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Macular Degeneration

Macular Degeneration

Age-related macular degeneration (AMD) is visual impairment due to changes in the macula Macula An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the posterior pole of the eye and slightly below the level of the optic disk. It is characterized by the presence of a yellow pigment diffusely permeating the inner layers, contains the fovea centralis in its center, and provides the best phototropic visual acuity. It is devoid of retinal blood vessels, except in its periphery, and receives nourishment from the choriocapillaris of the choroid. Eye: Anatomy, the area responsible for high-acuity vision Vision Ophthalmic Exam. It is marked by central vision Vision Ophthalmic Exam loss with peripheral vision Vision Ophthalmic Exam relatively spared. Risk factors include advanced age, smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases, family history Family History Adult Health Maintenance, and cardiovascular disease. The 2 types of AMD are exudative (wet) or non-exudative (dry). The difference between these 2 types is the presence of choroidal neovascularization in wet AMD, which manifests as visual distortion Distortion Defense Mechanisms or loss. The more frequently occurring dry AMD is usually asymptomatic but in a minority of cases leads to vision Vision Ophthalmic Exam loss. There is no treatment for early dry AMD but Age-Related Eye Disease Study 2 (AREDS 2) supplements are recommended for advanced disease. Inhibitors of vascular endothelial growth factor Vascular endothelial growth factor A family of angiogenic proteins that are closely-related to vascular endothelial growth factor a. They play an important role in the growth and differentiation of vascular as well as lymphatic endothelial cells. Wound Healing are used for wet AMD.

Last updated: 8 Jan, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Contents

Overview

Definition

Age-related macular degeneration (AMD):

  • Degenerative changes Degenerative Changes Spinal Stenosis involving the macula Macula An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the posterior pole of the eye and slightly below the level of the optic disk. It is characterized by the presence of a yellow pigment diffusely permeating the inner layers, contains the fovea centralis in its center, and provides the best phototropic visual acuity. It is devoid of retinal blood vessels, except in its periphery, and receives nourishment from the choriocapillaris of the choroid. Eye: Anatomy, the central part of the retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy, that cause central vision Vision Ophthalmic Exam impairment
  • Often affects bilateral vision Vision Ophthalmic Exam, but can be asymmetrical
  • Peripheral vision Vision Ophthalmic Exam is rarely lost.

Anatomy

  • Macula Macula An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the posterior pole of the eye and slightly below the level of the optic disk. It is characterized by the presence of a yellow pigment diffusely permeating the inner layers, contains the fovea centralis in its center, and provides the best phototropic visual acuity. It is devoid of retinal blood vessels, except in its periphery, and receives nourishment from the choriocapillaris of the choroid. Eye: Anatomy: 
    • An oval area at the center of the retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy, where light is focused by the lens Lens A transparent, biconvex structure of the eye, enclosed in a capsule and situated behind the iris and in front of the vitreous humor (vitreous body). It is slightly overlapped at its margin by the ciliary processes. Adaptation by the ciliary body is crucial for ocular accommodation. Eye: Anatomy and cornea Cornea The transparent anterior portion of the fibrous coat of the eye consisting of five layers: stratified squamous corneal epithelium; bowman membrane; corneal stroma; descemet membrane; and mesenchymal corneal endothelium. It serves as the first refracting medium of the eye. Eye: Anatomy
    • Contains the fovea Fovea An area approximately 1. 5 millimeters in diameter within the macula lutea where the retina thins out greatly because of the oblique shifting of all layers except the pigment epithelium layer. It includes the sloping walls of the fovea (clivus) and contains a few rods in its periphery. In its center (foveola) are the cones most adapted to yield high visual acuity, each cone being connected to only one ganglion cell. Eye: Anatomy, which holds the highest density of cone cells (photoreceptors sensitive to colors under bright light conditions)
    • Function: 
      • Central, high-acuity, and color vision Vision Ophthalmic Exam
      • Provides the ability to read, drive, and see in great detail 
  • Other structures:
    • Photoreceptor cells in outer retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy: light-sensing rods and cones
    • Retinal pigment epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium: Histology (RPE)
      • Protects from damaging effects of sunlight
      • Eliminates waste products and damaged cells
      • Regulates transport of nutrients
    • Bruch’s membrane:
      • Barrier and filter separating the retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy from blood vessels
      • A defect can be a site of blood vessel growth.
    • Capillary bed in the inner choroid Choroid The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. Eye: Anatomy (choriocapillaris): 
      • Nourishment and oxygen to RPE and outer layers of the retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy 
      • Main blood supply for fovea Fovea An area approximately 1. 5 millimeters in diameter within the macula lutea where the retina thins out greatly because of the oblique shifting of all layers except the pigment epithelium layer. It includes the sloping walls of the fovea (clivus) and contains a few rods in its periphery. In its center (foveola) are the cones most adapted to yield high visual acuity, each cone being connected to only one ganglion cell. Eye: Anatomy
  • Schematic diagram of the human eye

