to the development of glaucoma remains to be established. primarily in the region of the meshwork closest to Schlemm's canal. It appears that this phagocytic capacity may be at some long-term cost to the meshwork. a progressive.72 and exogenous particulates such as latex microspheres. age-related reduction in the number of trabecular endothelial cells has been observed. have a limited capacity for cell division. because phagocytosis appears to prompt endothelial cells to detach from their beams and migrate out of the eye.77 . like corneal endothelial cells. Light micrograph of non-glaucomatous 47-year-old human trabecular meshwork.

These cells are capable of producing a range of substances that likely play critical roles in regulating the extracellular matrix of the meshwork thereby influencing outflow. and exogenously applied agents such as dexamethasone.78 MMPs are zinc-dependent.Slide 14b. gelatinase A and B. trabecular endothelial cells should not be thought of as inert. serve to limit MMP activity. Whether an imbalance in these forces represents a contributing or initiating event in the development of glaucoma remains to be established. MMPs including interstitial collagenase. calciumstabilized endopeptidases used by an array of connective tissues to initiate and regulate turnover of extracellular matrix. particularly in the juxtacanalicular region. cytokines. also made by the meshwork. and stromelysin are made in the trabecular meshwork and degrade extracellular material.78 TIMPs. . Two groups of compounds produced by the meshwork that are likely involved in regulation of outflow are the matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]). Although their mitotic activity is limited. Light micrograph of a non-glaucomatous 79-year-old human trabecular meshwork shows age-related decrease in hyaluronate staining. An array of modulators influences the balance between these two forces including growth factors.

Boston University. called TIGR (trabecular meshwork inducible glucocorticoid response [myocilin]) is an olfactomedin-related glycoprotein that increases in amount in response to glucocorticoid exposure.) The Cribriform or Juxtacanalicular Meshwork .79. TIGR staining was observed to be more intense and more widely distributed. In most glaucomatous eyes examined. Most recently. MD. (Courtesy of Haiyan Gong. eds. 1993. Reprinted with permission from Freddo T. a novel protein induced by exposure of trabecular cell cultures to glucocorticoids has been identified. Transmission electron micrograph demonstrating the appearance of cells in the juxtacanalicular (JCT) region of the trabecular meshwork. Ocular anatomy and physiology related to aqueous production and outflow.80 In normal human eyes.81 TIGR is presently under intense investigation as playing a possible role in steroid-induced glaucoma and possibly even POAG.Slide 14c. These cells lack a basal lamina and are enmeshed within a connective tissue matrix that includes fibrillar collagen. Fingeret M. This protein. PhD. In: Lewis T. Conn: Appleton and Lange. These cells commonly extend paddle-like processes (arrows) to reach the endothelial cells lining Schlemm's canal (SC). Stamford. Slide 15. Primary Care of the Glaucomas. along with its gene. TIGR is immunohistochemically localized to the inner uveal meshwork region and the anterior portion of the meshwork. Light micrograph of a glaucomatous 79-year-old human meshwork shows even less staining for hyaluronate.

84 Slide 16a. an open connective tissue matrix is found. which contains fibroblast-like cells that lack a basal lamina (Slide 15). At the other end. these fibers are connected to the basal surface of the endothelial cells that line the inner wall of Schlemm's canal. calculations of outflow resistance in the juxtacanalicular meshwork. This anatomical system. The resulting new view demonstrates a substantially more complex matrix present in the JCT region than could previously be demonstrated (Slide 16A and Slide 16B). Running through this matrix is a plexus of elastin-containing fibers that are connected at one end to tendons from the longitudinal bundle of the ciliary muscle. The "Open" Spaces of the Trabecular Meshwork. Preliminary morphometric and modeling studies . it is now possible to obtain an electron microscopic view of the JCT region that does not require the series of chemical extractions employed using conventional methods.83 Underscoring the physiological importance of these various anatomical connections is the work of Kaufman and Bárány. called the cribriform plexus. Transmission electron micrograph of conventionally prepared normal human trabecular meshwork shows ample "open-space" in the juxtacanalicular (JCT) region beneath Schlemm's canal (SC) (x40.85 This fact has led some to seek alternate methods of tissue preparation that may better preserve the complex extracellular matrix presumed to reside in the juxtacanalicular tissue (JCT) region. have been shown to fall two orders of magnitude short of generally accepted values for outflow resistance. who first demonstrated that surgical disinsertion of the ciliary muscle eliminates the outflow-enhancing effects of pilocarpine. Nevertheless. for it is the cribriform region of the aqueous outflow system that is generally held to represent the principal site of aqueous outflow resistance.400). it appears that there is ample "openspace" even in an early to moderate stage of POAG. Such changes are likely of clinical importance. using a mathematical model that assumed the "open" spaces seen in conventional electron micrographs to be real. Using a recently developed method known as Quick-Freeze/Deep-Etch. In photomicrographs of trabecular meshwork prepared using conventional methods of tissue preparation.The tissue found in the region of the meshwork lying between the innermost corneoscleral trabecular beam and the inner wall of Schlemm's canal does not have a beam configuration.82 has the potential to affect alterations in the permeability of this region.82 The region of the meshwork occupied by these cells and the extracellular matrix with which these cells are associated represent the cribriform or juxtacanalicular region of the trabecular meshwork. Instead.

