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Ophthalmology Management

Article

Shedding Light on Geographic Atrophy

How to diagnose this disease and monitor progression and visual function

By: Elizabeth Yeu, MD, Margaret Chang, MD
Ophthalmology Management July 1, 2023 Vol 27, Issue July 2023 Page(s): 24, 26, 27, 50

Geographic atrophy (GA) is an advanced stage of AMD, a progressive degenerative disease of the retina.1 The prevalence of GA is approximately 5 million worldwide and increases with age.1,2 GA is defined by sharply demarcated, atrophic retinal lesions resulting from progressive loss of photoreceptors, retinal pigment epithelium (RPE) and the underlying choriocapillaris, which results in gradual irreversible vision loss as the disease progresses.1 Patients with GA may not notice much change in functional vision at first clinical presentation because most patients present with nonfoveal lesions, which are associated with less severe visual impairment than foveal GA.3,4 However, lesions often expand, inducing a noticeable scotoma, and can include the fovea as early as 2.5 years after diagnosis.4-7

Until this year, no therapies for GA were FDA-approved. Now, we have one approved therapy available (Syfovre, Apellis Pharmaceuticals) and one therapy under FDA review (avacincaptad pegol, Iveric Bio).8,9 Guidance within the eye-care professional community on identifying patients who are at risk of developing GA and/or patients who are at risk for higher rates of GA progression is necessary in order to aid in potential treatment.

IDENTIFYING GA

Overview

Many patients initially present to optometrists and general ophthalmologists with early signs of dry AMD, such as drusen and RPE changes. They may be asymptomatic at first or only notice mild blurring. Others with more significant atrophy may experience visual disturbances such as metamorphopsia, problems reading or tracking a ball, or central vision loss. Fundus imaging is useful for AMD screening and detection, and serial imaging is especially useful to track GA progression over time.

Imaging modalities

GA is a heterogeneous disease, and progression rates for GA can vary and be unpredictable, ranging from 0.53-2.6 mm2/year.1,10 Therefore, measuring GA lesion size is critical for assessing the progression of disease.11 Multimodal imaging may be necessary for more reliable measurement of GA lesion size compared to single imaging.12

GA is seen on fundus photography as a sharply demarcated, atrophic lesion of the outer retina. Large choroidal vessels are usually visible through the area of GA because of the loss of overlying photoreceptors, RPE and choriocapillaris. Cases that are less clear on fundus photography are better imaged with fundus autofluorescence (FAF). The loss of RPE lipofuscin in GA areas leads to high-contrast images, with GA areas detected as regions of hypoautofluorescence; sequential FAF images may help with observing the rate of lesion progression and can be shown to patients to inform them about how quickly their lesion is growing over time.

However, the foveal area may be difficult to assess with FAF, and it may not be ideal for patients with parafoveal lesions.1,12

GA lesions can also often be identified with confocal near-infrared reflectance (NIR) images, which are commonly obtained at the same time as optical coherence tomography (OCT) images.13 Because no flash is required, the laser can penetrate media opacities more easily than conventional color fundus imaging, and the imaging is quite comfortable for the patient. Areas of GA correspond to increased NIR intensity and hyperreflectivity. Although NIR is often a useful substitution for FAF, GA can be isoreflective or hyperreflective and can be difficult to identify in NIR images in patients with thin choroid.14

In addition, since these images are not as high contrast as FAF, GA progression with serial imaging can be more difficult to demonstrate to the patient. GA lesions are easily identified on fluorescein angiography (FA). The GA areas appear hyperfluorescent with good visibility of choroidal vessels. FA has the added advantage of detecting occult choroidal neovascular membranes, which can occur at the edges of GA lesions; however, some patients have severe nausea with FA, and there is a small risk of fluorescein allergy and anaphylaxis.

Spectral-domain optical coherence tomography (SD-OCT) and swept-source OCT have many advantages in observing GA lesion growth. These include cross-sectional and en-face imaging with three-dimensional quantitative assessment of atrophy between different retinal layers and wider imaging areas and greater detail of the choroid, respectively.11,12 The Classification of Atrophy Meeting (CAM) group proposed a framework based on changes visualized on OCT that denoted the evolution of the atrophic process. The group agreed that GA and nascent GA are considered subsets of complete RPE and outer retinal atrophy (cRORA) and incomplete RPE and outer retinal atrophy (iRORA) in the absence of choroidal neovascularization (CNV), respectively.15

FIGURE. A. Color photograph of a geographic atrophy (GA) lesion. B. Fundus autofluorescence reveals distinct, sharply demarcated areas of hypofluorescence corresponding to the GA lesion. C. Near infrared image of GA on the left, with the green arrow demonstrating plane of OCT image; OCT image on the right reveals complete loss of photoreceptors and the retinal pigment epithelium in the areas of GA. Despite significant progression of GA, BCVA for the patient was 20/40 OS. However, the patient was experiencing significant problems with their ability to read due to blind spots and no longer drives. This highlights that BCVA may not always reflect visual function and its impact on daily activities.

