Unlocking geographic atrophy

(Image Credit: AdobeStock)

Geographic atrophy (GA) affects 5 million individuals worldwide and is an advanced stage of dry age-related macular degeneration (AMD), leading to vision loss and accounting for 20% of legal blindness cases in North America.^1-3 There are no standard treatment guidelines for GA, but early detection is important because a new therapy approved for GA and another under FDA review can slow GA growth.^4-8

AMD can be divided into early, intermediate, and advanced stages, and these stages are defined by the size and amount of drusen and degeneration of the photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris.^1,2 Clinical features identifiable upon funduscopic examination and with multimodal retinal imaging can be useful for the clinical diagnosis and staging of AMD.⁹ In addition, several clinical features have been associated with a greater likelihood and faster progression to GA from earlier stages of AMD.^1,10

Several classification systems, including the Modified International Classification, the Age-Related Eye Disease Study (AREDS), the Beckman classification, and the Three Continent AMD Consortium, have been used to categorize the different stages of AMD. Progression has been denoted by specific anatomical features of drusen (type, size, area)or pigmentary changes (hyperpigmentation, hypopigmentation) visible on retinal images.^5,11

Among such classification systems, the International Classification of Diseases (ICD) facilitates reporting, tracking, and classification of diseases, including AMD. Updates and revisions are published by the World Health Organization.^12,13 The ICD, Tenth Revision (ICD-10) codes for AMD are H35.31xx for dry AMD (no neovascularization present) and H35.32xx for wet AMD (neovascularization present).¹⁴ The sixth character specifies laterality (1 = right eye, 2 = left eye, 3 = bilateral), and the seventh character indicates staging (1 = early dry AMD, 2 = intermediate dry AMD, 3 = advanced atrophic dry AMD without subfoveal involvement, 4 = advanced atrophic dry AMD with subfoveal involvement).14 Clinical features denoting the progression of AMD and described by ICD-10 can be identified through various imaging modalities, including color fundus photography (CFP), fundus autofluorescence (FAF), and optical coherence tomography (OCT).¹⁵ These imaging modalities can also rapidly and effectively identify additional subtle alterations that may not be as easily observable through initial funduscopy and may hold important prognostic implications for progression of disease.^16,17

Clinical features of early and intermediate AMD and biomarkers associated with GA development

Early detection is key for prompt implementation of patient management strategies.⁵ Early dry AMD is characterized by numerous small-size drusen (≤ 63 μm), a few intermediate-size drusen (> 63 μm and ≤ 124 μm), and potentially mild RPE abnormalities, although the last of these has been more commonly observed during intermediate stages of AMD.^2,14 As AMD progresses, more extensive intermediate-size drusen (> 63 µm and ≤ 124 µm) or at least 1 large-size drusen (> 125 µm) can be observed.^2,14

Drusen, a clinical hallmark of AMD, are extracellular deposits found beneath the RPE.^15,18 On FAF, smaller (hard) drusen, which are characteristic of early AMD, typically exhibit hypoautofluorescent foci, sometimes surrounded by increased autofluorescence.¹⁵ In contrast, larger (soft) drusen found in more intermediate AMD stages display moderate hyperautofluorescence but may exhibit heterogeneous signals for even larger sizes.¹⁵ Additionally, OCT enables cross-sectional retinal imaging so that drusen size, location, and subtype can be determined.^15,19

Viewed on OCT, small and hard drusen appear as small, hyperreflective, sub-RPE deposits, whereas large and soft drusen appear as large, round elevations of the RPE that can appear hyporeflective internally.15 On ophthalmoscopy or CFP, large and soft drusen often have indistinct borders and may coalesce as they enlarge.¹⁵

Another clinical feature sometimes visible in patients with early- or intermediate-stage AMD is reticular pseudodrusen (RPD) or subretinal drusenoid deposits. These are located above the RPE and are associated with a greater likelihood of progression to GA.^20,21 On ophthalmoscopy or CFP, RPD appear as clusters of yellowish, more discrete punctate deposits.²⁰ On FAF imaging, RPD are commonly visualized as a hypofluorescent, interconnected network.^15,16

With OCT, RPD are characterized by nodular, hyperreflective deposits. Although these deposits are above the RPE, their exact location within the retina will depend on the disease stage of development: between the RPE and ellipsoid zone (EZ) during the first 2 stages, breaking through the ellipsoid line at stage III, and being reabsorbed and disappearing at stage IV.^15,22 Patients should be monitored for the RPD phenotype at early and intermediate stages. When identified, these eyes should be monitored frequently to detect early GA development.¹⁶

As AMD progresses, RPE disruption and photoreceptor degradation may occur.²³ The ability to obtain high-resolution cross-sectional images of the retina with OCT enables visualization of retinal abnormalities such as the thinning of retinal layers and elevations within the RPE that can sometimes be seen at earlier stages.^19,23 Although FAF imaging is better at visualizing atrophic lesions in later stages of AMD, the initial disruption of photoreceptors noted above drusen has nevertheless been associated with hyper-FAF signals indicative of the earliest signs of initial drusen-associated atrophy.²⁴

Many high-risk imaging biomarkers that predispose the future development of GA have been identified.^2,19,25 CFP features includepigmentary abnormalities as well as crystalline deposits and refractile drusen.^19,26 OCT can detect the earliest atrophic lesions before they become clinically apparent with CFP or FAF imaging.¹⁷ Impending GA lesions may be characterized by EZ or external limiting membrane (ELM) loss, subsidence (sinking) of the inner nuclear and outer plexiform layers posteriorly, ELM descent or downward deflection, and a pair of hyporeflective wedges or triangles that often border outer retinal loss and less-affected adjacent retina.^17,26-28

