Susan B. Bressler,
Diana V. Do,
Neil M. Bressler
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in individuals age 55 and older.[1] AMD may be classified into a neovascular (exudative) form (discussed in Chapter 146) and a non-neovascular (nonexudative) form. The non-neovascular form features drusen and abnormalities of the retinal pigment epithelium (RPE), such as geographic atrophy (GA), nongeographic areas of atrophy, and focal areas of hyperpigmentation within the macula. Clinical features, clinicopathologic correlation, differential diagnosis, natural course, and treatment of the non-neovascular form of AMD are reviewed in this chapter. (The epidemiology of AMD is discussed in Chapter 38.)
CLINICAL FEATURES AND CLINICOPATHOLOGIC CORRELATION
DRUSEN
Multiple small, yellow-white lesions located within Bruch's membrane in the macula, commonly found in patients older than 50 years, are called drusen. The term drusen is German and is the plural for geode, a nodular stone with an interior cavity lined with crystals.[2] The relationship of drusen to AMD may be somewhat confusing as drusen may vary greatly in appearance and several types of yellow-white lesions may be seen at the level of the RPE within the macula. These lesions may be conveniently categorized into (1) small, hard drusen; (2) large, soft drusen; and (3) cuticular (basal laminar) drusen. Large, soft drusen, identified within two disc diameters of the foveal center, are the form of drusen most commonly considered to be a feature of AMD.
Small, Hard Drusen
Small drusen have been defined in most studies as having a greatest linear dimension of less than 50 ?m[3,4] or less than 63 ?m in diameter (Fig. 144.1).[5-7] The latter definition has been adopted, internationally, as the standard and was incorporated into the Age-Related Eye Disease Study (AREDS) classification of AMD.[8,9] The borders of small drusen are almost always distinct and well defined, contributing to the designation of hard drusen.[3,4]
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FIGURE 144.1 Hard drusen usually appear clinically as small yellow punctate lesions at the level of the retinal pigment epithelium (RPE) with sharp discrete borders. These changes have been shown to correspond to lipoid degeneration of a few discrete RPE cells without evidence of diffuse thickening of the inner aspect of Bruch's membrane throughout the macula. |
The fluorescein angiographic characteristics of drusen can vary depending on their size, content, and RPE depigmentation on their surface. Small drusen may appear as well-defined focal spots of hyperfluorescence within the first few minutes of the angiogram.[10] In the late frames these minute spots frequently fade. Fluorescein angiography may also reveal the presence of many more drusen than are apparent on slit-lamp biomicroscopy. Indocyanine green angiography (ICG) of drusen has demonstrated several patterns of fluorescence. Drusen may appear hyperfluorescent (brighter than the background fluorescence), hypofluorescent (darker than the background fluorescence), or isofluorescent (unable to be distinguished from the background fluorescence).[11] In a case series of 180 consecutive eyes, small, hard drusen appeared as isofluorescent spots that were difficult to discern from the background fluorescence.[11]
Small, hard drusen are not sufficient to diagnose AMD for the following reasons:
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The presence of at least one small drusen in the macula is nearly ubiquitous on fundus photographs[3,6] and postmortem examination[12] in individuals older than 40 years. |
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The incidence of small, hard drusen is not age-related.[13] |
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The presence of small drusen is not associated with an increased risk of the development of the neovascular form of AMD when compared with the risk associated with large, soft drusen.[4,14,15] |
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Clinicopathologic correlation demonstrates that these small lesions represent either a lipidization of a few RPE cells[16] or a localized accumulation (nodule) of hyaline material in the inner collagenous zone of Bruch's membrane,[16] which can be otherwise totally normal on either side of this nodule. The presence of these localized accumulations in an otherwise normal Bruch's membrane makes it unlikely that these small, hard drusen are a feature of a diffusely dysfunctioning RPE-Bruch's membrane-choriocapillaris complex. |
However, many small drusen may be a precursor lesion for the development of AMD, as the Chesapeake Bay Waterman Study and the Beaver Dam Eye Study have each found that eyes with numerous small, hard drusen are at increased risk of developing soft or large drusen over time.[13,17] The AREDS also reported that roughly one-third of eyes with extensive small drusen progress to extensive numbers of medium size drusen or develop large drusen within 5 years; thus the presence of many small drusen do increase the chances in the long run that an eye may develop more substantial evidence of AMD.[15]
Large, Soft Drusen
Large drusen have been defined in most studies as having a dimension that is greater than or equal to 63 ?m.[5-8] The borders of large drusen are generally poorly demarcated, without sharp edges,[3,5,8]contributing to the designation of soft drusen. Soft drusen are typically indistinct (Fig. 44.2a) meaning the density of the deposit decreases from center to periphery and the edges are fuzzy. In contast, some large drusen may be considered soft distinct drusen as they have a solid appearance with distinct edges, appreciable thickness, and a more uniform pigment distribution.
Large drusen vary in size, shape, and degree of confluence (merging of their borders) with neighboring drusen. Sizes of 'large' drusen have more recently been classified into 64 to >125 ?m (medium), 125 to >250 ?m (large), and ?250 ?m (very large). Histologically, three types of soft drusen have been identified:
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localized detachments of RPE and basal linear deposit (diffuse drusen) in eyes with diffuse basal linear deposits, |
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localized detachments of RPE and basal laminar deposit in eyes with diffuse basal laminar deposits, and |
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localized RPE detachments due to focal accumulation of basal linear deposit in eyes without diffuse basal linear deposits.[18,19] |
Basal linear deposit, also known as diffuse drusen or diffuse thickening of the inner aspect of Bruch's membrane, lies external to the RPE basement membrane or within the inner collagenous zone of Bruch's membrane, in contrast to basal laminar deposit, which is situated between the plasma membrane and the basement membrane of the RPE. These deposits also differ in their ultrastructural characteristics. Basal linear deposits consist of granular and vesicular lipid-rich material and may contain widely spaced collagen, whereas basal laminar deposits consist mainly of widely spaced collagen.[20] Clinically, one cannot detect the diffuse thickening of the inner aspect of Bruch's membrane associated with basal linear or basal laminar deposit; however, when there are areas of RPE hypopigmentation overlying this diffusely thickened Bruch's membrane or when this diffuse thickening weakens the inner aspect of Bruch's membrane and predisposes it to separation, or both, one recognizes these areas clinically as soft drusen (Fig. 144.2b).
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FIGURE 144.2 (a) Soft drusen are seen clinically as large yellow lesions with amorphous, ill-defined borders (arrow) at the level of the RPE. (b) It is suspected that the soft drusen noted clinically usually correspond to areas of diffuse thickening of the inner aspect of Bruch's membrane at the point at which focal areas of RPE hypopigmentation have developed in areas overlying this diffuse thickening or at the point at which fracturing of the diffusely thickened inner aspect of Bruch's membrane has separated from the remaining outer aspect of Bruch's membrane. (c) and (d) It is suspected that drusen may stain more intensely (arrows) in the late phases of the angiogram when this fracturing is present, presumably because the fluorescein molecules collect between the detached inner aspect and the remainder of Bruch's membrane. |
Clinically, soft drusen are believed to be a feature of nonneovascular AMD for the following reasons:
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The incidence and prevalence of soft drusen have been shown to be age related among many different population-based studies both nationally and abroad.[3,6,13,17,21-25] |
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Soft drusen are associated with an increased risk of development of RPE abnormalities,[13] GA,[13,15] and choroidal neovascularization (CNV).[4,13-15,25,26] |
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Clinicopathologic correlation demonstrates that the presence of soft drusen represents diffuse thickening of the inner aspect of Bruch's membrane throughout the macula.[27,18] |
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In the neovascular form of AMD (see Chapter 146) pathologic features, including CNV or disciform scarring, are usually noted in eyes that also have diffuse thickening of the inner aspect of Bruch's membrane throughout the macular region.[27,18-20] |
During fluorescein angiography staining of drusen (Fig. 144.2c and 144.2d) may be noted in areas in which overlying RPE hypopigmentation allows increased visualization of choroidal fluorescence or in areas in which fracturing of this diffuse thickening provides a space for fluorescein molecules to pool (Fig. 144.2d). Some investigators have suggested that the hydrophobic or hydrophilic properties of drusen, determined by their lipid composition, may account for hypo- or hyperfluorescence, respectively.[28] However, this latter theory does not as yet have direct fluoroangiographic-pathologic correlation. Indocyanine green imaging of soft large drusen (?125 ?m) with indistinct margins may demonstrate hypofluorescent spots with a thin hyperfluorescent margin on the outside border of the drusen in the early phase which persists in the late phase.[11] The thin hyperfluorescent margin may represent localization of indocyanine green to the periphery of the drusen with poor penetration into the substance of the drusen.
