Publication

Article

Digital Edition
Ophthalmology Times: August 2023
Volume 48
Issue 8

Unlocking geographic atrophy

Staging AMD accurately and identifying clinical features that are linked with disease progression are key.

(Image Credit: AdobeStock)

(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.
References:
1.Holz FG, Strauss EC, Schmitz-Valckenberg S, van Lookeren Campagne M. Geographic atrophy: clinical features and potential therapeutic approaches. Ophthalmology. 2014;121(5):1079-1091. doi:10.1016/j.ophtha.2013.11.023
2.Fleckenstein M, Mitchell P, Freund KB, et al. The progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmology.2018;125(3):369-390. doi:10.1016/j.ophtha.2017.08.038
3.Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health.2014;2(2):e106-e116. doi:10.1016/S2214-109X(13)70145-1
4.Schultz NM, Bhardwaj S, Barclay C, Gaspar L, Schwartz J. Global burden of dry age-related macular degeneration: a targeted literature review. Clin Ther.2021;43(10):1792-1818. doi:10.1016/j.clinthera.2021.08.011
5.García-Layana A, Cabrera-López F, García-Arumí J, Arias-Barquet L, Ruiz-Moreno JM. Early and intermediate age-related macular degeneration: update and clinical review. Clin Interv Aging.2017;12:1579-1587. doi:10.2147/CIA.S142685
6.Ford J. FDA approves Syfovre as first treatment for geographic atrophy. Retinal Physician. February 20, 2023. Accessed March 3, 2023. https://www.retinalphysician.com/issues/2023/january-february-2023/fda-approves-syfovre-as-first-treatment-for-geogra
7.Boyer DS, Schmidt-Erfurth U, van Lookeren Campagne M, Henry EC, Brittain C. The pathophysiology of geographic atrophy secondary to age-related macular degeneration and the complement pathway as a therapeutic target. Retina. 2017;37(5):819-835. doi:10.1097/IAE.0000000000001392
8.Schloesser P. FDA accepts Iveric Bio’s NDA, grants priority review for GA drug. Endpoint News. February 17, 2023. Accessed March 9, 2023. https://endpts.com/fda-accepts-iveric-bios-nda-grants-priority-review-for-ga-drug/
9.Fleckenstein M, Keenan TDL, Guymer RH, et al. Age-related macular degeneration. Nat Rev Dis Primers.2021;7(1):31. doi:10.1038/s41572-021-00265-2
10.Chakravarthy U, Bailey CC, Scanlon PH, et al. Progression from early/intermediate to advanced forms of age-related macular degeneration in a large UK cohort: rates and risk factors. Ophthalmol Retina.2020;4(7):662-672. doi:10.1016/j.oret.2020.01.012
11.Thee EF, Meester-Smoor MA, Luttikhuizen DT, et al; EyeNED Reading Center. Performance of classification systems for age-related macular degeneration in the Rotterdam study. Transl Vis Sci Technol.2020;9(2):26. doi:10.1167/tvst.9.2.26
12.Hirsch JA, Nicola G, McGinty G, et al. ICD-10: history and context. AJNR Am J Neuroradiol. 2016;37(4):596-599. doi:10.3174/ajnr.A4696
13.International Classification of Diseases, Tenth Revision (ICD-10). CDC. Updated December 2021. Accessed May 10, 2023. https://www.cdc.gov/nchs/icd/icd10.htm#:~:text=The%20Tenth%20Revision%20(ICD%2D10,categories%20rather%20than%20numeric%20categories
14.Lum F, Repka MX, Vicchrilli S. How to use the ICD-10 codes for age-related macular degeneration. Amercian Academy of Ophthalmology. September 2017. Accessed May 7, 2023. https://www.aao.org/eyenet/article/how-to-use-the-icd-10-codes-for-amd
15.Khan KN, Mahroo OA, Khan RS, et al. Differentiating drusen: drusen and drusen-like appearances associated with ageing, age-related macular degeneration, inherited eye disease and other pathological processes. Prog Retin Eye Res. 2016;53:70-106. doi:10.1016/j.preteyeres.2016.04.008
16.Ly A, Nivison-Smith L, Assaad N, Kalloniatis M. Fundus autofluorescence in age-related macular degeneration. Optom Vis Sci. 2017;94(2):246-259. doi:10.1097/OPX.0000000000000997
