Geographic atrophy

From EyeWiki



Geographic atrophy
Classification and external resources
ICD-10 H35.3
ICD-9 362.51


Geographic atrophy is a chronic progressive degeneration of the macula and can be seen as part of late-stage age-related macular degeneration (AMD). The condition leads to central scotomas and permanent loss of visual acuity.

Disease Entity

  • ICD-9-CM: 362.51 Nonexudative senile macular degeneration
  • ICD-10-CM: H35.31 Nonexudative age-related macular degeneration

Disease

Geographic atrophy (GA) is a chronic progressive degeneration of the macula, as part of late-stage AMD. The disease is characterized by localized atrophy of retinal tissue and choriocapillaris, leading to central scotomas and permanent loss of visual acuity.

Risk Factors

Several risk factors have been noted by several studies. The most pronounced risk factor is increasing age and family history of AMD. [1] Smoking history increases the risk of GA significantly. Both active smokers, but also former smokers are at greater risk of developing geographic atrophy. [2] No studies have found any gender difference in the prevalence of geographic atrophy.[1] [3][3] The Age-Related Eye Disease Study also found an increased risk of GA in users of thyroid hormones or antacids. People with higher education were at a lower risk of GA. Other studies have pointed out an increase in risk of GA in patients with coronary heart disease as well as in patients with lens opacities or previous cataract surgery. [4]

General Pathology

The pathogenesis of GA remains unclear. The natural course of AMD begins with early stages that are characterized by presence of drusen that are yellow deposits between the retinal pigment epithelium and Bruch’s membrane. Pigment displacement is also seen. [5] Late stages of AMD is either characterized by choroidal neovascularization, or GA. GA is recognized as a sharply defined area in the posterior pole, with atrophy of the retinal pigment epithelium, the overlying photoreceptors and the choriocapillaris. The defect in structures allows the observer to see the larger underlying choroidal vessels.[6] Especially reticular pseudodrusen are associated with the development of GA [7]The progression rate varies, but is relatively slowly progressing over years. As the atrophic area expands, visual function decreases. [8] Clinically, the exudative and non-exudative AMD are very different, but these late stages of AMD are far from exclusive. Individuals with GA are in high risk of developing choroidal neovascularizations, and patients with exudative AMD are in high risk of developing atrophic areas.

The cause of GA is not fully known, though it has been studied extensively. Genetic and environmental factors seems to contribute substantially. Complent factor H variant Y402H and ARMS2 have been associated with increased risk of GA development. [9] [10] Drusen are shown to contain multiple complement components, [11][12] indicating that localized inflammation mediated by the complement system is an important element in AMD. This has been suggested to be a systemic immune-dysfunction, with retinal manifestation.[13] Oxidative stress seems to play a role in AMD [14] and low-grade inflammation is part of the disease mechanism. [15][16]. In donor eyes with GA, choroidal T-lymphocytes and macrophages are producing highly proinflammatory cytokines.[17] Furthermore, it has been found that mononuclear phagocytes accumulated in the subretinal space is clearly associated with GA.[18] Their possible role in photoreceptor rescue or degeneration is unknown.

Diagnosis

The diagnosis of geographic atrophy is clinical, and can be made by ophthalmoscopy.

History

The typical patient with geographic atrophy is above 60 years of age, with gradually progressing loss of visual function.

Physical examination

Ophthalmoscopy with visualization of the fundus, enables the trained ophthalmologist to observe drusen, as well as the atrophic area. In some cases the atrophic area is unifocal, but in many cases it shows as a multifocal disease within the macula area.

Signs

Geographic atrophy is one of the two forms of late stage AMD. The first signs are drusen, which varies in size and number according to stage of disease. The first atrophic lesion is small and slowly grows in size as disease progresses.

Symptoms

In cases of GA, the fovea can be sparred for a long time, so that the measured visual acuity can remain nearly normal, but the contrast sensibility as well as the ability to read suffers. The patient experiences relatively rapid function loss, when the fovea is involved due to loss of visual acuity.

Clinical diagnosis

The diagnosis of geographic atrophy is clinical, and is made by ophthalmoscopy or on fundus photo. The ophthalmologist will see a macula decorated with drusen and a sharply demarcated area in the macular region whit a thinning of the retina, lacking pigmentation and visible underlying choroidal vessels.

