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

Updated: Oct 09, 2019
Author: F Ryan Prall, MD; Chief Editor: Andrew A Dahl, MD, FACS 

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. Approximately 10-20% 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.[1, 2] See the image below.

Age-related macular degeneration (AMD), exudative. Age-related macular degeneration (AMD), exudative.

Signs and symptoms

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

  • 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), for example, 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 reading level and the legal driving level. However, peripheral visual acuity is usually retained.

See Clinical Presentation for more detail.

Diagnosis

After a thorough dilated examination of the fundus with slit lamp biomicroscopy, the following imaging studies are frequently performed on many patients with signs and symptoms of exudative AMD:

  • Color photography of the fundus
  • Fluorescein angiography (FA) - Helps to identify and confirm the source of CNV
  • Optical coherence tomography (OCT) - Can identify soft drusen, RPE detachments, subretinal and intraretinal fluid, CNV, and cystoid macular edema; can accurately measure foveal and macular thickness; and can demonstrate the integrity of the photoreceptor and RPE layers
  • OCT angiography - Uses laser light reflectance from the surface of mobile red blood cells to create an image of the retinal vasculature without the need for intravenous dye

See Workup for more detail.

Management

Antiangiogenic agents

Animal and clinical studies have established vascular endothelial growth factor (VEGF) as a key mediator in ocular angiogenesis.[3, 4] Therefore, particular attention has been focused on the development of pharmaceutical agents to block or neutralize VEGF expression. The following agents, delivered via intravitreal injection, have been proven effective in clinical trials:

  • Pegaptanib sodium
  • Ranibizumab
  • Bevacizumab
  • Aflibercept

Results from treatment with anti-VEGF agents have been promising, although there continues to be a subset of patients who have disappointing visual outcomes.[5, 6, 7]

Laser treatments

Laser treatments include the following:

  • Thermal laser photocoagulation - Until the advent of anti-VEGF agents, ophthalmologists traditionally used thermal laser destruction of CNV as the primary treatment of exudative AMD.
  • Photodynamic therapy with verteporfin (PDT) - To avoid creating a central, blinding scotoma when treating subfoveal CNV with thermal lasers, clinicians turned to PDT; effective in some forms of CNV, although its use is sometimes limited by cost.

See Treatment and Medication for more detail.

Background

Types of macular degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the industrialized world.[8, 9, 10] See the images below.

Age-related macular degeneration (AMD), exudative. Age-related macular degeneration (AMD), exudative.
Age-related macular degeneration (AMD), exudative. Age-related macular degeneration (AMD), exudative.

Physicians have traditionally recognized two 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 course if left untreated. Approximately 10-20% 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.[1, 2]

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.[11]

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 4-8 were considered to have early AMD, and steps 9-11 defined advanced AMD. Patients meeting criteria for steps 1-3 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 one risk factor for the presence of one or more large (>125 microns) drusen and one risk factor for the presence of any pigmentary abnormality. The presence of intermediate-sized drusen in both eyes constitutes one 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%.[12]

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.[13]

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.[14] An alternative classification scheme uses a 9-step severity scale to allow for risk stratification and reproducibility of age-related macular changes.[15]

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.

Pathophysiology

AMD is a degenerative retinal disease, presumably caused by both genetic and environmental factors. While age, race, sex, and family history demonstrate a consistently strong association with AMD in large epidemiological studies, smoking, hypertension, obesity, and dietary fat intake are also reported modifiable risk factors contributing to the advancement of AMD.[16, 17, 18, 19, 20, 21, 22]

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.[23] This buildup can now be imaged with the advent of autofluorescence imaging.[24] 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 have also 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.

Recent 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[25, 26, 16, 27] and the PLEKHA1 and LOC387715 genes on chromosome 10.[28] 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.[27, 29]

CFH is an inhibitor of the complement pathways; thus, abnormal CFH activity allows for complement cascade activation and subsequent inflammatory response to subretinal tissues.[27] Drusen have been found to contain inflammatory components from the cascade pathway.[30] In addition, smoking, which decreases levels of CFH, significantly increases the odds of developing AMD over nonsmokers with the CFH polymorphism.[31, 32] Similarly, the complement factor B and complement component 2 genes, which are usually 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.[29]

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.

Mortality/Morbidity

AMD leads to an increase in the rate of depression[33, 34] and frequent falls.[35]

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[36] 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), while 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.[37]

Race

Whites are far more likely to have late age-related maculopathy and vision loss from AMD than blacks[38] or Hispanic persons.[39] However, studies have failed to show consistent differences between whites and persons of Asian descent.[40, 41]

Sex

Data from several large population-based studies, including the Beaver Dam study,[42] the Third National Health and Nutrition Examination Survey,[43] and the Framingham study[44] 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.[14] Nearly every large population-based study has shown a positive correlation between the prevalence, incidence, and progression of AMD with increasing age.[2, 42, 45, 46, 47]

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 more than 10% of the population aged 65-74 years and 25% of the population older than 74 years.[48]

Approximately 10%-20% 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.[2, 48]

The population of individuals older than 85 years will have increased an estimated 107% from 1990 to 2020.[49] The overall prevalence of advanced AMD (geographic atrophy and/or CNV) is expected to increase from 1.75 million individuals in 2003 to 2.95 million individuals in 2020.[2]

 

Presentation

History

Patients with age-related maculopathy are often asymptomatic or sometimes notice mild symptoms, including minimally blurred central visual acuity, contrast and color disturbances, and mild metamorphopsia (distorted vision). If geographic atrophy develops in the macular region, patients may notice a scotoma (blind spot), which can slowly enlarge over months to years before eventually stabilizing.

