Ординатура / Офтальмология / Английские материалы / Shields Textbook of Glaucoma, 6th edition_Allingham, Damji, Freedman_2010

acid, which is secreted against a large concentration gradient by the sodium-dependent vitamin C transporter 2, or SVCT2 (32), and certain amino acids, which are secreted by at least three carriers (33). Osmotic Flow

Third, the osmotic gradient across the ciliary epithelium, which results from the active transport of the above substances, favors the movement of other plasma constituents by ultrafiltration and diffusion. The mechanisms by which water moves from the ciliary body stroma, across the ciliary epithelium, and into

the posterior chamber are complex and only partially understood. There is evidence that Na+ is the driving cationic force (29). Supporting this concept is the restricted expression of the water channels, aquaporin-1 and aquaporin-4, in the nonpigmented ciliary epithelium (26). A specific water channel antagonist has not yet been identified. The functional significance of these channels has not been extensively studied and the rare individuals with mutations of the gene encoding these water channels have a normal IOP (55).

Rate of Aqueous Humor Production

The turnover of aqueous humor within the anterior chamber is estimated to be approximately 1.0% to 1.5% of the anterior chamber volume per minute (34). The rate at which aqueous humor is formed (inflow) is measured in microliters per minute (as discussed in Chapter 2). By using the technique of scanning ocular fluorophotometry in more than 519 healthy persons, the mean (±standard deviation [SD]) rate of aqueous humor flow between 8 am and noon was 3.0 ± 0.8 µL/min (35). The normal range (i.e., 95% of the sample) was 1.5 to 4.5 µ/min and showed a Gaussian distribution of flow rates. In 490 persons, the afternoon flow rate decreased to 2.7 ± 0.6 µ/min, while the mean rate in 180 persons between midnight and 6 am was 1.3 ± 0.4 µL/min, wit h a range of 0.4 to 2.1 µL/min. A later study showed that individuals show concordance in aqueous humor flow, whereby those individuals who show a high aqueous flow in the morning also show a lower but relative higher flow at night (36). These changes in aqueous humor flow throughout the day reflect a biological pattern, also known as circadian rhythm, but the changes in this flow cannot account alone for the circadian patter in IOP (see modified Goldmann equation in Chapter 3) (37).

Circadian Rhythm of Aqueous Humor Flow

As noted above, there is a circadian rhythm of aqueous humor flow in humans, with rates during sleep being approximately one half of those in the morning. The mechanisms that control this biological rhythm are only partly understood and cannot be overcome entirely by light, ambulation, or activity level. The hormonal basis for the diurnal fluctuation in the rate of aqueous humor flow, or circadian rhythm, in humans is not completely understood (35). The strongest evidence suggests that physiologic changes in the level of circulating epinephrine available to the ciliary epithelia are the major driving force. Topical epinephrine has been shown to stimulate flow by 19% during the day and by 47% during the evening. Norepinephrine has also been shown to stimulate flow, but not as effectively as epinephrine. In patients who have had surgical adrenalectomy, a normal circadian rhythm of aqueous humor flow persists. In patients with Horner syndrome, where there is reduced or absent sympathetic innervation on one side, the circadian flow pattern is maintained. Systemically administered melatonin, hormones related to pregnancy, and antidiuretic hormone also do not appear to influence the normal circadian rhythm of flow. The effect of corticosteroids is more complex, in that exogenous corticosteroid appears to augment the effect of epinephrine-mediated stimulation of flow.

Other Factors Influencing Aqueous Humor Flow

Aqueous humor flow is also reduced in patients with diabetes mellitus, regardless of type (38). In myotonic dystrophy, the relative hypotony has been attributed to both reduction inflow rate and enhanced uveoscleral outflow route through the atrophic ciliary muscle (39). This causes a decrease in inflow (96), possibly related to a disruption in ciliary epithelium (97). Aqueous humor production can be reduced with inflammation (iridocyclitis) and by cyclodialysis (40).

