Age-related Macular Degeneration

Age-related macular degeneration (AMD or ARMD) is the leading cause of irreversible central visual loss in people over 50 years in the developed world. It is a degenerative disorder of the macula — specifically the photoreceptor–RPE–Bruch's membrane–choriocapillaris complex — that spares peripheral vision but devastates central, reading, and face-recognition vision. NEET PG loves the dry-versus-wet dichotomy, drusen, anti-VEGF, and the imaging patterns, so these notes are built around exactly those discriminators.

Definition & basic anatomy you must own

AMD is a chronic, progressive, bilateral (often asymmetric) disease of the central retina in patients ≥50 years, characterised by drusen, retinal pigment epithelial (RPE) changes, geographic atrophy, and/or choroidal neovascularisation (CNV).

Key anatomy that the questions hinge on:

• The macula is ~5.5 mm, centred temporal to and slightly below the optic disc; the fovea (1.5 mm) is its centre, the foveola its floor, and the foveal avascular zone (FAZ) has no retinal capillaries — it is nourished entirely by the choriocapillaris.
• The retina here is dominated by cones → high-acuity, colour, photopic vision.
• The four critical layers in AMD pathology (outer to inner from choroid): choriocapillaris → Bruch's membrane → RPE → photoreceptors. Drusen sit between RPE and Bruch's membrane.

High-yield: AMD destroys central vision and spares the periphery, so patients retain ambulatory/navigation vision but lose reading and driving. Contrast this with retinitis pigmentosa (peripheral loss first, central spared late) and glaucoma (peripheral/arcuate loss).

Classification

AMD is classically split into dry (non-exudative, ~85–90%) and wet (exudative/neovascular, ~10–15%). Wet AMD is far less common but responsible for the majority of severe (legal) blindness from AMD.

Feature	Dry (Non-exudative) AMD	Wet (Exudative/Neovascular) AMD
Frequency	85–90%	10–15%
Hallmark lesion	Drusen, RPE atrophy, geographic atrophy	Choroidal neovascularisation (CNV)
Onset of vision loss	Gradual, over years	Sudden / rapid, days–weeks
Metamorphopsia	Mild/late	Early & prominent
Fluid / haemorrhage	Absent	Sub-/intra-retinal fluid, lipid, haemorrhage
Disciform scar	No	End-stage
Severe blindness risk	Lower (unless GA at fovea)	High
Treatment	Supplements (AREDS2), monitoring	Anti-VEGF injections

High-yield: Dry AMD can convert to wet AMD at any time — that is why Amsler grid self-monitoring at home is prescribed to every dry AMD patient. New metamorphopsia or a scotoma → urgent review.

A useful clinical severity staging (from AREDS classification):

1. Early AMD → medium drusen (63–125 µm), no/mild pigment change.
2. Intermediate AMD → large drusen (>125 µm) and/or pigment abnormalities.
3. Advanced AMD → either geographic atrophy (GA) involving the fovea or neovascular (wet) AMD.

Drusen — the single most tested lesion

Drusen are yellowish-white deposits of lipid, protein and complement debris that accumulate between the RPE and Bruch's membrane.

Type	Size / appearance	Significance
Hard drusen	Small (<63 µm), discrete, well-defined	Common with ageing, low progression risk
Soft drusen	Large (>63–125 µm), ill-defined, may coalesce	Higher risk of progression to advanced AMD
Confluent/large soft drusen	>125 µm, merging	Highest risk; can cause drusenoid PED
Basal laminar drusen	Numerous tiny uniform nodules, younger patients	Cuticular drusen — "stars-in-the-sky" on FFA
Reticular pseudodrusen	Subretinal drusenoid deposits (above RPE)	Strong risk factor for GA and CNV

High-yield: Soft, large, confluent drusen + focal hyperpigmentation are the strongest fundus predictors of progression to advanced (especially wet) AMD.

Etiology & risk factors

AMD is multifactorial — ageing + genetics + oxidative stress + complement-mediated inflammation.