Patients with exudative age-related macular degeneration (AMD) typically describe painless progressive blurring of their central visual acuity, which can be acute or insidious in onset. Patients who develop subretinal hemorrhage from CNV, for example, typically report an acute onset. Other patients with CNVM may experience insidious blurring secondary to shallow subretinal fluid or pigment epithelial detachments (PEDs). They also report relative or absolute central scotomas, metamorphopsia, and difficulty reading.

The natural history of exudative AMD or occasionally nonexudative AMD results in a stable central scotoma in which the visual acuity falls below the reading level and the legal driving level. However, peripheral visual acuity is usually retained.

An association between AMD and Alzheimer disease has been reported.[50]

Physical

AMD occurs bilaterally, but it is often asymmetric. Visual acuity is variably reduced. Amsler grid testing typically reveals relative central scotomas or metamorphopsia.

The sine qua non of exudative AMD is CNVM. Eyes with exudative AMD present with subretinal fluid, retinal PEDs, subretinal hemorrhage, and, occasionally, subretinal lipid deposits. In addition, RPE hypertrophy, RPE atrophy, and drusen are usually present. The CNV itself may be seen as yellow-green subretinal discoloration and is sometimes surrounded by a pigment ring. Subretinal hemorrhage typically develops at the margins of the CNV and sometimes obscures the entire complex. On occasion, the subretinal hemorrhage can progress and lead to vitreous hemorrhage. Subretinal disciform scarring of the macula is a common end-stage morphology.

Causes

In addition to age (see Age), strong risk factors include the following: family history,[26, 51] white race,[16] and a history of tobacco use.[52, 53]

Other risk factors reported fairly consistently include hypertension.[16, 54]

The role of dietary fat intake has been studied extensively. Studies have indicated that diets high in total fat and trans-fat may increase risk of AMD, while diets high in omega-3 fatty acids and fish may lower risk.[55]

Patients with AMD, glaucoma, or diabetic retinopathy should be asked about cognitive status, as these degenerative diseases have been linked to Alzheimer disease.[50]

 

DDx

 

Workup

Laboratory Studies

No laboratory studies assist in the diagnosis of age-related macular degeneration (AMD).

Imaging Studies

After a thorough dilated examination of the fundus with slit lamp biomicroscopy, stereo color photography of the fundus, rapid-sequence fluorescein angiography (FA), and optical coherence tomography (OCT) are performed on many patients with signs and symptoms of exudative AMD.

FA is an office-based procedure to help identify and confirm the source of the CNV. During the procedure, fluorescein dye is injected intravenously and serial photographs with a blue filter of the retina are taken to document the progression of the dye through the choroidal and retinal vasculature. Abnormalities are identified in areas where the dye collects (hyperfluorescence) or is absent (hypofluorescence).

Findings on FA consistent with exudative AMD include the following: increasing hyperfluorescence secondary to dye leakage from the CNV and hypofluorescent blockage from subretinal hemorrhage. Additional findings consistent with any form of AMD include the following: hyperfluorescence of drusen and RPE atrophy and hypofluorescence from RPE hypertrophy. See the image below.

Color photograph of the fundus shows nonexudative Color photograph of the fundus shows nonexudative age-related macular degeneration (AMD) with geographic atrophy of the retinal pigment epithelium (RPE) and drusen. Absolute atrophy of the RPE occupies the foveal region in this case of nonexudative AMD. The central atrophic region causes a corresponding central scotoma. Note the large choroidal vessels, which are visible through the RPE defect. Drusen surround the region of geographic atrophy. Photo by Tim Steffens.

A disciform scar, which is the end stage of exudative AMD, is hyperfluorescent from fluorescein staining. Depending on the distance from the foveal avascular zone, the leakage is classified as subfoveal, juxtafoveal (1-199 µm), or extrafoveal (200-250 µm). CNV is sometimes defined as classic or occult based on the FA leakage pattern.

Classic CNV results in discrete and early hyperfluorescence with late leakage of fluorescein dye into the surrounding interstitial spaces.

Occult CNV is categorized into 2 basic forms, as follows: late leakage of undetermined source or fibrovascular PED. Both forms manifest as a region of ill-defined leakage in the early and late frames without a distinct source of leakage.

When a treatment other than a vascular endothelial growth factor (VEGF) inhibitor is planned, angiography is customarily performed within 72 hours of treatment because the morphology and resulting treatment parameters can evolve rapidly.

Indocyanine green (ICG) angiography can be performed as an adjunctive study in patients with subretinal hemorrhage, suspected retinal angiomatous proliferation, or polypoidal choroidal vasculopathy.

The near-infrared light (795-810 nm) absorbed by ICG tends to penetrate hemorrhage and RPE better than the shorter wavelength that is absorbed by fluorescein.