In comparing different types of glaucoma, there are similar aqueous humor flow rates in patients with normal-tension glaucoma and healthy persons (41). Patients with ocular hypertension showed flow patterns similar to those of healthy persons during the morning hours, but the IOP and resistance to outflow values were higher in the patients with ocular hypertension (42). In patients with pigment

dispersion syndrome, aqueous humor flow rate was slightly higher than in control participants because of the larger volume of the anterior chamber in the patients than in the controls (43). In patients with chronic open-angle glaucoma (COAG), aqueous humor flow during sleep was higher than in controls (44).

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With aging, there is a decline in aqueous humor production—2.4% to 3.2% per decade after 10 years of age (45). There appears to be a trend of lower flow in women than in men, but this may be related to small differences in the size of the ocular structures (35). An elevation of IOP was once thought to be associated with a decline in aqueous humor production, which was referred to as “pseudofacility,” but it is now understood that aqueous humor flow is pressure insensitive (35). The osmotic stress of drinking 1000 mL of water is associated with a significant increase in aqueous humor flow after 90 minutes (46). Caffeine does not have any clinically significant effect on aqueous humor flow in the normal human eye (47).

The pharmacologic agents that reduce aqueous humor flow in the treatment of glaucoma are discussed in Section III. These agents include the (ß-adrener gic receptor antagonists or (ß-blockers (see Chapte r 29), the nonspecific adrenergic and selective a2-adrenergic receptor agonists (Chapter 30), and the

carbonic anhydrase inhibitors (Chapter 31). Function and Composition of Aqueous Humor Function

The circulating aqueous humor has at least the following functions: (a) maintaining proper IOP, which is important in early ocular development as well as in maintaining globe integrity throughout life; (b) providing substrates and removing metabolites from the cornea, lens, and trabecular meshwork; (c) delivering high concentrations of ascorbate; (d) participating in local paracrine signaling and immune responses; and (e) providing a colorless and transparent medium as a part of the eye's optical system. Composition

The following statements, summarized in Table 1.3, describe the general characteristics of aqueous humor, expressed relative to plasma. Aqueous humor of both the anterior and the posterior chambers is slightly hypertonic compared with plasma. It is acidic, with a pH of 7.2 in the anterior chamber (48). The two most striking characteristics of aqueous humor are (a) a marked excess of ascorbate (15 times greater than that of arterial plasma) and (b) a marked deficit of protein (0.02% in aqueous humor compared with 7% in plasma) (32, 49, 50 and 51).

To illustrate the constant metabolic interchanges that occur with various ocular tissues, the cornea takes glucose and oxygen from the aqueous humor and releases lactic acid and a small amount of CO2 into the

aqueous humor (52). The lens takes up glucose, K+, and amino acids from the aqueous humor and generates lactate and pyruvate; however, close similarities in aqueous humor composition between the phakic and aphakic eye of the same individual suggest that lens metabolism has practically no influence on the composition of aqueous humor (53). The exchange between the vitreous and retina with aqueous humor has been shown for amino acids and glucose passing into the vitreous from the aqueous humor (33).

The relative concentrations of free amino acids in human aqueous humor vary, with ratios of aqueous humor to plasma concentrations ranging from 0.08 to 3.14, supporting the concept of active transport of amino acids (54). The concentrations of most other ions and non-electrolytes are very close to those in the plasma, and conflicting statements in the literature primarily represent differences with regard to species and measurement techniques. In general, human aqueous humor has a slight excess of chloride and a deficiency of bicarbonate and CO2 (48, 55). Lactic acid is reported to be in relative excess in

human aqueous humor, although this determination varies widely with the technique of measurement. Sodium in rabbits and glucose in human eyes show a relative deficiency in the aqueous humor (54).

Table 1.3 General Character of Human Aqueous Humor (Expressed Relative to Plasma)

Slightly hypertonic

Acidic

Marked excess of ascorbate

Marked deficit of protein

Slight excess of

Chloride

Lactic acida

Slight deficit of

Sodium (rabbit study)

Bicarbonatea

Carbon dioxide

Glucose

Other reported constituents/features

Amino acids (variable concentrations)

Sodium hyaluronate

Norepinephrine

Coagulation properties

Tissue plasminogen activator

Latent collagenase activity

a Varies with measurement technique.

