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

monkey, this layer is 94% RGC axons and 5% astrocytes (15). The axonal bundles acquire progressively more interaxonal glial tissue in the intraocular portion of the nerve head as this structure is followed posteriorly (15).

Prelaminar Region

The prelaminar region is also called the anterior portion of the lamina cribrosa (16). The predominant structures at this level are nerve axons and astrocytes, with a significant increase in the quantity of astroglial tissue.

Lamina Cribrosa Region

This portion contains fenestrated sheets of scleral connective tissue and occasional elastic fibers. Astrocytes separate the sheets and line the fenestrae (16), and the fascicles of neurons leave the eye through these openings.

Retrolaminar Region

This area is characterized by a decrease in astrocytes and the acquisition of myelin that is supplied by oligodendrocytes. The axonal bundles are surrounded by connective tissue septa.

The posterior extent of the retrolaminar region is not clearly defined. An India ink study of monkey eyes showed nonfilling with the ink for 3 to 4 mm behind the lamina cribrosa when the IOP was elevated (17). However, a similar study using unlabeled microspheres showed an increased blood flow in the retrolaminar region close to the lamina even when the IOP was elevated high enough to stop retinal blood flow (18).

Vasculature Arterial Supply

Posterior ciliary artery circulation is the main source of blood supply to the optic nerve head (19), except for the nerve fiber layer—which is supplied by the retinal circulation. The blood supply in the optic nerve head has a sectoral distribution (20). The four divisions of the optic nerve head correlate roughly with a four-part vascular supply (Fig. 4.3).

The surface nerve fiber layer is mainly supplied by arteriolar branches of the central retinal artery, which anastomose with vessels of the prelaminar region and are continuous with

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the peripapillary retinal and long radial peripapillary capillaries (14, 19, 21). The temporal region may also be supplied by one or more of the ciliary-derived vessels from the posterior ciliary artery circulation in the deeper prelaminar region, which may occasionally enlarge to form cilioretinal arteries (14). The cilioretinal artery, when present, usually supplies the corresponding sector of the surface layer (20). In elderly rhesus monkeys, central retinal artery occlusion for less than 100 minutes produced no apparent evidence of optic nerve damage. However, longer occlusion produced a variable degree of damage (22).

Figure 4.3 Vascular supply of the optic nerve head. CRA, central retinal artery; RPC, radial peripapillary capillaries; PV, pial vessels; SPCA, short posterior ciliary arteries; PCV, peripapillary choroidal vessels; ZH, “ circle” of Zinn— Haller.

The prelaminar and laminar regions are supplied primarily by short posterior ciliary arteries, which form a perineural, circular arterial anastomosis at the scleral level, called the circle of Zinn-Haller (14, 19, 21, 23). Branches from this circle penetrate the optic nerve to supply the prelaminar and laminar regions and the peripapillary choroid (19). The circle is not present in all eyes, in which case direct branches from the short posterior ciliary arteries supply the anterior optic nerve. The peripapillary choroid may also minimally contribute to anterior optic nerve (14, 19, 21, 23).

The retrolaminar region is supplied by both the ciliary and retinal circulations, with the former coming from recurrent pial vessels. Medial and lateral perioptic nerve short posterior ciliary arteries anastomose to form an elliptical arterial circle around the optic nerve, which has also been referred to as the circle of Zinn-Haller (24, 25). This perioptic nerve arteriolar anastomosis, which supplies the retrolaminar optic nerve, was found to be complete in 75% of 18 human eyes in one study (24). The central retinal artery provides centripetal branches from the pial system and frequently, but not always, gives off centrifugal vessels (20).

Continuity between small vessels from the retrolaminar region to the retinal surface has been observed (21), and the optic nerve head microvasculature is said to represent an integral part of the retina-optic nerve vascular system (23).

Capillaries

Although derived from both the retinal and ciliary circulations, the capillaries of the optic nerve head

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resemble more closely the features of retinal capillaries than of the choriocapillaris. These characteristics include (a) tight junctions, (b) abundant pericytes, and (c) nonfenestrated endothelium (23). They do not leak fluorescein and may represent a nerve-blood barrier, supporting the concept of the retina-nerve vasculature as a continuous system with the central nervous system (21, 23). The capillaries decrease in number posterior to the lamina, especially along the margins of the larger vessels (26).