Unlike fluorescein, ICG is strongly bound to plasma proteins, which prevents diffusion of the compound through the normally fenestrated choroidal capillaries and improves delineation of choroidal detail.[56]

Optical coherence tomography (OCT) is a useful noninvasive adjunct for identifying retinal and subretinal pathology secondary to CNV. OCT provides a cross-sectional view of the retina with an axial resolution of about 4 µm. OCT can identify soft drusen, RPE detachments, subretinal and intraretinal fluid, CNV, cystoid macular edema, as well as the integrity of the photoreceptor and RPE layers.[57, 58, 59, 60] OCT is useful for monitoring therapeutic response.[59, 61, 62]

OCT angiography is a newer technology that uses laser light reflectance off moving red blood cells to create an image of the retinal and choroidal vasculature. It has been used to diagnose and classify choroidal neovascular membranes without the need for intravenous dye.[63]

 

Treatment

Medical Care

Antiangiogenic agents

VEGF inhibitors

Animal and clinical studies have established vascular endothelial growth factor (VEGF) as a key mediator in ocular angiogenesis.[3, 4] In clinical trials, particular attention has focused on the development of pharmaceutical agents to block or neutralize VEGF expression.

Pegaptanib sodium

Pegaptanib sodium (Macugen; OSI Pharmaceuticals, Inc, Melville, NY and Pfizer, Inc, New York, NY) is an anti-VEGF pegylated aptamer that demonstrated both safety and efficacy in clinical trials compared to placebo. This intravitreally administered polyethylene glycol (PEG)–conjugated oligonucleotide was specifically designed to bind and neutralize VEGF165, hypothesized to be the predominant VEGF isomer associated with CNV in humans.

The VEGF Inhibition Study in Ocular Neovascularization (VISION) Study was composed of 2 phase II-III multicenter, randomized, placebo-controlled trials. Enrollment of 1186 subjects was completed in July 2002. The 12-month data for all types of CNV showed that 70% of subjects receiving a 0.3-mg intravitreous injection every 6 weeks lost less than 3 lines of vision versus 55% of control subjects receiving sham injection (P< 0.001).[64] This was a similar efficacy to PDT, the standard treatment at that point.

The FDA accepted a new drug application (NDA) for wet age-related macular degeneration (AMD) in August 2004, as did the European Medicines Agency (EMEA) in September 2004.[65] On December 17, 2004, the FDA approved the drug, which became available for consumer use in the United States in January 2005.[66]

Ranibizumab

Ranibizumab (Lucentis; Genentech Inc, South San Francisco, CA, and Novartis Ophthalmics, Basel, Switzerland), an intravitreally injected, recombinant, humanized, monoclonal antibody fragment designed to actively bind and inhibit all isoforms of VEGF, has become an FDA-approved common treatment for exudative AMD.

The Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab (formerly, RhuFab) in the Treatment of Neovascular AMD (MARINA) was a phase III randomized, prospective, double-blind, placebo-controlled comparison of ranibizumab against sham controls. Investigators enrolled 716 patients to receive 24 monthly intravitreal injections (0.3 mg or 0.5 mg) or sham injections. At 12-month follow-up, 95% of those treated with monthly ranibizumab injections had improved or stable vision versus 62% of control subjects receiving sham treatment (P< 0.001). More importantly, 34% of participants receiving the 0.5-mg dose experienced at least a 15-letter improvement that was maintained over 2 years, while 26% of participants receiving the 0.3 mg dose and 4% of the sham injection group achieved this level of improvement (P< 0.001).[62] This was the first treatment for AMD that had demonstrated significant visual gains.

The Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) trial was another prospective, randomized, multicenter, double-blind phase III trial designed to compare ranibizumab versus verteporfin in 423 subjects with predominantly classic exudative AMD. Similar to MARINA, 96% of subjects receiving 0.5 mg monthly of ranibizumab had improved or stable vision versus 64% receiving verteporfin (P< 0.001). Visual acuity improved in 40% of subjects receiving the 0.5-mg dose versus 6% in the verteporfin group (P< 0.001).[67]

These trials altered the treatment paradigm of exudative AMD from a condition in which vision loss could only be slowed or stabilized to one in which visual acuity improvement was a real possibility. Clinicians are now attempting to maximize visual acuity while minimizing the number of retreatments to eyes with exudative AMD. The PIER trial gave 3 monthly injections of ranibizumab followed by quarterly injections over a 24-month interval. The 3-month results mirrored MARINA and ANCHOR; however, visual acuity gains declined once quarterly dosing began. The PIER data suggest that quarterly injections are less effective than monthly dosing.[68]

The HORIZON extension study, including patients from MARINA, ANCHOR, and FOCUS, documented adverse events and visual acuity results in patients treated with ranibizumab over 4 or more years. Rates of adverse events, including stroke and myocardial infarction continued to be low with long-term treatment. Some visual acuity gains achieved with monthly treatment during the initial phases of the studies were lost as patients were followed and treated less frequently during the latter years of the HORIZON study.[69]

The EXCITE trial measured the response to quarterly dosing and again confirmed that the regimen is less effective than monthly dosing.[70] In clinical practice, most ophthalmologists and retina specialists, use an induction phase, usually with 3 monthly injections, followed by an as-needed (prn) phase based on visual response, clinical examination, and imaging results. Several studies have attempted to compare this as-needed approach to the results found in MARINA and ANCHOR.