More recently, drusen have been imaged by optical coherence tomography (OCT) and morphologic changes may be present at the level of the external highly reflective band that represents the RPE/Bruch's membrane/choriocapillaris complex.[29] In eyes with soft, large drusen, OCT may demonstrate irregularity in the contour of the external highly reflective band consistent with accumulation of material within or beneath Bruch's membrane. In eyes with drusenoid pigment epithelial detachments, a term generally used to describe a confluent mound of large drusen, OCT shows focal elevation of the external highly reflective band with moderately reflective material underneath this band.
ABNORMALITIES OF THE RPE
The development of diffuse thickening of the inner aspect of Bruch's membrane associated with the clinical recognition of soft drusen may also be accompanied by abnormalities of the RPE. These abnormalities include GA of the RPE, non-GA of the RPE (also known as RPE depigmentation), focal hyperpigmentation, and dystrophic calcification of Bruch's membrane.
Geographic Atrophy of the RPE
GA of the RPE (also called areolar atrophy) consists of one to several areas, usually 175 ?m or larger in diameter and circular, of discrete absence or attenuation (depigmentation) of the RPE overlying choriocapillaris atrophy such that larger-caliber choroidal vessels may be seen (Fig. 44.3a). The neurosensory retina overlying GA may appear thinned. GA represents the most advanced form of nonneovascular AMD. Although it is far less common than other manifestations of nonneovascular AMD, when it involves the foveal center it accounts for 12-21% of the cases of legal blindness attributed to AMD.[30-32] Both the incidence and the prevalence of GA are age-related.[1,6,13,21,22] After the age of 70 prevalence of this nonneovascular AMD feature rises sharply.
Clinically, four patterns have been suggested to lead to GA in eyes that are presumed to have AMD:
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Areas of large, soft, confluent drusen may regress and lead to GA in multiple areas. These multifocal areas eventually enlarge and coalesce with other similarly derived areas and forms a ring around the fovea. |
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Alternatively, the central macula may contain tiny areas of reticulated hypo- and hyperpigmentation, which may progress to one large area of GA that spreads fairly contiguously in a horseshoe pattern around the fovea, eventually completely surrounding it leading to a bull's-eye maculopathy. After many years, doughnut-shaped areas of GA finally spread to include the foveal center. |
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Spontaneous flattening of a serous pigment epithelial detachment can also give rise to GA. |
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Lastly, resorption of drusenoid pigment epithelial detachments, can evolve to GA.[33] Drusenoid pigment epithelial detachments (PEDs) may be defined as elevated mounds of large drusen or many confluent drusen that have coalesced. These lesions have well-defined borders, are pale yellow to white in color, and have a minimum diameter of 360 microns. Nearly half of the 139 eyes monitored within AREDS that had drusenoid PEDs at or shortly after study entry developed central GA during follow-up of up to 9 years. |
Clinicopathologic correlation has shown replacement of soft drusen with fibrous tissue or dystrophic calcification.[34] The RPE overlying these areas ultimately disappears, producing small areas of GA. The underlying choriocapillaris may be sclerosed, with thickening of the intercapillary septae.[27] The areas of GA are usually accompanied by loss of overlying photoreceptors, accounting for the visual loss that is noted using scanning laser ophthalmoscopy over these regions. Dystrophic calcification may accompany GA and appears clinically as glistening, bright yellow specks within drusen that are undergoing atrophy (Fig. 144.3b), contributing to the term calcified drusen.
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FIGURE 144.3 Abnormalities of the RPE secondary to age-related macular degeneration. (a) An area of GA, with well-demarcated loss of pigmentation of the RPE and overlying thinning of the sensory retina with more apparent underlying choroidal vasculature. (b) Calcified drusen that correspond histologically to dystrophic calcification at the level of the outer retina. (c) Focal hyperpigmentation or pigment clumps correspond to clumps of pigment at the level of the RPE or within the outer aspects of the sensory retina. (d) Non-GA refers to a finding of tiny mottled areas of hypo- and hyperpigmentation that may show some thinning of the overlying sensory retina. |
Angiography of GA demonstrates early and discrete hyperfluorescence of atrophic areas, presumably resulting from increased transmission of choroidal fluorescence because of hypopigmentation, attenuation, or lack of RPE. The choriocapillaris may fill slowly or may be entirely absent within these zones, and the size and shape of these areas do not change during the study. In the late frames, persistent staining of the areas of GA will be noted, owing to increased visibility of the fluorescein staining of the choroidal and scleral tissue through the atrophic RPE. OCT imaging of GA demonstrates disruption, attenuation, or absence of the RPE/Bruch's membrane complex with variable thinning of the overlying neurosensory retina due to loss of photoreceptors.[29] In addition, areas of GA have a highly reflective signal from the choroid corresponding to enhanced penetration and reflection of the signal from the choroid due to attenuation of the RPE/Bruch's membrane/choriocapillaris complex (Fig. 144.4).
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FIGURE 144.4 (a) Fundus photograph of GA that involves the center of the fovea and (b) corresponding optical coherence tomography demonstrates a highly reflective signal from the choroid corresponding to enhanced penetration and reflection of the signal from the choroid due to attenuation of the RPE/Bruch's membrane/chorio-capillaris complex. |
Focal Hyperpigmentation
Focal hyperpigmentation of the RPE consists of areas or clumps of increased gray or black pigmentation at the level of the outer retina or subretinal space (Fig. 44.3c). It may be punctate, linear, or reticular. During fluorescein angiography, areas of focal hyperpigmentation block background choroidal fluorescence.
The incidence and prevalence rates of focal hyperpigmentation increase with age,[6,13,17,21-23] and eyes with soft or large drusen are more likely to develop increased retinal pigment than eyes with no drusen or small drusen.[13] Clinical studies have shown that eyes with focal clumps of hyperpigmentation identified on color fundus photographs have an increased risk of development of soft drusen,[13] GA,[13] and CNV.[4,14,35,36] Some investigators hypothesized that areas of focal hyperpigmentation may be associated with an increased risk of CNV because the areas of hyperpigmentation represent disturbances of the RPE overlying existing occult CNV.[37] However, clinicopathologic correlation has shown that the areas of focal pigment can correlate with areas of subretinal or intraretinal pigment migration to the level of the photoreceptor nuclei, overlying diffuse thickening of the inner aspect of Bruch's membrane without evidence of CNV.[19]
Nongeographic Atrophy
Non-GA of the RPE (also known as RPE degeneration or RPE depigmentation) consists of areas of stippled, punctate hypopigmentation and pigment mottling in which the underlying choroidal vessels are not more readily apparent than in areas without non-GA, but in which the overlying sensory retina appears to be thinned on stereoscopic examination (Fig. 144.3d).3 In comparison to GA, areas of nongeographic atophy are less well defined, less regular in shape, and less severe. Fluorescein angiography of these areas reveals diffuse hyperfluorescence with a pattern of reticular or punctate blockage corresponding to the pigment clumping. Clinicopathologic correlation has shown mottled areas of relative RPE hypopigmentation or atrophy overlying diffuse basal linear and basal laminar deposit.[19] These areas are similar to the pathologic correlate of large, soft drusen identified clinically, except the areas of non-GA have minute foci of hypopigmentation often interspersed with clumps of hyperpigmentation, whereas clinically apparent soft drusen have broader areas of RPE hypopigmentation, but often do not have clumps of hyperpigmentation within the drusen.
