Nonexudative Macular Degeneration

The patients who develop exudative AMD are older, with an average age of 70.5 years, than the patients with nonexudative AMD, with an average age of 56.8 years as noted in the study by Smiddy and Fine in 1984 (12).

III.ASSOCIATED FACTORS

Epidemiological, clinical, and histological studies suggest different factors are associated with macular degeneration (5,7,13–18). Hereditary influence, photic injury, nutritional deficiency, toxic insult, and systemic cardiovascular factors have been implicated in epidemiological studies (10,19,20). We can group these risk factors into the following categories: (1) personal characteristics, which include age, sex, race, eye color, smoking, and genetic predisposition.(21–23); (2) systemic disease, especially hypertension, cardiovascular disease, and blood lipid levels (1,10,15,24–26); and (3) environmental influences such as sunlight and nutrition (15,24,27–29).

A.Personal Characteristics

1.Age

The prevalence of AMD increases after 65 years of age; 27.9% of individuals between the age of 75 and 85 have macular degeneration (1,7,22). The number of drusen and the presence of confluent drusen correlates with increasing age (12,13).

2.Sex

AMD has been reported to be more prevalent in females (25,30). The Beaver Dam Study, after adjusting for age, revealed that the incidence of early AMD was 2.2% higher in women 75 years of age and older than in men in this age group (25). The prevalence of early age-related maculopathy was higher in men than women in each age category in the Blue Mountains Eye Study (6). Others have not noted such a difference between males and female (3).

3.Race

Drusen and pigmentary changes have been reported to be twice more common in whites than blacks (31).

4.Family History

AMD is known to run in families (1). Stone and co-workers have reported a genetic mutation that predisposes to drusen formation in malatia Leventinese and certain patients with macular degeneration (21,22,32). Further studies are needed.

5.Hyperopia

Hyperopia has been associated with AMD (23,33). Persons with brown iris color were shown to have a lower risk of developing AMD (33).

B.Systemic Diseases

1.Hypertension and Cardiovascular Disease

The Framingham Eye Study (1) and other studies (34) including the Macular Photocoagulation Study (MPS) (26) found a positive correlation between AMD and hypertension. This was, however, not seen in the studies by Hyman et al. (24), the Beaver Dam Study (3), and the Eye Disease Case-Control Study (35). Hyman et al. (33), on the other hand, found positive association of AMD with stroke, arteriosclerosis, and ischemic attacks. In their most recent case-control series, a strong association was found between neovascular AMD and moderate to severe hypertension, particularly in patients on antihypertensive therapy (24,26,30).

2.Hypercholesterolemia

The association between lipid profile and AMD has been inconsistent in various studies. The Beaver Dam Eye Study (28) noted a positive correlation between high intake of saturated fat and cholesterol and early AMD. A positive relationship was found with high-density lipoprotein (HDL) levels in men, and total serum cholesterol was inversely related to early AMD in women (25). Hyman and colleagues recently reported a positive association between dietary cholesterol and high levels of HDL with neovascular AMD (24).

C.Environmental Influences

1.Photic Injury

Although not scientifically proven, it has been suggested that accumulative exposure to light may cause gradual loss of photoreceptor cells in the macula (36).

2.Nutrition

It has been suggested that oxidative stress may play an important role in the etiology of AMD. Light induces the superoxide radicals to form that can damage the outer segments of photoreceptors (27,29). Antioxidants may prevent this damage (27). Antioxidants like ascorbate and vitamin E (alpha-tocopherol) may be deficient in elderly individuals, which may increase their susceptibility to light damage. It is also known that the retina and particularly the macula is highly susceptible to oxidative stress due to a high polyunsaturated fatty acid content that is prone to lipid peroxidation (27). One study tested the hypothesis that ascorbate could protect the retina from oxidative damage in rats: rats fed supplementary vitamin C were noted to have much milder damage to the retina than the rats that were exposed to the same amount of light but no supplementary ascorbate (37). In the POLA Study (27), an inverse association was found between AMD and levels of plasma alphatocopherol. This study and the Eye Disease Case-Control Study found no association between AMD and plasma ascorbate levels (27,38). Obviously, further randomized studies are needed to evaluate completely the role of antioxidants in the prevention of neovascular AMD. The Age-Related Eye Diseases Study (AREDS) (39) is an ongoing study looking at the effects of antioxidant and zinc supplementation. No results are available.