The Prospective OCT Imaging of Patients with Neovascular AMD Treated with Intra-Ocular Lucentis (PrONTO) Study was a small, uncontrolled open-label study, that treated patients with 3 monthly ranibizumab injections followed by monthly follow-up and redosing on an as-needed basis. The visual acuity improvements remained near the level of MARINA and ANCHOR, but the average number of retreatments dropped to 5.6 over 12 months.[71] Another as-needed dosing study, the SUSTAIN study, tested 3 monthly injections followed by an as-needed treatment regimen. During the as-needed phase, injections were given if there was a vision loss of 5 letters or an increase of 100 microns in central retinal thickness on OCT. According to results, the best improvement in vision occurred after the first 3 monthly injections, but dropped slightly when the as-needed regimen was initiated.[72]

Other clinicians are adopting the "treat and extend" approach, where patients are treated with 3 serial monthly ranibizumab injections followed by gradually extending the interval between subsequent injections until fluid reaccumulates. If a time pattern of recurrence develops, tailored treatments can be adopted.[73, 74] Two studies have demonstrated results similar to MARINA and ANCHOR with this approach.[75, 76]

The long-term safety of intravitreal ranibizumab 0.5-mg injections in neovascular AMD was examined in the SECURE study, a 24-month, open-label, multicenter trial involving 234 patients previously treated with ranibizumab for 12 months in the EXCITE/SUSTAIN study. Ranibizumab administered as per a visual acuity-guided flexible dosing regimen was well tolerated during the two-year study, and no new safety signals were identified in patients who were treated with ranibizumab for up to three years. On average, patients lost best-corrected visual acuity from baseline, probably because of either disease progression or undertreatment.[77]

Bevacizumab

Prior to the commercial availability of ranibizumab, bevacizumab (Avastin, Genentech Inc, South San Francisco, CA) was attempted as an off-label VEGF inhibitor to control exudative AMD. Bevacizumab is a full-length humanized monoclonal antibody against human VEGF, whereas ranibizumab is a fragmented humanized monoclonal antibody against human VEGF, with a molecular weight of about one third that of bevacizumab. The FDA approved bevacizumab for the treatment of metastatic colorectal cancer on February 26, 2004.[78]

Researchers initiated the Systemic Avastin for Neovascular ARMD (SANA) Study, an open-label uncontrolled pilot study of 9 subjects with subfoveal CNV, to evaluate the efficacy of systemic intravenous bevacizumab. Patients were infused with 5 mg/kg bevacizumab every 2 weeks for 2-3 treatments. Follow-up through 12 weeks revealed significant improvements in mean visual acuity (P = 0.008) and central retinal thickness (P = 0.001) over baseline with a marked reduction in leakage on FA.[79]

To allay concerns about systemic morbidity, an intravitreal injection route was detailed in a case report in 2005 that demonstrated marked reduction of subretinal fluid and stable visual acuity.[80] Numerous small studies have subsequently supported the use of intravitreal bevacizumab by demonstrating decreased retinal thickness and improved visual acuity over baseline.[81, 82, 83, 84, 85]

Because ranibizumab ($1950/dose) and bevacizumab ($50-75/dose) have an enormous price differential, and many retina physicians have felt they have comparable effectiveness, a good portion of patients are treated with bevacizumab, which has not been FDA approved for ocular indications. The National Eye Institute funded a large randomized controlled trial to directly compare the safety and efficacy of bevacizumab and ranibizumab in the Comparison of Age-Related Macular Degeneration Treatment Trial (CATT). The study, whose findings were printed in The New England Journal of Medicine (May 19, 2011), showed that ranibizumab and bevacizumab have equivalent effects on visual acuity after one year.[86] These results were maintained after two years. Patients treated on an as-needed basis had slightly less visual acuity gain than those who continued on the monthly treatment regimen, but they received, on average, 10 fewer injections during the 2-year study period. No significant differences were noted in the number of significant adverse events associated with each drug.[87]

Intravitreal injections carry a small risk of endophthalmitis, with reported risk of 0.009-0.541%.[88, 89, 90, 91, 92] A meta-analysis of endophthalmitis cases following intravitreal injection revealed multiple cases secondary to Streptococcus species, in addition to the usual Staphylococcus species.[93] This led the authors to hypothesize that aerosolized oral flora may be responsible. Wen et al investigated the amount of bacterial dispersal associated with speech by having volunteers read over a blood agar plate with and without a face mask.[94] They found significant growth of Streptococcal bacterial colonies associated with uncovered speech and suggested wearing a face mask or minimizing speech during the procedure.