Other molecules that have been identified in human aqueous humor may be considered potential paracrine signaling molecules (56), meaning that these molecules are circulated and distributed to local tissues. Sodium hyaluronate, a glycosaminoglycan, was reported to have a mean value of 1.14 ± 0.46 mg/g in human aqueous humor obtained before cataract extraction, with no substantial difference in patients with diabetes or glaucoma (57). Signaling molecules, such as the catecholamine, norepinephrine, and nitric oxide, have been identified in human aqueous humor (58, 59). Various components of the coagulation and anticoagulation pathways may be present in human aqueous humor (60), with an overall trend toward fibrinolytic activity. Various components involved in the maintenance of extracellular matrix have been detected in aqueous humor, which may influence the trabecular meshwork activity and subsequently the IOP (61). Several growth factors, which are polypeptides involved in the homeostatic balance of cells in a tissue, have been detected in human aqueous humor, P.14

and receptors for many of these factors have been identified on appropriate target tissues, such as trabecular meshwork and cornea (56). Of interest, myocilin has been detected in normal aqueous humor, but it is absent in the aqueous humor of patients with myocilin-associated glaucoma (62).

BIOLOGY OF AQUEOUS HUMOR OUTFLOW

As noted earlier, most of the aqueous humor leaves the eye at the anterior chamber angle through the system consisting of trabecular meshwork, the Schlemm canal, intrascleral channels, and episcleral and conjunctival veins. This pathway is referred to as the conventional or trabecular outflow. In the unconventional or uveoscleral outflow, aqueous humor exits by passing through the root of the iris, between the ciliary muscle bundles, then through the suprachoroidal-scleral tissues.

The relative contribution of these outflow pathways depends on the species studied. Furthermore, there is an age-dependent change in aqueous humor outflow in both the trabecular and the uveoscleral pathways. In general, the trabecular outflow in human eyes accounts for approximately 70% to 95% of the aqueous humor egress from the eye, with the lower values corresponding to younger eyes and the higher values corresponding to older eyes (63). The other 5% to 30% of the aqueous humor leaves primarily by the uveoscleral outflow pathway, with a decline in the contribution of this pathway with age (64). Whereas both total outflow facility and trabecular outflow facility also decline with age, the relative contributions of trabecular and uveoscleral outflow show an age-related shift, with a relative increase in the contribution in the trabecular pathway. Because uveoscleral outflow is relatively

independent of IOP in the physiologic range, decreased uveoscleral outflow and increased trabecular outflow resistance with age simply mean that IOP must increase sufficiently to drive a higher proportion of total flow (which remains rather constant with age) across the increased trabecular resistance. Cellular Organization of the Trabecular Outflow Pathway

Scleral Spur

The posterior wall of the scleral sulcus is formed by a group of fibers, the scleral roll, which run parallel to the limbus and project inward to form the scleral spur (Fig. 1.1), which is composed of 75% to 80% collagen and 5% elastic tissue (65). Myofibroblast-like scleral spur cells, in close association with varicose axons characteristic of mechanoreceptor nerve endings, suggest there is a mechanism for measuring stress or strain in the scleral spur, as might occur with ciliary muscle contraction or changes in IOP (66).

Schwalbe Line

Just anterior to the apical portion of the trabecular meshwork is a smooth area, which varies in width from 50 to 150 µm and has been called zone S (67). The anterior border of this zone consists of the transition from trabecular to corneal endothelium and the thinning and termination of the Descemet membrane. The posterior border is demarcated by a discontinuous elevation, called the Schwalbe line, which appears to be formed by the oblique insertion of uveal trabeculae into limbal stroma. Clusters of secretory cells, called Schwalbe line cells, have been observed just beneath this ridge in monkey eyes and are believed to produce a phospholipid material that facilitates aqueous humor flow through the canalicular system (68).

