Ординатура / Офтальмология / Английские материалы / Mechanisms of the Glaucomas_Shields, Tombran-Tink, Barnstable_2008

and also the inner wall of Schlemm’s canal, as discussed below, may cause the cells to sense the stretch caused by the mechanical deformation of the meshwork as IOP changes (3,10). Loss of the connecting fibril connections in disease could be detrimental to the presumed self-regulating activity of the meshwork.

The second major function is preventing blood reflux from Schlemm’s canal into the eye. When IOP becomes lower than the episcleral venous pressure and pressure in Schlemm’s canal, blood fills the canal. This may occur during coughing, straining, Valsalva maneuvers, bending over, or hanging upside down. The trabecular meshwork changes shape in relation to IOP, with collapse of the intertrabecular spaces and condensation of the cribriform region as the pressure in Schlemm’s canal increases (3,10), effectively preventing blood reflux into the eye.

The third function of the trabecular meshwork is phagocytic. Trabecular cells are actively phagocytic, ingesting blood, pigment, and other debris (11,12). The multiple layers of trabecular sheets, each covered with cells, provide a large surface area for aqueous to pass over as it travels through the meshwork. Not only does this keep the aqueous humor clear for visual purposes, but it also captures debris before it can reach the sensitive site of aqueous outflow resistance, effectively keeping it from becoming plugged (13).

ANATOMY

The trabecular meshwork consists of seven layers of collagenous sheets (see Figs 1 and 2). The two innermost layers, facing the anterior chamber, comprise the uveal meshwork (see Fig. 2). This is a series of round collagenous beams or cords, each with a central elastic fiber surrounded by collagen fibers embedded in a ground substance. These in turn are covered by trabecular cells. The middle layers, the corneoscleral meshwork, are a series of flat beams extending circumferentially around the eye. These sheets are not solid, but rather incomplete, with holes and gaps in them resembling Swiss cheese (see Figs 2 and 3). The sheets also have a central elastic core surrounded by collagen fibers all covered by trabecular cells (see Figs 4 and 5). The trabecular lamellae including their elastic fibers are also connected to each other in the inward– outward direction, thereby forming a three-dimensional sponge-like structure.

In the outermost layer of the trabecular meshwork, the cribriform or juxtacanalicular meshwork, the trabecular lamellae are incomplete, but the elastic network is still present. The elastic fibers are continuous with the outermost lamellae and are connected to the inner wall endothelium by the so-called connecting fibrils (see Figs 6 and 7).

The elastic fibers in the trabecular meshwork, scleral spur, and sclera differ profoundly from those seen in Bruch’s membrane, posterior tendons of the ciliary muscle, or the choroids. Their central core contains only little elastin, embedded in an osmophilic substance of yet unknown nature. These fibers are surrounded by fibrils that are cross linked periodically. These cross-links cannot be digested by proteases. Type VI collagen fibers have been shown to enter the fibrillar sheath of the elastic fibers.

The cribriform elastic network is surrounded by a loose arrangement of cells, patches of extracellular matrix usually in contact with the cells, and apparently empty spaces for aqueous flow (see Figs 4 and 5). The extracellular matrix has an amorphous

Fig. 7. Diagram of elastic fibers in cribriform region. Sheath material (light gray) surrounds fibers and is of normal thickness in picture on right. Picture on left shows thickening of sheath material as may occur in older age and in primary open-angle glaucoma (POAG).

The exact site and tissue or cells that create the resistance to aqueous outflow is unknown. Because the spaces between the trabecular lamellae are large (about 15 μm), they do not create significant outflow resistance (18). Although the empty spaces in the cribriform region are smaller, they are still large enough and numerous enough that they would not create resistance to aqueous outflow unless they were filled with glycosaminoglycans (19). This continues to be an area of intense study. The endothelial lining of Schlemm’s canal seems a likely site of resistance to aqueous flow, as it is the only continuous anatomic barrier in the trabecular meshwork region. These endothelial cells are “special,” however, as they are confronted with aqueous flowing from their basal to apical regions. This differs from the usual arrangement of a vascular channel, in which vascular cells have the intravascular pressure pushing against their apices, pressing them into their basement membrane. The canal endothelial lining cells react to this “backward” pressure gradient by forming out pouchings, termed giant vacuoles (20,21). In addition, intercellular pores and intracellular pores also form, providing channels for aqueous flow. Current thought is that the pores act hydrodynamically with the adjacent extracellular material, effectively “funneling” aqueous into regions near the pores (22). This synergy between cellular pores and extracellular matrix can create outflow resistance greater than would occur with either structure alone. The “washout” phenomena of non-human eyes may relate to the loss of the “funneling” effect when the inner wall of the canal separates from its underlying extracellular matrix because of fewer elastic tendons anchoring the wall of the canal (17,23).

AGING CHANGES

Three major changes occur with age: loss of trabecular cells, thickening of the trabecular lamellae, and thickening of the elastic fiber sheaths (24–26). Trabecular cells are lost at a rate of about 0.5% per year, similar to rates of corneal endothelial

sole cause of the elevated pressure (32). Instead, some other factor(s) is likely to cause the elevated IOP and increase in tendon material.