Diagnostic procedures

Fundus autofluorescence picture of healthy eye
The clinical examination is key in diagnosing geographic atrophy, but other imaging techniques can be useful, especially in monitoring disease.

Fundus autofluorescense is currently the standard imaging technology to visualize the retinal pigment epithelium (RPE) in geographic atrophy. Vital RPE contains intracellular lipofuscin. When exposed to light at a specific wavelength, lipofuscin absorbes this, and emits light in another wavelength, from where the fluorescence signal originates. In the fovea, the signal diminishes physiologically, due to absorption by the macular pigment. If atrophy of RPE occurs, this causes a distinct dark area, due to absence of lipofuscin-containing cells, and therefore lack of fluorescent signal. These sharp contrasts between completely dark and light grey, has made it possible to introduce a semiautomated segmentation algorithm, to detect and quantify the size of the atrophic area. Previously the preffered method was to manually outline the borders. Besides helping quantify the atrophic lesion, fundus autofluorescense also provides important information on expected progression rate through the amount of hyperfluorescense in the junctional zone of the lesion. Hyperfluorescense is an accumulation of lipofuscin in the RPE cells, and is thought to be due to suffering/dying cells, as it is typical to observe atrophy in the hyperfluorescent area. The amount of hyperfluorescense correlates well with the rate of GA progression.[19][20]

Fundus autofluorescence image of eye with GA

Optical coherence tomography (OCT) also provides important information. The atrophy of the retinal layers become very obvious by this technique, and it has been demonstrated that some morphologic changes, such as a split between RPE and Bruch’s membrane in the junctional zone can be an indication of fast progression. Patients suffering from geographic are at higher risk of developing choroidal neovascularizations, which can cause an even faster loss of visual function. Therefore, OCT can help early recognition of intraretinal fluid, which is important in order to start treatment and remain function.

Ordinary measuring of visual acuity often provides poor information on the actual function of the retina, due to foveal sparring, and parafoveal scotomas. Better tools to evaluate the function is: Microperimetry, stimulates the macula over 20 degrees, in various spots, with varying intensity of light, and depends on the patients ability to report recognition of the stimuli. In this way, low-luminance visual acuity and contrast sensitivity is measured. Studies using microperimetry have shown that the sensitivity of non-atrophic retina also suffers from decreased sensitivity,[21] and that this loss correlates with progression of GA over time.[22]

Multifocal electroretinography, where light stimuli is performed in patterns across the retina, and photoreceptor signaling is detected by an electrode. By varying the light stimuli, the retina is mapped with information on functionality and sensitivity. Reading ability, or reading speed, can be quantified by the number of correctly read words in a limited amount of time. Radner and MNREAD reading charts are validated in several languages. Patients with GA and BCVA≥20/50 have shown to be significantly slower at reading compared to patients with intermediate AMD.[23]

Microperimetry-result of 2 patients with geographic atrophy and different sensibility in non-atrophic retina, measured in decibel. 

Laboratory test

Geographic atrophy is a clinical diagnosis, and so far, there are no laboratory tests as part of the diagnostic or monitoring of disease.

Differential diagnosis

Any atrophy of the retina can be differential diagnosis to geographic atrophy, such as: atrophy secondary to anti-VEGF treatment, atrophy secondary to pattern dystrophy or central areolar choroidal dystrophy.

Management

General treatment

At this time, there is no treatment available, medical or surgical, that can halt or reverse the progression of geographic atrophy. Visual rehabilitation is often necessary, even in cases of tolerable visual acuity, as contrast sensibility and reading ability can suffer in cases of foveal sparring and parafoveal scotoma.[24][25] Monitoring is important in early diagnosis of choroidal neovascularizations, as this group of patients are at higher risk. The AREDS study showed that patients with visual loss due to AMD were in high risk of developing neovascular AMD, and that vitamin supplements decreases the odds by 38% of developing neovascular AMD, in patients with visual impairment due to AMD.[26] The study did not show any beneficial effects on slowing down the progression of geographic atrophy. Currently, a phase-3-study, is investigating a new drug, Lampalizumab. This potential treatment is administered intravitreally, and hoped to halt the progression through inhibition of the alternative complement pathway, targeting complement factor D.[27]

Prognosis

Fundus autofluorescence (left), and progression in one year (right)

The prognosis is poor, as there are no available treatment, and the disease is chronic and progressive. Progression of GA is associated with extensive decrease in visual acuity, a study has shown that 31% of patients with GA lose at least three lines of vision in 2 years,[28] and the growth rate median is 2.1 mm2/year, but with variation up to 10.2mm2/year.[29] The rate of progression differs between patients, but signs of fast progression is high amounts of hyperfluorescense shown on fundus autofluorescence, and a decrease retinal function regarding contrast sensitivity or reading ability.