Trabecular Meshwork

As previously discussed, the scleral sulcus is converted into a circular channel, called the Schlemm canal, by the trabecular meshwork. This tissue consists of a connective tissue core surrounded by endothelium and may be divided into three portions: (a) uveal meshwork; (b) corneoscleral meshwork; and (c) juxtacanalicular tissue, which is sometimes referred to as the cribriform layer (Fig. 1.8) (63). Uveal Meshwork

This innermost portion is adjacent to the aqueous humor in the anterior chamber and is arranged in bands or ropelike trabeculae that extend from the iris root and ciliary body to the peripheral cornea. The arrangement of the trabecular bands creates irregular openings that vary in size from 25 to 75 µm acro ss. Corneoscleral Meshwork

This portion extends from the scleral spur to the anterior wall of the scleral sulcus and consists of sheets of trabeculae that are perforated by elliptical openings. These holes become progressively smaller as the trabecular sheets approach the Schlemm canal, with a diameter range of 5 to 50 µm. The anterior tendons of the longitudinal ciliary muscle fibers insert on the scleral spur and posterior portion of the corneoscleral meshwork. This anatomic arrangement suggests an important mechanical role for the cholinergic innervation of ciliary muscle on trabecular meshwork function.

Both the uveal and corneoscleral trabecular bands or sheets are composed of four concentric layers. First, an inner connective tissue core is composed of typical collagen fibers with the usual 640 Å periodicity. Indirect immunofluorescent studies of human trabecular meshwork indicate that the central core contains collagen types I and III and elastin (69). Second, “elastic” fibers are composed of otherwise typical collagen, arranged in a spiraling pattern with an apparent periodicity of 1000 Å. Th ese spiral fibrils may wind loosely or tightly and may provide flexibility to the trabeculae. Third, “glas s membrane” is a name given to the layer between the spiraling collagen and the basement membrane of the endothelium. It is a broad zone composed of delicate filaments embedded in a ground substance (70). Fourth, an outer endothelial layer provides a continuous covering over the trabeculae.

The trabecular endothelial cells are larger, are more irregular, and have less prominent borders than corneal endothelial cells. They are joined by gap junctions and desmosomes, which provide stability, but allow aqueous humor to freely traverse

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the patent endothelial clefts (71). Two types of microfilaments have been found in the cytoplasm of

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human trabecular endothelium. Sixty Å filaments are located primarily in the cel l periphery, around the nucleus, and in cytoplasmic processes. These appear to be actin filaments (72), which are involved in cell contraction and motility, phagocytosis, pinocytosis, and cell adhesion. Intermediate filaments of 100 Å are more numerous in the cells and are composed o f vimentin and desmin, according to immunocytochemical studies of cultured human trabecular cells (73). These molecular markers in the trabecular endothelial cells suggest a myocyte or muscle cell-like phenotype, which further implies important contractile and motility functions.

Figure 1.8 Three layers of trabecular meshwork (shown in cutaway views): uveal, corneoscleral, and juxtacanalicular.

Juxtacanalicular Tissue

This portion of the trabecular meshwork differs histologically from the other parts of the meshwork and has been given various names, including juxtacanalicular connective tissue, pore tissue, cribriform layer, and endothelial meshwork, depending on how one defines the anatomic limits of the tissue. In the broadest sense, this structure has three layers, discussed here beginning with the innermost portion. The inner trabecular endothelial layer is continuous with the endothelium of the corneoscleral meshwork and might be considered as a part of this layer. The central connective tissue layer has variable thickness and is unfenestrated with several layers of parallel, spindle-shaped cells loosely arranged in a connective tissue ground substance (168, 177). This tissue contains collagen type III but no collagen type I or elastin (69). Connective tissue cells in human and rabbit trabecular meshwork contain coated pits and coated vesicles in the plasma membrane, which are involved in receptor-mediated endocytosis (74).

The outermost portion of the trabecular meshwork—th at is, the last tissue that aqueous humor must traverse before entering the canal—is the inner wal l endothelium of the Schlemm canal. This endothelial layer has significant morphologic characteristics, which distinguish it from the rest of the endothelium in both the trabecular meshwork and in the Schlemm canal. The surface is bumpy due to protruding nuclei,

cyst-like vacuoles, and fingerlike projections bulging into the canal (75, 76). The fingerlike projections have been described as endothelial tubules with patent lumens, although there is lack of agreement as to whether they communicate between the anterior chamber and Schlemm canal (77). Actin filaments, as P.16

previously described in the uveal and corneoscleral trabecular endothelium, are also present in the inner wall endothelium of Schlemm canal (72).