17.Sadda SR, Guymer R, Holz FG, et al. Consensus definition for atrophy associated with age-related macular degeneration on OCT: classification of atrophy report 3. Ophthalmology. 2018;125(4):537-548. doi:10.1016/j.ophtha.2017.09.028
18.Crabb JW, Miyagi M, Gu X, et al. Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci U S A. 2002;99(23):14682-14687. doi:10.1073/pnas.222551899
19.Holz FG, Sadda SR, Staurenghi G, et al; CAM Group. Imaging protocols in clinical studies in advanced age-related macular degeneration: recommendations from classification of atrophy consensus meetings. Ophthalmology. 2017;124(4):464-478. doi:10.1016/j.ophtha.2016.12.002
20.Pumariega NM, Smith RT, Sohrab MA, Letien V, Souied EH. A prospective study of reticular macular disease. Ophthalmology. 2011;118(8):1619-1625. doi:10.1016/j.ophtha.2011.01.029
21.Klein R, Meuer SM, Knudtson MD, Iyengar SK, Klein BE. The epidemiology of retinal reticular drusen. Am J Ophthalmol. 2008;145(2):317-326. doi:10.1016/j.ajo.2007.09.008
22.Querques G, Canouï-Poitrine F, Coscas F, et al. Analysis of progression of reticular pseudodrusen by spectral domain-optical coherence tomography. Invest Ophthalmol Vis Sci. 2012;53(3):1264-1270. doi:10.1167/iovs.11-9063
23.Acton JH, Smith RT, Hood DC, Greenstein VC. Relationship between retinal layer thickness and the visual field in early age-related macular degeneration. Invest Ophthalmol Vis Sci. 2012;53(12):7618-7624. doi:10.1167/iovs.12-10361
24.Chen L, Messinger JD, Ferrara D, Freund KB, Curcio CA. Stages of drusen-associated atrophy in age-related macular degeneration visible via histologically validated fundus autofluorescence. Ophthalmol Retina. 2021;5(8):730-742. doi:10.1016/j.oret.2020.11.006
25.Flores R, Carneiro Â, Vieira M, Tenreiro S, Seabra MC. Age-related macular degeneration: pathophysiology, management, and future perspectives. Ophthalmologica. 2021;244(6):495-511. doi:10.1159/000517520
26.Jaffe GJ, Chakravarthy U, Freund KB, et al. Imaging features associated with progression to geographic atrophy in age-related macular degeneration: classification of atrophy meeting report 5. Ophthalmol Retina. 2021;5(9):855-867. doi:10.1016/j.oret.2020.12.009
27.Ly A, Yapp M, Nivison-Smith L, Assaad N, Hennessy M, Kalloniatis M. Developing prognostic biomarkers in intermediate age-related macular degeneration: their clinical use in predicting progression. Clin Exp Optom. 2018;101(2):172-181. doi:10.1111/cxo.12624
28.Wu Z, Luu CD, Hodgson LAB, et al. Prospective longitudinal evaluation of nascent geographic atrophy in age-related macular degeneration. Ophthalmol Retina. 2020;4(6):568-575. doi:10.1016/j.oret.2019.12.011
29.Sarks JP, Sarks SH, Killingsworth MC. Evolution of soft drusen in age-related macular degeneration. Eye (Lond). 1994;8(pt 3):269-283. doi:10.1038/eye.1994.57
30.Curcio CA. Soft drusen in age-related macular degeneration: biology and targeting via the oil spill strategies. Invest Ophthalmol Vis Sci. 2018;59(4):AMD160-AMD181. doi:10.1167/iovs.18-24882
31.Flaxel CJ, Adelman RA, Vemulakonda GA, et al; AAO PPP Retina/Vitreous Committee; Hoskins Center for Quality Eye Care. Age-related macular degeneration PPP 2019. October 2019. Accessed May 2, 2023. https://www.aao.org/education/preferred-practice-pattern/age-related-macular-degeneration-ppp
32.Sacconi R, Corbelli E, Querques L, Bandello F, Querques G. A review of current and future management of geographic atrophy. Ophthalmol Ther. 2017;6(1):69-77. doi:10.1007/s40123-017-0086-6