Incidence and prevalence rates of this AMD feature are also age dependent[6,13,22,23] and eyes with large drusen are more likely to develop this characteristic than eyes without large drusen.[13] Similarly, eyes with non-GA are more likely to develop other features of AMD including soft drusen,[13] GA,[13,38] and CNV.[13,38]
GRADING DRUSEN AND RPE ABNORMALITIES AND FORMING CLINICALLY RELEVANT CLASSIFICATION OF AMD
The Age-Related Eye Disease Study (AREDS), a prospective multicenter randomized clinical trial involving 4757 participants designed to evaluate the effects of high-dose vitamin and mineral supplements on the development and progression of AMD, has also supplied a wealth of natural history information about AMD.[9,15,38] Features of nonneovascular AMD that impart a greater degree of risk of progression of AMD have been clearly identified by performing detailed evaluation of baseline stereoscopic color fundus photographs of the macula and monitoring patients annually with sequential color fundus photographs to document clinically relevant outcomes of advanced AMD such as foveal GA or CNV.
The AREDS system for classifying age-related macular degeneration was based on reasonable quality film based stereoscopic color fundus photographs of the disc (field 1) and macula (field 2) of each eye of study participants.[9] A standard grid template adapted from the Early Treatment Diabetic Retinopathy Study composed of three circles concentric with the center of the macula was used to identify the area of interest.[39] All features of AMD found within the outer circle were recorded. The outer circle has a radius of 3000-3600 ?m (two disc diameters using 1500-1800 ?m for the standard disc). An additional standard template which consisted of a set of graduated circles was used to estimate maximum drusen size, maximum area occupied by drusen, and total area involved by pigment abnormalities. Figure 144.5 illustrates the grading grid and the graduated measurement circles with their corresponding diameters.
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FIGURE 144.5 (a) Maculopathy grading grid used in the Age-Related Eye Disease Study. The grid is affixed to a fundus photograph of a left eye to illustrate the three circles concentric with the center of the fovea and four radial lines in the 1:30, 4:30, 7:30, and 10:30 meridians. The radius of the inner circle corresponds to 1/3 disc diameter (500 ?m), the radius of the middle circle to 1 disc diameter (1500 ?m), and the radius of the outer circle to 2 disc diameters (3000 ?m). (b) A set of standard measurement circles for estimating the area involved by various abnormalities. Three groups of open circles are available and designated C for central, I for inner, and O for outer subfields. For each subfield, circle 1 corresponds to 1/64 of the subfield area and circle 2 to 1/16 of the area. |
The detailed AREDS system for classifying AMD features was found to have good reproducibility with kappa statistics ranging from 0.54 to 0.88; however, this system was dependent on photographs with at least fair quality read by trained and experienced readers.[38] A simpler grading method to anticipate risk of developing advanced AMD was also developed for use in clinical practice (see section on Data from Cohorts of Participants with Bilateral Non-Neovascular AMD and Progression to CNV or Foveal GA).[40] Nevertheless, the AREDS system for grading non-neovascular AMD features has led to a simple classification of AMD that can be easily adapted for clinical practice by estimating the number of drusen of a particular size and the presence, type, and location of pigment abnormalities.
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Age-Related Eye Disease Study Simplified Severity Scale
Scoring System Assess whether large drusen and pigment abnormalities are present in each eye and add the number of risk factors. The number of risk factors correlates with the patient's estimated risk of progression to advanced AMD in five years. |
AREDS has provided the following clinical classification which can be used to describe adults at risk for AMD or vision loss from AMD:[9]
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No AMD. Absence of any drusen or presence of a few small drusen (>63 ?m diameter drusen occupying >125 ?m diameter circle [equivalent to 5-15 small drusen]) in the absence of any RPE abnormalities or any later stages of AMD. |
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Early AMD. Extensive small drusen (occupies at least 125 ?m diameter circle), or nonextensive medium size drusen (63 to >125 ?m diameter drusen) with or without pigment abnormalities (increased pigment or depigmentation) and no other later stages of AMD. |
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Intermediate AMD. Extensive medium drusen (occupying an area of at least 360 ?m diameter circle, which is equivalent to 20 drusen) if the boundaries are indistinct or occupying an area of 656 ?m diameter circle (equivalent to 65 drusen) if the boundaries are distinct or at least one large druse (?125 ?m, approximately the width of a retinal vein as it crosses the optic nerve) or the presence of GA that spares the foveal center (nonfoveal GA). |
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Advanced AMD. Geographic atrophy involving the center of the fovea or CNV or disciform scar. |
DIFFERENTIAL DIAGNOSIS
A variety of maculopathies might be confused with the non-neovascular features of AMD, and they should be differentiated from drusen or abnormalities of the RPE. These other conditions often have a different prognosis from the non-neovascular features of AMD. A variety of factors, including demographic, morphologic features, and distribution of the fundus and angiographic changes, will help to differentiate these conditions from AMD.
CUTICULAR (BASAL LAMINAR) DRUSEN
Innumerable small, uniformly sized, discretely round, slightly raised, yellow subretinal lesions (Fig. 144.6a) that are best seen with angiography (Fig. 144.6b) and usually present in middle age (forties to sixties) are called cuticular (basal laminar) drusen.[41-43] They may be differentiated from more typical soft drusen in that retroillumination biomicroscopically demonstrates semitranslucency of innumerable similar-sized basal laminar drusen, as opposed to variable-sized, more typical soft drusen that appear opaquely yellow and are not semitranslucent. During fluorescein angiography, cuticular drusen will demonstrate early, bright, uniform hyperfluorescence compared with the variable, less bright hyperfluorescence of more typical soft drusen. With ICG angiography, basal laminar drusen may appear as hyperfluorescent spots early in the study which persist in the late phase of the angiogram.[11]
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FIGURE 144.6 Basal laminar or cuticular drusen. (a) Color photograph shows innumerable small, uniformly sized, discretely round, and slightly raised yellow subretinal lesions and dull yellow material in the central macula referred to as a pseudovitelliform detachment. (b) Angiogram helps highlight basal laminar drusen. In addition, hypofluorescence, presumably from the associated pseudovitelliform detachment, blocks the underlying fluorescence of the choriocapillaris. (c) Progressive staining of the pseudovitelliform detachment material becomes apparent in the middle- and late-transit phases of the angiogram. (d) With time, the pseudovitelliform detachment can clear spontaneously. Geographic atrophy will sometimes develop with clearing. |
The term basal laminar drusen should not be confused with the term basal laminar deposits, which refers to the wide-spaced collagen located between the plasma membrane and the basement membrane of the RPE, or the term basal linear deposits, which refers to the granular, electron-dense, lipid-rich material seen ultrastructurally external to the basement membrane of the RPE. In fact, the term basal linear deposits corresponds to the diffuse thickening of the inner aspect of Bruch's membrane, which was described previously as diffuse drusen. Clinicopathologic correlation has shown that cuticular drusen consist of an extremely thick inner aspect of Bruch's membrane with overlying nodular excrescences, all beneath the RPE. Since no cuticle exists, and to avoid the use of the confusing terms basal laminar and basal linear deposits, it has been proposed that the clinical features depicted in Figure 144.6, typical of cuticular or basal laminar drusen be called diffuse drusen with overlying nodular excrescences to more accurately describe what they are.
