The defining lesion of the nonneovascular form of AMD is the druse. Other indicators are abnormalities of the RPE, including hyperpigmentation and atrophy.
Clinically, drusen are small, round, yellow lesions located along the basal surface of the RPE, mostly in the postequatorial retina (Fig 4-2). Histologically, this material corresponds to the abnormal thickening of the inner aspect of Bruch membrane shown in Figure 4-1. Ultrastructurally, basal laminar deposits (granular, lipid-rich material and widely spaced collagen fibers between the plasma membrane and basement membrane of the RPE cell) and basal linear deposits (phospholipid vesicles and electron-dense granules within the inner collagenous zone of Bruch membrane) are present (see Fig 4-1).
Figure 4-2 Drusen. A, Color fundus photograph shows soft, confluent, large drusen in a patient with nonneovascular (dry) age-related macular degeneration (AMD). B, Corresponding spectral-domain optical coherence tomography (SD-OCT) image of the soft drusen. C, Autofluorescence image of an eye with areas of confluent drusen.
(Courtesy of David Sarraf, MD.)
The thickened inner aspect of Bruch membrane, along with the RPE, may separate from the rest of Bruch membrane, resulting in pigment epithelial detachment (PED). When small, such a detachment may be identified as a large or soft druse, and when larger, it may be recognized as a drusenoid PED.
Because drusen variably affect the overlying photoreceptors, there may be associated mild to moderate vision loss, decreased contrast sensitivity and color vision, and impairment of dark adaptation. Increasing size, number, and confluence of the drusen confer increasing risk of progression to CNV or geographic atrophy (GA), which the Age-Related Eye Disease Study (AREDS) referred to as stage 4 or the advanced stage of AMD. Drusen are categorized by size as small (usually <63 μm diameter), intermediate (usually 63–124 μm), or large (usually ≥125 μm). Drusenoid PEDs are confluent large drusen that coalesce into a PED (>350 μm diameter). In AREDS, the risk of progression to stage 4 AMD over a 5-year period for patients with early AMD (many small drusen or few intermediate drusen, stage 2) was 1.3%. In contrast, the risk for patients with many intermediate drusen or even a single large druse (stage 3) was 18%.
Drusen can be further distinguished by their boundaries: hard (discrete and well demarcated), soft (amorphous and poorly demarcated; see Fig 4-2A, B), or confluent (contiguous drusen without clear boundaries; see Fig 4-2C). Hard drusen are well-defined focal areas of lipidization or hyalinization of the RPE–Bruch membrane complex. Soft drusen are associated with the presence of diffuse thickening of the inner aspects of Bruch membrane, that is, basal linear deposits. An eye with soft, and perhaps confluent, drusen is more likely to progress to atrophy or CNV than an eye with only hard drusen.
Reticular pseudodrusen or subretinal drusenoid deposits are similar in appearance to drusen; they can be recognized by their reticular-like network, seen best on fundus autofluorescence (Fig 4-3) and infrared imaging. These lesions are typically smaller than soft drusen, are located on the apical surface of the RPE, and commonly distribute in the superior macular region. Although they share some proteins with drusen (eg, apolipoprotein E, complement factor H, and vitronectin), they contain different lipids and do not contain shed disk remnants. Their presence has been associated with progressive atrophy of the photoreceptor layer, GA, and a greater risk of CNV.
Drusen occurring in patients younger than 50 years are discussed in the section “Early-onset ‘drusenoid’ macular dystrophies” in Chapter 13.
Fluorescein angiography of drusen Drusen appearance on fluorescein angiography (FA) can vary. Typically, small hard drusen hyperfluoresce early in FA studies because of a window defect, whereas larger soft and confluent drusen and drusenoid PEDs slowly and homogenously stain late because of pooling of the fluorescein dye in the sub-PED compartment.
Optical coherence tomography of drusen Spectral-domain optical coherence tomography (SD-OCT) imaging of small and large drusen typically reveals sub-RPE nodular elevations or even small RPE detachments with a notable absence of intraretinal and subretinal fluid (see Fig 4-2). Reticular pseudodrusen are identified above the RPE and beneath the inner segment ellipsoid layer and are graded according to their degree of elevation (see Fig 4-3).