The FDA issued a safety alert regarding repackaged intravitreal injections of bevacizumab (Avastin), an anti-VEGF antibody. Serious eye infections caused by Streptococcus endophthalmitis have been reported in 12 patients who received the injections. The infections were the result of contamination that occurred during the repackaging of bevacizumab from 100 mg/4 mL single-use, preservative-free vials into individual 1-mL syringes for off-label use to treat wet macular degeneration.[95]

Aflibercept

Aflibercept (Eylea; Regeneron Pharmaceuticals Inc, Tarrytown, NY) was approved in November 2011 for intravitreal injection for ocular indications. It is a newer therapeutic agent that improves visual outcomes while requiring less frequent injections. Aflibercept is a fusion protein designed to bind to all forms of VEGF-A. Two phase 3 studies, VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW 1 and 2) trials compared aflibercept to ranibizumab. VIEW 1 and 2 demonstrated safety and tolerability with visual results proving noninferior to the active control, ranibizumab.[96]

In VIEW 1 (n=1217), conducted in the United States, and VIEW 2 (n=1240), conducted in Europe, all regimens of the drug, including 2 mg dosed every 2 months (after 3 monthly loading doses), successfully met the primary endpoint of statistical noninferiority compared with monthly intravitreal ranibizumab, which was then the most potent FDA-approved treatment option for wet AMD.

The proportions of patients who maintained or improved vision over the course of 52 weeks in VIEW 1 were 96%, 95%, and 95% of patients receiving aflibercept 0.5 mg monthly, 2 mg monthly, and 2 mg every 2 months, respectively. This compared with 94% of patients receiving the standard 0.5-mg monthly dose of ranibizumab.

For the secondary endpoint, visual acuity, the new drug was better. Patients receiving 2 mg monthly had a greater mean improvement in visual acuity at week 52, with a gain of 10.9 letters compared with 8.1 letters with ranibizumab (P < .01). All other dose groups were not significantly different from ranibizumab with respect to this secondary endpoint.[97]

Results from the CLEAR-IT 2 study, a phase 2 study of as-needed dosing with VEGF-trap, demonstrated that good visual results obtained after a fixed dosing regimen were maintained with a subsequent as-needed dosing schedule. After an initial 3 monthly injections, the 159 patients were treated on an as-needed basis for the remainder of the year. On average, patients needed 2 further injections to maintain the visual results.[98, 99]

In August 2018, the FDA approved an extended dosing frequency for aflibercept of every 12 weeks after 1 year of effective therapy, although it is not as effective as the recommended every-8-week dosing regimen. Approval was based on the VIEW-1 and VIEW-2 clinical extension trials.[100]

Brolucizumab

Brolucizumab (Beovu; Novartis Pharmaceuticals Corp, East Hanover, NJ) was approved by the FDA in October 2019 for the treatment of neovascular (wet) age-related macular degeneration (nAMD). Approval was based on 2 phase III trials (n=1817) that compared intravitreal brolucizumab with aflibercept for nAMD. At 48 weeks, brolucizumab was demonstrated as noninferior to aflibercept in mean best-corrected visual acuity (BCVA). At week 16, after identical treatment exposure, fewer eyes treated with brolucizumab 6 mg had disease activity compared with aflibercept in HAWK (24% vs 34.5%; P = 0.001) and HARRIER (22.7% vs 32.2%; P = 0.002).[101]

Statins

Because of the association of serum lipid levels with AMD, using statins in an effort to prevent AMD has been considered. Some positive effects have been demonstrated in several studies, but overall, data are conflicting and sufficient evidence is lacking to support their use for AMD.[102, 103]

Laser treatments

Thermal laser photocoagulation

Until the advent of anti-VEGF agents, ophthalmologists traditionally used thermal laser destruction of CNV as the primary treatment of exudative AMD based on the results of the Macular Photocoagulation Study (MPS). This study, which was initiated in the 1980s and supported by the National Institutes of Health, demonstrated that laser photocoagulation of extrafoveal, juxtafoveal, and subfoveal CNV limited the risk of severe reductions in visual acuity compared with observation alone.

Patients were eligible for laser photocoagulation if they had classic CNV, as determined by FA. However, only 13-26% of all patients with exudative AMD presented with this inclusion pattern. Therefore, it was unclear whether laser photocoagulation was beneficial to a majority of patients with exudative AMD.[104, 105, 106, 107, 108, 109] Moreover, at least one half of the enrolled subjects had persistent or recurrent CNV within 2 years of treatment.[105, 106]

Today, thermal laser photocoagulation is usually reserved for CNV outside the fovea and for treatment of variants of exudative AMD, including retinal angiomatous proliferation (RAP) and polypoidal choroidal vasculopathy.[30, 110] Although data from the subfoveal CNV arm of the MPS suggested that laser photocoagulation was better than observation, most clinicians do not treat subfoveal CNV with thermal photocoagulation because of the induction of an immediate, iatrogenic, central scotoma.[106, 107] Researchers have searched for alternative methods of treating subfoveal CNV with laser, including feeder-vessel photocoagulation[111] and transpupillary thermotherapy[112] ; however, these methods are not widely used clinically.