Patients with this unusual form of drusen may experience pseudovitelliform detachments consisting of yellowish material at the level of the outer retina. The material appears to obscure details of the RPE, suggesting that it is present between the sensory retina and the RPE. During fluorescein angiography, these detachments show early hypofluorescence (Fig. 144.6b), presumably because of the ability of the yellowish material to block the underlying fluorescence of the choriocapillaris. Progressive staining of the yellowish material becomes apparent in the middle- and late-transit phases of the angiogram (Fig. 144.6c), likely due to incompetence of the RPE's zonula occludens, which fails to keep fluorescein from diffusing from the choriocapillaris to the subsensory retinal space, with subsequent staining of the yellowish material. Pseudovitelliform detachments appear as a mound of highly reflective material under the neurosensory retina without any adjacent subretinal fluid on OCT imaging.[29] This highly reflective substance appears to be located between the retina and RPE.
Since the fluorescein hyperfluorescence of a vitelliform lesion may mimic CNV, one must recognize its appearance in order to avoid unnecessary delivery of treatment intended to manage CNV. The natural course of these detachments can be spontaneous clearing (Fig. 44.6d) with extremely slow development of atrophy or rapid clearing associated with marked GA.
These pseudovitelliform detachments should be differentiated from true vitelliform detachments seen in Best's disease (in which the electrooculogram will be abnormal) and from pattern dystrophies of the RPE that may show pseudovitelliform-like detachments.
Patients with basal laminar or cuticular drusen have a diseased Bruchs membrane and are at risk of development of CNV. Therefore, careful scrutiny of any bright hyperfluorescence that appears to leak in these patients is needed to determine whether the features are due to the presence of CNV or to progressive staining of the pseudovitelliform detachment. Sometimes this differentiation is extremely difficult to make.
DOMINANT DRUSEN IN YOUNG INDIVIDUALS
Patients in their teens or twenties may present with large (<63 ?m), discrete nodular drusen. Typically these drusen are bilateral and in a very symmetric distribution between the two eyes, such as temporal to the fovea. Even the young children of these individuals, those under age 10 years, may have discrete drusen (Fig. 144.7). In the experience of the authors, these patients may go years without CNV or atrophy developing and therefore suffer no significant visual loss. When these lesions are in the macula, they could presumably cause focal disturbances of Bruch's membrane and may increase the risk of the development of CNV but there are no natural history studies of this condition to date.
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FIGURE 144.7 Dominant drusen. (a) A young woman in her twenties demonstrates typical large drusen, some of which have discrete boundaries. Similar findings are noted in her 9-year-old son (b) and her 6-year-old son (c). |
PATTERN DYSTROPHY OF THE RPE (ADULT VITELLIFORM DYSTROPHY, ADULT-ONSET FOVEAL PIGMENT EPITHELIAL DYSTROPHY, BUTTERFLY-SHAPED PIGMENT DYSTROPHY, RETICULAR DYSTROPHY OF THE PIGMENT EPITHELIUM)
Patients with pattern dystrophy of the RPE will show a reticulated pattern of pigmentation, usually fairly symmetric between the two eyes and often without the presence of more typical soft drusen (Fig. 144.8).[44] These dystrophies may have a yellow deposit at the level of the outer retina (pseudovitelliform detachment), often with a central area of greenish hyperpigmentation (sometimes best seen with transillumination of the yellowish material), and occasionally surrounded by a petaloid pattern of hyperpigmentation, which is more obvious on fluorescein angiography (Fig. 144.8b). These lesions have been observed both within families and sporadically. Although, they are often located in the center of the macula, they may present eccentrically (Fig. 144.9), accounting for the variety of appearances on presentation. The pseudovitelliform detachments will not show disruption or layering of the yellow pigment dependently, as is seen in the vitelliform lesions of Best's disease.
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FIGURE 144.8 Pattern dystrophy of the RPE. (a) Typical pattern dystrophy in which blocked fluorescence on angiography corresponds to pigment clumping or greenish discoloration seen at the level of the RPE, surrounded by hyperfluorescence corresponding to dull yellowish material that has sometimes been termed a pseudovitelliform detachment. (b)The angiogram highlights not only the blocked fluorescence but also very prominent staining with persistent bright hyperfluorescence in the late phase of the angiogram, but no leakage. The absence of leakage helps confirm the absence of choroidal neovascularization. |
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FIGURE 144.9 Pattern dystrophy of the RPE in which the blocked fluorescence and hyperfluorescence occur in a multifocal distribution outside of the foveal center. |
Clinicopathologic correlation of pattern dystrophies of the RPE has shown a thick layer of slightly granular, eosinophilic, periodic acid-Schiff (PAS)-positive material lying between a thinned atrophic RPE and Bruch's membrane, with central pigment clumping from large pigment-laden cells and extracellular melanin pigment lying between the sensory retina and Bruch's membrane.[45] A recent (unpublished) clinicopathologic correlation of an eye with pattern dystrophy and pseudovitelliform lesion demonstrated lipofuscin at the outer retinal level to account for the yellow deposit. The diffuse disturbance of Bruch's membrane histologically presumably places these patients at increased risk of development of CNV through breaks in the outer aspect of Bruch's membrane.
More recently, OCT imaging and correlation with fluorescein angiographic features of eyes with pseudovitelliform lesions has provided additional morphologic information on the location of the yellow deposit. In sixteen eyes with adult-onset foveomacular vitelliform dystrophy, the yellow foveal lesion demonstrated early hypofluorescence on fluorescein angiography with staining and absence of leakage in the late frames.[46] Corresponding OCTs in these eyes revealed a hyperreflective structure located between the photoreceptors and RPE. The retina overlying the hyperreflective structure was raised by the pseudovitelliform lesion with subsequent loss of the normal foveal depression but the RPE layer was not elevated. In five eyes in which fluorescein angiography demonstrated persistent central hypofluorescence in the late frames corresponding to the yellow deposit, OCT revealed no hyperreflective structure between the photoreceptors and RPE layers. In these eyes, OCT demonstrated focal thickening of the hyperreflective RPE layer but no distinguishable substance between the RPE and retina. Further studies are needed to confirm these observations.
BULL'S-EYE MACULOPATHY
A variety of conditions may produce a bull's-eye maculopathy (usually referring to an area of central pigmentation of the retina surrounded circumferentially by an area of relative hypopigmentation and sometimes surrounded, once again circumferentially, by an area of increased pigmentation). This condition may progress to GA of the RPE, which typically is similar to the GA seen in AMD.[47] These conditions usually can be differentiated from GA associated with AMD. The bull's-eye maculopathies result in a central area of GA with no associated soft drusen, whereas GA in AMD is usually multifocal, with preservation of the fovea until the very late stages. In addition, the bull's-eye maculopathies occur in early or midlife, whereas GA is seen most often in patients in their late 70s and 80s, with increasing prevalence into the 90s. The causes of some of these maculopathies include central areolar choroidal-RPE dystrophy, the Bardet-Biedl syndrome, concentric annular macular dystrophy, chloroquine retinopathy, cone dystrophy, fenestrated sheen macular dystrophy, the Hallervorden-Spatz syndrome, and fundus flavimaculatus.
NATURAL COURSE
DRUSEN AND RPE ABNORMALITIES
The natural course of an eye with non-neovascular AMD may ultimately lead to foveal GA, CNV, or both forms of advanced AMD. The probability that an eye with non-neovascular AMD will progress to CNV depends on whether the fellow eye in that individual has non-neovascular AMD in the absence of CNV or disciform scarring or whether the eye with drusen or RPE abnormalities, or both, is the fellow eye of a person whose contralateral eye has already developed the neovascular form of AMD.