    Schematic of the human eye showing the location of the macula Macula An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the posterior pole of the eye and slightly below the level of the optic disk. It is characterized by the presence of a yellow pigment diffusely permeating the inner layers, contains the fovea centralis in its center, and provides the best phototropic visual acuity. It is devoid of retinal blood vessels, except in its periphery, and receives nourishment from the choriocapillaris of the choroid. Eye: Anatomy. The enlarged section of the retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy shows the retinal layers and the relationship Relationship A connection, association, or involvement between 2 or more parties. Clinician–Patient Relationship of the photoreceptors with the RPE, Bruch’s membrane, and the choriocapillaris.

    Image: “Schematic diagram of the human eye” by Institute of Human Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics, Newcastle University, International Centre for Life, Newcastle Upon Tyne NE1 3BZ, United Kingdom. License: CC BY 2.5
  • Retinal image

    Retinal image showing the macula Macula An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the posterior pole of the eye and slightly below the level of the optic disk. It is characterized by the presence of a yellow pigment diffusely permeating the inner layers, contains the fovea centralis in its center, and provides the best phototropic visual acuity. It is devoid of retinal blood vessels, except in its periphery, and receives nourishment from the choriocapillaris of the choroid. Eye: Anatomy, blood vessels, and optic disc Optic disc The portion of the optic nerve seen in the fundus with the ophthalmoscope. It is formed by the meeting of all the retinal ganglion cell axons as they enter the optic nerve. Eye: Anatomy

    Image: “Retinal image showing blood vessels and OD OD Refractive Errors” by Department of ECE, SACS MAVMM Engineering College, Madurai, Tamil Nadu 625 301, India. License: CC BY 3.0

Classification

  • Dry AMD (non-exudative or atrophic)
    • 90% of all cases
    • Often asymptomatic with gradual onset of visual changes 
    • In a minority of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship: advances to central visual-field loss or wet AMD
    • Associated with drusen Drusen Colloid or hyaline bodies lying beneath the retinal pigment epithelium. They may occur either secondary to changes in the choroid that affect the pigment epithelium or as an autosomal dominant disorder of the retinal pigment epithelium. Nephritic Syndrome:
      • Deposits of extracellular material or waste beneath the RPE
      • Few are found in people > 50 years old as part of aging.
    • Increased size and/or number of drusen Drusen Colloid or hyaline bodies lying beneath the retinal pigment epithelium. They may occur either secondary to changes in the choroid that affect the pigment epithelium or as an autosomal dominant disorder of the retinal pigment epithelium. Nephritic Syndrome → AMD
  • Wet AMD (exudative or neovascular)
    • 10% of cases but accounts for majority of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with advanced AMD
    • Presents as insidious or rapid progression of central vision Vision Ophthalmic Exam loss
  • Caused by growth of abnormal blood vessels in the subretinal space Subretinal Space Retinal Detachment, frequently from the choroidal circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment (choroidal neovascularization (CNV))
  • Macular degeneration examples

    Fundus Fundus The superior portion of the body of the stomach above the level of the cardiac notch. Stomach: Anatomy photographs Photographs Ultrasound (Sonography) showing different stages of AMD progression.
    (a) Large and intermediate drusen Drusen Colloid or hyaline bodies lying beneath the retinal pigment epithelium. They may occur either secondary to changes in the choroid that affect the pigment epithelium or as an autosomal dominant disorder of the retinal pigment epithelium. Nephritic Syndrome at intermediate stage of AMD
    (b) Neovascular AMD: right eye Right Eye Refractive Errors with subretinal fluid, hemorrhage, and hard exudate Exudate Exudates are fluids, cells, or other cellular substances that are slowly discharged from blood vessels usually from inflamed tissues. Pleural Effusion in the presence of choroidal neovascularization
    (c) Fluorescein angiography Fluorescein Angiography Visualization of a vascular system after intravenous injection of a fluorescein solution. The images may be photographed or televised. It is used especially in studying the retinal and uveal vasculature. Retinal Vessel Occlusion of the neovascular AMD: left eye Left Eye Refractive Errors showing hyperfluorescence of the fluorescein Fluorescein A phthalic indicator dye that appears yellow-green in normal tear film and bright green in a more alkaline medium such as the aqueous humor. Pseudomonas angiogram corresponding to the area of the choroidal neovascularization
    (d) Central geographic atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation: right eye Right Eye Refractive Errors with evidence of geographic atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation involving the center of the fovea Fovea An area approximately 1. 5 millimeters in diameter within the macula lutea where the retina thins out greatly because of the oblique shifting of all layers except the pigment epithelium layer. It includes the sloping walls of the fovea (clivus) and contains a few rods in its periphery. In its center (foveola) are the cones most adapted to yield high visual acuity, each cone being connected to only one ganglion cell. Eye: Anatomy with evidence of large drusen Drusen Colloid or hyaline bodies lying beneath the retinal pigment epithelium. They may occur either secondary to changes in the choroid that affect the pigment epithelium or as an autosomal dominant disorder of the retinal pigment epithelium. Nephritic Syndrome temporally

