Senile Macular DegenerationSenile Macular Degeneration

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Senile (Age-Related) Macular Degeneration (AMD / ARMD)

Definition & Epidemiology

Age-related macular degeneration (AMD) - also called senile macular degeneration - is a progressive neurodegenerative disease that primarily affects the retinal pigment epithelium (RPE) of the macula, typically presenting in the sixth to ninth decades of life. It is the most common cause of blindness in older individuals in industrialized countries, accounting for approximately 8.5% of the world's blindness. In the United States alone, more than 1.75 million persons are affected, and prevalence increases with each decade after age 55.

Goldman-Cecil Medicine, p. 662
Histology: A Text and Atlas (Eroschenko), p. 2402

Anatomy Involved

The pathological changes center on a structural and functional unit comprising:

Retinal Pigment Epithelium (RPE) - nourishes photoreceptors
Bruch membrane - basement membrane of the RPE
Choriocapillaris - innermost layer of choroidal vasculature

Disturbance to any component damages overlying photoreceptors and causes vision loss.

Classification: Two Major Forms

1. Dry (Atrophic / Non-exudative) AMD - ~90% of cases

The most common form. Characterized by:

Drusen - focal thickenings/abnormal lipoprotein deposits within the RPE basement membrane complex (Bruch membrane); soft drusen >60 μm are most significant
Geographic atrophy - well-defined pigment loss and RPE atrophy
Lipofuscin accumulation in stressed RPE cells (oxidation products of polyunsaturated fatty acids and vitamin A dimers)
Obliteration of capillaries in the underlying choroid

Progression is slow (months to decades). May precede subjective visual change by years to decades.

2. Wet (Exudative / Neovascular) AMD - ~10% of cases

Considered a complication of dry AMD. Characterized by:

Choroidal neovascularization (CNV) - frail new vessels from choriocapillaris penetrate through a breach in Bruch membrane into the subretinal space
These thin, fragile vessels leak producing exudates, subretinal hemorrhage, and intraretinal fluid
Progresses to fibrosis and scarring with rapid, severe central vision loss
Responsible for the most profound vision loss, especially if untreated

Dry and wet AMD may coexist; dry AMD is not always a precursor to wet AMD - each can develop through distinct pathways.

Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 1221
Histology: A Text and Atlas, p. 2402

Dry vs. Wet AMD Diagram (Robbins)

Schematic comparing Dry AMD (drusen, RPE damage, photoreceptor loss) vs Wet AMD (neovascularization, subretinal hemorrhage, intraretinal fluid). Risk factors: aging, genetic predisposition, oxidative stress, complement activation.

Fundus Appearance

Dry AMD - Fine drusen (fundus photograph):

Dry AMD with fine drusen - Wills Eye Manual

Note the scattered yellow-white drusen deposits in the macular region with surrounding normal retina and visible optic disc.

Histopathology

Wet AMD - Histology of neovascular membrane (Robbins):

Wet AMD - RPE and Bruch membrane histology

A neovascular membrane is positioned between the retinal pigment epithelium (RPE) and Bruch membrane (BM). Arrows indicate focal calcification (blue discoloration) of BM.

Pathogenesis

Genetic Factors

CFH (Complement Factor H), Complement Factor I (CFI), and other complement regulatory gene polymorphisms are strongly associated with AMD
These suggest AMD stems partly from excess complement activation, injuring photoreceptors
ARMS2 gene polymorphisms also confer increased risk
Therapy targeting complement may slow geographic atrophy progression

Environmental Factors

Cigarette smoking - increases risk 2- to 3-fold; the single most modifiable risk factor; dose-dependent
Ultraviolet (UV) irradiation and oxidative stress
Poorly controlled hypertension, hyperlipidemia, diabetes

Pathological Sequence (Dry AMD)

Oxidative stress → RPE dysfunction → Lipofuscin accumulation → Drusen formation → Complement activation → Chronic inflammation → Geographic atrophy → Photoreceptor death

Pathological Sequence (Wet AMD)

Drusen/geographic atrophy → Breach in Bruch membrane → VEGF upregulation → Choroidal neovascularization → Vessel leakage + hemorrhage → Scarring → Rapid central vision loss

Robbins, Cotran & Kumar, p. 1222

Clinical Features

Symptoms

Feature	Dry AMD	Wet AMD
Onset	Slow, insidious	Acute to subacute
Central vision	Gradually reduced	Acute severe loss
Scotoma	Present (late)	Central/paracentral
Metamorphopsia	Rare	Common (wavy lines)
Photopsias	Absent	May be present
Peripheral vision	Preserved	Preserved

