Thomas F. Freddo,
Mortimer Civan,
Haiyan Gong
INTRODUCTION
Elevated intraocular pressure (IOP) is a prime risk factor for the development of glaucoma. Elevated pressure is considered a risk factor rather than the cause of glaucoma because some patients with pressures in the statistically normal range develop the pattern of vision loss typical of glaucoma. Such patients are diagnosed as having normal tension or low-tension glaucoma. Conversely, some patients are able to tolerate pressures nominally higher than the statistically normal range, seemingly without consequence.
Despite demotion of IOP from cause to mere risk factor in the past 20 years, a clear understanding of the principles underlying the production and drainage of aqueous humor (AH) remains an imperative foundation for embarking upon management of this group of diseases. The reason why understanding AH production and drainage remains so important is that all currently used therapeutic interventions for treating glaucoma are aimed at reducing the pretreatment pressure, whether it was high or low.
AH AND ITS FORMATION
AH is a remarkable, clear nutritive fluid, designed to support the metabolic needs of the avascular tissues of the ocular anterior segment including the lens, the cornea and the trabecular meshwork. To operate efficiently as an optical system the optical and the sensory elements of the eye must remain at relatively constant distances from each other. In the absence of an exoskeleton, this is accomplished by pressurizing the inside of the eye. And while vascular changes, especially in the choroid, can influence IOP,[1] it is the back-pressure created in draining the constantly produced AH that serves to keep the intraocular tissues in proper place.
AH is derived from a filtrate of plasma and secreted by the ciliary epithelium into the posterior chamber of the eye. The rate of AH production is traditionally considered to be ?2.5-3.0 microliters/min. Recent studies have challenged this value, suggesting that the rate may be as high as 7-8 microliters/min when diffusional losses into the vitreous are considered.[2] Given that the combined volumes of the anterior (200 microliters/min) and posterior (50 microliters/min) chambers of the eye total 250 microliters, it is simple to calculate that, excluding diffusional losses to the vitreous, the entire volume of the AH is replaced approximately every 100 min.
Numerous studies have compared the relative concentrations of the various constituents in plasma and AH. These are summarized in Table 191.1. Although many similarities exist between the aqueous and plasma, several significant differences are found as well. As one example, AH has a substantially higher concentration of ascorbate, now widely assumed to be present as an antioxidant and scavenger of superoxide radicals.[3] Free amino acid levels vary with respect to their relative concentrations in plasma. Certain of these, including arginine, isoleucine, leucine, methionine, phenylalanine, serine, threonine, tyrosine and valine are in higher concentration in the aqueous than in plasma, suggesting active transport mechanisms are involved.[4]
TABLE 191.1 -- Constituents of Human Aqueous Humor vs Plasma[*]
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Constituent (?mol/mL) |
Anterior Chamber Aqueous Plasma |
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Ascorbate 0.04 |
1.06 |
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Bicarbonate 26 |
22 |
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Calcium 4.9 |
2.5 |
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Chloride 107 |
131 |
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Glucose 5.9 |
2.8 |
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Lactate 1.9 |
4. |
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Magnesium 1.2 |
1.2 |
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Phosphate 1.1 |
0.6 |
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Potassium 26 |
22 |
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Sodium 148 |
152 |
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Urea 7.3 |
6.1 |
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Protein (gm/dL) 7.0 |
0.024 |
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pH 7.40 |
7.21 |
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* |
adapted from Krupin T, Civan M: Physiologic basis of aqueous humor formation. In: Ritch R, Shields MB, Krupin T, eds. The glaucomas. 2nd edn., St Louis, MO: CV Mosby; 1996. |
The protein concentration of AH, in aliquots obtained from the anterior chamber, is less than 1% of that found in plasma (ratio of aqueous/plasma =0.024/7 gm/dL).[5] Improvements in protein chemistry methods have permitted a more complete analysis of this protein spectrum.[6,7] 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 iron scavenging protein.[8]
Recent evidence suggests that the amount of plasma-derived protein present in the AH of the anterior chamber is supplemented just prior to its entry into the outflow pathway. Using fluorophotometry and, more recently, magnetic resonance imaging with contrast materials (Fig. 191.1) 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, through the uninterrupted stromal pathway to the root of the iris, by-passing the posterior chamber.[9-11]
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FIGURE 191.1 High-resolution magnetic resonance images of the ciliary body, anterior and posterior chambers of normal human eye before (left) and 90 min after (right) 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 indicating direct entry into the anterior chamber via the iris root, rather than through the pupil from the posterior chamber. |
In the absence of an epithelium on the anterior iris surface, this additional protein enters the AH. Proteins entering the anterior chamber along this pathway are prevented from returning to the posterior chamber by tight junctions joining the posterior epithelial cells of the iris.[12] Via this pathway, the protein content of the AH is supplemented just prior to the entry of AH into the outflow pathway (Fig. 191.2). The question of whether any of these additional proteins might play a role in creating aqueous outflow resistance remains to be fully evaluated.[13] There is some evidence to support the theory that certain of the proteins added to AH, particularly those of low molecular weight and known as 'fies' may play a role in generating normal outflow resistance as they are carried by aqueous flow into the trabecular meshwork.[14,15]
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FIGURE 191.2 Sketch denoting the principal pathway of macromolecular solutes into the aqueous humor of the normal eye. |
Additional, locally produced proteins are also present in AH. A remarkably comprehensive cataloging of ciliary epithelial gene products has been produced by Coca-Prados and others.[16] Foremost among the locally produced proteins are growth factors, the most intensively studied of which is transforming growth factor-beta (TGF-beta). TGF-beta has been shown to play an array of important roles in the unique immunoregulatory processes of the anterior chamber.[17] A most provocative fiding has been preliminary data suggesting that TGF-beta2 may be elevated in the AH of patients with primary open-angle glaucoma (POAG).[18] The significance of this fiding remains to be fully explored, but it speaks to the importance of further inquiry into the mechanisms of these important classes of proteins in AH.[19]
AQUEOUS CIRCULATION
To pass from the posterior to the anterior chamber, aqueous must flow forward through the pupil. The pupillary margin rests on the anterior lens capsule, creating a one-way valve. Changes in the anatomical relationship between the pupillary margin and anterior capsule of the lens can reduce the flow of AH into the anterior chamber (relative pupillary block). Similarly, inflammation-induced adhesions of the pupillary margin to the anterior surface of the lens (posterior synechiae) can obstruct aqueous flow.