    Image: “ Fundus Fundus The superior portion of the body of the stomach above the level of the cardiac notch. Stomach: Anatomy photographs Photographs Ultrasound (Sonography)” by Neurobiology-Neurodegeneration and Repair Laboratory, National Institutes of Health, Bethesda, MD, USA. License: CC BY 2.5

Epidemiology

  • The leading cause of  irreversible blindness Blindness The inability to see or the loss or absence of perception of visual stimuli. This condition may be the result of eye diseases; optic nerve diseases; optic chiasm diseases; or brain diseases affecting the visual pathways or occipital lobe. Retinopathy of Prematurity in developed countries
  • Worldwide prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency of 8.7%
  • Women are affected more than men. 
  • Risk factors:
    • Advanced age: ↑ incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency in > 60 years of age
    • Caucasians Caucasians Esophageal Cancer > African Americans or Hispanics
    • Smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases 
    • Heavy alcohol use (> 3 drinks per day)
    • Family history Family History Adult Health Maintenance 
    • Genetic predisposition (complement H gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics)
    • Obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity
    • Hypercholesterolemia Hypercholesterolemia A condition with abnormally high levels of cholesterol in the blood. It is defined as a cholesterol value exceeding the 95th percentile for the population. Lipid Disorders
    • Cardiovascular disease
    • HIV HIV Anti-HIV Drugs/ AIDS AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS
    • Chronic myeloproliferative disease
    • Cataract Cataract Partial or complete opacity on or in the lens or capsule of one or both eyes, impairing vision or causing blindness. The many kinds of cataract are classified by their morphology (size, shape, location) or etiology (cause and time of occurrence). Neurofibromatosis Type 2 surgery
  • Decrease the risk of AMD: ↑ fish FISH A type of in situ hybridization in which target sequences are stained with fluorescent dye so their location and size can be determined using fluorescence microscopy. This staining is sufficiently distinct that the hybridization signal can be seen both in metaphase spreads and in interphase nuclei. Chromosome Testing intake, ↑ omega-3, and omega-6 polyunsaturated fatty acids Polyunsaturated fatty acids Fatty Acids and Lipids

Related videos

5:06
Macular Degeneration and Retinal Detachment

Pathophysiology

Dry AMD

  • Exact mechanism is still unclear.
  • Known risk factors (such as aging and genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics), oxidative stress Oxidative stress A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products. Cell Injury and Death, and inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation lead to pathologic changes:
    • Aging Bruch’s membrane: membrane thickens and accumulates apolipoproteins → ↑ inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and debris  →  nodular basal deposits become soft drusen Drusen Colloid or hyaline bodies lying beneath the retinal pigment epithelium. They may occur either secondary to changes in the choroid that affect the pigment epithelium or as an autosomal dominant disorder of the retinal pigment epithelium. Nephritic Syndrome
    • RPE degeneration → dissociates from Bruch’s membrane → RPE dysfunction → photoreceptor loss
    • Loss of choriocapillaris:  
      • Correlates with ↑ size and number of soft drusen Drusen Colloid or hyaline bodies lying beneath the retinal pigment epithelium. They may occur either secondary to changes in the choroid that affect the pigment epithelium or as an autosomal dominant disorder of the retinal pigment epithelium. Nephritic Syndrome 
      • Precedes the damage of RPE (geographic atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation)

