Geographic atrophy: What to know and why

Geographic atrophy (GA) is a finding associated with advanced stage of age-related macular degeneration (AMD). Some even consider it to be an advanced form of AMD.

GA is a progressive and irreversible degeneration of the retinal pigment epithelium and outer retina, which can result in irreversible vision loss. The vision loss associated with GA is not always appreciated in Snellen acuity and other vision function testing and is more of a “functional vision loss.”

Although visual acuity main remain reasonably well, patients often complain about difficulty functioning in dim light, reading, driving, etc.

Risk factors

Risk factors for GA are not that different from AMD itself; it is a multifactorial and complex problem. There are most likely aspects of it that are still elusive. Aging and family history; inflammation; lifestyle choices such as smoking, poor diet, lack of physical activity; and comorbidities such as obesity, systemic hypertension, and lipid disorders all play a role.¹

Genetic prediction is one of the complicated associated risk factors that has received a great deal of attention and it will likely play a role in potential treatments for GA that do not yet exist.

Pathophysiology

The visual cycle and sight would not be possible without the retinal pigment epithelium (RPE), one of the most biologically active tissues in the body. As a result of this high degree of activity, the RPE is under a great deal of oxidative distress.² Inflammation and apoptosis are other physiological factors.³

The complement system—which is the innate component of the immune system—also plays a pivotal role. The complement system is a complex cascade containing multiple proteins and regulators and is always active to protect from offending agents such as bacteria and viruses.

However, there are mechanisms to keep it in check. With aging and genetic mutation, these mechanisms become less effective, resulting in overactivation of this system.

A large, genome-wide association study of AMD showed the genetic mutation of regulators and the complement factor supporting the involvement of this system as a genetic risk factor for AMD.⁴ Studies have also shown accumulation of complex inside RPE cells,⁴ whereas postmortem examinations have detected complement deposition in drusen and RPE cells.⁵

Given this, these concepts well establish the role of genetics and the complement system in cell degeneration associated
with AMD.

Clinical findings

Examination to detect GA should have 2 objectives: the actual presence of GA, either in funduscopic examination or detection by multimodal imaging; and the detection of pre-GA lesions or GA predictors. Both will play an important role in the current and future management of patients.

Predictors for GA include the presence of GA in the fellow eye, detectable reticular pseudodrusen, as well as the presence of large or confluent drusen, drusenoid pigment epithelial detachments, and lipofuscin.

Recognition of pre-GA biomarkers on imaging techniques such as infrared or near-infrared photographs, fundus autofluorescence, and particularly examination of tomographic cross-section of the macular region by optical coherence tomography play a crucial role (see Patient 1 Examination).

The presence of GA also requires clinical examination of the retina and the use of aforementioned imaging techniques (see Patient 2 Examination).

Once GA is detected, there are also prognostic indicators for progression of the disease. Further, imaging plays a crucial role in the assessment and management of patients (see Further Examination).

Management of GA

As of fall 2022, there are still no available treatments for GA. Although the Age-Related Eye Disease Studies (AREDS) showed that the use of certain antioxidant are beneficial in risk reduction for neovascular AMD (nAMD), they failed to show benefits for GA prevention.⁶ Smoking cessation and management of comorbidities should play a role.

However, there are no equivalents to anti–VEGF inhibitors that have revolutionized the treatment of nAMD. Several novel agents are currently in various clinical trial phases, with many of these agents aiming to inhibit or block the cleavage of an assortment of factors of the complement cascade (such as C3 and C5).

The downstream effect of these factors will result in the formation of protein complexes such as inflammasome and membrane attack complex, which are responsive in cellular death; in this case, RPE and photoreceptors. There are positive indications that these complement inhibitors can be instrumental in the treatment of GA and prevention of vision loss.

Conclusion

GA is a common condition affecting over 1 million patients in the United States.⁷ With an aging population, there is an increasing incidence among patients across the country.

GA is a progressive and irreversible condition, resulting in the loss of visual function. Although there are no definitive remedies—and with potential treatment over the horizon—eye care providers should begin to pay closer attention to their patients who have or are at risk of developing GA. This can be done by starting a dialogue about these conditions and establishing referral protocols for when treatments are available and announced.

References

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