The Carotene and Retinol Efficacy Trial (CARET) Study (40) found that individuals who smoked and were assigned to beta-carotene and retinol were developing lung cancer at a rate of about 28% more than those assigned to placebo. This study was stopped after 4 years. A trial study in Finland (41) also suggested an increase in mortality from cancer and cardiovascular disease in patients on beta-carotene supplements. These studies did not take into account AMD but they do implicate possible adverse effects of high-dose vitamin intake in AMD patients who smoke (40,41).

Recently, much attention has been given to the dietary importance of carotenoids specially lutein and zeaxanthine (38). Seddon et al. reported the results of further investigations from the Eye Disease Case-Control Study (EDCCS), which showed that a high dietary intake of carotenoids, in particularly dark-green leafy vegetables, was associated with a 43% lower risk of AMD (38). A recent report in the British Journal of Ophthalmology analyzed various fruits and vegetables to establish which ones contain lutein and/or zeaxanthine and can serve as possible dietary supplements for these two carotenoids (15).

IV. DRUSEN

Drusen were first described in 1854 by Donders (42). These are deposits of membranous debris, extracellular material between the RPE and its basement membrane (basilar laminar drusen) or between the RPE basement layer and the inner collagenous layer of Bruch’s membrane (basilar linear drusen) (17), (43–46). Drusen lead to secondary Bruch’s membrane thickening and RPE degeneration. Visual loss due to macular degeneration is the result of degeneration of photoreceptor cells and the choriocapillaris, which ensues soon after RPE atrophy (47).

A.Etiology

Drusen form as a deposition of membranous material between the plasma membrane and the basement membrane of the RPE and are found as early as the second decade of life. They thus may represent a normal aging change (48). Stone and colleagues have identified a genetic mutation in patients with Malattia Leventinese, which also has been attributed to drusen formation in Best’s disease and macular degeneration (32). Experimental and postmortem human studies show that the drusen are RPE-derive (49–51). Different theories have been entertained regarding the pathogenesis of the drusen.

Ishibashi et al. described the formation of drusen using electron microscopy as follows:

(1) evagination or budding of the RPE cell in the subepithelial space; (2) separation of the evaginated portion from the parent RPE cell; (3) degeneration and disintegration of this evaginated cell components devoid of a nucleus; (4) accumulation of granular, vesicular, tubular, and linear material in the sub-RPE space (16). The etiology of the evagination is unknown.

The pathology of the aging changes in the retina is discussed in other chapters.

B.Types

Different types of drusen are noted in the retina: (1) hard, nodular drusen, (2) soft drusen,

(3) crystalline drusen, and (4) cuticular or basal laminar drusen (14).

1.Hard Drusen

Hard drusen are discrete, small, round, yellow, nodular hyaline deposits found in the subRPE space, between the basement membrane of RPE and the inner collagenous layer of the Bruch membrane (52). These drusen are smaller than 50 microns in diameter (Fig. 1).

Focal densifications of Bruch’s membrane, termed microdrusen, may precede the formation of hard drusen (53). Preclinical drusen appear ultrastructurally as “entrapment sites” with coated membrane-bound bodies that form adjacent to the inner collagenous layer of Bruch’s membrane (53). These are structurally different from basal linear deposit.

Figure 1 Color photograph of hard drusen in a 65-year-old asymptomatic man. See also color insert, Fig. 4.1.

(4)

(5)

Figures 3, 4, and 5 Fluorescein angiogram: early form of basal laminar drusen from a 35-year- old asymptomatic patient. Fluorescein angiogram: mid and late frames demonstrating “starry night” appearance.

Basal laminar deposit is composed mainly of collagen, laminin, membrane-bound vesicles and fibronectin. It tends to accumulate over thickened Bruch’s membrane suggesting that the accumulation of the debris may be a local response to altered filtration at these sites (52). These hyperfluoresce early on fluorescein angiography and give an appearance of “starry night” as discussed by Gass (54). They have been reported to be anatomically and histologically similar to soft drusen (Figs 4 and 5).