Wet AMD

  • Risk factors + oxidative stress Oxidative stress A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products. Cell Injury and Death + activated complement → inflammatory changes 
  • Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation → RPE and other retinal cells secrete vascular endothelial growth factor Vascular endothelial growth factor A family of angiogenic proteins that are closely-related to vascular endothelial growth factor a. They play an important role in the growth and differentiation of vascular as well as lymphatic endothelial cells. Wound Healing (VEGF)-A and vasculogenic molecules → CNV and RPE dysfunction
  • New immature blood vessels grow from the choroid Choroid The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. Eye: Anatomy → perforate Bruch’s membrane and extend toward the retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy
  • These blood vessels leak fluid and blood below or within the retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy → RPE detachment and hemorrhage

Clinical Presentation

Dry AMD

  • Symptoms
    • Asymptomatic in most cases
    • As disease progresses:
      • Difficulty with night vision Vision Ophthalmic Exam
      • Visual fluctuation
      • Reading difficulty
      • Cannot make out faces
      • Prolonged time to adapt to low light levels
      • Metamorphopsia (distorted straight lines) in advanced disease
  • Signs (funduscopic examination and slit-lamp biomicroscopy)
    • Yellow-white deposits ( drusen Drusen Colloid or hyaline bodies lying beneath the retinal pigment epithelium. They may occur either secondary to changes in the choroid that affect the pigment epithelium or as an autosomal dominant disorder of the retinal pigment epithelium. Nephritic Syndrome) between Bruch’s membrane and RPE
    • RPE pigmentary mottling: increased pigmentation
    • Geographic (RPE) atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation: 
      • Seen in advanced dry AMD
      • Hypopigmentation Hypopigmentation A condition caused by a deficiency or a loss of melanin pigmentation in the epidermis, also known as hypomelanosis. Hypopigmentation can be localized or generalized, and may result from genetic defects, trauma, inflammation, or infections. Malassezia Fungi or depigmentation Depigmentation Vitiligo of the RPE
      • Represents cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death in adjacent areas of RPE and photoreceptors 
  • Stages
    • Early stage: 
      • > 15 small drusen Drusen Colloid or hyaline bodies lying beneath the retinal pigment epithelium. They may occur either secondary to changes in the choroid that affect the pigment epithelium or as an autosomal dominant disorder of the retinal pigment epithelium. Nephritic Syndrome or < 20 medium-sized drusen Drusen Colloid or hyaline bodies lying beneath the retinal pigment epithelium. They may occur either secondary to changes in the choroid that affect the pigment epithelium or as an autosomal dominant disorder of the retinal pigment epithelium. Nephritic Syndrome
      • No vision Vision Ophthalmic Exam loss
    • Intermediate stage:
      •  At least 1 large druse, ≥ 20 drusen Drusen Colloid or hyaline bodies lying beneath the retinal pigment epithelium. They may occur either secondary to changes in the choroid that affect the pigment epithelium or as an autosomal dominant disorder of the retinal pigment epithelium. Nephritic Syndrome or non-central geographic atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation ( fovea Fovea An area approximately 1. 5 millimeters in diameter within the macula lutea where the retina thins out greatly because of the oblique shifting of all layers except the pigment epithelium layer. It includes the sloping walls of the fovea (clivus) and contains a few rods in its periphery. In its center (foveola) are the cones most adapted to yield high visual acuity, each cone being connected to only one ganglion cell. Eye: Anatomy not involved)
      • May have vision Vision Ophthalmic Exam loss
    • Advanced stage: 
      • Central geographic atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation ( fovea Fovea An area approximately 1. 5 millimeters in diameter within the macula lutea where the retina thins out greatly because of the oblique shifting of all layers except the pigment epithelium layer. It includes the sloping walls of the fovea (clivus) and contains a few rods in its periphery. In its center (foveola) are the cones most adapted to yield high visual acuity, each cone being connected to only one ganglion cell. Eye: Anatomy involved)
      • Noticeable vision Vision Ophthalmic Exam loss
  • Age-related macular degeneration

    Early AMD: There are irregular pale dots at the macula Macula An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the posterior pole of the eye and slightly below the level of the optic disk. It is characterized by the presence of a yellow pigment diffusely permeating the inner layers, contains the fovea centralis in its center, and provides the best phototropic visual acuity. It is devoid of retinal blood vessels, except in its periphery, and receives nourishment from the choriocapillaris of the choroid. Eye: Anatomy, which are called drusen Drusen Colloid or hyaline bodies lying beneath the retinal pigment epithelium. They may occur either secondary to changes in the choroid that affect the pigment epithelium or as an autosomal dominant disorder of the retinal pigment epithelium. Nephritic Syndrome. They are caused by a build-up of waste products from photoreceptor metabolism. Although drusen Drusen Colloid or hyaline bodies lying beneath the retinal pigment epithelium. They may occur either secondary to changes in the choroid that affect the pigment epithelium or as an autosomal dominant disorder of the retinal pigment epithelium. Nephritic Syndrome are associated with AMD, most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with drusen Drusen Colloid or hyaline bodies lying beneath the retinal pigment epithelium. They may occur either secondary to changes in the choroid that affect the pigment epithelium or as an autosomal dominant disorder of the retinal pigment epithelium. Nephritic Syndrome will not develop severe AMD.

