Residency · Residency · Ophthalmology

Age-Related Macular Degeneration: Dry and Wet AMD

Epidemiology and Risk Factors

Age-related macular degeneration is the leading cause of irreversible vision loss in developed countries among individuals over the age of 50. The strongest risk factor is age itself, while smoking is the most important modifiable risk factor. Other significant risk factors include family history, Caucasian race, female sex, and cardiovascular disease. Genetic studies have identified several susceptibility loci, most notably complement factor H (CFH), ARMS2/HTRA1, complement component 3 (C3), and complement factor B (CFB), underscoring the central role of complement dysregulation in AMD pathogenesis. Protective factors include AREDS2 supplementation, dietary omega-3 fatty acids, and regular physical activity.

Classification

AREDS Simplified Severity Scale

The AREDS classification system grades AMD severity based on the presence of large drusen (greater than 125 micrometers) and pigmentary changes. Category 1 represents no AMD, with only a few small drusen under 63 micrometers. Category 2 is early AMD, characterized by multiple small drusen, a few intermediate drusen (63 to 124 micrometers), or mild RPE changes. Category 3 is intermediate AMD, defined by extensive intermediate drusen, at least one large drusen, or non-central geographic atrophy. Category 4 is advanced AMD, encompassing geographic atrophy involving the center of the macula or neovascular AMD.

Simplified 5-Year Risk Assessment

A practical risk assessment tool counts two factors in each eye: the presence of large drusen (one point per eye) and pigmentary changes (one point per eye), for a maximum of four points. The five-year risk of progression to advanced AMD rises steeply with increasing score: zero factors confers a 0.5% risk, one factor 3%, two factors 12%, three factors 25%, and four factors 50%.

<image>Fundus photographs demonstrating the AREDS AMD classification from early AMD with small drusen through intermediate AMD with large drusen and pigmentary changes to advanced AMD with geographic atrophy and choroidal neovascularization</image>

Dry AMD (Non-Neovascular)

Drusen

Drusen are extracellular deposits that accumulate between the basal lamina of the RPE and the inner collagenous layer of Bruch membrane. They are composed of lipids, complement components, amyloid, and vitronectin, among other constituents. Not all drusen carry equal clinical significance. Small drusen under 63 micrometers are age-related and not considered pathologic. Intermediate drusen measuring 63 to 124 micrometers represent an AMD risk factor. Large drusen of 125 micrometers or greater carry a significant risk for disease progression. Drusen morphology also matters: soft drusen, which have indistinct borders and tend to become confluent, pose a higher risk than hard drusen with sharp, well-defined edges.

Geographic Atrophy (GA)

Geographic atrophy represents the advanced form of dry AMD and is characterized by well-demarcated areas of RPE loss, photoreceptor degeneration, and choriocapillaris atrophy. The atrophic patches typically begin in the perifoveal region and expand centripetally, often sparing the fovea until relatively late in the disease course. Fundus autofluorescence imaging is the key modality for monitoring GA: atrophic areas appear hypoautofluorescent due to the loss of RPE lipofuscin, while the surrounding hyperautofluorescent border -- the junctional zone -- represents areas of active degeneration where RPE cells are stressed and accumulating excess lipofuscin. The average rate of GA progression is approximately 1.5 to 2.5 square millimeters per year, and bilateral involvement occurs in roughly 50% of cases. Vision loss is gradual, with patients experiencing progressive reading difficulty and scotomas.

Complement Inhibitors for GA

Until recently, no treatment existed for geographic atrophy. Two complement inhibitors have now received FDA approval. Pegcetacoplan (Syfovre) is a C3 inhibitor administered as an intravitreal injection monthly or every other month. The OAKS and DERBY trials demonstrated that monthly dosing reduced GA growth by 17 to 22% over 24 months. However, treatment was associated with an increased risk of new-onset neovascular AMD, occurring in approximately 7% of treated eyes compared with 3% of sham-treated eyes. Pegcetacoplan became the first FDA-approved treatment for GA in 2023.

Avacincaptad pegol (Izervay) is a C5 inhibitor administered as a monthly intravitreal injection. The GATHER1 and GATHER2 trials showed a reduction in GA growth of approximately 35% at 12 months, though this agent also carries an increased risk of exudative conversion. The clinical significance of complement inhibitors for GA remains debated: the anatomical benefit is modest, the functional benefit in terms of preserved vision is unclear, and the safety signal of increased neovascularization requires careful patient counseling and monitoring.

Wet AMD (Neovascular)

CNV Subtypes Comparison

Choroidal Neovascularization (CNV) Subtypes

Neovascular AMD is classified by the anatomic location and origin of the choroidal neovascularization. Type 1 CNV (historically called occult or sub-RPE) grows beneath the RPE, presenting as a fibrovascular pigment epithelial detachment, and is the most common subtype. Type 2 CNV (classic or subretinal) grows above the RPE and beneath the neurosensory retina, producing a well-defined lesion on fluorescein angiography. Type 3 CNV, also known as retinal angiomatous proliferation (RAP), originates within the retinal vasculature and extends downward into the sub-RPE space; it is often associated with pigment epithelial detachments and retinal-retinal anastomoses. Polypoidal choroidal vasculopathy (PCV) is characterized by aneurysmal dilations of the inner choroidal vasculature and is more common in patients of Asian and African descent. PCV is best visualized on indocyanine green angiography, which reveals a branching vascular network terminating in polypoidal lesions.

Clinical Features

Patients with neovascular AMD typically present with a sudden decrease in central vision, metamorphopsia (distortion of straight lines), or a central scotoma. Examination reveals subretinal or sub-RPE fluid, hemorrhage, and lipid exudates. If left untreated, the CNV complex undergoes fibrosis, producing a disciform scar that represents the end stage of neovascular AMD with permanent, severe central vision loss.

