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

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the normal mean diameter atrophy more rapidly in glaucomatous eyes, although no fiber size is spared from damage (146, 147). This preferential loss of large fibers appears to be due to a higher proportion of the fibers in

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the inferior and superior poles, and an inherent susceptibility to injury by glaucoma (146, 147).

In the retina of glaucomatous monkey eyes, there is also a selective loss of the larger ganglion cells in both the midperiphery and fovea, and it has been suggested that psychophysical testing should be aimed at these cells in the early stages of glaucoma (148, 149). The same animal studies suggest that RGCs in glaucoma die by apoptosis, a genetically programmed process of cell death, characterized histologically by chromatin condensation and intracellular fragmentation (150). This apoptosis is possibly related to loss of trophic influences resulting from inhibited transmission of neurotrophic signals from axon terminals to neuronal cell bodies; histologic studies have also shown a significant decrease of corpora amylacea, which are homogeneous oval bodies believed to correlate with axonal degeneration, in RGCs and the optic nerve of human eyes with advancing stages of glaucoma (151, 152). One study revealed a significant reduction in photoreceptor count in human eyes with angle-closure glaucoma associated with trauma (153), although this was not observed in human eyes with COAG or in monkey eyes with experimental glaucoma (154, 155).

Secondary degeneration has been reported to occur after experimental injury of RGCs, causing loss of neighboring RGCs as an indirect effect of the injury and death of transected RGCs. Glutamate levels in the vitreous did not increase at 3 months after injury, suggesting the need for further investigations of the mechanisms of secondary degeneration (156).

Blood-Flow Studies

Blood flow in the optic nerve head of cats is relatively high compared with that in more posterior portions of the nerve, and autoregulation appears to compensate for alterations in mean arterial blood pressure (157). With elevation of IOP, blood flow in the optic nerve head, retina, and choroid of cat eyes is only slightly affected before the pressure is within 25 mm Hg of the mean arterial blood pressure, and flow in the lamina cribrosa is reduced only with extreme pressure elevations, again suggesting autoregulation in the optic nerve head (158). Another study, however, suggests that the electrical function of ganglion cell axons in cat eyes depends on the perfusion pressure and not on the absolute height of the IOP (159). Real-time analysis of optic nerve head oxidative metabolism in cats indicates that the metabolic response is dependent on IOP or mean arterial pressure and that lowering the IOP can reverse metabolic dysfunction (160).

Short-term IOP elevation in monkey eyes did not alter optic nerve head blood flow until it exceeded 75 mm Hg, and longterm glaucoma in monkeys had no apparent influence on mean blood flow in the nerve head (161); others have shown that the threshold of IOP that is needed to affect blood flow is partly determined by the animal's systemic blood pressure (162). A study of oxygen tension in the monkey optic nerve head suggested that autoregulation compensates for changes in perfusion pressure (163), and a noninvasive phosphorescence imaging technique in cats revealed well-maintained oxygen tension in the optic nerve head and retina despite increasing IOP, until blood flow to the eye was stopped (164). Blood-flow measurements in the optic nerve head of human eyes, using laser Doppler, demonstrate autoregulatory compensation to reduced perfusion pressure secondary to elevated IOP (165). In glaucomatous eyes, however, Doppler studies show reduced flow velocity in the nerve head (166, 167, 168 and 169). Blood flow of the optic nerve head lamina, rim area, and retrobulbar flow is decreased with increasing glaucomatous damage (170, 171). Eyes with glaucoma also appear to have more diurnal fluctuation of optic nerve blood flow (172).

A technique of continuously monitoring disc brightness during and after an abrupt artificial elevation of IOP also showed that the extent to which a glaucomatous eye can adjust to the pressure changes is significantly reduced from that of nonglaucomatous eyes (173). Diminished autoregulatory response to postural changes in the retinal vasculature of patients with glaucoma is also seen (174). Age may influence the vascular responses to IOP. One study showed that major retinal vessels at the disc border

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increased in caliber in response to IOP reduction in patients with COAG who were 55 years or younger, but not after that age (175). In children, intracranial pressure also affects optic nerve blood flow (176). It may be that ischemia of the optic nerve head in glaucoma involves faulty autoregulation, which may worsen with age and is also affected by systemic blood pressure and intracranial blood pressure (158, 177, 178). Molecules such as endothelin and nitric oxide are being investigated for their possible role in the normal and altered autoregulatory responses (179, 180).