    Image: “Early AMD” by Africa Regional Medical Advisor: Fred Hollows Foundation, Kigali, Rwanda. License: CC BY 2.0
  • Oxidative stress, innate immunity, and age-related macular degeneration

    Drusen Drusen Colloid or hyaline bodies lying beneath the retinal pigment epithelium. They may occur either secondary to changes in the choroid that affect the pigment epithelium or as an autosomal dominant disorder of the retinal pigment epithelium. Nephritic Syndrome are yellow deposits under the retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy, the light-sensitive tissue at the back of the eye. Drusen Drusen Colloid or hyaline bodies lying beneath the retinal pigment epithelium. They may occur either secondary to changes in the choroid that affect the pigment epithelium or as an autosomal dominant disorder of the retinal pigment epithelium. Nephritic Syndrome consist of lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids and fatty protein.

    Image: “ Oxidative stress Oxidative stress A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products. Cell Injury and Death, innate immunity Innate immunity The capacity of a normal organism to remain unaffected by microorganisms and their toxins. It results from the presence of naturally occurring anti-infective agents, constitutional factors such as body temperature and immediate acting immune cells such as natural killer cells. Innate Immunity: Phagocytes and Antigen Presentation, and age-related macular degeneration” by Department of Ophthalmology and Shiley Eye Institute, University of California San Diego, San Diego, CA CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts), USA. License: CC BY 4.0

Wet AMD

  • Symptoms
  • Signs (funduscopic examination and slit-lamp biomicroscopy)
    • Neovascularization in the macula Macula An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the posterior pole of the eye and slightly below the level of the optic disk. It is characterized by the presence of a yellow pigment diffusely permeating the inner layers, contains the fovea centralis in its center, and provides the best phototropic visual acuity. It is devoid of retinal blood vessels, except in its periphery, and receives nourishment from the choriocapillaris of the choroid. Eye: Anatomy: gray-green discoloration 
    • Subretinal hemorrhage
    • Retinal pigment epithelial detachments (PEDs): separation of RPE from Bruch’s membrane
    • Subretinal lipid deposits on occasions
    • Disciform scars
  • Eye disease simulation normal vision

    Example of normal vision Vision Ophthalmic Exam

    Image: “An example of normal vision Vision Ophthalmic Exam” by National Eye Institute. License: Public Domain
  • Eye disease simulation age-related macular degeneration

    Vision Vision Ophthalmic Exam affected by AMD

    Image: “The same view with age-related macular degeneration” by National Eye Institute. License: Public Domain
  • Subretinal fibrotic scarring

    Subretinal fibrotic scarring Scarring Inflammation is the end-stage manifestation of neovascular AMD.

    Image: “Subretinal fibrotic scarring Scarring Inflammation” by Retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA. License: CC BY 4.0
  • Retinal hemorrhage

    Neovascular AMD can also present with significant retinal hemorrhage.

    Image: “Neovascular age-related macular degeneration” by Retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA. License: CC BY 4.0

