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Tuesday / November 12.
HomemieyecareGeographic Atrophy Three Tell-Tale Signs

Geographic Atrophy Three Tell-Tale Signs

Treatment options are on the near horizon for geographic atrophy (GA). Academic and clinician Angelica Ly explains why this makes it important for optometrists to familiarise themselves with the fundamental appearance of this disease and commence baseline imaging for patients with it.

Geographic atrophy (GA) is a subtype of late, non-neovascular age-related macular degeneration (AMD) that affects an estimated five million people globally and is most common in European individuals.1 It is phenotypically defined by anatomical loss of the photoreceptor layers, the retinal pigment epithelium (RPE), and the choriocapillaris.

Patients with GA may initially experience paracentral scotomas. Central visual acuity at this stage is often preserved due to foveal sparing; however, as the lesion/s progress, over one-third of individuals with GA will experience a three-line or worse reduction in visual acuity over a two-year period.2 Two-thirds of individuals will be ineligible to drive within two years and approximately 42% of patients with GA will be legally and permanently blind.3,4

Using colour fundus photography, GA was originally defined as ‘any sharply delineated roughly round or oval area of hypopigmentation or depigmentation or apparent absence of the RPE in which choroidal vessels are more visible than in surrounding areas that must be at least 175μm in diameter’.5 Recording presence, location, and area of atrophy is also helpful. Consistent with the consequences on vision, GA lesions typically start in the parafovea. Over time, lesions may coalesce to form a ring of atrophy surrounding the fovea, with eventual end-stage foveal involvement. Lesions can also vary considerably in size, ranging anywhere from the minimum size of 175μm to exceed the full 6mm diameter of the macula. They may be single (unilobular), multiple (multilobular), and involve one or both eyes.

While this description may appear relatively straightforward, GA can be difficult to assess. Small lesions are often missed, especially without stereoscopic fundus examination and appropriate imaging. Additionally, other AMD lesions, such as drusen, can sometimes obscure the visibility of atrophic areas. Imaging technologies can significantly reduce this ambiguity. Optical coherence tomography (OCT) is becoming increasingly accessible in optometric practice, while fundus autofluorescence forms the gold standard for evaluating GA.

A new treatment for GA has recently received FDA approval (pegcetacoplan, a complement inhibitor) in the United States,6 making it ever more important for eye care professionals to accurately identify persons with GA so that they may go on to receive timely, sight-saving treatment to delay the risk of progression, where appropriate.

Here are three tell-tale signs which may hint that GA is present. These features are commonly seen in areas of GA and can help optometrists identify atrophy and direct management appropriately.

Tell-Tale Sign One

Well-delineated areas of decreased fundus autofluorescence (hypo-autofluorescence) of a similar intensity to the optic nerve head or retinal blood vessels.

Any well-delineated, focal, approximately round, hypo-autofluorescent area in the macula should arouse suspicion for GA. The high contrast between hypo-autofluorescent atrophic areas versus the surrounding nonatrophic background makes lesions relatively easy to identify, compared with fundoscopy or fundus photography. Consequently, fundus autofluorescence is now the primary method for detecting, monitoring, and quantifying atrophic lesions.7 Fundus autofluorescence images can also be helpful for assessing foveal involvement, taking care not to mistake the natural reduction in signal that occurs centrally due to absorption of short wavelength light by macular pigment, which may be more problematic in blue light (e.g., the Spectralis HRA2, Heidelberg Engineering, Heidelberg, Germany) versus green-light fundus autofluorescence systems (Optos systems, Dunfermline, Scotland; Figure 1).

Figure 1. (A) Colour fundus photograph from an 88-year-old female with late AMD showing small, hard-to-discriminate areas of GA in the parafovea and associated refractile drusen. (B) Magnified insert showing well-delineated atrophic areas of outer retinal, RPE, and choroidal thinning, which are easier to identify using (C) fundus autofluorescence.

CLINICAL PEARL
Patients with or suspected of GA should have baseline fundus autofluorescence imaging performed either in-house or via referral to a colleague.

Tell-Tale Sign Two

Choroidal hypertransmission in the parafovea using OCT.

Many OCT instruments provide either a scanning laser ophthalmoscopy or reconstructed en face infrared image of the fundus. This overview image can be especially helpful for allowing accurate orientation of cross-sectional b-scans at anatomic sites of interest and provides a coronal full macular view. In a normal healthy eye, the image appears uniformly grey with decreased reflectance at the blood vessels and fovea centre. A tell-tale sign of GA is the appearance of circular, hyper-reflective regions, particularly within the parafovea (Figure 2B).

Figure 2. (A) Cirrus OCT (Carl Zeiss Meditec, Jena, Germany) macular thickness analysis whereby the (B) en face fundus overview image reveals several bright round areas due to increased penetration of light into the choroid, corresponding with the areas of GA. (C) Manually adjusted sub-RPE view to show the same areas with increased contrast.

