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Summary Table

Feature	Detail
Risk Factors	Age > 50 (strongest), smoking (strongest modifiable), Caucasian race, family history, female sex, obesity, cardiovascular disease, prolonged UV exposure
Etiology	Degenerative changes in the macula due to accumulation of drusen (lipid-protein deposits beneath retinal pigment epithelium), oxidative stress, and chronic low-grade inflammation
Patient Presentation	Gradual, painless, bilateral loss of central vision; difficulty reading, recognizing faces, or performing fine detail tasks; peripheral vision preserved
Classic Physical Exam	Fundoscopy: drusen (yellow-white deposits), RPE atrophy (dry); subretinal hemorrhage, exudates, retinal edema (wet). Amsler grid: metamorphopsia (wavy/distorted lines), central scotoma
Key Diagnostic Results	Fundoscopy with drusen or neovascularization; OCT showing drusen, RPE changes, subretinal/intraretinal fluid; fluorescein angiography (FA) showing choroidal neovascularization (CNV) in wet AMD
Management	Dry AMD: AREDS2 supplementation, lifestyle modification, monitoring. Wet AMD: intravitreal anti-VEGF injections (bevacizumab, ranibizumab, aflibercept)
Keywords	"Drusen," "gradual central vision loss," "metamorphopsia," "Amsler grid distortion," "macular changes in elderly," "painless vision loss," "subretinal hemorrhage"

1. Pathophysiology

AMD targets the macula, the central region of the retina responsible for high-acuity vision. The disease process begins with dysfunction of the retinal pigment epithelium (RPE), a monolayer of cells that supports photoreceptor health by recycling visual pigments, phagocytosing shed photoreceptor outer segments, and maintaining the outer blood-retinal barrier.

Over decades, metabolic byproducts accumulate between the RPE and Bruch's membrane (the basement membrane separating RPE from the choroidal vasculature). These deposits, called drusen, are composed of lipids, complement proteins, and inflammatory mediators. Drusen physically separate the RPE from its choroidal blood supply, impairing nutrient exchange and waste removal. This explains why the disease is slowly progressive and why central vision deteriorates first: the macula has the highest metabolic demand of any retinal region.

In dry (atrophic) AMD, the process remains non-neovascular. Progressive RPE atrophy leads to photoreceptor death, producing a slowly expanding area of central scotoma known as geographic atrophy. Vision loss is gradual and corresponds directly to the area of RPE and photoreceptor dropout.

In wet (neovascular/exudative) AMD, chronic hypoxia and inflammatory signaling trigger upregulation of vascular endothelial growth factor (VEGF). VEGF drives the growth of abnormal new blood vessels from the choroid through Bruch's membrane into the subretinal space, a process called choroidal neovascularization (CNV). These fragile vessels leak fluid, lipid, and blood beneath and within the retina, causing acute distortion and rapid central vision loss. This is why wet AMD presents more suddenly than dry AMD and why anti-VEGF therapy is the cornerstone of treatment: it directly targets the molecular driver of neovascularization.

A critical teaching point: dry AMD can convert to wet AMD at any time. Approximately 10-15% of patients with dry AMD progress to the wet form, but wet AMD accounts for roughly 90% of severe vision loss from AMD. This conversion risk is why monitoring with the Amsler grid is emphasized.

2. Classification and Clinical Manifestation

Classification	Fundoscopic Findings	Clinical Manifestation	Prognosis
Early Dry AMD	Medium-sized drusen (63-124 micrometers), no pigmentary changes	Often asymptomatic or mild blurriness in central vision	Low risk of progression; monitor annually
Intermediate Dry AMD	Large drusen (>125 micrometers) and/or pigmentary abnormalities	Mild to moderate central blur, may notice difficulty in dim lighting	Moderate risk of progression; AREDS2 supplementation indicated
Advanced Dry AMD (Geographic Atrophy)	Well-demarcated areas of RPE and photoreceptor atrophy	Pronounced central scotoma, difficulty reading, preserved peripheral vision	Irreversible; slow progression over years
Wet (Neovascular) AMD	CNV, subretinal fluid/hemorrhage, hard exudates, RPE detachment, disciform scar (late)	Acute or subacute metamorphopsia, rapid central vision decline, sudden scotoma	Most visually threatening form; requires urgent treatment