Diagnosis

  • Clinical findings, dilated funduscopic examination with slit-lamp biomicroscopy
  • Amsler grid Amsler Grid Ophthalmic Exam test: detects metamorphopsias and scotomas Scotomas A localized defect in the visual field bordered by an area of normal vision. This occurs with a variety of eye diseases (e.g., retinal diseases and glaucoma); optic nerve diseases, and other conditions. Chorioretinitis
  • Angiography Angiography Radiography of blood vessels after injection of a contrast medium. Cardiac Surgery
    • Fundus Fundus The superior portion of the body of the stomach above the level of the cardiac notch. Stomach: Anatomy fluorescein angiography Fluorescein Angiography Visualization of a vascular system after intravenous injection of a fluorescein solution. The images may be photographed or televised. It is used especially in studying the retinal and uveal vasculature. Retinal Vessel Occlusion (FFA):
      • IV injection of fluorescein dye Fluorescein Dye Ophthalmic Exam, which follows the course of choroid Choroid The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. Eye: Anatomy and retinal vessels
      • Hypofluorescence: hemorrhage
      • Hyperfluorescence: drusen Drusen Colloid or hyaline bodies lying beneath the retinal pigment epithelium. They may occur either secondary to changes in the choroid that affect the pigment epithelium or as an autosomal dominant disorder of the retinal pigment epithelium. Nephritic Syndrome, RPE atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation, CNV membranes, serous PEDs 
    • Indocyanine green angiography Angiography Radiography of blood vessels after injection of a contrast medium. Cardiac Surgery
      • Uses a water-soluble tricarbocyanine dye
      • Detects choroidal neovascularization  and PEDs
  • Ocular coherence Coherence A view of the world and the individual’s environment as comprehensible, manageable, and meaningful, claiming that the way people view their life has a positive influence on their health. Neurological Examination tomography (OCT)
    • Non-invasive imaging test utilizing light waves
    • Produces high-resolution cross-sectional retinal images
    • Detection of:
      • Drusen Drusen Colloid or hyaline bodies lying beneath the retinal pigment epithelium. They may occur either secondary to changes in the choroid that affect the pigment epithelium or as an autosomal dominant disorder of the retinal pigment epithelium. Nephritic Syndrome as nodular elevation of RPE
      • Retinal edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema and subretinal fluid
    • Monitors treatment response in wet AMD
  • Color fundus Fundus The superior portion of the body of the stomach above the level of the cardiac notch. Stomach: Anatomy photography: used to monitor AMD
  • Fundus Fundus The superior portion of the body of the stomach above the level of the cardiac notch. Stomach: Anatomy autofluorescence Autofluorescence Cystoisospora/Cystoisosporiasis and Cyclospora/Cyclosporiasis
    • No contrast
    • Identifies lipofuscin accumulation (↑ in cellular aging)
    • Defines areas of geographic atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation
Amsler grid

1. Amsler grid Amsler Grid Ophthalmic Exam: normal vision Vision Ophthalmic Exam (left); 2. Amsler grid Amsler Grid Ophthalmic Exam: AMD with metamorphopsia (right). Note the distorted lines.

Image: “ Amsler Grid Amsler Grid Ophthalmic Exam” by Africa Regional Medical Advisor: Fred Hollows Foundation, Kigali, Rwanda. License: CC BY 2.0
  • Choroidal neovascularization

    Choroidal neovascularization is the hallmark of neovascular AMD. (A): There is often thickening or elevation of the retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy seen clinically through stereoscopic biomicroscopy (area within arrowheads). (B): On fluorescein angiography Fluorescein Angiography Visualization of a vascular system after intravenous injection of a fluorescein solution. The images may be photographed or televised. It is used especially in studying the retinal and uveal vasculature. Retinal Vessel Occlusion, neovascular membranes appear as hyperfluorescent lesions deep in the retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy (arrow) that leak over time. (C): Spectral-domain optical coherence tomography Optical Coherence Tomography Glaucoma allows for detailed cross-sectional imaging of retinal anatomy. In this patient, there was subretinal fluid (white arrow) and a small adjacent pigment epithelial detachment. Visual acuity Visual Acuity Clarity or sharpness of ocular vision or the ability of the eye to see fine details. Visual acuity depends on the functions of retina, neuronal transmission, and the interpretative ability of the brain. Normal visual acuity is expressed as 20/20 indicating that one can see at 20 feet what should normally be seen at that distance. Visual acuity can also be influenced by brightness, color, and contrast. Ophthalmic Exam was 20/32. (D): After 3 monthly intravitreal injections of ranibizumab, the fluid resolved, and visual acuity Visual Acuity Clarity or sharpness of ocular vision or the ability of the eye to see fine details. Visual acuity depends on the functions of retina, neuronal transmission, and the interpretative ability of the brain. Normal visual acuity is expressed as 20/20 indicating that one can see at 20 feet what should normally be seen at that distance. Visual acuity can also be influenced by brightness, color, and contrast. Ophthalmic Exam improved to 20/20.

    Image: “Age-Related Macular Degeneration” by Retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA. License: CC BY 4.0