33.Khan H, Aziz AA, Sulahria H, et al. Emerging treatment options for geographic atrophy (GA) secondary to age-related macular degeneration. Clin Ophthalmol. 2023;17:321-327. doi:10.2147/OPTH.S367089
34.Yonekawa Y, Kim IK. Clinical characteristics and current treatment of age-related macular degeneration. Cold Spring Harb Perspect Med. 2014;5(1):a017178. doi:10.1101/cshperspect.a017178
35.Holz FG, Bindewald-Wittich A, Fleckenstein M, Dreyhaupt J, Scholl HPN, Schmitz-Valckenberg S; FAM-Study Group. Progression of geographic atrophy and impact of fundus autofluorescence patterns in age-related macular degeneration. Am J Ophthalmol. 2007;143(3):463-472. doi:10.1016/j.ajo.2006.11.041
36.Biarnés M, Arias L, Alonso J, et al. Increased fundus autofluorescence and progression of geographic atrophy secondary to age-related macular degeneration: the GAIN study. Am J Ophthalmol. 2015;160(2):345-353.e5. doi:10.1016/j.ajo.2015.05.009
37.Liu J, Laiginhas R, Corvi F, et al. Diagnosing persistent hypertransmission defects on en face OCT imaging of age-related macular degeneration. Ophthalmol Retina. 2022;6(5):387-397. doi:10.1016/j.oret.2022.01.011
38.Shi Y, Yang J, Feuer W, Gregori G, Rosenfeld PJ. Persistent hypertransmission defects on en face OCT imaging as a stand-alone precursor for the future formation of geographic atrophy. Ophthalmol Retina. 2021;5(12):1214-1225. doi:10.1016/j.oret.2021.02.004
39.Liao DS, Grossi FV, El Mehdi D, et al. Complement C3 inhibitor pegcetacoplan for geographic atrophy secondary to age-related macular degeneration: a randomized phase 2 trial. Ophthalmology. 2020;127(2):186-195. doi:10.1016/j.ophtha.2019.07.011
40.Jaffe GJ, Westby K, Csaky KG, et al. C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2/3 trial. Ophthalmology. 2021;128(4):576-586. doi:10.1016/j.ophtha.2020.08.027
41.Kalkman J. Fourier-domain optical coherence tomography signal analysis and numerical modeling. Int J Opt. 2017;2017:9586067.
42.Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science. 1991;254(5035):1178-1181. doi:10.1126/science.1957169
43.Niu S, de Sisternes L, Chen Q, Rubin DL, Leng T. Fully automated prediction of geographic atrophy growth using quantitative spectral-domain optical coherence tomography biomarkers. Ophthalmology. 2016;123(8):1737-1750. doi:10.1016/j.ophtha.2016.04.042
44.Pfau M, von der Emde L, de Sisternes L, et al. Progression of photoreceptor degeneration in geographic atrophy secondary to age-related macular degeneration. JAMA Ophthalmol. 2020;138(10):1026-1034. doi:10.1001/jamaophthalmol.2020.2914
45.Reiter GS, Told R, Schranz M, et al. Subretinal drusenoid deposits and photoreceptor loss detecting global and local progression of geographic atrophy by SD-OCT imaging. Invest Ophthalmol Vis Sci. 2020;61(6):11. doi:10.1167/iovs.61.6.11
46.Fleckenstein M, Grassmann F, Lindner M, et al. Distinct genetic risk profile of the rapidly progressing diffuse-trickling subtype of geographic atrophy in age-related macular degeneration (AMD). Invest Ophthalmol Vis Sci. 2016;57(6):2463-2471. doi:10.1167/iovs.15-18593
47.Sarici K, Abraham JR, Sevgi DD, et al. Risk classification for progression to subfoveal geographic atrophy in dry age-related macular degeneration using machine learning-enabled outer retinal feature extraction. Ophthalmic Surg Lasers Imaging Retina. 2022;53(1):31-39. doi:10.3928/23258160-20211210-01
48.Sunness JS, Rubin GS, Applegate CA, et al. Visual function abnormalities and prognosis in eyes with age-related geographic atrophy of the macula and good visual acuity. Ophthalmology. 1997;104(10):1677-1691. doi:10.1016/s0161-6420(97)30079-7
Related Videos
Katherine Talcott, MD, presenting slides
Katherine Talcott, MD, presenting slides
© 2024 MJH Life Sciences

All rights reserved.