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Key Features |
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The Age-Related Eye Disease Study Clinical Classification of Age-Related Macular Degeneration (AMD)
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Data from Fellow Eye Studies and Progression to CNV
Prior to the AREDS much of the detailed information generated on the natural course of eyes with non-neovascular AMD had been acquired by studying the fellow eyes of patients with unilateral neovascular maculopathy that have participated in the Macular Photocoagulation Study (MPS) Trials. In these investigations, a standardized classification was used to grade macular characteristics on the baseline fundus photographs of the eyes with nonneovascular AMD. Fundus photograph readers had no knowledge of the subsequent course of these eyes. In the 5 year prospective study of fellow eyes of participants in the Extrafoveal AMD Trial of the MPS, eyes with no large drusen and no focal hyperpigmentation were at a 10% risk of developing CNV within 5 years.[4] Eyes with large drusen or focal hyperpigmentation had a 30% risk of developing CNV, and eyes with both large drusen and focal hyperpigmentation had about a 60% risk of acquiring CNV within 5 years.[4] Subsequent analyses on a larger number of fellow eyes, ? 670, among the individuals participating in the Juxtafoveal and Subfoveal AMD Trials of the MPS have confirmed the heightened risk associated with large drusen and have permitted more precise quantification of that risk. In these subsequent studies, fellow eyes with large drusen had a 46% chance of developing CNV, those with focal pigment had a 38% chance, and those eyes with both factors were at greatest risk with incidence rates of 73% at 5 years.[14] Systemic hypertension and numerous drusen (?5) were also found to be independent risk factors; an individual with hypertension, numerous and large drusen, and an area of pigment had an 87% risk of progressing to CNV within 5 years.[14] The development of severe visual loss in these fellow eyes with nonneovascular AMD at baseline occurred almost exclusively in the eyes in which CNV developed during follow-up. Among the fellow eyes that did not develop CNV, the average visual acuity loss over the 5 year follow-up period was only 0.4 lines.[48]
In 2001, the AREDS Group reported on the risk of progression to advanced AMD among individuals who were assigned to the placebo group.[15] The risk of progression to advanced AMD (CNV or foveal GA) within 5 years was 1.3% for individuals with early AMD, 18% for individuals with intermediate AMD, and 43% for the remaining eye among individuals with unilateral advanced AMD (fellow eyes). Among AREDS participants who had neovascular AMD in their first eye affected with advanced AMD about 37% progressed to neovascular AMD in their second eye during a mean follow-up period of 6.2 years. Three ocular risk factors (largest drusen size, total area occupied by drusen, and pigmentary abnormalities) were identified as imparting increased risk that a fellow eye would develop CNV. Logistic regression analysis adjusted for age, gender, and AREDS treatment assignment was used to predict development of CNV in the second eye. The strongest predictive factor for fellow eye CNV development was total drusen area, however, substitution of largest drusen size and presence of focal hyperpigment had nearly the same predictive value. Fellow eyes with only small drusen with or without focal pigment were at relatively low risk for CNV with rates of 5% over 5 years; whereas fellow eyes with very large drusen and pigment were at the highest risk of approximately 50% for incident CNV during follow-up.[49]Treatment with high-dose antioxidants and zinc resulted in an overall 25% risk reduction for development of advanced AMD in individuals who had intermediate or unilateral advanced AMD. The greatest absolute reduction in risk was identified among the fellow eyes of participants with unilateral advanced AMD.
Data from Cohorts of Participants with Bilateral Non-Neovascular AMD and Progression to CNV or Foveal GA
In addition to evaluating the use of micronutrient supplements for AMD, another goal of the AREDS was to develop an AMD severity scale that could provide baseline risk categories to track progression of AMD in an orderly fashion to approximate risks of progression to advanced AMD. Furthermore, development of a severity scale might aid in providing surrogate outcomes for advanced AMD. A nine-step severity scale was created that combines six progessive levels of total drusen area and five progressive levels of pigmentary abnormalities (increased pigment, depigmentation, and nonfoveal GA).[38] Five-year rates of progression to advanced AMD were as low as less than 1% in step 1 (eyes with minimal drusen area and absence of pigment abnormalities) of the scale to ?50% in step 9 (eyes with variable drusen area in the presence of nonfoveal GA) of the scale. The risk of neovascular AMD increased from steps 1 through 8 in the scale and then decreased in step 9. The risk of foveal GA was low from steps 1 through 5 and then increased steadily from steps 5 through 9, an area of the scale that is associated with a greater degree of pigmentary abnormalities. Additional AREDS analyses identified presence of calcified drusen as another independent risk factor for development of GA.[50]
Although this nine-step severity scale may have utility in a research setting this scale does not lend itself to use in clinical practice. Therefore, the AREDS Group developed a simplified scale for clinical use to predict risk for progression to advanced AMD. The simple scale was formulated on several observations made during the construct of the research severity scale, notably: (1) there was a strong association between drusen area and largest drusen size; (2) there was a very low frequency of RPE depigmentation and/or GA in the absence of increased pigment; and (3) bilateral large drusen is a stronger risk factor than unilateral large drusen. In the simplified scale, clinicians are asked to assess the presence of only two fundus characteristics: (1) large drusen and (2) pigmentary abnormalities (hyperpigmentation or hypopigmentation, or nonfoveal GA).[40] Each eye of a person is graded separately for (1) and (2) and for each factor present the eye receives a score of 1 (please refer to Key Features: Age-Related Eye Disease Study Simplified Severity Scale on page 5). For example, an individual with large drusen in the right eye and focal pigment in the left eye would generate a person score of 2, whereas the individual with bilateral large drusen and bilateral pigment abnormalities would have a person score of 4. The scale can be adapted for use in persons with unilateral advanced AMD by scoring the eye with advanced AMD as 2 and then continuing on to the contralateral eye to assess features (1) and (2). The range of person scores is 0-4. The 5 year risk for developing advanced AMD is 0.5% for individuals with a score of 0, 3% for a score of 1, 12% for a score of 2, 25% for a score of 3, and 50% for a score of 4. The AREDS simplified scale[40] and the nine-step severity scale[38] both confirm previous observations made in the MPS fellow eye studies: drusen size and pigmentary abnormalities are independent risk factors for progression to the advanced stage of AMD.
In addition to the MPS and AREDS, several large population-based studies have also described the evolution of non-neovascular AMD fundus manifestations. In the Beaver Dam Study, 7-12% of eyes with intermediate or large drusen demonstrated new areas of drusen (progression) and 10-33% had areas of drusen disappear (regression) over a 5 year period.[13] Eyes with RPE abnormalities also showed significant change over time with 32-39% developing additional areas of pigment and 28% demonstrating less involvement during the 5 year period.[13] The Chesapeake Bay Waterman follow-up study had also found drusen and RPE abnormalities to progress in some and spontaneously regress in others.[17] Regarding risk factors for progression, Beaver Dam eyes with large drusen (?125 ?m) were more likely to develop increased drusen area, confluence, focal hyperpigmentation, non-GA, GA, or neovascular AMD, than were eyes with smaller drusen.[13] Eyes with RPE abnormalities were more likely to develop soft drusen, increased drusen area, confluent drusen, GA, or neovascular AMD compared with eyes without pigmentary abnormalities.[13] Ten-year data from the Beaver Dam eye study also confirmed that eyes with soft indistinct drusen or pigmentary abnormalities at baseline were more likely to develop advanced AMD at follow-up than eyes without these lesions (15.1% vs 0.4% for soft indistinct drusen and 20% vs 0.8% for pigmentary abnormalities).[51] Therefore, characteristics of large drusen and pigmentary abnormalities appear to confer increased risk of developing more advanced AMD and vision loss, whether found in an individuals with bilateral nonneovascular disease or individuals with unilateral neovascular maculopathy. Furthermore, these observations have been made in prospective clinical trials and confirmed in population based studies.