Management

Dry AMD

  • For all patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship: smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases cessation
  • Monitoring of progression with regular Regular Insulin follow-up
  • For intermediate AMD and advanced AMD: AREDS 2 (Age-Related Eye Disease Study 2) supplement daily
    • Vitamin C Vitamin C A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. Water-soluble Vitamins and their Deficiencies 500 mg
    • Vitamin E Vitamin E A generic descriptor for all tocopherols and tocotrienols that exhibit alpha-tocopherol activity. By virtue of the phenolic hydrogen on the 2h-1-benzopyran-6-ol nucleus, these compounds exhibit varying degree of antioxidant activity, depending on the site and number of methyl groups and the type of isoprenoids. Fat-soluble Vitamins and their Deficiencies 400 international units (IU)
    • Zinc Zinc A metallic element of atomic number 30 and atomic weight 65. 38. It is a necessary trace element in the diet, forming an essential part of many enzymes, and playing an important role in protein synthesis and in cell division. Zinc deficiency is associated with anemia, short stature, hypogonadism, impaired wound healing, and geophagia. It is known by the symbol zn. Trace Elements oxide 80 mg
    • Cupric oxide 2 mg
    • Lutein 10 mg
    • Zeaxanthin 2 mg

Wet AMD

  • AREDS 2
  • Intravitreal anti-VEGF 
    • First-line therapy; antiangiogenic
    • Ranibizumab: 
      • Recombinant humanized antibody fragment ( Fab Fab Univalent antigen-binding fragments composed of one entire immunoglobulin light chain and the amino terminal end of one of the immunoglobulin heavy chains from the hinge region, linked to each other by disulfide bonds. Fab contains the immunoglobulin variable regions, which are part of the antigen-binding site, and the first immunoglobulin constant regions. This fragment can be obtained by digestion of immunoglobulins with the proteolytic enzyme papain. Immunoglobulins: Types and Functions) that binds VEGF
      • 0.5 mg monthly for 3 months
    • Bevacizumab Bevacizumab An anti-vegf humanized murine monoclonal antibody. It inhibits vegf receptors and helps to prevent pathologic angiogenesis. Targeted and Other Nontraditional Antineoplastic Therapy: 
      • Monoclonal antibody against VEGF
      • 1.25 mg monthly for 3 months
      • Lower cost than ranibizumab
    • Aflibercept: 
      • Recombinant fusion protein Fusion protein Proteins that catalyze membrane fusion. Measles Virus that acts as a VEGF receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors decoy
      • 2 mg every month for 3 months then every 2 months
    • Adverse effects: 
      • Endophthalmitis Endophthalmitis Endophthalmitis is an inflammatory process of the inner layers of the eye, which may be either infectious or sterile. Infectious endophthalmitis can lead to irreversible vision loss if not treated quickly. Based on the entry mode of the infectious source, endophthalmitis is divided into endogenous and exogenous types. Endophthalmitis
      • Increased intraocular pressure Intraocular Pressure The pressure of the fluids in the eye. Ophthalmic Exam 
      • Retinal detachment Retinal detachment Retinal detachment is the separation of the neurosensory retina from the retinal pigmented epithelium and choroid. Rhegmatogenous retinal detachment, the most common type, stems from a break in the retina, allowing fluid to accumulate in the subretinal space. Retinal Detachment
      • Thrombotic events reported
    • Thermal laser photocoagulation
      • Rarely used due to recurrence of disease and poor visual outcomes
    • Photodynamic therapy Photodynamic Therapy Actinic Keratosis
      • Application of light of specific wavelength and IV administration of verteporfin
      • Results in slowed CNV progression
      • Rarely used but an option in cases of failed anti-VEGF treatment
    • Surgery
      • Intravitreal tissue plasminogen activator Tissue plasminogen activator A proteolytic enzyme in the serine protease family found in many tissues which converts plasminogen to fibrinolysin. It has fibrin-binding activity and is immunologically different from urokinase-type plasminogen activator. The primary sequence, composed of 527 amino acids, is identical in both the naturally occurring and synthetic proteases. Hemostasis with pneumatic displacement Displacement The process by which an emotional or behavioral response that is appropriate for one situation appears in another situation for which it is inappropriate. Defense Mechanisms
      • Required in rare cases of submacular hemorrhage