Figure 4-3 Reticular pseudodrusen. A, SD-OCT image demonstrates the location of reticular pseudodrusen above the RPE. B, Corresponding autofluorescence image shows the reticular network of these pseudodrusen.
(Courtesy of David Sarraf, MD.)
Enhanced depth imaging (EDI) OCT provides more details of choroidal architecture and a clearer definition of the choroidal-scleral interface, which is helpful in characterizing AMD. Choroidal thickness is often reduced in AMD.
Abnormalities of the retinal pigment epithelium
Characteristic RPE abnormalities seen in patients with nonneovascular AMD include focal hyperpigmentation, focal atrophy, and geographic atrophy. Focal RPE hyperpigmentation appears as increased pigmentation at the level of the outer retina. These areas typically produce blockage of fluorescence on FA, and appear as hyperreflective outer retinal foci on SD-OCT. The incidence of focal hyperpigmentations increases with age; their presence is associated with a greater risk of progression to the more advanced forms of AMD.
Focal atrophy appears as noncontiguous areas of pigment mottling or frank depigmentation. If such lesions are contiguous and have a diameter greater than 175 μm, they are described as geographic atrophy (GA) of the RPE. In areas of GA, absence or depigmentation of the RPE unmasks the choroidal vessels, making them visible. The overlying outer retina typically appears thin, and the underlying choriocapillaris is attenuated or atrophied. On FA, GA appears as well-circumscribed round to oval window defects; SD-OCT reveals the progressive loss of RPE, the overlying inner segment ellipsoid, and the photoreceptor layers. Areas of GA are densely hypoautofluorescent, making fundus autofluorescence a useful, noninvasive technique for monitoring disease progression (Fig 4-4).
Geographic atrophy often spares the fovea until late in the course of the disease. It may first present as 1 or more noncontiguous patches of atrophy around the fovea. These patches enlarge and coalesce, leaving the affected individual with dense paracentral scotomas, which can limit tasks such as reading. The rate of disease progression has been estimated at 1.79 mm2/year, but this may vary from individual to individual. Patients with GA may demonstrate good visual acuity (VA) until late in the disease, when the fovea becomes involved and VA declines due to central blindness, forcing the patient to use eccentric fixation on noncentral retina to read and perform other visual tasks.
Although not all eyes with drusen or drusenoid PED will develop atrophy, the incidence of atrophy appears to increase with age. Twelve to 20% of patients with GA experience severe vision loss, and 10% of patients with AMD and a VA of 20/200 or less have GA. Decreased contrast sensitivity and reduction in microperimetry sensitivity values reflect the presence of pseudodrusen prior to progression to GA.
Other abnormalities Chronic nonneovascular AMD can lead to progressive RPE atrophy and GA. As drusen resorb over time, atrophy of the RPE often remains. Dystrophic lipidization and calcification (“refractile” or “calcific” drusen) may occur, resulting in the development of refractile or crystalline lesions in the macula. Furthermore, pigment or pigment-laden cells (either RPE cells or macrophages that have ingested the pigment) may migrate to the photoreceptor level, resulting in focal clumps or a reticulated pattern of hyperpigmentation.
Figure 4-4 Geographic atrophy (GA). Top, Color fundus photographs of right (left panel) and left (right panel) eyes, demonstrating advanced GA. Bottom, Corresponding autofluorescent images of GA in the same patient with atrophic AMD. The areas of RPE atrophy are hypoautofluorescent (dark gray or black), the areas of “sick” RPE are hyperautofluorescent (brighter than background), and the areas of healthy RPE are gray.
(Courtesy of David Sarraf, MD.)