Fluorescein Angiography Normal Fluorescein Pattern

The normal fluorescein pattern of the optic nerve head is usually described as having three phases (14): In the first phase, an initial filling, or preretinal arterial, phase is thought to represent filling of the prelaminar and lamina cribrosa regions by the posterior ciliary arteries. Fluorescein in the retrobulbar vessels may also contribute to this phase (181).

The peak fluorescence, or retinal arteriovenous phase, is primarily due to filling of the dense capillary plexus on the nerve head surface from retinal arterioles. With increasing age, there is a decrease in the filling time of both the retinal and choroidal circulations (182).

A late phase consists of 10 to 15 minutes of delayed staining of the nerve head, probably because of fluorescein in the connective tissue of the lamina cribrosa. Tracer studies in monkeys suggest that the leakage may come from the adjacent choroid (183).

Effect of Artificially Elevated IOP

The effect of artificially elevated IOP on the fluorescein angiographic pattern has provided an understanding of the relative vulnerability of ocular vessels to elevated pressure in the normal and glaucomatous eyes. There is a general delay in the entire ocular circulation in response to an elevation of the IOP. The prelaminar portion of the nerve head appears to be the most vulnerable portion of the ocular vascular system to elevated pressure in monkeys (14, 184).

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Studies regarding the vulnerability of the peripapillary choroid to IOP elevation have provided conflicting results. Fluorescein angiography of monkey eyes has suggested a marked susceptibility of this vascular system to elevated pressure (14, 184), and fluorescein studies of human eyes with glaucoma have shown similar delays in peripapillary choroidal filling (184, 185, 186, 187, 188). The delay appears to be sensitive to elevated IOP (185). It has been suggested that this vascular disturbance of the peripapillary choroid contributes to glaucomatous optic atrophy (187). However, fluorescein angiographic studies of normal human eyes have shown similar delayed or irregular choroidal filling at normal pressures (189, 190), and the peripapillary choroidal capillaries of normal human eyes were relatively resistant to artificial pressure elevations (191). Furthermore, a fluorescein study of patients with low-tension glaucoma or COAG provided no evidence that hypoperfusion of the peripapillary choroid contributed to optic nerve hypoperfusion (192).

A selective nonfilling of the retinal radial peripapillary capillaries during India ink perfusion has been demonstrated in cats (193). As previously discussed, however, histopathologic observations differ regarding alterations of this vascular system in glaucomatous eyes (122, 123). Most studies of monkey and normal human eyes have shown the choroidal circulation in general to be more vulnerable than that of the retina to elevated IOP (14, 184, 187, 194), although one study found the two systems to fill at the same level of increased pressure (195). Regional differences in circulation of the optic nerve head, retina, and peripapillary choroid have been reported (196).

Studies of Glaucomatous Eyes

Fluorescein angiographic studies of glaucomatous and nonglaucomatous eyes have revealed two types of filling defects of the optic nerve head: (a) persisting hypoperfusion and (b) transient hypoperfusion (192, 197).

Persisting hypoperfusion, or absolute filling defects, is more common in eyes with glaucoma, especially low-tension glaucoma, and are said to correlate with visual field loss (192, 197, 198). The characteristics of a filling defect include decreased blood flow, a smaller vascular bed, narrower vessels, and increased

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permeability of the vessels (199). The filling defect may be either focal or diffuse. The former is thought to reflect susceptible vasculature with or without elevated IOP, and is the typical defect in low-tension glaucoma (192). Focal defects occur primarily in the inferior and superior poles of the optic nerve head (197, 198, 200). In glaucomatous eyes, they are most often seen in the wall of the cup, whereas in nonglaucomatous eyes they occur more commonly in the floor of the cup (201). The diffuse defect is thought to represent prolonged pressure elevation (192).