The Blue Mountains Eye Study also explored the incidence of advanced AMD among a population based sample in Australia.[52] In this cohort, the 5 year incidence of developing neovascular AMD or GA (foveal or nonfoveal) was 1.1%. Several ocular risk factors were associated with progression to advanced AMD; among right eyes that had non-neovascular AMD at baseline, the following features conveyed risk: large drusen (?125 ?m, age-adjusted relative risk [RR] 5.7 [95% confidence interval (CI) 3.6-9.0]), indistinct soft drusen (RR 9.9 [95% CI 6.4-15.4]), location of drusen within 1500 ?m of the foveal center (RR 11.6 [95% CI 6.7-21.1]), area involved by large drusen equal to at least one half of the optic disc (RR 13.5 [95% CI 8.0-22.8]), and presence of hyperpigmentation (RR 8.0 [95% CI 5.4-11.9]). In addition, eyes classified as having AREDS category 3 (intermediate AMD) or 4 (unilateral advanced AMD) at baseline were 3.9 times (95% CI 2.3-6.7) more likely to develop advanced AMD over the 5 year period compared to eyes with category 1 or 2.
The Rotterdam Study, another population-based cohort performed in the Netherlands, also evaluated the incidence of advanced AMD. The 2 year cumulative incidence of advanced AMD (neovascular AMD or GA) was 0.2% among all study participants, although this incidence increased to 1.8% among participants 85 years of age and older.[53] Baseline fundus features that increased the odds that an eye would progress to advanced AMD included more than 10% of the macular area covered by drusen (odds ratio (OR) 5.7, 95% CI 2.9-11.3), presence of depigmentation (OR 4.0, 95% CI 2.5-6.4), presence of hyperpigmentation (OR 3.4, 95% CI 2.1-5.4), and ?10% drusen confluence (OR 2.5, 95% CI 1.7-3.8). Although the incidence of advanced AMD is quite low in this population given the limited 2 year follow-up, the results suggest again that drusen area and pigmentary abnormalities are important risk factors for progression to advanced stages of AMD.
More recently, the Copenhagen City Eye Study described the incidence and progression of many AMD features.[54] In this population-based cohort study, 359 persons of the original 946 subjects were able to participate in the 14 year follow-up examination. Older subjects at baseline were more apt to develop features of AMD at follow-up. Among subjects 75-80 years of age at baseline, medium size drusen were 1.8 times as likely to develop and large drusen were 3.5 times as likely to develop compared with subjects 60-64 years of age. In addition, the incidence of soft drusen increased significantly with age from 21.4% among persons aged 60-64 years to 45.2% among persons aged 75-80 years. Pigmentary abnormalities also increased with age such that persons aged 75-80 years were 1.8 times as likely to have hyperpigmentary abnormalities compared to persons aged 60-64 years. The risk of developing the advanced stage of AMD was strongly associated with the presence of soft indistinct drusen (OR 12.2, 95% CI 3.2-47.0), increased drusen size (63-124 ?m: OR 5.0, 95% CI 1.7-14.4; <125 ?m: OR 7.6, 95% CI 1.0-20.2).
NATURAL COURSE OF GEOGRAPHIC ATROPHY: DEVELOPMENT AND PROGRESSION
The natural progression of non-neovascular AMD fundus features to GA has been described in several population-based studies (as summarized above); however, additional information gathered from serial color fundus photographs from AREDS participants has provided greater detail on predisposing anatomic features and the sequence of events leading to the formation of GA. Among a cohort of 95 eyes from two AREDS clinical centers in which GA developed at least 4 years after their initial study evaluation (range 4-11 years), the following lesions were determined to have been present at the site of future GA formation: drusen 95/95 eyes (100%), large drusen (<125 mm) 91/95 eyes (95.8%), focal hyperpigmentation 91/95 eyes (95.8%), confluent drusen 89/95 eyes (93.7%), very large drusen (<250 ?m) 79/95 eyes (83.2%), hypopigmentation 77/95 eyes (81%), and calcification 20/57 eyes (35%).[33] The average interval from the time of appearance of these specific lesions to the development of GA was <6.5 years for drusen or confluent drusen, 4.0 years for hyperpigmentation, 2.3 years for hypopigmentation, and 1.5 years for calcification. Among this subset of AREDS participants, the sequence of events leading to GA appeared to be accumulation of very large, confluent drusen, followed by hyperpigmentation appearing at the site and then regression or fading of drusen with loss of hyperpigmentation leading to hypopigmentation and then formation of GA.
Several authors have concentrated on eyes that already manifest GA and monitored them prospectively to learn more about the natural course of this feature of non-neovascular AMD. Earlier studies have tried to learn similar information by identifying eyes with GA and evaluating case files retrospectively. One area of interest has been quantifying the rate of enlargement of the atrophic areas.[34,55,56] Schatz and McDonald retrospectively reviewed 50 eyes with GA; 40% had multifocal regions of GA to study.[55] The average greatest horizontal linear dimension of the GA was 509 ?m at presentation; although the range was 200-5300 ?m. This dimension expanded at an average rate of 139 ?m/yr (?1/10 of a disc diameter). Patients under age 75 years tended to progress faster than patients 75 years and over, but great variability was noted in both the magnitude and the direction of progression in the cases reviewed. Sarks and colleagues reported on a series of 208 eyes with GA.[34] They noted that GA tended to start outside the foveal center, and as the atrophy encroached within 750 ?m of the foveal center, it approached one disc diameter. Total involvement of the fovea occurred only in the later stages, such that the average affected area in eyes with complete GA of the fovea measured more than seven disc areas (DAs). Visual acuity was related to the percentage of fovea affected, but it varied widely, such that it was difficult to predict visual acuity within a narrow margin of certainty from the anatomic appearance of the atrophy alone. Nevertheless, central fixation tended to be lost when atrophy occupied 85% or more of the fovea.
Patients with GA often have bilateral and symmetric disease, although there may be differences in onset and progression rates between the two eyes.[34,55,56] One-half of the subjects in Sarks and colleagues' study had bilateral GA,[34] whereas 13% of the Beaver Dam population-based study participants with pure GA had bilateral involvement at baseline.[6] However, individuals with uniocular GA at baseline were at increased risk of developing GA in their fellow eye by the time of the 5 year follow-up examination. Among the 12 patients with uniocular GA at the initial examination, three (25%) developed GA during the 5 year follow-up. After 10 years of follow-up, individuals with uniocular GA at baseline were 6.3 times (95% CI 0.9-42.1) as likely to develop advanced AMD in the uninvolved, fellow eye as those individuals with early AMD in both eyes at baseline.
Sunness and coworkers prospectively followed 74 patients with bilateral GA and documented median total area of involvement of 4.4 DA at presentation (range 0.1-27.7 DA).[56] There was a strong correlation between the two eyes of a patient for the size of the atrophic area. The median rate of spread was 0.73 DA/yr, taking into account changes in all dimensions of an atrophic area. The median absolute difference in rates of progression between eyes of a patient was 0.38 DA/yr.
Central visual acuity loss may be gradual and progressive in eyes with GA, with the degree of impairment directly related to foveal involvement.[57] Since GA involves the foveal center late in the course of the disease, visual acuity is a poor guide to the extent of the atrophy or visual impairment a patient may have. In a study on 83 patients with bilateral GA, with a median visual acuity of 20/54 in the better-seeing eye, the majority reported difficulty reading, a need to use low-vision devices, difficulty seeing in a dim environment, trouble recognizing faces, and an awareness of a blurry area.[58] These symptoms remained frequent even in a subgroup of 39 patients with visual acuity better than 20/50 (median 20/35). Scanning laser ophthalmoscope testing demonstrated dense scotomas in all patients; therefore, GA-induced scotomas may have a significant impact on visual function even when they do not involve the foveal center.
