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    Drugs & Diseases>Ophthalmology

    Exudative (Wet) Age-Related Macular Degeneration (AMD)

    Updated: Aug 28, 2023
    • Author: F Ryan Prall, MD; Chief Editor: Andrew A Dahl, MD, FACS  more...
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    Overview

    Practice Essentials

    In the wet, or exudative, form of age-related macular degeneration (AMD or ARMD), pathologic choroidal neovascular membranes (CNVM) develop under the retina. The CNVM can leak fluid and blood and, if left untreated, ultimately cause a centrally blinding disciform scar. [1] Approximately 10% [1] of patients with nonexudative AMD eventually progress to the exudative form, which is responsible for the majority of the estimated 1.75 million cases [2, 3]  of advanced AMD in the United States.

    Age-related macular degeneration (AMD), exudative.Age-related macular degeneration (AMD), exudative.
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    Signs and symptoms

    AMD usually occurs bilaterally, but it often is asymmetrical. Patients with exudative AMD present with the following [1] :

    • Subretinal fluid
    • Retinal pigment epithelial (RPE) detachments
    • Subretinal hemorrhage
    • Choroidal neovascularization
    • Subretinal lipid deposits (occasionally)

    Patients with exudative AMD typically describe painless, progressive blurring or distortion of their central vision, which can be acute or insidious in onset.

    Patients who develop subretinal hemorrhage from choroidal neovascularization (CNV) typically report an acute onset. Other patients with CNV may experience insidious blurring secondary to shallow subretinal fluid or RPE detachments. They also report relative or absolute central scotomas, metamorphopsia, and difficulty reading.

    The natural history of exudative AMD (and occasionally nonexudative AMD) results in a stable central scotoma in which the patient’s visual acuity falls below the

    Background

    Types of macular degeneration

    Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the industrialized world. [1, 7]

    Age-related macular degeneration (AMD), exudative.Age-related macular degeneration (AMD), exudative.
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    Age-related macular degeneration (AMD), exudative.Age-related macular degeneration (AMD), exudative.
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    Physicians have traditionally recognized 2 types of macular degeneration: dry and wet. The hallmark of the dry, or nonexudative form, is the deposition of extracellular material beneath the retinal pigment epithelium (RPE) that leads to the formation of drusen. Both atrophic and hypertrophic changes occur in the RPE underlying the central macula and can lead to the loss of retinal photoreceptors.

    Patients with nonexudative AMD can progress to the wet, or exudative, form of AMD, in which pathologic choroidal neovascular membranes (CNVM) develop under the retina. The CNVM can leak fluid and blood, and, ultimately, cause a centrally blinding disciform scar over a relatively short time if left untreated. Approximately 10%  [1, 2, 3] of patients with nonexudative AMD eventually progress to the exudative form, which is responsible for the majority of the estimated 1.75 million cases of advanced AMD in the United States. [8, 9]

    Several classification systems are used to define AMD both clinically and for research purposes. The Wisconsin Age-Related Maculopathy Grading System defined early AMD as the absence of signs of advanced AMD and the presence of (1) soft indistinct or reticular drusen or (2) hard distinct or soft distinct drusen with pigmentary abnormalities (RPE depigmentation or increased retinal pigment). Late AMD was defined as the presence of either (1) geographic atrophy or (2) exudative AMD. Exudative AMD was defined as the presence of any of the following exudative lesions: pigment epithelial detachment or age-related retinal detachment, subretinal hemorrhage, subretinal scar (subretinal fibrous scar), or prior laser treatment for exudative AMD. [10]

    The Age-Related Eye Disease Study Group (AREDS) developed an 11-step scale to document the severity of AMD in fundus photographs. Patients were graded based on the presence or absence of drusen characteristics (size, shape, area); RPE pigmentary abnormalities (hypopigmentation or hyperpigmentation and geographic atrophy); and retinal findings, such as subretinal scar, hemorrhage, or detachment. Steps 4 to 8 were considered to have early AMD, and steps 9 to 11 defined advanced AMD. Patients meeting criteria for steps 1 to 3 did not have AMD.

    Based on data from the AREDS, a simplified severity scale was developed that was designed to be used clinically to stratify patients with early AMD into risk categories predictive of development of advanced AMD. The system assigns 1 risk factor for the presence of 1 or more large (>125 microns) drusen and 1 risk factor for the presence of any pigmentary abnormality. The presence of intermediate-sized drusen in both eyes constitutes 1 risk factor. These risk factors are added between both eyes and result in a numerical score between 0 and 4. The approximate 5-year risk of developing advanced AMD can then be calculated: 0 factors, 0.5%; 1 factor, 3%; 2 factors, 12%; 3 factors, 25%; and 4 factors, 50%. [11]

    Klein et al developed another risk assessment model, again using data from AREDS, but incorporating genetic, environmental, and phenotypic variables. Scores from the simplified severity score were included with patient age, smoking history, age, family history, and genetic information to determine a more precise risk assessment. A risk calculator was developed and is available here. [12]

    In 1995, the International ARM Epidemiologic Study Group redefined AMD from the traditional wet and dry designations. The criteria for the diagnosis of AMD subsequently became stricter. Patients with minimal or moderate nonexudative age-related changes in the macula were reclassified as having age-related maculopathy (ARM). By definition, advanced RPE atrophy (ie, geographic atrophy) or choroidal neovascularization (CNV) was required to establish a diagnosis of nonexudative AMD and exudative AMD, respectively. [13] An alternative classification scheme uses a 9-step severity scale to allow for risk stratification and reproducibility of age-related macular changes. [14]

    As a result of the International ARM Epidemiologic Study Group efforts, patients with age-related maculopathy account for 85-90% of individuals with age-related macular changes and have only mild drusen, RPE atrophy, and/or RPE hypertrophy. They tend to be asymptomatic or only minimally symptomatic with mild blurred central vision, color and contrast disturbances, and metamorphopsia (waviness). Conversely, the 10-15% of patients with macular changes defined as AMD tend to report painless, progressive, moderate-to-severe blurring of central vision and moderate-to-severe metamorphopsia, which can be acute or insidious in onset.

