“Geographic atrophy (GA) is a complex and evolving condition,” says Steven Ferrucci, OD, FAAO. “With new treatments and better understanding of diagnostics and progression, it's an exciting time for those of us managing age-related macular degeneration (AMD) in clinical practice to think about GA.” To demonstrate this, he gathered three experts—Jeffry Gerson, OD, FAAO; Carolyn Majcher, OD, FAAO; and Mile Brujic, OD, FAAO—to test their GA knowledge through a friendly round of Jeopardy!
If you’re not quite ready to jump straight into the GA Jeopardy! challenge yourself, have no fear. Here are some revision notes to help you brush up on your knowledge before you play alongside the experts.
The fundamentals
GA is one of the two advanced forms of AMD, being specifically characterized by atrophic lesions that initially appear in the outer retina but progressively expand across the macula and fovea, ultimately resulting in permanent vision loss over time.1 It is a condition that affects an estimated 1.5 million people in the United States,2 accounting for over one-fifth of the global estimated GA prevalence, which currently stands at over 5 million.3
GA is also a growing problem, with 160,000 new US cases being identified each year—but this incidence—which mirrors that of neovascular AMD, the other form of late-stage AMD—is expected to increase in the coming decade as a result of increases in the aging population.3 At present, the average age of a GA patient is 79 years; however, as the age demographic that a patient resides in increases, so does the GA prevalence, which quadruples every 10 years, from 0.16% at 60 years of age to 2.91% at 80.1
Age and family history are the risk factors with the highest correlation to GA. Additionally, there are other leading risk factors such as genetic mutation and smoking.1
In the image
Although GA results in a loss of vision, not all GA patients will experience decreased visual acuity (VA), and even in those who do, VA may not consistently parallel the progression of central GA.4 Instead, to identify GA within a patient, the ideal approach is to examine clinical features using ophthalmoscopy and imaging to identify several features, including cell layer loss with clearly defined borders, alongside the loss of retinal pigment epithelium (RPE), photoreceptors, and underlying choriocapillaris.1Often a multimodal imaging approach is employed, including fundus autofluorescence (FAF), optical coherence tomography (OCT), and color fundus photography (CFP).1
FAF is considered the gold standard for detecting GA and assessing the size and growth of GA lesions in clinical trials. Because RPE cells contain intrinsic fluorophores, such as the pigment lipofuscin, their loss in GA lesions results in these areas appearing hypoautofluorescent. Additionally, hyperautofluorescence in the areas around the lesions may be indicative of activity and potential GA progression.5
The cross-sectional and en face views that OCT offers enable the retinal layers to be evaluated and, over time, can reveal the progressive loss of these layers. OCT imaging can also be used as a predictive tool to determine the potential progression of drusen to GA, as the detection of choroidal hypertransmission defects can highlight.6 Alternatively, it can identify the increased likelihood of GA progression, as signposted by hyperreflective foci (HRH).7
CFP is the historical standard for imaging GA, in which lesions are highlighted as clearly demarcated areas of RPE hypopigmentation, with underlying choroidal vessels that are plainly visible. However, CFP can’t be used to identify lesions associated with progressive GA, meaning that by the time you notice a lesion using this modality, things have likely progressed from the early stages.
Together such imaging can enable practitioners, to not only identify the presence and progression of GA lesions, but also signs that may influence the rate at which a GA patient’s condition is likely to progress—characteristics such as focality, location, and lesion size can all affect this, with larger, multifocal lesions that are located in the extrafoveal part of the retina having the highest expected rate of progression. On average, it takes around two-and-a-half years for a lesion to reach the macula—so intervention as early as possible is crucial.8
Preventing (further) progression
At present, we don’t have any GA therapeutics designed to reverse lesions; instead, current efforts look to slow down any future progression. The first FDA-approved treatment for GA, SYVOFRE, came to market in early 2023,9 followed later on in the year by IZERVAY. Both work by targeting the underlying, complement signaling cascade, which forms part of the innate immune system but causes problems when overactivated.10 Although there are a number of signaling pathways that comprise the complement cascade, they converge at the protein C3 and then travel down through to C5, which is why C5 is targeted by IZERVAY while SYVOFRE acts earlier on in the process at the upstream C3.
However, a lot of work is being done in this area. Alongside investigation into several complement factors—such as CFB, CFD, CFH, and CFI—as possible therapeutic targets, recent research has also highlighted the potential of oral micronutrient supplementation, such as those taken by the participants in the Age-Related Eye Disease Study (AREDS) and AREDS2, multicenter randomized placebo-controlled trials (0 mg lutein/2 mg zeaxanthin, 350 mg docosahexaenoic acid/650 mg eicosapentaenoic acid, combination).11 As Dr. Ferrucci said, it’s an exciting time to be working in the GA space!
A challenger approaches…
So, are you ready to take on Drs. Gerson, Majcher, and Brujic in the GA Jeopardy! challenge? There’s only one more thing to keep at the forefront of your mind as you play along: always answer in the form of a question!