(Toluidine blue stain, × 1030.) (From Tripathi RC. Ultrastructure of the trabecular wall of the Schlemm canal in relation to aqueous humor outflow. Exp Eye Res. 1968;7:335, with permission.) B: Electron microscopic view of trabecular wall of SC of normotensive human eye, showing vacuolated endothelial cells (V) containing flocculent material (FL). OZ, occluding zonules; BM, basement membrane; OS, open spaces in endothelial meshwork (× 15,000). (Fr om Tripathi RC. Ultrastructure of the trabecular wall of Schlemm's canal: a study of normotensive and chronic simple glaucomatous eyes. Trans Ophthalmol Soc U K. 1970;89:449-465, with permission.)

The intercellular spaces are 150 to 200 Å wide and the adjacent cells are connected by various intercellular junctions. It is not clear as to how tightly these junctions maintain the intercellular connections, although they will open to permit the passage of red blood cells (78). Zonula occludens have been demonstrated in primate studies, which are traversed by meandering channels of extracellular space or slit pores, although it is estimated that this accounts for only a small fraction of the aqueous humor that leaves the eye by the conventional route (71).

Openings in the inner wall endothelium of the Schlemm canal have been described, and in general, the openings consist of minute pores and giant vacuoles that vary in size ranging from 0.5 to 2.0 µm (79) (Fig. 1.9). Evidence in support of their role in the transcellular outflow is based on injection of tracer elements into the anterior chamber with demonstration of the tracers in the vacuoles and pores (80). The observation that the concentration of tracer material in the giant vacuoles is not always the same as in the juxtacanalicular connective tissue suggests a dynamic system in which the vacuoles intermittently open and close to transport aqueous humor from the juxtacanalicular tissue to the Schlemm canal.

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This transcellular transport has active and passive mechanisms. Indirect evidence for active transport includes the demonstration of enzymes and microscopic structures compatible with an active transport system in or near the endo — thelial layer (81, 82) . However, the bulk of evidence supports the theory of passive (pressure-dependent) transport, because the number and size of the vacuoles increase with progressive elevation of the IOP (83). It has been proposed that potential transcellular spaces exist in the inner wall endothelium of the Schlemm canal, which open as a system of vacuoles and pores, primarily in response to pressure, to transport aqueous humor from the juxtacanalicular connective tissue to the Schlemm canal. If intracellular transport through the inner wall endothelium of the Schlemm canal exists, it has been calculated, on the basis of the estimated size and total number of pores and giant vacuoles, that resistance to outflow through this system accounts for only a small fraction of the total resistance to aqueous humor outflow (84). It is also possible that only a portion of the juxtacanalicular tissue actually filters. It has been suggested that aqueous humor flows preferentially through those regions of the juxtacanalicular connective tissue nearest the inner wall pores creating a “funneling effect,” which increases apparent flow resistance i n the connective tissue by approximately 30-fold (85). An alternative theory to that of transcellular transport is paracellular routes between the inner wall endothelial cells. Perfusion of monkey eyes with cationized ferritin revealed separation of adjacent cell membranes between tight junctions forming openings and tunnellike channels, which stained with the tracer indicating intercellular passage (86). These paracellular pathways were larger at higher perfusion pressure, and apparent giant vacuoles were often dilatations of the paracellular spaces.

Figure 1.10 Schematic of aqueous humor outflow distal or beyond the “ conventional” or trabecular pathway and into the canal of Schlemm. The canal divides into two or more portions intermittently. The drawing is divided into four portions by the dotted lines. The internal collector channels of Sondermann are labeled in the upper right sector as they extend into the trabecular meshwork. The external collector channels are seen in the upper and lower right sectors, arising from the canal and uniting with the deep intrascleral plexus of extending directly to the episcleral veins. The deep and intrascleral venous plexuses are external to the canal. In the upper left sector, an aqueous vein arises from the deep scleral plexus and another arises from the Schlemm canal and runs directly to the episcleral venous plexus. External collector veins are seen to arise from the canal and join the deep scleral plexus. In the lower left sector, the arteries of the deep sclera are seen to be in close relation to the canal of Schlemm. (Modified from Hogan MA, Alvarado J, Weddell J. Histology of the Human Eye. Philadelphia: WB Saunders; 1971, with permission.)