Venous Drainage

The venous drainage from the optic nerve head is almost entirely through the central retinal vein (19), although a small portion may occur through the choroidal system (27). Occasionally, these communications are enlarged as retinociliary veins, which drain from the retina to the choroidal circulation, or cilio-optic veins, which drain from the choroid to the central retinal vein (28). Astroglial Support

Astrocytes provide a continuous layer between the nerve fibers and blood vessels in the optic nerve head (29). In the rhesus monkey, astrocytes occupy 5% of the nerve fiber layer, increase to 23% of the laminar region, and then decrease to 11% in the retrolaminar area (15). The astrocytes are joined by “gap junctions,” which resemble tight junctions but have minute gaps between the outer membrane leaflets (30).

Thickand thin-bodied astrocytes have been described. The thin-bodied astrocytes accompany the axons in the nerve fiber layer, and the thick-bodied astrocytes direct axons in the prelaminar region toward the laminar region (31).

The astroglial tissue also provides a covering for portions of the optic nerve head (Fig. 4.4). The internal limiting membrane of Elschnig separates the nerve head from the vitreous and is continuous with the internal limiting membrane of the retina (29, 32, 33 and 34). The central portion of the internal limiting membrane is referred to as the central meniscus of Kuhnt (33). Although the central meniscus of Kuhnt is traditionally described as a central thickening of the internal limiting membrane, ultrastructural studies of the monkey optic nerve head revealed a thinning of 20 nm centrally, which thickened to 70 nm peripherally (34). The Müller cells are a major con stitutional element of the intermediary tissue of Kuhnt (35), which separates the nerve from the retina, whereas the border tissue of Jacoby separates the nerve from the choroid (16, 33).

Astrocytes also play a major role in the remodeling of the extracellular matrix of the optic nerve head and synthesizing growth factors and other cellular mediators that may affect the axons of the RGCs and contribute to health or susceptibility to disease (36).

Figure 4.4 Supportive structures of the optic nerve head: internal limiting membrane of Elschnig (a); continuous with the internal limiting membrane of the retina (b); central meniscus of Kuhnt (c); intermediary tissue of Kuhnt (d); border tissue of Jacoby (e); border tissue of Elschnig (f); lamina cribrosa (g); meningeal sheaths (h).

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Connective Tissue Support Lamina Cribrosa

This structure is not simply a porous region of the sclera but also a specialized extracellular matrix that consists of fenestrated sheets of connective tissue and occasional elastic fibers lined by astrocytes (16, 37). Astrocytes may respond to changes in IOP in glaucoma, leading to axonal loss and RGC degeneration at the level of lamina cribrosa (36). Extracellular matrix components in the lamina cribrosa differ from those in sclera or pial septa (38), which may be important in the pathogenesis of glaucomatous optic nerve damage. Hyaluronate was found surrounding the myelin sheaths in the retrolaminar nerve, playing an important role in the maintenance of the hydrodynamic properties of the extracellular matrix. Hyaluronate decreases with age and is further reduced in eyes with chronic openangle glaucoma (COAG), possibly increasing susceptibility to elevated IOP (39). The lamina cribrosa has also been found to be significantly thinner in glaucomatous eyes than in nonglaucomatous eyes (40). Analysis of the pores in the lamina cribrosa with a confocal scanning laser ophthalmoscope shows nearly round pores in the eyes with physiologic cupping, whereas eyes with COAG frequently have compressed pores (41). There are regional differences in the fenestration or pores through which the axons pass. The superior and inferior portions, compared with the nasal and temporal regions, have larger single pore areas and summed pore areas and thinner connective tissue and glial cell support (42,

43, 44 and 45) (Fig. 4.5). The ratio of single and summed pore areas between the laminar regions decreases with increasing lamina cribrosa area, but does not correlate with age or sex (45). A majority of RGC axons take a direct course through the lamina cribrosa (46), but about 10% of axons exit more peripherally, where the lamina cribrosa is more curvilinear, which may influence the regional susceptibility for glaucomatous optic nerve fiber loss (47). The size of the laminar openings for the retinal vessels does not correlate with the lamina cribrosa area (45).

Figure 4.5 Gross anatomic photograph of lamina cribrosa showing central openings for central retinal vessels (arrow) and surrounding fenestrae of lamina for passage of axon bundles. Note larger size of fenestrae in superior and inferior quadrants. S, superior; T, temporal. (Courtesy of Harry A. Quigley, MD.)