Boston University. When subjected to pressure. the inner wall of Schlemm's canal exhibits unusual structures termed giant vacuoles (Slide 17). As IOP is increased (within physiological limits). The canal usually appears slit-like and. as exists in vivo.86 supporting previous work by others concluding that the JCT region is the principal site of resistance.36.) The Canal of Schlemm The canal of Schlemm is a continuous. Transmission electron micrograph of juxtacanalicular region of normal human trabecular meshwork at the same magnification as in Slide 16A. The formation of these vacuoles is pressure dependent but not energy dependent. MD. when IOP is reduced.suggest that this new view of the JCT region correlates better with fluid dynamic predictions. shows much less "open-space. at several points around the circumference of the eye. circumferentially oriented channel. Despite this connection.88 Conversely. The outer wall of Schlemm's canal directly abuts the sclera. the size of vacuoles in the inner wall of Schlemm's canal also increases.89 . but prepared using quickfreeze/deep-etch. The lumen of the canal has direct connections to the venous system of the eye. at least in the normal eye. PhD. vacuoles also are reduced." (Courtesy of Haiyan Gong. The inner wall of Schlemm's canal faces the juxtacanalicular region of the meshwork. situated deep within the internal scleral sulcus. as in paracentesis. it divides into two parallel channels that rejoin after a short distance.87 Slide 16b. blood usually is not seen in the canal unless IOP falls below that of episcleral venous pressure.

similar vacuoles are present in the arachnoid villi of the meninges.500). the border pore. thus creating a temporary focal opening between endothelial cells. these data raise the prospect that border pores could represent focal areas where the number of tight junctional strands has been reduced to zero. From Schlemm's Canal to the Episclera . using the technique of freeze-fracture electron microscopy. Conn: Appleton and Lange. Another vacuole is seen in the process of formation (arrow) (JCT) (x6.Slide 17. gap junctions and discontinuous tight junctions in monkey94 and normal human eyes. As odd as these vacuoles appear. Primary Care of the Glaucomas. but only one of them. correlates with perfusion pressure. Ultrastructural studies. have demonstrated that the endothelial cells of the inner wall are joined by two types of intercellular junctions.93 The significance of these two classes of pores remains to be established.91 Small openings called pores are found both in vacuoles and in non-vacuole-containing areas of the inner wall.90. surrounding the brain.96 Taken together. eds. Fingeret M. Stamford.95 More recent studies also have documented that the complexity of the junctions between inner wall cells decreases with increasing pressure. In: Lewis T. Transmission electron micrograph demonstrates a giant vacuole (GV) in the inner wall of Schlemm's canal (SC).93 Border pores occur along the intercellular cleft between adjacent endothelial cells. Ocular anatomy and physiology related to aqueous production and outflow.) Giant vacuoles rarely are found if the tissue has not been fixed under conditions of active flow. where they are believed to play a role in the resorption of cerebrospinal fluid.92 Pores are presumed to represent the actual flow pathways used by aqueous to traverse the inner wall of Schlemm's canal. Two types of pores have recently been examined: socalled intracellular pores and "border" or intercellular pores. 1993. (Reprinted with permission from Freddo T.88.

Absent the tortuous pathway taken by most of the aqueous. the recently identified presence of contractile . As a consequence. During this passage. aqueous flows circumferentially toward one of approximately 30 external collector channels. aqueous veins are readily identified by biomicroscopy as blood vessels appearing only half filled with blood. These are outlined in the right side of Slide 18. carotid-cavernous sinus fistula) can give rise to significant elevations of IOP.97 Current estimates are that less than 20% of total resistance resides in the portion of the outflow pathway beyond Schlemm's canal.97 Few in number. left side). aqueous and blood are mixed.) Slide 18. aqueous humor flows by one of two pathways to join the venous blood of the episcleral vessels. 1971. (Modified from Hogan M. External collector channels arising from the outer wall of Schlemm's canal (upper right) lead to deep and intrascleral plexi and then to the episcleral vessels. however.Upon reaching the lumen of Schlemm's canal. aqueous flows successively through a deep scleral plexus and an intrascleral venous plexus before reaching the episcleral veins. Aqueous veins (upper left) arising from either external collector channels or the outer wall of Schlemm's canal. Diagrammatic representation of the distal portion of the aqueous outflow pathways from Schlemm's canal to the episcleral vessels. bypass this more convoluted pathway. elevations of episcleral venous pressure (e. directly to the episclera (Slide 18. the aqueous veins lead from either the outer wall of Schlemm's canal or an external collector channel. Within Schlemm's canal. the blood and aqueous have not mixed by the time they reach the episclera. Weddell J. Alvarado J. From the external collector channels. As a consequence. Philadelphia. A smaller volume of aqueous humor bypasses the complex pathway outlined above by entering aqueous veins (of Ascher). Histology of the Human Eye.g. Pa: WB Saunders.. The most commonly used pathway from Schlemm's canal to the episcleral vasculature is via a complex system of tortuous pathways that obliquely traverse the thickness of the sclera.