Although GA-induced scotomas impair visual function, patients with GA often develop an eccentric retinal locus for fixation. A prospective natural history study of patients with central GA has demonstrated that 77% of eyes had an eccentric preferred retinal locus for fixation at baseline.[59] After a median follow-up period of 5.3 years, 91% of eyes had an eccentric preferred retinal locus for fixation with 81% of eyes retaining the baseline preferred retinal locus. The most common fixation patterns were fixation with the scotoma to the right and fixation with the scotoma superior. Eyes that fixated with the scotoma to the left tended to have lower reading rates (reading speed) than eyes that fixated with right or superior patterns.
The precise rate of visual acuity loss in patients with GA has recently been evaluated prospectively in 74 patients with visual acuity of 20/50 or better at presentation.[60] Rates of vision loss over a 2 year period are substantial, with 50% doubling their visual angle (a loss of three or more lines of acuity) and 25% quadrupling their visual angle (a loss of six or more lines of acuity). Furthermore, these patients presented with reduced reading speeds, and this visual function significantly deteriorated during the 2 year follow-up period as well. Therefore, all eyes with GA, even those with a parafoveal location, are at high risk of significant visual impairment within a few years of presentation.
Patients with GA report gradual progression of their vision loss, even when a more precipitous loss of visual acuity is documented between visits as an atrophic area enlarges and involves more of the foveal center. Generally, patients with GA will use central fixation if there is a small foveal region without atrophy and eccentric fixation when the fovea is totally involved. However, as the atrophy progressively encroaches on the foveal center, these patients may go through a transitional period in which they alternate between central and eccentric fixation, and this gradual transfer of the fixation focus may explain the lack of perception of a sudden alteration in acuity.[61] Alternatively, the explanation may lie within the nature of the residual central vision in eyes with preservation of small foveal islands. As the foveal island progressively decreases in size, the size of the central visual field gets progressively smaller, such that fewer words or facets of the visual image fit into the functional region, even though relatively good acuity with letters may be preserved. At the point at which the patient transfers fixation to an eccentric locus, the amount of useful functional central retina may not provide better vision than the eccentric region.
GA appears to act as a barrier for CNV, such that CNV does not begin within and rarely progresses through atrophic areas. However, CNV may occur contiguous to these regions and course along the external perimeter of the area. Since patients with progressive GA rarely complain of abrupt changes in visual acuity, any such change should prompt an investigation for the development of CNV. Forty-five to 49% of the fellow eyes with non-neovascular maculopathy and zones of GA at study entry into the MPS AMD trials of laser photocoagulation progress to CNV within 5 years.[14,48] Among 45 patients with unilateral GA and a fellow eye with neovascular maculopathy followed prospectively for natural history of GA, 23% developed CNV at the edge of GA within 2 years, whereas CNV did not develop in any of the 92 patients with bilateral GA during the same time interval, suggesting that patients with bilateral GA without evidence of CNV are at low risk for developing CNV.[62]
The development of subretinal hemorrhage in eyes with GA does not necessarily imply the presence of CNV. Nasrallah and associates reported on eight patients in whom small subretinal hemorrhage spontaneously cleared over a 15 month period without evidence of CNV at the time of the hemorrhage nor evidence of CNV or disciform scarring with clearing of the hemorrhage.[63] These subretinal hemorrhages may reflect rupture of normal choriocapillaris, as is seen in subretinal hemorrhages occurring in myopic patients with lacquer cracks in which CNV is not growing through the lacquer crack. However, fluorescein angiographic signs of active CNV in patients with extensive GA are often fairly subtle, such that careful scrutiny of these angiograms is needed, particularly with reference to previous studies, to determine whether or not CNV has developed.
MANAGEMENT
The risk of visual loss in eyes with drusen or pigment abnormalities results from the development of advanced AMD either in the form of CNV or foveal GA. Accordingly, management is aimed at preventing CNV or GA. There has been speculation that ultraviolet or visible light exposure may lead to the generation of reactive oxygen species in the outer retina,[64,65] which may in turn cause lipid peroxidation of photoreceptor outer segment membranes potentially contributing to the development of AMD. However, observational epidemiologic studies have failed to provide support for the theory that cumulative sunlight exposure is associated with AMD. No association was identified between cumulative ultraviolet or visible light exposure and the presence of non-neovascular AMD in the Chesapeake Bay Waterman Study.[66] However, there was a significantly higher exposure to blue light and all wavelengths in the visible spectrum within the 20 year period immediately preceding study participation among the eight participants with advanced AMD in the cohort when compared with age-matched control subjects.[67] The Eye Disorder Case-Control Study also failed to demonstrate any positive relationship between lifetime sunlight exposure and the presence of neovascular AMD.[68] A limited association between light and AMD was noted in the Beaver Dam population, with increased outdoor summertime exposure being associated with increased retinal pigment among male subjects and late AMD in male and female subjects.[69] Thus, the available data are inconsistent and inconclusive in regard to a relationship between light and AMD. Since the Waterman Study has shown that ultraviolet light is associated with lenticular opacities[70] and because sunglasses are inexpensive and associated with few side effects, it seems reasonable not to discourage their use.
Multiple epidemiologic studies have reported positive associations between cigarette smoking[71,72] and non-neovascular AMD, so possible prevention of AMD would seem to be yet another reason for physicians to recommend cessation of smoking. Although there are inconsistent data from epidemiologic studies with regard to an association between hypertension, cardiovascular disease, and increased cholesterol and saturated fat intake[31,68,73-75] and AMD, it would seem reasonable to recommend routine medical examinations with a generalist physician to monitor blood pressure, cholesterol levels, and treatable cardiovascular disease in this elderly population.
AMD has been identified as having a familial component based on clustering of the disease within multiple family members within different generations and greater concordance rates among monozygotic versus dizygotic twins.[76-78] These observations fuel the search to identify specific genetic components of AMD. Several investigators have identified a common variant (Y402H) of the complement factor H gene (CFH), located on chromosome 1q31, as a major AMD risk gene.[79-81] This finding further suggests that inflammation may play an important role in the pathogenesis of AMD as CFH is a component of the immune system. CFH helps to regulate the body's inflammatory response by protecting against uncontrolled complement activation, and the Y402H variant is located within the binding sites for heparin and C-reactive protein. In a retrospective case-control study, the CFH variant was associated with an increased risk of developing GA (OR 3.22, 95% CI 1.87-5.55) as well as neovascular AMD (OR 2.50, 95% CI 1.74-3.60) compared to controls with no AMD.[82] Further investigation is needed to determine how this gene variant may increase the risk of AMD. In time, this may lead to new screening strategies to identify individuals with greater risk for development or progression of AMD. Furthermore, identification of the role this gene variant may play in pathogenesis may open possibilities for new management strategies to prevent progression.
In a small pilot trial, oral zinc administration was associated with less vision loss in patients with non-neovascular AMD when followed for a period of up to 2 years.[83] However, a randomized prospective trial evaluating oral zinc administration versus placebo in decreasing vision loss and development of CNV in 112 patients at risk of neovascular AMD in their second eye did not find treatment to be beneficial.[84]Exploring the hypothesis that AMD may be caused by cumulative oxidative insults, cross-sectional and case-control epidemiologic investigations have evaluated blood antioxidant levels, dietary ingestion of antioxidant-containing food sources, and uses of micronutrient supplements.[73,85-88] These studies have suggested a small to moderate protective role of antioxidants on varying levels of AMD; however, the results for specific nutrients and specific AMD types have been inconsistent and therefore inconclusive. These types of studies also have several important limitations. Blood levels may reflect recent behaviors rather than general body stores, blood levels may not reflect tissue levels, dietary consumption histories may be imprecise, and the likely effects of uncontrolled confounding factors. A cause-and-effect relationship between antioxidants and AMD cannot be concluded from these investigations. Therefore, the AREDS was designed to prospectively evaluate the use of antioxidants and zinc in individuals at risk of developing advanced AMD.