Upon entering the anterior chamber, aqueous circulates in a convection current driven by the temperature difference between the warmer iris and the cooler cornea. Rising posteriorly and falling anteriorly, the AH fially leaves the eye, via two principal pathways described later. Because the AH is normally free of particulates, this circulation is difficult to appreciate. However, when particulates are present, such as uveal pigment in pigment dispersion syndrome or inflammatory cells in anterior uveitis, one can confirm the existence of this circulation by noting that the particulates in the posterior portion of the anterior chamber are rising while those just posterior to the cornea are falling. As the aqueous falls along the inward curvature of the inferior cornea, particulates such as pigment tend to sediment out and are phagocytosed by the corneal endothelium. If sufficient pigment is released, a vertically oriented line of pigment gradually becomes evident decorating the inferior half of the central cornea (Krukenberg's spindle).[20]
THE CILIARY BODY AND AQUEOUS PRODUCTION
The ciliary body performs functions relating to both aqueous production and aqueous outflow. It is the sole source of AH production and it facilitates aqueous outflow by contracting a group of its smooth muscle fibers and their tendons that alter the adjacent trabecular meshwork and outflow pathways (described later).
The ciliary body extends anteriorly from the ora serrata to the root of the iris. In the adult eye, the ciliary body extends posteriorly ?7 mm from the limbus temporally and 6 mm on the nasal side of the eye. It is grossly subdivided into two portions, the pars plicata anteriorly and posteriorly the pars plana, which extends to the ora serrata.
The inner surface of the pars plicata, exhibits ?75 undulated, radially oriented, fi-like ridges, each of which is termed a ciliary process (Fig. 191.3). These processes are divided into major and minor processes based upon their relative height and both major and minor processes are readily discernable by scanning electron microscopy (Fig. 191.4). This figure is somewhat misleading, however, because all of the zonular fibers have been removed from this specimen. Normally, the entire inner surface of the pars plana is covered with these fibers. Upon reaching the posterior edge of the pars placata, all of these fibers are chanelled into the valleys between the adjacent ciliary processes, leaving only the tips of each process exposed to the posterior chamber (Fig. 191.5).
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FIGURE 191.3 Macrophotograph of the anterior segment of a normal human eye showing the lens surrounded by a ring of fi-like ciliary processes of the pars plicata region of the ciliary body. External to the ring of ciliary processes is the smooth-surfaced pars plana region, extending to the ora serrata. |
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FIGURE 191.4 Scanning electron micrograph of the inner surface of the iris and ciliary body with the lens and zonules removed. |
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FIGURE 191.5 Scanning electron micrograph demonstrating the channeling of zonular fibers into the valleys between adjacent ciliary processes. |
In meridional sections, the ciliary body appears as shown in Figure 191.6. The entire inner surface of the ciliary body is lined by a bilayered epithelium (Fig. 191.7). These two layers are named for their relative content of melanin pigment. The layer closest to the posterior chamber is free of pigment and is termed the nonpigmented ciliary epithelium. The layer closest to the ciliary body stroma is termed the pigmented ciliary epithelium for its melanosome content (Fig. 191.7). The nonpigmented ciliary epithelium is continuous with the posterior pigmented epithelium (PE) of the iris anteriorly and with the neurosensory retina posteriorly at the ora serrata. The pigmented ciliary epithelium continues anteriorly as the anterior myoepithelium of the iris (which includes the iris sphincter muscle) and posteriorly as the PE of the retina. The double layer of epithelium covering the ciliary body actually represents two simple epithelia that come to be joined at their apical surfaces following the invagination of the optic cup during embryogenesis. As a result, the basement membrane of the nonpigmented ciliary epithelium faces the posterior chamber and that of the pigmented ciliary epithelium joins both epithelial layers to the ciliary body stroma.
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FIGURE 191.6 Composite light micrograph of the ciliary body. (a) iris, (b) iris root, (c) pars plicata, (d) pars plana, (e) ciliary epithelium. |
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FIGURE 191.7 Light micrograph of a ciliary process demonstrates a fibrovascular core surrounded by two layers of epithelium. The epithelial layer closest to the stromal core is pigmented and the layer closest to the surface is nonpigmented. |
The ciliary body stroma is composed of a loose connective matrix that supports the nerves and blood vessels that travel within it. This connective tissue matrix extends into the core of each ciliary process. The ciliary body stroma is directly continuous with the stroma of the iris anteriorly and with the choroidal stroma posteriorly. Since the anterior surface of the iris has no epithelial covering, substances released into the ciliary body stroma have access to the anterior chamber by diffusing from the ciliary body stroma to the iris surface.[9-11] Similarly, fluid entering the ciliary body stroma from the anterior chamber can reach the choroid by traveling along the uveoscleral outflow pathway described later.
PRODUCTION OF AH
To provide anatomical correlations for the physiology of AH formation, it is most convenient to describe the process in two steps[1]: elaboration of a plasma filtrate from which AH is derived, and[2] formation of AH from this filtrate. Although these steps are not independent, the first is related primarily to the ciliary body microvasculature and the second to the ciliary epithelium.
The Ciliary Body Microvasculature
When viewed in cross-section each ciliary process contains a vascularized connective tissue core (Fig. 191.7). The arterioles that serve the ciliary body stroma, arise from the discontinuous major circle of the iris.[21] Each major process is served by a set of anterior and posterior arterioles (Figs 191.8 and 191.9).[21] The anterior arterioles supply the large diameter capillaries, near the tips of the processes, while the posterior arterioles supply the smaller caliber capillaries deep within each process. The direction of blood flow in both of these systems is from anterior to posterior, toward the choroid, ultimately leaving the eye via the vortex veins.
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FIGURE 191.8 Scanning electron micrograph of the microvasculature within a single ciliary process. The major arterial circle (MAC) gives rise to an anterior (arrow) and posterior (arrowhead) arteriole. Both sets of vessels drain into choroidal veins (CV). |
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FIGURE 191.9 Diagrammatic representation of the vascular cast shown in Figure 8. |
The capillaries derived from the posterior arterioles, which serve the ciliary muscle, are nonfenestrated and do not leak plasma-proteins under normal conditions. By contrast, the capillaries derived from the anterior arteriole, which pass within the stromal core of each ciliary process, lack tight junctions and are lined by fenestrated endothelial cells (Fig. 191.10). Using tracers for plasma protein leakage such as horseradish peroxidase (HRP), the capillaries of the ciliary body stroma are seen to be very permeable to macromolecules as well as ions and fluid (Fig. 191.11). As such, these vessels are limited in their capacity to serve as a selective permeability barrier. That function is one of several reserved for the ciliary epithelium.
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FIGURE 191.10 Transmission electron micrograph of a fenestrated capillary in the ciliary body stroma. Arrowheads denote endothelial fenestrations. |
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FIGURE 191.11 Transmission electron micrograph of a fenestrated capillary in the ciliary body stroma filled with granular tracer. Granular tracer is also seen decorating the surrounding stroma, having leaked through fenestrations indicated by arrowheads. |
Elaboration of a plasma filtrate from the microvasculature of the ciliary body
The physiological process in which fluid is forced across a membrane by pressure is termed filtration. The amount of filtrate crossing a membrane depends upon the pressure difference across the membrane and the surface area over which filtration can occur. The composition of the filtrate is determined largely by the size of the pores in the membrane; that is by the permeability of the blood vessel wall. A filtrate of plasma is produced across the walls of the microvasculature within the ciliary processes.