The nature of the defect in COAG is thought to be specific, and fluorescein angiography of the optic nerve head may help to differentiate COAG from other conditions that have similar clinical changes in the optic disc (202). Computed image analysis has been used to objectively quantify fluorescein angiograms of the optic disc and has shown that increases in fluorescein-filling defect areas correlate with glaucomatous progression (203).

In patients with low-tension glaucoma, retinal arteriovenous passage times are prolonged in fluorescein angiography, possibly from the increased resistance in the central retinal and posterior ciliary arteries. Arteriovenous passage correlated with the size of the optic nerve head, visual field indices, and contrast sensitivity (204).

Axoplasmic Flow

Physiology of Axoplasmic Flow

Axoplasmic flow, or axonal transport, refers to the movement of material (axoplasm) along the axon of a nerve (the dendrite may also have transport) in a predictable, energy-dependent manner. This movement has been characterized as having fast and slow components, although numerous intermediate rates may also exist (205). The fast phase moves approximately 410 mm/day in various species and may supply material to synaptic vesicles, the axolemma, and agranular endoplasmic reticulum of the axon; the slow phase moves at 1 to 3 mm/day and is believed to subserve growth and maintenance of axons (205). The flow of axoplasm may be orthograde (from retina to lateral geniculate body) or retrograde (lateral geniculate body to retina) (206).

Experimental Models of Axoplasmic Flow

Animal models (usually in monkeys) have been developed for studying axoplasmic flow by injecting radioactive amino acids, such as tritiated leucine, into the vitreous. In other animal models, the results may have less generalizability to human glaucoma because of species differences of the lamina cribrosa region; some animals do not have a lamina. The amino acid is incorporated into the protein synthesis of RGCs and then moves down the ganglion cell axon into the optic nerve, allowing histologic study of the orthograde movement of radioactively labeled protein (207). In addition, retrograde flow can be studied by observing the accumulation of certain unlabeled neuronal components, such as mitochondria by electron microscopy (208), or by injecting tracer elements, such as horseradish peroxidase into the lateral geniculate body and studying its movement toward the retina (209). These models can be used to study factors that cause abnormal blockade of axoplasmic flow, which may relate to glaucomatous optic atrophy in the human eye.

Influence of IOP on Axoplasmic Flow

Elevated IOP in monkey eyes causes obstruction of axoplasmic flow at the lamina cribrosa and the edge of the posterior scleral foramen (206, 210, 211, 212, 213, 214 and 215). Axonal transport in monkey eyes with chronic IOP elevation is also preferentially decreased in the magnocellular layers of the dorsal lateral geniculate nucleus, to which the large RGCs project (216). The obstruction in general involves both the fast and slow phases, and the orthograde and retrograde components (206, 211, 213, 214). In monkey eyes, the obstruction to fast axonal transport preferentially involves the superior, temporal, and inferior portions of the optic nerve head (217). The height and duration of pressure elevation influence the onset, distribution, and degree of axoplasmic obstruction in the optic nerve head (214, 218, 219). The mechanism by which elevated IOP leads to obstruction of axoplasmic flow is uncertain, but there are two popular theories: mechanical and vascular.

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The mechanical theory suggests that physical alterations in the optic nerve head lead to misalignment of

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the fenestrae in the lamina cribrosa and may result in axoplasmic flow obstruction (116, 130, 214). In support of this hypothesis is the observation that elevated IOP leads to blockage of axonal transport despite an intact nerve head capillary circulation and an elevated arterial pO2 (206, 220). Furthermore,

obstruction of axoplasmic flow has also been reported in response to ocular hypotony (211, 213, 221), leading some investigators to suggest that a pressure differential across the optic nerve head, whether due to a relative increase or decrease in IOP, causes mechanical changes with compression of the axonal bundles (211, 213, 221, 222). In the laminar portion of pig ganglion cell axons, cytoskeletal changes are seen before disruption of axoplasmic flow; the disruption of axoplasmic flow was observed to be greater in the axons of the periphery of the optic nerve, favoring a mechanical issue as the primary pathologic process (223).