Differential diagnosis of nonneovascular AMD
Disorders that include RPE abnormalities may be misinterpreted as nonneovascular AMD. Central serous chorioretinopathy (CSC; discussed in Chapter 9) may produce RPE changes similar to those in AMD. In patients with CSC, EDI-OCT reveals a thickened choroid in the affected and fellow eyes, as opposed to the normal or thin choroid in eyes with AMD. Pattern dystrophies of the RPE present as areas of reticular or butterfly-shaped hyperpigmentation of the macula, which are often symmetrical in each eye. Patients with adult-onset vitelliform maculopathy may present with yellow subretinal lesions beneath the outer retina. On SD-OCT this condition appears as a hyperreflective, dome-shaped central lesion (Fig 4-5). FA shows early blocked fluorescence with a surrounding zone of hyperfluorescence. Late staining of the vitelliform material may occur and may help distinguish these cases from AMD. These features may occur in younger individuals (younger than 50 years). On the other hand, these changes may also be present in older individuals who have the more typical drusen and RPE abnormalities associated with AMD.
Figure 4-5 Color fundus photograph (left) and corresponding SD-OCT image (right) of adult-onset vitelliform maculopathy. The foveal region has a yellowish discoloration resembling an egg yolk. OCT demonstrates that the lesion is elevated.
(Courtesy of David Sarraf, MD.)
The retinal signs of drug toxicity, such as concentric macular atrophy caused by hydroxychloroquine toxicity, may resemble progressive geographic atrophy of AMD. Central RPE mottling associated with deferoxamine, pentosan polysulfate sodium, or cisplatin may also resemble nonneovascular AMD. A history of specific drug ingestion and lack of large drusen may help differentiate these abnormalities from AMD (see Chapter 15).
Management of nonneovascular AMD
Education and follow-up Eyes with soft drusen and RPE hyperpigmentation are at increased risk of developing GA and CNV. Because of this risk, patients with nonneovascular AMD should be educated about the symptoms of advanced AMD and instructed to contact an ophthalmologist promptly should these symptoms occur; ophthalmology office staff should respond to patient concerns without delay. If reduced VA or reduced vision function (eg, difficulty reading despite good measured visual acuity) is noted, a low vision evaluation should be considered after treatable pathology has been ruled out. Periodic examinations are advised to monitor for concurrent, treatable eye disease (eg, cataract, glaucoma) and to reevaluate low-vision needs. To learn about the American Academy of Ophthalmology’s Initiative in Vision Rehabilitation and obtain a patient handout, visit the Low Vision and Vision Rehabilitation page on the ONE Network at www.aao.org/low-vision-and-vision-rehab.
Amsler grid testing Patients can use the Amsler grid at home to monitor for exudative macular degeneration; the test card contains white grid lines on a black background and a central dot for fixation. Each eye is tested individually with reading glasses and at reading distance to check for any new metamorphopsia, scotoma, or other significant changes in central vision. Any changes noted by the patient should be evaluated promptly. Recent online or smart-phone application versions of the Amsler grid offer greater convenience for both patients and clinicians; the test results are instantly uploaded to alert the treating ophthalmologist of any acute visual changes.
Hyperacuity testing Vernier acuity measures a patient’s ability to detect deviations in alignment of visual objects, for example 2 line segments. Hyperacuity is what helps the viewer discern minute deviations, down to even a single point on a line. Hyperacuity is extremely sensitive to any geometric shift in the outer retinal morphology, producing a perception of distortion. Preferential hyperacuity perimetry (PHP), which has been studied extensively, can detect recent-onset CNV in intermediate AMD patients with high sensitivity (82%), and high specificity (88%). One of those studies, the HOME study, which was a phase 3 randomized clinical trial with 1520 participants, demonstrated the efficacy and potential benefit of PHP in earlier CNV detection.
Shape-discrimination hyperacuity (SDH) employs a similar principle but instead tests for discrimination of shapes, such as the ability to discern a perfect circle from a distorted contour. A handheld SDH test, which is currently in trials, can be implemented as a smartphone application for frequent, regular home monitoring.
Chew EY, Clemons TE, Harrington M, et al; AREDS2-HOME Study Research Group. Effectiveness of different monitoring modalities in the detection of neovascular age-related macular degeneration: the Home Study, Report Number 3. Retina. 2016;36(8):1542–1547.
Keane PA, de Salvo G, Sim DA, Goverdhan S, Agrawal R, Tufail A. Strategies for improving early detection and diagnosis of neovascular age-related macular degeneration. Clin Ophthalmol. 2015;9:355–366.