The ions, fluid and plasma proteins leave the fenestrated microvasculature driven by the hydrostatic pressure within the capillaries of the ciliary processes.[22] 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. The hydrostatic pressure within the microvasculature is augmented by a significant oncotic pressure, resulting from the leakage of plasma proteins into the the ciliary body stroma.
Evidence suggests that blood flow in the ciliary body is regionalized and these various regions respond differently to agents such as epinephrine.[23] Adrenergic nerve endings are associated with the ciliary body microvasculature which prompt a reduction in blood flow following sympathetic stimulation.[24,25] This reduction in blood flow is likely mirrored in reductions in filtrate production.
These vascular forces are opposed by the interstitial fluid pressure of the ciliary body stroma. The interstitial fluid pressure increases with IOP.[25] Thus, moderate elevations of IOP can actually suppress aqueous inflow, leading to a decrease in IOP. The dynamics of this relationship are actually more complex, and the effect is insufficient to serve as a protective mechanism against the elevated pressure that characterizes POAG.
Pseudofacility
Nonetheless, there is an important clinical consequence of the relationship between IOP and inflow, but this effect is manifested on the measurement of aqueous outflow. Certain methods for measuring outflow facility, such as tonography and in vivo ocular pressure perfusion techniques, rely upon artificially elevating the IOP and then calculating the outflow facility from the rate of decrease in the elevated pressure over time.[26,27] Since reduction in aqueous production contributes a fraction of this drop in IOP, the apparent outflow facility is proportionally increased. The portion of total outflow facility resulting from the pressure-induced reduction in aqueous production is termed pseudofacility. The percent of total outflow represented by pseudofacility appears to vary markedly among species. Early estimates suggested that pseudofacility might account for as much as 20% of total outflow in humans.[28] But with methodological refiements, reduced estimates to 5-10% of the total human outflow have resulted.[29]
The Ciliary Epithelium
The two cell layers that constitute the ciliary epithelium are named for their relative content of melanin pigment. The layer closest to the ciliary body stroma is called the pigmented ciliary epithelium and that closest to the posterior chamber of the eye is called the nonpigmented ciliary epithelium (Fig. 191.7). The morphology of the ciliary epithelium varies along the surface of the ciliary body, in accord with the different demands placed upon it in various locations.[30] From this analysis, it appears that it is primarily the epithelia at the tips of the ciliary processes that are involved in the production of AH. Recall that only the tips project above the stacks of zonular fibers filling the valleys between processes (Fig. 191.5). Immunoelectron microscopic studies have clearly documented that both Na-K-ATPase activity and carbonic anhydrase activity are limited to the exposed portions of the ciliary processes.[31,32] Both are known to be central to the production of AH and one of them, (carbonic anhydrase), is regularly targeted for pharmacological inhibition to reduce IOP in glaucoma.[33] Mechanisms of these systems are detailed below.
The blood-aqueous barrier in the ciliary body
While free amino acid levels in AH are nearly equivalent to those found in plasma,[4] the protein content of AH in the anterior chamber is less than 1% of that found in plasma.[5] Proteins create turbidity that scatters light, degrading the optical efficiency of the eye. The nonspecific entry of plasma-derived proteins such as albumin can bring with it unwanted or harmful growth factors, potential antigens and other plasma components deleterious to the pristine environment required within the eye. To prevent this, and to ensure that potential antigens in the bloodstream are prevented from reaching the anterior and posterior chambers of the eye, the lens, vitreous and retina, a selective barrier must be positioned between the bloodstream and the AH. As noted earlier, the microvasculature of the ciliary body stroma is composed of fenestrated capillaries that readily leak fluids, ions and plasma proteins in order to provide the reservoir from which the ciliary epithelium secretes AH. (Figs 191.10 and 191.11). To ensure that the protein-laden fluid in the ciliary body stroma and the composition of the AH remain different, a barrier to macromolecular diffusion is interposed between the ciliary body stroma and the posterior chamber by the ciliary epithelium.[30] Protein leaked into the ciliary body stoma diffuses to the ciliary epithelium and easily moves between adjacent pigmented ciliary epithelial cells, filling the intercellular clefts (Fig. 191.12). Upon reaching the interface between the juxtaposed apical surfaces of the pigmented and nonpigmented layers, the HRP is again able to freely permeate the intercellular cleft between these cell layers. But when the HRP attempts to diffuse along the intercellular cleft between adjacent nonpigmented ciliary epithelial cells, its progress toward the AH in the posterior chamber is blocked by an apicolateral junctional complex composed of a zonula occludens (aka, tight junction), a zonula adherens and desmosome (Fig. 191.12).[30] Disruption of this junctional complex has been shown to occur in experimental anterior uveitis, resulting in increased amounts of protein in the AH.[34] This extra protein scatters the light of the slit lamp and is described clinically as 'flare'.
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FIGURE 191.12 Transmission electron micrograph of ciliary epithelium following intravenous injection of horseradish peroxidase, a protein tracer. Black granular, HRP fills the ciliary body stroma (asterisk) and permeates the intercellular space between adjacent pigmented ciliary epithelial cells. Tracer also permeates the intercellular cleft between the pigmented and nonpigmented epithelial layers. But tracer is prevented from reaching the posterior chamber by tight junctions (arrowheads in main figure and arrows in high magnification inset) between adjacent nonpigmented ciliary epithelial cells. |
Although not involved directly in the barrier properties of the ciliary epithelium, another intercellular junction, the gap junction, has been shown to play an important role in aqueous production. Gap junctions are known to provide a means for metabolic and electrotonic coupling of cells. In the ciliary epithelium, cells of both layers are interconnected by these junctions and they provide a low resistance pathway for the passage of current and ions between cells, allowing them to function as a syncytium in the coordinated secretion of AH.[30,35]
Many more gap junctions link apposing PE and nonpigmented epithelium (NPE) cells than connect PE-PE or NPE-NPE cell couplets.[30] Furthermore, the gap junctions between PE and NPE cells are homomeric, homotypic arrays of CX43 and CX40 connexins, the family of proteins that constitute gap junctions.[36] The gap junctions linking NPE cells are also homomeric and homotypic, but consist of CX26 and CX31 connexins, while the connexin composition of the junctions linking the PE cells is unknown. PE-NPE gap junctions appear more resistant than either PE-PE or NPE-NPE gap junctions to experimental stress because of the differences in density and/or composition of the junctions.[37] This observation has led to the view that secretion proceeds through parallel PE-NPE couplets transferring solute and water from the ciliary body stroma to the AH.[37]
When the ciliary body is inflamed, as in anterior uveitis, it has been shown that gap junctions largely disappear, likely contributing to a reduction in aqueous secretion and to the lower IOP that often accompanies inflammation of the anterior uvea.[34] Attempts to exploit gap junction uncoupling as a means of reducing aqueous production in glaucoma remain unexplored.