In conflict with the mechanical theory is the observation that elevated intracranial pressure in monkeys neither caused obstruction of rapid axoplasmic flow nor prevented it in response to elevated IOP, despite reduction in the pressure gradient across the lamina (224). This suggests that more than a simple mechanical or hydrostatic mechanism may be involved with obstruction of axoplasmic flow in response to elevated IOP (224). Also against the simple mechanical theory are the observations that axon damage is diffuse within bundles, rather than focal, as might be expected with a kinking effect (225), and the location of transport interruption does not correlate with the cross-sectional area of fiber bundles, the shape of the laminar pores, or the density of interbundle septa (226, 227).

The vascular theory suggests that ischemia at least plays a role in the obstruction of axoplasmic flow in response to elevated IOP. Interruption of the short posterior ciliary arteries in monkeys has been reported to block both slow and fast axoplasmic flow, although it did not cause glaucomatous cupping (228, 229,and 230). Central retinal artery occlusion has been associated with obstruction of rapid orthograde and retrograde axonal transport (231). Furthermore, accumulation of tracer at the lamina cribrosa was inversely proportional to the perfusion pressure in cat eyes (232), and IOP-induced blockage of axonal transport was increased in eyes with angiotensin-induced systemic hypertension (233). In monkey eyes with elevated IOP, leakage from microvasculature of the nerve head has been associated with blockade of axonal transport at the lamina cribrosa (234).

Arguing against a vascular mechanism for pressure-induced obstruction of axoplasmic flow is the observation that ligation of the right common carotid artery in monkeys, which reduced the estimated ophthalmic artery pressure by 10 to 20 mm Hg, does not significantly affect the extent to which IOP elevation interrupts axonal transport (235). When obstruction to retrograde axoplasmic flow was studied in rat eyes, a direct relationship with IOP was still found, although the influence of the blood circulation was removed and the lamina cribrosa is only a single laminar sheet (209). It may be, therefore, that factors other than, or in addition to, ischemia and kinking of axons by a multilayered lamina cribrosa are involved in the IOP-induced obstruction to axoplasmic flow.

One study has found that partial constriction of axoplasmic flow may be present at the lamina cribrosa in orthograde and retrograde directions, and that accumulations of mitochondria at that level were more common in unmyelinated axons than in adjacent, myelinated axons. The authors suggested that the constriction may be a factor in glaucoma wherein IOP is not elevated (236). Endothelin-1, which produces vasoconstriction, reduces fast axonal transport in rats (237).

The effects on axoplasmic flow in the laminar region that are seen in monkeys with experimental glaucoma are similar to those seen in one of the few species to develop spontaneous glaucoma, the American Cocker Spaniel (238).

Cerebrospinal Fluid Pressure and Glaucomatous Optic Neuropathy

Anatomically, the cerebrospinal fluid (CSF) extends anteriorly in the optic nerve sheath and the subarachnoid space to the posterior aspect of the lamina cribrosa. Although IOP has been known to play a role in glaucomatous optic neuropathy, only relatively recently has there been speculation about any effect the CSF pressure may have (239, 240). Studies in dogs have shown that the biomechanical effect of altering CSF pressure on the lamina cribrosa is equal to or greater than an equivalent change in IOP (241). Studies of the optic nerve architecture in human eyes have shown that the lamina cribrosa is relatively thin and bowed posteriorly in human eyes with glaucoma (40, 242) (Fig. 4.8). A recent

retrospective study found that the CSF pressure in patients with COAG was significantly decreased (243). In a subsequent study, CSF pressure was also lower in patients with normal-tension glaucoma and higher in patients with ocular hypertension, compared with control participants (244). A prospective study confirmed that persons with COAG have significantly lower CSF pressures than controls do; in addition, CSF pressure was lower in patients with normal-tension glaucoma than in patients with COAG (245). In this study, IOP, CSF pressure, and blood pressure were positively correlated, suggesting a dynamic interplay among these factors. Although preliminary, these studies suggest that translaminar pressure—the difference between IOP and CSF pressur e— plays an important role in the pathogenesis of glaucomatous optic neuropathy.