The AREDS Group conducted a prospective multicenter clinical trial to evaluate the effect of daily supplementation with high-dose anti-oxidant vitamins and zinc supplements on the development of advanced AMD.[15] A total of 3640 subjects were randomized to one of four treatment groups in a double masked fashion: (1) antioxidants (500 mg vitamin C, 400 IU vitamin E, 15 mg beta carotene), (2) zinc (80 mg zinc oxide and 2 mg cupric oxide to prevent potential anemia), (3) combination of antioxidants and zinc, or (4) placebo. Results from the AREDS demonstrate that the combination supplements (anti-oxidants plus zinc) result in a 25% risk reduction for development of advanced AMD in individuals at risk of progression and a 21% risk reduction in rates of moderate vision loss (doubling of the visual angle). Individuals at risk of progression are those with intermediate AMD or unilateral advanced AMD with a fellow eye at risk. Individuals with early AMD did not benefit from micronutrient supplementation. Therefore, individuals should consider taking an antioxidant and zinc supplement such as that used in AREDS only if they meet the AREDS classification of intermediate AMD or unilateral advanced AMD. Potential risks associated with this daily supplementation are small and include a mild increase in genitourinary hospitalizations in participants taking zinc (7.5% in the zinc group vs 4.9% in the placebo group) and a change in skin color (8.3% in the antioxidant group vs 6.0% in the placebo group. Although the AREDS type micronutrient supplementation is generally safe, cigarette smokers have an increased risk of developing lung cancer and increased risk of mortality when taking high doses of beta carotene.[89,90] Smokers should be counseled regarding this increased risk and consider avoidance of high dose betacarotene exposure. In AREDS supplementation with zinc (in the absence of antioxidants) was found to significantly reduce anatomic progression of AMD, and maybe considered as an alternate treatment regimen in smokers.
A second multicenter, prospective clinical trial is now underway called AREDS 2. This study will evaluate additional supplements consisting of lutein/zeaxanthine and omega-3 poly-unsaturated fatty acids (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)). Evidence supporting the performance of AREDS 2 involves observational data from many epidemiologic studies as well as case-control studies within AREDS which identify individuals who consume higher amounts of food sources rich in these ingredients to have a reduced odds or risk of manifesting varying forms of AMD when compared to individuals who have lower exposures. AREDS 2 is not expected to reach any conclusions for at least 5-8 years from now. Until AREDS 2 reports its findings, the safety and efficacy of lutein/zeathanine and fish oil in the management of AMD will remain unknown.
Another form of treatment that has been extensively evaluated in the management of eyes with nonneovascular AMD to potentially alter the course of the disease is photocoagulation, either directly or adjacent to soft drusen. Several clinical trials have now been completed and have not found this treatment to be beneficial in the management of patients with soft drusen. The Choroidal Neovascularization Prevention Trial (CNVPT), halted recruitment when it was recognized that study eyes in the fellow eye group randomly assigned to laser treatment had a significantly greater rate of CNV formation within the first 2 years of follow-up when compared with the natural history eyes.[91] Another prospective study, the Prophylactic Treatment of Age-Related Macular Degeneration Research Group (PTAMD Study Group) found similar results in fellow eyes assigned to grid threatment with the 810 nm diode laser.[92] In this trial, the rate of CNV development in laser treated eyes consistently exceeded the rate found among the observation eyes. After 1 year of follow-up, 15.8% of laser-treated eyes developed CNV compared to 1.4% of observation eyes (P = 0.05). More recently, results from the largest investigation of prophylactic laser treatment, the Complications of Age-Related Macular Degeneration Prevention Trial (CAPT) demonstrated that low intensity laser treatment to one eye of individuals with bilateral nonneovascular AMD characterized by multiple large drusen did not demonstrate benefit in vision or anatomic outcomes.[93] The laser protocol specified 60 spots of barely visible burns in a grid pattern within an annulus of 1500 and 2500 ?m of the foveal center. Cumulative 5 year incidence rates for develop-ment of CNV (13.3% laser treated vs 13.3% observed) and GA (7.4% laser treated vs 7.8% observed,) were similar between the two groups. In addition, at 5 years the proportion of subjects with ?3 line loss of visual acuity from baseline was similar between the laser treated eyes (20.5%) and observed eyes (20.5%). Therefore, laser photocoagulation is not recommended in eyes with bilateral large drusen since it does not alter the natural history of AMD in these eyes.
At the present time, the most important aspect of management in patients with drusen is education. Patients should be informed that AMD does not, in the majority of cases, cause legal blindness and that even in the worst cases, peripheral vision is almost always retained. These patients are at increased risk of acquiring CNV, especially if one eye has already been affected, and data suggest that diagnosis at the earliest onset of the CNV provides the greatest chance of successful treatment.[94,95] Therefore, patients should monitor their central vision every day in each eye at risk for the development of CNV, and they should contact their ophthalmologist promptly if they notice any metamorphopsia or scotoma, which may suggest the onset of CNV. Evaluation by an ophthalmologist should include careful contact lens biomicroscopy for the presence of subretinal fluid or hemorrhage and, if necessary, an OCT and a fluorescein angiography to determine whether or not CNV is present.
Recently, a new perimetry device, the Preferential Hyperacuity Perimeter (PreView PHP, Carl Zeiss Meditec, Dublin, CA) was developed to detect metamorphopsia in patients with AMD. A pilot study demonstrated that the PHP had a sensitivity of 94% compared to 34% for the Amsler grid in detecting CNV secondary to AMD.[96] In addition, a larger clinical trial demonstrated that the PHP has a sensitivity of 82% and a specificity of 88% in detecting newly diagnosed CNV in a cohort of individuals comprised of recent-onset CNV or intermediate AMD.[97] Additional clinical trials evaluating the PHP as a screening tool in patients with high risk macular characteristics are underway. Data from these studies may provide information on the role of PHP testing in the management of patients at risk of CNV.
Unfortunately, some patients develop CNV in the absence of appreciable symptoms,[98] and many ophthalmologists recommend that patients who have drusen be followed at 6 month intervals in the hope of detecting asymptomatic CNV that might be amenable to treatment.[99]
GEOGRAPHIC ATROPHY OF THE RPE
Management of eyes with GA requires patient education, self-monitoring of symptoms and vision, and routine clinical examination by an ophthalmologist to monitor for conversion to neovascular AMD. In addition, since extension of GA through the foveal center can result in severe central visual loss patients may benefit from low-vision aids. We advise patients to maintain an open dialog with a low-vision specialist to discuss changes in their needs and new aids that may become available.
CONCLUSIONS AND FUTURE RESEARCH
In recent years, standardized descriptions of non-neovascular features of AMD have been developed and substantial natural history data on AMD utilizing these standard definitions has been accumulated. Complex and simple scales describing the evolution of AMD have been developed. Limited information on the cause or progression of AMD exists. It is hoped that current and future studies will lead to better understanding of the pathogenesis of this disease. The AREDS has confirmed that antioxidant and zinc supplements can reduce progression of AMD and vision loss in eyes at risk. Additional interventional trials may allow us to gain more insight into the disease pathogenesis and reduce the burden of vision loss associated with this condition.
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