Elena Biffi, OD, MSc, FAAO, dives into AMD, a multifactorial disease that requires a multimodal diagnostic imaging approach.

Reviewed by Elena Biffi, OD, MSc, FAAO.

Age-related macular degeneration (AMD) has received more and more attention over the years due to the increasing number of people affected in the United States and around the world due to the aging population.

The prevalence of the disease is expected to increase exponentially.

In 2004 in the United States, 1.75 million Americans had advanced disease; this statistic is expected to climb to 25 million by 2040, according to various projection models,1 says Elena Biffi, OD, MSc, FAAO, Associate Professor, New England College of Optometry, Boston.

About 20% of these cases are neovascular in nature and about 80% nonexudative; of these, 10% progress to the neovascular form.

Non-modifiable risk factors for AMD include increasing age; ethnicity, with Caucasians more often affected than other groups; a mutation in the complement factor H embarrassed; and increased C-reactive protein values ​​and erythrocyte sedimentation rate.

AMD has a complex genetic makeup and genetic testing may not provide management benefits. Modifiable risk factors are smoking; low levels of systemic antioxidants of vitamins C and E, lutein and zeaxanthin, zinc and omega-3; hypertension; and increased waist-to-hip ratio.

Related: Advances in Managing Dry AMD

The take-home message, Dr. Biffi noted, is that AMD is a multifactorial disease that requires a multimodal diagnostic imaging approach.

Diagnosis of AMD

A number of imaging options help establish the diagnosis. These include assessment of the posterior pole using a fundus camera; optical coherence tomography (OCT) to detect structural changes in the retina; OCT-Angiography (OCTA), which detects vascular changes; and fundus autofluorescence (FAF), which provides functional/structural information showing the metabolic activity of cells in the retinal pigment epithelium and photoreceptors.

In dry AMD, geographic atrophy (GA) is characterized by hypo-FAF detecting loss of retinal pigment epithelium (RPE) and photoreceptor integrity line.

Additionally, hypo-FAF may reveal the presence of RPE mottling and RPE hyperpigmentation. Hyper-FAF is characteristic of accumulation of drusen and lipofuscin, as well as stressed or dying EPR and photoreceptors.

OCT provides a wealth of information with new generations, spectral domain (Cirrus HD-OCT, Zeiss; Spectralis, Heidelberg; Avanti and RTVue, Optovue; and Maestro, Topcon) and swept source (DRI Triton, Topcon; PlexElite 9000, Zeiss ). There are many prognostic biomarkers that can be identified with OCT imaging technology.

Specific features of drusen, the earliest clinical sign of AMD, have been associated with a higher risk of progression to advanced forms of AMD, including: soft drusen, drusen size greater than 125 microns, and increased volume of drusen.

Drusen regression, particularly of a large drusen, is considered a negative precursor that may precede progression. Other prognostic biomarkers associated with progression to knee OA include the presence of cuticular drusen (5-year risk is 25%), calcified drusen (26%), hyperreflective foci (47%), d incomplete atrophy of the RPE (74%) and reticular pseudo-reticle. -drusen (15 A diffuse perilesional hyper-FAF pattern also indicates an enlargement of the GA area.

In neovascular AMD, the presence of cuticular drusen increases the risk of progression to neovascular AMD (AnAMD) by 10%, hyperreflective foci by 50% and confluent pseudo-drusen by 30%.

Unilateral nAMD is associated with a high risk of developing advanced AMD in the other eye in 22% to 50% of cases. This risk can be reduced by nearly 36% over 10 years with AREDS (Age-Related Eye Disease Study) vitamins (Bausch & Lomb).

OCTA, a relatively new technology, eliminates the need for fluorescein injection and facilitates visualization of the retinal and choroidal vasculature.

It allows three-dimensional visualization of perfused structures, vascular abnormalities and ischemic retinal changes. It is particularly useful in the early detection of choroidal neovascular membrane (CNVM) associated with nAMD.