Xalatan (latanoprost. Pharmacia) has become available commercially.98 Uveoscleral Outflow A smaller but important fraction of total aqueous outflow leaves the eye in a pressureindependent fashion via a pathway beginning at the face of the ciliary body band and. Thus. the uveoscleral pathway has been the subject of increased interest with the discovery that several prostaglandin analogs are capable of augmenting uveoscleral outflow. prolonged use stimulates melanin pigment production in the uvea leading to a progressive . Two interesting discoveries have emerged as clinical use of this medication has increased.elements within the walls of the external collector channels in human eyes has spurred renewed interest in these issues. through the sclera (uveoscleral) or the scleral emissaria provided for the vortex veins (uveovortex). First. 1977.) connective tissue septae that separate the fascicles of smooth muscle fibers in the ciliary muscle (Slide 19). it is not surprising that pilocarpine reduces uveoscleral outflow. possibly by solubilizing elements of the intramuscular connective tissue matrix of the ciliary body. (Reprinted with permission from Tripathi RC.101 One of these.99 The amount of total outflow represented by uveoscleral flow at normal IOP varies significantly among species.5). ultimately.100 Current estimates are that in the normal human eye. The tracer has moved from the anterior chamber (AC) posteriorly through the angle tissues (a) including the connective tissue septae of the ciliary muscle (b) to the supraciliary and suprachoroidal spaces (arrows).25[suppl]:305. uveoscleral flow accounts for less than 10% of the total. Note the tracer enters the iris stroma (c) but does not cross the iris into the posterior chamber (x38. The pathway can be followed using tracer molecules and appears to pass within the Slide 19. Contraction of this muscle reduces the available space for uveoscleral flow.100 In recent years. Light micrograph demonstrates the distribution of fluoresceinated dextran after intracameral perfusion. Exp Eye Res. however. Uveoscleral drainage of aqueous humor.

105 Fin = Fout = 2. Under these circumstances the equations can be simplified as follows: Fin = Fin= Ctrab(?P) + Fu Kaufman has provided an illustrative example of this modified equation using measured values for the normal human eye. Fluid Mechanics of Trabecular Outflow From the previous discussion. This latter factor is referred to as facility of outflow. has been developing empirical evidence that pilocarpine and Xalatan are additive in reducing IOP. A general appreciation for how the major factors involved in this process interact is. Accounting for each of them in attempting to understand aqueous humor dynamics is difficult. These equations assume that trabecular outflow occurs in an entirely passive manner as a bulk flow down a pressure gradient. Ample resources are available to the reader interested in developing an in-depth understanding of the . episcleral pressure is a negligible variable.104 Since pilocarpine has been shown to profoundly reduce uveoscleral outflow.5 µL/min Ctrab = 0. useful. contributes to the measured IOP at any point in time. and a factor that represents the ability of aqueous to leave the eye. some known and some yet to be elucidated.4 In an overview such as this.darkening of iris color.5 = 0.102 Most surprising. it is clear that an array of basic factors.103. Under steady-state conditions. They also assume that all outflow is trabecular. and the facility of outflow through the trabecular meshwork is predominant. These factors were first incorporated into simplified mathematical constructs by Goldmann as follows: ?P = IOP .9) = 7 Fu = 0.3(7) + 0. the pressure in the venous system of the episclera. however.episcleral venous pressure and facility of trabecular outflow = aqueous flow rate/?P where IOP and episcleral venous pressure are measured in millimeters of mercury and aqueous flow is in microlitlers per minute at steady state. which is the inverse of outflow resistance. however. These major factors include the measured IOP. certain oversimplifications and omissions are inevitable.4 µL/min Substitution of these values into the equation Fin = Fout = Ctrab(?P) + Fu gives the following: 2.3 µL/min/mm Hg IOP = 16 mm Hg episcleral venous pressure = 9 mm Hg ?P = (16 . the flow rate of aqueous humor. this eventuality clearly demonstrates that our knowledge of the anatomy and physiology of uveoscleral outflow is incomplete and further study is warranted.

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