Photodynamic therapy

To avoid creating a central blinding scotoma when treating subfoveal CNV with thermal laser, clinicians turned to PDT. After intravenous infusion of a photosensitizing dye and a sufficient delay to concentrate it into pathologic choroidal neovascular tissue, the photosensitizer is stimulated with a specific wavelength of light that is directed at the CNV. The dye reacts with water to create oxygen and hydroxyl free radicals, which, in turn, induce occlusion of the pathologic vasculature by means of massive platelet activation and thrombosis while preserving the normal choroidal vasculature and nonvascular tissue.[113, 114, 115]

Verteporfin therapy

In April 2000, the US Food and Drug Administration (FDA) approved PDT with verteporfin (Visudyne; QLT Therapeutics, Inc, Vancouver, British Columbia, Canada, and Novartis Ophthalmics, Bulach, Switzerland) for use in patients with predominantly classic, subfoveal CNV caused by AMD. Marketing approval was granted in Europe in July 2000, and the drug is currently commercially available in more than 70 countries for the treatment of predominantly classic CNV.[116]

Verteporfin is a modified porphyrin with an absorption peak near 689 nm that is delivered intravenously for 10 minutes. After a 5-minute delay, the CNV complex is irradiated through the pupil with a large-spot diode laser at 689 nm for 83 seconds. The laser energy activates the intravascular photosensitizer and stimulates the photodynamic action within the pathologic CNV. Verteporfin is cleared rapidly from the body, resulting in minimal skin photosensitivity by 5 days.

In 2001, the 2-year results of the Treatment of AMD with PDT (TAP) trial were published. The TAP trial consisted of 2 randomized, prospective, double-blind, placebo-controlled phase III trials with 609 subjects. Second-year data showed that 59% of treated eyes lost less than 15 letters on a standardized eye chart compared to 31% in the control group when the lesion was predominantly classic.[33] The TAP trial was unmasked after 2 years of follow-up, and investigators continued with an open-label extension (to 36 months) in 124 of the 159 original TAP participants with predominantly classic CNV. The data revealed that visual acuity remained nearly constant and the number of required repeat treatments decreased.[117]

Although standard PDT with verteporfin has shown promise in treating some forms of CNV, it is expensive, typically slows vision loss rather than improves it, and requires numerous repeat treatments. Therefore, other interventions to treat subfoveal CNV membranes were developed.

Combination therapies

Results from treatment with anti-VEGF agents have been promising, although there continues to be a subset of patients who have disappointing visual outcomes. In some cases, different forms of macular degeneration, such as polypoidal vasculopathy and retinal angiomatous proliferation, may respond dissimilarly to anti-VEGF agents. Other failures may be caused by the maturation of choroidal neovascular membranes that make them less susceptible to changes in VEGF levels.[5, 6, 7] Several clinical researchers have performed a variety of treatment combinations attempting to maximize visual acuity recovery while minimizing the number of retreatments in exudative AMD.[118, 119]

Because evidence can be found that PDT causes an increased expression of VEGF, there may be a theoretical advantage to various combinations of PDT and anti-VEGF treatments.[120] In two studies, the efficacy of reduced-fluence PDT combined with bevacizumab versus bevacizumab alone was tested. Both found that the number of injections needed in the combination groups was reduced by about half without significant differences in visual outcome.[121, 122] However, in another study using standard-fluence, visual acuity in the combination group was similar to monthly bevacizumab, but there was no drop in the number of bevacizumab injections required.[123]

Larger randomized clinical trials have addressed combination therapy. In the DENALI study, ranibizumab, as monotherapy or combined with verteporfin PDT, improved best-corrected visual acuity (BCVA) at month 12, but did not demonstrate that combination regimens were noninferior to ranibizumab monotherapy.[124] In the MONT BLANC study, the combination of verteporfin PDT and ranibizumab was effective in achieving BCVA gain comparable with ranibizumab monotherapy, but combination therapy did not show benefits with respect to reducing the number of ranibizumab retreatment over 12 months.[125]

In a randomized, multicenter trial, Jackson et al found that a single dose of stereotactic radiotherapy (SRT) reduced the number of ranibizumab injections required for patients with neovascular AMD. The study evaluated 230 patients in whom neovascular AMD had developed within the previous 3 years; who had, within the preceding year, received at least 3 injections of ranibizumab or bevacizumab; and who required continuing treatment with either of these drugs.[126]

Randomized into 4 groups, the patients received ranibizumab (on as as-needed basis), as well as, depending on the group, a single dose of 16 Gy SRT, sham 16 Gy SRT, 24 Gy SRT, or sham 24 Gy SRT. The investigators found that patients in the 16 and 24 Gy SRT groups received significantly less ranibizumab (mean 2.64 and 2.43 injections, respectively) than did patients in the sham SRT groups (mean 3.74 injections) but with comparable retention of visual acuity over the course of 1 year.[126]

Surgical Care

Vitreoretinal surgeons have attempted to remove CNVM with direct surgical excision of the CNV complex. In 1998, the National Eye Institute of the National Institutes of Health awarded funding to the Submacular Surgery Trial (SST). This study was a large randomized clinical trial comparing submacular CNVM removal versus observation. Patients were followed for 2 years and assessed for stabilization or deterioration of their visual acuity, a change in contrast sensitivity, cataract development, surgical complications, and quality of life. The trials did not demonstrate significant benefit of submacular surgery over observation.[127, 128]

Consultations

A neurologist should be consulted for patients with AMD who exhibit signs of cognitive dysfunction, since an association with Alzheimer disease has been found.[50]

 

Medication

Medication Summary

Visudyne for PDT of subfoveal, predominantly classic CNVM was approved in 2000, as outlined Medical Care.

Macugen (pegaptanib) was approved by the FDA in 2002. Because of relatively low efficacy, it is rarely used today.

Ranibizumab (Lucentis) was approved by the FDA in 2006.