• Age — the dominant risk; rises steeply after 60.
• Smoking — the strongest modifiable risk factor (2–4× risk); doubles wet AMD risk. Counsel cessation in every patient.
• Genetics — Complement Factor H (CFH, chromosome 1q) polymorphism (Y402H) and ARMS2/HTRA1 (chromosome 10q) are the best-established loci.
• Race — commoner and more severe in Caucasians; pigment is protective.
• Cardiovascular — hypertension, hyperlipidaemia, obesity, diet poor in antioxidants.
• Light/oxidative stress, low dietary lutein/zeaxanthin.
• Female sex, family history, hypermetropia (weaker associations).

High-yield: Two genes to remember — CFH (1q) and ARMS2/HTRA1 (10q). The CFH link explains the complement/inflammatory theory of drusen formation.

Pathophysiology — the mechanism flow

Dry AMD pathway: Ageing + oxidative damage → impaired RPE clearance of photoreceptor outer-segment debris → lipofuscin (A2E) accumulation in RPE → drusen deposition under RPE → thickening of Bruch's membrane → RPE dysfunction & complement activation → photoreceptor loss → geographic atrophy (sharply demarcated RPE/photoreceptor/choriocapillaris loss).

Wet AMD pathway: Hypoxia & inflammation at the RPE/Bruch's interface → upregulation of VEGF → new fragile vessels from the choriocapillaris breach breaks in Bruch's membrane → CNV grows into sub-RPE/subretinal space → these vessels leak (oedema), bleed (haemorrhage) and exude lipid → disciform fibrovascular scar → permanent central scotoma.

Stepwise summary: Oxidative stress → RPE/Bruch's damage → drusen + complement → (a) photoreceptor atrophy = GA (dry) OR (b) VEGF ↑ → CNV → leak/bleed → disciform scar (wet).

High-yield: VEGF is the central driver of wet AMD — this is why anti-VEGF is the cornerstone of treatment, and why the MCQ answer for wet AMD management is almost always an anti-VEGF agent.

Clinical features

Dry AMD

• Gradual, painless blurring of central vision over years.
• Difficulty reading, need for brighter light, slow dark adaptation.
• Small central/paracentral scotomas as GA enlarges.
• Mild metamorphopsia possible.

Wet AMD

• Sudden central visual loss or distortion (days–weeks).
• Metamorphopsia — straight lines (door frames, grid) appear wavy/bent.
• Central scotoma, micropsia/macropsia, dyschromatopsia.
• Positive Amsler grid test (distortion or missing area).

Fundus signs:

• Dry → drusen, RPE mottling, pigment clumping, well-demarcated geographic atrophy (large choroidal vessels visible through atrophic RPE).
• Wet → grey-green subretinal CNV membrane, sub-/intra-retinal fluid, haemorrhage, hard exudates (lipid), serous/haemorrhagic PED (pigment epithelial detachment), and in late stage a disciform scar.

High-yield: Metamorphopsia + sudden central loss in an elderly patient = wet AMD until proven otherwise. Send for OCT/anti-VEGF urgently.

Diagnosis & investigations

A stepwise approach: History (age, smoking, sudden vs gradual) → Visual acuity & Amsler grid → Dilated fundus exam → OCT → FFA (± ICG, OCT-A).

Amsler grid

A 10 × 10 cm grid of squares with a central dot, held at ~30 cm with reading glasses, one eye at a time.

• Wavy/bent lines = metamorphopsia.
• Missing/grey area = scotoma. It is the simplest screening and home self-monitoring tool for macular disease.

Optical Coherence Tomography (OCT) — investigation of choice for monitoring

• Non-invasive cross-sectional imaging; first-line to detect and follow fluid.
• Shows intraretinal/subretinal fluid, PED, CNV, and drusen.
• The standard tool to decide anti-VEGF re-treatment (presence of fluid → re-inject).

