AMD is a completely different disease than it was 20 years ago.
Before the advent of anti-VEGF injections, AMD was a devastating disease because people would inexorably lose their vision in their senior years. Patients could no longer read, no longer recognize faces, and retina specialists had few effective treatments. Genetics played a strong role – if parents had the disease, there was a good chance the patient would develop it too. For a long time, we felt helpless in halting progression towards serious vision loss. Then came anti-VEGF agents, and we suddenly had a treatment to halt and even reverse the vision loss associated with AMD.
This quick summary of AMD gives you a framework to start learning about this huge disease.
Causes of AMD
The biggest risk factor for age-related macular degeneration is age – it’s in the name. Smoking is the biggest modifiable risk factor for disease. Some single gene risk factors have been identified, including ARMS2 and CFH. About 1.6% of people over 50 and 14% of white women over 80 have the disease.
The pathophysiology is complex and difficult to study. The disease may be caused by oxidative, ischemic, lipidic, or other insults to the choroid, choriocapillaris or RPE, which results in RPE dysfunction and accumulation of extracellular lipofuscin-containing debris called drusen. AMD is generally classified as “dry” or “wet”, depending on the absence of presence of choroidal neovascularization.
Non-exudative (dry) AMD
The three classic findings in dry AMD are drusen, pigmentary changes and geographic atrophy.
|Exam appearance||OCT appearance|
|No classic OCT appearance|
Drusen are classified as small (<65 um), medium (65 – 124 um) or large (>125 um). Hard, small drusen convey less risk of progression to advanced AMD. Confluent/large, soft drusen convey greater risk.
Pigmentary changes can sometimes be difficult to distinguish from drusen. The biggest difference is that drusen are usually yellowish, but pigmentary changes can be yellow, brown, or black. Drusen are also relatively circular compared to pigmentary changes.
The AREDS study was a landmark study which helped classify AMD into various stages.
- No AMD: no drusen or a few small drusen
- Early AMD: many small drusen or a few medium-sized drusen
- Intermediate AMD: many medium-sized drusen, or at least one large druse
- Advanced AMD: wet AMD or center-involving (macula-involving) geographic atrophy
The AREDS study also showed the benefit of the AREDS formulation of vitamins and minerals to decrease progression to advanced AMD if the patient already had at least intermediate AMD. These vitamins are sold at CVS, Target and other drugstores under brand names such as Ocuvite or PreserVision. The AREDS2 study further refined the recommended formula – see the landmark trials section below for more information.
Here are some more examples of drusen and pigmentary changes:
Early dry AMD with small drusen and pigmentary changes
Geographic atrophy consists of well circumscribed areas of RPE atrophy which may be small focal areas distributed in the macula or a single central/paracentral lesion. They classically start paracentrally surrounding the fovea in a horseshoe configuration and eventually involve the fovea, leading to severe vision loss.
Here are some examples of geographic atrophy:
Exudative (wet) AMD
Conversion to wet AMD happens quickly with symptoms of blurry vision, a central or paracentral scotoma, and metamorphopsia. The term “wet” comes from fluid accumulation in the retina due to choroidal neovascularization which cause distortion of the retinal contour and disruption of the normal function of the retina. The most common findings are intraretinal or subretinal fluid, pigment epithelial detachments (PEDs), subretinal hemorrhage, choroidal neovascular membrane, or an end-stage disciform scar.
Choroidal neovascularization (CNV) in wet AMD can be classified into Type I, II, or III.
- Type I CNV arises from the choroid, erupts through Bruch’s membrane and causes fluid between the RPE and Bruch’s membrane. This is the most common.
- Type II CNV arises in the subretinal space leading to fluid accumulation between the retina and the RPE.
- Type III CNV arises from within the retina and grows downward to the RPE and choroid.
Now that you know the features of dry and wet AMD, we can discuss how modern imaging can help us diagnose these entities, classify disease, and monitor treatment response.
Color fundus photographs have been the traditional way to document the findings of dry AMD.
In dry AMD, Spectral-domain OCT (SD-OCT) can be being used to monitor, count and quantify drusen and geographic atrophy which can be followed through time. SD-OCT has the advantage of being faster and has higher resolution than the older time-domain OCT (TD-OCT) systems.
Fundus autofluorescence (FAF or AF)
Fundus autofluorescence can be used to track the progression of geographic atrophy. With wet AMD, OCT can be used to guide treatment decisions with anti-VEGF agents, as the presence of retinal edema, intraretinal fluid and subretinal fluid can easily be detected.