Sheath material is also present in the outer wall of Schlemm’s canal and in the interstitial spaces between the anterior tips of the ciliary muscle fibers. It is increased in the outer wall in cases of POAG and also increased in the ciliary muscle tips (30).

One of the challenges in histologic study of diseased tissue is distinguishing the primary disease process from secondary changes. These secondary changes could be due to drug treatments, reactive changes from surgery, or reactive fibrosis to the inciting cause of the disease. Two studies suggest the thickened tendon sheaths are not changes secondary to drug treatment or reactive fibrosis (33,34). Trabeculectomy specimens from patients who received no or only minor mediation prior to surgery were similar to previous findings: thickened tendon sheath material, thickened lamellae, and abundant long-spacing collagen (33). Another study looked at POAG eyes removed at autopsy, again at earlier stages of the disease than those requiring surgery. Comparison of eyes on beta-adrenergic blockers with those on other medications (usually pilocarpine or prostaglandin analogs) did not show a difference (34). If chronic aqueous suppression caused secondary changes in the meshwork (“silting in” with debris and extracellular material) (35,36), this would have been apparent in the cribriform region and probably accompanied by fusion of lamellae in the corneoscleral region. These were not found: specimens from each treatment group were similar.

Trabecular cells are decreased in number in eyes with POAG (25,37). It is not known whether these eyes initially had normal numbers of cells or had fewer trabecular cells at birth. This distinction becomes important in understanding the pathogenesis of the disease. If a pathologic process causes an increased loss of trabecular cells in glaucoma, finding and ultimately stopping this process would “cure” glaucoma. In contrast, if eyes with POAG had fewer numbers of cells to begin with, the normal age-associated loss may cause glaucoma from a simple lack of enough trabecular cells to perform the requisite physiologic functions of these cells in maintaining aqueous outflow. Unfortunately, most of the specimens in one study were from surgical trabeculectomies (37). Handling artifact due to tissue distortion and flexion can damage trabecular cells, especially in the uveal and corneoscleral regions (38). A study that included whole eyes removed at autopsy and trabeculectomy specimens found cell damage and handling artifact in the trabeculectomy specimens and concluded that caution must be used when interpreting cellularity from trabeculectomy specimens (38).

PSEUDOEXFOLIATION SYNDROME

In a recent study it has been shown that most of the patients with Pseudoexfoliation glaucoma (PEXG) show changes in exon 1 of LOXL1 gene. The gene product of LOXL1 gene is involved in the modification of elastin fibers (39). The composition of PEX-material is still not known (40). Multiple intraocular structures produce PEX material, most prominently the ciliary epithelia. These grayish-white flakes seen on the lens capsule, or on the anterior surface of intraocular lenses, can be seen to float within the anterior chamber and become deposited on the corneal endothelium and trabecular meshwork. On ultrastructural examination, these flakes appear as clumps of a fine fibrillar material (40,41) (see Fig. 11). The fibers are short and randomly arranged, being seen in both cross-section and longitudinal section in these clumps.

Fig. 13. Trabecular meshwork in pseudoexfoliation glaucoma. Separation of inner wall of Schlemm’s canal and cribriform region from remaining meshwork. Connecting fibrils appear broken by lytic activity. SC, Schlemm’s canal.

glaucoma, differing from the pathophysiology of POAG. Obstruction to outflow could also occur in the corneoscleral region in this condition if PEX fiber clumps occlude the spaces or cause damage to adjacent structures. PEX fibrils can adhere to bare basement membrane regions of the corneoscleral meshwork, serving as a kind of glue and potentially leading to fusion of adjacent beams if adjacent areas are also devoid of trabecular cells (42).

Separation of the connecting fibril tendons from their usual insertion locations in the cribriform meshwork and inner wall of Schlemm’s canal was also found (41) (see Fig. 13). This appeared associated with lytic activity. Loss of tension on the inner wall of the canal could lead to increased resistance to aqueous outflow, as trabecular and canal cells would not sense the stretch caused by ciliary muscle tension or by changes in IOP (15,17).

PIGMENTARY GLAUCOMA

Pigment granules are ingested by trabecular cells and commonly cause pigmentation of the meshwork as seen on gonioscopic examination. Although they are carried by aqueous humor to this location, they rarely remain free in the intertrabecular spaces (38,43). Pigment first accumulates in regions of higher aqueous flow, usually marking the entrance to collector channels (44). If enough pigment is present, it not only fills these regions but can be found throughout the meshwork. Richardson theorized that trabecular cells ingesting large amounts of pigment could migrate from the trabecular beams or perhaps die because of excess pigment ingestion (45). In either case, the bare beams can adhere to each other, obliterating the aqueous spaces between them (38,45). As theorized in PEX glaucoma, loss of these aqueous spaces in enough regions around the meshwork could lead to increased resistance to aqueous outflow.

In a recent study that included whole eyes removed at autopsy and also specimens from trabeculectomies removed at surgery, a spectrum of changes in the meshworks was found (38). Some regions of an eye appeared to have normal meshwork, whereas