Secretion of AH from the plasma filtrate by the ciliary epithelium
NaCl is the dominant solute transferred in aqueous production, since the solute compositions of the AH and protein-free serum are largely similar. Energy for secretion is supplied as ATP to Na+-K+-activated ATPase, predominantly localized in the basolateral plasma membranes of the NPE cells abutting the AH. ATP is utilized not only to support the direct exchange of intracellular Na+ for extracellular K+, but also thereby to establish the transmembrane gradients needed to drive solute movement through a complex array of co-transporters (symports), counter-transporters (antiports), facilitated-diffusion carrriers (uniports) and ion channels (Fig. 191.13).
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FIGURE 191.13 (a) Unidirecitonal secretory pathways in aqueous humor production. (b) Potential reabsorptive pathways within the bilayer of the ciliary epithelium. |
Sequential steps in ciliary epithelial secretion
AH formation is initiated by the uptake of stromal solute through two sets of electroneutral transporters of the PE cells (Fig. 191.13a).[38-42] NaCl can be taken up by the Na+-K+-2Cl? symport, with the accumulated K+ largely recirculating back into the stroma; thus, K+ acts as a catalyst, enhancing the thermodynamic force driving the symport. The net driving force for solute uptake through the symport is strongly dependent on the intracellular Cl? concentration. Net uptake is predicted to cease at an intracellular Cl? concentration of ?50 mM.[43] In parallel with the symport, NHE-1 and AE2 antiports underlie uptake of Na+ and Cl? in exchange for H+ and HCO3? respectively.[44] Cytoplasmic carbonic anhydrase II increases the turnover of these parallel antiports both by enhancing the delivery rate of H+ and HCO3?and by directly stimulating both exchangers (Fig. 191.13a). Carbonic anhydrase inhibitors used in the treatment of glaucoma, likely reduce inflow and IOP by inhibiting the NHE-1 and AE2 antiports.
Following uptake from the stromal fluid, solute is transferred from the PE cells to the NPE cells through the gap junctions.[45-48] Thereafter, the NPE cells extrude Na+ through Na+-K+-activated ATPase and release Cl? through Cl? channels into the AH. Bicarbonate can likely be released through Cl?-HCO3? antiports[49,50] and Cl? channels.[50,51] The molecular identity of the Cl? channels is unclear, although results obtained with antisense knockdown[52] and blocking antibody[53,54] suggest that ***ClC-3 plays a role in the trafficking, regulation or composition of the Cl?-channel complex.
The sequential mechanisms for transfer of water are less well understood than for solute. The aquaporin water channels AQP1 and AQP4 facilitate release of water from the NPE cells into the AH, and knockouts of these aquaporins reduce inflow and IOP.[55] No known aquaporin has been found to be expressed by the PE cells, so it is unclear whether water is taken up from the stroma through water channels or simply by diffusion across the plasma membranes.
Potential reabsorption across the ciliary epithelium
All of the transport mechanisms discussed thus far provide the bases for secretion of the AH. Solute and water transfer can also proceed in the opposite (reabsorptive) direction through transporters at each of the three sequential barriers to inflow (Fig. 191.13b).[56] Such flexibility is advantageous in assuring that the rate of net fluid delivery from the stromal surface can be released at the aqueous surface into the posterior chamber. For example, sustained uptake of stromal fluid at a higher rate than its release into the AH would inevitably lead to swelling of the epithelium. Such an event is forestalled at the stromal surface through autocrine regulation by the PE cells. Swelling of PE and NPE cells is known to release ATP from both cell sources.[57] Binding of ATP to PE-cell P2Y2 receptors[58] triggers a signaling pathway that leads to cyclic-3',5'-adenosine monophosphate (cAMP) formation.[59] The cAMP directly stimulates maxi-Cl? ion channels,[60] permitting excess Cl? to be released into the stroma (Fig. 191.14). The anion can be accompanied by K+ released through ion channels and by Na+ extruded through Na+-K+-activated ATPase located at the stromal surface.
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FIGURE 191.14 Schematic outline of major steps in signal transduction pathways following binding of ?1-, ?2- and ?2-receptors. |
At the aqueous surface, several transporters could underlie reuptake of solute and water from the AH. These mechanisms have been identified in the course of studying the response of isolated, cultured NPE cells to anisosmotic shrinkage.[49,61] However, at least some of these mechanisms can be detected in the intact ciliary epithelium, as well. For example, electron-probe X-ray microanalyses of intact rabbit ciliary epithelium suggest that Na+ re-absorption from the AH can become highly significant, at least under certain in vitro experimental conditions.[37] After re-absorption from the AH into the NPE cells, solute could return to the PE cells through the gap junctions.
It is, as yet, unclear whether reverse transfer at the aqueous and stromal surfaces ever results in physiologically significant net re-absorption of AH back into the stroma. However, the expression of these absorptive transporters at both epithelial surfaces might provide the basis for novel strategies to lower net inflow by enhancing unidirectional reabsorption.
Functional topography of ciliary epithelial secretion
In addition to the structural differences displayed by the pars plicata and pars plana, regional differences have been noted in the expression of a number of biologically active peptides and proteins, including the isoforms of Na+-K+-activated ATPase.[56] Recently, electron probe X-ray microanalysis has indicated that the turnover rate of Na,+ K+ and Cl? is far more rapid in the anterior than posterior rabbit ciliary epithelium.[37] This datum raises the possibility that secretion and reabsorption might vary significantly across different regions of the epithelium. The implications of this topographic-dependent net ciliary secretion remain to be defied.
Site of rate-limiting step of secretion
The intracellular Cl? concentration in the NPE cells is several-fold higher[47] than the equilibrium distribution calculated from the membrane potential,[35] so that uptake of Na+ and Cl? at the stromal surface is unlikely to limit secretion. The intracellular potential[37] and ion contents[47] of neighboring PE and NPE cells are very similar, so that transfer of NaCl through the gap junctions cannot be rate-limiting, either. By exclusion, the rate-limiting process in ciliary epithelial secretion is likely at the basolateral surface of the NPE cells and AH.