Classic description: A patient can walk down a street without difficulty (peripheral retinal function) but cannot recognize facial features of people they encounter (macular function). - Goldman-Cecil Medicine

Signs on Examination

Macular drusen (critical sign in both forms)
Clumps of pigment in outer retina
RPE atrophy (almost always bilateral)
Geographic atrophy (confluent choriocapillaris atrophy)
In wet AMD: subretinal fluid, hemorrhage, exudate, CNV membrane

Visual Field Defect

Central vision loss in AMD - Histology A Text and Atlas

Simulated photo showing central visual field loss (black scotoma centrally) with preserved peripheral vision - characteristic of macular disease. Patients are instructed to use eccentric fixation.

Diagnosis & Workup

Amsler grid testing - detects metamorphopsia (distortion), indicates CNV development; home monitoring also via PHP (ForseeHome device)
Dilated fundus examination - drusen, RPE changes, atrophy
Fluorescein angiography (FA) - identifies CNV in wet AMD
Optical Coherence Tomography (OCT) - gold standard for detecting subretinal/intraretinal fluid; defines extent of CNV

Differential Diagnosis

Condition	Distinguishing Features
Peripheral drusen	Drusen outside macular area only
Myopic degeneration	Peripapillary changes, no drusen
CSCR	Age <50, serous elevation, no drusen/hemorrhage
Stargardt disease	Age <50, familial, lipofuscin accumulation
Chloroquine toxicity	Bull's-eye maculopathy, drug history
Multifocal choroiditis	Vitreous cells, no drusen

Treatment

Dry AMD

No curative treatment exists
AREDS/AREDS2 formula (Age-Related Eye Disease Study) supplementation for moderate-to-advanced dry AMD:
- Vitamin C, Vitamin E, Zinc, Copper
- Lutein + Zeaxanthin (replaced beta-carotene in AREDS2)
- Note: Beta-carotene avoided in smokers (increased lung cancer risk)
High dietary omega-3 fatty acids (cold-water fish, nuts)
Cessation of smoking is the most important modifiable intervention
Control of blood pressure, blood sugar, blood lipids
Complement-targeting therapies are in development for geographic atrophy
iPSC-derived RPE cell replacement therapy - experimental; surgical insertion of RPE-seeded biofilm into subretinal space (early trials in Japan)
Low-vision aids, special glasses, video magnification aids

Wet AMD - Anti-VEGF Therapy (Mainstay)

Intravitreal injections targeting VEGF reduce the risk of visual loss and can achieve gains in vision when administered promptly:

Drug	Mechanism
Ranibizumab (Lucentis)	Anti-VEGF antibody fragment
Bevacizumab (Avastin)	Full anti-VEGF antibody (off-label)
Aflibercept (Eylea)	VEGF trap (soluble decoy receptor)
Faricimab (Vabysmo)	Dual inhibitor of Ang-2 and VEGF-A

Other Treatments for Wet AMD

Photodynamic therapy (PDT) - verteporfin activated by laser; for subfoveal CNV
Laser photocoagulation - for extrafoveal CNV (destroys pathologic vessels); risks scotoma
Macular translocation surgery - retina detached, translocated, reattached away from CNV tissue; for advanced cases

Monitoring & Follow-Up

Dry AMD: Follow every 6-12 months; daily Amsler grid self-monitoring; return immediately if new distortion or visual change develops (may indicate conversion to wet AMD)
Wet AMD: Monitoring interval tailored to treatment response; OCT-guided injection schedules (treat-and-extend, PRN)
Wills Eye Manual, p. 832-837
Goldman-Cecil Medicine, p. 672-674

Key Points Summary

Feature	Details
Cause	Multifactorial - aging, genetic (CFH), environmental
Prevalence	>1.75 million in USA; #1 cause of blindness in elderly (developed world)
Onset	6th-9th decade
Vision loss type	Central only; peripheral preserved
Dry AMD	90%, drusen + geographic atrophy, slow progression
Wet AMD	10%, CNV, rapid severe vision loss
Key pathology	RPE degeneration, Bruch membrane changes
First-line Rx (wet)	Intravitreal anti-VEGF injections
Dry AMD Rx	AREDS2 supplements, lifestyle modification
Monitoring	Amsler grid, OCT, fluorescein angiography

Sources: Goldman-Cecil Medicine (2025), Robbins Cotran & Kumar Pathologic Basis of Disease, Histology: A Text and Atlas (Eroschenko), Wills Eye Manual, Harrison's Principles of Internal Medicine 22E

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