Fluorescein angiography (FA) and indocyanine green (ICG)
FA is used to rule in or rule out equivocal cases of conversion to wet AMD, confirm the OCT findings of wet AMD, or differentiate between other neovascular diseases in the differential.
End stage wet AMD leads to the formation of subretinal fibrosis and atrophy of the outer retina.
The original AREDS formulation was:
- Vitamin C 500 mg
- Vitamin E 400 IU
- Beta-carotene 15mg (a form of vitamin A)
- Zinc 80 mg
- Copper 2mg (added to prevent copper deficiency in those taking high dose zinc)
However, beta-carotene was associated with an increased list of lung cancers in smokers. The AREDS2 study showed that substituting lutein and zeathanxine for beta-carotene maintained the same benefit.
The AREDS2 formulation is:
- Vitamin C 500 mg
- Vitamin E 400 IU
- Lutein 10mg
- Zeaxanthin 2mg
- Zinc 80mg
- Copper 2mg
Anti-VEGF agents inhibit the signaling molecule (VEGF) that usually stimulates neovascularization and thus slow down the progression of wet AMD. The oldest intravitreal anti-VEGF agent pegaptanib (Macugen) is not commonly used anymore due to much lower efficacy. The FDA-approved anti-VEGF agents for exudative AMD are ranibizumab (Lucentis) and aflibercept (Eylea). Many new agents are under investigation. Off-label use of bevacizumab (Avastin) is common due to lower cost. These injections are frequently given in a q1 month, q2 month, as needed, a treat-and-extend regimen.
When a patient transitions from dry to wet AMD, we often start with a series of 3 injections and then evaluate with OCT. The goal is to find the optimal regimen for patients to stay dry. Every retina specialist has his/her preferred regimen, but they generally follow a variation of the following:
- Scheduled injections: injections are given even if the OCT shows a dry, flat macula to prevent fluid accumulation
- PRN injections: injections are given only when the OCT shows fluid
- Treat-and-extend: injections are given until the OCT is dry, then longer intervals between injections are scheduled until patient’s optimal schedule is determined
Photodynamic therapy (PDT) was used before the advent of anti-VEGF agents to treat predominantly classic CNV. It involved intravenous injection of verteporfin (Visudyne), a photoreactive agent, and ocular exposure to blue wavelength light. It slowed the progression of CNV. We don’t commonly use this in the anti-VEGF era.
Thermal laser was used for extrafoveal CNV but suffered from high recurrence rates.
We’ll discuss a few landmark trials here. Just as you cannot discuss cardiology without discussing the AFFIRM trial (remember rate vs rhythm?), many of our practice patterns in retina are evidence based.
High dose vitamin and zinc supplementation decreases the risk of progression to advanced AMD by 25%.
Adding lutein and zeaxanthin provided an additional 20% decreased progression to advanced AMD in persons who had a low dietary intake of lutein and zeaxanthin. Replacing beta-carotene with lutein and zeaxanthin worked just as effectively in the AREDS2 formulation. Omega-3 fatty acids, did not decrease the risk of progression of AMD. The supplement did not affect cataract development.
The 1st Phase III Lucentis (ranibizumab) trial in eyes with minimally classic/occult CNV. 95% of eyes maintained vision. 40% of eyes had improved vision. Remember, PDT (photodynamic therapy) was the standard of care for predominantly classic lesions, which is why they only studied minimally classic/occult CNV. In comparison to Lucentis, 67% of eyes maintained vision when they were treated with PDT in the TAP study.
The 2nd Phase III Lucentis (ranibizumab) trial in eyes with predominantly classic CNV. 95% of eyes maintained vision. 40% of eyes had improved vision.
- AMD can be separated into dry and wet forms
- Serious vision loss is caused by wet AMD and geographic atrophy
- SD-OCT is classically used to monitor AMD and treatment response over time
- In the dry form, AREDS2 vitamins helps prevent wet AMD
- In the wet form, anti-VEGF injections decrease retinal edema and help maintain vision
- AREDS Research Group. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss. Archives of Ophthalmology 2001.
- Rosenfeld PJ, Brown DM, Heier JS et al. Ranibizumab for neovascular age-related macular degeneration. N. Engl. J. Med 2006.
- Brown DM, Michels M, Kaiser PK et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology 2009.