Identifying predictors

Because irreversible vision loss can occur as GA progresses, identifying predictors of disease progression can be critical for preserving vision. Risk factors for GA development can include older age, smoking, diet and genetics.16-18

Predictors of GA development and disease progression can also include imaging features or biomarkers. Imaging features that have been shown to be associated with the development of GA in patients with AMD include specific drusen (eg, soft, reticular, close distance to the fovea, calcified, larger area), pigmentary (eg, presence of RPE depigmentation, hyperpigmentation) and lesion (eg, intraretinal hyperreflective foci, persistent hypertransmission defects) characteristics.17,19-22 Larger baseline lesion size, multifocal lesions, banded/diffuse perilesional FAF patterns, nonfoveal location in the affected eye, reticular pseudodrusen (RPD), bilateral GA and fellow eye CNV are some lesion characteristics linked to higher rates of GA progression.1,23-26 OCT imaging features associated with faster GA progression rates include changes in photoreceptors, the ellipsoid zone, outer retinal layer thickness and the junctional zone area.27-31

TIPS AND PERSPECTIVES

Dr. Elizabeth Yeu: Dr. Chang, as a retina specialist, how do you monitor your patients with GA, and how do you determine which patients are more likely to progress once diagnosed with GA?

Dr. Margaret Chang: At each visit, I perform FAF, OCT and BCVA. FA can also be useful to detect hidden CNV lesions at the edge of the GA lesion, although fluid will usually be present in that area on OCT. The fellow eye of a patient with central GA is definitely at higher risk of GA progression and vision loss, especially if it has any parafoveal lesions. Some central drusenoid pigment epithelial detachments (PEDs) will reabsorb and become central GA; if the height of a drusenoid PED decreases, central GA can follow in as little as 6-12 months.

MC: Dr. Yeu, which imaging and functional tests do you prefer for diagnosing and monitoring disease progression in the clinic?

EY: In my clinic, most of my patients are anterior segment (ie, cataract, LASIK, corneal) surgical evaluation patients. Patients often know they have a diagnosis of “macular degeneration,” but I end up providing the more specific diagnosis of GA from the OCT macula that is routinely performed on all the surgical evaluations. The OCT macula is also performed for all follow-up examinations of AMD patients. Currently, I am working more diligently with the referring optometrists to get GA patients connected with a retina colleague. We check the Amsler grid and BCVA at 12.5% contrast sensitivity. Upon history intake, we routinely inquire about reading speed, quality of life and any interim changes in vision with respect to driving and lifestyle changes due to vision.

MONITORING GA PROGRESSION

Focus on visual function

Newly diagnosed patients with GA may experience early preservation of best-corrected visual acuity (BCVA) but report impairment in other visual features such as reading, which can negatively impact patients on a daily basis.3,11 However, patients with GA and good BCVA (≥20/50) are at high risk for future visual decline, with one study reporting 40% of patients experiencing a 2-year rate of ≥3-line letter loss.32-34 Therefore, it is important to monitor the impact of disease worsening on visual function.

Patients often seek guidance from their retina specialist regarding the utility of new refractions and cataract surgery when there is a decline in vision. A coordinated effort between the retina specialist and the referring general ophthalmologist or optometrist is necessary to offer the patient an optimal visual outcome. Although a gold standard in assessing visual acuity, BCVA may also underrepresent deficits in visual function, particularly in eyes with nonfoveal lesions, and the correlation between changes in BCVA and GA lesion size are not robust; therefore, other assessments may be needed to comprehensively evaluate visual declines that are also relevant to a patient’s quality of life (QoL).3,7,11,32,35,36

Reading ability

Patients with GA often experience difficulties with reading, even if they have good BCVA.36 Changes in patients’ ability to read can prevent them from enjoying or partaking in hobbies and contribute to feelings of loss of independence.37,38 Reading difficulties can also indicate presence of a scotoma, which a patient may not even realize they have, especially when they have good central vision.39 Assessing reading speed (whether patients can read full sentences and words rather than single letters) will provide information on how well the central visual field is preserved.3,39

Several studies report reduced reading speed in patients with GA.3,40-43 In one study, reading speed was worse in patients with GA compared to those with early/intermediate AMD and decreased significantly within 2 years for patients with GA,3 suggesting reading speed can be used to monitor disease worsening.

Visual impairment and functional testing

Amsler grid monitoring can also be used by patients at home to detect new scotomas or distortions that may indicate a change in AMD status. A drawback of this test is that it may not be sensitive enough to detect small changes.44,45

Further, patient questionnaires such as the National Eye Institute Visual Function Questionnaire, Activities of Daily Vision Scale and the Functional Reading Independence Index can provide an understanding of how visual impairment is affecting a patient’s daily activities,46-48 which can be a valuable tool for monitoring disease progression that may complement other functional testing.