Key clinical distinction: dry AMD is bilateral and symmetric in its progression, while wet AMD may present unilaterally with sudden worsening, though the fellow eye is at high risk. Patients often describe that straight lines appear wavy (metamorphopsia), which is the hallmark symptom prompting evaluation for conversion to wet AMD.

3. Diagnostic Workup

Test	Role	Key Findings
Amsler Grid	Screening/self-monitoring tool	Wavy lines (metamorphopsia), missing areas (scotoma) in central field
Dilated Fundoscopy	Best initial test	Drusen, RPE changes, hemorrhage, exudates, geographic atrophy
Optical Coherence Tomography (OCT)	Most important imaging modality; distinguishes dry vs. wet	Drusen beneath RPE, subretinal/intraretinal fluid, RPE detachment, retinal thickening in wet AMD
Fluorescein Angiography (FA)	Confirmatory for wet AMD / Gold standard for CNV	Hyperfluorescence from leaking choroidal neovascular membrane; classic vs. occult CNV patterns
OCT Angiography (OCTA)	Non-invasive alternative to FA	Detects CNV without dye injection; increasingly used in clinical practice
Fundus Autofluorescence (FAF)	Evaluates RPE health in dry AMD	Hypoautofluorescence in areas of geographic atrophy; hyperautofluorescence at margins indicates progression risk

Workup logic: The Amsler grid is used for home monitoring, not diagnosis. When a patient over 50 presents with gradual central vision loss, the first step is dilated fundoscopy, which reveals drusen and macular changes. If drusen alone are seen without fluid or hemorrhage, the diagnosis is dry AMD, and OCT is performed to characterize severity and monitor for progression.

If fundoscopy reveals hemorrhage, exudates, or subretinal fluid suggesting wet AMD, OCT is the next step to confirm the presence of intraretinal or subretinal fluid. Fluorescein angiography is then performed to visualize and characterize the choroidal neovascular membrane, guiding treatment decisions. FA remains the gold standard for confirming CNV, but OCT has become the primary tool for ongoing monitoring of treatment response because it is non-invasive and highly sensitive to fluid changes.

The exam commonly tests whether you can distinguish dry from wet AMD based on fundoscopic and OCT findings. Drusen alone without fluid equals dry. Any evidence of fluid, hemorrhage, or neovascularization equals wet and demands urgent referral.

4. Management and Treatment

Stage	Treatment	Details
Early Dry AMD	Observation + lifestyle modification	Smoking cessation, UV protection, healthy diet rich in leafy greens and omega-3 fatty acids; annual dilated exam
Intermediate Dry AMD	AREDS2 formula	Vitamin C 500 mg, Vitamin E 400 IU, Lutein 10 mg, Zeaxanthin 2 mg, Zinc 80 mg, Copper 2 mg; taken daily
Advanced Dry AMD (Geographic Atrophy)	Low-vision rehabilitation + emerging therapies	Pegcetacoplan (complement C3 inhibitor) and avacincaptad pegol (complement C5 inhibitor) are FDA-approved intravitreal injections that slow geographic atrophy progression
Wet AMD	Intravitreal anti-VEGF injections (first-line)	Bevacizumab (1.25 mg), ranibizumab (0.5 mg), aflibercept (2 mg), or faricimab; monthly injections initially, then treat-and-extend protocol
Wet AMD (refractory)	Combination or alternative therapy	Photodynamic therapy (PDT) with verteporfin for select cases; switching anti-VEGF agents; brolucizumab for refractory disease

Acute management of wet AMD: When wet AMD is diagnosed, intravitreal anti-VEGF injection is the first-line treatment and the next best step. These agents bind and neutralize VEGF, reducing vascular permeability and inhibiting new vessel growth. The standard induction protocol involves monthly injections for the first three months, followed by a treat-and-extend approach where the interval between injections is gradually lengthened based on OCT findings. Patients require ongoing monitoring with OCT at each visit to assess for recurrent fluid.