It is likely that Cl?-channel activity specifically limits the rate of secretion at this aqueous surface of the NPE cells,[56,62] since Cl? is the predominant anion in the AH, and the NPE Cl?-channel activity can be markedly altered by several experimental conditions. It is unknown whether changes in Cl?-channel activity might possibly be one mediator of the striking diurnal rhythm of AH inflow.[63] The diurnal rhythm of IOP, which is higher in the early morning and lower at night, serves as a reminder that time of day should accompany all measurements of IOP.
Regulation of AH Inflow
A number of perturbations are known to act on the putative rate-limiting step, Cl? release through Cl? channels at the aqueous surface.[56] These include swelling of the NPE cells, agonist occupancy of A3adenosine receptors (ARs), reduced protein kinase C (PKC) activity and elevated concentration of cAMP (Fig. 191.15). Swelling-activation of the NPE Cl? channels may well be the dominant regulator of these channels over time scales of minutes. Excessive delivery of fluid from the PE cells should thereby stimulate increased AH release into the posterior chamber. Swelling also activates PE-cell Cl?channels at the stromal surface[64] that would favor re-absorption (Fig. 191.13b). Presumably because of the differential density and gating properties of the Cl? channels at the two surfaces, swelling of the entire ciliary epithelium produces a net stimulation of net Cl? secretion.[65]
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FIGURE 191.15 Drawing of the limbus to illustrate the structures evident by microscopic examination. (a) conjunctival vessels, (b) corneal arcades, (c) episcleral vessels, (d) intrascleral plexus, (e) deep scleral plexus, (f) scleral spur, (g) longitudinal bundle of the ciliary muscle, (h) Canal of Schlemm, (i) trabecular meshwork (j) ciliary body band, (k) iris process. Single arrow represents the terminus of Bowman's membrane and double arrow represents the terminus of Descemet's membrane, also known as Schwalbe's line. |
Modulation of NPE-cell Cl? channels by occupancy of A3 ARs by adenosine may also be of special importance in regulating AH inflow. Patch-clamp and volumetric study of isolated NPE cells have indicated that A3 AR agonists enhance Cl? and water release, and that antagonists to these receptors block these stimulations.[56] Overexpression of A3 ARs has been found in NPE cells from patients with the pseudoexfoliation syndrome.[66]
Despite considerable progress, a comprehensive understanding of inflow regulation has proven elusive. In large part, this limitation reflects the complex interactions of the intracellular signaling cascades and the large number of transporters targeted by these cascades. A further complexity is that the same second messenger can exert opposing effects on secretion. For example, cAMP has been reported to stimulate Cl? channels both at the aqueous surface, favoring inflow, and at the stromal surface, opposing inflow.[56] Coordination of such opposing effects is likely attained by compartmentation of cAMP[67]and of other second messengers, such as Ca[2+][68] as well. Their net effects on inflow ultimately rest on the changes in their concentrations in the immediate vicinities of the transporters targeted.
Relevance to IOP
The concepts presented above are largely based on in vitro studies. Two aspects of the model (Fig. 191.13), at the stromal and aqueous surfaces, have been tested by measuring IOP in the mouse. This species is particularly advantageous in that it displays a trabecular meshwork and Schlemm's canal, as in the human conventional outflow pathway,[69] and transgenic animals are readily generated.
The first step in secretion is the uptake of NaCl at the stromal surface, in part mediated by NHE-1 Na+-H+ antiports (Fig. 191.13). Each of several blockers of these antiports has been found to lower IOP, as predicted.[70] Interestingly, blocking the other known mediator of stromal NaCl uptake (the Na+-K+-2Cl? symport) has no effect in either mouse[70] or monkey.[71] Once, however, the Na+-H+ antiports are blocked, the subsequent inhibition of the symport inhibitor indeed lowers IOP.[70] Possibly, the intracellular Cl? concentration can sometimes be raised so high just by parallel Na+-H+ and Cl?-HCO3? antiport activity that the thermodynamic driving force acting on the symport is substantially reduced. This possibility is consistent with electron-probe X-ray microanalyses of rabbit ciliary epithelium.[37]
The fial step of secretion occurs at the aqueous surface, mediated in part by NPE-cell Cl? channels (Fig. 191.13). As predicted, adenosine raises and A3 AR antagonists reduce mouse IOP.[72,73] Furthermore, A3 AR knockout mice display both lower baseline IOP and reduced IOP responses to A3 AR agonists and antagonists.[73] Although the predictions were based on measurements of ciliary epithelial cell transport, it is possible that the IOP actions of adenosine are actually mediated at another site, such as by increasing ciliary blood flow. Interestingly, very recent measurements in the living rabbit have confirmed that adenosine increases AH flow without altering ciliary blood flow.[74]
Receptor Systems Related to Aqueous Production
An array of receptors have been identified in the ciliary body of various species, including those for natriuretic peptides and others.[75] Moreover, a host of additional neuropeptides (e.g., vasoactive intestinal peptide, neuropeptide Y, opioids, substance P) have been identified within the tissues of the ocular anterior segment. Uncovering possible roles for these agents in aqueous dynamics is at a very early stage. Also of interest is a proposed role for various nitrovasodilators in control of IOP, possibly mediated via nitric oxide (NO).[76,77] Indeed, NO donors have recently been shown to inhibit Na, K-ATPase activity in the nonpigmented ciliary epithelium.[78]
Beta-adrenergic receptors
The most thoroughly examined of the receptor systems relating to aqueous production is that of the beta-adrenergic receptor, which appears to have its effects primarily through the adenyl-cyclase enzyme-receptor complex. Beta-adrenergic receptors have been localized to the ciliary epithelium.[79,80] Stimulation of these receptors initiates a signal transduction cascade beginning with activation of a regulatory intramembranous G-protein. In the case of beta-adrenergic stimulation, the G-protein activates the second messenger adenyl cyclase, which has also been localized to the ciliary body.[80,81] This, in turn, leads to elevation of cAMP levels resulting in phosphorylation of protein kinase-A (Fig. 191.15).
What is currently unclear is the mechanism through which these events lead to the ultimate effect on AH inflow. It has at least been established that cAMP levels influence Na, K-ATPase activity.[82]Regardless of the molecular mechanisms at work, it does seem clear that beta-antagonists such as timolol maleate lead to reductions in both aqueous inflow and IOP.[83]
Alpha-adrenergic receptors
Alpha2-adrenergic receptors are also present in the ciliary body.[84] Like beta-receptors, they are also coupled through G-proteins to adenyl cyclase, but in a negative fashion that serves to block the elevations of cAMP levels induced by beta-agonists (Fig. 191.15). If this is the actual mechanism it remains paradoxical that both alpha-adrenergic agonists and antagonists have been reported to lower IOP.[85] They appear to act through suppression of aqueous inflow without an apparent effect on outflow facility,[86] although effects mediated via reductions in episcleral venous pressure and ciliary body vascular flow have also been reported.[87] Initially approved only for use prophylactically, to prevent acute elevations of IOP that often follow argon laser trabeculoplasty,[88,89] apraclonidine and the more recent brimonidine are now available for management of glaucoma and add useful alternatives to our armamentarium.