Of historical interest, the Sondermann canals, although originally described as endothelial-lined channels communicating between the Schlemm canal and intertrabecular spaces, have subsequently been interpreted as tortuous communications wandering irregularly and obliquely through the meshwork (87).

Schlemm Canal

This 360-degree, endothelial-lined channel averages 190 to 370 mm in diameter with occasionally branching into a plexus-like system (Fig. 1.10) (88). The endothelium of the outer wall is a single cell

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layer that is continuous with the inner wall endothelium but has a smoother surface with larger, less numerous cells and no pores (89). The outer wall also differs in having numerous, large outlet channels, which are described below. Smoothmuscle myosin-containing cells have been localized in the human aqueous humor outflow pathway adjacent to the collector channels, slightly distal to the outer wall of the Schlemm canal (90). Torus or liplike thickenings have been observed around the openings of the outlet channels, and septa have been noted to extend from these openings to the inner wall of the Schlemm canal, which presumably help keep the canal open (88). The endothelium is separated from the collagenous bundles of the limbus by a basement membrane and fibroblasts (89).

Episcleral and Conjunctival Veins

The Schlemm canal is connected to episcleral and conjunctival veins by a complex system of intrascleral channels (Fig. 1.10). The aqueous veins of Ascher (91), which are now more commonly referred to as collector channels (92), have been

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defined as originating at the outer wall of the Schlemm canal and terminating in episcleral and conjunctival veins in a lamination of aqueous humor and blood, referred to as the laminated vein of Goldmann. Two systems of intrascleral channels have been identified: (a) a direct system of large caliber vessels, which run a short intrascleral course and drain directly into the episcleral venous system, and (b) an indirect system of more numerous, finer channels, which form an intrascleral plexus before eventually draining into the episcleral venous system (88). The intrascleral aqueous channels do not connect with vessels of the uveal system, except for occasional fine communications with the ciliary muscle (93).

The aqueous vessels join the episcleral and conjunctival venous systems by several routes (91). Most aqueous vessels are directed posteriorly and drain into episcleral veins, whereas a few cross the subconjunctival tissue and drain into conjunctival veins. Some aqueous vessels proceed anteriorly to the limbus, with most running a short course parallel to the limbus before turning posteriorly to conjunctival veins. Casting studies in rabbit and dog eyes revealed a wide venous plexus in the limbic region of the episcleral vasculature anastomosing with a small arteriolar segment, the latter of which contains smoothmuscle cells that may have a role in regulating aqueous humor drainage by the episcleral venous plexus and subsequently influencing the IOP (94). In the rhesus monkey, the conjunctival vessels receiving aqueous humor drainage have a diameter consistent with that of capillaries, whereas most of the vessels in the episcleral plexus are the size of venules (95). Both types of vessels have simple walls composed of endothelium and a discontinuous layer of pericytes, through which tracer element (e.g., horseradish peroxidase) and presumably aqueous humor freely diffuse into subconjunctival and episcleral loose connective tissue. The episcleral veins drain into the cavernous sinus via the anterior ciliary and superior ophthalmic veins, whereas the conjunctival veins drain into superior ophthalmic or facial veins via the palpebral and angular veins (96).

Cellular Organization of the Uveoscleral Pathway

The unconventional outflow for aqueous humor outflow has not been studied as extensively as the trabecular outflow pathway. Historically, two unconventional pathways have been discriminated: (a) through the anterior uvea at the iris root, which is referred to the uveoscleral pathway, and (b) through transfer of fluid into the iris vessels and vortex veins, which has been described as uveovortex outflow. Uveoscleral Outflow

Tracer studies have shown that aqueous humor passes through the root of the iris and interstitial spaces of the ciliary muscle to reach the suprachoroidal space (97). From there it passes to episcleral tissue via scleral pores surrounding ciliary blood vessels and nerves, vessels of optic nerve membranes, or directly through the collagen substance of the sclera. Studies with cynomolgus monkeys revealed a lower hydrostatic pressure in the suprachoroidal space than in the anterior chamber, and it was suggested that this pressure differential is the driving force for uveoscleral outflow (98). The extracellular matrix of normal human ciliary muscle contains collagen types I, III, and IV; fibronectin; and laminin in association with muscle fibers and blood vessels, and it has been suggested that the biosynthesis and