This occurs due to increased signal transmission into the choroid, courtesy of the atrophy-related absence of the RPE and choriocapillaris.8,9 For added sensitivity, the en face image can be manually adjusted to display a sub-RPE representation of the macula by adjusting the segmentation reference boundaries to approximately 65μm to 400μm below the RPE fit (Figure 2C).8 Line by line inspection of the constituent b-scans should reveal a corresponding abrupt increase in choroidal transmission and loss of the absorbing outer retina and RPE, often likened to a ‘waterfall’ effect (Figure 3A).10,11

CLINICAL PEARL
Inspect the en face OCT fundus image and corresponding b-scans closely in patients with AMD. Focal areas of choroidal hypertransmission, especially in the parafovea, may indicate the presence of GA.

Tell-Tale Sign Three

Refractile drusen visible using fundoscopy or colour fundus photography.

Drusen, the hallmark sign of AMD, have been variously described as hard, soft, confluent, cuticular, and calcified among other terms. ‘Refractile’ drusen are a feature of AMD frequently seen in, or just preceding, the development of GA.12-14 They are a subtype of calcified drusen that present as white, glistening deposits with highly reflective dots in the macula using colour fundus photography. On OCT, the overlying RPE is typically absent with associated loss of the outer retina and choroidal hypertransmission (Figure 3B). All eyes with calcified drusen at the macula should be carefully inspected for concurrent GA.

Figure 3. (A) Cirrus OCT b-scans through the areas of GA show a ‘waterfall effect’ i.e., abrupt choroidal hypertransmission and overlying loss of the outer nuclear layer, ellipsoid zone, and RPE/BM, with a similar appearance around (B) calcified drusen, indicated by the arrow. All images courtesy of the School of Optometry and Vision Science, UNSW Sydney.

CLINICAL PEARL
Refractile drusen are a feature frequently seen in eyes with GA or shortly preceding its development.

Prepare For Treatment Now

The long-awaited time is nigh; patients with GA in Australia may soon be offered a treatment, which has never before been available. It is important that eye care practitioners familiarise themselves with the fundamental appearance of GA, so that these cases don’t slip through the cracks. Relying on patient self-reported symptoms or visual acuity, especially in the initial stages, has limited sensitivity. All patients with GA should have baseline imaging, including fundus autofluorescence, performed. Readers are encouraged to apply the tell-tale signs described in this article to increase their clinical sensitivity for diagnosing GA.

Dr Angelica Ly BOptom(Hons) GradCertOcTher PhD FAAO is a Senior Lecturer at the School of
Optometry and Vision Science, UNSW Sydney.

She is a consultant to Apellis Australia.

The author thanks Associate Professor Lauren Ayton for reviewing.

References
1. Wong W.L., 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 metaanalysis. Lancet Glob Health 2014; 2: e106-116.
2. Schmitz-Valckenberg S., Nadal J., Fimmers R. et al., Modeling visual acuity in geographic atrophy secondary to age-related macular degeneration. Ophthalmologica 2016; 235: 215-224.
3. Chakravarthy U., Bailey C.C., Johnston R.L. et al., Characterizing disease burden and progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmology 2018; 125: 842-849.
4. Klein R., Wang Q., Klein B.E. et al., The relationship of age-related maculopathy, cataract, and glaucoma to visual acuity. Investigative Ophthalmology & Visual Science 1995;
36: 182-191.
5. Bird A.C., Bressler N.M., Bressler S.B. et al., An international classification and grading system for agerelated maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group. Surv Ophthalmol 1995; 39: 367-374.
6. Apellis. FDA Approves SYFOVRE (pegcetacoplan injection) as the first and only treatment for geographic atrophy (GA), a leading cause of blindness. 2023. Available from: investors.apellis.com/news-releases/news-releasedetails/fda-approves-syfovretm-pegcetacoplan-injection-first-and-only [accessed 22 March 2023].
7. Schmitz-Valckenberg S., Sahel J-A., Danis R. et al., Natural history of geographic atrophy progression secondary to age-related macular degeneration (geographic atrophy progression study). Ophthalmology 2016; 123: 361-368.
8. Yehoshua Z., Garcia Filho C.A., Penha F.M. et al., Comparison of geographic atrophy measurements from the OCT fundus image and the sub-RPE slab image. Ophthalmic Surg Lasers Imaging Retina 2013; 44: 127-132.
9. Pilotto E., Guidolin F., Convento E. et al., En face optical coherence tomography to detect and measure geographic atrophy. Investigative Ophthalmology & Visual Science 2015; 56: 8120-8124.
10. Fleckenstein M., Mitchell P., Freund K.B. et al., The progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmology 2018; 125: 369-390.
11. Gune S., Abdelfattah N.S., Karamat A. et al., Spectral-Domain OCT- based prevalence and progression of macular atrophy in the HARBOR study for neovascular age-related macular degeneration. Ophthalmology 2020; 127: 523-532.
12. Jaffe G.J., Chakravarthy U., Freund K.B. et al., Imaging features associated with progression to geographic atrophy in age-related macular degeneration: classification of
atrophy meeting report 5. Ophthalmol Retina 2021; 5:855-867.
13. Suzuki M., Curcio C.A., Mullins R.F. et al., Refractile drusen: Clinical imaging and candidate histology. Retina 2015; 35: 859-865.
14. Klein M.L., Ferris F.L. 3rd, Armstrong J. et al., Retinal precursors and the development of geographic atrophy in age-related macular degeneration. Ophthalmology 2008; 115: 1026-1031.

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