EXUDATIVE (WET) MACULAR DEGENERATION

Signs and Symptoms

Age-related macular degeneration (AMD) is a complex, progressive degenerative disease involving multiple genetic, lifestyle, systemic and environmental factors.1-15 It is the leading cause of acquired blindness in elderly individuals living in western countries.1-5 As the disease progresses through the non-exudative (dry) form, metabolic conditions arise that trigger processes which result in the release of vascular endothelial growth factors (VEGF).1,13-19 This produces the choroidal neovascularization that defines exudative (wet) AMD.6-10 Approximately 30% of adults aged 75 years or older have some signs of dry AMD with 6% to 8% of these individuals progressing to significant vision loss via advanced stages.7

All variants of the process begin in the subretinal tissues under the retinal pigment epithelium (RPE).1-12 The non-exudative stages develop from pathology that takes root in the RPE/Bruch’s membrane, maturing to involve the photoreceptors.1-12 The earliest observable manifestations of AMD are visible hard and soft drusen (focal thickenings of Bruch’s membrane).12,13 Macular pigmentary changes and geographic atrophy follow and are observed as pigment mottling and clumping.12,13,15

As the disease progresses, chronic oxidative stress and inflammation ultimately lead to degeneration of the RPE with visible large coalesced soft drusen. This drives the process into an imbalance between antiangiogenic and proangiogenic factors that ultimately produces choroidal neovascularization.14-16 Here, yellow subretinal, protein-laden fluid, yellow-white exudate and subretinal blood, seen as an amorphous reddish-brown accumulation under the retina/RPE, catastrophically disrupt function.1-14

The visual symptoms associated with exudative AMD depend on its severity, location and distribution. The vision loss that occurs in both symptomatic wet and dry disease is painless. The dry form produces subtle losses with gradual metamorphopsia and color alterations. As it advances more significant losses of acuity occur.17 The wet form produces severe, sudden losses (in many cases, resulting in visual loss of six Snellen lines or more), dark adaptation dysfunction and a positive scotoma upon facial or formal Amsler grid testing.17,18

The clinical retinal signs of advanced exudative AMD include the disorganization of the RPE in the macular area, macular RPE hyperplasia, degeneration of the outer retinal layers with circumscribed areas of geographic atrophy of the RPE, subretinal bleeding, subretinal serosanguinous fluid accumulation, circular-shaped multilayered fibrovascular scarring (disciform scarring), intraretinal hemorrhage and, in severe cases, preretinal or vitreous hemorrhage.1-19 Choroidal neovascular membranes (CNVM) not obscured by blood or fluid may appear to the observer as a grayish-green subretinal hue.1-16

Retinal angiomatous proliferations (RAP) and polypoidal choroidal vasculopathy (PCV) are considered subsets of exudative AMD.20,21 In retinal angiomatous proliferations, neovascularization originating in the retina extends posteriorly into the subretinal space, eventually communicating with either the choroidal vasculature or sub-retinal CNV.20 RAP is a manifestation of end-stage AMD.21 Polypoidal choroidal vasculopathy (PCV) is a retinal disease typically seen more commonly in Asian and African populations. It is characterized by subretinal polypoidal lesions with or without a branching vascular network. The clinical features of PCV include recurrent subretinal hemorrhage, serosanguinous PED subretinal exudation and serous retinal detachment.21

Pathophysiology

The essential features of dry AMD (drusen, RPE changes, aging, choroidal thinning, vitreoretinal adhesion, genetic influences, cardiovascular disease, obesity, UV light exposure, smoking) prime the tissues for hypoxic stress, resulting in hypoxia and VEGF accumulation.19-24 These proceedings cause the RPE to degenerate, resulting in photoreceptor loss. As the photoreceptors disintegrate, the inner nuclear layer collapses, causing it to contact Bruch’s membrane, initializing the degeneration of the outer retinal layers.2-5 UV-induced oxidation and free radical formation within these structures occurs concurrently.25 Genetics, diet, smoking and many cardiovascular factors are linked with this disease, with increasing evidence that long-term oxidative stress, impaired autophagy and mediated inflammation are involved in the pathogenesis.1

Wet AMD results when the RPE/Bruch’s barrier becomes compromised by new, weak and leaky blood vessels that grow from the choriocapillaris. Linked to isolated regions of choriocapillaris vascular failure, when hypoxic levels cross the threshold, fluid effusion and neovascularization result.19,22-24 These occult (i.e., boundaries poorly defined) or classic (i.e., boundaries well defined) subretinal choroidal neovascular membranes leak serosanguinous fluid, causing RPE detachment, sensory retinal detachment, subretinal or intraretinal bleeding, fibrovascular disciform scarring and geographic choroidal atrophy.1-25

Studies have identified that interference with retinal oxygen metabolism by confluent drusen, serous or hemorrhagic retinal detachment, retinal edema and vitreoretinal adhesion advance the disease process.19 Drusen and serous retinal elevation increase the distance between the choriocapillaris and retina and vitreoretinal adhesion reduces the diffusion of oxygen towards hypoxic retina, both contributing to retinal hypoxia.19 Hypoxia-inducible-factor (HIF) is a cytokine known to exist in subretinal neovascularization; hypoxia being the main stimulus for HIF production along with the release of VEGF.1,19 These features alone are not by themselves capable of producing enough hypoxia and VEGF accumulation to stimulate wet AMD, but when they combine the impetus is present.19