Electrophysiologic Studies

When the IOP is artificially elevated in healthy human eyes, a significant reduction in the amplitudes of electroretinographic components and visual-evoked potentials occurs only when the pressure approaches or exceeds the ophthalmic blood pressure (246, 247). However, the perfusion-pressure amplitude curve of the visual-evoked potential in normal eyes showed a kink, suggestive of vascular autoregulation, which was not observed in patients with glaucoma (248), again pointing to a possible deficiency in autoregulation in glaucoma. As previously noted, the electrical function of RGCs in cat eyes was found to depend more on perfusion pressure than the absolute height of the IOP (159).

The pattern electroretinography is believed to originate in the RGCs and is expected to be reduced in glaucoma. Therefore, it might be used to detect ganglion cell loss, but it failed

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to separate glaucoma patients from healthy individuals when used alone (249). However, a study of patients with ocular hypertension showed that pattern electroretinographic amplitude correlates with various optic disc morphometric parameters, particularly in sectors considered to be at risk for early glaucomatous damage (250). Although still early in its development, pattern electroretinography, as well as multifocal electroretinography, shows promise in the roles of diagnosis and functional assessment of ganglion cell loss (251, 252, 253 and 254).

Figure 4.8 A: Histologic section (PAS) of the optic nerve in a nonglaucomatous eye. The lamina cribrosa is indicated. B: Histologic section of the optic nerve in a glaucomatous eye. Compared with A, the lamina cribrosa is thinner and bowed posteriorly. Note the reduction in distance between the subarachnoid space, containing cerebrospinal fluid, and the laminar tissues. (Reproduced from Jonas JB, Berenshtein E, Holbach L. Anatomic relationship between lamina cribrosa, intraocular space, and cerebrospinal fluid space. Invest Ophthalmol Vis Sci. 2003;44:5189-5195, with permission.) Comparison with Nonglaucomatous Optic Atrophy

Studies of other ocular disorders provide some indirect insight into the possible mechanism of glaucomatous optic atrophy. For example, a histopathologic study of severe peripapillary choroidal atrophy revealed a normal optic nerve head, suggesting that the vascular supply of these two structures may be independent (255). Studies of nonglaucomatous optic atrophy have been used both to support and to refute an ischemic basis for glaucomatous optic atrophy. In patients with anterior ischemic optic neuropathy, cupping similar to that seen in glaucoma is frequently observed when the ischemia is due to

giant cell arteritis, but it is less common in nonarteritic cases (256, 257 and 258). These observations have led to the suggestion that glaucoma and anterior ischemic optic neuropathy have the same vasogenic basis of optic nerve damage, but differ according to the rate of change (256). It has also been suggested that acute ischemic optic neuropathy may be one of several mechanisms of optic nerve disease in chronic glaucoma (259). If this is true, the difference in visual field loss suggests that there is also a difference in the nature or distribution of the ischemia (258). In addition, the pattern of optic nerve fiber loss in nonarteritic anterior ischemia optic neuropathy involves primarily the superior half of the nerve and is unlike that found in glaucoma (260).

In contrast to the studies already described, a review of 170 eyes with nonglaucomatous optic atrophy of various etiologies revealed a small but significant increase in cupping (261). However, the cups were morphologically different from those seen in glaucoma, which was suggested as evidence against a vascular etiology in glaucomatous cupping. Furthermore, a study of 18 patients with vasogenic shock and poor peripheral tissue perfusion revealed no evidence of glaucomatous optic nerve head or visual field change (262).

