Geographic atrophy (GA), also known as atrophic age-related macular degeneration (AMD) or advanced dry AMD, is an advanced form of age-related

macular degeneration Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, som ...

that can result in the progressive and irreversible loss of

retina The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...

l tissue ( photoreceptors,

retinal pigment epithelium The pigmented layer of retina or retinal pigment epithelium (RPE) is the pigmented cell layer just outside the neurosensory retina that nourishes retinal visual cells, and is firmly attached to the underlying choroid and overlying retinal visual ce ...

, choriocapillaris) which can lead to a loss of visual function over time. It is estimated that GA affects over 5 million people worldwide and approximately 1 million patients in the US, which is similar to the prevalence of

neovascular Neovascularization is the natural formation of new blood vessels ('' neo-'' + ''vascular'' + '' -ization''), usually in the form of functional microvascular networks, capable of perfusion by red blood cells, that form to serve as collateral circu ...

(wet) AMD, the other advanced form of the disease. The incidence of advanced AMD, both geographic atrophy and neovascular AMD, increases exponentially with age. The aim of most current clinical trials is to reduce the progression of GA lesion enlargement.

Presentation

Geographic atrophy is a chronic disease, which leads to visual function loss. This often results in difficulties performing daily tasks such as reading, recognizing faces, and driving, and ultimately has severe consequences on independence. Initially, patients often have good visual acuity if the GA lesions are not involved in the central macular, or foveal, region of the retina. As such, a standard vision test may underrepresent the visual deficit experienced by patients who report challenges reading, driving or seeing in low light conditions. Reading speed is often initially unaffected due to foveal sparing, but worsens progressively as the area of atrophy enlarges. As the disease progresses, vision-related quality-of-life declines markedly. While

fluorescein angiography Fluorescein angiography (FA), fluorescent angiography (FAG), or fundus fluorescein angiography (FFA) is a technique for examining the circulation of the retina and choroid (parts of the fundus) using a fluorescent dye and a specialized camera. S ...

and

optical coherence tomography Optical coherence tomography (OCT) is an imaging technique that uses low-coherence light to capture micrometer-resolution, two- and three-dimensional images from within optical scattering media (e.g., biological tissue). It is used for medical ...

are today well established for diagnosing and tracking progression in geographic atrophy more complex diagnostic assessments may be required in the context of clinical trials. In February 2023, the

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

approved Pegcetacoplan for the treatment of people with geographic atrophy secondary to age-related macular degeneration.

Pathogenesis

The pathogenesis of GA is not fully understood yet. It is likely multifactorial and triggered by intrinsic and extrinsic stressors of the poorly regenerative retinal pigment epithelium (RPE), particularly

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...

caused by the high metabolic demand of photoreceptors, photo-oxidation, and environmental stressors such as cigarette smoke. Variations in several genes, particularly in the

complement system The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and at ...

, increase the risk of developing GA. This is an active area of research but the current hypothesis is that with aging, damage caused by these stressors accumulates, which coupled with a genetic predisposition, results in the appearance of

drusen Drusen, from the German word for ''node'' or ''geode'' (singular, "Druse"), are tiny yellow or white accumulations of extracellular material that build up between Bruch's membrane and the retinal pigment epithelium of the eye. The presence of a ...

and lipofuscin deposits (early and intermediate AMD). These and other products of oxidative stress can trigger inflammation via multiple pathways, particularly the complement cascade, ultimately leading to loss of photoreceptors, RPE, and choriocapillaris, culminating in atrophic lesions that grow over time. Age-related macular degeneration (AMD) is characterized by retinal

iron Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in f ...

accumulation and

lipid peroxidation Lipid peroxidation is the chain of reactions of oxidative degradation of lipids. It is the process in which radical (chemistry), free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by ...

Ferroptosis Ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides, and is genetically and biochemically distinct from other forms of regulated cell death such as apoptosis. Ferroptosis is ini ...

is initiated by lipid peroxidation and is characterized by iron-dependent accumulation. Studies on iron accumulation and elevated lipid peroxidation in the aging retina, and their intimate role in ferroptosis, have implicated ferroptosis in AMD pathogenesis.

Risk factors for GA progression

A plethora of ''in vivo'' risk factors for GA progression have been published and validated. Recent studies indicate that geographic atrophy may be due to deficiencies in blood flow within the choriocapillaris. These studies used swept-source optical coherence tomography angiography to examine the choriocapillaris. Using imaging algorithms, they then determined which regions of the choriocapillaris had deficient blood flow, thus creating a

heat map A heat map (or heatmap) is a data visualization technique that shows magnitude of a phenomenon as color in two dimensions. The variation in color may be by hue or intensity, giving obvious visual cues to the reader about how the phenomenon is c ...

of the blood supply to the retinal pigment epithelium. They went on to use fundus

autofluorescence Autofluorescence is the natural emission of light by biological structures such as mitochondria and lysosomes when they have absorbed light, and is used to distinguish the light originating from artificially added fluorescent markers (fluorophores) ...

to image the retinal pigment epithelium over the course of a year, this allowed them to map out the direction and magnitude with the geographic atrophy spread. They then found that regions of the choriocapillaris which had less blood flow were more likely to degenerate and become geographic atrophy. Since the choriocapillaris is the main blood supply of the retinal pigment epithelium, it is leading some to believe that geographic atrophy is primarily an ischemic disease (disease due to decreased blood flow). It was also shown that non-exudative neovascular membranes, which can recapitulate the choriocapillaris, are associated with a markedly slower GA progression. This further supports the vascular insufficiency hypothesis.

Diagnosis

Diagnosis of geographic atrophy is made by an ophthalmologist in the clinic. Fundus autofluorescence and optical coherence tomography angiography are imaging modalities that can be used in the diagnosis. While fundus autofluorescence is the standard modality for viewing geographic atrophy, optical coherence tomography can offer unique benefits. Optical coherence tomography angiography can help the physician see if there is any subretinal fluid in the eye. This is useful because it could indicate that the patient may be developing wet AMD. Since patients with geographic atrophy are at higher risk for developing advanced wet AMD (neovascular AMD), this could be especially useful in the monitoring of patients with geography atrophy. If signs of neovascular AMD found, the physician can initiate treatment of wet age-related macular degeneration.

Quantification of GA progression

Traditionally, GA progression is quantified in terms of the area of retinal pigment epithelium atrophy. Multiple imaging methods can be applied to quantify this area of retinal pigment epithelium atrophy including short-wavelength (blue) fundus autofluorescence imaging, green fundus autofluorescence imaging, and '' en face'' optical coherence tomography imaging. However, more recent data suggest that photoreceptor degeneration is not limited to the area of retinal pigment epithelium atrophy, but extends beyond this area. These more subtle changes can be quantified by volumetric analyses of optical coherence tomography data.

Treatment

In February 2023, Apellis Pharmaceuticals received the first FDA approval of pegcetacoplan for the treatment of this condition. Avacincaptad pegol (Izervay) was approved in the United States in August 2023 for the treatment of geographic atrophy secondary to age-related macular degeneration.

References

{{Eye pathology Eye diseases Disorders of choroid and retina