Additional Resources

References

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  2. 1.     Chakravarthy U, Augood C, Bentham GC, de Jong PT, Rahu M, Seland J, Soubrane G, Tomazolli L, Topouzis F, Vingerling JR, Vioque J, Young IS, Fletcher AE. Cigarette smoking and age-related macular degeneration in the EUREYE Study. Ophthalmology 2007 jun;114(6):1157-63.
  3. 3.0 3.1 Smith W, Assink J, Klein R, Mitchell P, Klaver CC, Klein BE et al. Risk factors for age-related macular degeneration: Pooled findings from three continents. Ophthalmology 2001;108:697-704. 
  4. Fraser-Bell S, Donofrio J, Wu J, Klein R, Azen SP, Varma R et al. Sociodemographic factors and age-related macular degeneration in Latinos: the Los Angeles Latino Eye Study. American Journal of Ophthalmology 2005;139:30-8.
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  9. Sepp T, et al. Complement factor H variant Y402H is a major risk determinant for geographic atrophy and choroidal neovascularization in smokers and nonsmokers. Invest Ophthalmol Vis Sci 2006;47:536-540.
  10. Cameron DJ, et al. HTRA1 variant confers similar risks to geographic atrophy and neovascular age-related macular degeneration. Cell Cycle 2007;6:1122-1125.
  11. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 2001;20:705-732.
  12. Anderson DH, Radeke MJ, Gallo NB, Chapin EA, Johnson PT, Curletti CR, et al. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res 2010;29:95-112.
  13. Scholl HPN, Issa PC, Walier M, et al. Systemic complement activation in age related macular degeneration. PLoS ONE 2008;3:e2593.
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  16. Buschini E, Piras A, Nuzzi R, Vercelli A. Age related macular degeneration and drusen: neuroinflammation in the retina. Prog Neurobiol 2011;95:14-25.
  17. Camelo S. Association of Choroidal Interleukin-17-producing T Lymphocytes and Macrophages with Geographic Atrophy. Ophthalmologica 2016;236:53-58.
  18. Sennlaub F, Auvynet C, Calippe B, Lavalette S, Poupel L, Hu SJ, et al. CCR2(+)  monocytes infiltrate atrophic lesions in age-related macular disease and mediate photoreceptor degeneration in experimental subretinal inflammation in CX3CR1 deficient mice. EMBO Mol Med 2013;5:1775-1793.
  19. Holz FG, Bindewald-Wittich A, Fleckenstein M, et al. Progression of geographic atrophy and impact of fundus autofluorescence patterns in age-related macular degeneration. Am J Ophthalmol 2007;143:463-472.
  20. Bearelly S, Khanifar AA, Lederer DE, et al. Use of fundus autofluorescense images to predict geographic atrophy progression. Retina 2011;31:81-86
  21. Owsley C, Jackson GR, Cideciyan AV, et al. Psychophysical evidence for rod vulnerability in age-related macular degeneration. Invest Ophthalmol Vis Sci 2000;41:267-273.
  22. Meleth AD, Mettu P, Agron E, et al. Changes in retinal sensitivity in geographic atrophy progression as measured by microperimetry. Invest Ophthalmol Vis Sci 2011;52:1119-1126.
  23. Sunnes JS, Rubin GS, Applegate CA et al. Visual function abnormalities and prognosis in eyes with age-related geographic atrophy of the macula and good visual acuity. Ophthalmology 1997;104:1677-1691.
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  26. The Age-Related Eye Disease Study Research Group: A randomized, placebo-controlled clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol 2001;119(10):1439-1452
  27. ClinicalTrials.gov Identifier: NCT02247479: A Study Investigating the  Efficacy and Safety of Lampalizumab Intravitreal Injections in Participants With Geographic Atrophy Secondary to Age-Related Macular Degeneration (CHROMA) 
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