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 vision, blurred or vision loss, no vision in the center of the visual field. Early on there are often no sym ...

that can result in the progressive and irreversible loss of

retina The retina (; or retinas) is the innermost, photosensitivity, light-sensitive layer of tissue (biology), tissue of the eye of most vertebrates and some Mollusca, molluscs. The optics of the eye create a focus (optics), focused two-dimensional ...

l tissue ( photoreceptors,

retinal pigment epithelium The pigmented layer of retina or retinal pigment epithelium (RPE) is the pigment A pigment is a powder used to add or alter color or change visual appearance. Pigments are completely or nearly solubility, insoluble and reactivity (chemistry), ...

choriocapillaris The capillary lamina of choroid or choriocapillaris is a part of the choroid of the eye. It is a layer of capillaries immediately adjacent to Bruch's membrane of the choroid. The choriocapillaris consists of a dense network of freely anastomosin ...

) which can lead to a loss of central vision 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 circul ...

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

Presentation

Geographic atrophy is a chronic disease, which leads to visual function loss centrally. 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

fovea Fovea () (Latin for "pit"; plural foveae ) is a term in anatomy. It refers to a pit or depression in a structure. Human anatomy *Fovea centralis of the retina * Fovea buccalis or dimple * Fovea of the femoral head * Trochlear fovea of the fr ...

, 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. ...

and

optical coherence tomography Optical coherence tomography (OCT) is a high-resolution imaging technique with most of its applications in medicine and biology. OCT uses coherent near-infrared light to obtain micrometer-level depth resolved images of biological tissue or oth ...

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 Pegcetacoplan, sold under the brand name Empaveli, among others, is a medication used to treat paroxysmal nocturnal hemoglobinuria and geographic atrophy of the retina. Pegcetacoplan is a complement inhibitor. The most common side effects in ...

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 detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...

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 humoral, innate immune system and enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inf ...

, 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; it has symbol Fe () 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, forming much of Earth's o ...

accumulation and

lipid peroxidation Lipid peroxidation, or lipid oxidation, is a complex chemical process that leads to oxidative degradation of lipids, resulting in the formation of peroxide and hydroperoxide derivatives.{{Cite journal , last1=Ayala , first1=Antonio , last2=Muñoz ...

Ferroptosis Ferroptosis (also known as oxytosis) is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides. Ferroptosis is biochemically, genetically, and morphologically distinct from other forms of regulat ...

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 2-dimensional data visualization technique that represents the magnitude of individual values within a dataset as a color. The variation in color may be by hue or intensity. In some applications such as crime analy ...

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

fundus ''Fundus'' (Latin for "bottom") is an anatomical term referring to that part of a concavity in any organ, which is at the far end from its opening. It may refer to: Anatomy * Fundus (brain), the deepest part of any sulcus of the cerebral cortex * F ...

autofluorescence Autofluorescence is the natural fluorescence of biological structures such as mitochondria and lysosomes, in contrast to fluorescence originating from artificially added fluorescent markers (fluorophores). The most commonly observed autofluoresc ...

to image the retinal pigment epithelium over 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 that 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 in the macula, which has no retinal blood supply, 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

, 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 geographic atrophy. If signs of neovascular AMD are 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 EN or En or en may refer to: Businesses * Bouygues (stock symbol EN) * Island Rail Corridor, formerly known as the Esquimalt and Nanaimo Railway (reporting mark EN) * Euronews, a news television and internet channel Language and writing * N, 14t ...

'' 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 and new findings

In February 2023, Apellis Pharmaceuticals received the first FDA approval of

pegcetacoplan Pegcetacoplan, sold under the brand name Empaveli, among others, is a medication used to treat paroxysmal nocturnal hemoglobinuria and geographic atrophy of the retina. Pegcetacoplan is a complement inhibitor. The most common side effects in ...

for the treatment of this condition.

Avacincaptad pegol Avacincaptad pegol, sold under the brand name Izervay, is a medication used for the treatment of age-related macular degeneration. Avacincaptad pegol is a complement inhibitor. Avacincaptad pegol was approved for medical use in the United Sta ...

(Izervay) was approved in the United States in August 2023 for the treatment of geographic atrophy secondary to age-related macular degeneration. It was recently discovered that the aging pigment lipofuscin can be broken down with the help of melanin and drugs through a newly discovered mechanism (chemical excitation). Lyu Y, Tschulakow AV, Wang K, Brash DE, Schraermeyer U. Chemiexcitation and melanin in photoreceptor disc turnover and prevention of macular degeneration. Proc Natl Acad Sci U S A. 2023;120(20):e2216935120. The pigment lipofuscin plays a central role in the development of dry AMD and geographic atrophy. This breakdown can be supported by medication. This discovery can be translated into the development of a therapy to treat dry AMD.

References

{{Eye pathology Eye diseases Disorders of choroid and retina