Age-related macular degeneration

Retina & Vitreous

Key Points

•AMD is the leading cause of irreversible central vision loss in the developed world, affecting ~196 million people globally
•Wet AMD accounts for only 10–15% of cases but causes ~90% of severe vision loss — anti-VEGF therapy stabilises vision in ~95% and improves it in ~30–40% (ANCHOR/MARINA)
•AREDS2 supplementation reduces progression from intermediate to advanced AMD by ~25% — lutein/zeaxanthin replaced beta-carotene
•CFH Y402H and ARMS2/HTRA1 account for >50% of genetic risk; smoking is the strongest modifiable risk factor (2–4× risk)
•Treat-and-extend is the preferred anti-VEGF regimen — CATT proved bevacizumab non-inferior to ranibizumab; VIEW 1&2 confirmed aflibercept non-inferior with less frequent dosing

1. Definition

Age-related macular degeneration (AMD) is a progressive degenerative disease of the central retina (macula) occurring in individuals over 50 years, characterised by drusen, pigmentary changes, geographic atrophy (GA), or choroidal neovascularisation (CNV). It is the leading cause of irreversible central vision loss in the developed world (AAO PPP 2019).

2. Epidemiology

Prevalence increases with age: ~2% at 50–59 years, rising to ~12% in those over 80 (Wong et al., Lancet Glob Health 2014). AMD affects approximately 196 million people worldwide (2020 estimates). More common in Caucasians than in Africans or Asians. Women are slightly more affected than men. Early AMD is far more prevalent than late AMD. Neovascular (wet) AMD accounts for only 10–15% of all AMD cases but is responsible for ~90% of severe vision loss from AMD (AAO PPP 2019).

3. Aetiology and causes

Multifactorial:

Genetic susceptibility: complement factor H (CFH) Y402H polymorphism and ARMS2/HTRA1 locus account for >50% of genetic risk. Other loci: C3, CFB, CFI
Smoking: strongest modifiable risk factor — 2–4× increased risk (dose-dependent)
Oxidative stress: chronic light exposure damages RPE and photoreceptors
Lipid accumulation in Bruch's membrane impairs metabolic exchange
Dietary deficiency of antioxidants (lutein, zeaxanthin) and omega-3 fatty acids may contribute
Age itself: progressive RPE dysfunction and complement dysregulation

4. Pathogenesis

Ageing changes in the retinal pigment epithelium (RPE) lead to impaired phagocytosis of photoreceptor outer segments and reduced metabolic function.
Lipofuscin accumulates in RPE cells; its component A2E is photo-toxic.
Drusen (extracellular deposits) accumulate between the RPE basement membrane and the inner collagenous layer of Bruch's membrane.
Bruch's membrane thickens and calcifies, impairing nutrient/waste exchange between RPE and choriocapillaris.
Complement dysregulation drives chronic inflammation — membrane attack complex (MAC) deposition damages RPE and choriocapillaris.
In dry AMD: progressive RPE and photoreceptor atrophy → geographic atrophy.
In wet AMD: hypoxia-driven upregulation of VEGF leads to choroidal neovascularisation — type 1 (sub-RPE), type 2 (subretinal), or type 3 (retinal angiomatous proliferation [RAP]), with exudation, haemorrhage, and fibrosis.

5. Classification

AREDS Classification:

Category 1 (No AMD): few or no small drusen (<63 µm)
Category 2 (Early AMD): multiple small drusen, few intermediate drusen (63–124 µm), or mild RPE changes
Category 3 (Intermediate AMD): extensive intermediate drusen, ≥1 large drusen (≥125 µm), or non-central geographic atrophy
Category 4 (Advanced AMD): geographic atrophy involving the foveal centre (dry) OR neovascular AMD (wet)

Wet AMD subtypes by CNV location:

Classic (type 2): well-defined on FFA, early hyperfluorescence with late leakage
Occult (type 1): poorly defined on FFA, stippled/late leakage
Retinal angiomatous proliferation (RAP/type 3): intraretinal neovascularisation extending to subretinal space
Polypoidal choroidal vasculopathy (PCV): branching vascular network with polyps on ICG — more common in Asians