Aflibercept (Eylea) was approved by the FDA in 2011. It is currently the most widely used anti-VEGF agent with FDA-approved labelling for ocular indications.

Brolucizumab (Beovu) was approved by the FDA in 2019.

Bevacizumab (Avastin) is an FDA-approved drug for intravenous use for the labelled indication of treatment of colorectal cancer. It is used by ophthalmologists off-label for ocular indications and requires dilution for intravitreal use by a compounding pharmacy.

In addition, various experimental protocols (eg, other antiangiogenic agents) are currently under investigation; some of these are outlined in Medical Care.

Phototherapy Agents

Class Summary

These agents are used for PDT in cases of subfoveal, predominantly classic CNV membranes.

Verteporfin (Visudyne)

Benzoporphyrin derivative monoacid (BPD-MA), consisting of equally active isomers BPD-MAC and BPD-MAD, which can be activated by low-intensity, nonthermal light of 689-nm wavelength. After activation and with oxygen, forms cytotoxic oxygen free radicals and singlet oxygen, which damages biologic structures in range of diffusion, leading to local vascular occlusion, cell damage and cell death.

Phase III data from the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Study Group showed that 61% of 402 eyes treated lost < 15 letters of visual acuity at 12 months vs 46% of 207 eyes receiving placebo (P< .001). In subgroup analysis, visual-acuity benefit persisted (67% vs 37%, P< .001) when CNV membrane was predominantly classic (50% or more of area of entire complex). Visual acuity not significantly different when the area of classic CNV membranes < 50% entire complex. Patients needed mean of about 3 treatments in first y. At most recent follow-up, patients needed mean of 5 treatments in first 2 y.

Anti-VEGF Therapy

Class Summary

This treatment reduces the risk of visual loss similar to that seen with PDT.

Aflibercept intravitreal (Eylea)

Binds and prevents activation of vascular endothelial growth factors (all forms of VEGF-A) and placental growth factor (PIGF). Indicated for neovascular (wet) age-related macular degeneration (AMD). Initial injection frequency is every 4 weeks for 3 months. After 3 once-monthly loading doses, maintenance doses may be administered every 2 months. Although not as effective as the recommended every-8-week dosing regimen, after 1 year of effective therapy, may treat with 1 dose every 12 weeks.

Brolucizumab intravitreal (Beovu, brolucizumab-dbll)

Human VEGF inhibitor; binds to the 3 major VEGF-A isoforms (eg, VEGF110, VEGF121, VEGF165), thereby preventing interaction with receptors VEGFR-1 and VEGFR-2. By inhibiting VEGF-A, brolucizumab suppresses endothelial cell proliferation, neovascularization, and vascular permeability. Indicated for adults with nAMD.

Pegaptanib (Macugen)

Selective VEGF antagonist that promotes vision stability and reduces visual acuity loss and progression to legal blindness. VEGF causes angiogenesis and increases vascular permeability and inflammation, all of which contribute to neovascularization in wet AMD

Ranibizumab (Lucentis)

Recombinant humanized IgG1-kappa isotype monoclonal antibody fragment designed for intraocular use. Indicated for neovascular (wet) AMD. In clinical trials, about one third of patients had improved vision at 12 months that was maintained by monthly injections. Binds to VEGF-A, including biologically active, cleaved form (ie, VEGF110). VEGF-A has been shown to cause neovascularization and leakage in ocular angiogenesis models and is thought to contribute to AMD disease progression. Binding VEGF-A prevents interaction with its receptors (ie, VEGFR1, VEGFR2) on surface of endothelial cells, thereby reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation. After 3 once-monthly loading doses, maintenance doses may be administered every 1 month.

Bevacizumab (Avastin)

Murine-derived monoclonal antibody that inhibits angiogenesis by targeting and inhibiting VEGF. Inhibiting new blood vessel formation denies blood, oxygen, and other nutrients needed for vascular growth. Off-label indication for exudative AMD. The need to repackage the drug from the available size vial into a smaller dose increases risk for transmission of infection if proper aseptic technique is jeopardized.

 

Questions & Answers

Overview

What is exudative (wet) age-related macular degeneration (AMD)?

What are the symptoms of exudative (wet) age-related macular degeneration (AMD)?

How does exudative (wet) age-related macular degeneration (AMD) affect visual acuity?

Which imaging studies are performed for suspected (wet) age-related macular degeneration (AMD)?

Which anti–vascular endothelial growth factor (VEGF) agents are used in the treatment of exudative (wet) age-related macular degeneration (AMD)?

Which laser treatments are used to treat exudative (wet) age-related macular degeneration (AMD)?

What is the most common cause of irreversible vision loss?

What is the difference between nonexudative (dry) and exudative (wet) age-related macular degeneration (AMD)?

How is age-related macular degeneration (AMD) severity classified by The Wisconsin Age-Related Maculopathy Grading System?

How is age-related macular degeneration (AMD) severity classified by The Age-Related Eye Disease Study Group (AREDS)?

What is the predictive model for development of advanced age-related macular degeneration (AMD) in patients with early AMD?

How has the classification and diagnosis of age-related macular degeneration (AMD) changed from the traditional wet and dry designations?

What are the symptoms of age-related maculopathy?