Cavernous atrophy of the optic nerve, as originally described by Schnabel (108), has been considered to be a form of glaucomatous optic atrophy caused by severe elevations of IOP. However, this also occurs in patients with normal pressures, in which case it may represent an aging change associated with generalized arteriosclerosis and a chronic vascular occlusive disease of the proximal optic nerve (263, 264).

Conclusions Regarding Pathophysiology

The present evidence suggests that obstruction to axoplasmic flow may be involved in the pathogenesis of glaucomatous optic atrophy. However, it is still unclear whether mechanical or vascular factors are primarily responsible for this obstruction, or whether other alterations are also important in the ultimate loss of axons. All of these factors may be involved to some degree, or there may be more than one mechanism of optic atrophy in eyes with glaucoma (197, 265). For example, the observed differences in glaucomatous visual field defects between patients with low-tension and high-tension glaucomas have led to the suggestion that ischemia may be the predominant factor in those glaucomas at the lower end of the IOP scale, whereas a more direct mechanical effect of the pressure may prevail in cases with higher IOP (266).

CLINICAL APPEARANCE OF OPTIC NERVE HEAD

While investigators continue to study the pathophysiology of glaucomatous optic atrophy, the practicing physician has a responsibility to become thoroughly familiar with the clinical morphology of this condition, because it provides the most reliable early evidence of damage in glaucoma.

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Figure 4.9 Normal optic nerve heads. A: Note that size of cups is symmetric between the two eyes and that neural rims are even for 360 degrees. C, cup; CM, cup margin; DM, disc margin; K, kinking of vessels at cup margin; NR, neural rim; RV, retinal vessels. B: Fundus photo of a normal right eye. C, approximation of the cup; NR, neural rim.

Morphology of the Normal Optic Nerve Head

To recognize pathologic alterations of the optic nerve head, one must first be familiar with the wide range of normal variations.

General Features

The ophthalmoscopic appearance of the optic nerve head is generally that of a vertical oval, although there is considerable variation in size and shape. Clinical studies have revealed a greater than sixfold difference in the area of normal nerve heads (267, 268), which is consistent with histologic studies cited earlier (2, 3 and 4). The central portion of the disc usually contains a depression, the cup, and an area of pallor, which represents a partial or complete absence of axons, with exposure of the lamina cribrosa. Although the size and location of cup and pallor are normally the same, this is not always the case, especially in disease states (121), and these two parameters should not be thought of as being synonymous. The tissue between the cup and disc margins is referred to as the neural rim. It represents the location of the bulk of the axons and normally has an orange-red color because of the associated capillaries. Retinal vessels ride up the nasal wall of the cup, often kinking at the cup margin before crossing the neural rim to the retina (Fig. 4.9).

Physiologic Neural Rim

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By tradition, more is said about the cup than the neural rim of normal and glaucomatous optic nerve heads. However, it is actually alterations in the neural rim of an eye with glaucoma that lead to changes in the cup and to loss of visual field. The cup-to-disc ratio is only an indirect measure of the amount of neural tissue in the optic nerve head and may be misleading, because a larger diameter of the nerve head may be associated with a thinner neural rim width and larger cup size despite a stable number of axons (269, 270). It is important, therefore, to pay close attention to the appearance of the neural rim.

The neural rim of the normal optic nerve head is typically broadest in the inferior quadrant, followed by the superior

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and then the nasal rims, with the temporal rim being the thinnest (267). Several studies have attempted to correlate the area of the neural rim with that of the disc, and there is general agreement that the two are positively correlated—that is, larger discs hav e larger neural rim areas (267, 271, 272 and 273).

However, the contour of the cup influences this correlation, in that the relative rim area is typically larger in discs with flat temporal sloping than in those with circular steep cups (273). The increase in neural rim area with increasing disc area appears to be due, at least in part, to a greater number of ganglion cell axons (4).

Figure 4.10 Gray crescents in the optic nerve head of a patient with large physiologic cups. The thin crescent is seen just inside the scleral lip in the temporal quadrant of the right eye (A) and the inferotemporal quadrant of the left (B).