6. Risk factors and associations

Non-modifiable: age >50 (strongest risk factor), Caucasian race, female sex, family history (first-degree relative confers 4× risk), genetic variants (CFH, ARMS2/HTRA1, C3, CFB).
Modifiable: smoking (strongest modifiable factor — 2–4× risk, dose-dependent), obesity (BMI >30), hypertension, high-fat diet, low dietary antioxidants/zinc, excessive sunlight exposure.
Protective: dietary lutein/zeaxanthin, omega-3 fatty acids, AREDS2 supplementation, Mediterranean diet.

7. Clinical features

Symptoms:

Gradual painless central vision loss (dry) or sudden metamorphopsia and central scotoma (wet)
Difficulty reading, recognising faces, driving
Positive Amsler grid distortion in wet AMD
Peripheral vision preserved

Signs — Dry AMD:

Drusen — hard: small, discrete, low-risk; soft: larger, confluent with indistinct edges, high-risk for progression
RPE hyper/hypopigmentation
Geographic atrophy: well-demarcated areas of RPE and choriocapillaris atrophy with visible underlying choroidal vessels

Signs — Wet AMD:

Subretinal/sub-RPE fluid, haemorrhage, lipid exudates
RPE detachment (dome-shaped elevation)
Grey-green subretinal membrane
Disciform scar (end-stage fibrosis)

8. Investigations

Amsler grid: metamorphopsia and scotoma detection (home monitoring tool)
OCT (macula): drusen volume, subretinal/intraretinal fluid, PED, subretinal hyperreflective material (SHRM), RPE atrophy; essential for monitoring anti-VEGF response
OCT angiography (OCTA): non-invasive detection of CNV; delineates flow within neovascular networks without dye injection
Fundus fluorescein angiography (FFA): classic CNV — early well-defined hyperfluorescence with late leakage; occult CNV — stippled or ill-defined leakage; staining of drusen without leakage in dry AMD
Indocyanine green angiography (ICG): superior for detecting PCV (branching vascular network with polyps), occult CNV, and RAP
Fundus autofluorescence (FAF): hypo-AF in geographic atrophy; hyper-AF ring at GA margins (predicts expansion rate)
Dark adaptation testing: prolonged rod-intercept time is the earliest functional biomarker of AMD

9. Differential diagnosis

Central serous chorioretinopathy (CSR): younger males, serous PED, smokestack/inkblot pattern on FFA, no drusen
Polypoidal choroidal vasculopathy (PCV): subtype/mimic, more common in Asians, orange-red nodules, branching vascular network on ICG
Myopic CNV: high myope, lacquer cracks, peripapillary atrophy, Fuchs spot
Angioid streaks (with CNV): bilateral crack-like lines radiating from disc; association with pseudoxanthoma elasticum (PXE), Paget disease, sickle cell
Macular dystrophies (Stargardt, Best, pattern dystrophy): younger onset, characteristic autofluorescence patterns, may mimic dry AMD
Epiretinal membrane: can cause metamorphopsia but OCT shows membrane on inner surface, no drusen or CNV

10. Complications

Dry AMD: progressive central scotoma from geographic atrophy expansion (median ~1.78 mm²/year), eventual bilateral legal blindness.

Wet AMD: subretinal fibrosis (disciform scar), massive subretinal/vitreous haemorrhage (especially with anticoagulant use), RPE tears (may occur spontaneously or after anti-VEGF injection, especially with large vascularised PEDs), secondary glaucoma.

Anti-VEGF complications: endophthalmitis (~0.02–0.05% per injection), retinal detachment, intraocular inflammation, sustained IOP elevation, macular atrophy (associated with long-term anti-VEGF use — reported in CATT and IVAN 5-year follow-up).