As mentioned previously, the lamina cribrosa of the human optic nerve head contains a specialized extracellular matrix composed of collagen types I through VI, laminin, and fibronectin (48, 49 and 50). Studies of young human donor eyes show that the cribriform plates are composed of a core of elastin fibers with a sparse, patchy distribution of collagen type III, coated with collagen type IV and laminin (48). Cell cultures of human lamina cribrosa reveal two cell types, which appear to synthesize this

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extracellular matrix (51). The expression of mRNA for collagen types I and IV in both fetal and adult human optic nerve heads suggests that these extracellular matrix proteins are synthesized in this tissue throughout life (52). Proteoglycans, which are macromolecular components of connective tissue believed to have a role in the organization of other extracellular matrix components and in the hydration and rigidity of tissue, have been identified in the cores of the laminar plates in association with collagen fibers (53, 54). Cell adhesive proteins, including vitronectin and thrombospondin, have been found in human lamina cribrosa (38). Abnormalities of this extracellular matrix in the lamina cribrosa may influence optic nerve function and its susceptibility to glaucomatous damage caused by elevated IOP. Lamina cribrosa cells from glaucomatous eyes express more profibrotic genes than cells from normal lamina cribrosa do (55). These differences in extracellular matrix probably translate into difference in biomechanical properties (56, 57).

Nerve Sheaths

A rim of connective tissue, the border tissue of Elschnig, occasionally extends between the choroid and optic nerve tissues, especially temporally (33) (Fig. 4.4). Posterior to the globe, the optic nerve is surrounded by meningeal sheaths (pia, arachnoid, and dura), which consist of connective tissue lined by meningothelial cells, or mesothelium (58). Lymphatic capillaries in the dura of the human optic nerve have been described (59). Vascularized connective tissue extends from the undersurface of the pia mater to form longitudinal septa, which partially separate the axonal bundles in the intraorbital portion of the optic nerve (33).

Axons

Retinal Nerve Fiber Layer

As the axons traverse the nerve fiber layer from the ganglion cell bodies to the optic nerve head, they are distributed in a characteristic pattern (Fig. 4.6). Fibers from the temporal periphery originate on either side of a horizontal dividing line, the median raphe, and arch above or below the fovea as the arcuate nerve fibers, while those from the central retina, the

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papillomacular fibers, and the nasal fibers take a more direct path to the nerve head. The significance of this anatomy to the visual field defects of glaucoma is discussed in Chapter 5. The axons in monkeys and rabbits are grouped into fiber bundles by tissue tunnels composed of elongated processes of Müller cells (60, 61 and 62). These bundles, especially on the temporal side, become larger as they approach the nerve head, primarily because of lateral fusion of bundles (63), and are normally visible by ophthalmoscopy as retinal striations (62). The axons in the bundles vary in size, with larger fibers coming from the more peripheral retina (63). One study also demonstrated that intra-RGC axons contain numerous bulb-shaped varicosities in humans of different ages (64).

Figure 4.6 Distribution of retinal nerve fibers. Note arching above and below the fovea of fibers temporal to the optic nerve head. Inset depicts crosssectional arrangement of axons, with fibers originating from peripheral retina running closer to choroid and periphery of optic nerve, while fibers originating nearer to the nerve head are situated closer to the vitreous and occupy a more central portion of the nerve.

Axons in Optic Nerve Head

The arcuate nerve fibers occupy the superior and inferior temporal portions of the optic nerve head, with axons from the peripheral retina taking a more peripheral position in the nerve head (Fig. 4.6) (65). The arcuate fibers are the most susceptible to early glaucomatous damage. The papillomacular fibers spread over approximately one third of the distal optic nerve, primarily inferior temporally, where the axonal density is higher (66, 67). They intermingle with extramacular fibers, which may explain the retention of central vision in early glaucomatous optic atrophy.

The mean axonal population in the normal human optic nerve head, as measured by computed image analysis of sections throughout the nerve, ranges from approximately 700,000 fibers to 1.2 million fibers (67, 68, 69 and 70). The optic nerve fiber count has been shown to increase significantly with the optic nerve head area in human and monkey eyes, although another study of human eyes showed no such

correlation (69, 71, 72). A positive correlation has also been demonstrated between the retinal photoreceptor count and optic nerve area (73). The reported mean axonal fiber diameter ranges from 0.65 to 1.10 µm (67, 68, 74). Axons of all sizes ar e mixed throughout the nerve area, although higher mean diameters appear to be more common in the nasal segment (67).

EMBRYOLOGY OF THE RETINA AND OPTIC NERVE

The retina and optic nerve develop from the optic cup and the contiguous optic stalk (75, 76, 77, 78, 79 and 80).