Micronutrients Ophthalmologists should counsel patients about various epidemiologic studies that have demonstrated positive associations between the intake of certain micronutrients and a decreased risk of AMD, although only some micronutrients have been studied.
AREDS (Age-Related Eye Disease Study) first established the benefit of vitamin and zinc supplementation in reducing the risk of vision loss in nonexudative AMD. In the study, after supplementation with the antioxidant vitamins C (500 mg) and E (400 IU), beta carotene (15 mg), and the micronutrient zinc (80 mg zinc oxide and 2 mg cupric oxide to prevent zinc-induced anemia), patients with intermediate or advanced AMD showed a 25% risk reduction for progression to more-advanced stages of AMD and a 19% risk reduction in rates of moderate vision loss (≥3 lines of visual acuity) at 5 years. The study defined intermediate (stage 3) AMD as the presence of at least 1 large druse (≥125 μm), extensive intermediate drusen (63–124 μm diameter), or nonsubfoveal GA; advanced (stage 4) AMD was defined as vision loss due to neovascular AMD or subfoveal GA in only 1 eye. At 10 years, 44% of placebo recipients compared with 34% of the supplement recipients had advanced AMD (a 23% risk reduction). Among participants with no AMD or with only early-stage AMD (a few small drusen), there was no measurable benefit. There was no increased mortality among patients taking the formula recommended by AREDS.
AREDS developed a simplified 4-point grading scale for classifying the severity of AMD and predicting the disease course based on the following findings:
presence of 1 or more large (≥ 125-μm diameter) drusen (1 point)
presence of any pigment abnormalities (1 point)
for patients with no large drusen, presence of bilateral intermediate (63–124 μm) drusen (1 point)
presence of neovascular AMD (2 points)
Risk factors were totaled across both eyes to reach a number between 0 and 4 that was used to estimate patients’ 5- and 10-year risk of developing advanced AMD in 1 eye (Table 4-1).
A follow-up study, AREDS2, tested whether replacing beta carotene with xanthophylls (lutein and zeaxanthin) and adding omega-3 long-chain polyunsaturated fatty acids (LCPUFAs: docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) would further help reduce AMD progression in a large prospective trial. The response of the 4000 participants in the study confirmed the overall risk reduction found in the original AREDS study and concluded that lutein and zeaxanthin had similar effects to beta carotene, but without its increased risk for lung cancer in current and former smokers (reported in other studies). It also confirmed that 80 mg of zinc is an appropriate dose for AMD prophylaxis. The addition of LCPUFAs did not decrease the rate of progression to advanced AMD. The study’s final recommendation was to modify the original AREDS supplement, replacing beta carotene with lutein and zeaxanthin, and not to add LCPUFAs (Table 4-2). Currently, patients with stage 3 or 4 AMD are advised to take the AREDS2 supplement.
Table 4-1 Five- and 10-Year Risksa of Advanced AMD in 1 Eye
Table 4-2 AREDS2 Recommendations for Nutritional Supplementationa
Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013;309(19):2005–2015.
Ferris FL, Davis MD, Clemons TE, et al; Age-Related Eye Disease Study (AREDS) Research Group. A simplified severity scale for age-related macular degeneration: AREDS report no. 18. Arch Ophthalmol. 2005;123(11):1570–1574.
Lifestyle changes With increasing evidence that environment and health habits influence the development and progression of AMD, patients should be counseled to alter behaviors that put them at risk. Of particular importance are smoking cessation, obesity reduction, and blood pressure control. Cataract surgery has not been linked consistently to the progression of AMD, nor is there strong evidence linking UV (UV-A or UV-B) light exposure to the progression of AMD. It should be noted, however, that there are no adverse effects from wearing UV-protective glasses.
Disproven treatment approaches for nonneovascular AMD
Macular laser photocoagulation has been shown to stimulate drusen resolution or reduction, but there is no associated change in the natural course of vision loss or CNV development. No role was demonstrated for rheopheresis (filtering blood to alter its viscosity) in treatment of nonneovascular AMD. Lampalizumab (also known as anti-factor D), which selectively inhibits activation of the alternative complement pathway, has been studied in large phase-3 studies of patients with GA and was not found to be effective in preventing progression of the disease.
Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.