11. Management

Dry AMD:

AREDS2 supplementation: vitamin C 500 mg, vitamin E 400 IU, lutein 10 mg, zeaxanthin 2 mg, zinc 80 mg, copper 2 mg daily — reduces progression to advanced AMD by ~25% in intermediate/advanced cases (AREDS2 trial)
Smoking cessation, UV protection, healthy diet (Mediterranean diet)
Monitor with Amsler grid and regular OCT
Geographic atrophy: pegcetacoplan (intravitreal C3 inhibitor, every 1–2 months) or avacincaptad pegol (C5 inhibitor, monthly) — FDA-approved for GA; pegcetacoplan slows expansion by ~22% (OAKS/DERBY), avacincaptad pegol by ~14% (GATHER trials)

Wet AMD:

First-line: intravitreal anti-VEGF injections:
Ranibizumab (Lucentis) 0.5 mg — monthly or treat-and-extend (ANCHOR/MARINA)
Aflibercept (Eylea) 2 mg — monthly ×3 then q8 weeks (VIEW 1&2); or 8 mg (Eylea HD) q12–16 weeks
Bevacizumab (Avastin) 1.25 mg — off-label, non-inferior to ranibizumab (CATT, IVAN)
Brolucizumab (Beovu) 6 mg — monthly ×3 then q8–12 weeks (risk of intraocular inflammation/vasculitis)
Faricimab (Vabysmo) 6 mg — bispecific anti-VEGF/anti-Ang-2, up to q16-week dosing
Treatment regimens: monthly, PRN (pro re nata), or treat-and-extend (preferred — fewer visits with similar outcomes; TREX-AMD, LUCAS trials)
Photodynamic therapy (PDT) with verteporfin: largely replaced by anti-VEGF; still used in PCV (combination PDT + anti-VEGF; EVEREST-II trial)
Port delivery system (ranibizumab): surgically implanted refillable reservoir, refill every 6 months
Low vision rehabilitation for advanced bilateral disease

12. Prognosis

Dry AMD: slow progression over years; 5-year risk of progression from intermediate to advanced AMD ~26% (reduced to ~20% with AREDS2). Geographic atrophy expands at ~1.5–2.5 mm²/year; foveal involvement leads to legal blindness.

Wet AMD with anti-VEGF: MARINA/ANCHOR trials showed ~95% stabilisation and ~30–40% gained ≥15 letters with monthly ranibizumab over 2 years. Real-world outcomes are generally worse due to undertreatment. Long-term (≥5 years): mean VA gradually declines due to macular atrophy and fibrosis despite continued treatment. Fellow eye involvement: ~40% develop wet AMD in the second eye within 5 years if one eye is affected.

Poor prognostic factors: large CNV, subfoveal location, sub-RPE fibrosis, poor baseline VA, delayed treatment initiation.

Clinical Pearls

Soft, confluent drusen carry a much higher risk of progression to wet AMD than hard drusen — these patients need closer monitoring with OCT every 6–12 months.

Any new metamorphopsia or sudden vision drop in a patient with dry AMD should prompt urgent OCT to rule out conversion to wet AMD — early treatment gives the best visual outcomes.

The AREDS2 formula replaced beta-carotene with lutein/zeaxanthin due to increased lung cancer risk in smokers taking beta-carotene.

Anti-VEGF treat-and-extend strategy achieves similar visual outcomes to monthly injections with fewer visits — TREX-AMD and LUCAS trials. This is now the preferred regimen in most centres.

PCV should be suspected in Asian patients with haemorrhagic PED or poor response to anti-VEGF monotherapy — ICG angiography is diagnostic, and combination PDT + anti-VEGF is often superior (EVEREST-II trial).

RPE tears are a dreaded complication of anti-VEGF treatment, especially with large vascularised PEDs — monitor PED height and morphology at each visit.

Long-term anti-VEGF therapy is associated with macular atrophy (CATT 5-year data) — this is an area of active research and debate.

Exam trap — Drusen types matter: Hard drusen (<63 μm, discrete, round) are common and benign in isolation. Soft drusen (>63 μm, indistinct edges) are the hallmark of AMD and indicate risk of progression. Cuticular (basal laminar) drusen are small, numerous, 'starry sky' on FFA — associated with vitelliform detachments and younger onset.