What causes age-related macular degeneration (AMD)?

What is the pathophysiology of age-related macular degeneration (AMD)?

What is the retinal pigment epithelium (RPE)?

What is the role of retinal pigment epithelium (RPE) cells in the development of age-related macular degeneration (AMD)?

What is the role of complement factor H (CFH) in the development of age-related macular degeneration (AMD)?

What is the role of drusen formation in the development of age-related macular degeneration (AMD)?

How does age-related macular degeneration (AMD) affect quality of life?

Does age-related macular degeneration (AMD) have a racial predilection?

Is age-related macular degeneration (AMD) more common in men or women?

Is age-related macular degeneration (AMD) diagnosed in young adults?

What is the prevalence of age-related macular degeneration (AMD) in the US?

Presentation

What are the symptoms of age-related maculopathy?

What are the symptoms of exudative (wet) age-related macular degeneration (AMD)?

Which physical finds indicate exudative (wet) age-related macular degeneration (AMD)?

What are the risk factors for development of age-related macular degeneration (AMD)?

DDX

What are the differential diagnoses for Exudative (Wet) Age-Related Macular Degeneration (AMD)?

Workup

Which lab studies are useful in the diagnosis of exudative (wet) age-related macular degeneration (AMD)?

Which imaging studies are performed in the diagnosis of exudative (wet) age-related macular degeneration?

What is the role of fluorescein angiography (FA) in the diagnosis of exudative (wet) age-related macular degeneration (AMD)?

How is choroidal neovascularization (CNV) classified in exudative (wet) age-related macular degeneration (AMD)?

When is angiography performed in patients with exudative (wet) age-related macular degeneration (AMD)?

What is the role of indocyanine green (ICG) angiography in the diagnosis of age-related macular degeneration (AMD)?

What is the role of optical coherence tomography (OCT) and OCT angiography in the diagnosis of exudative (wet) age-related macular degeneration (AMD)?

Treatment

What is the role of vascular endothelial growth factor (VEGF) inhibitors in the treatment of exudative (wet) age-related macular degeneration (AMD)?

Is pegaptanib sodium (Macugen) used in the treatment of exudative (wet) age-related macular degeneration (AMD)?

How effective is pegaptanib sodium (Macugen) in the treatment of exudative (wet) age-related macular degeneration (AMD)?

Is ranibizumab (Lucentis) used in the treatment of exudative (wet) age-related macular degeneration (AMD)?

How effective is ranibizumab (Lucentis) in the treatment of exudative (wet) age-related macular degeneration (AMD)?

Is ranibizumab (Lucentis) effective in improving visual acuity in exudative (wet) age-related macular degeneration (AMD)?

What are the adverse effects of ranibizumab (Lucentis) in patients with exudative (wet) age-related macular degeneration (AMD)?

What are the dosage regimen options of ranibizumab (Lucentis) in the treatment of exudative (wet) age-related macular degeneration (AMD)?

What are the adverse effects of long-term ranibizumab (Lucentis) therapy in patients with exudative (wet) age-related macular degeneration (AMD)?

Is bevacizumab (Avastin) used in the treatment of exudative (wet) age-related macular degeneration (AMD)?

How effective is bevacizumab (Avastin) in the treatment of exudative (wet) age-related macular degeneration (AMD)?

Has bevacizumab (Avastin) been FDA approved for ocular use in the treatment of exudative (wet) age-related macular degeneration (AMD)?

What are the adverse effects of ocular bevacizumab (Avastin) therapy in the treatment of exudative (wet) age-related macular degeneration (AMD)?

Is aflibercept (Eylea) effective in the treatment of exudative (wet) age-related macular degeneration (AMD)?

Are statins effective in preventing exudative (wet) age-related macular degeneration (AMD)?

When is thermal laser photocoagulation used in the treatment of exudative (wet) age-related macular degeneration (AMD)?

How is photodynamic therapy (PDT) used in the treatment of exudative (wet) age-related macular degeneration (AMD)?

Is verteporfin (Visudyne) FDA approved for use in the treatment of exudative (wet) age-related macular degeneration (AMD)?

How is verteporfin (Visudyne) used with photodynamic therapy (PDT) in the treatment of exudative (wet) age-related macular degeneration (AMD)?

When are combination therapies beneficial in the treatment of exudative (wet) age-related macular degeneration (AMD)?

How effective is photodynamic therapy (PDT) combined with bevacizumab (Avastin) in the treatment of exudative (wet) age-related macular degeneration (AMD)?

Is verteporfin (Visudyne) combined with ranibizumab (Lucentis) effective in the treatment of exudative (wet) age-related macular degeneration (AMD)?

Is stereotactic radiotherapy (SRT) combination therapy effective in the treatment of exudative (wet) age-related macular degeneration (AMD)?

What surgical procedures may be used in the treatment of exudative (wet) age-related macular degeneration (AMD)?

Medications

Which medications are approved for treatment of exudative (wet) age-related macular degeneration (AMD)?

Which medications in the drug class Phototherapy Agents are used in the treatment of Exudative (Wet) Age-Related Macular Degeneration (AMD)?

Which medications in the drug class Anti-VEGF Therapy are used in the treatment of Exudative (Wet) Age-Related Macular Degeneration (AMD)?