The inner layer of the cup contains the pluripotent retinal progenitor cells, which differentiate in a specific chronologic sequence and defined histogenic order into the final seven retinal cell types (see Fig. 1.3 in Chapter 1). In general, the RGCs differentiate first (81, 82), followed by the cone photoreceptors, amacrine cells, horizontal cells, and finally, the rod photoreceptors, bipolar cells, and Müller cells. Retinal neurogenesis starts in the ce ntral optic cup region and then fans out concentrically in a wavelike pattern into the periphery. There is a basic topographic organization of the optic cup with dorsoventral and nasotemporal patterning (83), which involves certain genetic cues, including that of the Otx genes (84).

The optic fissure of the optic stalk closes to convert it into a cylinder, into which the RGC axons grow. The lumen of the

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optic stalk is obliterated by axons by approximately the third fetal month. Apoptosis, or selective cell death, and cell cycle regulators are important in normal ocular development (85, 86 and 87). The optic nerve axon count in humans peaks at approximately 3.7 million by fetal week 16 to 17 and then rapidly declines to near adult levels of around 1 million by term (88). Epithelial cells in the walls of the stalk differentiate into the neuroglia of the optic nerve. Mesenchymal tissue gives rise to the optic nerve septa in the third month and to the lamina cribrosa in the final month of gestation.

Key regulatory genes involved in the early development of the eye and the fate of retinal cells include Pax6, Rxl, Six3/6, Lhx2, and certain basic helix-loop-helix transcription factors. The expression of these genes and their effect on retinal neurogenesis and differentiation are considered “cell-intrinsic” mechanisms, whereas “extrinsic” mechanisms include thyroid hormones and their receptors, fibroblast growth factors and other “growth factors,” hedgehog proteins, various neurotrophins, and nitric oxide (75, 89, 90, 91, 92, 93, 94 and 95).

The optic nerve cross-sectional area reaches 50% of the adult size by 20 weeks' gestation, 75% at birth, and 95% before 1 year of age (96). At birth, the optic nerve is nearly unmyelinated (97), and myelination, which proceeds from the brain to the eye during gestation, is largely completed in the retrolaminar region of the optic nerve by the first year of life (98). The connective tissue of the lamina cribrosa is also incompletely developed at birth, which may account for the increased susceptibility of the infant nerve head to glaucomatous cupping and its potential for reversible cupping (99). With increasing age, the cores of the cribriform plates enlarge, and the apparent density of collagen types I, III, and IV and elastin increases (100, 101). Not only does elastin increase with age, but also elastic fibers become thicker, tubular, and surrounded by densely packed collagen fibers (101). Proteoglycan filaments in the human lamina cribrosa also decrease in length and diameter with age (102). Also with increasing age, there appears to be a progressive loss of axons with a decrease of the nerve fiber layer thickness (103, 104) and a corresponding increase in the cross-sectional area occupied by the leptomeninges and fibrous septa (67, 68, 69 and 70). The loss of axons has been estimated to be between 4000 and 12,000 per year, with most studies nearer the lower figure (67, 69, 70, 105). One study suggested a selective loss of large nerve fibers with age (68), although this has not been confirmed by others (67, 74).

PATHOPHYSIOLOGY OF GLAUCOMATOUS OPTIC NERVE DAMAGE Theories

The pathogenesis of glaucomatous optic atrophy has remained a matter of controversy since the mid19th century, when two concepts were introduced in the same year. In 1858, Müller (106) proposed that

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the elevated IOP led to direct compression and death of the neurons (the mechanical theory), while von Jaeger (107) suggested that a vascular abnormality was the underlying cause of the optic atrophy (the vascular theory). In 1892, Schnabel (108) proposed another concept in the pathogenesis of glaucomatous optic atrophy, suggesting that atrophy of neural elements created empty spaces, which pulled the nerve head posteriorly (Schnabel cavernous atrophy).

Initially, the mechanical theory received the greatest support (109, 110 and 111). This concept held sway through the first quarter of the 20th century until LaGrange and Beauvieux (112) popularized the vascular theory in 1925. In general, this belief held that glaucomatous optic atrophy was secondary to ischemia, whether the primary result of the elevated IOP or an unrelated vascular lesion (113, 114 and 115). In 1968, however, the role of axoplasmic flow in glaucomatous optic atrophy was introduced (116), which revived support for the mechanical theory, but did not exclude the possible influence of ischemia.

Evidence

Continued investigation into the pathogenesis of glaucomatous optic atrophy has led to the following bodies of information.

Anatomic and Histopathologic Studies

Histopathologic observations of human eyes with glaucoma provide the most direct method of studying the alterations associated with glaucomatous optic atrophy, although they do not fully explain the mechanisms that caused the damage. One of the limiting factors has been that many of the specimens studied have come from eyes with advanced glaucomatous change, which led to possible misconceptions regarding the early pathogenic features. More recent studies, which have attempted to correlate clinical observations with histopathologic changes in optic nerve heads from eyes with varying stages of glaucoma, appear to clarify many of these points.