Figure 6 Color photograph showing soft drusen in a mildly symptomatic 70-year-old patient (mild distortion on Amsler grid testing). See also color insert, Fig. 4.6.

3.Soft Drusen

Soft drusen appear clinically as yellowish lesions with poorly defined edges. Histologically, they represent small, shallow RPE detachments. They are usually greater than 50 microns and are found after age 55 (Fig. 6). On fluorescein angiography, soft drusen show early hypofluorescence or hyperfluorescence with no late leakage.

Clinical and histological studies show that soft drusen precede macular degeneration (55,56). Drusen lead to secondary Bruch’s membrane thickening and RPE degeneration and subsequent overlying retinal photoreceptor loss and predispose to the ingrowth of choroidal neovascularization (CNV) (14,46,57).

4.Crystalline Drusen

Crystalline drusen are discrete calcific refractile drusen (Fig. 7). These are dehydrated soft drusen that predispose to geographical atrophy (11,54).

C.High-Risk Drusen Characteristics

Drusen characteristics associated with a high risk of progression to exudative age-related maculopathy include drusen type (soft), drusen number (greater than five), large size ( 63 microns), confluence, and associated findings such as hyperpigmentation (8,17,30,55–57). The risk of developing exudative maculopathy increases if there is a history of CNV in the fellow eye and with a positive family history (4,21,30,58).

The 5-year risk of eyes with bilateral drusen and good visual acuity to develop CNV is 0.2–18% (5,12,47,57). This risk increases to 7%–87% if the fellow eye has CNV (30,46,55,58). Bressler et al., in their age-adjusted analysis, showed that greater than 20 drusen, the presence of soft drusen, confluent drusen, and focal RPE hyperpigmentation were more often noted in the fellow eyes with unilateral exudative maculopathy than in eyes with bilateral drusen (56). Focal hyperpigmentation and confluence of drusen are

Figure 7 Color photograph of geographic atrophy and drusen. See also color insert, Fig. 4.7.

Figure 8 Color photograph showing the end-stage appearance of the fellow eye of the patient in Figure 6 with high-risk drusen. See also color insert, Fig. 4.8.

associated with an increased risk of progression to exudative AMD (7). In his discussion of Smiddy and Fine, Jampol explains that focal hyperpigmentation may be associated with subclinical subretinal neovascularization that cannot be detected by fluorescein angiography (59). It may also reflect that changes have occurred already in the RPE, Bruch’s membrane, and choriocapillaris, which facilitate future development of CNV and may simply suggest the chronicity of the disease process (59) (Fig. 8).

V.DISAPPEARANCE OF DRUSEN

A.Natural History

Various reports have described the spontaneous disappearance of drusen (5,60). Bressler et al. noted in their Waterman study that large drusen disappeared in 16 (34%) of 47 individuals in 5 years of follow-up (55).

Areolar atrophy may ensue as drusen disappear (12). With loss of the RPE, photoreceptor and choriocapillaris loss follows quickly. Atrophy of overlying RPE is noted as drusen disappear.

B.Laser to Drusen Studies

Various pilot studies have shown mixed results in an attempt to answer the question regarding the risk of exudative AMD and the disappearance of drusen (61,62). Two multicenter trials of laser to drusen have been undertaken, the Choroidal Neovascularization Prevention Trial (CNVPT) and the Prophylactic Treatment of AMD Study (PTAMD). The two subsets of AMD patients are: (1) patients with bilateral soft large drusen and good visual acuity and (2) patients with soft large drusen and good visual acuity in the fellow eye of those with exudative AMD in one eye. Results from the CNVPT study demonstrated an increased risk of exudative AMD in the fellow eye randomized to light argon laser treatment (61,63). The PTAMD trial, using subthreshold diode laser, has shown similar findings of increased risk of exudative maculopathy in fellow eyes of patients treated with laser. A recent paper in the British Journal of Ophthalmology by Guymer et al. (64) looked at the effect of laser photocoagulation on choroidal capillary cytoarchitecture and found that qualitative differences were seen following laser. They postulate that these changes brought on by laser at just suprathreshold levels may carry a risk of inducing choroidal neovascularization as these processes may play a part in the clearance of debris from Bruch’s membrane, and represent an early stage of angiogenesis (64). This side effect is discussed in another chapter. The bilateral drusen arms of both trials are still in progress though the pilot subthreshold paper by Olk et al. does show efficacy of diode laser for drusen (62) (Fig. 9).