AREDS2 supplementation is indicated for intermediate and advanced AMD to reduce the risk of progression to advanced disease. The original AREDS formula contained beta-carotene, which was replaced with lutein and zeaxanthin in AREDS2 because beta-carotene increases lung cancer risk in current and former smokers. This is a commonly tested fact: never prescribe beta-carotene-containing supplements to smokers.

Contraindications and cautions: Anti-VEGF injections carry a small risk of endophthalmitis, retinal detachment, and thromboembolic events. Active ocular infection is a contraindication to injection. Brolucizumab, while effective, has been associated with retinal vasculitis and should be used with caution.

Low-vision rehabilitation (magnifying devices, large-print materials, adaptive technology) is an important adjunct for patients with advanced disease of either type, as AMD does not cause total blindness due to preservation of peripheral vision.

5. Differential Diagnosis and Distractors

Differential Diagnosis	Why It Is Similar	Key Discriminator
Diabetic Macular Edema (DME)	Central vision loss, macular edema on OCT, treated with anti-VEGF	History of diabetes, presence of diabetic retinopathy features (microaneurysms, dot-blot hemorrhages, cotton wool spots); no drusen
Central Serous Chorioretinopathy (CSCR)	Central vision loss, subretinal fluid on OCT, metamorphopsia	Younger patient (30-50), often male, associated with stress/corticosteroid use; FA shows "smokestack" or "inkblot" leakage pattern, no drusen
Epiretinal Membrane (Macular Pucker)	Metamorphopsia, central vision distortion	OCT shows membrane on retinal surface causing wrinkling, not subretinal pathology; no drusen or hemorrhage
Macular Hole	Central scotoma, reduced central acuity	OCT shows full-thickness defect in the fovea; no drusen; often post-vitreous detachment
Polypoidal Choroidal Vasculopathy (PCV)	Subretinal hemorrhage, exudates, CNV-like appearance	More common in Asian and Black populations; indocyanine green angiography (ICGA) shows polypoidal lesions; may respond better to combination PDT + anti-VEGF
Optic Neuritis	Vision loss in a relatively younger patient	Painful eye movement, afferent pupillary defect, associated with multiple sclerosis; normal macula on fundoscopy

6. Traps and High-Yield Pearls

The most common way students get AMD questions wrong is by failing to distinguish dry from wet AMD in a vignette and selecting the wrong treatment. A stem describing gradual vision loss with drusen on fundoscopy is dry AMD, and AREDS2 supplementation is the answer. A stem describing sudden worsening of vision, metamorphopsia, or subretinal hemorrhage is wet AMD, and anti-VEGF injection is the answer. Choosing anti-VEGF for dry AMD or AREDS2 alone for wet AMD are both classic errors.

Another frequently tested trap involves the AREDS2 formulation and smoking. If the vignette mentions a patient who smokes, the correct supplement is the AREDS2 formula with lutein/zeaxanthin, not the original AREDS formula with beta-carotene. Selecting beta-carotene for a smoker is a designed distractor.

Students also lose points by not recognizing that wet AMD is an ophthalmologic emergency requiring urgent referral, while dry AMD is managed with monitoring and supplementation. The vignette may describe a patient already diagnosed with dry AMD who now reports new-onset metamorphopsia or sudden vision change. The next best step is not reassurance or continued observation; it is urgent evaluation with OCT and possible fluorescein angiography to rule out conversion to wet AMD.

Finally, remember that AMD causes central vision loss with preserved peripheral vision. If a vignette describes peripheral field loss (e.g., tunnel vision, arcuate scotoma), think glaucoma or retinitis pigmentosa instead. The pattern of visual field loss is one of the strongest discriminators on the exam.

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