On low-light settings

Patients with GA can experience increased visual impairment under low-light settings, which may affect their ability to read and drive at night.3,7,49 Low-luminance visual acuity (LLVA) measures visual function under reduced illumination and is rapid and simple to perform.32 Low-luminance deficit, the difference between BCVA and LLVA, may predict future visual acuity loss in patients with GA.32 Interestingly, one study reported that patients with early AMD with good night vision were less likely to develop GA than those with poor night vision.50 However, some suggest LLVA may have limited sensitivity in measuring retinal function outside of the fovea.35,51 Patients with GA have also been shown to have reduced contrast sensitivity despite good BCVA.3,11 Further, contrast sensitivity has been shown to impact vision-related QoL in patients with all stages of AMD, suggesting it may be affected earlier in the disease course and could be a potential tool for monitoring disease progression.52-54

Microperimetry

Compared to LLVA and contrast sensitivity, a more detailed and sensitive visual function assessment that encompasses specific areas of the retina can be achieved with microperimetry.11,33 Strengths of microperimetry are that it employs eye-tracking technology to provide fundus-controlled testing and mapping of retinal sensitivity that are reliable and precise.11,55 Microperimetry can be a valuable tool for evaluating progression from intermediate AMD to GA or GA progression, because it provides data that correlate functional and anatomical features of visual impairment, and changes in microperimetry have been associated with GA disease progression.35,55-57 However, microperimetry requires complex instrumentation,58 machines that are not readily available in most offices, and the test can be quite tiring and time-consuming for the patient.35,59

CONCLUSION

GA is a progressive eye disease resulting in irreversible vision loss. Guidelines to identify which patients are at risk for developing GA and to monitor GA progression are currently lacking. With a new GA therapy approved, another under FDA review, and others under investigation, identifying which patients are at risk for GA progression is critical for preserving vision and providing patients with more control over their disease. OM

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Elizabeth Yeu, MD, is a cataract, corneal and refractive surgeon at Virginia Eye Consultants/EyeCare Partners in Norfolk, Va., and an assistant professor at Eastern Virginia Medical School in Norfolk, Va. She is the current president of the American Society of Cataract and Refractive Surgery. Disclosures: Dr. Yeu is a consultant for AcuFocus, Advanced Vision Group, Aldeyra, Allergan, Aurion, Avellino, Bausch & Lomb, BioTissue, BlephEx, Bruder, BVI, Centricity, CorneaGen, Dompe, Elios, Expert Opinion, Eyenovia, Glaukos, Guidepoint, Iveric Bio, J&J Vision, Kala Pharmaceuticals, LayerBio, LensAR, Melt, Merck, New World Medical, Novartis, OCuSOFT, OSRX, Samsara, ScienceBased Health, Sight Sciences, STAAR, Surface, Tarsus, Thea, Visus and Zeiss. She has participated in speaker bureaus for Alcon and has conducted research with AcuFocus, Alcon, BioTissue, New World Medical, OSRX and Tarsus. She is a director for Avellino, OSRX, STAAR and Tarsus.

Elizabeth Yeu, MD, is a cataract, corneal and refractive surgeon at Virginia Eye Consultants/EyeCare Partners in Norfolk, Va., and an assistant professor at Eastern Virginia Medical School in Norfolk, Va. She is the current president of the American Society of Cataract and Refractive Surgery. Disclosures: Dr. Yeu is a consultant for AcuFocus, Advanced Vision Group, Aldeyra, Allergan, Aurion, Avellino, Bausch & Lomb, BioTissue, BlephEx, Bruder, BVI, Centricity, CorneaGen, Dompe, Elios, Expert Opinion, Eyenovia, Glaukos, Guidepoint, Iveric Bio, J&J Vision, Kala Pharmaceuticals, LayerBio, LensAR, Melt, Merck, New World Medical, Novartis, OCuSOFT, OSRX, Samsara, ScienceBased Health, Sight Sciences, STAAR, Surface, Tarsus, Thea, Visus and Zeiss. She has participated in speaker bureaus for Alcon and has conducted research with AcuFocus, Alcon, BioTissue, New World Medical, OSRX and Tarsus. She is a director for Avellino, OSRX, STAAR and Tarsus.

Margaret A. Chang, MD, MS, is a senior partner at Retinal Consultants in Sacramento, Calif. Disclosures: Dr. Chang is a consultant for Genentech/Roche, Inc., REGENXBIO and Iveric Bio. She receives research/grant support from Allergan, EyeBio, Mylan, NGM Biopharmaceuticals, Novartis, OcuTerra, Ophthea and Regeneron.

Margaret A. Chang, MD, MS, is a senior partner at Retinal Consultants in Sacramento, Calif. Disclosures: Dr. Chang is a consultant for Genentech/Roche, Inc., REGENXBIO and Iveric Bio. She receives research/grant support from Allergan, EyeBio, Mylan, NGM Biopharmaceuticals, Novartis, OcuTerra, Ophthea and Regeneron.

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