AQUEOUS OUTFLOW
Most of the AH drains from the anterior chamber through progressively smaller channels of the trabecular meshwork and into a circumferentially oriented vessel called Schlemm's canal. From Schlemm's canal AH ultimately enters the venous system of the episclera.
In the absence of active pumping, fluid movement in tissues results from gradients in hydrostatic and osmotic pressure. AH and the blood are essentially isotonic. As such, aqueous outflow through this system is the flow of fluid down a hydrostatic pressure difference between the IOP and the episcleral venous pressure. In this regard it is clinically important to appreciate that any event resulting in elevation of episcleral venous pressure (e.g., carotid-cavernous sinus fistula) will result in elevation of IOP to whatever level is required to again exceed episcleral pressure, in order for aqueous outflow to resume.
THE TRABECULAR MESHWORK
The trabecular meshwork is a wedge-shaped band of tissue encircling the anterior chamber angle (Fig. 191.14). The apex of this wedge is attached to the peripheral edge of Descemet's membrane of the cornea that is called Schwalbe's line. Expanding as it moves posteriorly from this point, the trabecular meshwork attaches to the sclera and to the stromas of the ciliary body and the peripheral iris. Indeed, slender stalks of pigmented tissue often rise from the peripheral iris to meet the trabecular meshwork. These are called iris processes.
Projecting into the base of this triangle is a shelf-like lip of sclera termed the scleral spur. An imaginary line drawn from the scleral spur to Schwalbe's line separates the trabecular meshwork into two major parts. The portion of the trabecular meshwork closer to the anterior chamber than this imaginary line is termed the uveal meshwork because it extends from Schwalbe's line to the stromas of the ciliary body and iris. The meshwork just external to the imaginary line also extends from Schwalbe's line, but connects to the scleral spur. This portion of the meshwork is termed the corneoscleral meshwork.
Those involved in the clinical management of the glaucomas must be able to visualize the anatomy of the angle as seen from two perspectives; one view obtained from meridional sections and the other obtained gonioscopically. These two views are compared in Figures 191.16 and 191.17. Figure 191.16 shows a macrophotograph of the angle in a meridional view while Figure 191.17 shows the angle of a monkey eye with Schlemm's canal filled with blood to show its relative position. Figure 191.17 shows the angle from the same perspective as obtained by gonioscopy. One can clearly see the light reflection from Schwalbe's line, and below it, the trabecular meshwork overlying the blood-filled Schlemm's canal. Below Schlemm's canal the lighter coloration given by the scleral spur is evident and fially, below the scleral spur, the very dark coloration given by the pigment in the ciliary body stroma is seen. This lowest 'layer' of the meshwork, seen from the gonioscopic perspective, is referred to as the ciliary body band.
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FIGURE 191.16 Macrophotograph of a section through the anterior chamber showing the posterior trabecular meshwork as a pigmented triangle of tissue in the anterior chamber angle. |
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FIGURE 191.17 Macrophotograph of structures visible in the anterior chamber angle of a rhesus monkey eye. The darkest band, just above the iris surface, corresponds to the ciliary body band. Above it, the lighter band corresponds to the scleral spur. Above the scleral spur, Schlemm's canal, filled with blood in this specimen, is visible through the trabecular meshwork. Above Schlemm's canal is Schwalbe's line, the peripheral terminus of Descemet's membrane of the cornea. Centrally, an iris process rises from the surface of iris and blends into the trabecular meshwork. |
For comparison, these same structures are shown in a goniophotograph of a normal open angle in Figure 191.18. A series of alternating dark and light bands is evident corresponding to the areas shown in Figure 191.19. The upper-most dark band is Schwalbe's line, which is commonly decorated with various amounts of pigment, even in the normal eye. The lighter line below that represents the anterior meshwork. This portion of the meshwork has no Schlemm's canal behind it. As such, the amount of flow in this portion of the meshwork is small and the amount of pigment phagocytosed by the trabecular cells in this region is small as well. Below this lighter line is a darker line corresponding to the posterior meshwork. This is the portion of the meshwork leading most directly to Schlemm's canal. Here the flow is greater and thus the amount of pigment phagocytosed by the trabecular endothelial cells in this area is greater. Below this dark line is another lighter line corresponding to the scleral spur. Finally, below that, the lowest dark line corresponds to the ciliary body band.
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FIGURE 191.18 Goniophotograph of a normal, open angle SL, Schwalbe's line; SS, scleral spur; CBB, ciliary body band. 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. |
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FIGURE 191.19 Sketch showing the structures visible in the anterior chamber angle. The dark bands correspond to the alternating bands of greater and lesser pigmentation seen in the goniophotograph in Figure 191-18. |
THE UVEAL AND CORNEOSCLERAL MESHWORK
The uveal meshwork is composed of branching and anastomosing beams (Fig. 191.20). The avascular cores of these beams are composed of collagen and elastin surrounded by a continuous wrapping of endothelial cells that are capable of removing particulates from the flow pathways by phagocytosis (Fig. 191.21).[90] Phagocytosis would seem to be at some long-term cost to the meshwork. As in the corneal endothelium, mitotic rates are inadequate to fully replenish this population, resulting in an age-related loss of endothelial cells.[91] Whether this progressive loss contributes to the development of glaucoma remains uncertain.[91,92]
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FIGURE 191.20 Scanning electron micrograph of the face of the uveal meshwork showing intersecting trabecular beams. |
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FIGURE 191.21 Light micrograph of trabecular meshwork demonstrates phagocytosis of melanin by trabecular endothelial cells in posterior meshwork. Note abrupt reduction in the amount of pigmentation in the anterior meshwork beyond the anterior edge of Schlemm's canal (line). This difference in pigmentation is evident clinically. See Figures 17, 18 and 19. |