VI. NONEXUDATIVE MACULAR DEGENERATION

Clinical and histological studies show that soft drusen precede macular degeneration (47,55).

The mere presence of drusen does not account for significant loss of vision (45). Soft drusen lead to RPE atrophy with resultant overlying photoreceptor atrophy and vision loss. When the vision falls below or equal to 20/30, the disease process is termed nonexudative or dry macular degeneration.

Subretinal fluid, subretinal hemorrhage, retinal pigment epithelium detachment, hard exudates, subretinal fibrosis, all signs of exudative maculopathy, are absent in dry macular degeneration.

Focal hyperpigmentation along with the increased number ( 5) and confluence of soft, large ( 63 microns) drusen is associated with increased risk of progression of RPE atrophy and choroidal atrophy. These eyes have a higher incidence of developing CNV (45,46).

Figure 9 Example of pre (upper left and upper right) and post (lower left and lower right) subthreshold diode laser showing drusen disappearance in a 45-year-old man with a hereditary form of AMD. See also color insert, Fig. 4.9.

Geographic atrophy (GA) is a form of advanced dry macular degeneration. This involves marked choriocapillaris and small choroidal vessel atrophy along with the RPE atrophy. This progresses slowly over years and often spares the center of the foveal avascular zone until late in the course of the disease (65). Almost 3.5% of individuals older than 75 years of age suffer from GA, which causes visual loss of 20/200 or worse. This severe form of GA accounts for at least 20% of all patients with 20/200 or worse vision from advanced macular degeneration (66).

Although nonexudative AMD is more prevalent, it accounts for only 10% of the severe vision loss due to AMD (25,66). Bressler et al. reported a prevalence of 1.8% of AMD in men 50 years of age or older in the Chesapeake Bay study. Of these, almost 75% had the nonexudative maculopathy (8).

The Beaver Dam Eye Study (4) and Chesapeake Bay Waterman Study (5) were population-based eye studies that provided data on 5-year incidence and progression of AMD. Soft drusen and retinal pigmentary changes were found to increase with age. In the 5-year period of the Beaver Dam Eye Study, people 75 years or older were 3.3–8.4 times as likely to develop large drusen between 63 microns and 250 microns in diameter and 40.7 times more likely to develop drusen greater than or equal to 250 microns in diameter as compared to persons 43–54 years of age. Also, persons 75 years of age or over were 16 times more likely to develop confluent drusen when compared to people 43–54 years of age (4). There was a much higher incidence of dry macular degeneration clinical findings in people over 75 years of age (Table 2). This was consistent with the results of the Blue Mountains Australian (6), Rotterdam (67), and Colorado-Wisconsin (68) studies of AMD.

Source: Ref. 4.

VII. MONITORING NONEXUDATIVE AMD

Amsler-grid testing is a sensitive indicator of progression of the disease process. Straight door and window frames may be crude ways to check for any metamorphopsia.

Patients are encouraged to seek medical help if visual distortion, metamorphopsia, loss of central vision, or any new symptoms occur. These herald the growth of choroidal neovascular membranes. The early detection of the choroidal neovascular membranes may facilitate treatment with either laser photocoagulation, photodynamic therapy, transpupillary thermotherapy, or macular translocation, as described in other chapters.

VIII. SUMMARY

Prevalence of AMD increases with age. Nonexudative AMD is the most common form of AMD. Factors associated with AMD include increased age, heredity, photic injury, nutrition, toxic insults, and cardiovascular risk factors. High-risk characteristics of drusen for development of CNV include: soft drusen, large drusen, greater than five drusen, confluence, and focal hyperpigmentation. Disappearance of drusen can occur spontaneously or may follow laser to drusen (CNVPT and PTAMD). Disappearance of drusen may result in geographic atrophy. Monitoring visual acuity and visual symptoms for the progression of AMD is of utmost importance in applying timely treatment.

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