Other high-risk OCT features include intraretinal hyperreflective foci for deposits, which often correspond to hyperpigmentation on CFP due to anterior RPE migration; sub-RPE hyperreflective columns, which appear as narrow columns of choroidal hyperreflectivity and signify compromised RPE integrity; drusen with hyporeflective cores, which often correlate with calcific-type drusen; and hyperreflective crystalline deposits or sub-RPE plaques, which on OCT appear as linear hyperreflective deposits within the sub-RPE space and correspond to refractile drusen.^17,26,27 In some instances, GA formation may be preceded by collapse or regression of large and soft drusen.^15,26,29,30

Once a diagnosis of AMD has been made, patient management involves identification and correction of modifiable risk factors such as smoking, dietary changes, etc.⁵ In addition, AREDS2 antioxidant vitamin and mineral supplementation and home screening strategies should be considered in individuals with intermediate or advanced AMD in 1 eye.³¹

Patients with early and intermediate AMD are suggested to have follow-up visits of 12-month and 6-month intervals, respectively.⁵ Advanced imaging techniques and prompt referral for potentially manageable features of advanced AMD become especially important in patients with intermediate-stage AMD.³¹

Clinical features of late-stage AMD: A focus on GA

Advanced-stage AMD is characterized by GA or macular neovascularization (MNV).^1,2,32 These are not mutually exclusive of each other, and patients with GA should be monitored regularly and treated promptly with anticomplement and with anti-VEGF therapy should exudative MNV occur.^1,33 For dry AMD, the ICD-10 codes categorize advanced late stages into 2 categories: advanced atrophic without subfoveal involvement (H35.31x3) and with subfoveal involvement (H35.31x4).¹⁴

With ophthalmoscopy or CFP, GA lesions appear as hypopigmented areas with well-demarcated borders, indicating significant RPE degeneration and revealing underlying choroid vessels.^2,34 Generally, CFP is ineffective at detecting early GA lesions and tracking enlargement over time.¹⁹ In contrast, GA is strikingly imaged on FAF imaging because of loss of lipofuscin-containing RPE that results in dark, hypoautofluorescent areas.³⁴ High-risk GA phenotypic FAF patterns have also been identified. GA with a continuous band of surrounding hyperautofluorescence or GA in eyes with hyperautofluorescence at the margin but diffusely present throughout the posterior pole were found to enlarge faster compared with GA that had no surrounding hyperautofluorescence or only focal patches of hyperautofluorescence on the GA margin.^35,36

Using OCT, GA lesions are depicted in greater detail by a variable degree of loss (atrophy) or thinning (attenuation) of the following layers: ELM, outer nuclear layer, EZ, cone outer segment tips and interdigitation zone, and the RPE.^17,34 RPE loss results in choroidal hypertransmission defects caused by increased light passing through the choroid.³⁷ En face OCT analysis using a sub-RPE slab can depict areas of choroidal hypertransmission corresponding to areas of GA in a 2-dimensional format, and Carl Zeiss Meditech AG has developed software algorithms that are able to automatically delineate areas of GA and graph quantitative area measures and the closest distance to the fovea over time.³⁸

Despite their ability to help us view different stages of AMD, imaging modalities have limitations.¹⁹ Although FAF imaging is one of the predominant imaging modalities for assessing GA lesion size and is accepted by regulators and used within clinical trials to assess GA lesion growth, it is difficult to accurately identify atrophy near the fovea. This is because FAF imaging relies on blue-light excitation, which is blocked by macular pigment and results in weaker signal near the fovea. As such, FAF use alone may not be ideal for patients with foveal GA lesions.^2,19,39,40 OCT does not have this limitation because it uses interference and reflectivity vs blue-light excitation.^19,41,42 To this effect, the Classification of Atrophy Meeting (CAM) group of retina specialists recommends a multimodal imaging approach for the optimal characterization of atrophic lesions, using OCT as a starting point.¹⁷ Additionally, they have created an OCT-based framework to describe the different stages of atrophy, including complete RPE and outer retinal atrophy (cRORA) as well as incomplete RPE and outer retinal atrophy (iRORA). GA is considered a subset of cRORA.17 cRORA is described as an area of photoreceptor and RPE loss of 250 μm or more in diameter with corresponding homogeneous choroidal hypertransmission.¹⁷ Should this area of loss involve the fovea, the code for advanced atrophic with subfoveal involvement (H35.31x4) should be used. If it spares the fovea, the code for advanced atrophic without subfoveal involvement (H35.31x3) is appropriate.¹⁴

There are certain risk factors associated with a faster growth of atrophic lesions, including extrafoveal lesion location, larger lesion size, and the presence of multifocal lesions.² Additionally, changes in photoreceptors, the EZ, outer retinal layer thickness, the junctional zone area, and distinct abnormal FAF patterns such as banded patterns, diffuse patterns, and diffuse trickling have been associated with a higher rate of GA enlargement and faster progression.^2,43-47

Because patients with advanced-stage GA may still retain good central vision until lesions expand to the fovea, it is important to diligently screen for early GA using multimodal imaging in eyes with intermediate-stage AMD.⁴⁸ The identification and appropriate staging of AMD before its development into GA is essential to determine appropriate management strategies. Earlier detection of GA will hopefully enable more options and better control of disease progression.

Lejla Vajzovic, MD, FASRS1

P: 919-681-3937

Vajzovic is an ophthalmologist, pediatric retinal specialist, and retinal surgeon at Duke Eye Center at Duke University School of Medicine in Durham, North Carolina.

Carolyn Majcher, OD, FAAO

E: majcher@nsuck.edu

Carolyn Majcher is an optometrist and a fellow of the American Academy of Optometry affiliated with the Oklahoma College of Optometry at Northeastern State University in Tahlequah.

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