Fundus Fluorescein Angiography (FFA) — to characterise CNV

FFA defines CNV type and is classically tested:

CNV type	FFA pattern
Classic CNV	Early, well-defined lacy hyperfluorescence with late leakage
Occult CNV	Ill-defined, stippled/late hyperfluorescence (fibrovascular PED)
Geographic atrophy	Window defect — early hyperfluorescence, no late leakage
Drusen (hard)	Stain late, no leakage

High-yield: OCT is the best test for detecting fluid and monitoring treatment; FFA is the best for demonstrating and classifying CNV (leakage). OCT-Angiography (OCT-A) is the newer dye-free way to image CNV flow. ICG angiography is preferred for occult CNV, PED and polypoidal choroidal vasculopathy (PCV).

Management

Dry AMD

• No specific drug reverses it. Management is risk reduction + monitoring.
• AREDS2 supplements for intermediate or advanced AMD in one eye — slow progression to advanced AMD by ~25%.
  • AREDS2 formula: Vitamin C 500 mg, Vitamin E 400 IU, Lutein 10 mg + Zeaxanthin 2 mg, Zinc 80 mg (often reduced to 25 mg), Copper 2 mg.
  • Beta-carotene was REMOVED (lutein/zeaxanthin replaced it) because beta-carotene increased lung cancer risk in smokers.
• Stop smoking, control BP/lipids, antioxidant-rich diet (leafy greens, fish/omega-3), UV protection.
• Amsler grid home monitoring; low-vision aids and rehabilitation.
• Newer: complement C3 inhibitor pegcetacoplan and C5 inhibitor avacincaptad pegol (intravitreal) approved to slow geographic atrophy — emerging exam point.

High-yield: AREDS2 dropped beta-carotene because it raised lung cancer risk in smokers and added lutein + zeaxanthin. AREDS supplements are not indicated for early AMD or for people with no/few small drusen.

Wet AMD — anti-VEGF is the drug of choice

Intravitreal anti-VEGF injection is first-line and the treatment of choice.

Anti-VEGF agent	Notes
Ranibizumab (Lucentis)	Humanised Fab fragment; FDA-approved for AMD
Bevacizumab (Avastin)	Full antibody; off-label, cheap, widely used (esp. India)
Aflibercept (Eylea)	VEGF-trap fusion protein; longer dosing interval
Brolucizumab / Faricimab	Newer; faricimab is a bispecific anti-VEGF + anti-Ang-2

• Typical regimen: monthly loading (3 doses) then PRN / treat-and-extend guided by OCT fluid.
• Improves or stabilises vision in the majority; a true advance over older therapy.

Older / adjunct options (largely historical, still examinable):

• Photodynamic therapy (PDT) with verteporfin — IV verteporfin activated by 689 nm laser; selective closure of CNV. Now mainly reserved for PCV and refractory classic subfoveal CNV.
• Thermal laser photocoagulation — only for extrafoveal/well-defined CNV; risks scotoma; rarely used now.
• Surgery (submacular surgery, macular translocation) — largely abandoned.

High-yield: Drug of choice for wet AMD = intravitreal anti-VEGF (ranibizumab / bevacizumab / aflibercept). Bevacizumab is the off-label, economical workhorse in Indian practice.

Complications

• Disciform scar — end-stage fibrovascular subretinal scar → dense permanent central scotoma.
• Massive subretinal / vitreous haemorrhage from CNV.
• RPE tear — may follow PED, sometimes precipitated by anti-VEGF.
• Geographic atrophy progression with foveal involvement → severe central loss.
• Permanent legal blindness (best-corrected VA ≤ 6/60 or central field <10–20°) — peripheral/navigation vision typically preserved.
• Injection-related: endophthalmitis (most feared), raised IOP, traumatic cataract, retinal detachment, intraocular inflammation (notably with brolucizumab).
• Charles Bonnet syndrome — formed visual hallucinations in patients with severe AMD-related vision loss but intact cognition.