The presence of abnormal vasculature in the choroid and avascular facial layers, especially when associated with fluid in the retina, has a high diagnosis of nAMD.

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Considering all the advantages of different imaging devices, multimodal imaging including color fundus photography, macular thickness measurement by OCT, OCT-A, FAF and FA is the best approach.

Although OCT is noninvasive, fluorescein angiography remains the gold standard for the diagnosis of active choroidal neovascularization.

Differential diagnosis of AMD

Other causes of drusen are familial dominant drusen, Bietti’s crystal dystrophy, and fundus albipunctatus.

Other diseases that cause choroidal neovascularization are idiopathic CNVM, angioid streaks, lacquer fissures, choroidal tumor, chronic uveitis, traumatic choroidal rupture, toxoplasmosis, and presumptive ocular histoplasmosis syndrome.

AMD General Guidelines

Monitoring and early detection are key, Biffi stressed, emphasizing family history, smoking status with cessation advice, regular follow-up appointments, use of the Home Amsler grid, self-monitoring and rapid assessment of the onset of new symptoms.

It is important to note that in the presence of wet AMD, early detection and rapid treatment improve the visual outcome.

Patient education about the disease is important, as is referral for vision rehabilitation if needed.

Related: Case Report: The “Other” AMD

Biffi also advised the use of multimodal imaging to detect features of high-risk drusen and for early diagnosis of CNVM. Particular attention should be paid to drusen size, drusen type, drusen location, laterality and volume, which are associated with a higher risk of progression to GA and CNVM.

Optometrists should also look for hyperreflective foci, RPE changes, and reticular pseudo-drusen that are associated with a higher risk of AG and CNVM; calcified drusen have a higher risk of knee OA.

Incomplete RPE atrophy is a higher risk for AG, and a perilesional hyper-FAF pattern indicates a higher risk for AG hypertrophy.

In these cases, the other eye has a higher risk of developing AMD; another caveat is that AMD drusen regression may precede its progression.


No treatment has been approved to treat or prevent dry AMD.

Current treatments aim to reduce the risk of progression to advanced AMD. AREDS vitamins appear to have no benefit in the early stages of AMD but should be prescribed for intermediate and advanced stages.

This supplementation, containing vitamins C and E, zinc, copper, lutein, zeaxanthin and omega-3 fatty acids, was associated with a 25% reduction in the risk of progression of intermediate to advanced AMD .

Those currently under study are Pegcetacoplan (APL-2, Apellis Pharmaceuticals), which inhibits complement 3; neuroprotective agents, brimonidine tartrate, elamipretide (Stealth Biotherapeutics); visual cycle modulators, ALK-001 (Alkeus Pharmaceuticals), an oral synthetic vitamin A capsule; cell therapies, stem cell therapy that delivers RPE to the subretinal space; and anti-inflammatory agents.

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Wet AMD treatment includes anti-vascular endothelial growth factor (VEGF) therapies (off-label bevacizumab, Genentech), pegaptanib sodium (Macugen, Eyetech Pharmaceuticals), ranibizumab (Lucentis, Genentech), aflibercept (Eylea, Regeneron Pharmaceuticals) , brolucizumab (Beovu, Novartis), and Byooviz (ranibizumab, Biogen and Samsung Bioepis), a biosimilar.

Other treatments include thermal laser photocoagulation which may be considered for the treatment of extrafoveal CNVM and photodynamic therapy which may be an option for classic subfoveal or occult subfoveal (

A new treatment on the horizon for wet AMD includes long-lasting anti-VEGF growth factor, sustained-release intravitreal agents, and gene therapies.

For patients with severe visual loss of 20/160 to 20/800 caused by bilateral end-stage AMD, a recently FDA-approved surgical procedure can be performed to implant the Miniature Implantable Telescope (VisionCare Ophthalmic Technologies, Inc.)

A number of potential future therapies for dry and wet AMD are beginning or completing phase 3 clinical trials.

1. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Global Health 2014;2:E106-E116; https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(13)70145-1/fulltext