Glial Alterations

It was once suggested that loss of astroglial supportive tissue precedes neuronal loss (117), which was thought to explain the early and reversible cupping in infants (118). However, subsequent studies have shown that glial cells are not selectively lost in early glaucoma and are actually the only remaining cells after loss of axons in advanced cases (119, 120).

Vascular Alterations

It was also once proposed that loss of small vessels in the optic nerve head accompanies atrophy of axons (121), and one histologic study suggested a selective loss of retinal radial peripapillary capillaries in eyes with chronic glaucoma (122). However, subsequent investigations revealed neither a correlation between atrophy of this vascular system and visual field loss nor a major selective loss of optic nerve head capillaries in human eyes with glaucoma (119, 120, 123, 124). In animal models of optic atrophy, created by either sustained IOP elevation, sectioning of the optic nerve, or photocoagulation of the RNFL, the resulting disc pallor was not associated with a decrease in the ratio of capillaries to neural tissue, although the caliber of the vessels diminished (124, 125, 126, 127 and 128). Instead, these studies showed a proliferation or reorganization of glial tissue, which obscures ophthalmoscopic visualization of the vessels (125, 126, 128).

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Alterations of the Lamina Cribrosa

Backward bowing of the lamina cribrosa has long been recognized as a characteristic feature of late glaucomatous optic atrophy (129, 130), and as an early change in the infant eye with glaucoma (99). Further study, however, has suggested that alterations in the lamina may actually be a primary event in the pathogenesis of glaucomatous optic atrophy. In enucleated human eyes, acute IOP elevation causes a backward bowing of the lamina (131, 132), and similar changes are observed in primate glaucoma models (133, 134) with compensatory remodeling and fibrosis (135).

Most of the posterior displacement occurred in the peripheral lamina cribrosa, corresponding to the region of early axonal loss (132). In a histopathologic evaluation of 25 glaucomatous human eyes, compression of successive lamina cribrosa sheets was the earliest detected abnormality, and backward

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bowing of the entire lamina occurred later and involved primarily the upper and lower poles (136).

In the early stages of adult glaucoma, the magnitude of backward bowing is not sufficient to explain the ophthalmoscopically observed cupping, but may be enough to produce a pressure gradient along the axoplasm of exiting optic nerve axons, compromise the circulation (137), and cause compression of the axons. It has been suggested that the structure of the lamina cribrosa may be an important determinant in the susceptibility of the optic nerve head to damage from elevated IOP (119, 120). However, racial comparison of the relative connective tissue support and regional pore size of the lamina cribrosa did not explain the increased susceptibility of blacks to glaucomatous damage (138). The extracellular matrix of the lamina cribrosa may play an important role in the progression of glaucomatous damage (139, 140 and 141). In glaucomatous monkey eyes, increased collagen type IV and laminin lined the margins of the laminar beams (140, 141), and collagen types I, III, and IV were found in the pores of the beams (140). Elastin, which is the major protein of elastic fibers and responsible for elastic recoil, appeared curled instead of straight and seemed disconnected from other elements of the connective tissue matrix in glaucomatous eyes of humans and monkeys (142). Elastin mRNA expression in human eyes with COAG suggests synthesis of abnormal elastic fibers (143). These changes may be secondary to longstanding elevation of IOP and may modify the course of glaucomatous optic atrophy.

Figure 4.7 A: Light microscopic view of normal optic nerve head on cross section with darkly staining axon bundles and intervening glial supportive tissue surrounding openings for central retinal vessels. B: Light microscopic cross-sectional view of optic nerve head with glaucomatous atrophy showing loss of axon bundles predominantly in the inferior and superior quadrants (compare with normal nerve head in A). INF, inferior; NAS, nasal; SUP, superior; TEM, temporal. (Courtesy of Harry A. Quigley, MD.) Axonal Alterations

The actual cause of early optic nerve head cupping in glaucoma appears to be the loss of axonal tissue (119, 120, 144). Experimental models of primate eyes exposed to chronic IOP elevation suggest that the damage is associated with a posterior and lateral displacement of the lamina cribrosa, which compresses the axons and disrupts axoplasmic flow (145). The damage first involves axonal bundles throughout the nerve with somewhat greater involvement of the inferior and superior poles (136). With continued optic nerve damage, the susceptibility of the polar zones becomes more prominent (Fig. 4.7) (119, 120, 136, 144). Histologic studies of both monkey and human optic nerves indicate that nerve fibers larger than