Differential Diagnosis

  • Cataracts: a decrease in vision Vision Ophthalmic Exam due to clouding of the lens Lens A transparent, biconvex structure of the eye, enclosed in a capsule and situated behind the iris and in front of the vitreous humor (vitreous body). It is slightly overlapped at its margin by the ciliary processes. Adaptation by the ciliary body is crucial for ocular accommodation. Eye: Anatomy, which presents as painless, blurry vision Vision Ophthalmic Exam and glare problems. Cataracts are the leading cause of blindness Blindness The inability to see or the loss or absence of perception of visual stimuli. This condition may be the result of eye diseases; optic nerve diseases; optic chiasm diseases; or brain diseases affecting the visual pathways or occipital lobe. Retinopathy of Prematurity worldwide. The condition can occur at any age, but most cases affect Affect The feeling-tone accompaniment of an idea or mental representation. It is the most direct psychic derivative of instinct and the psychic representative of the various bodily changes by means of which instincts manifest themselves. Psychiatric Assessment those > 60 years old.
  • Diabetic retinopathy Diabetic retinopathy Disease of the retina as a complication of diabetes mellitus. It is characterized by the progressive microvascular complications, such as aneurysm, intraretinal edema, and intraocular pathologic neovascularization. Chronic Diabetic Complications: a visual impairment due to microvascular end-organ damage from diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus. Diabetic retinopathy Diabetic retinopathy Disease of the retina as a complication of diabetes mellitus. It is characterized by the progressive microvascular complications, such as aneurysm, intraretinal edema, and intraocular pathologic neovascularization. Chronic Diabetic Complications is classified as non-proliferative Non-Proliferative Fibrocystic Change and proliferative retinopathy Retinopathy Degenerative changes to the retina due to hypertension. Alport Syndrome. Non-proliferative Non-Proliferative Fibrocystic Change retinopathy Retinopathy Degenerative changes to the retina due to hypertension. Alport Syndrome is characterized by microaneurysms, intraretinal hemorrhages, exudates, and macular edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema. The distinguishing feature of the proliferative type is the presence of retinal or optic disc Optic disc The portion of the optic nerve seen in the fundus with the ophthalmoscope. It is formed by the meeting of all the retinal ganglion cell axons as they enter the optic nerve. Eye: Anatomy neovascularization. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are initially asymptomatic but in the late stages present with decreased or fluctuating vision Vision Ophthalmic Exam, possibly with floaters Floaters Chorioretinitis.
  • Retinal detachment Retinal detachment Retinal detachment is the separation of the neurosensory retina from the retinal pigmented epithelium and choroid. Rhegmatogenous retinal detachment, the most common type, stems from a break in the retina, allowing fluid to accumulate in the subretinal space. Retinal Detachment: separation of the retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy from the retinal pigment epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium: Histology. This results in rapid photoreceptor damage. Symptoms include painless vision Vision Ophthalmic Exam changes such as sudden flashes of light, floaters Floaters Chorioretinitis, worsening peripheral vision Vision Ophthalmic Exam, or having a shadow in the field of vision Vision Ophthalmic Exam. Retinal detachment Retinal detachment Retinal detachment is the separation of the neurosensory retina from the retinal pigmented epithelium and choroid. Rhegmatogenous retinal detachment, the most common type, stems from a break in the retina, allowing fluid to accumulate in the subretinal space. Retinal Detachment is a medical emergency requiring corrective surgery.

References

  1. Ambati, J., Fowler, B. (2012 ) Mechanism of age-related Macular Degeneration. https://pubmed.ncbi.nlm.nih.gov/22794258/
  2. Arroyo, J., Gardiner, M., Schmader, K., Givens, J. (2020). Age-related macular degeneration: Treatment and prevention. UpToDate. Retrieved September 18, 2020, from https://www.uptodate.com/contents/age-related-macular-degeneration-treatment-and-prevention?search=macular%20degeneration&source=search_result&selectedTitle=1~66&usage_type=default&display_rank=1
  3. Arroyo, J., Gardiner, M., Schmader, K., Givens, J. (2020). Age-related macular degeneration: Clinical presentation, etiology, and diagnosis. UpToDate. Retrieved September 18, 2020, from https://www.uptodate.com/contents/age-related-macular-degeneration-clinical-presentation-etiology-and-diagnosis?search=macular%20degeneration&source=search_result&selectedTitle=2~66&usage_type=default&display_rank=2
  4. Handa, J., Rickman, C., Dick, A., Gorin, M., Miller, J., Toth, C.,Ueffing, M., Zarbin, M., Farrer, L. (2019). A systems biology approach towards understanding and treating non-neovascular age-related macular degeneration. Nature 10, 3347. https://doi.org/10.1038/s41467-019-11262-1
  5. Jonas, JB, Cheung, C., Panda-Jonas, S. (2017). Updates on the Epidemiology of Age-related Macular Degeneration. Asia Pacific J Ophthalmol 6 (6):493-497. doi: 10.22608/APO.2017251
  6. Maturi, R., Franklin, A. (2018). Nonexudative (Dry) Age-Related Macular Degeneration. Medscape. Retrieved September 19, 2020, from https://emedicine.medscape.com/article/1223154-overview
  7. Prall, F.R., Ciulla, T.,  Dahl, A. (2019). Exudative (Wet) Age-Related Macular Degeneration. Medscape. Retrieved September 19, 2020, from https://emedicine.medscape.com/article/1226030-overview
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