Diagnosis

Multimodal imaging is essential for the diagnosis and characterization of neovascular AMD. OCT reveals subretinal fluid, intraretinal fluid, sub-RPE fluid, pigment epithelial detachments, and hyperreflective material representing the CNV complex itself. Fluorescein angiography demonstrates early hyperfluorescence with late leakage in classic CNV, while occult CNV shows stippled hyperfluorescence or late leakage from an indeterminate source. Indocyanine green angiography is the best modality for delineating PCV and Type 1 CNV. OCT angiography can detect CNV flow without dye injection and is increasingly useful for diagnosis and monitoring, though it does not provide leakage information.

<image>Multimodal imaging of neovascular AMD showing OCT with subretinal fluid and pigment epithelial detachment, fluorescein angiography with classic CNV leakage pattern, and OCTA en face flow image delineating the CNV membrane</image>

Anti-VEGF Treatment for Wet AMD

Agents

Anti-VEGF therapy has fundamentally transformed the management of neovascular AMD. Ranibizumab (Lucentis) was the first agent to demonstrate dramatic visual acuity gains, with the MARINA and ANCHOR trials establishing anti-VEGF as the standard of care. Aflibercept (Eylea) was shown in the VIEW 1 and VIEW 2 trials to be non-inferior to monthly ranibizumab with a less frequent every-eight-week dosing schedule. Bevacizumab (Avastin), the off-label full-length antibody, was demonstrated in the CATT trial to have comparable efficacy to ranibizumab at a fraction of the cost, making it the most cost-effective option. Brolucizumab (Beovu) showed longer durability in the HAWK and HARRIER trials but raised significant safety concerns, including intraocular inflammation and retinal vasculitis, which have limited its adoption. Faricimab (Vabysmo), a bispecific antibody targeting both VEGF-A and angiopoietin-2, was evaluated in the TENAYA and LUCERNE trials and achieved dosing intervals of up to every 16 weeks in some patients. High-dose aflibercept (8 mg) demonstrated extended durability with 12- to 16-week dosing intervals in the PULSAR trial.

Treatment Protocols

Treatment typically begins with a loading phase of three monthly injections to achieve initial disease control. Maintenance therapy then follows one of two main approaches. The treat-and-extend protocol, the most widely used strategy, extends the interval by two-week increments when the macula is stable and shortens it when fluid recurs, with typical maintenance intervals ranging from every 8 to every 16 weeks. The PRN approach treats only upon detection of recurrent disease activity. OCT is monitored at every visit, and any recurrence of fluid triggers retreatment. Most patients require lifelong treatment, and under-treatment consistently leads to vision loss.

Treatment Targets

The primary treatment target is resolution of subretinal and intraretinal fluid on OCT, along with stable or improving visual acuity and reduced CNV activity. A small amount of sub-RPE fluid may be tolerated, particularly in eyes with Type 1 CNV and pigment epithelial detachments, where complete resolution may not be achievable without excessively aggressive treatment.

AREDS2 Supplementation

Formula

The AREDS2 formulation consists of vitamin C 500 mg, vitamin E 400 IU, lutein 10 mg, zeaxanthin 2 mg, zinc 80 mg (or 25 mg in the alternative formulation), and copper 2 mg. Beta-carotene, which was included in the original AREDS formula, was removed from AREDS2 because of its association with increased lung cancer risk in smokers. Lutein and zeaxanthin were substituted and have been shown to provide equivalent or superior benefit.

Indications

AREDS2 supplementation is indicated for patients with intermediate AMD (AREDS Category 3) or those with advanced AMD in one eye. It reduces the risk of progression to advanced AMD by approximately 25%. Importantly, AREDS2 supplementation is not indicated for patients with early AMD or no AMD, as no benefit has been demonstrated in these groups.

<image>Fundus autofluorescence image showing geographic atrophy with sharply demarcated hypoautofluorescent areas of RPE loss and surrounding hyperautofluorescent junctional zone indicating areas of active degeneration</image>

Clinical Pearls

Any patient over 50 presenting with new metamorphopsia or a central scotoma requires urgent evaluation for AMD, as these symptoms may herald the onset of treatable neovascular disease. Patients with intermediate or advanced AMD should be instructed in daily Amsler grid monitoring at home and told exactly what changes to report. Anti-VEGF therapy has transformed wet AMD from a rapidly blinding disease into a manageable chronic condition, but this success depends on lifelong treatment adherence -- discontinuation leads to recurrence and irreversible vision loss. Before initiating complement inhibitors for geographic atrophy, the risk of neovascular conversion must be thoroughly discussed with the patient. PCV should be suspected in Asian patients who present with a hemorrhagic pigment epithelial detachment, and indocyanine green angiography is essential for confirming the diagnosis. Photodynamic therapy with verteporfin remains a consideration for PCV, either alone or in combination with anti-VEGF. When both eyes have wet AMD, the worse eye is typically treated first, followed by the second eye if needed; treating both eyes on the same day is acceptable when separate sterile preparations are used for each eye to minimize endophthalmitis risk. Smoking cessation is the single most impactful modifiable intervention and should be counseled at every visit.

References

• Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration (AREDS2). JAMA. 2013;309(19):2005-2015.
• CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration (CATT). N Engl J Med. 2011;364(20):1897-1908.
• Liao DS, et al. Complement C3 inhibitor pegcetacoplan for geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY). Ophthalmology. 2020;127(12):1537-1549.
• Heier JS, et al. Intravitreal aflibercept for diabetic macular edema (VIEW 1 and VIEW 2). Ophthalmology. 2012;119(12):2537-2548.
• American Academy of Ophthalmology. Basic and Clinical Science Course, Section 12: Retina and Vitreous.

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