Exam trap — PCV vs typical AMD: Polypoidal choroidal vasculopathy (PCV) presents with orange-red subretinal nodules, recurrent serosanguineous pigment epithelial detachments, and is more common in Asian and African populations. ICG angiography (not FFA) is the gold standard for diagnosis. PCV responds better to combination anti-VEGF + photodynamic therapy (PDT) than anti-VEGF alone (EVEREST II trial).

Exam trap — Do NOT give anti-VEGF for dry AMD: There is NO approved anti-VEGF treatment for dry/atrophic AMD. The only treatments for geographic atrophy are pegcetacoplan (complement C3 inhibitor, FDA 2023) and avacincaptad pegol (complement C5 inhibitor, FDA 2023). Giving anti-VEGF to a dry AMD patient is inappropriate.

Exam trap — AREDS2 formulation: The current recommended formulation is AREDS2 (not AREDS1): Vitamin C 500mg + Vitamin E 400 IU + Lutein 10mg + Zeaxanthin 2mg + Zinc 80mg + Copper 2mg. Beta-carotene was REMOVED because it increased lung cancer risk in smokers. Lutein/zeaxanthin replaced it.

Oral-exam questions

What is the most common cause of irreversible central vision loss in the developed world? — Age-related macular degeneration (AAO PPP 2019). Wet AMD causes 90% of severe vision loss despite being only 10–15% of cases.
What is the AREDS2 formula? — Vitamin C 500 mg, vitamin E 400 IU, lutein 10 mg, zeaxanthin 2 mg, zinc 80 mg, copper 2 mg. Reduces progression by ~25%. Beta-carotene was removed due to lung cancer risk in smokers.
Name the genetic loci most strongly associated with AMD — CFH (complement factor H, Y402H polymorphism) and ARMS2/HTRA1 account for >50% of genetic risk (Kanski 9th Ed).
What did the CATT trial show? — Bevacizumab is non-inferior to ranibizumab for nAMD (+8.0 vs +8.5 letters). PRN dosing reduces injection frequency while maintaining efficacy (CATT, NEJM 2011).
How does PCV differ from typical wet AMD? — PCV shows branching vascular network with polyps on ICG angiography; more common in Asians; may respond poorly to anti-VEGF monotherapy; combination PDT + anti-VEGF preferred (EVEREST-II trial).
What are the new treatments for geographic atrophy? — Pegcetacoplan (C3 inhibitor, OAKS/DERBY trials) slows GA expansion by ~22%; avacincaptad pegol (C5 inhibitor, GATHER trials) slows it by ~14%. First FDA-approved treatments for dry AMD/GA.
What is the risk of fellow eye wet AMD? — ~40% develop wet AMD in the second eye within 5 years if one eye is affected. Patients must monitor with Amsler grid and report new symptoms immediately.
What are the new FDA-approved treatments for geographic atrophy (dry AMD)? — Pegcetacoplan (Syfovre, FDA Feb 2023) — complement C3 inhibitor, intravitreal injection every 25–60 days; reduces GA growth rate by ~22% at 2 years. Avacincaptad pegol (Izervay, FDA Aug 2023) — complement C5 inhibitor, monthly injection; reduces GA growth by ~14%. Both slow progression but do not reverse GA. Neither improves visual acuity.
Why is ICG angiography essential for PCV diagnosis? — PCV lesions appear as hyperfluorescent 'hot spots' (polypoidal structures) on ICG that are NOT visible on FFA. FFA may show a non-specific PED or occult CNV pattern. ICG is the gold standard for PCV diagnosis. PCV is often misdiagnosed as typical wet AMD without ICG.
What is the AREDS severity scale and how does it guide treatment? — Category 1: No drusen/small drusen → no supplements needed. Category 2: Extensive small or few intermediate drusen → no supplements. Category 3: Extensive intermediate or ≥1 large drusen, non-center GA → START AREDS2 supplements (25% risk of progression to advanced AMD at 5 years). Category 4: Advanced AMD in one eye → supplements for fellow eye.

