Geographic atrophy (GA) has long represented one of the most significant unmet clinical needs in the treatment of age-related macular degeneration (AMD). The prevalence of advanced forms of AMD, such as GA or choroidal neovascularization (CNV), continues to increase significantly as a population ages.^1,2 Although patients with wet AMD have benefitted from the advent of anti-VEGF agents, patients with GA have faced a slow, inexorable path of vision loss. The natural history of GA involves progressive enlargement of atrophic lesions with increasing visual disability.³ Discrete areas of atrophy of the retinal pigment epithelium (RPE) and overlying retina enlarge slowly, resulting in growing scotomata that may eventually involve central vision. Chronic inflammation, through dysregulation of the complement cascade, plays a pivotal role in the growth of GA lesions.⁴ The results of recent clinical trials involving inhibition of the complement cascade, and the advent of pegcetacoplan (Syfovre; Apellis Pharmaceuticals) becoming the first FDA approved drug to treat GA, provide an opportunity to slow the course of this heretofore untreatable disease. Avacincaptad pegol (Iveric Bio) is also on a course toward FDA approval for GA, with a PDUFA date of August 19, 2023. New treatment options will mean new challenges for retina specialists in terms of patient identification and education as well as in the development of efficient routines for delivering care.

RAISING AWARENESS AMONG PATIENTS

One of the simplest, yet most important, aspects of initiating care in patients with GA will be raising awareness that treatment is now available. Currently, most patients with nonexudative AMD and GA are followed on an annual or semiannual basis. Given that no active treatments were available in the past, many patients have returned to their primary eye-care specialist for monitoring. Moreover, a great many more may never have been referred to a retina specialist due to the perceived inability to treat the condition. It will be beneficial for retinal physicians to reach out to their referral sources to raise awareness that treatment for GA has now become a reality. In addition, it will be important to highlight the fact that GA tends to be underdiagnosed without the aid of ancillary tests that are more commonly available in retina practices. For those patients who have been previously seen but are lost to follow-up, a review of medical records with the appropriate diagnosis codes may allow for re-engagement and a discussion of the new treatment. The use of social media or practice websites may also be helpful in raising awareness. Given that the effect of treatment has been shown to increase with the duration of therapy, offering intervention as soon as clinically warranted would be most beneficial for patients suffering from GA.

CONVERSATIONS WITH PATIENTS

The next step in the process will be an informed discussion with patients regarding treatment and expected outcomes. Although many patients are already somewhat familiar with the concept of intravitreal injections for wet macular degeneration, the risk-to-benefit ratio of treating GA will likely be a more nuanced conversation. The main difference is that treatment for GA is largely preventative and slows the growth of the lesion(s), something that may not be readily perceived by the patient.

Although they may be aware that they have a problem with tasks such as reading, patients will need to understand that the treatments will not restore vision, but rather slow further deterioration. In addition to discussing their progressive symptoms, it is often more illustrative to review enlarging GA lesions with the patients using their own fundus photographs, near infrared images, optical coherence tomography (OCT) images, or fundus autofluorescence images. If the patient’s serial images are not available, representative images can be reviewed. Furthermore, it is important to emphasize that starting treatment early and continuing for longer periods compounds the benefits, thereby effectively preserving remaining vision for a longer period during the patient’s lifetime.

Because ongoing treatment is planned, patients should be counseled that there will likely be some injection fatigue. In addition, attention should be paid to potential side effects. Besides the known side effects of the intravitreal injection procedure, there is a low rate of exudative macular degeneration that occurred in both the monthly and every-other-month treatment protocols.⁵ Patients, as well as referring doctors, will understandably have some trepidation regarding this. However, it is reassuring to note that those patients who developed exudation during the trials did well with standard anti–vascular endothelial growth factor (anti-VEGF) treatment. If needed, an anti-VEGF injection can be given the same day, after waiting for the intraocular pressure to normalize, or at a separate visit.

IMAGING FOR PATIENTS WITH GEOGRAPHIC ATROPHY

Optical coherence tomography remains an integral part of managing wet AMD, but also can play a role in the management of GA. Geographic atrophy lesions are typically associated with hypertransmission of the signal into the choroid. The Classification of Atrophy Meeting (CAM) has defined incomplete retinal pigment epithelial and outer retina atrophy (iRORA) as a region of signal hypertransmission into the choroid with corresponding attenuation or disruption of the RPE and evidence of overlying photoreceptor degeneration.⁴ These precursor lesions can progress to complete retinal pigment epithelial and outer retinal atrophy (cRORA) defined as a region of hypertransmission of at least 250 μm in diameter with a zone of attenuation or disruption of the RPE of at least 250 μm in diameter and evidence of overlying photoreceptor degeneration in the absence of an RPE tear. While monitoring these findings may be better suited for clinical trials than for daily clinical practice, OCT plays an integral role in detecting the presence of other concomitant pathology. Reticular pseudodrusen represent a risk factor for progression to GA as well as CNV.⁶ These yellow-white deposits occur in a reticular pattern and are seen between the RPE and ellipsoid zone as granular hyperreflective deposits on OCT. Another important use of OCT to consider when treating patients with GA is to look for lesions that can predispose to exudation later during treatment. The presence of a double layer sign, seen as 2 hyperreflective bands with a hyporeflective band in between, may indicate type 1 CNV even in the absence of subretinal fluid. If noted prior to or during treatment for GA, the clinician should be alerted to a potential higher risk for exudation and the need to initiate treatment with an anti-VEGF agent should it occur.

Fundus autofluorescence (FAF) likely will see expanded use in patients with GA. Fundus autofluorescence shows GA as well-defined areas of significantly decreased autofluorescence. These areas can be unifocal or multifocal, and the growth in lesion area in terms of mm² can be measured over time. Fundus autofluorescence often highlights subtle lesions and facilitates identifying risk factors for progression. These include the presence of multifocal lesions or simply GA in the fellow eye. Extrafoveal lesions also tend to exhibit faster growth. Patterns of increased autofluorescence in the areas surrounding GA lesions can also be predictive of progression. These areas may indicate locations of abnormal cellular metabolism. Notable patterns of increased autofluorescence include focal, banded, patchy, and diffuse.^7,8 Patients with a focal pattern demonstrate small spots of increased autofluorescence surrounding the GA lesion. Those with a banded pattern show a continuous band of hyperautofluorescence encircling the area of atrophy. A patchy pattern denotes multiple focal areas of increased hyperfluorescence, but of less intensity than the focal pattern. In the diffuse pattern, which is most common, there are areas of increased autofluorescence scattered throughout the posterior pole. Notably, some patients do not show increased hyperfluorescence surrounding their GA lesions. Patients with no increased autofluorescence or a focal pattern tend to progress slowly, whereas those with a banded or diffuse pattern tend to progress more rapidly.

CONCLUSION

There is little doubt that the availability of a treatment for GA will allow retina specialists to modify the course of this disease and preserve visual function for patients. While the opportunity is exciting, the influx of new patients requiring intravitreal treatment will likely burden clinics that are already full of patients requiring intravitreal injections for other conditions and that are struggling to maintain adequate staffing levels. Hence, it will be important to develop efficient protocols for patient outreach and for patient discussions as well as imaging routines to identify those at risk for progression and to monitor those undergoing treatment. Nonetheless, the ability to treat GA represents a great step forward in the fight against advanced AMD. RP

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