Several factors can interfere with the interpretation of the neural rim width. A gray crescent in the optic nerve head has been described, which typically is slate gray and located in the temporal or inferotemporal periphery of the neural rim (274). It is more common in blacks and apparently represents a variation of the normal anatomy. However, mistaking the gray crescent for a peripapillary pigmented crescent could result in the physiologic neural rim's being misinterpreted as pathologically thin in that area (Fig. 4.10).

Figure 4.11 Oblique insertion of optic nerve heads in myopic eyes can obfuscate the interpretation of the neuroretinal rim and creates a wide temporal peripapillary crescent. In this case, the asymmetry and loss of the superonasal rim of the right eye corresponds to glaucomatous damage.

Another source of error in interpreting the neural rim is the optic nerve head in myopia, in which the oblique insertion of the nerve may lead to distortion of the temporal neural rim from ophthalmoscopic view, suggesting pathologic thinning of this tissue (Fig. 4.11). Other features of highly myopic discs that may interfere with interpretation include a relatively large disc area; a shallower-than-usual cup, which may mask the deepening of the cup in glaucoma; and a temporal peripapillary crescent, which may be confused with peripapillary pigmentary changes that are seen more frequently around some glaucomatous discs (275).

The rim area appears to decline with age and with increasing IOP (276, 277). It has also been observed that patients with diabetes mellitus may have an increase in the neural rim over time, which could be due to nerve swelling (278).

Physiologic Peripapillary Retina Retinal Nerve Fiber Layer

Striations in the RNFL are normally seen ophthalmoscopically as light reflexes from bundles of nerve fibers (62, 279) (Fig. 4.1).

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They are visible only after the bundles reach a critical thickness and are consequently seen best in the posterior pole and peripapillary regions, especially at the vertical poles of the disc and extending temporally from them (280). Under white light, the nerve fiber layer appears as a whitish haze over the retina and retinal vessels. In one large study, the RNFL was most visible in the inferior temporal arcade, followed by the superior temporal arcade, then the temporal macular area, and finally the nasal area (281). The nerve fiber layer has been noted to decrease with age (104, 281). The visibility of the nerve fiber layer has been shown to correlate with the width of the neural rim and the caliber of the retinal artery (282). The relative height of the nerve fiber layer, especially when combined with visual field mean defect, has been shown to discriminate best between glaucomatous and nonglaucomatous eyes (283).

Peripapillary Pigmentary Variations

The normal optic nerve head may be surrounded by zones that vary in width, circumference, and pigmentation. A clinicopathologic study has revealed several clinical configurations with anatomic correlations (284, 285). A scleral lip, which appears commonly as a thin, even, white rim that marks the

disc margin, usually for the full 360 degrees, represents an anterior extension of sclera between the choroid and optic nerve head. A chorioscleral crescent, also called zone beta (Fig. 4.12), is a broader but more irregular and incomplete area of depigmentation, which represents a retraction of retinal pigment epithelium from the disc margin, often associated with a thinning or absence of choroid next to the disc, with exposure of the sclera. It is commonly seen with a tilted scleral canal, as in myopia. Large zone beta area-to-disc area ratio was found to be associated with an increased risk for glaucomatous damage in patients with ocular hypertension (286). A peripapillary crescent of increased pigmentation has been called zone alpha and may represent a malposition of the embryonic fold with a double layer or irregularity of retinal pigment epithelium. It may be peripheral to zone beta or may be adjacent to the disc if the zone beta is absent.

Figure 4.12 Zones of the optic nerve head and peripapillary pigmentation. 1. Cup. 2. Neuroretinal rim. 3. Scleral lip. 4. Zone beta. 5. Zone alpha.

Physiologic Cup Size

The size of the optic nerve head cup, which is commonly described as the horizontal and vertical cup-to- disc ratio, varies considerably in the normal population, possibly because of normal variation in disc diameter (4). Reports of cup-to-disc ratio distribution in the general population differ according to the