Mnemonics

AMD RISK

A — Age >50 (strongest risk factor) M — Macular drusen (soft, confluent = high risk) D — Diet deficient in antioxidants R — Race (Caucasian) I — Inheritance (CFH, ARMS2 genes) S — Smoking (strongest modifiable factor) K — Kin (family history = 4× risk)

ANCHOR-MARINA-CATT

ANCHOR — Anti-VEGF superior to PDT (classic CNV) MARINA — Anti-VEGF effective for occult/minimally classic CNV CATT — Bevacizumab equivalent to ranibizumab (cost-effective)

Comparison Tables

Anti-VEGF Agents for Neovascular AMD

Anti-VEGF Agents for Neovascular AMD
Agent	Molecular Type	Target	Dosing After Loading	Key Trial	Distinguishing Feature
Ranibizumab 0.5 mg	Fab fragment	VEGF-A	Monthly or T&E	ANCHOR, MARINA	First approved; gold standard
Aflibercept 2 mg	Fusion protein (decoy receptor)	VEGF-A, VEGF-B, PlGF	q8 weeks	VIEW 1&2	Less frequent dosing; broader VEGF blockade
Bevacizumab 1.25 mg	Full-length antibody	VEGF-A	Monthly or PRN	CATT, IVAN	Off-label; most cost-effective; non-inferior to ranibizumab
Brolucizumab 6 mg	scFv	VEGF-A	q8–12 weeks	HAWK/HARRIER	Smallest molecule; risk of retinal vasculitis
Faricimab 6 mg	Bispecific antibody	VEGF-A + Ang-2	Up to q16 weeks	TENAYA/LUCERNE	Dual pathway; longest dosing interval

Ranibizumab 0.5 mg

Molecular Type: Fab fragment
Target: VEGF-A
Dosing After Loading: Monthly or T&E
Key Trial: ANCHOR, MARINA
Distinguishing Feature: First approved; gold standard

Aflibercept 2 mg

Molecular Type: Fusion protein (decoy receptor)
Target: VEGF-A, VEGF-B, PlGF
Dosing After Loading: q8 weeks
Key Trial: VIEW 1&2
Distinguishing Feature: Less frequent dosing; broader VEGF blockade

Bevacizumab 1.25 mg

Molecular Type: Full-length antibody
Target: VEGF-A
Dosing After Loading: Monthly or PRN
Key Trial: CATT, IVAN
Distinguishing Feature: Off-label; most cost-effective; non-inferior to ranibizumab

Brolucizumab 6 mg

Molecular Type: scFv
Target: VEGF-A
Dosing After Loading: q8–12 weeks
Key Trial: HAWK/HARRIER
Distinguishing Feature: Smallest molecule; risk of retinal vasculitis

Faricimab 6 mg

Molecular Type: Bispecific antibody
Target: VEGF-A + Ang-2
Dosing After Loading: Up to q16 weeks
Key Trial: TENAYA/LUCERNE
Distinguishing Feature: Dual pathway; longest dosing interval

Dry AMD vs Wet AMD — Key Differences

Dry AMD vs Wet AMD — Key Differences
Feature	Dry AMD	Wet AMD
Proportion	~85–90% of AMD	~10–15% of AMD
Vision loss mechanism	Geographic atrophy (slow)	CNV with exudation/haemorrhage (acute)
Symptoms	Gradual central blur	Sudden metamorphopsia, scotoma
Key signs	Drusen, RPE changes, GA	Subretinal fluid/haemorrhage, PED
Investigation	FAF (GA mapping), OCT	FFA, OCT, ICG (for PCV)
Treatment	AREDS2, pegcetacoplan/avacincaptad pegol for GA	Anti-VEGF injections (ranibizumab, aflibercept, bevacizumab)
Prognosis	Slow decline over years	Rapid if untreated; ~95% stabilised with anti-VEGF

Proportion

Dry AMD: ~85–90% of AMD
Wet AMD: ~10–15% of AMD

Vision loss mechanism

Dry AMD: Geographic atrophy (slow)
Wet AMD: CNV with exudation/haemorrhage (acute)