VEGF is naturally secreted by the RPE and serves as a protective surviving factor for the choriocapillaris, Müller cells, neuronal cells and RPE cells.1 When pooled in elevated levels in combination with defects in Bruch’s membrane and other cytokines, the potential for CNVM growth increases.1,19 Choroidal ischemia in AMD has also been demonstrated to decrease oxygen delivery to the outer retina.19,26-28 Tractional or serous retinal elevation and choroidal ischemia can combine forces to critically reduce oxygen delivery to the outer retina, creating retinal hypoxia.19 Once the hypoxic cycle is started, VEGF production increases and retinal effusion follows, initiating the cascade of retinal detachment, intraretinal edema, increasing retinal hypoxia and increased VEGF production.19

Management

The best management for wet AMD is prevention. This strategy includes early detection via semiannual dilated fundus exams, patient self-monitoring of vision, lifestyle counseling and oral supplement recommendations in high-risk patients.29,30

Researchers have demonstrated that oral antioxidants like vitamins C, E and oral zinc may play a role in reducing early drusen formation by terminating the chemical reactions initiated by free radicals.29,30 Advanced formulations containing carotenoids such as zeaxanthin and mesozeaxanthin along with polyunsaturated fish oils have also been advocated.31 Multiple vitamins, oral zinc or products specifically designed for this purpose, such as Ocuvite (Bausch + Lomb), Icaps (Alcon) and Preservision (Bausch + Lomb), to name just a few, have been shown to be useful in slowing the progression of AMD from the dry to wet forms.29-31

Smokers or patients with a history of smoking must be advised to use the smokers supplement formulation.29,30,32 Beta carotene has been shown to in-crease the risk of lung cancer and has been replaced in these formulations.29,30,32 Smoking cessation should be discussed with patients.

The treatment of exudative AMD depends on the type, location and size of the lesion.33,34 In the 1980s and 1990s, laser therapy was guided by the Macular Photocoagulation Study.34 This strategy employed the use of intravenous fluorescein angiography and indocyanine green angiography to locate focal argon laser photocoagulation to destroy neovascular complexes with heavy confluent burns that extended outside the boundaries of well-defined CNVMs.34 Unfortunately, poorly defined (i.e., occult) membranes could not be fully and thoroughly treated and frequent recurrence was documented, causing protracted intervention.33,34

Photodynamic therapy (PDT) offered new hope via a photosensitive dye (verteporfin) designed to bind with the CNVM and involute it when exposed to a standard wavelength of laser light.35 While the procedure was far less damaging than photocoagulation, it offered limited, temporary improvement in function and required multiple procedures to maintain a diminishing effect.33,35 Additionally, it was thought that PDT caused an upregulation of VEGF that could actually prove worse for the patient long term. The Submacular Surgery Trial demonstrated that surgical removal of CNVM was not beneficial compared to photocoagulation.36

Currently, the most effective approach to treating exudative AMD relies on vascular endothelial growth factor inhibitors such as bevacizumab, (Avastin, Genentech), ranibizumab, (Lucentis, Genentech) and aflibercept (Eylea, Regeneron) as monotherapy or in combination with laser and PDT.33 By interfering with VEGF effects (e.g., increased vascular permeability, angiogenesis, induced microvessel formation), disease progression can be limited and even regressed.33,37

Studies have concluded that these intravitreally injected agents are superior to PDT in the treatment of predominantly classic CNVM.37 Other studies (ANCHOR, MARINA, PIER) have demonstrated effectiveness compared to sham treatment for minimally classic or occult CNVM in AMD.37 Monthly injections are generally well tolerated and induce low rates of ocular or systemic adverse events.37 Less frequent dosing has been evaluated in a strategy known as “treat and extend” with the goal of reducing the inconvenience, risk and cost of monthly injections.37 In the landmark Comparison of Age-related Macular Degeneration Treatments Trial (CATT), monthly monitoring with retreatment as needed (treat and extend) was found equivalent to monthly treatment for vision gain at one year while reducing the number of injections (and the related cost) by approximately half.38

In head-to-head comparisons, aflibercept administered bimonthly was non-inferior to ranibizumab administered monthly (VIEW 1 and 2), bevacizumab administered monthly was equivalent to ranibizumab administered monthly and bevacizumab administered as needed was equivalent to ranibizumab administered as needed.37,38 This was important because bevacizumab has been widely used off-label for economic reasons, providing evidence-based flexibility for the interchangeable use of these agents.37

In cases where bilateral central visual acuity has been lost, low vision and vision rehabilitation specialists may be able to offer training, optical devices and non-optical devices which improve patients’ quality of life.

Clinical Pearls

In patients who have already lost one eye to wet AMD, over the course of five years the risk of developing wet stage disease in the fellow eye is 10% for patients whose fellow eye has neither large drusen or pigment clumps, 30% for fellow eyes containing either large drusen or pigment clumps and 50% for fellow eyes with both pigment clumps and large drusen present.

Genetic testing for AMD is available (e.g., RetnaGene, ArcticDx) for family members of high-risk patients. This test may offer an advantage in predicting the likelihood of being affected, affording these individuals the opportunity for closer follow-up care as well as early, proactive lifestyle modifications.

Despite the tremendous advancements in anti-VEGF therapy, exudative AMD still carries a guarded prognosis. Sustained interruption to the anti-VEGF regimen can allow AMD to progress. Also, repeated injections may increase the risk of geographic atrophy or increase the risk of endopthalmitis or pigment epithelial detachment.

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38. Maguire MG, Daniel E, Shah AR, et al. Incidence of choroidal neovascularization in the fellow eye in the comparison of age-related macular degeneration treatments trials. Ophthalmology. 2013;120(10):2035-41.