Geographic Atrophy and Age-Related Macular Degeneration
Age-Related macular degeneration (AMD) is one of the most common causes of visual loss in the US. During later stages, visual acuity is worsened due to choroidal neovascularization (CNV) and geographic atrophy (GA).
GA occurs when dry AMD becomes advanced. In early dry AMD, protein deposits, called drusen, are seen scattered on the retina, which can cause visual distortions. In some patients, these become larger and closer together becoming softer in appearance. At this point, it is likely that wet AMD will develop. On the other hand, advanced dry AMD leads to GA. Here, there is not just scattered locations of drusen but rather islands of lost receptor cells are observed. Usually, GA starts around the center of the macula and progresses outward. Wherever these cells are lost, black spots are seen in the vision. Patients usually maintain good central vision until late stages of the diseases, but this is variable.
In the US, AMD affects approximately 11 million individuals. Globally 170 million people are affected. The greatest risk factor of AMD is aging therefor, as the population ages, the prevalence is expected to increase to 22 million by the year 2050. To put it into perspective, the prevalence of AMD in the US is more than all cases of invasive cancers combined and double that of Alzheimer’s disease. It equals approximately $4.6 billion in direct healthcare costs.
GA has a prevalence of 0.37% which rose to 0.5 % among Europeans. In the Beaver Dam Eye Study, it was found that 42% of GA patients were considered to be legally blind. GA occurs most often in patients over 85 years of age. In the majority of cases of Drusen-assocaited GA, there is a gradual collapsing of large drusen with overlying loss of pigmentation in the retina pigment epithelial layer (RPE). Also, pigment migration to the neuroretina is observed. A gradual thinning of the photoreceptor layer is seen. First, shortening of the outer segments occurs followed by cell death and thinning of the outer nuclear retina of the retina. Finally, the RPE layer is lost, and combined with the atrophy of photoreceptor layer, the outer plexiform layer against Bruch’s membrane appears.
How is GA diagnosed?
- Fundoscopic exam: Usually, a well-circumcised oval or round area of atrophy of pigment epithelium is seen. It usually spares the fovea until late stages. Precursor lesions can also be observed: large drusen (greater than 125 microns), focal pigmentation changes, and refractile deposits.
- Fluorescein angiography: A sharply delineated window defect caused by atrophy of overlying layers of RPE of observed. It is reserved for use in atypical cases.
- Optical coherence tomography (OCT): Thinning of hyperreflective external band along with attenuation to RPE/Bruch’s complex and deeper hyperreflectivity due to loss of the outer retina layers is observed. Atrophic layers are seen at different levels, segmented plaques of outer bands, and elevations with variable relectivity are also observed.
- Fundus autofluorescence (FAF): An accumulation of lipofuscin in the lysosomes of RPE cells is observed. When exposed to blue light, the compound is found as a micometer-sized spherical particle with yellow autofluorescence. The use of this test remains controversial.
The development of AMD appears to be multifactorial involving both genetic and environmental factors. Numerous genetic studies have demonstrated several genes that appear to play a role. In fact, the Retina International Database have identified 16 genes that demonstrate some link with AMD. Important genes include Complement Factors H, B, 2, and 3. Another study showed possibly 36 genes play some role.
One study showed that a significant correlation between GA lesion size and the number of risk alleles at the ARMS2_rs10490924 loci. The growth rate of the GA lesion appears to have some relationship with the C3 locus. Many genetic studies are on-going.
No treatment is available to prevent the onset of GA or to slow its progression. One medication that is being used is Sirolimus, or Rapamycin. It is an immunosuppressant oral medication that has been approved to prevent organ prevention following renal transplantation. This medication interacts with and inhibits protein kinase. This protein kinase regulates several cell functions including metabolism, growth, proliferation, and survival. In the current study, an ocular formulation was developed. Participants were over the age of 55 years and had been diagnosed with b/l GA related to AMD. The medication was used in one eye and the contralateral eye was assigned to observation without treatment. The drug was administered every 3 months for 24 months. While there were no safety issues seen in the trial, there was also no functional benefit seen.
Another study investigated the medication OT-551 in the treatment of GA. This medication was topically applied to one randomly assigned eye three times a day. This medication was also found to be safe but provided little benefit.
Ranibizumab and Bevacizumab were evaluated in another study. These medications were administered monthly or as needed for 2 years. There were no differences between the 2 medications observed. There was a slightly higher adverse risk profile with Bevacizumab although the reasons were unclear.
In light of the fact that AMD and GA is a leading cause of blindness and there are no good treatments available, more research is urgently needed. Screening is imperative to identify risk factors and early stages.
About the Author
Linda Girgis MD, FAAFP is a family physician practicing in South River, New Jersey and Clinical Assistant Professor at Rutgers Robert Wood Johnson Medical School. She was voted one of the top 5 healthcare bloggers in 2016. Follow her on twitter @DrLindaMD.