Key differentials

Condition	Discriminator from AMD
Diabetic maculopathy	Diabetic; microaneurysms, dot-blot haemorrhages, hard exudates in ring; younger; OCT shows DME
Polypoidal choroidal vasculopathy (PCV)	More in Asians, orange-red subretinal nodules, recurrent haemorrhagic PED; ICG shows polyps
Central serous chorioretinopathy (CSR)	Young men, type-A personality/steroids; serous neurosensory detachment; smokestack/inkblot leak on FFA; usually self-limiting
Myopic CNV	High myopia, younger, lacquer cracks, Fuchs spot
Macular hole	Central scotoma + positive Watzke–Allen sign; OCT full-thickness defect
Best disease / Stargardt	Young, hereditary; vitelliform "egg-yolk" / fundus flavimaculatus
Macular telangiectasia	Perifoveal telangiectatic capillaries, right-angle venules

High-yield: In an Asian patient with recurrent haemorrhagic PED and orange subretinal nodules, think PCV (polypoidal CV) — diagnose with ICG and treat with PDT ± anti-VEGF, not standard wet-AMD protocol alone.

Mnemonics & named facts

• "DRY = Drusen, RPE atrophy, Years (slow); WET = Vessels (CNV), Water (fluid), Worsening fast."
• AREDS2 = "CE-LZ-ZnCu" → C, E, Lutein, Zeaxanthin, Zn, Cu (no beta-carotene).
• Drusen location: "between RPE and Bruch's" — picture the debris layered on Bruch's membrane.
• Genes: CFH (1) and ARMS2/HTRA1 (10) → "1 complement, 10 ARMS."
• Disciform scar = Fuchs–Kuhnt end-stage macular degeneration (eponym).

Recently asked / exam angle

• Most common cause of irreversible central blindness in the elderly (developed world) → AMD.
• Where do drusen lie? → Between RPE and Bruch's membrane.
• Best modifiable risk factor / strongest environmental risk → Smoking.
• Investigation of choice to monitor anti-VEGF response / detect fluid → OCT.
• Best test to classify CNV / show leakage → FFA (occult/PCV → ICG).
• Why was beta-carotene removed from AREDS2? → Lung cancer risk in smokers; replaced by lutein + zeaxanthin.
• Drug of choice for wet AMD → Intravitreal anti-VEGF (ranibizumab/bevacizumab/aflibercept).
• Home self-monitoring tool → Amsler grid (detects metamorphopsia/scotoma).
• Genes associated → CFH and ARMS2/HTRA1.
• Formed hallucinations with preserved insight in AMD → Charles Bonnet syndrome.
• Verteporfin is used in PDT (light-activated, 689 nm).
• Newer GA drugs: pegcetacoplan (C3), avacincaptad pegol (C5).

Rapid revision

1. AMD = leading cause of irreversible central vision loss in age >50; periphery spared.
2. Dry (85–90%) = drusen, RPE atrophy, geographic atrophy, slow loss.
3. Wet (10–15%) = CNV, fluid/haemorrhage, sudden loss & metamorphopsia; causes most severe blindness.
4. Drusen lie between RPE and Bruch's membrane; soft/large/confluent drusen = high progression risk.
5. Smoking is the strongest modifiable risk; CFH (1q) & ARMS2/HTRA1 (10q) are key genes.
6. VEGF drives CNV → anti-VEGF is the rational therapy.
7. OCT = best for fluid/monitoring; FFA = classifies CNV (classic = lacy + late leak; occult = stippled); ICG = occult/PCV.
8. Amsler grid = home monitoring; metamorphopsia is the red flag for conversion to wet.
9. AREDS2 (C, E, lutein, zeaxanthin, Zn, Cu — no beta-carotene) slows progression in intermediate/advanced AMD; not for early disease.
10. Wet AMD DOC = intravitreal anti-VEGF: ranibizumab, bevacizumab (off-label, cheap), aflibercept (VEGF-trap), faricimab (bispecific).
11. End-stage = disciform (Fuchs–Kuhnt) scar; most feared injection complication = endophthalmitis.
12. PCV (Asians, ICG polyps) and CSR (young men, steroids, smokestack leak) are the classic wet-AMD mimics; Charles Bonnet = formed hallucinations with insight.