Symptoms

Dry AMD: Gradual central blur
Wet AMD: Sudden metamorphopsia, scotoma

Key signs

Dry AMD: Drusen, RPE changes, GA
Wet AMD: Subretinal fluid/haemorrhage, PED

Investigation

Dry AMD: FAF (GA mapping), OCT
Wet AMD: FFA, OCT, ICG (for PCV)

Treatment

Dry AMD: AREDS2, pegcetacoplan/avacincaptad pegol for GA
Wet AMD: Anti-VEGF injections (ranibizumab, aflibercept, bevacizumab)

Prognosis

Dry AMD: Slow decline over years
Wet AMD: Rapid if untreated; ~95% stabilised with anti-VEGF

Landmark Anti-VEGF Trials for nAMD

Landmark Anti-VEGF Trials for nAMD
Trial	Year	Comparison	Key Result	Clinical Impact
ANCHOR	2006	Ranibizumab vs PDT	+11.3 vs -9.5 letters	Established anti-VEGF superiority over PDT for classic CNV
MARINA	2006	Ranibizumab vs sham	+7.2 vs -10.4 letters	Proved anti-VEGF efficacy for occult/minimally classic CNV
CATT	2011	Bevacizumab vs ranibizumab	+8.0 vs +8.5 letters (non-inferior)	Established bevacizumab as cost-effective alternative
VIEW 1&2	2012	Aflibercept vs ranibizumab	Non-inferior; q8w dosing after loading	Reduced injection burden with aflibercept
IVAN	2012	Bevacizumab vs ranibizumab (UK)	Non-inferior; continuous > discontinuous	Confirmed CATT; supported continuous dosing

ANCHOR

Year: 2006
Comparison: Ranibizumab vs PDT
Key Result: +11.3 vs -9.5 letters
Clinical Impact: Established anti-VEGF superiority over PDT for classic CNV

MARINA

Year: 2006
Comparison: Ranibizumab vs sham
Key Result: +7.2 vs -10.4 letters
Clinical Impact: Proved anti-VEGF efficacy for occult/minimally classic CNV

CATT

Year: 2011
Comparison: Bevacizumab vs ranibizumab
Key Result: +8.0 vs +8.5 letters (non-inferior)
Clinical Impact: Established bevacizumab as cost-effective alternative

VIEW 1&2

Year: 2012
Comparison: Aflibercept vs ranibizumab
Key Result: Non-inferior; q8w dosing after loading
Clinical Impact: Reduced injection burden with aflibercept

IVAN

Year: 2012
Comparison: Bevacizumab vs ranibizumab (UK)
Key Result: Non-inferior; continuous > discontinuous
Clinical Impact: Confirmed CATT; supported continuous dosing

Self-Assessment (5)

MCQ

A 72-year-old woman presents with sudden metamorphopsia and positive Amsler grid distortion in her left eye. She has a history of bilateral soft drusen. OCT shows subretinal fluid and a pigment epithelial detachment. What is the most appropriate next step?

MCQ

Which investigation is the gold standard for diagnosing polypoidal choroidal vasculopathy (PCV)?

MCQ

The AREDS2 formula replaced beta-carotene with lutein and zeaxanthin. What was the primary reason for this change?

MCQ

According to the CATT trial, which of the following is TRUE regarding bevacizumab for neovascular AMD?

MCQ

A 68-year-old Asian man with neovascular AMD has a large haemorrhagic PED and poor response to 3 monthly ranibizumab injections. What is the most likely diagnosis and next step?

References

AAO Preferred Practice Pattern: Age-Related Macular Degeneration (2019)
Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration (MARINA). N Engl J Med. 2006;355(14):1419-1431.
Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration (ANCHOR). N Engl J Med. 2006;355(14):1432-1444.
CATT Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration (CATT). N Engl J Med. 2011;364(20):1897-1908.
Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration (VIEW 1&2). Ophthalmology. 2012;119(12):2537-2548.
Age-Related Eye Disease Study 2 (AREDS2) Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration (AREDS2). JAMA. 2013;309(19):2005-2015.
Kanski JJ, Bowling B. Clinical Ophthalmology: A Systematic Approach, 9th Edition
Ryan SJ, Sadda SR, et al. Ryan's Retina, 6th Edition

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