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 that can result in the progressive and irreversible loss of retinal tissue (photoreceptors, retinal pigment epithelium, choriocapillaris) which can lead to a loss of visual function over time. [1] [2] [3] [4] It is estimated that GA affects over 5 million people worldwide and approximately 1 million patients in the US, [5] [6] which is similar to the prevalence of neovascular (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. [7]
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. [8] [9] [10]
Initially, patients often have good visual acuity if the GA lesions are not involved in the central macular, or foveal, region of the retina. [7] [11] 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. [12] Reading speed is often initially unaffected due to foveal sparing, but worsens progressively as the area of atrophy enlarges. [13] [14] [15] As the disease progresses, vision-related quality-of-life declines markedly. [16]
While fluorescein angiography and optical coherence tomography 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. [17] In February 2023, the FDA approved Pegcetacoplan for the treatment of people with geographic atrophy secondary to age-related macular degeneration. [18]
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 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, 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 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. [19] [20]
A plethora of in vivo risk factors for GA progression have been published and validated. [21]
Recent studies indicate that geographic atrophy may be due to deficiencies in blood flow within the choriocapillaris. [22] [23] [24] 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 of the blood supply to the retinal pigment epithelium. They went on to use fundus autofluorescence 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. [25] This further supports the vascular insufficiency hypothesis.
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. [26] 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. [27]
Traditionally, GA progression is quantified in terms of the area of retinal pigment epithelium atrophy. [28] Multiple imaging methods can be applied to quantify this area of retinal pigment epithelium atrophy including short-wavelength (blue) fundus autofluorescence imaging, [29] green fundus autofluorescence imaging, [30] and en face optical coherence tomography imaging. [31]
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. [32] [33]
In February 2023, Apellis Pharmaceuticals received the first FDA approval of Pegcetacoplan for the treatment of this condition. [34] Cases should be regularly followed by an ophthalmologist so that if patients develop neovascular AMD, they can be treated for that. [35]
Macular degeneration, also known as age-related macular degeneration, 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, some people experience a gradual worsening of vision that may affect one or both eyes. While it does not result in complete blindness, loss of central vision can make it hard to recognize faces, drive, read, or perform other activities of daily life. Visual hallucinations may also occur.
The Age-Related Eye Disease Study (AREDS) was a clinical trial sponsored by the National Eye Institute that ran from 1992-2001. The study was designed to:
Bruch's membrane is the innermost layer of the choroid of the eye. It is also called the vitreous lamina or Membrane vitriae, because of its glassy microscopic appearance. It is 2–4 μm thick.
A cone dystrophy is an inherited ocular disorder characterized by the loss of cone cells, the photoreceptors responsible for both central and color vision.
Drusen, from the German word for node or geode, 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 few small ("hard") drusen is normal with advancing age, and most people over 40 have some hard drusen. However, the presence of larger and more numerous drusen in the macula is a common early sign of age-related macular degeneration (AMD).
Stargardt disease is the most common inherited single-gene retinal disease. In terms of the first description of the disease, it follows an autosomal recessive inheritance pattern, which has been later linked to bi-allelic ABCA4 gene variants (STGD1). However, there are Stargardt-like diseases with mimicking phenotypes that are referred to as STGD3 and STGD4, and have a autosomal dominant inheritance due to defects with ELOVL4 or PROM1 genes, respectively. It is characterized by macular degeneration that begins in childhood, adolescence or adulthood, resulting in progressive loss of vision.
Sattler's layer, named after Hubert Sattler, an Austrian ophthalmologist, is one of five layers of medium-diameter blood vessels of the choroid, and a layer of the eye. It is situated between the Bruch's membrane, choriocapillaris below, and the Haller's layer and suprachoroidea above, respectively. The origin seems to be related to a continuous differentiation throughout the growth of the tissue and even further differentiation during adulthood.
Presumed ocular histoplasmosis syndrome (POHS) is a syndrome affecting the eye, which is characterized by peripheral atrophic chorioretinal scars, atrophy or scarring adjacent to the optic disc and maculopathy.
Optic disc drusen (ODD) are globules of mucoproteins and mucopolysaccharides that progressively calcify in the optic disc. They are thought to be the remnants of the axonal transport system of degenerated retinal ganglion cells. ODD have also been referred to as congenitally elevated or anomalous discs, pseudopapilledema, pseudoneuritis, buried disc drusen, and disc hyaline bodies.
Choroidal neovascularization (CNV) is the creation of new blood vessels in the choroid layer of the eye. Choroidal neovascularization is a common cause of neovascular degenerative maculopathy commonly exacerbated by extreme myopia, malignant myopic degeneration, or age-related developments.
A maculopathy is any pathological condition of the macula, an area at the centre of the retina that is associated with highly sensitive, accurate vision.
Intraocular hemorrhage is bleeding inside the eye. Bleeding can occur from any structure of the eye where there is vasculature or blood flow, including the anterior chamber, vitreous cavity, retina, choroid, suprachoroidal space, or optic disc.
Macular telangiectasia is a condition of the retina, the light-sensing tissue at the back of the eye that causes gradual deterioration of central vision, interfering with tasks such as reading and driving.
Lampalizumab (INN) is an antigen-binding fragment of a humanized monoclonal antibody that binds to complement factor D; it was developed as a potential treatment of geographic atrophy secondary to age-related macular degeneration.
Microperimetry, sometimes called fundus-controlled perimetry, is a type of visual field test which uses one of several technologies to create a "retinal sensitivity map" of the quantity of light perceived in specific parts of the retina in people who have lost the ability to fixate on an object or light source. The main difference with traditional perimetry instruments is that, microperimetry includes a system to image the retina and an eye tracker to compensate eye movements during visual field testing.
Brolucizumab sold under trade name Beovu among others, is a humanized single-chain antibody fragment for the treatment of neovascular (wet) age-related macular degeneration (AMD).
Faricimab, sold under the brand name Vabysmo, is a monoclonal antibody used for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Faricimab is the first bispecific monoclonal antibody to target both vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang-2). By targeting these pathways, faricimab stabilizes blood vessels in the retina. It is given by intravitreal injection by an ophthalmologist.
Conbercept, sold under the commercial name Lumitin, is a novel vascular endothelial growth factor (VEGF) inhibitor used to treat neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME). The anti-VEGF was approved for the treatment of neovascular AMD by the China State FDA (CFDA) in December 2013. As of December 2020, conbercept is undergoing phase III clinical trials through the U.S. Food and Drug Administration’s PANDA-1 and PANDA-2 development programs.
Stem cell therapy for macular degeneration is the use of stem cells to heal, replace dead or damaged cells of the macula in the retina. Stem cell based therapies using bone marrow stem cells as well as retinal pigment epithelial transplantation are being studied. A number of trials have occurred in humans with encouraging results.
Focal choroidal excavation (FCE) is a concavity in the choroidal layer of the eye that can be detected by optical coherence tomography. The disease is usually unilateral and not associated with any accompanying systemic diseases.