Geographic atrophy in patients with advanced dry age-related macular degeneration: current challenges and future prospects

Abstract

Geographic atrophy (GA) of the retinal pigment epithelium (RPE) is a devastating complication of age-related macular degeneration (AMD). GA may be classified as drusen-related (drusen-associated GA) or neovascularization-related (neovascular-associated GA). Drusen-related GA remains a large public health concern due to the burden of blindness it produces, but pathophysiology of the condition is obscure and there are no proven treatment options. Genotyping, cell biology, and clinical imaging point to upregulation of parainflammatory pathways, oxidative stress, and choroidal sclerosis as contributors, among other factors. Onset and monitoring of progression is accomplished through clinical imaging instrumentation such as optical coherence tomography, photography, and autofluorescence, which are the tools most helpful in determining end points for clinical trials at present. A number of treatment approaches with diverse targets are in development at this time, some of which are in human clinical trials. Neovascular-associated GA is a consequence of RPE loss after development of neovascular AMD. The neovascular process leads to a plethora of cellular stresses such as ischemia, inflammation, and dramatic changes in cell environment that further taxes RPE cells already dysfunctional from drusen-associated changes. GA may therefore develop secondary to the neovascular process de novo or preexisting drusen-associated GA may continue to worsen with the development of neovascular AMD. Neovascular-associated GA is a prominent cause of continued vision loss in patients with otherwise successfully treated neovascular AMD. Clearly, treatment with vascular endothelial growth factor (VEGF) inhibitors early in the course of the neovascular disease is of great clinical benefit. However, there is a rationale and some suggestive evidence that anti-VEGF agents themselves could be toxic to RPE and enhance neovascular-associated GA. The increasing prevalence of legal blindness from this condition due to the aging of the general population lends urgency to the search for a therapy to ameliorate GA.

Keywords: age-related macular degeneration; clinical trials; fundus autofluorescence; geographic atrophy; optical coherence tomography.

Figure 1

Right eye of patient with drusen-associated GA imaged by color photograph (A), fundus autofluorescence (B), infrared reflectance (C), and OCT (D). Notes: On color photography, sharp demarcation between regions of RPE loss and intact RPE is seen (blue arrows). Within the regions of GA, the large choroidal vessels are seen. (A) An area of relative foveal sparing, manifest as somewhat intact RPE, can be seen (yellow arrow). (B) Autofluorescence shows the peripheral margins of GA in high contrast from bright to black areas (blue arrows). The area of subfoveal RPE sparing is not well seen due to overlying retina luteal pigments blocking the blue excitation light (yellow arrow). Peripheral to the GA is an irregular mottled appearance of abnormal autofluorescence. (C) The infrared image also shows regions of GA with good contrast. (D) The OCT scan shows drusen in an area of intact RPE (yellow arrow), absence of the RPE in an area of GA (orange arrow), and a demarcation seen near the fovea where the intact RPE line ends at the margin of GA (blue arrow). The OCT B-scan corresponds to the horizontal green line of the infrared image (C). Abbreviations: GA, geographic atrophy; RPE, retinal pigment epithelium; OCT, optical coherence tomography.

Figure 2

The same eye as shown in Figure 1 after 1 year. Notes: The color image (A) shows slight increase in the margins and enlargement of the total area of GA. Autofluorescence imaging (B) also illustrates how the earlier GA regions have enlarged and begun to coalesce. The infrared image (C) likewise provides a good definition of the outer margins of the GA, whereas the area under the fovea is encroached upon by progressive atrophy. The OCT (D) shows that the margin of GA has advanced slightly toward the fovea compared to 1 year previously (blue arrow). Abbreviations: GA, geographic atrophy; OCT, optical coherence tomography.

Figure 3

An eye with neovascularization-associated RPE atrophy at the baseline (A) and 30 months after anti-VEGF treatment (B). Notes: With resolution of subretinal fluid, fibrin, and thin fibrovascular material at the baseline, the eye has developed marked RPE loss in the central macula. Abbreviations: RPE, retinal pigment epithelium; VEGF, vascular endothelial growth factor.