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Age-related macular degeneration

Updated: Nov 16, 2022

Summary

Age-related macular degeneration (ARMD) is an acquired degenerative disorder affecting the macula, with the hallmark being the presence of ‘drusen’ in the macula. There are two main subtypes, which we will describe in the following article.

Aetiology


ARMD is usually classified into two types: Dry ARMD (non-exudative, non-neovascular), and Wet ARMD (exudative, neovascular). The former makes up 90% of cases, whilst the latter is less common, however is associated with rapid progression to advanced vision loss. Another, temporal classification of the condition exists, where the disease is classified as ‘early’, ‘intermediate’, or ‘advanced’ ARMD.


A combination of genetic and environmental risk factors are thought to interact to modify the Bruch's membrane/choroid complex, the retinal pigment epithelium (RPE) and photoreceptor cells. Drusen, the main histopathological hallmark of the condition, are extracellular eosinophilic deposits located between the RPE and Bruch’s membrane, thought to be derived from immune-mediated and metabolic processes in the RPE. Age-related drusen are common after the 6th decade, but these are biochemically distinct from the drusen we see in ARMD.


Risk factors:

  • Age is the biggest risk factor

  • White race

  • Family history: two polymorphisms on chromosome 10q26, Tyr402His (Complement factor H locus, CFH) and Ala69Ser (ARMS2) may be responsible for up to 50-75% of the genetic risk. The former helps to protect cells from complement-mediated damage.

  • Smoking doubles the risk

  • Hypertension

  • High fat intake and obesity

  • Aspirin may increase the risk of neovascular disease (but limited evidence!


Epidemiology


💡 ARMD is the most common cause of irreversible vision loss in the developed world.


In the UK, significant visual impairment (binocularly 6/18 or worse) from AMD affects about 4% of the population aged over 75 years and 14% of those over 90.


Dry Age-Related Macular Degeneration


Dry ARMD is also known as non-exudative, or non-neovascular ARMD. Vision declines over a period of months/years, usually in both eyes, however they may be asymmetrically affected. The main clinical sign is soft drusen. With progression, the end result of dry ARMD is geographic atrophy (GA): well circumscribed areas of RPE atrophy, with variable loss of the retina and choriocapillaris. OCT may show drusen: in addition to loss of RPE in geographic atrophy.


Fundus photographs at different stages of age-related macular degeneration (AMD) progression. (a) Large and intermediate drusen at intermediate stage of AMD. (b) Neovascular AMD—right eye with evidence of sub-retinal fluid, hemorrhage, and hard exudate in the presence of choroidal neovascularization. (c) Fluorescein angiography of the neovascular AMD—Left eye showing the hyperfluorescence of the fluorescein angiogram corresponding to the area of the choroidal neovascularization. (d) Central geographic atrophy—Right eye with evidence of geographic atrophy involving the center of the fovea with evidence of large drusen temporally. - Image Courtesy of Ratnapriya et al

Wet Age-Related Macular Degeneration


Wet ARMD, also known as exudative or neovascular ARMD, is differentiated from early or dry ARMD by the presence of choroidal neovascularization (CNV), where new blood vessels from the choroid penetrate through the Bruch membrane and proliferate either between Bruch’s membrane and the RPE or in the subretinal space. Around 10% of cases of dry ARMD will ultimately lead to the development of CNV. With progression, the end result of wet ARMD is disciform macular degeneration.


CNV (choroidal neovascularisation) and PED (pigment epithelial detachment, where the pigment epithelium detaches from the inner collagenous layer of the Bruch membrane) are two of the main manifestations of neovascular ARMD, however two other conditions, retinal angiomatous proliferation (RAP) and polypoidal choroidal vasculopathy (PCV), have also been included under the umbrella of neovascular AMD.


Clinical classification

Normal ageing

Only drupelets (drusen <63nm) No AMD pigmentary abnormalities

Early ARMD

Medium drusen (>63 μm but <125 μm)

No AMD pigmentary abnormalities

Intermediate AMD

Large drusen (>125 μm) Any AMD pigmentary

abnormalities

Late AMD

Neovascular AMD and/or any geographic atrophy


Pigmentary abnormalities refers to hyper- or hypopigmentary abnormalities associated with medium/large drusen and not due to other known disease.