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    Pathophysiology

    AMD is a degenerative retinal disease, presumably caused by both genetic and environmental factors. Although age, race, sex, and family history demonstrate a consistently strong association with AMD in large epidemiologic studies, smoking, hypertension, obesity, and dietary fat intake are also reported modifiable risk factors contributing to the advancement of AMD. [1, 15, 16, 17, 18, 19, 20, 21]

    The exact pathophysiology of AMD is relatively poorly understood; however, recent discoveries are advancing our understanding. Research has concentrated on the RPE/photoreceptor/Bruch's membrane complex. The RPE is a metabolically active layer that supports the function of the retinal photoreceptor. RPE cells phagocytose the shed outer segments of the photoreceptor cells and continually recycle and process the metabolic materials required for photoreceptor function.

    As the RPE cells age, they accumulate intracellular residual bodies that contain lipofuscin. [22] This buildup can be imaged with the advent of autofluorescence imaging. [23] The RPE cells extrude material to be removed by the vascular choriocapillaris; however, decreased RPE function and changes in the permeability of Bruch's membrane may lead to deposition of material between the RPE and Bruch's membrane, accounting for the formation of drusen. Scientists also have found that the choriocapillaris is thin in patients with AMD, and this raises the possibility that decreased clearance of extracellular material may contribute to drusen formation.

    Study findings suggest that drusen formation may initiate an inflammatory cascade that may play a role in AMD progression. Studies in genetics have pointed toward the complement pathway as a primary mechanism. A strong association was discovered between AMD and a single nucleotide polymorphism in the complement factor H (CFH) gene on chromosome 1 [15, 24, 25, 26] and the PLEKHA1 and LOC387715 genes on chromosome 10. [27] Conversely, protective effects were reported for polymorphisms in the complement factor B and complement component 2 genes on chromosome 6 and various haplotypes on the CFH gene. [26, 28]

    CFH is an inhibitor of the complement pathways; thus, abnormal CFH activity allows for complement cascade activation and subsequent inflammatory response to subretinal tissues. [26] Drusen contain inflammatory components from the cascade pathway. [29] In addition, smoking, which decreases levels of CFH, significantly increases the odds of developing AMD over nonsmokers with the CFH polymorphism. [30, 31] Similarly, the complement factor B and complement component 2 genes, which usually are involved in the activation of the complement cascade, could limit complement pathway activation with a protective polymorphism and, thus, minimize the degree of chronic inflammation. [28]

    Drusen formation is not only a sign of RPE dysfunction but is also thought to be a cause of RPE loss and, in turn, photoreceptor loss. Further degeneration of the RPE can lead to dysfunction in Bruch's membrane, which separates the choriocapillaris from the RPE. Breakdown of Bruch's membrane and a rise in vascular endothelial growth factors can lead to the growth of abnormal choroidal vessels beneath the RPE and potentially under the retina. These vessels go through a period of leakage and occasionally bleed before they eventually involute and result in scar formation. The end-stage of exudative AMD is the formation of a disciform scar in the macula that results in permanent loss of central vision.

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    Mortality/Morbidity

    AMD leads to an increase in the rate of depression [32, 33] and frequent falls. [34]

    Because many activities of daily living require functional central visual acuity, AMD decreases all aspects of the patient's quality of life, including the patient's ability to drive independently [35] and to read. Studies measuring the quality of life in patients with vision loss demonstrate that they hold in high priority treatments that can improve their vision or prevent vision loss. A questionnaire from Wills Eye Hospital showed that when it came to an average person with 20/40 vision in the better seeing eye, they were willing to trade 2 of every 10 years of life in order to retain perfect vision (utility value of 0.8), whereas an average person with counting fingers vision in the better eye would trade roughly 5 of every 10 years of remaining life (utility value of 0.52) to have perfect vision. [36]

    Race

    Whites are far more likely to have late age-related maculopathy and vision loss from AMD than Black [37] or Hispanic persons. [38] However, studies have failed to show consistent differences between Whites and persons of Asian descent. [39, 40]

    Sex

    Data from several large population-based studies, including the Beaver Dam study, [41] the Third National Health and Nutrition Examination Survey, [42] and the Framingham study [43] have suggested that women are at increased risk for AMD compared with men.

    Age

    According to the International Classification System, AMD cannot be diagnosed in patients younger than 50 years. [13] Nearly every large population-based study has shown a positive correlation between the prevalence, incidence, and progression of AMD with increasing age. [9, 41, 44, 45, 46]

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    Epidemiology

    Frequency

    United States

    AMD is the leading cause of irreversible visual loss in the United States, with variable degrees of age-related macular changes occurring in 19.8 million (12.6%) of the population aged 40 years and older in 2019. Just under 1% (1.49 million) of these had vision-threatening illness. The prevalence of AMD rose with age from 2% among individuals aged 40 to 44 years to 46.6% among persons aged 85 years and older. [7]

    Approximately 10% of patients with nonexudative AMD progress to the exudative form. [1]  Thus, severe vision loss in many of the at least 1.75 million individuals who currently have advanced AMD is secondary to the effects of CNV from AMD. [9, 47]

    The overall prevalence of advanced AMD (geographic atrophy and/or CNV) is expected to increase from 2 million individuals in 2020 to 5.44 million individuals in 2050. [9]

     

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