Clearly in the uveal meshwork there are ample open spaces for aqueous flow. As one progresses deeper into the meshwork, however, the spaces become progressively smaller. The basic structure of the corneoscleral meshwork is similar to that of the uveal meshwork including a central core of collagen and elastic fibers enveloped in a thin endothelium. This is a very open and porous network negligible flow resistance is expected in the region. These studies notwithstanding, for years, it was assumed that the apparently 'open-spaces' of the trabecular meshwork were filled completely with a resistance-generating glycosaminoglycan gel, composed principally of hyaluronic acid.[93] The natural extension of this argument was that an age-related increase in this material occurred, increasing the resistance further and resulting in the elevated pressure that characterizes POAG. In the past few years, however, it has been possible to histochemically localize hyaluronan and it is now clear that most of the 'open spaces' in the uveal and corneoscleral regions of the trabecular meshwork are not filled with a gel (Fig. 191.22a). Some hyaluronan is found in the juxtacanalicular (JCT) region but it appears that the amount decreases with age (Fig. 191.22b) and decreases even further in POAG. (Fig. 191.22c), raising doubts regarding the long-held theory explaining the increased resistance in POAG.[94,95]
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FIGURE 191.22 (a) Light micrograph of nonglaucomatous 47-year-old human trabecular meshwork. Red stain denotes location of hyaluronate, primarily in the region of the meshwork closest to Schlemm's canal. (b) Light micrograph of a nonglaucomatous 79-year-old human trabecular meshwork shows age-related decrease in hyaluronate staining. (c) Light micrograph of a glaucomatous 80-year-old meshwork shows even less staining for hyaluronate. |
The JCT Region
The portion of the trabecular meshwork between the corneoscleral beams and the inner wall of Schlemm's canal has a fundamentally different structure from the uveal and corneoslceral meshwork. The JCT region is an open connective tissue matrix in which fibroblast-like cells, rather than endothelial cells, are found (Fig. 191.23). Another important distinction is the presence of tendons from the longitudinal bundle of the ciliary muscle extend into the meshwork, culminating in a system of elastic fibers that connect to the inner wall of Schlemm's canal and are termed the cribriform plexus (Fig. 191.24a,b).[96]
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FIGURE 191.23 Transmission electron micrograph demonstrating the appearance of cells in the juxtacanalicular (JCT) region of the trabecular meshwork. Note the absence of a basal lamina and the loose matrix of collagen (C). These cells make paddle-like connections (arrowheads) with endothelial cells lining Schlemm's canal (SC). |
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FIGURE 191.24 (a) Tendons (T) extending from the longitudinal bundle of the ciliary muscle (CM) attach to the scleral spur (SP) but also extend elastic (E) connecting fibrils (CF) to attach to the endothelial cells (E) lining Schlemm's canal (Sc). (b) High magnification electron micrograph demonstrating detail of an elastic connecting fibril (c) of the cribriform plexus making connection with the inner wall of Schlemm's canal. |
The extracellular matrix of the JCT region exhibits collagen types I, II, IV, V and VI (but not type II).[97] Also present are elastin, laminin, fibronectin, and glycosaminoglycans, particularly chondroitin sulfate, dermatan sulfate and hyaluronic acid.[98,99] A regulable system of matrix metalloproteinases and their inhibitors are also present in the trabecular meshwork. They remain interesting prospects for contributing to outflow resistance.[100] With age, and in POAG, there is also an accumulation of a material called plaque,[101] but current consensus suggests that this material cannot explain the increased resistance in POAG.
Another important molecule discovered in the trabecular meshwork is ***TIGR/myocilin. It was originally identified as a glucocorticoid-inducible protein by Polansky et al in trabecular meshwork cell cultures and was called TIGR.[102] When sequencing was completed, TIGR was found to be myocilin, a glycoprotein with a molecular weight of ?55-57 kDa. In parallel studies, a linkage-analysis study performed on a single large family with juvenile-onset POAG led to identification of a region of chromosome 1q that contained a gene for juvenile-onset POAG.[103] This locus was called GLC1A and it was found that this gene encodes for myocilin. Since that time, it has been found that mutations in GLC1A may account for as many as 4.6% of cases of adult-onset POAG. The exact function of myocilin in the normal and glaucomatous eye remains uncertain but several comprehensive reviews have been published providing detail beyond the scope of this chapter.[104-106]
To estimate hydraulic conductivity of the JCT region several groups have used an approach of combining morphometric data with computational flow modeling.[107,108] Based upon studies of conventional electron micrographs, Ethier et al concluded that the JCT region, as visualized using conventional electron microscopy (EM) techniques, could not generate an appreciable fraction of aqueous outflow resistance unless this region was filled with an extracellular matrix gel that is not visualized using conventional EM techniques.[107]
In the hope of better preserving extracellulat matrix, Gong et al[108] used the quick-freeze/deep-etch (QFDE) method to examine the apparent open spaces in the JCT region in greater detail. Using this technique, a much more elaborate and extensive extracellular matrix was seen in the JCT than seen using conventional techniques (Fig. 191.25). Despite the enhanced matrix visibility, however, openings nearly a micron in size were still seen in this region, fidings again inconsistent with a conclusion that a significant fraction of outflow resistance could be generated by this tissue. It may be that even using QFDE, GAGS are likely collapsed and thus, an ideal morphological tool to produce accurate assessments of JCT matrix complexity, remain elusive. This leaves uncertainty on whether the JCT region generates significant outflow resistance.
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FIGURE 191.25 (a) Transmission electron micrograph of JCT region with elastic fibers (E) and inner wall of Schlemm's canal showing giant Vacuole (V) and pore leading into Schlemm's canal (arrowhead). (b) Quick-freeze, deep-etch micrograph of similar region shows greater detail of extracellular material including elastic fibers (EL) in the JCT region. A giant vacuole (V) and a pore (arrowhead) leading into Schlemm's canal (SC) are evident. |
Nonetheless, studies of Mapea and Bill[109] using micropressure measurements in the outflow pathway have shown that the principal pressure drop occurs within 14 mm of the inner wall of Schlemm's canal, pointing to the JCT region and/or the inner wall of Schlemm's canal as the most probable location of a majority of outflow resistance in the normal eye.
Schlemm's Canal
From the JCT region, AH must traverse the continuous endothelial lining of Schlemm's canal to enter its lumen (Fig. 191.25). How AH traverses the endothelium of Schlemm's canal remains one of the enigmatic problems of ocular anatomy/physiology. The wall of the Schlemm's canal closest to the anterior chamber, termed the inner wall of Schlemm's canal, manifests unusual structures termed 'giant vacuoles' (Figs 191.25 and 191.26). These vacuoles are not intracellular. They appear to be pressure-dependent and are not found unless the inner wall is fixed under conditions of flow.[110] Though opinion is not unanimous, the most popular theory is that aqueous traverses the inner wall of Schlemm's canal though tiny openings induced to form within the walls of these vacuoles or in other portions of the inner wall and termed 'pores' (Figs 191.25 and 191.26).[111] How pores form and whether they contribute to outflow resistance remains uncertain.