Diagnosis


Clinical features

Dry ARMD:

  • Gradual vision loss

  • Central scotoma

  • Soft drusen

  • Geographic atrophy

Wet ARMD:

  • Visual distortion, also known as metamorphopsia

  • Central scotoma of sudden onset

  • Pigment epithelial detachment

  • Cystoid macular oedema

  • Subretinal fibrosis


Investigations


OCT (Ocular Coherence Tomography)

OCT is a non invasive means of providing a cross-sectional image of the posterior segment, and is particularly helpful in monitoring disease progression as well as response to treatment in ARMD.


FFA (Fundus fluorescein angiography)

Useful if there is suspicion of exudative ARMD. This can demonstrate hypofluorescent and hyperfluorescent changes. Most lesions are hyperfluoerecent, (e.g. drusen, RPE atrophy, choroidal neovascular membranes, subretinal fibrosis) rather than hypofluorescent (haemorrhage, lipid exudation, and pigment hyperplasia). FFA also helps distinguish CNV patterns, with a ‘classic’ pattern showing leakage infront of the RPE, and an ‘occult’ lesion being sub-RPE.


Management


Dry ARMD

  • AREDS2 (The Age Related Eye Disease Study 2) suggested a regimen of vitamin E, vitamin C, lutein, zeaxanthin, zinc and copper may reduce the risk of development to advanced ARMD in individuals with certain features of dry ARMD.

  • Modifying risk factors: a diet of green leafy vegetables, smoking cessation

  • Amsler grid testing: should be provided for home use, with instructions to regularly self test and to seek urgent advice in the event of any change (distortion on the grid is a sign of metamorphopsia and potential development to exudative ARMD).


Wet ARMD

  • Treatment with intravitreal injection of anti-VEGF agents: these work to slow and reverse the growth of new vessels.

  • NICE guidelines suggest first line treatment is Ranibizumab (Lucentis®) - this is often a monthly injection

  • Bevacizumab (Avastin®) is currently unlicensed in the UK however is commonly used as it is a cost effective regime

  • NICE guidelines suggest that ranibizumab, within its marketing authorisation, is recommended as an option for the treatment of wet age-related macular degeneration if all of the following apply:

  • The best-corrected visual acuity is between 6/12 and 6/96

  • There is no permanent structural damage to the central fovea

  • The lesion size is less than or equal to 12 disc areas in greatest linear dimension

  • There is evidence of recent presumed disease progression (blood vessel growth, as indicated by fluorescein angiography, or recent visual acuity changes)

Visual and anatomical mejoramiento after 3 aflibercept injections in a ranibizumab resistant AMD case. a. Large-septa cysts are seen on OCT following 11 ranibizumab injections, b: The cysts have completely disappeared after a single aflibercept injection, c. There is no cyst on OCT and VA has been increased after the third aflibercept injection. Image courtesy of Batioglu et al

References

  1. Bowling, Brad. Kanski’s Clinical Ophthalmology: A Systematic Approach . 2016. Open WorldCat, http://public.ebookcentral.proquest.com/choice/publicfullrecord.aspx?p=2029294.

  2. Hobbs, Samuel D., and Kristine Pierce. ‘Wet Age-Related Macular Degeneration (Wet AMD)’. StatPearls, StatPearls Publishing, 2022. PubMed, http://www.ncbi.nlm.nih.gov/books/NBK572147/.

  3. Ratnapriya, R., and E. Y. Chew. ‘Age-Related Macular Degeneration – Clinical Review and Genetics Update’. Clinical Genetics, vol. 84, no. 2, Aug. 2013, pp. 160–66. PubMed Central, https://doi.org/10.1111/cge.12206.

  4. Batioglu, Figen, et al. ‘Short-Term Outcomes of Switching Anti-VEGF Agents in Eyes with Treatment-Resistant Wet AMD’. BMC Ophthalmology, vol. 15, Apr. 2015, p. 40. PubMed Central, https://doi.org/10.1186/s12886-015-0025-z.

  5. Recommendations | Age-Related Macular Degeneration | Guidance | NICE https://www.nice.org.uk/guidance/ng82/chapter/Recommendations#pharmacological-management-of-amd. Accessed 10 Oct. 2022

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