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FIGURE 191.26 Scanning electron micrograph of the luminal surface of the inner wall of Schlemm's canal demonstrating numerous bulging giant vacuoles. Several pores are evident (arrowheads), shown at higher magnification in the inset. |
The Flow Pathways beyond Schlemm's Canal
Approximately 30 external collector channels lead from the outer wall of Schlemm's canal toward the surface of the sclera. External collector channels have been shown to exhibit smooth muscle actin implying that these vessels could constrict and in doing so regulate outflow.[112] But, the contribution of this portion of the outflow pathway to overall resistance is presumed to be small. Grant removed the entire trabecular meshwork and opened the anterior chamber to Schlemm's canal. Under these circumstances 75% of the resistance to outflow was removed.[113]
When presented in series, resistances are additive. Thus, wherever the site of normal outflow resistance truly resides, it is not necessarily the case that glaucoma results from the addition of more resistance at this same location. Indeed, recent morphological studies of normal and glaucomatous has revealed that the openings of collector channels in glaucomatous eyes have, within them, herniations of inner wall and JCT tissue.[114] Such hernations can be produced in normal eyes by elevating pressure, but subsequent reduction of pressure prompts their reversal. This line of evidence is just emerging but it merits further study.
From the external collector channels aqueous passes into a tortuous system of passages termed the deep scleral plexus that leads in turn to the deep scleral veins and fially, to the episcleral veins (Fig. 191.27). Through this tortuous route the aqueous and blood are mixed. But a smaller number of unique vessels termed aqueous veins (of Ascher) bypass this tortuous pathway and connect directly to the episcleral veins.[115] Although their significance remains unknown, these unique vessels are readily identified clinically near the limbus because the AH and blood within them have yet to mix. In these vessels a laminar flow of blood and aqueous is readily visible.
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FIGURE 191.27 Sketch depicting the portion of the aqueous outflow pathways from Schlemm's canal to the episcleral vessels. External collector channels emerging from the outer wall of Schlemm's canal (upper right) lead to deep and intrascleral plexi and then to the episcleral vessels. Aqueous veins (upper left) arising from either external collector channels or the outer wall of Schlemm's canal, by-pass this more convoluted pathway. They are often visible near the limbus as vessels exhibiting a laminar flow of blood and clear aqueous humor. |
PURPORTED ROLES OF THE CILIARY MUSCLE IN OUTFLOW
ROLE IN TRABECULAR OURTFLOW
Attached to the posterior surface of the scleral spur are the smooth muscle fibers of the longitudinal bundle of the ciliary muscle. As mentioned earlier, when these fibers contract, they pull the lip of the shelf posteriorly and in doing so, separate the layers of the corneoscleral meshwork attached to the anterior surface of the spur. Opening the meshwork in this fashion appears to facilitate aqueous drainage. But in addition, tendons from these fibers, termed the cribriform plexus, extend into the trabecular meshwork and make anatomical connections with the inner wall of Schlemm's canal.[96] These attachments may serve to resist the collapse of Schlemm's canal that would generate increased outflow resistance.[116] These two actions (opening the meshwork and resisting collapse of Schlemm's canal) are most likely the basis of action by which muscarinic agents (e.g., pilocarpine) act to decrease outflow resistance.[117,118]
ROLE IN UVEOSCLERAL OUTFLOW
A fraction of the AH flows out of a second pathway know as the 'unconventional' outflow pathway. Unlike the pathway for aqueous outflow through the trabecular meshwork, discussed below, flow through the uveoscleral pathway is thought to be pressure independent, except at very low pressures.[119] This pathway is also referred to as the uveoscleral or uveovortex outflow. The anatomical course of this pathway begins at the trabecular meshwork, specifically the portion that is identified gonioscopically as the ciliary body band. The fluid appears to then flow within the connective tissue fascicles that interweave with the smooth muscle fibers of the ciliary muscle. Ultimately, the fluid reaches the inner surface of the sclera. Although not an obvious feature, the ciliary body is separated from the sclera, over most of its length, by a potential space, the supraciliary space, which is continuous posteriorly with the suprachoroid. Aqueous moves posteriorly within the potential space of the suprachoroid as shown in Figure 191.28, leaving the eye by either diffusing through the sclera (uveoscleral) or by diffusing through the scleral emissaria for the vortex veins (uveovortex) flow.[119]
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FIGURE 191.28 Light micrograph of the ocular anterior segment demonstrates the distribution of fluoresceinated dextran after intracameral perfusion. The tracer has moved from the anterior chamber (AC) posteriorly through the ciliary body band (a) into the connective tissue septae of the ciliary muscle (b) and fially to the supraciliary and suprachoroidal spaces (arrows). |
Current estimates suggest that under normal conditions, this pathway carries less than 10% of the total flow in the adult human eye and decreases with age.[120] But this pathway has recently taken on much greater significance with demonstration that certain prostanoids can dramatically enhance total aqueous outflow by augmenting uveoscleral outflow, most likely by altering matrix metalloproteinase activity, dissolving the connective tissue matrix between fascicles of the ciliary muscle, allowing for increased fluid flow.[121] Since prostanoids are endogenously released in intraocular inflammatory diseases (e.g., anterior uveitis), it should be of no surprise that this class of medications, applied exogenously, are of little value in reducing inflammation-induced elevations of IOP.
THE GOLDMANN EQUATION
From the above discussion it becomes evident that many known factors, and others yet to be understood, contribute to the IOP at any given time. A useful way to simplify these elements, and in doing so provide a summary of these processes, is through the Goldmann equation. The major elements of Goldmann's equation include the measured IOP, the pressure in the episcleral venous system, the flow rate of AH and a factor that represents the ability of aqueous to leave the eye; known as outflow facility and taken to be the inverse of outflow resistance.
?P = IOP - Episcleral venous pressure, and Facility of trabecular outflow = Aqueous flow rate/?P
where the intraocular and episcleral venous pressures are measured in mmHg and aqueous flow is in microliters/minute at steady state. Trabecular outflow is taken to be an entirely passive bulk flow down a pressure gradient.
Since under steady-state conditions, episcleral pressure does not vary, under these circumstances the equations can be simplified:
Flow in = F out = C ?P + Fu
Substituting clinically relevant gives the following:
F in = F out = 2.5 microliters/min
C = 0.3 microliters/min/mmHg
IOP = 16 mmHg
Episcleral venous pressure = 9 mmHg
?P =[16-9] = 7
Fu = 0.4 microliters/min
Flow in = F out = C ?P + Fu
2.5 = 2.5 = 0.3[5] + 0.4
This discussion is meant to serve as a relevant overview and synthesis for the clinician in training and an updated review for the clinician in practice. It should help to form the basis of understanding for the factors that contribute to the only treatable risk for glaucoma; elevation in the IOP.
ACKNOWLEDGEMENTS
The original work of TFF reported in this chapter was supported by NEI EY-04567 and NEI EY-13825.
The original work of MC reported in this chapter was supported in part by NEI EY-08343 and EY-13624.
The original work of HG reported in this chapter was supported in part by NEI EY-09699 and National Glaucoma Research, a program of the American Health Assistance Foundation.
The authors gratefully acknowledge the input of Mark Johnson, Ph.D. Department of Biomedical Engineering, Northwestern University.
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